Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([O-:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[Na+].Br[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[NH:25][CH:26]=[N:27]2>CS(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([C:23]2[N:31]=[CH:30][N:29]=[C:28]4[C:24]=2[N:25]=[CH:26][NH:27]4)(=[O:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1
Reactant: Brc1ncnc2nc[nH]c12
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=S(=O)(c1ccc2cc(-c3ccc(F)cc3)ccc2c1)c1ncnc2[nH]cnc12
Temperature: 80 °C
Reaction time: 22 h
Yield: 25 %

Procedure:
A mixture of sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate [prepared according to the method of Example 10(a) Steps 1-2] (104 mg, 0.34 mmol) and 6-bromopurine (70 mg, 0.35 mmol) in dimethylsulfoxide (4 mL) was stirred at 80° C. (oil bath temperature) under nitrogen for 22 hours. The cooled reaction mixture was diluted with water (20 mL), the preciptate formed collected under suction, washed with water and dried in vacuo. Purification by flash chromatography, eluting with 5% methanol in dichloromethane, gave the title compound as a white solid (33 mg, 25%). 1H NMR (500 MHz, DMSO-d6) δ 14.06 (1H, br s), 9.04 (1H, s), 8.92 (1H, s), 8.86 (1H, s), 8.38 (1H, s), 8.35 (1H, d, J 8.7 Hz), 8.23 (1H, d, J 8.7 Hz), 8.05 (2H, m), 7.92 (2H, m), 7.38 (2H, m); m/z (ES+) 405 [MH+].
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([O:8][CH2:9][C:10]1([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11]1)(=[O:7])[CH3:6]>>[C:5]([O:8][CH2:9][C:10]1([C:14]([Cl:3])=[O:16])[CH2:13][CH2:12][CH2:11]1)(=[O:7])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)OCC1(C(=O)O)CCC1
Product: CC(=O)OCC1(C(=O)Cl)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (1.65 ml, 22.7 mmol) was added to neat 1-acetoxymethylcyclobutanecarboxylic acid (3.3 g, 18.9 mmol). The resulting mixture was stirred at room temperature for 1 hour, then heated on a steam bath for 5 minutes. After cooling, the excess thionyl chloride, HCl and SO2 were removed under reduced pressure (water aspirator). The remained residue was purified by distillation to provide the desired product as a colorless oil: bp 51°-3° C. (0.02 mm); NMR (CDCl3) δ=1.8~2.7 (9H, m containing a singlet at 2.04 δ), 4.40 (2H, s).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:16][N:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[OH:26])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH:34]([C:39]([O:41][CH3:42])=[O:40])[C:35]([O:37][CH3:38])=[O:36]>C(#N)C.CC(=O)OCC>[CH3:38][O:37][C:35](=[O:36])[CH:34]([O:26][C:4]1[C:5]([CH3:25])=[CH:6][C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([CH2:21][CH:22]([CH3:23])[CH3:24])=[CH:16][N:15]=3)[O:11][N:10]=2)=[CH:8][C:3]=1[CH2:1][CH3:2])[C:39]([O:41][CH3:42])=[O:40]
Reactant: COC(=O)C(Cl)C(=O)OC
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OC(C(=O)OC)C(=O)OC
Temperature: 65 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
To a solution of the compound of Example 32 (100 mg, 285 μmol) in acetonitrile (2 mL), K2CO3 (56 mg, 427 μmol) followed by dimethyl chloromalonate (57 mg, 341 μmol) is added. The mixture is stirred at 65° C. for 18 h. The mixture is diluted with EA and washed with water. The org. extract is concentrated and the crude product is purified on prep. TLC plates using heptane:EA 4:1 to give 2-{2-ethyl-4-[5-(5-isobutyl-4-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-malonic acid dimethyl ester (95 mg) as a colourless oil; LC-MS: tR=1.17 min, [M+H]+=482.01. This material (95 mg, 197 μmol) is dissolved in ethanol (10 mL) and treated with NaBH4 (60 mg, 1.58 mmol). The mixture is stirred at 60° C. for 1 h before the reaction is quenched with water. The mixture is extracted twice with EA and the combined extracts are concentrated. The crude product is purified on prep. TLC plates using heptane:EA 1:1 to give the title compound (44 mg) as a colourless oil; LC-MS: tR=1.02 min, [M+H]+=426.01; 1H NMR (CDCl3): δ1.00 (d, J=6.5 Hz, 6H), 1.31 (t, J=7.3 Hz, 3H), 1.95 (hept, J=6.3 Hz, 1H), 2.08 (t br, J=5.5 Hz, 2H), 2.42 (s, 3H), 2.47 (s, 3H), 2.63 (d, J=7.0 Hz, 2H), 2.80 (q, J=7.5 Hz, 2H), 3.91-4.05 (m, 4H), 4.19 (quint, J=4.5 Hz, 1H), 7.95 (s, 1H), 7.98 (s, 1H), 8.10 (s, 1H), 8.55 (s, 1H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]([OH:15])=[O:14])[O:10][C:11]=1[CH3:12].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[CH3:12][C:11]1[O:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][C:7]=1[CH2:6][O:5][C:4]1[CH:3]=[C:2]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([C:20]([F:31])([F:30])[F:19])[CH:26]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Cc1oc(C(=O)O)cc1COc1cccc(I)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: Cc1oc(C(=O)O)cc1COc1cccc(-c2cccc(C(F)(F)F)c2)c1

Procedure:
Compound (109) was prepared from compound (107) and (3-trifluoromethyl-phenyl)-boronic acid by adapting the procedure of Example 26A(c). LC/MS System B; Rt=1.97 mins, m/z (ES−)=375 (M−H for C20H15F3O4).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][NH:11][CH2:10][CH:9]([NH:13][C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][N:20]=[C:19]4[C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[O:15])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1COCO[CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCl>[CH3:32][N:11]1[CH2:12][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH:9]([NH:13][C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[C:19]3[C:25]2[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=2)=[O:15])[CH2:10]1
Reactant: C1OCOCO1
Reactant: O=C(NC1CNCC(c2ccccc2)C1)c1ccc2[nH]nc(-c3ccncc3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CC(NC(=O)c2ccc3[nH]nc(-c4ccncc4)c3c2)CC(c2ccccc2)C1
Reaction time: 1 h

Procedure:
In a flask, dichloromethane (1 mL) and acetic acid (1 drop) was added to N-(5-phenylpiperidin-3-yl)-3-(pyridin-4-yl)-1H-indazole-5-carboxamide (0.05 mmol) and 1,3,5-trioxane (0.2 mmol). The reaction was stirred for 60 minutes. Sodium triacetoxyborohydride (1 mmol) was added in one portion. The reaction was stirred for 1 h. The reaction was concentrated in vacuo and purified using prep LC/MS.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=[O:7].Cl.[CH3:14]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([O:8][CH3:14])=[O:7]
Reactant: COc1cc(C(=O)O)ccc1C
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(C)c(OC)c1

Procedure:
A solution of 3-methoxy-4-methylbenzoic acid (10 grams) in 200 mL of methanol was saturated with hydrochloric acid gas. The resulting solution was warmed on a steam bath for 4 hours. The reaction was allowed to cool and the methanol was evaporated. The residue was dissolved in ethyl acetate and the ethyl acetate layer was washed with water, dried over sodium sulfate and evaporated to give the title compound. NMR (CDCl3) δ:2.15 (s, 3H), 3.80 (s, 3H), 7.48-7.18 (m, 3H).
Reaction SMILES: Cl.[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]([N:13]1[CH2:16][CH:15]([C:17]2[C:22]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)=[N:21][CH:20]=[CH:19][N:18]=2)[CH2:14]1)=[O:12].CCN(CC)CC.[C:36](Cl)(=[O:38])[CH3:37]>C(Cl)Cl>[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]([N:13]1[CH2:14][CH:15]([C:17]2[C:22]([C:23]3[CH2:24][CH2:25][N:26]([C:36](=[O:38])[CH3:37])[CH2:27][CH:28]=3)=[N:21][CH:20]=[CH:19][N:18]=2)[CH2:16]1)=[O:12]
Reactant: CC(=O)Cl
Reactant: O=C(c1nc2ccccc2[nH]1)N1CC(c2nccnc2C2=CCNCC2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC=C(c2nccnc2C2CN(C(=O)c3nc4ccccc4[nH]3)C2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a solution of (1H-benzoimidazol-2-yl)-{3-[3-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone hydrochloride (187 mg, 0.47 mmol) in dry CH2Cl2 (10 mL) was added Et3N (1 mL). The reaction mixture was cooled to 0° C. with an ice bath, and acetyl chloride (39 mg, 0.50 mmol) was added dropwise. After 1 h, the reaction mixture was warmed to RT, and stirred overnight. Then the reaction mixture was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product (170 mg, 0.42 mmol, 90% yield). ESI-MS (M+1): 403 calc. for C22H22N6O2 402.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([OH:12])=O)[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.ClC(OCC)=O.[C:26]1([CH:32]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:33]2[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH2:35][CH2:34]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][N:36]2[CH2:37][CH2:38][N:33]([CH:32]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:34][CH2:35]2)=[O:12])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)C=Cc1cncc(F)c1
Reactant: NCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(C=Cc1cncc(F)c1)NCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 2 h
Yield: 36.6 %

Procedure:
To a stirred suspension of 0.29 g of 3-(5-fluoro-3-pyridyl)acrylic acid in 15 ml of dry tetrahydrofuran, 0.24 g of triethylamine is added at room temperature. The resulting solution is cooled to between -10° C. and -5° C., and a solution of 0.25 g of ethyl chloroformate in 2 ml of tetrahydrofuran is added slowly. After the mixture is stirred at the same temperature for 2 hours, a solution of 0.75 g of 4-(4-diphenylmethyl-1-piperazinyl)butylamine in 2 ml of dry tetrahydrofuran is added. The mixture is stirred for 1 hour at between -10° C. and -5° C. and then at room temperature overnight. The insoluble materials are filtered off, and the filtrate is concentrated. The residue is chromatographed on silica gel with chloroform-methanol (40:1) to give 0.3 g of the title compound. m.p. 128°-129° C. (recrystallized from toluene-hexane)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:11]=2[CH:29]=1.[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([SH:37])=[CH:33][CH:32]=1>>[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([S:37][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[C:11]=3[CH:29]=2)=[CH:33][CH:32]=1
Reactant: O=C1Nc2ccc(OCCCCCl)cc2C(C2CCCCC2)(C2CCCCC2)O1
Reactant: Cc1ccc(S)cc1
Product: Cc1ccc(SCCCCOc2ccc3c(c2)C(C2CCCCC2)(C2CCCCC2)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dicyclohexyl-4H-3,1-benzoxazin-2-one and 4-methyl-thiophenol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:16]#[C:17][NH2:18].Cl.[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:15][C:17]([NH2:18])=[NH:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CN
Reactant: Nc1cccc(OCc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: N=C(N)Nc1cccc(OCc2ccccc2)c1
Temperature: 80 °C
Yield: 98.3 %

Procedure:
To a suspension of 3-benzyloxy-phenylamine (20.0 g, 100.35 mmol) in 150 ml 1,4-dioxane in a 500 ml round bottom flask was added cyanamide (7.39 g, 175.95 mmol) followed by HCl in 1,4-dioxane (4M, 44 ml, 176.00 mmol). The resulting suspension was stirred and heated at 80° C. overnight. The reaction mixture was cooled to ambient temperature then NaOH (6N, 35 ml, 210.00 mmol) was added. The volume of solution was reduced to 50 ml, in vacuo, and the resulting precipitate was collected by filtration. The solid product was dried in vacuo overnight to afford the aryl guanidine 9 (23.8 g) in 98.4% yield. 1H NMR (MeOH-d4) δ 6.4-7.5 (m, 9H), 5.1 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[F:18][C:19]1[C:20]([C:26](O)=[O:27])=[N:21][CH:22]=[C:23]([F:25])[CH:24]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:20]3[C:19]([F:18])=[CH:24][C:23]([F:25])=[CH:22][N:21]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: O=C(O)c1ncc(F)cc1F
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: C[C@]1(c2cc(NC(=O)c3ncc(F)cc3F)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 3,5-difluoro-pyridine-2-carboxylic acid (CAS 745784-04-7) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=383.3 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([CH3:11])[CH:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[OH:4].Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH3:11][CH:2]1[CH:3]([C:5]2[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=2)[O:4][C:13](=[O:15])[NH:1]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(N)C(O)c1cccnc1
Solvent: ClCCl
Product: CC1NC(=O)OC1c1cccnc1
Yield: 32.5 %

Procedure:
A solution of 2-nitro-1-pyridin-3-yl-butan-1-ol (3.20 g, 17.6 mmol) in ethanol (90 mL) was purged with argon, and 200 mg of Raney-Nickel was added at room temperature. The reaction mixture was three times evacuated and refilled with hydrogen. The reaction was stirred for 16 hours under H2 at room temperature. Raney-Nickel was then filtered over Hyflo, and the Hyflo washed with EtOH. The filtrate was then concentrated in order to give 2-amino-1-pyridin-3-yl-propan-1-ol as a product (2.35 g, 88%), which was used in the next reaction step without purification. To a solution of 2-amino-1-pyridin-3-yl-propan-1-ol (700 mg, 4.60 mmol) in CH2Cl2 (20 mL) was added under argon Et3N (1.60 mL, 11.5 mmol) at 0° C., followed by triphosgene (819 mg, 2.76 mmol, dissolved in 5 mL of CH2Cl2). The reaction temperature was allowed to warm from 0° C. to room temperature within one hour. The reaction mixture was then quenched with ice cold water and a 2 M solution of Na2CO3, extracted with CH2Cl2, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using EtOAc in hexane from 0% to 100% in order to give the product (160 mg, 20%). LC-MS: [M+H] 179.1; Rt 0.31 min; (LCMS method 1).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:31][N:32]([CH3:39])[CH2:33]/[CH:34]=[CH:35]/[C:36](O)=[O:37]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:36](=[O:37])/[CH:35]=[CH:34]/[CH2:33][N:32]([CH3:39])[CH3:31])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Reactant: CN(C)C/C=C/C(=O)O
Product: CN(C)C/C=C/C(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Yield: 46.6 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from the compound described in intermediate 2b and (E)-4-(dimethylamino)but-2-enoic acid, to afford the title compound (11.8 mg, 46.6%). Data: UPLC (C) Rt: 1.29 min; m/z 511.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29](O)=[O:30])[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].Cl.[NH:36]1[CH2:40][CH2:39][CH:38]([C:41]#[N:42])[CH2:37]1>>[C:41]([CH:38]1[CH2:39][CH2:40][N:36]([C:29](=[O:30])[CH:28]([N:26]2[CH:27]=[C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:33])([F:1])[F:34])=[O:6])[CH:13]=[CH:12][CH:11]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)[CH:24]=[N:25]2)[CH3:32])[CH2:37]1)#[N:42]
Reactant: N#CC1CCNC1
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Agent: Cl
Product: CC(C(=O)N1CCC(C#N)C1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and pyrrolidine-3-carbonitrile hydrochloride (Tyger and Cat. No. P76159). LCMS (M+H)+: m/z=552.2.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:17])=[C:13]([Cl:16])[CH:14]=2)[C:9](=[O:18])[N:8]([CH3:19])[C:7]=1[CH:20]=[O:21])[CH2:2][CH2:3][CH3:4].O1CCC[CH2:23]1.O1CCCC1.C[Mg]Br>O>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:17])=[C:13]([Cl:16])[CH:14]=2)[C:9](=[O:18])[N:8]([CH3:19])[C:7]=1[CH:20]([OH:21])[CH3:23])[CH2:2][CH2:3][CH3:4]
Reactant: C1CCOC1
Reactant: CCCCOc1c(C=O)n(C)c(=O)c2cc(Cl)c(Cl)cc12
Agent: C[Mg]Br
Solvent: O
Product: CCCCOc1c(C(C)O)n(C)c(=O)c2cc(Cl)c(Cl)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
To a solution of 4-butoxy-6,7-dichloro-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinealdehyde (0.98 g, 24 mmol) in tetrahydrofuran (20 mmol) was added 3N methylmagnesium bromide tetrahydrofuran solution (1.5 ml, 4.5 mmol) at 0° C. and the obtained mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-n-hexane to give 4-butoxy-6,7-dichloro-3-(1-hydroxyethyl)-2-methyl-1(2H)-isoquinolinone (0.95 g, 92.2%) as crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH:12]2[CH2:17][N:16]([CH3:18])[C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[O:13]2)[CH:3]=1.[C:23]([C:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)([CH3:28])[CH3:27])([OH:25])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:8][C:6]1[N:7]=[C:2]([C:31]2[CH:30]=[C:29]([C:26]([CH3:28])([CH3:27])[C:23]([OH:25])=[O:24])[CH:34]=[CH:33][CH:32]=2)[CH:3]=[C:4]([NH:10][CH2:11][CH:12]2[CH2:17][N:16]([CH3:18])[C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[O:13]2)[N:5]=1
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
Reactant: COc1nc(Cl)cc(NCC2CN(C)c3ccccc3O2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(NCC2CN(C)c3ccccc3O2)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Temperature: 85 °C
Yield: 68.3 %

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl)-amine (200 mg, 0.62 mmol), 3-(1-carboxy-1-methyl-ethyl)-phenyl-boronic acid (190 mg, 0.94 mmol), and Cs2CO3 (0.51 g, 1.6 mmol) in ethylene glycol dimethyl ether (10 mL) and water (2 mL) is degassed by bubbling with Ar gas for 5 minutes, and treated with tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.03 mmol) at room temperature. The mixture is heated at 85° C. for 6 h. The mixture is diluted with H2O (20 mL), and extracted with EtOAc (20 mL). The aqueous layer is separated, acidified to pH 3 with 1M HCl solution, and extracted with EtOAc (2×30 mL). The extracts are dried (MgSO4), filtered, and concentrated. The residue is chromatographed on SiO2 (70% EtOAc in heptane) to afford 2-(3-{2-methoxy-6-[(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl)-amino]-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid (190 mg, Example 92). LCMS: RT=2.59 minutes; MS: 449 (M+H). IC50=278 nM
Reaction SMILES: [OH-].[Na+].[C:3]1([S:9]([N:12]([C:22]2[C:26]([Br:27])=[C:25]([CH3:28])[O:24][N:23]=2)S(C2C=CC=CC=2)(=O)=O)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[Br:27][C:26]1[C:22]([NH:12][S:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)(=[O:11])=[O:10])=[N:23][O:24][C:25]=1[CH3:28]
Reactant: Cc1onc(N(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1onc(NS(=O)(=O)c2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 30 h

Procedure:
Sodium hydroxide (1.3 g, 30.6 mmol) was added to a solution of N-(benzenesulfonyl)-N-(4-bromo-5-methyl-3-isoxazolyl)benzene-sulfonamide (7 g, 15.3 mmol, prepared as described in (a)) in methanol (100 ml). The resulting solution was stirred at 25° C. for 30 h. Excess methanol was removed under reduced pressure. The residue was dissolved in water (50 ml) and acidified (pH 3-4) by the addition of concentrated HCl with cooling. The mixture was extracted with dichloromethane (2×100 ml) and the combined organic layer was dried over anhydrous magnesium sulfate. Removal of the solvent gave N-(4-bromo-5-methyl-3-isoxazolyl)benzenesulfonamide which was purified by crystallization from ethyl acetate/hexanes (4.5 g, 92% yield). The compound is identical to the one isolated in step (b).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([CH3:25])=[CH:22][CH:23]=2)[N:18]=[C:17]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[OH:32])[N:16]=1.C(N(CC)CC)C>C(Cl)Cl>[OH:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:17]1[N:16]=[C:15]([N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)[C:24]2[C:19](=[CH:20][C:21]([CH3:25])=[CH:22][CH:23]=2)[N:18]=1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CC[C@H](NC(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
tert-Butyl(S)-pyrrolidin-3-ylcarbamate (245 mg, 1.31 mmol) was dissolved in 1.8 mL of anhydrous CH2Cl2 and cooled to 0° C. 2-(4-Chloro-7-methylquinazolin-2-yl)phenol (300 mg, 1.1 mmol) dissolved in 1.8 mL of anhydrous CH2Cl2 was added dropwise to the mixture followed by triethylamine (134 mg, 184 μL, 1.32 mmol). The reaction was allowed to warm to room temperature and was stirred overnight. Purification via silica gel chromatography using 10-100% ethyl acetate/hexanes gave tert-butyl(S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate. LC/MS: m/z 421.0 (M+H)+ at 2.84 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[C:4]([C:3]1[C:2]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:20][CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:26])[CH2:23][CH2:24]3)=[CH:17][CH:18]=2)=[N:10][C:9]([Cl:11])=[CH:8][CH:7]=1)(=[O:5])[NH2:6]
Reactant: Nc1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: NC(=O)c1ccc(Cl)nc1Nc1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
To a mixture of 2,6-dichloronicotinamide (3 g, 15.71 mmol) and benzyl 4-(4-aminophenyl)piperazine-1-carboxylate (5.38 g, 17.28 mmol) in THF (100 mL) was added lithium bis(trimethylsilyl)amide (55.0 mL, 55.0 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 20 min. and at rt for 2 h. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic layers were washed with water and concentrated. The residue was purified by MPLC chromatography (ISCO, 6% NH4OH/MeOH/CH2Cl2, 40 g+12 g stacked column) to give 6.8 g of benzyl 4-(4-(3-carbamoyl-6-chloropyridin-2-ylamino)phenyl)piperazine-1-carboxylate as a brown solid. LCMS: (M+H)+=466.2, 468.2 (Cl pattern).