Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:14])[CH2:7][N:8]1[CH2:12][CH2:11][C@@H:10]([NH2:13])[CH2:9]1)[CH3:4].[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1>>[CH2:3]([O:5][C:6](=[O:14])[CH2:7][N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH2:9]1)[CH3:4]
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)CN1CC[C@@H](N)C1
Agent: Cl
Product: CCOC(=O)CN1CC[C@@H](NC(=O)c2ccc(Cl)cc2)C1

Procedure:
5.1 Using general procedure D ((R)-3-amino-pyrrolidin-1-yl)-acetic acid ethyl ester dihydrochloride (example 1.2) was coupled with 4-chlorobenzoic acid to give [(R)-3-(4-chloro-benzoylamino)-pyrrolidin-1-yl]-acetic acid ethyl ester. Solid. MS 311.3 ([M+H]+)<
Reaction SMILES: C(=[N:14][NH2:15])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[Br:22][C:23]1[CH:24]=[CH:25][C:26](F)=[C:27]([C:29]([C:31]2[CH:36]=[C:35]([CH:37]([CH3:39])[CH3:38])[CH:34]=[C:33]([CH:40]([CH3:42])[CH3:41])[C:32]=2[O:43][CH2:44][CH3:45])=O)[CH:28]=1>C1COCC1>[Br:22][C:23]1[CH:28]=[C:27]2[C:26](=[CH:25][CH:24]=1)[NH:15][N:14]=[C:29]2[C:31]1[CH:36]=[C:35]([CH:37]([CH3:39])[CH3:38])[CH:34]=[C:33]([CH:40]([CH3:42])[CH3:41])[C:32]=1[O:43][CH2:44][CH3:45]
Reactant: CCOc1c(C(=O)c2cc(Br)ccc2F)cc(C(C)C)cc1C(C)C
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1c(-c2n[nH]c3ccc(Br)cc23)cc(C(C)C)cc1C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.4 %

Procedure:
Benzophenone hydrazone (232 mg, 1.2 mmol) was added to a solution of potassium t-butoxide (132 mg, 1.2 mmol) in 10 ml of THF. After stirring for 30 min. at ambient temperature under a nitrogen atmosphere, a solution of (5-bromo-2-fluoro-phenyl)-(2-ethoxy-3,5-diisopropyl-phenyl)-methanone (400 mg, 1.0 mmol) in THF (10 mL) was added and the reaction was stirred for 12 h, then quenched with saturated ammonium chloride solution (20 mL) and extracted with ether (2×20 mL). The organic layers were combined, dried over MgSO4 and evaporated to a residue. The residue was dissolved in ethanol (10 mL) and 1N HCl solution (10 mL) and refluxed for 1 h. After cooling, the reaction was partitioned between ether and water. The organic layer was dried over MgSO4 and evaporated to a residue. The residue was purified by silica gel column (10% ethyl acetate in hexanes) to give 5-bromo-3-(2-ethoxy-3,5-diisopropyl-phenyl)-1H-indazole as a clear oil (61.8 mg, 16%). 1H NMR (250 MHz, CDCl3): δ 7.87 (bs, 1H), 7.22-7.02 (m, 3H), 6.55 (bd, 1H, J=9.4), 3.32 (m, 1H), 3.26 (q, 2H, J=7.5), 2.73 (m, 1H), 1.05 (s, 6H), 1.03 (s, 6H), 0.77 (t, 3H, J=7.5). MS [EI+] 401, 403 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].[CH3:25][O:26][C:27]([C:29]1[N:30]=[N:31][C:32](Cl)=[CH:33][CH:34]=1)=[O:28]>>[CH3:25][O:26][C:27]([C:29]1[N:30]=[N:31][C:32]([O:9][CH2:8][C:6]2[CH:5]=[CH:4][C:3]([CH:10]([CH3:24])[C:11]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=3)([OH:16])[C:12]([F:15])([F:14])[F:13])=[C:2]([Cl:1])[CH:7]=2)=[CH:33][CH:34]=1)=[O:28]
Reactant: COC(=O)c1ccc(Cl)nn1
Reactant: CC(c1ccc(CO)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Product: COC(=O)c1ccc(OCc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)nn1

Procedure:
The title compound was prepared in analogy to Example 93, step 7 from 3-(2-chloro-4-hydroxymethyl-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (obtained in Example 120, stepl) by alkylation with methyl-6-chloropyridazine-3-carboxylate [CAS Reg. No. 65202-50-8]. MS (m/e)=516.1 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[CH3:19][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI.S(=O)(=O)(O)O>COCCOCCOC>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:7](=[O:9])[N:8]([CH3:19])[C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=c1[nH]c2cc(Br)ccc2n1-c1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: COCCOCCOC
Solvent: CI
Product: Cn1c(=O)n(-c2ccc(F)cc2)c2ccc(Br)cc21
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
To a stirred room temperature suspension of 5-bromo-1-(4-fluorophenyl)-1,3-dihydro-benzimidazol-2-one (160 mg, 0.52 mmol) in anhydrous bis(2-methoxyethyl)ether (5 mL) was added lithium bis(trimethylsilyl)amide (0.55 mL of 1.06 M solution in THF, 0.58 mmol). After 30 minutes, methyl iodide (125 μL, 2 mmol) was added. After 2 hours, the mixture was poured into 1 N sulfuric acid containing ice. The resulting precipitate was filtered, washed with water, and dried to afford 160 mg of 5-bromo-1-(4-fluorophenyl)-3-methyl-1,3-dihydro-benzimidazol-2-one as an off-white solid. MS m/z 321/323 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Reactant: C1CCNC1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1C(F)(F)F)N1CCCC1
Yield: 96.1 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride (0.50 g, 1.54 mmol) and pyrrolidine (0.32 mL, 3.85 mmol) were stirred together in dry dichloromethane (2 mL) for 16 hours. 1-{[4-bromo-2-(trifluoromethyl)phenyl]sulfonyl}pyrrolidine (0.53 g, 96%) was provided after purification. MS (ESI) m/z 358. HPLC purity 100.0% at 210-370 nm, 9.8 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)=[CH:9][CH:8]=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[O:39]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40]1>C1COCC1>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:13](=[C:14]2[CH2:15][C:16]([CH3:22])([CH3:23])[CH2:17][C:18]([CH3:20])([CH3:21])[CH2:19]2)[C:10]2[CH:11]=[CH:12][C:7]([C:41]3[CH:42]=[CH:43][O:39][CH:40]=3)=[CH:8][CH:9]=2)=[CH:25][CH:26]=1
Reactant: OB(O)c1ccoc1
Reactant: CC1(C)CC(=C(c2ccc(F)cc2)c2ccc(OS(=O)(=O)C(F)(F)F)cc2)CC(C)(C)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(F)cc2)c2ccc(-c3ccoc3)cc2)CC(C)(C)C1
Yield: 40.3 %

Procedure:
The procedure described for 28 was utilized using triflate 25 (150 mg, 0.319 mmol), PdCl2 (Ph3P)2 (23 mg, 0.032 mmol), 2 N aqueous Na2CO3 (320 uL, 0.638 mmol), 3-furanylboronic acid (71 mg, 0.638 mmol), and THF (10 mL). The reaction mixture was refluxed for 15 h. Standard work-up followed by purification gave 50 mg (40%) of the title product 29 (40%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 7.71 (s, 1H), 7.45 (s, 1H), 7.40 (d, J=8.0 Hz, 2H), 7.18-7.12 (m, 4H), 6.96 (app. t, J=8.4 Hz, 2H), 6.68 (s, 1H), 2.0 (s, 2H), 1.96 (s, 2H), 1.30 (s, 2H), 0.94 (s, 6H), 0.93 (s, 6H). LCMS (APCI): m/z 389 (M+H)+.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]1([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][C:6]1[CH:11]=[CH:10][C:9]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:8][CH:7]=1)[CH3:17]
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)Cc1ccccc1
Product: CCOC(=O)Cc1ccc(S(=O)(=O)Cl)cc1
Temperature: 40 °C
Yield: 56.3 %

Procedure:
The chlorosulfonic acid (16.6 mL, 250 mmol) was added dropwise into ethyl phenylacetate (8.2 g, 50 mmol) under stirring at 40° C. Thereafter, the mixture was stirred for 0.5 hour at room temperature, and then poured on ice and extracted with dichloromethane. The combined organic phase was washed by saline, dried with sodium sulfate and concentrated under reduced pressure. The concentrate was separated through column chromatography (petroleum ether/ethyl acetate=6/1, v/v) to obtain yellow oil (7.4 g, yield: 56%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]#[N:12].Cl.[NH2:14][OH:15].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11](=[N:14][OH:15])[NH2:12]
Reactant: N#Cc1sccc1C1OCCO1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=NO)c1sccc1C1OCCO1
Temperature: 40 °C

Procedure:
To a solution of the foregoing nitrile (5.0 g, 27.59 mmol) in ethanol (20 ml) was added a solution of hydroxylamine hydrochloride (3.7 equivalents) and sodium carbonate (1.7 equivalents) in water (50 ml). The resulting mixture was heated to 40° C. for 5 h, then cooled to room temperature. The colourless precipitate was isolated by filtration, dried under a stream of air and azeotroped with toluene (2×) to give 3-(1,3-dioxolan-2-yl)thiophene-2-amidoxime as an off-white solid (4.36 g). 1H NMR (DMSO-d6): δ 9.83 (1H, s), 7.48 (1H, d, J 5.18), 7.15 (1H, d, J 5.18), 6.05 (1H, s), 5.77 (2H, bs), 4.05 (2H, m), 3.91 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][C@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)[CH:7]=[C:6]2[CH3:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([C:31](O)=[O:32])[CH2:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O.CN(C=O)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2([C:31]([N:16]3[CH2:17][CH2:18][C@H:14]([NH:13][C:8]4[CH:7]=[C:6]([CH3:19])[C:5]5[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=4)[CH2:15]3)=[O:32])[CH2:30][CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: COc1ccc2nc(N[C@H]3CCNC3)cc(C)c2c1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2nc(N[C@H]3CCN(C(=O)C4(c5ccc(Cl)cc5)CCC4)C3)cc(C)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.6 %

Procedure:
To a mixture of (S)-6-methoxy-4-methyl-N-(pyrrolidin-3-yl)quinolin-2-amine (0.50 g), 1-(4-chlorophenyl)-1-cyclobutane carboxylic acid (0.41 g), and DMF (6 mL) were added HOBt (0.39 g) and EDC.HCl (0.56 g), and the mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with ethyl acetate and water, followed by addition of a saturated sodium hydrogencarbonate solution to extract the mixture. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform/methanol, and NH silica gel, ethyl acetate) to obtain colorless amorphous (S)-(1-(4-chlorophenyl)cyclobutyl)-(3-(6-methoxy-4-methylquinolin-2-ylamino)pyrrolidin-1-yl)methanone (0.67 g).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([C:14]2[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([NH:76][CH2:77][CH2:78][C:79]1[N:80]=[CH:81][N:82]([CH3:84])[CH:83]=1)=[N:25][C:26]=2[NH:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH:37][C:38]2[N:46]=[C:45]([NH:47][CH2:48][CH2:49][C:50]3[N:51]=[CH:52][N:53]([CH3:55])[CH:54]=3)[N:44]=[C:43]3[C:39]=2[N:40]=[CH:41][N:42]3[C@H:56]2[C@H:60]([O:61]C(=O)C)[C@H:59]([O:65]C(=O)C)[C@@H:58]([C:69]3[N:70]=[N:71][N:72]([CH2:74][CH3:75])[N:73]=3)[O:57]2)[CH2:33][CH2:32]1)(=O)C.C[O-].[Na+]>CO>[C@H:34]1([NH:37][C:38]2[N:46]=[C:45]([NH:47][CH2:48][CH2:49][C:50]3[N:51]=[CH:52][N:53]([CH3:55])[CH:54]=3)[N:44]=[C:43]3[C:39]=2[N:40]=[CH:41][N:42]3[C@H:56]2[C@H:60]([OH:61])[C@H:59]([OH:65])[C@@H:58]([C:69]3[N:70]=[N:71][N:72]([CH2:74][CH3:75])[N:73]=3)[O:57]2)[CH2:33][CH2:32][C@H:31]([NH:30][C:26]2[N:25]=[C:24]([NH:76][CH2:77][CH2:78][C:79]3[N:80]=[CH:81][N:82]([CH3:84])[CH:83]=3)[N:23]=[C:22]3[C:27]=2[N:28]=[CH:29][N:21]3[C@H:6]2[C@H:5]([OH:4])[C@H:9]([OH:10])[C@@H:8]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=3)[O:7]2)[CH2:36][CH2:35]1
Reactant: CCn1nnc([C@H]2O[C@@H](n3cnc4c(N[C@H]5CC[C@H](Nc6nc(NCCc7cn(C)cn7)nc7c6ncn7[C@@H]6O[C@H](c7nnn(CC)n7)[C@@H](OC(C)=O)[C@H]6OC(C)=O)CC5)nc(NCCc5cn(C)cn5)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCn1nnc([C@H]2O[C@@H](n3cnc4c(N[C@H]5CC[C@H](Nc6nc(NCCc7cn(C)cn7)nc7c6ncn7[C@@H]6O[C@H](c7nnn(CC)n7)[C@@H](O)[C@H]6O)CC5)nc(NCCc5cn(C)cn5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
A solution of Stage 3 (28.6 g; assume 24.7 mmol) in methanol (515 ml) was treated with sodium methoxide (0.44 g, 8.13 mmol) for 90 minutes before being treated with a further portion of sodium methoxide (0.44 g, 8.13 mmol). After 30 minutes Dowex 50 [H+] was added to neutralise the solution. The resin was filtered off and the filtrate was evaporated to leave the title Compound as a foam (24 g).
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1.[CH3:29][S:30][C:31]1[N:36]=[C:35]([C:37]#[C:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([N+:45]([O-:47])=[O:46])[CH:40]=2)[CH:34]=[CH:33][N:32]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>O>[CH3:29][S:30][C:31]1[N:36]=[C:35]([C:37]2[C:38]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([N+:45]([O-:47])=[O:46])[CH:40]=3)=[N:14][N:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][C:20]=23)[CH:34]=[CH:33][N:32]=1
Reactant: CSc1nccc(C#Cc2cccc([N+](=O)[O-])c2)n1
Reactant: N[n+]1ccc(OCc2ccccc2)cc1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nccc(-c2c(-c3cccc([N+](=O)[O-])c3)nn3ccc(OCc4ccccc4)cc23)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 10.6 %

Procedure:
A solution of 1-amino-4-[(phenylmethyl)oxy]pyridinium 2,4,6-trimethylbenzenesulfonate (13.8 mmol; crude) and 2-(methylthio)-4-[(3-nitrophenyl)ethynyl]pyrimidine (6.30 g, 9.22 mmol) in dry-DMF (70 mL) was cooled to 0° C. Aq. K2CO3 (2.75 mL, 18.4 mmol) was added. The mixture was stirred at rt overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic phase was combined, washed with brine, and dried (MgSO4). The solvent was evaporated under reduced pressure. Chromatography on silica gel eluting with hexane/EtOAc gradient (15-50% EtOAc) gave yellow solid (460 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=2[C:10]([NH:12][NH:13][C:14]([NH2:16])=[O:15])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=2[CH:10]2[NH:12][NH:13][C:14](=[O:15])[NH:16]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)NNC(N)=O)cc1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2ccccc2C2NNC(=O)N2)cc1
Yield: 78.6 %

Procedure:
1-[2-(4-Methylphenyl)benzoyl]semicarbazide (4.6 g) and phosphorus oxychloride (10.3 g) were suspended in benzene (100 ml), and the suspension was heated for 3 hours under reflux. The reaction mixture was concentrated to dryness under reduced pressure. To the residue was added water, and resulting crystalline precipitate was collected by filtration. Recrystallization from methanol afforded the title compound as colorless needles (3.4 g, 79%), m.p.245°-246° C. (decomp.).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([NH2:18])[CH2:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([NH:18][CH2:15][CH2:16][CH3:17])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCOCc1ccccc1
Reactant: CCCN
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCCNC(=O)CCCOCc1ccccc1
Reaction time: 18 h
Yield: 79.8 %

Procedure:
A mixture of 4-benzyloxybutyric acid (2.69 g, 13.8 mmol), propylamine (0.82 g, 13.8 mmol), HOBt (2.05 g, 15.2 mmol), N-methylmorpholine (1.68 g, 16.6 mmol) and EDC (2.91 g, 15.2 mmol) in DMF (6 mL) is stirred at 20–25 degrees C. for 18 hours. The mixture is diluted with ethyl acetate (40 mL) and washed with water (10 mL), hydrochloric acid (1 N, 10 mL), saturated sodium bicarbonate (10 mL), and saline (10 mL). The organic phase is separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 4-(benzyloxy)-N-propylbutanamide (2.59 g), APCI-MS (m/z) [M+H]+=236.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[Cl:59][C:60]1[N:68]=[CH:67][CH:66]=[CH:65][C:61]=1[C:62](Cl)=[O:63]>>[CH3:55][O:54][C:52](=[O:53])[C@@H:51]([N:46]1[CH2:45][C:44]2[C:48](=[CH:49][C:41]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:62](=[O:63])[C:61]4[CH:65]=[CH:66][CH:67]=[N:68][C:60]=4[Cl:59])=[CH:40][CH:39]=3)=[CH:42][CH:43]=2)[C:47]1=[O:50])[CH:56]([CH3:58])[CH3:57]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cccnc4Cl)cc3)cc2C1=O
Yield: 96 %

Procedure:
The compound of example 208 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 2-chloro nicotinoyl chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:3]=12.[C:20]1([S:26]([N:29]2[C:37]3[CH:36]=[C:35]([Sn](C)(C)C)[CH:34]=[C:33]([NH2:42])[C:32]=3[CH:31]=[N:30]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>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.CN(C)C=O>[C:20]1([S:26]([N:29]2[C:37]3[CH:36]=[C:35]([C:2]4[CH:7]=[CH:6][N:5]=[C:4]5[N:8]([S:11]([C:14]6[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=6)(=[O:13])=[O:12])[CH:9]=[CH:10][C:3]=45)[CH:34]=[C:33]([NH2:42])[C:32]=3[CH:31]=[N:30]2)(=[O:27])=[O:28])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Nc1cc(-c2ccnc3c2ccn3S(=O)(=O)c2ccccc2)cc2c1cnn2S(=O)(=O)c1ccccc1
Temperature: 100 °C
Yield: 27.3 %

Procedure:
4-Bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.546 g, 4.59 mmol), 1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (2 g, 4.59 mmol) and Pd(Ph3P)4 (0.265 g, 0.229 mmol) were added to N,N-dimethylformamide (30 mL) under nitrogen. The mixture was heated at 100° C. for 2 days then cooled at room temperature and concentrated in vacuo. The mixture was purified by column chromatography on silica (70 g) eluting with ammonia and methanol in DCM, then again using the Companion and eluting with a gradient of 30 to 85% MeCN (+0.1% TFA)/H2O (0.1% TFA). Fractions containing desired product were combined and the solvent was removed to afford the title compound as a brown solid (663 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][N:10](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[NH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:9]#[N:10])[CH:7]=1
Reactant: CN(C)C=O
Reactant: Nc1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(N)ccn1
Temperature: 145 °C
Yield: 20 %

Procedure:
A mixture of 2-chloro-pyridin-4-ylamine (0.642 g, 5 mmol), Zn(CN)2 (0.323 g, 2.75 mmol) and Pd(PPh3)4 (0.288 g, 0.025 mmol) in 5 mL of DMF was heated at 145° C. for 20 hours. After the reaction mixture cooled to room temperature, it was partitioned between ethyl acetate and H2O. The aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 9:1 hexanes/ethyl acetate to provide 0.29 g (20%) of the desired product. MS (DCI) m/e 120 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.08 (d, J=5.76 Hz, 1H), 6.94 (d, J=2.34 Hz, 1H), 6.68 (dd, J=5.76, 2.37 Hz, 1H), 6.59 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[N:12]=[C:11](SC)[C:10]2[C:5](=[C:6]([NH:15][CH:16]=[O:17])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.ClC1C=CC=C(C(OO)=O)C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+].[CH3:49][C:50]1[NH:54][N:53]=[C:52]([NH2:55])[CH:51]=1>C(Cl)Cl.C1COCC1>[F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[N:12]=[C:11]([NH:55][C:52]2[CH:51]=[C:50]([CH3:49])[NH:54][N:53]=2)[C:10]2[C:5](=[C:6]([NH:15][CH:16]=[O:17])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2c(NC=O)cccc12
Reactant: Cc1cc(N)n[nH]1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3c(NC=O)cccc23)n[nH]1
Reaction time: 0.67 h
Yield: 34.6 %

Procedure:
To N-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazolin-8-yl)formamide (168 mg, 0.462 mmol) in DCM (5 mL) at 0° C. was added 3-chloroperbenzoic acid (70%, 171 mg, 0.69 mmol) and the mixture stirred for 40 min. The mixture was diluted with DCM and then aq sodium thiosulfate and saturated aq sodium bicarbonate were added. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. To the residue were added THF (4 mL) and 5-methyl-1H-pyrazol-3-amine (135 mg, 1.38 mmol) and the mixture was stirred at rt for 20 min. The mixture was concentrated under reduced pressure and purified by preparative HPLC (Varian C-18 reverse phase column, eluted with gradient of solvent B=0.05% formic acid/ACN and solvent A=5% ACN/0.05% formic acid/H2O) to afford N-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-8-yl)formamide (66 mg, 35%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.17 (s, 3H) 5.89 (s, 1H) 7.61 (t, J=8.10 Hz, 1H) 7.96-8.11 (m, 2H) 8.37 (d, J=8.29 Hz, 1H) 8.66 (d, J=11.87 Hz, 2H) 8.79 (d, J=7.72 Hz, 1H) 10.24 (s, 1H) 10.77 (br s, 1H) 11.81-12.73 (m, 1H); LC-MS (ESI) m/z 414 (M+H)+.
Reaction SMILES: [CH:1]1([CH:4]([OH:15])[C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6])[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:22](O)(=[O:24])[CH3:23].O>C(OCC)(=O)C>[C:22]([O:15][CH:4]([CH:1]1[CH2:2][CH2:3]1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])(=[O:24])[CH3:23]
Reactant: CC(=O)O
Reactant: O=C(OCc1ccccc1)C(O)C1CC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(C(=O)OCc1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
900 mg of benzyl cyclopropyl(hydroxy)acetate, 9.0 ml of pyridine, and 820 μL of anhydrous acetic acid were added, followed by stirring at room temperature overnight. To the reaction mixture were added water and ethyl acetate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 1.45 g of benzyl acetoxy(cyclopropyl)acetate.