Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[N:20]=[CH:21][S:22][CH:23]=3)(=[O:17])=[O:16])=[CH:11][C:10]=2[C:24]#[N:25])=[C:4]([C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)[CH:3]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.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>[C:24]([C:10]1[CH:11]=[C:12]([S:15]([NH:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:6]=[N:7][C:2]([C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=2)=[CH:3][C:4]=1[C:26]1[CH:27]=[N:28][NH:29][CH:30]=1)#[N:25]
Reactant: OB(O)c1cccc(F)c1
Reactant: N#Cc1cc(S(=O)(=O)Nc2cscn2)ccc1Oc1cnc(Cl)cc1-c1cn[nH]c1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc(S(=O)(=O)Nc2cscn2)ccc1Oc1cnc(-c2cccc(F)c2)cc1-c1cn[nH]c1
Reaction time: 0.33 h
Yield: 34.7 %

Procedure:
25.0 mg (0.05 mmol) of 4-((6-chloro-4-(1H-pyrazol-4-yl)pyridin-3-yl)oxy)-3-cyano-N-(thiazol-4-yl)benzenesulfonamide was dissolved in 1.5 mL of 1,4-dioxane, and 10.5 mg (0.08 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 5.8 mg (10 mol %) of Pd(PPh3)4, 20.7 mg (0.15 mmol) of K2CO3, and 0.3 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 20 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=1:1) to obtain 9.0 mg (31.9% yield) of the title compound.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[S:31][C:30]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:29][CH:28]=1>>[F:13][C:12]([F:15])([F:14])[C:11]1[N:6]2[CH:5]=[N:4][C:3]([C:1]#[C:2][C:27]3[S:31][C:30]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:29][CH:28]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: NS(=O)(=O)c1ccc(C#Cc2ncn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 8-ethynyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (example C.17) (178 mg, 0.5 mmol) and commercially available 5-bromo-thiophene-2-sulfonamide (121 mg, 0.5 mmol) according to general procedure II. Obtained as a red solid (159 mg, 62%). MS (ISN) 517.1 [(M+H)+]; mp 255° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:13][C:12]2([CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1.[S:22]([OH:26])([OH:25])(=[O:24])=[O:23].CS[C:29](=[NH:31])[NH2:30]>C(O)C.O.CCOCC>[S:22]([OH:26])([OH:25])(=[O:24])=[O:23].[NH:1]([CH2:2][CH2:3][N:4]1[CH2:13][C:12]2([CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)[C:29]([NH2:31])=[NH:30].[NH:1]([CH2:2][CH2:3][N:4]1[CH2:13][C:12]2([CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)[C:29]([NH2:31])=[NH:30]
Reactant: NCCN1Cc2ccccc2C2(Cc3ccccc3O2)C1
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: N=C(N)NCCN1Cc2ccccc2C2(Cc3ccccc3O2)C1
Yield: 112.6 %

Procedure:
To a solution of 2'-(2-aminoethyl)spiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (3.6 g) in ethanol (15 ml) is added a solution of 2-methyl-2-thiopseudourea sulfate (1.8 g) in water (25 ml). After stirring at reflux (110°) for 20 hours, the mixture is cooled and diluted with ether (100 ml). The resultant precipitate is collected, washed with ether and dried to yield product (4.0 g, 83%). Recrystallization from methanol/ether yields the analytical sample as an off-white solid, mp 234°-239° (dec.).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:26]1(B(O)O)[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[CH:19]1[C:20]2=[C:21]3[C:12](=[CH:13][CH:14]=[C:15]2[C:2]([C:3]2[CH:4]=[CH:5][C:6]([C:27]4[C:28]5=[CH:12][CH:11]=[C:10]6[C:15]([CH:2]=[C:3]7[C:8]([CH:7]=[CH:6][CH:5]=[CH:4]7)=[CH:9]6)=[C:29]5[CH:30]=[CH:31][CH:26]=4)=[CH:7][CH:8]=2)=[CH:17][CH:18]=1)[CH:11]=[C:10]1[C:23]([CH:24]=[CH:25][CH:16]=[CH:9]1)=[CH:22]3
Reactant: OB(O)c1ccc(B(O)O)cc1
Reactant: Brc1c2ccccc2c(-c2ccc3ccccc3c2)c2ccccc12
Product: c1ccc2cc3c(ccc4c(-c5ccc(-c6cccc7c6ccc6cc8ccccc8cc67)cc5)cccc43)cc2c1

Procedure:
Preparation analogous to Example 7. 9-Bromo-10-(2-naphthyl)anthracene is replaced by 4.1 g (25 mmol) of benzene-1,4-diboronic acid. Recrystallisation five times from o-dichlorobenzene (about 20 ml/g); sublimation (p=5×10−5 mbar, T=400° C.). Yield: 11.1 g (21 mmol), 84.0%, purity 99.9% (HPLC).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][NH2:29])[CH:22]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:17])[NH:29][CH2:28][CH2:27][C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: NCCc1cccnc1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)NCCc2cccnc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 2-pyridin-3-yl-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C19H22N2O5 [M+H]+: 359.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][Cl:6].[F:7][C:8]1[CH:22]=[CH:21][C:11]2[C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:13][O:14][C:10]=2[CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:6][CH2:5][CH2:4][CH2:3][CH2:2][N:18]1[CH2:17][CH2:16][CH:15]([C:12]2[C:11]3[CH:21]=[CH:22][C:8]([F:7])=[CH:9][C:10]=3[O:14][N:13]=2)[CH2:20][CH2:19]1
Reactant: ClCCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc2c(C3CCN(CCCCCl)CC3)noc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 29 %

Procedure:
1-bromo-4-chlorobutane (9.4 g, 60 mmol) is dissolved in 50 ml of DMF, and thereto 4-(6-fluoro-1,2-benzisoxazolyl)-piperidine (4.4 g, 20 mmol) and anhydrous potassium carbonate powder (8.2 g, 60 mmol) is added. The mixture is stirred at room temperature for 48 hours and the reaction is terminated. To the reaction solution is added 100 ml of water and 100 ml of ethyl acetate. The mixture is shaked and the aqueous layer is further extracted with 100 ml of ethyl acetate. The ethyl acetate layers are combined, backwashed with 200 ml of water, dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated to 50 ml volume and extracted with 5% HCl (30 ml×3). The extracting solution is combined, adjusted to pH 7 with 5% NaOH, and further extracted with ethyl acetate (30 ml×3). The extracting solution is combined, dried and evaporated to dryness to obtain 1.8 g of 3-(1-(4-chlorobutyl)-4-piperidinyl)-6-fluoro-benzisoxazole, with a yield of 30%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.[CH:26]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27]1>C(Cl)Cl>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:30]([CH:26]2[CH2:29][CH2:28][CH2:27]2)=[O:31])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Reactant: O=C(Cl)C1CCC1
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1)C1CCC1
Yield: 16.4 %

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.100 g, 0.271 mmol), TEA (1.0 mL), DCM (10 mL), cyclobutanecarbonyl chloride (0.041 g, 0.352 mmol) to afford 0.020 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 2.05 (m, 614), 3.08 (m, 1H), 4.29 (m, 2H), 7.44 (m, 1H), 7.60 (m, 2H), 7.86 (m, 2H), 8.17 (m, 3H), 12.69 (s, 1H); MS (m/z): 451.07 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:17][S:18]([O:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:20])=[O:19]
Reactant: OC1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OC1CCOCC1
Reaction time: 0.17 h
Yield: 99.6 %

Procedure:
To a solution of tetrahydro-2H-pyran-4-ol (2.5 g, 24.5 mmol) in DCM (40 mL) was added DIEA (6.40 mL, 36.7 mmol) at 0° C. and allowed to stir under nitrogen for 10 minutes. Methane sulfonyl chloride (2.18 mL, 28.1 mmol) was added slowly. The reaction was allowed to proceed for 1 hour at 0° C. The reaction was partitioned between 100 mL of DCM and 50 mL of 0.5 M hydrochloric acid. The layers were separated and the organic layer was then washed sequentially with water, saturated sodium bicarbonate, and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure and dried on high vacuum to afford tetrahydro-2H-pyran-4-yl methanesulfonate (4.4 g, 24.4 mmol, 99.7% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:17])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:27][C:28]([C:30]1([C:33](O)=[O:34])[CH2:32][CH2:31]1)=[O:29].[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH2:36]([NH:43][C:33]([C:30]1([C:28]([NH:27][C:3]2[CH:4]=[CH:5][C:6]([O:8][C:9]3[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]4[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]4)=[O:17])[CH:10]=3)=[CH:7][C:2]=2[F:1])=[O:29])[CH2:32][CH2:31]1)=[O:34])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)O)CC4)c(F)c3)ccn2)CC1
Reactant: NCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)NCc5ccccc5)CC4)c(F)c3)ccn2)CC1
Reaction time: 32 h
Yield: 57 %

Procedure:
To a solution of 1-(2-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)carbamoylcyclopropanecarboxylic acid (40 mg) in N,N-dimethylformamide (1.0 ml) were added benzylamine (0.018 ml), triethylamine (0.023 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (72.9 mg) at room temperature, followed by stirring for 32 hr. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=97:3). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (27.1 mg, 57%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:10]2[C:11]3[C:12](=[O:18])[CH2:13][CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[BH4-].[Na+]>C(O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:10]2[C:11]3[CH:12]([OH:18])[CH2:13][CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(=O)CC3
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)C(O)CC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
To a stirred solution of Intermediate 3 (0.12 g, 0.37 mmol) in ethanol (2 ml) was added NaBH4 (28 gm, 0.74 mmol). The reaction mixture was allowed to stir at RT for 1 hour. The reaction mixture was diluted with water and extracted with DCM (3×). The combined DCM extracts were washed with brine, dried (Na2SO4), and solvent evaporated in vacuo to give the sub-titled compound as a colorless oil (104 mg) which was used as obtained in the next step. MS: ESI (positive): 276 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]2[CH:13]=[C:12]([CH2:14][CH3:15])[O:11][N:10]=2)=[CH:4][N:3]=1.[CH3:16][S-:17].[Na+]>C(O)(C)(C)C>[Cl:8][C:7]1[C:2]([S:17][CH3:16])=[N:3][CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([CH2:14][CH3:15])[O:11][N:10]=2)[CH:6]=1
Reactant: CCc1cc(-c2cnc(Cl)c(Cl)c2)no1
Reactant: C[S-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CCc1cc(-c2cnc(SC)c(Cl)c2)no1
Reaction time: 3 h
Yield: 82.6 %

Procedure:
3-(2,3-Dichloro-5-pyridyl)-5-ethylisoxazole (0.71 g, 2.9 mmol) was dissolved in t-butanol (15 mL) and sodium methanethiolate (0.3 g, 4.3 mmol) added. The reaction mixture was heated under reflux with stirring for 3 hours, cooled, and poured onto ice. The resulting cream precipitate was collected by filtration, dissolved in dichloromethane (50 mL) and dried over anhydrous sodium sulphate. Evaporation of the solvent under reduced pressure gave the desired product (0.61 g, 83%) as a cream solid, melting point. 59-62° C.
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:6])[CH2:4][CH3:5].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:17]([O:24][C:25]1[CH:30]=[C:29]([CH2:31]Br)[CH:28]=[CH:27][C:26]=1[N+:33]([O-:35])=[O:34])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:17]([O:24][C:25]1[CH:30]=[C:29]([CH2:31][CH:2]([CH3:1])[C:3](=[O:6])[CH2:4][CH3:5])[CH:28]=[CH:27][C:26]=1[N+:33]([O-:35])=[O:34])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCC(=O)CC
Reactant: O=[N+]([O-])c1ccc(CBr)cc1OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(=O)C(C)Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of pentan-3-one (516 mg, 6 mmol) in THF (5 mL) at −78° C. is added dropwise LiHMDS (6.6 mL of 1.0 M solution in THF, 6.6 mmol) over a period of 15 min. The solution is stirred at −78° C. for 2 h then a solution of 2-benzyloxy-4-bromomethyl-1-nitrobenzene (Example 83, step C) (963 mg, 3 mmol) in THF (5 mL) is added dropwise. The mixture is allowed to warm to RT overnight and is quenched with saturated ammonium chloride solution. The mixture is extracted with EtOAc and the organic phase is washed with brine then dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using a gradient of 10-50% EtOAc/hexane as eluent to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[F:12].C(N(C(C)C)CC)(C)C.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1.O>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:22][CH:23]2[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]2)[CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)c(Cl)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)c(F)cc2[N+](=O)[O-])CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
1-Chloro-2,5-difluoro-4-nitrobenzene (D1) (1.18 mmol, 228 mg) was dissolved in dry dimethylformamide (2 ml) and diisopropylethylamine (1 eq., 1.18 mmol, 0.209 ml), 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (1 eq., 1.18 mmol, 236 mg) were added at room temperature and the mixture was stirred at 50° C. overnight. The crude mixture was then cooled to room temperature and water (150 ml) was added; the aqueous solution was extracted with ethyl acetate (2×); organics were alternatively washed with brine and water (2×). The organics were combined dried over Na2SO4, filtered and the solvent was evaporated to afford the title compound, 340 mg, 80%, bright orange solid, M+−H=372.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH:18]=[O:19].Cl([O-])=[O:21].[Na+].[Na]>C(O)(C)(C)C.CC(=CC)C.O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:3]=1[C:18]([OH:21])=[O:19]
Reactant: [O-][Cl+][O-]
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)C1=C(Cl)c2ccccc2OC1c1ccccc1
Reaction time: 5 h

Procedure:
To a stirred solution of 5.8 g 4-chloro-3-formyl-flav-3-ene in 500 ml tert-butanol and 100 ml 2-methylbut-2-ene at room temperature is added dropwise a solution of 17.9 g sodium chlorite and 17.9 g sodium dihydrogenophosphate in 200 ml water. Stirring is continued for 5 hours. The solution is concentrated in vacuo and water is added to the residue to give a suspension. The mixture is extracted with hexane and the clear organic extracts are discarded. Subsequently, the aqueous suspension is acidified to pH 3 and the mixture is extracted with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulfate, filtered and evaporated. The residual solid is recrystallized in a mixture of chloroform and hexane. Pure 4-chloro-3-carboxy-flav-3-ene is obtained as yellow crystals; m.p. 210° C.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[C:15]([C:28]([O:30][CH3:31])=[O:29])=[C:16]([O:24]COC)[C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[C:15]([C:28]([O:30][CH3:31])=[O:29])=[C:16]([OH:24])[C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: COCOc1c(C(=O)OC)c(OCCCCNC(=O)OC(C)(C)C)cc2ccccc12
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1c(OCCCCN)cc2ccccc2c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.6 %

Procedure:
To a mixture of methyl 3-{4-[(tert-butoxycarbonyl)amino]butoxy}-1-(methoxymethoxy)-2-naphthoate (28 mg, 0.064 mmol) was added 4M HCl in dioxane (1 mL). The mixture was stirred at ambient temperature for 30 minutes, concentrated under reduced pressure to provide the titled compound (19 mg, 100%) as its hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([CH3:13])=[C:5]2[N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20](I)[CH:21]=2)[C:16]([CH3:25])([CH3:24])[CH2:15]1.OC(C(O)(C)C)(C)C.[N:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([CH3:13])=[C:5]2[N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:37]3[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=3)[CH:21]=2)[C:16]([CH3:25])([CH3:24])[CH2:15]1
Reactant: OB(O)c1ccncc1
Reactant: Cc1nc2ccc(Cl)cc2c(N2CC(C)(C)c3ccc(I)cc32)c1C
Agent: CC(C)(O)C(C)(C)O
Product: Cc1nc2ccc(Cl)cc2c(N2CC(C)(C)c3ccc(-c4ccncc4)cc32)c1C

Procedure:
Prepared according to procedure W using 6-chloro-4-(6-iodo-3,3-dimethylindolin-1-yl)-2,3-dimethylquinoline (0.15 g, 0.32 mmol) and pyridine-4-boronic acid pinacol (0.1329 g, 0.65 mmol) to give 6-chloro-4-(3,3-dimethyl-6-(4-pyridinyl)-2,3-dihydro-1H-indol-1-yl)-2,3-dimethylquinoline as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (2H, d, J=4.3 Hz), 8.02 (1H, d, J=9.0 Hz), 7.82 (1H, d, J=2.3 Hz), 7.60 (1H, dd, J=9.0, 2.3 Hz), 7.28-7.35 (3H, m), 7.04 (1H, dd, J=7.6, 1.4 Hz), 6.12 (1H, d, J=1.2 Hz), 3.63-3.88 (2H, m), 2.75 (3H, s), 2.27 (3H, s), 1.60 (3H, s), 1.54 (3H, s); Mass Spectrum (ESI) m/e=414.1 (M+1).
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5]2.[H-].[Na+].[CH2:18](Br)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[I-].[K+]>CN(C)C=O>[CH2:18]([N:8]1[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[NH:5][C:4]2=[CH:3][S:2][CH:1]=[C:10]2[C:9]1=[O:11])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCCc1ccccc1
Reactant: O=C1Nc2ccccc2Nc2cscc21
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2cscc2Nc2ccccc2N1CCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 17.28 g. of 4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 100 ml. of dimethylformamide is added 4.2 g. of 50% sodium hydride in mineral oil. The mixture is stirred for one hour and 16.0 g. of phenethyl bromide and 20 mg. of potassium iodide are added. The mixture is stirred for 48 hours. The solution is evaporated. The residual gum is washed with water and hexane, dissolved in methylene chloride, washed with water, dried over magnesium sulfate and filtered through magnesol. The crystals which form in the filtrate are removed by filtration. This filtrate is evaporated in vacuo giving the desired product as dark brown crystals.
Reaction SMILES: [C:1]([NH:7][C:8](=[O:30])[NH:9][C:10]1[N:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=O)[O:25]C(C)=C)[CH:18]=2)=[CH:12][CH:11]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:31]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH3:32].CN1CCCC1>O1CCOCC1.CC#N.O>[CH2:31]([N:33]1[CH2:38][CH2:37][N:36]([C:24]([NH:23][C:19]2[CH:18]=[C:17]([O:16][C:13]3[CH:14]=[N:15][C:10]([NH:9][C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:30])=[CH:11][CH:12]=3)[CH:22]=[CH:21][N:20]=2)=[O:25])[CH2:35][CH2:34]1)[CH3:32]
Reactant: C=C(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2)ccn1
Reactant: CCN1CCNCC1
Agent: CN1CCCC1
Solvent: CC#N
Solvent: O
Solvent: C1COCCO1
Product: CCN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)C(C)(C)C)nc3)ccn2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.1 %

Procedure:
A mixture of Example C2 (0.203 g, 0.491 mmol), N-ethyl piperazine (0.1 mL, 0.79 mmol) and N-methylpyrrolidine (0.021 g, 0.25 mmol) in dioxane (5 mL) was heated at 80° C. for 3 h, cooled to RT, and concentrated to dryness. The residue was dissolved in DCM and stirred with sat'd NaHCO3 for ˜15 min. The aqueous layer was back-extracted with DCM (3×) and the organic phases combined, dried (Na2SO4) and concentrated to afford a light brown oil. The crude residue was purified via silica gel chromatography (MeOH/DCM) to afford a colorless oil, which was suspended in MeCN/H2O, sonicated, frozen and lypholized overnight to afford 4-ethyl-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide as a white solid (74 mg, 32%). 1H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 10.44 (s, 1H), 9.25 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.12 (d, J=5.7 Hz, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.71 (dd, J=9.0, 2.9 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H), 6.61 (dd, J=5.7, 2.4 Hz, 1H), 3.44-3.35 (m, 4H), 2.35-2.23 (m, 6H), 1.21 (s, 9H), 0.98 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 470.3 (M+H+).