Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:34])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([C:16]3[S:20][C:19]([C@@:21]4([OH:33])[CH2:26][CH2:25][C@H:24]([C:27]([O:29]C)=[O:28])[C:23]([CH3:32])([CH3:31])[CH2:22]4)=[N:18][CH:17]=3)[CH:12]=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[C:3]([CH3:34])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([C:16]3[S:20][C:19]([C:21]4([OH:33])[CH2:26][CH2:25][CH:24]([C:27]([OH:29])=[O:28])[C:23]([CH3:31])([CH3:32])[CH2:22]4)=[N:18][CH:17]=3)[CH:12]=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(C)cc(Nc4ncc(F)c(C)n4)c3)s2)CC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(Nc2ncc(F)c(C)n2)cc(-c2cnc(C3(O)CCC(C(=O)O)C(C)(C)C3)s2)c1
Temperature: 110 °C
Yield: 85.7 %

Procedure:
To a solution of racemic methyl (1S,4R)-4-(5-{3-[(5-fluoro-4-methylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (70 mg, 0.14 mmol) in Methanol (1 mL) was added sodium hydroxide (1M, 0.87 ml, 0.87 mmol). The resulting suspension was heated to 110° C. for 10 min under microwave irradiation. The reaction was cooled to ambient temperature, and the pH was adjusted to a range of 3-4 (pH paper) using HCl (1 N in water). The resulting mixture was extracted with 10% IPA:CHCl3 (3×). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide racemic 4-(5-{3-[(5-fluoro-4-methylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid (58 mg, 0.12 mmol, 58% yield). The racemate was subjected to purification by chiral supercritical fluid chromatography (35%/65% Methanol/CO2, with a flow rate of 70 ml/min and a 4 minute run time).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[Cl:15][C:16]1[S:20][C:19]([C:21]2[O:25][N:24]=[C:23]([CH2:26][NH2:27])[CH:22]=2)=[CH:18][CH:17]=1.C(N(CC)CC)C.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:27][CH2:26][C:23]2[CH:22]=[C:21]([C:19]3[S:20][C:16]([Cl:15])=[CH:17][CH:18]=3)[O:25][N:24]=2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCc1cc(-c2ccc(Cl)s2)on1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(NCc2cc(-c3ccc(Cl)s3)on2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 634.4 mg (3.19 mmol) 4-Fluoro-3-nitro-benzoic acid methyl ester in 12 mL DMF were added 800.0 mg (3.19 mmol) C-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-yl]-methylamine and 0.88 mL (6.37 mmol) triethylamine. The reaction mixture was stirred at room temperature for 16 h. 12 mL water was added. The precipitate was filtered off and washed with water. The yellow crystalline material was dried under reduced pressure at 40° C.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].[CH3:24][C@@H:25]1[CH2:27][O:26]1>C1COCC1>[N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:24][C@H:25]([OH:26])[CH3:27])=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(O)ccc23)cc1
Reactant: C[C@@H]1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](O)COc1ccc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2c1
Temperature: 30 °C
Reaction time: 18 h
Yield: 29.8 %

Procedure:
To a suspension of 4-(4-nitrophenoxy)quinolin-7-ol (10 g, 35.5 mmol) in THF (35 mL)/aq. NaOH (37.8 g, 7.4%) was added (R)-2-methyloxirane (10.3 g, 177.3 mmol). The reaction was stirred at 30° C. for 18 hours then concentrated in vacuo. The mixture was diluted with EtOAc (50 mL). The organic phase was separated and concentrated in vacuo. The residue was purified by a column chromatography on silica gel (EtOAc/PE=1:1) to furnish the title compound as a yellow solid (3.6 g, 29.9%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl.[NH2:8][C@:9]([C:13]([OH:15])=[O:14])([CH3:12])[CH2:10][CH3:11].[Cl:16][C:17]1[N:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=1.Cl>O.C(O)(C)C>[Cl:16][C:17]1[N:22]=[C:21]([NH:8][C@:9]([CH3:12])([CH2:10][CH3:11])[C:13]([OH:15])=[O:14])[CH:20]=[CH:19][N:18]=1
Reactant: CC[C@@](C)(N)C(=O)O
Reactant: Clc1ccnc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CC[C@@](C)(Nc1ccnc(Cl)n1)C(=O)O
Temperature: 87.5 °C
Reaction time: 0.17 h
Yield: 89.5 %

Procedure:
To a solution of K2CO3 (526.2 mg, 3.80 mmol) in water (1.6 mL, 6 volume) was added isovaline-HCl (292.4 mg, 1.90 mmol). The resulting solution was stirred for 10 minutes. A solution of [14C] enriched 2,4-dichloropyrimidine (11a**) (0.261 g, 90 mCi) in isopropanol (5.2 mL, 20 volume) was added dropwise at room temperature, and the resulting mixture was heated at 85-90° C. for 18 hours. The mixture was then concentrated to 4 volumes, then 1N NaOH (6 mL) and isopropyl acetate (6 mL) were added. The aqueous phase was separated and the organic phase was extracted with 1N NaOH (6 mL×2). The combined aqueous layer was acidified to pH=3.0-3.5 using 6N HCl (aq). The resulting solution was extracted with isopropyl acetate (15 mL×3). The collected organic layer was concentrated to 3-4 volumes, then 1N HCl etherate (1.73 mL, 1.73 mmol) was added drop wise at 0° C. and stirred for 15 minutes. The organic solvent was decanted and the solid was washed with isopropyl acetate (5 mL×2). The solid was dried under vacuum and obtained 360 mg of (R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid (2a**) with 70% radiochemical purity by instant imager to provide (R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid (2a**).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]1[O:11][C:10]2[C:12]([N+:16]([O-:18])=[O:17])=[CH:13][CH:14]=[CH:15][C:9]=2[CH:8]=1)([OH:3])=O>S(Cl)(Cl)=O.C1(C)C=CC=CC=1>[N+:16]([C:12]1[C:10]2[O:11][C:7]3[CH2:6][CH2:5][CH2:4][C:1](=[O:3])[C:8]=3[C:9]=2[CH:15]=[CH:14][CH:13]=1)([O-:18])=[O:17]
Reactant: O=C(O)CCCc1cc2cccc([N+](=O)[O-])c2o1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C1CCCc2oc3c([N+](=O)[O-])cccc3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
A solution of 2-(3-carboxypropyl)-7-nitrobenzo[b]furan (500 mg) in thionyl chloride (5 ml) was refluxed for 1.5 hours. The reaction mixture was diluted with toluene and concentrated in vacuo. The residue was dissolved in dichloromethane (15 ml) and to the mixture was added aluminum chloride (435 mg) at 4° C. The mixture was stirred at ambient temperature for 2 hours and partitioned between 1N-hydrochloric acid and dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from a mixture of ethyl acetate and n-hexane to give 6-nitro-1-oxo-1,2,3,4-tetrahydrodibenzofuran (282 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[CH2:33]([O:32][C:30](=[O:31])[NH:19][CH2:18][CH:15]1[CH2:14][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[C:17]=2[O:16]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COc1ccccc1-c1cccc2c1OC(CN)C2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1cccc2c1OC(CNC(=O)OCc1ccccc1)C2
Yield: 83.9 %

Procedure:
Treatment of (±)-1-[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.296 g, 1.01 mmol) with diisopropylethylamine (1.52 g, 1.5 mmol) and benzyl chloroformate (0.190 g, 1.11 mmol) generally according to the procedure described for Intermediate 12 afforded 0.33 g (84%) (±)-benzyl[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate of a colorless oil Rf=0.72 (silica, ethyl acetate:hexanes 2:8); Anal. calcd. for C24H23NO4: C, 74.02; H, 5.95; N, 3.6. Found: C, 73.68H, 5.81; N, 3.43.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[N:17]3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:34][NH:35][C@H:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH2:38][CH2:37]1.C(N(CC)CC)C>>[CH3:34][N:35]([C@H:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH2:38][CH2:37]1)[C:21]([C:19]1[CH:18]=[N:17][N:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:8](=[O:9])[CH2:7][N:6]3[C:2]([CH3:1])=[CH:3][C:4]([C:24]([F:25])([F:26])[F:27])=[N:5]3)[CH2:11][CH2:12]2)[CH:20]=1)=[O:23]
Reactant: CN[C@@H]1CCCc2ccccc21
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(n2cc(C(=O)O)cn2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(n2cc(C(=O)N(C)[C@@H]3CCCc4ccccc43)cn2)CC1
Yield: 65.8 %

Procedure:
By a procedure analogous to that of Example 32, Step D, 1-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidin yl]-1H-pyrazole-4-carboxylic acid (0.081 g, 0.21 mmol) (i.e. the product of Example 33, Step C) was reacted with oxalyl chloride (0.05 mL) and the resulting product was reacted with (R)—N-methyl-1,2,3,4-tetrahydronaphthalen-1-ylamine (0.038 g, 0.23 mmol) and triethylamine (0.038 mL, 0.27 mmol) to afford 0.073 g of the title compound, a compound of the present invention as an oil after purification by medium pressure liquid chromatography.
Reaction SMILES: N1C=CN=C1.C([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([OH:32])[CH:26]=3)=[N:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[O:33][CH3:34])C1C=CC=CC=1.[Si:35](Cl)([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])O.[Na+]>CN(C=O)C.CO.C(OCC)(=O)C.[Pd]>[Si:35]([O:32][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[CH3:31])[NH:24][C:18]1[C:17]2[C:22](=[CH:23][C:14]([OH:13])=[C:15]([O:33][CH3:34])[CH:16]=2)[N:21]=[CH:20][N:19]=1)([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COc1cc2c(Nc3ccc(C)c(O)c3)ncnc2cc1OCc1ccccc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc2c(Nc3ccc(C)c(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)c3)ncnc2cc1O
Temperature: 25 °C
Yield: 42.8 %

Procedure:
Imidazole (1.45 g, 21.6 mmol) was added to 7-benzyloxy-4-(3-hydroxy-4-methylanilino)-6-methoxyquinazoline (4.11 g, 9.69 mmol) in DMF (50 ml) and the mixture was stirred at ambient temperature until complete dissolution was achieved. t-Butyldiphenylsilyl chloride (2.5 ml, 9.6 mmol) was added dropwise and the reaction mixture stirred at ambient temperature for 72 hours. Saturated aqueous sodium hydrogen carbonate solution was added, and the product was extracted with methylene chloride. The solvent was removed by evaporation to give a damp solid which was dissolved in a mixture of DMF (40 ml), methanol (40 ml), and ethyl acetate (40 ml). 10% Palladium-on-charcoal catalyst (500 mg) was added and the mixture stirred under hydrogen at 1 atmosphere pressure for 36 hours. The catalyst was removed by filtration through diatomaceous earth, and the solvent removed from the filtrate by evaporation. The crude product was purified by flash chromatography eluting with methanol/methylene chloride (1/9) to give 4-(3-t-butyldiphenylsilyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline (2.2 g, 42% over two steps) as a yellow solid.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:19]1([S:29](Cl)(=[O:31])=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[C:19]1([S:29]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]4)[CH2:2][CH2:3]2)(=[O:31])=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(N3CCN(S(=O)(=O)c4cccc5ccccc45)CC3)cccc2n1
Yield: 39 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 1-Naphthalene-sulfonyl chloride (92.9 mg; 0.41 mmol) to obtain 33.7 mg. (39% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J=8.4 Hz, 1H), 8.38 (br s, 1H), 8.32 (d, J=8.4 Hz, 1H), 8.21 (d, J=7.2 Hz, 1H), 8.14 (d, J=7.6 Hz, 1H), 7.73 (m, 3H), 7.36 (t, J=7.6 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 6.91 (br s, 1H), 6.77 (d, J=7.2 Hz, 1H), 5.91 (br s, 2H), 3.83 (d, J=12 Hz, 2H), 3.10 (d, J=12.0 Hz, 2H), 2.90 (t, J=11.5 Hz, 1H), 2.75 (t, J=11.5 Hz, 2H). ESIMS+436.0 m/z
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][CH2:13][C:14]2([C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH:27]1([CH:30]=O)[CH2:29][CH2:28]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)CCl.CCOC(C)=O>[CH:27]1([CH2:30][N:17]2[CH2:18][CH2:19][C:14]([CH2:13][NH:12][C:10](=[O:11])[CH2:9][C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)([C:20]3[CH:21]=[CH:22][C:23]([I:26])=[CH:24][CH:25]=3)[CH2:15][CH2:16]2)[CH2:29][CH2:28]1
Reactant: O=C(Cc1cc(F)cc(F)c1)NCC1(c2ccc(I)cc2)CCNCC1
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(Cc1cc(F)cc(F)c1)NCC1(c2ccc(I)cc2)CCN(CC2CC2)CC1
Reaction time: 0.5 h
Yield: 950 %

Procedure:
To a stirred solution of 4-{[2-(3,5-difluoro-phenyl)-acetylamino]-methyl}-4-(4-iodo-phenyl)-piperidine (0.038 g, ˜0.08 mmol) in ClCH2CH2Cl (0.5 mL) at room temperature under Ar was added cyclopropanecarboxaldehyde (0.008 mL, 0.096 mmol, 1.2 eq.) and HOAc (0.05 mL, 1% v/v). The mixture was stirred for 0.5 h then Na(OAc)3BH (0.026 g, 0.12 mmol, 1.5 eq.) was added and the mixture stirred for 16 h then diluted with EtOAc (5 mL) and washed with saturated aqueous NaHCO3 solution (5 mL) and saturated brine (5 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated by rotary evaporation, and dried under high vacuum to give N-[1-cyclopropylmethyl-4-(4-iodo-phenyl)-piperidin-4-ylmethyl]-2-(3,5-difluoro-phenyl)-acetamide (0.040 g, 0.76 mmol, 95%). MS (ESI): 525.2/526.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:36]=[CH:35][C:25]([C:26]([NH:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:27])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:36]=[CH:35][C:25]([C:26]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:27])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CNC(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CNC(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 26.4 g. of ethyl N-{4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoyl}glycinate, 110 ml. of 1N sodium hydroxide solution; and 100 ml. of ethanol is stirred at ambient temperature for 2 hours and then partially evaporated. The aqueous solution is washed with diethyl ether, acidified with 6N hydrochloric acid, and filtered. The white solid is dried in vacuo and recrystallized from acetone to yield N-{4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoyl}glycine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24]([C:26](=[O:31])N(OC)C)[CH:23]=[CH:22][N:21]4[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:40][Mg]Cl.[NH4+].[Cl-]>C1COCC1>[C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24]([C:26](=[O:31])[CH3:40])[CH:23]=[CH:22][N:21]4[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)c1ccn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1ccn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of (1-{4-[7-(methoxy-methyl-carbamoyl)-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester [prepared in a manner analogous to that described in Int-24-0] (250 mg, 0.48 mmol) in THF (10 mL) under an atmosphere of argon at 0° C. was added a 3 M solution of methyl-magnesium chloride in THF (0.4 mL, 1.2 mmol, 2.5 equiv). The resulting was stirred for 1 h at 0° C., then for 5 h at room temperature. The resulting material was added to a saturated aqueous NH4Cl solution (10 mL). The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic phases were dried (Na2SO4 anh) and concentrated under reduced pressure. The remaining material was purified using MPLC (Biotage Isolera; 25 g SNAP cartridge: 100% hexane for 1 min., gradient to 75% hexane/25% EtOAc over 1 min., 75% hexane/25% EtOAc for 3 min., gradient to 50% hexane/50% EtOAc over 1 min., 50% hexane/50% EtOAc for 4.5 min, gradient to 25% hexane/75% EtOAc over 2.5 min., gradient to 100% EtOAc over 2 min., 100% EtOAc for 10.6 min.) to give {1-[4-(7-acetyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (151 mg, 66%):
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:38]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[O:39])[CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: O=C(Cl)N1CCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(N1CCCC1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.20 mmol) (from Example 25a supra) in tetrahydrofuran (3 mL) was added triethylamine (32 mg, 0.3 mmol) (Aldrich), followed by the addition of 1-pyrrolidinecarbonyl chloride (34 mg, 0.24 mmol) (Aldrich). The mixture was stirred at 50° C. for 1 hour, then cooled to room temperature. The mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with another two portions of ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue were triturated with dichloromethane-hexanes to give rac-6-chloro-3-(3-chloro-benzyl)-3-[1-(pyrrolidine-1-carbonyl)-piperidin-3-yl]-1,3-dihydro-indol-2-one as a white solid. (Yield 50 mg, 50%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:10][C:3]=12.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[F:23].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CS(C)=O.ClCCl.[Cu]Cl.O>[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:10][C:3]=23)=[CH:18][C:17]=1[F:23]
Reactant: COC(=O)c1cc2nccc(Cl)c2s1
Reactant: Nc1ccc(O)cc1F
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2nccc(Oc3ccc(N)c(F)c3)c2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 7-chlorothieno[3,2-b]pyridine-2-carboxylate (5 g, 0.022 mol) and the 4-amino-3-fluorophenol (3.3 g, 0.026 mol) were added to a round bottom flask containing cesium carbonate (14.8 g, 0.045 mol), ethyl-2-cyclohexanone carboxylate (0.73 g, 0.004 mol), and copper (I) chloride (0.22 g, 0.002 mol). The mixture was diluted with DMSO (250 mL) and stirred at 70 C under an atmosphere of nitrogen for 2 hours. The dark reaction mixture was cooled to room temperature and poured into ethyl acetate (500 mL)/water (1 L) with vigorous stirring. The mixture was filtered through celite and the organic portion of the filtrate was separated and dried over magnesium sulfate. The solution was filtered and the filtrate was concentrated to give a purple viscous liquid. The crude product was taken up in dichloromethane and passed through a silica gel column eluting with 1:1 hexane/ethyl acetate. Fractions containing the product were combined and concentrated to afford methyl 7-(4-amino-3-fluorophenoxy)thieno[3,2-b]pyridine-2-carboxylate as red solid. Yield: 1.62 g (23%); MS [M+H]+ 319.1
Reaction SMILES: [C-]#N.[Na+].[Cl:4][C:5]1[C:10]([Cl:11])=[C:9]([O:12]C)[CH:8]=[CH:7][C:6]=1[C:14]([C:16]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]=[CH:18][CH:17]=1)=[O:15].O.C(O)(=O)C>CS(C)=O>[Cl:11][C:10]1[C:5]([Cl:4])=[C:6]([C:14]([C:16]2[N:20]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:19]=[CH:18][CH:17]=2)=[O:15])[CH:7]=[CH:8][C:9]=1[OH:12]
Reactant: COc1ccc(C(=O)c2ccnn2Cc2ccccc2)c(Cl)c1Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=C(c1ccc(O)c(Cl)c1Cl)c1ccnn1Cc1ccccc1
Temperature: 100 °C
Yield: 40.6 %

Procedure:
0.95 g of sodium cyanide is added to a solution of 1.0 g of (2,3-dichloro-4-methoxyphenyl)(1-benzyl-5-pyrazolyl)methanone in dimethylsulfoxide and the mixture is heated at 100° C. for 4 hours under argon gas atmosphere. After cooling, cold water is added to the reaction mixture. The mixture is adjusted to pH 5-6 with acetic acid and then extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography to give 0.39 g of 2,3-dichloro-4-(1-benzyl-5-pyrazolylcarbonyl)phenol.