Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:9](=[O:10])[O:8][C:6](=[O:7])[CH2:5]1)=[O:2].C([O-])(=O)C.[Na+].Cl.[CH3:17][O:18][C:19](=[O:29])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH2:21]>C(Cl)Cl>[CH3:17][O:18][C:19](=[O:29])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH:21][C:6](=[O:7])[CH2:5][C@@H:4]([C:9]([OH:8])=[O:10])[NH:3][CH:1]=[O:2]
Reactant: O=CN[C@H]1CC(=O)OC1=O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)C[C@H](NC=O)C(=O)O

Procedure:
In 179.4 g of methylenechloride, 14.3 g (0.1 mole) of N-formyl-L-aspartic anhydride was suspended, and 9.2 g (0.11 mole) of sodium acetate was added at 20°-25° C. with stirring, and 21.6 g (0.1 mole) of L-phenylalanine methyl ester hydrochloride was added at the same temperature during 30 minutes. The mixture was reacted for 5 hours with stirring at the same temperature. Precipitated crystals were filtered, washed and dried. Crystals of a mixture of N-formyl-α-L-aspartyl-L-phenylalanine methyl ester, and N-formyl-β-L-aspartyl-L-phenylalanine methyl ester were obtained in a yield of 30.0 g. The crystals obtained were analyzed by high performance liquid chromatography to give a ratio of α-isomer:β-isomer of 75.0:25.0. The crystals were purified by a conventional method to obtain pure crystals of N-formyl-α-L-aspartyl-L-phenylalanine methyl ester. The yield was 16.1 g (50% yield on L-phenylalanine methyl ester hydrochloride).
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1)[NH2:6].[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Cl:39])[C:36]([Cl:40])=[CH:35][C:31]=3[C:32](O)=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12>>[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Cl:39])[C:36]([Cl:40])=[CH:35][C:31]=3[C:32]([NH:6][C@@H:5]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=3)[C:4]([OH:3])=[O:16])=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12
Reactant: COC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(F)c(Br)c1)C(=O)O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
The title compound was prepared from 3-bromo-4-fluoro-L-phenylalanine methyl ester hydrochloride and 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoic acid as in Example 1, Part C, followed by hydrolysis of the resulting methyl ester as in EXAMPLE 2, Part E. HPLC: RT=10.10 min. MS (ESI−): mass calcd. for C22H14BrCl2FN4O5S2, 648.31; m/z found, 645/647/649 [M−H]−. 1H NMR (400 MHz, acetone-d6): 11.58 (s, 1H), 8.47-8.42 (m, 1H), 8.34-8.20 (m, 2H), 7.92-7.85 (m, 1H), 7.85-7.80 (m, 1H), 7.75-7.70 (m, 1H), 7.67-7.60 (m, 1H), 7.42-7.35 (m, 1H), 7.25-7.18 (m, 1H), 4.96-4.87 (m, 1H), 3.40-3.32 (m, 1H), 3.20-3.10 (m, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([NH2:12])[N:9]=[C:8]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:7]=1[N+:21]([O-])=O.[N:24](OCCC(C)C)=O>CCO.CCOC(C)=O.[Pd]>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[N:21]=[N:24][N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1
Reactant: CC(C)CCON=O
Reactant: Nc1nc(NCc2ccccn2)c([N+](=O)[O-])c(-c2ccco2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1nc(-c2ccco2)c2nnn(Cc3ccccn3)c2n1
Temperature: 100 °C
Reaction time: 6 h
Yield: 46 %

Procedure:
A solution of 6-(2-furyl)-5-nitro-N4-(2-pyridylmethyl)pyrimidine-2,4-diamine (270 mg, 0.864 mmol) and 10% Pd/C (92 mg, 0.086 mmol) in EtOH (30 mL) and EtOAc (10 mL) was stirred under an hydrogen atmosphere for 1 h, filtered through Celite and concentrated in vacuo. The resulting yellow oil was dissolved in dioxane (25 mL), treated with isoamyl nitrite (0.109 mL, 0.815 mmol), stirred at 100° C. for 6 h, cooled to room temperature, filtered through Celite, concentrated in vacuo and triturated with Et2O to give the title compound (110 mg, 46%) as a yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[CH3:6][O:7][C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[S:22][CH3:23])[NH:11][C:10]=2[CH:9]=1>>[CH3:6][O:7][C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[S:22][CH3:23])[N:11]([CH2:2][CH2:3][CH2:4][Cl:5])[C:10]=2[CH:9]=1
Reactant: COc1ccc2c(c1)Nc1cccc(SC)c1S2
Reactant: ClCCCBr
Product: COc1ccc2c(c1)N(CCCCl)c1cccc(SC)c1S2
Yield: 35.9 %

Procedure:
2-Methoxy-6-methylthio-10-(3-chloropropyl)-phenothiazine (10.1 g.) is prepared by reacting 1-bromo-3-chloropropane (47.5 g.) with 2-methoxy-6-methylthiophenothiazine (22.0 g.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)([CH3:18])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:7]=1.C(N(CC)CC)C.[Cl:37][CH:38]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:39](Cl)=[O:40]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]([N:19]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:39](=[O:40])[CH:38]([Cl:37])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([CH3:18])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:13])[CH:7]=1
Reactant: COc1ccc(CN[C@@](C)(CO[Si](C)(C)C(C)(C)C)c2cc(Br)ccc2F)cc1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(CN(C(=O)C(Cl)c2ccccc2)[C@@](C)(CO[Si](C)(C)C(C)(C)C)c2cc(Br)ccc2F)cc1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
A solution of [(R)-1-(5-bromo-2-fluoro-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-(4-methoxy-benzyl)-amine (1.035 g, 2.15 mmol) in acetonitrile (16 ml) was treated with triethylamine (0.36 ml, 2.57 mmol). The mixture was cooled to 10° C. and a solution of (RS)-2-chloro-2-phenyl-acetyl chloride (0.34 ml, 2.36 mmol) in acetonitrile (2 ml) was added slowly. The reaction mixture was allowed to warm to room temperature and was stirred for 3 hours. Because the transformation was not complete, triethylamine (0.33 ml, 2.36 mmol) was again added, the reaction mixture cooled to −5° C., then treated with a solution of (RS)-2-chloro-2-phenyl-acetyl chloride (0.31 ml, 2.15 mmol) in acetonitrile (1 ml). The reaction mixture was allowed to warm to room temperature and was stirred for 22 hours. Thereafter, the mixture was evaporated at reduced pressure and without further workup directly purified by chromatography on Silicycle-Si-amine column using a gradient of heptane and ethyl acetate=100/0 to 70/30 as the eluent. (RS)-N-[(R)-1-(5-bromo-2-fluoro-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-2-chloro-N-(4-methoxy-benzyl)-2-phenyl-acetamide was obtained as a white foam (1.068 g, 78% of theory). Mass (calculated) C31H38BrClFNO3 [635.09]; (found) [M+H]+=638, [M+2-H]+=636, [M+4-H]+=634.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:13][N:14]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH3:40])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)[C:15]([CH:17]1[CH2:19][CH:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])(C)(C)C.ClCCl.Cl>O1CCOCC1>[NH2:7][C@@H:8]([C@@H:9]([CH3:12])[CH2:10][CH3:11])[CH2:13][N:14]([C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH3:40])=[CH:34][CH:33]=2)=[CH:30][CH:31]=1)[C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:16]
Reactant: CCCc1ccc(-c2ccc(N(C[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)CC)C(=O)C3CC3c3ccccn3)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCc1ccc(-c2ccc(N(C[C@@H](N)[C@@H](C)CC)C(=O)[C@@H]3C[C@H]3c3ccccn3)cc2)cc1
Temperature: 25 °C
Yield: 99.3 %

Procedure:
A solution of ((1S,2S)-1-{[(4′-propyl-biphenyl-4-yl)-(2-pyridin-2-yl-cyclopropanecarbonyl)-amino]-methyl}-2-methyl-butyl)-carbamic acid tert-butyl ester (48 mg, 0.084 mmol) and dichloromethane (4 mL) was treated with a solution of HCl in dioxane (4 N, 0.5 mL) and the resulting reaction mixture was maintained at room temperature for 12 h. The reaction was then concentrated to dryness to afford (1R,2R)-2-pyridin-2-yl-cyclopropanecarboxylic acid ((2S,3S)-2-amino-3-methyl-pentyl)-(4′-propyl-biphenyl-4-yl)-amide (38 mg, 95% yield) as a white solid: 1H NMR (400 MHz, MeOD) δ 8.31 (d, J=5.1 Hz, 1H), 7.86-7.95 (m, 1H), 7.57 (d, J=8.1 Hz, 2H), 7.33-7.43 (m, 5H), 7.30 (d, J=8.1 Hz, 1H), 7.17 (d, J=8.1 Hz, 2H), 4.21 (dd, J=14.9, 9.1 Hz, 1H), 3.65 (d, J=14.9 Hz, 1H), 3.23-3.29 (m, 1H), 2.64-2.73 (m, 1H), 2.53 (t, J=7.6 Hz, 2H), 1.96-2.05 (m, 1H), 1.70-1.78 (m, 1H), 1.61-1.70 (m, 1H), 1.57 (dd, J=15.2, 7.6 Hz, 2H), 1.43-1.51 (m, 1H), 1.22-1.36 (m, 1H), 1.05-1.17 (m, 1H), 0.82-0.90 (m, 6H), 0.75 (t, J=7.3 Hz, 3H); LRMS (ESI) m/e 456.3 [(M+H)+, calcd for C30H38N3O 456.3].
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[N:31]=[C:30]([O:32]C)[C:29]2[C:24](=[CH:25][C:26]([O:36][CH3:37])=[C:27]([O:34][CH3:35])[CH:28]=2)[N:23]=1>C(O)CCCC>[C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:22]3[NH:31][C:30](=[O:32])[C:29]4[C:24](=[CH:25][C:26]([O:36][CH3:37])=[C:27]([O:34][CH3:35])[CH:28]=4)[N:23]=3)[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2nc(Cl)nc(OC)c2cc1OC
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCNCC2)cc1
Solvent: CCCCCO
Product: COc1cc2nc(N3CCC(Nc4ccc(C(=O)OC(C)(C)C)cc4)CC3)[nH]c(=O)c2cc1OC
Temperature: 120 °C
Reaction time: 12 h
Yield: 32 %

Procedure:
4-(Piperidin-4-ylamino)benzoic Acid tert-Butyl Ester (49) (0.47 mmol) was added to a solution of 2-chloro-4,6,7-trimethoxy-quinazoline (0.1 g, 0.39 mmol) in n-pentanol (5 mL) at 25° C. The mixture was stirred at 120° C. for 12 h. The reaction mixture was then cooled to room temperature and the desired product was filtered and rinsed with acetone to give 0.06 g (32%) of (15): TLC (Rf =0.30; 5% CH3OH/CH2Cl2); 1H NMR (DMSO) δ 11.24 (s, 1H), 7.61 (d, 2H, J=8.4), 7.26 (s, 1H), 6.76 (s, 1H), 6.60 (d, 2H, J=8.7), 6.36 (d, 1H, J=7.8), 4.24 (d, 2H, J=13.6), 3.83 (s, 3H), 3.78 (s, 3H), 3.60 (m, 1H), 3.09 (m, 2H), 1.94 (d, 2H, J=10.4), 1.48 (s, 9H), 1.40 (m, 2H) 13C NMR (DMSO) δ 165.2, 162.4, 154.9, 151.4, 150.1, 146.7, 145.6, 130.9, 117.6, 111.2, 109.2, 106.0, 105.3, 78.9, 55.7, 55.5, 48.4, 43.9, 30.9, 28.0; HRMS (FAB) m/z 481.2444 (M+H)+ (C26H32N4O5 requires 481.2443); Anal. (C26H32N4O5 ·1/2HCl) C, H, N.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=O)[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH2:31][CH3:32]>CC(C)=O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][N:13]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[CH2:30][CH2:31][CH3:32])[CH:7]=[CH:8][CH:9]=1
Reactant: CCCI
Reactant: COc1cccc(CCNC(=O)Cc2cccc(OC)c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCN(CCc1cccc(OC)c1)CCc1cccc(OC)c1
Yield: 97.3 %

Procedure:
A suspension of 8.75 g of the product of Step A, 17.5 g of calcined neutral potassium carbonate, 17.5 g of propyl iodide and 180 ml of acetone was refluxed for 61/2 hours under nitrogen and the mixture was then filtered. The filtrate was evaporated to dryness and the residue was taken up in ether. The ether solution was washed with water, dried and evaporated to dryness to obtain 8.3 g of 3-methoxy-N-[2-(3-methoxyphenyl)-ethyl]-N-propyl-benzene-ethanamine which was used as is for the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[CH:25]([OH:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.N.[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36]>CO.C(Cl)Cl.C(#N)C>[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].[CH3:34][O:27][CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25](=[O:26])[N:17]1[CH2:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1
Reactant: O=C1c2ccccc2C(O)N1CCCN1CCN(c2ccc(F)cc2)CC1
Agent: N
Agent: O=C(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: ClCCl
Solvent: CC#N
Product: COC1c2ccccc2C(=O)N1CCCN1CCN(c2ccc(F)cc2)CC1
Reaction time: 5 h
Yield: 141.7 %

Procedure:
The same procedure is followed as in Example 2, starting from an agitated solution of 2-[3-(4-(4-fluorophenyl)-1-piperazinyl)propyl]-3-hydroxy-1 -isoindolinone (6.8 g) in methanol (170 cc) to which 33.5 cc of concentrated sulphuric acid is added at a temperature close to 20° C. in the course of 15 minutes. Agitation is continued for 5 hours at a temperature close to 65° C. After cooling the solution to a temperature close to 0° C., 83 cc of a 33% aqueous solution of ammonia is added in the course of 1 hour. The precipitate formed is filtered and washed with methanol (50 cc). The filtrate is diluted with distilled water (200 cc) and a 33% aqueous solution of ammonia (50 cc) and extracted with methylene chloride (3×200 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in methylene chloride (20 cc) and the solution is poured onto silica (500 g) contained in a column of 8 cm diameter. Elution is carried out with a mixture of methylene chloride and methanol (99-1 by volume). The first 300 cc are eliminated and the next 3500 cc are evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. The residue obtained is dissolved in acetonitrile (50 cc). A solution of oxalic acid (1.1 g) in acetonitrile (25 cc) is added and agitation continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration. 4.1 g of 3-methoxy-2-[3-(4-(4-fluorophenyl)-1-piperazinyl)propyl]-1-isoindolinone oxalate are thus obtained, melting at 177° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[C:8]([CH3:21])[CH:9]=[C:10]([CH3:20])[C:11]=2[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]([CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])[CH2:5]1)(=O)C.[OH-].[K+]>CCO.O>[C:24]([CH2:23][CH2:22][CH:6]1[C:7]2[C:12](=[C:11]([NH:13][C:14](=[O:19])[C:15]([CH3:17])([CH3:16])[CH3:18])[C:10]([CH3:20])=[CH:9][C:8]=2[CH3:21])[NH:4][CH2:5]1)([OH:26])=[O:25]
Reactant: CCOC(=O)CCC1CN(C(C)=O)c2c(NC(=O)C(C)(C)C)c(C)cc(C)c21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2c(c1NC(=O)C(C)(C)C)NCC2CCC(=O)O
Yield: 70.4 %

Procedure:
N-[1-Acetyl-3-(2-ethoxycarbonylethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide (2.6 g) was dissolved in EtOH (40 ml), and a solution of KOH (1.3 g) in water (10 ml) was added, which was followed by refluxing for 20 hr. EtOH was evaporated under reduced pressure, and the mixture was adjusted to pH 5 with 2N hydrochloric acid and extracted with CHCl3 (100 ml). The CHCl3 layer was washed with water and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure to give 1.5 g of N-[3-(2-carboxyethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.[CH3:18][C:19]1[N:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O>CS(C)=O.[Cu]I>[CH3:18][C:19]1[N:24]=[CH:23][C:22]([O:25][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]3)=[CH:21][CH:20]=1
Reactant: Cc1ccc(O)cn1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(Br)cc2C1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: Cc1ccc(Oc2ccc3c(c2)C[C@@H](NS(=O)(=O)C(C)C)C3)cn1
Temperature: 190 °C
Yield: 23.3 %

Procedure:
A reaction mixture of N-[(2S)-5-bromo-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (100 mg, 0.31 mmol, Description 1), 6-methyl-3-pyridinol (35 mg, 0.32 mmol), caesium carbonate (308 mg, 0.94 mmol), copper(I) iodide (66 mg, 0.35 mmol) and N,N-dimethylglycine (39 mg, 0.38 mmol) in DMSO (1.5 ml) was heated in a microwave at 190° C. for 30 minutes. The reaction mixture was then partitioned between dichloromethane and water and the organic solution was dried (MgSO4) and evaporated under reduced pressure to yield the crude product. The crude product was purified using MDAP. The resulting solution was diluted with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic solution was dried (MgSO4) and evaporated under reduced pressure to obtain the title compound as a yellow gum (25 mg).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[N:15][N:16]4[C:21]([CH3:22])=[C:20]([C:23]([O:25]CC)=[O:24])[CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+]>O1CCOCC1>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)=[N:15][N:16]4[C:21]([CH3:22])=[C:20]([C:23]([OH:25])=[O:24])[CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1c(C(=O)O)ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.6 %

Procedure:
To a solution of ethyl 3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-α]pyridine-6-carboxylate (40 mg, 0.087 mmol) in dioxane (600 μL) was added lithium hydroxide (300 μL, 1M aqueous, 0.30 mmol). The reaction mixture was stirred at room temperature 16 hours. The reaction mixture was concentrated in vacuo to remove dioxane, then diluted with water. The aqueous mixture was acidified with 1 N aqueous hydrochloric acid. Upon standing for 72 hours, a solid precipitate had formed which was collected by filtration to provide 3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-α]pyridine-6-carboxylic acid (31 mg, 82%). Rf 0.10 (19:1 dichloromethane:methanol); MS m/z 432 (M+1).
Reaction SMILES: [C:1]([C:5]([NH:7][C:8]1[N:9]=[C:10]([OH:27])[C:11]2[CH2:17][CH:16]([CH2:18][O:19][Si](C(C)(C)C)(C)C)[CH2:15][NH:14][C:12]=2[N:13]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>C1COCC1.O>[C:1]([C:5]([NH:7][C:8]1[N:9]=[C:10]([OH:27])[C:11]2[CH2:17][CH:16]([CH2:18][OH:19])[CH2:15][NH:14][C:12]=2[N:13]=1)=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)Nc1nc(O)c2c(n1)NCC(CO[Si](C)(C)C(C)(C)C)C2
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1nc(O)c2c(n1)NCC(CO)C2
Temperature: 22 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
To a mixture of 5.0 g of 2-t-butylcarbonylamino-4-hydroxy-6-[t-butyl(dimethyl)silyloxymethyl]-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine in 50 ml of THF and 50 ml of water were added 150 ml of glacial acetic acid. The mixture was stirred 18 hours at 22° C. and then evaporated to a viscous oil. Water was added and the resulting white precipitate collected by filtration to give 3.1 g of the title compound: mp 236°-238° C.; Anal. Calcd for C19H34N4O3Si: C, 55.70; H, 7.19; N, 19.99. Found: C, 55.96; H, 7.25; N, 19.69.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH2:14])[C:10]([CH3:13])([OH:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[C:15](N1C=CN=C1)(N1C=CN=C1)=[O:16]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:10]([CH3:11])([CH3:13])[O:12][C:15](=[O:16])[NH:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(O)C(N)c1ccc(F)c(F)c1
Solvent: ClCCl
Product: CC1(C)OC(=O)NC1c1ccc(F)c(F)c1
Yield: 50 %

Procedure:
A mixture of 1-(3,4-difluorophenyl)-2-methyl-2-hydroxypropylamine (3.00 g, 14.9 mmol) and carbonyldiimidazole (2.418 g, 14.9 mmol) in dichloromethane (150 mL) was heated at reflux temperature for 36 h and the solvent evaporated. The residue was purified by column chromatography on silica gel using chloroform/ethyl acetate (9:1) to give the product as a viscous oil which solidified on standing (1.80 g, 50% yield). The product was used in the next step without further characterization.
Reaction SMILES: [NH:1]([C:8]1[S:9][CH:10]=[C:11]([CH:13]=[C:14]2[S:18][C:17](=[S:19])[N:16]([CH2:20][C:21]([OH:23])=[O:22])[C:15]2=[O:24])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25](O)[CH3:26].Cl>O1CCOCC1>[NH:1]([C:8]1[S:9][CH:10]=[C:11]([CH:13]=[C:14]2[S:18][C:17](=[S:19])[N:16]([CH2:20][C:21]([O:23][CH2:25][CH3:26])=[O:22])[C:15]2=[O:24])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)CN1C(=O)C(=Cc2csc(Nc3ccccc3)n2)SC1=S
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)CN1C(=O)C(=Cc2csc(Nc3ccccc3)n2)SC1=S

Procedure:
Following a procedure similar to that described in Example 30, the desired compound was prepared from 1 g of 5-(2-anilinothiazol-4-ylmethylene)rhodanine-3-acetic acid, 2 g of ethanol and 10 ml of a 4N dioxane solution of hydrogen chloride. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:38]=[CH:39][CH:40]=1)[NH:18][C:19]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:20]=1[C:21]([NH:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:22]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([N:18]2[C:19]3[C:20](=[CH:32][C:33]([F:37])=[C:34]([F:36])[CH:35]=3)[C:21](=[O:22])[N:23]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:1]2=[O:2])[CH:38]=[CH:39][CH:40]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cccc(Nc2cc(F)c(F)cc2C(=O)NOCc2ccccc2)c1
Product: COc1cccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(F)cc32)c1
Yield: 18.7 %

Procedure:
Using General Method 3, the reaction of carbonyldiimidazole (5.5 g, 33.8 mmol) and crude 2-(3-methoxy-anilino)-N-benzyloxy-4,5-difluoro-benzamide (Example X, 6.5 g, 16.9 mmol) provided 1.3 g of the title compound as a solid, mp 157-158° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[OH:11].Cl[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[C:16]([C:23]3[NH:31][C:30]4[CH2:29][CH2:28][NH:27][C:26](=[O:32])[C:25]=4[CH:24]=3)[CH:17]=[CH:18][CH:19]=2)[N:14]=1.C(O)(C(F)(F)F)=O>CN(C=O)C.CS(C)=O>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[O:11][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[C:16]([C:23]3[NH:31][C:30]4[CH2:29][CH2:28][NH:27][C:26](=[O:32])[C:25]=4[CH:24]=3)[CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: Oc1c(F)cccc1Cl
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Oc5c(F)cccc5Cl)nc34)cc21
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 29.4 %

Procedure:
To NaH (60 wt % in mineral oil; 0.071 g, 1.763 mmol) in 1 mL DMF was added 2-chloro-6-fluorophenol (0.258 g, 1.763 mmol). After 10 min, a clear/colorless solution resulted. 2-(2-Chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.075 g, 0.252 mmol) was added and the reaction became dark red. The reaction was heated at 70° C. for 1 h, then at 90° C. for 2 h, then at 110° C. for 14 h. The reaction was cooled to 0° C. and quenched with TFA (0.136 ml, 1.763 mmol), diluted with 1 mL DMSO, filtered, and purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 15-100% ACN/H2O with 0.1% TFA); product-containing fractions were concentrated in vacuo then treated with saturated aq. NaHCO3 and DCM. The organic layer was separated and the aq. layer was extracted 3×DCM. The combined organic extracts were then dried over Na2SO4, filtered, and concentrated in vacuo to give 2-(2-(2-chloro-6-fluorophenoxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.030 g, 0.074 mmol, 29% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.91 (1H, br. s), 8.57 (1H, d, J=8.8 Hz), 8.05-8.15 (1H, m), 7.84 (1H, dt, J=7.7, 0.8 Hz), 7.38-7.69 (5H, m), 6.87-6.91 (1H, m), 6.85 (1H, d, J=2.3 Hz), 3.32-3.38 (2H, m), 2.54-2.50 (2H, m). m/z (ESI, +ve) 408.2 (M+H)+.