Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=4)[O:28][CH2:29][C:30]([O:32]CC)=O)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:38]>O1CCCC1>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=4)[O:28][CH2:29][C:30]([NH2:38])=[O:32])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N
Reactant: CCOC(=O)COc1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Solvent: C1CCOC1
Product: NC(=O)COc1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 24 h

Procedure:
To a solution of ethyl (S)-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}phenoxy}acetate (0.5 g) in tetrahydrofuran (5 ml) was added NH3 (5 ml, 4N methanol solution). After being stirred for 24 hours, the solvent was removed. The residue was purified by chromatography on silica gel to give (S)-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}phenoxy}acetamide (220 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]3[CH2:13][N:14]([CH3:16])[CH2:15][C@H:9]23)=[CH:4][CH:3]=1.[C:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(=[O:19])[CH3:18].CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:16][N:14]1[CH2:13][C@@H:10]2[C@@H:9]([N:8]([C:5]3[CH:6]=[CH:7][C:2]([N:23]4[CH2:24][CH2:25][N:20]([C:17](=[O:19])[CH3:18])[CH2:21][CH2:22]4)=[CH:3][CH:4]=3)[CH2:12][CH2:11]2)[CH2:15]1
Reactant: CN1C[C@H]2CCN(c3ccc(Br)cc3)[C@H]2C1
Reactant: CC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)N1CCN(c2ccc(N3CC[C@@H]4CN(C)C[C@@H]43)cc2)CC1
Temperature: 150 °C

Procedure:
The product of Example 7C (500 mg, 1.78 mmole), 1-acetylpiperazine (274 mg, 2.13 mmole), tris(dibenzylideneacetone)dipalladium (32.6 mg, 0.036 mmole), (r)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthylwere (44.3 mg, 0.071 mmole), sodium tert-butoxide (256 mg, 2.67 mmole) and 5 ml of toluene were mixed under N2 in a Emrys process vials. The vial was sealed, then heated in the microwave for 20 minutes at 150° C., using the Emrys Creator microwave reactor. The mixture was diluted with water and extracted with dichloromethane (4×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography (eluting with a mixture of 10% methanol and 1% ammonium hydroxide in dichloromethane) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 6.87-6.91 (m, 2H) 6.53-6.60 (m, 2H) 4.05-4.07 (m, 1H) 3.73-3.79 (m, 2H) 3.57-3.63 (m, 2H) 3.46-3.54 (m, 1H) 3.12-3.20 (m, 1H) 2.96-3.03 (m, 4H) 2.56-2.71(m, 5H) 2.34 (s, 3H) 2.14-2.18 (m, 1H) 2.13 (s, 3H) 1.87-1.97 (m, 1H). MS: (M+H)+=329.
Reaction SMILES: C([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([CH2:19][C:20]([F:23])([F:22])[F:21])(=[O:18])=[O:17])(OC(C)(C)C)=O.[ClH:24]>O1CCOCC1>[ClH:24].[F:23][C:20]([F:21])([F:22])[CH2:19][S:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH2:8])(=[O:18])=[O:17]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1S(=O)(=O)CC(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: NCc1ccccc1S(=O)(=O)CC(F)(F)F

Procedure:
To a stirred solution of N-Boc-2-(2,2,2-trifluoroethylsulfonyl)benzylamine (480 mg) in dioxane (4.0 mL) at room temperature was added excess 4.0 M HCl in dioxane. The mixture was stirred until no starting material remained by TLC and was then concentrated in vacuo to afford the title compound as an off-white solid:
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:10][CH:11]([CH3:13])[CH3:12])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1.C([O:16][C:17](=[O:29])[CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[C:22]([F:28])[CH:21]=1)C>>[F:26][C:24]1[CH:25]=[C:20]([CH2:19][CH2:18][C:17]([OH:29])=[O:16])[CH:21]=[C:22]([F:28])[C:23]=1[O:27][CH2:2][C:3]1[C:4]([S:10][CH:11]([CH3:13])[CH3:12])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: Cc1ccc(CCl)c(SC(C)C)n1
Product: Cc1ccc(COc2c(F)cc(CCC(=O)O)cc2F)c(SC(C)C)n1
Yield: 78 %

Procedure:
3-Chloromethyl-2-isopropylsulfanyl-6-methyl-pyridine obtained in Step D of Preparation Example 9 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (236 mg, 1.02 mmol) obtained in Step D of Preparation Example 2 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (278 mg, 78%).
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH:18]3[CH2:23][CH2:22][C:21](=[CH:24][C:25](O)=[O:26])[CH2:20][CH2:19]3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.Cl.[CH3:60][NH:61][O:62][CH3:63]>ClCCl>[CH3:63][O:62][N:61]([CH3:60])[C:25](=[O:26])[CH:24]=[C:21]1[CH2:22][CH2:23][CH:18]([CH2:17][CH2:16][N:13]2[CH2:12][CH2:11][N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([F:28])([F:29])[F:2])[CH:5]=3)[CH2:15][CH2:14]2)[CH2:19][CH2:20]1
Reactant: CNOC
Reactant: O=C(O)C=C1CCC(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C=C1CCC(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Reaction time: 0.25 h
Yield: 70.7 %

Procedure:
To a solution of 200 mg (0.46 mmol) of (4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexylidene)acetic acid, hydrochloride in 5 mL of dichloromethane stabilized on amylene are successively added 63 mg (0.46 mmol) of 1-hydroxybenzotriazole, 88 mg (0.46 mmol) of 3-ethyl-1-(3-dimethylaminopropyl)carbodiimide hydrochloride and 140 mg (1.4 mmol) of triethylamine. The mixture is stirred for 15 minutes then 45 mg (0.46 mmol) of N,O-dimethylhydroxylamine hydrochloride are added. The mixture is stirred overnight at room temperature, then evaporated under reduced pressure. The residue is dissolved in ethyl acetate and washed twice with water. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified over 10 g of silica gel (eluant dichloromethane/methanol 98/2) to give 143 mg (71%) of N-methoxy-N-methyl-2-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexylidene)acetamide as an oil.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([CH:15]1[CH2:20][CH2:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:23][CH:22]=2)=[CH:17][CH2:16]1)[CH2:13][CH3:14]>CCOCC>[CH2:27]([C:24]1[CH:25]=[CH:26][C:21]([C@H:18]2[CH2:19][CH2:20][C@H:15]([CH2:12][CH2:13][CH3:14])[CH2:16][C:17]2=[O:9])=[CH:22][CH:23]=1)[CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCc1ccc(C2=CCC(CCC)CC2)cc1
Solvent: CCOCC
Product: CCCCCc1ccc([C@H]2CC[C@H](CCC)CC2=O)cc1
Reaction time: 16 h

Procedure:
15 g of m-chloroperbenzoic acid are added at 0° to a solution of 20 g of p-(4-n-propylcyclohex-1-en-1-yl)-n-pentylbenzene (German Offenlegungsschrift 3,006,666) in 100 ml of ether, and the mixture is stirred for 16 hours. The reaction mixture is extracted several times with 10% sodium hydroxide solution, and the organic phase is dried with sodium sulfate. 40 ml of BF3 /ether complex (50% of BF3) are added to the resulting solution of epoxide, and the mixture is stirred for 5 minutes and is then poured onto ice. Working up in the customary manner gives trans-2-(p-n-pentylphenyl)-5-n-propylcyclohexanone. b.p. (0.1 mm Hg) 140°, c.p. -10°.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[C:22](Cl)=[N:21][CH:20]=[CH:19][N:18]=1.CS(C)=O.CC(C)([O-])C.[Na+]>O>[Cl:16][C:17]1[C:22]([O:15][CH:13]2[CH2:14][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:12]2)=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: O=C(OCc1ccccc1)N1CC(O)C1
Reactant: Clc1nccnc1Cl
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CC(Oc2nccnc2Cl)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
To a solution of 3-hydroxy-azetidine-1-carboxylic acid benzyl ester (5.19 g, 27.4 mmol, purchased from Ace Synthesis), 2,3-dichloropyrazine (4.116 g, 27.6 mmol, Oakwood) and DMSO (40 mL) was added sodium tert-butoxide (2.64 g, 27.4 mmol) in three portions. The solution was allowed to stir at room temperature. After 2 hours, the reaction was poured into water (200 mL) and the aqueous solution was extracted with ether (3×50 mL). The combined ether layers were washed with water (50 mL), brine (50 mL), and then concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (80 g), eluting with 0% to 20% EtOAc in hexane, to provide benzyl 3-(3-chloropyrazin-2-yloxy)azetidine-1-carboxylate (5.4 g, 61.6% yield), as a yellow oil. MS (ESI) m/z 320.1 (MH+). IC50 (uM): 1.33.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1.Br[CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29].N>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][N:23]([CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])[CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1
Reactant: Clc1cccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c1Cl
Reactant: CC(C)=CCBr
Agent: N
Product: CC(C)=CCN1CC[C@H]2[C@@H](C1)c1cc(-c3cccc(Cl)c3Cl)cc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 382 as a yellow oil (27 mg, 76%) from (7aS,11aR)-2-(2,3-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.083 mmol) and 4-bromo-2-methyl-2-butene (25 mg, 0.17 mmol). MS (CI, NH3): 427.1 (base, M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH2:12]([N:14]1[CH2:18][CH:17]([NH2:19])[CH2:16][N:15]1[CH2:20][CH3:21])[CH3:13]>C1(C)C=CC=CC=1>[CH2:12]([N:14]1[CH2:18][CH:17]([NH:19][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])[CH2:16][N:15]1[CH2:20][CH3:21])[CH3:13]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CCN1CC(N)CN1CC
Solvent: Cc1ccccc1
Product: CCN1CC(NC(=O)c2ccccc2OC)CN1CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
A solution of 2-methoxybenzoyl chloride (3.41 g, 0.020 mole) in 50 ml of toluene was added dropwise to a stirred solution of 1,2-diethyl-4-aminopyrazolidine (2.86 g. 0.020 mole) in 100 ml of toluene. The mixture was stirred at ambient temperature for 2 hrs, and then at reflux temperature for 2 hrs. After standing for 16 hrs, the mixture was extracted with 100 ml of 10% sodium bicarbonate solution. The toluene layer was dried over magnesium sulfate and concentrated to give 4.32 g (81.6%) of oil. The liquid was distilled over magnesium sulfate, b.p. 160° C./0.020 mm Hg, to give 2.52 g of a clear, yellow oil.
Reaction SMILES: Cl.[CH3:2][NH:3][CH:4]([CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([NH:16][CH3:17])=[O:15])=[CH:8][CH:7]=1.C(N(CC)CC)C.Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH3:2][N:3]([CH:4]([CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([NH:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29]
Reactant: CNC(=O)COc1ccc(CC(C)NC)cc1
Reactant: O=C(CBr)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)COc1ccc(CC(C)N(C)CC(=O)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
N-methyl-2-(4-methylaminocarbonylmethoxyphenyl)-1-methylethanamine hydrochloride (2.73 g) was suspended in tetrahydrofuran (10 ml) containing triethylamine (6 ml) and a solution of α-bromoacetophenone (1.99 g) in tetrahydrofuran (10 ml) was added dropwise. After stirring overnight this solution was treated with saturated sodium carbonate solution, extracted with dichloromethane, the organic phase was dried (magnesium sulphate), filtered and evaporated to give a red oil which was used without further purification.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[N:9]2[C:10]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([Br:32])[C:11]=3[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)=[N:13][CH2:14][C:8]2=[N:7][N:6]=1.[CH3:34][NH2:35]>>[CH3:34][NH:35][C:3](=[O:2])[CH2:4][C:5]1[N:9]2[C:10]3[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[C:24]([Br:32])[C:11]=3[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)=[N:13][CH2:14][C:8]2=[N:7][N:6]=1
Reactant: CN
Reactant: COC(=O)Cc1nnc2n1-c1ccc(C(F)(F)F)c(Br)c1C(c1cccc([N+](=O)[O-])c1)=NC2
Product: CNC(=O)Cc1nnc2n1-c1ccc(C(F)(F)F)c(Br)c1C(c1cccc([N+](=O)[O-])c1)=NC2

Procedure:
In the manner given in Preparation 3, 7-bromo-8-trifluoromethyl-6-(m-nitrophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine-1-acetic acid methyl ester is reacted with methylamine in diemethylformamide to give N-methyl-7-bromo-8-trifluoromethyl-6-(m-nitrophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine-1-acetamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24](=[O:32])[CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH2:15][C@@H:14](OS(C)(=O)=O)[CH2:13]1)[CH:6]=[CH:5]2.[CH3:33][NH2:34]>C(O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24](=[O:32])[CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:34][CH3:33])[CH2:13]1)[CH:6]=[CH:5]2
Reactant: CN
Reactant: CS(=O)(=O)O[C@@H]1CCCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Solvent: CCO
Product: CNC1CCCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Temperature: 80 °C

Procedure:
N-[6-Chloro-2-[(3R)-3-[(methylsulfonyl)oxy]-1-piperidinyl]-5-quinolinyl]-cyclohexaneacetamide (Example 80(a)) (0.2 g) and 8M methylamine in ethanol (5 ml) were placed into a 10 ml microwave vial and heated at 80° C. for 60 minutes within a single mode microwave. The reaction was pre-absorbed onto silica and purified (SiO2, 7M ammonia in methanol:methanol:dichloromethane 1:3:96 as eluant). The resulting product was recrystallised from acetonitrile to afford the title compound (0.007 g).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:37]#[C:38][CH2:39][CH2:40][CH2:41][CH2:42][OH:43])[CH:28]=[CH:29][C:30]=1[N:31]1[CH:35]=[N:34][C:33]([CH3:36])=[N:32]1.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:37]#[C:38][CH2:39][CH2:40][CH2:41][CH:42]=[O:43])[CH:28]=[CH:29][C:30]=1[N:31]1[CH:35]=[N:34][C:33]([CH3:36])=[N:32]1
Reactant: COc1cc(C#CCCCCO)ccc1-n1cnc(C)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CC#N
Product: COc1cc(C#CCCCC=O)ccc1-n1cnc(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
Dess-Martin reagent (4.99 g) was added to a mixture of 6-[3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]hex-5-yn-1-ol (2.80 g) in acetonitrile (30 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium thiosulfate solution were added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.11 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([CH3:14])[C:11]([NH2:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O.C([O-])=O.[NH4+]>C1COCC1.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]([CH3:14])[C:11]([NH2:13])=[O:12])=[CH:8][CH:9]=1
Reactant: C[C@@H](C(N)=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](C(N)=O)c1ccc(N)cc1
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
(2R)-2-(4-Nitrophenyl)propanamide (4.9 g, 25.2 mmol) was dissolved in a mixture of THF (30 mL) and CH3OH (30 mL) and the resulting solution cooled at T=0-5° C. Ammonium formate (8 g, 126.mmol) was added and, then, also 10% Pd/C (1.6 g) was added portionwise and carefully. The resulting mixture was left stirring at room temperature overnight, until complete disappearance of the starting material (by TLC). After under vacuum filtration over a celite cake, and solvents evaporation at reduced pressure, the pure (2R)-2-(4-aminophenyl)propanamide was isolated as white powder (4 g, 24.24 mmol). Yield 96.2%. m.p. 110-112° C.; [α]D25 (c=0.6, CH3OH): −1.9°; 1H-NMR (CDCl3) δ 7.10 (d, 2H, J=7 Hz), 6.65 (d, 2H, J=7 Hz), 5.35 ((bs, 2H, CONH2), 3.52 (m, 1H), 1.50 (d, 3H, J=7 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]2[CH2:13][S:14][CH2:15][C:3]=12.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1>C(O)CCC>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:8](=[O:10])[C:7]3[C:2]([C:3]4[CH2:15][S:14][CH2:13][C:4]=4[NH:5][CH:6]=3)=[N:24]2)=[CH:19][CH:18]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(c1Cl)CSC2
Solvent: CCCCO
Product: O=c1c2c[nH]c3c(c-2nn1-c1ccc(Cl)cc1)CSC3

Procedure:
A mixture of 0.6 g of ethyl 4-chloro-5,7-dihydrothieno[3,4-b]pyridine-3-carboxylate, p-chlorophenylhydrazine(0.35 g) and 10 ml of n-butanol is heated at reflux for 24 hours, then evaporated to dryness. To the residue is added additional p-chlorophenylhydrazine (0.35 g) and 10 ml of N-methyl-2-pyrrolidone, and the mixture is heated at 150° for 18 hours, then evaporated to dryness. The residue is treated with 20 ml of 2N NaOH and 40 ml of ether. Alkaline layer is separated and pH adjusted to 6.5 depositing solid which is dissolved in methanol; the solution is decolorized with charcoal and concentrated to deposit crystals. Recrystalization from methanol affords -(p-chlorophenyl)-2,3,6,8-tetrahydrothieno[3,4-b]pyrazolo[3,4-d]pyridin-3(5H)-one, mp>330°; IR(cm-1)1600, 1570, 1470, 1000, 931, 835, 830 and 762; (the compound of formula IA wherein R1 =p-chlorophenyl, R2 and R3 =H and A represents ##STR27## The starting material is prepared as follows
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[C:34]([C:39](O)=[O:40])[C:33]2=[O:42])=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:39]([C:34]5[C:33](=[O:42])[N:32]([C:29]6[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=6)[C:37]([CH3:38])=[CH:36][CH:35]=5)=[O:40])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.1 %

Procedure:
To a solution of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.306 mmol) and 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (90.8 mg, 0.367 mmol) in N,N-dimethylformamide (1.0 mL) were added HATU (151 mg, 0.397 mmol) and N,N-diisopropylethylamine (105 μL, 0.612 mmol), and the mixture was stirred at room temperature for 20 hr. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give a white solid. The obtained white solid was washed with ethyl acetate to give the title compound (131 mg, 77%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:26]=[C:25]([Cl:27])[C:24]([F:28])=[CH:23][C:3]=1[C:4]([C:6](=[CH:12][NH:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([F:21])=[CH:16][C:15]=1[F:22])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:27][C:25]1[N:26]=[C:2]2[C:3]([C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][N:13]2[C:14]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[CH:16][C:15]=2[F:22])=[CH:23][C:24]=1[F:28]
Reactant: CCOC(=O)C(=CNc1c(F)cc(F)cc1F)C(=O)c1cc(F)c(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2c(F)cc(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.3 %

Procedure:
With ice cooling, 5 ml of a toluene solution containing 1.39 ml of 2,4,6-trifluoroaniline was added dropwise to 10 ml of a toluene solution containing 6.40 g of ethyl 2-(2,6-dichloro-5-fluoronicotinoyl)-3-ethoxyacrylate and stirred overnight at room temperature. The solvent was distilled off then to the residue, ethanol was added. The resulting crystals were collected by filtration and washed with diethyl ether, to give ethyl 2,6-dichloro-5-fluoronicotinoyl-3-(2,4,6-trifluorophenyl)aminoacrylate. To 9 ml of a N,N-dimethylformamide solution containing 2.0 g of ethyl 2,6-dichloro-5-fluoronicotinoyl-3-(2,4,6-trifluorophenylamino)acrylate was added 0.63 g of potassium carbonate. The solution was stirred for 90 minutes at room temperature. The reaction solution was poured into ice water, the precipitated solid was collected by filtration and washed with ethanol and diethyl ether, to give 1.38 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1>CC(O)C.CCCCCC>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2cc(-c3ccc(OC)nc3)oc2C)cc1
Solvent: CCCCCC
Solvent: CC(C)O
Product: COc1ccc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)c(C)o2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
Ethyl 3-[{[4-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (12.0 g) which is a synthetic intermediate in Example 149 was dissolved in 2-propanol-hexane (8:2, volume ratio), and the solution was subjected to HPLC using CHIRALPAK AD (50 mmID×500 mmL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.) and eluted with 2-propanol-hexane (8:2, volume ratio) as mobile phase at 30° C., a flow rate 60 mL/min. The fractions showing a peak with retention time 44.7 min were collected, and concentrated. The obtained amorphous compound (5.58 g) was dissolved in ethanol (20 mL) and tetrahydrofuran (20 mL) and 1N lithium hydroxide (20 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (30 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (5.0 g, 94%).