Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[CH3:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:32]=1>C(#N)C>[CH:1]1([C:4]([N:40]2[CH2:41][CH2:42][N:37]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([C:23]4[N:22]([CH3:21])[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[N:24]=4)[CH:32]=3)[CH2:38][CH2:39]2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CC1
Reactant: Cn1c(-c2cccc(N3CCNCC3)c2)nc2ccccc21
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: Cn1c(-c2cccc(N3CCN(C(=O)C4CC4)CC3)c2)nc2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.8 %

Procedure:
To a solution of cyclopropanecarboxylic acid (0.06 g, 0.68 mmol) in acetonitrile (8 mL) was added CDI (0.11 g, 0.68 mmol) and the resulting suspension was stirred at room temperature for 5 h. 1-Methyl-2-(3-piperazin-1-yl-phenyl)-1H-benzoimidazole dihydrochloride (0.20 g, 0.55 mmol) was added and the resulting solution heated at 65° C. overnight. The reaction was then cooled to room temperature, the solvent removed under reduced pressure. The crude product was redissolved in dichloromethane (15 mL) and washed with saturated NaHCO3 solution (2×3 mL) The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (eluent: cyclohexane:EtOAc, gradient from 100% cyclohexane to 100% ethyl acetate) to afford 0.17 g (85%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[C:25]([CH3:34])=[CH:24][CH:23]=2)[C:4]([S:7][CH2:8][C:9]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[Cl:21])=[O:10])=[N:5][N:6]=1.BrC1N(C2C3C(=CC=C(OC)C=3)C(C)=CC=2)C(S[CH2:42][C:43](NC2C=CC(C(O)=O)=CC=2Cl)=O)=NN=1.O>CN(C=O)C>[NH2:1][C:2]1[N:3]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[C:25]([CH:34]3[CH2:43][CH2:42]3)=[CH:24][CH:23]=2)[C:4]([S:7][CH2:8][C:9]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[Cl:21])=[O:10])=[N:5][N:6]=1
Reactant: COc1ccc2c(C)ccc(-n3c(N)nnc3SCC(=O)Nc3ccc(C(=O)O)cc3Cl)c2c1
Reactant: COc1ccc2c(C)ccc(-n3c(Br)nnc3SCC(=O)Nc3ccc(C(=O)O)cc3Cl)c2c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(C3CC3)ccc(-n3c(N)nnc3SCC(=O)Nc3ccc(C(=O)O)cc3Cl)c2c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Compound 10 (100 mg, 0.32 mmol) and 3-chloro-4-(2-chloroacetamido)benzoic acid (11) (79 mg, 0.32 mmol) were dissolved in DMF (2 mL) and the mixture was stirred at 50° C. for 18 hours. Water was then added to the mixture and the precipitate formed collected to give the crude 4-[2-(5-amino-4-[4-cyclopropyl-7-methoxynaphthalen-1-yl]-4H-1,2,4-triazol-3-ylthio)acetamido]-3-chlorobenzoic acid (12) which was used in next step without further purification.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:10][C:11]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[F:10][C:11]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=[CH:8][N:9]=2)=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cc(O)ccc1F
Reactant: O=Cc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1cccnc1Oc1ccc(F)c(C(=O)O)c1
Temperature: 80 °C

Procedure:
To 2-chloronicotinaldehyde (381 mg, 2.69 mmol), 2-fluoro-5-hydroxybenzoic acid (300 mg, 1.92 mmol) and cesium carbonate (1.25 g, 3.84 mmol) was added DMSO (2.5 mL). The mixture was heated to 80° C. in a sealed tube for 3 hours. The cooled reaction was diluted with water and extracted with EtOAc. The aqueous layer was acidified with TFA (pH˜3) and extracted with EtOAc. This layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was washed with Et2O dried to yield 2-fluoro-5-(3-formylpyridin-2-yloxy)benzoic acid as an off-white solid. MS m/z=262 [M+1]+. Calc'd for C13H8FNO4: 261.21.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10]3=[N:12][N:13]=[C:14](S(C)(=O)=O)[N:9]3[CH:8]=[CH:7][C:6]=2[CH:19]=1.[CH3:20][O-:21].[Na+]>>[CH3:20][O:21][C:14]1[N:9]2[C:10]([CH2:11][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:19][C:6]=3[CH:7]=[CH:8]2)=[N:12][N:13]=1
Reactant: C[O-]
Reactant: Cc1ccc2c(c1)C=Cn1c(nnc1S(C)(=O)=O)C2
Agent: [Na+]
Product: COc1nnc2n1C=Cc1cc(C)ccc1C2

Procedure:
The reaction of 8-methyl-3-methylsulfonyl-11H-s-triazolo[3,4-b][3]benzazepine with sodium methoxide yielded 3-methoxy-8-methyl-11H-s-triazolo[3,4-b][3]benzazepine. Colorless prisms (as recrystallized from ethyl acetate), melting point: 148°-149° C.
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[Na+].C([O-])(O)=O.[Na+].CO.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16](Cl)[C:15]=1[N+:24]([O-])=O>[Pt].O>[CH3:2][C:1]([NH:20][C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[C:15]([NH2:24])[CH:16]=1)=[O:4]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1Cl
Reactant: CC(=O)[O-]
Agent: [Pt]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)Nc1ccc(Cl)c(N)c1
Yield: 85 %

Procedure:
A hydrogenation reactor is charged with 15 parts of sodium acetate, 60 parts of NaHCO3, 1320 parts of MeOH and 1015 parts of 1-chloro-2,4-dinitrochlorobenzene under nitrogen at 50° C. and then 11 parts of 1% Pt/C, 0.15 parts of NH4VO3 and 66 parts of water are added.The hydrogenation is carried out at 60° C. and 18 bar. The product is isolated as 3-amino-4-chloroacetanilide (785 parts, 85% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[CH3:19])[N:10]([CH:12]=[O:13])[CH3:11].[CH2:20]=O.[C:22]1(=[O:28])[NH:26][C:25](=[O:27])[CH2:24][CH2:23]1>C(O)C>[O:28]=[C:22]1[CH2:23][CH2:24][C:25](=[O:27])[N:26]1[CH2:20][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[CH3:19])[N:10]([CH:12]=[O:13])[CH3:11]
Reactant: Cc1ccsc1C(Cc1ccccc1N)N(C)C=O
Reactant: C=O
Reactant: O=C1CCC(=O)N1
Solvent: CCO
Product: Cc1ccsc1C(Cc1ccccc1NCN1C(=O)CCC1=O)N(C)C=O
Temperature: 98 °C
Reaction time: 24 h

Procedure:
A stirred solution of 8 g of 2-amino-N-formyl-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine in 30 ml of 95% ethanol was treated with 2.4 ml of a 37% formaldehyde solution and 3.6 g of succinimide. The solution was heated for 6 hours at 98° C. and then allowed to stand at ambient temperature for 24 hours. The resulting precipitate was filtered, washed (95% ethanol; 3×50 ml), and dried in vacuo (40° C.) to afford 7.62 g of 2-[(2,5-dioxo-1-pyrrolidinyl)methyl]amino-N-formyl-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine, mp 160°-164° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:24])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCCCC2)no1
Temperature: 60 °C
Yield: 101.4 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (300 mg, 0.76 mmol) in ethanol (4 ml) was treated dropwise with piperidine (0.75 ml, 7.60 mmol) and the resulting mixture was heated at 60° C. under a nitrogen atmosphere for 9 hours. The mixture was cooled and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:ethyl acetate (80:20) to afford the title compound as a pale yellow oil (334 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.C([Li])CCC.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCCC1.C(Cl)(Cl)Cl>[C:18]1([S:24]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Reaction time: 0.5 h
Yield: 11.1 %

Procedure:
4.8 mg of indole-3-carboxylic acid was dissolved in 1 mL of tetrahydrofuran, 0.042 mL of n-butyllithium (1.58 M hexane solution) was added to the solution at 0° C., the resulting mixture was stirred for 30 minutes. Then 5.3 mg of benzenesulfonyl chloride was added to the mixture, and the resulting mixture was stirred at 0° C. overnight. Water and chloroform were added to the mixture, the organic layer was separated and concentrated under reduced pressure, and the residue was purified by HPLC to obtain 1.0 mg of 1-(phenylsulfonyl)-1H-indole-3-carboxylic acid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:15](Br)[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.CC(C)=O>[CH2:17]([O:14][C:11]1[CH:10]=[CH:9][C:8]([C@H:5]2[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]2)=[CH:13][CH:12]=1)[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: Oc1ccc([C@H]2CC[C@H](O)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)=O
Product: C=CCOc1ccc([C@H]2CC[C@H](O)CC2)cc1
Reaction time: 72 h

Procedure:
10.6 g of trans-4-(4-hydroxycyclohexyl)phenol (55.13 mmol, 14 eq.) are dissolved in 150 mL of a 2/1 mixture of DMF and acetone, to which are added with stirring 4.8 mL of allyl bromide (55.13 mmol, 14 eq.), followed by 11.43 g (82.7, 1.5 eq.) of potassium carbonate. After 3 days, the reaction medium is poured into 300 mL of water, filtered, washed with water and dried to give 12.6 g of trans-4-(4-allyloxyphenyl)cyclohexanol.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])=[CH:11][CH:10]=1.C(N(CC)CC)C.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:21]=[C:30]=[O:32])=[CH:11][CH:10]=1
Reactant: Nc1ccccc1-c1ccc(COC2CCCCO2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C=Nc1ccccc1-c1ccc(COC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 200 mg (0.70 mmol) of 4-(tetrahydropyranyloxy)methyl-2'-amino-1,1'-biphenyl (Example 1, Step N) and 0.40 mL of triethylamine in 10 mL of methylene chloride under a nitrogen atmosphere was treated with triphosgene (420 mg, 0.24 mmol). The reaction mixture was stirred at room temperature for 30 minutes when thin layer chromatography on silica (hexanethyl acetate; 2:1) revealed no remaining amine. The reaction mixture was evaporated under vacuum to yield the crude product which was used in the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26](Br)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[S:40]1[CH:44]=[CH:43][C:42](NC)=[CH:41]1.[CH3:47][N:48](C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C(O[Na])(C)(C)C>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].O1CCOCC1>[C:1]([O:5][C:6](=[O:39])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:48][CH2:47][C:42]5[CH:43]=[CH:44][S:40][CH:41]=5)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(Br)n4)nn(COCC[Si](C)(C)C)c3n2)CC1
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: CNc1ccsc1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(NCc5ccsc5)n4)nn(COCC[Si](C)(C)C)c3n2)CC1
Temperature: 102 °C
Reaction time: 12 h

Procedure:
A sealed tube was charged with {4-[3-(6-bromo-pyridin-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 33 supra) (500 mg, 0.809 mmol), thiophen-3-yl-methylamine (118 mg, 1.044 mmol), Pd2(dba)3 (47 mg, 0.0817 mmol), DavePhos (64 mg, 0.163 mmol), t-BuONa (109 mg, 1.135 mmol) and dioxane (20 mL). The mixture was stirred at 102° C. under an atmosphere of N2 for 12 hours. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 12 g, 200-300 mesh, eluting with petroleum ether:ethyl acetate, 3:1) to give {4-[3-{6-[(thiophen-3-ylmethyl)-amino]-pyridin-2-yl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester. (Yield 415 mg, 79%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl[C:12]1[CH:17]=[CH:16][N:15]2[N:18]=[C:19]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[C:20]([C:21]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:22])=[C:14]2[C:13]=1[F:39].CC1C=CC(C(O)=O)=CC=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCOCC1>[C:26]([O:25][C:24]([N:23]([CH3:31])[C:21]([C:20]1[C:19]([C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)=[N:18][N:15]2[CH:16]=[CH:17][C:12]([C:3]3[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=3[CH3:1])[C:6]([OH:8])=[O:7])=[C:13]([F:39])[C:14]=12)=[O:22])=[O:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: CN(C(=O)OC(C)(C)C)C(=O)c1c(-c2ccc(F)cc2)nn2ccc(Cl)c(F)c12
Reactant: Cc1ccc(C(=O)O)cc1
Agent: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)O)cc1-c1ccn2nc(-c3ccc(F)cc3)c(C(=O)N(C)C(=O)OC(C)(C)C)c2c1F
Temperature: 95 °C
Reaction time: 18 h

Procedure:
3-(3-(tert-butoxycarbonyl)methyl)carbamoyl)-4-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-methylbenzoic acid. To a degassed solution containing tert-butyl 5-chloro-4-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbonyl(methyl)carbamate (0.10 g, 0.24 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.078 g, 0.30 mmol), sodium carbonate (0.075 g, 0.71 mmol), dioxane (2.0 mL) and water (0.40 mL) was added tetrakis(tiphenylphosphine)palladium(0) (0.008 g, 0.007 mmol). The mixture was stirred at 95° C. for 18 h. The solution was cooled to room temperature, filtered to remove solids and adjusted to below pH 4 with 1 N aqueous hydrochloric acid (2.0 mL). Water was added (10 mL) and the aqueous portion was extracted with ethyl acetate (2×15 mL). The combined organic portions were washed with brine (20 mL) and dried over magnesium sulfate. The mixture was filtered and concentrated to afford 3-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-4-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-methylbenzoic acid as a residue which was used without further purification. LCMS retention time: 2.467 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Sunfire C18, 5 micron, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 522 (MH+).
Reaction SMILES: [SH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].CO[C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[O:21][CH:20]2[C:22]([NH2:24])=[O:23])=[CH:15][CH:14]=1.C(Cl)Cl.[C:28]([O:31][CH2:32][CH3:33])(=O)C>C1(C)C=CC=CC=1>[OH:21][CH:20]([CH:19]([S:1][CH2:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:16]1[CH:15]=[CH:14][CH:13]=[CH:18][C:17]=1[C:3]1[CH:2]=[CH:33][C:32]([O:31][CH3:28])=[CH:6][CH:5]=1)[C:22]([NH2:24])=[O:23]
Reactant: COc1ccc(C2OC2C(N)=O)cc1
Reactant: CCOC(C)=O
Reactant: O=C(CS)c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(-c2ccccc2C(SCC(=O)c2ccccc2)C(O)C(N)=O)cc1

Procedure:
To a solution of 8.1 g (0.053 mol) of 2-mercapto-1-phenylethanone in 100 mL of toluene under nitrogen was added 10.2 g (0.053 mol) of 3-(4-methoxyphenyl)oxiranecarboxamide and the mixture was stirred and heated in an oil bath at 120o for 3 hrs. The solvent was removed under reduced pressure to give 18.1 g of crude product, which was dissolved in a minimum amount of a mixture of methylene chloride--ethyl acetate (8:2) and chromatographed using a Waters Prep. LC-system 500 A. Eluted with the same solvents and 200 mL fractions were collected. Fractions 18-21 provided 9.3 g of crude product of which was rechromatographed using ethyl acetate--hexane (75:25) as elutants. Fraction 7 after removal of the solvent yielded a residue, which after crystallization from ethyl acetate gave 0.9 g (5%) of rac.-(R,*R*)-α-hydroxy-4-methoxyphenyl-β-[ (2-oxo-2-phenylethyl)thio]benzenepropanamide, mp 132°-134°.
Reaction SMILES: [CH2:1]([NH:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([NH:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1ccc(C2(NCc3ccccc3)CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(C2(NCc3ccccc3)CC2)cc1
Temperature: 70 °C
Yield: 73.9 %

Procedure:
Using General Procedure D; benzyl-[1-(4-bromophenyl)-cyclopropyl]-amine (Intermediate 124, 110.0 mg, 0.36 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (10.0 mg, 0.05 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (38.0 mg, 0.05 mmol). The resulting reaction mixture was heated to 70° C. for 5 d. The title compound 85 mg (74%) was isolated by chromatography (1-10% EtOAc-hexanes).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][CH2:9]1)[CH2:5][CH:6]=O.[CH2:25]1[C:27]2([CH2:32][CH2:31][NH:30][CH2:29][C@H:28]2[OH:33])[CH2:26]1>>[ClH:22].[CH3:1][O:2][C:3](=[O:24])[C@@H:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][CH2:9]1)[CH2:5][CH2:6][N:30]1[CH2:31][CH2:32][C:27]2([CH2:25][CH2:26]2)[C@H:28]([OH:33])[CH2:29]1
Reactant: COC(=O)[C@H](CC=O)N1CCN(c2ccc(Cl)c(Cl)c2)CCC1=O
Reactant: O[C@@H]1CNCCC12CC2
Product: COC(=O)[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(c2ccc(Cl)c(Cl)c2)CCC1=O
Product: Cl

Procedure:
In analogy to the procedure described for example 1E, (S)-2-[4-(3,4-dichloro-phenyl)-7-oxo-[1,4]diazepan-1-yl]-4-oxo-butyric acid methyl ester and (S)-6-aza-spiro[2.5]octan-4-ol; hydrochloride (intermediate 2) gave the title compound in 60% yield as light yellow foam. MS: 484.3 (MH+, 2Cl).
Reaction SMILES: [CH3:1][N:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]([CH:5]1[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]#[N:19])[CH:14]=3)[NH:9][C:8]=2[CH2:7][CH2:6]1)=[O:4].CC([O-])(C)C.[K+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].OP([O-])(O)=O.[K+]>CN(C=O)C>[C:18]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]1[CH2:7][CH2:6][CH:5]([C:3](=[O:4])[N:2]([CH3:1])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:17][C:16]2=1)#[N:19]
Reactant: CN(C(=O)C1CCc2[nH]c3ccc(C#N)cc3c2C1)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2c(c3cc(C#N)ccc31)CC(C(=O)N(C)c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
To a stirred solution of (±)-6-cyano-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid methyl-phenyl-amide (0.14 g, 0.43 mmol) in dry DMF (1.5 ml) is added KOtBu (58 mg, 0.52 mmol) and ethyl bromoacetate (79 mg, 0.47 mmol). The reaction mixture is stirred at rt overnight, then poured into saturated aqueous KH2PO4 and extracted with CH2Cl2. The combined organic layers are washed with H2O and brine, dried over Na2SO4, filtered and evaporated. The residue is purified by column chromatography on silica gel (hexane/EtOAc 1:1) to provide subtitle compound (91 mg) as a beige solid in 51% yield. tR (LC-3) 1.15 min; ESI-MS (positive ion): m/z 416.09 [M+H]+ (calcd 415.19 for C25H25N3O3). 1H-NMR (CDCl3): 1.13 (t, J=7.0 Hz, 3H); 1.79 (m, 1H); 2.05 (m, 1H); 2.25 (m, 1H); 2.65 (m, 1H); 2.72 (m, 2H); 3.19 (s, 3H); 3.24 (m, 1H); 4.07 (q, J=7.0 Hz, 2H); 5.00 (d, J=3.3 Hz, 2H); 7.33 (m, 1H); 7.41 (m, 5H); 7.50 (d, J=8.0 Hz, 1H); 7.87 (s, 1H).
Reaction SMILES: [OH-].[Na+].CO.[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([O:36]C)=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[CH:11]=[C:10]([O:39][CH:40]([CH3:42])[CH3:41])[C:9]=2[C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)[CH2:7][CH2:6]1.Cl>C(OCC)(=O)C.C1COCC1>[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([OH:36])=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[CH:11]=[C:10]([O:39][CH:40]([CH3:42])[CH3:41])[C:9]=2[C:43]2[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=2)[CH2:6][CH2:7]1
Reactant: CCCc1nc2c(cc1C(=O)OC)C(=O)N(C1CCN(Cc3cc(OC(C)C)c(-c4ccc(F)cc4)c(C4CC4)c3)CC1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1nc2c(cc1C(=O)O)C(=O)N(C1CCN(Cc3cc(OC(C)C)c(-c4ccc(F)cc4)c(C4CC4)c3)CC1)CC2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.50 mL) was added at room temperature to a methanol (5 mL)-THF (5 mL) solution of methyl 6-(1-((2-cyclopropyl-4′-fluoro-6-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (470 mg), and the mixture was stirred at 60° C. for 30 minutes. The reaction mixture was neutralized with hydrochloric acid at room temperature. Then, ethyl acetate was added thereto, and the solvent was distilled off under reduced pressure. The deposited solid was collected by filtration and washed with diethyl ether. The obtained solid was recrystallized (DMSO/ethanol/hexane) to obtain the title compound (389 mg).