Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14]OS(C)(=O)=O)=[CH:10][C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:8]2)=[CH:4][CH:3]=1.[CH3:31][NH:32][CH3:33]>>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14][N:32]([CH3:33])[CH3:31])=[CH:10][C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:8]2)=[CH:4][CH:3]=1
Reactant: CNC
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccc(Cl)cc3)n2)cc1F
Product: COc1ccc(-c2cc(CN(C)C)c(=O)n(Cc3ccc(Cl)cc3)n2)cc1F
Yield: 74.7 %

Procedure:
Following the procedure of Example 7, 2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and dimethylamine were reacted to yield the title compound as a slightly-yellow crystalline powder (yield: 74.7%).
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([N:21]3[CH2:25][C@H:24]([CH2:26][N:27]4[CH:31]=[C:30]([CH3:32])[N:29]=[N:28]4)[O:23][C:22]3=[O:33])=[CH:16][C:15]=2[F:34])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.ClC(OC(Cl)=O)C>ClCCl>[F:34][C:15]1[CH:16]=[C:17]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[N:28]3)[O:23][C:22]2=[O:33])[CH:18]=[C:19]([F:20])[C:14]=1[C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=1
Reactant: Cc1cn(C[C@H]2CN(c3cc(F)c(C4=CCN(Cc5ccccc5)CC4)c(F)c3)C(=O)O2)nn1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cn(C[C@H]2CN(c3cc(F)c(C4=CCNCC4)c(F)c3)C(=O)O2)nn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(5R)-3-[4-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)-3,5-difluorophenyl]-5-[(4-methyl-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one (Example 39) (1.74 g, 3.74 mmol) was dissolved in dichloromethane (20 ml) and cooled to 0° C. Diisopropylethylamine (0.13 ml, 0.75 mmol) was added, followed by addition of 1-chloroethylchloroformate (0.48 ml, 4.48 mmol). It was stirred for 30 minutes, then allowed to warm to room temperature. After 16 hours, the reaction mixture was concentrated under vacuum. The intermediate chloroethylcarbamate was dissolved in methanol (20 ml) and heated to reflux. After 30 min, the reaction mixture was cooled to room temperature and concentrated under vacuum to give the title compound as the hydrochloride salt (1.5 g), which was used without further purification.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[NH:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:12]([N:14]([CH3:16])[CH3:15])=[O:13].[C:27](Cl)(=O)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>C(Cl)(Cl)Cl>[CH3:26][N:24]([CH3:25])[CH2:23][CH2:22][CH2:21][N:20]1[C:19]2[CH:18]=[CH:17][C:11]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])=[CH:10][C:9]=2[N:8]=[C:44]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH3:27]
Reactant: CN(C)CCCNc1ccc(C(=O)N(C)C)cc1N
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCc1nc2cc(C(=O)N(C)C)ccc2n1CCCN(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
Triethylamine (1.46 ml) was added to a solution containing 3-amino-4-{[3-(dimethylamino)propyl]amino}-N,N-dimethylbenzamide (2.57 g) in chloroform (20 ml), and then stearoyl chloride (2.89 g) was added thereto while being cooled with ice. After being stirred for 2 hours at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (7.5 ml) was added to a solution containing the residue (5.53 g) in ethanol (30 ml). After being stirred for 3 hours at 90° C., the reaction mixture was neutralized with 5N sodium hydroxide aqueous solution (18 ml) and concentrated. The residue, with ethyl acetate added thereto, was washed with water and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (4.33 g) was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=10:1), thereby yielding the entitled compound (4.21 g) as pink wax.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:18])[NH:15][CH2:16][CH2:17][C:12]=3[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:10]2)=[CH:5][CH:4]=1.I[C:25]1[CH:30]=[CH:29][C:28]([C:31]([CH3:35])([CH3:34])[C:32]#[N:33])=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>[Cu]I.CS(C)=O>[C:32]([C:31]([CH3:35])([CH3:34])[C:28]1[CH:29]=[CH:30][C:25]([N:15]2[CH2:16][CH2:17][C:12]3[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:10][N:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[C:13]=3[C:14]2=[O:18])=[CH:26][CH:27]=1)#[N:33]
Reactant: CC(C)(C#N)c1ccc(I)cc1
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCNC2=O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(C(C)(C)C#N)cc1)C2=O
Temperature: 130 °C
Yield: 45.9 %

Procedure:
Part D. To a DMSO (4 mL, degassed) solution of ethyl 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (0.6 g, 1.9 mmol), and 2-(4-iodophenyl) 2-methylproprionitrile (0.6 g, 2.2 mmol), and K2CO3 (0.66 g, 4.8 mmol) and was added CuI (73 mg, 0.3 mmol). The reaction was heated to 130° C. for 18 h. The reaction was cooled, extracted with EtOAc, washed with H2O, and dried (MgSO4). Purification by chromatography on silica gel (1:1 hexanes/ethyl acetate) afforded the title compound 0.4 g (45.9%) of a pale yellow solid; Mass Spec (M+H)+ 459.3.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22](=[O:43])[C:23]([CH3:42])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][CH3:41])=[C:35]([CH:39]=2)[C:36](O)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22](=[O:43])[C:23]([CH3:42])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][CH3:41])=[C:35]([CH:39]=2)[C:36]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC)c(C(=O)O)c2)=C(C)C1=O
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC)c(C(=O)N3CCCCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 26.6 %

Procedure:
Piperidine (0.027 g, 0.318 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.091 g, 0.477 mmol) were added to a methylene chloride solution (5 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-methoxybenzoic acid (0.055 g, 0.159 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate) to obtain the titled compound (0.0175 g, 0.0423 mmol, 27%).
Reaction SMILES: [Br:1][C:2]([C:24](Cl)=[O:25])=[CH:3][C:4]1[CH:5]=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])[CH:7]=[CH:8][C:9]=1[Cl:10].[CH2:27]([S:29][CH2:30][CH2:31][OH:32])[CH3:28].C(N(CC)CC)C.O>O1CCCC1>[Br:1][C:2]([C:24]([O:32][CH2:31][CH2:30][S:29][CH2:27][CH3:28])=[O:25])=[CH:3][C:4]1[CH:5]=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CCSCCO
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=C(Br)C(=O)Cl)c2)c1=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCSCCOC(=O)C(Br)=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Reaction time: 5 h

Procedure:
2.36 g of 3-[3-(2-bromo-2-chlorocarbonylethenyl)-4-chlorophenyl]-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine in 20 ml of tetrahydrofuran were added dropwise to a solution of 0.58 g of 2-ethylmercaptoethanol and 0.56 g of triethylamine in 30 ml of tetrahydrofuran, and stirring was carried out for 5 hours. 100 ml of water were added and the aqueous phase was extracted with twice 100 ml of dichloromethane. The combined organic phases were washed three times with water, dried with sodium sulfate and evaporated down. The solid residue was stirred with diisopropyl ether, removed, washed with diisopropyl ether and petroleum ether and dried.
Reaction SMILES: [CH2:1]([NH:5][C:6]([C:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17]C)=[CH:16][C:11]=2[O:10][C:9]=1[CH3:19])=[O:7])[CH:2]([CH3:4])[CH3:3].B(Br)(Br)Br>>[CH2:1]([NH:5][C:6]([C:8]1[C:12]2[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=2[O:10][C:9]=1[CH3:19])=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccc2c(C(=O)NCC(C)C)c(C)oc2c1
Agent: BrB(Br)Br
Product: Cc1oc2cc(O)ccc2c1C(=O)NCC(C)C

Procedure:
This material was prepared from 6-methoxy-2-methyl-benzofuran-3-carboxylic acid isobutyl amide 84a by treatment with BBr3 in a manner as previously described for example 1d. 1H NMR (DMSO-d6) δ 9.53 (1H, s), 7.90 (1H, t, J=6.1 Hz), 7.44 (1H, d, J=8.3 Hz), 6.86 (1H, s), 6.74 (1H, dd, J=8.6, 1.8 Hz), 3.07 (2H, t, J=6.1 Hz), 2.52 (3H, s), 1.81 (1H, m). 0.90 (6H, d, J=6.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([OH:22])[CH:11]=[N+:12]([O-])[C:13]=3[C:17]([O:19][CH3:20])=[O:18])[C:8]2=[O:23])=[CH:4][CH:3]=1.C(OC(=O)C)(=[O:28])C.C[O-].[Na+]>>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([OH:22])[C:11](=[O:28])[NH:12][C:13]=3[C:17]([O:19][CH3:20])=[O:18])[C:8]2=[O:23])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1c2c(c(O)c[n+]1[O-])C(=O)N(Cc1ccc(F)cc1)CC2
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)c1[nH]c(=O)c(O)c2c1CCN(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To methyl 6-(4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate 2-oxide (0.178 g, 0.514 mmol) was added acetic anhydride (0.157 g, 1.542 mmol) and refluxed. After 1 hour, the reaction mixture was concentrated under vacuum, then sodium methoxide (30 wt. % in methanol, 0.083 g, 1.540 mmol) was added. After stirring at room temperature for 1 hour, the product mixture was concentrated under vacuum. The residue was purified by reverse phase HPLC eluting with 5%-95% acetonitrile (0.1% TFA) in H2O (0.1% TFA) to afford the title compound as a pale yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][N:13]=2)=[C:6]([NH2:21])[CH:5]=1.C(N(CC)CC)C.[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35](Cl)=[O:36].[OH-].[Na+].Cl>C1COCC1.CO>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](/[CH:11]=[CH:10]/[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:22])=[CH:5][C:6]=2[NH:21][C:35]([C:31]2[O:30][CH:34]=[CH:33][CH:32]=2)=[O:36])=[N:13]1
Reactant: COC(=O)c1ccc(C=Cc2n[nH]c3ccccc23)c(N)c1
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)c(NC(=O)c2ccco2)c1
Reaction time: 4 h
Yield: 83 %

Procedure:
A solution of 3-amino-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid methyl ester (0.30 g, 1.0 mmol) obtained in Step 1 of Example 217 and triethylamine (0.43 ml, 3.1 mmol) in THF (10 mL) was added with furan-2-carbonyl chloride (0.11 mL, 1.1 mmol), followed by stirring for 4 hours. The reaction mixture was extracted with ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was concentrated under reduced pressure to obtain crude product. Further, the product was dissolved in methanol (20 mL) and added with 2 mol/L aqueous sodium hydroxide solution (5.0 mL), followed by stirring at 60° C. for 1 hour. The reaction mixture was acidified by hydrochloric acid (6 mol/L) and the precipitated crystal was collected by filtration to obtain (E)-4-[2-(1H-indazol-3-yl) vinyl]-3-[(furan-2-carbonyl)amino]benzoic acid (0.31 g, 82%).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13](OCC)=O)=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.C(O[C:21](=[O:25])[O:22][CH2:23][CH3:24])C.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>O1CCCC1.C(OCC)(=O)C.O>[CH:1]1([C:4]([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][CH:13]([C:21]([O:22][CH2:23][CH3:24])=[O:25])[C:21]([O:22][CH2:23][CH3:24])=[O:25])=[CH:10][CH:11]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: CCOC(=O)Cc1ccc(C(=O)C2CC2)cc1
Reactant: CCOC(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(Cc1ccc(C(=O)C2CC2)cc1)C(=O)OCC
Reaction time: 28 h
Yield: 26.4 %

Procedure:
Dissolve 4-(cyclopropylcarbonyl)benzeneacetic acid, ethyl ester (6.5 g, 28 mmol) and diethylcarbonate (4.0 g, 34 mmol) in tetrahydrofuran (100 mL). Add 62 mL (62 mmol) of a 1.0 molar solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran over 0.5 hours. Stir 28 hours. Add iodomethane (5.3 g, 35 mmol). Stir 2 days. Add water and ethyl acetate. Wash organic phase with brine, dry over anhydrous magnesium sulfate and concentrate. Purify by flash chromatography (200 g silica gel, ethyl acetate/heptane as eluent) to give the title compound (1.43 g, 17%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6]2([C:19]3[C:11](=[CH:12][C:13]4[CH2:14][CH2:15][N:16]([C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]6[CH:33]=[CH:32][C:31]([C:34]([NH:36][NH2:37])=[O:35])=[CH:30][C:29]=6[CH3:38])=[CH:24][CH:23]=5)=[O:21])[C:17]=4[CH:18]=3)[O:10][CH2:9]2)[CH2:5][CH2:4]1)[CH3:2].[C:39](OC(=O)C)(=[O:41])[CH3:40]>C(Cl)(Cl)Cl>[C:39]([NH:37][NH:36][C:34]([C:31]1[CH:32]=[CH:33][C:28]([C:25]2[CH:24]=[CH:23][C:22]([C:20]([N:16]3[C:17]4[CH:18]=[C:19]5[C:6]6([CH2:9][O:10][C:11]5=[CH:12][C:13]=4[CH2:14][CH2:15]3)[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]6)=[O:21])=[CH:27][CH:26]=2)=[C:29]([CH3:38])[CH:30]=1)=[O:35])(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: CCN1CCC2(CC1)COc1cc3c(cc12)N(C(=O)c1ccc(-c2ccc(C(=O)NN)cc2C)cc1)CC3
Solvent: ClC(Cl)Cl
Product: CCN1CCC2(CC1)COc1cc3c(cc12)N(C(=O)c1ccc(-c2ccc(C(=O)NNC(C)=O)cc2C)cc1)CC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 2623.7 %

Procedure:
To a stirred solution of 1'-ethyl-5-(4'-hydrazinocarbonyl-2'-methylbiphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E61, 1.00 g, 1.96 mmole) in chloroform (30 ml), acetic anhydride (5.76 ml, 0.06 mmole) was slowly added. The solution was stirred at room temperature for approximately 1 hour, then concentrated in vacuo. Toluene was used to azeotrope out the excess acetic anhydride. The residue was dissolved in chloroform, washed with 10% Na2CO3 solution and the organic phase dried (Na2SO4), then concentrated in vacuo. The residue beige solid was chromatographed on silica gel, eluting with 0-12% methanol in chloroform to afford the title compound as a yellow solid (0.87 g, 80%) m.p. 154-157° C.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[C:35]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)#[N:36]>>[C:35]([C:37]1[CH:38]=[C:39]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:34])=[O:3])[CH:11]=[C:12]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)[CH:13]=2)[CH:40]=[CH:41][CH:42]=1)#[N:36]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(C#N)c2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 3-cyano-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, MeOD) δ ppm 0.88 (dd, J=6.60, 3.18 Hz, 6H), 1.47 (dt, J=13.45, 6.72 Hz, 1H), 1.66 (ddd, J=13.63, 7.09, 6.91 Hz, 1H), 1.91-2.00 (m, 1H), 3.77 (t, J=7.83 Hz, 1H), 7.61 (dd, J=4.16, 1.71 Hz, 2H), 7.68 (d, J=8.31 Hz, 2H), 7.73-7.81 (m, 7H).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[N:6]=1.[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3([C:26](O)=[O:27])[CH2:25][CH2:24]3)=[CH:22][C:17]=2[O:16][CH2:15]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3([C:26]([NH:11][C:10]4[CH:12]=[CH:13][C:7]([C:5]5[N:6]=[C:2]([CH3:1])[S:3][CH:4]=5)=[CH:8][CH:9]=4)=[O:27])[CH2:24][CH2:25]3)=[CH:22][C:17]=2[O:16][CH2:15]1
Reactant: Cc1nc(-c2ccc(N)cc2)cs1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc(-c2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc2)cs1
Reaction time: 16 h

Procedure:
4-(2-Methylthiazol-4-yl)aniline (19 mg, 0.10 mmol) and 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (20.6 mg, 0.100 mmol) were dissolved in acetonitrile (1.0 mL) containing triethylamine (42 μL, 0.30 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and the resulting solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(4-(2-methylthiazol-4-yl)phenyl)cyclopropane-carboxamide. ESI-MS m/z calc. 378.1, found; 379.1 (M+1)+; Retention time 2.72 minutes. 1H NMR (400 MHz, DMSO-d6) δ 1.04-1.10 (m, 2H), 1.40-1.44 (m, 2H), 2.70 (s, 3H), 6.03 (s, 2H), 6.88-6.96 (m, 2H), 7.01 (d, J=1.4 Hz, 1H), 7.57-7.61 (m, 2H), 7.81-7.84 (m, 3H), 8.87 (s, 1H).
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][N:5]([CH:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][CH:17]=C)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7].[BH4-].[Na+]>CO>[OH:1][CH2:17][CH2:16][CH:15]([N:5]([CH3:4])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C=CCC(c1ccccc1)N(C)S(=O)(=O)c1ccccc1
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C(CCO)c1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
Ozone was bubbled through a solution of the product of Step 1 (1.0 g, 3.3 mmol) in MeOH (50 mL) at −78° C. for 30 min, then after appearance of a pale blue colour, the reaction was purged with N2 for several minutes and NaBH4 (245 mg, 6.6 mmol) was added. The resulting solution was allowed to warm to RT and stirred for a further 15 min at RT. The reaction was quenched by the addition of NH4Cl solution (10 mL) and then concentrated under reduced pressure. H2O (50 mL) was added and then extracted with EtOAc (100 ml and 50 mL). The combined organic extracts were dried (MgSO4) and then concentrated under reduced pressure to yield the alcohol (0.94 g, 93%). 1H NMR (CDCl3, 400 MHz) δ 7.81 (2H, d, J=7.2 Hz), 7.65–7.45 (3H, m), 7.20–7.13 (3H, m), 6.93 (2H, d, J=7.5 Hz), 5.25 (1H, dd, J=9.1, 6.3 Hz), 3.90–3.80 (1H, m), 3.74–3.59 (1H, m), 2.63 (3H, s), 2.13–1.98 (2H, m).
Reaction SMILES: COC1C=CC(C[S:8][CH2:9][C@@H:10]([C:12]([NH:14][C:15](=[O:29])[C:16]([S:19]CC2C=CC(OC)=CC=2)([CH3:18])[CH3:17])=[O:13])[NH2:11])=CC=1.[Na].[Cl-].[NH4+]>N>[SH:19][C:16]([CH3:18])([CH3:17])[C:15]([NH:14][C:12](=[O:13])[C@H:10]([CH2:9][SH:8])[NH2:11])=[O:29]
Reactant: COc1ccc(CSC[C@H](N)C(=O)NC(=O)C(C)(C)SCc2ccc(OC)cc2)cc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(S)C(=O)NC(=O)[C@@H](N)CS
Yield: 33.3 %

Procedure:
To a solution of S-p-methoxybenzyl-N-(2-p-methoxybenzylthio-2-methylpropionyl)-L-cysteine amide(500 mg) in liquid ammonia(10 ml), metallic sodium(0.15 g) was added under nitrogen atomosphere at -78° C. Ammonium chloride was added to the solution and ammonia was evaporated. Methanol and methylene chloride were added to the residue and filtered. The filtrate was concentrated in vacuo and the oily residue was purified by a silica gel column chromatography to give 80 mg(32%) of the titled compound.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][CH:7]=[C:8]([C:14]([O:16][CH3:17])=[O:15])[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:4]2[N:3]=[N:2]1.[H-].[Na+].I[CH3:21]>CN(C)C=O>[CH3:21][N:1]1[C:5]2=[CH:6][CH:7]=[C:8]([C:14]([O:16][CH3:17])=[O:15])[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:4]2[N:3]=[N:2]1
Reactant: CI
Reactant: COC(=O)c1ccc2[nH]nnc2c1C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(nnn2C)c1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of dimethyl 1H-benzotriazole-4,5-dicarboxylate (10.1 g, 43 mmol) in dimethylformamide is treated portion-wise, with cooling, with sodium hydride. When gas evolution has ceased, the reaction mixture is treated dropwise with iodomethane (6.7 g, 46 mmol) stirred at room temperature for 2 hours, concentrated in vacuo and diluted with a mixture of chloroform and water. The layers are separated; the organic layer is washed with brine, dried over MgSO4 and concentrated in vacuo to give a residue. The residue is chromatographed using silica gel and 35% ethyl acetate in hexanes to give the title product as a white solid, 3.15 g, mp 146°-147° C. The structure is determined by NMR NOE experiments.
Reaction SMILES: [F:1][C:2]([F:11])([C:7]([F:10])([F:9])[F:8])[C:3](I)([F:5])[F:4].C1([Mg]Br)C=CC=CC=1.[Br:20][CH2:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24].C(O)(=O)C>C(OCC)C.O>[Br:20][CH2:21][C:22]([OH:27])([C:3]([F:5])([F:4])[C:2]([F:11])([F:1])[C:7]([F:10])([F:9])[F:8])[C:23]([F:26])([F:25])[F:24]
Reactant: FC(F)(F)C(F)(F)C(F)(F)I
Reactant: O=C(CBr)C(F)(F)F
Agent: Br[Mg]c1ccccc1
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O
Product: OC(CBr)(C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: -20 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
Heptafluoropropyl iodide (5 g, 16.9 mmole) was stirred in dry diethyl ether (20 ml) at -78° C. Phenylmagnesium bromide (10 ml of a 1.88M solution in ether) was then added dropwise, keeping the temperature below -65° C. When the addition was complete, the reaction mixture was stirred at -20° C. for one hour. It was then cooled to -78° C. and 3-bromo-1,1,1-trifluoropropanone (4.87 g, 18.0 mmole) in dry diethylether (20 ml) was added dropwise, keeping the temperature below -65° C. When the addition was complete, the mixture was stirred at between -20° and -50° C. for four hours. Glacial acetic acid (3 ml) in diethyl ether (5 ml) was then added slowly, followed by water (15 ml). The mixture was then allowed to warm to 5° C. and the phases were separated. The aqueous phase was washed with ether (2×25 ml). The ethereal extracts were combined, dried (MgSO4) and evaporated to give crude 2-bromomethyl-decafluoropentan-2-ol (5.0 g).
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:14]=[C:15]4[CH:21]=[CH:20][NH:19][C:16]4=[N:17][CH:18]=3)[CH:9]=[C:8]([C:22]([O:24]C)=[O:23])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].O[Li].O>>[CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:14]=[C:15]4[CH:21]=[CH:20][NH:19][C:16]4=[N:17][CH:18]=3)[CH:9]=[C:8]([C:22]([OH:24])=[O:23])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(-c2cnc3[nH]ccc3c2)cc2c1cnn2C(C)C
Agent: [Li]O
Solvent: O
Product: CC(C)n1ncc2c(C(=O)O)cc(-c3cnc4[nH]ccc4c3)cc21
Temperature: 80 °C

Procedure:
The title compound was prepared in the same manner as described for example 35 (step b) from methyl 1-isopropyl-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-indazole-4-carboxylate 1 (0.6 g, 1.79 mmol) and LiOH.H2O (0.22 g, 5.37 mmol) wherein the mixture was heated at 80° C. for 5 h. The product was collected as an off-white solid (0.5 g, 87.7%). 1H NMR (DMSO-d6, 400 MHz): δ 1.530 (d, J=6.4 Hz, 6H), 5.199-5.265 (m, 1H), 6.552 (d, J=1.6 Hz, 1H), 7.550 (t, J=2.4 Hz, 1H), 8.11 (s, 1H), 8.328 (s, 1H), 8.383 (d, J=1.6 Hz, 1H), 8.401 (s, 1H), 8.671 (d, J=1.6 Hz, 1H), 11.77 (brs, 1H). LCMS (ES+) m/z: 321.24.