Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[C:4]([C:18]([OH:20])=[O:19])=[CH:5][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[C:7]=1[CH3:8].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:6]2[C:7]([CH3:8])=[C:2]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([C:23]([F:34])([F:33])[F:22])[CH:29]=3)[C:3](=[O:21])[C:4]([C:18]([OH:20])=[O:19])=[CH:5]2)=[CH:11][CH:12]=1)#[N:17]
Reactant: Cc1c(Br)c(=O)c(C(=O)O)cn1Cc1ccc(C#N)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1c(-c2cccc(C(F)(F)F)c2)c(=O)c(C(=O)O)cn1Cc1ccc(C#N)cc1
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-1-(4-cyano-benzyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 5b, 2.55 g, 7.34 mmol), 3-(trifluoromethyl)phenylboronic acid (1.65 g, 8.69 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (340 mg, 0.47 mmol) and Cs2CO3 (4.20 g, 12.9 mmol) in dioxane (20.0 mL) is heated for 72 h at 80° C. The reaction mixture is filtered over silica and the filtrate is concentrated under reduced pressure and purified by preparative reversed phase HPLC (first purification: Sunfire, gradient of methanol in water, 0.1% TFA; second purification: Xbridge, gradient of methanol in water, 0.1% NH4OH, 60° C.). Yield: 514 mg (17% of theory); ESI mass spectrum: [M+H]+=413; r.t. HPLC: 1.37 min (Z002_005).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([S:15]([CH3:18])(=[O:17])=[O:16])=[C:5]2[C:10]3[N:11]=[C:12]([NH2:14])[S:13][C:9]=3[CH2:8][CH2:7][C:6]=12.[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[S:3][C:4]([S:15]([CH3:18])(=[O:17])=[O:16])=[C:5]2[C:10]3[N:11]=[C:12]([NH:14][S:25]([C:22]4[CH:21]=[CH:20][C:19]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:24][CH:23]=4)(=[O:27])=[O:26])[S:13][C:9]=3[CH2:8][CH2:7][C:6]=12
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CS(=O)(=O)c1sc(Cl)c2c1-c1nc(N)sc1CC2
Product: CS(=O)(=O)c1sc(Cl)c2c1-c1nc(NS(=O)(=O)c3ccc(-c4ccccc4)cc3)sc1CC2

Procedure:
The title compound was prepared from 6-chloro-8-(methylsulfonyl)4,5-dihydrothieno[3,4-e][1,3]benzothiazol-2-amine (61 mg, synesized according to METHOD I from 1-chloro-3-(methylsulfonyl)-4,5,6,7-tetrahydrobenzo-[c]thiophen-4-one) and 4-biphenylsulfonyl chloride (52 mg) as described in the synthetic METHOD A to give a beige solid (5.9 mg) with a purity >90%: MS-ES (neg) m/z 535.2.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].C1C(=O)N([Br:24])C(=O)C1.C(OOCC1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:24][CH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[C:13]([F:15])([F:14])[F:16]
Reactant: CCOC(=O)c1ccc(C)c(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(COOCc2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(CBr)c(C(F)(F)F)c1
Temperature: 90 °C

Procedure:
To a solution of ethyl 4-methyl-3-(trifluoromethyl)benzoate (for a preparation see Intermediate 19)(2.25 g, 9.69 mmol) in carbon tetrachloride (25 ml) was added NBS (1.90 g, 10.7 mmol, Aldrich) and then benzyl peroxide (0.030 g, 0.124 mmol, Acros). The suspension was heated overnight at 90° C. under nitrogen. The suspension was filtered through a hydrophobic frit and the residue washed with carbon tetrachloride (10 ml). The filtrate was concentrated in vacuo to leave a mobile colourless oil (3.1 g). The residue was loaded in dichloromethane and purified on silica (100 g×2) using 0-100% dichloromethane-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white crystalline solid (1.6 g). LCMS: (System 4) MH+=312, tRET=3.32 min
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:22]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:27]1.CN1CCOCC1>CN1CCCC1=O>[CH:23]([C:21]1[CH:22]=[C:17]([C:14]2[N:13]=[CH:12][C:11]3[CH:10]=[N:9][N:8]([C:6]4[N:7]=[C:2]([N:26]5[CH2:31][CH2:30][CH2:29][C@H:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH2:27]5)[CH:3]=[CH:4][CH:5]=4)[C:16]=3[CH:15]=2)[CH:18]=[N:19][CH:20]=1)([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: CC(C)c1cncc(-c2cc3c(cn2)cnn3-c2cccc(F)n2)c1
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: CC(C)c1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)c1
Temperature: 120 °C

Procedure:
A mixture of 1-(6-fluoro-2-pyridyl)-6-(5-isopropyl-3-pyridyl)pyrazolo[4,3-c]pyridine (0.3032 mmol; 120.0 mg), tert-butyl N-[(3S)-3-piperidyl]carbamate (0.9095 mmol; 182.2 mg), and N-methylmorpholine (3.032 mmol; 310 mg; 0.337 mL) in 1-Methyl-2-pyrrolidinone (3 mL) in a sealed pressure vial was heated at 120° C. overnight. The mixture was cooled to room temperature, and then partitioned between EtOAc and water. The organic layer was concentrated to afford tert-butyl N-[(3S)-1-[6-[6-(5-isopropyl-3-pyridyl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate, which was used without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]4[NH:24][N:23]=[N:22][N:21]=4)[CH:15]=3)(=[O:12])=[O:11])=[C:7]([CH3:25])[C:6]=2[CH:26]=1.[Li+].C[Si]([N-:32][Si](C)(C)C)(C)C>>[NH2:32][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]4[NH:24][N:23]=[N:22][N:21]=4)[CH:15]=3)(=[O:12])=[O:11])=[C:7]([CH3:25])[C:6]=2[CH:26]=1
Reactant: Cc1c(S(=O)(=O)Nc2cccc(-c3nnn[nH]3)c2)sc2ccc(Br)cc12
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: Cc1c(S(=O)(=O)Nc2cccc(-c3nnn[nH]3)c2)sc2ccc(N)cc12
Yield: 2 %

Procedure:
The product was prepared from 5-bromo-3-methyl-N-[3-(1H-tetrazol-5-yl)phenyl]-1-benzothiophene-2-sulfonamide (Example 34) (45 mg, 0.1 mmol) and LiHMDS (1M in THF, 120 μL, 0.12 mmol) according to the General Procedure 4, described in Example 45, using a modified reaction time (130° C., 300 s, microwave reactor). The title compound was obtained in 2% yield (0.6 mg). MS (ESI+) calcd for C16H14N6O2S2 386.061965, found 386.061875.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([OH:14])=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH2:9][CH2:8]2.[C:15](Cl)(=[O:19])[O:16][CH2:17][CH3:18].Cl>[OH-].[Na+]>[CH2:17]([O:16][C:15]([NH:2][C:3]1[CH:4]=[CH:5][C:6]([OH:14])=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH2:9][CH2:8]2)=[O:19])[CH3:18]
Reactant: Nc1ccc(O)c2c1NC(=O)CC2
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)Nc1ccc(O)c2c1NC(=O)CC2
Temperature: 25 °C
Yield: 63.8 %

Procedure:
10.7 g of 8-amino-5-hydroxy-3,4-dihydrocarbostyril hydrochloride was dissolved in 200 ml of a 10% aqueous sodium hydroxide solution, 5.4 g of ethyl chlorocarbonate was added to the solution while stirring at room temperature followed by stirring for one hour at 30° C. After completion of the reaction, the reaction mixture was rendered acidic with hydrochloric acid under ice-cooling, the precipitated crystals were recovered by filtration, washed with water and dried. Recrystallization of the dried crystals from ethanol yielded 7.95 g of 8-ethoxycarbonylamino-5-hydroxy-3,4-dihydrocarbostyril as colorless needle crystals having a melting point of 283.8°-284.6° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[C:6]2=[O:13].[CH3:16][C:17]([NH2:20])([CH3:19])[CH3:18]>C(O)(=O)C>[C:17]([N:20]1[C:6](=[O:13])[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:15])[F:14])[CH:4]=2)[C:8]1=[O:12])([CH3:19])([CH3:18])[CH3:16]
Reactant: O=C1OC(=O)c2cc(C(F)(F)F)ccc21
Reactant: CC(C)(C)N
Solvent: CC(=O)O
Product: CC(C)(C)N1C(=O)c2ccc(C(F)(F)F)cc2C1=O
Temperature: 100 °C

Procedure:
A suspension of 5-(trifluoromethyl)isobenzofuran-1,3-dione and 2-methylpropan-2-amine in acetic acid was heated at 100° C. overnight, concentrated, diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated to give crude 2-tert-butyl-5-(trifluoromethyl)isoindoline-1,3-dione, which was used without purification.
Reaction SMILES: [O:1]([C:3]#[N:4])[K].C(O[C:8](=[O:20])[CH:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([CH3:19])[CH:13]=1)[CH3:10])C.CC(O)=O>CCO.O>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([N:11]2[CH:9]([CH3:10])[C:8](=[O:20])[NH:4][C:3]2=[O:1])=[CH:13][C:14]=1[CH3:19]
Reactant: N#CO[K]
Reactant: CCOC(=O)C(C)Nc1ccc(Br)c(C)c1
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(N2C(=O)NC(=O)C2C)ccc1Br
Temperature: 60 °C
Reaction time: 11 h

Procedure:
KOCN (326 mg, 4.02 mmol) was added to a mixed solution of 2-(4-bromo-3-methyl-phenylamino)-propionic acid ethyl ester (383 mg, 1.34 mmol) in EtOH (5.30 mL) and H2O (2.68 mL). The mixture was stirred at room temperature for three hours and at 60° C. for 11 hours, and AcOH (1 mL) was then added, followed by further stirring for two hours. KOCN (163 mg, 2.01 mmol) was added, followed by further stirring for three hours. The reaction solution was cooled. H2O (50 mL) was added to the reaction solution at room temperature, and this aqueous layer was then extracted with ethyl acetate (20 mL×3). The organic layers were concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane-methanol) to give 1-(4-bromo-3-methyl-phenyl)-5-methyl-imidazolidine-2,4-dione as a yellow form (134 mg, 35%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([OH:15])(=O)[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1C=CC=CC=1>[C:8]1([CH:7]2[C:8]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:5](=[O:15])[CH2:6]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)C=Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C1CC(c2ccccc2)c2ccccc21
Yield: 85.4 %

Procedure:
To 25.0 g of aluminum chloride, 8.5 g of cinnamic acid and 37.5 ml of benzene were added and the mixture was reacted under reflux for 5 hours. The reaction solution was processed by a usual method to obtain 5.1 g of 3-phenyl-1-indanone.
Reaction SMILES: [O:1]=[C:2]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([CH3:32])([CH3:31])[C:26]([O:28]CC)=[O:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:17])([CH3:16])[C:11]([O:13]CC)=[O:12].[OH-].[K+]>>[O:1]=[C:2]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([CH3:32])([CH3:31])[C:26]([OH:28])=[O:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:17])([CH3:16])[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)C(C)(C)CCCCCCCC(=O)CCCCCCCC(C)(C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Product: CC(C)(CCCCCCCC(=O)CCCCCCCC(C)(C)C(=O)O)C(=O)O

Procedure:
Compound 107n was prepared likewise Method D starting from 106n (11.63 g, 25.6 mmol) and KOH (4.31 g, 77.0 mmol) to give, after recrystallization from iPr2O/heptane, 107n (7.56 g, 74%) as white crystals. mp=74-77° C. 1H NMR: (CD3OD) δ 2.43 (t, J=7.3 Hz, 4H), 1.57-1.50 (m, 8H), 1.33-1.21 (m, 16H), 1.14 (s, 12H). 13C NMR: δ 214.5, 182.1 (2×), 43.6 (2×), 43.2 (2×), 42.0 (2×), 31.2 (2×), 30.4 (2×), 30.38 (2×), 26.2 (2×), 25.9 (4×), 25.0 (2×). Anal calcd for C23H42O5: C, 69.31; H, 10.62. found: C, 69.41; H, 10.73.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[O:21][C:20]([C:23]#[N:24])=[C:19]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:18]=3[CH:17]=[C:16]([CH3:32])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:22]3[O:21][C:20]([C:23]#[N:24])=[C:19]([CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:18]=3[CH:17]=[C:16]([CH3:32])[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2oc(C#N)c(Cc3ccccc3)c2c1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)c2oc(C#N)c(Cc3ccccc3)c2c1
Reaction time: 40 h

Procedure:
The crude 4-(3-benzyl-2-cyano-5-methyl-benzofuran-7-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester from step 1 was dissolved in ethanol, and 10% palladium on carbon was added. The mixture was shaken under hydrogen (2.76 Bar) for 40 hours. After filtering off the catalyst, the mixture was concentrated under reduced pressure and purified using preparative thin layer chromatography (1/9 ethyl acetate/hexanes) to give 4-(3-benzyl-2-cyano-5-methyl-benzofuran-7-yl)-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([C:13]1[CH:17]=[C:16]([CH3:18])[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([Li])CCC.[C:24](=[O:26])=[O:25]>O1CCCC1>[CH2:1]([C:13]1[CH:17]=[C:16]([CH2:18][C:24]([OH:26])=[O:25])[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C=O
Reactant: CCCCCCCCCCCCc1cc(C)on1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1cc(CC(=O)O)on1
Temperature: -75 °C

Procedure:
To a cold (-75° C.), stirred suspension of 3-dodecyl-5-methylisoxazole (3.40 g, 0.0135 mol) in dry tetrahydrofuran (900 mL) was added in one portion a 1.6M solution (8.5 mL, 0.014 mol) of n-butyl lithium in hexanes, and the mixture was stirred for 1.5 hours. The mixture was poured onto freshly crushed dry ice and allowed to warm overnight. The mixture was rotoevaporated, and the residue was partitioned between petroleum ether and 0.5M NaOH. The aqueous layer was washed (petroleum ether), acidified with concentrated hydrochloric acid to pH ~1-2, and extracted (CHCl3). The extract was dried (MgSO4) and rotoevaporated to a waxy solid. The solid was recrystallized from toluene to give a white solid; yield 0.65 g (16%); mp 79°-80° C.
Reaction SMILES: [OH:1][C@H:2]([CH:30]([CH3:32])[CH3:31])[C:3]([N:5]1[CH2:29][CH2:28][CH2:27][C@H:6]1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH2:18][NH:19]C(OC(C)(C)C)=O)=[O:8])=[O:4]>CCOC(C)=O>[OH:1][C@H:2]([CH:30]([CH3:32])[CH3:31])[C:3]([N:5]1[CH2:29][CH2:28][CH2:27][C@H:6]1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH2:18][NH2:19])=[O:8])=[O:4]
Reactant: CC(C)[C@@H](O)C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CNC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: CC(C)[C@@H](O)C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CN
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1-((2R)-Hydroxy-3-methylbutanoyl)-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)-L-prolinamide from the previous step (0.26 g, 0.56 mmol, HPLC RT=3.21 min) was dissolved in EtOAc (20 mL) and cooled with stirring to 0° C. HCl gas was bubbled through the solution for 10 minutes. After 2 hours at 0° C., HPLC analysis indicated complete consumption of the starting material, and the solvent was removed under reduced pressure. The resulting solid was triturated in EtOAc, filtered, and dried in vacuo to give the hydrochloride salt of the title compound as a white solid (TLC Rf=0.3 (90:10:0.5 CH2Cl2:MeOH:NH4OH); HPLC RT=2.38 min, method A; LC-MS m/z=368; 1H NMR, 400 MHz, DMSO-d6, ˜3.5:1 mixture of rotamers, selected signals: 8.84 ppm (minor) and 8.64 ppm (major) (t, J=6 Hz, 1H), 0.87, 0.83 ppm (major) and 0.74, 0.58 ppm (minor) (two doublets, J=7 Hz, 3H)).
Reaction SMILES: C(N(C(C)C)CC)(C)C.O.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:27]3[C:22](=[CH:23][C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:26]=3)[N:21]([CH:33]([CH3:35])[CH3:34])[CH:20]=2)=[CH:15][C:14]=1[F:36])#[N:12].C(OP(=S)(OCC)[SH:41])C>COOOC>[F:36][C:14]1[CH:15]=[C:16]([C:19]2[C:27]3[C:22](=[CH:23][C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:26]=3)[N:21]([CH:33]([CH3:34])[CH3:35])[CH:20]=2)[CH:17]=[CH:18][C:13]=1[C:11]([NH2:12])=[S:41]
Reactant: CCOP(=S)(S)OCC
Reactant: CC(C)n1cc(-c2ccc(C#N)c(F)c2)c2ccc(NS(C)(=O)=O)cc21
Agent: COOOC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1cc(-c2ccc(C(N)=S)c(F)c2)c2ccc(NS(C)(=O)=O)cc21
Yield: 90.4 %

Procedure:
Add a drop of di-isopropylethylamine and a drop of water to N-[3-(4-Cyano-3-fluoro-phenyl)-1-isopropyl-1H-indol-6-yl]-methanesulfonamide (100 mg, 0.27 mmol) in 10 mL of dimethoxy ether. Heat to reflux, followed by addition of dithiophosphoric acid O,O′-diethyl ester (151 mg, 0.81 mmol), and reflux in a sealed tube overnight. Evaporate the solvent. Purification of the residue using silica gel chromatography eluted with EtOAc and hexane gradient to give 99 mg (91%) of the desired product.
Reaction SMILES: [F:1][C:2]([C:9]1[CH:13]=[CH:12][S:11][C:10]=1[S:14]([NH2:17])(=[O:16])=[O:15])=[C:3]([F:8])[C:4]([F:7])([F:6])[F:5].C1([O:24][C:25](=O)[NH:26][C:27]2[N:32]=[C:31]([O:33][CH3:34])[N:30]=[C:29]([O:35][CH3:36])[N:28]=2)C=CC=CC=1.O.Cl>C(#N)C>[CH3:34][O:33][C:31]1[N:30]=[C:29]([O:35][CH3:36])[N:28]=[C:27]([NH:26][C:25]([NH:17][S:14]([C:10]2[S:11][CH:12]=[CH:13][C:9]=2[C:2]([F:1])=[C:3]([F:8])[C:4]([F:7])([F:6])[F:5])(=[O:16])=[O:15])=[O:24])[N:32]=1
Reactant: NS(=O)(=O)c1sccc1C(F)=C(F)C(F)(F)F
Reactant: COc1nc(NC(=O)Oc2ccccc2)nc(OC)n1
Agent: Cl
Solvent: CC#N
Solvent: O
Product: COc1nc(NC(=O)NS(=O)(=O)c2sccc2C(F)=C(F)C(F)(F)F)nc(OC)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
According to steps (1) to (4) in Preparation Examples 1, 3-(1,2,3,3,3-pentafluoropropen-1-yl)-2-thiophenesulfonamide was prepared. A portion (0.3 g) of this substance and 0.311 g of phenyl-N-(4,6-dimethoxy-1,3,5-triazin-2-yl)carbamate were dissolved in 4 ml of dry acetonitrile. To the solution, 0.175 g of 1,8-diazabicyclo-(5,4,0)-7-undecene was added dropwise, and the mixture was subjected to reaction under stirring for 2.5 hours at room temperature. After completion of the reaction, the resulting product was poured into water and acidified with hydrochloric acid. The precipitated crystals were filtered, washed with water and dried to obtain 0.47 g of the object compound having a melting point of 149° to 153° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11]C)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br>C(O)(=O)C>[Cl:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1cccc(C(=O)O)c1Cl
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1cccc(O)c1Cl
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-3-methoxybenzoic acid (52.1 g, 279 mmol) in acetic acid (200 mL) was added 40% hydrobromic acid (50 mL), and the mixture was heated under reflux for 4 days. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure to give 2-chloro-3-hydroxybenzoic acid as a colorless solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]1[N:11]=[C:12]([NH:15][C:16](=[O:19])[CH2:17][Cl:18])[S:13][CH:14]=1)[C:5]([O:7]CC)=[O:6].[OH-].[K+]>O.C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:10]1[N:11]=[C:12]([NH:15][C:16](=[O:19])[CH2:17][Cl:18])[S:13][CH:14]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(=NOC)c1csc(NC(=O)CCl)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CON=C(C(=O)O)c1csc(NC(=O)CCl)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.7 %

Procedure:
12.66 g of ethyl α-methoxyimino-α-[2-(chloroacetamido)-thiazol-4-yl]acetate is added to a solution of 11.74 g of potassium hydroxide in a mixture of 25 ml of water and 500 ml of ethanol. After stirring for 20 minutes at room temperature, the reaction solution is subjected to the distillation of ethanol under reduced pressure. The residue is added to water, and the resultant solution is made acidic with addition of N-hydrochloric acid, followed by separating the insoluble materials by filtration. The procedure yields 10.54 g of α-methoxyimino-α-[2-(chloroacetamido)thiazol-4-yl]acetic acid. Melting point: 182°-183° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[CH:4]=[N:3]1.[NH:37]1[CH2:41][CH2:40][C@@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]([NH:7][C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([NH:27][C:28]([N:37]2[CH2:41][CH2:40][C@@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:46])([CH3:48])[CH3:47])[CH2:38]2)=[O:29])[CH:4]=[N:3]1
Reactant: Cn1ncc(NC(=O)Oc2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(NC(=O)N2CC[C@@H](NC(=O)OC(C)(C)C)C2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 61.7 %

Procedure:
To a suspension of phenyl [1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]carbamate (950 mg) and tert-butyl (3R)-3-pyrrolidinylcarbamate (560 mg) in methylene chloride (20 ml) was added N-ethyldiisopropylamine (390 mg), and the mixture was stirred under reflux for 23 hours. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 4% methanol/chloroform to give tert-butyl [(3R)-1-({[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}carbonyl)-3-pyrrolidinyl]carbamate (700 mg) as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].C(N(CC)CC)C.[N+:21]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([N+:33]([O-:35])=[O:34])[CH:32]=1)[C:27](Cl)=[O:28])([O-:23])=[O:22]>C1C=CC=CC=1>[N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH:6][C:27](=[O:28])[C:26]1[CH:25]=[C:24]([N+:21]([O-:23])=[O:22])[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Yield: 8.1 %

Procedure:
2,4-dinitroaniline (18.05 g), triethylamine (12.97 g) and benzene (750 ml) were placed in a reaction vessel and stirred under the nitrogen atmosphere. To the reaction mixture, 3,5-dinitrobenzoyl chloride (25.00 g) was added and refluxed under heating for 6 hours. The reaction mixture was filtered in hot state and the filtrate was cooled to deposit crystals of 2',3,4',5-tetranitrobenzanilide which was collected by filtration. The product of 2',3,4',5-tetranitrobenzanilide (3.00 g) thus obtained, platinum/carbon (5%) (0.18 g) and dioxane (85 ml) were placed in a pressurized vessel and allowed to react under the hydrogen pressure of 1 to 3 kg/cm2 at 80° C. for 10 hours. After cooling, the catalyst was removed by filtration and dioxane was distilled off under the reduced pressure to obtain powder of 2',3,4',5-tetraaminobenzanilide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([Br:17])=[C:15]([Br:18])[N:14]=[C:13]2Br)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C(Cl)Cl.C([Mg]Br)C.Cl.[CH2:28]([O:30]CC)C>CN(C)C=O>[Br:18][C:15]1[N:14]=[C:13]([CH:28]=[O:30])[N:12]([CH2:11][C:3]2[C:2]([Cl:1])=[CH:10][C:6]3[O:7][CH2:8][O:9][C:5]=3[CH:4]=2)[C:16]=1[Br:17]
Reactant: Clc1cc2c(cc1Cn1c(Br)nc(Br)c1Br)OCO2
Reactant: CCOCC
Agent: CC[Mg]Br
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=Cc1nc(Br)c(Br)n1Cc1cc2c(cc1Cl)OCO2
Reaction time: 0.33 h

Procedure:
20 g of the product obtained in Stage 1 above is introduced into 200 ml of anhydrous methylene chloride to which 500 ml of anhydrous ethyl ether is added. A 3M solution of ethyl magnesium bromide in ethyl ether is added and the whole is left under agitation for 20 minutes at ambient temperature. Then an excess (15 ml) of anhydrous dimethylformamide is added. After 2 hours at ambient temperature, hydrolysis is carried out with 200 ml of 1N hydrochloric acid followed by extraction 3 times with 300 ml of ethyl acetate. The organic phase is washed with saturated sodium chloride then dried and evaporated to dryness. In this way 14.5 g of expected product is obtained.