Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=O.[C:12]1([O:18][CH2:19][CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH2:7][C:15]2[CH:16]=[CH:17][C:12]([O:18][CH2:19][CH3:20])=[CH:13][CH:14]=2)[CH:10]=1
Reactant: CCOc1ccccc1
Reactant: Cc1ccc(Br)cc1C(=O)O
Product: CCOc1ccc(Cc2cc(Br)ccc2C)cc1

Procedure:
Synthesis was performed by a similar method as in Preparation Example 14 using 5-bromo-2-methylbenzoic acid (synthesized in reference to International Patent Publication WO0127128) and phenetole.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)=[O:3].[OH:21][CH2:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH:14]1([CH2:13][C:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:26]3[CH2:27][CH2:28][CH:23]([CH2:22][OH:21])[CH2:24][CH2:25]3)=[O:3])=[CH:6][CH:7]=2)=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: OCC1CCNCC1
Reactant: O=C(CC1CCCCC1)Nc1ccc(OC(=O)Cl)cc1
Product: O=C(CC1CCCCC1)Nc1ccc(OC(=O)N2CCC(CO)CC2)cc1

Procedure:
The title compound was prepared from 4-(2-cyclohexyl-acetylamino)-phenyl chloroformate and 4-hydroxymethyl-piperidine, preparative HPLC (Method C) (37%, off-white crystals). HPLC-MS m/z=375.2 (M+1), Rt: 3.41 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH-].[Na+]>Cl.O1CCOCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccc(NC2CCNCC2)cc1
Yield: 74.7 %

Procedure:
A solution of D1 (1.44 g) in 2M HCl (5 ml) and 1,4-dioxane (20 ml) was heated at 60° C. for 24 h. On cooling, the solution was diluted with water, basified with 2M NaOH solution and extracted with EtOAc (×3). The combined organics were dried (MgSO4) and concentrated in vacuo to give the title compound as a yellow oil (0.71 g). δH (CDCl3) 1.29 (2H, m), 2.05 (2H, m), 2.70 (2H, m), 3.20 (1H, m), 3.30 (2H, m), 6.54 (2H, dd), 6.88 (2H, t).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[C:4]([CH:10]=[CH:11][C:12]([CH3:16])([OH:15])[CH:13]=[CH2:14])=[C:3]1[CH3:17].C(N(CC)CC)C.[CH3:25][Si:26]([CH3:29])([CH3:28])Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:1]=[C:2]1[CH2:7][CH2:6][C:5]([CH3:8])([CH3:9])[C:4]([CH:10]=[CH:11][C:12]([CH3:16])([O:15][Si:26]([CH3:29])([CH3:28])[CH3:25])[CH:13]=[CH2:14])=[C:3]1[CH3:17]
Reactant: C=CC(C)(O)C=CC1=C(C)C(=O)CCC1(C)C
Reactant: C[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(C)(C=CC1=C(C)C(=O)CCC1(C)C)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1-(3-oxo-2,6,6-trimethyl-1-cyclohexen-1-yl)-3-methyl-1,4-pentadiene-3-ol (2.34 g, 10 mmoles)(prepared as described in J. Org. Chem. 47. 2130-2134 (1982)) in methylenechloride is added triethylamine (2.08 ml, 15 mmoles), trimethylchlorosilane (1.9 ml, 15 mmoles), and N,N-dimethyl-4-aminopyridine (5 mg, catalytic amount). The mixture is stirred at room temperature for four hours, followed by concentration in vacuo and trituration with dry diethylether. The suspension is filtered and the filtrate is concentrated in vacuo yielding the title compound as a slightly yellow oil.
Reaction SMILES: [CH2:1]([C:4]1([S:7]([O-:10])(=O)=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[K+].S(Cl)([Cl:14])=O>CN(C=O)C>[CH2:1]([C:4]1([S:7]([Cl:14])(=[O:10])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: O=S(Cl)Cl
Reactant: C=CCC1(S(=O)(=O)[O-])CC1
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCC1(S(=O)(=O)Cl)CC1

Procedure:
A solution of potassium 1-allylcyclopropane-1-sulfonate (3.44 g, 17.2 mmol), thionyl chloride (10 ml) and DMF (5 drops) was refluxed at 60° C. for 16 h. The volatiles evaporated under reduced pressure and the residue extracted with CH2Cl2 (50 ml). The extract was washed with water, dried (MgSO4) and evaporated to obtain the crude product as yellow gummy oil which was washed with hexane and used in the next reaction without further purification (2.7 g, 15 mmol, 87%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[N+:17]([O-:19])=[O:18])[CH2:4][CH2:3]1.[C:20](O)(=[O:22])[CH3:21].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:20]([O:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[N+:17]([O-:19])=[O:18])[CH2:4][CH2:3]1)(=[O:22])[CH3:21]
Reactant: N#Cc1ccc(N[C@H]2CC[C@H](O)CC2)c([N+](=O)[O-])c1
Reactant: CC(=O)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1CC[C@@H](Nc2ccc(C#N)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(trans-4-hydroxycyclohexylamino)-3-nitrobenzonitrile (1.0 g), acetic acid (345 mg) and diethyl azodicarboxylate (2.17 g, 40% solution in toluene) in anhydrous tetrahydrofuran (25 mL) was added portionwise triphenylphosphine (1.31 g) at 0° C., and the mixture was stirred at ambient temperature for 2 hours. The mixture was evaporated in vacuo and the residue was subjected to a silica gel column chromatography eluting with a mixture of n-hexane and ethyl acetate (5:1 to 3:1) and then chloroform. The obtained substance was triturated with methanol to give 4-(cis-4-acetoxycyclohexylamino)-3-nitrobenzonitrile (530 mg) as yellow powders.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:18]([C:19]#[N:20])=[C:17]([N:21]=[CH:22][N:23](C)C)[NH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)N>CO>[Cl:27][C:28]1[CH:34]=[C:33]([NH:20][C:19]2[N:23]=[CH:22][N:21]=[C:17]3[NH:16][N:15]=[C:14]([N:11]4[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]4)[C:18]=23)[CH:32]=[CH:30][CH:29]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CN(C)C=Nc1[nH]nc(N2CCN(C(=O)OC(C)(C)C)CC2)c1C#N
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)CC1

Procedure:
With the exclusion of air, 16.2 9 (46.6 mmol) of N′-[3-(4-tert-butoxycarbonyl-piperazin-1 -yl)-4-cyano-1H-pyrazol-5-yl]-N,N-dimethyl-formamidine in 130 ml methanol are heated to boiling with 11.47 g (70 mmol) of 3-chloro-aniline hydrochloride. After 9 hours the reaction mixture is cooled, filtered and washed with methanol and DIPE. Stirring the crude product in boiling ethanol, cooling and filtration yield 4-(3-chloro-phenylamino)-3-(4-tert-butyloxycarbonyl-piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine; HPLC: tRet(grad20-100/20)=15.7; IR (KBr) interalia 1706 s, 1631 s, 1610 s, 1589 s, 1508 m, 1482 s, 1425 m, 1364 m, 1304 m, 1283 m, 1245 m, 1170 m, 1122 m.
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=[C:12](Cl)[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][S:31]([NH2:34])(=[O:33])=[O:32].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[NH:1]([C:8]1[N:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]2[N:11]=[C:12]([NH:34][S:31]([CH3:30])(=[O:33])=[O:32])[CH:13]=[C:14]([C:19]([F:22])([F:21])[F:20])[C:15]=2[C:16](=[O:18])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(Cl)cc(C(F)(F)F)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)Nc1cc(C(F)(F)F)c2c(=O)cc(Nc3ccccc3)n(-c3ccccc3)c2n1
Temperature: 120 °C
Reaction time: 24 h
Yield: 4 %

Procedure:
To a solution of 2-anilino-7-chloro-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (100 mg, 0.241 mmol) in DMSO (5 mL) was added methyl sulfonamide and K2CO3 (76.5 mg, 0.554 mmol). The reaction was stirred at 120° C. for 24 h. The reaction was then cooled to room temperature, quenched with water and extracted with Et2O. The organic layers were dried over MgSO4, and concentrated in vacuo. The crude residue was then passed through a plug of silica gel eluting with 1:1 Hex:EtOAc to 9:1 CH2Cl2:MeOH to afford N-[7-anilino-5-oxo-8-phenyl-4-(trifluoromethyl)-5,8-dihydro-1,8-naphthyridin-2-yl]methanesulfonamide as a white solid (4.4 mg, 4%): LCMS RT: 2.45, MH+: 475.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[CH3:12]C(OC(C)=O)=O>C(OC(OCC)OCC)C>[Br:8][C:5]1[N:4]=[C:3]2[C:2](=[N:7][CH:6]=1)[N:1]=[CH:12][NH:11][C:9]2=[O:10]
Reactant: NC(=O)c1nc(Br)cnc1N
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(OCC)OCC
Product: O=c1[nH]cnc2ncc(Br)nc12
Temperature: 90 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
To a solution of 3-amino-6-bromopyrazine-2-carboxamide (200 mg, 0.92 mmol) in triethoxymethane (10 mL) was added Ac2O (2 mL). The mixture was stirred at 130° C. for 1 h and 90° C. for 3 h. After being cooled to RT and extracted with EtOAc, the combined organic phases were basified to pH=8 with a.q. NaHCO3, washed with brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by prep-TLC (DCM:MeOH=50:1) to give the product of 6-bromopteridin-4(3H)-one (100 mg, yield: 48%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.59 (s, 1H), 7.89 (s, 1H). MS (M+H)+: 227/229.
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([I:18])=[C:14]([O:19][CH3:20])[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.ClCCl>>[I:18][C:15]1[CH:16]=[CH:17][C:10]2[O:9][C:8]([C:6]([OH:7])=[O:5])=[C:12]([CH3:13])[C:11]=2[C:14]=1[O:19][CH3:20]
Reactant: COc1c(I)ccc2oc(C(=O)OC(C)(C)C)c(C)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(I)ccc2oc(C(=O)O)c(C)c12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100.4 %

Procedure:
To 140 mg (0.36 mmol) of 5-iodo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was added 3 mL of TFA/dichloromethane (1:1) and the solution was stirred at room temperature for 2.5 h. When the reaction was done, the solvents were removed by vacuum and the residue was triturated with hexane/dichloromethane. Filtration of the suspension gave 120 mg (100% yield) of 5-iodo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=2)[S:6][CH:7]=1>Cl>[Cl:1][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:16][CH:17]=2)[S:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2nc(CCl)cs2)cc1
Agent: Cl
Product: O=C(O)c1ccc(-c2nc(CCl)cs2)cc1
Yield: 78.8 %

Procedure:
An aqueous solution of HCl (6N, 200 mL) was added to methyl 4-[4-(chloromethyl)-1,3-thiazol-2-yl]benzoate (20.0 g, 0.075 mol) and refluxed overnight. The reaction mixture was allowed to cool to ambient temperatures and the solid was filtered and then dried in vacuo at 40° C. to give the title compound (15.0 g, 75%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[CH2:12]([N:19]1[CH:27]=[C:26]2[C:21]([CH:22]=[C:23](B3OC(C)(C)C(C)(C)O3)[CH:24]=[CH:25]2)=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:12]([N:19]1[CH:27]=[C:26]2[C:21]([CH:22]=[C:23]([C:2]3[C:10]4[N:5]([NH:6][CH:7]=[N:8][C:9]=4[NH2:11])[CH2:4][CH:3]=3)[CH:24]=[CH:25]2)=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnn2ccc(Br)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC1=C2C(c3ccc4cn(Cc5ccccc5)nc4c3)=CCN2NC=N1
Yield: 37.9 %

Procedure:
A stirred mixture of 5-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.47 mmol), 2-benzyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (188 mg, 0.56 mmol), sodium carbonate (119 mg, 1.13 mmol), N,N-dimethylformamide (4 mL) and water (0.3 mL) was degassed with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (54 mg, 0.04 mmol) was added, and the reaction was irradiated in a microwave reactor at 150° C. for 15 minutes. The reaction mixture was filtered through Celite®, the pad washed with methanol, and the filtrate concentrated in vacuo. The residue was partitioned between dichloromethane and 1N aqueous hydrochloric acid. The dichloromethane extracts were washed with 5% aqueous sodium bicarbonate solution, then brine, dried (anhydrous sodium sulfate); filtered and concentrated in vacuo to afford 61 mg (38% yield) of yellow solid. 1H-NMR (CD2Cl2): δ 8.04 (d, 1 H), 7.86 (s, 1 H), 7.77 (dd, 1 H), 7.75 (d, 1 H), 7.65 (d; 1 H), 7.40-7.32 (m, 5 H), 7.21 (dd, 1 H), 6.77 (d, 1 H), 6.91 (br s, 2 H), 5,61 (s, 2 H). MS: LC/MS (+esi), m/z=341 [M+H]. RT=2.44 min.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:32])([F:33])[F:19])=[CH:26][CH:25]=3)=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)s2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)n2)s1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 02: tR=1.04 min; [M+H]+=420.19.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+].CO.C1C[O:27][CH2:26]C1>>[CH3:26][O:27][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:8])=[CH:5][CH:4]=1
Reactant: C1CCOC1
Reactant: COc1ccccc1NC(=O)c1ccc(CCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCc1ccc(C(=O)Nc2ccccc2OC)cc1
Reaction time: 14 h
Yield: 92.9 %

Procedure:
4-Chloromethyl-N-(2-methoxyphenyl)benzamide (138 mg, 0.50 mmol) was dissolved in a methanol-THF (1:1) mixture solution (6 ml) to which was subsequently added 10% sodium hydroxide aqueous solution (3 ml) at room temperature. After 14 hours of stirring at the same temperature, the reaction solution was subjected to 3 hours of ultrasonic treatment. After removing the organic solvent by evaporation, the resulting residue was extracted with methylene chloride and dried on anhydrous magnesium sulfate. After removing the solvent by evaporation, the resulting colorless oily material was purified by silica gel column chromatography (ether:hexane=1:2) to obtain 126 mg (92.9%) of the title compound in the form of colorless oil.
Reaction SMILES: [H-].[Na+].C[C:4]([CH3:7])([OH:6])C.[NH2:8][CH2:9][CH2:10][C:11]([NH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][N:18]=[C:17]2[NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)=[C:27]([Cl:40])[CH:26]=1)=[O:12]>C1COCC1>[Cl:40][C:27]1[CH:26]=[C:25]([NH:24][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([NH:13][C:11](=[O:12])[CH2:10][CH2:9][NH:8][C:11](=[O:12])[CH2:10][O:6][CH2:4][CH2:7][N:18]([CH3:19])[CH3:17])[CH:15]=3)[N:20]=[CH:19][N:18]=2)[CH:30]=[CH:29][C:28]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1
Reactant: NCCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Reactant: CC(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCOCC(=O)NCCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1

Procedure:
44 mg of sodium hydride (60%, oil suspension) dissolved in 2 ml of THF was reacted with 0.03 ml of dimethylethanol for 30 mins, 100 mg of the compound obtained (20-1) of Example 20 dissolved in 5 ml of THF was added thereto at 0° C., and the resulting solution was reacted for 3 hours while heating to room temperature. The reacted solution was diluted with saturated sodium bicarbonate solution, extracted with chloroform, dried over anhydrous magnesium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-chloroform:methanol=15:1) to obtain the title compound (70 mg, 64%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:5]([C:7](Cl)=[O:8])[N:6]=1.[Br:17][C:18]1[C:26]2[N:25]=[C:24]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]3)[NH:23][C:22]=2[CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>ClCCl>[Br:17][C:18]1[C:26]2[N:25]=[C:24]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][N:29]3[C:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][C:4]=3[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[O:8])[NH:23][C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)Cl)c(-c2ccc(F)cc2)s1
Reactant: Brc1cccc2[nH]c(CC3CCCCN3)nc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc3c(Br)cccc3[nH]2)c(-c2ccc(F)cc2)s1
Yield: 89 %

Procedure:
2-Methyl-5-(4-fluorophenyl)thiazole-4-carbonyl chloride (383 mg, 1.5 mmol) was added portionwise over 5 min. to a stirred solution of (RS)-4-bromo-2-piperidin-2-ylmethyl-1H-benzoimidazole, D39 (400 mg, 1.4 mmol) and triethylamine (0.57 ml, 5.0 mmol) in dichloromethane (20 ml) at room temperature. After 20 h the mixture was washed with saturated sodium hydrogen carbonate. The organic layer was dried (Na2SO4) and the solvent removed in vacuo. Chromatography (silica gel, 10-100% ethyl acetate-hexane then 1-10% methanol-ethyl acetate) afforded the title compound as a pale brown amorphous solid (620 mg, 89%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([CH2:14][OH:15])[CH2:3]1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[S:23]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([CH2:14][O:15][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH2:3]1)([C:20]1[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OS(=O)(=O)c3ccc(C)cc3)CN2C(=O)OC(C)(C)C)cc1
Reaction time: 72 h
Yield: 47.1 %

Procedure:
(2S,4R)-tert-butyl 4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (5.40 g, 25.84 mmol) and 4-methylbenzene-1-sulfonyl chloride (14.22 g, 74.6 mmol) were combined in pyridine (50 mL) at 0° C. and store in the refrigerator for 3 days. The reaction mixture was concentrated to half the volume under vacuo and some water (300 mL) was added slowly. The mixture was stirred 1 h until a white solid formed. The solid was filtered and dried on the pump on high-vacuum over night. The solid was recrystallized from MeOH (˜20 ml) and water (few drops) to afford title compound 204 (6.40 g, 49%). LRMS: (calc) 525.15 (found) 426.4 (MH-Boc)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.I[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C=O>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][N:10]1[C:11]2[C@@:12]3([CH3:22])[C:19]([CH3:21])([CH3:20])[C@H:15]([CH2:14][CH2:13]3)[C:16]=2[C:17](=[O:18])[N:9]1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[CH3:29]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: CCOC(=O)CI
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2c(c(=O)n1-c1ccc(F)cc1F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 39.6 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 256 mg, 0.84 mmol) and ethyl iodoacetate (500 μL, 4.22 mmol) in dimethylformamide (5 mL) was heated at 100° C. for 2 h. The solvent was evaporated, dichloromethane (75 mL) was added and the solution was washed with 1:1 water/aqueous sodium thiosulfate (25 mL). The aqueous layer was back-extracted with dichloromethane (25 mL) and the combined organic layers were washed with brine (25 mL). The solution was dried (magnesium sulfate), filtered, evaporated, purified using an ISCO 12 g column, eluting with 40-100% ethyl acetate/petroleum ether, and dried under high vacuum at 70° C. overnight to give [(4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-3-oxo-2,3,4,5,6,7-hexahydro-4,7-methano-indazol-1-yl]-acetic acid ethyl ester (130 mg, 40%) as a light yellow solid. APCI(+)-MS (M+H) 391.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:29][CH3:30])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][N:21]([CH2:27][CH3:28])[C:22]([CH:24]2[CH2:26][CH2:25]2)=[O:23])[CH:9]=1)#[N:2].C(=O)([O-])[O-:32].[K+].[K+].OO>CS(C)=O>[C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:29][CH3:30])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:12][C:11]=2[CH2:20][N:21]([CH2:27][CH3:28])[C:22]([CH:24]2[CH2:25][CH2:26]2)=[O:23])[CH:9]=1)(=[O:32])[NH2:2]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC#N)ccc1OC)C(=O)C1CC1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(N)=O)ccc1OC)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of cyclopropanecarboxylic acid (5′-cyanomethyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-ethyl-amide (0.064 g, 0.15 mmol) and potassium carbonate (0.064 g, 0.46 mmol) in DMSO (1 mL) at 0° C. was added hydrogen peroxide (30%; 0.44 mL), and the reaction was warmed to room temperature and stirred for 3 hours. The mixture was partitioned between EtOAc and aqueous Na2S2O4, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound. M+H is 435.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.FC(F)(F)C(O)=O.[CH3:26][S:27]([N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1)(=[O:29])=[O:28]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[O:9])=[CH:6][CH:5]=[C:4]([NH:36][CH:33]2[CH2:34][CH2:35][N:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:31][CH2:32]2)[N:3]=1
Reactant: COc1cccc(C(=O)c2ccc(Cl)nc2N)c1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(C(=O)c2ccc(NC3CCN(S(C)(=O)=O)CC3)nc2N)c1

Procedure:
The title compound was prepared from (2-Amino-6-chloro-pyridin-3-yl)-(3-methoxy-phenyl)-methanone (Example 17) and 1-methanesulfonyl-piperidin-4-ylamine (Step A, Example 6) using the procedure described in Step B. Example 6. HRMS, 405.1595 observed:, Calcd for (M+H)+: 405.1591.