Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:8]1.C([O:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30]([CH2:32]Br)[CH:29]=[CH:28][C:27]=1[O:34][CH3:35])C>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:32][C:30]3[CH:29]=[CH:28][C:27]([O:34][CH3:35])=[C:26]([CH:31]=3)[C:25]([OH:36])=[O:24])[CH2:18][CH2:17]2)=[CH:8]1
Reactant: c1coc(Cn2cc(C3CCNCC3)c3ccccc32)c1
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Product: COc1ccc(CN2CCC(c3cn(Cc4ccco4)c4ccccc34)CC2)cc1C(=O)O

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 1.9 g (6.5 mmol) of 1-furan-2-ylmethyl-3-piperidin-4-yl-1H-indole (example 83, part B) and 1.9 g (7.1 mmol) of 5-bromomethyl-2-methoxy-benzoic acid ethyl ester. After standard work-up and recrystallisation with ethanol, 0.5 g (16% of yield) of the expected acid were obtained.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([OH:19])[CH:5]=2.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.[CH3:39][N:40]([CH3:45])[CH2:41][CH2:42][CH2:43]O>>[CH3:39][N:40]([CH3:45])[CH2:41][CH2:42][CH2:43][O:19][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([C:11]3[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([F:17])[CH:16]=3)=[C:2]([Br:1])[C:3]2=[O:20])=[CH:8][CH:7]=1
Reactant: CN(C)CCCO
Reactant: O=C1C(Br)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Product: CN(C)CCCOc1ccc2c(c1)C(=O)C(Br)=C2c1cc(F)cc(F)c1
Reaction time: 96 h
Yield: 86 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-hydroxy-1H-inden-1-one obtained in Step 5 of Example 36 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, 3-(dimethylamino)propanol instead of 4-(2-hydroxyethyl)morpholine, being stirred for 4 d, and being purified by silica gel column chromatography (CH2Cl2/EtOAc=1:1) to obtain the title compound (86%).
Reaction SMILES: [CH2:1]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:38](#[N:41])[CH:39]=[CH2:40]>>[CH2:20]([N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:40][CH2:39][C:38]#[N:41])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Reactant: C=CC#N
Product: CCCCCCCCCCCCCCCCCCN(CCC#N)CCCCCCCCCCCCCCCCCC

Procedure:
3-(Dioctadecylamino)propionitrile is prepared by refluxing a mixture of dioctadecylamine (200 g.) and acrylonitrile (1903.8 ml.) for eighteen hours. The mixture is then concentrated to a waxy semi-solid which is slurried in acetone, filtered, and air dried overnight.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17](CC#N)=[CH:16][CH:15]=2)=[C:4]([CH3:23])[N:3]=1.[C:24]([OH:27])(=[O:26])[CH3:25]>CO.[OH-].[K+].O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:25][C:24]([OH:27])=[O:26])=[CH:18][CH:19]=2)=[C:4]([CH3:23])[N:3]=1
Reactant: CC(=O)O
Reactant: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1

Procedure:
The product from step (v) in MeOH (10 ml) and 5M KOH in water (3 ml) was heated under reflux for 18 h. The mixture was neutralised with acetic acid then purified by RPHPLC to afford the subtitle compound, 0.168 g.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH3:15][O:16][CH2:17][CH2:18][CH2:19]N>>[CH3:15][O:16][CH2:17][CH2:18][CH2:19][NH:1][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: COCCCN
Product: COCCCNc1cccc([N+](=O)[O-])c1C#N
Yield: 83 %

Procedure:
Prepared as in Example 90c from 2,6-dinitrobenzonitrile and 3-methoxypropylamine in 83% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.76-1.81 (m, 2H), 3.23 (s, 3H), 3.28-3.33 (m, 2H), 3.40 (t, J=5.6 Hz, 2H), 6.66 (t, J=4.8 Hz, NH), 7.30 (d, J=8.8 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.60 (t, J=8.0 Hz, 1H).
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.[Br:6][C:7]1[CH:25]=[CH:24][C:10]([O:11][CH:12]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH:13]([OH:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=1.C(N(CC)CC)C>C1COCC1>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][CH:12]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH:13]([O:18][Si:2]([CH3:5])([CH3:4])[CH3:1])[C:14]([CH3:16])([CH3:17])[CH3:15])=[CH:24][CH:25]=1
Reactant: CC(C)(C)C(O)C(Oc1ccc(Br)cc1)n1cncn1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)C(O[Si](C)(C)C)C(Oc1ccc(Br)cc1)n1cncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
At 0° C., a solution of 8.5 g of trimethylchlorosilane in 20 ml of THF is dripped into a solution of 3.4 g of 1-p-bromophenoxy-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-ol and 1.5 g of triethylamine in 40 ml of tetrahydrofuran. The mixture is stirred overnight at room temperature and evaporated, and the residue is taken up in CHCl3, washed several times with water and dried over Na2SO4. After evaporation, the crude product is chromatographed (SiO2, CHCl3). There is obtained 2 g of 1-p-bromophenoxy-3,3-dimethyl-2-trimethylsiloxy-1-(1,2,4-triazol-1-yl)-butane as a colorless resin.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.C(OC([NH:28][CH2:29][C:30]1([CH3:35])[CH2:34][CH2:33][NH:32][CH2:31]1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[NH2:28][CH2:29][C:30]1([CH3:35])[CH2:34][CH2:33][N:32]([C:11]2[CH:12]=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([CH3:16])[C:10]=2[F:15])[CH2:31]1
Reactant: CC1(CNC(=O)OC(C)(C)C)CCNC1
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(F)c(N2CCC(C)(CN)C2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
A mixture of 0.61 g (2.18 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.56 g (2.61 mmol) of 3-[(t-butoxycarbonyl)aminomethyl]-3-methylpyrrolidine, 0.66 g (6.54 mmol) of triethylamine, and 25 ml of acetonitrile was refluxed for six hours, then stirred overnight at room temperature. The precipitate was filtered and washed with acetonitrile and ether. The crude product was suspended in 20 ml of 6N hydrochloric acid and 20 ml of glacial acetic acid and was stirred at room temperature for three hours. The solution was concentrated and the residue was triturated with ether. The solid was filtered and washed with ether to give 0.61 g of the title compound as the hydrochloride, mp 250°-252° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:9]([F:12])([F:11])[F:10])([C:5]([F:8])([F:7])[F:6])[O-:4].[Li+].[S:16](F)([F:19])([F:18])[F:17]>C(OCCCC)CCC>[F:1][C:2]([F:13])([F:14])[C:3]([C:5]([F:8])([F:7])[F:6])([C:9]([F:11])([F:12])[F:10])[O:4][S:16]([F:19])([F:18])[F:17]
Reactant: [O-]C(C(F)(F)F)(C(F)(F)F)C(F)(F)F
Reactant: FS(F)(F)F
Agent: [Li+]
Solvent: CCCCOCCCC
Product: FC(F)(F)C(OS(F)(F)F)(C(F)(F)F)C(F)(F)F
Temperature: -70 °C
Yield: 20.9 %

Procedure:
A solution of 10.5 g (0.043 mol) of lithium 2,2,2-trifluoro-1,1-bis(trifluoromethyl)ethoxide in 60 ml of dibutyl ether was added dropwise to a solution of 8 ml (measured at -78° C., 0.15 mol) of sulfur tetrafluoride in 50 ml of dibutyl ether cooled to -70° C. The reaction mixture was warmed to 25° C., and the volatiles were distilled out at reduced pressure and condensed in a cold trap at -78° C. The condensate was fractionated to give (A) 2.91 g of 2,2,2-trifluoro-1,1-bis(trifluoromethyl)ethoxysulfur trifluoride as a colorless liquid: bp 56° to 60°; 19F NMR (CCl3F) δ -71.4 ppm (q, J=3.0 Hz, 9F) and 44.0 ppm (broad, 3F) and (B) 3.60 g of bis[2,2,2-trifluoro-1,1-(trifluoromethy)ethoxy]sulfur difluoride as a colorless liquid: bp 35° to 37° C. (20 mm); 19F NMR (CCl3F) δ -71.7 ppm (t, J=1.5 Hz), 18F) and +32.1 ppm (broad, 2F).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[N+:16]([O-])([OH:18])=[O:17].Cl>CC(OC(C)=O)=O.CC(O)=O>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[C:12]([N+:16]([O-:18])=[O:17])[CH:13]=2)[CH2:6][CH2:7]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(OC)cc2)CC1
Reactant: O=[N+]([O-])O
Agent: Cl
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C1(c2ccc(OC)c([N+](=O)[O-])c2)CC1
Yield: 98.1 %

Procedure:
To a solution of 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (30.0 g, 146 mmol) in Ac2O (300 mL) was added a solution of HNO3 (14.1 g, 146 mmol, 65%) in AcOH (75 mL) at 0° C. The reaction mixture was stirred at 0˜5° C. for 3 h before aq. HCl (20%) was added dropwise at 0° C. The resulting mixture was extracted with EtOAc (200 mL×3). The organic layer was washed with sat. aq. NaHCO3 then brine, dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-(4-methoxy-3-nitro-phenyl)-cyclopropanecarboxylic acid methyl ester (36.0 g, 98%), which was directly used in the next step. 1H NMR (CDCl3, 300 MHz) δ 7.84 (d, J=2.1 Hz, 1H), 7.54 (dd, J=2.1, 8.7 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 3.97 (s, 3H), 3.65 (s, 3H), 1.68-1.64 (m, 2H), 1.22-1.18 (m, 2H).
Reaction SMILES: S(O)(=O)(=O)C.[NH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9]([SH:14])[N:8]=1.[H-].[Na+].Cl[CH:18]([C:20]1[N:21]=[CH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:19].O>CN(C)C=O>[NH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9]([S:14][CH:18]([C:20]2[N:21]=[CH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:19])[N:8]=1
Reactant: CC(Cl)c1cc2ccccc2cn1
Reactant: Nc1cc(Cl)nc(S)n1
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Sc1nc(N)cc(Cl)n1)c1cc2ccccc2cn1
Reaction time: 1 h
Yield: 57.3 %

Procedure:
4-Amino-6-chloro-2-mercapto-pyrimidine mesylate salt (1.79 g, 6.94 mmole) is dissolved in 12 ml dry dimethylformamide in a 50 ml one neck round bottom flask under nitrogen. The solution is treated with 60% sodium hydride (605 mg, 15.1 mmole) (exotherm) and the mixture is stirred one hour. 3-(1-chloroethyl)-isoquinoline (1.33 g, 6.94 mmole) in 2×3 ml dry dimethylformamide, is added to the reaction and the mixture is stirred 6 hours at room temperature. The reaction mixture is poured into 300 ml water and is extracted with 3×100 ml ethyl acetate. The combined organics are backwashed with 4×50 ml 50% saturated sodium chloride. The organics are dried over potassium carbonate and are concentrated in vacuo to a yellow oil. The crude material is chromatographed over 75 g silica gel (230-400 mesh), eluting with 40% acetone/hexane while collecting 9 ml fractions. Fractions 26-39 are combined and concentrated to afford 1.26 g (57%) of 4-Amino-6-chloro-2-(1-(3-isoquinolyl)ethyl)thio-pyrimidine as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[NH:7][C:8](=[N:23][C:24](=[O:41])[CH2:25][C:26]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH:39]=[CH2:40])=[CH:33][CH:32]=1)=[N:27][O:28][CH2:29][CH3:30])[CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:18](=[O:21])[CH2:19]Br)=[C:12]([Cl:22])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:43]([NH2:46])[CH:44]=[CH2:45]>ClCCl>[C:1]([O:5][C:6](=[O:42])[NH:7][C:8](=[N:23][C:24](=[O:41])[CH2:25][C:26]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH:39]=[CH2:40])=[CH:33][CH:32]=1)=[N:27][O:28][CH2:29][CH3:30])[CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:18](=[O:21])[CH2:19][NH:46][CH2:43][CH:44]=[CH2:45])=[C:12]([Cl:22])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCN
Reactant: C=CCOc1ccc(C(CC(=O)N=C(Cc2cc(Cl)c(NC(=O)CBr)c(Cl)c2)NC(=O)OC(C)(C)C)=NOCC)cc1
Solvent: ClCCl
Product: C=CCNCC(=O)Nc1c(Cl)cc(CC(=NC(=O)CC(=NOCC)c2ccc(OCC=C)cc2)NC(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl-1-(3-(4-(allyloxy)phenyl)-3-(ethoxyimino)-propanoylimino)-2-(4-(2-bromoacetamido)-3,5-dichlorophenyl)ethylcarbamate (100 mg) in dichloromethane (0.30 mL) at room temperature was added allylamine (32 μL), and the resulting solution was stirred at room temperature for 2 h. The solvents were removed in vacuo to give the title compound as a white solid, which was used in Step H without purification. retention time: 2.07 min (method A). MS (ESI) (M+H)+ 675.20.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]2[C:19]([CH2:25][CH3:26])([C:22]([OH:24])=O)[CH2:20][CH2:21][C:15]2=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32](=[O:44])[NH:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([CH2:42][NH2:43])=[CH:38][CH:37]=1)=[NH:35])([CH3:30])([CH3:29])[CH3:28]>>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]1[C:17](=[O:18])[N:16]2[C:19]([C:22](=[O:24])[NH:43][CH2:42][C:39]3[CH:40]=[CH:41][C:36]([C:34]([NH:33][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:44])=[NH:35])=[CH:37][CH:38]=3)([CH2:25][CH3:26])[CH2:20][CH2:21][C:15]2=[N:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC1(C(=O)O)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CN)cc1
Product: CCC1(C(=O)NCc2ccc(C(=N)NC(=O)OC(C)(C)C)cc2)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Yield: 100 %

Procedure:
According to the procedure for the preparation of intermediate 19c, intermediate 22b (34.5 mg, 0.0965 mmol) was coupled with [(4-aminomethyl-phenyl)-imino-methyl]-carbamic acid tert-butyl ester to afford 57 mg (100%) of intermediate 22c.
Reaction SMILES: [C:1]1([CH2:7][C:8](O)=[O:9])[CH2:6][CH:5]=[CH:4][CH2:3][CH:2]=1.Cl.[C:12]1([C:18]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:26]3[CH:22]([CH2:23][NH:24][CH2:25]3)[C:21](=[O:27])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[C:1]1([CH2:7][C:8]([CH:25]2[CH:26]3[CH:22]([C:21](=[O:27])[CH2:20][CH2:19][C:18]3([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23][NH:24]2)=[O:9])[CH2:6][CH:5]=[CH:4][CH2:3][CH:2]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: O=C(O)CC1=CCC=CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2C1CNC2C(=O)CC1=CCC=CC1
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
N,N'-Carbonyldiimidazole (3.6 g) is added to a solution of (cyclohexa-1,4-dien-1-yl)acetic acid (2.35 g) in dry dichloromethane (50 cc), cooled to +5° C. The mixture is stirred for 30 minutes at +5° C. and a solution of 7,7-diphenyl-4-perhydroisoindolone hydrochloride (6.55 g) and triethylamine (5.6 cc) in dichloromethane (30 cc) is then added. The reaction mixture is stirred for 1 hour at +5° C. and then for 16 hours at 20° C. and is washed with normal hydrochloric acid (150 cc) and an aqueous saturated sodium chloride solution (150 cc). The organic phase is dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.2-0.063 mm, diameter 6 cm, height 30 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture (3 liters) of cyclohexane and ethyl acetate (50/50) and then with ethyl acetate (2 liters) and collecting 100 cc fractions. Fractions 10 to 48 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from acetonitrile (15 cc). The crystals are drained, washed with acetonitrile (5 cc) and isopropyl ether (25 cc) and dried. (3aRS,7aRS)-2-(cyclohexa-1,4-dien-1-yl)-acetyl-7,7-diphenyl-4-perhydroisoindolone (5.7 g) is obtained. m.p.=186° C.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](/[CH:12]=[CH:13]/[C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)=[N:8][NH:9]2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].C1COCC1>CO>[C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](/[CH:12]=[CH:13]/[C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[N:8][NH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(/C=C/c2n[nH]c3cc(C#N)ccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccc2c(/C=C/c3ccc(C(=O)O)cc3)n[nH]c2c1
Temperature: 25 °C

Procedure:
To a round bottom flash containing (E)-methyl 4-(2-(6-cyano-1H-indazol-3-yl)vinyl)benzoate (606 mg, 2 mmol) was added 2 M NaOH (20 mL, 40 mmol), followed by THF (10 mL) and MeOH (10 mL). The resulting mixture was stirred O/N at rt. After removal of THF and MeOH via rotavap, the residue was cooled to 0° C. and treated with 2 M HCl (25 mL) and stirred for 2 min at that temp. The precipitates collected by suction filtration were rinsed with H2O to give crude (E)-4-(2-(6-cyano-1H-indazol-3-yl)vinyl)benzoic acid as a brown red solid. It was redissolved in HOAc/pyridine/DMF (4 mL/8 mL/6 mL) and a solution of NaH2PO2 (704 mg, 8 mmol) in H2O (4 mL) was added, followed by Raney-Nickel 2400 (slurry in H2O, 0.4 mL). The resulting mixture was heated for 1 h at 55° C. (oil temp.). Usual aqueous workup, followed by trituration with H2O gave the title compound (332 mg, 54%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 13.81 (s, 1H), 12.90 (s, br, 1H), 10.14 (s, 1H), 8.39 (d, J=8.0 Hz, 1H), 8.19 (s, 1H), 7.96 (d, J=8.0 Hz, 2H), 7.86 (d, J=8.0 Hz, 2H), 7.76 (d, J=16.8 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.64 (d, J=16.4 Hz, 1H); MS ESI 293.0 [M+H]+, calcd for [C17H12N2O3+H]+ 293.1.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([O:17]CC)=O)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[NH2:24][NH2:25]>C(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:24][NH2:25])=[O:17])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: CCOC(=O)CN1CCN(Cc2ccc(C(F)(F)F)cc2)CC1
Solvent: CCO
Product: NNC(=O)CN1CCN(Cc2ccc(C(F)(F)F)cc2)CC1

Procedure:
Synthesized according to General Procedure C: 6{15} (4.76 g, 14.4 mmol, 1 equiv.), anhydrous hydrazine (1.4 mL, 43.2 mmol, 3 equiv.), ethanol (28.9 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{15} (3.70 g, 81%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 8.13 (br s, 1H), 7.55 (d, 2H, J=8.0 Hz), 7.41 (d, 2H, J=8.0 Hz), 3.84 (br s, 2H), 3.53 (s, 2H), 3.07 (s, 2H), 2.53 (br s, 4H), 2.45 (br s, 4H). 13C-NMR (125 MHz, CDCl3): δ 170.3, 142.2, 129.3 (q, JC-F=32.0 Hz), 129.0, 125.1 (q, JC-F=3.8 Hz), 19624.1 (q, JC-F=270.5 Hz) 129.1, 62.2, 60.5, 53.6, 53.0. 19F-NMR (470 MHz, CDCl3): δ-62.8.
Reaction SMILES: [C:1]([O:6][C:7]1([CH2:17][CH3:18])[CH:14]2[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:16][CH:8]1[CH2:9]3)[CH2:13]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:19]([O:23][C:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][C:26]([OH:34])([CH2:27]3)[CH2:25]1)[CH2:31]2)(=[O:22])[CH:20]=[CH2:21].[C:35]([O:40][CH:41]1[CH2:46][CH2:45][O:44][C:42]1=[O:43])(=[O:39])[C:36]([CH3:38])=[CH2:37].N(C(C)(C)C#N)=NC(C)(C)C#N>CCCCCCC.C(C(C)=O)C(C)C>[C:1]([O:6][C:7]1([CH2:17][CH3:18])[CH:8]2[CH2:16][CH:12]3[CH2:11][CH:10]([CH2:15][CH:14]1[CH2:13]3)[CH2:9]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:19]([O:23][C:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][C:26]([OH:34])([CH2:27]3)[CH2:25]1)[CH2:31]2)(=[O:22])[C:20]([CH3:35])=[CH2:21].[C:35]([O:40][CH:41]1[CH2:46][CH2:45][O:44][C:42]1=[O:43])(=[O:39])[C:36]([CH3:38])=[CH2:37]
Reactant: C=CC(=O)OC12CC3CC(CC(O)(C3)C1)C2
Agent: C=C(C)C(=O)OC1(CC)C2CC3CC(C2)CC1C3
Agent: C=C(C)C(=O)OC1CCOC1=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCCC
Solvent: CC(=O)CC(C)C
Product: C=C(C)C(=O)OC12CC3CC(CC(O)(C3)C1)C2
Temperature: 85 °C
Reaction time: 5 h
Yield: 60 %

Procedure:
2-ethyl-2-adamantyl methacrylate, 3-hydroxy-1-adamantyl acrylate and α-methacryloyloxy-γ-butyrolactone were charged in a molar ratio of 2:1:1 (20.0 g:8.9 g:6.5 g), and methyl isobutyl ketone of twice weight of the total monomer weight was added to this to prepare a solution. To this was added azobisisobutyronitrile as an initiator in an amount of 2 mol % based on the total monomer amount, and the temperature was raised to 85° C. and the mixture was stirred for about 5 hours. The reaction mass was cooled, then, poured into a large amount of heptane, to cause precipitation; this operation Was repeated three times for purification. As a result, a copolymer having a weight-average molecular weight of about 8000 was obtained in a yield of 60%. This resin is called Resin AX.
Reaction SMILES: [CH:1]1([CH:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C@@H:11]2[C@H:18]3[C@H:14]([CH2:15][NH:16][CH2:17]3)[CH2:13][CH2:12]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:32][C:33]([F:45])([F:44])[C:34]1[CH:35]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1>ClCCl>[CH:19]1([CH:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]([NH:10][C@@H:11]2[C@H:18]3[C@H:14]([CH2:15][N:16]([S:40]([C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([C:33]([F:32])([F:44])[F:45])[CH:35]=4)(=[O:42])=[O:41])[CH2:17]3)[CH2:13][CH2:12]2)=[O:9])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21)C(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,2-Dicyclohexyl-N-((3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl)acetamide from Example 53 (101 mg, 0.304 mmol), triethylamine (0.042 mL, 0.304 mmol), and 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.049 mL, 0.304 mmol) were combined in dichloromethane (2 mL). A catalytic amount of N,N-dimethylaminopyridine was added. The reaction was stirred at room temperature for 1 hour, LCMS showed product, and TLC showed no more starting material. The reaction was quenched with aqueous sodium bicarbonate and the aqueous layer was separated. The organic layers was concentrated to give a precipitate. The precipitate was washed with water and ether and dried under a stream of nitrogen to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.49 (d, J=6.3, 1H), 8.34 (s, 1H), 8.19 (d, J=7.9, 1H), 7.93 (d, J=7.8, 1H), 7.73 (t, J=7.8, 1H), 4.46-4.38 (m, 1H), 3.73 (dd, J=3.4, 9.3, 1H), 3.17 (dd, J=2.8, 9.7, 1H), 3.07 (ddd, J=6.4, 12.0, 23.6, 3H), 2.49 (dd, J=8.0, 15.9, 1H), 2.12 (t, J=7.2, 1H), 2.02-1.77 (m, 8H), 1.73 (dd, J=5.3, 9.0, 4H), 1.68-1.58 (m, 3H), 1.52 (ddd, J=3.2, 12.5, 14.7, 1H), 1.43 (ddd, J=3.1, 12.6, 15.0, 1H), 1.37-1.03 (m, 9H); MS (ESI+) m/z 541 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[S:3]([O:6][C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[N:8]=1)(=[O:5])=[O:4].[Cl:28]N1C(=O)CCC1=O.O>CN(C=O)C>[F:27][C:2]([F:26])([F:1])[S:3]([O:6][C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[C:15]([Cl:28])[C:10]=2[N:9]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[N:8]=1)(=[O:5])=[O:4]
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncc(Cl)c2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
Temperature: 50 °C
Yield: 47.8 %

Procedure:
To a solution (10 mL) of 1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (500 mg) obtained in Step C of Example 35 in DMF was added N-chlorosuccinimide (215 mg) at room temperature. The reaction mixture was heated at 50° C. for 21 hr, and the mixture was allowed to be cooled to room temperature. To the reaction mixture was added water under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (259 mg).