Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:23]I>C1COCC1.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([O:20][CH3:23])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2)CC1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 66.7 %

Procedure:
4-Hydroxy-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.8 mmol) was dissolved in dry THF (15 mL) and sodium hydride (60% disp. in mineral oil; 0.076 g, 1.9 mmol) added and the mixture stirred for 1 hour. Methyl iodide (0.16 mL; 2.7 mmol) was then added and the mixture stirred overnight. Brine was added and the product extracted into ethyl acetate, dried over sodium sulphate, filtered and the solvent removed by evaporation. The residue was purified by flash chromatography on silica eluting with 0-10% ethyl acetate/hexane. The fractions containing the desired product were concentrated under vacuum to give the title compound as a clear colourless oil (0.35 g).
Reaction SMILES: C([N:8]([CH2:25][C@@H:26]1[CH2:30][C@@H:29]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:28][N:27]1C([O-])=O)[CH2:9][C:10](=O)[CH:11](C1C=CC=CC=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C1C=CC=CC=1.[C:42](O)(=O)[CH3:43]>CO.[Pd]>[CH:11]([CH:10]1[N:27]2[CH2:28][C@H:29]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:30][C@H:26]2[CH2:25][NH:8][CH2:9]1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:43]1[CH:42]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)O
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CN(CC(=O)C(c2ccccc2)c2ccccc2)Cc2ccccc2)N(C(=O)[O-])C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H]2CNCC(C(c3ccccc3)c3ccccc3)N2C1
Yield: 227.3 %

Procedure:
A solution of (2S,4R)-2-[[N-benzyl-N-(2-oxo-3,3-diphenylpropyl)amino]methyl]-4-[(tert-butyldimethylsilyl)oxy]-1-pyrrolidinecarboxylate (4.82 g) and acetic acid (0.87 g) in methanol (100 ml) was hydrogenated over 10% palladium-charcoal (50% wet, 1.0 g) at room temperature under 2-3 atoms for 15 hours. After removal of the catalyst by filtration, the filtrate was evaporated under reduced pressure to give bis(acetic acid) salt of (7R,8aS)-4-benzhydryl-7-[(tert-butyldimethylsilyl)oxy]octahydropyrrolo[1,2-a]pyrazine (4.05 g) as a syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([NH2:8])[CH:7]=1.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[S:19](Cl)(=[O:21])=[O:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([NH:8][S:19]([C:13]2[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=2[F:11])(=[O:21])=[O:20])[CH:7]=1
Reactant: CSc1ccc(Cl)cc1N
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Product: CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(F)cc1F
Yield: 93.9 %

Procedure:
Following General Procedure B, the title compound (358 mg, 94%) was prepared from 5-chloro-2-methylsulfanyl-phenylamine (189 mg, 1.09 mmol) and 2,4-Difluoro-benzenesulfonyl chloride (231 mg, 1.09 mmol).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:8]([CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH:6]=[CH:5][CH2:4]1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24]([O:1][CH2:2][C@H:3]2[C@@H:8]([CH2:9][O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][CH:6]=[CH:5][CH2:4]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: OC[C@@H]1CC=CC[C@@H]1COCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CC=CC[C@@H]2COCc2ccccc2)cc1
Reaction time: 8 h
Yield: 84.2 %

Procedure:
The alcohol/benzyl ether (2) (10 g) in 20 ml of dry pyridine is added slowly at 0° C. to p-toluenesulphonyl chloride (10.4 g) in pyridine (60 ml). The mixture is kept overnight at room temperature and is then quenched by pouring over crushed ice with vigorous shaking. The product is extracted with ether, washed consecutively with water, 0.1M sodium carbonate and brine, dried (MgSO4), and concentrated in vacuo at room temperature. The crude product is purified on a silica gel column, eluting with benzene-ethyl acetate (95%: 5% v/v) to give the title compound (14 g, 90%). The i.r. spectrum shows the absence of a hydroxyl group.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:5]=2[N:6]=1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:11][C:7]1[C:5]2[N:6]=[C:2]([CH3:1])[O:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1nc2c([N+](=O)[O-])cccc2o1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1nc2c(N)cccc2o1
Temperature: 65 °C
Reaction time: 3 h
Yield: 69.1 %

Procedure:
Compound 474A (6.78 g, 38.1 mmol) was dissolved in a 1:1 mixture of 10% acetic acid/ethyl acetate (100 mL total volume) and heated to 65° C. Iron powder (10.63 g, 190.2 mmol) was added portionwise. After stirring for 3 h, TLC indicated complete consumption of starting material. The cooled reaction mixture was filtered through a pad of Celite and the pad was washed with 50 mL of ethyl acetate. The organic layer was separated, washed with water (2×25 mL), brine (1×25 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel eluting with 25% ether/CH2Cl2 to give 3.90 g (69%) of compound 474B as a light brown solid. HPLC: 95.8% at 2.43 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 149.11 [M+H]+.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16]2[CH:17]=[C:18]([C:21]3[C:22]4[CH:49]=[C:48]([Cl:50])[CH:47]=[CH:46][C:23]=4[N:24]([CH2:37][C:38]4[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=4)[C:25](=[O:36])[C@H:26]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[Cl:35])[N:27]=3)[CH:19]=[CH:20][C:15]=2[NH:14][C:13]1=[O:51])(C(C)(C)C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:50][C:48]1[CH:47]=[CH:46][C:23]2[N:24]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=3)[C:25](=[O:36])[C@H:26]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[N:27]=[C:21]([C:18]3[CH:19]=[CH:20][C:15]4[NH:14][C:13](=[O:51])[N:12]([CH2:11][CH2:10][CH2:9][OH:8])[C:16]=4[CH:17]=3)[C:22]=2[CH:49]=1
Reactant: COc1ccc(CN2C(=O)[C@H](Cc3ccccc3Cl)N=C(c3ccc4[nH]c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c4c3)c3cc(Cl)ccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN2C(=O)[C@H](Cc3ccccc3Cl)N=C(c3ccc4[nH]c(=O)n(CCCO)c4c3)c3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(S)-5-(3-(3-((tert-Butyldimethylsilyl)oxy)propyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-7-chloro-3-(2-chlorobenzyl)-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (100 mg, 0.134 mmol) was dissolved in DCM (˜10 mL) and treated with 0.5 mL trifluoroacetic acid. After 1.5 hr, the reaction was ˜30% complete by TLC. Another 0.5 mL trifluoroacetic acid was added. After another 1.5 hr, another 0.5 mL trifluoroacetic acid was added. This mixture was allowed to stir at room temperature overnight. It was still mostly starting material by TLC. The solvent was evaporated and azeotroped 3× from DCM. 4 M HCl in 1,4-dioxane (3 mL) was added. This mixture was stirred at RT under nitrogen for 1 hr. TLC (quenched in Et3N-DCM) showed all starting material had converted. The solvent was evaporated to give the title compound as a yellow oil, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[S:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:4][CH:3]=1.[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32]Cl)[CH3:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[S:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:32][CH2:31][CH2:30][N:29]([CH2:34][CH3:35])[CH2:27][CH3:28])=[CH:24][CH:25]=2)(=[O:19])=[O:18])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(O)cc1)c1oc2ccccc2c1-c1ccc(Cl)cc1
Reactant: CCN(CC)CCCCl
Product: CCN(CC)CCCOc1ccc(S(=O)(=O)c2oc3ccccc3c2-c2ccc(Cl)cc2)cc1

Procedure:
Reaction of 3-(4-chlorophenyl)-2-(4-hydroxyphenylsulfonyl)benzofuran with 3-diethylaminopropyl chloride by the method described in Example 1 gives the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8](OC)=[O:9])[C:5]([O:12][CH3:13])=[N:4][CH:3]=1.[NH3:14]>CO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH2:14])=[O:9])[C:5]([O:12][CH3:13])=[N:4][CH:3]=1
Reactant: N
Reactant: COC(=O)c1nc(N)cnc1OC
Solvent: CO
Product: COc1ncc(N)nc1C(N)=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
In 70 mL of methanol is dissolved 3.50 g of methyl 6-amino-3-methoxy-2-pyrazinecarboxylate. Gaseous ammonia is introduced to saturate the solution with ammonia. The solution is stirred at ambient temperature for 14 hours. The solvent is distilled off from the reaction mixture under reduced pressure to obtain 3.1 g of 6-amino-3-methoxy-2-pyrazinecarboxamide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]1([C:26]2[NH:27][C:28]3[C:33]([C:34]=2[CH3:35])=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:18][CH2:17][C:16]([N:23]([CH3:25])[CH3:24])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:14]1.[C:36]1([N:42]=[C:43]=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(#N)C.[OH-].[Na+]>[CH2:19]([C:16]1([N:23]([CH3:25])[CH3:24])[CH2:17][CH2:18][C:13]([C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH2:3][CH2:2][NH:1][C:43]([NH:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:44])=[CH:11][CH:10]=[CH:9][CH:8]=3)([C:26]2[NH:27][C:28]3[C:33]([C:34]=2[CH3:35])=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:14][CH2:15]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCC1(N(C)C)CCC(c2[nH]c3ccccc3c2C)(c2[nH]c3ccccc3c2CCN)CC1
Reactant: O=C=Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCC1(N(C)C)CCC(c2[nH]c3ccccc3c2C)(c2[nH]c3ccccc3c2CCNC(=O)Nc2ccccc2)CC1

Procedure:
4-(3-(2-aminoethyl)-1H-indol-2-yl)-1-butyl-N,N-dimethyl-4-(3-methyl-1H-indol-2-yl)cyclohexylamine (120 mg, 0.255 mmol, mixture of the two possible diastereoisomers in a ratio of approx. 30:70) was mixed in acetonitrile (2.4 ml) with phenyl isocyanate (0.042 ml, 0.386 mmol). After a reaction time of 2 h at 24° C. the reaction mixture was diluted with 1N sodium hydroxide solution (20 ml) and extracted with dichloromethane (4×10 ml). The combined organic phases were dried with Na2SO4 and then filtered. The volatile constituents of the filtrate were completely removed in a vacuum. The residue (yellow solid, 150 mg) was purified by column chromatography [silica gel 60 (25 g); cyclohexane/ethyl acetate 2:1 (300 ml), ethyl acetate/methanol 1:1 (300 ml]. The product was obtained as a white solid with a yield of 115 mg (76%) (melting point 115-120° C., mixture of the two possible diastereoisomers in a ratio of approx. 25:75).
Reaction SMILES: C([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C:19]1([O:45][CH2:44][C@H:31]([O:32][CH2:33][P:34]([O:40][CH:41]([CH3:43])[CH3:42])([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[C@H:21]1[O:22]C(=O)C1C=CC=CC=1)[OH:20])(=O)C1C=CC=CC=1.N>CO>[N:18]1[C:10]([NH2:9])=[C:11]2[C:15]([N:14]([C:19]3([O:45][CH2:44][C@H:31]([O:32][CH2:33][P:34]([O:40][CH:41]([CH3:43])[CH3:42])([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[C@H:21]3[OH:22])[OH:20])[CH:13]=[N:12]2)=[N:16][CH:17]=1
Reactant: CC(C)OP(=O)(CO[C@H]1COC(O)(n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@@H]1OC(=O)c1ccccc1)OC(C)C
Agent: N
Solvent: CO
Product: CC(C)OP(=O)(CO[C@H]1COC(O)(n2cnc3c(N)ncnc32)[C@@H]1O)OC(C)C
Yield: 83.8 %

Procedure:
A solution of 11 (431 mg, 0.80 mmol) in MeOH saturated with ammonia (100 mL) was stirred at room temperature overnight. The mixture was concentrated, and the residue was purified by column chromatography (CH2Cl2:MeOH=9:1) to give compound 15 (278 mg, 0.67 mmol) as a white powder in 84% yield which was characterized as follows:
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2].Cl[C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([C:30]4([OH:34])[CH2:33][O:32][CH2:31]4)[CH2:26][CH2:25]3)[N:19]2[CH3:22])=[C:15]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:14]=1>>[CH2:1]([C:3]1[N:4]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[C:18]([CH2:23][N:24]4[CH2:25][CH2:26][CH:27]([C:30]5([OH:34])[CH2:33][O:32][CH2:31]5)[CH2:28][CH2:29]4)[N:19]3[CH3:22])=[C:15]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:14]=2)[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCC(C3(O)COC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C4(O)COC4)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-ethylbenzimidazole and 3-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)oxetan-3-ol were reacted to give 263. LCMS m/z: 533.3 (MH+)
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][S:25][CH2:26][C:27](O)=[O:28])=[C:18]([C:31]([O:33]C)=[O:32])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][S:25][CH2:26][C:27](=[O:28])[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:18]([CH:17]=1)[C:31]([OH:33])=[O:32]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CSCC(=O)O
Reactant: Nc1ccccc1Oc1ccccc1
Product: O=C(CSCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1ccccc1Oc1ccccc1

Procedure:
Using the same method as in Example 1-(ii), 2-phenoxyaniline was reacted with the [(2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethyl)sulfanyl]acetic acid obtained in Example 12-(i) to give 5-chloro-2-([((2-oxo-2-[(2-phenoxyphenyl)amino]ethyl)sulfanyl)acetyl]amino)benzoic acid.methyl ester (yield: 72%).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:22][CH:23]3[CH:28]4[CH:24]3[CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27]4)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O1CCOCC1.[ClH:44]>C(Cl)Cl>[ClH:44].[CH:24]12[CH:23]([NH:22][C:20](=[O:21])/[CH:19]=[CH:18]\[N:15]3[CH:16]=[N:17][C:13]([C:5]4[CH:4]=[C:3]([C:2]([F:1])([F:36])[F:37])[CH:8]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:6]=4)=[N:14]3)[CH:28]1[CH2:27][NH:26][CH2:25]2
Reactant: CC(C)(C)OC(=O)N1CC2C(C1)C2NC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NC1C2CNCC21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
(Z)-tert-butyl 6-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylamido)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.05 g, 1.0 eq.) was dissolved in DCM (3 mL) and cooled to 0° C. where dioxane:HCl (0.2 mL) was added dropwise and stirred for 30 min. The reaction was allowed to warm to room temperature and stirred for 30 min, concentrated under reduced pressure. The crude product was triturated with ether to afford (Z)—N-(3-azabicyclo[3.1.0]hexan-6-yl)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylamide hydrochloride (0.015 g, 37.5% yield). 1H NMR (400 MHz, DMSO) δ, 9.61 (s, 1H), 8.75 (s, 2H), 8.60 (s, 2H), 8.30 (s, 1H), 7.38-7.40 (d, J=10.4 Hz, 1H), 5.87-5.89 (d, J=10.4 Hz, 1H), 2.91 (s, 1H), 2.14 (s, 2H), 1.23 (s, 3H); LCMS for Chemical Formula: C18H16F6N5O [M+H]+ 432.34 found 432.19 at retention time 2.302 min.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[B-](F)(F)(F)F.CN(C(O[N:31]1[C:36](=[O:37])[CH2:35][CH2:34][C:32]1=[O:33])=[N+](C)C)C>CN(C=O)C>[CH2:35]1[C:36](=[O:37])[N:31]([O:7][C:6]([C:5]2[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=2)=[O:8])[C:32](=[O:33])[CH2:34]1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(ON1C(=O)CCC1=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To the solution of 4-iodobenzoic acid (1)(1.24 g, 5.0 mmol) and triethylamine (0.71 mL, 5.0 mmol) in DMF (30 mL) was added TSTU (1.51 g, 5.0 mmol). The solution was stirred at room temperature for 2 hours. The reaction was quenched by addition of 10% HCl (50 mL). The precipitate was collected by filtration, washed with water and dried in vacuo to yield the title compound (2) as a white powder (1.42 g, 82%); m.p. 130-132° C.; vmax/cm−1(neat) 1769 (C═O, ester), 1719 (C═O, amide); (Found C, 38.40; H, 2.41; N, 4.15. C11H8INO4 requires C, 38.28; H, 2.34; N, 4.06%.); δH (300 MHz, CDCl3) 7.92 (2H, d, J 12.0 Hz, H2/6), 7.85 (2H, d, J 12.0 Hz, H3/5), 2.92 (4H, s, CH2); δc (75 MHz, CDCl3) 169.0 (OCO), 162.0 (NCO), 138.7 (C2/6), 132.0(C3/5), 125.3 (C1), 103.3(C4), 26.0 (CH2); m/z (E.I.), 345 (M+, 5%), 231 (100%), 202 (20%), and 76 (48%); HRMS for C11H8INO4 requires 344.9493 found 344.9493.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15]C)=[O:14])[CH:6]=[CH:7][C:8]=1[OH:9])#[N:2].[CH:20]1([CH2:24]Br)[CH2:23][CH2:22][CH2:21]1>>[C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH2:24][CH:20]1[CH2:23][CH2:22][CH2:21]1)#[N:2]
Reactant: BrCC1CCC1
Reactant: COC(=O)c1ccnc(-c2ccc(O)c(C#N)c2)c1
Product: N#Cc1cc(-c2cc(C(=O)O)ccn2)ccc1OCC1CCC1

Procedure:
Using methyl 2-(3-cyano-4-hydroxyphenyl)isonicotinate and cyclobutylmethyl bromide, 2-[3-cyano-4-(cyclobutylmethoxy)phenyl]isonicotinic acid was obtained according to the method of Example 2. Then, 150 mg of the compound was suspended in 5 ml of methanol, and 32 mg of sodium methoxide was added to the suspension at 0° C., followed by stirring for 3 hours with gradual elevation of the temperature to room temperature. The reaction solution was concentrated under reduced pressure to obtain 115 mg of sodium 2-[3-cyano-4-(cyclobutylmethoxy)phenyl]isonicotinate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH3:14][C:15](=[CH:17][CH2:18][CH2:19][C:20](=[CH:22][CH:23]=[O:24])C)C.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([N:6]2[CH:10]=[CH:9][N:8]=[CH:7]2)[CH:23]([OH:24])[CH:22]=[CH:20][CH2:19][CH2:18][CH:17]=[CH:15][CH3:14])[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)=CCCC(C)=CC=O
Reactant: Clc1cccc(Cn2ccnc2)c1
Solvent: O
Solvent: C1CCOC1
Product: CC=CCCC=CC(O)C(c1cccc(Cl)c1)n1ccnc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
26 ml (40 mmol) of 1.55 molar n-butyllithium-hexane solution were added dropwise to a solution of 7.70 g (40 mmol) of N-(3-chlorobenzyl)-imidazole in 100 ml of absolute THF at -70° C. in the course of 15 minutes. The mixture was stirred for 30 minutes at -70° C., after which a solution of 6.10 g (40 mmol) of citral (cis/trans mixture) in 50 ml of absolute THF was added dropwise at -70° C., stirring was continued for 45 minutes at about -70° C., the mixture was allowed to warm up to room temperature in the course of about 2 hours, 300 ml of water were added, while cooling, and the mixture was extracted with CH2Cl2. The combined CH2Cl2 extracts were dried, filtered and evaporated down in vacuo. The residue (13.2 g) from the extract was chromatographed over a silica gel S/n-hexane column (diameter 2.5 cm, height 56 cm), with elution with hexane/ethanol mixtures having an increasing ethanol content (up to a maximum of 20% of ethanol). The course of the elution was monitored by means of thin layer chromatography. This showed that the desired compound was present in the form of 4 stereoisomers in similar amounts. Fractions which were shown to be pure by thin layer chromatography were combined and evaporated down in vacuo until the weight remained constant. In this way, 1.2 g of virtually pure stereoisomer (a), having the highest Rf value, were obtained. In addition, 8.2 g of a mixture of the stereoisomers (b), (c)≥(a), (d) were obtained. Finally, 2.6 g were eluted, which were found by thin layer chromatography to contain a high concentration of the stereoisomer (d) (lowest Rf value). This product was subjected to a second chromatography by the same procedure, over a silica S/hexane column (diameter 2 cm, height 22 cm). 1.2 g of a steroisomer (d) which was shown to be virtually completely pure by thin layer chromatography was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>ClCCl.C(O)(=O)C>[CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(N)cc1
Reactant: CCCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCCCCNc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
A mixture of 3.50 g of N,N-dimethyl-p-phenylenediamine, 4.592 g of heptanal, 9.095 g of triacetoxyborohydride, 1.841 g of acetic acid and 257 ml of dichloromethane was stirred at room temperature for one hour. A saturated sodium hydrogen carbonate solution is added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed and dried, and the solvent was removed under reduced pressure. The residue obtained was purified by silica gel column chromatography (solvent; hexane:ethyl acetate=2:1) to give 2.819 g of N,N-dimethyl-N'-heptyl-p-phenylenediamine (yield: 39%, oily product, IR (film): 3375, 2927, 1519 cm-1).
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[NH:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([NH2:44])[CH:42]=2)[N:37]([CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][O:46]2)[N:36]=1>CN(C=O)C>[NH:28]1[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:26]=[C:27]1[C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([NH:44][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:6])[CH:42]=2)[N:37]([CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][O:46]2)[N:36]=1
Reactant: Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Reactant: O=C(O)C1CC1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)C1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.4 %

Procedure:
Cyclopropanecarboxylic acid (6.46 mg, 0.075 mmol), HOBT (15.20 mg, 0.112 mmol), EDC (21.56 mg, 0.112 mmol) and sodium bicarbonate (6.30 mg, 0.075 mmol) was added to a solution of 3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (25 mg, 0.075 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash column chromatography (6% CH3OH/CH2Cl2) afforded the title compound (20 mg) as a solid. 1H NMR: (400 MHz, CD3OD): δ 8.50 (d, 1H, J=1.6 Hz), 7.96 (s, 1H), 7.75 (dd, 1H, J=2.0 and 8.8 Hz), 7.65 (m, 2H), 7.26 (m, 2H), 5.86 (dd, 1H, J=2.0 and 9.2 Hz), 3.97 (m, 1H), 3.81 (m, 1H), 2.63 (m, 1H), 2.14 (m, 2H), 1.82 (m, 2H), 1.68 (m, 2H), 0.99 (m, 2H), 0.87 (m, 2H); ESI-MS [M+H]+: 402.22.