Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[N:14]=[CH:13][C:12]([NH:15][C:16]2[S:17][C:18]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)=[C:19]([CH3:21])[N:20]=2)=[CH:11][CH:10]=1>CS(C)=O>[CH3:31][S:28]([C:25]1[CH:26]=[CH:27][C:22]([C:18]2[S:17][C:16]([NH:15][C:12]3[CH:13]=[N:14][C:9]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:10][CH:11]=3)=[N:20][C:19]=2[CH3:21])=[CH:23][CH:24]=1)(=[O:30])=[O:29]
Reactant: Cc1nc(Nc2ccc(Cl)nc2)sc1-c1ccc(S(C)(=O)=O)cc1
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Product: Cc1nc(Nc2ccc(N3CCN(C)CC3)nc2)sc1-c1ccc(S(C)(=O)=O)cc1
Yield: 117.6 %

Procedure:
A stirred solution of N-methyl piperazine (0.184 g, 1.84 mmol) and (6-chloro-pyridin-3-yl)-[5-(4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amine (31c) (0.070 g, 0.184 mmol) in DMSO (2 ml) is heated in a microwave (PROLABO SYNTHEWAVE s402™) at 60% power (180 W) for 10 hours. The solvent is removed and the residue is purified by chromatography on silica eluting with ethyl acetate-methanol (9:1) to give the title compound as a yellow solid (0.096 g).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](Cl)=[O:8])=[N:4][C:3]=1[C:10]1[N:14]2[N:15]=[CH:16][CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1.C(OC(=O)[NH:25][C@H:26]1[CH2:31][CH2:30][CH2:29][C:28]([F:33])([F:32])[C@@H:27]1[NH2:34])(C)(C)C>ClCCl>[NH2:25][C@@H:26]1[C@@H:27]([NH:34][C:7]([C:5]2[S:6][C:2]([Cl:1])=[C:3]([C:10]3[N:14]4[N:15]=[CH:16][CH:17]=[CH:18][C:13]4=[N:12][CH:11]=3)[N:4]=2)=[O:8])[C:28]([F:33])([F:32])[CH2:29][CH2:30][CH2:31]1
Reactant: O=C(Cl)c1nc(-c2cnc3cccnn23)c(Cl)s1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC(F)(F)[C@@H]1N
Solvent: ClCCl
Product: N[C@H]1CCCC(F)(F)[C@@H]1NC(=O)c1nc(-c2cnc3cccnn23)c(Cl)s1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
5-Chloro-4-(imidazo[1,2-b]pyridazin-3-yl)-1,3-thiazole-2-carbonyl chloride (59.5 mg, 0.199 mmol) and tert-butyl[(1S,2R)-2-amino-3,3-difluorocyclohexyl]carbamate (54.8 mg, 0.219 mmol) were dissolved in dry dichloromethane (3 mL). The reaction mixture was left to stir at room temperature for 42 h. After consumption of the starting material, trifluoroacetic acid (2 mL) was added to the reaction mixture and left to stir at room temperature for 2 h. The solution was then concentrated and the residue purified by prep HPLC. The compound was neutralized by taking the fractions and adding an aqueous saturated sodium bicarbonate solution and extracting three times with ethyl acetate. The combined organics were dried with magnesium sulfate, filtered, and concentrated to afford the title compound as a yellow solid. 1H NMR (500 MHz, CD3SOCD3) δ 8.73 (d, 1H); 8.66 (s, 1H); 8.24 (d, 1H); 7.45 (dd, 1H); 4.05 (m, 1H); 2.85 (m, 1H); 2.08 (m, 1H); 1.22-2.08 (m, 6H). LRMS (APCI) calc'd for (C16H15ClF2N6OS) [M+H]+, 413.1. found 413.0.
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[S:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:2].Cl.N.[CH2:21]1CCCCC1>O.C(Cl)Cl>[C:1]([NH:3][C:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[S:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:2])[CH3:21]
Reactant: O=CNc1c(-c2ccccc2)sc2ccccc12
Reactant: C1CCCCC1
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1c(-c2ccccc2)sc2ccccc12
Reaction time: 8 h

Procedure:
67.0 g (0.265 mol) of 3-formamido-2-phenyl-benzo(b)thiophene and 700 milliliters of HCl at 25% are refluxed with stirring for 8 hours. After cooling, it is diluted with water, neutralised by ammonia and the product is dissolved in CH2Cl2. By evaporating the organic phase dried over K2CO3, 58.7 g (98% of theory) of 2-phenyl-3-amino-benzo-(b)thiophene are obtained; yellow plates melting between 110° and 112° C. (cyclohexane).
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[CH3:9][N+:10]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24]([O:26][CH3:27])=[O:25])=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[CH:15]2>CO>[CH3:9][N:10]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]([C:24]([O:26][CH3:27])=[O:25])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=2
Reactant: COC(=O)c1c2ccccc2[n+](C)c2ccccc12
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CO
Product: COC(=O)C1c2ccccc2N(C)c2ccccc21

Procedure:
A solution of methyl 10-methylacridinium-9-carboxylate trifluoromethanesulfonate (75), 4.25 parts, in methanol is reduced as described in Example I to give 3.2 parts of methyl 10-methylacridan-9-carboxylate and the isolated product has the following structure confirmed by NMR.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7][C:8]([OH:10])=O.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:32][N:33]([CH3:44])[CH2:34][CH2:35][NH:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([CH3:43])[CH2:39][CH2:38]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:32][N:33]([CH3:44])[CH2:34][CH2:35][N:36]([C@H:37]1[CH2:38][CH2:39][C@H:40]([CH3:43])[CH2:41][CH2:42]1)[C:8](=[O:10])[CH:7]=[CH:6][C:5]1[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:1])([F:15])[F:14])[CH:4]=1
Reactant: O=C(O)C=Cc1cccc(C(F)(F)F)c1
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCN(C(=O)C=Cc1cccc(C(F)(F)F)c1)[C@H]1CC[C@H](C)CC1

Procedure:
Using 1.3 g of 3-trifluoromethylcinnamic acid, 1.4 ml of diethyl chlorophosphate, 1.4 ml of triethylamine, 60 ml of methylene chloride, 1.4 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.25 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 81 was carried out. As a result, 2.25 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-3-trifluoromethylcinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: C(OC(C1C=CC=CC=1O[C:9]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:22][C:12]2[NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1)=O)C.Cl.[NH:40]1[CH2:47][CH2:46][CH2:45][C@H:41]1[C:42]([NH2:44])=[O:43]>>[CH3:34][S:31]([C:28]1[CH:29]=[CH:30][C:25]([O:24][C:23]2[C:9]([N:40]3[CH2:47][CH2:46][CH2:45][C@H:41]3[C:42]([NH2:44])=[O:43])=[CH:10][C:11]3[NH:15][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[N:13][C:12]=3[CH:22]=2)=[CH:26][CH:27]=1)(=[O:32])=[O:33]
Reactant: CCOC(=O)c1ccccc1Oc1cc2nc(-c3ccccn3)[nH]c2cc1Oc1ccc(S(C)(=O)=O)cc1
Reactant: NC(=O)[C@@H]1CCCN1
Agent: Cl
Product: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2N2CCC[C@H]2C(N)=O)cc1

Procedure:
The entitled compound was obtained as a pale yellow solid in the same method as in Example 15 or in accordance with the method or by combining it with an ordinary method but using 5-fluoro-4-(4-methanesulfonyl-phenoxy)-2-nitro-phenylamine obtained in Example 14, and L-prolinamide hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][CH:19]=[O:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.Br[C:22]1[C:23]([CH3:29])=[N:24][N:25]([CH3:28])[C:26]=1[CH3:27]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][C:19]([C:22]3[C:23]([CH3:29])=[N:24][N:25]([CH3:28])[C:26]=3[CH3:27])=[O:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: Cc1nn(C)c(C)c1Br
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CC=O)cc1
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)c2c(C)nn(C)c2C)cc1

Procedure:
Prepared from (6-methyl-2-p-tolyl-imidazo[1,2-a]pyridine-3-yl)-acetaldehyde 6b and 4-bromo-1,3,5-trimethyl-1H-pyrazole using the procedure of Method B described above. 1H NMR (400 MHz, CDCl3) δ 2.33 (s, 3H), 2.38 (s, 3H), 2.52 (s, 3H), 2.53 (s, 3H), 3.78 (s, 3H), 4.43 (s, 2H), 7.04 (d, J=8.8 Hz, 1H), 7.22 (m, 3H), 7.57 (m, 3H). Mass spectrum (m/e) 373 (M+).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([C:13]2([C:19](O)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:7]1([C:13]2([CH2:19][OH:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)C1(c2ccccc2)CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCC1(c2ccccc2)CCCCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a suspension of LAH (3.8 g, 0.1 mol) cooled to 0° C. was slowly added 1-phenyl-cyclohexanecarboxylic acid (10.2 g, 50.0 mmol). After stirring from 0° C. to rt overnight, the reaction mixture was quenched with H2O (3.8 mL), 15% NaOH (3.8 mL), H2O (11.4 mL) and filtered. The salt was washed with Et2O and the combined organic phase dried over anhydrous sodium sulfate to give (1-phenyl-cyclohexyl)-methanol (8.48 g, 89%) as a white solid. 1H NMR (CDCl3, 300 MHz) δ (ppm) 1.30–1.70 (9H, m), 2.15–2.36 (2H, m), 3.51 (2H, s), 7.20–7.27 (1H, m), 7.34–7.41 (4H, m). Mass Spec [M+H]+=191.1.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.O=S(Cl)[Cl:25]>C(Cl)Cl>[Cl:25][CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)n1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccc(CCl)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
To a solution of ethyl 6-[(tert-butoxycarbonyl)amino]pyridine-2-carboxylate (456 mg, 1.71 mmol) in anhydrous ethanol (20 ml) was added pulverized CaCl2 (395 mg, 3.42 mmol). The suspension was stirred and cooled to 0° C. and NaBH4 (325 mg, 8.55 mmol) was added slowly. The reaction was stirred at 0° C. for 2 h, quenched with water, and extracted with CHCl3 (×3). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (30→50% ethyl acetate in hexane) to yield a colorless syrup (308 mg) as a mixture containing tert-butyl [6-(hydroxymethyl)pyridin-2-yl]carbamate as the major component (˜4:1 ratio). To a solution of the above mixture in CH2Cl2 (10 ml) was added pyridine (144 μl, 1.79 mmol) and SOCl2 (120 μl, 1.65 mmol). The reaction was stirred at room temperature for 4 h, quenched with water and saturated Na2CO3, and extracted with CHCl3. The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (10% ethyl acetate in hexane) to yield the title compound as a colorless syrup (208 mg, 50% over 2 steps).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13](=[O:26])[NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:25])([F:24])[F:23])[CH:16]=2)[CH2:11][CH2:10][C@@H:9]1[CH2:27]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:33]=[N+:34]=[N-:35].[Na+].CCOC(C)=O.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13](=[O:26])[NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:24])([F:23])[F:25])[CH:16]=2)[CH2:11][CH2:10][C@@H:9]1[CH2:27][N:33]=[N+:34]=[N-:35])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1[C@@H](COS(C)(=O)=O)CC[C@H]1C(=O)Nc1cccc(OC(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H](CN=[N+]=[N-])CC[C@H]1C(=O)Nc1cccc(OC(F)(F)F)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of (2R,5S)-2-methanesulfonyloxymethyl-5-(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (465 mg, 0.97 mmol) in DMF (3 mL) was added a solution of sodium azide (313 mg, 4.82 mmol) in water (0.5 mL) and the mixture was stirred at 80° C. under nitrogen atmosphere overnight. EtOAc and a saturated aqueous solution of NaHCO3 were added, the layers were separated and the aqueous one back-extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc gradient 100:0 to 1:1) to give the desired compound. MS (LC-MS): 330 [MH−Boc]+; tR (HPLC conditions b) 5.75 min.
Reaction SMILES: [O:1]=[C:2]1[NH:5][C@@H:4]([C:6](OC)=[O:7])[C@H:3]1[NH:10][C:11](=[O:20])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH4-].[Na+].[H][H].C(=O)(O)[O-].[Na+].[Cl-].[Na+]>O1CCCC1.O.C(O)(=O)C>[OH:7][CH2:6][C@H:4]1[C@@H:3]([NH:10][C:11](=[O:20])[CH2:12][O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2](=[O:1])[NH:5]1
Reactant: [H][H]
Reactant: COC(=O)[C@@H]1NC(=O)[C@@H]1NC(=O)COc1ccccc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: O=C(COc1ccccc1)N[C@H]1C(=O)N[C@H]1CO
Reaction time: 0.67 h

Procedure:
To a solution of 13.5 g (0.049 mole) of methyl cis-4-oxo-3-phenoxyacetylaminoazetidine-2-carboxylate in 975 ml of tetrahydrofuran and 100 ml of water at 0° (ice bath) was added a cold solution of 3.75 g (0.099 mole) of sodium borohydride in 250 ml of water over a period of 10 min. The solution was stirred at 0° for 40 min and then glacial acetic acid was added dropwise until hydrogen evolution ceased. Solid sodium bicarbonate and sodium chloride were added and this mixture was extracted five times with 250 ml portions of ethyl acetate. After drying the combined extracts (MgSO4), the solvent was removed in vacuo. The resulting residue was dissolved in ethyl acetate, clarified with Norite and allowed to crystallize to give the title compound; tlc: ethyl acetate, silica gel GF, Rf = 0.10; mp 153°-154 ° (ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([CH3:20])=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([CH3:28])[CH:27]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:32]2[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:30][CH2:31]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([CH3:20])=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(C)c(C)cc2nc1OC
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: COc1nc2cc(C)c(C)cc2nc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 58 %

Procedure:
Ethyl N-(2-methoxy-6,7-dimethylquinoxalin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 183 to obtain the titled compound (yield, 58%). 1H NMR (300 MHz, CDCl3) δ 2.29-2.40 (m, 12H), 3.20-3.29 (m, 4H), 3.80-3.83 (m, 3H), 4.10 (s, 4H), 5.12 (br s, 1H), 6.59 (s, 3H), 7.36-7.60 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4](I)[CH:3]=1.[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:12])([F:21])[F:22])[CH:15]=2)[CH:3]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1ccc(Cl)cc1I
Product: O=C(O)c1ccc(Cl)cc1Oc1cccc(C(F)(F)F)c1

Procedure:
In a manner analogous to that described in Example 1, 4-chloro-2-iodobenzoic acid is reacted with 3-trifluoromethyl-phenol, and there is obtained 4 -chloro-2-(3-trifluoromethyl-phenoxy)-benzoic acid having a melting point of 146° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[C:7]=1[C:8]#[N:9])[CH:2]([CH3:4])[CH3:3]>CC(O)=O.C1COCC1.CCOC(C)=O.[Fe]>[NH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:6]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])[C:7]=1[C:8]#[N:9]
Reactant: CC(C)COc1cccc([N+](=O)[O-])c1C#N
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)COc1cccc(N)c1C#N
Temperature: 25 °C
Yield: 55.3 %

Procedure:
To a solution of 2-isobutoxy-6-nitrobenzonitrile (Example 41c, 34.3 g, 0.156 mol) in AcOH/THF (1:1 by volume, 250 mL) was added iron powder (17.36 g, 0.311 mol) in one portion. The stirred suspension was heated to reflux for 30 minutes. After it was cooled down to room temperature, the reaction solution was diluted with EtOAc (1 L). The solid was removed by filtration, and the filtrate was washed subsequently with water (300 mL×2), 1N NaOH (300 mL), saturated Na2CO3 aqueous solution (300 mL), brine (300 mL), and dried over Na2SO4. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluting with 20% EtOAc in hexanes to give the title compound as a yellow oil (16.4 g, 83%). 1H NMR (400 MHz, DMSO-d6) δ 0.96 (d, J=6.8 Hz, 6H), 1.96-2.02 (m, 1H), 3.75 (d, J=6.4 Hz, 2H), 5.96 (s, 2H), 6.17 (d, J=8.4 Hz, 1H), 6.30 (d, J=8.4 Hz, 1H), 7.15 (t, J=8.8 Hz, 1H). MS 191 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:18](=[O:20])[CH3:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(N)cc1Cl
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(C)=O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
A solution of 3-chloro-4-methoxyphenylamine (6.3 g) and triethylamine (4.04 g) in dichloromethane (100 mL) was chilled in an ice bath, acetyl chloride (3.45 g) was added dropwise and the mixture was stirred at ambient temperature overnight. The reaction mixture was extracted with water (2×30 mL) and brine (2×30 mL) and the organic layer was dried with magnesium sulfate. The drying agent was removed by filtration and the filtrate was evaporated to give N-(3-chloro-4-methoxyphenyl)acetamide (7.45 g) as a dark oil, which solidified on standing. MS: 200 (M+H)+.
Reaction SMILES: C(OC([O:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:23][CH:22]3[CH:20]([CH:21]3[N:24]([CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)[CH2:19]2)=[N:16][CH:17]=1)=[O:11])C)C(C)C.Cl.O1CCOCC1>C(Cl)Cl>[OH:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:19][CH:20]3[CH:22]([CH:21]3[N:24]([CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)[CH2:23]2)=[N:16][CH:17]=1)=[O:11]
Reactant: CCN(CC)CCN(Cc1ccc2ccccc2c1)C1C2CN(c3ncc(C(=O)NOC(C)OCC(C)C)cn3)CC21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCN(CC)CCN(Cc1ccc2ccccc2c1)C1C2CN(c3ncc(C(=O)NO)cn3)CC21
Yield: 56.2 %

Procedure:
N-(1-Isobutoxyethoxy) 2-{6-[(2-diethylaminoethyl)naphthalen-2-ylmethylamino]-3-azabicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide (18 mg, 0.03 mmol) was dissolved in dry DCM (3 ml) and treated with 4M HCl in dioxane (0.015 ml, 0.06 mmol). A white precipitate immediately formed. This was filtered and washed with DCM to give the title compound as a white solid (8 mg, 57%). LCMS purity 98%, m/z 475 [M+H]+, 1H NMR (300 MHz, CD3OD) δ: 1.39 (6H, t, J=7.2 Hz), 2.26 (2H, br s), 2.77 (1H, s), 3.37 (4H, m), 3.55 (2H, d, J=10.5 Hz), 3.81 (4H, br s), 3.93 (2H, br d, J=10.5 Hz), 4.71 (2H, br s), 7.61 (2H, m), 7.76 (1H, d, J=8.4 Hz), 7.95-8.04 (3H, m), 8.20 (1H, s), 8.71 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]([CH2:15][CH:16](O)[CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:13]2[C:23]([N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:24][CH:25]=[CH:26][C:12]=2[N:11]=1.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2=[N:11][C:12]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[C:13]=3[N:14]2[CH2:15][CH:16]1[CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: CCN(CC)c1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CC(O)CC(=O)OC)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCN(CC)c1cccc2nc3n(c12)CC(CC(=O)OC)N3c1ccc(Cl)cc1Cl
Yield: 84.2 %

Procedure:
To a solution of methyl 4-[2-[(2,4-dichlorophenyl)amino]-7-(diethylamino)-1H-benzimidazol-1-yl]-3-hydroxybutanoate (Reference Example 83; 200 mg, 0.430 mmol) in pyridine (4 mL) was added methanesulfonyl chloride (0.166 mL, 2.14 mmol) at 0° C. After the resultant mixture was stirred at room temperature for 16 hr, the mixture was diluted with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting mesylate was diluted with N,N-dimethylformamide (9 mL) and to the solution was added potassium carbonate (119 mg, 0.862 mmol) at room temperature. After the resultant mixture was stirred at 80° C. for 2 hr, the mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a solid (162 mg, 0.362 mmol, 84%). Analytically pure material was obtained by recrystallization from ethyl acetate/n-hexane.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]([O:18][C:19]2[CH:34]=[CH:33][C:22]([C:23]([O:25]CC3C=CC=CC=3)=[O:24])=[CH:21][CH:20]=2)=[O:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1>[Pd].C(OCC)(=O)C>[CH3:1][C:2]1[C:3]([C:16]([O:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:33][CH:34]=2)=[O:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: Cc1cc2c(cc1C(=O)Oc1ccc(C(=O)OCc3ccccc3)cc1)C(C)(C)CCC2(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1C(=O)Oc1ccc(C(=O)O)cc1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 430 mg (0.94 mmol) of benzyl 4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthoyloxy)benzoate, 60 mg of 10% palladium on carbon and 6 ml of ethyl acetate was stirred under a hydrogen atmosphere at room temperature for 3 hours. A further 6 ml of ethyl acetate was then added to the reaction mixture and mixture heated at 50° C. for 3 hours. The reaction mixture was then cooled, filtered through celite and the residue washed with 5 ml of warm ethyl acetate. The filtrate was then concentrated in-vacuo and the resultant residue recrystallized from a mixture of ethyl acetate and hexanes to give the title compound as a white, crystalline solid.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].[NH:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[NH2:11].C(O)(=O)C>CCO.C1COCC1>[NH2:6][C:5]1[N:10]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:19][CH:20]=2)[N:11]=[C:3]([C:2]([CH3:9])([CH3:8])[CH3:1])[CH:4]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)C(=O)CC#N
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2ccc(C(=O)O)cc2)n1
Yield: 98.6 %

Procedure:
A mixture of 4,4-dimethyl-3-oxo-pentanenitrile (4.52 g, 36.15 mmol), 4-hydrazinobenzoic acid (5.00 g, 32.86 mmol), and acetic acid (2 mL) in EtOH/THF (1:1) was refluxed for 16 h. After cooling, the solvent was concentrated at reduced pressure, and the crude was re-dissolved in EtOAc. The organic layer was washed with aqueous saturated Na2CO3 solution and brine, dried over MgSO4, filtered, and concentrated to half its volume. The resulting residue was filtered, and the solids were washed with cold EtOAc and dried under high vacuum to afford the title compound as a white solid (8.4 g, 99%). 1H-NMR (DMSO-d6) δ 12.91 (s, 1H), 7.99 (d, J=6.0 Hz, 2H), 7.75 (d, J=9.0 Hz, 2H), 5.42 (s, 1H), 5.39 (s, 2H), 1.21 (s, 9H); MS LC-MS [M+H]+=260, RT=1.83 min.