Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]1[C:9](=O)[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]1)[CH3:2].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:18]([NH:25][C@H:9]1[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5][C@H:4]1[O:3][CH2:1][CH3:2])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NCc1ccccc1
Yield: 86.7 %

Procedure:
The same operation as in Example (90c) was performed using tert-butyl 3-ethoxy-4-oxopiperidine-1-carboxylate obtained in Example (90b) (3.4 g, 14 mmol), benzylamine (1.65 g, 15.4 mmol), sodium (triacetoxy)borohydride (5.93 g, 28 mmol) and 1,2-dichloroethane (40 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, 1/1, 1/3, 0/1) to obtain 4.06 g of the title compound as a colorless oily substance (87%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH:19]([CH3:20])[CH2:18][O:17][CH2:16][CH:15]3[CH3:21])[N:11]=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][CH3:32])=[O:30])=[CH:24][CH:23]=3)[N:9]=2)=[CH:4][CH:3]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][C:40](=O)[O:41]C2C=CC=CC=2)[CH:34]=1>>[CH3:21][CH:15]1[CH2:16][O:17][CH2:18][CH:19]([CH3:20])[N:14]1[C:12]1[N:11]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[NH:31][CH3:32])=[CH:24][CH:23]=2)[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:40]([NH:39][C:35]3[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=3)=[O:41])=[CH:7][CH:6]=2)[N:13]=1
Reactant: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3C(C)COCC3C)n2)cc1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(NC(=O)Nc4cccnc4)cc3)nc(N3C(C)COCC3C)n2)cc1
Yield: 6 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl pyridin-3-ylcarbamate. Yield 77 mg, 6% yield.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][N:7]=[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=1)[C:9]([OH:11])=[O:10]>N1C=CC=CC=1>[CH3:5][O:6][N:7]=[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:1](=[O:3])[CH3:2])[CH:13]=1)[C:9]([OH:11])=[O:10]
Reactant: CON=C(C(=O)O)c1cccc(O)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CON=C(C(=O)O)c1cccc(OC(C)=O)c1
Temperature: 0 °C
Yield: 100.4 %

Procedure:
Acetyl chloride (4.1 g.) was added with stirring and ice-cooling to a solution of 2-methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (5 g.) in pyridine (20 ml.) and the mixture was stirred for 50 minutes at ambient temperature. The reaction mixture was poured into ice-water, adjusted to pH 2.1 and extracted three times with ether. The extract was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was thoroughly removed under reduced pressure to give 2-methoxyimino-2-(3-acetoxyphenyl)acetic acid (syn isomer) (6.1 g.).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:33](Cl)=[O:34])[CH:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:36]1([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:33]([N:44]3[CH2:45][CH2:46][CH:41]([N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:42][CH2:43]3)=[O:34])[C@H:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C@H:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
cis-4-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 20) was reacted with 4-pyrrolidin-1-yl-piperidine (Aldrich) to give cis-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C35H42N6O2Cl2 [(M+H)+] 649.2819, observed 649.2822.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:3]=[O:4].[CH2:13]=[CH:14][CH:15](O)[CH2:16][CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][C:2]([CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH2:13]/[CH:14]=[CH:15]/[CH2:16][CH3:17])[CH:3]=[O:4]
Reactant: C=CC(O)CC
Reactant: CC(C=O)CSc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC/C=C/CC(C)(C=O)CSc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Methyl-3-phenylthiopropanal (9.07 g, 0.05 mole), 1-penten-3-ol (21.67 g, 0.25 mole), and p-toluenesulfonic acid (0.24 g, 0.0013 mole) are added to 90 ml of xylenes. The reaction mixture is heated to reflux using a Dean-Stark trap to collect water. After 3 hours, the mixture is cooled to room temperature and quenched with 30 ml of saturated NaHCO3 solution. The two phases are separated and the aqueous phase is extracted with 30 ml of ethyl acetate. The combined organic extracts is washed with 30 ml of brine and dried with Na2SO4. After removing solvents, the crude product is purified by chromatography. The product is obtained in 77% as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8]([NH:14][C:15]([CH3:17])=[O:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7].[C:18]([N:25]1[C:37]2[CH:36]=[CH:35][C:34]([CH2:38]Br)=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1COCC1>[CH2:12]([O:11][C:9](=[O:10])[C:8]([NH:14][C:15](=[O:16])[CH3:17])([CH2:38][C:34]1[CH:35]=[CH:36][C:37]2[N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:26]3[C:31]([C:32]=2[CH:33]=1)=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:6]([O:5][CH2:4][CH3:3])=[O:7])[CH3:13]
Reactant: CC(C)(C)OC(=O)n1c2ccccc2c2cc(CBr)ccc21
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc2c(c1)c1ccccc1n2C(=O)OC(C)(C)C)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Yield: 27.5 %

Procedure:
To a stirred suspension of sodium hydride (100 mg of a 60% dispersion in oil, 2.5 mmol) in THF (10 mL) at about 0° C. under an atmosphere of argon, was added dropwise a solution of acetamido diethyl malonate (241 mg, 1.1 mmol) in THF (1 mL). The stirred reaction mixture was allowed to warm to room temperature over about 30 minutes, cooled to about 0° C. and a solution of N-Boc 3-bromomethylcarbazole (400 mg, 1.1 mmol) in THF (2 mL) was added. The stirred reaction mixture was heated at about 60° C. for about 6 h. The cooled reaction mixture was quenched with brine (10 mL), and extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with water (10 mL), dried (MgSO4) and solvent was removed in vacuo. The crude product was purified using column chromatography on silica gel with 1:1 hexane/ethyl acetate as eluant to afford the product (150 mg, 27% yield). ES-MS (M+H)+ 497.3 (calc. 497.2).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:11])[NH:10][C:5]2=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N+:18]([O-])([OH:20])=[O:19]>>[CH3:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:11])[NH:10][C:5]2=[CH:4][C:3]=1[C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1
Reactant: Cc1nc2[nH]c(=O)[nH]c2cc1-c1ccccc1
Reactant: O=[N+]([O-])O
Product: Cc1nc2[nH]c(=O)[nH]c2cc1-c1ccc([N+](=O)[O-])cc1
Temperature: -2 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
1,3-Dihydro-5-methyl-6-phenyl-2H-imidazo[4,5-b]pyridin-2-one (Example 4c, 8.06 g) was added in small portions to 80 ml 90% nitric acid cooled to -2° C. The reaction mixture was stirred at 0° C. for 2 hours and then poured portion wise into ice-water. The solid product was collected, washed with water and ether, and dried in high vacuum at 110-130° C. to give 9.3 g (97%) of 1,3-dihydro-5-methyl-6-(4-nitrophenyl)-2H-imidazo[4,5-b]pyridin-2-one, m.p. above 300° C. Further purification was accomplished by repeated recrystallization from aqueous dimethylformamide.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C@H:7]2[N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.[C:19]1([NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C.C(O)(=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C@H:7]2[N:12]1[CH2:17][CH2:16][CH:15]([NH:25][C:20]2[C:19]([NH2:26])=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13]1
Reactant: Cc1cccc2c1CCC[C@H]2N1CCC(=O)CC1
Reactant: Nc1ccccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1cccc2c1CCC[C@H]2N1CCC(Nc2ccccc2N)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.1 %

Procedure:
(R)-1-(5-Methyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidin-4-one (1.84 g) was dissolved in dichloroethane (55 ml), and 1,2-phenylenediamine (1.23 g) was added. To the solution were added sodium triacetoxyborohydride (3.61 g) and acetic acid (0.97 ml). The mixture was stirred at room temperature for 24 hr, alkalified with saturated sodium hydrogen carbonate, and extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (R)-N-[1-(5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidin-4-yl]-benzene-1,2-diamine (1.83 g) as a pale-brown solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6]
Reactant: O=C(O)c1cccc(I)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-Iodobenzoic acid (12.4 g) was dissolved in DMF (100 mL) and potassium carbonate (7.6 g) was added. Benzyl bromide (6.5 mL) was then added dropwise over approximately 10 minutes causing a slight exotherm to 24° C. The suspension was stirred at room temperature for 1.5 hours. The suspension was then poured into water (approximately 300 mL) and was extracted with diethyl ether. The combined organic phase was back washed with water and brine and dried over sodium sulfate. The solvent was stripped to yield a crude product as a colourless oil (17.0 g). The crude product was applied to a silica gel column and was eluted with cyclohexane-ethyl acetate (95:5) to give a colourless oil (13.08 g).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH2:18][CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)[CH3:29]>>[CH2:18]([N:13]1[C:12]([C:33]2[CH:34]=[CH:35][C:30]([CH2:28][CH3:29])=[CH:31][CH:32]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH3:19]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: CCn1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CCc1ccc(-c2c3c(nn2CC)CCNCC3)cc1
Yield: 100.9 %

Procedure:
The title compound (140 mg) was prepared according to Example 193 using 213 mg of 2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 193, Step A) and 232 mg of 4-ethylphenylboronic acid. MS (ESI): exact mass calculated for C17H23N3, 269.19; found, m/z 270.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.40-7.39 (m, 2H), 7.27-7.26 (m, 2H), 4.65 (br s, 2H), 4.05-4.00 (m, 2H), 3.8-3.6 (m, 2H), 3.18-3.00 (m, 2H), 2.88-2.81 (m, 2H), 2.76-2.71 (m, 2H), 1.32-1.24 (m, 6H).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@H:9]1[CH2:14][C@H:13]2[CH2:15][C@H:11]([C:12]2([CH3:17])[CH3:16])[C@@H:10]1[CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>C(Cl)Cl>[S:27]([NH:8][C@H:9]1[CH2:14][C@H:13]2[CH2:15][C@H:11]([C:12]2([CH3:17])[CH3:16])[C@@H:10]1[CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)([CH3:30])(=[O:29])=[O:28]
Reactant: CC1(C)[C@H]2C[C@H](N)[C@@H](CCOC3CCCCO3)[C@@H]1C2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)[C@H]2C[C@H](NS(C)(=O)=O)[C@@H](CCOC3CCCCO3)[C@@H]1C2
Reaction time: 1 h

Procedure:
Triethylamine (1.9 ml) was added to a solution of (1S,2S,3S,5R)-3-amino-2-[2-(2-tetrahydropyranyloxy)ethyl]-6,6-dimethylbicyclo[3.1.1]heptane (3.25 g) in methylene chloride (30 ml). The reaction solution was cooled. To the above solution, mesyl chloride (1.0 ml) was dropped slowly. The reaction solution was allowed to stand for 1 hour. The reaction solution was extracted with methylene chloride. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane-ethyl acetate) to give the title compound (3.05 g) having the following physical data.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@@H:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:9]1.[C:21]1([CH2:27][CH2:28][CH2:29][CH:30]=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[C:21]1([CH2:27][CH2:28][CH2:29][CH2:30][N:8]2[CH2:12][CH2:11][C@@H:10]([S:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH2:9]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=CCCCc1ccccc1
Reactant: Oc1ccc(S[C@@H]2CCNC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Oc1ccc(S[C@@H]2CCN(CCCCc3ccccc3)C2)cc1

Procedure:
The title compound, MS: m/e=328.3 (M+H+) and [α]D20 +10.15° (c=0.56, chloroform) was prepared from (R)-4-(pyrrolidin-3-yl-sulfanyl)-phenol trifluoroacetic acid salt and 4-phenyl-butyraldehyde.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:8])[CH2:4][CH2:5][CH2:6][SH:7].Cl[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][OH:17])[C:11]=1[CH3:18]>CN(C=O)C.C(O)(=O)C>[OH:17][CH2:16][C:12]1[C:11]([CH3:18])=[C:10]([S:7][CH2:6][CH2:5][CH2:4][CH2:3][SH:8])[CH:15]=[CH:14][N:13]=1
Reactant: Cc1c(Cl)ccnc1CO
Reactant: SCCCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1c(SCCCCS)ccnc1CO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4.2 g (145 mmol) of sodium hydride (80% in paraffin) are initially introduced in 100 ml of DMF with ice-cooling. 35.5 g (290 mmol) of 1,4-butanedithiol are slowly added dropwise. After the evolution of gas has ended, 15.3 g (97 mmol) of 4-chloro-2-hydroxymethyl-3-methylpyridine in 20 ml of DMF are added drop-wise. After about 30 minutes, the mixture is allowed to come to RT and is stirred at this temperature for 12 h. It is diluted with 800 ml of ice-water and neutralized with acetic acid. The mixture is extracted 3 times with dichloromethane. The combined organic phases are washed 4 times with water, dried over magnesium sulfate, filtered and concentrated. The crude product is chromatographed on silica gel using ethyl acetate/conc. ammonia=99/1. The title compound is obtained as a yellow crystallizate. M.p. 58°-63° C.; yield 13 g (55% of theory).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[CH:11]1[CH:16]=[CH:15][C:14]([CH2:17]Br)=[CH:13][CH:12]=1>CC#N>[CH2:17]([N:1]([C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH2:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[O:9])[CH2:4][CH2:3]1)[CH2:17][C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1)[C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: N[C@H]1CC[C@H](C(=O)O)CC1
Solvent: CC#N
Product: O=C(OCc1ccccc1)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To an 80° C. heated mixture of trans-4-Aminocyclohexanecarboxylic acid (8 g, 55.97 mmol) and K2C03 (23.4 g) in 112 mL of CH3CN, was added dropwise a solution of BnBr (23.3 mL, 195.5 mmol) in 70 mL of CH3CN by addition funnel. Reaction stirred overnight at 80° C. The reaction was cooled to room temperature and filtered. Precipitate did not form in filtrate like it did with the cis-isomer so the filtrate was concentrated to an oil and carried on to next step (23.01 g, 99% yield).
Reaction SMILES: [ClH:1].[C:2]([C:4]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)#[N:3]>CCOC(C)=O>[ClH:1].[C:2]([C:4]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3]
Reactant: Cc1ccccc1C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccccc1C1(C#N)CCNCC1

Procedure:
A solution of EtOAc saturated with HCl (200 ml) was added to 4-cyano-N-(1,1-dimethylethoxy)carbonyl-4-(2-methylphenyl)piperidine (31 mg, 0.097 mmol). The resulting mixture was allowed to react for 1 hour at room temperature. The EtOAc was removed in vacuo affording 4-cyano-4-(2-methylphenyl)piperidine hydrochloride as a white solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[N:7][NH:8]2)=[CH:4][C:3]=1[F:17].[CH:18]1([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=2)[CH2:20][CH2:19]1.C(=O)([O-])O.[Na+]>C(O)(C)C.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>[CH:18]1([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([C:2]3[CH:10]=[C:9]4[C:5]([C:6]([C:11]5[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=5)=[N:7][NH:8]4)=[CH:4][C:3]=3[F:17])[CH:24]=2)[CH2:19][CH2:20]1
Reactant: Fc1cc2c(-c3ccncc3)n[nH]c2cc1Br
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
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: CC(C)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2[nH]nc(-c3ccncc3)c2cc1F
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 36.7 %

Procedure:
A suspension of 6-bromo-5-fluoro-3-(4-pyridinyl)-1H-indazole (Intermediate 4, 20 mg), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (21 mg), tetrakis(triphenylphosphine)palladium(0) (2 mg) and aqueous sodium hydrogen carbonate (1M, 1 ml) in isopropanol (2 ml) was stirred in a microwave oven at 150° C. for 15 min. The mixture was partitioned between water and ethyl acetate and the organic layer was washed with water and brine, dried using a hydrophobic filter tube and concentrated under vacuum. The residue was purified on an SPE cartridge (silica, 5 g) eluting with cyclohexane:ethyl acetate (1:1 to 1:4) to give the title compound as a white solid (9.72 mg).
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)[CH:13]=[CH:12][N:11]=2)C=CC=CC=1.[CH3:27][NH:28][CH:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1>CN(C)C=O>[N+:23]([C:20]1[CH:19]=[CH:18][C:17]([O:16][C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C:8](=[O:26])[N:28]([CH3:27])[CH:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[CH:15]=2)=[CH:22][CH:21]=1)([O-:25])=[O:24]
Reactant: CNC1CCN(C)CC1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)Oc1ccccc1
Solvent: CN(C)C=O
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3)ccn2)CC1
Reaction time: 1 h
Yield: 21051 %

Procedure:
[4-(4-Nitrophenoxy)pyridin-2-yl]carbamic acid phenyl ester (150 mg) was dissolved in N,N-dimethylformamide (4 ml) under a nitrogen atmosphere, and then N-methyl-N-(1-methylpiperidin-4-yl)amine (0.186 mg) was added thereto, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate (40 ml) and a saturated aqueous solution of ammonium chloride (10 ml). The organic layer was washed with a saturated aqueous solution of ammonium chloride, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:1, then ethyl acetate). Fractions containing the target compound were concentrated under a reduced pressure to provide 3-[4-(4-nitrophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (117.7 mg, 71.5%) as a crude product.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[C:5]([CH2:7][CH2:8][NH:9][N:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:6]>C1C=CC=CC=1>[C:5]([CH2:7][CH2:8][N:9]([C:3](=[O:4])[NH:2][CH3:1])[N:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:6]
Reactant: CN=C=O
Reactant: N#CCCNN=Cc1ccccc1
Solvent: c1ccccc1
Product: CNC(=O)N(CCC#N)N=Cc1ccccc1

Procedure:
0.57 g (10-2 moles) of methyl isocyanate is added, at 25° C., to a solution of 10-2 moles of benzaldehyde (2-cyanoethyl)hydrazone in 30 ml of anhydrous benzene. The mixture is then heated to boiling temperature and left under reflux for 30 minutes. On cooling, the acylated compound crystallizes. It is filtered, drained and then recrystallized from a mixture of benzene and cyclohexane. Its melting point is 145° C. The reaction yield is 48%.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+]>O.C1(C)C=CC=CC=1>[CH2:16]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[C:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: ClCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(Cn2c(-c3ccccc3)cc3ccccc32)cc1
Temperature: 25 °C
Yield: 13.2 %

Procedure:
A mixture of 19.33 g (0.1 mole) of 2-phenylindole, 13.92 g (0.11 mole) of benzyl chloride, 33 g (0.5 mole) of 85% KOH, 14 mL of H2O, 2.5 g (2.5 mmoles) of PEG-1000, and 100 mL of toluene was stirred and heated at 55°-60° for 24 hours. After cooling to room temperature, 100 mL of H2O was added. The layers were separated. The aqueous layer was extracted with 100 mL of toluene. The combined toluene phases were washed with 2N HCl (2×50 mL), H2O (2×50 mL), and 50 mL of brine and dried over MgSO4. Evaporation of the solvent left 32.3 g of dark brown oil. The oil was chromatographed on a 1100 g column of silica gel. The column was elut4d with 25% CH2Cl2 -Skellysolve B and 200 mL fractions were collected. The fractions were assayed by silica gel tlc (1×4") (25% CH2Cl2 -Skellysolve B). Fractions 18-20 were combined giving 3.74 g (13%) of 1-benzyl-2-phenylindole as a solid.