Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH:25]=[CH:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH2:25][CH:26]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)[CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: CN1CCNCC1
Reactant: CCCC=CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Product: CCCC(CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1)N1CCN(C)CC1
Yield: 40 %

Procedure:
N-Cyclopropyl-N-{1-[3-(4-methylpiperazin-1-yl)hexanoyl]piperidin-4-yl}-3-trifluoromethylbenzenesulfonamide (31) was prepared by reacting N-cyclopropyl-N-(1-hex-2-enoyl-piperidin-4-yl)-3-trifluoromethyl-benzenesulfonamide (30) (250 mg, 0.56 mmol) and N-methyl-piperazine (2 mL) as described in Example 26 above. The residue was chromatographed over flash silica eluting with ethyl acetate:methanol:ammonia (100:10:1) to give the title compound 31 (120 mg, 40%) as a white solid. LC: 100%. MS: m/z=545.3, 546.3 (M+H). 1H NMR (400 MHz, CDCl3): (1:1 mixture of rotamers) δ 8.14 (1H, s), 8.07 (1H, d, J=7.5 Hz), 7.88 (1H, d, J=7.5 Hz), 7.70 (1H, t, J=7.5 Hz), 4.74 (1H, d, J=13 Hz), 4.09 (1H, t, J=13 Hz), 3.95 (1H, d, J=13 Hz), 3.08 (2H, m), 2.67-2.33 (9H, m), 2.26 (3H, s), 2.15 (1H, dd, J=8.8 Hz), 1.96 (1H, m), 1.85-1.65 (3H, m), 1.52-1.22 (4H, m), 0.98 (1H, m), 0.98-0.70 (6H, m).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][CH2:28][C:29]#[N:30]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH2:28][C:29]#[N:30])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CCCCl
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCCSc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (60 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and 3-chloropropionitrile (65 mg, 0.73 mmol) in order. The mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo, and to the residue was added water. The mixture was extracted with chloroform and the organic layer was dried on sodium sulfate. After removal of the solvent in vacuo, the residue was purified by silica gel chromatography (5% methanol/chloroform) to give the subject compound (72 mg, yield 45%).
Reaction SMILES: [CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[CH3:5])[CH:2]=[CH2:3].[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1F>>[CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[Br:20])[CH:15]=[CH:14]2)[CH3:5])[CH:2]=[CH2:3]
Reactant: Fc1ccccc1Br
Reactant: C=CCN(C)CCCCCc1ccc2[nH]ccc2c1
Product: C=CCN(C)CCCCCc1ccc2c(ccn2-c2ccccc2Br)c1

Procedure:
In analogy to example 4.6, Allyl-[5-(1H-indol-5-yl)-pentyl]-methyl-amine and 1-bromo-2-fluoro-benzene were converted to yield Allyl-{5-[1-(2-bromo-phenyl)-1H-indol-5-yl]-pentyl}-methyl-amine as yellow oil, MS: 411 (MH+, 1Br).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH2:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=1>C(#N)C>[C:10]([C@@H:9]1[N:5]([C:3](=[O:4])[CH2:2][NH:25][C:22]([CH3:24])([CH3:23])[CH2:21][C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)[C@H:6]([C:12]#[N:13])[CH2:7][CH2:8]1)#[CH:11]
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reactant: CC(C)(N)Cc1ccc(F)cc1
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC(C)(C)Cc1ccc(F)cc1
Reaction time: 48 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.05 g, 0.25 mmol, Example 8D) in acetonitrile (3 mL) at room temperature under nitrogen was added 1-(4-fluorophenyl)-2-methyl-2-propylamine (0.09 g, 0.508 mmol). The reaction mixture was stirred for two days and then concentrated under reduced pressure. The residue was flash chromatographed with 1-2% MeOH/CH2Cl2 to provide the desired compound as a white powder. MS (DCI) m/z 328 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.01-2.04(2H, m), 2.05 (2H, s), 2.07 (2H, s), 3.03 (1H, m), 3.04 (6H, s), 3.5-4.57 (2H, m), 4.57-4.58 (1H, m), 4.58-5.59 (1H, m), 7.0-7.03 (4H, m).
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(Cl)Cl>[CH2:22]([O:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCBr
Reactant: O=C(c1ccc(O)nc1)N1CCC[C@H]1CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCOc1ccc(C(=O)N2CCC[C@H]2CN2CCCC2)cn1
Temperature: 85 °C
Reaction time: 10 h
Yield: 50.6 %

Procedure:
A mixture of (6-hydroxy-pyridin-3-yl)-(S)(+)-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (85 mg, 0.31 mmol), 1-bromo butane (0.04 mL, 0.36 mmol), cesium carbonate (195 mg, 0.60 mmol), and catalytic KI in dioxane (5 mL) is stirred under nitrogen at 80-90° C. for 10 h. The reaction is diluted with CH2Cl2, filtered, and washed with brine. The organic portion is dried over Na2SO4, filtered and evaporated. The crude product is partially purified by a SCX column (MeOH wash, elution with 2M NH3 in MeOH. Further purification is accomplished using silica-gel column chromatography (gradient: 100% CH2Cl2 to 10% 2M NH3 in MeOH/CH2Cl2) to give the title compound (52 mg, 50%). MS (ES+) 332.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH:7]([O:11][C:12](=[O:14])[CH3:13])[C:8]([CH3:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH3:22]>CN(C=O)C>[C:1]([O:5][C:6](=[O:15])[C:7]([O:11][C:12](=[O:14])[CH3:13])([C:8](=[O:9])[CH3:10])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)OC(C(C)=O)C(=O)OC(C)(C)C
Reactant: CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCC(OC(C)=O)(C(C)=O)C(=O)OC(C)(C)C
Yield: 67.8 %

Procedure:
According to the general alkylation method, tert-butyl-2-acetoxy-aceto-acetate (219a) (7.12 g, 32.9 mmol), NaH (900 mg, 37.5 mmol) and pentylbromide (4.97 g, 32.9 mmol) were reacted in DMF (64 mL) to give 2-acetoxy-2-acetyl-heptanoic-acid-tert-butylester (250j) (6.40 g, 22.3 mmol, 68%) as a slightly yellow oil after Kugelrohr distillation at 185° C. and 1.0 mbar. Then, 250j (6.40 g, 22.3 mmol) and 402 mg (2.11 mmol) p-TsOH.H2O were stirred in 65 mL benzene according to decarboxylation method A. Kugelrohr distillation at 1.0 mbar and 125° C., followed by column chromatography (ethyl acetate:petroleum ether=1:4) gave 251j (1.6 g, 8.59 mmol, 39%) as a colorless oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.C(NC(C)C)(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCc1cccc(I)c1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CS(=O)(=O)OCCCCc1cccc(I)c1

Procedure:
4-(3-Iodophenyl)butan-1-ol (1.7 g) was stirred with diisopropylamine (1.74 ml) and methanesulfonyl chloride (0.66 ml) in dichloromethane (50 ml) at 21° for 2 h. The solution was washed successively with sodium bicarbonate solution, water, water acidified with a few drops of 2M HCl and water, each time back extracting with dichloromethane. The combined organic layers were dried (MgSO4) and evaporated to give the title compound (2.23 g), tlc Rf=0.28 (1:3 ethyl acetate in cyclohexane)
Reaction SMILES: [C:1]([O:20]C)(=O)[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][C:15](OC)=O>C1CCCCC1>[C:1]1(=[O:20])[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]1
Reactant: COC(=O)CCCCCCCCCCCCCC(=O)OC
Solvent: C1CCCCC1
Product: O=C1CCCCCCCCCCCCCC1
Yield: 62.1 %

Procedure:
The same procedures as described in Example 1 were repeated except that a solution of 110 g of dimethyl n-pentadecanedioate in 250 ml of cyclohexane was used as a starting material. There was obtained 51 g of cyclopentadecanone, which corresponded to 62.1% of a theoretical value based on the starting compound.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C1(C)C(C)=CC=CC=1.[C:18]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25](Cl)[CH:24]=1)(=[O:20])[CH3:19]>C1(C)C=CC=CC=1>[C:18]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:24]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OCc1cccc(Cl)c1
Reactant: Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: CC(=O)OCc1cccc(Oc2ccccc2)c1
Yield: 73 %

Procedure:
18.07 g. (0.192 mole) of phenol, 8.42 g. (0.15 mole) of potassium hydroxide and 20 cm3 of xylene are weighed together. The water is azeotropically distilled with stirring and boiling then the xylene is also distilled. To the reaction mixture 1.0 g. of copper(I) chloride and 1.0 g. of activated copper are added and in oil bath of 160° C. 18.07 g. (0.1 mole) of 3-chlorobenzyl acetate are dropped during 70 minutes then stirred at the same temperature for four hours. After cooling 25 cm3. of toluene are added to the reaction mixture, then the reaction mixture is filtered off and washed with 25 cm3. of toluene. The filtrate is washed with a mixture of 30 cm3. 15% sodium chloride solution and 2 cm3. 40% sodium hydroxide solution. The organic phase is evaporated and the residue is distilled in vacuo. 17.68 g. of 3-phenoxybenzyl acetate are obtained. Boiling point 138°-144° C./40 Pa, nD20 : 1.562, yield 73%.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:7])[CH2:5][OH:6].[Cl:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11](Cl)[N:10]=1>C1COCC1>[Cl:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11]([O:6][CH2:5][CH:4]([CH3:7])[CH3:3])[N:10]=1
Reactant: CC(C)CO
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)COc1cncc(Cl)n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A flame-dried round bottom flask was charged with a suspension of 95% NaH (1.1 eq) in anhydrous THF (0.3 M). The stirring mixture was cooled to 0° C. in an ice-water bath and 2-methyl-1-propanol (1 eq) was added drop wise via syringe. After 30 min 2,6-dichloropyrazine (1 eq) was added, the reaction was warmed to rt and stirred for 3 h. The crude mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic phases were washed once each with H2O and brine, then dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was dissolved in CH2Cl2, loaded onto a SiO2 column, and purified by flash chromatography (9:1 hexanes/EtOAc eluent) to give 2-chloro-6-isobutoxypyrazine. LC/MS (m/z): 187.1 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[C:10]([S:14][C:15](=[O:20])[CH2:16][C:17](=[O:19])[CH3:18])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([S:14][C:15](=[O:20])[CH:16]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1)[C:17](=[O:19])[CH3:18])([CH3:13])([CH3:11])[CH3:12]
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(=O)CC(=O)SC(C)(C)C
Product: CC(=O)C(Cc1ccc(Cl)cc1)C(=O)SC(C)(C)C

Procedure:
The title compound was prepared by the method of Preparation 34a using 1-bromomethyl-4-chlorobenzene and 3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:21]([O:22][CH3:23])=[N:20][C:7]2[CH2:8][CH2:9][N:10]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:11][CH:12]([CH3:13])[C:6]=2[CH:5]=1)[CH3:2].C1C(=O)N([Cl:31])C(=O)C1>CC#N>[Cl:31][C:5]1[C:6]2[CH:12]([CH3:13])[CH2:11][N:10]([C:14](=[O:19])[C:15]([F:17])([F:16])[F:18])[CH2:9][CH2:8][C:7]=2[N:20]=[C:21]([O:22][CH3:23])[C:4]=1[NH:3][CH2:1][CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCNc1cc2c(nc1OC)CCN(C(=O)C(F)(F)F)CC2C
Solvent: CC#N
Product: CCNc1c(OC)nc2c(c1Cl)C(C)CN(C(=O)C(F)(F)F)CC2
Yield: 36.5 %

Procedure:
To a solution of N-ethyl-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (99.0 mg, 0.30 mmol) in MeCN (5 ml) was added NCS (44.0 mg, 0.33 mmol) at room temperature and the mixture was refluxed for 30 minutes. The reaction was quenched with excess of sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo and purified by column chromatography to give 40 mg (36%) of 4-chloro-N-ethyl-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H-NMR (CDCl3) δ 4.39 (0.5H), 4.04 (0.5H), 3.94 (3H), 3.83 (1H), 3.78 (1H), 3.72 (1H), 3.45 (1H), 3.35 (2H), 3.25 (1H), 3.09 (1H), 1.19 (6H) ppm. A mixture of 4chloro-N-ethyl-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (37.0 mg, 0.10 mmol), K2CO3 (40 mg), MeOH (1.5 ml) and H2O (0.3 ml) was stirred for 16 h at room temperature. After removal of solvent under reduced pressure, the mixture was taken into aq. NaHCO3 and extracted with DCM. The organic layer was dried and concentrated in vacuo to give 27 mg (93%) of 4-chloro-N-ethyl-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H-NMR (CDCl3) δ 3.85 (s, 3H), 3.47 (m, 1H), 3.23 (m, 2H), 3.16 (m, 2H), 3.08 (m, 1H), 2.89 (dd, 2H), 2.69 (dd, 1H), 1.22 (d, 3H), 1.09 (t, 3H) ppm.
Reaction SMILES: [ClH:1].C(OC([N:9]1[C@H:14]([C:15]2[NH:16][C:17]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH:26]=[C:25]([C:30]3[CH:35]=[CH:34][C:33]([C:36]5[NH:40][C:39]([C@@H:41]6[CH2:46][C@@H:45]7[C@@H:43]([CH2:44]7)[N:42]6[C:47]([O:49][CH2:50][C:51]6[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=6)=[O:48])=[N:38][CH:37]=5)=[CH:32][CH:31]=3)[CH:24]=[CH:23]4)=[CH:18][N:19]=2)[CH2:13][C@@H:12]2[C@H:10]1[CH2:11]2)=O)(C)(C)C>O1CCOCC1>[ClH:1].[C@@H:10]12[CH2:11][C@@H:12]1[CH2:13][C@@H:14]([C:15]1[NH:16][C:17]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH:26]=[C:25]([C:30]3[CH:31]=[CH:32][C:33]([C:36]5[NH:40][C:39]([C@@H:41]6[CH2:46][C@@H:45]7[C@@H:43]([CH2:44]7)[N:42]6[C:47]([O:49][CH2:50][C:51]6[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=6)=[O:48])=[N:38][CH:37]=5)=[CH:34][CH:35]=3)[CH:24]=[CH:23]4)=[CH:18][N:19]=1)[NH:9]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6C[C@H]7C[C@H]7N6C(=O)OCc6ccccc6)[nH]5)cc4)ccc3c2)[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc([C@@H]6C[C@H]7C[C@H]7N6)[nH]5)ccc4c3)cc2)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 118.4 %

Procedure:
A solution of 4.0 M HCl (1.167 mL, 4.67 mmol) in dioxane was added to a stirred solution of (1R,3S,5R)-benzyl 3-(5-(4-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (228 mg, 0.311 mmol) in dioxane (3 mL) and the reaction was stirred vigorously at rt for 3 h. The reaction was concentrated to yield an HCl salt of (1R,3S,5R)-benzyl 3-(5-(4-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hex an-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (233 mg) as a yellow solid. LC-MS retention time 3.988 min; m/z 633.18 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, MeOD) δ ppm 8.44 (s, 1H), 8.28 (s, 1H), 8.08-8.18 (m, 3H), 7.92-8.02 (m, 4H), 7.84 (br. s., 3H), 7.31 (br. s., 5H), 5.21 (d, J=12.1, 1 H), 4.95-5.05 (m, 2H), 4.80-4.91 (m, 1H), 3.70-3.77 (m, 1H), 3.59-3.67 (m, 1H), 2.77-2.93 (m, 2H), 2.74 (dd, J=13.4, 9.2 Hz, 1H), 2.46 (dt, J=13.5, 6.7 Hz, 1H), 2.12-2.22 (m, 1H), 1.83-1.96 (m, 1H), 1.27-1.35 (m, 1H), 1.09 (q, J=7.9 Hz, 1H), 0.95 (ddd, J=8.7, 5.9, 5.8 Hz, 1H), 0.75-0.83 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:17][C:18]([C:20]1[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([NH2:29])=[CH:24][CH:23]=2)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([NH:29][C:12]([C:10]1[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=1)=[O:14])=[CH:24][CH:23]=2)=[O:19])[CH3:16]
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Reactant: O=C(O)c1ccc(-c2ccccc2)o1
Product: CCOC(=O)c1cc2cc(NC(=O)c3ccc(-c4ccccc4)o3)ccc2[nH]1

Procedure:
5-Phenyl-furan-2-carboxylic acid (56) (35 mg, 0.19 mmol) was coupled to 5-amino-1H-indole-2-carboxylic acid ethyl ester (42 mg, 0.20 mmol) using Method D to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[O:15])[CH2:11][CH:10]2[C:24](=[O:26])[CH3:25])[CH:5]=[CH:6][C:7]=1[Cl:8].[Li+].[BH4-]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:10]([CH:24]([OH:26])[CH3:25])[CH2:11][N:12]([C:14]([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[O:15])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(C(=O)N2CC(C(C)=O)C(c3ccc(Cl)c(Cl)c3)C2)cn1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: COc1ccc(C(=O)N2CC(c3ccc(Cl)c(Cl)c3)C(C(C)O)C2)cn1
Temperature: 25 °C
Yield: 23.7 %

Procedure:
To a stirred solution of 1-[(3SR,4RS)-4-(3,4-dichloro-phenyl)-1-(6-methoxy-pyridine-3-carbonyl)-pyrrolidin-3-yl]-ethanone (XIV-1) (0.64 g, 1.60 mmol) in MeOH (10 mL) at −78° C. was added LiBH4 (0.047 g, 1.70 mmol). The temperature was slowly raised to RT (over 1 hour), and the reaction mixture was quenched by addition of H2O. The product was extracted with EtOAc, the combined organic phases were dried over Na2SO4. The two diastereoisomers were separated by column chromatography (SiO2) to yield 0.15 g (23%) of [(3RS,4SR)-3-(3,4-dichloro-phenyl)-4-((RS)-1-hydroxy-ethyl)-pyrrolidin-1-yl]-(6-methoxy-pyridin-3-yl)-methanone (XV-A-1) as a white solid ES-MS m/e: 395.3 (M+H+) and 0.48 g (75%) of [(3RS,4SR)-3-(3,4-dichloro-phenyl)-4-((SR)-1-hydroxy-ethyl)-pyrrolidin-1-yl]-(6-methoxy-pyridin-3-yl)-methanone (XV-B-1) as a white solid ES-MS m/e: 395.3 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:6][CH:7]=1.[C:15]([NH:18][NH2:19])(=O)[CH3:16]>C(O)CCC>[Cl:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:3]([C:15]([CH3:16])=[N:18][N:19]=3)[N:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cccc(-c2ccc(Cl)nn2)c1
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3cccc(Cl)c3)nn12

Procedure:
A mixture of 2.0 g. of 3-chloro-6-(m-chlorophenyl)pyridazine, 50 ml. of n-butanol and 1.32 g. of acetylhydrazine is refluxed for 18 hrs. The mixture is concentrated to dryness under vacuum and the residue dissolved in methylene chloride. The solution is passed through a short column of hydrous magnesium silicate. The eluent is refluxed while hexane is gradually added until crystals separated. Cooling and filtering gives 1.50 g. of crystals, m.p. 171°-172.5° C.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[C:20]([F:26])=[CH:19][C:8]=1[NH:9]S(C1C=CC=CC=1)(=O)=O>O>[F:6][C:7]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[C:20]([F:26])=[CH:19][C:8]=1[NH2:9]
Reactant: O=[N+]([O-])c1cc(F)c(NS(=O)(=O)c2ccccc2)cc1F
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1cc(F)c([N+](=O)[O-])cc1F
Temperature: 70 °C

Procedure:
10 ml of water are added with due care to 75 ml of concentrated sulphuric acid; the temperature rises to 70° C. 0.105 mole (33 g) of 2,5-difluoro-4-nitro-N-benzenesulphonylaniline prepared in the previous stage is then added. The temperature is maintained at 70° C. for 2 hours. The reaction mixture is poured onto 1 kg of ice and water and the expected product precipitates. After filtration and washing to neutrality the product is recrystallized from 100 ml of 96° ethanol. It melts at 153° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22](O)=[O:23])=[CH:16][CH:15]=1.O>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:22](=[O:23])[CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=C(O)CCc1ccc(Cl)cc1
Reactant: COc1ccc(CCN)cc1C
Solvent: Cc1ccccc1C
Solvent: O
Product: COc1ccc(CCNC(=O)CCc2ccc(Cl)cc2)cc1C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
Heat a solution of 2-(3-methyl-4-methoxyphenyl)ethylamine (64.4 g) and 3-(4-chlorophenyl)-propionic acid (70.2 g) in xylene (600 mL) at reflux over a Dean-Stark trap for 5.5 h. Pour the hot reaction mixture into water an allow to stand overnight. Filter to collect the solid and recrystallize from ethanol to give N-[2-(3-methyl-4-methoxyphenyl)ehtyl]-3(4-chlorophenyl) propionamide (101.1 g), mp=142°-144° C.
Reaction SMILES: Br[C:2]1[C:19]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:18]([CH3:28])[C:5]2[CH:6]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=3)[CH2:7][O:8][C:4]=2[C:3]=1[CH3:29].CCCCCC.[C:36](OCC)(=[O:38])C>>[CH:15]([C:12]1[CH:11]=[CH:10][C:9]([CH:6]2[C:5]3[C:18]([CH3:28])=[C:19]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])[C:2]([O:38][CH3:36])=[C:3]([CH3:29])[C:4]=3[O:8][CH2:7]2)=[CH:14][CH:13]=1)([CH3:17])[CH3:16]
Reactant: CCOC(C)=O
Reactant: Cc1c(Br)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Solvent: CCCCCC
Product: COc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Yield: 37 %

Procedure:
Using N-(6-bromo-3-(4-isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 87, the title compound was synthesized in the same manner as in Example 36. Yield: 37%. Melting point: 162-163° C. (hexane-ethyl acetate).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][NH2:10]>>[CH3:9][NH:10][C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1nccnc1Cl
Reactant: CN
Product: CNc1nccnc1C

Procedure:
2-chloro-3-methylpyrazine (124 mg, 1.0 mmol) and methylamine (5 mL, 2M solution in THF) was irradiated in a microwave oven at 190° C. for 10 hours. The solution is evaporated and the residue was dissolved in CH2Cl2 (10 mL). It was partitioned with NaOH (1 mL, 5N), dried with NaSO4, filtered and volatiles removed in vacuo to afford N,3-dimethylpyrazin-2-amine. 1H NMR (400 MHz, CDCl3): 7.92 (d, 1H), 7.70 (d, 1H), 4.40 (s, br, 1H), 3.03 (d, 3H), 2.36 (s, 3H). MS (ES+): M/Z 124 (M+1).