Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([OH:16])[C@H:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([OH:16])[C@H:10]([O:15][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24])[C:11]([O:13][CH3:14])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H](O)[C@H](O)c1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](OS(=O)(=O)c1ccc(C)cc1)[C@H](O)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 72 h
Yield: 72.4 %

Procedure:
Under argon atmosphere, a solution of 955 mg of methyl (2S,3R)-3-(2,4-difluorophenyl)-2,3-dihydroxypropionate dissolved in 30 ml of dichloromethane was cooled to 0° C., and to the solution was added 940 mg of p-toluenesulfonyl chloride and 624 mg of triethylamine. After the mixture was stirred at 0° C. for 3 days, the reaction mixture was washed with water and dried, and the solvent was removed. The residue was purified by silica gel column chromatography (solvent; hexane:ethyl acetate=2:1) to obtain 1.15 g of methyl (2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-(p-toluenesulfonyloxy)propionate.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)(=[O:4])=[O:3].Cl.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([CH:26]2[CH2:31][CH2:30][N:29]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:15][CH:14]=3)=[O:13])[CH2:28][CH2:27]2)=[O:25])=[CH:22][CH:23]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Reactant: CS(=O)(=O)NCc1ccc(C(=O)O)cc1
Agent: Cl
Product: CS(=O)(=O)NCc1ccc(C(=O)N2CCC(C(=O)c3ccc(Cl)cc3)CC2)cc1
Yield: 54.5 %

Procedure:
Using 4-(methanesulfonylaminomethyl)benzoic acid (100 mg) and (4-chlorophenyl)(piperidin-4-yl)methanone hydrochloride (113 mg) and by the reaction and treatment in the same manner as in Example 86, the title compound (103 mg) was obtained.
Reaction SMILES: Cl[C:2](OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].CCN(C(C)C)C(C)C.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][C@H:25]1[CH2:31][OH:32].[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1>C(Cl)Cl>[F:33][C:34]1[CH:35]=[CH:36][C:37]([N:40]2[CH2:45][CH2:44][N:43]([C:2]([O:32][CH2:31][C@@H:25]3[CH2:26][N:27]([CH3:30])[CH2:28][CH2:29][N:24]3[CH3:23])=[O:3])[CH2:42][CH2:41]2)=[CH:38][CH:39]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN1CCN(C)[C@H](CO)C1
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(C)[C@H](COC(=O)N2CCN(c3ccc(F)cc3)CC2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
4-Nitrophenyl chloroformate (5.17 g, 25.7 mmol) was dissolved in DCM (200 mL) at room temperature and the reaction mixture was cooled to 0° C. and DIPEA (6.94 g, 9.38 mL, 53.9 mmol) and 1,4-dimethyl-(S)-2-hydroxymethyl piperazine (Intermediate 3; 3.70 g, 25.7 mmol) were added. The reaction mixture was stirred at room temperature for 2 h, and then split into three equal volumes. To one portion was added 1-(4-fluoro-phenyl)-piperazine (1.53 g, 8.5 mmol) and the mixture was stirred for 48 h. The solvent was removed in vacuo and the residue partitioned between EtOAc (500 mL) and 1.0M NaOH solution (200 mL). The organic layer was washed with 10M aq NaOH solution (5×125 mL), brine (100 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was dissolved in DCM (100 mL) and isocyanate resin (3 g) was added, the reaction mixture was shaken for 14 h, filtered and the solvent was removed in vacuo. The residue was purified by reverse phase column chromatography (LiChroprep RP-18, 40-63 μm, 460×26 mm (100 g), 30 mL/min, gradient 0% to 30% (over 75 min) to 100% (over 13 min) MeOH in water with 1% formic acid). The residue was de-salted using K2CO3 in DCM to give [(2S)-1,4-dimethylpiperazin-2-yl]methyl 4-(4-fluorophenyl)piperazine-1-carboxylate (1.78 g, 60.0%) as a light yellow gum.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1.[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)#[N:18].[CH3:27][C:28](=O)[CH2:29][C:30](=[O:32])[CH3:31].FC(F)(F)C(O)=O>C(OC(C)C)(C)C>[C:30]([C:29]1[CH:23]([C:22]2[CH:25]=[CH:26][C:19]([C:17]#[N:18])=[CH:20][CH:21]=2)[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([CH3:16])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[C:28]=1[CH3:27])(=[O:32])[CH3:31]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(=O)CC(C)=O
Reactant: CCOC(=O)/C=C(\C)Nc1cccc(C)c1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1=C(C)N(c2cccc(C)c2)C(C)=C(C(C)=O)C1c1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
100 mg (0.46 mmol) Ethyl(2E)-3-{[3-(methyl)phenyl]amino}-2-butenoate, 75 mg. (0.57 mmol) 4-cyanobenzaldehyde, 38 mg (0.38 mmol) 2,4-pentanedione, and 87 mg (0.76 mmol) trifluoroacetic acid are dissolved in 2 ml diisopropyl ether. The reaction mixture is stirred under reflux overnight. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by preparative HPLC.
Reaction SMILES: N[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[N:10]1.[CH2:18]=O>CCO>[N:9]1([CH2:18][C:2]2[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[N:10]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: Cc1cccnc1N
Reactant: C=O
Solvent: CCO
Product: Cc1cccnc1Cn1nnc2ccccc21
Temperature: 20 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
A mixture of 2-amino-3-methylpyridine (43.28 g, 0.4 mol) and benzotriazole (47.65 g, 0.4 mol) in EtOH (500 mL) was treated over 5 minutes with formaldehyde (32.2 g of 37% solution, 0.4 mol). The mixture was stirred at 20° C. overnight, then cooled and filtered to give 2-[(1-benzotriazolyl)methyl]-3-methyl pyridine (30 g, 31%). A sample was crystallized from EtOH; mp 175°-177° C.
Reaction SMILES: [CH2:1]([C:3]1([CH2:22][CH3:23])[C:8]2[CH:9]=[C:10]([C:13]3[N:17]([CH3:18])[C:16]([C:19]#[N:20])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=O)[O:4]1)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH2:22][CH3:23])[C:8]2[CH:9]=[C:10]([C:13]3[N:17]([CH3:18])[C:16]([C:19]#[N:20])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[S:33])[O:4]1)[CH3:2]
Reactant: CCC1(CC)OC(=O)Nc2ccc(-c3ccc(C#N)n3C)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC1(CC)OC(=S)Nc2ccc(-c3ccc(C#N)n3C)cc21
Yield: 15.2 %

Procedure:
5-(4,4-diethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile (0.5 g, 1.6 mmol) and Lawesson's Reagent (0.33 g, 0.81 mmol) were heated to 100° C. in toluene (20 mL). Upon completion by TLC, the reaction was poured into saturated sodium carbonate (100 mL) and extracted with ethyl acetate (50 mL), dried over magnesium sulfate, and concentrated. The purification with column gave 5-(4,4-diethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile (0.040 g, 8%) as a tan solid. 1H NMR (DMSO-d6): δ 12.15 (s, 1H), 7.44 (d, 1H, J=8.3, 1.8 Hz), 7.37 (d, 1H, J=1.8 Hz), 7.12 (d, 1H, J=8.3 Hz), 7.04 (d, 1H, J=4.03 Hz), 6.35 (d, 1H, J=4.2 Hz), 3.7 (s, 3H), 2.07 (m, 2H, J=7.4 Hz), 1.95 (m, 2H, J=7.4 Hz), 0.79 (t, 6H, J=7.4 Hz). MS (ESI) m/z 326 ([M+H]+); MS (ESI) m/z 324 ([M−H]−). HRMS: calcd for C18H19N3OS, 325.1249; found (ESI_FT), 326.13187.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:8]=2[NH2:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:15](OC(=O)CC1N=C(N)SC=1)C.[CH2:27]([O:29][C:30](=[O:53])[CH2:31][C:32]1[N:33]=[C:34]([NH:37][C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][C:42]=2[O:48][CH2:49][CH:50]2[CH2:52][CH2:51]2)=[O:39])[S:35][CH:36]=1)[CH3:28]>>[CH2:27]([O:29][C:30](=[O:53])[CH2:31][C:32]1[N:33]=[C:34]([NH:37][C:38]([NH:9][C:8]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:7]=2[O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:39])[S:35][CH:36]=1)[CH3:28].[CH:49]1([O:48][C:42]2[CH:43]=[C:44]([CH3:47])[CH:45]=[CH:46][C:41]=2[NH:40][C:38](=[O:39])[NH:37][C:34]2[S:35][CH:36]=[C:32]([CH2:31][C:30]([OH:29])=[O:53])[N:33]=2)[CH2:15][CH2:51][CH2:52][CH2:50]1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: Cc1ccc(N)c(OC2CCCC2)c1
Reactant: CCOC(=O)Cc1csc(NC(=O)Nc2ccc(C)cc2OCC2CC2)n1
Product: CCOC(=O)Cc1csc(NC(=O)Nc2ccc(C)cc2OC2CCCC2)n1
Product: Cc1ccc(NC(=O)Nc2nc(CC(=O)O)cs2)c(OC2CCCC2)c1
Yield: 91 %
Yield: 62 %

Procedure:
{2-[3-(2-Cyclopentyloxy-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester (250 mg, 62%) was prepared from 2-cyclopentyloxy-4-methyl-aniline (191 mg, 1.0 mmol) and (2-amino-thiazol-4-yl)-acetic acid ethyl ester (186 mg, 1.0 mmol) following the general procedure D. {2-[3-(2-Cyclopentyloxy-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid (170 mg, 91%) was prepared from {2-[3-(2-cyclopropylmethoxy-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester (200 mg, 0.5 mmol) following the general procedure J.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][NH:8][C:9]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][CH:28]=[C:27]([F:32])[C:26]=3[F:33])=[N:13][CH:12]=2)=[O:10])[C:4]([CH3:34])=[N:3]1.[H-].[Na+].I[CH2:38][CH3:39].O>CN(C=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][N:8]([CH2:38][CH3:39])[C:9]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][CH:28]=[C:27]([F:32])[C:26]=3[F:33])=[N:13][CH:12]=2)=[O:10])[C:4]([CH3:34])=[N:3]1
Reactant: CCI
Reactant: Cc1nn(C)cc1CNC(=O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(Cc1cn(C)nc1C)C(=O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Reaction time: 0.25 h

Procedure:
To a solution of N-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazole-5-carboxamide (508) (70 mg, 0.143 mmol) in DMF (1.5 mL) was added sodium hydride (60% in mineral oil, 7 mg, 0.172 mmol) and the reaction was stirred for 15 minutes. Iodoethane (13 mL, 0.172 mmol) was added and stirred for 1 hour. Water was added slowly and the reaction was extracted with 1:1 EtOAc:Hexane, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (90-100% EtOAc in hexanes) to afford N-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-N-ethyl-1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazole-5-carboxamide (519). 1H NMR (400 MHz, CDCl3) δ: 7.33 (s, 1H), 7.18-6.91 (m, 6H), 6.82-6.73 (m, 1H), 4.37 (s, 2H), 4.34 (s, 2H), 3.77 (s, 3H), 3.37 (q, J=7.0, 2H), 2.16-2.06 (m, 3H), 1.25-1.00 (m, 3H). LC-MS ESI m/z; found 518.0 [M+H]+.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([CH2:7][CH2:8][CH2:9][P+](CC)(CC)CC)=[O:6])[CH3:3].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(C)([O-])C.[K+]>CC(OC)(C)C>[C:18]1(/[CH:17]=[CH:9]\[CH2:8][CH2:7][C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)CCC[P+](CC)(CC)CC
Reactant: O=Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: COC(C)(C)C
Product: CCOC(=O)CC/C=C\c1ccccc1
Reaction time: 8 h

Procedure:
3-Ethoxycarbonylpropyltriethylphosphonium bromide (5.488 g, 12.00 mmol), benzaldehyde (3.820 g, 36.00 mmol) and potassium tert-butoxide (4.040 g, 36.00 mmol) were taken up in MTBE (300 mL) at room temperature and was stirred overnight. The reaction mixture was washed with water (1×100 mL) and the aqueous phase was extracted with MTBE (3×100 mL). Solvent was removed from the combined organic phase under reduced pressure and the resulting oil purified by column chromatography (0-10% EtOAc/n-hexane, silica) to give (Z)-ethyl 5-phenylpent-4-enoate as a pale yellow oil. 1H NMR (CDCl3): δ 7.36-7.31 (m, 2H), 7.28-7.21 (m, 3H), 6.47 (d, 1H, J=11.6, Ph-CH), 5.63 (dt, 1H, J1=11.6, J2=7.2), 4.14 (q, 2H, J=7.2), 2.66 (dq, 2H, J1=7.3, J2=1.7), 2.43 (t, 2H, J=7.6), 1.24 (t, 3H, J=7.1). Contains ca. 33% (E)-ethyl 5-phenylpent-4-enoate
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.FC(F)(F)[C:13]1[CH:14]=[C:15]([C:19]([CH:21]=O)=[O:20])[CH:16]=[CH:17][CH:18]=1.C1(C(C=O)=O)C=CC=CC=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH2:21][CH:19]([OH:20])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CCN)cc1
Reactant: O=CC(=O)c1cccc(C(F)(F)F)c1
Agent: O=CC(=O)c1ccccc1
Product: Cc1ccc(CCNCC(O)c2ccccc2)cc1

Procedure:
The title compound was prepared in the manner described in Example 9, replacing 2-(4-methylphenyl)-1,1-dimethylethanamine by 2-(4-methylphenyl)ethanamine and 3-trifluoromethylphenylglyoxal by phenylglyoxal. The chromatographed material was recrystallised from hexane to give the title compound, mp 95°-97°.
Reaction SMILES: [CH2:1]1[C:8]2[C:7]3[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[CH2:3][CH2:2]1.[C:14]([CH2:18][C:19](Cl)=[O:20])([CH3:17])([CH3:16])[CH3:15]>N1C=CC=CC=1>[CH2:1]1[C:8]2[C:7]3[CH:9]=[C:10]([NH:13][C:19](=[O:20])[CH2:18][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[CH2:3][CH2:2]1
Reactant: Nc1ccc2oc3c(c2c1)CCC3
Reactant: CC(C)(C)CC(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)CC(=O)Nc1ccc2oc3c(c2c1)CCC3
Yield: 60.4 %

Procedure:
Following the procedure of Example 1, 2,3-dihydro-1H-cyclopenta[b]benzofuran-7-ylamine (0.87 g, 5.0 mmol) and t-butylacetyl chloride (0.77 mL, 5.5 mmol) in pyridine (10 mL) provided N-(2,3-dihydro-1 H-cyclopenta[b]benzofuran-7-yl)-3,3-dimethyl-butyramide (0.82 g). Mp 195.5-197.0 ° c; MS (El) m/z 272 ([M+H]+); Anal. Calcd. for C17H21NO2: C, 75.25; H, 7.80; N, 5.16; Found: C, 75.34; H, 7.82; N, 5.14.
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4]([C:6]1([CH:12]([C:15]#[N:16])[C:13]#[N:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[CH2:5]>C(O)CCC>[CH:4]([C:6]1([C:12]2[C:13]([NH2:14])=[N:2][NH:3][C:15]=2[NH2:16])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[CH2:5].[NH2:14][C:13]1[C:12]([C:6]2([CH2:4][CH3:5])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)=[C:15]([NH2:16])[NH:3][N:2]=1
Reactant: NN
Reactant: C=CC1(C(C#N)C#N)CCCCC1
Solvent: CCCCO
Solvent: O
Product: C=CC1(c2c(N)n[nH]c2N)CCCCC1
Product: CCC1(c2c(N)n[nH]c2N)CCCCC1
Temperature: 100 °C

Procedure:
Hydrazine monohydrate (0.098 mL, 1.69 mmol) was added to a solution of the product from Example 145B (295 mg, 1.69 mmol) in n-butanol (5 mL), and the mixture was heated at 100° C. under nitrogen for 36 hours. The reaction solution was cooled to room temperature and concentrated under vacuum. The residue was dilute with water (15 mL) and extracted with EtOAc (2×15 mL). The combined organic phase was dried (MgSO4), filtered, and concentrated under vacuum to provide the title compound as an inseparable 1:1 mixture with 3,5-diamino-4-(1-ethylcyclohexyl)pyrazole, used directly in the next step.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[N+:20]([O-])=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:14]=1[NH:20][CH:2]=[CH:1]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1OCc1ccccc1
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Clc1ccc(OCc2ccccc2)c2[nH]ccc12
Temperature: -40 °C
Reaction time: 2 h

Procedure:
M Vinyl magnesium bromide solution in tetrahydrofuran (80 ml) was added to a stirred solution of 2-benzyloxy-5-chloronitrobenzene (5.28 g, 20 mmol) in tetrahydrofuran (160 ml) at -40° C. The mixture was stirred for 2 hours at -40° C. then poured onto saturated ammonium chloride solution (500 ml) and extracted with ether. The extract was dried and evaporated and the residue was chromatographed on silica in ethyl acetate-hexane (1:8) to give a yellow oil.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[CH2:7][PH3+].C([Li])CCC.CCCCCC.[Si:27]([O:34][C:35]1[C:42]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])=[CH:41][CH:40]=[CH:39][C:36]=1[CH:37]=O)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>O1CCCC1.O>[CH3:2][O:3][C:4]1[CH:5]=[C:6](/[CH:7]=[CH:37]\[C:36]2[C:35]([O:34][Si:27]([C:30]([CH3:33])([CH3:31])[CH3:32])([CH3:29])[CH3:28])=[C:42]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:45])[CH3:46])[CH:41]=[CH:40][CH:39]=2)[CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13]
Reactant: COc1cc(C[PH3+])cc(OC)c1OC
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1O[Si](C)(C)C(C)(C)C
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(/C=C\c2cccc(O[Si](C)(C)C(C)(C)C)c2O[Si](C)(C)C(C)(C)C)cc(OC)c1OC
Temperature: -40 °C
Reaction time: 1 h

Procedure:
A suspension of 3,4,5-trimethoxybenzylphosphonium bromide (1.047 g, 2 mmol) in 12 mL dry tetrahydrofuran was stirred under nitrogen while cooling to −40° C. then adding 1.52 mL of 1.6M butyllithium in hexane (2.44 mmol) dropwise over six minutes below −25° C. The mixture was kept at −15° C. for ten minutes before cooling to −70°. 7 (0.748 g, 2.04 mmol) was added as a solution in 3 mL THF dropwise below −60° C. and the pale orange solution allowed to reach 20° C. over a period of one hour. After stirring for a further three hours the mixture was allowed to stand overnight. Water (8.5 mL) was added slowly and the mixture extracted three times with 8.5 mL t-butyl methyl ether. The organics were washed with brine, dried and evaporated at 30° C. The crude was purified by flash chromatography (cyclohexane:AcOEt 95:5) after removing triphenylphosphine oxide by filtration to give a colourless oil 8 which solidified on standing (0.70 g):
Reaction SMILES: Cl.C(OC([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18](OC3CCNC3)[CH:19]=2)[NH:14][C:13]=1C)=O)C1C=CC=CC=1.CC(C)=O.C([BH3-])#[N:33].[Na+]>CO>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[C:13]1[NH2:33]
Reactant: Cc1[nH]c2ccc(OC3CCNC3)cc2c1C(=O)OCc1ccccc1
Reactant: [BH3-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: Nc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 189.2 %

Procedure:
Crude 2-methyl-5-(pyrrolidin-3-yloxy)-1H-indole-3-carboxylic acid benzyl ester, hydrochloride (0.040 g, 0.100 mmol, 1 eq, Example 47, Step A) was suspended in methanol (5 mL). Acetone (0.100 mL) was added followed by the addition of sodium cyanoborohydride (0.013 g, 0.2 mmol, 2.0 eq). The reaction mixture was kept at pH 6 and stirred at room temperature. After 24 hours, the reaction was quenched with aqueous sodium bicarbonate, extracted several times with CH2Cl2. The combined organic layers were dried over sodium sulfate, loaded on silica gel and chromatographed (ethyl acetate/methanol/triethylamine 87/10/3. 0.025 g (64% yield) of the indole-amine was obtained as a brown semisolid, and converted to the corresponding HCl salt: LC/MS (ESI+) 393 (M+1), Anal. (C24H28N2O3.HCl) C, H, N.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].N1C=CC=CC=1.[CH:20]1([CH2:26][C@H:27]([OH:36])[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>O1CCOCC1>[C:2](=[O:3])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[O:36][C@H:27]([C:28]([N:30]1[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1)=[O:29])[CH2:26][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C([C@@H](O)CC1CCCCC1)N1CCOCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H](CC1CCCCC1)C(=O)N1CCOCC1
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 73.3 %

Procedure:
A solution of 4-nitrophenyl chloroformate (20.55 g, 102 mmol) in dioxane (150 mL) is treated with pyridine (50 mL) resulting in a suspension. This material is heated to 70° C. and a solution of 3 (12.30 g, 51.0 mmol) in dioxane (50 mL) is added via pressure equalizing dropping funnel over ˜5 minutes. After stirring for an additional 5 minutes, the reaction is allowed to cool to room temperature and the solvent is removed by rotary evaporation. The resulting mass is partitioned between ethyl acetate and water. The organic layer is collected and the aqueous phase is extracted once more with ethyl acetate and discarded. The combined organics are dried over MgSO4 and the solvent is removed. The resulting solid is dissolved in a minimal amount of hot dichloroethane and treated with dichloromethane. The mixture is then kept in a −4° C. refrigerator overnight and filtered. The mother liquor is concentrated and purified over 330 g of silica gel using a gradient of 0-100% ethyl acetate in hexane to afford 15.2 g (73% yield) of (S)-2-cyclohexyl-1-(morpholine-4-carbonyl)ethyl 4-nitro-phenyl carbonate (4) as a slightly yellow oil; 1H NMR (CDCl3, 400 MHz) δ 0.97-1.08 (m, 2H), 1.09-1.36 (m, 3H), 1.48-4.62 (m, 2H), 1.65-1.68 (m, 4H), 1.82-1.97 (m, 2H), 3.41-3.60 (m, 3H), 3.64-3.80 (m, 5H), 5.29-5.36 (m, 1H), 7.38-7.44 (m, 2H), 8.24-8.30 (m, 2H); HPLC-MS calculated for C20H26N2O7 (M+H+) 407.2, found 407.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[C@H:10]([CH3:23])[N:9]=1.[C:24](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:24])[C:11](=[O:22])[C@H:10]([CH3:23])[N:9]=1
Reactant: C[C@@H]1N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2NC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: C[C@@H]1N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
57.5 g (0.18 M) of (S)-5-(o-fluorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-one are dissolved in 600 ml of absolute acetone. The solution is treated with 48 g of powdered potassium carbonate and 21 ml of methyl iodide and stirred at room temperature for 5 hours. The mixture is concentrated and the residue is treated with ice-water and extracted several times with methylene chloride. The methylene chloride solution is washed with water, dried over sodium sulphate, filtered and concentrated. The residue is crystallised from ether/petroleum ether and there is obtained (S)-5-(o-fluorophenyl)-1,3-dihydro-1,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one which melts at 118°-126° C. with decomposition; [α]25D =+563.1° (in methylene chloride; 1%).
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]1([C:14]2([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=[O:24]>N1C=CC=CC=1>[C:8]1([C:14]2([NH:20][C:23](=[O:24])[C:22]([CH3:27])([CH3:26])[CH3:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NC1(c2ccccc2)CCCCC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)NC1(c2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.3 %

Procedure:
Into a 200 ml four-necked flask, there were charged toluene (150 ml), 1-phenylcyclohexylamine (10.5 g) and pyridine (5.2 g), and trimethylacetyl chloride (7.2 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. After completion of the reaction, the reaction mixture was washed with water to remove pyridine hydrochloride. The toluene layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give 9.8 g of N-(1-phenylcyclohexyl)trimethylacetamide. M.P., 129°-130.5° C.