Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[C:6]([F:15])[CH:5]=1)([O-])=O.C(O)C.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:14]=[CH:13][C:7]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[C:6]([F:15])[CH:5]=1
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(CCC(=O)O)c(F)c1
Reaction time: 3 h
Yield: 81.2 %

Procedure:
4-nitro-2-fluorocinnamic acid (3.32 g, 17 mmol) was dissolved in ethyl acetate (50 mL) and ethanol (10 mL) in the reaction flask of a PAR reactor. Pd/C (100 mg) was added and the reactor charged with 100 psi hydrogen. The reactor was recharged to 100 psi after 3 hours and the reaction stirred overnight. The reaction mixture was filtered through a bed of celite and the product isolated in vacuo, 2.53 g 3-(4-amino-2-fluorophenyl)propionic acid (81.2%).
Reaction SMILES: [O:1]=[C:2]1[CH:6]([CH2:7][CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>[Pd].CO>[O:1]=[C:2]1[CH:6]([CH2:7][CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[N:10]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CN1CCC(CCc2ccc3cccnc3n2)C1=O
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CN1CCC(CCc2ccc3c(n2)NCCC3)C1=O
Reaction time: 2 h

Procedure:
A mixture of 2-6 (0.87 g, 2.6 mmol), 10% Pd/C (0.5 g), and CH3OH (25 mL) was stirred under a hydrogen atmosphere (1 atm) for 2 hr. The catalyst was then removed by filtration through a celite pad followed by concentration of the filtrate. Flash chromatogrphy (silica, EtOAc→5% CH3OH/EtOAc) gave 2-7 as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]([CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:8]2=[NH:27])=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:43]=[CH:42][C:34]([CH2:35][N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:33][CH:32]=1.CC(C)([O-])C.[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:30][C:31]1[CH:43]=[CH:42][C:34]([CH2:35][N:36]2[CH2:41][CH2:40][N:39]([C:2]3[CH:29]=[CH:28][C:5]([CH2:6][N:7]4[C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=5[N:9]([CH2:16][CH2:17][CH2:18][O:19][C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=5)[C:8]4=[NH:27])=[CH:4][CH:3]=3)[CH2:38][CH2:37]2)=[CH:33][CH:32]=1
Reactant: N=c1n(CCCOc2ccc(F)cc2)c2ccccc2n1Cc1ccc(Br)cc1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: N=c1n(CCCOc2ccc(F)cc2)c2ccccc2n1Cc1ccc(N2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Temperature: 105 °C
Yield: 17.7 %

Procedure:
To a solution 1-(4-bromo-benzyl)-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (0.25 g, 0.55 mmol) in toluene (20 ml) was added 1-(4-chloro-benzyl)-piperazine (0.16 g, 0.55 mmol), potassium t-butoxide (216 mg, 1.93 mmol), Pd2(dba)3 (35 mg, 0.038 mmol) and BINAP (48 mg, 0.077 mmol). Nitrogen was bubbled through the suspension for 5 min and then the reaction was heated to 105° C. for 24 h. After this time, the mixture was cooled to rt and filtered. The collected solids were washed with additional toluene and then the combined filtrate and washings were concentrated under reduced pressure. The crude product was purified by chromatography on silica to provide 1-{4-[4-(4-chloro-benzyl)-piperazin-1-yl]-benzyl}-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (57 mg, 18%). HPLC-MS 584 [M+1]+, 293.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[CH2:11]([O:13][C:14](=[O:25])[C:15](=[CH:21]OCC)[C:16](OCC)=[O:17])[CH3:12].C([O-])([O-])=O.[K+].[K+]>O>[C:9]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([N:1]2[C:16]([OH:17])=[C:15]([C:14]([O:13][CH2:11][CH3:12])=[O:25])[CH:21]=[N:2]2)[CH:8]=1)#[N:10]
Reactant: N#Cc1ccnc(NN)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cnn(-c2cc(C#N)ccn2)c1O
Temperature: 100 °C
Reaction time: 4 h
Yield: 24.2 %

Procedure:
A mixture of 2-hydrazinylpyridine-4-carbonitrile (5.36 g, 40 mmol, PREPARATION 2), diethyl(ethoxymethylidene)propanedioate (8.64 g, 40 mmol) and K2CO3 (10.76 g, 80 mmol) in H2O (100 mL) was stirred at 100° C. for 4 h. The reaction mixture was cooled to rt and filtered to afford the title compound (2.5 g, 24%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 1.19 (3H, t, J=7.2 Hz), 4.02 (2H, q, J=7.2 Hz), 7.38 (1H, dd, J=4.8, 1.6 Hz), 7.53 (1H, s), 8.53 (1H, d, J=5.2 Hz), 8.79 (1H, s). [M+H] Calc'd for C12H10N4O3, 259; Found, 259.
Reaction SMILES: [H-].[Na+].O1CCCC1.[C:8](=[O:13])([O:11][CH3:12])OC.[N:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:24][C:23]([C:25](=[O:27])[CH3:26])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1>>[O:27]=[C:25]([C:23]1[S:24][C:20]([C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)=[CH:21][CH:22]=1)[CH2:26][C:8]([O:11][CH3:12])=[O:13]
Reactant: COC(=O)OC
Reactant: CC(=O)c1ccc(-c2ccncc2)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CC(=O)c1ccc(-c2ccncc2)s1
Temperature: 60 °C
Reaction time: 18 h
Yield: 38.3 %

Procedure:
To a 100 mL round bottom flask was added a suspension of sodium hydride (0.1574 g, 3.936 mmol) in tetrahydrofuran (16.000 mL, 197.26 mmol). Dimethyl carbonate (0.663 mL, 7.872 mmol) was added followed by 1-(5-pyridin-4-yl-2-thienyl)ethanone (0.400 g, 1.968 mmol) which was added in portions. The red reaction mixture was heated to 60° C. and allowed to stir for 18 hours. The reaction was cooled to ambient temperature and quenched by the dropwise addition of water (5.00 mL). The mixture was neutralized to pH 7 by the addition of a saturated aqueous solution of ammonium chloride (10.00 mL) and extracted with EtOAc (70.00 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was dry loaded onto silica gel and then purified using ISCO (12 g cartridge, gradient hexanes to 100% EtOH over 30 min) to afford the title compound (0.197 g, 36%) as a yellow oil. LC/MS (AA) ES+ 262. 1H NMR (dmso-d6, 400 MHz): δ 8.67-8.65 (m, 2H), 8.08 (d, 1H), 7.94 (d, 1H), 7.78-7.77 (m, 2H), 4.20 (s, 2H), 3.67 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:35][CH2:36]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:36][CH2:35][C:21]3[N:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=4)[S:24][C:20]=3[CH3:19])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCO
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCOc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with 2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethanol [PCT Int. Appl. (2001), WO 01/00603 A1] in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate to yield (6-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester as colorless oil.
Reaction SMILES: [OH:1][C@H:2]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[C@@H:3]([NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[C:12]([O:17][CH2:18][C:19]([O-:21])=[O:20])[CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[CH3:4].[OH-].[Li+].Cl>O1CCCC1.O>[OH:1][C@H:2]([C:22]1[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=1)[C@@H:3]([NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[C:12]([O:17][CH2:18][C:19]([OH:21])=[O:20])[CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[CH3:4]
Reactant: C[C@H](NCCc1c[nH]c2c(OCC(=O)[O-])cccc12)[C@H](O)c1ccc(O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](NCCc1c[nH]c2c(OCC(=O)O)cccc12)[C@H](O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 11 h
Yield: 100 %

Procedure:
To a solution of ethyl (((3-(2-(((1S,2R)-2-hydroxy-2-(4-hydroxy-phenyl)-1-methylethyl)amino)ethyl)-1H-indol-7-yl)oxy)acetate (115 mg, 0.279 mmol) in tetrahydrofuran (5 mL) and water (0.5 mL) is added lithium hydroxide (10 mg, 0.418 mmol), and the mixture is stirred at room temperature for 11 hours. The pH value of the mixture is adjusted to pH 7 with 1N aqueous hydrochloric acid solution, and the solvent is distilled off. The obtained crude product is purified by octadecylsilyl (ODS) column chromatography (water→10% aqueous methanol) to give (((3-(2-(((1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl)amino)ethyl)-1H-indol-7-yl)oxy)acetic acid (108 mg, 0.279 mmol, yield: 100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][CH:11]2[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][CH2:12]2)[CH2:7][N:6]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:4].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[C:19]([N:6]1[CH2:7][C@@H:8]([N:10]([CH:11]2[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][CH2:12]2)[S:27]([CH3:26])(=[O:29])=[O:28])[CH2:9][C@H:5]1[C:3]([O:2][CH3:1])=[O:4])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@H](NC2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](N(C2CCC(C)(C)CC2)S(C)(=O)=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 528.4 %

Procedure:
To a solution of methyl (2S,4S)-1-BOC-4-[(4,4-dimethylcyclohexyl)amino]pyrrolidine-2-carboxylate (2.37 g, 6.7 mmol) prepared in Step A of Example A1 in DCM (10 ml) was added TEA (1.36 g, 13.4 mmol), slowly added dropwise methanesulfonylchloride (104 mg, 0.91 mmol) at 0° C., and stirred at rt for 30 min. After the reaction finished, the solvent was concentrated in vacuo, the residue was extracted with water and EtOAc. The organic layer was dried over MgSO4, concentrated in vacuo, and purified by column chromatography (eluent: EtOAc/Hex ═1/1) to give the title compound (2.08 g, 72%).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH:11]=[CH2:12])[C:5]=1[OH:13])[CH:2]=[CH2:3].[OH-].[Na+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[CH2:16]([O:13][C:5]1[C:4]([CH2:1][CH:2]=[CH2:3])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:10][CH:11]=[CH2:12])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: C=CCc1cccc(CC=C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCc1cccc(CC=C)c1OCc1ccccc1

Procedure:
2,6-Diallylphenol (3.48 gm, 0.025 mol) was diluted with methanol (50 ml) and sodium hydroxide (0.8 gm 0.02 mol) was added to the solution followed by the benzyl chloride (3.60 gm, 0.2 mol.). The solution was refluxed for 2 hr, cooled, poured onto water and extracted with hexane. After washing with water and dilute sodium hydroxide, the organic layer was dried over MgSO4, filtered and evaporated to give 2,6-diallylphenyl benzyl ether. MS m/z 264 (M+ calcd for C19H20O=264). H NMR (300 MHz, CDCL3) d 3.45–3.55 (d, 4, CH2 allyl), 4.85 (s, 2, CH2 benzyl), 5.05–5.20 (m, 4, CH2 vinyl), 5.96–6.15 (m, 2, CH vinyl), 7.10–7.25 (m, 3, aromatic), 7.35–7.70 (m, 5, aromatic). Oxidation of the product as described in Example 1 gave 2,6-di(2,3-epoxyypropyl) phenyl benzyl ether as an oil. MS m/z 296 (M+ calcd for C+H20O3=296). H NMR (300 MHz, CDCl3) d 2.60–2.70 (m, 2, CH2 epoxypropyl), 2.75–3.10 (m, 6, CH2 epoxypropyl), 2.31–2.46 (m, 2, CH2 epoxypropyl), 4.75 (s, 2, CH2O), 7.10–7.25 (m, 1, aromatic) 7.45–7.60 (m, 2, aromatic), 7.60–8.15 (m, 5, aromatic).
Reaction SMILES: [CH3:1][CH:2]([NH2:14])[CH2:3][O:4][C:5]1[C:10]([Br:11])=[CH:9][C:8]([Br:12])=[CH:7][C:6]=1[Br:13].[F:15][CH:16]([F:26])[C:17]1[C:21]([C:22](O)=[O:23])=[CH:20][N:19]([CH3:25])[N:18]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1.O>[CH3:1][CH:2]([NH:14][C:22]([C:21]1[C:17]([CH:16]([F:26])[F:15])=[N:18][N:19]([CH3:25])[CH:20]=1)=[O:23])[CH2:3][O:4][C:5]1[C:6]([Br:13])=[CH:7][C:8]([Br:12])=[CH:9][C:10]=1[Br:11]
Reactant: CC(N)COc1c(Br)cc(Br)cc1Br
Reactant: Cn1cc(C(=O)O)c(C(F)F)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(COc1c(Br)cc(Br)cc1Br)NC(=O)c1cn(C)nc1C(F)F
Temperature: 0 °C
Reaction time: 12 h
Yield: 27.5 %

Procedure:
A mixture of 0.3 g (0.8 mmol) 1-methyl-2-(2,4,6-tribromo-phenoxy)-ethylamine (compound Z1.193, prepared as described in example P7) and 0.15 g (0.9 mmol) 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid in 2 ml pyridine under a nitrogen atmosphere is cooled to 0° C. Phosphorus oxychloride (0.08 ml, 0.9 mmol) is added dropwise and the reaction mixture is stirred at 80° C. for 12 h. The reaction mixture is diluted with water and 3-times extracted with ethyl acetate. The combined ethyl acetate layers are washed with 1.5 N HCl, saturated NaHCO3, water and brine, dried over sodium sulphate and evaporated to dryness. The residue is purified by column chromatography (using 60-120 mesh-silica gel in hexane; eluent: ethyl acetate) to yield 0.12 g 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [1-methyl-2-(2,4,6-tribromo-phenoxy)-ethyl]-amide (27% of theory) as a yellow solid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:6]=1[I:20].[H-].C([Al+2])C(C)C.[H-].[NH4+].[Cl-]>ClCCl>[F:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][O:11][C:9]2[CH:8]=[CH:7][C:6]([I:20])=[C:5]([CH2:4][CH:3]=[O:2])[CH:10]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)Cc1cc(OCc2ccc(F)cc2)ccc1I
Agent: CC(C)C[Al+2]
Agent: [Cl-]
Agent: [H-]
Solvent: ClCCl
Product: O=CCc1cc(OCc2ccc(F)cc2)ccc1I
Temperature: -78 °C
Reaction time: 6 h
Yield: 103.2 %

Procedure:
[5-(4-Fluoro-benzyloxy)-2-iodo-phenyl)-acetic acid methyl ester (12.6 g, 31.4 mmol), was dissolved under argon in 126 mL of dichloromethane and then, at −78° C., isobutylaluminum hydride (29.1 mL, 34.8 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 6 h until the TLC indicated the end of the reaction. A saturated solution of NH4Cl was added and the reaction mixture was allowed to come to room temperature. Dichloromethane was added, the organic phase was separated and the aqueous layer extracted with dichloromethane. Drying over magnesium sulfate and concentration in a rotatory evaporator gave the aldehyde (12 g, 100%) that was used in the next step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[C:20]3[O:19][CH2:18][C:17](=[O:21])[N:16]([CH3:22])[C:15]=3[CH:14]=[CH:13][CH:12]=2)=[O:10])=[C:4]([Cl:23])[CH:3]=1.[H-].[Na+].[CH3:26]I>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([C:11]2[C:20]3[O:19][CH2:18][C:17](=[O:21])[N:16]([CH3:22])[C:15]=3[CH:14]=[CH:13][CH:12]=2)=[O:10])=[C:4]([Cl:23])[CH:3]=1
Reactant: CI
Reactant: CN1C(=O)COc2c(C(=O)Cc3ccc(Br)cc3Cl)cccc21
Agent: [H-]
Agent: [Na+]
Product: CC(C(=O)c1cccc2c1OCC(=O)N2C)c1ccc(Br)cc1Cl

Procedure:
In analogy to Example 1, step 2, 8-[2-(4-bromo-2-chloro-phenyl)-acetyl]-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with sodium hydride and methyl iodide to give the title compound as an orange oil. MS (m/e)=408.3 [M+H+].
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.Cl.C([O-])([O-])=O.[Na+].[Na+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C1COCC1.O.CCOC(C)=O>[CH2:20]([O:19][C:17](=[O:18])[NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(N[C@H]1CC[C@H](O)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 50 g (0.33 mol) of trans-4-aminocyclohexanol•hydrochloride and 77 g (0.726 mol, 2.2 eq) of Na2CO3 in 650 mL of THF and 150 mL of water, 51.2 mL (0.363 mol, 1.1 eq) of benzyl chloroformate were added at 5° C. over a period of 20 min. The reaction mixture was stirred at RT for 2 h, diluted with EtOAc and the phases were separated. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. Trituration from n-hexane yielded 162.4 g (98%) of trans-4-hydroxy-cyclohexylcarbamic acid benzyl ester as white crystals, MS: 249 (M) [in analogy to: Venuti et al., J.Med.Chem. 30:303-318 (1987)].
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][Si:5]([CH3:35])([CH3:34])[CH2:6][CH2:7][C:8]1[C:20]2[CH2:19][N:18]3[C:13](=[CH:14][C:15]4[C@:25]([CH2:27][CH3:28])([OH:26])[C:24](=[O:29])[O:23][CH2:22][C:16]=4[C:17]3=[O:21])[C:12]=2[N:11]=[C:10]2[CH:30]=[CH:31][CH:32]=[CH:33][C:9]=12.C[O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1>CN(C)C=O>[CH3:34][Si:5]([CH3:35])([CH2:4][CH2:3][CH2:2][N:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]1=[O:37])[CH2:6][CH2:7][C:8]1[C:20]2[CH2:19][N:18]3[C:13](=[CH:14][C:15]4[C@:25]([CH2:27][CH3:28])([OH:26])[C:24](=[O:29])[O:23][CH2:22][C:16]=4[C:17]3=[O:21])[C:12]=2[N:11]=[C:10]2[CH:30]=[CH:31][CH:32]=[CH:33][C:9]=12
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCI
Reactant: COc1ccccn1
Solvent: CN(C)C=O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCn1ccccc1=O
Yield: 60 %

Procedure:
A solution of Compound 12 (60 mg) and 2-methoxypyridine (0.1 mL) in N,N-dimethylformamide (1 mL) was heated at 70° C. for 16 hours. The reaction mixture was concentrated under vacuum and the residue was directly eluted on a silica gel column using 4% ethanol in dichloromethane to obtain the required product in 60% yield (34 mg).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH3:17])=[CH:11][C:10]=2[O:18][CH3:19])[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[N:4]([CH3:24])[C:3]1=[O:25].[CH3:26][C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1>>[CH3:19][O:18][C:10]1[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[C:7]1[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[N:4]([CH3:24])[C:3](=[O:25])[CH:2]([NH:1][C:34]([NH:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([CH3:26])[CH:28]=2)=[O:35])[N:8]=1
Reactant: COc1cc(C)cc(OC)c1C1=NC(N)C(=O)N(C)c2ccccc21
Reactant: Cc1cccc(N=C=O)c1
Product: COc1cc(C)cc(OC)c1C1=NC(NC(=O)Nc2cccc(C)c2)C(=O)N(C)c2ccccc21
Yield: 94 %

Procedure:
By using 3-amino-1,3-dihydro-5-(2,6-dimethoxy-4-methylphenyl)-1-methyl-1,4-benzodiazepin-2-one as above and by condensing it as above with 3-methylphenyl isocyanate, 1,3-dihydro-5-(2,6-dimethoxy-4-methylphenyl)-1-methyl-3-(3-methylphenylureido)-1,4-benzodiazepin-2-one is obtained; m.p.=260° C.; Yield=94%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][CH:5]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6]1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.[O-]S([O-])(=O)=O.[Mg+2].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH:5]1[C:9](=[O:10])[N:8]([CH2:19][C:18]2[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[C:7](=[O:11])[NH:6]1
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)CC1NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CC1NC(=O)N(Cc2ccc(OC)cc2)C1=O
Temperature: 45 °C
Yield: 21.7 %

Procedure:
A solution of (2,5-dioxo-imidazolidin-4-yl)-acetic acid methyl ester (26.6 g, 0.155 mol) in DMF (500 mL) was treated with 4-methoxybenzyl chloride (26.6 g, 0.170 mol), MgSO4 (18.6 g, 0.154 mol) and then 325 mesh K2CO3 (42.71 g, 0.309 mol) at 0° C. The resultant mixture was warmed to room temperature under N2 and then heated at 45° C. for 4 h. The reaction mixture was filtered, and then aqueous 1N HCl (200 mL) was added to the filtrate. The filtrate was extracted with EtOAc and the organic layer dried (MgSO4). The solvent was removed in vacuo to give 11.43 g crude product which was purified by flash chromatography using a gradient of 3:1 to 1:1 hexanes:acetone to give 9.81 g (22%) [1-(4-methoxy-benzyl)-2,5-dioxo-imidazolidin-4-yl]-acetic acid methyl ester. MS (ES+) Calc'd for C14H17N2O5 (M+1) 293. Found m/z 293 (100%). 1H NMR.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][Br:10]
Reactant: Cc1cccc(Br)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccc(Br)c1CBr
Yield: 45 %

Procedure:
A mixture of 3-bromo-o-xylene (15 g, 81 mmol), N-bromo succinimid (15.1 g, 85.1 mmol), dibenzoylperoxid (0.65 g) and tetrachloromethane (150 ml) was refluxed for 5 hours. After filtration the filtrate was washed with sodium hydrogensulfite and water. The organic layer was dried over sodium sulfate and evaporated in vacuo. Chromatography (SiO2) (petroleum ether:ethyl acetate, 100:4) gave a 16.8 g fraction of a mixture containing 45% of the title compound. This mixture was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].Cl[C:19]1[N:26]=[CH:25][CH:24]=[CH:23][C:20]=1[C:21]#[N:22].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:21]([C:20]1[C:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])=[N:26][CH:25]=[CH:24][CH:23]=1)#[N:22]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Reactant: N#Cc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCC1Cc1c[nH]c2ccc(Nc3ncccc3C#N)cc12
Temperature: 110 °C
Yield: 32 %

Procedure:
(R)-5-Amino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole and 2-chloronicotinonitrile were used. Sodium carbonate were used as base. N,N-dimethylformamide was used as solvent, and the reaction was heated at 110° C. for 20 hours. Column chromatography afforded the title compound (32%) as an orange amorphous solid: Rf =0.4 in 9:1:0.1 [methylene chloride/methanol/ammonium hydroxide]; 13C NMR (CDCl3) δ157.7, 152.7, 141.7, 134.2, 129.8, 128.1, 123.1, 122.2, 118.7, 116.8, 113.6, 113.2, 111.5, 102.2, 66.6, 57.5, 40.8, 31.5, 30.0, 21.9; FAB HRMS calculated for [C20H21N5.H]332.2073, found 332.1871.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@H:4]([OH:26])[CH2:5][N:6]([CH2:18][C:19]([CH3:25])([CH3:24])[CH2:20][CH2:21][C:22]#[N:23])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)(=[O:9])=[O:8].C(N(C(C)C)CC)(C)C.[C:43](=O)([O:51]C1C=CC([N+]([O-])=O)=CC=1)[O:44][CH:45]1[CH2:50][O:49][CH2:48][O:47][CH2:46]1>C(Cl)Cl>[O:47]1[CH2:46][CH:45]([O:44][C:43](=[O:51])[NH:2][C@@H:3]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@H:4]([OH:26])[CH2:5][N:6]([CH2:18][C:19]([CH3:25])([CH3:24])[CH2:20][CH2:21][C:22]#[N:23])[S:7]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)(=[O:8])=[O:9])[CH2:50][O:49][CH2:48]1
Reactant: COc1ccc(S(=O)(=O)N(C[C@@H](O)[C@@H](N)Cc2ccccc2)CC(C)(C)CCC#N)cc1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1COCOC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC2COCOC2)CC(C)(C)CCC#N)cc1
Yield: 64.7 %

Procedure:
N-(2R,3S)-(3-Amino-2-hydroxy-4-phenyl-butyl)-N-(4-cyano-2,2-dimethyl-butyl)-4-methoxy-benzenesulfonamide hydrochloride (0.111 g, 0.22 mmol) was dissolved in CH2Cl2 and treated with diisopropylethylamine (0.120 ml, 0.67 mmol) and 1,3-dioxan-5-yl 4-nitrophenyl carbonate (0.066 g, 0.25 mmol) at ambient temperature under argon with stirring. After 15 h the reaction mixture was concentrated in vacuo, taken up in EtOAc, washed with sat. aq. NaHCO3, and brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuo. Purification by column chromatography (1% to 3% MeOH in CH2Cl2) gave 0.084 g of a white solid. MS (ES): 590 (M+1).