Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.[CH:19]1([N:25]=[C:26]=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:26]([NH:25][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:27])[CH2:6][CH2:7]2)=[CH:17][CH:16]=1
Reactant: O=C=NC1CCCCC1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Solvent: C1CCOC1
Product: O=C(NCCCN1CCN(Cc2ccc(Cl)cc2)CC1)NC1CCCCC1
Yield: 55 %

Procedure:
A solution of 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine (2.0 g; 7.5 mmole) and cyclohexyl isocyanate (1.6 g; 12.8 mmole) in tetrahydrofuran (5 ml) was stirred at room temperature for 30 minutes. The reaction mixture was evaporated under reduced pressure, and the residual oil was dissolved in ethanol (10 ml). The crude product was precipitated as a white solid by the addition of water, collected by filtration and recrystallized twice from cyclohexane to yield 1-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}-3-cyclohexylurea (1.62 g; 56% yield) as a white crystalline solid, m.p. 109°-112° C. This product in methylene chloride (20 ml) was precipitated as the dihydrochloride by the addition of excess anhydrous hydrogen chloride. Recrystallization from water provided the title compound as colorless crystals, m.p. 184°-187° C.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]2[NH:7][C:8]([C:10]3([C:17]4[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]5[C:18]=4[CH:19]=[CH:20][NH:21]5)[CH2:12][CH:11]3[C:13]([O:15]C)=[O:14])=[N:9][C:5]=2[CH:4]=1)#[N:2].[I-].[Li+]>N1C=CC=CC=1>[C:1]([C:3]1[CH:30]=[CH:29][C:6]2[NH:7][C:8]([C:10]3([C:17]4[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]5[C:18]=4[CH:19]=[CH:20][NH:21]5)[CH2:12][CH:11]3[C:13]([OH:15])=[O:14])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: COC(=O)C1CC1(c1nc2cc(C#N)ccc2[nH]1)c1c(OC)cc(C)c2[nH]ccc12
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: COc1cc(C)c2[nH]ccc2c1C1(c2nc3cc(C#N)ccc3[nH]2)CC1C(=O)O
Temperature: 125 °C
Reaction time: 8 h

Procedure:
To a solution of (±)-methyl 2-(5-cyano-1H-benzo[d]imidazol-2-yl)-2-(5-methoxy-7-methyl-1H-indol-4-yl)cyclopropanecarboxylate (Example 142-C) (40 mg, 0.1 mmol) in pyridine (5.0 mL) was added lithium iodide (800 mg, 59.8 mmol) and this mixture was stirred at 125° C. overnight. The reaction was partitioned between EtOAc and cold 0.5N HCl solution and the layers separated. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by RP-HPLC (HC-B) to give the title compound. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.75 (br.s., 1H), 7.55 (br.s., 1H) 7.27-7.55 (m, 1H) 7.17 (br.s., 1H) 6.79 (s, 1H) 6.50 (d, J=3.03 Hz, 1H) 3.81 (s, 3H) 2.52 (s, 3H) 2.22 (d, J=7.33 Hz, 1H) 1.30 (t, J=6.57 Hz, 1H), 0.88-0.92 (m, 1H). HRMS calcd. for C22H18N4O3 (M+H)+ 387.1412. found 387.1443.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[F:16])[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:18])[C:7](=[O:17])[NH:8][N:9]=1.[CH:19]([N:32]1[CH2:35][C:34](OS(C)(=O)=O)([CH3:36])[CH2:33]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:19]([N:32]1[CH2:35][C:34]([NH:1][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][C:15]=2[F:16])[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:18])[C:7](=[O:17])[NH:8][N:9]=2)([CH3:36])[CH2:33]1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC1C(=O)NN=C2COc3cc(F)c(N)cc3N21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1C(=O)NN=C2COc3cc(F)c(NC4(C)CN(C(c5ccccc5)c5ccccc5)C4)cc3N21
Temperature: 80 °C
Reaction time: 8 h
Yield: 28.3 %

Procedure:
A mixture of 6-amino-7-fluoro-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Example #56, Step F, 0.100 g, 0.400 mmol), methanesulfonic acid 1-benzhydryl-3-methyl-azetidin-3-yl ester (Preparation #3, Step B, 0.159 g, 0.480 mmol) and K2CO3 (0.166 g, 1.199 mmol) in DMF (2 mL) was stirred at 80° C. overnight. The reaction mixture was cooled to ambient temperature and poured into water (8 mL). The aqueous mixture was extracted with EtOAc (3×10 mL) and the combined organic phase was washed with brine (3×10 mL), dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5-10% EtOAc in petroleum ether) to give 6-(1-benzhydryl-3-methyl-azetidin-3-ylamino)-7-fluoro-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one as a white solid (0.055 g, 28%). LC/MS (Table 1, Method 2) Rt=1.199 min.; MS m/z: 486 [M+H]+.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:21])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>N1C=CC=CC=1.C1C=CC=CC=1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[O:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2OC(=O)c1ccccc1

Procedure:
Treat 13β-ethyl-17β-hydroxy-gon-4-en-3-one (2 g.) in pyridine (20 cc.) with benzoyl chloride (3 cc.) in benzene (10 cc.) at -10°. Keep the mixture at that temperature for 18 hours and then pour into 2N hydrochloric acid (200 cc.). Extract the product with ether and wash, dry and evaporate the extracts. Triturate the residue with a mixture of ether and hexane. Filter the crystalline material obtained and dissolved in benzene and purify by chromatography on neutral alumina. Recrystallize from a mixture of ethyl acetate and hexane to give the title compound, m.p. 141°-9°; ultraviolet light absorption peak at 237 mμ(ε27,300).
Reaction SMILES: [CH2:1]([N:4]1[C:8]2=[C:9]([CH:13]=O)[N:10]=[CH:11][CH:12]=[C:7]2[C:6]([CH3:15])=[C:5]1[CH3:16])[CH:2]=[CH2:3].[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>C(O)C>[CH2:1]([N:4]1[C:8]2=[C:9]([CH:13]=[N:22][C:21]3[CH:23]=[CH:24][C:18]([F:17])=[CH:19][CH:20]=3)[N:10]=[CH:11][CH:12]=[C:7]2[C:6]([CH3:15])=[C:5]1[CH3:16])[CH:2]=[CH2:3]
Reactant: Nc1ccc(F)cc1
Reactant: C=CCn1c(C)c(C)c2ccnc(C=O)c21
Solvent: CCO
Product: C=CCn1c(C)c(C)c2ccnc(C=Nc3ccc(F)cc3)c21
Temperature: 25 °C
Yield: 132 %

Procedure:
A solution of 1-allyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-carbaldehyde (1.214 g, 5.67 mmol) prepared in Preparation 3 and 4-fluoroaniline (0.54 ml, 5.67 mmol) in ethanol (10 ml) was refluxed for 1 hour. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure to give 2.3 g of the titled compound as a brown solid. The product was used in the subsequent step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Br:32])C(=O)C1.C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:9]2=[C:10]([Br:32])[N:11]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2Cc1ccccc1

Procedure:
Prepared in analogy to that of Example 103(a) from 1-benzyl-2,3-dibromo-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, NBS and BzOOBz. The title compound, ESI MS (m/z): 531 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([S:11](Cl)(=[O:13])=[O:12])=[C:8]([CH3:15])[C:7]=2[CH:16]=1.[NH2:17][C:18]1[CH:19]=[C:20]([C:24]2[NH:28][N:27]=[N:26][N:25]=2)[CH:21]=[CH:22][CH:23]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([S:11]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[NH:28][N:27]=[N:26][N:25]=4)[CH:19]=3)(=[O:13])=[O:12])=[C:8]([CH3:15])[C:7]=2[CH:16]=1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: COc1ccc2sc(S(=O)(=O)Cl)c(C)c2c1
Product: COc1ccc2sc(S(=O)(=O)Nc3cccc(-c4nnn[nH]4)c3)c(C)c2c1
Yield: 44.2 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from 5-methoxy-3-methylbenzothiophene-2-sulfonyl chloride (Intermediate 8) (42 mg, 0.15 mmol) and 5-(3-amino-phenyl)tetrazole (49 mg, 0.30 mmol) giving 26.6 mg (44%) of the title compound. MS (ESI+) calcd for C17H15N5O3S2 401.061631, found 401.062391.
Reaction SMILES: [N+:1]([C:4]1[C:9]([F:10])=[CH:8][C:7]([O:11][CH3:12])=[CH:6][C:5]=1[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)([O-])=O.O.NN>C(O)C.[Ni]>[NH2:1][C:4]1[C:9]([F:10])=[CH:8][C:7]([O:11][CH3:12])=[CH:6][C:5]=1[NH:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1
Reactant: COc1cc(F)c([N+](=O)[O-])c(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1cc(F)c(N)c(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
1,1-Dimethylethyl 4-[(2-nitro-3-fluoro-5-methoxyphenyl)amino]-piperidine-carboxylate (D12) (380 mg, 1 mmol) was dissolved in ethanol (10 ml) and Raney nickel (50% aqueous suspension, 1 ml) was added at room temperature; the mixture was heated to 40° C. and hydrazine monohydrate (0.5 ml) was added over dropwise. After 30 min more, the reaction mixture was cooled to room temperature, filtered through Celite and the solvent evaporated. The product was purified by silica gel chromatography eluting with 20 to 50% ethyl acetate in hexane to yield the title compound, 250 mg. M+−H=340.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[C:28]([CH3:29])=[CH:27][C:26]([N+:30]([O-:32])=[O:31])=[C:25]3[C:21]=2[CH2:22][CH2:23][CH2:24]3)=[CH:15][C:12]=1[CH:13]=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO.Cl>O1CCCC1>[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[C:28]([CH3:29])=[CH:27][C:26]([N+:30]([O-:32])=[O:31])=[C:25]3[C:21]=2[CH2:22][CH2:23][CH2:24]3)=[CH:15][C:12]=1[CH2:13][OH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(OCc3ccccc3)c(C=O)c1)CCC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(OCc3ccccc3)c(CO)c1)CCC2
Reaction time: 6 h
Yield: 94.4 %

Procedure:
To a suspension of sodium borohydride (340 mg) in tetrahydrofuran (10 mL) was added 2-benzyloxy-5-(5-methyl-7-nitroindan-4-yloxy)benzaldehyde (3.30 g) under ice-cooling. After adding dropwise methanol (1 mL) at room temperature, the mixture was stirred for 6 hours. The reaction mixture was acidified with diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (3.13 g).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH:16]1[CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH:29]([C@H:31]1[CH2:35][O:34][C:33]([CH3:37])([CH3:36])[N:32]1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:30]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@H:15]([CH:16]1[CH2:17][CH2:18]1)[C@H:29]([C@H:31]1[CH2:35][O:34][C:33]([CH3:37])([CH3:36])[N:32]1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[OH:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Reactant: O=C(CC1CC1)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@@H]([C@H](O)[C@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)C2CC2)COC1(C)C
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 50.5 %

Procedure:
To a −40° C. solution of (4R)-4-benzyl-3-(cyclopropylacetyl)-1,3-oxazolidin-2-one (2.0 g, 7.7 mmol) in anhydrous DCM (45 mL), a solution of 1.0 M titanium tetrachloride in DCM (9.3 mL) was added drop-wise under an atmosphere of nitrogen to form a yellow slurry. After 10 min., DIPEA (3.36 mL, 19.3 mmol) was added drop-wise, changing the color from yellow to deep purple. The reaction mixture was allowed to warm gradually to −20° C. while stirring over 1 h. The reaction mixture was again cooled to −40° C., and a solution of tert-butyl (4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.8 g, 7.85 mmol) (Aldrich) in anhydrous DCM (5 mL) was added drop-wise. The reaction mixture was allowed to warm gradually to 0° C. over 1 h and then allowed to stir for an additional 1.5 h at 0° C. The reaction was quenched by the addition of saturated NH4Cl (aq.) (15 mL). After separation of the two layers that resulted, the organic layer was washed with water and brine, dried over Na2SO4, concentrated under reduced pressure and purified by flash chromatography (120 g silica gel, eluting with 0-60% EtOAc/hexanes) to afford the sub-title compound (1.9 g, 50%). LC/MS (ESI) m/z calc. for C26H36N2O7Na: 511.2 [M+Na]+. found 511.1.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][C:4]=2[C:5]2[NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[CH2:21]([O:18][CH:15]1[CH2:14][C:4]2[C:5]3[NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]=3[CH:11]=[C:2]([Br:1])[C:3]=2[CH2:17][CH2:16]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]c2cc(Br)c3c(c2[nH]c1=O)CC(O)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(Br)c3c(c2[nH]c1=O)CC(OCc1ccccc1)CC3
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-bromo-9-hydroxy-1,4,7,8,9,10-hexahydrobenzo[f]quinoxaline-2,3-dione (0.1 g, 0.32 mmol) and sodium hydride (16 mg, 0.4 mmol) in dimethylformamide (1 mL) was stirred at 0° C. for 30 min, and then treated with benzyl bromide (70 mg, 0.4 mmol). The reaction mixture was stirred for 48 h and warmed to room temperature during that time. The solvent was removed by rotoevaporation, the residue triturated in ethyl acetate, and the solid collected by filtration and dried. CI MS m/e (M+1) 402, 404. H-NMR (200 MH2, dmso): 1H, s, 12.05; 1H, s, 11.95; 5H, m, 7.4-7.2; 1H, s, 7.05; 2H, s, 5.4; 1H, s, 4.75; 1H, m, 3.9; +ring protons.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:9][S:10][CH3:11])[NH:5][C:6](=[O:8])[CH3:7].[CH3:13][NH:14][NH2:15]>C(O)C>[CH3:13][N:14]([C:3](=[O:2])[C@H:4]([CH2:9][S:10][CH3:11])[NH:5][C:6](=[O:8])[CH3:7])[NH2:15]
Reactant: COC(=O)[C@H](CSC)NC(C)=O
Reactant: CNN
Solvent: CCO
Product: CSC[C@H](NC(C)=O)C(=O)N(C)N
Reaction time: 3 h
Yield: 51 %

Procedure:
In 20 ml of ethyl alcohol was dissolved 1.91 g (10 mmole) of S-methyl-N-acetyl-L-cysteine methylester and 5.4 ml (100 mmole) of methylhydrazine was added. The mixture was stirred for 3 hours at boiling temperature and then allowed to stand for 1 day at room temperature. After the precipitate was removed, the ethyl alcohol and the excess methylhydrazine were distilled off in vacuo to leave crystals. Thus, 1.05 g (5.1 mmole) of N-methyl-N-(S-methyl-N-acetylcysteinyl)-hydrazine was obtained in 51% yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)#[N:2].Cl.[CH3:18][O:19][C:20](=[O:23])[CH2:21][NH2:22].O1CCCC1.C([BH3-])#N.[Na+]>CO>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH:22][CH2:21][C:20]([O:19][CH3:18])=[O:23])=[CH:13][CH:14]=1)#[N:2]
Reactant: N#Cc1ccccc1-c1ccc(C=O)cc1
Reactant: COC(=O)CN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CNCc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A mixture of 2.0 g of 2'-cyano-4-formyl-biphenyl, 1.22 g of 2-aminoethanoic acid methyl ester hydrochloride, 9.6 g of molecular sieve 5 A and 26 ml of tetrahydrofuran is stirred at room temperature for 36 hours and then cooled to 0° to 5°. 680 mg of sodium cyanoborohydride (90%) dissolved in 4.8 ml of methanol are added. The mixture is stirred at room temperature for 24 hours and then concentrated in vacuo. The crude product is purified by means of flash chromatography (180 g of silica gel; ethyl acetate/petroleum ether=1:1). 1H-NMR (DMSO-d6): 3.63 ppm (s, 3 H); 3.79 ppm (s, 2H); 7.4 to 8.0 ppm (m, 10H); 2.6 ppm (1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][NH2:30])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][NH:30][S:12]([C:3]2[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[Cl:1])(=[O:14])=[O:13])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)c2c(Cl)ccc([N+](=O)[O-])c2Cl)CC1
Yield: 78.6 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.2 g, 4.13 mmol), N-(tert-butoxycarbonyl)4-aminomethyl piperidine (0.88 g, 4.13 mmol) and triethylamine(0.86mL, 6.20 mmol) were reacted to form the desired product (1.52 g, 79%). LC-MS (m/z) 468.2 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[C:14]=1[OH:15])=[O:5])[CH3:2].[CH2:16]([CH:18]1[O:20][CH2:19]1)Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:4]([C:6]1[NH:7][C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[C:14]=1[O:15][CH2:16][CH:18]1[O:20][CH2:19]1)([O:3][CH2:1][CH3:2])=[O:5]
Reactant: BrCC1CO1
Reactant: CCOC(=O)c1[nH]c2c(c1O)CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1[nH]c2c(c1OCC1CO1)CCCC2
Yield: 100.1 %

Procedure:
Using the method described in Example V, 130 g of 3-hydroxy-4,5,6,7-tetrahydroindole-2-carboxylic acid ethyl ester, 170 g of epibromohydrin and 172 g of anhydrous potassium carbonate in 500 ml of acetone give 165 g of 1-(2-carboethoxy-4,5,6,7-tetrahydro-indol-3-oxy)-2,3-epoxypropane, of melting point 102°-104° C.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)(=O)=O.O.[NH2:18][NH2:19]>O>[NH:18]([CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)[NH2:19]
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(NN)C1
Temperature: 95 °C
Yield: 88.9 %

Procedure:
A suspension of tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (Preparation 35, 7.11 g, 28.3 mmol) in neat hydrazine monohydrate (13.7 mL, 283 mmol) was heated to 95° C. for 18 hours. The reaction was cooled to room temperature, then water (100 mL) was added and the mixture extracted with dichloromethane (5×100 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a the title compound as a clear oil (4.71 g, 89%). The compound was used without further purification in the next step.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:2].[CH3:20][Mg]Br>>[OH:2][C@H:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCCCc1ccccc1C=O
Reactant: C[Mg]Br
Product: C[C@H](O)c1ccccc1CCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 33-5 (0.385 g, 1.462 mmol) in was treated with methylmagnesium bromide (5.1 ml, 15.3 mmol, 3M in diethylether) at 0° C. After stirring overnight at RT, the reaction was quenched with NH4Cl solution. Extracted with Ethyl acetate, washed with brine and dried over sodium sulfate. Material was purified by reverse phase column chromatography (C18 column, 5-95% MeCN in water with 0.1% TFA) to yield a white solid. Racemic material was separated by chiral chromatography (ChiralTech IC column) to yield 33-6.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][OH:8].[Br:9]N1C(=O)CCC1=O>C1COCC1>[Br:9][C:6]1[N:2]([CH3:1])[C:3]([CH2:7][OH:8])=[N:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1ccnc1CO
Solvent: C1CCOC1
Product: Cn1c(Br)cnc1CO
Temperature: 25 °C
Yield: 40.9 %

Procedure:
1-Methylimidazole-2-methanol (3.15 g, 28 mmol) (R. J. Sundberg; P. V. Nguyen; Med.Chem. Res. 7, 2, 1997, 123-136) was suspensed in THF (75 ml) at −20° C. and treated slowly (within 30 min) with N-bromosuccinimide (4.9 g, 27 mmol). The reaction mixture was allowed to warm up slowly to room temperature and quenched with saturated aqueous NaHCO3 solution (50 ml). The aqueous layer was extracted 3 times with AcOEt. The combined extracts were washed with saturated aqueous NaHCO3 solution, dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was chromatographed (silica, elution first with AcOEt/hexane=1:1, then with CH2Cl2/MeOH=95:05) to provide the title compound (2.11 g, 67%) as a white solid. MS: m/e=191.2 (M+).
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[CH:9]=[C:10]([OH:35])[CH:11]=[CH:12][C:13]=2[O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:37]([CH3:44])([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:41]([O:40][C:38](=[O:39])[C:37]([O:35][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:24]=[CH:25][C:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:27][CH:28]=3)[O:20][C:21]=2[CH3:22])=[C:8]([CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)([CH3:44])[CH3:43])[CH3:42]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(O)cc1CC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)c(CC2CCCCC2)c1
Temperature: 55 °C

Procedure:
A mixture of 3-cyclohexylmethyl-4-[2-(5-methyl-2-biphenyl-4-yl-oxazole-4-yl)ethoxy]phenol (0.90 mmol), ethyl 2-bromo-2-methylpropanoate (2.25 mmol) and cesium carbonate (0.45 g, 1.38 mmol) in anhydrous DMF (4 mL) was heated for 24 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and water (40 mL), washed with brine, dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using radial chromatography eluting with 2% ethyl acetate/dichloromethane to give 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-cyclohexylmethylphenoxy}-2-methylpropionic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ8.04 (d, J=8.8 Hz, 2H), 7.65 (q, J=8.3 Hz, 4H), 7.46 (t, J=7.6 Hz, 2H), 7.37 (t, J=7.3 Hz, 1H), 6.72-6.64 (m, 3H), 4.25-4.18 (m, 4H), 2.96 (t, J=6.4 Hz, 2H), 2.40 (s, 3H), 2.38 (t, J=7.3 Hz, 2H), 1.59-1.55 (m, 11H), 1.47-1.42 (m, 1H), 1.27 (t, J=7.1 Hz, 3H), 1.13-1.05 (m, 3H), 0.88-0.75 (m, 2H), MS (ES) m/e 582 (M+1).