Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:5]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17].[NH:26]1[CH:30]=[N:29][N:28]=[N:27]1>>[F:15][C:12]1[CH:13]=[CH:14][C:9]([CH:6]2[N:5]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:17])=[O:18])[CH:4]([CH2:3][CH2:2][N:26]3[CH:30]=[N:29][N:28]=[N:27]3)[CH2:8][CH2:7]2)=[CH:10][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCl)CCC2c2ccc(F)cc2)cc1
Reactant: c1nnn[nH]1
Product: Cc1ccc(S(=O)(=O)N2C(CCn3cnnn3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=416.1 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(2-chloro-ethyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-tetrazole.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]=[O:13].[CH3:14][OH:15]>>[CH3:14][O:15][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]=[O:13]
Reactant: CO
Reactant: Cn1c(Cl)c(C=O)c(=O)n(C)c1=O
Product: COc1c(C=O)c(=O)n(C)c(=O)n1C

Procedure:
The process described in Method C was followed. 6-Chloro-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (0.270 g, 1.33 mmol) and methanol were used to obtain the title compound. The crude product was purified by column chromatography with a mixture of n-hexane:ethyl acetate (4:1) as the eluent.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>CS(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][CH:12]([O:15][CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: ClCc1cccc2ccccc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(OCc2cccc3ccccc23)C1
Reaction time: 3 h
Yield: 80.2 %

Procedure:
1.27 g of an 80% strength suspension of sodium hydride in paraffin (44 mmol) were added in small portions at 0° C. to a solution of 7.49 g (40 mmol) of 1-tert.butoxycarbonyl-3-hydroxy-pyrrolidine in 40 ml of dry dimethyl sulphoxide. 7.77 g (44 mmol) of 1-chloromethyl-naphthalene were subsequently slowly added dropwise. After 3 hours at room temperature, the mixture was poured into 200 ml of saturated ammonium chloride solution, extracted a number of times using ether, dried (MgSO4) and concentrated. Flash chromatography (petroleum ether-toluene, then toluene-ethyl acetate gradients) gave 10.5 g of the title compound (76%) as a yellowish oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:16])=[CH:9][C:10]([CH3:15])([CH3:14])[O:11]2)=[CH:6][C:5]=1/[C:17](/[CH2:30][CH3:31])=[C:18](/[F:29])\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([O:25]CC)=[O:24])[CH3:2].[OH-].[Na+]>C(O)C.C1COCC1>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:16])=[CH:9][C:10]([CH3:15])([CH3:14])[O:11]2)=[CH:6][C:5]=1/[C:17](/[CH2:30][CH3:31])=[C:18](/[F:29])\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([OH:25])=[O:24])[CH3:2]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/CC)c1cc2c(cc1OCC)OC(C)(C)C=C2C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1/C(CC)=C(F)\C=C\C(C)=C\C(=O)O)C(C)=CC(C)(C)O2

Procedure:
Following General Procedure G, a solution of ethyl 7-(7-ethoxy-2,2,4-trimethyl-2H-chromen-6-yl)-6-fluoro-3-methyl-nona-2E,4E,6E-trienoate (Compound 119, 103 mg, 0.24 mmol) in ethanol and THF was hydrolyzed with 1M NaOH. Purification by flash chromatography (silica gel, 75:25 hexane/ethyl acetate) afforded the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[N:5]=[C:4]([NH2:19])[N:3]=1.[CH2:20]([OH:23])[CH:21]=[CH2:22]>>[CH2:20]([O:23][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[N:5]=[C:4]([NH2:19])[N:3]=1)[CH:21]=[CH2:22]
Reactant: C=CCO
Reactant: Nc1nc(Cl)c(-c2ccncc2)c(-c2ccco2)n1
Product: C=CCOc1nc(N)nc(-c2ccco2)c1-c1ccncc1

Procedure:
The title compound was synthesized in a similar manner to Example 3 using 4-chloro-6-(2-furyl)-5-(4-pyridyl)-2-pyrimidinylamine and allyl alcohol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH3:12][C:13]1[CH:14]=[N:15][NH:16][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(=NO)C1C(=CC=CC=1)O>ClCCl.C(#N)C>[CH3:12][C:13]1[CH:14]=[N:15][N:16]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=2)[CH:17]=1
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: Cc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cnn(-c2ccc(C)c([N+](=O)[O-])c2)c1
Temperature: 80 °C
Yield: 60 %

Procedure:
A dried flask under nitrogen was charged with 4-bromo-1-methyl-2-nitro-benzene (40 mmol), 4-methylpyrazole (20 mmol), Cs2CO3 (13 g), Cu2O (290 mg, 2 mmol), salicylaldoxime (1.1 g, 8 mmol) and 12 mL of acetonitrile. The mixture was heated at 80° C. for 24 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane and filtered through celite. The filtrate was washed with water, dried and concentrated under reduced pressure. Column chromatography on silica gel (DCM/Hexane 30-100%) gave 4-methyl-1-(4-Methyl-3-nitro-phenyl)-1H-pyrazole as a yellow solid (60% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:3]=1.[NH:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1.C1(O)C=CC=CC=1>O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:4]2[CH:3]=[C:2]([N:20]3[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)=[CH:14][CH:15]=1
Reactant: NC(=O)C1CCNCC1
Reactant: Cc1ccc2nc(-c3ccc(F)cc3)cc(Cl)c2c1
Solvent: Oc1ccccc1
Solvent: O
Product: Cc1ccc2nc(-c3ccc(F)cc3)cc(N3CCC(C(N)=O)CC3)c2c1

Procedure:
A mixture of 2.0 g of 4-chloro-2-(4-fluorophenyl)-6-methylquinoline, 1.88 g (10 mmol) of isonipecotamide, and 4 g of phenol was stirred and heated in an oil bath at 165°-170° for 2 hr. It was then cooled and diluted with water. Crystallization was induced by the addition of ethanol and scratching. The solid was collected and washed with ether to give 1.9 g of crude product, mp 264°-271° dec. Recrystallization from pyridine gave the titled product as off-white prisms, mp 275°-277° dec.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([C:8]([Cl:11])=[CH:9][CH:10]=1)[CH:5]=[N:6][OH:7].[CH2:13]=[CH2:14].[O-]Cl.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([C:5]2[CH2:14][CH2:13][O:7][N:6]=2)[C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: C=C
Reactant: Cc1c(Cl)ccc(Cl)c1C=NO
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: Cc1c(Cl)ccc(Cl)c1C1=NOCC1
Reaction time: 8 h

Procedure:
In a pressure container, 50 g (0.25 mol) of 3,6-dichloro-2-methylbenzaldoxime are dissolved in 750 ml of methylene chloride. 16 g of ethylene are applied, and 620 g of a 12.5% strength solution of NaOCl are then pumped in at room temperature, and the mixture is stirred overnight. The pressure vessel is vented, and the organic phase is then separated off, washed once with water and dried, and the solvent is removed under reduced pressure. This gives 58 g of product (95% pure) (95% of theory). 1H-NMR (DMSO-D6): 2.3 ppm (s, 3H, Me), 3.3 ppm (t, 2H, CH2), 4.5 ppm (t, 2H, CH2), 7.45 ppm (d, 1H, arom-H), 7.6 ppm (d, 1H, arom-H).
Reaction SMILES: [ClH:1].[N:2]1([C:7]([C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1>C(O)(C)C>[ClH:1].[NH:11]1[CH2:12][CH2:13][CH2:14][C@@H:9]([C:7]([N:2]2[CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:8])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)N2CCCC2)C1
Agent: Cl
Solvent: CC(C)O
Product: O=C([C@@H]1CCCNC1)N1CCCC1
Temperature: 22.5 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Over a period of 1 h, hydrochloric acid (9.8 kg) was added to the solution of (R)-tert-butyl 3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate in isopropanol from the previous step, maintaining a temperature of 20-25° C. The reaction mixture was heated to 50-55° C. and was held at that temperature for 6 h. Solvent was removed by distillation under reduced pressure at 50° C. Four cycles of solvation and then distillation under reduced pressure at 50° C. were conducted sequentially: isopropanol (2×14.5 L), toluene (18.5 L), and tetrahydrofuran (12.0 L). Another portion of tetrahydrofuran (12.0 L) was added and the mixture was stirred at 25-30° C. for 1 h. The mixture was centrifuged and the mother liquor was removed; the resulting cake was washed with tetrahydrofuran (3.7 L), then was dried at 40-50° C. to afford (R)-piperidin-3-yl(pyrrolidin-1-yl)methanone hydrochloride (4.8 kg, 84% over two steps). HPLC retention time: 1.67 min (Column: Halo C18, 4.6×150 mm, 2.7 μm; Mobile Phase A: 0.1% orthophosphoric acid and 2% acetonitrile in water, Mobile Phase B: acetonitrile; Gradient: 20% B to 90% B over 7 min, then held for 3 min; Flow: 0.8 mL/min; Temperature: 25° C.; UV detection at 210 and 226 nM).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:16][CH2:17][C:18]3([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:12]([O:14]C)=[O:13])[CH:10]=1)[NH:7][N:6]=[CH:5]2.C(OC(N1CCC(COC(C2C3C(=CN(COCC[Si](C)(C)C)N=3)C=C(Cl)C=2)C(O)=O)(C2C=CC(F)=CC=2)CC1)=O)(C)(C)C>ClCCl.CO>[C:27]([O:26][C:24]([N:21]1[CH2:20][CH2:19][C:18]([CH2:17][O:16][CH:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][N:6]=[CH:5]3)[C:12]([OH:14])=[O:13])([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:23][CH2:22]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: COC(=O)C(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn[nH]c12
Agent: CC(C)(C)OC(=O)N1CCC(COC(C(=O)O)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(COC(C(=O)O)c2cc(Cl)cc3cn[nH]c23)(c2ccc(F)cc2)CC1

Procedure:
Prepared according to the procedure used to prepare tert-butyl 4-((1-(5-chloro-1H-indazol-7-yl)-2-methoxy-2-oxoethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate using 2-((1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)piperidin-4-yl)methoxy)-2-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)acetic acid as the starting material and using dichloromethane/methanol in its purification. tR=3.03 min (Phenomenex C18 3.0×50 mm, A=90% H2O/10% methanol, B=90% methanol/10% H2O, Modifier 0.1% TFA, 0.00 min=0% B, 3.0 min=100% B, 5.0 min=100% B, Flow rate=4 mL/min). Mass spec.: 518.22 (MH)+.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH3:10])=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]3[C:32](=[O:33])[N:31]([CH3:34])[C:24]4[N:25]=[C:26](SC)[N:27]=[CH:28][C:23]=4[CH:22]=3)[C:18]([Cl:35])=[CH:17][C:16]=2[F:36])=[O:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:48][NH2:49]>C1COCC1>[C:1]([N:5]1[C:9]([CH3:10])=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]3[C:32](=[O:33])[N:31]([CH3:34])[C:24]4[N:25]=[C:26]([NH:49][CH3:48])[N:27]=[CH:28][C:23]=4[CH:22]=3)[C:18]([Cl:35])=[CH:17][C:16]=2[F:36])=[O:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4C)c(F)cc3Cl)c(=O)n(C)c2n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4C)c(F)cc3Cl)c(=O)n(C)c2n1
Yield: 62 %

Procedure:
Using a procedure analogous to Example A1, 1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (80 mg, 0.151 mmol), MCPBA (47 mg, 0.189 mmol) and 2.0N methylamine in THF (0.8 mL) were combined to afford 1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (48 mg, 62% yield). 1H NMR (300 MHz, DMSO-d6): δ 1.49 (s, 9H), 2.27 (s, 3H), 2.89 (s, 3H), 3.49-3.56 (m, 3H), 7.39 (s, 1H), 7.49 (d, 1H), 7.74 (s, 1H), 7.94 (br. s, 1H), 8.17 (d, 1H), 8.29 (s, 1H), 8.62-8.74 (m, 2H); MS (ESI) m/z: 513.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1)([CH3:5])[C:3]#[N:4]>C(OCC)(=O)C.[Pd]>[NH2:12][C:8]1[CH:7]=[C:6]([C:2]([CH3:5])([CH3:1])[C:3]#[N:4])[CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C#N)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1cccc(N)c1
Reaction time: 10 h
Yield: 100 %

Procedure:
To a solution of 2-methyl-2-(3-nitrophenyl)propanenitrile (0.35 g, 1.8 mmol) in ethyl acetate (10 mL) was added 10% palladium/carbon (35 mg), and the mixture was stirred for 10 hr under hydrogen atmosphere. The residual catalyst was filtered through celite, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the title compound (0.35 g, 1.8 mmol) as a pale-yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])(C)[CH3:9])=[CH:6][C:5]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][C:3]=1[N:16]1[N:20]=[C:19]2[CH:21]=[CH:22][C:23]([CH2:25][CH2:26][CH2:27][CH3:28])=[CH:24][C:18]2=[N:17]1.Cl.N([O-])=O.[Na+].[CH:34](C1C=C(C(C)(C)C)C=CC=1O)(CC)C>C(O)C.O.[OH-].[Na+]>[OH:1][C:2]1[C:7]([CH:8]([CH2:11][CH3:34])[CH3:9])=[CH:6][C:5]([C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:4][C:3]=1[N:16]1[N:20]=[C:19]2[CH:21]=[CH:22][C:23]([CH2:25][CH2:26][CH2:27][CH3:28])=[CH:24][C:18]2=[N:17]1
Reactant: CCC(C)c1cc(C(C)(C)C)ccc1O
Reactant: CCCCc1ccc2nn(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3O)nc2c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCc1ccc2nn(-c3cc(C(C)(C)C)cc(C(C)CC)c3O)nc2c1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
110 g of 2-nitro-4-n-butyl-aniline (prepared as described in Example 1) were suspended in 400 ml of toluolated ethanol and 300 ml of concentrated hydrochloric acid and diazotized at 5°-10° C. with 34 g of sodium nitrite dissolved in 100 ml of water, following the same procedure as described for Example 1. The clear diazonium solution was added very slowly to a cold solution obtained by dissolving 74 g of 2-sec.-butyl-4-tert.-butylphenol in 200 ml of ethanol and 150 ml of sodium hydroxide 30% aqueous solution. The mixture obtained was stirred for 2 hours keeping the temperature at 0° C. The solution was then cooled at -10° C. and the gummy solid obtained, 2-(2'-hydroxy-3'-sec.-butyl-5'-tert.-butyl-phenyl)-3-nitro5-n-butyl-azobenzene, was filtered on a Buchner funnel and washed with cold water. The product was dissolved in 300 ml of ethanol and 20 ml of sodium hydroxide 30% water solution and 130 g of zinc powder were slowly added to the well-stirred solution to keep the temperature below 30° C. At the end of the addition the reaction mixture was heated to reflux under stirring for two hours, cooled to 30° C. and filtered. The filtered solution was poured onto 1,000 ml of ice and water and acidified with 500 ml of concentrated hydrochloric acid, thus obtaining the separation of the product as oil. This oil was extracted with ethyl ether, the ethereal extracts dried over anhydrous sodium sulfate overnight. After filtration and removal of the solvent, the oil was purified by distillation under vacuum, collecting the fraction boiling at 218°-219° C./0.5 mm Hg. The structure has been confirmed by N.M.R. and the acidimetric title (--OH) of the compound resulting in 97% Spectral properties: λmax =342 nm.; εmolar =1.8.104.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][C:5]([C:15](=O)[C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=3[Cl:25])=[C:6]([CH2:10][C:11](OC)=[O:12])[CH:7]=2)[O:2]1.O.[NH2:28][NH2:29].C(O)C>>[Cl:25][C:17]1[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:16]=1[C:15]1[C:5]2[CH:4]=[C:3]3[O:2][CH2:1][O:9][C:8]3=[CH:7][C:6]=2[CH2:10][C:11](=[O:12])[NH:29][N:28]=1
Reactant: COC(=O)Cc1cc2c(cc1C(=O)c1ccc([N+](=O)[O-])cc1Cl)OCO2
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2Cl)=NN1)OCO3

Procedure:
The title compound was prepared from methyl 4,5-methylenedioxy-2-(2-chloro-4-nitrobenzoyl)phenylacetate (11 g, 29 mmol) and hydrazine hydrate (5.0 mL, 88 mmol) in ethanol (60 mL) as a yellow solid (1.4 g, 3.9 mmol, 13%), mp: 202°-204° C. 1H NMR (CDCl3) 8.64 (s, 1H), 8.29-8.26 (m, 2H), 7.82 (d, J=8.2, 1H), 6.84 (s, 1H), 6.28 (s, 1H), 6.02 (s, 2H), 3.59 (s, 2H). Anal. Calcd. for C16H10N3O5.(1/2)H2O: C, 52.12; H, 3.01; N, 11.40. Found: C, 52.50; H, 3.36; N, 10.35.
Reaction SMILES: Br.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:3]1.[C:16]1([CH2:22][CH2:23][CH2:24][CH:25]=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([CH2:22][CH2:23][CH2:24][CH2:25][N:2]2[CH2:7][CH2:6][CH2:5][CH:4]([S:8][C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=3)[CH2:3]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=CCCCc1ccccc1
Reactant: Oc1ccc(SC2CCCNC2)cc1
Agent: Br
Product: Oc1ccc(SC2CCCN(CCCCc3ccccc3)C2)cc1

Procedure:
The title compound, MS: m/e=342.3 (M+H+) was prepared from (RS)-4-(piperidin-3-yl-sulfanyl)-phenol hydrobromide and 4-phenyl-butyraldehyde.
Reaction SMILES: [H-].[Na+].[CH:3]([S:6]([NH2:9])(=[O:8])=[O:7])([CH3:5])[CH3:4].F[C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].Cl>CS(C)=O>[CH:3]([S:6]([NH:9][C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15])(=[O:8])=[O:7])([CH3:5])[CH3:4]
Reactant: O=C(c1ccccc1)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(C)S(N)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)S(=O)(=O)Nc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Yield: 95 %

Procedure:
To 50 ml. of dimethylsulfoxide (DMSO) was added 1.01 g. (0.021 m.) of 50% sodium hydride in oil. After the initial gas evolution ceased, 2.53 g. (0.0206 m.) of isopropylsulfonamide [prepared according to Duguet, Rec. Trav. Chim., 25, 215 (1906)]was added. The mixture was stirred under a calcium chloride drying tube for ten minutes after which time 4.90 g. (0.020 m.) of 3-fluoro-4-nitrobenzophenone was added, followed by 20 ml. of DMSO. After stirring for five hours at room temperature, the reaction solution was poured into a mixture of ice and lN hydrochloric acid which was then extracted several times with ethyl acetate. The extracts were combined, washed with water, and dried over magnesium sulfate. The oil remaining after evaporation was triturated with isopropanol to give 6.65 g. (95% yield) of 3-(isopropylsulfonyl)amino-4-nitrobenzophenone as a yellow powder. Crystallization from isopropanol gave pale yellow needles, m.p. about 115°-116° C.
Reaction SMILES: [CH2:1]([C@:3]1([OH:9])[CH2:7][CH2:6][NH:5][C@H:4]1[CH3:8])[CH3:2].[F:10][C:11]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14].C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:1]([C@:3]1([OH:9])[CH2:7][CH2:6][N:5]([C:17]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([F:10])[CH:18]=2)[C@H:4]1[CH3:8])[CH3:2]
Reactant: N#Cc1ccc(F)cc1F
Reactant: CC[C@]1(O)CCN[C@H]1C
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@]1(O)CCN(c2ccc(C#N)c(F)c2)[C@H]1C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-3-ethyl-2-methylpyrrolidin-3-ol 0.5 oxalate (257 mg), 2,4-difluorobenzonitrile (411 mg) and lithium carbonate (218 mg), the title compound was obtained as a colorless solid (yield: 250 mg, yield: 68%).
Reaction SMILES: [H-].[K+].[CH2:3]([N:10]1[CH2:19][CH2:18][C:17]23[C:20]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:21]=4[O:22][CH:16]2[CH:15]2[CH2:29][CH2:30][C:12]3([CH:13]([CH2:31][OH:32])[CH2:14]2)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:33]I.Cl>O1CCCC1.CCCCCC>[CH2:3]([N:10]1[CH2:19][CH2:18][C:17]23[C:20]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:21]=4[O:22][CH:16]2[CH:15]2[CH2:29][CH2:30][C:12]3([CH:13]([CH2:31][O:32][CH3:33])[CH2:14]2)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: COc1cccc2c1OC1C3CCC4(CN(Cc5ccccc5)CCC214)C(CO)C3
Agent: Cl
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCC1CC2CCC13CN(Cc1ccccc1)CCC31c3cccc(OC)c3OC21
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.1 %

Procedure:
To a suspension of 12.0 g of 35% potassium hydride in oil, prewashed with hexane, in 100 mL of tetrahydrofuran was added a solution of 9.91 g of 3-benzyl-5-hydroxymethyl-9-methoxy-1,2,3,4,5,6,7,7a-octahydro-4a,7-ethanobenzofuro[3,2-e]isoquinoline (E. Ciganek and B. K. Wong, coassigned pending application, U.S. Ser. No. 774,025) in 50 mL of tetrahydrofuran and the mixture was heated under reflux for 4 hours. Methyl iodide (5.2 g dissolved in 10 mL of tetrahydrofuran) was added to the cooled mixture which was then stirred at room temperature for 18 hours. Addition of 5% hydrochloride acid followed by aqueous ammonium hydroxide solution and extraction with methylene chloride gave 10.47 g of 3-benzyl-9-methoxy-5-methoxymethyl-1,2,3,4,5,6,7,7a-octahydro4a,7-ethanobenzofuro[3,2-e]isoquinoline. NMR spectrum (δ in CDCl3): 7.5-7.2 (m, 7H); 6.8 (m, 2H); 4.4 (s, 1H); 3.9 (s, 3H), 3.7 (d, J=12 Hz, 1H); 3.5 (d, J=12 H, 1H) and 3.2 (s, 3H), among others.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[C:24]([O:31][CH2:32][CH3:33])=[N:25][C:26]([S:29][CH3:30])=[N:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1.[N:34]1([C:40](=[O:48])[CH2:41][N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:45]3[CH2:44][CH2:43][N:42]([CH2:41][C:40]([N:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)=[O:48])[CH2:47][CH2:46]3)=[O:21])[C:10]([C:23]3[C:24]([O:31][CH2:32][CH3:33])=[N:25][C:26]([S:29][CH3:30])=[N:27][CH:28]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1nc(SC)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Product: CCOc1nc(SC)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1

Procedure:
cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12) was reacted with 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) to give cis-2-{4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C33H38N7O4SCl2 [(M+H)+] 698.2078, observed 698.2078.
Reaction SMILES: [CH3:1][N:2]([C@H:23]([CH3:28])[C:24]([O:26]C)=[O:25])[C:3](=[O:22])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=2)=[CH:8][CH:7]=1)[CH3:5].[Li+].[OH-].Cl>C1COCC1>[CH3:1][N:2]([C@H:23]([CH3:28])[C:24]([OH:26])=[O:25])[C:3](=[O:22])[CH:4]([C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=2)=[CH:10][CH:11]=1)[CH3:5]
Reactant: COC(=O)[C@@H](C)N(C)C(=O)C(C)c1ccc(OCc2cc(C)cc(C)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(COc2ccc(C(C)C(=O)N(C)[C@H](C)C(=O)O)cc2)c1
Yield: 99.6 %

Procedure:
A solution of methyl 2-{N-methyl-N-[(R/S)-α-methyl-4-(3,5-dimethylbenzyloxy)phenylacetyl]amino}-(R)-propionate 46b (107 mg, 0.28 mmol) in THF (5 mL) was treated with 1 N LiOH (1 mL) for 40 min. The solution was acidified with 1 N HCl (1.5 mL) and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to give the acid (103 mg, 100%) as a solid. MS (CI—NH3): (M+H)+=370.