Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6]C=C[C:3]=1[C:8]1[O:9][CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]([OH:14])[CH2:12][N:13]=1.C(NC(C1[S:34]C=CC=1)=O)/C=C/C1C=CC=CC=1>>[C:15]1([CH:10]2[O:9][C:8]([C:3]3[S:34][CH:6]=[CH:7][CH:2]=3)=[N:13][CH2:12][CH:11]2[OH:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OC1CN=C(c2ccccc2F)OC1c1ccccc1
Reactant: O=C(NC/C=C/c1ccccc1)c1cccs1
Product: OC1CN=C(c2cccs2)OC1c1ccccc1

Procedure:
(5RS, 6SR)-6-Phenyl-2-(2-thienyl)-5,6-dihydro-4H-1,3-oxazin-5-ol may be obtained in the following manner: working as described in Example 22 for the preparation of (5RS, 6SR)-2-(2-fluorophenyl)-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol, but starting with (E)-N-cinnamyl-2-thiophenecarboxamide (5 g), a 0.55 M solution (38 cc) of 3-chloroperbenzoic acid in dichloromethane and boron trifluoride etherate (3.2 g), and after recrystallization in dichloromethane, (5RS, 6SR)-6-phenyl-2-(2-thienyl)-5,6-dihydro-4H-1,3-oxazin-5-ol (2.9 g), m.p. 158° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[C:49]1([CH:55]([OH:59])[CH2:56][CH2:57][CH3:58])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38](=[O:40])[O:59][CH:55]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:56][CH2:57][CH3:58])=[CH:18][CH:17]=1
Reactant: CCCC(O)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCC(OC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1)c1ccccc1
Temperature: 25 °C
Yield: 31.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (76 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (115 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 1-phenyl-1-butanol (57 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (38 mg, yield 29%).
Reaction SMILES: CN[C@H](C(N[C@H:13]([C@@H:21]([OH:27])[CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=O)CC1N=CNC=1.C([N:30](CC)CC)C.C(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl>[NH2:30][CH:14]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:13][C@@H:21]([OH:27])[CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: CCN(CC)CC
Reactant: CN[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CCC(C)C
Agent: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(C)CC[C@H](O)CC(N)C1CCCCC1
Reaction time: 1 h
Yield: 270.1 %

Procedure:
To a solution of 2(S)-(Nα -methyl-L-histidyl)amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (900 mg) and triethylamine (494 mg) in methylene chloride (20 ml) was added trityl chloride (696 mg) at 0° C. The mixture was stirred at the same temperature for 1 hour. After evaporation of the solvent, the residue was dissolved in ethyl acetate (30 ml) and the solution was washed with 1M sodium bicarbonate solution and water successively, and dried over magnesium.sulfate. Evaporation of the solvent gave 2(S)-(Nα -methyl-Nim -trityl-L-histidyl)amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (1.46 g) as an amorphous powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11](=[S:14])[NH:12][N:13]=2)=[CH:5][CH:4]=1)[CH3:2].Br.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:13][N:12]=[C:11]([S:14][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(-c2n[nH]c(=S)[nH]2)cc1
Reactant: BrCc1ccccn1
Agent: Br
Product: CCc1ccc(-c2nc(SCc3ccccn3)n[nH]2)cc1
Yield: 71 %

Procedure:
Prepared in a similar manner to example 1 using 5-(4-ethylphenyl)-2H-1,2,4-triazole-3(4H)-thione (example 4a) and 2-(bromomethyl)pyridine hydrobromide. Yield 71%. 1H NMR (500 MHz, dMSO): δ 1.18-1.22 (t, 3H), 2.64-2.66 (t, 2H), 4.52 (s, 2H), 7.30-7.88 (m, 8H), 14.3 (bs, 1H). MS (M+H, 297).
Reaction SMILES: C(C1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][C:20](O)=[CH:19][N:18]=2)=CC=1)=CCCCCCCCC.N1C=CC=[CH:26][CH:25]=1>ClCCl>[N:22]1([C:21]2[CH:20]=[CH:19][N:18]=[CH:26][CH:25]=2)[CH2:16][CH2:15][CH2:14][CH2:17]1
Reactant: CCCCCCCCC=Cc1ccc(-c2ncc(O)cn2)cc1
Reactant: c1ccncc1
Solvent: ClCCl
Product: c1cc(N2CCCC2)ccn1

Procedure:
A reactor was charged with 1.0g (2.67 mmol) of the 2-{4-(1-decenyl)-phenyl}-5-hydroxypyrimidine obtained above, 2 ml of pyridine, 0.01 g of 4-pyrrolidinopyridine and 20 ml of dichloromethane. While cooling the mixture to a temperature not higher than 0° C. in an atmosphere of nitrogen gas, 1.13 g (4 mmol) of trifluoromethanesulfonic acid anhydride was dropwise added and stirred for two hours. After extraction with water, the organic layer was washed successively with 1 N-hydrochloric acid and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent, purification of the residue by silica gel column chromatography gave 1.06 g (yield 90%) of 2-{4-(1-decenyl)-phenyl}-5-trifluoromethylsulfonyloxypyrimidine.
Reaction SMILES: [Na].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].[C:11](#[N:14])[CH:12]=[CH2:13]>CCO>[C:11]([CH2:12][CH2:13][CH:3]([C:4](=[O:5])[CH3:6])[C:2]([O:8][CH2:9][CH3:10])=[O:7])#[N:14]
Reactant: CCOC(=O)CC(C)=O
Reactant: C=CC#N
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCC#N)C(C)=O
Reaction time: 4 h

Procedure:
A solution of solid sodium metal (450 mg, 19.75 mmol) in EtOH at 30° C. was treated with ethyl acetoacetate (103 g, 790 mmol) maintaining temperature. Then acrylonitrile (41.9 g, 790 mmol) was added dropwise over 15 minutes. The reaction was capped and stirred for 4 hours. The solution was concentrated and the resulting solid was dissolved in 20 mL of water and 3 mL of acetic acid, and washed with 50 mL of DCM. The organic layer was dried over Na2SO4 and concentrated to an oil. Distillation was performed under reduced pressure (0.5 mm) with a bath temperature of 80° C. Fractions were collected and concentrated to provide A-1 as a colorless oil. Data for A-1: LC/MS: m/z (M+H)=183.87 found; 183.20 required
Reaction SMILES: [CH3:1][C:2]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15](C3C=CC(CO)=CC=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9].OCC1C=CC(B(O)O)=CC=1.Br[C:45]1[CH:46]=[N:47][N:48]([CH2:50][C:51]2[CH:52]=[C:53]([CH:63]=[CH:64][CH:65]=2)[CH2:54][NH:55][C:56](=[O:62])[O:57][C:58]([CH3:61])([CH3:60])[CH3:59])[CH:49]=1>>[CH3:1][C:2]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15]([C:45]3[CH:46]=[N:47][N:48]([CH2:50][C:51]4[CH:52]=[C:53]([CH:63]=[CH:64][CH:65]=4)[CH2:54][NH:55][C:56](=[O:62])[O:57][C:58]([CH3:61])([CH3:60])[CH3:59])[CH:49]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4ccc(CO)cc4)cccc32)c1C
Reactant: CC(C)(C)OC(=O)NCc1cccc(Cn2cc(Br)cn2)c1
Agent: OCc1ccc(B(O)O)cc1
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(CNC(=O)OC(C)(C)C)c5)c4)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to 4-(2,3-dimethylphenoxy)-1-(5-(4-(hydroxymethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)butan-1-one except that 4-(hydroxymethyl)phenylboronic acid was replaced with tert-butyl 3-((4-bromo-1H-pyrazol-1-yl)methyl)benzylcarbamate. LCMS, [M+H]+=609.4.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:14]([C:16]2[C:17]([CH3:28])=[N:18][O:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)[OH:15])[CH:11]=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:38]=[CH:39][C:40]([C:24]3[CH:23]=[CH:22][C:21]([C:20]4[O:19][N:18]=[C:17]([CH3:28])[C:16]=4[CH:14]([C:10]4[CH:11]=[N:12][CH:13]=[C:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:9]=4)[OH:15])=[CH:26][CH:25]=3)=[CH:41][CH:42]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cncc(Cc2ccccc2)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cncc(Cc5ccccc5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 17, Step 1, using (5-benzyl-pyridin-3-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.C1COCC1.[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18]>CCOCC>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH:9][C:20]([NH:19][CH2:17][CH3:18])=[O:21])=[O:7])=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: CCN=C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCNC(=O)NNC(=O)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
A stirred suspension of 4-chlorobenzoic acid, hydrazide (17.1 g, 1.00×10-1 mole), and THF (425 ml) was warmed until homogeneous, at which time ethyl isocyanate (8.7 ml, 1.1×10-1 mole) was added via syringe. A precipitate soon formed. After stirring overnight the reaction was diluted with Et2O and the precipitate was collected by filtration affording a colorless powder: 23.7 g (98%). Crystallization from ethanol gave a colorless solid: 21.4 g (88%), Mp 237°-239° C.
Reaction SMILES: [C:1](#[N:3])[CH3:2].CC([O-])(CC)C.[K+].C1(C)C=CC=CC=1.[C:18]12([C:28](OCC)=O)[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2.Cl.[C:34]1([CH3:42])[CH:39]=[CH:38][C:37]([NH:40][NH2:41])=[CH:36][CH:35]=1.Cl>C1COCC1>[C:18]12([C:28]3[CH:2]=[C:1]([NH2:3])[N:40]([C:37]4[CH:38]=[CH:39][C:34]([CH3:42])=[CH:35][CH:36]=4)[N:41]=3)[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2
Reactant: Cc1ccc(NN)cc1
Reactant: CC#N
Reactant: CCOC(=O)C12CC3CC(CC(C3)C1)C2
Agent: CCC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C34CC5CC(CC(C5)C3)C4)cc2N)cc1
Temperature: 25 °C

Procedure:
To a solution of acetonitrile (200 μL, 160 mg, 1.60 mmol) in THF (10 mL) at RT was added a solution of potassium 2-methylbutan-2-olate in toluene (1.7 M, 6.7 mL, 11 mmol) followed by the dropwise addition of ethyl adamantane-1-carboxylate (798 mg, 3.8 mmol) and the reaction mixture maintained at RT for 16 hr. The resulting mixture was concentrated in vacuo to a volume of ˜10 mL and was then diluted with EtOH (10 mL), treated with p-tolylhydrazine hydrochloride (607 mg, 3.83 mmol) and was acidified to pH 1 by the addition of conc hydrochloric acid. The resulting heterogeneous mixture was heated to 70° C. for 2 hr, was cooled to RT and concentrated in vacuo to a volume of ˜10 mL. The mixture was diluted with water (30 mL) and was adjusted to pH 12 by the addition of 2M aq NaOH and was then extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (30 mL), dried, and then evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, EtOAc in isohexane, 0-50%, gradient elution) and the impure product so obtained was triturated with isohexane (20 mL) to afford the title compound, Intermediate A29, as an impure beige solid (730 mg, 65% purity, 40%) containing approximately 35% w/w 3-(adamantan-1-yl)-3-oxopropanenitrile; Rt 4.92 min (Method 1 basic); m/z 308 (M+H)+, (ES+). This material was used in subsequent steps without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([CH:32]([NH2:34])[CH3:33])=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:34][CH:32]([C:31]1[CH:35]=[CH:36][C:28]([Cl:27])=[CH:29][CH:30]=1)[CH3:33]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(N)c1ccc(Cl)cc1
Product: CC(Nc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1ccc(Cl)cc1
Yield: 37.8 %

Procedure:
Use a method similar to the General Procedure 5-3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (852 mg, 2.0 mmol) and (±)-4-chloro-(α-methyl)benzylamine (622 mg, 4.0 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1) to obtain (±)-7-chloro-6-[1-(4-chlorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (326 mg, 38%). MS (ES+) m/z: 431 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[C:6]2[CH:7]=[C:8]([S:11]([N:14]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:17][C:16]([CH:25]=O)=[CH:15]3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3]1.CO.[CH3:30][NH2:31].[BH4-].[Na+]>>[O:1]=[S:2]1(=[O:27])[C:6]2[CH:7]=[C:8]([S:11]([N:14]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:17][C:16]([CH2:25][NH:31][CH3:30])=[CH:15]3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3]1
Reactant: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc3c(c2)S(=O)(=O)CC3)c1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc3c(c2)S(=O)(=O)CC3)c1
Yield: 65 %

Procedure:
Using 1-[(1,1-dioxido-2,3-dihydro-1-benzothiophen-6-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde (114 mg), 40% methylamine methanol solution (0.3 mL) and sodium borohydride (10.8 mg), a procedure as in Example 126 was performed to give the title compound as a white solid (yield 76.3 mg, 65%).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][N:16](C(OCC4C=CC=CC=4)=O)[CH2:15][CH:14]3[O:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]4[O:39][CH2:38][CH2:37][N:36]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:35]=4[CH:45]=3)=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.CO.[OH-].[K+]>O1CCOCC1.O>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH:14]3[O:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]4[O:39][CH2:38][CH2:37][N:36]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:35]=4[CH:45]=3)=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(Cn4ccnc4)cc3)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: COCCCN1CCOc2ccc(COC3CNCCC3c3ccc(Cn4ccnc4)cc3)cc21
Temperature: 100 °C
Reaction time: 5 h

Procedure:
0.0978 g of benzyl 4-(4-imidazol-1-ylmethylphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate is dissolved in 3 ml of dioxane. 3 ml each of methanol and 40% KOH are added and the reaction mixture is stirred in a sealed flask at 100° C. over 5 hours. The reaction mixture is subsequently cooled to room temperature, diluted with 10 ml of water and extracted with ethyl acetate (3×30 ml). The combined organic phases are washed with 10 ml of water, then 10 ml of brine, dried over sodium sulphate, filtered and concentrated. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: C[CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11](CO)=[CH:10][C:9]=2[N+:16]([O-:18])=[O:17])[CH2:4][CH2:3]1.[CH:19]([N-]C(C)C)(C)C.[Li+].[C:27]([O:34][CH2:35][CH3:36])(=[O:33])[C:28](OCC)=[O:29]>C1COCC1.O.CCOCC>[CH2:35]([O:34][C:27](=[O:33])[C:28](=[O:29])[CH2:19][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([N:5]2[CH2:4][CH2:3][CH2:2][CH2:7][CH2:6]2)[C:9]=1[N+:16]([O-:18])=[O:17])[CH3:36]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC1CCN(c2ccc(CO)cc2[N+](=O)[O-])CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(=O)Cc1cccc(N2CCCCC2)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 1-(3-methyl-2-nitro-phenyl)-piperidine (i) in THF is treated with lithium diisopropylamide (“LDA”) (1 eq), followed by diethyl oxalate (1.05 eq), at 0° C. The reaction is allowed to warm to room temperature over 90 min. The reaction is diluted with water and ether, partitioned, and the aqueous layer is washed with ether. The combined organic layers are dried over MgSO4, filtered and concentrated. Chromatography gives 3-(2-nitro-3-piperidin-1-yl-phenyl)-2-oxo-propionic acid ethyl ester (ii).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=O)=[CH:4][CH:3]=1.[CH3:12]N.N.[CH2:15]1[CH:24]2[CH:19](CCC3C=CC=C[C:23]=32)[NH:18][C:17](=[O:29])[CH2:16]1>C(O)CO.CC(O)C>[CH3:12][N:18]1[C:19]2[C@@:8]([CH3:9])([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=3[CH2:23][CH:24]=2)[CH2:15][CH2:16][C:17]1=[O:29].[CH3:12][N:18]1[C@@H:19]2[C@:8]([CH3:9])([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=3[CH2:23][CH2:24]2)[CH2:15][CH2:16][C:17]1=[O:29]
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: O=C1CCC2c3ccccc3CCC2N1
Reactant: CN
Agent: N
Solvent: OCCO
Solvent: CC(C)O
Product: CN1C(=O)CC[C@@]2(C)C1=CCc1cc(Cl)ccc12
Product: CN1C(=O)CC[C@@]2(C)c3ccc(Cl)cc3CC[C@H]12

Procedure:
By following the procedures described in Example 40, Steps A, B, C, D, E and F using p-chlorophenylacetic acid as the starting material and in Step F using methylamine rather than ammonia and 2-propanol rather than ethylene glycol, the compound (R)(+)-4-methyl-8-chloro-10b-methyl-1,2,3,4,6,10b-hexahydro-benzo[f]quinolin-3-one was prepared. This hexahydrobenzo[f]quinolin-3-one was reduced according to the procedure described in Example 40, Step G. The crude product was purified by chromatography on SiO2 (ethyl acetate as eluent) to afford 5.6 g of the title compound as a pale oil which solidified on standing. Melting point 60°-61° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][N:12]1[C:17]([CH3:18])=[C:16]([Cl:19])[N:15]=[C:14](Cl)[C:13]1=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C[CH2:33][O:34]C(C)=O>>[CH3:33][O:34][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][NH:24][C:14]2[C:13](=[O:21])[N:12]([CH2:11][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[C:17]([CH3:18])=[C:16]([Cl:19])[N:15]=2)=[CH:31][CH:30]=1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Reactant: CCOC(C)=O
Reactant: CONCc1ccccc1
Product: COc1ccc(CNc2nc(Cl)c(C)n(CC(=O)OCc3ccccc3)c2=O)cc1

Procedure:
A solution of the pyrazinone 18-3 (5 g, 15.3 mmol) and 4 methoxybenzylamine (6.0 mL, 45.9 mmol) in EtOAc (60 mL) was heated at 80° C. for 2 h. The solution was cooled and filtered. The filtrate was concentrated in vacuo, the residue swished with MeOH and filtered to afford the title compound as a solid:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCN(C)C1=O>C1(C)C=CC=CC=1>[C:18]1([CH3:21])[CH:19]=[CH:20][C:15]([O:13][C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][CH:11]=2)=[CH:16][CH:17]=1
Reactant: Cc1ccc(Cl)cc1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN1CCN(C)C1=O
Product: Cc1ccc(Oc2ccc(-c3ccccc3)cc2)cc1
Reaction time: 5 h
Yield: 95 %

Procedure:
A four-necked flask equipped with a thermometer, a stirrer, and a reflux condenser with a water trap was charged with 554.7 g of p-phenylphenol, 607.7 g of p-chlorotoluene, 265.4 g of potassium carbonate, 8.0 g of 8-hydroxyquinoline-copper complex and 82 g of 1,3-dimethyl-2-imidazolidinone. The mixture was stirred at 140° to 180° C. under nitrogen for 5 hours while the temperature was raised gradually. The material which was collected in the trap was removed from time to time. After 15 hours of further heating at 170° to 185°C. with stirring, the ratio of p-phenylphenol and 4-biphenylyl p-tolyl ether in the reaction mixtures was found to be 1.5:98.5 as determined by GLC (gas-liquid chromatography) on the area ratio basis. Thereafter, the resulting mixture was concentrated under reduced pressure (10 mmHg) to give 270 g of a distillate composed of p-chlorotoluene and 1,3-dimethyl-2-imidazolidinone. Toluene (400 ml) was added to the residue for dissolving the reaction product. The organic layer was washed with a 10% sodium hydroxide solution, 10% sulfuric acid, and water, in that order. The toluene was then distilled off under reduced pressure to give 796 g of crude, light brown 4-biphenylyl p-tolyl ether in 95% yield. Distillation of the crude product under reduced pressure (2 mmHg) at 190° to 195° C. to give 775 g (92% yield) of white 4-biphenylyl p-tolyl ether melting at 97° to 99° C.
Reaction SMILES: [C:1]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[N:13]([C:31](Cl)=[O:32])[C@H:14]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:16]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:37]1([C:43](=[O:51])[CH2:44][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[ClH:11].[C:1]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[N:13]([C:31]([N:48]3[CH2:47][CH2:46][N:45]([CH2:44][C:43]([N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)=[O:51])[CH2:50][CH2:49]3)=[O:32])[C@H:14]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:16]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: CCOc1cc(C(C)(C)C)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1
Product: Cl

Procedure:
2-{4-[(4S,5R)-2-(4-tert-Butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12h) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 742.4 [(M+H)+]
Reaction SMILES: [ClH:1].[CH3:2][NH:3][S:4](/[CH:7]=[CH:8]/[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH:23]=1)(=[O:6])=[O:5]>CN(C=O)C.O.CO.[Pd]=O>[ClH:1].[CH3:2][NH:3][S:4]([CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]1[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]1)(=[O:5])=[O:6]
Reactant: CNS(=O)(=O)/C=C/c1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Agent: O=[Pd]
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CNS(=O)(=O)CCc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Reaction time: 24 h

Procedure:
A mixture of (E)-N-methyl-2-[3-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)-1H-indol-5-yl]ethenesulphonamide hydrochloride (500 g) and 10% palladium oxide on charcoal (50% wet paste, 700 g added as three charges) in DMF (3 L), water (3 L) and methanol (1.5 L) was hydrogenated at atmospheric pressure over 24 hr. The suspension was filtered and the filter cake washed with water (500 mL). The filtrate was concentrated to approximately 2 L by distillation in vacuo. Ethyl acetate (5 L) was added over 10 mins and the mixture cooled to 5°. The product was filtered off, washed with ethyl acetate (1 L) and dried in vacuo at 45° overnight (453 g, 90.1% of theory). Recrystallisation from hot water (1.36 L) afforded white crystals (324.0 g, 71.2% of theory).