Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]2=[N:6][C:7]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[N:4]2[N:3]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([C:2]2[CH:14]=[CH:13][C:5]3=[N:6][C:7]4[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=4[N:4]3[N:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Clc1ccc2nc3c(n2n1)CCCC3
Reactant: C1CCNCC1
Product: c1cc2nc3c(n2nc1N1CCCCC1)CCCC3
Temperature: 0 °C

Procedure:
A solution of 5.0 g of 2-chloro-6,7,8,9-tetrahydropyridazino[1,6-a]benzimidazole in 30 ml of piperidine was stirred and heated at reflux for 72 hours. The reaction mixture was poured into 200 ml of ice water and the tan solid which formed was separated by filtration and air dried. It was then recrystallized from a mixture of ethanol and water to give 2-(1-piperidinyl)-6,7,8,9-tetrahydropyridazino[1,6-a]benzimidazole melting at about 184°-185° C.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[N:7]=[C:6]1Cl)[C:2]#[C:3][CH3:4].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:6]2[N:5]([CH2:1][C:2]#[C:3][CH3:4])[C:13]3[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=3[N:7]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC#CCn1c(Cl)nc2c1c(=O)n(C)c(=O)n2C
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Yield: 56.9 %

Procedure:
8-Chlorotheophylline (4.9 g) and potassium carbonate (5 g) were dissolved in N,N-dimethylformamide (100 ml), and 1-bromo-2-butyne (2.4 ml) was added thereto. After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate, and washed with water. Insoluble white solid was collected through filtration, and washed with ethyl acetate to give 3.8 g of 7-(2-butynyl)-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione. Then, the resulting 7-(2-butynyl)-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione (1.8 g) and 1-piperazine carboxylic acid tert-butyl ester (3.7 g) were stirred at 150° C. for 1 hour. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over an hydrous magnesium sulfate. The solvent was removed by distillation at reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.6 g of the title compound from a fraction eluted with hexane-ethyl acetate (1:4).
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[O:3][CH2:2]1.[CH3:12][NH:13][CH3:14].C([BH3-])#N.[Na+]>C(O)(=O)C>[CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][CH:7]([N:13]([CH3:14])[CH3:12])[CH2:6][CH2:5]2)[O:3][CH2:2]1
Reactant: CNC
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)C1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To a solution of 5.0 gm (32 mMol) 1,4-cyclohexanedione mono-ethylene ketal and 10.80 gm (240 mMol) dimethylamine were added 2.0 mL acetic acid and the mixture was stirred at 0° C. for 1.5 hours. To this solution were then added 3.62 gm (58 mMol) sodium cyanoborohydride and the reaction stirred for an additional hour at ambient. The pH of the reaction mixture was adjusted to ~7 with 16 mL acetic acid and stirred 18 hours at ambient. The volatiles were removed under reduced pressure and the residue dissolved in cold 5% tartaric acid solution and then the aqueous phase was made basic with 5N sodium hydroxide. This aqueous phase was extracted well with dichloromethane. These organic extracts were combined and concentrated under reduced pressure to give 5.04 gm (85%) of the title compound as an oil.
Reaction SMILES: C1(N2CCOCC2)CCCC=1.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15]C=1.Cl.[CH:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH:15](=[C:16]1[CH2:17][CH2:18][CH2:13][C:12]1=[O:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccccc1
Reactant: c1ccccc1
Agent: C1=C(N2CCOCC2)CCC1
Agent: Cl
Product: O=C1CCCC1=Cc1ccccc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
With reflux device installed, 36.8 g (0.24 mol) of N-cyclopentenyl morpholine, 27.2 g (0.20 mol) of benzaldehyde and 200 mL of benzene were added to a round bottom flask and heated under reflux for 20 h. The resulting solution was cooled to 30° C., and slowing stirring while 62 mL of hydrochloric acid (6 mol/L) was added to the solution. After stirring for 2 h at room temperature, the benzene layer was separated and washed with water to neutral, and dried over anhydrous sodium sulfate overnight. Then the mixture was filtered and benzene was recovered by evaporation under reduced pressure. The residue was cooled and solidified, then recrystallized in cyclohexane/ethanol to yield 2-benzylidene-cyclopentanone with a yield of 84.6%.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[SH:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[NH4+].I[CH3:26]>C(O)C>[CH2:1]([N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[S:21][CH3:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Sc1nc2cnc3ccccc3c2n1Cc1ccccc1
Reactant: CI
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1nc2cnc3ccccc3c2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Benzyl-1H-imidazo[4,5-c]quinoline-2-thiol (4.15 g, 14.2 mmol), deionized water (35 mL), ethanol (35 mL), and aqueous ammonium hydroxide (3.2 mL) were combined, and iodomethane (1.06 mL, 17.0 mmol) was added. The reaction was stirred at room temperature for one hour, and a precipitate formed. The precipitate was collected by filtration, washed with diethyl ether (5×100 mL), and dried under vacuum to provide 1-benzyl-2-(methylthio)-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:14])([CH3:13])[C@H:8]1[CH2:12][CH2:11][CH2:10][NH:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20](Br)[CH:21]=1.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.CC(C)([O-])C.[Na+]>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]>[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([N:9]2[CH2:10][CH2:11][CH2:12][C@@H:8]2[C:7]([CH3:14])([CH3:13])[O:6][SiH2:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:21]=1
Reactant: Brc1cncc(Br)c1
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@H]1CCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)[SiH2]OC(C)(C)[C@H]1CCCN1c1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-3 [B], (R)-2-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidine was reacted with 3,5-dibromopyridine in the presence of Pd2(dba)3, rac-BINAP and sodium tert-butoxide to give the title compound as a yellow oil. MS: 371.0, 372.9 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2CCC(=O)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc([C@H]2CC[C@H](O)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-(4-Methoxyphenyl)cyclohexanone (400 mg, 1.958 mmol) was dissolved in MeOH (20 mL) and cooled to 0° C. NaBH4 (222 mg, 5.87 mmol) was added, and the reaction was stirred at 0° C. for 30 min. The reaction was then quenched with 5 mL of water, stirred for 5 min, and then diluted with EtOAc (50 mL). The organic layer was washed with water (3×50 mL) and brine (50 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0 to 70% EtOAc/hexanes) to afford trans-4-(4-methoxyphenyl)cyclohexanol. 1H NMR (500 MHz, CDCl3): δ 7.12 (d, J=8.5 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H), 3.79 (s, 3H), 3.68 (m, 1H), 2.46 (m, 1H), 2.07-2.12 (m, 2H), 1.86-1.94 (m, 3H), 1.38-1.54 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]2[NH:25][C:26](=[O:28])[NH:27][C:23]=2[CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:20][C:21]3[CH:30]=[CH:29][C:24]4[NH:25][C:26](=[O:28])[NH:27][C:23]=4[CH:22]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(Cl)cc2)CC1
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Product: O=C(Nc1ccc2[nH]c(=O)[nH]c2c1)C(=O)N1CCC(Cc2ccc(Cl)cc2)CC1

Procedure:
The title compound is prepared from [4-(4-chloro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 33b) and 5-amino-1,3-dihydro-benzimidazol-2-one according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 299-300° C. (isopropanol)
Reaction SMILES: [C:1]([O-])(=O)C.[Na+].C(OCOC)(=O)C.[C:13]([O:16][C@:17]1([C@:37]2([CH3:38])[C@H:23]([C@H:24]3[C@H:34]([CH2:35][CH2:36]2)[C@:32]2([CH3:33])[C:27](=[CH:28][C:29](=[O:39])[CH2:30][CH2:31]2)[CH2:26][CH2:25]3)[CH2:22][CH2:21]1)[C:18](=[O:20])[CH3:19])(=[O:15])[CH3:14]>C(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)=O>[C:13]([O:16][C@:17]1([C@:37]2([CH3:38])[C@H:23]([C@H:24]3[C@H:34]([CH2:35][CH2:36]2)[C@:32]2([CH3:33])[C:27](=[CH:28][C:29](=[O:39])[CH2:30][CH2:31]2)[C:26]([CH3:1])=[CH:25]3)[CH2:22][CH2:21]1)[C:18](=[O:20])[CH3:19])(=[O:15])[CH3:14]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: CC(=O)[O-]
Agent: COCOC(C)=O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 70 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
A suspension of 0.5 g of sodium acetate in 60 ml of anhydrous chloroform and 2 ml of distilled phosphorus oxychloride is refluxed under agitation for 30 minutes at a bath temperature of 70° C. After adding 15 ml of methoxymethyl acetate and 2.0 g of 17α-acetoxy-4-pregnene-3,20-dione, the reaction solution is further stirred for 5 hours at 70° C. Subsequently such an amount of a saturated soda solution is added dropwise at room temperature that the aqueous phase remains alkaline. The organic phase is separated, washed with water, and dried over sodium sulfate. After concentration, the crude product is purified on 100 g of silica gel with a hexane-ethyl acetate gradient (0-50% ethyl acetate), thus isolating 1.26 g of 17α-acetoxy-6-methyl-4,6-pregnadiene-3,20-dione, mp 217°-219° C.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Br[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:25][C:26]=1[CH3:27]>>[CH2:17]([O:16][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[S:25][C:26]=1[CH3:27])[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: Cc1sc(-c2ccccc2)nc1CBr
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccccc3)sc2C)c1)C(=O)O
Yield: 1 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-bromomethyl-5-methyl-2-phenyl-thiazole, the title compound was obtained in 1% yield as a yellow oil. MS: (M+H)+ 421.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]([CH3:14])([CH3:13])[C:11]#N)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CC(C[AlH]CC(C)C)C.Cl.C1C[O:28]CC1>>[Br:1][C:2]1[CH:3]=[C:4]([C:10]([CH3:14])([CH3:13])[CH:11]=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: C1CCOC1
Reactant: COc1ccc(C(C)(C)C#N)cc1Br
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Product: COc1ccc(C(C)(C)C=O)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(3-bromo-4-methoxy-phenyl)-2-methyl-propionitrile (12.71 g, 0.050 mol) in dry THF (100 mL) was cooled to −10° C. under argon. DIBALH (1M in THF, 100 mL, 0.10 mol) was added keeping the temperature below 0° C. The mixture was stirred for 30 min/0° C. and then 2 h/25° C. The clear solution was carefully poured into icecold hydrochloric acid (2M, 100 mL). The THF was removed under reduced pressure to give clear oil. The oil was destilled (b.p. 114-130° C./4.3×10−3 mbar) Yield: 7.40 g (58%). GCMS: >99%
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[CH:18]3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[Cl:30]C1C=CC=CC=1N1CCNCC1>>[Cl:30][C:6]1[CH:7]=[CH:8][CH:3]=[CH:4][C:5]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18]2)[CH2:11][CH2:10]1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: O=c1c2ccccc2ncn1CCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Product: O=c1c2ccccc2ncn1CCN1CCN(c2ccccc2Cl)CC1

Procedure:
This compound was prepared in compliance with the procedure described in 1c, using 1-(2-chlorophenyl)piperazine instead of 1-(3-(trifluoromethyl)phenyl)piperazine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[NH:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=3)[N:9]=2)=[CH:4][CH:3]=1>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[NH:25][C:26]3[CH:27]=[CH:28][C:29]([NH2:32])=[CH:30][CH:31]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2nc3cccc(Nc4ccc([N+](=O)[O-])cc4)c3nc2-c2ccc(C)cc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3cccc(Nc4ccc(N)cc4)c3nc2-c2ccc(C)cc2)cc1

Procedure:
5.9 g (13.2 mmol) of 2,3-di(4-methylphenyl)-5-(4-nitrophenyl)aminoquinoxaline was dissolved in 70 ml of tetrahydrofuran, and a reaction container was purged with nitrogen. Thereafter, 2.0 g of 5% Pd/C (hydrous) was added, followed by sufficient purging with nitrogen again. This system was purged with hydrogen, followed by reaction at room temperature for 13 hours. After completion of the reaction, the system was filtered, and the resulting filtration residue was washed with tetrahydrofuran and filtered again. The solvent was removed from the resulting filtrate, and a reaction product was extracted with a silica gel column.
Reaction SMILES: Br[C:2]1([C:8]2[O:9][C:10]3[C:18]([CH2:19][C:20]#[N:21])=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH2:22]>>[C:2]1([C:8]2[O:9][C:10]3[C:18]([CH2:19][C:20]([NH2:21])=[O:22])=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1
Reactant: N#CCc1cccc2c(=O)cc(C3(Br)CCCCC3)oc12
Reactant: O
Product: NC(=O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
2-(1-Bromocyclohexyl)-8-cyanomethyl-4-oxo-4H-[1]-benzopyran (3.0 g) was added to polyphosphoric acid (120 ml) and the mixture was heated on an oil bath at about 120° C. for 2 hours. After standing overnight, water (about 300 ml) was added to decompose polyphosphoric acid. Crystals deposited were filtered off and recrystallized form the mixed solvent of dichloromethane and methanol to obtain the title compound, yield 57%.
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:7][C:6](=[O:8])[NH:5][CH2:4][CH2:3]1.[H-].[Na+].[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br>C1COCC1>[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][N:5]1[CH2:4][CH2:3][C:2]([CH3:1])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:7][C:6]1=[O:8]
Reactant: BrCc1cccc(Br)c1
Reactant: CC1(c2ccccc2)CCNC(=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(c2ccccc2)CCN(Cc2cccc(Br)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.8 %

Procedure:
A solution of 6-methyl-6-phenyl-1,3-oxazinan-2-one (500 mg, 2.62 mmol) and NaH (189 mg, 7.86 mmol) in dry THF (10 mL) was stirred for 1 h. A solution of m-bromobenzyl bromide (1.31 g, 5.24 mmol) in dry THF (3 mL) was added. The mixture was stirred overnight at rt. The reaction mixture was quenched water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by preparative TLC to afford 3-(3-bromobenzyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (300 mg, 32%). 1H NMR (CDCl3): 1.60-1.70 (s, 3H), 2.15-2.30 (m, 1H), 2.35-2.48 (m, 1H), 2.79-2.90 (m, 1H), 3.00-3.10 (m, 1H), 4.30-4.40 (m, 1H), 4.50-4.60 (m, 1H), 6.90-7.00 (m, 1H), 7.00-7.10 (m, 1H), 7.20-7.45 (m, 7H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[O:4].COCN[C:21]([CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22]>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:21]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])=[CH:8][C:9]=1[NH:10][C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[O:4]
Reactant: COCNC(=O)C1CCCC1
Reactant: COC(=O)c1sccc1NC(=O)C(F)(F)F
Product: COC(=O)c1sc(C(=O)C2CCCC2)cc1NC(=O)C(F)(F)F

Procedure:
3-(2,2,2-Trifluoroacetylamino)thiophene-2-carboxylic acid methyl ester and cyclopentanecarboxylic acid methoxymethylamide were reacted by method M. The product with the molecular weight of 349.33 (C14H14F3NO4S) was obtained in this way; MS (ESI): 350 (M+H+).
Reaction SMILES: CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C.[F:28][C:29]1[CH:56]=[CH:55][CH:54]=[C:53]([F:57])[C:30]=1[C:31]([NH:33][C:34]1[CH:38]=[CH:37][N:36]([CH2:39][C:40]2[CH:45]=[C:44]([N+:46]([O-])=O)[CH:43]=[CH:42][C:41]=2[C:49]([F:52])([F:51])[F:50])[N:35]=1)=[O:32]>[Pd].C(O)C>[NH2:46][C:44]1[CH:43]=[CH:42][C:41]([C:49]([F:51])([F:52])[F:50])=[C:40]([CH2:39][N:36]2[CH:37]=[CH:38][C:34]([NH:33][C:31](=[O:32])[C:30]3[C:29]([F:28])=[CH:56][CH:55]=[CH:54][C:53]=3[F:57])=[N:35]2)[CH:45]=1
Reactant: O=C(Nc1ccn(Cc2cc([N+](=O)[O-])ccc2C(F)(F)F)n1)c1c(F)cccc1F
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: CCO
Product: Nc1ccc(C(F)(F)F)c(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c1

Procedure:
To 10% palladium on activated carbon degussa type E101 NE/W (wet) (440 mg, 4.14 mmol, Aldrich) was added a slight suspension of the 2,6-difluoro-N-(1-{[5-nitro-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)benzamide (for a preparation see Intermediate 40) (2.0 g, 4.69 mmol) in a solution of ethanol (80 ml) under vacuum. A further amount of 10% palladium on activated carbon degussa type E101 NE/W (wet) (0.2 g) was added after 2 h. The suspension was hydrogenated for a total of 4 h at ambient temperature. The suspension was filtered and the residue washed with ethanol (50 ml). The solvent was removed in vacuo to leave a pale yellow foam (1.79 g); LCMS: (System 4) MH+=397, tRET=2.65 min.
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.C1(C2C3C=CC=CC=3N([CH2:57][C:58](C3(C)CCCCC3)=[O:59])C(=O)N(CC(O)=O)N=2)CCCCC1.C(OC(=O)CSC1C=CC=C(N)C=1)C.C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[CH2:58]([O:59][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:57]
Reactant: CC1(C(=O)CN2C(=O)N(CC(=O)O)N=C(C3CCCCC3)c3ccccc32)CCCCC1
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: CCOC(=O)CSc1cccc(N)c1
Agent: COC(=O)c1cccc(N)c1
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1), except that {5-cyclohexyl-1-[2-(1-methyl-cyclohexyl)-2-oxo-ethyl]-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl}-acetic acid (Example 133, step a) and (3-amino-phenylsulfanyl)-acetic acid ethyl ester were used instead of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (CDCl3) 8.40 (1H, s), 7.48 (3H, m), 7.31 (2H, m), 7.20 (1H, t), 7.10 (1H, d), 7.02 (1H, d), 4.76 (1H, d), 4.58 (1H, d), 4.23 (2H, m), 3.67 (2H, s), 2.79 (1H, m), 1.99-1.25 (20H, m), 1.19 (3H, s). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 58.41; H, 7.21; N, 8.18%; C33H40N4O5S.C7H17NO5.1.4H2O requires: C, 58.17; H, 7.31; N, 8.48%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[CH:7]3[C:14]4([CH2:15][CH2:16][C:5]=2[CH:4]=1)[CH:10]([CH2:11][NH:12][CH2:13]4)[CH2:9][CH2:8]3.C(N(CC)CC)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[CH:7]3[C:14]4([CH2:15][CH2:16][C:5]=2[CH:4]=1)[CH:10]([CH2:11][N:12]([C:26](=[O:28])[CH3:27])[CH2:13]4)[CH2:9][CH2:8]3
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)CCC13CNCC1CCC23
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CCC13CN(C(C)=O)CC1CCC23
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
2-Methoxy-5,6,6a,7,8,9,10,11-octahydro-4bH-benzo[4,5]indeno[1,7a-c]pyrrole (Example 1A, compound 1A-b) (50.0 mg, 0.21 mmol) and triethylamine (86 μL, 0.61 mmol) were dissolved in CH2Cl2 (2 mL). Acetic anhydride (24 μl, 0.25 mmol) was added dropwise. The mixture was stirred at rt for 2 hr. It was then quenched with water (2 mL), and extracted with CH2Cl2 (5 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 5% methanol in dichloromethane, providing 59.1 mg (100%) of the title compound.
Reaction SMILES: C[C:2]1[C:3]([Cl:10])=[N:4][C:5]([Cl:9])=[N:6][C:7]=1Cl.[F:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH2:14][NH2:15].C(N(CC)CC)C>CO>[Cl:9][C:5]1[N:6]=[C:7]([NH:15][CH2:14][C:13]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:12]=2[F:11])[CH:2]=[C:3]([Cl:10])[N:4]=1
Reactant: Cc1c(Cl)nc(Cl)nc1Cl
Reactant: NCc1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: CO
Product: Fc1ccc(CNc2cc(Cl)nc(Cl)n2)c(F)c1
Reaction time: 1 h
Yield: 37.97 %

Procedure:
A suspension of methyl 2,4,6-trichloropyrimidine (1 g, 4.87 mmol) in methanol (20 ml) was cooled −20° C., to this 2,4-difluoro benzylamine (0.627 mg, 4.39 mmol) and triethylamine (0.98 mg, 9.74 mmol) were added. RM was stirred at same temperature for 1 hr then at room temperature for 4 hrs. Methanol was removed under vacuum. The residue was purified by column chromatography to get the title compound.