Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[Mg].II.[N:16]1[N:17]([CH:21]([CH3:26])[C:22](OC)=[O:23])[N:18]=[N:19][CH:20]=1.Cl>O1CCCC1.O>[F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:22]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:11])[F:12])=[CH:9][CH:8]=2)([OH:23])[CH:21]([N:17]2[N:18]=[N:19][CH:20]=[N:16]2)[CH3:26])=[CH:6][CH:5]=1
Reactant: COC(=O)C(C)n1ncnn1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CC(n1ncnn1)C(O)(c1ccc(OC(F)(F)F)cc1)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
A solution of 4-trifluoromethoxybromobenzene (45.79 g) in dry tetrahydrofuran (200 cm3) was added carefully to a stirred mixture of magnesium turnings (4.56 g), iodine (1 crystal) and dry tetrahydrofuran (70 cm3). The reaction commenced after about 20 cm3 of the solution had been added, and the reaction was maintained at the reflux temperature whilst the remainder of the solution was added, and thereafter for a further 1 hour. The mixture was cooled to the ambient temperature and a solution of methyl 2-(1,2,3,4-2H-tetrazol-2-yl)propionate (13.95 g), in dry tetrahydrofuran (60 ml) added dropwise, after which the mixture was heated at the reflux temperature for 30 minutes. The mixture was cooled and poured into water (500 cm3) and acidified with 2N hydrochloric acid (250 cm3). The aqueous mixture was extracted with diethylether (3×400 cm3), the ethereal extracts combined, dried over anhydrous magnesium sulphate, and concentrated by removal of the solvent by evaporation under reduced pressure. The residual oil (30.5 g) was subjected to purification by chromatography using a silica gel column eluted with a mixture of hexane (4 parts by volume) and ethylacetate (1 part by volume), and by hplc to yield 1,1-bis(4-trifluoromethoxyphenyl)-2-(1,2,3,4-2H-tetrazol-2-yl)propan-1-ol as a colourless oil (10 g) which crystallized on standing (mp. 55°-58° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][NH:10][CH3:11])[CH:6]=[CH:7][CH:8]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[Cl:23])[C:16](=[O:19])[CH2:17]Br>C(N(CC)CC)C>[Cl:12][C:13]1[CH:14]=[C:15]([C:16](=[O:19])[CH2:17][N:10]([CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:11])[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Reactant: CNCc1cccc(OC)c1
Solvent: CCN(CC)CC
Product: COc1cccc(CN(C)CC(=O)c2ccc(Cl)c(Cl)c2)c1

Procedure:
1-(3-Methoxyphenyl)-N-methylmethanamine is reacted with 3,4-dichlorophenacyl bromide in the presence of triethylamine to give 1-(3,4-dichlorophenyl)-2-((3-methoxybenzyl)(methyl)amino)ethanone. Reduction of this ketone by sodium borohydride yields 1-(3,4-dichlorophenyl)-2-(3-methoxybenzyl)(methyl)amino)ethanol, which undergoes acid mediated cyclization to give 4-(3,4-dichlorophenyl)-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline. This racemic tetraisoquinoline derivative can be separated via chiral HPLC or supercritical fluid chromatography (SFC) to give the single enantiomers. Alternatively, the chiral separation can be achieved by recrystallization using chiral acids such as di-p-toluoyl-D-tartaric acid or di-p-toluoyl-L-tartaric acid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[F:10])[NH2:6])#[CH:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[F:10])[NH2:6])[CH3:2]
Reactant: [H][H]
Reactant: C#Cc1cc(N)ccc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cc(N)ccc1F
Yield: 68.5 %

Procedure:
To a solution of 3-ethynyl-4-fluoroaniline (220 mg, 1.62 mmol) in ethyl acetate (10 mL) was added 10% palladium on carbon (wet). The resulting mixture was subjected to an atmosphere of hydrogen for approximately 1 h. The palladium on carbon was removed by filtration through celite. The filtrate was concentrated in vacuo to provide 3-ethyl-4-fluoroaniline (154 mg, 1.11 mmol, 69% yield) as a brown oil. 1H NMR (400 MHz, CDCl3): 6.77 (dd, 1H), 6.50 (dd, 1H), 6.45-6.41 (m, 1H), 3.47 (br s, 2H), 2.57 (q, 2H), 1.19 (t, 3H); MS (EI) for C8H10FN: 140 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)(=[O:3])[CH3:2].Cl.[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2[O:25][C:24]([CH2:26][CH2:27][NH2:28])=[CH:23][CH:22]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]>>[C:1]([C:4]1[CH:8]=[C:7]([C:9]([NH:28][CH2:27][CH2:26][C:24]2[O:25][C:21]([C:16]3[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=3)=[CH:22][CH:23]=2)=[O:11])[NH:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Agent: Cl
Product: CC(=O)c1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)[nH]n1
Yield: 49.7 %

Procedure:
The title compound was prepared using the method of Example 20 but starting from 3-acetyl-1H-pyrazole-5-carboxylic acid (215 mg; 1.37 mmol) and 2-(5-(3,4-dichlorophenyl)furan-2-yl)ethanamine hydrochloride (400 mg; 1.37 mmol). Crude product was purified by chromatography (CombiFlash, silica column, eluent: 0-100% EtOAc/heptane) to obtain 267 mg (50%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.50 (s, 3H—overlapping with DMSO), 2.93 (t, 2H), 3.54-3.60 (m, 2H), 6.33 (d, 1H), 7.02 (d, 1H), 7.30 (s, 1H), 7.58-7.64 (m, 2H), 7.82 (d, 1H), 8.65 (broad s, 1H), 14.21 (s, 1H).
Reaction SMILES: C[C:2]1([C:22]([O-:24])=[O:23])[CH2:6][CH:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4](=[O:14])[N:3]1C(OC(C)(C)C)=O.O1CCOC[CH2:26]1>Cl>[CH3:26][O:24][C:22](=[O:23])[C@@H:2]1[CH2:6][CH:5]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:4](=[O:14])[NH:3]1
Reactant: CC(C)(C)OC(=O)N1C(=O)C(Cc2ccccc2)CC1(C)C(=O)[O-]
Reactant: C1COCCO1
Agent: Cl
Product: COC(=O)[C@@H]1CC(Cc2ccccc2)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(1,1-Dimethylethyl) 2-methyl-5-oxo-4-(phenylmethyl)-1,2-pyrrolidinedicarboxylate (0.415 g, 1.24 mmol) was dissolved in 4M hydrogen chloride in dioxane (2 ml) and stirred at room temperature for 2 hrs. The solvent was evaporated to give a colourless oil which crystallized on standing to give methyl-5-oxo-4-(phenylmethyl)-prolinate as a creamy/white solid (0.205 g). This was used without further purification in the next step.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:13](OC)(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[SH:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:21]=[C:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[S:16][C:1]([C:3]2[N:8]=[C:7]([CH2:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:5][CH:4]=2)=[N:2]1
Reactant: N#Cc1cccc(CC(N)=S)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: NC(=S)Cc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 43.3 %

Procedure:
(6-Cyano-2-pyridyl)thioacetamide (0.47 g, 2.43 mmol) and methyl thiosalicylate (0.45 g, 2.67 mmol) were dissolved in toluene (50 ml), and triethylamine (0.51 ml, 3.64 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.33 g, 41%) as white crystals.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]>CC(C)=O>[CH2:17]([O:16][C:8]([CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C@H:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH2:2]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C1C=CCCC1
Solvent: CC(C)=O
Product: CCOC(=O)C(C(=O)OCC)[C@H]1CCCC(=O)C1
Temperature: 30 °C
Reaction time: 48 h
Yield: 64.4 %

Procedure:
Under an atmosphere of argon, 24.0 mg (0.04 mmol, S/C=50) of RuH[(R,R)-Tsdpen] (1,3,5-trimethylbenzene), 194 μL (2.0 mmol) of 2-cyclohexenone, 304 μL (2.0 mmol) of diethyl malonate, and 2 mL of acetone were placed in a 20 mL Schlenk tube and stirred at 30° C. for 48 hours. This solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2) to give 330 mg (64% yield) of the title compound. After this was converted into an ethylene ketal derivative as shown below, the optical purity was measured by HPLC (CHIRALCEL OD manufactured by Daicel Chemical Industries, Ltd., hexane: 2-propanol=97:3, flow rate 0.5 mL/min, detection at 210 nm) and it was found to be 77% ee.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.C(OCC)C>CN(C)C=O>[C:21]1([CH2:20][C:12]2([S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:10])=[O:11])[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:25][CH:26]=1
Reactant: COc1ccc(S(=O)(=O)C2SC(=O)NC2=O)cc1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)C2(Cc3ccc(-c4ccccc4)cc3)SC(=O)NC2=O)cc1

Procedure:
Prepared analogously to Example 9 from from 5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione and 4-(bromomethyl)biphenyl in N,N-dimethylformamide. Trituration with diethyl ether provided an off-white solid. 1H NMR: δ 7.98 (s, 1H), 7.93, (dd, J=7.0, 2.0 Hz, 2H), 7.34-7.57 (m, 7H), 7.23-7.26 (m, 2H), 7.06 (dd, J=7.0, 2.0 Hz, 2H), 3.97 (A of AB, J=13.7 Hz, 1H), 3.92 (s, 3H), 3.39 (B of AB, J=13.7 Hz, 1H). MS (m/e): 452.1 (M−H)−. Anal: Calc for C23H19NO5S2.C3H7NO: 59.30% C, 4.98% H, 5.32% N; Found: 59.13% C, 4.89% H, 5.24% N. MP: 119-122° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[F:23]>CCOC(C)=O>[F:23][C:15]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=1[N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: C1CCNC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
To a solution of pyrrolidine (0.78 g, 11 mmol) in EtOAc (15 mL) and Et3N (1.52 g, 15 mmol) was added 1,2-difluoro-4-nitrobenzene (1.59 g, 10 mmol) in an ice bath. The mixture was stirred at rt overnight and filtered. The filter cake was washed with water and dried to give the title compound as a yellow solid (1.60 g, 76%).
Reaction SMILES: O[CH:2]([C:31]1[CH:36]=[CH:35][C:34]([CH:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=1)[C:3]1[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=1[CH3:30]>CCCCCC.C(OCC)(=O)C>[CH:37]([C:34]1[CH:35]=[CH:36][C:31]([CH2:2][C:3]2[C:11]3[O:10][CH2:9][CH:8]([C:12]4[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=4)[C:7]=3[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=2[CH3:30])=[CH:32][CH:33]=1)([CH3:38])[CH3:39]
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1C(O)c1ccc(C(C)C)cc1)OCC2c1ccc(C(C)C)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(Cc2ccc(C(C)C)cc2)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Yield: 64 %

Procedure:
Using N-(7-(hydroxy(4-isopropylphenyl)methyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 95, the title compound was synthesized in the same manner as in Example 96. Yield: 64%. Melting point: 157-158° C. (hexane-ethyl acetate).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][CH2:10][C:9]1([CH3:18])[C:15]([OH:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:24]O>>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][CH2:10][C:9]1([CH3:18])[C:15]([O:17][CH3:24])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C(=O)O)COCC(=O)N1Cc1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1(C)COCC(=O)N1Cc1ccccc1
Temperature: 50 °C

Procedure:
Dissolve 4-benzyl-3-methyl-5-oxomorpholine-3-carboxylic acid (1 eq) in MeOH (10 volumes) and stir. Add sulfuric acid (3 eq) dropwise. Heat at 50° C. for 24 hours. Cool to room temperature and concentrate. Add EtOAc (25 volumes) wash with water (7 volumes), followed by saturated aqueous NaHCO3 (5 volumes), and then water (7 volumes). Dry the EtOAc layer and concentrated to give methyl 4-benzyl-3-methyl-5-oxomorpholine-3-carboxylate.
Reaction SMILES: [CH2:1]([C@H:8]([C@H:15]([OH:22])[C:16]([O:18]C(C)C)=[O:17])[C:9]([O:11]C(C)C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([C@H:8]([C@H:15]([OH:22])[C:16]([OH:18])=[O:17])[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)[C@@H](O)[C@@H](Cc1ccccc1)C(=O)OC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H](O)[C@@H](Cc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 48 h
Yield: 48.5 %

Procedure:
Diisopropyl (2R,3S)-2-benzyl-3-hydroxysuccinate (2.90 g; 15.9 mmol; 1.0 eq.) was taken in THF (44 mL), cooled to 0° C. and was treated with KOH (3.17 g, 56.4 mmol) in water (14.5 mL). The resulting mixture was stirred at RT for 48 h. THF was removed and the residue was taken in water. The aqueous layer was washed with ether (100 mL) and was acidified with an aqueous solution of HCl (1.5 N), then was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and then concentrated to give the title product as white solid (1.73 g, 82%).
Reaction SMILES: Cl.O1CCOCC1.OC(C(F)(F)F)=O.[CH3:15][O:16][C:17]1[CH:47]=[CH:46][C:20]([O:21][CH2:22][C:23]([N:25]2[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH:26]2[CH2:38][O:39][C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)=[O:24])=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([O:21][CH2:22][C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH:26]2[CH2:38][O:39][C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)=[O:24])=[CH:46][CH:47]=1
Reactant: COc1ccc(OCC(=O)N2CCN(C(=O)OC(C)(C)C)CC2COc2cccnc2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: COc1ccc(OCC(=O)N2CCNCC2COc2cccnc2)cc1
Reaction time: 12 h
Yield: 19 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to tert-butyl 4-(2-(4-methoxyphenoxy)acetyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (182 mg, ≦0.305 mmol). After 12 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The desired chromatography fractions were brought to pH ˜12 with 1 N NaOH and were extracted with EtOAc (3×10 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure, yielding 20.9 mg (19%) of the desired product as a thick oil. LC-MS: RT=3.76 min, [M+H]+=358.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[CH2:15]([O:17][C:18](=[O:26])/[CH:19]=[CH:20]\[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:16]>>[CH2:15]([O:17][C:18](=[O:26])[C@H:19]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11])[CH3:16]
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: CCOC(=O)/C=C\C(=O)OCC
Product: CCOC(=O)C[C@H](NCCC[Si](OCC)(OCC)OCC)C(=O)OCC
Temperature: 30 °C
Reaction time: 8 h

Procedure:
221.0 g (1.0 mol) of 3-aminopropyltriethoxysilane were introduced into a standard stirrer apparatus. 172.0 g (1.0 mol) of maleic acid diethyl ester were added dropwise at room temperature over a period of about 4 hours. The exothermic reaction was maintained at about 30° C. by cooling the apparatus in a water bath. Stirring was then continued for a further 8 hours at room temperature. A clear, colorless liquid having a viscosity of about 30 mPa.s (23° C.) was obtained. Base titration showed almost complete conversion. The amine equivalent weight was about 398 g (theory: 393 g).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:3]=1[CH2:4][N:5]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:6][CH3:7].[Br:20]Br>C(Cl)Cl>[NH2:1][C:2]1[C:17]([Br:20])=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:3]=1[CH2:4][N:5]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:6][CH3:7]
Reactant: CCN(Cc1cc(OC)ccc1N)C1CCCCC1
Reactant: BrBr
Solvent: ClCCl
Product: CCN(Cc1cc(OC)cc(Br)c1N)C1CCCCC1

Procedure:
2-Amino-3-bromo-N-cyclohexyl-N-ethyl-5-methoxy-benzylamine was prepared from 2-amino-N-cyclohexyl-N-ethyl-5-methoxy-benzylamine and bromine analogous to Example 9. Proof of structure by IR-, UV- and NMR-spectra. IR-spectrum (methylenechloride): 3240 cm-1NH2 ; 3410 cm-1NH2 ; 2860 cm-1 aliphatic hydrocarbon; 2940 cm-1 aliphatic hydrocarbon; 2830 cm-1OCH3 ; 2800 cm-1N-ethyl (shoulder); 1480 cm-1C=C; 1590 cm-1C=C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.F[C:21]1[CH:22]=[CH:23][C:24]([N+:29]([O-:31])=[O:30])=[C:25]([CH:28]=1)[CH:26]=[O:27]>CS(C)=O>[CH:26]([C:25]1[CH:28]=[C:21]([N:10]2[CH2:11][CH2:12][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:9]2)[CH:22]=[CH:23][C:24]=1[N+:29]([O-:31])=[O:30])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(C=O)c2)CC1
Reaction time: 8 h
Yield: 86.6 %

Procedure:
15 ml of dimethylsulfoxide, 4.2 g (30.4 mmol) of potassium carbonate and 5.66 g (30.4 mmol) of tert-butyl piperazine-1-carboxylate, respectively, are added to 5 g (29.6 mmol) of 5-fluoro-2-nitrobenzaldehyde. The solution is carried at 90° C. under stirring for 8 h. After cooling, the reaction mixture is poured over crushed ice. The yellow precipitate formed is filtered, rinsed with water, and then dried to yield 8.6 g (88%) of tert-butyl 4-(3-formyl-4-nitrophenyl)piperazine-1-carboxylate in the form of a yellow solid.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].[S:22]1[CH:26]=[CH:25][C:24]([C:27](Cl)=[O:28])=[CH:23]1>>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH3:20])[C:3](=[O:21])[CH:2]([NH:1][C:27]([C:24]2[CH:25]=[CH:26][S:22][CH:23]=2)=[O:28])[N:8]=1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2F)c2ccccc21
Reactant: O=C(Cl)c1ccsc1
Product: CN1C(=O)C(NC(=O)c2ccsc2)N=C(c2ccccc2F)c2ccccc21

Procedure:
The procedure of Example 134 was carried out using equivalent amounts of 3(R,S)-amino-1,3-dihydro- 1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one and 3-thiophenecarbonyl chloride. The product was purified by chromatography on silica gel (5% (v/v) Et2O in CH2Cl2 elution). The combined product fractions were evaporated to dryness in vacuo to give the title compound which was dried at 65° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CS(C)=O.O>[F:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:12]=[CH:13]2
Reactant: O=S(=O)(c1ccc(Cl)cc1)n1ccc2cc(F)ccc21
Reactant: C1CNCCN1
Solvent: O
Solvent: CS(C)=O
Product: O=S(=O)(c1ccc(N2CCNCC2)cc1)n1ccc2cc(F)ccc21
Yield: 48.9 %

Procedure:
A solution of 1-(4-Chlorobenzenesulfonyl)-5-fluoro-1H-indole (0.210 g, 0.7 mmole) and anhydrous piperazine (0.3 g, 3.4 mmole) in dimethylsulfoxide (3.0 mL) was heated at 100° in a sealed tube for 16 h. The reaction mixture was diluted with 15 mL water and extracted with 20 mL ethyl acetate. The organic phase was washed with three 10 mL portions of water, 10 mL saturated sodium chloride, dried (magnesium sulfate), and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to provide the 5-Fluoro-1-(4-piperazin-1-yl-benzenesulfonyl)-1H-indole (0.123 g), m.p. 77–78°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24](=[O:32])[CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH2:15][C@@H:14](OS(C)(=O)=O)[CH2:13]1)[CH:6]=[CH:5]2.[CH3:33][NH2:34]>C(O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24](=[O:32])[CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:34][CH3:33])[CH2:13]1)[CH:6]=[CH:5]2
Reactant: CS(=O)(=O)O[C@@H]1CCCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Reactant: CN
Solvent: CCO
Product: CNC1CCCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Temperature: 80 °C

Procedure:
N-[6-Chloro-2-[(3R)-3-[(methylsulfonyl)oxy]-1-piperidinyl]-5-quinolinyl]-cyclohexaneacetamide (Example 80(a)) (0.2 g) and 8M methylamine in ethanol (5 ml) were placed into a 10 ml microwave vial and heated at 80° C. for 60 minutes within a single mode microwave. The reaction was pre-absorbed onto silica and purified (SiO2, 7M ammonia in methanol:methanol:dichloromethane 1:3:96 as eluant). The resulting product was recrystallised from acetonitrile to afford the title compound (0.007 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]([NH2:18])=[S:17])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:20](I)[CH2:21][CH3:22]>>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[NH:18])[S:17][CH2:20][CH2:21][CH3:22])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCI
Reactant: CC(C)(C)OC(=O)NCc1cccc(NC(N)=S)c1
Product: CCCSC(=N)Nc1cccc(CNC(=O)OC(C)(C)C)c1
Yield: 99 %

Procedure:
Using the compound obtained in Example 24 as a starting material and also using n-propyl iodide as a reagent, reaction was performed as in Example 29 to give 227 mg of the titled compound (yield, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][C:12]1[N:17]=[CH:16][C:15]([C:18]2([CH2:24][NH2:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:14][N:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:25][CH2:24][C:18]1([C:15]2[CH:16]=[N:17][C:12]([CH3:11])=[N:13][CH:14]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:6]
Reactant: Cc1ncc(C2(CN)CCOCC2)cn1
Reactant: O=C(O)c1ccccc1Cl
Product: Cc1ncc(C2(CNC(=O)c3ccccc3Cl)CCOCC2)cn1

Procedure:
From 2-chlorobenzoic acid and (4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methanamine. LCMS (MH+): m/z=346.1, tR (minutes, Method F)=1.55
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][NH:6][C:7]([CH:9]1[CH2:12][N:11]([C:13]2[S:14][CH2:15][C:16](=[O:18])[N:17]=2)[CH2:10]1)=[O:8].[Cl:20][C:21]1[CH:38]=[CH:37][C:24]([CH2:25][N:26]2[C:34]3[C:29](=[CH:30][C:31]([CH:35]=O)=[CH:32][CH:33]=3)[CH:28]=[N:27]2)=[C:23]([C:39]([F:42])([F:41])[F:40])[CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][NH:6][C:7]([CH:9]1[CH2:10][N:11]([C:13]2[S:14][C:15](=[CH:35][C:31]3[CH:30]=[C:29]4[C:34](=[CH:33][CH:32]=3)[N:26]([CH2:25][C:24]3[CH:37]=[CH:38][C:21]([Cl:20])=[CH:22][C:23]=3[C:39]([F:42])([F:40])[F:41])[N:27]=[CH:28]4)[C:16](=[O:18])[N:17]=2)[CH2:12]1)=[O:8]
Reactant: COC(=O)CCNC(=O)C1CN(C2=NC(=O)CS2)C1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Product: COC(=O)CCNC(=O)C1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1

Procedure:
3-[(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carbonyl)-amino]-propionic acid methyl ester was prepared from 3-{[1-(4-oxo-4,5-dihydro-thiazol-2-yl)-azetidine-3-carbonyl]-amino}-propionic acid methyl ester and 1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde following General Procedure D.