Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([NH2:10])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14](CCC2C=NC(C)=CC=2)[N:13]=1.[NH3:31].O>CCOC(C)=O>[CH:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH2:2][CH2:1][C:4]3[CH:9]=[N:31][C:7]([CH3:8])=[CH:6][CH:5]=3)=[CH:14][N:13]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(CCc2cc3ccccc3c(Cl)n2)cn1
Reactant: N
Reactant: CC(C)[C@H]1CC[C@H](N)CC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(CCc2cnc(N[C@H]3CC[C@H](C(C)C)CC3)c3ccccc23)cn1

Procedure:
Under a N2 atmosphere, 600 mg (4.25 mmol) of trans-4-isopropyl-cyclo-hexylamine [for preparation see Arzneim. Forsch. 19 (1969), 140] and 120 mg (0.424 mmol) of 1-chloro[2-(6-methyl-pyridin-3-yl)-ethyl]-isoquinoline are heated to 140° C. in an ampulla for 10 h. The reaction mixture is suspended in EtOAc, and mixed with 0.25 ml of NH3 solution (25%) and water. The separated aqueous phase is extracted twice more with EtOAc, the organic phases washed with water and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2; hexane/EtOAc 1:1) yields trans 1-(4-isopropyl-cyclohexylamino)-4-[2-(6-methyl-pyridin-3-yl)-ethyl]-isoquinoline; 1H NMR (DMSO-d6) δ 8.27 (m, 2H), 7.88 (d, 1H), 7.65 (t, 1H), 7.60 (s, 1H), 7.54 (m, 1H), 7.14 (d, 1H), 6.84 (d, 1H), 3.88 (m, 1H), 3.00 (m, 2H), 2.84 (m, 2H), 2.40 (s, 3H), 2.00 (m, 2H), 1.71 (m, 2H), 1.5-1.0 (m, 6H), 0.86 (d, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15](C([O-])=O)[C:16]([O-:18])=[O:17])=[C:11]([N+:22]([O-:24])=[O:23])[CH:10]=2)=[CH:5][CH:4]=1>Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[C:11]([N+:22]([O-:24])=[O:23])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc(C(C(=O)[O-])C(=O)[O-])c([N+](=O)[O-])c2)cc1
Agent: Cl
Product: COc1ccc(-c2ccc(CC(=O)O)c([N+](=O)[O-])c2)cc1

Procedure:
Crude 4′-methoxy-3-nitro-biphenyl-4-malonate was heated at 100° C. in 60 mL 6 N hydrochloric acid for 15 hours and cooled. The precipitate which formed was collected by filtration, washed with water and hexane, and dried to give 7.2 g of crude 4′-methoxy-3-nitrobiphenyl-4-acetic acid as a light tan solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Si](C)(C)C)[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[C:14]([N+:24]([O-:26])=[O:25])=[C:15]2[S:23][CH2:22][CH2:21][N:16]2[C:17](=[O:20])[C:18]=1[CH3:19].[I:27]Cl.C(OC(=O)C)C>C(Cl)Cl.CCCCCC.F[B-](F)(F)F.[Ag+]>[F:1][C:2]1[CH:7]=[C:6]([I:27])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[C:14]([N+:24]([O-:26])=[O:25])=[C:15]2[S:23][CH2:22][CH2:21][N:16]2[C:17](=[O:20])[C:18]=1[CH3:19]
Reactant: Cc1c(Nc2ccc([Si](C)(C)C)cc2F)c([N+](=O)[O-])c2n(c1=O)CCS2
Reactant: ClI
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1c(Nc2ccc(I)cc2F)c([N+](=O)[O-])c2n(c1=O)CCS2
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
7-(2-Fluoro-4-trimethylsilanyl-phenylamino)-6-methyl-8-nitro-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (0.5 g, 1.27 mmol) in DCM (10 mL) was added to silver tetrafluoroborate (0.74 g, 3.81 mmol) in DCM (10 mL) previously degassed with nitrogen at −60° C. and the resulting mixture was stirred at −60° C. for 30 minutes. This was followed by the addition of iodine monochloride (1.3 mL, 1.399 mmol) and continued stirring for a further 30 minutes at −60° C. to −50° C. The reaction was monitored by TLC (50% ethylacetate in hexane). The reaction mixture was diluted with DCM, quenched with sodium thiosulphate solution, filtered through celite and the filtrate was extracted with DCM. The organic layer was washed with NH3 solution, brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (40% ethylacetate in hexane) afforded 0.45 g of the product (80% yield).
Reaction SMILES: C1(C#C)C=CC=CC=1.Cl[CH2:10][CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Li]CCCC.BrCCCCl.[I-:31].[Na+]>C1COCC1>[I:31][CH2:10][CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [I-]
Reactant: ClCCCC#Cc1ccccc1
Agent: ClCCCBr
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C#Cc1ccccc1
Product: ICCCC#Cc1ccccc1
Temperature: -78 °C
Reaction time: 5 h
Yield: 80.8 %

Procedure:
To a solution of THF (200 mL) into reaction flask was added (5-chloropent-1-ynyl)benzene Phenylacetylene (10 g, 97.91 mmol). Then the reaction mixture was cooled to −78° C. in a dry ice bath. nBuLi (95.95 mmol, 38.39 mL) was added dropwise and allowed to react for 0.5 h at −78° C. At −78° C., 1-bromo-3-chloropropane was added. Stirred for 5 hours during which the reaction was allowed to warm up to room temperature. Then reaction was refluxed at 90° C. for 3 hours. The solvent was distilled off, then water (150 mL) and ether (150 mL) was added. The crude product was extracted, ether was distilled off and the resulting crude mixture was dissolved in acetone. Sodium iodide (22.92 mmol, 3.44 g) was added into the solution. The reaction mixture, with reflux condenser attached, was heated to 70° C. for two days. Acetone was distilled off using short path distillation apparatus. Ether (150 mL) and water (150 mL) was added and carried out extraction. Ether was then dried over magnesium sulfate and distilled off resulting in 5.00 g of product (yield 98%). No further purification was carried out. 1H NMR (500 MHz, CDCl3) □2.072 (m, 2H, CH2); 2.605 (t, 2H, CH2); 3.697 (m, 2H, CH2); 7.276 (m, 2H, Phenyl); 7.389 (m, 2H, phenyl); 7.484 (m, 1H, phenyl).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[N+:23]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30])([O-:25])=[O:24].C([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[N+:23]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([NH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1)=[O:30])([O-:25])=[O:24]
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(NC(=O)c2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
To a stirring solution of tert-butyl (3-aminophenyl)carbamate (2.00 g, 9.6 mmol) and triethylamine (1.40 mL, 10 mol) in dry tetrahydrofuran (27.3 mL) at 0° C. was slowly added a solution of 3-nitrobenzoyl chloride (1.87 g, 10.1 mmol) in tetrahydrofuran (7.8 mL). The resulting mixture was slowly warmed up to rt and stirred for one additional hour at rt. The reaction mixture was treated with Na2CO3 (aq). The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the desired product as a white powder (3.4 g, 99%). LCMS for C18H19N3O5 (M-tBu+H)+: m/z=302.0. 1H NMR (400 MHz, CD3OD): δ 8.79 (t, J=2.0 Hz, 1H), 8.43 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 8.31 (ddd, J=6.4, 2.4, 1.2 Hz, 1H), 7.87 (t, J=2.1 Hz, 1H), 7.77 (t, J=8.0 Hz, 1H), 7.60 (ddd, J=8.0, 4.0, 2.4, 1H), 7.25 (t, J=8.0 Hz, 1H), 7.19 (d, J=1.2 Hz, 1H), 1.52 (s, 9H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:27]=[CH:26][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[O:28]1[CH2:30][C@H:29]1[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])=[CH:35][CH:34]=1>C(Cl)(Cl)Cl.CO>[CH2:18]([NH:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:30][C@H:29]([OH:28])[CH2:31][O:32][C:33]3[CH:34]=[CH:35][C:36]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])=[CH:37][CH:38]=3)=[CH:27][CH:26]=2)[CH2:10][CH2:11]1)=[O:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Reactant: CS(=O)(=O)Nc1ccc(OC[C@@H]2CO2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(NS(C)(=O)=O)cc3)cc2)CC1
Yield: 12.1 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide (0.245 g, 0.58 mmol) was reacted with N-(4-[(2S)oxiranylmethoxy]phenyl)methanesulfonamide (0.13 g, 0.53 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.04 g, 0.064mmol).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[C:3]([C:12](=[O:17])[C:13]([CH3:14])([CH3:16])[CH3:15])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(C)c1C(=O)C(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(CBr)c1C(=O)C(C)(C)C

Procedure:
A mixture of methyl 3-methyl-2-(2,2-dimethylpropanoyl)benzoate, N-bromosuccinimide and benzoylperoxide in of anhydrous carbon tetrachloride is stirred at reflux for about 1.5 hours. After cooling to room temperature the formed succinimide is collected by suction and washed with cold carbon tetrachloride. The mother liquors are evaporated to dryness in vacuo and the residue is rinsed with diethyl ether and collected by suction filtration to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[S:26]1[CH:30]=[CH:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:34]([CH2:35][NH2:36])[C:27]1=2.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CC#N.CN(C)C=O>[S:26]1[CH:30]=[CH:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:34]([CH2:35][NH:36][C:22]([C:10]3[N:11]=[C:12]4[N:17]([C:18](=[O:19])[C:9]=3[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:16][CH2:15][O:14][C:13]4([CH3:20])[CH3:21])=[O:24])[C:27]1=2
Reactant: NCc1cccc2ccsc12
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1cccc3ccsc13)c(OCc1ccccc1)c2=O
Temperature: 23 °C
Reaction time: 60 h
Yield: 220.6 %

Procedure:
To a solution of intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylic acid (0.200 g, 0.60 mmol) in CH3CN:dimethylformamide (30 mL: 5 mL) was added intermediate 139, benzo[b]thiophen-7-ylmethanamine hydrochloride (0.069 g, 0.266 mmol), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP) (0.347 g, 0.670 mmol) and diisopropylethylamine (420 μL, 2.40 mmol). The reaction mixture was stirred at 23° C. for 60 h. The solvents were then removed in vacuo and 1N HCl (50 mL) added. This was extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified on a Biotage system using a silica gel column with hexane:ethyl acetate (1:1) to (1:5) gradient as eluent to afford the title compound (0.279 g, 87% yield): 1H NMR (400 MHz, DMSO-d6) δ: 9.11 (1H, dd, J=5.6 Hz), 7.81 (1H, m), 7.77 (1H, d, J=5.6 Hz), 7.52 (1H, d, J=5.6 Hz), 7.48–7.26 (6H, m), 5.09 (2H, s), 4.67 (2H, d, J=5.2 Hz), 4.04 (2H, m), 3.90 (2H, m), 1.58 (6H, s), LCMS (M+H)+ m/z 476.
Reaction SMILES: C(CCC1C=CC([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=CC=1)(O)=O.[CH3:44][S:45]([C:48]1[CH:53]=[CH:52][C:51](B(O)O)=[CH:50][CH:49]=1)(=[O:47])=[O:46].B(O)O>>[CH3:40][C@:18]12[C@@:17]3([CH3:41])[C@@H:26]([C@:27]4([CH3:30])[C@@H:14]([CH2:15][CH2:16]3)[C:13]([CH3:42])([CH3:43])[C:12]([C:51]3[CH:52]=[CH:53][C:48]([S:45]([CH3:44])(=[O:47])=[O:46])=[CH:49][CH:50]=3)=[CH:29][CH2:28]4)[CH2:25][CH2:24][C@@H:23]1[C@H:22]1[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]1([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]2
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(CCC(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: OBO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(S(C)(=O)=O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for compound (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(2-carboxyethyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (example 4a) using 4-(methylsulfonyl)phenylboronic acid as the reactant boronic acid. The product was isolated as a white solid (3.5 mg, 20%). LCMS: m/e 591.61 (M−H)−, 6.74 min (method 3). 1H NMR (400 MHz, <DMSOmix>) δ ppm 0.92 (s, 6H), 0.98 (s, 6H), 1.00 (s, 3H), 1.02-1.77 (m, 17H), 1.68 (s, 3H), 1.79-1.97 (m, 2H), 2.05-2.23 (m, 2H), 2.32 (t, J=13.47 Hz, 1H), 2.90-3.06 (m, 1H), 3.19 (s, 3H), 4.58 (s, 1H), 4.71 (s, 1H), 5.29 (d, J=5.57 Hz, 1H), 7.36 (d, J=6.44 Hz, 2H), 7.85 (d, J=8.20 Hz, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([C:31]=3[CH3:32])=[CH:29][CH:28]=[CH:27][C:26]=4[O:33][CH3:34])=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C[O:36][C:37]([C@H:39]1[CH2:44][CH2:43][C@H:42]([C:45](O)=[O:46])[CH2:41][CH2:40]1)=[O:38].O[Li].O>>[CH3:34][O:33][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[NH:24][C:23]([C:21]([NH:20][C:17]1[CH:18]=[CH:19][C:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:45]([C@H:42]4[CH2:41][CH2:40][C@H:39]([C:37]([OH:38])=[O:36])[CH2:44][CH2:43]4)=[O:46])[CH2:13][CH2:12]3)=[CH:15][CH:16]=1)=[O:22])=[C:31]2[CH3:32]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: COc1cccc2c(C)c(C(=O)Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)[nH]c12
Agent: [Li]O
Solvent: O
Product: COc1cccc2c(C)c(C(=O)Nc3ccc(C4CCN(C(=O)[C@H]5CC[C@H](C(=O)O)CC5)CC4)cc3)[nH]c12

Procedure:
With a procedure similar to the example above, trans-4-(4-{4-[(7-methoxy-3-methyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-cyclohexanecarboxylic acid was prepared from 4-{4-[(7-methoxy-3-methyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester and trans-cyclohexane-1,4-dicarboxylic acid monomethyl ester, followed by a standard LiOH—H2O saponification procedure to remove the methyl ester. LCMS calcd for C30H35N3O5 (m/e) 517, obsd 518 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:38])C(=O)C1>C1C=CC=CC=1>[Br:1][C:2]1[C:3]([CH2:12][Br:38])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(Br)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: COC(=O)c1cccc(Br)c1CBr
Yield: 100 %

Procedure:
A suspension of methyl 3-bromo-2-methylbenzoate (26.6 mmol), benzoyl peroxide (2.7 mmol) and NBS (32 mmol) in benzene (80 mL) was allowed to stir at reflux for 5 hr. The reaction mixture was filtered and the solid was washed with diethyl ether. The organic solutions were combined and washed with 10% Na2S2O3 and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give methyl 3-bromo-2-(bromomethyl)benzoate (26.6 mmol, 100%) as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:8][CH2:7][C:6]([NH:11][CH3:12])([C:9]#N)[CH2:5][CH2:4]1>C(OCC)C>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:3]2([N:2]([CH3:21])[CH3:1])[CH2:4][CH2:5][C:6]([NH:11][CH3:12])([C:9]3[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=3)[CH2:7][CH2:8]2)=[CH:18][CH:17]=1
Reactant: CNC1(C#N)CCC(c2ccc(OC)cc2)(N(C)C)CC1
Solvent: CCOCC
Product: CNC1(c2ccccc2)CCC(c2ccc(OC)cc2)(N(C)C)CC1
Temperature: 35 °C
Reaction time: 1 h

Procedure:
Phenyl lithium (12.9 mL, 23.3 mmol, 1.8 M solution in dibutyl ether) was provided in argon and mixed in drops with a solution of the title compound from step 3 (2.23 g, 7.76 mmol) in abs. diethyl ether (30 mL) at RT. During this, the reaction solution heated to 35° C. and a solid separated out. The reaction mixture was stirred for 1 h with reflux (bath 50° C.), then hydrolysed in the ice bath (0-10° C.) with 20% NH4Cl solution (20 mL) and the organic phase was separated. The aqueous phase was extracted with ether (3×50 mL). The combined organic solutions were dried over Na2SO4 and concentrated to low volume in a vacuum. By means of flash chromatography (100 g silica gel) with ethyl acetate/methanol (20:1→9:1→MeOH→MeOH+2% NH3) the non-polar diastereoisomer was obtained in a mixed fraction with starting substance and ketone and lastly the polar diastereoisomer. The mixed fraction with non-polar diastereoisomer was purified again by flash chromatography with dichloromethane/methanol (50:1→20:1→9:1→4:1)
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:48])[N:20]([CH2:39][C:40]2[CH:41]=[N:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:48])[N:20]([CH2:39][C:40]2[CH:41]=[N:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(Cc2ccc(OC)nc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(Cc2ccc(OC)nc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
A mixture of hydroxylammonium chloride (2.37 g), sodium hydrogen carbonate (3.83 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-({4-butyl-1-[(6-methoxypyridin-3-yl)methyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (1.09 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.44 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.38 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 5 with water and 1 M hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.38 g, 32%).
Reaction SMILES: [K].[C:2](#[N:4])[CH3:3].C([O:7][C:8](=O)[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH2:20][CH2:19]2)[CH2:12][CH2:11]1)C.[ClH:35]>O1CCCC1.C(OCC)(=O)C>[ClH:35].[ClH:35].[O:7]=[C:8]([CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH2:22][CH2:23]2)[CH2:12][CH2:11]1)[CH2:3][C:2]#[N:4]
Reactant: CCOC(=O)CN1CCC(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Reactant: CC#N
Agent: Cl
Agent: [K]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CCC(=O)CN1CCC(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Reaction time: 0.5 h
Yield: 14 %

Procedure:
A solution of 0.77 mL (1.3 mmol) of potassium tert-pentoxyde solution (1.7M in toluene) is added dropwise at room temperature to a stirred solution of 52 mg (1.27 mmol) of acetonitrile in 2.5 mL of tetrahydrofuran followed by dropwise addition of 0.19 g (0.44 mmol) of (4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)acetic acid ethyl ester in 1 mL of tetrahydrofuran. After 30 minutes at room temperature, the reaction mixture is diluted with 10 mL of an aqueous 0.2N aqueous hydrochloric acid solution and 50 mL of ethyl acetate forming an emulsion. The mixture is concentrated under reduced pressure and the product is purified over 10 g of silica gel (eluant dichloromethane/methanol 95/5). The oily product is dissolved in 2 mL of diethyl ether and acidified with a hydrochloric acid diethyl ether solution. The precipitate is filtered, washed with diethyl ether and dried under reduced pressure to give 30 mg (14%) of 3-oxo-4-(4-{2[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)butanenitrile, dihydrochloride.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].C(O)C.O.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:21](=O)[O:22]C2C=CC([N+]([O-])=O)=CC=2)=[CH:15][CH:14]=1)([O-:12])=[O:11]>C(N(CC)CC)C>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19][O:20][C:21]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:22])=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCC(=O)O
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(O)CNC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
One and one half grams of glycine is slurried in 235 ml of a 80/20 mixture of ethyl alcohol/water. To this is added 5.6 ml of triethylamine, solution occurs, followed by 6.36 g of product from Example 254. A precipitate forms and the reaction is stirred overnight at room temperature. The reaction mixture is concentrated in vacuo. The resulting oil is dissolved in water and ethyl alcohol, the pH is adjusted to 1.5 with concentrated hydrochloric acid and the volume is reduced. The reaction mixture is extracted with methylene chloride, the organic layer is washed with water and concentrated in vacuo. The residue is purified by chromatography (Silica gel: ethyl acetate) to give 2.83 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6](C)[C:5]2(O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.N[OH:23]>COCCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N+:6]([O-:23])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NO
Reactant: CN1C(=O)Nc2ccc(Cl)cc2C1(O)c1ccccc1
Agent: Cl
Solvent: COCCO
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)[n+]1[O-]
Yield: 51.3 %

Procedure:
A stirred mixture of 2.89 g (0.01 mole) of 6-chloro-3,4-dihydro-4-hydroxy-3-methyl-4-phenyl-2(1H)-quinazolinone and 2.09 g (0.03 mole) of hydroxylamine hydrochloride in 50 ml of 2-methoxyethanol (ethylene glycol monomethyl ether) was refluxed for 2 hours, and then cooled to 0°. The solid that formed was collected on a filter, washed with ethanol, and dried in air to give 1.40 g (51%) of 6-chloro-4-phenyl-2(1H)-quinazolinone 3-oxide as yellow crystals, mp 267°-269°.