Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:15][C:14]([C:26](O)=[O:27])=[CH:13]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:55][O:56][C:57](=[O:64])[C@H:58]([C:60]([CH3:63])([CH3:62])[CH3:61])[NH2:59].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:55][O:56][C:57](=[O:64])[C@@H:58]([NH:59][C:26]([C:14]1[N:15]=[C:16]([CH2:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:9][C:8]1[CH:29]=[CH:30][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=1)=[CH:19][CH:18]=2)=[O:27])[C:60]([CH3:63])([CH3:62])[CH3:61]
Reactant: CC(C)(C)c1ccc(Oc2ccc3c(CC4CCCC4)nc(C(=O)O)cc3c2)cc1
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)c1cc2cc(Oc3ccc(C(C)(C)C)cc3)ccc2c(CC2CCCC2)n1)C(C)(C)C
Yield: 35 %

Procedure:
To a solution of 6-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid (50 mg, 0.124 mmol) in dry DMF (1.25 mL) was added HBTU (1.5 eq., 0.19 mmol, 71 mg), tert-butylglycine methyl ester (1.1 eq., 0.14 mmol, 25 mg) and DIEA (3.0 eq., 0.37 mmol, 0.065 mL) according to general procedure A. Purification by chromatography on silica afforded 23 mg of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2
Reactant: Oc1ccc2ncccc2c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Product: COc1cc2nccc(Oc3ccc4ncccc4c3)c2cc1OC
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinoline (90 mg) with 6-hydroxyquinoline (176 mg) was stirred at 180° C. for 30 min. The reaction solution was cooled to room temperature, and was then purified by column chromatography on silica gel using acetone-hexane to give the title compound (62 mg, yield 46%).
Reaction SMILES: [OH-].C([N+](C)(C)C)C1C=CC=CC=1.[OH:13][CH2:14][CH2:15][C:16]1[S:20][CH:19]=[C:18]([CH2:21][CH2:22][N:23]2[CH2:43][CH2:42][C:26]3([O:31][CH2:30][CH2:29][N:28]([C:32]([C:34]4[N:35]=[C:36]([CH:39]([CH3:41])[CH3:40])[S:37][CH:38]=4)=[O:33])[CH2:27]3)[CH2:25][CH2:24]2)[CH:17]=1.[C:44]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])(=[O:47])[CH:45]=[CH2:46].C(#N)C>C1(C)C=CC=CC=1>[CH:39]([C:36]1[S:37][CH:38]=[C:34]([C:32]([N:28]2[CH2:27][C:26]3([CH2:42][CH2:43][N:23]([CH2:22][CH2:21][C:18]4[CH:17]=[C:16]([CH2:15][CH2:14][O:13][CH2:46][CH2:45][C:44]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[S:20][CH:19]=4)[CH2:24][CH2:25]3)[O:31][CH2:30][CH2:29]2)=[O:33])[N:35]=1)([CH3:40])[CH3:41]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4csc(CCO)c4)CC3)C2)cs1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4csc(CCOCCC(=O)OC(C)(C)C)c4)CC3)C2)cs1
Reaction time: 18 h

Procedure:
Benzyltrimethylammonium hydroxide (40% in water, 0.27 mL) was added in one portion to a stirred solution of (9-(2-(5-(2-hydroxyethyl)thiophen-3-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone [Example 78, step b] (0.92 g) and tert-butyl acrylate (0.38 g) in toluene (1 mL). The resultant mixture was stirred vigorously at 20° C. for 4 hours. Acetonitrile (1 mL) was added and the mixture was stirred for 18 hours and then purified without work up. The crude product was purified by flash silica chromatography, using 6% methanol in ethyl acetate with 1% triethylamine as solvent. Fractions containing the product were evaporated to dryness to afford the subtitled compound. Yield 0.84 g.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[OH:34])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1.[H-].[Na+].[Cl:46][C:47]1[CH:52]=[C:51](Cl)[N:50]=[CH:49][N:48]=1.O>CN(C)C=O.C(OCC)(=O)C>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[O:34][C:51]1[CH:52]=[C:47]([Cl:46])[N:48]=[CH:49][N:50]=1)[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:13]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2O)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2Oc2cc(Cl)ncn2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (300 mg) is dissolved in N,N-dimethylformamide (5 ml) and thereto are added sodium hydride (60%) (29 mg) and 4,6-dichloro-pyrimidine (107 mg) under ice-cooling, and the mixture is stirred for 30 minutes, and the reaction solution is cooled to room temperature, and thereto is added 4,6-dichloro-pyrimidine (107 mg), and the mixture is stirred for 30 minutes. To the reaction solution are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=49:1→17:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(6-chloro-pyrimidin-4-yloxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (244 mg). MS (m/z): 738/740 [M+H]+
Reaction SMILES: COC(C1N(CC=O)C=C(C(=O)NCC2C=CC(F)=CC=2)C(=O)C=1OCC1C=CC=CC=1)=O.Cl.Cl.N[C@@H](C)CCNC1CCC1.[CH:46]1([N:50]2[CH2:55][CH2:54][C@H:53]([CH3:56])[N:52]3[C:57](=[O:85])[C:58]4[N:59]([CH:61]=[C:62]([C:74]([NH:76][CH2:77][C:78]5[CH:83]=[CH:82][C:81]([F:84])=[CH:80][CH:79]=5)=[O:75])[C:63](=[O:73])[C:64]=4[O:65]CC4C=CC=CC=4)[CH2:60][C@@H:51]23)[CH2:49][CH2:48][CH2:47]1>>[CH:46]1([N:50]2[CH2:55][CH2:54][C@H:53]([CH3:56])[N:52]3[C:57](=[O:85])[C:58]4[N:59]([CH:61]=[C:62]([C:74]([NH:76][CH2:77][C:78]5[CH:83]=[CH:82][C:81]([F:84])=[CH:80][CH:79]=5)=[O:75])[C:63](=[O:73])[C:64]=4[OH:65])[CH2:60][C@@H:51]23)[CH2:47][CH2:48][CH2:49]1
Reactant: C[C@H]1CCN(C2CCC2)[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4)c(=O)c(OCc4ccccc4)c3C(=O)N12
Agent: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Agent: C[C@H](N)CCNC1CCC1
Agent: Cl
Product: C[C@H]1CCN(C2CCC2)[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4)c(=O)c(O)c3C(=O)N12

Procedure:
In a similar manner to that described in example Z-35a, from 16 (18 mg, 0.39 mmol) and [(3S)-3-Aminobutyl]cyclobutylamine bis-hydrochloride (23 mg, 0.107 mmol), (4S,12aS)-1-cyclobutyl-N-[(4-fluorophenyl)methyl]-4-methyl-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide was prepared as a white solid. This material was deprotected in a second step similar to that described in example Z-37 to give the title compound as a white solid after purification by HPLC (4.5 mg, 25% 2 steps). 1H NMR (CDCl3) δ 12.54 (s, 1H), 10.48 (s, 1H), 8.20 (s, 1H), 7.31 (m, 2H), 6.98 (m, 2H), 5.02 (m, 1H), 4.61-4.57 (m, 2H), 4.26-4.14 (m, 3H), 3.05 (m, 1H), 2.90 (m, 1H), 2.49 (m, 1H), 2.12 (m, 1H), 2.05-1.87 (m, 3H), 1.84-1.61 (m, 3H), 1.46 (m, 1H), 1.32 (m, 3H); ES+ MS: 455 (M+1).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].N1C=CC=CC=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O>C(Cl)Cl>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[S:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=1)(=[O:24])=[O:23]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCNCCO
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(S(=O)(=O)N(CCO)CCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
Diethanolamine (8.40 g, 80 mmol, 1.50 equiv) was dissolved in CH2Cl2 (30 mL) and pyridine (5.1 mL, 63.6 mmol, 1.2 equiv). A solution of 4-methoxybenzenesulfonyl chloride (10.9 g, 53 mmol, 1.0 equiv) n CH2Cl2 (30 mL) was added quickly and the resulting mixture was stirred at rt overnight, then poured into H2O and extracted with EtOAc. The organic layers were washed with 1M HCl and brine, dried (MgSO4), filtered, and the filtrate was concentrated to give an oil which was purified by column chromatography (95/5 CH2Cl2/MeOH) to give 12 g (83%) of the sulfonamide as an oil which crystallized on standing: 1H NMR (500 MHz) 7.75 (d, J=8.8, 2H, HAr); 6.99 (d, J=8.8, 2H, HAr); 3.87 (a, 3H, H3CO); 3.86 (t, J=4.9, 4 H, H2C(1′); 3.42 (br s, 2H, OH); 3.26 (t, J=4.9, 4H, H2C(2′)). 13C NMR (100 MHz) 163.05; 129.85; 129.37; 114.37; 62.25; 55.61; 52.90.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][N:14]2[CH:18]=[N:17][N:16]=[N:15]2)=[C:9]([Cl:19])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:20][N:21]1[C:25]([OH:26])=[CH:24][C:23]([CH3:27])=[N:22]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][N:14]2[CH:18]=[N:17][N:16]=[N:15]2)=[C:9]([Cl:19])[CH:8]=[CH:7][C:3]=1[C:4]([O:26][C:25]1[N:21]([CH3:20])[N:22]=[C:23]([CH3:27])[CH:24]=1)=[O:5]
Reactant: Cc1cc(O)n(C)n1
Reactant: O=C(Cl)c1ccc(Cl)c(OCCn2cnnn2)c1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(OC(=O)c2ccc(Cl)c(OCCn3cnnn3)c2Cl)n(C)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.7 %

Procedure:
2,4-Dichloro-3-[2-(1H-tetrazol-1-yl)ethoxy]benzoyl chloride (0.60 g) was dissolved in tetrahydrofuran (5 ml), this solution was added dropwise to a tetrahydrofuran (5 ml) solution of 1,3-dimethyl-5-hydroxypyrazole (0.22 g) and triethylamine (0.23 g) at 5° C. and the mixture was stirred at room temperature for 6 hours. After the reaction, the mixture was extracted with ethyl acetate (100 ml) and then washed with diluted hydrochloric acid and an aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off to obtain the desired 5-{2,4-dichloro-3-[2-(1H-tetrazol-1-yl)ethyloxy]-benzoyloxy}-1,3-dimethylpyrazole (0.65 g).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Cl.[CH3:14][C:15]([CH3:24])([CH3:23])[C:16]#[C:17]/[CH:18]=[CH:19]/[CH2:20][NH:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[ClH:1].[CH3:14][C:15]([CH3:24])([CH3:23])[C:16]#[C:17]/[CH:18]=[CH:19]/[CH2:20][N:21]([CH3:22])[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: ClCc1cccc2ccccc12
Reactant: CNC/C=C/C#CC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(C/C=C/C#CC(C)(C)C)Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a solution of 1.77 g (10 mmol) of 1-chloromethylnaphthalene in 10 ml of dimethyl sulfoxide were added 1.88 g (10 mmol) of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)methylamine hydrochloride and 1.66 g (12 mmol) of potassium carbonate under ice cooling. The mixture was stirred for 16 hours at room temperature, poured into 200 ml of ethyl acetate, washed with 100 ml ×2 of water, a mixture of 80 ml of water and 10 ml of 2N hydrochloric acid, and 50 ml of saturated sodium chloride aqueous solution respectively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to crystallize. The crystals were suspended in 10 ml of ethyl acetate, cooled, filtered and dried under reduced pressure to obtain 2.95 g (yield: 90%) of the above identified compound as off-white crystalline powder.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>CN(C1C=CN=CC=1)C.O.C(OCC)(=O)C>[Si:21]([O:20][CH2:19][C:4]1[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=[C:2]([I:1])[CH:3]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cc(I)cc(Nc2nccc(C(F)(F)F)n2)c1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(I)cc(Nc2nccc(C(F)(F)F)n2)c1
Reaction time: 2 h
Yield: 96.2 %

Procedure:
To a flask containing the product of Step 2 (2.79 g, 7.06 mmol) in AMY (71 mL) were added tert-butyldimethylsilyl chloride (1.60 g, 10.59 mmol), imidazole (0.96 g, 14.12 mmol) and DMAP (86 mg, 0.71 mmol). After two hours, The reaction was diluted with water and ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated. Column chromatography on silica gel was used for purification to yield N-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-iodophenyl]-4-(trifluoromethyl)pyrimidin-2-amine (3.46 g, 6.79 mmol, 96% yield). MS ESI: [M+H]+ m/z 510.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:7]([OH:8])[C:6]([CH3:10])([CH3:9])[CH:5]([OH:11])[C:4]([CH3:13])([CH3:12])[CH:3]1[OH:14].[C:16]([C:20]1[CH:21]=[C:22]([CH2:31][CH2:32][C:33](Cl)=[O:34])[CH:23]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:25]=1[OH:26])([CH3:19])([CH3:18])[CH3:17]>N1C=CC=CC=1>[C:16]([C:20]1[CH:21]=[C:22]([CH2:31][CH2:32][C:33]([O:14][CH:3]2[C:2]([CH3:15])([CH3:1])[CH:7]([O:8][C:33](=[O:34])[CH2:32][CH2:31][C:22]3[CH:23]=[C:24]([C:27]([CH3:28])([CH3:30])[CH3:29])[C:25]([OH:26])=[C:20]([C:16]([CH3:19])([CH3:17])[CH3:18])[CH:21]=3)[C:6]([CH3:9])([CH3:10])[CH:5]([O:11][C:33](=[O:34])[CH2:32][CH2:31][C:22]3[CH:23]=[C:24]([C:27]([CH3:28])([CH3:30])[CH3:29])[C:25]([OH:26])=[C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:21]=3)[C:4]2([CH3:13])[CH3:12])=[O:34])[CH:23]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:25]=1[OH:26])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC1(C)C(O)C(C)(C)C(O)C(C)(C)C1O
Reactant: CC(C)(C)c1cc(CCC(=O)Cl)cc(C(C)(C)C)c1O
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(CCC(=O)OC2C(C)(C)C(OC(=O)CCc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)C(C)(C)C(OC(=O)CCc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)C2(C)C)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred cooled solution of 2.16 g (0.010 mole) of 2,2,4,4,6,6-hexamethyl cyclohexane-1,3,5-triol in 50 ml of pyridine is added in several portions over a 20 minute period, 10.69 g (0.036 mole) of 3-(3,5-di-t-butyl-4hydroxyphenyl)propionyl chloride. This mixture is stirred for 30 minutes at 0° to 5°C and then for 15 hours at 45° to 50°C. The mixture is cooled to room temperature and poured into ice water. This mixture is then extracted several times with ethyl ether and these extracts are in turn washed with 2N sulfuric acid, water, 5% aqueous sodium carbonate solution, water and finally saturated sodium chloride solution. The ethereal extracts are then dried over sodium sulfate and evaporated to yield the product. Further purification is achieved by means of chromatography through silica gel, eluting successively with heptane and benzene. Removal of solvent and drying to constant weight at 100°/0.1 mm affords the product, m.p. 105°-115°C.
Reaction SMILES: [S:1]1[C:12]2[C:4](=[CH:5][CH:6]=[C:7]3[C:11]=2[C:10](=O)[C:9](=[O:14])[NH:8]3)[N:3]=[CH:2]1.Cl.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1>>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]/[N:24]=[C:10]2\[C:9](=[O:14])[NH:8][C:7]3[C:11]\2=[C:12]2[S:1][CH:2]=[N:3][C:4]2=[CH:5][CH:6]=3)=[CH:19][CH:18]=1
Reactant: NNc1ccc(Br)cc1
Reactant: O=C1Nc2ccc3ncsc3c2C1=O
Agent: Cl
Product: O=C1Nc2ccc3ncsc3c2/C1=N/Nc1ccc(Br)cc1
Yield: 62 %

Procedure:
Prepared according to Example 96 with 6H-1-thia-3,6-diaza-as-indacen-7,8-dione (Procedure A) and 4-bromophenylhydrazine hydrochloride in 62% yield.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[F:23])([OH:8])[CH2:4][CH2:3]1.[C:24]([Cl:28])(=[O:27])[CH2:25][CH3:26]>>[ClH:28].[F:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:5]1([O:8][C:24](=[O:27])[CH2:25][CH3:26])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: Cc1ccc(Cc2ccccc2C2(O)CCN(C)CC2)c(F)c1
Reactant: CCC(=O)Cl
Product: CCC(=O)OC1(c2ccccc2Cc2ccc(C)cc2F)CCN(C)CC1
Product: Cl

Procedure:
By following the manipulative procedure outlined above in Example 24, 1.97 g of 1-methyl-4-[α-(2-fluoro-4-methylphenyl)-2-tolyl]-4-piperidinol, Example 4, is treated with 6.3 ml of propionyl chloride to produce 4-[α-(2-fluoro-4-methylphenyl)-2-tolyl]-4-propionyloxy-1-methylpiperidine hydrochloride which is recrystallized from an acetone-ether mixture affording a product having an mp of 183°-186° C.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[NH:8][C:9](=[O:11])[CH3:10])=[O:4].[NH2:15][C:16]1[S:17][CH2:18][CH2:19][N:20]=1>CC(C)=O>[BrH:1].[NH:15]=[C:16]1[N:20]([CH2:2][C:3]([C:5]2[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=2)[NH:8][C:9](=[O:11])[CH3:10])=[O:4])[CH2:19][CH2:18][S:17]1
Reactant: NC1=NCCS1
Reactant: CC(=O)Nc1cccc(C(=O)CBr)c1
Solvent: CC(C)=O
Product: Br
Product: CC(=O)Nc1cccc(C(=O)CN2CCSC2=N)c1
Reaction time: 1.5 h

Procedure:
A solution of 5.12 g. (0.020 mole) of 3'-bromoacetylacetanilide in 70 ml. of acetone is added to a stirred solution of 2.04 g. (0.020 mole) of 2-amino-2-thiazoline in 30 ml. of acetone. The mixture is stirred 1.5 hours and the precipitate then filtered, washed with acetone and dried to give 6.00 g. of white solid, which on recrystallization from water gives the product, melting point 275°-277°C. Anal. Calcd. for C13H16BrN3O2S: C, 43.58; H, 4.50; Br, 22.31; N, 11.73; S, 8.95. Found: C, 43.99; H, 4.66; Br, 22.51; N, 11.72; S, 9.14.
Reaction SMILES: C(OCCCC)CCC.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:20])[CH2:18][CH3:19])=[CH:13][CH:12]=1.BrBr.[CH2:23]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO>[CH3:19][CH:18]([N:33]1[CH2:34][CH2:35][CH:30]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:31][CH2:32]1)[CH:17]([OH:20])[C:14]1[CH:15]=[CH:16][C:11]([OH:10])=[CH:12][CH:13]=1
Reactant: c1ccc(Cc2ccncc2)cc1
Reactant: CCC(=O)c1ccc(O)cc1
Agent: BrBr
Solvent: CCCCOCCCC
Solvent: CO
Product: CC(C(O)c1ccc(O)cc1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To 15 ml of di-n-butyl ether were added 6.0 g of 4'-hydroxypropiophenone. 6.6 Grams of bromine were added dropwise to the mixture with stirring at room temperature. The reaction liquid was stirred for an additional 10 minutes and then nitrogen was introduced thereinto at a flow rate of 200 ml/minute for one hour at room temperature. To the treaction liquid were then added 7.5 g of 4-benzylpyridine and 100 ml of methanol, and the mixture was refluxed under heating for 5 hours. After stopping the heating, the reaction mixture was treated in the same manner as described in Example 35, whereby 11.3 g (73.4%) of ifenprodil were obtained as white crystals.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([C:42]([OH:44])=[O:43])[NH:9][C:10](=[O:41])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](=[O:40])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23]([C:37]([OH:39])=[O:38])[NH:24][C:25](=[O:36])[NH:26][C@H:27]([C:33]([OH:35])=[O:34])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[N+:2]=[N-:3].[NH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]([NH:54][C:55](=[O:71])[CH:56]([NH:66][C:67](=[O:70])[C:68]#[CH:69])[CH2:57][CH2:58][CH2:59][CH2:60][NH:61][C:62](=[O:65])[C:63]#[CH:64])[C:51]([OH:53])=[O:52].[O:72]=[C:73]1[O:79][C@H:78]([C@H:80]([CH2:82]O)O)[C:76]([O-])=[C:74]1O.[Na+]>O.CC(O)(C)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[NH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]([NH:54][C:55](=[O:71])[CH:56]([NH:66][C:67]([C:68]1[N:1]=[N:2][NH:3][C:69]=1[CH2:82][CH2:80][CH2:78][CH2:76][CH:74]([C:73]([OH:79])=[O:72])[NH:9][C:10](=[O:41])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](=[O:40])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23]([C:37]([OH:39])=[O:38])[NH:24][C:25](=[O:36])[NH:26][CH:27]([C:33]([OH:35])=[O:34])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:70])[CH2:57][CH2:58][CH2:59][CH2:60][NH:61][C:62]([C:63]1[N:3]=[N:2][N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([C:42]([OH:44])=[O:43])[NH:9][C:10](=[O:41])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](=[O:40])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23]([C:37]([OH:39])=[O:38])[NH:24][C:25](=[O:36])[NH:26][CH:27]([C:33]([OH:35])=[O:34])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:64]=1)=[O:65])[C:51]([OH:53])=[O:52]
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Reactant: C#CC(=O)NCCCCC(NC(=O)C#C)C(=O)NC(CCCCN)C(=O)O
Reactant: [N-]=[N+]=NCCCCC(NC(=O)CCCCCCC(=O)NCCCC[C@H](NC(=O)N[C@@H](CCC(=O)O)C(=O)O)C(=O)O)C(=O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: NCCCCC(NC(=O)C(CCCCNC(=O)c1cn(CCCCC(NC(=O)CCCCCCC(=O)NCCCC[C@H](NC(=O)NC(CCC(=O)O)C(=O)O)C(=O)O)C(=O)O)nn1)NC(=O)c1nn[nH]c1CCCCC(NC(=O)CCCCCCC(=O)NCCCC[C@H](NC(=O)NC(CCC(=O)O)C(=O)O)C(=O)O)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 1 (49 mg, 76.7 μM) and 4 (0.5 eq, 14.5 mg, 38.3 μM) were dissolved in 1 mL H2O/t-BuOH (1/1). To that solution, sodium ascorbate (6 mg, 30 μM) and Cu(OAc)2 (3 mg, 15 μM) were added consecutively, the mixture was purged with N2 gas and stirred at ambient temperature overnight. Compound 2 was purified using C18 SepPak® Vac 2 g column through which the product was successfully eluted using 70/30 water/acetonitrile (0.1% TFA). Compound 2 was further purified by HPLC (Method 1). Rt: 13.9 min. ESI-MS m/Z: 1638 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9](=[C:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=1)[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][C:40](=O)[O:41]C2C=CC=CC=2)[CH:34]=1.C(N(CC)CC)C>CS(C)=O>[Br:8][C:9]([C:10]1[CH:26]=[CH:25][CH:24]=[C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][N:15]=2)[CH:11]=1)=[C:27]1[CH2:32][CH2:31][N:30]([C:40]([NH:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[O:41])[CH2:29][CH2:28]1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C(Br)=C3CCNCC3)c2)nc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: O=C(Nc1cccnc1)N1CCC(=C(Br)c2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
A solution of 2-(3-(bromo(piperidin-4-ylidene)methyl)phenoxy)-5-(trifluoromethyl)pyridine trifluoroacetate (624 mg, 0.995 mmol) and phenyl pyridin-3-ylcarbamate (213 mg, 0.995 mmol) in DMSO (5 mL) was treated with triethyamine (0.28 mL, 201 mg, 1.99 mmol) and the mixture was heated to 60° C. After 4 h, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate. The combine organic layers were washed with brine and dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0-5% MeOH/CH2Cl2) to afford the title compound as a white foam (329 mg, 62% yield). MS (APCI 10V) AP+ 535.15; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (2H) 2.65 (2H) 3.46 (2H) 3.63 (2H) 6.99 (d, J=8.38 Hz, 1H) 7.05 (2H) 7.12 (dd, 1H) 7.35 (1H) 7.62 (1H) 7.87 (dd, J=8.87, 2.05 Hz, 1H) 8.13 (1H) 8.41 (1H) 8.65 (1H) 8.93 (1H) 9.20 (1H)