Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]=[C:17]([CH2:46][CH2:47][CH3:48])[N:18]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:34][CH:33]=2)[C:19](=[O:30])[C:20]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH3:29])[CH:23]=1)[CH3:14]>C(OCC)(=O)C>[CH2:13]([C:15]1[N:16]=[C:17]([CH2:46][CH2:47][CH3:48])[N:18]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]3[NH:3][C:4](=[O:7])[O:5][N:45]=3)=[CH:34][CH:33]=2)[C:19](=[O:30])[C:20]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH3:29])[CH:23]=1)[CH3:14]
Reactant: CCCc1nc(CC)c(Oc2cccc(CC)c2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(Oc2cccc(CC)c2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
A mixture of hydroxylammonium chloride (0.67 g), sodium hydrogen carbonate (0.95 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-ethyl-5-(3-ethylphenoxy)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.54 g) was added, and the mixture was stirred at 90° C. for 12 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. The residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.27 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, and the mixture was stirred at room temperature for 2 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 purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.47 g, 78%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:19][C:18](=O)[C:17]2[C:12](=[CH:13][C:14]([CH3:21])=[CH:15][CH:16]=2)[N:11]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:33].C([O-])(O)=O.[Na+]>C1C=CC=CC=1.C(Cl)Cl>[Cl:33][C:18]1[C:17]2[C:12](=[CH:13][C:14]([CH3:21])=[CH:15][CH:16]=2)[N:11]=[C:10]([C:3]2[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:19]=1
Reactant: COc1cccc(F)c1-c1nc2cc(C)ccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Solvent: c1ccccc1
Solvent: ClCCl
Product: COc1cccc(F)c1-c1nc(Cl)c2ccc(C)cc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.4 %

Procedure:
Under an N2 atmosphere, 2-(2-fluoro-6-methoxyphenyl)-7-methylquinazolin-4(3H)-one (20 g, 70.35 mmol) was suspended in benzene (300 mL), followed by the addition of N,N-dimethylaniline (26.8 mL, 211.05 mmol), then POCl3 (13.11 mL, 140.7 mmol). The reaction was heated at reflux, and completion of product formation was observed after 1.5 h. After cooling to room temperature, the mixture was slowly poured over 1 liter of ice. The solution was then diluted with CH2Cl2, and the pH was adjusted to 7 using a saturated aqueous NaHCO3 solution. The layers were partitioned, separated and extracted with CH2Cl2. All organic layers were combined, dried over Na2SO4, filtered, and concentrated to a dark oil. The crude material was purified by silica gel chromatography using 75% CH2Cl2/25% hexanes to obtain 4-chloro-2-(2-fluoro-6-methoxyphenyl)-7-methylquinazoline as a yellow solid (18.82 g, 88%). LC/MS: m/z 302.9 (M+H)+ at 3.28 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J=8.5 Hz, 1H), 7.95 (s, 1H), 7.60 (dd, J=8.6, 1.5 Hz, 1H), 7.42-7.40 (m, 1H), 6.86-6.84 (m, 2H), 3.81 (s, 3H), 2.64 (s, 3H)
Reaction SMILES: C([O-])(=O)C.[NH4+].[CH2:6]([N:13]1[CH2:18][CH:17]([CH2:19][CH3:20])[C:16](=O)[CH:15]([CH2:22][CH3:23])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([BH3-])#[N:25].[Na+]>CO>[NH2:25][CH:16]1[CH:17]([CH2:19][CH3:20])[CH2:18][N:13]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:14][CH:15]1[CH2:22][CH3:23]
Reactant: [BH3-]C#N
Reactant: CCC1CN(Cc2ccccc2)CC(CC)C1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC1CN(Cc2ccccc2)CC(CC)C1N
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Ammonium acetate (10 g, 130 mmol) was added to the stirred solution of 1-benzyl-3,5-diethyl-4-piperidone (3.5 g, 14.3 mmol) in methanol (50 ml) and stirring was continued for 4 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (0.45 g, 7.14 mmol) was added to it. Cooling was removed after 10 min. and resulting mixture was stirred for 10 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 2) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1M sodium hydroxide solution (pH 10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 4-amino-1-benzyl-3,5-diethylpiperidine. Yield 3.4 g (97%), C16H26N2, m/z 247 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)=[O:8])[NH:5][CH:6]=1.Br[CH2:21][CH2:22]Br>>[Br:1][C:2]1[CH:3]=[C:4]2[C:7](=[O:8])[N:9]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=3)[CH2:22][CH2:21][N:5]2[CH:6]=1
Reactant: BrCCBr
Reactant: COc1ccc(NC(=O)c2cc(Br)c[nH]2)cc1OC
Product: COc1ccc(N2CCn3cc(Br)cc3C2=O)cc1OC

Procedure:
Following the procedure described in Example 1 step D, the product of step A (140 mg) was alkylated with 1,2-dibromoethane to yield 143 mg of the title compound. MS (ESI) 351, 353 (M+H)+.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH2:23][CH3:24])[NH:10][C:11](=[O:14])[C:12]=1[NH2:13].S(=O)(=O)(O)O.[CH:30](N)=O>>[CH2:22]([O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:9]1[N:8]=[C:7]2[C:12](=[N:13][CH:30]=[N:6]2)[C:11](=[O:14])[N:10]=1)[CH2:23][CH3:24]
Reactant: CCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Reactant: NC=O
Agent: O=S(=O)(O)O
Product: CCCOc1ccccc1C1=NC(=O)C2=NC=NC2=N1

Procedure:
A stirred mixture of 4,5-diamino-2-(propoxyphenyl)pyrimidin-6-one sulphate (1.5 g) (prepared by the addition of concentrated sulphuric acid to an ethanolic solution of the free base) and formamide (15 ml) was heated in an oil bath (temp. 190°-200° C.) for 70 minutes. When cool the mixture was filtered and the collected solid was washed with ethanol to give a crude product (1.1 g), m.p. 254°-259° C., which was recrystallised from ethanol to give the title compound, 0.72 g, m.p. 263°-265° C.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[C:5]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C(OC(=O)C)(=O)C>ClCCl.[Cl-].[Zn+2].[Cl-]>[C:2](=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]([O:13][CH2:14][CH3:15])=[O:12])([CH3:4])[CH3:1]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(C(=O)OCC)=C(C)C
Temperature: 90 °C
Yield: 32.3 %

Procedure:
Diethyl isopropylidenemalonate was prepared according to the procedure of E. L. Eliel, R. O. Hutchins, and Sr. M. Knoeber, Organic Synthesis Coll. Vol VI, 442, 1988, with following modifications. A mixture of acetone (54 g, 0.93 mol Mallinckrodt), diethyl malonate (100 g, 0.62 mol, Aldrich), acetic anhydride (81 g, 0.78 mol, Mallinckrodt), and zinc chloride (12.5 g, 0.78 mol, Aldrich) was refluxed (90° C. oil bath) for 18 h while protected from moisture. The reaction solution was diluted with dichloromethane (500 ml) and washed with cold water (3×50 ml). The aqueous washes were combined and extracted with dichloromethane. All dichloromethane layers were combined and concentrated by spin evaporation in vacuo. The residual oil was distilled under vacuum and the fractions boiling at 102-138° C. at 12 Torr were combined with the pot residue and heated for 6 h with a 200° C. oil bath. The dark oil was redistilled to give 40.1 g (32%) of diethyl isopropylidenemalonate as a clear oil, b.p., 110-115° C./12 mmHg:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][CH3:16])=[CH:12][CH:11]=[C:10]([NH2:17])[C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=[O:8].N1C=CC=CC=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C1COCC1.O>[NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][CH3:16])=[CH:12][CH:11]=[C:10]([NH:17][S:25]([CH3:24])(=[O:27])=[O:26])[C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: CCOc1ccc(N)c2sc(C(N)=O)c(N)c12
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOc1ccc(NS(C)(=O)=O)c2sc(C(N)=O)c(N)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.6 %

Procedure:
To a stirred mixture of the above amide (0.2 g, 0.8 mmol) and pyridine (2.0 mL) in THF at 0° C. was added methanesulfonyl chloride (0.46 g, 4.0 mmol). The reaction was stirred at room temperature overnight. It was next diluted with water and extracted with dichloromethane (20 mL). The solvent was removed and purified by preparative TLC (5% EtOAc in CH2Cl2) to afford the title compound (20 mg, 7.6%).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]\[CH:14]=[CH:15]\[C:16](\[CH3:21])=[CH:17]\[C:18]([OH:20])=[O:19].[H][H].[OH-].[K+].Cl.[CH3:28][CH2:29]OC(C)=O.CCCCCC>CO>[CH3:21]/[C:16](/[CH:15]=[CH:14]/[CH:13]=[C:12](/[CH3:22])\[CH:11]=[CH:10]\[C:3]1[C:4]([CH3:8])([CH3:9])[CH:5]=[CH:6][CH2:7][C:2]=1[CH3:1])=[CH:17]\[C:18]([O:20][CH2:28][CH3:29])=[O:19]
Reactant: CC1=C(/C=C/C(C)=C\C=C\C(C)=C\C(=O)O)C(C)(C)CCC1
Reactant: CCOC(C)=O
Reactant: [H][H]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCCC
Product: CCOC(=O)/C=C(C)/C=C/C=C(C)\C=C\C1=C(C)CC=CC1(C)C
Temperature: 0 °C

Procedure:
(XI where R1, R2, R3, R4 and R5 are methyl, R7 is hydrogen) The crude product IX was dissolved in 5 mL of MeOH, followed by addition of 2 mL of 5N aqueous KOH. The reaction was heated to reflux for 30 min., cooled to 0 ° C., and acidified with 1N aqueous HCl. The product was extracted with EtOAc (3×5 mL), and the combined extract was washed with brine, dried over MgSO4 and concentrated. HPLC purification (C18 -ODS, 65% CH3CN-35% H2O-0.5% AcOH) gave 3.2 Curies of pure 3H2 !-9-cis-retinoic acid XI, specific activity >60 Ci/mmol. TLC (20% EtOAc-hexane) Rf 0.26; UV(MeOH) λmax 343 nm; 1H-NMR (CD3OD) δ 1.05 (s, 1-(CH3)2), 1.48 (t, J=3, 9 Hz, 2-CH2), 1.64 (dtt, J=11, 6, 3 Hz, 3-CH2), 1.71 (s, 18-CH3), 1.98 (s, 19-CH3), 2.04 (t, J=6 Hz, 4-CH2), 2.29 (s, 20-CH3), 5.79 (s, 14-CH), 6.11 (d, J=12 Hz, 10-CH), 6.30 (brd, J=16 Hz, 7-CH+12-CH), 6.70 (d, J=17 Hz, 8-CH), 7.11 (dd, J=12 Hz, 16 Hz, 11-CH); 3H-NMR (CD3OD) δ 1.48 (d, J=3 Hz, 2-C3H), 1.64 (d, J=3 Hz, 3-C3H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][O:29][CH2:30][CH2:31][C:32](O)=[O:33]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][CH2:30][O:29][CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: COCCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: COCCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (65 mg, 62%), MS (ISP) m/z=417.4 [(M+H)+], mp 246.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 3-methoxypropionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([NH2:10])[S:9][C:5]=2[CH:4]=1.C(N(CC)CC)C.[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21]>CS(C)=O>[CH2:20]([NH:22][C:23]([NH:10][C:8]1[S:9][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=2[N:7]=1)=[O:24])[CH3:21]
Reactant: COc1ccc2nc(N)sc2c1
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCNC(=O)Nc1nc2ccc(OC)cc2s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6-Methoxy-1,3-benzothiazol-2-amine (5.00 g, 27.74 mmol) was dissolved in anhydrous DMSO (20 mL) and triethylamine (15.50 mL, 110.97 mmol) followed by ethyl isocyanate (4.39 mL, 55.49 mmol). The mixture was stirred at rt under N2 for 4 h then quenched with water (˜200 mL) and stirred for 1 h. A white solid formed, was collected by filtration, rinsed with water then washed with acetone (100 mL) and the filtrate collected separately to the aqueous filtrate. The solid was partially soluble in acetone so the filtrate was concentrated to dryness under reduced pressure and combined with the solid collected by filtration to obtain the desired compound as a white solid, 6.27 g (90%). m/z: 251.96 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3](=[CH:9][CH:10]=[C:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:15][CH3:16])=O)[C:4](OCC)=S.F[B-](F)(F)F.CN(C)[C:31]([C:37]1C=CC=[CH:39][CH:38]=1)=[CH:32]C=[N+](C)C.CC[O-].[Na+].C1([S:54]CC(OCC)=O)C=CC=CC=1>C(O)C>[CH3:23][N:2]([CH3:1])[C:3]([C:4]1[CH:39]=[CH:38][CH:37]=[CH:31][CH:32]=1)=[CH:9][CH:10]=[C:11]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:12]([O:14][CH2:15][CH3:16])=[S:54]
Reactant: CN(C)C(=CC=[N+](C)C)c1ccccc1
Reactant: CCOC(=O)CSc1ccccc1
Reactant: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)c1ccccc1
Agent: CC[O-]
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CCO
Product: CCOC(=S)C(=CC=C(c1ccccc1)N(C)C)c1ccccc1

Procedure:
The procedure is as in Example 2 for the preparation of diethyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate, starting with N-(3-dimethylamino-3-phenylpropenylidene)-N-methylmethanaminium tetrafluoroborate (15.4 g), a 2M solution of sodium ethylate (26.5 cc) and ethyl (phenylthio)acetate (10.4 g) in ethanol (150 cc). After purification by chromatography on a silica column with dichloromethane as eluent, ethyl 5-dimethylamino-5-phenyl-2-phenylthio-2,4-pentadienoate (9.7 g), m.p. 99° C., is obtained.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH3:9].OP(O)(O)=O>C1(C)C=CC=CC=1>[CH2:6]([N:10]([CH2:11][CH2:12][CH2:13][CH3:14])[C:3](=[O:4])[CH2:2][Br:1])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCNCCCC
Reactant: O=C(Br)CBr
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Product: CCCCN(CCCC)C(=O)CBr
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of bromoacetyl bromide (72.3 mL, 830 mmol) in toluene (500 mL) cooled to 0° C. was added a solution of dibutylamine (280.0 mL, 1.66 mol) in toluene (220 mL) via an addition funnel maintaining the reaction temperature below 10° C. Upon completion of the addition, the reaction mixture was stirred at 0° C. for 15 minutes. A solution of 2.5% aqueous H3PO4 (500 mL) was slowly introduced, and the reaction mixture was allowed to warm to room temperature with vigorous stirring. The solution is 2.5% phosphoric acid by weight. The layers were separated and the organic phase washed with water (500 mL) and concentrated to provide the bromoacetamide as a solution in toluene.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([NH2:13])=[C:9]([NH2:12])[CH:10]=2)[NH:5][C:4](=[O:14])[CH2:3]1.[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)#[N:17]>C(O)C>[CH3:1][C:2]1([CH3:15])[C:11]2[CH:10]=[C:9]3[NH:12][C:22]([C:21]4[CH:24]=[CH:25][C:18]([C:16]#[N:17])=[CH:19][CH:20]=4)=[N:13][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:14])[CH2:3]1
Reactant: CC1(C)CC(=O)Nc2cc(N)c(N)cc21
Reactant: N#Cc1ccc(C=O)cc1
Solvent: CCO
Product: CC1(C)CC(=O)Nc2cc3nc(-c4ccc(C#N)cc4)[nH]c3cc21

Procedure:
4.1 g. 4,4-dimethyl-6,7-diamino-1,2,3,4-tetrahydro-quinolin-2-one and 2.6 g. 4-cyanobenzaldehyde were stirred in 100 ml. ethanol for 7 days at 25° C. with the action of air. Subsequently, the reaction mixture was evaporated to 10 ml., mixed with 10 ml. water, filtered off with suction and recrystallised from ethanol/water (1:1 v/v) to give 5 g. of the title compound; m.p. 228 -233° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]CCCC([Br:14])=O.[NH+:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.[OH:22][N:23]1[C:27]2C=[CH:29][CH:30]=[CH:31][C:26]=2N=N1.C(N(CC)CC)C.Cl>>[CH2:19]([C:20]([NH2:15])=[O:22])[CH2:18][CH2:17][CH2:16][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH+:23]1[CH:29]=[CH:30][CH:31]=[CH:26][CH:27]=1.[Br-:14]
Reactant: On1nnc2ccccc21
Reactant: CCCCCCCCCCCC(=O)Br
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCC(N)=O
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
PAMAM generation 2.0 core (0.0479 mmol; 50 mg) was evaporated from a 0.5 ml solution in MeOH and then re-dissolved in 10 ml of water. 1-N-pyridinium 12-dodecanoic acid bromide (0.14 g; 0.384 mmol), N-hydroxybenzotriazole hydrate [HOBT] (52 mg; 0.384 mmol); triethylamine (531 0.384 mmol) and 1-(3-diethylaminopropyl-3-ethyl) carbodiimide .HCl [EDC] (74 mg; 0.384 mmol), were added to the solution. This reaction mixture was stirred overnight at room temperature. The volume was reduced to a third under reduced pressure and the solution was chromatographed on a LH20 column using water as the eluent. Fractions containing the product were collected and pyridinium dodecylcarboxamide PAMAM 2.0 bromide isolated as a fluffy white solid by freeze drying.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CO.[H][H]>[Ni].ClC1C=CC=CC=1Cl>[CH3:20][NH:19][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: Clc1ccccc1Cl
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 0.86 %

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), methanol (300 ml), Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (50 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 6 to 7 hrs at about 28° C. to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml methanol. The cis to trans ratio is 87 to 89/9 to 13. The amount of dehalogenated by product is <0.1%. Sertraline racemate free base thus formed is treated with hydrochloric acid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate is filtered [Cis>98%, trans<2%, dehalogenation product<0.1%, yield 0.86 to 0.88%].
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH3:16])[C:4]([N:6]([CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:7][C:8]([OH:10])=[O:9])=[O:5].[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.CCOCC>[C:17]1([NH:23][C:24]([S:1][CH2:2][CH:3]([CH3:16])[C:4]([N:6]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:7][C:8]([OH:10])=[O:9])=[O:5])=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(CS)C(=O)N(CC(=O)O)C1CCCC1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(CSC(=O)Nc1ccccc1)C(=O)N(CC(=O)O)C1CCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4.9 g (0.02M) of N-(3-mercapto-2-methyl propanoyl)-N-cyclopentyl glycine and 8 ml of phenyl isocyanate in 5 ml methylene chloride was stirred at room temperature for 72 hours. The mixture was diluted with ether and filtered. The ether solution was washed with water, dried over MgSO4 and evaporated to dryness. The crude residue was dissolved in acetonitrile, treated with charcoal and crystallized by addition of ether, m.p. 170°-172° C.
Reaction SMILES: Br[C:2]1[CH:21]=[N:20][C:5]2[N:6]([CH2:18][CH3:19])[C:7]3[N:16]=[C:15]([F:17])[CH:14]=[CH:13][C:8]=3[N:9]([CH3:12])[C:10](=[O:11])[C:4]=2[CH:3]=1.Br[C:23]1[CH:24]=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2.[CH:33]#[CH:34]>>[CH2:18]([N:6]1[C:5]2[N:20]=[CH:21][C:2]([CH2:33][CH2:34][C:23]3[CH:24]=[N:25][C:26]4[C:31]([CH:32]=3)=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:3][C:4]=2[C:10](=[O:11])[N:9]([CH3:12])[C:8]2[CH:13]=[CH:14][C:15]([F:17])=[N:16][C:7]1=2)[CH3:19]
Reactant: CCN1c2ncc(Br)cc2C(=O)N(C)c2ccc(F)nc21
Reactant: Brc1cnc2ccccc2c1
Reactant: C#C
Product: CCN1c2ncc(CCc3cnc4ccccc4c3)cc2C(=O)N(C)c2ccc(F)nc21

Procedure:
By a procedure analogous to that described in Example 51b, 60 mg (0.20 mmol) of 5,11-dihydro-11-ethyl-8-ethynyl-2-fluoro-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diaepin-6-one [prepared from 8-bromo-5,11-dihydro-11-ethyl-2-fluoro-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (see Example 38) by a route analogous to that described in Example 51a] was coupled with 3-bromoquinoline. Hydrogenation of the resultant acetylene was accomplished as described in Example 3b to provide 6 mg of the title compound, m.p. 154°-156° C. (petroleum ether).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Br[C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[F:42])[CH:37]=[O:38].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18]([C:34]4[CH:35]=[C:36]([CH:37]=[O:38])[CH:39]=[CH:40][C:41]=4[F:42])[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(C=O)ccc4F)cc23)CC1
Temperature: 160 °C

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (200 mg, 0.434 mmol) in dioxane (3.0 mL) and H2O (1.0 mL) was added 3-bromo-4-fluorobenzaldehyde (264 mg, 1.30 mmol), and K2CO3 (360 mg, 2.60 mmol) in microwave tube. The reaction mixture was degassed for 5 min before addition of tetrakis(triphenylphosphosphine) palladium (0) (48 mg, 0.043 mmol). The reaction was heated in a microwave for 30 min at 160° C. The organic layer was separated and concentrated. The residue was dissolved in MeOH until solid precipitated to yield 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-formylphenyl)-1H-indole-7-carboxamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([C@@H:18]2[CH2:20][C@H:19]2[C:21](=[O:41])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)[CH:23]=2)[CH:15]=[CH:14][C:4]=1[O:5][CH2:6][C:7]([O:9]C(C)(C)C)=[O:8].[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43].C(Cl)Cl>>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([C@@H:18]2[CH2:20][C@H:19]2[C:21](=[O:41])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]3)[CH:23]=2)[CH:15]=[CH:14][C:4]=1[O:5][CH2:6][C:7]([OH:9])=[O:8].[F:45][C:44]([F:47])([F:46])[C:42]([OH:48])=[O:43]
Reactant: COc1cc([C@@H]2C[C@H]2C(=O)c2cccc(N3CCN(C(=O)OC(C)(C)C)CC3)c2)ccc1OCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc([C@@H]2C[C@H]2C(=O)c2cccc(N3CCNCC3)c2)ccc1OCC(=O)O

Procedure:
Cyclopropyl adduct 300a was deprotected with TFA/CH2Cl2 in the usual way to provide a pale grey solid. IR(KBr): cm-1 3200-2500(br), 1738, 1680. HR-MS: Calc'd 411.1920, Found 411.1925.