Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][CH3:15])[CH:8]=2)=[O:4].[Br:16]N1C(=O)CCC1=O>CN(C=O)C>[Br:16][C:13]1[C:12]2[C:7](=[CH:8][C:9]([O:14][CH3:15])=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1cc2ccc(OC)cc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COC(=O)c1[nH]c2cc(OC)ccc2c1Br
Temperature: 0 °C
Yield: 54.9 %

Procedure:
2-Methoxycarbonyl-6-methoxy-1H-indole (1.00 g; mfd. by Aldrich) was dissolved in DMF (51.2 mL) under an argon atmosphere, followed by stirring at 0° C. A solution of N-bromosuccinimide (1.02 g) in DMF (21.7 mL) was added dropwise over 30 minutes. The reaction mixture was maintained at 0° C. and stirred for 2.5 hours. The reaction mixture was poured into an ice water. After stirring, the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (4:1-3:1 hexane/ethyl acetate) to yield the title compound (760 mg).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:12][C:13]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[C:14]=1[C:15](O)=[O:16]>>[F:12][C:13]1[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:19]=[C:18]([C:26]([F:27])([F:28])[F:29])[C:14]=1[C:15]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:16]
Reactant: O=C(O)c1c(F)cc(C(F)(F)F)cc1C(F)(F)F
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: O=C(N[C@@H]1CCC[C@@H]1N1CCCC1)c1c(F)cc(C(F)(F)F)cc1C(F)(F)F

Procedure:
The title compound, white solid, MS: m/e=413.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-fluoro-4,6-bis-trifluoromethyl-benzoic acid.
Reaction SMILES: [ClH:1].Cl.C([N:10](CC1C=CC=CC=1)[C@H:11]1[CH2:16][CH2:15][C@@H:14]([N:17]2[CH2:22][CH:21]([CH3:23])[O:20][CH:19]([CH3:24])[CH2:18]2)[CH2:13][CH2:12]1)C1C=CC=CC=1>CO.[Pd]>[ClH:1].[ClH:1].[CH3:23][CH:21]1[O:20][CH:19]([CH3:24])[CH2:18][N:17]([C@H:14]2[CH2:15][CH2:16][C@H:11]([NH2:10])[CH2:12][CH2:13]2)[CH2:22]1
Reactant: CC1CN([C@H]2CC[C@@H](N(Cc3ccccc3)Cc3ccccc3)CC2)CC(C)O1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC1CN([C@H]2CC[C@H](N)CC2)CC(C)O1

Procedure:
9.8 g (21 mmol) cis-dibenzyl-[4-(2,6-dimethyl-morpholin-4-yl)-cyclohexyl]-amine-dihydrochloride are placed in 150 ml of methanol and 2 g palladium/charcoal (10%) are added. The mixture is hydrogenated at 50 psi and 50° C. Then the catalyst is suction filtered, the mother liquor is concentrated by evaporation. The precipitate formed is suction filtered and washed with diethyl ether. Yield: 5.5 g. The trans isomer may be prepared analogously.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[N:17][C:16]([C:19](OCC)=[O:20])=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[N:17][C:16]([CH2:19][OH:20])=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ncn(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cnc(CO)n2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(3-ethoxycarbonyl-[1,2,4]triazol-1-yl) -piperidine-1-carboxylic acid tert-butyl ester (from Step 1, 0.64 g, 2.06 mmol) in THF (10 mL) at 0° C. was added lithium aluminum hydride (0.078 g, 2.06 mmol). The solution was allowed to warm to room temperature and stirred for 4 hours. The solution was diluted with THF, cooled to 0° C., and 1 mL of water was added followed by 1 mL of 15% NaOH and 3 mL of water. The solution was allowed to warm to room temperature and stirred for 15 minutes. MgSO4 was then added and the solution was stirred an additional 15 minutes, filtered and concentrated in vacuo. The residue was purified by flash chromatograph on silica gel with MeOH and CH2Cl2 to afford the desired product. 1H NMR (CDCl3): δ 8.03 (1H, s), 4.79 (2H, d), 4.25 (3H, m), 2.95 (2H, m), 2.58 (1H, t), 2.19 (2H, m), 1.98 (2H, m), 1.43 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([NH:16][C:17](=[O:34])[CH:18]([N:22]3[C:26]([CH:27]=[CH2:28])=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=[C:23]3[CH3:33])[CH2:19]C=C)[CH:10]=[N:9]2)=[CH:4][CH:3]=1>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([NH:16][C:17]([CH:18]3[N:22]4[C:23]([CH3:33])=[N:24][C:25]([C:29]([F:30])([F:32])[F:31])=[C:26]4[CH:27]=[CH:28][CH2:19]3)=[O:34])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: C=CCC(C(=O)Nc1cnn(-c2ccc(Cl)cc2)c1C(C)C)n1c(C)nc(C(F)(F)F)c1C=C
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Product: Cc1nc(C(F)(F)F)c2n1C(C(=O)Nc1cnn(-c3ccc(Cl)cc3)c1C(C)C)CC=C2
Temperature: 45 °C
Reaction time: 3 h
Yield: 21.5 %

Procedure:
To N-[1-(4-chlorophenyl)-5-isopropylpyrazol-4-yl]-2-[2-methyl-4-(trifluoromethyl)-5-vinyl-imidazol-1-yl]pent-4-enamide (147 mg, 0.298 mmol) was added CH2Cl2 (10 mL) and benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (Grubb's first generation catalyst, 122.6 mg, 0.149 mmol), and the resulting mixture was stirred at 45° C. for 3 h. The reaction mixture was then directly adsorbed on SiO2 and purified by flash chromatography (SiO2, 80% EtOAc/hexanes) to furnish N-[1-(4-chlorophenyl)-5-isopropylpyrazol-4-yl]-3-methyl-1-(trifluoromethyl)-5,6-dihydroimidazo[1,5-a]pyridine-5-carboxamide (30 mg, 0.064 mmol, 22% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]#[N:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](=O)CCCC)CCC.C[Si]([N:33]=[N+:34]=[N-:35])(C)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[NH:35][N:34]=[N:33][N:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CC1CCCN(C(=O)OCc2ccccc2)C1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCCC(c2nnn[nH]2)C1
Temperature: 95 °C
Reaction time: 6 h
Yield: 84.9 %

Procedure:
To a mixture of 3-cyano-piperidine-1-carboxylic acid benzyl ester (1 g, 4.1 mmol), and dibutyltinoxide (153 mg, 0.6 mmol) in toluene (8 mL) is added trimethylsilylazide (1.1 mL, 8.2 mmol) at room temperature. After the mixture is heated at 95° C. for 15 h, more trimethylsilylazide (2 mL, 15 mmol) is added and the stirring is continued for 6 h at 95° C. The mixture is concentrated, and the resulting solid is triturated with heptane (30 mL) and filtered to afford 3-(1H-tetrazol-5-yl)-piperidine-1-carboxylic acid benzyl ester (1 g). LCMS: RT=2.31 minutes, MS: 288 (M+H).
Reaction SMILES: [C:1]([C:5]([C:7]1[N:12]2[C:13](=[O:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10](=[O:19])(=[O:18])[CH:9]([S:20][C:21]2[N:25]([CH3:26])[N:24]=[N:23][N:22]=2)[C:8]=1[CH2:27][S:28][C:29]1[N:33]([CH3:34])[N:32]=[N:31][N:30]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH2:35](N(CC)CC)C.CI>C(#N)C>[C:1]([C:5]([C:7]1[N:12]2[C:13](=[O:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10](=[O:18])(=[O:19])[C:9]([CH3:35])([S:20][C:21]2[N:25]([CH3:26])[N:24]=[N:23][N:22]=2)[C:8]=1[CH2:27][S:28][C:29]1[N:33]([CH3:34])[N:32]=[N:31][N:30]=1)=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CO[C@H]1C(=O)N2C(C(=O)C(C)(C)C)=C(CSc3nnnn3C)C(Sc3nnnn3C)S(=O)(=O)[C@H]12
Reactant: CCN(CC)CC
Solvent: CI
Solvent: CC#N
Product: CO[C@H]1C(=O)N2C(C(=O)C(C)(C)C)=C(CSc3nnnn3C)C(C)(Sc3nnnn3C)S(=O)(=O)[C@H]12
Reaction time: 0.5 h

Procedure:
A solution of 4-tert-butylcarbonyl-7α-methoxy-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-3-(1-methyl-1,2,3,4-tetrazol -5-yl)thiomethyl-3-cephem 1,1-dioxide (100 mg), prepared as described in PTC EP 90/02189 in acetonitrile (2 ml) was treated at room temperature with triethylamine (0.040 ml) and methyl iodide (0.060 ml). The reaction mixture was stirred for 30 minutes and the organic solvent completely removed in vacuo. The resulting crude residue was eventually taken up in dichloromethane and purified by flash chromatography affording the title compound as a yellowish solid (40 mg).
Reaction SMILES: ClCCCC(OC(=O)C)CCCCC.Cl[CH2:16][CH2:17][CH2:18][CH:19]([O:27]C(=O)C)[C:20]([CH3:26])([CH3:25])[CH2:21][CH2:22][CH2:23][CH3:24].C(OC(C(C)(C)CCCC)CCCC(CCCCCCC(OCC)=O)(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)(=O)C.C(C(CCCC(OC(=O)C)CCCCC(F)(F)F)CCCCCCC(OCC)=O)(O)=O.ClC(C(CCCC(OC(=O)C)CCCCC(F)(F)F)CCCCCCC(OCC)=O)=O.[C:134]([CH:137](CCCC(OC(=O)C)CCCCC(F)(F)F)[CH2:138][CH2:139][CH2:140][CH2:141][CH2:142][CH2:143][C:144]([O:146]CC)=[O:145])(=[O:136])[NH2:135].C(C(CCCC(O)CCCC(C)(C)C)CCCCCCC(O)=O)(=O)N>>[C:134]([CH:137]([CH2:16][CH2:17][CH2:18][CH:19]([OH:27])[C:20]([CH3:25])([CH3:26])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:138][CH2:139][CH2:140][CH2:141][CH2:142][CH2:143][C:144]([OH:146])=[O:145])(=[O:136])[NH2:135]
Reactant: CCOC(=O)CCCCCCC(CCCC(CCCCC(F)(F)F)OC(C)=O)C(N)=O
Reactant: CCCCC(C)(C)C(CCCCl)OC(C)=O
Agent: CC(C)(C)CCCC(O)CCCC(CCCCCCC(=O)O)C(N)=O
Agent: CCCCC(C)(C)C(CCCC(CCCCCCC(=O)OCC)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OC(C)=O
Agent: CCCCCC(CCCCl)OC(C)=O
Product: CCCCC(C)(C)C(O)CCCC(CCCCCCC(=O)O)C(N)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1, except that, in Step B, the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-chloro-4-acetoxy-5,5-dimethylnonane (Example G, Step 3). The product of Step B is thus: di-tert.-butyl 2(4-acetoxy-5,5-dimethylnonyl)-2-(6-ethoxycarbonylhexyl)malonate. Subsequent steps yield: ethyl 8-carboxy-12-acetoxy-13,13-dimethylheptadecanoate (C); ethyl 8-chlorocarbonyl-12-acetoxy-13,13-dimethylheptadecanoate (D); ethyl carbamoyl-12-acetoxy-13,13-dimethylheptadecanoate (E); and 8-carbamoyl-12-hydroxy-13,13-dimethylheptadecanoic acid (F).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:9][NH2:10]>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([NH:9][NH2:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncccc1Br
Reactant: NN
Solvent: c1ccncc1
Product: NNc1ncccc1Br
Temperature: 60 °C
Reaction time: 24 h
Yield: 60.6 %

Procedure:
To a stirring solution of 3-bromo-2-chloropyridine (8.56 g, 45 mmol) in pyridine (40 mL) was added anhydrous hydrazine (4.0 g, 125 mmol). The resulting mixture was stirred at 60° C. for 24 h. Analysis by HPLC indicated that about 50% of starting material was consumed. Additional hydrazine (4.0 g, 125 mmol) was added and the reaction mixture was stirred at 80° C. for another 16 h (total 40 h). After cooling to room temperature, the resulting white suspension was filtered. The collected solid was washed with water (2×50 mL), and dried in a 50° C. vacuum oven for 16 h to afford 5.13 g (61%) of the title compound as a white solid. HPLC/MS (Method C): retention time=0.38 min, [M+H]+=188.0.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1)=O.[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20]>>[OH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][CH2:1][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1
Reactant: NCCCCCO
Reactant: CCOC(=O)c1ccnc(C=O)c1
Product: CCOC(=O)c1ccnc(CNCCCCCO)c1

Procedure:
Prepared by General Procedure A from ethyl 2-formylpyridine-4-carboxylate (1.0 equiv.) and 5-aminopentan-1-ol (1.2 equiv.). Purification by column chromatography (DCM/MeOH (85:15) gave the title compound as greenish oil. 1H-NMR (300 MHz, CDCl3): δ 8.60 (d, 1H), 7.80 (s, 1H), 7.00 (d, 1H), 4.30 (q, 2H), 3.90 (s, 2H), 3.50 (t 2H), 3.10 (s, 2H), 2.60 (m, 2H), 1.50 (m, 4H), 1.30 (t, 3H) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10](=[O:27])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]2[CH2:25][OH:26])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[BH4-].[Na+]>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]([OH:27])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][C@H:13]2[CH2:25][OH:26])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)c2ccc(F)c(C#N)c2)[C@H](CO)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CC(O)c2ccc(F)c(C#N)c2)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl (3S)-4-[2-(3-cyano-4-fluorophenyl)-2-oxoethyl]-3-(hydroxymethyl)piperazine-1-carboxylate (800 mg, 2.12 mmol) was dissolved in ethanol (50 mL) then sodium borohydride (321 mg, 8.48 mmol) was added and the mixture was stirred at RT for 16 h. LC-MS analysis showed product to be present. The ethanol was removed and the residue was redissolved in EtOAc and stirred with 1N HCl for 5 min. The mixture was then neutralized with saturated aqueous NaHCO3 and extracted twice with EtOAc. The organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated to dryness to yield the title compound. LC-MS: M+1=280.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([O:23]C4C(F)=C(F)C(F)=C(F)C=4F)(=[O:22])=O)=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)=[C:4]([O:35][CH3:36])[CH:3]=1.[S:37]1[C:41]([NH2:42])=[N:40][CH:39]=[N:38]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>CCOC(C)=O.Cl>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([NH:42][C:41]4[S:37][N:38]=[CH:39][N:40]=4)(=[O:23])=[O:22])=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: COc1cc(Cl)c(C#N)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Nc1ncns1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(Cl)c(C#N)cc1-c1nccc2cc(S(=O)(=O)Nc3ncns3)ccc12
Reaction time: 1 h
Yield: 58.6 %

Procedure:
A vial was charged with perfluorophenyl 1-(4-chloro-5-cyano-2-methoxyphenyl)isoquinoline-6-sulfonate (INTERMEDIATE VVVV, 154.38 mg, 0.285 mmol), 1,2,4-thiadiazol-5-amine (34.6 mg, 0.343 mmol), and cesium carbonate (279 mg, 0.856 mmol). Acetonitrile (1427 μl) was added, and the mixture was stirred for 1 h. The mixture was diluted with EtOAc and 0.5 N aq. HCl. The layers were separated, and the organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-10% MeOH/DCM, product eluted over a long period of time). The resulting white solid was taken up in MeOH and filtered. The collected solid was washed with MeOH (2×), dried under a stream of N2 (g), then dried under vacuum to give 1-(4-chloro-5-cyano-2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (76.6 mg, 0.167 mmol, 58.6% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=7.43 (d, J=5.7 Hz, 1H), 7.32 (d, J=1.7 Hz, 1H), 7.21 (s, 1H), 6.90 (d, J=5.6 Hz, 1H), 6.70 (s, 1H), 6.62-6.55 (m, 1H), 6.52-6.46 (m, 1H), 6.37 (s, 1H), 2.50 (s, 3H). m/z (ESI) 458.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[N+:17]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br)([O-:19])=[O:18]>>[N+:17]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3)([O-:19])=[O:18]
Reactant: Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Product: O=c1[nH]c2ncccc2c2cc(NCc3cccc([N+](=O)[O-])c3)ccc12
Yield: 11.5 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 458 using 70 (115 mg, 0.55 mmol) and 3-nitro-benzyl bromide (113 mg, 0.66 mmol) to provide 465 (22 mg, 11% yield) as a white powder. LC-MS (M+H=347, obsd.=347). 1H NMR (400 MHz, DMSO-D6) δ 8.47 (m, 2H), 8.13 (s, 1H), 8.05 (m, 2H), 7.74 (d, J=7.7 , 1H), 7.58 (t, J=7.9, 1H), 7.42 (d, J=2.0, 1H), 7.37 (dd, J=4.7, 7.8, 1H), 6.91 (dd, J=2.0, 8.7, 1H), 6.24 (s, 2H), 5.76 (s, 2H).
Reaction SMILES: [C:1]1([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH2:10]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14]C1C=CC=CC=1C(=O)C>CCOC(C)=O>[Cl:14][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH3:10]
Reactant: CC(=O)c1ccccc1Cl
Reactant: CCC(=O)CC(=O)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)c1ccccc1Cl

Procedure:
The title compound was prepared (as described above for Intermediate 16) from 2.0 g of 2′-chloroacetophenone and 2.53 mL of EtOAc to yield 0.5 g of Intermediate 30: TLC analysis: Rf=0.76 (2/1, hexanes/EtOAc); 1H NMR (400 MHz, CDCl3, enol form) δ7.6-7.55 (m, 1H), 7.45-7.43 (m, 1H), 7.4-7.32 (m, 1H), 6.05 (s, 1H), 2.18 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:10](=O)[CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5])[CH3:2].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC(O)=O.C([BH3-])#N.[Na+]>CCO>[CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([NH:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CC1=O
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.7 %

Procedure:
To a solution of (RS)-4-oxo-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (commercial; 1 g, 3.9 mmol) in EtOH (15 mL) were added benzylamine (0.85 mL, 7.77 mmol) and AcOH (0.45 mL, 7.77 mmol) and the mixture was stirred 3 h at rt. Sodium cyanoborohydride (0.98 g, 15.5 mmol) was then added at rt and the mixture was heated to 75° C. for 5 h, then 15 h to 50° C. and again 1 h to 75° C. The mixture was concentrated under reduced pressure, water was added and the mixture extracted 3× with EA. The combined org. extracts were washed with brine dried over MgSO4 and concentrated under reduced pressure. The residue was purified by CC (Hep/EA from 2:1 to 1:1) to afford the title intermediate as a yellow oil (0.73 g, 54%).
Reaction SMILES: [CH3:1][S-:2].[Na+].[Cl:4][C:5]1[CH:10]=[C:9]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2F)(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=1[NH:21][C:22](=[O:30])[C@:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25].[Cl-].[NH4+]>CN1C(=O)CCC1>[Cl:4][C:5]1[CH:10]=[C:9]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:2][CH3:1])(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=1[NH:21][C:22](=[O:30])[C@:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25]
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2F)cc1Cl)C(F)(F)F
Reactant: C[S-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CSc1ccccc1S(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1
Temperature: 120 °C
Yield: 62.5 %

Procedure:
Sodium methanethiolate (49.5 mg) was added to a solution of (R)-N-[2-chloro-4-(2-fluorophenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 63) (0.15 g) in NMP (1.5 ml) and the mixture was heated at 120° C. for 18 hours then cooled. Saturated aqueous ammonium chloride solution (15 ml) was added and the mixture was extracted with ethyl acetate (2×50 ml). The organic extracts were combined, washed with brine and dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-20% ethyl acetate/hexane to give the title compound (0.10 g) as a solid. NMR: (CDCl3): 1.75 (s, 3H), 2.4 (s, 3H), 3.6 (brs, 1H), 7.3 (t, 1H), 7.35 (t, 1H), 7.55 (m, 1H), 7.9 (dd, 1H), 8.05 (d, 1H) 8.25 (dd, 1H), 8.6 (d, 1H), 9.25 (brs, 1H); MS (ESP−): 452.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[CH3:18][C:19]1[CH:20]=[C:21]([SH:26])[CH:22]=[CH:23][C:24]=1[Br:25]>>[CH3:18][C:19]1[CH:20]=[C:21]([S:26][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]3)[CH:22]=[CH:23][C:24]=1[Br:25]
Reactant: Cc1cc(S)ccc1Br
Reactant: O=c1ccc2cc(OCCCCBr)ccc2[nH]1
Product: Cc1cc(SCCCCOc2ccc3[nH]c(=O)ccc3c2)ccc1Br

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p. 189°-199° C.) and 3-methyl-4-bromo-thiophenol.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][N:20]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:13][CH2:12]1.O.NN>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][NH2:20])[CH2:15][CH2:16]1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1CCN(c2ccc3ccccc3n2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCN1CCN(c2ccc3ccccc3n2)CC1
Yield: 96.5 %

Procedure:
To a solution of 1.52 g of 2-[3-(4-quinolin-2-ylpiperazin-1-yl)propyl]isoindol-1,3-dione in 30 ml of ethanol, another solution of 1.50 g of hydrazine monohydrate in 10 ml of ethanol was added, and heated under reflux for 7 hours. Cooling the reaction mixture, insoluble matter was separated by filtration, and the solvent was distilled off under reduced pressure. The residue was made alkaline with 5N-sodium hydroxide, extracted with chloroform, washed with saturated brine and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, 0.99 g (96%) of 3-(4-quinolin-2-ylpiperazin-1-yl)propylamine was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:4]=2[O:3]1.[CH2:15](Br)[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]1([CH3:14])[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([O:13][CH2:17][CH:16]=[CH2:15])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CC1(C)NC(=O)c2cc(O)ccc2O1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1ccc2c(c1)C(=O)NC(C)(C)O2

Procedure:
A solution of 9.65 g of 2,3-dihydro-2,2-dimethyl-6-hydroxy-4H-1,3-benzoxazin-4-one and 9.1 g of allyl bromide in 150 ml of acetonitrile is refluxed for 5 hours, whilst stirring, with the addition of 10.3 g of dry potassium carbonate. The reaction mixture is filtered whilst warm, the filtrate is concentrated by evaporation and the remaining crystals are suction-filtered after trituration with ether. The crude 2,3-dihydro-2,2-dimethyl-6-(1-propen-3-yloxy)-4H-1,3-benzoxazin-4-one obtained in this manner melts at 137°-138°.
Reaction SMILES: I[Si](C)(C)C.[O:6]=[S:7]1(=[O:41])[C:13]2[CH:14]=[CH:15][C:16]([O:18][C:19]3[CH:20]=[C:21]([CH:32]=[C:33]([O:35][C@@H:36]([CH3:40])[CH2:37][O:38]C)[CH:34]=3)[C:22]([NH:24][C:25]3[CH:30]=[N:29][C:28]([CH3:31])=[CH:27][N:26]=3)=[O:23])=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1.CO.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[O:41]=[S:7]1(=[O:6])[C:13]2[CH:14]=[CH:15][C:16]([O:18][C:19]3[CH:20]=[C:21]([CH:32]=[C:33]([O:35][C@@H:36]([CH3:40])[CH2:37][OH:38])[CH:34]=3)[C:22]([NH:24][C:25]3[CH:30]=[N:29][C:28]([CH3:31])=[CH:27][N:26]=3)=[O:23])=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCCS3(=O)=O)cc(C(=O)Nc2cnc(C)cn2)c1
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc4c(c3)OCCCS4(=O)=O)cc(O[C@@H](C)CO)c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
Iodotrimethylsilane (0.416 mL, 2.92 mmol) was added to a solution of 3-[(5,5-dioxido-3,4-dihydro-2H-1,5-benzoxathiepin-8-yl)oxy]-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide (150 mg, 0.29 mmol) in acetonitrile (7 mL) and the reaction stirred at RT overnight. Methanol (35 mL) was added, the reaction stirred for 1 hour, then a saturated aqueous solution of sodium thiosulphate (30 mL) was added and the reaction stirred for a further 20 minutes. The mixture was evaporated in vacuo, and the product was extracted away from the inorganic residues by the addition of 20% methanol in DCM (40 mL) with stirring. The organics were reduced in vacuo to a volume of approximately 5 mL. The residue was chromatographed on silica, eluting with 0-20% methanol in DCM, to give the desired compound as a cream solid (79 mg).