Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[O:6][C:5]([NH:7][CH2:8][CH2:9][CH3:10])=[N:4][N:3]=1.[CH:11]1([C:15](Cl)=[O:16])[CH2:14][CH2:13][CH2:12]1.[CH2:18](N(CC)CC)C>C1C=CC=CC=1>[CH3:18][N:4]1[N:3]=[CH:2][O:6][CH:5]1[N:7]([CH2:8][CH2:9][CH3:10])[C:15]([CH:11]1[CH2:14][CH2:13][CH2:12]1)=[O:16]
Reactant: CCN(CC)CC
Reactant: CCCNc1nnc(C)o1
Reactant: O=C(Cl)C1CCC1
Solvent: c1ccccc1
Product: CCCN(C(=O)C1CCC1)C1OC=NN1C

Procedure:
5-Methyl-2-n-propylamino 1,3,4-oxadiazole (6 g, 0.04 mol) prepared as in (b) above, was refluxed with cyclobutanecarboxylic acid chloride (5.5 g, 0.05 mol) in benzene (25 ml) in the presence of triethylamine (4.72 g, 0.05 mol) for 2 hours. The mixture was filtered and the filtrate washed with dilute HCl, saturated solution NaHCO3 and water; dried over magnesium sulphate, filtered, solvent evaporated off to yield a reddish brown liquid which was distilled twice in a vigreux flask to yield the title compound as a slightly pink liquid (b.p. 110°-111° C./0.27 mm Hg).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[O:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[NH:19][C:18](=[O:20])[CH:17]=[N:16][CH:15]=2)[CH2:8][CH2:7]1.[H-].[Na+].[CH3:27]I.O>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[O:4][CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][C:14]2[N:19]([CH3:27])[C:18](=[O:20])[CH:17]=[N:16][CH:15]=2)[CH2:10][CH2:11]1
Reactant: CI
Reactant: O=c1cncc(CCN2CCC(COc3ccccc3F)CC2)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(CCN2CCC(COc3ccccc3F)CC2)cncc1=O
Reaction time: 1 h
Yield: 34 %

Procedure:
After dissolving 330 mg of 6-[2-[4-(2-fluorophenoxymethyl)piperidino]ethyl]-1H-pyrazin-2-one in 3 ml of N,N-dimethylformamide, 44 mg of sodium hydride (70% suspension in oil) was added while stirring, and the stirring was continued for 1 hour at room temperature. Next, 0.068 ml of methyl iodide was added and the mixture was stirred overnight at room temperature. Water was added to the reaction solution and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: ethyl acetate). Diethyl ether was added and the mixture was filtered to obtain the title compound (116 mg, 34% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[O:5]=[CH:6][C@@H:7]([C@H:9]([C@H:11]([C@@H:13]([CH2:15][OH:16])[OH:14])[OH:12])O)[OH:8].I.N1C=C[CH:21]=[CH:20][CH:19]=1>>[CH3:1][C:2]1([CH3:4])[O:12][C@H:11]2[C@H:9]([C@@H:7]([CH2:6][OH:5])[O:8][C@@H:15]3[O:16][C:20]([CH3:21])([CH3:19])[O:14][C@@H:13]32)[O:3]1
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: c1ccncc1
Reactant: CC(C)=O
Agent: I
Product: CC1(C)O[C@H]2[C@@H](O1)[C@@H](CO)O[C@@H]1OC(C)(C)O[C@@H]12
Temperature: 60 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To 200 ml of acetone were added 10.0 g of D-galactose and 175 mg of hydriodic acid (57%) and the mixture was refluxed with stirring in a water bath at 60° C. for 8 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the cooling jacket. After completion of the reaction, a small amount of pyridine was added. The acetone was then distilled off under reduced pressure and the residue was dissolved in benzene, washed with aqueous sodium bicarbonate and water and dried over anhydrous magnesium sulfate. The benzene was distilled off and the residue was further distilled under reduced pressure, whereby 8.5 g (59%) of 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose was obtained as a fraction boiling at 129°-133° C./0.2 mmHg.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Cl)=[O:15])=[CH:8][C:7]=1[O:24][CH3:25])[CH2:2][CH2:3][CH3:4].[I-:26].[Na+]>>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][I:26])=[O:15])=[CH:8][C:7]=1[O:24][CH3:25])[CH2:2][CH2:3][CH3:4]
Reactant: [I-]
Reactant: CCCCOc1ccc(/C=C/C(=O)OCCCCCCCl)cc1OC
Agent: [Na+]
Product: CCCCOc1ccc(/C=C/C(=O)OCCCCCCI)cc1OC

Procedure:
Preparation can be carried out analogously to Example 1 using 4.00 g (10.84 mmol) 6-chlorohexyl (2E)-3-(4-butoxy-3-methoxyphenyl)-2-propenoate and 9.75 g (65.05 mmol) sodium iodide, to yield 6-iodohexyl (2E)-3-(4-butoxy-3-methoxyphenyl)-2-propenoate.
Reaction SMILES: [CH2:1]([C:3]1[N:4]2[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=[O:12])[C:5]2=[N:6][N:7]=1)C.[Li+].[OH-]>C1COCC1.O.CO>[CH3:1][C:3]1[N:4]2[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=[O:12])[C:5]2=[N:6][N:7]=1
Reactant: CCc1nnc2n1CCC2C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1nnc2n1CCC2C(=O)O
Temperature: 60 °C

Procedure:
To a solution of ethyl 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]-triazole-7-carboxylic acid (400 mg, 2.05 mmol) in THF/water/MeOH was added LiOH (250 mg, 10.25 mmol) and the resulting solution was heated via oil bath to 60° C. for 16 h. (Round bottom was equipped with a condenser.) The solution was cooled to room temperature and concentrated to remove organic solvents. The aqueous layer was then acidified to pH of ˜5 using 2N HCl. The mixture was concentrated to dryness under vacuum, azeotroping with toluene (2×20 mL) to make sure all water was removed. The material was used without further purification with lithium chloride as a by-product. LC-MS: m/z (ES)=168 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][S:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([O:40][CH3:41])=[O:39])=[CH:34][CH:33]=3)=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].ClC1C=CC=C(C(OO)=[O:50])C=1>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][S:31]([C:32]3[CH:33]=[CH:34][C:35]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:37]=3)=[O:50])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1ccc(SCc2ccc(Cn3c(C(=O)OC)c(-c4ccccc4)c4cc(Br)ccc4c3=O)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)Cc2ccc(Cn3c(C(=O)OC)c(-c4ccccc4)c4cc(Br)ccc4c3=O)cc2)cc1
Yield: 49 %

Procedure:
To a solution of 6-bromo-2-[4-(4-methoxycarbonylphenylsulfanylmethyl)benzyl]-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (189 mg) in dichloromethane (20 ml) was added 3-chloroperbenzoic acid (74 mg) under ice-cooling and the mixture was stirred under ice-cooling for 1 hr. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=7/3→1/4) to give the title compound (95 mg, 49%).
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=4)[N:18]([CH:26]4[CH2:29][NH:28][CH2:27]4)[N:17]=3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=4)[N:18]([CH:26]4[CH2:27][NH:28][CH2:29]4)[N:17]=3)[N:14]=2)[NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C4CNC4)c4cc(F)ccc34)nc12
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(C4CNC4)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.3 %

Procedure:
To a solution of 2-(1-azetidin-3-yl-6-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide (36 mg, 0.69 mmol) in CH2Cl2 (1 mL) was added TFA (0.5 mL, 6.5 mmol). The reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was redissolved in CH2Cl2 (1 mL) and ethylene diamine (0.2 mL, 3.00 mmol) was added. The reaction mixture was stirred at room temperature for 1 h then quenched with water and extracted with 5% MeOH/CH2Cl2 (3×). The combined organic layers were dried over MgSO4 and concentrated. The residue was triturated with EtOAc to afford 17 mg (63%) of 2-(1-azetidin-3-yl-6-fluoro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide as a pale yellow powder. MS: (M+H)+=394; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 9.14 (s, 1H), 8.40-8.50 (m, 2H), 8.04 (d, J=7.6 Hz, 1H), 7.78-7.86 (m, 1H), 7.13-7.24 (m, 1H), 5.65-5.76 (m, 1H), 4.12-4.28 (m, 3H), 3.86 (t, J=7.9 Hz, 2H), 1.30 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[NH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:15]=1.O.O.[Sn](Cl)Cl.C(OCC)(=O)C.[OH-].[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]1[NH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:15]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(-c2ncc(-c3ccccc3)[nH]2)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)c(-c2ncc(-c3ccccc3)[nH]2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-(2-chloro-5-nitro-phenyl)-5-phenyl-1H-imidazole (430 mg, 1.43 mmol) and tin (II) chloride dihydrate (1.15 g, 5.02 mmol) in EtOH (15 ml) is heated at reflux for 3 hours. The mixture is cooled down to room temperature and the solvent is removed in vacuo. The residue obtained is treated with ethyl acetate (80 ml) and 1N NaOH solution is added until the pH is raised to around 12. The suspension is kept stirring for 10 minutes and then filtered through Celite cake. The solution obtained is concentrated to yield 4-chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenylamine as a dark red foam-like solid.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([N:9]1[CH:13]([C:14]([OH:16])=O)[CH2:12][S:11][CH2:10]1)=[O:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CN(C=O)C.C(OCC)C>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([N:9]1[CH:13]([C:14]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:16])[CH2:12][S:11][CH2:10]1)=[O:8]
Reactant: O=C1CC[C@@H](C(=O)N2CSCC2C(=O)O)N1
Reactant: C1COCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C1CC[C@@H](C(=O)N2CSCC2C(=O)N2CCOCC2)N1
Reaction time: 1 h
Yield: 69.4 %

Procedure:
4.84 g (0.02 moles) of 3-pyroglutamyl-thiazolidine-4-carboxylic acid are suspended in 20 ml of DMF and treated with 3.25 g (0.02 mole) of carbonyldiimidazole. After no more gas is developed, 1.72 g (0.02 moles) of morpholine dissolved in 10 ml of DMF is added thereto and shaken for 1 hour. After diluting with 2 volumes of ethyl ether, the solid is filtered and water recrystallized yielding 4.35 g (70%) of product. m.p. 187°-188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][CH2:12][NH2:13])=[C:9]([Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[NH:8][C:5]2=[N:6][CH:7]=1.[F:21][C:22]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:23]=1[CH2:24][C:25]1[O:29][N:28]=[C:27]([C:30](O)=[O:31])[CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][CH2:12][NH:13][C:30]([C:27]3[CH:26]=[C:25]([CH2:24][C:23]4[CH:33]=[C:34]([F:37])[CH:35]=[CH:36][C:22]=4[F:21])[O:29][N:28]=3)=[O:31])=[C:9]([Si:14]([CH2:15][CH3:16])([CH2:19][CH3:20])[CH2:17][CH3:18])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Reactant: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCNC(=O)c1cc(Cc2cc(F)ccc2F)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
A mixture of 2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanamine (0.128 g; 0.413 mmol), 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid intermediate 74 (0.104 g; 0.434 mmol), HATU (N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate) (0.165 g: 0.434 mmol) and N,N-diisopropylethylamine (0.108 mL; 0.619 mmol) in DMF (3 mL) was stirred overnight at room temperature and concentrated under reduced pressure. The crude material was dissolved in dichloromethane and the organic layer was washed with water and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent: 1 to 10% of ethyl acetate in dichloromethane) to give 0.108 g (49%) of N-(2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9].[CH3:12][O:13][CH2:14][CH2:15]Br>>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH2:15][CH2:14][O:13][CH3:12])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9]
Reactant: COCCBr
Reactant: OCc1c(F)cc(O)cc1Cl
Product: COCCOc1cc(F)c(CO)c(Cl)c1
Yield: 52 %

Procedure:
This compound was prepared from 3-chloro-5-fluoro-4-hydroxymethyl-phenol and (2-bromoethyl) methyl ether according to the procedure described in Example 179 to give the product as a yellowish oil (209 mg, 52%); MS (EI): 234.1 (M)+.
Reaction SMILES: [OH:1]O.[C:3]([C:5]1[C:6]([CH3:17])=[C:7]([C:12]([S:15][CH3:16])=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:4].[OH-].[Na+]>C(O)C.O>[CH3:11][O:10][C:8]([C:7]1[C:6]([CH3:17])=[C:5]([CH:14]=[CH:13][C:12]=1[S:15][CH3:16])[C:3]([NH2:4])=[O:1])=[O:9]
Reactant: OO
Reactant: COC(=O)c1c(SC)ccc(C#N)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(=O)c1c(SC)ccc(C(N)=O)c1C
Temperature: 65 °C

Procedure:
Hydrogen peroxide (30%, 18 ml) was added dropwise with stirring to a solution of methyl 3-cyano-2-methyl-6-methylsulphenylbenzoate (10.0 g) in ethanol (100 ml) in an atmosphere of nitrogen. A solution of sodium hydroxide (0.43 g) in water (2 ml) was added dropwise and the resultant rapid exotherm was controlled by ice cooling. After the exotherm had ceased the mixture was stirred and heated at 65° C. for 0.5 hours. The orange solution was poured into a mixture of ice and water (400 ml) and it was extracted with ether (3×100 ml). The combined organic extracts were washed with water (100 ml), aqueous ferrous sulphate solution (100 ml), water (2×100 ml), dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 3-methoxycarbonyl-2-methyl-4-methylsulphenylbenzamide (4.2 g) as an orange oil, NMR (CDCl3) 2.3(s,3H), 2.4(s,3H), 3.9(s,3H), 6.5(bs,2H), 6.95(d,1H), 7.25(d,1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2O[C:13](=O)[C:12]([C:16]#[N:17])=[C:11]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH2:26]1[CH2:30]O[CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:5]3[C:4]4[C:27](=[CH:26][CH:30]=[CH:8][CH:3]=4)[CH2:28][C:13]=3[C:12]([C:16]#[N:17])=[C:11]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(N3CCCCC3)c(C#N)c(=O)o2)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2cc(N3CCCCC3)c(C#N)c3c2-c2ccccc2C3)cc1

Procedure:
A mixture of 6-(4-methoxyphenyl)-2-oxo-4-(piperidin-1-yl)-2H-pyran-3-carbonitrile (310 mg), indanone-2 (132 mg) and NaH (40 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 202-204° C.; MS 380 (M+); IR (KBr) 2210 cm−1 (CN).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C:10](=O)[CH2:9][CH2:8]2.[NH2:14][CH:15]1[CH:20]2[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]2)[CH2:16]1.C(O)(=O)C>>[N:17]12[CH2:22][CH2:21][CH:20]([CH2:19][CH2:18]1)[CH:15]([NH:14][CH:10]1[CH2:9][CH2:8][C:7]3[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=3)[CH2:11]1)[CH2:16]2.[CH:3](=[O:2])[CH2:12][CH3:11]
Reactant: NC1CN2CCC1CC2
Reactant: COc1cccc2c1CC(=O)CC2
Solvent: CC(=O)O
Product: CCC=O
Product: COc1cccc2c1CC(NC1CN3CCC1CC3)CC2

Procedure:
1.60 g (5.6 mmol) of 2-(quinuclidin-3-yl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalene (obtained from 8-methoxy-2-tetralone and 3-aminoquinuclidine by reductive amination in the conventional fashion), 3.20 g (56 mmol) of propionaldehyde and 1.70 g (28 mmol) of glacial acetic acid were stirred for 30 minutes at 0° C. 0.80 g (11 mmol) of sodium cyanoborohydride was then added, and the mixture was stirred for 15 hours at room temperature. The reaction mixture was concentrated, taken up in toluene and reconcentrated, taken up in tert.-butyl methyl ether, and stirred vigorously for 30 minutes with 20% strength sodium hydroxide solution. The aqueous phase was extracted carefully with tert.-butyl methyl ether. Washing the combined organic phases with water and saturated sodium chloride solution, drying over potassium carbonate, and concentrating in a rotary evaporator yielded the crude product as an oil (2.0 g). Chromatography on silica gel (toluene/ethanol 3:1) supplied the title compound as a syrup.
Reaction SMILES: C(OC(N1C[CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C[O:32][C:33](=[O:41])[CH2:34][CH:35]1CCNC[CH2:36]1.O1C2C(=NC=CC=2)O[C@@H](C2C=CC(CN3CCC(C(O)=O)CC3)=CC=2)C1>>[O:23]1[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[O:30][C@@H:21]([C:18]2[CH:17]=[CH:16][C:15]([CH2:14][N:11]3[CH2:10][CH2:9][CH:35]([CH2:34][C:33]([OH:41])=[O:32])[CH2:36][CH2:12]3)=[CH:20][CH:19]=2)[CH2:22]1
Reactant: COC(=O)CC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Agent: O=C(O)C1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Product: O=C(O)CC1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1

Procedure:
The title product GG is prepared from compound GG-1 (prepared from Intermediate C and piperidin-4-yl-acetic acid methyl ester according to General Method F) according to the procedure used to synthesize Intermediate K.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([O:21][CH3:22])=[CH:10][CH:9]=2.C(N(CC)CC)C.Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]Br>CC(O)(C)C>[ClH:1].[CH3:22][O:21][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:23])[N:6]([CH3:24])[C:5]([CH2:4][CH2:3][N:2]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCCCCCBr
Reactant: COc1ccc2c(=O)n(C)c(CCN)c(-c3ccccc3)c2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: COc1ccc2c(=O)n(C)c(CCN3CCCCC3)c(-c3ccccc3)c2c1
Temperature: 150 °C
Reaction time: 24 h

Procedure:
To a solution of 3-(2-aminoethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one hydrochloride (100 mg, 0.290 mmol) in 15 mL of 2-methyl-2-propanol in a pressure tube was added triethylamine (0.142 mL, 1.02 mmol), followed by 1,5-dibromopentane (0.047 mL, 0.348 mmol). The mixture was heated at 150° C. overnight. Another portion of 1,5-dibromopentane was added (0.023 mL), and the heating continued for another 24 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC. The pure fractions were concentrated in vacuo, taken up in EtOAc and washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The product was taken up in dichloromethane, treated with excess ethereal HCl, and concentrated in vacuo to provide the HCl salt. Proton NMR for the product was consistent with the titled compound. ESI+MS: 377.19 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.C(=O)(O)[O-].[Na+].Cl[C:17]([O:19][CH3:20])=[O:18]>O>[C:7]([C:5]1[NH:4][N:3]=[C:2]([NH:1][C:17](=[O:18])[O:19][CH3:20])[CH:6]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1cc(N)n[nH]1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)Nc1cc(C(C)(C)C)[nH]n1
Yield: 73.9 %

Procedure:
42 g of Compound [II] and 30 g of sodium bicarbonate were dissolved in 2 l of water, and 34 g of methyl chloroformate was added dropwise to the solution over 1.5 hours at 10° C. The mixture was allowed to react at 10° C. for one hour. After completion of the reaction, the solid product was collected by filtration, washed with water and dried to obtain 44 g of methyl N-(5-t-butyl-3-pyrazolyl)carbamate.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[C:10]([O:11][CH2:12][CH2:13][OH:14])=[CH:9][CH:8]=[CH:7][N:6]=1>CN(C=O)C>[CH3:1][S:2][C:5]1[C:10]([O:11][CH2:12][CH2:13][OH:14])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: C[S-]
Reactant: OCCOc1cccnc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ncccc1OCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.8 %

Procedure:
To a suspension of sodium thiomethoxide (3.01 g, 42.9 mmol) in dry DMF (30 mL) was 2-[(2-chloro-3-pyridinyl)oxy]ethanol (7.82 g, 45.1 mmol, from Example 193, Step 1) added and the reaction mixture was stirred at ambient temperature for 1 h.. The solvent was removed under reduced pressure and the residue was partitioned between brine/1 M aqueous NaOH and CHCl3. The aqueous phase was extracted with an additional portion of CHCl3 and the combined organic layers were dried (MgSO4) and concentrated. The resulting red oil was purified by column chromatography on silica using toluene/Et3N/MeOH (96:2:2) as eluent to give 3.0 g (36%) of the title compound as brownish crystals: mp 80° C. Anal. (C7H11NO2S) C, H, N.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@H:18]3[CH2:19][CH2:20][NH:21][C@H:17]3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10]2)=[CH:5][CH:4]=1.[C:22]([NH:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]1[C:37](O)=[O:38])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.CCOC(OC(OCC)=O)=O>CN(C=O)C>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@H:18]3[CH2:19][CH2:20][N:21]([C:37]([C@H:32]4[CH2:33][CH2:34][CH2:35][CH2:36][C@H:31]4[NH:30][C:22](=[O:29])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[O:38])[C@H:17]3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10]2)=[CH:7][CH:8]=1
Reactant: O=C(N[C@@H]1CCCC[C@@H]1C(=O)O)c1ccccc1
Reactant: CSc1ccc([C@@H]2Nc3ccccc3[C@@H]3NCC[C@H]23)cc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1ccc([C@@H]2Nc3ccccc3[C@H]3[C@@H]2CCN3C(=O)[C@H]2CCCC[C@H]2NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.5 %

Procedure:
To a suspension of (3aS,4R,9bR)-4-[4-(methylthio)phenyl]-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline (1.10 g, 3.0 mmol) and (1S,2R)-2-(benzoylamino)cyclohexanecarboxylic acid (0.74 g, 3.0 mmol) in DMF (20 ml) were added under ice-cooling, triethylamine (0.91 g, 9.0 mmol), and then a solution of DEPC (0.49 g, 3.0 mmol) in DMF (5 ml). The reaction mixture was stirred at room temperature for 16 hrs., the reaction mixture was poured into ice water and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (2:1-1:1, v/v) to give N-[(1R,2S)-2-({(3aR,4R,9bR)-4-[4-(methylthio)phenyl]-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl}carbonyl)cyclohexyl]benzamide (0.45 g, 29%) from the first eluted fraction.