Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][C:10]([OH:12])=O)=[O:4].[NH2:16][CH2:17][C@@H:18]([OH:36])[CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[C:28]=2[CH3:35])[CH2:22][CH2:21]1>>[Cl:34][C:29]1[C:28]([CH3:35])=[C:27]([CH:32]=[CH:31][C:30]=1[Cl:33])[O:26][CH:23]1[CH2:22][CH2:21][N:20]([CH2:19][C@H:18]([OH:36])[CH2:17][NH:16][C:10](=[O:12])[CH2:9][O:8][C:7]2[CH:6]=[C:5]([CH:15]=[CH:14][CH:13]=2)[C:3]([O:2][CH3:1])=[O:4])[CH2:25][CH2:24]1
Reactant: COC(=O)c1cccc(OCC(=O)O)c1
Reactant: Cc1c(OC2CCN(C[C@H](O)CN)CC2)ccc(Cl)c1Cl
Product: COC(=O)c1cccc(OCC(=O)NC[C@@H](O)CN2CCC(Oc3ccc(Cl)c(Cl)c3C)CC2)c1

Procedure:
Prepared as for Example 15, Step 2 using [3-(methoxycarbonyl)phenoxy]acetic acid [Asian Journal of Chemistry 1992, 4(4), 920-3] and (2R)-1-amino-3-[4-(3,4-dichloro-2-methylphenoxy)piperidin-1-yl]propan-2-ol to yield the subtitle compound as a pale yellow oil (0.11 g).
Reaction SMILES: C(O)C.CS[C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:19][CH:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)[CH2:22][CH2:21]3)=[CH:13][CH:14]=2)[CH2:9]1)=[NH:7].[ClH:32].[CH3:33][NH2:34].C([O-])(=O)C.[Na+]>O>[ClH:32].[ClH:32].[CH3:33][NH:34][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:19][CH:20]3[CH2:21][CH2:22][N:23]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)[CH2:24][CH2:25]3)=[CH:13][CH:14]=2)[CH2:9]1)=[NH:7]
Reactant: CSC(=N)N1CCc2ccc(OCC3CCN(c4ccncc4)CC3)cc2C1
Reactant: CN
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CNC(=N)N1CCc2ccc(OCC3CCN(c4ccncc4)CC3)cc2C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 119.4 %

Procedure:
To an ethanol solution (2 ml) of 7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carbothioimidic acid methyl ester (100 mg) were added methylamine hydrochloride (20 mg) and sodium acetate (25 mg), and the mixture was stirred at 80° C. for 3 hours. After completion of the reaction, water was added and the mixture was washed with chloroform. Thereto was added aqueous sodium hydrogencarbonate solution and the mixture was washed with chloroform. To the aqueous layer was added 4N aqueous sodium hydroxide solution and the mixture was extracted with chloroform. The extract was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated and the obtained residue was treated with hydrogen chloride—ethanol solution and dried under reduced pressure to give the title compound (80 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[N:5]2.C([Sn](CCCC)(CCCC)[C:18]([O:20][CH2:21][CH3:22])=[CH2:19])CCC>O1CCOCC1.CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:18]([O:20][CH2:21][CH3:22])=[CH2:19])[CH:6]=[N:5]2
Reactant: Clc1cnc2cc(Br)ccc2n1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CO
Product: C=C(OCC)c1cnc2cc(Br)ccc2n1
Temperature: 110 °C
Reaction time: 2 h
Yield: 52.4 %

Procedure:
Dichlorobis(triphenylphosphine)-palladium(II) (17.30 mg, 0.025 mmol) was added to a solution of 6-bromo-2-chloroquinoxaline (60 mg, 0.246 mmol) and tributyl(1-ethoxyvinyl)stannane (107 mg, 0.296 mmol) in dioxane (1.5 mL) and the mixture was stirred at 110° C. for 2 h. The reaction was diluted with MeOH, and purified by prep HPLC (H2O-MeOH with 10 mM NH4OAc buffer) to yield 6-bromo-2-(1-ethoxyvinyl)quinoxaline (36 mg, 0.129 mmol, 52.3% yield) as white solid. LC-MS retention time 2.76 min; m/z 279 [M+H]+. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water:10% methanol:0.1% TFA. Solvent B=10% water:90% methanol:0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH2:42][CH3:43])=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH2:42][CH3:43])=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(6-ethyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K23) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (324 mg, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1CO.COC1C=C[N:16]=[CH:15]C=1CN>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[NH:16][CH3:15]
Reactant: COc1ccncc1CO
Reactant: COc1ccncc1CN
Product: CNc1cnccc1OC

Procedure:
(4-Methoxy-pyridin-3-yl)-methanol was then converted to C-(4-methoxy-pyridin-3-yl)-methylamine through standard procedures as described in the previous compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=O)[C:5]2=[O:12].Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[N:14][OH:15])[C:5]2=[O:12]
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C1C(=NO)Nc2ccc(Br)cc21
Yield: 76 %

Procedure:
3.3 g of 5-bromoisatin, 0.8 g of hydroxylamine hydrochloride and 1.6 g of sodium acetate are held at reflux in 50 ml of water for 1.5 hrs. The yellow crystals are filtered off and dried. 2.11 g of 5-bromoisatin oxime are isolated. Yield: 83%. M.p.=215° (decomposition).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:14]1([N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C=O>[C:14]1([N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21](=[O:22])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)c1csc(NC(=O)N(c2ccccc2)c2ccccc2)n1

Procedure:
Following a procedure similar to that described in Preparation 13, the desired compound was prepared from 5 g of ethyl 2-aminothiazol-4-ylglyoxylate, 7 g of diphenylcarbamoyl chloride, 30 ml of triethylamine and 20 ml of dimethylformamide. The resulting product was a brown oil having the following physical properties.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=1>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: FC(F)(F)c1cccc(Br)n1
Product: Cc1onc(-c2ccccc2)c1C#Cc1cccc(C(F)(F)F)n1
Yield: 82 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-bromo-6-(trifluoromethyl)pyridine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 135 mg, 82%) which was obtained as a light yellow solid. MS: m/e=329.3 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[CH3:17]O>>[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=1
Reactant: CO
Reactant: Nc1ccc(CCC(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1ccc(N)cc1
Reaction time: 0.17 h
Yield: 99 %

Procedure:
Under ice-cooling, thionyl chloride (15 mL, 206 mmol) was added dropwise to methanol (60 mL), and the mixture was stirred for 10 min. 3-(4-Aminophenyl)propanoic acid (10.1 g, 61.1 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 18 hr. The solvent and excess thionyl chloride were evaporated under reduced pressure, and water and saturated aqueous sodium hydrogencarbonate were added. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained solid was washed with hexane to give the title compound (10.9 g, yield 99%) as pale-brown prism crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][N:6]=1)=[O:4].[F:14][C:15]([F:31])([F:30])[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([N:22]2[CH2:27][CH2:26][CH:25]([CH2:28][NH2:29])[CH2:24][CH2:23]2)[N:17]=1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:29][CH2:28][CH:25]2[CH2:26][CH2:27][N:22]([C:18]3[N:17]=[C:16]([C:15]([F:31])([F:30])[F:14])[CH:21]=[CH:20][N:19]=3)[CH2:23][CH2:24]2)=[O:11])=[CH:7][N:6]=1)=[O:4]
Reactant: NCC1CCN(c2nccc(C(F)(F)F)n2)CC1
Reactant: COC(=O)c1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NCC2CCN(c3nccc(C(F)(F)F)n3)CC2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.3 %

Procedure:
To a solution of 6-(methoxycarbonyl)nicotinic acid (250 mg, 1.39 mmol) and 1-{1-[4-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl}methanamine (INTERMEDIATE 6, 361 mg, 1.39 mmol) in dimethylformamide (5.0 ml) were added hydroxybenzotriazole (225 mg, 1.67 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (320 mg, 1.67 mmol), and N,N-diisopropylethylamine (291 μl, 1.67 mmol). The reaction was allowed to stir at ambient temperature for 18 h. After removal of the solvent by evaporation, the residue was purified by flash chromatography on a silica gel column, eluting with a gradient of 0-100% ethyl acetate in hexanes to give the title compound as a white solid (272.2 mg). Mass spectrum (ESI) 425 (M+1). 1H NMR (500 MHz, CDCl3) δ 9.13 (s, 1H), 8.49 (d, 1H, J=4.8 Hz), 8.33 (d, 1H, J=8.0 Hz), 8.24 (d, 1H, J=8 Hz), 6.73-6.77 (m, 2H), 4.87 (d, 2H, J=13.5 Hz), 4.05 (s, 3H), 3.44-3.47 (m, 2H), 2.90-2.98 (m, 2H), 1.90-2.00 (m, 1H), 1.90 (d, 2H, J=12.6 Hz), 1.27-1.36 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([C:7]1[CH:8]=[CH:9][C:10]2[N:16]([CH2:17][CH3:18])[C:15](=[O:19])[CH2:14][N:13]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:11]=2[CH:27]=1)(=O)[CH3:5].C([BH3-])#N.[Na+]>CO.Cl>[CH3:1][N:2]([CH3:3])[CH:4]([C:7]1[CH:8]=[CH:9][C:10]2[N:16]([CH2:17][CH3:18])[C:15](=[O:19])[CH2:14][NH:13][CH:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:11]=2[CH:27]=1)[CH3:5]
Reactant: CCN1C(=O)CN=C(c2ccccc2F)c2cc(C(C)=O)ccc21
Reactant: CNC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN1C(=O)CNC(c2ccccc2F)c2cc(C(C)N(C)C)ccc21

Procedure:
To a solution, stirred at room temperature, of 9.1 ml of dimethylamine in 140 ml of methanol and 0.1 ml of 5 N methanolic hydrochloric acid are added 7.0 g (21.7 mmol) of 7-acetyl-1-ethyl-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one, followed by 0.24 g of sodium cyanoborohydride. The mixture is stirred at room temperature for 14 days, with 924 mg of sodium cyanoborohydride being added after 2 days and after 7 days. The solvent is removed in vacuo and the residue is adjusted to pH 10 with 10 N sodium hydroxide and then taken up in chloroform. The organic phase is washed with water, dried and evaporated. The residue is chromatographed on 200 g of silica gel using chloroform as the elution agent and there is obtained 7-[1-(dimethylamino)ethyl]-1-ethyl-5-(o-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one as an oil.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH3:27]>>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][C@H:13]([CH2:12][NH2:27])[O:18][C:17]=2[CH:19]=1)(=[O:25])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: N
Product: CS(=O)(=O)c1ccc2c(c1)O[C@@H](CN)CO2
Temperature: 120 °C

Procedure:
A mixture of [(2R)-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (1.1 g, 2.5 mmol), NH3 (4 ml, 7N in methanol) was heated under microwave radiation at 120° C. for 20 min. The product was evaporated to dryness and was purified by flash column chromatography (EtOAc/MeOH). Yield 0.31 g. MS m/z (rel. intensity, 70 eV) 243 (M+, 35), 214 (bp), 199 (35), 79 (25), 56 (22).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1.[CH3:16]O>S(=O)(=O)(O)O>[CH3:16][O:12][C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([S:3][C:2]([F:14])([F:1])[F:15])[CH:5]=1
Reactant: O=C(O)Cc1cccc(SC(F)(F)F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cccc(SC(F)(F)F)c1
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 3-(trifluoromethylthio)phenylacetic acid (5.00 g, 21.17 mmol) in methanol (50 mL) was treated slowly with 10 drops of concentrated sulfuric acid. The resulting reaction mixture was heated under reflux for 18 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The residue was diluted with ethyl acetate (100 mL). The organic phase was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to afford (3-trifluoromethylsulfanyl-phenyl)-acetic acid methyl ester (5.28 g, 99%) as a pale yellow oil which was used without further purification: EI-HRMS m/e calcd for C10H9F3O2S (M+) 250.0275, found 250.0274.
Reaction SMILES: [CH:1]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:37])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C:16](OS(C(F)(F)F)(=O)=O)=[CH:15][CH2:14]2)[CH2:11][CH2:10]3)([CH3:3])[CH3:2].[CH3:48][O:49][C:50]([C:52]1[CH:57]=[CH:56][C:55](B(O)O)=[CH:54][CH:53]=1)=[O:51].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:38]([O:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[O:39])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:37])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:27])([CH3:28])[C:16]([C:55]1[CH:56]=[CH:57][C:52]([C:50]([O:49][CH3:48])=[O:51])=[CH:53][CH:54]=1)=[CH:15][CH2:14]2)[CH2:11][CH2:10]3)([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C2=CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(C(=O)OCc6ccccc6)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Temperature: 90 °C
Yield: 88.9 %

Procedure:
A mixture of (1S,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-benzyl 1-isopropyl-5a,5b,8,8,11a-pentamethyl-9-(trifluoromethylsulfonyloxy)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate (3.5 g, 5.16 mmol), 4-(methoxycarbonyl)phenylboronic acid (1.206 g, 6.70 mmol), Pd(Ph3P)4 (0.179 g, 0.155 mmol) and sodium carbonate (1.639 g, 15.47 mmol) in dioxane (20 mL) and water (20 mL) was heated up at 90° C. for 2 h. TLC indicated starting material was consumed and a new spot was present. The reaction mixture was purified by biotage with 0-10% ethyl acetate/hexanes to provide the title compound as white solid (3.05 g, 89%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.92 (d, J=8.24 Hz, 2H), 7.48-7.28 (m, 5H), 7.19 (d, J=7.93 Hz, 2H), 5.28 (dd, J=6.26, 1.68 Hz, 1H), 5.19-5.00 (m, 2H), 3.90 (s, 3H), 2.38-2.20 (m, 3H), 2.11 (dd, J=17.09, 6.41 Hz, 1H), 1.89-1.75 (m, 2H), 1.72-1.61 (m, 2H), 1.53-1.07 (m, 16H), 0.95 (s, 6H), 0.92 (s, 3H), 0.90 (s, 3H), 0.85 (d, J=6.71 Hz, 3H), 0.80 (s, 3H), 0.75 (d, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[C:34]([OH:36])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:37]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[C:34]([O:36][CH2:11][C:8]3[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=3)[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2cc(O)c3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOCc3ccccc3)cc2)C(OCc2cc(OCc3ccccc3)c3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1(g), by two-fold alkylation of tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(4-hydroxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with benzyl bromide there was obtained tert-butyl (3RS,4RS)-4-[4-(2-benzyloxy-ethoxy)-phenyl]-3-(4-benzyloxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylate.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][CH:13]=2)[NH:8][CH:7]=1)([O-:3])=[O:2].[BH4-].[Na+]>C1COCC1.CO>[N+:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][CH:13]=2)[NH:8][CH:7]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1ccc2c(C=C[N+](=O)[O-])c[nH]c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(CC[N+](=O)[O-])c[nH]c2c1
Reaction time: 1.5 h

Procedure:
Combine 3-(2-nitrovinyl)-6-ethoxycarbonyl-1H-indole (4.0 g, 15.37 mmol) and NaBH4 (726.7 mg, 19.21 mmol) in 100 ml of THF/Methanol (9:1) and stir at ambient temperature. After 1.5 hours, concentrate to residue. Partition the residue between brine and ethyl acetate, wash with brine, combine the organic layers, dry (Na2SO4), then evaporate to give the title compound as a yellow powder: mp 124-127° C. MS (ACPI): m/e 263.0 (M+1). Analysis for C13H14N2O4: Calcd: C, 59.54; H, 5.38; N, 10.68. found: C, 59.40; H, 5.36; N, 10.53.
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]([CH3:19])[CH:5]=[CH:6][C:7]([C:9]1[CH:10]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:12]=[CH:13][CH:14]=1)=[O:8].[CH2:20](I)[CH3:21]>CN(C)C=O>[CH3:19][N:4]([CH3:3])[CH:5]=[CH:6][C:7]([C:9]1[CH:10]=[C:11]([N:15]([CH2:20][CH3:21])[C:16](=[O:18])[CH3:17])[CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: CC(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCN(C(C)=O)c1cccc(C(=O)C=CN(C)C)c1
Reaction time: 6 h

Procedure:
36.2 gm Powdered potassium hydroxide was added portion wise to a clear solution of a mixture of 100 gm N-[3-[3-(Dimethylamino)-1-oxo-2-propenyl]phenyl] acetamide and 70 ml ethyl iodide in 1000 ml of dimethyl formamide at 39°-42° C. over 60 min. the reaction mixture was stirred for 6 hrs. after completion, the reaction mixture was quenched in water and extracted in dichloromethane. The dichloromethane layer was washed with water, dried over sodium sulphate and concentrated to get oil, which upon trituration in hexane gave a solid product which was filtered and dried at 40° C. under vacuum to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:23][Si:24]([C:27]#[C:28][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[N:6][CH:7]=1)([CH3:26])[CH3:25]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cncc(C#C[Si](C)(C)C)c1
Yield: 62.6 %

Procedure:
Into a reaction flask were added tert-butyl (5-bromopyridin-3-yl)carbamate (3.0 g, 11.0 mmol), tetrahydrofuran (30 mL), and triethylamine (1.7 mL, 12 mmol). The reaction mixture was stirred under N2 bubbling for 5 min. (Trimethylsilyl)acetylene (1.60 g, 16.3 mmol), copper(I) iodide (84 mg, 0.44 mmol), and bis(triphenylphosphine)palladium(II) chloride (0.31 g, 0.44 mmol) were then added. The resultant mixture was heated at 50° C. overnight. The solvent was removed under vacuum and the residue was diluted with EtOAc and water. After separation, the organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column chromatography to give the desired product as a white powder (2.0 g, 63%). LCMS for C15H23N2O2Si (M+H)+: m/z=291.1.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[CH:4][C:3]=1[CH3:9].[NH2:10][C:11]1[C:20]2[C:15](=[C:16]([O:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[NH:14][C:13](=[O:29])[CH:12]=1>>[CH:24]1([O:23][C:16]2[C:17]([O:21][CH3:22])=[CH:18][CH:19]=[C:20]3[C:15]=2[NH:14][C:13](=[O:29])[CH:12]=[C:11]3[NH:10][C:2]2[C:7]([CH3:8])=[CH:6][N:5]=[CH:4][C:3]=2[CH3:9])[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: Cc1cncc(C)c1Br
Reactant: COc1ccc2c(N)cc(=O)[nH]c2c1OC1CCCC1
Product: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OC1CCCC1

Procedure:
The title compound was prepared from 4-bromo-3,5-dimethylpyridine and 4-amino-8-(cyclopentyloxy)-7-methoxyquinolin-2(1H)-one (Example 1, Step 6) following the procedure outlined in Example 8. 1H NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1H), 8.44 (s, 1H), 8.40 (s, 2H), 7.88 (d, 1H), 7.03 (d, 1H), 4.96 (m, 1H), 4.51 (s, 1H), 3.90 (s, 3H), 2.13 (s, 6H), 1.80-1.54 (m, 8H); MS (ESI): 380.2.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:15][CH2:14][CH2:13][C:4]=2[N:5]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:7]=1.[NH2:16][C:17]1[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][OH:23])=[CH:19][CH:18]=1>CN1C(=O)CCC1.O>[CH:8]1([C:6]2[N:7]=[C:2]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][OH:23])=[CH:19][CH:18]=3)[C:3]3[CH2:15][CH2:14][CH2:13][C:4]=3[N:5]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Nc1ccc(CCO)cc1
Reactant: Clc1nc(C2CCCC2)nc2c1CCC2
Solvent: O
Solvent: CN1CCCC1=O
Product: OCCc1ccc(Nc2nc(C3CCCC3)nc3c2CCC3)cc1
Temperature: 120 °C
Yield: 51.4 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-cyclopentyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.132 g, 0.59 mmol) and 4-aminophenethyl alcohol (0.162 g, 1.18 mmol) in NMP (4 mL). The resulting mixture was heated at 120° C. under microwave irradiation for 2 h. The reaction mixture was cooled, diluted with water (40 mL) to afford a solid. The solid was isolated by filtration then purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent to afford the title compound (0.098 g, 51%) as a light brown solid. MW=323.43. M.p. 178-180° C. 1H NMR (DMSO-d6, 500 MHz) δ 8.47 (s, 1H), 7.70 (d, J=8.5 Hz, 2H), 7.12 (d, J=8.5 Hz, 2H), 4.59 (t, J=5.0 Hz, 1H), 3.61-3.55 (m, 2H), 3.09 (quin, J=8.0 Hz, 1H), 2.77 (q, J=7.5 Hz, 4H), 2.67 (t, J=7.0 Hz, 2H), 2.01 (quin; J=7.5 Hz, 2H), 1.97-1.90 (m, 2H), 1.87-1.78 (m, 2H), 1.78-1.68 (m, 2H), 1.65-1.55 (m, 2H); APCI MS m/z 324 [M+H]+.