Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16](I)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][C:21]([O:31][CH2:32][CH2:33][O:34][CH3:35])([C:24]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[O:25])[CH2:20][CH2:19]2)[CH:9]=1.[C:46]1([N:52]2[CH:56]=[C:55](B3OC(C)(C)C(C)(C)O3)[CH:54]=[N:53]2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:55]3[CH:54]=[N:53][N:52]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH:56]=3)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][C:21]([O:31][CH2:32][CH2:33][O:34][CH3:35])([C:24]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[O:25])[CH2:20][CH2:19]2)[CH:9]=1
Reactant: COCCOC(=O)C1(OCCOC)CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Reactant: CC1(C)OB(c2cnn(-c3ccccc3)c2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COCCOC(=O)C1(OCCOC)CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnn(-c5ccccc5)c4)c3n2)CC1
Temperature: 90 °C
Yield: 73 %

Procedure:
A mixture of 2-methoxyethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)-1-(2-methoxyethoxy)cyclohexanecarboxylate (3.06 g, 3.93 mmol), 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.38 g, 5.11 mmol), PdCl2(dppf)CH2Cl2 (321 mg, 0.393 mmol), and K3PO4 (2.50 g, 11.8 mmol) in dioxane/H2O (40/4 mL) was degassed and then heated at 90° C. for 16 h. LCMS showed very good conversion to the desired product (795), and about 10% de-iodination byproduct (653). The reaction mixture was diluted with EtOAc and washed with H2O and brine, dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-40% EtOAc/Hexanes, Rf=0.6 in 50% EtOAc/Hexanes) to afford 2-methoxyethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(2-methoxyethoxy)cyclohexanecarboxylate as a brown oil (2.28 g, 73%).
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][S:6]([CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[CH2:12]I)(=[O:8])=[O:7])[CH3:3].[C-:16]#[N:17].[K+].CS(C)=O>O.C1OCCOCCOCCOCCOCCOC1>[C:16]([CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][CH2:9][S:6]([N:5]=[CH:4][N:2]([CH3:3])[CH3:1])(=[O:8])=[O:7])#[N:17]
Reactant: CN(C)C=NS(=O)(=O)CCC(C)(C)CI
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)C=NS(=O)(=O)CCC(C)(C)CC#N
Temperature: 100 °C
Reaction time: 14 h
Yield: 84.7 %

Procedure:
A mixture of 1.85 g of 4-(N,N-dimethylaminomethylene)aminosulfonyl-1-iodo-2,2-dimethylbutane, 0.49 g of potassium cyanide, 0.06 g of 18-crown-6 and 30 ml of dimethyl sulfoxide was stirred at 100° C. for 14 hours. After cooling, the reaction mixture was diluted with 100 ml of water and extracted with ethyl acetate. The extract was washed with water and dried (MgSO4) and the solvent was distilled off. The residue was subjected to silica gel (70 g) column chromatography and elution was carried out with ethyl acetate-hexane (9:1). The fractions containing the objective compound were pooled and concentrated and the residue was recrystallized from ethyl ether to provide 1.11 g of the title compound. m.p. 53°-54° C.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CCOC(=O)c1ccc(I)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: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.009 g of Pd(PPh3)4 was added to a solution of 0.091 g of ethyl 4-iodobenzoate in 0.96 ml of degassed toluene and stirred at room temperature for 10 minutes. Then a solution of 0.047 g of 2,4-difluorophenylboronic acid in 0.114 ml of ethanol and 0.201 ml of a 2N Na2CO3 solution was added to the reaction solution. The solution was heated at 100° C. overnight. The reaction mixture was then concentrated in vacuo, and water/ethyl acetate were added to the residue. The aqueous phase was extracted three times with ethyl acetate and dried over sodium sulfate, and the solvent was removed in vacuo and purified by preparative HPLC.
Reaction SMILES: CO[C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([NH2:12])=[C:7]([Cl:13])[N:6]=1)=[O:4].[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH2:18]>>[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH:18][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([NH2:12])=[C:7]([Cl:13])[N:6]=1)=[O:4]
Reactant: CN(C)CCN
Reactant: COC(=O)c1nc(Cl)c(N)nc1N
Product: CN(C)CCNC(=O)c1nc(Cl)c(N)nc1N

Procedure:
3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid methyl ester (25.0 g, 0.12 mol) and N,N-dimethylethylenediamine (100 mL) are heated at 100° C. in a miniclave for 20 h. The reaction mixture is concentrated in vacuo and the pale yellow crystals that form are collected by filtration, washed with MeOH and dried under vacuum to afford the title compound. [M+H]+ 259.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].CO>C(OCC)(=O)C>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:18][CH2:17][C:16]([OH:15])([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: COc1cccc(C2(O)CCNCC2)c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cccc(C2(O)CCN(C[C@H](O)COc3cccc4[nH]ccc34)CC2)c1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-hydroxy-4-(3-methoxyphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 76% overall yield. FDMS m/e=396 (M+ of free base). α[D]589 =-8.13 (c=0.69, methanol).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[NH2:26].Cl>C(C#N)(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[NH:26][C:18]1[CH:19]=[CH:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][C:17]=1[F:16]
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: CC(=O)C#N
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc([N+](=O)[O-])cc3F)c2cc1OC
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-quinazoline (548 mg, 2.4 mmol), 2-fluoro-4-nitro-phenylamine (392 mg, 2.5 mmol), AcCN (10 ml), and conc'd HCl (0.050 ml) was heated to reflux for several hrs. After the reaction mixture was allowed to cool to room temperature, the resulting solids were filtered, washed with AcCN and air-dried to give (6,7-dimethoxy-quinazolin-4-yl)-(2-fluoro-4-nitro-phenyl)-amine (673 mgs, 80%). 1H-NMR (400 MHz, DMSO): 12.18 (br s, 1H), 8.91 (s, 1H), 8.45 (s, 1H), 8.36 (dd, 1H), 8.24 (dd, 1H), 7.91 (dd, 1H), 7.44 (s, 1H), 4.04 (s, 3H), 4.02 (s, 3H). LC/MS Calcd for [M+H]+ 345.1, found 345.4.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[C:6]=2[N:7]=1.CCO.[NH3:25]>>[N:18]1[C:19]2[C:14](=[CH:13][C:12]([CH2:11][N:8]3[C:6]4[N:7]=[C:2]([NH2:25])[N:3]=[CH:4][C:5]=4[N:10]=[N:9]3)=[CH:21][CH:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Clc1ncc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: N
Solvent: CCO
Product: Nc1ncc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 120 °C
Yield: 90 %

Procedure:
A suspension of 6-((5-chloro-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)methyl)quinoline (134 mg, 0.453 mmol) in NH3 saturated EtOH (3 mL) was heated at 120° C. in a sealed pressure tube for 2.5 h. After cooling to room temperature, EtOH (20 mL) was added to the reaction mixture. The precipitate was collected by filtration and dried to afford the desired product (112 mg, 90%). 1H NMR (300 MHz, DMSO-d6) δ 5.87 (s, 2H), 7.39 (br s, 2H), 7.51-8.04 (m, 4H), 8.34 (m, 1H), 8.89 (m, 1H), 9.21 (s, 1H); LCMS (APCI) m/z 278.2 (M+H+).
Reaction SMILES: [CH:1]1([P:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)([SH:9])=[S:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CC(C)=O>[CH:1]1([P:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)([S:9][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])=[S:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: S=P(S)(C1CCCCC1)C1CCCCC1
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCSP(=S)(C1CCCCC1)C1CCCCC1
Yield: 77.8 %

Procedure:
To 14.0 g. (0.05 m.) of the ammonium salt of dicyclohexylphosphinodithioic acid in 250 mls. of acetone was added 16.67 g. (0.05 m.) of n-octadecylbromide and the mixture was refluxed for 15 hours. The precipitate was then separated by filtration and the filtrate was cooled to precipitate a crystalline solid. The crystalline material was filtered off and recrystallized from acetone to obtain 20 g. (77.8% yield) of product which melted at 67°-69° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=1.O>CN(C)C=O>[CH3:37][C:32]1[C:31]([CH2:30][O:3][C:4]2[CH:28]=[CH:27][C:7]([CH2:8][N:9]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]3)=[CH:6][CH:5]=2)=[CH:36][CH:35]=[CH:34][N:33]=1
Reactant: Cc1ncccc1CCl
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccnc3C)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.4 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 3-Chloromethyl-2-methylpyridine (212 mg) was added to the mixture, which was stirred at room temperature for 15 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[4-(2-methyl-3-pyridylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (581 mg, yield: 85%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH3:14])[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:19]([OH:21])=[O:20]>CN(C=O)C.[Cu]>[CH3:26][O:25][C:24]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][C:16]=1[O:13][C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:14]
Reactant: COc1ccc(C(=O)O)cc1Br
Reactant: Cc1ccccc1O
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)O)cc1Oc1ccccc1C
Temperature: 165 °C
Reaction time: 2 h
Yield: 53.7 %

Procedure:
Potassium carbonate (1.20 g, 8.66 mmol), o-cresol (468 mg, 4.33 mmol), copper powder (28 mg, 0.43 mmol) and 3-bromo-4-methoxybenzoic acid (1.00 g, 4.33 mmol) were suspended in DMF (5 ml) and heated to 165° C. overnight. Potassium carbonate (1.20 g, 8.66 mmol) and o-cresol (468 mg, 4.33 mmol) were added once again and heating was continued for another 2 h. The crude mixture was partitioned between EA and 2 N hydrochloric acid, the aqueous phase extracted with EA, and the combined organic phases were dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) to yield 600 mg of the title compound.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:13][C:14](=[O:28])[CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:17].Cl>C1COCC1>[N:1]1([CH2:7][CH2:8][O:9][CH2:13][C:14](=[O:28])[CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCN1CCCCC1
Reactant: O=C(CCl)CC(=O)OCCCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(COCCN1CCCCC1)CC(=O)OCCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
2-(1-Piperidinyl)ethanol (15 mL, 113 mmol) in THF (50 mL) was added dropwise to a suspension of sodium hydride (7 g, 175 mmol) in THF (200 mL) at 0° C. The mixture was then stirred for 1 h at room temperature, cooled to 0° C., 3-phenylpropyl 4-chloroacetoacetate (22 mL, 103 mmol) in THF (50 mL) was added dropwise and the reaction mixture was then stirred for 18 h whilst warming to room temperature. 1N Hydrochloric acid was added until the mixture was acidic and the aqueous layer was then separated. The organic layer was extracted twice more with 1N hydrochloric acid. The combined acid layers were made basic to pH 8 with sodium hydrogen carbonate and extracted with chloroform. The combined extracts were washed with brine, dried and evaporated to give the title compound (24 g) as an oil. Electrospray MSm /z 348 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.CC1C=C(C)N2N=C(C=O)N=C2N=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][C:32]2([CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[O:37][C:36](=[O:38])[CH2:35][C:34](=[O:39])[CH2:33]2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].ClC1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=CC=1OC(C)C>>[Cl:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][C:32]2([CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[O:37][C:36](=[O:38])[CH:35]([CH2:6][C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[C:34](=[O:39])[CH2:33]2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: O=Cc1nccs1
Agent: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cc3nccs3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example B(31), where 1,3-thiazole-2-carbaldehyde was substituted in place of 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was substituted in place of 6-[2-(3-chloro-4isopropoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione in final Step of that example. 1H NMR (CDCl3): δ 1.44-1.70 (bm, 8H), 2.0 (m, 2H), 2.40 (m, 1H), 2.60 (m, 3H), 2.76 (d, J=17.90 Hz, 1H), 3.88 (s. 3H), 4.56 (d, J=15.07 Hz, 1H), 4.76 (d, J=15.07 Hz, 1H), 6.70 (d, J=2.07 Hz, 1H), 6.98, (d, J=2.07 Hz, 1H), 7.11 (s, 1H), 7.63, (d, J=3.96 Hz, 1H), 7.87 (d, J=3.96 Hz, 1H). Anal. Calcd. For C24H28O3SNCl: C, 64.63; H, 6.33; N, 3.14. Found: C, 64.55; H, 6.64; N, 3.10.
Reaction SMILES: [C:1]1([S:7]([NH:10][C@H:11]([CH2:15][C:16]#[CH:17])[C:12]([OH:14])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:37][O:38][CH:39]([O:42][CH3:43])[CH2:40][NH2:41].CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:37][O:38][CH:39]([O:42][CH3:43])[CH2:40][NH:41][C:12](=[O:14])[C@H:11]([NH:10][S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9])[CH2:15][C:16]#[CH:17]
Reactant: COC(CN)OC
Reactant: C#CC[C@@H](NS(=O)(=O)c1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CC[C@@H](NS(=O)(=O)c1ccccc1)C(=O)NCC(OC)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (R)-2-(benzenesulfonamido)pent-4-ynoic acid (11.66 g, 46.04 mmol), HOBt (7.46 g, 55.24 mmol), iPr2NEt (7.13 g, 55.24 mmol), (2,2-dimethoxyethyl)amine (5.81 g, 55.24 mmol), and EDCI (10.53 g, 55.24 mmol) in DMF (100 mL) was stirred for 24 h at RT. The reaction mixture was concentrated and taken up in H2O (100 mL). The aqueous layer was extracted with EtOAc (3×), dried over MgSO4, and concentrated to afford the title compound. 1H NMR (400 MHz, CDCl3): δ 2.43 (m, 2H), 2.71 (s, 3H), 2.85 (s, 1H), 2.89 (s, 3H), 2.96 (m, 2H), 3.98 (t, 7.1 Hz, 3H), 4.15 (t, 5.5 Hz, 1H), 7.55 (m, 3H), 7.80 (d, 8.0 Hz, 2H), 7.97 (s, 1H), 8.11 (t, 5.5 Hz, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([CH3:24])[C:17]=2[CH3:25])[NH:12]1)=[O:10])[CH3:7].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:6]([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([CH3:24])[C:17]=2[CH3:25])[N:12]1[C:3](=[O:4])[CH2:2][Cl:1])=[O:10])[CH3:7]
Reactant: CCOC(=O)[C@H]1CC[C@@H](c2ccc(OC)c(C)c2C)N1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@@H](c2ccc(OC)c(C)c2C)N1C(=O)CCl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Chloroacetyl chloride (1.7 mL, 21.5 mmol) To a solution of cis-5-(4-methoxy-2,3-dimethylphenyl)pyrrolidine-2-carboxylic acid ethyl ester (16.56 mmol) and Et3N (3.5 mL, 24.8 mmol) in CH2Cl2 (80 mL) at 0° C. The reaction mixture is stirred at 0° C. for 15 min and then at room temperature for 45 min. The mixture then poured into half-saturated aq. NaHCO3 (100 mL) and extracted with EtOAc. The extract is further washed with water (1×50 mL) and brine (1×50 mL). The aqueous washes are reextracted once with EtOAc, and the combined extracts are dried over Na2SO4, and concentrated. The crude material is used in the next step without further purification. 1H NMR (CDCl3, 400 MHz): 7.90 (d, J=8.6 Hz, 1H), 6.78 (d, J=8.6 Hz, 1H), 5.30 (dd, J=7.6, 3.6 Hz, 1H), 4.53 (t, J=8.0 Hz, 1H), 4.37-4.21 (m, 2H), 3.81 (s, 3H), 3.77, 3.65 (ABq, J=13.2 Hz, 2H), 2.50-2.41 (m, 1H), 2.26 (s, 3H), 2.24-2.14 (m, 1H), 2.19 (s, 3H), 2.09-2.00 (m, 1H), 1.96-1.89 (m, 1H), 1.35 (t, J=7.2 Hz, 3H). Electrospray MS: m/z 354 [M+1].
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[C:10]([CH:21]=O)=[C:9]1[CH:23]([CH3:25])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([F:35])[CH:34]=1)[CH2:30][NH2:31].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[C:10]([CH2:21][NH:31][CH2:30][C:29]2[CH:28]=[C:27]([F:26])[CH:34]=[C:33]([F:35])[CH:32]=2)=[C:9]1[CH:23]([CH3:25])[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1cc(F)cc(F)c1
Reactant: COCOc1ccc2c(c1)c(C=O)c(C(C)C)n2Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COCOc1ccc2c(c1)c(CNCc1cc(F)cc(F)c1)c(C(C)C)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-benzyl-2-isopropyl-5-(methoxymethoxy)-1H-indole-3-carboxaldehyde (Compound 4, 103 mg, 0.31 mmol) in methanol (5.0 ml) was added 3,5-difluorobenzylamine (49 μl, 0.40 mmol), and acetic acid (2 drops). After stirring at room temperature for 1 h, sodium cyanoborohydride (29 mg, 0.47 mmol) was added and the reaction was stirred for 5 h. More 3,5-difluorobenzylamine (50 μl, 0.40 mmol) was added, and the reaction was stirred for 64 h. The solvent was removed and the crude reaction mixture was purified by flash chromatography on silica gel eluting with 10-50% EtOAc-hexanes to yield 1-(1-benzyl-2-isopropyl-5-(methoxymethoxy)-1H-indol-3-yl)-N-(3,5-difluorobenzyl)methanamine (Compound 5) as a light greenish yellow oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([OH:7])[CH:3]=1.[CH:8]#[C:9][C:10](=[O:12])[CH3:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:12]=[C:10]([CH:9]=[CH:8][N:5]1[C:4](=[O:7])[CH:3]=[C:2]([Cl:1])[S:6]1)[CH3:11]
Reactant: Oc1cc(Cl)sn1
Reactant: C#CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=Cn1sc(Cl)cc1=O

Procedure:
A stirred solution of 5-chloro-3-hydroxyisothiazole (1.5 g, 0.011 mole), 1-butyn-3-one (3.5 g, 0.05 mole) and p-toluenesulfonic acid (0.02 g) in 25 ml of toluene was heated at 80° C. for 24 hours. Upon cooling, the dark brown reaction mixture was concentrated and the residual oil was column chromatographed on silica gel, using diethyl ether/hexane as eluant. Compound 11 was obtained as a yellowish solid; 1.8 g; mp 137°-139° C.; IR (KBr) 1675, 1620 cm-1 ; NMR (CDCl3) δ8.2 (d,1H,J=13.9 Hz); 6.35 (s,1H); 5.85 (d,1H,J=13.9 Hz); 2.35 (s,3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([CH2:48][CH3:49])=[CH:45][C:46]=2[CH3:47])[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([CH2:48][CH3:49])=[CH:45][C:46]=2[CH3:47])[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: CCc1cc(C)c(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: CCc1cc(C)c(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(6-ethyl-4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K35) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous red substance (229 mg, 48%).
Reaction SMILES: [NH2:1][O:2][CH3:3].Cl.CC(O[Na])=O.[CH3:10][NH:11][C:12]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=2[Cl:25])[C:17](=O)[CH2:16][CH2:15][CH2:14][CH2:13]1>CO.O.O>[CH3:3][O:2][N:1]=[C:13]1[CH2:14][CH2:15][CH2:16][CH2:17][C:12]1([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=1[Cl:25])[NH:11][CH3:10]
Reactant: CNC1(c2ccccc2Cl)CCCCC1=O
Reactant: CON
Agent: CC(=O)O[Na]
Agent: Cl
Solvent: O
Solvent: CO
Product: CNC1(c2ccccc2Cl)CCCCC1=NOC
Temperature: 25 °C

Procedure:
To as solution of NH2OMe. HCl and CH3COONa. H2O in MeOH:H2O (7:3) stirred at room temperature for 15 minutes, was added ketamine and the resulting solution was stirred at reflux for 16 hrs before cooling to room temperature. The reaction mixture was filtered and the filtrate was partitioned between CH2Cl2 and sat. NaHCO3 solution. The filtrate was extracted with CH2Cl2 (2×30 mL) and the combined organic layer was washed with brine solution. The organic layer was dried over anhydrous. Na2SO4 and concentrated under reduced pressure. The crude reaction mixture received was purified over silica gel column chromatography by eluting with initially CH2Cl2 and later with (1:9) MeOH:CH2Cl2 to receive methoxime 3 as pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.9-8.0 (m, 1H), 7.2-7.4 (m, 3H), 3.91-4.0 (m, 3H), 3.3 (td, J=4.10, 13.96 Hz, 1H), 3.2 (td, J=4.49, 13.73 Hz, 1H), 2.4-2.5 (m, 3H), 2.1-2.3 (m, 1H), 1.6-1.8 (m, 3H), 1.4-1.5 (m, 1H), 1.2-1.4 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 156.3, 135.5, 132.4, 132.2, 131.9, 131.0, 128.3, 67.4, 62.7, 39.4, 28.8, 26.1, 24.7, 22.0.