Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]([CH3:21])[CH2:13][CH2:12][NH:11][CH2:10][C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>O1CCOCC1>[CH2:1]([N:8]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]([CH3:21])[CH2:13][CH2:12][N:11]([C:31](=[O:32])[NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([CH3:23])[CH:25]=2)[CH2:10][C:9]1=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CCNCC(=O)N(Cc2ccccc2)c2ccccc21
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1COCCO1
Product: Cc1cccc(NC(=O)N2CCC(C)c3ccccc3N(Cc3ccccc3)C(=O)C2)c1

Procedure:
A solution of 1-benzyl-7-methyl-2-oxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine (96 mg, 0.33 mmol) and 3-methylphenylisocyanate (47 μl, 0.36 mmol) was stirred in dioxan (2 ml) at room temperature for 2 hours. Evaporation of the solvent and chromatography on silica gel with ethyl acetate-hexane (1:2) as eluant gave the product. (102 mg, 72%).
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].C[O-].[Na+].[C:10]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O)([OH:12])=[O:11].CS(O)(=O)=O>CO>[CH3:3][O:2][P:1]([CH:15]1[C:14]2[C:13](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10](=[O:12])[O:11]1)(=[O:6])[O:4][CH3:5]
Reactant: O=Cc1ccccc1C(=O)O
Reactant: COP([O-])OC
Agent: CS(=O)(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COP(=O)(OC)C1OC(=O)c2ccccc21
Temperature: 20 °C

Procedure:
Dimethyl phosphite (22.0 g, 0.2 mol) was added drop-wise to a solution of sodium methoxide (43.0 g) in methanol (100 ml) at 0° C. 2-Carboxybenzaldehyde (21.0 g, 0.1 mol) was then added portion-wise to the reaction mixture as a slurry in methanol (40 ml), with the temperature kept below 5° C. The resulting pale yellow solution was warmed to 20° C. over 1 hour. Methanesulphonic acid (21.2 g, 0.22 mol) was added to the reaction drop-wise and the resulting white suspension was evaporated in vacuo. The white residue was quenched with water and extracted into chloroform (3×100 ml). The combined organic extracts were washed with water (2×100 ml), dried over MgSO4, and evaporated in vacuo to yield (3-oxo-1,3-dihydro-isobenzofuran-1-yl)phosphonic acid dimethyl ester as a white solid (32.0 g, 95%, 95% purity). This was then used without further purification in the next stage.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.[C:20]1([C:30](Cl)=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>ClCCl.N1C=CC=CC=1>[CH3:1][C:2]1[C:7]([NH:8][C:30]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[O:31])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1
Reactant: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N
Reactant: O=C(Cl)c1cccc2ccccc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1NC(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.1 %

Procedure:
To a solution of 2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamine (0.025 g, 0.096 mmol) in dichloromethane (3 mL) and pyridine (0.5 mL) was added 1-naphthoyl chloride (0.055 g, 0.288 mmol). The reaction mixture was allowed to stir for 16 hours at room temperature. The reaction mixtures were filtered through a 2.0 g Varian Bond Elut SCX (stong cation-exchange) cartridge eluting with 20 mL of methanol, followed by 7N ammonia in methanol (20 mL), and concentrated under vacuum. The crude product was purified over a silica gel column eluting with methanol in dichloromethane (0-10%) over 30 minutes to obtain 0.0247 g (62%) of the compound.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14](Br)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2.[N+:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:18]([O-:20])=[O:19])[CH:26]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)o1
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: COCCOC
Solvent: O
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(-c2cccc([N+](=O)[O-])c2)o1

Procedure:
Prepared by a method analogous to that described in Example 1 from (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and 3-nitrophenylboronic acid, using tetrakis(triphenylphosphine)palladium(0) and sodium carbonate in a mixture of ethylene glycol dimethyl ether and water. The compound was purified by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The product-containing fractions were then evaporated and the residue dissolved in methanol. Excess hydrogen chloride solution (1M in diethyl ether) was added and the solution was evaporated. Recrystallisation from methanol/diethyl ether gave the hydrochloride salt of the title compound as a yellow solid; MS (ES+) 342 (MH+).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:17]=3)[NH:12][N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.[CH3:38][NH:39][CH3:40]>>[C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][N:39]([CH3:40])[CH3:38])[CH:17]=3)[NH:12][N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4ccccc4)c3c2)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc2[nH]nc(S(=O)(=O)c3ccccc3)c2c1
Yield: 67.1 %

Procedure:
A solution of toluene-4-sulfonic acid 2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl ester (0.341 g, 0.722 mmol) in 2.0 N dimethylamine in THF (9 mL, 18 mmol) of was stirred at 70° C. for 6 hours in a sealed tube. After cooling somewhat, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with water and brine. It was dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was partitioned in ethyl acetate/aqueous potassium carbonate. The organic phase was washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. [2-(3-Benzenesulfonyl-1H-indazol-5-yloxy)-ethyl]-dimethyl-amine as a light yellow-brown solid (0.167 g, 67.1%) resulted. The compound was dissolved in methanol, and ethereal hydrochloride was added. After concentrating and drying in vacuo for 12 hours at 70° C., the hydrochloride as a light orange foam (94.0 mg) was obtained; Mass Spectrum (+EI, [M+H]+) m/z 346. 1HNMR (500 MHz, DMSO-d6): δ14.22 (s, 1H), 10.00 (br, 1H), 7.97-7.99 (m, 2H), 7.56-7.68 (m, 4H), 7.42 (d, 1H, J=2.20 Hz), 7.17-7.20 (m, 1H), 4.39-4.42 (m, 2H), 3.52-3.53 (m, 2H), 2.84 ppm (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:15]([OH:21])([CH3:20])[CH2:16][C:17](=[NH:19])[NH2:18].C(=O)(O)[O-].[K+].Br[CH2:28][C:29](=O)[C:30]([CH3:33])([CH3:32])[CH3:31]>O1CCCC1.O>[C:30]([C:29]1[N:19]=[C:17]([CH2:16][C:15]([C:3]2[CH:4]=[CH:5][C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]=3)=[CH:7][C:2]=2[F:1])([OH:21])[CH3:20])[NH:18][CH:28]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CC(O)(CC(=N)N)c1ccc(-c2ccc(F)cn2)cc1F
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1c[nH]c(CC(C)(O)c2ccc(-c3ccc(F)cn3)cc2F)n1

Procedure:
A solution of the di(trifluoroacetate) salt of (±)-3-[2-fluoro-4-(5-fluoropyridin-2-yl)phenyl]-3-hydroxybutanimidamide (50 mg, 0.10 mmol), potassium bicarbonate (19 mg, 0.19 mmol) and 1-bromo-3,3-dimethylbutan-2-one (52 mg, 0.29 mmol) in tetrahydrofuran (1 mL) and water (0.25 mL) were stirred at ambient temperature overnight. Volatiles were removed in vacuo and the residue was purified by HPLC (Gilson; KR100-5C18 100×21.2 mm column; 10-100% MeCN/H2O) over 12 min to afford the title compound as a white solid. 1H NMR (500 MHz, CD3OD) δ 8.51 (d, J=2.8 Hz, 1H), 7.90 (dd, J=4.3, 8.8 Hz, 1H), 7.76-7.58 (m, 4H), 6.99 (s, 1H), 3.45 (AB, J=14.9 Hz, 2H), 3.30 (bs, 1H), 1.732 (s, 3H), 1.23 (s, 9H).
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C([N:12](CC)CC)C.S(O)(O)(=O)=O.NO>O>[NH2:9][C:8]1[CH:7]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[O:6][N:12]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)C(=O)CC#N
Agent: NO
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(C)c1cc(N)no1
Yield: 81.7 %

Procedure:
A suspension of pivaloylacetonitrile (12.52 g) and triethylamine (11.27 g) in water (200 ml) is stirred and mixed with hydroxylamine sulfate (9.03 g). pH 8.22. The reaction mixture is treated as in Example 2 to give 3-amino-5-t-butylisoxazole (11.45 g; yield, 81.7%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)[N:6]=1.[C:27]([Cl:31])(=[O:30])[CH2:28][CH3:29].[ClH:32]>O1CCCC1.N1C=CC=CC=1>[ClH:31].[ClH:32].[CH:14]([N:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:27](=[O:30])[CH2:28][CH3:29])[S:3][CH:4]=2)[CH2:9][CH2:10]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCC(=O)Cl
Reactant: Nc1nc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cs1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCC(=O)Nc1nc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cs1

Procedure:
To a solution of 2-amino-4-(4-benzhydrylpiperazin-1-ylmethyl)thiazole (1.1 g) in tetrahydrofuran (10 ml) and pyridine (5 ml) was added dropwise propionyl chloride (0.92 ml) under ice-cooling with stirring, and the stirring was continued at the same temperature for an hour. After concentration of the reaction mixture the residue was extracted with ethyl acetate, followed by washing with an aqueous solution of sodium bicarbonate and water and drying over anhydrous magnesium sulfate. Removal of the solvent gave an oil, which was transformed into its hydrochloride in a conventional manner, followed by recrystallization from a mixture of methanol and diethyl ether to obtain white crystals (0.8 g) of 4-(4-benzhydrylpiperazin-1-ylmethyl)-2-propionamidothiazole dihydrochloride, mp 181°-184° C. (dec.).
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.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:25]3[CH2:26][CH2:27][CH:22]([C:19]4[CH:18]=[CH:17][C:16]([CH3:15])=[CH:21][CH:20]=4)[CH2:23][CH2:24]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: Cc1ccc(C2CCNCC2)cc1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(C2CCN(C[C@H](O)COc3cccc4[nH]ccc34)CC2)cc1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(4-methylphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 78% overall yield. FDMS m/e=364 (M+ of free base). α[D]589 =-11.77 (c=0.34, methanol).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][CH2:6][C:5]([CH:8]([CH3:11])[CH2:9][OH:10])=[C:4]2[C:12]([CH3:18])([CH3:17])[CH:13]3[CH2:16][C:3]12[CH2:15][CH2:14]3.[CH2:20]1COCC1.[H-].[Na+].CI>CN(C=O)C>[CH3:20][O:10][CH2:9][CH:8]([C:5]1[CH2:6][CH2:7][C:2]([CH3:1])([CH3:19])[C:3]23[CH2:16][CH:13]([CH2:14][CH2:15]2)[C:12]([CH3:18])([CH3:17])[C:4]=13)[CH3:11]
Reactant: C1CCOC1
Reactant: CC(CO)C1=C2C(C)(C)C3CCC2(C3)C(C)(C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COCC(C)C1=C2C(C)(C)C3CCC2(C3)C(C)(C)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A solution of 3b (1.0 g, 3.8×10−3 mol) in DMF (5 ml) was added to a THF (8 ml) suspension of sodium hydride (0.27 g of 50% dispersion in mineral oil, washed twice with hexane, 5.6×10−3 mol). After 3 h stirring at r. t., methyl iodide (1.6 g, 0.011 mol) was added under cooling and the reaction mixture was stirred at r. t. for additional 4 h, poured into ice-cold 2M HCl (100 ml) and extracted with MTBE (2×100 ml). The organic phase was washed with brine (2×50 ml), dried (MgSO4), concentrated in vacuo and purified by flash chromatography (MTBE/hexane 1:20) to give 5-(1-methoxyprop-2-yl)-2,2,7,7-tetramethyltricyclo[6.2.1.01,6]undec-5-ene (8b, 0.73 g, 69% yield, colourless oil).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:27]([O-])([N+]([O-])=O)=[O:28]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:27]=[O:28])[C:5]([N:7]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CC(C)CN(C(=O)NCCCl)C1OC[C@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)CN(C(=O)N(CCCl)N=O)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 67.9 %

Procedure:
3.1 g of 1-(2-chloroethyl)-3-isobutyl-3-L-arabinopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.3 g of 1-(2-chloroethyl)-1-nitroso-3-isobutyl-3-L-arabinopyranosylurea are thereby obtained as pale yellow caramel.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12].C(Br)C#C>CN(C)C=O>[CH2:3]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])[C:2]#[CH:1]
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1cccc(O)c1
Agent: C#CCBr
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cccc(C=O)c1
Temperature: 110 °C

Procedure:
Potassium tert-butoxide (6.16 g, 0.055 mole), 3-hydroxybenzaldehyde (6.1 g, 0.05 mole), and dry dimethylformamide (DMF, over Na2SO4 ; 30 mL) were stirred briefly at 25° C., and then propargyl bromide (6.6 g, 0.055 mole) was added in 30 mL of dry DMF according to the method of F. Albericio et al., "Preparation and Application of the5-(4-(9-Fluorenylmethyloxycarbonyl)-Aminomethyl-3,5-Dimethoxyphenoxy)-ValericAcidHandle for the Solid Phase Synthesis of C-Terminal Peptide Amides under Mild Conditions," J. Org. Chem. vol. 55, pp. 3730-3743 (1990). The reaction mixture was heated to 110° C. for 8 h, and the solvent was then removed under high vacuum. Ethyl acetate was added, inorganic salts were removed by filtration, and the organic extract was washed sequentially with water, 2 M NaOH, and saturated aqueous NaCl. The organic phase was dried overnight (MgSO4), and the solvent was removed to yield a yellow liquid that was purified by silica gel chromatography using hexane-ethyl acetate (8.5:1.5) as the eluting solvent. Yield: 6.5 g (81%). 1H NMR (CDCl3): d 2.54 (t, 1H, CH), 4.73 (t, 2H,--OCH2 --), 7.2-7.48 (m, 4H, Aromatics), 9.96 (s, 1H, CHO). GC-MS (m/z): M+ =160.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[N:7][CH:8]=1.[S:10]([CH:13]([CH3:17])[C:14](=O)[CH3:15])[C:11]#[N:12]>>[ClH:9].[Cl:9][C:6]1[N:7]=[CH:8][C:3]([N:2]2[C:14]([CH3:15])=[C:13]([CH3:17])[S:10][C:11]2=[NH:12])=[CH:4][CH:5]=1
Reactant: CC(=O)C(C)SC#N
Reactant: Nc1ccc(Cl)nc1
Agent: Cl
Product: Cc1sc(=N)n(-c2ccc(Cl)nc2)c1C

Procedure:
The title compound was prepared from 5-amino-2-chloropyridine hydrochloride and 3-thiocyano-2-butanone as described for Example 160A.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH2:10](Br)[CH:11]=[CH2:12].[Cl:14][C:15]1[CH:16]=[C:17]2[NH:24][C:23]([S:25]([CH3:28])(=[O:27])=[O:26])=[N:22][C:18]2=[N:19][C:20]=1[I:21]>C1COCC1>[CH2:10]([N:24]1[C:17]2[C:18](=[N:19][C:20]([I:21])=[C:15]([Cl:14])[CH:16]=2)[N:22]=[C:23]1[S:25]([CH3:28])(=[O:27])=[O:26])[CH:11]=[CH2:12]
Reactant: CS(=O)(=O)c1nc2nc(I)c(Cl)cc2[nH]1
Reactant: C=CCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CCn1c(S(C)(=O)=O)nc2nc(I)c(Cl)cc21
Temperature: 60 °C

Procedure:
N,N-diisopropylethylamine (0.69 ml, 3.95 mmol) and allyl bromide (0.32 ml, 3.70 mmol) were added to a stirred suspension of 6-chloro-5-iodo-2-methylsulfonyl-1H-imidazo[4,5-b]pyridine (1.0824 g, 3.03 mmol) in THF (12.0 ml). The reaction mixture was heated to 60° C. for 18 h, then cooled to room temperature. The reaction mixture was partitioned between EtOAc (50 ml) and brine (50 ml). The organic layer was washed with brine (1×50 ml). The combined aqueous layers were extracted with EtOAc (1×50 ml). The organic layers were combined, dried over Na2SO4, filtered, and evaporated under reduced pressure to give the title compound as a yellow foam. This material was a mixture of the allyl regioisomers and was used without further purification. LC-MS: calculated for C10H9ClIN3O2S 396.91 observed m/e: 397.89 (M+H)+ (Rt 1.12 and 1.17/2 min).
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:11](=[O:13])[CH2:10][CH2:9][CH2:8][C:7]=2[O:6][C:5](=O)[CH:4]=1)[CH3:2].[NH3:15]>>[CH2:1]([C:3]1[C:12]2[C:11](=[O:13])[CH2:10][CH2:9][CH2:8][C:7]=2[NH:15][C:5](=[O:6])[CH:4]=1)[CH3:2]
Reactant: CCc1cc(=O)oc2c1C(=O)CCC2
Reactant: N
Product: CCc1cc(=O)[nH]c2c1C(=O)CCC2

Procedure:
Prepared from 4-ethyl-5,6,7,8-tetrahydro-cumarin- 5-one (prepared from ethyl 3-oxo-n-valeriate and cyclohexan-1,3dione) and methanolic ammonia in an autoclave for 1 hour at 140° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:6][CH:5]=1.Cl.[CH3:20][NH:21][O:22][CH3:23].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH3:23][O:22][N:21]([CH3:20])[C:14](=[O:16])[CH2:13][CH2:12][C:11]#[C:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:18])[F:17])=[CH:9][CH:8]=1
Reactant: O=C(O)CCC#Cc1ccc(OC(F)(F)F)cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)CCC#Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A solution of 1.00 g (3.87 mmol) of 5-(4-trifluoromethoxy-phenyl)-pent-4-ynoic acid (example 29D]) in 50 ml CH2Cl2 was treated with 0.45 g (4.65 mmol) N,O-dimethylhydroxylamine hydrochloride, 0.55 ml (5.03 mmol) N-methylmorpholine and at 0° C. with 0.97 g (5.03 mmol) N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI). The reaction was naturally warmed to ambient temperature over night and partitioned between aqueous 10% KHSO4/ether (three times). The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl and dried (Na2SO4) to give 1.165 g of the title compound as brown oil.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([CH:25]([CH3:27])[CH3:26])=[N:7][C:8]([CH:22]([CH3:24])[CH3:23])=[C:9](CCOC)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:4].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1[CH2:38][O:37][CH2:36][CH2:35]1>>[CH:25]([C:6]1[C:5]([CH2:3][OH:4])=[C:10]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[C:9]([CH:36]([O:37][CH3:38])[CH3:35])=[C:8]([CH:22]([CH3:23])[CH3:24])[N:7]=1)([CH3:27])[CH3:26]
Reactant: COCCc1c(C(C)C)nc(C(C)C)c(C(=O)OC)c1-c1ccc(F)cc1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COC(C)c1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
The intermediate obtained in Step A (359 mg, 0.961 mmol) was dissolved in 40 mL of dry THF, for a dropwise addition of a solution of LAH (1M/THF, 1.92 mL, 2 eq.). The reaction mixture was stirred at reflux for 24 hours then cooled to room temperature and quenched with water (80 μL), 20% NaOH (80 μL), and water (160 μL). After filtration, the solvent was evaporated to afford a residue which was filtered through to a pad of silica (10% ethyl acetate/hexane) to afford the title compound as a white solid (281 mg, 0.72 mmol, 85%). 1H NMR (300 MHz, CDCl3): δ 7.13 (m, 4 H), 4.32 (dq, J=5.2 J=11.4 Hz, 1 H), 4.11 (q, J=6.3 Hz, 1 H), 3.77 (septet, J=6.6 Hz, 1 H), 3.42 (septet, J=6.6 Hz, 1 H), 3.10 (s, 3 H), 1.29 (m, 16 H). FAB-MS: calcd for (C21H28FNO2) 345, found 346 (M+H). Anal. Calcd for C21H28NO2F: C, 76.84; H, 8.69; N, 3.90. Found: C, 76.67; H, 8.76; N, 3.77. mp 151-153° C. Rf=0.4 (20% ethyl acetate/hexane).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl.N1C=CC=CC=1>[N:22]1([CH2:21][C@@H:17]2[CH2:18][CH2:19][CH2:20][N:16]2[C:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:28]([CH3:27])(=[O:30])=[O:29])=[N:7][CH:6]=3)=[CH:13][CH:12]=2)=[O:15])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Procedure LL: To a stirring solution of [4-(6-amino-pyridin-3-yl)-phenyl]-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (1.0 mmol) in 3:1 dichloromethane/pyridine (0.10M), add methanesulfonyl chloride (1.3 mmol) and stir at room temperature for 48 hours. After this time, wash the reaction with 1N hydrochloric acid while extracting with dichloromethane. Using 2N sodium hydroxide, make the aqueous phase basic and extract with 10% isopropanol/dichloromethane. The product remains in the aqueous layer during the acid/base workup. Concentrate the aqueous layer in vacuo and purify the title compound via radial chromatography eluting with 2M ammonia and dichloromethane. MS (m/e): 429.2 (M+1)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.[H][H]>CCO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[O:19])[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: CN1CCN(C(=O)Cc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCN(C(=O)Cc2ccc(N)cc2)CC1

Procedure:
A solution of 1-methyl-4-[(4-nitrophenyl)acetyl]piperazine (1.5 g, 5.70 mmol) in EtOH (30 mL) was reduced over palladium/charcoal (10% wt, 50% wet, 150 mg) with hydrogen under atmospheric pressure and RT for 18 h. The catalyst was separated by filtration through Celite® and the solvent evaporated to the title compound as a brown oil, 1.12 g.