Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[CH3:46][O:47][C:48](=[O:56])[C:49]1[CH:54]=[CH:53][C:52]([NH2:55])=[N:51][CH:50]=1.N1C=CC=CC=1>C(Cl)Cl.O>[CH3:46][O:47][C:48](=[O:56])[C:49]1[CH:54]=[CH:53][C:52]([NH:55][C:35](=[O:37])[C@@H:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[CH2:33][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)=[N:51][CH:50]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(Cl)c(Cl)c2)nc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 83.4 %

Procedure:
A solution of triphenylphosphine (1.23 g, 4.69 mmol) in methylene chloride (15 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (947 mg, 5.32 mmol). The resulting brown-purple solution was stirred at 0° C. for 5 min and then treated with 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionic acid (prepared as in Example 54A, 900 mg, 3.13 mmol). The reaction mixture was stirred at 0° C. and then allowed to warm to 25° C. over 45 min. The reaction mixture was then treated with 6-aminonicotinic acid methyl ester (620 mg, 4.07 mmol) and pyridine (0.38 mL, 4.7 mmol), and the reaction mixture was allowed to stir at 25° C. for 20 h. The resulting reaction mixture was diluted with water (15 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 9/1 hexanes/ethyl acetate) afforded 6-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinic acid methyl ester (1.10 g, 84%) as a white foam: [α]23589=−68.0° (c=0.128, chloroform); FAB-HRMS m/e calcd for C21H22Cl2N2O3 (M+H)+ 421.1086, found 421.1079.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.[Br:27][CH2:28][C:29](Br)=[O:30].O>C(Cl)Cl>[Br:27][CH2:28][C:29]([N:9]1[CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)=[O:30]
Reactant: O=C(Br)CBr
Reactant: c1ccc(CC2Cc3ccccc3CN2)cc1
Solvent: CN(C)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)N1Cc2ccccc2CC1Cc1ccccc1
Yield: 96.4 %

Procedure:
89 mg of 3-benzyl-1,2,3,4-tetrahydroisoquinoline obtained in Example 1-d) was dissolved in 2 mL of methylene chloride, and 53 mg of N,N-dimethylaniline, 73 mg of bromoacetylbromide were added thereto, followed by stirring under ice-cooling for 30 minutes. After completion of the reaction, water was added thereto, followed by extraction with chloroform. The chloroform layer was washed with brine and then dried over anhydrous sodium sulfate, and the solvent was removed by evaporation, followed by purification using PLC (hexane:ethyl acetate=1:1) to obtain 120 mg (yield 88%) of 2-(2-bromoacetyl)-3-benzyl-1,2,3,4-tetrahydroisoquinoline as a yellow oily substance. 34 mg of this product was dissolved in 10 mg of aniline, 15 mg of potassium carbonate, and 1 mL of acetonitrile, followed by stirring at 60° C. for 4 hours. After completion of the reaction, the reaction liquid was filtered with ethyl acetate, concentrated under reduced pressure, and purified using PTLC (chloroform:methanol=10:1) to obtain 28 mg (yield 72%) of a title compound as a yellow oily substance.
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.Br[C:13]1[CH:14]=[CH:15][C:16]2[N:22]([CH3:23])[CH2:21][CH2:20][C:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:18][C:17]=2[CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:23][N:22]1[C:16]2[CH:15]=[CH:14][C:13]([C:3]3[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=3)=[CH:31][C:17]=2[CH:18]=[C:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21]1
Reactant: Cc1ccc(OB([O-])[O-])cc1
Reactant: CN1CCC(C(=O)OC(C)(C)C)=Cc2cc(Br)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)OC(C)(C)C)CCN3C)cc1
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
In water:ethanol:toluene (1:1:10, 18.0 ml) were dissolved 4-methylphenyl borate (276 mg) and tert-butyl 7-bromo-1-methyl-2,3-dihydro-1-benzoazepine-4-carboxylate (571 mg), and to the mixture was added potassium carbonate (560 mg). The mixture was stirred under argon atmosphere for 30 minutes, and to the mixture was added tetrakistriphenylphosphine palladium (78 mg). Under argon atmosphere, the mixture was refluxed for 19.5 hours. The mixture was diluted with ethyl acetate (300 ml) and washed with water (100 ml) and saturated brine (100 ml). The organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (120 g, hexane→hexane:ethyl acetate=10:1) to give tert-butyl 1-methyl-7-(4-methylphenyl)-2,3-dihydro-1-benzoazepine-4-carboxylate (422 mg, 72%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[CH2:42][CH2:43][C:44]#[N:45])=[CH:32][C:31]=1[CH3:46])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[Cl:29])=[CH:13][CH:12]=1)(C)(C)C.I[Si](C)(C)C>C(#N)C.C([O-])(O)=O.[Na+]>[NH2:7][CH2:8][CH:9]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[CH2:42][CH2:43][C:44]#[N:45])=[CH:32][C:31]=1[CH3:46])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[Cl:29])=[CH:15][CH:16]=1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(-c4ccccc4CCC#N)cc3C)cc2)c(Cl)c1
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(CN)c3ccc(-c4ccccc4CCC#N)cc3C)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl(2-[2′42-cyanoethyl)-3-methylbiphenyl-4-yl]-3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}propyl)carbamate from step 1 (1 eq.) in acetonitrile (0.05M) at room temperature was added iodo trimethylsilane (2 eq.). The reaction mixture was stirred for 10 min at room temperature poured in saturated aqueous NaHCO3 and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered and concentrated. Purification by column chromatography on silica gel, eluting with CH2Cl2/MeOH(NH3 2M) 4%, afforded the title compound as a foam. 1H NMR (500 MHz, CDCl3): δ 7.38-7.25 (m, 5H), 7.16 (dd, 1H), 7.13 (s, 2H), 7.03 (d, 1H), 6.98 (d, 2H), 6.84 (d, 2H), 4.38-4.32 (m, 4H), 3.34-3.30 (m, 1H), 3.10-2.94 (m, 3H), 3.01 (t, 2H), 2.81 (dd, 1H), 2.37 (t, 2H), 2.30 (s, 3H), 2.19 (s, 3H). LRMS ESI [M+H]; 572.9
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:7](Br)[N:6]=1)=[O:4].[CH:18]1([CH2:21][OH:22])[CH2:20][CH2:19]1.[H-].[Na+].[OH-].[K+]>CN(C=O)C.C(O)=O>[CH:18]1([CH2:21][O:22][C:7]2[N:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:10]=[N:9][C:8]=2[N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:20][CH2:19]1
Reactant: OCC1CC1
Reactant: COC(=O)c1cnc(N2CCCCC2)c(Br)n1
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=CO
Product: O=C(O)c1cnc(N2CCCCC2)c(OCC2CC2)n1
Temperature: 45 °C
Yield: 9.9 %

Procedure:
A mixture of 0.12 g (0.4 mmol) 6-bromo-5-piperidin-1-yl-pyrazine-2-carboxylic acid methyl ester, 0.029 g (0.4 mmol) cyclopropyl methanol and 0.018 g (0.41 mmol) NaH (55% suspension in oil) in 2 mL DMF was shaken for an extended period of time. Afterwards, 0.1 mL KOH (5N aq.) was added and the mixture was heated to 45° C. for 1 h. After addition of formic acid the mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The combined product fractions were evaporated to yield 11 mg (10%) of the title compound. m/z (ES+): 278.1 (M+H).
Reaction SMILES: C[O-].[Na+].[CH2:4]([O:6][CH:7]([O:10][CH2:11][CH3:12])[C:8]#[N:9])[CH3:5].Cl.[CH3:14][NH:15][N:16]=[C:17](N)[CH2:18][CH3:19].C([O-])(=O)C.[Na+]>CO>[CH2:4]([O:6][CH:7]([O:10][CH2:11][CH3:12])[C:8]1[N:15]([CH3:14])[N:16]=[C:17]([CH2:18][CH3:19])[N:9]=1)[CH3:5]
Reactant: CCOC(C#N)OCC
Reactant: CCC(N)=NNC
Agent: CC(=O)[O-]
Agent: C[O-]
Agent: Cl
Solvent: CO
Product: CCOC(OCC)c1nc(CC)nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.4 %

Procedure:
A solution of sodium methoxide (3.30 g, 0.0611 mol) in methanol (100 mL) was added at room temperature to a solution of diethoxyacetonitrile (78.9 g, 0.611 mol) in methanol (600 mL). The resulting mixture was stirred at room temperature overnight, and a solution of crude N′-methylpropanehydrazonamide hydrochloride from Step 2 (84.1 g, ˜0.60 mol) in methanol (200 mL) was added. Anhydrous sodium acetate (50.0 g, 0.61 mol) was added, and the resulting mixture was refluxed under an atmosphere of Ar for 20 h. Then methanol was evaporated, and the dark oily residue was extracted with ether (3×250 mL). The ether solution was passed through a layer of silica gel, and the filtrate was evaporated. The residue was distilled in vacuo to give 35.0 g (27%) of the title product (bp 68° C. at 0.1 mm Hg). Note: There is a higher-boiling second fraction (15 g; bp 120° C. at 0.1 mm Hg) that is a triazole impurity containing two acetal groups.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([CH3:17])[C:6]([CH3:16])=[C:7]([O:11]CC(C)=C)[CH:8]=2)[N:3]1[CH:18]=[O:19]>C(N(CC)C1C=CC=CC=1)C.C(OCC)C>[OH:11][C:7]1[C:8]([CH2:6][C:5]([CH3:17])=[CH2:4])=[C:9]2[C:4](=[C:5]([CH3:17])[C:6]=1[CH3:16])[N:3]([CH:18]=[O:19])[CH:2]([CH3:1])[CH2:10]2
Reactant: C=C(C)COc1cc2c(c(C)c1C)N(C=O)C(C)C2
Solvent: CCN(CC)c1ccccc1
Solvent: CCOCC
Product: C=C(C)Cc1c(O)c(C)c(C)c2c1CC(C)N2C=O
Yield: 137.5 %

Procedure:
A solution of 2,3-dihydro-2,6,7-trimethyl-5-[(2-methyl-2-propenyl)oxy]-1H-indole-1-carbaldehyde (0.59 g, 2.3 mmol) in N,N-diethylaniline (3 mL) was stirred at 200° C. for 4.5 hours under the nitrogen atmosphere. The reaction mixture was dissolved in diethyl ether, washed with 1N hydrochloric acid, water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to obtain 0.41 g of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].[C:5]1(=[O:12])[O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>[Zn].O>[OH:12][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:1][CH2:2][CH2:3][SH:4])=[O:11]
Reactant: O=C1CCCCCO1
Reactant: NCCS
Agent: [Zn]
Solvent: O
Product: O=C(CCCCCO)NCCS
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture, under an inert atmosphere, of 5 g of cysteamine and 7.2 cm3 of ε-caprolactone is stirred for 6 hours at ambient temperature. It is then left to stand overnight, after which the mixture is heated for 4 hours at a temperature of about 60° C. At the end of this time all the ε-caprolactone is transformed. The mixture is then poured into 100 cm3 of water to which 10 g of acid resin, "Dowex 50" are added and then 3 g of powdered zinc. The whole is stirred for 4 hours at ambient temperature. The water is then removed under reduced pressure and there are obtained 10 g of 6-hydroxy N-(2-mercaptoethyl) caproamide in the form of a viscous liquid at ambient temperature whose NMR1H spectrum and thiol dosages and residual amine correspond to the expected structure.
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6](=O)[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[O:17][N:16]=2)=[CH:11][CH:10]=1)C>C1COCC1>[OH:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[O:17][N:16]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)COc1ccc(-c2cc(COC(N)=O)on2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(=O)OCc1cc(-c2ccc(OCCO)cc2)no1
Reaction time: 12 h

Procedure:
5 equivalents of NaBH4 was added to 200 mg of the compound [4-(5-carbamoyloxymethyl-isoxazol-3-yl)-phenoxy]-acetic acid ethyl ester in Example 47 while stirring in the presence of a 10 ml THF/5 ml water solvent. After stirring for 12 hours, the solvent was distilled off under reduced pressure and 20 ml of 1-N HCl solution was added to the reactants, followed by extraction three times with 20 ml of ethyl acetate. The obtained organic layer was put under reduced pressure to obtain carbamic acid 3-[4-(2-hydroxy-ethoxy)-phenyl]-isoxazol-5-ylmethyl ester as a desired compound.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3](=O)[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1>C1COCC1>[CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][O:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH2:10][CH2:11]1
Reactant: CN(C)C(=O)COC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: C1CCOC1
Product: CN(C)CCOC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
Benzyl 4-(2-(dimethylamino)-2-oxoethoxy)piperidine-1-carboxylate (81) (4.5 g, 14.05 mmol) was dissolved in dry THF (50 mL), to this was added borane-methyl sulfide complex (10.53 mL, 21.07 mmol) and the reaction was stirred at 40° C. for 3 hours then at ambient temperature overnight. The gummy mixture was evaporated and was quenched with 2.0 N Na2CO3 (50 mL), extracted with EtOAc (3×75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford the desired material as a colourless liquid (4.00 g, 93% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.60-1.51 (2H, m), 1.88-1.78 (2H, m), 2.65 (6H, s), 2.97 (2H, t), 3.29-3.22 (2H, m), 3.54-3.48 (1H, m), 3.79-3.73 (2H, m), 3.85 (2H, t), 5.12 (2H, s), 7.36-7.28 (5H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:23]=1.O>CN(C)C=O>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][O:17][C:4]3[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]4[CH:16]=[CH:15][N:14]=[N:13]4)=[C:2]([CH3:1])[CH:3]=3)[N:23]=2)=[CH:33][CH:32]=1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Reactant: ClCc1cccc(-c2ccc(Cl)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2cccc(-c3ccc(Cl)cc3)n2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
A solution of 97 mg (0.42 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 17 mg (0.42 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 100 mg (0.42 mmol) 2-Chloromethyl-6-(4-chloro-phenyl)-pyridine [ZA 6706809] were added and stirred continued at r.t. over night. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water and n-heptane. The residue was dried at 40° C. to give 143 mg (78%) of the title compound as white powder.
Reaction SMILES: C([CH:4]([C:10](=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)C.C(O)C.[O-]CC.[Na+]>O>[CH3:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:10](=[O:19])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(C(C)=O)C(=O)Cc1ccccc1C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC(=O)Cc1ccccc1C

Procedure:
Following the method of Hunsdiecker [Berichte, 75, 454 (1942)], 26 parts of ethyl 2-acetyl-4-(2-methylphenyl)-3-oxobutanoate was stirred for 10 hours at room temperature with 100 parts ethanol and 6.8 parts of sodium ethoxide. The mixture was diluted with water and extracted with ether. The solvent was then evaporated to give ethyl 4-(2-methylphenyl)-3-oxobutanoate.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:22]I.O>CN(C=O)C>[CH3:22][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=2)[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:10]1
Reactant: COC(=O)c1ccc2c(-c3ccccc3)c[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(-c3ccccc3)cn(C)c2c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
NaH (60% dispersion in mineral oil, 4.52 mmol, 186 mg) was added portion-wise to a solution of methyl 3-phenyl-1H-indole-6-carboxylate (2.07 mmol, 757 mg) in DMF at 0° C. and the mixture was stirred for 20 min. Methyl iodide (2.28 mmol, 0.14 mL) was added and the reaction mixture was maintained at 0° C. for 1 h. Water was then added and the reaction was extracted with EtOAc. The organics were concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give 16c.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([CH:27]=[O:28])[CH:22]=2)=[O:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][Mg]Cl>C(=O)(O)[O-].[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([CH:27]([OH:28])[CH3:29])[CH:22]=2)=[O:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(C(=O)NCC2CCN(C(=O)OCc3ccccc3)CC2)ccn1
Reactant: C[Mg]Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(O)c1cc(C(=O)NCC2CCN(C(=O)OCc3ccccc3)CC2)ccn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-{[(2-formyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid benzyl ester (EXAMPLE 166, Step 6) (50 mg, 0.131 mmol) in TBF (2 mL) at −78° C. was added 3.0M methylmagnesium chloride (45 μL, 0.135 mmol). The mixture was stirred for 5 min and allowed to warm to rt. The reaction was diluted with 10% aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (25 mL). The ethyl acetate extract was concentrated and chromatographed on silica using 100% ethyl acetate to ethyl acetate/methanol (95/5) to give the 4-({[2-(1-hydroxy-ethyl)-pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylic acid benzyl ester.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][C:9]3[C@H:14]([CH2:15][CH2:16][OH:17])[O:13][CH2:12][CH2:11][C:10]=3[CH:18]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].CS(OCC[C@H]1C2C=CC(C(N)=O)=CC=2CCO1)(=O)=O>>[CH3:19][S:20]([O:17][CH2:16][CH2:15][C@H:14]1[C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)=[CH:18][C:10]=2[CH2:11][CH2:12][O:13]1)(=[O:22])=[O:21]
Reactant: OCC[C@@H]1OCCc2cc(-n3cccn3)ccc21
Reactant: CS(=O)(=O)Cl
Agent: CS(=O)(=O)OCC[C@@H]1OCCc2cc(C(N)=O)ccc21
Product: CS(=O)(=O)OCC[C@@H]1OCCc2cc(-n3cccn3)ccc21

Procedure:
Prepared from 2-[(1S)-6-(1H-pyrazol-1-yl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethanol and methanesulfonyl chloride, as described for the preparation of 2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl methanesulfonate.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.O>CS(C)=O>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:12][C:10]1=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
27 g of 2,3,4,6-tetra-O-benzyl-D-glucopyranose (50 mmol) was dissolved in 153 mL of DMSO to form a clear solution. 102 mL of acetic anhydride was added dropwise. The resultant clear solution was allowed to stir at room temperature overnight. After 17 hours, GC-MS showed the lactone was gone and a new compound was observed. The yellow solution was poured into 600 mL of water and sat in a separation funnel overnight. The precipitated oil was passed through a silica gel column, eluted first with cyclohexane then gradually increasing polarity by adding acetone until the final eluent was cyclohexane: acetone=2:1. The appropriate portions were collected and evaporated to give a pale syrup. 25.2 g, yield: 94%. IR (v cm−1) 2867,1752.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=O)[N:3]2[CH:8]=[N:9][CH:10]=[C:2]12.C(N(CC)CC)C.Cl.[NH2:19][OH:20]>C(O)C>[S:1]1[CH:5]=[C:4]([CH:6]=[N:19][OH:20])[N:3]2[CH:8]=[N:9][CH:10]=[C:2]12
Reactant: NO
Reactant: O=Cc1csc2cncn12
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: ON=Cc1csc2cncn12
Temperature: 60 °C
Reaction time: 1 h
Yield: 546.1 %

Procedure:
0.12 g of the imidazo[5,1-b]thiazole-3-carbaldehyde prepared in Preparation 43 was dissolved in 3 ml of ethanol. To this solution were added 1 ml of triethylamine and 0.06 g of hydroxylamine hydrochloride, and the mixture was stirred at 60° C. for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a 20:1 mixture of chloroform and methanol to give 0.72 g (yield 56%) of the title compound.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]1([CH2:12][NH2:13])[CH2:11][CH2:10]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([NH:13][CH2:12][CH:9]1[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC1CC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: c1ccc(CNCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A mixture of benzaldehyde (3 mL, 29.55 mmol), cyclopropanemethylamine (2.53 mL, 29.55 mmol), AcOH (1.7 mL, 29.55 mmol) in 1,2-dichloroethane (150 mL) is stirred at RT for 25 minutes. Sodium triacetoxyborohydride (8.8 g, 41.37 mmol) is added and the mixture further stirred overnight at RT. Sodium triacetoxyborohydride (3.13 g, 15 mmol) is again added to complete the reaction. The mixture is quenched by the addition of NaOH 1N (50 mL), the layers are separated and the aqueous phase is extracted twice with ether. The combined organic extracts are dried (Na2SO4), filtered and concentrated. The crude material is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH 95:5 to 80:20+5% NH3) to give the title product. tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 4.91 min.