Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH:6]([OH:14])[C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[N:11][CH:12]=1)[CH3:2].[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(OCC)(=O)C.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH:6]([O:14][C:16](=[O:18])[CH3:17])[C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[N:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)CC(O)c1ccc(C)nc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(OC(C)=O)c1ccc(C)nc1
Temperature: 20 °C
Reaction time: 6 h
Yield: 100.9 %

Procedure:
45.9 g (0.22 mol) of 3-hydroxy-3-(2-methyl-5-pyridyl)-propionic acid ethyl ester was dissolved in 100 ml of ethyl acetate, and 50 ml (0.53 mol) of acetic anhydride and 0.1 g (0.82 mmol) of 4-dimethylaminopyridine were added. The solution was stirred for 6 hours at 20° C. and then evaporated. The residue was dissolved in 50 ml methylene chloride and 50 ml of 5 percent sodium hydroxide solution, the phases were separated and the organic phase was evaporated. 55.8 g of raw 3-acetoxy-3-(2-methyl-5-pyridyl)-propionic acid ethyl ester was obtained. This raw product was dissolved in 300 ml of acetic acid with 3.0 g of 5 percent palladium on carbon and fed into a 1-liter autoclave. The autoclave was put under 8 bars of hydrogen and stirred at 70° C. Hydrogenation was ended after 6 hours. The autoclave was cooled and opened, and the solution was filtered and evaporated. The residue was dissolved in 50 ml of water and brought to pH 8 by potassium carbonate. The solution was extracted three times with 100 ml of methylene chloride and the organic extracts were evaporated. 42.5 g of raw 2-methyl- pyridine-5-propionic acid ethyl ester was obtained. The raw product was distilled (b.p. 100°-110° C./1.0 mbar). 22.0 g of 2-methylpyridine-5-propionic acid ethyl ester was obtained, with a GC content of 92 percent. The yield, in relation to the 6-methyl nicotinoyl propionic acid ethyl ester, was 62.9 percent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=O)[CH:6]=[N:7][CH:8]=1.[F:11][C:12]1[CH:13]=[C:14]([NH:19][CH3:20])[C:15]([NH2:18])=[CH:16][CH:17]=1>CN(C=O)C.O.C(OCC)(=O)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]2[N:18]=[C:9]([C:5]3[CH:6]=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[N:19]([CH3:20])[C:14]=2[CH:13]=1
Reactant: CNc1cc(F)ccc1N
Reactant: COc1cncc(C=O)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cncc(-c2nc3ccc(F)cc3n2C)c1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of 5-methoxypyridine-3-carbaldehyde (0.052 g, 0.378 mmol) in DMF (1.89 mL) were added the title compound from Example 1 Step B (0.053 g, 0.38 mmol) and Na2S2O5 (0.288 g, 1.51 mmol). The resulting mixture was stirred at 120° C. overnight, then cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel (50% ethyl acetate in hexanes, then 100% ethyl acetate) provided the title compound: LCMS m/z 258.17 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.56 (d, J=1.6 Hz, 1 H), 8.46 (d, J=2.9 Hz, 1 H), 7.66 (dd, J=8.6, 4.8 Hz, 1 H), 7.65 (t, J=2.1, 2.1 Hz, 1 H), 7.12-7.06 (m, 2 H), 3.95 (s, 3 H), 3.88 (s, 3 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([N:16]2[CH2:19][CH:18]([NH:20][C:21](=[O:22])[CH2:23][NH:24][C:25](=[O:36])[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[CH:27]=3)[CH2:17]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Product: CC(C)(C)OC(=O)NC1CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1

Procedure:
The title compounds were prepared as white solids from the reductive amination of (4-oxo-cyclohexyl)-carbamic acid tert-butyl ester (Asta) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH3:3].Cl[CH2:11][CH2:12][CH2:13][C:14]#[CH:15].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:2]([N:4]1[CH2:9][CH2:8][N:7]([CH2:15][CH2:14][CH2:13][C:12]#[CH:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:1]
Reactant: C#CCCCCl
Reactant: CC(C)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCCCN1CCN(C(C)C)CC1
Temperature: 80 °C
Yield: 35.4 %

Procedure:
A mixture of 1-(1-methylethyl)piperazine (6 g, 46.8 mmol), 5-chloro-1-pentyne (4.91 mL, 46.8 mmol) and sodium bicarbonate (3.93 g, 46.8 mmol) in N,N-dimethylformamide (75 mL) was heated at 80° C. overnight. The reaction mixture was cooled to room temperature then partitioned between ether (100 mL) and water (100 mL). The organic phase was washed with brine (25 mL) then dried using a hydrophobic frit and evaporated. The crude material was purified on a 50 g SCX cartridge (preconditioned with MeOH) eluted with MeOH and flushed with 2M NH3/MeOH. The appropriate fractions were concentrated and dried under vacuum to obtain the title compound as a light brown oil (3.22 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:12])[C:9]=1[O:10][CH3:11])[CH:5]=O.[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17]2>>[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2=[CH:5][C:4]1[CH:3]=[C:2]([CH3:1])[C:9]([O:10][CH3:11])=[C:8]([CH3:12])[CH:7]=1
Reactant: COc1c(C)cc(C=O)cc1C
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: COc1c(C)cc(C=C2C(=O)Nc3ccc(Cl)cc32)cc1C

Procedure:
3,5-Dimethyl-4-methoxybenzaldehyde was condensed with 5-chloro-2-oxindole to give 0.3 g of 5-chloro-3-(4-methoxy-3,5-dimethylbenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [OH-].[Na+].Cl[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]1[CH:18]([CH3:24])[N:17]([C:25](=[O:27])[CH3:26])[CH2:16][CH2:15][C:14]2=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:25]([N:17]1[CH2:16][CH2:15][C:14]2[C:13]3[C:21](=[CH:22][CH:23]=[C:11]([O:10][CH3:9])[CH:12]=3)[N:20]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:19]=2[CH:18]1[CH3:24])(=[O:27])[CH3:26]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc2[nH]c3c(c2c1)CCN(C(C)=O)C3C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)n1c2c(c3cc(OC)ccc31)CCN(C(C)=O)C2C
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
Sodium hydroxide (3 g), tetrabutylammonium hydrogen sulphate (1.87 g) and ethyl chloroformate (2.2 mL) are successively added to a solution of 1-(6-methoxy- 1-methyl-2,3,4,9-tetrahydro-1H-β-carbolin-2-yl)-1-ethanone (1.45 g) in dichloromethane (100 mL). The mixture is stirred at room temperature for 3 h. After separation on silica gel (chloroform/methanol eluent), the ethyl 2-acetyl-6-methoxy-1 -methyl-2,3,4,9-tetrahydro-1H-β-carboline-9-carboxylate is obtained (70% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[CH2:15]=[CH:16][CH2:17][C:18](=[N:22][OH:23])[C:19](=O)[CH3:20]>C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:19]([CH3:20])[C:18](=[N:22][OH:23])[CH2:17][CH:16]=[CH2:15]
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: C=CCC(=NO)C(C)=O
Solvent: CCOCC
Product: C=CCC(=NO)C(C)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
2,6-Dichloro-4-trifluoromethylphenylhydrazine (6.6 g) and 1-hexene-4,5-dione 4-oxime (3.4 g) were stirred in diethyl ether (200 ml) for 18 hours. The solvent was removed under reduced pressure to give 1-hexene-4,5-dione 5-(2,6-dichloro-4-trifluoromethylphenylhydrazone) 4-oxime, m.p. 86°-88°.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH2:16][CH:9]1[CH2:10][C:11](=[N:17]O)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Ni]>[NH2:17][CH:11]1[CH2:10][CH:9]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:13]([CH2:14][CH2:15][CH2:16]2)[CH2:12]1
Reactant: ON=C1CC2CCCC(C1)N2Cc1ccccc1
Agent: [Ni]
Solvent: CCO
Product: NC1CC2CCCC(C1)N2Cc1ccccc1
Yield: 60.9 %

Procedure:
9-Benzyl-9-azabicyclo-(3.3.1)-nonan-3-one oxime (4.0 g; 0.0164 mole), m.p. 134°, was dissolved in ethanol (100 ml) and hydrogenated at 50°-60° at 250 psi in the presence of Raney nickel. The mixture was filtered after 24 hours through kieselguhr and evaporated in vacuo. The resulting oil was dissolved in dilute hydrochloric acid (50 ml) extracted with ethyl acetate (3×150 ml), the aqueous layer was basified and re-extracted with ethyl acetate (3×150 ml). The combined organic extracts were dried (K2CO3), filtered and evaporated in vacuo to yield 3-amino-9-benzyl-9-azabicyclo-[3.3.1]-nonane (2.3 g; 61%), used without further purification.
Reaction SMILES: NC(CCCCCCCCC(N)C(C)C)C(C)C.[CH3:19][CH2:20][CH:21]([CH:24]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH:27]([CH:36]([CH2:39][CH3:40])[CH2:37][CH3:38])[NH:26][NH:25]1)[CH2:22][CH3:23]>>[NH2:25][CH:24]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH:27]([NH2:26])[CH:36]([CH2:37][CH3:38])[CH2:39][CH3:40])[CH:21]([CH2:22][CH3:23])[CH2:20][CH3:19]
Reactant: CCC(CC)C1CCCCCCCCC(C(CC)CC)NN1
Agent: CC(C)C(N)CCCCCCCCC(N)C(C)C
Product: CCC(CC)C(N)CCCCCCCCC(N)C(CC)CC

Procedure:
The procedure described in (a) is repeated, starting from 49 g (0.16 mole) of 3,12-di-(3-pentyl)-1,2-diazacyclododecane and using correspondingly reduced amounts of catalyst and solvent, affording after purification by chromatography 37.5 g (75% of theory) of 4,13-diamino-3,14-diethylhexadecane as a colourless oil [nD20 =1.4664; IR spectrum (liquid) includes bands at 3330, 1626 cm-1 ].
Reaction SMILES: Cl.C[N:3]1[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[C@H:5]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[CH2:4]1.[Cl:29]C(OC(Cl)C)=O>ClCCCl>[ClH:29].[CH2:27]1[O:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH2:18][C@H:5]3[C@H:6]([C:9]4[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=4)[CH2:7][CH2:8][NH:3][CH2:4]3)=[CH:21][C:22]=2[O:28]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: CN1CC[C@@H](c2ccc([N+](=O)[O-])cc2)[C@H](COc2ccc3c(c2)OCO3)C1
Agent: Cl
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc([C@@H]2CCNC[C@H]2COc2ccc3c(c2)OCO3)cc1
Yield: 64.7 %

Procedure:
Was prepared from compound (1) (2.4 g) by treatment with 1-chloroethyl chloroformate (1.02 g) in 1,2-dichloroethane (100 ml) as described by Olofson et. al (J. Org. Chem. 49 (1984) 2081). Rinse up on a silica gel column gave 1.5 g of compound (6). M.p. 95°-100° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@@H:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27](O)=[O:28])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2[C:45]([NH2:46])=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:35][CH:34]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CN(C)C1C=CN=CC=1.CCOC(C)=O>[O:39]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:45]=1[NH:46][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([CH2:23][C@@H:19]2[CH2:20][CH2:21][CH2:22][C@H:18]2[C:9]2[O:10][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH:25]=1)[C:36]1[CH:35]=[CH:34][CH:33]=[CH:38][CH:37]=1
Reactant: Nc1ccccc1Oc1ccccc1
Reactant: O=C(O)c1cccc(C[C@@H]2CCC[C@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1Oc1ccccc1)c1cccc(C[C@@H]2CCC[C@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
To a mixture of 3-{[(1S,2R)-2-(4,5-diphenyloxazol-2-yl)-1-cyclopentyl)methyl}benzoic acid (120 mg, 0.284 mmol) and 2-aminodiphenyl ether (68 ml, 0.369 mmol) in DMF (5 ml) was added 1-hydroxybenzotrioxazole (58 mg, 0.426 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (109 mg, 0.568 mmol), and 4-dimethylaminopyridine (27 mg, 0.284 mmol). After stirring the mixture at room temperature for 2 hours, the reaction mixture was heated at 80° C. for 3 hours. Then, the resultant mixture was diluted with EtOAc (30 ml), washed with 1N hydrochloric acid, water, saturated sodium hydrogencarbonate solution, water, and brine. The resultant mixture was dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:EtOAc, 4:1 elution) to give N-(2-phenoxyphenyl)-3-{[(1S,2R)-2-(4,5-diphenyloxazol-2-yl)-1-cyclopentyl]methyl}benzamide (84.7 mg, 51%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[S:7].[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:27]=1[C:28](Cl)=[O:29].C(N(C(C)C)CC)(C)C.O>ClCCl>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:28]([C:27]2[C:26]([Cl:25])=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:35])=[O:29])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[S:7]
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=S)c1c(C)cccc1Cl
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=S)c1c(C)cccc1Cl
Reaction time: 15 h
Yield: 99.8 %

Procedure:
To a solution of 4-amino-N-[(2-chloro-6-methylphenyl)thioxomethyl]-L-phenylalanine methyl ester (3.57 mmol, 1.296 g) and 2,6-dichlorobenzoyl chloride (3.75 mmol, 0.785 g) in dichloromethane (20 mL) was added diisopropylethylamine (5.35 mmol, 0.93 mL) at room temperature. The solution was stirred for 15 h at which time TLC analysis of the mixture indicated the absence of starting material. After the addition of water (30 mL), the layers were separated and the aqueous phase was extracted with dichloromethane (20 mL). The combined extracts were washed with brine (50 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 4:1 to 1:1) to obtain 1.91 g (83%) of N-[(2-chloro-6-methylphenyl)thioxomethyl]4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester as an amorphous colorless solid. HRMS: Obs. mass, 535.0399. Calcd. mass, 535.0416 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:13][CH:12]([OH:14])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17].O>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH:12]([O:14][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:13]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(N2CC(O)C2)cc1
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)OC1CN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
1-(4-Nitro-phenyl)-azetidin-3-ol (which was obtained in Example 396) (5.0 g, 25.8 mmol) was added to a solution of methanesulfonyl chloride (2.2 mL, 28.3 mmol) in dry pyridine (35 mL) and stirred at room temperature overnight. Water was added and the resultant precipitate was captured on a filter, washed with water, methanol, and hexanes to give 3.72 g of the desired product as an orange solid; 1H NMR (DMSO-d6) δ3.35 (s, 3H), 4.15 (m, 3H), 4.45 (m, 2H), 5.48 (m, 1H), 6.53 (d, 2H, J=9.12 Hz), 8.09 (d, 2H, J=9.12 Hz); MS (ES) m/z: 273.5 (MH+); Anal. Calcd. for C10H12N2O5S: C, 44.1 1; H, 4.44; N, 10.29. Found: C, 44.50; H, 4.48; N, 10.64.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][CH2:9][C@H:10]([CH3:45])[O:11][C:12]1[CH:13]=[C:14]([C:29]2[NH:33][C:32]([C:34]3[CH:44]=[CH:43][C:37]([C:38](OCC)=[O:39])=[CH:36][N:35]=3)=[CH:31][CH:30]=2)[CH:15]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH:17]=1.O.[OH-].[Na+]>O1CCCC1>[CH3:7][O:8][CH2:9][C@H:10]([CH3:45])[O:11][C:12]1[CH:13]=[C:14]([C:29]2[NH:33][C:32]([C:34]3[N:35]=[CH:36][C:37]([CH2:38][OH:39])=[CH:43][CH:44]=3)=[CH:31][CH:30]=2)[CH:15]=[C:16]([O:18][C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=2)[CH:17]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(-c3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(O[C@@H](C)COC)c3)[nH]2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3ccc(CO)cn3)[nH]2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
Lithium aluminum hydride (12 mg, 0.316 mmol) was suspended in tetrahydrofuran (2 mL). Ethyl 6-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)nicotinate (56.0 mg, 0.102 mmol) synthesized in Example (11c) was dissolved in tetrahydrofuran (2 mL), followed by dropwise addition at 0° C. under nitrogen atmosphere. After stirring at 0° C. for 30 minutes, water (12 μL) and an aqueous sodium hydroxide solution (5M, 48 μl) were added dropwise slowly and sequentially. After filtration through Celite, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-100%) to afford the desired compound (33 mg, yield 64%) as a pale yellow solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=3)[N:6]=2)[CH2:2]1.[CH3:17][C:18]1[N:22]2[CH:23]=[C:24]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:25]([C:27]3[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=3)=[N:26][C:21]2=[N:20][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.C(O)(=O)C.C(N(CC)CC)C>[CH3:17][C:18]1[N:22]2[CH:23]=[C:24]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:25]([C:27]3[CH:34]=[CH:33][C:30]([CH2:31][N:1]4[CH2:4][CH:3]([C:5]5[N:6]=[C:7]([C:10]6[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=6)[NH:8][N:9]=5)[CH2:2]4)=[CH:29][CH:28]=3)=[N:26][C:21]2=[N:20][CH:19]=1
Reactant: Cc1cccc(-c2n[nH]c(C3CNC3)n2)n1
Reactant: Cc1cnc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2nc(C3CN(Cc4ccc(-c5nc6ncc(C)n6cc5-c5ccccc5)cc4)C3)n[nH]2)n1
Reaction time: 1 h

Procedure:
168 mg 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-6-methylpyridine×2HCl (intermediate example 44.1; 60% pure) are dissolved in 2.8 ml NMP. After addition of 0.1 ml triethylamine the reaction mixture is stirred for one hour. 100 mg (0.32 mmol) 4-(3-Methyl-6-phenylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde (intermediate example 12.0) and 0.03 mL acetic acid are added and the reaction mixture is stirred overnight at room temperature. 74.4 mg (0.35 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature for 20 hours. The reaction mixture is treated with saturated NaHCO3 and the precipitate filtered off, washed with water and dried. After chromatography of the precipitate on silica gel (dichloromethane/methanol) 36.6 mg (21%) of the desired product are obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH2:6]2.C(OCC)(=O)C.ClCCl>O1CCCC1.[O-2].[O-2].[Mn+4]>[O:12]=[C:8]1[C:9]2[C:5](=[CH:4][C:3]([CH:2]=[O:1])=[CH:11][CH:10]=2)[CH2:6][O:7]1
Reactant: O=C1OCc2cc(CO)ccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)COC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
5-(Hydroxymethyl)-1 (3H)-isobenzofuranone (2.94 g, 17.9 mmol) obtained from Example 4-(2) was dissolved in tetrahydrofuran (100 ml), and activated manganese dioxide (31 g) was added thereto. The mixture was stirred at room temperature for 30 minutes, and an additional amount of activated manganese dioxide (3 g) was added thereto. The resulting mixture was stirred for a further 30 minutes and then filtered. The solid filtered off was washed with tetrahydrofuran, and the washings were combined with the previous filtrate, then the combined solution was concentrated under reduced pressure to give a solid residue. The residue was subjected to chromatography on a silica gel (150 g) column (eluent; ethyl acetate:dichloromethane=0:1˜1:10). The eluate was concentrated under reduced pressure to afford a solid compound, which was washed with a mixed solvent of ethyl acetate-hexane (1:2) to afford the title compound (2.01 g, 69% yield) as a solid (mp. 160° C.)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si](C(C)C)(C(C)C)C(C)C)[CH:9]=[CH:10][C:3]=12.[Li]C(CC)C.[F:26]N(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O.[Cl-].[NH4+].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C.O>[F:1][C:2]1[C:7]([F:26])=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)ccnc21
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cnc2[nH]ccc2c1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 59.8 %

Procedure:
4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (2.00 g, 6.84 mmol) in THF (20 mL) was added to s-BuLi (12.5 mL, 15.0 mmol, 1.4M in cyclohexane) at −78° C. for 30 minutes. N-Fluoro-N-(phenylsulfonyl)benzenesulfonamide (5.39 g, 17.1 mmol) in THF (15 mL) was added, and it was stirred at −78° C. for 20 minutes. A saturated ammonium chloride solution (20 mL) was added and extracted with hexanes (50 mL), washed with brine, and dried over sodium sulfate. After removal of the solvent, the residue was dissolved in THF (10 mL), and TBAF (6.84 mL, 6.84 mmol) in THF (6.84 mL, 6.84 mmol) was added. The reaction was stirred at room temperature for 10 minutes, and water (20 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, washed with brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by chromatography (ethyl acetate) to give 4,5-difluoro-1H-pyrrolo[2,3-b]pyridine (0.63 g, 60% yield) as a solid. LCMS (APCI+) m/z 155.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[NH:4][CH:5]=[C:6]([C:12](=[O:24])[C:13]1[C:18]([CH3:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[C:14]=1F)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+]>C1COCC1>[F:20][C:17]1[C:18]([CH3:19])=[C:13]2[C:14](=[C:15]([F:22])[C:16]=1[F:21])[N:4]([C:3]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:2]=1[F:1])[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]2=[O:24]
Reactant: CCOC(=O)C(=CNc1ccc(F)cc1F)C(=O)c1c(C)c(F)c(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)c(C)c2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a cold (5° C.) solution of 2.77 g (6.64 mmol) of ethyl 3-(2,4-difluoroanilino)-2-(2, 3,4,5-tetrafluoro-6-methylbenzoyl)acrylate in 60 mL of dry THF was added 0.32 g of 60% sodium hydride. The solution was stirred overnight at room temperature, then concentrated to an orange foam. The residue was partitioned between methylene chloride and 1N HCl. The organic phase was washed with water, dried over magnesium sulfate, and concentrated to an orange solid which was recrystallized (ethyl acetate:hexane) to give 1.55 g of the title compound, mp 152°-154° C.