Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([CH2:10][C:11]([O-:13])=O)=[N:4][C:3]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[Na+].[CH3:21][C@H:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23]1>>[F:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([CH2:10][C:11]([N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:30][C@@H:22]2[CH3:21])=[O:13])=[N:4][C:3]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)c(F)c1=O
Reactant: C[C@H]1Cc2ccccc2N1
Agent: [Na+]
Product: C[C@H]1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)c(F)c(=O)n1C
Yield: 51.7 %

Procedure:
The product is prepared by following the procedure described in example 1a (step 5a) using 88 mg of sodium (5-fluoro-1-methyl-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate described in step 2a and 40 mg of (S)-2-methyl-2,3-dihydro-1H-indole (which can be prepared according to Krasnov, V. P. et al. (Mendeleev Commun. (2002), 12(1), 27-28). After silica column purification: eluent 98/02 dichloromethane/methanol, 60 mg of 5-fluoro-3-methyl-2-[2-((S)-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: C(O[C:6]([C:8]1[N:13]=[C:12](Br)[C:11]2[CH:15]=[C:16]([S:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:17][C:10]=2[C:9]=1[OH:25])=[O:7])CCC.C([O:30][C:31]([C:33]1C(O)=C2C=C(SC3C=CC=CC=3)SC2=C(Br)[N:38]=1)=[O:32])CCC>>[OH:25][C:9]1[C:10]2[S:17][C:16]([S:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][C:11]=2[CH:12]=[N:13][C:8]=1[C:6]([NH:38][CH2:33][C:31]([OH:32])=[O:30])=[O:7]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Sc3ccccc3)sc2c1O
Reactant: CCCCOC(=O)c1nc(Br)c2sc(Sc3ccccc3)cc2c1O
Product: O=C(O)CNC(=O)c1ncc2cc(Sc3ccccc3)sc2c1O

Procedure:
The title compound was prepared from a mixture of 4-bromo-7-hydroxy-2-phenylsulfanyl-thieno[3,2-c]pyridine-6-carboxylic acid n-butyl ester and 7-bromo-4-hydroxy-2-phenylsulfanyl-thieno[2,3-c]pyridine-5-carboxylic acid n-butyl ester, example 17.b, under conditions analogous to experimental example 1.g. The products were purified by column chromatography eluting from silica gel with a gradient of 20-60% ethyl acetate in hexanes. Product A, (Lower Rf product); MS: (+) m/z 360.01 (M+1); Product B, (Higher Rf product); MS: (+) m/z 360.02 (M+1).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@@H:4]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)[NH:3]1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C(Cl)Cl>[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([N:3]2[C@@H:2]([CH3:1])[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C@H:4]2[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[O:30])=[CH:24][CH:23]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: C[C@H]1Cc2ccccc2[C@@H](c2ccc(C(=O)O)cc2)N1
Solvent: ClCCl
Product: C[C@H]1Cc2ccccc2[C@@H](c2ccc(C(=O)O)cc2)N1C(=O)Nc1ccc(F)cc1
Reaction time: 5 h

Procedure:
To a solution of 4-((1R,3S)-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoic acid (22 mg, 82 μmol) in CH2Cl2 (0.5 mL) at RT was added 1-fluoro-4-isocyanatobenzene (28 mg, 206 μmol). The reaction was stirred 5 h and directly purified by HPLC to give 4-((1R,3S)-2-((4-fluorophenyl)carbamoyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoic acid as a white solid. MS (ESI pos. ion) m/z: 405 (M+1).
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:8]=1)(=[O:3])[CH3:2].[CH3:14][Mg]I.CCOCC>C1COCC1>[OH:3][C:1]([C:4]1[O:5][CH:6]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:8]=1)([CH3:14])[CH3:2]
Reactant: C[Mg]I
Reactant: CCOC(=O)c1coc(C(C)=O)n1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1coc(C(C)(C)O)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Into a flask containing a solution of ethyl 2-acetyloxazole-4-carboxylate (2.0 g, 10.9 mmol) in THF (50 ml), 3M solution of MeMgI in ether (5.0 ml, 13.11 mmol) was added at 0° C. The resulting mixture was stirred at RT for 5 h. The mixture was quenched with aqueous NH4Cl solution and extracted with EtOAc. The organic layer was concentrated and purified with flash chromatography. Yield 1.0 g. 1H-NMR (400 MHz; CDCl3): δ 1.59 (s, 3H), 1.66 (s, 6H), 2.70 (s, 1H), 4.39 (q, 2H), 8.17 (s, 1H).
Reaction SMILES: O([C:8]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:9]=1[C:10]1C(COC)=C(C3C=CON=3)N=CC=1N2)C1C=CC=CC=1.ClC1C=CC([O:34][C:35]2[CH:47]=[CH:46][CH:45]=[C:44]3[C:36]=2[C:37]2[C:38]([CH2:56][O:57][CH3:58])=[C:39]([C:48]4[CH:52]=[C:51]([CH2:53][O:54][CH3:55])[O:50][N:49]=4)[N:40]=[CH:41][C:42]=2[NH:43]3)=CC=1>>[CH2:10]([O:34][C:35]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:36]=1[C:37]1[C:38]([CH2:56][O:57][CH3:58])=[C:39]([C:48]3[CH:52]=[C:51]([CH2:53][O:54][CH3:55])[O:50][N:49]=3)[N:40]=[CH:41][C:42]=1[NH:43]2)[C:9]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:8]=1
Reactant: COCc1cc(-c2ncc3[nH]c4cccc(Oc5ccc(Cl)cc5)c4c3c2COC)no1
Reactant: COCc1c(-c2ccon2)ncc2[nH]c3cccc(Oc4ccccc4)c3c12
Product: COCc1cc(-c2ncc3[nH]c4cccc(OCc5ccccc5)c4c3c2COC)no1

Procedure:
5-phenoxy-4-methoxymethyl-3-(3-isoxazolyl)-β-carboline, 5-(4-chlorophenoxy)-3-(5-methoxymethyl-3-isoxazolyl)-4-methoxymethyl-β-carboline;
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.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[C:25]#[CH:26])=[O:19])([CH3:16])([CH3:15])[CH3:14].O>N(C(C)C)C(C)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.[Cu]I>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[C:25]#[C:26][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#CC1CCCN1C(=O)OC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1ccc(C#CC2CCCN2C(=O)OC(C)(C)C)cc1
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
A suspension of ethyl 4-iodobenzoate (1.7 mL, 10 mmol), Pd(PPh3)4 (578 mg, 0.5 mmol), and CuI (190 mmol, 1 mmol) in i-Pr2NH (20 mL) was stirred for 0.5 hr under N2. To this mixture was added a solution of 1-(tert-butoxycarbonyl)-2-ethynylpyrrolidine (1.95 g, 10 mmol) in i-Pr2NH (20 ml) for over 10 min. After stirring for 3 hr at room temp, the mixture was poured into H2O and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, and evaporated. The residue was chromatographed on silica-gel with n-hexane-AcOEt (10:1, v/v) as eluent to give 2.77 g (81%) 1-(tert-butyloxycarbonyl)-2-(2-(4-ethoxycarbonylphenyl)ethynyl)pyrrolidine as a colorless oil. 1H-NMR (CDCl3) δ1.37 (3 H, t, J=6.8 Hz), 1.49 (9 H, s), 1.85-2.12 (4 H, m), 3.37-3.51 (2 H, m), 437 (2 H, q, J=6.8 Hz), 4.54-4.77 (1 H, m), 7.44 (2 H, d, J=7.8 Hz), 7.96 (2 H, d, J=7.8 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][CH:11]=[CH:12][C:13](=[O:15])[CH3:14])[CH2:7][N:6]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:4].CCCCCC>C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu].[Cu].[Cu].[Cu].[Cu].[Cu]>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][CH2:11][CH2:12][C:13](=[O:15])[CH3:14])[CH2:7][N:6]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:4]
Reactant: COC(=O)C1CC(CC=CC(C)=O)CN1C(=O)OC(C)(C)C
Agent: [Cu]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COC(=O)C1CC(CCCC(C)=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 4-(4-oxo-pent-2-enyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (193 mg, 0.5 mmol, 1 equiv) in benzene (0.9 mL) was added a solution of triphenylphosphine-copper (I) hydride hexamer in benzene (3.6 mL). The mixture was stirred at rt overnight and hexane (13 mL) was added. The mixture was filtered and the filtrate was evaporated. The residue was purified by chromatography to give 4-(4-oxo-pentyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (127 mg, 65%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[C:16](OC(=O)C)(=[O:18])[CH3:17].O>N1C=CC=CC=1>[C:16]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(C)c1ccc(O)c(N)c1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C(C)c1ccc(O)c(NC(C)=O)c1
Yield: 65.7 %

Procedure:
A solution of ethyl 2-(3-amino-4-hydroxyphenyl)propionate (10.46 g.) and acetic anhydride (5.6 g.) in dry pyridine (50 ml.) was heated on a steam bath for 1.25 hours. The reaction mixture was poured into water (500 ml.), precipitating an oil. On cooling the oil solidified. The solid was removed by filtration and washed with water. After drying, ethyl 2-(3-acetamido-4-hydroxyphenyl)propionate (8.25 g.) was obtained, m.p. 137°-141°C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:24])[C:12]3[CH:19]=[C:18]([C:20]#[C:21][CH2:22][OH:23])[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(Cl)Cl.C(O)C>C(O)C.[Pd]>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:24])[C:12]3[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][OH:23])[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)sc21
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCCO)sc21
Yield: 40 %

Procedure:
A solution of N-(4-chlorobenzyl)-2-(3-hydroxy-1-propynyl)-7-methyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Example No. 24) (0.520 g) in 1/1 CH2Cl2/ethanol (160 mL) is hydrogenated over 10% Pd/C (0.156 g) at 35 psi for 2 h. The reaction mixture is filtered through a Celite pad, and the filtrate is concentrated in vacuo. The resulting pale yellow solid is purified via column chromatography (CH2Cl2:CH3OH; 98:2). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield a pale yellow solid (this material contains a small amount of partially reduced product). This material is dissolved in ethanol (100 mL) and hydrogenated over 10% Pd/C (0.156 g) at 35 psi for 1 h. The reaction mixture is filtered through a Celite pad, and the filtrate is concentrated in vacuo. The resulting off-white solid is recrystallized from ethanol to yield 0.211 g (40%) of the desired product as an off-white solid.
Reaction SMILES: O.C([O-])(=O)C.[K+].[F:7][C:8]1[C:13](B(O)O)=[CH:12][CH:11]=[CH:10][N:9]=1.Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[CH:19]=1>CC#N>[F:7][C:8]1[C:13]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[CH:19]=2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: OB(O)c1cccnc1F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Nc1cc(-c2cccnc2F)ccn1
Temperature: 85 °C

Procedure:
A pressure vessel was charged with 6.35 mL of water and degassed with nitrogen for 0.5 h. To this vessel was added potassium acetate (2.31 g, 23.5 mmol), 2-fluoropyridine-3-boronic acid (2.48 g, 17.6 mmol), 4-chloropyridin-2-amine (1.51 g, 11.7 mmol), dichloro-bis(di-tert-butylphenylphosphino)Pd(II) (0.146 g, 0.235 mmol) and 58.5 mL CH3CN. The mixture was purged under nitrogen for several additional minutes, and the pressure bottle was sealed. The reaction mixture was heated to 85° C. for 15 h. Upon cooling the layers were separated, and the organic portion was dried with Na2SO4 and concentrated. The resulting solid was triturated with ethyl acetate/diethyl ether to provide 4-(2-fluoropyridin-3-yl)pyridin-2-amine as a tan solid. MS m/z=190 [M+H]+. Calc'd for C10H8FN3: 189.19.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16](O)[CH:17]2[CH2:22][CH2:21][O:20][N:19]([CH2:23][CH3:24])[C:18]2=[O:25])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[C:10]=1[OH:11])[CH:16]=[C:17]1[CH2:22][CH2:21][O:20][N:19]([CH2:23][CH3:24])[C:18]1=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN1OCCC(C(O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCN1OCCC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 45.2 %

Procedure:
The dihydro-4-[(3,5-di-tert-butyl-4-hydroxyphenyl)hydroxymethyl]-2-ethyl-2H-1,2-oxazin-3(4H)-one (15 g, 41 mmol) obtained according to Step B was added to 100 ml of benzene and 0.4 g of p-toluenesulfonic acid monohydrate and refluxed for 13 hours. The mixture was concentrated to a solid, taken up in 150 ml of methylene chloride, washed with dilute sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated to a brown solid (14.1 g) which was recrystallized from acetone to yield 6.4 g of crystalline dihydro-4-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-ethyl-2H-1,2-oxazin-3(4H)-one having a melting point of 166°-167° C.
Reaction SMILES: [C:1]([CH2:3][C@@H:4]([OH:9])[CH2:5][C:6]([OH:8])=[O:7])#[N:2].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:21](O)[CH:22]([CH3:24])[CH3:23]>>[CH2:21]([O:7][C:6](=[O:8])[CH2:5][C@H:4]([OH:9])[CH2:3][C:1]#[N:2])[CH:22]([CH3:24])[CH3:23]
Reactant: N#CC[C@@H](O)CC(=O)O
Reactant: CC(C)CO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)COC(=O)C[C@H](O)CC#N
Yield: 92 %

Procedure:
(R)-4-cyano-3-hydroxybutyric acid (1.0 mol) in isobutanol (500 ml) and conc. sulfuric acid (5 g) were refluxed for 5 hours. The reaction mixture was neutralized with sodium carbonate and filtered. The filtrate was concentrated in vacuo to afford (R)-4-cyano-3-hydroxybutyric acid isobutyl ester (157 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[C:4]=1[NH2:5].[C:14](Cl)(Cl)=[O:15]>C1(C)C=CC=CC=1.CCOCC>[CH3:13][O:12][C:6]1[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=[C:3]([O:2][CH3:1])[C:4]=1[N:5]=[C:14]=[O:15]
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1cc(OC)c(N=C=O)c(OC)c1
Reaction time: 3 h

Procedure:
A suspension of 2,4,6-trimethoxyaniline (71.1 g, 0.324 mol) in a 12.5% wt/wt solution (540 mL) of phosgene in toluene was heated on a steam bath with periodic swirling for 3 hours. Additional phosgene in toluene solution (2×270 mL) was added after 1 and 2 hours. The suspension was allowed to cool, placed under house vacuum, and stirred for 2.5 days. The mixture was rotoevaporated to a dark purple solid. The residue was dissolved in ether (450 mL), filtered, rotoevaporated, and dried in vacuo to give a purple amorphous solid; yield 66.9 g (98.7%), mp 67°-70° C.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH:15]1([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][C:19]=2[F:26])[CH2:17][CH2:16]1>>[CH:15]1([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][O:1][C:2]3[N:6]([C:7]4[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=4)[N:5]=[CH:4][CH:3]=3)=[CH:20][C:19]=2[F:26])[CH2:17][CH2:16]1
Reactant: OCc1ccc(C2CC2)c(F)c1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(C3CC3)c(F)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-cyclopropyl-3-fluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 0.71-0.75 (2H, m), 0.96-1.02 (2H, m), 2.06-2.10 (1H, m), 5.17 (2H, s), 5.72 (1H, d, J=1.6 Hz), 6.88-6.92 (1H, m), 7.07-7.10 (2H, m), 7.40 (1H, dd, J=1.6 Hz, 5.2 Hz), 7.55 (1H, d, J=2.0 Hz), 8.02 (1H, s), 8.70 (1H, d, J=5.2 Hz). [M+H] Calc'd for C19H15FN4O, 335. Found, 335.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([NH:21][C:22]([C@H:24]3[CH2:29][CH2:28][C@H:27]([N:30]4[CH2:34][CH2:33][CH2:32][C:31]4=[O:35])[CH2:26][CH2:25]3)=[O:23])=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)=[O:12])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>N1C=CC=CC=1>[CH3:36][S:37]([NH:1][C:2]1[C:7]2[C:8]([NH:21][C:22]([C@H:24]3[CH2:25][CH2:26][C@H:27]([N:30]4[CH2:34][CH2:33][CH2:32][C:31]4=[O:35])[CH2:28][CH2:29]3)=[O:23])=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)=[O:12])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCCC4=O)CC3)c12
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCCC4=O)CC3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trans-4-amino-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (27 mg) obtained in Example 426 is dissolved in pyridine (2 ml), and thereto is added methanesulfonyl chloride (7 μl) under ice-cooling. The mixture is stirred at room temperature overnight, and thereto are further added pyridine (3 ml) and methanesulfonyl chloride (500 μl) under ice-cooling. The mixture is stirred at room temperature for 6 hours. Water is added to the reaction solution, and the mixture is extracted with chloroform. The solvent is evaporated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (eluent: chloroform, then chloroform/methanol=9/1) to give the title compound (21.2 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[O:19][CH3:18])[N:3]=1
Reactant: COc1ccccc1CN
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: COc1ccccc1CNc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 2-methoxybenzylamine in DME. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]4[NH:25][C:24]([C:26]([F:29])([F:28])[F:27])=[N:23][C:20]4=3)[O:15][CH2:14]2)(=O)=O)=CC=1.[F:30][C:31]1[CH:39]=[C:38]2[C:34]([C:35]([C:40]3[CH2:41][CH2:42][NH:43][CH2:44][CH:45]=3)=[CH:36][NH:37]2)=[CH:33][CH:32]=1>CS(C)=O.C(OCC)(=O)C>[F:30][C:31]1[CH:39]=[C:38]2[C:34]([C:35]([C:40]3[CH2:41][CH2:42][N:43]([CH2:12][CH:13]4[O:22][C:21]5[C:16](=[CH:17][CH:18]=[C:19]6[NH:25][C:24]([C:26]([F:29])([F:28])[F:27])=[N:23][C:20]6=5)[O:15][CH2:14]4)[CH2:44][CH:45]=3)=[CH:36][NH:37]2)=[CH:33][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4[nH]c(C(F)(F)F)nc4c3O2)cc1
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Fc1ccc2c(C3=CCN(CC4COc5ccc6[nH]c(C(F)(F)F)nc6c5O4)CC3)c[nH]c2c1
Temperature: 85 °C

Procedure:
A mixture of 0.50 g (1.2 mmole) of [(8R)-2-trifluoromethyl-7,8-dihydro-3H-6,9-dioxa-1,3-diaza-cyclopenta[a]naphthalen-8-yl]methyl 4-methylbenzenesulfonate and 0.90 g (4.2 mmole) of 6-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 8.0 mL of DMSO was heated at 85° C. under nitrogen for 6 hours. The reaction was allowed to come to room temperature, diluted to 400 mL with ethyl acetate, washed with 400 mL portions of saturated aqueous sodium bicarbonate and water, dried over sodium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on silica gel with 1% methanol in chloroform as eluant and recrystallized from ethanol with the addition of 0.10 g of fumaric acid to give 0.16 g of the (S)-enantiomer of the title compound as a yellow solid hemifumarate, hydrate, m.p. 215-220° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1.[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>O>[CH3:15][C:14]([NH:18][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1)([CH3:17])[CH3:16]
Reactant: CC(C)(C)N
Reactant: CC(=O)c1ccc(OCCCl)cc1
Solvent: O
Product: CC(=O)c1ccc(OCCNC(C)(C)C)cc1
Temperature: 120 °C

Procedure:
A mixture of 6.5 g of the product of Step A in 30 ml of tert.-butylamine was heated at 120° C. for 30 hours and was then diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over a deshydrant, filtered and evaporated to dryness. The residue was chromatographed over silica and eluted with a 9-1 ethyl acetate-triethylamine mixture to obtain 7.264 g of 1-[4-{-2-(1,1-dimethylethylamino)-ethoxy}-phenyl]-ethanone.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)=[C:19]([O:26][CH2:27][CH2:28][OH:29])[N:18]=[C:17]([C:30]3[N:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:38][C:39]1[CH:40]=[N:41][C:42](Cl)=[N:43][CH:44]=1.Cl>O1CCCC1.CC(N(C)C)=O>[Br:38][C:39]1[CH:40]=[N:41][C:42]([O:29][CH2:28][CH2:27][O:26][C:19]2[N:18]=[C:17]([C:30]3[N:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[N:16]=[C:15]([NH:14][S:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=3)(=[O:12])=[O:13])[C:20]=2[C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)=[N:43][CH:44]=1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2nc(-c3ncccn3)nc(OCCO)c2-c2cccs2)cc1
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2nc(-c3ncccn3)nc(OCCOc3ncc(Br)cn3)c2-c2cccs2)cc1
Reaction time: 0.33 h
Yield: 26.4 %

Procedure:
To a solution of 4-tert-butyl-N-{6-(2-hydroxyethoxy)-5-(2-thienyl)-2-(2-pyrimidinyl)-pyrimidin-4-yl}benzenesulfonamide (1790 mg) in tetrahydrofuran (20 ml) is added sodium hydride (60% dispersion, 413 mg) at room temperature, and thereto is added dimethylacetamide (4 ml), and the mixture is stirred for 20 minutes. To the reaction mixture is added 5-bromo-2-chloro-pyrimidine (952 mg), and the mixture is stirred at room temperature for 46 hours. The mixture is acidified with 10% hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=4:1) to give the title compound (617 mg) as a crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([CH3:11])[CH:4]=1.C([Li])CCC.CN(C)[C:19](=[O:21])[CH3:20].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([CH2:11][C:19](=[O:21])[CH3:20])[CH:4]=1
Reactant: COc1cnc(C)cc1OC
Reactant: CC(=O)N(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cnc(CC(C)=O)cc1OC
Temperature: 0 °C

Procedure:
To a stirred solution of 4,5-dimethoxy-2-methylpyridine (2.92 g) in tetrahydrofuran (30 ml) was added a solution of n-butyllithium in n-hexane (1.63M, 14 ml) dropwise at −50° C. under a nitrogen atmosphere, and the mixture was warmed to 0° C. The mixture was cooled to −50° C., and N,N-dimethylacetamide (2.31 ml) was added dropwise. Then the mixture was warmed to room temperature, poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 ml×4). The combined organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 100 g, n-hexane:ethyl acetate=1:1) to give 1-(4,5-dimethoxypyridin-2-yl)propan-2-one (1.59 g).