Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[NH2:40][CH:41]1[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:40][CH:41]5[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]5)=[O:28])=[CH:24][CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Reactant: CN1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a mixture of 0.11 g (0.27 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-20), 0.19 mL (1.1 mmole) of ethyldiisopropyl amine and 0.034 g (0.30 mmole) of 4-amino-1-methyl-piperidine in 3.0 mL of dimethylformamide was added 0.13 g (0.30 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-75:25) gave 0.10 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide (I-21) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[CH2:15]([C:17]1([CH2:27][CH3:28])[C:22](=[O:23])[O:21][CH2:20][C:19]([CH3:26])([CH2:24][OH:25])[NH:18]1)[CH3:16]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:27]([C:17]1([CH2:15][CH3:16])[C:22](=[O:23])[O:21][CH2:20][C:19]([CH3:26])([CH2:24][O:25][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])[NH:18]1)[CH3:28]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCC1(CC)NC(C)(CO)COC1=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1(CC)NC(C)(COC(=O)C(C)(C)C)COC1=O
Reaction time: 20 h

Procedure:
2.4 ml (0.017 mol) of triethylamine and then 2.15 g 2 (0.018 mol) of pivaloyl chloride are added dropwise to a solution of 3.45 g (0.017 mol) of 3,3-diethyl-5-methyl-5-hydroxymethylmorpholin-2-one and 0.1 g of 4-dimethylaminopyridine in 20 ml dichloromethane at 15° C. After stirring for 20 hours, the precipitated triethylaminehydrochloride is removed by filtration and the filtrate is washed with water, dried over MgSO4 and concentrated by evaporation in a rotary evaporator. The residue is recrystallised from hexane. This gives 3.9 g (77%) of compound (217), m.p. 51-53° C.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:33])[CH2:11][N:12]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:15])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:1][O:8][NH:9][C:10](=[O:33])[CH2:11][N:12]([S:22]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)(=[O:24])=[O:23])[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:15]
Reactant: [H][H]
Reactant: COc1ccc(S(=O)(=O)N(CC(=O)NOCc2ccccc2)CC(=O)N2CCOCC2)cc1
Agent: [Pd]
Solvent: CO
Product: CONC(=O)CN(CC(=O)N1CCOCC1)S(=O)(=O)c1ccc(OC)cc1

Procedure:
To a solution of N-benzyloxy-[(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino]acetamide (0.33 grams, 0.69 mmol) in methanol (35 mL) was added 5% palladium on activated carbon (85 mg). The mixture was agitated under 2 atmospheres hydrogen in a Parr shaker for 1.5 hours. The catalyst was removed by filtration through nylon (pore size 0.45 μm) and the solvent was evaporated. The residue was chromatographed on silica gel eluting with 5% methanol in methylene chloride to afford N-methoxy-[(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino]acetamide as a white solid, 65 mg (24%); 1H NMR (CD3OD): δ 7.82 (d, J=9.0 Hz, 2H), 7.08 (d, J=9.0 Hz, 2H), 4.24 (s, 2H), 3.88 (s, 3H), 3.84 (s, 2H), 3.68-3.64 (m, 4H), 3.581-3.50 (m, 4H); MS (thermospray): m/z 388 (M+1), 387 (M); HRMS calculated for C16H22N3O7S (M+H): 388.1178, Found 338.1180.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6][CH:5]=1.[CH3:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].O>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[CH3:12])=[N:6][CH:5]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: COC(=O)c1ccc(N)nc1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)c2ccccc2C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To a solution of 6-aminonicotinic acid methyl ester (4 g) in pyridine (40 ml) is added with stirring 2-methylbenzoyl chloride (6.73 g) under ice-cooling, and the mixture is stirred at room temperature overnight. To the reaction solution is added water, and the precipitated crystals are collected by filtration, and dried to give 6-(2-methylbenzoylamino)nicotinic acid methyl ester (5.7 g) as white powder.
Reaction SMILES: Br[CH2:2][C:3]([NH2:5])=[O:4].[CH2:6]([NH:8][CH2:9][CH3:10])[CH3:7]>C(Cl)(Cl)Cl>[CH2:6]([N:8]([CH2:9][CH3:10])[CH2:2][C:3]([NH2:5])=[O:4])[CH3:7]
Reactant: NC(=O)CBr
Reactant: CCNCC
Solvent: ClC(Cl)Cl
Product: CCN(CC)CC(N)=O
Temperature: 25 °C
Yield: 79 %

Procedure:
2 g of 2-bromoacetamide (0.015 mol) were slowly added to diethylamine (40 mL, 0.387 mol) and the reaction mixture was heated to reflux for 20 h. After cooling to room temperature, the reaction mixture was filtered and precipitate discarded. The filtrate was concentrated under vacuum to result in slightly yellow solid. This solid was dissolved in chloroform (10 mL) and washed with aqueous saturated solution of Na2CO3 (3×10 mL). Combined organic phases were dried over Na2S04. The filtrate was concentrated under vacuum to result in 1.49 g (79% yield) of light yellow solid, which was azeotropically dried with benzene prior to use in the following reactions. 1H NMR (500 MHz, CDCl3, J=Hz): δ 6.19 (2H, s, br, NH2), 3.01 (2H, s, CH2), 2.56 (4H, q, J 7.2, NEt2), 1.04 (6H, t, J 7.3, NEt2). 13C NMR (125.8 MHz, CDCl3): δ 175.6 (C═O), 57.4 (CH2), 48.6, 12.3 (NEt2). HRMS (ESIMS) m/z for C6H15N2O [M+H]+ calcd 131.1184, found 131.0907.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:29])[C:19]([C:23]3[N:24]=[C:25]([NH2:28])[S:26][CH:27]=3)=[N:20][O:21]C)[C:15](=[O:30])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C(OCC1CS[C@@H]2C(NC(=O)C(C3N=C(N)SC=3)=NOC)C(=O)N2C=1C([O-])=O)(=O)C.[Na+].C(OCC1CS[C@@H]2C(NC(=O)C(C3N=C(N)SC=3)=NOC(C)C)C(=O)N2C=1C(O)=O)(=O)C>>[NH2:28][C:25]1[S:26][CH:27]=[C:23]([C:19](=[N:20][OH:21])[C:18]([NH:17][CH:16]2[C:15](=[O:30])[N:10]3[C:11]([C:12]([OH:14])=[O:13])=[C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:7][S:8][C@H:9]23)=[O:29])[N:24]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC(C)C)c3csc(N)n3)[C@H]2SC1
Agent: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Agent: [Na+]
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2SC1

Procedure:
Gelules were prepared with 250 mg of 3-acetoxymethyl 7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylic acid or sodium 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylate or 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-(1-methylethoxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid or the syn isomer of 7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-3-acetoxymethyl-ceph-3-eme-4-carboxylic acid and sufficient excipient to obtain a final weight of 400 mg.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[CH3:18][S:19][CH2:20][CH2:21][OH:22].CNCCNC.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:5]2[N:4]=[CH:3][C:2]([O:22][CH2:21][CH2:20][S:19][CH3:18])=[CH:7][N:6]=2)=[CH:11][CH:12]=1
Reactant: CSCCO
Reactant: COc1ccc(CNc2ncc(Br)cn2)cc1
Agent: CNCCNC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2ncc(OCCSC)cn2)cc1
Temperature: 110 °C
Reaction time: 66 h
Yield: 55.2 %

Procedure:
Colorless amorphous solid of 5-bromo-2-(4-methoxybenzylamino)pyrimidine (300 mg, 1.02 mmol) was suspended in toluene (20 mL), the suspension was added with cuprous iodide (200 mg, 1.05 mmol), 2-methylthioethanol (1.06 g, 11.5 mmol), N,N′-dimethyldiaminoethane (0.83 g, 9.42 mmol) and cesium carbonate (400 mg, 1.22 mmol), and the mixture was stirred at 110° C. for 66 hours in an argon atmosphere. The reaction mixture was separated by silica gel column chromatography, and then purified by preparative silica gel thin layer chromatography to obtain 2-(4-methoxybenzylamino)-5-(2-methylthioethoxy)pyrimidine as colorless amorphous solid (172 mg).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(N(C(C)C)CC)(C)C.[CH2:20]([O:22][CH2:23]OCl)[CH3:21]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:20]([O:22][CH2:23][O:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:21]
Reactant: Cc1cccc(C=O)c1O
Reactant: CCOCOCl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOCOc1c(C)cccc1C=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 52 %

Procedure:
To a stirred solution of 2-hydroxyl-3-methylbenzaldehyde (1.46 g, 10.7 mol), diisopropyl ethylamine (3.3 mL, 20.0 mmol) and 4-(dimethylamino)pyridine (122 mg, 1.0 mmol) in dichloromethane (35 mL) was added ethoxymethoxyl chloride (1.85 mL, 20.0 mmol) at RT. The mixture was stirred at RT for 17 h. The reaction was quenched with water (30 mL). The product was extracted with CH2Cl2 (3×40 mL). The combined organic extracts were washed with water (50 mL), and brine (50 mL), dried over anhydride Na2SO4. The residue was purified by flash column chromatography (hexanes/ethyl acetate=5:1, v/v) to provide the title compound (2.02 g, 97%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][N:18]([C:21](Cl)=[O:22])[CH2:17][CH2:16]1.[N:24]1([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH:28]=[CH:27][N:26]=[CH:25]1.CCN(C(C)C)C(C)C>C1COCC1>[N:24]1([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:21]([N:18]3[CH2:19][CH2:20][CH:15]([C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)[CH2:16][CH2:17]3)=[O:22])=[CH:31][CH:30]=2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: Nc1ccc(-n2ccnc2)cc1
Reactant: COc1cc2ncnc(C3CCN(C(=O)Cl)CC3)c2cc1OC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(-n5ccnc5)cc4)CC3)c2cc1OC
Temperature: 65 °C
Reaction time: 3 h
Yield: 8.7 %

Procedure:
4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carbonyl chloride (16.5 mg, 0.05 mmol), prepared as described in Example 3a, was dissolved in anhydrous THF (2 mL) and to it was added 4-imidazol-1-yl-phenylamine (12 mg, 0.075 mmol) followed by DIEA (14 μL, 0.075 mmol) and the mixture was stirred at 65° C. for 3 h. It was then concentrated in vacuo and the residue was purified by Preparative TLC (silica gel, 5% MeOH/DCM) to obtain 2 mg (5%) of pure 4-(6,7-dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-imidazol-1-yl-phenyl)-amide. 1H-NMR (300 MHz, CDCl3) δ 9.04 (s, 2H), 7.63 (m, 3H), 7.55-7.40 (m, 5H), 7.33 (s, 1H), 4.37 (m, 2H), 4.07 (s, 6H), 3.76-3.58 (m, 2H), 3.14 (m, 2H), 2.18-1.90 (m, 3H). LC/MS (ESI): calcd mass 458.2, found 459.5 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8](OS(C)(=O)=O)[CH2:7][N:6]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:4].[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C)C=O.O>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([N:22]=[N+:23]=[N-:24])[CH2:7][N:6]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Yield: 86.3 %

Procedure:
Heat a mixture of (2S,4R)-4-methanesulfonyloxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.60 mol, 185 g) and sodium azide (1.20 mol, 78 g,) in N,N-dimethylformamide (1 L) to 80° C. for 16 h. Dilute the reaction mixture with water and extract with ethyl acetate. Wash the combined organic layers with 0.5 N hydrochloric acid, saturated sodium bicarbonate solution, and brine. Dry over anhydrous sodium sulfate, filter, and concentrate under vacuum to obtain the title compound (140 g, 88%) as a thick, yellow oil. ES-MS m/z 271.2 [M+1]+, 171.0 [M−Boc]+.
Reaction SMILES: I[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[C:16]([Si:18]([CH3:21])([CH3:20])[CH3:19])#[CH:17]>C1COCC1.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[N:3][C:2]([C:17]#[C:16][Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:7][N:6]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(-c2cnc(I)cn2)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(-c2cnc(C#C[Si](C)(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2.30 g (7.37 mmol) 2-iodo-5-(4-methoxyphenyl)pyrazine and 1.56 mL (11.1 mmol) ethynyltrimethylsilane in 30 mL THF is charged with 0.12 g (0.15 mmol) bis(triphenylphosphine)dichloropalladium, 0.03 g (15.0 mmol) CuI and 3.01 mL (22.1 mmol) TEA. After stirring at r.t. for 4 h the reaction mixture is diluted with DCM and washed with 50 mL aq. 5% ammonia solution (1×) and 50 mL water (1×). The organic layer is dried with MgSO4 and the solvent is removed in vacuo. The residue is treated with PE/EtOAc (8/2), filtered through a plug of silica gel and the solvent is again removed in vacuo. The product is used without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][NH:13][CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl>[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][N:13]([C:36](=[O:38])[CH3:37])[CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1
Reactant: Clc1ccc2c(c1)CNCc1nnc([C@H]3CC[C@H](c4ccccc4)CC3)n1-2
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3ccccc3)CC2)C1
Reaction time: 19 h

Procedure:
To a solution of trans-8-chloro-1-(4-phenyl-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride (0.090 g, 0.22 mmol) and triethylamine (0.063 ml, 0.46 mmol) in dichloromethane (5 ml) was added acetyl chloride (0.017 ml, 0.24 mmol) at room temperature. After stirring for 19 h the reaction mixture was concentrated in vacuo. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.082 g, 90%) as white solid. MS m/e: 421 (M+H+)
Reaction SMILES: [C:1]1([N:7]2[C:16]([OH:17])=[C:10]3[N:11]=[CH:12][N:13]=[C:14]([SH:15])[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.C(=O)([O-])[O-].[K+].[K+].Br[C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>O>[C:1]1([N:7]2[C:16]([OH:17])=[C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH3:35])[CH3:34])[C:9]3=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1c2ncnc(S)c2nn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)(C)Sc1ncnc2c(O)n(-c3ccccc3)nc12
Temperature: 80 °C
Reaction time: 6 h

Procedure:
3.66 g of 2-phenyl-3-hydroxy-7-mercapto-pyrazolo [4,3-d]pyrimidine was suspended in a solvent mixture comprising 150 ml of ethanol and 30 ml of water, and 2.5 g of anhydrous potassium carbonate was added thereto. While heating the mixture to 80° C., 3.5 g of ethyl α-bromoisobutyrate was dropwise added thereto, and the heating was continued for further 6 hours. Then, the solvent was distilled off. Water was added to the residue and the residue was dissolved. The solution was acidified with hydrochloric acid, and then extracted with chloroform. The starting material insoluble in both the aqueous layer and the chloroform layer was collected by filtration and recovered (recovered amount: 1.5 g). The chloroform layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The remaining solid was recrystallized from acetone.
Reaction SMILES: Cl.[NH2:2][O:3][CH2:4][CH3:5].[C:6]([CH:9]1[CH2:12][N:11]([C:13](=[O:27])/[CH:14]=[CH:15]/[C:16]2[CH:17]=[C:18]3[C:23](=[N:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]3)[CH2:10]1)(=O)[CH3:7]>CO.ClCCl>[CH2:4]([O:3]/[N:2]=[C:6](\[CH:9]1[CH2:12][N:11]([C:13](=[O:27])/[CH:14]=[CH:15]/[C:16]2[CH:17]=[C:18]3[C:23](=[N:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]3)[CH2:10]1)/[CH3:7])[CH3:5]
Reactant: CC(=O)C1CN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)C1
Reactant: CCON
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCO/N=C(/C)C1CN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)C1
Reaction time: 8 h

Procedure:
1-(Aminooxy)ethane hydrochloride (23 mg, 0.23 mmol) was added to a solution of (E)-6-(3-(3-acetylazetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (50.0 mg, 0.16 mmol) in a mixture methanol/dichloromethane (8:2, 3.5 mL) at room temperature. The reaction mixture was stirred overnight. After concentration to dryness, the residue was purified by chromatography on silica gel using ethyl acetate/methanol (95:5) as eluent. The title product was obtained as a white solid (20 mg, 35%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CCN(C(C)C)C(C)C>CC(O)C>[C:11]([N:18]1[CH2:19][CH2:20][N:21]([C:6]2[N:7]=[CH:2][C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=2)[CH2:22][CH2:23]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ncc3cc[nH]c3n2)CC1
Reaction time: 18 h

Procedure:
A solution containing 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 32.6 mmol), Boc-piperazine (15 g, 81 mmol), and DIEA (19.8 mL, 114 mmol) in 130 mL IPA was stirred at 80 C for 18 hours, after which the reaction was concentrated. The crude was flashed on silica gel (20:1 DCM:MeOH) to give a yellow powder, which was recrystallized from MeOH/minimal DCM to give 4-Boc-piperazin-1-yl-7H-pyrrolo[2,3-d]pyrimidine as a white crystalline solid (3 crops). 1H NMR (CDCl3, 400 MHz) δ 11.37 (br s, 1H), 8.34 (s, 1H), 7.12 (d, J=3.3 Hz, 1H), 6.49 (d, J=3.5 Hz, 1H), 4.01-3.94 (m, 4H), 3.64-3.56 (m, 4H), 1.48 (s, 9H). HPLC Rt 2.05 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:12]([NH:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])[CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([N:14]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])[CH3:13]
Reactant: CCNCCOc1ccccc1C
Reactant: Clc1ncnc2ccccc12
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCN(CCOc1ccccc1C)c1ncnc2ccccc12
Reaction time: 5.5 h
Yield: 54.2 %

Procedure:
To a solution of 2.5 g (0.015 mole) of 4-chloroquinazoline in toluene were added 2.7 g (0.015 mole) of N-ethyl-2-(2-methylphenoxy)ethylamine and 1.5 g (0.015 mole) of triethylamine. The mixture was then refluxed, with stirring, for 5.5 hours. After completion of the reaction, the toluene was removed from the reaction mixture by evaporation under reduced pressure. Water was then added to the residue and the mixture was extracted with chloroform and the extract was dried. The chloroform was removed by evaporation and the crystals which separated out were recrystallized from isopropanol, giving 2.5 g (54%) of the desired Compound No. 2, in the form of colourless prisms melting at 85°-87° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](N)=[CH:5][CH:4]=1.S(=O)(=O)(O)O.C(C(CCCC)CO)C.N(OCCCCC)=O.[C:32]([O:36][CH2:37][CH:38]([CH2:43][CH3:44])[CH2:39][CH2:40][CH2:41][CH3:42])(=[O:35])[CH:33]=[CH2:34]>O.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:34]=[CH:33][C:32]([O:36][CH2:37][CH:38]([CH2:43][CH3:44])[CH2:39][CH2:40][CH2:41][CH3:42])=[O:35])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: C=CC(=O)OCC(CC)CCCC
Agent: [Pd]
Agent: CCCCCON=O
Agent: O=S(=O)(O)O
Solvent: CCCCC(CC)CO
Solvent: O
Product: CCCCC(CC)COC(=O)C=Cc1ccc(OC)cc1
Temperature: 10 °C
Reaction time: 0.67 h

Procedure:
12.3 g of 4-anisidine (4-methoxyaniline) are mixed while stirring with 10 ml of concentrated sulphuric acid and 60 ml of 2-ethylhexanol and the mixture is cooled to about 10° C. Subsequently 11.7 g of amyl nitrite are added and after addition is complete the mixture is stirred for a further 40 minutes. The reaction mixture is subsequently admixed with 20.2 g of 2-ethylhexyl acrylate and 100 mg of Pd (5% Pd on activated carbon) and heated to 65° C. over a period of 1 hour and stirred for a further 12 hours at this temperature. The mixture is diluted with 100 ml of water and extracted with 200 ml of dichloromethane. As examination by thin-layer chromatography and gas chromatography shows, 2-ethylhexyl p-methoxycinnamate has not been formed in even the smallest amounts. The 2-ethylhexyl acrylate employed is essentially present in unchanged form.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][CH:9]1[CH2:17][C:18]#[N:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:23]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=1.Cl>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[C:17]([C:23]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=1)[C:18]#[N:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2NC1CC#N
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C(=C(C#N)c2nccc(C(F)(F)F)n2)Nc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
A solution of 2-[1-(tert-butoxycarbonyl)benzimidazol-2(3H)-yl]acetonitrile (6 g, 23 mmol) in THF (50 mL) was added to a suspension of 60% sodium hydride in mineral oil (1.38 g, 35 mmol) in tetrahydrofuran (85 mL) at 0° C. over 10 min. The suspension was stirred at 0° C. for 15 min, and 2-chloro-4-trifluoromethylpyrimidin (2.79 mL, 23 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight, and water (300 mL) and then 1N hydrochloric acid (40 mL) were added. The crude product was extracted into chloroform and washed twice with water (100 mL each). The organic phase was dried over magnesium sulfate, and the solvent was removed under vacuum to give 2-[1-(tert-butoxycarbonyl)benzimidazol-2(3H)-ylidene]-2-(4-trifluoromethylpyrimidin-2-yl)acetonitrile (8.17 g) as a brown oil.