Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([CH3:15])([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CC)[CH3:4])#[N:2].N[CH2:17][CH2:18][OH:19]>C(O)CCC.O.O.C([O-])(=O)C.[Cd+2].C([O-])(=O)C>[CH3:15][C:3]([C:1]1[O:19][CH2:18][CH2:17][N:2]=1)([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:4]
Reactant: CCCCCCCCCCC(C)(C)C#N
Reactant: NCCO
Agent: CC(=O)[O-]
Agent: [Cd+2]
Solvent: O
Solvent: CCCCO
Product: CCCCCCCCC(C)(C)C1=NCCO1

Procedure:
100 mmoles of 2-cyano-2-methyldodecane is reacted with 120 mmoles of 2-aminoethanol in 50 ml of 1-butanol in presence of 2.5 mmoles of cadmium acetate dihydrate as outlined under Example 1 to give 2-(2-methyl-2-decyl)-2-oxazoline.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10](Cl)=[CH:9][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:7][C:6]=12.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][NH2:33])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][NH:33][C:10]2[N:5]3[N:4]=[CH:3][C:2]([Br:1])=[C:6]3[N:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:9]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: Clc1ccccc1-c1cc(Cl)n2ncc(Br)c2n1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CNc2cc(-c3ccccc3Cl)nc3c(Br)cnn23)CC1
Temperature: 75 °C
Yield: 101.2 %

Procedure:
3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine (300 mg, 0.875 mmoles) (prepared as described in Preparative Example 129) was dissolved in anhydrous 1,4-dioxane (6.8 mL). 4-(aminomethyl)piperidine-1-carboxylic acid tert-butyl ester (225 mg, 1.05 mmoles) and diisopropyl ethylamine (0.3055 mL, 1.75 mmoles) were added and the mixture was heated at 75° C. for 24 h. The solution was evaporated to dryness and the residue was chromatographed on a silica gel column (15×5 cm) using dichloromethane as the eluant to give 4-{[3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester (461.2 mg, 100%): FABMS: m/z 520.1 (MH+); HRFABMS: m/z 520.1111 (MH+). Calcd. for C23H28N5O2BrCl: m/z 520.1115; δH (CDCl3) 1.30 (2H, m, CH2), 1.51 (9H, s, —COOC(CH3)3), 1.85 (2H, d, CH2), 1.95 (1H, m, CH), 2.76 (2H, m, CH2), 3.40 (2H, m, CH2), 6.37 (1H, s, H6), 6.55 (1H, m, NH), 7.42 (2H, m, Ar—H), 7.52 (1H, m, Ar—H), 7.76 (1H, m, Ar—H) and 8.07 ppm (1H, s, H2); δC (CDCl3) CH3: 28.5, 28.5, 28.5; CH2: 29.1, 29.1, 43.5, 43.5, 47.9; CH: 36.3, 87.5, 127.2, 130.2, 130.3, 131.6, 143.9; C: 79.7, 83.3, 132.1, 138.6, 145.4, 146.3, 154.7, 158.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]3[O:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[O:21][CH2:20]3)=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.[CH:30](=O)[CH3:31].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]3[O:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[O:21][CH2:20]3)=[CH:15][CH:14]=2)[CH2:30][CH3:31])=[CH:8][CH:9]=1
Reactant: CC=O
Reactant: COC(=O)c1ccc(CNCc2ccc([C@H]3COc4ccccc4O3)cc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCN(Cc1ccc(C(=O)OC)cc1)Cc1ccc([C@H]2COc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-{[(S)-4-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-benzylamino]-methyl}-benzoic acid methyl ester (prepared according to General Method E) (130 mg, 0.33 mmol), acetaldehyde (0.03 mL, 0.50 mmol), and sodium cyanoborohydride (42 mg, 0.67 mmol) in MeOH (15 mL) is treated with 2 drops of acetic acid. The mixture is stirred at room temperature for 16 h, and concentrated. The residue is purified by flash chromatography eluting with a gradient of 0-10% MeOH in DCM to give 4-({[(S)-4-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-ethyl-amino}-methyl)-benzoic acid methyl ester.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.C(N(CC)CC)C.[C:23]([CH2:25][C:26]([OH:28])=O)#[N:24].[C:29]([N:37]1[CH2:42][CH2:41][NH:40][C@H:39]([CH3:43])[CH2:38]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[C:29]([N:37]1[CH2:42][CH2:41][N:40]([C:26](=[O:28])[CH2:25][C:23]#[N:24])[C@H:39]([CH3:43])[CH2:38]1)(=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1
Reactant: N#CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)CC#N
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.1 %

Procedure:
DCC (2.43 g) and triethylamine (5 ml) were added into a solution of cyanoacetic acid (1.00 g) and (R)-N-benzoyl-3-methylpiperazine (2.84 g) in THF (50 ml). After reaction stirred at room temperature for 12 hours, solvents were removed under vacuum to give a residue which was purified by silica gel column chromatography to afford 3 g of (R)-N-benzoyl-3-methyl-N′-(2-cyano-acetyl)piperazine. MS m/z: (M+H)+ calcd for C15H18N3O2 272.14, found 272.17. HPLC retention time: 0.93 minutes (column H).
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]=2[O:4][C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Br:24]N1C(=O)CCC1=O.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:24][CH2:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]=2[O:4][C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cccc2c(=O)c(C)c(-c3ccccc3)oc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cccc2c(=O)c(CBr)c(-c3ccccc3)oc12
Yield: 79.6 %

Procedure:
A mixture of 9.2 g of ethyl 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylate (prepared as described by Da Re et al., J. Med. Chem., 2, 263 (1960)), 6.4 g of N-bromosuccinimide and 0.04 g of benzoylperoxide in 80 ml of anhydrous carbon tetrachloride was stirred at reflux for 1.5 hours. After cooling to room temperature the formed succinimide was collected by suction and washed with cold carbon tetrachloride. The mother liquors were evaporated to dryness in vacuo and the residue was rinsed with diethyl ether and collected by suction yielding 9.2 g of the title compound melting at 133°-134° C. after crystallization from acetone-n-hexane.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([O:17][CH3:18])=[C:14]([NH2:16])[CH:15]=1.[C:19]([C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[S:30])=[CH:24][CH:23]=1)([OH:21])=[O:20]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([O:17][CH3:18])=[C:14]([NH:16][C:29](=[S:30])[NH:28][C:25]2[CH:24]=[CH:23][C:22]([C:19]([OH:21])=[O:20])=[CH:27][CH:26]=2)[CH:15]=1
Reactant: O=C(O)c1ccc(N=C=S)cc1
Reactant: COc1ccc(-c2cc3ccccc3[nH]2)cc1N
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3ccccc3[nH]2)cc1NC(=S)Nc1ccc(C(=O)O)cc1

Procedure:
The product from Example 1, Step B, 5-(1H-indol-2-yl)-2-methoxy-phenylamine (0.286 g, 1.0 mmol) was mixed with 4-carboxyphenyl isothiocyanate (0.185 g, 1.03 mmol) in tetrahydrofuran (40 mL). The solvent was boiled off on the rotary evaporator (no vacuum), and ethyl acetate was added to the residue and the insoluble material was collected by filtration. The collected solid was taken up in tetrahydrofuran, concentrated to dryness, and triturated again with ethyl acetate to give the product as a white solid (0.180 g), mp 201-203° C.
Reaction SMILES: [C:1]1([CH2:9]Cl)[CH:6]=[CH:5][C:4]([CH2:7]Cl)=[CH:3][CH:2]=1.[C:11]([O-:14])(=[O:13])[CH3:12].[K+]>C(O)(=O)C>[C:11]([O:14][CH2:9][C:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:14][C:11](=[O:13])[CH3:12])=[CH:3][CH:2]=1)(=[O:13])[CH3:12]
Reactant: ClCc1ccc(CCl)cc1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)OCc1ccc(COC(C)=O)cc1
Yield: 63 %

Procedure:
438 gms (2.5 moles) of p-xylylene dichloride were added slowly to a refluxing solution of 539 gms (5.5 moles) of anhydrous potassium acetate in 2000 mls of glacial acetic acid. The resultant mixture was refluxed for a further 2 hours and then cooled. The solution was extracted several times with hot benzene, and the benzene extracts were washed with water until neutral. After distilling off the benzene, the residue was recrystallised from petroleum ether to yield 350 gms of p-xylylene diacetate.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[N:8][C:7]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[C:23]([CH3:28])=[N:24][O:25][C:26]=4[CH3:27])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[C:29](N=C(N(C)C)N(C)C)([CH3:32])([CH3:31])[CH3:30].BrCC(C)C>C(#N)C>[CH:1]1([C:4]2[N:9]=[N:8][C:7]([N:10]([CH2:30][CH:29]([CH3:32])[CH3:31])[S:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]4[C:23]([CH3:28])=[N:24][O:25][C:26]=4[CH3:27])=[CH:18][CH:19]=3)(=[O:12])=[O:13])=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Nc2ccc(C3CC3)nn2)cc1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Solvent: CC(C)CBr
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C3CC3)nn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.8 %

Procedure:
To a solution of N-(6-cyclopropylpyridazin-3-yl)-4-((3,5-dimethylisoxazol-4-yl)methoxy)benzenesulfonamide (51 mg, 0.127 mmol) in acetonitrile (0.1 mL) stirred at room temperature, was added 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (0.051 mL, 0.255 mmol). The mixture was stirred at room temperature for 1 hour, then 1-bromo-2-methylpropane (0.028 mL, 0.255 mmol) added. The reaction was then heated by microwaves to 150° C., for 30 minutes. After cooling the solvent was removed under a stream of nitrogen and the crude sample purified by mass directed autoprep (formic acid modifier) to give the title product (2.8 mg). LCMS (2 min, formic) Rt 1.21 min, m/z (ES+) 457 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](I)=[CH:4][C:3]=1[CH3:10].[Br-].[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[Zn+].O1CCCC1>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.O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:13]2[S:12][CH:16]=[CH:15][N:14]=2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(I)cc(C)c1Br
Reactant: [Zn+]c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2nccs2)cc(C)c1Br
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 2-bromo-5-iodo-1,3-dimethyl-benzene (0.28 g), 2-thiazolylzinc bromide (0.5 mol/L in tetrahydrofuran; 1.9 mL), tetrakis(triphenylphosphine)palladium(0) (52 mg), and tetrahydrofuran (5 mL) under argon atmosphere is stirred at 100° C. for 3 h. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate) to give the title compound. LC (method 9): tR=1.19 min; Mass spectrum (ESI+): m/z=268/270 (Br) [M+H]+.
Reaction SMILES: [CH:1]([Si:4]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[SH:5])([CH3:3])[CH3:2].[H-].[Na+].[C:14]([C:16]1([C:23]2[CH:28]=[CH:27][CH:26]=[C:25](I)[CH:24]=2)[CH2:21][CH2:20][O:19][CH:18]([CH3:22])[CH2:17]1)#[N:15].O>C1(C)C=CC=CC=1.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>[C:14]([C:16]1([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([S:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:6]([CH3:8])[CH3:7])[CH:9]([CH3:11])[CH3:10])[CH:24]=2)[CH2:21][CH2:20][O:19][CH:18]([CH3:22])[CH2:17]1)#[N:15]
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Reactant: CC1CC(C#N)(c2cccc(I)c2)CCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1CC(C#N)(c2cccc(S[Si](C(C)C)(C(C)C)C(C)C)c2)CCO1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 96.5 %

Procedure:
To a stirred solution of triisopropylsilanethiol (Tetrahedron Lett. 1994, 35, 3221.; 684 mg, 3.6 mmol) in toluene (5 ml) was added sodium hydride (60% oil dispersion, 144 mg, 3.6 mmol) under a nitrogen atmosphere. After stirring for 15 min, the resulting solution was added to a mixture of (2SR, 4RS)-4-cyano-4-(3-iodophenyl)-2-methyl-3,4,5,6-tetrahydro-2H-pyran (1.07 g, 3.27 mmol) and tetrakis(triphenylphosphine)palladium(0) (114 mg, 0.1 mmol) in toluene (20 ml), and the mixture was heated at 80° C. for 1 h. The resulting mixture was cooled, poured into water (50 ml) and extracted with Et2O (100 ml). The organic extract was washed with water (50 ml), brine (50 ml), dried (MgSO4) and concentrated. Purification by silica gel column chromatography, eluting with ethyl acetate-hexane (1:9), gave 1.23 g (96%) of the titled compound as a red oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[C:11]([OH:18])[CH:12]=[CH:13][C:14]=2[N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1.[CH3:19][O:20][C:21](=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>>[CH3:19][O:20][C:21](=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:18][C:11]1[CH:12]=[CH:13][C:14]([N+:15]([O-:17])=[O:16])=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:10]=1
Reactant: Cc1ccc(Nc2cc(O)ccc2[N+](=O)[O-])cc1
Reactant: COC(=O)CCCCCBr
Product: COC(=O)CCCCCOc1ccc([N+](=O)[O-])c(Nc2ccc(C)cc2)c1

Procedure:
990 mg of 3-(4-methylphenyl)amino-4-nitrophenol was reacted with 6-bromohexanoic acid methyl ester according to general operating instructions 2. 1.5 g was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[ClH:32]>C(O)(C)C.O1CCOCC1>[ClH:1].[ClH:32].[N:26]1([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:2]3[N:11]=[C:10]([NH:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)=[CH:25][CH:24]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Clc1nc(Nc2ccccc2)c2ccccc2n1
Reactant: Nc1ccc(N2CCCCC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: c1ccc(Nc2nc(Nc3ccc(N4CCCCC4)cc3)nc3ccccc23)cc1

Procedure:
A mixture of 2-chloro-4-phenylamino-quinazoline (0.18 g) and N-(4-aminophenyl)-piperidine (0.164 g) is heated for 3 min to produce a melt which is dissolved in isopropanol (4 ml). 4N HCl in dioxane (1 ml) is added. Recrystallization from ethanol and diethylether yields 2-[4-(piperidin-1-yl)-phenylamino]-4-phenylamino-quinazoline dihydrochloride, Rf (A1) 0.64, FAB-MS: (M+H)+ =396. m.p.: (decomposition).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH:7][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]=O)[CH:3]=1.[C:16](OCC)(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].N1CCCCC1>C(O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([N:7]2[C:8]3[C:9](=[CH:10][CH:11]=[CH:12][N:13]=3)[CH:14]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]2=[O:23])[CH:3]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1cc(Nc2ncccc2C=O)no1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2cccnc2n(-c2cc(C)on2)c1=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
3.3 g (16 mmol) of (2-(5-methyl-3-isoxazolyl)amino)nicotinaldehyde was dissolved in ethanol (60 mL), and 3.9 g (24 mmol) of diethyl malonate and 0.56 g (6.5 mmol) of piperidine were added thereto. The resulting mixture was stirred overnight at 90° C. The reaction mixture was cooled, and then the solvent was distilled off. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:4 to 7:3), and thus 2.7 g of the title compound was obtained as pale yellow crystals (yield: 55%).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[F:32][C:33]1[CH:34]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1>>[CH:27]1([CH2:26][N:10]2[C:9]3[N:8]=[C:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][S:39]([C:35]5[CH:36]=[CH:37][CH:38]=[C:33]([F:32])[CH:34]=5)(=[O:41])=[O:40])=[CH:31][CH:30]=4)[NH:15][C:14]=3[C:13](=[O:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:11]2=[O:25])[CH2:28][CH2:29]1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Product: O=c1c2[nH]c(Cc3ccc(NS(=O)(=O)c4cccc(F)c4)cc3)nc2n(CC2CC2)c(=O)n1Cc1ccccc1F

Procedure:
Prepared from 8-(4-amino-benzyl)-3-cyclopropylmethyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 3-fluoro-benzenesulfonyl chloride. Tan solid; EI-HRMS m/e calculated for C29H25F2N5O4S (M+) 577.1595, found 577.1599.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N[C:24]1C=CC(C)=C[CH:25]=1>>[CH3:13][C:12]1[C:7]([NH:6][C:1]2[CH:5]=[CH:4][C:3]([CH3:2])=[CH:25][CH:24]=2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cc1ccc(N)cc1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1ccc(Nc2nc(NCc3ccccn3)nc(C)c2C)cc1

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using p-toluidine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.06 (s, 3H), 2.31 (s, 3H), 2.33 (s, 3H), 4.71 (d, J=2.8 Hz, 2H), 5.75 (bs, 1H), 6.28 (s, 1H), 7.06 (d, J=7.3 Hz, 2H), 7.15 (t, J=6.8 Hz, 1H), 7.30-7.38 (m, 3H), 7.61 (t, J=7.4 Hz, 1H), 8.58 (d, J=4.0 Hz, 1H); MS (ESI) m/z 320.7 (M+1)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].Cl.[CH3:9][CH:10]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]1=[O:17].N1C=CC=CC=1>C(Cl)Cl>[C:1]([N:14]1[CH2:15][CH2:16][CH:10]([CH3:9])[C:11](=[O:17])[CH2:12][CH2:13]1)(=[O:3])[CH3:2]
Reactant: CC1CCNCCC1=O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCC(=O)C(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
Acetic anhydride (0.437 mL, 4.62 mmol) was added at 0° C. to a solution of 5-methyl-azepan-4-one hydrochloride (0.740 g, 3.08 mmol) in DCM (20 mL) and pyridine (0.25 mL, 3.08 mmol). The reaction mixture was stirred at RT for 8 hours before being partitioned between DCM and H2O. The organic layer was dried (Na2SO4), filtered, and evaporated. The crude residue was purified by SiO2 chromatography (100% EtOAc) to give 0.220 g of 1-acetyl-5-methyl-azepan-4-one (42% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[N:11]2[CH:12]=[C:13]([O:16][C@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@@H:20]([NH2:27])[CH2:19][CH2:18]3)[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1.ClC(Cl)(Cl)C[O:31][C:32](=O)[NH:33][C:34]1[N:35]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH2:50][CH2:51][O:52]C3CCCCO3)[CH:44]=2)[N:36]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:39]([C:37]1[CH:38]=[C:34]([NH:33][C:32]([NH:27][C@@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([C@@H:3]5[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])=[N:8][N:9]=4)[CH:12]=3)[CH2:18][CH2:19]2)=[O:31])[N:35]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH2:50][CH2:51][OH:52])[CH:44]=2)[N:36]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Temperature: 90 °C
Reaction time: 4.5 h
Yield: 85.9 %

Procedure:
A mixture of Intermediate 5c (150 mg, 0.410 mmol) and Intermediate 39b (230 mg, 0.430 mmol) in 1,4-dioxane (4 mL) and DIPEA (113 μL, 0.65 mmol) was stirred at 90° C. for 4.5 h. The mixture was concentrated in vacuo. The residue was purified by FCC twice, using 0-10% MeOH in DCM, to give the title compound as a pale yellow foam (234 mg, 76%). LCMS (Method 3): Rt 3.03 min, m/z 749.2 [MH+].
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[NH:4][N:3]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>N1C=CC=CC=1>[CH3:24][S:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([NH:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[NH:1][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:13])=[O:14])(=[O:23])=[O:22]
Reactant: O=C(Cl)c1ccccc1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(N)c2c1
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(NC(=O)c3ccccc3)c2c1

Procedure:
N-[5-(2-Methylsulfonylbenzenesulfonylamino)-1H-indazol-3-yl]benzamide can be obtained as described in Example 28 from 0.5 g of N-(3-amino-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide, 3 ml of pyridine and 0.158 ml of benzoyl chloride. 435 mg of N-[5-(2-methylsulfonylbenzenesulfonylamino)-1H-indazol-3-yl)benzamide are thus obtained in the form of a pink solid which decomposes at approximately 200° C. (analysis C21H18N4O5S2.0.22CH2Cl2 % calculated C, 53.60; H, 3.86; N, 11.91; O, 17.00; S, 13.63. % found C, 53.59; H, 3.89; N, 12.10; S, 13.53).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([CH3:17])[S:16][C:10]=2[S:9][CH2:8][CH2:7]1.[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K].O>CN(C)C=O>[OH2:13].[C:18]1(=[O:28])[N:22]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH3:17])[S:16][C:10]=3[S:9][CH2:8][CH2:7]2)[C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1cc2c(s1)SCCN(CCCCCl)C2=O
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(s1)SCCN(CCCCN1C(=O)c3ccccc3C1=O)C2=O
Reaction time: 6 h
Yield: 212.4 %

Procedure:
To a solution of 3.0 g of 4-(4-chlorobutyl)-2,3-dihydro-7-methylthieno[3,2-f][1,4]thiazepin-5(4H)-one in 30 ml of dimethylformamide was added 2.3 g of potassium phthalimide and stirred at 70°-80° C. for 6 hours. After cooling, the mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated in vacuo. The resulting crude crystals were recrystallized from methanol to give 4.6 g of 4-(4-phthalimidobutyl)-2,3-dihydro-7-methylthieno[3,2-f][1,4]thiazepin-5(4H)-one hydrate as white crystals, melting at 120°-121° C.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21]3[C:20]4[CH:19]=[CH:18][CH:17]=[N:16][C:15]=4[N:14]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:13](=[O:28])[C:12]=3[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.COC1C=CC(N)=CC=1.NC1C=CC=CC=1>>[C:6]1([N:9]2[C:21]3[C:20]4[CH:19]=[CH:18][CH:17]=[N:16][C:15]=4[N:14]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:13](=[O:28])[C:12]=3[CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=1
Reactant: COc1ccc(N2CCc3c2c2cccnc2n(-c2ccccc2)c3=O)cc1
Solvent: Nc1ccccc1
Solvent: COc1ccc(N)cc1
Product: O=c1c2c(c3cccnc3n1-c1ccccc1)N(c1ccccc1)CC2

Procedure:
This procedure will also produce 1,2,3,5-tetrahydro-1-(4-methoxyphenyl)-5-phenyl-4H-pyrrolo [3,2-c][1,8]naphthyridin-4-one when 4-methoxyaniline (also known as p-anisidine) is substituted for aniline.