Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[NH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: CCCCN
Product: CCCCNc1c(C(=O)OCC)cnc2c(OC)cccc12

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (300 mg, 1.13 mmol) was treated with 1-aminobutane following general procedure B to afford 4-butylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (295 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into the corresponding ethylamide (220 mg) following general procedure E.
Reaction SMILES: [N:1]1[NH:2][CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6][C:5]=12.[Br:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:18][C:19]1[N:24]=[CH:23][C:22]([N:2]2[CH:3]=[C:4]3[C:5]([CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]3)=[N:1]2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c[nH]nc2CC1
Reactant: OB(O)c1ccc(Br)nc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(Br)nc3)nc2CC1
Reaction time: 192 h

Procedure:
A mixture of 1,1-dimethylethyl 4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 9) (207 mg, 0.87 mmol), (6-bromo-3-pyridinyl)boronic acid (204 mg, 1.74 mmol), copper acetate (472 mg, 2.61 mmol), pyridine (140 μl, 1.74 mmol) and molecular sieves (4 Å, 750 mg) in dichloromethane (10 ml) was stirred open to the atmosphere for 8 days. Crude mixture was then filtered through a pad of celite and washed with dichloromethane and ammonia. After evaporation in vacuo, the residue was purified by SCX cartridge eluting with methanol first then 2M ammonia in methanol. The methanol fractions containing the product were combined and evaporated in vacuo. The residue was then purified by column chromatography on silica gel eluting with a mixture of hexane in ethyl acetate (10:1 to 1:1) to afford the title compound (D17). MS (ES+) m/e 393 and 395 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20](=[O:23])[CH2:21]Br>CN(C)C=O>[CH3:18][O:19][C:20](=[O:23])[CH2:21][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: COC(=O)CBr
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 4-chloro-3-nitrophenol (25 g), N,N-dimethylformamide (200 mL), potassium carbonate (60 g) and bromoacetic acid methyl ester (15.5 mL) was stirred at room temperature for 2.5 hours. The mixture was partitioned between ethyl acetate and water, and the aqueous phase extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The residue was washed with diethyl ether to afford title compound as a white solid (30 g).
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:6][CH2:5][N:4]([C:7](=[O:16])[CH:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH3:9])[CH2:3]1.[C:18]([O:22][C:23]([N:25]1[C@@H:29]([C@H:30]([OH:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][CH2:27][C@H:26]1[CH2:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:18]([O:22][C:23]([N:25]1[C@@H:29]([C@H:30]([OH:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][CH2:27][C@H:26]1[CH2:38][C:39]1[CH:47]=[CH:46][C:42]([C:43]([N:13]2[CH2:12][CH2:11][N:10]([CH:8]([CH3:9])[C:7]([N:4]3[CH2:5][CH2:6][C:2]([F:1])([F:17])[CH2:3]3)=[O:16])[CH2:15][CH2:14]2)=[O:44])=[CH:41][CH:40]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Reactant: CC(C(=O)N1CCC(F)(F)C1)N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)N1CCC(F)(F)C1)N1CCN(C(=O)c2ccc(C[C@@H]3CC[C@H]([C@H](O)c4ccccc4)N3C(=O)OC(C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a stirred solution of 12 mg (0.049 mmol) of 4-(2-(3,3-Difluoropyrrolidin-1-yl)-1-methyl-2-oxoethyl)piperazine (TEA salt), and 20 mg (0.049 mmol) of 4-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)benzoic acid (i-1) in 1 mL anhydrous N,N-dimethylformamide under nitrogen atmosphere was added 0.042 mL (0.24 mmol) of N,N-diisopropylethylamine and 37 mg (0.097 mmol) of 2-(1H-7-azabezotriazole-1-yl)-1,1,3,3,-tetramethyl uranium hexafluoro phosphate methanium. The resulting reaction mixture was stirred at ambient temperature overnight. The reaction was purified by reverse-phase HPLC (TMC Pro-Pac C18; 10-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient) to give 23 mg of the title compound. LC/MS: (M+1)=641.2.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12]C(=O)C)=[C:8]([N+:16]([O-:18])=[O:17])[CH:7]=1)([CH3:5])[CH2:3][CH3:4].O.[OH-].[Na+]>CO>[CH3:5][C:2]([C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([N+:16]([O-:18])=[O:17])[CH:7]=1)([CH3:1])[CH2:3][CH3:4]
Reactant: CCC(C)(C)c1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(C)(C)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
To a stirred solution of N-[4-(1,1-dimethylpropyl)-2-nitrophenyl]acetamide (Preparation 95, 15 g, 60 mmol) in MeOH:water (120 mL:80 mL) at 0° C. was added sodium hydroxide (5 g, 125.4 mmol) and the reaction stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and extracted with EtOAc. The organic layer was collected, dried over Na2SO4 and concentrated in vacuo to afford the title compound (11 g, 88%).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=O)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)([Br:15])=O>>[Br:15][C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: O=c1[nH]c(-c2ccccc2)cs1
Reactant: O=P(Br)(Br)Br
Product: Brc1nc(-c2ccccc2)cs1
Temperature: 100 °C
Yield: 73.5 %

Procedure:
A mixture of 4-phenylthiazol-2(3H)-one (300 mg, 1.7 mmol) and POBr3 (4.85 g, 17.0 mmol) was heated to 100° C. in a sealed tube for 10 h. The reaction mixture was poured in ice water and the organic product was extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 1% EtOAc in petroleum ether) to get 2-bromo-4-phenylthiazole (300 mg, yield 73%) as light brown colored liquid. 1H NMR (300 MHz, CDCl3) δ 7.88-7.85 (m, 2H), 7.46-7.35 (m, 4H). MS (ESI) m/z: Calculated for C9H6BrNS: 240.94. found: 242.0 (M+H)+
Reaction SMILES: [CH3:1][C:2]([O:39]C(=O)C)([CH3:38])[C:3]([N:5]1[CH2:8][CH:7]([CH2:9][C:10]2[N:11]([CH3:37])[C:12]3[C:17]([N:18]=2)=[C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:15]=[C:14]([N:25]2[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=[C:26]2[CH:34]([CH3:36])[CH3:35])[N:13]=3)[CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.CO>[OH:39][C:2]([CH3:38])([CH3:1])[C:3]([N:5]1[CH2:8][CH:7]([CH2:9][C:10]2[N:11]([CH3:37])[C:12]3[C:17]([N:18]=2)=[C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:15]=[C:14]([N:25]2[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=[C:26]2[CH:34]([CH3:35])[CH3:36])[N:13]=3)[CH2:6]1)=[O:4]
Reactant: CC(=O)OC(C)(C)C(=O)N1CC(Cc2nc3c(N4CCOCC4)nc(-n4c(C(C)C)nc5ccccc54)nc3n2C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)C(C)(C)O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.5 %

Procedure:
A mixture of acetic acid 1,1-dimethyl-2-{3-[9-methyl-2-(2-isopropylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purin-8-ylmethyl]azetidin-1-yl}-2-oxoethyl ester (56 mg, 0.17 mmol) and LiOH (84 μL, 0.33 mmol, 4M solution) in THF (3 mL) and MeOH (1 mL) was allowed to stir at r.t. for 18 h. Further LiOH (495 μL, 1.98 mmol, 4M solution) and the mixture stirred at 50° C. for 5 days. The reaction mixture was concentrated in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-5%) then partitioned between DCM and H2O, the organic phase dried (Na2SO4) and concentrated in vacuo. The resulting residue was dissolved in a mixture of MeCN and H2O and allowed to freeze-dry affording 854 as a white solid (62 mg, 70%). LCMS (method I): RT 3.15 min, [M+H]+ 533.4. 1H NMR (DMSO, 400 MHz): δ 7.87-7.86 (1 H, m), 7.65-7.64 (1 H, m), 7.25-7.24 (2 H, m), 5.02 (1 H, brd s), 4.57 (1 H, t, J=8.92 Hz), 4.25 (4 H, brd s), 4.18 (1 H, dd, J=10.40, 5.66 Hz), 4.03 (1 H, t, J=9.00 Hz), 3.91-3.90 (1 H, m), 3.76 (4 H, t, J=4.59 Hz), 3.72 (3 H, s), 3.68 (1 H, dd, J=9.99, 5.41 Hz), 3.22-3.21 (3 H, m), 1.36 (3 H, s), 1.34 (3 H, s), 1.25 (6 H, d, J=2.06 Hz)
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[Br-].[CH2:11]([Zn+])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]=[CH:4][N:3]=1
Reactant: Cc1c(Cl)ncnc1Cl
Reactant: [Zn+]Cc1ccccc1
Agent: [Br-]
Product: Cc1c(Cl)ncnc1Cc1ccccc1

Procedure:
Prepared from 4,6-dichloro-5-methylpyrimidine and benzyl zinc bromide (0.5 M solution in tetrahydrofuran) according to the procedure described in WO 2007/146824 as a colorless oil. 1H NMR (400 MHz, CDCl3): 8.78 (s, 1H), 7.33-7.18 (m, 5H), 4.19 (s, 2H), 2.36 (s, 3H); MS (EI) for C12H11ClN2: 219 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7][C:6]=2[CH:17]=1.[CH3:18][N:19](C)C=O>>[C:18]([C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7][C:6]=2[CH:17]=1)#[N:19]
Reactant: O=C1Cc2ccccc2Sc2cc(Br)ccc21
Reactant: CN(C)C=O
Product: N#Cc1ccc2c(c1)Sc1ccccc1CC2=O
Temperature: 0 °C

Procedure:
36.45 G. 3-bromo-10,11-dihydro-11-oxodibenzo[b,f]thiepin and 32.11 g. cuprous cyanide are refluxed in 450 cc. dimethylformamide for five and one half hours. The reaction mixture is cooled down and poured into 2 l. of ice water with good mechanical stirring. The resulting solid is filtered, washed with water, then extracted into 1.7 l. chloroform. The insoluble copper salts are filtered and the filtrate evaporated to dryness. The residue is triturated in methanol and the insoluble yellow product is filtered and weighs 22.4 g. (74.6%), m.p. 166°-170° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[C:3]([NH:5][C:6]1[CH:10]=[CH:9][N:8]([CH3:11])[CH:7]=1)=[O:4].[H-].[Na+].I[CH3:16].O>CN(C)C=O>[CH3:16][N:5]([C:6]1[CH:10]=[CH:9][N:8]([CH3:11])[CH:7]=1)[C:3](=[O:4])[CH:2]([CH3:12])[CH3:1]
Reactant: CI
Reactant: CC(C)C(=O)Nc1ccn(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(=O)N(C)c1ccn(C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Methyl-N-(1-methylpyrrol-3-yl)propanamide (2.50 g, 0.015 mol) in dry dimethylformamide (10 ml) was cooled to below 0° C. and stirred under nitrogen during the addition of 50% sodium hydride/oil (0.73 g, 0.0152 mol). After the addition, the mixture was stirred at 0° C. for 30 minutes and then brought to 15° C. when iodomethane (4.30 g, 0.0302 mol) was added. The mixture was stirred at room temperature overnight and then poured into water (200 ml) and the mixture extracted with ether (4 × 50 ml). The combined extracts were washed with water (3 × 50 ml) and dried over magnesium sulphate. The solvent was removed in vacuo to leave a solid which separated from pentane at -10° C as white flakes (2.11 g, 78%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Ni]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(C2CCNCC2)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1ccc(C2CCNCC2)cc1
Yield: 72.9 %

Procedure:
A solution of the 4-(4-nitrophenyl) piperidine (29.3 g, 0.144 mol) obtained in (i) in ethyl acetate (150 ml) was hydrogenated at 3 atmospheres over Raney Nickel (5 g) until uptake of hydrogen ceased. Evaporation afforded a brown oil which was crystallised from ether to give the desired product as light yellow crystals (18.5 g, 74% yield), M.pt. 85°-87° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16]([CH3:33])([CH3:32])[C:17](=[O:31])[N:18]3[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCO.C(OCC)C>CCO>[F:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][N:18]1[C:19]2[C:15](=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:22]=[CH:21][CH:20]=2)[C:16]([CH3:33])([CH3:32])[C:17]1=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2C(C)(C)C(=O)N3Cc2cccc(F)c2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CC1(C)C(=O)N(Cc2cccc(F)c2)c2cccc(N3CCNCC3)c21

Procedure:
4-[1-(3-Fluoro-benzyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (260 mg) was dissolved in 3 mL of EtOH and 0.5 mL of 2.0 N HCl/EtOH was added. After heating for 30 minutes at reflux, the solution was cooled and diethyl ether was added to precipitate out 1-(3-Fluoro-benzyl)-3,3-dimethyl-4-piperazin-1-yl-1,3-dihydro-indol-2-one as a hydrochloride salt (121 mg). MS: 354 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([CH3:21])=[CH:16][N:15]=1>O1CCCC1.BrCCBr.C[Si](Cl)(C)C.[Zn].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>[Cl:13][C:14]1[N:19]=[C:18]([CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=2)[C:17]([CH3:21])=[CH:16][N:15]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: Cc1cnc(Cl)nc1Cc1cccc(C(F)(F)F)c1
Yield: 41.9 %

Procedure:
To a suspension of zinc dust (2.5 g, 38 mmol) stirred in 25 mL of tetrahydrofuran were added 2 drops of 1,2-dibromoethane and the mixture was heated to reflux. The suspension was then cooled and 2 drops of trimethylsilyl chloride were added followed by portionwise addition of 3-(trifluoromethyl)benzyl bromide (6.0 g, 25 mmol) with heating. When the reaction temperature reached 55° C., a strong exotherm occurred and the reaction mixture was allowed to heat at reflux. The cooled reaction solution was decanted into a solution of 2,4dichloro-5-methylpyrimidine (3.3 g, 20 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.44 g, 0.63 mmol) stirring in 15 mL of tetrahydrofuran. Upon heating, the reaction mixture exothermed strongly again at 55° C. and was then heated to reflux. The reaction mixture was allowed to cool and partitioned between diethyl ether and water. The organic layer was separated, washed with 1 N aqueous hydrochloric acid and brine, dried over magnesium chloride and concentrated under reduced pressure to give a crude oil. Purification by flash chromatography on silica gel (15 to 25% ethyl acetate in hexane) yielded 2.4 g of the title compound of Step A as an oil. 1H NMR (CDCl3): δ8.35 (s, 1H), 7.60-7.35 (m, 4H), 4.15 (s, 2H), 2.25 (s, 3H).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.C(O)(=O)C.[CH3:12][S-:13].[Na+]>C1(C)C=CC=CC=1>[CH3:12][S:13][CH:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH2:2]1
Reactant: O=C1C=CCCC1
Reactant: C[S-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CSC1CCCC(=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
Cyclohex-2-enone (3.80 g, 95% Aldrich, 39.5 mmol uncorrected), toluene (15.31 g, HPLC grade) and glacial acetic acid (2.85 g, 47.4 mmoles, 1.20 eq, 99.7+% Aldrich) were combined in a 50 mL 3-necked round bottom flask equipped with a magnetic stirrer, reflux condenser with nitrogen oil bubbler vented to a bleach scrubber, thermometer with Therm-o-watch controller and septum. To the stirred solution was added 15 wt % sodium thiomethoxide (19.4 g of solution, 2.91 g, 41.5 mmol, 1.05 eq of NaSCH3) in portions via syringe during 19 min. The reaction temperature increased from 28.0° C. to 36.4° C. during the addition. The two-phase mixture was stirred at ambient temperature overnight. The reaction mixture was heated to about 50° C. and stirred for 7.5 h. The mixture was then allowed to cool to room temperature with stirring overnight. The phases were allowed to settle for 30 min. The lower aqueous phase was removed. The upper organic phase was washed with water (2×10 mL), dried through a cone of anhydrous magnesium sulfate and concentrated on the rotary evaporator (29 in. Hg vacuum/48° C.) to afford 4.91 g of 3-(methylthio)cyclohexanone as a clear pale yellow oil. Area % conversion by GC 95%. Raw area % 91.1%. Mass recovery 86%.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O[CH:22](OCC)[N:23]([CH3:25])[CH3:24])C>C1(C)C=CC=CC=1>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:22][N:23]([CH3:25])[CH3:24])[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(OCC)N(C)C
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Solvent: Cc1ccccc1
Product: CN(C)C=Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reaction time: 5 h

Procedure:
With the exclusion of moisture, 200 mg (0.767 mmol) of 3-amino-4-(3-chlorophenylamino)-1 H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) are suspended in 3.2 ml of toluene; 150 μl (0.87 mmol) of N,N-dimethylformamide diethyl acetal in 6 ml of toluene are added and the reaction mixture is heated to boiling. After 5 hours, filtration is carried out, followed by thorough washing with toluene. 4-(3-Chloro-phenylamino)-3-(dimethylaminomethyleneamino)-1H-pyrazolo[3,4-d]pyrimidine is obtained; m.p. 243-245° C.; HPLC: tRet(grad20-100/20)=9.7; FAB-MS: (M+H)+=316.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:22].[CH3:23][N:24]([CH3:37])[CH2:25][CH2:26][NH:27][S:28]([C:31]1[S:32][C:33](Br)=[CH:34][CH:35]=1)(=[O:30])=[O:29]>>[CH3:23][N:24]([CH3:37])[CH2:25][CH2:26][NH:27][S:28]([C:31]1[S:32][C:33]([C:21]#[C:20][C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH:14]([F:15])[F:16])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:22])[CH:4]=4)=[N:9][C:10]=23)=[CH:34][CH:35]=1)(=[O:30])=[O:29]
Reactant: CN(C)CCNS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C#Cc4ccc(S(=O)(=O)NCCN(C)C)s4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-7-difluoromethyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.16) (159 mg, 0.5 mmol) and 5-bomo-thiophene-2-sulfonic acid (2-dimethylamino-ethyl)-amide (example B.49) (157 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (200 mg, 73%). MS (ISN) 548.1 [(M−H)−]; mp 149° C.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]([C:12]1[C:13](=[O:23])[O:14][C:15]([OH:22])=[C:16]([C:19](=O)[CH3:20])[C:17]=1[OH:18])(=[O:11])[CH3:10]>CO>[C:9]([C:12]1[C:13](=[O:23])[O:14][C:15](=[O:22])[C:16](=[C:19]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH2:8])[CH3:20])[C:17]=1[OH:18])(=[O:11])[CH3:10]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: Nc1ccccc1N
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccccc2N)C(=O)OC1=O

Procedure:
o-Phenylenediamine (2.1 g., 0.02 m.) is added to a hot solution of 4.2 g. (0.02 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in methanol and the resulting mixture is refluxed for two hours. The reaction mixture is cooled and filtered to yield 5-acetyl-3-[1-(o-aminophenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 179°-181° C.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([CH2:14][OH:15])[N:2]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([O:15][CH2:14][C:3]1[N:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3)(=[O:18])[CH3:17]
Reactant: OCc1cc2c(cn1)[nH]c1ccccc12
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCc1cc2c(cn1)[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 9H-β-carboline-3-methanol (99 mg, 0.50 mmol) in acetic anhydride (10 mL) was stirred for 4 hours at room temperature, during which time the starting material dissolved. Removal of the acetic anhydride in vacuo afforded a tan solid (122 mg). Purification by flash chromatography on silica gel with ethyl acetate as the eluent afforded 82 mg (68%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ9.49 (s, 1H), 8.99 (s, 1H), 8.13 (d, J=8.0, 1H), 8.07 (s, 1H), 7.56-7.61 (m, 2H), 7.26-7.34 (m, 1H), 5.43 (s, 2H), 2.15 (s, 3H). LRMS calcd for C14H12N2O2 (M+H) 241, found 241.0.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>S(Cl)(Cl)=O>[C:17]([C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[NH:14][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[Cl:1])#[N:18]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: N#Cc1ccccc1N
Solvent: O=S(Cl)Cl
Product: N#Cc1ccccc1NC(=O)c1ccc([N+](=O)[O-])cc1Cl
Yield: 29.1 %

Procedure:
A solution of 2-chloro-4-nitrobenzoic acid (6.00 g, 29.8 mmol) in thionyl chloride (20 ml) was heated at reflux for 2.5 hours. The reaction was cooled, the excess thionyl chloride was evaporated in vacuo and the residue was azeotroped with toluene (2×25 ml). The residue was taken up in toluene (35 ml), 2-aminobenzonitrile (1.75 g, 14.8 mmol) was added and the reaction heated at reflux for 2 hours. The reaction was cooled, the solvent was removed in vacuo and the residue was absorbed onto silica gel. Purification by flash chromatography on silica gel, eluting with dichloromethane, yielded N-(2-cyanophenyl)-2-chloro-4-nitrobenzamide (1.30 g, 27% yield) as a pale yellow solid:
Reaction SMILES: [C:1]1([CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[K+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:30])(=O)=O)=CC=1.O>CCOCC>[C:1]1([C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[F:30])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(F)(C(=O)OCC)c1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
1 millimole of diethyl phenylmalonate was stirred with potassium hydride in 2 milliliters ether for 30 minutes at -25° C. 1.2 molar equivalents N-fluorobenzenesulfonimide prepared according to Example 1 above in 2 milliliters ether were dropped into the mixture which was stirred for 1 hour at -20° C. The mixture was allowed to warm up to room temperature and water was added. The product was extracted into ether which was dried and evaporated. Purification was carried out on a silica gel column. C6H5CF(COOCH2CH3)2 was obtained in 47% yield.