Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH:25]1[CH2:30][CH2:29][CH:28]([NH:31][S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8](=[O:9])[NH:10][C:11]2[S:12][C:13]([CH2:16][N:25]3[CH2:26][CH2:27][CH:28]([NH:31][S:32]([CH:35]([CH3:37])[CH3:36])(=[O:33])=[O:34])[CH2:29][CH2:30]3)=[CH:14][N:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: CC(C)S(=O)(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: CC(C)S(=O)(=O)NC1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CC1
Yield: 10.9 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (21 mg, 0.07 mmol), propane-2-sulfonic acid piperidin-4-yl amide hydrochloride (17 mg, 0.077 mmol) and sodium triacetoxyborohydride (19 mg, 0.09 mmol) to afford 4 mg (11%) of the desired product after purification.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=2[N:6]=1.O1CCCC1.[CH3:19][NH:20][CH3:21].O>O1CCCC1>[CH3:19][N:20]([CH3:21])[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])c1ccc2sc(Cl)nc2c1
Reactant: CNC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1nc2cc([N+](=O)[O-])ccc2s1
Reaction time: 16.5 h

Procedure:
In 7.4 ml of tetrahydrofuran was dissolved 160 mg of 2-chloro-5-nitro-1,3-benzothiazole, and thereto was added 1.86 ml of a 1M dimethylamine tetrahydrofuran solution, followed by 16.5 hours of stirring. Water was added to the reaction solution and the organic layer was extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by evaporation. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain 173 mg of N,N-dimethyl-5-nitro-1,3-benzothiazol-2-amine as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH:4]=[O:5].[CH3:7][C:8]([CH3:12])=[CH:9][CH2:10][OH:11].[N+]([O-])(O)=O>O>[CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][O:5][CH:10]([O:11][CH2:4][CH:3]=[C:2]([CH3:6])[CH3:1])[CH:9]=[C:8]([CH3:12])[CH3:7]
Reactant: CC(C)=CCO
Reactant: CC(C)=CC=O
Solvent: O
Solvent: O=[N+]([O-])O
Product: CC(C)=CCOC(C=C(C)C)OCC=C(C)C
Reaction time: 4.5 h

Procedure:
690 g (8.2 moles) of 3-methyl-but-2-en-1-al, 1730 g (20 moles) of 3-methyl-but-2-en-1-ol and 23 mg of 65% strength nitric acid (corresponding to 0.62 × 10-4 % by weight of 100% strength HNO3, based on 2,420 g of starting compounds) are boiled under 60 mm Hg in a 4 liter flask surmounted by a packed column (filled with 5 mm Raschig rings). The bottom temperature assumes a value of 76-88° C. The packed column has a diameter of 45 mm and has 30 theoretical plates. The water formed in the reaction is taken off at the top of the column and the organic material which separates from the water is returned continuously into the top of the column. With a reflux of 600 g/hour, quantitative conversion of the aldehyde is achieved after 4.5 hours. 1,1-Bis-(3-methyl-but-2-en-1-yl-oxy)-3-methyl-but-2-ene is obtained about 99% pure after distilling off the excess alcohol, the yield being 98.6% based on 3-methyl-but-2-en-1-al and 98.2% based on 3-methyl-but-2-en-1-ol.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]([CH2:28][CH2:29][CH2:30]O)[C:20]4=[O:32])[CH2:15][CH2:14]2)[CH2:5][CH2:4][CH:3]3[CH2:2]1.[S:33]1[CH2:37][C:36](=[O:38])[NH:35][C:34]1=[O:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:22]=[CH:27][CH:26]=[CH:25][C:24]=5[N:21]([CH2:28][CH2:29][CH2:30][N:35]5[C:36](=[O:38])[CH2:37][S:33][C:34]5=[O:39])[C:20]4=[O:32])[CH2:15][CH2:14]2)[CH2:5][CH2:4][CH:3]3[CH2:2]1
Reactant: O=C1CSC(=O)N1
Reactant: O=c1n(CCCO)c2ccccc2n1C1CCN(C2CCC3CCc4cccc2c43)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1CSC(=O)N1CCCn1c(=O)n(C2CCN(C3CCC4CCc5cccc3c54)CC2)c2ccccc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1-[1-(1,2,2a,3,4,5-Hexahydroacenaphthylen-5-yl)piperidin-4-yl]-3-(3-hydroxypropyl)-1,3-dihydro-2H-benzimidazol-2-one and 2,4-thiazolidinedione (314 mg) were dissolved in THF (25 ml), 40% solution (1.22 ml) of triphenylphosphine (702 mg) and diethyl azodicarboxylate (DEAD) in toluene was added, and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (160 mg).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:15]4=[O:22])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[F:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:27]5[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=5)=[CH:16][C:15]4=[O:22])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(CO)cc3=O)cc21
Reactant: Oc1ccc(F)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(COc4ccc(F)cc4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 20.2 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-(hydroxymethyl)pyridin-2(1H)-one (150 mg), 4-fluorophenol (114 mg) and tributylphosphine (307 mg) in THF (5 ml) was added 1,1′-(azodicarbonyl)dipiperidine (385 mg), and the mixture was stirred at 60° C. for 4 h. The mixture was concentrated in vacuo, and diluted with DCM. The mixture was washed with water and brine successively, dried over Na2SO4, concentrated in vacuo and purified by column chromatography (MeOH/DCM) to afford the title compound (40 mg) as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[N:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(-c2ccc(F)cc2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccc(F)cc2)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 37 %

Procedure:
Combine 6-bromopyridine-3-carboxylic acid methyl ester (1.03 g, 4.78 mmol), 4-fluorophenylboronic acid (1.88 g, 13.41 mmol), and cesium fluoride (2.55 g, 16.78 mmol) in DMF (25 mL) and water (4 mL) with stirring. Place the hetereogeneous reaction mixture, open to the air, in an oil bath maintained at 80° C. After 5 minutes of heating, add Pd(OAc)2 (150 mg, 0.67 mmol) in one portion. After 17 hours, cool the reaction to room temperature, dilute with ethyl acetate and filter through a short plug of celite with additional ethyl acetate. Wash the organics with water, dry over MgSO4, filter and evaporate. Purification by flash column chromatography yields 6-(4-fluorophenyl)pyridine-3-carboxylic acid methyl ester as a yellow solid. Dissolve the purified ester in THF (0.25 M) and add an equal volume of 1 M NaOH. Stir vigorously at room temperature for 15 hours. Upon completion, acidify the reaction with conc. HCl and collect the white precipitate by filtration. Drying under vacuum yields 385 mg (37%) of the title compound. MS (ES): m/z 218.1 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:21])=[O:20])[CH:14]=1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([NH:34][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:21])=[O:20])[CH:14]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=S(=O)(c1cccc(CCCCOCCCCCCBr)c1)C1CCCC1
Reactant: NCc1ccccc1
Product: O=S(=O)(c1cccc(CCCCOCCCCCCNCc2ccccc2)c1)C1CCCC1

Procedure:
1-{4-[(6-Bromohexyl)oxy]butyl}-3-(cyclopentylsulfonyl)benzene (Example 11ii) (50 mg) was dissolved in benzylamine (0.5 ml), and heated in a microwave oven at 150° for 10 min. Excess benzylamine was removed in vacuo and the residue purified on a silica SPE bond elut cartridge, eluting with EtOAc-cyclohexane mixtures, to give the title compound, (40 mg) LCMS RT=2.74 min
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH:13]([CH2:18][C:19]([OH:21])=[O:20])[C:14]2=[O:17])=[CH:9][CH:8]=1.[CH3:22]O>>[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH:13]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:14]2=[O:17])=[CH:9][CH:8]=1
Reactant: CO
Reactant: COc1ccc2c(c1)C(=O)C(CC(=O)O)CC2
Solvent: O=S(Cl)Cl
Product: COC(=O)CC1CCc2ccc(OC)cc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under cooling, 1.8 ml of thionyl chloride was dropwise added slowly to 20 ml of methanol. After 10 minutes, 1.5 g of 7-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-acetic acid was added and stirred overnight at room temperature. The solvent was distilled off under reduced pressure to obtain 1.6 g of methyl 7-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-acetate.
Reaction SMILES: C([O:6][CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH2:9]1)(=O)CCC.C[O-].[Na+].CO.C(Cl)(Cl)Cl.Cl>CO>[F:20][C:16]1[CH:15]=[C:14]([N:10]2[CH2:9][C@H:8]([CH2:7][OH:6])[O:12][C:11]2=[O:13])[CH:19]=[CH:18][CH:17]=1
Reactant: CCCC(=O)OC[C@H]1CN(c2cccc(F)c2)C(=O)O1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C1O[C@@H](CO)CN1c1cccc(F)c1

Procedure:
A mixture of (R)-[3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl butyrate (PREPARATION 12, 2.789 g, 9.91 mmol) in methanol (10 ml) is treated with a 25 wt. % mixture of sodium methoxide in methanol (57 μl, 0.99 mmol) at 20°-25°. After 45 min as measured by TLC (methanol/chloroform, 5/95) the starting material has been consumed. The reaction mixture is carefully quenched by the addition of hydrochloric acid (1N, 0.99 ml 0.99 mmol) and then concentrated under reduced pressure. Chromatography of the concentrate over silica gel, eluting first with hexane/ethyl acetate (1/1), and then ethyl acetate, pooling and concentrating the appropriate fractions gives the title compound, mp 106.5°-107.5°; [α]25D -66.8° (c 1.1, CH3CN); IR (mineral oil mull): 3520, 1724, 1612, 1590, 1496, 1428, 1420, 1232 and 1199 cm-1 ; NMR (CDCl3, 300 MHz) δ 7.44, 7.32, 7.23, 6.84, 4.77, 4.07-3.96, 3.76 and 2.44; MS (m/z) 211, 180, 136, 124, 95; HRMS (m/z) 211.0641 (calc'd for C10H10FNO3 : 211.0645).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:15]([CH3:17])=[C:14]([CH3:18])[N:13]=[C:12](OC3C=CC=CC=3)[C:11]=2[N:10]=[C:9]1[CH2:26][CH2:27][CH3:28])(=[O:4])=[O:3].C([O-])(=O)C.[NH4+:33]>>[CH3:1][S:2]([CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:15]([CH3:17])=[C:14]([CH3:18])[N:13]=[C:12]([NH2:33])[C:11]=2[N:10]=[C:9]1[CH2:26][CH2:27][CH3:28])(=[O:4])=[O:3]
Reactant: [NH4+]
Reactant: CCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCCS(C)(=O)=O
Agent: CC(=O)[O-]
Product: CCCc1nc2c(N)nc(C)c(C)c2n1CCCS(C)(=O)=O
Yield: 67.2 %

Procedure:
Using the general method of Example 89 Part H, 1-[3-(methanesulfonyl)propyl]-6,7-dimethyl-4-phenoxy-2-propyl-1H-imidazo[4,5-c]pyridine (2.1 g, 5.23 mmol) was reacted with ammonium acetate (25 g) and purified to provide 1.14 g of 1-[3-(methanesulfonyl)propyl]-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-4-amine as white needles, mp 153.5–155.0° C. 1H NMR (300 MHz, CDCl3) δ 4.83 (br s, 2H), 4.48–4.42 (m, 2H), 3.07 (t, J=7.1 Hz, 2H), 2.95 (s, 3H), 2.82–2.77 (m, 2H), 2.45 (s, 6H), 2.35–2.25 (m, 2H), 1.94–1.81 (m, 2H), 1.07 (t, J=7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 153.2, 148.3, 147.1, 138.9, 125.4, 104.0, 51.2, 42.9, 41.3, 29.5, 24.3, 22.1, 21.5, 14.0, 13.1;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:12]C(C)(C)C(C)(C)[O:9]2)=[CH:4][N:3]=1.Br[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(O)C>COCCOC>[CH2:23]([O:22][C:20]([C:19]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([B:8]([OH:9])[OH:12])=[CH:4][N:3]2[CH:18]=1)=[O:21])[CH3:24]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)c1cn2cc(B(O)O)ccc2n1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 2.5 g of 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in 50 mL of 1,2-dimethoxyethane are added 2.14 mL of ethyl 3-bromo-2-oxopropionate. The reaction mixture is stirred for 3.5 hours at 25° C., 50 mL of ethanol are then added and the resulting mixture is refluxed for 16 hours. The reaction mixture is cooled and concentrated to dryness. The residue is suspended in 100 mL of water at 0° C. and treated, while stirring vigorously, with solid sodium carbonate until a pH of 8-9 is obtained. The precipitate is filtered off by suction and washed with 100 mL of water at 0° C. and then dissolved in 150 mL of methanol. The solution is dried over magnesium sulfate, filtered, concentrated and dried under vacuum to give 2.36 g of 2-ethoxycarbonylimidazo[1,2-a]pyridine-6-boronic acid in the form of a cream-coloured solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][N:19]=3)=[O:17])=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:27])[N:3]=1>[Pd].CO.C1COCC1>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]3[CH:5]=[C:4]([CH3:27])[N:3]=[C:2]([NH2:1])[N:7]=3)=[CH:14][CH:13]=2)=[O:17])=[N:19][CH:20]=1
Reactant: Cc1cc(Nc2ccc(NC(=O)c3ccc([N+](=O)[O-])cn3)cc2)nc(N)n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Nc2ccc(NC(=O)c3ccc(N)cn3)cc2)nc(N)n1
Reaction time: 5 h
Yield: 135.3 %

Procedure:
To a suspension of 20 (523 mg, 1.43 mmol) was suspended in 1:1 MeOH/THF (100 ml) was added 10% Pd/C (100 mg) and hydrogenated at 55 Hg mm. for 5 h. The reaction mixture was filtered and evaporated to dryness and recrystallized from DCM/Pet.ether to give 21 (649 mg, 96%); mp (DCM/Pet.ether)>290° C.; 1H NMR [(CD3)2SO] δ 10.05 (s, 1H, NH), 8.85 (s, 1H, NH), 8.25 (d, J=2.5 Hz, 1H, H-6), 7.82 (d, J=8.6 Hz, 1H, H-3), 7.73 (d, J=9.0 Hz, 2H, H-2′, 6′), 7.60 (d, J=9.0 Hz, 2H, H-3′, 5′), 7.03 (dd, J=8.5, 2.7 Hz, 1H, H-4), 6.04 (brs, 2H, NH2), 6.03 (brs, 2H, NH2), 5.85 (s, 1H, H-5″), 2.08 (s, 3H, CH3); Anal. calc. for C17H17N7).0.25H2O C, 60.1; H, 5.2; N, 28.9; found, C, 60.0; H, 5.2; N, 28.7%.
Reaction SMILES: OS(O)(=O)=O.[C:6]([OH:15])(=[O:14])[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH2:9].[N+]([C:19]1[CH:28]=[CH:27][C:22]([CH:23]=[CH:24][CH:25]=O)=[CH:21][CH:20]=1)([O-])=O.[OH-].[K+]>CC(O)=O.O>[C:22]1([C:23]2[CH:24]=[CH:25][C:10]3[C:8](=[C:7]([C:6]([OH:15])=[O:14])[CH:13]=[CH:12][CH:11]=3)[N:9]=2)[CH:27]=[CH:28][CH:19]=[CH:20][CH:21]=1
Reactant: O=CC=Cc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccccc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cccc2ccc(-c3ccccc3)nc12
Temperature: 105 °C

Procedure:
A mixture of conc. H2SO4 (45 mL), water (5 mL), AcOH (5 mL), anthranilic acid (XI; R2 =H) (20.5 g) and H3AsO4 (80% w/w; 32 g) was heated with stirring to 105° C., and then treated with cinnamaldehyde (VIII; R1 =H) (25 g) at the rate which maintained the temperature at 105°-110° C. The reaction mixture was stirred for a further 3 h at 110°-115° C., then cooled and strongly basified with aqueous KOH. The aqueous layer was decanted from a quantity of tar, washed with CHCl3 and then acidified with AcOH. The resulting precipitate was chromatographed on SiO2 and eluted with a gradient of MeOH in CH2Cl2 to give a low yield of the desired acid, mp 160°-161° C., identical in all respects to the compound obtained in Example A. This compound was elaborated to compound 1 of Table I by the method outlined in Example A.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[N:7]([CH2:11][CH3:12])[C:6](=[O:13])[CH2:5]2.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](Cl)=[O:20]>CN(C)C1C=CN=CC=1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[N:7]([CH2:11][CH3:12])[C:6](=[O:13])[CH:5]2[C:19]([C:15]1[O:14][CH:18]=[CH:17][CH:16]=1)=[O:20]
Reactant: CCN1C(=O)Cc2cc(Cl)cnc21
Reactant: O=C(Cl)c1ccco1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C(=O)c2ccco2)c2cc(Cl)cnc21

Procedure:
The title compound was prepared from 5-chloro-1-ethyl-7-azaoxindole (Example 53D) according to the procedure of Example 53E, using 5-chloro-1-ethyl-7-azaoxindole (405 mg, 2.06 mmol), 4-dimethylaminopyridine (500 mg, 4.09 mmol), 2-furoyl chloride (0.22 mL, 2.23 mmol) and DMF (10 mL). The solid product obtained following chromatography was recrystallized from hexane. The yield was 110 mg (18%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:15]=[CH:14][C:7]([NH:8][C:9](=[O:13])[CH2:10][O:11][CH3:12])=[CH:6][C:5]=1[N+:16]([O-])=O)[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:30]([N:37]1[C:41](=[O:42])[C:40](=[C:43]2[N:47]([CH3:48])[C:46]3[CH:49]=[C:50]([O:53][CH2:54][CH2:55][Cl:56])[CH:51]=[CH:52][C:45]=3[S:44]2)[S:39][CH2+:38]1SC)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([N:37]1[C:41](=[O:42])[C:40](=[C:43]2[N:47]([CH3:48])[C:46]3[CH:49]=[C:50]([O:53][CH2:54][CH2:55][Cl:56])[CH:51]=[CH:52][C:45]=3[S:44]2)[S:39][C:38]1=[N:16][C:5]1[CH:6]=[C:7]([NH:8][C:9](=[O:13])[CH2:10][O:11][CH3:12])[CH:14]=[CH:15][C:4]=1[NH:3][CH2:1][CH3:2])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CS[CH2+]1SC(=C2Sc3ccc(OCCCl)cc3N2C)C(=O)N1Cc1ccccc1
Reactant: CCNc1ccc(NC(=O)COC)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(NC(=O)COC)cc1N=C1SC(=C2Sc3ccc(OCCCl)cc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 4′-ethylamino-2-methoxy-3′-nitroacetanilide was hydrogenated and then condensed with 3-benzyl-5-[5-(2-chloroethoxy)-3-methylbenzothiazol-2-ylidene]-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. MS(ESI): 638(MH+).
Reaction SMILES: [C:1]([N:8]([CH2:23][CH2:24][N:25]1C(=O)C2=CC=CC=C2[C:26]1=[O:35])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])=[CH:11][CH:10]=1)(C(OCC)=O)=[O:2]>C(O)C>[F:21][C:17]([F:22])([CH:18]([F:20])[F:19])[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([N:8]2[CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:1]2=[O:2])=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(=O)N(CCN1C(=O)c2ccccc2C1=O)c1ccc(OCC(F)(F)C(F)F)cc1
Solvent: CCO
Product: O=C1NCCN(c2ccc(OCC(F)(F)C(F)F)cc2)C1=O
Yield: 36.5 %

Procedure:
The mixture of the obtained N-ethoxalyl-N-(2-phthalimido)ethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline (3.4 g), hydradine hydrate (0.7 ml) and ethanol (80 ml) was refluxed for 9 hours. The crystals separated out were filtered off before cooling and the solvent of the filtrate was distilled off under reduced pressure. Water (150 ml) and ethyl acetate (300 ml) were added to the residue to fractionate. The ethyl acetate layer was washed with 5% aqueous solution of sodium bicarbonate and then with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent; ethyl acetate:dichloromethane:methanol=7:7:1 v/v) to give 1-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,3-piperazinedione (0.8 g) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28][N:27]=2)[CH:21]=1)=O)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28][N:27]=4)[CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ncn1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: Cc1ccccc1C
Product: Cc1cc(-c2cccc(C3=Nc4cc(Cl)c(Cl)cc4NC(=O)C3)c2)ncn1

Procedure:
The title compound was prepared from 4,5-dichlorophenylenediamine (89 mg, 0.5 mmol) and 3-[3-(6-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K41) (172 mg, 0.55 mmol) by refluxing in xylene according to the general procedure M. Obtained as a light yellow solid (63 mg).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.O[NH:27][C:28](=[NH:39])[C:29]1[CH:34]=[CH:33][C:32]([S:35](=[O:38])(=[O:37])[NH2:36])=[CH:31][CH:30]=1>>[F:25][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[O:14][N:39]=[C:28]([C:29]4[CH:30]=[CH:31][C:32]([S:35]([NH2:36])(=[O:37])=[O:38])=[CH:33][CH:34]=4)[N:27]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=2)[CH:4]=1
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1ccc(-c2noc(-c3cnn4c(C(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)n2)cc1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) (179 mg, 0.5 mmol) and N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by column chromatography (dichloromethane/MeOH/NH4OH) and crystallization (ethyl acetate/hexane) as a light yellow solid (159 mg, 59%). MS (ISN) 535.3 [(M−H)−]; mp 283° C.
Reaction SMILES: C(OC(=O)[N:10]([C:15]1[N:44]=[C:18]2[N:19]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=3)[C:20]([CH3:33])=[C:21]([C:31]#[N:32])[C@@H:22]([C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[N:17]2[N:16]=1)[CH2:11][CH:12]1[CH2:14][CH2:13]1)C1C=CC=CC=1>CO.[Pd]>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([C@H:22]2[N:17]3[N:16]=[C:15]([NH:10][CH2:11][CH:12]4[CH2:13][CH2:14]4)[N:44]=[C:18]3[N:19]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:41])[F:43])[CH:35]=3)[C:20]([CH3:33])=[C:21]2[C:31]#[N:32])=[CH:28][CH:27]=1)#[N:30]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N(CC3CC3)C(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NCC3CC3)nc2N1c1cccc(C(F)(F)F)c1

Procedure:
Under an atmosphere of argon protective gas, benzyl{(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}(cyclopropyl-methyl)carbamate (20.0 mg, 33 μmol) was dissolved in degassed methanol (5 ml). After addition of palladium on activated carbon (10%; 5 mg), the mixture was hydrogenated under a hydrogen atmosphere (˜1 atm) at RT for 1.75 h. The reaction mixture was then filtered, the filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (Kromasil C18 column, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (10.9 mg, 70% of theory).
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:24][CH3:25])[N:13]2[CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[C:9]([NH2:26])[N:8]=1)[CH2:3][CH2:4][CH3:5].I[CH2:28][CH3:29].C(N(CC)CC)C>CN(C=O)C>[CH2:28]([N:20]1[CH2:21][CH2:22][CH2:23][CH:18]([CH2:17][CH2:16][N:13]2[C:12]([O:24][CH3:25])=[N:11][C:10]3[C:14]2=[N:15][C:7]([O:6][C@@H:2]([CH3:1])[CH2:3][CH2:4][CH3:5])=[N:8][C:9]=3[NH2:26])[CH2:19]1)[CH3:29]
Reactant: CCI
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1

Procedure:
A solution of 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9-[2-(3-piperidinyl)ethyl]-9H-purin-6-amine (45 mg, 0.124 mmol), iodoethane (0.012 ml, 0.149 mmol) and triethylamine (0.035 mL, 0.248 mmol) in DMF (3 ml) was heated at 50° C. for 18 hours.