Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C(N(CC)CC)C.C(Cl)Cl.[CH3:27][OH:28].CN([CH:32]=[O:33])C>>[CH3:27][O:28][C:32]([C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:33]
Reactant: O=c1c2ccccc2oc2cc(Br)ccc12
Reactant: CO
Reactant: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(=O)c3ccccc3oc2c1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A sample of Compound 3a (20 g, 72.2 mmol) was dissolved in a 2:1 MeOH/DMF solution (600 mL). To this solution was added triethylamine (40 mL, 290 mmol) and the solution was degassed with Argon. To this was added dichlorobis(triphenylphosphine) palladium (II) (2.0 g, 2.85 mmol), and the reaction was transferred to a bomb and charged with 150 psi of CO (g). The reaction was stirred at 90° C. for 24 h. Upon completion, the reaction was cooled to 40° C. and CH2Cl2 was added. The reaction was filtered while warm and evaporated to provide the crude product. Recrystallization from ethanol gave 16.62 g (65.4 mmol) of Compound 4a. MS m/z (MH+) 255.
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]1[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=1[CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17]2[N:22]=[C:21]([NH2:23])[C:20]([NH2:24])=[C:19]([NH2:25])[N:18]=2)=[N:9]1.Cl[C:31]([O:33][CH3:34])=[O:32]>N1C=CC=CC=1>[NH2:25][C:19]1[C:20]([NH:24][C:31](=[O:32])[O:33][CH3:34])=[C:21]([NH2:23])[N:22]=[C:17]([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:8]([CH2:7][C:6]3[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=3[F:4])[N:9]=2)[N:18]=1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1N
Reactant: COC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)Nc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
30.5 g (87.0 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5,6-pyrimidinetriamine trihydrochloride from Example 8A are dissolved in 30 ml of pyridine. The resulting solution is cooled to 0° C. 8.22 g (87.0 mmol) of methyl chloroformate are added, and the mixture is stirred at 0° C. for a further 2 hours. It is subsequently allowed to warm to room temperature and is stirred for a further 12 hours. After concentration in vacuo, the residue is washed with water and dried. Further purification is effected by stirring in 300 ml of boiling diethyl ether. The precipitated product is filtered off with suction and dried in vacuo.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[N:4]=1.[CH:17]1([C:21]([Cl:23])=[O:22])[CH2:20][CH2:19][CH2:18]1>N1C=CC=CC=1>[ClH:23].[CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[C:3]1[N:4]=[C:5]([NH:9][C:21]([CH:17]2[CH2:20][CH2:19][CH2:18]2)=[O:22])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)C1CCC1
Reactant: CN1CCC(N(C)c2cccc(N)n2)CC1
Solvent: c1ccncc1
Product: CN1CCC(N(C)c2cccc(NC(=O)C3CCC3)n2)CC1
Product: Cl
Yield: 88.1 %

Procedure:
Prepare according to procedure in Example 69 starting with N-Methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation 34) (175 mg, 0.794 mmol), cyclobutanecarbonyl chloride (136 μL, 1.19 mmol), and pyridine (15 mL) to yield 237 mg (88%) of the title compound: mass spectrum (ion spray): m/z=303.1 (M+1); Analysis Calcd for C17H27N4OCl.0.1H2O: C, 59.93; H, 8.05; N, 16.45. Found: C, 59.81; H, 7.93; N, 16.45. mp 258-60° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:9]=[C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)[O:11][C:24]2=[O:25])=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(NNc1ccc(Cl)cc1)c1cccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1oc(-c2cccs2)nn1-c1ccc(Cl)cc1
Yield: 81.6 %

Procedure:
A mixture of N′-(4-chlorophenyl)thiophene-2-carbohydrazide (20 g, 79.3 mmol), triethylamine (10 mL) and carbonyldiimidazole (16.2 g, 100 mmol) was refluxed in THF (100 mL) for 1 hour. The crude product obtained after the removal of the solvent was triturated with water, filtered, and dried, followed by recrystallization from ethyl acetate/hexanes to provide 3-(4-chloro-phenyl)-5-(thiophene-2-yl)-1,3,4-oxadiazol-2(3H)-one (18 g, 64.7 mmol, yield 81%). The HPLC purity of the final product was 99.9%. LC-MS [M+H] 279.9 (C12H7ClN2O2S+H, expected 279.72). The 1H-NMR spectrum was in accordance with the chemical structure.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[H][H].[C]=O>C1(C)C=CC=CC=1.[Pd].[C]>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: [C]=O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(C(F)(F)F)cc1
Yield: 82.9 %

Procedure:
In an apparatus as in Example 2, 100 g of 4-trifluoromethylbenzoyl chloride which had been prepared analogously to Example 1 were hydrogenated in the course of 4 hours at 90° C. in 700 ml of dry toluene with the aid of 3.5 g of Pd-carbon (Pd content: 5% by weight); the conversion was 95%. The Pd-carbon catalyst had been exposed, before the hydrogenation, for 30 minutes in toluene at the boil to a mixture containing 50% by volume each of hydrogen and carbon monoxide. By distillation it was possible to obtain 69.2 g of 4-trifluoromethylbenzaldehyde which had a boiling point of 70°-71° C./20 mbars and an nD20 of 1.4639. Yield: 83% of theory.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][C:9]=2[CH3:16])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[CH3:16][C:9]1[C:8]([C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[N+:13]([O-:25])[C:12]([C:14]#[N:15])=[CH:11][CH:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(C#N)nc1-c1ccc(F)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C#N)[n+]([O-])c1-c1ccccc1
Temperature: 50 °C
Yield: 9.2 %

Procedure:
A solution of 6-(4-fluorophenyl)-5-methylpyridine-2-carbonitrile (750 mg, 3.86 mmol) and m-chloroperbenzoic acid (purity 69%, 2.4 g, 96.5 mmol) in tetrahydrofuran (8 mL) was stirred with heating at 50° C. for 3 days. Saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/3→1/2) to give the title compound (74.8 mg, 9%) as white crystals.
Reaction SMILES: [N:1]([CH:4]([C:12]([O:14][CH3:15])=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[C:2]=[O:3].[NH2:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[N:22][C:21]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:20]2[OH:32]>N1C=CC=CC=1>[OH:32][C:20]1[C:19]2[C:24](=[CH:25][CH:26]=[C:17]([NH:16][C:2]([NH:1][CH:4]([C:12]([O:14][CH3:15])=[O:13])[CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)=[O:3])[CH:18]=2)[N:23]=[N:22][C:21]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: COC(=O)C(Cc1ccccc1)N=C=O
Reactant: CCOC(=O)c1nnc2ccc(N)cc2c1O
Solvent: c1ccncc1
Product: CCOC(=O)c1nnc2ccc(NC(=O)NC(Cc3ccccc3)C(=O)OC)cc2c1O
Reaction time: 8 h

Procedure:
1-Isocyanato-1-methoxycarbonyl-2-phenylethane (1.2 g.) was added to a stirred solution of ethyl 6-amino-4-hydroxycinnolin-3-yl carboxylate (1.17 g.) in pyridine (20 ml.). The mixture was stirred overnight and the solid which separated was washed successively with pyridine (10 ml.) and ether (100 ml.). The solid was dissolved in boiling ethanol (1 l.), and the solution was filtered whilst hot. The filtrate was evaporated to approximately 300 ml. After standing at 0° C. overnight, the mixture was filtered and the solid residue washed successively with ethanol (50 ml.) and ether (100 ml.) to give ethyl 4-hydroxy-6-[3-(α-methoxycarbonylphenethyl)ureido]cinnolin-3-yl carboxylate, m.p. 242°-243° C.
Reaction SMILES: N1C=CC=CC=1.ClC(Cl)(O[C:11](=[O:17])[O:12][C:13](Cl)(Cl)Cl)Cl.OC[C@:21]1([CH3:32])[O:25][C:24]2=[N:26][C:27]([N+:29]([O-:31])=[O:30])=[CH:28][N:23]2[CH2:22]1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)=[CH:36][CH:35]=1.Cl>C(Cl)Cl>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)[C:11](=[O:17])[O:12][CH2:13][C@:21]2([CH3:32])[O:25][C:24]3=[N:26][C:27]([N+:29]([O-:31])=[O:30])=[CH:28][N:23]3[CH2:22]2)=[CH:36][CH:35]=1
Reactant: Clc1ccc(Nc2ccc(Cl)cc2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@]1(CO)Cn2cc([N+](=O)[O-])nc2O1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@]1(COC(=O)N(c2ccc(Cl)cc2)c2ccc(Cl)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35.4 %

Procedure:
Pyridine (0.37 ml, 4.5 mmol) and triphosgene (0.16 g, 0.5 mmol) were added to a suspension of (R)-2-hydroxymethyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole prepared in Example 37 (0.30 g, 1.5 mmol) in methylene chloride (15 ml) with cooling on ice-bath followed by stirring at room temperature for 2.5 hours. To the reaction mixture, bis(4-chlorophenyl)amine (0.39 g, 1.6 mmol) was added, and the resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was cooled on ice-bath and added 10% hydrochloric acid. The resulting mixture was extracted with methylene chloride, and the extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silicagel column chromatography (methylene chloride/ethyl acetate=19/1) and recrystallized from isopropanol to afford (R)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl bis(4-chlorophenyl)carbamate (82 mg, yield 12%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16]CCC#N)=[O:15])=[C:12]([CH3:21])[NH:11][C:10]([CH2:22][O:23][CH2:24][CH2:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[C:9]2[C:32]([O-])=[O:33])[CH:5]=[CH:6][CH:7]=1.CCN=C=NCCCN(C)C.Cl.[C:47]1([CH:53]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH2:54][CH2:55][NH2:56])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9]([C:32](=[O:33])[NH:56][CH2:55][CH2:54][CH:53]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:10]([CH2:22][O:23][CH2:24][CH2:25][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)[NH:11][C:12]([CH3:21])=[C:13]2[C:14]([OH:16])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)[O-])=C(COCCC2CCCCC2)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C(C(=O)NCCC(c2ccccc2)c2ccccc2)=C(COCCC2CCCCC2)N1

Procedure:
0.25 g (0.51 mmol) of 5-(2-cyanoethyl) 4-(3-chlorophenyl)-2-(2-cyclohexylethoxymethyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate, 0.12 g (0.63 mmol) of WSC hydrochloride and 0.13 g (0.62 mmol) of 3,3-diphenylpropylamine were stirred together in 5 ml of dichloromethane at room temperature for 16 hours. 0.1 N hydrochloric acid was added to the reaction mixture. After the extraction with dichloromethane, the organic layer was concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=1/1) to obtain the title compound.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[C:21]12(O)[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2.B(F)(F)F.CCOCC>CCCCC>[C:21]12([C:8]3[C:9]([OH:20])=[CH:10][C:11]4[CH2:12][CH2:13][C@@H:14]5[C@@H:5]([C:6]=4[CH:7]=3)[CH2:4][CH2:3][C@@:2]3([CH3:1])[C@H:15]5[CH2:16][CH2:17][C:18]3=[O:19])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCCCC
Product: C[C@]12CC[C@@H]3c4cc(C56CC7CC(CC(C7)C5)C6)c(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reaction time: 0.25 h
Yield: 76.7 %

Procedure:
Estrone [3-hydroxyestra-1,3,5(10)-trien-17-one, 270 mg, 1 mmol) and 1-adamantanol (170 mg, 1 mmol) were added to anhydrous n-pentane (6 mL) and the stirred mixture was cooled with an ice bath. Boron trifluoride etherate (BF3.EtOEt, 0.4 mL) was added over a 10 minute period. After an additional 15 minutes, the ice bath was removed and stirring was continued for an additional 45 minutes at room temperature. During the 45 minute period, solids present in the reaction mixture were dissolved and a yellow oil formed. Crushed ice was then added while shaking and swirling the reaction flask and a pink solid was formed. The filtered, crude pink product was washed with water until the filtrate had a neutral pH, and then the solid was dried in a vacuum oven at 50° C. The crude pink powder (0.4 g) was purified by flash chromatography (silica gel eluted with 20% ethyl acetate in hexanes) to get the pure product (0.31 g, 76.7%). The product was recrystallized from a mixture of chloroform and isopropyl alcohol and characterized as follows: (i) melting point=322-324° C. (see, e.g., Lunn, W. H. W.; Farkas, E., Adamantyl Carbonium Ion as a Dehydrogenating Agent: Its Reactions with Estrone, Tetrahedron 1969, 24, 6773-76, citing melting point as 295-296° C.); (ii) 1H NMR (CDCl3, 300 MHZ) δ0.94 (s, 3H, C18—CH3), 2.8 (m, 2H, C6CH2), 4.7 (s, 1H, C3—OH), 6.4 (5, 1H, C4—H), 7.12 (5, 1H, C1—H); (iii) 13C NMR CDCl3, 300 MHZ) δ3.76, 21.47, 25.93, 26.41, 28.63, 28.95 (3×C), 31.56, 35.81, 36.56, 36.98 (3×C), 38.42, 40.69 (3×C), 44.25, 47.99, 50.35, 116.87, 124.11, 131.59, 134.00, 135.02, 152.44, 221.43. (Chemical Abstracts Registry Number [21003-01-0].)
Reaction SMILES: [CH:1]([S:4][C:5]1[N:6]([CH3:11])[C:7]([SH:10])=[N:8][N:9]=1)([CH3:3])[CH3:2].[H-].[Na+].Cl[C:15]1[C:16]([C:21]#[N:22])=[N:17][CH:18]=[CH:19][N:20]=1>CN(C=O)C.C1C=CC=CC=1>[CH:1]([S:4][C:5]1[N:6]([CH3:11])[C:7]([S:10][C:15]2[C:16]([C:21]#[N:22])=[N:17][CH:18]=[CH:19][N:20]=2)=[N:8][N:9]=1)([CH3:3])[CH3:2]
Reactant: N#Cc1nccnc1Cl
Reactant: CC(C)Sc1nnc(S)n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(C)Sc1nnc(Sc2nccnc2C#N)n1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared according to Example 1 by using 5-(isopropylthio)-4-methyl-4H-1,2,4-triazole-3-thiol (379 mg, 2.00 mmol), NaH (60% dispersion in mineral oil, 88 mg, 2.20 mmol), and 3-chloropyrazine-2-carbonitrile (280 mg, 2.00 mmol) in DMF and benzene (6 ml, 1/1) by stirring at room temperature under nitrogen atmosphere for 2 hr.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]([CH3:13])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][NH2:29])=[CH:24][CH:23]=1.Cl.ClC1C=CC(NN)=CC=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:8](=[O:10])[C:7]3=[CH:6][NH:5][C:4]([CH3:13])=[C:3]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:2]3=[N:29]2)=[CH:24][CH:23]=1
Reactant: NNc1ccc(F)cc1
Reactant: CCOC(=O)c1cnc(C)c(-c2ccccc2)c1Cl
Agent: Cl
Agent: NNc1ccc(Cl)cc1
Product: Cc1[nH]cc2c(=O)n(-c3ccc(F)cc3)nc-2c1-c1ccccc1
Yield: 19 %

Procedure:
Following a similar procedure to that described in Example 4, except using ethyl 4-chloro-2-methyl-3-phenyl-5-pyridinecarboxylate and 4-fluorophenylhydrazine hydrochloride instead of ethyl 4-chloro-3-propyl-5-pyridinecarboxylate and 4-chlorophenylhydrazine hydrochloride, the title compound was prepared, after further purification by flash chromatography (silica gel, 5% MeOH/CH2Cl2), in 19% yield as a yellow solid; mp 303-317° C. (CH2Cl2-MeOH-EtOAc); 1H NMR (360 MHz, DMSO-d6) δ2.25 (3H, s), 7.20 (2H, t, J 9.0 Hz), 7.42 (1H, m), 7.50-7.51 (4H, m), 8.09 (2H, dd, J 9.2, J′5.2 Hz), 8.55 (1H, d), 12.43 (1H, br s); MS (ES+) m/z 320 [MH]+. Anal. found: C, 69.91; H, 4.15; N, 13.25. C19H14FN3Oe.0.3H2O requires: C, 70.27; H, 4.53; N, 12.94%.
Reaction SMILES: S(=O)(=O)(O)N.Cl([O-])=O.[Na+].[CH2:10]([O:17][C@@H:18]1[C@@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@H:22]([CH2:41][O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[O:21][C:19]1([C:50]1[CH:55]=[C:54]([CH:56]([O:59]C)[O:57]C)[CH:53]=[CH:52][C:51]=1[CH3:61])[OH:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC(C)=O.O>[CH3:61][C:51]1[CH:52]=[CH:53][C:54]([C:56]([OH:59])=[O:57])=[CH:55][C:50]=1[C:19]1([OH:20])[C@H:18]([O:17][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:23]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C@@H:22]([CH2:41][O:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[O:21]1
Reactant: COC(OC)c1ccc(C)c(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1
Agent: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)O)cc1C1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 3 h
Yield: 65.3 %

Procedure:
Sulfamic acid (0.4 g) and sodium chlorite (0.4 g) were added dropwise to a solution of 2,3,4,6-tetra-O-benzyl-1-C-[5-(dimethoxymethyl)-2-methylphenyl]-D-glucopyranose (2.4 g) in acetone-water (ratio: 5:1, 12 ml) at room temperature and the mixture was stirred for three hours. Acetone was evaporated from the reaction mixture and water was added. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain 4-methyl-3-[(3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]-2-hydroxytetrahydro-2H-pyran-2-yl]benzoic acid (1.5 g).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[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.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[N:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[CH2:37][NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:32]=[CH:31][CH:30]=1)(=[O:34])=[O:35]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)NCc2ccccn2)c1
Product: O=C(Nc1cccc(S(=O)(=O)NCc2ccccn2)c1)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-pyridin-2-ylmethyl-benzenesulfonamide (example B.6) according to general procedure II. Yellow solid. MS (ISP) 601.1 [(M−H−]; mp 208° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[N:6][CH:7]=1.[H-].[Na+].[C:17](Cl)#[C:18][CH2:19][CH2:20][CH3:21].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[N:12]([CH2:17][C:18]#[C:19][CH2:20][CH3:21])[N:13]=2)=[N:6][CH:7]=1
Reactant: O=C1CCC(c2ccc(Cl)cn2)=NN1
Reactant: CCCC#CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC#CCN1N=C(c2ccc(Cl)cn2)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
To a 100 mL 3 neck flask equipped with magnetic stirrer, addition funnel, and nitrogen inlet was charged 200 milligrams (mg) of 6-(5-chloropyridin-2-yl)-4,5-dihydropyridazin-3(2H)-one (0.95 mmol), 3.8 mg of 60% sodium hydride (oil dispersion) (0.95 mmol), and 20 mL of dry DMF. The reaction mixture was stirred for about 30 minutes at ambient temperature followed by the dropwise addition of 0.1 ml of pentynyl chloride (0.95 mmol) in about 5 mL of dry DMF. The reaction was stirred overnight at ambient temperature, and checked by TLC and GC the next morning. No starting material remained, and one new product was formed. The reaction was poured into about 100 mL of water, and extracted with 3×50 mL of ethyl acetate. The combined ether extract was washed with 100 mL of water, 100 mL of saturated aqueous sodium chloride solution, dried, and stripped to afford 240 mg of a tan solid 92% isolated yield. The NMR data is a 1 follows: 300 MHz 1H NMR (CDCl3, TMS=0 ppm) 1.15 (t, 3H); 2.20 (m, 2H); 2.60 (t, 2H); 3.25 (t, 2H); 4.70 (s, 2H); 7.75 (d, 1H); 8.15 (d, 1H); 8.50 (s, 1H).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:12]1([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]([CH3:31])[CH2:26][C:27](=[O:30])[NH:28][N:29]=3)=[CH:20][C:19]=2[N+:32]([O-:34])=[O:33])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>O1CCOCC1>[C:1]([NH:9][C:10]([N:15]1[CH2:16][CH2:17][N:12]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]([CH3:31])[CH2:26][C:27](=[O:30])[NH:28][N:29]=3)=[CH:20][C:19]=2[N+:32]([O-:34])=[O:33])[CH2:13][CH2:14]1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CC(=O)NN=C1c1ccc(N2CCNCC2)c([N+](=O)[O-])c1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1COCCO1
Product: CC1CC(=O)NN=C1c1ccc(N2CCN(C(=S)NC(=O)c3ccccc3)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
27.0 g (0.165 mol) of benzoyl isothiocyanate are added at room temperature to 52.4 g (0.165 mol) of 6-[4-(1-piperazinyl)-3-nitro-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone in 1200 ml of 1,4-dioxane. The reaction mixture is stirred at room temperature for 2 hours and then concentrated to 700 ml under vacuum and left to crystallize. 76 05 g (96% of theoretical) of orange-yellow crystals melting at 174.5°-177° C. are obtained after suction filtration.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]#[N:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:13]1[CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH2:15][CH2:14]1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([F:31])[CH:30]=1.C(=O)([O-])[O-:36].[K+].[K+]>O1CCOCC1.O>[F:24][C:25]1[CH:26]=[C:27]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:12])=[O:36])[CH:10]=2)[NH:7][N:6]=[C:5]3[CH:13]2[CH2:14][CH2:15][N:16]([S:19]([CH2:22][CH3:23])(=[O:20])=[O:21])[CH2:17][CH2:18]2)[CH:28]=[C:29]([F:31])[CH:30]=1
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C#N)cc(Br)cc23)CC1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cc(F)cc(F)c4)cc23)CC1
Yield: 26.8 %

Procedure:
Following the general procedure of Example 66, a mixture of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indazole-7-carbonitrile (Intermediate 10) (61.3 mg, 0.125 mmols), 3,5-difluorophenyl boronic acid (59 mg, 0.375 mmols), potassium carbonate (104 mg, 0.75 mmol), and chloro(di-2-norbonylphosphine)-(2-dimethylaminomethyl-forrocen-1-yl)palladium (15 mg, 0.025 mmol) in dioxane/water (3/1, 4 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (15 mg, 33%)