Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C:8](=[N:10][O:11][CH3:12])[CH2:7][NH:6]1)=[O:4].[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22][CH:21]=1.C(Cl)Cl.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:12][O:11]/[N:10]=[C:8]1\[CH2:9][C@@H:5]([C:3]([O:2][CH3:1])=[O:4])[N:6]([C:26]([C:23]2[CH:22]=[CH:21][C:20]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH3:13])=[CH:25][CH:24]=2)=[O:27])[CH2:7]\1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: CON=C1CN[C@H](C(=O)OC)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CO/N=C1\C[C@@H](C(=O)OC)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
Method A (e.g. methyl (2S,4EZ)-4-4-(methoxyimino-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxylate): A solution of methyl-(2S,4EZ)-4-(methoxyimino)-2-pyrrolidinecarboxylate (0.564 g, 3.28 mmol), 2′-methyl[1,1′-biphenyl]-4-carboxylic acid (0.765 g, 3.60 mmol) and 4-dimethylaminopyridine (0.880 g, 7.21 mmol) in a 7:3 mixture of DCM and DMF (30 ml) was made. EDC (0.691 mg, 3.60 mmol) was added slowly at 0° C. The reaction mixture was stirred overnight at r.t. It was washed with water (twice 20 ml), dried over MgSO4, filtrated and evaporated in vacuo. The resulting crude product mixture, methyl (2S,4EZ)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxylate, was purified by flash chromatography, unsing cyclohexane/EtOAc 8:2 as eluent. After several further chromatographies, (E)- and (Z)-isomers could be separated: methyl (2S,4E)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxylate (261 mg, 22%) was isolated as a colorless powder in 98.3% purity by HPLC, and methyl (2S,4Z)-4-(methoxyimino)-1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxylate (237 mg, 20%) was isolated as a colorless powder in 98.3% purity by HPLC.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([S:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:20][C@H:19]1[CH2:33][OH:34])=[O:17])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([S:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:20][C@H:19]1[CH:33]=[O:34])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1ccc(CS[C@@H]2C[C@@H](CO)N(C(=O)OC(C)(C)C)C2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccc(CS[C@@H]2C[C@@H](C=O)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
To 4.2 ml (48.65 mmol, 1.2 eq) oxalyl chloride in 100 ml CH2Cl2 were added 6.5 ml (89.19 mmol, 2.2 eq) DMSO in 20 ml CH2Cl2 at −65° C., followed after 10 min by 14.33 g (40.54 mmol, 1.0 eq) (2S,4R)-2-hydroxymethyl-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in 60 ml CH2Cl2 over a period of 20 min. The solution was stirred at −68° C. for 1.5 h before 28 ml (162.16 mmol, 4 eq) iPr2NEt were added, and the reaction mixture was warmed to room temperature. The solution was extracted with 1M KHSO4, the combined inorganic phases were extracted with CH2Cl2 and the organic phase dried over Na2SO4 and evaporated, yielding 14.18 g (99%) (2S,4R)-2-formyl-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester. The crude product was subjected to the following reaction without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:10]2[C:11]3[C:12](=[N:24][NH:25][N:26]=2)[CH:13]=[C:14]([CH2:19][C:20]([NH:22][CH3:23])=[O:21])[C:15]=3[CH2:16][S:17][N:18]=1.Cl.[Cl:28][C:29]1[C:30]([CH2:38]Cl)=[N:31][CH:32]=[C:33]([CH3:37])[C:34]=1[O:35][CH3:36].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:8][C:9]1[C:10]2[C:11]3[C:12](=[N:24][N:25]([CH2:38][C:30]4[C:29]([Cl:28])=[C:34]([O:35][CH3:36])[C:33]([CH3:37])=[CH:32][N:31]=4)[N:26]=2)[CH:13]=[C:14]([CH2:19][C:20]([NH:22][CH3:23])=[O:21])[C:15]=3[CH2:16][S:17][N:18]=1
Reactant: COc1c(C)cnc(CCl)c1Cl
Reactant: CNC(=O)Cc1cc2n[nH]nc3c-2c1CSN=C3N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)Cc1cc2nn(Cc3ncc(C)c(OC)c3Cl)nc3c-2c1CSN=C3N
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 84.4 %

Procedure:
Dimethylformamide (1 ml) was added to 2-(4-amino-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-yl)-N-methylacetamide trifluoroacetate (28 mg), 3-chloro-2-(chloromethyl)-4-methoxy-5-methylpyridine hydrochloride (36 mg), and potassium carbonate (69 mg). The resulting mixture was stirred at 60° C. for 2.5 hours. Thereafter, the insoluble matter was removed by filtration, and the solvent was then distilled away in a nitrogen stream. The resulting residue was dissolved in dimethyl sulfoxide (1 ml), and it was then purified by preparatory reverse-phase HPLC. The solvent was distilled away under reduced pressure, so as to obtain the title compound (27.0 mg) as a solid (amorphous substance).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].[N:21]1[C:31]2[C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[NH:28][CH2:27][CH2:26][C:25]=2[CH:24]=[N:23][CH:22]=1>N1C=CC=CC=1>[N:21]1[C:31]2[C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[N:28]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:2]=4[Cl:1])=[CH:8][CH:9]=3)=[O:12])[CH2:27][CH2:26][C:25]=2[CH:24]=[N:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccc(Cl)cc2Cl)cc1
Reactant: c1ccc2c(c1)NCCc1cncnc1-2
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(=O)N2CCc3cncnc3-c3ccccc32)cc1)c1ccc(Cl)cc1Cl

Procedure:
As described for Example 1, 5 mmol of 4-[(2,4-dichlorobenzoyl)amino]benzoyl chloride is reacted with 5 mmol of 5,6-dihydro-7H-pyrimido[5,4-d][1]benzazepine in pyridine to give the product as a solid.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([O:16][CH3:17])=[C:8]2[C:18](Cl)=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:21][CH2:22][CH:23]([OH:30])[CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27].C(N(CC)CC)C>C(Cl)Cl>[CH2:26]([N:25]([CH2:24][CH:23]([OH:30])[CH2:22][NH:21][C:18]([C:8]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:15]2[C:10]([C:9]=1[O:16][CH3:17])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:19])[CH2:28][CH3:29])[CH3:27]
Reactant: CCN(CC)CC(O)CN
Reactant: COc1c(C(=O)Cl)n(-c2ccccc2)c2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)CC(O)CNC(=O)c1c(OC)c2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The resulting ethereal solution of N-phenyl-3-methoxyindole-2-carboxylic acid chloride is added dropwise to a solution of 579 g of 1-amino-2-hydroxy-3-diethylaminopropane and 40 g of triethylamine in 70 ml of methylene chloride, whilst cooling with ice. The reaction mixture is stirred at room temperature for 1 hour and then extracted with dilute hydrochloric acid. The hydrochloric acid extract is rendered alkaline by addition of sodium hydroxide solution and is extracted with ether. The ether solution is washed with water, dried over sodium sulphate and evaporated. 110 g of 2-[3-(N,N-diethylamino)-2-hydroxypropylaminocarbonyl]-3-methoxy-1-phenylindole remain as an oily base. This base is dissolved in isopropanol and converted into its hydrochloride. Yield: 110 g of the hydrochloride=60.6%, melting point: 148°-150° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH:8]([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].N12CCCN=C1CCCCC2.[C:38](Cl)([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.O>C(Cl)Cl>[CH3:7][N:6]1[C:2]([NH:1][C:38]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[C:3]([CH:8]([CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:16])[CH3:14])[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:4]=[N:5]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(C(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C)c1N
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Cn1ncc(C(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 80.8 %

Procedure:
To a solution of di-tert-butyl [2-(5-amino-1-methyl-1H-pyrazol-4-yl)-1,3-propanediyl]biscarbamate (1.27 g) in methylene chloride (10 ml) were added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.05 g) and trityl chloride (1.44 g) at room temperature. The mixture was stirred for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:1) to give di-tert-butyl {2-[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]-1,3-propanediyl}biscarbamate (1.7 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:9]([OH:11])[CH3:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.O[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:3]([CH:9]([O:11][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: CC(O)c1nc(Cl)ccc1Cl
Reactant: COC(=O)c1ccc(O)cc1
Product: COC(=O)c1ccc(OC(C)c2nc(Cl)ccc2Cl)cc1

Procedure:
The title compound was prepared from the intermediate from Step A and methyl 4-hydroxybenzoate using the Mitsunobu conditions described in EXAMPLE 4. 1H NMR (500 MHz, CDCl3): δ 7.97 (d, J=8.2 Hz, 2H); 7.67 (d, J=8.4 Hz, 1H); 7.26 (d, J=8.3 Hz, 1H); 6.94 (d, J=8.7 Hz, 2H); 5.85 (q, J=6.5 Hz, 1H); 3.90 (s, 3H); 1.78 (d, J=6.5 Hz, 3H). LCMS1 3.68 min. (M-OPhCO2Me)=174
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[CH:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25].[C:27](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:28].[Na+].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:16][CH2:15]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=CCCC(=O)O
Reactant: c1ccc(CN2CCN(C3CCNCC3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCCN1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere a mixture of 3.11 g (12.0 mmol) 1-benzyl-4-piperidin-4-yl-piperazine and 7.50 mL (12.0 mmol, 15% in water) 4-oxo-butyric acid in 70 mL THF was adjusted to a pH of 5 with ACOH and stirred for 1 h at RT. After cooling to 0° C., 5.35 g (24.0 mmol) sodium triacetoxyborohydride were added batchwise and the reaction mixture was stirred overnight at RT. Within 15 min 80 mL of 30% K2CO3 solution were added dropwise, the aqueous phase was washed twice with EtOAc and evaporated down by half i. vac. 1 M KHSO4 solution was added, the precipitate formed was removed by suction filtering, the filtrate was washed with EtOAc and the aqueous phase was evaporated to dryness i. vac. The residue was taken up in 150 mL ethanolic HCl (1.25 M) and the reaction mixture was stirred overnight at RT. It was evaporated down i. vac., the residue was taken up in a little 15% K2CO3 solution, extracted exhaustively with EtOAc and the combined organic phases were dried over Na2SO4. After elimination of the desiccant and solvent the residue was further reacted without any further purification.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Cl-].[CH3:14][O:15][NH3+:16].C(N(CC)CC)C.[NH2:24][C:25]1[CH:26]=[C:27]([CH:44]=[CH:45][C:46]=1[F:47])[O:28][C:29]1[CH:30]=[CH:31][C:32]2[N:33]([CH:35]=[C:36]([NH:38][C:39]([CH:41]3[CH2:43][CH2:42]3)=[O:40])[N:37]=2)[N:34]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[F:47][C:46]1[CH:45]=[CH:44][C:27]([O:28][C:29]2[CH:30]=[CH:31][C:32]3[N:33]([CH:35]=[C:36]([NH:38][C:39]([CH:41]4[CH2:43][CH2:42]4)=[O:40])[N:37]=3)[N:34]=2)=[CH:26][C:25]=1[NH:24][C:1]([NH:16][O:15][CH3:14])=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: CO[NH3+]
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CONC(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 27.4 %

Procedure:
A solution of 1,1′-carbonyldiimidazole (297 mg, 1.833 mmol), O-methylhydroxyammonium chloride (153 mg, 1.833 mmol) and triethylamine (0.25 mL, 1.833 mmol) in N,N-dimethylformamide (4.0 mL) was stirred at room temperature for 30 min. A solution of N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.611 mmol) in N,N-dimethylformamide (2.0 mL) was further added to the mixture, and the mixture was stirred at room temperature for 2 days. Under ice-cooling, aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was recrystallized from tetrahydrofuran/ethanol to give the title compound (67 mg, 27%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH:10]([CH3:12])[CH3:11].ClC(C)[CH2:15][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1.CC1C=CC=C(C)C=1[NH2:31].Cl.CC1C=CC=C(C)C=1N>>[F:24][C:23]([F:26])([F:25])[C:19]1[CH:18]=[C:17]([N:16]2[CH2:11][CH:10]([CH3:12])[N:9]([C:3]3[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:15]2=[NH:31])[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cccc(C)c1NC(C)C
Reactant: Cc1cccc(C)c1N
Reactant: CC(Cl)CNc1cccc(C(F)(F)F)c1
Agent: Cl
Product: Cc1cccc(C)c1N1C(=N)N(c2cccc(C(F)(F)F)c2)CC1C
Yield: 55.6 %

Procedure:
1-(3'-Trifluoromethylphenyl)-amino)-2-(2',6'-dimethylphenyl-amino)-propane, applied as starting substance, is prepared by reacting N-(β-chloropropyl)-3-trifluoromethylaniline, a compound obtained as described in Example 23, point (b), with 2,6-dimethylaniline. The reaction is performed as described in Example 16, point (c) with the difference that crystalline 2,6-dimethylaniline hydrochloride is separated from the reaction mixture by trituration with ethyl acetate. The aimed product is obtained with a yield of 55.6%; m.p.: 95°-98° C. (dihydrochloride).
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=1[C:12]#[C:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C1COCC1.[NH4+].[Cl-]>[Zn].CO>[NH2:24][C:22]1[CH:21]=[CH:20][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=2[C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[C:2]([F:1])[CH:23]=1
Reactant: Nc1nccc(Oc2ccc([N+](=O)[O-])cc2F)c1C#Cc1ccccn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2ccnc(N)c2C#Cc2ccccn2)c(F)c1
Temperature: 60 °C
Yield: 78 %

Procedure:
A mixture of 4-(2-fluoro-4-nitrophenoxy)-3-(2-(pyridin-2-yl)ethynyl)pyridin-2-amine (35 mg, 0.1 mmol), THF (1.5 mL) and MeOH (1.5 ml) was treated with zinc dust (65 mg, 1.0 mmol) and NH4Cl (53 mg, 1.0 mmol) and heated at 60° C. for 45 min. The reaction mixture was cooled, filtered and concentrated under vacuum. The residue was partitioned between EtOAc and saturated aq. NaHCO3 solution. The organic phase was separated, washed with brine, dried (MgSO4) and concentrated to give the title compound (25 mg, 78%) as a brown solid. MS(ESI+): m/z 321.2 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.[OH:25][CH2:26][C:27]([NH:30][S:31]([C:34]1[S:38][C:37](Cl)=[N:36][CH:35]=1)(=[O:33])=[O:32])([CH3:29])[CH3:28]>>[OH:25][CH2:26][C:27]([NH:30][S:31]([C:34]1[S:38][C:37]([C:14]#[C:13][C:12]2[CH:11]=[N:10][N:9]3[C:4]([CH:1]4[CH2:3][CH2:2]4)=[CH:5][C:6]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=4)=[N:7][C:8]=23)=[N:36][CH:35]=1)(=[O:33])=[O:32])([CH3:29])[CH3:28]
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cnc(Cl)s1
Product: CC(C)(CO)NS(=O)(=O)c1cnc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-cyclopropyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.7) (82 mg, 0.25 mmol) and 2-chloro-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (68 mg, 0.25 mmol) (Example B.14) according to general procedure II. Obtained as a yellow solid (24 mg, 17%). MS (ISP) 562.0 [(M+H)+]; mp 243-245° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][S:39]([C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1)(=[O:41])=[O:40].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:45]2[CH:46]=[CH:47][C:42]([S:39]([CH3:38])(=[O:41])=[O:40])=[CH:43][CH:44]=2)=[CH:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCCO2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(C(=CC2CCCCO2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 71 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-yl)-vinyl ester (0.52 g, 0.97 mmol), 4-(methanesulfonyl)phenylboronic acid (0.48 g, 2.4 mmol) and dichlorobis(triphenylphosphine)palladium (II) (68 mg, 0.1 mmol) in dioxane (6 mL) was added an aqueous sodium carbonate solution (2 M, 1.2 mL). The resulting mixture was subjected to microwave irradiation for 4 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 30% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-2-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (0.36 g, 57%) as a white solid: LC/MS m/e calcd for C27H26N2O5S2 [M+H]+ 523.65, observed 523.1.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].O=O.[C:7]([OH:10])(=[O:9])[CH3:8]>>[C:7]([O:10][C:1]([O:10][C:7](=[O:9])[CH3:8])=[CH:2][CH2:3][CH3:4])(=[O:9])[CH3:8]
Reactant: CC(=O)O
Reactant: C=CC=C
Agent: O=O
Product: CCC=C(OC(C)=O)OC(C)=O

Procedure:
In the invention, a zone in which the reaction product is yielded, e.g., a zone wherein a solid catalyst is present in a liquid phase comprising butadiene and acetic acid, is referred to as a reaction zone. Namely, the reaction zone as a whole is occupied by a liquid phase. An oxygen-containing gas is introduced into the liquid phase of the reaction zone so as to form fine bubbles, whereby diacetoxybutene is yielded.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl[CH2:11][CH:12]=O>CCO>[N:1]1[CH:11]=[CH:12][N:9]2[CH:8]=[CH:7][CH:6]=[C:3]([C:4]#[N:5])[C:2]=12
Reactant: O=CCCl
Reactant: N#Cc1cccnc1N
Solvent: CCO
Product: N#Cc1cccn2ccnc12
Temperature: 120 °C
Yield: 99.9 %

Procedure:
To a solution of 2-aminonicotinonitrile (1.0 g, 8.39 mmol) in EtOH (10 ml) in a 20 ml sealed vial was added 2-chloroacetaldehyde (1.611 ml, 9.23 mmol) vial was then sealed and heated to 120° C. overnight. Reaction was cooled to RT and quenched with 2N Na2CO3, removed EtOH in vaccuo and extracted with DCMx3. Combined organics and washed with water then brinex2. Dried over sodium sulfate and removed solvent to give title compound as a yellow brown solid (1.2 g, 8.38 mmol, 100% yield) was verified by MS (ES+) C8H5N3 requires: 143 found: 144 [M+H]+
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][C:11]([C:16]([O:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])([C:13](O)=[O:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=N[CH:33]=[CH:32]2)=O)C=1.C([CH:38](C([O-])=O)[C:39]([O-:41])=[O:40])C.[Mg+2].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][CH:9]1[CH2:10][C:11]([C:13](=[O:14])[CH2:38][C:39]([O:41][CH2:32][CH3:33])=[O:40])([C:16]([O:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCC(C(=O)[O-])C(=O)[O-]
Reactant: CC(C)CCOC(=O)C1(C(=O)O)CC(OCc2ccccc2)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)C1(C(=O)OCCC(C)C)CC(OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A 21.49 g (67.08 mmol) portion of 1-benzyloxy-3-(isoamyloxycarbonyl)cyclobutane-3-carboxylic acid was dissolved in 200 ml of tetrahydrofuran to which, while cooling in an ice bath with stirring, was added 13.05 g (80.49 mmol) of N,N-carbonyldiimidazole. After 10 minutes of 2stirring, the ice bath was detached and the reaction mixture was stirred at room temperature for 3 hours. To the reaction solution which was cooled in an ice bath and stirred was added dropwise 100 ml of tetrahydrofuran solution containing 23.06 g (80.49 mmol) of magnesium ethylmalonate. After 1 hour of stirring, the ice bath was detached, and the reaction mixture was stirred at room temperature for 10 hours. While cooling in an ice bath and stirring, the reaction mixture was mixed with 10% citric acid aqueous solution and then with ethyl acetate to effect separation of layers, and the resulting organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, the solvent was evaporated under a reduced pressure and then the resulting residue was purified by a silica gel column chromatography (n-hexane:ethyl acetate=2:1) to give 11.37 g (29.12 mmol) of the title compound.
Reaction SMILES: Cl[S:2]([C:5]1[C:16]([CH3:17])=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=1[CH3:18])(=[O:4])=[O:3].[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][S:2]([C:5]2[C:16]([CH3:17])=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=2[CH3:18])(=[O:4])=[O:3])=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: COC(=O)COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)COc1cc(C)c(S(=O)(=O)Nc2ccc(OC)cc2[N+](=O)[O-])c(C)c1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A mixture of methyl (4-chlorosulfonyl-3,5-dimethylphenoxy)acetate (Intermediate A1, 7.6 g, 0.026 mol), 4-methoxy-2-nitroaniline (4.0 g, 0.024 mol), and pyridine (50 mL) was stirred at room temperature for 16 hr, in a 90° C. bath for 5 hr, and in a 130° C. bath for 30 min. The mixture was cooled and stirred with toluene for 10 min. The resulting suspension was filtered, and the filtrate was concentrated, diluted with 150 mL toluene and 100 mL ethyl acetate, washed with 1 M hydrochloric acid and water, and concentrated to about 50 mL. The mixture was left overnight in a freezer. The solid was collected and washed with several portions of cold toluene. After drying, it weighed 8.2 g (74%). Another 0.45 g portion of the title compound was recovered from extraction of aqueous phases and crystallization of a second crop from the toluene filtrate.