Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[C:7]2[CH:16]=[C:15]([CH2:17][CH3:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:8]=2[N:9]=[C:10](SC)[N:11]=1>C(OCC)(=O)C.CO.C(Cl)Cl.[Ni]>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[C:7]2[CH:16]=[C:15]([CH2:17][CH3:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: CCc1cc2c(OCC(=O)OC)nc(SC)nc2n1Cc1cccc(Cl)c1
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CCc1cc2c(OCC(=O)OC)ncnc2n1Cc1cccc(Cl)c1
Yield: 85 %

Procedure:
A solution of 186 mg (0.458 mmol) of [[2-(methylthio)-6-ethyl-7-[(3-chlorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester in 4 mL of ethyl acetate and 1 mL of methanol was heated to reflux and treated with 1.05 g of Raney Ni in portions over 3 hours. The reaction was diluted with 2 mL of methylene chloride and the solids were removed by filtration through a filter aid. The reaction mixture was dried with sodium sulfate and concentrated to provide 140 mg (85%) of [[6-ethyl-7-[(3-chlorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a solid. nmr (500 MHz, CDCl3) δ1.29 (t, J=7.4 Hz, 3H), 2.62 (q, J=7.4 Hz, 2H), 3.80 (s, 3H), 5.09 (s, 2H), 5.42 (s, 2H), 6.41 (s, 1H), 6.88 (d, J=6.9 Hz, 1H),. 7.04 (s, 1H), 7.21 (m, 2H), 8.38 (s, 1H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[O-:13][CH2:14][CH3:15].[Na+]>C(O)C.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:13][CH2:14][CH3:15]
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccnc2ccc(Br)cc12
Temperature: 120 °C
Yield: 90.2 %

Procedure:
To a solution of 6-bromo-4-chloroquinoline (17 g, 70.10 mmol) in ethanol (400 mL) was added sodium ethoxide (23.85 g, 350.5 mmol) at room temperature. Then, the reaction mixture was heated to 120° C. for 15 h in a sealed reaction flask. After cooling to room temperature, the ethanol was removed under the vacuum and the residue was diluted with water. The aqueous suspension was neutralized with 3.0N hydrochloric acid until the precipitate formed and later it was diluted with saturated sodium bicarbonate solution. Then, the solids were collected by filtration and washed with water. After drying in air, 15.94 g (90.2% yield) of 6-bromo-4-ethoxy-quinoline was isolated as a white solid which can be crystallized from acetonitrile: EI-HRMS m/e calcd for C11H10BrNO (M+) 250.9946, found 250.9946.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:38]=[CH:37][C:15]([CH2:16][C:17]2[CH:18]=[C:19]([C@@:24]34[O:31][C@@:28]([CH2:32][OH:33])([CH2:29][O:30]3)[C@@H:27]([OH:34])[C@H:26]([OH:35])[C@H:25]4[OH:36])[CH:20]=[CH:21][C:22]=2[Cl:23])=[CH:14][CH:13]=1)C1C=CC=CC=1.C(O)=O>C(O)C.O1CCCC1.[Pd]>[Cl:23][C:22]1[CH:21]=[CH:20][C:19]([C@@:24]23[O:31][C@@:28]([CH2:32][OH:33])([CH2:29][O:30]2)[C@@H:27]([OH:34])[C@H:26]([OH:35])[C@H:25]3[OH:36])=[CH:18][C:17]=1[CH2:16][C:15]1[CH:37]=[CH:38][C:12]([O:11][CH2:10][CH2:9][OH:8])=[CH:13][CH:14]=1
Reactant: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCCOCc5ccccc5)cc4)c3)(O1)[C@H](O)[C@@H](O)[C@@H]2O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O=CO
Product: OCCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of intermediate (1S,2S,3S,4R,5S)-5-(3-(4-(2-(Benzyloxy)ethoxy)benzyl)-4-chlorophenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol (4 mg, 0.007 mmol) in a mixture of ethanol and tetrahydrofurane (1 mL, 4 to 1 in volume) was successively added formic acid (12 microL, 0.30 mmol) and palladium black (7.5 mg, 0.07 mmol). The reaction mixture was stirred at room temperature for 2 hours, the palladium was filtered through a pad of Celite®, the filtrate was evaporated and the residue was dried under high vacuum to afford 2.6 mg (80% yield) of the desired product. LCMS 453.5 (M+H+; positive mode). 1H NMR (500 MHz, METHANOL-d4) delta ppm 3.56 (d, J=7.8 Hz, 1 H), 3.58-3.72 (m, 4 H), 3.79 (d, J=7.8 Hz, 1 H), 3.82-3.88 (m, 2 H), 4.02 (t, J=4.9 Hz, 2 H), 4.05 (s, 2 H), 4.16 (d, J=7.6 Hz, 1 H), 6.84-6.89 (m, 2H), 7.11 (d, J=8.5 Hz, 2 H), 7.35-7.42 (m, 2 H), 7.47 (d, J=2.0 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:19]>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH2:11][Br:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cc(Br)ccc1OCc1ccccc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: BrCc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
A solution of 2-benzyloxy-5-bromobenzyl alcohol (14.75 g, 50.2 mmol) in anhydrous ethyl ether (150 ml) was cooled to 4° C. A solution of PBr3 (13.68 g, 50 mmol) in anhydrous ether (40 ml) was added dropwise keeping the temperature below 10° C. The reaction was allowed to warm to ambient temperature and stirred for 1 hour. The reaction was filtered through silica gel (200 g). The silica gel was washed with ethyl ether to remove all the product. The filtrate was washed with water (1×150 ml), aqueous saturated sodium hydrogen carbonate (1×150 ml) and brine (1×150 ml). The organic layer was dried (Na2SO4) and evaporated to give 2-benzyloxy-5-bromobenzylbromide as a pale yellow oil (15.2 g, 85%) which crystallised on standing.
Reaction SMILES: C(OC(C1(C2C=CC=CC=2)CCCC(=O)CN1)=O)C.[OH:20][NH:21][C:22]([C@H:24]1[C@@H:30]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34]C=2)[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[S:38]([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)(=[O:40])=[O:39])=[O:23]>>[C:31]1([C@@H:30]2[CH2:29][CH2:28][CH2:27][CH2:26][N:25]([S:38]([C:41]3[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=3)(=[O:39])=[O:40])[C@H:24]2[C:22]([NH:21][OH:20])=[O:23])[CH:32]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1ccc(S(=O)(=O)N2CCCC[C@H](Cc3ccccc3)[C@@H]2C(=O)NO)cc1
Agent: CCOC(=O)C1(c2ccccc2)CCCC(=O)CN1
Product: COc1ccc(S(=O)(=O)N2CCCC[C@@H](c3ccccc3)[C@@H]2C(=O)NO)cc1

Procedure:
trans-3-Phenyl-1-(4-methoxybenzenesulfonyl)-azepane-2-hydroxamic acid was synthesized from 2-Phenyl-6-oxo-azepane 2-carboxylic acid ethyl ester in the same manner as the procedures used for the preparation of cis-3-Benzyl-1-(4-methoxybenzenesulfonyl)-azepane-2-carboxylic acid-hydroxyamide.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1([CH2:34][O:35][CH3:36])[CH2:33][O:32][CH2:31]1>C(#N)C>[CH3:21][O:20][C:3]1[C:2]([O:1][CH2:29][C:30]2([CH2:34][O:35][CH3:36])[CH2:33][O:32][CH2:31]2)=[C:7]([O:8][CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][CH2:13][C:14]2=[O:19]
Reactant: COCC1(CBr)COC1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCC1(COc2c(OC)ccc(-c3cccc4c3CCC4=O)c2OC)COC1
Temperature: 80 °C
Yield: 17.9 %

Procedure:
To a stirring solution of 4-(3-hydroxy-2,4-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.281 mmol) in acetonitrile (5 mL) was added potassium carbonate (155 mg, 1.124 mmol) and 3-bromomethyl-3-methoxymethyl-oxetane (82 mg, 0.422 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 17.9%).
Reaction SMILES: C([O:9][C@@H:10]1[C@H:17]([O:18]C(=O)C2C=CC=CC=2)[C@@H:16]([CH2:27][O:28]C(=O)C2C=CC=CC=2)[O:15][C@H:11]1[C:12]([OH:14])=O)(=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=C(SSC2N=CC=CC=2)N=CC=1.[CH3:70][O:71][C:72]1[CH:79]=[CH:78][C:75]([NH:76][CH3:77])=[CH:74][CH:73]=1>C1COCC1>[OH:9][C@@H:10]1[C@H:17]([OH:18])[C@@H:16]([CH2:27][OH:28])[O:15][CH:11]1[C:12]([N:76]([C:75]1[CH:78]=[CH:79][C:72]([O:71][CH3:70])=[CH:73][CH:74]=1)[CH3:77])=[O:14]
Reactant: CNc1ccc(OC)cc1
Reactant: O=C(OC[C@H]1O[C@@H](C(=O)O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: C1CCOC1
Product: COc1ccc(N(C)C(=O)C2O[C@H](CO)[C@@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
3,4,6-Tri-O-benzoyl-2,5-anhydro-D-allonic acid (2 g, 4 mmol) was dissolved in anhydrous THF (40 mL) under argon, and triphenylphosphine (2.1 g, 8 mmol) was added to the mixture. The resultant mixture was stirred until the triphenylphosphine was completely dissolved and subsequently 2,2′-dipyridyldisulfide (1.8 g, 8 mmol) was added. The mixture was stirred at room temperature for 2 hours, after which the 4-methoxy-N-methyl-aniline (0.768 g, 5.6 mmol) was added and stirring was continued at room temperature for 16 hours. The solvent was evaporated to dryness, the residue was dissolved in chloroform (150 mL) and washed twice with 0.1M NaOH solution (100 mL), twice with 0.2 M HCl solution (100 mL), once with saturated NaHCO3 solution (100 mL) and dried (Na2SO4). The solvent was evaporated to dryness and the residue was dissolved in 7M ammonia solution in methanol (250 ml) and stirred for 16 hours at room temperature and then evaporated to dryness. The residue was dissolved in chloroform and applied to a column of silica gel. Elution with a mixture of chloroform methanol (3:1) and evaporation of the appropriate fractions yielded the title compound as an off-white solid (0.77 g, 2.6 mmol, 65%): MS (ES) m/z 320 [M+Na]+.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=3Br)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH:22]1(B(O)O)[CH2:24][CH2:23]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]12([CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=3[CH:22]3[CH2:24][CH2:23]3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: OB(O)C1CC1
Reactant: N#Cc1ccc(OCC23CC4CC(CC(C4)C2)C3)c(Br)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Temperature: 100 °C
Yield: 92.7 %

Procedure:
A solution of 4-(adamantan-1-ylmethoxy)-3-bromobenzonitrile (6.93 g, 20.00 mmol), cyclopropylboronic acid (2.58 g, 30.00 mmol) and potassium phosphate (19.10 g, 90.00 mmol) in toluene (100 mL) and water (5 mL) was bubbled with a nitrogen atmosphere for 10 min, tricyclohexylphosphine tetrafluoroborate (0.74 g, 2.00 mmol) and palladium acetate (0.23 g, 1.00 mmol) was added to this reaction mixture. The reaction mixture was heated to 100° C. for 18 h and then cooled to ambient temperature. Water (50 mL) was added and the mixture, extracted with ethyl acetate (100 mL×3), the combined organics were washed with brine; dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was titrated in methanol (50 mL), the solid was filtered and dried to give the title compound as a colorless solid (5.70 g, 92%): 1H NMR (300 MHz, CDCl3) δ 7.43-7.38 (m, 1H), 7.11-7.10 (m, 1H), 6.82-6.78 (m, 1H), 3.52 (s, 2H), 2.16-1.98 (m, 4H), 1.00-1.64 (m, 12H), 0.99-0.91 (m, 2H), 0.66-0.59 (m, 2H); MS (ES+) m/z: 308.2 (M+1).
Reaction SMILES: [C:1]([O:4][C:5]12[O:21][N:13]([CH2:14][CH:15]3[CH:17]1[N:16]3[C:18](=[O:20])[CH3:19])[C:12]1[C:7](=[C:8]([OH:24])[CH:9]=[C:10]([CH:22]=[O:23])[CH:11]=1)[CH:6]2[CH2:25][O:26][C:27](=[O:29])[NH2:28])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:36](I)[CH2:37][CH2:38][CH3:39].C(Cl)(Cl)Cl>CC(C)=O.CO>[C:1]([O:4][C:5]12[O:21][N:13]([CH2:14][CH:15]3[CH:17]1[N:16]3[C:18](=[O:20])[CH3:19])[C:12]1[C:7](=[C:8]([O:24][CH2:36][CH2:37][CH2:38][CH3:39])[CH:9]=[C:10]([CH:22]=[O:23])[CH:11]=1)[CH:6]2[CH2:25][O:26][C:27](=[O:29])[NH2:28])(=[O:3])[CH3:2]
Reactant: CCCCI
Reactant: CC(=O)OC12ON(CC3C1N3C(C)=O)c1cc(C=O)cc(O)c1C2COC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCOc1cc(C=O)cc2c1C(COC(N)=O)C1(OC(C)=O)ON2CC2C1N2C(C)=O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of 11-acetyl-8-carbamoyloxymethyl-4-formyl-6-hydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-9-yl acetate (80 mg) in acetone (1 ml) were added potassium carbonate (110 mg) and n-butyl iodide (90 μl), and the mixture was stirred at 50° C. for 4 hours. The reaction mixture was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (20:1, v/v) to afford 11-acetyl-6-butoxy-8-carbamoyloxymethyl-4-formyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-9-yl acetate (61 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.Br[C:31]1[N:32]=[C:33]([CH2:52][CH3:53])[C:34]([NH:39][CH:40]2[C:49]3[C:44](=[C:45]([O:50][CH3:51])[CH:46]=[CH:47][CH:48]=3)[CH2:43][CH2:42][CH2:41]2)=[N:35][C:36]=1[CH2:37][CH3:38]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:31]1[N:32]=[C:33]([CH2:52][CH3:53])[C:34]([NH:39][CH:40]2[C:49]3[C:44](=[C:45]([O:50][CH3:51])[CH:46]=[CH:47][CH:48]=3)[CH2:43][CH2:42][CH2:41]2)=[N:35][C:36]=1[CH2:37][CH3:38]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1nc(NC2CCCc3c(OC)cccc32)c(CC)nc1Br
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1NC1CCCc2c(OC)cccc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.51, 7.33, 7.23, 7.07, 6.81, 5.50, 4.68, 3.89, 2.87–2.80, 2.72–2.61, 2.12–2.01, 1.91, 1.30–1.19; HRMS (FAB) calcd for C25H27Cl2N3O+H 456.1609, found 456.1627.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23](Br)[CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37]>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:38]([CH2:39][CH3:40])[CH2:36][CH3:37])[CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CCNCC
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2cccc(Br)c2)[C@H](c2ccccc2)C1
Product: CCN(CC)c1cccc([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]2c2ccccc2)c1

Procedure:
The title compound, MS: m/e=549.2 (M+), was prepared in accordance with the general method of example 10 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(3-bromo-phenyl)-3-phenyl-piperidin-1-yl]-methanone and diethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:38])[C:10]([N:12]([CH3:37])[C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:16][N:15]([C:25]([O:27]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:14]2)=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:39][S:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:42])=[O:41].O>CN1CCCC1=O>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]([CH3:38])[C:10]([N:12]([C@H:13]2[C@H:17]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH2:16][N:15]([C:25]([N:46]3[CH2:47][CH2:48][N:43]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:44][CH2:45]3)=[O:27])[CH2:14]2)[CH3:37])=[O:11])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CN(C(=O)N(C)[C@@H]1CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C[C@H]1c1ccc(F)cc1)c1cc(Cl)cc(Cl)c1
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: CN(C(=O)N(C)[C@@H]1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccc(F)cc1)c1cc(Cl)cc(Cl)c1
Yield: 49.4 %

Procedure:
A solution of the compound (0.31 g) obtained in Example 419 and 1-(methylsulfonyl)piperazine (0.14 g) in 1-methyl-2-pyrrolidone (5 mL) was stirred at 110° C. for 24 hr and at 135° C. for 14 hr. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The extract was washed with saturated aqueous ammonium chloride solution and saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 75→100% ethyl acetate/hexane) to give the title compound (0.16 g, 48%) as a pale-yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[N:9]1[CH:14]=[CH:13][N:12]=[C:11]2[C:15]([O:17][C:18](=[O:19])[C:10]=12)=[O:16]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15]([C:11]2[C:10]([C:18]([OH:19])=[O:17])=[N:9][CH:14]=[CH:13][N:12]=2)=[O:16])=[N:3][CH:4]=1
Reactant: O=C1OC(=O)c2nccnc21
Reactant: Nc1ccc(Cl)cn1
Product: O=C(O)c1nccnc1C(=O)Nc1ccc(Cl)cn1
Yield: 85 %

Procedure:
The addition of 2-amino-5-chloropyridine to pyrazine 2,3-dicarboxylic acid anhydride (II) in a lot wise manner at room temperature in a molar ratio of 1.05:1 surprisingly accelerates the reaction to completion in resulting the product, 3-(5-chloropyrid-2-yl)carbamoyl-pyrazine-2-carboxylic acid (III) having high purity (>99%) with a good yield of 85 to 90% when compared with the prior art processes.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (178 mg, 0.5 mmol) and commercially available 4-bromo-benzenesulfonamide (118 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (106 mg, 42%). MS (ISN) 509.2 [(M−H)−]; mp 264° C.
Reaction SMILES: [CH3:1][S-:2].[Na+].[Cl:4][C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:6]=1>C1COCC1>[Cl:4][C:5]1[CH:10]=[C:9]([S:2][CH3:1])[N:8]=[C:7]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:6]=1
Reactant: Clc1cc(Cl)nc(OCc2ccccc2)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1cc(Cl)nc(OCc2ccccc2)n1

Procedure:
Aqueous sodium thiomethoxide (15%, 2.75 g, 0.0059×1.0 mol) was added dropwise in 4,6-dichloro-2-(phenylmethoxy)pyrimidine (Compound No. II-26) (1.5 g, 0.0059 mol) dissolved in THF at room temperature. After allowed to react for 2 hours, the reaction solution was partitioned between ethyl acetate and aqueous saturated sodium hydrogen carbonate. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated, then purified on a silica gel column to obtain 4-chloro-6-methylthio-2-(phenylmethoxy)pyrimidine (Compound No. II-15) as an intermediate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([CH:19]=[C:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:27]=1.C(N(CC)CC)C>CS(C)=O.O>[Br:1][C:2]1[CH:18]=[C:17]([CH:16]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=2)[CH:3]=1)[CH:19]=[C:20]1[CH2:25][CH2:24][N:23]([C:33]([NH:32][C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)=[O:34])[CH2:22][CH2:21]1
Reactant: FC(F)(F)c1ccc(Oc2cc(Br)cc(C=C3CCNCC3)c2)nc1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnc1)N1CCC(=Cc2cc(Br)cc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Reaction time: 8 h
Yield: 67 %

Procedure:
2-(3-Bromo-5-(piperidin-4-ylidenemethyl)phenoxy)-5-(trifluoromethyl)pyridine (0.58 g, 1.4 mmol) and phenyl pyridin-3-ylcarbamate (0.3 g, 1.4 mmol) were dissolved in DMSO (3 mL). Triethylamine (0.59 mL, 4.21 mmol) was added and the reaction was stirred overnight. The reaction mixture was diluted with water and extracted with ethyl acetate three times. The organic layer was washed with brine, dried over Na2SO4, and evaporated to dryness. The residue was purified by silica gel column chromatography (35% acetone in hexane) to give the title compound (0.5 g, 67%). 1H NMR (500 MHz, DMSO-d6): δ 8.44 (s, 2H), 8.25 (d, J=4.4 Hz, 1H), 7.99 (d, J=7.8 Hz, 1H), 7.92 (d, J=10.45 Hz, 1H), 7.22 (m, 2H), 7.20 (s, 1H), 7.04 (d, J=8.6 Hz, 1H), 6.93 (s, 1H), 6.83 (s, 1H), 6.34 (s, 1H), 3.60 (m, 2H), 3.52 (m, 2H), 2.56 (m, 2H), 2.44 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 165.16, 154.72, 153.51, 145.38, 143.81, 141.22, 140.33, 139.66, 136.99, 136.36, 128.85, 127.64, 123.63, 123.26, 122.83, 122.48, 120.73, 111.68, 45.59, 44.60, 35.71, 29.29, 29.17; m/z (533.2, 535.2, M+ H+); HPLC: 99.0%.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[CH2:14][C:15]1[S:19][C:18]2=[CH:20][N:21]=[CH:22][N:17]2[C:16]=1[CH3:23].[CH2:24]([O:27][C:28]([NH:30][S:31]([NH2:34])(=[O:33])=[O:32])=[O:29])[CH:25]=[CH2:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.O1CCCC1>[CH2:24]([O:27][C:28]([N:30]([CH2:14][C:15]1[S:19][C:18]2=[CH:20][N:21]=[CH:22][N:17]2[C:16]=1[CH3:23])[S:31]([NH2:34])(=[O:33])=[O:32])=[O:29])[CH:25]=[CH2:26]
Reactant: Cc1c(CO)sc2cncn12
Reactant: C=CCOC(=O)NS(N)(=O)=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCOC(=O)N(Cc1sc2cncn2c1C)S(N)(=O)=O
Reaction time: 1.83 h
Yield: 29.1 %

Procedure:
Under an argon atmosphere at -37° C., 0.51 ml of diethyl azodicarboxylate was added dropwise to 6.7 ml of an anhydrous tetrahydrofuran solution containing 365 mg of 2-hydroxymethyl-3-methylimidazo[5,1-b]thiazole, 586 mg of N-allyloxycarbonyl-N-aminosulfonylamine and 854 mg of triphenylphosphine, and the mixture was then stirred at -37° C. to -20° C. for 110 minutes. The solvent was evaporated under reduced pressure to obtain an oil, and this oil was then suspended in 50 ml of dichloromethane. Further, the suspension was extracted with 2N hydrochloric acid (15 ml×2), and the combined aqueous layer was then washed with 20 ml of dichloromethane. After alkalified with anhydrous potassium carbonate, the solution was further extracted with dichloromethane (30 ml×3). The combined organic layer was washed with a semi-saturated saline solution, dried (anhydrous magnesium sulfate:anhydrous potassium carbonate=1:1), and then filtered, and the solvent was evaporated under reduced pressure. Afterward, the resulting oil was purified by a silica gel column chromatograph and successively Cephadex LH-20 to obtain 208.5 mg of the title compound as a milky white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:12]Cl)=[C:8]([CH2:10]Cl)[CH:9]=1)=[O:4].[CH3:14][NH2:15]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH2:12][N:15]([CH3:14])[CH2:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(CCl)c(CCl)s1
Reactant: CN
Solvent: CC#N
Product: COC(=O)c1cc2c(s1)CN(C)C2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4,5-Bis(chloromethyl)-2-thiophenecarboxylic acid methyl ester (D. J. Zwanenburg and Hans Wynberg, J. Org. Chem., 34, 333-340, (1969)) (520 mg) was dissolved in acetonitrile (600 mL). Methylamine (40% methanol solution, 722 μL) was added thereto, followed by stirring at room temperature for 3 days. The solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=1:0→19:1), to thereby give the title compound (176 mg).