Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].C(N(CC)CC)C.[F:16][C:17]([F:23])([F:22])[S:18](F)(=[O:20])=[O:19]>C(Cl)(Cl)Cl>[F:16][C:17]([F:23])([F:22])[S:18]([O:4][CH2:3][C:2]([F:8])([F:1])[CH:5]([F:7])[F:6])(=[O:20])=[O:19]
Reactant: O=S(=O)(F)C(F)(F)F
Reactant: OCC(F)(F)C(F)F
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=S(=O)(OCC(F)(F)C(F)F)C(F)(F)F
Reaction time: 0.75 h

Procedure:
2,2,3,3-tetrafluoropropan-1-ol (244.3 g, 1.85 mol, obtained from Sinochem Corp.), triethylamine (187.2 g, 1.85 mol, obtained from Aldrich Chemical Co.) and 500 mL of chloroform were combined in a 2-liter Parr pressure reactor and sealed. The reactor temperature was set to −10° C. Trifluoromethanesulfonyl fluoride (281.33 g, 1.85 mol, obtained from 3M Company) was added at such a rate that the temperature did not exceed −5° C. Once the addition was complete, the mix was held at −10° C. for 45 minutes. The reaction mix was then emptied and washed with 2×500 mL portions of water and 1×250 mL portion of 1N HCl. GC analysis of the reaction mixture indicated a 97 percent conversion to the product. The chloroform solvent was removed by rotary evaporation. The product was dried over anhydrous magnesium sulfate which was then filtered from the product.
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[C:15]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][NH:24][CH3:25])[CH2:18][CH2:17]2)=[CH:14][CH:13]=[CH:12][N:11]=1.[CH3:26][N:27]1[CH:31]=[C:30]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[N:28]1>ClCCl.C(=O)(O)[O-].[Na+]>[Cl:9][C:10]1[C:15]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:25])[S:32]([C:30]3[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=3)(=[O:34])=[O:33])[CH2:18][CH2:17]2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Reactant: CNCCN1CCN(c2cccnc2Cl)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCN1CCN(c2cccnc2Cl)CC1)S(=O)(=O)c1cnn(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Add triethylamine (3.403 mL, 24.414 mmol) to a stirring solution of {2-[4-(2-chloro-pyridin-3-yl)-piperazin-1-yl]-ethyl}-methyl-amine hydrochloride salt (2.000 g, 6.103 mmol) in dichloromethane (100 mL). Add 1-methyl-1H-pyrazole-4-sulfonyl chloride (1.102 g, 6.103 mmol) at room temperature. Stir at room temperature for 30 min. Dilute with dichloromethane and saturated aqueous sodium bicarbonate. Separate phases and extract the aqueous phase with dichloromethane. Combine the organic phases, dry over sodium sulfate, filter, and concentrate. Purify the resulting material by silica gel chromatography eluting with hexanes:acetone 1:1 to afford the title preparation (1.600 g, 66% yield). MS ES: m/z=399 [M+H]+.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].C(N(CC)CC)C.[CH:28]1([C:34]#[CH:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.S>CN(C)C=O.C(Cl)(Cl)Cl.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>[CH:28]1([C:34]#[C:35][C:2]2[N:3]=[C:4]([NH2:20])[C:5]3[N:6]=[CH:7][N:8]([C:18]=3[N:19]=2)[C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C#CC1CCCCC1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: S
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nc(C#CC2CCCCC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 90 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
1.95 g (5 mmol) of 2-iodoadenosine was dissolved in 20 ml of N,N-dimethylformamide (DMF), to which were added 0.18 g of bis(triphenylphosphine)palladium dichloride, 0.1 g of cuprous iodide, 2.8 ml of triethylamine and 0.8 ml of cyclohexylacetylene. The resulting mixture was stirred at a temperature of 90° C. for two hours. The reaction solution after being allowed to cool, was concentrated to dryness. The residue obtained was dissolved in chloroform, into which was vigorously introduced hydrogen sulfide gas over one minute. The solution was then dried under reduced pressure. The residue was purified by silica gel column chromatography, followed by recrystallization from ethanol-water, thereby obtaining 1.11 g (2.97 mmol) of crystalline 2-(cyclohexylethynyl)adenosine (yield: 59%).
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[C:10]([N:17]1[CH2:20][CH:19](I)[CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[Cl:22][C:23]1[C:28](Cl)=[N:27][CH:26]=[CH:25][N:24]=1.C(Cl)Cl>CC(N(C)C)=O.[Zn].[Cu]I>[Cl:22][C:23]1[C:28]([CH:19]2[CH2:20][N:17]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:18]2)=[N:27][CH:26]=[CH:25][N:24]=1
Reactant: Clc1nccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CC(=O)N(C)C
Solvent: BrCCBr
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(c2nccnc2Cl)C1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 34.9 %

Procedure:
A 12 L 3-neck round bottom flask fitted with a magnetic stirrer under nitrogen was charged with zinc dust (745 g, pre-activated, 11.4 mol, 2 eq.) and DMA (2 L, anhydrous). 1,2-dibromoethane (71 mL, 0.855 mol, 0.15 eq, Aldrich) was then added over 10 minutes, followed by TMSCl (108 mL, 0.855 mol, 0.15 eq, Acros) over 20 minutes. The reaction mixture was stirred for 25 minutes at room temperature. A solution of N-Boc-3-iodoazetidine (2420 g, 8.55 mol, 1.5 eq, CNH Technologies) in DMA (5 L, anhydrous) was added via a 2 L addition funnel over 2 h keeping the internal temperature below 65° C. using a water bath. The suspension was stirred for 1 hour at RT at which point it was degassed with nitrogen. Stirring was stopped and the suspension was allowed to stand. A 22 L 3-neck round bottom flask fitted with a mechanical stirrer was charged with 2,3-dichloropyrazine (850 g, 5.70 mol, 1.0 eq, AK Scientific), PdCl2dppf.CH2Cl2 (140 g, 171 mmol, 0.03 eq, Aldrich), CuI (67.3 g, 353 mmol, 0.062 eq, Aldrich), and DMA (5 L, anhydrous). The solution was degassed with nitrogen. The clear zinc reagent solution above the residual solid zinc was poured into the 22 L flask under nitrogen. The brown solution was degassed with nitrogen and heated to 80° C. for 16 hours at which point LCMS indicated complete conversion of 2,3-dichloropyrazine. The reaction mixture was transferred to brine (8 L) in 50 L reparatory funnel. Water (8 L) and EtOAc (15 L) were added and the layers were separated. The aqueous layer was extracted with EtOAc (2×10 L). The combined organics were washed with water (3×10 L) and brine (5 L), dried over sodium sulfate and evaporated. The resulting residue was purified by column chromatography (eluting with hexanes/ethyl acetate=10:1) to get 536 g of pure tert-butyl 3-(3-chloropyrazin-2-yl)azetidine-1-carboxylate and 121 g of mixed fractions. The impure material was distilled under high vacuum to remove the impurity (N-Boc-azetidine) to give 81 g of pure tert-butyl 3-(3-chloropyrazin-2-yl)azetidine-1-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:12]=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[N:10]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>CC(=O)CC>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[N:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:14]=1
Reactant: Cc1ccc(-c2nc(-c3ccc(C)cc3)nc(-c3ccc(O)cc3O)n2)cc1
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(-c2nc(-c3ccc(C)cc3)nc(-c3ccc(C)cc3)n2)c(O)c1
Yield: 79 %

Procedure:
55.4 g (0.15 mol) of 2-(2,4-dihydroxyphenyl)-4,6-bis-(4-methylphenyl)-1,3,5-triazine are dissolved in refluxing 2-butanone (11) in the presence of 27.6 g (0.2 mol) of K2CO3. A catalytic amount (0.2 g) of KI is added, and 36.8 g (0.3 mol) of ethyl chloroacetate are added dropwise over 1 h30. After refluxing for 25 h, the reaction mixture is cooled in ice, the precipitate is filtered off, washed with water to neutrality and then with methanol. Drying in the oven yields the analytically pure 2-(2-hydroxy-4-ethoxycarbonylmethoxyphenyl)-4,6-bis-(4-methylphenyl)-1,3,5-triazine (54 g, m.p. 166°-167° C.) (Compound No. 47).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][N:12]([C@H:23]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:24][CH:25]=[CH2:26])[C:13](=[O:22])[C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CSC.B.[OH:35]O.[OH-].[Na+]>C1COCC1.O>[CH2:1]([O:8][C:9]([NH:11][N:12]([C@H:23]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:24][CH2:25][CH2:26][OH:35])[C:13](=[O:22])[C:14]1[CH:15]=[C:16]([CH3:21])[CH:17]=[C:18]([CH3:20])[CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC[C@H](N(NC(=O)OCc1ccccc1)C(=O)c1cc(C)cc(C)c1)C(C)(C)C
Reactant: OO
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CSC
Product: Cc1cc(C)cc(C(=O)N(NC(=O)OCc2ccccc2)[C@@H](CCCO)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.2 %

Procedure:
To a solution of (S)—N′-(1-tert-butyl-but-3-enyl)-N′-(3,5-dimethyl-benzoyl)-hydrazinecarboxylic acid benzyl ester (200 mg, 0.49 mmol) in THF (3 mL), was added borane dimethyl sulfide (2 M in THF, 125 μL, 0.25 mmol) at 0° C. The mixture was stirred at room temperature for 16 h. Excess borane and THF was removed in vacuo, and additional THF (3 mL), followed by H2O2 (61 microliters, 0.54 mmol) and 3N NaOH (90 microliters, 0.27 mmol) were added. After stirring at 50-55° C. for 1 h, more water was added, the mixture was extracted with ether, and the ether layer was dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography to give (S)—N′-(1-tert-butyl-4-hydroxy-butyl)-N′-(3,5-dimethyl-benzoyl)-hydrazinecarboxylic acid benzyl ester as a white solid (128 mg, yield 61%). Rf=0.30 (1:1 EtOAc:n-hexane). 1H NMR (400 MHz, DMSO-d6) δ 9.71+9.63 (2 s, 1H), 7.44-6.88 (m, 8H), 5.06 (dd, J=3.6, 12.8 Hz, 1H), 4.79 (dd, J=12.4, 25.2 Hz, 1H), 4.43 (d, J=10.8 Hz, 1H), 4.28 (t, J=5.2 Hz, 1H), 3.47 (m, 2H), 2.27 (s, 6H), 1.86-1.21 (m, 4H), 1.01 (s, 9H); HRMS (ESI) m/z calcd for C25H35N2O4 [M+H]+ 427.2597, found 427.2587, calcd for C25H34N2NaO4 [M+Na]+ 449.2416, found 449.2407.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]2)[C:6]=1[C:7]#[N:8])([O-:4])=[O:3].C(N(CC)CC)C.[CH2:28]([N:30]=[C:31]=[O:32])[CH3:29]>C1COCC1.O>[C:7]([C:6]1[C:5]([N+:2]([O-:4])=[O:3])=[CH:12][CH:11]=[CH:10][C:9]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[C:31]([NH:30][CH2:28][CH3:29])=[O:32])#[N:8]
Reactant: N#Cc1c(OCC2CCCCN2)cccc1[N+](=O)[O-]
Reactant: CCN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)N1CCCCC1COc1cccc([N+](=O)[O-])c1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.9 %

Procedure:
To a solution of 2-nitro-6-(piperidin-2-ylmethoxy)benzonitrile hydrochloride (Example 26d, 0.5 g, 1.68 mmol) in THF were added triethylamine (0.514 mL, 3.7 mmol) and ethylisocyanate (0.2 mL, 2.52 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 3 hours. The solution was then diluted with water and extracted with EtOAc, the combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated to give 2-((2-cyano-3-nitrophenoxy)methyl)-N-ethylpiperidine-1-carboxamide (0.485 g, 87%) which was used in the next step without further purification. MS 333 (MH+).
Reaction SMILES: CC([N:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([CH:26]([F:28])[F:27])[CH:22]=[CH:23][CH:24]=3)[C:19]([N:29]([S:39]([C:42]3[S:43][C:44]([Cl:47])=[CH:45][CH:46]=3)(=[O:41])=[O:40])[S:30]([C:33]3[S:34][C:35]([Cl:38])=[CH:36][CH:37]=3)(=[O:32])=[O:31])=[N:18]2)[CH:11]=1)C(=O)[O-])(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:5][CH2:9][C:10]1[CH:11]=[C:12]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([CH:26]([F:27])[F:28])[CH:22]=[CH:23][CH:24]=3)[C:19]([N:29]([S:39]([C:42]3[S:43][C:44]([Cl:47])=[CH:45][CH:46]=3)(=[O:40])=[O:41])[S:30]([C:33]3[S:34][C:35]([Cl:38])=[CH:36][CH:37]=3)(=[O:32])=[O:31])=[N:18]2)[CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)N(Cc1cccc(Cn2nc(N(S(=O)(=O)c3ccc(Cl)s3)S(=O)(=O)c3ccc(Cl)s3)c3c(C(F)F)cccc32)c1)C(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cccc(Cn2nc(N(S(=O)(=O)c3ccc(Cl)s3)S(=O)(=O)c3ccc(Cl)s3)c3c(C(F)F)cccc32)c1
Reaction time: 1 h
Yield: 54 %

Procedure:
1,1-Dimethylethyl[(3-{[3-{bis[(5-chloro-2-thienyl)sulfonyl]amino}-4-(difluoromethyl)-1H-indazol-1-yl]methyl}phenyl)methyl]carbamate (for a preparation see Intermediate 69) (60 mg, 0.079 mmol) was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (0.125 mL) was added to the solution. and stirred for 1 h under nitrogen. The solution was concentrated under a stream of nitrogen and the off-white residue was dissolved in methanol and loaded onto a methanol conditioned sulphonic acid (SCX-2) cartridge (10 g). The cartridge was washed well with methanol, followed by 2M ammonia in methanol. Evaporation of the solvent from the ammoniacal fractions gave the title compound (26 mg, 54%) as a white solid. LCMS (System A) RT=1.11 min, ES+ve m/z 663/665 (M+H)+.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:19][C:20]([N:22]1[CH2:31][CH2:30][C:29]2[CH:28]=[N:27][C:26]([NH:32][CH:33]([CH3:36])[CH2:34][F:35])=[N:25][C:24]=2[CH2:23]1)=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)(C(C)(C)C)(C)C.Cl.CC(O)C>C(Cl)Cl>[Cl:18][C:13]1[CH:12]=[C:11]([C@H:10]([NH:19][C:20]([N:22]2[CH2:31][CH2:30][C:29]3[CH:28]=[N:27][C:26]([NH:32][CH:33]([CH3:36])[CH2:34][F:35])=[N:25][C:24]=3[CH2:23]2)=[O:21])[CH2:9][OH:8])[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: CC(CF)Nc1ncc2c(n1)CN(C(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)c1ccc(Cl)c(Cl)c1)CC2
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(CF)Nc1ncc2c(n1)CN(C(=O)N[C@H](CO)c1ccc(Cl)c(Cl)c1)CC2
Reaction time: 1 h

Procedure:
To a solution of 240 (0.500 g, 0.898 mmol) and DCM (5 mL) at RT was added 6M HCl in IPA (1.50 mL, 8.98 mmol) and the reaction was stirred for 1 h and then concentrated to dryness. The residue was partitioned between aq. Na2CO3 and DCM. The organic fraction was dried, filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (500:30 to 500:35) to afford 0.34 g (85.6%) of I-60 as a mixture of diastereomers: MS m/z (APCI-pos) M+1=442. The racemic mixture was resolved by chiral supercritical fluid chromatography.
Reaction SMILES: [Cl:1]Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH3:14])[C:12](=[O:15])[C:11]([CH3:17])([CH3:16])[N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:8]=2[CH:25]=1>Cl>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH3:14])[C:12](=[O:15])[C:11]([CH3:17])([CH3:16])[N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:8]=2[C:25]=1[Cl:1]
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc(N)ccc21
Reactant: ClCl
Agent: Cl
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2c1ccc(N)c2Cl

Procedure:
Chlorine gas is conducted slowly at between -5° and 0° through a solution of 6 g (0.019 mol) of 7-amino-5-(o-fluorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one in 70 ml of concentrated hydrochloric acid until the starting material has almost completely been consumed. The reaction mixture is poured into a mixture of ice and soda solution, whereupon it is extracted with methylene chloride and the extract is dried and evaporated. The residue is chromatographed on 300 g of silica gel with methylene chloride/ethyl acetate (10:1) as the elution agent. From ether-petroleum ether there is obtained 7-amino-6-chloro-5-(o-fluorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one of melting point 192°-193°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O1CCCC1.[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19]>O>[NH2:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:17](=[O:21])[C:18]([CH3:20])=[CH2:19])=[CH:3][CH:4]=1)(=[O:9])=[O:10]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: C=C(C)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)C(=O)Nc1ccc(S(N)(=O)=O)cc1
Temperature: 60 °C

Procedure:
170.2 g (1.0 mole) of p-aminobenzenesulfonamide and 700 ml of tetrahydrofuran were placed in one liter three-necked flask equipped with a stirrer, a cooling coil and a dropping funnel and stirred in an ice-water bath. 52.3 g (0.5 mole) of methacrylic acid chloride was added dropwise from the dropping funnel to the mixture over a period of about one hour. After the completion of dropping, the ice-water bath was removed and the mixture was stirred at room temperature for 30 minutes and then stirred further for one hour while heating it in an oil bath at 60° C. After the completion of the reaction, the reaction mixture was introduced into 3 l of water with stirring, stirred for 30 minutes and filtered to obtain N-(p-aminosulfonylphenyl)methacrylamide as a white solid. The white solid was purified by recrystallizing it from a mixed solvent of water-acetone (yield: 39.3 g).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[C:20]1([CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][NH2:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:28][CH2:27][CH:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CC(C)(C)N1C(=O)C(NCC(c2ccccc2)c2ccccc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 2,2-diphenylethanamine in a similar manner as described for Example 1. 1H NMR (500 MHz CDCl3): δ 7.59-7.54 (m, 2H), 7.48-7.43 (m, 3H), 7.27 (t, 4H), 7.22 (t, 2H), 6.97 (d, 4H), 5.25 (t, 1H), 3.96 (t, 1H), 3.50 (dd, 2H), 1.70 (s, 9H); 13C NMR (125 MHz CDCl3): δ 159.6, 140.8, 135.0, 131.7, 129.9, 129.0, 128.0, 127.3, 125.3, 108.1, 61.7, 50.7, 48.3, 27.8; Mass Spectrum: M+H+ 461.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[C:17]1([CH2:23][CH2:24][CH2:25][OH:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[O:26][CH2:25][CH2:24][CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCCCc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Cl
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(OCCCc2ccccc2)c(Cl)c(-c2ccco2)n1

Procedure:
From 5-chloro-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, 3-phenyl-1-propanol and DBU in dioxane. ES-MS m/e (%): 332 (M{37Cl}+H+, 50), 330 (M{35C,}+H+, 100).
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[S:22][C:23](B2OC(C)(C)C(C)(C)O2)=[C:24]([CH3:26])[N:25]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:20][C:21]1[S:22][C:23]([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[C:24]([CH3:26])[N:25]=1
Reactant: Cc1nc(C)c(B2OC(C)(C)C(C)(C)O2)s1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1nc(C)c(-c2cccc3c2OCCN(C(=O)OC(C)(C)C)C3)s1
Temperature: 85 °C
Reaction time: 12 h
Yield: 66.6 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (328 mg, 1.00 mmol), 2,4-dimethyl-1,3-thiazol-5-ylboronic acid pinacol ester (239 mg, 1.00 mmol), saturated aqueous sodium carbonate solution (6 ml) and tetrakis(triphenylphosphine)palladium(0) (32.6 mg, 0.0282 mmol) in dimethoxyethane (10 ml) was stirred at 85° C. for 12 hr under a nitrogen atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (240 mg, 66.7%) as an oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6]Cl.C(O)C.[S:11]([O-:14])([O-:13])=[O:12].[Na+:15].[Na+].C(OCC)C>O>[Cl:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][S:11]([O-:14])(=[O:13])=[O:12].[Na+:15]
Reactant: O=S([O-])[O-]
Reactant: ClCCOCCCl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: O=S(=O)([O-])CCOCCCl
Reaction time: 2 h

Procedure:
Bis(2-chloroethyl)ether (94.4 g), ethanol (250 ml) and water (90 ml) were stirred together under reflux, and a solution of sodium sulphite (25.0 g) in distilled water (90 ml) was added to the stirred, refluxing reaction mixture over a period of 2 hours. After the addition, refluxing was continued for two hours after which time the excess alcohol and bis(2-chloroethyl) ether were removed by distillation. The remaining aqueous solution was evaporated to dryness on a water bath to give a white crystalline solid, which was stirred with diethyl ether and filtered to yield sodium 2-chloroethoxyethyl sulphonate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C[Al](C)C.C([O:15][C:16]([C:18]1[NH:22][N:21]=[C:20]([CH3:23])[CH:19]=1)=O)C>C(Cl)Cl>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:16]([C:18]2[NH:22][N:21]=[C:20]([CH3:23])[CH:19]=2)=[O:15])=[N:3][CH:4]=1
Reactant: CCOC(=O)c1cc(C)n[nH]1
Reactant: Nc1ccc(Br)cn1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)Nc2ccc(Br)cn2)[nH]n1
Reaction time: 4 h
Yield: 49.1 %

Procedure:
A solution of 2-amino-5-bromopyridine (0.200 g, 1.16 mmol 1.0 equiv), in 5 mls of methylene chloride, under argon, was treated with trimethylaluminum (0.312 mL, 2.0 N in hexanes, 4.0 equiv) at room temperature for 30 min. To the solution was added ethyl-3-methylpyrazole-5-carboxylate (0.356 g, 2.0 equiv). After 4 hrs, the volatile was evaporated, and the residue was redissolved into EtOAc, washed with 0.5N HCl, 0.2 N K2CO3, and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered, evaporated and purified via flash chromatography on silica gel to give N-(5-bromo-2-pyridinyl)-(3-methyl)5-pyrazolecarboxamide (0.160 g, 49%). MS found for C10H9BrN4O (M+H)+: 281, 283. Step 2: A solution of N-(5-bromo-2-pyridinyl)-(3-methyl)5-pyrazolecarboxamide (0.060 g, 0.213 mmol, 1.0 equiv) in 2 mL of acetonitrile was treated with triphosgene (0.063 g, 1.0 equiv) at room temperature for 5 min under argon. To the solution was added 4-[(2-t-butylaminosulfonyl)phenyl]phenylamine (0.071 g, 1.1 equiv) After 1 hr, the volatile was evaporated and the residue was redissolved into EtOAc, washed with 0.5N HCl, 0.2 N K2CO3, and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered, evaporated, purified via flash chromatography on silica gel and then reacted in 2 mL of trifluoroacetic acid for 16 hrs at room temperature. TFA was then evaporated and the residue was redissolved into EtOAc, washed with 0.5N HCl, 0.2 N K2CO3, and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered, evaporated, and triturated with diethyl ether to give N-(5-bromo-2-pyridinyl)-(2-4-[(2-aminosulfonyl)phenyl]phenylaminocarbonyl)5-methyl-pyrazolcarboxamide (0.0024 g, 2%). MS found for C23H19BrN6O4S (M+H)+: 555, 557.