Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=1>O>[N:5]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:15])([F:16])[F:17])[CH:7]=1)=[C:1]=[S:2]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: S=C(Cl)Cl
Solvent: O
Product: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Thiophosgene (10 g, 87.71 mmol) was dissolved in water and stirred at room temperature for 10 min. 4-Amino-2-trifluoromethyl-benzonitrile was added portionwise at room temperature. The reaction mixture was stirred at room temperature for 2 h. The product was extracted with dichloromethane, and the organic layer was washed with water, brine, dried over sodium sulfate and evaporated to obtain 12 g of product. 1H NMR (CDCl3): δ (ppm) 7.84 (d, 1H), 7.58 (s, 1H), 7.48 (d, 1H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Cl:13][C:14]1[N:19]=[C:18]([NH:20][CH3:21])[N:17]=[C:16]([N:22]2[C@H:27]([CH3:28])[CH2:26][O:25][C@H:24]([CH2:29][OH:30])[CH2:23]2)[CH:15]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:8][S:9]([O:30][CH2:29][C@H:24]1[O:25][CH2:26][C@@H:27]([CH3:28])[N:22]([C:16]2[CH:15]=[C:14]([Cl:13])[N:19]=[C:18]([NH:20][CH3:21])[N:17]=2)[CH2:23]1)(=[O:11])=[O:10]
Reactant: CNc1nc(Cl)cc(N2C[C@@H](CO)OC[C@H]2C)n1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNc1nc(Cl)cc(N2C[C@@H](COS(C)(=O)=O)OC[C@H]2C)n1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 96.2 %

Procedure:
Triethylamine (1.95 mL, 14.07 mmol) and methanesulfonyl chloride (0.52 mL, 6.67 mmol) were added dropwise to a solution of {(2S,5R)-4-[6-chloro-2-(methylamino)-4-pyrimidinyl]-5-methyl-2-morpholinyl}methanol (1.52 g, 5.57 mmol) in CH2Cl2 (50 mL) at 0° C., and the mixture was stirred at 0° C. under nitrogen for 45 minutes. It was then poured into saturated aqueous NaHCO3 (100 mL) and extracted with CH2Cl2 (3×100 mL). The extracts were dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (1.88 g) as a foam that was crushed into an off-white solid. LC-MS (ES) m/z=351, 353 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:13][C@H:12]2[CH2:14][C@@H:9]1[CH2:10][N:11]2[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1)C1C=CC=CC=1>CO.C(O)=O.[Pd]>[CH:19]([OH:21])=[O:20].[C@@H:12]12[CH2:14][C@@H:9]([NH:8][CH2:13]1)[CH2:10][N:11]2[C:15]1[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1ccc(N2C[C@H]3C[C@@H]2CN3Cc2ccccc2)cc1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CCOC(=O)c1ccc(N2C[C@H]3C[C@@H]2CN3)cc1
Yield: 216.6 %

Procedure:
Title compound 207 (0.32 g, 0.878 mmol) and Pd/C (0.093 g, 0.088 mmol) were combined in methanol (16.73 mL) and formic acid (0.836 mL). The reaction mixture was stirred at reflux for 2 h. The mixture was filtered and concentrated to afford title compound 208 (0.278 g, 99%) as a clear oil. LRMS: (calc) 246.14. (found) 247.3 (MH)+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].[OH:6][C:7]1[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[CH:10]=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:5][O:4][CH2:3][CH2:2][O:6][C:7]1[CH:16]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[C:9]([CH:8]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc(C(=O)OC)cc(C(=O)OC)c1
Yield: 93.7 %

Procedure:
1-bromo-2-methoxyethane(5.8 mmol), dimethyl 5-hydroxyisophthalate(5 mL), K2CO3 (6 mmol) in DMF(10 mL) were stirred for 12 h at 60° C., then the solution was poured into water and the aqueous phase was extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4), filtered, and concentrated to give dimethyl 5-(2-methoxyethoxy)isophthalate (93.7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][C:27]=1[C:28](O)=[O:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][C:27]=1[C:28]([N:15]1[CH2:16][CH2:17][N:12]([C:3]2[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=2[F:1])[CH2:13][CH2:14]1)=[O:29])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CS(=O)(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: CS(=O)(=O)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OCc3ccccc3)CC2)c(F)c1

Procedure:
The title compound was prepared in analogy to example 5 from 1-(2-Fluoro-4-methanesulfonyl-phenyl)-piperazine (commercial) and 2-Benzyloxy-5-methanesulfonyl-benzoic acid (compound 7.5). MS (m/e): 547.4 (MH+, 100%)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O=[C:8]1[NH:14][CH:13]2[CH2:15][CH2:16][N:10]([CH2:11][CH2:12]2)[CH2:9]1>O1CCCC1>[N:10]12[CH2:16][CH2:15][CH:13]([CH2:12][CH2:11]1)[NH:14][CH2:8][CH2:9]2
Reactant: O=C1CN2CCC(CC2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C1CN2CCC(CC2)N1
Yield: 64.4 %

Procedure:
Lithium aluminum hydride (2.0 g, 51.4 mmoles) was slurried in 250 ml of dry tetrahydrofuran and 3-oxo-1,4-diazabicyclo[3.2.2]nonane (3.6 g, 25.7 mmoles) was added carefully as a solid in one portion at room temperature. The resulting mixture was then heated to a gentle reflux for 20 hours. The reaction was cooled to room tempeature and quenched by slow addition of 2.5 ml water. The salts were filtered and washed several times with diethyl ether totaling 1.0 1. These washings and the supernatant were combined, dried over magnesium sulfate and concentrated to give 2.09 g (64.5%) of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:10][C:9]2[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=2[NH:7][C:6]1=[O:24])=[O:4].C[Si](C)(C)[N-][Si](C)(C)C.[K+].C1(C)C=CC=CC=1.[O:42]=O>O1CCCC1>[OH:42][C:5]1([C:3]([O:2][CH3:1])=[O:4])[CH:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[CH2:10][C:9]2[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=2[NH:7][C:6]1=[O:24]
Reactant: COC(=O)C1C(=O)Nc2ccccc2CC1c1ccc(OC)cc1
Reactant: O=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C1(O)C(=O)Nc2ccccc2CC1c1ccc(OC)cc1
Reaction time: 2.5 h

Procedure:
Dry oxygen gas was bubbled through a cooled (ice bath) solution of 1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-2H-1-benzazepin-2-one (13 g, 40.2 mmol) in 130 ml of dry tetrahydrofuran for 30 minutes. Potassium hexamethyldisilazide in toluene (180 ml, 0.67M, 120.5 mmol) was then added over a 7 minute period under a continuous stream of oxygen. After stirring for 2.5 hours, the oxygen flow was terminated and the reaction was quenched by the addition of 200 ml of 5% potassium bisulfate. Solid sodium sulfite (15 g) was then added followed by the addition of 100 ml of methanol and the mixture was stirred for an additional 30 minutes. The mixture was then extracted twice with ethyl acetate and the combined organic layers were washed three times with 1M hydrochloric acid, once with saturated bicarbonate solution followed by brine and then dried over sodium sulfate. Concentration afforded 15 g of crude product which was triturated with ether-hexane to yield 9.3 g of high purity product.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([OH:21])=[O:20])(=O)=O)C=CC=CC=1.[CH3:22]O>[OH-].[Na+]>[CH3:22][O:21][C:19]([C:11]1[NH:10][C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH:12]=1)=[O:20]
Reactant: O=C(O)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1cc2cccnc2[nH]1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
0.495 g (1.64 mmol) of 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid was dissolved in 5 mL of methanol and 3 mL of 2N aqueous sodium hydroxide. The reaction was stirred at 40° C. for 8 h. The solvent was removed under reduced pressure. Residual volatiles were removed by twice codistilling with toluene. The residue was suspended in methanolic hydrochloric acid and stirred for 16 h at RT. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. The organic phase was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:15][CH3:16])[S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:17])=[CH:5][C:4]=2[N:3]=1.Cl[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:15][CH3:16])[S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:17][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CCc1nc2c(N)nc3cc(O)ccc3c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCc1nc2c(N)nc3cc(Oc4ccc(C(=O)OC)cn4)ccc3c2s1

Procedure:
A round bottom flask was charged with 4-amino-2-ethylthiazolo[4,5-c]quinolin-7-ol (1.0 eq., 2.0 mmol), methyl 6-chloronicotinate (1.0 eq., 2.0 mmol), cesium carbonate (3.0 eq. 6.0 mmol), and anhydrous 1,4-dioxane (45 mL). The mixture was heated to reflux for 24 hours. The reaction was monitored by HPLC. The reaction mixture was concentrated to dryness. The resulting solid was then dissolved in methanol and adsorbed onto silica gel (6 g) for purification by HPFC (0-15% CMA in chloroform, 1440 mL). Pure fractions were combined and concentrated; the resulting solid was recrystallized from acetonitrile to provide methyl 6-[(4-amino-2-ethyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]nicotinate as a light peach colored crystalline solid, mp 213-214° C. MS (APCI) m/z 381 (M+H)+. Anal. calcd for C19H16N4O3S: C, 59.99; H, 4.24; N, 14.73. Found: C, 59.76; H, 4.19; N, 14.71.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[CH2:13][C@H:12]2[NH:14]C(=O)OC(C)(C)C)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[ClH:22]>O1CCOCC1>[ClH:22].[NH2:14][C@@H:12]1[CH2:13][C@H:11]1[C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc([C@@H]2C[C@H]2NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc([C@@H]2C[C@H]2N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To tert-butyl ((trans)-2-(4-acetamidophenyl)cyclopropyl)carbamate, step 1 (900 mg, 3.10 mmol) was added 4M HCl (3.444 mL, 13.78 mmol) in 1,4-dioxane and stirred for 2 h at RT. The reaction mixture was concentrated and triturated with EtOAc (10 mL) and dried under vacuum to afford N-(4-((trans)-2-aminocyclopropyl)phenyl)acetamide, hydrochloride (700 mg, 99% yield) as off white solid. LCMS (ES) m/e 190.2 (M+H).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)NC(=O)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1CCc2ccc(O)cc2N1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.1 %

Procedure:
A solution of 7-methoxy-3,4-dihydro-1H-quinolin-2-one (1.30 g, 7.34 mmol) in CH2Cl2 (100 mL) at 0° C. is treated with BBr3 (14.7 mL, 1.0 M in CH2Cl2) added dropwise. The mixture is stirred for 48 hours at room temperature and then quenched with water dropwise. The suspension is filtered and the solid is rinsed with MeOH (2 mL) and dried under vacuum to obtain the product (0.90 g, 75%).
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][C:8]12[CH2:15][CH2:14][C:11]([C:16]([O:18]C)=[O:17])([CH2:12][CH2:13]1)[CH2:10][CH2:9]2)(=[O:5])=[O:4])[CH3:2].[OH-].[K+]>O.CO>[CH2:1]([S:3]([CH2:6][CH2:7][C:8]12[CH2:13][CH2:12][C:11]([C:16]([OH:18])=[O:17])([CH2:14][CH2:15]1)[CH2:10][CH2:9]2)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)CCC12CCC(C(=O)OC)(CC1)CC2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCS(=O)(=O)CCC12CCC(C(=O)O)(CC1)CC2
Temperature: 60 °C
Yield: 98.4 %

Procedure:
Ester 1-3 (880 mg, 3 mmol) was dissolved in 10% water/methanol solution (100 mL) and treated with 1 g of potassium hydroxide. The reaction was heated at 60° C. for 1 h then at 45° C. overnight. The mixture was concentrated in vacuo then acidified to pH 2 with 1M HCl and extracted with three portions of methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate and evaporated to give 4-[2-(ethylsulfonyl)ethyl]bicyclo[2.2.2]octane-1-carboxylic acid (1-4) (810 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.CCN(CC)CC.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19]>C(Cl)Cl>[CH3:16][C:17]([CH3:22])([CH3:21])[C:18]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1)=[O:19]
Reactant: Cc1ccc(N)nc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C(C)(C)C)nc1
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a stirred solution of 5-methylpyridin-2-amine (200 g, 1.85 mol) in anhydrous CH2Cl2 (1000 mL) was added dropwise a solution of Et3N (513 mL, 3.70 mol) and 2,2-dimethyl-propionyl chloride (274 mL, 2.22 mol) at 0° C. under N2. The ice bath was removed and stirring was continued at room temperature for 2 hours. The reaction was poured into ice (2000 g). The organic layer was separated and the remaining aqueous layer was extracted with CH2Cl2 (3×). The combined organics were dried over Na2SO4 and evaporated to afford 2,2-dimethyl-N-(5-methyl-pyridin-2-yl)-propionamide (350 g), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J=8.4 Hz, 1H), 8.06 (d, J=1.2 Hz, 1H), 7.96 (s, 1H), 7.49 (dd, J=1.6, 8.4 Hz, 1H), 2.27 (s, 1H), 1.30 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][N:6]=1)=O.[CH:13]1([CH2:16][NH:17][C:18]([NH2:20])=[S:19])[CH2:15][CH2:14]1.C(=O)(O)[O-].[Na+]>C(O)C>[CH:13]1([CH2:16][NH:17][C:18]2[S:19][CH:2]=[C:3]([C:5]3[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][N:6]=3)[N:20]=2)[CH2:15][CH2:14]1
Reactant: N#Cc1ccc(C(=O)CBr)nc1
Reactant: NC(=S)NCC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(-c2csc(NCC3CC3)n2)nc1
Temperature: 25 °C
Yield: 90 %

Procedure:
Slurry crude 6-(2-bromo-acetyl)-nicotinonitrile (5.2 g), cyclopropylmethyl-thiourea (2.7 g, 20.8 mmol) and sodium bicarbonate (1.95 g, 23.1 mmol) in ethanol (135 mL) at room temperature. Stir the mixture at reflux for 1 h under a nitrogen atmosphere. Cool the mixture to room temperature and concentrate in vacuo to a solid. Recrystallize from ethanol (20 mL) and water (100 mL) at 5° C. to obtain the desired intermediate as a tan solid (4.8 g, 81%). MS (ES+) m/z: 257 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([CH2:28][NH2:29])[CH:25]=[CH:26][CH:27]=2)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].N(CCO)CCO>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([CH2:28][NH:29][S:38]([CH3:37])(=[O:40])=[O:39])[CH:25]=[CH:26][CH:27]=2)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(CCc2cccc(CN)c2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: OCCNCCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(CCc2cccc(CNS(C)(=O)=O)c2)c1
Temperature: 0 °C

Procedure:
3-[2-[5-[[1-(tert-Butoxycarbonyl)-(2S)-azetidinyl]methoxy]-3-pyridyl]ethyl]phenylmethylamine and triethylamine (1-2 equiv.) are dissolved in anhydrous CH2Cl2, and with exclusion of moisture and ice cooling a solution of methanesulfonyl chloride (1-1.5 equiv.) in CH2Cl2 is added dropwise. The mixture is stirred in the ice bath until no more starting amine is observed, then diethanolamine (0.2-0.7 equiv.) is added to quench the excess of methanesulfonyl chloride. The reaction mixture is evaporated and the residue chromatographed on silica gel with CH2Cl2/methanol. The product-containing fractions are evaporated, and the residue is dried in vacuo to obtain the sulfonamide.
Reaction SMILES: C([S:4][CH:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])[CH2:7]/[C:6]/1=[CH:24]\[C:25]1[N:26]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:27]=[CH:28][CH:29]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH:14]1([C:12](=[O:13])[CH:11]([N:8]2[CH2:9][CH2:10][CH:5]([SH:4])/[C:6](=[CH:24]/[C:25]3[N:26]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:27]=[CH:28][CH:29]=3)/[CH2:7]2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:16][CH2:15]1
Reactant: CCOC(=O)Cn1cccc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1SC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)Cn1cccc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a solution of (E)-4-(acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-{[1-(ethoxycarbonylmethyl)pyrrol-2-yl]methylidene}piperidine (1.41 g) in ethanol (30 ml) was added potassium carbonate (4.00 g) under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hours. After filtration, water was added to the filtrate, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed in vacuo, and the residue was purified by a preparative HPLC (YMC-Pack ODS-A; YMC, mobile phase: 80% acetonitrile/water) to afford the title compound (0.49 g, yield: 38%) as a colourless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:21][CH3:22])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2.[Cl:23]Cl>C(O)(=O)C>[Cl:23][C:5]1[C:4]([O:21][CH3:22])=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[CH:7]=[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]([C:12]([F:15])([F:14])[F:13])[O:10]2
Reactant: ClCl
Reactant: CCOC(=O)C1=Cc2cc(OC)cc(Cl)c2OC1C(F)(F)F
Solvent: CC(=O)O
Product: CCOC(=O)C1=Cc2c(Cl)c(OC)cc(Cl)c2OC1C(F)(F)F
Reaction time: 0.33 h
Yield: 7.4 %

Procedure:
To a solution of ethyl 8-chloro-6-methoxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in U.S. Pat. No. 6,271,253 B1 Example 40 (2.32 g, 6.89 mmole) in glacial acetic acid (100 mL) was added Cl2 gas for 0.5 minutes. After standing for 20 min, the solvent was removed in vacuo and the remaining acetic acid was azeotroped with hexanes to give a crystalline solid containing a mixture of regioisomers. The crude product was purified by recrystallization from ethyl acetate-hexanes to give 189 mg (7.4% yield) of the product as colorless needles: EIHRMS m/z 369.9986 (M+, C14H11C2lF3O4, Calc'd 369.9986).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:7][C:8]([F:36])([F:35])[C:9]1[CH:34]=[CH:33][CH:32]=[CH:31][C:10]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[N:24]=[N:23][C:22]([N:25]3[CH2:29][CH2:28][NH:27][C:26]3=[O:30])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:12]>>[CH2:2]([N:27]1[CH2:28][CH2:29][N:25]([C:22]2[N:23]=[N:24][C:19]([N:16]3[CH2:17][CH2:18][N:13]([C:11](=[O:12])[C:10]4[CH:31]=[CH:32][CH:33]=[CH:34][C:9]=4[C:8]([F:35])([F:36])[F:7])[CH2:14][CH2:15]3)=[CH:20][CH:21]=2)[C:26]1=[O:30])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(N3CCNC3=O)nn2)CC1
Reactant: CCCCCI
Product: CCCCCN1CCN(c2ccc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)nn2)C1=O
Yield: 13 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 1-iodopentane in place of 1-iodo-3-methylbutane to react with 1-{6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazin-3-yl}imidazolidin-2-one, the title compound was obtained as a white solid in 13% yield (7.4 mg). 1H NMR (300 MHz, CDCl3) δ 8.45 (d, J=9.9 Hz, 1H), 7.71 (d, J=7.5 Hz, 1H), 7.47-7.64 (m, 2H), 7.33 (d, J=7.5 Hz, 1H), 6.99 (d, J=9.9 Hz, 1H), 3.82-4.13 (m, 4H), 3.43-3.65 (m, 6H), 3.23-3.34 (m, 4H), 1.48-1.62 (m, 2H), 1.20-1.36 (m, 4H), 0.87 (d, J=7.5 Hz, 3H). MS (ES+) m/z 491 (M+1).
Reaction SMILES: C(O[C:6](=O)[NH:7][C@@H:8]([CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C)(C)C.Cl.C(=O)[CH2:36][CH:37]([CH3:39])[CH3:38].C(O)(=O)C.C([BH3-])#N.[Na+]>O1CCOCC1.CO>[Si:11]([O:10][CH2:9][C@@H:8]([NH:7][CH2:6][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:28][CH2:29][CH2:30][CH2:31][OH:32])([C:24]([CH3:26])([CH3:27])[CH3:25])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CC(C)CC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)CCN[C@@H](CCCCO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Material from Step 4 (9.8 g, 20.78 mmol) was dissolved in a solution of 4 M HCl (51.9 mL, 208 mmol) in dioxane. The reaction mixture was stirred at room temperature for 1 hour. It was concentrated in vacuo, then dichloromethane was added and concentrated again in vacuo. The residue (1.75 g, 4.29 mmol) was dissolved in methanol (30 mL), and isovaleraldehyde (0.35 mL, 4.50 mmol) and acetic acid (0.25 mL, 4.29 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes. Sodium cyanoborohydride (0.323 g, 5.15 mmol) was then added to the mixture and it was stirred at room temperature overnight. The reaction mixture was concentrated, and partitioned between EtOAc and saturated aqueous NaHCO3 and extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to yield the title compound, which was used without further purification.
Reaction SMILES: CN1CCNCC1.BrC1OC(C=O)=CC=1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[O:27][C:26]([CH:28]=O)=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:35][C:36]#[N:37]>>[CH3:30][O:31][C:32]1[CH:33]=[C:34](/[C:35](=[CH:28]/[C:26]2[O:27][C:23]([N:20]3[CH2:19][CH2:18][N:17]([CH3:16])[CH2:22][CH2:21]3)=[CH:24][CH:25]=2)/[C:36]#[N:37])[CH:38]=[CH:39][C:40]=1[O:41][CH3:42]
Reactant: CN1CCN(c2ccc(C=O)o2)CC1
Reactant: COc1ccc(CC#N)cc1OC
Agent: CN1CCNCC1
Agent: O=Cc1ccc(Br)o1
Product: COc1ccc(/C(C#N)=C/c2ccc(N3CCN(C)CC3)o2)cc1OC
Yield: 30.4 %

Procedure:
Through the procedure as employed in Production step 1, an amine moiety derived from 1-methylpiperazine (1.03 g) was introduced into 5-bromo-2-furaldehyde (602 mg), to thereby yield 5-(4-methyl-piperazin-1-yl)-furan-2-carbaldehyde (yield: 447 mg, 67%). The produced 5-(4-methyl-piperazin-1-yl)-furan-2-carbaldehyde (388 mg) was condensed with 3,4-dimethoxybenzyl cyanide (355 mg) through Method A (production step 2), to thereby yield the target product (yield: 215 mg, 30%).
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:20])([F:19])[S:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1)(=[O:7])=[O:6].Cl>O>[CH3:1][NH:2][S:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][S:5]([C:4]([F:20])([F:19])[F:3])(=[O:7])=[O:6])=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: CN
Reactant: O=S(=O)(Cl)c1ccc(NS(=O)(=O)C(F)(F)F)cc1
Agent: Cl
Solvent: O
Product: CNS(=O)(=O)c1ccc(NS(=O)(=O)C(F)(F)F)cc1
Reaction time: 8 h
Yield: 44.1 %

Procedure:
A mixture of a 40% aqueous solution of methylamine (0.7 g), 4-(trifluoromethanesulfonamido)benzenesulfonyl chloride (1.5 g) and water (20 ml) was allowed to stand overnight and made acidic with hydrochloric acid to pecipitate crystals, which were then recrystallized from a mixture of water and ethanol to give 0.65 g of N-methyl-4-(trifluoromethanesulfonamido)benzenesulfonamide (Compound No. 2). M.P., 156°-157° C.