Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[C:25]([O:29][C:30](=O)[O:31]C(C)(C)C)([CH3:28])([CH3:27])[CH3:26]>CO.C(Cl)(Cl)Cl>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 97.4 %

Procedure:
3.31 g of 1-cyclopropyl-6-fluoro-7-(piperazin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was dissolved in a mixture of 30 ml of methanol and 20 ml of chloroform, and the resulting solution was stirred at 50° C. for 5 hours after addition of 2.29 g of di-t-butylcarbonate thereto. The solvent was removed under reduced pressure to obtain 4.2 g of the object compound
Reaction SMILES: C([O:3][C:4](=O)[C:5](=[O:19])[CH:6]([C:17]#[N:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])C.C([OH:23])C.O>CS(O)(=O)=O>[OH:19][C:5]1[C:4](=[O:3])[NH:18][C:17](=[O:23])[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCO
Reactant: CCCCCCCCCCC(C#N)C(=O)C(=O)OCC
Agent: CS(=O)(=O)O
Solvent: O
Product: CCCCCCCCCCC1=C(O)C(=O)NC1=O
Reaction time: 8 h

Procedure:
1 G. of the 3-cyano-2-oxotridecanoic acid ethyl ester is dissolved in 5 ml of methanesulfonic acid and the mixture allowed to stand overnight at room temperature. The reaction mixture is worked up by first pouring into ethanol-water (20 ml ethanol--5 ml water). After standing for several hours, the ethanol is removed by evaporation. The aqueous acidic residue is diluted further with water and then extracted with chloroform. The chloroform solution is then washed well with water, dried and evaporated to give the desired 3-hydroxy-4-(n-decyl)-3-pyrroline-2,5-dione. Recrystallization from hexane or cyclohexane provides pure 3-hydroxy-4-(n-decyl)-3-pyrroline-2,5-dione, mp 109°-111° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][C:24]([O:26]CC2C=CC=CC=2)=[O:25])[C:18]1=[O:34])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]([C@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][C:24]([OH:26])=[O:25])[C:18]1=[O:34])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCc1ccccc1)[C@H]1CCCN(CC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCc1ccccc1)[C@H]1CCCN(CC(=O)O)C1=O
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To a solution of 43 (1.06 g, 2.27 mol) in 35 mL of methanol was added 10% Pd/C catalyst (127 mg) and the mixture was hydrogenated on a Parr shaker apparatus at 45 PSI for 2 hrs. The solution was filtered, evaporated, and the residue was dried by pumping at <1 mm Hg vacuum for 10 hrs to afford 0.836 g (98% yield) of product 44 as a colorless foam. TLC (silica; CH2Cl2, methanol, acetic acid: 27, 3, 1) Rf=0.40.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[N:30]1([CH2:35][CH2:36][CH2:37][NH2:38])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[F:23][C:22]1[CH:21]=[C:20]([CH3:24])[CH:19]=[C:18]([F:25])[C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:38][CH2:37][CH2:36][CH2:35][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:29])[S:14][N:13]=1
Reactant: NCCCN1CCCC1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCN3CCCC3)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 3-pyrrolidin-1-yl-propylamine by the procedure analogous to Example 1. MS (APCI, m/z): 454 [M+H]+.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:14])[C:5]1=[O:23])([CH3:3])[CH3:2].[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH:25]=[CH2:26]>C1COCC1.C([O-])(O)=O.[Na+]>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH:15][CH2:16][CH:17]2[CH2:18][CH2:19][N:20]([CH2:26][CH2:25][C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:22]2)=[O:14])[C:5]1=[O:23])([CH3:3])[CH3:2]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CC(C)n1c(=O)n(C(=O)NCC2CCNCC2)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)n1c(=O)n(C(=O)NCC2CCN(CCC(=O)OC(C)(C)C)CC2)c2ccccc21
Yield: 15.8 %

Procedure:
A mixture of 3-isopropyl-2-oxo-N-(piperidin-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide (0.50 g, 1.58 mmol, Step2), tert-butyl acrylate (0.340 mL, 2.37 mmol) and iPrNEt (0.275 mL, 2.37 mmol) in THF (20 mL) was refluxed for 18 h. After cooling, the reaction mixture was diluted with sat. NaHCO3 aq. (100 mL), extracted with CH2Cl2 (100 mL) for three times. The combined extracts were dried over Na2SO4, filtered and concentrated. The residue was chromatographed on a column of silica gel eluted with MeOH/CH2Cl2 (1:20→1:10) and then NH-silica gel eluted with EtOAc/hexane (1:5→1:2) to give 0.111 g (16%) of title compound as colorless syrup.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[H-].[Na+].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:24]=1>CN(C)C=O.C(OCC)(=O)C>[N+:16]([C:9]1[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=1[N:7]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:25][CH:24]=1)[C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])([O-:18])=[O:17]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCC(=O)Nc1ccc(OC)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1)c1ccc(OC)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
2.5 g (0.01 mol) of 2-pentanoylamino-5-methoxy-nitrobenzene are dissolved in 30 ml of dimethylformamide, treated with 550 mg (0.11 mol) of sodium hydride (50% in oil) and stirred for 30 minutes at 80° C. 3.5 g (0.01 mol) of tert.butyl 4'-bromomethyl-biphenyl-2-carboxylate are then added and stirred for a further 2 hours at 80° C. The solvent is distilled off in vacuum, the oily residue obtained is dissolved in ethyl acetate, washed with water and evaporated in vacuum after drying over sodium sulphate. A yellowish oil is obtained after column chromatography (silica gel: 0.06-0.2 mm, eluting agent: methylene chloride).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:23]O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15]([O:17][CH3:23])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1cnoc1-c1cccc(Cl)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1cccc(Cl)c1
Yield: 93 %

Procedure:
A mixture of 3-[5-(3-chlorophenyl)-4-isoxazolyl]propionic acid (3.10 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(3-chlorophenyl)-4-isoxazolyl]propionate (3.06 g, yield 93%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio). NMR (CDCl3) δ: 2.59–2.71 (2H, m), 2.93–3.05 (2H, m), 3.69 (3H, s), 7.36–7.50 (2H, m), 7.54–7.65 (1H, m), 7.69–7.73 (1H, m), 8.23 (1H, s).
Reaction SMILES: [CH:1]([NH:4][S:5]([CH2:8][Cl:9])(=[O:7])=[O:6])([CH3:3])[CH3:2].[Cl:10][C:11](Cl)([S:15]Cl)[CH:12]([Cl:14])[Cl:13]>C(N(CC)CC)C>[CH:1]([N:4]([S:15][C:11]([Cl:10])=[C:12]([Cl:14])[Cl:13])[S:5]([CH2:8][Cl:9])(=[O:7])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NS(=O)(=O)CCl
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)N(SC(Cl)=C(Cl)Cl)S(=O)(=O)CCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 32.3 g (0.32 mol) sample of triethylamine was added dropwise to a cooled (0° C.) solution of 50 g (0.29 mol) N-isopropyl chloromethanesulfonamide and 70 g (0.29 mol) 1,1,2,2-tetrachloroethylsulfenyl chloride. After the addition was completed, the reaction was stirred at ambient temperature for 30 minutes and then under reflux for 3 hours. The reaction mixture was then cooled, washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give the N-isopropyl-N-(trichlorovinylthio)-chloromethanesulfonamide product, which after crystallization from pet. ether melted at 71°-73° C. The product is reported as Compound 1.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=2)[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29][CH2:30][CH3:31])[N:10]=1.CN(C=O)C>O>[CH2:30]([S:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:11]1[N:10]=[CH:9][C:18]2[C:13](=[CH:14][C:15]([C:19]([F:21])([F:22])[F:20])=[CH:16][CH:17]=2)[N:12]=1)[CH3:31]
Reactant: CCSc1ccccc1-c1nc(N)c2ccc(C(F)(F)F)cc2n1
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1ccccc1-c1ncc2ccc(C(F)(F)F)cc2n1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 15.3 %

Procedure:
324 mg of t-butyl nitrite was added to a mixture of 506 mg of 4-amino-2-(2-ethylsulfanylphenyl)-7-trifluoromethylquinazoline and 10 ml of DMF at 100° C., and the mixture was stirred at 100° C. for 45 minutes. Water was added to the cooled reaction mixture, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 74 mg of 2-(2-ethylsulfanylphenyl)-7-trifluoromethylquinazoline (Compound of Present Invention 11).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:32]([F:35])([F:34])[F:33])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:26][C:25](=[O:27])[NH:24][CH2:23]4)=[O:21])=[C:16]([C:28]([F:31])([F:30])[F:29])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].FC(F)(F)S(O[CH2:44][C:45]([F:48])([F:47])[F:46])(=O)=O>CN(C)C=O.[Cl-].[Na+].O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:32]([F:33])([F:35])[F:34])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:26][C:25](=[O:27])[N:24]([CH2:44][C:45]([F:48])([F:47])[F:46])[CH2:23]4)=[O:21])=[C:16]([C:28]([F:31])([F:30])[F:29])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2C(F)(F)F)CN1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2C(F)(F)F)CN1CC(F)(F)F
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 1-([4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)phenyl]carbonyl)imidazolidin-4-one (300 mg, 0.56 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), sodium hydride (26 mg, 1.08 mmol, 2.00 equiv), 2,2,2-trifluoroethyl trifluoromethanesulfonate (260 mg, 1.12 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at 20° C. The resulting solution was diluted with 50 mL of brine. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined and dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/5). This resulted in 58.8 mg (17%) of 1-([4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)phenyl]carbonyl)-3-(2,2,2-trifluoroethyl)imidazolidin-4-one as a off-white solid. (ES, m/z): [M−H]− 620; 1H NMR (300 MHz, CDCl3) δ: 8.01-8.03 (m, 2H), 7.53 (s, 3H), 7.47 (s, 1H), 5.20 (s, 1H), 4.65 (s, 1H), 4.32 (s, 1H), 4.17 (s, 1H), 4.02-4.11 (m, 2H), 3.73-3.84 (m, 2H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH:14]([N:17]=[C:18]=S)([CH3:16])[CH3:15].[Cl-].CN(C=O)C>[Cu].CO>[Cl:8][C:6]1[CH:5]=[C:4]([Cl:9])[C:3]2[S:10](=[O:12])(=[O:11])[N:13]=[C:18]([NH:17][CH:14]([CH3:16])[CH3:15])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)cc(Cl)c1S(N)(=O)=O
Reactant: CC(C)N=C=S
Agent: [Cu]
Agent: [Cl-]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)NC1=NS(=O)(=O)c2c(Cl)cc(Cl)cc2N1
Temperature: 100 °C

Procedure:
A mixture of 2-amino-4,6-dichlorobenzenesulfonamide (1.0 g), isopropyl isothiocyanate (0.84 g), copper(l) chloride (0.4 g), and DMF (1.5 ml) was heated at 100° C. for 2 h. Then 5 ml of methanol was added and the precipitated material was removed by filtration. Evaporation of the solvent in vacuo and subsequent treatment of the residue with 25 ml of ethyl acetate gave a yellow precipitate, which was collected by filtration and recrystallized from ethanol to give the title compound as white crystals; m.p. 291-293° C.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:31]=[CH:30][C:29]([S:32]([NH:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])(=[O:34])=[O:33])=[CH:28][CH:27]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: CN(C)CCNS(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CN(C)CCNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 4-bromo-N-(2-dimethylamino-ethyl)-benzenesulfonamide (example B.30) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (260 mg, 45%). MS (ISP) 564.3 [(M+H)+]; mp 157-159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH2:8])[CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][C:18]=1[C:27]([F:30])([F:29])[F:28]>N1C=CC=CC=1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:24])=[O:25])=[CH:19][C:18]=1[C:27]([F:30])([F:28])[F:29]
Reactant: Nc1cc(Cl)ccc1Oc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)ccc1Oc1ccccc1)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-2-phenoxy-phenylamine (75 mg, 0.34 mmol) in anhydrous pyridine (0.5 mL) was added drop wise a solution of 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (95 mg, 0.341 mmol) in pyridine (0.5 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was separated by preparative HPLC using acetonitrile-water solvent mixture and pure product fractions were lyophilized to provide pure product as a solid. 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J =2.0 Hz, 1 H), 7.80 (dd, J=8.4, 2.0 Hz, 1 H), 7.70 (d, J=2.4 Hz, 1 H), 7.51 (d, J=8.4 Hz, 1 H), 7.27-7.23 (m, 2 H), 7.14-7.10 (m, 1 H), 7.05-7.02 (m, 2 H), 6.66 (d, J=8.4 Hz, 1 H), 6.60-6.56 (m, 2 H). MS m/z:484.0 (M+Na).
Reaction SMILES: Cl.[CH2:2]([N:9]([CH2:31][C@@H:32]([C:34]1[CH:45]=[CH:44][C:37]2[O:38]C(C)(C)[O:40][CH2:41][C:36]=2[CH:35]=1)[OH:33])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([S:27]([NH2:30])(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C>[CH2:2]([N:9]([CH2:31][C@H:32]([OH:33])[C:34]1[CH:45]=[CH:44][C:37]([OH:38])=[C:36]([CH2:41][OH:40])[CH:35]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([S:27]([NH2:30])(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC1(C)OCc2cc([C@@H](O)CN(CCCCCCOCCCCc3cccc(S(N)(=O)=O)c3)Cc3ccccc3)ccc2O1
Agent: Cl
Solvent: CCO
Product: NS(=O)(=O)c1cccc(CCCCOCCCCCCN(Cc2ccccc2)C[C@H](O)c2ccc(O)c(CO)c2)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Hydrochloric acid (80 ml, 1M) was added dropwise to a stirred solution of 3-{4-[(6-{benzyl[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide (20 g) in ethanol (100 ml) at 0° C. Upon complete addition the mixture was stirred at 5° C. for 1 h before being allowed to warm to room temperature. A portion (50 ml) of the ethanol was removed under reduced pressure and the remaining mixture was diluted with ethyl acetate (250 ml). The mixture was then washed with water (100 ml), saturated sodium bicarbonate solution (100 ml) and brine (100 ml) before being dried over anhydrous Na2SO4. The suspension was filtered and concentrated under reduced pressure to give the title compound (16 g) as an oil. LC RT=4.02 min, δ (DMSO-d6) 9.15 (1H, s), 7.65 (1H, s), 7.64 (1H, d, J 8.8 Hz), 7.45 (2H, m), 7.27 (8H, m), 6.94 (1H, dd, J 8.2 Hz), 6.67 (1H, d, J 8.2 Hz), 4.92 (1H, t, J 5.7 Hz), 4.67 (1H, s), 4.56 (1H, m), 4.45 (2H, d, J 5.7 Hz), 3.61 (2H, m), 3.34 (2H, t, J 6.3 Hz), 3.28 (2H, t, J 6.2 Hz), 2.66 (2H, m), 2.50 (2H, m), 2.39 (2H, m), 1.61 (2H, m), 1.50 (2H, m), 1.39 (4H, m), 1.16 (4H, m).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH2:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([N:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=O)=[CH:24][C:19]=2[N:18]([CH2:27][CH3:28])[C:17]1=[O:29])[CH3:15].S([O-])([O-])(=O)=O.[Mg+2]>ClCCl>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]=[CH:25][C:23]2[CH:22]=[CH:21][C:20]3[N:16]([CH2:14][CH3:15])[C:17](=[O:29])[N:18]([CH2:27][CH3:28])[C:19]=3[CH:24]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: CCn1c(=O)n(CC)c2cc(C=O)ccc21
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CCn1c(=O)n(CC)c2cc(C=N[C@@H]3CCN(Cc4ccccc4)C3)ccc21
Temperature: 22 °C
Reaction time: 20 h
Yield: 103.9 %

Procedure:
To a dry flask charged with a stir bar was added (3R)-(−)-1-benzyl-3-aminopyrrolidine (202 mg, 1.15 mmoles) (commercial from TCI-US), 1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carbaldehyde (250 mg, 1.15 mmoles), magnesium sulfate (500 mg) and 5 ml of dichloromethane (0.23 M). The flask was sealed with a plastic cap and the resulting mixture was stirred for 20 hours at 22° C. The mixture was filtered through a nylon disk via syringes, rinsing with dichloromethane and the yellow filtrate was concentrated to give 450 mg of the title compound as a yellow gum/foam.
Reaction SMILES: [N:1]([CH3:4])=[C:2]=[O:3].[F:5][C:6]1[C:7]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[O:31][CH3:32])=[N:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][S:20]([CH3:23])(=[NH:22])=[O:21])[CH:14]=2)=[N:10][CH:11]=1.C(N(CC)CC)C>CN(C=O)C.[Cl-].[Na+]>[F:5][C:6]1[C:7]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[O:31][CH3:32])=[N:8][C:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=2)[CH2:19][S:20]([CH3:23])(=[O:21])=[N:22][C:2]([NH:1][CH3:4])=[O:3])=[N:10][CH:11]=1
Reactant: CN=C=O
Reactant: COc1cc(F)ccc1-c1nc(Nc2cccc(CS(C)(=N)=O)c2)ncc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)N=S(C)(=O)Cc1cccc(Nc2ncc(F)c(-c3ccc(F)cc3OC)n2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 41.7 %

Procedure:
Isocyanatomethane (7.3 μL; 0.12 mmol) was added to a solution of (rac)-5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}pyrimidin-2-amine (50 mg; 0.12 mmol) in DMF (2.0 mL) and triethylamine (17.2 μL; 0.12 mmol) at RT. The batch was stirred for 17 hours at RT. The batch was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2×). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by chromatography (DCM/EtOH 95:5) to give the desired product (24 mg; 0.05 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27]([NH:29][CH2:30][CH2:31][OH:32])=[O:28])[C:9]2=[O:33])=[CH:4][CH:3]=1.[OH-].[Na+:35]>C(O)C.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([O-:26])=[C:10]([C:27]([NH:29][CH2:30][CH2:31][OH:32])=[O:28])[C:9]2=[O:33])=[CH:4][CH:3]=1.[Na+:35]
Reactant: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: O=C(NCCO)c1c([O-])c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Reaction time: 1 h
Yield: 92 %

Procedure:
1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxyethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (311 mg, 0.690 mmol) described in example 200 was suspended in ethanol (10 mL) and 1 N sodium hydroxide was added (0.68 mL) and the resulting white suspension was stirred for 1 hour. The mixture was diluted with diethyl ether (50 mL) and the solid was collected by vacuum filtration to afford sodium 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-3-{[(2-hydroxyethyl)amino]carbonyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-4-olate (300 mg, 92% yield) as a white solid. 1H NMR (DMSO-d6) δ 10.53 (br s, 1 H), 8.15 (s, 1 H), 7.31 (m, 2 H), 7.19 (m, 2 H), 7.11 (m, 2 H), 7.03 (m, 2 H), 6.48 (s, 1 H), 4.71 (br s, 1 H), 3.85 (s, 2 H), 3.41 (m, 2 H), 3.26 (m, 2 H); MS m/z 452 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C([O-])([O-])=O.[K+].[K+].[C:15](Cl)(=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.CC(C)=O>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:15](=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Nc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(C=Cc1ccccc1)Nc1ccccc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
To a mixture of 2-bromoaniline (0.976 g, 5.81 mmol, Sigma-Aldrich) and K2CO3 (1.16 g, 8.71 mmol) in water (5.5 mL) and acetone (4.5 mL) was added cinnamoyl chloride (1 g, 5.81 mmol, Sigma-Aldrich) and the reaction was stirred for 2 h at 0° C. The mixture was treated with ice cold water (25 mL) to obtain a brownish precipitate. The precipitate was filtered and dried under vacuum. The crude material was further treated with petroleum ether to give N-(2-bromophenyl)cinnamamide (1.1 g, 64%) as off-white solid. MS (ESI, pos. ion) m/z: 303.2 (M+1).