Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)(=[O:3])[CH3:2].B(F)(F)F.CCOCC.[Br:32]Br>ClCCl>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:4]([C:1](=[O:3])[CH2:2][Br:32])=[C:5]2[C:10]=1[NH:9][C:8](=[O:22])[CH:7]=[CH:6]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrBr
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 134.3 %

Procedure:
The product from step (c) (20.0 g, 68.2 mmol) was dissolved in dichloromethane (200 mL) and cooled to 0° C. Boron trifluoride diethyl etherate (10.4 mL, 82.0 mmol) was added via syringe and the mixture was warmed to room temperature to give a thick suspension. The suspension was heated at 45° C. (oil bath) and a solution of bromine (11.5 g, 72.0 mmol) in dichloromethane (100 mL) was added over 40 min. The mixture was kept at 45° C. for an additional 15 min and then cooled to room temperature. The mixture was concentrated under reduced pressure and then triturated with 10% aqueous sodium carbonate (200 mL) for 1 hour. The solids were collected on a Buchner funnel, washed with water (4×100 mL) and dried under reduced pressure. The product of two runs was combined for purification. The crude product (52 g) was triturated with 50% methanol in chloroform (500 mL) for 1 hour. The product was collected on a Buchner funnel and washed with 50% methanol in chloroform (2×50 mL) and methanol (2×50 mL). The solid was dried under reduced pressure to give the title compound (34.1 g) as a powder.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[CH2:12]([O:15][C:16]([N:18]1[CH2:22][C:21](=[O:23])[CH2:20][C@H:19]1[C:24]([O:26][CH3:27])=[O:25])=[O:17])[CH:13]=[CH2:14]>O1CCCC1.[Cl-].[NH4+].C(OCC)(=O)C>[CH2:12]([O:15][C:16]([N:18]1[CH2:22][C:21]([OH:23])([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH2:20][CH:19]1[C:24]([O:26][CH3:27])=[O:25])=[O:17])[CH:13]=[CH2:14]
Reactant: C#C[Si](C)(C)C
Reactant: C=CCOC(=O)N1CC(=O)C[C@H]1C(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOC(=O)N1CC(O)(C#C[Si](C)(C)C)CC1C(=O)OC
Reaction time: 1 h
Yield: 57.7 %

Procedure:
To a solution of trimethylsilylacetylene (5 g) in tetrahydrofuran (60 ml) was added n-butyllithium (32 ml) slowly and dropwise at -50° C. After completion of the dropwise addition, the mixture was stirred at -50° C. for 30 minutes, at the end of which time a tetrahydrofuran solution (10 ml) of (2S)-1-allyloxycarbonyl-2-methoxycarbonyl-4-oxopyrrolidine (10 g) was added below -50° C. The mixture was stirred for 1 hour and, then, diluted with saturated aqueous ammonium chloride solution and ethyl acetate. After standing, the aqueous layer was separated and extracted with ethyl acetate twice and the organic layers were combined, washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, water and aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Finally the solvent was distilled off under reduced pressure to give 1-allyloxycarbonyl-4-hydroxy-2-methoxycarbonyl-4-trimethylsilylethynylpyrrolidine (8.26 g).
Reaction SMILES: [N+:1]([CH:4]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:5][CH:6]([P:15]([O:20][CH2:21][CH3:22])(=[O:19])[O:16][CH2:17][CH3:18])[P:7]([O:12][CH2:13][CH3:14])(=[O:11])[O:8][CH2:9][CH3:10])([O-])=O.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:1][CH:4]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:5][CH:6]([P:15]([O:20][CH2:21][CH3:22])(=[O:19])[O:16][CH2:17][CH3:18])[P:7]([O:8][CH2:9][CH3:10])(=[O:11])[O:12][CH2:13][CH3:14]
Reactant: CCCCCC(CC(P(=O)(OCC)OCC)P(=O)(OCC)OCC)[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCCCCC(N)CC(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Reaction time: 24 h
Yield: 92.3 %

Procedure:
To a stirred solution of tetraethyl 3-nitrooctane-1,1-bisphosphonate (0.70 g, 1.62 mmol) in methanol (4 mL) was added ammonium formate (0.45 g, 6.9 mmol) and 10% palladium on carbon (0.070 g). After 24 hours, more 10% palladium on carbon (0.035 g) and ammonium formate (0.45 g, 6.9 mmol) were added. After stirring for a total of 4 days, the reaction mixture was filtered, rinsing the residue with methanol, and concentrated. The residue was taken up in brine (5 mL) and extracted with dichloromethane (4×15 mL), dried (Na2SO4) and concentrated to give the title compound (0.60 g, 95%) as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CN(C=O)C.O>[O:30]1[CH2:31][CH2:32][N:27]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]4[S:17][CH:18]=[CH:19][N:20]=4)(=[O:14])=[O:13])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH2:28][CH2:29]1
Reactant: C1COCCN1
Reactant: O=S(=O)(Nc1nccs1)c1ccc2c(Cl)nccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(Nc1nccs1)c1ccc2c(N3CCOCC3)nccc2c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
1-chloro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.200 g, 0.614 mmol) and potassium carbonate (0.424 g, 3.07 mmol) were dissolved in DMF (4.09 ml). Morpholine (0.535 ml, 6.14 mmol) was added and the reaction was stirred overnight at 110° C. The reaction was diluted with water and extracted twice with ethyl acetate. The aqueous layer was acidified to a pH of about 1 with concentrated HCl solution and extracted twice with ethyl acetate. The aqueous layer was passed through an SCX ion exchange column (pre-wetted with methanol) (Biotage AB, Uppsala, SE), then the column was washed several times with methanol. The product was liberated with ammonia solution in methanol. The process was repeated with the aqueous filtrate and a new SCX column. The product-containing filtrates were combined and concentrated to afford crude product as an orange solid. The material was purified by silica gel chromatography (40 g column, gradient elution 0-10% MeOH:DCM) to afford 1-morpholino-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=12.86 (br. s., 1H), 8.38 (d, J=1.9 Hz, 1H), 8.28-8.19 (m, 2H), 7.86 (dd, J=1.9, 8.9 Hz, 1H), 7.62 (d, J=5.5 Hz, 1H), 7.28 (d, J=4.6 Hz, 1H), 6.87 (d, J=4.6 Hz, 1H), 3.88-3.80 (m, 4H), 3.35-3.26 (m, 4H). m/z (ESI) 377.2 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:12][CH2:13][CH2:14][OH:15].Cl.N1C=CC=CC=1>C(C(C)=O)C>[C:1]([O:15][CH2:14][CH2:13][Br:12])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: OCCBr
Agent: Cl
Solvent: CCC(C)=O
Solvent: c1ccncc1
Product: O=C(C=Cc1ccccc1)OCCBr
Temperature: 25 °C
Yield: 86.9 %

Procedure:
35.3 g (0.212 mol) of cinnamic acid chloride and 100 mL of methyl ethyl ketone were placed in a reaction vessel and stirred at room temperature under a nitrogen atmosphere. Then 28.2 g (0.225 mol) of 2-bromoethanol and 21 g of pylidine were dissolved in 100 mL of methyl ethyl ketone. The resulting solution was added dropwise in the aforementioned reaction vessel at room temperature, and then refluxed with stirring for 2 hours. After cooling the solution, pyridine hydrochloride was precipitated and then separated from the solution by filtration. The filtrate was concentrated and then dissolved in methylene chloride. The solution of methylene chloride was poured into a separating funnel and washed with water. Then the solution was dried with sodium sulfuric anhydride and concentrated. Thus 47 g (86.9% yield) of 2-bromoethyl cinnamate was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:17]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[S:5][C:6]=1[Cl:7].[CH3:33]B(O)O.O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Cl:7][C:6]1[S:5][C:4]([C:8]2[C:17]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:3][C:2]=1[CH3:33]
Reactant: CB(O)O
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3-c3cc(Br)c(Cl)s3)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc2nccc(Oc3cc4ccccc4nc3-c3cc(C)c(Cl)s3)c2cc1OC
Temperature: 100 °C
Reaction time: 96 h
Yield: 76 %

Procedure:
4-[2-(4-Bromo-5-chloro-thiophen-2-yl)-quinolin-3-yloxy]-6,7-dimethoxy-quinoline (20 mg) was dissolved in dioxane (3 ml) to prepare a solution. Tetrakistriphenylphosphine palladium (25 mg), methylboronic acid (0.1 ml), water (0.3 ml), and cesium carbonate (182 mg) were added to the solution, and the mixture was stirred at 100° C. for 4 days. The reaction solution was filtered, and the solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (13 mg, yield 76%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3]OS(C(F)(F)F)(=O)=O.CN(C)C=O.[Cl:19][C:20]1[N:28]=[C:27]2[C:23]([N:24]=[CH:25][NH:26]2)=[C:22]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]2[CH3:35])[N:21]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:19][C:20]1[N:28]=[C:27]2[C:23]([N:24]=[CH:25][N:26]2[CH2:3][C:2]([F:13])([F:12])[F:1])=[C:22]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]2[CH3:35])[N:21]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2[nH]cnc12
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1ncn2CC(F)(F)F
Temperature: 50 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
2,2,2-Trifluoroethyltrifluoromethyl sulfonate (83 μl, 0.57 mmol) was added to an N,N-dimethylformamide (5 ml) suspension of 2-chloro-6-[(3S)-3-methylmorpholin-4-yl]-9H-purine (132 mg, 0.52 mmol) and potassium carbonate (86 mg, 0.62 mmol) with ice cooling. The reaction mixture was stirred at 50° C. for 2 hours and returned to room temperature. Water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate and, after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (30% ethyl acetate:hexane) to give the title compound (133 mg, 76%) as a solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH2:24])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=[CH:30][C:29]([C:32](Cl)=[O:33])=[CH:28][CH:27]=1>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH:24][C:32]([C:29]2[CH:30]=[CH:31][C:26]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:27][CH:28]=2)=[O:33])[CH2:20][CH:21]([CH3:22])[CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)C[C@H](N)CN1CCC[C@H]1C(=O)NCCCCc1ccccc1
Product: CC(C)C[C@@H](CN1CCC[C@H]1C(=O)NCCCCc1ccccc1)NC(=O)c1ccc(-c2ccccc2)cc1
Yield: 75.1 %

Procedure:
Using the procedure described in Example 7, treatment of 1-[2-(S)-amino-4-methylpentyl]-L-proline 4-phenylbutylamide (112 mg) with 4-biphenyl carbonyl chloride (95 mg) provided 128 mg (83%) of the title compound. The 1H NMR and Mass spectrum analysis of this compound was consistent with the structure.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:10].Cl[C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=1>>[CH3:29][C:27]1[CH:26]=[CH:25][N:24]=[C:23]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)=[O:10])[CH2:3]3)[CH2:6]2)[CH:28]=1
Reactant: Cc1ccnc(Cl)c1
Reactant: O=C(c1ccccc1-c1cccs1)N1CC2CNCC2C1
Product: Cc1ccnc(N2CC3CN(C(=O)c4ccccc4-c4cccs4)CC3C2)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 37 and 2-chloro-4-methyl-pyridine. MS (ESI): mass calculated for C23H23N3OS, 389.52; m/z found 390.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.00 (d, J=5.2, 1H), 7.56-7.47 (m, 1H), 7.45-7.31 (m, 3H), 7.25-7.11 (m, 2H), 7.09-6.90 (m, 1H), 6.42 (d, J=5.2, 1H), 6.06 (br s, 1H), 3.98-2.59 (m, 10H), 2.27 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9].S(Cl)([Cl:15])(=O)=O.O>ClCCl>[CH3:1][O:2][C:3](=[O:11])[CH:4]([Cl:15])[C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCC(=O)CC(=O)OC
Solvent: ClCCl
Solvent: O
Product: CCCCC(=O)C(Cl)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.0 g 3-Oxo-heptanoic acid methyl ester were dissolved in 80 ml dry dichloromethane and 2.82 ml sulfurylchloride were added. The reaction mixture was stirred at room temperature for 30 minutes. 20 ml of water were added and the reaction mixture extracted five times with portions of 30 ml of dichloromethane. The combined organic extracts were washed with water and saturated NaHCO3 solution and brine and dried over MgSO4. The solvent was removed under reduced pressure to obtain 6.0 g 2-Chloro-3-oxo-heptanoic acid methyl ester as raw material. This material was used without further purification. 6.0 g 2-Chloro-3-oxo-heptanoic acid methyl ester were dissolved in 50 ml ethanol and 6.4 g 4-(Trifluoromethyl)thiobenzamide were added. The reaction mixture was heated under reflux overnight. The solvent was removed under reduced pressure and the residue purified by chromatography with the eluent n-heptane:ethyl acetate=100:1=>60:1. This gives 7.4 g 4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-carboxylic acid methyl ester as yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH2:17]>CN(C)C=O>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH:17][C:10]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][CH:2]=[CH:3]2)=[O:12]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CN(C)CCN
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)c1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.6 %

Procedure:
Indole-7-carboxylic acid (3.20 g, 0.020 mole) was dissolved in 50 ml of dimethylformamide (DMF) and 3.3 g (0.020 mole) of N,N'-carbonyldiimidazolewas added. After stirring for 2 hours at room temperature, 2.0 g (0.023 mole) of N,N-dimethylethylenediamine was added, and stirring was continuedfor an additional 1 hour. At the end of this time the solvent was removed at a pressure of 0.1 mm Hg (50° C.) and the remaining residue was triturated with a minimum of H2O and the crude product was filtered off and dried and concentrated to give a solid. Recrystallization from ether-pentane gave 2.20 g of N-[2-(dimethylamino)ethyl]-1H-indole-7-carboxamide (48%), m.p. 100°-102° C.
Reaction SMILES: [CH3:1][C:2](OC(C)=O)=[O:3].[CH2:8]([O:15][C@@H:16]1[C@:20]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([CH:21]([F:23])[F:22])[O:19][C@@H:18]([N:33]2[CH:38]=[CH:37][C:36](=[O:39])[NH:35][C:34]2=[O:40])[C@H:17]1[OH:41])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:2]([O:41][C@H:17]1[C@H:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@:20]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([CH:21]([F:22])[F:23])[O:19][C@H:18]1[N:33]1[CH:38]=[CH:37][C:36](=[O:39])[NH:35][C:34]1=[O:40])(=[O:3])[CH3:1]
Reactant: O=c1ccn([C@@H]2O[C@@](COCc3ccccc3)(C(F)F)[C@@H](OCc3ccccc3)[C@@H]2O)c(=O)[nH]1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1[C@H](n2ccc(=O)[nH]c2=O)O[C@@](COCc2ccccc2)(C(F)F)[C@H]1OCc1ccccc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
Ac2O (0.5 mL) was added into a solution of compound 34 (0.114 g, 0.24 mmol) in dry pyridine (4 mL). The reaction mixture was stirred at 20° C. for 3 h and then quenched by saturated aqueous NaHCO3 solution (2 mL). The organic phase was extracted with dichloromethane and then evaporated to dryness under reduced pressure. Purification by silica gel chromatography [petroleum ether:ethyl acetate (4:1)] afforded 35 (0.12 g, 88%) as a white solid. LC-MS: (M+H)+=517.2
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.ClC1C=CC=C(C(OO)=[O:29])C=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCl.O>[Br:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=3[O-:29])[C:6]=2[CH:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)N=C(c2ccccn2)c2cc(Br)c(Cl)cc2O1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC1(C)N=C(c2cccc[n+]2[O-])c2cc(Br)c(Cl)cc2O1
Reaction time: 5 h
Yield: 25.8 %

Procedure:
To a solution of Compound 88(10.0 g) in dichloromethane (130 ml) was added 70% m-chloroperbenzoic acid (20.0 g) at 0° C. and the mixture was stirred at 2° to 4° C. for 5 hours. A solution of sodium sulfite (32 g) in water (130 ml) was added slowly and stirred for 1 hour with ice-cooling. The organic layer was separated, washed successively with 5% aqueous sodium carbonate solution and saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by chromatography on silica gel and crystallized from diethyl ether to obtain 2-(6-bromo-7-chloro-2,2-dimethyl-2H-1,3-benzoxazin-4-yl)pyridine 1-oxide (2.7 g) (Compound 89).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([NH:7][C:8](=[O:12])[CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.N1C=CN=C1.[H-].[Na+].[C:24](Cl)(=[O:28])/[CH:25]=[CH:26]/[CH3:27]>O1CCCC1>[C:10](/[C:9](=[C:24](\[OH:28])/[CH:25]=[CH:26][CH3:27])/[C:8]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:14][CH:13]=1)=[O:12])#[N:11]
Reactant: C/C=C/C(=O)Cl
Reactant: N#CCC(=O)Nc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC=C/C(O)=C(/C#N)C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
0 6.0 g (0.026 mole) of 4'-trifluoromethyl-cyanoacetanilide in 200 ml of dry tetrahydrofuran were stirred under nitrogen during the addition of 0.02 g of imidazole and 1.95 g (0.065 mole) of sodium hydride 80% oil dispersion. The suspension was stirred for 2 hours at room temperature and then was cooled to -78° C. before the dropwise addition of 3.06 ml (0.031 mole) of freshly distilled crotonyl chloride. The mixture was stirred at -78° C. for 2 hours, poured onto a mixture of dilute hydrochloric acid/ice and filtered. The solid was dissolved in dichloromethane, washed with water, dried over magnesium sulfate and the solvent was removed under reduced pressure to obtain 7.65 g (99%) of colorless crystals of the expected compound.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([NH:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=2)[S:7][C:8]=1[NH:9][C:10]([C:12]1[CH:31]=[CH:30][C:15]([CH2:16][N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[CH:14][CH:13]=1)=[O:11])(=[O:3])[NH2:2]>Cl.O1CCOCC1>[CH:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:41]=[CH:42][C:33]=1[NH:32][C:6]1[S:7][C:8]([NH:9][C:10](=[O:11])[C:12]2[CH:13]=[CH:14][C:15]([CH2:16][N:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)=[CH:30][CH:31]=2)=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(=O)Nc3sc(Nc4ccc5ccccc5c4)nc3C(N)=O)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)c1ccc(CN2CCNCC2)cc1
Yield: 66.8 %

Procedure:
A solution of tert-butyl 4-(4-{[4-carbamoyl-2-(naphthalen-2-ylamino)thiazol-5-yl]carbamoyl}benzy)piperazine-1-carboxylate (0.025 g, 0.04 mmol) in 4N HCl-dioxane (5 mL) was stirred for 2 hrs at rt under N2-atmosphere. The solvent was evaporated in vacuo, and the residue was washed with ether and purified by silica gel column chromatography eluted with 50% EtOAc in hexane to give 0.013 g (68% yield) of the titled compound.
Reaction SMILES: [NH3:1].Cl[S:3]([C:6]1[CH:7]=[C:8]([C:16]([OH:18])=[O:17])[C:9]2[O:14][CH2:13][CH2:12][O:11][C:10]=2[CH:15]=1)(=[O:5])=[O:4]>O>[S:3]([C:6]1[CH:7]=[C:8]([C:16]([OH:18])=[O:17])[C:9]2[O:14][CH2:13][CH2:12][O:11][C:10]=2[CH:15]=1)(=[O:5])(=[O:4])[NH2:1]
Reactant: N
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cc2c1OCCO2
Solvent: O
Product: NS(=O)(=O)c1cc2c(c(C(=O)O)c1)OCCO2
Temperature: 25 °C
Yield: 86.4 %

Procedure:
209 g of 34% ammonia and 97 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid were introduced into a balloon flask provided with an agitator and a thermometer at a temperature of 5°-10° C. The mixture was agitated at ambient temperature and then the precipitate was dissolved in 415 cm3 of water. The solution was filtered and treated with 140 cm3 of concentrated hydrochloric acid. The crystals were dried off, washed with water and dried. 78 g of 7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 272°-274° C.; yield: 87%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:10][C:9]([Cl:20])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>CO>[ClH:1].[Cl:1][C:2]1[C:11]([NH:12][S:13]([C:16]([F:19])([F:17])[F:18])(=[O:14])=[O:15])=[CH:10][C:9]([Cl:20])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(Cl)cc(NS(=O)(=O)C(F)(F)F)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(Cl)cc(NS(=O)(=O)C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Crude methyl 2,5-dichloro-3-{[(trifluoromethyl) sulfonyl]amino}benzoate (4.0 g) was dissolved in methanol (30 ml) and 4N NaOH (30 ml) was added while stirring at room temperature for 18 hrs. Removed solvent and added 4N HCl (10 ml). Stirred at room temperature for 4 hours. Filtered off solid to give 2,5-dichloro-3-{[(trifluoromethyl) sulfonyl]amino}benzoic acid hydrochloride in quantitative yield.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.O>CS(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([O:8][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN1CCC(O)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN1CCC(Oc2ccc([N+](=O)[O-])cc2)(c2ccccc2)CC1
Reaction time: 1 h
Yield: 48.8 %

Procedure:
A solution of 1-methyl-4-phenyl-4-piperidinol (7.65 g, 40 mM) in dry DMSO (100 ml) was treated with sodium hydride (2.0 g of a 50% dispersion in oil, 42 mM). The reaction mixture was stirred for 1 hour then treated with 4-fluoronitrobenzene (5.65 g, 40 mM). After 24 hours the reaction mixture was poured on to water (500 ml) and extracted with ether (4×500 ml). The organic extracts were washed with brine, dried and the solvents removed under reduced pressure. Recrystallisation of the residue from IPA gave the title compound (6.1 g) m.p. 136°-8°.