Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[C:21]3[CH2:22][CH2:23][CH2:24][CH2:25][C:20]=3[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:16]2[C:21]3[CH2:22][CH2:23][CH2:24][CH2:25][C:20]=3[S:19][C:17]=2[N:18]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Clc1nc(Cl)c2c3c(sc2n1)CCCC3
Product: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc4c(c23)CCCC4)c1

Procedure:
Following the procedure of Example 1, the reaction of 3-nitrobenzylamine with 2,4-dichloro-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidine yields 2-chloro-5,6,7,8-tetrahydro-4-(3-nitrobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[CH2:2][C:3]1[S:7][CH:6]=[N:5][C:4]=1[Cl:8].[CH3:9][C:10]1[N:15]=[C:14]([SH:16])[N:13]=[C:12]([OH:17])[CH:11]=1.C(N(CC)CC)C>C(O)C>[Cl:8][C:4]1[N:5]=[CH:6][S:7][C:3]=1[CH2:2][S:16][C:14]1[N:13]=[C:12]([OH:17])[CH:11]=[C:10]([CH3:9])[N:15]=1
Reactant: Clc1ncsc1CBr
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2scnc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
A mixture of 5-(bromomethyl)-4-chloro-1,3-thiazole (8.4 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (850 mg, 6.0 mmol), and triethylamine (3.5 mL, 25 mmol) in absolute ethanol (45 mL) was stirred at room temperature overnight. The mixture was evaporated to dryness and then co-evaporated with EtOAc (20 mL). The residue was treated with water (100 mL). The solid material was recovered by filtration and washed with water (3×25 mL), diethyl ether (2×25 mL), and hexanes (2×25 mL). The solid material was dried in vacuo. The crude product was purified by flash chromatography (0-4% MeOH/DCM), affording the title compound (491 mg, 31% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.15 (s, 3H), 4.62 (s, 2H), 6.05 (s, 1H), 8.82 (s, 1H); M+ 274.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].C[N+]1C=CN([C:26]([N:28]2[CH2:33][CH2:32][CH:31]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:30][CH2:29]2)=[O:27])C=1>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:26]([N:28]3[CH2:29][CH2:30][CH:31]([CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:32][CH2:33]3)=[O:27])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: C[n+]1ccn(C(=O)N2CCC(Cc3ccccc3)CC2)c1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [I-]
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 1-methyl-3-(4-benzyl-piperidine-1-carbonyl)-3H-imidazol-1-ium iodide. The crude product was purified by flash chromatography using a Quad flash 25 (ethyl acetate/heptane (1:6), (72%, white crystals). HPLC-MS m/z=457.2 (M+1), Rt: 6.0 min.
Reaction SMILES: [C:1]([O:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(OC(C)(C)C)=O.OC1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[C:22]([CH3:30])[C:18]=1[C:19]([OH:21])=[O:20]>C(O)(C)(C)C.O1CCCC1>[C:12]([O:11][C:9]([O:8][C:1]1[C:25]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:23]=[C:22]([CH3:30])[C:18]=1[C:19]([O:21][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:20])=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: Cc1ccc(C(F)(F)F)c(O)c1C(=O)O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: Cc1ccc(C(F)(F)F)c(OC(=O)OC(C)(C)C)c1C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
N,N-Dimethylaminopyridine (0.7 g, 5.7 mmol) and di-tert-butyl dicarbonate [(tBuOCO)2O] (16.7 g, 76.5 mmol) were added to a solution of 2-hydroxy-6-methyl-3-(trifluoromethyl)benzoic acid (4.21 g, 19.1 mmol) obtained in Example (28-3) in a mixture of tert-butyl alcohol-tetrahydrofuran (2:1, 60 ml), and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=9/1) to give tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-methyl-3-(trifluoromethyl)benzoate (6.27 g, yield: 87%).
Reaction SMILES: Br[C:2]([C@:4]([C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C@@:6]([C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C@:8]([C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH2:10][OH:11])[OH:9])[OH:7])[OH:5])=[O:3].O>CC(C)=O.C(=O)([O-])[O-].[Ag+2]>[C:28]([C@@:4]([C@@:6]([C:20](=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C@:8]([C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([CH2:10][OH:11])[OH:9])[OH:7])([OH:5])[CH:2]=[O:3])(=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(Br)[C@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(CO)C(=O)c1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: O=C[C@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(CO)C(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 73.1 %

Procedure:
Crude 1-bromo-2,3,4-tri-benzoyl-L-xylose 17 (14.1 g, 26.8 mmol) was dissolved in acetone (150 mL) and water (5 ml, 277 mmol) at 0° C. Silver carbonate (6.61 g, 24.0 mmol) was added over 5 min and the reaction was brought to room temperature after 15 min and stirred an additional 30 min. The solids were removed by filtration and washed with acetone (100 mL), the filtrate was concentrated in vacuo, water was removed via azeotropic distillation with ethanol and toluene and the residue was purified by silica gel flash chromatography (4:1 Hexanes:EtOAc to EtOAc) to yield 18 as white solid (9.1 g, 19.6 mmol, 74%).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]([O:15]C(C)(C)C)=[O:14])=[N:5][CH:4]=1)=[O:2].Cl.CCOCC>C(Cl)Cl>[CH:1]([C:3]1[S:7][C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]([OH:15])=[O:14])=[N:5][CH:4]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1c1ncc(C=O)s1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1cnc(N2CCC[C@H]2C(=O)O)s1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Following the procedure as described in Example 68, except using material from Example 79 (33.4 mg, 0.118 mmol), anhydrous CH2Cl2 (3 mL), HCl, 1.0M in Et2O (6 mL, 6.0 mmol) stirring at room temp for 48 h, the title compound (quantitative yield) is isolated as an HCl salt that is used directly “as is” in the next step. LC/MS (Condition A): ret. T=1.88 min, (M+H)+ 227.05.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>CS(C)=O>[Br:1][C:2]1[C:3]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([Cl:12])=[CH:14][CH:15]=2)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Reactant: Nc1ccc(Cl)cc1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cnc(Nc2ccc(Cl)cc2)c(Br)c1
Temperature: 90 °C
Yield: 68.5 %

Procedure:
A mixture of 3-bromo-2-chloro-5-nitropyridine (2.374 g, 10 mmol) and 4-chloroaniline (2.55 g, 20.00 mmol) in dimethylsulfoxide (20 mL) was heated at 90° C. for 2 hours. After cooling to ambient temperature, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with 1:20 ethyl acetate/heptanes to give the crude product. This material was then triturated with 10% ethyl acetate in heptanes to give title compound (2.25 g, 6.85 mmol, 68.5% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:25]([O:27][C:28](=[O:39])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([SH:37])=[CH:33][C:32]=1[CH3:38])[CH3:26].O>C(#N)C>[CH2:25]([O:27][C:28](=[O:39])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37][CH2:2][C:3]2[O:7][C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)=[N:5][C:4]=2[CH3:18])=[CH:33][C:32]=1[CH3:38])[CH3:26]
Reactant: CCOC(=O)COc1ccc(S)cc1C
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)COc1ccc(SCc2oc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Reaction time: 6 h
Yield: 78.1 %

Procedure:
To a suspension of 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (0.30 g, 1.8 mmol) and Cs2CO3 in 8 mL acetonitrile is added (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (0.25 g, 1.1 mmol). The solution is stirred for 6 hrs and poured into water (50 mL) and extracted with ethyl acetate (3×25 mL). The combined organics are washed with water (10 mL) and brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product is purified using flash column chromatography (10%-20% ethyl acetate/hexanes) to afford 0.40 g (79%) of {2-Methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-ylmethylsulfanyl]-phenoxy}-acetic acid ethyl ester. To a stirred solution of this ester (0.21 g, 0.44 mmol) is added m-CPBA (50%) (0.31 g, 0.89 mmol) at 0° C. After 10 min. the solution is poured into water (50 mL) and extracted with methylene chloride (3×20 mL). The combine methylene chloride layers are washed with 1 N NaOH (25 mL), water (25 mL) and brine (25 mL), dried (Na2SO4), filtered and concentrated in Vacuo. The crude sulphone is purified using flash column chromatography (10%-25% ethyl acetate hexanes) to give 0.15 g (68%) of {2-Methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-ylmethanesulfonyl]-phenoxy}-acetic acid ethyl ester. Hydrolysis of this sulphone (0.15 g, 0.30 mmol) occurred under the usual conditions (3 eq. of a 1N solution of LiOH in 1 mL of a 3:2:1 solution of THF:MeOH:H2O) to provide the title compound 0.11 g (78%) after workup with aq. NH4Cl and ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([NH:14][C:15]3[CH:16]=[N:17][NH:18][CH:19]=3)=[N:12][CH:13]=[C:8]2[CH:7]=[N:6]1.[O-:24][C:25]#[N:26].[K+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([NH:14][C:15]3[CH:19]=[N:18][N:17]([C:25]([NH2:26])=[O:24])[CH:16]=3)=[N:12][CH:13]=[C:8]2[CH:7]=[N:6]1
Reactant: Fc1ccccc1Cn1ncc2cnc(Nc3cn[nH]c3)nc21
Reactant: N#C[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NC(=O)n1cc(Nc2ncc3cnn(Cc4ccccc4F)c3n2)cn1
Reaction time: 0.5 h

Procedure:
To a solution of 1-(2-fluorobenzyl)-N-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (Example 88), (111 mg, 0.36 mmol) in ACN/H2O (9:1, 4 mL) was added potassium cyanate (35 mg, 1.2 eq). After 30 min at rt, the reaction mixture was neutralized with saturated sodium carbonate and the aqueous phase extracted with DCM. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to give the title product. 1H NMR (d6-DMSO) δ 10.12 (s, 1H), 9.00 (s, 1H), 8.57 (s, 1H), 8.12 (s, 1H), 7.94 (s, 1H), 7.80 (s, 1H), 7.71 (s, 1H), 7.41-7.28 (m, 2H), 7.26-7.14 (m, 2H), 5.58 (s, 2H); LC-MS method B, (ES+) 353.0, RT=7.75 min.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][C:6]=1[N+:21]([O-:23])=[O:22])[CH:2]([CH3:4])[CH3:3].[NH2:24][C:25]1[C:30]([O:31][CH3:32])=[N:29][C:28]([CH3:33])=[CH:27][N:26]=1>N1C=CC=CC=1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([S:17]([NH:24][C:25]3[C:30]([O:31][CH3:32])=[N:29][C:28]([CH3:33])=[CH:27][N:26]=3)(=[O:19])=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][C:6]=1[N+:21]([O-:23])=[O:22])[CH:2]([CH3:4])[CH3:3]
Reactant: COc1nc(C)cnc1N
Reactant: CC(C)Cc1ccc(-c2ccccc2S(=O)(=O)Cl)cc1[N+](=O)[O-]
Solvent: c1ccncc1
Product: COc1nc(C)cnc1NS(=O)(=O)c1ccccc1-c1ccc(CC(C)C)c([N+](=O)[O-])c1
Temperature: 75 °C
Yield: 39.5 %

Procedure:
4'-Isobutyl-3'-nitro-2-biphenylsulphonyl chloride (0.353 g) was added to a solution of 2-amino-3-methoxy-5-methylpyrazine (0.139 g) in pyridine (10 ml) at 0° C. The solution w?as heated at 75° C. for 18 hours and then volatile material was removed by evaporation. The residue was purified by elution with dichloromethane through a silica gel Mega Bond Elut column and the resulting foam was triturated with ether/hexane (1:1 v/v) to give 4'-isobutyl-N-(3-methoxy-5-methyl-2-pyrazinyl)-3'-nitro-2-biphenylsulphonamide (0.18 g), m.p. 114-115° C.; mass spectrum (+ve CI): 457 (M+H)+.
Reaction SMILES: [C:1]([O:7][C:8]1[CH:42]=[CH:41][C:11]([C:12]([O:14][C:15]2[CH:16]=[C:17]([C:37](=[O:40])[CH2:38][Br:39])[CH:18]=[C:19]([O:21][C:22](=[O:36])[C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:25][CH:24]=3)[CH:20]=2)=[O:13])=[CH:10][CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[BH4-].[Na+].Cl>O1CCOCC1.O>[C:30]([O:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([O:21][C:19]2[CH:18]=[C:17]([CH:37]([OH:40])[CH2:38][Br:39])[CH:16]=[C:15]([O:14][C:12](=[O:13])[C:11]3[CH:41]=[CH:42][C:8]([O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4])=[CH:9][CH:10]=3)[CH:20]=2)=[O:36])=[CH:28][CH:27]=1)(=[O:35])[C:31]([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)C(=O)Oc1ccc(C(=O)Oc2cc(OC(=O)c3ccc(OC(=O)C(C)(C)C)cc3)cc(C(=O)CBr)c2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)C(=O)Oc1ccc(C(=O)Oc2cc(OC(=O)c3ccc(OC(=O)C(C)(C)C)cc3)cc(C(O)CBr)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7.8 g (0.012 moles) of 3',5'-bis-(4-pivaloyloxybenzoyloxy)-2-bromoacetophenone in 200 ml of dioxane and 40 ml of water was added portionally 0.45 g (0.012 moles) of NaBH4 dissolved in 30 ml of water. After each addition pH was adjusted with 1 N HCl so that the pH of the reacting mixture never exceeded pH 7. The mixture was stirred at ambient temperature for 1 h, whereafter the solution was evaporated to dryness and the residue taken up in diethyl ether. The ether phase was washed with water, dried over MgSO4 and then evaporated to dryness to yield a crystalline residue. The identity of the product was confirmed with NMR.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][N:13]=[C:14]([CH3:15])[N:4]2[N:3]=1.[NH2:16][CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.O>COCCO>[CH3:15][C:14]1[N:4]2[N:3]=[C:2]([NH:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[C:5]2=[N:12][N:13]=1
Reactant: Cc1nnc2c3c(c(Cl)nn12)CCCC3
Reactant: NCCN1CCCC1
Solvent: O
Solvent: COCCO
Product: Cc1nnc2c3c(c(NCCN4CCCC4)nn12)CCCC3

Procedure:
A solution of 10.0 g of 6-chloro-3-methyl-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine and 12.8 g of 1-(2-aminoethyl)pyrrolidine in 50 ml of 2-methoxyethanol was heated at reflux for 15 hours. The reaction mixture was poured into 150 ml of cold water and the white precipitate which formed was separated by filtration and air dried to give 3-methyl-6-[2-(1-pyrrolidinyl)ethylamino]-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine melting at about 184°-186° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:12][CH2:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(F)cc1CBr

Procedure:
574 g (3.70 mol) of 5-fluoro-2-nitrotoluene and 659 g (3.70 mol) of N-bromosuccinimide were introduced into 3.7 l of chloroform, 30.0 g (183 mmol) of 2,2′-azobis-2-methylpropanenitrile were added, and the mixture was heated under reflux with irradiation by a UV lamp for 18 h. Cooling was followed by filtration with suction, and the filtrate was concentrated, the residue was taken up in diethyl ether and filtered with suction, and the filtrate was concentrated. The residue was dissolved in dichloromethane and petroleum ether and purified by flash chromatography (mobile phase: petroleum ether/ethyl acetate gradient) to result in 92.0 g (10% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][CH:12]=[N:11][C:10]=2[C:14]([O:16]CC)=[O:15])[CH:5]=[C:6]([F:8])[CH:7]=1>O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][CH:12]=[N:11][C:10]=2[C:14]([OH:16])=[O:15])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)c1ncsc1-c1cc(F)cc(F)c1
Solvent: O
Product: O=C(O)c1ncsc1-c1cc(F)cc(F)c1
Yield: 97 %

Procedure:
The ethyl 5-(3,5-difluorophenyl)-4-thiazolecarboxylate was saponified in an analogous manner to that described in Example 1(D), whereby after acidification there was obtained 5-(3,5-difluorophenyl)-4-thiazolecarboxylic acid in 97% yield, melting point 200° (from water).
Reaction SMILES: [CH2:1]([C:3](=[CH:8][CH3:9])[CH:4]=[CH:5][CH2:6][NH2:7])[CH3:2].ClCCl.[CH3:13][N:14]([CH3:19])[S:15](Cl)(=[O:17])=[O:16]>C(N(CC)CC)C>[CH3:13][N:14]([CH3:19])[S:15]([NH:7][CH2:6][CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH3:9])(=[O:17])=[O:16]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CC=C(C=CCN)CC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC=C(C=CCNS(=O)(=O)N(C)C)CC
Reaction time: 0.5 h

Procedure:
A mixture of N-(4-ethyl-2,4-hexadien-1-yl)phthalimide (3.0 g), hydrazine monohydrate (0.88 g), and ethanol (30 ml) was refluxed for 40 minutes under nitrogen atmosphere. After cooling, the precipitate was filtered and washed with ethanol. Evaporation of the filtrate gave a crystalline residue which was dissolved in 1N sodium hydroxide solution and extracted with dichloromethane. The organic extract was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated to give 4-ethyl-2,4-hexadien-1-ylamine as an oil. To a mixture of crude 4-ethyl-2,4-hexadien-1-ylamine, triethylamine (1.79 g), and dichloromethane (30 ml) at 0° C. was added dropwise dimethylsulfamoyl chloride (2.03 g) during 10 minutes. After 30 minutes, triethylamine (0.6 g) and dimethylsulfamoyl chloride (0.85 g) were added to the reaction mixture. After 1 hour at 0° C., the reaction mixture was washed with water and aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (dichloromethane-hexane, 7:3) to give N,N-dimethyl-N'-(4-ethyl-2,4-hexadien-1-yl)sulfamide (924 mg) as an oil.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1.O>O1CCCC1>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([S:24]([N:8]2[CH:9]=[C:10]([CH:12]=[O:13])[N:11]=[C:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(S(=O)(=O)n2cc(C=O)nc2-c2ccccc2)c1
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
To a solution of 2-phenyl-1H-imidazole-4-carbaldehyde (520 mg) in tetrahydrofuran (100 mL) was added sodium hydride (60% in oil, 182 mg) at room temperature, and the mixture was stirred for 30 min. 3-Methoxybenzenesulfonyl chloride (750 mg) was added to the reaction mixture, and the mixture was stirred for 1.5 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diethyl ether to give the title compound as colorless crystals (yield 894 mg, 87%).
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Cl:13][C:14]1[CH:40]=[CH:39][C:17]([CH2:18][O:19][C:20]2[CH:21]=[C:22]([CH:36]=[CH:37][CH:38]=2)[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32](=[O:35])(=[O:34])[NH2:33])=[O:24])=[CH:16][CH:15]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][O:19][C:20]2[CH:21]=[C:22]([CH:36]=[CH:37][CH:38]=2)[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([NH:33][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:34])=[O:35])=[O:24])=[CH:39][CH:40]=1
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(Cl)cc2)c1
Reactant: CCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
In a stream of nitrogen and at 0° C., 0.27 ml (1.30 mmol) of decanoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 500 mg (1.20 mmol) of 3-(4-chlorobenzyloxy)-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 4 and 293 mg (2.40 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 640 mg (yield: 93.0%) of the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)=[CH:24][CH:23]=2)(=[O:20])=[O:21])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CCN(Cc2ccccc2)CC1

Procedure:
1-Benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid was prepared starting from 1-benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester (2.11 g, 4.1 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.11 g (56%); white solid; mp 201° C.; MS: 485.9 (M+H)+
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH3:13][NH:14][CH3:15]>CO>[CH3:13][N:14]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[CH3:15]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CNC
Solvent: CO
Product: COC(=O)c1ccc(CN(C)C)cc1
Reaction time: 0.42 h
Yield: 99 %

Procedure:
Methyl 4-(bromomethyl)benzoate (2.0 g, 8.73 mmol) was added to a saturated solution of dimethylamine in methanol. After stirring for 25 min, the solution was concentrated and the residue was partitioned between 1N NaOH and ethyl acetate. The organic layer was washed with saturated brine, dired (MgSO4), filtered, and concentrated to provide the title compound as a colorless liquid (1.67 g, 99%). 1H NMR (250 MHz, CDCl3) δ 8.00 (d, 2H), 7.39 (d, 2H), 3.91 (s, 3H), 3.47 (d, 2H), 2.25 (s, 6H).