Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][P:16]([CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])([CH3:18])=[O:17])[CH3:14].[N+:26]([CH:29]=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([O-:28])=[O:27].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[N+:26]([CH2:29][CH:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:18][P:16]([CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])(=[O:17])[O:15][CH2:13][CH3:14])([O-:28])=[O:27]
Reactant: CCOC(OCC)P(C)(=O)OCC
Reactant: O=[N+]([O-])C=Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(OCC)P(=O)(CC(C[N+](=O)[O-])c1ccccc1)OCC
Reaction time: 0.17 h

Procedure:
The starting material may be prepared as follows: To a solution of 5.8 g of diisopropylamine in 40 ml of tetrahydrofuran at -78° C. under an atmosphere of nitrogen are added 35.7 ml of a 1.6M solution of n-butyllithium in hexane. This solution is then stirred for a period of 10 minutes at this temperature, after which time a solution of 10.0 g of ethyl(diethoxymethyl)methylphosphinate in 20 ml of tetrahydrofuran is added. This mixture is then stirred for a period of 1 hour at -78° C. after which time a solution of 8.5 g of β-nitrostyrene in 20 ml of tetrahydrofuran is introduced. This mixture is then allowed to warm to room temperature when 40 ml of a saturated ammonium chloride solution is added. The aqueous layer is then extracted with 2×25 ml of diethyl ether and the organic extracts are combined and dried over magnesium sulphate. The solvent is then evaporated under reduced pressure and the crude product chromatographed on silica gel using ethyl acetate as an eluent to give ethyl 3-nitro-2-phenylpropyl(diethoxymethyl)phosphinate as a viscous oil, 31P=+42.3 and +42.0 ppm (CDCl3).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:14]([O:17]C(Cl)=O)(Cl)Cl>O1CCOCC1>[F:11][C:9]1[CH:10]=[C:2]2[NH:1][C:14](=[O:17])[O:6][C:4](=[O:5])[C:3]2=[CH:7][C:8]=1[I:12]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc(F)c(I)cc1C(=O)O
Solvent: C1COCCO1
Product: O=c1[nH]c2cc(F)c(I)cc2c(=O)o1
Yield: 90.4 %

Procedure:
Anhydrous dioxane (0.5 liters), 2-amino-4-fluoro-5-iodo-benzoic acid (46 grams, 164 mmoles), and trichloromethylchloroformate (97.4 grams, 492 mmoles) were added to a one liter one neck flask equipped with a magnetic stir bar and reflux condenser. The solution was placed under anhydrous nitrogen, stirred and heated to reflux for 16 hours. The reaction mixture was allowed to cool and was poured into one liter of hexanes. The solid was collected by suction filtration, washed with an additional 0.5 liters of hexanes, and dried under vacuum at room temperature to yield 45.5 grams (90%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 11.86(s, 1H), 8.24(d, 1H), 6.84(d, 1H). ESI-MS m/z 308 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:25][C:26]1[N:30]([CH3:31])[N:29]=[C:28]([CH3:32])[C:27]=1[S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>>[Cl:25][C:26]1[N:30]([CH3:31])[N:29]=[C:28]([CH3:32])[C:27]=1[S:33]([N:22]1[CH2:23][CH2:24][CH:19]([C:10]2[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[NH:12][CH:11]=2)[CH2:20][CH2:21]1)(=[O:34])=[O:35]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1

Procedure:
Following the general procedure in example 267, 5-(phenyl)-3-(4-piperidinyl)-1H-indole-7-carboxamide (32 mg, 0.1 mmol), 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride (34.5 mg, 0.15 mmol) and triethylamine (0.06 mL, 0.3 mmol) were reacted to form the desired product which was purified by Gilson HPLC (CH3CN/Water, 0.1% TFA) (22 mg, 43%).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][C@@:10]1([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([C:33]([F:36])([F:35])[F:34])[CH2:29][CH2:28]4)[CH:22]=3)[CH:17]=2)[CH2:14][O:13][C:12](=[O:15])[NH:11]1>C(Cl)Cl.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[I:1][C:22]1[C:21]([O:26][C@H:27]2[CH2:28][CH2:29][C@H:30]([C:33]([F:36])([F:34])[F:35])[CH2:31][CH2:32]2)=[CH:20][CH:19]=[C:18]2[C:23]=1[CH:24]=[CH:25][C:16]([C@:10]1([CH3:9])[CH2:14][O:13][C:12](=[O:15])[NH:11]1)=[CH:17]2
Reactant: O=C1CCC(=O)N1I
Reactant: C[C@@]1(c2ccc3cc(O[C@H]4CC[C@H](C(F)(F)F)CC4)ccc3c2)COC(=O)N1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: C[C@@]1(c2ccc3c(I)c(O[C@H]4CC[C@H](C(F)(F)F)CC4)ccc3c2)COC(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-Iodosuccinimide (588 mg, 0.00261 mol, Acros) and zirconium tetrachloride (98 mg, 0.00042 mol, Strem) was added to a solution of repurified (R)-4-methyl-4-[6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-oxazolidin-2-one (786 mg, 0.00200 mol) in methylene chloride (30 mL, Acros) and were stirred at room temperature for 30 min. Silica gel was added and the reaction was evaporated to dryness. The residue was purified by silica gel chromatography using 0-100% ethyl acetate in hexanes as eluent. Cis and trans isomers were fully resolved and isolated was 822 mg (79%) of pure trans product (Rf=0.31 in 1:1 hexanes/ethyl acetate).
Reaction SMILES: [CH:1](=[N:9][CH2:10]C(N=CC1C(=CC=CC=1)O)C)C1C(=CC=CC=1)O.[C:22]1(C)[C:23](C)=[CH:24][CH:25]=[CH:26][CH:27]=1>>[CH:22]1([N:9]([CH3:10])[CH3:1])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: Cc1ccccc1C
Reactant: CC(CN=Cc1ccccc1O)N=Cc1ccccc1O
Product: CN(C)C1CCCCC1

Procedure:
1.6% N,N'-disalicylidene-1,2-propanediamine as an 80% solution in xylene; and
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2].[NH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: O=C(O)c1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1
Yield: 54.4 %

Procedure:
4-carboxyphthalic anhydride (1.0 g, 0.0052 mol) and p-aminobenzoic acid (0.714 g, 0.0052 mol) were refluxed as above overnight. A clean product from the mother liquor fraction was not obtained. Crystallisation of the precipitated product from MeOH/H2O yielded 0.88 g (55%) of 105 as a white solid: mp=377-379° C.; Rf0.90 (A): Rf0.76 (B): Rf0.46 (D): IR (cm−1): 2750-3200 (OH), 3077 (C═CH), 2652 (C—H), 1777 (C═O), 1731 (C═O), 1699 (C═O), 1604 (C═C), 1512 (C═C), 1485 (C═C), 1428 (C═C), 1376 (C—O), 1310 (C—O), 1092 (C—O), 723 (C═CH); MS m/z (rel intensity) 311 (23), 310 (100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH2:15])=[CH:5][CH:4]=1.[C:16]([O-])(=[O:18])[CH3:17].[Na+].C(O)C.C(OC(=O)C)(=O)C>O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1
Reactant: CC(=O)[O-]
Reactant: COc1ccc2cccc(CCN)c2c1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Solvent: O
Product: COc1ccc2cccc(CCNC(C)=O)c2c1
Yield: 80 %

Procedure:
In a reactor, 5 g of the compound obtained in Step C and 2 g of sodium acetate are introduced into ethanol. The mixture is stirred, 2.3 g of acetic anhydride are then added, the reaction mixture is heated to reflux and 20 ml of water are added. The reaction mixture is allowed to return to ambient temperature and the precipitate obtained is filtered off, washed with an ethanol/water 35/65 mixture to yield the title product in a yield of 80% with a chemical purity of 99%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[O:16][N:15]=[C:14]([CH3:17])[C:13]=2[CH3:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]=[O:21]>CN(C)C=O>[CH2:26]([O:25][C:23]([CH2:22][NH:19][C:20](=[O:21])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[O:16][N:15]=[C:14]([CH3:17])[C:13]=2[CH3:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1)=[O:24])[CH3:27]
Reactant: Cc1noc(NS(=O)(=O)c2ccc(N)cc2)c1C
Reactant: CCOC(=O)CN=C=O
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)Nc1ccc(S(=O)(=O)Nc2onc(C)c2C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.8 %

Procedure:
4-amino-N-(3,4-dimethyl-5-isoxazolyl)benzenesulfonamide (545 mg, 2.0 mmol) was dissolved in dry dimethylformamide (10 ml). Ethyl isocyanatoacetate (463 ml, 4.0 mmol) was added. The reaction was stirred at room temperature for 3 h and then heated at 80° C. for an additional 8 h. Dimethylformamide was removed under reduced pressure and the residue was recrystallized from acetonitrile/water to give 807 mg (90% yield) brownish solid, m.p. 115°-125° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.CS(O[C@@H:18]([C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)[CH2:19][CH2:20][C@@H:21](OS(C)(=O)=O)[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)(=O)=O.C(OCC)(=O)C.CCCCCC>CN(C=O)C>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([C@@H:21]2[CH2:20][CH2:19][C@@H:18]([C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)[N:1]2[C:2]2[CH:3]=[CH:4][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[CH:6][CH:7]=2)=[CH:23][CH:24]=1)([O-:30])=[O:29]
Reactant: CC(C)(CO)c1ccc(N)cc1
Reactant: CS(=O)(=O)O[C@H](CC[C@@H](OS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(CO)c1ccc(N2[C@H](c3ccc([N+](=O)[O-])cc3)CC[C@H]2c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 50 °C
Yield: 34.1 %

Procedure:
The product from Example 194C (0.595 g, 3.60 mmole) was combined in DMF (3 mL) with (1R,4R)-1,4-bis(4-nitrophenyl)butane-1,4-diyl dimethanesulfonate (0.259 g, 0.530 mmole), prepared as described in Example 37C, then heated overnight under nitrogen in an oil bath at 50° C. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was water washed (3×25 mL), dried over MgSO4, filtered and concentrated to an oil. Chromatography on silica gel eluting with ethyl acetate-hexane provided the title compound (0.0835 g, 34.1% yield) as an orange semi-solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[N:8][OH:9])[CH2:4][CH2:3]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[F:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([F:37])[CH:36]=1)[C:31]([OH:33])=[O:32]>>[F:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([F:37])[CH:36]=1)[C:31]([O:33][C:5]1([N:8]=[O:9])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:32]
Reactant: CN1CCC(=NO)CC1
Reactant: O=C(O)c1cc(F)cc(F)c1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: CN1CCC(N=O)(OC(=O)c2cc(F)cc(F)c2)CC1

Procedure:
1-Methyl-4-nitrosopiperidin-4-yl 3,5-difluorobenzoate is prepared from 1-methyl-piperidin-4-one oxime, lead tetraacetate and 3,5-difluorobenzoic acid using conditions of General Method 3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH:18]([NH:20]C(OCC2C=CC=CC=2)=O)[CH3:19])[CH:12]=1)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].C1CC=CCC=1>CO.[Pd]>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH:18]([NH2:20])[CH3:19])[CH:12]=1)([CH3:10])[CH3:9])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(Cc1cccc(C(C)(C)NC(=O)OC(C)(C)C)c1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CO
Product: CC(N)Cc1cccc(C(C)(C)NC(=O)OC(C)(C)C)c1

Procedure:
To a mixture of {1-[3-(2-benzyloxycarbonylamino-propyl)-phenyl]-1-methyl-ethyl}-carbamic acid tert-butyl ester (0.28 g, 0.65 mmol), 1,4-cyclohexadiene (0.31 mL, 3.25 mmol) and Pd/C (cat.) in methanol was heated to reflux for 17 h. The mixture was filtered through celite and concentrated to afford light yellow oil. M+1=293.
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-].[Cs+].[Cs+].[S:7]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=[C:8]1[C:15]([OH:17])=[O:16].[CH2:18]1[O:28][C:27]2[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][C:20]=2[O:19]1.ClCCl.Cl>CN(C)C=O.O>[O:3]1[C:27]2[CH:26]=[CH:25][C:22]([CH:23]([O:16][C:15]([C:8]3[S:7][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=3)=[O:17])[C:22]3[CH:25]=[CH:26][C:27]4[O:28][CH2:18][O:19][C:20]=4[CH:21]=3)=[CH:21][C:20]=2[O:4][CH2:1]1
Reactant: O=C([O-])[O-]
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: O=C(O)c1ccc(C(=O)O)s1
Agent: Cl
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(C(=O)OC(c2ccc3c(c2)OCO3)c2ccc3c(c2)OCO3)s1
Reaction time: 0.08 h

Procedure:
Cesium carbonate (4.7 g, 14.4 mmol) was added to a stirred solution of 2,5-thiophenedicarboxylic acid in dimethylformamide (35 mL) under an inert atmosphere at room temperature. After 5 minutes, a solution of 3,4-methylenedioxybenzyl chloride in dichloromethane (3.7 mL, 14.3 mmol) was added. After 24 hours the mixture was stirred into water (150 mL) and acidified with dilute aqueous HCl. After several hours, the precipitate was filtered off, rinsed with water, and dried to afford 0.6 g of thiophene-2,5-dicarboxylic acid di-1,3-benzodioxol-5-ylmethyl ester. Recrystallization of a sample from ethanol gave product with a mp 141-148° C.
Reaction SMILES: [N+:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([OH:11])=[O:10])[CH:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C.O>[N+:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([O:11][CH2:20][CH:19]=[CH2:18])=[O:10])[CH:8]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1csc([N+](=O)[O-])c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)c1csc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
2-Nitro-4-thiophenecarboxylic acid (2.5 g, 14.45 mmol) was suspended in DMF (25 ml) in the presence of potassium carbonate (4 g, 28.9 mmol) at ambient temperature. Allyl bromide (5 ml, 57.8 mmol) was added to this solution and the mixture stirred at ambient temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. After concentration, the residue was purified by silica gel chromatography using ethyl acetate/petroleum ether as eluant (10:30) to give the title compound (2.45 g, 77%).
Reaction SMILES: [CH3:1][C@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:10](OCC)=[O:11]>>[CH3:1][C@H:2]([NH:9][CH:10]=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC=O
Reactant: C[C@H](N)c1ccccc1
Product: C[C@H](NC=O)c1ccccc1
Temperature: 55 °C

Procedure:
(S)-(−)-α-Methylbenzylamine (1 molar eq.) was treated with ethyl formate (80 molar eq.; Aldrich). A precipitate formed immediately. The suspension was heated to reflux (55° C.) for 3 hours. The precipitate went into solution upon heating. The solution was cooled to ambient temperature and concentrated via rotary evaporation. The resultant solid was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:18]O>>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([C:8]([O:10][CH3:18])=[O:9])=[N:6][CH:7]=1
Reactant: CO
Reactant: COc1cc(Cl)cnc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ncc(Cl)cc1OC
Temperature: 0 °C
Yield: 67 %

Procedure:
In a 350-mL resealable vessel, 5-chloro-3-methoxypicolinic acid (intermediate 14, 7.51 g, 40.0 mmol) was dissolved in MeOH (120 mL). The solution was cooled to 0° C., and concentrated sulfuric acid (7.57 mL, 140 mmol) was added. The vessel was sealed and heated to 95° C. for 1.5 h. The reaction mixture was cooled to 0° C., and quenched with Na2CO3 (1M, 140 mL). The reaction mixture was concentrated under reduced pressure and the residue was extracted with EtOAc (3×100 mL). The combined organics extracts were dried over MgSO4 and the filtrate was concentrated under reduced pressure. The residue was by silica gel chromatography (gradient 20%-33% EtOAc/hexane) to afford the title compound as a yellow solid (5.59 g, 27.7 mmol, 67%). MS m/z=202 [M+H]+. Calculated for C8H8ClNO3: 201. 1H NMR in CDCl3 δ: 8.24 (d, 1H, J=1.9), 7.37 (d, 1H, J=1.9), 3.97 (s, 3H), 3.94 (s, 3H).
Reaction SMILES: [H-].[Na+].[C:3]1([B:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1.O1CC[CH2:29][CH2:28]1>>[N:22]1([B-:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:26]=[CH:25][CH:24]=[CH:23]1.[CH2:23]([N+:22]([CH2:21][CH3:16])([CH2:28][CH3:29])[CH2:26][CH3:25])[CH3:24]
Reactant: c1ccc(B(c2ccccc2)c2ccccc2)cc1
Reactant: C1CCOC1
Reactant: c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Product: CC[N+](CC)(CC)CC
Product: c1ccc([B-](c2ccccc2)(c2ccccc2)n2cccc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixtue of sodium hydride (0.45 g, 19 mmole) and triphenylboron (3.6 g, 15 mmole) in tetrahydrofuran (100 ml) was slowly added to a stirred solution of pyrrole (1.01 g, 15 mmole) in anhydrous tetrahydrofuran. The mixture was stirred for five hours under nitrogen at room temperature, and the resulting dark solution was filtered through filter paper and diluted with an equal amount of water. An excess of tetraethylammonium chloride solution was added slowly and the precipitate which formed was collected, dissolved in acetone and purified by addition of the acetone solution to water. The product tetraethylammonium (1-pyrrole)triphenylborate was collected (4.52 g, 72%).
Reaction SMILES: ClC1=[C:3]([C:21]([O:23][CH3:24])=[O:22])[NH:4][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:6]/[C:7]/1=[N:8]\OS(C)(=O)=O.[CH3:25][NH2:26].[CH2:27]1COCC1>CS(C)=O.O>[NH2:26][C:25]1[C:3]([C:21]([O:23][CH3:24])=[O:22])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:6][C:7]=1[NH:8][CH3:27]
Reactant: COC(=O)C1=C(Cl)/C(=N/OS(C)(=O)=O)CC(c2ccc(Cl)cc2)N1
Reactant: CN
Reactant: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: CNc1cc(-c2ccc(Cl)cc2)nc(C(=O)OC)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution (E)-methyl 3-chloro-6-(4-chlorophenyl)-4-(((methylsulfonyl)oxy)imino)-1,4,5,6-tetrahydropyridine-2-carboxylate (100 mg, 0.254 mmol) in DMSO (2 mL) was added 2 M methanamine in THF (0.8 mL, 1.6 mmol). The reaction mixture was stirred at ambient temp for 30 min, and then it was diluted with H2O. The product crashed out of solution, and was collect in a Buchner funnel, and dried under vacuum to yielded a brown solid (49 mg, 66%): mp 178-200° C.; 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J=8.4 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 6.95 (s, 1H), 5.39 (s, 1H), 4.07 (s, 1H), 3.98 (s, 1H), 2.98 (d, J=5.1 Hz, 1H); ESIMS m/z 292 ([M+H]+), 290 ([M−H]−).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-])=O)[C:3]=1[F:12].CCO.O.[Cl-].[NH4+]>C1COCC1.[Fe]>[Br:1][C:2]1[C:3]([F:12])=[C:4]([NH2:9])[C:5]([NH2:6])=[CH:7][CH:8]=1
Reactant: Nc1ccc(Br)c(F)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(Br)c(F)c1N
Temperature: 80 °C
Reaction time: 16 h
Yield: 83.8 %

Procedure:
To a solution of 4-bromo-3-fluoro-2-nitroaniline (3.0 g, 12.8 mmol) in THF (30 mL) was added EtOH (30 mL) and H2O (10 mL) followed by iron powder (3.6 g, 63.8 mmol) and ammonium chloride (1.0 g, 19.2 mmol). The resulting mixture was stirred at 80° C. for 16 hours. The mixture was cooled to room temperature and filtered through diatomaceous earth. The solid was washed with EtOH until no further color came through the filter. The filtrate was concentrated in vacuo and the crude product was purified by column chromatography on silica gel using a solvent gradient of 0-40% EtOAc in hexane to give the title compound (2.2 g, 84%).
Reaction SMILES: C(OC(=O)CCCNC(NC1SC(C2C=CC(S(C)(=O)=O)=C(F)C=2)=C(C)N=1)=O)C.[NH2:30][C:31]1[S:32][C:33]([C:37]2[CH:42]=[C:41]([Cl:43])[C:40]([S:44]([N:47]([CH3:49])[CH3:48])(=[O:46])=[O:45])=[C:39]([Cl:50])[CH:38]=2)=[C:34]([CH3:36])[N:35]=1.[CH2:51]([O:53][C:54](=[O:60])[CH2:55][CH2:56][N:57]=[C:58]=[O:59])[CH3:52]>>[CH2:51]([O:53][C:54](=[O:60])[CH2:55][CH2:56][NH:57][C:58]([NH:30][C:31]1[S:32][C:33]([C:37]2[CH:42]=[C:41]([Cl:43])[C:40]([S:44](=[O:46])(=[O:45])[N:47]([CH3:49])[CH3:48])=[C:39]([Cl:50])[CH:38]=2)=[C:34]([CH3:36])[N:35]=1)=[O:59])[CH3:52]
Reactant: CCOC(=O)CCN=C=O
Reactant: Cc1nc(N)sc1-c1cc(Cl)c(S(=O)(=O)N(C)C)c(Cl)c1
Agent: CCOC(=O)CCCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Product: CCOC(=O)CCNC(=O)Nc1nc(C)c(-c2cc(Cl)c(S(=O)(=O)N(C)C)c(Cl)c2)s1

Procedure:
The title compound is prepared by the same procedure as 4-{3-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyric acid ethyl ester (Example 164) by replacing 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) with 4-(2-amino-4-methyl-thiazol-5-yl)-2,6-dichloro-N,N-dimethyl-benzenesulfonamide (171b) and replacing ethyl-4-isocyanatobutyrate with 3-isocyanato-propionic acid ethyl ester.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15].Br[CH2:17][C:18]#[N:19]>CC(C)=O>[C:18]([CH2:17][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH3:7])#[N:19]
Reactant: COc1ccccc1O
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccccc1OCC#N
Yield: 84.2 %

Procedure:
Potassium carbonate (24 g) was added to a solution of of 2-methoxy phenol (18.94 g, 0.152 mol) in acetone (500 ml) at room temperature. A solution of bromoacetonitrile (17.43 g, 0.145 mol) in acetone (500 ml) was then added and the resulting suspension was heated at reflux for 10 h. The reaction vessel was then cooled and the solution was concentrated under reduced pressure and taken up into water (150 ml). Chloroform (250 ml) was added and the two layers separated. The organic phase was washed with brine (100 ml) and 10% aqueous NaOH (100 ml). The organic phase was dried (MgSO4) and concentrated under reduced pressure to give the product (19.91 g, 80%) as an oil. 1H NMR (CDCl3, 250 MHz) 7.0 (4H m), 4.8 (2H, s), 3.9 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[CH3:19])[N:11]([CH3:20])[N:10]=1.[Br:21]Br>C(O)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[S:15][C:16]([Br:21])=[CH:17][C:18]=2[CH3:19])[N:11]([CH3:20])[N:10]=1
Reactant: Cc1ccsc1-c1nc(-c2c(F)cccc2Cl)nn1C
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(Br)sc1-c1nc(-c2c(F)cccc2Cl)nn1C
Temperature: 25 °C
Reaction time: 120 h
Yield: 81.1 %

Procedure:
3-(2-fluoro-6-chlorophenyl)-5-(3-methyl-2-thienyl)-1-methyl-1,2,4-triazole (1.18 mmol., 364 mg) was dissolved in glacial acetic acid (4 ml). Bromine (2.36 mmol, 0.124 ml) was added in two portions and the reaction allowed to stir 5 days at room temperature. Diluted with water and extracted into diethyl ether, washed with saturated NaHCO3 and brine, dried over MgSO4. Concentrated to a white solid. Wgt. 0.51 g, recrystallized from hexane ethyl acetate to afford the product as a white solid (0.37 g, 81%) MP 117-118° C.; Anal. Calcd. For C14H10BrClFN3S; C, 43.44; H, 2.60; N, 10.86. Found; C, 43.46; H, 2.71; N, 10.81.