Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[C:6](Cl)=[N:5][S:4][N:3]=1.[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C)C.C(OCC)C>[Cl:1][C:2]1[C:7](=[O:8])[C:6]([S:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][S:4][N:3]=1
Reactant: O=c1c(Cl)nsnc1Cl
Reactant: Sc1ccccc1
Agent: CN(C)C
Solvent: CCOCC
Product: O=c1c(Cl)nsnc1Sc1ccccc1
Reaction time: 3 h

Procedure:
In one portion 2.5 g of trimethylamine was added to a solution of 4.6 g of 3,5-dichloro-4H-1,2,6-thiadiazin-4-one in 75 ml of ethyl ether in a 250 ml flask. A solution of 2.8 g of thiophenol in 25 ml of ethyl ether was then added dropwise to the flask during a 15 minute period. The reaction was allowed to stir for 3 hrs. after which it was filtered. The filter cake was washed with ether, and the filter cake was discarded. Successively, the ether solution was washed twice with 50 ml of water and once with 50 ml of saturated sodium chloride solution. The ether solution was then dried over anhydrous sodium sulfate. The ether was evaporated, leaving a solid residue which was recrystallized from 75 ml of cyclohexane. The yellow-orange 3-chloro-5-phenylthio-4H-1,2,6-thiadiazin-4-one weighed 3.6 g, mp 99.5°-101.5° C. (Lit. mp 102.5°-103.5° C., J. Geevers and W. P. Trompen, supra.) The ir spectrum was consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][OH:10].Cl[C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[C:20]([CH3:24])([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][O:10][C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[C:20]([CH3:24])([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1cc(F)ccc1F
Product: CN1c2cc(OCc3cc(F)ccc3F)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (2,5-difluorophenyl)methanol and 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:13]1([CH2:16][C:17]([NH2:19])=[O:18])[CH2:15][CH2:14]1>>[CH:13]1([CH2:16][C:17]([NH:19][C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[O:18])[CH2:15][CH2:14]1
Reactant: COC(=O)c1cc(C)nc(Cl)c1
Reactant: NC(=O)CC1CC1
Product: COC(=O)c1cc(C)nc(NC(=O)CC2CC2)c1
Yield: 67 %

Procedure:
The title compound is prepared in 67% yield (316 mg) from methyl 2-chloro-6-methylisonicotinate (350 mg, 1.89 mmol) and 2-cyclopropylacetamide (243 mg, 2.45 mmol) by the similar manner in Step-1 of Carboxylic acid-4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([NH2:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1.[CH:15]1([CH2:20][C:21](O)=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH3:1][O:2][C:3](=[O:14])[CH:4]([NH:13][C:21](=[O:22])[CH2:20][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1
Reactant: COC(=O)C(N)Cc1cccc(O)c1
Reactant: O=C(O)CC1CCCC1
Product: COC(=O)C(Cc1cccc(O)c1)NC(=O)CC1CCCC1
Yield: 54.9 %

Procedure:
12.5 g (54.3 mmol) of 2-amino-3-(3-hydroxy-phenyl)-propionic acid methyl ester was reacted with cyclopentyl acetic acid (6.97 g, 54.3 mmol) as described in general procedure A. The compound was purified using gradient elution with 10% to 100% ethyl acetate in hexanes to yield 9.1 g of 2-(2-cyclopentyl-acetylamino)-3-(3-hydroxy-phenyl)-propionic acid methyl ester.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][C@@H:12]([N:25]2[C:29]([N:30]3[C:34](=[O:35])[C:33]4=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]4[C:31]3=[O:40])=[C:28]([C:41](=[O:45])[CH:42]=[N+]=[N-])[N:27]=[CH:26]2)[C@H:11]1[F:46])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:47].C(OCC)C>ClCCl>[C:1]([O:9][C@@H:10]1[C@@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][C@@H:12]([N:25]2[C:29]([N:30]3[C:34](=[O:35])[C:33]4=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]4[C:31]3=[O:40])=[C:28]([C:41](=[O:45])[CH2:42][Cl:47])[N:27]=[CH:26]2)[C@H:11]1[F:46])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl
Reactant: [N-]=[N+]=CC(=O)c1ncn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@@H]2F)c1N1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(OC[C@H]1O[C@@H](n2cnc(C(=O)CCl)c2N2C(=O)c3ccccc3C2=O)[C@@H](F)[C@@H]1OC(=O)c1ccccc1)c1ccccc1

Procedure:
The solid containing compound (14) obtained in step (5) above was dissolved in dichloromethane (5 ml), to which was then added a 1M hydrogen chloride-diethyl ether solution (0.5 ml), and the resultant mixture was allowed to react for 0.5 hours to produce the titled compound (15). The reaction solution so obtained was diluted with dichloromethane and washed with water, and the organic layer obtained was dried over anhydrous sodium sulfate and then concentrated to yield the titled compound (15) as a solid (190 mg). Yield from compound (12): 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH:17]2[CH2:19][CH2:18]2)=[C:6]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=1.[CH3:20][N:21]([CH:23](OC)OC)[CH3:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH:17]2[CH2:19][CH2:18]2)=[C:6]([CH:7]=1)[C:8]([C:9](=[CH:20][N:21]([CH3:23])[CH3:22])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:15]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1cc(Cl)ccc1OC1CC1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Cl)ccc1OC1CC1

Procedure:
Ethyl 3-(5-chloro-2-cyclopropoxyphenyl)-3-oxopropanoate (21.8 g, 77 mmol) was dissolved in 150 mL of DMF-DMA. The mixture was heated to reflux for 2 hours. Evaporation gave a yellow solid which was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ: 7.69 (s, 1H), 7.39 (s, 1H), 7.29 (dd, J=2.4, 8.8 Hz, 1H), 7.15 (d, J=8.8 Hz, 1H), 3.92 (q, J=6.8 Hz, 2H), 3.69-3.65 (m, 1H), 3.10 (br, 6H), 0.88 (t, J=6.8 Hz, 3H), 0.77-0.71 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)NCC2
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cccc(CN2CCc3ccc(Br)cc32)c1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of 6-bromoindoline (750 mg, 3.79 mmol), 1-(bromomethyl)-3-fluorobenzene (697 pt, 5.68 mmol) and cesium carbonate (1.851 g, 5.68 mmol) in N,N-dimethylformamide (7.573 mL) was stirred at 110° C. for 2 hours. The mixture was cooled, diluted with 100 mL ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel flash chromatography (Isco®, Redi-Sep® column), eluting with a gradient of 2-50% ethyl acetate/hexane, afforded the title compound. LCMS: 306 (M+H)+.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][CH:7]=1.[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][N:11]=1
Reactant: Cc1ccc(CO)cn1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(COc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66.4 %

Procedure:
Thionyl chloride (1 mL) was added to (6-methyl-pyridin-3-yl)-methanol (300 mg, 2.44 mmol) at 0° C., and the solution was stirred at room temperature for 20 minutes. The reaction solution was partitioned in an aqueous solution of saturated sodium bicarbonate and ethyl acetate. This organic layer was separated, washed with brine, and then, dried over anhydrous magnesium sulfate. The organic layer was filtered, then, the solvent was evaporated in vacuo. N,N-dimethylformamide (5 mL), phenol (230 mg, 2.44 mmol) and potassium carbonate (674 mg, 4.88 mmol) were added to this residue at room temperature. This reaction mixture was stirred at room temperature for 40 minutes, then, further stirred for at 60° C. 40 minutes. The reaction solution was partitioned in water and ethyl acetate. The organic layer was separated, washed with water and brine, and then, dried over anhydrous magnesium sulfate. The organic layer was filtered, then, the solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (heptane/ethyl acetate=2/1), and the title compound (323 mg, 66%) was obtained as a white solid.
Reaction SMILES: [CH:1](OCC#N)=[O:2].Cl.[CH3:8][O:9][C:10](=[O:20])[C@H:11]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH2:12].C(N(CC)CC)C>ClCCl>[CH:1]([NH:12][CH:11]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([O:9][CH3:8])=[O:20])=[O:2]
Reactant: N#CCOC=O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(Cc1ccccc1)NC=O
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Cyanomethyl formate (Aldrich, Order No. 453579, 5.05 g, 59.3 mmole) was suspended together with the phenylalanine methyl ester hydrochloride (Aldrich, Order No. 525472, 12.80 g, 59.3 mmole) in 80 ml dichloromethane and cooled to 0° C. in an ice bath. Triethylamine (6.01 g, 59.3 mmole) dissolved in 15 ml of dichloromethane was then added and the mixture was stirred for 16 hours at room temperature. A clear solution formed. In order to work up the mixture the latter was diluted with 100 ml of dichloromethane and washed firstly with 200 ml of saturated NaHCO3 solution and then twice with saturated NaCl solution. The organic phase was dried over magnesium sulfate and concentrated by evaporation. The product obtained was used without further purification for the next stage.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[C:25]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=3)[N:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: Cc1cc(Nc2cc3ccccc3c(-c3cccc(C(F)(F)F)c3)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-trifluoromethyl-phenylboronic acid to give [1-(3-trifluoromethyl-phenyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 369(MH+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][O:15]C2CCCCO2)[C:11]([C:22]([F:25])([F:24])[F:23])=[CH:10][C:9]=1[NH:26][C:27](=[O:44])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[CH:38]=2)[CH:32]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:15][CH2:14][C:12]1[C:11]([C:22]([F:24])([F:23])[F:25])=[CH:10][C:9]2[NH:26][C:27](=[O:44])[CH2:28][C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]4[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[CH:38]=4)[CH:32]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(COC4CCCCO4)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(CO)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from [2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(tetrahydro-pyran-2-yloxymethyl)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M241) (156 mg, 0.28 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (50 mg, 42%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([Cl:26])=[N:10][C:11]([Cl:25])=[C:12]([C:16]=1[NH:17]C(OC(C)(C)C)=O)[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[NH2:17][C:16]1[C:12]([C:13]([OH:15])=[O:14])=[C:11]([Cl:25])[N:10]=[C:9]([Cl:26])[C:8]=1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)Nc1c(C(=O)O)c(Cl)nc(Cl)c1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1c(Cl)nc(Cl)c(C(=O)O)c1N

Procedure:
In scheme (V), 5-(tert-butoxycarbonyl)-4-(tert-butoxycarbonylamino)-2,6-dichloronicotinic acid (4) is first treated with 25% trifluoracetic acid (TFA) in dichloromethane (DCM) at room temperature (25° C.) for 2 hours, removing one of the two Boc groups and forming 4-amino-5-(tert-butoxycarbonyl)-2,6-dichloronicotinic acid (5). A stronger condition (reflux at 60° C., 25% TFA in DCM, 2 h) is then used to maximize hydrolysis of the tert-butyl ester of 4-amino-5-(tert-butoxycarbonyl)-2,6-dichloronicotinic acid (5) and obtain 4-amino-2,6-dichloropyridine-3,5-dicarboxylic acid (6).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH3:17])=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:8]=2[CH:25]=1)([O-:3])=[O:2].[CH2:26]=[O:27]>C1(C)C(C)=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][CH2:26][OH:27])=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:8]=2[CH:25]=1)([O-:3])=[O:2]
Reactant: C=O
Reactant: Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCO)n1-2

Procedure:
In the manner given in Example 1, 8-nitro-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepine in xylene was heated in an oil bath with repeated additions of portions of paraformaldehyde to give 8-nitro-1-(2-hydroxyethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[N:10][NH:9][C:8]1=[S:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[C:27]([O:32][CH3:33])[CH:26]=[C:25]3[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=2)=[O:21])=[CH:16][CH:15]=1.O>C1COCC1>[Cl:40][C:36]1[CH:35]=[C:34]([C:25]2[C:24]3[C:29](=[CH:30][CH:31]=[C:22]([C:20]([C:17]4[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=4)([C:11]4[N:7]([CH3:6])[C:8]([SH:12])=[N:9][N:10]=4)[OH:21])[CH:23]=3)[N:28]=[C:27]([O:32][CH3:33])[CH:26]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: Cn1cn[nH]c1=S
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3nnc(S)n3C)ccc2n1
Temperature: -70 °C
Reaction time: 1 h
Yield: 34.5 %

Procedure:
BuLi (0.233 mol) was added dropwise at −70° C. to a solution of 2,4-dihydro-4-methyl-3H-1,2,4-triazole-3-thione (0.0612 mol) in THF (350 ml) under N2 flow. The mixture was stirred at −70° C. for 1 hour and then brought to 0° C. The mixture was stirred at 0° C. for 45 minutes and then cooled to −70° C. A solution of intermediate (56) (0.0612 mol) in THF (150 ml) was added. The mixture was then brought to 0° C., poured out into water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: Cyclohexane/EtOAc 70/30; 15–35 μm). The pure fractions were collected and the solvent was evaporated, yielding 11.06 g (35%) of 4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(5-mercapto-4-methyl-4H-1,2,4triazol-3-yl)-2-methoxy-6-quinolinemethanol (intermediate 57), mp. >260° C.
Reaction SMILES: BrBr.[O:3]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]2[C:23]([NH2:24])=[N:22][C:21]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([S:32](=[O:35])(=[O:34])[NH2:33])=[CH:28][CH:27]=3)=[N:20]2)=[S:18])=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>ClCCl.C(O)(=O)C>[NH2:24][C:23]1[N:19]([C:17]2[S:18][C:12]3[CH:11]=[C:10]([O:3][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:15]=[CH:14][C:13]=3[N:16]=2)[N:20]=[C:21]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([NH2:33])(=[O:34])=[O:35])=[CH:28][CH:27]=2)[N:22]=1
Reactant: Nc1nc(Nc2ccc(S(N)(=O)=O)cc2)nn1C(=S)Nc1ccc(Oc2ccccc2)cc1
Agent: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1nc(Nc2ccc(S(N)(=O)=O)cc2)nn1-c1nc2ccc(Oc3ccccc3)cc2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 7 %

Procedure:
Bromine (7 μl, 1 equivalent) was added to a stirred suspension of 5-amino-3-(4-sulfamoyl-phenylamino)-[1,2,4]triazole-1-carbothioic acid (4-phenoxy-phenyl)-amide in dichloromethane (3 ml). The reaction mixture was stirred at room temperature for 18 hours. A solution of bromine (7 μl) in acetic acid (1 ml) was then added to push the reaction to completion: the reaction mixture was stirred for a further four hours. A white solid precipitated and was removed by filtration to afford the title compound (5 mg; 7% yield). 1H NMR (400 MHz, DMSO-d6) 7.05-7.20 (8H, m), 7.35-7.50 (4H, m), 7.70-7.75 (2H, d), 7.80-7.85 (2H, d), 9.90-9.95 (1H, s); MS (ES+) m/e=480
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C.C(OCC)C>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[F:7])[CH3:22])[CH3:21]
Reactant: Oc1ccccc1F
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C(C)Oc1ccccc1F
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 94.1 %

Procedure:
Cesium carbonate (65.69 g, 201.61 mmol) is added to a solution of 2-fluorophenol (9 mL, 100.84 mmol, d=1.256) in anhydrous DMF (300 mL) at room temperature under an atmosphere of nitrogen. After five minutes, ethyl 2-bromopropionate (130.1 mL, 100.84 mmol, d=1.394) is added rapidly dropwise and the resultant mixture is allowed to stir at 90° C. for 18 h. The reaction mixture is diluted with diethyl ether, then extracted twice with 1N HCl and twice with water. The organic layer is dried, concentrated, and purified by flash chromatography (25% ether in hexanes) to provide the titled compound (20.14 g, 94%). 1H NMR (400 MHz, CDCl3): □. 7.07-6.96 (m 2H), 6.93-6.87 (m, 2H), 4.73, 4.71 (ABq, 1H, J=6.7 Hz). 4.21-4.15 (m, 2H), 1.61 (d, 3H, J=6.7 Hz), 1.21 (t, 3H, J=6.7 Hz). MS [EI+] 507 (M+H)+.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:14])[C@H:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:22][O:23][CH2:24][C:25](Cl)=[O:26]>C1COCC1>[CH3:22][O:23][CH2:24][C:25]([NH:9][C@@H:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:14])=[O:26]
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(=O)N[C@H](C(=O)OC(C)(C)C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 114 %

Procedure:
A solution of L-tert-Leucine tert-butyl ester hydrochloride (0.20 g, 0.90 mmol) in THF (9 mL) at 0° C. was treated with triethylamine (0.38 mL, 2.73 mmol) and methoxyacetyl chloride (0.09 mL, 0.98 mmol), stirred at 0° C. for 15 minutes and then at 25° C. for 2 hours. The reaction was partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-33% ethyl acetate/chloroform to give the title compound (0.266 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]([OH:15])(=[O:14])[CH:12]=[CH2:13].C(OC(=O)C)(=O)C>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:13][CH2:12][C:11]([OH:15])=[O:14]
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: C=CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)CCc1c[nH]c2ccc(F)cc12
Temperature: 90 °C
Yield: 57.5 %

Procedure:
Thus, a solution of 5-fluoroindole (1.35 g, 0.010 mol) in 10 mL of acetic acid containing acrylic acid (1.5 mL, 0.022 mol) and acetic anhydride (1.9 mL, 0.02 mol) was heated (oil bath) at 90° C. under Ar for 5 days. The volatiles were then removed in vacuo and the residue was taken up in 3N NaOH. Insoluble material was removed by filtration and the filtrate was acidified with conc. HCl and then extracted with CH2Cl2. The organic extract was dried (Na2SO4) and evaporated to give the product (1.191 g, 57%) as a solid which was used without further purification: IR (neat) 3420, 1710 cm-1 ; 1Hnmr (200 MHz, CDCl3) δ7.94 (br s, 1H), 7.28-7.18 (m, 3H), 7.05 (d, J=2.5 Hz, 1H), 6.93 (dt, J=9.0, 2.6 Hz, 1H), 3.05 (t, J=7.5 Hz, 2H), 2.73 (t, J=7.6 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)=[O:4].[CH:17]([N:20](CC)C(C)C)([CH3:19])[CH3:18].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CC(N)C>ClCCl>[CH:17]([NH:20][C:9]([C:8]1[CH:12]=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=1[N+:14]([O-:16])=[O:15])=[O:11])([CH3:19])[CH3:18]
Reactant: COC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)N
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NC(C)C)c([N+](=O)[O-])c1
Reaction time: 0.25 h
Yield: 81.2 %

Procedure:
To a solution of 4-(methoxycarbonyl)-2-nitrobenzoic acid (0.50 g, 2.22 mmol) in dichloromethane (20 mL) was added N,N-diisopropylethylamine (1.16 mL, 6.66 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.89 g, 2.33 mmol). The reaction mixture was stirred for 15 min. Propan-2-amine (0.20 mL, 2.33 mmol) was added and the reaction mixture was stirred at rt overnight. The reaction mixture was then concentrated and the crude residue was purified by flash silica gel chromatography (30% to 60% EtOAc/hexanes) to afford methyl 4-[(isopropylamino)carbonyl]-3-nitrobenzoate (0.48 g, 80%). LC-MS: (FA) ES+ 268.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]([C:16]([O:18][CH:19](Cl)[CH3:20])=[O:17])[C:7]3[C:12]([S:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]2[CH:22]=[CH:23][CH:24]=[CH:25][C:3]=12.[C:26]([O-:29])(=[O:28])[CH3:27].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[OH:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]([C:16]([O:18][CH:19]([O:29][C:26](=[O:28])[CH3:27])[CH3:20])=[O:17])[C:7]3[C:12]([S:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]2[CH:22]=[CH:23][CH:24]=[CH:25][C:3]=12
Reactant: CC(=O)[O-]
Reactant: CC(Cl)OC(=O)N1c2ccccc2Sc2cc(O)c3ccccc3c21
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC(C)OC(=O)N1c2ccccc2Sc2cc(O)c3ccccc3c21

Procedure:
The product from Step 2 (4 g) and sodium acetate (6 g) were refluxed together in glacial acetic acid (60 ml) for 1 hour. The mixture was cooled, diluted with ethyl acetate (300 ml) and washed with water (3×100 ml), then with aqueous sodium bicarbonate and again with water, dried and evaporated down. The residue was chromatographed on a column of silica gel eluting with a 1:9 mixture of ethyl acetate-hexane to afford, after trituration in ether and filtration, the pure title compound (1.2 g), m.p. 195°-196° C.