Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[Br:9]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[N:3]=[N:4][C:5]([CH2:8][Br:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)nn1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(Br)nn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
A solution of 1.00 g (5.78 mmol) of 3-bromo-6-methylpyridazine and 1.03 g (5.79 mmol, 1.0 eq) of recrystallized N-bromosuccinimide in 20 mL of carbon tetrachloride was added 95 mg of AIBN. The reaction mixture was purged twice with argon and evacuated and set to reflux under argon. After 3 h, the reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated to give a yellow oil. The mixture was directly purified by silica gel chromatography using hexanes/dichloromethane (1:9) as eluant (5×12 cm column), to give a colorless oil, 444 mg, 30% yield.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][C:6]=1[CH3:12])(=[O:4])=[O:3].[Cl:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[Cl:20].C([O-])([O-])=O.[K+].[K+]>S1(CCCC1)(=O)=O>[CH3:12][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][C:5]=1[S:2]([CH3:1])(=[O:4])=[O:3])[O:21][C:16]1[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(Cl)ccc1S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: Cc1cc(Oc2ccc(Cl)c(Cl)c2)ccc1S(C)(=O)=O
Yield: 63.4 %

Procedure:
A slurry of 6.14 g of 4-chloro-2-methylphenyl methyl sulfone, 8.35 g of 3,4-dichlorophenol and 7.08 g of K2CO3 in 150 ml of sulfolane was heated at 170° C. for 7 hrs. The product (6.3 g, 63.4% yield) was isolated from the reaction mixture essentially as described in Example 18. Recrystallization from ethanol afforded purified 4-(3-methyl-4-(methylsulfonyl)phenoxy)-1,2-dichlorobenzene, mp 154°-156° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:21][CH2:22][CH2:23][OH:24])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:20])[C:6]([CH3:19])=[C:7]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH:8]=2)[O:3]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH3:1][C:2]1([CH2:21][CH2:22][CH:23]=[O:24])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:20])[C:6]([CH3:19])=[C:7]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH:8]=2)[O:3]1
Reactant: Cc1c(OC2CCCCO2)cc2c(c1C)OC(C)(CCCO)CC2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1c(OC2CCCCO2)cc2c(c1C)OC(C)(CCC=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
A mixture of 3-[2,7,8-trimethyl-6-(tetrahydro-pyran-2-yloxy)-chroman-2-yl]-propan-1-ol (200 mg), pyridinium chlorochromate (PCC) (350 mg), and 4 A° molecular sieves (100 mg) in dichloromethane (15 mL) was stirred at RT for overnight. The mixture was passed through a silica gel column chromatography eluting with 30% EtOAc in hexane to give 40 mg of 3-[2,7,8-trimethyl-6-(tetrahydro-pyran-2-yloxy)-chroman-2-yl]-propionaldehyde as an oily product. 1H-NMR (300 MHz, CDCl3) δ (ppm): 9.79 (s, 1H, CHO), 6.67 (s, 1H), 5.23 (d, J=2.2 MHz, 1H), 3.90 (m, 1H), 3.58 (m, 1H), 2.75-2.60 (m, 4H), 2.15, 2.08 (2s, 6H), 2.00-1.58 (m, 10H), 1.23 (s, 3H). 13C-NMR (CDCl3, 75 MHz) δ (ppm): 202.64, 148.26, 145.87, 125.57, 125.41, 117.39, 112.93, 112.87, 97.34, 97.22, 74.33, 62.11, 62.05, 38.58, 32.34, 32.09, 31.60, 31.53, 30.76, 25.41, 23.85, 23.64, 22.36, 19.11, 19.08, 12.11, 11.96. MS (m/z): 333 (MH+), 355 (M+Na+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][C:22]1([CH3:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([N:25]2[CH2:26][CH2:27][C:22]([CH3:28])([CH3:21])[CH2:23][CH2:24]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CC1(C)CCNCC1
Product: CC1(C)CCN(C(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (200 mg, 0.56 mmol) and 4,4-dimethyl piperidine (83 mg, 0.65 mmol). The title compound was obtained as a solid (34 mg, 14% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.97 (2H, s), 7.90 (1H, s), 3.57 (4H, m), 1.33 (4H, m), 0.95 (6H, s). MS m/z: 446.21, 448.23 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([CH2:24][OH:25])([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].CI.[C:28](O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CS(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][C:13]([CH2:24][O:25][CH3:28])([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:14][CH2:15]1)=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: Cc1ccccc1CC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CI
Product: COCC1(Cc2ccccc2C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a 0° C. suspension of sodium hydride (19 mg, 0.80 mmol) in 1.5 ml of THF, was added a solution of N-t-butoxycarbonyl-4-hydroxymethyl-4-(2-methylbenzyl)piperidine (200 mg, 0.63 mmol) in 1 ml THF. The mixture was allowed to warm to room temp. To this suspension was added 0.35 ml of anhydrous DMSO and the mixture was heated to 60° C. and stirred 5 h until the solution was almost homogeneous. The reaction mixture was allowed to cool to room temp. and to this solution was added methyl iodide (0.070 ml, 1.12 mmol). The resulting heterogeneous mixture was stirred at room temp. overnight. The reaction mixture was treated with 10% aqueous citric acid and extracted with ether (3×). The combined ether extracts were washed successively with saturated aqueous NaHCO3 and brine, dried (MgSO4), and concentrated in vacuo to a yellow gum. Purification by column chromatography on silica with 9% EtOAc/hexane as eluent afforded the product as a colorless gum.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].N(OCCC(C)C)=O>O1CCCC1>[F:13][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[CH:2]=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:4]=[N:5]2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1N
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1
Reaction time: 2 h
Yield: 75.2 %

Procedure:
Ethyl 5-amino-1-(4-fluorophenyl)pyrazole-4-carboxylate (15 g) was dissolved in tetrahydrofuran (150 ml) and isoamyl nitrite (21.2 g) was added. The mixture was stirred at a refluxing temperature for 2 h. After cooling, the precipitated crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (10.6 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])([CH3:4])([CH3:3])[CH3:2].[C:26](OC(=O)C)(=[O:28])[CH3:27].N1C=CC=CC=1>N1C=CC=CC=1.O>[C:26]([N:8]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])[C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:20]([OH:21])=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)c1cc(Nc2cccc(C(=O)O)c2)cc(C(C)(C)C)c1O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N(c1cccc(C(=O)O)c1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5.6 g of 3-(3,5-di-t-butyl-4-hydroxyanilino)benzoic acid (from Example 13) and 15 ml of acetic anhydride was heated under a nitrogen atmosphere at 70°-120° C. for about 90 minutes. The mixture was cooled to 80° C., 5 drops of pyridine were added and the reaction was reheated to 120° C. for 10 minutes. An additional 0.25 ml of pyridine was added at about 80° C., followed by the gradual addition of 10 ml of water to hydrolyze the excess acetic anhydride and the mixed anhydride of the product. Heating was continued until a precipitate formed. The reaction mixture was allowed to cool to room temperature, and the precipitate was then collected, rinsed with a cold mixture of methanol and water, and dried to give 4.3 g of off-white solid m.p. 204°-205.5° C. This material was recrystallized first from a mixture of 30 ml of ethanol and 5 ml of water, and then from a mixture of 30 ml of isopropanol and 5 ml of hexane to give 3.3 g of white solid N-acetyl-3-(3,5-di-t-butyl-4-hydroxyanilino)benzoic acid m.p. 214.5°-215.5° C. Analysis: Calculated for: C23H29NO4.1/2(CH3)2CHOH: % C, 71.2; % H, 8.0; % N 3.4. Found: % C, 71.4; % H, 8.1; % N, 3.2.
Reaction SMILES: C(O[C:4](=[N:14][CH3:15])[CH2:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[F:13])C.[C:16]([NH2:22])(=[O:21])[C:17]([NH:19][NH2:20])=O.N>CN1CCOCC1.ClCCl>[F:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([F:13])[C:6]=1[CH2:5][C:4]1[N:14]([CH3:15])[C:17]([C:16]([NH2:22])=[O:21])=[N:19][N:20]=1
Reactant: NNC(=O)C(N)=O
Reactant: CCOC(Cc1c(F)cccc1F)=NC
Agent: N
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cn1c(Cc2c(F)cccc2F)nnc1C(N)=O

Procedure:
320 mg (1.5 mmol) of 1-ethoxy-2-(2,6-difluorophenyl)-1-(N-methylimino)-ethane and 155 mg (1.5 mmol) of oxalic acid monoamide monohydrazide are dissolved under a nitrogen atmosphere in 5 ml of N-methylmorpholine and the whole is heated under reflux for 41 hours. After cooling, the reaction mixture is diluted with 20 ml of dichloromethane and extracted by shaking in succession twice with water, twice with 2N hydrochloric acid and again with water The last three acidic aqueous phases obtained are combined, rendered alkaline with concentrated ammonia solution and extracted three times with dichloromethane. The combined organic phases are dried over magnesium sulphate and concentrated. Recrystallisation of the crude product from ethanol yields 102 mg (27% of the theoretical yield) of the desired 5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxamide which melts at 189°-190°.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([SH:28])[CH:25]=[CH:26][CH:27]=1>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([S:28][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: COc1cccc(S)c1
Product: COc1cccc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)c1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3-methoxy-thiophenol.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].S(OC)(O[CH3:18])(=O)=O.S(=O)(=O)(O)O>O>[CH3:18][O:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(O)c1
Reactant: COS(=O)(=O)OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(C)ccc1C(=O)O
Temperature: 10 °C
Reaction time: 144 h

Procedure:
A stirred mixture of 2-hydroxy-4-methylbenzoic acid (75 g, 0.50 mol), sodium hydroxide (42 g, 1.0 mol) and water (250 ml) was cooled to 10° C. and treated dropwise with dimethyl sulphate (126 g, 1.0 mol). The mixture was stirred for 6 days, poured into water (4000 ml), acidified with sulfuric acid and extracted with dichloromethane (4×600 ml). The extracts were combined, washed with water, dried over sodium sulfate and the solvent was evaporated off under reduced pressure. The resulting oil was treated with aqueous sodium hydroxide (1000 ml of 2M) and heated under reflux for 2 hours. The mixture was acidified with hydrochloric acid and extracted with dichloromethane (3×300 ml). The combined extracts were dried over sodium sulfate and the solvent was evaporated off under reduced pressure to give the crude product as an oil. The crude product was purified by column chromatography (silica gel, chloroform) and recrystallized from chloroform-hexane to yield 2-methoxy-4-methylbenzoic acid as a colorless crystalline solid, having a melting point of 108°-109° C.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8]/[C:7]/1=[N:16]\[NH2:17])[CH2:2][CH2:3][CH2:4][CH3:5].[C:18]([NH:28][CH2:29][C:30](O)=[O:31])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[O:31]=[C:30]([NH:17]/[N:16]=[C:7]1\[NH:8][C:9](=[O:15])[C:10]2[NH:11][CH:12]=[N:13][C:14]=2[N:6]\1[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:29][NH:28][C:18](=[O:19])[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCn1/c(=N/NC(=O)CNC(=O)OCc2ccccc2)[nH]c(=O)c2[nH]cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 144.8 %

Procedure:
The mixture of (2E)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (0.50 g, 0.0021 mol), N-carbobenzyloxyglycine (0.49 g, 0.0023 mol), benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (1.0 g, 2.3 mmol) and triethylamine (0.59 mL, 0.0042 mol) in DMF (20 mL) was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with water (4×) and brine (1×). The aqueous was extracted with EtOAc (2×). The combined organic layers were dried (MgSO4) and concentrated to give the desired product (1.30 g, 86%). LCMS calculated for C20H26N7O4 (M+H): 428.2. Found 428.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH:6]=[N:7][NH:8]C(OC(C)(C)C)=O.[OH-].[Na+].O.[C:22]([O:25]CC)(=[O:24])C.[C:28]1([CH3:34])[CH:33]=CC=C[CH:29]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][N:7]([NH2:8])[C:22]([O:25][C:28]([CH3:34])([CH3:33])[CH3:29])=[O:24]
Reactant: CCOC(C)=O
Reactant: COc1cccc(C=NNC(=O)OC(C)(C)C)c1
Reactant: Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(CN(N)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of sodium dihydrido-bis(2-methoxy-ethoxy)aluminate (66 ml of a 3.5 M solution in toluene) in tetrahydrofuran (15 ml) was added to t-butyl 3-methoxy-benzylidenecarbazate (28.8 g) dissolved in tetrahydrofuran (200 ml) at 20° C. during 45 minutes. After the addition the solution was stirred at room temperature for 3 hours. The reaction mixture was treated carefully with aqueous sodium hydroxide (40 ml, 5%), after which water (200 ml) and ethyl acetate (500 ml) were added. The organic phase was separated, dried and concentrated to dryness giving t-butyl 3-methoxy-benzylcarbazate (28 g) as an oil.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][C:3]=2[O:2]1.O1CCCC1.C([Li])CCC.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl.O.C(Cl)Cl>[CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[S:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:31])=[O:30])=[CH:4][C:3]=2[O:2]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1cc2cc3c(cc2[nH]1)OCO3
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1ccc2cc3c(cc21)OCO3
Temperature: 25 °C
Yield: 109.4 %

Procedure:
To a solution of 5,6-methylenedioxyindole (11.5 gm, 71 mmol) in freshly distilled tetrahydrofuran (60 ml) under a nitrogen atomosphere at -70° C. was added dropwise 1.6M n-butyllithium (50 ml, 80 mmol) over a one-half hour period. Then benzenesulfonyl chloride (10.5 ml, 82 mmol) was added dropwise. The reaction mixture was gradually warmed to room temperature and poured into water/methylene chloride The methlene chloride layer was separated, dried (anhydrous Na2So4), filtered and evaporated to give 23.4 gm of crude product. This solid was triturated with diethyl ether and the purified product collected by filtration (18.0 gm), mp 142°-145° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([NH:5][CH2:6][C:7]1[C:8]([F:19])=[CH:9][C:10]([Cl:18])=[C:11]([CH:17]=1)[C:12]([N:14]=[C:15]=[O:16])=O)=[O:4].[F:22][C:23]([F:40])([F:39])[C:24]1[N:29]=[CH:28][C:27]([NH:30][NH:31]C(OC(C)(C)C)=O)=[CH:26][CH:25]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:10]1[C:11]([C:12]2[NH:14][C:15](=[O:16])[N:30]([C:27]3[CH:28]=[N:29][C:24]([C:23]([F:22])([F:39])[F:40])=[CH:25][CH:26]=3)[N:31]=2)=[CH:17][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:21])([F:20])[F:1])=[C:8]([F:19])[CH:9]=1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl
Reactant: CC(C)(C)OC(=O)NNc1ccc(C(F)(F)F)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1cc(-c2nn(-c3ccc(C(F)(F)F)nc3)c(=O)[nH]2)c(Cl)cc1F)C(F)(F)F
Yield: 47.9 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzoyl isocyanate (Intermediate-69, 0.350 g), tert-butyl 2-[6-(trifluoromethyl)pyridin-3-yl]hydrazinecarboxylate (Intermediate-61, 0.350 g), DCM (20 mL) and TFA (5.0 mL) to afford 0.250 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[C:4]([CH3:11])[CH:3]=1.Cl.[NH2:13][CH2:14][C:15]([NH2:17])=[O:16].[CH2:18](N(CC)CC)[CH3:19]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:10])[NH:13][CH2:14][C:15]([NH2:17])=[O:16])=[C:4]([CH3:11])[CH:3]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:15](=[O:16])[CH2:14][N:13]=[C:9]2[S:10][CH2:18][CH3:19])=[C:4]([CH3:11])[CH:3]=1
Reactant: NCC(N)=O
Reactant: CCN(CC)CC
Reactant: Cc1cc(Cl)ccc1N=C=S
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCSC1=NCC(=O)N1c1ccc(Cl)cc1C
Product: Cc1cc(Cl)ccc1NC(=S)NCC(N)=O

Procedure:
2-[3-(4-Chloro-2-methylphenyl)-thioureido]-acetamide was prepared by the procedure described in Example 11 using 18.36 g of 4-chloro-2-methylphenylisothiocyanate, 11.05 g of glycinamide hydrochloride, 10.1 g of triethyl amine, and 300 mL of chloroform. 21.4 Grams of the desired compound was obtained, m.p. 170°-172° C. (dec.). Mass spectrum (El, M.+) m/z 257/259. 1H-NMR (DMSO-d6 ; 400 MHz) δ9.38 (s, 1H), 7.62 (broad s, 1H), 7.45 (s, 1H), 7.35 (d, 1H), 7.32 (d, 1H), 7.21 (m, 1H), 7.12 (s, 1H), 4.06 (d, 2H), and 2.17 ppm (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]([CH:7]1[CH:12]([CH3:13])[CH2:11][C:10]([OH:19])([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH2:9][CH:8]1[CH3:20])=[O:6])[CH3:3].C1C(=O)N([Br:28])C(=O)C1.S([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>CN(C=O)C.O>[CH3:3][CH:2]([O:4][C:5]([CH:7]1[CH:8]([CH3:20])[CH2:9][C:10]([C:14]2[S:15][C:16]([Br:28])=[CH:17][N:18]=2)([OH:19])[CH2:11][CH:12]1[CH3:13])=[O:6])[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)OC(=O)C1C(C)CC(O)(c2nccs2)CC1C
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)C1C(C)CC(O)(c2ncc(Br)s2)CC1C
Temperature: 55 °C
Yield: 87.3 %

Procedure:
To a solution of the product of Step 2 (2.0 g, 6.7 mmol) in DMF (16 mL) was added NBS (1.38 g, 7.73 mmol) and the resulting solution heated to 55° C. After 60 min the reaction was cooled and a solution of sodium sulfite (500 mg) in water (30 mL) was added followed by EtOAc. The layers were separated, the aqueous layer was back extracted with EtOAc (2×). The combined organics were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography to afford propan-2-yl-4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxy-2,6 dimethylcyclohexanecarboxylate (2.2 g, 5.85 mmol) MS ESI: [M+H]+ m/z 375.9.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](C2C=CC=CC=2)=[CH:4][CH:3]=1.CC[O:16][CH2:17][CH3:18].[Cl:19][S:20]([OH:23])(=O)=[O:21].S(Cl)(Cl)(=O)=O.P([O-])([O-])([O-])=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][C:17]2[CH:18]=[CH:4][C:3]([S:20]([Cl:19])(=[O:23])=[O:21])=[CH:2][CH:7]=2)=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(Oc2ccc(Br)cc2)cc1
Temperature: 25 °C
Yield: 159.9 %

Procedure:
To a solution of 12.45 g (50 mmol) of 4-bromobiphenyl ether in 50 mL of dichloromethane at -5° C. was added 9.9 mL (17.4 g, 150 mmol) of chlorosulfonic acid dropwise. After the addition was complete, the reaction was allowed to warm to room temperature for one hour (needed to completely convert the initially formed sulfonic acid to the sulfonyl chloride). The reaction mixture was added to cold pH 7 phosphate buffer (ca. 0.5M) and twice extracted with 50 mL of dichloromethane. The organic extracts were combined and washed with brine, dried over sodium sulfate, and concentrated. Addition of hexane to the residual syrup and re-concentration gave 13.9 g (80%) of 4-(4-bromophenoxy)benzenesulfonyl chloride as a white powder: mp 80.9° C.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[O:16][C:15](=[O:18])[CH2:14][CH2:13]2.[OH-:20].[K+]>CO>[OH:16][C:17]1[C:8]([O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:19])=[CH:9][CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][C:15]([OH:20])=[O:18]
Reactant: [OH-]
Reactant: Cc1ccccc1Oc1cccc2c1OC(=O)CC2
Agent: [K+]
Solvent: CO
Product: Cc1ccccc1Oc1cccc(CCC(=O)O)c1O
Yield: 17.3 %

Procedure:
A mixture of 8-(o-tolyloxy)chroman-2-one (5.4 g) and potassium hydroxide (2 g) in methanol (50 ml) was refluxed under heating for 30 minutes. After cooling, the reaction mixture was evaporated, and the oily residue was dissolved in water, washed with diethyl ether, acidified with conc. hydrochloric acid and then extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate and evaporated. The residue was recrystallized twice from a mixture of ethyl acetate and n-hexane to give 3-[2-hydroxy-3-(o-tolyloxy)phenyl]propionic acid (1.0 g). mp 106°-107° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=O)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14].Cl.[NH2:24][OH:25]>N1C=CC=CC=1>[F:1][C:2]1[C:3](/[C:15](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:24]\[OH:25])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14]
Reactant: NO
Reactant: Cc1ccncc1-c1ccnc(C(=O)c2ccccc2)c1F
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccncc1-c1ccnc(/C(=N\O)c2ccccc2)c1F
Temperature: 25 °C
Yield: 88.4 %

Procedure:
A solution of (3′-fluoro-4-methyl-3,4′-bipyridin-2′-yl)(phenyl)methanone (0.025 g, 0.086 mmol) and hydroxylamine hydrochloride (0.040 g, 0.582 mmol) in pyridine (Volume: 0.428 ml) was refluxed for 2.5 hr, allowed to cool to room temperature, and then concentrated in vacuo. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed (required a few drops of MeOH). Purification of the crude material by silica gel chromatography using an ISCO machine (4 g column, 18 mL/min, 80-100% EtOAc in hexanes over 10 min, tr=0.3, 1.5, 2 min) gave the title compound (23.7 mg, 0.076 mmol, 89% yield) as a yellow residue. ESI MS (M+H)+=308.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]2([CH3:14])[CH3:13].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22].ClC1C=CC=CC=1Cl>C(OCC)C>[Br-:15].[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N+:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[C:6]([CH3:14])([CH3:13])[C:7]=1[CH3:12])([OH:23])=[O:22]
Reactant: COc1ccc2c(c1)C(C)(C)C(C)=N2
Reactant: O=C(O)CCCCCBr
Solvent: Clc1ccccc1Cl
Solvent: CCOCC
Product: COc1ccc2c(c1)C(C)(C)C(C)=[N+]2CCCCCC(=O)O
Product: [Br-]
Temperature: 100 °C
Yield: 80.9 %

Procedure:
To 5-methoxy-2,3,3-trimethyl-3H-indole (1.9 g) was added 6-bromohexanoic acid (3 g) and 1,2-dichlorobenzene (10 ml). The mixture was heated to 100° C. for 3 hours and then allowed to cool to room temperature. Diethyl ether was added and the precipitated material removed by filtration. Drying in a vacuum oven gave the product (3.12 g).