Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:46]=[CH:47][CH:48]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:33][CH3:34])=[C:25]([NH:27][S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:26]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[C:8]([CH3:45])=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:46]=[CH:47][CH:48]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:33][CH3:34])=[C:25]([NH:27][S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:45])=[N:7]1
Reactant: CCS(=O)(=O)Nc1cc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)ccc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCS(=O)(=O)Nc1cc(-c2cnc3[nH]cc(-c4c(C)nn(Cc5cccc(F)c5)c4C)c3c2)ccc1OC
Yield: 16.5 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxy phenyl)ethane sulfonamide (200 mg, 0.291 mmol) was hydrolyzed by lithium hydroxide (36 mg, 0.87 mmol) in THF/Methanol/Water (10/3/2 ml) to give 25 mg (16.5% yield) after purification by flash chromatography. 1H NMR (DMSO-d6, 300 MHz): δ 11.9 (s, 1H), 9.02 (s, 1H), 8.45 (s, 1H), 7.79 (s, 1H), 7.54-7.49 (m, 3H), 7.19-7.0 (m, 4H), 5.33 (s, 2H), 3.86 (s, 3H), 3.06-3.04 (m, 2H0, 2.17-2.13 (d, 6H), 1.27-1.23 (t, 3H). MS: m/z=534.8 (M+1), HPLC: 90.27% (Method-B).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Si:6]([O:13][C:14]1[C:15]([F:22])=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCl>[Si:6]([O:13][C:14]1[C:15]([F:22])=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1F
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(CN2CCCC2)c1F
Yield: 90.9 %

Procedure:
Pyrrolidine (6.8 mL, 82 mmol) was added to a solution of intermediate 32, 3-{[tert-butyl(dimethyl)silyl]oxy}-2-fluorobenzaldehyde (16.7 g, 66 mmol) in dichloromethane (200 mL). The reaction mixture was cooled on ice bath, and sodium triacetoxyborohydride (17.4 g, 82 mmol) was added in portions under stirring. The reaction mixture was intensively stirred for 12 h at RT. Water (100 mL) was added. The organic layer was separated. The aqueous one was extracted with CH2Cl2 (2×100 mL). The organic layer was washed with brine, dried over Na2SO4 and evaporated in vacuo to give the title compound (19 g, 94%, 60 mmol). 1H NMR data (DMSO-d6): 6.92-7.03 (m, 2H, H—Ar), 6.83-6.91 (m, 1H, H—Ar), 3.58 (d, 2H, J=1.7 Hz, Ar—CH2); 2.38-2.46 (m, 4H), 1.63-1.70 (m, 4H) 0.97 (s, 9H, t-Bu), 0.16 (s, 6H, 2CH3).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([Cl:9])[CH:3]=1.C(OC([NH:17][C@@H:18]([C@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:23])[C:19](O)=[O:20])=O)(C)(C)C.O(Cl)Cl.FC(F)(F)C(O)=O>N1C=CC=CC=1>[NH2:17][C@@H:18]([C@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:23])[C:19]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[Cl:9])=[O:20]
Reactant: Nc1ccc(Br)cc1Cl
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: ClOCl
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: C[C@@H](c1ccccc1)[C@H](N)C(=O)Nc1ccc(Br)cc1Cl
Temperature: -20 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
4-Bromo-2-chloro-aniline (325 mg, 1.58 mmol) and (S,S)-2-tert-butoxycarbonylamino-3-phenyl-butyric acid (440 mg, 1.58 mmol) in pyridine (5 mL) were cooled to −30° C. Phosporus oxychloride (0.158 mL, 1.7 mmol) was added and stirred at −20° C. for 2 hours. The mixture was poured into ice water and extracted with ethyl acetate (3×). The combined organic extracts were washed with water, brine, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in dichloromethane (5 mL) at 0° C. and trifluoroacetic acid (3 mol) added. Stirring was continued for 2 hours at 0° C. The mixture was evaporated and the residue dissolved in ether. The ether solution was basified with saturated aqueous sodium bicarbonate and extracted with ether. The organic extracts were washed with brine, dried over sodium sulfate and evaporated to give (2S,3S)-2-amino-N-(4-bromo-2-chloro-phenyl)-3-phenyl-butyramide (325 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH3:20])[CH:13]=2)[C:6]=1[CH2:7][C:8]([OH:10])=[O:9].C[Si](I)(C)C>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH3:20])[CH:13]=2)[C:6]=1[CH2:7][C:8]([OH:10])=[O:9]
Reactant: COc1ccc(Cn2c(-c3ccccc3)nc(Cl)c2CC(=O)O)cc1C
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: Cc1cc(Cn2c(-c3ccccc3)nc(Cl)c2CC(=O)O)ccc1O
Temperature: 90 °C
Reaction time: 48 h
Yield: 57.2 %

Procedure:
4-Chloro-1-(4-methoxy-3-methylbenzyl)-2-phenylimidazole-5-acetic acid (2 g) was suspended in 150 ml of acetonitrile, and 4 ml of trimethylsilyl iodide was added. The mixture was stirred in an argon stream at 90° C. for 48 hours. The reaction mixture was concentrated to dryness and the residue was shaken with 100 ml each of chloroform and water. The chloroform layer was washed with water and dried under reduced pressure. The residue was purified by column chromatography using 100 g of silica gel and recrystallization from acetone-diethyl ether to give 1.1 g of 4-chloro-1-(4-hydroxy-3-methylbenzyl)-2-phenylimidazole-5-acetic acid as colorless needles, m.p. 193°-195° C. (decompn.).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@H:13]([C:18]([NH:20][CH:21]([CH:30]([OH:33])[CH2:31][F:32])[CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16].[C:34]1([C:40]2[CH:50]=[CH:49][CH:48]=[CH:47][C:41]=2[O:42][CH2:43][C:44](O)=[O:45])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:34]1([C:40]2[CH:50]=[CH:49][CH:48]=[CH:47][C:41]=2[O:42][CH2:43][C:44]([NH:12][C@H:13]([C:18]([NH:20][CH:21]([C:30](=[O:33])[CH2:31][F:32])[CH2:22][C:23]([OH:25])=[O:24])=[O:19])[CH2:14][CH:15]([CH3:16])[CH3:17])=[O:45])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)C[C@H](N)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Reactant: O=C(O)COc1ccccc1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)C[C@H](NC(=O)COc1ccccc1-c1ccccc1)C(=O)NC(CC(=O)O)C(=O)CF

Procedure:
Starting with (3RS,4RS)-3-(leucinyl)amino-5-fluoro-4-hydroxypentanoic acid, tert-butyl ester, p-toluenesulfonate salt and following the methods described in Example 53, Parts C through E utilizing (2-phenylphenoxy)acetic acid in place of (1-naphthyloxy)acetic acid in Part C, gave the title compound as a white solid. MS(ES) for C25H29FN2O6 (MW 472.51): positive 495(M+Na), 511(M+K); negative 471(M−H), 585(M+TFA).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[F:9].C([N-]C(C)C)(C)C.[Li+].B(OC)(OC)[O:19]C.C(OO)(=O)C>O1CCCC1.O>[Br:1][C:2]1[C:3]([F:9])=[C:4]([OH:19])[C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: Fc1cc(Cl)ccc1Br
Reactant: COB(OC)OC
Agent: CC(=O)OO
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Oc1c(Cl)ccc(Br)c1F
Temperature: -20 °C
Yield: 63 %

Procedure:
A solution of 1-bromo-4-chloro-2-fluorobenzene (20.4 g, 0.100 mol) in tetrahydrofuran (THF; 50 mL) was slowly added to lithium diisopropylamide (LDA; 0.125 mol) in THF (600 mL) at −50° C. After addition, the solution was warmed to −20° C. and then cooled to −50° C. A solution of trimethyl borate (13.5 g, 0.130 mol) in THF (20 mL) was added slowly and the temperature was warmed to −20° C. The mixture was then cooled to −70° C. and a solution of peracetic acid (32% in acetic acid, 0.150 mol) was slowly added and the mixture was warmed to ambient temperature. Water (250 mL) was added and the solution was extracted with ethyl acetate (2×200 mL). The combined organic phases were dried and concentrated. The black oil was purified by column chromatography (20% ethyl acetate in hexanes) to give 3-bromo-6-chloro-2-fluorophenol (14.1 g, 0.063 mol) 1H NMR (CDCl3): δ 7.05 (m, 2H), 5.5 (br s, 1H).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1I)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:3][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[NH:4][CH:1]=1
Reactant: C=CCNc1ccc(C(F)(F)F)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: Cc1c[nH]c2ccc(C(F)(F)F)cc12
Temperature: 80 °C
Yield: 37.6 %

Procedure:
A mixture of allyl-(2-iodo-4-trifluoromethyl-phenyl)-amine (1.75 g, 5.35 mmol), tetrabutylammonium chloride (1.68 g, 5.35 mmol), palladium acetate (120 mg, 0.54 mmol) and potassium carbonate (2.22 g, 16.0 mmol) in DMF (50 mL) is heated at 80° C. for 1.5 h. The reaction is quenched with water and extracted three times with DCM. The combined organic layer is dried (Na2SO4), filtered and concentrated. The residue is chromatographed through silica gel eluting with 0-40% EtOAc in heptane to afford 3-methyl-5-trifluoromethyl-1H-indole (401 mg). 1H NMR (300 MHz, CDCl3): δ=8.09 (broad s, 1H), 7.90 (s, 1 H), 7.44 (s, 1H), 7.10 (s, 1H), 2.38 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][N:12]=1)[C:7]([NH2:9])=[O:8])([O-:3])=[O:2].[CH:13]([N:16]=[C:17]=[O:18])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[CH:13]([NH:16][C:17](=[O:18])[NH:9][C:7]([C:6]1[CH:10]=[CH:11][N:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:8])([CH3:15])[CH3:14]
Reactant: CC(C)N=C=O
Reactant: NC(=O)c1ccnc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: CC(C)NC(=O)NC(=O)c1ccnc([N+](=O)[O-])c1

Procedure:
To 30 ml. of toluene were added 0.8 g of 2-nitroisonicotinamide and 1.7 g. of isopropyl isocyanate, and the mixture was refluxed for 6 hours. The reaction mixture was cooled and filtered removing 0.4 g. of the insoluble starting material. The filtrate was concentrated, and the residue was purified by silica gel chromatography and recrystallized from ethyl acetate - n-hexane to yield 0.08 g. of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1N.[Na+].[Br-:11].Br.N([O-])=O.[Na+]>[O-]S([O-])(=O)=O.[Cu+2].O>[Br:11][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:2]=1[Cl:1]
Reactant: [Br-]
Reactant: Nc1cccc(Cl)c1Cl
Agent: [Cu+2]
Agent: Br
Agent: O=N[O-]
Solvent: O
Product: Clc1cccc(Br)c1Cl
Temperature: 35 °C
Reaction time: 0.25 h
Yield: 97.4 %

Procedure:
32.7 g 2,3-Dichloroaniline (0.20 mole) is added to a mixture of 21.4 g of NaBr (0.20 mole, 1.0 equivalent), 110.0 g of 48% aqueous HBr (0.66 mole, 3.3 equivalents) and 70 ml water at 30-40° C. The mixture is stirred for 15 minutes at 30-40° C. and then heated to 45° C. Then 5.1 g CuSO4*5H2O (0.02 mole, 0.10 equivalent) is added and the mixture is stirred for 15 minutes at 45° C. After this, an aqueous solution of NaNO2 (40% solution in water, 37.6 g, 0.22 mole, 1.1 equivalents) is added via subsurface feeding over a period of 2 hours at 45° C. The reaction mixture is stirred for 30 minutes at 45° C. After this, the reaction mixture is heated to 60-65° C. The organic phase containing the reaction product is separated from the aqueous phase and is cooled to ambient temperature, leading to solidification of the reaction product. The remaining liquid is discarded and the crude product is washed twice with 10 ml water and dried under vacuum. 44.0 g (83% of theory) of 1-bromo-2,3-dichlorobenzene is obtained in the form of a light brown solid (purity: 85%).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)Cl.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl.[CH3:28][NH:29][O:30][CH3:31]>CN(C=O)C>[CH3:31][O:30][N:29]([CH3:28])[C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([CH3:11])=[N:10][C:2]=1[CH3:1]
Reactant: Cc1ccc(C(=O)O)c(C)n1
Reactant: CNOC
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(C)nc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a flask containing 2,6-dimethylnicotinic acid (2.80 g, 18.5 mmol) was added CH2Cl2 and DMF (6 mL). The suspension was stirred at room temperature as carbonyl diimidazole (3.50 g, 21.6 mmol) was added. The suspension remained throughout the day and was allowed to stir overnight at room temperature. After 18 hours, N,O-dimethylhydroxylamine hydrochloride (3.00 g, 30.8 mmol) was introduced and the mixture was stirred at room temperature again for 24 hours. The reaction mixture was quenched with water and 1 N NaOH, and extracted with CH2Cl2 (4×50 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to give a colorless oil. Flash chromatography on silica gel (50% EtOAc-hexane) afforded the title compound as a colorless oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:22])[CH:7]=[C:8]([Br:21])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH:18]([CH3:20])[CH3:19])[CH:12]=1.ClC1C=CC(S(O[CH2:34][P:35](=[O:40])([O:38][CH3:39])[O:36][CH3:37])(=O)=O)=CC=1>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([Br:21])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH:18]([CH3:20])[CH3:19])[CH:12]=1)[O:22][CH2:34][P:35](=[O:40])([O:38][CH3:39])[O:36][CH3:37]
Reactant: COP(=O)(COS(=O)(=O)c1ccc(Cl)cc1)OC
Reactant: CC(C)c1cc(Oc2c(Br)cc(O)cc2Br)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COP(=O)(COc1cc(Br)c(Oc2ccc(O)c(C(C)C)c2)c(Br)c1)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring mixture of DMF (20.0 mL) and NaH (0.074 g, 1.86 mmol) at 0° C. was added 3,5-dibromo-4-(3-isopropyl-4-hydroxy-phenoxy)phenol (Intermediate for the synthesis of compound 8-1, 0.75 g, 1.86 mmol) dissolved in DMF (2.0 mL). The reaction mixture was allowed to stir at rt for 1 hr and cooled to 0° C. Dimethyl 4-chloro-benzenesulfonyloxymethylphosphonate (0.11 g, 0.36 mmol) was added and the reaction mixture was stirred at rt for 16 h. The reaction was quenched with ice H2O, the pH was adjusted to 1 with 2 M HCl, and the mixture was partitioned with ethyl acetate and H2O. The organic layer was concentrated and coevaporated with acetone (2×). The residue was treated with a hexane/ethyl acetate mixture and sonicated to afford dimethyl [3,5-dibromo-4-(4-hydroxy-3-iso-propyl-phenoxy)phenoxy]methylphosphonate as a white solid precipitate (0.070 g, 34%): 1H NMR (200 MHz, DMSO-d6): δ 9.00 (s, 1H), 7.47 (s, 2H), 6.65 (m, 2H), 6.23 (m, 1H), 4.60 (d, J=10.0 Hz, 2H), 3.75 (d, J=10.0 Hz, 6H), 3.12 (m, 1H), 1.09 (d, J=6.0 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate; Rf=0.60
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O-])=[O:15])=[CH:12][N:11]=[CH:10][C:9]=2[F:17])=[C:4]([F:18])[CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([F:17])=[CH:10][N:11]=[CH:12][C:13]=2[CH2:14][OH:15])=[C:4]([F:18])[CH:3]=1
Reactant: O=C([O-])c1cncc(F)c1-c1ccc(Cl)cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cncc(F)c1-c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a solution of 4-(4-chloro-2-fluorophenyl)-5-fluoronicotinate (300 mg, 1.058 mmol) in tetrahydrofuran (7 mL) cooled to 0° C. was added LAH (0.441 mL, 1.058 mmol) in THF dropwise and the solution was stirred for 30 min. The reaction was then warmed to room temperature and stirred for 12 h. The reaction was quenched with saturated aqueous ammonium chloride (5 mL) and extracted with ethyl acetate (2×5 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to afford (4-(4-chloro-2-fluorophenyl)-5-fluoropyridin-3-yl)methanol (200 mg, 0.782 mmol, 74% yield) as a pale brown oil. LCMS (ESI) m/e 255.9 [(M+H)+, calcd for C12H9ClF2NO 256.0]; LC/MS retention time (Method F): tR=0.89 min.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:20]=C)[CH:18]=3)[N:13]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)[C:12]=2[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:37].[Na+].O>O1CCCC1.[Os](=O)(=O)(=O)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:20]=[O:37])[CH:18]=3)[N:13]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)[C:12]=2[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc2c(c1)c(-c1ccc(C(C)(C)C)cc1)c(C(=O)OCC)n2Cc1cccc(OC)c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(C=O)ccc2n1Cc1cccc(OC)c1
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
Ethyl 3-(4-tert-butylphenyl)-1-(3-methoxybenzyl)-5-vinyl-1H-indole-2-carboxylate (Example 129, 2.28 g, 4.9 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL), and osmium tetroxide (2.5 weight % solution in 2-methyl-2-propanol, 1.5 mL, 0.15 mmol) was added. After ten minutes, the reaction mixture was cooled with an ice bath. Sodium periodate (2.10 g, 9.8 mmol) was added followed by a minimum volume of water to dissolve the solids. The reaction was allowed to return to room temperature, and after 30 minutes, the reaction was partitioned between water and diethyl ether. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated. The resulting crude oil was passed through a pad of silica gel with 20% ethyl acetate/hexane. The filtrate was concentrated in vacuo without heat to provide the title compound as a brown oil (1.70 g, 75%). The product had: 1H NMR (300 MHz, acetone-d6) 10.01 (s, 1 H), 8.15 (d, 1 H), 7.88 (d, 1 H), 7.75 (d, 1 H), 7.54 (d, 2 H), 7.44 (d, 2 H), 7.21-7.19 (m, 1 H), 6.81-6.79 (m, 1 H), 6.72-6.69 (m, 2 H), 5.92 (s, 2 H), 4.12 (q, 2 H), 3.71 (s, 3 H), 1.39 (s, 9 H), 0.78 (t, 3 H).
Reaction SMILES: [OH-].[Li+].[F:3][CH2:4][C:5]1[N:6]([C:17]2[C:26]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:20]([CH3:27])=[CH:19][CH:18]=2)[C:7]([S:10][CH2:11][C:12]([O:14]CC)=[O:13])=[N:8][N:9]=1>C1COCC1.O>[F:3][CH2:4][C:5]1[N:6]([C:17]2[C:26]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:20]([CH3:27])=[CH:19][CH:18]=2)[C:7]([S:10][CH2:11][C:12]([OH:14])=[O:13])=[N:8][N:9]=1
Reactant: CCOC(=O)CSc1nnc(CF)n1-c1ccc(C)c2c1CCCC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-n2c(CF)nnc2SCC(=O)O)c2c1CCCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Lithium hydroxide solution (1M aqueous, 0.59 mL, 0.59 mmol) is added to a solution of ethyl 2-(5-(fluoromethyl)-4-(4-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate (107 mg, 0.294 mmol) in THF/water (3/1, 1.2 mL) and the mixture stirred at room temperature for 18 h. The crude reaction mixture is concentrated, acidified with HCl (1N, 3 mL) and extracted with ethyl acetate (3×3 mL). The combined organic extracts are dried over sodium sulfate, filtered and concentrated to afford 2-(5-(fluoromethyl)-4-(4-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:16][C:17](=[O:19])[CH3:18])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1>C(OCC)(=O)C.C1COCC1.[Pd]>[NH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[S:5][C:4]([NH:16][C:17](=[O:19])[CH3:18])=[N:3][C:2]=2[CH3:1])=[CH:12][CH:11]=1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc([N+](=O)[O-])cc2)s1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(C)c(-c2ccc(N)cc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[4-Methyl-5-(4nitro-phenyl)-thiazol-2-yl]-acetamide (J. Liebscher, E. Mitzner, Synthesis, 1985, (4), p 414) (10.0 g, 3.6 mmol) is dissolved in ethyl acetate/THF (5/1, 600 ml) and stirred at room temperature under an atmosphere of argon. The solution is then treated with 10% palladium on carbon (10 g). The reaction mixture is purged three times with nitrogen and placed under an atmosphere of hydrogen overnight. The mixture is then filtered through Celite™ filter material and the catalyst is washed with tetrahydrofuran (600 ml). The solvent is removed in vacuo to leave N-[5-(4-amino-phenyl)4-methyl-thiazol-2-yl]-acetamide as an off-white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.ClC1[S:12][C:13]([N+:17]([O-:19])=[O:18])=[C:14]([Cl:16])[N:15]=1.O>C(#N)C>[Cl:16][C:14]1[N:15]=[C:1]([N:2]([CH3:9])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[S:12][C:13]=1[N+:17]([O-:19])=[O:18]
Reactant: CN(C)c1ccccc1
Reactant: O=[N+]([O-])c1sc(Cl)nc1Cl
Solvent: O
Solvent: CC#N
Product: CN(c1ccccc1)c1nc(Cl)c([N+](=O)[O-])s1
Yield: 95.7 %

Procedure:
12.7 g (0.105 mol) of N,N-dimethylaniline are added to a solution of 19.9 g (0.1 mol) of 2,4-dichloro-5-nitrothiazole in 250 ml of acetonitrile and the reaction mixture is stirred under reflux for 75 hours The solvent is then stripped off in vacuo and the solid residue is stirred into water, filtered off, washed with water and dried. 25.8 g (95.7% of theory) of 4-chloro-2-(N-methyl-N-phenylamino)-5-nitrothiazole are obtained. The compound can be recrystallized from cyclohexane and can be sublimed at about 110° C. to 120° C./0.1 mbar. Melting point 136° C. to 137° C.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:5][CH2:4]1.[H-].[Na+].I[CH2:24][CH2:25][OH:26]>O1CCCC1>[CH3:1][N:2]([CH3:20])[CH:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH2:24][CH2:25][OH:26])[C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:5][CH2:4]1
Reactant: CN(C)C1CCC(NC(=O)OCc2ccccc2)CC1
Reactant: OCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C1CCC(N(CCO)C(=O)OCc2ccccc2)CC1
Temperature: 2.5 °C
Yield: 150.9 %

Procedure:
To a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added a solution of benzyl N-[4-(dimethylamino)cyclohexyl]carbamate (2 g, 7.24 mmol, 1.00 equiv) in tetrahydrofuran (20 mL). This was followed by the addition of a solution of sodium hydride (320 mg 60% W/W, 7.971 mmol, 1.1 equiv) in tetrahydrofuran (10 mL) dropwise with stirring at 0-5° C. The resulting solution was stirred for 2 h at room temperature. To this was added 2-iodoethan-1-ol (2.5 g, 14.54 mmol, 2.01 equiv) dropwise with stirring at 0-5° C. The resulting solution was allowed to react, with stirring, for an additional 4 days at room temperature. The reaction was then quenched by the addition of 10 mL of water and concentrated under vacuum. The residue was washed with a solution of dichloromethane/methanol (10:1, 20 mL×4) and the organic layers combined, dried and concentrated to give 3.5 g (crude) of benzyl N-[4-(dimethylamino)cyclohexyl]-N-(2-hydroxyethyl)carbamate as a yellow oil. MS: m/z 321 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:9]=[C:8]([CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:27]([N:29]3[CH2:34][CH2:33][S:32][CH2:31][CH2:30]3)=[O:28])[CH2:11]2)[O:7][N:6]=1)([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:43])C=1>>[CH:1]([O:4][C:5]1[N:9]=[C:8]([CH:10]2[CH2:15][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[CH:20][CH:21]=3)[CH2:13][N:12]([C:27]([N:29]3[CH2:34][CH2:33][S:32](=[O:43])[CH2:31][CH2:30]3)=[O:28])[CH2:11]2)[O:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CC(C)Oc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCS(=O)CC3)C2)n1

Procedure:
170 mg (0.340 mmol) of the compound from Example 33 were reacted according to General Method 2 with 117 mg (0.340 mmol) of meta-chloroperbenzoic acid. Yield: 44.8 mg (26% of theory).