Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[C:10](=[O:14])/[CH:11]=[CH:12]/[CH3:13]>O1CCOCC1>[CH3:1][C:2]12[C:12]([CH3:13])=[CH:11][C:10](=[O:14])[CH:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH:6]=[CH:7]2
Reactant: C/C=C/C(=O)C1=C(C)C=CCC1(C)C
Solvent: C1COCCO1
Product: CC1=CC(=O)C2C(C)(C)CC=CC12C

Procedure:
A solution of 2,6,6-trimethyl-1-crotonoyl-1,3-cyclohexadiene (1.0 g.) in 10 ml. of dioxan was heated under the same conditions as described in Example 49 with acidic diatomaceous earth (0.2 g.).
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([O:12]C)=[O:11])[CH2:6][C@H:5]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N+:2]=[N-:3].[OH-].[Li+].O>O1CCCC1>[N:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([OH:12])=[O:11])[CH2:6][C@H:5]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N+:2]=[N-:3]
Reactant: COC(=O)[C@H]1CC[C@H](N=[N+]=[N-])[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](C(=O)O)CC[C@@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 36.5 h

Procedure:
(1S,2R,4S)-1-Azido-2-(N-tert-butoxycarbonylamino)-4-methoxycarbonylcyclohexane (509 mg) was dissolved in tetrahydrofuran (40.0 ml), lithium hydroxide (111 mg) and water (5.0 ml) were successively added under ice cooling, and the mixture was stirred at room temperature for 36.5 hours. The solvent was distilled off under reduced pressure, water and 1N hydrochloric acid (4.64 ml) were added to the residue, and the solvent was distilled off again under reduced pressure to obtain crude (1S,2R,4S)-1-azido-2-(N-tert-butoxycarbonylamino)-4-carboxycyclohexane. Dichloromethane (25 ml) and N,N-dimethylformamide (260 μl) were added to this crude product, and the mixture was stirred under ice cooling. Further, oxalyl chloride (216 μl) was added to continuously stir the mixture at room temperature for 1 hour. tert-Butylamine (1130 μl) was added to the reaction mixture under ice cooling to stir the mixture at room temperature for 14 hours. After water and dichloromethane were added to the reaction mixture to conduct liquid separation, the resultant organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane:ethyl acetate=2:1) to obtain the title compound (197 mg) as a pale yellow amorphous substance.
Reaction SMILES: [CH2:1]([N:8](C)[CH2:9][CH2:10][O:11][CH2:12][CH:13]1[CH2:20][N:19]2[C:21]3[CH:22]=[C:23]([C:34]([NH:36][S:37]([N:40]([CH2:42][CH:43]([O:46][CH3:47])[O:44][CH3:45])[CH3:41])(=[O:39])=[O:38])=[O:35])[CH:24]=[CH:25][C:26]=3[C:27]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[C:18]2[C:17]2[CH:48]=[CH:49][CH:50]=[CH:51][C:16]=2[O:15][CH2:14]1)C1C=CC=CC=1.CC(O)=O>CO.[Pd]>[CH:28]1([C:27]2[C:26]3[CH:25]=[CH:24][C:23]([C:34]([NH:36][S:37]([N:40]([CH2:42][CH:43]([O:46][CH3:47])[O:44][CH3:45])[CH3:41])(=[O:39])=[O:38])=[O:35])=[CH:22][C:21]=3[N:19]3[C:18]=2[C:17]2[CH:48]=[CH:49][CH:50]=[CH:51][C:16]=2[O:15][CH2:14][CH:13]([CH2:12][O:11][CH2:10][CH2:9][NH:8][CH3:1])[CH2:20]3)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: COC(CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(COCCN(C)Cc1ccccc1)COc1ccccc1-3)OC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CNCCOCC1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)N(C)CC(OC)OC)cc3n2C1
Reaction time: 12 h

Procedure:
A solution of (7R or 7S)-7-({2-[benzyl(methyl)amino]ethoxy}methyl)-14-cyclohexyl-N-{[(2,2-dimethoxyethyl)(methyl)amino]sulfonyl}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxamide in MeOH (0.06 M) was treated with AcOH (1 eq) and Pd/C (2 eq). The resulting mixture was stirred for 12 h under an H2 atmosphere. The mixture was filtered and then concentrated in vacuo to afford the title compound. The crude material was used in the next step without further purification. (ES+) m/z 643 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([N+:32]([O-])=O)[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][C:22]4=[O:27])=[CH:16][CH:15]=3)[S:13][C:6]=12.[NH4+].[Cl-]>CO.O.[Zn]>[NH2:32][C:30]1[CH:29]=[CH:28][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[N:19]=[CH:18][C:17]([CH2:20][N:21]5[CH2:26][CH2:25][O:24][CH2:23][C:22]5=[O:27])=[CH:16][CH:15]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:31]=1
Reactant: O=C1COCCN1Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCOCC5=O)cn4)sc23)c(F)c1
Yield: 51.4 %

Procedure:
To a suspension of 121 (135 mg, 0.281) in MeOH (10 mL) was added Zinc powder (184 mg, 2.81 mmol) and NH4Cl (60.1 mg, 1.124 mmol) in water (1 mL) and the reaction mixture was stirred at reflux for 5 hours then stirred at RT for 2 days. The mixture was filtered, concentrated, dissolved in DCM and MeOH and the resultant solution was then washed with water. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated. The resultant solid 122 (65 mg, 51% yield) was used directly in the next step with no additional purification. MS (m/z)=451.49 (M+H)
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[C:19]3[C:27](=[O:37])[N:28](C(OC(C)(C)C)=O)[CH2:29][C:18]=3[C:17]=2[F:38])[CH2:13][CH2:12][O:11][CH2:10]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[C:19]3[C:27](=[O:37])[NH:28][CH2:29][C:18]=3[C:17]=2[F:38])[CH2:13][CH2:12][O:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2cccs2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1COCC[C@H]1Nc1nc(-c2cccs2)c2c(c1F)CNC2=O
Yield: 83.5 %

Procedure:
A solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-7-fluoro-3-oxo-4-(thiophen-2-yl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (30 mg, 0.055 mmol) in TFA/DCM (1:1, 10 mL) was stirred at RT for 2 h. The solvent was removed and the resulting crude material was reconstituted in MeOH/DCM (20 mL) and purified via preparative HPLC. The collected fractions were combined and stripped to dryness via rotary evaporation to yield the title compound (16 mg, 85%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.79 (d, J=9.76 Hz, 1 H), 2.12 (qd, J=12.94, 5.13 Hz, 1 H), 3.56-3.68 (m, 1 H), 3.75 (d, J=11.72 Hz, 1 H), 3.89 (br s, 1 H), 4.02 (d, J=11.72 Hz, 2 H), 4.28-4.37 (m, 1 H), 4.38-4.49 (m, 2 H), 7.10-7.20 (m, 1 H), 7.28 (d, J=4.88 Hz, 1 H), 7.59-7.70 (m, 1 H), 7.93 (br s, 2 H), 8.52 (s, 1 H), 9.02 (dd, J=3.91, 0.98 Hz, 1 H). [M+H] calc'd for C16H17FN4O2S, 349; found, 349.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:32])[CH2:16][O:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][N:20]3C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1>C(OCC)(=O)C.C(OCC)C>[ClH:1].[ClH:1].[ClH:1].[CH3:2][N:3]1[CH2:4][CH2:5][CH:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:32])[CH2:16][O:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][NH:20]3)[CH2:11][CH2:10]2)[CH2:7][CH2:8]1
Reactant: CN1CCC(N2CCN(C(=O)COCC3CCCCN3C(=O)OC(C)(C)C)CC2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CN1CCC(N2CCN(C(=O)COCC3CCCCN3)CC2)CC1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
Hydrogen chloride (26.0 ml, 52.10 mmol, 2 M solution in diethyl ether) was added at room temperature to a solution of tert-butyl 2-((2-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-2-oxoethoxy)methyl)piperidine-1-carboxylate (4.57 g, 10.42 mmol) in a mixture of ethyl acetate (15 ml) and diethyl ether (50 ml). The reaction mixture was stirred for 2 h at 45° C. Then the resulting white solid was filtered off and dried.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([C:9](Cl)=[O:10])=[CH:7][N:6]=[CH:5][CH:4]=1.[CH3:12][NH2:13]>C1COCC1>[Cl:2][C:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:8]=1[C:9]([NH:13][CH3:12])=[O:10]
Reactant: O=C(Cl)c1cnccc1Cl
Reactant: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)c1cnccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
To a suspension of crude 4-chloronicotinoyl chloride hydrochloride in 25 mL of THF was added methylamine solution (2M in THF, 20 mL, 40 mmol, 4.0 eq) at 0° C. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The crude material was dissolved in ethylacetate (75 mL) and water/brine/saturated sodium bicarbonate solution (1/1/1, 75 mL). The separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with water/brine/saturated sodium bicarbonate solution (1/1/1, 25 mL) and brine (25 mL) and dried over sodium sulfate. Removal of the solvent under reduced pressure afforded the title compound as orange solid (400 mg, 24%), which was used without further purification. MH+=171.0, Rt=0.55 min.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]([CH2:20][C:21]([OH:23])=[O:22])[O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C[O-].[Na+:26].CO.CCOC(C)=O>CO>[O:1]=[C:2]1[NH:3][C:4]2[C:9](/[C:10]/1=[C:11]1\[O:12][CH:13]([CH2:20][C:21]([O-:23])=[O:22])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]\1=3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Na+:26]
Reactant: O=C(O)CC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C([O-])CC1O/C(=C2/C(=O)Nc3ccccc32)c2ccccc21
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a slurry of [3-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-yl]-acetic acid (430 mg, 1.40 mmol) in MeOH (100.0 ml) at room temperature was added 0.5M NaOMe/MeOH (2.80 ml). The solution was rapidly stirred for 15 minutes and then rotary evaporated (combined 116 mg of product obtained from previously run reaction). The solid was chased with MeOH (20 ml), and then with EtOAc (2×15 ml) to give sodium [(3E)-3-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)-1,3-dihydro-2-benzofuran-1-yl]acetate as a yellow solid (576 mg, 100%).
Reaction SMILES: C(OC(N=NC(OCC)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:32][C:33]([F:43])([F:42])[C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36]O.[NH:44]=[N+:45]=[N-:46]>C1(C)C=CC=CC=1>[F:32][C:33]([F:43])([F:42])[C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][N:44]=[N+:45]=[N-:46]
Reactant: [N-]=[N+]=N
Reactant: OCc1ccccc1C(F)(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NCc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
First a solution of 17.4 g (0.1 mol) of azodicarboxylic acid diethyl ester in 50 ml of toluene is added dropwise at 10°-20° to a solution of 26.2 g (0.1 mol) of triphenylphosphine in 260 ml of toluene and then, at 5°-10°, a solution of 17.6 g (0.1 mol) of o-trifluoromethylbenzyl alcohol in 120 ml of a 1N solution of hydrazoic acid in toluene is added dropwise thereto and the whole is stirred at room temperature for 2 hours. The precipitated hydrazinodicarboxylic acid ester is filtered off with suction, the toluene solution is concentrated by evaporation and the residue is treated with cyclohexane. The cyclohexane solution is decanted off from the insoluble portions, filtered through a small amount of silica gel and concentrated by evaporation at 50° in vacuo. In this manner o-trifluoromethylbenzyl azide is obtained in the form of a colourless liquid.
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N:11]([S:13]([C:16]2[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH3:12])[C:3]=1[CH3:23].[OH:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([C:32]1[O:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[CH:36]=1)=[O:31]>>[O:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[CH:36]=[C:32]1[C:30]([NH:29][CH2:28][CH2:27][CH2:26][CH2:25][O:24][C:19]1[CH:18]=[CH:17][C:16]([S:13]([N:11]([CH3:12])[C:4]2[C:3]([CH3:23])=[CH:2][CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])(=[O:14])=[O:15])=[CH:21][CH:20]=1)=[O:31]
Reactant: O=C(NCCCCO)c1cc2ccccc2o1
Reactant: Cc1ccc(C(=O)O)c(N(C)S(=O)(=O)c2ccc(F)cc2)c1C
Product: Cc1cccc(C(=O)O)c1N(C)S(=O)(=O)c1ccc(OCCCCNC(=O)c2cc3ccccc3o2)cc1
Yield: 51 %

Procedure:
The product of Example 2 (0.40 g, 1.24 mmol) was coupled to N-(4-hydroxybutyl)-1-benzofuran-2-carboxamide, prepared according to Example 17, (0.29 g, 1.24 mmol) using the procedure of Example 3 to provide 0.34 g (51% yield) of an off white powder. MP>200° C.; 1H NMR (DMSO-d6): δ 1.35-1.62 (m, CH2, CH2), 1.9 (s, CH3), 3.20 (s, CH3), 3.32-3.41 (m, CH2, CH2), 7.0-7.1 (m, 4 Ar H), 7.35 (t, 1 Ar H), 7.45 (t, 1 Ar H), 7.54 (s, 1 Ar H), 7.65 (d, 1 Ar H), 7.77 (d, 1 Ar H), 7.92 (m, 3 Ar H) 8.8 (t, NH), Electrospray Mass Spec: m/z 537.2 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:24][CH2:23][N:11]2[C:12](=[O:22])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[Cl:21])=O)(C)(C)C.Cl>>[ClH:21].[Cl:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[C:18]2[C:13]=1[C:12](=[O:22])[N:11]1[CH2:23][CH2:24][NH:8][CH2:9][C@H:10]12
Reactant: COc1cc(Cl)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C2=O
Agent: Cl
Product: COc1cc(Cl)c2c(c1)[C@@H]1CNCCN1C2=O
Reaction time: 0.02 h

Procedure:
To N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-chloro-9-methoxy-pyrazino[2,1-a]isoindol-6(2H)-one (16 mg, 0.05 mmol) was added concentrated aqueous hydrochloric acid (1 mL, 12N). After 1 min, the solution was concentrated, diluted with water, and lyopholized to give a white solid (13 mg, quant). MS (ESI) 253.2, 255.2 (M−Cl).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:18])[C:6]([F:17])([F:16])[CH2:7][C:8]1[N:9]=[C:10]([N+:13]([O-:15])=[O:14])[NH:11][CH:12]=1.N1C=CC=CC=1.Cl[C:26]([O:28][CH3:29])=[O:27]>C(Cl)(Cl)Cl>[N+:13]([C:10]1[NH:11][CH:12]=[C:8]([CH2:7][C:6]([F:17])([F:16])[C:5]([NH:4][CH2:3][CH2:2][O:1][C:26]([O:28][CH3:29])=[O:27])=[O:18])[N:9]=1)([O-:15])=[O:14]
Reactant: O=C(NCCO)C(F)(F)Cc1c[nH]c([N+](=O)[O-])n1
Reactant: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)OCCNC(=O)C(F)(F)Cc1c[nH]c([N+](=O)[O-])n1

Procedure:
3-(2'-Nitroimidazolyl)-2,2-difluoropropionic acid hydroxyethylamide (6.0 g, 22.7 mmol) was dissolved in a solvent mixture of methyl chloroformate (30 ml) and chloroform (30 ml) and cooled by ice. To the solution, a solution of pyridine (6.0 ml) in chloroform (30 ml) was dropwise added over 2 hours. The completion of the reaction was confirmed by thin-layer chromatography. Then, the reaction solution was washed with dilute hydrochloric acid and water, dried over magnesium sulfate, concentrated and subjected to silica gel column chromatography to obtain methyl 3-(2'-nitroimidazolyl)-2,2-difluoropropionamidoethoxyformate (6.89 g). m.p. 50.5°-52.5° C.
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]([CH3:30])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][C:9]=1[CH3:29])[CH3:6])C.[OH-].[Na+]>C1COCC1.CO>[CH3:30][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[O:20][C:21]=2[CH3:22])=[CH:10][C:9]=1[CH3:29])([CH3:6])[C:4]([OH:31])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCCc2nc(-c3ccccc3)oc2C)ccc1OC(C)(C)C(=O)O
Temperature: 55 °C

Procedure:
A solution of 2-methyl-2-{2-methyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}propionic acid ethyl ester (5.00 g, 11.8 mmol) in THF (30 mL) and MeOH (60 mL) was treated with 5N aqueous NaOH (20 mL). The solution was heated at 55° C. for 1 h, cooled to ambient temperature, and concentrated in vacuo. The residue was treated with ice water (20 mL), acidified with 5N aqueous HCl (25 mL), and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (40 mL), dried (Na2SO4), and concentrated to a white solid (4.46 g, 96%): mp 117° C.; 1H NMR (400 MHz, CDCl3) δ 1.53 (s, 6H), 2.19 (s, 3H), 2.38 (s, 3H), 2.98 (t, 2H, J=6.6 Hz), 4.15 (t, 2H, J=6.6 Hz), 6.58 (dd, 1H, J=3.4, 8.8 Hz), 6.70 (d, 1H, J=2.9 Hz), 6.80 (d, 1H, J=8.8 Hz), 7.38-7.45 (m, 3H), 7.97-8.00 (m, 2H); MS (FIA) m/e 394.2 [M−1].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:37]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][Cl:37])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(OCc2ccccc2)cn1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: ClCc1ccc(OCc2ccccc2)cn1
Temperature: 25 °C

Procedure:
To a carbon tetrachloride (10 mL) solution of (5-benzyloxy-pyridin-2-yl)-methanol (500 mg) described in Manufacturing Example 127-1-2 was added triphenylphosphine (791 mg), which was refluxed for 19 hours and 35 minutes under nitrogen atmosphere. The reaction mixture was cooled to room temperature and then concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=3:1) to obtain the title compound (386 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]Br)=[C:6]([Cl:10])[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[Cl:13].[OH2:14]>CN(C=O)C>[Cl:1][C:2]1[C:7]([CH2:8][OH:14])=[C:6]([Cl:10])[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[Cl:13]
Reactant: Clc1c(Cl)c(Cl)c(CBr)c(Cl)c1Cl
Reactant: O
Solvent: CN(C)C=O
Product: OCc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl

Procedure:
A solution of 20.7 g of pentachlorobenzyl bromide in 300 ml DMF containing 30 ml of water was heated at reflux for two hours. On dilution with water solids precipitated. The solid was filtered out and washed on the filter until the wash water was free of bromide ions. On drying, 15.2 g of pentachlorobenzyl alcohol of m.p. 193°-195° C. were obtained.
Reaction SMILES: [CH:1]([C:4]1[C:12]([C:13](=[O:26])[CH:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][C:16]([O:18]C)=[O:17])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].C(O)C.[OH-].[Na+].Cl>O>[CH:1]([C:4]1[C:12]([C:13](=[O:26])[CH:14]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:15][C:16]([OH:18])=[O:17])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)CC(C(=O)c1c(C(C)C)nn2ccccc12)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1nn2ccccc2c1C(=O)C(CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
The compound (1.58 g) of Example 25 was dissolved into ethanol (15 ml), and, after adding IN aqueous solution of sodium hydroxide (5 ml), the mixture was stirred for 1 hour at room temperature. water was added to the reaction liquor, then 10% hydrochloric acid was added to make pH 3, which was extracted with methylene chloride. After the organic layer was dried over anhydrous sodium sulfate, solvent was distilled off under reduced pressure to obtain aimed product (1.50 g) as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[C:6]([S:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[NH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].[OH:26]O>C(O)(=O)C>[Cl:1][C:2]1[C:6]([S:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:26])=[O:8])=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[NH:4][C:3]=1[C:22]([F:24])([F:23])[F:25]
Reactant: O=S(c1ccccc1)c1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Cl
Reactant: OO
Solvent: CC(=O)O
Product: O=S(=O)(c1ccccc1)c1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Cl
Temperature: 50 °C
Reaction time: 7 h

Procedure:
A mixture of 3-chloro-5-(p-chlorophenyl)-4-(phenylsulfinyl)-2-(trifluoromethyl)pyrrole (0.335 g, 0.83 mmol) and 30% hydrogen peroxide solution (0.28 mL, 2.49 mmol) in acetic acid is stirred at 50° C. for 7 hours, cooled and poured into an ice-water mixture. The resultant aqueous mixture is filtered to obtain a solid which is washed with water and dried to give the title product as a colorless solid (mp 158°-161° C.).
Reaction SMILES: [OH-].[Na+].Cl[S:4]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][CH:8]=1)(=[O:6])=[O:5].[NH:16]([CH2:18][C:19]([OH:21])=[O:20])[CH3:17].C1(C)C=CC=CC=1>O>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([S:4]([N:16]([CH2:18][C:19]([OH:21])=[O:20])[CH3:17])(=[O:6])=[O:5])=[CH:8]1
Reactant: CNCC(=O)O
Reactant: O=S(=O)(Cl)c1csc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(CC(=O)O)S(=O)(=O)c1csc2ccccc12
Temperature: 60 °C
Reaction time: 6.5 h

Procedure:
6 g of NaOH, 23.27 g of 3-chlorosulphonyl-benzothiophene and 13.36 g of sarcosine are added to a mixture of 200 ml of toluene and 200 ml of water and stirred for 6.5 hours at 60° C. For working up, the aqueous phase is separated off and the organic phase is extracted with 100 ml of 2 N NaOH solution. The combined aqueous phases are acidified with conc. HCl and then extracted twice with 300 ml of ethyl acetate. After washing with saturated aqueous saline solution and drying over magnesium sulphate the organic phase is concentrated by evaporation. The crude product obtained is recrystallised from 100 ml of dichloroethane. Yield: 13.14 g. M.p.: 139-140° C.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]=1[Br:11].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:12]1([S:18]([N:1]([C:2]2[O:6][N:5]=[C:4]([C:7]([CH3:8])([CH3:10])[CH3:9])[C:3]=2[Br:11])[S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)c1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1noc(N(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)c1Br
Temperature: 50 °C
Reaction time: 16 h
Yield: 60.1 %

Procedure:
5-Amino-4-bromo-3-tert-butylisoxazole (440 mg, 2.0 mmol) was dissolved in dry pyridine (2 ml). Benzenesulfonyl chloride (344 mg, 2.0 mmol) and 4-dimethylamino-pyridine (5 mg) was added and the reaction was stirred at 50° C. for 16 h. The reaction mixture was diluted with ethyl acetate (20 ml), washed with 1N HCl (2×10 ml) and the organic phase was dried over magnesium sulfate. The solvent was removed under reduced pressure to yield a crude product, which was recrystallized from ethyl acetate/hexanes to give 300 mg (60% yield) of N-benzenesulfonyl-N-(4-bromo-3-tert-butyl-5-isoxazolyl)benzenesulfonamide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:14][CH3:15])=[N:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[CH:16]1(Br)[CH2:19][CH2:18][CH2:17]1>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:14][CH3:15])=[N:10][N:11]2[CH:16]2[CH2:19][CH2:18][CH2:17]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: BrC1CCC1
Reactant: CCc1n[nH]c2cc(C(=O)OC)ccc12
Product: CCc1nn(C2CCC2)c2cc(C(=O)OC)ccc12
Yield: 32.4 %

Procedure:
This compound was prepared according to the method of Preparation 3, using 750 mg (3.67 mmol, 1.0 equiv) 3-ethyl-1H-indazole-6-carboxylic acid methyl ester and 0.38 mL (4.04 mmol, 1.1 equiv) cyclobutyl bromide as starting materials to give 307 mg (32%) of a clear oil: HRMS calcd for C15H18N2O2+H: 259.1447. Found: 259.14550.