Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[CH2:3]([N:5]1[CH2:9][CH2:8][C@@H:7]([CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[S:18]([NH:21][C:22]2[C:31]([C:32]([O:34]C)=[O:33])=[C:30]3[C:25]([CH:26]4[CH2:36][CH:27]4[CH2:28][O:29]3)=[CH:24][CH:23]=2)(=[O:20])=[O:19])[CH2:6]1)[CH3:4]>O1CCOCC1.O>[CH2:3]([N:5]1[CH2:9][CH2:8][C@@H:7]([CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[S:18]([NH:21][C:22]2[C:31]([C:32]([OH:34])=[O:33])=[C:30]3[C:25]([CH:26]4[CH2:36][CH:27]4[CH2:28][O:29]3)=[CH:24][CH:23]=2)(=[O:19])=[O:20])[CH2:6]1)[CH3:4]
Reactant: CCN1CC[C@@H](Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCN1CC[C@@H](Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OCC2CC32)C1
Temperature: 85 °C
Yield: 67.3 %

Procedure:
Lithium hydroxide (0.111 g) was added to a solution of methyl (1aRS,7bSR)-5-[2-((R)-1-ethyl-pyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 95, 0.13 g) in a mixture of dioxane (4 mL) and water (1 mL) and the mixture was stirred and heated at 85° C. overnight. After cooling, the mixture was filtered and the filtrate was acidified by addition of 10% aqueous citric acid (1 mL) and then extracted with DCM. The organic extract was dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was triturated with diethyl ether and the solid was collected by filtration to give (1aRS,7bSR)-5-[2-((R)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.085 g) as a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:11].O[CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:25][N:22]1[CH2:23][CH2:24][CH:19]([O:11][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH2:20][CH2:21]1
Reactant: CN1CCC(O)CC1
Reactant: OC(c1ccccc1)c1nc2ccccc2s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CN1CCC(OC(c2ccccc2)c2nc3ccccc3s2)CC1
Temperature: 25 °C

Procedure:
A mixture of benzothiazol-2-ylphenylmethanol (0.36 g), 4-hydroxy-1-methylpiperidine (0.17 g) and para-toluenesulfonic acid (0.57 g) in toluene (22 mL) is heated overnight in a Dean-Stark apparatus. The mixture is cooled back to room temperature and poured into water, alcalinised with 1N sodium hydroxide and extracted twice with ethyl acetate. Pooled organic extracts are washed with brine, dried over magnesium sulfate and concentrated. The residue is purified by column chromatography over silica gel (gradient dichloromethane/methanol from 98/2 to 90/10) to give 2-[(1-methylpiperidin-4-yloxy)phenylmethyl]benzothiazole melting at 115° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH:15][CH2:16][CH3:17])[C:7]=12.[CH2:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH:15][CH2:16][CH3:17])[C:7]=12)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCc1ccccc1
Reactant: CCC=CCn1c(C)c(C)c2cnnc(Cl)c21
Product: CCC=CCn1c(C)c(C)c2cnnc(OCc3ccccc3)c21
Yield: 75.9 %

Procedure:
The title compound (trans) was prepared as a white powder in 75.9% yield in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-(2-pentenyl)pyrrolo[2,3-d]pyridazine (trans) and benzyl alcohol.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])C.CO.[Li+].[OH-]>C1COCC1>[C:16]([C:12]1[C:9]2[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[O:7][C:8]=2[CH:15]=[CH:14][CH:13]=1)#[N:17]
Reactant: CCOC(=O)c1oc2cccc(C#N)c2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)oc2cccc(C#N)c12
Reaction time: 2 h

Procedure:
To 550 mg of 4-cyano-3-methyl-benzofuran-2-carboxylic acid ethyl ester (2.4 mmol) in 15 mL of THF was added 5 mL of MeOH and 5 mL of 1N LiOH. The reaction was complete in 2 h. After quenching with 5 mL of 1 N HCl and work up, 4-cyano-3-methyl-benzofuran-2-carboxylic acid was obtained in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.7 (s, 3 H) 7.7 (m, 1 H) 7.9 (d, J=7.3 Hz, 1 H) 8.1 (m, 1 H).
Reaction SMILES: [CH2:1]([N:3]([O:21][CH3:22])[S:4]([C:7]1[C:15]2[O:14]C(C(C)(C)C)=[N:12][C:11]=2[CH:10]=[CH:9][C:8]=1[Cl:20])(=[O:6])=[O:5])[CH3:2].S(=O)(=O)(O)O.O>O1CCOCC1>[NH2:12][C:11]1[C:15]([OH:14])=[C:7]([S:4]([N:3]([O:21][CH3:22])[CH2:1][CH3:2])(=[O:6])=[O:5])[C:8]([Cl:20])=[CH:9][CH:10]=1
Reactant: CCN(OC)S(=O)(=O)c1c(Cl)ccc2nc(C(C)(C)C)oc12
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: CCN(OC)S(=O)(=O)c1c(Cl)ccc(N)c1O
Temperature: 80 °C

Procedure:
2-tert-Butyl-6-chloro-benzooxazole-7-sulfonic acid ethyl-methoxy-amide (2.7 g, 7.78 mmol) in dioxane (15 ml) was treated with a mixture of concentrated sulphuric acid (3.5 ml) and water (3.5 ml). The reaction mixture was heated at 80° C. for a total of 8 h and then allowed to cool to RT. Dioxane was removed in vacuo and the resulting aqueous mixture was treated with 1M NaOH (aq) until pH7 was attained. The reaction mixture was extracted with EtOAc, dried (MgSO4) and concentrated in vacuo to afford the title compound as a brown solid; [M+H]+ 281.1.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38]S(CC1C=CC=CC=1)(=O)=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][S:57](Cl)(=[O:59])=[O:58])=[C:52]([N+:61]([O-:63])=[O:62])[CH:51]=1>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:57]([CH2:56][C:53]1[CH:54]=[CH:55][C:50]([Cl:49])=[CH:51][C:52]=1[N+:61]([O-:63])=[O:62])(=[O:59])=[O:58])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CS(=O)(=O)Cl
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccc(Cl)cc3[N+](=O)[O-])n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 74 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 6, Example 1) was added (4-chloro-2-nitro-phenyl)-methanesulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 74% yield.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:6]=1)=[O:4].S(Cl)([Cl:19])(=O)=O.CCOCC>CC#N>[NH2:11][C:9]1[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:6]=[C:5]([C:3]([OH:2])=[O:4])[C:10]=1[Cl:19]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)c1cc(N)cc(C(F)(F)F)n1
Solvent: CCOCC
Solvent: CC#N
Product: Nc1cc(C(F)(F)F)nc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.5 %

Procedure:
To a solution containing 4-amino-6-trifluoromethylpyridine-2-carboxylic acid methyl ester (0.75 g, 3.4 mmol) in 5 mL of CH3CN was added dropwise a solution of sulfuryl chloride (0.27 mL, 3.4 mmol) in 1 mL of CH3CN. After stirring at RT for 1 hr, reaction mixture was added to 50 mL of Et2O and washed with aqueous NaHCO3, dried over MgSO4, filtered and concentrated to give a solid. The crude product was purified by chromatography, eluting with 10% ethyl acetate-hexane to give 200 mg of product as a white solid; mp 131-3° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15])([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=1)=[O:15])([O-:11])=[O:10]
Reactant: Nc1cccc(F)c1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Product: O=C(Nc1cccc(F)c1)c1ccccc1[N+](=O)[O-]
Yield: 76.1 %

Procedure:
Using the procedure described in Example 93, Part A, 3-fluoroaniline (15.6 mmol) and 2-nitrobenzoyl chloride (17.2 mmol) yielded 3.09 g (76%) of the title compound.
Reaction SMILES: [C:1]([NH:5][NH:6]C(OC(C)(C)C)=O)([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])=[CH:22][C:16]=1[C:17]([N:19]=[C:20]=[O:21])=O.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([N:5]1[C:20](=[O:21])[NH:19][C:17]([C:16]2[CH:22]=[C:23]([CH:24]=[CH:25][C:15]=2[Cl:14])[CH2:26][NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NNC(=O)OC(C)(C)C
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)n1nc(-c2cc(CNC(=O)C(F)(F)F)ccc2Cl)[nH]c1=O
Yield: 22.1 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using tert-butyl 2-tert-butylhydrazinecarboxylate (Intermediate-74, 0.233 g, 1.2 mmol), 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 0.400 g, 1.2 mmol), DCM (10 mL), trifluoro acetic acid (5.0 mL) to afford 0.100 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 1.52 (s, 9H), 4.42 (s, 2H), 7.39 (d, 1H), 7.41 (s, 1H), 7.58 (d, J=2.1 Hz, 2H), 10.0 (br s, 1H), 12.0 (br s, 1H); MS (m/z): 377.20 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[N:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.O1CCCC1.[CH2:26]([Mg]Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Cl-].[NH4+]>O>[CH2:26]([C:8]1([NH:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(CN=C2CCC3(CC2)OCCO3)cc1
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNC2(Cc3ccccc3)CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In a heated flask a 0.6 M solution of (1,4-dioxaspiro[4,5]dec-8-ylidene)-(4-methoxybenzyl)amine in tetrahydrofuran (17 ml, 10 mmol) was added slowly dropwise under argon and with ice cooling to a 2 M solution of benzyl magnesium chloride in tetrahydrofuran (10 ml, 20 mmol). The mixture was stirred for 20 h at room temperature and then added dropwise to 20% ammonium chloride solution (20 ml) with iced water cooling. The organic phase was separated off and the aqueous phase was extracted with diethyl ether (3×20 ml). The combined organic phases were washed with 2 N sodium hydroxide solution (20 ml) and water (20 ml), dried with sodium sulfate and concentrated to small volume under vacuum. The crude product (3.7 g) was purified by flash chromatography (370 g, 22×7.5 cm) with ethyl acetate/cyclohexane (1:2) with 1% triethylamine. Yield: 1.27 g (34%), yellowish oil.
Reaction SMILES: C([C:5]1[C:13]2[N:12]=[C:11]([CH:14]([F:16])[F:15])[N:10]([C:17]3[N:22]=[C:21]([N:23]4[CH2:27][CH2:26][CH2:25][CH:24]4[CH2:28][OH:29])[CH:20]=[C:19]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[N:18]=3)[C:9]=2[C:8](C)=[C:7](C)[C:6]=1O[SiH3])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH2:58]>C1COCC1>[F:15][CH:14]([F:16])[C:11]1[N:10]([C:17]2[N:22]=[C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH:24]3[CH2:28][OH:29])[CH:20]=[C:19]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[N:18]=2)[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([OH:58])[C:13]=2[N:12]=1
Reactant: Cc1c(O[SiH3])c(C(C)(C)C)c2nc(C(F)F)n(-c3nc(N4CCOCC4)cc(N4CCCC4CO)n3)c2c1C
Reactant: O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCC1CCCN1c1cc(N2CCOCC2)nc(-n2c(C(F)F)nc3c(O)cccc32)n1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
213 mg (0.38 mmol) of 2-(4-tert-butyldimethyl-silyloxy-2-difluoromethylbenzimidazol-1-yl)-4-(2-hydroxymethylpyrrolidin-1-yl)-6-morpholinopyrimidine dissolved in anhydrous THF (7 ml) was added with tetra-n-butylammoniumfluoride (0.4 ml, 1M THF solution) at room temperature and stirred for 30 minutes. The reaction solution was added with water, extracted several times with ethyl acetate, washed with saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was removed under the reduced pressure and the residue was purified by silica gel column chromatography (n-hexane ethyl acetate=1:4) to obtain 101 mg (yield: 60%) of the titled compound as colorless crystals.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([CH3:20])[C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[NH:9][C:8]=2[CH:7]=1)C.[OH-].[K+].CO>O>[OH:19][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]1[CH:7]=[C:6]([CH:5]([CH3:20])[C:4]([OH:21])=[O:3])[CH:18]=[CH:17][C:16]2=1
Reactant: CCOC(=O)C(C)c1ccc2c(c1)[nH]c1ccc(O)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C(=O)O)c1ccc2c(c1)[nH]c1ccc(O)cc12
Yield: 48.5 %

Procedure:
A mixture consisting of 6-hydroxy-a-methyl carbazole-2-acetic acid ethyl ester (5.0 g, 0.021 mol), potassium hydroxide (5.0 g, 0.089 mol), methanol (300 mL), and water (20 mL) is refluxed for 15 hours. The reaction mixture is cooled concentrated and acidified with a 1:1 solution of concentrated HCl and water to pH 1. The aqueous layer is extracted with ether (4×300 mL), washed with water (200 mL), brine (200 mL), dried over MgSO4, filtered and concentrated to give 2.6 g of product as a foam.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][SH:8].C[O-].[Na+].Cl[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C@H:25]2[CH2:42][C@@:40]3([CH3:41])[C@@H:36]([CH2:37][CH2:38][C@@H:39]3[OH:43])[C@H:35]3[C@H:26]2[C:27]2[CH:28]=[CH:29][C:30]([OH:44])=[CH:31][C:32]=2[CH2:33][CH2:34]3)=[CH:21][CH:20]=1>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][S:8][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C@H:25]2[CH2:42][C@@:40]3([CH3:41])[C@@H:36]([CH2:37][CH2:38][C@@H:39]3[OH:43])[C@H:35]3[C@H:26]2[C:27]2[CH:28]=[CH:29][C:30]([OH:44])=[CH:31][C:32]=2[CH2:33][CH2:34]3)=[CH:23][CH:24]=1
Reactant: SCc1ccccn1
Reactant: C[C@]12C[C@H](c3ccc(OCCCCCCl)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@]12C[C@H](c3ccc(OCCCCCSCc4ccccn4)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O

Procedure:
A solution containing 0.17 cm3 of 2-pyridine methanethiol, 81 mg of sodium methylate, 234 mg of the product obtained in Stage D of Example 3 and 4 cm3 of methanol is heated for 3 hours under reflux. The methanol is distilled off, the residue is taken up with ethyl acetate, washed with water, dried and brought to dryness under reduced pressure. 360 mg of residue is collected which is chromatographed on silica (eluant ethyl acetate-essence G 8/2) and in this way 280 mg of expected product is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12](Cl)(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[CH2:16]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(CC)CC>C1COCC1>[CH2:24]([N:23]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[S:12]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=2)[CH:9]=1)(=[O:14])=[O:13])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccc2ccc(Br)cc2c1
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc2ccc(Br)cc2c1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92 %

Procedure:
A mixture of 207 (1.50 g, 4.92 mmol), dibenzylamine (1.45 g, 7.38 mmol), and Et3N (0.75 g, 7.38 mmol) in THF (15 mL) was stirred at room temperature for 48 h. The solvents were evaporated under reduced pressure and the residue was extracted with EtOAc. The EtOAc extracts were washed with water and brine, then dried and evaporated. The residue was purified by chromatography on silica gel eluting with petroleum ether/EtOAc (95:5 then 1:1) to give N,N-dibenzyl-7-bromo-2-naphthalenesulfonamide (208) (2.11 g, 92%). A sample was recrystallised from petroleum ether/EtOAc as colorless crystals: mp 127-129° C.; 1H NMR (CDCl3) δ 8.25 (d, J=1.4 Hz, 1H), 8.05 (d, J=1.6 Hz, 1H), 7.91 (d, J=8.7 Hz, 1H), 7.79 (dd, J1=8.6, 1.8 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.71 (dd, J=8.8, 1.9 Hz, 1H), 7.22-7.15 (m, 6H), 7.09-7.04 (m, 4H), 4.39 (s, 4H); 13C NMR δ 138.9, 135.4, 133.3, 133.0, 132.1, 131.2, 129.4, 129.3, 128.6, 128.5, 127.8, 127.3, 123.0, 121.6, 50.6. Anal. (C24H20BrNO2S. 1/10Bn2NH) C, H, N.
Reaction SMILES: [OH-].[K+].[C:3]([NH:6][NH:7][C:8](=[O:10])[CH3:9])(=[O:5])[CH3:4].[CH2:11]([O:14][CH2:15][CH2:16]Cl)[CH2:12]Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.CS(C)=O>[C:3]([N:6]1[N:7]([C:8](=[O:10])[CH3:9])[CH:16]=[CH:15][O:14][CH:11]=[CH:12]1)(=[O:5])[CH3:4]
Reactant: CC(=O)NNC(C)=O
Reactant: ClCCOCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CC(C)O
Product: CC(=O)n1ccoccn1C(C)=O
Temperature: 70 °C

Procedure:
105.6 g of finely pulverised potassium hydroxide are introduced into a solution of 92.9 g of N,N′-diacetylhydrazine and 1410 g of dimethyl sulfoxide. When the heat of reaction has died away, 229.9 g of 2,2′-dichlorodiethyl ether are added and then 221.1 g of finely ground potassium carbonate are introduced. The reaction mixture is heated to 70° C. and maintained at 70 to 75° C. for 2 hours, then cooled to 20 to 25° C. and filtered, and the filtration residue is washed with dimethyl sulfoxide. Concentration of the combined filtrates by evaporation yields an oil, to which 157 g of isopropanol are added. After cooling to −10° C., filtration is carried out and the crystalline residue is washed with isopropanol. After drying of the residue, 99.4 g (65.1%) of 4,5-diacetyl-[1,4,5]-oxadiazepine are obtained in a purity of 97.6%.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[C:12]([OH:13])=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[N:9]=1)=[O:7])[CH3:4].[CH2:28](Br)[CH:29]=[CH2:30].C(OCC)(=O)C>CS(C)=O>[CH2:3]([O:5][C:6]([C:8]1[C:12]([O:13][CH2:30][CH:29]=[CH2:28])=[C:11]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[N:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[N:9]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C=CCOc1c(C(=O)OCC)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 0.75 h

Procedure:
To a slurry of sodium hydride (39 mg of 60% in oil) in DMSO (2.4 ml) was added 5-(4-chlorophenyl)-1-(2-chlorophenyl)-4-hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester I-1d (300 mg, 0.8 mmol) and the mixture was agitated for 45 minutes. Allyl bromide (0.1 ml, 1.2 mmol) was added and stirring was continued for 4.5 hours. The reaction solution was diluted into ethyl acetate, washed with water (2×), brine, dried (Na2SO4) and concentrated in vacuo to afford the title compound (I-1e) as an orange oil, 340 mg. This material was taken onto the next step without further purification.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3]\[CH2:4][OH:5].[OH-].[K+].Br[CH2:15][C:16]([C:18]1[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([OH:28])=[C:20]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:19]=1)=[O:17].Cl>O.CN1CCCC1=O>[C:24]([C:22]1[CH:23]=[C:18]([C:16](=[O:17])[CH2:15][O:5][CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH:19]=[C:20]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:21]=1[OH:28])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)=CCC/C(C)=C/COCC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
A mixture of 9.6 g (62 mmol) of (E)-3,7-dimethyl-octa-2,6-dien-1-ol, 8.4 g (150 mmol) of potassium hydroxide and 20 ml of n-methylpyrrolidone are stirred for one hour at room temperature. Then 10.0 g (33 mmol) of 2-bromo-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-ethanone is added in portions and stirring is continued at room temperature for 20 hours. After the addition of 30 ml of water the mixture is neutralized with 6N hydrochloric acid while cooling with an ice bath and then extracted with ethyl acetate. The organic phases are washed twice with brine, dried over sodium sulfate and evaporated. The residue is purified by column chromatography and crystallisation of the pure fractions from hexane gives 6.1 g (50%) of compound 116; m.p. 50° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:8]([C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1[OH:18])[CH:9]=[CH2:10].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:8]([C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1[O:18][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:9]=[CH2:10]
Reactant: C=CCc1cc(Br)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCc1cc(Br)ccc1OCC(=O)OCC
Temperature: 25 °C
Yield: 70.2 %

Procedure:
Ethyl bromoacetate (1.68 g) was added to a stirred suspension of 2-allyl-4-bromophenol (2.13 g) and potassium carbonate (1.50 g) in butan-2-one (15 ml). The mixture was heated at reflux for 16 hours. The reaction mixture was cooled to ambient temperature and filtered. Water (100 ml) was added to the filtrate and the aqueous phase was extracted with ethyl acetate (3×50 ml). The ethyl acetate extracts were combined, washed with brine (2×25 ml), dried (MgSO4) and evaporated to give a solid which crystallised from hexane to give ethyl 2-allyl-4-bromophenoxyacetate (2.10 g), mp 70.5° C.; microanalysis, found: C, 52.0; H, 5.10%; C13H15BrO3 requires: C, 52.2; H, 5.05%; NMR (CDCl3) 1.29 (3H, t), 3.42 (2H, d), 4.25 (2H, q), 4.58 (2H, s), 5.07-5.17 (2H, m), 5.88-6.18 (1H, m), 6.60 (1H, d) and 7.20-7.27 (2H, m); m/z 300 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH:25]4[CH2:29][CH2:28][CH2:27][O:26]4)=[C:18]([O:30][CH3:31])[CH:17]=3)=[O:14])[NH:11][CH:12]=2)=[CH:4][CH:3]=1.Br[CH2:33][CH2:34]Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:13](=[O:14])[N:15]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH:25]5[CH2:29][CH2:28][CH2:27][O:26]5)=[C:18]([O:30][CH3:31])[CH:17]=4)[CH2:34][CH2:33][N:11]3[CH:12]=2)=[CH:4][CH:3]=1
Reactant: BrCCBr
Reactant: COc1cc(NC(=O)c2cc(-c3ccc(Cl)cc3)c[nH]2)ccc1OCCC1CCCO1
Product: COc1cc(N2CCn3cc(-c4ccc(Cl)cc4)cc3C2=O)ccc1OCCC1CCCO1

Procedure:
Following the procedure described in Example 1 step D, the product of step B (120 mg) was alkylated with 1,2-dibromoethane to yield 20 mg of the title compound. MS (ESI) 467 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([S:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:3]=1.[O:18](S(C(F)(F)F)(=O)=O)[S:19]([C:22]([F:25])([F:24])[F:23])(=O)=[O:20]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:20])=[O:18])=[C:4]([S:9]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)(=[O:10])=[O:11])[CH:3]=1
Reactant: O=S(=O)(c1cc(F)ccc1O)N1CCOCC1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(c1cc(F)ccc1OS(=O)(=O)C(F)(F)F)N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.5 %

Procedure:
To a solution of 4-fluoro-2-(morpholinosulfonyl)phenol (0.4 g, 1.5 mmol) and DMAP (0.28 g 2.29 mmol) in CH2Cl2(10 ml), Tf2O (0.93 ml 5.5 mmol) was added dropwise at 0° C. The mixture was stirred at room temperature for 4 h, after which the mixture was washed with hydrochloric acid (1N, 20 ml) and then extracted with EA. The extracts were combined, washed with brine, dried over sodium sulfate and evaporated into dryness. The resulting residue was purified by column chromatography using PE/EA (10/1) as eluent to give the desired product (469 mg, yield 78%).