Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([NH:15][NH:16][C:17]([C@H:19]2[CH2:25][CH2:24][C@@H:23]3[CH2:26][N:20]2[C:21](=[O:32])[N:22]3[O:27][S:28]([OH:31])(=[O:30])=[O:29])=[O:18])=[O:14])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([NH:15][NH:16][C:17]([C@H:19]2[CH2:25][CH2:24][C@@H:23]3[CH2:26][N:20]2[C:21](=[O:32])[N:22]3[O:27][S:28](=[O:30])(=[O:29])[OH:31])=[O:18])=[O:14])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)NNC(=O)[C@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NNC(=O)[C@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O)[C@@H]1CCNC1

Procedure:
By using the procedure described in Step-4 of Example-1, and by using tetrabutylammonium salt of trans-3-[N′-(6-sulfooxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)-hydrazinocarbonyl]-(R)-pyrrolidin-1-carboxylic acid tert-butyl ester (15 gm, 0.021 mmol), dichloromethane (37 ml) and trifluoroacetic acid (37 ml) to provide the title compound in 7.7 gm quantity as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.C([O-])(O)=O.[Na+].[Cl:18][CH2:19][C:20](Cl)=[O:21]>>[Cl:18][CH2:19][C:20]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[CH:5]=[CH:4][CH:3]=1)=[O:21]
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc2ccc(O)cc12
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(CCl)Nc1cccc2ccc(O)cc12
Reaction time: 1 h

Procedure:
To a solution of 8-amino-2-naphthol (10.0 g, 62.8 mmol) in 240 mL of 1:1EtOAc/saturated NaHCO3 solution was added chloroacetyl chloride dropwise (5.5 mL, 69.1 mmol). After one hour, the solution was filtered, the layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[OH:11])[CH3:2].[C:12](O)(=[O:14])C>>[CH2:1]([C:3]1[CH:8]=[C:7]([CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[OH:11])[CH:12]=[O:14])[CH3:2]
Reactant: CCc1cccc(CC)c1O
Reactant: CC(=O)O
Product: CCc1cc(C=O)cc(CC)c1O
Temperature: 120 °C
Yield: 39.9 %

Procedure:
To a solution of 2,6-diethylphenol (3.80 g, 25.3 mmol) in acetic acid (30 mL) hexamethylenetetraamine (5.3 g, 37.9 mmol) is added and the mixture is heated to 120° C. A first fraction of the solvent is distilled off (Dean-Stark), then the mixture is refluxed for 3 h. The mixture is cooled to rt, diluted with water (100 mL) and extracted twice with EA (2×200 mL). The organic extracts are washed with sat. aq. NaHCO3, dried and the solvent is removed in vacuo. The crude product is purified by column chromatography eluting with DCM containing 2% of methanol to give 3,5-diethyl-4-hydroxybenzaldehyde (1.8 g) as colourless solid; 1H NMR (CDCl3): δ 9.85 (s, 1H), 7.57 (s, 2H), 5.32 (s, 1H), 2.69 (q, J=7.6 Hz, 2H), 1.30 (t, J=7.6 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1>>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:3]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: Cc1ccc(N)cc1
Product: COC(=O)c1cccc(Nc2ccc(C)cc2)c1

Procedure:
Reaction of methyl 3-bromobenzoate with p-toluidine according to general procedure A provided methyl ester of Compound 12 as a yellow oil (69% yield). 1H NMR (CDCl3, 500 MHz): δ=7.68 (s, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.29 (t, J=7.7 Hz, 1H), 7.19 (m, 1H), 7.13 (d, J=8.0 Hz, 2H), 7.03 (d, J=8.3 Hz, 2H), 5.77 (s, 1H), 3.91 (s, 3H), 2.34 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ=167.4, 144.6, 139.8, 131.9, 131.5, 130.2, 129.5, 121.3, 120.8, 119.7, 117.5, 52.2, 20.9.
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH2:6].CC(C)([O-])C.[K+].[Cl:13][C:14]1[CH:39]=[CH:38][C:17]([O:18][C:19]2[C:24]([F:25])=[CH:23][C:22]([S:26](OC3C=CC(Cl)=CC=3)(=[O:28])=[O:27])=[C:21]([F:37])[CH:20]=2)=[C:16]([C:40]2[N:45]3[CH:46]=[CH:47][N:48]=[C:44]3[CH:43]=[CH:42][CH:41]=2)[CH:15]=1.Cl>CS(C)=O.C(OCC)(=O)C.O>[Cl:13][C:14]1[CH:39]=[CH:38][C:17]([O:18][C:19]2[C:24]([F:25])=[CH:23][C:22]([S:26]([NH:6][C:2]3[S:1][CH:5]=[N:4][N:3]=3)(=[O:27])=[O:28])=[C:21]([F:37])[CH:20]=2)=[C:16]([C:40]2[N:45]3[CH:46]=[CH:47][N:48]=[C:44]3[CH:43]=[CH:42][CH:41]=2)[CH:15]=1
Reactant: O=S(=O)(Oc1ccc(Cl)cc1)c1cc(F)c(Oc2ccc(Cl)cc2-c2cccc3nccn23)cc1F
Reactant: Nc1nncs1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: O=S(=O)(Nc1nncs1)c1cc(F)c(Oc2ccc(Cl)cc2-c2cccc3nccn23)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42 %

Procedure:
To a stirred solution of 1,3,4-thiadiazol-2-amine (0.083 g, 0.8 mmol) in anhydrous dimethylsulfoxide (1.0 mL) at ambient temperature was added potassium tert-butoxide (0.092 g, 0.8 mmol). The mixture was stirred at ambient temperature for 10 minutes and 4-chlorophenyl 4-(4-chloro-2-(imidazo[1,2-a]pyridin-5-yl)phenoxy)-2,5-difluorobenzenesulfonate (0.15 g, 0.27 mmol) was added. The reaction mixture was stirred for 1 h at ambient temperature and water (6 mL), 1 M hydrochloric acid (0.85 mL) and ethyl acetate (25 mL) were added. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 0-10% gradient of methanol in ethyl acetate to afford 4-(4-chloro-2-(imidazo[1,2-a]pyridin-5-yl)phenoxy)-2,5-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide as a beige solid in 42% yield (0.060 g): 1H NMR (300 MHz, DMSO-d6) δ8.76 (s, 1H), 7.79 (d, J=2.6 Hz, 1H), 7.71-7.57 (m, 5H), 7.37-7.28 (m, 3H), 7.00 (dd, J=7.0, 0.9 Hz, 1H); MS (ES+) m/z 519.8 (M+1), 521.8 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[N:10][O:11][CH2:12][CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]([CH2:19][CH:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[CH:17][CH:16]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([O:1][C:2]1[CH:3]=[C:4]([C:8](=[N:10][O:11][CH2:12][CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]([CH2:19][CH:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[CH:17][CH:16]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1cccc(O)c1
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc(C(C)=NOCCOc2ccc(CC3SC(=O)NC3=O)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 0.30 g of 5-(4-{2-[1-(3-hydroxyphenyl)ethylideneaminooxy]ethoxy}benzyl)thiazolidine-2,4-dione (prepared as described in Example 50), 0.092 ml of acetic anhydride and 15 ml of pyridine was stirred at room temperature for 1.5 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and then the resulting residue was diluted with water and then extracted with ethyl acetate. The extract was washed with 1N aqueous hydrochloric acid and with an aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:2 by volume mixture of ethyl acetate and hexane as the eluent, to give 0.23 g of the title compound, melting at 30°-50° C. (softening point).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=O)=[O:9])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(C(C)C)C(C)C)C.Cl.[NH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47]>O1CCCC1>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([NH:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])=[O:16])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)O
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)CCc1cc(Cl)ccc1C(=O)CCCNC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.75 g (0.006 mol) of 2-(4-acetamidobutyryl)-5-chlorohydrocinnamic acid and 0.95 g (0.006 mol) of 1,1'-carbonyldiimidazole are stirred at room temperature in 15 ml of tetrahydrofuran and 1.0 ml (0.006 mol) of N-ethyldiisopropylamine and 0.82 g (0.006 mol) of ethyl glycinate hydrochloride are then added thereto. After stirring at room temperature for 1 hour, the solution is concentrated, extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Chromatography on aluminum oxide with ethyl acetate-ethanol (9:1) and crystallization from methylene chloride/t-butyl methyl ether gives ethyl N-[2-(4-acetamidobutyryl)-5-chlorohydrocinnamoyl]-glycinate as white crystals with melting point 96°.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:12]=[N:11][C:10]([NH2:13])=[N:9][CH:8]=2)=[N:4][CH:3]=1.[CH3:14][N:15](C=O)C>C(Cl)Cl.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:13][C:10]1[N:11]=[N:12][C:7]([C:5]2[S:6][C:2]([C:14]#[N:15])=[CH:3][N:4]=2)=[CH:8][N:9]=1
Reactant: Nc1ncc(-c2ncc(Br)s2)nn1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: ClCCl
Product: N#Cc1cnc(-c2cnc(N)nn2)s1
Temperature: 160 °C

Procedure:
6-(5-Bromothiazol-2-yl)-1,2,4-triazin-3-amine (300 mg, 1.15 mmol), zinc cyanide (340 mg, 2.30 mmol), Pd(PPh3)4 (133 mg, 0.13 mmol), and DMF (5 mL) were combined and heated to 160° C. for 12 h. The reaction mixture was cooled, diluted with CH2Cl2 (30 mL), filtered through silica gel, eluted with EtOAc, and concentrated. The crude product was then purified using silica gel chromatography to afford 30 mg of 2-(3-amino-1,2,4-triazin-6-yl)thiazole-5-carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]([N:32]2[CH2:36][CH:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:34]([C:43]3[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=3)=[N:33]2)[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)(OC)[O:21]C)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C1COCC1.CO.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]([N:32]2[CH2:36][CH:35]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:34]([C:43]3[CH:44]=[CH:45][C:46]([Cl:49])=[CH:47][CH:48]=3)=[N:33]2)[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[O:21])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(CCCCCCNC(=NS(=O)(=O)c1ccc(Cl)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1)(OC)c1ccc(F)cc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CCCCCCNC(=NS(=O)(=O)c1ccc(Cl)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 115.8 %

Procedure:
Part B: 4-Chloro-N-{[3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl]-[7-(4-fluoro-phenyl)-7,7-dimethoxyheptylamino] methylene}-benzenesulfonamide (0.200 g, 0.258 mmol) was dissolved in a 1:1 mixture of THF/methanol (30 ml) and 1 N hydrochloric acid (5 ml) was added and the resulting mixture was stirred at room temperature for 20 hours. The mixture was quenched with 5% aqueous NaHCO3. Most of the THF and methanol were removed by evaporation in vacuo. The remaining water layer was twice extracted with ethylacetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The obtained crude 4-chloro-N-{[3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl]-[7-(4-fluorophenyl)-7-oxo-heptylamino] methylene}benzenesulfonamide (203 mg) was not further purified. Some characteristic aromatic 1H-NMR signals are: (400 MHz, CDCl3) δ 7.12 (d, J˜8, 2H), 7.22-7.33 (m, 5H) 7.39 (d, J˜8, 2H), 7.50 (d, J˜8, 2H), 7.72 (d, J˜8, 2H), 7.84 (d, J˜8, 2H), 8.05 (d, J˜8, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][CH2:13][OH:14])=[CH:3]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>>[CH3:15][S:16]([O:14][CH2:13][CH2:12][CH2:11][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)(=[O:18])=[O:17]
Reactant: Cn1cc(CCCO)c2ccccc21
Reactant: CS(=O)(=O)Cl
Product: Cn1cc(CCCOS(C)(=O)=O)c2ccccc21

Procedure:
3-(1-methyl-3-indolyl)-1-propyl methanesulfonate was prepared by following the general procedure of Example 43 for mesylation as a colorless oil (291 mg, 84%) from 3-(1-methyl-3-indolyl)-1-propanol (245 mg, 1.30 mmol) and methanesulfonyl chloride (223 mg, 1.94 mmol). 1H NMR (CDCl3, 300 MHz) δ2.15 (qu, 2H, J=7.0 Hz), 2.90 (t, 2H, J=7.0 Hz), 2.99 (s, 3H), 3.76 (s, 3H), 4.27 (t, 2H, J=6.2 Hz), 6.88 (s, 1H), 7.11 (dt, 1H, J=1.1, 6.9 Hz), 7.23 (dt, 1H, J=1.1, 7.0 Hz), 7.29 (d, 1H, J=8.5 Hz), 7.57 (d, 1H, J=8.1 Hz) ppm.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][C:8](Cl)=[O:9].[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(=S)=S>[Cl:5][CH2:6][CH2:7][C:8]([C:14]1[CH:15]=[CH:16][C:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:12][CH:13]=1)=[O:9]
Reactant: COC(=O)CCCCCc1ccccc1
Reactant: O=C(Cl)CCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)CCCCCc1ccc(C(=O)CCCl)cc1
Reaction time: 0.17 h

Procedure:
17.2 g of AlCl3, 18.5 ml of CS2 and 3.6 ml of β-chloro-propionyl chloride are placed in a stirring flask with a reflux condenser. 7.06 g of methyl 6-phenylcaproate are allowed to drop into this mixture at room temperature within 10 minutes (rinsing is carried out with 4 ml of CS2). The reaction mixture is subsequently stirred for a further 15 minutes warmed slightly and then cooled. The reaction mixture is then pipetted into a stirred mixture of ice water and ether. The organic phase is washed neutral with bicarbonate solution and water. After drying over MgSO4 the solvent is removed, 10.2 g of crystalline product identified as methyl p-[β-chloropropionyl]-6-phenyl-caproate are obtained.
Reaction SMILES: [CH2:1]([N:4]([C:9]([O:11]C)=O)[C:5](=O)[CH2:6][NH2:7])[C:2]#[CH:3].[OH-:13].[Na+].Cl>CO>[CH2:1]([N:4]1[CH2:5][C:6](=[O:13])[NH:7][C:9]1=[O:11])[C:2]#[CH:3]
Reactant: [OH-]
Reactant: C#CCN(C(=O)CN)C(=O)OC
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C#CCN1CC(=O)NC1=O
Temperature: 70 °C

Procedure:
2.0 g of N-propargyl-N-methoxycarbonylglycinamide were added to the mixture of 5 ml of methanol and 2.5 ml of 20% aqueous solution of sodium hydroxide and maintained at 70° C. for an hour. After cooled down to room temperature; the reaction mixture was neutralized with concentrated hydrochloric acid followed by concentrating and drying the same by an evaporation under reduced pressure. Then it was extracted with acetonitrile and sodium chloride was removed off from the extract by filtration. The solvent was evaporated off from the filtrate to obtain 1.4 g of 1-propargyl-2,4-dioxoimidazolidine (melting point: 124°-125° C.).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][O:11]2)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cc(O)ccc1O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cc(OC2CCCCO2)ccc1O

Procedure:
A solution of 2,5-dihydroxy-benzaldehyde (152 mmol), 3,4-dihydro-2H-pyran (167 mmol) and a catalytic amount of pyridinium p-toluenesulfonate in CH2Cl2 (480 mL) was left overnight at room temperature. The organic phase was washed with 1 N Na7CO3 (aq) (3×100 mL) and dried (Na2SO4). Evaporation in vacuo gave the desired product as brown crystals that was used without further purification. 1H-NMR (CDCl3) δ 10.72 (s, 1H), 9.88 (s, 1H), 7.32-7.29 (m, 2H), 6.96 (d, 1H), 5.38 (bs, 1H), 3.99-3.91 (m, 1H), 3.69-3.64 (m, 1H), 2.06-1.63 (m, 6H).
Reaction SMILES: [H-].C(O[Al](OCCCC)OCCCC)CCC.[Li+].[CH2:19]([C@@H:21]1[CH:47]=[C:46]([CH3:48])[CH2:45][C@H:44]([CH3:49])[CH2:43][C@H:42]([O:50][CH3:51])[C@H:41]2[O:52][C@:37]([OH:56])([C@H:38]([CH3:55])[CH2:39][C@@H:40]2[O:53][CH3:54])[C:36](=[O:57])[C:35](=[O:58])[N:34]2[C@@H:29]([CH2:30][CH2:31][CH2:32][CH2:33]2)[C:28](=[O:59])[O:27][C@H:26](/[C:60](/[CH3:71])=[CH:61]/[C@@H:62]2[CH2:67][CH2:66][C:65](=[O:68])[C@H:64]([O:69][CH3:70])[CH2:63]2)[C@H:25]([CH3:72])[C@@H:24]([OH:73])[CH2:23][C:22]1=[O:74])[CH3:20]>C1COCC1>[CH2:19]([C@@H:21]1[CH:47]=[C:46]([CH3:48])[CH2:45][C@H:44]([CH3:49])[CH2:43][C@H:42]([O:50][CH3:51])[C@H:41]2[O:52][C@:37]([OH:56])([C@H:38]([CH3:55])[CH2:39][C@@H:40]2[O:53][CH3:54])[C:36](=[O:57])[C:35](=[O:58])[N:34]2[C@@H:29]([CH2:30][CH2:31][CH2:32][CH2:33]2)[C:28](=[O:59])[O:27][C@H:26](/[C:60](/[CH3:71])=[CH:61]/[C@@H:62]2[CH2:67][CH2:66][C@H:65]([OH:68])[C@H:64]([O:69][CH3:70])[CH2:63]2)[C@H:25]([CH3:72])[C@@H:24]([OH:73])[CH2:23][C:22]1=[O:74])[CH3:20]
Reactant: CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CCC(=O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Agent: CCCCO[Al](OCCCC)OCCCC
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Temperature: -70 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
Lithium tri-n-butoxyaluminum hydride (0.2 mL, 1M in THF) was slowly added to a stirred solution of the product from Example 15 (0.058 g) in 1 mL of anhydrous THF at -70° C. under a nitrogen atmosphere. After stirring at -70° C. for 3 hours, the mixture was partitioned between 50 mL of ether and 10 mL of 1N-HCl. The etheral solution was washed with brine, dried over magnesium sulfate anhydrous. The obtained crude product was purified by preparative TLC, using 35% acetone in hexane as a solvent to afford 0.025 g of the title compound.
Reaction SMILES: [Cl:1][C:2]([Cl:19])=[CH:3][CH2:4][O:5][C:6]1[CH:16]=[C:15]([Cl:17])[C:9]([O:10][CH2:11][CH2:12][CH2:13]O)=[C:8]([Cl:18])[CH:7]=1.C(Br)(Br)(Br)[Br:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]([Cl:19])=[CH:3][CH2:4][O:5][C:6]1[CH:16]=[C:15]([Cl:17])[C:9]([O:10][CH2:11][CH2:12][CH2:13][Br:21])=[C:8]([Cl:18])[CH:7]=1
Reactant: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 42 h
Yield: 188.3 %

Procedure:
A stirred solution of 3.5 grams (0.010 mole) of 3-[4-(3,3-dichloroprop-2-enyloxy)-2,6-dichlorophenoxy]propan-1-ol and 3.3 grams (0.010 mole) of carbon tetrabromide in 50 mL of methylene chloride was cooled to 0–4° C. and 2.9 grams (0.011 mole) of triphenylphosphine was added portion-wise. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it stirred during a 42 hour period. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 1:3 methylene chloride:hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 7.7 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:19]2[NH:27][C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]=[CH2:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][NH:29][CH3:30].CO>>[CH:1]1([CH2:6][CH:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH2:18][N:29]([CH3:30])[CH3:28])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[C:19]2[NH:27][C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Reactant: CNC
Solvent: CO
Product: CN(C)CCS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 12 %

Procedure:
A mixture of 2-[2-cyclopentyl-1-(4-ethenesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (150 mg, 0.39 mmol) and dimethylamine solution in methanol (2 M, 3 ml, 6 mmol) was stirred at 25° C. for 20 min. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded (2-{4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-ethyl]-benzenesulfonyl}-ethyl)-dimethyl-amine (20 mg, 12%) as a white solid: LC/MS m/e calcd for C24H31N3O2S [M+H]+ 426.60, observed 426.1; 1H NMR (400 MHz, CD3OD) δ ppm 8.08 (d, J=4.5 Hz, 1H), 7.83-7.91 (m, 2H), 7.61 (d, J=8.1 Hz, 1H), 7.04 (dd, J=7.6, 5.1 Hz, 1H), 6.39 (s, 1H), 5.49 (s, 7H), 4.32 (t, J=7.8 Hz, 1H), 3.33-3.39 (m, 2H), 2.64-2.71 (m, 1H), 2.21-2.33 (m, 1H), 2.07-2.19 (m, 5H), 1.59-1.86 (m, 4H), 1.43-1.59 (m, 2H), 1.15-1.34 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([CH:18]=O)=[CH:11][C:12]2[N:13]([CH:15]=[CH:16][N:17]=2)[CH:14]=1.[CH3:20][C:21]([S:24]([NH2:26])=[O:25])([CH3:23])[CH3:22]>C(Cl)Cl.[Ti]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](/[CH:18]=[N:26]/[S:24]([C:21]([CH3:23])([CH3:22])[CH3:20])=[O:25])=[CH:11][C:12]2[N:13]([CH:15]=[CH:16][N:17]=2)[CH:14]=1
Reactant: O=Cc1cc2nccn2cc1-c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)S(N)=O
Agent: [Ti]
Solvent: ClCCl
Product: CC(C)(C)S(=O)/N=C/c1cc2nccn2cc1-c1ccc(Cl)cc1Cl
Temperature: 45 °C
Reaction time: 14 h
Yield: 72.2 %

Procedure:
To a solution of 6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbaldehyde (104 mg, 0.36 mmol) in DCM (5 mL) were successively added 2-methyl-2-propane-sulfinamide (47.6 mg, 0.39 mmol) and titanium tetraisopropoxyde (0.21 mL, 0.72 mmol) at RT, then the mixture was heated at 45° C. and stirred for 14 h. The reaction mixture was cooled to RT, quenched by the successive addition of MeOH (2 mL) and several drops of a saturated NaHCO3 solution in water. The resulting precipitate was filtered through a Na2SO4 pad, the solid was washed with AcOEt and the filtrate was evaporated to dryness. The remaining residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→100% TBME) to yield the title compound (101 mg, 0.26 mmol, 72%). MS: 394 [M+1]+; HPLC: AtRet=1.58; TLC: RF 0.33 (hexane/DCM/TBME 1:1:6).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1.BrCC1CCCCO1.[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[C:22]1([C:33]3=[CH:34][C:35]4[O:39][CH2:38][O:37][C:36]=4[CH:40]=[C:32]3[O:31][CH2:30]1)[C:23](=[O:29])[NH:24]2>>[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[C:22]1([C:33]3=[CH:34][C:35]4[O:39][CH2:38][O:37][C:36]=4[CH:40]=[C:32]3[O:31][CH2:30]1)[C:23](=[O:29])[N:24]2[CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1
Reactant: CC(C)c1nc(CCl)cs1
Reactant: O=C1Nc2cccc(Cl)c2C12COc1cc3c(cc12)OCO3
Agent: BrCC1CCCCO1
Product: CC(C)c1nc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3c(Cl)cccc32)cs1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 4-(chloromethyl)-2-isopropylthiazole to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 4′-chlorospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 4′-chloro-1′-[(2-isopropyl-1,3-thiazol-4-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1H)-one was obtained (62%) as a colorless solid: mp 147-148° C. (diethyl ether/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 7.47 (s, 1H), 7.31 (dd, J=8.0, 8.0 Hz, 1H), 7.04 (d, J=8.0 Hz, 2H), 6.65 (s, 1H), 6.33 (s, 1H), 5.94 (s, 2H), 5.09 (d, J=16 Hz, 1H), 4.93 (d, J=9.7 Hz, 1H), 4.91 (d, J=16 Hz, 1H), 4.76 (d, J=9.7 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 177.5, 176.1, 156.1, 149.5, 148.5, 144.1, 141.4, 130.3, 129.6, 128.1, 123.2, 116.9, 115.2, 108.5, 102.7, 101.4, 92.8, 76.9, 57.9, 40.2, 32.4, 22.7, 22.6; MS (ES+) m/z 455.3 (M+1), 457.3 (M+1).