Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][C:23](OC)=[O:24])[CH2:18][CH2:17]2)[C:5](=[O:15])[C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[BH4-].[Li+].CO>C1COCC1>[CH:1]1([N:4]([C@H:16]2[CH2:17][CH2:18][C@H:19]([CH2:22][CH2:23][OH:24])[CH2:20][CH2:21]2)[C:5](=[O:15])[C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:13])[CH3:14])=[CH:8][CH:7]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)C[C@H]1CC[C@H](N(C(=O)c2ccc(C(C)C)cc2)C2CC2)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1ccc(C(=O)N(C2CC2)[C@H]2CC[C@H](CCO)CC2)cc1
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(trans-4-(N-cyclopropyl-4-isopropylbenzamido)cyclohexyl)acetate (0.100 g, 0.28 mmol) in THF (3 mL) was added lithium borohydride (2 M solution in THF, 0.14 mL, 0.28 mmol) at 0° C. The reaction mixture was checked after being stirred overnight. HPLC-MS showed product and starting material. More lithium borohydride (0.14 mL) (2 M solution in THF) and MeOH (0.1 mL) were added to the mixture. After being stirred overnight, the reaction mixture was quenched with saturated NH4Cl (10 mL) and then extracted with EtOAc twice. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel chromatography eluting with 55% EtOAc-hexane. The alcohol product was obtained as a sticky white solid (80 mg). MS: 330 (M+1), C2131NO2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:5](=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[NH2:6].S(Cl)([Cl:17])(=O)=O>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:5](=[CH:7][C:8]([O:11][CH3:12])=[C:9]([Cl:17])[CH:10]=1)[NH2:6]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)c1ccc(OC)cc1N
Product: COC(=O)c1cc(Cl)c(OC)cc1N
Yield: 90 %

Procedure:
Treatment of methyl-4-methoxyanthranilate with sulfuryl chloride as described above afforded methyl-4-methoxy-5-chloroanthranilate, M.P., 197°-200° C. in 90% yield.
Reaction SMILES: O1CCOC1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:13]=[C:14]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH3:29])[CH2:24][CH2:23]2)[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2.Cl.[CH3:31][OH:32]>>[CH2:28]([N:25]1[CH2:26][CH2:27][N:22]([C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:21]=[C:12]([C:7]3[CH:8]=[CH:9][C:10]([CH:31]=[O:32])=[CH:11][CH:6]=3)[N:13]=2)[CH2:23][CH2:24]1)[CH3:29]
Reactant: CCN1CCN(c2nc(-c3ccccc3C3OCCO3)cc3ccccc23)CC1
Reactant: CO
Agent: Cl
Product: CCN1CCN(c2nc(-c3ccc(C=O)cc3)cc3ccccc23)CC1

Procedure:
3-[(1,3-Dioxolan-2-yl)phenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline (4.50 g) was dissolved in methanol (50 ml), a 1N hydrochloric acid (50 ml) was added thereto, and then the mixture was reacted at 50° C. for 1 hr. The reaction solution was evaporated, basified with sodium carbonate, and extracted with ethyl acetate. The resulting organic layer was washed with water and brine in this order, dried and concentrated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 3.62 g of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:3][C:2]=1[F:1]
Reactant: Cc1ccc(-c2nc3ccccc3o2)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(-c2nc3ccccc3o2)ccc1CBr

Procedure:
To a solution of 5.1 gm. of 2-(3-fluoro-4-methylphenyl)benzoxazole in 60 ml. of carbon tetrachloride is added 6.23 gm. N-bromosuccinimide and 100 mg. of dibenzoyl peroxide. The reaction mixture is refluxed for 6 hours, filtered to remove succinimide and the filtrate concentrated to dryness. The residue is chromatographed on 500 gm. of silica gel. Elution with 1% ether in petroleum ether gives 2-(4-bromomethyl-3-fluorophenyl)benzoxazole, m.p. 150°-152° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[CH:5][CH:4]=1.[Cl:12][CH2:13][Si:14]([CH3:17])([CH3:16])Cl.Cl>O1CCCC1>[Cl:12][CH2:13][Si:14]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[CH:5][CH:4]=1)([CH3:17])[CH3:16]
Reactant: CCOc1ccc(Br)cc1
Reactant: C[Si](C)(Cl)CCl
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOc1ccc([Si](C)(C)CCl)cc1
Temperature: -78 °C
Yield: 23.1 %

Procedure:
To a mixture of 5.1 g (0.21 mole) of powdered magnesium metal in 100 ml of dry tetrahydrofuran was added dropwise 40 g (0.20 mole) of ethyl 4-bromophenyl ether. Upon completion of addition this mixture was heated at reflux for one hour. In a second flask was placed 28.5 g (0.199 mole) of (chloromethyl)dimethylchlorosilane in 100 ml of tetrahydrofuran, and this flask was cooled to -78° C. The contents of the first flask were added dropwise to the second flask. The temperature of the reaction mixture was maintained at -78° C. for one hour after addition was complete, and it was then poured into 200 ml of 10% hydrochloric acid. The organic phase was washed once with 10% hydrochloric acid. The aqueous phase was extracted with diethyl ether, and these extracts were combined with the organic phase. After being dried, filtered, and having the solvent evaporated under reduced pressure, the residue was vacuum distilled, yielding 10.5 g of (chloromethyl)(4-ethoxyphenyl)dimethylsilane, b.p. 99°-110° C./0.12 mm of Hg. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([Si:5]([CH3:38])([CH3:37])[O:6][C@H:7]1[C@H:20](/[CH:21]=[CH:22]/[C@@H:23]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C@H:10]2[CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([OH:19])[C:17]=3[CH2:18][C@H:9]2[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:41](Cl)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O1CCCC1>[C:41]([O:19][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH2:18][C@H:9]1[CH2:8][C@@H:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:37])[CH3:38])[C@H:20](/[CH:21]=[CH:22]/[C@@H:23]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C@H:10]1[CH2:11]2)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2Cc3cccc(O)c3C[C@H]2C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: O=C(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2Cc3cccc(OC(=O)c4ccccc4)c3C[C@H]2C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.5 %

Procedure:
2 g (3.58 mmole, from Example 18) of (1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-(tert-butyldimethyl-silyoxy)-1-((S,E)-3-(tert-butyldimethylsilyoxy)oct-1-enyl)-1H-cyclopenta[b]naphthalen-5-ol, which contains 6% para-cyclized isomer, in dry tetrahydrofuran (20 ml) was treated with sodium hydride (0.29 g, 7.16 mol) at 0° C. and stirred for 10 minutes at room temperature, followed by dropwise addition of benzoyl chloride (0.63 ml, 5.37 mmol). After 30 minutes, the reaction was cooled to 10° C., diluted with ice cold brine (10 ml) and extracted with ethyl acetate (10 ml). The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. 2.1 g of (1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-(tert-butyldimethylsilyoxy)-1-((S,E)-3-(tert-butyldimethylsilyoxy)oct-1-enyl)-1H-cyclopenta[b]naphthalen-5-yl benzoate was obtained. The product was then dissolved in tetrahydrofuran (4.2 ml), and treated with acetic acid (12.6 ml) and distilled water (4.2 ml) overnight at room temperature. The reaction then was diluted with saturated sodium bicarbonate aqueous (50 ml) and extracted with ethyl acetate (60 ml). The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. The product was obtained in a crystalline form. MP: 140˜141° C. Yield: 68%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[C:11]([OH:13])=O.[CH:14]([NH2:16])=O>>[NH:8]1[C:9]2[C:5]([CH:4]=[C:3]3[C:2]([CH:10]=2)=[N:1][CH:14]=[N:16][C:11]3=[O:13])=[CH:6][NH:7]1
Reactant: NC=O
Reactant: Nc1cc2[nH]ncc2cc1C(=O)O
Product: O=c1ncnc2cc3[nH][nH]cc3cc12
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
450 mg (2.5 m-mol) of 6-amino-indazole-5-carboxylic acid (formula 20, prepared according to Example XIII) in 3 ml of formamide were heat-melted and kept at a temperature of 140° during a period of 4.5 hours and then at a temperature of 180° during another period of 1.5 hours. The mass obtained was cooled to room temperature. The product was filtered under suction, washed well with water until the filtrate became clear, and then washed with a small amount of ethanol. The target product (formula 3) was recovered in an amount of 167 mg (36%) in the form of a greyish-brown, finely crystalline material, m.p. 330°. The product was uniform as evidenced by chromatography; pmr (DMSO-d6): δ 7.78, 8.10, 8.44, 8.76 (4 broad s, 4, H3, H4, H7, H9), 11.92, 13.36 (2 with D2O exchangeable broad m, 2, N1H, N6H), (DMSO-d 6 /D2O): δ 7.83, 8.10, 8.45, 8.78 (4 sharp s, 4, H3, H4, H7, H9); ms (70 eV): m/e 186 (100%, M+).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[N:10]=[C:9]2[CH2:11][O:12]C(C3C=CC=CC=3)[O:14][C:8]2=[CH:7][CH:6]=1)[OH:4].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][C:33]1[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:40]>CN(C)C=O.C(N(C(C)C)CC)(C)C>[Cl:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:40])[C:33]=1[CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:1][CH2:2][CH:3]([C:5]1[N:10]=[C:9]([CH2:11][OH:12])[C:8]([OH:14])=[CH:7][CH:6]=1)[OH:4]
Reactant: NCC(O)c1ccc2c(n1)COC(c1ccccc1)O2
Reactant: Clc1cccc(Cl)c1COCCOCCCCCCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: OCc1nc(C(O)CNCCCCCCOCCOCc2c(Cl)cccc2Cl)ccc1O
Temperature: 70 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
A mixture of 2-amino-1-(2-phenyl-4H-[1,3]dioxino[5,4-b]pyridin-6-yl)ethanol (EP220054A2) (93 mg) and 2-({2-[(6-bromohexyl)oxy]ethoxy}methyl)-1,3-dichlorobenzene (98 mg) in dimethylformamide (1 ml) and diisopropylethylamine (0.2 ml) was heated to 70° C. for 4 h and then at 20° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water, brine, dried and evaporated to dryness. The residue was dissolved in ethanol and applied to an SCX-2 cartridge (10 g) eluting with ethanol, followed by 10% aqueous ammonia in ethanol. The ammoniacal fractions were concentrated under reduced pressure, and the residue was dissolved in acetic acid (5 ml) and water (2 ml) and the mixture was heated to 70° C. for 40 min. The solvent was removed under reduced pressure and the residue was purified by chromatography on a silica SPE cartridge (10 g) eluting with 10% aqueous ammonia in ethanol-dichloromethane (1:9 to 1:3). Appropriate fractions were combined and concentrated and the residue dissolved in acetic acid and re-evaporated to dryness to give the title compound (124 mg). LCMS RT=2.46 min, ES+ve m/z 487/489/491 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C:14]1=[O:22].N1CCCCC1.Cl>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[C:15]1[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:13][C:14]1=[O:22])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: O=C1Cc2ccccc2N1
Agent: Cl
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCC2=C1C(=O)Nc2ccccc21
Temperature: 130 °C
Yield: 2.3 %

Procedure:
A mixture of 0.5 g 5-methoxy-1-indanone, 1.23 g oxindole and 2.7 ml piperidine in 4 ml dimethylforamide was heated in a sealed tube at 130° C. for 3 days to yield a greenish-black suspension. The mixture was added to 1N hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. Chromatography afforded 20 mg of 3-(5-methoxyindan-1-ylidene)-1,3-dihydroindol-2-one as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@H:14](O)[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1(P([N:35]=[N+:36]=[N-:37])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:35]=[N+:36]=[N-:37])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCC[C@@H]2O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)COc1cccc2c1CCC[C@H]2N=[N+]=[N-]
Temperature: 2.5 °C
Reaction time: 0.75 h

Procedure:
The toluene solution of chiral alcohol XI prepared above (36.19 mmol, assumed 100% conversion) was diluted with an additional 100 mL of toluene, and cooled in an ice-water bath, then treated with diphenylphosphoryl azide (13.64 g, 49.57 mmol). To this solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 8.0 g, 52.46 mmol), dropwise over 20 minutes at such a rate so as to maintain the internal temperature between 1-4° C. The reaction mixture was then stirred at an internal temperature of 1-2° C. for an additional 45 minutes, then warmed to room temperature (with a water bath), and stirred at room temperature overnight. After 20 hours, the reaction mixture was treated with ice-cold water (50 mL), while maintaining the internal temperature below 24° C. The organic layer was separated and washed with 1 M aqueous citric acid solution (50 mL), saturated aqueous sodium bicarbonate (50 mL), and water (50 mL). The resulting organic phase was then concentrated under vacuum at 20 mmHg/26° C., to provide 15 g of an oil, which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.CN(C=O)C>[CH2:19]([N:11]([C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(O)CCN(Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of N-benzyloxycarbonyl-β-alanine (11.16 g, 50.00 mmol) in anhydrous THF (160 mL) and DMF (40 mL) at 0° C. was slowly added NaH (60% in oil, 6.000 g, 150.0 mmol). After stirring at 0° C. for 15 min, benzyl bromide (9.10 mL, 75.00 mmol) was added. The reaction mixture was stirred at rt for 22 h. It was quenched with water (90 mL), followed by 1 N HCl (110 mL), and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by Combiflash (40-60% EtOAc/hexane) to afford 3-{benzyl[(benzyloxy)cabonyl]amino}propanoic acid as a viscous pale yellow oil (14.2 g, 91% in yield). MS (ESI): 312.0 (M−H).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C:14]([F:43])([C:33]([F:42])([F:41])[C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[N:24][CH:25]=1.[CH2:44](O)[CH2:45][CH2:46][CH2:47]/[CH:48]=[CH:49]\[CH2:50][CH3:51].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:43][C:14]([F:13])([C:33]([F:41])([F:42])[C:34]([F:39])([F:40])[C:35]([F:36])([F:37])[F:38])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[N:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:51][CH2:50][CH2:49][CH2:48]/[CH:47]=[CH:46]\[CH2:45][CH3:44])=[CH:30][CH:31]=2)=[N:22][CH:21]=1
Reactant: CC/C=C\CCCCO
Reactant: Oc1ccc(-c2ncc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cn2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC/C=C\CCCCOc1ccc(-c2ncc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cn2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of DEAD (0.261 g, 1.50 mmol) in THF (20 ml) was added dropwise to a stirred solution of 4-[5-(5,5,6,6,7,7,8,8,8-nonafluorooctyloxy)-pyrimidin-2-yl]-phenol (0.858 g, 1.50 mmol), cis-5-octene-1-ol (0.192 g, 1.50 mmol) and triphenylphosphine (0.939 g, 1.50 mmol) in THF (30 ml) and the reaction mixture stirred at room temperature for 24 h. The solvent was removed in vacuo and the residues purified by column chromatography [silica gel, eluted with hexane/ethyl acetate (4:1)] to yield a colorless solid, which was recrystallized from ethanol.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[N:4]=1.FC(F)(F)C(O)=O>ClCCl>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccc(C(F)(F)F)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccn(C2CCNCC2)n1
Yield: 127.7 %

Procedure:
To a dichloromethane solution (1.5 mL) of tert-butyl 4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (150 mg, 0.50 mmol) synthesized in Reference Synthesis Example 33, trifluoroacetic acid (0.7 mL) was added at room temperature, and the resultant solution was stirred for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and water was added to the concentrated reaction solution, followed by extraction from the resultant mixture with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (140 mg, quantitative).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH3:10])=[CH:4][C:3]=1[SH:11].CN(C=O)C.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25](=[O:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28]>O>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH3:10])=[CH:4][C:3]=1[S:11][CH2:24][C:25](=[O:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: COc1cc(C)cc(S)c1F
Reactant: COC(=O)CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)CSc1cc(C)cc(OC)c1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 2-fluoro-3-methoxy-5-methylbenzenethiol (289.4 mg) and DMF (dry) (12 mL) were added K2CO3 (255 mg) and methyl 4-chloro-3-oxobutanoate (0.217 mL) at 0° C. The mixture was stirred at room temperature for 1.5 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (330 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[S:7]1(=[O:24])=[O:23].[CH3:25][NH2:26].Cl>>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[CH2:11][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:26][CH3:25])[S:7]1(=[O:24])=[O:23]
Reactant: CN
Reactant: O=S1(=O)N(CCCCBr)Cc2ccccc2N1c1ccccc1F
Agent: Cl
Product: CNCCCCN1Cc2ccccc2N(c2ccccc2F)S1(=O)=O
Yield: 82 %

Procedure:
In an analogous manner to Example 11 step 5, 3-(4-bromobutyl)-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.11 g, 0.26 mmol) was reacted to methylamine and then treated with HCl to provide 4-[1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine (0.078 g, 82%) as a white solid:
Reaction SMILES: [C:1]1([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[C:23](OC=C)(=O)[CH3:24]>C1(C)C=CC=CC=1>[C:1]1([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH:23]=[CH2:24])=[O:21])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1
Reactant: C=COC(C)=O
Reactant: O=C(O)CCCc1ccc2ccc3cccc4ccc1c2c34
Solvent: Cc1ccccc1
Product: C=COC(=O)CCCc1ccc2ccc3cccc4ccc1c2c34
Temperature: 60 °C
Reaction time: 62 h

Procedure:
To a 500 mL, two neck flask equipped with a stir bar, argon inlet, and stopper is added 4-(1-Pyrenyl)butyric acid (10.0 grams, 34.7 mmol, obtained from Sigma-Aldrich, Milwaukee, Wis.), palladium acetate 1,10-phenanthroline complex (403 milligrams, 1 mmol) and vinyl acetate (128 milliliters, 1.39 mol, obtained from Sigma-Aldrich, Milwaukee, Wis.). Next, toluene (200 milliliters) is added, the solution is purged with argon and stirred magnetically at 60° C. for 62 hours. The excess vinyl acetate, along with acetic acid (co-product) is removed, an additional vinyl acetate (32 mL, 0.35 mol) is added, and the reaction is continued for 48 hours at 60° C. under argon to complete the reaction. The excess vinyl ester is removed, and the crude product is filtered to remove suspended catalyst residue, and the toluene is removed in vacuo to famish vinyl 4-(pyren-1-yl)butanoate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][NH:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=2)[C:14]([CH3:22])=[CH:13]1.C([O-])([O-])=O.[K+].[K+].[CH3:29][N:30]=[C:31]=[O:32]>O1CCCC1>[CH3:29][NH:30][C:31](=[O:32])[O:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:12]([NH:11][CH2:10][CH2:9][CH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[F:1])[CH:13]=[C:14]2[CH3:22]
Reactant: Cc1cn(NCCCc2ccncc2F)c2ccc(O)cc12
Reactant: CN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1ccc2c(c1)c(C)cn2NCCCc1ccncc1F
Reaction time: 15 h

Procedure:
To a solution consisting of 1-[(3-fluoro-4-pyridinyl)propylamino]-3-methyl-1H-indol-5-ol (2.10 g) and tetrahydrofuran (47 ml) was added milled K2CO3 (1.02 g) followed by dropwise addition of methyl isocyanate (0.46 ml) at room temperature under nitrogen. Stirring was continued for 15 hours, at which time the reaction mixture was filtered through a pad of celite and the solids washed with EtOAc. Concentration afforded the crude product. Purification via flash column chromatography (silica gel, 50% EtOAc/dichloromethane) afforded 2.35 g of the desired carbamate as a solid. The product was recrystallized from ether, m.p. 163°-164° C.