Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH2:11]([OH:15])[C:12]#[C:13][CH3:14].CC(C)([O-])C.[K+].Cl>CN(C=O)C>[CH2:11]([O:15][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1)[C:12]#[C:13][CH3:14]
Reactant: O=C(O)c1cnc(Cl)cn1
Reactant: CC#CCO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cnc(C(=O)O)cn1
Temperature: 65 °C
Yield: 11.4 %

Procedure:
To a slurry of 5-chloro-pyrazine-2-carboxylic acid (0.79 g, 5.00 mmol) in DMF (35 mL) were added 2-butyn-1-ol (3.74 mL, 50.0 mmol) and potassium tert-butoxide (2.24 g, 20.0 mmol). The resulting mixture was heated at 65° C. overnight. The reaction mixture was neutralized with 2 M HCl and then concentrated in vacuo. A part (400 mg) of the crude material was partitioned between 0.5 M NaOH and a 1:1 mixture of heptane and EtOAc. The aqueous phase was made slightly acidic (pH-3-4) by addition of 1 M HCl. To the obtained suspension was added NaCl (s) and the mixture was extracted twice with EtOAc. The combined organic phases were dried (Na2SO4) and evaporated to give 0.11 g of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.84 (t, 3 H), 5.06 (q, 2 H), 8.42 (d, 1 H), 8.82 (d, 1 H), 13.38 (br. s., 1 H); MS (ES+) m/z 193 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[N:7][N:6]([C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[CH2:17][OH:18])[CH2:3][CH2:2]1.[CH3:19][O:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][C:28]([C:32]3[CH:37]=[CH:36][C:35](O)=[CH:34][C:33]=3[CH3:39])=[CH:29][CH:30]=2)[N:25]([CH:40]([CH3:42])[CH3:41])[N:24]=1)=[O:22].C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:19][O:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][C:28]([C:32]3[CH:37]=[CH:36][C:35]([O:18][CH2:17][C:5]4[N:6]([C:9]5[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=5[Cl:16])[N:7]=[N:8][C:4]=4[CH:1]4[CH2:3][CH2:2]4)=[CH:34][C:33]=3[CH3:39])=[CH:29][CH:30]=2)[N:25]([CH:40]([CH3:42])[CH3:41])[N:24]=1)=[O:22]
Reactant: COC(=O)c1nn(C(C)C)c2cc(-c3ccc(O)cc3C)ccc12
Reactant: OCc1c(C2CC2)nnn1-c1c(Cl)cccc1Cl
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1nn(C(C)C)c2cc(-c3ccc(OCc4c(C5CC5)nnn4-c4c(Cl)cccc4Cl)cc3C)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
Nitrogen is bubbled through a solution of [5-cyclopropyl-3-(2,6-dichloro-phenyl)-3H-[1,2,3]triazol-4-yl]-methanol (0.23 g, 0.80 mmol) and 6-(4-hydroxy-2-methyl-phenyl)-1-isopropyl-1H-indazole-3-carboxylic acid methyl ester (0.2 g, 0.62 mmol) in toluene (10 mL) for 10 minutes. Tri-n-butyl phosphine (0.21 mL, 1.05 mmol) is added. Nitrogen is bubbled for an additional 10 min followed by addition of 1,1′-(azocarbonyl)-dipiperidine (0.27 g, 1.05 mmol). The reaction is stirred at room temperature for 18 h. The crude reaction is concentrated onto silica and chromatographed (40 g SiO2, 0% to 40% EtOAc/Hexanes) to yield the title compound (0.11 g, 30%). LC-ES/MS m/e 590.0 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])[C:4]=1[CH3:19].[C-:20]#[N:21].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:11]=1[CH2:10][O:9][C:5]1[C:4]([CH3:19])=[C:3]([CH2:2][C:20]#[N:21])[CH:8]=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: Cc1cccc(C)c1COc1cccc(CBr)c1C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1COc1cccc(CC#N)c1C

Procedure:
The solution of 1-(bromomethyl)-3-(2,6-dimethylbenzyloxy)-2-methylbenzene (Step D, 4.28 g, 13.41 mmol) and NaCN (0.789 g, 16.10 mmol) in dry DMF (20 ml) was heated at 120° C. for 3 hours then cooled and diluted with EtOAc (50 ml). The organic layer was washed with water (30 ml), brine, dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex: ethyl acetate 4:1) to give the title compound.
Reaction SMILES: [C:1]([CH:5]([CH:21]1[CH2:24][C:23](=[O:25])[C:22]1(Cl)Cl)[C:6]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[O:7][SiH3:8])([CH3:4])([CH3:3])[CH3:2].C(OCC)C>C(O)(=O)C.[Zn]>[C:1]([CH:5]([CH:21]1[CH2:22][C:23](=[O:25])[CH2:24]1)[C:6]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[O:7][SiH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(C1CC(=O)C1(Cl)Cl)C(O[SiH3])(c1ccccc1)c1ccccc1
Agent: [Zn]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)(C)C(C1CC(=O)C1)C(O[SiH3])(c1ccccc1)c1ccccc1
Temperature: 60 °C
Yield: 44 %

Procedure:
Zinc dust (15.7 g, 0.24 mol) was added to a solution of 3-(tert-butyl-diphenyl-siloxyethyl)-2,2-dichlorocyclobutanone (17 g, 0.04 mol) in glacial acetic acid (68 mL) at room temperature. The reactants were heated at 60° C. for 1 hr, after which time dry diethyl ether was added to the cooled products, which were then filtered. The residue was washed with diethyl ether and the combined filtrate and washings were concentrated under reduced pressure. The residue was dissolved in CH2Cl2, which was washed with saturated NaHCO3 twice and water once. The organic phase was dried over MgSO4 and the solvent was evaporated to give an oily product, which was purified by silica gel flash chromatography (Hexane: EtOAc=12:1) to give a colorless oil (6.2 g, 43.7%). 1H NMR (CDCl3, 400 MHz): δ 1.06 (s, 9H), 1.82-1.87 (m, 2H), 2.48-2.60 (m, 1H), 2.65-2.71 (m, 2H), 3.07-3.14 (m, 2H), 3.69-3.73 (t, J=6.0, 6.4, 2H), 7.37-7.46 (m, 6H), 7.65-7.73 (m, 4H). 13C NMR (CDCl3, 100 MHz): δ 19.37, 26.76, 27.06, 39.02, 52.87, 62.87, 127.91, 129.88, 129.92, 133.86, 208.89. IR (neat) νmax 2957, 2930, 2857, 1784, 1472, 1428, 1388, 1112, 822, 739, 702.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH2:15]=O.O.[CH3:18][C:19]([CH3:21])=[O:20]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH2:15][CH2:18][C:19](=[O:20])[CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(C2CCCN2)cc1Cl
Reactant: C=O
Reactant: CC(C)=O
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CC(=O)CCN1CCCC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To the solution of 4 g (18.5 mmol) 2-(3,4-dichlorophenyl)-pyrrolidine in 10 ml acetone, during ice-water cooling, the mixture of 10 ml acetone and 1.6 ml cc. hydrochloric acid is added. The mixture is stirred for 15 minutes under cooling for 10 minutes at room temperature, then the solution of 0.83 g (9.3 mmol) paraformaldehyde in 9.2 ml iso-propanol is added and the reaction mixture is heated at reflux temperature for 4 hours. After cooling, 15 ml of water is added and the mixture is extracted with 3×20 ml dichloromethane, dried over sodium sulfate and evaporated in vacuum. The residue is crystallized in hexane to obtain 2.11 g title compound. Mp: 160-162° C.
Reaction SMILES: F[C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[OH-:18].[Na+].Cl>O>[F:12][C:11]1[CH:10]=[C:9]2[C:4]([NH:5][C:6](=[O:14])[C:7](=[O:13])[NH:8]2)=[C:3]([N+:15]([O-:17])=[O:16])[C:2]=1[OH:18]
Reactant: O=c1[nH]c2cc(F)c(F)c([N+](=O)[O-])c2[nH]c1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c2cc(F)c(O)c([N+](=O)[O-])c2[nH]c1=O
Temperature: 105 °C
Yield: 80.4 %

Procedure:
A mixture of 24 mg (0.098 mmol) of 6,7-difluoro-5-nitro-1,4-dihydroquinoxaline-2,3-dione and 19 mg (0.47 mmol) of sodium hydroxide in 0.6 mL of D2O was heated at 105° C. for 24 h. The mixture was added to 2 mL of water and acidified with 2 N HCl to pH=1. The precipitate was filtered, washed with water, and dried to leave a red solid (19 mg, 80%); mp>360° C.; 1H NMR (DMSO-d6), 7.101 (1, d, J=10.9), 11.10 (mb, 1), 11.70 (mb, 1), 11.99 (s, 1). 19F NMR, −137.4 (mb). MS 242 (M++1, 100), 195 (50), 152 (20), 140 (25). HRMS, Calcd for C8H4FN3O5 241.0131, found 241.0110.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[CH:16]=[N:17][C:18]([C:21]#[N:22])=[N:19][CH:20]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:23]O.[OH-].[Na+]>C(O)C.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[CH:16]=[N:17][C:18]([C:21]([NH2:22])=[O:23])=[N:19][CH:20]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OO
Reactant: COc1ccc(-c2cnc(C#N)nc2)cc1OC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cnc(C(N)=O)nc2)cc1OC1CCCC1
Reaction time: 0.25 h

Procedure:
To a stirred mixture of the compound of Example 14 (1.3 g) in ethanol (8 ml) was added hydrogen peroxide (40 vols, 15 ml) and 6M aqueous NaOH (6 ml). After 15 min, the reaction mixture was diluted with water (75 ml) andthe white solid filtered off. Recrystallisation from acetonitrile furnishedthe title compound (200 g) as small white plates (mp235°-238°C.). Found C, 65.06; H, 6.09; N, 13.44. C17H19N3O3 requires C, 65.16; H, 6.11; N, 13.41%.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]([CH:17]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=3)[CH2:18]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[CH:33]1([NH2:36])[CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)[Cl:52]>>[ClH:52].[C:1]([N:5]1[C:9]([NH:10][C:11](=[O:16])[C:12]([F:15])([F:13])[F:14])=[CH:8][C:7]([CH:17]2[CH2:18][CH:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:36][CH:33]4[CH2:35][CH2:34]4)[CH:22]=3)[CH2:20]2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCl
Reactant: CC(C)(C)n1nc(C2CC(c3cccc(C=O)c3)C2)cc1NC(=O)C(F)(F)F
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)n1nc(C2CC(c3cccc(CNC4CC4)c3)C2)cc1NC(=O)C(F)(F)F
Product: Cl
Reaction time: 0.5 h

Procedure:
To a stirring solution of N-{2-tert-butyl-5-[3-(3-formyl-phenyl)-cyclobutyl]-2H-pyrazol-3-yl}-2,2,2-trifluoro-acetamide (0.49 g, 1.25 mmol) in CH2Cl2 (13 mL) was added acetic acid (86 uL, 1.5 mmol), followed by cyclopropylamine (103 uL, 1.5 mmol). After 30 min, sodium triacetoxyborohydride (0.53 g, 2.5 mmol) was added. The reaction was quenched after four hr. with a saturated solution of NaHCO3. The aqueous layer was extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. Formation of the hydrochloride salt was accomplished using 2M HCl in Et2O to give the title compound (0.53 g). This material was used without further purification.
Reaction SMILES: [CH2:1]([C:5]1[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[H][H].Br[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=2[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:24][CH:25]=1>CN(C=O)C>[CH2:1]([C:5]1[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[N:7]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=3[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:24][CH:25]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)c1ccccc1-c1ccc(CBr)cn1
Reactant: CCCCc1n[nH]c(CCCC)n1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc(CCCC)n(Cc2ccc(-c3ccccc3C(=O)OCC)nc2)n1
Temperature: 0 °C

Procedure:
Under nitrogen, 630 mg (3.5 mmol) of 3,5-dibutyl-1H-1,2,4-triazole from step 3 of Example 1 was added in small portions to 5.4 mmol of sodium hydride in 8 mL of DMF; stirring was continued until hydrogen evolution had ceased. The anion solution was cooled to 0° C. and treated with a solution of the crude ethyl 2-(5-bromomethyl-2-pyridinyl)benzoate from step 7 in 10 mL of DMF. The reaction was stirred at ambient temperature overnight, quench with 1 mL of absolute ethanol, and concentrated in vacuo; the resulting residue was redisolved in methylene chloride, filtered, and reconcentrated in vacuo to give crude ethyl 2-[5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-pyridinyl]benzoate.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][C:14]=1[N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[CH2:25][CH2:24]1>N1C=CC=CC=1>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:5]=[C:6]([NH:7][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:12])=[C:14]([N:23]3[CH2:28][CH2:27][N:26]([C:29](=[O:34])[C:30]([F:33])([F:31])[F:32])[CH2:25][CH2:24]3)[CH:15]=2)(=[O:21])=[O:20])[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1N1CCN(C(=O)C(F)(F)F)CC1
Reactant: Nc1cccc(OC(F)F)c1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cccc(OC(F)F)c2)cc1N1CCN(C(=O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.3 %

Procedure:
0.429 g of 3-(difluoromethoxy)-aniline (2.7 mmol) were dissolved in 5 mL of pyridine. 1 g of 4-methyl-3-[4-(2,2,2-trifluoro-acetyl)-piperazin-1-yl]-benzenesulfonylchloride (2.7 mmol) were added slowly at room temperature. After stirring for 16 h at room temperature, the reaction mixture was evaporated several times after addition of toluene. The residue was dissolved in dichloromethane and washed several times with 5% aqueous ammonium chloride. The organic phase was then washed with saturated aqueous sodium chloride, dried over sodium sulphate, filtered, and the solvent evaporated. The crude product was purified via silica gel chromatography using dichloromethane/methanol (0-5%) to yield 0.63 g of product.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH:26]2[O:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:19][CH:18]=1)=[O:16].C(O)C.[BH4-].[Na+].Cl>O1CCCC1.O>[OH:16][CH:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH:26]2[O:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:19][CH:18]=1)[CH2:14][CH2:13][C:3]1[N:4]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:6][C:2]=1[CH3:1]
Reactant: Cc1oc(-c2ccccc2)nc1CCC(=O)c1ccc(CCCC2OC(=O)NC2=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1CCC(O)c1ccc(CCCC2OC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
To a solution of 5-[3-[4-[3-(5-methyl-2-phenyl-4-oxazolyl)propionyl]phenyl]propyl]-2,4-oxazolidinedione (0.25 g) in tetrahydrofuran (THF) (10 ml)-ethanol (10 ml), sodium borohydride (0.05 g) was added, followed by stirring at room temperature for 2 hours. The reaction mixture was poured over water, neutralized with 2N HCl and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and then concentrated under reduced pressure; the residue was purified by silica gel column chromatography. From the fraction eluted with ethyl acetate-chloroform (1:1), 5-[3-[4 -[1-hydroxy-3-(5-methyl-2-phenyl-4oxazoly) propyl]phenyl]propyl]-2,4-oxazolidinedione (0.16 g, 64%) was obtained, which was then recrystallized from acetone-isopropyl ether to yield colorless needles having a melting point of 150°-151° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O>C(Cl)(Cl)Cl>[C:12]1([C:10]2[N:1]=[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]3[CH:9]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1ccccn1
Solvent: ClC(Cl)Cl
Product: c1ccc(-c2cn3ccccc3n2)cc1

Procedure:
0.1 m. Quantitites of 2-aminopyridine and α-bromoacetophenone are heated in 150 ml. of chloroform at reflux for 2 hours. The chloroform is evaporated and the oily residue taken up in 10% HCl, warmed, charcoal added and filtered. The filtrate is neutralized with NH4OH and the solid product isolated and recrystallized from ethanol. The yield of product is 12.7 g., melts at 135°-137° C. and has the structure: ##STR13##
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[CH2:16](N(CC)CC)C.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28].C(OCC)(=O)C>C(Cl)Cl>[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](=[O:28])[CH2:16][NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CCN(CC)CC
Reactant: COC(=O)c1[nH]c2cc(Cl)ccc2c1N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1[nH]c2cc(Cl)ccc2c1NCC(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Suspend the 3-amino-2-carbmethoxy-6-chloroindole (1 g, 4.45 mmol) in methylene chloride (50 mL) and add triethylamine (0.416 mL, 4.6 mmol) to produce a mostly clear solution. Add the m-fluorobenzoyl chloride (0.561 mL, 4.6 mmol) and stir for five minutes at room temperature to produce a thick white precipitate. Dilute the reaction with ethyl acetate (700 mL), rinse with water, dry over magnesium sulfate, filter and concentrate in vacuo to 300 mL. Recrystallize by adding hot hexane (150 mL) to the already hot solution of ethyl acetate to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.[I:25]I.Cl>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])[C:5]([I:25])=[CH:4][CH:3]=1
Reactant: II
Reactant: CC(C)(C)C(=O)Nc1cccc(Cl)n1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1nc(Cl)ccc1I
Reaction time: 3 h

Procedure:
To a dry solution of N-(6-chloropyridin-2-yl)-2,2-dimethyl propionamide (Preparation 107, 8.0 g, 37.6 mmol) in THF (120 mL), cooled to −78° C., was added dropwise, a solution of tert-butyllithium in pentane (1.7M, 48.7 mL, 82.8 mmol) over 40 min. The reaction was stirred at —78° C. for 3 h before adding a solution of iodine (11.46 g, 45.1 mmol) in THF (40 mL) dropwise. The mixture was brought up to rt and stirred for 16 h. 2M HCl (3 mL) was added to the reaction, and after 20 min the solvent was removed in vacuo. Crude material was partitioned between ethyl acetate (200 mL) and water (150 mL). Organics were separated and washed with 10% sodium thiosulfate solution (4×100 mL) then NaHCO3 solution (2×100 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2) to give the title compound. m/z (ES+)=338.93 [M+H]+.
Reaction SMILES: [CH:1]1([CH:4]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:9]=2)[CH2:3][CH2:2]1.[Br:29]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH:1]1([CH:4]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:5][CH2:6][CH:7]([Br:29])[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: Fc1ccc(CCCC(c2ccc(Cl)cc2)C2CC2)cc1Oc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(C(Br)CCC(c2ccc(Cl)cc2)C2CC2)cc1Oc1ccccc1
Yield: 88.6 %

Procedure:
A stirred solution of 2.0 grams (0.005 mole of 1-cyclopropyl-1-(4-chlorophenyl)-4-(4-fluoro-3-phenoxyphenyl)butane and 0.9 gram (0.005 mole) of N-bromosuccinimide in 50 mL of carbon tetrachloride was irradiated for 2 hours with a sun lamp. The reaction mixture was cooled and filtered. The filtrate was concentrated under reduced pressure, yielding 2.1 grams of 1-cyclopropyl-1-(4-chlorophenyl)-4-bromo-4-(4-fluoro-3-phenoxyphenyl)butane. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([C:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)C1C=CC=CC=1.[CH:17]1C(Cl)=CC=C(Cl)C=1>CCCCCC>[CH2:10]1[CH:11]2[CH:12]3[CH:13]=[CH:14][CH:15]([CH:16]2[CH:1]=[CH:8]1)[CH2:17]3
Reactant: Clc1ccc(Cl)cc1
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Solvent: CCCCCC
Product: C1=CC2C3C=CC(C3)C2C1

Procedure:
A one mole equivalent sample of product II and two mole equivalent of dibenzylketone is heated for 4 hours in a mechanically stirred dichlorobenzene solution. The mixture is diluted with addition of hexane and the solid product is filtered, washed with hexane and dried. Purification of this product may be carried out by recrystallization from acetone or methyl ethyl ketone. ##STR41## where: Ph=phenyl rings.
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:18]
Reactant: OCCOc1ccccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCCCCCC
Product: CCOC(=O)COCCOc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
To a solution of 2-phenoxyethan-1-ol (1.5 mL, 12.7 mmol) in dichloromethane (50 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (1.1 mL, 10.5 mmol). The reaction mixture is stirred at rt overnight. The reaction mixture is diluted with heptane, and filtered. The filtrate is evaporated, and the residue vacuum distilled to give 1.95 g of the product 440. 1H NMR (CDCl3) δ 7.40-7.25 (m, 2H), 7.10-6.90 (m, 3H), 4.30-4.15 (m, 5H), 4.15-4.05 (m, 1H), 4.05-3.90 (s, 2H), 1.28 (t, 3H)
Reaction SMILES: OO.C(O[C:10]([C:12](F)(F)F)=[O:11])(C(F)(F)F)=O.C(C1N=[N+:20]([O-:34])[C:21]2[CH:30]=[C:29]3[C:25]([CH2:26][CH:27](CCO)[CH2:28]3)=[CH:24][C:22]=2[N:23]=1)C.C(O)(C(F)(F)F)=[O:36]>C(Cl)Cl.C(Cl)(Cl)Cl.N>[N+:20]([C:21]1[CH:30]=[C:29]2[C:25]([CH2:26][CH2:27][CH2:28]2)=[CH:24][C:22]=1[NH:23][C:10](=[O:11])[CH3:12])([O-:34])=[O:36]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCc1nc2cc3c(cc2[n+]([O-])n1)CC(CCO)C3
Reactant: O=C(O)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
H2O2 (70%, 0.27 mL, ca. 5.6 mmol) was added dropwise to a stirred solution of TFAA (0.77 mL, 5.6 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C. and added to a solution of 1-oxide 161 (144 mg, 0.56 mmol) and TFA (0.1 mL, 1.2 mmol) in CHCl3 (10 mL) at 0° C. The solution was stirred at 20° C. for 22 h, diluted with dilute aqueous NH3 solution until basic and extracted with CHCl3 (3×20 mL). The combined organic fraction was stirred with Et3N for 45 min, dried and the solvent evaporated. The residue was purified by chromatography, eluting with EtOAc/pet. ether, to give (i) starting material 161 (35 mg, 24%) and (ii) 1,4-dioxide 162 (92 mg, 60%) as a yellow solid: mp 152-155° C.; 1H NMR δ 8.29 (s, 1H, H-9), 8.24 (s, 1H, H-5), 3.77-3.82 (m, 2H, CH2O), 3.29-3.38 (m, 2H, H-6, H-8), 3.20 (q, J=7.5 Hz, 2H, CH2), 2.73-2.90 (m, 3H, H-6, H-7, H-8), 1.84 (q, J=6.6 Hz, 2H, CH2), 1.43 (t, J=7.5 Hz, 3H, CH3), 1.34 (t, J=4.9 Hz, 1H, OH); 13C NMR δ 155.8, 154.3, 149.8, 139.2, 133.8, 115.9, 113.9, 61.3, 39.6, 39.1, 37.8, 37.5, 23.9, 9.3. Anal. calcd for C14H17N3O3: C, 61.1; H, 6.2; N, 15.3. Found: C, 60.8; H, 6.3; N, 14.9%.
Reaction SMILES: [C@@H:1]1([C:8]([OH:10])=[O:9])[CH2:4][CH2:3][C@@H:2]1[C:5]([OH:7])=[O:6].OS(O)(=O)=O.[CH2:16](O)[CH2:17][CH2:18][CH3:19]>>[C@@H:1]1([C:8]([O:10][CH2:4][CH2:1][CH2:2][CH3:3])=[O:9])[CH2:4][CH2:3][C@@H:2]1[C:5]([O:7][CH2:16][CH2:17][CH2:18][CH3:19])=[O:6]
Reactant: O=C(O)[C@H]1CC[C@H]1C(=O)O
Reactant: CCCCO
Agent: O=S(=O)(O)O
Product: CCCCOC(=O)[C@H]1CC[C@H]1C(=O)OCCCC

Procedure:
1 g (6.94 mmol) of cis-cyclobutane-1,2-dicarboxylic acid in 50 ml of n-butanol were heated under reflux with 0.3 g of conc. H2SO4 for 90 min. The mixture was then concentrated to about 5 ml and poured into dil. NaHCO3 solution, extracted with ethyl acetate, dried over sodium sulphate and concentrated. Purification was carried out chromatographically over silica gel (mobile phase: petroleum ether:ethyl acetate 100:2>100:5).