Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)[CH2:18][CH2:17]1.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][N:23]3[CH2:24][CH2:25][CH:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[CH2:27][CH2:28]3)[CH2:18][CH2:17]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: c1cc(C2CCN(CC3CCNCC3)CC2)ccn1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCC(CN2CCC(c3ccncc3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.5 %

Procedure:
A solution of 4-trifluoromethylphenylsulphonyl chloride (394 mg) in methylene chloride (4 ml) was added dropwise over 15 minutes to a mixture of 1-(4-piperidinylmethyl)-4-(4-pyridyl)piperidine hydrochloride (550 mg) and triethylamine (1.07 ml) in dichloromethane (10 ml) at 0° C. The solution was stirred at ambient temperature for 18 hours. The solution was diluted with dichloromethane and washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 2% methanol in dichloromethane. Recrystallisation from ethyl acetate/hexane gave, as a solid 1-[1-(4-trifluoromethylphenylsulphonyl)-(4-piperidinylmethyl)]-4-(4-pyridyl)piperidine (395 mg): NMR (CDCl3): 1.30 (m, 2H), 1.45 (m, 1H), 1.80 (m, 6H), 2.00 (dt, 2H), 2.20 (d, 2H), 2.30 (dt, 2H), 2.40 (m, 1H), 2.90 (d, 2H), 3.80 (d, 2H), 7.10 (d, 2H), 7.80 (d, 2H), 8.50 (d, 2H); m/z 468 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20](Cl)=[O:21])[CH:16]=[CH:17][CH:18]=1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:20](=[O:21])[CH2:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]ccc1C
Reactant: O=C(Cl)Cc1cccc(F)c1
Product: CCOC(=O)c1[nH]cc(C(=O)Cc2cccc(F)c2)c1C

Procedure:
4-[2-(3-Fluorophenyl)-acetyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester was synthesized from 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84) and (3-Fluorophenyl)-acetyl chloride following the procedure described in Example 32. Crude yield: 93%. 1H-NMR (400 MHz, CDCl3): δ 1.37 (t, 3H), 2.61 (s, 3H), 4.03 (s, 2H), 4.35 (q, 2H), 7.00 (m, 3H), 7.27 (m, 1H), 7.49 (d, 1H), 9.57 (s broad, 1H) ppm. 13C-NMR (100 MHz, CDCl3): □ 11.76, 14.38, 46.93, 60.84, 113.64, 116.30, 125.13, 127.17, 129.94, 137.42, 161.64, 193.02 ppm. DEPT (100 MHz, CDCl3): CH3 carbons: 11.76, 14.38; CH2 carbons: 46.93, 60.84; CH carbons: 116.30, 125.13, 127.17, 129.94 ppm. LC/MS: 91.29%, m/z=289.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[C:12]([F:14])[C:9]([CH2:10][OH:11])=[C:8]([Cl:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](Cl)=[O:30])[C@H:25]([CH2:32][CH3:33])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[CH2:1]([O:5][C:6]1[CH:13]=[C:12]([F:14])[C:9]([CH2:10][O:11][C:29]([N:26]2[CH2:27][CH2:28][N:23]([C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22])[CH2:24][C@H:25]2[CH2:32][CH3:33])=[O:30])=[C:8]([Cl:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Reactant: CCCCOc1cc(F)c(CO)c(Cl)c1
Product: CCCCOc1cc(F)c(COC(=O)N2CCN(C(=O)OC(C)(C)C)C[C@H]2CC)c(Cl)c1
Yield: 90 %

Procedure:
This compound was prepared from 4-butoxy-2-chloro-6-fluoro-benzylalcohol and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedure described in Example 179 to give the product as a colorless oil (505 mg; 90%); MS (ISP): 490.4 (M+NH4)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]([O:14][CH3:15])(=[O:13])[CH2:11][SH:12].CC(C)([O-])C.[K+]>CN(C=O)C>[CH3:15][O:14][C:10]([C:11]1[S:12][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]=1[NH2:5])=[O:13]
Reactant: N#Cc1ccccc1F
Reactant: COC(=O)CS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc2ccccc2c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a solution of 2-fluorobenzonitrile (9.0 g, 74.3 mmol) and methyl thioglycolate (13.3 mL, 148.6 mmol) in DMF (50 mL) at 0° C. was added potassium tert-butoxide portionwise (16.7 g. 149 mmol) over 15 min with vigorous stirring. The orange solution was warmed to rt and stirred for 1 h before being poured into 700 mL of vigorously stirring ice water. The precipitate was filtered and air-dried to give a pale yellow solid (13.6 g, 88%) that was used without purification. 1H NMR (CD3OD): 8.16-8.12 (m, 1H), 7.85-7.82 (m, 1H), 7.54-7.49 (m, 1H), 7.43-7.38 (m, 1H), 7.19 (s, 2H), 3.79 (s, 3H).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[C:7]([CH3:15])[C:6]=1[CH:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24]CC)=[O:23]>C(O)C>[CH3:3][O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[C:7]([CH3:15])[C:6]=1[CH:16]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)C(C)(C)CCCCC(c1ccccc1)c1c(C)c(OC)c(C)c(C)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(C)c(C)c(OC)c(C(CCCCC(C)(C)C(=O)O)c2ccccc2)c1C
Temperature: 90 °C
Reaction time: 15 h
Yield: 99 %

Procedure:
3N Sodium hydroxide (9 ml) was added to a solution of 1.20 g (2.73 mmole) of ethyl 7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-2,2-dimethyl-7-phenylheptanoate in ethanol (12 ml), followed by stirring at 90° C. overnight (15 hours). After cooling by standing at room temperature, the ethanol was distilled off under reduced pressure, and the residue was made acid by adding a 10% aqueous phosphoric acid solution, followed by extraction of the product with isopropyl ether. The isopropyl ether layer was washed with aqueous sodium hydrochloride solution, dried (magnesium suflate) and evaporated to give 1.11 q (99%) of 7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-2,2-dimethyl-7-phenylheptanoic acid. Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 14.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([OH:15])[C:10]([N:12]([CH3:14])[CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CC=CC=1.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([O:15][C:23]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[C:10]([N:12]([CH3:13])[CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C)C(=O)N(O)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC(C)O
Solvent: c1ccncc1
Product: CN(C)C(=O)N(OC(=O)Oc1ccccc1)c1ccc(Cl)c(Cl)c1

Procedure:
A solution of 1-(3,4-dichlorophenyl)-1-hydroxy-3,3-dimethylurea (12.5 grams; 0.05 mol) in isopropyl alcohol (40 ml), and pyridine (6 ml) are charged into a glass reaction flask equipped with a mechanical stirrer. Phenyl chloroformate (7.8 grams; 0.05 mol) is added to the flask, with stirring, at a temperature of about 10° to 15°C. After the addition is completed, the reaction mixture is stirred for an additional period of about one-half hour resulting in the formation of a precipitate. After this time, the reaction mixture is poured onto ice and the precipitate is recovered by filtration and is dried. The dried precipitate is recrystallized to yield 1-(3,4-dichlorophenyl)-1-phenoxycarbonyloxy-3,3-dimethylurea.
Reaction SMILES: [C:1]1(=[N:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:15]1[C:22](Cl)=[N:21][C:19](Cl)=[N:18][C:16]=1Cl>N1C=CC=CC=1>[C:1]1(=[N:13][O:14][C:16]2[N:18]=[C:19]([O:14][N:13]=[C:1]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[N:21]=[C:22]([O:14][N:13]=[C:1]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[N:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: ON=C1CCCCCCCCCCC1
Solvent: c1ccncc1
Product: C1CCCCCC(=NOc2nc(ON=C3CCCCCCCCCCC3)nc(ON=C3CCCCCCCCCCC3)n2)CCCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 35.4 %

Procedure:
To a cold (0° C.) solution of cyclododecanone oxime (7.89 g, 0.04 mol) in dry pyridine (30 ml) is added cyanuric chloride (1.84 g, 0.01 mol). An exothermic reaction occurs and the temperature rises to 20° C. The solution is then stirred 20 h at room temperature and then poured into 300 ml of ice-cold water. The precipitated solid is filtered off and chromatographed (silica gel, CH2Cl2—C2H5O(CO)CH3 95:5). The pure fraction is recrystallized from ethylacetate-hexane to afford 2.36 g of the title compound as a white solid, m.p. 104-107° C.
Reaction SMILES: Br[C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.[CH:16](=[O:18])[CH3:17]>>[OH:18][CH2:16][CH2:17][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2cc3ccccc3cc12
Reactant: CC=O
Product: OCCc1cccc2cc3ccccc3cc12

Procedure:
For instance, a Grignard reagent prepared from bromonaphthalene is reacted with acetophenone to obtain 1-phenyl-1-naphthylethanol which is then dehydrated to obtain 1-phenyl-1-naphthylethylene. Further, a Grignard reagent prepared from bromoanthracene is reacted with acetaldehyde to obtain hydroxyethylanthracene which is then dehydrated to obtain vinylanthracene.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].O>N1C=CC=CC=1>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH:10][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[F:11]
Reactant: O=C(Cl)c1ccccc1F
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(NNc1ccccc1Cl)c1ccccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.7 %

Procedure:
To a stirred solution, under nitrogen, of 89.5 g of 2-chlorophenylhydrazine hydrochloride in 600 ml of pyridine, cooled in an ice bath, was added, dropwise, 87.2 g of 2-fluorobenzoyl chloride, such that the reaction temperature did not exceed 15° C. The reaction mixture was stirred at ambient temperature for 16 hours and then poured into water. Crystallization of the resultant oil was induced by scratching. Recrystallization from toluene yielded 65.7 g (60%) of 2-fluorobenzoic acid, 2-(2-chlorophenyl)hydrazide, m.p. 105°-107° C.
Reaction SMILES: [C:1]1(=[C:8]([C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=2)[C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.O>C(Cl)Cl>[C:1]1(=[C:8]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C(=C2CCCCCC2)c2ccc(C#N)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Reaction time: 3 h
Yield: 85.9 %

Procedure:
To a cold (5° C.) solution of 4-{cycloheptylidene[4-(methyloxy)phenyl]methyl}benzonitrile (207) (0.300 g, 0.94 mmol) in CH2Cl2 (20 mL) was added BBr3 (0.358 mL, 3.79 mL). The resultant reaction mixture was stirred between 5° C. and 20° C. for 3 h. Reaction mixture was poured into water (125 mL) and then extracted with CH2Cl2 (3×50 mL). The combined organic layer was dried and concentrated under reduced pressure to afford the crude product. The product was purified by flash column chromatography to give 0.245 g (86%) of compound 208 as a white solid. mp 110-111° C. IR (film): 3391, 2921, 2852, 2229, 1609, 1509, 1213, 829, 731 cm−1. 1H NMR (300 MHz, CDCl3): δ 7.57 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.7 Hz, 2H), 6.79 (d, J=8.4 Hz, 2H), 4.97 (br s, 1H), 2.35 (br s, 2H), 2.29 (br s, 2H), 1.60 (br s, 8H). LCMS (ESI): m/z 302 (M−H)−. Anal. Calcd for C21H21NO, C, 83.13; H, 6.98; N, 4.62; Found: C, 83.13; H, 6.96; N, 4.62.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][C:31](Br)=[CH:32][CH:33]=4)[N:28]([CH3:36])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[O:24][CH3:25])(=[O:16])=[O:15])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:37]([O:39]CC)=[CH2:38].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:37]([C:31]1[CH:30]=[C:29]2[C:34]([C:26]([CH:10]([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[O:24][CH3:25])(=[O:16])=[O:15])=[O:12])=[CH:27][N:28]2[CH3:36])=[CH:33][CH:32]=1)(=[O:39])[CH3:38]
Reactant: C=COCC
Reactant: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(Br)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(C(C)=O)ccc12
Reaction time: 0.75 h

Procedure:
A mixture of 3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-6-bromo-1-methyl-1H-indole (from Example 85, 300 mg, 0.53 mmol), ethyl vinyl ether (0.063 ml), palladium(II)acetate (6 mg), tri-o-tolylphosphine (13 mg) and triethylamine (0.1 ml) in acetonitrile (5 ml) was heated at reflux for 18 hours under a nitrogen atmosphere. After cooling, the solvent was evaporated in vacuo and the residue was stirred with 2N hydrochloric acid (~6 ml) for 45 minutes. The mixture was twice extracted with ethyl acetate, and then washed with water, and brine. The organic layer was dried (magnesium sulphate) and the solvents were evaporated in vacuo. The residue was flash chromatographed using a gradient elution of a mixture of 90% hexane and 10% ethyl acetate, through to 40% hexane and 60% ethyl acetate, to give the title compound (80 mg).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[N:8][C:7]([C:15](=[NH:17])[NH2:16])=[N:6]1.[C:22]1([N:28]=[N:29][CH:30]([C:33]#[N:34])[C:31]#[N:32])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[N:8][C:7]([C:15]2[N:16]=[C:31]([NH2:32])[C:30]([N:29]=[N:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:33]([NH2:34])[N:17]=2)=[N:6]1
Reactant: N#CC(C#N)N=Nc1ccccc1
Reactant: N=C(N)c1nc(-c2nccs2)n(Cc2ccccc2F)n1
Solvent: CCO
Product: Nc1nc(-c2nc(-c3nccs3)n(Cc3ccccc3F)n2)nc(N)c1N=Nc1ccccc1
Temperature: 110 °C
Yield: 99 %

Procedure:
A suspension of 1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carboximidamide (Intermediate-6, 0.38 mmol) and 2-(phenyldiazenyl)malononitrile (1 equiv) in ethanol (6 mL) in a sealed tube was heated at 110° C. for 2 h. The reaction was conc. to afford 2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)-5-(phenyldiazenyl)pyrimidine-4,6-diamine as an orange solid (>99% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][CH:10]=[N:9][CH:8]=1.[O:12]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](O)=[O:28])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[O:28]=[C:27]([C:10]1[O:11][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:8][N:9]=1)[CH2:26][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:20][CH:21]=1
Reactant: c1ccc(-c2cnco2)nc1
Reactant: O=C(O)CCc1ccc(Oc2ccccc2)cc1
Product: O=C(CCc1ccc(Oc2ccccc2)cc1)c1ncc(-c2ccccn2)o1
Yield: 37 %

Procedure:
The title compound (11f) was prepared from 5-(2-pyridyl)oxazole and 3-(4-phenoxyphenyl)propanoic acid (S30) using General Procedure B. PTLC (SiO2, 50% EtOAc-hexanes) afforded 11f (83 mg, 0.22 mmol, 37%) as a pale yellow solid: 1H NMR (CDCl3, 500 MHz) 8.69 (m, 1H), 7.89-7.86 (m, 2H), 7.82 (td, 1H, J=7.8, 1.8 Hz), 7.34-7.30 (m, 3H), 7.24 (d, 2H, J=8.5 Hz), 7.10-7.07 (m, 1H), 6.98 (d, 2H, J=12.1 Hz), 6.94 (d, 2H, J=8.6 Hz), 3.47 (t, 2H, J=7.4 Hz), 3.10 (t, 2H, J=7.4 Hz); 13C NMR (CDCl3, 100 MHz) 187.2, 157.4, 157.1, 155.5, 153.3, 150.1, 146.2, 137.1, 135.2, 129.7, 129.6, 126.9, 124.1, 123.0, 120.4, 119.1, 118.6, 40.7, 29.0; IR (film) νmax 3055, 2930, 1698, 1589, 1504, 1488, 1425, 1380, 1237, 1167, 1065, 871, 784, 692 cm−1; ESI-TOF m/z 371.1388 (C23H18N2O3+H+ requires 371.1396).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:17]([C:21]([O:23]CC)=[O:22])=[C:18]([CH3:20])[N:19]=2)[CH:9]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:11]=1.[OH-].[Li+].Cl>C1COCC1.CO>[F:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:17]([C:21]([OH:23])=[O:22])=[C:18]([CH3:20])[N:19]=2)[CH:9]=[C:10]([N:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[CH:11]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(N3CCCC3)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2c(OCc3c(F)cccc3F)cc(N3CCCC3)cn2c1C(=O)O
Temperature: 40 °C
Reaction time: 20 h

Procedure:
90 mg of ethyl 8-[(2,6-difluorobenzyl)oxy]-2-methyl-6-(pyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carboxylate (Example 32A; 0.217 mmol, 1 equivalent) were dissolved in 6 ml of THF/methanol 5:1, 1.1 ml of 1N aqueous lithium hydroxide solution (1.1 mmol, 5 equivalents) were added and the mixture was warmed to 40° C. and stirred at this temperature for 20 h. The mixture was cooled, acidified to pH 4 with 6 N hydrochloric acid and concentrated. Water was added to the solid formed and the product was triturated, filtered off with suction, washed with water and dried under reduced pressure. This gave 87 mg of the title compound (93% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[CH2:20]([N:23]=[C:24]=[O:25])[CH2:21][CH3:22]>C1C=CC=CC=1>[N+:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:24]([NH:23][CH2:20][CH2:21][CH3:22])=[O:25])=[CH:19][C:6]=2[C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: CCCN=C=O
Reactant: Nc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Solvent: c1ccccc1
Product: CCCNC(=O)Nc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1

Procedure:
To a solution of 2 g. of 5-amino-2-nitro-3-phenylbenzofuran in 100 ml. of hot benzene is added 4 ml. of n-propyl isocyanate. The mixture is heated on a steam bath for 30 minutes, then evaporated to dryness. The residue is recrystallized from aqueous methanol to provide orange crystals of 2-nitro-3-phenyl-5-(n-propyl)ureidobenzofuran, m.p. 199°-201° C., having the structure ##STR21##
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][O:7][C@H:8]1[O:13][CH2:12][CH2:11][NH:10][C@@H:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36]>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CCOC(C)=O>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=1)[CH2:6][O:7][C@H:8]1[O:13][CH2:12][CH2:11][N:10]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)CCCCCBr
Reactant: FC(F)(F)c1cc(CO[C@H]2OCCN[C@@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCN1CCO[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccccc1
Temperature: 60 °C
Yield: 64.4 %

Procedure:
To a solution of 0.259 g (0.64 mmol) of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine (from example 33) in 2 mL of DMF were added 0.16 g (0.77 mmol) of methyl 6-bromohexanoate, 0.155 g (1.12 nmmol) of K2C03 and 2 crystals of nBu4NI. The resulting solution was heated in a 60° C. bath for 36 h, at which time a tlc indicated incomplete reaction. The bath temperature was raised to 100° C. After 3 h the reaction mixture was cooled and diluted with EtOAc. The EtOAc solution was washed with water (2×), brine and dried over Na2SO4. The filtrate was concentrated and the residue was chromatographed using 30% EtOAc/hexane to isolate 220 mg (65%) of the product. 1H-NMR (400 MHz, CDCl3): δ 1.0-1.4 (m, 4 H), 1.47 (m, J=8 Hz, 2H), 1.95 (m, 1H), 2.2 (t, J=8 Hz, 2H), 2.35 (m, 2H), 2.9 (d, J=13 Hz, 1H), 3.07 (d, J=7 Hz, 1H), 3.62 (s, 3H), 3.81 (td, J=8 Hz and 2 Hz, 1 H), 4.04 (dd, J=10 Hz and 2 Hz, 1H), 4.36 (d, J=7 Hz, 1H), 4.4 (d, J=13 Hz, 1H), 4.79 (d, J=13 Hz, 1H), 7.2-7.4 (m, 7H), 7.66 (s, 1H).
Reaction SMILES: [C:1]1([S:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17][CH2:18][C:19]#[CH:20])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.C1(C)C=CC(S(O)(=O)=[O:30])=CC=1>COCCOC>[C:1]1([S:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[S:17][CH:18]=[C:19]([CH2:20][OH:30])[C:15]=3[CH:16]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C#CCSc1ccc(OS(=O)(=O)c2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCOC
Solvent: O
Product: O=S(=O)(Oc1ccc2scc(CO)c2c1)c1ccccc1
Reaction time: 2 h
Yield: 187.8 %

Procedure:
The compound (3) (65.47 g, 183 mmol) obtained in above (2) was dissolved in 1,2-dimethoxyethane (1.6L) and the solution was refluxed for 4 hours. To the solution were added water (64 ml) and p-toluenesulfonic acid monohydrate (19.2 g, 100 mmol) and refluxing was continued for 2 hours. The reaction mixture was concentrated under reduced pressure. After water (200 ml) was added to the resulting oil, the mixture was extracted with ethyl acetate (300 ml). The organic layer was washed with aqueous sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure to provide 60.18 g of the title compound (4) as oil. Crude yield: 103%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@H:18]([OH:27])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:33]([Si:37]([CH3:40])([CH3:39])Cl)([CH3:36])([CH3:35])[CH3:34]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@H:18]([O:27][Si:37]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:40])[CH3:39])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CC[C@H]2O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)ccc4[C@H]3CC[C@]12C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
To a solution of 3-benzyloxyestra-1,3,5(10)-trien-17α-ol (49, 1.45 g, 4.0 mmol) in DMF (5.0 mL) were added imidazole (0.408 g, 6.0 mmol) and tert-butyldimethylchlorosilane (0.784 g, 5.2 mmol) at room temperature. The reaction mixture was stirred for 2 h, and quenched with saturated aqueous NaHCO3 at 0° C., and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and then dried (Na2SO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using n-hexane:CHCl3 :EtOAc (50:50:1→20:20:1, v/v) to afford 1.91 g of 50 (100% yield).