Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[CH2:9][N:10]([C:11]([NH:13][NH2:14])=[O:12])[C:4]=2[CH:3]=1.C(=O)(O)[O-].[Na+].[Cl:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32]>C(#N)C>[Cl:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([NH:14][NH:13][C:11]([N:10]1[CH2:9][C:8]2[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=2[O:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]1=2)=[O:12])=[O:32]
Reactant: O=C(Cl)CCCCCl
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C(CCCCCl)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 0.5 part of 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carboxylic acid hydrazide (U.S. Pat. No. 3,534,019) and 19.6 parts of acetonitrile is added 0.298 part of sodium bicarbonate followed by 0.6 part of 5-chloropentanoyl chloride. The solution is stirred for 48 hours at room temperature, after which time the solvent is removed under reduced pressure and the resulting residue is purified by recrystallization from ethyl acetate-cyclohexane to afford 1-(5-chloropentanoyl)-2-(8-chloro-10,11-dihydrodibenz[b,f]-[1,4]oxazepine-10-carbonyl)hydrazine, which has a melting point at about 148°-149° and is structurally represented by the following formula ##STR9## 14.8 Parts of the above chloride is reacted with 7.94 g of sodium iodide in 145 parts by volume of acetone containing a catalytic amount of sodium thiosulfate. The reaction mixture is stirred in the dark and refluxed for 5 hours and allowed to stand at room temperature. The solvent is removed and the residue taken up in benzene containing 1% sodium thiosulfate. The benzene is washed with aqueous sodium chloride and dried over sodium sulfate to provide an approximately 50-50 mixture of 1-(5-iodopentanoyl)-2-(8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carbonyl)hydrazine and the (5-chloropentanoyl) derivative. 8 Parts of this mixture is reacted with 1.65 parts of morpholine in 80 parts by volume of acetone for 48 hours. The acetone is removed and 10% hydrochloric acid and benzene is added to the benzene layer. The benzene layer is separated and the aqueous acid layer is made basic with 5% potassium hydroxide and then extracted with benzene. The benzene layer is washed with sodium chloride solution and dried over sodium sulfate. The solvent is removed and the residue is crystallized from ethyl acetatecyclohexane to provide 1-(5-morpholinopentanoyl)-2-(8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carbonyl)-hydrazine melting at 107°-114° C and having the following structural formula ##STR10##
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].N1C=CC=CC=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 4-fluoro-3-nitroaniline (0.5 g, 0.023 mol) in DCM (10 ml) and pyridine (0.98 g, 0.012 mol) was added methanesulfonyl chloride (0.54 g, 0.0048 mol) portion wise at 0° C. with constant stirring. The reaction mixture was allowed to stir at 0° C. for 4 h. The reaction mixture was concentrated and diluted with water (20 ml) and extracted with DCM (3×15 ml). The combined organic layers were washed with 1 N HCl and NaHCO3 solution dried over Na2SO4 and concentrated in vacuo to afford the desired product N-(4-fluoro-3-nitrophenyl)methane sulfonamide as off a white solid. 1H NMR (400 MHz, DMSO-d6), δ: 10.23 (s, 1H), 7.93-7.91 (d, J=8.4 Hz, 1H), 7.62-7.54 (m, 2H), 3.59 (s, 3H). LCMS (ES) m/e MS (M−1=233). Purity: 80%.
Reaction SMILES: O1CCOCCOCCOCCOCCOCC1.CC(C)([O-])C.[K+].[CH3:25][C:26]([CH3:46])([CH3:45])[CH2:27][C:28]([NH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:34]2)=[O:29].[F:47][C:48]([F:58])([F:57])[C:49]1[CH:56]=[CH:55][CH:54]=[CH:53][C:50]=1[CH2:51]Br>C1COCC1>[CH3:25][C:26]([CH3:45])([CH3:46])[CH2:27][C:28]([NH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([CH2:51][C:50]1[CH:53]=[CH:54][CH:55]=[CH:56][C:49]=1[C:48]([F:47])([F:57])[F:58])[C:35]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:34]2)=[O:29]
Reactant: CCOC(=O)c1cc2cc(NC(=O)CC(C)(C)C)ccc2[nH]1
Reactant: FC(F)(F)c1ccccc1CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(NC(=O)CC(C)(C)C)ccc2n1Cc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under argon, 35 mg (0.13 mmol) of 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6) are initially charged in 7 ml of THF, and 1.98 ml (1.98 mmol) of a 1-molar potassium tert-butoxide solution in THF and 400 mg (1.32 mmol) of ethyl 5-[(3,3-dimethylbutanoyl)amino]-1H-indole-2-carboxylate from Example LXII are added. The mixture is stirred at RT for 15 minutes and cooled to 0° C. A solution of 474 mg (1.98 mmol) of 2-trifluoromethylbenzyl bromide in 12 ml of THF is slowly added dropwise. The ice-bath is removed and the mixture stirred at RT for 1 hour. For work-up, the mixture is diluted with water and the THF is removed under reduced pressure using a rotary evaporator. The aqueous residue is extracted with ethyl acetate and the organic phase is washed with sat. sodium chloride solution, dried with sodium sulphate, filtered and dried under reduced pressure. The residue is purified by column chromatography (mobile phase: cyclohexane:ethyl acetate 5:1).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:38]1[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][C@@H:46]([NH:55][C:56]2[CH:61]=[CH:60][C:59]([S:62]([NH2:65])(=[O:64])=[O:63])=[CH:58][C:57]=2[N+:66]([O-:68])=[O:67])[CH2:47][S:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:40][CH2:39]1>>[Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:65][S:62]([C:59]3[CH:60]=[CH:61][C:56]([NH:55][C@H:46]([CH2:45][CH2:44][N:41]4[CH2:40][CH2:39][O:38][CH2:43][CH2:42]4)[CH2:47][S:48][C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)=[C:57]([N+:66]([O-:68])=[O:67])[CH:58]=3)(=[O:64])=[O:63])=[O:22])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: NS(=O)(=O)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c([N+](=O)[O-])c1
Product: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(N[C@H](CCN4CCOCC4)CSc4ccccc4)c([N+](=O)[O-])c3)cc2)CC1
Yield: 74.9 %

Procedure:
The title product (346.6 mg, yield: 75%) was prepared using a procedure similar to the one described for the synthesis of INTERMEDIATE 33. (R)-4-(4-((tert-Butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 13, 250.7 mg, 0.47 mmol) and (R)-4-(4-morpholino-1-(phenylthio)butan-2-ylamino)-3-nitrobenzenesulfonamide (INTERMEDIATE 74, 229.0 mg, 0.49 mmol) were used as starting materials. The resulting product was purified by column chromatography (ISCO, 12 g silica gel column, eluting with 0→10% MeOH/DCM), providing the title product.
Reaction SMILES: [O:1]=[C:2]([NH:16][CH2:17][CH2:18][C:19]([O:21]CC1C=CC=CC=1)=[O:20])/[C:3](/[CH2:11][S:12]C(=O)C)=[CH:4]\[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Li+].[OH-]>C1COCC1.O>[O:1]=[C:2]([NH:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])/[C:3](/[CH2:11][SH:12])=[CH:4]\[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)SC/C(=C/c1ccccc1)C(=O)NCCC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCNC(=O)/C(=C\c1ccccc1)CS
Yield: 63 %

Procedure:
To a solution of 2 mmol of the diester obtained in Example 1 (step D) dissolved in a THF/H2O (75/25) mixture, are added, at 0° C. and under an argon atmosphere, 8 mmol of LiOH with stirring for 2 hours. The THF is evaporated off and the aqueous phase is washed with ether and acidified with aqueous 3N HCl solution. It is extracted with ether and the ether extract is washed with saturated aqueous NaCl solution and dried over MgSO4. It is filtered and evaporated. Yield: 63% (after flash chromatography, eluent: ether) m.p. 80° C. IR (nujol): 3340, 1700, 1630, 1610 cm-1. 1H NMR (acetone D6): 10.90 to 10.60 (m, 1H); 7.65 (m, 1H); 7.45 to 7.35 (m, 5H); 7.20 (s, 1H); 3.75 to 3.50 (m, 4H); 2.60 (t, 2H, J=6.75 Hz); 2.30 (t, 1H, J=7.50 Hz) Microanalysis: C13H15O3NS Calc. % C=58.85 H=5.70 N=5.28 Found. % C=58.68 H=5.78 N=5.17
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][N:7]1C[CH2:11][CH2:10][CH2:9][C@@H:8]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1.CO>O>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C@H:8]3[CH2:9][CH2:10][CH2:11][N:7]3[CH2:6][CH2:5][CH2:4][C:3]([OH:2])=[O:29])=[CH:20][CH:19]=2)=[CH:27][CH:26]=1
Reactant: COC(=O)CCCN1CCCC[C@@H]1COc1ccc(Cc2ccc(Cl)cc2)cc1
Solvent: CO
Solvent: O
Product: O=C(O)CCCN1CCC[C@@H]1COc1ccc(Cc2ccc(Cl)cc2)cc1
Yield: 77 %

Procedure:
A slurry of 4-{(R)-2-[4-(4-chloro-benzyl)-phenoxymethyl]-piperidin-1-yl}-butyric acid methyl ester (570 mg, 1.42 mmol) in 4:1 methanol:water (6 mL) was stirred at 50° C. for 18 h. The solvent was removed in vacuo. The mixture was diluted with water (25 mL), brought to pH 7 with 2N HCl and extracted with ethyl acetate (100 mL). The aqueous layer was re-extracted with ethyl acetate (1×80 mL). The combined organic layers were dried over anhy. Na2SO4 and the solvent was removed in vacuo to obtain the title product as a white solid (424 mg, 77%); HPLC 99.2%; 1H NMR (400 MHz, DMSO-d6) δ 1.55-1.70 (m, 5H), 1.89-1.94 (m, 1H), 2.17-2.26 (m, 3H), 2.33-2.38 (m, 1H), 2.77-2.87 (m, 2H), 3.02-3.07 (m, 1H), 3.70-3.74 (dd, 1H J1=6.4 Hz, J2=10.8 Hz), 3.84-3.88 (m, 1H), 3.856 (s, 2H), 6.84 (d, 2H, J=8.8 Hz), 7.11 (d, 2H, J=8.8 Hz), 7.22 (d, 2H, J=8.4 Hz); 7.32 (d, 2H, J=8.4 Hz)
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[N:7][CH:6]=1)[NH2:4].[F:11][C:12]1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[CH:17][C:13]=1[C:14](Cl)=O.N>>[N:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:4]=[C:14]([C:13]3[CH:17]=[CH:18][C:19]([F:22])=[C:20]([F:21])[C:12]=3[F:11])[O:1][N:2]=2)=[CH:6][N:7]=1
Reactant: NC(=NO)c1ccnnc1
Reactant: O=C(Cl)c1ccc(F)c(F)c1F
Agent: N
Product: Fc1ccc(-c2nc(-c3ccnnc3)no2)c(F)c1F

Procedure:
The titled compound was prepared according to the procedure of Method D using the product of Example 83D and 2,3,4-trifluorobenzoyl chloride (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.40-7.50 (m, J=9.3, 9.3, 7.0, 2.2 Hz, 1H), 8.10-8.20 (m, 1H), 8.39 (dd, J=5.4, 2.4 Hz, 1H), 9.46 (dd, J=5.3, 1.2 Hz, 1H), 9.87 (dd, J=2.2, 1.2 Hz, 1H) ppm; MS (DCI/NH3) m/z=279 (M+H)+.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Br:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.[OH:33][CH:34]1[CH2:37][NH:36][CH2:35]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:36]4[CH2:37][CH:34]([OH:33])[CH2:35]4)[C:21]=3[Br:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: OC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Br)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(O)C4)c(Br)c32)c(F)cc1F
Temperature: 85 °C
Reaction time: 0.42 h
Yield: 81.8 %

Procedure:
To 270 mg of N,N-dimethylformamide were added 110 mg of 1-(6-amino-3,5-difluoropyridine-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 50 mg of 3-hydroxyazetidine hydrochloride, and 100 mg of N-methy-lpyrrolidine together with 3 drops of ethanol, and the mixture was stirred at 85° C. for 25 minutes. After adding 0.5 ml of ethanol, the solution was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 101 mg of the title compound as a pale yellow powder.
Reaction SMILES: Br[C:2]1[C:3]([C:20]2[S:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.[OH:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[Cl:25][C:22]1[S:21][C:20]([C:3]2[C:2]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([OH:26])[CH:32]=3)=[CH:7][N:6]=[C:5]([NH:8][CH2:9][CH2:10][N:11]3[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]3=[O:19])[N:4]=2)=[CH:24][CH:23]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2ccc(Cl)s2)n1
Reactant: OB(O)c1cccc(O)c1
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(-c2cccc(O)c2)c(-c2ccc(Cl)s2)n1

Procedure:
The title compound was prepared from 1-{2-[5-bromo-4-(5-chlorothiophen-2-yl)pyrimidin-2-ylamino]ethyl}-5,5-dimethylimidazolidine-2,4-dione and 3-hydroxyphenylboronic acid in a manner analogous to Example 269. MS (M+H)+ 458.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClC(Cl)C.[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[CH3:19][N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][C:26]#[N:27].Cl>>[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([C:24]1[N:20]([CH3:19])[C:21]([CH2:25][C:26]#[N:27])=[CH:22][CH:23]=1)=[O:13]
Reactant: Cn1cccc1CC#N
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cn1c(CC#N)ccc1C(=O)c1ccccc1Cl
Temperature: 25 °C

Procedure:
To a cooled suspension of 14 g. (0.105 mole) aluminum chloride in 45 ml. dichloroethane is added dropwise, 18.5 g. (0.1 05 mole) o-chlorobenzoyl chloride. The resulting solution is added dropwise to a cooled (0° C.) solution of 1-methylpyrrole-2-acetonitrile in 45 ml. dichloroethane keeping the temperature at approximately 10° C. The mixture is stirred at room temperature for about twenty minutes, and then refluxed for three minutes. It is poured into ice acidified with 3N hydrochloric acid, and the resulting two layers are separated. The aqueous fraction is extracted twice with chloroform. The organic fractions are combined and washed twice with N,N-dimethyl-1,3-propanediamine, once with 3N hydrochloric acid and once with saturated sodium chloride solution. The organic fraction is dried over anhydrous magnesium sulfate. The solvent is evaporated, and the resulting oil is chromatographed on a column packed with neutral alumina using benzene and ether as successive solvents. The first compound-bearing fractions contain the desired product. The solvent is evaporated and the resulting oil crystallizes upon treatment with methanol. The solid product, 5-(o-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile, is purified by recrystallization from benzene:cyclohexane solution, m.p. 80-85° C.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH:9]([C:16]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([OH:26])=[C:18]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>COCCOC>[C:22]([C:20]1[CH:21]=[C:16]([CH:17]=[C:18]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:19]=1[OH:26])[N:9]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C1CCCC(=O)O1
Reactant: CC(C)(C)c1cc(Nc2ccccc2)cc(C(C)(C)C)c1O
Solvent: COCCOC
Product: CC(C)(C)c1cc(N(C(=O)CCCC(=O)O)c2ccccc2)cc(C(C)(C)C)c1O

Procedure:
1.1 g (0.010 mole) of glutaric anhydride, 3.0 g (0.010 mole) of the known compound 4-anilino-2,6-di-t-butylphenol, and 30 ml of 1,2-dimethoxyethane were combined and heated at reflux for 24 hours. The volume of the reaction was reduced by two-thirds under a stream of nitrogen, and the reaction was heated for another 24 hours. The remaining solvent was removed under vacuum on a rotary evaporator. The resulting solid was recrystallized twice from a mixture of benzene and hexane and then twice from a mixture of ethanol and water to give 0.6 g of off-white crystalline 5-(3,5-di-t-butyl-4-hydroxy-N-phenylanilino)- 5-oxopentanoic acid, m.p. 168°-170° C. Analysis: Calculated for C25H33NO4 : % C, 73.0; % H, 8.1; % N, 3.4: Found: % C, 73.2; % H, 8.0; % N, 3.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:12][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[CH:14]=[CH2:13]
Reactant: COC(=O)c1cc(Cl)ccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(Cl)cc1C(=O)OC

Procedure:
A mixture of methyl 5-chloro-2-hydroxybenzoate (2c) (45.0 g, 0.24 mol), allyl bromide (62.6 ml, 0.75 mol) and ground potassium carbonate (66.67 g, 0.48 mol) in 750 ml of dry acetone was heated under reflux for 21/2 hours. The inorganic salt was removed by filtration, and the solvent and excess allyl bromide in the filtrate was evaporated to dryness to yield compound 3c quantitatively as a white solid, mp 25°-26° C. IR (nujol) 1738 (ester) cm-1. NMR (CDCl3) δ 7.63 (d, 1H, JBC =3 Hz, HC), 7.27 (d of d, 1H, JAB =9 Hz, HB), 6.77 (d. 1H, HA), 6.30-6.47 (m, 3H, olefinic protons) and 3.87 (s, 3H, CH3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([F:22])=[CH:24][CH:25]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Reactant: Fc1ccc(CBr)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2ccc(F)cc2)cc1
Yield: 49.8 %

Procedure:
Followed the same procedure as that of step 2 in Example 91 with the use of (R)-2-(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.5 mmol) and 4-fluoro-benzyl bromide (150 mg, 0.75 mmol) to afford the title product (100 mg, 50% yield); LCMS, 100% APCI+, Calcd. 401.48. Found: 402.34 m/z (M+1). 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.80-2.10 (m, 4H), 3.39 (br, 2H), 3.70-3.90 (m, 1H), 4.02-4.19 (m, 2H), 4.97 (s, 2H), 6.82-6.89 (m, 2H), 7.06 (t, J=8.0 Hz, 2H), 7.23-7.28 (m, 2H), 7.35-7.42 (m, 2H).
Reaction SMILES: [Cl:1][C:2]([Li])=[CH:3][O:4]CC.BrC(=[C:12]1[C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C:26](=[CH:27][CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][CH2:23]2)[CH2:18][CH2:17]3)[CH2:14][CH2:13]1)C=O>>[Cl:1][C:2](=[C:12]1[C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C:26](=[CH:27][CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:31])[CH:22]=[CH:23]2)[CH2:18][CH2:17]3)[CH2:14][CH2:13]1)[CH:3]=[O:4]
Reactant: [Li]C(Cl)=COCC
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=C(Br)C=O)CC[C@@H]12
Product: C[C@]12C=CC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=C(Cl)C=O)CC[C@@H]12

Procedure:
reacting androsta-1,3,5,9(11)-tetraene-17-one-3-diethylenamine with a cis-trans mixture of 2-chloro-2-lithio-1-ethoxyethylene to give a compound of the formula: ##STR38## (2) hydrolysis of the product of step (1) with acid to give 20-chloropregna 1,4,9(11),17(20)-tetraen-3-one-21-al (IVb) and
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]([N:15]([CH3:17])[CH3:16])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[N:36]1([CH2:45][C:46](O)=[O:47])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37]1>CO>[CH3:16][N:15]([CH3:17])[C:6]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:46](=[O:47])[CH2:45][N:36]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=[CH:37]2)[CH2:8][CH2:7]1
Reactant: CN(C)C1(c2ccccc2)CCC(CN)CC1
Reactant: O=C(O)Cn1ccc2ccccc21
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)Cn2ccc3ccccc32)CC1

Procedure:
A mixture of the diastereoisomers of (4-aminomethyl-1-phenylcyclohexyl)dimethylamine (465 mg, 2.0 mmol.) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (830 mg, 3 mmol.) was added to a solution of indol-1-ylacetic acid (350 mg, 2.0 mmol.) in abs. methanol (25 ml), and the reaction mixture was stirred for 2 d at RT. For working up, the mixture was concentrated, water (15 ml) was added to the residue, the pH was adjusted to 11 with 5M NaOH and extraction was carried out with EE (3×15 ml). The combined extracts were dried, filtered and concentrated. The residue was a diastereoisomeric mixture of the bases of the target products, which was separated by flash chromatography on silica gel (70 g) and purified (eluant: methanol/EE 500 ml 1:3, then 1000 ml 1:1). 244 mg of the non-polar diastereoisomer of N-(4-dimethylamino-4-phenylcyclohexylmethyl)-2-indol-1-yl-acetamide were obtained in the form of a viscous oil. 50 mg (0.128 mmol.) thereof were dissolved in 2-butanone (2 ml), and chlorotrimethylsilane (24.4 μl, 0.193 mmol.) was added thereto. There immediately formed a pale precipitate, which turned a strong colour within a few minutes. The solid was filtered off with suction, washed with ether (3×0.5 ml) and dried in vacuo. The hydrochloride 7/8 of the non-polar target product was thus obtained in a yield of 52 mg (brick-red solid, m.p. 176–186° C.).
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][NH2:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:14])[CH:8]=2)[N:3]=1.[C:15](OCC)(OCC)(OCC)[CH2:16][CH3:17]>>[Cl:1][C:2]1[C:11]2[N:10]([C:15]([CH2:16][CH3:17])=[N:13][N:12]=2)[C:9]2[C:4]([N:3]=1)=[CH:5][CH:6]=[C:7]([Cl:14])[CH:8]=2
Reactant: NNc1nc2cc(Cl)ccc2nc1Cl
Reactant: CCOC(CC)(OCC)OCC
Product: CCc1nnc2c(Cl)nc3ccc(Cl)cc3n12
Temperature: 25 °C
Yield: 62 %

Procedure:
2,6-Dichloro-3-hydrazinoquinoxaline (1.0 g., 0.0044 mole), the product of Preparation L(a), was refluxed with 15 ml. of triethyl orthopropionate for 4 hours and cooled to room temperature. The precipitate was recovered by filtration, washed with cyclohexane and air dried to afford 730 mg. (62% yield) of 4,8-dichloro-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. >250° C.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[Cl:12][C:13]1[C:19]([CH2:20][OH:21])=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>C(O)(=O)C>[Cl:12][C:13]1[C:19]([CH2:20][OH:21])=[CH:18][C:16]([N:17]2[C:1](=[O:11])[C:2]3[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=3[C:4]2=[O:6])=[CH:15][CH:14]=1
Reactant: Nc1ccc(Cl)c(CO)c1
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)c(CO)c1
Reaction time: 16 h
Yield: 38.4 %

Procedure:
To 50 ml of acetic acid, 2.47 g of 3,4,5,6-tetrahydrophthalic anhydride and2.56 g of 4-chloro-5-hydroxymethyl aniline were added and the mixture was heated to reflux under stirring for 16 hours. After cooling, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography (silica gel, benzene/ethyl acetate=10/1 (v/v)) to obtain 1.82 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]2[CH2:9][CH:8]2[C:10]([O:12]C(C)(C)C)=[O:11])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[S:6][C:5]([CH:7]2[CH2:9][CH:8]2[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C2CC2C(=O)OC(C)(C)C)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C2CC2C(=O)O)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl 2-(5-methylthien-2-yl)cyclopropanecarboxylate (100 mg, 0.42 mmol) in CH2Cl2 (3 mL) at RT was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at RT for 10 min and concentrated in vacuo. The crude 2-(5-methylthien-2-yl)cyclopropanecarboxylic acid was used without further purification. M.S.(M+1) 182