Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(CCCOCc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1ccc(CCCOCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
To a solution of 4-[3-(benzyloxy)propyl]benzaldehyde (1.86 g, 7.31 mmol) in ethanol (28 mL), sodium borohydride (83 mg, 2.19 mmol) was slowly added at room temperature. The mixture was stirred for 1 h. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (3×50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was used without purification.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]=[CH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](O)=[O:44])=[CH:30][CH:29]=1.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[OH:3][C:2]1[CH2:4][O:5][C:6](=[O:7])[C:1]=1[C:43](=[O:44])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH:35]=[CH:34][C:31]1[CH:30]=[CH:29][C:28]([Cl:27])=[CH:33][CH:32]=1
Reactant: O=C1COC(=O)C1
Reactant: O=C(O)CCCCCCCC=Cc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCCCCCCC=Cc1ccc(Cl)cc1)C1=C(O)COC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
To a stirring solution of 189 mg (1.89 mmol) of tetronic acid in 15 mL of dimethylformamide is added 290 μL (2.08 mmol) of triethylamine and 8 mg (66 μmol) of 4-dimethylaminopyridine at 0° C. Next, 427 mg (2.22 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 690 mg (2.20 mmol) of 10-(4-chlorophenyl)dec-9-enoic acid as a mixture of E and Z isomers are added and the reaction mixture is stirred overnight at room temperature. The reaction is acidified with 1.0N HCl and extracted three times with ethyl acetate. The combined organic layers are washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue is purified via flash chromatography on a 40 mm×150 mm silica gel column eluting with 5% methanol/ethyl acetate to give 400 mg (58%) of pure 4-hydroxy-3-[10-(4-chlorophenyl)-1-oxodec-9-enyl] -2(5H)-furanone as a mixture of E and Z isomers.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][S:12](=[O:22])(=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:6]=1[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1.[H-].[Na+].[Br:32][C:33]1[CH:34]=[N:35][C:36](Cl)=[N:37][CH:38]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Br:32][C:33]1[CH:34]=[N:35][C:36]([O:1][CH2:2][CH2:3][O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][S:12](=[O:21])(=[O:22])[NH:13][C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[C:6]=2[C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)=[N:37][CH:38]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Cc1ccc(NS(=O)(=O)Nc2ncnc(OCCO)c2-c2ccc(C)cc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(NS(=O)(=O)Nc2ncnc(OCCOc3ncc(Br)cn3)c2-c2ccc(C)cc2)cc1
Reaction time: 0.25 h
Yield: 52.5 %

Procedure:
To 4-methyl-phenyl sulfamic acid-[6-(2-hydroxy-ethoxy)-5-(p-tolyl)-4-pyrimidinyl]-amide (47 mg, Example 11) dissolved in THF (8 ml) was added sodium hydride (14.6 mg, 60% dispersion in mineral oil) and stirring was continued for 15 min followed by the addition of 5-bromo-2-chloro-pyrimidine (39 mg). Stirring was continued for 2 h at 50° C. and 80 h at r.t. The mixture was evaoprated and a 10% citric acid solution was added. The precipitate was filtered off, washed with water and purified by chromatography over silicagel with EtOAc/Hex=1/1 to give 4-methyl-phenyl sulfamic acid-[6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(p-tolyl)-4-pyrimidinyl]-amide (34 mg). tR=5.34 (LC); [M+H]+=573.02 (ES+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[C:22](Cl)=[N:21][CH:20]=[CH:19][N:18]=2)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:25][NH2:26]>CCO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:17]3[C:22](=[N:21][CH:20]=[CH:19][N:18]=3)[NH:26][N:25]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1nccnc1Cl
Solvent: O
Solvent: CCO
Product: c1ccc(COc2ccc(-c3n[nH]c4nccnc34)cc2)cc1

Procedure:
To a solution of [4-(benzyloxy)phenyl](3-chloropyrazin-2-yl)methanone (1.23 g) in EtOH (20 mL) was added hydrazine hydrate (0.37 mL) at room temperature, and the mixture was refluxed for 2 h. The mixture was concentrated under reduced pressure. The residue was partitioned between AcOEt/THF (1/1) and saturated NaHCO3 aqueous solution. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residual crystals were recrystallized from THF/AcOEt to give the title compound (0.60 g).
Reaction SMILES: [C:1]([O:5]O)(C)([CH3:3])[CH3:2].[CH:7]1[CH2:11][CH2:10][CH2:9][CH:8]=1>>[CH:1]1([OH:5])[CH2:3][CH2:8][CH:7]=[CH:2]1.[C:7]1(=[O:5])[CH2:11][CH2:10][CH:9]=[CH:8]1
Reactant: CC(C)(C)OO
Reactant: C1=CCCC1
Product: O=C1C=CCC1
Product: OC1C=CCC1
Yield: 10 %

Procedure:
East German Pat. No. 81650 issued on May 5, 1971 discloses the use of Rh(Pφ3)3Cl and a large amount of t-butyl hydroperoxide (with oxygen) for the oxidation of cyclopentene at 45° C. This reaction was slow giving 2-cyclopentenol in 7% yield along with 10% of 2-cyclopentenone.
Reaction SMILES: FC(F)(F)C1C=CC=CC=1[C:5]([NH:7][C@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[NH:13][C:14]1[CH:19]=[N:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1)=[O:6].Cl.FC(F)(F)C1N=CC(N[C@H]2CCC[C@@H]2N)=NC=1.[CH:48]1([C:51]2[C:52](C(O)=O)=[N:53][CH:54]=[CH:55][CH:56]=2)[CH2:50][CH2:49]1>>[CH:48]1([C:51]2[C:52]([C:5]([NH:7][C@H:8]3[CH2:12][CH2:11][CH2:10][C@@H:9]3[NH:13][C:14]3[CH:19]=[N:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)=[O:6])=[N:53][CH:54]=[CH:55][CH:56]=2)[CH2:50][CH2:49]1
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ccccc1C(F)(F)F
Reactant: O=C(O)c1ncccc1C1CC1
Agent: Cl
Agent: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ncccc1C1CC1

Procedure:
Prepared according to the procedure for 2-(trifluoromethyl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 62) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 75 mg, 0.30 mmol) and 3-cyclopropylpyridine-2-carboxylic acid (Intermediate 16; 50 mg, 0.31 mmol) to afford the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:25][S:26]([C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27].CC(C)([O-])C.[K+].Cl>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[C:19]([CH2:25][S:26]([C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)(=[O:27])=[O:28])[CH:20]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(OC2CCCN(Cc3ccccc3)C2)cc1
Reactant: O=S(=O)(CCl)c1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OC2CCCN(Cc3ccccc3)C2)cc1CS(=O)(=O)c1cccc2ccccc12
Temperature: -40 °C
Reaction time: 5 h
Yield: 73.2 %

Procedure:
A mixture of 1-benzyl-3-(4-nitrophenoxy)piperidine (1.0 g, 3.14 mmoles) and 1-chloromethanesulfonylnaphthalene (0.9 g, 3.8 mmoles) in THF at −78° C. was treated dropwise with a solution of 1M potassium t-butoxide (9 mL, 9 mmoles) over a 30 minute period, warmed to −40° C., stirred at −40° C. for 5 hours, poured into cold 2N HCl and extracted with EtOAc. The extracts were combined, dried over Na2SO4 and concentrated under vacuum. The resultant residue was purified by normal phase HPLC on a silica column, using as eluent 40% EtOAc/hexane, to afford the title compound as an off-white solid (1.2 g, 2.3 mmoles).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([CH3:9])=[C:6](Cl)[N:7]=1.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[O:27][CH3:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(COC)OC.C(Cl)(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[N:4][C:5]=2[CH3:9])=[CH:20][C:19]=1[O:27][CH3:28])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1nnc(Cl)nc1Cl
Reactant: COc1cc(B(O)O)ccc1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: COc1cc(-c2nc(Cl)nnc2C)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
A degassed solution of 3,5-dichloro-6-methyl-1,2,4-triazine (151 mg, 0.9 mmol), 4-(benzyloxy)-3-methoxybenzene boronic acid (236 g, 0.9 mmol), tetrakis(triphenylphosphine)palladium(0) (55 mg, 0.05 mmol) and tripotassium phosphate (249 mg, 1.2 mmol) in dimethoxyethane (5 mL) was heated at reflux for 24 h. Upon cooling to room temperature the solution was diluted with CHCl3 and filtered through Celite®. The filtrate was concentrated in vacuo and the product purified by column chromatography using ethyl acetate-hexane (25:75) as eluent to furnish (75 mg, 22%).
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.Cl[C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[CH2:42][C:41](=[O:43])[C:40]([CH3:45])([CH3:44])[CH2:39]2)=[C:34]([F:46])[CH:33]=1.[CH3:47][N:48]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N>[CH3:44][C:40]1([CH3:45])[C:41](=[O:43])[CH2:42][CH:38]([C:35]2[CH:36]=[CH:37][C:32]([C:47]#[N:48])=[CH:33][C:34]=2[F:46])[CH2:39]1
Reactant: CC1(C)CC(c2ccc(Cl)cc2F)CC1=O
Reactant: CN1CCCC1=O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC1(C)CC(c2ccc(C#N)cc2F)CC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
Di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (1.75 g, 4.11 mmol) is added to a solution of 4-(4-chloro-2-fluoro-phenyl)-2,2-dimethyl-cyclopentanone (33 g, 137.10 mmol), zinc cyanide (9.66 g, 82.26 mmol), and N-methylpyrrolidone (148.50 mL) at 125° C. and the mixture is stirred for 15 minutes. π-Allylpalladium(II) chloride dimer (0.76 g, 4.11 mmol) is added to the solution and the mixture is stirred for 30 minutes. Diatomaceous earth (15 g) is added and the mixture is cooled to rt. The mixture is filtered through diatomaceous earth and washed with MTBE (450 mL). Water (450 mL) is added and the mixture is extracted with MTBE (150 mL). The mixture is washed with brine, dried over MgSO4, filtered, and concentrated to dryness to give the title compound (34 g, 97%). 1H NMR (300.16 MHz, CDCl3) δ 7.47-7.33 (m, 3H), 3.76-3.63 (m, 1H), 2.83-2.76 (m, 1H), 2.43-2.33 (m, 1H), 2.25 (dd, J=6.3, 12.6 Hz, 1H), 1.91 (t, J=12.3 Hz, 1H), 1.168 (s, 3H), 1.147 (s, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(OC(=O)C)(=O)C.[N+:24]([O-])([OH:26])=[O:25]>O>[N+:24]([C:6]1[CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:10][C:5]=1[NH:4][C:1](=[O:3])[CH3:2])([O-:26])=[O:25]
Reactant: CC(=O)Nc1ccc(-c2ccccc2)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(-c2ccccc2)cc1[N+](=O)[O-]

Procedure:
To a mixture of 4-acetamido-1,1′biphenyl (21.1 g, 0.1 mol) and 150 mL of acetic anhydride maintained between 8° C. and 13° C. is slowly added dropwise over 32 minutes 12.7 mL of 70% nitric acid. The reaction mixture is added to 600 mL of a mixture of water and ice and the resultant precipitate is collected by filtration. The filter cake is washed with water and the residue is recrystallized from methanol (800 mL) to give 23.6 g of the title compound as a yellow crystalline solid melting at 129–132° C.
Reaction SMILES: FC(F)(F)C1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)N=1.ClC1N=C(C(F)(F)F)[CH:23]=[CH:22][N:21]=1.C([O-])([O-])=O.[K+].[K+].CCN(C(C)C)C(C)C>C(#N)C.CN(C=O)C>[CH3:23][C:22]1[C:5]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)=[N:6][CH:7]=[CH:8][N:21]=1
Reactant: FC(F)(F)c1ccnc(N2C[C@@H]3CCNC[C@@H]32)n1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nccnc1N1C[C@@H]2CCNC[C@@H]21

Procedure:
The title compound was prepared in a manner analogous to Intermediate 27, substituting 2-chloro-3-methylpyrazine for 2-chloro-4-(trifluoromethyl)pyrimidine. In addition, DMF and K2CO3 at 95° C. was used in place of DIPEA and ACN.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][OH:29])[CH2:23][CH2:22]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH:28]=[O:29])[CH2:23][CH2:22]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CCO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CCC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
159 g of oxalic acid chloride was dissolved in one liter of dichloromethane, in to which 195.8 g of dimethyl sulfoxide was dropped at -67° C., followed by agitation for 30 minutes. Thereafter, 200 ml of dichloromethane dissolving 66 g of 1-benzyloxycarbonyl-4-(2-hydroxyethyl)piperidine was dropped at -67° C. Subsequently, 380 g of triethylamine was dropped at -67° C., followed by agitation for about 1 hour. After removal of the solvent by distillation, ethyl acetate was added and insoluble matters were removed by filtration, and the resultant filtrate was washed with water and dried with anhydrous magnesium sulfate, followed by filtration and removal of the solvent by distillation. The resultant residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate: hexane=20:80) to obtain 55.0 g of the captioned compound (yield 84%).
Reaction SMILES: C1(N[N:8]=[C:9]([C:11]2[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:13][O:14][C:15]=2[CH3:16])[CH3:10])C=CC=CC=1>O>[CH3:16][C:15]1[O:14][N:13]=[C:12]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:11]=1[C:9]1[NH:8][C:17]2[C:22]([CH:10]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: CC(=NNc1ccccc1)c1c(-c2ccccc2)noc1C
Solvent: O
Product: Cc1onc(-c2ccccc2)c1-c1cc2ccccc2[nH]1
Reaction time: 3 h

Procedure:
To 1350 grams of polyphosphoric acid at 100° to 110° C., there is added portionwise 89.3 g. (0.307 mole) of 1-(5-methyl-3-phenyl-4-isoxazolyl)-1-ethanone phenyl hydrazone, while maintaining the temperature between 105° and 115° C. After addition is complete the mixture is stirred at 100° to 110° C. for 3 hours. The mixture is then poured onto ice and water and the resulting solid is filtered and washed with water. The solid is then dissolved in ether, washed with water, dried and evaporated partially and cooled in ice. The resulting solid is filtered and washed with cold ether to give 2-(5-methyl-3-phenyl-4-isoxazolyl)-indole; m.p. 145° to 146° C.
Reaction SMILES: [CH4:1].[C:2]([N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17])(OCC)=O.[C:18](=[O:21])([O-])[O-:19].[Na+].[Na+]>[OH-].[Na+]>[C:8]1(=[O:17])[N:7]([C@@H:2]([CH2:1][CH2:9][CH2:10][CH2:11][OH:12])[C:18]([OH:19])=[O:21])[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: O=C([O-])[O-]
Reactant: C
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Temperature: 35 °C
Reaction time: 8 h

Procedure:
The above crude reaction mixture was heated to 35° C. and treated with about 600 ml of 6N sodium hydroxide followed by 1N sodium hydroxide to adjust to pH of 7.5 (final volume was about 5.3 l). To this mixture was added 0.6 g of porcine kidney acylase I. After stirring overnight at 35° C the pH was 7.25. The pH was adjusted to 7.5 and an additional 300 mg of acylase was added. After stirring overnight, the reaction appeared to be about 90% complete. The reaction mixture was next treated with 20 g of charcoal and 20 g of Celite®, then heated to 85° C. and maintained at that temperature for 10 minutes, then cooled to 50° C. and filtered. At this point, the total volume of the filtrate was about 4.9 l. The filtrate was cooled to 5° C. and solid sodium carbonate was added to adjust the pH to 9.3. N-Carbethoxy-phthalimide (263.04 g, 1.2 mol) was added in one portion and sodium carbonate was added as needed to keep the pH at 9.3. After 2 hours at 5° C. followed by 3 hours at room temperature, the pH dropped to 8.5 and most of the reagents had dissolved. The reaction mixture was filtered, cooled to 5° C. and acidified to pH 2.3 with 6N hydrochloric acid. The precipitated solid was collected by filtration and washed with 200 ml of cold water, then dried in vacuo to yield 220 g of title product.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[N:11]([CH3:19])[C:10]=1[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)(O)=[O:2].S(Cl)([Cl:28])=O>C1(C)C=CC=CC=1>[Cl:28][C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[N:11]([CH3:19])[C:10]=1[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: Cn1c(-c2cccnc2)c(CCCCCC(=O)O)c2cc(Cl)ccc21
Solvent: Cc1ccccc1
Product: Cn1c(-c2cccnc2)c(CCCCCC(=O)Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 1.52 g of 3-(5-carboxypentyl)-5-chloro-1-methyl-2-(3-pyridyl)indole in 50 ml of toluene under nitrogen is added dropwise at room temperature 0.31 ml of thionyl chloride. The resulting mixture is heated under reflux for 1 hour. An additional 0.10 ml portion of thionyl chloride is added and the solution is stirred at room temperature overnight. The resulting suspension is evaporated to dryness to give 3-(5-chlorocarbonylpentyl)-5-chloro-1-methyl-2-(3-pyridyl)indole. A suspension of the acid chloride in 20 ml of concentrated ammonium hydroxide is stirred at room temperature overnight. The resulting solid is filtered off to yield 3-(5-carbamoylpentyl)-5-chloro-1-methyl-2-(3-pyridyl)indole.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[Cl:20])[NH2:16].P(Cl)(Cl)Cl>ClC1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:13]([Cl:12])[CH:14]=2)=[O:9])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: ClP(Cl)Cl
Solvent: Clc1ccccc1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1cc(Br)ccc1O
Reaction time: 18 h
Yield: 46.2 %

Procedure:
A slurry of 5-bromosalicylic acid (15 g, 69 mmol) and 3,4-dichloroaniline (19.85 g, 73 mmol) and phosphorous trichloride (4.74 g 34.5 mmol) in 300 ml of chlorobenzene was refluxed for 3 hr. The hot solution was filtered through a glasswool plug and allowed to stand at room temperature for 18 hr. The crystals which deposited were collected by filtration and washed with fresh chlorobenzene and then methylene chloride to give after drying 19 g (76%) of product mp 230-233°. HPLC tr 19.25 min (Vydac HS5215 C18 ODS, 2.1×150 mm, 0.2 mL/min, gradient, A: water−0.1% trifluoroacetic acid B: acetonitrile−0.1% trifluoroacetic acid, 90-10% A during 20 min, UV detection at 214 nm). Recrystallization from chlorobenzene and then acetone gave 11.5 g of crystals, mp 237-2380°. The structure was verified by X-ray crystallography.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:9].[Na+].[CH2:11]([CH:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14](Cl)=[O:15])[CH3:12]>O>[CH2:11]([CH:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]([CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][NH2:7])[C:1]([OH:8])=[O:9])=[O:15])[CH3:12]
Reactant: CCCCC(CC)C(=O)Cl
Reactant: O=C1CCCCCN1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CCCCC(CC)C(=O)C(CCCCN)C(=O)O
Temperature: 20 °C

Procedure:
113 g (1.0 mol) of ε-caprolactam are dissolved in 200 ml of water, and refluxed for 4 hours with 120 g (1.0 mol) of 33% sodium hydroxide solution. The batch is cooled to 20° C., and 158.4 g (0.975 mol) of 2-ethylhexanoic acid chloride as well as simultaneously about 120 g of 33% sodium hydroxide solution (for maintaining a pH of 12) are added dropwise within 1 hour at 20°-25° C. The solution is further stirred until no sodium hydroxide solution is consumed any longer, and subsequently acidified at 50° C. with semiconcentrated hydrochloric acid in order to obtain a pH of 1. Separation is carried out in warm state, and the acid is washed with 350 ml of water. Subsequently, it is dehydrated in a rotation evaporator at 75° C./100 mm Hg, and separated as nearly colorless viscous oil, which solidifies to crystals after some time. Yield 233 g (93%). Acid number 225, water content 0.4%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[N:7][C:6]([C:14]#[N:15])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[F:24].[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[NH:16][C:5]1[C:4]2[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)[CH:3]=2)[N:8]=[N:7][C:6]=1[C:14]#[N:15]
Reactant: COc1cc2nnc(C#N)c(Nc3ccc(C)cc3F)c2cc1Br
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc2nnc(C#N)c(Nc3ccc(C)cc3F)c2cc1-c1ccncc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 69.9 %

Procedure:
To a mixture of 6-bromo-4-(2-fluoro-4-methylphenylamino)-7-methoxycinnoline-3-carbonitrile (Method 38, 0.25 g, 0.65 mmol), pyridin-4-ylboronic acid (0.159 g, 1.29 mmol) and K2CO3 (0.357 g, 2.58 mmol) in DMA (3.0 ml) and water (0.30 ml), was added Pd(Ph3P)4 (0.224 g, 0.19 mmol). The reaction was stirred under argon at 90° C. for 12 hours, cooled, diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extract was dried (MgSO4), filtered, and the residue purified with silica chromatography (EtOAc) to give 0.175 g (64%) product. m/z 386.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:10][C:11]2[O:12][C:13]3[C:19]([NH2:20])=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH:31]=O.C([BH3-])#N.[Na+]>>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:10][C:11]2[O:12][C:13]3[C:19]([NH:20][CH2:31][C:27]4[NH:26][CH:30]=[CH:29][N:28]=4)=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(Cc2nc3cccc(N)c3o2)cc1OC1CCCC1
Reactant: O=Cc1ncc[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1ccc(Cc2nc3cccc(NCc4ncc[nH]4)c3o2)cc1OC1CCCC1
Yield: 31.4 %

Procedure:
By employing a procedure similar to that in Example 33 and using 2-(3-cyclopentyloxy-4-methoxybenzyl)-7-aminobenzoxazole (1.3 g, 0.0038 mol), imidazole-2-carboxaldehyde (0.54 g, 0.0056 mol) and sodium cyanoborohydride (0.38 g, 0.0060 mol), a yellow oil was obtained after workup. The oil was triturated with a 50:50 blend of hexane in ether and the solid product (0.5 g) which was obtained, was separated by filtration. This solid could be recrystallized from ethanol (1 g/14 ml) to give the title compound as white crystals, mp 179-180° C.