Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH:7]1[CH:14]2[CH:10]3[CH:11]([CH:16]([C:17](Cl)=[O:18])[CH:8]1[CH2:9]3)[C:12](=[O:15])[O:13]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].[F:20][C:21]([F:28])([S:24]([O-:27])(=[O:26])=[O:25])[CH2:22][OH:23].[C:29]1([S+:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[F:20][C:21]([F:28])([S:24]([O-:27])(=[O:26])=[O:25])[CH2:22][O:23][C:17]([CH:16]1[CH:11]2[CH:10]3[CH:14]([CH:7]([O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])[CH:8]1[CH2:9]3)[O:13][C:12]2=[O:15])=[O:18].[C:42]1([S+:35]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: O=S(=O)([O-])C(F)(F)CO
Reactant: C=C(C)C(=O)OC1C2CC3C1OC(=O)C3C2C(=O)Cl
Agent: Cl
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1C2CC3C1OC(=O)C3C2C(=O)OCC(F)(F)S(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To 2.8 g (10 mmol) of the 2-methacryloyloxy-5-oxo-4-oxa-tricyclo[4.2.1.03,7]-non-9-ylcarbonyl chloride were added 4.2 g (10 mmol) of triphenylsulfonium 1,1-difluoro-2-hydroxy-ethanesulfonate in Synthesis Example 1-13 and 20 g of methylene chloride. To the mixture under ice cooling, a solution containing 1.0 g (10 mmol) of triethylamine and 0.25 g (2 mmol) of N,N-dimethylaminopyridine in 5 g of methylene chloride was added at a temperature below 5° C., and the resulting mixture was stirred for 2 hours at room temperature. Thereafter, 11 g of 5% dilute hydrochloric acid was added to the reaction mixture. The organic layer was taken out and washed with water, from which methylene chloride was distilled off in vacuum. 30 g of methyl isobutyl ketone was added to the residue, from which the residual water was distilled off in vacuum together with methyl isobutyl ketone. The resulting residue was purified by silica gel chromatography, obtaining the target compound, triphenylsulfonium 1,1-difluoro-2-(9-methacryloyloxy-4-oxo-5-oxatricyclo[4.2.1.03,7]-non-2-ylcarbonyloxy)-ethane-1-sulfonate. Colorless solids, 4.0 g (yield 61%). The compound has the following structure.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:13][C@@H:14]2[CH2:19][O:18][C@@H:17]([CH2:20][C:21]#[N:22])[CH2:16][CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[C:5]([NH:13][C@@H:14]2[CH2:19][O:18][C@@H:17]([CH2:20][C:21]#[N:22])[CH2:16][CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1
Reactant: N#CC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CO1
Agent: [Pd]
Solvent: CO
Product: N#CC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CO1
Yield: 93.5 %

Procedure:
{(2R,5S)-5-[(6-Nitrothieno[3,2-b]pyridin-7-yl)amino]tetrahydro-2H-pyran-2-yl}acetonitrile (712 mg, 2.24 mmol) (first fraction from last step) and 10% palladium on carbon (360 mg) in methanol (15 mL) was subjected to balloon pressure of H2 at room temperature for 2 h. The reaction mixture was filtered and concentrated and purified with flash chromatography (15% methanol/dichloromethane) to give the desired product (604 mg, 94%). LCMS calculated for C14H17N4OS (M+H)+: m/z=289.1. Found: 289.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][O:11][CH2:12]OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH2:10][O:11][CH3:12])[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccnc(Br)c1
Reactant: COCOC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COCOCc1ccnc(Br)c1
Yield: 50 %

Procedure:
70 ml of 2-bromo-4-pyridinemethanol, 70 ml of dimethoxymethane and 2.15 g of p-toluenesulfonic acid monohydrate were suspended in 300 ml of benzene. The suspension was passed through a Soxhlet extractor containing 25 g of 3 Å molecular sieves, and refluxed for 20 hours. After cooling, the reaction mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate and water, dried, and concentrated under reduced pressure. The residue was distilled to give 13.2 g (yield 50%) of 2-bromo-4-(methoxymethoxymethyl)pyridine.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[C:29]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30].C(OC)(OC)OC.[BH4-].[Na+]>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:37][C:36]2[CH:39]=[CH:40][C:33]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:34][CH:35]=2)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: NCCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CC(C)(C)c1ccc(CNCCCCNC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (50.6 mg) obtained in Example 3-2 was dissolved in anhydrous methanol (2.0 ml) and added with 4-t-butyl-benzaldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (0.0330 ml) and trimethyl orthoformate (0.0430 ml), followed by stirring at room temperature for 30 minutes. Then, the solution was added with sodium borohydride (14.8 mg), followed by stirring at room temperature for 15 minutes. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (42.0 mg) of the subject compound as a white solid.
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:8])[CH:6]=[O:7])(=[O:3])[CH3:2].C(OCCC(O)=O)(=[O:11])C.C(OC(=O)C)(=O)C.C(O)(=O)C(C)O>>[C:1]([O:4][CH:5]([CH3:8])[C:6]([OH:11])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)C=O
Reactant: CC(=O)OCCC(=O)O
Agent: CC(O)C(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC(C)C(=O)O

Procedure:
α-Acetoxypropionaldehyde and β-acetoxypropionic acid were identified by elemental analysis, molecular weight, and nuclear magnetic resonance studies. An authentic sample of α-acetoxypropionic acid was prepared by the addition of acetic anhydride to lactic acid [A. Golomb and P. D. Ritchie, J CHEM SOC, 838 (1962)]. The corresponding aldehyde could not be prepared by an independent method.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl[CH2:11][CH2:12][CH2:13][CH2:14][N:15]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]([C:32](=[O:35])[CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH2:30]Cl)[C:16](=[O:19])[CH2:17][CH3:18].O>CS(C)=O>[N:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]([C:32](=[O:35])[CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH2:30][S:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:16](=[O:19])[CH2:17][CH3:18])=[CH:3][CH:4]=1
Reactant: CCC(=O)N(CCCCCl)c1ccccc1N(CCCCCl)C(=O)CC
Reactant: Sc1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCC(=O)N(CCCCSc1ccncc1)c1ccccc1N(CCCCSc1ccncc1)C(=O)CC
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To a solution of 525 mg (4.7 mmol) of 4-mercaptopyridine and 265 mg (4.7 mmol) of potassium hydroxide in 20 ml of dimethyl sulfoxide, 760 mg (1.89 mmol) of 1,2-bis[N-(4-chlorobutyl)-N-propionylamino]benzene was added at room temperature, and the mixture was stirred for 2 hours. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was dried and the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate to ethyl acetate/ethanol=20:1 to 10:1 to 5:1) to give 0.84 g of the desired product (81.0% yield, pale yellow crystals).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3I)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C@H:22]12[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:26]1[CH2:25][NH:24][CH2:23]2>>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[N:24]2[CH2:25][C@H:26]3[C@H:22]([CH2:28][N:27]3[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:23]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CNC[C@@H]21
Reactant: O=S(=O)(c1cccc(F)c1)c1cnc2c(I)cccc2c1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cccc4cc(S(=O)(=O)c5cccc(F)c5)cnc34)C[C@@H]21

Procedure:
0.153 g of (1S,5R)-tert-butyl 3-(3-(3-fluorophenylsulfonyl)quinolin-8-yl)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate were prepared by analogy to the method of Example 25.4 by coupling of 3-(3-fluorophenylsulfonyl)-8-iodoquinoline and (1S,5R)-tert-butyl 3,6-diazabicyclo[3.2.0]heptane-6-carboxylate.
Reaction SMILES: O.FCC(=O)C(O)=O.[NH2:9][C:10]([OH:16])([CH2:14][F:15])[C:11]([OH:13])=[O:12].[NH2:17][C:18]([NH2:24])([CH2:22][F:23])[C:19]([O-:21])=[O:20]>>[NH2:17][C:18]([NH2:24])([CH2:22][F:23])[C:19]([O-:21])=[O:20].[NH2:9][C:10]([OH:16])([CH2:14][F:15])[C:11]([O-:13])=[O:12]
Reactant: NC(O)(CF)C(=O)O
Agent: NC(N)(CF)C(=O)[O-]
Agent: O=C(O)C(=O)CF
Solvent: O
Product: NC(O)(CF)C(=O)[O-]

Procedure:
This reductive amination reaction is conveniently conducted by first equilibrating a salt of fluoropyruvic acid hydrate (e.g. lithium 2,2-dihydroxy-3-fluoro-propionate) in aqueous ammoniacal solution with formation of the corresponding salt of 2-amino-2-hydroxy-3-fluoro-propionic acid (e.g. lithium, sodium or ammonium 2-amino-2-hydroxy-3-fluoro-propionate) and the salt of 2,2-diamino-3-fluoro-propionate; the equilibrium ratio of 2,2-diamino-3-fluoro-propionate to 2-amino-2-hydroxy-3-fluoro-propionate thus formed is a function of ammonia concentration and, in concentrated aqueous ammonia (13 N), the ratio is approximately 95 to 5. Although not ordinarily preferred, lower aqueous ammonia concentrations may be used; for example with 6.5 N aqueous ammonium hydroxide, the equilibrium ratio is approximately 90 to 10. Upon reduction, this mixture would necessarily result in a reduced yield of 3-fluoro-DL-alanine and an increased amount of 3-fluoro-lactate by-product. The equilibration at 37° C. is a pseudo-first-order reaction with a half-life of 15 minutes; equilibration at 37° C. for 90 minutes provides six half-lives, and an effective ratio of 2,2-diamino-3-fluoropropionate to 2-amino-2-hydroxy-3-fluoro-propionate of 95 to 5. Although the 2,2-diamino-3-fluoropropionate salt is not isolated from the ammonia solution, its presence, in a purity of 95%, is readily demonstrated by NMR (nuclear magnetic resonance) measurement.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Si](C)(C)C)=[CH:11][CH:10]=2)[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[C:3]=1[Cl:23].[I:24]Cl>ClCCl>[NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([I:24])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[C:3]=1[Cl:23]
Reactant: ClI
Reactant: COC(=O)c1nc(-c2ccc([Si](C)(C)C)cc2)c(C)c(N)c1Cl
Solvent: ClCCl
Product: COC(=O)c1nc(-c2ccc(I)cc2)c(C)c(N)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.4 %

Procedure:
To methyl 4-amino-3-chloro-5-methyl-6-(4-(trimethylsilyl)phenyl)picolinate (0.95 g, 2.72 mmol) in dichloromethane (9 mL) was added iodine monochloride (920 mg, 5.67 mmol) in dichloromethane (4.5 mL) dropwise. The reaction was stirred at room temperature for 4 h, then quenched with saturated aqueous sodium thiosulfate, diluted with water, and extracted with dichloromethane (3×). The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography (0-30% ethyl acetate/hexanes) afforded the title compound as a red-orange solid (618 mg, 56%).
Reaction SMILES: C(NC(=O)[C@H](C)C[C@H](O)[C@@H](N)CC(C)(C)C[C:14]([N:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH:18]([CH:26]2[O:30][CH2:29][CH2:28][O:27]2)[CH2:17]1)=[O:15])CCC.[CH2:37]([O:44]C(N1C2C=CC=CC=2OC(C=O)C1)=O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(O)CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[CH2:37]([O:44][C:14]([N:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH:18]([CH:26]2[O:27][CH2:28][CH2:29][O:30]2)[CH2:17]1)=[O:15])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=CC1CN(C(=O)OCc2ccccc2)c2ccccc2O1
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)CC(C)(C)CC(=O)N1CC(C2OCCO2)Oc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: OCCO
Product: O=C(OCc1ccccc1)N1CC(C2OCCO2)Oc2ccccc21

Procedure:
The 2(R,S)-(dioxolan2-yl)-3,4-dihydro-2H-1,4-benzoxazine employed as the starting material is prepared by reaction of 500 mg of N-benzyloxycarbonyl-2(R,S)-formyl-3,4-dihydro-2H-1,4-benzoxazine (Example 107)with 0.28 ml of ethylene glycol in 25 ml of toluene under reflux, with azeotropic removal of water, overnight in the presence of 25 mg of p-toluenesulfonic acid hydrate. After customary working up and FC of the crude product over silica gel with a 6:1 mixture of toluene and ethyl acetate, N-benzyloxycarbonyl-2(R,S)-(dioxolan2-yl)-3,4-dihydro-2H-1,4-benzoxazine is obtained (Rf- (3:1 mixture of toluene and ethyl acetate)=0.52). Subsequent hydrogenolysis analogously to Example 1r) gives 2(R,S)-(dioxolan2-yl)-3,4-dihydro-2H-1,4-benzoxazine: Rf (P)=0.74; FAB-MS: (M+H)+ =208.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:38][C:39]1[CH:44]=[C:43]([CH3:45])[CH:42]=[CH:41][N:40]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:24]=[N:25][N:26]([CH2:38][C:39]2[CH:44]=[C:43]([CH3:45])[CH:42]=[CH:41][N:40]=2)[CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: Cc1ccnc(CCl)c1
Agent: Cl
Product: COc1ccc(N(Cc2cnn(Cc3cc(C)ccn3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 78.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.94 g) and 2-chloromethyl-4-methylpyridine hydrochloride (0.71 g) as starting materials, 5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.90 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]3[C:11]([Cl:20])=[C:12]([Cl:19])[C:13]([Cl:18])=[C:14]([N+:15]([O-])=O)[C:8]=3[O:7][C:6]=2[C:5]([N+:21]([O-])=O)=[C:4]([Cl:24])[C:3]=1[Cl:25]>C(O)C>[Cl:20][C:11]1[C:9]2[C:10]3[C:2]([Cl:1])=[C:3]([Cl:25])[C:4]([Cl:24])=[C:5]([NH2:21])[C:6]=3[O:7][C:8]=2[C:14]([NH2:15])=[C:13]([Cl:18])[C:12]=1[Cl:19]
Reactant: O=[N+]([O-])c1c(Cl)c(Cl)c(Cl)c2c1oc1c([N+](=O)[O-])c(Cl)c(Cl)c(Cl)c12
Solvent: CCO
Product: Nc1c(Cl)c(Cl)c(Cl)c2c1oc1c(N)c(Cl)c(Cl)c(Cl)c12

Procedure:
The corresponding amine was prepared by reducing 1,2,3,7,8,9-hexachloro-4,6-dinitrodibenzofuran with 3.6 mmol of NaSH in 5 ml of ethanol. The resulting 1,2,3,7,8,9-hexachloro-4,6-diaminodibenzofuran was isolated by extracting with five times 30 ml of diethyl ether. The resulting solution was washed twice with 10 ml of water and dried over magnesium sulfate. Subsequently, the amine was removed from the desiccant and isolated again.
Reaction SMILES: C([Li])CCC.Cl[CH2:7][CH2:8][CH2:9][C:10]#[CH:11].[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15].C([O-])(O)=O.[Na+]>CCCCCC.C1COCC1>[CH2:21]([Sn:16]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:17][CH2:18][CH2:19][CH3:20])[C:7]#[C:8][CH:9]1[CH2:11][CH2:10]1)[CH2:22][CH2:23][CH3:24]
Reactant: C#CCCCCl
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](C#CC1CC1)(CCCC)CCCC
Reaction time: 3 h

Procedure:
To n-butyllithium (7.28 mL of a 2.5 M solution in hexane, 18.2 mmol) at −5° C. was added dry THF (80 mL) dropwise, maintaining the temperature below 5° C. 5-Chloro-1-pentyne (7.75 mL , 73.1 mmol) was added at 5° C., and the solution was stirred for 3 hours. The reaction was quenched by the addition of tri-n-butyltin chloride (21.0 mL, 77.4 mmol), and was allowed to stir for an additional 10 min. The solution was poured into saturated aqueous NaHCO3 (500 mL) and hexane (500 mL). The hexane layer was washed with H2O (200 mL), then brine (200 mL), then dried over Na2SO4, filtered, and concentrated in vacuo to provide the titled product as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:25][CH:26]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1-c1ccc(O)cc1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOc1ccc(-n2c(C)ccc2-c2ccc(OCc3ccccc3)cc2)cc1
Yield: 78 %

Procedure:
A solution of 4-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]phenol (1.00 g, 2.82 mmol), 1-bromooctane (0.584 ml, 3.38 mmol) and potassium carbonate (466 mg, 3.38 mmol) in DMF (20 ml) was stirred at 80° C. for 4 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate anhydride, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 1.03 g (yield: 78.0%)
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:31]>>[ClH:31].[C:19]1([CH:17]=[CH:16][CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([CH:7]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:9][CH2:10]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OC(CCCN1CCC(C(c2ccccc2)c2ccccc2)CC1)c1ccccc1
Agent: Cl
Product: C(=Cc1ccccc1)CCN1CCC(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 4-(diphenylmethyl)-α-phenyl-1-piperidinebutanol and 400 ml of 37% HCl was refluxed for 16 hours after which the solvent was removed at reduced pressure. The remaining residue was dissolved in 1 liter of toluene, treated with charcoal and filtered. The filtrate was concentrated to 500 ml, and a solid formed which was recrystallized from butanone and toluene to give the desired product, M.P. 188.5°-209° C.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.C([O-])([O-])=O.[Na+].[Na+].[OH:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>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.COCCOC>[OH:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2/[C:4](=[CH:12]/[C:13]2[NH:14][CH:15]=[CH:16][CH:17]=2)/[C:5](=[O:11])[NH:6]3)=[CH:27][CH:26]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
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: [Na+]
Solvent: COCCOC
Product: O=C1Nc2cccc(-c3ccc(O)cc3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Yield: 79 %

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (45 mg, 0.134 mmol) (Starting Material 1), 2M aqueous Na2CO3 solution (134 μL , 0.268 mmol), (Ph3P)4Pd (5 mg, 0.004 mmol) (Aldrich), and 4-hydroxyphenylboronic acid (37 mg, 0.268 mmol) (prepared according to H. Gilman et al., J. Am. Chem. Soc. 79:3077-3081 (1957)) in 3 mL of a 3:1 mixture of 1,2-dimethoxyethane:distilled water was heated at reflux under a nitrogen atmosphere for 15 h. The reaction mixture was allowed to cool to room temperature and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 35% ethyl acetate-hexanes elution) to yield pure (Z)-1,3-dihydro-4-(4-hydroxyphenyl)-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (yield: 32 mg, 79%) as a yellow solid (mp 271-273° C.).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]=[C:12]([SH:14])[NH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:16]([CH3:20])[C:17]([OH:19])=[O:18].Cl.CCOCC>O.[OH-].[Na+]>[CH2:1]([S:8][C:9]1[N:13]=[C:12]([S:14][CH:16]([CH3:20])[C:17]([OH:19])=[O:18])[NH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(Br)C(=O)O
Reactant: Sc1nc(SCc2ccccc2)n[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CC(Sc1nc(SCc2ccccc2)n[nH]1)C(=O)O
Reaction time: 8 h
Yield: 48.7 %

Procedure:
3-Benzylthio-5-mercapto-1,2,4-triazole (56 g) was added with stirring and cooling to a solution of sodium hydroxide (10.1 g) in water (150 ml). A cold solution of 2-bromopropionic acid (38.4 g) in aqueous sodium hydroxide (10 g in 50 ml water) was added dropwise with stirring. The mixture was stirred for a further 6 hours at room temperature and allowed to stand overnight. After acidification with concentrated hydrochloric acid (30 ml), the precipitated white sticky solid was taken into ether. The ether solution was washed with water, dried, and the volume reduced to about 200 ml. The product crystallised, and was isolated by filtration to give 36.1 g of desired product, mp 123°-124° C. Successive reductions of the mother liquors gave further product, giving a total yield of 60 g.
Reaction SMILES: ON=[CH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14])=[O:5].C(N)(=[O:19])C>>[F:14][C:13]([F:16])([F:15])[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[NH:6][C:4](=[O:5])[C:3]2=[O:19]
Reactant: O=C(C=NO)Nc1ccccc1C(F)(F)F
Reactant: CC(N)=O
Product: O=C1Nc2c(cccc2C(F)(F)F)C1=O

Procedure:
Following the procedure of example 36.B. except using 2-hydroxyimino-N-(2-trifluoromethyl-phenyl)-acetamide as the acetamide component afforded the title compound as a solid. ESI (−) MS m/e=214 (MH−).