Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4](I)=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C(O)(C)C.C(N(CC)CC)C.[H][H]>O>[Br:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1nc(Br)[nH]c1I
Reactant: [H][H]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)O
Product: O=[N+]([O-])c1c[nH]c(Br)n1

Procedure:
A mixture consisting of 2-bromo-5-iodo-4-nitroimidazole (2.43 g, 7.64 mmol), isopropyl alcohol (12.2 ml), water (2.4 ml), triethylamine (2.32 g, 22.9 mmol), and 5% Pd-alumina (12.2 mg) was stirred while applying pressure (3 to 4 atmospheres) in a hydrogen atmosphere at 60° C. for 3 hours. The filtrate was concentrated and exsiccated under reduced pressure, and the resultant product was then dissolved in water (10 ml). The thus obtained solution was treated with activated carbon (243 mg) (which was stirred at room temperature for 1 hour). The filtrate was stirred under cooling on ice, and 35% concentrated hydrochloric acid (0.7 ml) was added thereto such that the pH of the solution became 2. The thus obtained solution was further stirred under cooling on ice for 1 hour. Thereafter, the precipitated crystals were collected by filtration and then dried at 50° C. for 16 hours.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C@H:18]([CH2:20][OH:21])[O:17][C:16]2=[O:22])=[CH:11][C:10]=1[F:23])C1C=CC=CC=1>C1COCC1.CO.[Pd]>[F:23][C:10]1[CH:11]=[C:12]([N:15]2[CH2:19][C@H:18]([CH2:20][OH:21])[O:17][C:16]2=[O:22])[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: O=C1O[C@@H](CO)CN1c1ccc(OCc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1O[C@@H](CO)CN1c1ccc(O)c(F)c1
Yield: 69.6 %

Procedure:
A solution of (R)-3-(4-benzyloxy-3-fluoro-phenyl)-5-hydroxymethyl-oxazolidin-2-one (6.34 g, prepared according to WO 2004/096221) in THF/MeOH (1:1; 200 ml) was hydrogenated over Pd/C 10% (1 g) overnight. The catalyst was filtered off, the filtrate evaporated under reduced pressure and the residue stirred in EA. The crystals were collected by filtration affording 3.16 g (70% yield) of a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][N:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])=[CH:19][N:18]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: ClCc1ccc(Cl)nc1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1Cc1ccc(Cl)nc1

Procedure:
The title compound, MS: m/e=343.1 (M+H30), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-chloro-5-chloromethyl-pyridine.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[N:10]1[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=1.N1CCCCC1.CC(O)=O>C(Cl)Cl>[N:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:12][CH:11]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1ccncc1
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C(Cc1ccncc1)C(C)=O
Reaction time: 8 h
Yield: 90.5 %

Procedure:
Ethyl acetoacetate (5.20 g), piridine-4-aldehyde (4.28 g), piperidine (0.4 ml) and AcOH (0.24 ml) are mixed in CH2Cl2 (150 ml) at room temperature under nitrogen atmosphere. The reaction mixture is stirred overnight and the solvent is removed. The residue is dissolved in EtOH (150 ml). 10% Pd/C (1.0 g) is added and reaction mixture is stirred at room temperature under hydrogen for 7 hours. Concentration under reduced pressure after Celite® filtration afford Ethyl 2-(4-piridylmethyl)acetoacetate (8.0 g) as colorless oil.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4](=O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[NH:13][NH2:14]>C1CCCCC1.CCCCCCC>[CH2:3]([C:4](=[N:14][NH:13][C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:2][CH3:1]
Reactant: CCCCCCC(=O)CCC
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCCCCCC
Solvent: C1CCCCC1
Product: CCCCCCC(CCC)=NNC(=O)OC(C)(C)C
Yield: 92.9 %

Procedure:
24.76 g (158 mmol) of 4-decanone and 20.94 g (158 mmol) of tert-butyl carbazate are heated for 90 minutes at 80° C. in 250 ml of cyclohexane/heptane mixture (1:1). After cooling, 39.71 g (93%) of a white solid are obtained by crystallization.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:21]2[S:20][CH2:19][C:18]=1N1CCOCC1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CN(C)C=O.C(O)(=O)C.O>[CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:21]2[S:20][CH2:19][CH:18]=1)=[O:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(N3CCOCC3)CS[C@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Temperature: 0 °C
Reaction time: 5 h

Procedure:
5.86 g (10 mmols) of 7β-phenoxyacetylamino-3-morpholino-3-cephem-4-carboxylic acid benzhydryl ester are dissolved in 25 ml of dimethyl formamide and 25 ml of glacial acetic acid. The solution is cooled to 0° C. and then 2.04 g of sodium borohydride are added in 100 mg portions over 1 hour, with vigorous evolution of gas occurring after each addition. The reaction mixture is stirred for further 5 hours at room temperature, then diluted with 300 ml of water and extracted with four 100 ml portions of methylene chloride. After neutralisation with aqueous sodium bicarbonate solution, the organic phase is concentrated in vacuo and the dimethyl formamide is distilled off in a high vacuum. The oily, orange residue is chromatographed on silica gel with toluene/ethyl acetate (96:5), affording pure 7β-phenoxyacetylamino-3-cephem-4-carboxylic acid benzhydryl ester as a white foam.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>>[Cl:1][CH2:2][C:3]([N:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: Brc1ccccn1
Reactant: O=C(CCl)Nc1ccccc1
Product: O=C(CCl)N(c1ccccc1)c1ccccn1
Yield: 93 %

Procedure:
Using 2-chloro-acetanilide (5.1 g) and 2-bromopyridine (9.5 g), a reaction was made in the same manner as in 1) of Production Example 14. The subsequent purification by silica gel column chromatography (developing solvent, ethyl acetate:hexane=1:2 to 1:1) produced 2-chloro-N-(2-pyridyl)acetanilide (6.9 g, crude product) as a red oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH:6](=O)[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[OH:9]>C(O)(=O)CC>[OH:9][C:8]1[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=1[C:6]1[C:5]2[NH:1][C:2]([C:6]([C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[OH:9])=[C:2]3[N:1]=[C:5]([C:6]([C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[OH:9])=[C:2]4[NH:1][C:5](=[C:6]([C:7]5[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=5[OH:9])[C:2]5[CH:3]=[CH:4][C:5]=1[N:1]=5)[CH:4]=[CH:3]4)[CH:4]=[CH:3]3)=[CH:3][CH:4]=2
Reactant: c1cc[nH]c1
Reactant: O=Cc1ccccc1O
Solvent: CCC(=O)O
Product: Oc1ccccc1-c1c2nc(c(-c3ccccc3O)c3ccc([nH]3)c(-c3ccccc3O)c3nc(c(-c4ccccc4O)c4ccc1[nH]4)C=C3)C=C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Pyrrole (1.0 equivalents) and salicylaldehyde (1.2 equivalents) are dissolved in propionic acid (1 liter/20 ml pyrrole) and the solution is refluxed for 30 minutes. The reaction mixture is allowed to cool to room temperature and stand for one day. The mixture is filtered and the product is recrystallized to yield 5,10,15,20-tetrakis(2′-hydroxyphenyl) porphyrin.
Reaction SMILES: CN(C)C=O.[CH:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH2:7].[NH2:12][C:13]1[C:22]2[N:23]=[C:24]([CH2:31][O:32][CH3:33])[N:25]([CH2:26][C:27]([CH3:30])([OH:29])[CH3:28])[C:21]=2[C:20]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[N:14]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[NH2:12][C:13]1[C:22]2[N:23]=[C:24]([CH2:31][O:32][CH3:33])[N:25]([CH2:26][C:27]([CH3:28])([OH:29])[CH3:30])[C:21]=2[C:20]2[CH:19]=[CH:18][C:17]([CH:7]=[CH:6][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:16][C:15]=2[N:14]=1
Reactant: C=CS(C)(=O)=O
Reactant: COCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CC#N
Product: COCc1nc2c(N)nc3cc(C=CS(C)(=O)=O)ccc3c2n1CC(C)(C)O
Temperature: 120 °C
Yield: 70.2 %

Procedure:
A thick walled glass tube, equipped with a stir bar, was charged with palladium (II) acetate (12 mg, 0.05 mmol), acetonitrile (20 mL), N,N-dimethylformamide (15 mL) triethylamine (1.10 mL, 7.92 mmol), tri-o-tolylphosphine (48 mg, 0.16 mmol), methyl vinyl sulfone (294 mg, 2.77 mmol) and 1-[4-amino-7-bromo-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (1.00 g, 2.64 mmol). The reaction mixture was purged with nitrogen. The tube was sealed and heated at 120° C. in an oil bath. The reaction was maintained at 120° C. for 18 hours and then cooled to ambient temperature. The reaction was filtered and the filtrate was concentrated under reduced pressure. The resulting solid was partitioned between chloroform (100 mL) and aqueous 1% sodium carbonate (100 mL). The fractions were separated and the aqueous fraction was extracted with chloroform (5×50 mL). The combined organic fractions were concentrated and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-6% gradient of methanol in dichloromethane) to provide 750 mg of 1-{4-amino-2-(methoxymethyl)-7-[2-(methylsulfonyl)ethenyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol as a yellow semi-solid. MS (ESI) m/z 405 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12](=[O:17])[CH2:13]S(C)=O.[CH:18]([CH:20]1[CH2:22][CH:21]1[C:23]([O:25][CH2:26][CH3:27])=[O:24])=O.N1CCCCC1>C1(C)C=CC=CC=1>[O:17]=[C:12]1[CH:13]=[C:18]([CH:20]2[CH2:22][CH:21]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:1][C:2]2[C:11]3[C:6]([CH:5]=[CH:4][C:3]1=2)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: CCOC(=O)C1CC1C=O
Reactant: CS(=O)CC(=O)c1ccc2ccccc2c1O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C1CC1c1cc(=O)c2ccc3ccccc3c2o1

Procedure:
A mixture of 12.4g of 1'-hydroxy-2-(methylsulfinyl)-2'-acetonaphthone, 7.1g of ethyl 2-formyl-1-cyclopropane carboxylate, 250ml of toluene and 0.5ml of piperidine was refluxed for 8 hrs. The toluene was then removed under reduced pressure, and the oily residue was recrystallized from Skelly B with the aid of charcoal, mp. 106°-07.5°; yield 6.5g (42%); λ max mμ (ε) 219 (50,000), 259 (36,800), 327 (3,990), 341 (4,100); ν max 760 (m), 825 (ms), 1195 (s), 1640 (s), 1650 (s), 1730 (s) cm-1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:40])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][N:9]2C(NC2C=CC=CC=2C(O)=O)=O)[CH:5]=[CH:6][CH:7]=1.[CH3:41][CH2:42][N:43](C(C)C)C(C)C.CN(C([O:57]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:40])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[CH2:10][N:9]2[CH2:41][C:42]([NH2:43])=[O:57])[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)C[C@@H]1CN(C(=O)Nc2ccccc2C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)C[C@@H]1CN(CC(N)=O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.37 h
Yield: 16 %

Procedure:
To a mixture rac-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetic acid (23.0 mg, 0.048 mmol, Example 51) in N,N-dimethyl formamide (2.5 mL) was added DIPEA (44.5 mg, 0.344 mmol) and HATU (29.6 mg, 0.078 mmol). After it was stirred at rt for 22 min, ground ammonium chloride (6.4 mg, 0.12 mmol,) was added. After 3 hrs the reaction mixture was extracted with EtOAc, and washed with water, 10% ammonium chloride, saturated sodium bicarbonate, water, and saturated NaCl. The organic phase was separated, and dried over Na2SO4. The reaction mixture was then purified by flash column to give rac-2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetamide (3.7 mg, 16.1%). HRMS (ES+) m/z Calcd for C24H25Cl2F2N3O+Na [(M+Na): 502.1235; Found: 502.1235.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH:12]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:13]([OH:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].CN.C(Cl)Cl.CO>C(O)C>[NH2:3][C@@H:12]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C@H:13]([OH:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: CN
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: CCOC(=O)[C@@H](O)[C@@H](N)Cc1ccccc1
Yield: 82 %

Procedure:
Analogously to Example 23, by reacting a solution of 10.42 g of a 95:5 mixture of the (2S,3S) and (2R,3S) isomers of ethyl 3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-hydroxy-4-phenylbutyrate (Example 20) in 10 ml of ethanol with 5.9 ml of a 33% solution of methylamine in ethanol there are obtained 5.39 g (82%) of ethyl (2S,3S)-3-amino-2-hydroxy-4-phenylbutyrate, TLC (SiO2, CH2Cl2 /methanol 10:1, UV254): Rf =0.34.
Reaction SMILES: C([O:5][C:6](=[O:20])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:19])[CH2:13][CH2:14][S:15][C:16](=[O:18])[CH3:17])(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[C:16]([S:15][CH2:14][CH2:13][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:20])=[O:5])=[O:19])(=[O:18])[CH3:17]
Reactant: CC(=O)SCCC(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)SCCC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
1-(3-Acetylthiopropanoyl)-L-proline-t-butyl ester (4.7 g.) is dissolved in a mixture of anisole (34 ml.) and trifluoroacetic acid (68 ml.) and the mixture is kept at room temperature for one hour. The solvents are removed in vacuo and the residue is precipitated from ether-hexane several times. The residue (3.5 g.) is dissolved in acetonitrile (25 ml.) and dicyclohexylamine (2.8 ml.) is added. The crystalline salt is filtered and recrystallized from isopropanol. Yield 3.8 g.. m.p. 176°-177°. The salt is reconverted to 1-(3-acetylthiopropanoyl)-L-proline as in Example 1, yield 1.25 g., m.p. 89°-90° (ethyl acetate-hexane).
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[Br:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][OH:10]>C(Cl)(Cl)(Cl)Cl>[Br:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][O:10][P:1]([Cl:5])([Cl:3])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(CO)CBr
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(CBr)COP(=O)(Cl)Cl
Reaction time: 8 h

Procedure:
To a solution of 18.35 g of phosphorous oxychloride in 55 ml of carbon tetrachloride was added dropwise a solution of 3 -bromo-2,2-dimethyl-1-propanol in 20 ml of carbon tetrachloride. This mixture was stirred overnight, evaporated in vacuo, then evaporated twice from toluene at 35° C. and dried. The residue was distilled on a Kugelrohr 100° C., 0.3 mm giving the desired compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][C:15]([CH3:18])=[N:14]2)[N:3]=1.SC[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH:17]=[CH:16][C:15]([CH3:18])=[N:14]2)[C:5]([C:11]#[N:12])=[C:6]([S:8][CH2:10][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:7]=1
Reactant: SCCc1ccccn1
Reactant: Cc1ccn(-c2nc(N)nc(S(C)=O)c2C#N)n1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccn(-c2nc(N)nc(SCCc3ccccn3)c2C#N)n1

Procedure:
From 2-amino-4-methanesulfinyl-6-(3-methyl-pyrazol-1-yl)-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 338 (M+H+, 100).
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[H-].[Na+].C1(C)C=CC=CC=1.Cl[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C)C=O>[N:23]1([CH2:22][CH2:21][CH2:20][O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[CH:1]=[O:9])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=Cc1ccccc1O
Reactant: ClCCCN1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OCCCN1CCCCC1

Procedure:
Salicylaldehyde (27 g) is treated first with 11 g of 50% sodium hydride in 175 ml of dimethylformamide and then with 150 ml of a 2 N toluene solution of N-(3-chloropropyl)-piperidine following the procedure described in Example 31A, yielding 47.7 g of the title compound as an oil, boiling point 155°-160° C. at 0.2-0.3 mm of Hg.
Reaction SMILES: [CH2:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([F:12])[CH:5]=1)[CH:2]=C.N1C=CC=CC=1.[O:19]=[O+][O-]>C(Cl)Cl.CO>[F:12][C:6]1[CH:5]=[C:4]([CH2:1][CH:2]=[O:19])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: O=[O+][O-]
Reactant: C=CCc1ccc(C#N)c(F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: N#Cc1ccc(CC=O)cc1F
Temperature: -78 °C
Reaction time: 8 h

Procedure:
A solution of 4-allyl-2-fluorobenzonitrile (1 g, 6.2 mmol) in 1:1 CH2Cl2/MeOH (40 mL) containing pyridine (1 mL, 12.4 mmol) was cooled to −78° C., and O3 was passed through until a blue color was present. N2 was then bubbled through to discharge the blue color and Me2S (5 ml) was added. The reaction mixture was allowed to warm and left overnight. The mixture was washed with 1 N HCl and aqueous NaHCO3 and then dried and concentrated to give crude 2-fluoro-4-(2-oxoethyl)benzonitrile. The material was carried on as the crude.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1I.[NH:10]1[C:18]2[C:13](=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:10]1[C:18]2[C:13](=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Reactant: Fc1ccc(I)c(F)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3ccc(F)cc3F)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 2,4-difluoro-1-iodobenzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 488.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([OH:15])=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.[ClH:17].[N:18]1([CH2:24][CH2:25][Cl:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[ClH:26].[ClH:17].[N:18]1([CH2:24][CH2:25][O:1][C:2]2[CH:14]=[CH:13][C:12]3[C:11]4[C:6](=[CH:7][C:8]([O:15][CH2:25][CH2:24][N:18]5[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]5)=[CH:9][CH:10]=4)[C:5](=[O:16])[C:4]=3[CH:3]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1c2cc(O)ccc2-c2ccc(O)cc21
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2cc(OCCN3CCCCC3)ccc2-c2ccc(OCCN3CCCCC3)cc21

Procedure:
A mixture of 5.3 g (0.025 mole) of 2,7-dihydroxyfluoren-9-one in 100 ml of toluene, 16.2 g (0.088 mole) of 2-piperidinoethylchloride hydrochloride and 5.0 g (0.125 mole) of sodium hydroxide in 40 ml of water is heated at reflux for 15 hours with stirring. Upon cooling, the layers are separated. The toluene layer is washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate is acidified to Congo Red with ethereal HCl, and the resulting precipitate is collected, washed with ether and recrystallized from butanone-methanol to give 2,7-bis(2-piperidinoethoxy)fluoren-9-one dihydrochloride, M.P. 304°-306° C.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:26]=[C:27]([C:31]3[NH:32][CH2:33][CH:34]([CH3:36])[N:35]=3)[CH:28]=[C:29]([CH3:30])[C:6]=2[N:5]=1)[CH2:2][CH3:3]>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:26]=[C:27]([C:31]3[NH:32][CH:33]=[C:34]([CH3:36])[N:35]=3)[CH:28]=[C:29]([CH3:30])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(C3=NC(C)CN3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCc1nc2c(C)cc(-c3nc(C)c[nH]3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1

Procedure:
A solution of 0.35 g (0.7 mMol) of methyl 4'-[[2-n-propyl-4-methyl-6-(4-methyl-imidazolin-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate in 10 ml of toluene is mixed with 0.16 g palladium (10% on activated charcoal) under nitrogen and the mixture is refluxed for 66 hours. Then the toluene is evaporated off, the residue is taken up in methylene chloride, filtered and evaporated down. The crude product is chromatographed on silica gel (particle size: 0.032-0.063 mm) using as eluant methylene chloride to start with, later followed by methylene chloride/ethanol/ammonia (50:1:0.05, 20:1:0.02, 10:1:0.01 and 5:1:0.005). The uniform fractions are combined and evaporated down.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[S:6][CH:7]=1.ClC1C=C(C(OO)=[O:29])C=CC=1>ClCCl>[Cl:1][CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:11]=[CH:12][C:13]([S:16]([C:17]([F:20])([F:19])[F:18])=[O:29])=[CH:14][CH:15]=2)[S:6][CH:7]=1
Reactant: FC(F)(F)Sc1ccc(C=Cc2nc(CCl)cs2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S(c1ccc(C=Cc2nc(CCl)cs2)cc1)C(F)(F)F
Yield: 51.2 %

Procedure:
A solution of 0.50 g (1.5 mmol) 4-chloromethyl-2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-thiazole in 20 ml dichloromethane was stirred with 0.31 g (1.8 mmol) 3-chloro-benzenecarboperoxoic acid at room temperature for 2 days. The solution was washed with diluted sodium hydroxide, dried, evaporated and purified on silica. Elution with ethyl acetate/heptane 1:6 yielded 270 mg (52%) 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-thiazole as off-white solid, melting at 98-99° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4]1[CH2:8][C:7](=[O:9])[CH2:6][N:5]1[C:10]([O:12][CH3:13])=[O:11].[H][H]>C(OCC)(=O)C.[Pt]>[CH3:1][O:2][C:3](=[O:14])[C@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][CH3:13])=[O:11].[CH3:1][O:2][C:3](=[O:14])[C@H:4]1[CH2:8][C@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: [H][H]
Reactant: COC(=O)[C@H]1CC(=O)CN1C(=O)OC
Agent: [Pt]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC
Product: COC(=O)[C@H]1C[C@H](O)CN1C(=O)OC
Reaction time: 18 h

Procedure:
A 5.0 mL solution of 0.125 g of N-(methoxycarbonyl)-4-keto-D-proline methyl ester in ethyl acetate was mixed with 12.5 mg of 5% platinum on alumina under 70 psig of hydrogen at 25° C. After 18 h, the yields of N-(methoxycarbonyl)-cis-4-hydroxy-D-proline methyl ester and N-(methoxycarbonyl)-trans-4-hydroxy-D-proline methyl ester were 98.7% and 1.3%, respectively, with no N-(methoxycarbonyl)-4-keto-D-proline methyl ester remaining.