Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[C:30](=[O:31])[N:6]2[CH:7]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[O:18])[C:8]([CH2:12][O:13][C:14](=[O:16])[CH3:15])([OH:11])[CH2:9][S:10][C@:5]12[S:32][CH3:33])=[N+:2]=[N-:3].CCN(CC)CC.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[N:1]([CH:4]1[C:30](=[O:31])[N:6]2[CH:7]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[O:18])[C:8]([CH2:12][O:13][C:14](=[O:16])[CH3:15])([O:11][S:42]([CH3:41])(=[O:44])=[O:43])[CH2:9][S:10][C@:5]12[S:32][CH3:33])=[N+:2]=[N-:3]
Reactant: CS[C@]12SCC(O)(COC(C)=O)C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N1C(=O)C2N=[N+]=[N-]
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS[C@]12SCC(COC(C)=O)(OS(C)(=O)=O)C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N1C(=O)C2N=[N+]=[N-]
Temperature: 0 °C
Yield: 68.3 %

Procedure:
To an ice-cold, stirring solution of p-nitrobenzyl 7-azido-6-methylthio-3-acetoxymethyl-3-hydroxy-cepham-4-carboxylate (2.72 g., 5.47 mMol) and Et3N (1.15 ml., 8.25 mMol) in anhydrous CH2Cl2 (20 ml.) is added dropwise a solution of methanesulfonyl chloride (0.51 ml., 6.56 mMol) in anhydrous CH2Cl2 (15 ml.). After stirring 15 more mins. in the cold, the solution is washed with H2O, 5% HCl, 5% NaHCO3, and brine, dried with MgSO4, filtered, and evaporated in vacuo. The residual oil is crystallized from CH2Cl2 --MeOh to afford p-nitrobenzyl 7-azido-6-methylthio-3-acetoxymethyl-3-methylsulfonyloxycepham-4-carboxylate (2.15 g.) as yellow crystals: mp 147° C.; ir (CHCl3) 4.72, 5.59, 5.71, 6.58 and 7.42μ; nmr (CDCl3)δ 2.17 (s, 3, COCH3), 2.20 (s, 3, SCH3), 3.00 (s, 3, SO2CH3), 3.22, 4.28 (ABq, 2, J=14Hz, SCH2, 4.67, 4.95 (ABq, 2, J=13Hz, CH2OAc), 4.88 (s, 1, H7), 5.20 (s, 1, H4), 5.35 (s, 2, CH2Ar), and 7.63, 8.25 (ABq, 4, J=9, ArH).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7])[C:2]1([CH:10]1[CH:15]([O:16][CH3:17])[CH:14]([OH:18])[CH2:13][CH2:12][C:11]1([CH2:20][S:21][CH3:22])[OH:19])[CH3:9].CN(C1C=CC=CN=1)C.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:34]>ClCCl.C(OCC)(=O)C>[O:35]([C:33]([O:18][CH:14]1[CH2:13][CH2:12][C:11]([CH2:20][S:21][CH3:22])([OH:19])[CH:10]([C:2]2([CH3:9])[O:1][CH:3]2[CH2:4][CH:5]=[C:6]([CH3:7])[CH3:8])[CH:15]1[O:16][CH3:17])=[O:34])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COC1C(O)CCC(O)(CSC)C1C1(C)OC1CC=C(C)C
Reactant: O=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC1C(OC(=O)Oc2ccccc2)CCC(O)(CSC)C1C1(C)OC1CC=C(C)C
Yield: 81 %

Procedure:
In dichloromethane (2 ml) were dissolved 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (200 mg) and dimethylaminopyridine (115 mg). To the solution was added, under ice-cooling, phenyl chloroformate (95 μl ), and the mixture was stirred for 16 hours. The reaction mixture was diluted with ethyl acetate (70 ml), washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent: ethyl acetate - hexane=1:4) to afford 4-O-phenoxycarbonyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (222mg: yield 81%) as a colorless oily product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:14]=[CH:15][CH:16]=1)([O-])=O.[H][H]>[Pd].C(O)C>[C:12]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:5]1[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1Nc1ccccc1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1Nc1ccccc1-c1ccccc1

Procedure:
N-(2-nitrophenyl)biphenyl-2-amine (19.69 g, 67.8 mmol), 10% palladium on carbon (0.29 g, 0.27 mmol), and 150 mL of ethanol was added to a Parr hydrogenator bottle. The mixture was hydrogenated on a Parr hydrogenator until no more hydrogen was taken up by the solution. The solution was filtered through Celite to remove the catalyst, Celite was washed with dichloromethane, the filtrate was evaporated to yield a brown oil, 14.8 g (84%). The product was used for the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]([C:15]([O:17]CC(Cl)(Cl)Cl)=O)C(OC(Cl)(Cl)Cl)=O)=[CH:5][CH:4]=[N:3]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:31]=[C:32]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[S:33][CH:34]=2)=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:31]=[C:32]([N:35]3[CH2:36][CH2:37][N:38]([C:15]([NH:7][C:6]4[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=4)=[O:17])[CH2:39][CH2:40]3)[S:33][CH:34]=2)=[CH:26][CH:25]=1
Reactant: Fc1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: Cn1nccc1N(C(=O)OCC(Cl)(Cl)Cl)C(=O)OC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1nccc1NC(=O)N1CCN(c2nc(-c3ccc(F)cc3)cs2)CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 39.5 %

Procedure:
A mixture of trichloromethyl 2,2,2-trichloroethyl (1-methyl-1H-pyrazol-5-yl)imidodicarbonate (255 mg, 0.570 mmol), 4-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]piperazine (300 mg, 1.14 mmol) and diisopropylethylamine (0.198 ml, 1.14 mmol) in dimethyl sulfoxide (3.8 ml) was stirred at 70° C. for 18 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over magnesium sulfate anhydrous, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 87.1 mg (39.6%) of the desired product as a solid.
Reaction SMILES: CC(C)([O-])C.[K+].C1COCC1.[OH:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.I[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>CN(C=O)C>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:12][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[CH:14]=1
Reactant: Oc1cccnc1
Reactant: N#Cc1ccc(I)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1ccc(Oc2cccnc2)cc1
Temperature: 160 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of potassium tert-butoxide in THF (1.0 M, 8.73 mmol) was slowly added to a solution of 3-hydroxypyridine (830 mg, 8.73 mmol) in anhydrous DMF (5.0 mL) and was stirred for 2 hours. A solution of 4-iodobenzonitrile in DMF (5.0 mL) was then added to the reaction mixture and was then heated at 160° C. for 18 hours. The mixture was cooled and partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organic layers were dried with MgSO4, filtered and concentrated in vacuo. The crude oil was placed on a silica gel column and purified (EtOAc/Hex 1:8) to give the product as a yellow oil (640 mg, 75%). 1H NMR (500 MHz, CDCL3) δ(ppm): 7.05 (2H, d, J=9.0 Hz), 7.10 (1H, dd, J=8.4, 4.6 Hz), 7.24 (1H, ddd, J=8.4, 2.6, 1.6 Hz), 7.65 (2H, d, J=9.0 Hz), 8.46 (1H, d, J=2.6 Hz), 8.22 (1H, dd, J=4.6, 1.6 Hz). 13C NMR (125 MHz, CDCL3) δ(ppm): 107.1, 118.3 (CH), 118.6, 124.7 (CH), 127.5 (CH), 134.5 (CH), 142.8 (CH), 146.4 (CH), 151.8, 160.9. MS (FAB+): 197 (MH+). HRMS for C12H8N2O (MH+): calculated: 197.0713; found 197.0696.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH3:10])[CH:5]=[C:4]([CH3:12])[C:3]=1[O:13][CH3:14].[C:15]1([NH:21]N)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.Cl>C(O)C.O>[CH3:14][O:13][C:3]1[C:4]([CH3:12])=[CH:5][C:6]([C:8]2[NH:21][C:15]3[C:20]([C:9]=2[CH3:10])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7][C:2]=1[CH3:1]
Reactant: CCC(=O)c1cc(C)c(OC)c(C)c1
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: COc1c(C)cc(-c2[nH]c3ccccc3c2C)cc1C
Yield: 62.6 %

Procedure:
5.0 g of 2,6-dimethyl-4-propionylanisole and 2.8 g of phenylhydrazine were dissolved in 30 ml of ethanol. A small amount of acetic acid was added under reflux for 30 minutes. After cooling, 10 ml of a 20% ethanol solution of hydrogen chloride was added to the reaction mixture, and the mixture was refluxed for 1.5 hours. The reaction mixture was cooled, poured into water, extracted with benzene, washed with water, and dried. The solvent was evaporated, and the residue was crystallized from benzene-hexane to give 4.3 g of 2-(4-methoxy-3,5-dimethylphenyl)-3-methylindole.
Reaction SMILES: COP([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])(OC)=O.C[Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Na+].[Na+].[C:27]([O:31][C:32](=[O:47])[NH:33][CH2:34][CH2:35][CH2:36][C:37]([C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)=O)([CH3:30])([CH3:29])[CH3:28]>O1CCCC1.C(OCC)(=O)C>[C:11]([O:10][C:8](=[O:9])[CH:7]=[C:37]([C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)[CH2:36][CH2:35][CH2:34][NH:33][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:47])([CH3:12])([CH3:13])[CH3:14]
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Reactant: COc1ccc(C(=O)CCCNC(=O)OC(C)(C)C)cn1
Agent: C[Si](C)(C)[NH-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C(=CC(=O)OC(C)(C)C)CCCNC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of t-butyl dimethylphosphonoacetate (6.86 g, 30.6 mmol) in tetrahydrofuran (150 mL) at −78° C. under argon was added a solution of sodium bis(trimethylsilylamide) (30.6 mL of a 1.0 M solution). After 15 min., a solution of 1-3 (3.0 g, 10.2 mmol) in tetrahydrofuran (30 mL) was added, and the reaction was warmed to ambient temperature, then heated to 40° C. for 1 h. The reaction mixture was then cooled to ambient temperature, diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate, then saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The reaction mixture was filtered and concentrated at reduced pressure to give an oil that was purified by flash column chromatography (silica gel, 15 to 25% ethyl acetate/hexanes) to give 1-4 and its 2 isomer.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([C:16](F)=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:21][CH2:22][CH2:23][SH:24].C(Cl)Cl.N1C=CC=CC=1>O>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([C:16](=[O:17])[NH:21][CH2:22][CH2:23][SH:24])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)F
Reactant: NCCS
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCCS
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an oven-dried, septaed 10 mL round-bottom flask, cooled under an argon atmosphere, and charged with 25m (136.0 mg, 0.51 mmol) and 2-aminoethanethiol hydrochloride (57.8 mg, 0.51 mmol) were added 2 mL freshly distilled CH2Cl2 and anhydrous pyridine (82 μL, 1.02 mmol). The reaction immediately clouded then cleared after 30 minutes. The reaction was stirred for 3 hours at room temperature, then poured into water and extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed once with 5% aqueous HCl, once with 10% aqueous sodium bicarbonate, once with saturated brine, then once with water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 123.0 mg (38% from 24m) of 26m as a colorless oil.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[C:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:11]([N:15](C(=O)C)[C:16](=[O:18])[CH3:17])[O:12]2)=[CH:7][CH:6]=1)(=O)C.O.NN>C(O)C.C(OCC)(=O)C>[C:16]([NH:15][C:11]1[O:12][C:13]2[C:8]([CH:9]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[C:10]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:7][CH:6]=[C:5]([OH:4])[CH:14]=2)(=[O:18])[CH3:17]
Reactant: CCOC(=O)C1=C(N(C(C)=O)C(C)=O)Oc2cc(OC(C)=O)ccc2C1c1cccnc1
Agent: NN
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(NC(C)=O)Oc2cc(O)ccc2C1c1cccnc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58.7 %

Procedure:
Ethyl 7-(acetyloxy)-2-(diacetylamino)-4-pyridin-3-yl-4H-chromene-3-carboxylate (6.989 g, 15.9 mmol) was dissolved in absolute ethanol (50 mL). Hydrazine hydrate (950 μL, 19.5 mmol) was added and the mixture stirred at room temperature for 6 h. The reaction mixture was evaporated to dryness to give an orange solid. The residue was dissolved in a mixture of ethyl acetate (200 mL) and ethanol (50 mL). Silica gel 60 (35 g) was added and the mixture evaporated to dryness. Purified by flash chromatography over silica gel 60, 40-63 μm (eluent: 75% ethyl acetate/petroleum spirits (54×100 mL fractions), packing height: 15 cm, column diameter: 5 cm). The fractions containing the major band (Rf 0.26, eluent: 75% ethyl acetate/petroleum spirits, fractions 15-53) were combined and evaporated to dryness to give the title compound (3.307 g, 59% yield) as a pale yellow powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>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.C1(C)C=CC=CC=1.CCO>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:7]=2)[CH2:9][CH2:10]1
Reactant: OB(O)c1ccccc1
Reactant: CN1CCN(c2ccnc(Cl)n2)CC1
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: CCO
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccnc(-c3ccccc3)n2)CC1
Temperature: 140 °C

Procedure:
To a microwave tube was added 2-chloro-4-(4-methyl-piperazin-1-yl)-pyrimidine (30 mg, 0.14 mmol), Pd(PPh3)4 (10 mg), phenylboronic acid (24 mg, 0.2 mmol), toluene/EtOH (4:1, 1 mL) and 2 M aqueous K2CO3 (0.2 mL). The resulting mixture was heated at 140° C. for 30 minutes using the microwave instrument. The resulting mixture was extracted with EtOAc. The organic layer was dried and concentrated, and the residue was purified by preparative TLC (hexanes/EtOAc) to yield the title compound as a solid.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[C:10]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[C:22]#[N:23])[CH2:15][CH2:14]1)(=[O:12])[CH3:11]>C(O)(=O)C>[C:10]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([N+:6]([O-:9])=[O:7])=[CH:19][C:20]=2[C:22]#[N:23])[CH2:15][CH2:14]1)(=[O:12])[CH3:11]
Reactant: CC(=O)N1CCc2cccc(C#N)c21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)N1CCc2cc([N+](=O)[O-])cc(C#N)c21
Temperature: 0 °C
Yield: 66.7 %

Procedure:
To a mixed solution of acetic acid (3.8 ml), concentrated sulfuric acid (4.7 ml) and funing nitric acid (0.8 ml), under cooling with stirring, were added only small portions of N-acetyl-7-cyano-indoline (2.42 g). After stirred at the temperature as such for 7.5 hours, the reaction mixture was poured into ice-water (50 ml). The deposited crystal was collected by filtration, washed with water and acetone, and then dried to give the intended compound 2.6 g (66.7%) as white powder. M.P.: 245°-255° C.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([O:6][C:7]2[C:12]([C:13]3[CH2:14][CH2:15][O:16][CH2:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:3]1.[N:19]1[CH:24]=[CH:23][C:22]([C:25](O)=[O:26])=[N:21][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[O:16]1[CH2:15][CH:14]=[C:13]([C:12]2[C:7]([O:6][CH:4]3[CH2:3][N:2]([C:25]([C:22]4[CH:23]=[CH:24][N:19]=[CH:20][N:21]=4)=[O:26])[CH2:5]3)=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:18][CH2:17]1
Reactant: O=C(O)c1ccncn1
Reactant: C1=C(c2cccnc2OC2CNC2)CCOC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccncn1)N1CC(Oc2ncccc2C2=CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To a solution of 2-(azetidin-3-yloxy)-3-(3,6-dihydro-2H-pyran-4-yl)pyridine hydrochloride (see PREPARATION P26.1; 100 mg, 0.45 mmol), pyrimidine-4-carboxylic acid (55 mg, 0.45 mmol) and triethylamine (96.13 mg, 0.95 mmol) in CH2Cl2 (10 mL) was added 4-Dimethylaminopyridine (DMAP) (55 mg, 0.47 mmol) and propyl phosphonic anhydride (500 mg, 0.9 mmol). The reaction mixture was stirred at room temperature for overnight. Then the reaction mixture was concentrated and the crude product was purified by silica gel column chromatography to give the desired compound (48 mg, 0.16 mmol, yield 66%). [M+1]: 339. IC50 (uM): 0.99.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]([C:17]([OH:19])=O)=[CH:15][C:14]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])=[N:13]2)=[O:10])=[N:6][CH:7]=1.Cl.[CH:29]([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)([CH3:31])[CH3:30].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl.CCN(CC)CC>[CH:29]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:17]([C:16]2[N:12]([CH2:11][C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[N:13]=[C:14]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[CH:15]=2)=[O:19])[CH2:34][CH2:33]1)([CH3:31])[CH3:30]
Reactant: COCCOCCOc1cc(C(=O)O)n(CC(=O)Nc2ccc(Cl)cn2)n1
Reactant: CC(C)N1CCC(N)CC1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOCCOc1cc(C(=O)NC2CCN(C(C)C)CC2)n(CC(=O)Nc2ccc(Cl)cn2)n1
Reaction time: 16 h

Procedure:
To 310 mg 2-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-5-[2-(2-methoxy-ethoxy)-ethoxy]-2H-pyrazole-3-carboxylic acid in 5 ml DCM and 0.3 ml NEt3, 110 mg 1-Isopropyl-piperidin-4-ylamine hydrochloride and 197 mg BOP-CL were added at RT and the mixture was stirred for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][S:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([OH:28])[C:20]=3[CH2:29][CH2:30][CH3:31])[CH:12]=2)[CH:5]=1.O.[OH-].[Li+].Cl>O1CCCC1.CO.O>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([S:18][CH2:17][C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:32])=[O:2])=[C:20]([CH2:29][CH2:30][CH3:31])[C:21]=1[OH:28])(=[O:27])[CH3:26]
Reactant: CCCc1c(SCc2cccc(Cc3cccc(C(=O)OC)c3)c2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCc1c(SCc2cccc(Cc3cccc(C(=O)O)c3)c2)ccc(C(C)=O)c1O
Temperature: 0 °C
Yield: 85.1 %

Procedure:
Dissolve 3-[3-(4-Acetyl-3-hydroxy-2-propyl-phenylsulfanylmethyl)-benzyl]-benzoic acid methyl ester (238 mg, 0.53 mmol) in tetrahydrofuran (5 ml) and methanol (4 ml). Add lithium hydroxide monohydrate (89 mg, 2.1 mmol) and water (1.5 ml), then stir at room temperature for 18 hours. Cool at 0° C. and adjust to pH 3 with 1 N hydrochloric acid. Dilute with water (35 ml) and extract with ethyl acetate (2×20 ml). Combine the organic extracts, dry over sodium sulfate, filter and concentrate to a solid. Purify the crude product via reverse phase HPLC using a gradient of 90:10 to 20:80 (water/0.1% TFA):acetonitrile as eluent to give the title compound (196 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=O)[NH:10][C:4]=2[CH:3]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)Cl.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[N:10][C:4]=2[CH:3]=1
Reactant: C1CNCCN1
Reactant: O=C1Nc2cc(Cl)ccc2Sc2ccccc21
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccc2c(c1)N=C(N1CCNCC1)c1ccccc1S2
Temperature: 100 °C
Reaction time: 2 h
Yield: 13.3 %

Procedure:
To a mixture of 8-chloro-10H-dibenzo[b,f][1,4]thiazepin-11-one (189JO13) (38 mg, 0.15 mmol) and N,N-dimethylaniline (46 μL, 0.36 mmol) in toluene was added POCl3 (27 μL, 0.29 mmol) and the resulting mixture was stirred for 2 h at 100° C., and then concentrated. Toluene (2 mL) and piperazine (62 mg, 0.73 mmol) were added, and the resulting mixture was stirred at 100° C. for 3 h, and then allowed to obtain room temperature. To the mixture was added aqueous HCl (1 mL, 2 M) and then the aqueous phase was extracted with EtOAc (2×2 mL). To the aqueous phase was added aqueous NaOH (3 mL, 2 M) and the resulting mixture was extracted with EtOAc (3×3 mL). The combined organic phases were concentrated and purified by HPLC to give 6.6 mg of the title compound (189JO16). MS (ESI) 330 (MH+). Purity for MH+ (UV/MS) 99/98.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][C:3]1[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[S:6][C:2]=1[Cl:1]
Reactant: BrBr
Reactant: COC(=O)c1ccc(Cl)s1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Br)c(Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a solution of methyl 5-chloro-2-thiophenecarboxylate (7 g, 39.6 mmol) and aluminum trichloride (7.93 g, 59.4 mmol) in chloroform (79 ml) at 25° C. was added bromine (2.86 ml, 55.5 mmol). The resulting solution stirred at 25° C. for 2 h. Ice chips were added to quench and the solution was partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 5% EtOAc in hexanes) affording methyl 4-bromo-5-chloro-2-thiophenecarboxylate (7.2 g, 28.2 mmol, 71.1% yield) as a white solid; LCMS (ES) m/z=255, 257 (M, M+2)+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][N:23]([CH:26]([CH3:29])[CH2:27][CH3:28])[C:22]4=[O:30])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.CC1(C)C2CC[C@@]1(CS([O-])(=O)=O)C(=O)C2.S([O-])([O-])=O.[Na+].[Na+].Br.C(=O)([O-])[O-].[K+].[K+]>O.ClCCl.C(O)CCC>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[N:24][N:23]([CH:26]([CH3:29])[CH2:27][CH3:28])[C:22]4=[O:30])=[CH:19][CH:20]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: CCC(C)n1ncn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)c1=O
Agent: Br
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)[O-])C(=O)C2
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCCCO
Solvent: O
Product: CCC(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 29.4 g of (+)-(S)-(2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]-phenyl]-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one, (S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonate (1:2) (intermediate (5)), 2.0 g of sodium sulfite and 151 ml of a hydrobromic acid solution 48% in water was stirred for 5 hours at reflux temperature. The reaction mixture was cooled to room temperature and water was added. The while was neutralized with potassium carbonate to pH 7 while stirring in a mixture of dichloromethane and 1-butanol (90:10 by volume). The separated organic layer was dried, filtered and evaporated in vacuo. The residue was triturated in methanol. The precipitated product was filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 10.4 g (77.7%) of (+)-(S)-(2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]-phenyl]-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one; mp. 180.6° C.: [α]D20 =+4.38° (conc.=1% in methanol) (interm. 7).