Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:5])(=[O:4])[CH2:2]C.[Na+].[C:7]([O-:12])(=[O:11])[CH:8]([CH3:10])O.[Na+].[C:14]([OH:18])(=[O:17])CC.C([O-])(=O)C(C)O>>[C:1]([O-:5])(=[O:4])[CH3:2].[C:7]([O-:12])(=[O:11])[CH2:8][CH2:10][C:14]([O-:18])=[O:17]
Reactant: CC(O)C(=O)[O-]
Reactant: CCC(=O)O
Reactant: CCC(=O)[O-]
Agent: [Na+]
Product: CC(=O)[O-]
Product: O=C([O-])CCC(=O)[O-]

Procedure:
The invention involves the anaerobic growth of S. ruminantium on lactic acid or glucose in a fermentation medium, preferably sterilized, which produces salts of propionic acid and other products in order to supply the energy and materials for growth. It comprises an improved process for preparing sodium propionate from sodium lactate, for instance, for conversion to propionic acid, in at least 1% and preferably 2% yield, and up to 2.4%, based on about 48 hours of fermentation of the lactate. Smaller amounts of acetate and succinate are concurrently produced.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[S:21][C:22]([CH2:25][NH:26][CH2:27][CH3:28])=[CH:23][N:24]=1.O>CN(C)C=O>[CH3:12][O:11][C:4]1[N:3]=[C:2]([N:26]([CH2:25][C:22]2[S:21][C:20]([Cl:19])=[N:24][CH:23]=2)[CH2:27][CH3:28])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CCNCc1cnc(Cl)s1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(Cc1cnc(Cl)s1)c1nc(OC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 57.8 %

Procedure:
1.26 g 2-chloro-6-methoxy-3-nitropyridine and 10 mL N,N-dimethylformamide (DMF), and 2.00 g of potassium carbonate were added into a 100 mL single neck flask, under stirring at room temperature, 1.20 g of 2-chloro-5-ethylaminomethylthiazole, prepared according to the example 1, in 5.0 mL DMF were added dropwise. After that, the reaction solution was heated to 40-80° C. and then reacted for 3-6 hr. After cooling down, the resulting mixture was added to water (50 mL), then treated by the method according to the example 1 to obtain 1.27 g of 6-methoxy-N-((2-chlorothiazole-5-yl)methyl)-N-ethyl-3-nitropyridine-2-amine, as a golden yellow solid, having the content of 98.6%, a yield of 58.3%, and the structure was confirmed by GC-Mass and 1H NMR.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][N:19]([CH2:27][CH2:28][OH:29])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:16][CH:15]=1.CCN(CC)CC>[Cl-].[Zn+2].[Cl-].ClCCCl.CC(O)(C)C>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:18][N:19]([CH2:27][CH2:28][OH:29])[C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[CH:30][CH:31]=2)[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N(CCO)Cc1ccc(N)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CCO)Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Zinc(II) chloride (1.0 M in Et2O; 3.30 mL, 3.30 mmol) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (0.658 g, 3.03 mmol) in 1:1 DCE/t-BuOH (20 mL) at 0° C. under nitrogen. After stirring for 1 hour at 0° C., a solution of tert-butyl 4-aminobenzyl(2-hydroxyethyl)carbamate (A70) (0.734 g, 2.75 mmol) in 1:1 DCE/t-BuOH (20 mL) was added followed by a solution of Et3N (0.423 mL, 3.03 mmol) in 1:1 DCE/t-BuOH (5 mL) at 0° C. The resulting mixture was vigorously stirred at 0° C. for 30 minutes, then at room temperature for 20 hours. The volatiles were evaporated in vacuo and the residue adsorbed onto silica gel then purified by column chromatography (CombiFlash Rf, 80 g SiO2 cartridge, 10-40% EtOAc in cyclohexane) to give the title compound A71 as a white solid (1.06 g, 85%); 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 7.59-7.52 (m, 3H), 7.28 (m, 2H), 4.49 (s, 2H), 3.74 (s, 2H), 3.43-3.20 (m, 3H), 1.50 (s, 9H). LCMS-B: rt 7.856 min; m/z 447 [M+H]+.
Reaction SMILES: [C:1]([OH:11])(=O)[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>N1C=CC=CC=1>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([C:1]([Cl:14])=[O:11])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=S(Cl)Cl
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: c1ccncc1
Product: O=Cc1ccc(C(=O)Cl)cc1

Procedure:
To 7.50 g of terephthalaldehydic acid (4-formylheuzoic acid) were added 20 ml of thionyl chloride and 1 ml of pyridine, followed by heating under stirring. After the reaction mixture became clear, stirring was further continued at reflux for 4 hours, followed by allowing to cool. The excess thionyl chloride was removed by distillation under reduced pressure, toluene was added to the residue, and any insoluble matter was separated by filtration. The toluene was removed from the filtrate by distillation to obtain 7.91 g of 4-formylbenzoyl chloride.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][OH:5].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.C1C=CC(N=NC2C=CC(N)=NC=2N)=CC=1.Cl.CC1C=CC(S(O)(=O)=O)=CC=1>ClCCl>[I:1][CH2:2][CH2:3][CH2:4][O:5][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1
Reactant: C1=COCCC1
Reactant: OCCCI
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: Nc1ccc(N=Nc2ccccc2)c(N)n1
Solvent: ClCCl
Product: ICCCOC1CCCCO1

Procedure:
A solution of 3-iodopropanol (15 g, 80.65 mole), dihydropyran (14.7 ml, 161.29 mole) and pyridium p-toluenesulfonate (500 g, 2.0 mole) in 100 ml of dry dichloromethane was stirred at room temperature under an atmosphere of nitrogen for 2.5 hours. The resulting mixture was diluted with dichloromethane (150 ml), washed with water and a saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was flash chromatographed on a silica gel to give 20.43 g of title A compound as an oil, with consistent spectral data.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19]C)=[O:17])[CH:9]=[CH:8][C:7]=1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27]C1CCCCO1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:9]=[CH:8][C:7]=1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]
Reactant: CCOC(=O)CCCOc1ccc(CCCCCCOC2CCCCO2)c(CCC(=O)OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)CCCOc1ccc(CCCCCCO)c(CCC(=O)OC)c1
Yield: 59 %

Procedure:
A solution of 4.26 g (8.91 mmol) of rac-2-[6-[(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxy]hexyl]-5-(4-ethoxy-4-oxobutoxy)benzenepropanoic acid methyl ester, 0.16 g of p-toluenesulfonic acid monohydrate, and 75 mL of methanol was stirred and refluxed for 24 hr. The solvent was removed in vacuo and the residue was dissolved in ether. The ether solution was washed with saturated sodium bicarbonate solution and processed in the usual manner giving an oil. This material was flash-chromatographed on silica gel, eluting with 1:1 hexane-ethyl acetate. There was obtained 2.0 g (59%) of 2-(6-hydroxyhexyl)-5-(4-methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17](O)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[NH2:29][C:30]1[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17]([NH:29][C:30]3[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])=[CH:32][CH:31]=3)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COCCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2OC(F)F)cc1=O
Product: COCCC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(OC)c(-c2cc(Cl)ccc2OC(F)F)cc1=O

Procedure:
90 mg (purity 77%, 0.17 mmol) of 2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methoxybutanoic acid (racemate) and 35 mg (0.18 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 66 mg (67% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13]C)=[O:12])=[CH:9][N:10]=2)[CH:7]=1.O[Li].O>C1COCC1.CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([OH:13])=[O:12])=[CH:9][N:10]=2)[CH:7]=1
Reactant: COC(=O)c1cnc2ccc(Br)cn12
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cnc2ccc(Br)cn12
Yield: 93.1 %

Procedure:
Reaction mixture containing N′-(5-bromopyridin-2-yl)-N,N-dimethylformimidamide (6.5 g, 28.5 mmol), methyl 2-bromoacetate (5.6 g, 3.5 mL, 37.0 mmol) and NaHCO3 (4.1 g, 48.8 mmol) in i-PrOH (60 mL) was heated at 90° C. under nitrogen. The heating was stopped after 12 h and cooled the dense heterogeneous reaction mixture to room temperature. The reaction mixture was concentrated and diluted with water. The resultant slurry was collected by suction filtration and obtained methyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (6.9 g) as a tan white solid upon drying. 1H NMR (300 MHz, DMSO-d6): δ 9.31 (d, J=1.8 Hz, 1H), 8.31 (s, 1H), 7.80 (d, J=9.5 Hz, 1H), 7.71 (dd, J=9.5, 1.6 Hz, 1H), 3.88 (s, 4H). Ester hydrolysis was done by stirring a solution of methyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (2.5 g), LiOH.H2O (1.2 g) in THF/MeOH/H2O (1/1/1, 75 mL) at room temperature. Reaction mixture was concentrated upon complete hydrolysis of ester to corresponding acid, diluted with water/ice and acidified with 2N. aq HCl until pH 6. The resulting solid was filtered, suction dried followed by drying under P2O5 under vacuum to obtain 6-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (2.2 g) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 13.27 (s, 1H), 9.36 (s, 1H), 8.24 (s, 1H), 7.77 (d, J=9.5 Hz, 1H), 7.67 (d, J=9.5, 1.7 Hz, 1H).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][S:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.CCN(C(C)C)C(C)C.Cl.[CH3:36][C@@H:37]1[NH:42][CH2:41][CH2:40][N:39]([C:43]2[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][CH:44]=2)[CH2:38]1>C(#N)CC.CS(C)=O>[CH3:36][C@@H:37]1[N:42]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][S:15][CH2:16][C@H:8]4[C:7](=[O:17])[NH:6][C:5]=3[CH:4]=2)[CH2:41][CH2:40][N:39]([C:43]2[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][CH:44]=2)[CH2:38]1
Reactant: O=C1Nc2cc(CO)cnc2N2CCSC[C@@H]12
Reactant: C[C@H]1CN(c2ccc(C#N)cc2)CCN1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Solvent: CS(C)=O
Product: C[C@H]1CN(c2ccc(C#N)cc2)CCN1Cc1cnc2c(c1)NC(=O)[C@@H]1CSCCN21
Temperature: 90 °C
Yield: 21.6 %

Procedure:
To a suspension of (R)-3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one (100 mg, 0.617 mmol) in propiononitrile (1.2 mL) was added (cyanomethyl)trimethylphosphonium iodide (180 mg, 0.74 mmol) and DIEA (0.323 ml, 1.80 mmol) and finally (S)-4-(3-methylpiperazin-1-yl)benzonitrile hydrochloride (0.147 g, 0.617 mmol). The vial was heated to 90° C. for 16 hours. The crude rxn was cooled to RT, DMSO (1 ml) was added, and purified via HPLC (55-90, basic) to give the product as a tan solid (58 mg, 22% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.62 (s, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.56 (d, J=9.1 Hz, 2H), 6.92-7.11 (m, 3H), 4.87 (dt, J=13.6, 2.7 Hz, 1H), 4.25 (dd, J=10.9, 3.0 Hz, 1H), 3.84 (d, J=13.4 Hz, 1H), 3.66 (d, J=10.6 Hz, 1H), 3.58 (d, J=12.6 Hz, 1H), 2.87-3.12 (m, 3H), 2.64-2.83 (m, 5H), 2.39-2.48 (m, 2H), 2.06-2.19 (m, 1H), 1.14 (d, J=6.1 Hz, 3H). [M+H] calc'd for C23H26N6OS, 434. found, 434.
Reaction SMILES: N1C=CC=CC=1.[OH-].[K+].[CH3:9][C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1.[CH3:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([CH3:35])[C:27]=1[S:28]([CH2:31][N+:32]([O-:34])=[O:33])(=[O:30])=[O:29])[NH2:24].Cl>O1CCCC1.O>[CH3:35][C:26]1[CH:25]=[C:23]([NH:24][S:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH3:9])[CH:11]=2)(=[O:18])=[O:17])[CH:22]=[C:21]([CH3:20])[C:27]=1[S:28]([CH2:31][N+:32]([O-:34])=[O:33])(=[O:30])=[O:29]
Reactant: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: Cc1cccc(S(=O)(=O)Nc2cc(C)c(S(=O)(=O)C[N+](=O)[O-])c(C)c2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.5 %

Procedure:
1.3 ml (16.1 mmol) of pyridine, dried over potassium hydroxide, and 2.3 g (12.1 mmol) of 3-methylbenzenesulphonyl chloride are successively added to a solution, maintained under a nitrogen atmosphere, of 2.0 g (8.19 mmol) of 3,5-dimethyl-4-[(nitromethyl]sulphonyl]aniline in 50 ml of anhydrous tetrahydrofuran. The reaction medium is stirred for 24 h at room temperature and then maintained at 40° C. for 1 h, after which it is poured into a mixture of 100 ml of water and 100 g of ice. This mixture is acidified to pH 3 by addition of 1N hydrochloric acid and is extracted with 3 times 100 ml of methylene chloride. The combined organic extracts are washed with 100 ml of water, dried over sodium sulphate and concentrated to dryness under reduced pressure. The residue obtained is purified by chromatography on a column of silica (eluent: methylene chloride) to give 2.3 g (71%) of N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-3-methylbenzenesulphonamide.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:12][NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)=[S:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>ClC(Cl)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:11][C:24](=[O:25])[N:13]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=3)[N:12]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1ccc(NNC(=S)c2ccc(C(C)C)cc2)cc1
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc(-n2nc(-c3ccc(C(C)C)cc3)sc2=O)cc1
Yield: 74.1 %

Procedure:
Methyl 4-{2-[(4-isopropylphenyl)carbonothioyl]hydrazino}benzoate (0.26 g, 0.8 mmol) and carbonyldiimidazole (0.19 g, 1.2 mmol) are stirred at 80° C. in dichloroethane (20 mL) overnight, and the mixture is subjected to chromatography directly (silica gel, 4:1 ethyl acetate-hexanes) to provide methyl 4-[5-(4-isopropylphenyl)-2-oxo-1,3,4-thiadiazol-3(2H)-yl]benzoate (0.21 g, 75%). MS (ES+): m/e 355.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][CH:14]([CH3:20])[CH2:15][CH2:16][C:17]([OH:19])=O.[NH2:21][C:22]1[C:23]([CH3:28])=[CH:24][CH:25]=[CH:26][CH:27]=1>ClCCl>[CH3:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:17](=[O:19])[CH2:16][CH2:15][CH:14]([CH3:13])[CH3:20]
Reactant: CC(C)CCC(=O)O
Reactant: Cc1ccccc1N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)CCC(C)C

Procedure:
Carbonyldiimidazole (65 g) was mixed with 500 ml of dry dichloromethane in a 2-L round bottom flask and stirred magnetically. A solution of 4-methylvaleric acid in 200 ml of dichloromethane was added dropwise over 45 minutes and the mixture was stirred for another 1.25 hours. o-Toluidine (45 g) in 100 ml of dichloromethane was then added over about 20 minutes. After stirring for 2 hours the mixture was washed with water and then the solvent was stripped on a rotary evaporator. The residue was mixed with 150 ml of methanol and 75 ml of water and put in the freezer. Filtration of the precipitate, dilution of the filtrate with water and refiltration of the precipitate gave 75 g (94%) of vacuum dried N-(2-methylphenyl)-4-methylvaleramide which was used without further treatment in the next step:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][N:9]2CC)[CH:5]=[CH:6][CH:7]=1.Cl.[F:23][C:24]([F:34])([F:33])C1C=C(NN)C=CC=1.C1C=CC=CC=1>C(N(CC)CC)C>[C:14]1([C:11]2[C:12](=[O:13])[N:8]([C:4]3[CH:3]=[C:2]([C:24]([F:34])([F:33])[F:23])[CH:7]=[CH:6][CH:5]=3)[NH:9][CH:10]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCn1cc(-c2ccccc2)c(=O)n1-c1cccc(Cl)c1
Reactant: NNc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=c1c(-c2ccccc2)c[nH]n1-c1cccc(C(F)(F)F)c1

Procedure:
A mixture of 8.2 grams of the atropic acid, methyl ester, (prepared in Example 11), 8.5 grams 3-(trifluoromethyl)-phenyl-hydrazine hydrochloride, 100 ml. benzene and 4 grams triethylamine, was refluxed overnight and worked up to yield 6.5 grams of 4-phenyl-1-(α,α, α-trifluoro-3-tolyl)-3-pyrazolin-5-one having a melting point of about 210°-213° C.
Reaction SMILES: [Br:1][C@@H:2]1[CH2:9][O:8][C@@H:4]([C:5]([OH:7])=O)[CH2:3]1.ON1C2C=CC=CC=2N=N1.[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(N=C=NC2CCCCC2)CCCCC1>O.CN(C)C=O.C(Cl)Cl>[C:21]1([CH2:20][O:27][C:28]([N:30]2[CH2:35][CH2:34][N:33]([C:5]([C@@H:4]3[O:8][CH2:9][C@@H:2]([Br:1])[CH2:3]3)=[O:7])[CH2:32][CH2:31]2)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)[C@H]1C[C@H](Br)CO1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: O=C(OCc1ccccc1)N1CCN(C(=O)[C@H]2C[C@H](Br)CO2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
A mixture of 0.941 g of product from Example 150, 0.652 g of 1-hydroxybenzotriazole, 1.17 g of 1-benzyloxycarbonyl piperazine, 1.39 g of dicyclohexylcarbodiimide and 8 ml of dry methylene chloride is stirred at room temperature for 1 hour. Five ml of dimethylformamide is added and the stirring continued overnight at room temperature. The reaction mixtureis diluted with water and extracted with chloroform. The organic layer is dried, concentrated in vacuo and the residue purified by chromatography (silica gel: 10-80% ethyl acetate/hexane) to give 1.1 g of the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6](Br)[CH:5]=[C:4](Br)[CH:3]=1.[CH2:10]([OH:15])[CH2:11][CH2:12][C:13]#[CH:14]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:15][CH2:10][CH2:11][CH2:12][C:13]#[C:14][C:2]1[CH:7]=[C:6]([C:14]#[C:13][CH2:12][CH2:11][CH2:10][OH:15])[CH:5]=[C:4]([C:14]#[C:13][CH2:12][CH2:11][CH2:10][OH:15])[CH:3]=1
Reactant: C#CCCCO
Reactant: Brc1cc(Br)cc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: OCCCC#Cc1cc(C#CCCCO)cc(C#CCCCO)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 73.9 %

Procedure:
1,3,5-Tribromobenzene (10 g, 31.76 mmol), 4-pentyn-1-ol (10.69 g, 127.06 mmol) and bis(triphenylphosphine)palladium(II) dichloride were stirred in triethylamine under nitrogen for 5 minutes. Copper(I) iodide (92 mg, 0.48 mmol) was added and the mixture was stirred for 6 hours at 80° C. The mixture was cooled to room temperature, filtered through a celite pad and rinsed with ethyl acetate. The combined filtrate was evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography (CHCl3:MeOH 10:1) to afford 7.61 g of 1,3,5-tris-(5-hydroxy-1-pentynyl)-benzene. Yield: 74%. 1H NMR (300 MHz, CDCl3) δ 7.31 (3, 3h), 3.81 (t, J=6.0 Hz, 6H), 2.52 (t, J=6.9 Hz, 6H), 1.85 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 133.8, 124.2, 90.5, 80.0, 61.9, 31.5, 16.2 ppm.
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=O)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[CH:1]1([S:4][C:5]2[CH:13]=[CH:12][C:8]([CH2:9][NH2:11])=[CH:7][CH:6]=2)[CH2:2][CH2:3]1
Reactant: NC(=O)c1ccc(SC2CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(SC2CC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4-cyclopropylsulfanyl-benzamide (preparation 63a, 137 mg, 0.71 mmol) in THF is added to lithium aluminium hydride (1 M in THF, 2.1 mL, 2.1 mmol) precooled at 0° C. The mixture is stirred at 0° C. for 1 h and then heated at reflux for 1 h. The mixture is cooled to room temperature and stirred for 1.5 h. Water is added, and the mixture is extracted twice with dichloromethane. The combined organic layers are dried over Na2SO4 and concentrated under reduced pressure. Yield: 75 mg (60% of theory); ESI mass spectrum: [M+H]+=180; r.t. HPLC: 0.51 min (X011_S03).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[N:6]=[C:5]2Cl.C(N(CC)CC)C.[OH:27][C@H:28]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[N:6]=[C:5]2[N:34]1[CH2:33][CH2:32][N:31]([C:29](=[O:30])[C@H:28]([OH:27])[CH2:37][CH:38]([CH3:39])[CH3:40])[CH2:36][CH2:35]1
Reactant: Oc1ccccc1-c1nc(Cl)c2cc(Br)ccc2n1
Reactant: CC(C)C[C@@H](O)C(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3ccc(Br)cc23)CC1
Reaction time: 3 h
Yield: 83.9 %

Procedure:
To a solution of 2-(6-bromo-4-chloroquinazolin-2-yl)phenol (228 mg, 0.68 mmol), triethylamine (129 μL, 0.92 mmol), and CH2Cl2 (6 mL) was added (R)-2-hydroxy-4-methyl-1-(piperazin-1-yl)pentan-1-one (185 mg, 0.92 mmol) dissolved in CH2Cl2 (3 mL). The flask was flushed with N2 and stirred for 3 hours. The reaction mixture was then transferred into a separatory funnel with CH2Cl2, and the organic phase was washed with H2O (2×), dried over Na2SO4, and concentrated. Purification via silica gel chromatography using 0 to 20% EtOAc and CH2Cl2:hexanes (1:1) gave (R)-1-(4-(6-bromo-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one (285 mg, 84%). LC/MS: m/z 500.30 (M+H)+ at 3.29 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]([C:9]([CH2:12][S:13]([CH:16]=[CH2:17])(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1CCC=CC=1.[C:26]1([CH3:32])[CH:31]=[CH:30]C=[CH:28][CH:27]=1>>[CH:17]12[CH2:30][CH2:31][CH:26]([CH:27]=[CH:28]1)[CH2:32][CH:16]2[S:13]([CH2:12][C:9]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([O:18][CH3:19])[C:2]([Br:1])=[CH:11][CH:10]=1)(=[O:15])=[O:14]
Reactant: C=CS(=O)(=O)Cc1ccc(Br)c(OC)c1C(=O)OC
Reactant: Cc1ccccc1
Solvent: C1=CCCC=C1
Product: COC(=O)c1c(CS(=O)(=O)C2CC3C=CC2CC3)ccc(Br)c1OC
Temperature: 125 °C

Procedure:
A solution of methyl 3-bromo-2-methoxy-6-(vinylsulphonylmethyl)benzoate (Intermediate 172, 0.5 g), and cyclohexadiene (0.343 g) in toluene (0.5 ml) was sealed in a vial and heated at 125° C. for 3 days. After cooling, the mixture was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 10-40% to give methyl 6-(bicyclo[2.2.2]oct-5-ene-2-ylsulphonylmethyl)-3-bromo-2-methoxybenzoate (0.455 g) as a white solid.