Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].CCO.[OH-].[Na+:36]>O>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:36]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21

Procedure:
A 250 round bottom flask was loaded with fluvastatin methyl ester (12.0 g), EtOH (60 ml), water (36 ml) and NaOH (1 eq.). After 2 h the ethanol was evaporated and the residue was divided to 4 fractions. Water was added (completing to 20 vol) and extracted twice with ethyl acetate. The product was isolated by distillation of water to obtain wet fluvastatin sodium crystal Form LXXVI. (the sample was kept at room temperature for 3 days).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH2:12]([S:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18])[CH3:13].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH2:12]([S:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]=1)=[O:18])[CH3:13]
Reactant: CCSc1ccccc1C(=O)O
Reactant: Nc1ccc(C(F)(F)F)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: CCSc1ccccc1C(=O)Nc1ccc(C(F)(F)F)cn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 36.8 %

Procedure:
A mixture of 0.81 g of 2-amino-5-trifluoromethylpyridine, 0.91 g of 2-ethylsulfanyl-benzoic acid, 1.15 g of EDCI hydrochloride, 0.06 g of HOBt and 10 mL of pyridine was stirred at 60° C. for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the cooled reaction mixture, and the precipitated solid was taken by filtration and washed with acetonitrile to obtain 0.60 g of 2-ethylsulfanyl-N-(5-trifluoromethyl-pyridin-2-yl)-benzamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]2.C1([O:19][C:20](=O)[NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)C=CC=CC=1>CS(C)=O>[OH:12][CH:9]1[CH2:10][C:11]2[C:2]([NH:1][C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:24][CH:23]=3)=[O:19])=[CH:3][CH:4]=[CH:5][C:6]=2[CH2:7][CH2:8]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)Oc1ccccc1
Reactant: Nc1cccc2c1CC(O)CC2
Solvent: CS(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)Nc1cccc2c1CC(O)CC2
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 21.2 %

Procedure:
A mixture of 8-amino-1,2,3,4tetrahydro-naphthalen-2-ol (32.6 mg, 0.20 mmol) and (4trifluoromethoxy-phenyl)-carbamic acid phenyl ester (59.5 mg, 0.20 mmol) in DMSO (1.0 ml) was stirred at 100° C. for 1.5 hours. The mixture-was concentrated under reduced pressure, and then purified by preparatory HPLC to obtain N-(7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-N′-(4-trifluoromethoxy-phenyl)-urea (15.5 mg, 21% yield).
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][CH:3]=[C:2]1[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1.[C:13]1([NH:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(O)C>[C:13]1([NH:19][N:20]=[CH:6][C:5]2[S:1][C:2]([C:8]3[S:9][CH:10]=[CH:11][CH:12]=3)=[CH:3][CH:4]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NNc1ccccc1
Reactant: O=Cc1ccc(-c2cccs2)s1
Solvent: CC(C)O
Product: C(=NNc1ccccc1)c1ccc(-c2cccs2)s1
Temperature: 25 °C

Procedure:
A mixture of 2,2′-bithiophene-5-carboxaldehyde (5.0 g, 0.0257 mole, obtained from TCI Europe nv, Boerenveldseweg 6, 2070 Zwijndrecht) and 10 ml of 2-propanol was added to a 100 ml, 2 neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. Heat was applied until all 2,2′-bithiophene-5-carboxaldehyde entered into solution. After all 2,2′-bithiophene-5-carboxaldehyde was dissolved, a hot solution of phenylhydrazine (3.05 g, 2.78 ml, 0.0309 mole, obtained from Aldrich) in 3 ml of 2-propanol was added to the 2,2′-bithiophene-5-carboxaldehyde solution. After the reaction mixture was refluxed for 6 hours, the mixture was cooled to room temperature. The crystals formed were filtered off, and then washed with a mixture of 2-propanol and hexane in 1:1 ratio by volume. The yield of the product, 2,2′-bithiophene-5-carboxaldehyde N-phenylhydrazone, was 6.95 g (94.9%). The product was recrystallized from 2-propanol and dried at 60° C. in a vacuum oven for 6 hours. The melting point of the product was found to be 156-158° C. An infrared absorption spectrum of the product was characterized by the following absorption wave numbers (KBr window, cm−1): 3306 (NH); 3104, 3061 (CHaromatic); 1599 (C═C, C—N). A 1H-NMR spectrum (300 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 7.77 (s, 1H, CH═N); 7.30-7.00 (m, 9H, Ph, Ht, NH); 6.95 (d, 1H, Ht); 6.87 (t, 1H, 4-H Ph). An elemental analysis yielded the following results in weight percent: C, 63.50; H, 4.16; N, 9.97, which compares with the following calculated elemental weight percent for a compound with the formula C15H12N2S2: C, 63.35; H, 4.25; N, 9.85.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].CCN(CC)CC.[C:33]1([CH3:61])[CH:38]=[CH:37][C:36]([S:39]([CH2:42][CH2:43][O:44][C:45](=[O:60])[CH2:46][CH2:47][C:48]2[CH:53]=[C:52]([S:54](Cl)(=[O:56])=[O:55])[CH:51]=[CH:50][C:49]=2[O:58][CH3:59])(=[O:41])=[O:40])=[CH:35][CH:34]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:33]1([CH3:61])[CH:38]=[CH:37][C:36]([S:39]([CH2:42][CH2:43][O:44][C:45](=[O:60])[CH2:46][CH2:47][C:48]2[CH:53]=[C:52]([S:54]([N:21]3[C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=[C:17]3[S:15]([CH2:14][C:3]3[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[CH:6]=[CH:5][N:4]=3)=[O:16])(=[O:56])=[O:55])[CH:51]=[CH:50][C:49]=2[O:58][CH3:59])(=[O:41])=[O:40])=[CH:35][CH:34]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1CCC(=O)OCCS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)n2c(S(=O)Cc3nccc(OCC(F)(F)F)c3C)nc3ccccc32)cc1CCC(=O)OCCS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To a heterogeneous solution of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl-methanesulfinyl]-1H-benzimidazole (LANSOPRAZOLE, 800 mg, 2.17 mmol) and 3 mL of Et3N in 20 mL of CH2Cl2 was added the chlorosulfonyl ester (Intermediate 60, 1.2 g, 2.60 mmol, 1.2 eq). About 1 g of solid NaHCO3 was added after the chlorosulfonyl ester has dissolved completely in the reaction mixture. The mixture was stirred at room temperature 1 h. Thereafter the solvent was removed by evaporation and the residual oil was purified by column chromatography (silica gel, CH2Cl2 to 1% MeOH in CH2Cl2) to give Intermediate 63 (1.2 g, 70%) as an off-white foam.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23]CC2C=CC(OC)=CC=2)=[CH:19][C:18]=1[C:33]1[S:34][C:35]([C:38]([F:41])([F:40])[F:39])=[N:36][N:37]=1.C1(OC)C=CC=CC=1>>[F:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[C:33]1[S:34][C:35]([C:38]([F:39])([F:40])[F:41])=[N:36][N:37]=1
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(-c3nnc(C(F)(F)F)s3)c2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(F)c(-c2ccc(O)cc2-c2nnc(C(F)(F)F)s2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.6 %

Procedure:
Trifluoroacetic acid (5.0 mL) was added to 2-(2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)-[1,1′-biphenyl]-2-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole (299 mg) and anisole (0.66 mL) at room temperature, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (200 mg) as a white solid.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:14](C(=O)C)[CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=[C:30](C=CC=1)[C:31]([O:33]O)=[O:32]>C(Cl)(Cl)Cl>[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[C:14]([O:33][C:31](=[O:32])[CH3:30])[CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1cc(S(=O)(=O)c2ccccc2)ccc1OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1cc(S(=O)(=O)c2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 30.5 %

Procedure:
A solution of 1-(5-benzenesulfonyl-2-benzyloxy-phenyl)-ethanone (2.16 g; 0.059 mol) and meta-chloroperoxybenzoic acid (3.98 g; 0.018 mol, max. 77%) in chloroform (20 mL) was heated under reflux for 18 hours. After cooling to ambient temperature the mixture was diluted with chloroform, filtered, washed with water and saturated sodium bicarbonate, dried (Na2SO4) and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (hexane-ethyl acetate; 1:1) to give acetic acid 5-benzenesulfonyl-2-benzyloxy-phenyl ester (2.1 g; 93%): M. p. 106.9-111.1° C.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2]>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[C:1]([C:5]1[C:6](=[O:7])[CH:8]=[CH:9][C:10](=[O:12])[CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(O)ccc1O
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CC(C)(C)C1=CC(=O)C=CC1=O
Temperature: 70 °C
Yield: 80 %

Procedure:
16.6 g (0.10 mol) of 2-tert-butylhydroquinone was placed in a 200 cc 3-neck flask. After adding 17.4 g (0.20 mol) of powdery manganese dioxide, 100 cc of toluene was added thereto, and the mixture was heated with stirring. The temperature was maintained at 70° C. for 3 hours. After cooling to room temperature, the manganese dioxide was removed by filtration by means of suction using Celite as a filter aid. Then the manganese dioxide was washed with 50 cc of toluene, and the toluene was evaporated to dryness, by which 2-tert-butyl-1,4-benzoquinone was obtained. The yield was 80% and the melting point was 48°-50° C.
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][NH2:14].[Cl:15][C:16]1[C:21]([CH3:22])=[C:20](Cl)[N:19]=[CH:18][N:17]=1>CC(N(C)C)=O.C(N(C(C)C)CC)(C)C>[Cl:15][C:16]1[N:17]=[CH:18][N:19]=[C:20]([NH:14][CH2:13][CH2:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[CH2:6][CH2:7][CH2:8][NH:9][C:10]=3[N:1]=2)[C:21]=1[CH3:22]
Reactant: Cc1c(Cl)ncnc1Cl
Reactant: NCCCc1ccc2c(n1)NCCC2
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)ncnc1NCCCc1ccc2c(n1)NCCC2
Reaction time: 9 h
Yield: 58 %

Procedure:
A mixture of 774.3 mg (4.05 mmoles) of 3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-ylpropylamine (prepared according to J. Org. Chem. 2004, 69, 1959-1966) and 600 mg (3.68 mmoles) of 4,6-dichloro-5-methyl-pyrimidine in 6 ml of dimethylacetamide and 1.2 ml of diisopropylethylamine is taken to 120° C. for 9 hours. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent evaporated off under reduced pressure (2 kPa). The residue is chromatographed on Alumina then on silica eluting with a gradient of 100% heptane to 100% ethyl acetate. 680 mg (Yield=58%) of expected product is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:5]=[N:6][CH:7]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: Fc1cccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)c1

Procedure:
The title compound was prepared from the product of Example 65A and 3-fluorophenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 324.0 (M+H)+, retention time 1.31 minutes.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=3)[N:9]=2)[CH:5]=[C:4]([CH3:20])[N:3]=1>O1CCOCC1.O>[CH2:5]([C:2]1[CH:7]=[C:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=3)[N:9]=2)[CH:5]=[C:4]([CH3:20])[N:3]=1)[CH:6]([CH3:8])[CH3:7]
Reactant: Cc1cc(-c2noc(-c3cc(C)nc(Cl)c3)n2)ccn1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2noc(-c3cc(C)nc(CC(C)C)c3)n2)ccn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 20.4 %

Procedure:
To a solution of 2-chloro-4-[3-(2-methyl-4-pyridinyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridine (200 mg, 0.698 mmol) in dioxane (10 mL), Pd(dppf) (11 mg, 14 μmol) and isobutyl zink bromide (2.8 mL, 0.5 M in THF) is added. The mixture is stirred at 80° C. for 3 h before another portion of isobutyl zink bromide (2.8 mL) is added. Stirring is continued at 80° C. for 72 h. The mixture is cooled to rt, diluted with water and extracted with EA. The org. extract is concentrated and the crude product is purified by prep. HPLC to give 2-isobutyl-4-[3-(2-methyl-4-pyridinyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridine (22 mg) as a beige solid; LC-MS: tR=0.71 min, [M+1]+=309.12.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]=[N:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=[C:4]([NH2:16])[N:3]=1.[C:17]1(=[O:24])[O:23][C:21](=[O:22])[CH2:20][CH2:19][CH2:18]1>O1CCCC1>[NH2:1][C:2]1[N:3]=[C:4]([NH:16][C:17](=[O:24])[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:5]=[CH:6][C:7]=1[N:8]=[N:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ccc(N=Nc2cccnc2)c(N)n1
Reactant: O=C1CCCC(=O)O1
Solvent: C1CCOC1
Product: Nc1nc(NC(=O)CCCC(=O)O)ccc1N=Nc1cccnc1
Yield: 38.6 %

Procedure:
To a mixture of 3.21 g (15 mmol) of 2,6-diamino-3-((pyridin-3-yl)azo)pyridine and 0.27 g (2.2 mmol) of N,N-dimethylamino-pyridine in 100 ml of tetrahydrofurane, 4.27 g (37.5 mmol) of glutaric anhydride was added at room temperature. The mixture was refluxed for 16 hours. The mixture was then filtered, the solvent was evaporated and the crude product was dissolved in ethylacetate and extracted three times with a 1N sodium hydroxide solution. The combined aqueous extracts were acidified with conc. HCI at 0° C. A precipitate was formed, and filtration yielded an orange solid. The solid so obtained was washed with water. After drying the product was recristallised in methanol/water mixture and 1.9 g (40% yield) of 5-[(6-amino-5-(3-pyridinyldiazenyl)-2-pyridinyl)amino]-5-oxopentanoic acid were obtained.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=4)[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH3:24][NH:25][CH3:26].C1COCC1>>[CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22][N:25]([CH3:26])[CH3:24])=[CH:18][CH:17]=4)[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: CNC
Reactant: Cc1cc2c(ccc3nnc(C)n32)n1Cc1ccc(CO)cc1
Solvent: C1CCOC1
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1ccc(CN(C)C)cc1

Procedure:
The title compound was prepared according to the procedures of Example 45, using the alcohol of Example 49 as starting material and using 2.0 M dimethylamine in THF (0.15 mL, 0.30 mmol, Aldrich) in the displacement (8.0 mg, 49%).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[CH:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:1]([CH2:3][C:4]([NH:13][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2]
Reactant: NC1CCCCC1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: N#CCC(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.1 %

Procedure:
Cyanoacetic acid (4.26 g, 50 mmol) and cyclohexylamine (4.96 g, 50 mmol) were dissolved in DCM (100 mL). EDCI (10.51 g, 55 mmol) was added and the mixture stirred at ambient temperature for 24 h. The reaction mixture was washed with water (2×100 mL), dried (MgSO4) and evaporated to leave a yellow solid residue which was purified by chromatography on silica gel eluting with an EtOAc/DCM gradient (0-100%) to provide the title compound as a white solid (5.66 g, 68%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Cl.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C=CC=CC=3C)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:25][C:26]3[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=3[CH3:28])[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: Cc1ccccc1CCl
Agent: Cc1ccccc1Cn1nc2c(c1-c1ccc(Cl)cc1)CCN(C(=O)OC(C)(C)C)CC2
Product: Cc1ccccc1Cn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Yield: 42.6 %

Procedure:
The title compound (0.03 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 2-methylbenzyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(2-methyl-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C21H22ClN3, 351.15; found, m/z 352.2 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.56 (d, J=8.5 Hz, 2H), 7.49 (d, J=8.5 Hz, 2H), 7.23-7.15 (m, 3H), 6.58 (d, J=7.5, 1H), 5.50 (s, 2H), 3.42-3.39 (br m, 4H), 3.15-3.12 (br m, 4H), 2.40 (s, 3H).
Reaction SMILES: [C:1]1([S:7]([N:10]=[C:11]=[S:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[N:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([O:22][CH3:23])[N:15]=1.C(#N)C.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>C(OCC)C>[CH3:21][O:20][C:18]1[N:17]=[C:16]([O:22][CH3:23])[N:15]=[C:14]([NH:13][C:11](=[S:12])[NH:10][S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])[N:19]=1
Reactant: COc1nc(N)nc(OC)n1
Reactant: O=S(=O)(N=C=S)c1ccccc1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCOCC
Solvent: CC#N
Product: COc1nc(NC(=S)NS(=O)(=O)c2ccccc2)nc(OC)n1

Procedure:
A mixture containing 20 g of benzenesulfonyl isothiocyanate, 15.6 g of 2-amino-4,6-dimethoxy-1,3,5-triazine, 250 ml of acetonitrile and a catalytic amount of dibutyltin dilaurate was stirred for 24 hours. After filtration to remove unreacted triazine, the evaporation of the acetonitrile yielded a gummy residue. Trituration of this material with ethyl ether resulted in the precipitation of the desired compound, which was isolated by filtration and melted at 148°-150° C.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=1.[OH-].[K+]>CC(C)=O.O.[OH-].[Na+]>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:16])=[O:2])[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)Cc1cccc(-c2ccco2)c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)Cc1cccc(-c2ccco2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a solution of 3-(2-furyl)phenylacetic acid methyl ester (0.047 g, 0.217 mmol, 1.0 eq) in acetone (3.0 ml) was added potassium hydroxide (0.5 ml of a 30% solution in H2O). The mixture was stirred at room temperature for 16 hours before diluting with 1 N NaOH (10 ml), and washing with CH2Cl2 (15 ml). The aqueous phase was acidified with 1 N HCl (15 ml) and the organics extracted with CH2Cl2 (3×20 ml). The extract was dried (Na2SO4) and concentrated under reduced pressure to yield 3-(2-furyl)phenylacetic acid (0.043 g, 100%) as a white solid; 1H-NMR (CDCl3, 400 MHz): δ 7.60 (1H, br s), 7.46 (1H, t, J=1.0 Hz), 7.34 (1H, t, J=7.5 Hz), 7.19 (2H, m), 6.65 (1H, d, J=3.2 Hz), 6.46 (1H, m), 3.67 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([OH:32])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.C(Br)(Br)(Br)Br.[P:38]([O:45]CC)([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([O:32][P:38]([O:42][CH2:43][CH3:44])([O:39][CH2:40][CH3:41])=[O:45])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=3)[CH2:17][CH2:16]2)=[CH:6][CH:7]=1
Reactant: CCOP(OCC)OCC
Reactant: CCOC(=O)c1ccc(N2CCC([C@@H](O)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Agent: BrC(Br)(Br)Br
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(N2CCC([C@@H](OP(=O)(OCC)OCC)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.1 %

Procedure:
A solution of (R)-ethyl 4-(4-((4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoate (INTERMEDIATE 11A, 600 mg, 1.33 mmol), CBr4 (575 mg, 1.73 mmol), and pyridine (2 ml) at 0° C. was treated dropwise over a 10 minute period with triethyl phosphite (0.56 ml, 3.33 mmol). The solution was stirred at 0° C. for about 10 minutes and then the ice bath was removed. The reaction was stirred overnight at r.t. whereupon the excess pyridine was removed under reduced pressure and the concentrate was taken up in 50 ml of DCM. The organic layer was washed successively with 50 ml each of 0.5 N aq. HCl, saturated aqueous sodium bicarbonate, and water. The organic layers were dried over sodium sulfate, filtered and adsorbed onto silica gel. Purification by column chromatography (ISCO, 80 g silica gel column, eluting with 0→100% EtOAc/hexanes over 24 minutes) gave the title compound (500 mg, yield: 64%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[N:10][N:9]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:17](Cl)(=[O:19])[CH3:18].Cl>C(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:17](=[O:19])[CH3:18])=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[N:10][N:9]=1
Reactant: Oc1ccccc1-c1nnn[nH]1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(O)c(-c2nnn[nH]2)c1
Yield: 39.2 %

Procedure:
A suspension of 16.2 g (0.1 mol) of 5-(2-hydroxyphenyl)-1H-tetrazole in 300 ml of dry methylene chloride is cooled in an ice bath, 39.9 g (0.3 mol) of anhydrous aluminum chloride are added and acetyl chloride 8.1 g (0.1 mol) is added via dropwise addition over a period of 5 minutes. The mixture is refluxed for 3.5 hours, cooled, and 200 ml of 2N HCl is added dropwise with stirring. The resulting precipitate is collected, washed with 2N HCl, water and recrystallized from an isopropanol-water mixture to yield 8.0 g of 1-[4-hydroxy-3-(1H-tetrazol-5-yl)phenyl]ethanone, m.pt. 260°-261° C. (dec.).