Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:14]([CH2:33][CH2:34]OS(C)(=O)=O)[O:13][C@@H:10]1[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:40].[Mg+2].[I-].O>CCOCC>[CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:14]([CH2:33][CH2:34][I:40])[O:13][C@@H:10]1[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:40]
Reactant: CO[C@H]1O[C@H](CCOS(C)(=O)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [I-]
Agent: [Mg+2]
Solvent: O
Solvent: CCOCC
Product: CO[C@H]1O[C@H](CCI)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 2,3,4-tri-O-benzyl-6-deoxy-7-O-methylsulfonyl-α-D-glucoheptopyranoside (0.38 g, 0.83 mmol) in ether (5 ml) was added at 0° C. a 0.375 M solution of magnesium iodide (6.7 ml). The mixture was stirred 15 min at 0° C. The excess of magnesium iodide was hydrolyzed with water. The reaction mixture was washed with sodium thiosulfate and Water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford an oil. Flash chromatography on silica gel and elution with a 2:8 mixture of ethyl acetate and hexane afforded the expected iodide methyl 2,3,4-tri-O-benzyl-6,7-dideoxy-7-iodo-α-D-glucoheptopyranoside which was crystallized from hexane (0.368 g, 91%); m.p. 66°-68° C.
Reaction SMILES: C(O[C:4]([CH2:6][C:7]([O:9][CH3:10])=[S:8])=[O:5])C.[C:11](#[N:13])[CH3:12].C[O-].[Na+]>CO>[C:11]([C:12]1[S:8][C:7]([O:9][CH3:10])=[CH:6][C:4]=1[OH:5])#[N:13]
Reactant: CC#N
Reactant: CCOC(=O)CC(=S)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(O)c(C#N)s1
Temperature: 20 °C
Yield: 54.2 %

Procedure:
81 g of O-methyl 2-ethoxycarbonyl-thioacetate and then 38 g of acetonitrile were added to a solution of 27 g of sodium methylate in 250 ml of methanol and the mixture was refluxed for one hour. A solution of 27 g of sodium methylate in 100 ml of methanol were added to the reaction which was cooled to 20° C. and concentrated to dryness. The residue was dissolved in water and the solution was washed with ether, acidified with concentrated hydrochloric acid and was vacuum filtered. The recovered crystals were dried to obtain 42 g of 2-cyano-3-hydroxy-5-methoxy-thiophene with a melting point of 138°-140° C. A microanalytically pure sample obtained by crystallization from isopropyl ether melted at 140° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]#[N:15])=[CH:5][CH:4]=1)=O.[C:16]1([CH3:28])[CH:21]=[CH:20][C:19]([S:22]([CH2:25][C:26]#[N:27])(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[C:26]([C:25]([S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:28])=[CH:17][CH:18]=1)(=[O:24])=[O:23])=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]#[N:15])=[CH:5][CH:4]=1)#[N:27]
Reactant: Cc1ccc(S(=O)(=O)CC#N)cc1
Reactant: N#Cc1ccsc1-c1ccc(C=O)cc1
Product: Cc1ccc(S(=O)(=O)C(C#N)=Cc2ccc(-c3sccc3C#N)cc2)cc1

Procedure:
In a manner analogous to the procedure set forth in example A-239, the title compound is prepared from 2-(4-formylphenyl)thiophene-3-carbonitrile, prepared directly above, and p-toluenesulphonylacetonitrile.
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[N:11]([CH3:22])[C:10]1=[O:23])C1C=CC=CC=1.[H][H]>C1COCC1.CO.[Pd]>[F:20][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][C:14]=1[F:21])[N:11]([CH3:22])[C:10](=[O:23])[N:9]([OH:8])[C:18]2=[O:19]
Reactant: Cn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(F)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(=O)n(O)c(=O)c2cc(F)c(F)cc21
Yield: 98.4 %

Procedure:
Twenty percent Pd/C (0.2 g) was added to a solution of 3-benzyloxy-6,7-difluoro-1-methyl-1H-quinazoline-2,4-dione (Example K, 1.55 g, 4.9 mmol) in 25 mL of THF and 25 mL of methanol. The mixture was shaken under 50 PSI of hydrogen for 1.5 hours, and filtered. The catalyst was rinsed with 200 mL of a 50/50 mixture of THF and methanol and concentrated to afford 1.1 g of the title compound as a solid, mp 239-241° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][O:37][C:38]1[CH:44]=[C:43]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][O:53][CH3:54])[CH2:47][CH2:46]2)[CH:42]=[CH:41][C:39]=1[NH2:40].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C(F)(F)F.N>CO.C(Cl)Cl>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]3[CH:41]=[CH:42][C:43]([N:45]4[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][O:53][CH3:54])[CH2:47][CH2:46]4)=[CH:44][C:38]=3[O:37][CH3:36])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COCCN1CCN(c2ccc(N)c(OC)c2)CC1
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: ClCCl
Solvent: OCC(F)(F)F
Solvent: CO
Product: COCCN1CCN(c2ccc(Nc3nccc(-c4c(-c5ccc(OC)c(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)c(OC)c2)CC1
Temperature: 100 °C
Yield: 66.7 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 2-(methyloxy)-4-{4-[2-(methyloxy)ethyl]-1-piperazinyl}aniline (Example 238, step A) (48 mg, 0.18 mmol), and p-toluenesulfonicacid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 1 mL of trifluoroethanol was added and the mixture was heated to 100° C. for 72 h. 2 mL of 2 N ammonia in MeOH was added. The solvent was rotovaped down. The residue was taken up in 3 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-absorbed solids were purified by flash chromatography to give the title compound (85 mg, 0.12 mmol, 64%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.78 (s, 1H), 9.36 (s, 1H), 8.45 (s, 1H), 8.20 (d, J=5.50 Hz, 1H), 8.10 (d, J=2.20 Hz, 1H), 7.77 (dd, J=8.80, 2.20 Hz, 1H), 7.69 (d, J=9.17 Hz, 1H), 7.34-7.46 (m, 3H), 7.28 (d, J=8.80 Hz, 1H), 7.18 (t, J=8.07 Hz, 2H), 6.90-6.98 (m, 1H), 6.67 (d, J=2.57 Hz, 1H), 6.52 (d, J=5.13 Hz, 1H), 6.45-6.51 (m, 1H), 3.98 (s, 3H), 3.79 (s, 3H), 3.46 (t, J=5.87 Hz, 2H), 3.24 (s, 3H), 3.10-3.17 (m, 4H), 2.53-2.58 (m, 4H), 2.51 (t, J=5.87 Hz, 2H); MS (ESI): 721 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16](I)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1.[CH3:31][CH:32]1[NH:37][CH2:36][CH2:35][NH:34][C:33]1=[O:38]>CN1CCCC1=O>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([N:37]3[CH2:36][CH2:35][NH:34][C:33](=[O:38])[CH:32]3[CH3:31])[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1
Reactant: CC1NCCNC1=O
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Solvent: CN1CCCC1=O
Product: CC1C(=O)NCCN1c1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2c1C(C)(C)C(=O)N2
Temperature: 220 °C

Procedure:
Under argon atmosphere, 200 mg (purity 62%, 0.24 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was suspended in 4 ml of absolute 1-methyl-2-pyrrolidone and 550 mg (4.82 mmol) of 3-methylpiperazin-2-one was added. The mixture was heated in the microwave for 3 h at 150° C. and for 3 h at 220° C. After cooling, the reaction mixture was purified by preparative HPLC (eluent: acetonitrile/water, gradient 20:80→100:0). 61 mg (purity 100%, 50% of theor.) of the target compound was obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH2:7][N:8]([CH3:12])[CH2:9]2)=[CH:4][CH:3]=1.[N:21]1[NH:22][C:23](=[O:27])[CH:24]=[CH:25][CH:26]=1>>[Cl:20][C:15]1[CH:14]=[C:13]([CH:6]2[C:5]3[C:10](=[CH:11][C:2]([N:22]4[C:23](=[O:27])[CH:24]=[CH:25][CH:26]=[N:21]4)=[CH:3][CH:4]=3)[CH2:9][N:8]([CH3:12])[CH2:7]2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: O=c1cccn[nH]1
Reactant: CN1Cc2cc(Br)ccc2C(c2ccc(Cl)c(Cl)c2)C1
Product: CN1Cc2cc(-n3ncccc3=O)ccc2C(c2ccc(Cl)c(Cl)c2)C1
Yield: 23 %

Procedure:
A procedure similar to the one in Step A of Example 17 was used to couple 7-bromo-4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline with pyridazin-3(2H)-one. 2-(4-(3,4-Dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3(2H)-one was obtained in 23% yield as an off-white foam: ESI MS m/z 386 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1.[OH-].[Na+]>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[CH:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:27]=[N:26][N:25]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH:24]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Reactant: ClCc1ccccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccccn3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.1 %

Procedure:
To a solution of 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.27 g) in methylene chloride (2 mL) were added tetra-n-butylammonium hydrogensulfate (0.66 g), 2-(chloromethyl)pyridine hydrochloride (0.19 g) and 1 mol/L-aqueous sodium hydroxide solution (2.26 mL), and the mixture was stirred at room temperature for one day. The reaction mixture was partitioned between water and chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give 5-benzyloxy-N-(4-isopropylphenyl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.19 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[C:26]4[CH2:27][CH2:28][CH2:29][CH2:30][C:25]=4[S:24][C:23]=3[NH:31][C:32]([C:34]3[CH:35]=[C:36]([S:40]([N:43]4[CH2:50][CH2:49][CH2:48][C@@:44]4([CH3:51])[C:45]([OH:47])=[O:46])(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=3)=[O:33])=[O:21])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[C:26]4[CH2:27][CH2:28][CH2:29][CH2:30][C:25]=4[S:24][C:23]=3[NH:31][C:32]([C:34]3[CH:35]=[C:36]([S:40]([N:43]4[CH2:50][CH2:49][CH2:48][C@@:44]4([CH3:51])[C:45]([OH:47])=[O:46])(=[O:41])=[O:42])[CH:37]=[CH:38][CH:39]=3)=[O:33])=[O:21])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)N5CCC[C@@]5(C)C(=O)O)c4)sc4c3CCCC4)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@]1(C(=O)O)CCCN1S(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)O)cc4)cc2)CCCC3)c1
Yield: 84.8 %

Procedure:
A mixture of 160 mg of 1-{[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)phenyl]sulfonyl}-2-methylproline, 1.0 mL of a 1.0 M aqueous sodium hydroxide solution, and 1.6 mL of methanol was heated and refluxed overnight. The reaction mixture was concentrated under reduced pressure and the residue was neutralized with 1.0 M hydrochloric acid. The precipitate was collected by filtration to obtain 133 mg of 1-[(3-{[3-({4-[2-(4-carboxyphenyl)ethyl]phenyl}carbamoyl)-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]carbamoyl}phenyl)sulfonyl]-2-methylproline as a pale yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1(C(OC)=O)[C:15](=[O:16])[CH2:14][CH2:13][CH2:12]1)C.S(=O)(=O)(O)O>O>[O:16]=[C:15]1[CH2:14][CH2:13][CH2:12][CH:11]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:21])=[O:3]
Reactant: CCOC(=O)CCCCCCC1(C(=O)OC)CCCC1=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CCCCCCC1CCCC1=O
Reaction time: 48 h

Procedure:
A suspension of 10.9 g. of ethyl-7-(1'-methoxycarbonyl-5'-oxocyclopentyl)-heptanoate in 100 ml. of distilled water containing 6 g. of conc. sulfuric acid was refluxed under nitrogen. Progress of the reaction was followed by gas chromatography/mass spectroscopy analysis of a sample at intervals. After 48 hours the reaction was virtually complete and the mixture was cooled and extracted with one volume of ethyl ether. The aqueous layer was separated and extracted and extracted again with one volume of ether and the combined ethereal extracts were dried over magnesium sulfate and evaporated to a colorless oil which was sufficiently pure for the next step in the process. Yield was 6.6 g., about 99%.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.[NH2:15][C@H:16]1[CH2:21][C:20]2[C:22]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:32][N:29]1[CH2:30][CH2:31][N:26]([C:22]2[C:20]3[CH2:21][C@H:16]([NH:15][C:8](=[O:10])[C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:14])[F:13])=[CH:12][CH:11]=4)[CH2:17][O:18][C:19]=3[CH:25]=[CH:24][CH:23]=2)[CH2:27][CH2:28]1
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(OC(F)(F)F)cc2)CO3)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
A mixture of 4-trifluoromethoxybenzoic acid (254 mg, 1.23 mmol) in thionyl chloride (5 mL) was heated at 60° C. for 25 min. The excess of thionyl chloride was removed under reduced pressure, and the remains were evaporated with two portions of toluene. The acid chloride was then dissolved in anhydrous methylene chloride (5 mL) and added to a stirred solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (277 mg, 1.12 mmol) and triethylamine (234 μL, 1.68 mmol) in methylene chloride (10 mL). The reaction mixture was stirred for 2 h at room temperature and was washed with a saturated solution of NaHCO3. The organic layer was dried (MgSO4), and the solvent was removed in vacuo. The product was purified by column chromatography on silica (eluent: chloroform/ethanol, 92:8+0.5% conc. NH3) affording 248 mg (51% yield) of the title compound as a white solid: mp 192-193. C.; [α]21D −75° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 435 (6, M+).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].C([O-])(O)=O.[Na+].Cl[C:40]1[CH:45]=[N:44][CH:43]=[CH:42][N:41]=1>COCCOC.ClCCl.Cl[Pd]Cl.O>[N:41]1[CH:42]=[CH:43][N:44]=[CH:45][C:40]=1[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Clc1cnccn1
Reactant: Brc1cccc2[nH]ccc12
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: c1cc(-c2cnccn2)c2cc[nH]c2c1
Temperature: 125 °C
Reaction time: 0.25 h

Procedure:
4-Bromoindole (0.1 g, 0.51 mmol), bis(pinacolato)diboron (0.172 g, 0.77 mmol), potassium acetate (0.075 g, 0.765 mmol) and PdCl2 (0.022 g, 0.031 mmol) were dissolved in DME (3 mL) and heated in the microwave for 900 seconds at 125° C. The reaction was cooled and NaHCO3 (0.129 g, 1.53 mmol), 2-chloropyrazine (0.087 g, 0.77 mmol) tetrakis(triphenylphosphine)palladium (0.0295 g, 0.026 mmol), H2O (1 mL) and DME (1 mL) were added and the mixture was stirred in the microwave for 900 seconds at 120° C. The mixture was diluted with dichloromethane and filtered. The filtrate was washed with water (2×), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography using 2.5% to 5% CH3OH in dichloromethane. Not pure, purified by flash chromatography using hexane/EtOAc 7:3 to 1:1 as the eluent. Yield: 93 mg (47%). White solid. MS (electronspray; [M+H]+) m/z 196.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:13]2[CH:17]=[N:16][N:15]=[N:14]2)=[C:6](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])[CH:7]=1.[H-].[Na+].[CH3:20]OP(CC(OC)=O)(OC)=O.ClC1C=CC(N2C=NN=N2)=C(C=1)C=O.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[CH3:20][O:11][C:10](=[O:12])/[CH:9]=[CH:8]/[C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N:13]1[CH:17]=[N:16][N:15]=[N:14]1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: O=C(O)/C=C/c1cc(Cl)ccc1-n1cnnn1
Agent: O=Cc1cc(Cl)ccc1-n1cnnn1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/c1cc(Cl)ccc1-n1cnnn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 57 %

Procedure:
(E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acrylic acid: To a cooled (0° C.) suspension of NaH (0.262 g, 6.56 mmol) in THF (27.3 mL) was added dropwise methyl 2-(dimethoxyphosphoryl)-acetate (1.150 mL, 7.10 mmol). The resulting thick, white suspension was diluted with additional THF (15 mL) to facilitate mixing, then allowed to warm to rt and stirred at rt for 45 min. Next, a slightly cloudy blue solution of 5-chloro-2-tetrazol-1-yl-benzaldehyde (1.14 g, 5.46 mmol), prepared according to a modification of the procedure described by Howard (J. Med. Chem., 2006, 49, 1346.), in THF (8 mL) was added. The yellow/green suspension was stirred vigorously. After 30 min, the reaction was poured into cold sat. ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give a green/blue solid weighing 1.76 g. The solid was dissolved in EtOAc and filtered through a plug of silica gel, eluting with EtOAc. The green filtrate was concentrated to give a greenish solid weighing 1.36 g. Recrystallization from EtOAc gave an off-white solid weighing 0.476 g. Additional product was obtained by concentrating the filtrate from recrystallization, adding methanol, sonicating, and collecting the solid product by filtration. A total of 0.829 g (57%) of (E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acrylic acid methyl ester was obtained. LCMS m/z 265.1 (M+H)+; 287.2 (M+Na)+. 1H NMR (CDCl3, 500 MHz) δ: 8.80 (s, 1H), 7.78 (d, J=2.2 Hz, 1H), 7.58 (dd, J=8.8, 2.2 Hz, 1H), 7.42 (d, J=8.2 Hz, 1H), 7.25 (d, J=16.0 Hz, 1H), 6.45 (d, J=16.0 Hz, 1H), 3.78 (s, 3H). To a white suspension of this ester (0.140 g, 0.529 mmol) in MeOH (3.0 mL) was added 1.0 M sodium hydroxide (1.587 ml, 1.587 mmol). The resulting suspension was stirred vigorously at rt for 2.5 h. The yellow suspension was neutralized with 1.0 N HCl (1.60 mL), and concentrated to give a beige solid. The solid was partitioned between 1.0 N HCl and EtOAc, and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give 0.137 g (100%) of (E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acrylic acid as a white solid. LCMS m/z 251.1 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ: 12.72 (s, 1H), 9.87 (s, 1H), 8.24 (d, J=2.2 Hz, 1H), 7.77 (dd, J=8.8, 2.2 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 6.98 (d, J=16.0 Hz, 1H), 6.70 (d, J=16.0 Hz, 1H).
Reaction SMILES: [CH2:1]([C:8]1[N:12]([CH2:13][C:14](=O)[CH3:15])[C:11]([S:17][CH3:18])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N>>[CH3:15][C:14]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH2:1][C:8]2=[N:9][N:10]=[C:11]([S:17][CH3:18])[N:12]2[CH:13]=1
Reactant: CSc1nnc(Cc2ccccc2)n1CC(C)=O
Agent: N
Product: CSc1nnc2n1C=C(C)c1ccccc1C2
Temperature: 0 °C

Procedure:
To 0.3 g of the 1-(3-benzyl-5-methylthio-4H-1,2,4-triazol-4-yl)-2-propanone obtained in Reference Example 7 was added 15.0 g of polyphosphoric acid and the mixture was heated on an oil bath at 160°-170° C. for 4 hours. The reaction mixture was poured into ice-water, neutralized with concentrated aqueous ammonia and extracted with chloroform. The chloroform layer was washed with water and dried over Na2SO4. The solvent was evaporated off and the residue was treated with isopropyl ether. By the above procedure, 6-methyl-3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine was obtained as crystals. Recrystallization from ethyl acetate gave colorless platelets melting at 129°-130° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([CH3:11])[CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:12][O:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([CH3:11])[CH:3]=1
Reactant: COCCCc1ccccc1B(O)O
Reactant: Cc1cc(Br)ccc1CC#N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCc1ccccc1-c1ccc(CC#N)c(C)c1
Temperature: 25 °C

Procedure:
To a solution of (4-bromo-2-methylphenyl)acetonitrile (1 eq.) and [2-(3-methoxypropyl)phenyl]boronic acid from EXAMPLE 3 step 1, in DMF (0.22M) was added aqueous Na2CO3 (2M; 3 eq.). Nitrogen was bubbled in the solution for 15 min before the addition of PdCl2(dppf)2 (0.05 eq.). The final mixture was stirred at 90° C. for 12 h, cooled to room temperature, poured in water and extracted with Et2O. The organic extract was washed with water, HCl (0.01M), brine, dried over MgSO4 filtered and concentrated. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (5 to 30% in 30 min) afforded the desired compound as a colorless oil.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:38][CH3:39])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]4([OH:36])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[C:24]([CH3:37])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:40])[CH:12]=1>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:12]=[C:7]([CH2:6][C:5]([OH:41])=[O:4])[CH:8]=[N:9][CH:10]=2)=[C:14]([CH3:40])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]2([OH:36])[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)=[C:24]([CH3:37])[CH:23]=1)[CH2:38][CH3:39])[CH3:21]
Reactant: CCC(CC)(c1ccc(/C=C/C2(O)CCOCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(/C=C/C2(O)CCOCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)O)c2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.165 mL, 0.165 mmol) was added to a solution of {5-[4-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-pyran-4-yl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid methyl ester (Example 133-(1); 29.1 mg, 0.055 mmol) in methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred at room temperature overnight. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:methanol=10:4) to give the target compound as a colorless oil (15.7 mg, 56%).