Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].[O:4]([C:11]1[N:16]=[CH:15][C:14]([C:17]2[NH:21][N:20]=[C:19]([C:22]([O:24]CC)=[O:23])[CH:18]=2)=[CH:13][N:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C.O>[O:4]([C:11]1[N:12]=[CH:13][C:14]([C:17]2[NH:21][N:20]=[C:19]([C:22]([OH:24])=[O:23])[CH:18]=2)=[CH:15][N:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1cc(-c2cnc(Oc3ccccc3)nc2)[nH]n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(-c2cnc(Oc3ccccc3)nc2)[nH]n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.2 %

Procedure:
To a solution consisting of lithium hydroxide monohydrate (0.13 g, 3.0 mmol) dissolved in ethanol (10 mL)/water (5 mL) was added ethyl 5-(2-phenoxypyrimidin-5-yl)-1H-pyrazole-3-carboxylate (Example 54, 90 mg, 0.29 mmol) and the mixture was stirred at room temperature for 18 hours. Ethanol was removed under reduced pressure and the solution diluted with water and subsequently was acidified with acetic acid to precipitate product. The solid precipitate was filtered, washed with water, and dried under high vacuum to afford the title compound as a white solid (64 mg, 79% yield); Rf 0.15 with 2% methanol in dichloromethane; 1H-NMR (300 MHz; DMSO-d6) δ 9.12 (s, 2H), 7.49 (dd, 2H), 7.25-7.43 (m, 4H); MS (ESI−) m/z 281 (M−1); H-PGDS FPBA IC50: 5 μM.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:15]([NH2:16])[C@@H:14]2[CH2:17][C@H:11]1[CH2:12][CH2:13]2.[N:19]1([S:24]([C:27]2[S:31][C:30]([C:32](O)=[O:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20]1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>O1CCCC1.O>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:15]([NH:16][C:32]([C:30]2[S:31][C:27]([S:24]([N:19]3[CH:23]=[CH:22][CH:21]=[CH:20]3)(=[O:26])=[O:25])=[CH:28][CH:29]=2)=[O:33])[C@@H:14]2[CH2:17][C@H:11]1[CH2:12][CH2:13]2
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cccc2)s1
Reactant: COC(=O)CCC/C=C\C[C@H]1[C@@H]2CC[C@@H](C2)[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCC/C=C\C[C@H]1[C@@H]2CC[C@@H](C2)[C@@H]1NC(=O)c1ccc(S(=O)(=O)n2cccc2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To a solution of 251 mg (1.0 mmol) of (5Z)-7-[(1R,2S,3S,4S)-3-aminobicyclo[2.2.1]hept-2-yl]-5-heptenoic acid methyl ester (1) in 4 ml of tetrahydrofuran were added 257 mg (1.0 mmol) of 5 -(pyrrol-1-ylsulfonyl)thiophen-2-carboxylic acid and 13.5 mg (0.1 mmol) of 1-hydroxybenzotriazole. Under ice-cooling, 186 mg (1.2 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide was added thereto. The mixture was warmed to room temperature and stirred at 25° C. for 16 h. The mixture was diluted with water and extracted with toluene. The organic layer was washed with dilute hydrochloric acid and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel (toluene/ethyl acetate=6:1) to give 412 mg of (5Z)-7-{(1R,2S,3S,4S)-3-[5-(pyrrol-1-ylsulfonyl)-thiophen-2-ylcarbonylamino]-bicyclo[2.2.1]hept-2-yl}-5-heptenoic acid methyl ester (I-la). Yield 83.9%.
Reaction SMILES: [O:1]1CC[CH2:3][CH2:2]1.C([O-])(O)=O.[Na+].[NH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[Cl:21])[C:15]([OH:17])=[O:16].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:2]([NH:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[Cl:21])[C:15]([OH:17])=[O:16])(=[O:1])[CH3:3]
Reactant: Nc1cc(C(=O)O)ccc1Cl
Reactant: C1CCOC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(C(=O)O)ccc1Cl
Temperature: 0 °C

Procedure:
Tetrahydrofuran (THF) room temperature (RT), NaHCO3 solution 101.9 g (582 mmol) of 3-amino-4-chlorobenzoic acid were suspended in 700 ml of acetic acid and then admixed with 64.8 ml (687 mmol) of acetic anhydride. The mixture was heated under reflux for 15 h and, after cooling, was added to 1.5 l of ice-water. The precipitated crystals were isolated by filtration with suction, washed with water, and dried in a vacuum cabinet at 70° C. for 17 h.
Reaction SMILES: Cl[CH:2]([O:4][C:5](=[O:32])[N:6]([C:29](=[O:31])[CH3:30])[CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[CH3:3].[I-].[Na+].[C:35]([O-:39])(=[O:38])[CH2:36][CH3:37].[Cs+].O>C(#N)C>[C:29]([N:6]([CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[C:5]([O:4][CH:2]([O:39][C:35](=[O:38])[CH2:36][CH3:37])[CH3:3])=[O:32])(=[O:31])[CH3:30]
Reactant: CCC(=O)[O-]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OC(C)Cl
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCC(=O)OC(C)OC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
Acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5(R)-ylmethyl}-carbamic acid 1-chloro-ethyl ester (11) (0.20 g, 0.41 mmol) and sodium iodide (0.061 g, 0.41 mmol) are placed in acetonitrile (25 mL) and stirred at RT overnight. Cesium propionate (0.17 g, 0.82 mmol) is then added and the reaction is heated at reflux overnight. After cooling to RT, water is added and the reaction mixture is extracted with EtOAc and then with dichloromethane. The organic phases are washed separately with brine and then the organic layers are combined, dried over MgSO4, filtered, and conc in vacuo. The isolated residue is subjected to silica gel flash chromatography, eluting with MeOH/CH2Cl2 gradient (0-5% MeOH over 1 hour and 20 minutes) to afford the title compound. Isolated yield: 67%. 1H NMR (400 MHz, CDCl3): δ 7.48-7.42 (m, 1H), 7.21-7.17 (m, 1H), 7.13-7.10 (m, 1H), 6.90-6.85 (m, 1H), 4.83-4.69 (m, 1H), 4.14-3.98 (m, 3H), 3.73-3.64 (m, 1H), 3.13-3.04 (m, 5H), 2.52 (d, 3H), 2.48-2.31 (m, 3H), 2.29-2.13 (m, 2H), 1.56-1.51 (m, 4H), 1.15-1.07 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH:14][CH:15]([CH3:17])[CH3:16])[N:11]3[C:18](=[O:21])[NH:19][N:20]=[C:10]3[C:9]=2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[CH3:29]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].CI>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH:14][CH:15]([CH3:17])[CH3:16])[N:11]3[C:18](=[O:21])[N:19]([CH3:29])[N:20]=[C:10]3[C:9]=2[C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CC(C)Nc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2n[nH]c(=O)n12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CC(C)Nc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2nn(C)c(=O)n12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of crude 7,8-bis(4-chlorophenyl)-5-(isopropylamino)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one, DMF (0.7 mL), and potassium carbonate (21 mg, 0.15 mmol) was added methyl iodide (213 mg, 1.5 mmol). The resulting reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then diluted with EtOAc, washed with water and saturated aqueous NaCl, dried (Na2SO4), and concentrated at reduced pressure. The residue was purified by preparative reverse phase HPLC to obtain 14 mg (65% over two steps) of the title compound as a light yellow solid. HPLC/MS: retention time=4.54 min, [M+H]30 =428.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:19][NH:20][CH3:21].C(N(CC)CC)C>C(O)CCC>[CH3:19][N:20]([CH3:21])[C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CNC
Reactant: N#Cc1cccc(-c2c[nH]c3ncnc(Cl)c23)c1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CN(C)c1ncnc2[nH]cc(-c3cccc(C#N)c3)c12
Temperature: 150 °C

Procedure:
A mixture of 3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (C14) (157 mg, 0.616 mmol), dimethylamine (189 mg, 4.19 mmol) and triethylamine (182 mg, 1.80 mmol) in n-butanol (12 mL) was heated under microwave irradiation at 150° C. for 25 minutes. After concentration in vacuo, the residue was purified by preparative HPLC (Column: Phenomenex Gemini C18, 8 μm; Mobile phase A: ammonia in water, pH 10; Mobile phase B: acetonitrile; Gradient: 25% to 65% B) to give the product as a white solid. Yield: 72.1 mg, 0.274 mmol, 44%. LCMS m/z 263.8 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ 12.15 (br s, 1H), 8.28 (s, 1H), 7.93 (br s, 1H), 7.78 (br d, J=7.8 Hz, 1H), 7.73 (br d, J=7.8 Hz, 1H), 7.62 (br dd, J=8.0, 7.8 Hz, 1H), 7.57 (br s, 1H), 2.73 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:8]2[CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:2]([CH3:1])=[CH:3][C:4]3[O:5][CH2:6][CH2:7][C:8]=3[CH:9]=2)=[CH:16][N:15]=1)=[O:22]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Cc1cc2c(cc1-c1ccc(N)nc1)CCO2
Product: Cc1cc2c(cc1-c1ccc(NC(=O)c3ccccc3F)nc1)CCO2
Yield: 74.2 %

Procedure:
Similarly, (2-fluorophenyl)-N-[5-(6-methyl(2,3-dihydrobenzo[b]furan-5-yl))(2-pyridyl)]carboxamide (163) (15.5 mg, yield: 74.2%, purity>95%) was prepared from 5-(6-methyl-2,3-dihydrobenzo[3,4-b]furan-5-yl)-2-pyridylamine (161) (13 mg, 0.06 mmol) and 2-fluorobenzoyl chloride (21 μl).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:16]=[CH:17]/[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-])=O>CO.C(OCC)(=O)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCc1ccc(-c2ccccc2)c(N)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
tert-Butyl trans-3-(3-nitro-4-phenylphenyl)acrylate (6.52 g, 20.0 mmol) was dissolved in methanol (100 mL) and ethyl acetate (100 mL), 10% palladium-carbon (500 mg) was added thereto, and the mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure to obtain tert-butyl 3-(3-amino-4-phenylphenyl)propionate (5.94 g).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O)[CH2:2][CH2:3][CH3:4].[CH3:19][NH:20][O:21][CH3:22].CN1CCOCC1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CCOC(C)=O>[CH2:1]([O:5][C:6]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:7]=1[C:8]([N:20]([O:21][CH3:22])[CH3:19])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CNOC
Reactant: CCCCOc1cc(C(F)(F)F)ccc1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CCCCOc1cc(C(F)(F)F)ccc1C(=O)N(C)OC
Yield: 103.1 %

Procedure:
2-Butoxy-4-trifluoromethyl-benzoic acid (687 mg) was reacted with N,O-dimethylhydroxy amine (331 mg), NMM (0.65 ml) and DMTMM (911 mg) as described above to yield the title compound (825 mg) after column chromatography (Hex/EtOAc=7.5/1).
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.Cl[Sn](Cl)(Cl)Cl.[CH:16]([O:19]C)(Cl)Cl>C(Cl)Cl>[OH:10][C:7]1[C:8]([CH:16]=[O:19])=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: COC(Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1cc2c(cc1O)OCO2
Temperature: 0 °C
Reaction time: 3 h

Procedure:
This Example was repeated on a larger scale. Sesamol (50.98 g, 369 mmol) was dissolved in 600 mL of CH2Cl2 followed by 52 mL (448 mmol) of SnCl4 and the solution was cooled to 0° C. Cl2CHOCH3 (35 mL, 387.5 mmol) was added dropwise as the reaction mixture warmed to room temperature, and was then stirred for 3 h. The mixture was poured over ice, the water layer was separated and extracted once with CH2Cl2 (30 mL). The organic extracts were combined, washed with 2M HCl (5×100 mL), and brine (50 mL), and then passed through a small column packed with MgSO4, which removed color. The solvent was evaporated to yield 28 g (46% yield): mp 119° C.; 1H-NMR (CDCl3) δ 9.63 (s, 1, CHO); 6.87 (s, 1, ArH); 6.47 (s, 1, ArH); 6.02 (s, 2, ArOCH2O); 1.54 (s, 1, ArOH); low resolution CIMS: m/z (rel. intensity) 167 (MH+, 100). Anal. Calcd. for C8H6O4: C, 57.84; H, 3.64. Found: C, 57.65; H, 3.76.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].CS([O:11][CH2:12][C:13]([CH3:18])([CH3:17])[CH2:14][O:15][CH3:16])(=O)=O.[Br:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23](O)=[CH:22][C:21]=1[CH3:28]>CN(C)C=O>[Br:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([O:11][CH2:12][C:13]([CH3:18])([CH3:17])[CH2:14][O:15][CH3:16])=[CH:22][C:21]=1[CH3:28]
Reactant: COCC(C)(C)COS(C)(=O)=O
Reactant: Cc1cc(O)cc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCC(C)(C)COc1cc(C)c(Br)c(C)c1
Temperature: 120 °C

Procedure:
In a microwave vial Cs2CO3 (3.3 g) and KI (50 mg) are added to a solution of 3-methoxy-2,2-dimethylpropyl methanesulfonate (407 mg) and 4-bromo-3,5-dimethylphenol (415 mg) in N,N-dimethylformamide (5 mL). The vial is sealed and the mixture is heated to 120° C. for 12 hours. The mixture is partitioned between ethyl acetate and water. The organic phase is washed with water and brine and is dried (MgSO4). The solvents are evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→80:20). The product thus obtained is purified by HPLC on reversed phase to give the title compound. Yield: 171 mg; LC (method 8): tR=1.02 min; Mass spectrum (ESI+): m/z=301 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([CH:11](OCC)[O:12]CC)[NH:10][C:4]=2[CH:3]=1>C1COCC1.O>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([CH:11]=[O:12])[NH:10][C:4]=2[CH:3]=1
Reactant: CCOC(OCC)c1cc2cnc(Br)cc2[nH]1
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc2cnc(Br)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.92 h
Yield: 105.9 %

Procedure:
To a solution of 6-Bromo-2-(diethoxymethyl)-1H-pyrrolo[3,2-c]pyridine (Preparation 137, 142 mg, 0.47 mmole) in THF (1.4 mL) and water (0.28 mL) was added tosic acid hydrate (134 mg, 0.705 mmole) and the reaction was stirred at 25° C. for 55 minutes. The reaction was partitioned between ethyl acetate (20 mL) and sodium bicarbonate (5 mL). The layers were separated and the aqueous layer again extracted with ethyl acetate (7 mL). The combined organic layers were washed with sodium bicarbonate and brine and concentrated in vacuo to afford the title compound (112 mg). 1H-NMR (CDCl3, 500 MHz): δ 7.37 (s, 1H), 7.62 (t, J=0.95 Hz, 1H), 8.88 (d, J=0.95 Hz, 1H), 9.32 (br s, 1H), 9.93 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](/[C:8](=[CH:13]\[C:14]1[CH:22]=[C:21]([F:23])[C:17]2[O:18][CH2:19][O:20][C:16]=2[CH:15]=1)/[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6]([C@@H:8]([CH2:13][C:14]1[CH:22]=[C:21]([F:23])[C:17]2[O:18][CH2:19][O:20][C:16]=2[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)/C(=C/c1cc(F)c2c(c1)OCO2)C(=O)OC(C)(C)C
Solvent: CO
Product: COC(=O)[C@H](Cc1cc(F)c2c(c1)OCO2)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 149.1 %

Procedure:
To a slurry of (Z)-methyl 2-(tert-butoxycarbonyl)-3-(7-fluorobenzo[d][1,3]dioxol-5-yl)acrylate (8000 mg) in 70 mL of methanol was added [(1S,1S,2R,2R′) [Rh (duanphos)cod]BF4 (41.64 mg, 58.94 μmol; Strem). The mixture was purged with hydrogen 5 times and then sealed at 50 psi of H2 and stirred for 8 hours. Concentration and purification of the reaction crude by silica gel chromatography provided (S)-methyl 2-(tert-butoxycarbonyl)-3-(7-fluorobenzo[d][1,3]dioxol-5-yl)propanoate (12.0 g, 99.4%) as a colorless oil.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[C:20]2[CH:21]=[C:22]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][CH:27]=3)[S:23][C:19]=2[N:18]2[C:34]([CH3:37])=[N:35][N:36]=[C:17]2[CH:16]([CH3:38])[N:15]=1>C(Cl)Cl>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[C:20]2[CH:21]=[C:22]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][CH:27]=3)[S:23][C:19]=2[N:18]2[C:34]([CH3:37])=[N:35][N:36]=[C:17]2[CH:16]([CH3:38])[N:15]=1
Reactant: Cc1nnc2n1-c1sc(CCc3ccc(CO)cc3)cc1C(c1ccccc1Cl)=NC2C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nnc2n1-c1sc(CCc3ccc(C=O)cc3)cc1C(c1ccccc1Cl)=NC2C
Yield: 57.4 %

Procedure:
To a suspension of 15 g of dry sellaite and 12 g of dry pyridine in 150 ml of methylene chloride is added 7.4 g of chromic anhydride under ice-cooling with stirring and then stirred for 20 minutes. To the mixture is added a solution of 7 g of 4-(2-chlorophenyl)-2-[2(4-hydroxymethylphenyl)ethyl]-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine, which was prepared by Example 1, in 20 ml of methylene chloride dropwise with stirring and stirred for an hour. The methylene chloride layer is separated by filtration and the sellaite is well washed with chloroform. The mixture of the washings and the methylene chloride solution is thoroughly washed with water and dried over anhydrous magnesium sulfate. After separating by filtration, the filtrate is concentrated under reduced pressure and the resulting oil is subjected to chromatography on silica gel to give 4 g of 4-(2-chlorophenyl)-2-[2-(4-formylphenyl)ethyl]-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.Br[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[C:24]([CH3:29])[CH:23]=[CH:22]2>>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[C:24]([CH3:29])[CH:23]=[CH:22]4)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: Fc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Reactant: Cc1ccc2cc(Br)ccc2n1
Product: Cc1ccc2cc(-n3c4c(c5cc(F)ccc53)CN3CCC4CC3)ccc2n1

Procedure:
The reaction of 9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (230 mg, 1.0 mmol; Example 161) and 6-bromo-2-methylquinoline (333 mg, 1.5 mmol; Oakwood) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.94-2.20 (m, 4H) 2.78 (s, 3H) 2.89-2.96 (m, 1H) 3.08-3.30 (m, 4H) 4.30 (s, 2H) 6.84 (td, J=9, 2 Hz, 1H) 7.04 (dd, J=9, 4 Hz, 1H) 7.11 (dd, J=9, 3 Hz, 1H) 7.54 (d, J=9 Hz, 1H) 7.67 (dd, J=9, 2 Hz, 1H) 7.90 (d, J=2 Hz, 1H) 8.14 (d, J=9 Hz, 1H) 8.33 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 372 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:12][C:13]3[C:14]([CH3:19])=[N:15][O:16][C:17]=3[CH3:18])[C:10]=2[N:11]=1.[Cl:20][C:21]1[C:26]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[F:38])(=[O:30])=[O:29])=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][N:22]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:20][C:21]1[C:26]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[F:38])(=[O:30])=[O:29])=[CH:25][C:24]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:12][C:13]4[C:14]([CH3:19])=[N:15][O:16][C:17]=4[CH3:18])[C:10]=3[N:11]=2)=[CH:23][N:22]=1
Reactant: Cc1noc(C)c1Nc1ncnc2ccc(Cl)nc12
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3F)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1noc(C)c1Nc1ncnc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4ccc(F)cc4F)c3)nc12
Temperature: 25 °C
Yield: 26.6 %

Procedure:
A mixture of N-(6-chloropyrido[3,2-d]pyrimidin-4-yl)-3,5-dimethylisoxazol-4-amine (Intermediate 21) (0.040 g, 0.145 mmol), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-2,4-difluorobenzenesulfonamide (Intermediate 3) (0.069 g, 0.160 mmol), PdCl2(dppf)-CH2Cl2Adduct (0.012 g, 0.015 μmol) and 1 N aq. sodium bicarbonate (0.290 ml, 0.290 mmol) in dioxane (1.40 ml) subjected to microwave irradiation for 1 hour at 110° C. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to give N-(2-chloro-5-(4-(3,5-dimethylisoxazol-4-ylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.021 g, 27%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.30 (3H, s), 2.45 (3H, s), 6.89-7.05 (2H, m), 7.27 (1H, s), 7.79-7.92 (1H, m), 8.20 (1H, d, J=8.8 Hz), 8.26 (1H, s), 8.36 (1H, d, J=8.8 Hz), 8.73 (1H, s), 8.76 (1H, s), 8.89 (1H, s). m/z=544.1 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[OH-].[K+].Cl[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1.O>CS(C)=O>[N:15]1[CH:16]=[CH:17][N:18]=[CH:19][C:14]=1[O: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: Oc1cccc2[nH]ccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: c1cc(Oc2cnccn2)c2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
A solution of 2.66 g of 4-hydroxyindole in 60 ml of DMSO is combined with 1.4 g of potassium hydroxide (pulverized) and stirred under an N2 atmosphere for one hour at room temperature. After adding 2.5 g of 2-chloropyrazine, the mixture is heated for 2 hours to 100° C., poured into water, and extracted with ethyl acetate. The residue from the organic phase is purified over silica gel, thus obtaining 2.95 g (70%) of 4-(2-pyrazinyloxy)indole, mp 192°- 193° C.