Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([CH:8]=[O:9])=[CH:5][CH:4]=1)[CH3:2].[N+:10]([CH:12](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:13])#[C-:11].C([O-])([O-])=O.[K+].[K+].O>CO>[CH2:1]([C:3]1[S:7][C:6]([C:8]2[O:9][CH:11]=[N:10][C:12]=2[CH3:13])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C=O)s1
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCc1ccc(-c2ocnc2C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.8 %

Procedure:
A mixture of 5-ethylthiophene-2-carbaldehyde (0.670 g, 4.78 mmol), 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (1.0 g, 4.8 mmol), and K2CO3 (0.859 g, 6.21 mmol) in MeOH (16 mL) was heated at reflux for 2 h, then cooled to room temperature and allowed to stand overnight. The mixture was poured into water and extracted with Et2O, and the combined extracts were concentrated in vacuo. The residue was chromatographed on silica gel (Analogix® SF40-115 column, 15% to 30% EtOAc/hexanes eluant, 18 minutes) to afford 0.94 g (102%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.26 (s, 1H), 7.15 (d, J=3.6, 1H), 6.91 (dt, J=3.7, 1.0 1H), 2.85 (qd, J=7.5, 0.8 2H), 2.29 (s, 3H), 1.26 (t, J=7.5, 3H). MS (DCI+) m/z 194 (M+H).
Reaction SMILES: [C:1]([C:3]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)#[N:2].[OH-:24].[Na+]>S(=O)(=O)(O)O>[C:1]([C:3]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)(=[O:24])[NH2:2]
Reactant: N#CC(CCc1ccccn1)(c1ccccc1)c1ccccc1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)C(CCc1ccccn1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of 2-(3-cyano-3,3-diphenylpropyl)pyridine (5.0 g, 16.8 mmol) (prepared as described in U.S. Pat. No. 2,649,455) in 90% sulphuric acid (10 ml) was heated at 95° C. for 3.5 hours, allowed to cool to room temperature, poured onto ice and basified with 5M aqueous sodium hydroxide solution. The resulting precipitate was collected, washed with water, dried and recrystallised from 2-propanol to give the title compound (4.5 g, 85%) as colourless crystals, m.p. 145°-146° C.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([O:23][C@@:9]2([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12][C@@H:13]3[C@H:8]2[CH2:7][CH2:6][N:5]3[C:3]([O:2][CH3:1])=[O:4])=[O:30])=[CH:27][CH:26]=1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: O=C(O)c1ccc(F)cc1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)c1ccc(F)cc1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 4-fluoro-benzoic acid to yield (3aR,4S,7aR)-methyl 4-(4-fluorobenzoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester eliminated ion); RT=4.093 min; HPLC Method III
Reaction SMILES: C[C:2]1[CH:6]=[C:5](C)[N:4]([C:8](=[NH:20])[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1.CS(O)(=O)=O.[NH2:26]N1C=CC=N1>>[NH2:20][C:8]([NH:4][C:5]1[NH:26][N:3]=[CH:2][CH:6]=1)=[N:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)n2nc(C)cc2C)cc1
Reactant: Nn1cccn1
Agent: CS(=O)(=O)O
Product: Cc1ccc(S(=O)(=O)N=C(N)Nc2ccn[nH]2)cc1

Procedure:
The compound of Example 17 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of 2-aminopyrazole solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 279.32; found mol. wt. (M+H) 280.3; 559.0 (Dimer)
Reaction SMILES: O/[N:2]=[C:3]1\[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[C:10]2[NH:11][C:12](=[O:19])[C:13]3[N:14]([CH:16]=[CH:17][N:18]=3)[C:15]\1=2.C.[C:21](O)(=[O:23])[CH3:22]>O.CN(C)C=O.[Zn]>[C:21]([NH:2][CH:3]1[C:15]2[N:14]3[CH:16]=[CH:17][N:18]=[C:13]3[C:12](=[O:19])[NH:11][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2)(=[O:23])[CH3:22]
Reactant: O=c1[nH]c2c(n3ccnc13)/C(=N/O)c1ccccc1-2
Reactant: CC(=O)O
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reaction time: 4 h

Procedure:
A suspension of 5.25 g of 10-(E-hydroxy-imino)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one and 2.9 g of zinc powder in 100 ml of acetic acid is heated for 2 hours at a temperature between 80° C. and 90° C. After addition of 100 ml of acetic acid, the mixture is filtered and the filtrate is concentrated to dryness under reduced pressure (10 mmHg; 2 kPa) at 65° C. The product obtained (3.8 g) is suspended in 100 ml of distilled water, filtered, washed with 10 ml of distilled water and with 10 ml of acetone and then dried under reduced pressure (15 mmHg; 2 kPa) at 20° C. The product obtained (2 g) is dissolved in 60 ml of boiling dimethylformamide and, after addition of 0.1 g of decolorizing charcoal, the solution is filtered while hot. The filter is washed with 10 ml of boiling dimethylformamide and the filtrate and the combined washings are then stored for 4 hours at a temperature in the region of 20° C. The crystals formed are separated out by filtration, washed successively with 10 ml of dimethylformamide, 10 ml of distilled water and 10 ml of acetone and dried to dryness under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 0.43 g of 10-acetamido-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is thus obtained, decomposing without melting at 330° C. [N.M.R. spectrum: (200 MHz; DMSO d6 ; δ in ppm): 2.00 (s, 3H: --CO--CH3); 6.13 (d, J=8.5 Hz, 1H: CH--N); 7.35 and 7.48 (2t, J=7.5 Hz, 1H each: --H7 and --H8); 7.48 and 7.85 (2d, J=7.5 Hz, 1H each: --H6 and --H9); 7.58 and 7.65 (2s broad, 1H each: --H of the imidazole); 8.58 (d, J=8.5 Hz, 1H: --NH--COCH3); 12.50 (cplx, 1H: --NH--)].
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:26][CH:27]1[CH2:29][CH2:28]1>C1COCC1>[CH:27]1([CH2:26][N:2]2[CH:3]=[C:4]([B:6]3[O:7][C:8]([CH3:9])([CH3:10])[C:11]([CH3:13])([CH3:12])[O:14]3)[CH:5]=[N:1]2)[CH2:29][CH2:28]1
Reactant: BrCC1CC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn(CC3CC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.4 %

Procedure:
To a stirred solution of pyrazole-4-boronic acid pinacol ester (0.25 g, 1.29 mmol) in THF (5 mL) was added a solution of sodium bis(trimethylsilyl)amide (0.71 mL, 2M in THF, 1.42 mmol), followed by (bromomethyl)cyclopropane (0.19 mL, 1.93 mmol). The reaction mixture was stirred at r.t. in a sealed tube for 16 h, then at 80° C. for 4 h. Additional (bromomethyl)cyclopropane (0.06 mL, 0.65 mmol) was added. The reaction mixture was stirred at 80° C. for 16 h, then concentrated in vacuo. EtOAc (30 mL) and aqueous sat. NH4Cl (15 mL) were added. The organic fraction was separated, washed with H2O (15 mL), then brine (15 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (0.27 g, 84%) as a clear yellow oil that was used without further purification. δH (CDCl3) 7.82 (1H, s), 7.80 (1H, s), 3.99 (2H, d, J 7.2 Hz), 1.32 (12H, s), 1.32-1.19 (1H, m), 0.70-0.59 (2H, m), 0.42-0.33 (2H, m). LCMS (ES+) 249.0 (M+H)+, RT 3.42 minutes (Method 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:13](=[CH:14][N:15]([CH3:18])[N:16]=3)[CH:12]=[CH:11][CH:10]=2)=[C:5]([CH3:19])[CH:4]=1.[Li]CCCC.[CH3:25][O:26][CH2:27][C:28](=[O:33])[CH2:29][CH2:30][O:31][CH3:32]>C1COCC1.CCOC(C)=O>[CH3:25][O:26][CH2:27][C:28]([C:14]1[N:15]([CH3:18])[N:16]=[C:17]2[C:13]=1[CH:12]=[CH:11][CH:10]=[C:9]2[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH3:19])([OH:33])[CH2:29][CH2:30][O:31][CH3:32]
Reactant: COCCC(=O)COC
Reactant: COc1ccc(-c2cccc3cn(C)nc23)c(C)c1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCC(O)(COC)c1c2cccc(-c3ccc(OC)cc3C)c2nn1C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 64.5 %

Procedure:
Indazole 4c (0.29 g, 0.79 mMol) was dissolved in 5 mL dry THF under a nitrogen atmosphere and cooled to −78° C. n-BuLi (0.4 mL of 2.5 M hexane solution, 1 mMol) was added dropwise via syringe, and stirred at −78° C. for 10 minutes. 1,4-dimethoxy-2-butanone (0.16 g, 1.18 mMol) was added dropwise at −78° C. and then the reaction mixture was allowed to warm to rt. The reaction mixture was diluted with EtOAc (50 mL) and washed successively with saturated ammonium chloride solution, brine and dried over magnesium sulfate. Evaporation of the solvent afforded crude material which was flash chromatographed on silica and eluted with hexane:EtOAc (3:1) which afforded 27c as an oil (0.196 g; 65%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][C:17](=[N:19][OH:20])[NH2:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[N:23]12[CH2:30][CH2:29][CH:26]([CH2:27][CH2:28]1)[CH:25]([C:31](OC)=O)[CH2:24]2.O>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][C:17]2[N:18]=[C:31]([CH:25]3[CH:26]4[CH2:29][CH2:30][N:23]([CH2:28][CH2:27]4)[CH2:24]3)[O:20][N:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CN2CCC1CC2
Reactant: NC(CCCC1CCN(Cc2ccccc2)CC1)=NO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CN2CCC(CCCc3noc(C4CN5CCC4CC5)n3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
A mixture of 4-(1-benzylpiperidin-4-yl)butanamide oxime (1.0 g), sodium hydride (0.15 g) and molecular sieves 4A (2.0 g) in tetrahydrofuran (50 ml) was stirred at ambient temperature for 30 minutes. To the mixture was added dropwise a solution of methyl 3-quinuclidine carboxylate (0.49 g) in tetrahydrofuran (10 ml) and refluxed for 6 hours. After cooling to room temperature, the mixture was poured into water and extracted with ethyl acetate. The extracts were successively washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on alumina eluting with chloroform to give 3-[3-(1-benzylpiperidin-4-yl)propyl]-5-(quinuclidin-3-yl)-1,2,4-oxadiazole (0.5 g) as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=2)[NH:19][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]([C:29]([CH3:31])=[O:30])=[CH2:28]>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH:28]=[CH:27][C:29](=[O:30])[CH3:31])[CH:24]=2)[NH:19][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Reactant: C=CC(C)=O
Solvent: CO
Product: CC(=O)C=Cc1ccc2[nH]cc(C[C@H]3CCCN3C(=O)OCc3ccccc3)c2c1

Procedure:
Obtained by a procedure similar to that described in Example 1, from 3-(N-benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-bromo-1H-indole (Preparation 1) and methyl vinyl ketone, as a foam. Rf 0.60 (SS 7). [α]D25 -51° (c=0.1, CH3OH). Found: C,74.16; H,6.39; N,6.92. C25H26N2O3 requires C,74.60; H,6.51; N,6.96%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[OH:13]S(O)(=O)=O>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:9])=[O:13])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1
Reactant: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: O=S(=O)(O)O
Product: NC(=O)c1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 73 %

Procedure:
A solution of 6-chloro-3-nitropicolinonitrile (1.00 g, 5.45 mmol) in 90% H2SO4 (15 mL) is warmed at 70° C. for 3.5 h, and then poured into ice-water. The mixture is extracted four times with EtOAc and the combined extracts worked up to give 6-chloro-3-nitropicolinamide (0.80 g, 73%). 1H NMR (DMSO) δ 8.55 (1H, d, J=8.5 Hz), 8.31, 8.04 (1H, 1H, 2 brs), 7.93 (1H, d, J=8.5 Hz).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])[CH:6]=[C:7]([O:12]C)[C:8]=1[CH:9]([CH3:11])[CH3:10].Cl.N1C=CC=CC=1>>[CH:9]([C:8]1[C:3]([OH:2])=[CH:4][C:5]([CH:14]=[CH:15][C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])=[CH:6][C:7]=1[OH:12])([CH3:11])[CH3:10]
Reactant: COc1cc(C=Cc2c(F)cc(F)cc2F)cc(OC)c1C(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)c1c(O)cc(C=Cc2c(F)cc(F)cc2F)cc1O
Yield: 14 %

Procedure:
This material was prepared from 1-(3,5-dimethoxy-4-i-propylphenyl)-2-(2,4,6-trifluorophenyl)ethene and pyridine hydrochloride in 14% yield in the same way as described in example 29. 1HNMR (CDCl3, ppm): δ 1.42 (d, J=7.1 Hz, 6H), 3.50 (qint, J=7.1 Hz, 1H), 4.77 (br, 2H), 6.55 (s, 2H), 6.59-7.24 (m, 4H).
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][C:5]2[O:8][C:9]3[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]=2[CH2:3]1.ClC(CC(Cl)=O)C>ClCCCl>[N+:15]([C:14]1[C:9]2[O:8][C:5]3[CH2:6][CH2:7][NH:2][CH2:3][C:4]=3[C:10]=2[CH:11]=[CH:12][CH:13]=1)([O-:17])=[O:16]
Reactant: CN1CCc2oc3c([N+](=O)[O-])cccc3c2C1
Agent: CC(Cl)CC(=O)Cl
Solvent: ClCCCl
Product: O=[N+]([O-])c1cccc2c3c(oc12)CCNC3
Temperature: 0 °C
Yield: 30.7 %

Procedure:
1,2,3,4-tetrahydro-2-methyl-6-nitrobenzofuro[3,2-c]pyridine (0.0224 mol), prepared according to the procedure described in J. Chem. Soc. (C), 1971, p53-60, was dissolved in 1,2-dichloroethane (40 ml), and cooled to 0° C. At this temperature, (1-chloroethyl) acetylchloride (0.0291 mol) was added dropwise. The suspension was stirred and refluxed for 2 hours. 1,2-dichloroethane was evaporated. The mixture was dissolved in methanol, stirred and refluxed for 2 hours, then filtered. Both the filtrate and crystals were treated with 2 N Na2CO3 and this mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered, and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 90/10). The desired fractions were collected and the solvent was evaporated, yielding 1.5 g 1,2,3,4-tetrahydro-6-nitrobenzofuro[3,2-c]-pyridine (intern. 4).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[C:20]([N:22]2[CH2:36][C:25]3=[C:26]4[N:31]([N:32]=[C:24]3[CH2:23]2)[C:30]([CH3:33])=[C:29]([Cl:34])[C:28]([CH3:35])=[N:27]4)=[O:21])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[C:20]([N:22]2[CH2:36][C:25]3=[C:26]4[N:31]([N:32]=[C:24]3[CH2:23]2)[C:30]([CH3:33])=[C:29]([Cl:34])[C:28]([CH3:35])=[N:27]4)=[O:21])[CH2:9]1
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1OC1CN(C(=O)OC(C)(C)C)C1)C3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1OC1CNC1)C3
Yield: 18.5 %

Procedure:
A solution of 3-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-5-fluoro-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester (472 mg; 0.91 mmol; 1 eq.) and TFA (4 mL) in DCM (4 mL) was stirred at room temperature for 1 hour then concentrated in vacuo. The residue was taken up in water, the pH was made basic with 5M NaOH and extracted with DCM (2×). The combined organic phase was dried over magnesium sulfate and concentrated in vacuo. The resulting solid was triturated in water and filtered off to afford the title compound (70 mg, 18%) as a white solid. 1H NMR (CDCl3) δ 7.38-7.31 (m, 1H), 6.80-6.72 (m, 1H), 6.38 (dt, J=10.5, 2.0 Hz, 1H), 5.04-4.96 (m, 3H), 4.65 (s, 2H), 3.93-3.87 (m, 2H), 3.79-3.72 (m, 2H), 2.91 (s, 2H), 2.86 (s, 1H), 2.69 (s, 1H), 2.63 (s, 2H). HPLC (max plot) 94.9%, Rt 2.56 min. UPLC/MS: (MS+) 416.2 ([M+H]+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][O:14][CH2:15][C:16]([CH3:28])([OH:27])[CH2:17][N:18]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[N:20]=[C:19]2Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>>[CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][O:14][CH2:15][C:16]2([CH3:28])[O:27][C:19]3=[N:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][N:18]3[CH2:17]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)(COCc1ccc(OCc2ccccc2)cc1)Cn1cc([N+](=O)[O-])nc1Br
Agent: [H-]
Agent: [Na+]
Product: CC1(COCc2ccc(OCc3ccccc3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Yield: 97 %

Procedure:
Ring closure of alcohol 126 with NaH (1.5 equiv.) as in Example 2A for 80 min, followed by chromatography of the product on silica gel, eluting with CH2Cl2, gave 26 (97%) as a cream solid: mp (CH2Cl2/hexane) 130-131° C.; 1H NMR (CDCl3) δ 7.48 (s, 1H), 7.45-7.29 (m, 5H), 7.16 (dt, J=8.7, 2.4 Hz, 2H), 6.94 (dt, J=8.7, 2.4 Hz, 2H), 5.06 (s, 2H), 4.52 (d, J=11.7 Hz, 1H), 4.47 (d, J=11.7 Hz, 1H), 4.32 (d, J=10.0 Hz, 1H), 3.86 (d, J=10.0 Hz, 1H), 3.67 (d, J=10.6 Hz, 1H), 3.53 (d, J=10.6 Hz, 1H), 1.62 (s, 3H). Anal. (C21H21N3O5) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[C:20]([C:22]3[S:23][CH:24]=[C:25]([CH3:27])[N:26]=3)[S:21][C:14]=12>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][C:13]1[CH:18]=[CH:17][N:16]=[C:15]3[CH:19]=[C:20]([C:22]4[S:23][CH:24]=[C:25]([CH3:27])[N:26]=4)[S:21][C:14]=13)=[CH:6][CH:5]=2
Reactant: Cc1csc(-c2cc3nccc(Cl)c3s2)n1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1csc(-c2cc3nccc(Nc4ccc5[nH]c(C)cc5c4)c3s2)n1

Procedure:
The title compound was prepared from 2-methyl-5-aminoindole and 7-chloro-2-(4-methyl-thiazol-2-yl)-thieno[3,2-b]pyridine by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ8.11 (d, 1H), 7.73 (s, 1H), 7.34 (s, 1H), 7.25 (d, 1H), 7.20 (s, 1H), 6.97 (d, 1H), 6.62 (d, 1H), 6.12 (s, 1H), 2.43 (s, 3H), 2.42 (s, 3H), RP18-HPLC RT: 5.41 minutes; API MS: 377 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:17]3[C:16](=[O:18])[N:15]([CH2:19][CH2:20][CH2:21]OC4CCCCO4)[C:14](=[O:29])[N:13]([CH3:30])[C:12]=3[S:11][C:10]=2[O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:42])([F:41])[F:40])[CH:33]=2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[C:17]3[C:16](=[O:18])[N:15]([CH2:19][CH2:20][CH2:21][O:52][C:51](=[O:57])[C:53]([F:56])([F:55])[F:54])[C:14](=[O:29])[N:13]([CH3:30])[C:12]=3[S:11][C:10]=2[O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:40])([F:41])[F:42])[CH:33]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Oc3cccc(OC(F)(F)F)c3)sc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O
Product: Cn1c(=O)n(CCCOC(=O)C(F)(F)F)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cccc(OC(F)(F)F)c3)sc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
To a solution of 5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethoxy)phenoxy)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 21, Step 2, 30 mg, 0.047 mmol) in TFA (2 mL) was added triethylsilane (1 mL). The reaction was stirred at RT for 3 h then diluted with DCM (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to give 3-(5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenoxy)-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propyl2,2,2-trifluoroacetate (25 mg, 83.9% yield) as an oil. LCMS: MH+ 637 and TR=2.274 min.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[F:19].BrC1C=CC(NC2N=C(Cl)C=CC=2C(O)=[O:32])=C(F)C=1.C[Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:5]2[NH:6][C:7](=[O:32])[CH:8]=[CH:9][C:4]=2[C:3]([OH:2])=[O:20])=[C:13]([F:19])[CH:14]=1
Reactant: COC(=O)c1ccc(Cl)nc1Nc1ccc(Br)cc1F
Reactant: O=C(O)c1ccc(Cl)nc1Nc1ccc(Br)cc1F
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: O=C(O)c1ccc(=O)[nH]c1Nc1ccc(Br)cc1F
Reaction time: 1 h
Yield: 93 %

Procedure:
Preparation of 2-(4-bromo-2-fluorophenylamino)-6-chloronicotinic acid methyl ester: To a suspension of 2-(4-bromo-2-fluorophenylamino)-6-chloronicotinic acid (5.00 g, 14.5 mmol) in methanol/benzene (1:1, 100 mL) under N2 was added (trimethylsilyl)diazomethane (2.0 M solution in hexanes) dropwise until the bubbling caused by gas evolution ceased. Solids precipitated out of solution. The reaction was allowed to stir for 1 hour. Excess (trimethylsilyl)diazomethane was quenched by the dropwise addition of glacial acetic acid. The precipitated solids were filtered and washed with methanol. The filtrate was concentrated to a smaller volume and additional solids precipitated out of solution that were filtered and washed with methanol. The solids were combined and dried under vacuum to yield 4.82 g (93%) of pure desired product as a dark pink solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[CH:5]=1.[H-].[Na+].[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27]Cl>COC>[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:4]([O:3][C:2]([F:1])([F:19])[F:20])=[CH:5][C:6]2[CH:18]=[CH:17][CH:16]=[CH:15][C:7]1=2
Reactant: CN(C)CCCCl
Reactant: FC(F)(F)OC1=Cc2ccccc2Nc2ccccc21
Agent: COC
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCCN1c2ccccc2C=C(OC(F)(F)F)c2ccccc21

Procedure:
10-Trifluoromethoxy-5H-dibenz[b,f]azepine (650 mg) was refluxed with NaH (600 mg, 57% suspension) in a solution of 3-dimethylaminopropyl chloride (ca. 2.0 g) in dimethyl ether (70 ml) overnight. The excess of NaH was destroyed with MeOH (10 ml) and the solvent removed under vacuum. The remaining gum was dissolved in ether (50 ml), washed with water (2×20 ml) and extracted into 2 N H2SO4 (2×20 ml). The extracts were combined, neutralized with NaHCO3 and extracted with ether (3×20 mls). The ether extracts were washed with water (2×20 mls), dried (Na2SO4) and the ether removed under vacuum.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:8](=[O:24])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1.[C:33](OCC)(=[O:35])C.C([O-])(=O)C.[Na+]>CN(C)C=O>[CH3:6][N:7]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:8](=[O:24])[CH2:9][C:10]1[CH:11]=[C:12]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:13]=[CH:14][C:15]=1[CH:33]=[O:35]
Reactant: CCOC(C)=O
Reactant: CN(CCc1ccccc1)C(=O)Cc1cccc(OCc2ccccc2)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(CCc1ccccc1)C(=O)Cc1cc(OCc2ccccc2)ccc1C=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Phosphorus oxychloride (1.61 ml, 0.0173 mol) is added dropwise to 1.34 ml of N,N-dimethylformamide (DMF) while the reaction mixture is maintained between 10° to 20° C. with an external cooling bath. A solution of N-methyl-N-phenethyl-2-(3-benzyloxyphenyl)acetamide (3.73 g, 0.0144 mol) in DMF is added dropwise, the resulting mixture is heated at 100° C. for 6 hours. After cooling to room temperature, the reaction mixture is poured into an ice/H2O mixture, ethyl acetate is added, followed by 7.3 g of sodium acetate. The resulting mixture is stirred for 1 hour. The layers are separated. The organic layer is washed with 10 ml of 1N aqueous HCl and brine; dried (MgSO4) and concentrated concentrated in vacuo. The residue obtained is purified by a flash column packed with silica gel and eluted with 5% ethyl acetate in CH2Cl2 to give N-methyl-N-phenethyl-2-(5-benzyloxy-2-formylphenyl)acetamide. NMR confirms this structure.