Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:5][C:6]2[N:7]=[N:8][C:9]([C:12]#[CH:13])=[CH:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:39]=[CH:38][C:18]([C:19]([NH:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([N:32]3[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]3)[CH:23]=2)=[O:20])=[CH:17][C:16]=1I>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[C:24]([N:32]3[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]3)[CH:23]=2)=[O:20])=[CH:38][C:39]=1[C:13]#[C:12][C:9]1[N:8]=[N:7][C:6]([NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:11][CH:10]=1
Reactant: Cc1cn(-c2cc(NC(=O)c3ccc(Cl)c(I)c3)cc(C(F)(F)F)c2)cn1
Reactant: C#Cc1ccc(NC2CCC2)nn1
Product: Cc1cn(-c2cc(NC(=O)c3ccc(Cl)c(C#Cc4ccc(NC5CCC5)nn4)c3)cc(C(F)(F)F)c2)cn1

Procedure:
The title compound was synthesized from N-cyclobutyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp: 225-227° C.; 1H NMR (300 MHz, DMSO-d6) δ: 10.82 (1 H, s), 8.35 (1 H, d, J=2.1 Hz), 8.27 (1 H, s), 8.13 (1 H, s), 7.99-8.03 (1 H, dd, J=2.1 and 8.1 Hz), 7.81-7.84 (1 H, d, J=8.7 Hz), 7.76 (1 H, s), 7.66-7.68 (2 H, m), 7.46-7.49 (1 H, d, J=9.0 Hz), 6.76-6.80 (1 H, d, J=9.3 Hz), 4.40 (1 H, m), 2.32-2.34 (2 H, m), 2.17 (3 H, brs), 1.87-1.97 (2 H, m), 1.71-1.76 (2 H, m). HRMS (ESI-TOF+): m/z [M+2H]+2 calcd for C28H24ClF3N6O: 276.0821. found: 276.0819.
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:6]=2[CH:7]=1)#[N:2].[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:12][C:9]1[CH:10]=[CH:11][C:5]2[O:4][C:3]([C:1]#[N:2])=[CH:7][C:6]=2[CH:8]=1
Reactant: N#Cc1cc2cc([N+](=O)[O-])ccc2o1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: N#Cc1cc2cc(N)ccc2o1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
A heterogeneous reaction mixture of 2-cyano-5-nitrobenzofuran (0.150 g, 0.789 mmol), iron powder (0.220 g, 3.9 mmol), NH4Cl (0.221 g, 3.9 mmol) in EtOH/H2O (5 mL each) was vigorously stirred at 60-70° C. for 1 hour. The resulting solution was filtered through a pad of Celite when hot and then washed with methanol. The filtrated was concentrated to dryness under a vacuum and resuspended into H2O (20 mL), saturated and the solid was isolated by filtration to obtain 5-amino-2-cyanobenzofuran. 1H NMR (DMSO-d6): δ 7.80 (s, 1H), 7.36 (d, 1H, J=8.7 Hz), 6.86 (dd, 1H, J=2.7 and 9.0 Hz), 6.76 (d, 1H, J=2.1 Hz), 5.16 (bs, 2H); LCMS: purity: 95%, MS (m/e): 159 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:20]([OH:22])=[O:21])=[C:11]([CH3:19])[C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:24]>C(Cl)Cl.CO>[CH2:1]([O:8][C:9]1[C:10]([C:20]([O:22][CH3:24])=[O:21])=[C:11]([CH3:19])[C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(OC(C)C)ncc(OCc2ccccc2)c1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1c(OCc2ccccc2)cnc(OC(C)C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
To a solution of 5-(benzyloxy)-3-methyl-2-(propan-2-yloxy)pyridine-4-carboxylic acid (131a, 1.4 g, 4.7 mmol) in dry CH2Cl2 (50 mL) and dry MeOH (5 mL) was added dropwise TMSCHN2 (2.6 mL, 5.1 mmol, 2M in hexane) at 0° C. under N2. The reaction mixture was stirred at room temperature for 2 hours then concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc, 10/1) to give methyl 5-(benzyloxy)-3-methyl-2-(propan-2-yloxy)pyridine-4-carboxylate (131b, 1.1 g, 75%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17](=[N:21][OH:22])[CH:18]([CH3:20])[CH3:19])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C[Si]([N:27]=[C:28]=[O:29])(C)C.N1C=CC=CC=1>C1COCC1>[C:28]([O:22][N:21]=[C:17]([C:16]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:9][N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12)[CH:18]([CH3:19])[CH3:20])(=[O:29])[NH2:27]
Reactant: CC(C)C(=NO)c1c(-c2ccc(F)cc2)nn2ccccc12
Reactant: C[Si](C)(C)N=C=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)C(=NOC(N)=O)c1c(-c2ccc(F)cc2)nn2ccccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.7 %

Procedure:
To a solution of 742 mg (2.5 mmol) of 1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one oxime in 5 ml of anhydrous THF was added 2 ml of trimethylsilyl isocyanate (85%) dropwise at 0° C. over 30 minutes. The mixture was stirred at room temperature over 48 hours, followed by addition of 50 μl pyridine. After stirring for another 4 hours, the solvent was removed and the residue was purified on an aluminum oxide column with hexane-dichloromethane-ethyl acetate as eluant to yield 482 mg (56.7%) of 1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one O-carbamoyl oxime. Compound 1020.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[C:24]([F:26])[CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[CH:21][CH:20]=[CH:19]4)(=O)=O)=CC=1.[NH:28]1[CH2:33][CH:32]=[C:31]([C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[NH:36][CH:35]=2)[CH2:30][CH2:29]1>CS(C)=O>[F:26][C:24]1[CH:25]=[C:16]2[O:15][CH2:14][CH:13]([CH2:12][N:28]3[CH2:29][CH:30]=[C:31]([C:34]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[NH:36][CH:35]=4)[CH2:32][CH2:33]3)[O:27][C:17]2=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3cc(F)c4ncccc4c3O2)cc1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Solvent: CS(C)=O
Product: Fc1cc2c(c3cccnc13)OC(CN1CC=C(c3c[nH]c4ccccc34)CC1)CO2
Temperature: 77.5 °C

Procedure:
0.40 g (1.02 mmole) of (2R)-6-fluoro-2,3-dihydro[1,4]dioxino[2,3-f]-quinolin-2-ylmethyl 4-methylbenzenesulfonate and 0.80 g (4.06 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole were combined in 50 mL of DMSO. The mixture was heated at 75-80° C. under nitrogen for 6 hours. After cooling to room temperature, the mixture was partitioned between 400 mL each of ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was removed, washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to a crude oil under vacuum. This oil was column chromatographed on silica gel using first 1% methanol in methylene chloride to elute impurities and then 5% methanol in methylene chloride to elute the product. The product-containing fractions were concentrated in vacuum to give 0.085 g of the (S)-enantiomer of the title compound as a yellow solid (m.p. 215° C.).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)=[CH:5][CH:4]=1.C1C(=O)N([Br:25])C(=O)C1.C([O-])(O)=O.[Na+]>C(#N)C>[Br:25][C:11]1[C:12]([NH2:15])=[N:13][CH:14]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][CH:7]=2)[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(-c2ccc(C(F)(F)F)cc2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Nc1ncc(-c2ccc(C(F)(F)F)cc2)cc1Br
Temperature: 23 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a solution of 5-(4-trifluoromethyl-phenyl)-pyridin-2-ylamine (example C.25 step 1) (3.9 g, 16 mmol) in acetonitrile (65 mL) at 0° C. was added NBS (2.914 g, 16 mmol) and the mixture was stirred at 23° C. for 2 h. Poured on ice with sat. NaHCO3-sol., extracted thrice with AcOEt, dried the combined organic layers over Na2SO4, filtered off and evaporated. The residue was purified by silica gel column chromatography with AcOEt followed by trituration with heptane and very little ether to give the title compound as a light brown solid (3.7 g, 71%). MS (ISP) 317 [(M+H)+], 319 [(M+2+H)+].
Reaction SMILES: [C:1]([Mg]Cl)#[CH:2].O1CCCC1.[O:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1.[Cl-].[NH4+]>C(OCC)C>[C:1]([C:13]1([OH:16])[CH2:14][CH2:15][O:10][CH2:11][CH2:12]1)#[CH:2]
Reactant: C#C[Mg]Cl
Reactant: O=C1CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#CC1(O)CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
A solution of ethynylmagnesium chloride in tetrahydrofuran (0.5 M, 12 ML, 6.0 mmol) was added with cooling in ah ice-water bath to a solution of tetrahydro-4H-pyran-4-one (0.496 g, 5.0 mmol) in diethyl ether (300 mL) dropwise over 15 min. The mixture was stirred at room temperature for 1 h. Aqueous saturated ammonium chloride solution (1.0.0 mL) was then added and mixture extracted with ether (2×20 mL). The ether layers were washed with saturated aqueous sodium chloride solution (20 mL), then combined, dried over MgSO4, filtered and concentrated to give 4-ethynyl-tetrahydro-pyran-4-ol as a colorless oil that solidified on standing. (0.60 g, 96.2% yield).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[NH:8][C:7](=[O:13])[C:6]=2[CH:14]=1.[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>C(O)CC(C)C.[Cu]>[CH3:11][C:9]1([CH3:12])[NH:8][C:7](=[O:13])[C:6]2[CH:14]=[C:2]([S:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:3]=[CH:4][C:5]=2[O:10]1
Reactant: Sc1ccccc1
Reactant: CC1(C)NC(=O)c2cc(I)ccc2O1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)CCO
Solvent: O
Product: CC1(C)NC(=O)c2cc(Sc3ccccc3)ccc2O1
Yield: 28.4 %

Procedure:
6-Iodo-2,2-dimethyl-3,4-dihydro-2H-1,3-benzoxazin-4-one (compound A-11, 10.0 g), thiophenol (17.2 g), potassium carbonate (10.0 g) and copper powder (1.0 g) were suspended in isoamyl alcohol (100 ml) and the suspension was heated to reflux for 3 hours under Ar. After air cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was successively washed with an aqueous sodium bicarbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate/hexane (2:1) to obtain 2,2- dimethyl-6-phenylthio-3,4-dihydro-2H-1,3-benzoxazin-4-one (2.67 g) (Compound A-12). The physical properties are shown in Table 1.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]1[C:14]3[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=3[O:12][CH2:11][C:10]2=1.CCN(CC)CC>C(Cl)Cl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:1](=[O:3])[CH3:2])[C:15]1[C:14]3[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=3[O:12][CH2:11][C:10]2=1
Reactant: COc1ccc2[nH]c3c(c2c1)COc1ccccc1-3
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)c1c(n2C(C)=O)-c2ccccc2OC1
Temperature: 25 °C

Procedure:
Acetyl chloride (0.064 mL, 0.896 mmoL) in CH2Cl2 (2 mL) was treated with 8-methoxy-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene (150 mg, 0.598 mmoL) followed by Et3N (0.896 mmol., 0.125 mL) at 0° C. The reaction mixture was then slowly warmed to room temperature over 2 hours. The reaction mixture was then partitioned between CH2Cl2 and saturated NaHCO3. The aqueous phase was extracted two times with CH2Cl2. The organic layers from the two extractions were then combined, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material was then purified by column chromatography (silica gel, hexanes:EtOAc 3:1 as eluent) to yield the title compound as a pale solid.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].Cl.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[N:21]([C:22]([C:24]3[CH:41]=[CH:40][C:27]([CH2:28][NH:29][C:30](=[O:39])[CH2:31][CH2:32][CH:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)=[CH:26][C:25]=3[CH3:42])=[O:23])[CH2:20][C:19]3[CH:18]=[N:17][N:16]([CH3:43])[C:15]=3[NH:14][C:13]=2[CH:44]=1>ClCCl.C(N(CC)CC)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[N:21]([C:22]([C:24]3[CH:41]=[CH:40][C:27]([CH2:28][NH:29][C:30](=[O:39])[CH2:31][CH2:32][CH:33]4[CH2:38][CH2:37][N:36]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:35][CH2:34]4)=[CH:26][C:25]=3[CH3:42])=[O:23])[CH2:20][C:19]3[CH:18]=[N:17][N:16]([CH3:43])[C:15]=3[NH:14][C:13]=2[CH:44]=1
Reactant: Cc1cc(CNC(=O)CCC2CCNCC2)ccc1C(=O)N1Cc2cnn(C)c2Nc2cc(Cl)ccc21
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCC(CCC(=O)NCc2ccc(C(=O)N3Cc4cnn(C)c4Nc4cc(Cl)ccc43)c(C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of ethanesulfonyl chloride (0.64 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of N-[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-methyl-benzyl]-3-piperidin-4-yl-propionamide hydrochloride (Compound number 1108) (2.97 mg, 0.005 mmol) in dichloro-methane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then sol-vents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=613.4
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[O:7])=[C:4]([F:19])[CH:3]=1.[F:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:24])I>CS(C)=O.O.[Cu]>[F:19][C:4]1[CH:3]=[C:2]([C:22]([F:25])([F:24])[C:21]([F:27])([F:26])[F:20])[CH:18]=[CH:17][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=[O:7]
Reactant: FC(F)(F)C(F)(F)I
Reactant: COc1cc(NC(=O)c2ccc(Br)cc2F)ccn1
Agent: [Cu]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(NC(=O)c2ccc(C(F)(F)C(F)(F)F)cc2F)ccn1
Temperature: 120 °C
Yield: 22.3 %

Procedure:
To a stirred solution of 4-bromo-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (800 mg, 2.46 mmol) and copper (1.6 g, 24.61 mmol) in DMSO (15 mL), in a pressure vessel was bubbled in 1,1,1,2,2-pentafluoro-2-iodo-ethane (4.1 g, 16.47 mmol) The vessel was sealed and heated at 120° C. for 16 hours. The reaction mixture was diluted with water and filtered through a plug of silica and then extracted with ethyl acetate (4×). The organics combined, washed with brine, dried over Na2SO4, filtered and evaporated to dryness to yield a crude mixture that was purified by column chromatography using a gradient of ethyl acetate in hexanes (0-40%) to give 2-fluoro-N-(2-methoxy-4-pyridyl)-4-(1,1,2,2,2-pentafluoroethyl)benzamide (200 mg, 22%) as an off white solid. ESI-MS m/z calc. 364.06, found 365.3 (M+1)+; Retention time: 1.39 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.11 (d, J=6.3 Hz, 1H), 7.95 (dd, J=7.4 Hz, 1H), 7.89 (d, J=9.9 Hz, 1H), 7.72 (d, J=9.1 Hz, 1H), 7.23-7.19 (m, 2H), 3.85 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br:14][C:15]1[S:19][C:18]([NH2:20])=[N:17][CH:16]=1>>[Br:14][C:15]1[S:19][C:18]([NH:20][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)=[N:17][CH:16]=1
Reactant: Nc1ncc(Br)s1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Product: O=C(Nc1ncc(Br)s1)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-chloro-3-nitrobenzoyl chloride was reacted with 5-Bromo-thiazol-2-ylamine to produce N-(5-Bromo-thiazol-2-yl)-4-chloro-3-nitro-benzamide according to the procedure of Example 10A, which was treated sequentially using the procedures from Examples 13A, 13B and 13C to provide the title product.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[C:2]#[C:3][CH3:4].[Cl:17]N1C(=O)CCC1=O.O>CN(C)C=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[C:6]1[Cl:17])[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.2 %

Procedure:
112 g of 7-(2-butynyl)-3-methyl-3,7-dihydropurine-2,6-dione was dissolved in 2200 ml of N,N-dimethylformamide, and 75.3 g of N-chlorosuccinimide was added thereto. The resulting mixture was stirred at room temperature for five hours. 2200 ml of water was added to the reaction solution, and the mixture was stirred at room temperature for 1.5 hour. The white precipitate was collected by filtration, and the white solid was washed with water and, with t-butyl methyl ether. Thus, 117 g of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[N+:7]([O-])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH3:13].C[Si]([C:18]#[N:19])(C)C.CCN(CC)CC.C([O-])(O)=O.[Na+]>CC#N>[Cl:1][C:2]1[N:7]=[C:6]([C:18]#[N:19])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH3:13]
Reactant: C[Si](C)(C)C#N
Reactant: Cc1cc(C(F)(F)F)c[n+]([O-])c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)c(C#N)nc1Cl
Temperature: 25 °C
Yield: 56.5 %

Procedure:
A mixture of 6-chloro-5-methyl-3-trifluoromethyl-pyridine-1-oxide (1.03 g, 5.30 mmol), trimethylsilyl cyanide (1.57 g, 16.0 mmol) and Et3N (1.34 g, 13.3 mmol) in dry CH3CN (30 mL) was heated at reflux for 64 h. The reaction mixture was then cooled to room temperature, and saturated aqueous NaHCO3 (20 mL) was added. After concentrated under reduced pressure the mixture was extracted with CH2Cl2 (3×30 mL). The extracts were combined and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (6:1 hexanes/EtOAc) to afford 6-chloro-5-methyl-3-trifluoromethyl-pyridine-2-carbonitrile as a colorless oil (0.660 g, 56%). 1H NMR (CDCl3) δ 2.56 (s, 3H), 7.95 (s, 1H).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH:13]=[C:12]([C:15]2[N:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[CH:25]=[N:26][N:27]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=4)[C:28]=3[CH3:29])=[O:23])=[CH:17][C:16]=2[CH3:40])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1.C(O)C.[C].[Pd]>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[CH:25]=[N:26][N:27]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:32][N:31]=4)[C:28]=3[CH3:29])=[O:23])=[CH:17][C:16]=2[CH3:40])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCN(C(=O)c2ccccc2)CC1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCN(C(=O)c2ccccc2)CC1
Temperature: 40 °C
Reaction time: 7 h
Yield: 79.7 %

Procedure:
N-{6-[1-Benzoyl-1,2,3,6-tetrahydropyridin-4-yl]-5-methylpyridin-3-yl}-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (110 mg) described in Example K40 was dissolved in 1,4-dioxane (5 ml) and ethanol (5 ml), 10% palladium-carbon (containing ca. 50% water; 90 mg) was added, and stirred at 40° C. under hydrogen atmosphere for seven hours. The reaction solution was filtered through Celite, washed with chloroform and ethanol and the solvent was evaporated in vacuo. The resulting residue was purified with silica gel chromatography (chloroform/methanol) to give the titled compound (88 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7](N)=[O:8].[CH2:10]([OH:12])[CH3:11]>CS(O)(=O)=O>[CH2:10]([O:12][C:7]([C:3]1[N:4]=[CH:5][NH:6][C:2]=1[NH2:1])=[O:8])[CH3:11]
Reactant: CCO
Reactant: NC(=O)c1nc[nH]c1N
Agent: CS(=O)(=O)O
Product: CCOC(=O)c1nc[nH]c1N
Yield: 45 %

Procedure:
A stirred solution of commercially available 5-amino-1H-imidazole-4-carboxamide (25 g, 198 mmol) in methanesulfonic acid (107 mL) and ethanol (400 mL) was stirred at reflux conditions for 12d, evaporated and water (300 mL) was added. While stirring and cooling (ice/water) sodium hydroxide solution (32%) was added until pH=6 was reached. The water layer was saturated with sodium chloride and extracted with ethyl acetate (3×200 mL). The combined organic layers were dried (MgSO4), evaporated and the crude product purified crystallization (ethyl acetate/ethanol) to yield 5-amino-1H-imidazole-4-carboxylic acid ethyl ester (13.7 g, 45%) as a light brown solid. MS (EI) 155.1 [(M)+]; mp 178° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C@@H:5]1[C:10]2[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:18])([CH3:17])[C@H:6]1[OH:19].CS[C:22](SC)=[N:23][C:24]#[N:25]>C1(C)C=CC=CC=1>[C:15]([C:12]1[CH:13]=[CH:14][C:9]2[O:8][C:7]([CH3:17])([CH3:18])[C@@H:6]([OH:19])[C@H:5]([N:4]3[CH2:3][CH2:2][NH:1][C:22]3=[N:23][C:24]#[N:25])[C:10]=2[CH:11]=1)#[N:16]
Reactant: CSC(=NC#N)SC
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](NCCN)[C@@H]1O
Solvent: Cc1ccccc1
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCNC2=NC#N)[C@@H]1O
Yield: 98.1 %

Procedure:
A mixture of trans-4-(2-aminoethylamino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol (D3) (0.39g) and dimethyl N-cyanodithioiminocarbonate (0.158g) was heated under reflux in toluene (30 ml) for 71 h. The solvent was evaporated in vacuo, and the residue column chromatographed (Kieselgel 60, gradient elution: 2-7% methanol-chloroform) giving the title compound as a white solid (0.33g). Recrystallisation from ethyl acetate-ether gave a sample of m.p. 257°-260° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2C)=[CH:4][CH:3]=1.[NH2:30][C:31]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[C:33](Cl)[N:32]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:33]5[N:32]=[C:31]([NH2:30])[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Cc1ncnc(N2CCOc3ccc(B(O)O)cc3C2)c1Cc1ccc(F)cc1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nc(-c2ccc3c(c2)CN(c2ncncc2Cc2ccc(F)cc2)CCO3)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 102.7 %

Procedure:
To a solution of (4-{5-[(4-fluorophenyl)methyl]pyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (example 8, step 2) (0.200 g, 0.509 mmol) and 2-amino-6-chloro-3-nitropyridine (0.106 g, 0.610 mmol) in dioxane (3 mL) and water (0.4 ml) was added potassium carbonate (0.211 g, 1.53 mmol). The solution was sparged with N2 (g) for five minutes before the addition of dichloro[1,1-bis(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (0.042 g, 10 mol %). The resulting suspension was heated at 90° C. for 20 h in a sealed tube vessel. On cooling to room temperature the mixture was diluted with acetonitrile (25 mL) then filtered and concentrated to afford 6-(4-{5-[(4-fluorophenyl)methyl]pyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-3-nitropyridin-2-amine (0.247 g, 100% yield) as an oil that was used without further purification. MS (EI) for C26H23FN6O3: 487 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][O:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=3[CH:16]=2)=[CH:26][CH:25]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)C1=Cc2cc(O)ccc2CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1=Cc2cc(OCc3ccc(F)cc3)ccc2CCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.3 %

Procedure:
To methyl 2-hydroxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (327 mg, 1.50 mmol) dissolved in DMF (6 ml) were added potassium carbonate (415 mg, 3.00 mmol) and 4-fluorobenzyl bromide (0.206 ml, 1.65 mmol), and the resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (40 ml) was added to the residue and the resulting mixture was washed with water (5 ml×3) and an aqueous saturated solution of sodium chloride (5 ml). The organic layer was dried with anhydrous magnesium sulfate and was then concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel: 15 g, ethyl acetate/hexane=1/25). The objective fractions were concentrated under reduced pressure to obtain methyl 2-(4-fluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (485 mg, 1.49 mmol, 99%).