Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:7][N:8]([C:11]2[N:16]=[C:15]3[N:17]([CH3:21])[N:18]=[C:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[CH2:22][NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[O:26][N:25]=2)[CH2:9][CH3:10])[CH2:6][CH2:5][CH2:4]1.[F:30][C:31]([F:45])([F:44])[C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:35]Br.C(OCC)(=O)C>CN(C=O)C.O>[F:30][C:31]([F:44])([F:45])[C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([C:40]([F:43])([F:41])[F:42])[CH:39]=1)[CH2:35][N:23]([CH2:22][C:12]1[CH:13]=[C:14]2[C:19]([CH3:20])=[N:18][N:17]([CH3:21])[C:15]2=[N:16][C:11]=1[N:8]([CH2:7][CH:3]1[CH2:6][CH2:5][CH2:4]1)[CH2:9][CH3:10])[C:24]1[CH:28]=[C:27]([CH3:29])[O:26][N:25]=1
Reactant: CCN(CC1CCC1)c1nc2c(cc1CNc1cc(C)on1)c(C)nn2C
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC1CCC1)c1nc2c(cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C)on1)c(C)nn2C
Temperature: 25 °C
Reaction time: 12 h
Yield: 28 %

Procedure:
Sodium hydride [0.06 g, (60% dispersion in mineral oil)] was added to a solution of cyclobutylmethyl-{1,3-dimethyl-5-[(5-methyl-isoxazol-3-ylamino)-methyl]-1H-pyrazolo[3,4-b]pyridin-6-yl}-ethyl-amine (0.225 g, 0.6 mmol) in anhydrous DMF (3 mL) while stirring at RT. After this mixture was stirred for 1 h, 3,5-bis-trifluoromethybenzyl bromide (0.13 mL, 0.7 mmol) was added slowly and stirring was continued for an additional 12 h. Ethyl acetate (30 mL) and water (30 mL) were added, and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude residue was purified by chromatography using silica gel (200-400 mesh) and eluted with 25-50% hexane:ethyl acetate to yield the title compound as a colorless thick liquid (0.10 g), yield: 29%.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:11]=2[CH:24]=1)=[O:6].[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC1C=CC=CC=1C>[O:2]=[C:3]([NH:33][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:12][C:11]=2[CH:24]=1)=[O:6]
Reactant: NCc1ccccc1
Reactant: COC(=O)CC(=O)c1ccc2c(c1)CN(C(=O)OC(C)(C)C)CCO2
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CCOc2ccc(C(=O)CC(=O)NCc3ccccc3)cc2C1
Temperature: 150 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
A mixture of 1,1-dimethylethyl 7-[3-(methyloxy)-3-oxopropanoyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (300 mg, 0.86 mmol) and benzylamine (92 mg, 0.86 mmol) in o-xylene (3 mL) was stirred at 150° C. for one hour. The reaction mixture was cooled and purified directly by silica gel chromatography (50% ethyl acetate in hexanes) to give 1,1-dimethylethyl 7-{3-oxo-3-[(phenylmethyl)amino]propanoyl}-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (220 mg, 60% yield). MS (EI) for C24H28N2O5: 425 (MH+).
Reaction SMILES: C([NH:3][C@H:4]([C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH2:5][C:6](=[O:8])[OH:7])=O.Cl.O.[CH3:25]O>>[CH3:25][O:22][C:20](=[O:21])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:11][C:9](=[O:10])[C@H:4]([CH2:5][C:6](=[O:8])[OH:7])[NH2:3]
Reactant: CO
Reactant: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O

Procedure:
deformylating formyl-α-L-aspartyl-L-phenylalanine in the presence of hydrogen chloride, methanol and water. Then, adding methanol and hydrogen chloride directly to the resulting solution to obtain the chloride salt of α-L-aspartyl-L-phenylalanine methyl ester.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[CH:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(Cl)Cl>[N+](C)([O-])=O>[CH2:1]1[O:3][CH:2]1[CH2:4][CH3:5].[C:5]1(=[O:3])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: c1ccccc1
Reactant: CC(C)=O
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: CCC1CO1
Product: O=C1CCCCC1

Procedure:
U.S. Pat. No. 3,288,867 discloses the stabilization of nitromethane by the addition thereto of a stabilizing liquid such as acetone, benzene, 1,2 butylene oxide, cyclohexanone, methylene chloride etc. to provide a safe method for the bulk transportation of nitromethane.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.[F-].[K+].O1CCOCC1.CCCC[Sn]([C:45]1[N:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)(CCCC)CCCC>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C@H:12]([O:11][C:10]1[C:5]2[O:4][CH:3]=[C:2]([C:49]3[CH:48]=[CH:47][CH:46]=[CH:45][N:50]=3)[C:6]=2[CH:7]=[N:8][C:9]=1[NH2:23])[CH3:13]
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H](Oc1c(N)ncc2c(-c3ccccn3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 100 °C

Procedure:
A mixture of 3-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-furo[3,2-c]pyridin-6-ylamine (49.0 mg, 0.117 mmol), KF (44 mg, 0.75 mmol), and Pd(PPh3)4 (13 mg, 0.011 mmol) in 1,4-dioxane (1.0 mL, 13 mmol) in a microwave reactor vial was evacuated and refilled with nitrogen (3×). 2-(1,1,1-Tributylstannyl)pyridine (90% pure; 60 μL, 0.17 mmol) was added, and the reaction mixture was heated to 100° C. for 45 min. Further 2-(1,1,1-tributylstannyl)pyridine (90% pure; 30 μL, 0.083 mmol) was added, and the reaction mixture was heated to 100° C. for a total of 2 h. The reaction mixture was diluted with DCM and washed with water. The DCM solution was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was redissolved in MeOH and pre-purified by passing through a thiol SPE cartridge (500 mg/6 mL, PL-Thiol MP SPE+). The material from the thiol SPE treatment was chromatographed on a SCX column (1 g/6 mL cartridge), and the fraction that eluted with NH3/MeOH was concentrated and chromatographed on silica gel [10 g/70 mL cartridge, eluting with DCM→10% EtOAc in DCM→15% EtOAc in DCM→20% EtOAc in DCM→30% EtOAc in DCM]. Fractions containing product were combined and concentrated in vacuo to give the title compound as a foam. 1H NMR (CDCl3, 400 MHz): δ=8.69 (d, J=5.6 Hz, 1H), 8.68 (s, 1H), 7.94 (s, 1H), 7.75 (dd, J=7.6, 7.6 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.29 (dd, J=8.4, 4.4, Hz, 1H), 7.23 (dd, J=7.2, 5.6 Hz, 1H), 7.05 (dd, J=8.4, 8.0 Hz, 1H), 6.56 (q, J=6.8 Hz, 1H), 4.78 (brs, 2H), 1.89 (d, J=6.8 Hz, 3H). MS (ES+): m/z=417.94/419.91/421.93 (100/80/15) [MH+], 228.03 (19) [MH+−3-F-2,6-di-Cl-Ph-CH═CH2]. HPLC: tR=3.27 min (polar—5 min, ZQ3).
Reaction SMILES: [C:1]([N:11]([C:13]1[CH:18]=[CH:17][C:16]2[O:19][CH2:20][O:21][C:15]=2[CH:14]=1)N)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Na].N#N.S([O-])([O-])=O.[C:29]([OH:36])(=[O:35])[CH2:30][CH2:31][C:32]([CH3:34])=O>O>[C:1]([N:11]1[C:13]2[C:18](=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[C:31]([CH2:30][C:29]([OH:36])=[O:35])=[C:32]1[CH3:34])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NN(C(=O)C=Cc1ccccc1)c1ccc2c(c1)OCO2
Reactant: CC(=O)CCC(=O)O
Agent: N#N
Agent: O=S([O-])[O-]
Agent: [Na]
Solvent: O
Product: Cc1c(CC(=O)O)c2cc3c(cc2n1C(=O)C=Cc1ccccc1)OCO3
Temperature: 25 °C

Procedure:
A mixture of 8 g of sodium N1 -cinnamoyl-3,4-methylenedioxyphenylhydrazine-N2 -sulfite, ##EQU11## and 45 ml of levulinic acid was heated in the presence of small amount of surfuric acid at 80° - 85°C for 3 hours. The reaction mixture was cooled to a room temperature and poured into water to give 1-cinnamoyl-2-methyl-5,6-methylenedioxy-3-indolylacetic acid. The crystals obtained by twice recrystallizing from acetone-water (5 : 1) showed a melting point of 190° - 192°C.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH3:12][C:13]1[O:14][C:15]2[CH:21]=[CH:20][C:19]([N:22]=[C:23]=S)=[CH:18][C:16]=2[CH:17]=1.[NH2:25][C@H:26]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]([CH2:33][C:34]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:35])[C:27]1=[O:41]>CN(C=O)C.[Hg](Cl)Cl>[CH3:8][O:7][C:5](=[O:6])[C:4](=[C:23]([NH:25][C@H:26]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]([CH2:33][C:34](=[O:35])[N:36]2[CH2:37][CH2:38][CH2:39][CH2:40]2)[C:27]1=[O:41])[NH:22][C:19]1[CH:20]=[CH:21][C:15]2[O:14][C:13]([CH3:12])=[CH:17][C:16]=2[CH:18]=1)[C:3]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CC(=O)OC
Reactant: N[C@H]1CCCCN(CC(=O)N2CCCC2)C1=O
Reactant: Cc1cc2cc(N=C=S)ccc2o1
Agent: Cl[Hg]Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)=C(Nc1ccc2oc(C)cc2c1)N[C@H]1CCCCN(CC(=O)N2CCCC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
Sodium hydride (95%, 11 mg, 0.44 mmol) was added to a solution of dimethyl malonate (40 mg, 0.30 mmol) in DMF (1.5 mL) at 0° C. The resulting mixture was warmed to room temperature, 2-methyl-5-isothiocyanatobenzofuran (56 mg, 0.30 mmol) was then added, and the resulting solution was stirred at at room temperature for 30 minutes. To the solution was then added 1-[[(3S)-3-aminohexahydro-2-oxo-1H-azepin-1-yl]acetyl]pyrrolidine (71 mg, 0.30 mmol) followed by mercury (II) chloride (82 mg, 0.30 mmol). The resulting dark mixture was stirred at room temperature for 2 h, then filtered through CELITE. The filtrate was concentrated, and the residue was purified by flash chromatography (silica, 1 to 5% methanol/dichloromethane) to afford the title compound as a pale yellow solid (63 mg, 40%): MS (ESI, pos. ion spectrum) m/z 527, HPLC (method A): tR 3.5 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:25][CH3:26])[C:5]([NH:20][CH2:21][CH2:22][O:23][CH3:24])=[C:6]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)[CH:7]=1.C(OCC)(=O)C>CC(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([O:25][CH3:26])[C:5]2[N:20]([CH2:21][CH2:22][O:23][CH3:24])[C:9]([C:10]3[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=3)=[N:8][C:6]=2[CH:7]=1
Reactant: COCCNc1c(NC(=O)c2ccc(C(C)C)cc2)cc(Br)cc1OC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(Br)cc(OC)c21
Yield: 87.6 %

Procedure:
A solution of 748 mg (1.77 mmol) N-[5-bromo-3-methoxy-2-(2-methoxy-ethylamino)-phenyl]-4-isopropyl-benzamide in 10 ml AcOH is stirred at 100° C. for 2 h. The reaction mixture is cooled to room temperature 200 ml ethyl acetate is added. The solution is washed with 4N NaOH (2×) and with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=3:1) to afford 625 mg of the title compound as a colorless solid.
Reaction SMILES: O=[C:2]1[NH:8][C:7]2[S:9][CH:10]=[CH:11][C:6]=2[CH2:5][N:4]2[CH:12]=[CH:13][CH:14]=[C:3]12.[B].CSC>>[S:9]1[C:7]2[NH:8][CH2:2][C:3]3[N:4]([CH:12]=[CH:13][CH:14]=3)[CH2:5][C:6]=2[CH:11]=[CH:10]1
Reactant: O=C1Nc2sccc2Cn2cccc21
Agent: [B]
Solvent: CSC
Product: c1cc2n(c1)Cc1ccsc1NC2

Procedure:
The synthesis of 9,10-dihydro-4H-furo[2,3-e]-pyrrolo[1,2-a][1,4]diazepin-9-one ##STR96## is reported by F. Povazunec, B. Decroix and J. Morel, J Her. Chem. 29, 1507 (1992) and is reduced to give the tricyclic heterocycle 9,10-dihydro-4H-furo [2,3-e]pyrrolo[1,2-a][1,4]diazepine. ##STR97## The tricyclic 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine ring system is reported by L. Cecchi and G. Filacchioni, J. Her. Chem., 20, 871 (1983); ##STR98## The synthesis of 9-oxo-9,10-dihydro-4H-pyrrolo[1,2-a]-thieno[2,3-e][1,4]diazepine is reported by A. Daich and B. Decroix, Bull. Soc. Chim. Fr 129, 360 (1992); ##STR99## and is reduced with boron-dimethylsulfide to give 9,10-dihydro-4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepine. ##STR100## Also reported by A. Daich and B. Decroix is 5-oxo-4,5-dihydropyrrolo[1,2 -a]thieno [3,2-e][1,4]diazepine ##STR101## which is also reduced to give 4,10-dihydro-5H-pyrrolo-[1,2-a]thieno[3,2-e][1,4]diazepine ##STR102## Reported by B. Decroix and J. Morel, J. Her. Chem., 28, 81 (1991) are 5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine; ##STR103## and 4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepine. The 10H-pyrrolo[1,2-a]thieno[3,4-e][1,4]diazepine is reported by A. Daich, J. Morel and B. Decroix, J, Heterocyclic Chem., 31, 341(1994). Reduction by hydrogen-Pd/C or chemical reduction with reagents such as sodium cyanoborohydride and acetic acid gives the dihydro tricyclic heterocycles ##STR104## The synthesis of the tricyclic 1,5-benzodiazepine ring system, 6,7-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepine, has been reported by F. Chimenti, S. Vomero, R. Giuliano and M. Artico, IL Farmaco, Ed. Sc., 32, 339 (1977). Annelated 1,5-benzodiazepines containing five membered rings have been reviewed by A. Chimirri, R. Gitto, S. Grasso, A. M. Monforte, G. Romeo and M. Zappala, Heterocycles, 36, No. 3, 604(1993), and the ring system 6,7-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepine is described. ##STR105##
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5]CC)=O.[Cl:12][C:13]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[Cl:12][C:13]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:14]=1[NH:15][C:3](=[O:5])[CH2:2][C:1]([NH:15][C:14]1[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:13]=1[Cl:12])=[O:9]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Nc1ccc(Cl)cc1Cl
Product: O=C(CC(=O)Nc1ccc(Cl)cc1Cl)Nc1ccc(Cl)cc1Cl
Temperature: 200 °C

Procedure:
A mixture of diethyl malonate (24 g, 0.15 mol) and 2,4-dichloro aniline (60.8 g, 2.5 eq) was heated at 200° C. upon passing nitrogen gas stream to distil out ethanol. Six hours later, the reactants were cooled to room temperature with adding diethylether. The solids produced were filtered and washed with diethylether (yield: 48 g, 82%): 1H NMR (CDCl3) δ10.04 (s, 2H) 8.04 (d, J=9 Hz, 2H) 7.42 (m, 2H) 7.26, (dd, J=2.4, 9 Hz, 2H) 3.74 (s, 2H)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]1[C:14]2[C:13]3[C:15]([C:23]4[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=4)=[C:16]4[C:21](=[CH:22][C:12]=3[S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH:20]=[CH:19][CH:18]=[CH:17]4.O>C(Cl)Cl.N1C=CC=CC=1>[CH:6]1[C:14]2[C:13]3[C:15]([C:23]4[CH:24]=[CH:25][C:26]([O:29][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:27][CH:28]=4)=[C:16]4[C:21](=[CH:22][C:12]=3[S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH:20]=[CH:19][CH:18]=[CH:17]4
Reactant: CS(=O)(=O)Cl
Reactant: Oc1ccc(-c2c3ccccc3cc3sc4ccccc4c23)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)Oc1ccc(-c2c3ccccc3cc3sc4ccccc4c23)cc1
Reaction time: 36 h
Yield: 114.3 %

Procedure:
Methylsulfonyl chloride (0.63 mL, 8.14 mmol) was added dropwise to a cold (ice bath) solution of 4-benzo[b]naphtho[2,3-d]thiophen-11-yl-phenol (2.00 g, 5.43 mmol) in dry methylene chloride (10 mL) and pyridine (2.08 mL). After stiring at ambient temperature for ca. 36 h. the reaction mixture was combined with water (100 mL). The organics were extracted with ether (100 mL), washed with 10% HCl (100 mL) and concentrated to give the title compound as a white solid (2.51 g, 100%); mp 136-139° C.; NMR (CDCl3); δ 8.38 (s, 1H), 7.97-7.95 (m, 1H), 7.80-7.78 (m, 1H), 7.60-7.50 (m, 6H), 7.43-7.35 (m, 2H), 7.07 (ddd, J=8, 7, 1 Hz, 1H), 6.68 (d, J=8 Hz, 1H), 3.33 (s, 3H); MS (EI): [M+] 404 (100%); Anal. calc. for C23H16O3S2+0.07 C6H14, C, 68.52, H, 4.17, N, 0.03. Found: C, 67.91, H, 3.85, N, 0.06.
Reaction SMILES: [C:1]([C:3]1[C:7]([CH:8]2[CH2:11][C:10](=O)[CH2:9]2)=[CH:6][N:5]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[N:4]=1)#[N:2].O.[CH2:26](OCC)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:3]1[C:7]([CH:8]2[CH2:11][C:10](=[CH2:26])[CH2:9]2)=[CH:6][N:5]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[N:4]=1)#[N:2]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C1CC(=O)C1
Reactant: CCOCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Product: C=C1CC(c2cn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)nc2C#N)C1
Temperature: -5 °C

Procedure:
Methyltriphenylphosphonium bromide (304 mg, 0.85 mmol) was suspended in dry diethyl ether (5 ml) in a nitrogen-flushed flask and cooled to -5° C. n-Butyl lithium (0.34 ml, 2.5M in hexanes) was added dropwise producing a yellow colour. The mixture was warmed to room temperature before heating to reflux for 1 hr. The amber homogeneous solution thus obtained was cooled to -78° C. and 3-cyano-4-(3-oxocyclobutyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (300 mg, 0.80 mmol, Example 3), dissolved in dry diethyl ether (5 ml), added dropwise keeping the internal temperature at ca. -70° C. The mixture was allowed to slowly warm to room temperature before refluxing for 1 hr. The mixture was then cooled, poured into water (20 ml) and extracted with diethyl ether (3×10 ml). The combined organics were washed with brine, dried (MgSO4), filtered and ether solvent evaporated in vacuo. The residue was purified by silica chromatography (eluting with 20% DCM/hexane) yielding 40 mg of a white solid. This was further purified by hplc (Microsorb™C18, eluting with acetonitrile/methanol/water 6:1:3 v/v) to give 18 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH2:26]([OH:29])[C:27]#[CH:28]>>[OH:29][CH2:26][C:27]#[C:28][C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: C#CCO
Reactant: Cc1cc(C(=O)CC(c2cccc(Br)c2)c2ccccc2C)ccn1
Product: Cc1cc(C(=O)CC(c2cccc(C#CCO)c2)c2ccccc2C)ccn1

Procedure:
In analogy to example 85, step 1, from 3-(3-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (example 98, step 5) and 2-propyn-1-ol was prepared the title compound as a white foam, MS (ESI+): m/z=370.18 ([M+H]+).
Reaction SMILES: CC1C=C(C=CC=1)C(O)=[O:6].O[N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=N1.[CH3:21][N:22]1CCC[C:23]1=O>>[NH:14]1[C:21]2=[N:22][CH:23]=[C:17]([C:16]([NH2:12])=[O:6])[CH:18]=[C:19]2[CH:20]=[CH:15]1
Reactant: CN1CCCC1=O
Reactant: On1nnc2ccccc21
Reactant: Cc1cccc(C(=O)O)c1
Product: NC(=O)c1cnc2[nH]ccc2c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of 3-methylbenzoic acid (22.4 mg) in 1-methyl-2-pyrrolidone (0.6 ml) were added 4-[(3-exo-8-azabicyclo[3.2.1]oct-3-yl)amino]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (42.8 mg) and 1-hydroxybenzotriazole (22.3 mg) Furthermore, 1M 1-ethyl-3-(3-dimethylaminopropyl)-1-carbodiimide/1-methyl-2-pyrrolidone solution (0.225 ml) was added, and the mixture was stirred for 4 hours at 50° C. After being cooled, the reaction solution was directly purified by preparative HPLC system (10 mM-NH4HCO3+NH3 (pH=9.2):CH3CN=98:2 to 30:70). The active fraction was concentrated and dried to hardness to obtain 4-{[(3-exo)-8-(3-methylbenzoyl)-8-azabicyclo[3.2.1]oct-3-yl)amino]}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (34.8 mg) as a solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[C:12](=O)([O:18]C(C)(C)C)[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].CCCCC>C1COCC1.CN(C)C1C=CN=CC=1>[C:14]([O:13][C:12]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1)=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCOC(=O)c1csc(N)n1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1csc(NC(=O)OC(C)(C)C)n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 66.4 %

Procedure:
Ethyl 2-aminothiazole-4-carboxylate 87 (10.0 g, 58.1 mmol) was taken up in 150 mL of anhydrous THF along with di-tert-butyl carbonate (12.67 g, 58.1 mmol) and 4-(dimethyl)aminopyridine (DMAP) (10 mg, 0.082 mmol). The reaction mixture was stirred at 50° C. for 4 h and then at room temperature for 18 h. It was then concentrated under reduced pressure to obtain a thick oil. Pentane was added and the resulting crystalline materials were collected by filtration and dried to afford 88 (10.5 g, 66% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:27]4[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(-c2cccc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)cc1
Yield: 85 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (11.2 g, 29.22 mmol) with 4-methylphenylboronic acid (5.96 g, 43.84 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (1.148 g, 1.46 mmol), and potassium carbonate (10.10 g, 73.07 mmol) generally according to the procedure described for Intermediate 37 afforded 9.8 g (85%) of (±)-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate a white solid. mp 145-147° C.; Anal. calcd. for C23H22O4S: C, 70.03; H, 5.62. Found: C, 69.91; H, 5.70.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.[C:30](Cl)(Cl)=[S:31].[CH2:34]([N:36]([CH2:40][CH3:41])[CH2:37][CH2:38][NH2:39])[CH3:35]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:30]([NH:39][CH2:38][CH2:37][N:36]([CH2:40][CH3:41])[CH2:34][CH3:35])=[S:31])=[CH:18][CH:17]=1
Reactant: CCN(CC)CCN
Reactant: S=C(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCNC(=S)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in N,N-dimethylformamide (2 ml) and triethylamine (1 ml) to prepare a solution. Thiophosgene (51 mg) was then added to the solution, and the mixture was stirred at room temperature for 5 hr. Next, N,N-diethylethylenediamine (50 mg) was added thereto, and the mixture was further stirred at room temperature for 15 hr. Ethyl acetate was added to the reaction solution, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (62 mg, yield 81%).