Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3](=O)[CH:4]=[CH:5][NH:6][CH:7]=[CH:8][C:9]#[N:10].C(=O)([O-])[O-].[K+].[K+].CCCCCC.C(OCC)(=O)C>CO>[C:9]([C:8]1[CH:7]=[N:6][CH:5]=[CH:4][C:3]=1[C:2]([F:13])([F:12])[F:1])#[N:10]
Reactant: N#CC=CNC=CC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: N#Cc1cnccc1C(F)(F)F
Yield: 32.7 %

Procedure:
3-[(4,4,4-Trifluoro-3-oxo-1-butenyl)amino]-2-propenenitrile (a mixture of IIa and IIb; 1.90 g, 10 mmol) was dissolved in methanol (20 ml), and potassium carbonate (2.10 g, 15 mmol) was added. The mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a eluting solvent: hexane/ethyl acetate=3/1) to obtain 653 mg (yield 32.7%) of the title compound.
Reaction SMILES: [Na].[CH3:2][CH:3]([CH3:7])[CH2:4][CH2:5][OH:6].Cl[C:9]1[C:10]2[C:11](=[N:21][N:22]([CH3:24])[CH:23]=2)[N:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=1.[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]\[C:28]([OH:30])=[O:29]>CCOCC.O>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]\[C:28]([OH:30])=[O:29].[CH3:24][N:22]1[CH:23]=[C:10]2[C:11]([N:12]=[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=[C:9]2[O:6][CH2:5][CH2:4][CH:3]([CH3:7])[CH3:2])=[N:21]1
Reactant: Cn1cc2c(Cl)cc(-c3ccccc3)nc2n1
Reactant: CC(C)CCO
Agent: O=C(O)/C=C\C(=O)O
Agent: [Na]
Solvent: O
Solvent: CCOCC
Product: CC(C)CCOc1cc(-c2ccccc2)nc2nn(C)cc12
Reaction time: 8 h

Procedure:
To a solution of 1.61 g. of sodium (0.07 mol.) in 200 ml. of 3-methyl butanol, 17.1 g. of 4-chloro-2-methyl-6-phenyl-2H-pyrazolo[3,4-b]pyridine (0.07 mol.) are added and the mixture is refluxed for six hours while stirring. The cooled solution is agitated with water, the organic layer dried and then evaporated in vacuo to give 20 g. (97%) of oil. To 18.5 g. of the oil (0.063 mol.), dissolved in 50 ml. of ether, a solution of 14.6 g. of maleic acid (0.126 mol.) in 500 ml. of ether is added. The precipitated maleate of 2-methyl-4-(3-methylbutoxy)-6-phenyl-2H-pyrazolo [3,4-b]pyridine, at first oily, crystallizes on standing overnight, yield: 24.6 g. (83%); m.p. 114°-116°. Recrystallization from ethyl acetate gives a product which melts at 119°-120°.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH2:10][C:9]3[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:8]=3[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:6][N:5]2[C:23]=1[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.[CH2:30]([O:32]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:31].Cl.N>C1(C)C=CC=CC=1.C(OCC)(=O)C.CN(C)C=O>[C:30]([C:2]1[N:3]=[C:4]2[CH2:10][C:9]3[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:8]=3[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:6][N:5]2[C:23]=1[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)(=[O:32])[CH3:31]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc2c(c1)C(c1ccccc1)=Nn1c(nc(Br)c1-c1cccnc1)C2
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(c1ccccc1)=Nn1c(nc(C(C)=O)c1-c1cccnc1)C2
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 26.6 %

Procedure:
82 mg of 2-bromo-3-(3-pyridyl)-8-methoxy-6-phenyl-11H-imidazo[1,2-c][2,3]benzodiazepine is mixed in 3 ml of toluene and 0.5 ml of dimethylformamide with 650 mg of (1-ethoxyvinyl)tributylstannane and 10 mg of palladium(O)tetrakistriphenylphosphine, and it is heated for 4 hours to a bath temperature of 120° C. Then, (1-ethoxyvinyl)tributylstannane and 10 mg of palladium(O)tetrakistriphenylphosphine are added again, and it is heated for 10 hours to a bath temperature of 120° C. After cooling, it is mixed with 2 ml of 1N hydrochloric acid, stirred for 10 minutes, made alkaline with ammonia and shaken out with ethyl acetate. The ethyl acetate phase is washed with water and saturated common salt solution, dried, filtered and concentrated by evaporation. After chromatography of the residue on silica gel with ethyl acetate as an eluant, 20 mg of 2-acetyl-3-(3-pyridyl)-8-methoxy-6-phenyl-11H-imidazo[1,2-c][2,3]benzodiazepine is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1>C(P[Pd](PC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(PC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)PC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>[C:10]1([C:2]2[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1ccc(Br)cn1
Agent: c1ccc(C(P[Pd](PC(c2ccccc2)(c2ccccc2)c2ccccc2)(PC(c2ccccc2)(c2ccccc2)c2ccccc2)PC(c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: N#Cc1ccc(-c2ccccc2)cn1
Yield: 136.7 %

Procedure:
A mixture comprising 5-bromopyridine-2-carbonitrile (0.09 g, 0.49 mmol), phenyl boronic acid (0.12 g, 0.98 mmol), 2M sodium carbonate ((0.98 mL, 1.96 mmol), tetrakis(tritylphosphanyl)palladium (0.06 g, 0.049 mmol), benzene (2 mL) and ethanol (2 mL) was heated at reflux for 1 hour and then partitioned between ethyl acetate and water. The organic layer was separated, washed with water, dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (25% ethyl acetate/hexanes) to provide 5-phenylpyridine-2-carbonitrile (0.12 g, 0.67 mmol). MS (CI), Calculated for C12H8N2, 180.2, Found (MH+): 182.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.Cl[CH2:28][CH:29]=[CH:30][CH2:31][OH:32].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:28]/[CH:29]=[CH:30]\[CH2:31][OH:32])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: OCC=CCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: OC/C=C\CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 57.5 °C
Reaction time: 5 h

Procedure:
A solution containing 1-benzhydrylpiperazine (3 g, 0.0119 mol), toluene (20 ml), 4-chloro-2-butene-1-ol (1.65 g, 0.0155 mol), diisopropylethylamine (3.81 g, 0.0295 mol), and DMF (3 ml) is stirred at 55-60° C. for 5 hrs. The reaction mass is quenched with water (20 ml), organic layer separated and the aqueous layer extracted with dichloromethane (2×20 ml). The organic extract is washed with water (10 ml), and concentrated to obtain crude product, which is purified by flash column chromatography on silica gel using dichloromethane-methanol (9.3:0.7) as mobile phase to obtain pure product.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[CH:5][C:4]=1[CH2:19]O.S(Cl)([Cl:25])=O>>[Cl:25][CH2:19][C:4]1[C:3]([C:2]([F:22])([F:21])[F:1])=[CH:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:6][CH:5]=1
Reactant: OCc1cnc(-c2ccc(C(F)(F)F)cc2)cc1C(F)(F)F
Reactant: O=S(Cl)Cl
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c(CCl)cn2)cc1

Procedure:
In analogy to the procedure described in example 1 g], [4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol was reacted with thionyl chloride to give the title compound as off-white crystals.
Reaction SMILES: CO[CH:3]1[O:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[CH2:5][O:4]1.CO[CH2:16][CH2:17]OC.[CH3:20]COCC>>[CH:20]([CH:3]1[O:4][CH2:5][C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH2:8][O:9]1)=[CH:16][CH3:17]
Reactant: CCOCC
Reactant: COCCOC
Reactant: COC1OCc2ccccc2CO1
Product: CC=CC1OCc2ccccc2CO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Crude 3-methoxy-1,5-dihydro-3H-2,4 benzodioxepine (361 mg, 2.2 mmol) was dissolved in dry DME (2 mL) p-toluenesulfonic acid (95.2 mg, 0.5 mmol) and chrotonaldehyde (0.166 mL, 2 mmol) were added. The mixture was stirred at rt. for 2 h. Ether (10 mL) was added and the organic layer washed with a saturated solution of NaHCO3 and water, then dried (Na2SO2). After removed the solvent the crude was purified by cc using AcOEt/Hexane (1:1) as eluent. 3-(1-Propenyl)-1,5-dihydro-3H-2,4-benzodioxepine 3 was obtained as an oil (175 mg, 46%). 1HNMR (CDCl3): δ 7.39-7.12 (m, 4H), 5.98 (dqd, J=15.5, 6.5 and 1.0 Hz, 1H), 5.53 (ddq, J=15.5, 4.7 and 1.4 Hz, 1H), 5.32 (dd, J=4.6 and 0.8 Hz, 1H), 4.94 (d, J=14.2 Hz, 2H), 4.86 (d, J=14.2 Hz, 2H), 1.74 (dqd, J=6.4, 1.5 and 0.8 Hz, h.). 13CNMR(CDCl3): δ 5 138.8, 130.1, 127.8, 127.1, 127.0, 104.7, 70.0, 17.6.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4](F)[CH:3]=1.[SH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].CCN(CC)CC.O>CS(C)=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]2[CH:6]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:11][C:4]=2[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CCOC(=O)CS
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2ccc(Br)cc2s1
Temperature: 80 °C

Procedure:
To a solution of 4-bromo-2-fluorobenzaldehyde (1.02 g, 4.83 mmol) in DMSO (4 mL), was added ethyl 2-mercaptoacetate (0.58 mL, 5.31 mmol), followed by Et3N (1.35 mL, 9.65 mmol), and the mixture was heated at 80° C. for 3 h. The resulting dark mixture was poured into water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with 10% NaCl, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound as a light yellow waxy solid (1.29 g, 94%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([OH:10])=O)[N:3]=[N:2]1.Cl.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=2)=[O:20])[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([NH:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)=[O:20])[CH2:17][CH2:18]2)=[O:10])[N:3]=[N:2]1
Reactant: O=C(O)CCc1c[nH]nn1
Reactant: NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCc1c[nH]nn1)NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-(1H-1,2,3-Triazol-4-yl)propanoic acid (step 2) (42 mg, 0.294 mmol) and 3,5-dichlorobenzyl 4-aminopiperidine-1-carboxylate hydrochloride (Example 17, step 2) (100 mg, 0.294 mmol) were dissolved in DMF (1 ml) and treated with DIPEA (257 μl, 1.472 mmol) followed by 50% T3P® solution in DMF (344 μl, 0.589 mmol). The reaction mixture was stirred at RT for 2 days and then concentrated under reduced pressure. The crude product was dissolved in DCM and washed with 10% citric acid. The organic portion was separated, dried over MgSO4 (anh), filtered and evaporated under reduced pressure. Purification by chromatography on silica eluting with 0-10% MeOH in EtOAc afforded the title compound;
Reaction SMILES: C1(S([CH:10]2[CH:12]([C:13]([F:16])([F:15])[F:14])O2)(=O)=O)C=CC=CC=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30](=[S:32])[NH2:31])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].N1(C(OC(C)(C)C)=O)CCNCC1.C(N1C=CN=C1)(N1C=CN=C1)=S.N>CN(C)C=O>[C:17]([O:21][C:22]([N:24]1[CH2:25][CH2:26][N:27]([C:30]2[S:32][C:12]([C:13]([F:14])([F:15])[F:16])=[CH:10][N:31]=2)[CH2:28][CH2:29]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=S(=O)(c1ccccc1)C1OC1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(C(N)=S)CC1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: N
Agent: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C(F)(F)F)s2)CC1
Temperature: 90 °C
Yield: 26 %

Procedure:
To a solution of 17.5 mmol 2-benzenesulfonyl-3-trifluoromethyl-oxirane in 20 ml N,N-dimethylformamide was added 15.9 mmol 4-thiocarbamoyl-piperazine-1-carboxylic acid tert-butyl ester (prepared from tert-butyl 1-piperazinecarboxylate, 1,1′-thiocarbonyldiimidazole and ammonia according to the procedure of J. Med. Chem. 1998, 41, 5037–5054). The mixture was heated at 90° C. for 10 h. The reaction mixture was then concentrated in vacuo and the residue purified by chromatography (SiO2, ethyl acetate/heptane) to afford the title compound as an orange crystalline solid (yield 26%). MS (m/e): 338.1 (M+H+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](NCC(O)=O)=[CH:4][CH:3]=1.[C:13](=[O:16])([O-])[O-:14].[Na+].[Na+].C(#N)C.[C:22]([N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37])(OCC)=O>O>[C:28]1(=[O:37])[N:27]([CH:22]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:13]([OH:14])=[O:16])[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]12
Reactant: O=C([O-])[O-]
Reactant: O=C(O)CNc1ccc(F)cc1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(O)C(c1ccc(F)cc1)N1C(=O)c2ccccc2C1=O
Reaction time: 1 h
Yield: 76 %

Procedure:
To a stirred solution of 4-fluorophenylglycine (3.38 g, 20.0 mmol) and sodium carbonate in 450 mL of 2:1 water:acetonitrile is added N-carbethoxyphthalimide (4.38 g, 20 mmol). After 1 hour, the reaction mixture is partially concentrated to remove the acetonitrile. The resulting slurry is filtered and the pH of the stirred filtrate is adjusted to 1-2 with 4 N hydrochloric acid and then stirred for an additional 30 minutes and filtered. The solid is air-dried and then dried in vacuo (60° C.,<1 mm) to afford 4.55 g (76%) of α-phthalimido4-fluorophenylacetic acid as a white powder: mp 180-183° C.; 1H NMR (DMSO-d6, 250 MHz)δ 8.10-7.80 (m, 4H), 7.65-7.45 (m, 4H), 7.3-7.10 (t, 2H), 6.10 (s, 1H); 13C NMR (DMSO-d6, 250 MHz) δ 168.9, 166.9, 163.6, 159.7, 135.0, 131.4, 131.3 (m), 130.9, 123.5, 115.0, 114.7, 54.4. Anal. Calculated for C18H10NO4F. Theoretical: C, 64.22; H, 3.37; N, 4.68. Found: C, 64.13; H, 3.33; N, 4.63.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:19]([C:23]([CH3:29])=[C:24]1[CH:28]=[CH:27][CH:26]=[CH:25]1)=[CH:20][CH2:21][CH3:22].C1([Li])C2CC3C(=CC=CC=3)C=2C=CC=1>C1COCC1.CCCCCC.O>[C:24]1([C:23]([CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)([CH3:29])[CH2:19][CH2:20][CH:21]=[CH2:22])[CH2:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCC=CC(C)=C1C=CC=C1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Agent: [Li]c1cccc2c1Cc1ccccc1-2
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(C)(C1=CC=CC1)C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution was prepared by dissolving 10 g of fluorene in 100 mL of THF and then this was slowly reacted with 37.6 mL of a 1.6 molar solution of n-butyllithium in hexane. This dark red solution was stirred overnight at room temperature. Then a solution was prepared by combining 8.8 g of 6-(butenyl)-6-methylfulvene with 50 mL of THF. This solution was then added dropwise over a period of one half hour to the solution of the fluorenyl lithium salt. That reaction mixture was stirred overnight at room temperature and then 100 mL of water was added. The organic phase was dried overnight over sodium sulfate and the solvent was evaporated in a vacuum. The yellow residue was dissolved in pentane and filtered using silica gel. The solvent was concentrated by means of evaporation. Crystallization took place at about -18° C. to give 5-cyclopentdienyl-5-(9-fluorenyl)-1-hexene in a form of a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23](=[O:24])[C:22]4[CH:25]=[CH:26][C:27]5[N:28]=[CH:29][N:30](COCC[Si](C)(C)C)[C:31]=5[C:21]=4[O:20][C:19]=3[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(OC(=O)NC1(C2C=CC(C3C(=O)C4C=CC5N(COCC[Si](C)(C)C)C=NC=5C=4OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23](=[O:24])[C:22]4[CH:25]=[CH:26][C:27]5[N:28]=[CH:29][NH:30][C:31]=5[C:21]=4[O:20][C:19]=3[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5ncn(COCC[Si](C)(C)C)c54)c3=O)cc2)CCC1
Agent: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5c4ncn5COCC[Si](C)(C)C)c3=O)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5nc[nH]c54)c3=O)cc2)CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a solution, containing a mixture of (1-{-4-[6-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,6-dihydro-chromeno[7,8-d]imidazol-7-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester and (1-{4-[6-oxo-8-phenyl-3-(2-trimethylsilanyl-ethoxymethyl)-3,6-dihydro-chromeno[7,8-d]imidazol-7-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester (11 mg, 0.017 mmol), in DCM (1.0 mL) was added TFA (0.25 mL). The reaction mixture was stirred at RT for 18 h. After this time the reaction mixture was concentrated in vacuo. The resultant residue was triturated with DCM (×2) and dried in vacuo to furnish the title compound (7.4 mg, 84%). LCMS (Method E): RT=2.76 min, [M+]+=408. 1H NMR (400 MHz, DMSO-d6): 8.69 (s, 1H), 8.67 (br s, 1H), 8.12 (d, J=8.6 Hz, 1H), 7.89 (d, J=8.7 Hz, 1H), 7.71-7.61 (m, 5H), 7.59-7.51 (m, 4H), 2.84-2.75 (m, 2H), 2.74-2.64 (m, 2H), 2.40-2.28 (m, 1H), 2.07-1.95 (m, 1H).
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:20]([N:22](CC)[CH2:23]C)C>CN(C)C=O>[N:1]1([C:10]2[N:18]=[C:17]([N:22]([CH3:23])[CH3:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)c1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Temperature: 90 °C

Procedure:
300 mg of product obtained in stage 1 above are mixed with 3 ml of DMF (dimethylformamide) and 0.17 ml (1.1 equivalents) of TEA (triethylamine). The mixture is heated at 90° C. for 2 hours. The precipitate is filtered off. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 90-9-9 mixture for eluent. 298 mg of expected product are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH3:58].C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:31][N:24]([CH2:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:8]2[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:5]3[CH:4]=[CH:3][C:2]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=4[O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH3:58])=[CH:32][C:6]=3[CH:7]=2)=[O:15])=[CH:18][CH:19]=1)[CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CCCOCCOc1ccccc1OB([O-])[O-]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCOCCOc1ccccc1-c1ccc2c(c1)C=C(C(=O)Nc1ccc(CN(C)C3CCOCC3)cc1)CCS2(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) was added toluene/ethanol/water (20/1/1, 13.9 ml) and then were added 2-(propoxyethoxy)phenyl borate (155 mg) and potassium carbonate (176 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was refluxed for 12 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-[2-(2-propoxyethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 114) (230 mg).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[C:13](F)=[CH:14][C:15]2[O:20][CH:19]([C:21]([F:24])([F:23])[F:22])[C:18]([C:25]([O:27]CC)=[O:26])=[CH:17][C:16]=2[CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([O:1][C:13]2[C:12]([Cl:11])=[CH:30][C:16]3[CH:17]=[C:18]([C:25]([OH:27])=[O:26])[CH:19]([C:21]([F:23])([F:24])[F:22])[O:20][C:15]=3[CH:14]=2)=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc(C(=O)O)cc3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 4-hydroxybenzoic acid and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4. (Note: In the step similar to step 3, an additional equivalent of potassium carbonate was added.) mp >300° C. 1H NMR (acetone-d6/300 MHz) 8.16 (d, 2H, J=8.9 Hz), 7.96 (s, 1H), 7.79 (s, 1H), 7.20 (d, 2H, J=8.9 Hz), 6.87 (s, 1H), 5.90 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz) −79.4 (d, J=7.2 Hz). ESHRMS m/z 413.0006 (M−H, Calc'd 413.0040). Anal. Calc'd for C18H10ClF3O6: C, 52.13; H, 2.43. Found: C, 51.81; H, 2.31.
Reaction SMILES: ClC1C(C([N:12]([CH:21]([C:25]2[CH:34]=[CH:33][C:28]3OC[CH2:31][O:32][C:27]=3[CH:26]=2)[C:22]([NH2:24])=[O:23])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=O)=NC(SC)=NC=1.[CH3:35][C:36]1[C:37]([C:42]([OH:44])=O)=[N:38][CH:39]=[CH:40][N:41]=1.COC1C=C(C=CC=1)C=O>>[CH3:35][C:36]1[C:37]([C:42]([N:12]([CH:21]([C:25]2[CH:34]=[CH:33][CH:28]=[C:27]([O:32][CH3:31])[CH:26]=2)[C:22]([NH2:24])=[O:23])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[O:44])=[N:38][CH:39]=[CH:40][N:41]=1
Reactant: CSc1ncc(Cl)c(C(=O)N(Cc2ccc(C)cc2)C(C(N)=O)c2ccc3c(c2)OCCO3)n1
Reactant: Cc1nccnc1C(=O)O
Agent: COc1cccc(C=O)c1
Product: COc1cccc(C(C(N)=O)N(Cc2ccc(C)cc2)C(=O)c2nccnc2C)c1

Procedure:
This was prepared in the same manner as the product from example 242 using 3-methylpyrazine-2-carboxylic acid (JOC, 2002, p556) and 3-methoxybenzaldehyde as the acid and aldehyde components to give the title compound as a foam, 0.5 g, (63%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C@@H:12]([CH3:22])[N:11](CC3C=CC(OC)=CC=3)[C:10]2=[O:32])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH:33](OCC)(OCC)OCC>>[NH:1]1[C:2]2[CH:3]=[C:4]([N:9]3[C@@H:13]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)[C@@H:12]([CH3:22])[NH:11][C:10]3=[O:32])[CH:5]=[CH:6][C:7]=2[N:8]=[CH:33]1
Reactant: CCOC(OCC)OCC
Reactant: COc1ccc(CN2C(=O)N(c3ccc(N)c(N)c3)[C@@H](c3ccc(OC)cc3)[C@H]2C)cc1
Product: COc1ccc([C@H]2[C@@H](C)NC(=O)N2c2ccc3nc[nH]c3c2)cc1
Reaction time: 0.5 h

Procedure:
(4R,5S)-1-(3,4-diaminophenyl)-3-(4-methoxybenzyl)-5-(4-methoxyphenyl)-4-methylimidazolidin-2-one (0.105 g, 0.24 mmol) obtained from step F was dissolved in 3 mL triethyl orthoformate. The reaction was stirred for 30 minutes at reflux. After cooling the solvent was removed and the remains were dissolved in 8 mL trifluoroacetic acid. The reaction was stirred for 14 hours at ambient temperature. The TFA was removed under reduced pressure and the residue was re-dissolved in 20 mL of buffer (pH7) and three times extracted by means of 25 mL dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtrated and the solvent was removed under reduced pressure. The final product was purified by FPLC using a chloroform-methanol gradient (0→10%). The product elutes at about 5% methanol.