Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[C:10]([Cl:18])[CH:9]=2)=[CH:4][CH:3]=1.Cl[C:20]1[S:21][C:22]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:23]=2[N:24]=1.Cl.O1CCOCC1>C(O)CCC>[F:29][C:27]1[CH:26]=[CH:25][C:23]2[N:24]=[C:20]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[C:10]([Cl:18])[CH:9]=4)=[CH:6][CH:7]=3)[S:21][C:22]=2[CH:28]=1
Reactant: Fc1ccc2nc(Cl)sc2c1
Reactant: COC(=O)c1ccc(-c2ccc(N)cc2)cc1Cl
Agent: Cl
Solvent: CCCCO
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)cc1Cl
Temperature: 65 °C

Procedure:
A mixture of methyl 4′-amino-3-chlorobiphenyl-4-carboxylate (0.45 g, 1.7 mmol) and 2-chloro-6-fluoro-1,3-benzothiazole (0.32 g, 1.7 mmol) in n-butanol (8 mL) was heated to 60-70° C., and then 4N HCl in 1,4-dioxane (0.19 mL, 0.77 mmol) was added dropwise with stirring. The reaction mixture was heated at 90° C. for 18 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure. The residue was triturated with ethanol, and the solid was collected by filtration. This yielded 0.399 g (56%) of the title compound as a beige solid. LC/MS m/z 411 (MH+), retention time 4.03 min. 1H NMR (400 MHz, DMSO-d6) δ 3.85 (s, 3H), 7.12 (t, 1H), 7.67-7.87 (m, 9H), 10.62 (br, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27].C(OCC)(=O)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[CH2:27][CH:26]=[CH2:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]ccc23)CC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCn1ccc2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc21
Reaction time: 48 h

Procedure:
A solution of 1-t-butoxycarbonyl-4-(1H-indol-4-yl)piperazine (prepared as described above) in tetrahydrofuran (50 mL) was added dropwise to a suspension of sodium hydride (0.7 g of a 60% mineral oil suspension) in tetrahydrofuran (150 mL) at room temperature. After stirring for further 30 min a solution of allyl bromide (3.5 mL) in tetrahydrofuran (50 mL) was added dropwise. After stirring for 48 h the mixture was poured onto ice-water followed by standard work-up with ethyl acetate giving an oil, which was purified by flash chromatography (eluent: heptane/ethyl acetate 85:15) giving 1-t-butoxycarbonyl-4-(1-allyl-1H-indol-4-yl)piperazine as an oil (3.2 g). The oil was dissolved in methanol (15 mL) and a saturated solution of HCl in diethyl ether (100 mL) was added. After stirring for 16 h at room temperature, the resulting colorless crystals consisting of the hydrochloride of the title compound (2.5 g) was collected by filtration and dried in vacuo.
Reaction SMILES: Br[CH:2]1[C:7](=O)[CH2:6][CH2:5][CH2:4][CH:3]1[C:9]([O:11][CH3:12])=[O:10].[C:13]([NH2:21])(=[S:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO>[C:14]1([C:13]2[S:20][C:2]3[CH:3]([C:9]([O:11][CH3:12])=[O:10])[CH2:4][CH2:5][CH2:6][C:7]=3[N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C1CCCC(=O)C1Br
Reactant: NC(=S)c1ccccc1
Solvent: CCO
Product: COC(=O)C1CCCc2nc(-c3ccccc3)sc21

Procedure:
A soln. of methyl 2-bromo-3-oxocyclohexanecarboxylate (100 mg, 0.43 mmol) and thiobenzamide (64 mg, 0.47 mmol) in EtOH (2 mL) was stirred at 85° C. overnight. Subsequently, the mixture was quenched with aq. sat. NaHCO3 and extracted with EtOAc. The comb. org. layers were washed with brine, dried over MgSO4, and conc. in vacuo. Purification by means of CC (2-15% EtOAc/Hept) provided a yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:36])[CH2:10][C:11]1([C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[O:35][CH:34]=[N:33][CH:32]=4)=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C.[CH:44]1([NH:47][C:48](OC2C=CC=CC=2)=[O:49])[CH2:46][CH2:45]1.C(OCC)(=O)C>CN(C)C=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:36])[CH2:10][C:11]1([C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[O:35][CH:34]=[N:33][CH:32]=4)=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[S:17](=[O:18])(=[O:19])[CH2:16][CH2:15][N:14]([C:48]([NH:47][CH:44]2[CH2:46][CH2:45]2)=[O:49])[CH2:13][CH2:12]1
Reactant: O=C(NC1CC1)Oc1ccccc1
Reactant: O=C(CC1(c2ccc(-c3ccc(-c4cnco4)cc3)s2)CCNCCS1(=O)=O)NOC1CCCCO1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CC1(c2ccc(-c3ccc(-c4cnco4)cc3)s2)CCN(C(=O)NC2CC2)CCS1(=O)=O)NOC1CCCCO1
Temperature: 50 °C
Yield: 56.2 %

Procedure:
To a solution of N-(2-tetrahydropyranyloxy)-2-[7-(5-(4-(5-oxazolyl)phenyl)-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (100 mg) in N,N-dimethylformamide (3 ml) was added triethylamine (57 mg) and cyclopropylaminocarbonyloxybenzene (40 mg) and the reaction mixture was heated at 50° C. for 4 hours. The mixture was added ethyl acetate and the solution was washed with successively water, a 5% aqueous citric acid-solution, a satuated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel 60 (2% methanol-chloroform) to give N-(2-tetrahydropyranyloxy)-2-[4-cyclopropylaminocarbonyl-7-(5-(4-(5-oxazolyl)phenyl)-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (65 mg) as a pale yellow powder.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]2[F:19].C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C]=O>>[F:19][CH:7]1[C:6]2[C:11](=[C:2]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=[CH:4][CH:5]=2)[CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1Cc2c(Br)cccc2C(F)C1
Agent: [C]=O
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc2c1CN(C(=O)OC(C)(C)C)CC2F
Reaction time: 0.08 h

Procedure:
To a flask containing tert-butyl 8-bromo-4-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (24-5) (316 mg, 0.957 mmol) was added TRIETHYLAMINE (0.6 mL, 4.30 mmol), followed by degassed anhydrous MeOH (6 mL) & DMSO (3 mL). This mixture was then degassed by bubbling N2 through with a vent needle while stirring for ˜5 minutes. Then added PdOAc2 (57 mg, 0.254 mmol) & DPPP (83 mg, 0.201 mmol) as solids in 1 portion. A balloon containing CARBON MONOXIDE (536 mg, 19.14 mmol) was then attached and the reaction was purged 3× (vacuum/CO), then the reaction mixture (clear tan, became darker with heat) was heated to 80 C while stirring in a hot oil bath in the hood under an atmosphere of CO. Followed by LC/MS. After 22 hours, the reaction mixture was suspended in EtOAc, washed with saturated NaHCO3, then H2O, then brine; organics dried over Na2SO4, filtered & concentrated. Purification by silica gel chromatography (0-40% EtOAc/Hex; 40 g ISCO); desired fractions concentrated to yield 2-tert-butyl 8-methyl 4-fluoro-3,4-dihydroisoquinoline-2,8(1H)-dicarboxylate (24-6). HRMS [M+H]: calculated; 310.1449, observed; 310.1439.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:34])=[C:23]([CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:38][CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1.CS(C)=O.C(N(CC)CC)C>C(#N)C>[N:42]1[CH:43]=[CH:44][CH:45]=[C:40]([CH2:39][NH:38][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[C:28]([CH3:34])=[CH:29][CH:30]=[CH:31][C:32]=5[CH3:33])=[C:23]([CH3:35])[CH:22]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])[CH:41]=1
Reactant: NCc1cccnc1
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1c(C)cccc1C
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)ccc1-c1c(C)cccc1C
Temperature: 80 °C
Yield: 50.9 %

Procedure:
A suspension of 2,2,2-trichloro-1-{10-[(2,2′,6′-trimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Step D (0.610 g, 1.1 mmol) and 3-(aminomethyl)pyridine (0.119 g, 1.0 mmol) in acetonitrile (15 mL), was treated with dimethylsulfoxide (0.432 g, 5.5 mmol) and triethylamine (0.246 g, 2.4 mmol). The mixture was heated under nitrogen at 80° C. overnight, and then concentrated. The residue was taken up in dichloromethane (25 mL), washed with brine and water, dried over anhydrous magnesium sulfate and concentrated. Flash chromatography of the residue on silica gel Merck-60 eluting with 85:10:5 ethylacetate:hexane:dichloromethane provided the title compound (0.275 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]([F:10])[C:7]=1[CH:8]=O.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][C@H:27]([NH:29][CH2:30][C:31]([F:35])([CH3:34])[CH2:32][OH:33])[CH3:28])=[CH:18]1.C(O)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]([F:10])[C:7]=1[C@@H:8]1[C:18]2[NH:17][C:25]3[C:20]([C:19]=2[CH2:26][C@@H:27]([CH3:28])[N:29]1[CH2:30][C:31]([F:35])([CH3:34])[CH2:32][OH:33])=[CH:21][CH:22]=[CH:23][CH:24]=3
Reactant: COC(=O)/C=C/c1cc(F)c(C=O)c(F)c1
Reactant: C[C@H](Cc1c[nH]c2ccccc12)NCC(C)(F)CO
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1cc(F)c([C@@H]2c3[nH]c4ccccc4c3C[C@@H](C)N2CC(C)(F)CO)c(F)c1
Temperature: 90 °C
Yield: 10.3 %

Procedure:
(E)-methyl 3-(3,5-difluoro-4-formylphenyl)acrylate (565 mg, 2.50 mmol) was added to a suspension of 3-(((R)-1-(1H-indol-3-yl)propan-2-yl)amino)-2-fluoro-2-methylpropan-1-ol (661 mg, 2.50 mmol) in toluene (11.3 ml)/acetic acid (1.25 ml). The reaction was heated to 90° C. for 5 h. After cooling, the volatiles were removed under vacuum, then the residue was passed through an SCX-2 column, eluting with methanol to remove unreacted aldehyde. The column was then eluted with NH3/MeOH to liberate the products. The basic filtrate was evaporated then the crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to afford (E)-methyl 3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-3-hydroxy-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (Isomer 1-122 mg, 10.3%) as a yellow solid and (E)-methyl 3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-3-hydroxy-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (Isomer 2-129 mg, 11% as a yellow/orange solid. Isomer 1-1H NMR (400 MHz, CDCl3, 27° C.) 1.10 (3H, d), 1.14 (3H, d), 2.54 (1H, dd), 2.62-2.73 (1H, m), 3.06-3.3 (2H, m), 3.40 (1H, dd), 3.56 (1H, t), 3.80 (3H, s), 3.87-4.08 (1H, m), 4.27 (1H, s), 5.16 (1H, s), 6.37 (1H, d), 7.01 (2H, d), 7.07-7.15 (2H, m), 7.14-7.24 (1H, m), 7.42-7.56 (2H min), 7.71 (1H, s). m/z (ES+), [M+H]+=473. Isomer 2—1H NMR (400 MHz, CDCl3, 27° C.) 1.15 (3H, d), 1.20 (3H, d), 2.65 (1H, dd), 2.79 (1H, t), 2.93-3.09 (2H, m) 3.57 (1H, dt), 3.70 (1H, dd), 3.78 (3H, s), 4.2-4.67 (1H, n), 5.42 (1H, s), 6.32 (1H, d), 6.94 (2H, d), 7.06-7.15 (2H, m), 7.19-7.27 (2H, n, 7.42 (1H, s), 7.51 (11H, dd), 8.02 (1H, s). m/z (ES+), [M+H]+=473.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:22]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=2[Cl:31])=[C:21]([F:32])[C:8]2[N:9]=[CH:10][N:11]([CH2:12][CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[C:7]=2[CH:6]=1)=[O:4].[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[OH:39][C:33]([C:35]([F:38])([F:37])[F:36])=[O:34].[CH3:1][O:2][C:3]([C:5]1[C:22]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=2[Cl:31])=[C:21]([F:32])[C:8]2[N:9]=[CH:10][N:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2c(ncn2CCC(=O)OC(C)(C)C)c(F)c1Nc1ccc(Br)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc2c(ncn2CCC(=O)O)c(F)c1Nc1ccc(Br)cc1Cl
Reaction time: 0.75 h
Yield: 88 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-3-(2-tert-butoxycarbonyl-ethyl)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester (0.050 g, 0.095 mmol) is dissolved in methylene chloride (0.5 mL) and TFA (0.5 mL) is added. After 45 minutes, the reaction mixture is concentrated to dryness to give 0.49 g (88%) desired product: LC/MS ESI (+) m/z 472, 470 (M+Br pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.20 (s, 1H), 8.13 (s, 1H), 7.64 (d, 1H), 7.29 (dd, 1H), 6.45 (dd, 1H), 4.55 (t, 2H), 2.89 (t, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:3]=1[CH2:4][O:5][CH2:6][CH2:7]CN(C)C.C(=O)([O-])[O-].[K+].[K+].O.N[C:26]1N=C(C(N2CC3C(=CC=CC=3)C2)=O)C2[C:28](=CC=C(B3OC(C)(C)C(C)(C)O3)C=2)[N:27]=1>C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:27]([CH3:28])[CH3:26]
Reactant: CN(C)CCCOCc1cc(F)c(F)cc1Br
Reactant: CC1(C)OB(c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: CN(C)CCOCc1cc(F)c(F)cc1Br
Temperature: 120 °C

Procedure:
88 mg of [3-(2-bromo-4,5-difluorobenzyloxy)propyl]dimethylamine, 80 mg of potassium carbonate, 5 μl of water and 12 mg of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride are added to a solution of 150 mg of [2-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone in 2 ml of ethanol under argon. The mixture is heated at 120° C. for 60 min. The solid is subsequently filtered off through kieselguhr with suction, and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 1 ml of DMSO and chromatographed by means of preparative HPLC (Agilent). The product fractions obtained are subsequently evaporated and freeze-dried.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[F:7][C:8]([F:17])([CH:11]([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][OH:10].COC1C=CC(OC)=CC=1>>[C:1]([O:10][CH2:9][C:8]([F:17])([F:7])[CH:11]([F:16])[C:12]([F:15])([F:13])[F:14])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: OCC(F)(F)C(F)C(F)(F)F
Reactant: C=C(C)C(=O)Cl
Agent: COc1ccc(OC)cc1
Product: C=C(C)C(=O)OCC(F)(F)C(F)C(F)(F)F

Procedure:
To 12 parts of methacrylic acid chloride were added 60 parts of 2,2,3,4,4,4-hexafluorobutyl alcohol as a reactant and a solvent and 0.1 part of hydroquinone dimethyl ether as a polymerization inhibitor. The mixture was heated at a temperature of 90° to 100° C. for 3 hours. The reaction mixture was distilled to give 15 parts of 2,2,3,4,4,4-hexafluorobutyl methacrylate (hereinafter referred to as "HFBMA") having a boiling point of 60° to 63° C./20 mmHg.
Reaction SMILES: [CH:1]([NH:3][C:4]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-])=O)([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5](OCC)=[O:6])=[O:2].[H][H]>[Pd].C(O)C>[CH:1]([NH:3][C:4]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:15][C:16]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:22][C:5]1=[O:6])=[O:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(Cc1ccccc1[N+](=O)[O-])(NC=O)C(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1(NC=O)Cc2ccccc2NC1=O
Yield: 100.7 %

Procedure:
A mixture of diethyl (formylamino)((2-nitrophenyl)methyl)propanedioate (8.54 g, 0.025 mol) and 10% palladium on carbon (2.0 g) in absolute ethanol (200 mL) was hydrogenated (50 lb initial H2 pressure) until hydrogen uptake ceased. The mixture was filtered through celite and refluxed for 2 hours to achieve cyclization. The solvent was removed under reduced pressure to give 6.6 g of product which was crystallized from methanol to give 5.0 g of white crystals, mp 187°-190° C. Anal. Calc'd for C13H14N2O4 : C, 59.53; H, 5.38; N, 10.68. Found: C, 59.77; H, 5.36; N, 10.75.
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[CH2:15]([O:17][C:18](=[O:34])[CH2:19][CH:20]1[CH2:33][C:24]2[S:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=3[C:23]=2[CH2:22][CH2:21]1)[CH3:16]>O1CCOCC1>[CH2:15]([O:17][C:18](=[O:34])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[C:27]3[C:28]([Cl:32])=[CH:29][CH:30]=[CH:31][C:26]=3[S:25][C:24]=2[CH:33]=1)[CH3:16]
Reactant: CCOC(=O)CC1CCc2c(sc3cccc(Cl)c23)C1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc2c(c1)sc1cccc(Cl)c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 1-l. three-necked flask provided with a condenser, stirrer and dropping funnel was added 11 g. of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and 500 ml. of dioxane. To the solution heated to reflux, was added at a rapid rate a solution of 6 g. of 9-chloro-1,2,3,4-tetrahydrodibenzothiophene-3-acetic acid ethyl ester in 100 ml. of dioxane. The solution was refluxed and stirred for 24 hours, cooled to room temperature and then filtered to remove the hydroquinone. The solvent was removed in vacuo on the steam bath, and the residue was dissolved in 200 ml. of methylene chloride. This solution was passed through a column containing about 150 g. of alumina (Woelm, grade 1). The solvent was removed on the steam bath and the residue was crystallized from alcohol. The yield of 9-chlorodibenzothiophene-3-acetic acid ethyl ester was 1.1 g., m.p. 82°-84°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.Cl.Cl.[N:15]1([CH2:21][CH2:22][CH2:23][N:24]2[C:30](=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([N:27]2[CH2:28][CH2:29][C:30](=[O:31])[N:24]([CH2:23][CH2:22][CH2:21][N:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:25][CH2:26]2)=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCNCCN1CCCN1CCCCC1
Reactant: O=C(O)/C=C/c1cccc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(/C=C/c1cccc(Cl)c1)N1CCC(=O)N(CCCN2CCCCC2)CC1
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To a suspension of (E)-3-(3-Chloro-phenyl)-acrylic acid acid (26 mg, 0.12 mmol), 4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one-dihydrochloride (intermediate 4) (24 mg, 0.1 mmol), O-(7-azabenotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (46 mg, 0.12 mmol) in DMF (1 ml) was added Et3N (21 ul, 0.15 mmol) and the mixture shaken for 1 h. The reaction was then directly purified by preparative HPLC affording the title product (28 mg, 69%) as a white powder. MS: 404.2 (MH+).
Reaction SMILES: C(OP([CH2:9][C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11])(OCC)=O)C.[H-].[Na+].[NH2:20][C:21]1[C:35]([Cl:36])=[CH:34][C:24]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=O)=[CH:23][C:22]=1[Cl:37].O>O1CCCC1>[NH2:20][C:21]1[C:22]([Cl:37])=[CH:23][C:24]([C:25]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[CH:9][C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[O:11])=[CH:34][C:35]=1[Cl:36]
Reactant: CCOP(=O)(CC(=O)N1CCOCC1)OCC
Reactant: Nc1c(Cl)cc(C(=O)c2ccc(Cl)cc2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(C(=CC(=O)N2CCOCC2)c2ccc(Cl)cc2)cc1Cl
Reaction time: 0.17 h

Procedure:
A solution of 5.3 g (0.02 mol) of diethylphosphonoacetic acid morpholide in 100 ml of dry tetrahydrofuran was slowly added dropwise, while stirring, to a suspension of 1 g of sodium hydride (0.02 mol, 50% in oil) in 50 ml of dry tetrahydrofuran. Slight heating and strong foaming occurred. After all had been added, the mixture was stirred for 10 minutes more. A solution of 3 g (0.01 mol) of 4-amino-3,4',5-trichlorobenzophenone in 20 ml of dry tetrahydrofuran was added dropwise to the resulting clear solution, and the mixture was heated for 16 hours at reflux temperature. After cooling, the solution was poured into water, and the aqueous mixture was extracted exhaustively with methylene chloride. The methylene chloride phase was dried with sodium sulfate and evaporated by evaporation in vacuo. The residue was crystallized from isopropanol/petroleum ether. The colorless crystals thus obtained, melting point 150°-155° C., contained the cis/trans isomers in a ratio of 1:3.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:21](=[O:22])[C:20]4=[CH:23][S:24][CH:25]=[C:19]4[NH:18][C:17]3=[O:26])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:31]I.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:21](=[O:22])[C:20]4=[CH:23][S:24][CH:25]=[C:19]4[N:18]([CH3:31])[C:17]3=[O:26])[CH2:10][CH2:9]2)=[O:7])=[CH:27][CH:28]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3cscc3c2=O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c(=O)c2cscc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The title compound was prepared by dissolving the 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]thieno[3,4-d]pyrimidine-2,4-dione from Example 10 (1.8 g, 4.6 mmol) in 10 ml of dimethylformamide at 0° C. After treating this solution with NaH (203 mg, 5 mmol) followed by 720 mg (5 mmol) of methyl iodide, the mixture was stirred at room temperature for 24 hours. The reaction was poured into water and extracted with CH2Cl2. The combined extracts were washed with water and brine and dried over MgSO4. Solvent removal produced a crude product which was purified by flash silica gel chromatography using 2% MeOH/CH2Cl2. The title compound was crystallized from CH2Cl2 /hexane to give a white solid (1.04 g, 54% yield), mp 176°-178° C.
Reaction SMILES: [C:1]([CH:6]([C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17](C(OCC)=O)[C:16]2=[O:29])=[CH:10][C:9]=1[CH2:30][CH3:31])([O:3]CC)=[O:2].C(O)C.[OH-].[Na+].Cl>C(Cl)Cl>[C:1]([CH:6]([C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[NH:17][C:16]2=[O:29])=[CH:10][C:9]=1[CH2:30][CH3:31])([OH:3])=[O:2]
Reactant: CCOC(=O)C(Oc1ccc(Cn2c(=O)n(C(=O)OCC)c3ccccc32)cc1CC)c1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CCc1cc(Cn2c(=O)[nH]c3ccccc32)ccc1OC(C(=O)O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
A round bottom flask was charged with 0.031 g (0.06 mmol) of the product of step C, 0.5 mL of ethanol and the flask and its contents were placed in a sonicator bath. Methylene chloride (0.2 mL) was then added in order to completely dissolve the starting material. Next, 23 μL of a 5.0 N solution of sodium hydroxide were added and the reaction was stirred at room temperature overnight. The reaction mixture was then adjusted to pH=5 with dropwise addition of 6 N hydrochloric acid, and then concentrated in vacuo. The residue was redissolved in methanol, filtered, and evaporated. The mixture was then purified on a silica gel flash chromatography column eluted with CHCl3 -MeOH-NH4OH (80: 15:1). Evaporation of the purified fractions and drying in vacuo afforded 0.012 g (48%) of the title compound.