Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)=[CH:8][C:7]=1[CH3:20].[Br:22][C:23]1[CH:24]=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:26]=[CH:27][C:28]=1F.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:28]3[CH:27]=[CH:26][C:25]([C:30]([F:33])([F:32])[F:31])=[CH:24][C:23]=3[Br:22])[CH:14]=2)=[CH:8][C:7]=1[CH3:20]
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Reactant: COC(=O)CCc1ccc(Oc2cccc(O)c2)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Temperature: 100 °C
Reaction time: 6 h
Yield: 82.3 %

Procedure:
A mixture of 3-[4-(3-hydroxy-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (8.18 g, 28.6 mmol), 3-bromo-4-fluorobenzotrifluoride (6.80 g, 28.0 mmol) and 325 mesh potassium carbonate (4.64 g, 33.68 mmol) in dry DMSO (80 mL) is heated to 100° C. and stirred for about 6 hours under N2. The reaction is cooled and acidified with 1 N HCl. The mixture is then diluted with water and extracted with Et2O. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 15/1 hexanes/ethyl acetate to afford about 11.74 g (81%) of the titled compound. Rf=0.76 (9/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C24H20O4F3Br 509, found 526 and 528 (M+NH4, 100%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[C:13]([Cl:16])([Cl:15])[Cl:14].S(=O)(=O)(O)O>>[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([N+:1]([O-:4])=[O:2])=[CH:8][C:7]=1[C:13]([Cl:16])([Cl:14])[Cl:15]
Reactant: O=[N+]([O-])O
Reactant: Clc1cccc(C(Cl)(Cl)Cl)c1Cl
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(Cl)c(Cl)c(C(Cl)(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
62 g of fuming nitric acid were added dropwise to 100 g of 2,3-dichlorobenzotrichloride at −10 to +10° C. in the course of 10 minutes, followed by 62 g of 96% by weight sulphuric acid. The reaction mixture was initially stirred at 20 to 30° C. for 2 hours, then cooled down, discharged onto ice and extracted 3× with 100 ml of dichloromethane each time. The combined organic phases were washed with 100 ml of water, 3×100 ml of saturated aqueous sodium bicarbonate solution and 100 ml of aqueous sodium chloride solution, dried over magnesium sulphate and evaporated. The crude product (99 g, purity 100%, 84.4% of theory) was recrystallized from ethanol to obtain 68 g (=58.2% of theory) of 2,3-dichloro-5-nitro-benzotrichloride (mp. 97 to 99° C.), while the other isomers ended up in the residue.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[H+].[B-:11]([F:15])([F:14])([F:13])[F:12].[N:16]([O-])=O.[Na+].C(OCC)C>CCO>[F:12][B-:11]([F:15])([F:14])[F:13].[Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[N+:4]#[N:16]
Reactant: O=N[O-]
Reactant: Nc1ccc(Cl)cc1Br
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: N#[N+]c1ccc(Cl)cc1Br
Yield: 96 %

Procedure:
A solution of 2-bromo-4-chloroaniline (10.0 g, 48.4 mmol) and HBF4 in EtOH (60 mL) kept at 0° C. was treated with an aqueous solution (20 mL) of NaNO2 (3.34g, 48.4 mmol). After completion of the addition, diethyl ether (200 mL) was added to the mixture. The solid was collected by filtration, washed with water and dried under high vacuum affording the title compound (14.2 g, 96%) as white crystals.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:7][NH:6]1)[CH3:3].[CH:21](O)=[O:22]>C1(C)C=CC=CC=1>[CH:21]([N:6]1[CH2:7][CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]1[CH2:4][N:2]([CH3:1])[CH3:3])=[O:22]
Reactant: O=CO
Reactant: CN(C)CC1NCC(c2ccccc2)c2ccccc21
Solvent: Cc1ccccc1
Product: CN(C)CC1c2ccccc2C(c2ccccc2)CN1C=O
Yield: 120 %

Procedure:
To a stirred solution of 1,2,3,4-tetrahydro-1-dimethylaminomethyl-4-phenylisoquinoline base (Example 2) (9.5 g, 0.035 m) in toluene (100 ml) under nitrogen was added formic acid (8.05 g, 0.175 m) and the mixture heated to reflux in a Dean and Stark apparatus. After 3 ml of water were collected, the mixture was cooled, treated with 250 ml of 5% NaOH, and extracted with ether (1×150 ml) and then chloroform (3×100 ml) and the combined organic extracts dried over MgSO4. Evaporation of the solvents gave 12.6 g of 1,2,3,4-tetrahydro-2-formyl-1-dimethylaminomethyl-4-phenylisoquinoline as a yellow oil. This material was used directly for additional chemical processing without further purification.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]([OH:9])=O)[CH2:2][CH2:3][CH3:4].[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:20])=[C:15]([N:17]=[C:18]=[S:19])[CH:16]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:5]1[CH2:6][C:7](=[O:9])[N:17]([C:15]2[CH:16]=[C:11]([Cl:10])[CH:12]=[CH:13][C:14]=2[CH3:20])[C:18]1=[S:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCC(=O)O
Reactant: Cc1ccc(Cl)cc1N=C=S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCN1CC(=O)N(c2cc(Cl)ccc2C)C1=S
Yield: 40.6 %

Procedure:
A mixture of N-butyl glycine (12.0 g), 5-chloro-2-methylphenyl-isothiocyanate (9.15 g), triethyl amine (12.0 g) and chloroform (200 mL) was heated at reflux for 5 hours. The solvent was evaporated. The residue was treated with diethyl ether (400 mL). The mixture was filtered. The solid was washed with diethyl ether then discarded. The filtrate was evaporated to dryness. Crystallization from ethanol afforded the title compound (6.0 g) as a tan solid, m.p. 102°-103° C. Anal. Calcd. for. C14H17Cl N2O S: C, 56.65; H, 5.77; N, 9.44. Found: C, 56.41; H, 5.97; N, 9.36. Mass spectrum (EI, M.+) m/z 296/298.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][C:12]1[C:13](/[CH:18]=[CH:19]/[C:20]([OH:22])=O)=[N:14][CH:15]=[CH:16][CH:17]=1)=[CH:5]2.[CH3:23][C:24]1[S:25][C:26]([S:30]([NH2:33])(=[O:32])=[O:31])=[C:27]([CH3:29])[N:28]=1>>[CH3:23][C:24]1[S:25][C:26]([S:30]([NH:33][C:20](=[O:22])/[CH:19]=[CH:18]/[C:13]2[C:12]([CH2:11][C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=4)=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:31])=[O:32])=[C:27]([CH3:29])[N:28]=1
Reactant: O=C(O)/C=C/c1ncccc1Cc1cc2cc(Cl)ccc2[nH]1
Reactant: Cc1nc(C)c(S(N)(=O)=O)s1
Product: Cc1nc(C)c(S(=O)(=O)NC(=O)/C=C/c2ncccc2Cc2cc3cc(Cl)ccc3[nH]2)s1

Procedure:
The acid of Step 4 (283 mg; 0.90 mmol) was coupled with 2,4-dimethyl-1,3-thiazole-5-sulfonamide (from Maybridge Chemical) according to step 5 of example 1 to yield 315 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:20]([CH3:22])[CH3:21])[C:16](=[O:19])[NH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:25][C:26]1([CH2:30][N:31]2[CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[CH:33]=[N:32]2)[CH2:29][O:28][CH2:27]1>>[CH:20]([N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:34]5[CH:33]=[N:32][N:31]([CH2:30][C:26]6([CH3:25])[CH2:27][O:28][CH2:29]6)[CH:35]=5)[CH:24]=[CH:23][C:5]=4[C:6]=3[N:7]=2)=[N:18][NH:17][C:16]1=[O:19])([CH3:22])[CH3:21]
Reactant: CC1(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)COC1
Reactant: CC(C)n1c(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)n[nH]c1=O
Product: CC(C)n1c(-c2nc3c(s2)CCOc2cc(-c4cnn(CC5(C)COC5)c4)ccc2-3)n[nH]c1=O

Procedure:
Similarly to as described in General Procedure C, 5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-4-isopropyl-2,4-dihydro-[1,2,4]triazol-3-one was reacted with 1-((3-methyloxetan-3-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. Purification of the crude reaction mixture by reverse phase HPLC gave 456. LCMS: 479.1
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[C:17]([CH2:20][CH2:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25]2)([OH:19])=[O:18]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:25]1[C:24]2[C:28](=[CH:29][CH:30]=[C:22]([CH2:21][CH2:20][C:17]([OH:19])=[O:18])[CH:23]=2)[NH:27][C:26]1=[O:31])([CH3:3])[CH3:2]
Reactant: O=C(O)CCc1ccc2c(c1)CC(=O)N2
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3ccc(CCC(=O)O)cc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5-(2-carboxyethyl)-2-oxindole to give 0.35 g of 3-[3-(3,5-diisopropyl-4-methoxybenzylidene)-2-oxo-2,3-dihydro-1H-indol-5-yl]-propionic acid as a yellow-orange solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1>CO.O>[NH2:11][C:10]1[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([CH:9]=1)[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)c1cnc(N)c([N+](=O)[O-])c1
Solvent: CO
Solvent: O
Product: NC(=O)c1cnc(N)c(N)c1
Temperature: 20 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
44.5 g of 6-amino-5-nitro-nicotinamide (0.24 mol; HPLC: 93% area) were suspended in methanol/water 1:1 (500 mL), 5.0 g of catalyst [Pd(4%)-Ru(1%)/C paste (62% H2O type: 485; Johnson Matthey); type: 485; Johnson Matthey] was added. Hydrogenation was carried out at 5 bar and 30° C. for 5 h. After completion the catalyst was filtered off and washed with methanol/water 1/1 (50 mL). 480 mL of the solvent was distilled off. The resulting suspension was cooled to 20° C. and filtered off. The solid was washed with methanol (20 mL) and TBME (30 mL). After drying (200-10 mbar; 40° C. bath temperature, 16 h) 27.3 g of the title compound (0.18 mol, 73%) were obtained.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12].[NH2:19][C:20]1[N:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([O:28][CH3:29])[N:21]=1.C>O1CCOCC1>[F:18][C:2]([F:1])([F:17])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]([NH:19][C:20]1[N:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([O:28][CH3:29])[N:21]=1)=[O:16])(=[O:13])=[O:12]
Reactant: COc1nc(N)nc(OC)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1CCC(F)(F)F
Solvent: C1COCCO1
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2CCC(F)(F)F)nc(OC)n1

Procedure:
5.6 g of 2-(3,3,3-trifluoropropyl)-phenylsulfonylisocyanate and 3.12 g of 2-amino-4,6-dimethoxy-1,3,5-triazine are stirred up in 60 ml of absolute dioxane at 70°-80° C. for 2 hours. The mixture is subsequently treated with active charcoal, filtered, and concentrated by evaporation to about 1/5 of the volume. There crystallise from the residue, after the addition of ether, 6.8 g of N-[2-(3,3,3-trifluoropropyl)-phenylsulfonyl]-N'-(4,6-dimethoxy-1,3,5-triazin-2-yl)-urea, m.p. 177°-178° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:4]=2[O:3]1.O[N:15]=[C:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.N>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]2[N:23]=[C:11]([C:9]3[CH:8]=[CH:7][C:5]4[NH:6][C:2](=[O:1])[O:3][C:4]=4[CH:10]=3)[O:13][N:15]=2)[CH:18]=1
Reactant: O=C(O)c1ccc2[nH]c(=O)oc2c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: O=c1[nH]c2ccc(-c3nc(-c4cccnc4)no3)cc2o1

Procedure:
The title compound was prepared according to Method C using 2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxylic acid (Eur. J. Med. Chem. 1974, 9, 491-6.) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 7.35 (d, J=8.7 Hz, 1H), 7.65 (dd, J=7.5, 4.4 Hz, 1H), 8.04 (d, J=1.6 Hz, 1H), 8.07 (s, 1H), 8.44 (dt, J=7.9, 2.0 Hz, 1H), 8.82 (dd, J=4.8, 1.6 Hz, 1H), 9.25 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 281 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:28]([O-])=O)[C:18]([NH:19][C@@H:20]4[CH2:25][CH2:24][CH2:23][C@H:22]([C:26]#[N:27])[CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:28][C:17]1[C:18]([NH:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][C@H:22]([C:26]#[N:27])[CH2:21]2)=[C:13]2[CH:12]=[CH:11][N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[C:14]2=[N:15][CH:16]=1
Reactant: N#C[C@H]1CCC[C@@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: N#C[C@H]1CCC[C@@H](Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 85 °C
Yield: 80.9 %

Procedure:
A mixture of cis 3-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-4-ylamino)cyclohexanecarbonitrile (730 mg, 1.72 mmol), ammonium chloride (552 mg, 10.3 mmol) and iron powder (384 mg, 6.88 mmol) in methanol/H2O (3:1, v/v) was heated at 85° C. for 3.5 hr. The cooled reaction mixture was filtered through celite and the filtrate concentrated under vacuum. The residue was dissolved in DCM, washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated under vacuum to a foam. The resulting residue was purified by column chromatography on silica gel (gradient: 0 to 4% MeOH in DCM) to afford 0.55 g (81%) of cis 3-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4-ylamino)-cyclohexanecarbonitrile. LCMS (Method H, ESI): RT=2.45 min, m+H=396.1; 1H NMR (400 MHz, DMSO) δ: 8.01 (d, 2H), 7.66 (m, 1H), 7.57 (m, 3H), 7.49 (d, 1H), 6.75 (d, 1H), 5.14 (d, 1H), 4.36 (s, 2H), 3.72 (m, 1H), 2.98 (m, 1H), 2.22 (m, 1H), 2.01-1.84 (m, 2H), 1.75 (m, 1H), 1.53-1.36 (m, 3H), 1.22 (d, 1H).
Reaction SMILES: [CH:1]1([NH:7][C:8]([C@H:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[C:19]([NH2:24])[N:18]=1.C(N(CC)CC)C>CC#N>[NH2:24][C:19]1[N:20]=[C:21]([N:12]2[CH2:13][CH2:14][CH2:15][C@H:10]([C:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[O:9])[CH2:11]2)[CH:22]=[C:17]([Cl:16])[N:18]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: O=C(NC1CCCCC1)[C@H]1CCCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)cc(N2CCC[C@H](C(=O)NC3CCCCC3)C2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To (3S)—N-cyclohexyl-3-piperidinecarboxamide (446 mg, 2.12 mmol) in CH3CN (10 mL) was added 4,6-dichloro-2-pyrimidinamine (382 mg, 2.332 mmol) and triethylamine (0.591 mL, 4.24 mmol), and the reaction mixture was stirred overnight at 50° C. LCMS show no starting material after 3 hours. The reaction was concentrated, and 3 mL of EtOAc was added until solid dissolved. Then 15 mL of hexane was added and solid crashed out of the solution. The solid was isolated by filtration to afford the title compound (430 mg) as a white solid. LC-MS (ES) m/z=338 [M+H]+.
Reaction SMILES: O=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([OH:15])=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:3]1>C(O)(=O)C.[H][H].[Pd]>[CH2:12]([C:11]1[C:6]2[O:5][C:4]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:3][CH2:2][C:7]=2[CH:8]=[CH:9][C:10]=1[OH:15])[CH2:13][CH3:14]
Reactant: CCCc1c(O)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCc1c(O)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2
Reaction time: 8 h
Yield: 19.8 %

Procedure:
The title product of Example 1 (4.19 g, 10.3 mmol) was dissolved in 50 ml of acetic acid, and then hydrogenated at 70° C. using 60 psi of hydrogen and 10% palladium on carbon as catalyst. After eight hours, the mixture was allowed to cool, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was chromatographed on silicagel column. Elution with 20% ethyl acetate/hexane afforded the title compound (0.80 g).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([OH:9])[N:4]=1.[I-].C[N+]1C=CN([C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)C=1.C(N(CC)CC)C>C(#N)C>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:4]=1
Reactant: Oc1nccc(C(F)(F)F)n1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C(=O)Oc1nccc(C(F)(F)F)n1)c1ccccc1
Yield: 39.3 %

Procedure:
A solution of 4-(trifluoromethyl)-2-pyrimidol (0.49 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 3 days. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (30:70)) yielding the title compound (0.35 g, 39% yield) as a colourless oil.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][NH2:8])=[CH:4][CH:3]=1.C([O:13][C:14](=O)[CH:15]=[C:16]([NH2:20])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:20][C:16]1[NH:8][N:7]([CH2:6][C:5]2[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=2)[C:14](=[O:13])[CH:15]=1
Reactant: NNCc1ccc(I)cc1
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccc(I)cc2)[nH]1
Reaction time: 8 h

Procedure:
A solution of 25.5 g of p-iodobenzylhydrazine in 100 ml of ethanol was added dropwise, under nitrogen, to a solution of 16.2 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulphonic acid in 250 ml of ethanol. After stirring overnight, the solvent was distilled off in vacuo and the compound identified above was obtained as a residue and recrystallised from ethanol. Melting point: 158°, 15 g (47%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:13]=[C:12]2[C:7]([C:8](=[O:19])[C:9]([C:16]([OH:18])=O)=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:6][CH:5]=1)[CH3:2].[NH2:20][C:21]1[NH:25][N:24]=[N:23][N:22]=1>CN(C)C=O>[CH2:1]([O:3][C:4]1[N:13]=[C:12]2[C:7]([C:8](=[O:19])[C:9]([C:16]([NH:20][C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[O:18])=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2c(=O)c(C(=O)O)cn(CC)c2n1
Reactant: Nc1nnn[nH]1
Solvent: CN(C)C=O
Product: CCOc1ccc2c(=O)c(C(=O)Nc3nnn[nH]3)cn(CC)c2n1

Procedure:
7-Ethoxy-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (2.0 g) and N,N'-carbonyldiimidazole (1.85 g) in dimethylformamide (40 ml) were stirred and heated to 100° for 7 hours. 5-Amino-1H-tetrazole (1.3 g) was added and the mixture heated at 100° for 1 hour and cooled. The solid was collected and dissolved in hot aqueous dimethylaminoethanol (20 ml, 5%). The hot solution was acidified with hydrochloric acid and the solid was filtered off, washed with water and dried, m.p. above 307° (d), (61 %).
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([F:20])=[C:12]([O:18][CH3:19])[C:13]=2[Cl:17])[C:8]1=[O:21])[CH2:4][CH2:5][CH3:6].[CH2:22](I)[CH:23]=[CH2:24]>>[CH2:24]([C:7]1([CH2:3][CH2:4][CH2:5][CH3:6])[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([F:20])=[C:12]([O:18][CH3:19])[C:13]=2[Cl:17])[C:8]1=[O:21])[CH:23]=[CH2:22]
Reactant: C=CCI
Reactant: CCCCC1CCc2c(cc(F)c(OC)c2Cl)C1=O
Agent: [H-]
Agent: [Na+]
Product: C=CCC1(CCCC)CCc2c(cc(F)c(OC)c2Cl)C1=O
Reaction time: 0.08 h

Procedure:
Sodium hydride (15 mg, 61% dispersion in mineral oil, 0.38 mmol) was placed in a flame dried flask, then washed with hexanes to remove mineral oil, and finally suspended in DMF (0.3 mL) under an atmosphere of N2. A solution of 2-butyl-5-chloro-7-fluoro-6-methoxy-3,4-dihydro-2H-naphthalen-1-one (54 mg in 0.2 mL DMF, 0.19 mmol) was added at room temperature to give a bright yellow reaction mixture. After five minutes, allyl iodide (0.055 mL, 0.6 mmol) was added. The reaction was stirred for 1.5 hours, then partitioned between EtOAc/H2O. The organic phase was washed twice with water, dried over MgSO4, filtered and then evaporated under vacuum. The crude product was purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate (Analtech, Newark, Del.), developing with 10:1 hexane-EtOAc. The product band at Rf 0.45-0.55 was eluted with 5% MeOH in CH2Cl2 and concentrated under vacuum to give 2-allyl-2-butyl-5-chloro-7-fluoro-6-methoxy-3,4-dihydro-2H-naphthalen-1-one as an oil.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10](=[O:25])[CH:11]=[CH:12][C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)[CH2:5][CH2:4]1.[CH2:26](Br)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>C(O)C.C(=O)([O-])O.[Na+]>[CH2:26]([N:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10](=[O:25])[CH:11]=[CH:12][C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)[CH2:5][CH2:4]1)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCCc1ccccc1
Reactant: O=C(C=CC1=Cc2cnc3cccc(n23)S1)NC1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(C=CC1=Cc2cnc3cccc(n23)S1)NC1CCN(CCc2ccccc2)CC1

Procedure:
In 10 ml of ethanol was suspended 0.998 g (2.5 mM) of N-(piperidin-4-yl)-3-(5-thia-1,8b-diazaacenaphthylen-4-yl)acrylamide dihydrochloride as well as 0.703 g (3.8 mM) of phenethyl bromide, followed by addition of 1.74 ml (12.5 mM) of triethylamine, and the mixture was refluxed for 5 hours. To this reaction mixture was further added 0.070 g (0.38 mM) of phenethyl bromide, and the mixture was refluxed overnight. This reaction mixture was diluted with 5% aqueous solution of sodium hydrogen carbonate and extracted with dichloromethane. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over Na2SO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-methanol=4/1) and concentrated and the residue was crystallized from ether to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:20](=[O:21])[C:19]3[C:18]([OH:22])=[C:17]4[CH:23]=[CH:24][CH:25]=[CH:26][C:16]4=[C:15]([OH:27])[C:14]=3[C:13]2=[O:28])=[C:8]([Cl:29])[CH:7]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:38][CH3:39]>CC(C)=O>[Cl:29][C:8]1[CH:7]=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:30])[CH:11]=[CH:10][C:9]=1[N:12]1[C:20](=[O:21])[C:19]2[C:18]([OH:22])=[C:17]3[CH:23]=[CH:24][CH:25]=[CH:26][C:16]3=[C:15]([O:27][CH2:38][CH3:39])[C:14]=2[C:13]1=[O:28]
Reactant: CCI
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(O)c4ccccc4c3O)C2=O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3O)C2=O)c(Cl)c1
Yield: 56.8 %

Procedure:
To a solution of ethyl[3-chloro-4-(4,9-dihydroxy-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetate (2.0 g, 4.70 mmol) in acetone (50 ml), was added potassium carbonate (0.656 g, 4.75 mmol) followed by iodoethane (0.38 ml, 4.75 mmol). This was heated at reflux for 24 hours. The solvent was evaporated and water added to the residue. The resulting gummy brown solid was collected by filtration and dried in the vacuum oven. This was purified using reverse phase chromatography to give the title compound (1.21 g, 2.67 mmol). LC/MS: Rt=3.66, [MH]+ 454.