Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH:17]=[CH:18][C:19](Cl)=[O:20]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH:17]=[CH:18][C:19]([NH:11][C:5]1[C:6](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:7]([OH:9])=[O:8])=[O:20]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: COc1ccc(C=CC(=O)Cl)cc1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(C=CC(=O)Nc2ccc(Cl)cc2C(=O)O)cc1OC
Yield: 43.2 %

Procedure:
In a mixture of 30 ml of chloroform and 3 ml of triethylamine is dissolved 3.4 g of 5-chloroanthranilic acid. To this solution is added a solution of 4.5 g of 3,4-dimethoxycinnamoylchloride in chloroform, and the mixture is heated under reflux for 2 hours. The reaction mixture is concentrated under a reduced pressure, and to the residue is added water and hydrochloric acid then added to make the mixture weakly acidic. The precipitated crystals are collected by filtration and recrystallized from ethanol to obtain 3.1 g of N-(3,4-dimethoxycinnamoyl)-5-chloroanthranilic acid as pale yellow needles.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][C:11](=[O:13])[NH:10][CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:27]I>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH3:27])[CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: O=C1NC(Cc2ccc(C(F)(F)F)cc2)C(c2ccc(F)cc2)O1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)OC(c2ccc(F)cc2)C1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.7 %

Procedure:
To a solution of (4RS,5SR)-5-(4-fluorophenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (5 g, 14.7 mmol) in N,N-dimethylformamide (30 ml) was added 60% sodium hydride (710 mg, 17.7 mmol) and the mixture was stirred at room temperature for 15 min. To the reaction solution was added methyl iodide (5 ml, 80 mmol) and the mixture was stirred for 1 hr. The reaction solution was diluted with water (300 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give (4RS,5SR)-5-(4-fluorophenyl)-3-methyl-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (4.76 g, 91%).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[CH:6][C:7]([CH3:21])=[CH:8][CH:9]([S:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[CH3:10])C.[NH2:23][OH:24].[OH-].[K+].CO.Cl>C1COCC1.O>[OH:24][NH:23][C:4](=[O:3])[CH:5]=[CH:6][C:7]([CH3:21])=[CH:8][CH:9]([S:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[CH3:10]
Reactant: NO
Reactant: CCOC(=O)C=CC(C)=CC(C)Sc1ccc(N(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C=CC(=O)NO)=CC(C)Sc1ccc(N(C)C)cc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
To a solution of 6-(4-dimethylaminophenylsulfanyl)-4-methylhepta-2,4-dienoic acid ethyl ester (0.576 g, 1.80 mmol) in dry THF (10 mL) was added at 0° C. an aqueous solution of hydroxylamine (50%, 1.1 mL, 16.6 mmol). To this mixture was added a solution of potassium hydroxide in methanol (1M, 2.9 mL, 2.9 mmol) over a period of 40 minutes at 0° C. The mixture was stirred at 20° C. for 16 hours, and water (10 mL) was then added. The solution was acidified to pH 5 by addition of concentrated hydrochloric acid (10 M, CAUTION), then extracted with ethyl acetate (50 mL). The organic layer was washed with brine (25 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The yellow oil was dissolved in a mixture of 1:1 diethyl ether:methanol (20 mL) and 20 drops of concentrated hydrochloric (10 M) were added. The crude mixture was evaporated to dryness to give an oil that was triturated with a mixture of diethyl ether and ethanol to give the title compound (0.34 g, 52%) as an off-white solid, mp 177-178° C. (decomp).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][N:14]2[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([N+:23]([O-])=O)[CH:16]=[N:15]2)=[CH:7][CH:6]=1)=[O:4].COC(C1C=CC(OCCN2C=C([N+]([O-])=O)C(C(OC)=O)=N2)=CC=1)=O.C1COCC1>[C].[Pd].CO>[NH2:23][C:17]1[CH:16]=[N:15][N:14]([CH2:13][CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc(OCCn2ncc([N+](=O)[O-])c2C(=O)OC)cc1
Agent: [Pd]
Agent: COC(=O)c1ccc(OCCn2cc([N+](=O)[O-])c(C(=O)OC)n2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCn2ncc(N)c2C(=O)OC)cc1

Procedure:
To a solution of a mixture of methyl 1-[2-({4-[(methyloxy)carbonyl]phenyl}oxy)ethyl]-4-nitro-1H-pyrazole-5-carboxylate and methyl 1-[2-({4-[(methyloxy)carbonyl]phenyl}oxy)ethyl]-4-nitro-1H-pyrazole-3-carboxylate (7.42 g) in a mixed solvent of THF (200 mL)-methanol (100 mL) was added 10% palladium carbon (1.17 g), and the mixture was subjected to catalytic reduction under hydrogen atmosphere (1 atm) at room temperature overnight. The catalyst was filtered off, and the filtrate was concentrated. The precipitated methyl 4-amino-1-[2-({4-[(methyloxy)carbonyl]phenyl}oxy)ethyl]-1H-pyrazole-3-carboxylate (3.62 g) was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give methyl 4-amino-1-[2-({4-[(methyloxy)carbonyl]phenyl}oxy)ethyl]-1H-pyrazole-5-carboxylate (2.18 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.FC1C(F)=CC=CC=1CSC1N=C(NS(N2CCC2)(=O)=O)C=C(OC(CO)CO)N=1.[CH3:49][C:50]([CH3:53])([O-:52])[CH3:51].[K+]>C1COCC1.O>[Cl:8][C:6]1[CH:7]=[C:2]([O:52][C:50]([CH3:53])([CH3:51])[CH3:49])[N:3]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:5]=1
Reactant: CC(C)(C)[O-]
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: O=S(=O)(Nc1cc(OC(CO)CO)nc(SCc2cccc(F)c2F)n1)N1CCC1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step (2 g) in THF (20 mL) was added potassium tert-butoxide (0.8 g) and the reaction mixture was stirred at ambient temperature for 20 h. Further potassium tert-butoxide (0.8 g) was added and the reaction mixture was stirred at ambient temperature for 411. The mixture was diluted with H2O and extracted with EtOAc (×3). The combined organic layers were washed with H2O and dried (MgSO4), filtered and evaporated. The resulting oil was purified by column chromatography on silica gel using MeOH/DCM (99:1 to 98:2 gradient) as eluent to give the subtitle compound as a clear, colourless oil. Yield: 0.68 g
Reaction SMILES: Cl.[Br:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([CH3:10])[C:4]=1[Cl:11].C([O-])(=O)C.[Na+].[I:17]N1C(=O)CCC1=O.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.C(O)(=O)C>[Br:2][C:3]1[CH:9]=[C:8]([I:17])[C:6]([NH2:7])=[C:5]([CH3:10])[C:4]=1[Cl:11]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1c(N)ccc(Br)c1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1c(N)c(I)cc(Br)c1Cl
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 96.4 %

Procedure:
To a mixture of 4-bromo-3-chloro-2-methyl aniline hydrochloride (1.0 g), sodium acetate (0.5 g), and acetic acid (15 mL) was added N-iodosuccinimide (1.0 g) under water-cooling. The reaction mixture was stirred at room temperature for 3.5 hours. To the reaction mixture were added ethyl acetate and water, and alkalified by adding potassium carbonate. Then, a liquid-separation operation was carried out, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-90:10) to obtain 4-bromo-3-chloro-6-iodo-2-methylaniline (1.3 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.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.COCCOC>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[OH:9])=[CH:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: OC(c1ccccc1)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: OC(c1ccccc1)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 56.7 %

Procedure:
To a solution of 11 (1 g, 3.80 mmol) and 4-fluorophenyl boronic acid (585 mg, 4.18 mmol) in a 2:1 mixture of DME:water (30 mL), was added Pd(PPh3)4 (307 mg, 0.27 mmol), tri-o-toly phosphine (81 mg, 0.27 mmol) and potassium carbonate (2.63 g, 19.0 mmol). The solution was heated to 80° C. and stirred for 16 hours. Then water (50 mL) was added and the organic residue was extracted with ethyl acetate (2×40 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified via prep-HPLC (ISCO) in silica gel column with a gradient of ethyl acetate (2-50%) in hexane to afford compound 12 as a white solid (600 mg, 57%). 1H NMR (DMSO-d6) δ (ppm): 7.67-7.63 (m, 2H), 7.56 (d, J=8.4 Hz, 2H), 7.45-7.38 (m, 4H), 7.32-7.17 (m, 5H), 5.93 (d, J=3.9 Hz, 1H), 5.73 (d, J=3.8 Hz, 1H).
Reaction SMILES: C(OCC[N:7]1[C:13]2[CH:14]=[CH:15][C:16](Cl)=[CH:17][C:12]=2[C:11]2(C3C=CC=CC=3F)OCC[N:10]2[CH2:9][C:8]1=O)(=O)C.[OH-:30].[Na+].O>CO>[N:7]1[C:13]2=[CH:14][CH2:15][CH2:16][C:17](=[O:30])[C:12]2=[CH:11][N:10]=[CH:9][CH:8]=1
Reactant: CC(=O)OCCN1C(=O)CN2CCOC2(c2ccccc2F)c2cc(Cl)ccc21
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1CCC=C2N=CC=NC=C12
Reaction time: 3 h

Procedure:
A solution of 0.5g (0.0012 M) of 7-(2-acetoxyethyl)-10-chloro-11b-(2-fluorophenyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d] [1,4]benzodiazepin-6(7H)-one in 5 ml of methanol was treated with 2 ml of 3N sodium hydroxide. After 3 hours, 50 ml of water was added and the solution was extracted with 40 ml of dichloromethane, which was then dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from a mixture of methanol and water to give 10-chloro-11b-(2-fluorophenyl)-7-(2-hydroxyethyl)-2,3,5,11b-tetrahydrooxazolo)3,2-d) [1,4]benzodiazepin-6(7H)-one as white prisms, m.p. and m.m.p. 141°-146°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.Br[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.C(P)(C)(C)C.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COc1ccc(Br)cc1
Reactant: COc1ccc2c(c1)C1CCCCC1CC2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P
Solvent: C1CCOC1
Product: COc1ccc(C2C(=O)c3ccc(OC)cc3C3CCCCC32)cc1
Reaction time: 18 h
Yield: 53.9 %

Procedure:
Combine 6-methoxy-2,3,4,4a,10,10a-hexahydro-1H-phenanthren-9-one (1.0 g, 4.3 mmol), 4-bromoanisole (0.81 g, 4.3 mmol), palladium acetate (49.0 mg, 0.218 mmol), t-butyl phosphine (0.133 g, 0.658 mmol), sodium t-butoxide (0.457 g, 4.7 mmol), tetrahydrofuran (38.0 mL), and stir under nitrogen atmosphere at 80° C. in a glass bomb. After 18 hours, quench reaction with acetic acid (5 mL) in a glove box and extract with ethyl acetate. Wash the ethyl acetate with sodium bicarbonate solution and then brine, dry over sodium sulfate, and concentrate in vacuo. Add diethyl ether and collect precipitate to yield the titled compound (0.78 g, 55%) as a white solid. TLC Rf=0.26 in 5:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 8.04 (d, 1H, J=8.8 Hz), 7.06 (d, 2H, J=8.4 Hz), 6.86 (m, 3H), 6.75 (m, 1H), 3.89 (m, 4H), 3.80 (s, 3H), 3.01 (m, 1H), 2.65 (m, 1H), 1.81 (m, 3H), 1.46 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[NH:15][NH:16]C(OC(C)(C)C)=O.[F:24][C:25]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:26]=1[C:27]([N:29]=[C:30]=[O:31])=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[N:15]1[C:30](=[O:31])[NH:29][C:27]([C:26]2[CH:32]=[CH:33][C:34]([C:36]([F:39])([F:38])[F:37])=[CH:35][C:25]=2[F:24])=[N:16]1
Reactant: O=C=NC(=O)c1ccc(C(F)(F)F)cc1F
Reactant: CC(C)(C)OC(=O)NNc1cc(CNC(=O)C2CC2)ccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(C(F)(F)F)cc3F)[nH]c2=O)c1)C1CC1
Yield: 58.2 %

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(2-chloro-5-(cyclopropanecarboxamidomethyl)phenyl)hydrazinecarboxylate (step-7 of Intermediate-48, 0.060 g, 0.17 mmol), 2-fluoro-4-(trifluoromethyl)benzoyl isocyanate (Intermediate-56, 0.035 g, 0.82 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.045 g of desired product. 1H NMR (400 MHz, DMSO d6): δ 0.67 (m, 4H), 1.60 (m, 1H), 4.3 (d, J=5.9 Hz, 2H), 7.37 (d, J=6.4 Hz, 1H), 7.46 (s, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.89 (d, J=10.56 Hz, 1H), 8.05 (t, J=7.7 Hz, 1H), 8.65 (t, J=5.8 Hz, 1H), 12.6 (br s, 1H); MS (m/z): 454.98 (M+).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([OH:19])=[CH:16]2)=[CH:11][C:10]=1[C:20]1[S:21][C:22]([N:25]([CH3:36])[CH:26]2[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]2)=[N:23][N:24]=1)C1C=CC=CC=1.B(Br)(Br)Br.CO>C(Cl)Cl>[CH3:36][N:25]([CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]1)[C:22]1[S:21][C:20]([C:10]2[C:9]([OH:8])=[CH:18][C:17]3[C:12]([CH:11]=2)=[CH:13][CH:14]=[C:15]([OH:19])[CH:16]=3)=[N:24][N:23]=1
Reactant: CN(c1nnc(-c2cc3ccc(O)cc3cc2OCc2ccccc2)s1)C1CC(C)(C)NC(C)(C)C1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CN(c1nnc(-c2cc3ccc(O)cc3cc2O)s1)C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Yield: 44.6 %

Procedure:
To a stirred, ice-bath cooled suspension of 7-(benzyloxy)-6-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)naphthalen-2-ol (49 mg, 0.112 mmol) in DCM (2 ml) under nitrogen was added BBr3 (1M solution in DCM, 0.56 mL, 0.56 mmol). The reaction mixture was quenched by addition of MeOH (2 mL) and the resulting solution was warmed to room temperature, then loaded onto a 1 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (˜15 mL) then flushed with 7M NH3 in MeOH (˜10 mL). The MeOH/NH3 was removed in vacuo to afford the crude product. The crude product was taken up in 1:1 MeOH:DMSO (2 mL), filtered via syringe filter, and the filtrate purified by preparative HPLC, under neutral conditions, running a gradient from 10-90% MeCN/water over 15 minutes. The relevant fractions were combined and concentrated in vacuo to afford the title compound as a dark green/brown solid (20.6 mg, 49.2% yield). LC-MS: Rt 0.85 min; MS m/z 413.3 [M+H]+ [Method B]. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (br. s., 1H) 9.81 (br. s., 1H) 8.31 (s, 1H) 7.74 (d, J=9.09 Hz, 1H) 7.07 (s, 1H) 6.87-6.94 (m, 2H) 4.25-4.34 (m, 1H) 3.01 (s, 3H) 1.64 (dd, J=12.13, 3.03 Hz, 2H) 1.45 (t, J=12.13 Hz, 2H) 1.22 (s, 6H) 1.10 (s, 6H).
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[CH:26]=[N:25][CH:24]=[CH:23]2>>[CH:26]1[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=[C:4]2[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]2)[CH:23]=[CH:24][N:25]=1
Reactant: Nc1cccc2ccncc12
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Agent: [I-]
Product: c1ccc2c(c1)C[C@H]1CSC(=Nc3cccc4ccncc34)N1C2
Yield: 71.1 %

Procedure:
By following the procedure of Example 2, but using (S)-3-methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (18.2 g) and 8-aminoisoquinoline (10.9 g) as the starting materials, (S)-3-(isoquinol-8-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (11.8 g) is obtained in the form of pale yellow crystals, m.p.=206° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][S:17](=[O:20])[CH2:16][CH2:15]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][S:17](=[O:20])[CH2:16][CH2:15]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: CSc1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Reactant: C1CNCCN1
Product: CSc1ncnc2c(N3CCS(=O)CC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 2 from 2-chloro-8-methylthio-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p. 252°-254° C.) and piperazine at 50° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[CH3:32][C:33]1[CH:42]=[C:41]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:29])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:46]4[CH2:47][CH2:48][N:43]([C:41]5[C:40]6[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=6)[N:34]=[C:33]([CH3:32])[CH:42]=5)[CH2:44][CH2:45]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: Cc1cc(N2CCNCC2)c2ccccc2n1
Product: Cc1cc(N2CCN(C(=O)c3cccc(-c4cnc5c(c4)N(Cc4cc(Cl)ccc4C(F)(F)F)CCN5)c3)CC2)c2ccccc2n1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-methyl-4-(1-piperazinyl)quinoline as in General Procedure 10 to give the title compound. LCMS: m/z=656.99 (M+H+); retention time=0.61 minutes.
Reaction SMILES: [CH3:1][C:2](OC(OC(OC(C)(C)C)=O)=O)(C)C.[CH2:16]([C@H:23]1[CH2:27][O:26][C:25](=[O:28])[N:24]1[C:29](=[O:50])[CH2:30][C@@H:31]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:38][CH:37]=1)[CH2:32][N+:33]([O-])=[O:34])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.C(Br)=C>[CH2:16]([C@H:23]1[CH2:27][O:26][C:25](=[O:28])[N:24]1[C:29](=[O:50])[CH2:30][C@@H:31]([C:36]1[CH:37]=[CH:38][C:39]([O:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[CH:40][CH:41]=1)[C:32]1[CH:2]=[CH:1][O:34][N:33]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=C(C[C@H](C[N+](=O)[O-])c1ccc(OCc2ccccc2)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: C=CBr
Agent: CN(C)c1ccncc1
Product: O=C(C[C@@H](c1ccc(OCc2ccccc2)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 93.3 %

Procedure:
(Boc)2O (6.9 g, 31.65 mmol) was added at room temperature to a solution of 7.3 (10 g, 21.1 mmol), vinyl bromide (230 mL, 1.0 M solution in THF), DMAP (256 mg, 2.1 mmol), and TEA (3.5 mL, 25.3 mmol). The mixture was stirred at room temperature for 2.5 days. During the reaction, more (Boc)2O (2 g twice) was added. After HPLC indicated that all 7.3 was consumed, the reaction mixture was taken into EtOAc (500 mL), and saturated sodium bicarbonate (400 mL) was added. The organic layer was separated, washed with brine, dried, and concentrated under vacuum. The crude product was taken into hot MeOH (70 mL). The mixture was stirred vigorously at 75° C. for 5 hours. The mixture was then cooled to room temperature and allowed to stand for 3 hours. The solid product was collected by filtration and washed with MeOH to give 7.4 (9.5 g). MS ESI (pos.) m/e: 483 (M+H). 1H NMR (CDCl3) δ 8.30 (d, 1H), 7.30 (m, 2H), 6.95 (d, 2H), 6.15 (d, 1H), 5.05 (s, 2H), 4.76 (dd, 1H), 4.64 (m, 1H), 4.15 (d, 2H), 4.05 (dd, 1H), 3.56 (dd, 1H), 3.23 (dd, 1H), 2.78 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([N:16]=C(C2C=CC=CC=2)C2C=CC=CC=2)([CH3:15])[C:13]#[N:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl>C(OCC)C>[ClH:1].[NH2:16][C:12]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:5][N:4]=1)([CH3:15])[C:13]#[N:14]
Reactant: CC(C#N)(N=C(c1ccccc1)c1ccccc1)c1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: CCOCC
Product: CC(N)(C#N)c1ncc(C(F)(F)F)cc1Cl
Reaction time: 36 h

Procedure:
To a vigorously stirred solution of the product from stage b) (5.5 g) in diethyl ether (100 ml) under nitrogen was added 2M aqueous hydrogen chloride (100 ml) and stirring continued for 36 hours. The phases were separated and the organic phase was extracted with 2M aqueous hydrogen chloride (2×20 ml). The combined aqueous phases were extracted with diethyl ether (2×20 ml) and the organic extracts discarded. The aqueous phase was evaporated in vacuo then azeotroped with toluene (3×50 ml). Trituration with diethyl ether followed by filtration and vacuum drying gave the title compound, m.p. 165-70° C.
Reaction SMILES: C([O:7][CH2:8][CH2:9][C@H:10]1[C@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:13][C:12]2([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[O:11]1)(=O)C(C)(C)C.C(OCC[C@H]1[C@H](C2C=CC=CC=2)OC2(CCCC2)O1)(=O)C(C)(C)C>>[C:15]1([C@@H:14]2[O:13][C:12]3([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[O:11][C@H:10]2[CH2:9][CH2:8][OH:7])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)C(=O)OCC[C@@H]1OC2(CCCCC2)O[C@H]1c1ccccc1
Agent: CC(C)(C)C(=O)OCC[C@@H]1OC2(CCCC2)O[C@H]1c1ccccc1
Product: OCC[C@@H]1OC2(CCCCC2)O[C@H]1c1ccccc1
Yield: 80 %

Procedure:
The substantially same method as described in Example 299 was conducted, except that 2-((2S,3S)-3-phenyl-1,4-dioxaspiro[4.5]decan-2-yl)ethyl pivalate (Preparation example 300) was used instead of that 2-((2S,3S)-3-phenyl-1,4-dioxaspiro[4.4]nonan-2-yl)ethyl pivalate (Preparation example 298), to obtain the title compound (1.2 g, 80˜95%)
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:24][CH2:23][C:9]2[N:10]3[C:19]4[C:18]([C:8]=2[CH2:7]1)=[CH:17][CH:16]=[CH:15][C:14]=4[N:13]([CH3:20])[CH2:12][C:11]3([CH3:22])[CH3:21])=[O:5])[CH3:2].[BH3-]C#N.[Na+]>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:24][CH2:23][CH:9]2[N:10]3[C:19]4[C:18]([CH:8]2[CH2:7]1)=[CH:17][CH:16]=[CH:15][C:14]=4[N:13]([CH3:20])[CH2:12][C:11]3([CH3:21])[CH3:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2c(c3cccc4c3n2C(C)(C)CN4C)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCC2C(C1)c1cccc3c1N2C(C)(C)CN3C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl-1,1,3-trimethyl-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (69 mg, 0.21 mmol) in TFA (2 mL) at 0° C. was added NaBH3CN (53 mg, 0.84 mmol). The mixture was stirred at rt for 4 hours, and then removed the TFA by N2. About 10 mL of H2O was added and then was extracted with EtOAc (2×10 mL). The combined extracts were dried over magnesium sulfate and concentrated to afford ethyl-1,1,3-trimethyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate as an oil which was used for the next reaction (45 mg, 65%). MS [M+H]+ 330.