Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][C@H:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[CH:31]1([NH2:41])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][C@H:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:41][CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH2:32]1)=[O:29]
Reactant: O=C(Br)CBr
Reactant: NC1CCCc2ccccc21
Reactant: COc1ccc(C[C@@H]2NCCc3cc(OC)c(OC)cc32)cc1OC
Product: COc1ccc(C[C@H]2c3cc(OC)c(OC)cc3CCN2CC(=O)NC2CCCc3ccccc32)cc1OC

Procedure:
prepared by reaction of (1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine
Reaction SMILES: C(O[C:4](=[O:31])[CH:5]([OH:30])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:29])[CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)C.[O-:32][C:33]#[N:34].[K+]>C(O)CCC>[CH3:22][C:21]1[O:20][C:19]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:18][C:17]=1[CH2:16][CH2:15][C:14]([C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][CH:5]2[O:30][C:33](=[O:32])[NH:34][C:4]2=[O:31])=[CH:9][CH:10]=1)=[O:29]
Reactant: N#C[O-]
Reactant: CCOC(=O)C(O)CCc1ccc(C(=O)CCc2nc(-c3ccccc3)oc2C)cc1
Agent: [K+]
Solvent: CCCCO
Product: Cc1oc(-c2ccccc2)nc1CCC(=O)c1ccc(CCC2OC(=O)NC2=O)cc1
Yield: 39.4 %

Procedure:
A mixture of 2-hydroxy-4-[4-[3-(5-methyl-2-phenyl-4-oxazolyl)propionyl]phenyl]butyric acid ethyl ester (1.43 g), powdered potassium cyanate (0.83 g) and butanol (30 ml) was heated under refluxing conditions for 2 days. After the solvent was distilled off under reduced pressure, the residue was acidified with 2N hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and then concentrated. The residue was purified by silica gel column chromatography. From the fraction eluted with chloroform-methanol (100:2), 5-[2-[4-[3-(5-methyl-2-phenyl-4-oxazolyl)propionyl]phenyl]ethyl]-2,4-oxazolidinedione (0.56 g, 39%) was obtained, which was then recrystallized from dichloromethane-methanol to yield colorless prisms having a melting point of 173°-174° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:12]1[CH:17]=[C:16](OS(C(F)(F)F)(=O)=O)[CH:15]=[CH:14][N:13]=1)[CH3:2].CC1(C)C(C)(C)OB([C:41]2[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=2)O1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.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>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:17]=[C:16]([C:41]2[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=2)[CH:15]=[CH:14][N:13]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH3:2]
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(OS(=O)(=O)C(F)(F)F)ccn1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
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: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccc(N)cc2)ccn1
Yield: 70.1 %

Procedure:
Compound II (52 mg, 0.109 mmol), Pd(PPh3)4 (12 mg, 0.011 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (48 mg, 0.218 mmol) and potassium carbonate (60 mg, 0.44 mmol) were stirred in toluene (3 mL) and water (1.5 mL) at 120° C. under microwave irradiation (300 W) for 30 min. The reaction mixture was then poured onto brine (50 mL) and extracted with EtOAc (2×20 mL). The organic phases were combined then dried over MgSO4, filtered, and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (90:10 then 0:100) to furnish III as a brown oil (32 mg, 70%).
Reaction SMILES: [N+](C1C=C(C=CC=1)C(C(C)CC#N)=O)([O-])=O.Cl.[N+:18]([C:21]1[CH:22]=[C:23]([CH:32]=[CH:33][CH:34]=1)[C:24]([CH:26]([CH3:31])[CH2:27][C:28](O)=[O:29])=O)([O-:20])=[O:19].O.[NH2:36][NH2:37]>C(O)C>[CH3:31][CH:26]1[C:24]([C:23]2[CH:32]=[CH:33][CH:34]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=2)=[N:37][NH:36][C:28](=[O:29])[CH2:27]1
Reactant: CC(CC(=O)O)C(=O)c1cccc([N+](=O)[O-])c1
Reactant: NN
Agent: CC(CC#N)C(=O)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1CC(=O)NN=C1c1cccc([N+](=O)[O-])c1

Procedure:
A 28 g. portion of 3-(m-nitrobenzoyl)butyronitrile [prepared as described in J. Org. Chem., Vol. 38, No. 23, 4044-4048 (1973)] is added to one liter of 6N hydrochloric acid and is stirred at reflux for one hour using a magnetic stirrer and a heating mantle. The reaction mixture is cooled and extracted with methylene chloride. The organic layer is separated and extracted with saturated sodium bicarbonate. The bicarbonate layer is added dropwise to a stirred cold hydrochloric acid solution and the resulting solid is kept cold in ice then is filtered and air dried to afford 27.24 g. of 3-m-nitrobenzoyl butyric acid as a white solid. The entire amount of the preceding compound is mixed with 12.8 ml. of 99% hydrazine hydrate in 140 ml. of ethyl alcohol and is stirred at reflux for 3 hours. A solid begins to appear after about half an hour. The reaction mixture is cooled in an ice bath and the resulting solid is filtered and air dried to afford the compound 4,5-dihydro-5 -methyl-6-(m-nitrophenyl)-3(2H)-pyridazinone as white to light yellow crystals.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([NH2:13])[N:10]=[C:9]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)=[CH:17][CH:16]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:40])C=1>C(Cl)(Cl)Cl>[O-:40][N+:25]1[CH:26]=[CH:27][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:9]3[CH:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:12]=[C:11]([NH2:13])[N:10]=3)=[CH:16][CH:17]=2)=[CH:23][C:24]=1[C:28]([F:30])([F:29])[F:31]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1nc(Nc2ccc(Oc3ccnc(C(F)(F)F)c3)cc2)cc(-c2ccccc2)n1
Solvent: ClC(Cl)Cl
Product: Nc1nc(Nc2ccc(Oc3cc[n+]([O-])c(C(F)(F)F)c3)cc2)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.4 %

Procedure:
To a solution of 6-phenyl-N4-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine (0.10 g, 0.24 mmol, Example 37) in CHCl3, m-CPBA (77%, 0.053 g, 0.24 mmol) was added and the mixture was stirred at rt overnight. Solvent was removed in vacuo, and the residue was taken up in DMF and purified by prep-HPLC to provide 11 mg of an off-white solid (11%). 1H NMR (DMSO-d6) 810.20 (s, 1H), 8.64 (d, J=5.7 Hz, 1H), 7.93 (s, 1H), 7.86-7.92 (m, 2H), 7.52-7.56 (m, 2H), 7.41-7.49 (m, 5H), 7.30-7.39 (m, 2H), 7.24 (dd, J=5.7 Hz, 1H), 6.71 (s, 1H). MS ES 440 (M+H)+, calcd 440, RT=2.97 min.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=[N:3]1.CCN(CC)CC.Cl[Si:25]([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[CH3:1][N:2]1[C:6]([N:7]2[CH2:8][CH:9]=[C:10]([O:13][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:11][CH2:12]2)=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=[N:3]1
Reactant: C[Si](C)(C)Cl
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(=O)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1ncc([N+](=O)[O-])c1N1CC=C(O[Si](C)(C)C)CC1
Temperature: 90 °C
Yield: 59 %

Procedure:
Three identical solutions of piperidin-4-one hydrochloride hydrate (1.84 g, 12.0 mmol), 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (1.3 g, 8.0 mmol) and potassium fluoride (1.86 g, 32 mmol) in dry DMSO (20 mL) were heated in a microwave at 100° C. for 12 hr. The mixtures were combined, poured into water (700 mL) and extracted into EtOAc (3×100 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-5% MeOH/DCM) gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-one as a yellow solid (1.97 g, 36%). To a solution of this ketone in DMF (40 mL) was added NEt3 (3.05 mL, 21.9 mmol) and chlorotrimethylsilane (1.55 mL, 12.3 mmol). The reaction vessel was sealed and the mixture heated at 90° C. for 16 hr. The mixture was cooled and the product extracted into EtOAc (2×50 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% Et2O/isohexane) gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)-4-(trimethylsilyloxy)-1,2,3,6-tetrahydropyridine as a yellow gum (1.53 g, 59%). This gum was dissolved in MeCN (130 mL) and cooled to 0° C. A solution of SelectFluor® (1.99 g, 5.61 mmol) in 2:1 MeCN:DMF (10 mL) was added dropwise over 20 min and the mixture stirred at between −5° C. and 0° C. for 2 hr. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (50 mL) and water (40 mL). The product was extracted into EtOAc (50 mL) and DCM (50 mL), and the combined organic layers passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 3-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-one as a pale yellow solid (1.23 g, 99%). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 5.04 (ddd, J=48.3, 8.2, 5.7 Hz, 1H), 3.89 (s, 3H), 3.77-3.64 (m, 2H), 3.64-3.51 (m, 1H), 3.50-3.43 (m, 1H), 2.88-2.72 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.CC1C=CC(C(C)C)=CC=1.O>C(O)C>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[OH:9])=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccccn1
Reactant: COc1ccc(C=O)cc1
Solvent: Cc1ccc(C(C)C)cc1
Solvent: O
Solvent: CCO
Product: COc1ccc(CC(O)c2ccccn2)cc1
Yield: 65 %

Procedure:
Ketone starting material for A-077 was prepared from picolinic acid and 4-methoxybenzaldehyde. To a solution of 50 g. (0.37 moles) of 4-methoxybenzaldehyde and 50 ml. p-cymene (heated to dissolve) in a 3-neck flask with reflux condenser and refluxed until boiling, 10 g. (0.08 moles) picolinic acid was added dropwise and then refluxed for three hours. The solution changed in color from reddish to brown at the end. The solution was cooled and extracted in a separatory funnel with 2 N HCl (twice with 50 ml.). The above acid layer was washed twice with 100 ml. diethyl ether. The ether layer was discarded. The acid layer was basified with ice cold concentrated ammonium hydroxide at 0° C. The basic layer was extracted with diethyl ether (3×100 ml.) until clear. The ether washings were collected and dried over anhydrous sodium sulfate. The filtered ethereal solutions were evaporated (under roto-vacuum) at room temperature until an oil formed. The oil was dissolved in minimal ethanol to solubilize, and hot water dropwise was added until turbidity was produced and then disappeared on further heating. On cooling, a cloudy layer formed an oil which was removed by hand aspiration rapidly because it precipitated quickly. The 4-methoxybenzyl(2-pyridyl) carbinol oil was recrystallized from ethanol-water (80:20) as a white powder, 65% yield, mp 110°-112° C. Calc. for C14H13NO2 : C, 74.01; H, 5.73; N, 6.16. Found: C, 74.09; H, 6.01; N, 6.04.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:29]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:41][CH2:40]1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:7][C@@H:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[O:21][CH2:45][CH:42]1[CH2:43][CH2:44][N:39]([C:37]([O:36][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:38])[CH2:40][CH2:41]1)=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccccc1)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](c1ccccc1)c1cccc(OCC2CCN(C(=O)OCc3ccccc3)CC2)c1
Temperature: 50 °C
Reaction time: 17 h
Yield: 96.7 %

Procedure:
To a mixture of (S)-tert-butyl((3-hydroxyphenyl)(phenyl)methyl)carbamate (8.0 g, 26.7 mmol) and cesium carbonate (13.1 g, 37.4 mmol) in DMF (130 ml) was added 4-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acid benzyl ester (12.94 g, 32.1 mmol). The resulting reaction mixture was stirred at 50° C. for 17 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were washed with brine (×3), dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was purified by flash column chromatography eluting with 0 to 50% ethyl acetate/iso-hexane to afford the title compound (13.7 g, 93%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])=[CH:4][CH:3]=1.[CH:12]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][CH2:12][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: N[C@@H]1C[C@H]1c1ccc(I)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CN[C@@H]2C[C@H]2c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
To a solution of trans-2-(4-iodophenyl)cyclopropanamine (1.0 g, 3.86 mmol) in methanol (15 mL) were added tert-butyl 4-formylpiperidine-1-carboxylate (0.741 g, 3.47 mmol), acetic acid (0.066 mL, 1.158 mmol), and the mixture was stirred at rt for 1 h. Sodium cyanoborohydride (0.364 g, 5.79 mmol) was added and the mixture was stirred at room temperature for 18 h. The mixture was concentrated and the residue was treated with water (2 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (silica gel, 0 to 100% EtOAc/hexanes) to give 730 mg of product as pale yellow oil. MS: (M+H)+=457.2. 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.99-1.18 (m, 3H), 1.45-1.51 (m, 9H), 1.69-1.81 (m, 3H), 1.87-1.94 (m, 1H), 2.29-2.37 (m, 1H), 2.62-2.90 (m, 3H), 4.00-4.20 (m, 2H), 6.86-6.88 (m, 2H), 7.57-7.59 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:11]=2)=[C:4]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[CH3:33])[CH:3]=1.[Cl-].C[Zn+].[CH3:37]N1CCN(C)C1=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCOC(C)=O>[F:32][C:30]1[CH:29]=[CH:28][C:27]([CH3:33])=[C:26]([C:4]2[CH:3]=[C:2]([CH3:37])[N:7]=[CH:6][C:5]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=[C:12]([S:20]([CH3:23])(=[O:21])=[O:22])[CH:11]=2)[CH:31]=1
Reactant: Cc1ccc(F)cc1-c1cc(Cl)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Reactant: CN1CCN(C)C1=O
Agent: C[Zn+]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2cc(F)ccc2C)c(N(C)C(=O)c2cc(C(F)(F)F)cc(S(C)(=O)=O)c2)cn1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of N-(6-chloro-4-(5-fluoro-2-methylphenyl)pyridin-3-yl)-N-methyl-3-(methylsulfonyl)-5-(trifluoromethyl)benzamide (0.055 g, 110 μmol, example 253) in THF (1.5 mL) were added methylzinc(II) chloride (82.4 μL, 165 μmol), 1,3-dimethyl-2-imidazolidinone (DMI) (0.3 mL) and PEPPSI-IPr (1.49 mg, 2.2 μmol, CAS RN 905459-27-0) and the clear solution was stirred at 50° C. for 2 hours. The reaction mixture was poured on 10% aqueous citric acid solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed once with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 5 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 100:100). The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.05% triethylamine) (20:80 to 98:2). Colorless foam (0.022 g; 41%). MS (ESI): m/z=481.12 [M+H]+.
Reaction SMILES: CN[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:13]([O-:15])=[O:14])[N:4]=1.[N:16]1[CH:21]=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[C:22]([C:3]1[C:12]([NH:16][CH3:21])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:13]([O-:15])=[O:14])[N:4]=1)(=[O:24])[CH3:23]
Reactant: CNc1ccc2c([N+](=O)[O-])cccc2n1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CNc1cc2c([N+](=O)[O-])cccc2nc1C(C)=O
Temperature: 60 °C
Reaction time: 4.5 h

Procedure:
580 mg (2.4 mmol) of 2-methylamino-5-nitroquinoline is stirred with 4 ml (50 mmol) of pyridine and 2 ml (21 mmol) of acetic anhydride for 15 hours at room temperature and stirred for 4.5 hours at 60° C. The batch is diluted with ethyl acetate, poured into saturated NaHCO3 solution, stirred for 30 minutes, and extracted with ethyl acetate. The extracts are dried (Na2SO4) and concentrated by evaporation. The residue is purified on silica gel with hexane-ethyl acetate: 660 mg of a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][N:6]=[C:5]3[C:11]4[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=4[C:13](=[O:15])[NH:14][C:3]=1[C:4]=23.[Br:20]N1C(=O)CCC1=O.C(OCC)(=O)C>CN(C)C=O>[Br:20][C:9]1[C:8]2[NH:7][N:6]=[C:5]3[C:11]4[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=4[C:13](=[O:15])[NH:14][C:3]([C:4]=23)=[C:2]([CH3:1])[CH:10]=1
Reactant: Cc1ccc2[nH]nc3c2c1NC(=O)c1ccccc1-3
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Br)c2[nH]nc3c2c1NC(=O)c1ccccc1-3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a solution of 50 mg of 5-methyl-6,7-dihydro-2H-benzo[5,6]azepino[4,3,2-cd]indazol-7-one prepared in Example 25-c in 1 ml dimethylformamide was added 40 mg of N-bromosuccinimide [CAS No. 128-08-5], followed by stirring at room temperature for 30 minutes. To the reaction mixture was added 2 ml of ethyl acetate and the precipitated crystals were collected by filtration. The crystals were washed with ethyl acetate and dried in vacuo, to give 45 mg of the title compound as ocher yellow crystals.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])C.[CH:8]([OH:10])=O.[NH2:11][C:12]1[N:16](CCO)[N:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O1CCCC1.O>[CH:8]([NH:11][C:12]1[N:16]([CH2:6][CH2:5][O:4][CH:1]=[O:3])[N:15]=[CH:14][CH:13]=1)=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: O=CO
Reactant: Nc1ccnn1CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=CNc1ccnn1CCOC=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of acetic anhydride (11.13 ml) and formic acid (5.93 ml) was stirred at ambient temperature for 30 minutes. To this solution was added 5-amino-1-(2-hydroxyethyl)pyrazole (5 g) under ice-cooling, and the mixture was stirred at 30°-40° C. for 1 hour. The reaction mixture was poured into a mixture of water, tetrahydrofuran and ethyl acetate and adjusted to pH 6 with aqueous sodium bicarbonate. The organic layer was separated, and the aqueous layer was extracted with a mixture of tetrahydrofuran and ethyl acetate for three times. The organic layers were combined, dried over magnesium sulfate and evaporated in vacuo to give 5-formamido-1-(2-formyloxyethyl)pyrazole (5.18 g).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([C:16]#[N:17])=[C:13]([CH3:15])[N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[SH2:25]>N1C=CC=CC=1>[C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([C:16](=[S:25])[NH2:17])=[C:13]([CH3:15])[N:14]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: Cc1nc(CNC(=O)OC(C)(C)C)sc1C#N
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1nc(CNC(=O)OC(C)(C)C)sc1C(N)=S
Reaction time: 48 h

Procedure:
2-(N-BOC-Aminomethyl)-5-cyano-4-methylthiazole [sic] (7.5 g, 29.61 mmol) was dissolved in pyridine (30 ml), and triethylamine (27 ml) was added. The solution was saturated with hydrogen sulfide at 0° C. and then left to stand for 48 hours at room temperature. The solvent was subsequently removed on a rotary evaporator, and the residue was taken up in ethyl acetate, washed with 20% strength potassium hydrogen sulfate solution and dried over magnesium sulfate. The solvent was removed on a rotary evaporator, and the crude product was dissolved in dichloromethane and precipitated with petroleum ether. The product which had precipitated was filtered off with suction and dried in a vacuum drying oven [lacuna] 40° C. Yield: 7.1 g (24.7 mmol, 83%).
Reaction SMILES: C([O:8][C:9](=[O:24])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C1C=CC=CC=1.[OH-].[Na+].[OH-].[K+]>>[CH2:17]([S:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([OH:24])=[O:8])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(OCc1ccccc1)c1ccccc1SCc1ccccc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccccc1SCc1ccccc1
Reaction time: 8 h

Procedure:
To a suspension of 2-benzylsulfanyl benzoic acid benzyl ester 2 (113 mg, 0.34 mmol) was added 1.6 mL of 1N NaOH. KOH (1 pellet) was added and the reaction was continued overnight. The acetone was removed and a small amount of water was added. The aqueous solution was washed with CH2Cl2(3). The aqueous phase was acidified until pH of 2–3 was reached then extracted with CH2Cl2(3X), dried with MgSO4 and filtered and concentrated to give a white solid.
Reaction SMILES: CS([N:5]1[C:9]([CH3:10])=[CH:8][C:7]([NH:11][C:12]2[N:13]=[C:14]([CH2:24]OS(C)(=O)=O)[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([O:22][CH3:23])=[CH:17][CH:16]=3)=[N:6]1)(=O)=O.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CCO>[CH3:23][O:22][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[C:14]([CH2:24][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[N:13][C:12]([NH:11][C:7]1[CH:8]=[C:9]([CH3:10])[NH:5][N:6]=1)=[CH:21]2
Reactant: C1CCNCC1
Reactant: COc1ccc2c(COS(C)(=O)=O)nc(Nc3cc(C)n(S(C)(=O)=O)n3)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(CN3CCCCC3)nc(Nc3cc(C)[nH]n3)cc2c1
Temperature: 120 °C
Yield: 12.5 %

Procedure:
A 2.0˜5.0 mL process vial was charged with 50 mg methanesulfonic acid 3-(1-methanesulfonyl-5-methyl-1H-pyrazol-3-ylamino)-6-methoxy-isoquinolin-1-ylmethyl ester, 50 mg piperidine, 75 mg K2CO3 in 3 mL THF/EtOH(1:1). The vial was heated at 120° C. for 30 min under microwave irradiation. After cooling, the reaction mixture was filtered through a short silica gel column, and the solvent was removed under reduced pressure. The residue in MeOH was sent to prep-HPLC to get 5 mg of (6-Methoxy-1-piperidin-1-ylmethyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine as a yellow solid. LC-MS m/e 352 (MH+).