Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:5]1[C:13]2[N:12]=[C:11]([CH2:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=4)[CH:18]=[N:17][CH:16]=3)[NH:10][C:9]=2[C:8](=[O:29])[N:7]([CH3:30])[C:6]1=[O:31])[CH:3]=[CH2:4].C(N(C(C)C)CC)(C)C.[OH-:41].[Na+].OO>C1COCC1>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[CH:18]=[N:17][CH:16]=[C:15]2[CH2:14][C:11]1[NH:10][C:9]2[C:8](=[O:29])[N:7]([CH3:30])[C:6](=[O:31])[N:5]([CH2:2][CH2:3][CH2:4][OH:41])[C:13]=2[N:12]=1
Reactant: C=CCn1c(=O)n(C)c(=O)c2[nH]c(Cc3cncc4cc(OC)c(OC)cc34)nc21
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2cncc(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CCCO)c2cc1OC
Temperature: 50 °C

Procedure:
A suspension of the product of Example 13, 3-allyl-8-(6,7-dimethoxy-isoquinolin4-ylmethyl)-1-methyl-3,7-dihydro-purine-2,6-dione hydrochloride salt (0.760 g, 1.87 mmol), 9-borabicyclo[2.2.0]nonane (0.5M THF solution, 18.7 ml, 9.35 mmol) and diisopropylethylamine (0.33 ml, 1.89 mmol) in THF (9 ml) is heated to reflux for 2.5 hours. Sodium hydroxide (4M aqueous solution, 6 ml) and hydrogen peroxide (27.5%, 3 ml) are added sequentially and the reaction heated at 50° C. for 1.5 hours. After evaporation, the crude product is purified by flash chromatography (19:1 CH2Cl2:-methanol elution) and triturated with water to afford 8-(6,7-dimethoxy-isoquinolin4-ylmethyl)-3-(3-hydroxy-propyl)-1-methyl-3,7-dihydro-purine-2,6-dione, [MH]+ 426.
Reaction SMILES: [CH3:1][C:2]([OH:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]1.[NH2-].[Na+].C1C=CC=CC=1>O>[CH2:28]([O:27][C:25]([N:22]1[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][O:15][C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:1])[CH2:24][CH2:23]1)=[O:26])[CH3:29]
Reactant: CC(O)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)N1CCN(CCCl)CC1
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)N1CCN(CCOC(C)(c2ccccc2)c2ccccc2)CC1
Yield: 71.8 %

Procedure:
A mixture of 1.8 g (9.1 mmole) of α-methylbenzhydrol, 2.0 g (9.1 mmole) of 1-(2-chloroethyl)-4-(ethoxycarbonyl)piperazine, 0.36 g (9.2 mmole) of sodium amide and 20 ml of benzene was heated under reflux overnight. At the end of this time, water was poured onto the reation mixture, and the mixture was extracted with ethyl acetate. The solvent was then removed from the mixture by distillation under reduced pressure, and the residue was subjected to column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, to obtain 2.5 g (yield 75%) of the title compound as an oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([F:23])[CH:17]=1)[C:12]([OH:14])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:24](Br)[CH:25]=[CH2:26]>CN(C=O)C>[CH2:26]([O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C@@H:11]([NH:10][C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[C:12]([OH:14])=[O:13])=[CH:17][C:18]=1[F:23])[CH:25]=[CH2:24]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(O)c(F)c1)C(=O)O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.3 %

Procedure:
1.18 g (60%, 29.39 mmol) of sodium hydride were added to a solution of 4.0 g (13.36 mmol) of (R)-2-tert-butoxycarbonylamino-3-(3-fluoro-4-hydroxyphenyl)propionic acid in 23 ml of DMF while stirring at 0° C., and the mixture was stirred at this temperature. After 15 min, 1.27 ml (1.78 g, 14.7 mmol) of allyl bromide were added, and stirring was continued for 1 h while the mixture reached RT. It was quenched with methanol and, after cooling, excess methanol was removed in a rotary evaporator. Dilution with diethyl ether was followed by acidification with 1N hydrochloric acid, and the aqueous phase was extracted twice more with diethyl ether, and the combined organic phases were washed with saturated sodium chloride solution, dried over NaSO4, filtered and concentrated. 4.50 g of a yellowish oil were obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[CH:8]1([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[CH:28]=[N:27][CH:26]=[CH:25][C:21]=3[C:22](O)=[O:23])=[O:18])[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1>>[O:7]=[C:2]1[NH:1][CH2:6][CH2:5][N:4]([C:22]([C:21]2[CH:25]=[CH:26][N:27]=[CH:28][C:20]=2[NH:19][C:17]([C:15]2[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=[C:11]([CH:8]3[CH2:10][CH2:9]3)[N:16]=2)=[O:18])=[O:23])[CH2:3]1
Reactant: O=C1CNCCN1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: O=C1CN(C(=O)c2ccncc2NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)CCN1
Yield: 14 %

Procedure:
According to the general method described in step 3 of example 53, reaction of piperazine-2-one with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (14%) as amorphous light yellow solid.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:8](=[O:10])[CH3:9])\[C:5]([OH:7])=[O:6].[BrH:11].BrBr>C(O)(=O)C.ClCCl>[Br:11][CH2:9][C:8](=[O:10])/[C:4](=[N:3]/[O:2][CH3:1])/[C:5]([OH:7])=[O:6]
Reactant: Br
Reactant: CO/N=C(/C(C)=O)C(=O)O
Agent: BrBr
Solvent: ClCCl
Solvent: CC(=O)O
Product: CO/N=C(\C(=O)O)C(=O)CBr

Procedure:
145 g of (Z)-2-methoxyimino-3-oxo-butyric acid are dissolved in 1000 ml of alcohol-free anhydrous dichloromethane. 10 ml of 30% hydrobromic acid in glacial acetic acid are added to this solution. Then, a solution of 37.5 ml of bromine in 112.5 ml of dichloromethane are added dropwise during about 2 hours, the temperature of the mixture being held at 20°-25° C. by means of slight cooling. Now, in order to remove hydrogen bromide from the mixture, nitrogen is vigorously blown through. Subsequently, 250 g of ice, 250 ml of water and 2 l of ether are successively added. The aqueous phase is separated and discarded. The organic phase is washed with 250 ml of water and 250 ml of saturated sodium chloride solution, dried with sodium sulphate and evaporated in vacuo. There remains a brown oil which is crystallized from carbon tetrachloride. There is obtained almost colourless (Z)-4-bromo-2-methoxyimino-3-oxo-butyric acid.
Reaction SMILES: [CH2:1]([C:4]1[C:5]2[CH:6]=[CH:7][C:8]([O:27][CH3:28])=[C:9]([O:25][CH3:26])[C:10]=2[CH2:11][NH+:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]4[O:24][CH2:23][O:22][C:17]=4[CH:18]=3)[C:13]=12)[CH:2]=[CH2:3].[Br-].[C:30]([Mg]Br)([CH3:32])=[CH2:31].O1CCCC1>C(OCC)C>[CH2:1]([C:4]1[C:5]2[CH:6]=[CH:7][C:8]([O:27][CH3:28])=[C:9]([O:25][CH3:26])[C:10]=2[CH:11]([C:30]([CH3:32])=[CH2:31])[N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]4[O:24][CH2:23][O:22][C:17]=4[CH:18]=3)[C:13]=12)[CH:2]=[CH2:3]
Reactant: C=C(C)[Mg]Br
Reactant: C=CCC1=C2c3cc4c(cc3CC[NH+]2Cc2c1ccc(OC)c2OC)OCO4
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCC1=C2c3cc4c(cc3CCN2C(C(=C)C)c2c1ccc(OC)c2OC)OCO4
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a suspension of 13-allyl-9,10-dimethoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; bromide (300 mg, 0.66 mmol) in anhydrous diethyl ether (20 mL) at 0° C. was added a solution of isopropenylmagnesium bromide in tetrahydrofuran (0.5 M, 20 mL, 10 mmol) dropwise. After stirring at 0° C. for 30 min, the reaction was quenched by adding saturated aqueous ammonium chloride solution (50 mL). The mixture was extracted with diethyl ether (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 13-allyl-8-isopropenyl-9,10-dimethoxy-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (75 mg, 27%). LC/MS m/e calcd for C26H27NO4 (M+H)+: 418.51, observed: 418.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (s, 3 H) 2.64-2.80 (m, 2 H) 2.97-3.06 (m, 1 H) 3.18-3.25 (m, 1 H) 3.72 (s, 3 H) 3.79 (s, 3 H) 4.63 (s, 1 H) 4.73 (s, 1 H) 5.06-5.18 (m, 3 H) 6.02 (s, 2 H) 6.05-6.15 (m, 1 H) 6.81 (m, 1 H) 6.86 (s, 1 H) 6.91 (m, 1 H) 6.98 (s, 1 H).
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:12][S:13](Cl)(=[O:15])=[O:14].[NH4+].[Cl-]>ClCCl>[I:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[N:4]([S:13]([CH3:12])(=[O:15])=[O:14])[S:13]([CH3:12])(=[O:15])=[O:14]
Reactant: Nc1ccc([N+](=O)[O-])cc1I
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CS(=O)(=O)N(c1ccc([N+](=O)[O-])cc1I)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-iodo-4-nitroaniline (1.02 g, 3.86 mmol) in dichloromethane (10 ml), has been added under stirring triethylamine (1.77 ml, 12.7 mmol). To this mixture, a solution of methanesulphonyl chloride (0.98 ml, 12.7 mmol) in dichloromethane (2 ml) has been added dropwise, very slowly and in an ice-bath. The mixture so obtained was left under stirring at room temperature overnight. The day after, the reaction mixture was neutralized with a saturated aqueous solution of NH4Cl. The organic phase was separated, and, after evaporation of the solvent, the residue has been washed with ethanol and filtered to give N-(2-iodo-4-nitrophenyl)-N-(methylsulfonyl)-methanesulfonamide as yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[NH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][C:20]#[N:21]>C(#N)C.O>[C:20]([CH2:19][C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[C:10]([NH:9][C:7]([NH:6][C:4](=[O:5])[O:3][CH2:1][CH3:2])=[S:8])[CH:11]=2)[NH:15][CH:14]=1)#[N:21]
Reactant: N#CCc1c[nH]c2ccc(N)cc12
Reactant: CCOC(=O)N=C=S
Solvent: CC#N
Solvent: O
Product: CCOC(=O)NC(=S)Nc1ccc2[nH]cc(CC#N)c2c1
Reaction time: 0.33 h

Procedure:
Ethoxycarbonyl isothiocyanate (1.2 ml) was added dropwise to a stirred solution of 5-amino-1H-indole-3-acetonitrile (1.7 g) in dry acetonitrile (50 ml). After 10 min. the resulting suspension was diluted with water (40 ml) and stirred for 20 min.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=1[Cl:36])[CH2:4][NH:5][C:6](=[O:28])[CH2:7][N:8]1[C:12](=[O:13])[N:11]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[N:9]1.[O-:37][C:38]#[N:39].[K+]>>[C:38]([NH:2][CH:3]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=1[Cl:36])[CH2:4][NH:5][C:6](=[O:28])[CH2:7][N:8]1[C:12](=[O:13])[N:11]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:17])[F:19])[C:10]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[N:9]1)(=[O:37])[NH2:39]
Reactant: N#C[O-]
Reactant: NC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(Cl)c1Cl
Agent: Cl
Agent: [K+]
Product: NC(=O)NC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(Cl)c1Cl

Procedure:
Analogously to Example 23, 30 mg (51 μmol) of the compound of Example 55A and potassium cyanate gave 19 mg (63% of theory) of the title compound.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Br[C:10]1[S:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:14]=1.[OH-].[Na+]>C(OCC)(=O)C.O1CCCC1>[F:3][C:4]([F:8])([F:7])[CH2:5][O:6][C:10]1[S:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:14]=1
Reactant: COC(=O)c1cnc(Br)s1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cnc(OCC(F)(F)F)s1
Yield: 79 %

Procedure:
To a tetrahydrofuran solution (5.0 mL) of sodium hydride (465 mg, 11.6 mmol) and 2,2,2-trifluoroethanol (1.70 mL, 23.3 mmol), methyl 2-bromothiazole-5-carboxylate (517 mg, 2.33 mmol) was added and the resultant mixture was stirred at room temperature for 2 hours. After completion of the reaction, 1 M sodium hydroxide aqueous solution was added to the reaction solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product of the title compound (444 mg).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][C:19]([CH2:23][NH:24][S:25]([C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=3)(=[O:27])=[O:26])=[CH:20][CH:21]=2)[CH:16]=[N:15]1>>[Cl:8][C:7]1[C:2]([N:24]([CH2:23][C:19]2[CH:18]=[C:17]3[C:22](=[CH:21][CH:20]=2)[N:14]([CH3:13])[N:15]=[CH:16]3)[S:25]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:36][CH:37]=2)(=[O:27])=[O:26])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(cnn3C)c2)cc1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(cnn3C)c2)c2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 4-(N-((1-methyl-1H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-1 of Example 3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]12[CH2:13][CH2:12]1.C([O-])(=O)C.[Na+].[Br:19]Br>C(Cl)Cl.CCOCC>[Br:19][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([F:1])[CH:3]=1)[NH:9][C:8](=[O:11])[C:7]12[CH2:13][CH2:12]1
Reactant: BrBr
Reactant: O=C1Nc2c(F)cccc2C12CC2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1Nc2c(F)cc(Br)cc2C12CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
7′-Fluorospiro[cyclopropane-1,3′-indol]-2′(1′H)-one (0.54 g, 3.05 mmol) was dissolved in 20 mL of CH2Cl2 and sodium acetate (0.28 g, 3.36 mmol) was added followed by bromine (0.173 mL, 3.36 mmol). The mixture was stirred at 25° C. for 16 h then diluted with ether and washed with Na2S3O3, sodium bicarbonate, water, brine, dried over MgSO4, and concentrated. Purification by flash chromatography (15% acetone/hexane) afforded 5′-Bromo-7′-fluorospiro[cyclopropane-1,3′-indol]-2′(1′H)-one (0.64 g, 82%) as a white solid:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([N+:32]([O-])=O)=[C:7]([CH:31]=1)[C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:9].Cl.O>[Fe].CCO>[NH2:32][C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:31][C:7]=1[C:8]([NH:10][CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:16][CH2:17]1)=[O:9]
Reactant: CSc1ccc([N+](=O)[O-])c(C(=O)NCC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CSc1ccc(N)c(C(=O)NCC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Step 2): A mixture of 5-methylthio-2-nitro-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide (500 mg, 1.05 mmol), Fe powder (587 mg, 1.05 mmol), conc. HCl (0.05 ml), H2O (8 ml) and EtOH (35 ml) was refluxed overnight. The insoluble precipitates were filtered off and then the filtrate was evaporated to give 2-amino-5-methylthio-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide as colorless powder, 450 mg (96%): mp 156°-157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC1C=C(N=C=S)C=C(Cl)C=1C#N.O=[C:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1.C(O)(=O)C>CO>[C:39]([O:38][C:36]([N:33]1[CH2:34][CH2:35][CH:30]([NH:15][C:13]2[NH:12][N:11]=[C:10]([NH:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:14]=2)[CH2:31][CH2:32]1)=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: N#Cc1c(Cl)cc(N=C=S)cc1Cl
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a stirred solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (122 mg, 0.5 mmol) in 10 ml of methanol, tert-butyl 4-oxopiperidine-1-carboxylate (102 mg, 0.512 mmol), was added acetic acid (0.05 mL). The mixture was stirred at rt for 15 min, after which picolineborane (112 mg, 1.047 mmol) was added. The mixture was stirred at rt overnight. LCMS indicated 87% product and 13% SM. Additional picolineborane (50 mg, 0.467 mmol) was added and the mixture was stirred for an additional 24 hours. The solvent was removed under reduced pressure and the residue was dissolved in methylene chloride and treated with saturated sodium bicarbonate to pH=9. The organic layer was separated and the aqueous layer was extracted with methylene chloride (3×10 mL). The solvent was reduced to about 4 mL and the residue was loaded onto a silica gel column. Eluting with 5% methanol/methylene chloride gave 188 mg (88%) of desired product as white solid. MS +m/z: 427.0 (M+H)+
Reaction SMILES: C([S@@]([N:7]=[CH:8][CH2:9][CH2:10][C:11]([CH3:23])([CH3:22])[C:12](OCC1C=CC=CC=1)=[O:13])=O)(C)(C)C.[F:24][C:25]1[CH:26]=[C:27]([Mg]Br)[CH:28]=[CH:29][C:30]=1[CH3:31]>C1(C)C=CC=CC=1.C1COCC1>[F:24][C:25]1[CH:26]=[C:27]([C@H:8]2[NH:7][C:12](=[O:13])[C:11]([CH3:23])([CH3:22])[CH2:10][CH2:9]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: Cc1ccc([Mg]Br)cc1F
Reactant: CC(C)(CCC=N[S@@](=O)C(C)(C)C)C(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc([C@@H]2CCC(C)(C)C(=O)N2)cc1F
Temperature: 25 °C

Procedure:
To a stirred solution of benzyl (Ss)-5-[(tert-butylsulfinyl)imino]-2,2-dimethylpentanoate (1.00 g, 2.96 mmol, described in Intermediate 3) in toluene (28 mL) at −78° C. was added 3-fluoro-4-methylphenylmagnesium bromide (11.9 mL of a 0.5 M solution in THF, 5.93 mmol). The reaction mixture was warmed to ambient temperature for 2 h, and then heated at reflux for 2 h. The solvent was removed in vacuo and the crude solid dissolved in DMSO (5 mL). The crude product was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=236 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[C:15]([CH2:16][CH2:17][NH2:18])=[C:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[O:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27].C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([C:3]1[C:15]([CH2:16][CH2:17][NH:18][C:26](=[O:28])[CH3:27])=[C:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[O:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCc1nn2ccc3oc(C)cc3c2c1CCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1nn2ccc3oc(C)cc3c2c1CCNC(C)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.9 %

Procedure:
To a solution of 2-(2-ethyl-8-methylfuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl)ethanamine (100 mg, 0.411 mmol) and triethylamine (85.9 μL, 0.616 mmol) in tetrahydrofuran (4 mL) was added acetyl chloride (58.3 μL, 0.617 mmol) under ice-cooling, and the mixture was stirred at room temperature for 10 min. A saturated aqueous sodium hydrogen carbonate solution (100 μL) was added and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) and recrystallization (ethyl acetate/hexane) to give the title compound (59.7 mg, yield 51%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[N:22]12[CH2:32][CH2:31][CH2:30][N:29]=[C:28]1[CH2:27]CC[CH2:24][CH2:23]2.C(NCC1CCNC1)C>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11]([N:29]4[CH2:28][CH2:27][CH:31]([CH2:32][NH:22][CH2:23][CH3:24])[CH2:30]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: C1CCC2=NCCCN2CC1
Agent: CCNCC1CCNC1
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Temperature: 60 °C
Reaction time: 18 h
Yield: 83.3 %

Procedure:
To 1.0 g (3.32 mmol) of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 9 ml of acetonitrile was added 0.5 g (one equivalent) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 0.42 g of N-ethyl-3-pyrrolidinemethanamine in 3 ml additional acetonitrile. The mixture was heated at 60° C. for four hours and stirred at 25° C. for 18 hours. The mixture was filtered and the solids washed with diethyl ether to give 1.12 g of the title compound, mp 247°-248° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[S:7][C:6]=2[CH:11]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16]([N:20]=[C:21]=[O:22])[CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>C(C(C)=O)C>[F:12][C:13]([F:23])([F:24])[C:14]1[CH:15]=[C:16]([NH:20][C:21]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8](=[O:10])[S:7][C:6]=3[CH:11]=2)=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: O=c1oc2ccc(O)cc2s1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(C(F)(F)F)c1)Oc1ccc2oc(=O)sc2c1

Procedure:
5-hydroxy-1,3-benzoxathiol-2-one (16.8 grams) was mixed with 3-(trifluoromethyl)phenyl isocyanate (18.7 grams) and 1.01 grams of triethylamine in 200 milliliters of methyl ethyl ketone. This solution was heated at reflux temperature for one hour, after which the solvent was removed by evaporation in vacuo. The resulting residue was recrystallized twice from ethyl acetate, leaving the desired purified product, 5-[3-(trifluoromethyl)phenylcarbamoyloxy]-1,3-benzoxathiol-2-one. The product was a white crystalline solid which exhibited a melting point of 166.5°-168° C. Elemental analysis calculated for C15H8F3NO4S (percent): carbon--50.71; hydrogen--2.27; nitrogen--3.94. Found: carbon--51.0; hydrogen--2.29; nitrogen--4.11.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)([OH:3])=[O:2].FC(F)(F)C(O)=O.[N+:22]([O-])([OH:24])=[O:23]>>[C:1]([CH2:4][CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:22]([O-:24])=[O:23])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)([OH:3])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)CCC1CCc2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC1CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-carboxyethylindane (28.8 g, 0.15 mol) and trifluoroacetic acid (300 mL) was cooled in an ice bath and then treated with fuming nitric acid (50 mL). The reaction mixture was slowly warmed to room temperature and allowed to stir for 18 h. After removing the solvent, the residue was dissolved in an either:water mixture. The ether layer was separated and washed with water, and then saturated NaCl, and dried over magnesium sulfate. The filtrate was evaporated to give a dark syrup (34.3 gm, 3:1 ratio of isomers).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.CN([C:15]([O:19][N:20]1N=NC2C=CC=N[C:21]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.CONC>CN(C=O)C>[CH3:15][O:19][N:20]([CH3:21])[C:9]([C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([Br:8])[N:4]=1)=[O:11]
Reactant: Nc1ncc(Br)nc1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-amino-6-bromo-pyrazine-2-carboxylic acid (0.62 g, 2.8 mmol), HATU (1.3 g, 3.4 mmol) and di-isopropylethylamine (1.72 ml, 3.5 mmol) in DMF (20 ml) is stirred at room temperature for 5 minutes. N-Methoxy-N-methylamine hydrochloride (0.33 g, 3.4 mmol) is added and the reaction is stirred at room temperature for 2 hours. The solvent is concentrated in vacuo and the residue dissolved in EtOAc (30 ml), and washed with sat. aq. NaHCO3 (20 ml), 0.1N HCl (20 ml), dried (MgSO4) and concentrated in vacuo to yield a brown oil. Purification by flash chromatography (SiO2, 30% EtOAc in iso-hexane) yields 3-amino-6-bromo-pyrazine-2-carboxylic acid methoxy-methyl-amide as a yellow solid [M+H]+ 261.