Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:36])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:33](O)=[O:34])[CH:32]=2)[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][NH2:45])=[CH:40][CH:39]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:36])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:33](=[O:34])[NH:45][CH2:44][C:41]3[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=3)[CH:32]=2)[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)O)nn2c1-c1cc(F)c2c(c1C)CCCO2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)NCc3ccc(F)cc3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.6 %

Procedure:
To a mixture of 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (21 mg, 0.042 mmol) and (4-fluorophenyl)methanamine (10.52 mg, 0.084 mmol) in DMF (1 mL) was added DIEA (0.037 mL, 0.210 mmol), HATU (32.0 mg, 0.084 mmol) and DMAP (1.027 mg, 8.41 μmol) and the resulting mixture was stirred at rt for 16 h. At this point LCMS indicated completion of reaction. The reaction mixture was then filtered and purified by prep HPLC to afford (2S)-ethyl 2-(tert-butoxy)-2-(7-(8-fluoro-5-methylchroman-6-yl)-2-((4-fluorobenzyl)carbamoyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (12 mg, 0.020 mmol, 47.1% yield) as off-white solid. 1H NMR (500 MHz, CDCl3) δ: 7.34-7.30 (m, 2H), 7.23 (t, J=6.4 Hz, 1H), 7.20 (s, 1H), 7.06-6.99 (m, 2H), 6.85 (d, J=10.7 Hz, 1H), 4.96 (s, 1H), 4.67-4.53 (m, 2H), 4.35 (t, J=5.3 Hz, 2H), 4.15 (q, J=7.0 Hz, 2H), 2.79 (s, 3H), 2.76 (t, J=6.6 Hz, 2H), 2.24-2.14 (m, 2H), 1.82 (s, 3H), 1.21 (t, J=7.2 Hz, 3H), 1.17 (s, 9H). LCMS (M+H)=607.4.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][C@@H:7]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH2:6][N:5]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15])(=[O:3])[NH2:2].CO[CH:29](OC)[N:30]([CH3:32])[CH3:31].C(OCC)(=O)C>ClCCl>[CH3:13][S:10]([O:9][C@H:7]1[CH2:6][N:5]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:4]([C:1](=[O:3])[N:2]=[CH:29][N:30]([CH3:32])[CH3:31])[CH2:8]1)(=[O:11])=[O:12]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: COC(OC)N(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)C=NC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To (2S,4R)-2-carbamoyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (3 g) was added N,N-dimethylformamide dimethylacetal (3 ml) and the mixture was stirred at 120° C. for 1 hour. The mixture was poured into a mixture of ethyl acetate and dichloromethane, washed with water and brine successively, and evaporated in vacuo to give (2S,4R)-4-methanesulfonyloxy-2-[N-(N,N-dimethylaminomethylene)carbamoyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine. The compound obtained above was dissolved in acetic acid (30 ml) and to this solution was added hydrazine hydrate (0.36 ml) at room temperature. After stirring at the same temperature for 2 hours, the mixture was poured into water and ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine successively, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was subjected to a column chromatography on silica gel (90 g) eluting with a mixture of methanol and dichloromethane (1:20 V/V) to give (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-(1H-1,2,4-triazol-3-yl)pyrrolidine (1.5 g).
Reaction SMILES: Br[C:2]1[N:3]=[N:4][C:5]([CH2:8][CH3:9])=[CH:6][CH:7]=1.[NH:10]1[CH2:20][CH2:19][CH:13]([C:14](OCC)=[O:15])[CH2:12][CH2:11]1.C(N(C(C)C)CC)(C)C.CN1CCCC1>O>[CH2:8]([C:5]1[N:4]=[N:3][C:2]([N:10]2[CH2:20][CH2:19][CH:13]([CH2:14][OH:15])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1)[CH3:9]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCc1ccc(Br)nn1
Agent: CN1CCCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(N2CCC(CO)CC2)nn1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
1.67 g (0.011 mol) of 3-bromo-6-ethylpyridazine was added to 1.5 mL (10 mmol) ethyl isonipecotate and 3.5 mL (20 mmol) diisopropylethylamine and 5 mL N methylpyrrolidine (NMP). This mixture was heated to 140° C. for 4 hours. Upon cooling 100 mL of water was added to the mixture and the contents were extracted with methylene chloride then washed twice with water and once with brine and the solvent evaporated in vacuo. The resulting oil was eluted through a short silica gel plug with 80% ethyl acetate and 20% hexanes and dried in vacuo. This intermediate was taken up in 25 mL THF and was exposed to 3-fold excess lithium aluminum hydride with stirring under nitrogen for 1 hour. The reaction was chilled on ice and quenched by dropwise addition of water. The slurry was dried, treated with charcoal and filtered yielding 6-ethyl-3-(4-hydroxymethyl-1-piperidinyl)pyridazine (Formula IV: R1 =C2H5 ; Y=CH2 ).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([OH:11])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.[C:15](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N+:12]([O-:14])=[O:13])[C:6]([O:11][CH3:15])=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1cc(O)c([N+](=O)[O-])cc1OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(OC)c([N+](=O)[O-])cc1OC
Temperature: 77.5 °C
Yield: 56.3 %

Procedure:
A mixture of 4,5-dimethoxy-2-nitro-phenol (2.00 g, 10 mmol), potassium carbonate (2.76 g, 20 mmol) and iodomethane (0.75 mL, 12 mmol) in DMF was placed in a sealed tube and heated at 75-80° C. for 20 h. The reaction was cooled and was filtered through Celite, washing with ethyl acetate. The filtrate was washed with water (the first wash was back-extracted with ethyl acetate), sodium bicarbonate and brine, was dried (sodium sulfate) and was evaporated. Purification by flash chromatography (SiO2) eluted with 1:1 ethyl acetate:hexanes provided 1,2,4-trimethoxy-5-nitro-benzene (1.20 g, 57% yield) as a yellow solid. 1H-NMR (CDCl3, 500 MHz) 7.53 (s, 1H), 6.50 (s, 1H), 3.92 (s, 3H), 3.91 (s, 3H), 3.84 (s, 3H) ppm; MS (FIA) 214.1 (M+H); HPLC (Method A) 3.253 min.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[NH:9][C:10](=[O:30])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[N:12]=1)C1C=CC=CC=1.C(OCC)(=O)C.[H][H]>[Pd].CO>[CH3:18][O:17][C:15]1[CH:14]=[C:13]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=2)[N:12]=[C:11]([C:10]([NH:9][NH2:8])=[O:30])[CH:16]=1
Reactant: [H][H]
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN(Cc2ccccc2)Cc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN)c1

Procedure:
4-methoxy-6-[3-(trifluoromethyl)phenoxy] picolinic acid, N',N'-dibenzyl hydrazide (7.38 g, 0.0145 mol) was mixed with a mixed solution of ethyl acetate (about 50 ml) and methanol (about 50 ml), and further with 10% palladium/carbon (1.0 g, 0.0145×0.065 mol) in a hydrogen atmosphere. The resultant mixture was stirred at a temperature of 50 to 60° C. for about 5 hours. The obtained reaction solution was filtered and concentrated, thereby obtaining an aimed product.
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([I:32])[CH:29]=[CH:28][C:3]=1[NH:4][C:5]1[C:6]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])=[O:22])=[CH:7][N:8]([CH2:12][CH2:13][O:14]C2CCCCO2)[C:9](=[O:11])[CH:10]=1.Cl.O1CCCCC1OC1CCCCO1>CCO>[F:1][C:2]1[CH:31]=[C:30]([I:32])[CH:29]=[CH:28][C:3]=1[NH:4][C:5]1[C:6]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])=[O:22])=[CH:7][N:8]([CH2:12][CH2:13][OH:14])[C:9](=[O:11])[CH:10]=1
Reactant: O=C(NCCCO)c1cn(CCOC2CCCCO2)c(=O)cc1Nc1ccc(I)cc1F
Agent: C1CCC(OC2CCCCO2)OC1
Agent: Cl
Solvent: CCO
Product: O=C(NCCCO)c1cn(CCO)c(=O)cc1Nc1ccc(I)cc1F

Procedure:
4-(2-Fluoro-4-iodoanilino)-N-(3-hydroxypropyl)-6-oxo-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,6-dihydro-3-pyridinecarboxamide was dissolved in EtOH and treated with 1 M HCl, as for example 22, step D, deprotecting the tetrahydropyranyl ether to give 4-(2-fluoro-4-iodoanilino)-1-(2-hydroxyethyl)-N-(3-hydroxypropyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a white solid which was recrystallised from EtOAc/MeOH (97%), m.p. (EtOAc/MeOH) 174-176° C. 1H NMR [(CD3)2SO, 400 MHz] δ 10.18 (s, 1H), 8.43 (t, J=5.4 Hz, 1H), 8.17 (s, 1H), 7.74 (dd, J=10.2, 1.8 Hz, 1H), 7.57 (br d, J=8.4 Hz, 1H), 7.28 (t, J=8.5 Hz, 1H), 5.57 (s, 1H), 4.93 (t, J=5.4 Hz, 1H), 4.50 (t, J=5.1 Hz, 1H), 3.86 (t, J=5.6 Hz, 2H), 3.60 (q, J=5.5 Hz, 2H), 3.46 (q, J=5.7 Hz, 2H), 3.31-3.23 (m, 2H), 1.66 (pentet, J=6.7 Hz, 2H). Anal. Calcd for C17H19FIN3O4: C, 43.0; H, 4.0; N, 8.8. Found: C, 43.3; H, 3.8; N, 8.9.
Reaction SMILES: Cl.[OH-:2].[Na+].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10](Cl)=[O:11]>CC(C)=O.O>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([OH:2])=[O:11]
Reactant: [OH-]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)O
Reaction time: 1 h

Procedure:
2.5 g of hydrochloride were dissolved in 25 ml of acetone and 0.8 g of NaOH in 20 ml of water. To this solution, there were added 2 g of 5-chloro-2-methoxy-benzoyl chloride in 20 ml of acetone and the whole was stirred for 1 hour. Then, water and dilute hydrochloric acid were added and the product was recrystallized from methanol. The 4-(2-<5-chloro-2-methoxy-benzamido>-ethyl)-5-chloro-2-methoxy-benzoic acid so obtained was found to melt at 171°-173° C.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:11](OC(=O)C)(=[O:13])[CH3:12]>COC1C=CC(C2OC(C3C=CC(OC)=C(OC)C=3)CCC2)=CC=1OC>[C:11]([O:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([OH:10])=[O:9])(=[O:13])[CH3:12]
Reactant: O=C(O)c1ccccc1O
Reactant: CC(=O)OC(C)=O
Agent: COc1ccc(C2CCCC(c3ccc(OC)c(OC)c3)O2)cc1OC
Product: CC(=O)Oc1ccccc1C(=O)O
Temperature: 100 °C

Procedure:
0.0072 moles of salicylic acid and 0.029 moles acetic anhydride (molar ratio=1:4) were taken in a 20 ml reaction vessel of reaction station. Nano-crystalline sulfated zirconia catalyst (SZ-1), activated at 450° C. in static air with salicylic acid to catalyst weight ratio 10:1, was added and the mixture was heated at 100° C. for 30 minutes. The reaction mixture was filtered to separate the catalyst. The acetyl salicylic acid was crystallized from the reaction mixture. The crude yield of acetyl salicylic acid was 73%. It was further re-crystallized with ethanol-water to obtain pure crystals of acetyl salicylic acid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32])[CH2:19]P(=O)(OCC)OCC.[H-].[Na+].O>O1CCCC1>[F:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32])[CH:19]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(F)c1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccc([N+](=O)[O-])c(F)c2)CC1
Reaction time: 4 h
Yield: 64.8 %

Procedure:
tert-Butyl 4-oxopiperidine-1-carboxylate (126 mmol, 25.04 g) and diethyl 3-fluoro-4-nitrobenzylphosphonate (126 mmol, 36.6 g) in tetrahydrofuran (220 mL) were stirred and sodium hydride (163 mmol, 6.54 g, 60% in oil) was added. The reaction was stirred for 4 hours and then water was added. The reaction was extracted with dichloromethane and the organics were dried (magnesium sulfate), filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with dichloromethane to give a bright yellow solid. This solid was filtered, washed with heptane and vacuum dried to afford the title compound (27.47 g). 1H NMR (CDCl3, 400 MHz): δ 8.1 (t, 1H), 7.1 (s, 1H), 7.05 (s, 1H), 6.35 (s, 1H), 3.55 (m, 2H), 3.45 (m, 2H), 2.52 (m, 2H), 2.4 (m, 2H), 1.49 (s, 9H)
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH:14]=[O:15])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al]([C:21]#[N:22])(CC)CC>C1COCC1>[OH:15][CH:14]([CH:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1)[C:21]#[N:22]
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Reactant: CC[Al](C#N)CC
Solvent: C1CCOC1
Product: N#CC(O)C1CCN(Cc2ccccc2)CC1
Reaction time: 1 h

Procedure:
To a solution of 1-(phenylmethyl)-4-piperidinecarbaldehyde (2.35 g, 11.6 mmol)[prepared according to Alfaro-Lopez, J.; et al. J. Med. Chem. 1999, 42, 5359] in THF (160 mL) at 0° C. was added dropwise Et2AlCN (25 mL, 1 M solution in toluene). After 1 h, the solution was partitioned between NaHCO3(sat)-DCM. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried (Na2SO4) and concentrated yielding the title compound as a yellow oil which was used directly without further purification: LCMS (ES) m/e 249 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]cnc2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc2cc(Br)cnc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-bromo-3H-imidazo[4,5-b]pyridine (1.0 g) in THF (20 mL) at 0° C. was added sodium hydride (187 mg) and the reaction stirred at 0° C. for 1 h. Then, 2-(trimethylsilyl)ethoxymethyl chloride (0.94 mL) was added and the reaction stirred at room temperature for 16 h. The reaction was quenched with water (20 mL) and extracted into ethyl acetate (2×20 mL). The combined organics were washed with aqueous brine solution (2×20 mL), dried (MgSO4), reduced in vacuo and purified by column chromatography to give 6-bromo-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridine.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[C:8]([C:18]([OH:21])([CH3:20])[CH3:19])[N:9]2C2CCCCO2)=[C:5]([Cl:22])[N:4]=1>C(Cl)Cl.CO>[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[C:8]([C:18]([OH:21])([CH3:20])[CH3:19])[NH:9]2)=[C:5]([Cl:22])[N:4]=1
Reactant: CC(C)(O)c1nc2c(Cl)nc(Cl)nc2n1C1CCCCO1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC(C)(O)c1nc2c(Cl)nc(Cl)nc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
HCl (5 mL, 5 mmol, 1 M aqueous solution) was added to a solution of 2-[2,6-dichloro-9-(tetrahydro-pyran-2-yl)-9H-purin-8-yl]-propan-2-ol (6.0 g, 20.66 mmol) in a mixture of DCM (15 mL) and methanol (15 mL) and the resulting solution stirred at RT for 1 h, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0 to 50% methanol in DCM) affording 2-(2,6-Dichloro-9H-purin-8-yl)-propan-2-ol as a dark solid (3.38 g, 66%). LCMS (method A): RT=2.12 min, [M−H]=245/247. 1H NMR (400 MHz, CDCl3): δ 1.50 (6H, s)
Reaction SMILES: [C:1]12([C:11]([S:13]C)=S)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O.[NH2:16][NH2:17]>CO>[C:1]12([C:11]([NH:16][NH2:17])=[S:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: NN
Reactant: CSC(=S)C12CC3CC(CC(C3)C1)C2
Solvent: CO
Solvent: O
Product: NNC(=S)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A solution of the product of step (a) (1 g) in methanol (50 ml) was treated with hydrazine hydrate (0.3 g) and the mixture stirred at room temperature for 1 hour. The solvent was evaporated, the residue triturated with water, and the pH adjusted to 7 to give the sub-title product (0.8 g) as a white solid.
Reaction SMILES: N1C=CC=CC=1.[C:7](OC(=O)C)(=[O:9])[CH3:8].[NH2:14][C:15]1[C:19]2[CH:20]=[C:21]3[C:34](=[C:35]([F:36])[C:18]=2[O:17][N:16]=1)[N:33]1[CH2:37][C@@H:38]([CH3:42])[O:39][C@@H:40]([CH3:41])[C@@H:32]1[C:23]1([C:28](=[O:29])[NH:27][C:26](=[O:30])[NH:25][C:24]1=[O:31])[CH2:22]3>C(Cl)CCl>[F:36][C:35]1[C:18]2[O:17][N:16]=[C:15]([NH:14][C:7](=[O:9])[CH3:8])[C:19]=2[CH:20]=[C:21]2[C:34]=1[N:33]1[CH2:37][C@@H:38]([CH3:42])[O:39][C@@H:40]([CH3:41])[C@@H:32]1[C:23]1([C:28](=[O:29])[NH:27][C:26](=[O:30])[NH:25][C:24]1=[O:31])[CH2:22]2
Reactant: C[C@@H]1CN2c3c(cc4c(N)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1noc2c(F)c3c(cc12)CC1(C(=O)NC(=O)NC1=O)[C@H]1[C@H](C)O[C@H](C)CN31
Temperature: 130 °C
Reaction time: 12 h

Procedure:
Pyridine (0.01 mL, 0.2 mmol) and acetic anhydride (0.10 mL, 0.14 mmol) were added sequentially to a solution of (2R,4S,4aS)-rel-8-amino-11-fluoro-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione (Example 1, 54 mg, 0.13 mmol) in ethylene dichloride, and the mixture was stirred at 130° C. for 12 hours. After cooling to room temperature, solvent was removed, and the residue was purified over a silica gel flash column using a gradient of methanol in chloroform to give the title compound as a racemic mixture in the form of a yellow solid. Yield: 7.5 mg, (13%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[C:8]([C:12]([OH:14])=O)=[CH:7][NH:6][C:5]=2[S:4][N:3]=1.[C:15]([C:19]1[C:27]2[C:22](=[CH:23][C:24]([NH2:28])=[CH:25][CH:26]=2)[NH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16].N1C=CC=CC=1>C(OCC)(=O)C>[C:15]([C:19]1[C:27]2[C:22](=[CH:23][C:24]([NH:28][C:12]([C:8]3[C:9](=[O:11])[C:10]4[C:2]([CH3:1])=[N:3][S:4][C:5]=4[NH:6][CH:7]=3)=[O:14])=[CH:25][CH:26]=2)[NH:21][CH:20]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1c[nH]c2cc(N)ccc12
Reactant: Cc1nsc2[nH]cc(C(=O)O)c(=O)c12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1nsc2[nH]cc(C(=O)Nc3ccc4c(C(C)(C)C)c[nH]c4c3)c(=O)c12
Temperature: 45 °C
Yield: 33.2 %

Procedure:
3-Methyl-4-oxo-4,7-dihydroisothiazolo[5,4-b]pyridine-5-carboxylic acid (100.0 mg, 475.7 μmol) and 3-tert-butyl-1H-indol-6-amine (89.56 mg, 0.4757 mmol) were added to a 20-mL vial and suspended in 2-methyl THF (1 mL), followed by propane phosphonic acid anhydride (T3P®, 50% solution in ethyl acetate, 757 mg, 1.19 mmol). Pyridine (75.26 mg, 76.95 μL, 951.4 μmol) was then added and the solution heated at 45° C. for 16 h. The reaction was diluted with 5 mL ethyl acetate and washed with water (1×10 mL). The organic layer was pulled off and concentrated. The residue was dissolved in 6 mL DMF and HPLC purified (RP-C18, 20-99% CH3CN/0.05% TFA). The pooled product fractions were concentrated to approximately 5 mL to provide a suspended white solid. The suspended material was filtered, washed with water and air dried to yield the product N-(3-tert-butyl-1H-indol-6-yl)-3-methyl-4-oxo-4,7-dihydroisothiazolo[5,4-b]pyridine-5-carboxamide (60 mg, 33% yield) as an off-white solid. LC/MS m/z 381.0 [M+H]+, retention time 1.79 min (RP-C18, 10-99% CH3CN/0.05% TFA over 3 min). 1H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 12.27 (s, 1H), 10.73 (s, 1H), 8.92 (s, 1H), 8.11 (d, J=1.7 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.02 (dd, J=9.5, 0.9 Hz, 1H), 6.98 (d, J=2.3 Hz, 1H), 2.79 (s, 3H), 1.40 (s, 9H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][C:10]([NH:12][CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=2)=[O:11])[CH:3]=1.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1>O1CCCC1>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][C:10]([NH:12][CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([N:23]3[CH:27]=[CH:26][N:25]=[CH:24]3)=[O:19])=[CH:16][CH:15]=2)=[O:11])[CH:3]=1
Reactant: c1c[nH]cn1
Reactant: O=C(NCc1ccc(C(=O)Cl)cc1)OCc1cccnc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(NCc1ccc(C(=O)n2ccnc2)cc1)OCc1cccnc1
Reaction time: 1 h
Yield: 55.4 %

Procedure:
1 g (2.9 mmole) of 4-[N-(pyridin-3-ylmethoxycarbonyl)aminomethyl]benzoyl chloride hydrochloride was added to a tetrahydrofuran (10 ml) solution including 0.6 g (8.8 mmole) of imidazole, followed by stirring for 1 hour. A deposited imidazole hydrochloride was removed by filtration, and the reaction solution was then concentrated. Ethyl acetate and water were added to the solution to carry out partition, and the organic layer was then treated in an ordinary manner to obtain 0.54 g (yield: 55%) of 1-{4-[N-(pyridin-3-ylmethoxycarbonyl)aminomethyl]benzoyl}imidazole.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[S:14](Cl)(=[O:16])=[O:15])([O-:3])=[O:2].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[S:14]([NH:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:22]2[C:23]=1[N:18]=[CH:19][CH:20]=[CH:21]2)(=[O:16])=[O:15])([O-:3])=[O:2]
Reactant: c1ccncc1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)cc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(C(F)(F)F)cc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 32 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoqunoline (550 mg, 3.8 mmol), 2-nitro-5-trifluoromethyl-benzenesulfonyl chloride (Intermediate 453) (1.43 g, 4.9 mmol), DMAP (cat.), pyridine (4 ml) and DCM (5 ml) gave the title compound (490 mg, 32%) after purification by column chromatography with n-hexane/EtOAc (90:10) as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2=[N:7][C:8]3[NH:9][CH:10]=[C:11]([C:16]#[N:17])[C:12](=O)[C:13]=3[CH:14]=[C:5]2[CH:4]=1.P(Cl)(Cl)([Cl:24])=O>CCCCCC>[Cl:24][C:12]1[C:13]2[CH:14]=[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:19]([O:20][CH3:21])=[CH:18][C:6]3=[N:7][C:8]=2[N:9]=[CH:10][C:11]=1[C:16]#[N:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2cc3c(=O)c(C#N)c[nH]c3nc2cc1OC
Solvent: CCCCCC
Product: COc1cc2cc3c(Cl)c(C#N)cnc3nc2cc1OC
Temperature: 25 °C
Yield: 49 %

Procedure:
A mixture of 7,8-dimethoxy-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carbonitrile (500 mg, 1.78 mmol) and 5 mL of phosphorous oxychloride is heated at reflux for one hour then cooled to room temperature. Hexane (20 mL) is added and the resultant solids are collected by filtration washing with hexane, water, methanol and ethyl acetate to provide 258 mg (49%) of 4-chloro-7,8-dimethoxybenzo[b][1,8]naphthyridine-3-carbonitrile as a brown solid, mp>300° C.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Br:8])=[C:5]([Br:7])[N:6]=1.[H-].[Na+].[CH3:11][Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][O:15][CH2:16]Cl>CN(C)C=O.O>[Br:1][C:2]1[N:3]([CH2:16][O:15][CH2:14][CH2:13][Si:12]([CH3:19])([CH3:18])[CH3:11])[C:4]([Br:8])=[C:5]([Br:7])[N:6]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1nc(Br)c(Br)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1c(Br)nc(Br)c1Br
Reaction time: 0.25 h

Procedure:
To a solution of 2,4,5-tribromo-1H-imidazole (10.3 g, 32 8 mmol) in anhydrous N,N-dimethylformamide (100 ml) is slowly added NaH (1.4 g, 36.1 mmol, 60% in mineral oil) at room temperature. The suspension is stirred for 15 minutes and 2-(Trimethylsilyl)ethoxymethyl chloride (5.8 ml, 32.8 mmol) is added. The mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with water (250 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layer is washed with water (50 ml), brine, dried over MgSO4, filtered, and concentrated in vacuo to yield 2,4,5-tribromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole as a yellow waxy solid 13.8 g, 97%.