Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.[O:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1>C1COCC1>[F:8][C:3]1[C:2]([C:17]2([OH:20])[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=C1CCOCC1
Reactant: Fc1ncccc1Br
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC1(c2cccnc2F)CCOCC1
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-2-fluoropyridine (0.93 g, 5.28 mmol) in THF (5 mL) was added dropwise isopropylmagnesium chloride (2.64 mL, 5.28 mmol, 2M solution) at room temperature. After overnight stirring, dihydro-2H-pyran-4(3H)-one (0.486 mL, 5.28 mmol) was added dropwise. Reaction was quenched with saturated NH4Cl solution and extracted with DCM. Purification by Biotage (0-10% MeOH/DCM) produced the desired product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.C(O)(=O)[CH2:10][C:11]([OH:13])=[O:12].N1CCCCC1.C(=O)=O>N1C=CC=CC=1>[N:1]1[CH:2]=[CH:3][C:4](/[CH:7]=[CH:10]/[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: O=Cc1ccncc1
Reactant: O=C(O)CC(=O)O
Agent: O=C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)/C=C/c1ccncc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
To a solution of 4-pyridine carboxaldehyde (36.7 mL, 0.384 mol) and malonic acid (40g, 0.384 mol) in 31 mL of pyridine was added piperdine (0.12 mL) and the mixture was warmed to 100° C. Caution: large volumes of CO2 evolved. After 0.5 h, the reaction was cooled to room temperature (RT) and the solution solidified. This was triturated with 240 mL of water and filtered, and washed with 2×50 mL portions of water. The solid was dried overnight at 42° C. under vacuum (10 mm Hg) to provide 37.1 g of a white solid; mp 295°-297° C.
Reaction SMILES: C([O:8][C:9](=[O:17])[C@@:10]1([C:13]([F:16])([F:15])[F:14])[O:12][CH2:11]1)C1C=CC=CC=1.[H][H]>[Pt]=O.CO>[O:12]1[CH2:11][C@@:10]1([C:13]([F:16])([F:15])[F:14])[C:9]([OH:17])=[O:8]
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)[C@]1(C(F)(F)F)CO1
Agent: O=[Pt]
Solvent: CO
Product: O=C(O)[C@]1(C(F)(F)F)CO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
Into a 500 ml three-necked round-bottomed flask equipped with a stirrer, (S)-2,3-epoxy-2-trifluoromethylpropionic acid benzyl ester (20.9 g, 84.9 mmol, 99 ee %) was charged, and 180 ml of methanol was added for dissolution. Platinum oxide (1.63 g) was added, and then, the reaction system was substituted by hydrogen. After stirring at room temperature for 4 hours, platinum oxide was filtered off. The solvent was distilled off under reduced pressure, whereupon (S)-2,3-epoxy-2-trifluoromethylpropionic acid (11.9 g) was obtained (yield: 90%).
Reaction SMILES: [S:1]([CH2:4][C:5]([CH3:12])([CH3:11])[CH2:6][S:7]([NH2:10])(=[O:9])=[O:8])C#N.[BH4-].[Na+]>C(O)C>[SH:1][CH2:4][C:5]([CH3:12])([CH3:11])[CH2:6][S:7]([NH2:10])(=[O:9])=[O:8]
Reactant: CC(C)(CSC#N)CS(N)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(CS)CS(N)(=O)=O
Yield: 16.8 %

Procedure:
To a solution of 5.15 g of 3-thiocyanato-2,2-dimethyl-1-propanesulfonamide in 100 ml of ethanol was little by little added 0.79 g of sodium borohydride with stirring and nitrogen gas atmosphere, taking an hour. The reaction mixture was refluxed for an hour and concentrated under reduced pressure. To the residue were added 20 ml of water and 30 ml of 1N-hydrochloric acid. The organic layer was collected, and the aqueous layer was washed with ethyl acetate (50 ml×3). The combined organic layers were dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was subjected to a silica gel chromatography, eluting with chloroform-methanol (10:1), to obtain 0.76 g of 3-mercapto-2,2,-dimethyl-1-propanesulfonamide.
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:19]=[CH:18][C:12]2[NH:13][C:14](=[O:17])[CH2:15][O:16][C:11]=2[CH:10]=1)[CH:3]([CH3:8])[CH2:4][C:5]([OH:7])=[O:6].[C:20](Cl)(=O)C>CO>[O:1]=[C:2]([C:9]1[CH:19]=[CH:18][C:12]2[NH:13][C:14](=[O:17])[CH2:15][O:16][C:11]=2[CH:10]=1)[CH:3]([CH3:8])[CH2:4][C:5]([O:7][CH3:20])=[O:6]
Reactant: CC(=O)Cl
Reactant: CC(CC(=O)O)C(=O)c1ccc2c(c1)OCC(=O)N2
Solvent: CO
Product: COC(=O)CC(C)C(=O)c1ccc2c(c1)OCC(=O)N2

Procedure:
4-Oxo-4-(3,4-dihydro-3-oxo-2H-1,4-benzoxazin-7-yl)-3-methylbutyric acid (5 g) was suspended in methanol (50 ml) and acetyl chloride (0.5 ml) added. The mixture was heated on a steam bath until all of the solid dissolved. The solvent was evaporated at reduced pressure providing the ester as a white foam which was recrystallized from ethyl acetate-methanol to give the product as white crystals, yield 5 g, mp 95°-98° C.
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([N:29]2[CH2:35][CH:34]3[N:36](C(OC(C)(C)C)=O)[CH:31]([CH2:32][CH2:33]3)[CH2:30]2)[C:9]=1[C:44]([O:46]CC)=[CH2:45].Cl>O>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([N:29]2[CH2:35][CH:34]3[NH:36][CH:31]([CH2:32][CH2:33]3)[CH2:30]2)[C:9]=1[C:44](=[O:46])[CH3:45]
Reactant: C=C(OCC)c1c(N2CC3CCC(C2)N3C(=O)OC(C)(C)C)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Agent: Cl
Solvent: O
Product: CC(=O)c1c(N2CC3CCC(C2)N3)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N

Procedure:
The tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (31 mg) was treated with 4N HCl in H2O (2 mL) and Dixoane (2 mL) until the disappearance of starting material in LCMS. Concentration afforded crude 1-(7-amino-5-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone, which was used for next step without further purification, LCMS tR=1.08 Min (10 min run, UV254nm). Mass calculated for, M+H 440.2, observed LC/MS m/z 440.2 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([O:16]C)=[O:15])=[N:12][CH:13]=2)[N:3]=[CH:2]1.[OH-].[Na+].Cl>O1CCOCC1>[S:1]1[CH:5]=[C:4]([CH2:6][O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[N:12][CH:13]=2)[N:3]=[CH:2]1
Reactant: COC(=O)c1cnc(OCc2cscn2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1cnc(OCc2cscn2)cn1
Reaction time: 16 h

Procedure:
To a solution of methyl 5-(thiazol-4-ylmethoxy)pyrazine-2-carboxylate (0.7606 g, 3.03 mmol) in 1,4-dioxane (15.14 ml) was added a 1 N solution of sodium hydroxide (4.54 ml, 4.54 mmol) at rt. The reaction mixture was allowed to stir for 16 hours. Hydrogen chloride (4.0M solution in 1,4-dioxane; 1.135 ml, 4.54 mmol, Sigma Aldrich) was added and after 10 minutes, the reaction mixture was concentrated in vacuo to give the title compound. MS m/z=237.9 [M+H]+. Calculated for C9H7N3O3S: 237.021. 1H NMR (400 MHz, DMSO-d6) δ ppm 5.59 (s, 2H) 7.86 (d, J=1.96 Hz, 1H) 8.45 (d, J=1.17 Hz, 1H) 8.83 (d, J=1.37 Hz, 1H) 9.14 (d, J=1.96 Hz, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[C:16]3[C:17]([F:22])=[CH:18][CH:19]=[C:20]([F:21])[C:15]=3[O:14][CH2:13][CH:12]2[CH2:23]OS(C)(=O)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Na+].[I-].C(O)(=O)C>COCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[C:16]3[C:15](=[C:20]([F:21])[CH:19]=[CH:18][C:17]=3[F:22])[O:14][CH2:13][CH:12]2[CH3:23])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CC(=O)O
Product: CC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Methanesulfonic acid O-[4-(4-chloro-benzenesulfonyl)-5,8-difluoro-3,4-dihydro-2H-1-benzopyran-3-yl-methyl]ester (0.5 g, 1.1 mmole), NaI (0.83 g, 5.5 mmole) Zinc dust (0.71 g, 11 mole) and 0.1 mL acetic acid were refluxed in 15 mL ethylene glycol dimethyl ether for 6 hours. The solid was filtered and the filtrate was partitioned between 100 mL 0.1N Na2SO3 solution and 100 mL EtOAc. The organic layer was washed with 0.5N NaOH solution (2×50 ml), brine, dried over Na2SO4 and concentrated. The residue was recrystallized from EtOAc/Hexane to pure product (0.33 g, 83%) 1H NMR (400 MHz, CDCl3) 7.71 (d, J=8.8 Hz, 2H), 7.50 (d, J=8.8 Hz, 2H), 7.03 (m, 1H), 6.40 (m, 1H), 4.92 (dd, J=11.7 and 2.9 Hz, 1H), 4.21 (m, 2H), 3.02 (m, 1H), 1.07 (d, J=7.3 Hz, 3H).
Reaction SMILES: C(OC([N:8]1[CH:14]2[CH2:15][O:16][CH2:17][CH:9]1[CH2:10][N:11]([C:19]1[CH:20]=[N:21][C:22]([NH:25][C:26]3[N:27]=[CH:28][C:29]4[CH:34]=[C:33]([C:35](=[O:39])[N:36]([CH3:38])[CH3:37])[N:32]([CH:40]5[CH2:44][CH2:43][CH2:42][CH2:41]5)[C:30]=4[N:31]=3)=[CH:23][CH:24]=1)[C:12](=[O:18])[CH2:13]2)=O)(C)(C)C.CN(C)C(C1NC2N=CN=CC=2C=1)=O>>[CH3:37][N:36]([CH3:38])[C:35]([C:33]1[N:32]([CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[C:30]2[N:31]=[C:26]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([N:11]4[C:12](=[O:18])[CH2:13][CH:14]5[NH:8][CH:9]([CH2:17][O:16][CH2:15]5)[CH2:10]4)=[CH:20][N:21]=3)[N:27]=[CH:28][C:29]=2[CH:34]=1)=[O:39]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC5COCC(CC4=O)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1
Agent: CN(C)C(=O)c1cc2cncnc2[nH]1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC5COCC(CC4=O)N5)cn3)nc2n1C1CCCC1
Yield: 58.8 %

Procedure:
Following deprotection method 1, 3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-4-oxo-8-oxa-3,10-diaza-bicyclo[4.3.1]decane-10-carboxylic acid tert-butyl ester (470 mg, 0.777 mmol) was converted to 7-Cyclopentyl-2-[5-(4-oxo-8-oxa-3,10-diaza-bicyclo[4.3.1]dec-3-0)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (231 mg, 0.457 mmol) in 58.8% yield. 1H NMR (400 MHz, D6 DMSO) δ 10.2 (s, 1H, broad), 9.05 (s, 1H, broad), 8.35 (s, 1H), 8.0 (d, 1H), 7.7 (d, 1H), 6.9 (s, 1H), 4.82 (m, 1H, broad), 4.6 (d, 1H), 4.25 (s, 1H, broad), 4.15 (s, 1H, broad), 3.82 (m, 1H, broad), 3.5 (d, 1H), 3.05 (s, 6H), 2.82 (m, 1H), 2.3 (m, 2H), 2.2-1.95 (m, 10H, broad), 1.89 (m, 1H), 1.65 (m, 2H) MS m/z 504.6 (M+H)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH:17]4[C:19]([OH:22])([CH3:21])[CH3:20])[N:13]([CH3:23])[C:12]=3[CH:24]=2)[C:4](=[O:25])[CH:3]=1.[F:26][C:27]1[CH:28]=[C:29]([CH2:34]O)[CH:30]=[CH:31][C:32]=1[F:33].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>CCOC(C)=O.C1COCC1>[F:26][C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:34][O:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH:17]4[C:19]([OH:22])([CH3:20])[CH3:21])[N:13]([CH3:23])[C:12]=3[CH:24]=2)[C:4](=[O:25])[CH:3]=1
Reactant: OCc1ccc(F)c(F)c1
Reactant: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(OCc4ccc(F)c(F)c4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-hydroxy-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (3,4-difluorophenyl)methanol (0.066 ml), tributylphosphine (0.219 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (223 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EtOAc, and quenched with water. The organic layer was separated, washed with water and brine successively, dried over MgSO4, filtered through NH silica gel pad, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from IPA-IPE to give the title compound (51.4 mg) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([CH2:13][S:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:5]=1.CO>C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([CH2:13][S:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:15])=[O:16])[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(CS(=O)(=O)c2cccc3ccccc23)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(N)c(CS(=O)(=O)c2cccc3ccccc23)c1
Yield: 64.1 %

Procedure:
A mixture of 3-(naphthalene 1-sulfonylmethyl)-4-nitro-benzoic acid methyl ester (1.5 g, 3.9 mmoles) and 10% Pd/C in THF (10 mL), and methanol (20 mL) was hydrogenated in a Parr hydrogenation bottle (250 mL) at 52 lb/in2 overnight. The mixture was filtered through Celite, and the filtrate was concentrated under vacuum to afford the title compound as an off-white solid (0.9 g, 2.5 mmoles).
Reaction SMILES: [C:1]([O:9]/[C:10](/[C:32]([O:34][CH3:35])=[O:33])=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:14]([CH3:26])[C:13]=1[CH2:27][O:28][C:29](=[O:31])[CH3:30])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>ClCCl.[B-](F)(F)(F)F.CC[C@H]1P(C2C(P3[C@H](CC)CC[C@H]3CC)=CC=CC=2)[C@H](CC)CC1.C1[CH][CH]CC[CH][CH]C1.[Rh]>[C:1]([O:9][C@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])=[C:14]([CH3:26])[C:13]=1[CH2:27][O:28][C:29](=[O:31])[CH3:30])[C:32]([O:34][CH3:35])=[O:33])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)/C(=C/c1ccc(NC(=O)OC(C)(C)C)c(C)c1COC(C)=O)OC(=O)c1ccccc1
Reactant: [H][H]
Agent: [Rh]
Agent: CC[C@@H]1CC[C@@H](CC)P1c1ccccc1P1[C@H](CC)CC[C@H]1CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1ccc(NC(=O)OC(C)(C)C)c(C)c1COC(C)=O)OC(=O)c1ccccc1

Procedure:
(Z)-1-(2-(acetoxymethyl)-4-(tert-butoxycarbonylamino)-3-methylphenyl)-3-methoxy-3-oxoprop-1-en-2-yl benzoate (20.00 g, 41.4 mmol) in dichloromethane (120.00 ml) was added (−)-1,2-bis((2R,5R)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium(I)tetrafluoroborate (280.00 mg, 0.424 mmol) under nitrogen atmosphere. The reaction mixture was hydrogenated at 60 psi pressure of hydrogen for 12h. The solvent was removed and crude product was carried to the next step as such. MS (ESI) 508 (M+H); Rf=2.53.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([F:9])[C:5]([F:8])=[N:6][CH:7]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[CH3:44][C:45]1[CH:49]=[C:48]([Sn](C)(C)C)[S:47][N:46]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:8][C:5]1[C:4]([F:9])=[CH:3][C:2]([C:48]2[S:47][N:46]=[C:45]([CH3:44])[CH:49]=2)=[CH:7][N:6]=1
Reactant: Cc1cc([Sn](C)(C)C)sn1
Reactant: Fc1cc(Cl)cnc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: Cc1cc(-c2cnc(F)c(F)c2)sn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
5-chloro-2,3-difluoropyridine (0.069 ml, 0.67 mmol), X-Phos (0.045 g, 0.094 mmol) and palladium (II) acetate (0.011 g, 0.047 mmol) were combined in 1,4-dioxane (0.2 M, 3.4 mL). To the reaction vessel was added 3-methyl-5-(trimethylstannyl)isothiazole (0.53 g, 2.0 mmol) and, after purging with argon, the reaction was stirred at 100° C. for 2 h and then concentrated in vacuo. The crude material was dissolved in minimal DCM and purified via MPLC (eluting first with 100% EtOAc followed by 20% EtOAc in hexanes -isocratic) to yield 2,3-difluoro-5-(3-methylisothiazol-5-yl)pyridine (0.139 g, 98% yield) as a yellow solid. 2,3-difluoro-5-(3-methylisothiazol-5-yl)pyridine was converted to the title compound using a procedure similar to 1-(4-methyl-6-phenylpyridazin-3-yl)hydrazine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:17](=[O:18])[C:12]3=[CH:13][CH2:14][CH2:15][CH2:16][N:11]3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:28]([CH3:32])[C:29](=[O:31])[CH3:30].[Cl-].[NH4+]>C(#N)C>[Cl:1][C:2]1[C:7]([O:8][CH:28]([C:29](=[O:31])[CH3:30])[CH3:32])=[CH:6][C:5]([N:9]2[C:17](=[O:18])[C:12]3=[CH:13][CH2:14][CH2:15][CH2:16][N:11]3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1
Reactant: CC(=O)C(C)Cl
Reactant: O=C1C2=CCCCN2C(=O)N1c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)C(C)Oc1cc(N2C(=O)C3=CCCCN3C2=O)c(F)cc1Cl
Yield: 91.8 %

Procedure:
An acetonitrile (10 mL) solution of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.57 g, 1.9 mmol), potassium carbonate (0.29 g, 2.1 mmol) and 3-chloro-2-butanone (0.21 mL, 2.1 mmol) was stirred for 5 hours under reflux. A saturated ammonium chloride solution (10 mL) was added to the resulting mixture, and the organic layer was separated and then the aqueous layer was extracted with diethyl ether (10 mL×2 times). The organic layer combined was washed with a saturated sodium chloride solution (20 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane =1/2) to obtain a white solid of 2-[4-chloro-2-fluoro-5-(3-oxo-2-butyloxy)phenyl]-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.64 g, yield:86.5%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[NH:12][C:11]2=[O:21])=[CH:6][CH:5]=1)([O-:3])=[O:2].CI.[C:24](=O)([O-])[O-].[K+].[K+]>O>[CH3:24][N:12]1[C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][C:15](=[O:16])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:11]1=[O:21]
Reactant: O=C([O-])[O-]
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1ccc([N+](=O)[O-])cc1
Agent: [K+]
Solvent: O
Solvent: CI
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc([N+](=O)[O-])cc2)c1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To the stirred reaction mixture containing the crude 3-(4-nitrophenyl)-6-trifluoromethyluracil (14.5 grams--0.048 mole) from the preceding step was added 13.6 grams (0.096 mole) of methyl iodide and 3.3 grams (0.096 mole) of potassium carbonate. Upon completion of the addition, the reaction mixture was stirred at ambient temperature for about five hours, after which the reaction mixture was poured into water, and the resultant solid was collected by filtration. The solid was washed with petroleum ether and dried, yielding 13.0 grams of 1-methyl-3-(4-nitrophenyl)-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=O.[K+].S(Cl)(Cl)=O.C(N(C(C)C)CC)(C)C.[NH2:25][C:26]1[C:27]([Br:34])=[N:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1>C(Cl)(Cl)Cl>[Br:34][C:27]1[C:26]([NH:25][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[N:10][C:2]=2[CH3:1])=[CH:31][CH:30]=[C:29]([O:32][CH3:33])[N:28]=1
Reactant: COc1ccc(N)c(Br)n1
Reactant: Cc1ncccc1C(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: COc1ccc(NC(=O)c2cccnc2C)c(Br)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
To a suspension of potassium 2-methylnicotinate (1.96 g) in chloroform (30 mL) was added thionyl chloride (2.5 mL). The mixture was stirred overnight at room temperature under a drying tube. Diisopropylethylamine (5 mL) was added followed by 3-amino-2-bromo-6-methoxypyridine (2.25 g). After 10 minutes additional diisopropylethylamine (5 mL) was added. After 2 hours the mixture was diluted with chloroform, washed with water, dried (Na2SO4,) filtered, and evaporated. Chromatography of the residue over silica gel (chloroform/methanol) gave N-(2-bromo-6-methoxy-3-pyridinyl)-2-methylnicotinamide (2.80 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](O)=[N:6][CH:7]=1.C(=O)([O-])O.[Na+].P(Cl)([Cl:26])(OC1C=CC=CC=1)=O>CCCC(C)C>[Cl:26][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]([I:1])=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Reactant: O=[N+]([O-])c1cc(I)cnc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCC(C)C
Product: O=[N+]([O-])c1cc(I)cnc1Cl
Temperature: 180 °C

Procedure:
A suspension of 5-iodo-3-nitro-pyridin-2-ol (20 g) in phenyl dichlorophosphate (60 ml) was heated at 180° C. for 30 minutes whereby a brown solution was obtained. The solution was allowed to cool then poured onto ice/water, neutralised by a portionwise addition of solid sodium hydrogen carbonate and extracted with ethyl acetate (300 ml) which was then washed twice with 5% sodium hydrogen carbonate solution (250 ml). The organic layer was dried (MgSO4), and evaporated to give a pale brown solid. The solid was stirred in isohexane for 2 h, filtered off, washed with isohexane and dried to afford the title compound (18.4 g).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3][OH:4].[C:15]1(=O)OCC[O:16]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:5]([CH:2]1[CH2:3][O:4][C:15](=[O:16])[NH:1]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCC(N)CO
Reactant: O=C1OCCO1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCC1COC(=O)N1
Yield: 91.5 %

Procedure:
26.465 g of 2-aminododecanol and 12.32 g of ethylene carbonate were heated at approximately 110° C. for 48 hours (preparation of the cyclic urethanes can be carried out without a solvent or in toluene solution)as a solvent. The reaction was followed by tlc and at the completion of the reaction the contents were cooled, dissolved in ethyl acetate and the organic solution was washed with brine and water. After drying, the filtrate was concentrated and the oily residue was kugelrohr distilled to give 27.33 g (96.56%) of colorless liquid, which slowly solidified, m.p. 31.5-32.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35](=[O:38])[CH2:36][CH3:37]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:34][C:35](=[O:38])[CH2:36][CH3:37])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Reactant: CCC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCC(=O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (0.3 g) obtained in Example 2 was suspended in dimethyl sulfoxide (20 ml), and to the suspension was added potassium carbonate (0.2 g), and the mixture was stirred at room temperature for 30 minutes. 1-bromo-2-butanone (0.1 ml) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water, and the precipitated crystals were recovered by filtration. The resulting crude crystals were washed with methanol and ethanol in succession to obtain the title compound (192 mg, 55%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH:8]=[N:9][NH:10][C:5]2=[C:4](O)[CH:3]=1.[OH-].[Na+].P(Cl)(Cl)([Cl:16])=O>>[CH3:1][C:2]1[N:7]=[C:6]2[CH:8]=[N:9][NH:10][C:5]2=[C:4]([Cl:16])[CH:3]=1
Reactant: Cc1cc(O)c2[nH]ncc2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(Cl)c2[nH]ncc2n1
Temperature: 25 °C
Yield: 87 %

Procedure:
The cyclized compound (12) (4.58 g, 30.7 mmol) in phosphorus oxychloride (30 mL) was heated at 110° C. for 30 minutes. The end of the reaction was checked by LC/MS (disappearance of 150, appearance of 168). After cooling down at room temperature, the reaction mixture was poured on ice and pH was adjusted with a 6N NaOH solution to pH=5. The solid was collected with filtration and the mother aqueous layer was extracted with ethyl acetate (3×250 ml). The above solid was dissolved in the combined organic phases, washed with a brine solution (1×250 ml) and dried with sodium sulfate, filtered and concentrated. The crude product was purified by running through a short silica gel chromatography column to give the desired product (13) as a pale yellow solid (4.50 g, 26.8 mmol, 87%). GC/MS: m/z=167 (100%);. LC/MS: [M+H]′=168.