Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]1[NH:12][C:13]([CH2:15][CH3:16])=[N:14][C:6]1=[N:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]1[N:12]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:13]([CH2:15][CH3:16])=[N:14][C:6]1=[N:5]2
Reactant: CCc1nc2nc3cc(Cl)ccc3nc2[nH]1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(CC)nc2nc3cc(Cl)ccc3nc21

Procedure:
A mixture of 100 parts of 6-chloro-2-ethyl-1H-imidazo[4,5-b]quinoxaline, 70 parts of anhydrous potassium carbonate, 75 parts of ethyl bromoacetate, and 600 parts of anhydrous dimethylformamide was heated at 100° for 2.5 hours. The mixture was filtered and the crude product was precipitated from the filtrate by addition of 1200 parts of water, collected by filtration, washed with water, ethanol, and ether, and airdried. Recrystallization from 95% ethanol afforded 63 parts of 6-chloro-2-ethyl-1-ethoxycarbonylmethyl-1H-imidazo[4,5-b]quinoxaline, m.p. 174°-175°.
Reaction SMILES: [N:1]#CN.[Pb].C[NH:6][C:7]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH3:19])=S.CN(C)C=O>C(#N)C>[CH3:19][C:15]1[N:16]=[CH:17][NH:18][C:14]=1[CH2:13][S:12][CH2:11][CH2:10][NH:9][C:7]([NH2:1])=[NH:6]
Reactant: CNC(=S)NCCSCc1[nH]cnc1C
Reactant: N#CN
Agent: [Pb]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1CSCCNC(=N)N
Reaction time: 24 h

Procedure:
Lead cyanamide (3.0 g.) was added to a solution of N-methyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)-ethyl]thiourea (2.44 g.) in acetonitrile (50 ml.). Dimethylformamide (20 ml.) was added subsequently and the suspension was heated under reflux, with stirring, for 24 hours. Filtration, followed by concentration under reduced pressure and purification of the product by chromatography on a column of silica gel with acetonitrile as eluant and recrystallisation from the same solvent afforded N-cyano-N'-methyl- N"[2-((4-methyl-5-imidazolyl)-methylthio)ethyl]guanidine, m.p. 139°-141°.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4](I)[CH:3]=1.[CH3:34][O:35][C:36]1[C:41](B(O)O)=[CH:40][CH:39]=[CH:38][N:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([C:41]2[C:36]([O:35][CH3:34])=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:3]=1
Reactant: COc1ncccc1B(O)O
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1I)c(OCc1ccccc1)c2=O
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: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ncccc1-c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Temperature: 90 °C
Yield: 72.6 %

Procedure:
Intermediate 174, N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.350 g, 0.62 mmol) in a mixture of acetonitrile (12 ml) and water (12 ml) was treated with 2-methoxypyridin-3-ylboronic acid (0.190 g, 1.24 mmol), sodium carbonate (0.20 g, 1.88 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.15 g). The reaction mixture was degassed, flushed with argon and heated at 90° C. for 30 min. The reaction mixture was then diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. Chromatography of the residue on silica gel (elution gradient of ethyl acetate in hexane) gave 0.245 g (72% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.63 (6H, s, 2×CH3), 3.89 (3H, s, OCH3), 4.04 (4H, m, 2×CH2), 4.37 (2H, broad, NCH2), 5.26 (2H, s, OCH2), 6.93 (1H, dd, J=2.5 Hz and J=9 Hz, aromatic), 7.0 (1H, dd, J=5 Hz and J=7 Hz, aromatic), 7.06 (1H, m, aromatic), 7.3–7.5 (8H, m, aromatics and NH), 8.24 (1H, m, aromatic). HRMS (ESI+) calculated for C30H30FN4O5 [M+H+]: 545.2200. Found: 545.2184.
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[C:8]([O:12][O:13][C:14]([CH3:23])([CH3:22])[CH2:15][CH2:16][C:17]([O:20][OH:21])([CH3:19])[CH3:18])([CH3:11])([CH3:10])[CH3:9]>>[CH3:6][C:5]([O:21][O:20][C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][C:14]([O:13][O:12][C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:23])[CH3:22])([CH2:4][C:2](=[O:1])[CH3:3])[CH3:7]
Reactant: CC(=O)C=C(C)C
Reactant: CC(C)(C)OOC(C)(C)CCC(C)(C)OO
Product: CC(=O)CC(C)(C)OOC(C)(C)CCC(C)(C)OOC(C)(C)C
Reaction time: 4 h
Yield: 84.4 %

Procedure:
A mixture of 19.62 g. (0.20 mole) of mesityl oxide, 61.40 g. (0.22 mole) of 4-t-butylperoxy-1,1,4,4-tetramethylbutyl hydroperoxide (84%) and 10.0 g. of Amberlyst 15® sulfonic acid type ion exchange resin was stirred for 16 hours at 28°-30° C. and then at 35° C. for 4 hours. The resin was separated by filtration and the filtrate subjected to steam distillation at 20 torr in the presence of sodium bicarbonate to maintain a slightly alkaline pH during the distillation. The distillation was ended when the removal of unreacted mesityl oxide was complete. The product was taken up in ether, the ether solution dried over anhydrous magnesium sulfate and the ether removed under reduced pressure. The product weighed 55.9 g. and was obtained in 84.4% yield.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCOCC>O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:1]([OH:3])(=[O:5])=[O:2]
Reactant: COc1ccccc1
Reactant: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Product: COc1ccccc1S(=O)(=O)O
Temperature: 50 °C
Reaction time: 12 h

Procedure:
560 g of 98% sulfuric acid was dropped into 600 g of methoxybenzene while stirring. Then, while the stirring was continued, the temperature was raised at 45 to 55° C., reacting for 12 hours. After the reaction, 500 g of distillation water was added. Then, 200 g of ether was added. The lower phase (water phase) of the two separated phases was taken, into which a step of distillation for condensation and addition of water was repeated twice, so as to obtain methoxybenzenesulfonic acid. As a result of analysis, the methoxybenzenesulfonic acid included the para compound thereof at a concentration of 86 mole % in the total of the methoxybenzenesulfonic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5]([C:9]([OH:11])=O)=[N:6][C:7]=1[CH3:8].[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[O:14][C:9](=[O:11])[C:5]2=[N:6][C:7]=1[CH3:8])(=[O:17])[CH3:16]
Reactant: Cc1nc(C(=O)O)c(C(=O)O)cc1O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1cc2c(nc1C)C(=O)OC2=O
Temperature: 140 °C

Procedure:
A suspension of 1.0 g (5.1 mmol) 5-hydroxy-6-methylpyridine-2,3-dicarboxylic acid and 5 ml acetic acid anhydride are heated at a bath temperature of 140° C. until a clear solution is produced. After compressing, the desired product is obtained.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[F:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.N1CCCCC1>C(OC(C)C)(=O)C>[F:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[C:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: O=Cc1ccccc1F
Reactant: N#CCC#N
Solvent: CC(=O)OC(C)C
Solvent: C1CCNCC1
Product: N#CC(C#N)=Cc1ccccc1F
Yield: 28.3 %

Procedure:
Malononitrile (3.303 g, 50 mmol), 2-fluorobenzaldehyde (6.205 g, 50 mmol), 1 g of molecular sieves, and 500 mg of a resin bound piperidine (described in Tetrahedron Lett., 1999, 40, 7031-33) were placed in a vessel which was irradiated in a 300 W single mode microwave for 15 seconds. The reaction mixture was taken up in iso-propyl acetate, filtered, evaporated, taken up in dichloromethane, filtered through a pad of Magnasol, evaporated, and recrystallized from ethanol to yield 2.435 g of the title material as a crystalline solid,
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:16][OH:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C=CN=C1.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:16][O:17][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:29])[CH3:28])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCCC1CO
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1CCCN1S(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a solution of [1-(4-bromo-benzenesulfonyl)-pyrrolidin-2-yl]-methanol (50.0 g, 0.16 mol) and 1H-imidazole (21.3 g, 0.31 mol) in CH2Cl2 (500 mL) was added tert-butylchlorodimethylsilane (35.5 g, 0.24 mol) in portions. After addition, the mixture was stirred for 1 hour at room temperature. The reaction was quenched with water (200 mL) and the separated aqueous layer was extracted with CH2Cl2 (100 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and evaporated under vacuum to give 1-(4-bromo-benzenesulfonyl)-2-(tert-butyldimethylsilanyloxymethyl)pyrrolidine (68.0 g, 99%). 1H NMR (300 MHz, CDCl3) δ 7.63-7.71 (m, 4H), 3.77-3.81 (m, 1H), 3.51-3.63 (m, 2H), 3.37-3.43 (m, 1H), 3.02-3.07 (m, 1H), 1.77-1.91 (m, 2H), 1.49-1.57 (m, 2H), 0.87 (s, 9 H), 0.06 (d, J=1.8 Hz, 6 H).
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.[Li]CCCC.C(O[K])(C)(C)C.[F:22][C:23]1([C:26](=[O:40])[CH2:27][C:28]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[O:38][CH3:39])([CH3:30])[CH3:29])[CH2:25][CH2:24]1>C1COCC1.C(OCC)(=O)C>[F:22][C:23]1([C:26]([OH:40])([CH2:27][C:28]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[O:38][CH3:39])([CH3:30])[CH3:29])[CH2:1][C:2]2[NH:10][C:5]3=[CH:6][N:7]=[CH:8][CH:9]=[C:4]3[CH:3]=2)[CH2:24][CH2:25]1
Reactant: Cc1cc2ccncc2[nH]1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C1(F)CC1
Agent: CC(C)(C)O[K]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc2ccncc2[nH]1)C1(F)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41.6 %

Procedure:
To a solution of 2-methyl-1H-pyrrolo[2,3-c]pyridine (80.0 mg, 0.605 mmol) in 2 mL of THF cooled to −78° C. was added 0.70 mL of n-BuLi (1.6 M in hexanes). After 5 minutes, tert-BuOK (1 M in THF, 0.75 mL) was added and the mixture was warmed to room temperature for 1 hour. The mixture was cooled to −78° C. and the above 1-(1-fluorocyclopropyl)-3-(5-fluoro-2-methoxyphenyl)-3-methylbutan-1-one (150 mg, 0.600 mmol) was added as a solution in 0.5 mL of THF. The mixture was stirred for 30 minutes at −78° C. and warmed to room temperature. 5 mL of ethyl acetate was added and the organic phase was washed with water, dried, filtered, and evaporated. Preparative layer chromatography (developer: dichloromethane-ethanol (95:5)) gave 100 mg of the title compound as an oil that solidified on standing (45% yield).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]2[O:9][CH2:10][O:11][C:5]=2[CH:4]=1.C1OC2C=CC([Mg]Br)=CC=2O1.[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27]([C:32]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:34](=[O:41])[C:33]=3[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:26][C:25]=2[O:24]1.Cl>C1COCC1.CCOCC.C1COCC1>[CH2:10]1[O:9][C:6]2[CH:7]=[CH:8][C:3]([C:34]3([OH:41])[C:35]4[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:32]([C:27]4[CH:28]=[CH:29][C:30]5[O:31][CH2:23][O:24][C:25]=5[CH:26]=4)=[C:33]3[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:4][C:5]=2[O:11]1
Reactant: Brc1ccc2c(c1)OCO2
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Agent: Br[Mg]c1ccc2c(c1)OCO2
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.6 %

Procedure:
To dry magnesium turnings (0.25 g, 10 mmol) under an argon atmosphere was added a solution of 4-bromo-1,2-methylenedioxybenzene (2.1 g, 10 mmol) in 1:10 THF/Et2O (22 ml). The resulting solution was allowed to stir at room temperature for 2 h. During this time, additional THF (4 ml) was added. The resulting 3,4-methylenedioxyphenylmagnesium bromide was added to a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (0.50 g, 2 mmol) in 1:4 THF/Et2O (25 ml) under an argon atmosphere at 0° C. The resulting mixture was stirred at 0° C. for 15 min, at which time 1M HCl (50 ml) was added. The phases were separated and the aqueous phase was extracted with Et2O. The combined organic extracts were washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 10% EtOAc/hexanes to afford the title compound as a yellow solid (0.29 g, 42%).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]([CH3:27])([CH3:26])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:25])=[CH:22][C:23]=2I)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:30][CH:31]1[CH2:36][CH2:35][CH:34](B(O)O)[CH:33]([CH3:40])[NH:32]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]([CH3:27])([CH3:26])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:25])=[CH:22][C:23]=2[C:34]2[C:33]([CH3:40])=[N:32][C:31]([F:30])=[CH:36][CH:35]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC1NC(F)CCC1B(O)O
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1I
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: [Na+]
Solvent: C1COCCO1
Product: Cc1nc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-(6-chloro-4-iodo-3-pyridinyl)-N,2-dimethylpropanamide (200 mg, 0.363 mmol), 2-fluoro-6-methylpiperidine-5 boronic acid (73 mg, 0.472 mmol), sodium carbonate solution (0.4 mL, 2M), tetrakistriphenylphosphinepalladium (4 mg, 0.00363 mmol) in dioxan (2 mL) were heated together in the microwave at 110° C. for 30 minutes. The mixture was partitioned between EtOAc and sat NaHCO3 solution. Aqueous layer extracted with EtOAc ×3. Combined extracts dried and evaporated. Residue purified on a 12+M horizon column eluting with Pet Et2O to 60% EtOAc/Pet Et2O. Solvent evaporated under reduced pressure to afford the title compound in quantative yield.
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[F:24][C:25]1[CH:26]=[C:27]([CH:45]=[C:46]([F:48])[CH:47]=1)[CH2:28][N:29]1[C@H:33]([CH3:34])[CH2:32][N:31]([C:35]2[S:36][C:37]([C:41]([OH:43])=O)=[C:38]([CH3:40])[N:39]=2)[C:30]1=[O:44]>>[F:24][C:25]1[CH:26]=[C:27]([CH:45]=[C:46]([F:48])[CH:47]=1)[CH2:28][N:29]1[C@H:33]([CH3:34])[CH2:32][N:31]([C:35]2[S:36][C:37]([C:41]([NH2:7])=[O:43])=[C:38]([CH3:40])[N:39]=2)[C:30]1=[O:44]
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: Cc1nc(N2C[C@@H](C)N(Cc3cc(F)cc(F)c3)C2=O)sc1C(=O)O
Product: Cc1nc(N2C[C@@H](C)N(Cc3cc(F)cc(F)c3)C2=O)sc1C(N)=O

Procedure:
Following the procedure as described in Example 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-thiazole-5-carboxylic acid with (R)-2-(3-(3,5-difluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid: mp 212-213° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.31 (br s, 2H), 7.18-7.07 (m, 3H), 4.57 (d, J=16.3 Hz, 1H), 4.39 (d, J=16.3 Hz, 1H), 4.22 (dd, J=10.0, 9.1 Hz, 1H), 3.87-3.79 (m, 1H), 3.58 (dd, J=10.0, 6.6 Hz, 1H), 2.46 (s, 3H), 1.22 (d, J=6.2 Hz, 3H); MS (ES+) m/z 366.9 (M+1).
Reaction SMILES: [CH2:1]([Li])CCC.[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1([C:17](=O)[C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][CH:19]=2)[CH2:16][O:15]1.[Cl-].[NH4+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1([C:17]([C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][CH:19]=2)=[CH2:1])[CH2:16][O:15]1
Reactant: O=C(c1ccc(I)cc1)C1(c2ccc(F)cc2F)CO1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=C(c1ccc(I)cc1)C1(c2ccc(F)cc2F)CO1
Temperature: -20 °C
Reaction time: 84 h
Yield: 92 %

Procedure:
n-Butyllithium (50 ml, 2.5 M in hexane, 125 mmol) was added dropwise over 10 minutes to a stirred suspension of methyltriphenylphosphonium bromide (45.0 g, 126 mmol) in dry THF (600 ml) under nitrogen at −70° C. The mixture was allowed to warm to −20° C., over 20 minutes, then a solution of 2-(2,4-difluorophenyl)-2-(4-iodobenzoyl)oxirane [37.46 g, 97 mmol, from step (d)] in dry THF (200 ml) was added over 5 minutes. The mixture was allowed to warm to room temperature and stirred for 84 hours. 10% Aqueous ammonium chloride (500 ml) was added, and the mixture was concentrated under reduced pressure. The product was extracted into ethyl acetate and the combined extracts were dried (MgSO4) and concentrated under reduced pressure. The solid residue was treated with boiling hexane (3×500 ml), and the residual solid discarded. The hexane solutions were combined, filtered through a short pad of silica gel, and concentrated under reduced pressure to give the title compound as a yellow oil (34.3 g, 92%), which was characterised by 1H-N.M.R. spectroscopy.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5](N)=[C:4]([CH3:10])[CH:3]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:20].[K+]>O>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([I:20])=[C:4]([CH3:10])[CH:3]=1
Reactant: [I-]
Reactant: Cc1cc(Br)cc(C)c1N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Cc1cc(Br)cc(C)c1I
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
To a stirred mixture of 4-bromo-2,6-dimethylaniline (75 g, 0.37 mol) in distilled water (75 ml) is added concentrated sulphuric acid (75 ml), followed by brief heating to 60° C. for 1 hour until dissolution is complete. The mixture is allowed to cool to room temperature then further cooled to approximately 0° C. in an ice/salt bath. To this slurry is added an aqueous solution of sodium nitrite (25.33 g, 0.36 mol) in distilled water (126 ml) dropwise over 15 minutes, maintaining the temperature below 5° C., followed by additional stirring for 30 minutes. The reaction mixture is allowed to come to room temperature and then a solution of aqueous potassium iodide (187.6 g, 1.13 mol) in distilled water (190 ml) is added dropwise at room temperature. After the addition is complete the solution is briefly heated to 80° C. then allowed to cool to room temperature again. The reaction mixture is extracted with ethyl acetate (750 ml×3) and the organic phase is washed with 1M aqueous hydrochloric acid (200 ml) and aqueous sodium thiosulfate (2×200 ml). The organic phase is dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-bromo-2,6-dimethyl-1-iodo benzene (75 g) as an orange liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:23]=[C:22]([O:24][CH3:25])[C:21]([F:26])=[CH:20][C:11]=1[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13].[CH3:27]OC(OC)N(C)C.C(OCC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2[C:11](=[CH:20][C:21]([F:26])=[C:22]([O:24][CH3:25])[N:23]=2)[C:12](=[O:13])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:27]1
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1cc(F)c(OC)nc1Nc1ccc(F)cc1F
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(OC)c(F)cc2c1=O
Yield: 63.3 %

Procedure:
In 4 ml of benzene was suspended 200 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinoyl]acetate, and 71 mg of N,N-dimethylformamide dimethylacetal was added thereto, after which the resulting mixture was subjected to reaction under reflux for 9 hours. The solvent was removed by distillation under reduced pressure, and to the residue thus obtained was added 2 ml of diethyl ether, after which the crystals thus deposited were collected by filtration to obtain 130 mg (yield 63.3%) of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-methoxy-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 190°-192° C.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][CH:6]=1)=[O:4].[NH2:22][CH:23]([CH3:26])[CH2:24][OH:25]>C1(C)C=CC=CC=1>[OH:25][CH2:24][CH:23]([NH:22][C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][CH:6]=1)=[O:4])[CH3:26]
Reactant: CC(N)CO
Reactant: CCCCc1noc(C)c1CCc1ncc(C(=O)OC)s1
Solvent: Cc1ccccc1
Product: CCCCc1noc(C)c1CCc1ncc(C(=O)NC(C)CO)s1
Yield: 44 %

Procedure:
To a stirred solution of 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid methyl ester (170 mg, 0.55 mmol) in toluene (0.5 mL) was added rac-2-amino-1-propanol (83 mg, 1.1 mmol) and TBD (23 mg, 0.017 mmol). After 15 h the reaction mixture was concentrated in vacuo then purified by chromatography (silica, 0 to 7% methanol in dichloromethane) to give the title compound (85 mg, 44%) as a pale yellow oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:40])[O:13][CH2:14][C@@H:15]([N:26]([CH3:39])[C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[Cl:38])=[O:28])[CH2:16][C:17]2[N:21]3[CH:22]=[CH:23][N:24]=[CH:25][C:20]3=[CH:19][N:18]=2)[N:2]=1.[H][H]>[Pd].CO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:40])[O:13][CH2:14][C@@H:15]([N:26]([CH3:39])[C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[Cl:38])=[O:28])[CH2:16][C:17]2[N:21]3[CH2:22][CH2:23][NH:24][CH2:25][C:20]3=[CH:19][N:18]=2)[N:2]=1
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2ccccc2cn1)Cc1ncc2cnccn12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2ccccc2cn1)Cc1ncc2n1CCNC2
Yield: 34.7 %

Procedure:
To a solution of (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-3-(imidazo[1,5-a]pyrazin-3-yl)propyl isoquinolin-3-ylcarbamate (100 mg, 0.178 mmol) and MeOH (5 mL) were added 10% Pd—C (100 mg). The resulting mixture was stirred under 12 psi of hydrogen for 5 h. The mixture was filtered and concentrated. The resulting residue was purified on prep-HPLC (ACN/H2O with 0.1% HCOOH) to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)propyl isoquinolin-3-ylcarbamate (35 mg, 35%). LRMS (M+H+) m/z 566.1.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([C:7]2[N:11]([CH3:12])[C:10]([S:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[N:9][N:8]=2)[NH2:6])[CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].C(N(CC)CC)C>ClCCl>[Cl:18][C:19]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21]([NH:6][CH:5]([C:7]1[N:11]([CH3:12])[C:10]([S:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[N:9][N:8]=1)[CH2:4][CH:1]1[CH2:2][CH2:3]1)=[O:22]
Reactant: Cn1c(SCC2CC2)nnc1C(N)CC1CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(SCC2CC2)nnc1C(CC1CC1)NC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of the amine obtained in step e in dichloromethane (3 mL) was added 2,4-dichlorobenzoyl chloride (210 μL, 1.5 mmol) and triethylamine (500 μL, 3.6 mmol). The reaction mixture was stirred at room temperature for 6 h. Following aqueous work-up, the residue was purified by chromatography on silica eluting with 40 to 50% ethyl acetate in hexanes to give the title compound. m/z (ES+) 427 (M+H), 425 (M+H).