Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]([OH:23])=O)[C:17]=3[CH:24]=2)[C:3]1=[O:25].C(Cl)(=O)C(Cl)=O.[Cu](C#N)C#N.[CH2:37]([Li])[CH2:38][CH2:39][CH3:40]>C(Cl)Cl.CN(C)C=O.O1CCCC1>[CH3:1][N:2]1[C:7]([C:8]([F:11])([F:9])[F:10])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21](=[O:23])[CH2:37][CH2:38][CH2:39][CH3:40])[C:17]=3[CH:24]=2)[C:3]1=[O:25]
Reactant: [Li]CCCC
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(=O)O)c3c2)c1=O
Agent: N#C[Cu]C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCC(=O)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: -78 °C
Yield: 63.9 %

Procedure:
To a solution of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxylic acid (0.200 g, 0.000540 mol) in methylene chloride is added N,N-dimethylformamide (one drop) followed by oxalyl chloride in methylene chloride (2.0 M, 0.540 ml, 0.00108 mol). The resultant mixture is stirred at room temperature for 90 minutes and concentrated in vacuo to a white solid, which is saved. To a suspension of copper cyanide (0.061 g, 0.000675 mol) in tetrahydrofuran, is added dropwise n-butyllithium (2.5 M in hexanes, 0.540 ml, 0.00135 mol) at −78° C. The reaction mixture is allowed to warm for 5 minutes and then cooled back to −78° C. The mixture is then treated with a solution of the white solid from the first step in tetrahydrofuran, and the resultant mixture stirred one hour at −78° C. The reaction mixture is quenched with saturated ammonium chloride and diluted with ethyl acetate. The organic layer is washed sequentially with saturated ammonium chloride, water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to a yellow syrup. Chromatography of the syrup on silica gel using hexanes:ethyl acetate gives the title compound as a colorless syrup (0.142 g, 64.0%) which is identified by NMR spectral analysis.
Reaction SMILES: C([NH:4][CH:5]([C:10]([OH:12])=[O:11])[CH2:6][CH2:7][S:8][CH3:9])(=O)C.[OH-].[Na+]>O>[NH2:4][C@H:5]([C:10]([OH:12])=[O:11])[CH2:6][CH2:7][S:8][CH3:9]
Reactant: CSCCC(NC(C)=O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 120 h
Yield: 31.2 %

Procedure:
717 g (3.75 mol) N-Acetyl-D,L-Methionine and 140 g (3.50 mol) sodium hydroxide were dissolved in water and made up to 1.5 liters. The pH value was adjusted to 7 with 50% aqueous sodium hydroxide solution. After addition of 3.6 g acylase (activity 31.000 E/g), the mixture was stirred for 5 days at room temperature. The suspension was cooled to 5° C. and the precipitate filtered off, washed with 300 ml of ice water and dried. There was obtained 174 g (1.17 mol) L-methionine. The filtrate (1800 g) which contained, in addition to 21.8 wt % N-Acetyl-D(L)-Methionine, 2.8 wt % L-Methionine was warmed to 60° C. and treated with 6 g (0.60 mol) acetic anhydride. After 30 minutes no methionine was detectable in the solution. There was added 223 g (1.17 mol) N-Acetyl-D,L-Methionine and concentrated under vacuum to 1200 g. The solution was concentrated to 752 g in a Sambay-evaporator under 170° C. and 10 mbar. Into the still warm melt were added 15 g of acetic anhydride, heated for 10 minutes at 140° C., then this was dissolved in water and made up to 1.5 liters. The specific rotation of the solution was 0. The content of N-Acetyldipeptide amounted to 0.8% relative to N-Acetyl-methionine. After the pH value was adjusted to 7 with aqueous sodium hydroxide as described above, acylase splitting was again carried out. The yield was 166 g (1.11 mol) L-Methionine.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:11])([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH3:5].C([Al]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH3:5][C:4]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)([CH3:11])[CH2:3][OH:2]
Reactant: COC(=O)C(C)(C)c1cccs1
Agent: CC(C)C[Al]CC(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(CO)c1cccs1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.5 %

Procedure:
A solution of 2-methyl-2-thiophen-2-yl-propionic acid methyl ester (2.085 g, 11.32 mmol) in CH2Cl2 (55 mL) at 0° C. is treated with diisobutylaluminum hydrde (Dibal-H, 1.0 M PhMe, 24.0 mL, 24.0 mmol) and warmed to rt after 4 min. After 1.5 h the reaction mixture is cooled to 0° C. and quenched with 1N tartaric acid (50 mL) and stirred for 2 d. The layers are separated and the aqueous layer is extracted with CH2Cl2 (1×50 mL). The combined extracts are dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted with hexanes using a gradient of 0% to 75% EtOAc to give 2-methyl-2-thiophen-2-yl-propan-1-ol (1.494 g, 84%) as a clear oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH2:9])=[O:8])=[C:5]([N+:10]([O-])=O)[CH:4]=[N:3]1.C1N=CN([C:18](N2C=NC=C2)=[O:19])C=1>C(#N)C>[CH3:1][N:2]1[C:6]2[C:7](=[O:8])[NH:9][C:18](=[O:19])[NH:10][C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc([N+](=O)[O-])c1C(N)=O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: Cn1ncc2[nH]c(=O)[nH]c(=O)c21
Temperature: 100 °C
Reaction time: 18 h
Yield: 91.7 %

Procedure:
This compound was prepared following the method described in WO2008/071650. To a stirred solution of 1-methyl-4-nitro-1H-pyrazole-5-carboxamide (1.27 g, 9.06 mmol) in acetonitrile (35.6 mL) refluxed at 100° C. was added N,N-carbonyldimidazole (1.91 g, 11.78 mmol, 1.3 eq.) proportion wise over 1 hour. The reaction mixture was stirred at 100° C. under N2 for 18 hours. The resultant precipitate was filtered, rinsed well with cold acetonitrile, and pumped dry on high-vac to yield 1.38 g (91.5%) of a white solid. 1H NMR (DMSO-d6, 500 MHz) δ ppm 11.04 (broad d, 2H), 7.34 (s, 1H), 4.04 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O.N(CCCC#N)=NCCCC#N>C(Cl)(Cl)(Cl)Cl>[Br:12][CH:6]1[C:5]2[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=2)[C:8](=[O:9])[O:7]1
Reactant: O=C1OCc2ccc(Br)cc21
Reactant: O=C1CCC(=O)N1Br
Agent: N#CCCCN=NCCCC#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OC(Br)c2ccc(Br)cc21

Procedure:
6-Bromophthalide (5.85 gms; 0.0275 mole), N-bromosuccinimide (4.89 gm; 0.0275 mole) and azobisbutyronitrile (0.1 gm) were gently refluxed in dry carbon tetrachloride (200 ml.) for 2 hours. On cooling, the succinimide was filtered off and the solvent removed in vacuo to give an oil, which was used immediately.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[CH2:7][CH:6]3[CH2:23][O:24][CH2:25][CH2:26][N:5]3[C:4]=2[N:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[C:37]3[CH:43]=[CH:42][NH:41][C:38]3=[N:39][CH:40]=2)O1>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:8]2[CH2:7][CH:6]3[CH2:23][O:24][CH2:25][CH2:26][N:5]3[C:4]3[N:3]=[C:2]([C:35]4[CH:36]=[C:37]5[CH:43]=[CH:42][NH:41][C:38]5=[N:39][CH:40]=4)[N:11]=[CH:10][C:9]2=3)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: CS(=O)(=O)c1ccc(CN2CC3COCCN3c3nc(Cl)ncc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(CN2CC3COCCN3c3nc(-c4cnc5[nH]ccc5c4)ncc32)cc1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 3 using 2-chloro-5-(4-(methylsulfonyl)benzyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x9, 50 mg, 0.127 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (61.8 mg, 0.253 mmol) and PdCl2(dppf) (4.63 mg, 6.33 μmol) in dioxane (2 mL) and aqueous saturated NaHCO3 (0.4 mL). 1H NMR (400 MHz, DMSO-d6) δ 3.14-3.26 (m, 2H), 3.31-3.45 (m, 6H), 3.54-3.65 (m, 2H), 3.93-4.03 (m, 1H), 4.03-4.13 (m, 1H), 4.62-4.72 (m, 2H), 6.51-6.61 (m, 1H), 7.44-7.53 (m, 1H), 7.53-7.60 (m, 1H), 7.60-7.68 (m, 2H), 7.89-7.96 (m, 2H), 8.67-8.73 (m, 1H), 8.99-9.07 (m, 1H), 11.76-12.07 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C24H24N6O3S, 477.16. found 477.3.
Reaction SMILES: CN(CCN(C)C)C.Br[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[CH:14]1[N:20]([CH3:23])[CH2:21][CH2:22][C:13]21[CH3:24].[C:25](OCCCC)(=[O:33])[C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27].[Cl-].[NH4+]>O1CCCC1>[O:33]=[C:25]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[CH:14]1[N:20]([CH3:23])[CH2:21][CH2:22][C:13]21[CH3:24])[C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27]
Reactant: CCCCOC(=O)C(=O)OCCCC
Reactant: CN1CCC2(C)c3cc(Br)ccc3N(C)C12
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCOC(=O)C(=O)c1ccc2c(c1)C1(C)CCN(C)C1N2C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a nitrogen purged 100 ml 3 neck round bottom flask was added anhydrous tetrahydrofuran (THF) (7.0 ml). Sec-butyllithium (1.3M in cyclohexane, 8.9 ml) was then added, the solution cooled to -78° C. and treated with TMEDA (1.6 ml; 11.0 mmol). A solution of 5-bromo-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indole (2.50 g) in anhydrous THF (6.0 ml) was added via canula and the mixture stirred at -78° C. for 11/2 hours and -20° C. for 1 hour. The resulting solution was then added via canula to a solution of freshly distilled dibutyl oxalate (5.5 ml) in THF (9.0 ml) at -78° C. and maintained at this temperature with stirring for 1 hour. After allowing the mixture to slowly come to room temperature, saturated ammonium chloride solution (10 ml) was added and the solvent removed under reduced pressure. The product was purified by preparative HPLC (silica gel, eluted with 10% methanol in ethyl acetate). The appropriate fractions were combined and evaporated to give 0.51 g of an oil, which upon trituration with hexane afforded 1,2,3,3a,8,8a-hexahydro-α-oxo-1,3a,8-trimethyl-5-pyrrolo[2,3]-indole acetic acid, n-butyl ester, as a solid, m.p. 56°-61° C.
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(Cl)(=[O:20])C1C=CC=CC=1.O>N1C=CC=CC=1.C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[OH:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[C:7](=[O:20])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)Cc2cccc(O)c2O1
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)Oc2c(O)cccc2C1=O
Temperature: 25 °C
Reaction time: 10 h

Procedure:
7-Hydroxy-2,3-dihydro-2,2-dimethylbenzofurane is dissolved in 100 ml pyridine. 0.5 mol benzoyl chloride is added dropwise at 0° C. within 4 h. Subsequently it is stirred for 10 h at room temperature. It is poured onto 200 ml ice water and aspirated. The residue is washed with 500 ml 2 M hydrochloric acid and then with 1000 ml water and dried in air. A solution of 0.906 mol chromium trioxide in 370 ml glacial acetic acid is added dropwise to a solution of this crude product (0.45 mol) in 600 ml glacial acetic acid in such a way that the temperature of the mixture does not exceed 20° C. After the dropwise addition is completed it is stirred for a further 1 hour at 40° C. and subsequently poured onto 2 l water. It is suction filtered. The residue is washed with 1 l water and recrystallized from ethanol/water 3:1. The benzoyl compound is fed into 400 ml 10% ethanolic potassium hydroxide solution and the mixture is heated for 1 hour to 70° C. It is admixed with 3 l water and suction filtered. The residue is recrystallized from 2 l water.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1>O1CCCC1.[Pd]>[F:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN1CCC(c2cccnc2F)=CC1=O
Agent: [Pd]
Solvent: C1CCOC1
Product: CN1CCC(c2cccnc2F)CC1=O

Procedure:
A solution of 4-(2-fluoropyridin-3-yl)-1-methyl-5,6-dihydropyridin-2(1H)-one (0.067 g, 0.325 mmol) in tetrahydrofuran (1.6 mL) was added palladium, 10 wt. % on activated carbon (0.035 g, 0.032 mmol) and hydrogenated (double-walled balloon pressure) at 40° C. for 3 h. The mixture was filtered via a pad of Celite, and the filtrate was concentrated in vacuo to give a relatively pure crop of 4-(2-fluoropyridin-3-yl)-1-methylpiperidin-2-one as a milky oil. [M+1]=209.0.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][O:10][C:11](=[O:20])[CH2:12][CH2:13][CH2:14][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1.C(OP(CCCCC1C=CSC=1Br)(=O)OCC)C>>[CH3:9][O:10][C:11](=[O:20])[CH2:12][CH2:13][CH2:14][C:15]1[S:16][C:17]([Br:8])=[CH:18][CH:19]=1
Reactant: COC(=O)CCCc1cccs1
Reactant: O=C1CCC(=O)N1Br
Agent: CCOP(=O)(CCCCc1ccsc1Br)OCC
Product: COC(=O)CCCc1ccc(Br)s1
Yield: 90 %

Procedure:
The NBS bromination of 1b according to the procedure outlined for the preparation of 2a gave >90% yield of 2b as a colorless oil. b.p.: 138° C. at 0.15 mmHg. 1H NMR (250 MHz, 25° C., CDCl3): δ6.82 (d, 1H, Ar—H), 6.52 (d, 1H, Ar—H), 3.64 (s, 3H, OCH3), 2.79 (t, 2H, CH2CO2Me), 2.33 (t, 2H, Ar—CH2), 1.93 (tt, 2H, CH2CH2CH2).
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17])=O.P(Cl)(Cl)(Cl)(Cl)Cl.[CH:24]([Cl:27])(Cl)[Cl:25]>CCOCC>[C:8]1(=[O:17])[N:7]([CH2:6][CH2:5][CH2:4][O:3][CH:24]([Cl:27])[Cl:25])[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]12
Reactant: ClC(Cl)Cl
Reactant: O=COCCCN1C(=O)c2ccccc2C1=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1CCCOC(Cl)Cl

Procedure:
A mixture of 3-(phthalimido)-propyl formate (17 g), phosphorus pentachloride (15.2 g) and alcoholfree chloroform was heated for 1 hour on the steam bath. After cooling and addition of ether, the crystalline product was isolated by filtration. M.p. 101°-103° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2OCO[C:6]=2[CH:5]=[C:4]([C:11]2[C:15]([C:16]([F:19])([F:18])[F:17])=[N:14][N:13]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[C:12]=2[NH2:26])[CH:3]=1.CO[CH:29]1[CH2:33][CH2:32][CH:31](OC)O1>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[C:15]([C:16]([F:19])([F:18])[F:17])=[N:14][N:13]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[C:12]=2[N:26]2[CH:29]=[CH:33][CH:32]=[CH:31]2)[CH:5]=[C:6]([C:16]([F:19])([F:18])[F:17])[CH:7]=1
Reactant: Nc1c(-c2cc(Cl)c3c(c2)OCO3)c(C(F)(F)F)nn1-c1ncccn1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(Cl)cc(-c2c(C(F)(F)F)nn(-c3ncccn3)c2-n2cccc2)c1
Yield: 114.5 %

Procedure:
A mixture of 4-(7-chloro-1,3-benzodioxol-5-yl)-2-pyrimidin-2-yl-5-(trifluoromethyl)pyrazol-3-amine (0.383 g, 1.00 mmol) and 2,5-dimethoxytetrahydrofuran (0.145 g, 1.10 mmol) in acetic acid was stirred under reflux for 1 hour. After cooling, the precipitate was filtered off and recrystallized from ethanol to give the title compound (0.262 g, 57%).
Reaction SMILES: C([O:4][C@H:5]1[CH2:9][C:8](=[O:10])[N:7]([CH:11]2[C:20]3[C:15](=[N:16][C:17]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=4[Cl:35])=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)[CH:19]=3)[O:14][C:13]([CH3:37])([CH3:36])[CH2:12]2)[C:6]1=[O:38])(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:19]=[C:20]3[CH:11]([N:7]4[C:8](=[O:10])[CH2:9][C@H:5]([OH:4])[C:6]4=[O:38])[CH2:12][C:13]([CH3:37])([CH3:36])[O:14][C:15]3=[N:16][C:17]=2[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])=[CH:22][CH:23]=1
Reactant: CC(=O)O[C@H]1CC(=O)N(C2CC(C)(C)Oc3nc(-c4ccc(Cl)cc4Cl)c(-c4ccc(Cl)cc4)cc32)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC1(C)CC(N2C(=O)C[C@H](O)C2=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Temperature: 85 °C

Procedure:
The product of Step A (38 mg, 0.7 mmol) was dissolved in MeOH (2 mL) and p-toluenesulfonic acid (6 mg, 0.03 mmol) was added. The reaction was heated at 85° C. for 2 h and concentrated. The residue was dissolved in EtOAc and the solution was washed with saturated aq NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel gradient eluted with 0-60% EtOAc in hexane to afford the title compound. Further separation on an AD chiral column, eluting with 50% IPA/heptane, afforded the diastereomers: (LC-2) HPLC/MS (fast isomer on AD): 531.0 (M+1), 533.0 (M+3); Rt=3.58 min. (LC-2) HPLC/MS (slow isomer): 531.0 (M+1), 533.0 (M+3); Rt=3.59 min.
Reaction SMILES: [CH3:1][CH2:2]/[C:3](/[C:7]1[C:12]2[N:13]([CH3:17])[C:14](=[O:16])[NH:15][C:11]=2[CH:10]=[CH:9][N:8]=1)=[CH:4]\[CH2:5][CH3:6]>C(O)C.[Pd]>[CH3:1][CH2:2][CH:3]([C:7]1[C:12]2[N:13]([CH3:17])[C:14](=[O:16])[NH:15][C:11]=2[CH:10]=[CH:9][N:8]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CC/C=C(\CC)c1nccc2[nH]c(=O)n(C)c12
Agent: [Pd]
Solvent: CCO
Product: CCCC(CC)c1nccc2[nH]c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.4 %

Procedure:
To a solution of 0.36 g (1.6 mmol) of (E)-4-(hex-3-en-3-yl)-3-methyl-1H-imidazo[4,5-c]pyridin-2(3H)-one in 30 mL of ethanol was added 0.99 g (10 mol % Pd) of palladium on carbon (50% wet, Degussa type). The reaction was kept under a hydrogen atmosphere via a balloon and stirred at room temperature for 6 h. The catalyst was removed via filtration and the filtrate was concentrated in vacuo to give 0.33 g (91%) of the title compound as a grey oil that solidified upon standing.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([C:25]4[CH:30]=[C:29]([C:31](=[O:42])[NH:32][C:33]5([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)[CH2:35][CH2:34]5)[CH:28]=[CH:27][C:26]=4[CH3:43])=[CH:18][C:11]=3[C:12]=2[C:13]([O:15]CC)=[O:14])=[CH:4][CH:3]=1>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([C:25]4[CH:30]=[C:29]([C:31](=[O:42])[NH:32][C:33]5([C:36]6[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=6)[CH2:34][CH2:35]5)[CH:28]=[CH:27][C:26]=4[CH3:43])=[CH:18][C:11]=3[C:12]=2[C:13]([OH:15])=[O:14])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3cc(C(=O)NC4(c5ccccc5)CC4)ccc3C)cc12
Solvent: CO
Product: Cc1ccc(C(=O)NC2(c3ccccc3)CC2)cc1-c1cc2c(C(=O)O)c(-c3ccc(F)cc3)oc2cc1[N+](=O)[O-]

Procedure:
Prepared by the hydrolysis of ethyl 2-(4-fluorophenyl)-5-(2-methyl-5-(1-phenylcyclopropylcarbamoyl)phenyl)-6-nitrobenzofuran-3-carboxylate. LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters MICROMASS®. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: XTERRA® MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)+=551.34, HPLC Rt=1.895 min.
Reaction SMILES: [Cl:1][C:2]1[C:27]([O:28][C@@H:29]([CH3:34])[C:30]([O:32]C)=[O:31])=[CH:26][C:5]2[C:6]([C:9]3[C:10]([CH2:23][CH2:24][CH3:25])=[N:11][C:12]([O:15][C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[OH-].[Na+].C(O)(=O)C>CO>[Cl:1][C:2]1[C:27]([O:28][C@@H:29]([CH3:34])[C:30]([OH:32])=[O:31])=[CH:26][C:5]2[C:6]([C:9]3[C:10]([CH2:23][CH2:24][CH3:25])=[N:11][C:12]([O:15][C:16]4[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CCCc1nc(Oc2ccc(Cl)cc2)ccc1-c1noc2cc(Cl)c(O[C@@H](C)C(=O)OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCCc1nc(Oc2ccc(Cl)cc2)ccc1-c1noc2cc(Cl)c(O[C@@H](C)C(=O)O)cc12

Procedure:
The ester from Step 1 (2.3 g, 4.5 mmol) was dissolved in methanol (45 mL) and treated with 2 N NaOH (4.5 mL, 9.0 mmol) at room temperature for 1 h. The reaction mixture was acidified with acetic acid (2.0 mL) and methanol was removed under reduced pressure. The residue was taken up in ethyl acetate and the resulting solution was washed with brine and dried over MgSO4. After removal of the solvent, the crude acid was recrystallized in ether-hexane (1:10) to give the title product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH3:20]>C1C=CC=CC=1.N1C=CC=CC=1>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:3]=1[C:4]([NH2:20])=[O:5]
Reactant: N
Reactant: O=C(O)c1c(C(F)(F)F)ccc(Cl)c1Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: NC(=O)c1c(C(F)(F)F)ccc(Cl)c1Cl
Temperature: 5 °C

Procedure:
To a solution of 250 g of 2,3-dichloro-6-trifluoromethylbenzoic acid in 2 liters of benzene was added 5 drops of pyridine and 172 g of thionyl chloride and then the mixture was heated at reflux for 22 hours. After cooling down, the solution was concentrated under reduced pressure, and 2,3-dichloro-6-trifluoromethylbenzyl chloride obtained was added into 1 liter of 28% aqueous ammonia solution, which has been cooled down to 5° C. over 10 minutes with stirring. Then, the solution was further stirred for 1 hour at room temperature. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water and then with saturated saline solution, and was dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure, and the crude crystals obtained were washed with n-hexane and then filtered to give 229 g of the title compound(mp. 118-20° C.).
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(C=CC=2)N)C=CN=1.[Cl:23][C:24]1[N:29]=[C:28]([C:30]2[S:34][C:33]([C:35]([CH3:38])([CH3:37])[CH3:36])=[N:32][C:31]=2[C:39]2[C:40]([F:53])=[C:41]([NH:46]C(=O)OCC=C)[CH:42]=[CH:43][C:44]=2[F:45])[CH:27]=[CH:26][N:25]=1>>[Cl:23][C:24]1[N:29]=[C:28]([C:30]2[S:34][C:33]([C:35]([CH3:38])([CH3:37])[CH3:36])=[N:32][C:31]=2[C:39]2[C:40]([F:53])=[C:41]([NH2:46])[CH:42]=[CH:43][C:44]=2[F:45])[CH:27]=[CH:26][N:25]=1
Reactant: C=CCOC(=O)Nc1ccc(F)c(-c2nc(C(C)(C)C)sc2-c2ccnc(Cl)n2)c1F
Agent: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)(C)c1nc(-c2c(F)ccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Yield: 81 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 13 using 2-propen-1-yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}carbamate (2.962 g, 6.37 mmol) (from composite batches prepared as described above) the title compound of Step B was obtained (1.96 g, 81% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.67 (d, J=5.3 Hz, 1H), 7.09 (d, J=5.3 Hz, 1H), 6.88-7.02 (m, 2H), 5.23 (s, 2H), 1.45 (s, 9H); MS (ESI): 380 [M+H]+.
Reaction SMILES: [Cl-].[C:2]1([N+:8]#[N:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC=CC=1.Cl.[NH2:18][C:19]1[N:20]=[C:21]([CH:26]([CH3:28])[CH3:27])[NH:22][C:23](=[O:25])[CH:24]=1.[OH-].[Na+]>O>[NH2:18][C:19]1[N:20]=[C:21]([CH:26]([CH3:28])[CH3:27])[NH:22][C:23](=[O:25])[C:24]=1[N:9]=[N:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#[N+]c1ccccc1
Reactant: CC(C)c1nc(N)cc(=O)[nH]1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Nc1ccccc1
Product: CC(C)c1nc(N)c(N=Nc2ccccc2)c(=O)[nH]1
Reaction time: 1 h

Procedure:
A cold solution of benzenediazonium chloride [prepared, by the method well known in the art, from 13.3 g. aniline in a 1:1 v/v mixture of water and concentrated hydrochloric acid (120 ml)] was added dropwise with stirring to a solution of 4-amino-2-isopropylpyrimid-6-one (28 g.) and sodium hydroxide (14.8 g.) in water (450 ml.) at 5° C. After stirring for a further 1 hour, the mixture was filtered. The filtrate was adjusted to pH 6 by the addition of aqueous sodium hydroxide solution, and the resultant solid was isolated to give crude 4-amino-2-isopropyl-5-phenylazopyrimid-6-one (33.5 g.), m.p. 215°-219° C. Recrystallisation from ethanol gave pure 4-amino-2-isopropyl-5-phenylazopyrimid-6-one (8.3 g.), m.p. 235°-236° C. (with decomposition).