Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[Br:19][CH2:20][CH2:21][CH2:22]Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:19][CH2:20][CH2:21][CH2:22][N:14]1[CH2:15][CH2:16][N:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C:2]([F:1])([F:17])[F:18])[CH2:12][CH2:13]1
Reactant: ClCCCBr
Reactant: FC(F)(F)COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)COc1ccccc1N1CCN(CCCBr)CC1
Temperature: 25 °C

Procedure:
A mixture of 4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine (2.37 g, 9.1 mmol), 1-bromo-3-chloropropane (14.34 g, 9 mL, 91.1 mmol), potassium carbonate (1.88 g, 13.6 mmol) and acetonitrile (40 mL) was heated 16 hours at reflux under argon. The reaction mixture was allowed to cool to 25° C., then filtered and concentrated in vacuo. The residue was further concentrated at 60° C. in vacuo to remove excess 1-bromo-3-chloropropane. The residue was purified by flash chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to give a mixture of 1-chloro- and 1-bromo-3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propane (1.4 g).
Reaction SMILES: [O:1]=[C:2]1[C:14]2[CH:13]=[C:12]([C:15](Cl)=[O:16])[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5]([C:18](Cl)=[O:19])=[CH:6][CH:7]=2.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>C(Cl)(Cl)Cl>[CH2:21]([N:23]([CH2:24][CH3:25])[C:18]([C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[C:14](=[CH:13][C:12]([C:15]([N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])=[O:16])=[CH:11][CH:10]=3)[C:2](=[O:1])[C:3]=2[CH:4]=1)=[O:19])[CH3:22]
Reactant: CCNCC
Reactant: O=C(Cl)c1ccc2c(c1)C(=O)c1cc(C(=O)Cl)ccc1-2
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)c1ccc2c(c1)C(=O)c1cc(C(=O)N(CC)CC)ccc1-2
Reaction time: 4 h

Procedure:
To a solution of 61.0 g (0.2 mole) of 9-oxofluorene-2,7-dicarbonyl chloride dissolved in 600 ml of chloroform(hydrocarbon stabilized and stored over molecular sieves) is added 58.4 g (0.8 mole) of diethylamine in small increments. The solution is refluxed with stirring for an additional 4 hours, cooled, washed 3 times with water, dried over anhydrous sodium sulfate, filtered, and the volatile materials removed on a steam bath under vacuum. The resulting oil so obtained is triturated with pentane to effect solidification. The residue when recrystallized three times from ethyl acetate yields N,N,N',N'-tetraethyl-9-oxofluorene-2,7-dicarboxamide, m.p. of 142°-3°C, λmaxMeOH 265, and E 1cm1% 2011.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[C:13]([O:27]C)(=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23]>CCCCCCC>[C:22]([O:24][CH:25]1[CH2:6][C:7]([CH3:9])([CH3:8])[N:2]([OH:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)(=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]([O:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([OH:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)=[O:27]
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: COC(=O)CCCCCCCCC(=O)OC
Solvent: CCCCCCC
Product: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Temperature: 75 °C
Reaction time: 24 h

Procedure:
To a 300 ml three-necked flask fitted with a stirrer, nitrogen inlet, thermometer, condenser and Dean-Stark trap is added 34.45 g (0.2 mol) of 1-oxyl-2,2,6,6-tetramethylpiperidin-4-ol, 23.0 g (0.1 mol) of dimethyl sebacate and 110 ml of heptane. The reaction mixture is heated to reflux to dry the contents of the flask and 15 ml of slightly turbid distillate is removed from the Dean-Stark trap. The mixture is cooled to about 75° C. and 0.5 g of tetraisopropyl orthotitanate and 15 ml of heptane is added to the flask. The mixture is heated to reflux and heating at reflux temperature 100°-105° C. is continued for 24 hours with methanol being collected in the Dean-Stark trap. Water (5 ml) is added and heating is continued till all or most of the water is removed. The reaction mixture is allowed to cool slightly, is filtered and washed with heptane. Orange crystals form on standing and are collected by filtration, and washed with heptane. The orange crystalline product melts at 99°-101° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH:7](C(OC)=O)[CH:6]2[CH2:18][C:19]([O:21][CH3:22])=[O:20].[Cl-].[Na+]>O.CS(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7][CH:6]2[CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CC1c2cc(OC)ccc2NC(=O)C1C(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)CC1CC(=O)Nc2ccc(OC)cc21
Temperature: 155 °C

Procedure:
A mixture of 67.0 g of 1,2,3,4-tetrahydro-6-methoxy-3-(methoxycarbonyl)-2-oxo-4-quinoline acetic acid, methyl ester and 13 g of sodium chloride in 23 ml of water and 300 ml of dimethyl sulfoxide was heated at 155° C. for 6 hours, cooled, and diluted with 1.2 l of a 1:1 mixture of ethyl acetate and water. The aqueous phase was separated and extracted with ethyl acetate, and the combined organic layers were washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford 1,2,3,4-tetrahydro-6-methoxy-2-oxo-4-quinoline acetic acid, methyl ester.
Reaction SMILES: [F:1][C:2]1[C:8](F)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.CCN(CC)CC>CS(C)=O.II>[F:1][C:2]1[C:8]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=2)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: II
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1cc(NCc2ccc(F)cc2)c(F)cc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 16 h
Yield: 57.9 %

Procedure:
To a stirred suspension of compound 2 (0.600 g, 3.40 mmol, 1.00 equiv) in dry DMSO (15 mL) was added 4-fluorobenzylamine (1.20 g, 10.0 mmol, 3.00 equiv) followed by Et3N (0.500 mL, 4.10 mmol, 1.20 equiv) and I2 (catalytic, 1.00 mg). The reaction mixture was heated to 120° C. and stirred at 120° C. for 16 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to RT, diluted with water (25 mL) and extracted with EtOAc (2×50 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude; which was purified by silica gel column chromatography (EtOAc/Hexane 2:3) to afford compound 3 (0.550 g, 52.0%) as yellow solid. TLC: 70% EtOAc/Hexane (Rf: 0.20); 1H NMR (400 MHz, DMSO-d6): δ 7.60-7.54 (m, 2H), 7.38-7.32 (m, 4H), 7.17 (t, J=8.8 Hz, 2H), 5.92 (d, J=8.0 Hz, 1H), 4.33 (d, J=6.0 Hz, 2H); LC-MS: m/z=278 (M+-1) at RT 3.59 (99.4% purity).
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([O:9][CH3:10])=[N:7][C:6]([O:11][CH3:12])=[CH:5][N:4]=1.[NH:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18]1[S:19][CH:20]=[CH:21][N:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:10][O:9][C:8]1[C:3]([CH2:2][N:13]2[CH:17]=[CH:16][N:15]=[C:14]2[C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[N:4][CH:5]=[C:6]([O:11][CH3:12])[N:7]=1
Reactant: COc1cnc(CCl)c(OC)n1
Reactant: c1c[nH]c(-c2nccs2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cnc(Cn2ccnc2-c2nccs2)c(OC)n1
Temperature: 45 °C
Reaction time: 16 h
Yield: 80.1 %

Procedure:
A mixture of 2-chloromethyl-3,5-dimethoxy-pyrazine (140 mg, 0.74 mmol), 2-(1H-imidazol-2-yl)-thiazole (106 mg, 0.70 mmol) and K2CO3 (307 mg, 2.22 mmol) in DMF (10 mL) is stirred at 45° C. for 16 hours. On cooling, the reaction is quenched with saturated NH4Cl (5 mL) and extracted with DCM (3×15 mL). The combined organic layers are dried and solvent removed. PTLC (silica gel) separation (10% MeOH in DCM) gives 170 mg of 3,5-dimethoxy-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-pyrazine as an oil. 1H NMR (CDCl3) 7.80 (d, 1H), 7.68 (s, 1H), 7.32 (d, 1H), 7.09 (s, 1H), 6.98 (s, 1H), 5.97 (s, 2H), 3.92 (s, 3H) 3.87 (s, 3H). E. 3-Chloro-2-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-methoxy-pyrazine (Compound 6) 1. Preparation of 3-Chloro-5-methoxy-pyrazine-2-carbaldehyde
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.Cl.[O:11]([NH2:13])[CH3:12]>>[CH3:12][O:11][N:13]=[CH:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=1
Reactant: O=Cc1cccc(F)c1
Reactant: CON
Agent: Cl
Product: CON=Cc1cccc(F)c1
Yield: 94 %

Procedure:
Reaction of 3-fluorobenzaldehyde with methoxylamine hydrochloride as described in the preparation of compound 3-A gave the title oxime ether as a clear oil. (94% yield). HPLC indicated a 88:12 mixture of E- and Z-isomer. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 3.98 (3H, s, OCH3), 7.03-7.08 (2H, m, aromatics), 7.26-7.36 (2H, m, aromatics), 8.02 (1H, s, CH).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4]([CH:5]=[C:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:11](O)=[O:12].S(Cl)([Cl:17])=O>>[CH3:1][C:2]1([CH3:14])[C@@H:4]([CH:5]=[C:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:11]([Cl:17])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C=C1CCCC1
Product: CC1(C)[C@H](C(=O)Cl)[C@@H]1C=C1CCCC1

Procedure:
A mixture of (1R,cis) 2,2-dimethyl-3-(cyclopentylidenemethyl)-cyclopropane-carboxylic acid and thionyl chloride in petroleum ether (b.p.=40° to 70° C.) was refluxed to obtain (1R,cis) 2,2-dimethyl-3-(cyclopentylidenemethyl)-cyclopropane-carboxylic acid chloride which was then reacted with R,S α-hydroxy-6-phenoxy-2-pyridine-acetonitrile in benzene in the presence of pyridine to obtain (R,S)α-cyano-(6-phenoxy-2-pyridyl)-methyl (1R,cis) 2,2-dimethyl-3-(cyclopentylidenemethyl)-cyclopropane-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]CC)=[O:14])=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:20][CH:19]=3)[C:9]=2[N:28]([CH3:30])[CH3:29])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24](=[O:26])(=[O:27])[NH2:25])=[CH:20][CH:19]=3)[C:9]=2[N:28]([CH3:30])[CH3:29])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)cc2)c(N(C)C)c1-c1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)c1c(-c2ccc(Cl)cc2)sc(C(=O)O)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 75 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
Ethyl 5-(4-chlorophenyl)-4-(dimethylamino)-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (compound 34e, 2.00 g, 4.30 mmol) was suspended in ethanol (30 ml) and solution of NaOH (0.86 g, 21.5 mmol) in water (4 ml) was added to it at 25° C. The reaction mixture was then heated at 75° C. under stirring for 2 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue so obtained was diluted with water (10 ml) and cooled using ice bath. To the cooled mixture was added aqueous 10% HCl to bring the pH od the solution to about 6. The mixture so obtained was extracted with ethyl acetate (3×30 ml). The combined organic layer was then dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain the title compound (1.60 g, 85.1%)
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:14]([NH:15][NH2:16])=[CH:13][C:11](=[O:12])[N:10]([CH2:17][CH2:18][CH3:19])[C:8]2=[O:9])=[CH:4][CH:3]=1.[CH3:22][N:23]=[C:24]=S.CO>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:14]3[NH:15][N:16]=[C:22]([NH:23][CH3:24])[C:13]=3[C:11](=[O:12])[N:10]([CH2:17][CH2:18][CH3:19])[C:8]2=[O:9])=[CH:20][CH:21]=1
Reactant: CN=C=S
Reactant: CCCn1c(=O)cc(NN)n(Cc2ccc(F)cc2)c1=O
Solvent: CO
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccc(F)cc2)c1=O
Yield: 36 %

Procedure:
A solution of 1-(4-fluorobenzyl)-6-hydrazino-3-propyluracil (1.5 g, 5.1 mM) and methyl isothiocyanate (1.2 ml, 17 mM) in DMF (20 ml) was heated at 120° C. for 24 hours. To the solution was added 50% methanol (10 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/methanol/water gave pale yellow crystals (0.62 g, 36%), m.p. 262°-265° C.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4]O.[C:6]1(=[O:16])[NH:10][C:9](=[O:11])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[O:1]1[CH2:3][C@@H:2]1[CH2:4][N:10]1[C:6](=[O:16])[C:7]2[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9]1=[O:11]
Reactant: OC[C@H]1CO1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Temperature: 0 °C
Reaction time: 48 h
Yield: 73.9 %

Procedure:
To a cold solution of (S)-1-oxiranylmethanol (5 g, 67.5 mmol) and phthalimide (9.9 g, 67.3 mmol) in tetrahydrofuran (200 mL) in ice bath was added triphenylphosphine (17.9 g, 68.2 mmol) and diethyl azodicarboxylate (12.3 g, 70.6 mmol). The mixture was stirred at 0° C. for 2 h and at ambient temperature for 48 h. The mixture was concentrated under vacuum, and the oily residue was purified by flash silica column chromatography, yielding the desired product (10.1 g) as pale yellow solid: Rf=0.51 in 1:1 EtOAc/hexane. 1H-NMR (CDCl3, 300 MHz): δ (ppm) 7.76-7.64 (m, 2H), 7.63-7.60 (m, 2H), 3.9-3.8 (dd, 1H), 3.70-3.65 (dd, 1H), 3.15 (m, 1H), 2.70-2.67 (dd, 1H), 2.58-2.55 (dd, 1H).
Reaction SMILES: [CH3:1][C@@:2]([S:43]([CH3:46])(=[O:45])=[O:44])([CH2:13][CH2:14][N:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C@H:29]3[CH2:34][CH2:33][C@H:32]([O:35]C4CCCCO4)[CH2:31][CH2:30]3)=[CH:23][CH:22]=2)=[CH:17][C:16]1=[O:42])[C:3]([NH:5][O:6]C1CCCCO1)=[O:4].ONC(=O)[C@](C)(S(C)(=O)=O)CCN1C=CC(C2C=CC(OC[C@H]3CC[C@@H](O)CC3)=CC=2)=CC1=O>>[OH:6][NH:5][C:3](=[O:4])[C@:2]([CH3:1])([S:43]([CH3:46])(=[O:45])=[O:44])[CH2:13][CH2:14][N:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C@H:29]3[CH2:30][CH2:31][C@H:32]([OH:35])[CH2:33][CH2:34]3)=[CH:23][CH:22]=2)=[CH:17][C:16]1=[O:42]
Reactant: C[C@@](CCn1ccc(-c2ccc(OC[C@H]3CC[C@H](OC4CCCCO4)CC3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: C[C@@](CCn1ccc(-c2ccc(OC[C@H]3CC[C@@H](O)CC3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Product: C[C@@](CCn1ccc(-c2ccc(OC[C@H]3CC[C@H](O)CC3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O

Procedure:
The title compound (300 mg, 83%) was prepared from (2R)-2-methyl-2-(methylsulfonyl)-4-[2-oxo-4-(4-{[trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}phenyl)pyridin-1(2H)-yl]-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (480 mg, 0.726 mmol) by a procedure analogous to that described for (2R)—N-hydroxy-4-[4-{4-[(cis-4-hydroxycyclohexyl)methoxy]phenyl}-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanamide Example 8, Step F. LCMS m/z 493.7 (M+1) 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92-1.23 (m, 4H) 1.54 (s, 3H) 1.58-1.72 (m, 1H) 1.81 (br. s., 4H) 2.06-2.21 (m, 1H) 2.41 (s, 1H) 3.08 (s, 3H) 3.25-3.41 (m, 1H) 3.74 (br. s., 1H) 3.80 (d, J=6.44 Hz, 2H) 3.98-4.17 (m, 1H) 6.48-6.71 (m, 2H) 6.85-7.06 (m, 2H) 7.52-7.78 (m, 3H) 11.15 (s, 1H)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](O)=[N:8][C:9]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[C:10]([N+:17]([O-:19])=[O:18])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2].CN(C=O)C.P(Cl)(Cl)([Cl:35])=O>>[Cl:35][C:7]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([N+:17]([O-:19])=[O:18])=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(O)nc(-c2ccc(O)cc2)c([N+](=O)[O-])c1C(=O)OCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Cl)nc(-c2ccc(O)cc2)c([N+](=O)[O-])c1C(=O)OCC
Temperature: 100 °C

Procedure:
In 2.5 ml of phosphorus oxychloride was suspended 130 mg of 3,4-diethoxycarbonyl-2-hydroxy-6-(4-hydroxyphenyl)-5-nitropyridine, whereto 0.4 ml of DMF was added. The mixture was heated at 100° C. for 30 minutes. Then, 0.4 ml of DMF was added and the mixture was heated for further 30 minutes. After the solvent was distilled off, ice-water was added, followed by neutralization with sodium hydrogencarbonate and extraction with ethyl acetate. After the organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried, the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent:ethyl acetate).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.C([O:17][B:18]([CH:24]=[CH2:25])OCCCC)CCC.Cl>C1COCC1.O>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:2][C:3]=1[CH:25]=[CH:24][BH:18][OH:17]
Reactant: C=CB(OCCCC)OCCCC
Reactant: Brc1cccnc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: OBC=Cc1ccccn1
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 3-bromopyridine (1.60 g, 10.0 mmol) in THF (15 mL) was added isopropylmagnesium chloride (2.0 M in THF) (5.0 mL, 10 mmol) under nitrogen atmosphere at room temperature, and the mixture was stirred for 1 h. To the mixture was added vinylboronic acid dibutyl ester (3.4 mL) drop wise, and the mixture was stirred at room temperature for 18 h. Water was added and the pH was adjusted to 7 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (1.04 g, 78%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[C:5]([F:11])=[C:4]([Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:3]=1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[CH3:31][O:32][CH2:33]OC.C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH2:9][CH2:31][O:32][CH3:33])[C:5]([F:11])=[C:4]([Si:12]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:17][CH3:18])[CH:3]=1
Reactant: COCOC
Reactant: CC[Si](CC)(CC)c1cc(Br)nc(C(C)=O)c1F
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CC[Si](CC)(CC)c1cc(Br)nc(C(=O)CCOC)c1F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 72 %

Procedure:
To a solution of 1-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-ethanone (11.6 g, 33.9 mmol, example 1, step b) in dichloromethane (50 ml) was added Hünigs-base (6.21 ml, 35.6 mmol) at 0° C. followed by TMS-triflate (6.43 ml, 35.52 mmol, 1.05 eq.) under nitrogen. The reaction mixture was stirred at 0° C. for 40 minutes. Dimethoxymethane (2.71 g, 35.6 mmol) and 2,6-di-tert-butylpyridine (0.648 g, 3.39 mmol) was added drop wise at 0° C. TMS-triflate (0.61 ml, 3.39 mmol) was then added to the reaction mixture. After 30 min the cooling bath was removed and stirring was continued at rt over night (18 h). The reaction mixture was poured onto cold brine, diluted with ethyl acetate and the organic phase was washed thoroughly with 10% NaHSO4 solution, sat. sodium bicarbonate solution (saturated with NaCl) and brine, dried over sodium sulfate, filtered and evaporated. The crude product (13.52 g) was chromatographed over silica gel (320 g, cyclohexane/ethyl acetate 95:5) to give the title compound as a yellow liquid: 9.18 g (72% yield).
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:18][C:19]3[CH:28]=[CH:27][C:22]4[O:23][CH2:24][CH2:25][O:26][C:21]=4[CH:20]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[O:23]1[C:22]2[CH:27]=[CH:28][C:19]([NH:18][C:14]3[C:15]4[CH2:16][CH2:17][NH:8][CH2:9][C:10]=4[N:11]=[CH:12][N:13]=3)=[CH:20][C:21]=2[O:26][CH2:25][CH2:24]1
Reactant: c1ccc(CN2CCc3c(ncnc3Nc3ccc4c(c3)OCCO4)C2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: c1nc2c(c(Nc3ccc4c(c3)OCCO4)n1)CCNC2
Reaction time: 24 h
Yield: 93.8 %

Procedure:
7-Benzyl-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-amine(700 mg, 1.8 mmol) was dissolved in methanol (25 mL) and palladium hydroxide was added (150 mg, 20% wt). The mixture was shaken on a Parr Shaker under H2(g) atmosphere (60 PSI) for 24 hours. The mixture was filtered through celite and evaporated to give 480 mg of material as a white solid, which was used as such for the next step.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[Cl:29])=[C:19]([F:30])[C:8]2[N:9]=[CH:10][N:11]([CH2:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[C:7]=2[CH:6]=1)=[O:4].O1CCCC1.O.[Li+].[OH-]>O.Cl.C(OCC)(=O)C.O1CCCC1>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:20]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]3[N:11]([CH2:12][CH:13]4[CH2:18][CH2:17][CH2:16][CH2:15][O:14]4)[CH:10]=[N:9][C:8]=3[C:19]=2[F:30])=[C:23]([Cl:29])[CH:24]=1
Reactant: COC(=O)c1cc2c(ncn2CC2CCCCO2)c(F)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1cc2c(ncn2CC2CCCCO2)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylic acid methyl ester 11q is suspended in 4:1 tetrahydrofuran/water (2.5 mL) and aqueous 1 M LiOH is added (2.5 mL). After stirring at room temperature for 16 hours, the reaction mixture is homogeneous and the reaction is complete. The reaction mixture is cooled to 0° C., diluted with water and aqueous 2 M HCl is added dropwise until the pH of the solution is 1-2, at which time it turns to a suspension. The reaction mixture is poured into a separatory funnel and diluted with ethyl acetate/tetrahydrofuran and water and the layers separated. The aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with brine, dried (Na2SO4) and concentrated under reduced pressure to yield 0.11 g (100%) of the pure desired product as a white solid. MS ESI (+) m/z 482, 484 (M+, Br pattern) detected.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.[C:23]([O:30][CH2:31][CH2:32][Cl:33])(=[O:29])[CH2:24][CH2:25][C:26]([O-])=[O:27].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:26]([O:8][C:7]1[CH:6]=[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])[C:4]([F:22])=[CH:3][C:2]=1[Cl:1])(=[O:27])[CH2:25][CH2:24][C:23]([O:30][CH2:31][CH2:32][Cl:33])=[O:29]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: O=C([O-])CCC(=O)OCCCl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OC(=O)CCC(=O)OCCCl)c(Cl)cc2F)c1=O

Procedure:
using 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione and mono (2-chloroethyl) succinate with N,N'-dicyclohexylcarbodiimide and 4-dimethylaminopyridine as the catalyst in methylene chloride there is obtained 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H) -pyrimidinyl]-4-fluorophenyl 2-chloroethyl succinate. m.p. 94°-96° C.;