Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][N:3]1[C:12](=[O:13])[C:11]2[C:6](=[C:7](OC)[C:8]([N:15]3[CH2:19][CH:18]([CH:20]([NH2:22])[CH3:21])[C:17]([CH3:24])(C)[CH2:16]3)=[C:9]([F:14])[CH:10]=2)[N:5]([CH:27]2[CH2:29][CH2:28]2)[C:4]1=[O:30].[C:31]([O:35]C(=O)NC(C1C(C)(C)CN(C2C(OC)=C3C(C(=O)N(N)C(=O)N3C3CC3)=CC=2F)C1)C)(C)([CH3:33])[CH3:32]>>[ClH:1].[NH2:2][N:3]1[C:12](=[O:13])[C:11]2[C:6](=[C:7]([Cl:1])[C:8]([N:15]3[CH2:19][C@@H:18]([C:17]4[CH:24]=[CH:33][C:31]([OH:35])=[CH:32][CH:16]=4)[C@H:20]([NH2:22])[CH2:21]3)=[C:9]([F:14])[CH:10]=2)[N:5]([CH:27]2[CH2:28][CH2:29]2)[C:4]1=[O:30]
Reactant: COc1c(N2CC(C(C)NC(=O)OC(C)(C)C)C(C)(C)C2)c(F)cc2c(=O)n(N)c(=O)n(C3CC3)c12
Reactant: COc1c(N2CC(C(C)N)C(C)(C)C2)c(F)cc2c(=O)n(N)c(=O)n(C3CC3)c12
Agent: Cl
Product: N[C@@H]1CN(c2c(F)cc3c(=O)n(N)c(=O)n(C4CC4)c3c2Cl)C[C@H]1c1ccc(O)cc1

Procedure:
(gggg) 3-Amino-7-[4-(1-aminoethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione hydrochloride (Compound 86) (mp 230° C., MS ES: m/z 406 (MH+)) from {1-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethyl}carbamic acid tert-butyl ester (Example 28w) using General Method A.
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([C:8]23[N:20]([C:21]([C:23]4[C:24]([CH3:28])=[N:25][O:26][CH:27]=4)=[O:22])[CH2:19][CH2:18][N:9]2[C:10](=[O:17])[C:11]2[N:12]([CH:14]=[CH:15][CH:16]=2)[CH2:13]3)=[CH:4][CH:3]=1.[C:29](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C.O>[CH3:28][C:24]1[C:23]([C:21]([N:20]2[C:8]3([C:5]4[CH:4]=[CH:3][C:2](=[O:1])[N:7]([CH3:29])[CH:6]=4)[CH2:13][N:12]4[CH:14]=[CH:15][CH:16]=[C:11]4[C:10](=[O:17])[N:9]3[CH2:18][CH2:19]2)=[O:22])=[CH:27][O:26][N:25]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1nocc1C(=O)N1CCN2C(=O)c3cccn3CC12c1ccc(O)nc1
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1nocc1C(=O)N1CCN2C(=O)c3cccn3CC12c1ccc(=O)n(C)c1
Reaction time: 2.5 h
Yield: 164 %

Procedure:
To a solution of 10a-(6-hydroxypyridin-3-yl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (142) (20 mg, 0.053 mmol) and cesium carbonate (10 mg, 0.031 mmol) in DMF (2 mL) was added methyl iodide (20 μL, 0.32 mmol). LCMS after 2.5 hours showed approx. 50% conversion so extra methyl iodide (30 μL, 0.48 mmol) was added. LCMS after a further 1.75 hours showed no additional progress, so extra cesium carbonate (15 mg, 0.046 mmol) was added. LCMS after 1.5 hours showed the reaction was almost complete, and after 2 hours the mixture was diluted with water (approx. 10 mL) and freeze-dried to yield a white solid. The solid was partitioned between water (5 mL) and dichloromethane (5 mL). The organic layer was separated and the aqueous layer extracted with dichloromethane (2×5 mL). The organic layers were combined, dried (MgSO4), and concentrated in vacuo to yield a white solid. The material was purified by flash chromatography using the Biotage SP4 (4 g cartridge, dichloromethane 3 CV, 0 to 10% methanol-dichloromethane 20 CV, hold 5 CV) and freeze-dried from acetonitrile-water to give 1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-10a-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (143) as a white solid (20 mg, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([Br:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22]>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][C:7]([O:9][CH2:19][CH2:20][CH2:21][Cl:22])=[C:6]([Br:10])[CH:5]=2)=[CH:12][CH:13]=1
Reactant: ClCCCBr
Reactant: COc1cc(O)c(Br)cc1-c1ccc(F)cc1
Product: COc1cc(OCCCCl)c(Br)cc1-c1ccc(F)cc1
Yield: 84 %

Procedure:
The title intermediate was prepared from 4-(2-methoxy-4-hydroxy-5-bromophenyl)fluorobenzene and 3-bromopropyl chloride in 84% yield by the procedure of Preparation 36. NMR
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=2)=[CH:4][C:3]=1[NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21]>C(O)(=O)C>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:21])[F:22])[CH:4]=2)=[N:10][CH:11]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cn2)ccc1Cl)C(F)(F)F
Solvent: CC(=O)O
Product: Nc1ccc(Oc2ccc(Cl)c(NC(=O)C(F)(F)F)c2)nc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
N-{2-Chloro-5-[(5-nitropyridin-2-yl)oxy]phenyl}-2,2,2-trifluoroacetamide (13 g, 35.9 mmol) was dissolved in acetic acid (200 mL), reduced iron (10 g, 179 mmol) was added, and the mixture was stirred at 60° C. for 3 hr. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The concentrated solution was diluted with ethyl acetate (150 mL), aqueous sodium hydrogen carbonate solution (200 mL) was slowly added, and the mixture was filtered through celite. The organic layer was collected, and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residual oil was dissolved in toluene, and the solution was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→20/80) to give the title compound (10.9 g, 91%) as a brown oil.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([CH3:31])([CH2:22][O:23][Si](C(C)(C)C)(C)C)[CH:4]([NH:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[CH3:20])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.CCCCC>C1COCC1>[CH3:32][N:2]([CH3:1])[C:3]([CH3:31])([CH2:22][OH:23])[CH:4]([NH:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[CH3:20])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cccc(C(=O)NC(c2ccccc2)C(C)(CO[Si](C)(C)C(C)(C)C)N(C)C)c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCC
Product: Cc1cccc(C(=O)NC(c2ccccc2)C(C)(CO)N(C)C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A solution of (±)-N-(2-(dimethylamino)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-methyl-1-phenylpropyl)-2,3-dimethylbenzamide D49 (56 mg; 0.12 mmol) in THF (5 ml) was treated with a solution of tetrabutylammonium fluoride (1.0M solution in THF; 0.2 ml, 0.2 mmol) and the mixture stirred at room temperature overnight. The mixture was poured directly onto a chromatography column (Flashmaster II; eluent 0-100% ethyl acetate/pentane) to afford the title compound (38 mg; 63%). 1H NMR (CDCl3) δ: 0.73 and 1.14 (3H, 2×s), 1.70-2.50 (1H, br s), 2.26 (6H, q), 2.38 and 2.48 (6H, 2×s), 3.17, 3.39, and 3.55 (2H, 3×d), 5.26 and 5.46 (1H, 2×d), 6.83 and 7.89 (1H, 2×br d), 7.07-7.46 (8H, br m). Mass spectrum (Electrospray LC/MS), API+: Found 341 (MH+), C21H28N2O2Si requires 340. Ret. time 1.71 and 1.76 min.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:17]([O:20][C:21]1[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:23](Cl)=[O:24])(=[O:19])[CH3:18].C(N(CC)CC)C>CCOCC.CCOC(C)=O>[C:17]([O:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([O:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:11]=1)=[O:24])(=[O:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(O)c1
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccccc1C(=O)Oc1cccc(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
To a solution of Compound 3 in Et2O (120 ml) were added acetylsalicyloyl chloride (Compound 4) (5.9 g, 0.028 mol) and triethylamine (Et3N) (6.6 ml, 0.047 mol) in sequence at RT. The reaction mixture was stirred at RT under argon for 3 days. The reaction mixture was diluted with EtOAc (100 ml) and washed with aqueous saturated NaHCO3 (3×100 ml), brine (1×100 ml), and dried over anhydrous Na2SO4. The crude product obtained upon concentration was purified by column chromatography (elution solvent: 5% EtOAc in hexanes) to produce 9.4 g of Compound 5 in 100% yield.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.[F:19][C:20]([F:39])([F:38])[C:21]1[CH:22]=[C:23]([C:31]2[O:35][N:34]=[C:33]([CH2:36]Cl)[N:32]=2)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1>>[F:39][C:20]([F:19])([F:38])[C:21]1[CH:22]=[C:23]([C:31]2[O:35][N:34]=[C:33]([CH2:36][N:5]3[C:6]4[C:11](=[C:10]([C:13]([F:14])([F:15])[F:16])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH:1]3[CH2:2][CH2:3]3)[N:32]=2)[CH:24]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:26]=1
Reactant: FC(F)(F)c1cc(-c2nc(CCl)no2)cc(C(F)(F)F)c1
Reactant: N#Cc1ccc2[nH]c(C3CC3)cc2c1C(F)(F)F
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2noc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 4 using 2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 5-[3,5-bis(trifluoromethyl)phenyl]-3-(chloromethyl)-1,2,4-oxadiazole: 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 2H), 8.09 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 6.50 (s, 1H), 5.68 (s, 2H), 2.14 (m, 1H), 1.16 (m, 2H), 0.93 (m, 2H); MS (ES) m/z 545 (M+1).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][CH:24]([CH2:27][CH:28]([CH3:31])[CH2:29][OH:30])[CH2:25][OH:26])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:32])=[N:5]1)([CH3:3])[CH3:2].CCN(CC)CC.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][CH:24]([CH2:25][O:26][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:27][CH:28]([CH3:31])[CH2:29][O:30][S:41]([CH3:40])(=[O:43])=[O:42])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:32])=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(CO)CC(C)CO)cc2OCC3)n(C(C)C)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(COS(C)(=O)=O)CC(C)COS(C)(=O)=O)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-4-methylpentane-1,5-diol (90 mg, 0.2038 mmol) and Et3N (85 uL, 0.6114 mmol) in DCM (10 mL) cooled at 0° C. was added methanesulfonyl chloride (40 uL, 0.51 mmol) and stirring at RT was continued for 1.5 h. The mixture was diluted with DCM, washed with a saturated solution of NaHCO3, followed by water, then dried (Na2SO4) and concentrated in vacuo affording Methanesulfonic acid 4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-5-methanesulfonyloxy-2-methylpentyl ester as a colorless gum (quantitative). LCMS: RT 3.07 min [M+H]+ 598.1
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>O1CCCC1>[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]([N:15]1[CH2:16][CH2:17][N:12]([C:10]2[S:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH2:13][CH2:14]1)=[O:34]
Reactant: O=C=Nc1ccccc1Br
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1Br)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 2-bromophenyl isocyanate (0.150 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 241 mg (66.8%) of the desired product as a solid.
Reaction SMILES: [Na].[C:2]([OH:7])(=[O:6])[C:3]([OH:5])=[O:4].Cl[C:9]1[C:10]([C:14]2[CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][CH:19]=2)=[N:11][S:12][N:13]=1>C(O)CCCCCC>[C:2]([OH:7])(=[O:6])[C:3]([OH:5])=[O:4].[CH2:2]([O:7][C:9]1[C:10]([C:14]2[CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][CH:19]=2)=[N:11][S:12][N:13]=1)[CH2:3][CH2:9][CH2:10][CH2:14][CH2:19][CH3:18]
Reactant: CN1CCC=C(c2nsnc2Cl)C1
Agent: O=C(O)C(=O)O
Agent: [Na]
Solvent: CCCCCCCO
Product: CCCCCCCOc1nsnc1C1=CCCN(C)C1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of sodium (120 mg, 5 mmol) in 1-heptanol (10 ml) was added 3-(4-chloro-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine oxalate (310 mg, 1 mmol). The reaction mixture was stirred at 50° C. for 18 h. After evaporation the residue was dissolved in water and extracted with ethyl acetate. The ethyl acetate phase was dried and evaporated to give an oil. Crystallization as the oxalate salt from acetone gave the title compound. Yield: 270 mg (70%). (M.p. 152° C.; M+ : 2g5; Compound 21).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[CH:3]=1.[CH2:13](O)[CH2:14][OH:15].COC(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:9]([CH3:10])[CH3:11])[O:15][CH2:14][CH2:13][O:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCCO
Reactant: CC(C)C(=O)c1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(OC)OC
Solvent: Cc1ccccc1
Product: CC(C)C1(c2cccc(Br)c2)OCCO1
Temperature: 60 °C
Reaction time: 48 h
Yield: 81.5 %

Procedure:
150 mg of 1-bromo-3-isobutyrylbenzene, 204 mg of ethylene glycol, 350 mg of trimethylorthoformate, and 10 mg of p-toluene sulfonic acid were dissolved in 4 mL of toluene, followed by stirring at 60° C. for 2 days. After completion of the reaction, water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was then washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 146 mg (yield 80%) of a title compound as a pale yellow oily substance.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH:6]([C:12](=O)[CH2:13][CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[NH4+].[OH-]>C(O)C>[NH2:1][C:2]1[S:3][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:12]([CH2:13][CH3:14])[N:4]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Br)C(=O)CC
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1sc(N)nc1CC
Temperature: 25 °C
Yield: 103.8 %

Procedure:
To a refluxing solution of thiourea (2.6 g, 34.3 mmol) in absolute ethanol (30 mL) was slowly added at reflux ethyl 2-bromo-3-oxopentanoate (7.3 g, 32.7 mmol). The solution was stirred at reflux for 1.5 hours. After cooling to room temperature, the solution was poured in ice/water (150 mL). The mixture was neutralized with concentrated NH4OH. The solid material was recovered by filtration, washed with water (2×50 mL) and hexanes (3×50 mL), and dried in vacuo, affording ethyl 2-amino-4-ethyl-1,3-thiazole-5-carboxylate (6.8 g, 94% yield). The product was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[N+:13]([CH:16](O)[CH3:17])([O-:15])=[O:14].C(Cl)(Cl)Cl.C(O)(=[O:25])C>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]([OH:7])[CH:16]([N+:13]([O-:15])=[O:14])[CH2:17][OH:25])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: CC(O)[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(C(O)C(CO)[N+](=O)[O-])cc1OC
Temperature: 5 °C
Reaction time: 5.5 h
Yield: 74.7 %

Procedure:
83.1 g (0.5 moles) of 3,4-dimethoxybenzaldehyde are suspended in 45.5 g (0.5 moles) of nitroethanol in the presence of 2.5 ml of triethylamine catalyst, and the mixture is stirred at 5° C. on an ice-water bath for 5.5 hours. 30 ml of chloroform are added to the reaction mixture in small portions within 5 hours. The mixture is allowed to stand for 12 hours under cooling and then acidified with 2 ml of acetic acid. The separated crystals are filtered off, washed with chloroform and ice-cold water and dried. 96.1 g (74.7%) of 1-(3,4-dimethoxyphenyl)-2-nitro-1,3-propanediol are obtained; m.p.: 134°-138° C.
Reaction SMILES: FCC1(NC(=O)CC2C(C(F)(F)F)=CC=CC=2C(N)=O)CCNC1.[F:25][CH2:26][C:27]1([NH:39][C:40](=[O:55])[CH2:41][NH:42][C:43](=[O:54])[C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:53])([F:52])[F:51])[CH:45]=2)[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]1.O1CCOCC1.[ClH:62]>C1COCC1>[ClH:62].[F:25][CH2:26][C:27]1([NH:39][C:40](=[O:55])[CH2:41][NH:42][C:43](=[O:54])[C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:53])([F:51])[F:52])[CH:45]=2)[CH2:31][CH2:30][NH:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCC(CF)(NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Agent: Cl
Agent: NC(=O)c1cccc(C(F)(F)F)c1CC(=O)NC1(CF)CCNC1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1(CF)CCNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(2-{[(3-(Fluoromethyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide. To a solution of 578 mg (1.29 mmol) of tert-butyl 3-(fluoromethyl)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidine-1-carboxylate in 5 mL of THF was added 2 mL of 4 N HCl dioxane solution. The reaction mixture was stirred at room temperature for 1 h and evaporated to give the yellow solid, N-(2-{[3-(fluoromethyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide HCl salt: MS (m/e): 347 (M+1)+.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25].C(OCC)C>C(#N)C>[Br-:20].[CH3:27][O:26][C:24]([C:23]1[CH:28]=[CH:29][CH:30]=[CH:31][C:22]=1[CH2:21][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:25]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1ccccc1CBr
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Reaction time: 1 h
Yield: 81 %

Procedure:
74.2 g of triphenylphosphine (0.28 M) in 200 ml of acetonitrile are added to a solution of 74.5 g of methyl 2-bromomethylbenzoate (0.32 M) in 170 ml of acetonitrile in a 2000 ml reactor. The reaction mixture is refluxed with stirring for one hour and then cooled. 1000 ml of diethyl ether are then added slowly. Stirring is continued for 2 hours. A white precipitate forms. The solid is filtered off and washed with acetone. After drying, 112.6 g of a white powder are obtained (81% yield).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cc(Br)oc1C
Reactant: COc1cccc(B(O)O)c1
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: COCCOC
Product: COC(=O)c1cc(-c2cccc(OC)c2)oc1C
Reaction time: 8 h
Yield: 93 %

Procedure:
A mixture of methyl 5-bromo-2-methyl-3-furancarboxylate (2.2 g), 3-methoxyphenylboronic acid (1.8 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.3 g, 92%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]2[NH:10][CH:11]=[CH:12][N:13]=2)[N:3]=1.[C:14]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]2[N:13]([CH3:14])[CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Clc1cc(-c2ncc[nH]2)nc(Cl)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cn1ccnc1-c1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Yield: 58.5 %

Procedure:
A solution of 2,4-Dichloro-6-(1-dimethylsulfamoylimidazole-2-yl)pyrimidine 83 (246 mg, 0.76 mmol) in 10 mL of 1.5 N HCl was refluxed for 1 h. After cooling to RT, the pH was adjusted to 8.5 with aq NaHCO3 and the product was extracted into CH2Cl2. After drying the CH2Cl2 layer was evaporated to give 110 mg of 2,4-dichloro-6-(imidazole-2-yl)pyrimidine. A mixture of 2,4-dichloro-6-(imidazole-2-yl)pyrimidine (121 mg, 0.56 mmol), K2CO3 (100 mg, 0.72 mmol) and CH3I (2.280 g, 1 mL, 16 mmol) in 15 mL of dry acetone was refluxed for 48 h. After cooling to RT, the solvent was evaporated and the residue was partitioned between water and CH2Cl2. The CH2Cl2 layer was washed successively with water and brine, and then the solvent was evaporated to give 75 mg of 2,4-dichloro-6-(1-methylimidazole-2-yl)pyrimidine 86.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#N)=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:27].[Na+].[OH2:29]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]([OH:29])=[O:27])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)c(C(F)(F)F)c2)CC1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)O)c(C(F)(F)F)c2)CC1

Procedure:
To a stirred solution of 4-(N-tert-butyloxy-carbonyl-4-piperidinyloxy)-2-trifluoromethylbenzonitrile (1.5 g, 3.7 mmol) from Step 1 above in EtOH (25 mL) was added aqueous NaOH (2.3 g, 57 mmol in 15 mL of water). The mixture was heated to reflux for 48 h. Water was added (50 mL) and the volume was concentrated under reduced pressure to ~50 mL. The mixture was extracted with CH2Cl2 (2×25 mL) and the aqueous phase was acidified to pH 3 by the addition of 5 N aqueous HCl. The mixture was extracted with CH2Cl2 (3×25 mL) and the combined organic extracts were dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give 4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-trifluoromethylbenzoic acid as an amorphous solid (HPLC retention time=10.0 min (method A)).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:9]([Cl:26])[CH:8]=1)C.Cl.C(O)(=O)C>O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][CH2:15][O:14][C:10]2[C:9]([Cl:26])=[CH:8][C:7]([O:6][CH2:5][CH:4]=[O:3])=[CH:12][C:11]=2[Cl:13])=[CH:20][CH:21]=1
Reactant: CCOC(COc1cc(Cl)c(OCCCOc2ccc(Cl)cc2)c(Cl)c1)OCC
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=CCOc1cc(Cl)c(OCCCOc2ccc(Cl)cc2)c(Cl)c1
Temperature: 25 °C
Yield: 59.5 %

Procedure:
4-(3-(4-Chlorophenoxy)propyloxy)-3,5-dichlorophenoxyacetaldehyde diethylacetal (manufactured in Production Example 1 of intermediate described hereinafter) (1.6 g) was added dropwise to a mixed solution of 1 ml of hydrochloric acid and 9 ml of acetic acid with stirring at room temperature. After stirring at room temperature for 30 minutes, the reaction solution was poured into iced water and extracted twice with 100 ml of diethyl ether. The ether layers were combined. washed with water, washed twice with aqueous 5% sodium hydrogencarbonate, washed with water, dried over anhydrous magnesium sulfate and then concentrated to obtain 0.8 g of 4-(3-(4-chlorophenoxy)propyloxy)-3,5-dichlorophenoxyacetaldehyde as a crude product.