Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH2:8].[CH2:22]1C[O:25][CH2:24][CH2:23]1.C(O)C#C>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:8][C:7]1[C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])=[CH:3][C:2]=1[C:22]#[C:23][CH2:24][OH:25]
Reactant: C1CCOC1
Reactant: Nc1c(I)cc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#CCO
Solvent: CCOC(C)=O
Product: Nc1c(C#CCO)cc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
3-Iodo-5-nitro-2′-trifluoromethyl-biphenyl-4-ylamine (466 mg, 1.14 mmol, as prepared in Example 9, step A), (Ph3P)2PdCl2 (0.05 eq., 40.1 mg, 0.057 mmol), and CuI (0.05 eq., 10.2 mg, 0.054 mmol) were placed in a 40 mL vial equipped with a magnetic stir bar. The vial was evacuated and backflushed with Ar, and anhydrous THF (6 mL) and TEA (4.0 eq., 0.64 mL, 4.56 mmol) were added via syringe. Propargyl alcohol (4 eq., 0.270 mL, 4.56 mmol) was added via syringe, and the reaction was stirred at RT for 16 h. The solution was diluted with EtOAc (20 mL) and filtered. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography on a 24-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 3:2, v/v over 20 min, yielding 279 mg (73%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 8.10 (d, J=2.0 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.53-7.59 (m, 1H), 7.53 (d, J=1.8 Hz, 1H), 7.43-7.51 (m, 1H), 7.29 (d, J=7.6 Hz, 1H), 6.82 (br. s., 2H), 4.59 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][C:14](CO)([OH:16])[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:13][C:14](=[O:16])[CH2:15]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: OCC1(O)CC(c2nc(I)c3c(Cl)nccn23)C1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C1CC(c2nc(I)c3c(Cl)nccn23)C1
Reaction time: 5 h

Procedure:
A solution of 3-(8-chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-1-hydroxymethyl-cyclobutanol (4.08 g, 0.011 mol) in THF (120 mL) and water (40 mL) was charged with sodium periodate (2.8 g, 0.013 mol) at 0° C. The reaction warmed to it and stirred for 5 h. The reaction mixture was diluted with ethyl acetate and then washed with brine. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound as a yellow solid; 1H NMR (CDCl3, 400 MHz) δ 7.56 (1 H, d, J=4.94), 7.32 (1 H, d, J=4.98), 3.64 (5 H, m); MS (ES+): m/z 347.82/349.85 (100/30) [MH+]; HPLC: tR=2.89 min. (OpenLynx, polar—5 min.).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=CC=C[CH:3]=1.[C:10]([O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)(=O)[C:11]([CH3:13])=C.Cl[C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1>>[C:1]([O:9][CH:11]([CH2:13][O:30][C:27]1[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=1)[CH2:10][O:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)(=[O:8])[C:2]([CH3:7])=[CH2:3]
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C(O)c1ccccc1
Reactant: C=C(C)C(=O)Oc1ccc(Cl)cc1
Product: C=C(C)C(=O)OC(COc1ccccc1)COc1ccc(Cl)cc1
Yield: 96 %

Procedure:
A reaction was conducted as described in Example 6 except that benzoic acid was replaced with the same molar amount of 4-chlorophenyl methacrylate, a compound represented by formula (3) where R2 is isopropenyl and OZ1 is an organic group derived from 4-chlorophenol. Desired 1-(4-chlorophenoxy)-3-phenoxy-2-propyl methacrylate was formed in an analytical yield of 96% and isolated in a yield of 90%.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:12]([NH:20][C:21](=[O:29])[NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.O>CN(C)C=O>[C:12]([NH:20][C:21]([NH:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)[CH2:25][CH2:24]1)=[O:29])(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)c1ccc(CCl)cc1
Reactant: O=C(NC(=O)c1ccccc1)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ccc(CN2CCC(NC(=O)NC(=O)c3ccccc3)CC2)cc1

Procedure:
4-Isopropylbenzyl chloride (0.84 g, 0.005 m), 4-benzoylureidopiperidine (1.28 g, 0.005 m) and triethylamine (0.6 g) in dimethylformamide (25 cm3) were stirred at room temperature for 24 hours. Water was added and the precipitated solid filtered off. The solid was suspended in isopropylalcohol and acidified with ethanolic HCl. The title compound was filtered off and dried (1.2 g), m.p. 240°-242° C. as the hydrochloride salt, hemihydrate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)N.ClC1C=C(Cl)C=C(Cl)C=1.[F-:19]>>[F:1][C:2]1[CH:3]=[C:4]([F:19])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: [F-]
Reactant: Nc1cc(F)cc(F)c1
Agent: Clc1cc(Cl)cc(Cl)c1
Product: Fc1cc(F)cc(F)c1

Procedure:
In a further embodiment, the present invention relates to a method for the two step preparation of 3,5-difluoroaniline from 1,3,5-trichlorobenzene. First, an amount of 1,3,5-trichlorobenzene is reacted with a fluoride-containing compound to obtain 1,3,5-trifluorobenzene. Second, the 1,3,5-trifluorobenzene is reacted with aqueous ammonia and a metal oxide or metal hydroxide to obtain the product 3,5-difluoroaniline.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10][N:11]=[C:12]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.CS([C:25]1[N:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH3:34])[N:26]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:34][O:33][C:27]1[CH:28]=[C:29]([O:31][CH3:32])[N:30]=[C:25]([O:1][C:2]2[C:3]([C:8]([O:10][N:11]=[C:12]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=2)[N:26]=1
Reactant: CCCCC(CCCC)=NOC(=O)c1ncccc1O
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(CCCC)=NOC(=O)c1ncccc1Oc1nc(OC)cc(OC)n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a mixture of 6.3 g of 5-nonanylidenamino 3-hydroxypicolinate, 2.5 g of 2-methylsulfonyl-4,6-dimethoxypyrimidine and 3.9 g of anhydrous potassium carbonate, 50 ml of N,N-dimethylformamide was added, and the mixture was stirred at 100° C. for 2 hours. After cooling, the reaction solution was poured into water and extracted with ethyl ether. The organic layer was further washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue thereby obtained was purified by silica gel column chromatography by using as a developing solvent a mixture of hexane/ethyl ether to obtain 5.2 g of the above identified compound as slightly yellow transparent viscous liquid.
Reaction SMILES: CC(O)C.C([C@@](C(O)=O)(O)[C@@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.[O:31]=[C:32]([N:46]1[CH2:51][CH2:50][N:49]2[C:52]([C:55]([F:58])([F:57])[F:56])=[N:53][N:54]=[C:48]2[CH2:47]1)[CH2:33][CH:34]([NH2:45])[CH2:35][C:36]1[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=1[F:44]>CO>[O:31]=[C:32]([N:46]1[CH2:51][CH2:50][N:49]2[C:52]([C:55]([F:58])([F:57])[F:56])=[N:53][N:54]=[C:48]2[CH2:47]1)[CH2:33][C@@H:34]([NH2:45])[CH2:35][C:36]1[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=1[F:44]
Reactant: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: O=C(O)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)O)C(=O)c1ccccc1
Solvent: CC(C)O
Solvent: CO
Product: N[C@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 62.5 °C
Reaction time: 1 h

Procedure:
In a 50 mL three neck flask IPA (5 mL) and Dibenzoyl-L-tartaric acid (1.75 g) were taken. It was heated to 60-65° C. 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (2.0 g, % purity-94%) dissolved in methanol (6 mL) was added into reaction mixture at 60-65. It was stirred for 60 min. at 60-65° C. Solid salt was precipitated. It was gradually cooled to room temperature over a period of 2 to 3 hrs. The salt was filtered and washed with a mixture of IPA: MeOH (2:1, 10 mL). An enantiomerically enriched desired Dibenzoyl-L-tartaric acid salt of mixture of (2R) and (2S)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine was obtained (Wt.-1.08 g, % Y-29%, Purity by HPLC-99.1%, % Chiral purity by HPLC of R-isomer 76.7%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6](Cl)[C:7]=1[Cl:8].Cl.[CH2:11]([O:13][C:14](=[O:17])[CH2:15][NH2:16])[CH3:12].C(N(C(C)C)CC)(C)C>C(O)C>[Cl:8][C:7]1[C:6]([NH:16][CH2:15][C:14]([O:13][CH2:11][CH3:12])=[O:17])=[CH:5][N:4]=[N:3][C:2]=1[Cl:1]
Reactant: CCOC(=O)CN
Reactant: Clc1cnnc(Cl)c1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)CNc1cnnc(Cl)c1Cl
Yield: 30.8 %

Procedure:
A solution of 3,4,5-trichloropyridazine (300 mg), glycine ethyl ester hydrochloride (228 mg) and diisopropylethyl amine (844 μL) in ethanol was stirred for 3 hours under reflux. After the reaction was completed, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9 to 1:1) to give 126 mg (31% yield) of the title compound as a pale pink amorphous.
Reaction SMILES: [OH-:1].[Na+:2].[CH:3]1([C:8]2[C:9](=[O:21])[O:10][C:11](=[O:20])[C:12]=2[C@H:13]2[CH2:18][CH2:17][C@@H:16]([OH:19])[CH2:15][CH2:14]2)[CH2:7][CH2:6][CH2:5][CH2:4]1>O1CCOCC1>[CH:3]1(/[C:8](=[C:12](\[C@H:13]2[CH2:18][CH2:17][C@@H:16]([OH:19])[CH2:15][CH2:14]2)/[C:11]([O-:10])=[O:20])/[C:9]([O-:21])=[O:1])[CH2:7][CH2:6][CH2:5][CH2:4]1.[Na+:2].[Na+:2]
Reactant: O=C1OC(=O)C([C@H]2CC[C@@H](O)CC2)=C1C1CCCC1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C([O-])/C(=C(\C(=O)[O-])[C@H]1CC[C@@H](O)CC1)C1CCCC1
Reaction time: 3 h

Procedure:
A 1 M NaOH (0.3 ml, 0.30 mmol) was added to a solution of 3-cyclopentyl-4-(cis-4-hydroxycyclohexyl)furan-2,5-dione (40 mg, 0.15 mmol) in 1,4-dioxane (1.0 ml) at room temperature, and the mixture was stirred for 3 hr. The reaction mixture was concentrated, and the residue was dried in vacuo to give the title compound as a colorless solid (50 mg, quantitative).
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=2)[CH:8]=1)[C:3](=[O:6])[CH2:4][CH3:5].[CH3:20][NH:21][C:22](=S)[NH:23][NH2:24]>C(O)C>[CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]3[N:15]([C:22]([NH:21][CH3:20])=[N:23][N:24]=3)[N:14]=2)[CH:8]=1)[C:3](=[O:6])[CH2:4][CH3:5]
Reactant: CNC(=S)NN
Reactant: CCC(=O)N(C)c1cccc(-c2ccc(Cl)nn2)c1
Solvent: CCO
Product: CCC(=O)N(C)c1cccc(-c2ccc3nnc(NC)n3n2)c1
Yield: 16 %

Procedure:
A solution of 5.0 g of N-methyl-N-[3-(6-chloro-3-pyridazinyl)phenyl]propanamide and 3.8 g 4-methylthiosemicarbazide in 200 ml ethanol was refluxed for 18 hours. The mixture was then treated and the product chromatographed as described in Example 70. Recrystalization of the product from dichloromethane-hexane afforded 0.9 g yellow powder, mp 212°-213° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[O:17])=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH:2]=1.B1(C2C=CC([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=NC=2)OC(C)(C)C(C)(C)O1>>[O:36]1[CH2:37][CH2:38][N:33]([C:6]2[N:1]=[CH:2][C:3]([C:7]3[C:15]4[C:10](=[CH:11][C:12]([CH:16]=[O:17])=[CH:13][CH:14]=4)[NH:9][N:8]=3)=[CH:4][CH:5]=2)[CH2:34][CH2:35]1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Reactant: O=Cc1ccc2c(-c3cccnc3)n[nH]c2c1
Product: O=Cc1ccc2c(-c3ccc(N4CCOCC4)nc3)n[nH]c2c1

Procedure:
According to procedure for the synthesis of 3-(pyridin-3-yl)-1H-indazole-6-carbaldehyde, except substituting 2-(4-morpholino)pyridine-5-boronic acid pinacol ester (64 mg, 0.22 mmol), the title compound was prepared as a yellow powder (35 mg, 62%). 1H NMR (400 MHz, d6-DMSO) δ ppm 13.71 (br s, 1H), 10.14 (s, 1H), 8.77 (d, J=1.9 Hz, 1H), 8.02-8.18 (m, 2H), 8.15 (dd, J=8.9 Hz, 2.5, 1H), 7.64 (d, J=8.6 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 3.73 (t, J=4.5 Hz, 4H), 3.53 (t, J=5.1 Hz, 4H); MS ESI 309.1 (100) [M+H]+, calcd for [C17H16N4O2+H]+ 309.13.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:22])[C:7]3[C:15](=[O:16])[N:14]([CH2:17][CH2:18]SC)[N:13]=[C:12]([OH:21])[C:8]=3[NH:9][C:10]=2[CH:11]=1.O[O:24][S:25]([O-:27])=O.[K+].[CH3:29]O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:22])[C:7]3[C:15](=[O:16])[N:14]([CH2:17][CH2:18][S:25]([CH3:29])(=[O:27])=[O:24])[N:13]=[C:12]([OH:21])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: CSCCn1nc(O)c2[nH]c3cc(Cl)ccc3c(=O)c2c1=O
Reactant: O=S([O-])OO
Reactant: CO
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)CCn1nc(O)c2[nH]c3cc(Cl)ccc3c(=O)c2c1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 7-chloro-4-hydroxy-2-(2-methylthioethyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione (0.11 g, 0.33 mM) in methanol (5 mL) stirred at room temperature, was added OXONE, a monopersulfate compound (250 mg, 1.0 mM) dissolved in water (1 mL). The resulting mixture was stirred at room temperature for 17 hours. Water (10 mL) was added and the reaction mixture was filtered. The crude product was again stirred with warm water to completely remove the oxidant. Filtration and vacuum drying yielded the product analytically pure as a white solid. Isolated 95 mg, 75%.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:36])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH2:23][CH2:22]3)[CH:16]=1)[C:11]([CH3:35])([CH3:34])[CH2:10]2)=[O:4].O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[Cl:36][C:7]1[CH:8]=[C:9]2[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1)[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH2:25][CH2:26]3)[CH:16]=1)[C:11]([CH3:35])([CH3:34])[CH2:10]2
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(N3CCN(c4ccccc4C)CC3)c1)C(C)(C)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccccc1N1CCN(c2cccc(C3Nc4c(cc(Cl)cc4C(=O)O)CC3(C)C)c2)CC1
Temperature: 60 °C
Reaction time: 12 h
Yield: 41.9 %

Procedure:
A mixture of 6-chloro-3,3-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (0.36 g, 0.73 mmol), lithium hydroxide hydrate (310 mg, 7.3 mmol), water (2.0 mL) in methanol (3 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 6-chloro-3,3-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (150 mg, 42%) as a white solid: LC/MS m/e calcd for C29H32ClN3O2M+: 490.05, observed: 490.1.
Reaction SMILES: COC.[CH2:4](O)[CH3:5].COC.[C:10]1([C:12](=[CH:14][C:15](=[C:17]([CH:19]=1)[CH3:18])[CH3:16])[CH3:13])[CH3:11]>CO>[CH3:18][C:17]1[CH:19]=[CH:10][C:12]([CH3:13])=[C:14]([CH3:15])[C:4]=1[CH3:5].[C:10]1([C:12](=[CH:14][C:15](=[C:17]([CH:19]=1)[CH3:18])[CH3:16])[CH3:13])[CH3:11]
Reactant: CCO
Agent: COC
Agent: Cc1cc(C)c(C)cc1C
Solvent: CO
Product: Cc1ccc(C)c(C)c1C

Procedure:
The entire reactor system is operated at elevated pressure, 50 to 100 atmospheres, with modest pressure decreases due to pressure drop as a result of flow through the catalysts, pipes, and heat exchangers. This pressure drop is maintained at modest values to economize on the size and cost of the recycle compressor. The high pressure enhances the conversion of synthesis gas to the methanol intermediate in the first stage, has no effect in the conversion of methanol to the intermediate dimethylether. However, it is known in the art (Yurchak) that the conversion of ethanol/dimethylether to gasoline in the third stage also produces heavy gasoline, principally ≧C8 aromatics, such as tri-methyl benzenes, tetramethyl benzenes, and durene. In particular, highly undesirable tetra-methyl benzene and durene are produced which have high melting points (79° C. or greater) and limited solubility in the hydrocarbon mixture even at room temperature. Their viscometric behavior cannot be tolerated in an all-weather commercial fuel. In the present process, however, this intermediate product, containing heavy gasoline, is converted to desirable hydrocarbon products in the fourth stage by significantly reducing the trimethylbenzene and tetramethylbenzene and durene isomer groups via hydrotreating and producing desirable fuel compounds such as toluene, xylenes and C4 to C8 hydrocarbons, principally C5 to C7 hydrocarbons. This conversion is obtained by the proper choice of catalyst, space velocity and temperature of the reactor. The presence of heavy gasoline in the product produced from the third reaction is undesirable because it increases the freezing temperature of the fuel which renders the fuel unusable in old weather. The fourth reactor converts the heavy gasoline to toluene, xylenes, and/or C4 to C8 hydrocarbons, which lowers the freezing point of the fuel product. Preferably, the fuel product coming out of the fourth reactor has a freezing point of less than about −5° C., preferably about −15 to about −20° C., while the product coming out of the third reactor has a freezing point of about 30-50° C.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1B(O)O>O1CCOCC1.O>[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Reactant: OB(O)c1ccco1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(COc2ccc(-c3ccco3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of intermediate 1; 74 mg, 0.2 mmol) in dioxane/water (10:1, 4.4 mL) was degassed for 20 min and then added to a reaction vial containing potassium carbonate (82 mg, 0.6 mmol) and furan-2-boronic acid (0.6 mmol; available from Aldrich Chemical Company, Inc., Milwaukee, Wis.). The solution was degassed for a further 2 min and then bis(tri-cyclohexylphosphine)palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 14 mg, 0.02 mmol) was added. The mixture was degassed for 30 seconds and then heated in a microwave oven at 170 degrees for 25 min. The reaction mixture was filtered through silica and the silica washed with dioxane (1 mL), dimethylacetamide (1 mL), and 20% methanol in dichloromethane (1 mL). The filtrate was placed in a vial and 2 M potassium hydroxide solution (0.4 mL) was added. The mixture was stirred at room temperature overnight, and then 1 M HCl was added until a solid formed (approxiamtely 2 mL). The vial was centrifuged and the solvent was removed. The product was dried overnight in the oven. Mass spectrum MH+=295.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][C:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:10])[CH2:6][CH2:5]1.[CH2:18]([N:25]([CH3:35])[C:26]1[CH:31]=[C:30]([N:32]=[C:33]=[O:34])[CH:29]=[CH:28][N:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:11]([C:7]1([OH:10])[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:33]([NH:32][C:30]2[CH:29]=[CH:28][N:27]=[C:26]([N:25]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:35])[CH:31]=2)=[O:34])[CH2:5][CH2:6]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NCCN1CCC(O)(Cc2ccccc2)CC1
Reactant: CN(Cc1ccccc1)c1cc(N=C=O)ccn1
Product: CN(Cc1ccccc1)c1cc(NC(=O)NCCN2CCC(O)(Cc3ccccc3)CC2)ccn1

Procedure:
The compound is prepared from 1-(2-amino-ethyl)-4-benzyl-piperidin-4-ol (93 mg, 0.40 mmol) and 2-(benzyl-methyl-amino)-4-isocyanato-pyridine (95.7 mg, 0.40 mmol) using the method described for Example 388D.
Reaction SMILES: [C:1]([NH:11][C:12]([CH3:17])([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH2:18][C@@H:19]1[CH2:25][CH2:24][C:23]2[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=[CH:29][C:22]=2[NH:21][C:20]1=[O:33].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH2:4]([O:3][C:1]([NH:11][C:12]([CH3:13])([CH3:17])[C:14]([NH:18][C@@H:19]1[CH2:25][CH2:24][C:23]2[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=[CH:29][C:22]=2[NH:21][C:20]1=[O:33])=[O:16])=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: N[C@@H]1CCc2cc([N+](=O)[O-])ccc2NC1=O
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2cc([N+](=O)[O-])ccc2NC1=O

Procedure:
Prepared from N-carbobenzyloxy-2-methylalanine and 3(R)-amino-7-nitro-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Step A) substituting benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate for benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate according to the procedure described in Example 1, Step I. 1H NMR (400 MHz, CDCl3): δ 1.48 (s, 3H), 1.49 (s, 3H), 2.00 (m, 1H), 2.73 (m, 2H), 2.92 (m, 1H), 4.45 (m, 1H), 5.07 (s, 2H), 5.30 (s, 1H), 7.05 (d, 8 Hz, 1H), 7.30 (m, 6H), 8.06 (dd; 8, 6 Hz; 1H), 8.13 (d, 2.5 Hz, 1H), 8.35 (s, 1H). FAB-MS: calculated for C22H24N4O6 424; found 425 (M+H, 100%).
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:5]=[N:4][N:3]=1.[O:11]=[CH:12][C:13]([Cl:16])([Cl:15])[Cl:14]>C1C=CC=CC=1>[OH:11][CH:12]([S:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:5]=[N:4][N:3]=1)[C:13]([Cl:16])([Cl:15])[Cl:14]
Reactant: CCCCn1cnnc1S
Reactant: O=CC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCCCn1cnnc1SC(O)C(Cl)(Cl)Cl

Procedure:
3-Mercapto-4-n-butyl-1,2,4-triazole (2.0 g. or 0.127 mole) and chloral (3.68 g. or 0.0254 mole) were heated in benzene (30 ml.) until a precipitate formed (10 minutes). The mixture was cooled, the precipitate was collected, dried, and recrystallized from ether-hexane to give 3-(1-hydroxy-2,2,2-trichloroethylmercapto)-4-n-butyl-1,2,4-triazole melting at 95°-97° C. The structure was confirmed by its nuclear magnetic resonance spectrum.
Reaction SMILES: C[C:2]1([CH3:10])CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]([CH3:30])([CH3:29])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][O:27][CH3:28])=[CH:21][N:20]=1.[OH2:31]>C1COCC1>[F:16][C:17]([CH3:30])([CH3:29])[CH2:18][C:19]1[CH:24]=[C:23]([CH:2]([OH:31])[CH3:10])[C:22]([O:25][CH2:26][O:27][CH3:28])=[CH:21][N:20]=1
Reactant: O
Reactant: COCOc1ccc(CC(C)(C)F)nc1
Reactant: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1cnc(CC(C)(C)F)cc1C(C)O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
2,2,6,6-Tetramethylpiperidine (8.26 ml, 49.0 mmol) was dissolved with 270 ml THF and 1-butyllithium (14.1 ml, 35.4 mmol) was added at −78° C. The mixture was stirred for 10 min in an ice bath and cooled back to −78° C. A solution of 2-(2-fluoro-2-methylpropyl)-5-(methoxymethoxy)pyridine (5.8000 g, 27.2 mmol) in 20 ml THF was added dropwise and the reaction was stirred for 20 min. Acetylaldehyde (7.65 ml, 136 mmol) was added to the dark red solution and the color disappeared. Stirring was continued for 20 min and the mixture was hydrolyzed with 50 ml of water. The mixture was warmed to RT and extracted 3× with CH2Cl2 (300 ml each). The combined organic extracts were dried over MgSO4 and evaporated and purified via glass col. chrom. (30-80% EtOAc in hex.) to provide 1-(2-(2-fluoro-2-methylpropyl)-5-(methoxymethoxy)pyridin-4-yl)ethanol a white solid. MS m/z: 258.2 (M+1).