Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([O:5][CH2:6][CH2:7][CH2:8][N:9]1[C:14](=[O:15])[C:13]2[C:16]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[S:18][C:12]=2[N:11]([CH3:34])[C:10]1=[O:35])=O.O[Li].O>C1COCC1.O.C(Cl)Cl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C:16]2[C:13]3[C:14](=[O:15])[N:9]([CH2:8][CH2:7][CH2:6][OH:5])[C:10](=[O:35])[N:11]([CH3:34])[C:12]=3[S:18][C:17]=2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[CH:32][CH:31]=1
Reactant: Cn1c(=O)n(CCCOC(=O)C(F)(F)F)c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3cccc(Cl)c3)sc21
Agent: [Li]O
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3cccc(Cl)c3)sc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.1 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-6-(3-chlorophenyl)-1-methyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propyl 2,2,2-trifluoroacetate (40 mg, 0.070 mmol) in THF (4 mL) and water (4 mL) was added LiOH.H2O (5.88 mg, 0.14 mmol). The reaction was stirred at RT for 15 min then diluted with DCM (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-6-(3-chlorophenyl)-3-(3-hydroxypropyl)-1-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (16 mg, 48.1% yield) as a white solid. 1H-NMR (DMSO-d6) δ: 7.49 (d, J=5.1 Hz, 2H), 7.40 (s, 1H), 7.36-7.32 (m, 1H), 7.29 (d, J=8.4 Hz, 2H), 7.04 (d, J=8.4 Hz, 2H), 4.45 (t, J=5.2 Hz, 1H), 4.30 (s, 2H), 3.97-3.82 (m, 2H), 3.52 (d, J=14.8 Hz, 3H), 3.42 (dd, J=11.7, 6.3 Hz, 2H), 1.67 (dd, J=14.2, 6.9 Hz, 2H). LCMS: MH+ 475 and TR=3.252 min.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH:6]([C:8]([OH:10])=[O:9])[CH2:5][N:4]=[CH:3]1.S(Cl)([Cl:13])=O.[CH2:15](O)[CH2:16][CH3:17]>>[ClH:13].[NH:4]1[CH2:5][CH:6]([C:8]([O:10][CH2:15][CH2:16][CH3:17])=[O:9])[CH2:7][N:2]=[CH:3]1
Reactant: CCCO
Reactant: O=C(O)C1CN=CNC1
Reactant: O=S(Cl)Cl
Agent: Cl
Product: CCCOC(=O)C1CN=CNC1
Yield: 56 %

Procedure:
1,4,5,6-Tetrahydropyrimidine-5-carboxylic acid hydrochloride (1.5 g, 9.1 mmol) was dissolved in 1-propanol (30 ml). To the mixture was added thionyl chloride (1.1 g, 9.1 mmol) and the solution was refluxed for 22h. The solvent was evaporated in vacuo to dryness. The residue was crystallized from methanol/THF to give 1.06 g (56%) of white crystals, mp 128°-130° C. 300 MHz nmr indicated product. Microanalysis calc.: C 46.49, H 7.26, N 13.56, found: C 46.21, H 6.96, N 17.41.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1)=[O:28].[CH2:40]([NH2:43])[CH:41]=[CH2:42]>>[F:37][C:36]([F:39])([F:38])[C:33]1[CH:34]=[CH:35][C:30]([O:29][C:27](=[O:28])[N:2]([C@H:3]2[CH2:4][CH2:5][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:43][CH2:40][CH:41]=[CH2:42])[CH2:7][CH2:8]2)[CH3:1])=[CH:31][CH:32]=1
Reactant: CN[C@H]1CC[C@H](CCCCCOS(C)(=O)=O)CC1
Reactant: O=C(Cl)Oc1ccc(C(F)(F)F)cc1
Reactant: C=CCN
Solvent: O=C(O)C(F)(F)F
Product: C=CCNCCCCC[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to examples 29.10 and 29.11, trans-Methansulfonic acid 5-(4-methyl amino-cyclohexyl)-pentyl ester.Trifluoroacetic acid salt and 4-trifluoromethyl-phenyl chloroformate were reacted, followed by treatment allylamine to give trans-{4-[5-(Allylamino)-pentyl]-cyclohexyl}-methyl-carbamic acid 4-trifluoromethyl-phenyl ester, MS: 427 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[NH2:12])=[O:4].Cl[C:14](OC1C=CC([N+]([O-])=O)=CC=1)=[O:15].C(N(C(C)C)CC)(C)C.[Cl:35][C:36]1[CH:45]=[C:44]2[C:39]([C:40]([N:47]3[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]3)=[CH:41][C:42]([NH2:46])=[N:43]2)=[CH:38][CH:37]=1>>[NH2:46][C:42]1[CH:41]=[C:40]([N:47]2[CH2:52][CH2:51][N:50]([C:14]([NH:12][CH:6]3[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:5]3[C:3]([O:2][CH3:1])=[O:4])=[O:15])[CH2:49][CH2:48]2)[C:39]2[C:44](=[CH:45][C:36]([Cl:35])=[CH:37][CH:38]=2)[N:43]=1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)C1CCCCCC1N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCCCCC1NC(=O)N1CCN(c2cc(N)nc3cc(Cl)ccc23)CC1

Procedure:
As described for 78, 2-methoxycarbonyl cycloheptyl amine, 4-nitrophenyl chloroformate, diisopropyl(ethyl)amine, and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product. LC-MS: 460 (M++1). 1H NMR (CDCl3) δ 7.72 (d, 1H), 7.60 (s, 1H), 7.18 (d, 1H), 6.15 (s, 1H), 5.50 (d, 1H), 4.70 (s, 2H), 4.15 (m, 1H), 3.70 (s, 3H), 3.60 (m, 4H), 3.10 (m, 4H), 2.95 (m, 1H), 2.00 (m, 1H), 1.85 (m, 3H), 1.65 (m, 5H), 1.45 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([S:14]([CH2:17][CH2:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)(=[O:16])=[O:15])[CH:5]=[CH:4][C:3]1=2.C(O)C.O>O1CCCC1>[CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([S:14]([CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=3)(=[O:16])=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc(CCS(=O)(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(S(=O)(=O)CCc3ccc(C(=O)O)cc3)ccc21
Reaction time: 4 h
Yield: 87.7 %

Procedure:
The methyl 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulphonyl)-ethyl]benzoate (3.54, 8.54 mmol) is placed in solution in 256 ml of tetrahydrofuran, 25.6 ml of ethanol and 12.8 ml of water in a round-bottomed flask. 3.54 g of lithia monohydrate are added. The whole mixture is stirred for 4 hours at reflux. Ambient the reaction medium is concentrated by half, taken up with ethyl acetate and water and then brought to pH6 with 2N HCl. After extraction, the organic phase is washed with a saturated NaCl solution, dried over MgSO4, concentrated and washed with ether. 3 g of 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulphonyl)ethyl]benzoic acid are obtained in the form of a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH2:17][CH3:18])[CH:3]=1.C([Li])CCC.C[O:25]B(OC)OC.Cl.OO>O1CCCC1.C1(C)C=CC=CC=1>[CH2:17]([C:4]1[CH:3]=[C:2]([OH:25])[CH:7]=[C:6]([CH3:8])[C:5]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:18]
Reactant: CCc1cc(Br)cc(C)c1OCc1ccccc1
Reactant: COB(OC)OC
Agent: Cl
Agent: OO
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1cc(O)cc(C)c1OCc1ccccc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
Then, 35.6 g of 4-bromo-2-ethyl-6-methyl-1-benzyloxybenzene was dissolved in 250 ml of tetrahydrofuran, and 69 ml of n-butyl lithium solution (in hexane; 1.69 mol/liter), while stirring at -70° C. After further stirring at -70° C. for 2 hours, a solution of 12.1 g of trimethoxyboron dissolved in 50 ml of tetrahydrofuran was added dropwise to the reaction mixture. After completion of the dropwise addition, the reaction mixture was returned to room temperature, stirred for 1 hour, and then poured into ice water. The mixture was made weak acidic by the addition of 10% hydrochloric acid, and extracted twice with 500 ml of diethyl ether. The ether layers was combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated to give a residue. To the residue was added 120 ml of toluene, and 33 ml of 30% aqueous hydrogen peroxide was added dropwise, while heating at 70° C. under stirring. After heating under reflux for 1 hours, the reaction mixture was returned to room temperature, washed once with water, twice with 10% aqueous ferrous ammonium sulfate and then once with water. The toluene layer was dried over anhydrous magnesium sulfate, and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 26.2 g of 3-ethyl-4-benzyloxy-5-methylphenol (93% yield).
Reaction SMILES: COC(=O)COC1C=C(OC)C(SCCC=O)=CC=1C.C(NCC)C1C=CC=CC=1.C[O:32][C:33](=[O:64])[CH2:34][O:35][C:36]1[CH:41]=[C:40]([O:42][CH3:43])[C:39]([S:44][CH2:45][CH2:46][CH2:47][N:48]([CH2:61][CH3:62])[C:49]2[CH:54]=[CH:53][C:52]([C:55]3[CH:60]=[CH:59]C=CC=3)=CN=2)=[CH:38][C:37]=1[CH3:63]>>[CH2:49]([N:48]([CH2:61][CH3:62])[CH2:47][CH2:46][CH2:45][S:44][C:39]1[C:40]([O:42][CH3:43])=[CH:41][C:36]([O:35][CH2:34][C:33]([OH:32])=[O:64])=[C:37]([CH3:63])[CH:38]=1)[C:54]1[CH:53]=[CH:52][CH:55]=[CH:60][CH:59]=1
Reactant: CCN(CCCSc1cc(C)c(OCC(=O)OC)cc1OC)c1ccc(-c2ccccc2)cn1
Agent: CCNCc1ccccc1
Agent: COC(=O)COc1cc(OC)c(SCCC=O)cc1C
Product: CCN(CCCSc1cc(C)c(OCC(=O)O)cc1OC)Cc1ccccc1

Procedure:
Compound 64A and benzyl-ethyl-amine were reacted in a manner analogous to Compound 64C to give the title product. MS m/z 418 (M+1). Step 3. Preparation of {4-[3-(Benzyl-ethyl-amino)-propylsulfanyl]-5-methoxy-2-methyl-phenoxy}-acetic acid (Compound 67)
Reaction SMILES: [Si]([N:8]1[CH:11](CC=O)[CH2:10][C:9]1=[O:15])(C(C)(C)C)(C)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([Mg:24][Br:25])=[CH:20][CH:19]=1>CCOCC>[NH:8]1[CH2:11][CH2:10][C:9]1=[O:15].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([Mg:24][Br:25])=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC=O
Agent: COc1ccc([Mg]Br)cc1
Solvent: CCOCC
Product: O=C1CCN1

Procedure:
Treatment of 1-(t-butyldimethylsilyl)-4-(2-oxoethyl)-2-azetidinone (0.01 mole) with p-methoxyphenyl-magnesium bromide (1.1 eq.; in ether at 0° C. gives 2-azetidinone with p-methoxyphenyl-magnesium bromide gives 1-(t-butyl dimethylsilyl)-4-(2-hydroxyethyl-2-p-methoxyphenyl)-2-azetidinone which is acetylated as described before (Ex. 3, Step C) to give 4-(2-acetoxy-2-p-methoxyphenyl)-2-azetidinone.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C(=O)(O)[O-].[K+].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:22](Cl)=[O:23]>C1C=CC=CC=1>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:22]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2)=[O:23]
Reactant: Nc1cccc2cnccc12
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: O=C([O-])O
Agent: [K+]
Solvent: c1ccccc1
Product: COc1ccc(C(=O)Nc2cccc3cnccc23)cc1OC

Procedure:
5-Aminoisoquinoline (8 g.) was dissolved in dry benzene (100 ml) and 0.5 g of dry potassium bicarbonate was added to the solution. A 0.1 mole excess of 3,4-dimethoxybenzoyl chloride was dissolved in dry benzene (50 ml) and this solution was poured into the solution of 5-aminoisoquinoline. A precipitate formed immediately. This was collected by filtration and washed with 10% sodium carbonate solution followed by water. The washings were discarded and the insoluble residue was recrystallized from benzene to yield 11.5 g of 5-(3,4-dimethoxybenzamido)isoquinoline as tan needles, m.p. 193°-194° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:16][CH2:17][CH:18](OS(C)(=O)=O)[CH2:19][N:20]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:21][CH2:22]OS(C)(=O)=O>C(O)C>[CH2:1]([N:8]1[CH2:22][CH2:21][N:20]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:19][CH:18]1[CH2:17][F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCN(Cc1ccccc1)CC(CF)OS(C)(=O)=O
Reactant: NCc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: FCC1CN(Cc2ccccc2)CCN1Cc1ccccc1

Procedure:
4.82 g (0.045 mole) of benzylamine and 9.09 g (0.09 mole) of triethylamine were added to a solution of N-(3-fluoro-2-methylsulfonyloxypropyl)-N-(2-methylsulfonyloxyethyl)benzylamine [prepared as described in step (b) above] dissolved in 200 ml of ethanol. The mixture was heated under reflux for 2 hours and then concentrated by evaporation under reduced pressure. 100 ml of ethanol and 40 ml of a 2N aqueous solution of sodium hydroxide were added to the residue, and the mixture was concentrated by evaporation under reduced pressure. The residue was mixed with ethyl acetate, and insoluble materials were removed by filtration. The filtrate was freed from the solvent by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel using a 9:1 by volume mixture of toluene and ethyl acetate as the eluent, to afford 3.60 g of 1,4-dibenzyl-2-fluoromethylpiperazine as a yellow oil.
Reaction SMILES: [C:1]([O:20][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\CCCCCCCC.C=C>>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:1]([O:20][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Agent: C=C
Product: C=CCCCCCCCC
Product: C=CCCCCCCCC(=O)OC

Procedure:
A process according to claim 17 wherein methyl oleate is reacted with ethylene to produce 1-decene and methyl 9-decen-1-oate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].C(Cl)(=O)C(Cl)=O.[CH2:17](O)[C:18]([CH3:21])([CH3:20])[CH3:19].CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([O:7][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:6]
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: CC(C)(C)CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)COC(=O)c1ccnc(Cl)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 81.1 %

Procedure:
2-Chloroisonicotinic acid (2.0 g, 13 mmol) was suspended in 50 mL dry CH2Cl2 and treated with oxalyl chloride (3.5 mL, 5.0 g, 39 mmol) plus 3 drops DMF. The mixture was stirred for 4 h, the volatiles removed in vacuo and the residue taken up in 50 mL CH2Cl2. After cooling to 0° C. and treating with neopentyl alcohol (1.7 ml, 1.4 g, 16 mmol), Et3N (2.5 mL, 1.8 g, 18 mmol) was added in portions. The mixture was warmed to 25° C., stirred for 15 h, washed sequentially with 15 mL H2O, 15 mL saturated aqueous NaHCO3, and 15 mL brine, then dried (Na2SO4), filtered, and concentrated in vacuo to give 2.4 g (80%) of 2-chloroisonicotinic acid, 2,2-dimethyl-propyl ester as an oil, used without additional purification: 1H NMR (300 MHz, CDCl3) δ 8.56 (d, J=5.6 Hz, 1H), 7.88 (s, 1H), 7.78 (d J=5.0 Hz, 1H), 4.06 (s, 2H), 1.05 (s, 9H).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH3:19])=[CH:16][C:11]=2[N:10]=[C:9]1[NH:27][C:28]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)=[O:29])C.[OH-].[Na+].Cl>CO.O.C(Cl)Cl>[CH:20]1([N:18]([CH3:19])[C:17]([C:15]2[CH:14]=[CH:13][C:12]3[N:8]([CH2:7][CH2:6][CH2:5][C:4]([OH:35])=[O:3])[C:9]([NH:27][C:28]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)=[O:29])=[N:10][C:11]=3[CH:16]=2)=[O:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)CCCn1c(NC(=O)c2cccs2)nc2cc(C(=O)N(C)C3CCCCC3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CN(C(=O)c1ccc2c(c1)nc(NC(=O)c1cccs1)n2CCCC(=O)O)C1CCCCC1
Reaction time: 4 h
Yield: 91.8 %

Procedure:
To a stirred solution of 4-{5-(N-cyclohexyl-N-methyl-carbamoyl)-2-[(thiophene-2-carbonyl)-amino]-benzoimidazol-1-yl}-butyric acid ethyl ester (Example 1) (0.5 g, 1.0 mmol) in MeOH (10 mL) and water (10 mL) was added solid NaOH (0.12 g, 3 mmol). The reaction was complete in 4 h. The mixture was acidified with 1N HCl, and was diluted with CH2Cl2 (20 mL). The organic layer was dried over magnesium sulfate, the solvent evaporated and the residue purified by flash chromatography with 10% MeOH/dichloromethane to give the title compound (0.43 g, 92%), m.p. 256-258° C.
Reaction SMILES: [Cl-:1].[NH4+:2].C[Al](C)C.[CH3:7][C:8]1[CH:16]=[CH:15][C:11]([CH2:12][C:13]#[N:14])=[CH:10][CH:9]=1.CO>C1(C)C=CC=CC=1.CCCCCC>[ClH:1].[CH3:7][C:8]1[CH:16]=[CH:15][C:11]([CH2:12][C:13]([NH2:2])=[NH:14])=[CH:10][CH:9]=1
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: Cc1ccc(CC#N)cc1
Agent: C[Al](C)C
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1ccc(CC(=N)N)cc1
Product: Cl
Temperature: 0 °C

Procedure:
10.8 g (201 mmol) of ammonium chloride are suspended under argon in 200 ml of dry toluene and the suspension is cooled to 0° C. 100 ml of a 2M solution of trimethylaluminium in hexane are added dropwise and the mixture is stirred at room temperature until the evolution of gas is complete. After addition of 13.2 g (100 mmol) of 4-methylbenzyl cyanide, the reaction mixture is stirred overnight at 80° C. (bath). The cooled reaction mixture is treated with 35 ml of methanol and then stirred at room temperature for a further 1 h. The solid is then first filtered off with suction, and the filter cake is washed several times with methanol. The filtrate is concentrated, resuspended in dichloromethane/methanol 10/1, and the insoluble solid is filtered off. The solvent is then again evacuated from the filtrate in vacuo.
Reaction SMILES: C1C[O:4][CH2:3]C1.[H-].[Na+].[NH2:8][C:9]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12].[C:21]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C@@H:34]([CH3:35])[CH2:33][N:32]([C:36](Cl)=[O:37])[C@H:31]([CH3:39])[CH2:30]2)=[CH:25][C:24]=1C(F)(F)F)#[N:22]>O>[C:11]([C:10]1[CH:13]=[CH:14][C:15]([C:17]([F:18])([F:19])[F:20])=[CH:16][C:9]=1[NH:8][C:36]([N:32]1[CH2:33][C@H:34]([CH3:35])[N:29]([C:26]2[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[C:24]([O:4][CH3:3])[CH:25]=2)[CH2:30][C@H:31]1[CH3:39])=[O:37])#[N:12]
Reactant: C[C@@H]1CN(c2ccc(C#N)c(C(F)(F)F)c2)[C@@H](C)CN1C(=O)Cl
Reactant: N#Cc1ccc(C(F)(F)F)cc1N
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1cc(N2C[C@@H](C)N(C(=O)Nc3cc(C(F)(F)F)ccc3C#N)C[C@@H]2C)ccc1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into 10 ml of THF was suspended 80 mg of 60% NaH, and then 337 mg of 2-amino-4-trifluoromethylbenzonitrile was added thereto at room temperature, followed by 30 minutes of stirring at room temperature. Then, 558 mg of (2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethylpiperazine-1-carbonyl chloride was added thereto, followed by 17 hours of stirring at room temperature. Water was added to the reaction solution, followed by extraction with chloroform. After the organic layer was washed with water, the solvent was removed by evaporation. The resulting residue was subjected to silica gel column chromatography to obtain 358 mg of the title compound from an eluate using hexane-ethyl acetate (1:1, v/v).
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:16][C:17]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20]>C(Cl)Cl.CN1CCOCC1.ClC(OCC(C)C)=O>[O:20]=[C:19]1[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([F:27])([F:28])[F:29])[C:17]=2[N:16]=[C:10]([C@@H:9]2[CH2:13][CH2:14][CH2:15][N:8]2[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[O:12]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2c(C(F)(F)F)cccc2c(=O)o1

Procedure:
Using the procedure of Step A of Example 7, a solution of 16.14 ml of BOC-L-proline in 150 ml of methylene chloride, 20.6 ml of N-methyl-morpholine, 19.5 ml of isobutyl chloroformate in 75 ml of methylene chloride and 15.4 g of 2-amino-3-trifluoromethylbenzoic acid in 150 ml of methylene chloride and 8.3 ml of N-methyl-morpholine were reacted for 20 hours. The mixture was extracted with methylene chloride and the residue was chromatographed on silica gel and was eluted with methylene chloride to obtain 16.4 g of 1,1-dimethylethyl (2S) 2-[4-oxo-8-(trifluoromethyl)-4H-3,1-benzoxazin-2-yl]-1-pyrrolidine carboxylate having a specific rotation of [α]D =-75°±2.5° (c=0.6% in CH3COOH).
Reaction SMILES: [Li+].C[CH:3]([N-:5][CH:6]([CH3:8])[CH3:7])[CH3:4].[CH2:9]1[CH2:13]OC[CH2:10]1.C(#N)C(C)=O>>[NH:5]1[C:6]2[C:7](=[CH:10][CH:9]=[CH:13][CH:8]=2)[CH:4]=[CH:3]1
Reactant: C1CCOC1
Reactant: CC(C)[N-]C(C)C
Agent: CC(=O)C#N
Agent: [Li+]
Product: c1ccc2[nH]ccc2c1
Reaction time: 1 h
Yield: 48 %

Procedure:
To a solution of 1 (426 mg, 1.26 mmol) in TBF (6 mL) at −78° C. was added dropwise a 1.8 M solution of LDA in THF (1.54 mL, 2.78 mmol) and the reaction stirred for 1 hour, then pyruvonitrile (0.208 mL, 2.78 mmol) was added dropwise and the reaction was stirred for 15 minutes turning homogeneous. The reaction was quenched by the addition of satd. NH4Cl (10 mL), the layers separated, and the aqueous extracted with Et2O (3×10 mL). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified on silica gel gradiently eluted with 20 to 40% EtOAc/hexanes to give 2 (230 mg, 48% yield) as an off-white solid. Rt=1.71 min using Phenomenex 30×4.6 5u column with flow rate of 5 mL/min over 2 min gradient. 0 to 100% B. Solvent A=10/90/0.1% MeOH/H2O/TFA. Solvent B=90/10/0.1%. [M+H]=380.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1.C1(C)C=CC(C(OC)=O)=CC=1>CCO>[O:4]1[CH2:5][CH2:6][N:1]([CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: COC(=O)c1ccc(C)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)c1ccc(CN2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 66.6 g of morpholine and 269 mL of triethylamine in 1.5 L of abs. EtOH under N2 at 0° C. was added dropwise over 30 min a solution of methyl 4-bromomethylbenzoate in 450 mL of abs. EtOH. The resulting solution was stirred at 0° C. for 2 h then slowly warmed up to rt over 4 h and stirred at rt overnight. The HPLC showed no unreacted methyl 4-bromomethylbenzoate but the remaining methyl p-toluate from the previous reaction. The solvent was removed under reduced pressure and the residue was taken up in 2 L of 1.5 N HCl. The acidic phase was washed with 3×350 mL of diethyl ether then with 1×350 mL of EtOAc and was neutralized to pH 7 with NaOH and then to pH 7.5 with 10% NaHCO3 in water. The product was extracted with 3×700 mL of EtOAc. The organic phase was dried over anhydrous Na2SO4 and concentrated under reduce pressure, affording an orange oil. The excess EtOAc was removed by toluene distillation. The title compound was used in the next step without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[N:14]1[C:18]([CH2:19][Cl:20])=[N:17][C:16]([C:21]([OH:23])=[O:22])=[N:15]1)=[O:6].[CH3:28]O>>[CH3:28][O:22][C:21]([C:16]1[N:17]=[C:18]([CH2:19][Cl:20])[N:14]([C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[C:5](=[O:6])[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]=2[Cl:2])[N:15]=1)=[O:23]
Reactant: CO
Reactant: O=C(O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Agent: Cl
Product: COC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1

Procedure:
270 ml of a 6 N solution of hydrogen chloride in methanol is added to a solution of 133.0 g (0.30 mole) of 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid (crystals containing an equimolar amount of methanol; see German `Offenlegungschrift` No. 2,159,527, page 32) in 1400 ml of methanol, and the whole is refluxed for 18 hours. The reaction mixture is then concentrated in vacuo; water is added to the residue and extraction is performed twice with methylene chloride. The organic phase is washed once with saturated potassium bicarbonate solution, twice with water and once with saturated sodium chloride solution; it is subsequently dried over sodium sulphate and concentrated in vacuo. The residue is recrystallised from 1 liter of methanol. After drying there is obtained 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester, m.p. 130°-132°.