Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10][N:9]([CH2:12][CH2:13]O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[ClH:21].S(Cl)([Cl:24])=O>C(Cl)Cl>[ClH:24].[CH2:1]([O:3][C:4]([C:6]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][Cl:21])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccccc2)CCN(CCO)CC1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C1(c2ccccc2)CCN(CCCl)CC1

Procedure:
A solution is prepared from 5.9 parts of the ester obtained in the preceding paragraph and 134 parts of methylene chloride. This solution is saturated with hydrogen chloride gas at below 10° and 5.1 parts of thionyl chloride is added. The mixture is refluxed for 1 hour and then cooled and volatile material is removed under reduced pressure. The residue is dissolved in 88 parts of benzene, and the solution evaporated under reduced pressure. The residue is then crystallized from a mixture of ethanol and ether to give 1-(2-chloroethyl)-4-phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride melting at about 216°-218°.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]1([C:12]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][NH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:13]1[CH2:14][CH2:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]1([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: c1ccc(C2(c3ccccc3)NCCc3ccccc32)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(CCl)N1CCc2ccccc2C1(c1ccccc1)c1ccccc1

Procedure:
Chloroacetyl chloride (0.151 mL) was added to a solution of 1,1-diphenyl-1,2,3,4-tetrahydroisoquinoline (339 mg) and p-toluenesulfonate monohydrate (11.3 mg) in toluene (5 mL). The mixture was heated under reflux for 3 hours. The solvent was evaporated under reduced pressure, and EtOAc and an aqueous 1 M HCl solution were added to the residue. The organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 2-(chloroacetyl)-1,1-diphenyl-1,2,3,4-tetrahydroisoquinoline (452 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[N:6][CH:7]=1.[NH2:11][CH2:12][C:13]([CH3:16])([OH:15])[CH3:14].C(N(C(C)C)C(C)C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C1COCC1>[OH:15][C:13]([CH3:16])([CH3:14])[CH2:12][NH:11][C:8]([C:3]1[C:2]([NH2:1])=[CH:7][N:6]=[CH:5][N:4]=1)=[O:10]
Reactant: Nc1cncnc1C(=O)O
Reactant: CC(C)(O)CN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(O)CNC(=O)c1ncncc1N
Temperature: 25 °C
Reaction time: 21 h
Yield: 71.3 %

Procedure:
To a stirred mixture of 5-aminopyrimidine-4-carboxylic acid (200 mg, 1.44 mmol) and 1-amino-2-methylpropan-2-ol (128 mg, 1.44 mmol) at rt in THF (5 ml) under an argon atmosphere were added N-ethyldiisoproplyamine (743 mg, 978 μl, 5.75 mmol) and 1-propanephosphonic acid cyclic anhydride (2.29 g, 2.16 ml, 3.59 mmol). The mixture was stirred at rt for 21 hrs, then concentrated. The crude product was purified by column chromatography with EtOAc/MeOH as eluent providing the title compound (216 mg, 72%) as off-white solid.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[C:7]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[I-].ClCC[S+](C)C.O>C(O)(C)(C)C>[CH2:1]1[C:8]2([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:7]2=[O:14])[CH2:2]1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCCCCC1
Agent: C[S+](C)CCCl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C1CCCCCC12CC2

Procedure:
To a suspension of potassium tert-butoxide (3.48 g) in tert-butanol (32 mL) was added cycloheptanone (1.9 mL) while stirring under nitrogen atmosphere, followed by stirring the mixture at room temperature for 0.5 hour. Then, to the reaction mixture was added (2-chloroethyl)-dimethylsulfonium iodide (3.7 g) in eight portions over 1.6 hours, followed by stirring the mixture at room temperature for 16.5 hours. To the reaction mixture was added water, followed by extraction with diethyl ether. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (diethyl ether:hexane (volume ratio)=1:15) to give spiro[2.6]nonan-4-one (1.40 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(#N)C.[CH:18]1(/[CH:22]=[CH:23]/[C:24]#[N:25])[CH2:21][CH2:20][CH2:19]1.N12CCCN=C1CCCCC2>>[CH:18]1([CH:22]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:23][C:24]#[N:25])[CH2:21][CH2:20][CH2:19]1
Reactant: N#C/C=C/C1CCC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1(C)OB(c2cnn(C(CC#N)C3CCC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (9.63 g, 0.0496 mol) in acetonitrile (124 mL, 2.37 mol) was added (E)-3-cyclobutylacrylonitrile (5.30 g, 0.0495 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (3.70 mL, 0.0248 mol). The resulting mixture was stirred at room temperature overnight, then evaporated to dryness. The mixture was purified on silica gel, eluting with 0 to 80% EtOAc in hexanes, to give the desired product as a racemic mixture (11.2 g, 75.2%). LCMS (M+H) 302.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[C:11]([CH3:18])[O:10][N:9]=1.F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)[CH:17]=2)=[C:11]([CH3:18])[O:10][N:9]=1
Reactant: Cc1onc(-c2ccccc2F)c1-c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: Cc1onc(-c2ccccc2F)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Yield: 87 %

Procedure:
As described for Example 36, 3-(2-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (100 mg, 0.41 mmol) using 1-fluoro-4-nitrobenzene instead of 4-fluoroacetophenone was converted to the title compound (130 mg, 87%) which was obtained as an off-white solid. MS: m/e=365.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7].[C:22](N1C=CN=C1)([N:24]1C=CN=C1)=O.CN(CCN)C.C(C1C=CC(N2CCNCC2)=CC=1)#N.[ClH:54]>O1CCCC1>[ClH:54].[C:22]([C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:21])[CH3:1])=[O:7])[CH2:9][CH2:10]2)=[CH:15][CH:16]=1)#[N:24]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)CCNC(=O)N1CCN(c2ccc(F)cc2)CC1
Agent: CN(C)CCN
Agent: Cl
Agent: N#Cc1ccc(N2CCNCC2)cc1
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)N1CCN(c2ccc(C#N)cc2)CC1

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 11. A mixture of 2.6 g (0.016 mole) of 1,1'-carbonyldiimidazole, 1.4 g (0.016 mole) of unsym-dimethylethylenediamine and 3.0 g (0.16 mole) of 1-(4-cyanophenyl)piperazine in a total volume of 250 ml of tetrahydrofuran gave an oil. The hydrochloride was formed in ethereal hydrogen chloride and the solid recrystallized from methanol-ethyl ether to give 1.2 g (20%) of the title compound as a white solid; m.p. 161°-164° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]([CH3:12])=O)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[CH3:13][N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH2:15]>C(O)C.C(O)(=O)C>[CH3:1][O:2][N:3]=[C:4]([C:10](=[N:15][N:14]([CH3:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:12])[C:5]([N:7]([CH3:9])[CH3:8])=[O:6]
Reactant: CN(N)c1ccccc1
Reactant: CON=C(C(C)=O)C(=O)N(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: CON=C(C(=O)N(C)C)C(C)=NN(C)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.1 %

Procedure:
1.0 g (5.8 mmol) of 2-methoxyimino-N,N-dimethylacetoacetamide was dissolved in 15 ml of ethanol and 0.5 ml of acetic acid, and 0.78 g (6.4 mmol) of N-methyl-N-phenylhydrazine was added and the mixture was stirred for 24 hours at room temperature. After distilling the solvent off, water was added and the mixture was extracted three times with 20 ml of diethylether. After washing with a dilute hydrochloric acid, water and a saturated aqueous sodium chloride, the mixture was dried over with anhydrous magnesium sulfate, and the solvent was distilled off, and finally the residue thus obtained was purified by a column chromatography on a silica gel (n-hexane/ethyl acetate) to obtain 1.38 g (yield: 86%) of 2-methoxyimino-N,N-dimethy-3-(N-methyl-N-phenylhydrazono)butyramide as a yellow oil. 1H-NMR(CDCl3) δ ppm:2.13(3H, s), 2.90(3H,s), 3.07(3H, s), 3.29(3H, s), 3.99(3H,s), 6.90-7.02(3H, m), 7.33-7.29(2H, m).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[C:25]([O:29][C:30](=[O:38])[N:31]([CH3:37])[CH:32]1[CH2:36][CH2:35][NH:34][CH2:33]1)([CH3:28])([CH3:27])[CH3:26]>CN1C(=O)CCC1.CC(OC)(C)C>[C:25]([O:29][C:30](=[O:38])[N:31]([CH:32]1[CH2:36][CH2:35][N:34]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][C:12]4[CH:13]=[C:14]5[C:19](=[CH:20][C:21]=4[F:22])[N:18]=[CH:17][CH:16]=[CH:15]5)=[CH:9][N:10]=3)[N:7]=2)[CH2:33]1)[CH3:37])([CH3:28])([CH3:26])[CH3:27]
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(Cl)nn12
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: COC(C)(C)C
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc3ncc(Cc4cc5cccnc5cc4F)n3n2)C1
Temperature: 170 °C
Reaction time: 1 h

Procedure:
6-(6-Chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (Stage 173.1, 150 mg, 0.474 mmol), KF (139 mg, 2.372 mmol) and (rac)-methyl-pyrrolidin-3-yl-carbamic acid tert-butyl ester (285 mg, 1.423 mmol) were suspended in NMP (1.5 mL). The RM was stirred at 170° C. for 1 h. The mixture was diluted with TBME and washed with water (3×). The aqueous phases were further extracted with TBME (1×). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was crystallized in Et2O to afford the title compound as a beige solid (tR 3.91 min (conditions 13), MH+=477).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11](O)=O)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)C=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH3:60][N:61]1[C:69]([CH2:70][CH:71]2CCN[CH2:73][CH2:72]2)=[N:68][C:67]2[C:62]1=[N:63][C:64]([N:83]1[C:87]3[CH:88]=[CH:89][CH:90]=[CH:91][C:86]=3[N:85]=[C:84]1[CH3:92])=[N:65][C:66]=2[N:77]1[CH2:82][CH2:81][O:80][CH2:79][CH2:78]1>>[CH3:60][N:61]1[C:69]([CH2:70][CH:71]2[CH2:11][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:73][CH2:72]2)=[N:68][C:67]2[C:62]1=[N:63][C:64]([N:83]1[C:87]3[CH:88]=[CH:89][CH:90]=[CH:91][C:86]=3[N:85]=[C:84]1[CH3:92])=[N:65][C:66]=2[N:77]1[CH2:78][CH2:79][O:80][CH2:81][CH2:82]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a solution of N-(tert-Butoxycarbonyl)-L-alanine (80.0 mg, 0.423 mmol) in N,N-Dimethylformamide (5.0 mL, 0.064 mol) was added HATU (0.154 g, 0.404 mmol), 1-hydroxybenzotriazole (HOBt, 0.00839 g, 0.0621 mmol) and triethylamine (0.10 mL, 0.72 mmol). The resulting yellow solution was stirred at room temperature for 5 minutes before the addition of 4-(9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-8-(piperidin-4-ylmethyl)-9H-purin-6-yl)morpholine 520 (0.150 g, 0.310 mmol;). The reaction was stirred at room temperature for 2 hours. The reaction mixture was partitioned between brine and EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (0-5% MeOH in DCM) to give tert-butyl 4-((9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)methyl)piperidine-1-carboxylate (0.15 g, 78%). LCMS m/z: 618.3 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][CH2:16][C:17]([OH:19])=[O:18]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][C:17]([OH:19])=[O:18])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: NCC(=O)O
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Product: O=C(O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 86.1 %

Procedure:
4-nitrophthalic anhydride (0.25 g, 0.0013 mol) and glycine (0.097 g, 0.0013 mol) were refluxed as above overnight. The clear solution was purified as per 120 to yield 0.28 g (86%) 140 as very pale yellow crystals: mp=195-96° C.; Rf0.79 (A): Rf0.75 (B): Rf0.28 (D): IR (cm−1): 2811-3150 (OH), 3115 (C═CH), 1787 (C═O), 1730 (bs, C═O), 1622 (C═C), 1551 (N═O), 1412 (C═C), 1391 (C—O), 1351 (N═O), 1117 (C—O), 720 (C═CH); MS m/z (rel intensity) 250 (7), 249 (62), 205 (100), 122 (10).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=4[Cl:30])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>CS(C)=O.C(OCC)C>[Cl:30][C:24]1[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:23]=1[C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[O:14][C@@H:13]([CH2:12][NH:32][CH3:31])[CH2:22][CH2:21]2
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3cccc(-c4cc(Cl)ccc4Cl)c3O2)cc1
Reactant: CN
Solvent: CS(C)=O
Solvent: CCOCC
Product: CNC[C@H]1CCc2cccc(-c3cc(Cl)ccc3Cl)c2O1
Temperature: 60 °C

Procedure:
To a suspension of [(2R)-8-(2,5-dichlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.324 mmol) in dimethylsulfoxide (0.5 mL) was added a solution of methylamine (2.0 M in tetrahydrofuran, 1.62 mL, 3.24 mmol) and the mixture heated to 60° C. in a sealed vial for 24 hours. The cooled reaction mixture was then diluted with diethyl ether (10 mL), washed with 1.0 M aqueous sodium hydroxide solution (5 mL) and water (5×5 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a yellow oil. Purification by flash chromatography using a solvent gradient of 0.5 to 5% ammonia saturated methanol solution in dichloromethane gave {[(2R)-8-(2,5-dichlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}methylamine as a colorless syrup. The product was dissolved in diethyl ether (1 mL) and a solution of hydrogen chloride (1.0 M in diethyl ether, 0.25 mL, 0.25 mmol) was added followed by 2-propanol (3 drops). The resulting white precipitate was filtered and the solid product triturated with diethyl ether (3×3 mL) to afford 56 mg (48%) of {[(2R)-8-(2,5-dichlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}methylamine hydrochloride as a white solid. MS (ESI) m/z 322.0 ([M+H]+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:6](=[O:19])[CH:7]=[C:8]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)O[CH:10]=1.O.[NH4+:21]>C(O)C>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:6](=[O:19])[CH:7]=[C:8]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[NH:21][CH:10]=1
Reactant: O=c1cc(COC2CCCCO2)occ1CCCO
Reactant: [NH4+]
Solvent: O
Solvent: CCO
Product: O=c1cc(COC2CCCCO2)[nH]cc1CCCO
Reaction time: 0.5 h

Procedure:
To a solution of 1.2 g of 5-(3-hydroxypropyl)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-4-one in 5 mL of ethanol, 16 mL of 25% ammonium water was added, and the mixture was heated under reflux while stirring for 9 hours 30 minutes. The solvent was distilled off under reduced pressure, and the resultant residue was purified by flash silica gel column chromatography using gradient elution with chloroform:methanol=95:5 to 90:10 to obtain 0.42 g of 5-(3-hydroxypropyl)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridin-4(1H)-one as a brown oily substance.
Reaction SMILES: O[CH:2]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[OH-:22].[Li+:23].[P].[S]>>[OH:22][CH:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([O-:15])=[O:14].[Li+:23]
Reactant: [OH-]
Reactant: CCCCCCC(O)CCCCCCCCCCC(=O)O
Agent: [Li+]
Agent: [P]
Agent: [S]
Product: CCCCCCCCCCCCCCCCC(O)C(=O)[O-]

Procedure:
A lithium hydroxystearate grease thickener was prepared by saponification of a mixture containing 12-hydroxystearic acid (50%) and the tri-glyceride thereof (25%) and 25% of C22 fatty acids containing no OH groups with lithium hydroxide in a mineral oil vehicle (ISO 150 viscosity grade of a 70/30 mixture of naphthenic and paraffinic stocks) at about 350° F. in a closed contactor. After depressuring and dehydration of the thickener in an open kettle sufficient mineral oil was added to reduce the thickener content to about 8%. The dropping point of this grease was 407° F. (208° C.). This grease contained no phosphorus or sulfur additives.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][CH:8]2[N:13]3[C:14](=[O:30])[CH:15]([NH2:29])[CH2:16][N:17]([S:18]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])(=[O:20])=[O:19])[CH:12]3[CH2:11][N:10]([CH:31]([CH3:33])[CH3:32])[C:9]2=[O:34])=[CH:5][CH:4]=1.ClCCCl.CO[CH:43]1[CH2:47][CH2:46][CH:45](OC)O1>O>[Cl:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][CH:8]2[N:13]3[C:14](=[O:30])[CH:15]([N:29]4[CH:43]=[CH:47][CH:46]=[CH:45]4)[CH2:16][N:17]([S:18]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])(=[O:20])=[O:19])[CH:12]3[CH2:11][N:10]([CH:31]([CH3:33])[CH3:32])[C:9]2=[O:34])=[CH:5][CH:4]=1
Reactant: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Reactant: COC1CCC(OC)O1
Agent: Br
Solvent: O
Solvent: ClCCCl
Product: CC(C)N1CC2N(C(=O)C(n3cccc3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
64 mg of 6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-3-amino-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione hydrobromide (Example 2) were suspended in 1 ml of water, and 1 ml of DCE was added. This mixture was mixed with 2 equivalents of 2,5-dimethoxytetrahydrofuran and stirred at 80° C. for 1 hour. The DCE phase was removed and the aqueous phase was extracted twice with DCE. The combined extracts were evaporated, and the crude substance was dissolved in a mixture of acetonitrile and water and freeze dried. The pure title compound was removed after purification by HPLC. The system and process described under “general processes” was used for this. MW=608.08 (calculated, monoisotopic); measured value (M+H)+: 609.4.
Reaction SMILES: [OH:1][C:2]1([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([C:20](O)=[O:21])[CH:14]=[CH:13]3)[C:9]2[N:5]([CH:6]=[N:7][CH:8]=2)[CH2:4][CH2:3]1.C([N:25]=C=NCCCN(C)C)C.Cl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:1][C:2]1([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([C:20]([NH2:25])=[O:21])[CH:14]=[CH:13]3)[C:9]2[N:5]([CH:6]=[N:7][CH:8]=2)[CH2:4][CH2:3]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc2cc(C3(O)CCn4cncc43)ccc2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2cc(C3(O)CCn4cncc43)ccc2c1
Temperature: 25 °C
Yield: 11.8 %

Procedure:
6-(7-Hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-7-yl)-2-naphthoic acid (449 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide•hydrochloride (321 mg) and 1-hydroxy-1H-benzotriazole•monohydrate (301 mg) were dissolved in DMF (7.6 ml), and diisopropylethylamine (216 mg) was added with stirring under ice cooling. The mixture was allowed to warm to room temperature and stirred for 18 hr. Silica gel (3 g) was added to the reaction mixture and the mixture was concentrated under reduced pressure to dryness. The obtained residue was purified by silica gel column chromatography (developing solution: chloroform/7% aqueous ammonia-containing methanol:19/1). The eluate was concentrated to dryness, and the residue was recrystallized from ethanol to give the title compound (53 mg).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[F:9][C:10]([F:19])([F:18])[C:11]1[CH:12]=[C:13](Cl)[CH:14]=[CH:15][CH:16]=1>[Cu]>[F:9][C:10]([F:19])([F:18])[C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:2][C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)[CH:16]=1
Reactant: FC(F)(F)c1cccc(Cl)c1
Reactant: Oc1ccc(O)cc1
Agent: [Cu]
Product: Oc1ccc(Oc2cccc(C(F)(F)F)c2)cc1

Procedure:
In an analogous manner to that described in the preceding paragraph, hydroquinone and 3-trifluoromethyl-chlorobenzene in the presence of a catalytic amount of copper powder yield p-(α,α,α-trifluoro-m-tolyloxy)-phenol which distils in the bulb-tube at 140° C./0.05 Torr; nD20 =1.5370.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=O)[CH2:22][CH2:23][C:24](OCC)=[O:25])=[C:17]([F:30])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:32][NH2:33]>C(O)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH2:22][CH2:23][C:24](=[O:25])[NH:33][N:32]=3)=[C:17]([F:30])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)CCC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C3=NNC(=O)CC3)c(F)c2)CC1

Procedure:
In a 250 mL round bottom flask, 4-[4-(3-ethoxycarbonyl-propionyl)-3-fluoro-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (4.1 g, 9.68 mmol), and hydrazine monohydrate (0.97 mL, 19.4 mmol), in isopropanol (100 mL) was heated to reflux 14 h. The reaction was cooled and the solvent concentrated under vacuum. Purification with silica gel chromatography eluting with methylene chloride/methanol (95:5) produced 945 mg (25%). Mp 146-148° C. MS m/z 392 (M+H).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[C:15]([S:18][CH2:19][CH:20]([CH2:24][S:25][CH3:26])[C:21](Cl)=[O:22])(=[O:17])[CH3:16].C(SCC(CSC)C(O)=O)(=O)C.S(Cl)(Cl)=O>O>[C:15]([S:18][CH2:19][CH:20]([CH2:24][S:25][CH3:26])[C:21]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:22])(=[O:17])[CH3:16]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CSCC(CSC(C)=O)C(=O)Cl
Agent: CSCC(CSC(C)=O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Product: CSCC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of L-proline (1.44 g.) and sodium carbonate (2.7 g.) in water (25 ml.) in an ice bath, 3-(acetylthio)-2-(methylthiomethyl)propanoic acid chloride (prepared from the acid of Example 15 with thionyl chloride) (3.6 g.) is added, and the mixture is vigorously stirred at room temperature for two hours. After extraction with ethyl acetate, the aqueous layer is acidified and extracted with ethyl acetate. The organic layer is dried and concentrated to dryness in vacuo to give 1-[3-(acetylthio)-2-(methylthiomethyl)propanoyl]-L-proline.