Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]3=[N:10][C:9]=2[C:18]2[CH:19]=[CH:20][C:21]([O:35][CH3:36])=[C:22]([CH:34]=2)[C:23]([NH:25][C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])=[O:24])[CH:5]=[CH:4][N:3]=1.[N:37]1([CH:43]2[CH2:48][CH2:47][N:46]([C:49]3[CH:55]=[CH:54][C:52]([NH2:53])=[C:51]([O:56][CH3:57])[CH:50]=3)[CH2:45][CH2:44]2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.Cl.O1CCOCC1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.CCCCCC>[N:37]1([CH:43]2[CH2:48][CH2:47][N:46]([C:49]3[CH:55]=[CH:54][C:52]([NH:53][C:2]4[N:7]=[C:6]([C:8]5[N:12]6[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]6=[N:10][C:9]=5[C:18]5[CH:19]=[CH:20][C:21]([O:35][CH3:36])=[C:22]([CH:34]=5)[C:23]([NH:25][C:26]5[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=5[F:33])=[O:24])[CH:5]=[CH:4][N:3]=4)=[C:51]([O:56][CH3:57])[CH:50]=3)[CH2:45][CH2:44]2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: COc1cc(N2CCC(N3CCCCC3)CC2)ccc1N
Reactant: COc1ccc(-c2nc3cc(F)ccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: OCC(F)(F)F
Solvent: CCCCCC
Solvent: C1COCCO1
Product: COc1cc(N2CCC(N3CCCCC3)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3cc(F)ccn23)n1
Temperature: 150 °C
Yield: 86.4 %

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)-7-fluoroimidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluoro-phenyl)-2-(methyloxy)benzamide (Example 197, step A) (114 mg, 0.22 mmol) and 4-(1,4′-bipiperidin-1′-yl)-2-(methyloxy)aniline (Example 22, step C) (65 mg, 0.22 mmol) in 2,2,2-trifluoroethanol (1.5 mL) was added 4 M HCl in dioxane (112 μL, 0.45 mmol). The mixture was stirred and heated on a microwave at 150° C. for 45 min, then cooled to rt. The mixture was neutralized with 0.5M sodium methoxide in MeOH. The mixture was concentrated under vacuum and the residue purified by silica gel chromatography to give a yellow oil. The oil was dissolved in minimal DCM, then hexane was added until a precipitate was formed. The slurry was cooled at −10° C. for 30 min, then poured through a Teflon filter, washing the solids with cold hexanes. The solids were dried under vacuum to give the title compound (147 mg, 0.19 mmol, 86%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.79 (s, 1H), 9.44 (br s, 1H), 8.49 (s, 1H), 8.20 (d, 1H, J=5.32 Hz), 8.09 (d, 1H, J=2.02 Hz), 7.75-7.79 (m, 1H), 7.58 (dd, 1H, J=2.66, 9.62 Hz), 7.35-7.43 (m, 2H), 7.29 (d, 1H, J=8.80 Hz), 7.19 (t, 2H, J=8.06 Hz), 6.98-7.04 (m, 1H), 6.68 (d, 1H, J=2.20 Hz), 6.48-6.53 (m, 2H), 3.99 (s, 3H), 3.70-3.81 (m, 5H), 2.61-2.69 (m, 2H), 2.41-2.48 (m, 4H), 2.29-2.37 (m, 1H), 1.76-1.83 (m, 2H), 1.44-1.60 (m, 6H), 1.34-1.41 (m, 2H). MS (ESI): 763 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[CH2:31][CH:30]([NH:32][CH2:33][CH2:34][OH:35])[CH2:29][CH2:28][CH2:27][C:26]=2[C:36]=1[O:37][CH3:38]>>[Cl:20][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]3[CH2:31][CH:30]([NH:32][CH2:33][CH2:34][OH:35])[CH2:29][CH2:28][CH2:27][C:26]=3[C:36]=2[O:37][CH3:38])=[N:3][CH:4]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COc1c(N)ccc2c1CCCC(NCCO)C2
Product: COc1c(Nc2ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n2)ccc2c1CCCC(NCCO)C2

Procedure:
The title compound was prepared from N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (100 mg, 0.30 mmol) and 2-(2-amino-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylamino)-ethanol (75 mg, 0.30 mmol) in an analagous manner to Example 946 to afford a tan solid. Mp: 92-4° C. LCMS (m/e) 553 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.93 (m, 2H), 7.40 (br s, 1H), 6.89 (d, J=8 Hz, 1H), 5.56 (d, J=8 Hz, 1H), 3.90 (m, 1H), 3.71 (s, 3H), 3.61 (m, 2H), 3.47 (s, 3H), 3.25 (m, 1H), 2.93-2.63 (m, 10H), 2.20 (m, 2H), 2.01 (m, 1H), 1.80 (m, 4H), 1.55 (m, 1H), 1.39 (m, 4H).
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][CH3:7])=S)#[N:2].[CH3:8][C:9]1[NH:13][CH:12]=[N:11][C:10]=1[CH2:14][S:15][CH2:16][CH2:17][NH2:18].S([O-])([O-])(=O)=O.[Na+].[Na+]>CC#N>[C:1]([N:3]=[C:4]([NH:18][CH2:17][CH2:16][S:15][CH2:14][C:10]1[N:11]=[CH:12][NH:13][C:9]=1[CH3:8])[NH:6][CH3:7])#[N:2]
Reactant: CNC(=S)NC#N
Reactant: Cc1[nH]cnc1CSCCN
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CNC(=NC#N)NCCSCc1nc[nH]c1C
Yield: 3.3 %

Procedure:
A suspension of N-cyano-N'-methylthiourea (DBU salt) (0.534 g), 2-(5-methylimidazol-4-ylmethylthio)ethylamine (1.03 g), HgO (0.868 g) and anhydrous sodium sulfate (2 g) in CH3CN (20 ml) was heated under reflux for 20 hrs. with vigorous stirring. The hot reaction mixture was filtered and the filtrate was dried up and subjected to chromatography on SiO2 [eluant: CH3CN-CH3OH (4:1)]. The resulting crude product was purified by preparative thin layer chromatography [SiO2, AcOEt--MeOH--28% aq. NH3 (10:1:1)] and recrystallized from CH3CN to give N"-cyano-N-methyl-N'-[2-(5-methylimidazol-4-ylmethylthio)ethyl]-guanidine (38.4 mg). Yield 7.6%, m.p. 136°-138° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])[CH3:2].C(O[CH:16](N(C)C)[N:17]([CH3:19])[CH3:18])(C)(C)C>>[CH3:16][N:17]([CH3:19])[CH:18]=[C:6]1[CH2:7][CH2:8][CH2:9][CH:4]([O:3][CH2:1][CH3:2])[C:5]1=[O:10]
Reactant: CCOC1CCCCC1=O
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CCOC1CCCC(=CN(C)C)C1=O

Procedure:
2-Ethoxy-cyclohexanone (142 mg, 1.0 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (232 mg) as a yellow oil which was used directly in the next step.
Reaction SMILES: C([O:9][C@H:10]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][C@@H:11]1[O:41][C@H:42]1[C@@H:60]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C@H:59]([O:69][CH2:70][C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[C@@H:58]([CH2:77][O:78][CH2:79][C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)[O:57][C@@H:43]1[O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][C:53]([O:55][CH3:56])=[O:54])(=O)C1C=CC=CC=1.[Na]>C1(C)C=CC=CC=1.CO>[CH2:17]([O:16][C@H:15]1[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][C@H:11]([O:41][C@H:42]2[C@@H:60]([O:61][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C@H:59]([O:69][CH2:70][C:71]3[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=3)[C@@H:58]([CH2:77][O:78][CH2:79][C:80]3[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=3)[O:57][C@@H:43]2[O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][C:53]([O:55][CH3:56])=[O:54])[C@H:10]1[OH:9])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)CCCCCCCCO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1O[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: [Na]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCCCCO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1O[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1O
Reaction time: 1 h
Yield: 89.9 %

Procedure:
540 mg (467 μmol) of compound 23 was dissolved in 5 ml of a methanol/dichloromethane 1/1 solvent mixture. Sodium (cat.) was then added to the mixture. After 1 hour at ambient temperature, the solution was neutralized with Amberlite resin IR 120 (H+). This was filtered and concentrated under vacuum. Chromatography of the crude product (elution: cyclohexane/ethyl acetate=2.75/1) yielded 442 mg (yield=90%) of product 24 in the form of a colorless oil.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1)[C:3]#[N:4].CO.[ClH:20].[O:21]1CCOC[CH2:22]1>C(OCC)C>[ClH:20].[OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:16])([F:17])[CH:13]([F:14])[F:15])[CH:6]=1)[C:3](=[NH:4])[O:21][CH3:22]
Reactant: C1COCCO1
Reactant: N#CC(O)c1cccc(OC(F)(F)C(F)F)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COC(=N)C(O)c1cccc(OC(F)(F)C(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 130A (249 mg, 1.0 mmol) in anhydrous diethyl ether (4 mL) at 0° C. was added MeOH (0.4 mL, 10 mmol) and 4.0 N HCl in dioxane (2.0 mL, 8 mmol). The mixture was stirred at 0° C. for 30 min and then at rt for 4.0 h. The solvent was removed to give methyl 2-hydroxy-2-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)acetimidate HCl salt. To this salt in CH2Cl2 (4.0 mL) was added H2O (8.0 mL). The mixture was stirred at rt for 30 min, then extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried and concentrated. The crude product was purified by silica gel chromatography to give 130B (170 mg, 60% yield) as a viscous oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.73 (s, 3H) 5.14 (s, 1H) 5.71-6.08 (m, 1H) 7.17 (d, J=7.03 Hz, 1H) 7.28 (s, 1H) 7.31-7.43 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:16].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Br:16][C:11]1[S:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [Br-]
Reactant: COC(=O)c1cc(-c2ccccc2)cs1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)c1cc(-c2ccccc2)c(Br)s1
Temperature: 25 °C
Reaction time: 45 h
Yield: 84.1 %

Procedure:
To a solution of methyl 4-phenylthiophene-2-carboxylate (1.8 g) in DCM (18 mL) was added portionwise pyridinium tribromide (13.2 g) at 0° C. The reaction liquid was warmed to 25° C. and then stirred for 45 hours. The reaction mixture was cooled to 0° C., and a saturated aqueous Na2S2O3 solution (100 mL) was slowly added dropwise. The reaction mixture was extracted with DCM (50 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 90:10) to obtain methyl 5-bromo-4-phenylthiophene-2-carboxylate (2.06 g) as a colorless liquid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([O:7][CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([O:7][CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(F)(F)F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(OC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.7 %

Procedure:
Tert-butyl 4-(4-trifluoromethylphenoxy)piperidine-1-carboxylate (1.13 g, 3.27 mmol) prepared in Reference Example 37 was dissolved in methylene chloride (10 ml). To which trifluoroacetic acid (10 ml) was added dropwise and the mixture was stirred at room temperature for 5 hours. After the reaction mixture was concentrated under reduced pressure, the residue was again dissolved in methylene chloride. The solution was neutralized with a sodium hydroxide aqueous solution, and the mixture was extracted with methylene chloride. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to afford 4-(4-trifluoromethylphenoxy)piperidine (727 mg, yield 91%) as a white powder.
Reaction SMILES: C(O)C.[NH:4]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[C:13]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].Cl>C(OCC)(=O)C.O>[NH:4]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH:12]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(Nc2ccccc2)cc1Nc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Nc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Yield: 100.2 %

Procedure:
To a suspension of ethanol 2.0 mL of methyl 4-anilino-2-(4-fluoroanilino)benzoate 0.25 g was added water 1.0 mL solution of sodium hydroxide 0.060 g at room temperature, and it was heated and refluxed for 2 hours. After the reaction mixture was cooled to room temperature,1.0 mol/L hydrochloric acid and ethyl acetate were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue, and solid matter was filtrated to give 4-anilino-2-(4-fluoroanilino)benzoic acid 0.24 g of white solid.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:6])[CH2:4][SH:5].OO>CO>[Cl:1][CH2:2][CH:3]([OH:6])[CH2:4][S:5][S:5][CH2:4][CH:3]([OH:6])[CH2:2][Cl:1]
Reactant: OC(CS)CCl
Agent: OO
Solvent: CO
Product: OC(CCl)CSSCC(O)CCl
Temperature: 10 °C

Procedure:
Epichlorohydrin (5563 g, 60.12 mol) and methanol (2500 g) were put into a 10-liter reactor. The reaction temperature was adjusted to 5° C. When the reaction temperature reached 5° C., sodium hydroxide (50% aq., 5 g) was added to the mixture. NaSH.xH2O (70% NaSH, 3660 g, 45.75 mol), methanol (1000 g) and water (500 g) were completely dissolved with stirring in another 10-liter reactor, and hydrochloric acid was slowly added dropwise thereto to generate hydrogen sulfide gas. The hydrogen sulfide gas was added to the epichlorohydrin solution to obtain 3-chloro-2-hydroxy-propane-1-thiol. The reaction was stopped when epichlorohydrin disappeared completely and 3-chloro-2-hydroxy-propane-1-thiol was formed, which was confirmed by GC. The reaction mixture was distilled under reduced pressure to obtain 6550 g of 3-chloro-2-hydroxy-propane-1-thiol. The 3-chloro-2-hydroxy-propane-1-thiol (1500 g, 11.85 mol) and methanol (1500 g) were put into a reactor. The mixture was cooled to 10° C., and then 35% hydrogen peroxide (575.61 g, 5.92 mol) was slowly added thereto dropwise, affording bis(3-chloro-2-hydroxypropyl)disulfide (BCPDS).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.S(=O)(=O)(O)O.[CH3:19]O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH3:19])=[O:12])=[CH:5]2
Reactant: CO
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
5-Chloroindole-2-carboxylic acid (0.95 g, 4.65 mmol) was dissolved in methanol (35 ml) and treated with sulphuric acid (0.5 ml). The mixture was refluxed for 5 h and cooled and the solvent was removed. The residue was recrystallized twice from methanol to give the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27]([NH:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].O.Cl>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH2:21][CH:22]3[CH2:23][CH2:24]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CNC(=O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Reaction time: 10 h

Procedure:
To a solution of 38 mg (73 μmol) of ethyl 2-(2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetamido)acetate (Example 49) in 0.75 mL of MeOH/THF/H2O (2/2/1) was added a 2M solution of lithium hydroxide in water (70 μl, 141 μmol) at 25° C. and the mixture was stirred for 10 h. The reaction was acidified (1N aq. HCl) and extracted with DCM (2×). The combined organic layers were successively washed with 10% aq. citric acid solution and sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by reversed phase HPLC (10 to 90% AcCN/H2O with 0.1% TFA in 45 min) provided the title compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][C:8]([CH2:9][N:10]2C(=O)C3=CC=CC=C3C2=O)=[C:7]([O:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].NN>C(O)C.C(Cl)Cl>[C:1]([C:5]1[CH:22]=[CH:21][C:8]([CH2:9][NH2:10])=[C:7]([O:23][CH:24]2[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2CN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2CN)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of N-[4-tert-butyl-2-(1-Boc-piperidin-4-yloxy)benzyl]phthalimide (0.243 g, 0.49 mmol) in 3 mL absolute ethanol was added hydrazine (0.062 mL, 1.98 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h, diluted with methylene chloride; and the resulting white solid filtered off. The solvent of the filtrate was evaporated in vacuo. The remaining material was re-dissolved in a minimum amount of chloroform, sonicated, and any additional white solid filtered off. The filtrate was concentrated in vacuo to afford the amine (0.170 g, 95%).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+].[OH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1>C(Cl)Cl.C(OCC)C>[C:26]([C:25]1[CH:30]=[CH:31][C:22]([CH2:21][CH2:20][CH2:19][CH:18]=[O:17])=[CH:23][CH:24]=1)([O:28][CH3:29])=[O:27]
Reactant: COC(=O)c1ccc(CCCCO)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)c1ccc(CCCC=O)cc1

Procedure:
To mixture of 4.19 g (1.5 eq) of pyridinium chlorochromate and 1.76 g (1.0 eq) of sodium acetate in 100 mL of dry methylene chloride are added, under nitrogen and with stirring, 2.70 g 1.0 eq) of methyl 4-(4-hydroxybutyl)benzoate in 50 mL of dry methylene chloride. The reaction mixture is stirred 12 hours, diluted with diethyl ether, and filtered. After concentration at reduced pressure, the residue is distilled under vacuum to yield 4-(4-carbomethoxyphenyl)-butanal as an oil, b.p. 131° C. at <1 torr; IR (film) νmax 2950, 2720, 1722, 1612, 1285, and 1110 cm-1 ; 1H NMR (CDCl3) delta 9.77 (m, 1H, --CHO), 7.98 (d, J=9 Hz, 2H, Ar), 7.24 (d, J=8.2 Hz, 2H, Ar), 3.90 (s, 3H, --CH3), 2.72 (t, 2H, benzyl), 2.47 (mm, 2H, --CH2CHO), 1.95 (m, 2H, --CH2).
Reaction SMILES: O1CC1COC1C=CC(NC(=O)C)=CC=1.[Cl:16][C:17]1[N:22]=[C:21]([CH:23]([OH:56])[CH2:24][N:25]([C@H:41]([CH3:55])[CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH2:50][CH2:51][O:52][CH2:53][CH3:54])=[CH:45][CH:44]=2)CC(O)COC2C=CC(NC(=O)C)=CC=2)[CH:20]=[CH:19][CH:18]=1>CO>[Cl:16][C:17]1[N:22]=[C:21]([CH:23]([CH2:24][NH:25][C@H:41]([CH3:55])[CH2:42][C:43]2[CH:44]=[CH:45][C:46]([O:49][CH2:50][CH2:51][O:52][CH2:53][CH3:54])=[CH:47][CH:48]=2)[OH:56])[CH:20]=[CH:19][CH:18]=1
Reactant: CCOCCOc1ccc(C[C@@H](C)N(CC(O)COc2ccc(NC(C)=O)cc2)CC(O)c2cccc(Cl)n2)cc1
Agent: CC(=O)Nc1ccc(OCC2CO2)cc1
Solvent: CO
Product: CCOCCOc1ccc(C[C@@H](C)NCC(O)c2cccc(Cl)n2)cc1

Procedure:
using 4'-(2,3-epoxypropoxy)acetanilide there were obtained from 1.0 g of (RS)-6-chloro-α-[[[(R)-p-(2-ethoxyethoxy)-α-methylphenethyl]amino]methyl]-2-pyridinemethanol (Example 4C) 530 mg of 4'-[(RS)-3-[[(RS)-2-(6-chloro-2-pyridyl)-2-hydroxyethyl][(R)-p-(2-ethoxyethoxy)-α-methylphenethyl]amino]-2-hydroxypropoxy]acetanilide, [α]D20° =-39` (c=0.4 in MeOH),
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:14]2[C:13]([Br:15])=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)(=O)C.[OH-].[Na+]>C(O)C>[Br:15][C:13]1[C:14]2[C:6]([CH2:5][OH:4])=[CH:7][CH:8]=[CH:9][C:10]=2[S:11][C:12]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)OCc1cccc2sc(-c3ccccc3)c(Br)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCc1cccc2sc(-c3ccccc3)c(Br)c12
Yield: 101.9 %

Procedure:
Hydrolysis of the compound from Example XV (1 g) in 100 ml of ethanol with 20 ml of 1N NaOH at room temperature gives, after 2 hours, 0.9 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH2:8][NH:9][CH2:10][CH2:11][NH:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.FC(F)(F)S(N=[C:45]([NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58])[NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])(=O)=O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH2:8][N:9]([CH2:10][CH2:11][NH:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:45]([NH:46][C:47]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:53])=[N:54][C:55]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:61]
Reactant: CC(C)(C)OC(=O)NC(=NS(=O)(=O)C(F)(F)F)NC(=O)OC(C)(C)C
Reactant: Cn1ncc(CNCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)c1N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cn1ncc(CN(CCNC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1N
Temperature: 25 °C
Reaction time: 96 h
Yield: 25.2 %

Procedure:
To a solution of N-[(5-amino-1-methyl-1H-pyrazol-4-yl)methyl]-N′-tritylethane-1,2-diamine (7.50 g) and triethylamine (2.86 g) in chloroform (100 ml) was added di-tert-butyl ({[(trifluoromethyl)sulfonyl]imino}-methylene)biscarbamate (11.05 g). The mixture was stirred at room temperature for 4 days. The reaction mixture was washed successively with 10% aqueous citric acid solution and brine, and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 3% methanol/chloroform to give N-[(5-amino-1-methyl-1H-pyrazol-4-yl)methyl]-N′,N″-bis(tert-butoxycarbonyl)-N-[2-(tritylamino)ethyl]guanidine (3.00 g) as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][C:9]2[S:8](=[O:13])(=[O:12])[N:7]=[CH:6][NH:5][C:4]=2[CH:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(OC)(=O)=O)=CC=1>C(#N)C.O>[CH3:14][N:5]1[C:4]2[CH:3]=[C:2]([CH3:1])[CH:11]=[N:10][C:9]=2[S:8](=[O:13])(=[O:12])[N:7]=[CH:6]1
Reactant: Cc1cnc2c(c1)NC=NS2(=O)=O
Reactant: O=C([O-])[O-]
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cnc2c(c1)N(C)C=NS2(=O)=O

Procedure:
A solution of 0.6 g of 6-methyl-4H-pyrido[3,2-e][1,2,4]thiadiazine 1,1-dioxide (Example 75) in 15 cm3 of acetonitrile is treated with 2.5 g of potassium carbonate and 0.9 g of methyl p-toluenesulfonate. After refluxing for 16 hours, the solvent is removed under partial vacuum and the solid obtained is taken up in 15 cm3 of water. The precipitate is collected on a filter, washed with water and dried.