Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][C:45]([F:48])([F:47])[CH2:44][N:43]6[C:49](=[O:62])[CH:50]([NH:57][C:58]([O:60][CH3:61])=[O:59])[CH:51]6[CH2:56][CH2:55][O:54][CH2:53][CH2:52]6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH3:69][O:70][C:71]([NH:73][CH:74]([C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)C(O)=O)=[O:72].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F>CCO.[Pd].C(Cl)Cl>[CH3:61][O:60][C:58](=[O:59])[NH:57][CH:50]([CH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1)[C:49]([N:43]1[CH2:44][C:45]([F:47])([F:48])[CH2:46][CH:42]1[C:39]1[NH:38][C:37]([C:34]2[CH:35]=[CH:36][C:31]([C:26]3[CH:25]=[CH:24][C:23]4[C:28](=[CH:29][CH:30]=[C:21]([C:18]5[NH:17][C:16]([CH:12]6[CH2:13][CH2:14][CH2:15][N:11]6[C:9](=[O:10])[CH:74]([NH:73][C:71]([O:70][CH3:69])=[O:72])[C:78]6[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=6)=[N:20][CH:19]=5)[CH:22]=4)[CH:27]=3)=[CH:32][CH:33]=2)=[CH:41][N:40]=1)=[O:62]
Reactant: COC(=O)NC(C(=O)O)c1ccccc1
Reactant: COC(=O)NC(C(=O)N1CC(F)(F)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)OCc6ccccc6)[nH]5)ccc4c3)cc2)[nH]1)C1CCOCC1
Agent: [Pd]
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC(F)(F)CN6C(=O)C(NC(=O)OC)C6CCOCC6)[nH]5)cc4)ccc3c2)[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 111 %

Procedure:
To a solution of 2-(5-{6-[4-(2-{4,4-Difluoro-1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid benzyl ester (0.13 g, 0.15 mmol) in EtOH (3.5 mL) was added Palladium on carbon (10%, 0.08 g, 0.08 mmol) and Potassium Carbonate (0.07 g, 0.48 mmol). The slurry was stirred at room temperature under an atmosphere of H2 for 3 h. The slurry was filtered through celite and washed with EtOH. The filtrate was concentrated to an oil and diluted with CH2Cl2 (3 mL) and filtered an additional time. Methoxycarbonylamino-phenyl-acetic acid (0.05 g, 0.03 mmol) and Potassium Phosphate (0.04 g, 0.16 mmol) were added and the resulting slurry was cooled to 0° C. (external, ice). COMU (0.09 g, 0.02 mmol) was added and the reaction was stirred at 0° C. for 2 h. The slurry was diluted with CH2Cl2 and filtered through celite. The filtrate was concentrated and purified by preparative HPLC (Gemini, 15→50% MeCN in H2O (0.1% TFA)) to provide to provide [2-(4,4-Difluoro-2-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamic acid methyl ester (0.03 g, 17%). LCMS-ESI+: calc'd for C49H50F2N8O7: 900.38 (M+); Found: 901.4 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C@@H:9]1[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:31][CH2:30][C@H:29]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:28]2)=[CH:23][CH:22]=1)=O)(C)(C)C.[ClH:37]>ClCCl.C(OCC)(=O)C>[ClH:37].[ClH:37].[ClH:37].[ClH:37].[N:32]1([C@H:29]2[CH2:30][CH2:31][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C@H:9]4[CH2:10][NH:11][CH2:12][CH2:13][NH:8]4)=[CH:26][CH:25]=3)[CH2:28]2)[CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(N3CC[C@H](N4CCCC4)C3)cc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: c1cc(N2CC[C@H](N3CCCC3)C2)ccc1[C@H]1CNCCN1
Reaction time: 3 h
Yield: 87 %

Procedure:
To a solution of (S)-1,4-di(t-butoxycarbonyl)-2-(4-((S)-3-(pyrrolidin-1-yl) pyrrolidin-1-yl)phenyl)piperazine (479 mg, 0.957 mmol) in dichloromethane (4 mL) was added 4 N hydrogen chloride in ethyl acetate (4 mL) at room temperature. After stirring for 3 h, the resulting precipitate was collected and dried in vacuo to afford (S)-2-(4-((S)-3-(pyrrolidin-1-yl)pyrrolidin-1-yl)phenyl)piperazine tetrahydrochloride (370 mg, 87%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:16])=[C:8]([O:12][CH2:13][CH2:14]Cl)[C:9]=2[CH3:11])[S:4][C:3]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C([O-])([O-])=O.[K+].[K+].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CC#N>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:16])=[C:8]([O:12][CH2:13][CH2:14][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:9]=2[CH3:11])[S:4][C:3]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: C1COCCN1
Reactant: Cc1nc2sc(C(=O)OC(C)(C)C)c(N)c2c(C)c1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc2sc(C(=O)OC(C)(C)C)c(N)c2c(C)c1OCCN1CCOCC1
Yield: 30 %

Procedure:
tert-Butyl 3-amino-5-(2-chloroethoxy)-4,6-dimethyl-thieno[2,3-b]pyridine-2-carboxylate, prepared above (50 mg, 0.22 mmol), was dissolved in CH3CN (5 mL), followed by the addition of K2CO3 (41 mg, 0.30 mmol), morpholine (26 mg, 0.30 mmol) and a catalytic amount of KI. The mixture was heated to reflux overnight, the solvent was removed under reduced pressure, water was added and the residue was extracted with ethyl acetate (10 mL), and the organic phases were washed with water (5 mL×3), brine, dried over anhydrous Na2SO4, concentrated and purified by preparative HPLC to furnish the title compound, tert-butyl 3-amino-4,6-dimethyl-5-(2-morpholin-4-yl-ethoxy)-thieno[2,3-b]pyridine-2-carboxylate (20 mg, 30%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1.[C:13](Cl)([CH3:16])([CH3:15])[CH3:14]>C(=S)=S>[C:13]([C:7]1[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:6]=1[F:5])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)Cl
Reactant: Cc1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: Cc1ccc(F)c(C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 65.3 %

Procedure:
To a solution of aluminum chloride (8.1 g, 60.7 mmol) in carbon disulfide (60 ml), 4-fluorotoluene (6.0 g, 54.5 mmol) was added and then under cooling with ice, tert-butyl chloride (6.0 ml, 54.5 mmol) was added, followed by stirring for 10 min. The reaction mixture was poured into ice water and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The thus obtained residue was subjected to silica gel column chromatography (developing solvent: n-hexane) to give the titled compound (5.92 g, 63%).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[C:11]=1I)[CH3:2].[Li]CCCC.[CH:18]([P:28]([O:33][CH2:34][CH3:35])(=[O:32])[O:29][CH2:30][CH3:31])([P:20]([O:25][CH2:26][CH3:27])(=[O:24])[O:21][CH2:22][CH3:23])C>C1COCC1>[CH2:30]([O:29][P:28]([CH:18]([P:20]([O:25][CH2:26][CH3:27])([O:21][CH2:22][CH3:23])=[O:24])[C:11]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH2:1][CH3:2])(=[O:32])[O:33][CH2:34][CH3:35])[CH3:31]
Reactant: CCc1nc2ccccn2c1I
Reactant: CCOP(=O)(OCC)C(C)P(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(c1c(CC)nc2ccccn12)P(=O)(OCC)OCC
Temperature: -78 °C

Procedure:
As shown in FIG. 8, 2-Ethyl-3-iodo-imidazo[1,2-α]pyridine 72 (Example 28) (5.0 g, 18.34 mmol) in anhydrous THF (80 mL) was stirred at −78° C., under argon, then n-BuLi (2.5 M, 14.7 mL, 36.76 mmol) in hexanes was added slowly, keeping the temperature below −70° C. The resulting mixture was stirred for 10 minutes, then tetraethyl ethene-1,1-bisphosphonate 3 (5.52 g, 18.38 mmol) in anhydrous THF (20 mL) was added slowly , keeping the temperature below −70° C. The reaction mixture was stirred for an additional 10 min, cooled to room temperature, then quenched with saturated NH4Cl (100 mL). The mixture was then extracted with CH2Cl2 (200 mL×3) and the organic phase washed with water (200 mL×2). The resultant organic phase was then dried (NaSO4), concentrated under reduced pressure and purified on silica gel (CombiFlash, EtOAc/MeOH elution) and HPLC to afford [(diethoxy-phosphoryl)-(2-ethyl-imidazo[1,2-α]pyridin-3-yl)-methyl]-phosphonic acid diethyl ester 74 as pale yellow oil with a yield of 900 mg, 11%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[CH2:5][NH:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].C(N(CC)C(C)C)(C)C.[Br:22][CH2:23][CH2:24][CH2:25]Br>C1(C)C=CC=CC=1>[Br:22][CH2:23][CH2:24][CH2:25][N:6]([CH2:5][C:4]([O:3][CH3:2])=[O:12])[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: BrCCCBr
Reactant: COC(=O)CNCC(=O)OC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN(CCCBr)CC(=O)OC
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 1 mmol iminodiacetic acid dimethylester hydrochloride salt, 5 mmol N,N-diisopropyl-ethylamine and 3 mmol 1,3-dibromopropane in 2 mL toluene was stirred at 90° C. for 16 h and then chromatographed to provide the title compound as an oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[C:10]2[O:13]C)=[CH:5][C:4]=1[O:15][CH:16]1[CH2:21][CH2:20][CH:19]([C:22]([NH2:32])([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH3:23])[CH2:18][CH2:17]1.C(#N)C.O>C(O)(C)C>[NH2:32][C:22]([CH:19]1[CH2:18][CH2:17][CH:16]([O:15][C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][C:3]=2[Cl:2])[C:10](=[O:13])[NH:9][CH:8]=[CH:7]3)[CH2:21][CH2:20]1)([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[CH3:23]
Reactant: COc1ccc(C(C)(N)C2CCC(Oc3cc4ccnc(OC)c4cc3Cl)CC2)cc1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Solvent: CC#N
Product: COc1ccc(C(C)(N)C2CCC(Oc3cc4cc[nH]c(=O)c4cc3Cl)CC2)cc1
Temperature: 100 °C
Yield: 97 %

Procedure:
Hydrochloric acid (0.4 mL of a 1M aqueous solution) was added to a solution of 1-[4-(7-chloro-1-methoxyisoquinolin-6-yloxy)-cyclohexyl]-1-(4-methoxyphenyl)-ethylamine (109, 30 mg, 0.07 mmol) in isopropanol (0.4 mL). The reaction mixture was heated in a microwave oven at 100° C. for 30 minutes. Isopropanol was removed under reduced pressure and the remaining aqueous solution freeze dried to give crude product as an amorphous powder. This was treated twice with acetonitrile/water and freeze dried to give 29 mg of the desired product Example 117 as a colourless hydrochloride salt. Rt=2.60 min (Method 2). Detected mass: 410.1 (M—NH3+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][C:12]#[N:13])=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N1CCOCC1)C>CN(C)C=O.O1CCCC1>[C:12]([CH2:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:15]([CH3:14])(=[O:17])=[O:16])=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2)#[N:13]
Reactant: N#CCc1ccc(N)c2[nH]ncc12
Reactant: CS(=O)(=O)Cl
Agent: CCN1CCOCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(CC#N)c2cn[nH]c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At 0° C., 1.7 g of 2-(7-amino-1H-indazol-4-yl)acetonitrile in 15 ml of dimethylformamide and 5 ml of tetrahydrofuran is combined with 0.96 ml of methanesulfonyl chloride and 1.56 ml of N-ethylmorpholine and agitated for 16 hours at room temperature. The mixture is concentrated, chromatographed over silica gel with methanol/dichloromethane (1:3), and recrystallized from methanol, thus producing 2.2 g of N-(4-cyanomethyl-1H-indazol-7-yl)methanesulfonamide, mp 223°-225° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[C:4]([Cl:16])[C:3]=1[CH:17]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:18](Cl)=[O:19].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.Cl>O>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([CH:17]([C:3]2[C:4]([Cl:16])=[CH:5][C:6]([N:8]3[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]3)=[CH:7][C:2]=2[Cl:1])[C:18]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:19])=[CH:26][CH:25]=1
Reactant: O=C(Cl)C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Reactant: C1CCNCC1
Agent: Cl
Solvent: O
Product: O=C(C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl)N1CCCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 44 %

Procedure:
A mixture of 2.28 parts of 2,6-dichloro-α-(4-chlorophenyl)-4(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetylchloride and 18 parts of piperidine was stirred for 17 hours at room temperature (exothermic reaction). After the addition of water, the solution was acidified with hydrochloric acid. The product was extracted with a mixture of trichloromethane and methanol (95:5 by volume). The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and acetic acid (95:4:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was washed with 2,2'-oxybispropane and dried, yielding 1 part (44.0%) of 1-[2-(4-chlorophenyl)-2-[2,6-dichloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)phenyl]acetyl]piperidine; mp. 216.9° C. (intermediate 34).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:27]=[CH:26][C:21]4[NH:22][C:23](=[O:25])[O:24][C:20]=4[CH:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[CH2:33](Br)[CH:34]=[CH2:35]>C1COCC1.CN(C=O)C.O>[CH2:35]([N:11]([CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[CH:27]=[CH:26][C:21]3[NH:22][C:23](=[O:25])[O:24][C:20]=3[CH:19]=2)[CH2:14][CH2:13]1)[CH:34]=[CH2:33]
Reactant: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccc(F)cc4)CC3)cc2o1
Reactant: C=CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=CCN(CCCc1ccc(F)cc1)[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Temperature: 25 °C

Procedure:
To a stirred suspension of 6-{trans-4-[3-(4-fluorophenyl)-propylamino]-cyclohexyl}-3H-benzoxazol-2-one (400 mg, 0.99 mmol) in THF (40 mL) and DMF (3 mL) was added NaHCO3 (180 mg, 2.2 mmol) and allyl bromide (130 mg, 1.1 mmol). After refluxing overnight, additional DMF (1.5 mL), allyl bromide (30 mg, 29 mmoL), and NaHCO3 (21 mg, 0.25 mmol) were added. The reaction mixture was refluxed for 12 hours and then cooled to room temperature. The material was diluted with water and extracted with EtOAc (3×). The combined organics were washed with water, saturated NaCl solution (3×), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica, 90:10 CH2Cl2:MeOH), followed by formation of the HCl salt, gave 6-(trans-4-{allyl-[3-(4-fluorophenyl)propyl]-amino}cyclohexyl)-3H-benzoxazol-2-one (138 mg, 31%), as a white solid: mp 224-230° C.; IR (KBr): 2943, 1770, 1510 cm−1; 1H NMR (500 MHz, DMSO-d6): δ 11.51 (s, 1H), 10.38 (br s, 1H), 7.31-7.28 (m, 2H), 7.17-7.11 (m, 3H), 7.00 (s, 2H), 6.11-6.04 (m, 1H), 5.55 (d, J=17 Hz, 1H), 5.45 (d, J=10 Hz, 1H), 3.87-3.71 (m, 2H), 3.38-3.31 (m, 1H), 3.19-3.13 (m, 1H), 3.05-2.92 (m, 1H), 2.70-2.51 (m, 3H), 2.18-2.12 (m, 2H), 2.07-1.99 (m, 2H), 1.92-1.87 (m, 2H), 1.72-1.50 (m, 4H); (ESI-MS (m/z): 409 [M+H]+; HPLC: method B, 11.34 minutes (98.1%); Anal. Calcd for C25H29FN2O2.HCl: C, 67.48; H, 6.80; N, 6.30. Found: C, 67.29; H, 6.93; N, 6.07.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[N:3]=[C:4]([CH3:6])[CH3:5].[Li+].CCC[CH2-].[Cl:13][C:14]1[C:15]([O:24][C:25]2[CH:35]=[CH:34][C:28]([O:29][CH:30]([CH3:33])[CH:31]=[O:32])=[CH:27][CH:26]=2)=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C(O)(=O)C>C1COCC1>[CH3:1][N:2]([CH3:7])[N:3]=[C:4]([CH2:6][CH:31]([OH:32])[CH:30]([O:29][C:28]1[CH:27]=[CH:26][C:25]([O:24][C:15]2[C:14]([Cl:13])=[CH:19][C:18]([C:20]([F:21])([F:22])[F:23])=[CH:17][N:16]=2)=[CH:35][CH:34]=1)[CH3:33])[CH3:5]
Reactant: CC(C=O)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Reactant: CC(C)=NN(C)C
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(CC(O)C(C)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)=NN(C)C
Reaction time: 0.5 h

Procedure:
To a solution of acetone N,N-dimethylhydrazone (0.48 g, 4.8 mmol) in 5 ml of THF is added N-butyllithium (4.8 mmol) at -65°, and the mixture is stirred for about 30 minutes. 2-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]propanal (1.50 g, 4.8 mmol) in 5 ml of THF is added dropwise. After several hours at -65°, the reaction mixture is allowed to warm to 0° and is poured onto ice made slightly acidic with 10% acetic acid. The organic phase is separated, washed with water and with NaCl and dried. Solvent is removed to give 4-hydroxy-5-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]-2-hexanone N,N-dimethylhydrazone.
Reaction SMILES: [NH:1]([CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH:8]2[N:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:12](=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:16][CH:17]=1
Reactant: O=C(O)CCCC(Nc1ccccc1)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C1CCCC(c2ccc(Cl)cc2)N1c1ccccc1
Temperature: 0 °C
Yield: 97.9 %

Procedure:
(2)-(a) A solution of 17.8 g of 5-anilino-5-(4-chlorophenyl)pentanoic acid in a mixed solution of 290 ml of toluene and 13.9 g of pyridine was cooled to -3° C. and stirred. To this solution was added 10 ml solution of 5.1 ml of thionyl chloride in toluene dropwise over 1 hour. After stirring at -3° C. for 1 hour and at room temperature for 1.5 hours, the reaction mixture was poured into ice-water. The toluene layer was washed with diluted hydrochloric acid, a saturated aqueous sodium chloride solution, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, dried and treated with activated charcoal. After removal of charcoal and the solvent, the residual solid was recrystallized from isopropyl ether to give 16.4 g of 6-(4-chlorophenyl)-1-phenyl-2-piperidone as colorless prisms.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:30])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=1)[C:10](=[O:17])[NH:11]2.[C:32](=O)([O-])[O-].[K+].[K+].IC.CN(C)C=O>O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:30])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=1)[C:10]([O:17][CH3:32])=[N:11]2
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c(=O)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)COc1ccc(Cl)c2nc(OC)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.4 %

Procedure:
A mixture of [8-chloro-4-methyl-2-oxo-3-(4-pyrazol-1-ylbenzyl)-1,2-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.35 g), potassium carbonate (0.33 g), iodomethane (0.50 mL) and N,N-dimethylformamide (5.0 mL) was stirred at room temperature for 16 hours. The mixture was diluted with water, acidified by the addition of glacial acetic acid and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure to afford title compound as a cream solid (0.37 g).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[Cl:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:38][CH3:39])[C:30]=2[C:34]([F:37])([F:36])[F:35])[C:25]=1[C:40]([N:42]([CH3:48])[CH2:43][C:44]([O:46][CH3:47])=[O:45])=O>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:38][CH3:39])[C:30]=2[C:34]([F:37])([F:36])[F:35])[C:25]=1[C:40](=[S:10])[N:42]([CH3:48])[CH2:43][C:44]([O:46][CH3:47])=[O:45]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)CN(C)C(=O)c1c(Cl)ccc2c(C(F)(F)F)c(OC)ccc12
Solvent: Cc1ccccc1
Product: COC(=O)CN(C)C(=S)c1c(Cl)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 25 °C
Yield: 51.4 %

Procedure:
Lawesson's reagent (1.9 g, 0.6 eq) was added to a stirred suspension of N-[[2-chloro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-methylglycine, methyl ester (3.00 g, 7.70 mmole) in toluene (30 mL) at room temperature under nitrogen. The reaction was heated to reflux for 42 hours with more Lawesson's reagent (3.9 g, 1.2 eq) added in three equal portions after 11/4, 171/2 and 231/2 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate absorbed onto silica gel and flash chromatographed (gradient elution:eluant 60/40, chloroform/petroleum ether →9/1 chloroform/acetonitrile) to provide the desired product as a foamy solid (0.98 g) and recovered starting material (1.23 g). The starting material (1.23 g, 3.08 mmole) was suspended in toluene (~15 mL) and treated with Lawesson's reagent as described above to give additional product (0.351 g, combined yield 43%), m.p. 67°-73° C. (softens at 50° C.).
Reaction SMILES: [CH2:1]([C:9]1[C:10](Cl)=[N:11][C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C@@H:28]([CH3:31])[CH2:29][CH3:30])=[CH:18][CH:17]=2)=[N:13][C:14]=1Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[O-2].[Mg+2].C(O)C>[C].[Pd].O>[CH2:1]([C:9]1[CH:14]=[N:13][C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C@@H:28]([CH3:31])[CH2:29][CH3:30])=[CH:18][CH:17]=2)=[N:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1c(Cl)nc(-c2ccc(OCCCCC[C@@H](C)CC)cc2)nc1Cl
Agent: [Pd]
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Solvent: CCO
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCC[C@@H](C)CC)cc2)nc1

Procedure:
Pour 1.88 g of optically active (s)-5-n-octyl-2-[4-(6-methyloctyloxy)phenyl]-4,6-dichloro-pyrimidine, 0.4 g of 10% palladium-carbon, 0.55 g of magnesium oxide, 60 ml of ethanol, and 45 ml of water, into a 200 ml flask, then add hydrogen under oil bath conditions at 50° C., until the logical amount of hydrogen has been absorbed. The catalyst is filtered and separated, then ether is extracted. After the ether layer is washed with water and with saturated salt water, and dried, the ether is evaporated. The resultant impure product is repeatedly refined, and 0.9 g of optically active (s)-5-n-octyl-2-[4-(6-methyloctyloxy)phenyl]-pyrimidine is obtained.
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([N:40]([CH3:42])[CH3:41])[C:13]2[CH2:25][C@@H:24]3[C:19](=[C:20]([OH:39])[C@:21]4([OH:38])[C:29](=[O:30])[C:28]([C:31]([NH2:33])=[O:32])=[C:27]([OH:34])[C@@H:26]([N:35]([CH3:37])[CH3:36])[C@@H:22]4[CH2:23]3)[C:17](=[O:18])[C:14]=2[C:15]=1[OH:16])=[O:8])([CH3:4])[CH3:3].[ClH:43]>C(Cl)Cl>[CH3:4][C:2]([NH:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([N:40]([CH3:42])[CH3:41])[C:13]2[CH2:25][C@@H:24]3[C:19](=[C:17]([OH:18])[C:14]=2[C:15]=1[OH:16])[C:20](=[O:39])[C@@:21]1([OH:38])[C@H:22]([C@H:26]([N:35]([CH3:36])[CH3:37])[C:27]([C:28]([C:31]([NH2:33])=[O:32])=[C:29]1[OH:30])=[O:34])[CH2:23]3)=[O:8])([CH3:1])[CH3:3].[ClH:43]
Reactant: CN(C)c1cc(NC(=O)CNC(C)(C)C)c(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]3(O)C(O)=C1C2=O
Agent: Cl
Solvent: ClCCl
Product: CN(C)c1cc(NC(=O)CNC(C)(C)C)c(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]3(O)C(=O)C1=C2O
Temperature: 25 °C

Procedure:
A suspension of Tigecycline was prepared by mixing a solid Tigecycline sample and methylenchloride in amounts as shown in Table C. The mixture was than stirred at room temperature and 5N hydrochloric acid was added in amounts corresponding to Table C. After stirring for about 92 hours the solid was filtered off and dried at room temperature under vacuum to obtain crystalline form B of Tigecycline hydrochloride.