Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[S:8][C:9]([S:13](Cl)(=[O:15])=[O:14])=[C:10]([CH3:12])[N:11]=1>C([O-])(O)=O.[Na+].C(OCC)(=O)C>[C:1]([NH:5][S:13]([C:9]1[S:8][C:7]([Cl:6])=[N:11][C:10]=1[CH3:12])(=[O:15])=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: Cc1nc(Cl)sc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1nc(Cl)sc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
To a stirred solution of commercially available tert-butylamine (3.76 mL, 35.5 mmol) in saturated NaHCO3 solution (30 mL) and ethyl acetate (50 mL) was added at 0° C. (ice water bath) a solution of commercially available 2-chloro-4-methyl-thiazole-5-sulfonyl chloride [CAS-No. 292138-59-1] (5.0 g, 21.5 mmol). The reaction mixture was stirred at room temperature for 16 h, ethyl acetate (50 mL) was added followed by extraction. The water layer was again extracted with ethyl acetate (50 mL). The combined organic layers were washed with 2N HCl solution (40 mL) and brine (40 mL), dried (MgSO4) and evaporated to yield the title compound (4.57 g, 79%) as a yellow solid. MS (ISN) 267.3 [(M−H)−].
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][NH:13][C:12](=O)[C@@H:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1.C(=O)(O)[O-].[Na+].O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][NH:13][C:12](=[S:33])[C@@H:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CNC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CNC1=S
Temperature: 40 °C
Reaction time: 16 h
Yield: 140.4 %

Procedure:
To a solution of tert-butyl [(3S,5S)-5-(2,3-difluorophenyl)-2-oxopiperidin-3-yl]carbamate (300 mg, 0.92 mmol) in toluene (9.2 mL) was added Lawesson's Reagent (190 mg, 0.47 mmol). The mixture was stirred at 40° C. After 16 h, the mixture was cooled to ambient temperature and saturated aqueous sodium bicarbonate was added. Water was added, and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase chromatography (C-18, 90% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (226 mg). MS 365.3 (M+Na).
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([OH:28])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][C:24]([F:27])([F:26])[F:25])[CH2:10]1)C1C=CC=CC=1.O>[Pd].CC(O)C>[ClH:1].[NH:9]1[CH2:14][CH2:13][O:12][C@@H:11]([C@:15]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([OH:28])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][C:24]([F:27])([F:26])[F:25])[CH2:10]1
Reactant: OC(Cc1ccccc1OC(F)(F)F)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: O[C@@](Cc1ccccc1OC(F)(F)F)(c1ccccc1)[C@H]1CNCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
Alternatively, the following method may be used. In a glass-lined nitrogen purged hydrogenator are charged 1-(4-Benzyl-morpholin-2-yl)-1-phenyl-2-(2-trifluoromethoxy-phenyl)-ethanol hydrochloride (150 g, 303.7 mmol), demineralized water (352 mL), i-PrOH (375 mL) and 5% Pd/C (30 g, 50% water, Johnson & Matthey type 440). The heterogeneous reaction mixture was then purged 5 times with 25 psi nitrogen then purged 5 times with 50 psi hydrogen, and the hydrogenation was performed at RT. The initial Tmass was 22° C. and the maximum Tmass during the hydrogenation was 23° C. The reactor was stirred vigorously. In-process analysis after 2 hours indicated complete hydrogenolysis. The hydrogenation was stopped after 3 hours. The nitrogen purged reaction mixture was then filtered at RT through an hyflo filter (56 g), impregnated beforehand with 75 mL of a 50/50 v/v isopropanol/water mixture and washed with 300 mL of a 50/50 v/v isopropanol/water mixture. The filtrates were stored overnight at RT. The filtrates were concentrated at 40-50° C. under reduced pressure (typical 622 g distilled). The reaction mixture was cooled to RT and post-agitated. After 3 hours, 1 mL of the solution was taken and cooled to 0° C. to initiate crystallization. These seeds were added to the reaction mixture and precipitation was observed within a few minutes. The mixture was post-agitated at RT for 2 hours. The crystals were filtered and rinsed with H20 (30 mL). Then, the precipitate was dried under reduced pressure (400 mmHg) with a nitrogen flow (0.1 bar) for 4 hours affording the title compound as the hydrate polymorph (103.5 g, 81% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:22][CH2:21][C:16]3[N:17]=[C:18]([NH2:20])[S:19][C:15]=3[CH2:14]2)[CH2:9][CH2:8]1.C(N(CC)CC)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:22][CH2:21][C:16]3[N:17]=[C:18]([NH:20][C:30](=[O:37])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[S:19][C:15]=3[CH2:14]2)[CH2:9][CH2:8]1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nc2c(s1)CC(N1CCN(c3ccccn3)CC1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1nc2c(s1)CC(N1CCN(c3ccccn3)CC1)CC2)c1ccccc1

Procedure:
A solution of (±)-4,5,6,7-tetrahydro-6-[4-(2-pyridinyl)-1-piperazinyl]-2-benzothiazolamine (10.0 g) (Example 1) in 200 ml of chloroform is treated with triethylamine (6.06 g) and benzoyl chloride (4.21 g). The resulting red solution is refluxed for two hours under nitrogen. Saturated sodium bicarbonate solution is added. The organic layer is dried (magnesium sulfate) and evaporated. The residue is purified by MPLC (silica; 1.5% methanol, 98.5% dichloromethane). The title compound is obtained as a yellow solid; mp 230°-232° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:7][C:6]([CH2:8][CH2:9][CH3:10])=[N:5][C:4]=1[I:11].[OH-].[Na+]>C(O)(=O)C.O>[I:11][C:4]1[N:5]=[C:6]([CH2:8][CH2:9][CH3:10])[NH:7][C:3]=1[CH:2]=[O:1]
Reactant: CCCc1nc(I)c(CO)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCCc1nc(I)c(C=O)[nH]1
Temperature: 20 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a solution of 35.8 g of 5-hydroxymethyl-4-iodo-2-n-propylimidazole in 325 mL of glacial acetic acid at 20° C. was added dropwise over 1 h 290 mL of 1.0N aqueous ceric ammonium nitrate solution. The resulting mixture was stirred at 20° C. for 1 h. The reaction mixture then was diluted with water, adjusted to pH 5-6 employing aqueous sodium hydroxide solution, and extracted with chloroform. The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude solid was recrystallized from 1-chlorobutane to furnish 29.9 g of product as a light yellow solid: mp 141°-142° C. NMR (CDCl3) δ 11.51 (br s,1H); 9.43 (s,1H); 2.81 (t,2H); 1.81 (sext., 2H); 0.97 (t,3H). ##STR84##
Reaction SMILES: O.[Sn](Cl)Cl.[C:5]([C:7]1[N:8]=[CH:9][C:10]([NH:13][C:14]2[CH:19]=[C:18]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)[C:17]([N+:35]([O-])=O)=[CH:16][N:15]=2)=[N:11][CH:12]=1)#[N:6]>C(O)C>[NH2:35][C:17]1[C:18]([NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:19][C:14]([NH:13][C:10]2[CH:9]=[N:8][C:7]([C:5]#[N:6])=[CH:12][N:11]=2)=[N:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2[N+](=O)[O-])CC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2N)CC1
Temperature: 70 °C
Yield: 91.4 %

Procedure:
Tin (II) chloride hydrate (678 mg, 5 eq) was added to a solution of tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate (273 mg) in ethanol (20 mL). The mixture was heated at 70° C. for 30 minutes then cooled to room temperature and evaporated to dryness. The residue was diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate. The suspension was filtered and the aqueous phase was separated and extracted twice with ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated to give crude tert-butyl 4-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (233 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47](O)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si](C(C)C)(C(C)C)C(C)C)[CH2:5][C:4]1=[O:66])[CH3:2].C(N(S(F)(F)[F:73])CC)C.C(#N)C>C1COCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([F:73])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:66])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C(C)C)(C(C)C)C(C)C)CC1=O)C(C)CC2OC
Reactant: CCN(CC)S(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(F)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC

Procedure:
Treatment of 17-ethyl-1-hydroxy-14-triisopropylsilyloxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]-octacos-18-ene-2,3,10,16-tetraone with diethylaminosulfur trifluoride (DAST) in THF followed by 48% aqueous HF/acetonitrile deblocking as in Example 64, yielded 17-ethyl-1,14-dihydroxy-12-[2'-(4"-fluoro-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]-octacos-18-ene-2,3,10,16-tetraone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]([N:19]3[CH2:26][CH2:25][C:22]4([CH2:24][CH2:23]4)[C@H:21]([OH:27])[CH2:20]3)=[O:18])[C:10](=[O:28])[C@@H:9]2[CH3:29])=[CH:4][C:3]=1[O:30][C:31]([F:34])([F:33])[F:32].CCO>CCCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]([N:19]3[CH2:26][CH2:25][C:22]4([CH2:24][CH2:23]4)[C@H:21]([OH:27])[CH2:20]3)=[O:18])[C:10](=[O:28])[C@H:9]2[CH3:29])=[CH:4][C:3]=1[O:30][C:31]([F:32])([F:33])[F:34]
Reactant: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1c1ccc(Cl)c(OC(F)(F)F)c1
Solvent: CCCCCCC
Solvent: CCO
Product: C[C@@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1c1ccc(Cl)c(OC(F)(F)F)c1
Yield: 25 %

Procedure:
The title compounds were prepared by chiral separation of (S)-4-(4-chloro-3-trifluoromethoxy-phenyl)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (61% ds) on a Reprosil Chiral NR, (40% EtOH in n-heptane) to give 25% of (R)-4-(4-chloro-3-trifluoromethoxy-phenyl)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (example 63) as white foam, MS: 504.19 (MH+, Cl) and 33% of (S)-4-(4-chloro-3-trifluoromethoxy-phenyl)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (example 62) as white foam, MS: 504.19 (MH+, Cl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:19]=[C:18]([N:20]3[CH2:25][CH2:24][CH2:23][C@H:22]([C:26]([NH:28][CH2:29][C:30]4[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=4)[C:33]([O:35]C)=[O:34])=[O:27])[CH2:21]3)[CH:17]=[CH:16][N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].O.[OH-].[Li+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:19]=[C:18]([N:20]3[CH2:25][CH2:24][CH2:23][C@H:22]([C:26]([NH:28][CH2:29][C:30]4[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=4)[C:33]([OH:35])=[O:34])=[O:27])[CH2:21]3)[CH:17]=[CH:16][N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1cccc(CNC(=O)[C@H]2CCCN(c3ccnc(Nc4cc(OC)c(OC)c(OC)c4)n3)C2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(Nc2nccc(N3CCC[C@H](C(=O)NCc4cccc(C(=O)O)c4)C3)n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 6 (353.7 mg, 0.660 mmol) in a mixture of dioxane (3302 μL) and water (3302 μL) was added lithium hydroxide monohydrate (27.7 mg, 0.660 mmol). The reaction was stirred at room temperature for 72 hours. The reaction mixture was then extracted with DCM. The aqueous layer was diluted with 1N HCl. A precipitate was formed and separated by filtration to give 7 as a light purple solid. 1H NMR (400 MHz, CDCl3 with 1% TFA) δ ppm 1.50-1.70 (m, 1H) 1.83-2.00 (m, 2H) 2.00-2.13 (m, 1H) 2.43-2.56 (m, 1H) 3.23-3.30 (m, 1H) 3.50-3.61 (m, 1H) 3.78-3.92 (m, 10H) 4.01 (d, J=14.08 Hz, 1H) 4.45 (d, J=10.76 Hz, 2H) 6.25-6.37 (m, 1H) 6.86 (s, 2H) 7.38-7.51 (m, 2H) 7.69 (d, J=7.43 Hz, 1H) 7.89-7.99 (m, 2H); M+H 522.23432.
Reaction SMILES: [CH:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]([OH:12])[C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:15]O>>[CH:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]([OH:12])[C:9]([O:11][CH3:15])=[O:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C(O)C(=O)O)cc1
Reactant: CO
Product: COC(=O)C(O)c1ccc(C(C)C)cc1

Procedure:
To a solution of 4-isopropylmandelic acid (17 g) in methanol (150 ml) was added Dowex-50X-400® and the mixture was refluxed for 4 hours. After cooling it was filtered through Celite® and the filtrate was evaporated to give a syrupy residue of methyl 4-isopropylmandelate (18.9 g), which solidified upon storing at room temperature.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11](=[O:14])[CH2:12]Cl)[N:6]2[N:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[I-].[K+].[CH2:23]([N:30]1[CH2:35][CH2:34][NH:33][CH:32]([CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11](=[O:14])[CH2:12][N:33]3[CH2:34][CH2:35][N:30]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:31][CH:32]3[CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:39])[CH3:40])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(C(=O)CCl)ccc12
Reactant: CC(C)(C)[Si](C)(C)OCC1CN(Cc2ccccc2)CCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1CN(Cc2ccccc2)CCN1CC(=O)c1ccc2c(N)ncnn12
Reaction time: 17 h
Yield: 81 %

Procedure:
To a solution of 1-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-chloroethanone (1.00 g, 4.75 mmol), K2CO3 (1.97 g, 14.2 mmol) and potassium iodide (79 mg, 0.47 mmol) in DMF (20 mL), was added 1-benzyl-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)piperazine (1.53 g, 4.79 mmol, prepared by the method of Naylor et al J. Med. Chem. 36, 2075). The reaction was allowed to stir for 17 hours. The mixture was partitioned between ethyl acetate (200 mL) and saturated, aqueous Na2CO3 solution (100 mL). The layers were separated and the organic was washed with brine, dried (Na2SO4), and evaporated. The crude material was purified by ISCO® chromatography using a gradient elution from 50% to 100% ethyl acetate in hexanes to obtain 1.9 g (81%) of the desired product LC-MS [M+H]+=495.6, RT=2.56 min.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCNCC1
Reaction time: 48 h

Procedure:
6 g of Pd/C (10%) are added to a solution of 0.224 mol of tert-butyl 1-benzyl-4-piperidinylcarbamate in 800 ml of anhydrous ethanol. The reaction mixture is placed under a hydrogen pressure of 4 bars, at 50° C., for 48 hours, and then filtered over Celite and concentrated under reduced pressure, enabling the expected product to be isolated.
Reaction SMILES: O[CH2:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[C:5]([NH:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:6].C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[C:5]1(=[O:6])[C:4]2[C:3](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:2][N:7]1[CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1
Reactant: O=C(NCCSc1ccncc1)c1ccccc1CO
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1c2ccccc2CN1CCSc1ccncc1
Temperature: 25 °C
Yield: 57.6 %

Procedure:
To a solution of 1.153 g (4.0 mmol) of 4-[2-(2-hydroxymethylbenzoyl)aminoethylthio]pyridine and 1.68 ml (12.1 mmol) of triethylamine in 50 ml of methylene chloride, 0.62 ml (8.0 mmol) of methanesulfonyl chloride was added with stirring at room temperature, and the mixture was stirred at room temperature for 30 minutes. The mixture was washed with saturated aqueous sodium bicarbonate, water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate) to give 623 mg of the desired compound (57.6% yield, colorless crystals), mp. 86°-87° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:18])C=1.[OH-].[Na+].C[O-].[Na+].CO>ClCCl.CO>[CH3:8][C:7]1[C:2]([CH:1]=[O:18])=[N:3][CH:4]=[C:5]([CH3:9])[CH:6]=1
Reactant: Cc1cnc(C)c(C)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Cc1cnc(C=O)c(C)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 79.2 %

Procedure:
In dichloromethane (15.0 ml), 2,3,5-trimethyl-pyridine (1.29 g) was dissolved. The reaction solution was cooled to 0° C. and added with meta-chloroperbenzoic acid (2.53 g), followed by stirring at room temperature for 1.5 hours. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. Subsequently, the organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. The drying agent was filtrated out and the solvent was then distilled off, followed by dissolving the resulting residue in dichloromethane (25.0 ml). The reaction solution was added with trifluoroacetic anhydride (2.8 ml) and subjected to thermal reflux for 3.5 hours. After the reaction solution had been cooled to room temperature, the solvent was distilled off. The residue obtained was dissolved in methanol (60.0 ml). After having been cooled to 0° C., the reaction solution was added with a 12.5% sodium methoxide/methanol solution to adjust to pH 10, followed by stirring at room temperature for 16.5 hours. After the solvent had been distilled off, the residue was added with distilled water and extracted with chloroform. The organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. The drying agent was filtrated out and the solvent was then distilled off, followed by dissolving the resulting residue in chloroform (30.0 ml). The reaction solution was added with manganese dioxide (chemically processed product) (6.10 g) and then stirred at room temperature for 18 hours. The reaction solution was filtrated through Celite. The solvent in the filtrate was distilled off and the residue obtained was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (1.14 g) as a yellow oily substance.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=O)[C:4]2=[CH:14][S:15][CH:16]=[C:3]12.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:18]>N1C=CC=CC=1>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[S:18])[C:4]2=[CH:14][S:15][CH:16]=[C:3]12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN1c2ccccc2NC(=O)c2cscc21
Solvent: c1ccncc1
Product: CN1c2ccccc2NC(=S)c2cscc21
Reaction time: 18 h

Procedure:
A mixture of 0.4 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b] [1,5] benzodiazepin-10-one and 0.5 g. of phosphorus pentasulfide in 5 ml. of dry pyridine is stirred and heated under reflux for 4 hours. The reaction mixture is concentrated to dryness and the residue is stirred with 10 ml. of 1N sodium carbonate solution for 18 hours. The precipitate is collected, washed with water and recrystallized from methanol to give gold crystals, m.p. 203°-204°C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][C:21]=1[C:30]([F:33])([F:32])[F:31]>N1C=CC=CC=1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[S:9][CH2:10][CH2:11][C:12](=[O:13])[N:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)(=[O:27])=[O:28])=[CH:22][C:21]=1[C:30]([F:33])([F:31])[F:32]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cc(Cl)ccc1SCCC(=O)N1CCCC1
Solvent: c1ccncc1
Product: O=C(CCSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)N1CCCC1
Yield: 17.2 %

Procedure:
Following General Procedure B, the title compound (242 mg, 17%) was prepared from 3-((2-amino-4-chlorophenyl)thio)-1-(pyrrolidin-1-yl)propan-1-one (758 mg, 2.67 mmol) and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride (745 mg, 2.67 mmol) in pyridine (10 ml).
Reaction SMILES: [CH:1]1([C@H:7]2[N:12]3[CH:13]=[C:14]([C:19]([OH:21])=O)[C:15]4[CH:16]=[CH:17][CH:18]=[C:10]([C:11]=43)[O:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:25])=O>ClCCl>[CH:1]1([C@H:7]2[N:12]3[CH:13]=[C:14]([C:19]([Cl:25])=[O:21])[C:15]4[CH:16]=[CH:17][CH:18]=[C:10]([C:11]=43)[O:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cn2c3c(cccc13)OC[C@H]2C1CCCCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)c1cn2c3c(cccc13)OC[C@H]2C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of (R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (362 mg, 1.23 mmol) in dichloromethane (20 ml) was added oxalyl chloride (0.215 ml, 2.46 mmol). The deep blue mixture was stirred at room temperature for 2 h and then the solvent was removed in vacuo to afford (R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid chloride (380 mg, 1.23 mmol) as a blue solid.
Reaction SMILES: C(NC(C)C)(C)C.[Li].[Br:9][C:10]1[CH:22]=[CH:21][C:13]([C:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:15])=[C:12]([CH3:23])[CH:11]=1.CON(C)[C:27](=[O:29])[CH3:28]>C1COCC1>[Br:9][C:10]1[CH:22]=[CH:21][C:13]([C:14]([N:16]([CH2:17][CH3:18])[CH2:19][CH3:20])=[O:15])=[C:12]([CH2:23][C:27](=[O:29])[CH3:28])[CH:11]=1
Reactant: CCN(CC)C(=O)c1ccc(Br)cc1C
Reactant: CON(C)C(C)=O
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(Br)cc1CC(C)=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A 2 M solution of lithium diisoproyl amine (35 ml, 70 mmol) in THF (180 mL) cooled to −78° C. was treated with slow addition of 4-bromo-N,N-diethyl-2-methylbenzamide (19 g, 70 mmol) in dry THF (180 mL). The reaction was allowed to stir at −78° C. for 1 hour before it was quenched with N-methoxy-N-methylacetamide (22 mL, 210 mmol) and allowed to slowly warm to room temperature. The reaction was stirred overnight and then partitioned between 1 N HCl (200 mL) and EtOAc (400 mL). The aqueous layer was further extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine (150 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was an orange/brown oil out of which the product crystallizes. The oil was decanted off and the solid was washed with hexanes and dried using a Büchner funnel to afford 4-bromo-N,N-diethyl-2-(2-oxopropyl)benzamide.