Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl:11][C:12]1[C:13](=[O:20])[CH:14]=[C:15]([Cl:19])[C:16](=[O:18])[CH:17]=1.Cl.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1.CCOC(C)=O>[Cl:11][C:12]1[C:13](=[O:20])[CH:14]=[C:15]([Cl:19])[C:16](=[O:18])[C:17]=1[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[CH3:1]
Reactant: Cc1cc2ccccc2[nH]1
Reactant: O=C1C=C(Cl)C(=O)C=C1Cl
Agent: Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1[nH]c2ccccc2c1C1=C(Cl)C(=O)C=C(Cl)C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.9 %

Procedure:
To a solution of 2-methylindole (0.500 g, 3.81 mmol) in THF (30 mL) was added 2,5-dichloro-1,4-benzoquinone (1.35 g, 7.62 mmol) at room temperature. To this mixture was added concentrated HCl (12 N, 0.38 mL, 4.57 mmol) dropwise. After the reaction mixture was stirred for 5 hours (5 h–12 h) at room temperature, DDQ (1.73 g, 7.62 mmol) was added. After stirring for 3 hours (3 h–12 h) at room temperature, the mixture was diluted with EtOAc (100 mL). The organic solution was washed with saturated NaHCO3 (3×100 mL) and brine (100 mL), and dried over Na2SO4. The residue was concentrated and purified by flash column chromatography using 15% EtOAc in hexane as eluent to afford pure 2,5-dichloro-3-(2-methyl-1H-indol-3-yl)-[1,4]benzoquinone (1.13 g, 97%) as a blue solid. Melting point 158–159° C. Rf=0.35 (3:7, EtOAc/hexane). 1H NMR (CDCl3) δ 8.40 (bs, NH), 7.24–7.11 (m, 5H), 2.26 (s, 3H). 1H NMR (d6-acetone): δ 10.60 (1H, br s), 7.39 (1H, s), 7.36 (1H, d, J=7.8 Hz), 7.24 (1H, d, J=7.8 Hz), 7.10 (1H, t, J=7.8 Hz), 7.01 (1H, t, J=7.8 Hz). 13C NMR (CDCl3) δ 177.7, 176.6, 144.3, 139.8, 139.3, 136.9, 135.1, 133.1, 126.6, 122.0, 120.5, 119.6, 110.8, 104.8, 13.9. IR (KBr): 3388, 3061, 1676, 1566, 1459, 1250, 1032, 749 cm−1. Anal. Calcd. for C15H9Cl2NO2: C, 58.85; H, 2.96; Cl, 23.16; N, 4.58. Found: C, 58.85; H, 2.96; Cl, 23.16; N, 4.58. HRMS (EI) Calcd. For C15H9Cl2NO2 [M+]: 305.0010. Found: 305.0002.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][N:12]=[C:11]2[NH:18][CH:19]=[C:20]([C:25]([O:27]C)=O)[C:21]([O:23][CH3:24])=[O:22])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[O:27]=[C:25]1[N:12]2[CH:13]=[N:14][C:15]3[CH:16]=[CH:17][C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:5])[CH3:4])=[CH:9][C:10]=3[C:11]2=[N:18][CH:19]=[C:20]1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C(=CNc1ncnc2ccc(NC(=O)C(C)(C)C)cc12)C(=O)OC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: COC(=O)c1cnc2c3cc(NC(=O)C(C)(C)C)ccc3ncn2c1=O
Temperature: 260 °C
Yield: 81.4 %

Procedure:
A mixture of dimethyl [{6-pivalamido--4-quinazolinylamino}methylene]propanedioate (24.5 g) and diphenyl ether (150 ml) was heated at 260° C. for 20 minutes and cooled to ambient temperature. To the reaction mixture was added hexane to give crystals, which were filtered off, washed with hexane and dissolved in chloroform (400 ml) under heating. Insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure to 200 ml and allowed to stand under cooling. The precipitated crystals were filtered off and washed with chloroform to give crystalline methyl 4-oxo-10-pivalamido--4H-pyrimido[1,2-c]quinazoline-3-carboxylate (18.29 g). The mother liqour was concentrated under reduced pressure to give crystals, which were purified by a column chromatography on silica gel (50 g) (Developing solvent: 5% methanol-chloroform solution) and recrystallized from chloroform to give the same object compound (3.2 g).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[OH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[O:10].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[CH:23]([F:44])[CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:35]=[C:34]3[CH2:36][NH:37][CH2:38][CH2:39][C:33]3=[N:32][C:31]=2[NH:40][CH:41]([CH3:43])[CH3:42])[CH2:26][CH2:25]1.N1C=CC=CC=1>C(Cl)Cl>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[CH:23]([F:44])[CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:35]=[C:34]3[CH2:36][N:37]([C:5](=[O:7])[CH3:6])[CH2:38][CH2:39][C:33]3=[N:32][C:31]=2[NH:40][CH:41]([CH3:42])[CH3:43])[CH2:26][CH2:25]1.[C:9]([OH:10])([C:11]([F:14])([F:13])[F:12])=[O:8]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(F)c3ccc(F)cc3F)CC1)CNCC2
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCc2nc(NC(C)C)c(N3CCC(C(F)c4ccc(F)cc4F)CC3)nc2C1
Reaction time: 1 h

Procedure:
Acetic anhydride (7 μL, 0.075 mmol) was added to a solution of 3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (20.1 mg, 0.038 mmol) and pyridine (9 μL, 0.113 mmol) in DCM (380 μL) at rt. After 1 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (20.1 mg, 93%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.29 (dd, J=6.4, 1.9 Hz, 6H), 1.46 (br s, 1H), 1.56-1.77 (m, 2H), 2.00 (d, J=12.9 Hz, 1H), 2.04-2.15 (m, 1H), 2.18 (s, 1.3H), 2.20 (s, 1.7H), 2.76 (qd, J=12.8, 2.4 Hz, 3H), 2.87 (t, J=5.9 Hz, 1H), 3.40-3.56 (m, 2H), 3.78-3.83 (m, 1.1H), 3.83-3.89 (m, 0.9H), 4.09-4.17 (m, 1H), 4.52 (s, 2H), 5.53 (dd, J=46.7, 7.6 Hz, 1H), 6.97-7.08 (m, 2H), 7.47-7.55 (m, 1H); ESI-MS m/z [M+H]+ 462.4.
Reaction SMILES: O=[CH:2][C:3](=[CH2:5])[CH3:4].[Cl:6][C:7]1[CH:8]=[C:9]([NH2:17])[C:10](=[C:14]([Cl:16])[CH:15]=1)[C:11]([OH:13])=[O:12].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.[Na+].S(=O)(=O)(O)O>O>[Cl:6][C:7]1[CH:15]=[C:14]([Cl:16])[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:8]=1[CH:2]=[C:3]([CH3:5])[CH:4]=[N:17]2
Reactant: C=C(C)C=O
Reactant: Nc1cc(Cl)cc(Cl)c1C(=O)O
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: Cc1cnc2c(C(=O)O)c(Cl)cc(Cl)c2c1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
14 g of methacrolein were added dropwise, at l00? C, to a solution of 20.6 g os 4,6-dichloroanthranilic acid and 19 g of sodium m-nitrobenzenesulfonate in 200 g of 57% strength sulfuric acid. The mixture was stirred for 1 hour at 130° C., after which it was diluted with 450 g of water and filtered under suction while hot. The pH was brought to 2-3 with concentrated sodium hydroxide solution, while cooling with ice. The precipitated solid was filtered off under suction, washed with water and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][C:12]([NH:15][C:16]3[CH:17]=[C:18]([NH2:23])[C:19]([CH3:22])=[N:20][CH:21]=3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C.[CH3:45][N:46]1[C:50]([NH2:51])=[CH:49][CH:48]=[N:47]1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][C:12]([NH:15][C:16]3[CH:17]=[C:18]([NH:23][C:28]([NH:51][C:50]4[N:46]([CH3:45])[N:47]=[CH:48][CH:49]=4)=[O:34])[C:19]([CH3:22])=[N:20][CH:21]=3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cnc(Nc3cnc(C)c(N)c3)nc2)cc1
Reactant: Cn1nccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cnc(Nc3cnc(C)c(NC(=O)Nc4ccnn4C)c3)nc2)cc1
Reaction time: 0.25 h

Procedure:
To a solution of N-(5-(4-methoxyphenyl)pyrimidin-2-yl)-6-methylpyridine-3,5-diamine 12 (0.06 mmol) in THF (2 mL) is added triphosgene (0.02 mmol) and DIEA (0.01 mmol). The reaction is stirred at it for 15 min then 1-methyl-1H-pyrazol-5-amine (0.1 mmol) is added and stirring continued for 2 h. The reaction is reduced to dryness and purified by silica gel chromatography with DCM:MeOH=95:5 as eluant to afford 1-(5-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)-2-methylpyridin-3-yl)-3-(1-methyl-1H-pyrazol-5-yl)urea C2 as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.72 (d, J=2.0 Hz, 1H), 8.70 (s, 2H), 8.60 (d, J=2.0 Hz, 1H), 7.54 (d, J=6.5 Hz, 2H), 7.40 (d, J=2.0 Hz, 1H), 7.03 (d, J=6.5 Hz, 2H), 6.28 (d, J=2.0 Hz, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 2.49 (s, 3H). MS (m/z) (M+1)+: 431.2.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[NH:26][CH:25]([C:27]([OH:29])=O)[CH2:24][S:23]2)[CH:17]=1.[CH2:30]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].ON1C2C=CC=CC=2N=N1.[C:54]([OH:61])(=[O:60])/[CH:55]=[CH:56]/[C:57]([OH:59])=[O:58]>C(OCC)(=O)C.C(O)C.CN(C)C=O>[C:54]([OH:61])(=[O:60])/[CH:55]=[CH:56]/[C:57]([OH:59])=[O:58].[CH2:30]([N:38]1[CH2:39][CH2:40][N:41]([C:27]([CH:25]2[CH2:24][S:23][CH:22]([C:18]3[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=3)[NH:26]2)=[O:29])[CH2:42][CH2:43]1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCN1CCNCC1
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)/C=C/C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCCCCN1CCN(C(=O)C2CSC(c3cccnc3)N2)CC1
Reaction time: 48 h
Yield: 51.5 %

Procedure:
Dicyclohexylcarbodiimide (0.82 g) was added to a mixture of 0.84 g of 2-(3-pyridyl)thiazolidine-4-carboxylic acid, 0.79 g of 1-octylpiperazine, 0.54 g of 1-hydroxybenzotriazole and 20 ml of N,N-dimethylformamide with ice cooling, and the resultant mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the insoluble matter was filtered off. The filtrate was washed in sequence with saturated aqueous solution of sodium hydrogen carbonate, water and saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. Ethyl acetate was added to the residue, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent 10% methanol-ethyl acetate), the oil obtained was dissolved in 25 ml of ethanol, and 0.32 g of fumaric acid was added. After allowing the mixture to stand for 2 days, the resultant crystals were collected by filtration, washed with cold ethanol and dried. Thus was obtained 0.72 g of 1-octyl-4-[2-(3-pyridyl)thiazolidin-4-ylcarbonyl]piperazine fumarate. Melting point 135° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([OH:16])=[C:11]([O:17][CH3:18])[C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][CH:29]1[CH2:31][O:30]1>C(C(C)=O)C>[CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH2:28][CH:29]2[O:30][CH2:31]2)=[C:11]([O:17][CH3:18])[C:10]=1[O:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(O)cc(C)c(OCc2ccccc2)c1OC
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1c(OCC2CO2)cc(C)c(OCc2ccccc2)c1OC

Procedure:
Then, using 3.69 g of the compound of Example 12, 1.82 g of anhydrous potassium carbonate, 1.5 ml of chloromethyloxirane and 100 ml of methyl ethyl ketone, reaction and workup carried out as in Example 1-A gave about 4.5 g of 1-(4-benzyloxy-2,3-dimethoxy-5-methylphenoxy)-2,3-epoxypropane as yellow oil. Using this epoxy compound, 3.05 g of 1-(2-methoxyphenyl)piperazine and 100 ml dioxane, reaction and workup carried out as in Example 1-A followed by purification by column chromatography (silica gel, elution with ethyl acetate:hexane=1:0.5) gave 4.61 g of yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][CH:14]([CH3:19])[CH2:15][C:16](O)=[O:17].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:16](=[O:17])[CH2:15][CH:14]([CH3:19])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)CC(=O)O
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Yield: 66.7 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 3-methylbutanoic acid (isovaleric acid) (222 mg, 2.17 mmol) and triethylamine (606 μL, 4.35 mmol) in CH2Cl2 (10 mL) was processed as described in Example 56, Step A, to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylbutanamide (182 mg, 67% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.04 (s, 1H), 9.46 (s, 1H), 8.34 (d, 1H), 7.56 (s, 1H), 2.20 (d, 2H), 2.11-2.05 (m, 1H), 0.96 (d, 6H); LCMS (APCI+) m/z 314, 316 (M+H)+, Retention time=3.02 minutes (Method 2).
Reaction SMILES: [OH-].[Na+].O.CC[O:6][C:7]([C@@H:9]([NH:18][C@H:19]([C:21]([N:23]1[C@H:31]([C:32]([OH:34])=[O:33])[CH2:30][C@@H:29]2[C@@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:22])[CH3:20])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8].C(O)CCC>C(O)C>[CH3:20][C@H:19]([NH:18][C@H:9]([C:7]([OH:8])=[O:6])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:21]([N:23]1[C@H:31]([C:32]([OH:34])=[O:33])[CH2:30][C@@H:29]2[C@@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:22]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1[C@H](C(=O)O)C[C@H]2CCCC[C@@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCO
Solvent: CCO
Product: C[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N1[C@H](C(=O)O)C[C@H]2CCCC[C@@H]21
Reaction time: 15 h

Procedure:
A solution of NaOH (6.5 g, 153.6 mmol; assay=94.52%), water (157 ml), ethanol (157 ml, technical grade, contains ˜5% 2-propanol) and Trandolapril (31.5 g, 72.94 mmol; assay=99.7%) was stirred at an internal temperature ranging from about 20° C. to about 25° C. for 15 hours. After an in-process control showed an almost complete saponification (by HPLC), the clear solution was concentrated in vacuo to an amount of 167.05 g, and n-butanol (160 ml) was added to the concentrated product. This mixture was heated to an internal temperature ranging from about 60° C. to about 70° C., and 2N aqueous hydrochloric acid was added (150.4 mmol), whereupon the pH dropped down from 12.09 to 3.66. The organic layer was separated at an internal temperature of 66° C., and the aqueous layer was extracted again with n-butanol (80 ml) at an internal temperature of 65° C. The combined organic layers were washed twice with water (each 40 ml) at an internal temperature ranging from about 63° C. to about 65° C. The organic layer then obtained (total amount 306.4 g) was concentrated in vacuo at a temperature ranging from about 50° C. to about 60° C., whereupon after concentration to an amount of 190 g a white solid precipitated. This suspension was further concentrated in vacuo to an amount of 75.1 g, and 80 ml MTBE was added to complete the precipitation. The suspension was stirred at an internal temperature ranging from about 20° C. to about 25° C. for 3.5 hours. After filtration, the wet product was washed twice with MTBE (each 80 ml) and dried in vacuo for 15 hours at 40° C. to give Trandolaprilat as disolvate with n-butanol (yield: 36.51 g, 66.67 mmol, 91.4%; assay (0.1N HClO4)=73.5%; HPLC purity=100%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C@H:3]([OH:16])[CH2:4][N:5]([CH3:15])[C:6](=[O:14])[O:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11].C1N=CN([C:29]([N:31]2[CH:35]=N[CH:33]=[CH:32]2)=[O:30])C=1.CCN(C(C)C)C(C)C.[Cl:45][C:46]1[CH:47]=[C:48]([C@@H:52]([C@@H:61]2[O:66]CCNC2)[O:53][CH2:54][CH2:55][NH:56][C:57](=[O:60])[O:58][CH3:59])[CH:49]=[CH:50][CH:51]=1>C(Cl)Cl>[Cl:45][C:46]1[CH:47]=[C:48]([C@@H:52]([C@@H:61]2[O:66][CH2:33][CH2:32][N:31]([C:29](=[O:30])[NH:1][C@H:2]([C@H:3]([OH:16])[CH2:4][N:5]([CH3:15])[C:6]([O:7][CH2:8][CH2:9][Si:10]([CH3:12])([CH3:13])[CH3:11])=[O:14])[CH2:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[CH2:35]2)[O:53][CH2:54][CH2:55][NH:56][C:57](=[O:60])[O:58][CH3:59])[CH:49]=[CH:50][CH:51]=1
Reactant: CN(C[C@@H](O)[C@@H](N)CC1CCOCC1)C(=O)OCC[Si](C)(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@H]1CNCCO1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@H]1CN(C(=O)N[C@@H](CC2CCOCC2)[C@H](O)CN(C)C(=O)OCC[Si](C)(C)C)CCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.6 %

Procedure:
To a solution of 2-(trimethylsilyl)ethyl (2R,3S)-3-amino-2-hydroxy-4-(tetrahydro-2H-pyran-4-yl)butyl(methyl)carbamate (50 mg, 0.12 mmol) and CDI (20 mg, 0.12 mmol) in anhydrous CH2Cl2 (10 mL) cooled in an ice bath, DIEA (78 mg, 0.6 mmol) was added. After addition, the mixture was stirred for 1 h at 0° C. and added to a solution of methyl 2-((S)-(3-chlorophenyl)((R)-morpholin-2-yl)methoxy)ethylcarbamate (59 mg, 0.18 mmol) in anhydrous CH2Cl2 (2 mL). The reaction mixture was allowed to warm to rt and stirred overnight. After the reaction was complete, the solvent was removed in vacuo. The product was purified by preparative tlc to afford the desired product (30 mg, 36%).
Reaction SMILES: [NH2:1][O:2][S:3]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[CH3:14])(=[O:5])=[O:4].[CH3:15][C:16]([Si:19]([CH3:29])([CH3:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([CH3:18])[CH3:17]>C(Cl)Cl>[CH3:12][C:11]1[CH:10]=[C:9]([CH3:13])[CH:8]=[C:7]([CH3:14])[C:6]=1[S:3]([O-:5])(=[O:4])=[O:2].[NH2:1][N+:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][Si:19]([C:16]([CH3:15])([CH3:17])[CH3:18])([CH3:29])[CH3:28])=[CH:23][CH:24]=1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cc[n+](N)cc1
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 2-[(aminooxy)sulfonyl]-1,3,5-trimethylbenzene (4.05 g, 18.8 mmol) in DCM (60 mL) was cooled to 0° C. 4-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-methyl)pyridine (3.50 g, 15.7 mmol) in DCM (2 mL) was added dropwise. Following complete addition, the mixture was stirred at rt for 45 min. The reaction mixture was evaporated under reduced pressure to give the product as a colorless foam.
Reaction SMILES: [ClH:1].CO.C(OC([N:14]1[CH2:33][CH2:32][N:17]2[C:18]3[C:23]([N:24]([C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH2:25][CH:16]2[CH2:15]1)=[CH:22][CH:21]=[CH:20][CH:19]=3)=O)C1C=CC=CC=1>[Pd].C(O)C>[ClH:1].[F:30][C:27]([F:28])([F:29])[C:26]([N:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]2[CH2:32][CH2:33][NH:14][CH2:15][CH:16]2[CH2:25]1)=[O:31]
Reactant: O=C(OCc1ccccc1)N1CCN2c3ccccc3N(C(=O)C(F)(F)F)CC2C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: O=C(N1CC2CNCCN2c2ccccc21)C(F)(F)F

Procedure:
A 80 μl portion of hydrochloric acid-methanol and 0.1 g of 10% Pd-C were added to 3 ml of ethanol solution containing 93 mg (0.22 mmol) of 3-benzyloxycarbonyl-2,3,4,4a,5,6-hexahydro-6-trifluoroacetyl-1H-pyrazino[1,2-a]quinoxaline, and 3 hours of catalytic hydrogenation was carried out at room temperature. The catalyst was filtered, the solvent was removed by evaporation under a reduced pressure and then the resulting residue was recrystallized from methanol-isopropyl ether to obtain 43 mg (61% in yield) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[Cl:18][C:19]1[C:26]([F:27])=[CH:25][C:22]([C:23]#[N:24])=[C:21](F)[CH:20]=1>CN(C)C=O>[Cl:18][C:19]1[C:26]([F:27])=[CH:25][C:22]([C:23]#[N:24])=[C:21]([CH:20]=1)[O:17][CH:12]([C:13]([F:14])([F:15])[F:16])[CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: N#Cc1cc(F)c(Cl)cc1F
Reactant: CN(CCC(O)C(F)(F)F)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CN(CCC(Oc1cc(Cl)c(F)cc1C#N)C(F)(F)F)C(=O)OC(C)(C)C

Procedure:
The subtitle compound was prepared according to the method of Example 3 step (b) using methyl-(4,4,4-trifluoro-3-hydroxybutyl)carbamic acid, 1,1-dimethylethyl ester and 4-chloro-2,5-difluorobenzonitrile in N,N-dimethylformamide.
Reaction SMILES: CI.[C:3]([C@@H:6]1[CH2:10][C@H:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:8][NH:7]1)(=[O:5])[NH2:4].[C:21](=O)(O)[O-].[Na+]>CN(C)C=O>[C:3]([C@@H:6]1[CH2:10][C@H:9]([S:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH2:8][N:7]1[CH3:21])(=[O:5])[NH2:4]
Reactant: O=C([O-])O
Reactant: COc1ccc(CS[C@@H]2CN[C@H](C(N)=O)C2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(CS[C@H]2C[C@@H](C(N)=O)N(C)C2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.07 ml of methyl iodide was added, whilst ice-cooling, to a solution of 0.6 g of (2S, 4S)-2-carbamoyl-4-(4-methoxybenzylthio)pyrrolidine [prepared as described in step (5) above] dissolved in 4.5 ml of dry dimethylformamide. The mixture was then stirred at 0° to 5° C. for 5 minutes and at room temperature for 20 minutes. At the end of this time, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and then the residue was subjected to column chromatography using a Lobar column (Merck, LiChroprep Si 60, size B), and 252 mg of the title compound, melting at 113°-114° C., were obtained as crystals from the fractions eluted with a 9:1 by volume mixture of ethyl acetate and methanol.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH:10]2[CH2:12][CH2:11]2)[N:4]=1)[NH2:2].C[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O.[CH2:23](O)C>>[CH3:9][C:7]1[CH:6]=[C:5]([CH:10]2[CH2:11][CH2:12]2)[N:4]=[C:3]([NH:1][N:2]=[C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=2[CH3:23])[CH3:14])[N:8]=1
Reactant: CCC(=O)c1ccccc1
Reactant: Cc1cc(C2CC2)nc(NN)n1
Reactant: CCO
Product: CC(=NNc1nc(C)cc(C2CC2)n1)c1ccccc1C

Procedure:
3.3 g of 2-hydrazino-4-methyl-6-cyclopropylpyrimidine and 2.7 g of 2-methylacetophenone are heated to boiling in 40 ml of ethanol and boiled under reflux for 20 hours with stirring. The reaction solution is then cooled and the solvent is evaporated off in vacuo. For purification, the oily residue is chromatographed using hexane/ethyl acetate (2:1) over a column of silica gel.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH3:36][N:37]([CH3:50])[C:38]([C:40]1([C:43]2[CH:48]=[CH:47][C:46](Br)=[CH:45][N:44]=2)[CH2:42][CH2:41]1)=[O:39]>>[CH3:36][N:37]([CH3:50])[C:38]([C:40]1([C:43]2[CH:48]=[CH:47][C:46]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:45][N:44]=2)[CH2:42][CH2:41]1)=[O:39]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CN(C)C(=O)C1(c2ccc(Br)cn2)CC1
Product: C[C@@H](c1ccc(-c2ccc(C3(C(=O)N(C)C)CC3)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 75 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 1-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid dimethylamide following a procedure analogous to that described in Example 1. Yield: 75% of theory; LC (method 1): tR=1.92 min; Mass spectrum (ESI+): m/z=542 [M+H]+.