Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:17][C@@H:18]([C:23]([NH2:25])=[O:24])[CH2:19][CH2:20][S:21][CH3:22].ClC(OCC(C)C)=O>>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:17][C@@H:18]([C:23]([NH2:25])=[O:24])[CH2:19][CH2:20][S:21][CH3:22])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CSCC[C@@H](N)C(N)=O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Product: CSCC[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(N)=O
Yield: 70 %

Procedure:
Condensation of BocLeuOH (3.49 g.) and HDMetNH2 (2.0 g.) by the mixed anhydride method using isobutyl chloroformate gave BocLeu-DMetNH2 in 70% yield. De-t-butoxycarbonylation of BocLeu-DMetNH2 (2.74 g.) using hydrogen chloride in ethyl acetate gave HLeu-DMetNH2 in 91% yield. Condensation of BocGlyOSu (2.66 g.) and HLeu-DMetNH2 (1.95 g.) by the active ester method gave BocGly-Leu-DMetNH2 in 92% yield. De-t-butoxycarbonylation of BocGly-Leu-DMetNH2 (2.30 g.) using hydrogen chloride in acetic acid gave HGly-Leu-DMetNH2 in 79% yield.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:8]([C:9]([NH2:11])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:14][N:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16](Cl)=[O:17]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][C:16](=[O:17])[N:15]([CH3:14])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:8]([C:9](=[O:10])[NH2:11])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(O)c(C(N)=O)c1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CC(=O)c1ccc(OC(=O)N(C)c2ccccc2)c(C(N)=O)c1

Procedure:
The title product was prepared from 5-acetylsalicylamide and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (87%, white solid). HPLC-MS: m/z=313.1 (M+1); Rt: 2.51 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:31]>>[Cl:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([F:30])[C:24]=1[CH2:23][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Fc1cccc(Cl)c1CBr
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(Cc3c(F)cccc3Cl)CC1)O2

Procedure:
Compound 129 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-(bromomethyl)-1-chloro-3-fluorobenzene and conditions outlined in procedure V. M.p.=90-92° C.; 300 MHz 1H NMR (CDCl3) δ 8.08-8.02 (m, 1H), 7.76-7.72 (m, 1H), 7.69-7.62 (m, 1H), 7.52-7.44 (m, 1H), 7.28-7.2 (m, 2H), 7.06-6.97 (m, 1H), 3.78 (d, J=2.1 Hz, 2H), 2.91 (s, 2H), 2.9-2.8 (m, 2H), 2.7-2.58 (m, 2H), 2.16-2.04 (m, 2H), 1.92-1.78 (m, 2H); LCMS: 444 [M+H].
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH3:21])[C:10]([O:12]CC)=[O:11])[N:8]=1)=[O:2].Cl>[OH-].[Na+]>[CH2:20]([O:19][CH2:18][CH2:17][O:16][N:15]=[C:9]([C:7]1[N:8]=[C:4]([NH:3][CH:1]=[O:2])[S:5][CH:6]=1)[C:10]([OH:12])=[O:11])[CH3:21]
Reactant: CCOCCON=C(C(=O)OCC)c1csc(NC=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOCCON=C(C(=O)O)c1csc(NC=O)n1
Yield: 80.7 %

Procedure:
A solution of ethyl 2-(2-formamidothiazol-4-yl)-2-(2-ethoxyethoxyimino)acetate (syn isomer, 4.35 g.) in 1 N aqueous sodium hydroxide (33 ml.) was stirred below 10° C. for 3 hours. The resultant solution was adjusted to pH 7.0 with conc. hydrochloric acid under ice cooling and washed with ethyl acetate. To the aqueous solution was added ethyl acetate and adjusted to pH 1.5 with hydrochloric acid under ice cooling. The ethyl acetate layer was separated and the aqueous layer was extracted with ethyl acetate. The extracts were combined together, washed with a saturated aqueous solution of sodium chloride, dried and then concentrated in vacuo. The oily residue was dissolved in diethyl ether and n-hexane was added to the solution until the solution became clear. The solution was stirred for an hour, and the precipitates were collected by filtration and washed with n-hexane to give 2-(2-ethoxyethoxyimino)-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer, 3.2 g.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[F:23][C:24]([F:41])([F:40])[C:25]1[CH:39]=[CH:38][C:28]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=2)=[CH:27][CH:26]=1>>[CH3:11][N:8]1[C:9]2[CH:10]=[C:2]([N:34]3[CH:35]=[CH:36][C:31]([O:30][CH2:29][C:28]4[CH:38]=[CH:39][C:25]([C:24]([F:40])([F:41])[F:23])=[CH:26][CH:27]=4)=[CH:32][C:33]3=[O:37])[CH:3]=[CH:4][C:5]=2[C:6]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(OCc2ccc(C(F)(F)F)cc2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(C(F)(F)F)cc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 25.1 %

Procedure:
The compound was prepared from tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (250 mg, 0.701 mmol) and 4-(4-(trifluoromethyl)benzyloxy)pyridin-2(1H)-one (142 mg, 0.526 mmol) according to the procedure in Example 1 (step c). Purification by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to 50:50 to 25:75 then 0:100) provided the title compound (73 mg, 19%) as a solid, that contained an impurity: ESI MS m/z 554 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH:9][CH:10]=[O:11])=[C:4]([Cl:12])[N:3]=1.[NH3:13]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:13])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([Cl:12])[N:3]=1
Reactant: N
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Product: Nc1nc(N)c(NC=O)c(Cl)n1
Yield: 89 %

Procedure:
N-(2-Amino-4,6-dichloro-5-pyrimidinyl)formamide (Example 3, 500 mg, 2.14 mmol) and ammonia (150 mL) was stirred in a Parr bomb at 50° C. for 18 hours. The ammonia was evaporated and the residual solid tritrated with water (10 mL). The solid was dried to give the title compound as red powder (400 mg, 89%), m.p. >300° C.; mass spectrum (CI/CH4): 190, 188 (M+1); 1H-NMR (DMSO-d6)δ: 9.05 and 8.60 (both br s, total 1, NHCHO), 8.1 and 7.8 (both br s, total 1, NHCHO), 6.80-6.20 (4 br s, total 4, 2 NH2).
Reaction SMILES: [CH3:1][N+:2]#[C-:3].[Li]CCCC.CCCCCC.[CH3:15][C:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:20])[C:17](Cl)=[O:18].[Na+].[Cl-]>C1COCC1>[CH3:20][C:16]([C:17]1[O:18][CH:1]=[N:2][CH:3]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:15]
Reactant: CC(C)(C(=O)Cl)c1ccccc1
Reactant: [C-]#[N+]C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)c1cnco1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 53.9 %

Procedure:
To a solution of methyl isocyanide (1.3 mmol, 1.3 eq.) in THF (5 mL) at −78° C. was added dropwise a solution of n-BuLi in Hexane (2.5 M, 1.3 mmol, 1.3 eq.). The resulting yellowish solution was stirred at −78° C. for an additional 45 min and 2-Methyl-2-phenylpropionyl chloride (1.0 mmol, 1.0 eq.) was slowly added. The mixture was stirred at −78° C. for an additional 1 h and allowed to warm to room temperature followed by the addition of saturated aqueous NaCl solution (5 mL). The mixture was extracted by EtOAc (3×5 mL) and the combined organic extracts were washed by saturated aqueous NaCl solution, dried by Na2SO4, filtered and evaporated in vacuo. The residue was further purified by flash chromatography (silica gel, 10% EtOAc/Hexanes) to afford 5-(1-Methyl-1-phenylethyl)oxazole as a colorless oil (101 mg, 54%). 1H NMR: δ (400 MHz, CDCl3) 7.74 (s,1H), 7.30 (m, 2H), 7.23 (m, 3H), 6.85 (s,1H), 1.69 (s, 6H). MS (M+H+): 188.1
Reaction SMILES: [F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[C:16]2[CH:25]=[C:24](C(OCC)=O)[NH:23][C:17]=2[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=1.C[Mg]Br.Cl.O1C[CH2:43][CH2:42][CH2:41]1>>[F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[C:16]2[CH:25]=[C:24]([C:42]([CH3:43])=[CH2:41])[NH:23][C:17]=2[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=1
Reactant: CCOC(=O)c1cc2c(-c3cc(S(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c(=O)c2[nH]1
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: Cl
Product: C=C(C)c1cc2c(-c3cc(S(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c(=O)c2[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
To a solution of Example 252f (0.10 g, 0.20 mmol) in tetrahydrofuran (6 mL) stirring at 0° C. was added methylmagnesium bromide (0.498 mL, 0.498 mmol). The reaction mixture was stirred at 0° C. for 1 hour, and then aqueous HCl (1 M, 2 mL) was added. The reaction mixture was concentrated and partitioned between saturated aqueous sodium chloride (10 mL) and ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase-HPLC (C 18 40-90% gradient acetonitrile:water (0.1% TFA)) to provide the title compound (25 mg, 25% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.05 (s, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.87 (dd, J=8.7, 2.4 Hz, 1H), 7.61-7.36 (m, 3H), 7.18 (t, J=8.6 Hz, 1H), 6.98 (d, J=8.3 Hz, 1H), 6.34 (d, J=2.2 Hz, 1H), 5.85 (s, 1H), 5.07 (s, 1H), 3.60 (s, 3H), 3.26 (s, 3H), 2.02 (s, 3H). MS (ESI+) m/z 471.1 (M+1)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]1)=O)(C)(C)C.[ClH:26].O1CCOCC1>>[ClH:26].[NH:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CNC(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NC[C@@H]1CCCNC1)OCc1ccccc1
Reaction time: 3 h

Procedure:
Benzyl ((S)-1-(tert-butoxycarbonyl)piperidin-3-yl)methylcarbamate (895 mg, 2.57 mmol) was treated with a 4.0 M HCl solution in dioxane (3.2 mL, 12.85 mmol). Formation of a white precipitate was observed. After 3 h, complete conversion of starting material was seen by TLC. The solvent and excess HCl were removed under reduced pressure to obtain benzyl ((R)-piperidin-3-yl)methylcarbamate hydrochloride as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:13])([CH3:12])[CH2:10][NH2:11])=[CH:5][CH:4]=1.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:13])([CH3:12])[CH2:10][NH:11][CH2:20][C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:24])[F:25])=[CH:23][CH:22]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(C)(C)CN)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Product: COc1ccc(C(C)(C)CNCc2ccc(C(F)(F)F)cc2)cc1
Yield: 84.1 %

Procedure:
Reductive amination of 2-(4-methoxyphenyl)-2-methylpropan-1-amine (500 mg; 2.79 mmol) with 4-(trifluoromethyl)benzaldehyde (0.38 ml; 2.79 mmol) as per general procedure A afforded N-[2-(4-methoxyphenyl)-2-methylpropyl]-N-[4-(trifluoromethyl)benzyl]amine (792 mg; 84% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12](I)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][C:27]1([CH3:34])[C:31]([CH3:33])([CH3:32])[O:30][BH:29][O:28]1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([B:29]2[O:30][C:31]([CH3:33])([CH3:32])[C:27]([CH3:34])([CH3:26])[O:28]2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OBOC1(C)C
Reactant: Cc1ccc(COCC(=O)OC(C)(C)C)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1ccc(COCC(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1

Procedure:
The procedure used in Example 3: step b was followed using (3-iodo-4-methyl-benzyloxy)-acetic acid tert-butyl ester ((Example 300: step a) 600 mg, 1.65 mmol), PdCl2(PPh3)2 (58 mg, 0.08 mmol), triethylamine (1.25 mL, 9.4 mmol), and 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.91 mL, 6.4 mmol) in dioxane (5 mL). Analogous aqueous workup and purification by SiO2 flash column chromatography yielded the title compound contaminated with the product resulting from halide reduction (569 mg, 95%). The material was used without further purification. 1H-NMR (CDCl3): δ 7.73 (d, 1H, J=1.9 Hz), 7.38 (dd, 1H, J=2.1, 7.9 Hz), 7.18 (d, 1H, J=7.9 Hz), 4.61 (s, 2H), 3.97 (s, 2H), 2.55 (s, 3H), 1.50 (s, 9H), 1.37 (s, 9H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]([CH2:25][CH2:26]Cl)[N:6]=[C:7]2[C:12]=1[C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH3:16])[C:9](=[O:17])[N:8]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([N:8]1[C:7]2=[N:6][N:5]3[CH2:25][CH2:26][NH:3][C:4]3=[C:12]2[C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH3:16])[C:9]1=[O:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCn1c(=O)c2c(N)n(CCCl)nc2n(Cc2ccccc2)c1=O
Agent: [H-]
Agent: [Na+]
Product: CCCn1c(=O)c2c3n(nc2n(Cc2ccccc2)c1=O)CCN3
Reaction time: 17 h

Procedure:
Sodium hydride (60% oil, 0.8 g) was added in portions to a stirring solution of 3-amino-7-benzyl-2-(2-chloroethyl) -5-propyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (4.9 g) under cooling with ice bath. The mixture was stirred for 17 hours and was concentrated to dryness. The residue was triturated with water and the resulting crystals were collected by filtration, washed with water and dried.
Reaction SMILES: [OH:1][B:2]([OH:11])[C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.[CH3:12][C:13]([CH3:18])([CH2:16]O)[CH2:14]O>C1COCC1>[CH3:12][C:13]1([CH3:18])[CH2:16][O:1][B:2]([C:3]2[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=2)[O:11][CH2:14]1
Reactant: CC(C)(CO)CO
Reactant: O=C(O)c1ccc(B(O)O)s1
Solvent: C1CCOC1
Product: CC1(C)COB(c2ccc(C(=O)O)s2)OC1
Yield: 100.5 %

Procedure:
5-(Dihydroxyboryl)-2-thiophenecarboxylic acid (527 mg, 3.1 mmol) and 2,2-dimethyl-propane-1,3-diol (361 mg, 3.4 mmol) are stirred in THF (10 mL) for 19 hours and concentrated in vacuo to afford 5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-thiophene-2-carboxylic acid (748 mg) as a solid. LCMS: RT=1.15 minutes; 1H NMR [300 MHz, (CD3)2SO]: □13.15 (1H, s); 7.7 (1H, m); 7.45 (1H, m); 3.75 (4H, s); 0.95 (6H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([O:19][CH3:20])([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)[CH:4]([OH:6])[CH3:5].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(N(CC)CC)C>[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([O:6][CH:4]([CH3:5])[C:3]([O:19][CH3:20])([O:2][CH3:1])[C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=3)[CH:8]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: COc1ccc2cc(C(OC)(OC)C(C)O)ccc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: COc1ccc2cc(C(OC)(OC)C(C)OS(=O)(=O)c3ccc(C)cc3)ccc2c1

Procedure:
1,1-dimethoxy-1-(6-methoxy-2-naphthyl)propan-2-ol is treated with a molar excess of p-toluenesulfonyl chloride in the presence of a molar excess of triethylamine in a manner similar to Example 25 to yield (S) 1,1-dimethoxy-1-(6-methoxy-2-naphthyl)prop-2-yl p-toluenesulfonate. That material is converted to (S) methyl 2-(6-methoxy-2-naphthyl)propionate in a manner similar to that described in Example 17.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.CS(O[CH2:15][CH2:16][N:17]=[N+:18]=[N-:19])(=O)=O.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[N:17]([CH2:16][CH2:15][N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]1=[O:9])=[N+:18]=[N-:19]
Reactant: COc1ccc[nH]c1=O
Reactant: CS(=O)(=O)OCCN=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cccn(CCN=[N+]=[N-])c1=O
Temperature: 25 °C
Yield: 0.1 %

Procedure:
3-methoxypyridine-2-one (0.40 g, 3.20 mmol), 156a (0.79 g, 4.80 mmol), and K2CO3 (1.32 g, 9.60 mmol) stirred overnight in THF at reflux temperature. Reaction mixture was cooled down to room temperature. Reaction mixture was partitioned between CH2Cl2 (60 mL) and water (50 mL). Organic layer washed with water (2×35 mL), brine (1×30 mL). Organic layer dried on Na2SO4 and evaporated in vacuo. Crude product was purified by flash chromatography with stepwise gradient of CH2Cl2 and acetone (max 15%) to give 0.34 mg of 157a (55%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 6.77 (dd, J=6.9, 1.6 Hz, 1H), 6.48 (dd, J=7.5, 1.6 Hz, 1H), 5.96 (m, 1H), 3.91 (m, 2H), 3.62 (s, 3H), 3.52 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 157.39, 149.41, 128.61, 112.16, 104.37, 55.36, 49.00, 48.91. HRMS (EI) calcd for C8H10N4O2 [M]+ 194.0804. found 194.0816.
Reaction SMILES: [CH2:1]([C:4]1([C:13]([C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)=[O:17])([CH3:15])[CH3:14])[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]1=[O:12])[CH:2]=[CH2:3].[H][H]>[Pd].C(O)C>[CH2:1]([C:4]1([C:13]([C:16]([O:18][C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=2)=[O:17])([CH3:15])[CH3:14])[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]1=[O:12])[CH2:2][CH3:3]
Reactant: C=CCC1(C(C)(C)C(=O)Oc2ccc(N)cc2)C(=O)NC(=O)NC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCC1(C(C)(C)C(=O)Oc2ccc(N)cc2)C(=O)NC(=O)NC1=O
Reaction time: 1 h

Procedure:
A solution of 750 g. of 5-allyl-5-(p-aminophenyloxycarbonyl-isopropyl)barbituric acid in 15 ml. of ethanol containing 100 mg. of 10% palladium-on-carbon as catalyst was subjected to hydrogenation at room temperature and atmospheric pressure. After one hour, the required amount (180 ml.) of hydrogen had been taken up. The reaction mixture was filtered through Celite, and the filtrate was evaporated to dryness. The residue was chromatographed on 13 g. of silica gel with ethyl acetate as the eluent. Fractions containing the desired product were evaporated. The remaining solid was recrystallized from chloroform/ether to afford 620 mg. (89%) of the ester, m.p. 212°-215°.
Reaction SMILES: [O-]CC.[Na+].[Na].[CH:6]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[C:16]([O:18][CH2:19][CH2:20][O:12][C:11]1[CH:6]=[C:7]([CH3:13])[CH:8]=[CH:9][CH:10]=1)(=[O:17])[CH3:15]
Reactant: CCOC(=O)CBr
Reactant: Cc1cccc(O)c1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CC(=O)OCCOc1cccc(C)c1
Yield: 59.4 %

Procedure:
To a solution of sodium ethoxide prepared from 25 g (1.1 mol) sodium metal in 800 ml ethanol was added 108 g (1.0 mol) m-cresol. After warming at reflux for 1.5 hr, 167 g (1.0 mol) ethyl bromoacetate was added dropwise as reflux continued. After 5.5 hr reflux, the reaction mixture was cooled and NaBr removed by filtration. The filtrate was concentrated to 200 ml volume and extracted with 3 × 300 ml ether. The combined ether layers were washed with pH 10.5 NaOH solution, saturated NaCl solution and were dried over anhydrous MgSO4. The ether was removed under reduced pressure and the residual yellow oil distilled at 105°/1 mm Hg to give 115.3 g m-tolyloxyethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH2:9][N:10]([CH3:25])[S:11]([C:14]2[C:15]3[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[C:16]=3[S:17][C:18]=2Br)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH3:27][O-:28].[Na+].CO.O>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH2:9][N:10]([CH3:25])[S:11]([C:14]2[C:15]3[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[C:16]=3[S:17][C:18]=2[O:28][CH3:27])(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1c(Br)sc2c1CCCC2=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1sc2c(c1S(=O)(=O)N(C)CC(O)c1ccc(F)cc1)CCCC2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-bromo-7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonic acid [2-(4-fluorophenyl)-2-hydroxy-ethyl]-methyl-amide (the compound of Preparation Example 58) (80 mg) in methanol (3 mL) was added a solution of 28% sodium methoxide/methanol (0.8 mL). After stirring at room temperature for 3 hours, the reaction solution was poured into water, extracted with ethyl acetate and dried with anhydrous magnesium sulfate. The residue resulting from the removal of the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (58 mg) was obtained as a light brown candy-like substance.
Reaction SMILES: [Cl:1][C:2]1([Cl:21])[CH2:4][CH:3]1[CH2:5][S:6][C:7]1[CH:20]=[CH:19][C:10]2[NH:11][C:12]([NH:14][C:15](=[O:18])[O:16][CH3:17])=[N:13][C:9]=2[CH:8]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl.CC(O)=O>[Cl:21][C:2]1([Cl:1])[CH2:4][CH:3]1[CH2:5][S:6]([C:7]1[CH:20]=[CH:19][C:10]2[NH:11][C:12]([NH:14][C:15](=[O:18])[O:16][CH3:17])=[N:13][C:9]=2[CH:8]=1)=[O:30]
Reactant: COC(=O)Nc1nc2cc(SCC3CC3(Cl)Cl)ccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1nc2cc(S(=O)CC3CC3(Cl)Cl)ccc2[nH]1
Reaction time: 4 h

Procedure:
To a solution of 3.4 g of [5-[(2,2-dichlorocyclopropylmethyl)thio]-1H-benzimidazol-2-yl]carbamic acid, methyl ester in 50 ml of CHCl3 and 50 ml of HOAc at -20° C there is added 2.1 g m-chloroperbenzoic acid in 20 ml of CHCl3. The mixture is allowed to reach room temperature and then is stirred for 4 hours. CHCl3 is removed in vacuo and the solution is neutralized with NaOH. The resulting oil solid is filtered and crystallized from glyme-ethyl ether to give the title compound.
Reaction SMILES: [Na].O[CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][O:6][C:5]1=[O:10].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][O:6][C:5]1=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: O=C1OCCCC1=CO
Agent: [Na]
Product: O=C1OCCCC1=CNCc1ccccc1
Yield: 36 %

Procedure:
Using 3-hydroxymethylenedihydropiran-2-one sodium salt (50 mmol) and benzylamine (55 mmol) and proceeding according to the abovementioned method A1, 3-benzylaminomethylenetetrahydropiran-2-one (3.91 g, efficiency: 69%) is produced in the form of a white powder.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][N:18]([S:22]([CH2:25][C@@H:26]([C@H:29]3[CH2:33][CH2:32][CH2:31][O:30]3)[NH:27][OH:28])(=[O:24])=[O:23])[CH2:19]2)=[CH:14][CH:13]=1>C1COCC1>[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][N:18]([S:22]([CH2:25][C@H:26]([N:27]([OH:28])[CH:1]=[O:3])[C@H:29]3[CH2:33][CH2:32][CH2:31][O:30]3)(=[O:23])=[O:24])[CH2:19]2)=[CH:14][CH:13]=1
Reactant: O=CO
Reactant: O=S(=O)(C[C@H](NO)[C@H]1CCCO1)N1CCc2ccc(Cl)cc2C1
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: O=CN(O)[C@@H](CS(=O)(=O)N1CCc2ccc(Cl)cc2C1)[C@H]1CCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of formic acid (0.5 ml) and acetic anhydride (0.125 ml) was stirred at 0° C. for 1 hour, then a solution of (1R)-2-[(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]-N-hydroxy-1-[(2R)-tetrahydrofuran-2-yl]ethanamine (80 mg, 0.22 mmol) in anhydrous THF (5 ml) was added and the resulting mixture was stirred at RT for 1 hour. The mixture was evaporated under reduced pressure. The residue was taken up with MeOH (5 ml) and heated at 55° C. for 1 hour. The reaction mixture was evaporated under reduced pressure. After purification by crystallization in EtOAc/pentane, the title compound (22) was obtained as a white powder (37 mg, 43%). HPLC, Rt: 3.0 min (purity: 94.1%). LC/MS, M+(ESI): 389.3, M−(ESI): 387.3.