Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(#N)C.[N:9]1([CH2:14][CH:15]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH2:16]2)[CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C>O>[CH3:1][S:2]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:24][CH:15]([CH2:14][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:16]1)(=[O:4])=[O:3]
Reactant: c1ccc2c(c1)CC(CN1CCCC1)CN2
Reactant: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC(CN2CCCC2)Cc2ccccc21
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.65 ml) was added dropwise to an acetonitrile (20 ml) solution of 3-(pyrrolidin-1-yl)methyl-1, 2,3, 4-tetrahydroquinoline (Reference Example 47; 1.5 g) and triethylamine (2.9 ml) under ice-cooling. The reaction mixture was stirred at the same temperature for one hour, to which was added water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, then dried and concentrated. The residue was purified by alumina column chromatography (eluent: hexane to hexane/ethylacetate=7/1). The crystals were washed with IPE to obtain the entitled compound (1.20 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[CH:5]=[C:4]([Cl:18])[N:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[N:25][CH:26]=1.[F-].[Cs+]>O1CCOCC1.O>[Cl:18][C:4]1[N:3]=[C:2]([C:23]2[CH:24]=[N:25][CH:26]=[C:21]([C:20]([F:31])([F:30])[F:19])[CH:22]=2)[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[CH:5]=1
Reactant: Fc1ccc(CNc2cc(Cl)nc(Cl)n2)c(F)c1
Reactant: OB(O)c1cncc(C(F)(F)F)c1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccc(CNc2cc(Cl)nc(-c3cncc(C(F)(F)F)c3)n2)c(F)c1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
A mixture of (2,6-Dichloro-pyrimidin-4-yl)-(2,4-difluoro-benzyl)-amine (1 g, 0.0034 mol) and 5-trifluoromethylpyridine-3-boronic acid (0.726 g, 0.0038 mol) were taken in dioxane:water (20:5) ml and to this CsF (2.1 g, 0.0138 mol) was added and degassed. Then bis-triphenylphosphine-palladium(II) chloride (0.24 g, 0.00034 mol) was added and degassed. The mixture was stirred at 60° C. for 12 hrs. The reaction was cooled to room temperature diluted with water (50 ml) and ethyl acetate (100 ml). After standard work-up, the residue was purified by column chromatography to get compound as white solid.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13].[NH2:18][C:19]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:18][C:19]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[O:13]
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)c1cccc(Br)c1
Reaction time: 1 h

Procedure:
0.056 mL of triethylamine and 0.029 mL of 3-bromobenzoyl chloride were added to 3.0 mL of methylene chloride solution containing 57 mg of tert-butyl 2-amino-4-phenoxybenzoate at room temperature sequentially and stirred at the same temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture. The organic layer was separated and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(3-bromobenzamido)-4-phenoxybenzoate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([C:15]2[S:22][C:21]([CH3:23])=[C:20]3[C:16]=2[CH2:17][C@H:18]2[C:24]([CH3:26])([CH3:25])[C@H:19]23)=[O:14])=[CH:7][CH:6]=1.CCN(C(C)C)C(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[O:14]=[C:13]([C:15]1[S:22][C:21]([CH3:23])=[C:20]2[C:16]=1[CH2:17][C@H:18]1[C:24]([CH3:26])([CH3:25])[C@H:19]12)[CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][O:1][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:6][CH:7]=1
Reactant: Cc1sc(C(=O)CCc2ccc(CCCO)cc2)c2c1[C@H]1[C@@H](C2)C1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1sc(C(=O)CCc2ccc(CCCOS(C)(=O)=O)cc2)c2c1[C@H]1[C@@H](C2)C1(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
A solution of 3-[4-(3-hydroxy-propyl)-phenyl]-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (147 mg, 0.40 mmol), DIPEA (0.11 mL, 0.642 mmol) in DCM (5 mL) is treated with methane sulfonylchloride (40 μL, 0.481 mmol) at 0° C. The solution is stirred at 0° C. for 30 min, then at rt for 1 h before it is diluted with DCM and washed with 0.1 N aq. NaOH solution, followed by 10% aq. citric acid solution. The organic layer is separated, dried over Na2SO4 and evaporated to give methanesulfonic acid 3-{4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propyl]-phenyl}-propyl ester (176 mg) as a colourless oil; LC-MS: tR=1.14 min, [M+1]+=447.25.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([S:20]([N:23]([CH2:30][P:31](=[O:34])([OH:33])[OH:32])[CH2:24][C:25]([O:27]CC)=[O:26])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1.[OH-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([S:20]([N:23]([CH2:24][C:25]([OH:27])=[O:26])[CH2:30][P:31]([OH:34])([OH:33])=[O:32])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)CN(CP(=O)(O)O)S(=O)(=O)c1cccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)N(CC(=O)O)CP(=O)(O)O)c2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.3 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of (3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-(2-ethoxy-2-oxoethyl)phenylsulfonamido)methylphosphonic Acid (Intermediate 8.4) (180 mg, 0.33 mmol, 1.00 equiv) in tetrahydrofuran/water (5/5 mL). This was followed by the addition of lithium hydroxide (39 mg, 1.62 mmol, 4.97 equiv) in several batches at room temperature. The resulting solution was stirred for 4 h at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 6 with 1M hydrogen chloride. The resulting mixture was concentrated under vacuum. The crude product (150 mg) was purified by preparative HPLC giving 59.2 mg (35%) of the title compound as a TFA salt. 1H-NMR (300 MHz, DMSO+D2O, ppm): 7.73˜7.74 (m, 1H), 7.67˜7.68 (m, 1H), 7.58˜7.62 (m, 2H), 7.49 (s, 1H), 7.00 (s, 1H), 4.71˜4.75 (m, 1H), 4.49 (d, J=16.2 Hz, 1H), 4.33 (d, J=15.9 Hz, 1H), 4.07 (s, 2H), 3.62˜3.64 (m, 1H), 3.45˜3.54 (m, 2H), 3.31˜3.40 (m, 1H), 2.88 (s, 3H). MS (ES, m/z): 523 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[OH:23])[CH:3]=1.[H-].[Na+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:10])=[O:11])[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:4]([CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[OH:23])[CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(O)c2ccccc2Cl)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(c1ccc(Cl)cc1C(O)c1ccccc1Cl)S(=O)(=O)c1ccc(OC)c(OC)c1
Reaction time: 1 h

Procedure:
To 6 g of N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxybenzenesulfonamide dissolved in 50 ml of DMF at 0° C. is added portionwise 0.674 g of sodium hydride. After 1 hour at 0° C., 1.4 ml of ethyl 2-bromoacetate are introduced and the mixture is left for 18 hours at room temperature. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with dichloromethane to give 1.3 g of the expected product.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:11][CH3:12].C(OC)(OC)OC.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH2:10]([N:13]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1)[CH2:14][CH2:15][CH3:16])[CH2:11][CH3:12]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCNCCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In methanol, 4-hydroxybenzaldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (1.00 g) was dissolved. Then, the solution was added with dipropylamine (1.24 ml), trimethyl orthoformate (1.0 ml), and acetic acid (500 μl) and stirred at room temperature for 15 minutes. The solution was cooled to 0° C. and added with sodium cyanoborohydride (773 mg), followed by stirring for 6 hours at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform, followed by the addition of water. The solution was adjusted to about pH 7 with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. The resulting organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (76.8 mg) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=2[NH:23][CH2:24][CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][N:27]2[CH3:31])=O)=[CH:6][CH:5]=1)[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl.O.[OH-].[NH4+]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[N:23]([CH2:24][CH2:25][CH:26]3[CH2:30][CH2:29][CH2:28][N:27]3[CH3:31])[C:15]3[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=3[N:13]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(CC(=O)Nc2cc([N+](=O)[O-])ccc2NCCC2CCCN2C)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(Cc2nc3cc([N+](=O)[O-])ccc3n2CCC2CCCN2C)cc1
Temperature: 25 °C
Yield: 38.2 %

Procedure:
2-(4-Ethoxy-phenyl)-N-{2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-5-nitro-phenyl}-acetamide 33 (60 mg, 0.141 mmol), Phosphorous pentachloride (33 mg, 0.158 mmol) were dissolved in anhydrous chloroform (10 mL) in a small, argon purged flask fitted with an condenser and magnetic stirbar. The solution was heated to reflux in an oil bath for 4.5 hours and cooled to room temperature overnight. The mixture was diluted with H2O and chloroform and 2M ammonium hydroxide solution added to adjust pH to 9-10. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with chloroform and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated to afford crude. The product was purified using silica gel column chromatography eluting with a solvent system of 5% 2M NH3 in methanol/95% dichloromethane to afford a pale yellow solid 34 2-(4-Ethoxy-benzyl)-1-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-5-nitro-1H-benzimidazole Yield: 22 mg (38.3%). 1H NMR (DMSO) δ; 1.29 (t, 3H, J=7.0), 1.38-1.51 (m, 2H), 1.51-1.70 (m, 3H), 1.75-1.87 (m, 1H), 1.96-2.05 (m, 2H), 2.07 (s, 3H), 2.85-2.95 (m, 1H), 3.97 (q, 2H, J=7.0), 4.21 (t, 2H, J=7.9), 4.32 (s, 2H), 6.87 (d, 2H, J=8.5), 7.19 (d, 2H, J=8.5), 7.70 (d, 1H, J=9.0), 8.14 (dd, 1H, J=8.9, 2.1), 8.47 (d, 1H, J=2.1); MS (ESI): 409 (MH+, 100%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.C1(CC#N)C=CC=CC=1.N[C:21]1[CH:34]=[CH:33][C:32](Cl)=[CH:31][C:22]=1[C:23](C1C=CC=CC=1)=[O:24].N1C2C=CC=CC=2C=CC=N1.C(OP(Cl)(=O)OCC)C.[H-].[Na+].[N+](CC(OCC)=O)#[C-]>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=1[C:23]([C:22]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:21]=1)=[O:24]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: C1=Cc2ccccc2NN=C1
Agent: CCOP(=O)(Cl)OCC
Agent: [C-]#[N+]CC(=O)OCC
Solvent: N#CCc1ccccc1
Product: Nc1ccc(I)cc1C(=O)c1ccccc1

Procedure:
2-Amino-5-iodo-benzophenone was prepared from p-iodonitrobenzene and phenylacetonitrile according to the literature. 2-Amino-5-chloro-benzophenone was commercially available from Acros. The benzodiazepine 60 was reacted with diethylphosphorochloridate in the presence of sodium hydride, followed by the addition of ethyl isocyanoacetate to provide the ester 62 (Hz120), as shown in Scheme 13.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]4[CH:33]=[CH:32][CH:31]=[CH:30][C:13]4=[C:14]([CH2:19][C:20]4[CH:21]=[CH:22][C:23]([C:26]([O:28]C)=[O:27])=[N:24][CH:25]=4)[CH:15]=3)[N:10]=[CH:9]2)[CH2:6][CH2:5][O:4][CH2:3]1.[OH-].[Li+]>O.C1COCC1>[OH:1][C@@H:2]1[C@@H:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]4[CH:33]=[CH:32][CH:31]=[CH:30][C:13]4=[C:14]([CH2:19][C:20]4[CH:21]=[CH:22][C:23]([C:26]([OH:28])=[O:27])=[N:24][CH:25]=4)[CH:15]=3)[N:10]=[CH:9]2)[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: COC(=O)c1ccc(Cc2cc3c(=O)n([C@H]4CCOC[C@@H]4O)cnc3c3ccccc23)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(Cc2cc3c(=O)n([C@H]4CCOC[C@@H]4O)cnc3c3ccccc23)cn1
Temperature: 50 °C

Procedure:
To a solution of methyl 5-({3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-4-oxo-3,4-dihydrobenzo[h]quinazolin-6-yl}methyl)pyridine-2-carboxylate (0.150 g, 0.337 mmol) in 2 mL of water and 2 mL of THF was added lithium hydroxide (0.016 g, 0.67 mmol). The mixture was heated to 50° C. for 2 h, cooled to rt, and quenched with saturated aqueous potassium phosphate to pH 5. The aqueous solution was extracted 3× with ethyl acetate and the combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 432.1560 for [M+H]+ [Calc'd for C24H22N3O5, [M+H]+=432.1554]: 1H NMR (400 MHz, CDCl3) δ 896-8.94 (m, 1H), 8.70 (s, 1H), 8.67 (s, 1H), 8.13-8.10 (m, 1H), 7.98 (s, 1H), 8.89 (d, J=8.2 Hz, 1H), 7.78-7.67 (m, 3H), 5.26 (d, J=5.3 Hz, 1H), 4.63 (s, 2H), 4.14-4.03 (m, 1H), 3.94-3.88 (m, 2H), 3.41 (t, J=11.0 Hz, 1H), 3.27 (br s, 1H), 3.12-3.08 (m, 2H), 2.28-2.19 (m, 1H), 1.87-1.83 (m, 1H).
Reaction SMILES: [N+]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][N:14]=2)=[CH:7][N:6]=1)([O-])=O.[CH3:21][C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH2:27][S:28][CH2:29][CH2:30]N.C(O)C>CC(O)C>[CH3:21][C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH2:27][S:28][CH2:29][CH2:30][NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][N:14]=2)=[CH:7][N:6]=1
Reactant: COc1ccnc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)c1
Reactant: Cc1[nH]cnc1CSCCN
Solvent: CCO
Solvent: CC(C)O
Product: COc1ccnc(Cc2cnc(NCCSCc3nc[nH]c3C)[nH]c2=O)c1

Procedure:
Reaction of 2-nitroamino-5-(4-methoxy-2-pyridylmethyl)-4-pyrimidone with 1.06 molar equivalents of 2-(5-methyl-4-imidazolylmethylthio)ethylamine in refluxing ethanol for 24 hours gave 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-methoxy-2-pyridylmethyl)-4-pyrimidone, m.p. 128-130° (from 2-propanol).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[CH:8](=O)[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:11].B.[Na]>[OH-].[Na+]>[OH:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[CH2:8][NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4]
Reactant: N[C@@H](CO)C(=O)O
Reactant: O=Cc1ccccc1O
Agent: B
Agent: [Na+]
Agent: [Na]
Product: O=C(O)[C@H](CO)NCc1ccccc1O
Reaction time: 1 h

Procedure:
L-serine (3.6 g) was dissolved in 17 ml of a 2N sodium hydroxide aqueous solution. To the solution were then added 3.6 ml of salicylaldehyde and 0.4 g of sodium boron hydride in this order. After the mixture was stirred for 1 hour, 3.6 ml of salicylaldehyde and 0.4 g of sodium boron hydride were added thereto again. After the resulting mixture was stirred overnight at room temperature, the insoluble matter was separated through filtration, and the filtrate was extracted with diethyl ether. The extract was adjusted to a pH of 7 with hydrochloric acid to obtain 4.8 g of N-(2-hydroxybenzyl)-L-serine. To 300 mg of the resulting N-(2-hydroxybenzyl)-L-serine were added 30 ml of ethanol to which a hydrogen chloride gas had been blown to saturation. The mixture was stirred overnight. The reaction solution was concentrated, and the resulting oil was purified through HPLC using Inertcil ODS-3 column (supplied by GL Science) in a high performance liquid chromatography (supplied by Hitachi) to obtain 114 mg of N-(2-hydroxybenzyl)-L-serine ethyl ester. Various N-(2-hydroxybenzyl) amino acid alkyl esters were obtained in the same manner. With respect to the novel compounds undescribed in the literature among these compounds, the results of the measurement of the mass spectrum are shown in Table 1.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([C:7](=O)[C:8]2[CH:13]=[CH:12][CH:11]=[N:10][CH:9]=2)C1=O.[OH-].[Na+].[BH4-].[K+]>Cl>[N:10]1[CH:9]=[C:8]([CH:7]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])[CH:13]=[CH:12][CH:11]=1
Reactant: CN1CCC(C(=O)c2cccnc2)C1=O
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Product: CN1CCCC1c1cccnc1
Temperature: 135 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
1-methyl-3-nicotinoyl-2-pyrrolidone (20.4 g, 0.1 mol) was dissolved in a 6N hydrochloric acid (150 mL) The solution was heated to 135° C. to react for 8 h and then cooled to room temperature. The pH of the mixture was adjusted to 7 by using NaOH under an ice bath, and then potassium borohydride (5.3 g, 0.1 mol) was added therein and the temperature was back to room temperature for 2 h. 200 mL distilled water was added and the mixture was stream-distilled. The distilled water phase was concentrated till dry to give 12.2 g racemic nicotine. HPLC purity 98.4%; 1H NMR (CDCl3, 300 MHz) δ: 8.52 (d, 1H), 8.48 (dd, 1H), 7.69 (dt, 1H), 7.25 (dd, 1H), 3.23 (t, 1H), 3.07 (t, 1H), 2.29 (m, 1H), 2.16 (s, 3H), 1.90-2.04 (m, 2H), 1.65-1.88 (m, 2H), ESI-MS 163.4 (M+H).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9](=[CH2:11])[CH3:10]>>[C:1]1([S:7][C:9]([CH3:11])([CH3:10])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(C)C
Reactant: Sc1ccccc1
Product: CC(C)(C)Sc1ccccc1
Yield: 93.8 %

Procedure:
To a mixture of 55 grams (0.5 mole) of thiophenol and 51 grams of boron trifluoride-phosphoric acid complex was slowly added, with stirring and cooling, 34 grams (0.6 mole) of isobutylene at 0° C. After addition was complete the mixture was stirred at 0° C. for two hours. The organic layer was separated from the catalyst layer and added to 200 ml of toluene. The toluene layer was distilled in a one-foot packed column to give 78 grams of tert-Butyl Phenyl Sulfide, b.p. 55°/3.0 mm (yield 94%). The nmr spectrum agreed with the proposed structure.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8]([NH2:17])([C:14]([OH:16])=[O:15])[CH2:9]2)[CH3:2].C(N(CC)CC)C.[C:25](=O)([O:41]N1C(=O)CCC1=O)[O:26][CH2:27][CH:28]1[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2>C(#N)C.O>[C:25]([CH:9]1[C:10]2[C:5](=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:7][C:8]1([NH2:17])[C:14]([OH:16])=[O:15])([O:26][CH2:27][CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35]2[C:40]1=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:41]
Reactant: CCOc1cccc2c1CCC(N)(C(=O)O)C2
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CCOc1cccc2c1CCC(N)(C(=O)O)C2C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 107.9 %

Procedure:
A mixture of racemic 5-ethoxy-2-aminotetraline-2-carboxylic acid (2.22 g, 9.44 mmole), triethylamine (2.00 ml, 14.3 mmole), 9-fluorenylmethyl succinimidyl carbonate (Fmoc-OSu, 4.81 g, 14.3 mmole) in acetonitrile (75 ml) and water (75 ml) was stirred at room temperature for two days. TLC analysis of the reaction indicated the presence of starting material amino acid. 9-fluorenylmethyl succinimidyl carbonate (645 mg) and triethylamine (1.0 ml) was added and the mixture was stirred at room temperature for another day. The reaction mixture was concentrated in vacuo to remove most of the acetonitrile, acidified to pH˜3 with 10% aqueous citric acid solution, and the white emulsion extracted three times with ethyl acetate. The combined organic layers were washed with water, brine, dried over magnesium sulfate. Filtration and concentration gave a crude oil which was purified by column chromatography (eluted with 3→5→10% methanol/methylene chloride) to give racemic Fmoc-5-ethoxy-2-aminotetraline-2-carboxylic acid (4.66 g, >quantitative yield) as a white solid. HRMS (FAB): C28H28NO5 (M+H) calc. 458.1967; observed: 458.1985.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][C:24]4[C:23]5=[N:33][N:34]=[C:35]([C:36]6[N:41]=[CH:40][CH:39]=[CH:38][N:37]=6)[N:22]5[CH:21]=[CH:20][C:19]=4[N:18]=3)=[CH:13][CH:12]=2)[CH2:9][CH:8]([CH3:10])[CH2:7]1)=O.[OH-].[Na+]>CCO.C(Cl)(Cl)Cl>[CH3:10][CH:8]1[CH2:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][C:24]4[C:23]5=[N:33][N:34]=[C:35]([C:36]6[N:41]=[CH:40][CH:39]=[CH:38][N:37]=6)[N:22]5[CH:21]=[CH:20][C:19]=4[N:18]=3)=[CH:13][CH:12]=2)([NH2:5])[CH2:9]1
Reactant: CC1CC(NC(=O)C(F)(F)F)(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC1CC(N)(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)C1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
A mixture of 2,2,2-trifluoro-N-(3-methyl-1-{-4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)acetamide (4-12) (3.3 mg, 0.006 mmol) and NaOH (5M in water, 0.30 mL) in EtOH (3 mL) was stirred at 70° C. for 15 hours. The mixture was diluted with CHCl3, washed with water and brine, dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative TLC eluting with 10% MeOH in CHCl3 to give 3-methyl-1-{-4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutanamine (4-13) as a white form. HRMS (M+H)+: observed=484.2250, calculated=484.2243.