Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C([O:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH:15]=[C:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][CH2:19][C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]2=3)[CH2:9][CH2:8]1)=[O:6])C.C(O)C.[OH-].[Na+].Cl>O>[ClH:1].[CH:26]1[C:21]2[CH2:20][CH2:19][C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[C:16](=[CH:15][CH2:14][CH2:13][N:10]3[CH2:9][CH2:8][CH:7]([C:5]([OH:6])=[O:4])[CH2:12][CH2:11]3)[C:22]=2[CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)C1CCN(CCC=C2c3ccccc3CCc3ccccc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CCN(CCC=C2c3ccccc3CCc3ccccc32)CC1
Temperature: 25 °C

Procedure:
A mixture of the above ester (0.105 g, 0.27 mmol), ethanol (15 ml) and 1 N sodium hydroxide (10 ml) was heated at reflux temperature for 3 h and then cooled to room temperature. Water (75 ml) was added, and the mixture was acidified with 5 N hydrochloric acid and extracted with dichloromethane (3×75 ml), dried (MgSO4) and evaporated in vacuo. The resulting foam was crystallised from acetone affording 0.080 g of the title compound as crystals.
Reaction SMILES: [C:1](O[BH3-])(=O)C.[Na+].[CH3:7][N:8]([CH3:49])[C:9]([C@@H:11]1[CH2:15][C@@H:14]([OH:16])[CH2:13][N:12]1[C:17]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[O:47][CH3:48])[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=2)[N:19]([S:27]([C:30]2[CH:39]=[C:38]3[C:33]([CH2:34][CH2:35][NH:36][CH2:37]3)=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:18]1=[O:40])=[O:10].C(O)(=O)C.C=O>>[CH3:7][N:8]([CH3:49])[C:9]([C@@H:11]1[CH2:15][C@@H:14]([OH:16])[CH2:13][N:12]1[C:17]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[O:47][CH3:48])[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=2)[N:19]([S:27]([C:30]2[CH:39]=[C:38]3[C:33]([CH2:34][CH2:35][N:36]([CH3:1])[CH2:37]3)=[CH:32][CH:31]=2)(=[O:28])=[O:29])[C:18]1=[O:40])=[O:10]
Reactant: [BH3-]OC(C)=O
Reactant: COc1ccccc1C1(N2C[C@H](O)C[C@H]2C(=O)N(C)C)C(=O)N(S(=O)(=O)c2ccc3c(c2)CNCC3)c2ccc(Cl)cc21
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccccc1C1(N2C[C@H](O)C[C@H]2C(=O)N(C)C)C(=O)N(S(=O)(=O)c2ccc3c(c2)CN(C)CC3)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.2 %

Procedure:
Sodium acetoxyborohydride (0.36 mmol, 76.27 mg) was added to a solution of Example 61 (0.24 mmol, 0.15 g), acetic acid (0.24 mmol, 14.4 mg) and aq. formaldehyde (37%, 0.26 mmol, 21.42 mg). The mixture was stirred at RT for 12 h and evaporated in vacuo. The residue was solved in H2O and extracted with ethyl acetate. The organic phase was dried, filtrated and evaporated. The crude product was then purified on a column of silica gel eluted with 5% MeOH in CH2Cl2 to afford 100 mg of the required product.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:7]([CH3:9])([CH3:8])[O:6][C:5](OC2C=CC([N+]([O-])=O)=CC=2)=[N:4][S:3]1(=[O:21])=[O:20].Cl.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C@@H:31]([NH2:33])[CH3:32]>ClCCl.C(N(CC)C(C)C)(C)C>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C@@H:31]([NH:33][C:5]1[O:6][C:7]([CH3:8])([CH3:9])[C:2]([CH3:1])([CH3:22])[S:3](=[O:20])(=[O:21])[N:4]=1)[CH3:32]
Reactant: CC1(C)OC(Oc2ccc([N+](=O)[O-])cc2)=NS(=O)(=O)C1(C)C
Reactant: C[C@H](N)c1ccccc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](NC1=NS(=O)(=O)C(C)(C)C(C)(C)O1)c1ccccc1Cl
Yield: 81.4 %

Procedure:
Under inert gas, 200 mg of 5,5,6,6-tetramethyl-2-(4-nitrophenoxy)-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide and 176 mg of (S)-1-(2-chlorophenyl)ethylamine hydrochloride were dissolved in 1 ml of dichloromethane and 0.21 ml of N,N-diisopropylethylamine, and the mixture was stirred at room temperature for 16 hours. Subsequently, the reaction solution was diluted with 50 ml of dichloromethane, washed three times with 30 ml of 10% aqueous ammonia solution, three times with 30 ml of 1 N aqueous hydrochloric acid and with 30 ml of saturated aqueous sodium hydrogencarbonate solution, dried over Na2SO4 and concentrated by rotary evaporation. This gave the product (171 mg) with a molecular weight of 344.94 g/mol (C15H21ClN2O3S); MS (ESI): m/e=345 (M+H+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.F[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1.[I-].[K+].CN(C)C(=O)C>O>[N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Yield: 33.3 %

Procedure:
A mixture of 13.6 parts of 1H-imidazole, 16.8 parts of ethyl 4-fluorobenzoate, 0.1 parts of potassium iodide and 54 parts of N,-N-dimethylacetamide was stirred and refluxed for 20 hours. The reaction mixture was cooled to room temperature and poured onto a lot of water. The product was extracted a few times with benzene. The combined extracts were washed thoroughly with water, dried, filtered and evaporated. The residue was stirred in hexane. The product was filtered off and dried, yielding 7.2 parts (33.3%) of ethyl 4-(1H-imidazol-1-yl)benzoate; mp. 100.3° C. (intermediate 18).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[S:10]([CH2:13][CH:14]([CH3:16])[CH3:15])(=[O:12])=[O:11])[CH2:3][CH2:2]1.[CH2:20]([O:22][C:23](=[O:30])[C:24]([NH2:29])([CH2:27][CH3:28])[CH2:25][CH3:26])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:30])[C:24]([NH:29][C:17]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([S:10]([CH2:13][CH:14]([CH3:15])[CH3:16])(=[O:11])=[O:12])[N:8]=1)=[O:19])([CH2:27][CH3:28])[CH2:25][CH3:26])[CH3:21]
Reactant: CCOC(=O)C(N)(CC)CC
Reactant: CC(C)CS(=O)(=O)c1nc(C(=O)O)ccc1C1CC1
Product: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(C2CC2)c(S(=O)(=O)CC(C)C)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid (Example 351 b) and 2-amino-2-ethyl-butanoic acid ethyl ester (CAN 189631-96-7) as starting materials. MS (EI): m/e=425.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[NH:19][CH:20]=[C:21]([CH2:25][C:26]4[CH:27]=[N:28][C:29]([O:32][CH3:33])=[N:30][CH:31]=4)[C:22](=[O:24])[N:23]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:34]([F:37])([F:36])[F:35].[CH3:38]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18]3[N:19]([CH3:38])[CH:20]=[C:21]([CH2:25][C:26]4[CH:31]=[N:30][C:29]([O:32][CH3:33])=[N:28][CH:27]=4)[C:22](=[O:24])[N:23]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:34]([F:37])([F:35])[F:36]
Reactant: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CI
Product: COc1ncc(Cc2cn(C)c(OCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
To the solution of 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-5-{[2-(methyloxy)-5-pyrimidinyl]methyl}-4(1H)-pyrimidinone (crude) (410 mg, 0.769 mmol) in DCM (1.5 mL) was added DIPEA (0.269 mL, 1.539 mmol) and MeI (0.072 mL, 1.154 mmol). The mixture was stirred at room temp overnight. Purification via MDAP then afforded the title compound (120 mg, 28.5% yield). LCMS: rt=3.48 min, [M+H+]=547
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[CH:9]=[C:10]([C:19]([OH:21])=[O:20])[CH:11]=[C:12]2[C:17]=1[NH:16][C:15](=[O:18])[CH2:14][CH2:13]2)([O-:7])=[O:6].[CH3:22]O>>[N+:5]([C:8]1[CH:9]=[C:10]([C:19]([O:21][CH3:22])=[O:20])[CH:11]=[C:12]2[C:17]=1[NH:16][C:15](=[O:18])[CH2:14][CH2:13]2)([O-:7])=[O:6]
Reactant: O=C1CCc2cc(C(=O)O)cc([N+](=O)[O-])c2N1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2c(c([N+](=O)[O-])c1)NC(=O)CC2

Procedure:
7 ml of thionyl chloride was added to a solution of 15 g of 8-nitro-6-carboxy-3,4-dihydrocarbostyril in 150 ml of methanol with ice-cooling. The mixture was refluxed by heating, for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was recrystallized from methanol to obtain 12.8 g of 8-nitro-6-methoxycarbonyl-3,4-dihydrocarbostyril as a light yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][CH2:7]2.[C:12]1([CH:19]=[CH:18][CH:17]=[C:15]([OH:16])[CH:14]=1)[OH:13].CC(C)([O-])C.[K+].Cl>CN1CCCC1=O.O>[OH:13][C:12]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[O:16][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH3:7])[C:11]=1[C:9]([OH:10])=[O:8]
Reactant: Oc1cccc(O)c1
Reactant: Cc1cccc2c1C(=O)OC2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cccc(COc2cccc(O)c2)c1C(=O)O
Temperature: 140 °C
Reaction time: 21 h
Yield: 77.7 %

Procedure:
7-Methylphthalide (30.1 g, 203 mmol), resorcinol (45.3 g, 407 mmol) and potassium tert-butoxide (47.6 g, 424 mmol) are suspended in 300 ml of N-methylpyrrolidone (NMP) and stirred at 140° C. for 21 h. After this time, a second amount of potassium tert-butoxide (2.4 g, 21.4 mmol) is added and stirring is continued at 140° C. for 2.5 h. The reaction mixture is cooled, 800 ml of water are added, and the mixture is acidified to pH=2 at 20° C. with concentrated hydrochloric acid. After stirring at 3 to 5° C. for 2 hours, the pale beige solid is filtered off with suction, washed with water and then dried. The isolated product contains 2-(3-hydroxyphenoxymethyl)-6-methylbenzoic acid and N-methylpyrrolidone as solvate molecule in a ratio of 1:1. Yield 77.7%, melting point 98 to 99° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.Cl[Sn]Cl.[OH2:16]>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:9])=[O:16])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1
Reactant: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: O
Agent: Cl[Sn]Cl
Solvent: CCO
Product: NC(=O)c1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 85 °C

Procedure:
A mixture of 6-chloro-3-nitropicolinonitrile (12 g, 65.4 mmol) and SnCl2.H2O (59 g, 262 mmol) in ethanol (144 ml) was heated to 85° C. for 3 hours. The solution was concentrated under reduced pressure, water was added and a saturated aqueous solution of sodium bicarbonate was added until pH=8. The mixture was extracted with ethyl acetate several times. The combined organic layers were dried (Na2SO4), and concentrated under reduce pressure to afford 6-chloro-3-nitropicolinamide in quantitative yield.
Reaction SMILES: O[CH:2]1[CH:7]([NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]=[C:11]3[CH:18]=[CH:19][S:20][C:10]=23)[CH2:6][CH2:5][N:4]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:3]1.COCCN(CCOC)S(F)(F)[F:34]>C(Cl)Cl>[F:34][CH:2]1[CH:7]([NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]=[C:11]3[CH:18]=[CH:19][S:20][C:10]=23)[CH2:6][CH2:5][N:4]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c([N+](=O)[O-])cnc3ccsc23)C(O)C1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2c([N+](=O)[O-])cnc3ccsc23)C(F)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.4 %

Procedure:
To a solution of tert-butyl 3-hydroxy-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]piperidine-1-carboxylate (716 mg, 1.82 mmol) in methylene chloride (4 mL) cooled at 0° C. was added slowly 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-λ(4)-sulfanyl)ethanamine (0.50 mL, 2.7 mmol). The reaction was stirred at room temperature for 4 h. The mixture was diluted with dichloromethane, washed with water, and concentrated. The residue was purified on silica gel (eluting with 0 to 30% EtOAc in dichloromethane) to give the desired product (0.32 g, 44%) as a mixture of cis- and trans-isomers mixture. LCMS calculated for C17H22FN4O4S (M+H)+: m/z=397.1. Found: 397.1.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([N:11]=1)=[C:9]1[NH:12][C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:14]([C:15]([NH2:17])=[O:16])[C:8]1=[CH:7][CH:6]=2.[C:24](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([N:11]=1)=[C:9]1[N:12]([CH3:24])[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:14]([C:15]([NH2:17])=[O:16])[C:8]1=[CH:7][CH:6]=2
Reactant: O=C([O-])[O-]
Reactant: NC(=O)c1c(-c2ccccc2)[nH]c2c1ccc1cnc(N)nc12
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(-c2ccccc2)c(C(N)=O)c2ccc3cnc(N)nc3c21
Temperature: 70 °C
Yield: 78 %

Procedure:
To a solution of 8-amino-2-phenyl-1H-1,7,9-triaza-cyclopenta[a]naphthalene-3-carboxylic acid amide N9 (0.16 mmol) in dry DMF (5 mL), caesium carbonate (0.7 mmol) and methyl iodide (0.7 mmol) were added. The reaction mixture was heated at 70° C. in a sealed tube for 1 h then the solvent was evaporated. The solid residue was washed with water and dried, giving the title compound (78% yield). ESI (+) MS: m/z 391 (MH+). 1H NMR: 4.21 (s, 3H), 6.15 (bs, 1H), 6.76 (bs, 2H), 7.08 (bs, 1H), 7.42 (d, J=8.50, 1H), 7.52-7.65 (m, 5H), 7.83 (d, J=8.50, 1H), 9.03 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([O:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(-c2nc3c(O)cccc3s2)cc1
Product: COc1ccc(-c2nc3c(OC(C)=O)cccc3s2)cc1

Procedure:
The 4-hydroxy-2-(4-methoxyphenyl)benzothiazole (4.0 g) obtained in Example 2 was added to 40 ml of acetic anhydride, and the mixture was refluxed for 1 hour. After the reaction, the reaction mixture was dried under reduced pressure. The residue was washed with a small amount of cyclohexane, and recrystallized from cyclohexane and ethyl acetate to give 4.0 g of 4-acetoxy-2-(4-methoxyphenyl)benzothiazole.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:28])[NH:6][C@@H:7]1[CH2:27][C:10]2[N:11]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:12]3[CH:13]=[CH:14][C:15]([CH:18]=O)=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].[OH-].[Na+].Cl.[CH3:32][O:33][NH2:34]>CO.C(OCC)(=O)C>[CH:1]([O:4][C:5](=[O:28])[NH:6][C@@H:7]1[CH2:27][C:10]2[N:11]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:12]3[CH:13]=[CH:14][C:15]([CH:18]=[N:34][O:33][CH3:32])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2]
Reactant: CON
Reactant: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3ccccn3)c3ccc(C=O)cc23)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CON=Cc1ccc2c(c1)c1c(n2Cc2ccccn2)C[C@@H](NC(=O)OC(C)C)C1
Yield: 27.2 %

Procedure:
Dissolve (S)-(7-formyl-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester (181 mg, 0.48 mmol) in methanol (10 mL) and 1.0 N sodium hydroxide (2.4 ml, 2.4 mmol). Add methoxyamine hydrochloride (120 mg, 1.44 mmol) and stir at room temperature overnight. Dilute with ethyl acetate, wash with 10% potassium carbonate, dry over anhydrous sodium sulfate, filter, and concentrate. Purify the crude product on a 12 g silica gel column eluting with 30% ethyl acetate/dichloromethane to obtain the pure title compound (53 mg, 27%). LCMS 407.1 (M+1).
Reaction SMILES: C1O[C:5]([OH:9])([CH2:7][OH:8])[CH2:4][O:3][C:2]1([OH:12])[CH2:10]O.[C:13](OC(=O)C)(=[O:15])[CH3:14].CO>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:13]([O:8][CH2:7][C:5]([CH2:4][O:3][C:2](=[O:12])[CH3:10])=[O:9])(=[O:15])[CH3:14]
Reactant: OCC1(O)COC(O)(CO)CO1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)OCC(=O)COC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an atmosphere of argon, 90 g of 1,3-dihydroxyacetone dimer and 250 mg of 4-(N,N-dimethylamino)pyridine were dissolved in 250 ml of pyridine. To the resulting solution, 225 ml of acetic anhydride was added droopowise at room temperature over 1 hour. After the resulting liquid was stirred at room temperature for 30 minutes, thereto was added 50 ml of methanol and the resulting liquid was further stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and the residue was subjected to a recrystallization from ether-petroleum ether to give 190 g of the desired compound.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=2[C:17]#[N:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[C:17]#[N:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1cc(N)ccc1Sc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 904.2 %

Procedure:
To a stirred slurry of 4-nitro-2-cyanophenyl phenyl sulfide (13.3 g, 5.19 mmol) and 100 mL of absolute ethanol was added stannous chloride dihydrate (58.6 g, 26 mmol) in one portion. The mixture was heated to 60° C. where an exothermic reaction caused the solution to strongly reflux. The mixture was allowed to stir at ambient temperature for 30 min., poured onto ice-water and made strongly basic by the addition of 350 mL of 15% NaOH. The mixture was extracted with methylene chloride (4×275 mL), the extracts dried (MgSO4), filtered, and the solvent removed in vacuo to yield an oil which was chromatographed on 300 g of silica gel using a methylene chloride (20%, 40%, 60% 80% and 100%) in hexane gradient. The proper fractions were combined and the solvent removed to yield the 4-amino-2-cyanophenyl phenyl sulfide (10.62 g, 91%) as a pale yellow solid; mp 73°-75° C. 1H-NMR (300 MHz, CDCl3): 4.01 (s, 2H, NH2), 6.78 (dd 1H, J=8.5, 2.6, aromatic), 6.95 (d, 1H, J=2.6, aromatic), 7.18-7.29 (m, 5H, aromatic), 7.34 (d, 1H, J=8.5, aromatic). MS (CI, CH4): 227(M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:41](Cl)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43]>C(Cl)Cl>[CH3:43][C:42]([CH3:45])([CH3:44])[C:41]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1)=[O:46]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(COC(=O)C(C)(C)C)cc2)C(OCc2ccc3ccccc3c2)C1
Yield: 73.4 %

Procedure:
A solution of 45 mg (0.1 mmol) of tert-butyl (3RS,4RS)-4-(4-hydroxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate, 12 mg (0.12 mmol) of triethylamine and 12 mg (0.1 mmol) of pivaloyl chloride in 5 ml of methylene chloride was stirred at room temperature for 15 hours. For the working-up, the reaction solution was diluted with 10 ml of methylene chloride, then washed with 5 ml of water, dried over sodium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica gel using a 4:1 mixture of hexane, and ethyl acetate as the eluent. There were obtained 39 mg (73% of theory) of tert-butyl (3RS,4RS)-4-[4-(2,2-dimethyl-propionyloxymethyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 549 (M+NH4)+.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:15][CH3:16])=[CH:6][C:7]2[CH2:12][O:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1)[CH:2]=[CH2:3].[H-].[Na+].I[CH3:20]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:4]1[C:5]([O:15][CH3:16])=[CH:6][C:7]2[CH2:12][O:11][C:10](=[O:13])[N:9]([CH3:20])[C:8]=2[CH:14]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cc2c(cc1OC)COC(=O)N2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCc1cc2c(cc1OC)COC(=O)N2C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.6 %

Procedure:
210 mg of 7-allyl-6-methoxy-1,4-dihydrobenz[d][1,3]oxazin-2-one was dissolved in 6 ml of N,N-dimethylformamide. Thereafter, 46 mg of 60% sodium hydride was added to the reaction solution while cooling on ice. The obtained mixture was then stirred at room temperature for 20 minutes. Thereafter, while cooling on ice, 0.20 g of iodomethane was added to the reaction solution. The obtained mixture was then stirred at room temperature for 2 hours. Thereafter, the reaction solution was diluted with ethyl acetate and then washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain 207 mg of the subject compound.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][C@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][OH:9])[CH2:5][CH2:4]1.Br[CH2:19][CH2:20][O:21][CH3:22]>C1COCC1>[CH:3]1([CH2:6][C@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH2:8][O:9][CH2:19][CH2:20][O:21][CH3:22])[CH2:5][CH2:4]1
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOC[C@H](CC1CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.3 %

Procedure:
NaH (70%, 0.504 g, 15 mmol) was added in portions to a solution of (S)-tert-butyl 1-cyclopropyl-3-hydroxypropan-2-ylcarbamate (1.6 g, 7.5 mmol) in THF (30 mL) at room temperature. The mixture was stirred at room temperature for 20 min. 1-Bromo-2-methoxyethane (2.07 g, 15 mmol) was added and stirring was continued for 2 h. The reaction was quenched by careful addition of H2O (5 mL). After evaporation of solvent the residue was diluted with ethyl acetate (20 mL) and H2O (20 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated to give the title product as yellow oil (1.01 g, 50%); MS (EI): m/e=296.2 [M+Na]+.
Reaction SMILES: CC(C)=O.Cl[C:6]1[N:11]=[C:10]([Cl:12])[N:9]=[C:8]([Cl:13])[N:7]=1.[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15].[OH-].[Na+]>O>[C:14]([NH:18][C:6]1[N:11]=[C:10]([Cl:12])[N:9]=[C:8]([Cl:13])[N:7]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)N
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)Nc1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
—400 ml of acetone cooled to 0° C. are added, under nitrogen stream, with 92.3 g of 2,4,6-trichloro-1,3,5-triazine, then with 38 g of tert-butylamine, always keeping the temperature at about 0° C. After keeping the resulting mixture at this temperature for 30 minutes, 66.7 g of a 30% NaOH aqueous solution, then 400 ml of water are dropped therein, and the resulting mixture is stirred for 1 hour at 0° C. After filtration and washing with water to neutral pH, the resulting precipitate is dried to obtain 108 g of 2-tert-butylamino-4,6-dichloro-1,3,5-triazine. M.p. 129-30° C.