Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.[C:23]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]([OH:36])=[O:35])[CH2:30][CH2:29]1)(=[O:27])[CH2:24][CH2:25][CH3:26].N12CCCN=C1CCCCC2.C(OC(C)C)(C)C>CN(C)C=O>[C:23]([N:28]1[CH2:29][CH2:30][CH:31]([C:34]([O:36][CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:3]2[C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]=2)=[O:35])[CH2:32][CH2:33]1)(=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: CCCC(=O)N1CCC(C(=O)O)CC1
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCC(=O)N1CCC(C(=O)OC2c3ccccc3C(=O)N2c2ccc3ccc(Cl)nc3n2)CC1
Yield: 40.6 %

Procedure:
The procedure is as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (9.9 g) in anhydrous dimethylformamide (100 cc), 1-butyryl-4-piperidinecarboxylic acid (6 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.6 g). The residue obtained is purified by chromatography on silica (0.063-0.2 mm; 250 g) contained in a column 4.2 cm in diameter [eluant: a mixture of methylene chloride and methanol (99:1 by volume)], collecting 70-cc fractions. Fractions 82 to 110 are combined and concentrated to dryness under reduced pressure (b 2.7 kPa). The solid obtained is taken up with stirring with isopropyl ether, then separated by filtration and dried. 2-(7-Chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 1-butyryl-4-piperidinecarboxylate (6 g), m.p. 165° C., is thereby obtained.
Reaction SMILES: IC.[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:18][CH:19]3[CH2:22][O:21][CH2:20]3)[CH2:13]2)=[CH:8][C:7]=1[O:23][CH:24]([CH3:26])[CH3:25])([O-:5])=[O:4].[C:27](=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:27][N:18]([CH:19]1[CH2:22][O:21][CH2:20]1)[C@@H:14]1[CH2:15][CH2:16][CH2:17][N:12]([C:9]2[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[C:7]([O:23][CH:24]([CH3:26])[CH3:25])[CH:8]=2)[CH2:13]1
Reactant: CC(C)Oc1cc(N2CCC[C@@H](NC3COC3)C2)ccc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cc(N2CCC[C@@H](N(C)C3COC3)C2)ccc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 15.4 %

Procedure:
65 μl of iodomethane are added, at a temperature of about 20° C., under an argon atmosphere and with magnetic stirring, to a mixture of 293 mg of (3R)-1-[4-nitro-3-(propan-2-yloxy)phenyl]-N-(oxetan-3-yl)piperidin-3-amine and 427 mg of caesium carbonate in 8 ml of anhydrous DMF. After stirring for 3 hours, 100 μl of iodomethane are added and the mixture is left to stir for a further 2 h. 10 ml of water are then added and the mixture is then extracted three times with 15 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated under vacuum so as to give an oily yellow residue. The residue is purified by flash chromatography on silica gel, using a dichloromethane/methanol (98/2) eluent, so as to obtain 47 mg of (3R)—N-methyl-1-[4-nitro-3-(propan-2-yloxy)phenyl]-N-(oxetan-3-yl)piperidin-3-amine in the form of an orangey-yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([C:21]3[S:25][C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)=[N:23][C:22]=3[CH3:36])=[O:20])[CH2:14]2)[CH:10]=[CH:9][C:8]=1[CH3:37])C.C(=O)([O-])[O-].[K+].[K+].CO>O>[CH3:37][C:8]1[CH:9]=[CH:10][C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([C:21]3[S:25][C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=4)=[N:23][C:22]=3[CH3:36])=[O:20])[CH2:14]2)=[CH:12][C:7]=1[NH:6][CH2:5][C:4]([OH:38])=[O:3]
Reactant: CCOC(=O)CNc1cc(C2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc(C2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)cc1NCC(=O)O
Temperature: 25 °C
Yield: 110.4 %

Procedure:
A mixture of (2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-phenylamino)-acetic acid ethyl ester (19 mg, 0.035 mmol), potassium carbonate (10 mg, 0.07 mmol), methanol (5 mL) and water (1 mL) was heated at reflux for 3 h, cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in water (50 mL), acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to yield 20 mg (99%) of (2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-phenylamino)-acetic acid as a white solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:14][S:15]([CH2:18][C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1)(=[O:17])=[O:16])[C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C.Cl.O1CCOCC1>C1COCC1>[NH2:8][C@@H:9]([CH2:14][S:15]([CH2:18][C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1)(=[O:16])=[O:17])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)[C@H](CS(=O)(=O)Cc1cnccn1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COC(=O)[C@@H](N)CS(=O)(=O)Cc1cnccn1
Reaction time: 48 h

Procedure:
Methyl 2(R)-tert-butoxycarbonylamino-3-(pyrazin-2-ylmethanesulfonyl)propionate was dissolved in THF (5 mL) and a solution of HCl/dioxane (4.0 M, 2.9 mL) was added. After stirring for 48 h, the solvent was removed in vacuo and the residue was precipitated with diethyl ether and dried under vacuum to give methyl 2(R)-amino-3-(pyrazin-2-ylmethanesulfonyl)propionate which was converted to the title compounds utilizing the procedure described in Example 4 above.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[CH:24])[CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:25][CH2:26][CH2:27][O:28][CH3:29].[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>CN(C=O)C>[ClH:2].[ClH:1].[C:23]([C:19]1[CH:18]=[C:17]([NH:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][N:30]4[CH:34]=[CH:33][N:32]=[CH:31]4)=[C:7]([O:25][CH2:26][CH2:27][O:28][CH3:29])[CH:8]=3)[N:13]=[CH:12][N:11]=2)[CH:22]=[CH:21][CH:20]=1)#[CH:24]
Reactant: C#Cc1cccc(Nc2ncnc3cc(OCCCl)c(OCCOC)cc23)c1
Reactant: c1c[nH]cn1
Agent: Cl
Solvent: CN(C)C=O
Product: C#Cc1cccc(Nc2ncnc3cc(OCCn4ccnc4)c(OCCOC)cc23)c1
Yield: 66.9 %

Procedure:
The title product from Example 34 (110 mg, 0.253 mmol) in DMF (2 mL) was treated with imidazole (172 mg, 2.53 mmol) at 110° C. for 48 hours. The reaction mixture was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product (119 mg) was chromatographed on silica using 10% methanol/CH2Cl2 to provide 85 mg of pure title product as its free base. This white solid was dissolved in a minimum volume of CHCl3, and titrated with 2 equivalents of 1M HCl in ether to precipitate the title product as a white solid (95 mg; 75%; M.P. 220°-227° C. (dec); LC-MS: 430 (MH+); anal. RP18-HPLC RT: 3.75 min.).
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[O:7])=[CH:4][CH:3]=1.[C:36]([N:40]=[C:41]=[O:42])([CH3:39])([CH3:38])[CH3:37]>>[C:36]([NH:40][C:41](=[O:42])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[O:7])=[CH:34][CH:35]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)N=C=O
Reactant: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(N)cc1
Product: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(NC(=O)NC(C)(C)C)cc1
Yield: 77.3 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(2-methoxyphenyl)benzamide (77.7 mg, 0.164 mmol) and tertbutyl isocyanate (0.022 ml, 0.196 mmol), the procedure of inventive Example 144 was repeated to obtain 72.9 mg (77.6%) of the title compound in a colorless oily form.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6](=[C:22]1[S:26][C:25](=[S:27])[N:24]([CH2:28][C:29]([OH:31])=[O:30])[C:23]1=[O:32])[C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[S:14])[S:10][CH:11]=1)=[O:5])[CH3:2].[CH2:33](O)[CH3:34].O1CCOCC1.Cl>O>[CH2:1]([O:3][C:4]([C:6](=[C:22]1[S:26][C:25](=[S:27])[N:24]([CH2:28][C:29]([O:31][CH2:33][CH3:34])=[O:30])[C:23]1=[O:32])[C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[S:14])[S:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCO
Reactant: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=S)Nc2ccccc2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CN1C(=O)C(=C(C(=O)OCC)c2csc(NC(=S)Nc3ccccc3)n2)SC1=S
Reaction time: 108 h

Procedure:
A mixture comprising 10 g of 5-{1-ethoxycarbonyl-1-[2-(3-phenylthioureido)thiazol-4-yl]methylene}rhodanine-3acetic acid 20 g of ethanol and 150 ml of a 4N dioxane solution of hydrogen chloride was left to stand at room temperature for 4.5 days. The reaction mixture was then poured into water and extracted with ethyl acetate. The extract was washed with aqueous potassium carbonate solution and then with aqueous sodium chloride solution, and was then dried over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography, using as eluent a 1:1 by volume mixture of hexane and ethyl acetate. The resulting crystalline product was recrystallised from a 1:5 by volume mixture of hexane and ethyl acetate, giving a yellow powder having the following physical properties.
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C1C=CC=CN=1)C.C(Cl)CCl.[NH2:34][C@H:35]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]1>ClCCl>[CH2:7]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:34][C@H:35]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]1)=[O:20])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: CN(C)c1ccccn1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (1 g, 3.62 mmol) in dry dichloromethane (30 mL) was added dimethylaminopyridine (884 mgL, 7.24 mmol), EDC (1.388 g, 7.24 mmol), and tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate (742 mg, 3.98 mmol) sequentially at room temperature under nitrogen. The reaction mixture was stirred at room temperature over the weekend. The reaction mixture was then concentrated under vacuum and the residue was purified by HPLC on a 30×100 mm Waters Sunfire column eluted with 15% to 100% CH3CN+0.05% TFA/water+0.05% TFA over 15 minutes to afford the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12]C(=O)[NH:10][CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:27])([F:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C>[NH2:10][CH:9]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([F:27])([F:26])[C:22]([CH3:23])([CH3:24])[CH3:25])=[CH:19][CH:20]=1)[CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:12]
Reactant: CC(C)(C)C(F)(F)c1ccc(CC2NC(=O)OC2c2cccc(Cl)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)C(F)(F)c1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Yield: 71.7 %

Procedure:
To a solution of (4RS,5SR)-5-(3-chlorophenyl)-4-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]-1,3-oxazolidin-2-one (3.82 g, 9.70 mmol) in ethanol (100 ml) was added 8N aqueous sodium hydroxide solution (6.1 ml, 48.5 mmol), and the mixture was heated under reflux for 4 hrs. After completion of the reaction, ethanol was evaporated under reduced pressure. The residue was diluted with water, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give (1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[4-(1,1-difluoro-2,2-dimethylpropyl)phenyl]-1-propanol (2.56 g, 72%) to give colorless crystals.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[OH-:7].[K+].[S:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[C:11]([CH2:18][OH:19])=[N:10]1>O>[S:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[C:11]([C:18]([OH:7])=[O:19])=[N:10]1
Reactant: [OH-]
Reactant: OCc1nsc2ncccc12
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1nsc2ncccc12
Reaction time: 0.08 h
Yield: 42 %

Procedure:
Potassium permanganate (2.25 mmol) and potassium hydroxide (1.79 mmol) were added to a solution of isothiazolo[5,4-b]pyridin-3-ylmethanol (1.08 mmol) in water (4 mL) and the resulting solution was allowed to react for 3 h at rt. The reaction mixture was filtered through Celite and was extracted with ethyl acetate (3×10 mL). The pH of the combined aqueous layers was adjusted to 2 by the addition of 0.6 M hydrochloric acid. The slurry was stirred for 5 min and the solids were collected by filtration to provide isothiazolo[5,4-b]pyridine-3-carboxylic acid in 42% yield as a light yellow solid.
Reaction SMILES: C(OCC)C.[H-].[Na+].[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]2[CH2:16][N:17]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:19][C:20]=2[CH:21]=1)=[O:12])[CH3:9].[C:25]([O:29][C:30](=O)[O:31]C(C)(C)C)([CH3:28])([CH3:27])[CH3:26]>CN(C)C=O>[C:25]([O:29][C:30]([N:14]1[C:15]2[CH2:16][N:17]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:19][C:20]=2[CH:21]=[C:13]1[C:11]([O:10][CH2:8][CH3:9])=[O:12])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cc2c([nH]1)CN(C(C)=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(n1C(=O)OC(C)(C)C)CN(C(C)=O)CC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49 %

Procedure:
A suspension of diethyl ether washed sodium hydride (0.28 g, 0.009 mole) in dry dimethylformamide (8 ml) at 0° C. was treated with a solution of 2-ethoxycarbonyl-6-acetyl-4,5,6,7-tetrahydro-6-azaindole from Example 2 (2 g, 0.0085 mole) in dry dimethylformamide (2 ml) and stirred for 20 minutes. The mixture was warmed to room temperature and stirred for 1 hour by which time solution was complete. The solution was cooled to 0° C., a solution of di-tert-butylcarbonate (1.85 g, 0.0085 mole) in dry dimethylformamide (2 ml) added dropwise over 10 minutes, and the solution stirred at room temperature for 4 hours. The mixture was quenched with water (200 ml), extracted with ethyl acetate (4×100 ml) the organic extracts washed with brine (3×100 ml), dried over sodium sulphate, and evaporated to give a yellow oil which was chromatographed on silica gel (20 g) eluting with dichloromethane:hexane (9:1) to give the title product as a pale yellow oil (1.4 g, 49%). Found: C, 60.12; H, 7.32; N, 8.15. C17H24N2O5 requires C, 60.70; H, 7.19; N, 8.33%.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH:13]([CH:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[C:20]([CH3:32])[CH:19]=3)[CH3:17])[CH2:14][CH3:15])=[CH:10][C:9]=2[CH:33]=1)=[O:4].[OH-].[Na+]>CO.C1COCC1>[CH3:30][C:27]([CH3:28])([CH3:29])[C:26](=[O:31])[CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH:16]([CH:13]([C:11]2[O:12][C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:33][C:9]=3[CH:10]=2)[CH2:14][CH3:15])[CH3:17])=[CH:19][C:20]=1[CH3:32]
Reactant: CCC(c1cc2cc(C(=O)OC)ccc2o1)C(C)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(c1cc2cc(C(=O)O)ccc2o1)C(C)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.4 %

Procedure:
A solution of 2-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-ethylpropyl}-benzofuran-5-carboxylic acid methyl ester (5.30 g, 11.8 μmmol) in methanol (30.0 mL) and THF (30.0 mL) is treated with NaOH (2.0 M, 60 mL). The resulting mixture is stirred at RT for 16 h. The mixture is concentrated and neutralized with HCl (5 N) till pH˜3, and extracted with EtOAc (2×100 mL). The organic layer is dried over Na2SO4, concentrated to afford the title compound (4.85 g, 94%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:7]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH2:6][CH2:5][C:4]([CH:15]=[O:16])=[CH:3]1.C(O)C.[BH4-].[Na+]>O1CCCC1>[CH3:1][C:2]1([CH3:17])[C@@H:7]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH2:6][CH2:5][C:4]([CH2:15][OH:16])=[CH:3]1
Reactant: CC1(C)C=C(C=O)CC[C@@H]1OC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)C=C(CO)CC[C@@H]1OC1CCCCO1
Reaction time: 2 h
Yield: 90.8 %

Procedure:
(4S)-3,3-dimethyl-4-tetrahydropyranyloxycyclohexene-1-carbaldehyde (8) (0.71 g, 2.98 mmoles) was dissolved in tetrahydrofuran (7 ml), and a 95% ethanol solution of sodium borohydride (0.38 g, 10 mmoles) was added dropwise over an ice bath. After the addition, the mixture was stirred for 2 hours at a temperature below 10° C. The solvent was evaporated under reduced pressure. The residue was diluted with water, and extracted twice with diethyl ether. The ethereal layer was dried over magnesium sulfate, filtered, concentrated, and purified by column chromatography (30 g of silica gel; n-hexane/ethyl acetate) to give 0.65 g (yield 91.3%) of a compound (9).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C>C1COCC1>[CH2:1]([S:3]([NH:7][CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH2:11][CH2:10][CH2:9]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: NC1CCCOc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)NC1CCCOc2ccccc21
Reaction time: 8 h
Yield: 70.6 %

Procedure:
0.86 g (6.7 mmol) of ethanesulfonyl chloride was added dropwise with ice cooling to a solution of 1.0 g (6.1 mmol) of 5-amino-2,3,4,5-tetrahydro-1-benzoxepine and 2.5 g (24 mmol) of triethylamine in 20 ml of THF. The mixture was allowed to come to room temperature and was stirred overnight, and the solvent was distilled off in vacuo. After stirring the residue with water, the deposited product was filtered off with suction. 1.1 g of 5-ethylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine were obtained, m.p. 109-111° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[C:24]1([C:34](O)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][N:25]=2)=[O:35])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Reactant: O=C(O)c1nccc2ccccc12
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2nccc3ccccc23)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with Isoquinoline-1-carboxylic acid. LC-MS (basic): tR=0.96 min; [M+H]+=503.3.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9](=[O:20])[C@@H:10]([OH:19])[C@@H:11]([N:16]=[N+]=[N-])[CH2:12][CH2:13][CH2:14][CH3:15]>[C].[Pd].CO>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9](=[O:20])[C@@H:10]([OH:19])[C@@H:11]([NH2:16])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCC[C@H](N=[N+]=[N-])[C@H](O)C(=O)N[C@H]1CCCC[C@@H]1O
Agent: [Pd]
Solvent: CO
Product: CCCC[C@H](N)[C@H](O)C(=O)N[C@H]1CCCC[C@@H]1O
Reaction time: 18 h
Yield: 91.3 %

Procedure:
To 30 ml of a methanol solution containing 1.45 g (5 mmol) of (2S,3S)-N-[(1S,2S)-2-hydroxycyclohexane-1-yl]-3-azido-2-hydroxyheptanamide was added 150 mg of 5% palladium carbon, and the resulting mixture was stirred under hydrogen atmosphere for 18 hours. Insoluble material was filtered off, and the filtrate was distilled under reduced pressure to obtain 1.18 g (Yield: 91%) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([N:20]([S:22]([C:25]3[C:33]4[O:32][C:31]([F:35])([F:34])[O:30][C:29]=4[CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])C)[CH:17]=[CH:16][C:15]=2[O:36][CH3:37])[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[Na+].[CH2:40](Br)[CH3:41].[ClH:43]>C(O)(C)C>[ClH:43].[CH2:40]([N:20]([C:18]1[CH:17]=[CH:16][C:15]([O:36][CH3:37])=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=1)[S:22]([C:25]1[C:33]2[O:32][C:31]([F:35])([F:34])[O:30][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=[O:23])=[O:24])[CH3:41]
Reactant: CCBr
Reactant: COc1ccc(N(C)S(=O)(=O)c2cccc3c2OC(F)(F)O3)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Product: CCN(c1ccc(OC)c(N2CCNCC2)c1)S(=O)(=O)c1cccc2c1OC(F)(F)O2

Procedure:
The compound was prepared by reaction of 4-{5-[(2,2-difluoro-benzo[1,3]dioxole-4-sulfonyl)-methyl-amino]-2-methoxy-phenyl}-piperazine-1-carboxylic acid tert-butyl ester with sodium hydride and ethylbromide, and subsequent deprotection of the tert.butoxycarbonyl group with hydrochlorid acid in isopropanol.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7].[C:13]([CH2:15][C:16]([NH2:18])=[O:17])#[N:14]>C(O)C>[NH2:14][C:13]1[N:5]([CH2:4][C:3]2[CH:8]=[CH:9][CH:10]=[C:11]([Cl:12])[C:2]=2[Cl:1])[N:6]=[N:7][C:15]=1[C:16]([NH2:18])=[O:17]
Reactant: N#CCC(N)=O
Reactant: [N-]=[N+]=NCc1cccc(Cl)c1Cl
Solvent: CCO
Product: NC(=O)c1nnn(Cc2cccc(Cl)c2Cl)c1N

Procedure:
In a manner analogous to that described in Example 2, by reacting 2,3-dichlorobenzyl azide with cyanoacetamide there is obtained 5-amino-1-(2,3-dichlorobenzyl)-1H-1,2,3-triazole-4-carboxamide having a melting point of 224°-226° (from ethanol). The starting material can be produced from 2,3-dichlorobenzyl alcohol as starting material by halogenation, for example with phosphorus tribromide, and reaction with sodium azide.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]2[N:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:3]1=[O:17].[H-].[Na+].[CH3:20][N:21]([CH3:36])[CH2:22][CH2:23][CH2:24]OS(C1C=CC(C)=CC=1)(=O)=O>C1(C)C(C)=CC=CC=1>[CH3:20][N:21]([CH3:36])[CH2:22][CH2:23][CH2:24][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3](=[O:17])[C:4]2[CH:16]=[CH:15][CH:14]=[N:13][C:5]1=2
Reactant: Cc1ccc(S(=O)(=O)OCCCN(C)C)cc1
Reactant: CN1C(=O)c2cccnc2Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CN(C)CCCN1c2ccccc2N(C)C(=O)c2cccnc21
Yield: 38.7 %

Procedure:
A mixture of 4.5 gm of 6,11-dihydro-6-methyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, 0.83 gm of 55% sodium hydride in mineral oil, and 100 ml of absolute xylene was refluxed for two hours. Thereafter, 7 gm of p-toluenesulfonic acid 3-dimethylamino-n-propyl ester were added, and the resulting mixture was refluxed for 14 hours more. After cooling, the reaction mixture was suction-filtered, and the filtrate was extracted with dilute acetic acid. From the acidic aqueous phase, the base was precipitated as an oil with concentrated ammonia and taken up in ether. After evaporation of the ether solution, the residue was distilled, yielding 2.4 gm of 11(3'-dimethylamino-n-propyl)-6,11-dihydro-6-methyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, b.p. 180°-183° C. at 0.03 mm Hg, which melted at 98.5°-100° C. after crystallization from cyclohexane and recrystallization from petroleum ether.