Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2].Cl[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:7]=[O:8])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: OCCCCCCCl
Product: CCOc1cc(C=O)ccc1OCCCCCCO
Yield: 84 %

Procedure:
3-ethoxy-4-[(6-hydroxyhexyl)oxy]benzaldehyde is prepared starting from 3-ethoxy-4-hydroxybenzaldehyde and 6-chlorohexan-1-ol according the same procedure following for example 7 in 84% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][CH2:13][OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:29]=[CH:28][C:19]([O:20][C:21]2[CH:22]=[C:23](O)[CH:24]=[CH:25][CH:26]=2)=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][CH2:13][O:14][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([O:20][C:19]3[CH:18]=[CH:17][C:16]([Cl:15])=[CH:29][CH:28]=3)[CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(CCO)C1
Reactant: Oc1cccc(Oc2ccc(Cl)cc2)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CCOc2cccc(Oc3ccc(Cl)cc3)c2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 72.6 %

Procedure:
A solution consisting of 3-(2-hydroxy-ethyl)-azetidine-1-carboxylic acid tert-butyl ester (4.39 g, 21.8 mmol), 3-(4-chloro-phenoxy)-phenol (4.81 g, 21.8 mmol) and THF (40 mL) was cooled at 0° C., treated with polymer supported triphenyl phosphine (10.9 g, 32.7 mmol) then diisopropyl azodicarboxylate (6.62 g, 32.7 mmol) dropwise over 30 min. After stirring for 15 min at 0° C., the reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was filtered, the filtrate evaporated, and the residue purified (FCC) to give the title compound as a clear oil (6.39 g, 73%). MS (ESI+): calcd. for C22H26ClNO4, 403.16. m/z found, 426.2 (M+Na)+. 1H NMR (d6-DMSO): 7.43 (d, J=9.0 Hz, 2H), 7.28 (t, J=8.2 Hz, 1H), 7.03 (d, J=9.0 Hz, 2H), 6.72 (dd, J=8.3, 1.5 Hz, 1H), 6.59-6.55 (m, 2H), 3.98-3.84 (m, 4H), 3.59-3.50 (m, 2H), 2.70-2.58 (m, 1H), 2.02-1.89 (m, 2H), 1.36 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.C1C=C[C:17]2N(O)N=[N:20][C:18]=2C=1.Cl.C(N)C.C(N(CC)CC)C.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH2:18]([NH:20][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([OH:1])[CH:3]=1)[CH3:17]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: On1nnc2ccccc21
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCNC(=O)c1ccc([N+](=O)[O-])c(O)c1
Temperature: 25 °C
Reaction time: 14.5 h
Yield: 381.6 %

Procedure:
3-Hydroxy-4-nitrobenzoic acid (6.06 g, 32.1 mmol), HOBt (0.876 g, 6.42 mmol, 0.2 eq.) and ethylamine hydrochloride (3.03 g, 35.3 mmol, 1.1 eq.) were suspended in DMF (80 ml), triethylamine (5.82 ml, 41.7 mmol, 1.3 eq.) was added, WSC (6.91 g, 35.3 mmol, 1.1 eq.) was added, and the mixture was stirred at room temperature for 14.5 hr. The reaction mixture was suspended in ethyl acetate-hexane (4:1, 250 ml) and washed sequentially with 8% acidic solution of ammonium chloride in water (×2), 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane (4:1, 150 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and the residue was diluted with diethyl ether. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a yellow powder (5.14 g, 24.5 mmol, 76.2%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[C:32]1([C@@H]2C[C@H]2C(O)=O)C=CC=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([N:11]([CH2:10][C@@H:9]2[CH2:32][C@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH2:26][CH2:27]1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(C[C@@H]2C[C@H]2c2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using trans-2-phenyl -cyclopropanecarboxylic acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1)[C:9](=[O:12])[CH2:10]Br)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C.C1COCC1>[C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]([C@H:9]1[CH2:10][O:12]1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)c(F)c1)C(=O)CBr
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)c(F)c1)[C@H]1CO1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of (1S)-[3-Bromo-1-(3,4-difluoro-benzyl)-2-oxo-propyl]-carbamic acid tert-butyl ester (0.14 g, 0.36 mmol) in ethanol:THF (2:1) (3 mL) was cooled to 0° C. and treated with sodium borohydride (0.014 g, 0.36 mmol) in one portion. After 30 minutes the cooling bath was removed and the reaction mixture was stirred at ambient temperature for 12 hours. The solvent was removed and the residue partitioned between saturated sodium bicarbonate solution (20 mL) and ethyl acetate (20 mL). The organic phase was washed with saturated sodium bicarbonate solution (25 mL), separated, dried (MgSO4) and the solvent removed at reduced pressure. The product was recrystallized from hexane to give the desired product as the major isomer (>9:1) by NMR (0.095 g, 90%). MS: 300 (M+H, 100%).
Reaction SMILES: [CH3:1][C:2]1([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH2:7][O:6][CH2:5][O:4][CH2:3]1.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30]>CN(C)C=O>[CH3:1][C:2]1([C:8](=[O:15])[CH:9]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH2:7][O:6][CH2:5][O:4][CH2:3]1
Reactant: Fc1ccccc1OCCCCBr
Reactant: CC1(C(=O)Cn2cncn2)COCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C(=O)C(CCCCOc2ccccc2F)n2cncn2)COCOC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
A solution of 42.2 g (0.2 mole) of 1-(5-methyl-1,3-dioxan-5-yl)-2-(1,2,4-triazol-1-yl)-ethan-1-one in 150 ml of absolute dimethylformamide is added dropwise, at from 20° to 25° C., to a stirred suspension of 5.3 g (0.22 mole) of sodium hydride in 50 ml of absolute dimethylformamide, the suspension being kept under nitrogen. Stirring is continued for 3 hours, after which a solution of 49.4 g (0.2 mole) of 1-bromo-4-(2-fluorophenoxy)-butane in 50 ml of absolute dimethylformamide is added dropwise at 60° C. and the reaction mixture is then refluxed for a further 5 hours. About 100 ml of ice water are then carefully added dropwise at room temperature, and the mixture is extracted with three times 300 ml of methylene chloride. The organic phase is then washed several times with water, dried over Na2SO4 and evaporated down. Distillation (bp.=248° C./0.005) gives 56 g (74%) of 1-(5-methyl-1,3-dioxan-5-yl)-2-(1,2,4-triazol-1-yl)-6(2-fluorophenoxy)-hexan-1-one as a yellowish resin.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+:13]([O-])([O-:15])=[O:14].[NH4+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]1[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1[nH]cnc1-c1ccccc1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: Cc1[nH]cnc1-c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared by nitrogenation of 5-methyl-4-phenyl-imidazole (melting point: 185-188° C.) in concentrated sulphuric acid with ammonium nitrate analogously to Example D.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]([NH:11][CH:12]([CH3:15])[CH2:13][CH3:14])=[N:7][C:8]=1[CH:9]=O)#[N:2].O.[NH2:22][NH2:23]>CO>[C:1]([C:3]1[C:8](=[CH2:9])[NH:7][C:6]([NH:11][CH:12]([CH3:15])[CH2:13][CH3:14])=[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:4]=1[NH:22][NH2:23])#[N:2]
Reactant: NN
Reactant: CCOC(=O)c1cc(C#N)c(C=O)nc1NC(C)CC
Solvent: CO
Solvent: O
Product: C=C1NC(NC(C)CC)=C(C(=O)OCC)C(NN)=C1C#N

Procedure:
2.8 g of 5-cyano-6-formyl-2-[(1-methylpropyl)amino]-3-pyridine-carboxylic acid, ethyl ester (0.01 mol) are dissolved in 10 ml of methanol and 1 g of hydrazine hydrate is added with stirring. After standing over night the title compound precipitates. Yield 2.1 g (73%); m.p. 120°-121° C. (methanol).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[CH2:11]([O:13][C:14](=[O:18])[CH2:15][NH:16][CH3:17])[CH3:12].[Br:19][C:20]1[CH:21]=[C:22]([NH:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH:37][C:38](=[O:43])[CH:39]=[CH:40][CH2:41]Br)[CH:35]=3)[N:30]=[CH:29][N:28]=2)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[Br:19][C:20]1[CH:21]=[C:22]([NH:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH:37][C:38](=[O:43])[CH:39]=[CH:40][CH2:41][N:16]([CH2:15][C:14]([O:13][CH2:11][CH3:12])=[O:18])[CH3:17])[CH:35]=3)[N:30]=[CH:29][N:28]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(C=CCBr)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: CCOC(=O)CNC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)CN(C)CC=CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reaction time: 8 h

Procedure:
13.94 ml of Hünig base are pipetted into a suspension of 9.37 g of sarcosine ethylester hydrochloride in 25 ml of tetrahydrofuran while cooling with an ice bath. Then a solution of 2.00 g of 4-[(3-bromophenyl)amino]-6-[(4-bromo-1-oxo-2-buten-1-yl)amino]-quinazoline in 10 ml of dimethylformamide is added dropwise within 15 minutes. The reaction mixture is allowed to come up to ambient temperature overnight in an ice bath. For working up, 25 ml of saturated sodium hydrogen carbonate solution and 50 ml of ethyl acetate are added. The organic phase is separated off and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The dark-brown oily residue is stirred with 50 ml of water, the precipitate formed is suction filtered and washed with water. The crude product is purified by chromatography on a silica gel column with methylene chloride/methanol (50:1 to 20:1). Yield: 1.00 g (46% of theory), Melting point: 182-183° C. Mass spectrum (ESI*): m/z=496, 498 [M−H]*
Reaction SMILES: Cl[CH2:2][C:3]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:11])=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].[C:17]([OH:22])(=[O:21])[C:18]([CH3:20])=[CH2:19]>CC(C)=O>[C:17]([O:22][CH2:2][C:3]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:11])=[CH:5][CH:4]=1)(=[O:21])[C:18]([CH3:20])=[CH2:19]
Reactant: C=C(C)C(=O)O
Reactant: O=Cc1cc(CCl)ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: C=C(C)C(=O)OCc1ccc(O)c(C=O)c1
Temperature: 0 °C

Procedure:
5-Chloromethylsalicylaldehyde (34 g) (prepared by the method of Angyal et al., J. Chem. Soc. 2141, (1950)) was added to a stirred mixture of acetone (250 ml), sodium hydrogen carbonate (33.6 g), and methacrylic acid (34.4 g) and the mixture was stirred under reflux for 21/2 hours. Addition of the mixture to ice water gave a grey precipitate which was collected, washed with water, dried, and crystallized from light petroleum (b.p. 60°-80° C.). Yield 32.1 g, m.p. 82°-4° C.
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:13]=[C:14]([C:18]2([CH3:23])[O:22][CH2:21][CH2:20][O:19]2)[CH:15]=[CH:16][CH:17]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[OH:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[CH:27][CH:26]=1.[O-]CC.[Na+]>C(O)C>[OH:5][C:4]([C:7]([F:9])([F:8])[F:10])([CH2:3][C:2]([CH3:1])([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2([CH3:23])[O:22][CH2:21][CH2:20][O:19]2)[CH:13]=1)[CH3:11])[CH2:6][N:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25](=[O:24])[CH:26]=[CH:27]1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cccc(C2(C)OCCO2)c1
Reactant: Oc1ccnc2ccccc12
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cccc(C2(C)OCCO2)c1
Temperature: 85 °C

Procedure:
A mixture of 2-{3-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]phenyl}-2-methyl-[1,3]dioxolane (0.514 g, 1.55 mmol), 4-hydroxyquinoline (0.433 g, 2.98 mmol), and sodium ethoxide (21 wt. % solution in ethanol, 0.55 mL, 1.49 mmol) in ethanol (4.2 mL) was heated at 85° C. for 14 hours, cooled to room temperature, quenched with water, and concentrated in vacuo to remove most of the ethanol. The residue was diluted with half saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate-hexanes as the eluent. The product-rich fractions were concentrated in vacuo to afford 1-{2-hydroxy-4-methyl-4-[3-(2-methyl-[1,3]dioxolan-2-yl)phenyl]-2-trifluoromethylpentyl}-1H-quinolin-4-one. Yield: 0.35 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[C:24]([N:25]([CH:27]([CH3:29])[CH3:28])[CH3:26])=[N:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:30]([O:32]C)=[O:31])[CH:21]=3)[N:16]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[C:24]([N:25]([CH:27]([CH3:28])[CH3:29])[CH3:26])=[N:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:30]([OH:32])=[O:31])[CH:21]=3)[N:16]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc2nc(-c3ccc(NC(=O)OC(C)(C)C)nc3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(NC(=O)OC(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
To a solution of methyl 2-(6-(tert-butoxycarbonylamino)pyridin-3-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (160.0 mg, 0.35 mmol) in methanol (30 mL) was added sodium hydroxide (43.0 mg, 1.06 mmol) and water (1 mL). The reaction mixture was stirred overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (30 mL) and adjusted to pH 6 with HCl (3N). The solids were collected, dried in an oven under reduced pressure to afford 2-(6-(tert-butoxycarbonylamino)pyridin-3-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (53.5 mg, 33%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH:5]([C:10]2[CH:11]=[C:12]([C:17]3[N:18]=[N:19][N:20]([CH3:22])[N:21]=3)[CH:13]=[C:14]([F:16])[CH:15]=2)[C:6]([F:9])([CH3:8])[CH3:7])[CH2:2]1.Br[CH:24]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29].CCN(C(C)C)C(C)C>C(#N)C>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([CH:24]([N:1]2[CH2:2][CH:3]([CH:5]([C:10]3[CH:11]=[C:12]([C:17]4[N:18]=[N:19][N:20]([CH3:22])[N:21]=4)[CH:13]=[C:14]([F:16])[CH:15]=3)[C:6]([F:9])([CH3:8])[CH3:7])[CH2:4]2)[C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[C:28]#[N:29])=[CH:38][CH:37]=1
Reactant: N#Cc1cccc(C(Br)c2ccc(Cl)cc2)c1
Reactant: Cn1nnc(-c2cc(F)cc(C(C3CNC3)C(C)(C)F)c2)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nnc(-c2cc(F)cc(C(C3CN(C(c4ccc(Cl)cc4)c4cccc(C#N)c4)C3)C(C)(C)F)c2)n1

Procedure:
A mixture of 240 mg (0.78 mmol) of 5-[3-(1-azetidin-3-yl-2-fluoro-2-methylpropyl)-5-fluorophenyl]-2-methyl-2H-tetrazole, 530 mg (1.56 mmol) of 3-[bromo(4-chlorophenyl) methyl]benzonitrile, 1.1 mL(6.26 mmol) of DIEA in 8 mL of acetonitrile was heated to reflux for 4 h. Then, it was concentrated. The mixture was poured into 30 mL of CH2Cl2 and 5 mL of aq NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The compounds were purified by silica gel chromatography. Single diastereomers were separated by a chiral AD column; Mass Spectrum: m/e=533 (M+1, 35Cl), 535 (M+1, 37Cl).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[C:19]4[C:18]5[CH2:20][NH:21][CH2:22][CH2:23][C:17]=5[NH:16][C:15]=4[N:14]=[CH:13][CH:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:24](OC(=O)C)(=[O:26])[CH3:25].C(N(CC)CC)C>ClCCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[C:19]4[C:18]5[CH2:20][N:21]([C:24](=[O:26])[CH3:25])[CH2:22][CH2:23][C:17]=5[NH:16][C:15]=4[N:14]=[CH:13][CH:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: c1cc(Nc2ccc3c(c2)OCO3)c2c3c([nH]c2n1)CCNC3
Reactant: CC(=O)OC(C)=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2[nH]c3nccc(Nc4ccc5c(c4)OCO5)c3c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
Benzo[1,3]dioxol-5-yl-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (50 mg, 0.16 mmol), acetic anhydride (18 μL, 0.19 mmol), and triethylamine (67 μL, 0.49 mmol) were dissolved in 1,2-dichloroethane (2 mL), and stirred overnight at room temperature. The reaction mixture was added directly to a Biotage column. The crude product was purified via Biotage eluting with a gradient of 0 to 10% MeOH in DCM. Lyophilization of the purified product provided 56 (25 mg, 44% yield) as a tan powder. LC-MS (M+H=351, obsd.=351).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][C@H:15]3[C@H:17]([NH2:20])[CH2:18][CH2:19][C@H:14]3[CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.C(=O)C(C)(C)C>>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:20][C@@H:17]2[C@@H:15]3[C@@H:14]([CH2:13][N:12]([S:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=4)(=[O:10])=[O:11])[CH2:16]3)[CH2:19][CH2:18]2)=[CH:26][CH:25]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Agent: CC(C)(C)C=O
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N1C[C@H]2CC[C@H](NCc3ccc(F)cc3)[C@H]2C1

Procedure:
The title compound was prepared by substituting (3aR,4S,6aS)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine from Step D of Example 252 for (3aS,4R,6aR)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine and 4-fluorobenzaldehyde for pivalaldehyde in the procedure described in Example 281: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.39-8.40 (bs, 1H), 8.22-8.24 (m, 1H), 7.93-7.95 (m, 1H), 7.75 (t, J=7.8 Hz, 1H), 7.41 (dd, J=8.3, 5.5 Hz, 2H), 7.13 (t, J=8.7 Hz, 2H), 3.71 (d, J=13.3 Hz, 1H), 3.67 (d, J=13.2 Hz, 1H), 3.39 (dd, J=9.8, 3.1 Hz, 1H), 3.16 (dd, J=9.6, 3.0 Hz, 1H), 3.06 (dd, J=9.8, 8.0 Hz, 1H), 2.96 (dd, J=9.6, 7.6 Hz, 1H), 2.85 (q, J=6.1 Hz, 1H), 2.47-2.56 (m, 1H), 2.30-2.35 (m, 1H), 1.93-2.07 (m, 1H), 1.87-1.94 (m, 1H), 1.79-1.87 (m, 1H), 1.29-1.38 (m, 1H), 1.20-1.29 (m, 1H); MS (ESI+) m/z 443 (M+H)+.
Reaction SMILES: N[C@H](C(N1CCC[C@H]1C(N[C@H](C(N1CCC[C@H]1C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(NCC([NH:73][C@H:74]([C:79](N[C@H](C(N)=O)CCSC)=[O:80])[CH2:75][CH:76]([CH3:78])[CH3:77])=O)=O)CC1C=CC=CC=1)=O)CC1C=CC=CC=1)=O)CCC(=O)N)=O)CCC(=O)N)=O)=O)CCCCN)=O)=O)CCCNC(=N)N.P([O-])([O-])([O-])=[O:97]>>[NH2:73][C@H:74]([C:79]([OH:80])=[O:97])[CH2:75][CH:76]([CH3:77])[CH3:78]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCCN)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCNC(=N)N)C(N)=O
Reactant: O=P([O-])([O-])[O-]
Product: CC(C)C[C@H](N)C(=O)O
Reaction time: 0 h

Procedure:
The degradation of H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 (SEQ ID NO: 112) (˜7.4×10−5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing carboxypeptidase A (1 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 2.0×10−2 min−1 and the corresponding half-life calculated to 35 min as previously described.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:40]#[C:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:40]#[C:41][C:42]3[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Reactant: Clc1ccc(C#CBr)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: CN1CCc2c(n(C#Cc3ccc(Cl)cc3)c3ccc(Cl)cc23)CC1
Temperature: 80 °C
Yield: 10 %

Procedure:
A mixture of 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (235 mg, 1 mmol), CuSO4.5H2O (50 mg, 0.2 mmol), 1,10-Phenanthroline (72 mg, 0.4 mmol), K3PO4 (425 mg, 2 mmol) and 1-(bromoethynyl)-4-chlorobenzene (237 mg, 1.1 mmol) in toluene (10 mL) was flushed with nitrogen heated 80° C. for 16 h. The reaction was monitored by LCMS. The reaction mixture was filtered through Celite, washed with DCM. The organic layer was concentrated and purified by column chromatography (silica gel, 60-80% ethyl acetate in hexane) to get 37 mg of product. 1H NMR (CDCl3, HCl salt) δ (ppm): 7.50 (s, 1H) 7.49-7.40 (m, 3H), 7.38-7.32(m, 2H), 7.25-7.20 (d, 1H), 3.22-3.18 (m, 2H), 3.0-2.90 (m, 6H), 2.60 (s, 3H).
Reaction SMILES: [OH-].[Na+].[CH3:3]Cl.[CH3:5][O:6][CH:7]([NH:9][C:10](=[O:12])[CH3:11])[CH3:8]>>[CH3:5][O:6][CH:7]([N:9]([CH3:3])[C:10](=[O:12])[CH3:11])[CH3:8]
Reactant: CCl
Reactant: COC(C)NC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: COC(C)N(C)C(C)=O
Reaction time: 3 h

Procedure:
1,800 g of 50% strength sodium hydroxide solution, 900 g of sodium hydroxide in the form of flakes and 300 g of methyl chloride are initially introduced into a pressure kettle provided with an anchor stirrer. 1,760 g of N-α-methoxyethyl-acetamide and 1,000 g of methyl chloride are uniformly metered in over a period of 3 hours. After a further 3 hours, the kettle is depressurized and the contents are degassed by passing in nitrogen. The reaction product with a lower specific gravity is separated from the inorganic constituents with a higher specific gravity in a centrifuge, and the reaction product is decanted off and distilled in vacuo. 1,804 g (91% of theory) of N-α-methoxyethyl-N-methylacetamide of boiling point1.0 48° are obtained.