Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]([NH:31][C:32](=[O:38])[O:33][C:34](C)([CH3:36])[CH3:35])[C@@H:9]([OH:30])[CH:10]([NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39](=O)([O:47]C1C=CC([N+]([O-])=O)=CC=1)[O:40]C1COCOC1.C(N(C(C)C)CC)(C)C.C(#N)C>FC(F)(F)C(O)=O>[CH2:1]([C@H:8]([NH:31][C:32](=[O:38])[O:33][CH:34]1[CH2:35][O:47][CH2:39][O:40][CH2:36]1)[C@@H:9]([OH:30])[CH:10]([NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:20])=[O:21])[O:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1COCOC1
Reactant: COc1ccc(S(=O)(=O)NC(OC2CCCCC2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)NC(OC2CCCCC2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC2COCOC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 19.2 %

Procedure:
tert-butyl N-((1S,2R)-1-benzyl-3-(cyclohexyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate (0.09 mmol, 50 mg) was stirred in 1 mL trifluoroacetic acid (TFA) at room temperature for 5 hours. The TFA was removed under vacuum, and the resulting residue was dissolved in ethyl acetate, washed with 5% aq. potassium carbonate solution, brine, dried over magnesium sulfate, and concentrated to a residue. The resulting free amine, 1,3-dioxan-5-yl 4-nitrophenyl carbonate (0.09 mmol, 25 mg), diisopropylethylamine (0.14 mmol, 0.024 mL), a crystal of N,N-dimethylaminopyridine, 4 Å molecular sieves and acetonitrile (0.5 mL) were combined and stirred at room temperature for 20 hours. The reaction solution was concentrated to a residue, dissolved in ethyl acetate, washed with 1N HCl, 5% aq. potassium carbonate solution, brine, dried over magnesium sulfate, and concentrated under vacuum. The crude residue was purified by silica gel chromatography (2:1 hexanes/ethyl acetate) and crystallization from ether and hexanes to yield 10 mg (19%) of white solid. Rf=0.2 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ 7.69 (2H,d), 7.29-7.18 (6H,m), 6.96 (2H,d), 5.01-4.93 (1H, m), 4.93-4.85 (1H,m), 4.74-4.70 (1H,m), 4.51-4.45 (1H,m), 4.22-4.11 (1H,m), 3.95-3.72 (7H,m), 3.86 (3H,s), 3.00-2.80 (3H,m), 2.10-1.97 (2H,m), 1.79-1.67 (2H,m), 1.61-1.53(2H,m), 1.38-1.02 (6H,m); MS (ESI): M+H=580.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](C=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=Cc1ccc2[nH]ccc2c1
Solvent: CN(C)C=O
Product: c1ccc2[nH]ccc2c1

Procedure:
Indole-5-carboxaldehyde (1.45 g) was dissolved into 8.6 mL of dry DMF in a dried and cooled 3 100 mL 3-necked round bottom flask.
Reaction SMILES: CO[C:3](=[O:17])[C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]#[N:16])=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=O.[C:18]1([CH2:30][C:31]([NH2:33])=[O:32])[C:28]2=[C:29]3[C:24](=[CH:25][CH:26]=[CH:27]2)[CH2:23][CH2:22][CH2:21][N:20]3[CH:19]=1>>[C:18]1([C:30]2[C:31](=[O:32])[NH:33][C:3](=[O:17])[C:4]=2[C:6]2[C:14]3[C:9](=[CH:10][C:11]([C:15]#[N:16])=[CH:12][CH:13]=3)[NH:8][CH:7]=2)[C:28]2=[C:29]3[C:24](=[CH:25][CH:26]=[CH:27]2)[CH2:23][CH2:22][CH2:21][N:20]3[CH:19]=1
Reactant: NC(=O)Cc1cn2c3c(cccc13)CCC2
Reactant: COC(=O)C(=O)c1c[nH]c2cc(C#N)ccc12
Product: N#Cc1ccc2c(C3=C(c4cn5c6c(cccc46)CCC5)C(=O)NC3=O)c[nH]c2c1

Procedure:
Beginning with 6-cyanoindole-3-glyoxylic acid methyl ester and 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.[CH2:22]1[O:24][CH2:23]1.[CH3:25][S:26]([OH:29])(=[O:28])=[O:27]>CO>[CH3:25][S:26]([OH:29])(=[O:28])=[O:27].[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[C:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][OH:24])[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1
Reactant: C1CO1
Reactant: Clc1ccc2c(c1)C(=C1CCNCC1)c1ccccc1O2
Agent: CS(=O)(=O)O
Solvent: CO
Product: OCCN1CCC(=C2c3ccccc3Oc3ccc(Cl)cc32)CC1
Temperature: 40 °C

Procedure:
A solution of 4-(2-chloro-9-xanthenylidene)piperidine (1.5 g., 5 mmol) in 50 ml. of methanol at 0° C. is treated with ethylene oxide (5 ml.). The solution is allowed to come to 23° C., then heated to 40° C. for one hour and the solvent evaporated. The residue is dissolved in acetonitrile and treated with one equivalent of methanesulfonic acid to give 4-(2-chloro-9-xanthenylidene)-1-(β-hydroxyethyl)-piperidine methanesulfonate, m.p. 242°-244° C.
Reaction SMILES: C([O:3][C:4]([C@:6]1([NH2:30])[C@H:11]([S:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)(=[O:14])=[O:13])[CH2:10][C@@H:9]2[C@H:7]1[C@@:8]2([F:29])[C:24]([O:26]CC)=[O:25])=[O:5])C.[OH-].[Na+]>S(=O)(=O)(O)O>[NH2:30][C@@:6]1([C:4]([OH:5])=[O:3])[C@H:11]([S:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)(=[O:14])=[O:13])[CH2:10][C@@H:9]2[C@H:7]1[C@@:8]2([F:29])[C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)[C@@]1(N)[C@H]2[C@@H](C[C@H]1S(=O)(=O)Cc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1S(=O)(=O)Cc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
108 mg of (1R,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfonyl)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester was stirred in 1.08 mL of 60% sulfuric acid (W/V %) for 3 days at 130° C. The reaction solution was ice-cooled, and neutralized with an aqueous solution of 5N sodium hydroxide. The mixture was stirred for 1 hour at room temperature, and then purified by ion exchange resin (AG 50W-X8 Resin (H form), eluent: water, a 30% aqueous solution of tetrahydrofuran, and a 10% aqueous solution of pyridine), thereby yielding 76 mg of (1R,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfonyl)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:46])[CH2:30][CH2:31][N:32]([S:40]([CH:43]([CH3:45])[CH3:44])(=[O:42])=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1>>[CH3:46][N:29]([CH3:28])[CH2:30][CH2:31][N:32]([C:33]1[CH:34]=[CH:35][C:36]([NH:39]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:37][CH:38]=1)[S:40]([CH:43]([CH3:45])[CH3:44])(=[O:42])=[O:41]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CC(C)S(=O)(=O)N(CCN(C)C)c1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCN(C)C)S(=O)(=O)C(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(2-dimethylamino-ethyl)-N-isopropylsulphonyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C30H34N4O5S
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH2:14][OH:15])[N:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([O:15][CH2:14][CH2:13][O:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[N:11][C:2]([CH3:1])=[N:3]2)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ncc2c(OCCO)cccc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ncc2c(OCCOS(C)(=O)=O)cccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a solution of 2-(2-methylquinazolin-5-yloxy)ethanol (0.330 g, 1.62 mmol) in dichloromethane (20 mL) and triethylamine (0.34 mL, 2.43 mmol) was added methane sulfonyl chloride (0.14 mL, 1.78 mmol) dropwise. The reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was diluted with further dichloromethane and partitioned with saturated NaHCO3 aq. The organic phase was washed with brine, dried (MgSO4) and evaporated in vacuo to give the title compound as a cream solid (0.452 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][C:7]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cnc2cc(Cl)ccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2cc(Cl)ccc2c1Cl

Procedure:
A mixture of 30 g. of 7-chloro-4-hydroxyquinoline-3-carboxylic acid, ethyl ester, m.p. 299°-301°, (0.12 mol.) and 250 ml. of phosphorus oxychloride is refluxed for 4.5 hours. After removing the excess phosphorus oxychloride, the residue is triturated with water and dissolved in ether. The ethereal solution is washed with aqueous sodium carbonate (5%) and water, dried with sodium sulfate and the solvent is removed. The residual 4,7-dichloroquinoline-3-carboxylic acid, ethyl ester is triturated with petroleum ether (40°-60°), filtered off and dried; yield: 22 g. (68%); m.p. 81°-82°.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5](N)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.N([O-])=O.[Na+].NC(N)=O.[I-:20].[K+]>S(=O)(=O)(O)O.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([I:20])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: [I-]
Agent: NC(N)=O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)ccc1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
To a suspension of 4-chloro-2-nitroaniline (5.18 g) in a 12 N sulphuric acid solution (60 ml) cooled to 10° a solution of sodium nitrite (2.76 g) in sulphuric acid (20 ml) and polyphosphoric acid (40 ml) were sequentially added. The reaction mixture was stirred for 3 hrs at r.t., then poured into crushed ice and urea was added until gas evolution ceases. The resulting solution was treated with an aqueous solution (20 ml) of potassium iodide (7.47 g) and heated at 70° for 1 h. The mixture was diluted with brine and extracted with EA then the organic phase was washed with brine, dried and concentrated in vacuo. The residue was purified by flash column chromatography (CH/EA=100/0 to 95/5 as eluant), obtaining the title compound as yellow solid (7.96 g). m.p. 55-56° C.
Reaction SMILES: C([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][C:30]([F:33])([F:32])[F:31])=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.C(O)CO.[OH-].[K+].CCOC(C)=O>O>[F:33][C:30]([F:31])([F:32])[O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:18]1[C:19]2[C:20]3[CH2:21][CH2:22][NH:9][CH2:10][CH2:11][C:12]=3[NH:13][C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cccc(-c4ccccc4OC(F)(F)F)c3c2CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3
Temperature: 170 °C
Reaction time: 1.5 h
Yield: 68.8 %

Procedure:
3-Benzoyl-10-[2-(trifluoromethoxy)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.55 g, 3.44 mmol) and ethylene glycol (50 mL) were combined and heated to 170° C. KOH (3.91 g, 69.7 mmol) was added and the reaction mixture was stirred at 170° C. for 1.5 h. The reaction mixture was cooled to rt and was combined with EtOAc (100 mL) and H2O (300 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to give crude product (5.22 g). The crude product was chromatographed (SiO2 100 g, eluted with 90:10:1 CH2Cl2:CH3OH:conc. NH4OH) to give 10-[2-(trifluoromethoxy)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.82 g) in 69% yield. 1H NMR (400 MHz, CD3OD) δ 2.24-2.36, 2.70-2.76, 2.95-3.03, 6.75, 7.06, 7.30, 7.36-7.42, 7.46-7.51; MS (ESI+) for C19H17F3N2O m/z 347.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1.[C:12]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1.CCCCCC>ClCCl>[CH2:10]([O:9][C:7]([C:4]1[S:3][C:2]([NH:1][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:16]([C:12]([CH3:14])([CH3:13])[CH3:15])=[CH:17][CH:18]=2)=[N:6][CH:5]=1)=[O:8])[CH3:11]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)c1cnc(N)s1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CCOC(=O)c1cnc(NC(=O)c2ccc(C(C)(C)C)cc2)s1
Yield: 88.2 %

Procedure:
A solution of ethyl 2-aminothiazole-5-carboxylate (0.52 g, 3.0 mmol), 4-t-butylbenzoyl chloride (1.3 mL, 6.7 mmol) and pyridine (1.2 mL) in dichloromethane (10 mL) was stirred at 0° C. for 1.25 h. It was then diluted with dichloromethane and washed with aqueous HCl (1 N) twice, saturated aqueous sodium bicarbonate, and brine. After drying over sodium sulfate, filtration and concentration in vacuo gave a burgundy oil. Trituration with hexane afforded the desired amide as a light tan solid (0.88 g, 88% yield): LC/MS RT=3.85 min; mass spectrum (M+H)+=333.16. B. 4-(1,1-Dimethylethyl)-N-[(5-hydroxymethyl)thiazol-2-yl]benzamide
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][Si](C)(C)C)[C:5]([NH2:14])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[C:8]([C:6]1[C:5]([NH2:14])=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)#[CH:9]
Reactant: Cc1ccc(N)c(C#C[Si](C)(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1nc(C)ccc1N
Temperature: 0 °C
Reaction time: 4 h
Yield: 75.2 %

Procedure:
(6-methyl-2-trimethylsilanylethynyl-pyridin-3-yl)amine (330 mg, 1.61 mmol) was dissolved in MeOH (3 ml) and cooled to 0° C., to the resulting solution was added 1 M solution of NaOH (1.6 ml). The ice bath was removed and the reaction mixture was stirred at room temperature for 4 h. 90 μl of acetic acid was added. The reaction mixture was partially concentrated and the residue was extracted with ethyl acetate. The organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated to yield 160 mg (1.21 mmole, 75%) of (2-ethynyl-6-methyl-pyridin-3-yl)amine as a brown solid which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14](=[N:16]O)[NH2:15].B(F)(F)F.CCOCC>O1CCOCC1.ClCCl>[Cl:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]1[N:16]=[C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])[O:5][N:15]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: NC(=NO)c1ccccc1Cl
Agent: FB(F)F
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: ClCCl
Product: Clc1ccccc1-c1noc(-c2ccccc2Cl)n1
Yield: 53.9 %

Procedure:
2-Chlorobenzoyl chloride (2.6 g) was dissolved in dioxan (90 ml) and 2-chlorobenzamidoxime (2.5 g) was added with stirring, followed by boron trifluoride etherate (0.2 ml). The solution was heated at reflux for 18 hours and was run down. The product was taken up in dichloromethane, and the solution was washed successively with saturated aqueous sodium bicarbonate, water, and saturated sodium chloride solution. It was then dried over magnesium sulphate, run down and recrystallised from ethanol to yield 2.3 g of desired product, mp 91°-92° C.
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:5][N:4]([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12](O)=[O:13])=[N:10][CH:11]=2)[CH2:3]1.[NH2:22][C:23]1([CH2:27][C:28]([NH:30][CH3:31])=[O:29])[CH2:26][O:25][CH2:24]1>>[F:21][C:2]1([F:1])[CH2:3][N:4]([C:6]2[C:7]([O:15][CH2:16][C:17]([F:18])([F:19])[F:20])=[CH:8][C:9]([C:12]([NH:22][C:23]3([CH2:27][C:28]([NH:30][CH3:31])=[O:29])[CH2:26][O:25][CH2:24]3)=[O:13])=[N:10][CH:11]=2)[CH2:5]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(N2CC(F)(F)C2)cn1
Reactant: CNC(=O)CC1(N)COC1
Product: CNC(=O)CC1(NC(=O)c2cc(OCC(F)(F)F)c(N3CC(F)(F)C3)cn2)COC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (Example 223b) and 2-(3-aminooxetan-3-yl)-N-methyl-acetamide (example 231a) as starting materials and isolated (25 mg, 43%); MS (ESI, m/z): 439.5 (M+H+).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][PH:18](=[O:22])[O:19]CC)[CH2:10]1)=O)(C)(C)C>Cl>[NH2:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][PH:18](=[O:19])[OH:22])[CH2:10]1
Reactant: CCO[PH](=O)CCCC[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Product: N[C@@H]1CC[C@H](CCCC[PH](=O)O)C1

Procedure:
A solution of (±)-cis-ethyl [3-(t-butyloxycarbonyl)aminocyclopentanyl]butylphosphinate (14) (1.07 g, 3.21 mmol) was dissolved in aqueous HCl (6 M, 40 cm3) and the solution heated at reflux for 30 hours. After cooling, the solution was evaporated to dryness under reduced pressure. The residue was dissolved in water (10 cm3) and applied to an ion exchange column (Dowex 50, H+). The column was eluted with water until the eluate was colourless and the pH 7. On further elution with aqueous pyridine (1 M), ninhydrin positive fractions were collected and the solvent removed in vacuo. Residual traces of pyridine were removed by repeatedly redissolving the compound in water (20 cm3) and re-evaporating (3 times). Recrystallisation from ethanol/acetone followed by drying gave the desired title compound (15) as an off white solid (450 mg, 68%, m.p. (dec.) 180-183° C.): 1H-NMR (300 MHz, D2O) δH 0.68 (3H, 2×d, J=6.9 and 7.2 Hz, PCH2CH2CH2CH3),1.02-2.43 (13H, m, C(1)—H, C(2)—H, C(2)—H′, C(4)—H, C(4)—H′, C(5)—H and C(5)—H′, PCH2CH2CH2CH3, PCH2CH2CH2CH3,PCH2CH2CH2CH3),3.56 (1H, m, C(3)—H); 13C-NMR (75 MHz, D2O) δC 13.46 (s, PCH2CH2CH2CH3), 24.11 and 24.31 (d, 3JPC=15.17 Hz, PCH2CH2CH2CH3), 24.31 (s, C(5)), 24.53 and 24.56 (d, 2JPC=2.87 Hz, PCH2CH2CH2CH3), 27.96 and 29.17 (d, JPC=91.32 Hz, PCH2CH2CH2CH3),31.12 and 31.20 (d, 2JPC=6.3 Hz, C(2)), 31.95 (s, C(4)), 36.14 and 37.38 (d, JPC=93.33 Hz, C(1)), 52.97 and 52.88 (d, 3JPC=7.15 Hz, C(3)); 31P-NMR (121MHz, D2O) δP 50.74; MS (ESI) m/z 205.9 (37%) (MH+), 411.3 (100), 484.3 (14), 102.4 (12).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8](OC)=[O:9])=[N:6][CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1cnc(Cl)cn1
Reaction time: 0.17 h
Yield: 35.6 %

Procedure:
In tetrahydrofuran (66 mL) was dissolved methyl 5-chloropyrazine-2-carboxylate (3.3 g), and 1M diisobutylaluminum hydride/hexane solution (38.3 mL) was added dropwise to the solution under nitrogen atmosphere at −70° C. or lower over 10 minutes, and the resulting mixture was further stirred for 10 minutes. At −60° C. or lower, 1M diisobutylaluminum hydride/hexane solution (31.3 mL) was added dropwise to the mixture over 20 minutes, and the mixture was further stirred at −70° C. or lower for 1 hour. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and after stirring at room temperature, filtered with Celite. The filtrate was extracted with ethyl acetate, washed with a saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 80:20) to obtain 5-chloropyrazine-2-carbaldehyde (970 mg).
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5]1[CH:30]=[C:29]([CH3:31])[C:8](C[P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:7]([CH3:32])[C:6]=1[CH3:33])[CH3:3].CC1C(C)=CC(C)=CC=1O>>[CH2:2]([O:4][C:5]1[CH:30]=[C:29]([CH3:31])[CH:8]=[C:7]([CH3:32])[C:6]=1[CH3:33])[CH3:3]
Reactant: CCOc1cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1C
Agent: Cc1cc(C)c(C)c(O)c1
Agent: [Cl-]
Product: CCOc1cc(C)cc(C)c1C

Procedure:
The 4-ethoxy-2,3,6-trimethyl-benzyl-triphenylphosphonium chloride employed as the starting material is prepared by the procedure described in Example 18 by alkylation of 2,3,5-trimethylphenol to give 2,3,5-trimethyl-phenyl ethyl ether (melting point 93°-95° C.), by haloformylation of the ether obtained to give 4-ethoxy-2,3,6-trimethyl-benzyl chloride (melting point 63°-64° C.) and by reaction of the latter compound with triphenylphosphine.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])([OH:3])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH:43]1([NH2:48])[CH2:47][CH2:46][CH2:45][CH2:44]1>C(#N)C>[CH:43]1([NH:48][C:1](=[O:3])[CH2:4][N:5]2[CH2:27][CH2:26][CH2:25][C@H:6]2[C:7]([N:9]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])[CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: NC1CCCC1
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)NC1CCCC1
Yield: 79.9 %

Procedure:
A -5° C. solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (0.212 g, 0.56 mmol, 1.0 eq), and triethylamine (96 uL, 65 mg, 0.65 mol, 1.15 eq), in acetonitrile (10 mL) was treated with isobutyl chloroformate (77 uL, 86 mg, 0.59 mmol, 1.05 eq) followed by cyclopentylamine (111 uL, 96 mg, 1.13 mmol, 2.0 eq). Workup as above provided 198 mg (79%) of L-isoleucine, N-[1-[2-(N-cyclopentylamino)-2-oxoethyl]-L-prolyl] benzylamide.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[N:5][CH:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.[CH:27](OC(=O)C)=[O:28]>ClCCl>[CH:27]([NH:1][CH2:2][C:3]1[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[N:5][CH:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)=[O:28]
Reactant: CC(=O)OC=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cccs3)nc2CN)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cccs3)nc2CNC=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
A 50 mL round bottom flask was charged with tert-butyl 4-(3-(aminomethyl)-5-(thiophen-2-yl)pyrazin-2-yl)piperazine-1-carboxylate (0.70 g, 1.86 mmol), acetic formic anhydride (270 mg, 3.72 mmol) and dichloromethane (20 mL). The resulting mixture was stirred at room temperature overnight. Work-up: the reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 50% EtOAc in petroleum ether, to afford 490 mg (65%) of the product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C1COCC1>[CH2:25]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:17][CH:16]=2)[CH:12]=[CH:13]1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: CCCCCCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCCCCn1ccc2cc(OCc3ccccc3)ccc21
Reaction time: 3 h

Procedure:
N-Octyl-5-benzyloxyindole was prepared by general method A. 5-Benzyloxyindole (500 mg, 2.24 mmol) was dissolved in THF (20 mL) and treated with 1M KOtBu in THF (3.81 mL, 3.8 mmol). After stirring for 3 hours, 1-bromooctane (0.39 mL, 2.24 mmol) was added and the reaction mixture was stirred for an additional 24 hrs. Standard aqueous workup and purification by silica gel chromatography, eluting with 3:1 hexane/ethyl acetate, provided N-octyl-5-benzyloxyindole. 1H NMR (200 MHz, CDCl3) δ 7.68 (m, 7H), 7.35 (m, 2H), 6.78 (d, J=2.9 Hz, 1H), 5.40 (s, 2H), 4.23 (t, J=7.0 Hz, 2H), 2.05 (broad t, J=6.5 Hz, 2H), 1.62 (broad s, 10H), 1.31 (t, J=6.2 Hz, 3H)