Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH2:22])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])C1C=CC=CC=1.[NH:24](C(OCC1C=CC=CC=1)=O)[C@H:25]([C:34]([NH:36][C@H:37]([C:41](O)=[O:42])[CH:38]([CH3:40])[CH3:39])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>>[NH2:24][C@@H:25]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[C:34]([NH:36][C@@H:37]([CH:38]([CH3:39])[CH3:40])[C:41]([NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19][P:10]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)(=[O:11])[OH:9])=[O:42])=[O:35]
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Product: CC(C)[C@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1

Procedure:
The title compound was prepared substantially following the procedures as set forth in Method B, Example 12, and employing ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride and N-Cbz-Tyr-Val-OH as the starting materials, which yielded the title compound as a white powder. 1H NMR (CD3OD, 300 MHz): δ 7.06 (d, 2H), 6.75 (d, 2H), 4.15-4.06 (m, 2H), 3.18-3.10 (m, 2H), 3.0-2.9 (m, 1H), 2.09-2.02 (m, 1H), 1.92-1.88 (m, 2H), 1.86-1.61 (m, 6H), 1.56-1.50 (m, 3H), 1.30-1.17 (m, 4H), 1.06-0.95 (m, 8H). 31P NMR (CD3OD, 300 MHz): δ 41.72. LCMS m/z: [M+H]+=498.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CO.O1CCCC1>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2c(ccn2Cc2ccc(F)cc2)c1-c1ccc(C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)c(C)nc3c2ccn3Cc2ccc(F)cc2)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
A solution of methyl 2-(tert-butoxy)-2-(1-(4-fluorobenzyl)-6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (44 mg, 0.093 mmol) in methanol (0.5 mL) and tetrahydrofuran (THF) (0.500 mL) was treated with LiOH (0.278 mL, 0.556 mmol) and stirred at 60° C. for 18 hours. The reaction was concentrated and purified with reverse phase HPLC (20-100% MeCN/H2O-0.1% TFA) to afford 2-(tert-butoxy)-2-(1-(4-fluorobenzyl)-6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid (30.8 mg, 0.066 mmol, 71.4% yield) as white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.69-7.56 (m, 1 H), 7.43-7.30 (m, 3 H), 7.29-7.25 (m, 2 H), 7.08-6.91 (m, 3 H), 6.24 (d, J=3.6 Hz, 1 H), 5.65-5.38 (m, 3 H), 2.77 (s, 3 H), 2.46 (s, 3 H), 0.94 (s, 9 H); LCMS (m/z) ES+=461 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:24]=[CH:23][C:12]2[CH:13]=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:15][CH2:16][O:17][C:11]=2[CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:24]=[CH:23][C:12]2[CH2:13][CH:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:15][CH2:16][O:17][C:11]=2[CH:10]=1
Reactant: CCOC(=O)C1=Cc2ccc(OCc3ccccc3)cc2OCC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CCOc2cc(O)ccc2C1
Yield: 105.9 %

Procedure:
Ethyl 8-(benzyloxy)-2,3-dihydro-1-benzoxepine-4-carboxylate (3.5 g) was dissolved in ethanol (50 mL), and the solution was subjected to catalytic reduction using 10% palladium on carbon (0.35 g) for 3 days. The catalyst was filtered off, and the solvent of the filtrate was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane) to give the title compound (2.7 g) as an oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:13])[CH3:12])=[CH:7][CH:6]=1)=[O:4].[CH3:14][C:15]1[CH:16]=[C:17]([OH:23])[CH:18]=[C:19]([CH3:22])[C:20]=1[CH3:21].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:14][C:15]1[CH:16]=[C:17]([CH:18]=[C:19]([CH3:22])[C:20]=1[CH3:21])[O:23][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:13])[CH3:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)c1ccc(C(=O)CBr)cc1
Reactant: Cc1cc(O)cc(C)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(OCC(=O)c2ccc(C(C)C)cc2)cc(C)c1C
Yield: 96 %

Procedure:
2-Bromo-1-(4-isopropylphenyl)ethanone obtained in Reference Example 164 (20 g, 82.9 mmol) and 3,4,5-trimethylphenol (10.3 g, 75.4 mmol) were added to a solution of potassium carbonate (12.5 g, 90.5 mmol) in acetonitrile solution (200 mL), and mixture was stirred with heating under reflux for 6 hours. The reaction solution was ice-cooled, was poured into cold water, which was extracted with ethyl acetate. The extract was washed with a saturated brine, and then was dried over sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10). The obtained oily matter was crystallized from hexane-ethyl acetate to obtain 21.5 g (yield 96%) of the title compound. Melting point: 96-98° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][NH:7][C:8]1[N:13]=[CH:12][C:11]([C:14]2[NH:22][C:21]3[C:20](=[O:23])[N:19]([CH2:24][CH2:25][CH3:26])[C:18](=[O:27])[N:17]([CH2:28][CH2:29][CH3:30])[C:16]=3[CH:15]=2)=[CH:10][CH:9]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>C1COCC1>[F:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:40])[N:7]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[NH:22][C:21]4[C:20](=[O:23])[N:19]([CH2:24][CH2:25][CH3:26])[C:18](=[O:27])[N:17]([CH2:28][CH2:29][CH3:30])[C:16]=4[CH:15]=3)=[CH:12][N:13]=2)[CH2:6][CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)=[CH:34][CH:33]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc(NCC4CCCO4)nc3)cc2n(CCC)c1=O
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(-c3ccc(N(CC4CCCO4)C(=O)Nc4ccc(F)cc4)nc3)cc2n(CCC)c1=O
Temperature: 94 °C
Reaction time: 72 h
Yield: 45 %

Procedure:
9b (30 mg) was suspended in THF (2 ml) in a pressure tube, 4-fluorophenyl isocyanate (300 mg) was added and the mixture was stirred at 94° C. for 3 days. After cooling to room temperature, the mixture was evaporated to almost dry and the solid was filtered, washed with ether and purified by column (14 g silica gel, RT Scientific) (CH2Cl2:MeOH=100:0 to 98:2) to give the product (11b) (18 mg). HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH 95%. Retention Time=11.60 min. 1H NMR (DMSO, d6): 0.83-0.95 (m, 6H), 1.53-2.00 (m, 8H), 3.60-4.20 (m, 9H), 6.85 (s, 1H), 7.15 (t, 2H, J=8.7 Hz), 7.51 (m, 3H), 8.30 (dd, 1H, J1=8.7 Hz, J2=2.4 Hz), 8.94 (d, 1H, J=2.4 Hz), 10.69 (s, 1H), 12.50 (s, 1H). MS: m/z 549 (M+H)+.
Reaction SMILES: C(OC(=O)[N:7]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[C:32]3[C:27](=[N:28][CH:29]=[C:30]([Cl:33])[CH:31]=3)[NH:26][CH:25]=2)=[O:23])=[CH:18][N:17]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:33][C:30]1[CH:31]=[C:32]2[C:24]([C:22]([C:19]3[CH:18]=[N:17][C:16]([NH:7][CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[F:15])=[CH:21][CH:20]=3)=[O:23])=[CH:25][NH:26][C:27]2=[N:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1F)c1ccc(C(=O)c2c[nH]c3ncc(Cl)cc23)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(NCc2ccccc2F)nc1)c1c[nH]c2ncc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.9 %

Procedure:
To [5-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-(2-fluoro-benzyl)-carbamic acid tert-butyl ester (584, 0.030 g, 0.062 mmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (1.0 mL, 0.013 mol). The reaction was stirred at room temperature overnight, then poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 2% to 15% methanol in dichloromethane to give the desired compound (P-0404, 2.8 mg, 12%). MS (ESI) [M+H+]+=381.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)SC)[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:26]1([NH2:30])[CH2:29][CH2:28][CH2:27]1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:30][CH:26]2[CH2:29][CH2:28][CH2:27]2)[NH:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CSC(Nc1cc(Cl)cc(Cl)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Reactant: NC1CCC1
Solvent: CC#N
Product: N#CC(=C(Nc1cc(Cl)cc(Cl)c1)NC1CCC1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 49 %

Procedure:
2-(4-Chloro-phenylsulfonyl)-3-(3,5-dichlorophenylamino)-3-methylsulfanyl-2-propenenitrile (0.90 g, 2.1 mmol), cyclobutylamine (0.50 ml, 6.3 mmol) and acetonitrile (2 ml) were stirred for 40 h at 100° C. under nitrogen in a sealed flask. Work-up as described in EXAMPLE 17, 2) gave 0.47 g (49%) of the title compound. 179.5-181.5° C. (EtOAc) 1H NMR (200 MHz, CDCl3): δ=1.65 (m, 2H), 1.95 (m, 2H), 2.1 (m, 2H), 3.65 (sextet, 1H), 6.88 (d, 2H), 7.18 (t, 1H), 7.47 (d, 2H), 7.78 (d, 2H); EI SP/MS: 459 (M+4), 357 (M+2) 455 (M+)
Reaction SMILES: C([NH:11][C@H:12]([C:17]([N:19]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH2:20][C:21]([OH:23])=[O:22])=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])(OCC1C=CC=CC=1)=O.[BrH:30]>C(O)(=O)C>[BrH:30].[NH2:11][C@H:12]([C:17]([N:19]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH2:20][C:21]([OH:23])=[O:22])=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14]
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=O)O)c1cccnc1
Agent: Br
Solvent: CC(=O)O
Product: CC[C@H](C)[C@H](N)C(=O)N(CC(=O)O)c1cccnc1

Procedure:
In a manner described in example 5B, N-carbobenzyloxy-L-isoleucyl-N-(3-pyridyl)-glycine was treated with anhydrous hydrogen bromide in acetic acid to yield L-isoleucyl-N-(3-pyridyl)glycine hydrobromide.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:17][C:18](=[O:21])[NH:19][OH:20])[CH:8]=[CH:9]2)[C:3]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].CS(C)=O.[CH3:31][N:32]=[C:33]=[O:34]>O>[NH2:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:17][C:18](=[O:21])[NH:19][O:20][C:33]([NH:32][CH3:31])=[O:34])[CH:8]=[CH:9]2)[C:3]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)c1c2ccc(CC(=O)NO)ccc-2c(C(=O)OCC)c1N
Reactant: CN=C=O
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1c2ccc(CC(=O)NOC(=O)NC)ccc-2c(C(=O)OCC)c1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 0.2 g (0.55 mmol) of diethyl 2-amino-6-[(hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate, 5 ml of dimethyl sulphoxide and 35 □l (0.6 mmol) of methyl isocyanate is stirred at room temperature for 18 hours. Thereafter, the mixture is diluted with water, extracted with dichloromethane and the extract is chromatographed on silica gel. Elution with ethyl acetate gives 60 mg (36% of theory) of the title compound of m.p. 222-224° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[CH3:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>>[CH3:29][N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:26])([F:25])[F:27])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1
Reactant: Cn1ccnc1
Product: Cn1ccnc1C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12f and 1-methylimidazole
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[NH:17][N:18]=[C:19]4[C:24]=3[CH2:23][CH2:22][C:21]3[CH:25]=[C:26]([CH:29]=C)[CH:27]=[CH:28][C:20]4=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CC[O:35]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[C:1]1([C:7]2[C:11]([C:12]([F:13])([F:14])[F:15])=[C:10]([C:16]3[NH:17][N:18]=[C:19]4[C:24]=3[CH2:23][CH2:22][C:21]3[CH:25]=[C:26]([CH:29]=[O:35])[CH:27]=[CH:28][C:20]4=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=Cc1ccc2c(c1)CCc1c-2n[nH]c1-c1onc(-c2ccccc2)c1C(F)(F)F
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc2c(c1)CCc1c-2n[nH]c1-c1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 109 %

Procedure:
To 3-phenyl-4-(trifluoromethyl)-5-(7-vinyl-4,5-dihydro-2H-benzo[g]indazol-3-yl)isoxazole (Preparation 22B, 0.15 g, 0.368 mmol) in THF (2 mL) were added sequentially N-methylmorpholine N-oxide (50% aq., 0.17 mL, 0.368 mmol) and osmium tetroxide (4% aq. 0.058 mL, 7.36 μmol) at room temperature under a nitrogen atmosphere. The reaction was stirred at room temperature for 45 min. and sodium periodate (0.118 g, 0.552 mmol) in water (1 mL) was added over a period of 1 min. at room temperature. The milky heterogeneous reaction mixture was stirred at room temperature for 45 min., concentrated, and partitioned between ethyl acetate (20 mL) and water (10 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated to yield 3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydro-2H-benzo[g]indazole-7-carbaldehyde (0.164 g, 0.401 mmol, quantitative yield) as a dark brown oil. LC/MS M+1=410.1.
Reaction SMILES: [O:1]1[C:6]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:8]([O:10]CC)=[O:9])=[CH:5][S:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[O:1]1[C:6]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:8]([OH:10])=[O:9])=[CH:5][S:4][CH2:3][CH2:2]1
Reactant: CCCCCCON=C(C(=O)OCC)C1=CSCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCON=C(C(=O)O)C1=CSCCO1
Temperature: 25 °C
Reaction time: 43 h
Yield: 25.4 %

Procedure:
Ethyl 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-hexyloxyiminoacetate (mixture of syn isomer and anti isomer, 186.8 g.), 1N aqueous solution of sodium hydroxide (472 ml.) and methanol (1.8 l.) were stirred at room temperature for 35 minutes and the insoluble substance was removed by filtration. The filtrate was stirred at room temperature for 43 hours and treated in a similar manner to that of Example I-(iii) to give 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-hexyloxyiminoacetic acid (syn isomer, 43 g.).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]([O:23][C:24]([CH2:26][CH2:27][C:28]1[O:29][C:30]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:31]([C:33](O)=[O:34])[N:32]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24](=[O:25])[CH2:26][CH2:27][C:28]1[O:29][C:30]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[C:31]([C:33](=[O:34])[NH:18][C:16]2[CH:15]=[N:14][N:13]([CH2:12][C:10]3[O:11][C:7]([C:2](=[O:6])[CH3:1])=[CH:8][CH:9]=3)[N:17]=2)[N:32]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: CC(C)(C)OC(=O)CCc1nc(C(=O)O)c(-c2ccccc2)o1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(CCC(=O)OC(C)(C)C)oc3-c3ccccc3)n2)o1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-(2-tert-butoxycarbonyl-ethyl)-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([C@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:20]>CO>[C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@H:16]([OH:17])[CH2:18][NH2:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.5 %

Procedure:
To a solution of ((S)-(S)-1-oxiranyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester (D101) (25 g, 95.1 mmol, 1 equiv)) in MeOH (350 ml) was added aqueous ammonia (32% w/w, 180 ml, 3.2 mol, 3.3 equiv). The resulting mixture was stirred at room temperature for 16 h then concentrated in vacuo to give ((1S,2R)-3-amino-1-benzyl-2-hydroxy-propyl)-carbamic acid tert-butyl ester (D102) (25.2 g, 95%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl.C[O-].[Na+]>>[O:17]1[CH2:16][CH:15]1[CH2:13][O:1][C:2]1[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: OCc1cc(O)c2cc[nH]c2c1
Reactant: ClCC1CO1
Agent: C[O-]
Agent: [Na+]
Product: OCc1cc(OCC2CO2)c2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.3 g. of the 4-hydroxy-6-hydroxymethyl-indole thus prepared were dissolved in 30 ml. epichlorohydrin. To this solution were added dropwise, while stirring at ambient temperature, over the course of 1 hour, 20 ml. 2N sodium methylate solution. After about 5 hours, the starting material had reacted. The solution was evaporated in a vacuum and the residue was mixed with water, as well as with a mixture of diethyl ether and ethyl acetate. The organic phase was shaken out several times with water, subsequently dried, treated with active charcoal and evaporated. The crude 4-(2,3-epoxypropoxy)-6-hydroxymethyl-indole thus obtained (about 5 g. of a brownish oil) contains, as by-product, some 4-(2-hydroxy-3-chloropropoxy)-6-hydroxymethyl-indole but was further used without further purification.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CN(C)C=O>[CH2:10]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCBr
Reactant: OCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCOCCCCO
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 7.1 ml of 1,4-butanediol in 40 ml of dimethylformamide, 1.8 gms of sodium hydride are added; and the reaction mixture is stirred at room temperature for 15 minutes. To this solution is added 7.6 ml of bromononane and the reaction mixture is stirred at room temperature for 44 hours. The reaction mixture is then partitioned between ethyl acetate and water and the organic layer is washed with brine, dried over sodum sulfate, filtered, and concentrated under vacuum. The residue is flash chromatographed with an 8/1 ratio of ethyl acetate and hexane to give 4-nonyloxybutanol as a clear colorless liquid.
Reaction SMILES: [CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19](O)=[O:20])=[CH:15][N:16]=1)=[CH:8]2.[N:30]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>O.CN(C)C=O>[CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19]([NH2:30])=[O:20])=[CH:15][N:16]=1)=[CH:8]2
Reactant: On1nnc2ccccc21
Reactant: CN(c1cccc2cc(-c3ncc(CCC(=O)O)s3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cccc2cc(-c3ncc(CCC(N)=O)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 127.2 %

Procedure:
To a mixture of 3-(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-5-yl)propanoic acid (1.15 g), 1H-1,2,3-benzotriazol-1-ol (0.54 g) and N,N-dimethylformamide (14 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.77 g) at room temperature. The mixture was stirred at room temperature for 1 hr, and 28% aqueous ammonia (1.0 mL) was added. The reaction mixture was stirred at room temperature overnight, and water was added. The resulting crystals were filtrated, washed with water and ethyl acetate, and dried to give the title compound (1.46 g, yield 98%) as yellow crystals. melting point 246-247° C.
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][CH:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:6][CH2:7][CH2:8][N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:10](=[O:12])[CH3:11].C(O)(=O)C>CCOCC>[OH:4][CH:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:6][CH2:7][CH2:8][N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:3])=[O:20])[C:10](=[O:12])[CH3:11]
Reactant: C=[N+]=[N-]
Reactant: CCCCCC(O)CCCN(CCCCCCC(=O)O)C(C)=O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCCC(O)CCCN(CCCCCCC(=O)OC)C(C)=O
Reaction time: 4 h

Procedure:
A solution of diazomethane (approx. 2.5 g., 0.06 mole) in ether (100 ml.) is mixed with a solution of 7-[N-(4-hydroxynonyl)acetamido]heptanoic acid (9.8 g., 0.03 mole) (Example 1, Step C) in ether (50 ml.). The resulting solution is allowed to stand 4 hours at room temperature. Acetic acid is then added to destroy the excess diazomethane and the solution is washed with dilute sodium bicarbonate solution and water and dried over sodium sulfate. Evaporation of volatile materials at reduced pressure yields methyl 7-[N-(4-hydroxynonyl)acetamido]-heptanoate as a viscous oil.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)[CH3:2].[CH3:12][N:13]([CH3:15])[NH2:14].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH3:12][N:13]([N:14]=[C:1]([CH3:2])[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:15]
Reactant: CCOC(=O)CCCC(C)=O
Reactant: CN(C)N
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCC(C)=NN(C)C
Yield: 61.4 %

Procedure:
15.8 g (100 mmol) of ethyl 4-acetyl-butanoate and 6 g (100 mmol) of anhydrous N,N-dimethyl hydrazine in 50 ml of toluene containing 0.1 ml of trifluoroacetic acid were heated at 70° C. for 5 hours. The mixture was then washed 20 with water, dried over anhydrous sodium sulfate and evaporated to give 12.3 g (79% yield) of the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[C:21]([F:30])=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24]([CH3:29])=[CH:23]4)=[CH:14][N:15]=[N:16]2)=[CH:11][C:10]=1[O:31][CH3:32])C1C=CC=CC=1.C([O-])=O.[NH4+].O>[Pd].CN(C=O)C>[F:30][C:21]1[C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:31][CH3:32])[CH:11]=3)[N:16]=[N:15][CH:14]=2)=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[C:24]([CH3:29])[NH:25]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1O
Yield: 75.6 %

Procedure:
A solution of 7-benzyloxy-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxycinnoline (500 mg, 1.17 mmol), (prepared as described in Example 3), ammonium formate (740 mg, 11.7 mmol), 10% palladium on charcoal (100 mg) and water (700 μl) in DMF (10 ml) was stirred for 2 hours at ambient temperature. The mixture was filtered on diatomaceous earth and the filtrate was evaporated under vacuum. The residue was triturated with a mixture of ether and pentane (1/1). The solid was filtered, washed with pentane and dried under vacuum to give 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (300 mg, quant.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[CH3:28][NH:29][CH3:30]>>[CH3:28][N:29]([CH3:30])[C:24]([CH2:25][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[N:7]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:6]=1[C:22]([OH:23])=[O:27])=[O:26]
Reactant: CNC
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Product: CN(C)C(=O)Cc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccc(F)cc12

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from example 34.1.) was ring opened with dimethylamine at 22° C. to give the title compound as a white solid. MS: 403.5 ([M−H]−).