Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([O:23][CH3:24])[CH:19]=3)[NH:14][C:13]=2[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CN(C)C=O>[C:1]([O:9][CH:10]1[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([O:23][CH3:24])[CH:19]=3)[N:14]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:13]=2[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2[nH]c3c(c2cc1OC)CC(OC(=O)c1ccccc1)CC3
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2c(c3cc(OC)c(OC)cc31)CC(OC(=O)c1ccccc1)CC2

Procedure:
The 3-benzoyloxy-6,7-dimethoxy-9-carbethoxymethyl-1,2,3,4-tetrahydrocarbazole was prepared by following an alkylation procedure similar to that described in Example 11 but using 17.6 g. of 3-benzoyloxy-6,7-dimethoxy-1,2,3,4-tetrahydrocarbazole (see Example 4) and 2.14 g. of sodium hydride (56% in mineral oil) in 200 ml. of dimethylformamide, and 8.4 g. of ethyl bromoacetate. The crude product in ethyl acetate was filtered through alumina, the filtrate was evaporated to dryness under reduced pressure and the residue was recrystallized from ethyl acetate to give 3-benzoyloxy-6,7-dimethoxy-9-carbethoxymethyl-1,2,3,4-tetrahydrocarbazole, m.p. 125°-127° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[CH2:9]2)=[CH:6][C:5]([C:22]#[N:23])=[CH:4][C:3]=1[NH:24][C:25]1[N:30]=[C:29]([N:31]([CH:41]2[CH2:43][CH2:42]2)CC2C=CC(OC)=CC=2)[C:28]2=[N:44][CH:45]=[C:46]([C:47]#[N:48])[N:27]2[N:26]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[O:15])[CH2:9]2)=[CH:6][C:5]([C:22]#[N:23])=[CH:4][C:3]=1[NH:24][C:25]1[N:30]=[C:29]([NH:31][CH:41]2[CH2:43][CH2:42]2)[C:28]2=[N:44][CH:45]=[C:46]([C:47]#[N:48])[N:27]2[N:26]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCOC(C(=O)N5CCOCC5)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CCOC(C(=O)N3CCOCC3)C2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.4 %

Procedure:
To a round bottom flask charged with 2-((2-chloro-5-cyano-3-(2-(morpholine-4-carbonyl)morpholino)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (64.9 mg, 0.097 mmol) in dichloromethane (485 μl) was added anisole (21.19 μl, 0.194 mmol), followed by TFA (224 μl, 2.91 mmol). The reaction mixture was stirred at room temperature for 16 h. Additional TFA (224 μl, 2.91 mmol) was added. Stir at room temperature ON. Additional TFA (224 μl, 2.91 mmol) was added and the reaction mixture was stirred at room temperature ON. Excess TFA was removed by concentration in vacuo. The crude residue was taken up in methanol and free based using a Phenomenex Strata 1 g SCX column. The column was flushed with 3 column volumes methanol and 3 column volumes 3.5 N ammonia/methanol. The ammonia layers were concentrated in vacuo. The crude material was purified by neutral phase preparatory LC/MS chromatography to provide (+/−)2-((2-chloro-5-cyano-3-(2-(morpholine-4-carbonyl)morpholino)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (13 mg).
Reaction SMILES: [CH3:1][C:2]12[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14][CH:3]1[N:4]1[CH2:13][CH2:12][O:11][C:6]3[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]1=3.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[CH3:1][C:2]12[CH2:17][NH:16][CH2:15][CH2:14][CH:3]1[N:4]1[CH2:13][CH2:12][O:11][C:6]3[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]1=3
Reactant: CC(C)(C)OC(=O)N1CCC2N3CCOc4cccc(c43)C2(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC12CNCCC1N1CCOc3cccc2c31
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.5 %

Procedure:
tert-Butyl 6b-methyl-1,2,6b,9,10,10a-hexahydro[1,4]-oxazino[2,3,4-hi]pyrido[4,3-b]indole-8(7H)-carboxylate (0.0711 g, 0.215 mmol) was dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (0.50 mL, 0.46 mmol) was added and the reaction mixture was stirred in a sealed reaction vessel for 4 hours at room temperature. The reaction mixture was cooled in an ice bath and 1N aqueous NaOH (15 mL) was added and the resulting mixture was extracted with CH2Cl2 (2×25 mL) and 25:1 CH2Cl2:CH3OH (1×26 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to yield a crude product (0.0464 g), which was purified by chromatography (SiO2 10 g, eluted with 90:10:1 CH2Cl2:CH3OH:concentrated aqueous NH4OH) to yield 6b-methyl-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole (0.0453 g) in 91% yield. 1H NMR (400 MHz, CD3OD) δ1.42 (s, 3 H), 1.78-1.87 (m, 1 H), 1.90-1.96 (m, 1 H), 2.68 (ddd, J=10.8, 9.5, 3.5 Hz, 1 H), 2.71 (d, J=13.3 Hz, 1H), 2.74 (d, J=13.3 Hz, 1 H), 2.81-2.94 (m, 3 H) 3.40 (ddd, J=11.0, 2.1, 2.1 Hz, 1 H), 4.37-4.47 (m,2H), 6.53 (dd, J=7.5, 1.7 Hz, 1 H), 6.59-6.65 (m, 2 H); 1.96 (m, 1 H MS (ESI+) for C14H18N2O m/z 231.1 (M+H)+.
Reaction SMILES: [CH:1]([N:3]([CH2:12][C@@H:13]([CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:14]([N:16]1[C@H:20]([C:21]([NH:23][C:24]2[N:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[O:22])[CH2:19][CH2:18][N:17]1C(OCC1C=CC=CC=1)=O)=[O:15])[O:4]CC1C=CC=CC=1)=[O:2]>CO.[OH-].[OH-].[Pd+2]>[CH:1]([N:3]([CH2:12][C@@H:13]([CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:14]([N:16]1[C@H:20]([C:21]([NH:23][C:24]2[N:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[O:22])[CH2:19][CH2:18][NH:17]1)=[O:15])[OH:4])=[O:2]
Reactant: CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)Nc2cccnn2)CCN1C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCCC[C@H](CN(O)C=O)C(=O)N1NCC[C@H]1C(=O)Nc1cccnn1
Reaction time: 2 h
Yield: 34.6 %

Procedure:
To a solution of phenylmethyl (3S)-2-[(2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)heptanoyl]-3-[(3-pyridazinylamino) carbonyl]-1-pyrazolidinecarboxylate (460 mg, 0.764 mmol) in methanol (15 mL) was added Pd(OH)2/C (300 mg). The mixture was stirred under an H2 atmosphere for 2 h and the catalyst was filtered off. The filtrate was concentrated and the residue was purified by pre-HPLC to provide the titled compound (100 mg, 30%) as a yellowish solid. LCMS: (M+H)+: 379.2.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([C:10]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[N:35]=[N:36][N:37]([C:39]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[N:38]=3)=[CH:24][CH:23]=2)[C:17]2[CH2:16][NH:15][CH2:14][CH2:13][C:12]=2[N:11]=1)[CH3:9].C(N(CC)CC)C>ClCCl>[C:1]([N:15]1[CH2:14][CH2:13][C:12]2[N:11]=[C:10]([CH2:8][CH3:9])[CH:19]=[C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[N:35]=[N:36][N:37]([C:39]([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)([C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)[C:52]5[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=5)[N:38]=4)=[CH:26][CH:27]=3)[C:17]=2[CH2:16]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2c(n1)CCNC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2c(n1)CCN(C(C)=O)C2
Reaction time: 20 h
Yield: 65.8 %

Procedure:
Acetic anhydride (78 mg) was added to a stirred solution of 2-ethyl-5,6,7,8-tetrahydro-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-yl)methoxy]-1,6-naphthyridine (500 mg) and triethylamine (150 mg) in dichloromethane (10 ml) under an atmosphere of argon. The solution was left to stand for 20 hours and then volatile material was removed by evaporation. The residue was purified by flash chromatography, eluting with a mixture of methanol/ethyl acetate (1:9 v/v), to give 6-acetyl-2-ethyl-5,6,7,8-tetrahydro-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-1,6-naphthyridine (350 mg), m.p. 97°-98° C.; NMR (d6 -DMSO, d4 -acetic acid): 1.25(t,3H), 2.15(s,3H), 2.75(q,2H), 2.9-3.0(m,3H), 3.7(m,2H), 4.5(d,2H), 5.2(s,2H), 6.8-7.7 (complex m,23H), 7.75-7.85(m,1H).
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[Br:9][C:10]1[N:15]=[CH:14][C:13]([CH2:16][CH2:17][CH:18]([S:24]([CH3:27])(=[O:26])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][CH:11]=1>CN(C=O)C.Cl>[Br:9][C:10]1[N:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([CH3:3])([S:24]([CH3:27])(=[O:26])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(CCc1ccc(Br)nc1)S(C)(=O)=O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(CCc1ccc(Br)nc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
A solution of methyl iodide (633 uL, 10.2 mmol, 2.2 equiv), potassium carbonate (895 mg, 6.5 mmol, 1.4 equiv), and ethyl 4-(6-bromopyridin-3-yl)-2-(methylsulfonyl)butanoate (1620 mg, 4.6 mmol, 1.0 equiv) in DMF (15 mL) was allowed to stir at room temperature overnight. The reaction was diluted with 0.5 M hydrochloric acid (220 mL) and was extracted with ethyl acetate (3×80 mL). The combined organic layers were washed with water (170 mL) and sodium thiosulfate (170 mL, 10% aq. solution), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (7:3 heptane/ethyl acetate) to provide the title compound as a white solid (1107 mg, 66%). MS (LCMS) m/z 364.1 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (t, J=7.22 Hz, 3H) 1.69 (s, 3H) 2.12-2.23 (m, 1H) 2.39-2.59 (m, 2H) 2.69-2.79 (m, 1H) 3.02 (s, 3H) 4.27 (qd, J=7.16, 2.73 Hz, 2H) 7.35-7.43 (m, 2H) 8.20 (d, J=1.95 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](Cl)=[O:11].[NH:14]1[CH:18]=[CH:17]N=N1.C(=O)([O-])[O-].[K+].[K+]>C1S(=O)(=O)CCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:11][CH:17]=[CH:18][N:14]=1
Reactant: COC(=O)c1ccccc1C(=O)Cl
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=S1(=O)CCCC1
Product: COC(=O)c1ccccc1-c1ncco1
Temperature: 140 °C
Yield: 18.8 %

Procedure:
A mixture of 2-Chlorocarbonyl-benzoic acid methyl ester (1.3 gram, 6.56 mmol), 1H-triazole (0.42 ml, 7.22 mmol) and potassium carbonate (2.78 g, 20 mmol) in 12 ml of tetramethylene sulfone was heated at 140° C. for half an hour. The mixture was cooled, diluted with ethyl acetate, washed with water 5 times, and dried. After concentration the crude was purified by flash column (50% ethyl acetate in hexane) to afford 250 mg of 2-Oxazol-2-yl-benzoic acid methyl ester as a light yellow liquid. MS: (M+H)/z=204.1.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[CH3:17][NH:18][CH2:19][CH2:20][CH3:21]>CCO>[CH3:17][N:18]([CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1)[CH2:19][CH2:20][CH3:21]
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Reactant: CCCNC
Solvent: CCO
Product: CCCN(C)CC1OCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 22 using 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (30 mg, 0.10 mmol), N-methylpropan-1-amine (0.50 ml, 4.9 mmol) and EtOH (1.0 ml). MS m/z (rel. intensity, 70 eV) 299 (M+, 1), 87 (6), 86 (bp), 77 (4), 58 (8).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:5]2=[N:6][CH:7]=1.[Cu](C#N)[C:21]#[N:22].O.N.O>CS(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:21]#[N:22])=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:5]2=[N:6][CH:7]=1
Reactant: N#C[Cu]C#N
Reactant: Fc1cnc2c(c1)c(I)nn2Cc1ccccc1F
Agent: N
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1nn(Cc2ccccc2F)c2ncc(F)cc12
Temperature: 150 °C
Reaction time: 2 h

Procedure:
A suspension of 16.03 g (43.19 mmol) of 5-fluoro-1-(2-fluorobenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridine (Example 7A) and 4.25 g (47.51 mmol) of copper cyanide was initially charged in DMSO (120 ml) and stirred at 150° C. for 2 h. After cooling, the contents of the flask were cooled to about 40° C., poured into a solution of conc. ammonia water (90 ml) and water (500 ml), ethyl acetate (200 ml) was added and the mixture was stirred briefly. The aqueous phase was separated off and extracted two more times with ethyl acetate (200 ml each). The combined organic phases were washed twice with 10% strength aqueous sodium chloride solution (100 ml each), dried and concentrated under reduced pressure. The crude product was reacted without further purification.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH3:22])[CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=O)[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]2)[CH2:3][CH2:2]1.[N:23]#[C:24][NH2:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:24]([NH:25][C:19]([C:17]1[CH:16]=[CH:15][N:14]=[C:13]([C:11]2[N:10]=[CH:9][N:8]([CH2:7][CH2:6][N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH3:22])[CH:12]=2)[CH:18]=1)=[O:21])#[N:23]
Reactant: CN(CCn1cnc(-c2cc(C(=O)O)ccn2)c1)CC1CC1
Reactant: N#CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CN(CCn1cnc(-c2cc(C(=O)NC#N)ccn2)c1)CC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
A mixture of 2-(1-{2-[(cyclopropylmethyl)(methyl)amino]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylic acid (10 mg, 0.03 mmol, Example 59), cyanamide (4 mg, 0.1 mmol), HATU (38 mg, 0.1 mmol), TEA (29 μL, 0.2 mmol) in DMF (2 mL) was stirred at r.t. for 1 hr. The reaction mixture was purified by ISCO flash column chromatography (MeOH/DCM=0-50%) to give the title compound as off-white solid (6 mg, 60%). 1HNMR (400 MHz, DMSO-d6): δ 0.43 (2H, m), 0.79 (2H, m), 1.15 (1H, m), 2.30 (5H, m), 2.76 (2H, m), 4.11 (2H, t, J=4.2 Hz), 7.29 (1H, m), 7.73 (1H, d, J=11.4 Hz), 8.27 (1H, s), 8.29 (1H, s), 8.49 (1H, s). [M+H] Calc'd for C17H20N6O, 325. Found, 325.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].Br[CH2:11][CH:12]1[O:17][CH2:16][CH2:15][CH2:14][O:13]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:11][CH:12]1[O:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH3:2]
Reactant: CCOC(CN)OCC
Reactant: BrCC1OCCCO1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(CNCC1OCCCO1)OCC

Procedure:
2,2-Diethoxyethylamine (23.3 grams), 2-bromomethyl-1,3-dioxane (29.2 grams), triethylamine (25 ml) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux overnight. After this time the mixture is cooled and filtered. The filtrate is then distilled under reduced pressure to yield the desired product N-(2,2-diethoxyethyl)-N-(1,3-dioxan-2-ylmethyl)amine.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)N.[C:12]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.Cl>C(O)(=O)C.O>[CH2:14]1[C:13]2[NH:1][C:3]3[C:11](=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=3)[C:12]=2[CH2:17][CH2:16][CH2:15]1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: O=C1CCCCC1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc2[nH]c3c(c2c1)CCCC3
Yield: 50.8 %

Procedure:
A mixture of 4-hydrazinobenzoic acid (5.0 g, 32.9 mmol) and cyclohexanone (3.3 g, 33 mmol) in 30 mL of acetic acid was heated under reflux for 4 hours, then cooled, diluted with water and acidified with HCl. The resultant solid was collected by filtration, washed with water and dried to give 3.6 g of the title compound as a crystalline solid.
Reaction SMILES: [CH:1]1([O:7][CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17]CC3C=CC=CC=3)=[CH:13][CH:12]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([O:7][CH2:8][CH2:9][C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(COC1CCCCC1)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: Oc1ccc(CCOC2CCCCC2)cc1

Procedure:
16 g (0.049 mol) of cyclohexyloxymethyl (4-benzyloxyphenyl) methanone are hydrogenated under a hydrogen pressure of 50 psi, at a temperature of 35 to 40° C., in solution in 150 cc of methanol containing a few drops of 70% HClO4 solution and 1 g of 5% palladium-on-charcoal. The catalyst is filtered off, the solvent is evaporated off in vacuo and the residual oil is chromatographed on a silica column (eluent: 8/2 cyclohexane/ethyl acetate). An oil is collected which has a refractive index nD18 =1.5335; boiling point 0.01=130° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:50])[C@H:4]([CH2:46][CH:47]([CH3:49])[CH3:48])[NH:5][C:6](=[O:45])[C@@H:7]([CH2:41][CH:42]([CH3:44])[CH3:43])[NH:8][C:9](=[O:40])[C@H:10]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[NH:11][C:12](=[O:31])[C@H:13]([CH2:29][OH:30])[NH:14][C:15](=[O:28])[C@H:16]([CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[NH2:17].[CH2:51]([O:58][C:59]([NH:61][C@H:62]([C:78](O)=[O:79])[CH2:63][C:64]1[CH:69]=[CH:68][C:67]([O:70][CH2:71][C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)=[CH:66][CH:65]=1)=[O:60])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:50])[C@H:4]([CH2:46][CH:47]([CH3:49])[CH3:48])[NH:5][C:6](=[O:45])[C@@H:7]([CH2:41][CH:42]([CH3:43])[CH3:44])[NH:8][C:9](=[O:40])[C@H:10]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([OH:39])=[CH:37][CH:38]=1)[NH:11][C:12](=[O:31])[C@H:13]([CH2:29][OH:30])[NH:14][C:15](=[O:28])[C@H:16]([CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[NH:17][C:78](=[O:79])[C@H:62]([CH2:63][C:64]1[CH:65]=[CH:66][C:67]([O:70][CH2:71][C:72]2[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=2)=[CH:68][CH:69]=1)[NH:61][C:59]([O:58][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:60]
Reactant: O=C(N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OCc1ccccc1

Procedure:
The above product, 2.0 g. of L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucine methyl ester, is dissolved in 70 ml. of dimethylformamide and cooled in an ice bath. Nα -Benzyloxycarbonyl-O-benzyl-L-tyrosine, 970 mg., 355 mg. of 1-hydroxybenztriazole and 545 mg. of dicyclohexylcarbodiimide are added. The reaction is stirred at ice bath temperature for several hours, then to room temperature and finally at room temperature for twenty-four hours. The mixture is filtered and the filtrate evaporated under reduced pressure. The residue is dissolved in 400 ml. of ethyl acetate, 20 ml. of water and 20 ml. of 0.5N hydrochloric acid. The ethyl acetate is separated, washed with saturated salt solution, with 0.5N sodium bicarbonate solution, again with saturated salt solution and is evaporated to a solid residue; 2.81 g.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][CH2:8][CH:9]1[CH:14]2[CH2:15][CH:16]([C@@H:17]([OH:30])[C:18]3[CH:19]=[CH:20][N:21]=[C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=34)[N:11]([CH2:12][CH2:13]2)[CH2:10]1>CO>[CH3:7][CH2:8][C@@H:9]1[C@@H:14]2[CH2:15][C@@H:16]([C@H:17]([OH:30])[C:18]3[CH:19]=[CH:20][N:21]=[C:22]4[C:23]=3[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27]4)[N:11]([CH2:12][CH2:13]2)[CH2:10]1
Reactant: CCC1CN2CCC1CC2[C@@H](O)c1ccnc2ccc(OC)cc12
Solvent: c1ccccc1
Solvent: CO
Product: CC[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12

Procedure:
A solution containing 1.25 g. of dihydroquinidinone in 50 ml. of benzene containing 0.5 ml. of methanol was maintained at 20° for 21/2 days under nitrogen. The solution was evaporated to complete dryness under vacuum, and the residue was redissolved in benzene and again evaporated to dryness. The resulting oily residue was dissolved in 50 ml. of dry benzene, and 3 ml. of a 25% solution of di-isobutyl aluminum hydride in toluene were added dropwise with stirring under an atomsphere of dry nitrogen. The reaction was quenched after about 30 minutes by adding 10 ml. of water-methanol (1:1), and the mixture was stirred vigorously for 30 minutes. The benzene layer was decanted. The aqueous aluminum suspension was washed several times with benzene and the combined benzene phases were dried over anhydrous magnesium sulfate and evaporated to dryness. The crude product (1.25 g. of colorless foam) was a practically pure mixture of dihydroquinidine and dhydroquinine (about 1:1) as determined by thin layer chromatography; and a specific rotation [α]D24,5 + 62.2° (c 1.64, ethanol). Crystallization from ethanol yielded 490 mg. of pure dihydroquinidine having a melting point of 167°-169°. Chromatographic separation from mother liquors gave 550 mp of dihydroquinine, m.p. 168°-170°, [α]D29 -137.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH:17]2[CH2:21][CH2:20][NH:19][CH2:18]2)=[O:15])=[CH:11][C:10]=1[N+:22]([O-:24])=[O:23].[CH:26]1(OCCO[Si](C)(C)C)[CH2:28][CH2:27]1.C(O)(=O)C.[C-]#N.[BH4-].[Na+]>CO>[CH:26]1([N:19]2[CH2:20][CH2:21][CH:17]([NH:16][C:14]([C:12]3[S:13][C:9]([S:8][C:7]4[C:6]([Cl:25])=[CH:5][N:4]=[CH:3][C:2]=4[Cl:1])=[C:10]([N+:22]([O-:24])=[O:23])[CH:11]=3)=[O:15])[CH2:18]2)[CH2:28][CH2:27]1
Reactant: C[Si](C)(C)OCCOC1CC1
Reactant: O=C(NC1CCNC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Agent: [BH4-]
Agent: [C-]#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(NC1CCN(C2CC2)C1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Yield: 5.4 %

Procedure:
To a solution of 5-((3,5-dichloropyridin-4-yl)thio)-4-nitro-N-(pyrrolidin-3-yl)thiophene-2-carboxamide (0.20 g, 0.48 mmol), (2-cyclopropoxyethoxy)trimethylsilane (498 mg, 2.86 mmol) and acetic acid (286 mg, 4.77 mmol) in methanol (10 mL) under nitrogen, was added sodium borohydride cyanide powder (150 mg, 2.38 mmol) by small portion. The resulting reaction mixture was heated under reflux for 4 hours. After this time, the reaction mixture was passed through a celite cartridge and the organic solution was concentrated. The resulting residue was dissolved in ethyl acetate and was washed with sodium bicarbonate solution and brine. The organic layer was separated, dried (Na2SO4) and concentrated. The crude was purified by reverse phase HPLC to afford the titled product as a solid (12.0 mg, 5% yield) 1H NMR (400 MHz, d6-DMSO) δ: 8.99 (2H, m), 8.87 (1H, d), 8.54 (1H, s), 4.23 (1H, m), 2.83 (2H, m), 2.07 (1H, m), 1.63 (2H, m), 1.23 (2H, m), 0.48 (2H, m), 0.38 (2H, m). MS m/z: 459.08, 461.07 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: c1csc(C2CCCN2)c1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCCC1c1cccs1

Procedure:
The title compound, white solid, m.p. 84° C. and MS: m/e=328.1 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-thien-2-yl-pyrrolidine and 4-chloro-benzenesulfonyl chloride.