Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH2:22][CH2:21][N:20]([C:23]([C:25]5[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=5[C:27](O)=[O:28])=[O:24])[CH2:19][CH2:18]4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[N:3]=1.N.C([N:47](CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[CH2:22][CH2:21][N:20]([C:23]([C:25]5[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=5[C:27]([NH2:47])=[O:28])=[O:24])[CH2:19][CH2:18]4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[N:3]=1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccccc2C(=O)O)CC1
Reactant: CCN(CC)CC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: ClCCl
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccccc2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
To a stirred solution of 2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo-[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzoic acid (69 mg, 0.12 mmol) in methylene chloride (4 mL) was added ammonia (1 mL, 0.5 M in dioxane), triethylamine (18 μL, 0.12 mmol) and HATU (46 mg, 0.12 mmol). The reaction mixture was stirred for 3 hours at ambient temperature before being diluted with methylene chloride and quenched with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate. After evaporation of the solvent, the crude product was purified by flash chromatography on silical gel, eluting with a gradient of 0-20% methanol in ethyl acetate to afford 2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzamide (57 mg, 83%) 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J=8.6 Hz, 1H), 7.56 (d, J=7.3 Hz, 1H), 7.46-7.42 (m, 2H), 7.38-7.34 (m, 2H), 7.30-7.21 (m, 4H), 7.18-7.08 (m, 3H), 6.91 (br, 1H), 5.74 (br, 1H), 4.63-4.54 (m, 1H), 4.26 (br, 1H), 3.47-3.08 (m, 5H), 2.54 (s, 3H), 2.40-2.30 (m, 3H), 2.11-2.06 (m, 1H), 1.97-1.80 (m, 10H), 1.59 (d, J=7.9 Hz, 2H). HRMS m/z (M+H)+ calcd: 576.3338, obsd: 576.3337.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:21][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([CH3:15])=[CH:17][CH:18]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: Cc1ccc(CN)cc1
Solvent: CO
Product: Cc1ccc(CN=C(NC#N)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (5 ml), and 4-methylbenzylamine (0.35 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from diethyl ether to give the title compound (0.60 g, 2.4 mmol, yield: 91%) as colorless powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1.O>CN(C)C=O>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([O:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:13][CH:14]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: OCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2ccccn2)nc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
2-Pyridylcarbinol (7.5 g, 0.069 mole) in dry dimethylformamide (190 ml) was cooled to −20° C. and treated with an 80% dispersion of sodium hydride in mineral oil (2.07 g, 0.069 mole) under argon. The mixture was stirred at −20° C. for two hours. 2-Chloro-5-nitropyridine (8.83 g, 0.058 mole) was added and the mixture was stirred at −20° C. for 0.5 hour then warmed to room temperature and stirred for 18 hours. Water was added dropwise and the solvent removed in vacuo. The residue was dissolved in dichloromethane, washed with 10% aqueous sodium hydroxide solution followed by water, dried (Na2SO4) and evaporated in vacuo to afford the title compound (12.2 g, 91%) as an orange solid.
Reaction SMILES: I[C:2]1[N:9]2[C:5]([S:6][C:7]([C:10]3[CH:11]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=3)=[N:8]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([C:35]([F:38])([F:37])[F:36])[C:31]([NH2:34])=[N:32][CH:33]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:34][C:31]1[N:32]=[CH:33][C:28]([C:2]2[N:9]3[C:5]([S:6][C:7]([C:10]4[CH:11]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=4)=[N:8]3)=[N:4][CH:3]=2)=[CH:29][C:30]=1[C:35]([F:38])([F:36])[F:37]
Reactant: CC(=O)Nc1cccc(-c2nn3c(I)cnc3s2)c1
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)cnc3s2)c1
Temperature: 110 °C
Yield: 4 %

Procedure:
A mixture of N-[3-(5-Iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-phenyl]-acetamide (0.16 g, 0.416 mmol, 1 eq), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (0.12 g, 0.416 mmol, 1 eq), 2M aq Na2CO3 (0.9 mL) and PdCl2(PPh3)2 (60 mg, 0.083 mmol, 0.2 eq) in dioxane (5 mL) was heated at 110° C. for 90 min. The solvent was removed under reduced pressure and the residue was redissolved in DCM and washed with water. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by flash-chromatography (DCM: MeOH, 5 to 15%) and by HPLC to afford the desired product (7 mg, 4%). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=4.74 min, [M+H]+ m/z 419.1; 1H NMR (300 MHz, DMSO) δ 10.30 (s, 1H), 8.89 (s, 1H), 8.32 (m, 2H), 7.81 (m, 2H), 7.62 (d, J=7.8 Hz, 1H), 7.54 (t, J=7.9 Hz, 1H), 6.75 (s, 2H), 2.09 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:29]#[C:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][O:13][C@@:12]([CH2:23][CH:24]([OH:27])CO)([CH3:22])[C:11]1=[O:28])=[O:4].O.I([O-])(=O)(=O)=O.[Na+].[BH4-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:29]#[C:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][O:13][C@@:12]([CH2:23][CH2:24][OH:27])([CH3:22])[C:11]1=[O:28])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@](C)(CC(O)CO)OC[C@H]1C1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@](C)(CCO)OC[C@H]1C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
3-[(2R,5R)-5-Cyclohexyl-2-(2,3-dihydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester from Example 7 Step 3 was dissolved in 4 ml THF, and 3.7 mL solution was taken out for the reaction. To the stirred solution was added THF (2.3 mL), water (2.0 mL), and then sodium periodate (0.28 g, 1.31 mmol, 1.6 equiv) at 0° C. The resulting solution was stirred at room temperature for 30 minutes. And then at 0° C. another portion of sodium periodate (0.09 g, 0.44 mmol, 0.5 equiv) was added to the mixture and stirred for another 30 minutes at room temperature. The reaction was quenched by adding brine solution (0.5 mL) and EtOAc (10 mL). The organic layer was separated, dried (over Na2SO4) and concentrated. The residue was dissolved in ethanol (6.0 mL) and to the resulting solution at 0° C. was added sodium borohydride (0.27 g, 7.0 mmol, 8.8 equiv). The mixture was stirred at 0° C. for 15 minutes after which the reaction was quenched by adding water (2.0 mL) and EtOAc (10 mL). The organic layer was separated, dried (over Na2SO4) and concentrated to give product 128 mg (yield 35%). The crude product was continued to the next step with no further purification. MS: 462 [M−H+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)([C:14]#N)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.[CH3:32][OH:33]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)([CH2:14][CH:32]=[O:33])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Br)cc2)CC1
Reactant: CO
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CC=O)(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4-(4-bromo-phenyl)-4-cyano-piperidine-1-carboxylic acid tert-butyl ester from Step 2 (5.67 g, 15.57 mmol, 1 eq) in 60 mL of dichloromethane was add a solution of DIBAL-H (1M in toluene, 23.36 mL, 23.36 mmol, 1.5 eq) in a drop-wise fashion. The resulting mixture was stirred at room temperature for 20 h and then 15 mL of methanol was added carefully. The mixture was stirred for 0.25 h and a precipitate formed. The resulting mixture was filtered through Celite and the salts were washed several times with ethyl acetate. The filtrate was adsorbed onto silica gel and purified by flash column chromatography eluting with a gradient of 5-20% ethyl acetate in hexane to give 1.78 g of 4-(4-bromo-phenyl)-4-(2-oxo-ethyl)-piperidine-1-carboxylic acid tert-butyl ester and 1.54 g of recovered starting material. 1H NMR (300 MHz, CDCl3): δ 9.35 (s, 1H), 7.50-7.46 (d, 2H), 7.15-7.10 (d, 2H), 3.82 (br. s, 2H), 3.11-3.04 (t, 2H), 2.35-2.28 (dt, 2H), 1.90 (br. s, 2H), 1.42 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=O)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.C(N(CC)CC)C.ClC(OCC)=O.[C:27]1([CH2:33][N:34]2[CH2:38][CH2:37][CH2:36][CH:35]2[CH2:39][NH2:40])[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=1>C(Cl)(Cl)Cl>[C:27]1([CH2:33][N:34]2[CH2:38][CH2:37][CH2:36][CH:35]2[CH2:39][NH:40][C:11]([C:4]2[C:5]3[O:9][CH2:8][CH2:7][C:6]=3[CH:10]=[C:2]([Cl:1])[CH:3]=2)=[O:13])[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=1
Reactant: NCC1CCCN1CC1=CCCCC1
Reactant: O=C(O)c1cc(Cl)cc2c1OCC2
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(NCC1CCCN1CC1=CCCCC1)c1cc(Cl)cc2c1OCC2
Reaction time: 0.5 h

Procedure:
32 g of 5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid, 130 ml of chloroform and 16 g of triethylamine were introduced into a 1-liter round-bottomed flask. The contents were cooled to 0°-5° C. and 17.5 g of ethyl chloroformate were then added dropwise and the mixture was stirred for 1 hour and 30 minutes. A solution of 34 g of 1-cyclohexenylmethyl-2-aminomethylpyrrolidine in 68 ml of chloroform was then poured in dropwise, between 5° and 10° C., and the mixture was then stirred for 1 hour at 5° C. and for 1 hour at ambient temperature.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[C:18]([CH:19]=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:29]([CH3:34])([CH3:33])[CH2:28][CH2:27][C:26]([CH3:36])([CH3:35])[C:25]=3[CH:24]=2)[CH:10]=[CH:11][CH:12]=1)=[O:5])[CH3:2].[O-:37]S(C(F)(F)F)(=O)=O>>[CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[C:18]([C:19]([OH:37])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:29]([CH3:34])([CH3:33])[CH2:28][CH2:27][C:26]([CH3:35])([CH3:36])[C:25]=3[CH:24]=2)[CH:10]=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: CCOC(=O)Cc1cccc(-c2c(C=O)cccc2OCc2ccc3c(c2)C(C)(C)CCC3(C)C)c1
Product: CCOC(=O)Cc1cccc(-c2c(OCc3ccc4c(c3)C(C)(C)CCC4(C)C)cccc2C(=O)O)c1

Procedure:
3'-Ethoxycarbonylmethyl-2-(5,6,7,8-tetrahydro-5,5,8,8 -tetramethyl-2-naphthalenyl)methoxy-1,1'-biphenyl-6-carboxaldehyde (16q) (0.394 g., 0.84 mmol) obtained above (as a mixture with triflate 20a) is oxidized via the method of Example 4 to yield 3'ethoxycarbonylmethyl-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)methoxy-1,1'-biphenyl-6-carboxylic acid (0.210 g., 0.43 mmol, 25% overall from triflate 20a): chromatographed on silica gel using methanol/CH2Cl2 to afford a yellow oil; 1H NMR (300 MHz, CDCl3) δ 7.49 (d, J=8 Hz, 1H, ArH), 7.33 (m, 2H, ArH), 7.26-7.15 (m, 5H, ArH), 7.05 (d, J=2 Hz, 1H, ArH), 6.89 (dd, J=2, 8 Hz, 1H, ArH), 4.94 (s, 2H, ArCH2O), 4.05 (q, J=7Hz, 2H, CO2CH2), 3.59 (s, 2H, ArCH2CO2), 1.63 (s, 4H, CH2CH2), 1.22 (s, 6H, 2×CH3), 1.15 (s, 6H, 2×CH3), 1.15 (t, J=7 Hz, 3H, CO2CH2CH3); 13C NMR (75 MHz, CDCl3) δ 171.68 (C=O) , 171.64 (C=O), 156.21, 144.87, 144.23, 136.72, 133.58, 133.44, 132.16, 130.56, 128.42, 128.37, 128.01, 127.89, 126.55, 124.67, 123.89, 122.57, 116.76, 70.69, 60.80, 41.43, 35.03, 34.19, 34.07, 31.82, 31.74, 14.12; IR (film) 2960, 2926, 1734, 1700, 1456, 1364, 1300, 1260, 1152, 758 cm-1 ; MS (DCI) m/e 501 (MH+), 483 (M-OH), 201 (C15H21+).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][C:21]=3[O:29][CH3:30])=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].[C:31](N1C=CN=C1)([N:33]1C=CN=C1)=O.CN>CN(C)C=O>[CH3:31][NH:33][C:24]([C:23]1[CH:27]=[CH:28][C:20]([O:19][C:17]2[CH:16]=[CH:15][C:12]3[CH2:13][CH2:14][N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:9][CH2:10][C:11]=3[CH:18]=2)=[C:21]([O:29][CH3:30])[CH:22]=1)=[O:26]
Reactant: COc1cc(C(=O)O)ccc1Oc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)CC2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
4-[(3-{[(1,1-Dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-(methyloxy)benzoic acid (E264, Step 4) (145 mg, 0.35 mmol) was dissolved in dry dimethylformamide (5 ml), treated with 1,1′-carbonyldiimidazole (85 mg, 0.53 mmol) and the resulting mixture stirred at room temperature for 3 hours. The mixture was treated with methylamine (0.53 ml, 1.05 mmol, 2M in THF) and stirred for 4 hours. The reaction mixture was concentrated in vacuo and the resulting residue purified by column chromatography (1:1 ethyl acetate:pentane) to afford the title compound (0.10 g); MS (ES+) m/e 327 [(M+H)—CO2tBu]+.
Reaction SMILES: [O:1]=[C:2]([CH2:4][N:5]([C:7](=[NH:9])[NH2:8])[CH3:6])[OH:3].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:28][C:29]1[CH:30]=[C:31]([N:35]=[C:36]=[O:37])[CH:32]=[CH:33][CH:34]=1.Cl>CO.CN(C=O)C.O>[NH2:9][C:7](=[N:8][C:36]([NH:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([Cl:28])[CH:30]=1)=[O:37])[N:5]([CH3:6])[CH2:4][C:2]([OH:3])=[O:1]
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: CN(CC(=O)O)C(=N)N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CN(CC(=O)O)C(N)=NC(=O)Nc1cccc(Cl)c1
Reaction time: 2 h
Yield: 30 %

Procedure:
A solution of 9.58 g (0.073 mole) of anhydrous creatine in 96 ml (0.073 mole) of 0.76M tetrabutylammonium hydroxide in methanol was evaporated to an oil in vacuo. The residue was dissolved in 100 ml of DMF. An 11.2 g (0.073 mole) sample of m-chlorophenylisocyanate was added dropwise and the reaction was stirred for two hours. The mixture was poured into 200 ml of water and 73 ml of 1N HCl. The gummy precipitate was induced to crystallize by scratching. The solid was collected and triturated with tetrahydrofuran to give 6.6 g (30% yield) of light yellow solid N-{amino[(3-chlorophenyl)aminocarbonyl]iminomethyl}-N-methylglycine. A hydrochloride salt was prepared from conc. HCl to yield a pink solid, m.p. 228°-234° C.
Reaction SMILES: [CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[O:21][C:20]=2[CH3:30])[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].O.Cl>CO.O1CCCC1>[CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[O:21][C:20]=2[CH3:30])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OC(c2cc(-c3cccnc3)oc2C)C2CCCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2cccnc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of cyclohexyl[2-methyl-5-(pyridin-3-yl)furan-3-yl]methanol (407 mg) obtained by the above-mentioned reaction and methyl 4-hydroxybenzoate (274 mg) in tetrahydrofuran (20 mL) were added tributylphosphine (0.7 mL) and 1,1′-(azodicarbonyl)dipiperidine (757 mg), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (5% ethyl acetate/hexane to 25% ethyl acetate/hexane) to give methyl 4-{cyclohexyl[2-methyl-5-(pyridin-3-yl)furan-3-yl]methoxy}benzoate as an amorphous compound. The obtained methyl 4-{cyclohexyl[2-methyl-5-(pyridin-3-yl)furan-3-yl]methoxy}benzoate was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), 2N sodium hydroxide (2.0 mL) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced-pressure, and the residue was crystallized from ethyl acetate/hexane to give the title compound (275 mg, 47%).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:13]([NH:15][C@H:16]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17][O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:14])=O)C1C=CC=CC=1>CCO.[Pd]>[NH2:11][C@H:12]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:13]([NH:15][C@H:16]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:17][O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:14]
Reactant: CC(C)(C)OC[C@H](NC(=O)[C@H](NC(=O)OCc1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC[C@H](NC(=O)[C@H](N)c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
tert-Butyl N-((2R)-2-{[(benzyloxy)carbonyl]amino}-2-phenylethanoyl)-O-(tert-butyl)-L-serinate (Method 5; 3.3 g, 6.8 mmol) was dissolved in EtOH (95%, 30 ml) and a cat amount of Pd/C (5%)(50% in water) was added and hydrogenation was performed at atmospheric pressure for 3 hours at room temperature. The reaction mixture was filtered through diatomaceous earth and the solvent was evaporated to give the title compound (2.35 g, 98%). NMR (500 MHz, CD3OD): 1.1 (s, 9H), 1.45 (s, 9H), 3.45-3.8 (m, 2H), 4.5 (t, 1H), 4.55 (s, 1H), 4.85 (s, 2H), 7.3-7.5 (m, 5H).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH2:21]([OH:23])[CH3:22].[OH-].[Na+]>O1CCOCC1.C(OC(=O)C)(=O)C>[C:21]([NH:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])(=[O:23])[CH3:22]
Reactant: CCO
Reactant: COc1cccc(CC(N)CCC(=O)OC(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: COc1cccc(CC(CCC(=O)OC(C)(C)C)NC(C)=O)c1
Reaction time: 1.33 h

Procedure:
To a solution of tert-butyl 4-amino-5-(3-methoxyphenyl)valerate (0.22 g) in 1,4-dioxane (0.2 ml), acetic anhydride (0.08 ml) was added and the solution was stirred for 80 minutes. To the solution, ethanol was added and the solution was stirred for 15 minutes. The pH of the solution was adjusted to 12 with sodium hydroxide solution and the solution was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to give tert-butyl 4-acetylamino-5-(3-methoxyphenyl)valerate (246 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][C:12]3[CH:21]=[CH:20][C:19]4[C:18]([NH2:22])=[CH:17][CH:16]=[CH:15][C:14]=4[N:13]=3)[C:4]=2[O:3]1.[CH3:23][N:24]([CH3:29])[S:25](Cl)(=[O:27])=[O:26]>>[CH3:23][N:24]([CH3:29])[S:25]([NH:22][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH:20]=[CH:21][C:12]([NH:11][C:10]1[C:4]3[O:3][CH:2]([CH3:1])[CH2:6][C:5]=3[CH:7]=[CH:8][CH:9]=1)=[N:13]2)(=[O:27])=[O:26]
Reactant: CC1Cc2cccc(Nc3ccc4c(N)cccc4n3)c2O1
Reactant: CN(C)S(=O)(=O)Cl
Product: CC1Cc2cccc(Nc3ccc4c(NS(=O)(=O)N(C)C)cccc4n3)c2O1

Procedure:
The title compound, MS: m/e=399.1 (M+H+), was prepared in accordance with the general method of example 19 from N2-(2-methyl-2,3-dihydro-benzofuran-7-yl)-quinoline-2,5-diamine and dimethylsulfamoyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([OH:13])=O)=[CH:7]2.Cl.CN(C)CCCN=C=NCC.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([N:30]1[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]1)=[O:13])=[CH:7]2
Reactant: CN1CCNCC1
Reactant: Cc1cccc2cc(C(=O)O)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1cccc2cc(C(=O)N3CCN(C)CC3)[nH]c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.2 %

Procedure:
A mixture of 7-methylindole-2-carboxylic acid (1.79 g, 10 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 2.88 g, 15 mmol) in CH2Cl2 (100 mL) was treated with N-methylpiperazine (2.22 mL, 20 mmol). The reaction mixture was stirred at ambient temperature for 16 h and then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (100 mL), washed with water (25 mL×2) and then brine (25 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. This product was purified via silica gel chromatography (5-10% methanol/dichloromethane) to give the title compound as a white solid (2.5 g, 97.3%). 1H NMR (400 MHz, CDCl3): δ 11.07 (br s, 1H), 7.43 (d, J=7.04 Hz, 1H), 7.00-6.92 (m, 2H), 6.71 (d, J=1.96 Hz, 1H), 3.86 (br s, 4H), 2.37 (s, 3H), 2.35-2.28 (m, 4H), 2.19 (s, 3H). MS (electrospray): exact mass calculated for C15H19N3O, 257.15; m/z found, 258.2 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([CH2:12][C:13](=O)[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[CH2:22]([NH2:25])[CH2:23][NH2:24].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[NH2:24][CH2:23][CH2:22][NH:25][C@H:13]1[CH2:14][CH2:15][C@@:16]2([CH3:17])[C@@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[CH2:19][CH2:20][C@@:3]2([CH3:4])[C@H:5]3[CH2:6][CH2:7][C@@H:2]2[OH:1])[CH2:12]1
Reactant: NCCN
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@]12CC[C@H](NCCN)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
17β-Hydroxy-5α-androstan-3-one (403 mg, 1.39 mmol)(Aldrich Chemical Company) was added to a stirred solution of 0.745 mL 1,2-ethylenediamine (11.1 mmol) and 1.44 mL acetic acid (25.2 mmol) in 16.0 mL dry methanol (MeOH), followed by 104 mg (1.65 mmol, 1.19 equiv.) of sodium cyanoborohydride. After stirring at room temperature for 15 h, the reaction concentrated under reduced pressure. The residue was partitioned between methylene chloride and aqueous 1N sodium hydroxide, shaken, and separated. The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was used without further purification.