Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:57][N:58]([CH3:76])[C:59]([CH:61]1[CH2:65][CH2:64][N:63]([CH2:66][C:67]2[CH:72]=[CH:71][C:70]([CH2:73][NH:74][CH3:75])=[CH:69][CH:68]=2)[CH2:62]1)=[O:60]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:74]([CH2:73][C:70]3[CH:69]=[CH:68][C:67]([CH2:66][N:63]4[CH2:64][CH2:65][CH:61]([C:59]([N:58]([CH3:57])[CH3:76])=[O:60])[CH2:62]4)=[CH:72][CH:71]=3)[CH3:75])=[O:23])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: CNCc1ccc(CN2CCC(C(=O)N(C)C)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(C(=O)N(C)C)C4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (40 mg, 0.11 mmol), EDCI (29 mg, 0.15 mmol), HOBt (22 mg, 0.16 mmol), DIPEA (0.04 mL, 0.22 mmol), N,N-dimethyl-1-{4-[(methylamino)methyl]benzyl}pyrrolidine-3-carboxamide dihydrochloride (42 mg, 0.13 mmol) and DCM (5 mL).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)[CH2:18][CH2:17]1>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH2:18][CH2:17]2)=[O:14])=[CH:4][CH:3]=1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(c3c[nH]c4ccccc34)CC2)cc1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (10 mg, 0.045 mmol) in dichloromethane (1 mL) was added 3-piperidin-4-yl-1H-indole (9.9 mg, 0.050 mmol, 1.1 eq.), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C24H23N3O2: 385.1790, found 385.1797.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[C:9](=S)=[S:10].[Cl-].[Cl-].[Ca+2]>CCO>[NH:7]1[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][C:3]=2[N:8]=[C:9]1[SH:10]
Reactant: Nc1ccncc1N
Reactant: S=C=S
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: Sc1nc2cnccc2[nH]1
Temperature: 25 °C

Procedure:
To a solution of pyridine-3,4-diamine (5 g) in EtOH (80 ml) was added carbon disulfide (10 mL) at room temperature. The mixture was stirred at 40° C. under a dry atmosphere (CaCl2 tube) for 10 h. The mixture was cooled to room temperature. The resulting white solid was collected by filtration and washed with ether to give 1H-imidazo[4,5-c]pyridine-2-thiol (6.1 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]([C:26]1[N:27]([CH3:38])[C:28]2[C:33]([C:34]=1O)=[CH:32][C:31]([O:36][CH3:37])=[CH:30][CH:29]=2)=[O:25].C(OCC)(=O)C>CCCCCC>[CH3:22][O:23][C:24]([C:26]1[N:27]([CH3:38])[C:28]2[C:33]([C:34]=1[O:20][C:19](=[O:21])[CH2:18][O:17][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=1)=[CH:32][C:31]([O:36][CH3:37])=[CH:30][CH:29]=2)=[O:25]
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: COC(=O)c1c(O)c2cc(OC)ccc2n1C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1c(OC(=O)COc2ncc(C(=O)Nc3ccc(F)cc3)cn2)c2cc(OC)ccc2n1C
Yield: 15 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 3-hydroxy-5-methoxy-1-methyl-1H-indole-2-carboxylic acid methyl ester (40 mg, 0.17 mmol) as the source alcohol. Chromatography (1:1 ethyl acetate:hexane) through SiO2 yielded 13 mg (15%) of the titled compound. ESI-MS m/z 509 (MH+), 507 (M−H−).
Reaction SMILES: [OH-:1].[Na+].O.[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1[O:10][C:11](=[O:26])/[C:12](=[CH:14]/[C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)/[N:13]=1.CO>CC(C)=O>[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([NH:13]/[C:12](=[CH:14]\[C:15]1[O:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:18][CH:19]=1)/[C:11]([OH:10])=[O:26])=[O:1]
Reactant: O=C1OC(c2ccco2)=N/C1=C\c1ccc(-c2ccccc2)o1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: O=C(O)/C(=C/c1ccc(-c2ccccc2)o1)NC(=O)c1ccco1
Temperature: 75 °C

Procedure:
1N NaOH (100 μL) and H2O (500 μL) is added to a solution of (4Z)-2-(2-furyl)-4-[(5-phenyl-2-furyl)methylene]-1,3-oxazol-5(4H)-one (10 mg, 0.0327 mmol), prepared as described above, in acetone (1 mL). The reaction mixture is heated to 75° C. for one hour and then cooled to 25° C. The crude mixture is loaded onto a QAX column, which was pre-treated with MeOH. After 2 minutes the column is washed with MeOH and the product is eluted with 3% HCl/MeOH. Subsequently, the column is washed with MeOH (2 mL) and the combined washings are concentrated under reduced pressure to provide 9.5 mg of (2Z)-2-(2-furoylamino)-3-(5-phenyl-2-furyl)prop-2-enoic acid.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:18][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[N:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:11][CH:6]2[CH2:5][CH2:4]1.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[CH:23]2.Cl>>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH2:2][CH:3]1[CH2:18][N:7]3[CH2:8][CH2:9][N:10]([C:12]4[N:17]=[CH:16][CH:15]=[CH:14][N:13]=4)[CH2:11][CH:6]3[CH2:5][CH2:4]1)[CH:24]=[CH:23]2
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: OCC1CCC2CN(c3ncccn3)CCN2C1
Agent: Cl
Product: Fc1ccc2c(ccn2CC2CCC3CN(c4ncccn4)CCN3C2)c1

Procedure:
The title compound was synthesized according to Example 9 from (7RS,9aSR)-7-hydroxymethyl-2-(pyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Preparation 3) and 5-fluoroindole. mp (.HCl) 70–72° C. HRMS calcd for C21H25FN5(MH+): 366.2094, found: 366.2104.
Reaction SMILES: Cl.[CH:2]1([C:6]([OH:22])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]([O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:8])[CH2:5][CH2:4][CH2:3]1.Br[CH2:24][CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH:2]1([C:6]([OH:22])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:7]([O:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])[CH2:14][CH2:15]2)=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=C(OC1CCNCC1)C(O)(c1ccccc1)C1CCC1
Reactant: CC(C)=CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCCN1CCC(OC(=O)C(O)(c2ccccc2)C2CCC2)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 61.4 %

Procedure:
50 mg of (piperidin-4-yl) 2-cyclobutyl-2-hydroxy-2-phenylacetate hydrochloride, 25 mg of 5-bromo-2-methyl-2-pentene, 25 mg of potassium iodide and 47 mg of anhydrous potassium carbonate were suspended in 5 ml of anhydrous N,N-dimethylformamide, and this suspension was stirred at 70° C. for 3 hours. The reaction mixture was cooled to room temperature, mixed with water, and then extracted with diethyl ether. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (developing solvent: chloroform/methanol=20/1) to obtain 35 mg of the title compound.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[N:9]=[C:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[S:11][CH:12]=2)[C:5](=[O:19])[CH2:4][N:3]1[C@@H:20]([C@@H:28]([CH3:31])[CH2:29][CH3:30])[C:21]([O:23]C(C)(C)C)=[O:22].FC(F)(F)C(O)=O>ClCCl>[O:1]=[C:2]1[N:6]([CH2:7][C:8]2[N:9]=[C:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[S:11][CH:12]=2)[C:5](=[O:19])[CH2:4][N:3]1[C@@H:20]([C@@H:28]([CH3:31])[CH2:29][CH3:30])[C:21]([OH:23])=[O:22]
Reactant: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CC(=O)N(Cc2csc(-c3cccnc3)n2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](C(=O)O)N1CC(=O)N(Cc2csc(-c3cccnc3)n2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 153.3 %

Procedure:
A solution containing the product from Example 57B (0.090 g, 0.220 mmol) in dichloromethane (2 mL) was treated with trifluoracetic acid (2 mL), stirred at 25° C. for 16 hours, and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (0.131 g, 90% yield) as the trifluoroacetic acid salt.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[CH2:10][CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([O:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[CH2:10][CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1CC(CC=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccccc1CC(CCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(benzyloxy)-4-o-tolylbutanal (4.0 g, 14.81 mmol) in MeOH (50 ml) was added NaBH4 (1.13 g, 29.62 mmol) at 0° C. and stirred at room temperature for 2 h. The reaction mixture was quenched with water and concentrated under reduced pressure to afford crude compound. The title compound was purified by separation methods A and E. (Yield 3.0 g).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[CH:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][CH2:17][CH3:18])[CH:11]=[C:10]2[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=1[O:30][CH3:31])=[O:6].[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1>[OH:6][CH:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][CH2:17][CH3:18])[CH:11]=[C:10]2[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=1[O:30][CH3:31])[CH:1]=[CH2:2]
Reactant: C=C[Mg]Br
Reactant: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(C=O)ccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC(O)c1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2CCC
Reaction time: 0.25 h
Yield: 95 %

Procedure:
Vinyl magnesium bromide (3.05 ml of a 1 molar solution in tetrahydrofuran) was added dropwise to a stirred solution of methyl 4-(5-formyl-1-propylindol-3-ylmethyl)-3-methoxybenzoate (1 g, prepared as described in Example 61, part a) in dry tetrahydrofuran (50 ml), at 0° under an atmosphere of nitrogen. The mixture was stirred at 0° for 15 min, and then poured rapidly into a stirred mixture of saturated aqueous ammonium chloride (100 ml) and ethyl acetate (150 ml). The aqueous layer was further extracted with ethyl acetate (75 ml), and the combined organic layers washed (water (twice), brine), dried (MgSO4) and evaporated to give methyl 4-[5-(1-hydroxyallyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate (1.03 g, 95%) as a yellow oil; partial NMR (250 MHz, DMSO-d6): 0.80(t, 3H, CH2CH3), 1.75(m, 2H, CH2CH3), 3.83(s, 3H, OCH3), 3.91(s, 3H, OCH3), 4.0(m, 4H, ArCH2Ar', NCH2), 5.0-5.3(m, 4H, H2C=CH, CH(OH)), 5.9(m, 1H, CH=CH2).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH:8]=[C:9]([NH:12][CH2:13][C:14](=O)[CH2:15][C:16]3([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])[CH2:19][CH2:18][CH2:17]3)[CH:10]=[CH:11][C:6]=2[C:5](=[O:31])[O:4][N:3]=1.[NH2:32][OH:33].Cl>CCO.O.CC([O-])=O.[Na+]>[CH3:1][C:2]1[C:7]2[CH:8]=[C:9]([NH:12][CH2:13][C:14](=[N:32][OH:33])[CH2:15][C:16]3([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])[CH2:19][CH2:18][CH2:17]3)[CH:10]=[CH:11][C:6]=2[C:5](=[O:31])[O:4][N:3]=1
Reactant: NO
Reactant: Cc1noc(=O)c2ccc(NCC(=O)CC3(c4ccccc4C(F)(F)F)CCC3)cc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1noc(=O)c2ccc(NCC(CC3(c4ccccc4C(F)(F)F)CCC3)=NO)cc12

Procedure:
A solution of 29 mg of 4-methyl-6-{2-oxo-3-[1-(2-trifluoromethyl-phenyl)-cyclobutyl]-propylamino}-benzo[d][1,2]oxazin-1-one in EtOH (8 ml) was treated with 1 ml of 50% NH2OH HCl solution in H2O and NaOAc (15 mg). The solution was heated under reflux for 2 h and evaporated. The residue was purified by column chromatography on silica gel (10%-40% EtOAc-hexane) to yield 2 mg of product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C(C)(C)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C)(C)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
To a solution of methyl 2-(3-nitrophenyl)-2-methylpropionate (1.8 g) in methanol (50 mL), 10% palladium carbon (200 mg) was added, followed by stirring at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane=1:2), whereby methyl 2-(3-aminophenyl)-2-methyl-propionate (1.5 g) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]([CH2:18][C@@H:19]([OH:29])[C@@H:20]([NH2:28])[CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:9]([O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])=[CH:5][CH:4]=1)#[N:2].[CH3:32][O:33][C:34]1[C:35](=O)[C:36](=[O:40])[C:37]=1[O:38]C.CCN(CC)CC>CCO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:18][C@@H:19]([OH:29])[C@@H:20]([NH:28][C:35]2[C:36](=[O:40])[C:37](=[O:38])[C:34]=2[O:33][CH3:32])[CH2:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[C:9]([O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])=[CH:30][CH:31]=1)#[N:2]
Reactant: COc1c(OC)c(=O)c1=O
Reactant: C[Si](C)(C)CCOC(=O)N(Cc1ccc(C#N)cc1)C[C@@H](O)[C@@H](N)CC1CCCCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1c(N[C@@H](CC2CCCCC2)[C@H](O)CN(Cc2ccc(C#N)cc2)C(=O)OCC[Si](C)(C)C)c(=O)c1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of (2R,3S)-1-(N-(4-cyanobenzyl)-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-2-hydroxy-3-amino-4-cyclohexylbutane (764 mg, 1.68 mmol) in EtOH (20 mL) was treated with 3,4-dimethoxycyclobut-3-ene-1,2-dione (300 mg, 2.10 mmol, 1.25 equiv) and Et3N (212 mg, 1.25 equiv). The resulting solution was allowed to stir at rt for 17 h. The excess 3,4-dimethoxycyclobut-3-ene-1,2-dione was removed by flash chromatography on silica gel, eluting with 0-65% EtOAc in hexanes. Analysis of the compound by LC-MS showed that it was of sufficient purity to employ in the subsequent steps.
Reaction SMILES: [N:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:8]2=[O:23])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[O:23]=[C:8]1[C:9]([CH2:16][C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CBr
Reactant: O=C1C(Cc2ccncc2)c2ccccc2N1N1CCOCC1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC1(Cc2ccncc2)C(=O)N(N2CCOCC2)c2ccccc21

Procedure:
The product obtained from Example 20 could be reacted with sodium hydride and ethyl bromoacetate in a manner similar to Example 8 to render the product as a crystalline white solid, m.p. 168°-170° C. (hexanechloroform). High Res. Mass Spec. Calcd. for C22H25N3O4 : 396.1923 (M+H) . Found: 396. 1922.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[C:20]1([O:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(Cl)Cl>[C:20]1([O:26][C:27](=[O:28])[NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[N:8][CH:9]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc(N2CCCCC2)nc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCCCC2)nc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-5′-ylamine (1.01 g, 5.7 mmol) and pyridine (12 ml) are stirred in dry CH2Cl2. Phenylchloroformate (1.3 g, 8.5 mmol) is added to this mixture and stirred for 24 h at room temperature. Water and a solution of 1:1 EtOAc/hexanes is added and the organic layer is separated. The organic layer is washed with 1N HCl three times and with brine once. The organic layer is dried over Na2SO4, filter, and evaporated in vacuo. Purify by flash column chromatography (0-10% EtOAc/CH2Cl2) to obtain (3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-carbamic acid phenyl ester. Mass spec.: M−1=280 (AP−).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]([NH:11][C:12]([CH:14]1[N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16][S:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[ClH:26]>C(Cl)Cl.O1CCOCC1>[ClH:26].[OH:1][CH2:2][CH2:3][C@H:4]([NH:11][C:12]([CH:14]1[NH:18][CH2:17][CH2:16][S:15]1)=[O:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCSC1C(=O)N[C@@H](CCO)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(N[C@@H](CCO)c1ccccc1)C1NCCS1
Reaction time: 0.75 h

Procedure:
A solution was made containing a compound of general structure (V) (Intermediate 6, 0.788 g, 2.15 mmol), e.g., tert-butyl 2-({[(1S)-3-hydroxy-1-phenylpropyl]amino}carbonyl)-1,3-thiazolidine-3-carboxylate, in anhydrous DCM (50 ml). At 0° C., 4M HCl solution in dioxane (50 ml) was added, or alternatively, HCl gas, previously dried with a H2SO4 cc trap, was bubbled slowly through the reaction and deprotection was monitored by TLC using cyclohexane/ethyl acetate (1/1) and stained with a pancaldi solution. After approximately 45 minutes, TLC showed no remaining starting materiel and DCM was then evaporated in vacuo without heating to avoid salt decomposition. More DCM (20 ml) was then added and evaporated again in vacuo to remove remaining potential HCl (2-3 times). The desired product, e.g., N-[(1S)-3-hydroxy-1-phenylpropyl]-1,3-thiazolidine-2-carboxamide hydrochloride, was isolated as a white solid and used for the next step without further purification and characterization.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([OH:15])[CH:9]=[CH:10][CH:11]=2)[N:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:28][C:29](=[O:31])[CH3:30]>C1COCC1>[C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([O:15][CH2:28][C:29](=[O:31])[CH3:30])[CH:9]=[CH:10][CH:11]=2)[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2cccc(O)c2n1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)COc1cccc2ccc(OC(C)=O)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A mixture of 5b (1.02 g, 5 mmol), potassium carbonate (0.69 g, 5 mmol) and dry N,N-dimethylformamide (DMF) (40 ml) was stirred at room temperature for 30 min and then chloroacetone (0.46 g, 5 mmol) in dry THF (10 ml) was added in one portion. The resulting mixture was continued to stir at room temperature for 24 h (monitored by TLC). After this period, it was poured into ice water (100 ml) and the pale yellow solid thus obtained was crystallized from dichloromethane and ether to afford 2-Acetoxy-8-(2-oxopropoxy)quinoline (5c) (0.85 g, 66%). mp: 79°-80° C.; 1H-NMR (CDCl3): δ2.16 (s, 3H, OAc), 2.42 (s, 3H, 3'-CH3), 4.85 (s, 2H, OCH2), 7.06 (d, 3-H), 7.26-7.67 (m, 3H, Ar--H), 8.08 (d, 4-H).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1([CH2:6][C:7](OC)=[O:8])[CH2:5][CH2:4]1.O.[OH-].[Na+].[ClH:15]>O1CCCC1.O1CCOCC1>[ClH:15].[CH3:1][N:2]([CH3:11])[C:3]1([CH2:6][CH2:7][OH:8])[CH2:5][CH2:4]1
Reactant: COC(=O)CC1(N(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C1(CCO)CC1
Temperature: 5 °C

Procedure:
10.2 g of the compound obtained in Step 3 dissolved in 200 ml of tetrahydrofuran are slowly added to a solution of 5 g of AlLiH4 in 300 ml of tetrahydrofuran. After refluxing for 2 hours, the reaction mixture is cooled to 5° C. and 10.7 ml of water, 10.7 ml of 4N sodium hydroxide and then 32.1 ml of water are added. After filtering and concentrating under reduced pressure, chromatography over silica gel (dichloromethane/methanol: 95/5) allows the expected product to be isolated, which is converted into its hydrochloride form by the action of a solution of hydrochloric acid in dioxane.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:11][CH2:12][CH2:13][C:3]=12.[OH:14][C:15]1([CH3:30])[C@@H:20]([CH3:21])[CH2:19][NH:18][CH2:17][C@H:16]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>C(O)(C)C>[OH:14][C:15]1([CH3:30])[C@@H:20]([CH3:21])[CH2:19][N:18]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH2:11][CH2:12][CH2:13][C:3]=23)[CH2:17][C@H:16]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: O=[N+]([O-])c1cnc2c(c1Cl)CCC2
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)C1(C)O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: C[C@H]1CN(c2c([N+](=O)[O-])cnc3c2CCC3)C[C@@H](NC(=O)OC(C)(C)C)C1(C)O
Temperature: 80 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (210 mg, 1.0 mmol), tert-butyl [(3R,5S)-4-hydroxy-4,5-dimethylpiperidin-3-yl]carbamate (255 mg, 1.04 mmol) and triethylamine (296 μL, 2.12 mmol) in isopropyl alcohol (1 mL) was stirred at 80° C. for 2 h. The solvent was evaporated under reduced pressure and the resulting residue was purified by chromatography on silica gel eluting with 25% EtOAc in hexanes to give the sub-title compound as a yellow oil (318 mg, 74%). LCMS calc. for C20H31N4O5 (M+H)+ m/z=407.2. found 407.2.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH2:3][NH2:4].OC1C=CC=CN=1.[C:14]([O:18][C:19](=[O:49])[NH:20][C@H:21]([C@@H:40]1[CH2:44][C@@H:43]([CH:45]([CH3:47])[CH3:46])[C:42](=[O:48])[O:41]1)[CH2:22][N:23]1[CH2:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[CH3:37])[CH2:25][C:24]1([CH3:39])[CH3:38])([CH3:17])([CH3:16])[CH3:15]>O>[C:14]([O:18][C:19](=[O:49])[NH:20][C@@H:21]([CH2:22][N:23]1[CH2:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[CH3:37])[CH2:25][C:24]1([CH3:38])[CH3:39])[C@@H:40]([OH:41])[CH2:44][C@H:43]([C:42](=[O:48])[NH:4][CH2:3][C:2]([CH3:6])([CH3:5])[CH3:1])[CH:45]([CH3:47])[CH3:46])([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)CN
Reactant: Cc1ccc(F)cc1N1CC(C)(C)N(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2C[C@@H](C(C)C)C(=O)O2)CC1=O
Agent: Oc1ccccn1
Solvent: O
Product: Cc1ccc(F)cc1N1CC(C)(C)N(C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@H](C(=O)NCC(C)(C)C)C(C)C)CC1=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 74.6 %

Procedure:
0.94 ml of (2,2-dimethylpropyl)amine (8.0 mmol) and 7.6 mg of 2-hydroxypyridine (0.08 mmol) were added to 202 mg of {(S)-2-[2,2-dimethyl-4-(5-fluoro-2-methylphenyl)-5-oxopiperazin-1-yl]-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (70f) (0.4 mmol), and the mixture was stirred at 70° C. for four hours. The reaction mixture was cooled and then water was added, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1) to obtain 177 mg of the title compound (yield: 75%).