Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1([S:13][CH2:14][N:15]2[C:19](=[O:20])[CH:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:17][S:16]2(=[O:29])=[O:28])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CI>C1COCC1>[C:7]1([S:13][CH2:14][N:15]2[C:19](=[O:20])[CH:18]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:17]([CH3:1])[S:16]2(=[O:28])=[O:29])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1C(Cc2ccccc2)NS(=O)(=O)N1CSc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(Cc2ccccc2)C(=O)N(CSc2ccccc2)S1(=O)=O
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
Potassium t-butoxide (5.65 g, 50.35 mmol) was added to a solution of 2-phenylthiomethyl-4-phenylmethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (14.61 g, 41.93 mmol) in 250 ml of THF at 0° C. and the mixture was stirred at this temperature for 1/2 hour. To the above mixture was added methyl iodide (35.69 g, 251.58 mmol) at 0° C. and the resulting mixture was allowed to stir for 4.5 hours at room temperature. The resulting mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate and the organic layer was washed with brine. The organic layer was dried, concentrated in vacuo, and the residue was purified by flash chromatography to afford 12.53 g (82.4%) of 2-phenylthiomethyl-4-phenylmethyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:14]1([C:2]2[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: N#Cc1ccc(C(F)(F)F)nc1Cl
Reactant: C1CCNC1
Product: N#Cc1ccc(C(F)(F)F)nc1N1CCCC1
Yield: 67 %

Procedure:
Prepared in 67% yield from 2-chloro-6-trifluoromethyl-nicotinonitrile and pyrrolidine according to the procedure described for Example 178A. MS (ESI+) m/z 242.9 (M+H)+; 1H NMR (DMSO-d6) δ 1.92-1.97 (m, 4H), 3.67-3.72 (m, 4H), 7.07 (d, J=7.8 Hz, 1H), 8.22 (d, J=7.8 Hz, 1H).
Reaction SMILES: [F:1][CH:2]([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4].[CH2:11]=[O:12]>>[OH:12][CH2:11][C:2]([F:1])([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: C=O
Reactant: COC(=O)C(F)C(=O)OC
Product: COC(=O)C(F)(CO)C(=O)OC

Procedure:
The process according to the invention is carried out in three stages: dimethyl α-fluoromalonate is first reacted with formaldehyde to give dimethyl α-hydroxymethyl-α-fluoromalonate, the latter is then hydrolyzed and the hydrolysis product is decarboxylated and dehydrated, and finally, the resuiting α-fluoroacrylic acid is esterified with a substituted phenol.
Reaction SMILES: B(F)(F)[F:2].N[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([Br:16])[CH:12]=[CH:11]2.C(ON=O)(C)(C)C>C1COCC1.C(COC)OC>[Br:16][C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[C:6]([F:2])[CH:7]=[CH:8][CH:9]=2)[CH:14]=1
Reactant: Nc1cccc2ccc(Br)cc12
Reactant: FB(F)F
Agent: CC(C)(C)ON=O
Solvent: COCCOC
Solvent: C1CCOC1
Product: Fc1cccc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
To a solution of BF3-etherate (0.86 ml, 1.25 M in THF, 6.5 mmol) in 12 ml dimethoxyethane was added at −5° C. a solution of 8-amino-2-bromo-naphthalene (1.20 g, 5.4 mmol) in dimethoxyethane (12 ml) over a periode of 35 min. After 1 hour a solution of tert-butylnitrite (0.62 ml, 5.4 mmol) in dimethoxyethane (24 ml) was added and the mixture was stirred for two hours at r.t. and the solvent was removed under reduced pressure. Chlorbenzene (120 ml) was added and the reaction mixture was refluxed for 50 min and the mixture was concentrated. The solid was diluted in methylene chloride and washed with NaHCO3. The organic phase was dried over MgSO4, filtered and reduced to give the crude product. Chromatography on silica gel (hexane) afforded 721 mg (59%) of the product as a brown oil. MS: m/e=242 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N+:15]([O-])=O)[CH:14]=1)[NH:11][C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:9]2)=[O:5])[CH3:2].[C:24]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([NH:15][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:14]=1)[NH:11][C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c2[nH]c(-c3ccccc3)cc2c1
Reactant: O=C1CCCC1
Product: CCOC(=O)c1cc(NC2CCCC2)c2[nH]c(-c3ccccc3)cc2c1

Procedure:
2-Phenyl-7-nitro-1H-indole-5-carboxylic acid ethyl ester prepared in Step A and cyclopentanone were reacted according to the same procedure as Example 1 to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2.[H-].[Na+].Cl.Cl[CH2:19][CH2:20][N:21]([CH3:23])[CH3:22].ClCCl>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:9][CH2:8][CH2:7]2
Reactant: CN(C)CCCl
Reactant: O=[N+]([O-])c1cc(F)c2c(c1)CCCN2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CN(C)CCN1CCCc2cc([N+](=O)[O-])cc(F)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
To a stirred solution of 8-fluoro-6-nitro-1,2,3,4-tetrahydroquinoline (670 mg, 3.42 mmol) in N,N-Dimethylformamide (15 ml), cooled to 0° C. was added sodium hydride, 60% (437 mg, 10.93 mmol) with vigorous stirring. When bubbling subsided, 2-chloro-N,N-dimethylethanamine hydrochloride (984 mg, 6.83 mmol) was added and the reaction mixture (dark red) was stirred at room temperature. After 2 h, no product was observed so the reaction was heated to 90° C. and stirred. After 1 h, TLC showed the reaction to be complete. The mixture was then cooled to room temperature, diluted with water and extracted with ethyl acetate (3×). The combined organics were then washed with 1:1 water:brine (2×), then brine (1×). The organic phase was dried, filtered and concentrated, then chromatographed in 0-10% (2M NH3 in methanol) in 1:1 ethyl acetate:dichloromethane, giving the desired 2-(8-fluoro-6-nitro-3,4-dihydroquinolin-1(2H)-yl)-N,N-dimethylethanamine (514 mg, 1.923 mmol, 56.3% yield). NMR (DMSO-d6) δ 7.77 (dd, J=15 Hz, 2.7 Hz, 1H); 7.72 (m, 1H); 3.55-3.48 (m, 2H); 3.43-3.39 (m, 2H); 2.78-2.74 (m, 2H), 2.49-2.44 (m, 2H); 2.16 (s, 6H); 1.88-1.79 (m, 2H). ESI-MS (m/z, %): 268 (MH+, 100); 223 (5).
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:10][C:11]1[CH:12]=[C:13]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=1)=[O:15]>C(O)(C(F)(F)F)=O.C(O)(C)C>[C:4]([C:3]1[C:2]([NH:10][C:11]2[CH:12]=[C:13]([CH:26]=[CH:27][C:28]=2[CH3:29])[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=2)=[O:15])=[N:9][CH:8]=[CH:7][CH:6]=1)#[N:5]
Reactant: N#Cc1cccnc1Cl
Reactant: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1N
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1Nc1ncccc1C#N
Temperature: 130 °C

Procedure:
To 2-chloronicotinonitrile (140 mg, 1.00 mmol) and 3-amino-N-(3-isopropyl-phenyl)-4-methyl-benzamide (80 mg, 0.30 mmol) was added isopropanol (0.8 mL) and TFA (12 drops). The mixture was heated to 130° C. for 16 hours in a sealed tube. The cooled mixture was purified by silica gel chromatography (25% EtOAc/hexanes) to yield 3-(3-cyanopyridin-2-ylamino)-N-(3-isopropylphenyl)-4-methylbenzamide. MS m/z [M+H]+=371; Calc'd for C23H22N4O: 370.46.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[S:23][N:22]=[C:21]([N:24]4[CH2:29][CH2:28][CH:27]([NH:30]C(=O)OC(C)(C)C)[CH2:26][CH2:25]4)[N:20]=3)[CH2:15][CH2:14]2)=[O:12])=[N:2]1.[ClH:38]>O1CCCC1.CO.C(OCC)(=O)C>[ClH:38].[ClH:38].[NH2:30][CH:27]1[CH2:28][CH2:29][N:24]([C:21]2[N:20]=[C:19]([N:16]3[CH2:15][CH2:14][N:13]([C:11]([NH:10][C:3]4[C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[O:1][N:2]=4)=[O:12])[CH2:18][CH2:17]3)[S:23][N:22]=2)[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: NC1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.5 %

Procedure:
To a solution of tert-butyl [1-(5-{4-[(1,2-benzisoxazol-3-ylamino)carbonyl]piperazin-1-yl}-1,2,4-thiadiazol-3-yl)piperidin-4-yl]carbamate (200 mg, 0.378 mmol) in tetrahydrofuran (10 ml) and methanol (10 ml) was added a solution of 4 N hydrogen chloride in ethyl acetate (10 ml), and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of methanol and diethyl ether to give 181 mg (95.5%) of the desired product as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH2:23])[O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][CH:11]=1.[N:24]#[C:25]Br>O1CCCC1.C(OCC)(=O)C>[NH2:24][C:25]1[NH:1][C:2]2[CH:3]=[C:4]([O:5][C:6]3[CH:7]=[C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][CH:11]=3)[CH:20]=[CH:21][C:22]=2[N:23]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc(N)c(N)c2)c1
Reactant: N#CBr
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc3nc(N)[nH]c3c2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 135 %

Procedure:
To a solution of tert-butyl [3-(3,4-diaminophenoxy)phenyl]carbamate (3.00 g, 9.51 mmol) in tetrahydrofuran (150 mL) was added cyanogen bromide (2.93 g, 27.7 mmol), and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate (300 mL), washed with saturated aqueous sodium hydrogencarbonate solution (100 mL×2) and saturated brine (100 mL), successively, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated to give the title compound (4.37 g) as a brown solid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C@H:9]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=2[F:21])[CH2:8][C@@H:7]([SH:22])[CH2:6]1)(=[O:4])=[O:3].[NH:23]([C:40]([CH3:42])=[O:41])[C@H:24]([C:37]([OH:39])=[O:38])[CH2:25][S:26]SC1N=CC=CC=1[N+]([O-])=O>>[C:40]([NH:23][C@@H:24]([CH2:25][S:26][S:22][C@@H:7]1[CH2:8][C@@H:9]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=2[F:21])[N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6]1)[C:37]([OH:39])=[O:38])(=[O:41])[CH3:42]
Reactant: CC(=O)N[C@@H](CSSc1ncccc1[N+](=O)[O-])C(=O)O
Reactant: CS(=O)(=O)N1C[C@H](S)C[C@H]1COCc1cc(F)c(F)cc1F
Product: CC(=O)N[C@@H](CSS[C@@H]1C[C@@H](COCc2cc(F)c(F)cc2F)N(S(C)(=O)=O)C1)C(=O)O
Reaction time: 2 h
Yield: 93.3 %

Procedure:
(3R,5S)-1-Methanesulfonyl-5-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-3-thiol (100 mg, 0.28 mmol) and Ac-Cys(Npys)-OH (89 mg, 0.28 mmol) were dissolved in argon-degassed DMF (abs. 2 ml) and degassed 0.1 M phosphate buffer (pH 6.2, 2 ml) was added. The reaction mixture was magnetically stirred for 2 h under argon. Work-up as above (Example 22a) yielded (R)-2-acetylamino-3-[(3R,5S)-1-methanesulfonyl-5-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidin-3-yldisulfanyl]-propionic acid (135 mg), MS: 515 (MH−).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:14]2[NH:15]C(=O)[O:17][C@H:13]2[CH2:12][C@H:11]([CH2:19][F:20])[C@H:10]1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.O.[OH-].[Na+]>[NH2:15][C@@H:14]1[C@@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:10]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@@H:11]([CH2:19][F:20])[CH2:12][C@@H:13]1[OH:17]
Reactant: O=C1N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CF)C[C@@H]2O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](CF)C[C@@H]1O
Yield: 96.7 %

Procedure:
A mixture of (3aS,4R,5R,6S,7aS)-4,5-bis(benzyloxy)-6-(fluoromethyl)hexahydrobenzo[d]oxazol-2(3H)-one (410 mg, 1.065 mmol) in ethanol (8 mL), water (8 mL) and 5 N NaOH (4 mL) was heated at reflux for 2 h. After cooling, the reaction was diluted with water (50 mL), extracted with DCM (3×25 mL) and dried with Na2SO4. The solvent was evaporated to give (1S,2S,3R,4R,5S)-2-amino-3,4-bis(benzyloxy)-5-(fluoromethyl)cyclohexanol as a white solid (370 mg, 97%) which was pure enough for next reaction. MS m/z 382.2 (M+23, 100%); 1H NMR (400 MHz, CDCl3) δ 7.29-7.39 (m, 10H), 5.03 (d, J=11.4 Hz, 1H), 4.91 (d, J=10.9 Hz, 1H), 4.78 (ddd, J=48.0 Hz, 9.0 Hz, 3.0 Hz, 1H), 4.67 (d, J=10.9 Hz, 1H), 4.65 (d, J=11.4 Hz, 1H), 4.37 (ddd, J=47.4 Hz, 9.1 Hz, 2.0 Hz, 1H), 3.88 (br s, 1H), 3.58 (t, J=9.4 Hz, 1H), 3.48 (t, J=9.9 Hz, 1H), 2.11-2.26 (m, 1H), 1.95 (dt, J=14.3 Hz, 3.1 Hz, 1H), 1.63 (t, J=13.6 Hz, 1H).
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][C:16](F)=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][C:33]([OH:38])([CH3:37])[CH2:34][CH2:35][OH:36].[OH-].[Li+].Cl>O1CCCC1.O>[CH:1]1([CH:7]([NH:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([O:36][CH2:35][CH2:34][C:33]([OH:38])([CH3:37])[CH3:32])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(O)CCO
Reactant: COC(=O)c1ccc(NC(c2cc(-c3ccc(F)nc3)oc2C)C2CCCCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccc(OCCC(C)(C)O)nc2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 80 °C
Reaction time: 10 h
Yield: 15.1 %

Procedure:
Methyl 4-({cyclohexyl[5-(6-fluoropyridin-3-yl)-2-methylfuran-3-yl]methyl}amino)benzoate (1.7 g) and 3-methyl-1,3-butanediol (2.1 g) were dissolved in tetrahydrofuran (10 mL), 2N lithium hydroxide (4 mL) was added, and the mixture was stirred at 80° C. for 10 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 purified by silica gel chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the title compound (0.3 g, 16%) as an amorphous compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])=[O:4].[S-:12][C:13]#[N:14].[K+].O>C(O)C>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][S:12][C:13]#[N:14]
Reactant: N#C[S-]
Reactant: O=C(CBr)c1ccccc1Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CSCC(=O)c1ccccc1Cl
Temperature: 25 °C
Yield: 75.3 %

Procedure:
A solution of 2-bromo-1-(2-chlorophenyl)ethanone (7.55 g, 32.3 mmol) and potassium thiocyanate (3.14 g, 32.3 mmol) in ethanol (70 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (70 ml) was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 5.15 g (75.3%) of the desired product as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][N:10]2[CH:14]=[CH:13][S:12][CH:11]2[NH:15][C:16](=[O:18])[CH3:17])=[CH:4][CH:3]=1>C(OCC)(=O)C.C(O)(=O)C.[C].[Pd]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][S:12][CH:11]2[NH:15][C:16](=[O:18])[CH3:17])=[CH:4][CH:3]=1
Reactant: CC(=O)NC1SC=CN1C=Cc1ccc(O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)NC1SC=CN1CCc1ccc(O)cc1
Yield: 95.8 %

Procedure:
N-{3-[2-(4-Hydroxyphenyl)vinyl]-1,3-thiazol-2-yl}acetamide (1.900 g, 7.299 mmol) was dissolved in a mixture of ethyl acetate (300 ml) and acetic acid (50 ml), and 10% palladium carbon (760 mg, containing 50% water) was added. The mixture was hydrogenated at room temperature under 4-5 atm. After the completion of the reaction, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate by heating, and recrystallized by cooling to give N-{3-[2-(4-hydroxyphenyl)ethyl]-1,3-thiazol-2-yl}acetamide (1.834 g, 6.993 mmol, yield 95.8%) as a white solid.
Reaction SMILES: [CH2:1]([NH:4][CH:5]([CH3:10])[C:6]([O:8]C)=O)[C:2]#[CH:3].[Cl:11][C:12]1[CH:13]=[C:14]([N:19]=[C:20]=[O:21])[CH:15]=[C:16]([Cl:18])[CH:17]=1>C1(C)C=CC=CC=1>[CH2:1]([N:4]1[CH:5]([CH3:10])[C:6](=[O:8])[N:19]([C:14]2[CH:15]=[C:16]([Cl:18])[CH:17]=[C:12]([Cl:11])[CH:13]=2)[C:20]1=[O:21])[C:2]#[CH:3]
Reactant: C#CCNC(C)C(=O)OC
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Solvent: Cc1ccccc1
Product: C#CCN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)C1C
Temperature: 100 °C
Yield: 86.5 %

Procedure:
To a solution of methyl 2-propargylaminopropionate (10 g, 0.07 mole) in toluene (100 mL) with 2 drops of stannous octonoate was added 3,5-dichlorophenylisocyanate (14.5 g, 0,077 mole) in small portions. The resulting mixture was heated at 100° C. for 3 hours. It was then washed with water twice and dried over sodium sulfate. Solvent was evaporated to give a thick, yellow oil. Material was further purified by passing it through a silica gel column using 30/70 ethyl acetate/hexane as eluent to give 18 grams of a light yellow oil which solidified on standing. The solids were triturated in boiling hexane and collected by suction filtration; mp 105°-106° C., NMR and elemental analysis confirmed the desired structure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:41]1([CH2:47][CH2:48][CH2:49][CH2:50][NH2:51])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14](=[O:15])[NH:51][CH2:50][CH2:49][CH2:48][CH2:47][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NCCCCc1ccccc1
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCCCCc1ccccc1

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid and 4-phenylbutylamine (46 uL) according to Method A to give the title compound (34 mg). 1H-NMR (400 MHz, CD3OD) d 7.76 (s, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.26-7.11 (m, 10H), 6.98 (d, J=8.5 Hz, 1H), 4.76 (s, 2H), 4.50 (t, J=6.9 Hz, 1H), 4.23 (dd, J=5.2 Hz, J=9.3 Hz, 1H), 3.17 (m, 1H), 3.09-2.91 (m, 4H), 2.75 (dd, J=9.4 Hz, J=13.6 Hz, 1H), 2.58 (t, J=7.5 Hz, 2H), 1.54 (m, 2H), 1.42 (m, 2H), 1.34 (s, 9H); IR (KBr) 3296, 2925, 1738, 1687, 1643 cm−1; HRMS m/z 661.2987 (calc. of monoisotopic mass for C36H43N3O9 gives 661.2999).
Reaction SMILES: [CH2:1]=[C:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1.[OH:23]O.[OH-].[Na+].O>CO>[O:23]1[C:19]23[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]12)[C@@H:13]1[C@H:4]([C@H:5]2[C@@:9]([CH2:11][CH2:12]1)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]2)[CH2:3][C:2]3=[CH2:1]
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)C=C12
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=C1C[C@H]2[C@@H]3CCC(=O)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C3OC132
Reaction time: 24 h
Yield: 80 %

Procedure:
To a solution of 6-methylenandrost-4-ene-3,17-dione (5 g, 16.7 mmole) in methanol (200 ml) cooled at 0° C. is added a cold 36% hydrogen peroxide solution (17 ml) and a cold 2% sodium hydroxide aqueous solution. The resulting reaction mixture is stirred at 0°-5° C. during 24 hrs, then it is poured into iced water (1400 ml) with vigorous stirring. The resulting precipitate is filtered, washed with water and dried in vacuo. There are obtained 4.2 g (80% yield) of the title compound,
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=13)[NH:8][CH2:7][N:6]([C@H:16]1[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]1[O:22][Si](C(C)(C)C)(C)C)[C:5]2=[O:30].Cl.[C:32]([O-])(O)=O.[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=13)[N:8]([CH3:32])[CH2:7][N:6]([C@@H:16]1[C@@H:17]([OH:22])[CH2:18][O:19][CH2:20][CH2:21]1)[C:5]2=[O:30]
Reactant: O=C([O-])O
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1COCC[C@@H]1N1CNc2c(cc(Br)c3ccccc23)C1=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CN([C@H]2CCOC[C@@H]2O)C(=O)c2cc(Br)c3ccccc3c21
Reaction time: 8 h

Procedure:
To a solution of 1,5-anhydro-3-(6-bromo-4-oxo-1,4-dihydrobenzo[h]quinazolin-3(2H)-yl)-2-O-[tert-butyl(dimethyl)silyl]-3,4-dideoxy-L-threo-pentitol (0.89 g, 1.8 mmol) in THF (17.5 mL) was added hydrochloric acid (1 N, 10 mL). Additional concentrated hydrochloric acid (2 mL) was added. After stirring overnight, the solution was basified by addition of saturated, aqueous NaHCO3, then extracted 2× with EtOAc. The organics were washed with brine, dried over MgSO4, filtered, concentrated, and dried to provide 1,5-anhydro-3-(6-bromo-1-methyl-4-oxo-1,4-dihydrobenzo[h]quinazolin-3(2H)-yl)-2,3-dideoxy-L-threo-pentitol that gave a mass ion (ES+) of 392.9 for [M+H]+.
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.O[CH2:71][C@@H:72]1[CH2:74][C@H:73]1[C:75]([O:77][CH2:78][CH3:79])=[O:76].C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCOC(C)=O.O>[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:71][C@@H:72]3[CH2:74][C@H:73]3[C:75]([O:77][CH2:78][CH3:79])=[O:76])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Reactant: CCOC(=O)[C@@H]1C[C@H]1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1COc1cc(CCCOC)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl(3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in toluene (0.1 M) was added 1,1′-(azodicarbonyl)dipiperidine (1.2 eq.), ethyl (1R,2R)-2-(hydroxyl-methyl)cyclopropanecarboxylate (2 eq.) from the previous step, and tri-n-butylphosphine (1.2 eq.). The reaction was heated to 80° C. and stirred for 18 h. While hot, the reaction was diluted with EtOAc/water. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 40% EtOAc in Hex) to afford the title compound as an oil.