Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(OC([N:71]1[C@@H:75]2[CH2:76][NH:77][CH2:78][CH2:79][CH2:80][C@@H:74]2[CH2:73][CH2:72]1)=O)C1C=CC=CC=1>CN(C=O)C.C(OCC)(=O)C.[Pd].CO>[CH3:28][N:26]([CH3:27])[C:25]([C:7]1[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:77]4[CH2:78][CH2:79][CH2:80][C@@H:74]5[CH2:73][CH2:72][NH:71][C@@H:75]5[CH2:76]4)=[O:21])=[CH:18][N:17]=3)[N:13]=[CH:14][C:9]=2[CH:8]=1)=[O:29]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Reactant: O=C(OCc1ccccc1)N1CC[C@H]2CCCNC[C@H]21
Agent: [Pd]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CCC[C@@H]5CCN[C@@H]5C4)cn3)nc2n1C1CCCC1
Temperature: 23 °C
Reaction time: 1.5 h

Procedure:
A solution of 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino) nicotinic acid (5 eq of Lithium Chloride) (0.088 g, 0.146 mmol), HBTU (0.086 mg, 0.226 mmol, 1.6 eq) and triethylamine (0.100 mL, 0.717 mmol, 4.9 eq) in DMF (3 mL) was stirred at 23° C. for 5 minutes, then (3aR,8aS)-Octahydro-pyrrolo[2,3-c]azepine-1-carboxylic acid benzyl ester (0.040 mg, 0.146 mmol, 1.0 eq) was added and the reaction stirred at 23° C. for 1.5 hr. The reaction mixture was diluted with Ethyl Acetate, the mixture washed with 0.5M HCl (aq), then water (3×), brine, the organic layer dried (Na2SO4), filtered, and the filtrate concentrated. The crude was purified using chromatography (Methanol/CH2Cl2) giving a white solid. To the resulting solid (42 mg) was added 10% Pd/C (15 mg) followed by methanol (5 mL). The suspension was blanketed with H2 balloon with stirring for 6 hr. The contents of the reaction were filtered through Celite and the filtrate concentrated to a white solid that was burified by trituration from Ethyl Acetate/Heptane followed by chromatography (methanol/CH2Cl2) mixtures gave 7-cyclopentyl-2-[5-((3aR,8aS)-octahydro-pyrrolo[2,3-c]azepine-7-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide. (20 mg, 0.039 mmol, 27%). 1H NMR (400 MHz, MeOD) δ ppm 1.62-1.84 (m, 5H) 1.84-1.99 (m, 2H) 1.99-2.20 (m, 4H) 2.31 (dd, J=13.05, 5.02 Hz, 1H) 2.47-2.62 (m, 2H) 2.63-2.80 (m, 1H) 3.18-3.27 (m, 1H) 3.38-3.61 (m, 2H) 3.77 (d, J=13.05 Hz, 1H) 3.84-3.98 (m, 1H) 4.04 (t, J=7.53 Hz, 1H) 4.06-4.19 (m, 1H) 4.80 (quin, J=9.03, 8.87 Hz, 1H) 6.67 (s, 1H) 7.93 (dd, J=8.78, 2.26 Hz, 1H) 8.45 (d, J=2.01 Hz, 1H) 8.53 (d, J=8.53 Hz, 1H) 8.82 (s, 1H); HRMS calc for m/z=517.3039. Found m/z=517.3044 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([CH2:10][N:11]2[C:17](=[O:18])[C@@H:16]([NH:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH:32]=[C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[NH:30][C:29]4=[O:39])[CH2:24][CH2:23]3)=[O:21])[CH2:15][NH:14][C@H:13]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:12]2)[CH2:9][CH2:8]1.[CH2:46](Br)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CC(C)=O>[CH2:46]([N:14]1[CH2:15][C@@H:16]([NH:19][C:20]([N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[CH:32]=[C:31]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[NH:30][C:29]3=[O:39])[CH2:24][CH2:23]2)=[O:21])[C:17](=[O:18])[N:11]([CH2:10][CH:7]2[CH2:9][CH2:8]2)[CH2:12][C@@H:13]1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=C(N[C@H]1CN[C@H](c2ccccc2)CN(CC2CC2)C1=O)N1CCC(n2cc(-c3ccccc3)[nH]c2=O)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(N[C@@H]1CN(Cc2ccccc2)[C@@H](c2ccccc2)CN(CC2CC2)C1=O)N1CCC(n2cc(-c3ccccc3)[nH]c2=O)CC1
Reaction time: 18 h
Yield: 77.3 %

Procedure:
Potassium carbonate (6.4 mg, 0.05 mmol) was added to a solution of N-[(3R,6S)-1-(cyclopropylmethyl)-7-oxo-3-phenyl-1,4-diazepan-6-yl]-4-(2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-yl)piperidine-1-carboxamide (12.2.0 mg, 0.023 mmol) and benzyl bromide (14 □L, 0.12 mmol) in acetone (0.5 mL). After 18 h, the mixture was concentrated. Purification by silica gel chromatography (1% methanol/dichloromethane→5% methanol/dichloromethane) gave the title compound (11 mg). MS 619.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1([C:9]([O:11]C)=[O:10])[C:4]([CH3:6])([CH3:5])[C:3]1([Cl:8])[Cl:7].S(=O)(=O)(O)O.O>C(O)=O>[Cl:1][C:2]1([C:9]([OH:11])=[O:10])[C:4]([CH3:6])([CH3:5])[C:3]1([Cl:8])[Cl:7]
Reactant: COC(=O)C1(Cl)C(C)(C)C1(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: O=CO
Product: CC1(C)C(Cl)(Cl)C1(Cl)C(=O)O
Yield: 36.2 %

Procedure:
Methyl 1,2,2-trichloro-3,3-dimethylcyclopropanecarboxylate (10 g) was dissolved in formic acid (20 ml), and concentrated sulfuric acid (0.1 g) was added. The mixture was gently heated under reflux for 12 hours. After cooling, water (60 ml) was added to the reaction mixture. The precipitated crystals were collected by filtration, and recrystallized from hexane to give the desired 1,2,2-trichloro-3,3-dimethylcyclopropanecarboxylic acid (3.4 g) represented by the following formula. mp. 148°-150° C. ##STR25##
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1.C(N(CC)CC)C.II.Cl.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.O1CCCC1.O>[N:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:13][CH:14]=1)=[C:1]=[S:3]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: S=C=S
Agent: Cl
Agent: II
Agent: O=S([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(CN=C=S)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 109 %

Procedure:
Carbon disulfide (0.26 mL, 4.4 mmol) was added to a mixture comprising 4-(aminomethyl) benzoic acid (0.23 g, 1.5 mmol), tetrahydrofuran (1.0 mL), water (1.0 mL) and triethylamine (0.51 mL, 3.6 mmol), followed by stirring at room temperature for 24 hours. To the obtained reaction mixture, a tetrahydrofuran (1.0 mL) solution of iodine (0.41 g, 1.6 mmol) was dropwise added over a period of 4 minutes at 0° C., followed by stirring at 0° C. for further two hours. Thereafter, 1M hydrochloric acid (1.5 mL) and sodium sulfite (38 mg, 0.30 mmol) were added and mixed. Then, ethyl acetate (6 mL) was added, and the organic layer was separated and the aqueous layer was extracted once with ethyl acetate (3 mL). The organic layers were combined and concentrated under reduced pressure to dryness. To the obtained residue, ethyl acetate (3 mL) was added and thoroughly mixed, and the insoluble matter was filtered off. Then, the filtrate was concentrated under reduced pressure to dryness to obtain 4-(isothiocyanatomethyl)benzoic acid as a cream-colored solid (0.32 g, yield: 109%, HPLC purity: 88%, HPLC retention time: 3.1 min). LC-MS ES-192 (retention time: 3.5 min, condition 2).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[S:5][C:4]=1[C:26]([N:28]([CH3:39])[CH2:29][CH2:30][NH:31]C(=O)OC(C)(C)C)=[O:27].C(OC(=O)C)C.[ClH:46]>C(OCC)(=O)C>[ClH:46].[NH2:31][CH2:30][CH2:29][N:28]([CH3:39])[C:26]([C:4]1[S:5][C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:8](=[O:25])[C:7]=2[C:3]=1[O:2][CH3:1])=[O:27]
Reactant: COc1c(C(=O)N(C)CCNC(=O)OC(C)(C)C)sc2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1c(C(=O)N(C)CCN)sc2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Yield: 48 %

Procedure:
A solution of the obtained tert-butyl {2-[{[3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno[3,2-c]quinolin-2-yl]carbonyl}(methyl)amino]ethyl}carbamate (230 mg) and 4N hydrogen chloride ethyl acetate solution (8 mL) in ethyl acetate (15 mL) was stirred at room temperature for 2 hr. The obtained precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure to give the title compound (178 mg, 48%) as a white powder.
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)[C:2]#[CH:3].[Li]CCCC.[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C1COCC1>[CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)[C:2]#[C:3][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCBr
Reactant: C#CCOC1CCCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCC#CCOC1CCCCO1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of tetrahydro-2-(2-propynyloxy)-2H-pyran (47) (2.8 g, 20 mmol) in THF (30 mL) was cooled to -78° C. and n-BuLi (2.5 M, 8 mL) was added over 15 minutes. The mixture was stirred for 30 minutes at which time octyl bromide (4.24 g, 2.2 mmol, 1.1 equiv) in THF (10 mL) was added. The reaction mixture was then stirred at -78° C. for 1 hour, allowed to warm to 0° C. and stirred for an additional 30 minutes. The reaction mixture was quenched with NH4Cl (10 mL) and poured into ether (150 mL) and water (150 mL). The organic layer was separated, dried (MgSO4) and concentrated by rotary evaporation to yield a yellow oil used in the next step without purification. ##STR21##
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH3:6])=[O:4].[CH3:7][CH:8]([C:12]([OH:14])=O)[C:9]([OH:11])=O.C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][N:2]1[C:9](=[O:11])[CH:8]([CH3:7])[C:12](=[O:14])[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: CNC(=O)NC
Reactant: CC(C(=O)O)C(=O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC1C(=O)N(C)C(=O)N(C)C1=O
Temperature: 90 °C
Yield: 41.5 %

Procedure:
75 g (0.85 mol) of 1,3-dimethylurea and 102 g (0.86 mol) of methyl malonic acid were dissolved in 300 ml of glacial acetic acid at 65° C. To the solution was added 330 ml of acetic anhydride, the temperature was gradually raised and the mixture was refluxed by heating at 90° C. for 6 hours. The reaction solution was concentrated under reduced pressure, and benzene was added to the residue. The crystals thus-deposited were collected by filtration and recrystallized from benzene to obtain 60 g of 1,3,5-trimethylbarbituric acid. Yield: 42%, Melting Point: 83° to 85° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][S:17][C:11]=2[NH:10][C:9]1=[O:18].[CH:19]1([CH2:22]Br)[CH2:21][CH2:20]1>CN(C)C=O.O>[CH3:7][N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][S:17][C:11]=2[N:10]([CH2:22][CH:19]2[CH2:21][CH2:20]2)[C:9]1=[O:18]
Reactant: Cn1c(=O)[nH]c2sccc2c1=O
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2ccsc2n(CC2CC2)c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Potassium carbonate (1.0 g) was added to a mixture of 3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (400 mg; J. Chem. Soc. Perkin Trans.1; 1980; 1853) and cyclopropylmethyl bromide (1.0 ml) in dry dimethylformamide (15 ml). The solution was stirred at room temperature for 20 hours and was then diluted with water and extracted thrice with diethyl ether. The combined organic extracts were washed with brine, then dried, filtered and evaporated. The residue was purified by column chromatography over silica, eluting with ethyl acetate: isohexane (1:4) to give the subtitle compound (180 mg).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:12]=[C:11]([CH2:13][C:14](=O)[CH2:15][CH2:16][OH:17])[C:10]2[C:5](=[C:6]([C:19]([F:22])([F:21])[F:20])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[BH4-].[Na+].CC[OH:29]>O>[F:1][C:2]([F:23])([F:24])[C:3]1[CH:12]=[C:11]([CH:13]([OH:29])[CH2:14][CH2:15][CH2:16][OH:17])[C:10]2[C:5](=[C:6]([C:19]([F:21])([F:22])[F:20])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CCO
Reactant: O=C(CCO)Cc1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: OCCCC(O)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A solution of 1-(2,8-bis(trifluoromethyl)-4-quinolinyl)-4-hydroxybutanone (748 mg, 2.13 mmol) in EtOH (4 mL) at 0° C. was treated with a solution of NaBH4 (81 mg, 2.13 mmol) in water (0.2 mL), stirred at 0° C. for 30 min, poured into water (15 mL), extracted with EtOAc (2×10 mL),dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; EtOAc-heptane (2:1)] to give the title compound (618 mg, 82%) as a colourless oil; IR νmax (Nujol)/cm−1 3600-3200, 2938, 2885, 1604,1588, 1430, 1310, 1189, 1144 and 1110; NMR δH (400 MHz, CDCl3) 1.81-1.91 (3H, m), 2.08-2.17 (1H, m), 2.45-2.70 (2H, br s),3.75-3.78 (1H, m), 3.80-3.88 (1H, m), 5.52 (1H, d, J 8.0 Hz), 7.71 (1H, t, J 7.9 Hz), 8.08 (1H, s), 8.15 (1H, d, J 7.2 Hz) and 8.23 (1H, d, J 8.7 Hz).
Reaction SMILES: [O:1]=[C:2]1[C:10](=[CH:11][C:12]2[NH:16][C:15]([CH3:17])=[C:14]([C:18]([OH:20])=O)[C:13]=2[CH3:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[NH2:22][CH2:23][CH:24]([OH:31])[CH2:25][N:26]1[CH:30]=[CH:29][N:28]=[N:27]1>>[OH:31][CH:24]([CH2:25][N:26]1[CH:30]=[CH:29][N:28]=[N:27]1)[CH2:23][NH:22][C:18]([C:14]1[C:13]([CH3:21])=[C:12](/[CH:11]=[C:10]2\[C:2](=[O:1])[NH:3][C:4]3[C:9]\2=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:16][C:15]=1[CH3:17])=[O:20]
Reactant: Cc1[nH]c(C=C2C(=O)Nc3ccccc32)c(C)c1C(=O)O
Reactant: NCC(O)Cn1ccnn1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccccc32)c(C)c1C(=O)NCC(O)Cn1ccnn1

Procedure:
5-(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (113 mg, 0.4 mmol) was condensed with 1-amino-3(1,2,3)triazole-1-yl-propan-2-ol (85 mg, 0.48 mmol) to precipitate 2,4-dimethyl-5-[2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-[1,2,3]triazol-1-yl-propyl)-amide (70 mg, 41%). 1H NMR (DMSO-d6) δ 2.45, 2.48 (2×s, 6H, 2×CH3), 3.35 (m, 2H), 4.02 (m, 1H), 4.32 (dd, J=7.6, 14 Hz, 1H), 4.53 (dd, J=3.4, 14 Hz, 1H), 5.43 (d, J=5.6 Hz, 1H, OH), 6.91 (d, J=7.6 Hz, 1H), 7.01 (t, J=7.6 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H), 7.66 (s, 1H), 7.12 (t, J=5.6 Hz, 1H), 7.74 (s, 1H), 7.77 (d, J=7.6 Hz, 1H), 8.11 (s, 1H), 10.93 (s, 1H, CONH), 13.68 (s, 1H, NH). LC-MS (m/z) 405.4 (M−1).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][NH:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[N+:18]([O-])=O)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>C(O)C.[Ni]>[CH2:1]([O:3][P:4]([CH2:9][NH:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[NH2:18])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(CNc1cc(F)ccc1[N+](=O)[O-])OCC
Agent: [Ni]
Solvent: CCO
Product: CCOP(=O)(CNc1cc(F)ccc1N)OCC
Reaction time: 2 h
Yield: 92.6 %

Procedure:
790 mg of N-(2-nitro-5-fluorophenyl)aminomethanephosphonic acid diethyl ester is mixed in 50 ml of ethanol with 2.5 g of Raney nickel and hydrogenated for 2 hours at room temperature under normal hydrogen pressure. After suctioning-off from the catalyst, it is concentrated by evaporation. 660 mg of N-(2-amino-5-fluorophenyl)aminomethanephosphonic acid diethyl ester is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.Cl>C(=S)=S>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: ClC1CCCCC1
Reactant: Clc1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: Clc1ccc(Cl)c(C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.3 %

Procedure:
To a solution of 1,4-dichlorobenzene (294 g) in anhydrous carbon disulfide (400 ml) was added anhydrous aluminum chloride (16.0 g). To the mixture was added dropwise chlorocyclohexane (96 g) with stirring at ambient temperature during 3 hours. After the stirring was continued for 3 hours at ambient temperature, the reaction mixture was allowed to stand overnight at ambient temperature. To the reaction mixture was added dil.hydrochloric acid with stirring. The organic layer was separated, washed with water, dried over magnesium sulfate, concentrated under reduced pressure and allowed to stand at ambient temperature for a while to give precipitates. The precipitates were removed by filtration. The filtrate was distilled under reduced pressure to give 1,4-dichloro-2-cyclohexylbenzene (47.0 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:5][C@H:6]([NH:22][C:23](=[O:25])[CH3:24])[C@H:7]([OH:21])[CH2:8][NH:9][CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](I)[CH:18]=2)[O:13][CH2:12][CH2:11]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].B(CC)(CC)[CH2:39][CH3:40]>C1COCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:5][C@H:6]([NH:22][C:23](=[O:25])[CH3:24])[C@H:7]([OH:21])[CH2:8][NH:9][C@@H:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:39][CH3:40])[CH:18]=2)[O:13][CH2:12][CH2:11]1
Reactant: CCB(CC)CC
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1CCOc2ccc(I)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1ccc2c(c1)[C@@H](NC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(C)=O)CCO2
Temperature: 65 °C
Reaction time: 2.5 h

Procedure:
N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(6-iodo-3,4-dihydro-2H-chromen-4-yl)amino]propyl}acetamide (1.0 g, 1.9 mmol) and Pd(dppf)Cl2 (0.078 g, 0.1 mmol) was dissolved in 20 mL of degassed THF. To the mixture was added 10 mL of 2.0 M K3PO4 followed by the addition of Et3B (3.8 mL, 3.8 mmol, 1.0 M in THF) via syringe. The reaction mixture was heated to 65° C. under a nitrogen atmosphere. After 2.5 h the reaction was determined to be complete and diluted with EtOAc (100 mL) and washed with brine (3×30 mL). The organic layer was dried over Na2SO4 and conc. in vacuo to yield brown solid. The diastereomers of the title compound were separated by preparative chiral HPLC (Chiralpak AD, 20% IPA/80%heptane, 0.1% DEA). MS (ESI+) for C23H26F2N2O3 m/z 419 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[OH:25])=[O:16].O>CN(C)C=O>[F:14][C:12]1[CH:13]=[CH:8][C:9]2[C:15](=[O:16])[C:17]3[C:18]([O:25][C:10]=2[CH:11]=1)=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3
Reactant: COc1ccc(C(=O)c2ccc(F)cc2F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(=O)c3ccc(F)cc3oc2c1
Temperature: 100 °C
Yield: 88.9 %

Procedure:
A mixture of potassium carbonate (2.13 g, 15.4 mmol) and (2,4-difluoro-phenyl)-(2-hydroxy-4-methoxy-phenyl)-methanone (3.4 g, 12.9 mmol) in N,N-dimethylformamide (50 mL) was heated at 100° C. for 2 h. The mixture was cooled and poured into water (˜150 mL). A solid was collected by filtration, washed with water, and dried in vacuo to give the title compound (2.8 g), which was used without purification in the subsequent step. MS: m/z 244.9 (MH+). 1H NMR (CDCl3): δ 3.94 (s, 1H), 6.88 (d, 1 H, J=2.4 Hz), 6.96 (d of d, 1 H, J=2.4 & 8.9 Hz), 7.07 (m, 2 H), 8.24 (d, 1 H, 8.9 Hz) and 8.34 (d of d, 1 H, J=6.5 & 8.8 Hz).
Reaction SMILES: Cl[CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[C:11]([O-:14])(=[S:13])[CH3:12].[K+].[Cl-].[Na+]>CN(C)C=O.O>[C:11]([S:13][CH2:2][P:3]([O:7][CH2:8][CH3:9])([O:4][CH2:5][CH3:6])=[O:10])(=[O:14])[CH3:12]
Reactant: CC([O-])=S
Reactant: CCOP(=O)(CCl)OCC
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(CSC(C)=O)OCC
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 17.527 g (93.938 mM) of diethyl chloromethylphosphonate in 50 ml of N,N-dimethylformamide was added 12.9 g (113 mM) of potassium thioacetate and the mixture was stirred at 100° C. for 3 hours. This reaction mixture was poured in water, saturated with sodium chloride, and extracted with 4 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate:3/1 to 1/1) to provide the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([O:24]CC)=[O:23])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12]CC)=[O:11])=[CH:5][CH:4]=1.[OH-].[Na+].O>C(O)C>[CH3:1][N:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([OH:24])=[O:23])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC(=O)Cc1ccc(N(C)Cc2ccccc2C(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(Cc1ccccc1C(=O)O)c1ccc(CC(=O)O)cc1
Yield: 72.4 %

Procedure:
The oily ester (20 g) so obtained was added to a solution of sodium hydroxide (25 g) in a mixed liquor of water (300 ml) and ethanol (100 ml). The mixture was heated under reflux for 2 hours. After most of ethanol was distilled off, the mixture was washed with ether. The aqueous layer was acidified by addition of acetic acid to the layer cooled with ice, and then extracted with ether. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was recrystallized from methanol-benzene to obtain N-methyl-N-(2-carboxybenzyl)-4-carboxymethylaniline (12.2 g) as colorless prismatic crystals.
Reaction SMILES: [C:1]([C:9]1[C:13]([S:14]C(=O)C2C=CC=CC=2)=[CH:12][N:11]([Si](C(C)C)(C(C)C)C(C)C)[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[CH2:36]([C:40]1([CH2:43][CH3:44])[CH2:42][NH:41]1)[CH2:37][CH2:38][CH3:39]>C(OCC)(=O)C.CO>[C:1]([C:9]1[C:13]([S:14][CH2:42][C:40]([NH2:41])([CH2:43][CH3:44])[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:12][NH:11][CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(SC(=O)c2ccccc2)c(C(=O)c2ccccc2)c1
Reactant: CCCCC1(CC)CN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCC(N)(CC)CSc1c[nH]cc1C(=O)c1ccccc1
Yield: 86.3 %

Procedure:
A mixture of the product from step (c) (24.9 g), 250 ml methanol and 106 ml 1N sodium hydroxide was warmed to reflux for 10 minutes then 1N hydrochloric acid (53 ml) was added followed by 2-butyl-2-ethylaziridine (7.7 g, Synthetic Example 1(f)). After one hour the reaction was diluted with ethyl acetate and washed with 1N sodium hydroxide and then water. The organic layer was dried, filtered and concentrated. The residue was chromatographed on silica gel eluting with ethyl acetate-ethanol (3:1) to give a tan viscous oil (15.32 g). 1H NMR is consistent with proposed structure.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:43]([O:46][C:47](=[O:54])[C@H:48]([CH2:50][CH:51]([CH3:53])[CH3:52])[NH2:49])[CH:44]=[CH2:45].ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl>C(Cl)Cl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:20]([NH:49][C@@H:48]([CH2:50][CH:51]([CH3:52])[CH3:53])[C:47]([O:46][CH2:43][CH:44]=[CH2:45])=[O:54])=[O:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: C=CCOC(=O)[C@@H](N)CC(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: C=CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 20.2 %

Procedure:
Following the procedure as described in Example 24, except using suspension of (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(tert-butoxycarbonylamino)propanoic acid (500 mg, 1.172 mmol), L-leucine allyl ester p-toluenesulfonate salt (411 mg, 1.196 mmol), 1-hydroxy-7-azabenzotriazole (80 mg, 0.586 mmol), CH2Cl2 (40 mL), N-methylmorpholine (0.258 mL, 2.345 mmol), and EDC (247 ing, 1.290 mmol), 137 mg (20.16%) of the title compound is isolated as a white solid. Purification is done by BIOTAGE® Silica gel chromatography on a 90 g Thompson Single Step silica cartridge using a linear gradient from 100% Hexanes to 100% (1:1 EtOAc/Hexanes) over 12 column volumes. LC/MS (Condition A): ret. T=4.50 min, (2M+Na) 1181.97.