Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:19]=[CH:18][C:17]3[N:16]([CH3:20])[C:15]4[CH2:21][CH:22]5[NH:26][CH:25]([C:14]=4[C:13]=3[C:12]=2C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[ClH:34]>O1CCOCC1>[ClH:34].[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15]2[CH2:21][CH:22]4[NH:26][CH:25]([C:14]3=2)[CH2:24][CH2:23]4)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4cccc(F)c4)ccc31)C1CCC(C2)N1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c2c(c3cc(S(=O)(=O)c4cccc(F)c4)ccc31)C1CCC(C2)N1

Procedure:
The product of step A (105 mg, 0.22 mmol) was treated with a solution of 4 M HCl in dioxane (1.5 mL). After 1.5 h the mixture was concentrated in vacuo and the residue partitioned with saturated sodium bicarbonate solution and chloroform. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 90:9:1 chloroform/methanol/ammonium hydroxide) to give 2-(3-fluorophenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride (45 mg, 50%, AUC HPLC 98.8%) as a white solid: mp 240-245° C.; 1H NMR (DMSO-d6, 300 MHz) δ 8.20-8.70 (m, 3H), 7.74-7.81 (m, 2H), 7.59-7.71 (m, 3H), 7.45-7.55 (m, 1H), 5.15-5.24 (m, 1H), 4.31-4.43 (m, 1H), 3.66 (s, 3H), 3.21-3.39 (m, 1H), 2.92 (d, J=16.8 Hz, 1H), 2.12-2.29 (m, 2H), 1.96-2.09 (m, 1H), 1.66-1.80 (m, 1H); ESI MS m/z 371 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:32]=[C:31]([N:33]4[CH2:38][CH2:37][N:36]([CH2:39][C:40]5[CH2:45][CH2:44][C:43]([CH3:47])([CH3:46])[CH2:42][C:41]=5[C:48]5[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=5)[CH2:35][CH2:34]4)[CH:30]=[CH:29][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22](Cl)=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=3)(=[O:18])=[O:17])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[O:55]1[CH2:60][CH2:59][CH:58]([N:61]2[CH2:64][CH:63]([NH2:65])[CH2:62]2)[CH2:57][CH2:56]1.C(N(CC)CC)C.CS(C)=O>O1CCOCC1.O>[Cl:54][C:51]1[CH:52]=[CH:53][C:48]([C:41]2[CH2:42][C:43]([CH3:47])([CH3:46])[CH2:44][CH2:45][C:40]=2[CH2:39][N:36]2[CH2:37][CH2:38][N:33]([C:31]3[CH:30]=[CH:29][C:12]([C:13]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][C:22]([NH:65][CH:63]5[CH2:62][N:61]([CH:58]6[CH2:59][CH2:60][O:55][CH2:56][CH2:57]6)[CH2:64]5)=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=4)(=[O:17])=[O:18])=[O:14])=[C:11]([O:10][C:8]4[CH:9]=[C:4]5[CH:3]=[CH:2][NH:1][C:5]5=[N:6][CH:7]=4)[CH:32]=3)[CH2:34][CH2:35]2)=[CH:49][CH:50]=1
Reactant: NC1CN(C2CCOCC2)C1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(Cl)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CN(C6CCOCC6)C5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
A suspension of 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-N-(4-chloro-3-nitrophenylsulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide (0.180 g), 1-(tetrahydro-2H-pyran-4-yl)azetidin-3-amine (0.078 g), and triethylamine (0.159 mL) in dioxane (2 mL) was degassed with nitrogen for 30 seconds then sealed. The reaction was heated to 110° C. After stirring for 16 hours, more triethylamine (10 equivalents total) and dimethylsulfoxide (1 mL) were added and the reaction stirred for an additional 18 hours at 110° C. The reaction was cooled, diluted with water (50 mL) and extracted with dichloromethane (2×150 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (GraceResolv 12 g) eluting with a gradient of 0.75% to 7.5% methanol/dichloromethane (Flow=36 mL/minutes) gave the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 11.59 (s, 1H), 8.49 (d, 1H), 8.40 (s, 1H), 7.97 (d, 1H), 7.77 (s, 1H), 7.47 (dd, 3H), 7.34 (d, 2H), 7.04 (d, 2H), 6.90-6.78 (m, 1H), 6.65 (d, 1H), 6.35 (s, 1H), 6.21 (s, 1H), 4.47-4.23 (m, 1H), 3.83 (s, 3H), 3.05 (s, 6H), 2.73 (s, 2H), 2.18 (s, 8H), 1.95 (s, 2H), 1.68 (s, 2H), 1.38 (s, 2H), 1.24 (s, 4H), 0.92 (s, 6H).
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:8](O)(=[O:16])[CH:9]([CH:11]([C:13](O)=[O:14])[OH:12])[OH:10]>C1(C)C=CC=CC=1>[CH2:1]([N:7]1[C:13](=[O:14])[CH:11]([OH:12])[CH:9]([OH:10])[C:8]1=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: CCCCCCN
Solvent: Cc1ccccc1
Product: CCCCCCN1C(=O)C(O)C(O)C1=O
Temperature: 100 °C

Procedure:
N-hexyl DL-tartarimide was prepared by the reaction of n-hexyl amine with DL-tartaric acid. DL-Tartaric acid (10.026 g, 66.80 mmole) and toluene (17.327 g) were weighed into a 250 mL 3-necked round-bottomed flask equipped with a teflon-coated magnetic stir bar. A Claisen adapter was placed in the center neck, a Dean-Stark trap was placed on top of the Claisen adapter, and a condenser was placed in the neck of the Dean-Stark trap. A nitrogen inlet adapter was placed on the condenser. In the left neck was placed a pressure-equalizing addition funnel containing n-hexyl amine (6.760 g, 66.80 mmole) and toluene (7.936 g, added to ensure complete transfer of the amine). In the right neck was placed a rubber septum which held a thermocouple. The apparatus was purged with nitrogen for 10-15 minutes and then heated to ˜100° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][CH:6]1Br)(=[O:3])[CH3:2].[CH3:20][C:21]1[N:22]=[C:23]2[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][N:24]2[CH:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@H:6]1[O:29][C:27]1[CH:26]=[CH:25][N:24]2[CH:30]=[C:21]([CH3:20])[N:22]=[C:23]2[CH:28]=1)(=[O:3])[CH3:2]
Reactant: Cc1cn2ccc(O)cc2n1
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(Br)[C@@H]1OC(C)=O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccn2cc(C)nc2c1
Yield: 38 %

Procedure:
By carrying out the process in a manner similar to example 7, starting from 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide and 2-methyl-7-hydroxyimidazo[1,2-α]-pyridine obtained according to preparation 3, the desired product is obtained in the form of a white solid with a yield of 38%. The product obtained is used directly in the deacetylation step.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Cl:13])[CH:12]=1)(=O)=O.C(N(CC)CC)C.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25].CCCCCC>CN/C(/NCCSC1OC(CN(C)C)=CC=1)=C\[N+]([O-])=O.Cl.[Cu]I.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.C(OCC)(=O)C>[Cl:13][C:11]1[CH:10]=[N:9][CH:8]=[C:7]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[CH:12]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=S(=O)(Oc1cncc(Cl)c1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CN/C(=C\[N+](=O)[O-])NCCSc1ccc(CN(C)C)o1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cncc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
5-Chloro-3-pyridinyl trifluoromethanesulfonate (4.0 g, 15 mmol) and CuI (580 mg, 3.0 mmol) were combined in DMFE (100 mL) and argon gas was bubbled through the suspension for several minutes to deoxygenate the mixture. Triethylamine (10.6 mL, 76.5 mmol), and PdCl2(PPh3)2 (1.1 g, 1.5 mmol) were added, then trimethylsilyl-acetylene (3.3 ml, 23 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 1 h at which time GC/MS analysis indicated that the reaction was complete. The mixture was filtered through Celite™, and the filter pad was washed thoroughly with ethyl acetate. The combined filtrates were concentrated in vacuo and the residue was dissolved in ethyl acetate (300 mL), washed with water (300 mL), brine (300 mL), dried over Na2SO4 filtered, and concentrated in vacuo. The residue was purified by column chromatography eluting with hexane then 99:1 hexane:ethyl acetate to afford 3-chloro-5-[(trimethylsilyl)ethynyl]pyridine (2.8 g, 87% yield) as a brown solid. 1H NMR (CDCl3, 300 MHz) δ 8.51 (s, 1H), 8.44 (s, 1H), 7.70 (s, 1H), 0.22 (s, 9H). MS (EI ionization) 209 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10](=[O:12])[CH3:11].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:28]1([CH2:34][S:35][CH:36]([C:40](O)=[O:41])[C:37](O)=[O:38])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[OH:41][C:40]1[CH:11]=[C:10]([C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[O:12][C:37](=[O:38])[C:36]=1[S:35][CH2:34][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: CC(=O)c1c(C)cc(C)cc1C
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(-c2cc(O)c(SCc3ccccc3)c(=O)o2)c(C)c1

Procedure:
The title compound was prepared by Method A using 2',4', 6'-trimethylacetophenone (1.86 g, 11.5 mmol), lithium bis(trimethylsilyl)amide (2.11 g, 12.65 mmol), chlorotrimethylsilane (1.60 mL, 12.65 mmol), THF (127 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (2.95 g, 10.4 mmol). m.p. 134-136° C.; 1H NMR (250 MHz, DMSO-d6) δ 2.11 (s, 6 H), 2.26 (s, 3 H), 3.98 (s, 2 H), 6.03 (s, 1 H), 6.96 (s, 2 H), 7.25 (m, 5 H), 11.85 (bs, 1 H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[I-:18].[Na+]>CC(C)=O>[I:18][CH2:2][C:3]([N:5]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: [I-]
Reactant: O=C(CCl)N(c1ccccc1)C1CCCCC1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(CI)N(c1ccccc1)C1CCCCC1
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-N-cyclohexyl-N-phenylacetamide (503 mg, 2.0 mmol) in acetone (30 mL) was added sodium iodide (800 mg, 5.6 mmol). The reaction mixture was heated at reflux for 4 hours before it was cooled to room temperature. The solid material was filtered off, and the solvent removed from the filtrate under reduced pressure, to afford 2-iodo-N-cyclohexyl-N-phenylacetamide, which was subjected to subsequent reactions without further purification. B. To a solution of 2-iodo-N-cyclohexyl-N-phenylacetamide (obtained from A. above) in anhydrous DMF (30 mL) was added sodium azide (325 mg, 5.0 mmol), and the contents were heated at 80° C. for 10 hours. The reaction mixture was filtered, the solids washed with acetone (2×5 mL), and the solvent removed from the filtrate under reduced pressure, to afford 2-azido-N-cyclohexyl-N-phenylacetamide. C. To a solution of 2-azido-N-cyclohexyl-N-phenylacetamide (obtained from B. above) dissolved in methanol (50 mL) was added 10% Pd/C (90 mg, 0.09 mmol), and the reaction suspension was hydrogenated at room temperature under hydrogen (50 psi) for 5 hours. After filtration and concentration, the crude product was purified on silica gel using a methanol/dichloromethane gradient (0% to 10% methanol) to furnish 2-amino-N-cyclohexyl-N-phenylacetamide (320 mg, 69% yield). D. To a solution of exo-2-chloro-syn-7-hydroxymethyl-5-oxo-bicyclo[2.2.1]heptane (35 mg, 0.20 mmol) in 1-butanol (6 mL) was added 2-amino-N-cyclohexyl-N-phenylacetamide (46 mg, 0.20 mmol) and triethylamine (50 μL, 0.36 mmol). The reaction mixture was stirred at 100° C. for 2 days, then cooled to room temperature, concentrated under reduced pressure, and the residue purified on silica gel (10% methanol/dichloromethane) to afford N-cyclohexyl-2-{[7-(hydroxymethyl)-5-oxobicyclo[2.2.1]hept-2-yl]amino}-N-phenylacetamide CVT-6440 (8 mg, 10% yield). (M+1)=371.15. B. Preparation of a Compound of Formula I in which X is —N— and Z is —C(O)—
Reaction SMILES: [Cl:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[S:12][C:11]([N:13]=[C:14]=[O:15])=[N:10][N:9]=2)[CH2:4][CH2:3]1.[CH2:16]([NH:18][CH2:19][CH:20]=[O:21])[CH3:17]>C1C=CC=CC=1>[CH2:16]([N:18]([CH2:19][CH:20]=[O:21])[C:14]([NH:13][C:11]1[S:12][C:8]([CH:5]2[CH2:4][CH2:3][CH:2]([Cl:1])[CH2:7][CH2:6]2)=[N:9][N:10]=1)=[O:15])[CH3:17]
Reactant: CCNCC=O
Reactant: O=C=Nc1nnc(C2CCC(Cl)CC2)s1
Solvent: c1ccccc1
Product: CCN(CC=O)C(=O)Nc1nnc(C2CCC(Cl)CC2)s1

Procedure:
A mixture of 5-(4-chlorocyclohexyl)-1,3,4-thiadiazol-2-yl isocyanate dimer (13 grams), the dimethyl acetal of 2-ethylaminoacetaldehyde (6.9 grams) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-{1-ethyl-3-[5-(4-chlorocyclohexyl)-1,3,4-thiadiazol-2-yl]ureido}acetaldehyde.
Reaction SMILES: C([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16]Cl)=[C:7]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:6]=1)(=O)C.[NH:31]1[CH2:36][CH2:35]C[CH2:33][CH2:32]1.C(NCC)C>>[NH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][N:31]([CH2:36][CH3:35])[CH2:32][CH3:33])=[C:7]([O:19][CH2:20][C:21]2[CH:22]=[C:23]([O:29][CH3:30])[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=2)[CH:6]=1
Reactant: C1CCNCC1
Reactant: COc1cc(COc2cc(NC(C)=O)c(Cl)cc2C(=O)CCCCCl)cc(OC)c1
Solvent: CCNCC
Product: CCN(CC)CCCCC(=O)c1cc(Cl)c(N)cc1OCc1cc(OC)cc(OC)c1

Procedure:
Proceeding as in Example 4, Step (c), but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentan-1-one with 1-[4-acetylamino-5-chloro-2-(3,5-dimethoxybenzyloxy)phenyl]-5-chloropentan-1-one and piperidine with diethylamine, gave 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzyloxy)phenyl]-5-diethylaminopentan-1-one, m.p. 105°-107° C.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16]([SH:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CC(N(C)C)=O>[CH2:16]([S:24][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: N#Cc1ccc(Cl)cc1
Reactant: CCCCCCCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCCCCCCSc1ccc(C#N)cc1
Temperature: 0 °C
Yield: 104.1 %

Procedure:
103.2 g (0.75 mol) of p-chlorobenzonitrile, 140 g of potassium carbonate and 143.2 ml (0.825 mol) of octanethiol in dimethylacetamide are stirred at 100° C. for about 16 hours in a sulfonation flask under a protective-gas atmosphere. The white suspension obtained is cooled, poured into ice water and extracted a number of times with dichloromethane. The organic phases are combined, washed with water, dried over MgSO4, filtered and evaporated, giving 193.1 g of crude product, which is distilled at 92° C./0.1 mm Hg.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C@@H:5]([C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])[CH2:4][C@H:3]1[NH:13]C(=O)OC(C)(C)C.CCN(CC)CC>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:13][C@@H:3]1[CH2:4][C@H:5]([C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])[C:2]1([CH3:21])[CH3:1]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)N2CCCC2)C1(C)C
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)[C@H](N)C[C@@H]1C(=O)N1CCCC1
Yield: 100 %

Procedure:
A solution of tert-butyl (1R,3S)-2,2-dimethyl-3-(pyrrolidine-1-carbonyl)cyclobutylcarbamate (step 1, 0.400 g, 1.351 mmol) in TFA:DCM (1:2) (3 ml) stirred at 0° C.-room temperature for about 1 hour. After completion of the reaction, the solvent was evaporated and the crude was dissolved in DCM and basified with Et3N (1.124 ml, 8.108 mmol) the resulting solution as such used for next reaction immediately. Wt: 0.264 g (Based on 100% yield calculated and proceeded for next reaction).
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:11])=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:10][C:7]1[N:6]=[C:5]([O:11][CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(C)Br
Reactant: O=[N+]([O-])c1ccc(Cl)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Oc1nc(Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of 8.8 grams of 3-nitro-6-chloro-2-pyridinol, 9 grams of ethyl α-bromopropionate and 6 grams of potassium carbonate was stirred in 50 ml of DMSO (dimethylsulfoxide) at ambient temperature for approximately 48 hours.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[CH2:16]([NH2:20])[CH:17]([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([NH:20][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)CNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C

Procedure:
In a DMF solution containing 2.0 g of Boc-Val-OH, 0.92 ml of isobutylamine, 1.40 g of HOBt and 2.28 g of DCC were added under ice cooling and the resultant mixture was stirred for 14 hr. The reaction mixture was treated similarly to that in Example 51 (Process 1) to give 1.89 g of the title compound.
Reaction SMILES: [CH2:1]([C@H:8]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:9]([OH:38])[CH2:10][CH:11]([NH:25][C:26](=[O:37])[C@@H:27]([NH:32][C:33]([O:35][CH3:36])=[O:34])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>O>[CH2:1]([C@H:8]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:9]([OH:38])[CH2:10][C@H:11]([NH:25][C:26](=[O:37])[C@@H:27]([NH:32][C:33]([O:35][CH3:36])=[O:34])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)N[C@H](C(=O)NC(Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: O
Solvent: CO
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 45 °C
Reaction time: 1 h
Yield: 35.6 %

Procedure:
A 12 L 3-necked round bottom flask was charged with 169.74 gm of the product of Example 111-12 and 3.5 L of methanol, warmed to 45° C., water (1.75 L) was slowly added, stirred at 45-48° C. for about 1 hour, and cooled to ambient temperature overnight. The slurry was filtered and washed with 2:1 methanol:water, suction dried for 1 hour and dried at 50° C. vacuum oven overnight to give 60.4 gm of the title compound (28:1 diastereomeric ratio as determined by HPLC (Column: XDB C8 15 cm, Eluent: CH3CN/10 mM Na2HPO4 with H3PO4 adjusted to pH 7, Gradient: 10% CH3CN to 90% CH3CN in 15 min, then hold for 10 min, column oven temperature: 35° C.).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.Br[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1.CN(C)CCN>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Cu]I>[F:22][C:19]1[CH:20]=[CH:21][C:16]([N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]2=[O:1])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: Fc1ccc(Br)cc1
Agent: [Cu]I
Agent: CN(C)CCN
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(F)cc2)C(=O)C1
Temperature: 80 °C
Yield: 27.2 %

Procedure:
To a solution of tert-butyl 3-oxopiperazine-1-carboxylate (prepared according to procedure reported in JP2005504737, 2.0 g, 9.99 mmol), 1-bromo-4-fluorobenzene (1.748 g, 9.99 mmol), N,N-dimethylethylenediamine (0.070 g, 0.799 mmol) and potassium hydrophosphate (KHPO4) (3.13 g, 17.98 mmol) in toluene (10 ml) was added copper (I)iodide (0.101 g, 0.529 mmol) at 25° C. The reaction mixture was heated to 80° C. for 16 h. Progress of the reaction was monitored by TLC. The reaction mixture was cooled to 25° C., diluted with ethyl acetate (25 ml) and filtered through a plug of celite and concentrated to give crude product. The crude product was purified over silica gel (100-200 mesh) by column chromatography using 30% ethyl acetate in hexane as eluent to obtain the title compound (0.8 g, 27.2%).
Reaction SMILES: Cl[CH2:2][C:3]([C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[CH:8]=1)([OH:6])[CH2:4]Cl.C(=O)(O)[O-].[Na+].[CH2:20]([NH2:22])[CH3:21].O>C(#N)C.COC(C)(C)C>[F:14][C:9]1[CH:8]=[C:7]([C:3]2([OH:6])[CH2:4][N:22]([CH2:20][CH3:21])[CH2:2]2)[CH:12]=[C:11]([F:13])[CH:10]=1
Reactant: CCN
Reactant: OC(CCl)(CCl)c1cc(F)cc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CC#N
Product: CCN1CC(O)(c2cc(F)cc(F)c2)C1
Yield: 23 %

Procedure:
1,3-dichloro-2-(3,5-difluorophenyl)propan-2-ol (1.0 g, 4.15 mmol) was dissolved in acetonitrile (10 ml) and sodium bicarbonate (1.39 g, 16.59 mmol and ethylamine in water (70%, 0.33 ml, 4.15 mmol) was added and the mixture was refluxed for 10 h. Water (50 ml) and tert-butyl methyl ether (50 ml) was added and the organic phase was collected. The aqueous phase was extracted with tert-butyl methyl ether (50 ml, the pooled organic phase was extracted with aqueous hydrochloric acid (10%, 50 ml). The aqueous phase was basified and extracted with tert-butyl methyl ether (2×50 ml), dried (Na2SO4) and evaporated to give 0.35 g crude product. Purification by flash column chromatography on silica gel (ethyl acetate/MeOH 1:0→1:1) gave the title compound (0.2 g, 23%). The amine was converted to the fumaric acid salt and recrystallized from ethanol/diethyl ether/diisopropyl ether: M.p. 140-141° C. MS m/z (relative intensity, 70 eV) 213 (M+, 1), 156 (36), 141 (37), 127 (64), 114(50), 58 (bp).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[N:12][C:13]([O:16][CH2:17][C@@H:18]3[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]3)=[CH:14][CH:15]=2)[C:5]([C:25]#[N:26])=[C:4]([SH:27])[N:3]=1.Cl[CH2:29][C:30]1[N:31]=[C:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[O:33][CH:34]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[N:12][C:13]([O:16][CH2:17][C@@H:18]3[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]3)=[CH:14][CH:15]=2)[C:5]([C:25]#[N:26])=[C:4]([S:27][CH2:29][C:30]2[N:31]=[C:32]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[O:33][CH:34]=2)[N:3]=1
Reactant: CC1(C)OC[C@@H](COc2ccc(-c3c(C#N)c(N)nc(S)c3C#N)cn2)O1
Reactant: ClCc1coc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](COc2ccc(-c3c(C#N)c(N)nc(SCc4coc(-c5ccc(Cl)cc5)n4)c3C#N)cn2)O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
200 mg (0.32 mmol) of the crude product from example 31A, 90 mg (0.36 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-oxazole and 82 mg (0.97 mmol) of sodium bicarbonate are added to 3.4 ml of dry DMF, and the mixture is stirred at RT for 20 h. The mixture is then purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).