Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9]1[N:10]=[C:11]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]1[O:16][CH2:15][CH:14]([C@H:23]3[CH2:28][CH2:27][C@H:26]([N:29]4[C:37](=[O:38])[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[C:30]4=[O:39])[CH2:25][CH2:24]3)[NH:13][C:12]2=1.IC>CN(C)C=O>[CH3:7][O:8][C:9]1[N:10]=[C:11]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]1[O:16][CH2:15][CH:14]([C@H:23]3[CH2:24][CH2:25][C@H:26]([N:29]4[C:30](=[O:39])[C:31]5[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:37]4=[O:38])[CH2:27][CH2:28]3)[N:13]([CH3:1])[C:12]2=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2ncc3c(c2n1)NC([C@H]1CC[C@H](N2C(=O)c4ccccc4C2=O)CC1)CO3
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc2ncc3c(c2n1)N(C)C([C@H]1CC[C@H](N2C(=O)c4ccccc4C2=O)CC1)CO3
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Cesium carbonate (119 mg, 0.36 mmol, 1.0 eq) is added at room temperature to a stirred solution of 2-[trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-isoindole-1,3-dione (190 mg, 0.36 mmol, 1.0 eq) in N,N-dimethylformamide (3 mL), followed by iodomethane (23 μL, 0.36 mmol, 1.0 eq). After 5 hours stirring at room temperature, one additional equivalent of iodomethane is added to the reaction mixture and, after 2 hours stirring, solvent is removed to give a residue that is extracted with ethyl acetate (3×10 mL) and water (10 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: cyclohexane:ethyl acetate:methanol, 1:3:0 to 0:1:0 to 0:9:1, v/v/v) to afford 2-[trans-4-(6-methoxy-4-methyl-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-isoindole-1,3-dione as an orange solid (113 mg, 54% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][NH:27][CH2:28][CH:29]([C:31]1[N:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[OH:30].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:27]([CH2:28][CH:29]([OH:30])[C:31]4[N:32]=[CH:33][CH:34]=[CH:35][N:36]=4)[CH3:26])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)c1ncccn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)CC(O)c2ncccn2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 72 h
Yield: 85.9 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 2-(methylamino)-1-pyrimidin-2-ylethanol (Preparation 61)(59 mg, 0.38 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was stirred for 72 hours at room temperature. The solution was diluted with water (7 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (5 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (110 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C.[C:32]([O:35][CH2:36][CH3:37])(=O)C.C[C:39](N(C)C)=[O:40]>>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C@@H:3]2[O:12][CH2:13][C@@H:32]3[C@H:1]([C@H:39]([OH:40])[CH2:37][CH2:36][O:35]3)[O:2]2)=[CH:5][CH:6]=1
Reactant: COc1ccc(C(OC)OC)cc1
Reactant: CC(=O)N(C)C
Reactant: CCOC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Product: COc1ccc([C@@H]2OC[C@H]3OCC[C@@H](O)[C@@H]3O2)cc1
Temperature: 62.5 °C
Reaction time: 5 h

Procedure:
5.0 g (33.8 mmol) of 2 and 8.30 g (45.8 mmol) of p-methoxybenzaldehyde dimethyl acetal were dissolved in 50 ml of anhydrous DMA, and a catalytic amount of 4-toluenesulfonic acid was added until the mixture was acidic. The reaction solution was agitated for about 5 hours in a rotary evaporator at 60-65° C. and a reduced pressure of 30 mbar. The reaction solution was neutralized using triethylamine. 300 ml of ethyl acetate were added, and the mixture was extracted three times with water. The organic phase was dried over Na2SO4, the drying agent was filtered off, and the residue was evaporated under reduced pressure. The crude product was dissolved in a little ethyl acetate, precipitated using n-hexane, filtered off with suction and dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:36])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:20](=[O:29])[C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=1>>[CH3:9][O:10][C:11](=[O:36])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)/[C:21](=[C:22](/[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)\[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)/[C:20]2=[O:29])[CH:13]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Reactant: Clc1ccc(I)cc1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(/c3ccccc3)c3ccc(Cl)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-4-iodo-benzene (commercially available) and 3-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 3.91 (s, 3H), 4.96 (s, 2H), 6.42 (d, 1H), 6.63-6.66 (m, 2H), 7.06 (t, 1H), 7.33-7.52 (m, 11H), 7.92 (d, 1H), 8.01 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19]1([CH3:22])[CH2:21][O:20]1.[CH:23]([NH2:26])([CH3:25])[CH3:24]>CN(C=O)C>[OH:20][C:19]([CH3:22])([CH2:21][NH:26][CH:23]([CH3:25])[CH3:24])[CH2:18][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)N
Reactant: CC1(CCl)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)NCC(C)(O)COc1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 26.2 %

Procedure:
A mixture of 4-nitrophenol (1.0 g, 7.1 mmol), potassium carbonate (1.30 g, 9.4 mmol) and 2-chloromethyl-2-methyloxirane (0.84 g, 7.9 mmol) in DMF (50 ml) was stirred for 12 hours and then heated at 80° C. for 12 hours. Insoluble material was removed by filtration and washed with DMF (10 ml). The combined filtrate and washings were concentrated and the residue was dissolved in methanol (20 ml). Isopropylamine (6.13 ml, 71 mmol) was added and the mixture was stirred for 12 hours. Volatile material was removed by evaporation and the residue was purified by bond elute chromatography, eluting with 0-5% methanol in DCM, to give the product as a yellow solid (0.5 g, 26%). MS (MH+): 269.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:28][C:29](=[O:31])[CH3:30])([CH2:23][O:24][C:25](=[O:27])[CH3:26])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[F:22])=[CH:11][CH:10]=1)(=[O:3])[CH3:2].[CH3:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:25]([O:24][CH2:23][C:6]([NH:28][C:29](=[O:31])[CH3:30])([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:36]3[CH:37]=[CH:38][C:33]([CH3:32])=[CH:34][CH:35]=3)=[CH:17][C:16]=2[F:22])=[CH:11][CH:10]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)NC(CCc1ccc(-c2ccc(O)cc2F)cc1)(COC(C)=O)COC(C)=O
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC(CCc1ccc(-c2ccc(Oc3ccc(C)cc3)cc2F)cc1)(COC(C)=O)COC(C)=O
Yield: 77.4 %

Procedure:
A solution of N-[1,1-bis(acetoxymethyl)-3-(2′-fluoro-4′-hydroxybiphenyl-4-yl)propyl]acetamide (278 mg), 4-methylphenylboronic acid (175 mg), copper(II) acetate (117 mg), pyridine (255 mg) and molecular sieves 4A (500 mg) in methylene chloride (5 mL) was stirred at room temperature for 9 hr. 2% Aqueous citric acid solution (100 mL) was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.26 g) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:13])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[N:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:15]=[O:16].C(OCC)(=O)C>CN(C=O)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][NH:14][C:15]([NH:13][C:4]1[S:5][C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:2]([CH3:1])[N:3]=1)=[O:16])[CH3:22]
Reactant: CCOC(=O)CN=C=O
Reactant: Cc1nc(N)sc1-c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CNC(=O)Nc1nc(C)c(-c2ccncc2)s1
Reaction time: 8 h

Procedure:
A stirred solution of 4-methyl-5-pyridin-4-yl-thiazol-2-ylamine (prepared according to the method described in European patent specification EP 117082 A2) (0.068 g, 3.56 mmol) in DMF (5 ml) is treated with ethyl isocyanatoacetate (0.043 ml, 3.916 mmol) and the solution is stirred overnight. The solvent is removed in vacuo and the crude product is partitioned between ethyl acetate (50 ml) and water (50 ml). The layers are separated and the aqueous portion is extracted with ethyl acetate (2×50 ml). The combined organic portions are washed with water, dried (MgSO4), filtered and concentrated in vacuo to yield an oil. Trituration with ethyl acetate yields the titled compound.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:11][CH:10]=2)=[CH:3]1>CO.[Pd]>[CH3:1][N:2]1[C:7](=[O:8])[CH2:6][CH2:5][CH:4]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:13][CH:14]=2)[CH2:3]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(=O)n(C)c3)cc2)C(=O)O1
Agent: [Pd]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCC(=O)N(C)C3)cc2)C(=O)O1
Reaction time: 16 h
Yield: 97.4 %

Procedure:
To a mixture of N-({(5S)-3-[4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (0.179 g. 0.52 mmol) in 20 mL of MeOH is added 0.05 g of 10% palladium on activated charcoal. The mixture is hydrogenated at 50 psi for 16 hours. The reaction mixture is filtered through celite, silica is added and the mixture is concentrated to dryness. The residue is loaded onto a SIM and purified on a Biotage 12S column with 2% MeOH in CH2Cl2 to yield the desired compound (0.175 g, 96%). 1H-NMR (DMSO) δ: 8.25, 7.41, 4.70, 4.10, 3.74, 3.39, 3.17, 2.83, 2.32, 2.01, 1.83
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[NH:5][CH3:6].C(NC(C)C)(C)C.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:10])=[C:4]([N:5]([CH3:6])[C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([F:18])=[CH:20][CH:21]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CNc1cccc(Br)c1F
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CN(C(=O)c1ccc(F)cc1)c1cccc(Br)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
Step 3 A solution of 3-bromo-2-fluoro-N-methylaniline (32 mg, 0.157 mmol) and diisopropylamine (0.055 mL, 0.314 mmol) in DCM (2 mL) was treated with 4-fluorobenzoyl chloride (0.028 mL, 0.235 mmol) and the mixture was stirred at rt for 2 h. The mixture was partitioned between DCM and NaHCO3 (aq). The organic phase was washed with brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 90:10 to 80:20 hexane-EtOAc) to provide N-(3-bromo-2-fluorophenyl)-4-fluoro-N-methylbenzamide as a white solid (35 mg, 68%). Mass spectrum m/z 326, 328 (M+H)+.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[Cs+].[Cs+].[CH2:7]([C:14]1[NH:19][C:18](=O)[CH:17]=[CH:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CI>CN(C=O)C.C1COCC1>[CH2:7]([C:14]1[N:19]([CH3:18])[C:1](=[O:4])[CH:17]=[CH:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=c1ccnc(Cc2ccccc2)[nH]1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1c(Cc2ccccc2)nccc1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Cs2CO3 (24.6 g, 75.7 mmol) was added to 2-benzyl-3H-pyrimidin-4-one (Step 1, 12.8 g) in DMF (80 mL) and THF (60 mL) at 0° C. After 10 min, MeI (4.3 mL, 68.8 mmol) was added, and the reaction was warmed to RT. After 3 h, the reaction was decanted, diluted with CH2Cl2, and washed with H2O, and aq. sat. NaCl solution. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Et2O and Hexane (1:1) were added and the solvent was evaporated to provide a brown solid. The solid was triturated with 30′ EtOAc/hexane to afford the title compound as a light brown solid. The filtrate was purified by chromatography with 0-5% MeOH/CHCl3 to afford additional compound. MS (ESI pos. ion) m/z: 201.0. (M+H). Calc'd for C12H12N2O: 200.09.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[N:7](S(C)(=O)=O)[CH:6]=[CH:5]2>[OH-].[Na+].C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[NH:7][CH:6]=[CH:5]2
Reactant: COc1cc2c(ccn2S(C)(=O)=O)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc2[nH]ccc2cc1Br
Yield: 99.3 %

Procedure:
The 1-methylsulphonylindole (D19, 21.2 g, 69.7 mmol) was heated under reflux in a mixture of 10% aqueous sodium hydroxide solution (170 ml) and ethanol (1.0 L) for 1.5 h. The mixture was evaporated almost to dryness, and the residue was dissolved in ethyl acetate and washed with water. The organic phase was dried and evaporated to give the title compound (15.65 g, 99%), mp 110-111° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:18][CH:19]=1)/[CH:6]=[CH:7]/[CH:8]=O.[S:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:18][CH:19]=1)[CH:6]=[CH:7][CH:8]=[C:30]1[S:26][C:27](=[O:32])[NH:28][C:29]1=[O:31]
Reactant: O=C1CSC(=O)N1
Reactant: COc1cc(/C=C/C=O)ccc1OCc1csc(-c2ccccc2)n1
Product: COc1cc(C=CC=C2SC(=O)NC2=O)ccc1OCc1csc(-c2ccccc2)n1
Yield: 49 %

Procedure:
According to the same manner as that described in Example 1, (E)-3-methoxy-4-(2-phenyl-4-thiazolylmethoxy)-cinnamaldehyde was condensed with 2,4-thiazolidinedione to give 5-[3-methoxy-4-(2-phenyl-4-thiazolylmethoxy)-cinnamylidene]-2,4-thiazolidinedione (yield: 49%). This product was recrystallized from chloroform-methanol. Yellow needles, mp: 248-249° C.
Reaction SMILES: ClC1C=CC([NH:8][N:9]=[C:10]([C:12]([NH2:14])=[O:13])[NH2:11])=CC=1COCC(F)(F)C(F)(F)C(F)(F)F.[CH:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>C(O)(=O)C>[C:29]1([CH:28]2[NH:8][N:9]=[C:10]([C:12]([NH2:14])=[O:13])[NH:11]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=Cc1ccccc1
Reactant: NC(=O)C(N)=NNc1ccc(Cl)c(COCC(F)(F)C(F)(F)C(F)(F)F)c1
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)C1=NNC(c2ccccc2)N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In 0.7 ml of acetic acid, 245 mg (0.6 mmol) of oxamide 4-chloro-3-[(2,2,-3,3,4,4,4-heptafluorobutoxy)methyl]phenylhydrazone was dissolved and nitrogen was saturated. The solution was added with 76 mg (0.72 mmol) of benzaldehyde under a nitrogen atmosphere and stirred at room temperature for 16 hours. Then water was added to the solution and the formed crystals were filtered out, washed with water and dried in vacuo. The resulting product was recrystallized from ethyl acetate/n-hexane with nitrogen saturated to obtain 257 mg (86.5% yield) of 1-[4-chloro-3-](2,2,3,3,4,4,4-heptafluorobutoxy)methyl]phenyl]-4,5-dihydro-5-phenyl-1H-1,2,4-triazole-3-carboxamide (m.p. 157°-159° C.).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Br[C:16]1[S:17][CH:18]=[C:19]([Br:21])[N:20]=1>>[Br:21][C:19]1[N:20]=[C:16]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[S:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Brc1csc(Br)n1
Product: CC(C)(C)OC(=O)N1CCC(Oc2nc(Br)cs2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-42 using tert-butyl 4-hydroxypiperidine-1-carboxylate and 2,4-dibromothiazole (0.1 g, 25%); MS: 363.2 (M+1).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[OH:11][NH:12][CH:13]([C:30]#[CH:31])[CH2:14][S:15]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:20][CH2:19]1)(=[O:17])=[O:16]>C1COCC1>[OH:11][N:12]([CH:13]([CH2:14][S:15]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:20][CH2:19]1)(=[O:16])=[O:17])[C:30]#[CH:31])[CH:5]=[O:7]
Reactant: C#CC(CS(=O)(=O)N1CCN(c2ccccn2)CC1)NO
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: C1CCOC1
Product: C#CC(CS(=O)(=O)N1CCN(c2ccccn2)CC1)N(O)C=O
Reaction time: 1 h
Yield: 13.6 %

Procedure:
Acetic anhydride (25 mg; 0.24 mmol; 5.0 eq.) was added to cold (0° C.) formic acid (111 mg; 2.42 mmol; 50.0 eq.). The mixture was stirred 1 h, then a 1 M solution of 1-{[2-(hydroxyamino)-3-butynyl]sulfonyl}-4-(2-pyridinyl)piperazine (15 mg; 0.05 mmol; 1.0 eq.) in THF was added. After 4 h, the solvents were evaporated and the crude product was purified on silicagel (80/20 EtOAc/c-Hex) to give the title compound (12) as a colorless oil (2.3 mg, 14% yield). LC/MS, M+(ESI): 339.2, M−(ESI): 337.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[N:5]([CH2:11][C:12]#[CH:13])[C:4](=[O:14])[CH:3]=1.[N:15]([O-])=[O:16].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[N:5]([CH2:11][C:12]#[CH:13])[C:4](=[O:14])[C:3]=1[N:15]=[O:16]
Reactant: C#CCn1c(=O)cc(N)n(CC)c1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C#CCn1c(=O)c(N=O)c(N)n(CC)c1=O
Temperature: 4 °C

Procedure:
A solution of 6-amino-1-ethyl-3-propargyluracil (5 g, 26 mmol) in 75 ml of 50% acetic acid was heated at 50-60° C. Subsequently sodium nitrite (2.5 g, 36 mmol) was added in small portions over a period of 5 min. The end of the reaction was indicated by the formation of brown nitric gases. The deep violet solution was highly concentrated under reduced pressure. The remaining violet crystals were was suspended in a minimum of water, cooled to 4° C., filtered under reduced pressure, washed with methanol and dried at 70° C. Yield: 5 g (87%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:21]([C:29]2[N:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=2)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:5]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:19][CH2:18][CH2:17][NH:16][C:15](=[O:20])[CH2:14]3)=[N:10][CH:9]=2)[CH:7]=1.C(N(CC)CC)C.[C:46](Cl)(=[O:48])[CH3:47]>ClCCl.C(OCC)(=O)C>[C:46]([NH:1][C:2]1[CH:3]=[C:4]([N:21]([C:29]2[N:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[CH:31][N:30]=2)[C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:27])[CH3:25])[CH:5]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:19][CH2:18][CH2:17][NH:16][C:15](=[O:20])[CH2:14]3)=[N:10][CH:9]=2)[CH:7]=1)(=[O:48])[CH3:47]
Reactant: CC(C)(C)OC(=O)N(c1cc(N)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1)c1nccc(C(F)(F)F)n1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2cnc(N3CCCNC(=O)C3)s2)cc(N(C(=O)OC(C)(C)C)c2nccc(C(F)(F)F)n2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.5 %

Procedure:
To a suspension of tert-butyl {3-amino-5-[2-(3-oxo-1,4-diazepan-1-yl)-1,3-thiazol-5-yl]phenyl}[4-(trifluoromethyl)pyrimidin-2-yl]carbamate (125 mg, 0.227 mmol) in dichloromethane (2.5 mL) at room temperature, under nitrogen, was added triethylamine (0.079 mL, 0.569 mmol) and acetyl chloride (0.024 mL, 0.341 mmol). The mixture was stirred at room temperature for 18 h after which time a solution was obtained. The mixture was diluted with ethyl acetate and washed with water and brine, and dried over sodium sulfate. Silica gel (1 g) was added and the solution concentrated to dryness. The resulting solid was purified by silica gel chromatography (ethanol/dichloromethane eluant) to afford 80 mg (0.135 mmol, 60% yield) of tert-butyl {3-(acetylamino)-5-[2-(3-oxo-1,4-diazepan-1-yl)-1,3-thiazol-5-yl]phenyl}[4-(trifluoromethyl)pyrimidin-2-yl]carbamate as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd]>[N:21]1[CH:22]=[CH:23][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([CH2:11][NH:10][C:5]3[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:13][CH2:14]2)=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1cccnc1NCC1CCN(c2ccncc2)CC1
Agent: [Pd]
Product: Nc1cccnc1NCC1CCN(c2ccncc2)CC1
Yield: 97.1 %

Procedure:
Using a similar procedure to that described in Example 2, Part C, 3-nitro-N-[1-(4-pyridyl)piperidin-4-ylmethyl]pyridine-2-amine (340 mg, 1.09 mmol) and 10% palladium on carbon (200 mg) yielded 300 mg of the title compound, which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:23][CH2:22][C@@H:21]3[CH2:24][C@H:18]2[C:19](=[O:32])[N:20]3[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:13]1=[O:33])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:34].[OH-].[Li+].O>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:23][CH2:22][C@@H:21]([NH:20][C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:24][C@H:18]2[C:19]([OH:34])=[O:32])[C:13]1=[O:33])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reactant: O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
A stirring solution of (1R,2S,5R)-tert-butyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-7-oxo-6-azabicyclo[3.2.1]octane-6-carboxylate (108 g, 0.236 mol) in THF (1 L) was charged with lithium hydroxide monohydrate (21.74 g, 0.519 mol). Water (0.3 L) was added slowly, such that the temperature did not exceed 20° C. The reaction was stirred at room temperature overnight and the volatiles were removed in vacuo. The pH was adjusted to ˜4 through the addition of 1N HCl (450 mL) and NaH2PO4. The resultant white precipitates were collected by filtration and washed with water (2×1 L). The solid was dissolved in dichloromethane (1.5 L) and water (˜1 L). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was dissolved in EtOAc (0.7 L) and the resultant solution was heated at reflux for 1 h. Solids separated after cooling to RT, and were collected via filtration. These solids were purified by recrystallization in isopropanol to afford the desired (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid as a white solid (104.5 g, 93% yield). LC/MS for primary peak: [M-tBu+H]+=420.2; [M-Boc+H]+=376.2; [M+H]+=476.2. 1H-NMR (400 MHz, d4-MeOH): δ 7.35 (m, 5H), 5.11 (s, 2H), 4.35 (m, 2H), 3.71 (m, 1H), 3.45-3.6 (m, 2H), 2.99 (m, 1H), 2.41 (m, 1H), 2.15 (m, 1H), 2.0 (m, 2H), 1.6-1.9 (m, 4H), 1.46 (s, 9H).