Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([NH:10][C@H:11]([C@@H:26]([OH:28])[CH3:27])[C:12]([NH:14][NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:30][C:31]([Si:34](Cl)([CH3:36])[CH3:35])([CH3:33])[CH3:32].N1C=CN=C1>>[Si:34]([O:28][C@@H:26]([CH3:27])[C@@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:29])[C:12]([NH:14][NH:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=1)=[O:13])([C:31]([CH3:33])([CH3:32])[CH3:30])([CH3:36])[CH3:35]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@H](C)O)ccc(C#N)c1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Yield: 83.8 %

Procedure:
N′-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-4-cyano benzohydrazide (12.1 g, 29.3 mmol) was reacted with TBDMSCl (13.2 g, 88.0 mmol) and imidazole (68.1 g, 146.0 mmol) in a manner analogous to that described for the preparation of intermediate 7b. Purification of the compound was accomplished by pouring the reaction mixture into ice-cold water and filtering off the solid precipitate. This was taken up in methylene chloride (400 mL) and sequentially washed with water (2×100 mL) and brine (100 mL). This was dried over sodium sulfate, filtered and concentrated down to roughly 100 mL. Hexanes were then added producing a white solid. This was filtered out and washed with hexanes to give the product as a white solid (12.92 g, 84%). 1H NMR (400 MHz, CDCl3, δ in ppm) 9.32 (m, 2H), 7.89 (AA′XX′, J=8.4 Hz, 2H), 7.71 (AA′XX′, J=8.6 Hz, 2H), 7.37 (d, J=8.4 Hz, 1H), 6.47 (d, J=8.8 Hz, 1H), 5.37 (d, J=6.2 Hz, 1H), 4.49 (m, 1H), 3.99 (m, 1H), 2.33 (s, 3H), 1.25 (d, J=6.2 Hz, 3H), 0.92 (s, 9H), 0.14 (s, 3H), 0.09 (s, 3H).
Reaction SMILES: CCCC[N+:5]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])CCCC.[F-]>C1COCC1.CCOC(C)=O>[NH:5]1[C:10]2[C:16](=[CH:17][CH:13]=[CH:12][CH:11]=2)[CH:15]=[CH:14]1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: c1ccc2[nH]ccc2c1

Procedure:
To a stirred solution of Intermediate 6 (250 mg, 0.4 mmol) in THF (10 mL) was a TBAF solution (1.0 M in THF, 10 mL, 10 mmol) and the resulting solution was heated to reflux for 22 hrs. Upon cooling, the reaction was diluted with EtOAc (250 mL), washed with H2O (7×15 mL) and brine, dried over Na2SO4, filtered, and concentrated to give the intermediate deprotected indole as a brown foam (252 mg, LC/MS (ESI) retention time: 2.01 min, m/z 501 (MH+)) which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.O>C1(C)C=CC=CC=1>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:15][CH2:14][C:13]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](C2CCC(=O)CC2)CC1
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC[C@H]1CC[C@H](C2CC=C(N3CCCC3)CC2)CC1

Procedure:
200 g of 4-(trans-4-propylcyclohexyl)cyclohexanone and 135.2 g of pyrrolidine were dissolved in 800 ml of toluene. The solution was heated and stirred for 6 hours while water which is evaporated by azeotropic distillation was removed. Azeotropic distillation of the solution was carried out with toluene so that excessive pyrrolidine was removed, and 1-(4-(trans-4-propylcyclohexyl)-cyclohexen-1-yl)-pyrrolidine was obtained. The product as it was was cooled to room temperature, and 800 ml of toluene was added again. The mixture was cooled in a water bath, and 150 ml toluene solution of 89 ml of methyl vinyl ketone was added dropwise over a period of 2 hours at 20° C. or less. After the dropwise addition was completed, the temperature was increased over a period of 2 hours to reach the reflux temperature. The solution was cooled to room temperature, and a buffer solution of pH 5 which was prepared from B5.2 g of sodium acetate, 104.2 ml of acetic acid, and 104.2 ml of water was added. Reflux was further continued for 5 hours. After the solution was cooled to room temperature, the organic phase was separated and rinsed with water and a saturated saline solution. The organic phase was dried on anhydrous sodium sulfate. The solvent was evaporated, and 313 g of 6-(trans-4-propylcyclohexyl)-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=O)[N:13]=2)=[O:7])=[CH:4][CH:3]=1.Cl.Cl.[NH:22]1[CH2:27][CH2:26][CH:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15](=[O:17])[N:22]3[CH2:27][CH2:26][CH:25]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:24][CH2:23]3)[N:13]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: c1ccc(OC2CCNCC2)nc1
Reactant: O=C(O)Cc1csc(NC(=O)c2ccc(Cl)cc2)n1
Agent: Cl
Product: O=C(Nc1nc(CC(=O)N2CCC(Oc3ccccn3)CC2)cs1)c1ccc(Cl)cc1

Procedure:
In analogy to example 1.3, [2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) was coupled with 2-(piperidin-4-yloxy)-pyridine dihydrochloride (CAS 313490-36-7) to give 4-chloro-N-(4-{2-oxo-2-[4-(pyridin-2-yloxy)-piperidin-1-yl]-ethyl}-thiazol-2-yl)-benzamide, using general procedure C. White amorphous solid. MS 457.6 ([M+H]+)
Reaction SMILES: O=[C:2]1[NH:7][CH:6]=[N:5][CH:4]=[C:3]1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].O=P(Cl)(Cl)[Cl:16]>O>[Cl:16][C:2]1[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:5]=[CH:6][N:7]=1
Reactant: CCOC(=O)Cc1cnc[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)Cc1cncnc1Cl
Temperature: 25 °C
Yield: 93 %

Procedure:
To ethyl 2-(6-oxo-1,6-dihydropyrimidin-5-yl)acetate (I107) (0.868 g, 4.77 mmol) was added POCl3 (6 mL) under an atmosphere of nitrogen and the resulting mixture was heated to reflux for 5 minutes and then cooled to room temperature. The reaction was slowly added to water (300 mL), the aqueous solution was extracted with DCM (3×100 mL), the combined organics were washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (I108) (0.885 g, 93% yield) as a pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 8.61 (s, 1H), 4.21 (q, J=7.1 Hz, 2H), 3.76 (s, 2H), 1.28 (t, J=7.1 Hz, 3H). LCMS Method C: rt 5.09 min; m/z 201.1, 203.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([OH:16])=O)=[CH:13][C:8]=2[N:7]=[C:6]1[NH:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:21]=2[N:22]=1.CN.[CH3:34][N:35](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:34][NH:35][C:14]([C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6]([NH:17][C:18]3[S:19][C:20]4[CH:26]=[C:25]([O:27][C:28]([F:29])([F:30])[F:31])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[N:7][C:8]=2[CH:13]=1)=[O:16]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COCCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CCOC
Yield: 44.7 %

Procedure:
1-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methylamide (46.0 mg) was prepared by following General Procedure F starting from 1-(2-methoxy-ethyl)-2-(6-trifluoromethoxy-benzo-thiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), methylamine (2.0 M solution in THF, 0.5 mL), HBTU (130.0 mg) and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 467; and 1H NMR (DMSO-d6, 400 MHz): δ 8.39 (1H, br. s), 8.07 (1H, br. s), 7.92 (1H, br. s), 7.74-7.72 (1H, br. m), 7.51-7.49 (1H, m), 7.37-7.35 (1H, m), 4.35 (4H, br. s), 3.73-3.72 (2H, br. t), 3.24 (3H, s), 2.82-2.80 (3H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][CH:22]=[C:23]([CH2:26]Cl)[C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1.[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][SH:33].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][CH:22]=[C:23]([CH2:26][S:33][CH2:32][CH2:31][N:30]([CH3:34])[CH3:29])[C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1
Reactant: CN(C)CCS
Reactant: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1scc(CCl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCSCc1csc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cc2)c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 34.4 %

Procedure:
To a solution of N-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide (0.70 g, 1.5 mmol) in DMF (5 mL) was added 2-(dimethylamino)ethanethiol (2.1 g, 15 mmol), followed by potassium carbonate (1.0 g, 7.2 mmol) and the reaction stirred at ambient temperature. After 24 hours, the mixture was poured into water (100 mL) and the resulting solid collected by filtration, washed with water and dried in vacuo. Purification by flash chromatography on silica gel afforded 0.28 g (35% yield) of N-(4-chlorophenyl)-2-[((3-chloro-4-(((2-(dimethylamino)ethyl)thio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide; as a cream-colored solid; NMR (DMSO-d6) 11.1 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 7.9 (d, 1), 7.8 (s, 1), 7.7 (d, 2), 7.6 (dd, 1), 7.4 (d, 2), 3.7 (s, 2), 2.5 (t, 2), 2.4 (t, 2), 2.1 (s, 6) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:25])[C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:5]([O:7]C)=[O:6].[OH-].[K+].Cl>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:25])[C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:5]([OH:7])=[O:6]
Reactant: CCCCCCCCCCCCOc1c(Cl)cc(C(=O)OC)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOc1c(Cl)cc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Methyl 3,5-dichloro-4-dodecyloxybenzoate, (˜0.78 mol, as above) was dissolved in methanol (1000 mL) and THF (500 mL). 85%-Potassium hydroxide (100 g, 1.52 mol) was dissolved in water (200 mL) and added to the solution. The starting material oiled out, but on gentle heating dissolution was achieved. After stirring at room temperature for 15 minutes the solution was poured into ice cold 2N-HCl with good stirring whereupon the product precipitated out. The white solid was filter off, washed well with water, and air-dried to remove as much of the water as possible. The solid was then suspended in acetonitrile (˜1000 mL) and stirred mechanically for about 1 hr. The solid was then filtered off washed with acetonitrile and air-dried. Yield, 290.6 g.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[CH:14][C:13]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:46][N:47]1[CH:51]=[CH:50][C:49]([NH2:52])=[N:48]1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[CH:14][C:13]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:12]2)[C:8]([NH:52][C:49]2[CH:50]=[CH:51][N:47]([CH3:46])[N:48]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)n1nc(Oc2ccccc2)ccc1=O
Reactant: Cn1ccc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cn1ccc(NC(=O)C(CC2CCCC2)n2nc(Oc3ccccc3)ccc2=O)n1
Temperature: 25 °C
Reaction time: 1.8 h
Yield: 21 %

Procedure:
A solution of 3-cyclopentyl-2-(6-oxo-3-phenoxy-6H-pyridazin-1-yl)-propionic acid (0.30 g, 0.91 mmol) in methylene chloride (9.0 mL, 0.10M) at 25° C. was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (164 μL, 0.92 mmol) and 1-hydroxybenzotriazole (0.13 g, 0.96 mmol). The solution was stirred at 25° C. for 1.8 h. After this time, the reaction was treated with a solution of 1-methyl-1H-pyrazol-3-ylamine in methylene chloride at 25° C. The reaction was stirred at 25° C. for 5 d. After this time, the reaction was diluted with methylene chloride (100 mL) and was washed with a 1N aqueous hydrochloric acid solution (2×100 mL), a saturated aqueous sodium bicarbonate solution (2×100 mL), water (1×100 mL), and a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed with methylene chloride and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 40 g, 50-100% ethyl acetate/hexanes gradient) afforded 3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(6-oxo-3-phenoxy-6H-pyridazin-1-yl)-propionamide (76.7 mg, 21%) as a white solid; ES+-HRMS m/e calcd for C22H25N5O3 [M+H+] 408.2030 found 408.2030. 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.87-0.98 (m, 1H), 1.17-1.31 (m, 1H), 1.35-1.63 (m, 7H), 1.69 (ddd, J=13.1, 9.3, 3.6 Hz, 1H), 1.88-2.00 (m, 1H), 3.73 (s, 3H), 5.29 (dd, J=11.1, 3.6 Hz, 1H), 6.33 (d, J=2.0 Hz, 1H), 7.09 (d, J=9.8 Hz, 1H), 7.17-7.26 (m, 3H), 7.34-7.43 (m, 2H), 7.46 (d, J=9.8 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 10.66 (s, 1H).
Reaction SMILES: C(O)C(N)(CO)C[OH:4].Cl.[CH2:10]1[C@H:14]([N:15]2[C:19]3[N:20]=[C:21]([NH2:25])[N:22]=[C:23](N)[C:18]=3[N:17]=[CH:16]2)[O:13][C@H:12]([CH2:26][OH:27])[C@H:11]1[OH:28]>>[C@@H:14]1([N:15]2[C:19]3[N:20]=[C:21]([NH2:25])[NH:22][C:23](=[O:4])[C:18]=3[N:17]=[CH:16]2)[O:13][C@H:12]([CH2:26][OH:27])[C@@H:11]([OH:28])[CH2:10]1
Reactant: Nc1nc(N)c2ncn([C@H]3C[C@H](O)[C@@H](CO)O3)c2n1
Reactant: NC(CO)(CO)CO
Agent: Cl
Product: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Yield: 99 %

Procedure:
The washed cells described above were added to 50 mM Tris-HCl buffer (pH 7.2) containing 20.0 g/l 2,6-diaminopurine-2′-deoxyriboside to a concentration of 5 g/l and reacted at 30° C. for 3 hours while keeping pH at 7.2. The concentration of 2′-deoxyguanosine produced in the reaction solution was measured by high performance liquid chromatography. The result showed that the concentration was 19.8 g/l (conversion molar yield: 99%), respectively.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:9]2[CH3:22])[CH:5]=[N:4][C:3]=1[C:23]#[N:24].Cl.[CH:26]1([N:31]2[CH2:36][CH2:35][CH:34]([C:37]3[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=3)[CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:23]([C:3]1[N:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:9]2[CH3:22])=[N:7][C:2]=1[NH:41][C:40]1[CH:42]=[CH:43][C:37]([CH:34]2[CH2:35][CH2:36][N:31]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:32][CH2:33]2)=[CH:38][CH:39]=1)#[N:24]
Reactant: Nc1ccc(C2CCN(C3CCCC3)CC2)cc1
Reactant: C[C@@H]1[C@H](NC(=O)OC(C)(C)C)CCCN1c1cnc(C#N)c(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1[C@H](NC(=O)OC(C)(C)C)CCCN1c1cnc(C#N)c(Nc2ccc(C3CCN(C4CCCC4)CC3)cc2)n1
Temperature: 115 °C
Reaction time: 5 h
Yield: 67.3 %

Procedure:
tert-Butyl (2R,3R)-1-(6-chloro-5-cyanopyrazin-2-yl)-2-methylpiperidin-3-ylcarbamate (311) (390 mg, 1.1 mmol), 4-(1-cyclopentylpiperidin-4-yl)aniline HCl salt (304) (406 mg, 1.7 mmol), fine-powder Cs2CO3 (1.1 g, 3.3 mmol), BINAP (207 mg, 0.33 mmol), and Pd(OAc)2 (75 mg, 0.33 mmol) were combined and suspended in dioxane (30 mL) and water (1 mL). The mixture was sparged with nitrogen stream for 10 minutes, and then stirred under nitrogen atmosphere in 115° C. oil bath for 5 hours. The mixture was cooled to RT, diluted with EtOAc (100 mL), stirred, filtered and concentrated under reduced pressure. The resulting residue was subjected to silica flash column chromatography (MeOH/DCM) to give tert-butyl (2R,3R)-1-(5-cyano-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-2-methylpiperidin-3-ylcarbamate (312) (430 mg, 0.74 mmol, 68% yield).
Reaction SMILES: [Cl:1][CH:2]([C:14](=[O:16])[CH3:15])[CH2:3][S:4][CH2:5][CH2:6][NH:7][C:8]([NH:11][C:12]#[N:13])=[N:9][CH3:10].[Cl:17][O-].[Na+].C(OCC)(=O)C>CO>[C:12]([NH:11][C:8]([NH:7][CH2:6][CH2:5][S:4][CH2:3][C:2]([Cl:17])([Cl:1])[C:14](=[O:16])[CH3:15])=[N:9][CH3:10])#[N:13]
Reactant: CN=C(NC#N)NCCSCC(Cl)C(C)=O
Reactant: [O-]Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN=C(NC#N)NCCSCC(Cl)(Cl)C(C)=O
Reaction time: 3 h
Yield: 25 %

Procedure:
In 1 ml of methanol was dissolved 131 mg of N-[2-(2-chloro-3-oxobutylthio)]ethyl-N'-cyano-N"-methylguanidine, and 0.63 ml of an aqueous solution of sodium hypochlorite was added to the solution and reaction was carried out at room temperature for 3 hours. Then, 15 ml of ethyl acetate was added to the reaction liquid and the organic layer was recovered. The obtained organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was refined by silica gel column chromatography (developing solvent: ethyl/ethanol=10/1) to obtain 37 mg of a colorless oily product (the yield was 25%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH:5]=[CH:6][C:7]([F:10])([F:9])[F:8])[CH3:2].CN(C)C(N(C)C)=N.[N+:20]([CH3:23])([O-:22])=[O:21]>C(OC(=O)CC(C)=O)C>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH:6]([CH2:23][N+:20]([O-:22])=[O:21])[C:7]([F:9])([F:10])[F:8])[CH3:2]
Reactant: CCOC(=O)C=CC(F)(F)F
Reactant: C[N+](=O)[O-]
Agent: CN(C)C(=N)N(C)C
Solvent: CCOC(=O)CC(C)=O
Product: CCOC(=O)CC(C[N+](=O)[O-])C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
1.0 g (5.94 mmol) of 4,4,4-trifluoro-2-butenoic acid ethyl ester and 0.15 mL (1.19 mmol) of 1,1,3,3-tetramethyl guanidine and 1.6 mL (29.8 mmol) of nitromethane were mixed. The resulting mixture was cooled to 0° C. and then stirred for 3 hours at room temperature, followed by addition of 100 mL of ethylacetoacetate. The reaction mixture was washed with water, and then an organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 1.1 g (4.80 mmol) of the title compound in a yield of 81%.
Reaction SMILES: COC(=O)CC1CC2C(=CC(OCCNC(OC(C)(C)C)=O)=CC=2)NC1=O.[CH3:28][O:29][C:30](=[O:63])[CH2:31][CH:32]1[CH2:41][C:40]2[C:35](=[CH:36][C:37]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][NH:47]C(OC(C)(C)C)=O)=[CH:38][CH:39]=2)[N:34]([CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:33]1=[O:62]>>[CH3:28][O:29][C:30](=[O:63])[CH2:31][CH:32]1[CH2:41][C:40]2[C:35](=[CH:36][C:37]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])=[CH:38][CH:39]=2)[N:34]([CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[C:33]1=[O:62]
Reactant: COC(=O)CC1Cc2ccc(OCCCCNC(=O)OC(C)(C)C)cc2N(Cc2ccccc2)C1=O
Agent: COC(=O)CC1Cc2ccc(OCCNC(=O)OC(C)(C)C)cc2NC1=O
Product: COC(=O)CC1Cc2ccc(OCCCCN)cc2N(Cc2ccccc2)C1=O

Procedure:
The title compound is prepared according to the procedure of Example 78 except that [7-(2-tert-butoxycarbonylamino-ethoxy)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-acetic acid methyl ester is replaced with [7-(4-tert-butoxycarbonylaminobutoxy)-1-benzyl-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]acetic acid methyl ester.
Reaction SMILES: [N:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=[C:2]=[O:3].[C:14]1([CH2:22][OH:23])[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:4]1([NH:1][C:2](=[O:3])[O:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:22][OH:23])=[CH:15][CH:16]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: OCc1ccc(CO)cc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Nc1cccc2ccccc12)OCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56 %

Procedure:
To a solution of 1-isocyanatonaphthalene (1.69 g, 10 mmol) and 1,4-phenylene-dimethanol (4.14 g, 30 mmol) in anhydrous DMF was added DMAP (0.06 g, 0.5 mmol). The resulting mixture was stirred at room temperature for 12 h. The solvent was removed in vacuo to give a solid, which was recrystallized using ethyl acetate to produce 7 (1.72 g, 5.6 mmol) as a white solid in 56% yield: m.p.: 158-159° C.; IR (thin film): 3325, 1691, 1542, 1420, 1245, 1237 cm−1; 1H NMR (500 MHz, CDCl3): 6 1H NMR (500 MHz, CDCl3) δ 7.95-7.83 (m, 3H), 7.68 (d, J=8.2 Hz, 1H), 7.58-7.47 (m, 4H), 7.44-7.35 (m, 3H), 5.27 (s, 2H), 4.73 (d, J=5.8 Hz, 2H), 1.70 (t, J=6.0 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3): δ 154.43, 141.33, 140.53, 136.51, 135.70, 134.28, 132.55, 128.98, 128.90, 127.44, 127.41, 126.49, 126.24, 126.02, 125.35, 120.61, 67.25, 65.24 ppm. HRMS (m/z): [M+Na]+ calcd. for C19H17NNaO3, 330.1100; found, 330.1095.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[F:10].[I:11]I>CCO.[O-]S([O-])(=O)=O.[Ag+].[Ag+]>[NH2:1][C:2]1[C:9]([I:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[F:10]
Reactant: N#Cc1ccc(N)c(F)c1
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: N#Cc1cc(F)c(N)c(I)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4-amino-3-fluorobenzonitrile (147 mmol), I2 (147 mmol) and Ag2SO4 (147 mmol) in EtOH (700 mL) was stirred at room temperature for 1.5 h. The mixture was filtered and concentrated. The residue was dissolved in EtOAc and washed (sat. Na2S2O3×3). The organic layer was dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (SiO2, 95:5 to 70:30 cyclohexane/EtOAc) to yield the desired product.
Reaction SMILES: [N+](/[C:4](=[CH:15]/[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])/[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([O-])=O.[N+](/C(/CCCCCCCC)=C/CCCCCCCC(O)=O)([O-])=O.[N+](C(CCCCCC/C=C\CCCCCCCC)C(O)=O)([O-])=O>>[C:12]([OH:14])(=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]/[CH:4]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCC/C=C(\CCCCCCCC(=O)O)[N+](=O)[O-]
Agent: CCCCCCCC/C(=C\CCCCCCCC(=O)O)[N+](=O)[O-]
Agent: CCCCCCCC/C=C\CCCCCCC(C(=O)O)[N+](=O)[O-]
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O

Procedure:
9-Nitrooleic acid and 10-nitrooleic acid are two regioisomers of nitrooleic acid (OA-NO2), which are formed by nitration of oleic acid in approximately equal proportions in vivo. The two compounds were purchased from Cayman Chemicals (Ann Arbor, Mich.) (9-nitrooleic acid: Cat#10008042; 10-nitrooleic acid: Cat#10008043) and used as an 1:1 mixture of the isomers.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[C:10](F)=[CH:11][C:12]2[O:17][CH:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22]([O:24]CC)=[O:23])=[CH:14][C:13]=2[CH:27]=1>>[Cl:8][C:9]1[C:10]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:11][C:12]2[O:17][CH:16]([C:18]([F:20])([F:19])[F:21])[C:15]([C:22]([OH:24])=[O:23])=[CH:14][C:13]=2[CH:27]=1
Reactant: Oc1ccccn1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccccn3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 2-hydroxypyridine and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 234.2-235.4° C. 1H NMR (acetone-d6/300 MHz) 8.14 (dd, 1H, J=4.8 Hz, 1.4 Hz), 7.92 (m, 2H), 7.70 (s, 1H), 7.14 (m, 2H), 6.99 (s, 1H), 5.88 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz) −79.4 (d, J=7.2 Hz). ESLRMS m/z 372 (M+H). ESHRMS m/z 372.0252 (M+H, Calc'd 372.0250). Anal. Calc'd for C16H9ClF3NO4: C, 51.70; H, 2.44; N, 3.77; Cl, 9.54. Found: C, 51.70; H, 2.44; N, 3.71; Cl, 9.65.