Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([N:28]2[C:39]3[C:31](=[C:32]4[C:36](=[CH:37][CH:38]=3)[NH:35][CH:34]([C:40]([O:42]C)=[O:41])[CH2:33]4)[CH:30]=[CH:29]2)=[O:27])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10](=[CH2:13])[CH:11]=[CH2:12])=[CH:5][CH:4]=1.C1COCC1.[Li+].[OH-]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([N:28]2[C:39]3[C:31](=[C:32]4[C:36](=[CH:37][CH:38]=3)[NH:35][CH:34]([C:40]([OH:42])=[O:41])[CH2:33]4)[CH:30]=[CH:29]2)=[O:27])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:10](=[CH2:13])[CH:11]=[CH2:12])=[CH:5][CH:4]=1
Reactant: C=CC(=C)C(NCCCCCC(=O)n1ccc2c3c(ccc21)NC(C(=O)OC)C3)(c1ccccc1)c1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=CC(=C)C(NCCCCCC(=O)n1ccc2c3c(ccc21)NC(C(=O)O)C3)(c1ccccc1)c1ccc(OC)cc1
Temperature: 55 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A mixture of 8 (0.47 g, 0.78 mmol), THF (9 ml), MeOH (6 ml) and 4M LiOH (3 ml) was stirred at 55° C. for 1 h. The resultant solution was cooled to give a white precipitate, the Li salt of the product. The solid was triturated with a small amount of cold 10% citric acid and filtered off. Washing with water and drying under vacuum gave 0.43 g (94%) of 9 as a white solid.
Reaction SMILES: [C:1]([O-])(=O)C.[NH4+].C[N:7]([CH3:19])[CH:8]=[CH:9][C:10]1[NH:15][C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][CH:11]=1>CN(C)C=O>[CH3:1][C:19]1[N:7]=[CH:8][CH:9]=[C:10]2[C:11]=1[CH:12]=[C:13]([C:17]#[N:18])[C:14](=[O:16])[NH:15]2
Reactant: CC(=O)[O-]
Reactant: CN(C)C=Cc1ccc(C#N)c(=O)[nH]1
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1nccc2[nH]c(=O)c(C#N)cc12
Temperature: 5 °C

Procedure:
The above preparation was also carried out using ammonium acetate in place of formamidine acetate as follows: A mixture containing 1.305 kg of 1,2-dihydro-6-(2-dimethylaminoethenyl)-2-oxo-3-pyridinecarbonitrile, 9 liters of dimethylformamide and 915 g of ammonium acetate was refluxed for five hours. The reaction suspension was cooled to 5° C. for three hours and the precipitated product was collected, washed twice with cold 60/40 by volume of dimethylformamide/water, twice with cold ethanol, once with ether and dried to yield 826 g of 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carbonitrile, m.p. 275°-277° C.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:9]3[C:10]([CH3:28])=[C:11]4[C:15](=[CH:16][CH:17]=3)[N:14]([CH2:18][CH2:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[CH2:13][CH2:12]4)=[N:8][C:4]=2[C:3]=1[CH3:31]>C1(C)C=CC=CC=1.O=[Mn]=O>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:9]3[C:10]([CH3:28])=[C:11]4[C:15](=[CH:16][CH:17]=3)[N:14]([CH2:18][CH2:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[CH:13]=[CH:12]4)=[N:8][C:4]=2[C:3]=1[CH3:31]
Reactant: Cc1c(-c2nc3c(C)c(F)ccc3[nH]2)ccc2c1CCN2CCCC1CCN(C)CC1
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: Cc1c(-c2nc3c(C)c(F)ccc3[nH]2)ccc2c1ccn2CCCC1CCN(C)CC1
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To a stirred solution of 5-fluoro-4-methyl-2-{4-methyl-1-[3-(1-methyl-piperidin-4-yl)-propyl]-2,3-dihydro-1H-indol-5-yl}-1H-benzoimidazole (40 mg, 0.10 mmol) in toluene (2 mL) was added MnO2 (44 mg, 0.51 mmol). After 1 h at 70° C., the mixture was cooled, filtered through diatamaceous earth, and concetrated. The crude residue was purified by FCC to give the title compound (35 mg, 84%). MS: mass calcd. for C26H31FN4, 418.25; m/z found, 421.3 [M+H]+. 1H NMR (CD3OD): 7.42-7.33 (m, 3H), 7.30 (d, J=3.2, 1H), 6.99 (dd, J=10.4, 8.7, 1H), 6.62 (d, J=2.7, 1H), 4.22 (t, J=6.9, 6.9, 2H), 2.86-2.78 (m, 2H), 2.65 (s, 3H), 2.50 (d, J=1.2, 3H), 2.22 (s, 3H), 2.00-1.83 (m, 4H), 1.73-1.56 (m, 2H), 1.31-1.11 (m, 5H).
Reaction SMILES: ClC1C=CC(C2(O)CCN(CCC=C3C4C(=NC=CC=4)[O:21]C4C=CC=C(OC(C(OCC)=O)(C)C)C=4C3)CC2)=CC=1.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2([OH:80])[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][CH:57]=[C:58]3[C:68]4[C:63](=[N:64][CH:65]=[CH:66][CH:67]=4)[O:62][C:61]4[CH:69]=[CH:70][CH:71]=[C:72]([C:73]5[O:74][C:75](C=O)=[CH:76][CH:77]=5)[C:60]=4[CH2:59]3)[CH2:51][CH2:50]2)=[CH:45][CH:44]=1>>[Cl:42][C:43]1[CH:44]=[CH:45][C:46]([C:49]2([OH:80])[CH2:50][CH2:51][N:52]([CH2:55][CH2:56][CH:57]=[C:58]3[C:68]4[C:63](=[N:64][CH:65]=[CH:66][CH:67]=4)[O:62][C:61]4[CH:69]=[CH:70][CH:71]=[C:72]([C:73]5[O:74][C:75]([OH:21])=[CH:76][CH:77]=5)[C:60]=4[CH2:59]3)[CH2:53][CH2:54]2)=[CH:47][CH:48]=1
Reactant: CCOC(=O)C(C)(C)Oc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Reactant: O=Cc1ccc(-c2cccc3c2CC(=CCCN2CCC(O)(c4ccc(Cl)cc4)CC2)c2cccnc2O3)o1
Product: Oc1ccc(-c2cccc3c2CC(=CCCN2CCC(O)(c4ccc(Cl)cc4)CC2)c2cccnc2O3)o1

Procedure:
The titled compound was prepared by following the procedure of example 199, but replacing the product of example 138 with the product of step 1.
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH2:20][NH:21][C:22]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=O)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].O(C1C=CC(P2(=S)SP(=S)(C3C=CC(OC4C=CC=CC=4)=CC=3)S2)=CC=1)C1C=CC=CC=1>C1COCC1.CCOC(C)=O.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[CH:24]1([C:22]2[N:19]3[C:14]4[CH:13]=[CH:12][N:11]([S:1]([C:4]5[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=5)(=[O:3])=[O:2])[C:15]=4[N:16]=[CH:17][C:18]3=[CH:20][N:21]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=O)C4CCCCC4)cnc32)cc1
Agent: CC(=O)[O-]
Agent: S=P1(c2ccc(Oc3ccccc3)cc2)SP(=S)(c2ccc(Oc3ccccc3)cc2)S1
Agent: [Hg+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc(C4CCCCC4)n23)cc1
Reaction time: 15 h
Yield: 25.9 %

Procedure:
To a solution of N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)cyclohexanecarboxamide (0.081 g, 0.196 mmol) in THF (1 mL) at rt was added 2,4-bis(4-phenoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (0.104 g, 0.196 mmol, TCI). After about 15 h at rt, the mixture was concentrated under reduced pressure. The residue was suspended in EtOAc/DCM (1:1) and filtered through a plug of silica gel (5 g) eluting with EtOAc/DCM (1:1, approximately 100 mL). The filtrate was concentrated under reduced pressure to provide a residue. The residue was dissolved in THF (1 mL) and mercury(II) acetate (0.0626 g, 0.196 mmol) was added. After about 30 min at rt, additional mercury(II) acetate (0.0626 g, 0.196 mmol) was added. After about 4 h at rt, the mixture was diluted with EtOAc, filtered, concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 50 to 95% EtOAc in heptane to provide 1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.020 g, 25%): LC/MS (Table 2, Method a) Rt=2.77 min; MS m/z: 395 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:27])[CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C[Si]([Cl:41])(C)C.CCOCC>CC(CC)=O>[ClH:41].[CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:27])[CH2:19][O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Agent: O=C(COc1ccccc1)N1CCC2(CC1)N[C@@H](Cc1ccccc1)C(=O)N2Cc1ccccc1
Solvent: O
Solvent: CCC(C)=O
Solvent: CCOCC
Product: Cl
Reaction time: 8 h

Procedure:
1,3-(S)-dibenzyl-8-(2-phenoxyacetyl)-1,4,8-triazaspiro[4,5]decan-2-one (410 mg, 0.9 mmol) was dissolved in ethyl methyl ketone (3.3 mL), water (9 μL), TMSCl (121 μL), and ether (30 mL) were added and the mixture was stirred overnight. The solid matter was isolated by filtration, washed with ether, and dried in vacuo. The product 1,3-(S)-dibenzyl-8-(2-phenoxyacetyl)-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 347 mg (79%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8](O)=[O:9])[CH2:7][CH2:6]1)=[O:4].ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[OH:9][CH2:8][C:5]1([C:3]([O:2][CH3:1])=[O:4])[CH2:7][CH2:6]1
Reactant: COC(=O)C1(C(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(CO)CC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
1-Methoxycarbonylcyclopropane carboxylic acid (16.4 g, 113.89 mmol), TEA (17.6 mL, 127.55 mmol), and THF (325 mL) are charged in a round bottom flask. The mixture is cooled to −10° C. and isobutyl chloroformate (16.5 mL, 127.55 mmol) is added dropwise. The solution is stirred for 1 h. In a separate flask, sodium borohydride (13 g, 341.67 mmol) is dissolved in a mixture of THF (165 mL) and water (40 mL) and cooled in an ice bath. The insoluble material is removed by filtration from the first solution. To the borohydride solution is added the 1-methoxycarbonylcyclopropane carboxylic acid solution described above, dropwise over a period of 1.5 h. The resulting solution is stirred at the same temperature for 1 h. The reaction mixture is poured into a cooled 20% aqueous solution of citric acid and extracted with ethyl acetate (3×150 mL). The combined organic layers are washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to afford the title compound (13.5 g, 91%). 1H NMR (400 MHz, CDCl3); δ 0.9-0.8 (m, 2H), 1.3-1.2 (m, 2H), 3.62 (s, 2H) 3.69 (s, 3H).
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[CH:5]=[CH:4][N:3]=1.C[Al](C)C.[CH2:14]1COC[CH2:15]1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH2:14][CH3:15])[C:7]=1[NH2:8]
Reactant: C1CCOC1
Reactant: Nc1c(Cl)ccnc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Al](C)C
Product: CCc1nccc(Cl)c1N

Procedure:
Following a modified synthetic procedure reported in J. Org. Chem. 2006, 71, 7322, a to a stirred solution of 2-bromo-4-chloropyridin-3-amine (prepared as described in US2002/0119982) (1.0 eq.), and Pd(Ph3P)4 (0.05 eq.) in dry THF (0.05M) under argon was added dropwise Me3Al (1.0M in hexane, 2.0 eq.) and the reaction mixture was refluxed for O/N. The volatiles were removed under reduced pressure and the crude product was purified by flash chromatography eluting with 5-100% EtOAc/petroleum ether affording the titled compound as orange oil. 1H NMR (300 MHz, DMSO-d6, 300K) δ 7.67 (1H, d, J=5.2 Hz), 7.11 (1H, d, J=5.2 Hz), 5.26 (2H, br. s), 2.69 (2H, q, J=7.3 Hz), 1.73 (3H, t, J=7.3 Hz). MS (ES) C7H9ClN2 requires: 156, found: 157, 159 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:76])[C@H:7]([CH2:67][CH2:68][C:69]([O:71]C(C)(C)C)=[O:70])[NH:8][C:9](=[O:66])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:65])[CH2:19][CH2:20][S:21][CH2:22][CH:23]([O:45][C:46](=[O:64])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH2:24][O:25][C:26](=[O:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:12][CH:11]=1)(C)(C)C>FC(F)(F)C(O)=O>[C:58]1([CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][C:46]([O:45][CH:23]([CH2:24][O:25][C:26](=[O:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:22][S:21][CH2:20][CH2:19][C:18]([NH:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([C:9]([NH:8][C@H:7]([C:6]([OH:76])=[O:5])[CH2:67][CH2:68][C:69]([OH:71])=[O:70])=[O:66])=[CH:11][CH:12]=2)=[O:65])=[O:64])[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(CNC(=O)CCSCC(COC(=O)CCCCCCCCCCCc2ccccc2)OC(=O)CCCCCCCCCCCc2ccccc2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC[C@H](NC(=O)c1ccc(CNC(=O)CCSCC(COC(=O)CCCCCCCCCCCc2ccccc2)OC(=O)CCCCCCCCCCCc2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A solution of 4-[6,7-bis(12-phenyldodecanoyloxy)-4-thiaheptanoylaminomethyl]benzoyl-glutamic acid di-t-butyl ester as obtained in Example 58 (255 mg) in trifluoroacetic acid (2 ml) was stirred at room temperature for 2 hours, after which the solvent was distilled off under reduced pressure, to yield the title compound (200 mg, yield 88%) as a syrup.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:20])([CH3:19])[CH2:9][NH:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][N:12]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1>C1COCC1>[NH2:16][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([NH:10][CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)([CH3:20])[CH3:19])=[N:12][CH:13]=1
Reactant: CC(C)(CNc1ccc(C#N)cn1)c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CNc1ccc(CN)cn1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
To a 100 mL round bottom flask was added 6-(2-(4-fluorophenyl)-2-methylpropylamino)nicotinonitrile (1.0 g, 3.7 mmol, 1.0 equiv) and THF (15 mL), followed by the addition of 1M lithium aluminum hydride/THF (14.8 mL, 14.8 mmol, 4.0 equiv). The reaction was heated to reflux for 3 h and allowed to cool to rt. The reaction mixture was then quenched by the sequential slow addition water (0.6 mL), 3N NaOH (0.6 mL), and water (1.7 mL). The resultant precipitate was filtered and the filtrate was then dried (Na2SO4) and concentrated to give 1.0 g (99%) of 5-(aminomethyl)-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridin-2-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:20])([C:16]([F:19])([F:18])[F:17])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([S:21][CH3:22])[C:3]=1[NH:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]([N+:33]([O-])=O)[CH:26]=1.[Sn](Cl)(Cl)(Cl)Cl.Cl>C(O)(C)C>[NH2:33][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[C:31]#[N:32])[C:24]([NH:23][C:3]1[C:4]([S:21][CH3:22])=[CH:5][C:6]([C:8]([F:20])([C:16]([F:17])([F:18])[F:19])[C:9]([F:14])([F:15])[C:10]([F:11])([F:12])[F:13])=[CH:7][C:2]=1[Cl:1])=[O:36]
Reactant: CSc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(Cl)c1NC(=O)c1ccc(C#N)c([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC(C)O
Product: CSc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(Cl)c1NC(=O)c1ccc(C#N)c(N)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
To a solution of N-[2-chloro-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)-6-methylthiophenyl]-4-cyano-3-nitrobenzamide (Example 1.4) (13.0 g, 23 mmol) in isopropanol (110 ml) was added tin chloride (15.69 g, 82.8 mmol). The mixture was cooled to 0° C. and aqueous hydrochloric acid (37% w/v) (22 ml) was added slowly. The mixture was stirred at 80° C. for 1 hours. About one third of the total volume of isopropanol was evaporated. Water (100 ml) was added to the mixture followed by aqueous sodium hydroxide (4N) to adjust the pH to 8 to 9. The aqueous phase was extracted three times with ethyl acetate (20 ml). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/cyclohexane 1:2 to 1:1) to give 3-amino-N-[2-chloro-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)-6-methylthiophenyl]-4-cyanobenzamide (5.65 g, 45.8% yield). LC-MS (Method 1): RT=2.03, [M−H]−=536.
Reaction SMILES: [C:1]([O:5][C@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16](Cl)[N:15]=1)[CH3:7])([CH3:4])([CH3:3])[CH3:2].CS(C)=O.Cl.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[S:34][C:35]([C@@H:38]([NH2:40])[CH3:39])=[CH:36][N:37]=2)=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>O.CCOC(C)=O.CCCCCCC>[C:1]([O:5][C@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:40][C@H:38]([C:35]2[S:34][C:33]([C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=3)=[N:37][CH:36]=2)[CH3:39])[N:15]=1)[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](N)c1cnc(-c2ccc(Cl)cc2)s1
Reactant: C[C@H](OC(C)(C)C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@H](C)OC(C)(C)C)n1)c1cnc(-c2ccc(Cl)cc2)s1
Temperature: 110 °C
Yield: 32.7 %

Procedure:
To a microwave vial with stir bar was added (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-chloropyrimidin-4-yl)oxazolidin-2-one (147 mg, 0.49 mmol) and DMSO (4 mL). To this reaction mixture was added (S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethanamine HCl (148 mg, 0.54 mmol) and DIEA (0.26 mL, 1.47 mmol). Vial capped and the reaction mixture was heated in a preheated sand bath at 110° C. for 42 hr. The reaction mixture was diluted with water and extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (82 mg, 0.16 mmol, 33% yield). 1H NMR (400 MHz, CDCl3) δ 0.82 (br. s., 9H) 0.90-0.98 (m, 3H) 1.71 (d, J=6.90 Hz, 3H) 4.13 (q, J=7.16 Hz, 1H) 4.21-4.32 (m, 1H) 4.42-4.51 (m, 1H) 4.56 (dd, J=8.31, 2.79 Hz, 1H) 5.39 (br. s., 1H) 7.34-7.45 (m, 2H) 7.57 (d, J=5.77 Hz, 1H) 7.64 (s, 1H) 7.76-7.86 (m, 2H) 8.22 (d, J=5.82 Hz, 1H). LCMS m/z 502.3 (M+H)+, Rt 0.92 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]=[CH:16][C:17]([O:19][CH3:20])=[O:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: COC(=O)C=CCN1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)CCCN1CCN(Cc2ccccc2)CC1
Yield: 60.6 %

Procedure:
A solution of methyl 4-(4-benzylpiperazin-1-yl)but-2-enoate (10.2 g, 0.04 moles) in methanol was added to 20% palladium hydroxide on carbon and placed under 40 psi hydrogen gas for 7 h. The resulting solution was filtered through celite and evaporated to afford methyl 4-(4-benzylpiperazin-1-yl)butanoate (6.70 g, 97%). MS (ESI+) for m/z 187 (M+H)+.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([CH:22]([CH3:24])[CH3:23])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(O)C.[Cl-].[Ca+2].[Cl-]>O.[Fe]>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:13]2[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=2)[NH2:19])[CH:22]([CH3:24])[CH3:23])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1)C2(c1cccc([N+](=O)[O-])c1)C(C)C
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CCCCCCN1CC2C(C1)C2(c1cccc(N)c1)C(C)C
Yield: 104.8 %

Procedure:
To a stirred suspension of 3-hexyl-6-isopropyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexane (Preparation 60, 0.18 g, 0.54 mmol), ethanol (15 ml) and iron powder (0.27 g, 4.88 mmol) was added calcium chloride (0.06 gm 0.54 mmol) in water (3 ml). The reaction mixture was heated under reflux for 3 h and then filtered through a pad of Celite®, the mother liquors were concentrated in vacuo. The residue was dissolved in dichloromethane and filtered again through a Sep-Pak® Plus cartridge containing silica (1.5 g), (Water Division Millipore), to remove any residual iron salts and then concentrated to give the crude title compound as a yellow solid (0.17 g, 100%).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1.[C:35]([N:42]1[CH2:47][CH2:46][CH:45]([C:48]([OH:50])=O)[CH2:44][CH2:43]1)([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>CN(C=O)C.CCOC(C)=O>[CH3:5][O:4][N:3]([CH3:2])[C:48]([CH:45]1[CH2:44][CH2:43][N:42]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:47][CH2:46]1)=[O:50]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Add N,O-dimethylhydroxylamine hydrochloride (2.52 g, 26 mmol), 1-hydroxybenzotriazole (HOBt) (2.8 g, 20.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl)(4 g, 20.8 mmol) and 4-methylmorpholine (5.28 g, 52 mmol) at 0° C. to the solution of N-Boc-piperidine-4-carboxylic acid (4 g, 17.4 mmol) in DMF (50 mL), stir the mixture overnight at room temperature. TLC (PE:EtOAc=1:1) shows the reaction is complete. Partition between ethyl acetate and water, collect the organic layer and wash with brine, dry over anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure to give the crude product (4.5 g, 95%) which is used in next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=1.CCN(CC)CC.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>ClCCl>[CH2:11]([O:10][C:8]([C:6]1[O:7][C:3]([CH2:2][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:4][CH:5]=1)=[O:9])[CH3:12]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1ccc(CCl)o1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(CN2CCOCC2)o1
Temperature: 45 °C
Reaction time: 24 h
Yield: 66.9 %

Procedure:
To a solution of ethyl 5-(chloromethyl)-2-furan-carboxylate (0.5 mL, 3.25 mmol) and Et3N (0.9 mL, 6.5 mmol) in dichloromethane under nitrogen was added morpholine (284 μL, 3.25 mmol) dropwise and a catalytic amount of KI. The reaction mixture was stirred at 45° C. for 24 hours, then it was concentrated in vacuo. The residue was dissolved in EtOAc and the organic layer was washed with water (2×) then brine, dried over sodium sulfate, filtered, concentrated, and dried in vacuo to give 520 mg (67% yield) of 5-morpholin-4-ylmethyl-furan-2-carboxylic acid ethyl ester as a light brown oil. 1H-NMR (d6-DMSO) δ: 7.22 (d, 1H), 6.51 (d, 1H), 4.25 (q, 2H), 3.54 (m, 6H), 2.37 (broad s, 4H), 1.27 (t, 3H).
Reaction SMILES: BrCCCC[N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[S:9][CH2:8][C:7]1=[O:18].[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1>[C:19]1([N:25]2[CH2:30][CH2:29][N:28]([CH2:17][CH2:10][CH2:11][CH2:12][CH:8]3[C:7](=[O:18])[NH:6][C:12](=[O:13])[C:11]4[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=4[S:9]3)[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C1CSc2ccccc2C(=O)N1CCCCBr
Solvent: C1COCCO1
Product: O=C1NC(=O)C(CCCCN2CCN(c3ccccc3)CC2)Sc2ccccc21
Yield: 197.9 %

Procedure:
To a solution of 115 mg of compound of Example 13 dissolved in 10 ml of dioxane was added 171 mg (3 equivalents) of N-phenylpiperazine, followed by heating under reflux for 4 hours. Next, dioxane was evaporated, aqueous sodium bicarbonate added and the mixture extracted with methylene chloride. After washing the extract with aqueous sodium chloride, the mixture was dried over anhydrous magnesium sulfate. Next, the residue obtained by concentration of the methylene chloride solution was purified by silica gel column chromatography (ethyl acetate:hexane=3:1) to obtain 142 mg of the desired compound (yield 99.0%). The fumarate was obtained by converting the product to a fumarate in a conventional manner, followed by recrystallization from acetone-ether.