Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7](Br)=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][NH2:13].O1CCCC1>C(Cl)Cl.O>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:13][CH3:12])[C:5]2=[N:4][CH:3]=1
Reactant: Brc1cncc2ncc(Br)n12
Reactant: CN
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CNc1nccn2c(Br)cnc12
Temperature: 70 °C
Yield: 50 %

Procedure:
3,5-Dibromo-imidazo[1,2-a]pyrazine (D) (2.0 g, 7 mol) was added to 2M methylamine in THF (tetrahydrofuran) (100 ml, 30 eq.). The mixture was heated at 70° C. in sealed tube for 3 hr. The mixture was then cooled to rt, diluted with DCM (200 ml) and water (100 ml). The organic layer was washed with brine, dried and concentrated. The residue was purified on a silica gel column to give (3-bromo-imidazo[1,2-a]pyrazin-8-yl)-methyl-amine (yield 50%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C:42]2[CH:43]=[N:44][N:45]([CH2:47][CH2:48][CH2:49][OH:50])[CH:46]=2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2.C(O)(C(F)(F)F)=O>>[OH:50][CH2:49][CH2:48][CH2:47][N:45]1[CH:46]=[C:42]([C:34]2[CH:33]=[CH:32][C:31]([NH:30][C:2]3[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=4[O:28][CH3:29])[N:3]=3)=[C:39]3[C:35]=2[CH2:36][N:37]([CH3:41])[C:38]3=[O:40])[CH:43]=[N:44]1
Reactant: CN1Cc2c(-c3cnn(CCCO)c3)ccc(N)c2C1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Temperature: 0 °C

Procedure:
A solution of diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 1E, 897 mg, 1.98 mmol) and 7-amino-4-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 1C, 634 mg, 2.21 mmol) in TFE (12 mL) was charged with TFA (654 mg, 5.74 mmol) and irradiated in a microwave reactor for 1 h at 105° C. The reaction mixture was transferred to a round bottom flask and concentrated in vacuo. The residue, dissolved in MeOH and cooled to 0° C., was charged with 7.0 M of NH3 in MeOH (5 mL) and then warmed to rt over 2 h. The suspension was concentrated in vacuo and purified using a Teledyne ISCO CombiFlash® Rf system (eluting with 0-10% MeOH:CH2Cl2) to isolate the desired compound as 1.10 g of a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 9.12 (s, 1H), 8.38 (s, 1H), 8.27 (s, 1H), 8.06-8.63 (m, 1H), 7.96 (s, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.41 (d, J=7.1 Hz, 1H), 7.10 (br. t, J=2.0 Hz, 1H), 6.96 (br td, J=2.3, 8.0 Hz, 1H), 4.53-4.67 (m, 3H), 4.21 (t, J=7.20 Hz, 2H), 4.00 (qd, J=7.1, 8.1 Hz, 4H), 3.74 (s, 3H), 3.43 (q, J=6.1 Hz, 2H), 3.36 (d, J=20 Hz, 2H), 3.11 (s, 3H), 1.97 (quin, J=6.6 Hz, 2H), 1.17 (t, J=7 Hz, 6H). MS (ESI): m/z 704.23 (100) [M+H]+. HPLC: tR=3.73 min (ZQ3: polar—5 min).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][CH2:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[H][H]>C(O)C>[Cl:7][CH2:8][C@@H:9]([OH:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: [H][H]
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C[C@H](O)CCl

Procedure:
In a stainless steel autoclave, 21 mg of sodium carbonate and 14.1 mg (0.008 mmol) of Ru2Cl4 ((-)-BIFLUP)2NEt3 were charged, and the air in the autoclave was replaced with nitrogen. Further, 6.6 ml of ethanol and 2.7 ml (20 mmol) of ethyl 4-chloroacetoacetate were added, and the nitrogen in the autoclave was replaced with hydrogen. At a hydrogen pressure of 10 kgf/cm2, the solution was stirred for 2 hours at 100° C. After termination of the reaction, the conversion ratio, selectivity and optical purity were measured by gas chromatography and liquid chromatography. At a conversion ratio of 100%, selectivity of 96.3% and optical purity of 96.8%ee, ethyl 4-chloro-(S)-3-hydroxybutyrate was obtained.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].O1CCCC1.[C:13](OCC)(=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(O)(=O)C>[O:20]=[C:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: CCCCCCC(=O)OCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCCC(=O)CP(=O)(OC)OC

Procedure:
n-Butyllithiium (130 ml. of 1.6 M. solution) is slowly added to a solution of dimethyl methylphosphonate (25.6 g.) in 475 ml. of tetrahydrofuran (THF) at about -65° C. To the mixture is added a solution of ethyl heptanoate (18.4 g.) in 50 ml. of THF, annd the resulting mixture is stirred at about -70° C. for 2 hrs. Then, 16 ml. of acetic acid is added, and the mixture is concentrated under reduced pressure. The residue is mixed with dichloromethane (about 400 ml.) and water (about 50 ml.) shaken, and separated. The organic phase is dried over magnesium sulfate and concentrated. Distillation yields the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:15]=3[N:16]=2)[C:5]([NH:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1.[CH:23]1[C:28]([C:29]([OH:31])=[O:30])=[CH:27][C:26]2[C:32]([O:34][C:35](=O)[C:25]=2[CH:24]=1)=[O:33]>>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:14]2[O:13][C:12]([C:4]3[CH:3]=[C:2]([N:1]4[C:32](=[O:33])[C:26]5[C:25](=[CH:24][CH:23]=[C:28]([C:29]([OH:31])=[O:30])[CH:27]=5)[C:35]4=[O:34])[CH:7]=[CH:6][C:5]=3[NH:8][CH2:9][CH2:10][CH3:11])=[N:16][C:15]=2[CH:17]=1
Reactant: CCCNc1ccc(N)cc1-c1nc2cc(OC)ccc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: CCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(OC)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-propylaminophenyl)-5-methoxybenzoxazole (74 mg, 0.25 mmol) and 1,2,4-benzenetricarboxylic anhydride (54 mg, 0.28 mmol) the title compound was obtained (68 mg, 58%). 1H NMR (DMSO) δ 8.46(t, 1H), 8.41(dd, 1H), 8.22(s, 1H), 8.07(m, 2H), 7.64(d, 1H), 7.45(dd, 1H), 7.37(d, 1H), 7.00(m, 2H), 3.84(s, 3H), 3.34(m, 2H), 1.75(m, 2H), 1.06(t, 3H). MS 470.1 m/z (M−H)−.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[OH:31])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([NH2:40])=[O:39]>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=5)=[CH:18]4)=[CH:13][C:12]=3[O:31][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38](=[O:39])[NH2:40])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: NC(=O)CCCCCBr
Reactant: COC(=O)c1ccc(-c2ccc3cc(O)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1
Product: NC(=O)CCCCCOc1cc2ccc(-c3ccc(C(=O)O)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Yield: 65.6 %

Procedure:
Following the procedure of Example 12(a), but reacting 640 mg (1.55 mmol) of methyl 4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate with 450 mg (2.32 mmol) of 6-bromohexanamide, 520 mg (65%) of the expected compound were obtained, which compound had a melting point of 209°-10° C.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:3]=1
Reactant: CCOC(=O)CCCCCN
Reactant: CCOC(=O)CC(=O)c1cccnc1
Product: CCOC(=O)C=C(NCCCCCC(=O)OCC)c1cccnc1

Procedure:
A mixture of 196 mg of ethyl nicotinoylacetate and 192 mg of ethyl 6-aminocaproate is heated at 120°-130° under nitrogen for 18 hours. The product is purified by preparative TLC (silica gel; chloroform, ethyl acetate 9.1) to yield ethyl β-(3-pyridyl)-β-(5-ethoxycarbonylpentylamino)acrylate;Rf =0.3.
Reaction SMILES: [CH:1]([O:4][NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH:8]=1)([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:39]>C(#N)C>[CH:1]([O:4][N:5]=[C:6]([Cl:39])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH:8]=1)([CH3:3])[CH3:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)CCc1cccc(C(=O)NOC(C)C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)CCc1cccc(C(Cl)=NOC(C)C)c1
Yield: 88 %

Procedure:
To 200 ml of acetonitrile were added 5.4 g (23.5 mmol) of O-isopropyl 3-isopentylbenzohydroxamic acid, 9.9 g (37.8 mmol) of triphenylphosphine, and 11.6 g (75.3 mmol) of carbon tetrachloride. The mixture was refluxed for 1 hour. The refluxed mixture was allowed to sit and cool naturally, and the solvent in the mixture was removed under reduced pressure. The residue was purified by column chromatography, thus obtaining the desired product of 5.1 g (yield: 88% ).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[N:35]([CH3:39])[N:34]=[CH:33]3)[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)CCl>[CH3:39][N:35]1[C:36]2[C:32](=[CH:31][C:30]([C:6]3[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:16]4[NH:15][C:14]5[C:9]([C:8]=4[CH:7]=3)=[CH:10][CH:11]=[C:12]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:13]=5)=[CH:38][CH:37]=2)[CH:33]=[N:34]1
Reactant: Cn1ncc2cc(-c3cc(C(N)=O)c4[nH]c5cc(N6CCN(C(=O)OC(C)(C)C)CC6)ccc5c4c3)ccc21
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1ncc2cc(-c3cc(C(N)=O)c4[nH]c5cc(N6CCNCC6)ccc5c4c3)ccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92.2 %

Procedure:
The crude product from Example 413B [168 mg, contains ˜0.16 mmol tert-butyl 4-(8-carbamoyl-6-(1-methyl-1H-indazol-5-yl)-9H-carbazol-2-yl)piperazine-1-carboxylate was suspended in ClCH2CH2Cl (20 ml). Addition of TFA (2 ml, 26.0 mmol) resulted in complete dissolution. The reaction mixture was stirred at room temperature for 2.5 hours, then evaporated to dryness. The product was purified by prep HPLC to give 62.6 mg 3-(1-methyl-1H-indazol-5-yl)-7-(piperazin-1-yl)-9H-carbazole-1-carboxamide. The “free base product” was suspended in MeOH. Addition of 1.0 equiv. HCl (147 ul of a 1.00 M aq. solution) resulted in complete dissolution. Evaporate to dryness gave 67.8 mg 3-(1-methyl-1H-indazol-5-yl)-7-(piperazin-1-yl)-9H-carbazole-1-carboxamide as its mono-HCl salt. MS (ESI) m/e+=425. HPLC retention time 5.82 min. (Sunfire C18 3.5 μm, 3.0×150 mm column, 15 min gradient, 10-100% B, 0.5 mL/min. Solvent A: 5% CH3CN—95% H2O—0.1% TFA; Solvent B: 95% CH3CN—5% H2O—0.1% TFA), then isocratic at 100% B. 1H NMR (CD3OD) δ ppm 8.46 (d, 1H, J=1.5), 8.17 (d, 1H, J=1.7), 8.13 (b, 1H), 8.11-8.07 (m, 2H), 7.91 (dd, 1H, J=1.8, 8.8), 7.67 (d, 1H, J=8.8), 7.23 (d, 1H, J=2.0), 7.03 (dd, 1H, J=8.5, 2.0), 4.12 (s, 3H), 3.56-3.52 (m, 4H), 3.47-3.43 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=1[C:15]([NH:17][CH2:18][CH2:19][CH2:20][N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)=[O:16].C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=2[C:15]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)=[O:16])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccccc1C(=O)NCCCn1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(NCCCn1ccnc1)c1ccccc1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.4 %

Procedure:
4-Chlorobenzenesulphonyl chloride (1.56 g) was added in portions over 2 minutes to a solution of 2-amino-N-(3-imidazol-1-ylpropyl)benzamide (1.8 g) in water (50 ml) at 80° C. on a steam bath. The mixture was stirred at 80°-90° C. for 3 hours, cooled to room temperature and brought to pH 7 with saturated aqueous sodium bicarbonate solution. The crude product which had precipitated was extracted into dichloromethane (2×100 ml); the resulting solution was dried over magnesium sulphate and evaporated to give a solid. The solid was recrystallised from ethanol to give 2-(4-chlorobenzenesulphonamido)-N-(3-imidazol-1-ylpropyl)benzamide (1.4 g), in the form of a white solid, m.p. 174°-176° C.
Reaction SMILES: Br[C:2]1[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=[C:5]([C:7]#[N:8])[N:6]=1.C([Mg]Cl)(C)C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)=O.CC(C)=O>ClCCl.CCOC(C)=O.CCCCCCC.O1CCCC1>[CH2:26]([O:25][C:23]([C:2]1[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=[C:5]([C:7]#[N:8])[N:6]=1)=[O:24])[CH3:27]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1Br
Reactant: CCOC(=O)Cl
Agent: CC(C)[Mg]Cl
Agent: O=C=O
Solvent: CCCCCCC
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C#N)cn1COCC[Si](C)(C)C
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
A 12-L, four-neck, round-bottom flask equipped with a mechanical stirrer, a temperature probe, and an addition funnel with a nitrogen inlet was charged with 2-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile [390 g, 1.29 mol, as prepared in the previous step) and anhydrous tetrahydrofuran (4.0 L). Agitation was initiated and the reaction mixture was cooled to −50° C. using a dry ice/acetone bath. Isopropylmagnesium chloride (2.0 M in THF, 760 mL, 1.52 mol) was added through the addition funnel over 30 min to maintain the internal temperature below −40° C. The reaction was stirred for a further 30 min at −43° C., after which time it was cooled to −78° C. Ethyl chloroformate (210 mL, 2.20 mol) was added through the addition funnel over 10 min to maintain the internal temperature below −60° C. The reaction was stirred for a further 40 min at −70° C., at which point the dry ice/acetone bath was removed and the reaction was allowed to warm to ambient temperature over 1.5 h. The reaction mixture was cooled in an ice bath to 0° C. and quenched by the slow addition of satd ammonium chloride solution (1.8 L) at such a rate that the internal temperature was maintained below 10° C. The reaction mixture was transferred into a 12-L separatory funnel, diluted with ethyl acetate (4.0 L), and the layers were separated. The organic layer was washed with brine (2×2.0 L) and concentrated under reduced pressure at 35° C. to give a brown oil. The crude oil was dissolved in dichloromethane (300 mL) and purified by chromatography (15×22 cm, 1.5 kg of silica gel, 10:1 to 4:1 heptane/ethyl acetate) to give a yellow oil, which was dissolved in EtOAc (100 mL), diluted with heptane (2.0 L), and stored in a refrigerator for 5 h. The resulting slurry was filtered to give the title compound as a crystalline white solid (141 g, 37%). The 1H and 13C NMR spectra were consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][C:5]([OH:10])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>ClCCl>[CH3:21][S:22]([O:10][C:5]1[CH:6]=[C:7]([CH2:8][CH3:9])[C:2]([Cl:1])=[CH:3][C:4]=1[N+:11]([O-:13])=[O:12])(=[O:24])=[O:23]
Reactant: CCc1cc(O)c([N+](=O)[O-])cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1cc(OS(C)(=O)=O)c([N+](=O)[O-])cc1Cl
Reaction time: 0.5 h

Procedure:
150 mg of 4-chloro-5-ethyl-2-nitrophenol was dissolved in 1.5 ml of dichloromethane, and 156 μl of triethylamine and 69 μl of methanesulfonylchloride were added at room temperature and stirred for 30 minutes. To the reaction mixture was added 50 ml of water, and extracted with 60 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to yield 200.7 mg of the title compound.
Reaction SMILES: O1CCC[CH2:2]1.[O:6]=[C:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][CH2:8]1.C[Li]>O>[OH:6][C:7]1([CH3:2])[CH2:8][CH2:9][CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:11][CH2:12]1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: [Li]C
Solvent: O
Product: CC1(O)CCC(NC(=O)OC(C)(C)C)CC1
Reaction time: 1.5 h

Procedure:
To a 6 ml anhydrous tetrahydrofuran solution of 303 mg (1.42 mmol) of tert-butyl N-(4-oxocyclohexyl)carbamate, 2.7 ml of methyl lithium (1.1M in hexane, 2.98 mmol) was dropwise added at −78° C. under an argon atmosphere and stirred for 1.5 hours, after adding 20 ml of water thereto to return room temperature, followed by extracting with 30 ml of methylene chloride after drying over anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain 150 mg (46%) of non-polar side diastereomer as a colorless crystal and 54 mg (17%) of polar side diastereomer as a colorless crystal.
Reaction SMILES: [NH2:1][C:2](=[O:42])[CH2:3][C:4]1[CH:41]=[CH:40][CH:39]=[CH:38][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][N:26]3C(OC(C)(C)C)=O)=[CH:21][CH:20]=2)[N:9]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]1[C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:10]2[N:9]=[C:8]([CH2:7][CH2:6][C:5]3[CH:38]=[CH:39][CH:40]=[CH:41][C:4]=3[CH2:3][C:2]([NH2:1])=[O:42])[C:13]([C:14]([F:17])([F:15])[F:16])=[CH:12][N:11]=2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCCCN3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 22 h
Yield: 88.2 %

Procedure:
tert-Butyl 2-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I41) (0.087 g, 0.15 mmol) was dissolved in dry DCM (5 mL) under an atmosphere of nitrogen. Trifluoroacetic acid (0.351 mL, 4.58 mmol) was added to the solution and the reaction was stirred at room temperature for 22 hours. Volatiles were removed in vacuo, EtOAc (20 mL) and sat. aq. NaHCO3 (15 mL) were added to the residue and the layers were separated. The aqueous layer was extracted with EtOAc (15 mL), the combined organics were washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo to give a pale yellow solid which was taken up in DCM (˜10 mL) and methanol (˜1 mL) and concentrated in vacuo. The process was repeated with only DCM twice to give the title compound (8) (0.064 g, 89% yield) as a pale yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.15 (s, 1H), 8.66 (s, 1H), 7.70-7.62 (m, 2H), 7.44 (s, 1H), 7.30 (d, J=8.6 Hz, 2H), 7.26-7.12 (m, 4H), 6.92 (s, 1H), 3.54-3.47 (m, 3H), 3.15-2.97 (m, 5H), 2.71-2.59 (m, 1H), 1.84-1.76 (m, 1H), 1.67 (d, J=12.4 Hz, 1H), 1.61-1.50 (m, 1H), 1.46-1.27 (m, 3H). LCMS Method C: rt 4.84 min; m/z 484.3 [M+H]+.
Reaction SMILES: [OH-].[Na+:2].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([CH3:21])[C:12]([CH3:20])=[C:13]([C:17](=[O:19])[CH:18]=2)[C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]([CH3:21])[C:12]([CH3:20])=[C:13]([C:17](=[O:19])[CH:18]=2)[C:14]([O-:16])=[O:15])=[CH:8][CH:9]=1.[Na+:2]
Reactant: Cc1c(C(=O)O)c(=O)cc(-c2ccc(Cl)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)[O-])c(=O)cc(-c2ccc(Cl)cc2)n1C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
0.52 g (0.0065 mol) of 50% aqueous sodium hydroxide is added to a suspension of 1.8 g (0.0065 mol) 6-(4-chlorophenyl)-1,2-dimethyl-4-oxonicotinic acid in 35 ml of methanol. The solution formed is allowed to stand at room temperature for 1 hr. and then is concentrated in vacuo. The concentrate is washed with two (25 ml) portions of diethyl ether and dried to afford 1.7 g (87% yield) of product.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:20])OCC(Cl)(Cl)Cl)=[CH:8][CH:7]=1)(=[O:4])[CH2:2][CH3:3].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[N:32]=[C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[S:30][N:29]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[N:32]=[C:31]([N:33]2[CH2:34][CH2:35][N:36]([C:13]([NH:12][C:9]3[CH:8]=[CH:7][C:6]([NH:5][C:1](=[O:4])[CH2:2][CH3:3])=[CH:11][CH:10]=3)=[O:20])[CH2:37][CH2:38]2)[S:30][N:29]=1
Reactant: CCC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: Fc1ccccc1-c1nsc(N2CCNCC2)n1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCC(=O)Nc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4F)ns3)CC2)cc1
Yield: 22.6 %

Procedure:
A solution of 2,2,2-trichloroethyl [4-(propionylamino)phenyl]carbamate (200 mg, 0.589 mmol), 1-[3-(2-fluorophenyl)-1,2,4-thiadiazol-5-yl]piperazine (145 mg, 0.589 mmol), diisopropylethylamine (0.206 ml, 1.18 mmol) and dimethyl sulfoxide (4 ml) was stirred at 70° C. for 24 hours, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 60.5 mg (22.6%) of the desired product as a solid.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C(=O)=O.[Li][CH2:15][CH2:16][CH2:17][CH3:18].[C:19]([OH:27])(=[O:26])[C:20]1C=[CH:24][N:23]=[CH:22][CH:21]=1.C(=O)CC>C1COCC1>[CH2:17]([CH:16]1[C:15]2[CH:24]=[N:23][CH:22]=[CH:21][C:20]=2[C:19](=[O:26])[O:27]1)[CH3:18]
Reactant: O=C(O)c1ccncc1
Reactant: [Li]CCCC
Agent: CC1(C)CCCC(C)(C)N1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CCC=O
Product: CCC1OC(=O)c2ccncc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
A solution of 2,2,6,6-tetramethyl-piperidine (20.3 ml, 120 mmol) in a 250 ml round bottomed flask equipped with a magnetic stirrer, is put under argon atmosphere and 60 ml of dry THF is added. The reaction mixture is cooled to −78° C. by adding a controlled amount of dry ice to an acetone bath. The cooled reaction mixture is treated dropwise with nBuLi solution (64 mL of a 2.5 M solution in hexanes, 160 mmol) and the reaction is let stir at −78° C. for 0.5 h. A solution of isonicotinic acid (4.92 g, 40 mmol) in THF (60 mL) is added dropwise to the reaction at −78° C. The reaction is stirred at −78° C. for 1 h and is then warmed to −20° C. The reaction mixture is treated with propionaldehyde (7.2 ml, 100 mmol, 2.5 eq) dropwise at −50° C. The reaction is stirred at −20° C. for 2 h and warmed to room temperature overnight. The reaction mixture is concentrated and the residue is dissolved in water and ether. The aqueous layer is collected and extracted with dichloromethane and ether (6×50 ml). The aqueous phase is concentrated and the residue is dissolved in EtOH (30 mL) and acetic acid (2 mL) and heated at reflux overnight under argon. The reaction mixture is cooled to room temperature and concentrated. The residue is purified by chromatography (silica gel, MeOH/chloroform) to give the title compound (0.674 g, 10%) as an oil.