Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]3)[C:8]2=O)=[CH:4][C:3]=1[CH3:19].[CH3:20][C:21]([S:24]([NH2:26])=[O:25])([CH3:23])[CH3:22].O>CCOC(C)=O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[CH3:19])[CH2:6][C:7]1([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]1)[C:8]2=[N:26][S:24]([C:21]([CH3:23])([CH3:22])[CH3:20])=[O:25]
Reactant: COC1CCC2(CC1)Cc1cc(C)c(Br)cc1C2=O
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: COC1CCC2(CC1)Cc1cc(C)c(Br)cc1C2=NS(=O)C(C)(C)C
Temperature: 25 °C
Yield: 44.6 %

Procedure:
6′-Bromo-4-methoxy-5′-methylspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (Intermediate 4, 1.38 g, 4.27 mmol) and 2-methylpropane-2-sulfinamide (0.931 g, 7.68 mmol) were dissolved in 2-Me THF (8 mL). Titanium(IV) ethoxide (1.78 mL, 8.53 mmol) was added and the resulting mixture was heated to reflux overnight. 2-Methylpropane-2-sulfinamide (0.259 g, 2.13 mmol) and titanium(IV) ethoxide (0.624 mL, 2.99 mmol) were added and heating was continued. After a total of 4 days, the reaction was allowed to cool to r.t. and diluted with EtOAc (25 mL). Water (12 mL) was added dropwise under vigorous stirring and after stirring for another 10 min, the mixture was allowed to stand without stirring for 1.5 h. The solids were filtered off and the solvent was evaporated. The residue was purified by flash chromatography using a gradient of 0-30% EtOAc in heptane as eluent to afford 812 mg (45% yield) of the title compound: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.23 (m, 9 H), 1.31 (m, 2 H), 1.58 (m, 4 H), 1.90 (m, 1 H), 2.02 (m, 1 H), 2.42 (s, 3 H), 2.98 (m, 2 H), 3.18 (m, 1 H), 3.25 (m, 3 H), 7.51 (m, 1 H), 8.53 (m, 1 H); MS (ES+) m/z 426, 428 [M+H]+.
Reaction SMILES: C[OH:2].[Cl:3][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1>N1C=CC=CC=1.O=O>[Cl:3][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:2])[C:6]=2[CH:5]=1
Reactant: Clc1ccc2c(c1)Cc1ccccc1-2
Reactant: CO
Agent: O=O
Solvent: c1ccncc1
Product: O=C1c2ccccc2-c2ccc(Cl)cc21

Procedure:
A methanol free, 40% solution of Triton B in pyridine (8 mL) was added to a stirred, room temperature solution of commercially available (Alpha) 2-chlorofluorene (17) (42 g, 0.21 mmoL) in pyridine (257 mL) and oxygen was bubbled through the mixture at a moderate rate for 18 h. The majority of the pyridine was then removed on the rotary evaporator at reduced pressure and 5% aqueous hydrochloric acid (500 mL) was added to the residue. The solid was collected by filtration and washed with 5% aqueous hydrochloric acid and water. After drying, the solid was extracted repeatedly with hexane to remove some hexane insoluble impurities. Evaporation of the hexane left 42.7 g(95%) of 2-chloro-9-fluorenone: mp 110°-113° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:34][CH2:35][CH3:36])([CH2:31][CH2:32][CH3:33])[C:7](=[O:30])[C:8]([C:13]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([NH:23][S:24]([NH2:27])(=[O:26])=[O:25])=[CH:22][C:16]=4[S:15](=[O:29])(=[O:28])[N:14]=3)=[C:9]2[OH:12])=[CH:4][CH:3]=1.[OH-].[Na+:38]>C(#N)C>[NH2:27][S:24]([NH:23][C:21]1[CH:20]=[CH:19][C:17]2[NH:18][C:13]([C:8]3[C:7](=[O:30])[C:6]([CH2:31][CH2:32][CH3:33])([CH2:34][CH2:35][CH3:36])[C:5]4[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=4)[C:9]=3[O-:12])=[N:14][S:15](=[O:29])(=[O:28])[C:16]=2[CH:22]=1)(=[O:25])=[O:26].[Na+:38]
Reactant: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(NS(N)(=O)=O)ccc3N2)=C(O)c2cc(F)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(NS(N)(=O)=O)ccc3N2)=C([O-])c2cc(F)ccc21
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
A solution of Example 17E (13 mg) was dissolved in acetonitrile (1 mL) and treated with sodium hydroxide solution (1.0 N, 24.3 μL, 0.0243 mmol). After stirring for 30 min, the solution was frozen and lyophilized to afford the title compound as a fluffy grey solid (12.8 mg, 55% overall). 1H NMR (300 MHz, DMSO-d6): δ 0.65 (m, 8 H) 0.86 (d, J=2.94 Hz, 2 H) 1.65 (d, J=3.68 Hz, 2 H) 2.05 (m, 2 H) 7.43 (m, 6 H) 9.58 (s, 1 H) 15.21 (s, 1 H).
Reaction SMILES: CC(C)(OC(N[C@H]([C:16]1[N:17](CC(=O)CC)[CH:18]=[C:19](C2C=CC=CC=2)[N:20]=1)CC1C=CC=CC=1)=O)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:17]1[C:18]2=[N:17][CH:18]=[CH:19][NH:20][CH:19]2[NH:20][CH2:16]1
Reactant: CCC(=O)Cn1cc(-c2ccccc2)nc1[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1=CNC2NCNC2=N1
Temperature: 20 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
2-[1(S)-{(1,1-Dimethylethoxy)carbonylamino}-2-phenylethyl]-1-(2-oxo-butyl)-4-phenyl-1H-imidazole (60 mg) in a mixture of 10% TFA in DCM was stirred at about 20° C. for about 3 hours and then concentrated under reduced pressure. The resulting intermediate dihydro-imidazo-pyrazine was dissolved in methanol and borohydride supported on resin (AMBERLITE® IRA 400, Aldrich, 2.5 mmol BH4−/g; 4 eq) was added. The pH was maintained at about 5 by addition of drops of TFA. After about 2 hours of stirring at about 20° C., the mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (ethyl acetate/Heptane 7:3; Rf=0.30). The tetrahydro-imidazo-pyrazine was obtained as a single diastereoisomer in 86% yield (38 mg) NMR (1H, 400 MHz, CDCl3) δ: 7.87-7.10 (m, 11H, arom, H), 4.28 (dd, 1H, 3J=10 Hz, 3J=3 Hz, H8), 3.95 (dd, 1H, 2J=11.5 Hz, 3J=3.6 Hz), 3.85 (dd, 1H, 2J=13.6 Hz, 3J=3.0 Hz), 3.60 (t, 1H, 2J=3J=11.5 Hz), 3.85 (dd, 1H, 2J=13.6 Hz, 3J=10, Hz), 2.98 (m, 2H), 1.85 (s, 1H, NH), 1.55 (m, 2H, CH2), 0.95 (t, 3H, CN3). NMR (13C, 100 MHz CDCl3): 146.3, 140.9, 138.0, 134.4, 129.4, 128.6, 128.5, 126.6, 126.5, 124.8, 113.8, 55.9, 54.4, 50.2, 40.0, 26.6, 10.0. LC/MS: calculated MW=317.43, m/z=318.20 (M+H).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][S:14]([O:17]C)(=[O:16])=[O:15])[O:3]1.Cl[C:20]1[S:24][C:23]([C:25]([NH2:27])=[O:26])=[N:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:25]([C:23]1[S:24][C:20]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]3[CH:4]([CH2:13][S:14]([OH:17])(=[O:15])=[O:16])[O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)=[N:21][N:22]=1)(=[O:26])[NH2:27]
Reactant: NC(=O)c1nnc(Cl)s1
Reactant: COS(=O)(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2nnc(C(N)=O)s2)cc2c1C(CS(=O)(=O)O)OB2O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl (1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)methanesulfonate (0.46 g, 1.71 mmol, 1 eq.) and 5-chloro-1,3,4-thiadiazole-2-carboxamide (0.42 g, 2.56 mmol, 1.5 eq.) in 10 ml DMF was added cesium carbonate (2.22 g, 6.82 mmol, 4 eq.) portionwise. The reaction was stirred at room temperature overnight. It was then quenched by water, extracted with EtOAc. The aqueous layer was collected and prep HPLC gave the product as white flakes. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.01 (s, 1H), 7.39 (d, J=2.4 Hz, 1H), 7.27 (d, J=2.4 Hz, 1H), 5.42 (d, 7.6 Hz, 1H), 3.04 (dd, J=14.4, 1.2 Hz, 1H), 2.46 (m, 1H), 2.27 (s, 3H).
Reaction SMILES: [Cl:1]Cl.[CH:3](=[N:10][OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)(Cl)Cl>[C:3]([Cl:1])(=[N:10][OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClCl
Reactant: ON=Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: ON=C(Cl)c1ccccc1
Yield: 60.5 %

Procedure:
Chlorine gas (7.9 g) was added to a cold (0° to -10°) solution of 12.1 g of benzaldoxime in 80 ml of chloroform. The mixture was stirred at -10° for half an hour and the solution of benzohydroximoyl chloride was used without further purification in an attempt to prepare the methanesulfonate as described in Example II-C. Work-up of the sulfonation mixture resulted in recovery of 9.4 g of unreacted benzohydroximoyl chloride, m.p. 50°-51°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1.S(=O)(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][N+:3]=1[O-:20]
Reactant: CC(C)(C)c1ccnc(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc[n+]([O-])c(Cl)c1
Yield: 90 %

Procedure:
2-Chloro-4-t-butylpyridine (5.0 g, 30 mmol) was dissolved in chloroform (75 mL), treated with MCPBA, ca. 75% (8.3 g, 36 mmol, 1.2 equivalents) and heated to reflux for 19 h. The mixture was stirred with sodium bisulfate solution until testing with starch-iodide paper indicated consumption of oxidant. The pH was adjusted to 7 with saturated aqueous NaHCO3 solution, the phases separated and the aqueous phase extracted once with CH2Cl2. The organic phases were pooled and washed twice with H2O, once with brine, dried (Na2SO4) and concentrated in vacuo to afford 2-chloro-4-t-butylpyridine-N-oxide (5.0 g, 90%), which crystallized to long white needles on standing.
Reaction SMILES: [SH:1][C:2]1[NH:10][C:9]2[C:4](=[N:5][CH:6]=[N:7][C:8]=2[NH2:11])[N:3]=1.[O:12]=[C:13]([CH2:25]Br)[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1>>[C:20]([C:19]1[CH:23]=[CH:24][C:16]([O:15][CH2:14][C:13](=[O:12])[CH2:25][S:1][C:2]2[NH:10][C:9]3[C:4](=[N:5][CH:6]=[N:7][C:8]=3[NH2:11])[N:3]=2)=[CH:17][CH:18]=1)([OH:22])=[O:21]
Reactant: Nc1ncnc2nc(S)[nH]c12
Reactant: O=C(CBr)COc1ccc(C(=O)O)cc1
Product: Nc1ncnc2nc(SCC(=O)COc3ccc(C(=O)O)cc3)[nH]c12

Procedure:
From 8-mercapto-adenine and p-(2-oxo,3-bromo propyloxy)-benzoic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:17].[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:11]3[C:6](=[C:7]([C:12]([F:14])([F:13])[F:15])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])=[CH:27][CH:26]=1
Reactant: O=C(c1ccccn1)c1cnc2c(C(F)(F)F)cccc2c1Cl
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=C(c1ccccn1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccc(Cl)cc1

Procedure:
This compound was prepared using the procedure of Example 1, step 5 using (4-chloro-8-trifluoromethyl-quinolin-3-yl)-pyridin-2-yl-methanone in place of [4-chloro-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 4-chlorophenylboronic acid in place of phenyl boronic acid; MS (ESI) m/z 413/415 ([M+H]+); Anal. Calcd for C22H12ClF3N2O: C, 64.01; H, 2.93; N, 6.79. Found: C, 63.66; H, 3.03; N, 6.60.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][NH:11][C:5]=2[CH:4]=[N:3]1.[H-].[Na+].[F:14][C:15]([F:33])([F:32])[C:16]1[CH:31]=[CH:30][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=2)=[O:21])=[CH:18][CH:17]=1.O>CN(C=O)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][N:11]([CH2:26][C:25]3[CH:28]=[CH:29][C:22]([C:20](=[O:21])[C:19]4[CH:30]=[CH:31][C:16]([C:15]([F:14])([F:32])[F:33])=[CH:17][CH:18]=4)=[CH:23][CH:24]=3)[C:5]=2[CH:4]=[N:3]1
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(C(F)(F)F)cc1
Reactant: Cn1ncc2[nH]ccc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc2c(ccn2Cc2ccc(C(=O)c3ccc(C(F)(F)F)cc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
A solution of 5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (298 mg) in DMF (10 ml) was dripped into a suspension of 60% sodium hydride-oil (96 mg) in DMF (8 ml) on an ice-water bath. The mixture was stirred at room temperature for 1 hour, after which a solution of 4-(4-trifluoromethylbenzoyl)benzyl bromide (755 mg) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 3 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=1:2) to provide the title compound as light-brown powder (436 mg, yield 53%).
Reaction SMILES: [Cl:1][C:2]([Cl:28])([Cl:27])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15]C(C)(C)C)=O)[N:8]1C(OC(C)(C)C)=O)=[O:6].FC(F)(F)C(O)=O.[C:36]([O:40][C:41]([NH:43][C@@H:44]([CH2:48][O:49][Si:50]([C:63]([CH3:66])([CH3:65])[CH3:64])([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)C(O)=O)=[O:42])([CH3:39])([CH3:38])[CH3:37].C(N(CC)C(C)C)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>ClCCl.C(#N)C>[Cl:28][C:2]([Cl:1])([Cl:27])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:15])[C@@H:44]([NH:43][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:42])[CH2:48][O:49][Si:50]([C:63]([CH3:66])([CH3:65])[CH3:64])([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[NH:8]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.5 %

Procedure:
To (S)-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-(2,2,2-trichloro-ethyl)ester (5.0 g, 10.8 mmol) in anhydrous dichloromethane (33 mL) at 0° C. and under an atmosphere of nitrogen was added trifluoroacetic acid (33 mL, 432 mmol). The solution was warmed to room temperature and stirred for 16 h. The reaction was concentrated in vacuo and the residue co-evaporated from toluene (3×). The resulting brown viscous oil was dissolved in anhydrous acetonitrile (5 mL) and added to a solution of (S)-2-tert-butoxycarbonylamino-3-(tert-butyl-diphenyl-silanyloxy)-propionic acid (2.39 g, 5.4 mmol, prepared as in PCT Int. Appl. 2006, WO 2006004880 A2), N,N-diisopropylethylamine (3.76 mL, 21.6 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (2.05 g, 5.4 mmol) in anhydrous acetonitrile (25 mL) that had been previously stirred at 0° C. for 20 minutes. The reaction was warmed to room temperature and stirred for 16 h before being concentrated in vacuo. The residue was purified by silica gel chromatography using iso-hexanes/ethyl acetate 4:1 to give the title compound (1.8 g, 49%) as a clear viscous oil. 1H NMR (300 MHz, CDCl3) δ 1.08 (s, 9H), 1.46 (s, 9H), 1.53-1.67 (m, 1H), 1.80-2.01 (m, 2H), 2.82-2.96 (m, 1H), 3.19-3.32 (m, 1H), 3.62 (d, J=10.9 Hz, 1H), 3.80-3.97 (m, 3H), 4.23-4.34 (m, 1H), 4.61 (d, J=12.0 Hz, 1H), 4.90 (d, J=12.0 Hz, 1H), 5.18-5.27 (m, 1H), 5.51-5.63 (m, 1H), 7.35-7.49 (m, 6H), 7.58-7.70 (m, 4H). LCMS (m/z) 686.2 [M+H], Tr=4.32 min.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH:10]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][OH:21])[CH2:14][CH2:13]1)[CH3:11])(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][CH:10]([N:12]1[CH2:13][CH2:14][CH:15]([NH:18][CH:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:20][OH:21])[CH2:16][CH2:17]1)[CH3:11]
Reactant: CC(CCNC(=O)OC(C)(C)C)N1CCC(NC(CO)c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(CCN)N1CCC(NC(CO)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.4 %

Procedure:
The above carbamate (159 mg, 0.407 mmol) was dissolved in CH2Cl2 (4 ml) and then cooled to 0° C. Trifluoroacetic acid (2.0 ml, 26 mmol) was added dropwise to the cooled solution and then the reaction was allowed to stir for 10 minutes at 0° C., and then 30 minutes at room temperature. The solution was concentrated and the residue dissolved in 9:1 CH2Cl2/MeOH (10 ml). mgSO4 was added and the reaction mixture stirred for 30 minutes, then potassium carbonate (373 mg, 2.70 mmol) was added and the solution was concentrated to afford 2-[1-(3-amino-1-methylpropyl)piperidin-4-ylamino]-2-phenylethanol as a light yellow oil (106 mg, 89%) following purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:26](=O)[C:27](O)=[O:28])[CH:20]=1>C(O)C>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([N:11]2[C:27](=[O:28])[C:26]([CH2:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)=[N:18][C:17]3[CH:16]=[CH:15][CH:14]=[N:13][C:12]2=3)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)C(=O)Cc1cccnc1
Reactant: CC(=O)Nc1cccc(Nc2ncccc2N)c1
Solvent: CCO
Product: CC(=O)Nc1cccc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1
Yield: 67.8 %

Procedure:
A mixture of 2-(3-acetamidophenylamino)-3-aminopyridine (1.0 g) and 3-(3-pyridyl)pyruvic acid (0.82 g) in ethanol (50 ml) was stirred under reflux for 6 hours. After evaporation of the solvent, crude residue was chromatographed on silica gel and crystallized from ethyl acetate to give 4-(3-acetamidophenyl)-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (1.04 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:21]#[N:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:6][C:7]=1Br.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[CH:33][C:34]3[C:40](=[O:41])[NH:39][CH2:38][CH2:37][NH:36][C:35]=3[CH:42]=2)O1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:21]#[N:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:6][C:7]=1[C:31]1[CH:32]=[CH:33][C:34]2[C:40](=[O:41])[NH:39][CH2:38][CH2:37][NH:36][C:35]=2[CH:42]=1
Reactant: CC1(C)OB(c2ccc3c(c2)NCCNC3=O)OC1(C)C
Reactant: N#CC1(c2ccc(-c3cnc(N)c(Br)n3)cc2)CCOCC1
Product: N#CC1(c2ccc(-c3cnc(N)c(-c4ccc5c(c4)NCCNC5=O)n3)cc2)CCOCC1
Yield: 32.9 %

Procedure:
General method C was applied to 4-(4-(5-amino-6-bromopyrazin-2-yl)phenyl)tetrahydro-2H-pyran-4-carbonitrile (215 mg, 0.6 mmol) and 8-(4,4,5,5-tetra methyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-benzo[e][1,4]diazepin-5(2H)-one (173 mg, 0.6 mmol) to provide 4-(4-(5-amino-6-(5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl)pyrazin-2-yl)phenyl)tetrahydro-2H-pyran-4-carbonitrile as a yellow solid (87 mg, 33% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.47 (s, 1H), 8.14 (d, J=8.3 Hz, 1H), 8.01 (d, J=8.3 Hz, 2 H), 7.58 (d, J=8.3 Hz, 2H), 7.21 (d, J=8.3 Hz, 1H), 7.04 (s, 1H), 6.40 (br. s., 1H), 4.93 (br. s., 2H), 4.57 (br. s., 1H), 4.12 (d, J=8.8 Hz, 2H), 3.94 (t, J=11.7 Hz, 2H), 3.50-3.73 (m, 4 H), 2.02-2.26 (m, 4H); MS (EI) m/z=441.5 [M+1]+.
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([OH:13])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:54][C:55]([F:64])([F:63])[C:56]1[N:60]=[C:59]([CH2:61][NH2:62])[O:58][N:57]=1>CN(C=O)C>[CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([NH:62][CH2:61][C:59]2[O:58][N:57]=[C:56]([C:55]([F:64])([F:63])[F:54])[N:60]=2)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Reactant: NCc1nc(C(F)(F)F)no1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
To a solution of 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 9c) (124 mg, 0.43 mmol) in DMF (4 mL) were added DIPEA (0.1 mL, 1.08 mmol) and HATU (204 mg, 0.54 mmol) at 25° C. The reaction mixture was stirred for 30 min at 25° C. To this was added C-(3-trifluoromethyl-1,2,4-oxadiazol-5-yl)-methylamine (CAN 944905-93-5) (60 mg, 0.36 mmol) and the reaction mixture was stirred for 12 h at 25° C. Volatiles were removed in vacuo and the resultant residue was purified by prep-HPLC to get 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-N-(3-trifluoromethyl-1,2,4-oxadiazol-5-ylmethyl)-nicotinamide (61 mg, 38.7%) as off-white solid; MS (ESI): 439 (M+H]+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:15][N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[N:17]1)=[N+]=[N-]>[Pd].CO>[N:16]1([CH2:15][C:7]2[N:6]([CH2:5][CH2:4][NH2:1])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[N:17]1
Reactant: [N-]=[N+]=NCCn1c(Cn2nnc3ccccc32)nc2ccccc21
Agent: [Pd]
Solvent: CO
Product: NCCn1c(Cn2nnc3ccccc32)nc2ccccc21
Reaction time: 5 h
Yield: 100.9 %

Procedure:
A mixture of 1-[1-(2-azido-ethyl)-1-H-benzimidazol-2-ylmethyl)-1H-benzotriazole (25 mg, 0.078 mmol) and 10% palladium on carbon in 1 mL of methanol was agitated under hydrogen at 55 psi for 5 hours. The reaction mixture was filtered through a pad of Celite and then through a Millipore membrane filter rinsing with methanol. The filtrate was stripped of solvent and dried under vacuum to give the amine (23 mg, quantitative yield) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[CH:12][CH:11]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1ccc2cccnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cc(Nc2ccc3cccnc3c2)ncn1

Procedure:
This compound could be prepared from 4,6-dichloro-pyrimidine and 7-aminoquinoline in the presence of K2CO3 and DMF.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH2:14])([O-:3])=[O:2].[Cl:15][CH2:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19].C(N(CC)CC)C>C(Cl)Cl>[Cl:15][CH2:16][C:17]([CH3:22])([CH3:21])[C:18]([NH:14][C:5]1[CH:6]=[CH:7][C:8]([C:10]([F:11])([F:12])[F:13])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])=[O:19]
Reactant: Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CC(C)(CCl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CCl)C(=O)Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 48 h

Procedure:
To a solution of 2-nitro-4-(trifluoromethyl)benzenamine (3.00 g, 14.9 mmol, 1.0 equiv) in CH2Cl2 (90 mL) at 25° C., was added 3-chloro-2,2-dimethylpropanoyl chloride (3.9 mL, 29.8 mmol, 2.0 equiv) followed by triethylamine (4.2 mL, 29.8 mmol, 2.0 equiv). The solution was heated to 40° C. After 48 h, the solution was washed with water (50 mL), and brine (50 mL). After concentration in vacuo, the residue was purified by silica gel chromatography (1:10 hexanes:EtOAc to 1:5 hexanes:EtOAc) to afford 3-chloro-2,2-dimethyl-N-(2-nitro-4-(trifluoromethyl)phenyl)propanamide. MS—No (MH+) observed.
Reaction SMILES: [OH-].[Na+].[CH3:3][NH:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23]CC)=[O:22])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[C:26]1[CH:35]=[CH:34][C:33]2[C:32]([CH3:37])([CH3:36])[CH2:31][CH2:30][C:29]([CH3:39])([CH3:38])[C:28]=2[CH:27]=1>O1CCCC1>[CH3:3][NH:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[C:26]1[CH:35]=[CH:34][C:33]2[C:32]([CH3:37])([CH3:36])[CH2:31][CH2:30][C:29]([CH3:39])([CH3:38])[C:28]=2[CH:27]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCNC)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CNCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 65.7 %

Procedure:
In a manner similar to that of Example 2a, by reaction of 400 mg (10 mmol) of sodium hydroxide with 500 mg (1 mmol) of ethyl 4′-(3-methylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate (Example 13a) in 30 ml of tetrahydrofuran. 310 mg of 4′-(3-methylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid are obtained in the form of a white solid (m.p.=242° C., yield=66%).