Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.[CH2:29](C(CC)(CC)C([O-])([O-])[O-])[CH3:30].C1(C)C=CC=CC=1>[Pt].C(O)(C)C>[CH3:29][C:30]1[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:1]=1
Reactant: O=C(NCCCCCNc1c([N+](=O)[O-])cnc2ccccc12)c1ccccc1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Agent: [Pt]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: Cc1nc2cnc3ccccc3c2n1CCCCCNC(=O)c1ccccc1

Procedure:
A catalytic amount of platinum on carbon was added to a suspension of N1-{5-[(3-nitroquinolin-4-yl)amino]pentyl}benzamide (3.4 g, 9 mmol) in isopropyl alcohol (250 mL). The reaction mixture was placed under a hydrogen atmosphere at 50 psi (3.4×104 pascals) on a Parr apparatus. After 2 hours the reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under vacuum to provide crude N1-{5-[(3-aminoquinolin-4-yl)amino]pentyl}benzamide. This material was combined with triethylorthoacetate (1.4 g, 9 mmol) and toluene (200 mL). The reaction mixture was heated overnight on a steam bath with a Vigreux column. The toluene was decanted from the reaction mixture and concentrated under vacuum to provide N1-[5-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)pentyl]benzamide as an oil.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])=[CH:8][CH2:7]1)(=O)=O.C1CCN2C(=NCCC2)CC1>O1CCCC1.C(OCC)(=O)C>[C:9]1([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[CH2:10][CH2:11][CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)OC1CC=C(c2ccncc2[N+](=O)[O-])CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=[N+]([O-])c1cnccc1C1=CC=CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(3-nitropyridin-4-yl)cyclohex-3-enyl methanesulfonate (1.0 equiv) in tetrahydrofuran (0.1M) was added DBU (1.8 equiv.) at room temperature. The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with ethyl acetate (200 mL), and washed with sat NaCl (30 mL). The organic was dried with MgSO4, filtered and concentrated. The residue was purified by column (5% methanol in 1:1 ethyl acetate and hexanes) to give 4-(cyclohexa-1,3-dienyl)-3-nitropyridine. LC/MS (m/z): MH+=203.2, Rt=0.85.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:17][N:18]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=O)C.CC(C)([O-])C.[K+]>C1COCC1>[CH2:23]([O:22][C:20]([CH:19]1[N:18]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=2[O:34][CH3:35])[CH2:17][C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:6]=2[C:4]1=[O:3])=[O:21])[CH3:24]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2ccccc2)sc1C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C1C(=O)c2sc(-c3ccccc3)nc2CN1Cc1ccc(OC)cc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 102.3 %

Procedure:
A yellow solution of 4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-2-phenyl-thiazole-5-carboxylic acid ethyl ester (5.60 g, 0.01 mol) in THF (45 mL) was added 1 M potassium tert-butoxide (KOtBu) in THF (24.7 mL, 0.02 mmol) at −78° C., a dark red suspension quickly appeared. The mixture was stirred at −78° C. for 20 min, warmed to room temperature and stirred at that temperature for 2 h before it was quenched with aqueous ammonium chloride, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 5-(2,4-dimethoxy-benzyl)-7-oxo-2-phenyl-4,5,6,7-tetrahydro-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester as a yellow oil (4.63 g). It was dissolved in dichloromethane (40 mL) and thionyl chloride (1.12 mL, 0.02 mmol) was added drop wise. The mixture was stirred at room temperature for 3.5 h before it was quenched with saturated sodium bicarbonate, extracted with dichloromethane. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a yellow solid (2.74 g): 1H NMR (CDCl3, 200 MHz): δ=11.52 (s, 1H), 9.00 (s, 1H), 8.13 (m, 2H), 7.55 (m, 3H), 4.58 (q, J=7.0 Hz, 2H), 1.53 (t, J=7.0 Hz, 3H); MS: (+) m/z 301.0 (M+1).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[C@H:14]([CH2:15][CH3:16])[CH2:13][C:12](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:11]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O.O>C1COCC1>[CH2:15]([C@H:14]1[C@@H:10]([CH2:9][OH:8])[CH2:11][C:12](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]1)[CH3:16]
Reactant: CCOC(=O)C=C1C[C@@H](CC)[C@@H](CO[Si](C)(C)C(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=C1C[C@@H](CC)[C@@H](CO)C1
Reaction time: 6 h
Yield: 95.4 %

Procedure:
To a solution of ethyl 2-((3S,4R)-3-((tert-butyldimethylsilyloxy)methyl)-4-ethylcyclopentylidene)acetate (1.00 g, 3.06 mmol) in THF (20 mL) was added TBAF (1M in THF, 4.59 mL, 4.59 mmol). After 6 h, EtOAc and water were added. The organic layer was separated, concd in vacuo and purified by chromatography on silica gel eluting with EtOAc/heptane to provide ethyl 2-((3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentylidene)acetate (0.620 g, 95%) as an oil. LC/MS (Table 1, Method a) Rt=1.96, 2.08 min; MS m/z: 213 (M+H)+.
Reaction SMILES: C([Si]([O:18][C@@H:19]1[C@H:26]2[C@H:22]([O:23][C:24]([CH3:28])([CH3:27])[O:25]2)[C:21]([CH2:29][O:30][C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:20]1[F:50])(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(OC)(C)C.[O-][Mn](=O)(=O)=O.[K+]>C1COCC1>[F:50][C:20]1[C@H:19]([OH:18])[C@@H:26]2[O:25][C:24]([CH3:28])([CH3:27])[O:23][C@@H:22]2[C:21]=1[CH2:29][O:30][C:31]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C(F)[C@@H]2O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=[Mn](=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C(F)[C@@H]2O
Temperature: 22.5 °C
Reaction time: 2 h

Procedure:
Compound 9 (1370 g, 1 wt, 1 eq) was dissolved in THF (5.5 L, 4 vol). TBAF (tetra-n-butylammonium fluoride) 1.0 M in THF (2.20 L, 1.61 vol) was added in one portion (not exothermic) and the resulting solution stirred at 20 to 25° C. After 2 h, TLC analysis (70:30 heptanes:TBME (methyl tert-butyl ether) 7:3, KMnO4 visualisation) indicated the reaction was complete by absence of starting material. The reaction mixture was concentrated to an oil under reduced pressure at 40° C. (water bath) on a rotary evaporator until solvent collection ceased. The residue was dissolved in TBME (11.0 L, 8 vol) and subsequently washed with water (2×4.1 L, 2×3 vol) and saturated sodium hydrogen carbonate (4.1 L, 3 vol). The organic phase was dried over Na2SO4 (1.37 kg, 1 wt), filtered and the cake washed with TBME (1.37 L×2,2×1 vol). The combined filtrates were concentrated under reduced pressure at up to 40° C. (water bath) on a rotary evaporator until the TBME content was <5% w/w by 1H NMR to give 10 as a thick pale yellow/orange oil. 1H-NMR (400 MHz, CDCl3) δ 7.7 ppm (d, 4H) TBDPS-F, 7.2-7.5 ppm, (m, 21H) Trityl and TBDPS-F, 5.1 ppm, (t, J=6.3 Hz, 1H) (CH), 4.7 ppm, (m, J=3.5 Hz, 1H) (CH), 4.4 ppm, broad (t, 6.3 Hz, 1H) (CH), 3.9 ppm, (d, J=11.9 Hz) 1H, 3.8 ppm, (d, J=9.9 Hz, 1.7 Hz, 1H) (CH2), δ 2.8 ppm, (d, J=9.4 Hz, 1H) (OH), 81.48 ppm, s, 3H CH3 Acetonide, 51.46 ppm, s, 3H CH3 Acetonide, δ 1.1 pm, s, 9H TBDPS-F (3×CH3), Solvents δ 3.2 ppm, 1.2 ppm TBME, δ 3.7 ppm, 1.7 ppm THF.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[CH2:7][N:6](CC1C=CC(OC)=CC=1)[CH2:5]2.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[CH2:7][NH:6][CH2:5]2
Reactant: COc1ccc(CN2Cc3cc(Cl)c(OC)cc3C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COc1cc2c(cc1Cl)CNC2
Yield: 70.6 %

Procedure:
A solution of 5-chloro-6-methoxy-2-(4-methoxy-benzyl)-2,3-dihydro-1H-isoindole (600 mg) and anisole (0.3 ml) in trifluoroacetic acid (6 ml) was heated at 180° C. (50 W) for 40 minutes in a CEM discover microwave synthesiser. The reaction mixture was evaporated and re-evaporated with toluene. The crude material was partitioned between DCM and water, the aqueous layer washed with DCM (×3) then evaporated and re-evaporated with toluene to give 5-chloro-6-methoxy-2,3-dihydro-1H-isoindole (256 mg) as green crystals. MS: [M+H]+ 184
Reaction SMILES: CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[Br:17][C:18]1[CH:19]=[C:20]2[C:30](=[N:31][CH:32]=1)[NH:29][C:28](=[O:33])[C:22]1([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:21]2.[CH:34]1([C:39](O)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Br:17][C:18]1[CH:19]=[C:20]2[C:30](=[N:31][CH:32]=1)[NH:29][C:28](=[O:33])[C:22]1([CH2:27][CH2:26][N:25]([C:39]([CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:40])[CH2:24][CH2:23]1)[CH2:21]2
Reactant: O=C1Nc2ncc(Br)cc2CC12CCNCC2
Reactant: O=C(O)C1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1CCCC1)N1CCC2(CC1)Cc1cc(Br)cnc1NC2=O
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 43.4 %

Procedure:
DIPEA (1.22 mL, 8.82 mmol) was added to a stirred solution of 6-bromo-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one 2,2,2-trifluoroacetate (Intermediate-14) (600 mg, 1.47 mmol), cyclopentanecarboxylic acid (250 mg, 2.20 mmol), HOBt (390 mg, 2.94 mmol) and EDC.HCl (700 mg, 3.67 mmol) in dry DMF (5 mL) at 20-35° C. and the reaction mixture was allowed to stir at 20-35° C. for 16 h. Then the reaction mixture was poured into ice water (100 mL), obtained solid was filtered, washed with water and dried under vacuum to get the desired compound as an off-white solid (250 mg, 43%); 1H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.23 (d, J=2.0 Hz, 1H), 7.86 (d, J=1.9 Hz, 1H), 3.76-3.67 (m, 3H), 3.47-3.41 (m, 1H), 2.99 (s, 2H), 2.96-2.94 (m, 1H), 1.90-1.72 (m, 4H), 1.71-1.56 (m, 4H), 1.55-1.42 (m, 2H), 1.38-1.23 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](OS(C(F)(F)F)(=O)=O)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:7]2[CH3:21].[CH3:30][N:31](C)C=O>O.[C-]#N.[Zn+2].[C-]#N.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:1][C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[C:7]([CH3:21])[C:6]=2[C:5]([C:30]#[N:31])=[CH:4][CH:3]=1
Reactant: Cc1nc2c(Cl)ccc(OS(=O)(=O)C(F)(F)F)c2c(C)c1Cc1ccc(Cl)cc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: Cc1nc2c(Cl)ccc(C#N)c2c(C)c1Cc1ccc(Cl)cc1
Temperature: 125 °C

Procedure:
A mixture of trifluoromethanesulfonic acid 8-chloro-3-(4-chlorobenzyl)-2,4-dimethyl-quinolin-5-yl ester (0.29 g), zinc cyanide (0.036 g), tetrakis(triphenylphosphine)palladium(0), (0.071 g) in N,N-dimethylformamide (8.0 mL) was heated by microwave irradiation at 125° C. for 10 minutes. The mixture was diluted with water and the resulting precipitate collected by filtration and then purified by column chromatography on silica gel, eluting with a mixture of cyclohexane, dichloromethane and ethyl acetate (1:1:0 to 0:1:0 to 0:20:1 by volume) to afford title compound as a white solid, 0.17 g.
Reaction SMILES: C([Li])CCC.[CH3:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1F>O1CCCC1>[Cl:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1[N:7]([CH3:6])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CNc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(c1ccccc1)c1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C

Procedure:
n-Butyl lithium (12.3 mL of a 2.5 M solution in hexanes) is added dropwise to a solution of N-methyl aniline (3.0 g) in tetrahydrofuran (75 mL) at 0° C. The mixture is allowed to warm slowly to room temperature and is then re-cooled to 0° C. and added by cannula to a solution of 3-chloro-4-fluoronitrobenzene (4.9 g) in tetrahydrofuran (35 mL) that is kept at −78° C. Following the addition, the reaction mixture is permitted to warm to room temperature over the course of 1 hour, and is then concentrated under reduced pressure, quenched by addition of saturated aqueous ammonium chloride, and extracted three times with ethyl acetate. The pooled organic layers are washed three times with 5% aqueous hydrochloric acid, once with water, once with saturated aqueous sodium bicarbonate, once with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. Following removal of the solvent under reduced pressure the residue is chromatographed over silica gel (5% diethyl ether in hexanes is used as the eluant) to provide the desired product as a clear colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][CH:6]=2.[C:12](=[O:19])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[NH2:13].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:4]1[C:5]2[C:10](=[N:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([NH:13][C:12](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: Brc1cnc2cccnc2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cnc2cccnc2c1
Temperature: 85 °C
Reaction time: 5 h
Yield: 88.3 %

Procedure:
Commercial 3-bromo-[1,5]naphthyridine (1.00 g, 4.8 mmol) was dissolved in 50 mL dioxane. To it were added t-butyl carbamate (0.85 g, 7.2 mmol), cesium carbonate (3.13 g, 9.6 mmol), Pd2(dba)3 (0.22 g, 0.24 mmol) and XantPhos (0.42 g, 0.72 mmol). The mixture was degassed with Ar stream and stirred under Ar in 85° C. bath for 5 h. The mixture was concentrated, taken into 400 mL EtOAc and 200 mL water. The organic phase was separated, dried, concentrated and subjected to flash column (0-30% EtOAc in DCM) to obtain tert-butyl 1,5-naphthyridin-3-ylcarbamate (1.04 g, 88% yield). This compound was treated with 50 mL 4N HCl in dioxane for overnight. To the suspension was poured diethyl ether 300 mL. The suspension was vigorously stirred. The solid product was collected by filtration as 1,5-naphthyridin-3-amine di-HCl salt.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([N:20]1[C:24]([CH:25]=O)=[CH:23][C:22]([CH2:27][CH:28]([CH3:30])[CH3:29])=[N:21]1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([N:20]1[C:24]([CH2:25][NH:15][CH2:14][CH2:13][N:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)=[CH:23][C:22]([CH2:27][CH:28]([CH3:30])[CH3:29])=[N:21]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: NCCN1CCN(c2ccccc2)CC1
Reactant: CC(C)Cc1cc(C=O)n(C(C)(C)C)n1
Product: CC(C)Cc1cc(CNCCN2CCN(c3ccccc3)CC2)n(C(C)(C)C)n1
Yield: 50.1 %

Procedure:
Compound 6 was prepared using the same method as that of Example 1 except that 4-phenylpiperazin-1-ylethylamine and 2-t-butyl-5-iso-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:60])[C@H:11]([NH:52]C(OC(C)(C)C)=O)[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH:37]([O:42][Si](C(C)(C)C)(C)C)[C:38]([CH3:41])([CH3:40])[CH3:39])=[C:31]([CH3:50])[CH:30]=3)([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])=[CH:14][CH:13]=1>ClCCl>[CH3:8][O:9][C:10](=[O:60])[C@H:11]([NH2:52])[C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:25][CH3:26])([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH:37]([OH:42])[C:38]([CH3:39])([CH3:40])[CH3:41])=[C:31]([CH3:50])[CH:30]=3)[CH2:27][CH3:28])=[CH:20][C:19]=2[CH3:51])=[CH:16][CH:17]=1
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)OC)cc2)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc([C@@H](N)C(=O)OC)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
Trifluoroacetic acid (0.1 mL) was added to a solution of (R)-t-butoxycarbonylamino-[4′-(1-{4-[3-(t-butyldimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2′-methyl-biphenyl-4-yl]-acetic acid methyl ester (Example 168-(1); 43.1 mg, 0.058 mmol) in dichloromethane (3 mL) at 0° C., and the mixture was stirred at room temperature for one hour. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (20.0 mg, 65%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([NH:27][CH:28]([CH3:30])[CH3:29])[N:21]=3)[N:16]=2)[CH:6]=[C:7]([CH3:14])[C:8]=1[O:9][CH2:10][C@@H:11]1[CH2:13][O:12]1)[CH3:2].[NH3:31]>CO>[NH2:31][CH2:13][CH:11]([OH:12])[CH2:10][O:9][C:8]1[C:7]([CH3:14])=[CH:6][C:5]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([NH:27][CH:28]([CH3:29])[CH3:30])[N:21]=3)[N:16]=2)=[CH:4][C:3]=1[CH2:1][CH3:2]
Reactant: N
Reactant: CCc1cc(-c2nc(-c3cc(C)nc(NC(C)C)n3)no2)cc(C)c1OC[C@@H]1CO1
Solvent: CO
Product: CCc1cc(-c2nc(-c3cc(C)nc(NC(C)C)n3)no2)cc(C)c1OCC(O)CN

Procedure:
A solution of (S)-{4-[5-(3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-6-methyl-pyrimidin-2-yl}-iso-propyl-amine (48 mg, 0.12 mmol) in 7M NH3 in MeOH (5 mL) is stirred at 65° C. for 24 h. Volatiles are removed in vacuo to give the crude 1-amino-3-{2-ethyl-4-[3-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-5-yl]-6-methyl-phenoxy}-propan-2-ol as a yellow oil (43 mg); LC-MS: tR=0.76 min; [M+H]+=426.80.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10](=O)[NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:9])(C)(C)C.[ClH:28]>O1CCOCC1>[ClH:28].[ClH:28].[F:18][C:15]1[CH:16]=[CH:17][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]=2[CH:14]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 60 °C

Procedure:
[(S)-1-(4-Fluoro-2-phenylaminophenylcarbamoyl)ethyl]carbamic acid tert-butyl ester (40 g, 0.11 mol) was dissolved in HCl in dioxane (4N, 135 mL) and the reaction mixture heated at 60° C. for 3 h. The reaction mixture was cooled to RT and seeded with a crystal of the desired product causing the product to crystallise. The product was collected by filtration and dried in vacuo to give the title compound as a purple solid (31.2 g, 89%). 1H NMR 400 MHz (DMSO-d6) δ: 8.94 (3H, br s), 7.81 (1H, dd, J=8.8, 4.9 Hz), 7.74-7.62 (5H, m), 7.25-7.18 (1H, m), 6.98 (1H, dd, J=9.0, 2.4), 4.41 (1H, quintet, J=6.3 Hz), 1.45 (3H, d, J=6.4 Hz). LCMS: RT=2.02 min, [M+H]+=256 (10%) [M−NH2]=239 (100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14](Br)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[C:27]([F:29])[CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:25]2[CH:24]=[C:23]([F:22])[CH:28]=[C:27]([F:29])[CH:26]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)c2ccccc2)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2cc(F)cc(F)c2)CC1
Temperature: 90 °C
Yield: 62.9 %

Procedure:
To a mixture of 4-(1-bromo-1-phenyl-methylene)-piperidine-1-carboxylic acid tert-butyl ester (0.115 g, 0.33 mmol) and 3,5-difluorophenylboronic acid (0.052 g 0.33 mmol) in DME (3 mL) was added 2M sodium carbonate (0.65 mL, 1.30 mmol). The reaction vessel was then flushed with Ar for 10 minutes, Pd2 dba3 (0.015 g, 0.016 mmol) was added, the vessel was sealed and the mixture was heated at 90° C. for 16 h. The cooled mixture was filtered (0.45 μm syringe filter) and the filtrate was evaporated. The residue was purified by preparative HPLC to give the title compound (0.080 g, 64%) as a white solid:
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Br:11])[CH:3]=1.OS(O)(=O)=O.[CH3:17][CH2:18]O>>[Br:11][C:4]1[CH:3]=[C:2]([I:1])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH2:17][CH3:18])=[O:7]
Reactant: CCO
Reactant: O=C(O)c1ccc(I)cc1Br
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(I)cc1Br
Temperature: 80 °C
Yield: 92 %

Procedure:
To a stirred solution of 4-iodo-2-bromobenzoic acid (5 g, 15.29 mmol) in EtOH (100 mL) was added H2SO4 (5 mL), and the reaction mixture was heated at 80° C. for 18 h. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was diluted with EtOAc (2×100 mL) and washed with water (100 mL). The combined EtOAc extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the compound as a pale yellow solid (5 g, 92%): 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J=1.2 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 4.41 (q, J=7.2 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[S:11]([OH:14])(=O)=[O:12].P(Cl)(Cl)([Cl:17])=O>>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[S:11]([Cl:17])(=[O:14])=[O:12]
Reactant: O=S(=O)(O)c1c(Cl)nc2ccccn12
Reactant: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1c(Cl)nc2ccccn12
Temperature: 0 °C

Procedure:
In 30 ml of phosphorus oxychloride is suspended 5.0 g of 2-chloroimidazo[1,2-a]pyridine-3-sulfonic acid and the suspension is refluxed for 5 hours. After cooling, the reaction mixture is poured in 250 ml of ice-water and extracted with dichloromethane. The dichloromethane layer is separated and dried over anhydrous sodium sulfate and the dichloromethane is distilled off under reduced pressure to give 4.6 g of the title compound as pale yellow crystals.