Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][CH2:5][CH2:6][C:7]1[N:8]=[C:9]([F:31])[N:10]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1)(=O)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[F:31][C:9]1[N:10]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[C:7]([CH2:6][CH2:5][NH:4][S:33]([CH3:32])(=[O:35])=[O:34])[N:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Product: CS(=O)(=O)NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
Using the same procedure as for the starting material of Example 29 but using methanesulphonyl chloride in place of acetyl chloride, there was obtained 2-fluoro-4-(2-methanesulphonylaminoethyl)-1-triphenylmethylimidazole, which was used without further characterisation.
Reaction SMILES: O=O.Cl[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]=[CH:15][C:14](=[O:18])[C:13]=2[CH:19]=1.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[C:20]1([N:26]2[CH2:31][CH2:30][N:29]([CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]3[CH:10]=[CH:11][C:12]4[O:17][CH:16]=[CH:15][C:14](=[O:18])[C:13]=4[CH:19]=3)[CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=c1ccoc2ccc(OCCCCCl)cc12
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: O=O
Product: O=c1ccoc2ccc(OCCCCN3CCN(c4ccccc4)CC3)cc12

Procedure:
The title compound was prepared by the method described above for the compounds of Formula I wherein X is oxygen. Thus, 6-(4-chlorobutoxy)-4H-1-benzopyran-4-one, as prepared above in Preparation 3, (3.79 g; 15 mmol) was reacted with 1-phenylpiperazine (2.59 g; 16 mmol) in the usual way, yielding 3.5 g of 6-[4-(4-phenyl-1-piperazinyl)butoxy]-4H-1-benzopyran-4-one as its dihydrochloride salt, mp 193°-195° C. (See Scheme I.)
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[N:7][N:6]=1>C(O)C>[CH:11]1[CH:12]=[CH:13][C:14]2[C:9](=[CH:8][N:7]=[N:6][C:5]=2[NH:2][NH2:3])[CH:10]=1
Reactant: NN
Reactant: Clc1nncc2ccccc12
Solvent: CCO
Solvent: O
Product: NNc1nncc2ccccc12
Temperature: 5 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
Again according to the disclosure in the '397 application, to a 2-L, 3-necked, round-bottomed flask fitted with a temperature probe and condenser were charged 700 mL of ethanol and 7.6 mole equivalents (630 mL) of hydrazine hydrate, and the solution was cooled to 5° C. (the '397 application discloses a temperature <10° C.). One (1) mole equivalent (280 g) of 1-chlorophthalazine (solid) was added in portions at a rate to maintain the solution temperature at <20° C. The solution was stirred and heated to 60-70° C. After one hour at that elevated temperature, the hot solution was filtered to remove any insoluble by-products (insoluble matter recovered was 12 g), and the filtrate was cooled to 0 to 5° C. A light yellow solid formed in the cold solution, which was isolated by filtration, washed with cold ethanol, and then dried to constant mass and characterized. The yield was 80% (the yield reported in the '397 application was 77-80%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1.[CH2:32]([N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[SH:39])[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:32]([N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[S:39][CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1)[CH3:33]
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: CCn1ccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(CSc2nccn2CC)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.4 %

Procedure:
A mixture of ethyl 2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (3.0 g), 1-ethyl-2-mercaptoimidazole (1.0 g), potassium carbonate (1.1 g) and N,N-dimethylformamide (30 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform/ethyl acetate (=3/2, v/v) gave ethyl 2-[(1-ethylimidazol-2-yl)thiomethyl]-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (2.8 g, 78%) which was then recrystallized from ethyl acetate-hexane.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH:11][C:12](=[O:23])[CH:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]C)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH3:24][CH:25]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[CH2:26][CH3:27]>>[CH:1]1[C:10]2[C:5](=[C:6]([NH:11][C:12](=[O:23])[CH:13]([O:34][C:31]3[CH:32]=[CH:33][C:28]([CH:25]([CH3:24])[CH2:26][CH3:27])=[CH:29][CH:30]=3)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CCCCCCCCC(Br)C(=O)Nc1cccc2cnccc12
Reactant: CCC(C)c1ccc(O)cc1
Product: CCCCCCCC(Oc1ccc(C(C)CC)cc1)C(=O)Nc1cccc2cnccc12

Procedure:
N-(isoquinolin-5-yl)-2-bromodecanoic amide, prepared according to the procedures described in Example 3 and 25, was coupled with 4-(1-methylpropyl)phenol according to the procedure described in Example 6 to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([Mg]Cl)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1COCC1.CN1C(=O)CCC1>[CH2:25]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCCC[Mg]Cl
Reactant: COC(=O)c1ccc(Cl)cc1
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCc1ccc(C(=O)OC)cc1
Reaction time: 0.05 h
Yield: 92 %

Procedure:
To a solution of methyl 4-chlorobenzoate (300 mg, 1.76 mmol) and Fe(acac)3 (71 mg, 0.2 mmol) in THF (7 mL) and NMP (1.1 mL) at −60° C. is added a solution of C14H29MgCl (1M in THF, 2.3 mL). The mixture immediately turns black and becomes viscous after 3 min. Work-up as described above provides methyl 4-(tetradecyl)benzoate as a low-melting solid (92%). Mp=28–29° C. 1H NMR (300 MHz, CDCl3): δ 7.92 (dd, 2H, J=6.5, 1.8 Hz), 7.21 (dd, 2H, J=6.4, 1.7 Hz), 3.87 (s, 3H), 2.63 (t, 2H, J=7.7 Hz), 1.60 (m, 2H), 1.38–1.06 (m, 24H), 0.86 (t, 3H, J=6.7 Hz). 13C NMR (75 MHz, CDCl3): δ 167.6, 148.9, 130.0, 128.8, 128.0, 52.3, 36.4, 32.3, 31.5, 30.09, 30.07, 30.05, 30.00. 29.95, 29.9, 29.8, 29.7, 23.1, 14.5. IR: 3091, 3061, 3031, 2925, 2854, 1726, 1611, 1574, 1510, 1466, 1435, 1415, 1377, 1309, 1277, 1191, 1178, 1109, 1021, 970, 854, 763, 722, 704 cm−1. MS m/z (rel. intensity) 332 (100, [M+]), 301 (1), 163 (34), 150 (60), 149 (29).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:18][O:19][CH2:20][CH3:21])[C:7]2=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:30])C=CC=CC=1>ClCCl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:30])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:18][O:19][CH2:20][CH3:21])[C:7]2=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CCOCc1cc2cnc(SC)nc2n(C2CCCC2)c1=O
Solvent: ClCCl
Product: CCOCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
8-Cyclopentyl-6-ethoxymethyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (4.60 g, 14.40 mmol) and 2-benzenesulfonyl-3-phenyl-oxaziridine (4.89 g, 18.72 mmol) were dissolved in dichloromethane (30 mL) and stirred at ambient temperature for 12 hours. The crude product was then purified by silica gel chromatography to give 8-cyclopentyl-6-ethoxymethyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one as a white waxy solid (2.67 g, 55.3%). 1H NMR δ(400 MHz, CDCl3) 8.94 (s, 1H), 7.81 (t, J=1.7 Hz, 1H), 5.98 (m, 1H), 4.50 (d, J=1.7 Hz, 1H), 3.68 (q, J=7.1 Hz, 2H), 2.96 (s, 3H), 2.22 (m, 2H), 2.12 (m, 2H), 1.94 (m, 2H), 1.69 (m, 2H), 1.31 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)=[C:11]([CH3:24])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:30])[N:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[C:11]([CH3:24])[CH:10]=1)[CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: Cc1cc(CN(CCC(C)C)C(=O)OC(C)(C)C)ccc1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(CN(CCC(C)C)C(=O)OC(C)(C)C)ccc1-c1ccc(N)cc1

Procedure:
(3-Methyl-butyl)-(2-methyl-4′-nitro-biphenyl-4-ylmethyl)-carbamic acid tert-butyl ester (I-9a: 0.150 mg, 0.364 mmol) in methanol (12.1 ml) was hydrogenated employing an H-cube apparatus (atmospheric pressure, flow rate=1 mL/min, hydrogen level=full hydrogen, temperature=35° C.). The reaction mixture was allowed to proceed through a palladium on carbon cartridge and the contents collected and concentrated under reduced pressure. The resulting title compound (I-8b) was carried on to the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:9])=[CH:5][C:6]=1[CH2:7]Br.C([O-])([O-])=O.[K+].[K+].[C:16]([O:20][C:21](=[O:24])[NH:22][NH2:23])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.C(OCC)(=O)C>[C:16]([O:20][C:21]([NH:22][NH:23][CH2:7][C:6]1[CH:5]=[C:4]([CH3:9])[O:3][C:2]=1[CH3:1])=[O:24])([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1cc(CBr)c(C)o1
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(CNNC(=O)OC(C)(C)C)c(C)o1
Temperature: 65 °C

Procedure:
To a stirred solution of 2,5-dimethyl-3-bromomethylfuran (5.95 mmol theor.) in DMF (30 mL) was added K2CO3 (1.64 g, 11.9 mmol) and tert-butylcarbazate (3.1 g, 23.8 mmol). The reaction was heated to 65° C. for 1 h. The reaction was cooled to room temperature, diluted with ethyl acetate and the layers separated. The organic layer was washed with saturated aqueous NH4Cl, water and brine and dried over Na2SO4. The mixture was filtered, concentrated and distilled on a Kuglerohr apparatus at 100° C. and 35 mTorr to remove the excess DMF and tert-butylcarbazate. This material was then purified using silica gel column chromatography (hexanes—4:1 hexanes:ethyl acetate as eluant) to afford the title compound as a dark yellow oil (670 mg, 2.79 mmol, 47% for the two steps). 1H NMR (300 MHz, DMSO-d6): δ 8.11 (br s, 1H); 5.91 (s, 1H); 4.38 (br s, 1H); 3.54 (s, 2H); 2.16 (s, 3H); 2.14 (s, 3H); 1.39 (s, 9H).
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[C:10]([C:28]2[N:32](C(OC(C)(C)C)=O)[C:31]3[CH:40]=[CH:41][CH:42]=[CH:43][C:30]=3[N:29]=2)=[N:11][C:12]([C:15]2[CH2:16][CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][CH:20]=2)=[CH:13][N:14]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:29]1[C:30]2[CH:43]=[CH:42][CH:41]=[CH:40][C:31]=2[N:32]=[C:28]1[C:10]1[C:9]([NH2:8])=[N:14][CH:13]=[C:12]([C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH:20]=2)[N:11]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3nc4ccccc4n3C(=O)OC(C)(C)C)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(C2=CCNCC2)nc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
A solution of tert-butyl 2-(3-(bis(tert-butoxycarbonyl)amino)-6-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-yl)-1H-benzo[d]imidazole-1-carboxylate (1.7248 g, 2.490 mmol) in DCM (17.25 mL) was treated with TFA (5 mL, 64.90 mmol) and left to stir at ambient temperature for 4 hours. The reaction mixture was concentrated in vacuo and triturated from MeOH/Toluene and the resultant orange solid was filtered off (622 mg, 48% Yield). 1H NMR (400.0 MHz, DMSO) d 2.90 (2H, m), 3.41 (2H, m), 3.96 (2H, m), 6.80 (1H, m), 7.09-7.30 (4H, m), 7.82 (2H, br s), 8.52 (1H, s) ppm; MS (ES+) 293.03
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:21]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: c1ccc(COc2cccc3[nH]ccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2c(OCc3ccccc3)cccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-benzyloxy-1H-indole (CAS#20289-26-3, 10.85 g, 48.6 mmol) in N,N-dimethylformamide (200 mL) at 0° C., was added sodium hydride (60% dispersion in oil, 2.24 g, 55.9 mmol). The reaction was permitted to stir for 15 minutes at 0° C. Then iodomethane (3.19 mL, 51.0 mmol) was added to the reaction mixture. The reaction was put at room temperature and permitted to stir 30 minutes. The reaction was then quenched with saturated aqueous ammonium chloride. The mixture was diluted with water and extracted with diethyl ether. The layers were separated and the aqueous layer was then extracted two additional times with diethyl ether. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 4-benzyloxy-1-methyl-1H-indole; MS: (ES+) m/z 238.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]4[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2c(-c3cnn(C)c3)cccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cccc(-c3cnn(C)c3)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:3]=1.[CH2:20]([Sn](CCCC)(CCCC)C=C)[CH2:21]CC>>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:4]2[CH:3]=[C:2]([CH:20]=[CH2:21])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=2)=[CH:14][CH:15]=1
Reactant: Oc1ccc(-c2cc(Br)c3cc(O)ccc3n2)cc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Product: C=Cc1cc(-c2ccc(O)cc2)nc2ccc(O)cc12
Yield: 69 %

Procedure:
This compound was prepared from 6a and tributyl(vinyl)tin according to method J. Yellow solid; Yield: 69%; mp>200° C. (dec.); 1H-NMR (400 MHz, DMSO-d6) δ 5.69 (d, J=11.7 Hz, 1H), 6.23 (dd, J=18.3, 1.0 Hz, 1H), 6.90 (d, J=8.5 Hz, 2H), 7.31 (dd, J=9.0, 2.7 Hz, 1H), 7.35 (d, J=2.2 Hz, 1H), 7.40 (dd, J=17.3, 11.0 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 8.11 (d, J=8.8 Hz, 2H), 9.73 (s, 1H), 9.98 (s, 1H); MS (ESI) m/z 262 ([M−H]−), 264 ([M+H]+); Anal. Calcd for C17H13NO2: C, 77.55; H, 4.98; N, 5.32. Found: C, 74.26; H, 5.38; N, 4.82.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][C:16]=4[CH3:23])[CH:11]=[C:10]([C:24]([NH:26][CH2:27][C:28]4[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=4[CH3:34])=[O:25])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)=[CH:17][C:16]=4[CH3:23])[CH:11]=[C:10]([C:24]([NH:26][CH2:27][C:28]4[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=4[CH3:34])=[O:25])[C:9]=3[CH:8]=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1COCCN1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)cc3C)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3C)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34 %

Procedure:
To a stirred solution of 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(4-formyl-2-methylphenyl)-1H-indazole-4-carboxamide (0.15 g, 0.31 mmol) in methanol (5 mL), morpholine (0.081 g, 0.93 mmol) and acetic acid (0.01 g, 0.311 mmol) were added at room temperature and reaction stirred at room temperature for 18 h. Then NaBH3CN (0.023 g, 0.37 mmol) was added and reaction stirred again at room temperature for 18 h. On completion, methanol was removed under reduced pressure and water added to the residue. The aqueous phase was extracted with 10% MeOH/DCM and the combined organic layers dried over sodium sulfate and concentrated to obtain crude material which was purified by column chromatography to afford 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(2-methyl-4-(morpholinomethyl)phenyl)-1H-indazole-4-carboxamide (34% yield). LCMS: 554.30 (M+1)+; HPLC: 95.54% (@ 254 nm) (Rt; 5.595); 1H NMR (DMSO-d6, 400 MHz) δ 11.49 (s, 1H), 8.52 (t, 1H), 8.38 (s, 1H), 7.78 (s, 1H), 7.54 (s, 1H), 7.02-7.28 (m, 3H), 5.86 (s, 1H), 5.22-5.26 (m, 1H), 4.34 (d, 2H, J=4.4 Hz), 3.58 (t, 4H), 3.47 (s, 2H), 2.37 (s, 4H), 2.25 (s, 3H), 2.18 (s, 3H), 2.09-2.06 (m, 2H), 2.09 (s, 3H), 1.98-2.03 (m, 2H), 1.86 (m, 2H), 1.66-1.69 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21](O)=[O:22])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15]([F:18])([F:17])[F:16])[CH:7]=1.[CH:24]([NH:27][NH:28][C:29]([C:31]1[O:32][CH:33]=[CH:34][CH:35]=1)=[O:30])([CH3:26])[CH3:25].C(NC(C)C)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21]([N:27]([CH:24]([CH3:26])[CH3:25])[NH:28][C:29]([C:31]2[O:32][CH:33]=[CH:34][CH:35]=2)=[O:30])=[O:22])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15]([F:16])([F:17])[F:18])[CH:7]=1
Reactant: CC(C)NNC(=O)c1ccco1
Reactant: O=C(O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccco1)C(=O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Yield: 44 %

Procedure:
A solution of (5-fluoro-2′-trifluoromethoxy-biphenyl-2-yloxy)-acetic acid (174 mg, 0.52 mmol) and furan-2-carboxylic acid N′-isopropyl-hydrazide (90 mg, 0.53 mmol) in DMF (5 ml) was treated with diisopropyl amine (0.235 ml, 1.32 mmol) and PyBroP (370 mg, 0.79 mmol) at room temperature overnight. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was successively washed with water and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-80% ethyl acetate in hexanes gradient to afford the product as a white solid (110 mg, 44%). MS m/e 481.38 (M+H+)
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]([C:11]2[N:15]=[C:14]([NH:16][C:17]3[N:22]=[CH:21][C:20]([S:23][CH2:24]CC(OC)=O)=[CH:19][C:18]=3[O:30][C:31]3[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=3)[S:13][N:12]=2)([CH3:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CC(C)([O-])C.[K+].[C:44]([O:47][CH2:48]CBr)(=[O:46])[CH3:45].O>C1COCC1>[C:44]([O:47][CH2:48][CH2:24][S:23][C:20]1[CH:21]=[N:22][C:17]([NH:16][C:14]2[S:13][N:12]=[C:11]([C:7]3([CH3:10])[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]3)[N:15]=2)=[C:18]([O:30][C:31]2[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:19]=1)(=[O:46])[CH3:45]
Reactant: COC(=O)CCSc1cnc(Nc2nc(C3(C)CCN(C(C)=O)CC3)ns2)c(Oc2cccnc2C)c1
Reactant: CC(=O)OCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OCCSc1cnc(Nc2nc(C3(C)CCN(C(C)=O)CC3)ns2)c(Oc2cccnc2C)c1
Reaction time: 0.01 h
Yield: 71.3 %

Procedure:
Methyl 3-(6-(3-(1-acetyl-4-methylpiperidin-4-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)propanoate (125 mg, 0.230 mmol) was dissolved in THF (10 mL) and potassium tert-butoxide (64.6 mg, 0.576 mmol) was added. The reaction was stirred for 30 seconds and 2-bromoethyl acetate (38.5 mg, 0.230 mmol) was added. The reaction was stirred for 3 hours. Water was added and the reaction was extracted with dichloromethane. The organic layer was concentrated, and the crude material was purified by silica gel chromatography (5-7% methanol in dichloromethane) to give 2-(6-(3-(1-acetyl-4-methylpiperidin-4-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)ethyl acetate (89 mg, 0.164 mmol, 71.2% yield).
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[N:10]=[C:9]2[C:11]([CH3:17])=[CH:12][C:13]([Cl:16])=[C:14]([CH3:15])[C:8]2=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[Cl:16][C:13]1[CH:12]=[C:11]([CH3:17])[C:9]2=[N:10][N:6]([CH2:5][C:2]([NH:1][C:25](=[S:26])[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=3)([C:3]#[N:4])[CH3:18])[N:7]=[C:8]2[C:14]=1[CH3:15]
Reactant: Cc1cc(Cl)c(C)c2nn(CC(C)(N)C#N)nc12
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: Cc1cc(Cl)c(C)c2nn(CC(C)(C#N)NC(=S)c3ccc(C(F)(F)F)cc3)nc12

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5-chloro-4,7-dimethyl-2H-benzotriazol-2-yl)-2-methylpropionitrile (120 mg, described in Example 48) and 4-trifluoromethylthiobenzoyl chloride (0.09 mL), the title compound was isolated as a white solid (180 mg, 85%). Rf=0.7 (1:1 EA/heptane). MS (ES): M/Z [M+H]=468. NMR: (400 MHz, DMSO-d6): 1.74 (s, 3H), 2.43 (s, 3H), 2.44 (s, 3H), 5.34 (d, J=13.3 Hz, 1H), 5.54 (d, J=13.3 Hz, 1H), 7.24 (d, J=0.7 Hz, 1H), 7.81-7.93 (m, 4H) and 8.86 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.1 (s, 3F).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][CH:18]([C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:39][O:40][C:41](=[O:45])[CH2:42][CH2:43][NH2:44].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:39][O:40][C:41](=[O:45])[CH2:42][CH2:43][NH:44][C:27](=[O:28])[C:26]1[CH:25]=[CH:24][C:23]([CH:18]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:10][CH:9]=3)=[CH:12][CH:13]=2)[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:31][CH:30]=1
Reactant: COC(=O)CCN
Reactant: CC(C)CC(Nc1ccc(-c2ccc(C(C)(C)C)cc2)cc1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Nc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a mixture of 4-[1-(4′-tert-butyl-biphenyl-4-ylamino)-3-methyl-butyl]-benzoic acid (310 mg, 0.75 mmol) in methylene chloride (7 mL) are added triethyl amine (0.31 mL, 2.24 mmol), DMAP (5.0 mg), 3-amino-propionic acid methyl ester (156 mg, 1.12 mmol) and EDCI (431 mg, 2.24 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, and eluted with hexanes using a gradient from 0-100% ethyl acetate to provide 230 mg of the titled compound as a white solid. 1H-NMR.