Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[N:6]=[C:5]2[C:24]([OH:26])=O.Cl.[OH:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH2:31][CH2:32][NH:33][CH2:34]2>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=1)[N:6]=[C:5]2[C:24]([N:33]1[CH2:32][CH2:31][C:30]2[C:35](=[CH:36][CH:37]=[CH:38][C:29]=2[OH:28])[CH2:34]1)=[O:26]
Reactant: COc1cc(-c2nc(C(=O)O)c3cc(F)ccc3n2)cc(OC)c1OC
Reactant: Oc1cccc2c1CCNC2
Agent: Cl
Product: COc1cc(-c2nc(C(=O)N3CCc4c(O)cccc4C3)c3cc(F)ccc3n2)cc(OC)c1OC
Yield: 15.4 %

Procedure:
Reaction of 6-fluoro-2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 5-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 107 (15.4% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.80 and 2.89 (2t, 2H), 3.59 and 4.07 (2t, 2H), 3.77-3.3.80 (m, 3H), 3.87 and 3.92 (2s, 6H), 4.51 and 4.95 (2s, 2H), 6.35-6.79 (m, 2H), 6.89-7.11 (m, 1H), 7.64-7.85 (m, 3H), 8.00-8.09 (m, 1H), 8.22-8.29 (m, 1H), 9.51 and 9.53 (2s, 1H); MS (ESI) m/z 490 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.Cl.[CH3:15]O>>[CH3:15][O:10][C:9](=[O:11])[CH2:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:12][CH3:13]
Reactant: CO
Reactant: COc1ccc(Br)cc1CC(=O)O
Agent: Cl
Product: COC(=O)Cc1cc(Br)ccc1OC
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To 5-bromo-2-methoxyphenylacetic acid (0.900 g, 3.7 mmol) in MeOH (20 mL) was added hydrogen chloride (4N in 1,4-dioxane; 4 mL), and the reaction was stirred at 80° C. for 6 hours. The mixture was then concentrated to dryness to give the title compound.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:22][CH:21]=2)=[CH:13][CH:12]=1.[OH-].[K+].Cl>CCO.CC(C)=O>[CH2:29]([N:26]([CH2:27][CH3:28])[C:23]1[CH:22]=[CH:21][C:20]([CH2:19][CH2:18][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:31])=[O:2])=[CH:12][CH:13]=2)=[CH:25][CH:24]=1)[CH3:30]
Reactant: CCN(CC)c1ccc(CCCc2ccc(Nc3ccccc3C(=O)OC)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)=O
Product: CCN(CC)c1ccc(CCCc2ccc(Nc3ccccc3C(=O)O)cc2)cc1
Yield: 99.9 %

Procedure:
To an emulsion of 2-{4-[3-(4-diethylaminophenyl)propyl]phenylamino}-benzoic acid methyl ester (1.68 g, 4.03 mmol) in EtOH (50 mL) was added aqueous 3 M-KOH solution (4.0 mL, 12.0 mmol) at room temperature, then the mixture was allowed to heat under reflux for 40 minutes. The reaction mixture was cooled to room temperature and neutralized with aqueous 1.0 M-HCl solution to pH 9.0. The mixture was concentrated under reduced pressure to remove EtOH, and the resulting aqueous solution was extracted with CHCl3 (50 mL, 3 times). The combined extract was washed with brine (10 mL) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and purification by column chromatography (silica gel 60N, conc NH4OH/MeOH/CHCl3 0.2:2:100 to 0.5:5:100) afforded a yellow oil. This oil was diluted with acetone, and the solution was concentrated under reduced pressure at room temperature to give the title compound as an amorphous solid (1.62 g, 99% for 0.2 hydrate).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])[C:11]=1F.Cl>C1COCC1>[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])[C:11]=1[O:6][CH2:5][C:4]([F:8])([F:7])[F:3]
Reactant: OCC(F)(F)F
Reactant: CS(=O)(=O)c1c(C(=O)O)ccc(Cl)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1c(C(=O)O)ccc(Cl)c1OCC(F)(F)F
Yield: 99.9 %

Procedure:
Sodium hydride (1.05 g of 80% powder) was suspended in THF and to this was added a solution of 2,2,2-trifluoroethanol (1.9 g) in THF, followed by a solution of 4-chloro-3-fluoro-2-methylsulphonylbenzoic acid (4 g) in THF. The resultant mixture was stirred for 2 hours and then acidified with 2M HCl. The mixture was extracted with ether, washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness yielding 4-chloro-2-methylsulphonyl-3-(2,2,2-trifluoroethoxy)benzoic acid (5.26 g) as a white solid, NMR (DMSO d6) 2.5(s,3H), 4.8(q,2H), 7.5(d,1H), 8.0(d,1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][C:8]=2[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH2:5]1)[CH3:2].C(O)(=O)C1C=CC=CC=1.[CH2:28]([O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][C:35](I)=[CH:34][CH:33]=1)[CH3:29]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:35]3[CH:36]=[CH:37][C:32]([C:31]([O:30][CH2:28][CH3:29])=[O:39])=[CH:33][CH:34]=3)=[CH:9][C:8]=2[C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(C2(OCC)CC2)c(C(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCC)CC3)c(C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
Using General Procedure F; 1-(1-ethoxycyclopropyl)-4-ethynyl-2-tert-butylbenzene (Intermediate 112, 70.0 mg, 0.30 mmol) and ethyl-4-iodo benzoate (Reagent A, 85.0 mg, 0.30 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (19.0 mg, 0.01 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (70 mg, 0.01 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (1-2% EtOAc-hexanes) afforded 70.0 mg (73%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([O:23][CH2:24][P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])[CH2:11][O:12][N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][CH:16]=[N:17][C:18]=2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:33]>>[CH2:1]([O:8][CH2:9][CH:10]([O:23][CH2:24][P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])[CH2:11][O:12][N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][CH:16]=[N:17][C:18]=2[NH2:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CCOP(=O)(COC(COCc1ccccc1)COn1cnc2c(Cl)ncnc21)OCC
Product: CCOP(=O)(COC(COCc1ccccc1)COn1cnc2c(N)ncnc21)OCC
Temperature: 25 °C
Yield: 64 %

Procedure:
A solution of 9-[3-benzyloxy-2-(diethoxyphosphorylmethoxy)propoxy]-6-chloropurine (570 mg, 1.18 mmol) in ethanolic ammonia (10 ml) was heated in a sealed vessel at 110° C. for 2 hours. After cooling to ambient temperature, the solvent was evaporated and the residue obtained chromatographed on silica (dichloromethane/methanol 95:5 as eluant) to give the title compound (350 mg, 64%). IR: νmax (film) 3320, 3200, 2980, 2900, 640, 1595, 1470, 1450, 1410, 1390, 1370, 1330, 1290, 1240, 1160, 1090, 1050, 1020, 970, 820, 790, 730, 700, cm-1. 1H NMR: δH [(CD3)2SO] 1.22 (6H, t, J=7 Hz, OCH2CH3)2), 3.6-3.75 (2H, m, CH2OCH2Ph), 3.95-4.2 (7H, m, (OCH2CH3)2 +CH2CHCH2 +OCH2P), 4.4-4.65 (2H, m, N-OCH2), 4.52 (2H, s, OCH2Ph), 7.25-7.4 (5H, m, aromatic), 7.39 (2H, br.s, D2O exchangeable NH2), 8.15(1H, s), 8.41 (1H, s). Found: C, 49.81; H, 5.75; N, 14.07%; C20H28N5O6P. H2O requires: C, 49.68; H, 6.25; N, 14.48%, m/z: C20H28N5O5P requires 465.1777; observed: 467.1757.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][S:10](Cl)(=[O:12])=[O:11]>ClCCl.N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:10]([CH3:9])(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Br)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(Br)cc1

Procedure:
A solution of 4-bromoaniline (1.00 g, 5.81 mmol) and methanesulfonyl chloride (1 eq) in dichloromethane (10 mL) and pyridine (5 mL) was stirred at rt for 18 h. The resultant mixture was then diluted with dichloromethane and washed with water and then brine. The organic phase was collected, dried (MgSO4) and concentrated in vacuo to give N-(4-bromophenyl)methanesulfonamide.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH:15]C(=O)OC(C)(C)C)[CH:9]([OH:14])[C:10]([NH:12][NH2:13])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1>C(O)C>[NH2:15][C@H:8]([CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH:9]([OH:14])[C:10]([NH:12]/[N:13]=[CH:34]/[C:33]1[CH:36]=[CH:37][C:30]([Cl:29])=[CH:31][CH:32]=1)=[O:11]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(O)C(=O)NN
Solvent: c1ccncc1
Solvent: CCO
Product: N[C@H](CC1CCCCC1)C(O)C(=O)N/N=C/c1ccc(Cl)cc1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
A solution of Example 14A (0.064 g, 0.20 mmol) in ethanol (3 mL) was treated with pyridine (2 mL) and 4-chlorobenzaldehyde (0.033 mL, 0.23 mmol), heated to 85° C., stirred for 16 hours, and concentrated. The concentrate was purified by flash column chormatography on silica gel with ethyl acetate in hexanes, and the purified concntrate was treated with 4N HCl in dioxane, stirred for 4 hours, concentrated, precipitated from diethyl ether, and collected by filtration to provide the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([C:10]1[CH2:19][C@@H:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[Cl:27][C:22]1[CH:21]=[C:20]([C@H:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]([CH:8]([NH:7][C:6](=[O:28])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:9])[CH2:19]2)[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: CC(NC(=O)OC(C)(C)C)C1=Cc2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(NC(=O)OC(C)(C)C)[C@@H]1Cc2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C1
Reaction time: 1 h
Yield: 61.2 %

Procedure:
To a solution of tert-butyl-1-((S)-4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-2-yl)ethylcarbamate 49b (Example 21.3) (60 mg, 0.14 mmol) in ethyl acetate (6 mL) was added palladium on charcoal (30 mg, 5%). The mixture was then stirred under hydrogen (1 atm) for 1 h. The catalyst was removed through a pad of Celite. The filtrate was concentrated. Chiral AD column separation (ethanol/methanol/hexane/DEA=3:2:95:0.1) afforded tert-butyl 1-((2S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-2-yl)ethylcarbamate (36 mg, 60%).
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]1=[O:11].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[N+:12]([C:3]1[C:2](=[O:11])[NH:1][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1)([O-:14])=[O:13]
Reactant: O=c1ccc2c([nH]1)CCCC2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=c1[nH]c2c(cc1[N+](=O)[O-])CCCC2
Temperature: 5 °C
Reaction time: 1 h
Yield: 54.6 %

Procedure:
5,6,7,8-Tetrahydro-2(1H)-quinolinone (0.134 mol) was added portionwise at 5° C. to sulfuric acid (200 ml). Then HNO3 (0.235 mol) was added portionwise while the temperature was kept below 10° C. The mixture was stirred at 5° C. for 1 hour, poured out carefully into a small amount of ice water and stirred at 0° C. for 10 min. The precipitate was filtered off and dried, yielding 14.2 g (55%) of 5,6,7,8-tetrahydro-3-nitro-2(1H)-quinolinone (intermediate 8)
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[S:6][C:5]=1[C:13]([O:15][CH3:16])=[O:14].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.O>[CH2:17]([O:3][C:4]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[S:6][C:5]=1[C:13]([O:15][CH3:16])=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1sc(S(C)(=O)=O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1sc(S(C)(=O)=O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
A mixture of NaH (3.18 g, 79.5 mmol) in dimethylformamide (DMF) is treated dropwise with a solution of methyl 3-hydroxy-5-(methylsulfonyl)-2-thiophenecarboxylate (15.0 g, 63.6 mmol) in DMF at 0° C., stirred for 10 minutes, treated with benzylbromide (8.30 ml, 70 mmol) at ice bath temperatures, allowed to warm to room temperature overnight and diluted with water. The resultant reaction mixture is filtered. The filtercake is washed with water, dried, stirred in a mixture of ethyl acetate/hexane (20 ml/130 ml), and filtered. The filtercake is washed with hexanes and dried in a Kugelrohr at 40° C. to give the title product as a white solid, 17. 4 g (84% yield), mp 125-126° C. identified by 1HNMR, 13CNMR, IR and mass spectral analyses.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=O)[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[NH2:48][C:49]([CH3:54])([CH2:52][OH:53])[CH2:50][OH:51]>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([NH:48][C:49]([CH2:52][OH:53])([CH3:54])[CH2:50][OH:51])=[O:44])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:3])([CH3:4])[CH3:5]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: CC(N)(CO)CO
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NC(C)(CO)CO)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with 2-amino-2-methyl-propane-1,3-diol (Fluka) to give the title compound. HR-MS (ES, m/z) calculated for C39H51Cl2N6O5 [(M+H)+] 753.3293, observed 753.3292.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[NH:7][CH2:6][C:5](=[O:13])[C:4]=2[CH:3]=1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[Mg]Br>C1COCC1>[Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:11])(=[O:12])[NH:7][CH2:6][C:5]([C:16]3[CH:15]=[CH:14][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)([OH:13])[C:4]=2[CH:3]=1
Reactant: O=C1CNS(=O)(=O)c2sc(Cl)cc21
Reactant: Br[Mg]c1ccc2ccccc2c1
Solvent: C1CCOC1
Product: O=S1(=O)NCC(O)(c2ccc3ccccc3c2)c2cc(Cl)sc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
6-chloro-2,3-dihydro-4H-thieno[3,2-e][1,2]thiazin-4-one 1,1-dioxide (0.800 g, 3.36 mmol) was dissolved in THF (30 mL) and 2-naphthylmagnesium bromide (0.5 M in THF, 33.6 mL, 16.8 mmol) was added. The solution was stirred at room temperature overnight. Reaction was quenched by addition of MeOH (20 mL) and evaporated. The residue was purified using column chromatography on silica gel (80 g Analogix column, gradient 10% EA in hexane to 40% EA in hexane over 20 minutes) to give the title compound (235 mg, 18%). LCMS (FA) ES−: 364, 366. 1H NMR (400 MHz, DMSO) δ 8.46-8.42 (m, 1H), 7.97-7.89 (m, 4H), 7.55-7.52 (m, 2H), 7.35-7.32 (m, 1H), 6.74 (s, 1H), 6.63 (s, 1H), 3.90-3.84 (m, 1H), 3.69-3.64 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([F:11])[C:8](Cl)=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[OH:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[OH-].[K+]>>[N+:1]([C:4]1[CH:10]=[C:9]([F:11])[C:8]([N:17]2[CH:18]=[CH:19][C:14](=[O:13])[CH:15]=[CH:16]2)=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: Nc1cc(Cl)c(F)cc1[N+](=O)[O-]
Reactant: Oc1ccncc1
Agent: [K+]
Agent: [OH-]
Product: Nc1cc(-n2ccc(=O)cc2)c(F)cc1[N+](=O)[O-]
Yield: 22.6 %

Procedure:
First, 3.811 g of 2-nitro-4-fluoro-5-chloroaniline, 2.473 g of 4-hydroxypyridine, and 1.827 g of powdered potassium hydroxide were allowed to react at 130° C. for 3 hours in a nitrogen atmosphere in the same way as in Reference Example 1 to give 1.125 g of 2-nitro-4-fluoro-5-(4-oxo-4H-pyridin-1-yl)-aniline.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[N:4][CH:3]=1.[CH:11]([O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])([CH3:13])[CH3:12]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:15]([O:14][CH:11]([CH3:13])[CH3:12])[CH:16]=2)=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: CC(C)Oc1cccc(N)c1
Reactant: O=C(Cl)c1cncc(Cl)n1
Solvent: ClCCl
Product: CC(C)Oc1cccc(NC(=O)c2cncc(Cl)n2)c1

Procedure:
The product from Example 15B was reacted with 3-isopropoxyaniline and TEA in CH2Cl2 as described in Example 15C to afford the title compound. MS (DCI/NH3) m/z 309 (M+H)+.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([C:15]3[C:16]([NH:31][C:32]4[CH:33]=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=4)=[N:17][CH:18]=[C:19]([CH:21]([N:23]4[CH2:26][CH:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:24]4)[CH3:22])[CH:20]=3)[N:12]=[C:11]([CH3:40])[N:10]=2)=CC=1.FC(F)(F)S(O)(=O)=O.[C:60]([OH:66])([C:62]([F:65])([F:64])[F:63])=[O:61]>>[F:63][C:62]([F:65])([F:64])[C:60]([OH:66])=[O:61].[CH3:39][O:38][C:35]1[N:34]=[CH:33][C:32]([NH:31][C:16]2[C:15]([C:13]3[N:12]=[C:11]([CH3:40])[N:10]=[C:9]([NH2:8])[N:14]=3)=[CH:20][C:19]([CH:21]([N:23]3[CH2:24][CH:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:26]3)[CH3:22])=[CH:18][N:17]=2)=[CH:37][CH:36]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N4CC(S(C)(=O)=O)C4)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(C(C)N3CC(S(C)(=O)=O)C3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 25 °C
Yield: 76 %

Procedure:
An orange solution of N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(3-(methylsulfonyl)azetidin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (70.0 mg, 0.098 mmol) and trifluoromethanesulfonic acid (0.030 mL, 0.338 mmol) in TFA (1.5 mL) was stirred at 75° C. for 18 h. The resulting mixture was subsequently cooled to 25° C. and concentrated in vacuo. The residue was taken up in DMSO (2.0 mL) and purified by rpHPLC (Phenomenex Luna 5 μm C18 30×150 mm, 35 mL/min, 5 to 100% CH3CN/H2O (plus 0.1% TFA, both solvents) to provide 4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(3-(methylsulfonyl)azetidin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine 2,2,2-trifluoroacetate (43.6 mg, 0.075 mmol, 76% yield) as an orange solid. 1H NMR (400 MHz, d4-MeOH) δ 9.10 (d, J=2.5 Hz, 1H), 8.70 (d, J=2.7 Hz, 1H), 8.40 (d, J=2.5 Hz, 1H), 8.19 (dd, J=9.0, 2.7 Hz, 1H), 7.07 (d, J=9.0 Hz, 1H), 4.65 (q, J=6.7 Hz, 1H), 4.54-4.61 (m, 1H), 4.38-4.53 (m, 4H), 4.02 (s, 3H), 3.05 (s, 3H), 2.66 (s, 3H), 2.52 (s, 3H), 1.67 (d, J=6.8 Hz, 3H). 19F NMR (376 MHz, d4-MeOH) δ −79.11 (s, 3F). m/z (ESI, +ve) 471.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[C:12]([NH2:13])=[CH:11][CH:10]=[N:9]2)=[CH:5][CH:4]=1.C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[OH:18][C:19]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[N:9]=[CH:10][C:11]=12
Reactant: COc1ccc(Cn2nccc2N)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1O
Temperature: 120 °C
Yield: 122.2 %

Procedure:
A mixture of 1-(4-methoxybenzyl)-1H-pyrazol-5-amine (3 g, 10 mmol) and (ethoxymethylene)propanedioic acid, diethyl ester (3.8 g, 18 mmol) was heated at 120° C. for 1.5 h, then allowed to cool. After cooling, the mixture was concentrated and the resulting residue was purified with CombiFlash® eluting with 0-30% EtOAc in hexanes to give an intermediate, LCMS (M+H): 374.1. The intermediate was dissolved in diphenyl ether (5 mL). The resulted solution was heated at 240° C. in microwave reactor for 1 h 20 min. After cooling, the solid crashed out was filtered and washed with hexanes to afford 4.0 g (80%) of the sub-title compound. LCMS calc. for C17H18N3O4 (M+H)+: m/z=328.1. Found: 328.1.
Reaction SMILES: [C:1]1(=[C:6]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21](COCC[Si](C)(C)C)[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]1(=[C:6]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)=C4CCCC4)c3)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCC(=C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 2 h
Yield: 33.3 %

Procedure:
A solution of 3-cyclopentylidene-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (0.030 g, 0.069 mmol) in DCM (3 mL) and TFA (2 mL) was stirred for 1 hour. The solvents were evaporated in vacuo and the product was stirred with sodium hydroxide, 50% aqueous solution (0.75 mL) and water (0.75 mL) and THF (1.5 mL) for 2 hours. The reaction mixture was neutralized by dropwise addition of concentrated HCl. The product was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by preparative-HPLC/MS (C18 column eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to afford the desired product (7 mg, 33%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([F:14])([F:13])[F:12].[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][O:15]1)[N:6]=[C:5]2[C:11]([F:14])([F:13])[F:12]
Reactant: C1=COCCC1
Reactant: FC(F)(F)c1n[nH]c2ccc(Br)cc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)c1nn(C2CCCCO2)c2ccc(Br)cc12
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of 5-bromo-3-(trifluoromethyl)-1H-indazole (500 mg, 1.887 mmol) in DCM (10 mL) was added 3,4-dihydro-2h-pyran (0.517 mL, 5.66 mmol) and p-toluenesulfonic acid monohydrate (35.9 mg, 0.189 mmol). The solution was stirred for 1 h. The solution was diluted with DCM, washed with saturated NaHCO3 and concentrated. The residue was purified by flash chromatography on silica gel with eluting with 10% EtOAc/Hexane to give 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-indazole as a colorless oil (610 mg, 93%). 1NMR: 400 MHz, CDCl3: δ ppm 1.69-1.75 (m, 7H), 2.12-2.17 (m, 2H), 2.48-2.51 (m, 1H), 3.61 (d, J=85.20 Hz, 3H), 3.72-3.78 (m, 2H), 3.87-3.99 (m, 3H), 4.56 (s, 1H), 5.77 (dd, J=4.00, 8.00 Hz, 1H), 7.52-7.60 (m, 2H), 7.96 (t, J=24.40 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:14]([O:16]C)=O)[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:19][NH2:20]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1([C:14]([NH:19][NH2:20])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCCC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(C(=O)NN)CCCC1

Procedure:
Methyl 1-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylate and hydrazine monohydrate were reacted in methanol under heating to obtain 1-[(tert-butoxycarbonyl)amino]cyclopentanecarbohydrazide.