Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[N:15]=[C:14]([NH:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH3:18])[C:13]([NH2:26])=[CH:12][CH:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[N:27]([O-])=O.[Na+]>C(O)(=O)C>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[N:15]=[C:14]4[N:16]([C@H:17]([C:19]5[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=5)[CH3:18])[N:27]=[N:26][C:13]4=[CH:12][CH:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=N[O-]
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)ccc1N)c1ccc(F)cc1
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@@H](c1ccc(F)cc1)n1nnc2ccc(Nc3cc(C4CC4)[nH]n3)nc21
Reaction time: 0.08 h
Yield: 50.9 %

Procedure:
To a solution of (S)—N6-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,3,6-triamine (Method 9; 0.08 g, 0.2 mmol), in aqueous acetic acid (5%, 3 ml) was slowly added the aqueous NaNO2 (0.01 g, 0.2 mmol, 1 ml H2O) solution at 25° C. The reaction was allowed to stir for an additional 5 minutes, then quenched with water (10 ml), and extracted with DCM (3×25 ml). The combined organic was washed with saturated NaHCO3 (50 ml), dried, filtered, and concentrated. The resulting solid was purified by column chromatography (DCM:MeOH=40:1) to give the title compound (0.037 g, 50%). NMR (400 MHz, CD3OD) 8.02 (d, J=8.9 Hz, 1H), 7.46-7.42 (m, 2H), 7.08-7.04 (m, 2H), 6.91 (d, J=8.9 Hz, 1H), 6.23-6.19 (m, 2H), 2.12 (d, J=7.0 Hz, 3H), 1.95-1.91 (m, 1H), 1.02-1.00 (m, 2H), 0.75-0.72 (m, 2H). MS: Calcd.: 363. Found: [M+H]+ 364.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6](Cl)=[N:7][CH:8]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH2:19][OH:20])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([O:12][C:13]2[CH:14]=[C:15]([CH2:19][OH:20])[CH:16]=[CH:17][CH:18]=2)=[N:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: OCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCc1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 100 °C
Yield: 100.1 %

Procedure:
To a solution of 5-trifluoromethyl-2-chloro-pyridine (150.0 g, 0.826 mol) in DMF (1.9 L) was added 3-hydroxy-phenyl-methanol (112.5 g, 0.906 mol) and of potassium carbonate (171.0 g, 1.237 mol). The solids were washed into the flask with 100 mL of DMF. The stirred mixture was heated to 95-105° C. for 5 h. It was cooled to ambient temperature and then poured into 5 L of stirred ice-water. The mixture was extracted with ether:hexane (2:1, 1.5 L, 1.0 L). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to dryness to give the product (222.5 g, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[C:13]([NH:18][C:19]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[O:20])[CH:14]=[CH:15][C:16]=3[Cl:17])[N:10]=2)[CH:7]=1.[Br-].[CH3:27][O:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:30]>CO>[Cl:17][C:16]1[CH:15]=[CH:14][C:13]([NH:18][C:19]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[CH:12][C:11]=1[C:9]1[N:10]=[C:5]2[N:4]=[CH:3][C:2]([C:35]3[CH:34]=[CH:33][C:32]([NH:31][C:29](=[O:30])[O:28][CH3:27])=[CH:37][CH:36]=3)=[CH:7][N:6]2[CH:8]=1
Reactant: COC(=O)Nc1ccc(B(O)O)cc1
Reactant: O=C(Nc1ccc(Cl)c(-c2cn3cc(Br)cnc3n2)c1)N1CCCC1
Agent: [Br-]
Solvent: CO
Product: COC(=O)Nc1ccc(-c2cnc3nc(-c4cc(NC(=O)N5CCCC5)ccc4Cl)cn3c2)cc1

Procedure:
Compound 24 was synthesized using N-(3-(6-bromoimidazo[1,2-a]pyrimidin-2-yl)-4-chlorophenyl)pyrrolidine-1-carboxamide (I-15) as the bromide and (4-((methoxycarbonyl)amino)phenyl)boronic acid using a suzuki coupling protocol as described in the synthesis of I-11. The residue was redissolved in methanol and precipitation yielded the compound. m/z (ESI) of 24: 491.2 (M+H+), 1H NMR (600 MHz, DMSO-D6) δ 9.86 (s, 1H), 9.30 (d, J=2.6, 1H), 8.94 (d, J=2.6, 1H), 8.55 (s, 1H), 8.47 (d, J=2.8, 2H), 7.73 (m, 3H), 7.62 (d, J=8.5, 2H), 7.41 (d, J=8.8, 1H), 3.70 (s, 3H), 3.40 (t, J=6.5, 4H), 1.86 (t, J=6.4, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:25]([F:28])([F:27])[F:26])[O:14][N:13]=[C:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[C:17]([CH3:24])[CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:62][C:63]([F:73])([F:72])[CH2:64][CH2:65][N:66]1[C:70](=[O:71])[CH2:69][NH:68][CH2:67]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:25]([F:27])([F:28])[F:26])[O:14][N:13]=[C:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:68]4[CH2:69][C:70](=[O:71])[N:66]([CH2:65][CH2:64][C:63]([F:62])([F:72])[F:73])[CH2:67]4)=[O:20])=[C:17]([CH3:24])[CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: O=C1CNCN1CCC(F)(F)F
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: Cc1cc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)N1CC(=O)N(CCC(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed N,N-dimethylformamide (2 mL), 4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylbenzoic acid (50 mg, 0.11 mmol, 1.00 equiv), HATU (174 mg, 0.46 mmol, 4.00 equiv), DIEA (60 mg, 0.46 mmol, 4.00 equiv), 3-(3,3,3-trifluoropropyl)imidazolidin-4-one (25 g, 137.25 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at room temperature. The crude product was purified by Prep-HPLC. This resulted in 22.1 mg (32%) of 1-([4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylphenyl]carbonyl)-3-(3,3,3-trifluoropropyl)imidazolidin-4-one as a white solid. 641 [Ms+CH3CN+H]+; (300 MHz, CD3OD, ppm): δ7.77-7.64 (m, 4H), 7.45-7.28 (m, 1H), 5.12-4.69 (m, 1H), 4.32-4.22 (m, 1H), 4.08-4.01 (m, 1H), 3.87-3.54 (m, 2H), 3.14-2.87 (m, 3H), 2.70-2.31 (m, 4H).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([C@@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@@H:6]1[NH:14]C(=O)OC(C)(C)C)=[O:4].C(O)C>C(Cl)Cl.[Br-].[Br-].[Zn+2]>[NH2:14][C@H:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][C@H:5]1[C:3]([N:2]([CH3:22])[CH3:1])=[O:4]
Reactant: CN(C)C(=O)[C@@H]1Cc2ccccc2[C@@H]1NC(=O)OC(C)(C)C
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCO
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1Cc2ccccc2[C@@H]1N
Reaction time: 18 h
Yield: 99.7 %

Procedure:
To a stirred solution of tert-butyl rel-{(1R,2R)-2-[(dimethylamino)carbonyl]-2,3-dihydro-1H-inden-1-yl}carbamate (690 mg, 2.15 mmol) in DCM (25.0 mL) was added zinc dibromide (970 mg, 4.31 mmol) and ethanol (0.25 mL, 4.31 mmol), and the mixture was stirred for 18 h. The reaction mixture was quenched by addition of water (20.0 mL) and the resulting mixture was stirred for 2 h. To this mixture was added 1.00 M NaOH (30.0 mL) and extracted with DCM (3×100 mL). The organic layers were combined, dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by flash chromatography (10 to 30% Methanol/DCM) to afford the title compound (438 mg, 95%) as a colorless oil. LC/MS: Rt=0.89 min, ES+ 205.2 (AA standard).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH:9][C:10]=1[CH2:11][CH2:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2)=[O:5])C.[CH3:29][O:30][C:31]([O:33][CH2:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38])=[O:32]>>[CH3:29][O:30][C:31]([O:33][CH2:34][C:35]1[CH:36]=[C:37]([NH:38][C:4]([C:6]2[N:7]=[C:8]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:9][C:10]=2[CH2:11][CH2:12][C:13]23[CH2:14][CH:15]4[CH2:21][CH:19]([CH2:18][CH:17]([CH2:16]4)[CH2:22]2)[CH2:20]3)=[O:5])[CH:39]=[CH:40][CH:41]=1)=[O:32]
Reactant: COC(=O)OCc1cccc(N)c1
Reactant: CCOC(=O)c1nc(-c2ccccc2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Product: COC(=O)OCc1cccc(NC(=O)c2nc(-c3ccccc3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-phenyl-1H-imidazole4-carboxylic acid ethyl ester (Example 46) was hydrolized according to the procedure of Example 20, step c. The acid was reacted with 3-methoxycarbonyloxymethyl-aniline using the procedure of Example 20, step d to produce 5-(2-adamantan-1-yl-ethyl)-2-phenyl-1H-imidazole-4-carboxylic acid (3-methoxycarbonyloxymethyl-phenyl)-amide, which was deprotected according to the procedure of Example 22, step b to afford the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) 12.69 (1H, br s), 9.56 (1H, s), 8.08 (2H, d), 7.80 (1H, s), 7.65 (1H, d), 7.48 (2H, t), 7.39 (1H, t), 7.26 (1H, t), 7.00 (1H, d), 5.16 (1H, m), 4.49 (2H, d), 2.99 (2H, m), 1.96 (3H, br s), 1.67-1.55 (12H, m), 1.43 (2H, m). Found: C, 76.26; H, 7.38; N, 9.09%; C29H33N3O2 requires: C, 76.45; H, 7.30; N, 9.22%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1.CCN(C(C)C)C(C)C.[N+:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33])([O-:25])=[O:24]>C(Cl)Cl>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([NH:4][CH2:3][CH2:2][NH:1][S:32]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N+:23]([O-:25])=[O:24])(=[O:33])=[O:34])=[N:6][CH:7]=1)([O-:13])=[O:12]
Reactant: NCCNc1ccc([N+](=O)[O-])cn1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(NCCNS(=O)(=O)c2ccccc2[N+](=O)[O-])nc1
Temperature: 23 °C
Reaction time: 6 h

Procedure:
To a suspension of resin-bound (2aminoethyl)(5-nitro(2-pyridyl))amine (30 g, 21 mmol), CH2Cl2 (250 mL) and iPr2NEt (18.3 mL, 105 mmol) at 23° C. was added 2-nitrobenzenesulfonyl chloride (23.3 g, 105 mmol). The resulting mixture was shaken at 23° C. for 6 h, filtered, washed with NMP, H2O and CH2Cl2 and air dried to yield polymer-bound {2-[(5-nitro(2-pyridyl))amino]ethyl}[(2-nitrophenyl)sulfonyl]amine.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].C(N(CC)CC)C.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])([O-:16])=[O:15].Cl>ClCCl>[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:2][CH2:3][C:4]([NH2:6])=[O:5])(=[O:25])=[O:24])([O-:16])=[O:15]
Reactant: NCC(N)=O
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.9 %

Procedure:
To a suspension of glycinamide hydrochloride (0.11 g) and triethylamine (0.35 mL) in dichloromethane (3 mL) was added 2-nitrobenzenesulfonyl chloride (0.27 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1) to give the title compound (72 mg).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[N:4]([CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[N:3]=1.C([Mg]Cl)(C)C.[CH2:22]([Sn:26]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:28][CH2:29][CH2:30][CH3:31])Cl)[CH2:23][CH2:24][CH3:25]>C1COCC1>[CH3:15][N:14]([CH3:16])[CH2:13][CH2:12][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=2)[C:2]([Sn:26]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:22][CH2:23][CH2:24][CH3:25])=[N:3]1
Reactant: Cc1ccc2c(I)nn(CCN(C)C)c2c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(CCN(C)C)c2cc(C)ccc12
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 203.1 %

Procedure:
A solution of 2-(3-iodo-6-methyl-1H-indazol-1-yl)-N,N-dimethylethanamine (450 mg, 1.4 mmol) in 20 mL of dry THF was cooled to −20° C. under nitrogen atmosphere, isopropylmagnesium chloride (1.4 mL, 2.8 mmol, 2 M in THF) was added and stirred for 15 min at −20° C. Then tributylchlorostannane (0.8 mL, 2.8 mmol) was added and allowed to warm to room temperature. The reaction was cooled in an ice bath and quenched with saturated ammonium chloride solution, extracted with ethyl acetate (3×30 mL), combined organics dried with sodium sulfate and concentrated to give 1.4 g of crude N,N-dimethyl-2-(6-methyl-3-(tributylstannyl)-1H-indazol-1-yl)ethanamine as an oil which was used in the next step directly without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[CH3:33][N:34]([CH3:44])[C:35]1[CH:40]=[CH:39][C:38]([C:41](Cl)=[O:42])=[CH:37][CH:36]=1>N1C=CC=CC=1.ClCCl>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:41](=[O:42])[C:38]4[CH:37]=[CH:36][C:35]([N:34]([CH3:33])[CH3:44])=[CH:40][CH:39]=4)=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(N(C)C)cc1
Temperature: -5 °C
Reaction time: 2.5 h
Yield: 53.3 %

Procedure:
A suspension of 3-(4-amino-3-methoxyphenyl)-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.398 g, 0.912 mmol) in pyridine (7 mL) at −5° C. was treated with a solution of 4-(dimethylamino)-1-benzenecarbonyl chloride (0.167 g, 0.912 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at −5° C. for 2.5 h, and the ice bath was removed. 1 N sodium hydroxide solution (10 mL) was added to the reaction mixture and stirred for 1 h. The organic layer was removed under reduced pressure, and dichloromethane (15 mL) was added. The layers were separated using an Empore extraction cartridge. The organic layer was removed under reduced pressure. The crude solid was purified two times by flash chromatography on silica gel using 12% (methanol with 5% ammonium hydroxide) in dichloromethane as eluent to give 0.284 g (53%) of N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(dimethylamino)benzamide. A hot solution of N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(dimethylamino)benzamide (0.284 g, 0.487 mmol) in ethyl acetate and a few drops of ethanol was treated with a hot solution of maleic acid (0.169 g, 1.46 mmol) in ethyl acetate. The precipitate formed was filtered under nitrogen and dried under high vacuum to give 0.409 g N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(dimethylamino)benzamide tris-maleate. 1H NMR (DMSO-d6, 400 MHz) δ 9.054 (s, 1H), 8.278 (s, 1H), 8.215-8.194 (m, 1H), 7.851-7.828 (m, 2H), 7.312-7.308 (m, 1H), 7.288-7.263 (m, 1H), 6.794-6.772 (m, 2H), 6.096 (s, 6H), 5.10-5.00 (m, 1H), 3.951 (s, 3H), 3.538 (s, 4H), 3.061 (s, 8H), 2.215-2.183 (m, 4H), 1.90-1.81 (m, 2H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 4.496 min (98%)
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:44])[NH:10]C1C=C(C2N=C(NC3C=C4C(=CC=3)N(C(OC(C)(C)C)=O)N=C4)C3C(=CC=CC=3)N=2)C=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([NH:8][C:9](=[O:44])[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)NCc5ccccc5)c4)nc4ccccc34)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)NCc1ccccc1

Procedure:
To tert-butyl 5-(2-(3-(3-benzylureido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (30 mg, 0.051 mmol) was added a solution of 1:1 TFA:CH2Cl2 (2 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and left under high vacuum for several hours. The crude product was triturated with ethyl ether to afford 14344-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-3-benzylurea. (25 mg, 100%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[CH:11]([NH:14][CH2:15][C:16](O)=[O:17])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[CH2:15][N:14]([CH:11]([CH3:13])[CH3:12])[C:9]2=[S:10])=[CH:4][CH:3]=1
Reactant: Fc1ccc(N=C=S)cc1
Reactant: CC(C)NCC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)N1CC(=O)N(c2ccc(F)cc2)C1=S
Yield: 50 %

Procedure:
The title compound was prepared by the procedure described in Example 45 using 15.3 g of 4-fluorophenyl-isothiocyanate,. 21.2 g of N-isopropyl glycine, 21.0 g of triethyl amine, and 300 mL of chloroform. Crystallization from ethanol afforded the title compound (12.6 g) as a peach solid, m.p. 184°-186° C. Anal. Calcd. for. C12H13F N2O S: C, 57.12; H, 5.19; N, 11.10. Found: C, 56.98; H, 5.09; N, 11.06. Mass spectrum (+FAB, [M+H]+) m/z 253.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([CH2:5][Cl:6])[CH:3]=[O:4].[CH3:8][C:9]1([C:12](=[O:19])[CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1>[Cl:6][CH2:5][C:2]([Cl:7])([Cl:1])[CH:3]([OH:4])[CH:13]([N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C:12]([C:9]1([CH3:8])[CH2:10][CH2:11]1)=[O:19]
Reactant: CC1(C(=O)Cn2cncn2)CC1
Reactant: O=CC(Cl)(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C(=O)C(C(O)C(Cl)(Cl)CCl)n2cncn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
11.3 g of 2,2,3-trichloropropionaldehyde were added dropwise to 9.2 g (0.056 mol) of 1-methyl-1-(1,2,4-triazol-1-yl-acetyl)-cyclopropane in 120 ml of tetrahydrofuran and 13.6 g (0.1 mol) of potassium carbonate, the temperature increasing slightly. The reaction solution was stirred overnight at room temperature and was thereafter introduced into 500 ml of water. The resulting precipitate was filtered off under suction and recrystallized from methanol. 5.5 g (30% of theory) of 1,2,2-trichloro-3-hydroxy-4-(1,2,4-triazol-1-yl)-5-(1-methylcycloprop-1-yl)-pentan-5-one of melting point 182° to 186° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH2:9][CH3:10])[CH:8]=1)[NH2:5].[CH2:11]([O:13][C:14]([C:16]#[C:17][C:18](OCC)=[O:19])=[O:15])[CH3:12]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:6]([C:18](=[O:19])[CH:17]=[C:16]([C:14]([O:13][CH2:11][CH3:12])=[O:15])[NH:5]2)=[C:7]([CH2:9][CH3:10])[CH:8]=1
Reactant: CCc1cc(N)cc(Cl)c1
Reactant: CCOC(=O)C#CC(=O)OCC
Product: CCOC(=O)c1cc(=O)c2c(CC)cc(Cl)cc2[nH]1

Procedure:
Reaction of 3-chloro-5-ethylaniline (0.9 g) with diethylacetylene dicarboxylate (0.93 ml) as described in Example 1b gave a mixture of the two 5,7-regioisomers (800 mg). The isomers were separated by silica chromatography to give ethyl 7-chloro-5-ethyl-4-oxo-1,4-dihydroquinoline-2 -carboxylate (250 mg), mp 222°-3° C.; δ (360 MHz, DMSO-d6) 1.15 (3H, t, CH2CH3), 1.36 (3H, t, CO2CH2CH3), 3.25 (2H, q, CH2CH3), 4.42 (2H, q, CO2CH2) 6.57 (1H, s, 3-H), 7.12 (1H, d, 8-H), 7.87 (1H, d, 6-H) and 11.75 (1H, bs, NH); and ethyl 5-chloro-7-ethyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (200 mg), mp 182°-3° C.; δ (360 MHz, DMSO-d6) 1.21 (3H, t, CH2CH3), 1.35 (3H, t, CO2CH2CH3), 2.67 (2H, q, CH2CH3), 4.40 (2H, q, CO2CH2) 6.56 (1H, s, 3-H), 7.28 (1H, d, 6-H), 7.73 (1H, d, 8-H) and 11.78 (1H, bs, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][N:7]([CH2:39][CH:40]([CH3:42])[CH3:41])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C@@H:18]3[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][C@H:19]3[O:28][Si](C(C)C)(C(C)C)C(C)C)=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:39][CH:40]([CH3:41])[CH3:42])[S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C@@H:18]3[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:25])=[O:26])[CH2:20][C@H:19]3[OH:28])=[CH:15][CH:16]=2)(=[O:9])=[O:10])=[CH:43][CH:44]=1
Reactant: CC(C)CN(Cc1ccc(Cl)cc1)S(=O)(=O)c1ccc(O[C@@H]2CCN(S(C)(=O)=O)C[C@H]2O[Si](C(C)C)(C(C)C)C(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CN(Cc1ccc(Cl)cc1)S(=O)(=O)c1ccc(O[C@@H]2CCN(S(C)(=O)=O)C[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
To a solution of N-(4-Chloro-benzyl)-N-isobutyl-4-((+/−)trans-1-methanesulfonyl-3-triisopropylsilanyloxy-piperidin-4-yloxy)-benzenesulfonamide (271 mg) in THF (5 mL) was added a 1 M solution of tetrabutylammonium fluoride in THF (609 μL, 609 mmol) and the reaction was stirred at room temperature for 30 minutes. Water was added and then extracted with EtOAc, washed with brine, dried with Na2SO4 then concentrated, purified by silica gel column chromatography (0-75% EtOAc in cyclohexane) and freeze dried to give the title compound (107 mg). 1H NMR (400 MHz, DMSO): δ 7.76 (d, 2H), 7.36-7.37 (m, 4H), 7.20 (d, 2H), 5.54 (d, 1H), 4.41 (td, 1H), 4.23 (s, 2H), 3.70-3.72 (m, 1H), 3.52 (dd, 1H), 3.42 (d, 1H), 3.04-3.08 (m, 1H), 2.94 (s, 3H), 2.90 (dd, 1H), 2.83 (d, 2H), 2.12-2.19 (m, 1H), 1.57-1.59 (m, 2H), 0.67 (d, 6H). LCMS (m/z, Method B) ES+ 531 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7](Cl)=[O:8])[S:5][CH:6]=1.CCN(C(C)C)C(C)C.[NH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:8])[S:5][CH:6]=1
Reactant: NCCN1CCOCC1
Reactant: O=C(Cl)c1cc(Br)cs1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCN1CCOCC1)c1cc(Br)cs1

Procedure:
To a solution of 4-bromo-2-thiophenecarbonyl chloride (1.0 g, 4.4 mmol) in DCM (10 ml) cooled to 0° C. was added DIPEA (0.85 ml, 4.8 mml) and 4-(2-aminoethyl)morpholine (0.6 ml, 4.6 mmol) dropwise. Stirring was continued until complete consumption of the starting material was observed by LC-MS. The reaction was quenched by the addition of water, which was washed with further portions of 2N HCl, dried over sodium sulfate, filtered and concentrated in vacuo to yield the desired compound without need for further purification (1.6 g, 98%). δH (500 MHz, CHLOROFORM-d) 7.38 (1H, d, 1.3 Hz), 7.37 (1H, d, 1.1 Hz), 3.72-3.80 (4H, m), 3.53 (2H, q, 5.6 Hz), 2.59 (2H, t, 6.0 Hz), 2.48-2.54 (4H, m), TR=0.8 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][S:11][CH3:12])[CH:5]=[C:4]([CH3:13])[C:3]=1[C:14]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]2[C:15]=1[CH2:16][CH2:17][C@H:18]2[O:24][C:25]1[CH:38]=[CH:37][C:28]2[C@H:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:30][O:31][C:27]=2[CH:26]=1.[K].[OH:40]OS([O-])=O.[K+]>CO.O>[CH3:13][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][S:11]([CH3:12])=[O:40])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:14]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]2[C:15]=1[CH2:16][CH2:17][C@H:18]2[O:24][C:25]1[CH:38]=[CH:37][C:28]2[C@H:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:30][O:31][C:27]=2[CH:26]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCCSC)cc5C)ccc(F)c43)ccc21
Reactant: O=S([O-])OO
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CO
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCCS(C)=O)cc5C)ccc(F)c43)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-((S)-6-((R)-4-(2,6-dimethyl-4-(2-(methylthio)ethoxy)phenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (230 mg) in methanol (4 mL) and water (2 mL) is added potassium peroxomonoslufate (Oxone®) (490 mg). The mixture is stirred for 1 hour at room temperature and then partitioned between dichloromethane and water. The organic phase is dried (MgSO4) and concentrated to give the crude product, which is directly in the next step. Yield: 220 mg; LC (method 4): tR=1.79 min; Mass spectrum (ESI+): m/z=553 [M+H]+.