Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[C:42]([O:45][CH:46]4[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1.C(N(C(C)C)CC)(C)C.[CH3:64][C:65]1[CH:69]=[C:68]([CH2:70][C:71](O)=[O:72])[O:67][N:66]=1>C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[C:42]([O:45][CH:46]4[CH2:47][CH2:48][N:49]([C:71](=[O:72])[CH2:70][C:68]5[O:67][N:66]=[C:65]([CH3:64])[CH:69]=5)[CH2:50][CH2:51]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Reactant: Cc1cc(CC(=O)O)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)Cc2cc(C)no2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.1 %

Procedure:
HATU (0.31 g) was added to a solution of N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and 3-methyl-5-isoxazoleacetic Acid (0.135 g) in methylene chloride (9 ml). The resulting mixture was stirred at room temperature for 2.5 hrs. Methylene chloride (20 ml) was added and the organics washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The crudes were then purified by flash column chromatography eluting with methanol/methylene chloride (2.5/97.5). Fractions containing the desired product were evaporated to a white foam which was triturated with diethyl ether (20 ml) to give N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({1-[(3-methylisoxazol-5-yl)acetyl]piperidin-4-yl}oxy)quinazolin-4-amine as a white solid (0.269 g). 1H NMR Spectrum: (DMSO d6 373K) 1.79 (m, 2H), 1.98 (m, 2H), 2.23 (s, 3H), 3.50 (m, 2H), 3.79 (m, 2H), 3.92 (s, 2H), 3.97 (s, 3H), 4.77 (m, 1H), 6.18 (s, 1H), 7.24 (m, 2H), 7.42 (m, 1H), 7.59 (m, 1H), 7.89 (s, 1H), 8.39 (s, 1H), 9.28 (br s, 1H); Mass Spectrum: (M+H)+ 526.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[N:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:14]1([C:6]2[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:2]([N:33]3[CH2:34][CH2:35][N:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)[CH2:31][CH2:32]3)[N:3]=[C:4]([C:20]([F:23])([F:22])[F:21])[N:5]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1nc(Cl)c(-c2ccccc2)c(-c2ccccc2)n1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1nc(-c2ccccc2)c(-c2ccccc2)c(N2CCN(c3ccccn3)CC2)n1
Temperature: 28 °C
Yield: 69.66 %

Procedure:
To a solution of 4-chloro-5,6-diphenyl-2-(trifluoromethyl)pyrimidine (0.5 g, 1.49 mmol, prepared according to the procedure described in PCT/IB03/02879) in DMF (5 ml) was added 1-pyridin-2-yl piperazine (0.107 g, 0.66 mmol) and anhydrous potassium carbonate (0.2 g) under stirring at 28° C. The reaction mixture was stirred for 4 hours and when TLC confirmed the completion, it was poured onto ice. The solid thus obtained was filtered and washed with water (20 ml). The above solid was then dissolved in dichloromethane (50 ml) and dried over anhydrous sodium sulphate. Evaporation of the solvent afforded the title compound (0.48 g, yield 69.66%, purity by HPLC 99.8%). m.p. 165-167° C. 1H-NMR (CDCl3) δ: 3.43 (s, 8H), 6.58-6.64 (m, 2H), 7.14-7.21 (m, 7H), 7.26-7.29 (m, 3H), 7.45-7.49 (t, 1H), 8.14-8.15 (d, 1H); IR cm−1 (KBr): 3436, 2839, 1591 and 1557; MS m/z: 462.1 (M++1).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB(/[CH:20]=[CH:21]/[CH2:22][O:23][CH3:24])O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[CH3:24][O:23][CH2:22]/[CH:21]=[CH:20]/[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC/C=C/c1ccc2c(c1)C(=O)CC2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 6-bromoindan-1-one (1 eq.) and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (1.3 eq.) in DMF (0.1 M) was added trans-bis(triphenylphosphine) palladium(II) bromide (0.05 eq.). The vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 M aq. Na2CO3 (3 eq.) was added and the resulting mixture was stirred at 100° C. for 1 h. The now black suspension was cooled to RT, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a beige solid.
Reaction SMILES: C(OC([NH:11][CH:12]([CH3:23])[C:13](=[O:22])[C:14]([CH3:21])([CH3:20])[C:15](OCC)=[O:16])=O)C1C=CC=CC=1>CO.[C].[Pd]>[CH3:20][C:14]1([CH3:21])[C:13](=[O:22])[CH:12]([CH3:23])[NH:11][C:15]1=[O:16]
Reactant: CCOC(=O)C(C)(C)C(=O)C(C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC1NC(=O)C(C)(C)C1=O
Reaction time: 8 h
Yield: 86.7 %

Procedure:
To a solution of ethyl 4-{[(benzyloxy)carbonyl]amino}-2,2-dimethyl-3-oxopentanoate (10.5 g) in methanol (150 mL) was added 10% palladium carbon (containing 50% water, 5.0 g), and the mixture was stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained solid was washed with hexane to give the title compound as a colorless solid (yield: 4.00 g, 87%).
Reaction SMILES: C([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)(OC(C)(C)C)=O.Cl.O1CCOCC1>C(OCC)(=O)C>[NH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: NCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 160.9 %

Procedure:
Ethyl acetate (1.5 mL) was added to 100 mg of Boc-Tyramine-PEM (α,γ-mixture) obtained in Reference Example 3 to suspend the compound, and then 4 N HCl/dioxane (0.5 mL) was added thereto. The mixture was stirred for one hour at room temperature. A precipitate thus obtained was filtered with a Kiriyama funnel and dried in a vacuum, and thus 93 mg of Tyramine-PEM (α,γ-mixture) was obtained. The compound is thought to be a dihydrochloride salt, based on yield.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][O:7][C:8]1[CH:13]=[C:12]([C:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=2)[C:11]([NH2:21])=[CH:10][C:9]=1[NH:22][C:23]1[N:28]=[C:27]([C:29]2[CH:30]=[N:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][C:33]=23)[CH:26]=[CH:25][N:24]=1>C(Cl)Cl.CO.C(Cl)Cl>[CH3:6][O:7][C:8]1[C:9]([NH:22][C:23]2[N:28]=[C:27]([C:29]3[CH:30]=[N:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][C:33]=34)[CH:26]=[CH:25][N:24]=2)=[CH:10][C:11]([NH:21][C:1](=[O:4])[CH:2]=[CH2:3])=[C:12]([C:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=2)[CH:13]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Solvent: ClCCl
Solvent: CO
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4c3CCCC4)n2)c(OC)cc1C1=CCN(C)CC1
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
A solution of acryloyl chloride (30 μL, 0.37 mmol) in CH2Cl2 (2 mL) was added dropwise over 5 minutes to 4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-N′-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 136, 154 mg, 0.36 mmol) in CH2Cl2 (5 mL), which was cooled in an ice/CH3OH bath. The mixture was then stirred for 0.5 h. The mixture was then diluted with 10% CH3OH/CH2Cl2 and the resulting solution was washed with sat. NaHCO3, dried (MgSO4) and then concentrated in vacuo. Purification by FCC, eluting with 0-10% methanolic ammonia in CH2Cl2 gave the title compound (104 mg, 60%) as an pale yellow solid after trituration with diethyl ether/heptane; 1H NMR: 1.76-1.84 (2H, m), 1.91-1.98 (2H, m), 2.27 (3H, s), 2.32-2.39 (2H, m), 2.48-2.56 (2H, m), 2.96-2.99 (2H, m), 3.08 (2H, t), 3.90 (3H, s), 4.11 (2H, t), 5.65-5.76 (2H, m), 6.21 (1H, d), 6.49 (1H, dd), 6.84 (1H, s), 7.07 (1H, d), 7.84 (1H, s), 8.10 (1H, s), 8.32-8.37 (2H, m), 9.33 (1H, s); m/z: ES+ MH+ 486.73.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].CO>C(OCC)(=O)C>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:30])([F:32])[F:31])[CH:23]=4)[CH2:17][CH2:18]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: OC1(c2ccc(Cl)c(C(F)(F)F)c2)CCNCC1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(O)(c2ccc(Cl)c(C(F)(F)F)c2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-hydroxy-4-(3-trifluoromethyl-4-chlorophenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 85% overall yield. FDMS m/e=469 (M+ of free base). α[D]589 =-11.53 (c=0.54, methanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:23][C:24]([NH:26][CH:27]([CH:34]([CH3:36])[CH3:35])[C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])=[O:25])[C:10](=[O:22])[C:11]([N:14](C(=O)C(F)(F)F)[CH3:15])=[CH:12][N:13]=2)=[CH:4][CH:3]=1.O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:23][C:24]([NH:26][CH:27]([CH:34]([CH3:36])[CH3:35])[C:28](=[O:33])[C:29]([F:30])([F:32])[F:31])=[O:25])[C:10](=[O:22])[C:11]([NH:14][CH3:15])=[CH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccc(F)cc2)ncc(N(C)C(=O)C(F)(F)F)c1=O)C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CNc1cnc(-c2ccc(F)cc2)n(CC(=O)NC(C(=O)C(F)(F)F)C(C)C)c1=O
Reaction time: 8 h

Procedure:
To a solution of 2-[2-(4-fluorophenyl)-5-(N-trifluoroacetyl-N-methylamino)-6-oxo-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3,-trifluoro-1-isopropyl-2-oxopropyl)acetamide (0.58 g) in tetrahydrofuran (5 mL) was added water (10 mL) followed by potassium carbonate (0.76 g). The mixture was stirred overnight, extracted into dichloromethane, washed (water, brine), dried (MgSO4) and evaporated. The residue was purified by chromatography, with dichloromethane:methanol (gradient, 99.5:0.5, 98.5:1.5) as the eluent, to give the title compound; TLC: Rf =0.34, dichloromethane:methanol (98:2); NMR: 0.70-1.0 (m,6), 2.03-2.33 (m,1), 2.71 (d,3), 4.00-4.70 (m,3), 5.63-5.73 (m,1), 7.03 (s,1), 7.17-7.30 (m,2), 7.43-7.60 (m,2), 8.81 (d,1); MS: m/z=429(M+1).
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O:11]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15](S(C)(=O)=O)[N:14]=1)[CH3:12].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:11]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([S:1][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[N:14]=1)[CH3:12]
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: O=C(O)c1cccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)nc(Sc2ncccc2C(=O)O)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
4.0 g (0.026 mol) of 2-mercaptonicotinic acid, 5.7 g (0.026 mol) of 4,6-dimethoxyl-2-methylsulfonylpyrimidine and 7.2 g (0.052 mol) of potassium carbonate were weighed, and 70 ml of dimethylformamide was added thereto and the mixture was stirred at 80° C. for 2 hours. The resultant mixture was poured into water, and was washed with 100 ml of ethyl acetate. The aqueous layer was then acidified with 10% HCl aqueous solution to precipitate a crystal. The crystal thus precipitated was filtrated out, and was washed with water and was dried. The crystal was then recrystallized with methanol to obtain 5.3 g of a light-yellowish crystal of the aimed product.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[CH2:15]([N:22]1[CH2:27][C@H:26]([CH3:28])[NH:25][C@@H:24]([CH3:29])[C:23]1=[O:30])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:15]([N:22]1[CH2:27][C@H:26]([CH3:28])[N:25]([C:2]2[O:3][C:4]3[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=3)[N:6]=2)[C@@H:24]([CH3:29])[C:23]1=[O:30])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Reactant: C[C@@H]1N[C@@H](C)CN(Cc2ccccc2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc2oc(N3[C@@H](C)CN(Cc4ccccc4)C(=O)[C@@H]3C)nc12
Temperature: 35 °C
Reaction time: 16 h
Yield: 59.9 %

Procedure:
A mixture of methyl 2-chlorobenzoxazole-4-carboxylate (970 mg, 4.58 mmol) and (3S,5S)-1-benzyl-3,5-dimethylpiperazin-2-one (1.00 g, 4.58 mmol) in DMF (20 mL), was stirred in a 35° C. oil bath. After 16 h, the reaction mixture was heated to 55° C. After 3 h, potassium carbonate (630 mg, 4.58 mmol) was added. The reaction mixture was stirred for 2 h at 55° C. and then at ambient temperature for 17 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with 0.5 N HCl (25 mL), H2O (25 mL), brine (25 mL), dried (Na2SO4), and concentrated under reduced pressure. Purification by chromatography (silica gel, 10 to 80% EtOAc in hexanes) gave methyl 2-((2S,6S)-4-benzyl-2,6-dimethyl-3-oxopiperazine-1-yl)benzoxazole-4-carboxylate (1.08 g, 60%). 1H NMR consistent.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH2:18][C:19]1[CH:20]=[C:21]([O:27][CH3:28])[C:22]([O:25][CH3:26])=[CH:23][CH:24]=1>CN(C=O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[N:7]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: COc1ccc(N)cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Nc2ncnc(Cl)n2)cc1OC
Temperature: 0 °C

Procedure:
2,4-Dichloro-1,3,5-triazine (12.6 g, 84 mmol) was dissolved into DMF (100 mL) under N2 and cooled to 0° C. DIEA (11.7 g, 90 mmol) was added, followed by 4-aminoveratrole (13.35 g, 87 mmol). The reaction solution was stirred with gradual warming to RT. The reaction was quenched after 3.5 h with water, which causes a gray precipitate to form. This precipitate was recovered by vacuum filtration, washed with cold water, dried under high vacuum, then eluted through a 28×4.5 cm column of silica gel (0.1% NH4OH(aq) buffered 1%, 2%, 3%, 4%, and 5% MeOH/CH2Cl2 step gradient) giving (4-chloro-[1,3,5]triazin-2-yl)-(3,4-dimethoxy-phenyl)-amine as an off white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[C:16]([F:18])[C:15]([C:19]([F:22])([F:21])[F:20])=[C:14]([Cl:23])[CH:13]=2)=[CH:7][C:3]=1[C:4](Cl)=[O:5].[OH-].[NH4+:25].O>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[C:16]([F:18])[C:15]([C:19]([F:22])([F:21])[F:20])=[C:14]([Cl:23])[CH:13]=2)=[CH:7][C:3]=1[C:4]([NH2:25])=[O:5]
Reactant: [NH4+]
Reactant: O=C(Cl)c1cc(Oc2cc(F)c(C(F)(F)F)c(Cl)c2)ccc1Br
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1cc(Oc2cc(F)c(C(F)(F)F)c(Cl)c2)ccc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-bromo-5-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl)oxy]benzoyl chloride (16 g, 0.036 mol) in methylene chloride is cooled to 0° C., treated dropwise with 9.2 mL of a 30% ammonium hydroxide solution (0.071 mol), stirred at 0° C. for 30 minutes, stirred at room temperature overnight and poured into water. The aqueous mixture is extracted with methylene chloride. The organic extracts are combined, washed sequentially with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as a white solid, mp 115°-116° C.
Reaction SMILES: CS(O[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[S:13][C:14]3[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:7]1)(=O)=O.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:22]1([C@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:7]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)O[C@@H]1CCCN(c2nc3ccc(Br)cc3s2)C1
Product: Brc1ccc2nc(N3CCC[C@H](N4CCCCC4)C3)sc2c1
Yield: 24 %

Procedure:
The title compound was prepared by the method of Example 34, substituting (R)-1-(6-bromobenzo[d]thiazol-2-yl)piperidin-3-yl methanesulfonate (Reference Example 12) in place of (S)-1-(6-bromobenzo[d]thiazol-2-yl)piperidin-3-yl methanesulfonate (Reference Example 10) and substituting piperidine in place of azetidine to give (S)-2-(1,3′-bipiperidin-1′-yl)-6-bromobenzo[d]thiazole (0.018 g, 24% yield). 1H NMR (300 MHz, CD3OD) δ ppm 1.45-1.55 (m, 2H), 1.56-1.73 (m, 6H), 1.82-1.95 (m, 1H), 2.04-2.12 (m, 1H), 2.46-2.57 (m, 1H), 2.59-2.74 (m, 4H), 3.04-3.18 (m, 2H), 3.96-4.05 (m, 1H), 4.22-4.30 (m, 1H), 7.33 (d, J=9 Hz, 1H), 7.39 (dd, J=2, 9 Hz, 1H), 7.79 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 380 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[N:10]([CH3:35])[C:11]2[C:16]([N:17]=1)=[C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:14]=[C:13]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH2:33][CH3:34])[N:12]=2.[OH:37][C:38]([CH3:43])([CH3:42])[C:39](O)=[O:40].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>C(Cl)Cl>[CH2:33]([C:25]1[N:24]([C:13]2[N:12]=[C:11]3[C:16]([N:17]=[C:9]([CH2:8][N:3]4[CH2:4][CH2:5][N:6]([C:39](=[O:40])[C:38]([OH:37])([CH3:43])[CH3:42])[CH2:7][C:2]4([CH3:1])[CH3:36])[N:10]3[CH3:35])=[C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:14]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=1)[CH3:34]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCNCC3(C)C)n(C)c2n1
Reactant: CC(C)(O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(=O)C(C)(C)O)CC3(C)C)n(C)c2n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 47.8 %

Procedure:
A mixture of 8-(2,2-dimethylpiperazin-1-ylmethyl)-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (100 mg, 0.20 mmol), 2-hydroxyisobutyric acid (24 mg, 0.23 mmol), HATU (85 mg, 0.22 mmol) and DIPEA (40 μL, 0.23 mmol) in DCM (2 mL) was allowed to stir at r.t. for 17 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-3%) affording 741 as a white solid (55 mg, 46%). LCMS (method I): RT 2.89 min, [M+H]+ 576.3. 1H NMR (CDCl3, 400 MHz): δ 8.02-8.02 (1 H, m), 7.76-7.75 (1 H, m), 7.33-7.22 (2 H, m), 4.40-4.20 (5 H, m), 3.92 (3 H, s), 3.88-3.83 (5 H, m), 3.63 (2 H, s), 3.53 (2 H, s), 3.36 (2 H, q, J=7.48 Hz), 2.59-2.53 (2 H, m), 1.50 (6 H, s), 1.45 (3 H, t, J=7.48 Hz), 1.23 (6 H, s)
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[N:7]=1)=[O:5])C.Cl>[OH-].[K+].CCO>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:8]1[C:9]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[C:10]([CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])[C:6]([C:4]([OH:5])=[O:3])=[N:7]1
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1CNC(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)NCc1c(C(=O)O)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Yield: 133.7 %

Procedure:
A solution of 1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-4-(isopropylamino-methyl)-1H-pyrazole-3-carboxylic acid ethyl ester I-4c (32 mg, 0.074 mmol) in a 1:4 solution of 1M KOH/EtOH (10 ml) was stirred at 50° C. for 6 hours and at 37° C. for 72 hours. The reaction mixture was treated with conc. HCl until the pH of the solution was approximately 1 and then concentrated in vacuo. The residue was diluted with EtOH and filtered. The filtrate was concentrated under vacuum to give I-4a as a white solid (40 mg, 100%): +APCI MS (M+1) 404.1.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]2[C:34](F)=[N:35][CH:36]=[CH:37][CH:38]=2)=[O:32])=[CH:26][CH:25]=1)([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=O)(C)(C)C.Cl.Cl.[NH:42]1[C:46]2=[N:47][CH:48]=[CH:49][C:50]([CH2:51][NH2:52])=[C:45]2[CH:44]=[CH:43]1>>[NH:42]1[C:46]2=[N:47][CH:48]=[CH:49][C:50]([CH2:51][NH:52][C:34]3[N:35]=[CH:36][CH:37]=[CH:38][C:33]=3[C:31]([NH:30][C:27]3[CH:26]=[CH:25][C:24]([C:15]([O:14][CH2:13][C@@H:9]4[CH2:10][CH2:11][CH2:12][NH:8]4)([C:16]([F:19])([F:17])[F:18])[C:20]([F:21])([F:22])[F:23])=[CH:29][CH:28]=3)=[O:32])=[C:45]2[CH:44]=[CH:43]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COC(c1ccc(NC(=O)c2cccnc2F)cc1)(C(F)(F)F)C(F)(F)F
Reactant: NCc1ccnc2[nH]ccc12
Agent: Cl
Product: O=C(Nc1ccc(C(OC[C@@H]2CCCN2)(C(F)(F)F)C(F)(F)F)cc1)c1cccnc1NCc1ccnc2[nH]ccc12

Procedure:
The titled compound was prepared from (S)-2-(2,2,2-trifluoro-1-{4-[(2-fluoro-pyridine-3-carbonyl)-amino]-phenyl}-1-trifluoromethyl-ethoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester and C-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine dihydrochloride by the method described in Example 1. MS (ES+): 593 (M+H). Calc'd. for C28H26F6N6O2—592.54.
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]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N: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][C:34]([CH3:45])([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:35](Cl)=[O:36].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:35](=[O:36])[C:34]([CH3:33])([CH3:45])[CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: CC(C)(Cc1ccccc1)C(=O)Cl
Reactant: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)C(C)(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of cis-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.23 mmol) in pyridine (2.5 mL) was treated with 2,2-dimethyl-3-phenylpropanoyl chloride (0.120 g, 0.61 mmol). The reaction mixture was stirred for 2 h at room temperature under a nitrogen atmosphere. Saturated sodium bicarbonate solution (10 mL) was added, and the reaction mixture was stirred for 20 min. Solvent was removed under reduced pressure. Dichloromethane and saturated sodium bicarbonate solution was added to the residue. The layers were separated using an Empore extraction cartridge. The organic solvent was removed under reduced pressure. The crude compound was purified by flash chromatography on silica gel, using 10% methanol in dichloromethane as eluent to give 0.085 g (62%) cis-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-2,2-dimethyl-3-phenylpropanamide. 1H NMR (CDCl3, 400 MHz) δ 8.595-8.574 (m, 1H), 8.372 (s, 1H), 7.985 (s, 1H), 7.292-7.158 (m, 7H), 4.923 (m, 1H), 3.891 (s, 3H), 3.050-3.013 (m, 1H), 2.965 (s, 2H), 2.65-2.55 (m, 5H), 2.440-2.346 (m, 4H), 2.244-2.166 (m, 4H), 1.854-1.823 (m, 3H), 1.688 (m, 3H), 1.334 (s, 6H); 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 5.517 min (100%).