Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:12])[CH2:6][CH2:5]1)[CH:2]=C.[O:24]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl>[CH3:14][C:13]([CH3:15])([CH3:16])[C@@H:11]([N:7]1[CH2:6][CH2:5][C:4]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([CH2:1][CH2:2][OH:24])[O:9][C:8]1=[O:10])[CH3:12]
Reactant: C=CCC1(c2ccc(F)cc2)CCN([C@@H](C)C(C)(C)C)C(=O)O1
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H](N1CCC(CCO)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 4 %

Procedure:
A solution of 6-allyl-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (80 mg, crude) in dry CH2Cl2 (5 mL) was treated with ozone at −78° C. until the mixture turned blue. The system was then flushed with oxygen to move excess ozone. NaBH4 (47 mg, 1.25 mmol) was added to the mixture in portions at rt. The mixture was stirred overnight at rt. The mixture was quenched with water and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×6 mL). The organic layer was combined, washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude product, which was purified by preparative TLC to give 3-((2S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (5 mg, yield: 4%).
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[CH:12]1([N:15]([CH2:25][C:26]2[CH:27]=[C:28]([C:32](=O)[CH3:33])[CH:29]=[CH:30][CH:31]=2)[CH2:16]/[CH:17]=[CH:18]/[C:19]#[C:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][CH2:13]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:12]1([N:15]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([CH3:33])=[CH2:1])[CH:27]=2)[CH2:16]/[CH:17]=[CH:18]/[C:19]#[C:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][CH2:13]1
Reactant: [Li]CCCC
Reactant: CC(=O)c1cccc(CN(C/C=C/C#CC(C)(C)C)C2CC2)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Product: C=C(C)c1cccc(CN(C/C=C/C#CC(C)(C)C)C2CC2)c1
Yield: 45.6 %

Procedure:
The procedure described in Example 9 was repeated, except that methyl triphenylphosphonium bromide (0.57 g; 1.61 mmol), n-butyl lithium in n-hexane (1.56 M: 1.0 ml; 1.61 mmol), and Compound 13 (0.33 g; 1.07 mmol) were used, to thereby yield 0.15 g of the target compound (yield: 45.6%).
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4([CH:36]=O)[CH2:35][CH2:34]4)=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:38][O:39]C(=O)C)(=O)C.N1C=CC=CC=1.Cl.[CH3:50][O:51][NH2:52]>C(O)C>[CH3:50][O:51][N:52]=[CH:36][C:33]1([C:30]2[CH:31]=[CH:32][C:27]([CH2:26][C:21]3[CH:20]=[C:19]([C@H:8]4[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:38][OH:39])[O:7]4)[CH:24]=[CH:23][C:22]=3[Cl:25])=[CH:28][CH:29]=2)[CH2:35][CH2:34]1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(C4(C=O)CC4)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=CC1(c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc2)CC1
Temperature: 80 °C
Yield: 118.1 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(1-formylcyclopropyl)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (300.0 mg, 0.44 mmol), in ethanol (5 mL) under nitrogen atmosphere, was added pyridine (0.17 mL, 2.20 mmol) and O-methylhydroxylamine hydrochloride (73.0 mg, 0.88 mmol). The reaction mixture was heated at 80° C. for 4 h. After completion of the reaction as confirmed by TLC, the solvent was evaporated. The crude compound was diluted with ethyl acetate (40 mL). The organic layer was washed with 5% HCl (10 mL), water (10 mL), dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1:4 EtOAc:Pet Ether) to afford the title compound (240 mg, 77%) as a white solid.
Reaction SMILES: C([N-]C(C)C)(C)C.C([Li])CCC.CCCCCC.C([N-]C(C)C)(C)C.[Li+].[N:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1.[Cl-].[Ce+3].[Cl-].[Cl-].[CH3:38][C:39]([CH3:56])([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH:47]([CH2:50][C:51]([O:53]CC)=O)[CH2:46][CH2:45]1)=[O:43])[CH3:40]>O1CCCC1.C(OCC)(=O)C.CCCCCC>[O:53]=[C:51]([CH2:33][C:30]1[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=1)[CH2:50][CH:47]1[CH2:46][CH2:45][N:44]([C:42]([O:41][C:39]([CH3:38])([CH3:40])[CH3:56])=[O:43])[CH2:49][CH2:48]1
Reactant: Cc1ccncc1
Reactant: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)Cc2ccncc2)CC1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 25 %

Procedure:
To a solution of diisopropylamide (6.15 mL, 43.91 mmol) in dry tetrahydrofuran (40 mL) at 0° C. was added 2.5 M butyl lithium solution in hexane (16.22 mL, 40.53 mmol) dropwise over 10 minutes. After the addition, the lithium diisopropylamide solution was stirred at 0° C. for 20 minutes, then cooled to −78° C. 4-Picoline (3.98 mL, 40.53 mmol) was added to the above lithium diisopropylamide solution under N2 dropwise over 10 minutes The resulting solution was stirred at −78° C. under N2 for 1.5 hours, then transfered into a suspension of anhydrous cerium chloride (10.0 g, 40.53 mmol) in tetrahydrofuran (40 mL) at −78° C. under N2. The mixture was stirred at −78° C. under N2 for 2 hours, then a solution of ethyl 1-[(1,1-dimethylethoxy)carbonyl]-4-piperidineacetate (from step 1 of this Example) (10.98 g, 40.53 mmol) in tetrahydrofuran (40 mL) was added slowly for 1 hour. The mixture was stirred under N2 from −78° C. to room temperature overnight. The reaction was quenched with water, diluted with ethyl acetate, and washed with a pH 7 buffer. The organic layer was washed with water and brine. After filtration, the solvent was removed under reduced pressure to give a crude product mixture. The desired product 1,1-dimethylethyl 4-[2-oxo-3-(4-pyridinyl)propyl]-1-piperidinecarboxylate (3.19 g, 25%) was isolated by chromatography (silica gel, 50:50-75:25-100:0 ethyl acetate/hexane). Step 3: Preparation of 1,1-dimethylethyl 4-[4-(4-fluorophenyl)-2-oxo-3-(4-pyridinyl)-3-butenyl]-1piperidinecarboxylate
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.CCN(CC)CC.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>C(Cl)Cl.O>[CH3:43][N:44]1[CH2:49][CH2:48][N:47]([C:20]([C@H:17]2[CH2:16][CH2:15][C@H:14]([CH2:13][NH:12][S:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:23])([F:1])[F:24])=[CH:4][CH:5]=3)(=[O:10])=[O:11])[CH2:19][CH2:18]2)=[O:22])[CH2:46][CH2:45]1
Reactant: CN1CCNCC1
Reactant: O=C(O)[C@H]1CC[C@H](CNS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CCN(C(=O)[C@H]2CC[C@H](CNS(=O)(=O)c3ccc(C(F)(F)F)cc3)CC2)CC1
Reaction time: 1 h

Procedure:
200 mg (0.54 mmol) of trans-4-[(4-trifluoromethyl-benzenesulfonylamino)-methyl]-cyclohexanecarboxylic acid, 210 mg (1.09 mmol, 2 eq) of EDCI, 221 mg (2.2 mmol, 4 eq) of Et3N and 274 mg (2.74 mmol, 5 eq) of 1-methyl-piperazine were dissolved in 5 mL of CH2Cl2. After 70 h reaction at RT, 1 mL of H2O was added and the reaction mixture was stirred vigorously for 1 h. The organic phase was separated, the aqueous phase was extracted with 10 mL of CH2Cl2 and the combined organic phases were washed with H2O and brine. After drying over anhydrous Na2SO4, the organic phase was evaporated. The residue was chromatographed on silicagel with CH2Cl2:MeOH:25% NH4OH (9:1:0.1) as eluent. 120 mg (49%) of trans-N-[4-(4-methyl-piperazine-1-carbonyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfonamide were obtained as colorless amorphous solid, MS: 448 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([C:22]([CH3:27])([CH3:26])[C:23](O)=[O:24])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:21]3[C:22]([CH3:27])([CH3:26])[C:23]2=[O:24])=[CH:11][CH:10]=1
Reactant: CC(C)(C(=O)O)c1cccnc1Nc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)N(c2ccc(Cl)cc2)c2ncccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Add trifluoroacetic acid (5 mL) to 2-[(4-chlorophenyl)amino-a,a-dimethyl-3-pyridineacetic acid (S) (3.00 g, 0.010 mole) in dichloromethane (40 mL). Stir for 16 hours at room temperature. Rotoevaporate to remove the solvent. Add saturated organic solution with MgSO4, filter, and rotoevaporate. Dissolve the oil in dichloromethane, and chromatograph on silica gel, eluting with dichloromethane. Combine the appropriate fractions, and concentrate under reduced pressure to give a solid. Recrystallize with diethyl ether-isopropyl ether to give the title compound AB as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.[Cl:15][C:16]1[CH:29]=[C:28]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:27]=[CH:26][C:17]=1[CH2:18][CH:19]([C:23](=O)[CH3:24])[C:20](=O)[CH3:21]>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:20]([CH3:21])=[C:19]([CH2:18][C:17]1[CH:26]=[CH:27][C:28]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:29][C:16]=1[Cl:15])[C:23]([CH3:24])=[N:13]2
Reactant: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1Cl)C(C)=O
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Solvent: O
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(S(C)(=O)=O)cc3Cl)c(C)c12
Temperature: 100 °C

Procedure:
A mixture of (3-amino-4-chlorophenoxy)acetic acid methyl ester (0.35 g), 3-(2-chloro-4-methanesulfonylbenzyl)pentane-2,4-dione (0.5 g) and polyphosphoric acid (5.0 g) was heated at 100° C. for 3.5 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (2:8 to 3:7 by volume) to afford title compound as a pale yellow waxy solid, 0.36 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:11](=[CH:12][CH:13]=1)[CH:10]1[CH2:14][CH:6]2[CH2:7][C:8](=O)[NH:9]1.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:11](=[CH:12][CH:13]=1)[CH:10]1[CH2:14][CH:6]2[CH2:7][CH2:8][NH:9]1
Reactant: COc1ccc2c(c1)C1CC(=O)NC2C1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C1CCNC2C1
Temperature: -10 °C

Procedure:
1 M Borane tetrahydrofuran complex (70 mL) is added dropwise to a solution of 4-methoxy-9-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-10-one (3.0 g) in tetrahydrofuran (20 mL) chilled in an ice bath. The resulting solution is stirred at reflux temperature for 5 h and then at room temperature overnight. The solution is cooled to ca. −10° C. and half-concentrated hydrochloric acid (50 mL) is added carefully. The mixture is stirred at room temperature for 1 h and an additional hour at reflux temperature. The solvent is removed and 2 M aqueous NaOH solution (50 mL) is added to the residue. The resulting mixture is extracted with dichloromethane and the combined organic extracts are dried (MgSO4). After removal of the solvent, the residue is taken up in ethanol (20 mL) and the resulting solution is treated with oxalic acid (3 mL) to obtain the oxalate salt of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:27])[CH2:18][CH2:17][C:16]([CH2:25][NH2:26])([N:19]2[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:26][CH2:25][C:16]1([N:19]2[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]2)[CH2:17][CH2:18][C:13]([F:12])([F:27])[CH2:14][CH2:15]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cc1cn(C2(CN)CCC(F)(F)CC2)cn1
Product: Cc1cn(C2(CNC(=O)c3cccc(Cl)c3Cl)CCC(F)(F)CC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and (4,4-difluoro-1-(4-methyl-1H-imidazol-1-yl)cyclohexyl)methanamine. LCMS (MH+): m/z=402.0, tR (minutes, Method E)=0.45
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24])[C:7]([NH:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:8])(=O)C.[OH-].[Na+].Cl>CO>[Cl:23][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:24])[C:17]=1[CH2:16][CH:6]([CH2:5][SH:4])[C:7]([NH:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:8]
Reactant: CC(=O)SCC(Cc1c(Cl)cccc1Cl)C(=O)NN1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NN1CCOCC1)C(CS)Cc1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85.7 %

Procedure:
Under an inert atmosphere, a solution of 1.7 g of the product of Example 5 in 400 ml of methanol was cooled to 0° C. and then over 15 minutes, 48 ml of 0.1N sodium hydroxide were added with stirring for 2 hours at 0° C. The reaction medium was neutralized with 5 ml of N hydrochloric acid, and the solvents were eliminated under reduced pressure at 30° C. The residual aqueous phase was extracted with methylene chloride and the combined organic phases were dried, and the solvents were eliminated under reduced pressure. After chromatography on silica (eluent:methylene chloride - methanol, 100-4), 1.30 g of the expected product melting at 142° C. were obtained.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:25][CH3:26])=[C:21]([OH:24])[CH:22]=2)[N:17]=[CH:16][N:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:46]([O:50][C:51]([N:53]1[CH2:58][CH2:57][CH2:56][CH:55](O)[CH2:54]1)=[O:52])([CH3:49])([CH3:48])[CH3:47]>ClCCl>[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:25][CH3:26])=[C:21]([O:24][CH:57]3[CH2:56][CH2:55][CH2:54][N:53]([C:51]([O:50][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:52])[CH2:58]3)[CH:22]=2)[N:17]=[CH:16][N:15]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Reactant: COc1cc2ncnc(Cl)c2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2ncnc(Cl)c2cc1OC1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 40 °C
Reaction time: 8 h
Yield: 45.5 %

Procedure:
Diethyl azodicarboxylate (9.41 ml, 40% solution in toluene) was added to a mixture of 4-chloro-6-hydroxy-7-methoxyquinazoline (2.90 g; prepared as described in Example 16-preparation of starting materials), triphenylphosphine (5.43 g) and tert-butoxycarbonyl-3-hydroxypiperidine (4.15 g) in dichloromethane (75 ml). The resulting solution was heated to 40° C. for 6 hours, and then allowed to stand overnight at room temperature. This was purified by flash column chromatography eluting with isohexane (79%), acetone (20%), and triethylamine (1%) to give 4-chloro-7-methoxy-6-[1-(tert-butoxycarbonyl)piperidin-3-yloxy]quinazoline as a white solid (2.47 g, 53%); 1H NMR Spectrum: (CDCl3) 1.5 (m, 9H); 1.6 (m, 1H); 1.9 (m, 2H); 2.1 (m, 1H); 3.5 (m, 1H); 3.6 (m, 1H); 4.0 (s, 3H); 4.2-3.9 (m, 2H); 4.5 (m, 1H); 7.3 (s, 1H); 7.4 (s, 1H); 8.9 (s, 1H); Mass Spectrum: (M+H): 394.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][NH:7][CH2:8][CH2:9][C:10]=2[N:11]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]([C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[CH:23]=[CH:24][CH2:25]Br)#[N:19].CCOCC>CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:25][CH:24]=[CH:23][C:22]3[CH:27]=[CH:28][CH:29]=[C:20]([C:18]#[N:19])[CH:21]=3)[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: N#Cc1cccc(C=CCBr)c1
Reactant: Nc1nc2c(s1)CCNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: N#Cc1cccc(C=CCN2CCc3nc(N)sc3CC2)c1
Yield: 48 %

Procedure:
Prepared analogously to Example 1 from 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine, potassium carbonate and 3-cyano-cinnamyl bromide (melting point: 52°-55° C.) in anhydrous dimethylformamide for 2 hours at 20° C. Yield: 48% of theory, Melting point: 136°-140° C. (ether).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1>C1COCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][CH:38]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1cccc(O)c1
Reactant: COC(=O)c1ccc(N)cc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc(NC(=O)CCc2cccc(O)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a solution of 3-(3-hydroxyphenyl)-propionic acid (198 mg, 1.19 mmol) in anhydrous THF (5 mL) were added N-methylmorpholine (1.2 equiv.) and isobutylchloroformate (1.2 equiv.) at 0° C. After 30 min, at 0° C., a solution of methyl 4-aminobenzoate (150 mg, 0.99 mmol) in anhydrous THF (1 mL) was added to the reaction mixture. After 5 min the temperature was allowed to warm up to rt and stir overnight. After extraction with EtOAc (100 mL), washing with HCl (0.1N, 50 mL) and a saturated aqueous solution of NaHCO3 (50 mL), the organic layer was dryed over sodium sulfate and evaporated under vacuo to give a yellow oil. Purification by flash chromatography using EtOAc/cyclohexane as eluant and recrystallization from DCM/MeOH/TEA (10/0.4/0.1) gave the title compound as a white solid (32%) in 98.9% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].Cl[C:35]([O:37][CH2:38][C:39]([Cl:42])([Cl:41])[Cl:40])=[O:36]>>[Cl:40][C:39]([Cl:42])([Cl:41])[CH2:38][O:37][C:35]([N:29]1[CH2:28][CH2:27][CH:26]([N:23]2[C:19]3=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]4[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=4)=[C:18]3[CH:25]=[N:24]2)[CH2:31][CH2:30]1)=[O:36]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OCC(Cl)(Cl)Cl)CC2)cc1

Procedure:
4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid 2,2,2-trichloro-ethyl ester was prepared according to General Procedure E by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoro-acetate salt (Intermediate 27) with 2,2,2-trichloroethyl chloroformate (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.96-2.08 (m, 4H), 3.30 (methyl sulfonyl and water peak), 4.11-4.20 (m, 2H), 4.86-4.89 (m, 2H), 5.05-5.10 (m, 1H), 7.59-7.62 (m, 2H), 8.03-8.05 (m, 2H), 8.36 (s, 1H), 8.54 (s, 1H). Mass spectrum MH+=548.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11][CH2:12]O>S(=O)(=O)(O)O>[CH2:11]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[N:3][CH:4]=1)[CH3:12]
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(N)nc1
Yield: 92 %

Procedure:
A solution of 6-aminonicotinic acid (2.0 g, 14.4 mmol) in anhydrous EtOH (70 mL) and concentrated sulfuric acid (14 mL) was heated to reflux for 16 h. The solution was concentrated under reduced pressure, neutralized with saturated aqueous Na2CO3 (50 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic phases were dried (MgSO4), filtered and concentrated to give 6-aminonicotinic acid ethyl ester (2.18 g, 92%) as a white powder. 1H NMR (CDCl3) δ1.37 (t, 3H, J=6.0 Hz), 4.34 (q, 2H, J=7.0 Hz), 4.89 (br s, 2H (NH2)), 6.46 (d, 1H, J=7.5 Hz), 8.02 (d, 1H, J=7.5 Hz), 8.73 (s, 1H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[S:19][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:6]=2[CH:5]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1>>[F:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][N:16]1[CH2:15][CH2:14][CH:13]([NH:12][C:11]2[C:6]3[CH:5]=[C:4]([Cl:3])[S:19][C:7]=3[N:8]=[CH:9][N:10]=2)[CH2:18][CH2:17]1
Reactant: Clc1cc2c(NC3CCNCC3)ncnc2s1
Reactant: Fc1cccc(CBr)c1
Agent: Cl
Product: Fc1cccc(CN2CCC(Nc3ncnc4sc(Cl)cc34)CC2)c1

Procedure:
The title compound was prepared (58 mg, 53%) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine dihydrochloride (100 mg, 0.29 mmol) and 1-(bromomethyl)-3-fluorobenzene (55 mg, 0.29 mmol) by following the general procedure described for Preparation 12. 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.28 (dd, 1H), 7.09 (d, 1H), 7.08 (d, 1H), 6.98 (s, 1H), 6.95 (dt, 1H), 4.85 (d, 1H), 4.19 (m, 1H), 3.49 (s, 2H), 2.87 (d, 2H), 2.23 (dt, 2H), 2.09 (d, 2H), 1.60 (m, 2H); MS (ESI) m/z: Calculated for C18H19ClFN4S, 377.1; Observed: 377.2 (M++1).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:10]=2)[CH:7]=1.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)#[CH:18]>>[F:25][C:21]1[CH:20]=[C:19]([C:17]#[C:18][C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[C:9]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[N:10]=3)[CH:7]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Brc1cnc2nc(N3CCOCC3)nn2c1
Reactant: C#Cc1cccc(F)c1
Product: Fc1cccc(C#Cc2cnc3nc(N4CCOCC4)nn3c2)c1

Procedure:
The title compound, a light brown solid, MS: m/e=324.3 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine (example 47, step 1) and ethynyl-3-fluorobenzene.
Reaction SMILES: [C:1]([C:4]1[C:12]2[N:11]=[C:10]([C:13]3[S:17][C:16]([CH:18]4[CH2:22][CH2:21][CH2:20][N:19]4C(OC(C)(C)C)=O)=[CH:15][CH:14]=3)[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[NH2:2]>ClCCl.C(O)(C(F)(F)F)=O>[NH:19]1[CH2:20][CH2:21][CH2:22][CH:18]1[C:16]1[S:17][C:13]([C:10]2[NH:9][C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:12]=3[N:11]=2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cccc2[nH]c(-c3ccc(C4CCCN4)s3)nc12

Procedure:
A solution of EXAMPLE 34D (2.1 g) in dichloromethane (20 mL) and TFA (5 mL) was stirred at ambient temperature overnight and concentrated. The concentrate was purified by HPLC (Zorbax, C-18, Mobile phase A: 0.1% TFA in water; B: 0.1% TFA in acetonitrile; 0-100% gradient). 1H NMR (CD3OD) δ 2.19-2.27 (m, 1H), 2.27-2.41 (m, 2H), 2.57-2.68 (m, 1H), 3.43-3.57 (m, 2H), 5.01 (dd, J=9.4, 6.9 Hz, 1H), 7.36 (t, J=7.7 Hz, 1H), 7.42 (d, J=4.6 Hz, 1H), 7.73 (dd, J=8.1, 1.1 Hz, 1H), 7.81 (d, J=4.0 Hz, 1H), 7.94 (dd, J=7.7, 0.9 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:32][N:33]1[CH:37]=[C:36]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[N:34]1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:38]([C:36]1[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=1)(=[O:40])=[O:39]
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1cc(S(=O)(=O)Nc2ccc(F)c(Nc3ncccc3-c3ncnc4c3ncn4C3CCCCO3)c2F)cn1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 1-methyl-1H-pyrazole-4-sulfonyl chloride (13 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.