Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH2:27][C:28](=[O:31])[CH2:29][CH3:30])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22](O)=[O:23])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[NH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([N:54]3[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)=[O:23])[C:17]1=[O:26])[CH2:27][C:28](=[O:31])[CH2:29][CH3:30])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: C1COCCN1
Reactant: CCC(=O)CN([C@H]1CCN([C@@H](C)C(=O)O)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)CN([C@H]1CCN([C@@H](C)C(=O)N2CCOCC2)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](2-oxobutyl)amino]-2-oxopyrrolidin-1-yl}propanoic acid (0.035 g) in DCM (2 ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.044 g), HOBT (0.031 g) and triethylamine (0.064 ml) and the mixture was stirred at room temperature for 30 min. Morpholine (0.02 ml) was added and the resultant mixture stirred at room temperature for 16 h. The mixture was partitioned between DCM and water. The aqueous layer was re-extracted with DCM and the combined, dried (over magnesium sulphate) organic extracts were concentrated under reduced pressure. The residue was purified using mass directed preparative h.p.l.c. to give the title compound (0.008 g) as a white solid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[C:10]1([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:22]([O-])(=O)C.[Na+].C=O>>[C:10]1([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:3]3[C:4]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[NH:1][CH:2]=3)[CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: c1cnc2[nH]ccc2c1
Reactant: CC(=O)[O-]
Agent: C=O
Agent: [Na+]
Product: c1ccc(N2CCN(Cc3c[nH]c4ncccc34)CC2)cc1

Procedure:
1H-pyrrolo[2,3-b]pyridine (47 mg, 0.40 mmol), 1-phenylpiperazine (64.9 mg, 0.48 mmol), sodium acetate (72 mg, 0.53 mmol), and formaldehyde (0.48 mmol) were processed as described in Example 18 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.62 (m, 4H) 3.14 (m, 4H) 4.03 (s, 2H) 5.60 (s, 1H) 7.09 (m, 3H) 7.84 (m, 3H) 8.06 (dd, J=8.31, 1.53 Hz, 1H) 8.20 (dd, J=4.75, 1.70 Hz, 1H). (ESI) m/z 293 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[CH3:31][CH:32]([CH3:36])[CH2:33][CH2:34][NH2:35].Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[CH2:34]([NH:35][C:8](=[O:10])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=1)[CH2:33][CH:32]([CH3:36])[CH3:31]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)CCNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
4-Nitrobenzoic acid (0.8 g, 4.79 mmol) and 1-hydroxybenzotriazole hydrate (1.1 g, 7.18 mmol) in dimethylformamide (20 mL) was treated with N-methylmorpholine (1.8 mL, 16.75 mmol) and 3-methylbutan-1-amine (0.724 mL, 6.22 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.38 g, 7.18 mmol). The reaction mixture was stirred at room temperature for 17 hours. Water was added and the resulting suspension was stirred for 2 hours. The suspension was filtered and the solid collected was washed with water and dried to provide the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:4].[C:15]([NH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C)C.Cl>CN(C)C=O>[CH2:11]1[C:12]2[C:7](=[CH:6][C:5]([C:3](=[O:4])[CH2:2][N:27]3[CH2:28][CH2:29][CH:24]([NH:23][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:25][CH2:26]3)=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: O=C(CCl)c1ccc2c(c1)CCCC2
Agent: CN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(CN1CCC(NC(=O)c2ccccc2)CC1)c1ccc2c(c1)CCCC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 6-chloroacetyl-1,2,3,4-tetrahydro napthalene (20.87 g.), 4-benzamidopiperidine (20.4 g.) and trimethylamine (11.1 g.) in dimethylformamide (200 ml.). was stirred for 3 days at room temperature. The crystals which had formed during this time were then filtered off, washed and dried. A portion of this crystalline solid (4.0 g.) was dissolved in ethanol (50 ml.) and acidified with ethanol hydrogen chloride to give 4.0 g. of the hydrochloride of the title compound, m.p. 270° C. (decomp.). (Found: C, 69.5; H, 7.2; N, 6.8; C24H28N2O2.HCl requires C, 69.8; H, 7.1; N, 6.8%).
Reaction SMILES: C([N:8]1[CH2:14][CH2:13][C:12]2[S:15][CH:16]=[N:17][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1.C(Cl)[Cl:19]>>[ClH:19].[S:15]1[C:12]2[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=2[N:17]=[CH:16]1
Reactant: ClCCl
Reactant: c1ccc(CN2CCc3ncsc3CC2)cc1
Product: Cl
Product: c1nc2c(s1)CCNCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere 1.7 g (12.3 mmol) 1-chloroethyl chloroformiate was added to 2.0 g (8.2 mmol) 6-benzyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine (CAS Registry Number: 1159094-24-2) in 20 mL DCM at 0° C. The reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated and 20 mL anhydrous methanol was added. The reaction mixture was stirred under reflux for 1 h and concentrated. The resulting crude product was washed with DCM, the solid was filtered and dried. Yield: 0.35 g (58% of theory). ESI-MS: m/z=199 (M+H)+; Rt(HPLC): 0.52 min (Method J).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C-:18]#[N:19].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH3:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:18]#[N:19])=[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=1
Reactant: [C-]#N
Reactant: Cc1ccc(CBr)c(OCc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(CC#N)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A two-phase mixture of crude 1-bromomethyl-4-methyl-2-phenylmethoxybenzene (21.84 g, 75 mmol), NaCN (11.0 g, 0.22 mol), tetrabutylammonium bromide (2.4 g, 7.5 mmol), water (25 ml) and CH2Cl2 (50 ml) was stirred at room temperature for 1 hour and the layers were separated. The organic layer was washed well with water to remove tetrabutylammonium salts and after drying (CaCl2) the solvent was removed to give (4-methyl-2-phenylmethoxyphenyl)acetonitrile (17.8 g, 100% crude yield) as an oil.
Reaction SMILES: [C:1]([C:3]1[C:8](F)=[CH:7][C:6]([F:10])=[CH:5][N:4]=1)#[N:2].[NH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.C(OCC)(=O)C>[C:1]([C:3]1[C:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:7][C:6]([F:10])=[CH:5][N:4]=1)#[N:2]
Reactant: N#Cc1ncc(F)cc1F
Reactant: NCCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ncc(F)cc1NCCc1ccccn1
Temperature: 115 °C
Yield: 37.8 %

Procedure:
841 mg of 2-cyano-3,5-difluoropyridine, 880 mg of 2-(2-aminoethyl)pyridine and 1.658 g of potassium carbonate in 12.5 ml of dimethyl sulphoxide are introduced into a 20 ml microwave tube reactor. The mixture is then heated in a microwave for 1 and a half hours at 115° C. The reaction medium is run into 100 ml of water and 100 ml of ethyl acetate. The aqueous phase is re-extracted twice with 50 ml of ethyl acetate. The combined organic phases are washed with water and then with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. After purification by flash chromatography on 70 g of silica gel, elution being carried out with a mixture of ethyl acetate and cyclohexane (40/60 by volume), and the first eluted product being recovered, 549 mg of 2-cyano-5-fluoro-3-(2-pyridin-2-ylethylamino)pyridine are thus obtained in the form of a beige powder, the characteristics of which are the following:
Reaction SMILES: Cl.N1([CH2:8][CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:18][CH3:19])[CH:15]=3)[C:10]2=[O:20])CCCCC1.[C-:21]#[N:22].[K+]>O.Cl>[C:21]([CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:18][CH3:19])[CH:15]=2)[C:10]1=[O:20])#[N:22]
Reactant: COc1ccc2c(c1)CC(CN1CCCCC1)C2=O
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: O
Product: COc1ccc2c(c1)CC(CC#N)C2=O

Procedure:
The starting material is prepared as follows: To the solution of 47.5 g of 2-piperidinomethyl-5-methoxy-1-indanone hydrochloride (m.p. 177°-180°) in 290 ml of water, 13.5 ml of concentrated hydrochloric acid are added, followed by the slow addition of the solution of 21 g of potassium cyanide in 160 ml of water, which is introduced below the surface of the liquid. The mixture is refluxed for 21/2 hours, cooled, the resulting precipitate filtered off and dried, to yield the 2-cyanomethyl-5-methoxy-1-indanone, melting at 117°-120°.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]([N:20]1[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(N(CC)CC)C>ClCCl.O>[Cl:1][C:2]1[N:11]=[C:10]([NH:25][C@H:22]2[CH2:23][CH2:24][N:20]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:21]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(Cl)nc3ccccc23)C1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A solution of 2,4-dichloroquinazoline (0.940 g, 4.70 mmol) in dichloromethane (50 mL) was treated with (S)-(−)-1-boc-3-aminopyrrolidine (0.863 mL, 4.70 mmol) followed by triethylamine (2 mL, 14.20 mmol) and the solution was stirred at room temperature for 36 hours. The mixture was diluted with water (20 mL) and extracted with diethyl ether (2×20 mL). The combined organic extracts were dried (MgSO4) and concentrated to give the title compound as a pale brown solid which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30]>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:15][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=3)[N:14]=2)(=[O:26])=[O:27])=[CH:21][C:20]=1[C:29]([F:32])([F:30])[F:31]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cccc(COCc2ccc(F)cc2)n1
Product: O=S(=O)(Nc1cccc(COCc2ccc(F)cc2)n1)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
This material was prepared in analogy to example 1 from 6-(4-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.058 g) and 4-chloro-3-(trifluoromethyl)-benzenesulfonyl chloride (0.077 g) as a light yellow gum (0.084 g). MS (ESI−): 472.8 ([M−H]−)
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=1)O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:20]1(=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:29])[NH:21]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1.C1COCC1>[Si:1]([O:8][CH2:9][C@@H:10]([N:21]1[C:22](=[O:29])[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]1=[O:30])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](O)c1ccc(Cl)c(F)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.7 %

Procedure:
To a solution of 64 (13.50 g, 44.28 mmol) and THF (150 mL) cooled to 0° C. was added isoindoline-1,3-dione (7.167 g, 48.71 mmol) and PPh3 (17.42 g, 66.42 mmol) followed by the dropwise addition of a 40% solution DEAD (26.15 mL, 66.42 mmol) in toluene. The reaction was warmed to RT and stirred for 20 h. The reaction was concentrated and dissolved in Et2O (might require sonication). The solids were filtered and the filtrate was concentrated. The crude residue was purified by SiO2 chromatography (Biotage 65) eluting with 10% EtOAc/hexane to afford 14.35 g of (74.67%) (S)-2-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)isoindoline-1,3-dione (66).
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1.[CH3:14][CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([CH3:24])=[CH:20][CH:21]=2)[C:16]1=O>O>[CH3:14][C:15]1([CH2:1][OH:4])[CH2:16][C:17]2[C:22](=[CH:21][CH:20]=[C:19]([CH3:24])[CH:18]=2)[CH2:23]1
Reactant: Cc1ccc2c(c1)C(=O)C(C)C2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)CC(C)(CO)C2
Reaction time: 2 h
Yield: 215.1 %

Procedure:
147.53 g of K2CO3, 875 g of toluene and 350 g of 2,6-dimethyl indanone were introduced, under nitrogen, into a Schmizo-type 1.5 l vessel provided with a condenser and a mechanical stirrer. The mixture was heated to 51°. 122.45 g of Formcel® 55% (origin: Hoechst) were then added over a period of 1 h. The mixture was stirred continuously at 51° for 2 h. The reaction medium was then cooled to 24° and 350 g of water were added. After being stirred for 10 mins, the mixture was decanted, then washed 3 times with water. Concentration in vacuo produced 404.71 g of raw product pure to 97.6% (GC).
Reaction SMILES: [O:1]1[CH2:5]CC[CH2:2]1.[CH:6]12B[CH:10]([CH2:11][CH2:12][CH2:13]1)[CH2:9][CH2:8]C2.[OH-:15].[Na+].OO>C(O)C>[CH2:2]1[C:12]2([CH2:11][CH2:10][CH:9]([CH2:8][OH:15])[CH2:6][CH2:13]2)[CH2:5][O:1]1
Reactant: C1CCOC1
Reactant: B1C2CCCC1CCC2
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: OCC1CCC2(CC1)COC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 25 mL round-bottomed flask was added EXAMPLE 351E (568 mg) and EXAMPLE 351F tetrahydrofuran (4.11 mL) to give a colorless solution. 9-Borabicyclo[3.3.1]nonane (0.5 M in tetrahydrofuran, 24.7 mL) was added and the reaction was allowed to stir for 2 hours at room temperature. Ethanol (11 mL) was added followed by aqueous NaOH (5M, 4.11 mL) and then hydrogen peroxide (2.1 mL) was added. The reaction was heated at 50° C. for 2 hours. The mixture was concentrated by rotary evaporation, and diluted with water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3×) and the combined organics were dried (Na2SO4), filtered and concentrated by rotary evaporation. The residue was purified by regular phase flash column chromatography (Analogix, 80 g Grace, 0-70% hexanes/ethyl acetate).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[C:16]1[CH:17]=[N:18][CH:19]=[N:20][CH:21]=1>>[N:18]1[CH:17]=[C:16]([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:21]=[N:20][CH:19]=1
Reactant: Brc1cncnc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cncnc1
Yield: 99 %

Procedure:
tert-Butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (330 mg, 1.6 mmol), prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), and 5-bromopyrimidine (purchased from Acros Scientific) were processed as described in Example 15C to provide the title compound (99% yield). MS (DCI/NH3) m/z 277 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:28]([O:27][C:24]1[CH:25]=[CH:26][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:23]=1)([CH3:30])[CH3:29]
Reactant: CC(C)Oc1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C1=Cc2cc(-c3ccc(OC(C)C)cc3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.80 g), 4-isopropoxyphenyl borate (0.48 g) and potassium carbonate (0.67 g) in toluene/ethanol/water (25/2.5/2.5 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (0.14 g), and the mixture was refluxed for 13 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (ethyl acetate/hexane=1:2) to give colorless crystals of methyl 7-(4-isopropoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (606.5 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5]([NH:7][CH3:8])=O)[CH3:2].C(Cl)(Cl)=O.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[CH2:22][C:23]([NH:25][NH2:26])=O.Cl>ClC(Cl)Cl.C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[N:7]([CH3:8])[C:23]([CH2:22][C:16]2[C:15]([F:14])=[CH:20][CH:19]=[CH:18][C:17]=2[F:21])=[N:25][N:26]=1)=[O:9])[CH3:2]
Reactant: CCOC(=O)C(=O)NC
Reactant: NNC(=O)Cc1c(F)cccc1F
Agent: Cl
Agent: O=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)c1nnc(Cc2c(F)cccc2F)n1C
Reaction time: 2 h

Procedure:
18.6 g (142 mmol) of oxalic acid monomethylamide monoethyl ester are dissolved under a nitrogen atmosphere in 63 ml of trichloromethane, and 59 ml of a 20% solution of phosgene in toluene are added thereto. At a temperature of 5°-10°, 9.2 ml of pyridine are added dropwise. The reaction mixture is then stirred for 2 hours at 0°, nitrogen being blown through the reaction mixture during the second hour. 17.6 g (95 mmol) of 2,6-difluorophenylacetic acid hydrazide are then added. The reaction mixture is subsequently stirred for 40 minutes at room temperature, then poured onto ice-water, acidified with concentrated hydrochloric acid and extracted three times with ether. The acidic aqueous phase is rendered alkaline with concentrated ammonia solution and extracted by shaking three times with dichloromethane. The combined dichloromethane phases are washed twice with water, dried over magnesium sulphate and concentrated by evaporation. The residue is taken up in 160 ml of xylene and stirred under reflux for 9 hours. The reaction mixture is then concentrated and chromatographed over silica gel using ethyl acetate as eluant. The eluate is concentrated by evaporation and the crystalline residue is recrystallised from ethyl acetate/ether. 5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxylic acid ethyl ester of m.p. 127°-128° is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:15][CH3:16])[C:13]=1[OH:14])[CH:6]=[CH:7][C:8]([OH:10])=[O:9].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C)C=O>[CH3:16][O:15][C:12]1[CH:11]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:13]=1[O:14][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1cc(/C=C/C(=O)O)cc(OC)c1O[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 86 %

Procedure:
3,5-dimethoxy-4-hydroxy-cinnamic acid (3 g, 13.38 mmol) and imidazole (2.73 g, 40.14 mmol) were charged in a 500 mL round-bottom flask and dissolved in 15 mL of dimethylformamide. Tert-butyldimethylsilyl chloride (4.23 g, 28.09 mmol) was added thereto at 0° C., followed by stirring for 1 hour. The reaction liquid was concentrated by distillation under reduced pressure and dichloromethane (50 mL) was added thereto, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate, concentrated and dissolved in tetrahydrofuran (59 mL)/methanol (167 mL), and a 0.00035M potassium carbonate aqueous solution (62 mL) was added thereto, followed by stirring for 1 hour. After being concentrated by distillation under reduced pressure, the resulting solid was filtered, washed with water, and dried under vacuum to afford the title compound.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7](O)=[O:8].C(Cl)(=O)C(Cl)=O.[I:17][C:18]1[C:26]2[C:21](=[N:22][CH:23]=[N:24][C:25]=2[NH:27]C(=O)OC(C)(C)C)[N:20]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][CH3:42])=[CH:37][N:36]=2)[N:19]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C=O)C>[NH2:27][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:20]([C:35]3[N:36]=[CH:37][C:38]([N:41]([CH3:42])[C:7](=[O:8])/[CH:6]=[CH:5]/[CH2:4][N:3]([CH3:10])[CH3:2])=[CH:39][CH:40]=3)[N:19]=[C:18]([I:17])[C:26]=12
Reactant: CNc1ccc(-n2nc(I)c3c(NC(=O)OC(C)(C)C)ncnc32)nc1
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C/C=C/C(=O)N(C)c1ccc(-n2nc(I)c3c(N)ncnc32)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a suspension of (E)-4-(dimethylamino)but-2-enoic acid (5) (185 mg, 1.12 mmol) and a drop of DMF in dry DCM (3 mL) was added oxalyl dichloride (427 mg, 3.36 mmol) slowly. The mixture was stirred at room temperature for 2 h and the solvent was removed in vacuo. The freshly generated acid chloride was dissolved in dry DCM (5 mL) and was added dropwise into a solution of tert-butyl 3-iodo-1-(5-(methylamino)pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylcarbamate (64) (400 mg, 0.86 mmol) in DCM (8 mL) at 0° C. The resulting mixture was stirred at room temperature for 3 h. TFA (2 mL) was introduced and the reaction mixture was stirred for 5 h. The solvent was removed and the residue was purified by column chromatography (silica gel, 0 to 7% methanol in dichloromethane) to provide (E)-N-(6-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyridin-3-yl)-4-(dimethylamino)-N-methylbut-2-enamide (65) (300 mg, 73%) as a white solid. LC-MS (ESI): m/z (M+1) 479.
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]([C:7]1[S:8][C:9]([Br:12])=[CH:10][CH:11]=1)=[O:6])C.[OH-].[Na+]>C1COCC1.CO.O>[Br:12][C:9]1[S:8][C:7]([C:5](=[O:6])[C:4]([OH:13])=[O:3])=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(=O)c1ccc(Br)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(=O)c1ccc(Br)s1

Procedure:
(5-Bromothiophen-2-yl)-oxo-acetic acid ethyl ester (45.6 g, 173 mmol) was dissolved in a mixture of 100 ml THF, 100 ml methanol, and 300 ml water, then treated with 10 N NaOH (26 ml, 260 mmol) at room temperature for 20 hours. Volatile solvents were removed by rotary evaporation. The residue was dissolved in 2 L water and extracted with diethyl ether (250 ml). The aqueous layer was acidified to pH 1 with 6 N HCl, and extracted three times with diethyl ether (3×300 ml). The combined diethyl ether extracts were dried over Na2SO4 and concentrated under vacuum to yield Preparation 1a (38.7 g, 95%). The product was then recrystallized from diethyl ether. m.p. 119-120° C.; MS (M−H)−: 235.1; 1H NMR (300 MHz, CDCl3) δ9.00 (1H, br s), 8.15 (1H, d, J=4.2 Hz), 7.16 (1H, d, J=4.2 Hz). 13C NMR (75 MHz, CDCl3) δ173.80, 159.58, 140.14, 137.17, 132.58, 130.48. IR (KBr) 3326, 3124, 1756, 1634, 1415, 1363, 1308, 1253 cm−1.