Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([CH2:12][C:13]([NH:15][CH:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:14])[CH:9]=[CH:8][C:5]=1[CH2:6]Cl)[CH3:2].[C-:35]#[N:36].[Na+].O>CS(C)=O>[CH2:1]([O:3][C:4]1[CH:11]=[C:10]([CH2:12][C:13]([NH:15][CH:16]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:14])[CH:9]=[CH:8][C:5]=1[CH2:6][C:35]#[N:36])[CH3:2]
Reactant: [C-]#N
Reactant: CCOc1cc(CC(=O)NC(c2ccccc2)c2ccccc2N2CCCCC2)ccc1CCl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1cc(CC(=O)NC(c2ccccc2)c2ccccc2N2CCCCC2)ccc1CC#N
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A solution of 2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzyl chloride (2.6 g, 5.45 mmol) in dimethylsulphoxide (10 ml) is added dropwise at 50°-60° C. to sodium cyanide (0.32 g, 6.5 mmol) in dimethylsulphoxide (40 ml). The mixture is then stirred for 5 hours at 60° C., added to water and extracted with chloroform. The extract is concentrated by evaporation in vacuo. The residue is purified by column chromatography on silica gel (toluene/ethyl acetate=5/1).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].[CH:16]([OH:19])([CH3:18])[CH3:17]>>[CH:16]([O:19][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])([CH3:18])[CH3:17]
Reactant: CC(C)O
Reactant: N#Cc1ccc(C(F)(F)F)cc1F
Agent: [H-]
Agent: [Na+]
Product: CC(C)Oc1cc(C(F)(F)F)ccc1C#N
Temperature: 50 °C

Procedure:
The 2-fluoro-4-(trifluoromethyl)-benzonitrile (0.5 mL, 3.59 mmol) was added in small portion to a mixture of NaH 60% (4 mol eq) in isopropanol (10 mL). The reaction mixture was heated at 50° C. overnight. The solvent was distilled and water was added to the residue. The aqueous solution was extracted with EtOAc (3×25 mL) and the organic phases were evaporated at reduced pressure to give e as a white solid (0.84 g, quantitative yield). 1HNMR (DMSO, 200 MHz) δ 1.23 (s, 3H), 1.34 (s, 3H), 4.99 (m, 1H), 7.44 (m, 2H), 8.01 (d, 1H, J=8).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]1[C:24]([N:26]([CH2:28][C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH3:27])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[NH2:33][CH2:32][C:29]([CH3:31])([CH3:30])[CH2:28][N:26]([CH3:27])[C:24]([C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]=1[C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1)=[O:25]
Reactant: CN(CC(C)(C)C#N)C(=O)c1c(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(CC(C)(C)CN)C(=O)c1c(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
To a stirred solution of SC-187 (31 mg, 0.276 mmol) in dry MeOH (3 mL) was added CoCl2 (54 4, 1.382 mmol) under an inert atmosphere. NaBH4 (199 mg, 5.25 mmol) was added in three equal portions under a nitrogen atmosphere at −5° C. The grey reaction mixture was stirred at room temperature during 30 min. and quenched with ice (20 mL) and aqueous 0.5 M KHSO4 (20 mL). DCM (10 mL) was added and both layers were filtered over Celite. The aqueous layer was extracted twice with DCM (10 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification was performed by flash chromatography (silica, CH2Cl2/MeOH, 9:1). The appropriate fractions were combined and solvents removed in vacuo. This product was combined with the crude batch from a previous experiment performed under the same reaction conditions. In this previous experiment SC-187 (14 mg, 0.023 mmol, purity: 76%), MeOH (1 mL), CoCl2 (5.72 μL, 0.148 mmol) and NaBH4 (21.2 mg, 0.561 mmol) were used. Further purification was performed by flash chromatography (silica, DCM/MeOH/Et3N, 9:1:0.1). The appropriate fractions were combined and solvents removed in vacuo. Concentration in vacuo gave SC-188 (67 mg, 46%) as a green oil.
Reaction SMILES: [CH2:1]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>CS(C)=O>[CH2:8]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCNCCCCCC
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CS(C)=O
Product: CCCCCCN(CCCCCC)c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 81.6 %

Procedure:
To a flask equipped with a magnetic stirrer, reflux condenser, and a nitrogen inlet was added di-n-hexylamine (14.1 grams, 0.3 moles), 1-fluoro-4-nitrobenzene (14.1 grams, 0.1 moles) and anhydrous methyl sulfoxide (40 ml). The contents of the flask were heated at 100° C. for 20 hours; cooled to room temperature; partitioned between diethyl ether (300 ml) and water (100 ml); filtered. The ether layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield a yellow oil containing excess dihexylamine. The yellow oil was purified by passing through a short column of silica gel and elating with hexane (300 ml) to yield 25.0 grams of product as a yellow oil. 1H NMR (CDCl3) δ 8.1(d, 2H), 6.5(d, 2H), 3.3 5(t, 4H), 1.6(pent, 4H), 1.2-1.4(m, 12H), 0.9(t, 6H).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:16])[C:7]2=[O:15].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[C:17]([O:21][C:22]([N:24]1[CH2:25][CH2:26][N:27]([CH:30]2[CH2:35][CH2:34][N:33]([C:2]3[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]4[C:3]=3[CH2:4][CH2:5][N:6]([CH3:16])[C:7]4=[O:15])[CH2:32][CH2:31]2)[CH2:28][CH2:29]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CN1CCc2c(F)ccc([N+](=O)[O-])c2C1=O
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCc2c(N3CCC(N4CCN(C(=O)OC(C)(C)C)CC4)CC3)ccc([N+](=O)[O-])c2C1=O
Temperature: 85 °C
Reaction time: 12 h
Yield: 41 %

Procedure:
A mixture of 5-fluoro-2-methyl-8-nitro-3,4-dihydro-2H-isoquinolin-1-one (11.65 g, 0.052 mol), 4-piperidin-4-yl-piperazine-1-carboxylic acid tert-butyl ester (28.0 g, 0.1039 mol), K2CO3 (8.98 g, 0.065 mol) in DMSO (350 mL) was stirred at 85° C. for 12 hours. After cooling to room temperature, ice-water (500 mL) was added. The mixture was extracted with AcOEt. The organic layer was washed with water followed by brine, dried over Na2SO4 and evaporated. The residue was purified by silica gel column chromatography (AcOEt; then AcOEt/MeOH=6/1) to give 10.09 g of the desired product 4-[1-(2-methyl-8-nitro-1-oxo-1,2,3,4-tetrahydro-isoquinolin-5-yl)-piperidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester as pale yellow solid in 41% yield.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:9][CH2:10][C:11]([OH:13])=O)=[N:6][C:7]=1[Br:8].[CH3:14][N:15](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CN>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:9][CH2:10][C:11]([NH:15][CH3:14])=[O:13])=[N:6][C:7]=1[Br:8]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Nc1ncc(CCC(=O)O)nc1Br
Agent: CN
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)CCc1cnc(N)c(Br)n1
Reaction time: 3 h
Yield: 74 %

Procedure:
To a solution of 3-(5-amino-6-bromopyrazin-2-yl)propanoic acid (32 mg, 0.130 mmol) in DMF (1300 μL) was added TBTU (62.6 mg, 0.195 mmol), DIEA (68.1 μL, 0.390 mmol), and methanamine hydrochloride (9.66 mg, 0.143 mmol). The reaction mixture was stirred for 3 h. The reaction mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude 3-(5-amino-6-bromopyrazin-2-yl)-N-methylpropanamide (74%) was obtained and was used for the next step without further purification. LCMS (m/z): 259/261 (MH+), 0.35 min.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([O:4][C:5]([N:7]([CH2:12][CH3:13])[CH2:8][C:9]([OH:11])=[O:10])=[O:6])[CH3:3].[CH2:15](O)[CH3:16].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH2:15]([O:10][C:9](=[O:11])[CH2:8][N:7]([C:5]([O:4][C:2]([CH3:14])([CH3:1])[CH3:3])=[O:6])[CH2:12][CH3:13])[CH3:16]
Reactant: CCO
Reactant: CCN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN(CC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a 3° C. solution of 86 g (423 mmole) of N-[(1,1-dimethylethoxy)carbonyl]-N-ethylglycine, 21.4 g (465 mmole) of ethanol and 5.17 g (42.3 mmole) of 4-dimethylaminopyridine in 600 mL of dichloromethane is added 47 g (46.2 mmole) of triethylamine, followed by portionwise addition of 89.1 g (46.5 mmole) of 3-N,N-dimethylaminopropylethylcarbodiimide hydrochloride. The stirred mixture is allowed to warm to ambient temperature and stir overnight. The reaction mixture is washed with water, saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give N-[(1,1-dimethylethoxy)carbonyl]-N-ethylglycine ethyl ester (88 g) as an oil. MS (FAB) 232 (M+H)+.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.[CH3:9][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>O1CCCC1>[CH3:9][C:4]1([C:7]#[N:8])[CH2:5][CH2:6][S:1][CH2:2][CH2:3]1
Reactant: N#CC1CCSCC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C#N)CCSCC1
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
A solution of tetrahydro-thiopyran-4-carbonitrile (3.05 g, 24 mmol) in anhydrous tetrahydrofuran (60 ml) was cooled to −78° C. and treated with lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 26.4 ml, 26.4 mmol) dropwise. After 30 minutes of stirring, iodomethane (1.8 ml, 29 mmol) was added dropwise. The cooling bath was removed, and the reaction mixture was allowed to slowly rise to room temperature and stir overnight. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving an orange oil. The oil was purified by silica gel chromatography using 5-50% EtOAc in hexanes as eluant to provide 1.81 g (53%) of 4-methyl-tetrahydro-thiopyran-4-carbonitrile as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=2[S:8][CH:7]=1)[CH3:2].CN(C=O)C.[Cl:22][C:23]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:24]=1[CH2:25]Cl.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:25][C:24]3[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:23]=3[Cl:22])=[CH:14][C:9]=2[S:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1csc2cc(O)ccc12
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1csc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Reaction time: 16 h
Yield: 84.2 %

Procedure:
To a mixture of ethyl(6-hydroxy-1-benzothiophen-3-yl)acetate (11.0 g) and DMF (200 mL) were added 2,4-dichlorobenzyl chloride (10.9 g) and K2CO3 (9.60 g). The mixture was stirred at 20° for 16 h. The mixture was diluted with EtOAc, and washed successively with water and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE) to give the title compound (15.5 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].C([O-])([O-])=O.[K+].[K+].[F:22][C:23]([F:40])([F:39])[C:24]1[CH:25]=[C:26]([NH:34][C:35](=[O:38])[CH2:36]Cl)[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1>CC#N>[F:22][C:23]([F:39])([F:40])[C:24]1[CH:25]=[C:26]([NH:34][C:35](=[O:38])[CH2:36][N:8]2[C:9](=[O:11])[C:10]3[C:2]([CH3:1])=[C:3]([C:12]([O:14][CH3:15])=[O:13])[S:4][C:5]=3[N:6]=[CH:7]2)[CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=1
Reactant: O=C(CCl)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)c1sc2nc[nH]c(=O)c2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1sc2ncn(CC(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c(=O)c2c1C
Yield: 93.9 %

Procedure:
To a suspension of methyl 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate (1.62 g, 7.2 mmol) in CH3CN (35 mL) was added K2CO3 (1.0 g, 7.24 mmol), KI (1.2 g, 7.23 mmol), and N-(3,5-bis(trifluoromethyl)phenyl)-2-chloroacetamide 1 (2.2 g, 7.19 mmol). The reaction mixture was refluxed overnight and quenched with H2O (100 mL). The resultant precipitate was filtered and dried to afford 3.33 g of methyl 3-(2-(3,5-bis(trifluoromethyl)phenylamino)-2-oxoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate, as a solid (yield: 90%).
Reaction SMILES: [C:1]([C:5]1[CH:29]=[CH:28][C:8]([CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=3)[N:12]([CH3:26])[C:11]2=[O:27])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:31]([CH3:38])([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:35]([O:34][C:32](=[O:33])[C:31]([O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][CH2:15][CH:13]2[CH2:14][N:10]([CH2:9][C:8]3[CH:28]=[CH:29][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=3)[C:11](=[O:27])[N:12]2[CH3:26])=[CH:19][C:20]=1[CH3:25])([CH3:38])[CH3:37])[CH3:36]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1cc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)cc1C
Temperature: 50 °C
Yield: 87.9 %

Procedure:
1-(4-tert-Butyl-benzyl)-4-[3-(4-hydroxy-3-methyl-phenyl)-propyl]-3-methyl-imidazolidin-2-one (0.060 g, 0.152 mmol) is dissolved in DMF (1.5 mL), to it is added ethyl 2-bromoisobutyrate (0.141 g, 0.760 mmol) followed by potassium carbonate (0.105 g, 0.760 mmol). After heating at 50° C. overnight, the reaction mixture is diluted with ethyl acetate (2 mL), washed with water (2 mL), the separated organic layer is passed through a chem elut tube, and the tube is washed with more DCM (50 mL). Evaporation of solvent followed by chromatography on silica gel, (gradient elution 0-40% ethyl acetate in hexane) to provide an oil (0.068 g, 88%). Mass [EI+] 510 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[C-:11]#[N:12].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:11]#[N:12]
Reactant: ClCc1cccc(Cl)c1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,3-Dichlorobenzylchloride (5.0 g, 25.5 mmol) was dissolved in 100 ml DMSO. 9.2 g NaCN (188 mmol) were added and the mixture stirred at room temperature for 16 hours. The reaction mixture was diluted with water, and the product extracted with ether. The organic layers were washed with water (2×) and brine, then dried over magnesium sulfate, filtered and concentrated. The product was used as. Crude yield˜quantitative. An analytical sample was purified by column chromatography on silica, using a gradient from 10% to 75% dichloromethane in hexanes as eluent. The combined aqueous layers and wash liquids were treated with 100 ml bleach to oxidize the excess cyanide to less toxic materials.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[CH:23]1([C:28]#[C:29][C:30]#[N:31])[CH2:27][CH2:26][CH2:25][CH2:24]1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>>[CH:23]1(/[C:28](/[N:1]2[CH:5]=[C:4]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH:3]=[N:2]2)=[CH:29]/[C:30]#[N:31])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: N#CC#CC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(/C(=C\C#N)C4CCCC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a stirred solution of 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (17, 7.260 g, 23.01 mmol) and 3-cyclopentylprop-2-ynenitrile (8, 6.140 g, 34.52 mmol, 1.5 equiv) in N,N-Dimethylformamide (DMF, 40.0 mL, 516 mmol) at room temperature was added solid potassium carbonate (K2CO3, 318 mg, 2.30 mmol, 0.1 equiv). The resulting reaction mixture was stirred at room temperature for 30 min. When LCMS showed the reaction was deemed complete, the reaction mixture was quenched with water (80 mL), extracted with EtOAc (2×150 mL). The combined organic layers were washed with water (80 mL) and brine (50 mL), dried over magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0-30% EtOAc/hexane gradient elution) to give (Z)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylonitrile (19, 8.256 g, 10.0 g theoretical, 82.6% yield) as a colorless syrup. For 19: 1HNMR (CDCl3, 300 MHz) δ ppm 9.15 (bs, 1H), 8.96 (s, 1H), 8.56 (s, 1H), 7.51 (d, 1H, J=3.5 Hz), 6.93 (d, 1H, J=3.5 Hz), 5.75 (s, 2H), 5.29 (s, 1H), 3.62 (m, 1H), 3.60 (t, 2H, J=8.2 Hz), 2.16 (m, 2H), 1.81 (m, 4H), 1.59 (m, 2H), 0.98 (t, 2H, J=8.2 Hz), 0.00 (s, 9H); C23H30N6OSi (MW, 434.61), LCMS (EI) m/e 435.2 (M++H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.[Cl:9]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:9][C:5]1[S:1][CH:2]=[C:3]([C:6]([OH:8])=[O:7])[CH:4]=1
Reactant: O=C(O)c1ccsc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: O=C(O)c1csc(Cl)c1
Yield: 67.4 %

Procedure:
Thiophene-3-carboxylic acid (17.51 g, 136.6 mmol) and 1-chloro-pyrrolidine-2,5-dione (23.7 g) was refluxed in acetic acid (200 ml) for 4 h under argon before pouring onto water (700 ml). Repeated extraction with several small portions of DCM, followed by back extraction from the combined organics with several small portions of 2 M aqueous sodium hydroxide, gave a combined alkaline aqueous solution that was washed with DCM before acidified with conc. HCl to precipitate the crude material. This precipitate was recrystallized from water to yield 14.98 g of the title compound as a grey solid contaminated with approximately 20 mol % of a dichlorinated byproduct as judged from MS and 1H-NMR. 1H NMR (DMSO-d6) d (ppm): 8.15 (d, 1H), 7.37 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[CH2:11]([O:13][C:14](=[N:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH:29]([F:31])[F:30])(=[O:21])=[O:20])OCC)[CH3:12]>O1CCCC1.CCOCC>[F:31][CH:29]([F:30])[O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([NH:18][C:14](=[N:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1)[O:13][CH2:11][CH3:12])(=[O:21])=[O:20]
Reactant: CCOC(=NS(=O)(=O)c1ccccc1OC(F)F)OCC
Reactant: COc1cc(C)nc(N)n1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=Nc1nc(C)cc(OC)n1)NS(=O)(=O)c1ccccc1OC(F)F
Temperature: 25 °C

Procedure:
To a solution of 11.2 g (0.1 mol) of potassium tertbutylate in 125 ml of tetrahydrofuran are added at room temperature, with stirring, 13.9 g (0.1 mol) of 2-amino-4-methoxy-6-methylpyrimidine. Stirring is maintained for 2 hours at room temperature, and 32.3 g (0.1 mol) of N-(2-difluoromethoxy-benzenesulfonyl)-imido carbonic acid diethyl ester (obtained according to Example 1) are then added, the reaction mixture being stirred for a further 20 hours. The mixture is subsequently concentrated by evaporation, and the residue is taken up in water and rendered acid with hydrochloric acid. The acid solution is extracted with ehtyl acetate; the organic phases are then collected, dried, and concentrated by evaporation to leave a solid residue, which is suspended in ether and again filtered off. The yield is 34.5 g (83% of theory) of the above sulfonylisourea, m.p. 131°-133° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[NH2:15][C:16]1C=CC=C[CH:17]=1.C=O>C(O)C>[O:7]1[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[CH:17]=[CH:16][NH:15]1
Reactant: Nc1ccccc1
Reactant: Oc1ccccc1
Agent: C=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: C1=Cc2ccccc2ON1
Yield: 80.5 %

Procedure:
At room temperature, phenol was dissolved in anhydrous ethanol; the pH was adjusted to 8-10; toluene, aniline and formalin were added according to the molar ratio of phenolic hydroxyl group:amine group:aldehyde group of 1:1:2. After being homogeneously stirred, the mixture was heated and refluxed, reacted for 4 h to vacuum distill off ethanol, water, toluene, and placed in a cooling unit. Butanone was added to obtain a yellowish, translucent viscous body. The viscous body was washed, purified and dried to obtain a benzoxazine intermediate having the following structural formula, wherein the yield is 80.5%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[CH3:13])=[N:10][CH:9]=[CH:8][CH:7]=2.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cnc2cccnc2c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cnc2cccnc2c1CBr
Temperature: 80 °C

Procedure:
To 3-methoxy-4-methyl-1,5-naphthyridine (0.26 g) dissolved in carbontetrachloride (6 ml) was added N-bromosuccinimide (1.2 eq) and benzoyl peroxide (0.3 eq) and heated at 80° C. for 4 h. The reaction was partitioned between satd. NaHCO3 and DCM, and the DCM layer then dried over Na2SO4 to give the title compound (120 mg) after concentration. MS (ESI+) for m/z 252 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:37]=[CH:36][C:15]([O:16][C:17]2[C:18]([CH:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)=[N:19][CH:20]=[CH:21][N:22]=2)=[CH:14][CH:13]=1)=[O:11].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:37]=[CH:36][C:15]([O:16][C:17]2[C:18]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:19][CH:20]=[CH:21][N:22]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(Oc2nccnc2C2CCNCC2)cc1)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a flask containing tert-butyl 4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidine-1-carboxylate (230 mg, 0.460 mmol) is added chloroform (5 mL) and 2,2,2-trifluoroacetic acid (0.709 mL, 9.21 mmol). The reaction was stirred at rt 18 h. The solution was concentrated, followed by azeotropic removal of residual trifluoroacetic acid by concentration from toluene (5 mL×2). The crude salt was freebased by dissolving in MeOH and application to a 5 g Bondesil-SCX ion exchange column. Elution of the product with NH3 in MeOH (2.0 M) and concentration of the product containing fractions gives (1H-benzo[d]imidazol-2-yl)(4-(3-(piperidin-4-yl)pyrazin-2-yloxy)phenyl)methanone as a brown solid. MS (ESI, pos. ion) m/z: 400.0 (M+1). IC50 (uM) +++++.