Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][CH2:7][CH2:8][CH:9]([N:17]=[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].I[CH2:44][CH2:45][CH2:46][CH2:47][B:48]1[O:52][C:51]([CH3:54])([CH3:53])[C:50]([CH3:56])([CH3:55])[O:49]1.O>O1CCCC1>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][CH2:7][CH2:8][C:9]([N:17]=[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:44][CH2:45][CH2:46][CH2:47][B:48]2[O:52][C:51]([CH3:54])([CH3:53])[C:50]([CH3:55])([CH3:56])[O:49]2)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CC1(C)OB(CCCCI)OC1(C)C
Reactant: CC(C)(C)OC(=O)C(CCOc1ccc(Cl)cc1)N=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)(CCOc1ccc(Cl)cc1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
While under a nitrogen atmosphere, a solution of tert-butyl 4-(4-chlorophenoxy)-2-(diphenylmethyleneamino)butanoate (450 mg, 1.0 mmol) in tetrahydrofuran (7 mL) was cooled to −78° C. and treated with sodium bis(trimethylsilyl)amide (2.0 mL, 1.0 M in tetrahydrofuran, 2.0 mmol) in a dropwise manner. After the addition was complete, stirring was continued for 30 minutes and 2-(4-iodobutyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (931 mg, 3.0 mmol) was slowly added to the reaction mixture. Stirring was continued for 2 more hours, and then slowly warmed to room temperature overnight. The resulting solution was poured into water, and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by flash column chromatography (silica gel, 0-15% ethyl acetate in heptane) gave tert-butyl 2-(2-(4-chlorophenoxy)ethyl)-2-(diphenylmethyleneamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate as a colorless oil (486 mg. 77%); 1H NMR (CDCl3, 300 MHz) δH 7.54 (d, J=7 Hz, 2H), 7.36 (m, 4H), 7.18-7.32 (m, 6H), 6.82 (d, J=9 Hz, 2H), 4.19 (m, 1H), 4.04 (m, 1H), 2.39 (ddd, J=14 Hz, J2=9.5 Hz, J3=5.0 Hz, 1H), 2.22 (ddd, J1=13.5 Hz, J2=9.5 Hz, J3=5.0 Hz, 1H), 1.73 (m, 2H), 1.14-1.46 (m, 4H), 1.34 (s, 9H), 1.18 (s, 12H) and 0.76 (t, J=7 Hz, 2H); MS (+CI): m/z for C37H47BClNO5: expected 631.3. found 632.3 (M+H)+, 576.3 (M+H-isobutene)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11](O)[CH2:12][CH2:13][OH:14].CO.C1C(=O)N(Br)C(=O)C1>ClCCl>[CH3:10][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[O:14][CH2:13][CH2:12][CH2:11][O:9]1
Reactant: CC(=O)c1ccc(C)cc1
Reactant: OCCCO
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(C2(C)OCCCO2)cc1
Temperature: 25 °C
Reaction time: 70 h
Yield: 25 %

Procedure:
To a stirred mixture of 4-methylacetophenone (1.3 mL, 10 mmol), triethylformate (2.0 mL, 12 mmol), 1,3-propanediol (2.2 mL, 30 mmol) and dry methanol (1.2 mL) in dry dichloromethane (50 mL) was added NBS (53 mg, 0.30 mmol). The mixture was protected from light and stirred at room temperature under an inert atmosphere of nitrogen for 70 h. After the mixture was washed with saturated sodium bicarbonate solution (20 mL), the aqueous phase was extracted with dichloromethane (3×30 mL). The combined organic solution was washed with water (2×20 mL), brine (1×20 mL), then dried (Na2SO4) and concentrated under reduced pressure. Flash column chromatography of the residue, eluting with 37% aqueous ammonia:ether:hexane (0.02:1:6) afforded 2-methyl-2-(4-methylphenyl)-1,3-dioxane (22) as a colourless oil (480 mg, 24%). 1H nmr (200 MHz, CDCl3) 1.50 (s, 3H, CH3), 1.96-2.25 (m, 2H, OCH2CH2CH2O), 2.37 (s, 3H, ArCH3), 3.70-4.00 (m, 4H, OCH2CH2CH2O), 7.23 (d, J=8.3 Hz, 2H, 2×ArH), 7.33 (d, J=8.3 Hz, 2H, 2×ArH).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1B(O)O>>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 2,4-dichlorophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C16H10Cl2N4, 330. Found, 329, 331.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[S:15][C:16](Br)=[N:17][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][O-:20].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[S:15][C:16]([O:20][CH3:19])=[N:17][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Br)sc2CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc2c(s1)CCN(C(=O)OC(C)(C)C)CC2

Procedure:
1.00 g (3.00 mmol) bromo-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepine-6-carboxylic acid tert-butyl ester, 0.40 g (7.00 mmol) sodium methylate in 15 mL methanol were heated at 100° C. for 4 h under microwave irradiation. The mixture was purified by chromatography.
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=[CH:7][N:8]=1)#[N:2].C(O)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[C:1]([CH2:3][C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)#[N:2]
Reactant: N#CCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: N#CCc1ncc[nH]1
Reaction time: 3 h

Procedure:
2-Cyanomethyl-1-tritylimidazole (25 g) was dissolved in trifluoroacetic acid (70 ml). After stirring for 3 hours, to the reaction mixture was added ethanol (70 ml) and the solvent was removed in vacuo. Resulting solid was collected and washed with diisopropyl ether to give 2-cyanomethylimidazole trifluoroacetate (12.67 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[C:10]([C:13]([OH:15])=O)[C:9]=2[CH3:16])[CH:5]=[CH:6][CH:7]=1.[CH2:17]([N:19]([CH2:25][CH3:26])[CH:20]1[CH2:24][CH2:23][NH:22][CH2:21]1)[CH3:18]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[C:10]([C:13]([N:22]3[CH2:23][CH2:24][CH:20]([N:19]([CH2:25][CH3:26])[CH2:17][CH3:18])[CH2:21]3)=[O:15])[C:9]=2[CH3:16])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)n[nH]c1-c1cccc(Br)c1
Reactant: CCN(CC)C1CCNC1
Product: CCN(CC)C1CCN(C(=O)c2n[nH]c(-c3cccc(Br)c3)c2C)C1
Yield: 91 %

Procedure:
In analogy to the procedure described in example 12D], 5-(3-bromo-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid and 3-(diethylamino)pyrrolidine gave the title compound in 91% yield as off-white foam. MS: 405.2 (MH+, 1 Br).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(C)C=CC=CC=1>CC1C=CC(C)=CC=1>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:11][CH2:12][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCC
Reactant: c1ccccc1
Solvent: Cc1ccccc1
Solvent: Cc1ccc(C)cc1
Product: CCCCCCCCCCCC

Procedure:
When the dispersion of the solid polymer electrolyte was added to organic solvents having a dielectric constant of less than 3, such as n-hexane, benzene, toluene, p-xylene and dodecane having dielectric constants of 1.89, 2.28, 2.38, 2.27 and 2.02, respectively, the solid polymer electrolyte produced a white precipitate and the polarization characteristics of the cells could hardly be taken out.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:23])=[C:4]([C:8]2[CH:9]=[C:10]([CH3:22])[C:11]([N:14]([CH3:21])[C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C.[CH2:28]([O:30][C:31]1(O[Si](C)(C)C)[CH2:33][CH2:32]1)C>CO>[CH3:28][O:30][C:31]1([NH:1][C:2]2[C:3]([CH3:23])=[C:4]([C:8]3[CH:9]=[C:10]([CH3:22])[C:11]([N:14]([CH3:21])[C:15](=[O:20])[C:16]([CH3:18])([CH3:19])[CH3:17])=[N:12][CH:13]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:33][CH2:32]1
Reactant: Cc1cc(-c2cccc(N)c2C)cnc1N(C)C(=O)C(C)(C)C
Reactant: CCOC1(O[Si](C)(C)C)CC1
Solvent: CO
Solvent: CC(=O)O
Product: COC1(Nc2cccc(-c3cnc(N(C)C(=O)C(C)(C)C)c(C)c3)c2C)CC1
Yield: 100 %

Procedure:
To a suspension of 5.70 g of N-[5-(3-amino-2-methyl-phenyl)-3-methyl-2-pyridyl]-N,2,2-trimethylpropanamide in 34.2 ml of methanol were added 4.40 g of acetic acid and 4.32 g of 1-ethoxy-1-trimethylsilyloxycyclopropane and the mixture was refluxed for 7 hours under a nitrogen atmosphere. Concentration of the reaction mixture under reduced pressure afforded 6.98 g of N-(5-{3-[(1-methoxycyclopropyl)amino]-2-methylphenyl}-3-methyl-2-pyridyl)-N,2,2-trimethylpropanamide.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29]([C:32]([O:34]CC)=[CH2:33])[C:28](=[O:37])[N:27]([CH:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(OCC)C>[C:32]([C:29]1[C:28](=[O:37])[N:27]([CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[C:25]2[N:26]=[C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:15][N:16]=3)[N:22]=[CH:23][C:24]=2[C:30]=1[CH3:31])(=[O:34])[CH3:33]
Reactant: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.4 %

Procedure:
Hydrogen chloride gas was bubbled into an ice-bath cooled solution of 4-{6-[8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (4.50 g, 0.00783 mol, prepared as in Example 2) in DCM (100 mL). The resulting suspension was stoppered and stirred at RT overnight, then diluted with diethyl ether (200 mL). The solid was collected by filtration, washed with diethyl ether, and dried to give the hydrochloride salt of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one as a yellow solid (4.01 g, 92%). Melting point 200° C. HPLC, C18 reverse phase, 10%-95% gradient of 0.1% TFA/CH3CN in 0.1% TFA/H2O during 22 minutes: 99.0% at 11.04 minutes. MS (APCI) M++1: calc'd, 448.2, found, 448.3. Anal. calc'd for C24H29N7O2.2.4H2O.1.85 HCl: C, 51.64; H, 6.44; N, 17.56, Cl (total), 11.75. Found: C, 51.31; H, 6.41; N, 17.20; Cl (total), 12.11.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([Cl:17])=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 104.5 %

Procedure:
To a suspension of 5-chloro-2-nitrobenzoic acid (21 g, 100 mmol) in dry methylene chloride (200 mL) at 0° C. were added several drops of DMF, followed by oxalyl chloride (13 mL, 150 mmol). The reaction was warmed to ambient temperature. After 16 hours the solvents were removed and the viscous oil dried in vacuo to afford 23 g (quantitative yield) of 5-chloro-2-nitrobenzoyl chloride; NMR (CDCl3) 8.1 (d, 1), 7.7 (m, 2) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:14]([CH2:18][CH2:19][C:20](Cl)=[O:21])([O:16][CH3:17])=[O:15].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:17][O:16][C:14](=[O:15])[CH2:18][CH2:19][C:20]([C:11]1[CH:10]=[CH:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:13][CH:12]=1)=[O:21]
Reactant: COC(=O)CCC(=O)Cl
Reactant: Fc1ccccc1-c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CCC(=O)c1ccc(-c2ccccc2F)cc1

Procedure:
In a manner similar to Example 2, Step (a), 2-fluoro-biphenyl (6.284 g, 0.0365 mol) was allowed to react with 3-carbomethoxypropionyl chloride (4.95 mL, 0.0402 mol) in the presence of anhydrous aluminum chloride (10.7 g, 0.0802 mol) in dichloromethane to give, after chromatography on silica gel (456 g, 230-400 mesh), eluting with chloroform (15×450 mL), 7.36 g of 4-(2′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a pale yellow solid; mp 75.5-77.5° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:12][CH3:13])=[C:4]([CH2:10]O)[C:5]([CH2:8][CH3:9])=[CH:6][CH:7]=1.S(Cl)([Cl:16])=O>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([CH2:10][Cl:16])[C:3]=1[CH2:12][CH3:13]
Reactant: O=S(Cl)Cl
Reactant: CCc1ccc(Br)c(CC)c1CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1ccc(Br)c(CC)c1CCl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5.84 g (24 mmol) (3-bromo-2,6-diethyl-phenyl)-methanol in 60 ml dichloromethane were added 10 drops N,N-dimethylformamide and drop-wise within 5 minutes 5.71 g (3.5 ml, 5.71 mmol) thionyl chloride. The mixture was stirred at ambient temperature over night, then the volatile parts distilled off under reduced pressure. 1-Bromo-3-chloromethyl-2,4-diethyl-benzene was obtained as an oily residue which was used immediately for the following reaction.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:35][C@@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH2:40][C@@H:36]([F:35])[CH2:37]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1
Reactant: F[C@@H]1CCNC1
Reactant: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(N3CC[C@@H](F)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-1-hydroxycyclohexylmethyl)-amide, DIPEA and (R)-3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.56 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 442 [M+H]
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:14][CH:15]=1
Reactant: C1CNCCN1
Reactant: Cc1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Product: Cc1ccc(-n2c(N3CCNCC3)c(C=O)c3ccccc32)cc1
Yield: 29 %

Procedure:
2-chloro-1-(4-methylphenyl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 1-(4-methylphenyl)-2-(piperazin-1-yl)-1H-indole-3-carboxaldehyde (29% yield). ESI/MS 320 (M+H); RT=2.64 min; NMR (CDCl3) 10.27 (1H, s); 8.27 (1H, d, J=9 Hz); 7.38-7.15 (6H, m); 6.96 (1H, d, J=6 Hz); 3.26 (4H, m); 2.81 (4H, m); 2.47 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH2:9].[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=O)=[CH:15][CH:14]=1)([O-:12])=[O:11]>O=P(Cl)(Cl)Cl>[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17]2[NH:9][C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(F)cc1N
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(-c2nc3ccc(F)cc3[nH]2)cc1

Procedure:
2-(4-Nitrophenyl)-5-fluoro benzimidazole was synthesized as follows: 1,2-diamino-4-fluorobenzene (1.26 g, 10.0 mmole was mixed with 4-nitrobenzoic acid (1.67 g, 9.8 mmole) and dissolved in POCl3 (10 ml) and heated to reflux for 2.5 hours. The reaction mixture was cooled and cautiously poured onto ice. The resulting solid was filtered, washed with NaHCO3 and used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:9]=1.[NH2:34][C:35]1[C:40]([CH:41]([OH:47])[C:42]([N:44]([CH3:46])[CH3:45])=[O:43])=[CH:39][C:38](Br)=[CH:37][N:36]=1.C(=O)(O)[O-].[Na+]>C(#N)C.O1CCCC1>[NH2:34][C:35]1[C:40]([CH:41]([OH:47])[C:42]([N:44]([CH3:45])[CH3:46])=[O:43])=[CH:39][C:38]([C:14]2[CH:15]=[C:16]3[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[CH:9][N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])[C:11]3=[N:12][CH:13]=2)=[CH:37][N:36]=1
Reactant: CN(C)C(=O)C(O)c1cc(Br)cnc1N
Reactant: CC1(C)OB(c2cnc3c(c2)c(-c2ccccc2F)cn3COCC[Si](C)(C)C)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CN(C)C(=O)C(O)c1cc(-c2cnc3c(c2)c(-c2ccccc2F)cn3COCC[Si](C)(C)C)cnc1N
Temperature: 80 °C
Yield: 39.3 %

Procedure:
3-(2-Fluoro-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (289 mg, 0.617 mmol), 2-(2-amino-5-bromo-pyridin-3-yl)-2-hydroxy-N,N-dimethyl-acetamide (168.5 mg, 0.617 mmol) and dichloro[1,1′-bis(diphenyl-phosphino)ferrocene]palladium(II) dichloromethane adduct (25 mg, 0.031 mmol) were combined in 1:1 acetonitrile/tetrahydrofuran (4 mL) under nitrogen. Saturated sodium bicarbonate was added (4 mL), also under nitrogen, and the mixture was capped and heated for 18 h at 80° C. After cooling, the aqueous layer was removed and the organic layer was purified by silica gel chromatography using DCM and MeoH as eluent to afford 2-{2-Amino-5-[3-(2-fluoro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-3-yl}-2-hydroxy-N,N-dimethyl-acetamide (130 mg, 39.3%). MS: m/z 536 (M+H+).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][C:11](=[CH:13][C:14]#[N:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:16]1[CH:20]=[C:19]([C:21]2[C:22]3[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]=3[N:24]=[CH:25][N:26]=2)[CH:18]=[N:17]1.N12CCCN=C1CCCCC2>C(#N)C>[CH2:1]([O:8][CH:9]1[CH2:12][C:11]([CH2:13][C:14]#[N:15])([N:16]2[CH:20]=[C:19]([C:21]3[C:22]4[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]=4[N:24]=[CH:25][N:26]=3)[CH:18]=[N:17]2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC=C1CC(OCc2ccccc2)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(OCc5ccccc5)C4)c3)ncnc21
Temperature: 50 °C

Procedure:
To a mixture of [3-(benzyloxy)cyclobutylidene]acetonitrile (0.1 g, 0.0005 mol) and 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.1 g, 0.0003 mol) in acetonitrile (5 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.05 mL, 0.0003 mol) under nitrogen. The mixture was heated at 50° C. overnight, then concentrated under reduced pressure. The residue was purified with combiflash (silica gel, 0-55% EtOAc/Hex) to give the desired product as cis- and trans-isomer mixture. LCMS calculated for C28H35N6O2Si(M+H)+: 515.3; Found: 515.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.[CH3:11][O:12][C:13](=[O:18])[C:14](Br)([CH3:16])[CH3:15].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:11][O:12][C:13](=[O:18])[C:14]([O:8][C:5]1[C:4]([CH:9]=[O:10])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)([CH3:16])[CH3:15]
Reactant: COC(=O)C(C)(C)Br
Reactant: O=Cc1cc(Cl)cnc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Oc1ncc(Cl)cc1C=O
Temperature: 126 °C
Yield: 47.2 %

Procedure:
A mixture of 5-chloro-2-hydroxy-pyridine-3-carbaldehyde (8 g, 51 mmol), 2-bromo-2-methyl-propionic acid methyl ester (27.6 g, 153 mol), Cs2CO3 (28 g, 86.7 mol) in DMF (80 mL) was heated at 126° C. for 3 h. After cooled to room temperature, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried and concentrated. The residue was purified by flash column to give the title compound (6.2 g).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[CH:15]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[Yb]>C(Cl)Cl>[OH:1][C@@H:2]([CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[CH:15]=1)[CH2:3][N:19]1[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1nc2cc(OC[C@H]3CO3)ccc2s1
Agent: [Yb]
Solvent: ClCCl
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(C(=O)OC(C)(C)C)CC3)ccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-[((2R)oxiran-2-yl)methoxy]-2-methylbenzothiazole, a compound of formula (3) (6.2 g, 28 mmol), and tert-butyl 1-piperazinecarboxylate, a compound of formula (4) (5.7 g, 31 mmol), in methylene chloride (200 ml), was added ytterbium (111) trifluoromethanesulfonate (1.73 g, 28 mmol). The resulting solution was allowed to stir at room temperature overnight. The solvent was evaporated (in vacuo), to yield a semi-solid, which was chromatographed on silica gel, eluting with 5% methanol/methylene chloride, to yield tert-butyl 4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinecarboxylate as a clear oil (9.5 g, 23 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[NH2:10][CH:11]([CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:12]([NH:14][C:15]1([C:22]#[N:23])[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)=[O:13].C(N(CC)C(C)C)(C)C>C(#N)C>[C:22]([C:15]1([NH:14][C:12](=[O:13])[CH:11]([NH:10][C:2]2[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=2)[CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]1)#[N:23]
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Reactant: N#Cc1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN1CCC(C#N)(NC(=O)C(CC2CCCCC2)Nc2nccc(C#N)n2)CC1
Yield: 52 %

Procedure:
2-Chloro-4-pyrimidinecarbonitrile (0.3 mmol, Daves, G. D. Jr., O'Brien, D. E., Cheng, C. C. J. Het. Chem, 1964, 1, 130) and 2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide (0.7 mmol) were dissolved in acetonitrile (10 mL) containing N,N-diisopropylethylamine (0.6 mmol). The solution was heated to a gentle reflux for 17 h. The volatiles were evaporated and the residue was subjected to chromatography (silica gel, eluant=EtOAc then MeOH). The methanolic fraction was concentrated to a colorless solid which was rechromatographed (10% MeOH/EtOAc) to afford the title compound as a colorless solid (52%). The material was recrystallized from dichloromethane/petroleum ether.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[N+:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])([O-])=[O:11].C1N2CCN(CC2)C1>C(O)C>[CH2:1]([CH:2]1[O:11][N:10]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:3]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: C=CCc1ccccc1
Agent: C1CN2CCN1CC2
Solvent: CCO
Product: CCOC(=O)C1=NOC(Cc2ccccc2)C1
Temperature: 80 °C
Yield: 84.3 %

Procedure:
To a mixture of allylbenzene (0.73 mL; 5.39 mmol) and ethyl 2-nitroacetate (1.53 mL; 13.48 mmol) in ethanol (12 mL) in an Ace pressure tube was added 1,4-diazobicyclo[2.2.2]octane (DABCO, 0.106 g; 0.92 mmol). The tube was heated at 80° C. for 60 h. The mixture was evaporated. The flash chromatography on silica gel (eluent: 15 to 100% of dichloromethane in heptane) of the residue provided 1.06 g (85%) of ethyl 5-benzyl-4,5-dihydroisoxazole-3-carboxylate as an oil.