Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][CH3:11].C([O-])(=O)C.[Na+].S(O)(=O)(=O)C.[CH:23]1([NH:29][NH2:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.Cl>C1(C)C=CC=CC=1>[CH:23]1([N:29]2[C:2]3[C:3](=[CH:4][CH:5]=[C:6]([F:8])[CH:7]=3)[C:9]([CH2:10][CH3:11])=[N:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCC(=O)c1ccc(F)cc1F
Reactant: NNC1CCCCC1
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Product: CCc1nn(C2CCCCC2)c2cc(F)ccc12
Temperature: 25 °C
Yield: 97.6 %

Procedure:
To a solution of 1-(2,4-difluoro-phenyl)-propan-1-one (21.29 g, 125.1 mmol) in toluene (120 mL) was added sodium acetate (26.75 g, 326.1 mmol) and cyclohexylhydrazine mesylate (34.0 g, 163 mmol). The reaction mixture was heated to reflux in a Dean-Stark apparatus for 12 hours. The reaction was cooled to room temperature and poured into 1N hydrochloric acid (100 mL). The toluene layer was separated and washed with water (75 mL) and brine (75 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated to yield 30.07 g of 1-cyclohexyl-3-ethyl-6-fluoro-1H-indazole (98% yield). 1H NMR (400 MHz, CDCl3) d 1.33 (t, 3, J=7.7), 1.35-1.44 (m, 2), 1.47-1.96 (m, 8), 2.93 (q, 2, J=7.7), 4.14-4.22 (m, 1), 6.81 (dt, 1, J=8.9, 2.1), 6.99 (dd, 1, J=9.8, 2.1), 7.40 (ddd, 1, J=8.7, 5.2, 0.4). 13C NMR (100 MHz, CDCl3) d 13.97, 20.53, 25.37, 25.84, 32.32, 58.18, 94.77 (d, J=27.4), 109.11 (d, J=26.0), 119.38, 121.75 (d, J=11.5), 139.89 (d, J=13.0), 146.61, 161.95 (d, J=242). IR 2968, 2934, 2856, 1624, 1507, 1174, 1125, 825 cm-1. Analysis calculated for C15H19FN2 : C, 73.14; H, 7.77; N, 11.37. Found: C, 73.33; H, 7.90; N, 11.46.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:8][CH2:9][C:10](O)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:21])=O>>[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:8][CH2:9][C:10]([Cl:21])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CSC(c1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CSC(c1ccccc1)c1ccccc1

Procedure:
2-[(Diphenylmethyl)thio]acetic acid (III), on reaction with thionyl chloride yielded the corresponding 2-[(diphenylmethyl)thio]acetylchloride (IV), which on reaction with ammonia produced 2-[(diphenylmethyl)thio]acetamide (I) which on oxidation with hydrogen peroxide resulted in modafinil (II).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]([C:18]4[O:19][CH:20]=[CH:21][CH:22]=4)=[CH:16][C:15]([C:23](O)=[O:24])=[N:14]3)[CH:8]=2)=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][C:34]2=[O:39])=[CH:29][CH:28]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl.CCN(CC)CC>[O:39]=[C:34]1[CH2:35][O:36][CH2:37][CH2:38][N:33]1[C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:23]([C:15]2[CH:16]=[C:17]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[N:14]=2)=[O:24])=[CH:32][CH:31]=1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Reactant: O=C(O)c1cc(-c2ccco2)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)c1cc(-c2ccco2)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Reaction time: 16 h

Procedure:
To 100 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-furan-2-yl-1H -pyrazole-3-carboxylic acid in 2 ml DCM and 0.1 ml NEt3, 62 mg 4-(4-Amino-phenyl)-morpholin-3-one and 67 mg BOP-Cl were added at RT and the mixture was stirred for 16 h. The mixture was was concentrated under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][CH2:22][C:10]2([N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:13][NH:12][C:11]2=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:26][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][CH2:22][C:10]2([N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:13][N:12]([CH3:26])[C:11]2=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)NCN2c1ccccc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1CN(c2ccccc2)C2(CCCN(C(=O)OC(C)(C)C)C2)C1=O
Temperature: 25 °C

Procedure:
A solution of 4-oxo-1-phenyl-1,3,7-triaza-spiro[4.5]decane-7-carboxylic acid tert-butyl ester (130 mg, 0.45 mmol) in dry THF (3 ml) under nitrogen was cooled to −78° C. and treated with 1M LHMDS in THF (0.55 ml, 0.55 mol). The reaction was allowed to warm to RT for 30 mins before cooling back to −78° C. and adding 2M MeI in THF solution (0.45 ml, 0.9 mmol). The reaction was left to warm to RT overnight. The reaction mixture was diluted with EtOAc (10 ml) and washed with brine (20 ml). The aqueous phase was extracted with EtOAc (10 ml). Organics portions were combined, dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-50% EtOAc in iso-hexane afforded the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C1CCC(N=C=NC2CCCCC2)CC1.[N:24]1([CH2:30][C:31]2[CH:32]=[C:33]([CH:46]=[CH:47][CH:48]=2)[O:34][CH2:35][CH2:36][CH2:37][NH:38][C:39](=[O:45])[CH2:40][S:41][CH2:42][CH2:43][NH2:44])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>ClCCl>[N:24]1([CH2:30][C:31]2[CH:32]=[C:33]([CH:46]=[CH:47][CH:48]=2)[O:34][CH2:35][CH2:36][CH2:37][NH:38][C:39](=[O:45])[CH2:40][S:41][CH2:42][CH2:43][NH:44][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)c1ccco1
Reactant: NCCSCC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CSCCNC(=O)c1ccco1)NCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 0.5 h
Yield: 26.1 %

Procedure:
There was dissolved 1.12 g of 2-furancarboxylic acid in 50 ml of dichloromethane and added 2.06 g (0.01 mol) of DCC under cooling with ice and the mixture was stirred for 30 minutes. Thereto was added 3.65 g (0.01 mol) of N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2-aminoethylthio)acetamide and the mixture was stirred for 18 hours at room temperature. The precipitate was filtrated off, and the filtrate was washed with water and dried over Glauber's salt. Then the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give 1.2 g of the titled compound as crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[S:16](Cl)(=[O:18])=[O:17])([O-:3])=[O:2].[CH3:20][NH:21][CH3:22].C(O)(=O)C>O>[CH3:20][N:21]([CH3:22])[S:16]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:4]=1[N+:1]([O-:3])=[O:2])[NH:11][C:10](=[O:14])[C:9](=[O:15])[NH:8]2)(=[O:18])=[O:17]
Reactant: CNC
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(S(=O)(=O)Cl)cc2[nH]c1=O
Solvent: CC(=O)O
Solvent: O
Product: CN(C)S(=O)(=O)c1cc2[nH]c(=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 81 %

Procedure:
A mixture of 4.58 g (0.015 mole) of 1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-6-quinoxalinesulfonyl chloride and 30 ml of 25% ethanolic dimethylamine is stirred at a temperature between 5° C. and 10° C. for 3 hours, and then allowed to stand for 16 hours. To the reaction mixture 5 ml of acetic acid and 60 ml of water are added, the separated crystals are filtered, washed with water and acetone, dried, dissolved in a slight amount of hot dimethyl sulfoxide and precipitated from this solution with water. Thus 3.80 g (81%) of N,N-dimethyl-1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-6-quinoxaline sulfonamide are obtained, m.p.: 318-332° C.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[CH3:32])[CH2:27][NH2:28]>>[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[CH3:32])[CH2:27][NH:28][C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=2[F:21])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5]
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O
Reactant: Cc1ccc(CN)cc1C
Product: Cc1ccc(CNC(=O)c2nc(-c3c(F)cccc3F)n(C)c(=O)c2O)cc1C

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 3,4-dimethylbenzylamine (68 mg, 0.5 mmol). The title product was obtained as an off-white solid (32.7 mg, 82% yield). 1HNMR (500 MHz, CDCl3) δ: 12.41 (1H, s), 7.74 (1H, br s), 7.51–7.45 (1H, m), 7.10–7.02 (5H, m), 4.51 (2H, d, J=6.10 Hz), 3.40 (3H, s), 2.24 (3H, s), 2.23(3H, s). HRMS (ESI) calcd for C21H20F2N3O3 (M+H): 400.1473; found: 400.01464.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[O:15][CH2:14][C:13]([F:17])([F:16])[CH2:12][O:11]1)C1C=CC=CC=1.[H][H]>[OH-].[Pd+2].[OH-].C(OCC)(=O)C>[F:16][C:13]1([F:17])[CH2:14][O:15][CH:10]([CH2:9][OH:8])[O:11][CH2:12]1
Reactant: [H][H]
Reactant: FC1(F)COC(COCc2ccccc2)OC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: OCC1OCC(F)(F)CO1
Yield: 97.4 %

Procedure:
A mixture of 2-((benzyloxy)methyl)-5,5-difluoro-1,3-dioxane (930 mg, 3.81 mmol), 20% palladium hydroxide (353 mg), and ethyl acetate (30 ml) was stirred in a hydrogen atmosphere at room temperature for 4 hours and 25 minutes. The reaction mixture was filtrated and the filtrate was concentrated under reduced pressure to obtain the title compound (572 mg, 97.4%) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].B.CSC.Cl>C1COCC1>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNC(=O)Cc1ccccc1OC
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: CCCCCCCNCCc1ccccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
N-Heptyl-2-(2-methoxyphenyl)acetamide (2.00 g, 7.594 mmol) was dissolved in THF (10 ml) and was cooled to zero degrees under argon atmosphere. (Methylthio)methane compound with borane (1:1) (1.442 g, 18.984 mmol) was added and the mixture was refluxed for 5 hours. After the mixture was cooled to room temperature, 5 ml HCl (10%) was gently added and the mixture was stirred overnight. The solvent was removed by evaporation. EtOAc (20 ml) was added and the organic phase was washed with K2CO3 (2M, 2×20 ml). The crude was purified by flash cromatography (started with isocratic heptane/EtOAc 50/50 and then the EtOAc concentration was increased to 100%, (silica gel 60 0.004-0.063 mm). The product containing fractions were pooled and the EtOAc was removed by evaporation to give 1.037 g of N-[2-(2-methoxyphenyl)ethyl]heptan-1-amine (yield 54.8%).
Reaction SMILES: N12CCCN=C1CCCCC2.[C:12]([O:16][C:17](=[O:47])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[C:25]#[C:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:44]=[C:43]3[C:38]([C:39]([NH2:45])=[N:40][CH:41]=[N:42]3)=[CH:37][CH:36]=2)[C:30](=[O:46])[CH2:29]1)([CH3:15])([CH3:14])[CH3:13].CN(C)C=O>CC#N.CCOC(C)=O.O>[C:12]([O:16][C:17]([N:18]1[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[CH:25]=[C:26]1[CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:44]=[C:43]3[C:38]([C:39]([NH2:45])=[N:40][CH:41]=[N:42]3)=[CH:37][CH:36]=2)[C:30](=[O:46])[CH2:29]1)=[O:47])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1C#CCN1CCN(Cc2ccc3c(N)ncnc3c2)C(=O)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(CN2CCN(Cc3ccc4c(N)ncnc4c3)C(=O)C2)cc2cnccc21
Temperature: 50 °C
Yield: 85.5 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (37 mg, 0.24 mmol) is added to a suspension containing (3-{3-[4-(4-amino-quinazolin-7-ylmethyl)-3-oxo-piperazin-1-yl]-prop-1-ynyl}-pyridin-4-yl)-carbamic acid tert-butyl ester (59 mg, 0.12 mmol) in anhydrous CH3CN (5 mL) and the mixture is warmed to 50° C. Dimethylformamide (1 mL) is added to solubilize and the homogeneous solution is maintained for 5 h at 50° C. The reaction mixture is diluted with EtOAc (50 mL) and water (50 mL) and the layers are separated. The aqueous layer is extracted twice with EtOAc (25 mL) and the combined organic phase is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to provide 50 mg of the product as a crude solid which is used directly without further purification. 1H NMR (300 MHz, CDCl3) δ1.64 (s, 9H), 2.78 (m, 2H), 3.30 (m, 2H), 3.37 (s, 2H), 3.95 (s, 2H), 4.74 (s, 2H), 6.24 (br s, 2H), 6.63 (s, 1H), 7.40 (dd, J=8.5, 1.6 Hz, 1H), 7.64 (s, 1H), 7.81 (d, J=5.8 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.99 (s, 1H), 8.39 (d, J=5.8 Hz, 1H), 8.58 (s, 1H), 8.77 (s, 1H) ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([N+:12]([O-])=O)=[CH:7][CH:8]=2)[C:3]1=[O:15].[Cl-].[NH4+].[Br:19]Br.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CN(C)C=O.C(OCC)(=O)C.[Fe].C(O)C.O>[NH2:12][C:6]1[C:5]([Br:19])=[C:4]2[C:9]([CH2:10][CH2:11][C:2]([CH3:16])([CH3:1])[C:3]2=[O:15])=[CH:8][CH:7]=1
Reactant: BrBr
Reactant: CC1(C)CCc2ccc([N+](=O)[O-])cc2C1=O
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC1(C)CCc2ccc(N)c(Br)c2C1=O
Yield: 56.8 %

Procedure:
A mixture of Example 362A (1.05 g, 4.79 mmol) in 4:1 ethanol/water (20 mL) was reduced with iron (1.1 g) in the presence of ammonium chloride (0.12 g) using the procedure described in Example 275A. The crude product (0.91 g, 4.79 mmol) was treated with bromine (0.245 mL, 4.79 mmol) in 9 mL of chloroform and 0.9 mL of N,N-dimethylformamide following the procedure described in Example 275B. The obtained hydrobromide salt was treated with 10% sodium hydrogen carbonate in ethyl acetate. The ethyl acetate layer was washed with brine (4×), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 10% ethyl acetate in n-hexane to provide 730 mg of the desired product. MS (ESI(−)) m/e 266 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 6.97 (m, 2H), 5.39 (m, 2H), 2.80 (t, 2H), 1.84 (t, 2H), 1.10 (s, 6H).
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[O:12]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:23](=[O:24])[C:22]3[CH:21]=[CH:20][C:19]([O:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:27][CH:26]=3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(Oc2ccccc2)cc1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 4-phenoxybenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.95 (d, J=13 Hz, 2H), 2.11 (s, 1H), 2.31 (d, J=13 Hz, 2H), 2.38 (s, 2H), 3.49 (s, 2H), 3.59 (s, 4H), 4.38 (s, 1H), 7.00-7.09 (m, 4H), 7.17-7.23 (m, 1H), 7.38-7.44 (m, J=8, 8 Hz, 2H), 7.81-7.89 (m, 2H); MS (APCI/NH3) m/z 349 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[C:25](Br)=[CH:24][C:23]([CH3:27])=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:36]([NH2:40])(=[O:39])[CH:37]=[CH2:38].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[C:25](/[CH:38]=[CH:37]/[C:36](=[O:39])[NH2:40])=[CH:24][C:23]([CH3:27])=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Br)c2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Reactant: C=CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(/C=C/C(N)=O)c2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
50 mg (0.09 mmol) {1-[4-(8-Bromo-6-methyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 13.4 mg (0.19 mmol) acryl amide, 4.86 mg (0.016 mmol) tri-2-tolylphosphane, 2.1 mg (0.009 mmol) palladium(II) acetate and 0.02 mL (0.1 mmol) triethylamine in 0.7 mL degassed acetonitrile were heated in the microwave at 110° C. for 60′. Due to an incomplete reaction additional 13.3 mg acrylamide and 4.2 mg palladium(II) acetate were added, and heating in the microwave was continued for two hours. The reaction mixture was poured on water/saturated ammonium chloride/dichloromethane and vigorously stirred for 30 minutes. The organic phase was separated and the aqueous phase was once more extracted with dichloromethane. The combined organic extracts were washed twice with brine, dried, and the solvent was removed. The crude product (76 mg) was purified by chromatography on silicagel (eluents: hexane/ethyl acetate) yielding 24.2 mg (49.3%) of the desired compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18](Br)=[CH:17][N:16]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:22]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([C:29]5[CH:30]=[CH:31][C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:27][CH:28]=5)=[CH:17][N:16]=4)[CH2:10][CH2:9]3)=[N:6][CH:7]=2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: Brc1ccc(N2CCCN(c3ccc(Br)cn3)CC2)nc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)(C)c1ccc(-c2ccc(N3CCCN(c4ccc(-c5ccc(C(C)(C)C)cc5)cn4)CC3)nc2)cc1
Yield: 42 %

Procedure:
Following the procedure of Example 1, crude crystals were obtained from the 1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (206.0 mg, 0.500 mmol) synthesized in Reference Example 1 and 4-t-butylphenylboronic acid: (226.0 mg, 1.20 mmol). The crude crystals were recrystallized from chloroform-hexane to yield the title compound as colorless needles (melting point: 268.0–270.0° C.) (117.0 mg, yield: 42%).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][N:5]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)[CH2:6][CH2:7][N:8]([CH3:10])[CH3:9]>CO.[Pd]>[CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][N:5]([CH2:6][CH2:7][N:8]([CH3:10])[CH3:9])[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1
Reactant: CN(C)CCN(CCN(C)C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCN(CCN(C)C)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 109.8 %

Procedure:
To a solution containing 1.23 g of product from step 1 (4 mmol) in 20 mL MeOH, was added 0.8 g of Pd (5 wt. % on activated carbon, 0.4 mmol). The resulting suspension was stirred under H2 (50 psi) at room temperature for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to yield the title compound as a colorless oil (1.10 g, 100%). MS (ES+) m/e 251 [M+H]+.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[CH2:16][C@@H:15]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][N:13]2[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[O:23])(=O)=O)=CC=1.[C:36]1(=[O:46])[NH:40][C:39](=[O:41])[C:38]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]12.[K]>CN(C)C=O>[N+:32]([C:29]1[CH:28]=[CH:27][C:26]([CH2:25][O:24][C:22]([N:13]2[CH2:14][C@H:15]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:16][C@H:12]2[CH2:11][N:40]2[C:36](=[O:46])[C:37]3=[CH:45][CH:44]=[CH:43][CH:42]=[C:38]3[C:39]2=[O:41])=[O:23])=[CH:31][CH:30]=1)([O-:34])=[O:33]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: CS(=O)(=O)O[C@@H]1C[C@@H](CN2C(=O)c3ccccc3C2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 60 °C
Reaction time: 7 h
Yield: 78.8 %

Procedure:
A mixture of (2S,4R)-1-p-nitrobenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol p-toluenesulfonate (25 g: 47.3 mmole) and potassium phthalimide (17.52 g: 2 eq.) in dimethylformamide (250 ml) is stirred at 60° C. for 7 hours. The reaction mixture is poured into ice water and filtrated. The resulting precipitate is dissolved in ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is recrystallized from methanol to give (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-phthalimidomethyl-4-methanesulfonyloxypyrrolidine (18.76 g). Yield: 79%. mp. 121° to 123° C. NMR δ(CDCl3) ppm: 2.03 to 2.60(m, 2H), 3.02(s, 3H), 3.50 to 4.15(m, 4H), 4.40 to 4.63(m, 1H), 5.10, 5.29(ABq, J=15 Hz, 2H), 5.10 to 5.30(m, 1H), 7.46 (d, J=9 Hz, 1H), 7.57(d, J=9 Hz, 1H), 7.63 to 7.88(m, 4H), 8.20(d, J=9 Hz, 2H) IR ν (CHCl3) cm-1 : 1773, 1715, 1605.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[C:10]([Cl:12])[C:7]([C:8]#[N:9])=[C:6](I)[C:5]=1[O:14][CH2:15][CH3:16])(=[O:3])[CH3:2].Cl.[CH3:18][O:19][CH:20]1[CH2:23][NH:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([C:4]1[CH:11]=[C:10]([Cl:12])[C:7]([C:8]#[N:9])=[C:6]([N:22]2[CH2:23][CH:20]([O:19][CH3:18])[CH2:21]2)[C:5]=1[O:14][CH2:15][CH3:16])(=[O:3])[CH3:2]
Reactant: COC1CNC1
Reactant: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1I
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: C1COCCO1
Product: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1N1CC(OC)C1
Temperature: 80 °C
Yield: 97.2 %

Procedure:
To a mixture of 4-acetyl-6-chloro-3-ethoxy-2-iodobenzonitrile (50 mg, 0.1 mmol, Example 318, Step 1), 3-methoxyazetidine hydrochloride (21 mg, 0.17 mmol Chem-Impex catalog#20140) and cesium carbonate (70.0 mg, 0.21 mmol) in 1,4-dioxane (4 mL) was added (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (40 mg, 0.07 mmol) and tris(dibenzylideneacetone)dipalladium (0) (60 mg, 0.07 mmol). The reaction mixture was degassed with N2. The reaction was heated at 80° C. for 2 hrs and was monitored by LC/MS. The reaction was allowed to cool to room temperature, was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give the crude product. The product was purified by FCC on silica gel eluting (hexanes: EtOAc 0-70%) gradient to give to 4-acetyl-6-chloro-3-ethoxy-2-(3-methoxyazetidin-1-yl)benzonitrile as clear oil (0.030 g, 70%). LCMS calculated for C15H18ClN2O3(M+H)+: m/z=309.1; found: 309.1.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:13]([NH:15][CH3:16])=[O:14])=[C:10]([CH3:12])[N:11]=[C:5]2[CH:4]=1.[Na].Cl.CO>CN(C=O)C>[OH:2][C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:13]([NH:15][CH3:16])=[O:14])=[C:10]([CH3:12])[N:11]=[C:5]2[CH:4]=1
Reactant: CNC(=O)c1c(C)nc2cc(OC)ccn12
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CO
Product: CNC(=O)c1c(C)nc2cc(O)ccn12
Temperature: 120 °C

Procedure:
To a solution of 7-methoxy-N,2-dimethylimidazo[1,2-α]pyridine-3-carboxamide (985 mg, 4.49 mmol) in DMF (20 ml) was added sodium thioethylate (80% pure, 1.86 g, 18 mmol) and the mixture heated to 120° C. for 2 hours. After cooling to ambient temperature, the reaction was neutralized to pH 6 with 1N HCl and concentrated in vacuo. The residue was dissolved in MeOH/H2O, pre-absorbed onto SiO2, and purified by flash chromatography (eluting with 90/10/1-80/20/5, DCM/MeOH/cNH3) to yield the crude product as a yellow solid, which was titrated with MeOH to yield 7-hydroxy-N,2-dimethylimidazo[1,2-α]pyridine-3-carboxamide 111-B, 700 mg, 78%, as a pale yellow solid.