Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[Li]CCCC.[F:12][C:13]([F:18])([F:17])[C:14]([CH3:16])=[O:15].[NH4+].[Cl-]>CCOCC>[F:12][C:13]([F:18])([F:17])[C:14]([CH3:16])([OH:15])[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(=O)C(F)(F)F
Reactant: C#C[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CC(O)(C#C[Si](C)(C)C)C(F)(F)F
Reaction time: 0.5 h

Procedure:
To a solution of (trimethylsilyl)acetylene (2.80 mL, 20.2 mmol) in Et2O (25 mL) at −78° C., was added n-BuLi (2.5 M in hexane, 8.10 mL, 20.2 mmol), while maintaining internal temperature below −70° C. After 30 min., a solution of 1,1,1-trifluoroacetone (3.62 mL, 40.5 mmol) in Et2O (10 mL) was added rapidly, keeping the internal temperature below −45° C. After 2 h at −78° C., a saturated solution of NH4Cl was added. The aqueous layer was extracted with Et2O, and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated under vacuum, at 25° C., affording the title compound a liquid containing Et2O (7.25 g). The crude product was used as such in Step 2. 1H NMR (400 MHz, acetone-d6): 5.92 (br s, 1H), 1.59 (s, 3H), 0.18 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>>[Cl:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][N:14]([C:27](=[O:28])[C:26]5[CH:30]=[CH:31][CH:32]=[C:24]([Cl:23])[CH:25]=5)[CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1
Reactant: O=C1C(=O)c2ccc(Cl)cc2C2=C1SCC1(CCNCC1)O2
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: O=C1C(=O)c2ccc(Cl)cc2C2=C1SCC1(CCN(C(=O)c3cccc(Cl)c3)CC1)O2

Procedure:
Compound 67 was synthesized using 9-chlorospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-chlorobenzoyl chloride and conditions outlined in procedure N. (81 mg, 95%); M.p.=125-130° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.90 (d, J=8.4 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.63 (dd, J=1.2 and 8.4 Hz, 1H), 7.55-7.48 (m, 3H), 7.42 (d, J=7.2 Hz, 1H), 4.4-4.2 (m, 1H), 3.84 (brs, 2H), 3.34-3.24 (m, 1H), 3.12 (s, 2H), 2.19-2.08 (m, 1H), 2.02-1.8 (m, 3H); LCMS: 474 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].[CH:20]1[C:30]2[C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[CH:27]=[CH:26][NH:25][C:24]=2[CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>>[CH:20]1[C:30]2[C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[CH2:27][CH2:26][N:25]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=4[CH3:1])=[CH:8][CH:9]=3)=[O:12])[C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: C1=Cc2ccccc2-c2ccccc2N1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCc3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
As described for Example 2, 1 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride, 1 mmol of 5H-dibenz[b,d]azepine and 2 mmol of triethylamine are stirred at room temperature for 5 hours to give the product as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([C:14]([O:16]CC)=[O:15])[C:3]=1[C:4]([OH:6])=[O:5].[CH2:19](O)[CH3:20]>>[Br:1][C:2]1[C:3]([C:4]([O:6][CH2:19][CH3:20])=[O:5])=[C:7]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(Br)c1C(=O)O
Reactant: CCO
Product: CCOC(=O)c1c(C(=O)O)ccc([N+](=O)[O-])c1Br

Procedure:
By boiling with ethanol, a mixture of 2-bromo-6-ethoxycarbonyl-3-nitro-benzoic acid and 3-bromo-2-ethoxycarbonyl-4-nitro-benzoic acid is obtained from the above.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:8]2[CH:9]=[C:10]([OH:15])[C:11]([O:13][CH3:14])=[CH:12][C:7]=2[N:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][C:4]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:22][CH3:23])[CH2:3]1.Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC#N>[O:28]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:15][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:11]([O:13][CH3:14])=[CH:12][C:7]=2[N:6]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:5][C:4]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:22][CH3:23])[CH2:3]1
Reactant: CCOC(=O)CBr
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(OC)c(O)cc2S(=O)(=O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(OC)c(OCC(=O)OCC)cc2S(=O)(=O)C1
Yield: 98.9 %

Procedure:
1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methoxy-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (WO 9616051; 1.0 g), ethyl bromoacetate (0.50 g), sodium carbonate (1.2 g) and tetrabutylammonium bromide (60 mg) in MeCN (15 ml) were refluxed overnight. The solvent was removed under reduced pressure and the residue was extracted (DCM/H2O). The organic layer was separated and the solvent was removed under reduced pressure. The residue purified by chromatography (DCM/EtOAc (90:10)) to give the title compound 1.2 g (98%). NMR (CD3OD) 0.75–0.85 (m, 6H), 1.00–1.30 (m, 8H), 1.35–1.55 (m, 4H), 3.20 (s, 2H), 3.65 (s, 3H), 3.70 (brs, 2H), 4.50 (s, 2H), 6.50 (s, 1H), 6.90–7.30 (m, 5H), 7.40 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O.Br[CH2:45][C:46]1[O:47][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:49][CH:50]=1.BrCC1CCCCO1>>[F:52][C:51]([F:54])([F:53])[C:48]1[O:47][C:46]([CH2:45][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C@:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])=[CH:50][CH:49]=1
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2[C@@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using (R)-(2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)-5-(trifluoromethyl)furan to replace 2-(bromomethyl)tetrahydro-2H-pyran, (R)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (92%) as a colorless solid: mp 64-68° C. (methanol/water); 1H NMR (300 MHz, CDCl3) δ7.30 (ddd, J=7.8, 7.7, 1.0 Hz, 1H), 7.18 (d, J=7.2 Hz, 1H), 7.07 (dd, J=7.5, 7.2 Hz, 1H), 6.99 (d, J=8.1 Hz, 1H), 6.76-6.72 (m, 1H), 6.50 (s, 1H), 6.38 (d, J=3.3 Hz, 1H), 6.19 (s, 1H), 5.06 (d, J=16.5 Hz, 1H), 4.89 (d, J=16.5 Hz, 1H), 4.90 (d, J=9.0 Hz, 1H), 4.64 (d, J=9.0 Hz, 1H), 4.22-4.16 (m, 2H), 4.14-4.09 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.2, 155.3, 152.2, 144.8, 141.8 (q, J=43.0 Hz), 141.5, 138.5, 132.2, 129.1, 124.2, 123.9, 120.9, 118.9 (d, J=267 Hz), 112.8 (d, J=2.8 Hz), 111.6, 109.3, 109.0, 99.5, 80.1, 64.6, 64.0, 58.1, 37.1; MS (ES+) m/z 443.9 (M+1).
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[CH:4][C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[C-:23]#[N:24].[Na+]>CN(C)C=O>[C:23]([C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[CH:4][C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:24]
Reactant: CCOC(=O)c1cnn(-c2ccc(Cl)cc2C(F)(F)F)c1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2ccc(Cl)cc2C(F)(F)F)c1C#N
Temperature: 0 °C
Yield: 32.6 %

Procedure:
A solution of 3.15 g of 5-chloro-1-[2-(trifluoromethyl)-4-chlorophenyl]-1H-pyrazole-4-carboxylic acid, ethyl ester and 1.1 g of sodium cyanide in 25 ml of dimethylformamide was heated at approximately 100° C. for four and one-half hours. The reaction mixture also contained approximately 3 g of molecular sieve to insure dryness. The reaction mixture was cooled and poured into approximately 300 ml of ice water. The precipitated solid was collected by filtration and recrystallized from ethanol (charcoal) to provide 1 g of 5-cyano-1-[2-(trifluoromethyl)-4-chlorophenyl]-1H-pyrazole-4-carboxylic acid, ethyl ester. mp=70°-72° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([OH:8])[CH2:3]1.C[O:10][C:11](=O)[C:12]([OH:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na]>C1CCCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([O:8][C:11](=[O:10])[C:12]([OH:25])([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:3]1
Reactant: CN1CCC[C@@H](O)C1
Reactant: COC(=O)C(O)(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: C1CCCCC1
Product: CN1CCC[C@@H](OC(=O)C(O)(c2ccccc2)c2ccccc2)C1
Temperature: 50 °C

Procedure:
To a mixture of (R)-1-methyl-piperidine-3-ol (4.61 g, 0.040 mol) and hydroxy-diphenyl-acetic acid methyl ester (9.63 g, 0.040 mol) in cyclohexane (50 ml) is added preactivated 4A molecular sieves and the mixture heated to 50° C. Sodium metal (50 mg) is then added and the resulting mixture heated to reflux. After 1 hour further sodium (50 mg) is added and reflux maintained for 5 hours. Concentration, re-dissolution in chloroform and washing with water followed by brine, drying over magnesium sulphate, filtration and evaporation gives a crude product. Purification by vacuum flash silica chromatography (gradient elution: DCM to DCM:methanol 20:1) gives, after evaporation, the title product as a foam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][C:19]=1I)[CH2:16][C@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.[CH3:21][N:22](C=O)C>O.[Zn].[C-]#N.[Zn+2].[C-]#N.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[NH2:1][C:2]1[CH:3]=[C:4]2[C:17]([CH2:16][C@@:6]3([CH2:5]2)[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]3=[O:15])=[CH:18][C:19]=1[C:21]#[N:22]
Reactant: CN(C)C=O
Reactant: Nc1cc2c(cc1I)C[C@]1(C2)C(=O)Nc2ncccc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1cc2c(cc1N)C[C@@]1(C2)C(=O)Nc2ncccc21
Temperature: 80 °C

Procedure:
To a suspension of (2S)-5-amino-6-iodo-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step A (750 mg, 1.99 mmol), zinc dust (15.6 mg, 0.24 mmol) and zinc cyanide (467 mg, 3.98 mmol) in DMF (3.4 mL) at ambient temperature was added bis(tri-t-butylphosphine)palladium (102 mg, 0.199 mmol). The reaction mixture was heated at 80° C. for 2 h, diluted with H2O, and extracted with EtOAc (3×). The combined organic layers were filtered through a plug of Celite, dried over MgSO4, filtered, and concentrated in vacuo. The oily residue was purified by silica gel chromatography, eluting with EtOAc:hexanes—80:20, to afford the title compound. MS: m/z=277 (M+1).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[O:10][C:9]([C:25]2[N:26]=[CH:27][C:28]3[C:33]([CH:34]=2)=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].O1CCCC1.CO>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[O:10][C:9]([C:25]2[N:26]=[CH:27][C:28]3[C:33]([CH:34]=2)=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(C#Cc3ccccc3)ccc12
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(CCc3ccccc3)ccc12
Yield: 60 %

Procedure:
A solution of 2-isoquinolin-3-yl-7-phenylethynyl-chromen-4-one O-tert-butyl oxime (60 mg, 0.13 mmol) (prepared using the procedure described in example 20 starting from example 2B) and Lindlar's catalyst (22.5 mg) in tetrahydrofuran (9.2 ml) and methanol (1.8 ml) was stirred at room temperature under 1 atmosphere of hydrogen for 18 h. The catalyst was removed by filtration and the solvent evaporated under reduce pressure to yield the title compound in 60% yield.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[N:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:19]2[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccncc2)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a stirred solution of 2,4-dichloro-5,7-difluoro-3-methylquinoline (1.0 g, 4.03 mmol) in toluene (8.06 mL) was added pyridin-4-ylboronic acid (0.743 g, 6.05 mmol), potassium carbonate (1.11 g, 8.06 mmol) and palladium tetrakistriphenylphosphine (0.466 g, 0.403 mmol). The reaction was stirred at 100° C. and stirring continued for 15 h. The reaction mixture was cooled to rt and concentrated in vacuo. The crude material was purified by column chromatography on silica gel, eluting with (0-50% EtOAc in hexanes) to provide 4-chloro-5,7-difluoro-3-methyl-2-(4-pyridinyl)quinoline as a white solid. Mass Spectrum (ESI) m/e=291.1 (M+1).
Reaction SMILES: Cl.[C:2]([C:4]([O:31][Si](C)(C)C)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:15]2)=[O:13])=[CH:7][CH:6]=1)#[N:3]>C1COCC1>[C:2]([C:4]([OH:31])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([CH:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:15]2)=[O:13])=[CH:9][CH:10]=1)#[N:3]
Reactant: C[Si](C)(C)OC(C#N)(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: N#CC(O)(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 105.4 %

Procedure:
) HCl 3N (0.010 mol) was added to a solution of (±)-N-[4-[cyano[(trimethylsilyl)oxy] phenylmethyl]phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide (0.010 mol) in THF (50 ml). The reaction mixture was stirred for 15 minutes at 65° C. The reaction mixture was washed with water and extracted with EtOAc. The separated organic layer was dried (Na2SO4), filtered and the solvent was evaporated, yielding 4.2 g of (±)-N-[4-(cyanohydroxyphenylmethyl)phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide (compound 495).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[CH3:14].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][O:27][CH:26]=2)=[O:24])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>>[CH3:15][C:16]1[C:17]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)=[CH:4][C:3]=2[CH3:14])=[CH:18][C:19]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][O:27][CH:26]=2)=[O:24])=[CH:20][CH:21]=1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nnc(-c2ccc(Br)c(C)c2)o1
Product: Cc1nnc(-c2ccc(-c3cc(NC(=O)c4ccoc4)ccc3C)c(C)c2)o1

Procedure:
Example 22 was prepared using 2-(4-bromo-3-methylphenyl)-5-methyl-[1,3,4]oxadiazole and N-[4-methyl-3-(4,4,5,5, -tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 25).
Reaction SMILES: [NH:1]([C:5]1[CH:16]=[CH:15][C:8]([N:9]([CH2:12][CH2:13][OH:14])[CH2:10][CH3:11])=[CH:7][C:6]=1[CH3:17])C(C)=O.C(O)(C)C.[S:22](=[O:26])(=[O:25])([OH:24])[OH:23]>>[S:22]([OH:26])([OH:25])(=[O:24])=[O:23].[NH2:1][C:5]1[CH:16]=[CH:15][C:8]([N:9]([CH2:12][CH2:13][OH:14])[CH2:10][CH3:11])=[CH:7][C:6]=1[CH3:17]
Reactant: CCN(CCO)c1ccc(NC(C)=O)c(C)c1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CCN(CCO)c1ccc(N)c(C)c1

Procedure:
23.6g (0.1 mole) of 4-acetamino-3-methyl-N-(β-hydroxyethyl)-N-ethylaniline were dissolved in 30g of 50% sulfuric acid. The system was reacted for 5 hours at 80° to 100° C while stirring, and then put into 300 ml of isopropyl alcohol and stirred therein while cooling. Crystals separated out, which were then filtered and dried to obtain 22.2g of 4-amino-3-methyl-N-(β-hydroxyethyl)-N-ethylaniline sulfate.
Reaction SMILES: [CH3:1][CH2:2][N:3]=[C:4]=[N:5][CH2:6][CH2:7][CH2:8]N(C)C.Cl.Br[C:14]1C=C(N)C(N)=CC=1.C(N1CCC[C@H]1C(O)=O)(OC(C)(C)C)=O.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.C(O)(=O)C>[N:5]1[C:6]2[CH:7]=[CH:8][CH:14]=[CH:1][C:2]=2[NH:3][CH:4]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: CCN=C=NCCCN(C)C
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1ccc2[nH]cnc2c1
Temperature: 65 °C
Reaction time: 19 h

Procedure:
EDCI.HCl (2.348 g, 12.25 mmol) was added to a mixture of 4-bromobenzene-1,2-diamine (2.078 g, 11.11 mmol), N-Boc-L-proline (2.311 g, 10.74 mmol) and 1-hydroxybenzotriazole (1.742 g, 12.89 mmol) in CH2Cl2 (40 mL), and stirred at ambient conditions for 19 h. The mixture was then diluted with CH2Cl2, washed with water (2×), dried (brine; MgSO4), filtered, and concentrated in vacuo to provide a brown foam. Acetic acid (40 mL) was added to the foam, and the mixture was heated at 65° C. for 90 min. The volatile component was removed in vacuo, and the residue was dissolved in EtOAc and washed carefully with saturated NaHCO3 solution (2×), and the organic phase was dried (brine; MgSO4), filtered, and concentrated in vacuo. The resultant crude material was submitted to flash chromatography (silica gel; EtOAc) to provide benzimidazole M1a as a tan foam (2.5 g). 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): 12.49-12.33 (four br s, 1H), 7.71 (d, J=2, 0.54H), 7.60 (app br s, 0.46H), 7.50 (d, J=8.6, 0.45H), 7.40 (d, J=8.4, 0.55H), 7.26 (m, 1H), 4.96-4.87 (m, 1H), 3.64-3.51 (m, 1H), 3.44-3.38 (m, 1H), 2.38-2.21 (m, 1H), 1.99-1.85 (m, 3H), 1.39 (s, 3.7H), 1.06 (s, 5.3H). LC/MS: Anal. Calcd. for [M+H]+ C16H2181BrN3O2; 368.03. found: 368.18.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]([CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:36])[CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:34])[CH2:18][CH2:17]1)[C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1.[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]([C:7]1[CH:15]=[CH:14][C:10]([C:11](=[O:12])[NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:9][CH:8]=1)[CH:16]1[CH2:17][CH2:18][N:19]([CH:22]([CH3:36])[CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:34])[CH2:20][CH2:21]1
Reactant: Nc1ccccc1
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(Cl)c2)c2ccc(C(=O)O)cc2)CC1
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(Cl)c2)c2ccc(C(=O)Nc3ccccc3)cc2)CC1
Yield: 70.4 %

Procedure:
Using general procedure E, 4-((3-chloro-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid (see EXAMPLE 86) (40 mg, 0.074) and aniline (8 μL, 0.08 mmol) afforded COMPOUND 89 as a white solid (32 mg, 71%). 1H NMR (CDCl3) δ 0.93-1.25 (m, 2H), 1.01 (d, 3H, J=6.3 Hz), 1.51-1.55 (m, 1H), 1.72-1.76 (m, 3H), 2.19 (t, 1H, J=11.1 Hz), 2.31 (s, 6H), 2.58 (t, 1H, J=11.1 Hz), 2.76-2.92 (m, 3H), 3.25-3.32 (m, 1H), 3.67-3.75 (m, 1H), 3.87 (s, 2H), 3.87-3.93 (m, 1H), 6.57 (d, 2H, J=8.7 Hz), 6.95-7.12 (m, 6H), 7.23-7.32 (m, 4H), 7.60 (d, 2H, J=7.8 Hz), 7.68 (d, 2H, J=8.4 Hz), 7.76 (s, 1H), 8.35 (br s, 1H). 13C NMR (CDCl3) δ 13.85, 19.55, 29.42, 30.70, 31.35, 40.22, 43.96, 48.59, 52.47, 56.25, 60.92, 112.50, 120.35, 122.88, 124.35, 124.61, 126.60, 127.47, 127.78, 128.89, 129.13, 129.37, 130.27, 134.44, 134.95, 138.80, 138.97, 142.01, 151.51, 165.65, 170.31. ES-MS m/z 623 (M+H). Anal. Calcd. for C38H43N4ClO2.0.2CH2Cl2: C, 71.65; H, 6.83; N, 8.75. Found. C, 71.64; H, 6.81; N, 8.84.
Reaction SMILES: [CH3:1][N-:2][CH3:3].[C:4]1([S:10][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](O)=O)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O=P(Cl)(Cl)Cl.N>C1(C)C=CC=CC=1.O>[CH3:1][N:2]([CH3:3])[C:12]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:10][C:11]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[N-]C
Reactant: O=C(O)C(Sc1ccccc1)c1ccccc1
Agent: N
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CN(C)c1c(-c2ccccc2)sc2ccccc12

Procedure:
A solution of 14.4 g (53 mmole) of the dimethylamide of α-phenylthio-phenylacetic acid, 24.5 milliliters (160 mmole) of POCl3 in 250 milliliters of absolute toluene is refluxed for 6 hours. After mixing with water, it is neutralised with ammonia and the organic phase is dried over a mixture of K2CO3 and activated charcoal and evaporated: 3-dimethylamino-2-phenyl-benzo(b)thiophene in the form of a crude oily produce which, triturated with methanol, yields 11.1 g (83% of theory) of colourless rods, mp 84°-85° (methanol).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([F:49])=[C:16]([NH:18][C:19](=[O:48])[NH:20][C:21]4[N:25]([CH2:26][CH2:27][N:28]5[CH2:33][CH2:32][N:31](C(OCC6C=CC=CC=6)=O)[CH2:30][CH2:29]5)[N:24]=[C:23]([C:44]([CH3:47])([CH3:46])[CH3:45])[CH:22]=4)[CH:17]=3)[C:9](=[O:50])[N:8]([CH3:51])[C:6]=2[N:7]=1>CCOC(C)=O.[OH-].[Pd+2].[OH-]>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([F:49])=[C:16]([NH:18][C:19]([NH:20][C:21]4[N:25]([CH2:26][CH2:27][N:28]5[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]5)[N:24]=[C:23]([C:44]([CH3:45])([CH3:46])[CH3:47])[CH:22]=4)=[O:48])[CH:17]=3)[C:9](=[O:50])[N:8]([CH3:51])[C:6]=2[N:7]=1
Reactant: Cn1c(=O)c(-c2ccc(F)c(NC(=O)Nc3cc(C(C)(C)C)nn3CCN3CCN(C(=O)OCc4ccccc4)CC3)c2)cc2cnc(N)nc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cn1c(=O)c(-c2ccc(F)c(NC(=O)Nc3cc(C(C)(C)C)nn3CCN3CCNCC3)c2)cc2cnc(N)nc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of benzyl 4-(2-(5-(3-(5-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)ureido)-3-tert-butyl-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate (0.11 g, 0.16 mmol) in EtOAc (10 mL) was added palladium hydroxide (10% of 10 mg) and the mixture was stirred under a H2 atmosphere for 18 h at RT. Then the mixture was filtered through a Celite pad, the pad was washed with EtOAc (2×5 ml). The filtrate was concentrated to afford a solid which was purified by chromatography using acetonitrile and water as eluents to afford 1-(5-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-(2-(piperazin-1-yl)ethyl)-1H-pyrazol-5-yl)urea as the amine hydrochloride salt (62 mg, 70% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.20 (brs, 1H), 9.16 (s, 1H), 8.71 (s, 1H), 8.41-8.39 (m, 1H), 7.91 (s, 1H), 7.31-7.29 (m, 2H), 6.18 (s, 1H), 4.44 (brs, 2H), 3.57 (s, 3H), 3.52-3.39 (m, 8H), 1.23 (s, 9H); MS (ESI) m/z: 562.8 (M+H+).
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:14]2[CH:15]=[C:16]([C:18]#[N:19])[O:17][C:13]=2[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:20][OH:21]>>[Si:1]([O:8][CH:9]1[C:14]2[CH:15]=[C:16]([C:18](=[N:20][OH:21])[NH2:19])[O:17][C:13]=2[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCCc2oc(C#N)cc21
Reactant: NO
Product: CC(C)(C)[Si](C)(C)OC1CCCc2oc(C(N)=NO)cc21

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1d) using 4-{[t-butyl(dimethyl)silyl]oxy}-4,5,6,7-tetrahydro-1-benzofuran-2-carbonitrile (3.0 g, 11 mmol) that was obtained in Example 7 (7c) and a 40% aqueous solution of hydroxylamine (3.0 ml). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:7) as the eluent to afford the title compound (2.7 g) in a yield of 82% as a white crystalline solid.