Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)C1C=CC=CC=1.[CH:17]1C(Cl)=CC=C(Cl)C=1>CCCCCC>[CH2:10]1[CH:11]2[CH:12]3[CH:13]=[CH:14][CH:15]([CH:16]2[CH:1]=[CH:8]1)[CH2:17]3
Reactant: Clc1ccc(Cl)cc1
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Solvent: CCCCCC
Product: C1=CC2C3C=CC(C3)C2C1

Procedure:
A one mole equivalent sample of product II and two mole equivalent of dibenzylketone is heated for 4 hours in a mechanically stirred dichlorobenzene solution. The mixture is diluted with addition of hexane and the solid product is filtered, washed with hexane and dried. Purification of this product may be carried out by recrystallization from acetone or methyl ethyl ketone. ##STR42##
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([F:28])=[CH:20][CH:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[F:28][C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:17])=[CH:19][CH:20]=1
Reactant: CCOC(=O)C1(NC(=O)c2ccc(F)c3ccccc23)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 103.8 %

Procedure:
The mixture of 2-[(4-fluoro-naphthalene-1-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (43) (180 mg, 0.48 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (10 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 6 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate formed. The precipitate is filtered to give a pure product (44) as white solid (174 mg, 100%).
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:5]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:2]=[CH2:3].[S:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][NH2:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCOC(C)=O>[CH2:1]([N:4]1[C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:32][CH2:31][CH:27]3[CH2:28][CH2:29][CH2:30][S:26]3)[C:7]=2[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:5]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:2]=[CH2:3]
Reactant: NCC1CCCS1
Reactant: C=CCn1c(-c2ccccc2)c(-c2ccccc2)c2c(Cl)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCn1c(-c2ccccc2)c(-c2ccccc2)c2c(NCC3CCCS3)ncnc21
Temperature: 120 °C
Reaction time: 0.08 h

Procedure:
To a solution of 7-allyl-4-chloro-5,6-diphenyl-7H-pyrrolo[2,3-d]pyrimidine (Example 3, Step B; 200 mg, 0.58 mmol) and 140 mg of (tetrahydrothiophen-2-yl)methylamine (1.20 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (200 mg, 1.45 mmol). The mixture was stirred for 5 minutes at 120° C. under microwave irradiation (using powerMAX™). The reaction mixture was then cooled and diluted with EtOAc (25 mL). The mixture was extracted twice with water (10 mL) and then brine. The organic layer was dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (C8 column, water, acetonitrile, 0.1% TFA) to give the title compound.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[F:26][C:27]([F:31])([F:30])[CH2:28][NH2:29]>>[F:26][C:27]([F:31])([F:30])[CH2:28][NH:29][C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5]
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccncc3)noc2C)nn1
Reactant: NCC(F)(F)F
Product: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)NCC(F)(F)F)nn1
Yield: 66 %

Procedure:
As described for example 67e, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethyl ester (100 mg, 0.29 mmol) was converted, using 2,2,2-trifluoroethylamine instead of aminomethylcyclopropane, to the title compound (76 mg, 66%) which was obtained as a white solid. MS: m/e=394.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[CH3:11].C(N(CC)CC)C.[C:19]([O:23][C:24]([NH:26][NH2:27])=[O:25])([CH3:22])([CH3:21])[CH3:20]>ClCCl>[C:19]([O:23][C:24]([NH:26][NH:27][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([CH3:11])[CH:4]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1cc(C(=O)Cl)ccc1Br
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)NNC(=O)OC(C)(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
54.3 g 4-bromo-3-methyl-benzoyl chloride was added to 23.3 g triethylamine and 30.4 g hydrazinecarboxylic acid tert-butyl ester in 1 L dichlormethane. The reaction was stirred 1 h at RT and extracted with water. The organic layer was evaporated and the residue was crystallized with diisopropylether to give 70 g desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH2:14][OH:15])=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([O:8][C:9]1[C:13]([CH:14]=[O:15])=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cn(-c2ccccc2)nc1OCc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1cn(-c2ccccc2)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
A mixture of (3-benzyloxy-1-phenyl-1H-pyrazol-4-yl)methanol (5.61 g), activated manganese dioxide (15.00 g) and tetrahydrofuran (75 mL) was stirred overnight at room temperature. Manganese dioxide was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 3-benzyloxy-1-phenyl-1H-pyrazole-4-carbaldehyde (5.03 g, yield 90%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:1, v/v). The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 153-154° C.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]([CH2:15][CH:16]=[CH2:17])[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:15]([CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH2:9][NH2:8])[CH:16]=[CH2:17]
Reactant: C=CCC(CNC(=O)OC(C)(C)C)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCC(CN)C(=O)OC
Reaction time: 3 h
Yield: 121.5 %

Procedure:
Dissolve N-(t-butyloxycarbonyl)-2-(2-propenyl)-β-alanine, methyl ester(5.6 g, 23.0 mmol) in methylene chloride (25 mL) and treat with trifluoroacetic acid (15 mL). Stir for three hours and remove the volatiles in vacuo. Treat the residue with water, make basic with sodium hydroxide (1.0 g, 25 mmol) and extract with ethyl acetate. Separate the organic phase and dry (Na2SO4). Evaporate to give 4.0 g of the title compound as an oil in ethyl acetate.
Reaction SMILES: [Na].C(OCC)(=O)[CH2:3][C:4]([O-:6])=[O:5].Br[CH:12]([CH2:14][CH2:15][CH3:16])[CH3:13].[Br-].[Na+]>C(O)C>[CH3:13][CH:12]([CH2:14][CH2:15][CH3:16])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CCCC(C)Br
Agent: [Br-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCCC(C)CC(=O)O
Temperature: 25 °C
Yield: 76.1 %

Procedure:
Sodium metal (42.0 g, 1.827 mol) was dissolved in absolute ethanol (500 ml) under argon atmosphere. Ethyl malonate (289.3 g, 1.806 mol) was added at a stretch to the solution with stirring. Further, 2-bromopentane (262.6 g, 1.738 mol) was added dropwise at first slowly and, after sodium bromide was precipitated, in such a rate that ethanol was slowly refluxed. After 3 hour reflux, the mixture was cooled to room temperature, and 50% aqueous potassium hydroxide solution (510 g) was added dropwise slowly. The mixture was again warmed slowly and refluxed for 4 hours. After distilling off ethanol, concentrated hydrochloric acid (500 ml) was added and the mixture was refluxed for one hour. The reaction mixture was cooled to room temperature, and extracted with ether (500 ml×3). The combined ether layers were washed with brine (200 ml×2) and dried over anhydrous sodium sulfate. After distilling off ether, the residue was heated at 180° C. until carbon dioxide was no longer generated. The resulting residue was distilled under reduced pressure to give dl-3-methylhexanoic acid (172 g, 1.323 mol, 76%, b.p.: 112°-113° C./15 mmHg).
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=3[O:24][CH3:25])[N:14]=2)[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1.C(Br)(Br)(Br)[Br:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[Br:29][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=3[O:24][CH3:25])[N:14]=2)[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COc1cc(OCCO)cc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc(OCCBr)cc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)c1
Temperature: 40 °C
Reaction time: 7 h

Procedure:
To a solution of 2-[3-(2-hydroxy-ethoxy)-5-methoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (8.00 g, 21.5 mmol) in anhydrous DMF (30 mL) was added carbon tetrabromide (9.80 g, 29.5 mmol) and triphenylphosphine (7.78 g, 29.5 mmol). The reaction mixture was stirred at 40° C. for 7 hours. DMF was removed under vacuum and dichloromethane (200 mL) was added. The organic phase was washed with water (150 mL), brine (100 mL), and dried over anhydrous sodium sulfate. Solvent was removed and the residue was washed three times with a mixture of ether and dichloromethane (20:1, 200 mL) to give 2-[3-(2-bromo-ethoxy)-5-methoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (5) as a white solid. Yield: 8.9 g (95%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.F[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([O:9][C:5]2[CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=[CH:7][CH:6]=2)=[N:12][CH:13]=1
Reactant: OCc1cccc(O)c1
Reactant: Cc1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1ccc(Oc2cccc(CO)c2)nc1
Temperature: 110 °C
Reaction time: 16 h
Yield: 52.7 %

Procedure:
3-Hydroxymethyl-phenol (5.04 g, 40.6 mmol), 2-fluoro-5-methyl-pyridine (4.1 g, 37 mmol,) and cesium carbonate (15.0 g, 46.1 mmol) were suspended in dimethylsulfoxide (50 mL) and heated to 110° C. After stirring for 16 h, the reaction was partitioned between water (500 mL) and ethyl acetate (500 mL). The organic layer was separated and the aqueous was extracted again with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10-20%, EtOAc:heptane) to afford the title compound (4.2 g, 53% yield) as a thick oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:32])[C:18]=1[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)=[O:21]>>[Cl:32][C:17]1[CH:16]=[N:15][CH:14]=[C:13]([Cl:12])[C:18]=1/[CH:19]=[C:20](\[O:21][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)/[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC
Product: COc1ccc(C(=O)O/C(=C\c2c(Cl)cncc2Cl)c2ccc(OC)c(OC)c2)cc1

Procedure:
The compound was obtained starting from 4-methoxy-benzoyl chloride and 2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethanone, following the procedure of Example 7.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])=[N:4][CH:5]=[C:6]([F:23])[C:7]=1[NH:8][C:9]1[C:14]([C:15]2[CH:20]=[C:19](SC)[N:18]=[CH:17][N:16]=2)=[N:13][CH:12]=[CH:11][N:10]=1.[CH2:31]([NH2:33])[CH3:32]>CC(O)C>[CH2:31]([NH:33][C:19]1[N:18]=[CH:17][N:16]=[C:15]([C:14]2[C:9]([NH:8][C:7]3[C:6]([F:23])=[CH:5][N:4]=[C:3]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])[C:2]=3[F:1])=[N:10][CH:11]=[CH:12][N:13]=2)[CH:20]=1)[CH3:32]
Reactant: CCCS(=O)(=O)Nc1ncc(F)c(Nc2nccnc2-c2cc(SC)ncn2)c1F
Reactant: CCN
Solvent: CC(C)O
Product: CCCS(=O)(=O)Nc1ncc(F)c(Nc2nccnc2-c2cc(NCC)ncn2)c1F
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A stirred mixture of N-(3,5-difluoro-4-(3-(6-(methylthio)pyrimidin-4-yl)pyrazin-2-ylamino)pyridin-2-yl)propane-1-sulfonamide (70 mg, 0.15 mmol), ethylamine (70% solution in water, 3 mL) and 2-propanol (3 mL) was heated with stirring at 120° C. for 16 h. The reaction mixture was cooled to rt and concentrated. The residue was chromatographed on silica gel (10-50% ethyl acetate in hexanes eluant) to provide the title compound.
Reaction SMILES: [CH2:1]([N:5]([CH2:24][CH2:25][CH2:26][CH3:27])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)=[C:8]([O:22][CH3:23])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:28]([C:30]1[C:31](=[C:38]([C:41]#[N:42])[C:39]#[N:40])[O:32][C:33]([CH3:37])([CH3:36])[C:34]=1[CH3:35])#[N:29].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[CH2:24]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[CH:35][C:34]3[C:33]([CH3:36])([CH3:37])[O:32][C:31](=[C:38]([C:39]#[N:40])[C:41]#[N:42])[C:30]=3[C:28]#[N:29])=[CH:16][CH:15]=2)=[C:8]([O:22][CH3:23])[CH:7]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)cc2)c(OC)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 92.5 %

Procedure:
In 15 ml of ethanol and 5 ml of tetrahydrofuran were dissolved 500 mg (1.37 mmol) of 4-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]benzaldehyde and 300 mg (1.51 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene) propanedinitrile. To this mixture was added 106 mg of ammonium acetate, and the mixture was stirred at room temperature for 23 hours. The solvent was evaporated off in a reduced pressure. The residue was washed with ethanol and then purified by silica gel column chromatography. The crystal was washed with ethanol to give 693 mg of a black powder (yield: 92.6%; mp: 258-260° C.)
Reaction SMILES: Cl[C:2]1N=C(C2C(C3C=C(NC(=O)C4C=C(F)C=CC=4F)C=CC=3)=NN3C=CC=CC=23)C=CN=1.[NH2:34][CH2:35][C:36]1[CH:37]=[C:38]([NH:42][C:43]2[N:48]=[C:47]([C:49]3[C:50]([C:58]4[CH:59]=[C:60]([NH:64][C:65](=[O:74])[C:66]5[C:71]([F:72])=[CH:70][CH:69]=[CH:68][C:67]=5[F:73])[CH:61]=[CH:62][CH:63]=4)=[N:51][N:52]4[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=34)[CH:46]=[CH:45][N:44]=2)[CH:39]=[CH:40][CH:41]=1>CC(O)C.Cl.CCOC(C)=O>[F:73][C:67]1[CH:68]=[CH:69][CH:70]=[C:71]([F:72])[C:66]=1[C:65]([NH:64][C:60]1[CH:61]=[CH:62][CH:63]=[C:58]([C:50]2[C:49]([C:47]3[CH:46]=[CH:45][N:44]=[C:43]([NH:42][C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([CH2:35][NH:34][CH3:2])[CH:37]=4)[N:48]=3)=[C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][N:52]3[N:51]=2)[CH:59]=1)=[O:74]
Reactant: NCc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)c1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1cc(F)ccc1F
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)c1
Temperature: 180 °C
Yield: 72.8 %

Procedure:
To a suspension of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,5-difluorobenzamide (100 mg, 0.22 mmol) (prepared according to a procedure similar to that described in Example 43, Step A) and N-[(3-aminophenyl)methyl]-2,2,2-trifluoroacetamide (59 mg, 0.27 mmol) (prepared as described in Example 180) in 2-propanol (3 mL) was added 2 drops of concentrated HCl. The mixture was heated to 180° C. in a microwave for 15 min. The reaction mixture was diluted with 25 mL EtOAc and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered, and purified by flash chromatography to give the title compound (90 mg, 64% yield). 1H NMR (400 MHz, d6-DMSO): δ 10.64 (s, 1H), 9.99 (t, J=5.7 Hz, 1H), 9.63 (s, 1H), 8.85 (d, J=7.0 Hz, 1H), 8.53 (d, J=8.8 Hz, 1H), 8.27 (d, J=5.3 Hz, 1H), 8.04 (s, 1H), 7.86 (d, J=8.1 Hz, 1H), 7.71 (s, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.42-7.55 (m, 5H), 7.35 (d, J=7.5 Hz, 1H), 7.24 (t, J=7.9 Hz, 1H), 7.14 (t, J=6.8 Hz, 4H), 6.85 (d, J=7.3 Hz, 1H), 6.54 (d, J=5.1 Hz, 1H), 4.35 (d, J=5.8 Hz, 2H). MS (ESI) m/z=645 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:8]2[CH2:11][CH:10]([O:12][N:13]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[NH2:13][O:12][CH:10]1[CH2:11][N:8]([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9]1
Reactant: O=C1c2ccccc2C(=O)N1OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: NN
Solvent: CCO
Solvent: O
Product: NOC1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 77.4 %

Procedure:
To a solution of 2-{[1-(diphenylmethyl)azetidin-3-yl]oxy}-1H-isoindole-1,3(2H)-dione (600 mg, 1.56 mmol; which may be prepared as described in Step 2) in ethanol (13.3 mL) was added hydrazine hydrate (100 μL, 2.06 mmol). The resulting mixture was heated to reflux for 2 h then concentrated under reduced pressure. The residue was taken up in dichloromethane/methanol mixture then filtered. The filtrate was concentrated and the residue purified on column chromatography (eluent: Dichloromethane/NH3 7N in MeOH, 2% to 5%) to give the title compound (307 mg, 77%) as a clear oil.
Reaction SMILES: [Li]CCCC.[C:6]1([S:12][CH3:13])[CH:11]=[CH:10]C=C[CH:7]=1.Cl[Si:15]([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[S:12]1[CH:13]=[CH:10][CH:11]=[C:6]1[CH2:7][Si:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CSc1ccccc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)Cc1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
To a stirred solution of 143 mL of 1.4 M n-BuLi (0.20 mol) in 55 mL of dry THF, was added dropwise at room temperature under a nitrogen atmosphere 24.8 g (0.20 mol) of thioanisole. Upon completion of the addition, the yellow mixture began to reflux spontaneously. The mixture was stirred at room temperature for 3 hours. Upon addition of 21.84 g (0.20 mol) of chlorotrimethylsilane, the mixture again began to reflux spontaneously. After stirring at room temperature overnight, the mixture was quenched with 100 mL of 5% of HC1. The aqueous layer was separated, and the organic layer was dried over MgSO4, filtered, and the solvent removed in vacuo from a water bath at 45° C. The crude product was distilled to give 19.22 g (49%) of the colorless sulfide, bp 84-°86° C./0.3 Torr; 1H NMR (CDCL3) δ 0.17 (s, 9H, Si(CH3)3), 2.13 (s, 2H, CH2S), 7.0-7.42 (m, 5H, phenyl).
Reaction SMILES: [C:1]1([OH:14])[C:2]([C:7]2[C:8]([OH:13])=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1.[P:15](Cl)(Cl)[Cl:16]>>[P:15]1([Cl:16])[O:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[O:14]1
Reactant: Oc1ccccc1-c1ccccc1O
Reactant: ClP(Cl)Cl
Product: Clp1oc2ccccc2c2ccccc2o1
Yield: 81 %

Procedure:
A solution of 2,2'-biphenol (28.1 g, 0.151 mol) in 49 mL phosphorus trichloride was heated at reflux for 2 hours. The excess PCl3 was removed by distillation. The residue was purified by vacuum distillation (140°-143° C. at 0.5 mm Hg) to give 30.70 g (81% yield) 1,1'-biphenyl-2,2'-diyl phosphorochloridite (as a clear viscous oil which solidified to a white solid upon standing at room temperature in an inert atmosphere for an extended period of time). 31P{1H}NMR (121.4 MHz, d8 -toluene): δ 180.1 (s) , 85% H3PO4 external reference. To a solution containing 1.018 g (2.84 mmoles) of 2,2'-dihydroxy-3,3'-di-t-butyl-5,5'-dimethoxy-1,1'-biphenyl and 0.575 g (5.68 mmoles) of NEt3 in 15 ml of tetrahydrofuran (THF) was added 1.412 g (5.68 mmoles) of 1,1'-biphenyl-2,2'-diyl phosphorochloridite in 5 ml of THF. The mixture was stirred overnight at room temperature. The mixture was filtered through celite, washed with THF and solvent removed to give 2.2 g of white solid. 31P{1H} nmr (121.4 MHz, C6D6): 145.15 s and 138.5 s. 1H nmr (300 MHz,C6D6): singlet at 3.15 and 1.3 along with aromatic resonances.
Reaction SMILES: F[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19])=O.O.[NH2:21][NH2:22]>CN(C1C=CN=CC=1)C>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:2]=1[NH:22][N:21]=[C:9]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19]
Reactant: COc1ccc(C(=O)c2cccc(Cl)c2F)c(C)c1
Reactant: NN
Agent: CN(C)c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(Cl)cccc23)c(C)c1
Yield: 49.7 %

Procedure:
Prepared according to Method D Step A from [2-fluoro-3-chlorophenyl](4-methoxy-2-methylphenyl)methanone (1.26 g, 4.52 mmol), hydrazine hydrate (1.61 mL, 51.7 mmol) and DMAP (0.632 g, 5.17 mmol) to give the product (0.613 g) as a yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[CH:22]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)=O>>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH:21][CH2:22][C:24]5[S:25][CH:26]=[CH:27][N:28]=5)[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1nccs1
Reactant: Nc1ccc2c(c1)COC(Nc1cccc(C3CC3)c1)=N2
Product: c1cc(NC2=Nc3ccc(NCc4nccs4)cc3CO2)cc(C2CC2)c1
Yield: 46.1 %

Procedure:
Prepared from N2-(3-cyclopropyl-phenyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (158 mg, 0.57 mmol) and 2-formylthiazole (70 mg, 0.62 mmol) according to the procedure described for example 88. Obtained the title compound as a yellow foam (99 mg, 46%), MS (ISP) m/e=377.2 [(M−H)+].
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]2[NH2:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](N1C=CN=C1)(N1C=CN=C1)=[O:26]>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([N:17]2[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]3[NH:24][C:25]2=[O:26])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC1CCCCC1NC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CC#N
Product: O=C(OCc1ccccc1)N1CCC(N2C(=O)NC3CCCCC32)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a solution of compound {4-(2-aminocyclohexylamino)-piperidine-1-carboxylic acid benzyl ester)} (1.48 g, 4.47 mmoles) in acetonitrile (50 mL), 1,1′-carbonyldiimidazole (0.86 g, 5.36 mmole) was added and the reaction mixture was stirred at room temperature for 18 h. Reaction mixture was concentrated under reduced pressure, dissolved again in dichloromethane (60 mL) washed with water (2×100 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound as a solid (1.45 g, 90%). MS: (M+1): 358.13