Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCOCC.C[Si]([C:10]#[C:11][C:12]1[CH:25]=[CH:24][C:15]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[CH:14][CH:13]=1)(C)C.[C:26]1([Li])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[C:11]([C:12]1[CH:25]=[CH:24][C:15]([C:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[OH:17])=[CH:14][CH:13]=1)#[CH:10]
Reactant: C[Si](C)(C)C#Cc1ccc(C(=O)c2ccccc2)cc1
Reactant: [Li]c1ccccc1
Solvent: O
Solvent: CCOCC
Product: C#Cc1ccc(C(O)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
To a flask containing a mixture of 4-bromobenzophenone (1.31 g, 5.0 mmol). PdCl2 (PPh3)2 (70 mg. 0.10 mmol), and CuI (10 mg, 0.050 mmol) was added Et2NH (50 mL) and trimethylsilyl-acetylene (0.85 mL, 6.0 mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature for 5 h. The solvent was removed under vacuum, and the residue was extracted with CH2Cl2 /H2O. The organic layer was collected, dried over MgSO4, filtered through Al2O3, and pumped dry. The residue was recrystallized from CH2Cl2 /hexane to afford pale brown crystalline 4-(trimethylsilylethynyl)benzophenone in 93% yield (1.30 g). 1H NMR (300 MHz, C6D6, 25° C., TMS): δ=0.25 (s, 9 H, CH3) 7.44-7.74 (m 9 H, Ph and C6H4); MS (EI) : m/e 278 (M+ --CH3) To a Et2O solution (100 mL) of 4-(trimethylsilylethynyl)benzophenone (1.39 g, 5.0 mmol) prechilled to -30° C. was slowly added a solution of phenyllithium (3.33 mL, 6.0 mmol, 1.8 M in cyclohexane-ether). The solution was slowly warmed to room temperature and stirred for 4 hours. 1 mL of H2O was added and the solution was stirred for 30 minutes. Additional H2O (>200 mL) was added and the organic layer was collected, dried over MgSO4, filtered through Al2O3, and pumped dry. The residue was chromatographed using CH2Cl2 /hexane (2:1) as eluent to afford (4-ethynylphenyl)-diphenylmethanol as a pale yellow oil in 81% yield (1.24 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br.Br[CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[C:15]([Cl:27])[CH:14]=1)=[O:11].[Cl:28][C:29]1[CH:30]=[C:31]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:33][C:34]=1[OH:35].CN(C=O)C>ClCCl>[Cl:28][C:29]1[CH:30]=[C:31]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:33][C:34]=1[O:35][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[C:15]([Cl:27])[CH:14]=1)=[O:11]
Reactant: Oc1ccc(-c2ccccc2)cc1Cl
Reactant: CCN(CC)CCOc1ccc(NC(=O)CBr)cc1Cl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(-c3ccccc3)cc2Cl)cc1Cl

Procedure:
65 mg (0.47 mmol) of potassium carbonate was added to a solution of 70 mg (0.159 mmol) of 2-bromo-N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-acetamide-hydrobromide (intermediate product Z1c) and 64 mg (0.314 mmol) of 3-chloro-biphenyl-4-ol in 1 mL of abs. DMF and the mixture was stirred for 1 hour at 40° C. and for 15 hours at RT. The reaction mixture was diluted with dichloromethane, the org. phase was washed with sat. aqueous sodium bicarbonate solution and water and dried over magnesium sulphate. Column chromatography (silica gel, dichloromethane/MeOH 9:1) yielded the product.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)[S:6][N:5]=1.Cl[C:17]1[N:22]=[C:21]([C:23]([OH:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[N:18]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[CH3:3][C:4]1[N:8]=[C:7]([N:9]2[CH2:10][CH2:11][CH:12]([NH:15][C:17]3[N:22]=[C:21]([C:23]([OH:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=4)[N:18]=3)[CH2:13][CH2:14]2)[S:6][N:5]=1
Reactant: CC(C)(O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Reactant: Cc1nsc(N2CCC(N)CC2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nsc(N2CCC(Nc3nc(-c4ccc(C(F)(F)F)cc4)cc(C(C)(C)O)n3)CC2)n1

Procedure:
A solution of 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-ylamine dihydrochloride (54.2 mg, 0.2 mmol), 2-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-propan-2-ol (69.7 mg, 0.22 mmol) and N,N-diisopropylethyl amine (120 L, 0.7 mmol) in dioxane (2 mL) was heated at 200° C. in a microwave oven for 2 hours. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with CH2Cl2/MeOH 19:1 (v/v) as eluent. The title compound was obtained as a brown viscous oil (26 mg, 27%). MS ISP (m/e): 479.1 (100) [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([CH:11]=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[O-:13]Cl=O.[Na+]>O.CS(C)=O>[Cl:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([OH:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1csc2c(Cl)ncnc12
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1csc2c(Cl)ncnc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
NaH2PO4.2H2O (170 mg, 1.07 mmol) was dissolved in water (0.6 mL) and 4-chlorothieno[3,2-d]pyrimidine-7-carbaldehyde (100 mg, 0.47 mmol) dissolved in DMSO (4.8 mL) was added thereto at 10° C. The reaction mixture was cooled to 0° C. and NaClO2 (170 mg, 1.88 mmol) dissolved in water (0.6 mL) was added thereto at 0° C. The reaction mixture was heated to room temperature, stirred for 2 hours, and water (10 mL) was added thereto. The reaction mixture was stirred for 2 hours and then filtered. The filtrate was concentrated to obtain the title compound as a white solid.
Reaction SMILES: N1C=CC=C(CN)C=1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][NH2:16].FC1C=CC(CN2[C@@H](C)CN(C3SC(C(O)=O)=C(C)N=3)C2=O)=CC=1.[F:41][C:42]1[CH:64]=[CH:63][C:45]([CH2:46][N:47]2[CH2:51][C@H:50]([CH3:52])[N:49]([C:53]3[S:54][C:55]([C:59](O)=[O:60])=[C:56]([CH3:58])[N:57]=3)[C:48]2=[O:62])=[CH:44][CH:43]=1>>[F:41][C:42]1[CH:64]=[CH:63][C:45]([CH2:46][N:47]2[CH2:51][C@H:50]([CH3:52])[N:49]([C:53]3[S:54][C:55]([C:59]([NH:16][CH2:15][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=4)=[O:60])=[C:56]([CH3:58])[N:57]=3)[C:48]2=[O:62])=[CH:44][CH:43]=1
Reactant: NCc1ccccn1
Reactant: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)C[C@@H]2C)sc1C(=O)O
Agent: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)C[C@@H]2C)sc1C(=O)NCc1ccccn1

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with pyridin-2-ylmethanamine and replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with (S)-2-(3-(4-fluorobenzyl)-5-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white solid (72%): mp 112-113° C. (diethyl ether/hexane); 1H NMR (300 MHz, DMSO-d6) δ 8.50-8.46 (m, 2H), 7.75-7.70 (m, 1H), 7.34-7.14 (m, 6H), 4.56-4.51 (m, 1H), 4.46-4.39 (m, 4H), 3.56-3.50 (m, 1H), 3.01 (dd, J=9.1, 3.4 Hz, 1H), 2.46 (s, 3H), 1.36 (d, J=6.2 Hz, 3H); MS (ES+) m/z 439.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]=O)=[C:4]([Cl:11])[N:3]=1.[CH3:12][NH:13][NH2:14]>CCO>[Cl:11][C:4]1[N:3]=[C:2]([Cl:1])[N:7]=[C:6]2[N:13]([CH3:12])[N:14]=[CH:9][C:5]=12
Reactant: CNN
Reactant: O=Cc1c(Cl)nc(Cl)nc1Cl
Solvent: CCO
Product: Cn1ncc2c(Cl)nc(Cl)nc21
Reaction time: 0.5 h

Procedure:
To a solution of 2,4,6-trichloro-pyrimidine-5-carbaldehyde (3.7 g, 17.5 mmol) in EtOH (50 mL) cooled to −78° C. was added methyl hydrazine (0.93 mL, 17.5 mmol) and TEA (8 mL). The mixture was stirred for 30 minutes at −78 C then 2 hr at 0 C. The solution was concentrated in vacuo without heating. To the reduced volume solution was added EtOAc and the solution washed with a sat NaHCO3 solution and concentrated in vacuo without heating. Filtration over a small silica gel plug (2:1 EtOAc:Hex) and concentration afforded the desired product as a yellow solid. It should be noted that the reaction with aromatic hydrazine compounds can be conducted at 0° C.
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]2[C:5]([C:6]([F:21])([F:20])[CH2:7][CH2:8][C@@:9]32[C:14]([F:16])([F:15])[CH2:13][O:12][C:11]([NH2:17])=[N:10]3)=[CH:4][CH:3]=1.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[N:27][CH:28]=1>>[F:20][C:6]1([F:21])[C:5]2[C:18](=[CH:19][C:2]([C:25]3[CH:26]=[N:27][CH:28]=[C:23]([F:22])[CH:24]=3)=[CH:3][CH:4]=2)[C@@:9]2([C:14]([F:16])([F:15])[CH2:13][O:12][C:11]([NH2:17])=[N:10]2)[CH2:8][CH2:7]1
Reactant: OB(O)c1cncc(F)c1
Reactant: NC1=N[C@@]2(CCC(F)(F)c3ccc(Br)cc32)C(F)(F)CO1
Product: NC1=N[C@@]2(CCC(F)(F)c3ccc(-c4cncc(F)c4)cc32)C(F)(F)CO1
Yield: 32 %

Procedure:
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-7-bromo-4,4,5′,5′-tetrafluoro-3,4,5′,6′-tetrahydro-2H-spiro[naphthalene-1,4′-[1,3]oxazin]-2′-amine (intermediate A6.4) with 5-fluoropyridin-3-ylboronic acid yielded the title compound (32% yield) as a pale yellow solid. MS (ISP): m/z=384.0 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][CH:10]([OH:17])[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:6][CH:5]=1.CN(C)P(N(C)C)(N(C)C)=O.Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH:10]([O:17][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:18][CH:19]=1
Reactant: CCCCCCCCCCBr
Reactant: OC(COc1ccc(Cl)cc1)Cn1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCCCOC(COc1ccc(Cl)cc1)Cn1ccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 56% dispersion of sodium hydride in mineral oil (480 mg.) is added under nitrogen to a solution of 2.52 g. of 1-[3'-(4"-chlorophenoxy)-2'-hydroxypropyl]imidazole in 6 ml. dry hexamethylphosphoramide. After stirring for 1 hours at room temperature, the temperature is increased to 45° C. and stirring is continued for 2 hours. The solution is then cooled in an ice bath and 2.5 g. of 1-bromodecane in 1 ml. of hexamethylphosphoramide is added. Thereafter, the solution is stirred for 2 hours at room temperature and then for 16 hours at 50° C. The reaction mixture is poured into water and the resultant aqueous mixture extracted with ether and the ether extracts washed with water. The organic phase is dried over magnesium sulfate and evaporated. The resulting residue is chromatographed on silica gel. Elution with 20% acetone in dichloromethane yields 1-[3'-(4"-chlorophenoxy)-2'-(n-decyloxy)propyl]imidazole.
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:17]=1[O:18][C:19]1[CH:27]=[CH:26][C:25]([C:28]([CH3:32])([CH3:31])[CH2:29][CH3:30])=[CH:24][C:20]=1[C:21]([O-:23])=[O:22].[F:41][C:42]([F:57])([F:56])[C:43]1[CH:44]=[C:45]([N:53]=[C:54]=[O:55])[CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1>N1C=CC=CC=1>[CH:1]([OH:14])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:41][C:42]([F:56])([F:57])[C:43]1[CH:44]=[C:45]([NH:53][C:54](=[O:55])[NH:15][C:16]2[CH:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=[CH:33][C:17]=2[O:18][C:19]2[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:32])[CH2:29][CH3:30])=[CH:24][C:20]=2[C:21]([O-:23])=[O:22])[CH:46]=[C:47]([C:49]([F:52])([F:50])[F:51])[CH:48]=1
Reactant: CCC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2N)c(C(=O)[O-])c1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: OC(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CCC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2NC(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(C(=O)[O-])c1

Procedure:
Benzhydrol-2-(2-amino-4-trifluoromethylphenoxy)-5-(1,1-dimethylpropyl)benzoate (200 mg, 0.0004 mol) and 3,5-di(trifluoromethyl)phenyl isocyanate (300 μL 0.002 mol) were mixed in pyridine, under argon, at room temperature for 16 h. The solvent was evaporated and the residue flash chromatographed (silica gel, ethyl acetate/hexane) to yield the title compound. 1H NMR (250 MHz, CDCl3) δ8.69 (d, 2H), 7.97 (d, 1H), 7.59 (s, 2H), 7.48 (d, 2H), 7.20-7.39 (m, 9H), 7.08 (d, 1H), 6.95 (s, 1H), 6.82 (dd, 2H), 2.05 (d, 1H), 1.64 (dd, 2H), 1.32 (s, 6H), 0.99 (d, 1H ), 0.72 (t, 3H).
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[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[N:22]([C:24](Br)=[C:25]([CH3:27])[N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:36]([O:40][CH3:41])(=[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>[CH3:41][O:40][C:36](=[O:39])/[CH:37]=[CH:38]/[C:24]1[N:22]2[N:23]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:8]4([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:35])[CH2:11][CH2:10][CH2:9]4)=[CH:13][CH:14]=3)[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:20][C:21]2=[N:26][C:25]=1[CH3:27]
Reactant: C=CC(=O)OC
Reactant: Cc1nc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn2c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)/C=C/c1c(C)nc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn12
Temperature: 110 °C
Reaction time: 3 h

Procedure:
200 mg (0.375 mmol) {1-[4-(3-Bromo-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, intermediate example Int-2-3, 64.5 mg (0.75 mmol) methyl acrylate, 19.4 mg (0.064 mmol) tri-2-tolylphosphane, 16.8 mg (0.075 mmol) palladium(II) acetate and 0.06 mL (0.427 mmol) triethylamine in 2.6 mL degassed acetonitrile were heated in the microwave at 110° C. for three hours. Due to an incomplete reaction additional 32.2 mg (0.375 mmol) methyl acrylate and 8.5 mg (0.037 mmol) palladium(II) acetate were added, and heating in the microwave was continued for three hours. The reaction mixture was poured on water/saturated ammonium chloride/dichloromethane and vigorously stirred for 30 minutes. The organic phase was separated, washed twice with brine, dried, and the solvent was removed. The crude product (300 mg) was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]([O:14][CH3:15])[CH2:10][N:11]=[C:12]=[O:13])[CH:6]=[CH:7][CH:8]=1.[OH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:21][CH:20]=1>C1C=CC=CC=1.O1CCCC1>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([CH:9]([O:14][CH3:15])[CH2:10][NH:11][C:12]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[NH:28][C:27]3=[O:32])=[CH:21][CH:20]=2)=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Reactant: COC(CN=C=O)c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: COC(CNC(=O)Oc1ccc(CC2SC(=O)NC2=O)cc1)c1cccc(C(F)(F)F)c1

Procedure:
A solution containing 1.5 g of the compound prepared in stage A in 10 ml of benzene is added to a solution containing 1.4 g of 5-[(4-hydroxyphenyl)methyl]-2,4-thiazolidinedione in 5 ml of tetrahydrofuran.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:5]2[CH2:12][CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1.N1C=CC=CC=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)(Cl)Cl>[C:36]([NH:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]2)[C:5]2[CH2:12][CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1)(=[O:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N)nc3c2CCCc2ccccc2-3)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1nc2c(c(N3CCN(C(=O)OC(C)(C)C)CC3)n1)CCCc1ccccc1-2
Temperature: 60 °C

Procedure:
The product from Example 83A (20 mg, 0.051 mmol) was treated with CHCl3 (0.080 mL), pyridine (0.020 mL, 0.25 mmol), and acetic anhydride (0.006 mL, 0.061 mmol), then heated at 60° C. overnight, cooled and purified by chromatography (eluting with 9:1, 4:1 and 2:1 CH2Cl2:EtOAc) to provide the title compound. MS (M+H)+ m/z 438.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[C:13](I)[C:14]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=4[N:16]=3)=[N:9][N:8]([CH2:24][C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[C:5]2=[N:6][CH:7]=1.C[N:33]1[CH2:37][CH2:36][CH2:35][C:34]1=O>NCC1CC1>[CH:36]1([CH2:37][NH:33][C:13]2[C:14]3[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=3[N:16]=[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=4)[N:8]([CH2:24][C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=4)[N:9]=3)[N:12]=2)[CH2:34][CH2:35]1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ncccc4F)c4ncc(F)cc34)nc(I)c21
Reactant: CN1CCCC1=O
Agent: NCC1CC1
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ncccc4F)c4ncc(F)cc34)nc(NCC3CC3)c21
Temperature: 150 °C

Procedure:
200 mg (0.206 mmol, approx. 55% purity) of the compound obtained in example 21A was dissolved in 1-methyl-2-pyrrolidone (4 ml) in a reaction vessel suitable for a microwave and 1 ml of aminomethylcyclopropane was added. Then it was sealed with a corresponding septum and it was heated in the microwave at 150° C. for 3 h. After cooling, the reaction mixture was purified by preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 64 mg of the title compound was obtained (65% of theor.).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]3[CH3:27])[N:16]=2)[CH:3]=1.[CH2:28]1[CH2:32]O[CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH2:30][CH2:29][C:28]2[CH:32]=[CH:4][CH:3]=[CH:2][CH:13]=2)=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]3[CH3:27])[N:16]=2)[CH:3]=1
Reactant: CON(C)C(=O)c1ccc(Cl)cc1Nc1cccc(-n2c(C)ccc2C)n1
Reactant: C1CCOC1
Product: Cc1ccc(C)n1-c1cccc(Nc2cc(Cl)ccc2C(=O)CCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-chloro-2-[6-(2,5-dimethyl-pyrrol-1-yl)-pyridin-2-ylamino]-N-methoxy-N-methyl-benzamide (1.59 g) in THF (20 mL) was cooled in an ice bath, and phenethyl-Grignard solution (10 mL, 1 M in THF) added via syringe. The mixture was stirred overnight at RT, quenched with NH4Cl (aq), extracted with EtOAc, and adsorbed on silica. The product was chromatographed on silica (80 g) (hexane/EtOAc 100:0 to 50:50) (or using DCM/MeOH) to provide 1-{4-chloro-2-[6-(2,5-dimethyl-pyrrol-1-yl)-pyridin-2-ylamino]-phenyl}-3-phenyl-propan-1-one.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([N:7]([C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=1[CH3:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6])C.[OH-].[Na+].C(OCC)C>C1COCC1>[C:15]1([CH3:22])[CH:16]=[C:17]([CH3:21])[CH:18]=[C:19]([CH3:20])[C:14]=1[N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5](=[O:6])[C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)C(=O)N(c1ccccc1)c1c(C)cc(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(C)c(N(C(=O)C(=O)O)c2ccccc2)c(C)c1
Reaction time: 2 h
Yield: 98.8 %

Procedure:
N-(Mesityl)-oxanilic acid ethyl ester (1.99 g, 8.5 mmol) was dissolved in THF (50 ml), forming a solution. To this solution was added 1M NaOH solution (40 ml), and the mixture was then stirred for 2 hours. Diethyl ether (25 ml) was then added, and the layers were separated. The organic layer was washed with 1 M NaOH solution (40 ml). The aqueous layer was then acidified with 2M HCl until precipitation occurred. The precipitate was then extracted with ethyl acetate (2×50 ml). The ethyl acetate was washed with brine (50 ml), and then dried over MgSO4. Removal of the solvent under reduced pressure provided the product as a white solid (1.74 g, 8.4 mmol, 99% yield). 1H NMR (300 MHz, CDCl3) δ 8.51 (s, 1H), 6.93 (s, 2H), 2.29 (s, 3H), 2.19 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 160.0, 156.1, 138.6, 134.7, 129.5, 128.9, 21.2, 18.5. Anal. Calcd for C11H13NO3: C, 63.76; H, 6.32; N, 6.76. Found: C, 63.59; H, 6.32; N, 6.79.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:11](=[O:20])[CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][C:14]2=[O:19])=[CH:4][CH:3]=1.[CH3:21][C:22]1[C:30]2[CH2:29][O:28][C:27](=[O:31])[C:26]=2[CH:25]=[CH:24][C:23]=1[C@@H:32]1[CH2:34][O:33]1>CCO>[F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:11](=[O:20])[CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:34][C@H:32]([OH:33])[C:23]3[CH:24]=[CH:25][C:26]4[C:27](=[O:31])[O:28][CH2:29][C:30]=4[C:22]=3[CH3:21])[CH2:15][C:14]2=[O:19])=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)CN2CCNCC2=O)ccc(F)c1C#N
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Solvent: CCO
Product: Cc1c(C(=O)CN2CCN(C[C@H](O)c3ccc4c(c3C)COC4=O)CC2=O)ccc(F)c1C#N
Temperature: 140 °C

Procedure:
A mixture of 6-Fluoro-2-methyl-3-[(2-oxopiperazin-1-yl)acetyl]benzonitrile (40 mg, 0.14 mmol) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (42 mg, 0.22 mmol) in EtOH (2 mL) was heated to 140° C. for 1 hour. The reaction mixture was concentrated to dryness, and dissolved in MeOH, filtered and shot into Mass-directed HPLC for separation to give the title product. LC-MS (IE, m/z): 466 [M+1]+.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]#[N:13])=[CH:4]1.[F:14][C:15]([F:24])([F:23])[CH2:16][CH2:17][CH:18]([C:21]#[N:22])[C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:12]([C:5]1[C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][N:3]([CH2:2][C:18]([CH2:17][CH2:16][C:15]([F:14])([F:23])[F:24])([C:19]#[N:20])[C:21]#[N:22])[CH:4]=1)#[N:13]
Reactant: N#Cc1cn(CCl)cc1C(F)(F)F
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cn(CC(C#N)(C#N)CCC(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
0.80 g of 1-chloromethyl-3-cyano-4-trifluoromethyl-1H-pyrole and 0.67 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 10 ml of N,N-dimethylformamide. 0.57 g of potassium carbonate was added to the solution under ice cooling, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.33 g of [(3-cyano-4-trifluoromethyl-1H-pyrole-1-yl) methyl](3,3, 3-trifluoropropyl) malononitrile (referred as the compound of the present invention (46), hereinafter) shown by below formula.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]3[CH:13]=[CH:14][C:15]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[N:18]=4)=[CH:16][C:9]=23)=[CH:4][CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]3[CH:13]=[CH:14][C:15]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[N:18]=4)=[CH:16][C:9]=23)=[CH:4][CH:3]=1
Reactant: Nc1nccc(-c2ccc3noc(-c4ccc(Cl)cc4)c3c2)n1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1nccc(-c2ccc3noc(-c4ccc(Cl)cc4)c3c2)n1
Temperature: 100 °C
Yield: 30 %

Procedure:
To a suspension of 4-[3-(4-chlorophenyl)-benzo[c]isoxazol-5-yl]-pyrimidin-2-ylamine in toluene (1.5 mL) at room temperature, was added acetic anhydride (0.5 mL). The mixture was heated at 100° C. for 3 hours. The reaction mixture was diluted with water (6 mL) and the precipitate filtered then washed with toluene (2×6 mL). Purification was achieved by silica gel chromatography (4:1 ethyl acetate/hexane then 2% methanol/dichloromethane), followed by a 5% aqueous sodium bicarbonate wash (1×50 mL) to give the title compound as a yellow solid (12 mg, 30% yield). 1H NMR (500 MHz, d6-DMSO) δ 10.62 (s, 1H), 8.85 (s, 1H), 8.75 (d, 1H), 8.31 (d, 1H), 8.25 (d, 2H), 8.02 (d, 1H), 7.85 (d, 1H), 7.75 (d, 2H), 2.3 (s, 3H) ppm. LC-MS (ES+) m/e=365.13 (M+H).