Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[CH:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[B]=O.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.B(OC(C)C)(OC(C)C)OC(C)C.N1CCCCC1.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.[Cl-].[Na+].O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6](/[CH:10]=[CH:11]/[C:12](=[O:17])[CH2:13][C:14](=[O:16])/[CH:15]=[CH:32]/[C:31]3[CH:30]=[CH:29][C:28]([O:27][CH2:26][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=4)=[CH:35][CH:34]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(=O)CC(=O)C=Cc1ccc2[nH]ccc2c1
Reactant: O=Cc1ccc(OCc2ccccn2)cc1
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCNCC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(/C=C/c1ccc(OCc2ccccn2)cc1)CC(=O)/C=C/c1ccc2[nH]ccc2c1
Temperature: 70 °C
Yield: 64.6 %

Procedure:
In a 20 mL reaction vessel were placed 31.0 mg (136 μmol) of 6-(1H-indol-5-yl)hex-5-ene-2,4-dione and 13.2 mg (0.190 mmol) of boron oxide and they were dissolved in 0.88 mL of ethyl acetate. To the mixture under stirring at 70° C., 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde and 62 μL (0.27 mmol) of triisopropyl borate were sequentially added. After the mixture was stirred at the same temperature for 1 hour, a solution of 2.7 μL (27 μmol) of piperidine in ethyl acetate (0.135 mL) was added and the mixture was further stirred for 1 hour. To the reaction mixture was added a 1:1 solution (0.4 mL) of 1 N hydrochloric acid and saturated brine at room temperature and the mixture was stirred for 5 minutes to 1 hour (further, the mixture was neutralized with a saturated sodium bicarbonate aqueous solution as needed). The resulting organic phase was directly subjected to purification by silica gel column chromatography (hexane/ethyl acetate or methylene chloride/methanol) to give 37.1 mg (65% yield) of the title compound as a yellow powder.
Reaction SMILES: [CH2:1]([C:4]1([C:19]2[CH2:24][CH2:23][N:22](C)[CH2:21][CH:20]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH:2]=[CH2:3].[Cl:26][C:27]([Cl:34])([Cl:33])[CH2:28][O:29][C:30](Cl)=[O:31].O>C1C=CC=CC=1>[CH2:1]([C:4]1([C:19]2[CH2:24][CH2:23][NH:22][CH:21]([C:30]([O:29][CH2:28][C:27]([Cl:34])([Cl:33])[Cl:26])=[O:31])[CH:20]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH:2]=[CH2:3]
Reactant: C=CCC1(C2=CCN(C)CC2)c2ccccc2CCc2ccccc21
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Product: C=CCC1(C2=CC(C(=O)OCC(Cl)(Cl)Cl)NCC2)c2ccccc2CCc2ccccc21
Temperature: 25 °C
Yield: 75.4 %

Procedure:
Dissolved 4-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-1-methyl-1,2,5,6-tetrahydropyridine (3.3 g, 10.0 mmol) in 50 mL of benzene, and added 2,2,2-trichloroethylchloroformate (3.0 mL, 4.6 g, 21.8 mmol). Refluxed for 20 hours under a nitrogen atmosphere. Cooled to room temperature, and added water. Extracted with ether. Dried combined organic extracts with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with dichloromethane. Combined appropriate fractions, and evaporated to give 3.7 g (75% yield) of 2,2,2-trichloroethyl 4-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-1,2,5,6-tetrahydro-pyridinecarboxylate as an oil.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[S:16][C:17]([C:20]2[N:25]=[C:24]([NH:26][C:27]3[CH:31]=[C:30]([CH:32]4[CH2:34][CH2:33]4)[NH:29][N:28]=3)[C:23]([C:35]#[CH:36])=[CH:22][N:21]=2)=[CH:18][CH:19]=1)(=[O:14])=[O:13])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:32]1([C:30]2[CH:31]=[C:27]([NH:26][C:24]3[C:23]([C:35]#[CH:36])=[CH:22][N:21]=[C:20]([C:17]4[S:16][C:15]([S:12]([NH:11][CH2:10][CH2:9][OH:8])(=[O:13])=[O:14])=[CH:19][CH:18]=4)[N:25]=3)[NH:28][N:29]=2)[CH2:34][CH2:33]1
Reactant: C#Cc1cnc(-c2ccc(S(=O)(=O)NCCO[Si](C)(C)C(C)(C)C)s2)nc1Nc1cc(C2CC2)[nH]n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cnc(-c2ccc(S(=O)(=O)NCCO)s2)nc1Nc1cc(C2CC2)n[nH]1
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To a solution of N-(2-(tert-butyldimethylsilyloxy)ethyl)-5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-ethynylpyrimidin-2-yl)thiophene-2-sulfonamide (100 mg, 0.18 mmol, 1 equiv.) in dry THF (4 mL) was added tetrabutylammonium fluoride (0.54 mL, 0.54 mmol, 3.0 equiv., 1.0 M solution in THF) dropwise. The reaction mixture was allowed to stir for 1 h. The reaction mixture was washed with NaHCO3 and water. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated and resulting residue was crystallized with THF, ether and ethanol to give title compound 5-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-5-ethynylpyrimidin-2-yl)-N-(2-hydroxyethyl)thiophene-2-sulfonamide (Compound 108) as pale solid (50 mg, 64%). LC-MS (m/z)=430.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.75-0.76 (m, 2H), 0.98-1.00 (m, 2H), 1.95 (m, 1H), 2.95 (q, J=5.2 Hz, 2H), 3.42 (q, J=6.0 Hz, 2H), 4.75 (t, J=5.2 Hz, 1H), 4.89 (s, 1H), 6.44 (s, 1H), 7.62 (d, J=3.6 Hz, 1H), 7.83 (d, J=3.6 Hz, 1H), 8.02 (s, 1H), 8.52 (s, 1H), 8.81 (s, 1H), 12.32 (s, 1H).
Reaction SMILES: [CH3:1][Si:2]([CH3:16])([C:10]#[C:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9]>C(O)C.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[CH3:16][Si:2]([CH3:1])([CH2:10][CH2:11][Si:12]([CH3:13])([CH3:14])[CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9]
Reactant: C[Si](C)(C)C#C[Si](C)(C)CCCCCCO
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[Si](C)(C)CC[Si](C)(C)CCCCCCO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of compound 16 (18.18 g, 0.071 mol) and palladium hydroxide on charcoal (2.46 g, 2.13 mmol) in ethanol and ethyl acetate (120 ml, 1:1) was stirred under an atmosphere of hydrogen for 24 h at room temperature. The reaction mixture was filtered (celite) and the solvent roved in vacuo to yield a clear oil.
Reaction SMILES: [C:1]([C:10]1[CH:18]=[C:14]([C:15]([OH:17])=[O:16])[C:13]([OH:19])=[CH:12][CH:11]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(=O)([O-])[O-].[Ca+2:24]>C(O)(C)C.O>[C:1]([C:10]1[CH:18]=[C:14]([C:15]([O-:17])=[O:16])[C:13]([OH:19])=[CH:12][CH:11]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Ca+2:24].[C:1]([C:10]1[CH:18]=[C:14]([C:15]([O-:17])=[O:16])[C:13]([OH:19])=[CH:12][CH:11]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)c1ccc(O)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCC(=O)c1ccc(O)c(C(=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
39.6 g of 5-octanoylsalicylic acid (0.15 mol) in 300 ml of isopropanol and 150 ml of water were introduced into a 500 ml round-bottomed flask. 7.5 g of calcium carbonate (0.075 mol) were then added portionwise. The mixture was left stirring at room temperature for 3 hours and was then concentrated to dryness under vacuum on a rotary evaporator.
Reaction SMILES: [Cl:1][C:2]1[C:3](B(O)O)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Br[C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH:21]([F:23])[F:22]>>[Cl:1][C:2]1[C:3]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[CH:21]([F:23])[F:22])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: FC(F)c1ccc(Cl)cc1Br
Reactant: COc1cc(B(O)O)c(Cl)cn1
Product: COc1cc(-c2cc(Cl)ccc2C(F)F)c(Cl)cn1

Procedure:
463 mg (purity 93%, 2.3 mmol) of (5-chloro-2-methoxypyridin-4-yl)boronic acid and 515 mg (2.1 mmol) of 2-bromo-4-chloro-1-(difluoromethyl)benzene in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. Yield: 305 mg (purity 77%, 34% of theory)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:16][CH3:17])[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(C=CC=1)C(OO)=[O:23]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:16][CH3:17])[CH2:13][CH2:12][N+:11]([O-:23])([CH2:14][CH3:15])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCN1CCC(OC)(c2ccc(F)c(F)c2)C1
Solvent: ClCCl
Product: CC[N+]1([O-])CCC(OC)(c2ccc(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of enantiomer 2 of 3-(3,4-difluorophenyl)-1-ethyl-3-methoxypyrrolidine (0.011 g, 0.045 mmol) in dichloromethane (2 ml) was added 3-chloroperoxybenzoic acid (77%) (0.0204 g, 0.09 mmol). The mixture was stirred at room temperature for 30 min and was then filtrated through a plug of aluminiumoxid (basic) which was eluted with dichloromethane:MeOH (9:1). The crude product was analyzed by LCMS (Qtrap, Applied Biosystems, Q1 MS). analysis showed <95% conversion: MS (m+1)/z; 258 (M+1, bp), 259 (23), 257 (3), 214 (7), 142 (5).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH:5]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:16])[C:9]=2[CH:8]=[CH:7][CH:6]=1.[Br:17]Br>Cl>[Br:17][C:7]1[CH:6]=[CH:5][C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:16])[C:9]=2[CH:8]=1
Reactant: O=C1CCCCc2ccccc21
Reactant: BrBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1CCCCc2ccc(Br)cc21
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 27.8 %

Procedure:
A 3-neck 250 mL flask fitted with a condenser was charged with aluminum trichloride (45.0 g, 337 mmol) which was then heated to 75° C. under nitrogen. 6,7,8,9-Tetrahydro-5H-benzo[7]annulen-5-one (20.0 g, 125 mmol) was added slowly dropwise via additional funnel. After complete addition, a dark brown slurry was formed. After stirring for 20 min, bromine (8.36 ml, 162 mmol) was added dropwise very slowly at 75° C., and the reaction mixture was stirred at 75° C. for an additional 20 min. The hot mixture was slowly poured into 400 g of ice and 30 mL of concentrated HCl. The resulting mixture was stirred for 30 min, then extracted with diethyl ether (3×400 mL). The ethereal extract was concentrated and the residue was purified using silica gel column chromatography (hexanes-10% EtOAc) to afford 3-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (8.3 g, 28%). 1H NMR (500 MHz, chloroform-d) δ 7.86 (d, J=2.1 Hz, 1H), 7.54 (dd, J=8.2, 2.1 Hz, 1H), 7.10 (d, J=8.2 Hz, 1H), 2.94-2.88 (m, 2H), 2.80-2.72 (m, 2H), 1.94-1.80 (m, 4H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[S:11](=O)(=[O:14])([OH:13])[OH:12].[CH2:16]=[O:17].[OH-].[Ca+2].[OH-]>O>[C:9]1([S:11]([OH:14])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1.[CH2:16]=[O:17]
Reactant: O=S(=O)(O)O
Reactant: c1ccc2ccccc2c1
Agent: C=O
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(O)c1cccc2ccccc12
Temperature: 25 °C

Procedure:
1 mol of naphthalene (128.2 g) was reacted with 1.28 mol of sulfuric acid (125.5 g) for 3 hours at 150° C. to 160° C. To the product (sulfonate) were added 44 g of water, and formalin (37% formaldehyde in water) in such amount as equal to 0.98 mol of formaldehyde dropwise over 3 hours at 90° C. The mixture was reacted for condensation for 10 hours at 100±2° C. The mixture was cooled to room temperature, neutralized to pH 5 with calcium hydroxide, and filtrated to remove generated precipitates (gypsum), resulting in an aqueous solution of a naphthalenesulfonic acid-formaldehyde condensate (B-1). The polymer was dried for 24 hours at 105° C. The aqueous solution was adjusted to an intended concentration to be used according to need.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.O(C(C)(C)C)[Na]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:17]3[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=3)=[CH:22][CH:23]=2)[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Ic1ccc(Cc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Cc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of 1-Boc-piperazine (2.5 g, 13.1 mmol) and 4-iododiphenylmethane (4.0 g, 13.1 mmol) in toluene were added the following reagents: Pd2(dba)3 (0.36 g, 0.3 mmol), PtBu3 (0.7 g 3.0 mmol) and NaO-t-Bu (1.26 g, 13.1 mmol). The reaction mixture was stirred at ambient temperature overnight and then filtered. The filtrate was purified using silica gel chromatography (1% MeOH in CH2Cl2) to yield the title compound as a light tan oil (4.6 g, 99%): MS (ESI) m/z 353 (M+H); 1H NMR (400 MHz, CDCl3) δ 1.47 (s, 9H), 3.08 (t, J=5.2 Hz, 4H), 3.56 (s, J=5.2 Hz, 4H), 3.91 (s, 2H), 6.85 (dd, J=2, 6.8 Hz, 2H), 7.09 (dd, J=2, 6.4 Hz, 2H), 7.16-7.19 (m, 3H), 7.25-7.29 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:3]=1.[CH3:20][NH:21][CH2:22][CH2:23][OH:24]>>[OH:24][CH2:23][CH2:22][N:21]([CH3:20])[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([N:21]([CH2:22][CH2:23][OH:24])[CH3:20])[CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[C:18]([N:21]([CH3:20])[CH2:22][CH2:23][OH:24])[CH:17]=[CH:16][N:15]=2)[CH:3]=1
Reactant: Clc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Reactant: CNCCO
Product: CN(CCO)c1ccnc(-c2cc(N(C)CCO)cc(-c3cc(N(C)CCO)ccn3)n2)c1

Procedure:
This compound is prepared in a manner analogous to that described in Example 7 with 4′-chloro-[2,2′;6′,2″]terpyridine, but instead the trichloro-substituted terpyridine L22 from Example 28, and 2-methylaminoethanol as amine component are used. 2-({4′,4″-Bis[(2-hydroxy-ethyl)-methyl-amino]-[2,2′;6′,2′]terpyridin-4-yl}methyl-amino)-ethanol, white solid. 13 C-NMR (90 MHz, DMSO-d6): 156.4 (quart.); 155.7 (quart.); 155.3 (quart.); 154.4 (quart.); 149.2 (tert.); 106.7 (tert.); 103.4 (tert.); 103.1 (tert.); 58.4 (2 signals, sec.); 58.2 (sec.); 53.6 (sec.); 53.5 (2 signals, sec.); 38.6 (prim.); 38.3 (2 signals, prim.).
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3](N)=O.F[B-](F)(F)F.C([O+](CC)CC)C.[O:19]1[CH2:24][CH2:23][CH2:22][C@H:21]([NH:25][C:26]2[C:31]([NH2:32])=[CH:30][N:29]=[C:28]3[CH:33]=[CH:34][S:35][C:27]=23)[CH2:20]1>O1CCCC1.C(O)C>[O:19]1[CH2:24][CH2:23][CH2:22][C@H:21]([N:25]2[C:26]3=[C:27]4[S:35][CH:34]=[CH:33][C:28]4=[N:29][CH:30]=[C:31]3[N:32]=[C:3]2[C@H:2]([OH:1])[CH3:6])[CH2:20]1
Reactant: Nc1cnc2ccsc2c1N[C@H]1CCCOC1
Reactant: C[C@@H](O)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCCOC1
Reaction time: 0.25 h
Yield: 64.8 %

Procedure:
A mixture of (2R)-2-hydroxypropanamide (from Aldrich, 5.4 mg, 0.060 mmol) and triethyloxonium tetrafluoroborate (12 mg, 0.062 mmol) in tetrahydrofuran (0.1 mL) became a solution after stirred for 15 min. After another 45 min, this solution was added to a mixture of N7-[(3S)-tetrahydro-2H-pyran-3-yl]thieno[3,2-b]pyridine-6,7-diamine (7.5 mg, 0.030 mmol) in ethanol (0.24 mL) and the resultant mixture was heated at reflux for 2 h. The crude mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (5.9 mg, 65%). LCMS calculated for C15H18N3O2S (M+H)+: m/z=304.1. Found: 304.0.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1>>[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:35][CH:36]=2)=[C:26]([C:28]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:29])[N:27]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(C(F)(F)F)cc2)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Product: Cc1nc(C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-(4-trifluoromethyl-phenyl)-thiazole-4-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[CH3:15].[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]O)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][C:3]=2[CH3:15])=[CH:19][CH:18]=1
Reactant: OCc1ccc(F)cc1
Reactant: Cc1cnn(-c2cc(C#N)ccn2)c1O
Product: Cc1cnn(-c2cc(C#N)ccn2)c1OCc1ccc(F)cc1

Procedure:
The title compound was prepared from 2-(5-hydroxy-4-methylpyrazol-1-yl)pyridine-4-carbonitrile and 4-fluorobenzyl alcohol according to the procedure for the preparation of Example 39, part C. 1H NMR (300 MHz, CDCl3): δ 1.91 (3H, s), 5.14 (2H, s), 7.26 (2H, s), 7.33-7.37 (3H, m), 7.46 (1H, s), 7.99 (1H, s), 8.62 (1H, d, J=5.1 Hz). [M+H] Calc'd for C17H13FN4O, 309; Found, 309.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Cl[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[O:20][N:19]=1>>[S:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[C:21]1[O:20][N:19]=[C:18]([CH2:17][N:7]2[C:8]3[C:4](=[C:3]([C:2]([F:14])([F:1])[F:15])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)[N:22]=1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Reactant: ClCc1noc(-c2cccs2)n1
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cccs3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 23 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-(2-thienyl)-1,2,4-oxadiazole: MS (ES) m/z 375 (M+1).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[OH:11])[CH2:8]2.CN(C)C1C=CC=CC=1.[C:21](Cl)([Cl:23])=[O:22].C(=O)=O>CCOCC.C1(C)C=CC=CC=1>[Cl:23][C:21]([O:11][CH:2]1[CH:3]2[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]1[CH2:8]3)[CH2:4]2)=[O:22]
Reactant: O=C(Cl)Cl
Reactant: OC1C2CC3CC(C2)CC1C3
Agent: O=C=O
Solvent: CN(C)c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Temperature: 25 °C

Procedure:
15.2 g (0.10 mole) of 2-adamantanol and 12.1 g (0.10 mole) of N,N-dimethylaniline were dissolved in 200 ml of dry ether and added to 105 ml (0.20 mole) of phosgene in toluene (20%) over a period of 1 hour. The reaction flask was kept at 0° C. and was equipped with a stirrer and a dry ice condensor. The product was stirred at room temperature for another hour, after which the solution was cooled on ice and 10 ml of ice cold water was added carefully. The water and the toluene phases were quickly separated and the toluene was quickly washed with 50 ml of 0.5 N HCl, 50 ml of 0.5 N NaOH and 50 ml of H2O. The toluene solution was dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in dry n-hexane and filtered. The hexane was evaporated and the residue was distilled in vacuo to give 2-adamantanyl chloroformate bp15 135° C., nD19 1.521, IR (CO) 1770 cm-1.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].I[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1.[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]=[C:16]1B(O)O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:14][C:11]1[CH:10]=[C:9]([C:16]2[O:15][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH:17]=2)[CH:8]=[CH:13][CH:12]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: Brc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2cc3ccccc3o2)c1

Procedure:
Under an argon atmosphere, 300 mL of toluene and 150 mL of a 2-M aqueous solution of sodium carbonate were added to 28.3 g (100 mmol) of 4-iodobromobenzene, 17.0 g (105 mmol) of benzofuran-2-boronic acid, and 2.31 g (2.00 mmol) of tetrakis(triphenylphosphine)palladium(0), and the mixture was refluxed under heat for 10 hours.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1B(O)O>>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Reactant: OB(O)c1ccc(F)cc1F
Product: Cc1c2n(c3c(-c4ccc(F)cc4F)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, off-white solid (40 mg, 46%), MS (ISP) m/z=352.5 [(M+H)+], mp 225° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 2,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[N:12]1[C:21]2[C:16](=[C:17]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[Cl:31])[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[CH:15]=[N:14][C:13]1=[O:32]>C1COCC1>[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[N:12]1[C:21]2[C:16](=[C:17]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[Cl:31])[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[CH2:15][N:14]([CH3:1])[C:13]1=[O:32]
Reactant: COc1cc(-c2ccc(F)cc2Cl)c2cnc(=O)n(-c3c(Cl)cccc3Cl)c2c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1cc(-c2ccc(F)cc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)N(C)C2
Temperature: 0 °C

Procedure:
A solution of methylmagnesium bromide (3.0M ethyl ether, 0.5 mL) was added dropwise to 1-(2,6-dichlorophenyl)-5-(2-chloro-4-fluorophenyl)-7-(methoxy)-2(1H)-quinazolinone (230 mg, 0.511 mmol) (INTERMEDIATE 56) in THF (10 mL) at −78C. After 20 min the solution was warmed to 0° C. After 40 min at 0° C. the solution was partitioned between NaHCO3 and EtOAc. The phases were separated and the organic phase washed with brine, dried over MgSO4, filtered and concentrated. The crude was absorbed on SiO2 and purified by silica gel chromatography using 2% acetone in DCM as the eluent to give 1-(2,6-dichlorophenyl)-3-methyl-5-(2-chloro-4-fluorophenyl)-7-methoxy-3,4-dihydro-2(1H)-quinazolinone. 1H NMR(CDCl3, 500 MHz): diastereomeric atropisomers δ 1.29 (m, 3H), 3.69 (s, 3H), 4.31 (m, 0.5H), 4.41 (m, 0.5H), 5.32 (m, 0.5H), 5.35 (m, 0.5H), 5.76 (m, 1H), 6.37 (d, 0.5H, J=2.5 Hz), 6.44 (d, 0.5H, J=2.2 Hz), 7.08-7.14 (m, 1H), 7.28-7.40 (m, 3H), 7.50-7.56 (m, 2H). MS(ES) 465 (M+H); LC 1: 3.63 min. and MS(ES) 465 (M+H); LC 1: 3.71 min.