Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]1[C:8]2[CH:9]=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]3)[CH:11]=[CH:12][C:7]=2[CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[C:31]1([CH2:37][S:38](Cl)(=[O:40])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[C:31]1([CH2:37][S:38]([N:5]2[CH2:6][C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:14][CH2:15][N:16]([C:19](=[O:21])[CH3:20])[CH2:17][CH2:18]4)=[CH:9][C:8]=3[O:2][CH2:3][CH2:4]2)(=[O:40])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(=O)N1CCN(c2ccc3c(c2)OCCNC3)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc3c(c2)OCCN(S(=O)(=O)Cc2ccccc2)C3)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.6 %

Procedure:
To a solution of 1-(4-(2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-8-yl)piperazin-1-yl)ethanone hydrochloride (80 mg, 0.26 mmol) and N,N-diisopropylethylamine (0.17 mL, 0.94 mmol) in dichloromethane (1.5 mL) was added phenylmethanesulfonyl chloride (76 mg, 0.39 mmol) and the reaction was stirred at ambient temperature for 16 hours. The reaction was then concentrated and purified by preparative reverse phase HPLC to yield 61 mg of 1-[4-(4-phenylmethanesulfonyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-8-yl)-piperazin-1-yl]-ethanone. 1H NMR (400 MHz, DMSO) δ 7.38-7.27 (m, 5H), 7.03 (d, J=8.3 Hz, 1H), 6.63-6.58 (m, 1H), 6.58-6.55 (m, 1H), 4.36 (s, 2H), 4.22 (s, 2H), 3.96-3.90 (m, 2H), 3.59-3.51 (m, 4H), 3.51-3.46 (m, 2H), 3.18-3.12 (m, 2H), 3.12-3.04 (m, 2H), 2.02 (s, 3H); LCMS (m/z) ES+ 430.1 [M+1]+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]3[NH:15][CH:16]=[C:17]([CH2:18][CH2:19][OH:20])[C:11]=3[CH:10]=2)=[CH:3][CH:2]=1.[C:21]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])(=O)[CH2:22][CH2:23][CH3:24].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][C:21]1([CH2:22][CH2:23][CH3:24])[C:16]2[NH:15][C:12]3[C:11]([C:17]=2[CH2:18][CH2:19][O:20]1)=[CH:10][C:9]([O:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[CH:14][CH:13]=3)[CH3:31]
Reactant: OCCc1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: CCCC(=O)CC(=O)OCC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
A solution of 5-benzyloxytryptophol (4.72 g, 17 mmol) and ethyl butyrylacetate (3.16 g, 20 mmol) in methylene chloride (75 ml) is treated dropwise with boron trifluoride etherate (3 mL) and stirred under nitrogen at room temperature overnight. The reaction mixture is diluted with methylene chloride (250 mL) and sequentially washed with 5% aqueous sodium bicarbonate (2×100 mL) and water (2×50 mL). The organic phase is dried (MgSO4), filtered, and evaporated to afford 7.0 g of a crude dark oil. Purification by flash column chromatography (ethyl acetate:hexane, 1:9 eluent) on silica gel (50:1 ratio, 230-400 mesh) affords the title compound (5.5 g, 79%) as a slightly amber oil homogeneous by TLC.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:45])[C:16]2[CH:21]=[C:20]([F:22])[C:19]([NH:23][C:24]3[N:25]=[CH:26][C:27]4[N:33]([CH3:34])[C:32](=[O:35])[C:31]([F:37])([F:36])[CH2:30][N:29]([CH:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)[C:28]=4[N:43]=3)=[CH:18][C:17]=2[F:44])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:38]1([N:29]2[CH2:30][C:31]([F:37])([F:36])[C:32](=[O:35])[N:33]([CH3:34])[C:27]3[CH:26]=[N:25][C:24]([NH:23][C:19]4[C:20]([F:22])=[CH:21][C:16]([C:15]([NH:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[O:45])=[C:17]([F:44])[CH:18]=4)=[N:43][C:28]2=3)[CH2:39][CH2:40][CH2:41][CH2:42]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)cc3F)ncc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)NC4CCNCC4)cc3F)ncc21
Yield: 96.7 %

Procedure:
A solution of 0.0781 g (0.123 mmole) 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,5-difluoro-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-239) in 3 mL of dichloromethane was stirred with 3 mL of trifluoroacetic acid for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of dichloromethane, washed with 15 mL of sodium carbonate solution, twice with 15 mL of brine and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 90:10-0:100) to give 0.0637 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,5-difluoro-N-piperidin-4-yl-benzamide (I-240) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:12]1[CH:17]=[CH:16][C:15]([CH2:18]O)=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[N:12]1[CH:17]=[CH:16][C:15]([CH2:18][O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:14][CH:13]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: OCc1ccncc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OCc2ccncc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.4 %

Procedure:
To a stirring solution of methyl 3-hydroxybenzoate (1.0 g, 6.58 mmol), 4-pyridylcarbinol (1.1 g, 9.87 mmol), and triphenylphosphine (2.6 g, 9.87 mmol) in THF (25 mL) at 0° C. was added diisopropyl azodicarboxylate (2.0 g, 9.87 mmol) dropwise. After stirring at room temperature for 16 h, the solution was concentrated and purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid (0.599 g, 37%). MS(ESI): 244.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24](=O)[CH2:25][C:26](=[O:28])[CH3:27])=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24](=[S:39])[CH2:25][C:26](=[O:28])[CH3:27])=[O:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1C(=O)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1C(=S)CC(C)=O

Procedure:
In analogy to the procedure described in example 192 g, (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-(3-oxo-butyryl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with Lawesson's reagent to give the title compound as brown solid.
Reaction SMILES: [OH-].[K+].[C:3]1([CH:9]=[CH:10][C:11](=O)[CH:12]([OH:26])[CH2:13][C:14](=[O:25])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.O.C(O)(=O)C(O)=O>C(Cl)(Cl)Cl>[OH:26][CH:12]1[CH2:13][C:14](=[O:25])[C:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[C:11]1[CH:10]=[CH:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)CCCCCCCC(=O)CC(O)C(=O)C=Cc1ccccc1
Agent: O=C(O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)CCCCCCC1=C(C=Cc2ccccc2)C(O)CC1=O

Procedure:
To 3000 parts by volume of an aqueous solution containing 6.7 parts of potassium hydroxide is added, with stirring at 21°-23° over a period of about 2 1/4 hours, a solution of 10.4 parts of dl- 14-phenyl-9,12-dioxo-11-hydroxytetradec-13-enoic acid in 187 parts of chloroform. After completion of the addition, the reaction mixture is stirred for an additional 2 hours, then is made acidic by adding 10 parts of oxalic acid dihydrate. The acidic mixture is extracted with chloroform and the organic layer is washed with dilute aqueous sodium chloride, then dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The resulting residue is recrystallized first from benzene, then from chloroform-ether to yield dl- 3-hydroxy-5-oxo-2-styrylcyclopent-1-eneheptanoic acid, which displays a melting point at about 118°. This compound displays an ultraviolet absorption maximum at about 325 millimicrons with a molecular extinction coefficient of about 36,400.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH2:9]1[C@H:10]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C@H:11]2[CH2:12][NH:8]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21
Temperature: 90 °C
Reaction time: 3 h

Procedure:
tert-Butyl(3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-ylcarbamate (100 mg, 0.316 mmol) from Step A and ammonium formate (100 mg, 1.580 mmol) were combined in ethanol. The reaction was deoxygenated at low temperature, and palladium on carbon (3.36 mg, 0.032 mmol) was added. The reaction was heated to reflux under nitrogen. After 3 hours, tlc and 1 cms showed mostly starting material. Degussa's catalyst and 5 equivalents more ammonium formate were added and the reaction mixture was refluxed under nitrogen overnight. More ammonium formate and Degussa's catalyst were added and the reaction heated to 90° C. After 2 hours, tlc and 1 cms show no remaining starting material. The reaction was filtered through diatomaceous earth containing carbonate functionalized silica gel (Silicycle, Quebec, Canada) with methanol. Solvent removal in vacuo gave tert-butyl(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylcarbamate: MS (ESI+) m/z 226 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[BH3-]C#N.[Na+].[CH2:10]([C@H:17]1[CH2:21][O:20][C:19](=[O:22])[N:18]1[C:23](=[O:53])[CH2:24][C@@H:25]([C:31]1[CH:52]=[CH:51][C:34]([O:35][CH2:36][C:37]2[S:41][C:40]([C:42]3[CH:49]=[CH:48][C:45]([CH:46]=O)=[CH:44][CH:43]=3)=[N:39][C:38]=2[CH3:50])=[CH:33][CH:32]=1)[C:26]1[CH:30]=[CH:29][O:28][N:27]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>ClCCCl>[CH2:10]([C@H:17]1[CH2:21][O:20][C:19](=[O:22])[N:18]1[C:23](=[O:53])[CH2:24][C@@H:25]([C:31]1[CH:32]=[CH:33][C:34]([O:35][CH2:36][C:37]2[S:41][C:40]([C:42]3[CH:49]=[CH:48][C:45]([CH2:46][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:44][CH:43]=3)=[N:39][C:38]=2[CH3:50])=[CH:51][CH:52]=1)[C:26]1[CH:30]=[CH:29][O:28][N:27]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCNCC
Reactant: Cc1nc(-c2ccc(C=O)cc2)sc1COc1ccc([C@H](CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)c2ccon2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Product: CCN(CC)Cc1ccc(-c2nc(C)c(COc3ccc([C@H](CC(=O)N4C(=O)OC[C@@H]4Cc4ccccc4)c4ccon4)cc3)s2)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Diethylamine (11 μL, 0.11 mmol) and NaCNBH3 (10 mg, 0.16 mmol) were added to a solution of compound 54.4 (54 mg, 0.089 mmol) in DCE (2 mL). The reaction mixture was stirred at 60° C. for 18 hours and then 1N HCl aqueous solution was added. The solution was stirred for 5 minutes and then partitioned between saturated aqueous NaHCO3 solution and DCM. The organic layer was collected, dried over MgSO4 and concentrated in vacuo. The crude product was used without further purification. MS ESI (pos.) m/e: 665 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH3:27])[CH:20]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH3:27])[CH:20]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[N:10]2)=[CH:3][C:2]=1[C:32]1[CH:33]=[N:28][CH:29]=[N:30][CH:31]=1
Reactant: COc1ccc(C2(c3ccc(F)c(Br)c3)N=C(N)c3ccccc32)cc1C
Reactant: OB(O)c1cncnc1
Product: COc1ccc(C2(c3ccc(F)c(-c4cncnc4)c3)N=C(N)c3ccccc32)cc1C
Yield: 41 %

Procedure:
The title compound was synthesized from 1-(3-bromo-4-fluorophenyl)-1-(4-methoxy-3-methylphenyl)-1H-isoindol-3-amine (Example 126) as described in Example 67 Scheme #10, D in 41% yield using pyrimidine-5-boronic acid. 1H NMR (DMSO-d6) δ 9.07 (s, 1 H), 8.78 (d, J=1.26 Hz, 2 H), 7.76-7.61 (m, 2 H), 7.43-7.24 (m, 4 H), 7.22-7.11 (m, 1 H), 7.01-6.90 (m, 2 H), 6.88-6.54 (m, 3 H), 3.58 (s, 3 H), 1.92 (s, 3 H); MS (ESI) m/z 425 [M+1]+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C[N:8]1[CH2:26][CH2:25][N:11]2[C:12]3[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=3[CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH:10]2[CH2:9]1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH2:9]1[CH:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][C:13]3[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=3[N:11]2[CH2:25][CH2:26][N:8]1[C:2]([O:4][CH2:5][CH3:6])=[O:3]
Reactant: CCOC(=O)Cl
Reactant: CN1CCN2c3ccccc3Cc3ccccc3C2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)N1CCN2c3ccccc3Cc3ccccc3C2C1
Temperature: 0 °C
Yield: 74.9 %

Procedure:
Ethyl chloroformate (19.53 g) was added dropwisely to a solution of 9.52 g of 1,2,3,4,10,14b-hexahydro-2-methyldibenzo[c,f]pyrazino[1,2-a]azepine in 48 ml of benzene at refluxed temperature and the mixture was refluxed for 5 hrs. Ice water was added to the reaction mixture and made alkaline with sodium bicarbonate. The mixture was extracted with benzene and the benzene layer was washed with water, dried and concentrated. The residue was chromatographed on silica gel using a mixture of n-hexane and ethyl acetate as an eluent (1:2) to give 8.70 g of pale yellow crystals, which were recrystallized from a mixture of isopropyl ether and n-pentane to give pale yellow prisms, mp 108.5°-109.5° C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:12]#[C:13]Br.[OH-].[Na+]>C(O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][NH:11][C:13]1=[NH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CBr
Reactant: NCCNCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N=C1NCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of N-benzylethane-1,2-diamine (1.00 g, 6.65 mmol) in absolute ethanol (25 mL) was added cyanogen bromide (0.92 g, 8.65 mmol). The reaction mixture was stirred at ambient temperature for 1 hour, then cooled in an ice water bath. The pH of the solution was adjusted to ˜10 by the addition of 1 M sodium hydroxide solution dropwise. The solvent was concentrated in vacuo. The residue was diluted with ethyl acetate (100 mL), washed with water (200 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the concentrated in vacuo. The residue was recrystallized in ethyl acetate and hexane to yield the title compound as a colorless solid in 96% yield (1.12 g): mp 165-167° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 7.39-7.24 (m, 6H), 4.47 (s, 2H), 3.49-3.33 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 159.4, 136.0, 129.1, 128.2, 128.1, 48.1, 47.4, 41.3; MS (ES+) m/z 176.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:1][C:2]1([CH3:16])[O:3][C:4](=[O:15])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[C:21]#[N:22])=[CH:8][C:7]1=2
Reactant: N#Cc1cccc(Br)c1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
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: O
Solvent: COCCOC
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(C#N)c3)cc21
Temperature: 85 °C
Yield: 25.2 %

Procedure:
A mixture of (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid (2.22 g, 10 mmol), 3-bromobenzonitrile (2.18 g, 12 mmol), tetrakis(triphenylphosphine)palladium (0) (0.6 g, 0.52 mmol), and sodium carbonate (2.2 g, 21 mmol) in a mixture of DME and water (70 mL/15 mL) was degassed to remove the oxygen and then heated at 85° C. under a blanket of nitrogen for 3 hours. The reaction mixture was cooled to ambient temperature and quenched with a saturated aqueous ammonium chloride solution (20 mL). Ethyl acetate (100 mL) was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine and dried with MgSO4. The solvent was removed in vacuo and the residue was purified by a silica gel flash chromatography (hexane:ethyl acetate/1:1) to give 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-benzonitrile as an off-white solid (0.7 g, 25%): mp 236-237° C.; 1H-NMR (DMSO-d6) δ10.34 (s, 1H, D2O exchangeable), 8.21 (s, 1H), 8.02 (d, 1H, J=8.1 Hz), 7.79 (d, 1H, J=7.7 Hz), 7.60-7.70 (m, 3H), 6.98 (d, 1H, J=8.2 Hz), 1.71 (s, 6H); Anal. Calc. For C17H14N2O2.0.1 H2O: C, 72.89; H, 5.11; N, 10.00. Found: C, 72.75; H, 5.05; N, 9.65.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[S:14]([OH:17])(=O)=[O:15].P(Cl)(Cl)([Cl:20])=O>>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[S:14]([Cl:20])(=[O:17])=[O:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1ccc2oc3ccccc3c2c1
Product: O=S(=O)(Cl)c1ccc2oc3ccccc3c2c1
Yield: 85 %

Procedure:
2-Dibenzofuransulfonic acid (12.8 mmol) was heated at 70° C. with phosphorus oxychloride (1.30 ml, 14.0 mol) for 2 h. Excess phosphorus oxychloride was removed under reduced pressure. The residue was decomposed with ice water and extracted with ethyl acetate. The extract was washed with 5% sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated to yield 2.9 g crude 2-dibenzofuransulfonyl chloride.
Reaction SMILES: F[B-](F)(F)F.C[O+:7]([CH3:9])[CH3:8].[N+:10]([C:13]1[CH:29]=[CH:28][C:16]([CH2:17][O:18][C:19]([N:21]2C[CH2:25][NH:24][C:23](=O)[CH2:22]2)=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11].C(=O)([O-])O.[Na+]>ClCCl>[CH3:8][O:7][CH:9]1[CH2:25][NH:24][CH2:23][CH2:22][N:21]1[C:19]([O:18][CH2:17][C:16]1[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:29][CH:28]=1)=[O:20]
Reactant: C[O+](C)C
Reactant: O=C1CN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CCN1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC1CNCCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 17 h

Procedure:
Trimethyloxonium tetrafluoroborate (97%, 3.7 g) was added to the dry dichloromethane (120 mL) solution of 4-p-nitrobenzyloxycarbonyl-piperazin-2one (6.7 g) at room temperature and stirred for 17 hours. The reaction mixture was treated with saturated sodium hydrogen carbonate aqueous solution, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3×100 mL), then the combined organic layer was washed with saturated sodium hydrogen carbonate aqueous solution and brine. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduce pressure and the title compound was obtained as a pale brown solid. Yield; 5.7 g, 80.6.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH2:18][CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH2:18]([N:13]1[C:12]([C:32]2[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH3:19]
Reactant: CCn1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: OB(O)c1ccc(F)cc1
Product: CCn1nc2c(c1-c1ccc(F)cc1)CCNCC2
Yield: 87.4 %

Procedure:
The title compound (114 mg) was prepared as in Example 177, Steps C and D, using 208 mg of 2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 193, Step A) and 211 mg of 4-fluorophenylboronic acid. MS (ESI): exact mass calculated for C15H18FN3, 259.15; found, m/z 260.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.41-7.35 (m, 2H), 7.32-7.26 (m, 2H), 3.99 (q, J=7.1 Hz, 2H), 3.43-3.38 (m, 2H), 3.33-3.28 (m, 2H), 3.18-3.12 (m, 2H), 2.80-2.75 (m, 2H), 1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:27](Br)[CH:28]=[CH2:29].O>CN(C=O)C>[CH2:3]([O:10][C:11]([N:13]([CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1)[CH2:29][CH:28]=[CH2:27])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)CC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN(C(=O)OCc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.9 %

Procedure:
Sodium hydride (47 mg of 60% oil dispersion, 1.2 mmol) was added to a solution of 4-(benzyloxycarbonylamino)-1-(t-butoxycarbonyl)piperidine (200 mg, 0.598 mmol) from Procedure 4, Step C and allyl bromide (0.251 mL, 351 mg, 2.9 mmol) in 2.0 mL of DMF, and the reaction was stirred overnight at rt. The reaction mixture was poured into 20 mL of water and extracted with 3×20 mL of ethyl ether. The combined organic layers were washed with 30 mL of brine, dried over sodium sulfate, and evaporated. The crude product was purified by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane, to give 246 mg of the title compound as a viscous oil.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[Br:8][C:6]1[N:7]=[C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: OB(O)c1ccccc1
Solvent: Cc1ccccc1
Product: Nc1ncc(Br)nc1-c1ccccc1
Temperature: 25 °C
Yield: 93.5 %

Procedure:
A mixture of 3,5-dibromopyrazin-2-amine (214 mg, 0.83 mmol) and phenyl boronic acid (100 mg, 0.8 mmol) in toluene (8 mL) was degassed and backfilled with nitrogen 3 times. Pd(PPh3)4 (46 mg) was added followed by 2M K3PO4 (0.8 mL) and EtOH (1 mL). The mixture was heated at reflux for 18 h. The solution was cooled to room temperature, partitioned between EtOAc (25 mL) and water (5 mL). The layers were separated and the organic layer dried over Na2SO4, filtered and concentrated to an oil which was purified via silica gel chromatography (15% EtOAc/heptane) to afford the product (187 mg, 95% yield).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([NH2:29])=[CH:26][CH:27]=3)[O:22][C:21]([CH3:31])([CH3:30])[C:20]=2[CH3:32])=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([NH:29][S:8]([CH3:7])(=[O:10])=[O:9])=[CH:26][CH:27]=3)[O:22][C:21]([CH3:31])([CH3:30])[C:20]=2[CH3:32])=[CH:15][CH:14]=1
Reactant: CC1=C(c2ccc(F)cc2)c2ccc(N)cc2OC1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC1=C(c2ccc(F)cc2)c2ccc(NS(C)(=O)=O)cc2OC1(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under ice-cooling, pyridine (55 μL) and Methanesulfonyl chloride (35 μL) were added dropwise to a solution of [4-(4-fluorophenyl)-2,2,3-trimethyl-2H-chromen-7-yl]amine (a compound of Reference Example 6(5), 64 mg) in chloroform (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by column chromatography on NH-silica gel (Chromatorex NH-silica gel, Solvent: chloroform/methanol=100/0 to 90/10) to give the titled compound (76 mg) as a colorless powder.