Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:22]([N:24]2[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]2)[CH3:23])[CH:19]=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([CH:22]([N:24]2[CH2:25][CH2:26][CH:27]([NH:30][C:2]3[C:3]4[CH:10]=[C:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[S:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH2:28][CH2:29]2)[CH3:23])[CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)Cc1cc2c(Cl)ncnc2s1
Reactant: CC(c1cccc(F)c1)N1CCC(N)CC1
Product: CC(C)Cc1cc2c(NC3CCN(C(C)c4cccc(F)c4)CC3)ncnc2s1

Procedure:
The title compound was prepared (291 mg, 64%) from 4-chloro-6-isobutylthieno[2,3-d]pyrimidine (250 mg, 1.1 mmol) and 1-(1-(3-fluorophenyl)ethyl)piperidin-4-amine (0.49 mg, 2.2 m. mol) by following the general procedure described for Preparation 6. 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.25 (m, 1H), 7.05 (m, 2H), 6.95 (m, 1H), 6.75 (s, 11H), 5.00 (m, 1H), 4.10 (m, 1H), 3.45 (m, 1H), 3.00 (d, 1H), 2.80 (d, 1H), 2.70 (d, 2H), 1.85–2.25 (m, 5H), 1.45–1.65 (m, 2H), 1.35 (d, 3H), 0.95 (d, 6H). MS (ESI) m/z: Calculated: 412.57; Observed: 413.3 (M++1).
Reaction SMILES: CN(C)C=O.[C:6]([O:10][C:11](=[O:51])[N:12]([CH2:40][C:41]1[CH:50]=[CH:49][C:44]2[O:45][CH2:46][CH2:47][O:48][C:43]=2[CH:42]=1)[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](OS(C(F)(F)F)(=O)=O)=[CH:23][C:22]2=[O:39])[CH2:15][CH2:14]1)([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[Na+].[Na+].[N:58]1[CH:63]=[CH:62][C:61](B(O)O)=[CH:60][CH:59]=1>O.C(OCC)(=O)C>[C:6]([O:10][C:11](=[O:51])[N:12]([CH2:40][C:41]1[CH:50]=[CH:49][C:44]2[O:45][CH2:46][CH2:47][O:48][C:43]=2[CH:42]=1)[CH:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][N:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([C:61]3[CH:62]=[CH:63][N:58]=[CH:59][CH:60]=3)=[CH:23][C:22]2=[O:39])[CH2:17][CH2:18]1)([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(OS(=O)(=O)C(F)(F)F)c3ccccc32)CC1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(-c3ccncc3)c3ccccc32)CC1
Temperature: 120 °C
Reaction time: 1.33 h
Yield: 33.6 %

Procedure:
To 2 mL of an N,N-dimethylformamide solution containing 0.14 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-(trifluoromethanesulfonyl)oxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 0.24 mL of 2.0 mol/L aqueous sodium carbonate solution, 12 mg of tetrakis triphenylphosphine palladium and 39 mg of 4-pyridineboronic acid were added, and stirred at 120° C. under nitrogen atmosphere for 80 min. The reaction mixture was cooled to the room temperature, ethyl acetate and water were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=10:1], to give 42 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxo-4-(pyridin-4-yl)quinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a pale yellow solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH2:9]([OH:11])[CH3:10]>C1C=CC=CC=1>[CH2:9]([O:11][C:1](=[NH:2])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:10]
Reactant: CCOC(=O)CC#N
Reactant: CCO
Solvent: c1ccccc1
Product: CCOC(=N)CC(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 110.6 %

Procedure:
Ethyl cyanoacetate (8 mL, 75 mmol) in anhydrous benzene (100 mL) was combined under nitrogen with anhydrous ethanol (6 mL, 105 mmol). The mixture was cooled to 10° C. (ice/acetone) and bubbled 20 minutes with dry hydrogen chloride gas. The mixture was slowly warmed to room temperature, sealed and stirred for approximately 18 hours. The mixture was diluted with diethyl ether (400 mL) and let stand for 5 hours at room temperature to give a crystalline solid. The solid was isolated by filtration, washed several times with anhydrous diethyl ether and dried to provide ethyl 3-ethoxy-3-iminopropionate (13.2 g, 90% yield) as a colorless, crystalline solid; 1H-NMR (300 Mhz, CDCL3): 7.84 (d, 1H, J=10.0 Hz), 7.19-7.36 (m, 5H), 7.00-7.06 (m, 2H), 4.10 (t, 2H, J=5.7 Hz), 2.73 (t, 2H, J=6.5 Hz), 1.89 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:6](=[O:18])[CH:5]2[C:19]1[C:28]([OH:29])=[CH:27][C:22]2[O:23][CH2:24][CH2:25][O:26][C:21]=2[CH:20]=1.[C:30](=O)([O-])[O-].[Cs+].[Cs+].ClCI.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:6](=[O:18])[C:5]12[C:19]2[C:28](=[CH:27][C:22]3[O:23][CH2:24][CH2:25][O:26][C:21]=3[CH:20]=2)[O:29][CH2:30]1
Reactant: O=C([O-])[O-]
Reactant: O=C1C(c2cc3c(cc2O)OCCO3)c2cc(Br)ccc2N1Cc1ccccn1
Agent: ClCI
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1N(Cc2ccccn2)c2ccc(Br)cc2C12COc1cc3c(cc12)OCCO3
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
To a solution of 5-bromo-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-(pyridin-2-ylmethyl)-1,3-dihydro-2H-indol-2-one (2.00 g, 4.40 mmol) in anhydrous N,N-dimethylformamide (25 mL) was added cesium carbonate (4.30 g, 13.2 mmol) and chloroiodomethane (0.85 g, 4.9 mmol). The solution was stirred at ambient temperature for 16 h and poured into water (100 mL). The mixture was extracted with ethyl acetate (3×50 mL) and the combined ethyl acetate extracts were washed with brine (2×35 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated in dichloromethane/diethyl ether (2/5, 14 mL) to afford 5′-bromo-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (1.44 g, 72%) as a beige solid: mp>250° C. (dichloromethane/diethyl ether); 1H NMR (300 MHz, CDCl3) 8.57-8.52 (m, 1H), 7.69-7.61 (m, 1H), 7.33-7.27 (m, 3H), 7.26-7.16 (m, 1H), 6.77 (d, J=8.3 Hz, 1H), 6.49 (s, 1H), 6.30 (s, 1H), 5.16 (d, J=15.8 Hz, 1H), 4.97-4.87 (m, 2H), 4.64 (d, J=9.0 Hz, 1H), 4.22-4.08 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 176.9, 155.2, 155.1, 149.6, 144.9, 141.1, 138.4, 137.2, 134.2, 131.7, 127.0, 122.9, 121.7, 120.4, 116.1, 111.7, 111.1, 99.5, 80.0, 64.5, 63.9, 58.2, 46.1; MS (ES+) m/z 465.0 (M+1), 467.0 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH:3]=1.B([C:27]1[CH:38]=[CH:37][C:30]([CH2:31][C@@H:32]([C:34]([OH:36])=[O:35])[NH2:33])=[CH:29][CH:28]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[NH2:33][CH:32]([CH2:31][C:30]1[CH:37]=[CH:38][C:27]([C:2]2[CH:3]=[C:4]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[CH:11]=3)[N:5]=[CH:6][N:7]=2)=[CH:28][CH:29]=1)[C:34]([OH:36])=[O:35]
Reactant: COc1ccc(CNc2cc(Cl)ncn2)cc1OC1CCCC1
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CNc2cc(-c3ccc(CC(N)C(=O)O)cc3)ncn2)cc1OC1CCCC1
Temperature: 150 °C
Yield: 6 %

Procedure:
An Emrys process vial (2-5 ml) for microwave was charged with (6-chloro-pyrimidin-4-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine (64 mg, 0.19 mmol), 4-borono-L-phenylalanine (40 mg, 0.19 mmol) and 2 ml of acetonitrile. Aqueous sodium carbonate (2 ml, 1M) was added to above solution followed by 5 mol percent of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol and purified with Prep-LC to give 5.3 mg of 2-amino-3-{4-[6-(3-cyclopentyloxy-4-methoxy-benzylamino)-pyrimidin-4-yl]-phenyl}-propionic acid, yield 6%. 1H-NMR (400 MHz, DMSO-d6): δ 1.46 (m, 2H), 1.62 (m, 4H), 3.01 (m, 2H), 3.08 (m, 2H), 3.65 (s, 3H), 4.20 (m, 1H), 4.46 (d, 2H), 4.68 (m, 1H), 6.82 (t, 2H), 6.87 (d, 2H), 7.40 (d, 2H), 7.90 (s, 2H), 8.25 (s, 2H), 8.6 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:47])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:46]=[CH:45][C:34]([CH2:35][CH2:36][NH:37]C(=O)OC(C)(C)C)=[CH:33][CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:37][CH2:36][CH2:35][C:34]1[CH:33]=[CH:32][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:47])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[CH:46][CH:45]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(CCNC(=O)OC(C)(C)C)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(CCN)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 1.5 h
Yield: 61.4 %

Procedure:
A solution of tert-butyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenethylcarbamate (77.3 mg, 0.113 mmol) in dichloromethane (3 ml) was treated with trifluoroacetic acid (2.23 g, 19.6 mmol) and stirred under argon. After 1.5 hrs, the reaction mixture was concentrated and the residue diluted with ethyl acetate, washed with saturated sodium carbonate, water and brine to give chiral (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-amino-ethyl)-phenyl]-amide (40.6 mg, 54.2%) as a white lyophilized solid.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][N:7]([CH3:9])[CH3:8])[CH:2]=[CH2:3].[CH3:10][O:11][SiH:12]([O:15][CH3:16])[O:13][CH3:14]>C([Si](C)(C)O[Si](C=C)(C)C)=C.[Pt].C1(C)C=CC=CC=1>[CH3:8][N:7]([CH3:9])[CH2:6][CH2:5][O:4][CH2:1][CH2:2][CH2:3][Si:12]([O:15][CH3:16])([O:13][CH3:14])[O:11][CH3:10]
Reactant: CO[SiH](OC)OC
Reactant: C=CCOCCN(C)C
Agent: [Pt]
Agent: C=C[Si](C)(C)O[Si](C)(C)C=C
Solvent: Cc1ccccc1
Product: CO[Si](CCCOCCN(C)C)(OC)OC
Reaction time: 24 h
Yield: 85.9 %

Procedure:
After adding toluene (200 mL) to a round-bottom flask containing 2-(allyloxy)-N,N-dimethylethanamine (0.398 mol) and dissolving trimethoxysilane (0.398 mol), a commercially available platinum(0)-1,3-divinyl-1,1,3,3-tetramethyldisiloxane solution was added and the mixture was stirred for 24 hours. Upon completion of reaction, after removing the solvent through distillation under reduced pressure, 0.342 mol (yield: 86%) of the target compound was obtained by extracting with water and diethyl ether. 1H and 13C NMR spectroscopic data of the purified N,N-dimethyl-2-(3-(trimethoxysilyl)propoxy)ethanamine are as follows.
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[Si:13]([O:20][CH2:21][C:22]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:26]=[C:25]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[F:34])[CH2:24][NH:23]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(N(CC)CC)C.O>C1COCC1>[Si:13]([O:20][CH2:21][C:22]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:26]=[C:25]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[F:34])[CH2:24][N:23]1[C:7]([Cl:10])=[O:6])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)OCC1(c2ccccc2)C=C(c2cc(F)ccc2F)CN1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC1(c2ccccc2)C=C(c2cc(F)ccc2F)CN1C(=O)Cl
Temperature: 25 °C

Procedure:
To a solution of 3.7 g (12.5 mmol) of triphosgene in THF at 0° C. was added dropwise a mixture of 2.5 g (6.2 mmol) of amine 1-8 and 1.74 mL (12.5 mmol) of triethylamine in THF. The reaction was allowed to warm to room temperature overnight with stirring. The mixture was then dumped into water, placed in a separatory funnel, and extracted twice with EtOAc. The combined organic extracts were combined, washed with water, dried over Na2SO4 and concentrated to obtain 6-1 as a brown solid. Data for 6-1: HRMS (ES) calc'd M+H for C24H28ClF2NO2Si: 464.1619. Found: 464.1625.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:16]([NH:18][C@H:19]([C:21]([O:23]C)=[O:22])[CH3:20])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].C(OC(=O)C)C.CN(C=O)C>CO>[C:1]1([CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:16]([NH:18][C@H:19]([C:21]([OH:23])=[O:22])[CH3:20])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)CCc1ccccc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)CCc1ccccc1)C(=O)N[C@@H](C)C(=O)O

Procedure:
By the same procedure used to prepare AcTyr(O-t-butyl)ValAlaOH, PhCH2CH2COValAlaOCH3 (508 mg, 1.52 mmole) and LiOH.OH (319 mg, 7.6 mmole) in 10% aqueous CH3OH (15 mL) gave, after quenching with sulfonic acid ion exchange resin (17.0 g, 38 meq), 511 mg (100%) of pure product as a white powder. Recyrstallization of a portion from ethylacetate gave an analytical sample: mp 205°-206° C.; 1H NMR (DMSO-d6) δ 0.76 (d, J=6.7 Hz, 3H), 0.81 (d, J=6.8 Hz, 3H), 1.24 (d, J=7.3 Hz, 3H), 1.8-1.95 (m, 1H), 2.35-2.55 (m, 2H, partially obscured by the DMSO-d5 peak), 2.75-2.85 (m, 2H), 4.1-4.25 (m, 2H), 7.1-7.3 (m, 5H), 7.84 (d, J=9.1 Hz, 1H), 8.23 (d, J=6.5 Hz, 1H); MS (LSIMS) m/e 321 (45, M+ +1), 232 (29), 204 (11), 157 (100); [α]D20 -2.0° (c=1.0, DMF); Analysis calculated for C17H24N2O4 : C, 63.73; H, 7.55; N, 8.75; found: C, 63.78; H, 7.30; N, 8.60.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14](B4OC(C)(C)C(C)(C)O4)[CH:15]=3)[CH:10]=2)[O:3]1.Br[C:30]1[CH:51]=[CH:50][C:33]2[NH:34][C:35]([C@@H:37]3[CH2:42][C@@H:41]4[C@@H:39]([CH2:40]4)[N:38]3[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[N:36][C:32]=2[CH:31]=1.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>[CH3:7][C:6]1([CH3:8])[C:2]([CH3:1])([CH3:28])[O:3][B:4]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([C:30]2[CH:51]=[CH:50][C:33]4[N:34]=[C:35]([C@@H:37]5[CH2:42][C@@H:41]6[C@@H:39]([CH2:40]6)[N:38]5[C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[NH:36][C:32]=4[CH:31]=2)[CH:13]=[CH:12]3)[O:5]1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2cc(Br)ccc2[nH]1
Reactant: CC1(C)OB(c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)OC1(C)C
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: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2ccc(-c3ccc4cc(B5OC(C)(C)C(C)(C)O5)ccc4c3)cc2[nH]1
Temperature: 100 °C
Yield: 50 %

Procedure:
Pd(Ph3P)4 (0.382 g, 0.330 mmol) was added to a degassed solution of 2,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene (2.51 g, 6.61 mmol), (1R,3S,5R)-tert-butyl 3-(5-bromo-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (2.5 g, 6.6 mmol) and sodium carbonate (2.78 g, 33.0 mmol) in DME (52.9 mL) and water (13.2 mL) at 80° C. The reaction was backfilled with nitrogen, sealed and heated at 100° C. overnight. The volatiles were removed under vacuum and the residue was taken in EtOAc, washed with water, and the water layer was extracted with EtOAc. The combined organic layers were filtered through a pad of diatomaceous earth (CELITE®) and dried over Na2SO4, concentrated and purified on a BIOTAGE® (dry loaded on silica gel, charged to a 90 g silica gel cartridge and eluted with a gradient of 0 to 70% ethyl acetate in hexanes, then flushed with 10% MeOH/DCM) to yield (1R,3S,5R)-tert-butyl 3-(6-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (1.8 g, 3.3 mmol, 49% yield) as yellowish solid. LC-MS retention time 1.905 min; m/z 552.47 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% MeOH/90% H2O/0.1% TFA and Solvent B was 10% H2O/90% MeOH/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[CH3:44][C:45]1[N:46]=[C:47]([CH:51]([NH2:53])[CH3:52])[S:48][C:49]=1[CH3:50]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:36]([NH:53][CH:51]([C:47]2[S:48][C:49]([CH3:50])=[C:45]([CH3:44])[N:46]=2)[CH3:52])=[O:42])=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: Cc1nc(C(C)N)sc1C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)NC(C)c4nc(C)c(C)s4)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(4,5-dimethyl-1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (14 mg, yield 29%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28].[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br.[H-].[Na+].O>CN(C)C=O>[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28]
Reactant: BrCCCCCBr
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCCCBr)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 1.2 h
Yield: 59.2 %

Procedure:
2.05 g (5.26mmol) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one obtained in Example 66 was dissolved in 50 mL of dimethylformamide under argon atmosphere, 3.6 mL (26.3 mmol) of 1,5-dibromopentane and 631 mg (15.8 mmol) of sodium hydride (60% oil dispersion) were added and the mixture was stirred at room temperature for 1.2 hours. The reaction solution was cooled on ice, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:ethyl acetate=60:l) to give 1.68 g of 5-(5-bromopentylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one (yield: 59%).
Reaction SMILES: O=[C:2]1[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][C:3]1([C:12](OCC)=[O:13])[CH2:4]3)[CH2:8]2.Cl.[Cl:18][C:19]1[CH:20]=[C:21]([NH:25][NH2:26])[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>C(O)C>[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[N:26]=[C:2]3[CH:9]4[CH2:10][CH:5]5[CH2:4][C:3]3([CH2:11][CH:7]([CH2:6]5)[CH2:8]4)[C:12]2=[O:13])[CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C12CC3CC(CC(C3)C1=O)C2
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1N(c2cccc(Cl)c2)N=C2C3CC4CC(C3)CC12C4
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of ethyl 2-oxoadamantane-1-carboxylate (5) (1.0 g, 4.5 mmol) and 3-chlorophenylhydrazine hydrochloride (3.6 g, 20 mmol) in 40 ml of ethanol is added triethylamine (2.0 g, 20 mmol). The reaction mixture is stirred at room temperature under a nitrogen atmosphere for 20 hours, then heated to reflux for 2 hours. After cooling to ambient temperature, the solvent is removed under reduced pressure and the crude residue solid is dissolved in 30 ml of methylene chloride. The organic extract is washed with 25 ml of diluted hydrochloric acid to remove the excess of 3-chlorophenylhydrazine, then dried over anhydrous magnesium sulfate. The solvent is evaporated to leave the title compound (6) as a dark-colored, viscous oil which is flash-chromatographed on silica gel using ether-pentane (2:8) as the eluent. Subsequent recrystallization from methanol provides the pure product as pale yellow needles melting at 119.5°-120.5° C. Anal. Calcd for C17H17ClN2O: C, 67.88; H, 5.70; N, 9:31; Cl, 11.79. Found: C, 67.54; H, 5.75; N, 9.12; Cl, 11.86.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]=2)=[CH:6][C:5]=1[N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([O-])=O>[Pd].C1(C)C=CC=CC=1.CO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]=2)=[CH:6][C:5]=1[N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(-c3ccccc3)c2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(-c3ccccc3)c2)ccc1N
Yield: 75 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-[2-nitro-5-(3-phenylphenoxy)phenyl]-N-methylcarbamate (8.7 g), palladium on carbon (10%, 0.69 g) and toluene/methanol=7/3 (100 ml) and the reaction mixture was purified to give the title compound (6.06 g).
Reaction SMILES: [H-].[Na+].[Br:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[CH:14]=[CH:13]2.[CH3:21]I.O>CN(C=O)C>[Br:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:21])[C:15](=[O:20])[CH:14]=[CH:13]2
Reactant: O=c1ccc2cc(OCCCCCBr)ccc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)ccc2cc(OCCCCCBr)ccc21
Temperature: 0 °C

Procedure:
Sodium hydride (60% in oil, 440 mg) was suspended in DMF(20 ml), and was cooled to 0° C. in ice water bath. 6-(5-Bromopentyloxy)-1H-quinolin-2-one(3.1 g) was added thereto at the same temperature, and the mixture was stirred at 0° C. for an hour. Methyl iodide(1.9 ml) was added thereto, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=4:1→1:1). The purified product was condensed to dryness under reduced pressure to give the title compound(2.68 g) as a yellow powder.