Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16](S(C)=O)=[N:17][CH:18]=3)[N:13]([CH2:24][CH3:25])[C:12]2=[O:26])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH2:27]([N:29]([CH2:35][CH3:36])[CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])[CH3:28].FC(F)(F)C(O)=O>C(#N)C>[CH2:27]([N:29]([CH2:35][CH3:36])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:16]1[N:15]=[C:14]2[N:13]([CH2:24][CH3:25])[C:12](=[O:26])[N:11]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)[CH2:20][C:19]2=[CH:18][N:17]=1)[CH3:28]
Reactant: CCN1C(=O)N(c2cc(OC)cc(OC)c2)Cc2cnc(S(C)=O)nc21
Reactant: CCN(CC)CCCCN
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCN(CC)CCCCNc1ncc2c(n1)N(CC)C(=O)N(c1cc(OC)cc(OC)c1)C2
Temperature: 90 °C
Yield: 56 %

Procedure:
A mixture of 3-(3,5-dimethoxy-phenyl)-1-ethyl-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one (0.5 g, 1.33 mmol), 4-diethylaminobutylamine (0.38 g, 2.66 mmol,) and trifluoroacetic acid (0.31 g, 2.66 mmol) in acetonitrile (6 mL) was heated in a sealed tube at 90° C. for 18 hours. The solvent was removed under reduced pressure and the residue taken up in 1N HCl. The solution was made basic with 50% NaOH and extracted twice with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and evaporated. The residue was purified by radial chromatography eluting with a solvent mixture of ethyl acetate/methanol/ethyl (89:10:1 v/v/v) to give 0.34 g (56%) of the titled compound: mp 83-85° C. Mass Spectrum (APCI, 80/20 CH3CN/H2O, Probe=450° C.) (m+1)/z 458.2
Reaction SMILES: [C:1]([O:4]C(C)(C)C)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24]([CH2:30][C:31]1[C:36](=[O:37])[CH2:35][CH2:34][CH2:33][C:32]=1OS(C(F)(F)F)(=O)=O)=[CH:25]2.FC(F)(F)C(O)=O>C1COCC1.C(Cl)Cl>[Br:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24]([CH2:30][C:31]1[C:36](=[O:37])[CH2:35][CH2:34][CH2:33][C:32]=1[CH2:2][C:1]([OH:4])=[O:3])=[CH:25]2
Reactant: CC(=O)OC(C)(C)C
Reactant: O=C1CCCC(OS(=O)(=O)C(F)(F)F)=C1Cc1ccc2c(Br)cccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(O)CC1=C(Cc2ccc3c(Br)cccc3c2)C(=O)CCC1
Reaction time: 1 h

Procedure:
In to a cold (-78° C.) solution of tert-butyl acetate (2.7 mL, 19.96 mmol) in THF (35 mL) was added lithium bis(trimethylsilyl)amide solution (1 .0M, 21.62 mL, 21.62 mmol). After stirring for 2 hours a solution of trifluoromethanesulfonic acid 2-(5-bromo-naphthalen-2-ylmethyl)-3-oxo-cyclohex-1-enyl ester (7.7 g, 16.63 mmol) in THF (15 mL) was added dropwise. The mixture was stirred for 1 hour, quenched with aqueous NH4Cl, poured in to H2O and extracted with EtOAc, The organic extracts were dried over MgSO4. Evaporation gave a yellow oil residue which was taken up in methylene chloride (100 mL) and treated with trifluoroacetic acid (10 mL). The mixture was stirred for 5 hours and then the volatiles were removed in vacuo. The residue was purified by flash chromatography on acidic silica gel (eluting solvent hexane/EtOAc 1/1) to give a yellow solid (4.1 g, 66% yield, m.p 56°-58 ° C.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].C([Si](Cl)(CC)CC)C.C(N(CC)CC)C.FC(F)(F)C(O[C:34]1[C:39]([F:40])=[C:38]([F:41])[C:37]([F:42])=[C:36]([F:43])[C:35]=1[F:44])=O>N1C=CC=CC=1.ClCCl.CCCCCCC.C(O)(=O)C>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][C:34]1[C:35]([F:44])=[C:36]([F:43])[C:37]([F:42])=[C:38]([F:41])[C:39]=1[F:40])=[O:12]
Reactant: O=C(O)CCCCCCCCCO
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Agent: CC[Si](Cl)(CC)CC
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: O=C(CCCCCCCCCO)Oc1c(F)c(F)c(F)c(F)c1F
Reaction time: 0.5 h

Procedure:
The 10-hydroxydecanoic acid (4.5 g, 23.9 mmole) was dried by co-evaporation with anhydrous pyridine twice. The residue was dissolved in anhydrous pyridine (100 mL) and triethylsilyl chloride (5.6 mL, 33.5 mmole) was added to the stirring solution at room temperature. Completion of the reaction was observed at 30 minutes by silica gel tlc (ethyl actetate, acetic acid (AcOH), heptane; 16%/1%/83%; Rf 0.31). The solvent was evaporated in vacuo. The product was carried on to the next reaction without purification. Crude triethylsilyl protected 10-hydroxydecanoic acid was dissolved in dichloromethane (20 mL) and chilled in an ice bath. Triethylamine (4.0 mL, 28.7 mmole) was added followed by the slow addition of pentafluorophenyl trifluoroacetate (2.7 mL, 15.9 mmole). The reaction was determined complete at 3 hours by silica gel tlc (ethyl actetate, acetic acid, heptane; 16%/1%/83%; Rf=0.80). The solvent was evaporated in vacuo. The hydroxyl was deprotected in 30 minutes with THF:AcOH:H2O (34 mL, 8:8:1), as observed by silica gel tlc (ethyl acetate, acetic acid, heptane; 16%/1%/83%; Rf 0.20). The mixture was evaporated to dryness. The crude product was purified by column chromatography (200 g EM Science silica gel 60 230-400 mesh; 10% ethyl actetate, 1% AcOH, heptane) yielding 2.6 g (30.7%). 1H NMR (CDDl3): δ3.65 (t, 2H, J=6.59 Hz), 2.66 (t, 2H, J=7.41 Hz), 1.82-1.72 (m, 2H), 1.60-1.53 (m, 2H), 1.41-1.31 (m, 10H). Mass spectrum (FAB+), m/z 355 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[CH:18]=[C:19]([C:39]3[CH:44]=[C:43]([CH:45]([CH3:47])[CH3:46])[CH:42]=[CH:41][C:40]=3[O:48][CH3:49])[C:20]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:21][C:22]=2[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.[Si]([N:60]=[N+:61]=[N-:62])(C)(C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]([C:17]3[CH:18]=[C:19]([C:39]4[CH:44]=[C:43]([CH:45]([CH3:47])[CH3:46])[CH:42]=[CH:41][C:40]=4[O:48][CH3:49])[C:20]([O:31][CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:21][C:22]=3[O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:62][N:61]=[N:60]2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1ccc(C(C)C)cc1-c1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1cc(-c2nnnn2C2CCN(C(=O)OC(C)(C)C)CC2)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 7 h
Yield: 59 %

Procedure:
A solution of 4-[(4,6-bis-benzyloxy-5′isopropyl-2′methoxy-biphenyl-3-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (6.1 g, 9.2 mmol), PCl5 (2.9 g, 13.8 mmol) and anhydrous dichloromethane (120 ml) was stirred at rt for 4 h. Then the TMSN3 (10.4 ml, 1.7 vols.) was charged and the mixture stirred for a further 7 h. The reaction was quenched very carefully with saturated NaHCO3 solution (100 ml) and stirred a further 1 h. The organics were then split off and aqueous washed with dichloromethane. The combined organics were then washed with brine before being dried (Na2SO4), filtered and evaporated to yield the crude product as a yellow solid. This material was purified using column flash chromatography (SiO2, ethyl acetate/hexanes), yielding 4-[5-(4,6-bis-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-3-yl)-tetrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (3.7 g, 59%). M.p.: 77-81° C.; 400 MHz 1H NMR (DMSO-d) δ: 7.45-7.09 (m, 14H), 6.96 (d, J=6.4 Hz, 1H), 5.26 (s, 2H), 5.23 (s, 2H), 4.45 (br s, 1H), 3.86 (m, 2H), 3.67 (s, 3H), 2.84 (m, 3H), 1.67 (m, 4H), 1.40 (s, 9H), 1.16 (d, J=6.4 Hz, 6H); LCMS: 690 [M+H].
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[CH:15][N:14]=1.[CH3:23][CH2:24][O:25]C(C)=O>C(OC(=O)C)(=O)C.OS(O)(=O)=O>[Cl:1][C:2]1[N:10]=[C:9]([NH:11][C:24](=[O:25])[CH3:23])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[CH:15][N:14]=1
Reactant: CCOC(C)=O
Reactant: COc1c(C)cnc(Cn2cnc3c(Cl)nc(N)nc32)c1C
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: COc1c(C)cnc(Cn2cnc3c(Cl)nc(NC(C)=O)nc32)c1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A suspension of 6-chloro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine (80 mg, 0.25 mmol) in acetic acid anhydride (2.2 g) was treated with one drop of concentrated H2SO4 and stirred at r.t. for 5 min. Work-up (EtOAc), drying (MgSO4) and evaporation gave the title compound as a white solid. HPLC Rt: 4.093 min. 1H-NMR (CDCl3): δ 8.20 (s, 1H), 8.10 (s, 1H), 5.46 (s, 2H), 3.78 (s, 3H), 2.54 (s, 3H), 2.38 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].Cl.[CH3:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]2([C:35](O)=[O:36])[CH2:34][CH2:33]2)[CH2:27]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:35]([C:32]2([N:28]3[CH2:29][CH2:30][CH2:31][CH:26]([CH3:25])[CH2:27]3)[CH2:34][CH2:33]2)=[O:36])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: CC1CCCN(C2(C(=O)O)CC2)C1
Agent: Cl
Product: CC1CCCN(C2(C(=O)N3C[C@H](S(=O)(=O)c4ccccc4Cl)C[C@H]3C(=O)NC3(C#N)CC3)CC2)C1
Yield: 41 %

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H with 1-(3-methylpiperidin-1-yl)cyclopropanecarboxylic acid hydrochloride 16B carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(3-methylpiperidin-1-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide as a light brown gum (41%). MS ISP (m/e): 519.3 (100) [(M+H)]+.
Reaction SMILES: [Na].O[C:3]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:4]=1[NH:5][C:6](=[O:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[Br:30][CH2:31][CH2:32][P:33](Cl)(Cl)=[O:34].O>C1C=CC=CC=1>[Br:30][CH2:31][CH2:32][P:33](=[C:3]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:4]1[NH:5][C:6](=[O:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:34]
Reactant: O=P(Cl)(Cl)CCBr
Reactant: CCCCCCCCCCCCCCCC(=O)Nc1cc([N+](=O)[O-])ccc1O
Agent: [Na]
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)NC1C=C([N+](=O)[O-])C=CC1=[P+]([O-])CCBr
Temperature: 10 °C
Reaction time: 72 h
Yield: 38 %

Procedure:
In 400 ml of benzene was suspended 4.15 g (10 mmol) of the sodium salt of 2'-hydroxy-5'-nitrohexadecananilide. The suspension was stirred and heated to boiling. Benzene, 100 ml was collected through a concentrator condenser. The condenser was then replaced with a reflux condenser on which a drying tube was mounted. The temperature of the mixture was lowered to 25° C and 4.84 g (20 mmol; 2.64 ml) of β-bromoethylphosphoryl dichloride was added. The slightly yellow solution was stirred for 1 hour at room temperature and then it was heated under reflux for 24 hours. After cooling to 10° C, 10 ml (0.56 mol) of water was added and the stirring was continued for 72 hours at room temperature. The precipitate 4.2 g was filtered from the mother liquor and washed with 100 ml of benzene. (Subsequent treatment of the mother liquor is described in part (d) of this example.) The dried and pulverized product was then suspended in 90 ml of 0.2 M sodium acetate buffer (pH 5.0) and stirred for 3 hours. The mixture was filtered through a coarse filter paper and the filtrate was acidified with 90 ml of 1 N hydrochloric acid and extracted twice with 180 ml of ethyl acetate. After evaporation of the solvent the residue (2.7 g) was recrystallized from 70 ml of acetone to yield 2.2 g (38%) of 2'-(β-bromoethylphosphoryl)-5'-nitrohexadecananilide. Mp 117°-118° C. The compound was water soluble as a sodium salt, 10-4M pH 3.7, and in 0.2 M sodium acetate buffer (pH 5.0), 100 mg per ml. It was insoluble in water; slightly soluble in ethyl ether; soluble in methyl and ethyl alcohol, ethyl acetate, acetone, methyl ethyl ketone, tetrahydrofuran, benzene and chloroform. Thin-layer chromatography: Chloroform-methanol-water (75:25:3). Rf 0.5. 2'-hydroxy-5'-nitrohexadecananilide, Rf 0.95). The ir spectrum displayed the following additional bands when compared with the spectrum of 2'-hydroxy-5'-nitrohexadecananilide, 1210 (P=0 str.), 1005, 950, 920 (P=0 (OH)), 730, 560 cm-1 (bromine ?).
Reaction SMILES: [O:1]=[C:2]1[C:7]([O:8]CC2C=CC=CC=2)=[CH:6][NH:5][C:4]([C:16]([NH:18][NH2:19])=[O:17])=[CH:3]1.FC(F)(F)C([O-])=O>C(#N)C>[OH:8][C:7]1[C:2](=[O:1])[CH:3]=[C:4]([C:16]([NH:18][NH2:19])=[O:17])[NH:5][CH:6]=1
Reactant: NNC(=O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Agent: O=C([O-])C(F)(F)F
Solvent: CC#N
Product: NNC(=O)c1cc(=O)c(O)c[nH]1
Reaction time: 1.5 h

Procedure:
The crude 1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid, hydrazide, trifluoroacetate (1:2) salt was dissolved in 250 ml of acetonitrile and stirred with cooling for 1 hour. The crystals were then filtered off and resuspended in 600 ml of acetonitrile. Bis(trimethylsilyl)acetamide (135 ml) was added followed by 28 g of 10% palladium on charcoal. Then hydrogen was passed through the stirred solution. The hydrogenation was complete after 90 minutes. After filtration, 70 ml of methanol and 2 ml of acetic acid were added. After stirring overnight, the crystals formed were filtered off, yielding 19.4 g of the title compound, melting point 290°-340° C., dec.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][N+:11]([O-])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:12]1[CH:13]=[C:8]([C:6](=[O:7])[C:5]2[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]=[CH:10][N:11]=1
Reactant: O=C(c1ccc(F)cc1)c1cc[n+]([O-])cc1
Reactant: O=P(Cl)(Cl)Cl
Product: O=C(c1ccc(F)cc1)c1ccnc(Cl)c1

Procedure:
0.88 g 4-(4-fluorobenzoyl)-pyridine N-oxide and 50 ml POCl3 are refluxed for 2 hrs. Excess POCl3 is distilled at normal pressure. The crude is treated with slightly alkaline cold water and then extracted with methylene chloride. Working as usual affords 0.80 g of title product, identical with that obtained by the Friedel-Crafts process (see Ex. 3d).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=3[F:25])=[C:13]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[N:12]=2)[N:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([CH:39]=[CH:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])O1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>CN(C=O)C.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].O>[CH3:28][C:27]([CH3:30])([CH3:29])[CH2:26][C:13]1[N:12]=[C:11]([CH2:10][O:9][C:6]2[N:5]=[CH:4][N:3]=[C:2](/[CH:39]=[CH:40]/[C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:7]=2[CH3:8])[CH:16]=[CH:15][C:14]=1[C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[F:25]
Reactant: COc1ccc(F)c(-c2ccc(COc3ncnc(Cl)c3C)nc2CC(C)(C)C)c1
Reactant: CCOC(=O)C=CB1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1ncnc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1C
Temperature: 90 °C
Reaction time: 6 h
Yield: 78.4 %

Procedure:
To a solution of 4-chloro-6-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-5-methylpyrimidine (200 mg) in DMF (5.0 mL) were added ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (212 mg), tris(dibenzylideneacetone)dipalladium (50 mg), cesium carbonate (230 mg) and dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (45 mg), and the mixture was stirred at 90° C. for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (180 mg) as a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]([CH:58]([CH3:60])[CH3:59])=[C:56]=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:56]([NH:55][CH:58]([CH3:60])[CH3:59])=[O:57])[CH2:49][CH2:48]1
Reactant: CC(C)N=C=O
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 58 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-isocyanatopropane as starting materials in 58% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.08 (s, 1H), 9.40 (m, 2H), 9.05 (s, 1H), 8.33 (m, 2H), 8.20 (s, 1H), 7.63 (m, 1H), 7.30 (m, 1H), 7.09 (m, 1H), 6.09 (m, 1H), 3.92 (m, 2H), 3.75 (m, 1H), 2.97 (s, 4H), 2.62 (m, 2H), 2.28 (m, 2H), 1.91 (m, 1H), 1.64 (m, 2H), 1.09 (m, 2H), 1.00 (d, 6H). LCMS for C28H34ClN8O2 (M+H)+: m/z=549.2.
Reaction SMILES: O.C(=O)([O-])O.[Na+].Cl.[Br:8][C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=1[CH2:11][C@H:12]([C:14]([O:16][CH3:17])=[O:15])[NH2:13].Cl[C:23]([O:25][CH3:26])=[O:24]>ClCCl>[Br:8][C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=1[CH2:11][C@H:12]([C:14]([O:16][CH3:17])=[O:15])[NH:13][C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)[C@H](N)Cc1ccccc1Br
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)N[C@H](Cc1ccccc1Br)C(=O)OC
Temperature: 20 °C
Yield: 91.1 %

Procedure:
Add water (2.94 L) and sodium hydrogen carbonate (648.25 g, 7.64 mol) to methyl 2-bromo-D-phenylalaninate hydrochloride (580 g, 1.91 mol) in dichloromethane (9.86 L) at 10° C. in an appropriate vessel. After 5 minutes add methyl chloroformate (198.53 g, 2.10 mol) and stir the mixture at 20° C. After 3 hours add water (2.5 L) and separate the layers. Extract the aqueous with dichloromethane, dry the combined organic extracts over sodium sulfate and concentrate under reduced pressure to give the title compound (556 g, 1.74 mol). MS (m/z): 315.8 (M+1 (79Br)), 317.8 (M+1 (81Br)).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][N:7]([CH3:20])[CH:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[CH:10](O)[CH2:9]1.[OH-].[NH4+].[Cl-].[Na+]>O1CCOCC1>[CH3:6][N:7]([CH3:20])[CH:8]1[CH:9]=[CH:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH2:13][CH2:14]1
Reactant: CN(C)C1CCc2ccccc2C(O)C1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: CN(C)C1C=Cc2ccccc2CC1
Yield: 49.3 %

Procedure:
16 ml of 18 N sulfuric acid were added to a refluxing mixture of 8 g of 7-dimethylamino-5-hydroxy-6,7,8,9-tetrahydro [5H] benzocycloheptene and 80 ml of dioxane and after one half hour of reflux, another 80 ml of dioxane were added thereto. The mixture was refluxed another 30 minutes and was then cooled. The pH was raised above 10 by addition of concentrated ammonium hydroxide and the mixture was saturated with sodium chloride and was extracted with ethyl acetate. The organic extracts were washed with aqueous sodium chloride and then were dried and evaporated to dryness. The residue was chromatographed over silica gel and was eluted with a 7-3-1 cyclohexane-ethyl acetate-triethylamine mixture to obtain 3.6 g of 7-dimethylamino-6,7-dihydro [5H] benzocycloheptene.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:47]=[CH:46][C:18]([CH2:19][N:20]2[C:24]3[CH:25]=[C:26]([O:29][CH2:30][C:31]4[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=4)[CH:27]=[CH:28][C:23]=3[N:22]=[C:21]2[CH2:37][C:38]([CH2:44][CH3:45])([CH2:42][CH3:43])[C:39]([OH:41])=[O:40])=[C:17]([F:48])[CH:16]=1>>[CH2:42]([C:38]([CH2:37][C:21]1[N:20]([CH2:19][C:18]2[CH:46]=[CH:47][C:15]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=3)=[CH:16][C:17]=2[F:48])[C:24]2[CH:25]=[C:26]([O:29][CH2:30][C:31]3[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=3)[CH:27]=[CH:28][C:23]=2[N:22]=1)([CH2:44][CH3:45])[C:39]([OH:41])=[O:40])[CH3:43]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCC(CC)(Cc1nc2ccc(OCc3ccn(C)n3)cc2n1Cc1ccc(Br)cc1F)C(=O)O
Product: CCC(CC)(Cc1nc2ccc(OCc3ccn(C)n3)cc2n1Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1F)C(=O)O

Procedure:
The title compound was prepared in a manner analogous to that in Example 144 using (4-(trifluoromethyl)phenyl)boronic acid and 2-((1-(4-bromo-2-fluorobenzyl)-6-((1-methyl-1H-pyrazol-3-yl)methoxy)-1H-benzo[d]imidazol-2-yl)methyl)-2-ethylbutanoic acid and (4-(trifluoromethyl)phenyl)boronic acid. MS (ESI): mass calcd. for C33H32F4N4O3, 608.24; m/z found, 609.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 7.81 (d, J=8.3, 2H), 7.73 (d, J=8.4, 2H), 7.57-7.54 (m, 1H), 7.54-7.52 (m, 1H), 7.49 (d, J=2.3, 1H), 7.41 (dd, J=8.0, 1.8, 1H), 7.03 (d, J=2.3, 1H), 6.93 (dd, J=8.8, 2.3, 1H), 6.88 (t, J=7.9, 1H), 6.28 (d, J=2.3, 1H), 5.61 (s, 2H), 5.01 (s, 2H), 3.81 (s, 3H), 3.12 (s, 2H), 1.90-1.73 (m, 4H), 0.88 (t, J=7.5, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](B(O)O)[CH:5]=[CH:4][N:3]=1.Cl[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][C:13]=1[F:20].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[F:20][C:13]1[CH:14]=[C:15]([CH2:18][NH2:19])[CH:16]=[CH:17][C:12]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: NCc1ccc(Cl)c(F)c1
Reactant: Cc1cc(B(O)O)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2ccc(CN)cc2F)ccn1
Temperature: 96 °C
Reaction time: 8 h

Procedure:
A mixture of (2-methylpyridin-4-yl)boronic acid 15-1 (822 mg, 6.2 mmol), (4-chloro-3-fluorophenyl)methanamine 15-2 (798 mg, 5.00 mmol), Pd(PPh3)4 (173 mg, 0.15 mmol) and K3PO4 (1.59 g, 7.50 mmol) in dioxane (10 mL) and water (1 mL) was stirred at 96° C. under argon overnight. After cooling to room temperature, the mixture was filtered through celite, washed with ethyl acetate, and dried with Na2SO4. The filtrate was concentrated by rotavap and the residue subjected to silica gel column chromatography with 6% ammonia-saturated methanol in dichloromethane as eluent to give (3-fluoro-4-(2-methylpyridin-4-yl)phenyl)methanamine 15-3 as an oil.