Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([NH:26]C(=O)OC(C)(C)C)[CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10](Br)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:35][C:36]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[C:38]([F:51])[C:37]=1[OH:52]>>[NH2:26][CH:23]1[CH2:24][CH2:25][N:21]([C:18]2[N:19]=[CH:20][C:15]([NH:14][C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([C:40]5[CH:39]=[C:38]([F:51])[C:37]([OH:52])=[C:36]([Cl:35])[CH:41]=5)[CH:11]=4)[N:6]=[CH:5][C:4]=3[C:1](=[O:3])[CH3:2])=[CH:16][CH:17]=2)[CH2:22]1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCC(NC(=O)OC(C)(C)C)C2)nc1
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCC(N)C2)nc1
Yield: 13.9 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(3-acetyl-6-bromoquinolin-4-ylamino) pyridin-2-yl)pyrrolidin-3-ylcarbamate (100 mg, 0.19 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (76 mg, 0.28 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (13 mg, 16% over two steps) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.29 (s, 1H), 8.29-8.20 (m, 2H), 8.05-7.99 (m, 2H), 7.84 (dd, J=9.2, 2.6 Hz, 1H), 7.15 (d, J=11.6 Hz, 1H), 7.07 (s, 1H), 7.00 (d, J=9.2 Hz, 1H), 4.17-4.09 (m, 1H), 4.07-4.00 (m, 1H), 3.90-3.81 (m, 1H), 3.80-3.71 (m, 2H), 2.79 (s, 3H), 2.65-2.52 (m, 1H), 2.36-2.25 (m, 1H); ESI MS m/z 492 [C26H23ClFN5O2+H]+; HPLC 97.6% (AUC), tR=9.73 min.
Reaction SMILES: C(OC(N1CCC(C([O:20][C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)CC)CC1)=O)C1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:50]([O:57][C:58](=[O:72])[C:59](Br)([CH3:70])[CH2:60][CH2:61][O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CC#N>[CH2:50]([O:57][C:58](=[O:72])[C:59]([O:20][C:21]1[CH:43]=[CH:42][C:24]2[C:25]3[N:29]([CH2:30][CH2:31][O:32][C:23]=2[CH:22]=1)[CH:28]=[C:27]([C:33]1[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=1)[N:26]=3)([CH3:70])[CH2:60][CH2:61][O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: CC(Br)(CCOCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CCC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)(CCOCc4ccccc4)C(=O)OCc4ccccc4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.9 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol from Example 4 (100 mg, 0.307 mmol) and Cs2CO3 (200 mg, 0.615 mmol) in CH3CN (1 mL) was added a solution of 4-benzyloxy-2-bromo-2-methylbutyric acid benzyl ester (0.345 mmol) in CH3CN (7 mL) and stirring at reflux temperature was continued for 3 h. After cooling to RT, the reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-10% MeOH in DCM) affording 4-Benzyloxy-2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-2-methylbutyric acid benzyl ester as a pale orange gum (36 mg, 19%). LCMS: RT 4.28 min [M+H]+ 622.3
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[H-].[Na+].Cl[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.Cl>CN(C=O)C.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([O:17][C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:14]=[C:15]([CH3:16])[C:7]=2[CH:6]([CH2:5][C:4]([OH:3])=[O:18])[O:10]1
Reactant: Clc1ncccn1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Oc2ncccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
To a solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.5 g, 2.0 mmol) in anhydrous DMF (10 mL) were added NaH (0.240 g, 6.0 mmol, 60% in mineral oil) and 2-chloro-pyrimidine (0.275 g, 2.4 mmol) at 0° C. After stirring at room temperature for 16 hours, the reaction mixture was cooled to 0° C., diluted with water (20 mL) and acidified to pH 2 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate and the organic extract washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in MeOH (10 mL) and aqueous LiOH (1N, 5 mL) was added at 0° C. After stirring at room temperature for 1 hour, the mixture was acidified to pH 3 using dilute hydrochloric acid and concentrated. The residue was purified by silica gel flash column chromatography (DCM/MeOH/AcOH=10:1:trace) to give the product (0.132 g, 22.0%). mp 118-120° C. 1HNMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.65 (d, J=4.68 Hz, 2H), 7.22-7.45 (m, 2H), 7.11 (s, 1H), 5.53 (dd, J=9.51, 1.90 Hz, 1H), 3.10 (dd, J=15.66, 2.49 Hz, 1H), 2.31 (s, 3H), 2.15 (dd, J=15.52, 9.66 Hz, 1H). MS (ESI) m/z=301 [M+H]+.
Reaction SMILES: C(O[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(C)(C)C.[NH2:13][C:14]1[S:15][C:16]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([O:28][CH3:29])=[O:27])[CH:21]=2)=[CH:17][N:18]=1>C1COCC1>[CH3:29][O:28][C:26](=[O:27])[C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([S:19][C:16]2[S:15][C:14]([NH:13][C:6]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:12])=[N:18][CH:17]=2)[CH:21]=1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(Sc2cnc(N)s2)c1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(Sc2cnc(NC(=O)OC(C)(C)C)s2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Di-t-butylcarbonate (4.36 g, 20 mmol) was added to a stirred solution of 2-amino-5-[(3-carbomethoxyphenyl)thio]thiazole(1.33 g, 5 mmol) and 4-N,N-dimethylaminopyridine (62 mg, 0.5 mmol) in THF (120 mL). The solution was stirred at rt. for 6 h and concentrated. The residue was purified using flash column chromatography on silica gel. Elution with 10% EtOAc in hexanes followed by 25% EtOAc in hexanes afforded a mixture of the titled compound and the corresponding bis(tert-butoxycarbonyl)amino adduct (1.8 g) as an oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[S:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.C1N2CN3CN(C2)CN1C3.Cl.C(O)(=[O:31])C>O>[C:12]1([C:11]2[C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([CH:2]=[O:31])[C:8]=3[S:9][CH:10]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1cccc2c(-c3ccccc3)csc12
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Product: O=Cc1cccc2c(-c3ccccc3)csc12
Reaction time: 3.5 h

Procedure:
7-Bromomethyl-3-phenylbenzo[b]thiophene (13.5 g; 44.6 mmole) was added to a solution of hexamine (14.0 g; 0.1 mole) in a mixture of acetic acid (50 ml) and water (25 ml) and the mixture refluxed with stirring for 3.5 hours. Concentrated hydrochloric acid (25 ml) was added and the mixture refluxed for a further 20 minutes. The solution was cooled, poured into water and extracted with diethyl ether. The combined ether extracts were dried over magnesium sulphate and evaporated. The crude product was purified by column chromatography on silica eluting with a mixture of methylene chloride and hexane. The relevant fractions were combined and evaporated to yield 3-phenylbenzo[b]thiophene-7-carboxaldehyde as an oil. (4.9 g).
Reaction SMILES: O[C@H:2]([CH2:22][CH3:23])[C@@H:3]([NH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:9])[C:4]([OH:6])=[O:5].O[C@@H](CC)[C@@H](NC(OCCCCCC1C=CC=CC=1)=O)C(O)=O.CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:8](=[O:9])[NH:7][C@H:3]2[C:4](=[O:6])[O:5][C@@H:2]2[CH2:22][CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC[C@@H](O)[C@@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Agent: CC[C@H](O)[C@@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H]1OC(=O)[C@@H]1NC(=O)OCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 57 %

Procedure:
Under nitrogen atmosphere, to a stirred mixture of (2R*,3R*)-3-hydroxy-2-(5-phenylpentoxy-carbonylamino)-pentanoic acid and (2R*,3S*)-3-hydroxy-2-(5-phenylpentoxy-carbonylamino)-pentanoic acid (0.155 g, 0.48 mmol) in dry CH2Cl2, (20.0 mL), at 0° C., Et3N (0.2 mL, 1.44 mmol) and subsequently TBTU (0.185 g, 0.58 mmol) were added. The mixture was left stirring at 0° C. for 1 h and at rt for 15 h. The organics were then removed under reduced pressure, and the resulting crude product purified by column chromatography, using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (from 100:0 to 80:20) to afford the title compound (0.075 g, 57%), as pure anti diastereoisomer, as white solid. MS (ESI) m/z: 323 [M−NH4]+; (ESI) m/z: 304 [M−H]−. 1H NMR (DMSO-d6) δ 0.90 (t, J=7.41 Hz, 3H), 1.26-1.38 (m, 2H), 1.58 (p, J=7.71, 8.27 Hz, 4H), 1.67-1.90 (m, 2H), 2.57 (t, J=7.65 Hz, 2H), 3.98 (t, J=6.60 Hz, 2H), 4.51 (td, J=4.28, 6.84 Hz, 1H), 4.69 (dd, J=4.32, 8.12 Hz, 1H), 7.09-7.32 (m, 5H), 8.06 (d, J=8.09 Hz, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[ClH:9].Cl.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(P(=O)(OCC)OCC)#N.Cl>C(OCC)(=O)C.O.CN(C)C=O.C(N(CC)CC)C>[ClH:9].[CH:2]1[S:1][CH:5]=[CH:4][C:3]=1[C:6]([N:20]1[CH2:19][CH2:18][N:17]([CH2:16][C:15]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([O:26][CH3:27])=[C:13]([O:12][CH3:11])[CH:14]=2)[CH2:22][CH2:21]1)=[O:8]
Reactant: O=C(O)c1ccsc1
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(CN2CCN(C(=O)c3ccsc3)CC2)cc(OC)c1OC
Reaction time: 1 h
Yield: 46.6 %

Procedure:
To a mixture of 3-thiophenecarboxylic acid (0.2 g), 1(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (0.56 g), triethylamine (0.6 g) and N,N-dimethylforamide (10 ml) is added dropwise at room temperature diethyl cyanophosphonate (0.6 ml), followed by stirring for one hour. After addition of water (100 ml) and ethyl acetate (100 ml), the reaction mixture is extracted with ethyl acetate. The extract is washed with water, dried, and concentrated under reduced pressure. The residue is purified by means of a silica gel column chromatography(hexane:acetone=2:1) to give an oily product, which is led to its hydrochloride, followed by crystallization from a mixture of ethyl acetate and ethyl ether to afford 1-(3-thenoyl)-4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride (0.3 g) as colorless needles, m.p. 201°-205° C. (decomp.).
Reaction SMILES: [H-].[K+].O1CCCC1.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@@:16]([OH:45])([CH2:39][N:40]1[CH:44]=[N:43][CH:42]=[N:41]1)[C@H:17]([S:19][C@@H:20]1[CH2:25][O:24][C@@H:23](/[CH:26]=[CH:27]/[CH:28]=[CH:29]/[C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=2[F:38])[O:22][CH2:21]1)[CH3:18].Cl[C:47]([O:49][CH2:50][CH2:51][Cl:52])=[O:48]>CCCCCC.C(OCC)(=O)C>[C:47](=[O:48])([O:45][C@:16]([C:10]1[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=1[F:8])([CH2:39][N:40]1[CH:44]=[N:43][CH:42]=[N:41]1)[C@H:17]([S:19][C@@H:20]1[CH2:25][O:24][C@@H:23](/[CH:26]=[CH:27]/[CH:28]=[CH:29]/[C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=2[F:38])[O:22][CH2:21]1)[CH3:18])[O:49][CH2:50][CH2:51][Cl:52]
Reactant: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C(Cl)OCCCl
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@@](Cn1cncn1)(OC(=O)OCCCl)c1ccc(F)cc1F
Temperature: 0 °C
Yield: 88.8 %

Procedure:
A mixture of potassium hydride (30% dispersion in mineral oil; 739 mg, 5.53 mmol) and tetrahydrofuran (8 ml) was cooled to 0° C., and 4-[(1E,3E)-4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-1,3-butadienyl]-3-fluorobenzonitrile (1.00 g, 1.84 mmol) described in Reference example 1 was added thereto with stirring, then the mixture was stirred at room temperature for 30 minutes. The mixture was cooled to 0° C., and then a mixture of 2-chloroethyl chloroformate (315 mg, 2.21 mmol) and tetrahydrofuran (1.5 ml) was added thereto with stirring. The resulting mixture was stirred at room temperature for 18 hours. After cooling, the mixture was partitioned between ethyl acetate and water, and the organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, and the solvent was distilled off under reduced pressure to give an oily residue. The residue was subjected to column chromatography (eluent; ethyl acetate:hexane=1:1) to afford the title compound (1.06 g, 88% yield) as a colorless oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[S:21][C:20]2[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:25][C:19]=2[CH:18]=1)=[O:16])(C)(C)C.NC1C=CC=CC=1NC(C1SC2C=CC(OCCOCCOC)=CC=2C=1)=O>>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[S:21][C:20]2[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:25][C:19]=2[CH:18]=1)=[O:16]
Reactant: COCCOc1ccc2sc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2c1
Agent: COCCOCCOc1ccc2sc(C(=O)Nc3ccccc3N)cc2c1
Product: COCCOc1ccc2sc(C(=O)Nc3ccccc3N)cc2c1

Procedure:
was prepared from (2-{[5-(2-Methoxy-ethoxy)-benzo[b]thiophene-2-carbonyl]-amino}-phenyl)-carbamic acid tert-butyl ester (30) in an analogous manner to that described for the preparation of (27) example 11, step 2; yellow solid, mp. 162–165° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([SH:16])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].Cl[C:18]1[CH:19]=[CH:20][C:21]([N+:33]([O-:35])=[O:34])=[C:22]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:23]=1.[H-].[Na+]>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([S:16][C:18]2[CH:19]=[CH:20][C:21]([N+:33]([O-:35])=[O:34])=[C:22]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH:23]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)ccc1[N+](=O)[O-]
Yield: 38 %

Procedure:
By using 476 mg of 3,5-di-t-butyl-4-hydroxybenzenethiol, 573 mg of t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate, 175 mg of sodium hydride (55% by weight) and 10 ml of anhydrous N,N-dimethylformamide, reaction and purification were carried out in a similar manner to that described in Reference Example 6, whereby 371 mg of the title compound were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:20])[N:3]=1.B([C:24]1[CH:35]=[CH:34][C:27]([CH2:28][C@@H:29]([C:31]([OH:33])=[O:32])[NH2:30])=[CH:26][CH:25]=1)(O)O.C(#N)C.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.O>[NH2:30][CH:29]([CH2:28][C:27]1[CH:34]=[CH:35][C:24]([C:2]2[N:3]=[C:4]([NH2:20])[N:5]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([F:13])([F:12])[F:11])[N:7]=2)=[CH:25][CH:26]=1)[C:31]([OH:33])=[O:32]
Reactant: Nc1nc(Cl)nc(OC(c2ccccc2)C(F)(F)F)n1
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: O
Solvent: CC#N
Product: Nc1nc(OC(c2ccccc2)C(F)(F)F)nc(-c2ccc(CC(N)C(=O)O)cc2)n1
Temperature: 150 °C
Yield: 7.4 %

Procedure:
A microwave vial was charged with 4-chloro-6-[2,2,2-trifluoro-1-phenyl-ethoxy]-[1,3,5]triazine-2-ylamine (33 mg, 0.1 mmol), 4-borono-L-phenylalanine (31 mg, 0.15 mmol), 1 ml of actonitrile, and 0.7 ml of water. Aqueous sodium carbonate (0.3 ml, 1M) was added to above solution followed by 5 mol percent dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes by microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, was then purified with Prep-LC to give 3.2 mg 2-amino-3-{4-[4-amino-6-(1-phenyl-2,2,2-trifluoro-ethoxy]-[1,3,5]triazin-2-yl]-phenyl)-propionic acid. 1H NMR (300 MHz, CD3OD) δ 8.22 (d, J=8.20 Hz, 2H), 7.52 (m, 2 H), 7.33 (m, 5H) 6.62 (m, 1H), 4.19 (t, 1 H), 3.1-3.33 (m, 2 H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>[Fe]>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12](=[O:14])[CH2:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(CCC(=O)O)cc1
Agent: [Fe]
Product: CC(C)c1ccc(CCC(=O)CCc2ccc(C(C)C)cc2)cc1
Temperature: 290 °C

Procedure:
3-(4-Isopropylphenyl)propionic acid (0.20 mole) and iron (hydrogen reduced, 6.15 g., 0.11 mole) are heated for 1.5 hours at 195° C. under a nitrogen atmosphere. After that time, the temperature is increased to 290° C. and maintained at that temperature for three hours. The cooled reaction mass is extracted well with ether, filtered through Celite, and the ethereal extracts concentrated under vacuum. The residue is stripped under vacuum to leave the product, 17.3 g. (51%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:8])[CH2:5][CH2:6][OH:7].[CH2:9](Br)[CH:10]=[CH2:11]>CC(C)=O>[CH2:11]([O:7][CH2:6][CH2:5][N:4]([CH3:8])[CH3:3])[CH:10]=[CH2:9]
Reactant: C=CCBr
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C=CCOCCN(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (17.5 g) and dimethyl formaldehyde (400 mL) were added to a 2-L round-bottom flask. After cooling the flask to 0° C. by immersing in an ice bath, 2-dimethylaminoethanol (0.398 mol) was added. After stirring for about 30 minutes and adding allyl bromide (0.4378 mol), the mixture was stirred for 3 hours after raising the temperature of the reactor to room temperature. Upon completion of reaction, the reaction was terminated by adding water to the flask and the product was extracted using diethyl ether. The extract was concentrated under reduced pressure and used in the next step without further purification. After filtration under reduced pressure, 2-(allyloxy)-N,N-dimethylethanamine was obtained through fractional distillation. Structural analysis was performed by nuclear magnetic resonance (NMR) spectroscopy.
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19]([B:25]([OH:27])[OH:26])[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.[Cl:38][C:39]1[C:40]2[C:50]([F:51])=[CH:49][CH:48]=[C:47]([F:52])[C:41]=2[S:42][C:43]=1[C:44](Cl)=[O:45]>C(Cl)Cl>[C:1]([N:8]([CH3:28])[CH:9]1[CH2:10][CH2:11][CH:12]([N:15]([CH2:16][C:17]2[CH:18]=[C:19]([B:25]([OH:26])[OH:27])[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[C:44]([C:43]2[S:42][C:41]3[C:47]([F:52])=[CH:48][CH:49]=[C:50]([F:51])[C:40]=3[C:39]=2[Cl:38])=[O:45])[CH2:13][CH2:14]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of boronic acid 4 (7.60 g, 19.4 mmol) in DCM (300 mL) at 0° C. is treated with DIPEA (7.40 mL, 42.7 mmol), followed by acid chloride 8 (6.21 g, 23.3 mmol) in one portion. After warming to RT, the solution is stirred 3 h. Analysis by LC/MS at this juncture confirmed the reaction is complete. Thus the solvent is removed in vacuo and the residue purified by chromatography (gradient elution—60% EtOAc in heptane with 0.5% triethylamine increasing to neat EtOAc with 0.5% triethylamine, then 10-20% MeOH in EtOAc with 0.5% triethylamine) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:23])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O[CH:29](N(C)C)[N:30]([CH3:32])[CH3:31])(C)(C)C.CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:29][N:30]([CH3:32])[CH3:31])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: COc1ccc(CCNC(=O)Cc2ccc(Cl)cc2)cc1OC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CCNC(=O)C(=CN(C)C)c2ccc(Cl)cc2)cc1OC
Temperature: 90 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
5.75 g (17.2 mmol) of N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(4-chlorophenyl) acetamide, 9.00 g (51.6 mmol) of t-butoxybis(dimethylamino)methane and 90 ml of N,N-dimethylformamide were mixed and stirred at 90° C. for 3 hours and then at 110° C. for 3 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 6.68 g of crude N-[2-(3,4-dimethoxyphenyl)ethyl]-3-dimethylamino-2-(4-chlorophenyl)acrylamide.
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([C:10]([F:13])([F:12])[F:11])[C:4]=1[OH:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[Br:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([C:10]([F:12])([F:13])[F:11])[C:4]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1c(Br)cc(F)cc1C(F)(F)F
Reactant: BrCc1ccccc1
Agent: [Na]
Solvent: CCO
Product: Fc1cc(Br)c(OCc2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.65 g (28 mmol) of sodium is dissolved in 35 ml of dry ethanol, 5.96 g (23 mmol) of 2-bromo-4-fluoro-6-(trifluoromethyl)-phenol is added and it is stirred for 20 minutes at room temperature, 7.17 g (42 mmol) of benzyl bromide is added and refluxed for 1 hour. Sodium bromide precipitates out crystalline from the solution The hot solution is filtered, the filtrate is evaporated to dryness and the residue is chromatographed on silica gel 60 with dichloromethane/hexane. 6.29 g (18 mmol) =78.3% of the theoretical yield is obtained as a predominantly crystalline solid.
Reaction SMILES: C(O)(=O)C.[CH2:5]([N:7]1[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][C:9]2[N:15]=[C:16]([N:19]3[CH2:24][CH2:23][N:22](CC4C=CC=CC=4)[CH2:21][CH2:20]3)[N:17]=[CH:18][C:8]1=2)[CH3:6].[H][H]>[Pd].C(O)C>[CH2:5]([N:7]1[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][C:9]2[N:15]=[C:16]([N:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)[N:17]=[CH:18][C:8]1=2)[CH3:6]
Reactant: [H][H]
Reactant: CCN1C(=O)CCCc2nc(N3CCN(Cc4ccccc4)CC3)ncc21
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCN1C(=O)CCCc2nc(N3CCNCC3)ncc21
Reaction time: 4 h
Yield: 100 %

Procedure:
To a mixed solvent of 30 ml of acetic acid and 10 ml of ethanol, 0.6 g (2.18 mmol, Referential Example 52) of 5-ethyl-2-(4-benzylpiperazino)-6-oxo-6,7,8,9-tetrahydro(5H)pyrimido[5,4-b]azepine and 0.06 g of 10% Pd-C were added. While causing hydrogen gas to flow through the reaction mixture, the reaction was allowed to proceed at 100° C. for 4 hours. Thereafter, the Pd/C was filtered off and the filtrate was dried to obtain 0.5 g of a light yellowish oily substance (yield: about 100%).