Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:7][CH:6]([N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])[C:5]1=[O:32])#[N:2].[N-:33]=[N+:34]=[N-:35].[Na+].Cl.C(N(CC)CC)C.Cl>CN1CCCC1=O>[C:15]1([C:8]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:4]([CH2:3][C:1]3[NH:35][N:34]=[N:33][N:2]=3)[C:5](=[O:32])[CH:6]([N:21]3[C:22](=[O:31])[C:23]4=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]4[C:25]3=[O:26])[N:7]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCN1C(=O)C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2)c2ccccc21
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=C1C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2)c2ccccc2N1Cc1nnn[nH]1
Temperature: 145 °C
Yield: 91.1 %

Procedure:
To a solution of (3RS)-1-cyanomethyl-1,3-dihydro-5-phenyl-3-phthalimido-2H-1,4-benzodiazepin-2-one (100.0 g) and sodium azide (46.4 g) in 1-methyl-2-pyrrolidone (1.74 l) was added triethylamine hydrochloride (49.1 g) under stirring. The mixture was heated on an oil-bath at 145° C. and stirred for 4 hours. The reaction mixture was poured into 5% hydrochloric acid (4.8 l) under cooling and stirring. The resultant precipitate was collected by filtration, washed with water several times and dried in vacuo at 50° C. for 5 hours to afford (3RS)-1,3-dihydro-5-phenyl-3-phthalimido-1-[(1H-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (100.39 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:12])[CH2:9][CH2:10][CH3:11])[CH:5]=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:33]([CH3:34])=[C:32]([C:35](Cl)=[O:36])[CH:31]=[N:30]2)=[CH:25][CH:24]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:12][C:35]([C:32]2[CH:31]=[N:30][N:29]([C:26]3[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=3)[C:33]=2[CH3:34])=[O:36])[CH2:9][CH2:10][CH3:11])[CH:5]=[N:6][CH:7]=1
Reactant: CCCC(N)c1cncc(Br)c1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC(NC(=O)c1cnn(-c2ccc(Cl)cc2)c1C)c1cncc(Br)c1
Reaction time: 15 h
Yield: 75.4 %

Procedure:
A solution of 1-(5-bromo-pyridin-3-yl)-butylamine (470 mg, 2.0 mmol), diisopropylethylamine (0.82 mL, 4.7 mmol) and DMAP (19 mg, 0.16 mmol) in CH2Cl2 (20 mL) is treated with 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carbonyl chloride (400 mg, 1.6 mmol) and stirred for 15 hours. The reaction mixture is then diluted with CH2Cl2 (50 mL), washed with saturated aqueous ammonium chloride (2×50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material is purified by flash chromatography on silica gel (eluted with 20 to 50% EtOAc/hexanes) to provide 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid [1-(5-bromo-pyridin-3-yl)-butyl]amide as a colorless foam-solid (540 mg, 78%).
Reaction SMILES: [CH3:1][N:2]([CH2:12][C:13]1[CH:14]=[C:15]([CH:51]=[CH:52][CH:53]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:21][C:20]=1[C:31]1[CH:32]=[C:33]([CH:48]=[CH:49][N:50]=1)[C:34]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40](C(F)(F)F)[CH:39]=1)=[O:35])=[O:17])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8](C)[CH2:7][CH2:6]1.C(OC(=O)C)(=O)C.N1C=CC=CC=1>O1CCCC1>[CH2:37]([NH:36][C:34](=[O:35])[C:33]1[CH:48]=[CH:49][N:50]=[C:31]([C:20]2[CH:21]=[C:22]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:23]=[CH:24][C:19]=2[NH:18][C:16](=[O:17])[C:15]2[CH:51]=[CH:52][CH:53]=[C:13]([CH2:12][N:2]([CH3:1])[CH2:3][CH2:4][N:5]3[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]3)[CH:14]=2)[CH:32]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CN1CCN(CCN(C)Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CN(CCN1CCNCC1)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3ccccc3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The free base of N-benzyl-2-(2-(3-((methyl(2-(piperazin-1-yl)ethyl)amino)methyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinamide was prepared as described in the preparation of 2-(2-(3-((methyl(2-(4-methylpiperazin-1-yl)ethyl)amino)methyl)benzamido)-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)-benzyl)isonicotinamide 40. Into a 50-mL round-bottom flask, was placed a solution of this free base (150 mg, 0.21 mmol, 1.00 equiv) in tetrahydrofuran (5 mL), acetyl acetate (26 mg, 0.25 mmol, 1.20 equiv), and pyridine (33 mg, 0.42 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 44 mg (17%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.25 (s, 1H), 9.56-9.52 (m, 1H), 8.93-8.91 (d, J=5.1 Hz, 1H), 8.33-8.26 (m, 2H), 8.04 (s, 1H), 7.96-7.93 (d, J=7.8 Hz, 1H), 7.85-7.83 (d, J=6.3 Hz, 1H), 7.70-7.55 (m, 6H), 7.29-7.26 (d, J=8.7 Hz, 1H), 4.64-4.62 (d, J=5.7 Hz, 2H), 4.29 (s, 2H), 3.54 (s, 4H), 3.30-3.21 (m, 6H), 3.03 (s, 2H), 2.80-2.73 (m, 3H), 2.66 (s, 3H), 1.99 (s, 3H), 1.73 (s, 4H), 1.60-1.59 (d, J=4.8 Hz, 1H). MS (ES, m/z): 756 [M+H]+.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)=[CH:12][C:11]=1[F:29])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:29][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3n3ccnc3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1ccncn1)c1cc(F)c(O[C@H]2CCCC[C@H]2n2ccnc2)cc1F
Yield: 93.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2S*)-2-(1H-imidazol-1-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (315 mg, 0.538 mmol) prepared in Example 32a, triethylsilane (0.40 mL), trifluoroacetic acid (4.0 mL) and dichloromethane (4.0 mL), to yield the title compound (220 mg, 94%) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:16]=2)([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[C:26]([CH3:29])([CH3:28])[CH3:27].[C:30]1(C)[CH:35]=CC(S(O)(=O)=O)=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[CH2:35]([O:12][C:11](=[O:13])[CH2:10][CH2:9][C:8]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:16]=1)([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:4]=1)[CH3:14])[CH2:30][CH2:31][CH3:32]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)c1cc(C(C)(CCC(=O)O)c2ccc(O)c(C(C)(C)C)c2)ccc1O
Solvent: Cc1ccccc1
Product: CCCCOC(=O)CCC(C)(c1ccc(O)c(C(C)(C)C)c1)c1ccc(O)c(C(C)(C)C)c1

Procedure:
39.8 g of 4,4-bis(4'-hydroxy-3'-tert.-butyl-phenyl) pentanoic acid were dissolved in 222 g of n-bitanol and 228 g of toluene and 1 g of p-toluene-sulfonic acid was added as an esterification catalyst. Azeotropic distillation was continued until no more water distilled over. After toluene and butanol had been distilled off, a resin-like residue was obtained. After recrystallization from hexane, the 4,4-bis(4'-hydroxy-3'-tert.-butyl-phenyl)pentanoic acid n-butyl ester was obtained as a white crystallized substance.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].OC1C=CC([C:13]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH3:14])=CC=1>>[C:1]([CH2:14][C:13]([O:21][C:18]1[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1)([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: CC(c1ccc(O)cc1)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: C=CC(=O)Cl
Product: C=CC(=O)CC(Oc1ccccc1)(c1ccc(O)cc1)c1ccc(O)cc1
Yield: 85 %

Procedure:
Acryloyl chloride (45.3 g, 0.5 mole) was dissolved in 50 g (0.63 mole) of pyridine anhydride in a reaction vessel. The exothermic reaction was cooled by placing the reaction vessel in a liquid nitrogen-isopropyl alcohol bath. Thereafter, 193 g (0.63 mole) of 1,1,1-tris(4-hydroxy phenyl)ethane was added dropwise to the reaction mixture and stirred. After the addition of 1,1,1-tris(4-hydroxy phenyl)ethane, the reaction vessel was removed from the cooling bath, and the reaction was stirred at room temperature for over 24 hours. The progress of the reaction was monitored by TLC. The reaction mixture was transferred to a separatory funnel, neutralized using 1 N aqueous sulfuric acid solution, and extracted with dichloromethane. The organic layer was washed with deionized water, concentrated under reduced pressure, and purified by distillation under reduced pressure to yield acryloyl phenoxy bis(-4-hydroxy phenyl)ethane monomer (yield 85%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6].[CH2:14]([O:16][C:17]1[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=1[O:19][CH2:20][CH2:21][NH2:22])[CH3:15].C(=O)([O-])[O-].[K+].[K+].[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35]>C(C(C)=O)C>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[C:8]1([S:5]([CH2:4][CH2:3][CH2:2][NH:22][CH2:21][CH2:20][O:19][C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[O:16][CH2:14][CH3:15])(=[O:7])=[O:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOc1ccccc1OCCN
Reactant: O=S(=O)(CCCBr)c1ccccc1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOc1ccccc1OCCNCCCS(=O)(=O)c1ccccc1
Yield: 7.1 %

Procedure:
A mixture of [(3-bromopropyl)sulfonyl]benzene (26.3 g, 100 mmol), 2-(2-ethoxyphenoxy)ethanamine (18.1 g, 100 mmol), and potassium carbonate (55.3 g, 400 mmol) in 200 mL of methyl ethyl ketone is heated at reflux for 18 hours. The reaction mixture is cooled, filtered, and the filtrate is evaporated. The residue is dissolved in warm 2-propanol and treated with oxalic acid (9.3 g, 101 mmol). The precipitated salt is filtered and recrystallized from 2-propanol to yield 3.2 g (7%) of product, mp 184-188° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.C1(C)C=CC(S(O[CH2:28][CH2:29][CH:30](O)[CH2:31][CH2:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)(=O)=O)=CC=1.CN(C)C=[O:44]>>[C:12]1(/[CH:11]=[CH:10]/[C:7]2[CH:6]=[CH:5][C:4]([O:3][CH2:28][CH:29]([OH:44])[CH2:30][CH2:31][CH2:32][C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)=[CH:9][CH:8]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)OCCC(O)CCc2cccnc2)cc1
Reactant: Oc1ccc(/C=C/c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: OC(CCCc1cccnc1)COc1ccc(/C=C/c2ccccc2)cc1

Procedure:
Prepared according to the method described in Example 96d) from sodium hydride (60% dispersion in mineral oil, 0.045 g), trans-4-hydroxystilbene (0.219 g) and (±)-3-hydroxy-5-(3-pyridyl)-1-pentyl para-toluenesulfonate (0.250 g) in anhydrous dimethylformamide (5 ml). The crude product was purified by column chromatography over silica eluting with methanol:dichloromethane (1:19) to give the title compound (0.167 g) as a solid which was recrystallised from ethyl acetate:hexane.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]([CH3:14])[CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:15][CH2:16][CH2:17][OH:18].[OH-].[Na+]>O>[CH3:13][N:12]([CH3:14])[C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[NH:15][CH2:16][CH2:17][OH:18]
Reactant: NCCO
Reactant: CN(C)c1ccc2nccc(Cl)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)c1ccc2nccc(NCCO)c2c1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A mixture of 4-chloro-6-dimethylaminoquinoline 12 (4.92 g, 24 mmol), prepared according to the method described by Riegel et al., J. Am. Chem. Soc., 1946, 68, 1264, and of 2-aminoethanol (43.99 g, 720 mmol) is heated, with magnetic stirring, at 150° C. for 15 min and then at 185° C. for 30 min. After returning to ambient temperature, the solid is suspended in 25 ml of a 10%, w/v, aqueous sodium hydroxide solution and 165 ml of water. The precipitate obtained is filtered through sintered glass, washed with water and then dried under vacuum. The product is obtained in the form of a white powder: 4.86 g (yield=88%).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[C:13]1([CH3:29])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C@@H:19]1[NH:24][CH2:23][CH2:22][N:21]2[C:25](=[O:28])[CH2:26][CH2:27][C@@H:20]12.[CH3:30][NH:31][C@@H:32]([C:34]1[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[C:36]([CH3:44])[CH:35]=1)[CH3:33]>CCOC(C)=O.CN(C1C=CN=CC=1)C>[CH3:30][N:31]([C@@H:32]([C:34]1[CH:39]=[C:38]([C:40]([F:41])([F:43])[F:42])[CH:37]=[C:36]([CH3:44])[CH:35]=1)[CH3:33])[C:5]([N:24]1[CH2:23][CH2:22][N:21]2[C:25](=[O:28])[CH2:26][CH2:27][C@H:20]2[C@@H:19]1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH3:29])=[O:11]
Reactant: Cc1ccccc1[C@@H]1NCCN2C(=O)CC[C@@H]12
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN[C@H](C)c1cc(C)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1cc([C@@H](C)N(C)C(=O)N2CCN3C(=O)CC[C@H]3[C@@H]2c2ccccc2C)cc(C(F)(F)F)c1
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To a solution of triphosgene (254 mg, 0.87 mmol) in EtOAc (5 mL) at 0° C. was added solution of (1S,8aS)-1-o-tolylhexahydropyrrolo[1,2-a]pyrazin-6(7H)-one (400 mg, 1.73 mmol), DMAP (21 mg, 0.173 mmol) and TEA (524 mg, 5.19 mmol in EtOAc (5 mL). The mixture was stirred for 1.5 h, followed by addition of (R)-N-methyl-1-(3-methyl-5-(trifluoromethyl)phenyl)ethanamine (563 mg, 2.6 mmol) in EtOAc (2 mL) and TEA (524 mg, 5.19 mmol). The reaction was stirred at 50° C. for 48 h and quenched with water. The resulting mixture was extracted with EtOAc and the organic layer was washed with 1 M aqueous HCl solution, dried over anhydrous Na2SO4 and then concentrated in high vacuum. The residue was purified by silica gel chromatography (DCM/MeOH=20/1 to 10/1) to give the title compound (350 mg, yield: 85%). 1H NMR (400 MHz, CDCl3) δ ppm 7.32 (s, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.19 (d, J=7.4 Hz, 2H), 7.14 (ddd, J=17.5, 10.0, 4.2 Hz, 2H), 7.00 (s, 1H), 5.48 (q, J=6.9 Hz, 1H), 4.22 (m, 2H), 3.71 (dd, J=17.0, 7.3 Hz, 1H), 3.29 (d, J=11.8 Hz, 1H), 3.11 (td, J=12.4, 2.7 Hz, 1H), 2.95 (td, J=11.9, 3.2 Hz, 1H), 2.64 (s, 3H), 2.54 (s, 3H), 2.48 (m, 2H), 2.34 (s, 3H), 1.87 (m, 1H), 1.67 (ddd, J=17.1, 13.1, 9.4 Hz, 1H), 1.37 (d, J=6.7 Hz, 3H); m/z (ES+): 474 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([Cl:14])P(CCC)(CCC)=O)[CH3:2].C([Li])CCC.[I:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C(OCC)(=O)C>O1CCCC1.CCCCCC>[CH2:1]([O:3][C:4](=[O:15])[C:5]([Cl:14])=[CH:26][C:25]1[CH:28]=[CH:29][C:22]([I:21])=[CH:23][CH:24]=1)[CH3:2]
Reactant: O=Cc1ccc(I)cc1
Reactant: CCCP(=O)(CCC)C(Cl)C(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cl)=Cc1ccc(I)cc1
Reaction time: 0.17 h

Procedure:
A stirred, cooled (−78° C.) solution of chloro-(dipropyl-phosphinoyl)-acetic acid ethyl ester (6.1 g, 23.5 mmol) in anhydrous tetrahydrofuran (700 mL) was treated with a 1.6M solution of n-butyl lithium in hexanes (14 mL, 22 mmol). After 10 min, the reaction mixture was cannulated into a cooled (−78° C.) solution of 4-iodo-benzaldehyde (2.61 g, 11.2 mmol) in tetrahydrofuran (25 mL). After 30 minutes, it was quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford an oil that was subjected to flash column, chromatography over silica gel (230–400 mesh) using 4–5% ethyl acetate in hexane as the eluent to afford the title compound as a 1:1 mixture of E and Z isomers (3.6 g, 95%).
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH2:3][CH3:4].CN(C)C=O.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1>ClCCl>[Si:12]([O:6][CH2:1][CH:2]([OH:5])[CH2:3][CH3:4])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CCC(O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(O)CO[Si](C)(C)C(C)(C)C
Reaction time: 10 h
Yield: 44.1 %

Procedure:
A 50 mL round bottom flask was charged with (±)-1,2-butanediol (1 g, 11.09 mmol) and to it was added dimethylformamide (8 mL) followed by tert-butyldimethylsilyl chloride (2.5 g, 16.64 mmol) and imidazole (1.88 g, 27.7 mmol). The reaction mixture was stirred for 10 hours after which it was diluted with dichloromethane and poured into a separatory funnel and washed with water (80 mL) and brine and dried over magnesium sulfate. After filtration and concentration the crude oil was purified by silica gel flash chromatography (hexanes:ethylacetate) to obtain 1 gm of pure desired product in 45% yield. 1H (CDCl3) δ(ppm): 3.6 (m, 1H). 3.5 (m, 1H), 3.4 (m, 1H), 2.4 (s, 1H), 1.44 (m, 2H), 0.99 (t, 3H), 0.9 (s, 9H), 0.06 (s, 6H).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:29])[CH2:6][N:7]([CH:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)[CH3:16])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>C1COCC1.CO.O>[C:20]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:19]=[CH:18][C:17]([CH:15]([N:7]([CH2:6][C:5]([OH:29])=[O:4])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:16])=[CH:22][CH:21]=1
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)C(C)c1ccc(-c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(c1ccc(-c2ccccc2)cc1)N(CC(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
LiOH (140 mg, 3.3 mmol) was added to a stirred solution of [(1-biphenyl-4-yl-ethyl)-tert-butoxycarbonyl-amino]-acetic acid methyl ester (202 mg, 0.54 mmol) in THF:MeOH:H2O (3:1:1, 10 mL), and the resulting mixture was stirred at room temperature for 12 hrs. The reaction mixture was concentrated under reduced pressure. Cold water was then added, the product was acidified with aqueous citric acid solution and then extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 190 mg (97.9% yield) of [(1-biphenyl-4-yl-ethyl)-tert-butoxycarbonyl-amino]-acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:26]([O-])=O)=[C:7]([CH:25]=1)[CH2:8][N:9]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:26][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:25][C:7]=1[CH2:8][N:9]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: CCOC(=O)CN(Cc1cc(OC)ccc1[N+](=O)[O-])C(=O)c1ccc(Cl)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(Cc1cc(OC)ccc1N)C(=O)c1ccc(Cl)cc1

Procedure:
1.0 g (2.5 mmol) of ethyl [(5-methoxy-2-nitrobenzyl)-(4-chlorobenzoyl)amino]acetate was dissolved in a mixture of 10 ml of ethyl acetate and 10 ml of ethanol. 360 mg of 10% palladium/carbon was added to the obtained solution, and they were stirred in the presence of hydrogen at room temperature for 4 hours. The reaction mixture was filtered through Celite and the solvent was evaporated. The obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>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>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[C:18]1[CH:19]=[C:14]([OH:13])[CH:15]=[CH:16][CH:17]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Brc1ccc2ccccc2n1
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: [K+]
Product: COc1cccc(-c2ccc3ccccc3n2)c1
Product: Oc1cccc(-c2ccc3ccccc3n2)c1
Temperature: 92.5 °C
Yield: 208.9 %

Procedure:
2-Bromoquinoline (3.19 g, 15.3 mmol, 1.0 eq), 3-methoxyphenyl boronic acid (2.79 g, 18.4 mmol, 1.2 eq) and K2CO3 (4.65 g, 33.7 mmol, 2.2 eq) were added to a dry 100 mL three-necked flask equipped with a magnetic stir bar and a condenser. Then the flask was evacuated and back-filled with nitrogen. The evacuation and back-fill procedure was repeated twice. Then solvent DME (38 mL), EtOH (12 mL) and H2O (17 mL) were added under nitrogen. The mixture was bubbled with nitrogen for 20 minutes and then Pd(PPh3)4 (0.53 g, 0.46 mmol, 0.03 eq) was added. The flask was then placed into an oil bath and heated to reflux (90-95° C.). The reaction was monitored by TLC, and about 19 hours later the starting material 2-bromoquinoline was consumed completely. Then the mixture was cooled to ambient temperature. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and then dried over sodium sulfate, and filtered and washed with ethyl acetate. The filtrate was concentrated and the residue was purified through column chromatography on silica gel using hexane and ethyl acetate (10:1) as an eluent to obtain the desired product 2-(3-methoxyphenyl)quinoline as a yellow liquid (3.76 g), which was used directly for the next step. A solution of the yellow liquid (3.75 g) in hydrogen bromide acid (25 mL, 48%) refluxed (110-120° C.) for 18 hours in an atmosphere of nitrogen. Then the mixture was cooled to ambient temperature and neutralized with a solution of K2CO3 in water until there was no gas to generate. Then the precipitate was filtered off and washed with water several times. The brown solid was dried in air under reduced pressure and product 3-(quinolin-2-yl)phenol 3.68 g was obtained. 1H NMR (DMSO-d6, 400 MHz): δ 6.74 (dd, J=8.0, 2.4 Hz, 1H), 7.18 (t, J=8.0 Hz, 1H), 7.43-7.48 (m, 3H), 7.65 (t, J=7.6 Hz, 1H), 7.86 (d, J=7.6 Hz, 1H), 7.92 (t, J=8.0 Hz, 2H), 8.37 (d, J=8.4 Hz, 1H), 9.52 (bs, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=[N:53][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C1(N)CCCC1>CN(C=O)C>[CH:48]1([NH:53][C:30](=[O:32])[C:29]2[CH:33]=[CH:34][CH:35]=[C:27]([C:10]3[C:11]4[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]5[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=5[F:26])[C:12]=4[N:13]=[C:8]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:36][CH3:37])[CH2:1][CH3:2])[N:9]=3)[CH:28]=2)[CH2:49][CH2:50][CH2:51][CH2:52]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)NC3CCCC3)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.4 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoic acid (30 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and cyclopentanamine (8.91 uL, 0.09 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (6.0 mg, 17%). LC-MS m/z 575 (M+H)+.