Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[O-]S([O-])(=O)=O.[Mg+2].[C:22]([C:26]1C=C(O)C(=[CH:31][CH:32]=1)O)(C)([CH3:24])[CH3:23].II>CC(C)=O>[C:4]([O:3][C:1](=[O:2])[NH:8][C:9]1[CH:10]=[C:11]2[C:12](=[CH:13][CH:14]=1)[NH:15][C:22]([CH3:24])([CH3:23])[CH:26]=[C:32]2[CH3:31])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)c1ccc(O)c(O)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Agent: II
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CC1=CC(C)(C)Nc2ccc(NC(=O)OC(C)(C)C)cc21

Procedure:
A mixture of N-Boc-1,4-phenylenediamine (75 g), MgSO4 (216 g), 4-tert-butylcathechol (1.8 g) and iodine (4.7 g) in anhydrous acetone (600 ml) was heated under reflux for 20 h. The MgSO4 was removed by filtration and the filtrate was concentrated in vacuo. The residue was chromatographed on a short plug of silicagel using heptane/ethyl acetate=8/2 (v/v) as the eluent to give the product as a brown oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@:10]1([CH3:19])[S:16][CH2:15][CH2:14][N:13]=[C:12](SC)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([C:30]([NH:32][NH2:33])=O)[CH2:29][CH2:28]2)=[CH:23][CH:22]=1>C(O)CCC>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2([C:30]3[N:13]4[CH2:14][CH2:15][S:16][C@:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])([CH3:19])[CH2:11][C:12]4=[N:33][N:32]=3)[CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: NNC(=O)C1(c2ccc(Br)cc2)CC1
Reactant: CSC1=NCCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C1
Solvent: CCCCO
Product: CC(C)(C)[Si](C)(C)OC[C@@]1(C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
Temperature: 140 °C
Reaction time: 6 h
Yield: 86.9 %

Procedure:
The compound (1.02 g, 3.19 mmol) obtained in Example 4-1) and the compound (0.81 g, 3.19 mmol) obtained in Example 16-3) were dissolved in 1-butanol (5 mL), and the mixture was stirred at 140° C. for 6 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, then the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate=0% to 20%) to obtain the title compound (1.41 g, 85%) in a white solid form.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:30])[NH:17][C:18]1[S:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)=[CH:21][N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:30])[NH:17][C:18]1[S:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:36]([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:37])=[CH:27][CH:28]=2)=[CH:21][N:22]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: Nc1ccc(-c2cnc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)s2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2cnc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)s2)cc1)C1CCCC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of (S)-2-[5-(4-Amino-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (Compound 5111, Example 111, 0.05 g, 0.12 mmol), Cyclopentanecarbonyl chloride (0.015 mL), and TEA (0.018 mL) in dichloromethane (3 mL) was stirred at 0° C. for 20 min. then was quenched with water. The mixture was concentrated in vacuo and the resulting residue was dissolved in DMF (5 mL) and water (0.5 mL) then purified by reverse phase prep. LC/MS to furnish the desired product; MS: 519.1 (M+H+).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[N:13]1[C:17]2=[N:18][CH:19]=[N:20][C:21](O)=[C:16]2[CH:15]=[N:14]1>>[Cl:3][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:13]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][C:7]=3[CH3:6])[N:14]=[CH:15][C:16]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccncc1-n1ncc2c(O)ncnc21
Product: Cc1ccncc1-n1ncc2c(Cl)ncnc21
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Phosphorus oxychloride (5.10 ml, 54.75 mmol) was added to 1-(4-methylpyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (0.622 g, 2.74 mmol). The resulting solution was stirred at 100° C. for 2 hours. The reaction mixture was evaporated. Toluene was added to the residue and the reaction mixture was concentrated. This was repeated to remove excess POCl3. The residue was dissolved in DMF (15 mL) and MP carbonate was added (˜3 g) and allowed to stir overnight. The DMF was evaporated in vacuo to afford crude product which was used without further purification. 1H NMR (400 MHz, DMSO) δ 2.1 (3H, s), 7.60 (1H, d), 8.65 (1H, d), 8.68 (1H, s), 8.82 (1H, s), 8.91 (1H, s); m/z (ES+) (M+H)+=246; HPLC tR=1.69 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[S:13])[NH2:12])=[CH:7][CH:6]=1)[CH3:2].Br[CH2:16][C:17]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=O.Br>C(O)(C)C.C(OCC)C>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:13][CH:16]=[C:17]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C(N)=S)cc1
Reactant: O=C(CBr)c1cccnc1
Agent: Br
Solvent: CC(C)O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(-c2nc(-c3cccnc3)cs2)cc1

Procedure:
4-Thiocarbamoyl-benzoic acid ethyl ester (CAS 78950-31-9) (0.4 g, 1.91 mmol), and 2-Bromo-1-pyridin-3-yl-ethanone; hydrobromide (CAS 17694-68-7) (0.537 g, 1.91 mmol) is placed in a 100 mL flask and dissolved in 20 mL of isopropyl alcohol. The mixture is heated to reflux for 1.5 hours and cooled and diluted with 40 mL of diethyl ether. The resulting solid is filtered and dissolved in a mixture of dichloromethane and saturated sodium bicarbonate solution. The organics are separated, dried over sodium sulfate, filtered and concentrated to provide 0.565 g of the titled compound. MS (m/e) 311.1 (M+1)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8](/[CH:10]=[CH:11]/[C:12]([O:14]C)=[O:13])[CH:7]=[CH:6][C:5]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH3:2].[OH-].[K+]>CO.O>[CH2:1]([O:3][C:4]1[CH:9]=[C:8](/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])[CH:7]=[CH:6][C:5]=1[C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH3:2]
Reactant: CCOc1cc(/C=C/C(=O)OC)ccc1-c1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOc1cc(/C=C/C(=O)O)ccc1-c1ccc(OC)cc1

Procedure:
The preparation is carried out analogously to Example 2 from 1.0 g (3.2 mmol) of methyl 3(E)-(2-ethoxy-4′-methoxybiphenyl-4-yl)acrylate, 50 ml of a 10% solution of potassium hydroxide in methanol and 2 ml of water and gives 3(E)-(2-ethoxy-4′-methoxybiphenyl-4-yl)acrylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8]O)[CH:7]=1.N1C=CC=CC=1.[Br:16]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][Br:16])[CH:7]=1
Reactant: OCc1cncc(Br)c1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: CC#N
Product: BrCc1cncc(Br)c1
Temperature: 0 °C

Procedure:
3-Bromo-5-hydroxymethylpyridine (16.1 mmol) [prepared according to the procedure of Ashimori et al, Chem. Pharm. Bull. 1990, 38(9), 2446] and pyridine (32.3 mmol) were dissolved in acetonitrile (32 mL) and cooled to 0° C. Dibromotriphenylphosphorane (20.9 mmol) added, and left reaction mixture to warm to room temperature in stoppered flask for 4 hours. The crude reaction mixture was purified by column chromatography directly on silica gel with diethyl ether:cyclohexane=1:1. 3-Bromo-5-bromomethylpyridine was isolated as a pale brown solid. 3-Bromo-5-bromomethylpyridine (7.7 mmol) and di-tert-butyliminodicarboxylate (10 mmol) were dissolved in tetrahydrofaran (20 mL), and sodium hydride (60% in mineral oil, 10 mmol) added at room temperature under argon. The reaction mixture was stirred at room temperature for 16 hours, quenched with saturated aqueous ammonium chloride, extracted into ethyl acetate, washed with brine, dried over magnesium sulfate, and concentrated to dryness. The crude residue was purified by column chromatography on silica gel with cyclohexane:diethyl ether=2:1. 3-bromo-5-(N,N-bis-tert-butoxycarbonyl)aminomethylpyridine was isolated as a pale yellow solid. MS (EI) 387 and 389 (M++H).
Reaction SMILES: C(O[C:4](=[O:32])/[CH:5]=[CH:6]/[C:7]1[C:8]([NH:23][C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[N:9][C:10](SC)=[N:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[CH3:20])C.[CH3:33][O-:34].[Na+]>CO>[F:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([F:31])[C:24]=1[N:23]1[C:8]2[N:9]=[C:10]([O:34][CH3:33])[N:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[CH3:20])[C:7]=2[CH:6]=[CH:5][C:4]1=[O:32]
Reactant: C[O-]
Reactant: CCOC(=O)/C=C/c1c(Nc2c(F)cccc2F)nc(SC)nc1-c1ccc(F)cc1C
Agent: [Na+]
Solvent: CO
Product: COc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Yield: 83 %

Procedure:
To a solution of the product of Example 30 (90 mg, 0.2 mmol) in methanol (5 mL) was added sodium methoxide (1 mL of 25% w/w solution in methanol, excess). The reaction mixture turned yellow and was heated under reflux for 2 h evaporated and H2O (5 mL), then EtOAc (20 mL), was added. The layers were separated. The organic layer was washed with satd aq NaCl, dried (MgSO4), filtered and evaporated. The yellow residue was then purified by Flash chromatography to afford 71 mg (83% yield) of 8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methoxy-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ 2.30 (s, 3H), 3.82 (s, 3H), 6.61 (d, 1H, J=9.7 Hz), 7.01-7.18 (m, 4H), 7.25 (m, 1H), 7.52 (m, 2H); LC MS (m/e)=398 (MH+).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17].[H-].[Na+].Cl>C(O)C>[CH3:13][S:10]([C:7]1[CH:6]=[CH:5][C:4]([C:2](=[O:3])[CH2:1][C:14]([O:15][CH2:16][CH3:17])=[O:18])=[CH:9][CH:8]=1)(=[O:12])=[O:11]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC(=O)c1ccc(S(C)(=O)=O)cc1
Reaction time: 2 h

Procedure:
To a mixed solution of 4-(methylsulfonyl)acetophenone (10 g, 42.2 mmol), ethanol (0.2 ml) and diethyl carbonate (50 ml) was added sodium hydride (3.37 g, 60% in oil, 84.4 mmol) by small portions at room and the mixture was stirred temperature for 2 hrs. and at 60° C. for 1 hr. The reaction solution was cooled, 1N hydrochloric acid (30 ml) was added and the mixture was extracted with ethyl acetate (100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to give the objective substance (3.76 g, 33%) as crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][Si](C)(C)C)=[C:10]([N+:19]([O-:21])=[O:20])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[C:25]=1[CH:26]=[O:27].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:26]([C:25]2[C:28]([O:32][CH3:33])=[CH:29][CH:30]=[CH:31][C:24]=2[Cl:23])[OH:27])=[C:10]([N+:19]([O-:21])=[O:20])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C[Si](C)(C)C)c([N+](=O)[O-])c1
Reactant: COc1cccc(Cl)c1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(Cl)c1C(O)Cc1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.6 %

Procedure:
A solution of (3-nitro-4-trimethylsilanylmethyl-phenyl)-carbamic acid tert-butyl ester (1.00 g, 3.08 mmol) and 2-chloro-6-methoxybenzaldehyde (526 mg, 3.08 mmol) in THF (10 mL) was added tetra-butylammonium fluoride (121 mg, 462 μmol) at 25° C., the color of the solution changed to dark blue after the addition. The reaction mixture was stirred at 25° C. for 30 min and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (70/30 hexanes/ethyl acetate) afforded {4-[2-(2-chloro-6-methoxy-phenyl)-2-hydroxy-ethyl]-3-nitro-phenyl}-carbamic acid tert-butyl ester (0.45 g, 35%) as an oil.
Reaction SMILES: [ClH:1].[C:2]([O:5][CH:6]([CH2:25][N:26]([CH3:28])[CH3:27])[CH2:7][O:8][CH:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])C)(=[O:4])[CH3:3].[CH3:29][CH2:30][CH2:31]CC>>[ClH:1].[C:2]([O:5][CH:6]([CH2:25][N:26]([CH3:27])[CH3:28])[CH2:7][O:8][CH2:9][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:29][CH2:30][CH3:31])(=[O:4])[CH3:3]
Reactant: CCCCC
Reactant: CCCCCCCCCCCCCCC(C)OCC(CN(C)C)OC(C)=O
Agent: Cl
Product: CCCCCCCCCCCCCCCCCCOCC(CN(C)C)OC(C)=O

Procedure:
1 l) (±)-3-dimethylamino-1-(2-hexadecyloxy)-2-propyl acetate hydrochloride; m.p. 78°-89° C. from n-pentane; yield 83.6%; and
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([NH:16][C:17](=[O:31])[C:18]2[CH:23]=[C:22]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:21]=[C:20]([F:30])[CH:19]=2)=[CH:8][CH:7]=1.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[F:30][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:21]=1)[C:17]([NH:16][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:7][CH:8]=1)=[O:31]
Reactant: C1CNCCN1
Reactant: O=C(Nc1ccc(OCCCCl)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Product: O=C(Nc1ccc(OCCCN2CCNCC2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from N-[4-(3-chloropropoxy)-naphthalen-1-yl]-3-fluoro-5-piperidin-1-yl-benzamide and piperazine according to conditions described in general procedure L. A yellow powder is produced (0.194 g, 69%). Mp: 70-72° C. 1H NMR (300 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.23 (m, 1H), 7.86 (m, 1H), 7.55 (m, 2H), 7.45 (s, 1H), 7.42 (d, J=8.1 Hz, 1H), 7.16 (d, J=9.0 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.93 (s, 1H), 4.21 (t, J=6.0 Hz, 2H), 3.32 (m, 4H), 2.71 (t, J=4.5, 4H), 2.53 (m, 2H), 2.35 (brs, 4H), 2.02 (m, J=7.2 Hz, 2H), 1.60 (brs, 6H). MS: 491.2 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6]([Cl:15])[N:5]=[CH:4][N:3]=1.[K+].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH-:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].O>CS(C)=O>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:30][C:2]2[C:7]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)=[C:6]([Cl:15])[N:5]=[CH:4][N:3]=2)(=[O:28])=[O:29])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: Cc1ccc(-c2c(Cl)ncnc2Cl)cc1
Reactant: CC(C)(C)c1ccc(S([NH-])(=O)=O)cc1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.3 %

Procedure:
A mixture of 0.8 g of 4,6-dichloro-5-(p-tolyl)-pyrimidine and 1.68 g of 4-tert.-butylbenzene sulfonamide potassium salt (Example 2a) in 20 ml of DMSO was stirred at room temperature for 24 h. The mixture was poured onto 200 ml of water and extracted twice with 100 ml of diethyl ether. The organic layers were extracted twice with 50 ml of water. The combined aqueous layers were acidified hydrochloric acid. The resulting fine suspension was extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4 and evaporated. The residue was dried under high vacuum to give 1.34 g 4-tert.-butyl-N-[6-chloro-5-(p-tolyl)-4-pyrimidinyl]-benzene sulfonamide as a white powder. LC-MS: tR=5.92 min, [M+1]+=416.20, [M−1]−=414.24.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:12])[CH:11]=1)[C:5](OC)=[O:6].CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:9]=[C:10]([I:12])[CH:11]=1
Reactant: COC(=O)c1cc(Cl)cc(I)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1cc(Cl)cc(I)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
Methyl 3-chloro-5-iodobenzoate was dissolved in anhydrous THF and cooled to 0° C. 1M DIBAL in toluene (13 mL) was added slowly to the reaction solution at that temperature. The reaction mixture was stirred overnight at room temperature. Next morning, another 10 mL of 1M DIBAL in toluene was added and stirred for additional 4 h. When the reaction was complete, the reaction mixture was quenched with saturated solution of potassium sodium tartrate. The reaction mixture wad then extracted with ethyl acetate (×3). The combined organic extracts were dried over Na2SO4 and concentrated to afford the desired (3-chloro-5-iodo-phenyl)-methanol (2.7 g, 98%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.[C:22]([O:26][C:27](=[O:54])[CH:28]([NH:38][C:39]([C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][CH:48]=2)=[CH:43][CH:42]=1)=[O:40])[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])([CH3:25])([CH3:24])[CH3:23].CCN(CC)CC>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:22]([O:26][C:27](=[O:54])[CH:28]([NH:38][C:39]([C:41]1[CH:42]=[CH:43][C:44]([C:47]2[CH:48]=[CH:49][C:50]([NH:53][C:8](=[O:10])[CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:51][CH:52]=2)=[CH:45][CH:46]=1)=[O:40])[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)CCC(NC(=O)c1ccc(-c2ccc(N)cc2)cc1)C(=O)OC(C)(C)C
Reactant: O=C(O)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCC(NC(=O)c1ccc(-c2ccc(NC(=O)Cc3ccccc3)cc2)cc1)C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 12.1 %

Procedure:
A solution of phenylacetic acid (89 mg, 0.65 mmol, 1 equiv) in DMF (10 mL) was added to EDCI (188 mg, 0.98 mmol, 1.5 equiv.). After stirring for 20 min, 2-[(4′-Amino-biphenyl-4-carbonyl)-amino]-pentanedioic acid di-tert-butyl ester (297 mg, 0.65 mmol, 1 equiv.) was added, followed by the addition of Et3N (0.23 mL, 1.64 mmol, 2.5 equiv.) and DMAP (16 mg, 0.13 mmol, 20%). The reaction mixture was allowed to stir at room temperature overnight. Reaction was complete as determined by TLC. DMF was removed and the residue was dissolved in EtOAc. The organic layer was washed with H2O and brine, and then dried over MgSO4. After solvent was evaporated, the crude residue was purified by HPLC to give 45 mg of 2-[(4′-Phenylacetylamino-biphenyl-4-carbonyl)-amino]-pentanedioic acid di-tert-butyl ester in 12% yield. MS (ESI) m/z 573.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7].Cl[C:14](=[CH2:17])[C:15]#[N:16]>C1(C)C=CC=CC=1>[C:15]([C:14]1[N:7]=[N:6][N:5]([CH2:4][C:3]2[C:2]([F:1])=[CH:11][CH:10]=[CH:9][C:8]=2[F:12])[CH:17]=1)#[N:16]
Reactant: C=C(Cl)C#N
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Solvent: Cc1ccccc1
Product: N#Cc1cn(Cc2c(F)cccc2F)nn1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 2,6-difluorobenzyl azide (34.2 g), 2-chloroacrylonitrile (26.6 g) and toluene (125 ml) is stirred at about 80° C. for 24 hours. Unreacted 2-chloroacrylonitrile and 2,6-difluorobenzyl azide as well as toluene are distilled off (distillate 100 ml) by raising the external temperature to about 130° C. After cooling to 80° C., n-heptane (100 ml) is allowed to run in. The mixture is cooled to about 20° C. and the suspension is stirred at about 20° C. for 1 hour. The product is isolated by filtration and washed with n-heptane (100 ml). The product is dried in vacuo at about 60° C. Yield: 22.31 g=50.7% (beige powder).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11]N=N[C:8]=2[CH:12]=1)([O-:3])=[O:2].[C:13]1([N:19]=[C:20]=[S:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:20](=[N:19][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:21][C:8]=2[CH:12]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2snnc2c1
Reactant: S=C=Nc1ccccc1
Product: O=[N+]([O-])c1ccc2sc(=Nc3ccccc3)sc2c1

Procedure:
A solution of 5-nitro-1,2,3-benzothiadiazole (4.6 g) in 50 ml of phenylisothiocyanate is heated at 220° C under an inert atmosphere until the evolution of nitrogen ceases (approximately 3 hours). The excess phenylisothiocyanate is removed in vacuo and the resultant residue chromatographed on 1000 ml of silica gel eluting with methylene chloride/pentane (1:4). The fractions containing the desired product are combined and concentrated in vacuo. The resultant solid is recrystallized from cyclohexane to yield 2.1 g of the title compound, melting point 136°-138° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:57])[C@@H:9]([CH3:56])[C:10]([NH:12][C@H:13]([C:34]([N:36]1[C@H:40]([C:41](=[O:53])[NH:42][C@H:43]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[CH2:46][CH2:45][CH2:44]2)[CH2:39][Si:38]([CH3:55])([CH3:54])[CH2:37]1)=[O:35])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[O:23])=[CH:17][CH:16]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CO.O>[C:1]([O:5][C:6]([N:8]([CH3:57])[C@@H:9]([CH3:56])[C:10]([NH:12][C@H:13]([C:34]([N:36]1[C@H:40]([C:41](=[O:53])[NH:42][C@H:43]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[CH2:46][CH2:45][CH2:44]2)[CH2:39][Si:38]([CH3:54])([CH3:55])[CH2:37]1)=[O:35])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)=[O:23])=[CH:19][CH:20]=1)=[O:11])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N3C[Si](C)(C)C[C@H]3C(=O)N[C@@H]3CCCc4ccccc43)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@@H](C(=O)N[C@@H](Cc1ccc(NC(=O)c2ccc(C(=O)O)cc2)cc1)C(=O)N1C[Si](C)(C)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)N(C)C(=O)OC(C)(C)C
Yield: 89.5 %

Procedure:
A solution of methyl 4-((4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3-((R)-3,3-dimethyl-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,3-azasilolidin-1-yl)-3-oxopropyl)phenyl)carbamoyl)benzoate (160 mg, 0.200 mmol) and LiOH (300 mg) in MeOH (6 mL) and H2O (2 mL) was stirred at rt for 2.5 h. Most of the MeOH was removed in vacuo and the residue was mixed with EtOAc and 1N HCl (60 mL). The organic layer was separated, dried over MgSO4 and concentrated in vacuo to obtain the title compound (140 mg, 0.179 mmol, 71% yield) as a white solid. MS(ESI+) m/z 784.4 (M+H)+.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH:17]1([C:20]([C:22]2[C:27]([F:28])=[CH:26][N:25]=[C:24]([O:29][CH3:30])[CH:23]=2)=O)[CH2:19][CH2:18]1.O>C1COCC1>[CH:17]1([C:20]([C:22]2[C:27]([F:28])=[CH:26][N:25]=[C:24]([O:29][CH3:30])[CH:23]=2)=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:18][CH2:19]1
Reactant: COc1cc(C(=O)C2CC2)c(F)cn1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=C(c1cc(OC)ncc1F)C1CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Under a nitrogen atmosphere, to a suspension of 60% sodium hydride (2.76 g) in THF (100 mL) was added ethyl diethylphosphonoacetate (15.2 mL) at 0° C., and the mixture was stirred at 0° C. for 5 min. To the obtained colorless solution was added cyclopropyl(5-fluoro-2-methoxypyridin-4-yl)methanone (entire amount) obtained in Example 42, step B, at 0° C., and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound as a brown oil. This compound was used for the next step without further purification.