Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[NH2:20][C:21]([CH3:35])([CH3:34])[CH2:22][NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([NH:20][C:21]([CH3:35])([CH3:34])[CH2:22][NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:12])[C:4]=2[CH:3]=1
Reactant: CC(C)(N)CNC(=O)OCc1ccccc1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CNC(=O)OCc1ccccc1)NC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reaction time: 17 h
Yield: 90.7 %

Procedure:
The title compound of Example 2 (5.0 g, 17.0 mmol) in 100 mL of CH2Cl2 was combined with molecular sieves #5A (5 g), the product of Example 17 (3.8 g, 17.0 mmol), and triethylamine (Et3N, 2.4 mL, 17.2 mmol). After stirring the reaction at room temperature for 17 hours, another 3.1 g of the product of Example 17 was added and stirring was continued for another 17 hours. The reaction was filtered and the filtrate was stripped of all solvent under reduced pressure to yield a white foam solid that was purified by HPLC on silica gel to give 7.4 g of the title material as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Cl[CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>CO>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1]/[C:11](=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])/[CH2:10]1
Reactant: Nc1ccccc1S
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CO
Product: CCOC(=O)/C=C1\CSc2ccccc2N1
Yield: 55.9 %

Procedure:
step 1—To a solution of 2-aminothiophenol (4.96 g, 39.6 mmol) in MeOH (200 mL) was added the ethyl 4-chloroacetoacetate (6.2 g, 38 mmol). After stirring at room temperature for 2 h the MeOH was removed under reduced pressure. The residue was dissolved in Et2O and washed with HCl (1N), saturated NaHCO3, and brine. The organic phase was dried over MgSO4, filtered and the solvent was removed under reduced pressure. The product was obtained from a minimum of EtOH to afford 5.0 g (54%) of 8: LCMS RT 3.7 min, M+H.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[NH:6][N:5]=[CH:4][C:3]=1[O:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13].C([O-])=O.[NH4+]>C(O)C.[Pd]>[O:8]=[C:7]1[NH:6][N:5]=[CH:4][C:3]([O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH2:14])=[O:13])=[CH:2]1
Reactant: NC(=O)c1ccccc1Oc1cn[nH]c(=O)c1Cl
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: NC(=O)c1ccccc1Oc1cn[nH]c(=O)c1
Temperature: 25 °C
Yield: 79.1 %

Procedure:
A solution of 2-(5-chloro-6-oxo-1,6-dihydro-pyridazin-4-yloxy)-benzamide (44.5 g, 0.17 mol) in ethanol (100 mL) was treated with 10% palladium on carbon (4.5 g) and ammonium formate (21.1 g, 0.34 mol). The resulting mixture was heated to reflux for 5 min. The reaction was then cooled to 25° C. and filtered. The filtrate was concentrated in vacuo. Silica gel column chromatography afforded 2-(6-oxo-1,6-dihydro-pyridazin-4-yloxy)-benzamide (31.1 g, 80%) as a white solid; ESI-MS 232 [M+H+]; HPLC: >95% (purity). 1H-NMR (300 MHz, CD3OD) δ 7.95-7.96 (d, 1H), 7.78-7.81 (m, 1H), 7.63-7.68 (m, 1H), 7.45-7.50 (m, 1H), 7.29-7.31 (d, 1H), 5.83-5.84 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](OC)=[C:6]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)[CH:7]=1.[C:17]1([CH2:23][CH2:24][Mg]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1.C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)[CH:7]=1
Reactant: Br[Mg]CCc1ccccc1
Reactant: COc1ccc(Br)cc1C1=NC(C)(C)CO1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)COC(c2cc(Br)ccc2CCc2ccccc2)=N1
Reaction time: 18 h
Yield: 103.1 %

Procedure:
To a solution of 2-(5-bromo-2-methoxyphenyl)-4,4-dimethyl-4,5-dihydrooxazole (31.21 g) in THF (40 ml) was added PhCH2CH2MgBr (0.22 mol) as a solution in diethyl ether (240 ml). The mixture was stirred for 18 hours, the solvents evaporated and the residue partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was separated, evaporated and the resulting residue purified by MPLC eluting with dichloromethane to give 2-(5-bromo-2-(phenethyl)phenyl)-4,4-dimethyl-4,5-dihydrooxazole (40.56 g).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[C:10]([CH2:18]O)=[CH:11][C:12]2[CH2:16][O:15][CH2:14][C:13]=2[CH:17]=1.[Cl:20]CCl.CS(Cl)(=O)=O>O>[Cl:20][CH2:18][C:10]1[C:9]([CH3:8])=[CH:17][C:13]2[CH2:14][O:15][CH2:16][C:12]=2[CH:11]=1
Reactant: ClCCl
Reactant: Cc1cc2c(cc1CO)COC2
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc2c(cc1CCl)COC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
Triethylamine (1.7 mL, 12 mmol) was added under ice cooling to a mixture of (6-methyl-1,3-dihydro-2-benzofuran-5-yl)methanol described in Production Example 1-5 (1.0 g, 6.1 mmol) and dichloromethane (10 mL), followed by the addition of methanesulfonyl chloride (470 μL, 6.1 mmol) at that temperature. The reaction mixture was stirred for 3 hours at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:10) to give the title compound (680 mg, 61% yield).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[O:8][CH:7]([CH2:9][OH:10])[CH2:6][O:5]1.Br[CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].[Cl-].[NH4+]>CN(C)C=O>[C:19]([Si:16]([O:15][CH2:14][CH2:13][O:10][CH2:9][CH:7]1[CH2:6][O:5][C:4]([CH3:11])([CH3:3])[O:8]1)([CH3:18])[CH3:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC1(C)OCC(CO)O1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(COCCO[Si](C)(C)C(C)(C)C)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
60% Sodium hydride (890 mg) was suspended in N,N-dimethylformamide (60 mL), and the suspension was cooled to 0° C. (2,2-Dimethyl-1,3-dioxolan-4-yl)methanol (2.3 mL) was added dropwise and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added (2-bromoethoxy)(tert-butyl)dimethylsilane (3 mL), and the mixture was stirred at 0° C. for 2 hrs. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=100:0→90:10) to give the title compound (1.04 g) as a yellow oil.
Reaction SMILES: [N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:31])[C:10]([C:26]([O:28]CC)=[O:27])=[CH:11][N:12]3[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[O:24][CH3:25])=[C:7]([CH3:32])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>O1CCOCC1>[N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:31])[C:10]([C:26]([OH:28])=[O:27])=[CH:11][N:12]3[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[O:24][CH3:25])=[C:7]([CH3:32])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3CCC3)cc(C)c2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Cn2cc(C(=O)O)c(=O)c3c(C)cc(N4CCC4)nc32)c(OC)c1
Temperature: 60 °C

Procedure:
A solution of EXAMPLE 18A (0.320 g) in 1,4-dioxane (7.3 mL) was treated with lithium hydroxide monohydrate (0.0919° g), heated at 60° C. for 18 hours then cooled, poured into 1M HCl, and filtered to provide the desired product.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[N:20][N:21]([CH2:23][CH3:24])[CH:22]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl.CO.[OH-].[NH4+]>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[N:20][N:21]([CH2:23][CH3:24])[CH:22]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCn1cc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)cn1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCn1cc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.4 %

Procedure:
To a solution of N-tert-butyl-2-(1-ethyl-1H-pyrazol-4-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (82 mg, 179 μmol) in dichloromethane (2.7 mL) was added trifluoroacetic acid (409 mg, 276 μL, 3.58 mmol) and the mixture stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue obtained diluted with dichloromethane (3 mL), methanol (1.5 mL) and ammonium hydroxide (0.4 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated then purified by chromatography (silica, 15-65% dichloromethane/[10% dichloromethane/methanol/0.5% ammonium hydroxide]) to give N-tert-butyl-2-(1-ethyl-1H-pyrazol-4-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (33 mg, 101 μmol, 56%) as a yellow solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.16 (s, 1H), 9.06 (s, 1H), 7.90 (d, J=3.3, 1 H), 7.85 (s, 1H), 7.84 (s, 1H), 7.73 (s, 1H), 7.59 (s, 1H), 4.08 (q, J=7.3, 2 H), 1.42 (s, 9H), 1.36 (t, J=7.3, 3 H); MS (EI/CI) m/z: 328.1 [M+H].
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]=O.N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[CH:21][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=3)[C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Reactant: O=Cc1ccccn1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: O=C1C(=Cc2ccccn2)CCc2ccc([N+](=O)[O-])cc21
Yield: 19.1 %

Procedure:
7-Nitro-1-tetralone (500 mg), pyridine-2-aldehyde (315 mg), piperidine (0.15 ml) and acetic acid (0.4 ml) are dissolved in toluene (10 ml), and the mixture is heated under reflux for 12 hours. The reaction solution is washed with water, and the organic layer is dried over sodium sulfate. The solvent is evaporated under reduced pressure. The residue is purified by silica gel chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give 7-nitro-1-oxo-2-(2-pyridylmethylidene)-1,2,3,4-tetrahydronaphthalene (140 mg).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH2:8][N:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=[CH:10]1.CN(C)CCN(C)C.[Cl:24][C:25]1[CH:39]=[CH:38][C:28]([C:29]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)=[O:30])=[CH:27][CH:26]=1.N>O1CCCC1>[Cl:24][C:25]1[CH:39]=[CH:38][C:28]([C:29]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)([C:10]2[N:9]([CH2:8][O:7][CH3:6])[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=2)[OH:30])=[CH:27][CH:26]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: COCn1cnc(C)c1C
Agent: CN(C)CCN(C)C
Agent: N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCn1c(C(O)(c2ccc(Cl)cc2)c2ccc(Cl)cc2)nc(C)c1C
Reaction time: 8 h

Procedure:
At a temperature of -60° C. and under a nitrogen atmosphere, 114 ml. (0.24 mol) of butyllithium solution (20% in hexane) were added drop-wise with stirring to a solution of 28 g. (0.20 mol) of 1-(methoxymethyl)-4,5-dimethylimidazole and 28 g. (0.24 mol) of N,N,N',N'-tetramethylethylenediamine in 200 ml. of anhydrous tetrahydrofuran. After 2 hours stirring, 50 g. (0.20 mol) of 4,4'-dichlorobenzophenone in 250 ml of anhydrous tetrahydrofuran were added drop-wise at -60° C. After being kept standing overnight, the reaction mixture was extracted with water and the organic phase was concentrated by distilling off the solvents. The residue was treated with 2 N hydrochloric acid and diethyl ether, which resulted in the formation of an organic and aqueous layer with an oily intermediate layer. The aqueous and oily layers were made alkaline with ammonia and extracted with diethyl ether. The extract was dried over sodium sulphate and the solvent was distilled off. The oily residue was thrice recrystallised from isopropyl alcohol. α,α-Bis(p-chlorophenyl)-1-(methoxymethyl)-4,5-dimethylimidazole-2-methanol was obtained. Melting point 151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:26][O:25][CH2:24][CH2:23][O:22]3)[C:17](O)=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1.[NH2:30][C:31]1[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:26][O:25][CH2:24][CH2:23][O:22]3)[C:17]([NH:30][C:31]3[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[CH:33][CH:32]=3)=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2COCCO2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: COc1cn(C(CC2COCCO2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
132 mg (purity 60%, 0.19 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,4-dioxan-2-yl)propanoic acid (mixture of racemic diastereomers) and 40 mg (0.21 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 106 mg (94% of theory)
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH2:11]O)=[O:8])=[C:4]([Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.S(Cl)([Cl:19])=O>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH2:11][Cl:19])=[O:8])=[C:4]([Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1
Reactant: C[Si](C)(C)c1cc(Cl)sc1C(=O)NCCO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: C[Si](C)(C)c1cc(Cl)sc1C(=O)NCCCl
Temperature: 0 °C

Procedure:
A solution of the compound of Example 263 (0.4 g) and 1 mL thionyl chloride in 6 mL CH2Cl2 was refluxed for 1 h, then cooled and poured into ice-water. Additional CH2Cl2 was added. The organic layer was separated, washed with brine, dried and concentrated. Flash chromatography of the residue with 5% ethyl acetate-hexane as eluent gave 0.4 g of the desired product as a white solid. m.p. 68-72 C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:24])OC2C=CC=CC=2)=[CH:11][N:10]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:35]=[C:34]2[C:30]([CH2:31][CH2:32][NH:33]2)=[CH:29][CH:28]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:33]2[C:34]3[C:30](=[CH:29][CH:28]=[C:27]([C:26]([F:25])([F:36])[F:37])[CH:35]=3)[CH2:31][CH2:32]2)=[O:24])=[CH:11][N:10]=1
Reactant: FC(F)(F)c1ccc2c(c1)NCC2
Reactant: O=C(Nc1ccc(OCc2ccccn2)nc1)Oc1ccccc1
Product: O=C(Nc1ccc(OCc2ccccn2)nc1)N1CCc2ccc(C(F)(F)F)cc21

Procedure:
Phenyl N-[2-(pyridin-2-ylmethyloxy)pyridin-5-yl]carbamate (D3) and 6-trifluoromethylindoline (WO 96/23783) were converted into the title compound using a method similar to that of Example 1, m.p. 178-179° C.
Reaction SMILES: C1([C:11]([O:13][C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:15])=[O:12])C2C(=CC=CC=2)C=CC=1.[Br:26]Br>>[CH:18]1[CH:17]=[C:16]2[C:14]([O:13][C:11](=[O:12])[C:24]3=[C:25]2[C:20](=[CH:21][C:22]([Br:26])=[CH:23]3)[CH:19]=1)=[O:15]
Reactant: BrBr
Reactant: O=C(OC(=O)c1cccc2ccccc12)c1cccc2ccccc12
Product: O=C1OC(=O)c2cc(Br)cc3cccc1c23
Temperature: 50 °C
Reaction time: 4 h
Yield: 22.7 %

Procedure:
Naphthalic anhydride 20 (100 g, 505 mmol) was slurried in c-nitric acid (70%, 2.0 L) and heated to 50° C. Bromine (19.4 mL, 379 mmol) was added evenly over 10 min, and the resulting solution was held at 50° C. for 4 h before cooling to 0° C. The resulting solid was isolated by filtration and dried in vacuo to provide the titled compound 21 (23.8 g, 17%) as a white solid.
Reaction SMILES: C([C:4]1[C:5]([C:26]([O-:28])=[O:27])=[C:6](C(C)C)[C:7]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:8]([CH:12]=1)[C:9]([O-:11])=[O:10])(C)C.C(C1C(C([O-])=O)=C(C(C)C)C(SCC2C=CC=CC=2)=C(C=1)C([O-])=O)(C)C.[OH-].[K+]>CO.O>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][S:13][C:7]1[CH:6]=[C:5]([C:26]([OH:28])=[O:27])[CH:4]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: COc1cccc(CSc2c(C(=O)[O-])cc(C(C)C)c(C(=O)[O-])c2C(C)C)c1
Agent: CC(C)c1cc(C(=O)[O-])c(SCc2ccccc2)c(C(C)C)c1C(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cccc(CSc2cc(C(=O)O)ccc2C(=O)O)c1
Yield: 100 %

Procedure:
Following the procedure of Preparation 3(a), but substituting 32 g. of diisopropyl-(m-methoxybenzylthio)-terephthalate for diisopropyl-(benzylthio)-terephthalate, using 350 ml. of methanol, 35 ml. of water and 18 g. of potassium hydroxide, and refluxing for three hours, there is obtained 25.2 g. (yield 100%) of (m-methoxybenzylthio)-terephthalic acid having a melting point of 255°-256° C. after recrystallization from methanol.
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[CH:13][C:12]([CH2:16][C:17]([CH3:19])=[CH2:18])=[C:11]([OH:20])[C:3]=1[C:4]([O:6]CC(C)=C)=[O:5]>C(O)=O>[F:15][C:14]1[C:2]([F:1])=[C:3]([C:4]([OH:6])=[O:5])[C:11]2[O:20][C:17]([CH3:19])([CH3:18])[CH2:16][C:12]=2[CH:13]=1
Reactant: C=C(C)COC(=O)c1c(O)c(CC(=C)C)cc(F)c1F
Solvent: O=CO
Product: CC1(C)Cc2cc(F)c(F)c(C(=O)O)c2O1
Yield: 61 %

Procedure:
A solution of 2-methylallyl 2,3-difluoro-6-hydroxy-5-(2-methylallyl)benzoate (734) in 96% formic acid (15 mL) was refluxed for 22 hours. The solvent was removed in vacuo, and the residue was purified by flash column chromatography eluting with hexanes-EtOAc (3:1) to afford 5,6-difluoro-2,2-dimethyl-3H-benzofuran-7-carboxylic acid (735) (0.76 g, 61%). 1H NMR (400 MHz, DMSO-d6) δ 7.43 (t, J=9.2 Hz, 1H), 2.98 (s, 2H), 1.41 (s, 6H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:29])[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].Br[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH2:20][OH:21])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:29][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3cn(CCO[Si](C)(C)C(C)(C)C)nn3)cc2[C@H](N)C[C@@H]1C
Reactant: Cc1cccc(Br)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3cn(CCO)nn3)cc2[C@H](Nc2cccc(C)n2)C[C@@H]1C
Temperature: 75 °C
Reaction time: 5 h
Yield: 22 %

Procedure:
To a solution of (2S,4R)-1-acetyl-6-[1-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-1H-1,2,3-triazol-4-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation, see Intermediate 44) (59 mg, 0.137 mmol) and 2-bromo-6-methylpyridine (70.9 mg, 0.412 mmol) in toluene (2.5 mL) were successively added sodium tert-butoxide (132 mg, 1.373 mmol), tris(dibenzylideneacetone)dipalladium(0) (25.2 mg, 0.027 mmol) and 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (DavePhos) (21.62 mg, 0.055 mmol). The reaction mixture was stirred at 75° C. for 5 h then cooled to room temperature and filtered through Celite. The insoluble material was washed with 5% MeOH in DCM and the combined filtrate and washings were concentrated in vacuo. The residue was dissolved in a 1:1 MeOH/DMSO mixture and was purified by MDAP (modifier: formic acid). The appropriate fractions were combined and the solvents evaporated using a blow down apparatus (nitrogen inlet) to give 2-(4-{(2S,4R)-1-acetyl-2-methyl-4-[(6-methyl-2-pyridinyl)amino]-1,2,3,4-tetrahydro-6-quinolinyl}-1H-1,2,3-triazol-1-yl)ethanol (12.5 mg, 0.031 mmol, 22%) as a viscous yellow oil.
Reaction SMILES: C([N:8]([C@@H:16]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@H:17]([OH:33])[C:18]([N:20]1[CH2:31][C@@H:30]([Cl:32])[CH2:29][C@H:21]1[C:22]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:19])CC1C=CC=CC=1)C1C=CC=CC=1>C(O)=O.CO.[Pd]>[NH2:8][C@@H:16]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@H:17]([OH:33])[C:18]([N:20]1[CH2:31][C@@H:30]([Cl:32])[CH2:29][C@H:21]1[C:22]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:19]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@@H](N)Cc1ccccc1
Reaction time: 2 h
Yield: 96.4 %

Procedure:
A solution of 20.0 g (35.6 mmol) of (4S)-1-[(2S,3S)-3-(N,N-dibenzylamino)-2-hydroxy-4-phenylbutyryl]-4-chloro-N-t-butyl-L-prolinamide dissolved in 200 ml of a 4.5% by volume solution of formic acid in methanol was stirred in the presence of 3 g of palladium black at room temperature for 3 hours and then at 40° C. for 2 hours. At the end of this time, the catalyst was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure. The concentrate was then diluted with ethyl acetate. The diluted solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was dissolved in benzene. Hexane was added to the resulting solution, to obtain 13.1 g of the title compound as a colorless powder, melting at 126°-130° C.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:25](=[O:33])[N:26]([CH3:32])[C:27]=2/[CH:28]=[CH:29]/[CH:30]=[O:31])=[CH:19][CH:18]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC.[Br-].[Zn+2].[Br-]>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[N:24]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:25](=[O:33])[N:26]([CH3:32])[C:27]=2/[CH:28]=[CH:29]/[CH:30]([OH:31])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6])=[CH:21][CH:22]=1
Reactant: Cn1c(/C=C/C=O)c(-c2ccc(F)cc2)n(-c2ccccc2)c1=O
Reactant: COC(=O)CC(C)=O
Agent: [Br-]
Agent: [Cl-]
Agent: [H-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)CC(=O)CC(O)/C=C/c1c(-c2ccc(F)cc2)n(-c2ccccc2)c(=O)n1C
Reaction time: 0.25 h

Procedure:
0.59 ml (5.4 mmol) of methyl acetoacetate is added dropwise under nitrogen to a suspension of 135 mg (5.6 mmol) of sodium hydride in 14 ml of tetrahydrofuran at -5° C. After 15 minutes, 4.0 ml (5.6 mmol) of 15% strength n-butyllithium in n-hexane are added dropwise at -5° C. the mixture is stirred for 15 minutes, a solution of 1.3 g (5.9 mmol) of zinc bromide in 20 ml of THF is added, the mixture is stirred for 15 minutes and a solution of 0.6 g (1.8 mmol) of the compound from Example 5 in 6 ml of tetrahydrofuran is added. After 30 minutes at -5° C., the mixture is hydrolyzed using saturated ammonium chloride solution, washed three times with dichloromethane, and the organic phase is dried and 380 mg are obtained after removing the solvent and washing the residue with petroleum ether.