Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([OH:13])=O)[CH2:8][CH:7]([OH:14])[C:6]=2[CH:15]=1.ClC1C=CC2OC(C(O)=O)CC(=O)C=2C=1.[BH4-].[Na+].[CH2:33]([NH2:36])[CH:34]=[CH2:35]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([NH:36][CH2:33][CH:34]=[CH2:35])=[O:13])[CH:8]=[C:7]([OH:14])[C:6]=2[CH:15]=1
Reactant: O=C(O)C1CC(O)c2cc(Cl)ccc2O1
Reactant: C=CCN
Agent: O=C1CC(C(=O)O)Oc2ccc(Cl)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C=CCNC(=O)C1C=C(O)c2cc(Cl)ccc2O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 512 mg of the ethyl ester of 6-chloro-3,4-dihydro-4-hydroxy-2H-1-benzopyran-2-carboxylic acid, (prepared by treating the ethyl ester of 6-chloro-3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxylic acid (Witiak et al., supra) with sodium borohydride), 570 mg of 2-propenamine and 20 ml of ethanol was stirred at room temperature for 72 hours, then stirred for 3 hours while heated by a steam bath. The solvent was stripped off and the residue was crystallized from methylene chloride/hexane to give 7, as white crystals, mp: 129°-130.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:6]([CH:18]=1)[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:8].[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:19][C:5]2[CH:4]=[CH:3][C:2]([C:32]3[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=3)=[CH:18][C:6]=2[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:8])=[CH:22][CH:23]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(OCc1ccc(F)cc1)c1cc(Br)ccc1OCc1ccc(F)cc1
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+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc(OCc3ccc(F)cc3)c(C(=O)OCc3ccc(F)cc3)c2)cn1
Temperature: 90 °C

Procedure:
A mixture of (4-fluorophenyl)methyl 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}benzoate (420 mg, 0.97 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (208 mg, 1.00 mmol), tetrakis(triphenylphosphine)palladium(0) (34.7 mg, 0.03 mmol) and K2CO3 (414 mg, 3 mmol) in 1,4-dioxane (10 ml) and water (2 ml) was stirred under nitrogen and heated at 90° C. for 16 hours. The solvent was removed, and the residue was dissolved in ethyl acetate (100 ml) and filtered. The filtrate was washed with water (50 ml) and brine (50 ml), dried over Na2SO4, and concentrated to give the crude product. The crude product was purified by a silica gel column (eluting with dichloromethane/methanol=50:1) yield the title compound as a white solid. 360 mg.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([CH3:11])=[CH:9][NH:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.CN(C1C=CC=CN=1)C>C(Cl)Cl.C(OC(=O)C)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[C:6]=2[N:7]=1
Reactant: Cc1c[nH]c2nc(Cl)nc(Cl)c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(C)c3c(Cl)nc(Cl)nc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.3 %

Procedure:
To a suspension of 2,4-dichloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.58 g, 2.86 mmol) in CH2Cl2 (6 mL) was added diisopropylethylamine (DIPEA) (0.56 mL, 3.14 mmol) and p-toluenesulfonyl chloride (TsCl) (0.57 g, 3.0 mmol), followed by dimethylaminopyridine (DMAP) (0.035 g, 0.286 mmol). After stirring at ambient temperature for 1 h, the solution was diluted with ethylacetate, and the organic layer was sequentially washed with 1N HCl, saturated NaHCO3, and brine. The organic extract was then dried over Na2SO4 and concentrated to give a crude residue, which was purified by flash column (hexanes/ethyl acetate, 5:1) to yield 2,4-dichloro-5-methyl-7-tosyl-pyrrolo[2,3-d]pyrimidine (0.38 g, 38%).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=O.O>N1C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([C:15]2[O:9][C:1](=[O:10])[C:2]3[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=3[N:4]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: O
Solvent: c1ccncc1
Product: O=c1oc(-c2cccc(Cl)c2)nc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a stirred solution of 76.5 g (0.56 mole) of anthranilic acid in 1000 ml of pyridine at room temperature was added 197 g (1.12 mole) of m-chlorobenzoyl chloride at a rapid dropwise rate. The temperature rose to 45°-50° and, midway through the addition, a precipitate began forming. After stirring one hour at room temperature the slurry was poured into 1500 ml of water and the precipitate was filtered, washed well with water and air dried to give 139 g (96.5%) of 2-(m-chlorophenyl)-4H-3,1-benzoxazin-4-one, m.p. 158°-60°. Crystallization from ethanol gave an analytical sample, m.p. 159°-60°.
Reaction SMILES: [C:1]1([N:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:8]([O:10][CH2:11][C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:13]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(=[O:37])C.[OH2:41]>C(#N)C.O=[Os](=O)(=O)=O>[OH:41][CH:13]1[C:14]2[C:19](=[C:18]([O:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][C:12]1([OH:37])[CH2:11][O:10][C:8](=[O:9])[N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)COc1cccc2c1CCC(COC(=O)N(c1ccccc1)c1ccccc1)=C2
Reactant: CCOC(C)=O
Reactant: O
Agent: O=[Os](=O)(=O)=O
Solvent: CC#N
Product: CCOC(=O)COc1cccc2c1CCC(O)(COC(=O)N(c1ccccc1)c1ccccc1)C2O
Reaction time: 4 h

Procedure:
To a solution of 2-(N,N-diphenylcarbamoyloxymethyl)-5-ethoxycarbonylmethyloxy-3,4-dihydronaphthalene (270 mg) in a mixture of acetonitrile (10 ml) and water (5 ml) were added 4-methylmorphorine N-oxide (0.34 ml) and OsO4 (1 ml, 2.5% in t-butyl alcohol) at 0° C. After being stirred for 4 hours, the solution was diluted into ethyl acetate. The mixture was washed with 1N--HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 1,2-dihydroxy-2-(N,N-diphenylcarbamoyloxymethyl)-5-ethoxycarbonylmethyloxy-1,2,3,4-tetrahydronaphthalene.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[Cl:10][SiH:11]([Cl:13])[Cl:12]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:2]1([CH3:1])[CH:9]=[CH:8][C:5]([CH:6]([Si:11]([Cl:13])([Cl:12])[Cl:10])[CH3:7])=[CH:4][CH:3]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: C=Cc1ccc(C)cc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccc(C(C)[Si](Cl)(Cl)Cl)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
Into a 3 liter round-bottom flask fitted with a reflux condenser, addition funnel and magnetic stir bar, was charged 4-methylstyrene (900 g, 7.6 mols) and Bis(triphenylphosphine)palladium (II) dichloride (1.8 g, 0.2% wt). The reaction mixture was heated to 70° C. and then trichlorosilane (1031 g, 7.6 mols) was added dropwise to the reaction mixture. During the addition, the reaction mixture was maintained between 80 to 100° C. After the addition was finished, the reaction mixture was kept at 70° C. for additional two hours. After distillation, pure (1-p-tolyl-ethyl)trichlorosilane (1400 g, 5.53 mols) was obtained (collected at 75° C./1 mmHg). The product structure was characterized by GC-MS and 13C NMR (δ˜14 ppm, CDCl3, Cl3Si—CH (CH3)-Ph; δ˜35 ppm, CDCl3, Cl3Si—CH(CH3)-Ph).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:14])=[CH:11][N:10]=2)[C:6]=1[O:7]C.[F:25][C:26]1[C:27](B(O)O)=[CH:28][C:29]([O:32][CH3:33])=[N:30][CH:31]=1>>[F:25][C:26]1[C:27]([C:2]2[CH:3]=[N:4][N:5]([C:9]3[CH:24]=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:14])=[CH:11][N:10]=3)[C:6]=2[OH:7])=[CH:28][C:29]([O:32][CH3:33])=[N:30][CH:31]=1
Reactant: COc1c(Br)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Reactant: COc1cc(B(O)O)c(F)cn1
Product: COc1cc(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2O)c(F)cn1

Procedure:
The title compound was prepared in a manner similar to Example 213 using 6-(4-bromo-5-methoxy-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (60.0 mg, 0.152 mmol), (5-fluoro-2-methoxypyridin-4-yl)boronic acid. 1H NMR (400 MHz, DMSO-d6) δ 1.15 (qd, J=12.3, 4.4 Hz, 2H) 1.55 (d, J=12.9 Hz, 2H) 1.74 (ddt, J=11.1, 7.4, 3.9, 3.9 Hz, 1H) 3.13 (t, J=6.3 Hz, 2H) 3.74-3.82 (m, 5H) 7.74 (d, J=4.8 Hz, 1H) 8.03 (d, J=3.0 Hz, 1H) 8.16 (d, J=2.5 Hz, 1H 8.30-8.45 (m, 2H) 8.66 (t, J=5.7 Hz, 1H) 8.84 (d, J=1.3 Hz, 1H). MS m/z [M+H]+ 428.5.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1.[O:8]=[C:9]1C(C#N)=CC=CN1.S(=O)(=O)(O)[OH:18]>>[O:1]=[C:2]1[C:7]([C:9]([OH:8])=[O:18])=[CH:6][CH:5]=[CH:4][NH:3]1
Reactant: N#Cc1ccc[nH]c1=O
Reactant: O=c1cccc[nH]1
Reactant: O=S(=O)(O)O
Product: O=C(O)c1ccc[nH]c1=O
Temperature: 200 °C

Procedure:
Synthetic Scheme II describes the three step preparation of 2-halopyridines from the oxo-pyridinecarbonitriles 8 (corresponding to oxopyridine 5 where R2 is cyano). In step 1, the oxo-3-pyridinecarbonitrile 8 is hydrolyzed by treating with a strong acid such as 85% sulfuric acid and heating at a high temperature, such as about 200° C. to give the oxopyridine-3-carboxylic acid 9. In step 2, the oxo-3-pyridinecarboxylic acid 9 from Step 1 is decarboxylated such as by heating at a high temperature such as about 330° C. to give the 1,2-dihydro-oxopyridine 10. In step 3, the 1,2-dihydro-oxopyridine 10 from Step 2 is halogenated with a reagent such as phosphorous oxychloride and heating in an autoclave at a high temperature, such as about 200° C., to give the desired 2-halopyridines 11 of the present invention. Alternatively, the 1,2-dihydro-oxopyridine 10 can be halogenated by treatment with a halogenating agent such as phenylphosphonic dichloride at an elevated temperature. A suitable temperature for this reaction is 200°. ##STR5##
Reaction SMILES: [CH:1]([CH:3]1[C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH:4]1[O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[O:2].[CH2:28]([Mg]Br)[CH3:29].C(=O)(O)[O-].[Na+]>C1COCC1.CCOCC>[OH:2][CH:1]([CH:3]1[C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH:4]1[O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])[CH2:28][CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(O[Si](C)(C)C(C)(C)C)C2C=O)CC1
Reactant: CC[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)C1C(O[Si](C)(C)C(C)(C)C)CCC12CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
A solution of tert-butyl 1-formyl-2-(tert-butyldimethylsilyloxy)-8-azaspiro[4.5]decane-8-carboxylate (0.284 g, 0.714 mmol) from Step C in THF (7 mL) was cooled to −70° C. and ethyl magnesium bromide (3.0M, 0.262 mL, 0.786 mmol) was added. The reaction was stirred for 30 min and then an additional aliquot of ethyl magnesium bromide (3.0M, 0.050 mL, 0.142 mmol) was added. After 5 min, the reaction was diluted with ether, poured into sodium bicarbonate, and extracted three times with ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography eluting with 10 to 20% ethyl acetate in hexanes to afford the title compound (0.248 g) as a mixture of isomers. MS/EI (acetonitrile/water): m/z 354 (100%, M+1–74 (t-BuOH)), 372 (M+1–56 (C4H8); 428 (M+1); retention time=4.29 min.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16](O)=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[CH3:35][NH:36][C:37]1[C:38]([NH2:43])=[CH:39][CH:40]=[CH:41][CH:42]=1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]2[N:36]([CH3:35])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[N:43]=2)[N:8]([C:6]([C:29]2[CH:28]=[CH:27][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH3:19])=[CH:31][CH:30]=2)=[O:7])[CH2:12]1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CNc1ccccc1N
Product: CON=C1C[C@@H](c2nc3ccccc3n2C)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 11, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and N1-methyl-1,2-benzenediamine, the title compound was obtained in 83% purity by HPLC. MS(ESI+): m/z=439.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([NH:29][C:30](=[O:32])[CH3:31])[CH:23]=2)CC2CCCC2)=[O:14])=[N:9][CH:8]=1)C.[CH:34]1(CN(C2C=CC(F)=C(F)C=2)C(=O)NC2SC=C(CC(O)=O)N=2)[CH2:38][CH2:37][CH2:36][CH2:35]1.N[C:62]1C=C(NC(=O)C)C=CC=1F.C1(C=O)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[C:30]([NH:29][C:24]1[CH:23]=[C:22]([N:15]([CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:13](=[O:14])[N:12]([CH3:62])[C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:3])=[O:33])=[CH:8][N:9]=2)[CH:27]=[CH:26][C:25]=1[F:28])(=[O:32])[CH3:31]
Reactant: CC(=O)Nc1ccc(F)c(N)c1
Reactant: O=C(O)Cc1csc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)n1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(F)c(NC(C)=O)c2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: O=CC1CCCC1
Product: CC(=O)Nc1cc(N(C(=O)N(C)c2ncc(SCC(=O)O)s2)C2CCCC2)ccc1F

Procedure:
The title compound was prepared via {2-[3-(3-acetylamino-4-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-(3-amino-4-fluoro-phenyl)-acetamide, cyclopentanecarbaldehyde and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:30][CH2:29][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([OH:28])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:31][C@H:32]([C:37]2[CH:42]=[CH:41][C:40](Br)=[CH:39][C:38]=2[N:44]2[CH:48]=[CH:47][C:46]([CH3:49])=[N:45]2)[C:33]([F:36])([F:35])[F:34])[N:3]=1.[CH3:50][O:51][C:52]1[CH:53]=[C:54](B(O)O)[CH:55]=[CH:56][C:57]=1[C:58]([O:60][CH3:61])=[O:59].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:30][CH2:29][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([OH:28])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:31][C@H:32]([C:37]2[CH:42]=[CH:41][C:40]([C:54]3[CH:55]=[CH:56][C:57]([C:58]([O:60][CH3:61])=[O:59])=[C:52]([O:51][CH3:50])[CH:53]=3)=[CH:39][C:38]=2[N:44]2[CH:48]=[CH:47][C:46]([CH3:49])=[N:45]2)[C:33]([F:36])([F:35])[F:34])[N:3]=1
Reactant: Cc1ccn(-c2cc(Br)ccc2[C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)O)N(C(=O)OCc3ccccc3)C4)nc(N)n2)C(F)(F)F)n1
Reactant: COC(=O)c1ccc(B(O)O)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc([C@@H](Oc3cc(N4CCC5(CC4)C[C@@H](C(=O)O)N(C(=O)OCc4ccccc4)C5)nc(N)n3)C(F)(F)F)c(-n3ccc(C)n3)c2)cc1OC
Temperature: 80 °C

Procedure:
To a solution of (S)-8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (product of Step 3, Example 10m) (135 mg, 0.18 mmol) in dioxane (2 mL) was added (3-methoxy-4-(methoxycarbonyl)phenyl)boronic acid (84 mg, 0.4 mmol) and Cs2CO3 (48 mg, 0.16 mmol). The reaction was heated to 80° C. for 16 h, cooled to RT, and filtered. The solvent was removed in vacuo. Purification via normal phase silica gel chromatography (CH2Cl2/Heptane) provided (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxy-4′-(methoxycarbonyl)-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as an off-white solid.
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:24](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O.CO>CC(C)=O>[CH3:24][O:22][C:21]([C:19]1[O:20][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:17][CH:18]=1)=[O:23]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)o1

Procedure:
A mixture of 10.0 g of (0.031 mole) of 5-tetradecyloxy-2-furoic acid, 200 ml of acetone and 4.3 g (0.031 mole) of potassium carbonate is stirred at room temperature after which 3.9 g (0.031 mole) of dimethylsulfate is added. The mixture is stirred with heating for about two and one-half hours during which time 10 ml of methanol is added. The mixture is then diluted with 100 ml of acetone, and filtered. The filtrate is evaporated to dryness and recrystallized from methanol to give 5-tetradecyloxy-2-furoic acid methyl ester, M.P. 56°-58° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])[C:13]([C:20]([O:22]C)=O)=[C:14](C)[N:15](C)[C:16]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([OH:35])C.CN(C)[CH:38]=[O:39].[CH2:41](O)C>>[CH3:33][O:35][C:38]([CH2:41][C:20](/[CH:13]=[CH:12]/[C:24]1[C:25]([N+:30]([O-:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:22])=[O:39].[CH2:1]([O:8][C:9](=[O:10])/[CH:11]=[C:16](\[NH:15][CH3:14])/[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: COC(=O)C1=C(C)N(C)C(C)=C(C(=O)OCc2ccccc2)C1c1ccccc1[N+](=O)[O-]
Reactant: CN(C)C=O
Product: CN/C(C)=C\C(=O)OCc1ccccc1
Product: COC(=O)CC(=O)/C=C/c1ccccc1[N+](=O)[O-]

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 2'-nitrobenzylideneacetoacetic acid methyl ester and 75 mmols of β-methylaminocrotonic acid benzyl ester in 120 ml of ethanol gave 1,2,6-trimethyl-3-methoxycarbonyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid benzyl ester of melting point 182° C (from ethanol/dimethylformamide).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH:13]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]1>>[Br:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4][C:5]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[N:6][CH:7]=1
Reactant: O=C1CCNCCN1
Reactant: FC(F)(F)c1nc(Cl)ncc1Br
Product: O=C1CCN(c2ncc(Br)c(C(F)(F)F)n2)CCN1
Yield: 82.3 %

Procedure:
Synthesised from 5-bromo-2-chloro-4-(trifluoromethyl)pyrimidine (1.14 g, 4.35 mmol) and 1,4-diazepan-5-one (490 mg, 4.30 mmol) in accordance with General Method B, giving the title compound (1.20 g, 81%) as a white solid. δH (300 MHz, DMSO-d6) 8.79 (s, 1H), 7.71 (t, J 4.8 Hz, 1H), 3.90 (m, 4H), 3.21 (m, 2H), 2.54 (m, 2H). LC-MS (pH 3) MH+ m/z 339.0, RT 1.93 minutes. LC-MS (pH 10) MH+ m/z 339.0, RT 1.91 minutes.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[C:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1O)([CH3:20])([CH3:19])[CH3:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>N1C=CC=CC=1.CN(C=O)C>[C:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:1][CH2:2][CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccccc2C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 121.8 %

Procedure:
To an ice-cold stirred solution of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (44.3 g, 193 mmol) in pyridine (30.0 mL) was added p-TsCl (5.63 g, 30.0 mmol). After stirring for 16 h at room temperature, the reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate (300.0 ml) and 1.0 N hydrochloric acid (200.0 mL) and separated. The organic layer was washed with water (2×100 mL), saturated sodium chloride (100 mL), dried (MgSO4), filtered and filtrate concentrated under reduced pressure. The residue was dissolved in DMF (100.0 mL), added to a stirred solution of 2-(tert-butyl)phenol (10.8 g, 72.0 mmol) and K3PO4 (45.8 g, 216 mmol) in DMF (60.0 mL) and the resulting reaction mixture was heated at 80° C. for 16 h. Then, the reaction mixture was cooled to room temperature, poured into water (150.0 mL) and extracted with ethyl acetate (2×100.0 mL). The combined organics were washed with water (2×150 ml), saturated sodium chloride (100 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 95:5 to 90:10 hexane/ethyl acetate) to provide tert-butyl 4-[2-(2-tert-butylphenoxy)ethyl]piperidine-1-carboxylate (31.7 g, 44%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19]([OH:21])=O)=[O:5].[CH:30]([NH2:33])([CH3:32])[CH3:31]>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:14])([CH3:15])[C:9]=2[C:8]=1[C:19]([NH:33][CH:30]([CH3:32])[CH3:31])=[O:21])=[O:5]
Reactant: CC(C)N
Reactant: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)O
Product: CC(C)NC(=O)c1c(NC(=O)c2c(F)cccc2C(F)(F)F)sc2c1C(C)(C)OC2(C)C

Procedure:
The title compound was prepared from the product of Example 45A and commercially available isopropylamine by the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 1.08 (d, J=6.4 Hz, 6H), 1.44 (s, 6H), 1.47 (s, 6H), 3.89-4.00 (m, 1H), 7.66-7.80 (m, 3H), 7.91 (d, J=7.8 Hz, 1H), 11.51 (br s, 1H). MS (ESI+) m/z 473 (M+H)+. Anal. calcd. for C22H24F4N2O3S: C, 55.92; H, 5.12; N, 5.93. Found: C, 56.03; H, 5.26; N, 5.89.