Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8]/[C:9](=[N:38]\C(OC(C)(C)C)=O)/[N:10]([CH3:37])[CH2:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][P+:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:13])=O)(C)(C)C.[Br-].[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>>[F:47][C:48]([F:53])([F:52])[C:49]([O-:51])=[O:50].[F:47][C:48]([F:53])([F:52])[C:49]([O-:51])=[O:50].[NH3+:38][C:9](=[NH:8])[N:10]([CH3:37])[CH2:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][P+:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:13]
Reactant: O=C(O)C(F)(F)F
Reactant: CN(CC(=O)NCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)/C(=N/C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Br-]
Product: CN(CC(=O)NCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(=N)[NH3+]
Product: O=C([O-])C(F)(F)F
Reaction time: 0.33 h
Yield: 31 %

Procedure:
N2—{(E)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}-N2-methyl-N-[3-(triphenylphosphonio)propyl]glycinamide bromide (290 mg, 0.41 mmol) was dissolved in trifluoroacetic acid (1 ml, 10 mmol). After 20 minutes at room temperature, the volatiles were removed under vacuum, and the crude was purified with reverse phase preparative HPLC to give the title compound in a 31% yield.
Reaction SMILES: CS[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[CH:10][CH:11]=2)[CH2:6]1)=[NH:4].[ClH:29].[OH:30][NH2:31].C([O-])(=O)C.[Na+].O>C(O)C>[ClH:29].[ClH:29].[N:26]1[CH:27]=[CH:28][C:23]([N:20]2[CH2:21][CH2:22][CH:17]([CH2:16][O:15][C:9]3[CH:8]=[C:7]4[C:12]([CH2:13][CH2:14][N:5]([C:3](=[N:31][OH:30])[NH2:4])[CH2:6]4)=[CH:11][CH:10]=3)[CH2:18][CH2:19]2)=[CH:24][CH:25]=1
Reactant: NO
Reactant: CSC(=N)N1CCc2ccc(OCC3CCN(c4ccncc4)CC3)cc2C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=NO)N1CCc2ccc(OCC3CCN(c4ccncc4)CC3)cc2C1
Temperature: 40 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
To a solution of 7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carbothioimidic acid methyl ester (135 mg) in ethanol (3 ml) were added hydroxyamine hydrochloride (47 mg) and sodium acetate (56 mg), and the mixture was stirred at 40° C. for 2 hours. After completion of the reaction, water was added and the mixture was washed with chloroform. Thereto was added 4N aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained solid was treated with hydrogen chloride—ethanol solution and dried under reduced pressure to give the title compound (82 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]([NH:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([S:24][CH3:25])[CH:18]=2)[OH:16])[CH3:12])=[CH:5][CH:4]=1.[OH:26]O>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]([NH:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([S:24]([CH3:25])=[O:26])[CH:18]=2)[OH:16])[CH3:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCC(C)NCC(O)c2ccc(C)c(SC)c2)cc1
Reactant: OO
Solvent: CO
Product: COc1ccc(CCC(C)NCC(O)c2ccc(C)c(S(C)=O)c2)cc1
Reaction time: 8 h

Procedure:
In 70 ml of methanol was dissolved 2.5 g of α-{[3-(4-methoxyphenyl)-1-methylpropylamino]-methyl}-4-methyl-3-methylthiobenzenemethanol and then 8 ml of an aqueous 30% hydrogen peroxide solution was added dropwise to the solution under ice-cooling. After allowing the reaction mixture to stand overnight at room temperature, methanol was distilled off and after adding 50 ml of water to the residue, the product was extracted with ethyl acetate. The ethyl acetate layer formed was dried with anhydrous magnesium sulfate and after distilling off the solvent, the residue was purified by a silica gel column chromatography (eluate: a mixture of benzene, ethyl acetate, and methanol (4:3:1 by volume ratio) to provide 2.0 g of the amorphous caramel-like powder of α-{[3-(4-methoxyphenyl)-1-methylpropylamino]methyl}-4-methyl-3-methylsulfinylbenzenemethanol.
Reaction SMILES: [CH3:1][N:2]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])=[O:21])[C:3]1[CH:4]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=O)=[CH:8]2.Cl.[C:29]([S:48][CH2:49][CH2:50][NH2:51])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O.C(N(CC)CC)C>[CH3:1][N:2]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:22])[C:3]1[CH:4]=[C:5]([O:15][C:16]([F:17])([F:18])[F:19])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH:51][CH2:50][CH2:49][S:48][C:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:14])=[CH:8]2
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(c1cc(OC(F)(F)F)cc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(c1cc(OC(F)(F)F)cc2cc(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.1 %

Procedure:
To a mixture of 7-[methyl(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxylic acid (0.30 g), 2-(tritylthio)ethylamine hydrochloride (0.32 g), triethylamine (0.13 mL) and N,N-dimethylformamide (10 mL) were added 1H-1,2,3-benzotriazol-1-ol (0.15 g) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.19 g) under ice-cooling, and the mixture was stirred at room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=5:95-20:80), and the obtained crystals were washed with diethyl ether-hexane to give the title compound (160 mg, yield 31%) as colorless crystals. melting point 222-223° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[CH3:19][N+:20]([CH3:24])=[C:21](Cl)[Cl:22].[Cl-]>ClCCCl>[Cl:22][C:21]([N:20]([CH3:24])[CH3:19])=[N:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18]
Reactant: CS(=O)(=O)c1ccc(-n2ncc(C#N)c2N)cc1
Reactant: C[N+](C)=C(Cl)Cl
Agent: [Cl-]
Solvent: ClCCCl
Product: CN(C)C(Cl)=Nc1c(C#N)cnn1-c1ccc(S(C)(=O)=O)cc1
Yield: 80.9 %

Procedure:
A solution of 5-amino-1-(4-methanesulfonyl-phenyl)-1H-pyrazole-4-carbonitrile (1.2 g, 4.57 mmol) and phosgeniminium chloride (0.900 g, 7.08 mmol) in dry 1,2-dichloroethane was refluxed for 4 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (30 to 50% ethyl acetate/hexanes) to yield 1-chloro-N′-[4-cyano-2-(4-methanesulfonyl-phenyl)-2H-pyrazol-3-yl]-N,N-dimethyl-formamidine (1.3 g, 80%) as a yellowish solid. Exact mass calculated for C14H14ClN5O2S 351.06, found 352.20 (MH+, 100%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][N:4]=1.[CH2:14]([O:16][P:17]([O:21]CC)[O:18][CH2:19][CH3:20])[CH3:15]>>[CH2:14]([O:16][P:17]([CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][N:4]=1)([O:18][CH2:19][CH3:20])=[O:21])[CH3:15]
Reactant: ClCc1cc(-c2ccccc2)on1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cc(-c2ccccc2)on1)OCC
Yield: 62.7 %

Procedure:
3-Chloromethyl-5-phenylisoxazole (2.07 g, 10 mmol) and triethylphosphite (1.72 ml, 10 mmol) were heated at reflux for 2 h then the mixture distilled under reduced pressure to yield the title compound (1.85 g, 6.27 mmol, 63%); b.p. 192° at 0.5 mm Hg; νmax (film) 2980, 2900, 1610, 1590, 1570, 1500, 1450, 1420, 1390, 1250, 1160, 1060-1010, 970, 760, 690 cm-1 ; δH (CDCl3) 1.30 (3H, t, J 7 Hz, OCH2CH3), 3.30 (2H, d, J 21 Hz, CH2 --P), 4.20 (2H, m, OCH2CH3), 6.60 (1H, s, CH-het), 7.2-7.9 (5H, m, Ph).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][O:23][CH3:24])[CH:12]=[CH:11][C:10]=1[N:25]1[S:29](=[O:31])(=[O:30])[N:28](CC[Si](C)(C)C)[C:27](=[O:38])[CH2:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+].Cl>CN(C=O)C.CCOC(C)=O.O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][O:23][CH3:24])[CH:12]=[CH:11][C:10]=1[N:25]1[S:29](=[O:31])(=[O:30])[NH:28][C:27](=[O:38])[CH2:26]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCc1ccccc1Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COCc1ccccc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a solution of 5-[2-benzyloxy-4-(2-methoxymethylbenzyl)-phenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (375 mg, 0.679 mmol) in DMF (5 mL) is added CsF (361 mg, 2.37 mmol) and the mixture is stirred at 65° C. for 3 h. The mixture is diluted with EtOAc and water then is acidified with 1N HCl. The organic phase is washed with 1N HCl, water and brine. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure to give the title compound as a foam.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9]O[C:6]=2[CH2:5][CH:4]([CH3:16])[CH2:3]1.C([O-])(=O)C.[NH4+:21]>CN(C=O)C>[O:1]=[C:2]1[CH2:3][CH:4]([CH3:16])[CH2:5][C:6]2[NH:21][CH:9]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:7]1=2
Reactant: [NH4+]
Reactant: CCOC(=O)c1coc2c1C(=O)CC(C)C2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]c2c1C(=O)CC(C)C2
Temperature: 100 °C
Yield: 37.8 %

Procedure:
A stirred mixture of ethyl 4-oxo-6-methyl-4,5,6,7-tetrahydrobenzofuran-3-carboxylate (15.7 g, 71 mmol) and ammonium acetate (9.54 g, 124 mmol) in N,N,-dimethylformamide (75 mL) was heated at 100° C. for 2 hours. The reaction mixture was concentrated in vacuo, ice water was added, and the precipitate collected, rinsed with water then diethyl ether and dried to give ethyl 4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylate (5.94 g). To this ester was added aqueous 5N sodium hydroxide (50 mL) and ethyl alcohol (10 mL) and the mixture heated at reflux for 40 minutes. The reaction mixture was cooled in an ice water bath, acidified with aqueous hydrochloric acid, and the precipitate collected, rinsed with water then diethyl ether and dried to give 4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (5.2 g). m.p. 210-211° C.
Reaction SMILES: [CH:1](Br)([CH3:3])[CH3:2].C([O:7][C:8]([C:10]1[CH:11]=[N:12][N:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][N:17]=2)[C:14]=1[CH3:15])=[O:9])C.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:1]([O:22][C:19]1[CH:20]=[CH:21][C:16]([N:13]2[C:14]([CH3:15])=[C:10]([C:8]([OH:9])=[O:7])[CH:11]=[N:12]2)=[N:17][CH:18]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2ccc(O)cn2)c1C
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)O)cnn1-c1ccc(OC(C)C)cn1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
Isopropylbromide (164 μl) was added to a suspension of 1-(5-hydroxypyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (333 mg) and potassium carbonate (558 mg) in N,N-dimethylformamide (1.5 ml) and stirred at 80° C. for 2.5 hours. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was reacted and treated in a similar manner as Reference Example 24(3) to give the titled compound (152 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]2[CH:6]([C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[C:7]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1[O:32][C:33]([CH2:36]Br)=[CH:34][CH:35]=1)=[O:30])[CH3:27]>>[CH3:1][C:2]1[CH:25]=[CH:24][C:5]2[CH:6]([C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[N:20]([CH2:36][C:33]4[O:32][C:31]([C:29]([O:28][CH2:26][CH3:27])=[O:30])=[CH:35][CH:34]=4)[CH:21]=3)[C:7]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Reactant: CCOC(=O)c1ccc(CBr)o1
Product: CCOC(=O)c1ccc(Cn2cc(C3c4ccc(C)cc4C=Cc4cc(C)ccc43)c(=O)[nH]c2=O)o1

Procedure:
The subtitle compound was prepared from the product of example 8 step (i) (2.3 g) and 5-bromomethyl-2-furancarboxylic acid ethyl ester (J. Chem. Soc. Perkin Trans. 1, 1981, 1125, Bull. Chem. Soc. Jpn. 1987, 60, 1807) (2.3 g) according to the method of example 1 step (iv). Purification was by chromatography eluting with 25% ethyl acetate in toluene. Yield 1.8 g. Used directly in the next step.
Reaction SMILES: [C:1]([O:8]CCCC)(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(OOC(C)(C)C)(C)(C)C>C(OCC)(=O)C>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCCCOC(=O)/C=C\C(=O)[O-]
Agent: CC(C)(C)OOC(C)(C)C
Solvent: C=Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)/C=C\C(=O)O
Reaction time: 2 h

Procedure:
Into a four-necked flask equipped with a stirrer, reflux condenser, thermometer and gas-inlet tube were introduced 600 parts of ethyl acetate which was heated and kept at 75° to 78° C. under a stream of nitrogen gas. A monomer mixture composed of 249 parts of monobutyl maleate, 151 parts of styrene and 4 parts of di-tert-butyl peroxide as a polymerization initiator was added dropwise into the flask taking about 2 hours to form a polymerization mixture which was agitated for further 2 hours at the same temperature to effect copolymerization of the monomers. After completion of the polymerization reaction, the polymerization mixture was freed from the solvent by stripping under reduced pressure to give a solid copolymeric resin of maleic acid and styrene.
Reaction SMILES: C[O:2][C:3](=[O:31])[C@@H:4]([NH:13][C:14](=[O:30])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[F:32][C:33](B(O)O)([F:35])[F:34].[C:39]([O-:42])([O-])=O.[Na+].[Na+]>[Pd]>[Cl:21][C:19]1[CH:18]=[CH:17][C:16]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[C:15]([CH:20]=1)[C:14]([NH:13][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:5]2[CH:6]=[CH:7][C:39]([O:42][C:33]([F:35])([F:34])[F:32])=[CH:3][CH:4]=2)=[CH:10][CH:11]=1)[C:3]([OH:2])=[O:31])=[O:30]
Reactant: OB(O)C(F)(F)F
Reactant: CCCCCCCOc1ccc(Cl)cc1C(=O)N[C@@H](Cc1ccc(Br)cc1)C(=O)OC
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: [Na+]
Product: CCCCCCCOc1ccc(Cl)cc1C(=O)N[C@@H](Cc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1)C(=O)O

Procedure:
The title compound was then prepared from 3-(4-bromo-phenyl)-(2S)-(5-chloro-2-heptyloxy-benzoylamino)-propionic acid methyl ester (0.090 g, 0.176 mmol) and trifluoromethyl boronic acid (0.067 g, 0.352 mmol) with Pd (PPh3) (0.020 g, 0.0176 mmol) and 2 N Na2CO3 (0.528 ml, 0.528 mmol) as per general procedure D to yield the (2S)-(5-chloro-2-heptyloxy-benzoylamino)-3-(4′-trifluoromethoxy-biphenyl-4-yl)-propionic acid methyl ester which was further hydrolyzed as per general procedure C to give the title compound (0.050 g).
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[CH3:12][C@:13]12[CH2:23][CH2:22][C@@H:21]3[CH2:24][C@:18]1([O:19][C:20]3([CH3:26])[CH3:25])[C:17]([CH2:27][CH2:28][CH2:29][OH:30])=[CH:16][CH2:15][CH2:14]2.CCOCC>C(Cl)Cl>[CH3:12][C@:13]12[CH2:23][CH2:22][C@@H:21]3[CH2:24][C@:18]1([O:19][C:20]3([CH3:25])[CH3:26])[C:17]([CH2:27][CH2:28][CH:29]=[O:30])=[CH:16][CH2:15][CH2:14]2
Reactant: CC1(C)O[C@]23C[C@H]1CC[C@]2(C)CCC=C3CCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC1(C)O[C@]23C[C@H]1CC[C@]2(C)CCC=C3CCC=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
300 mg (1.39 mmol) of PCC was added to a solution of 100 mg (0.38 mmol) of (1R,6S,9R)6,10,10-trimethyl-2-(3-hydroxypropyl)-11-oxatricyclo[7.2.1.01,6]dodec-2-ene from example 12 in 15 ml of methylene chloride and the reaction mixture was stirred at room temperature for 3 hours, then was added 15 mL of ether. After filtration, the filtrate was concentrated to give 90 mg of crude product.
Reaction SMILES: [I:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.Cl[C:23](=[O:30])[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]>ClCCl.N1C=CC=CC=1>[CH3:29][O:28][C:26](=[O:27])[CH2:25][CH2:24][C:23]([NH:14][C:11]1[N:10]=[C:9]([NH2:15])[C:8]([O:7][C:6]2[CH:16]=[C:2]([I:1])[C:3]([O:20][CH3:21])=[CH:4][C:5]=2[CH:17]([CH3:19])[CH3:18])=[CH:13][N:12]=1)=[O:30]
Reactant: COC(=O)CCC(=O)Cl
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCC(=O)Nc1ncc(Oc2cc(I)c(OC)cc2C(C)C)c(N)n1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.56 g, 1.4 mmoles) in dichloromethane (40 ml) and pyridine (4 ml) was slowly added methyl 4-chloro-4-oxobutyrate (1.3 ml, 7.5 mmoles). The mixture was stirred at room temperature for 60 hours, and then solvent was removed under reduced pressure. The residue was washed twice with water, dissolved in a mixture of concentrated aqueous ammonium hydroxide and methanol (10 ml/40 ml), and stirred at room temperature for one hour. Solvent was evaporated under reduced pressure and the residue was partitioned between dichloromethane and water. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (1% methanol in dichloromethane) to give crude N-[4-amino-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-yl]-succinamic acid methyl ester (0.54 g, not shown) as a foam, MS (M+H)=515.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[F:11][C:12]([F:16])([F:15])[CH2:13][OH:14].[H-].[Na+].Cl>CN(C)C(=O)C>[F:11][C:12]([F:16])([F:15])[CH2:13][O:14][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: OCC(F)(F)F
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccc(OCC(F)(F)F)nc1
Temperature: 90 °C
Reaction time: 21 h
Yield: 77.8 %

Procedure:
A mixture of 6-chloronicotinic acid (7.0 g, 44.4 mmol), 2,2,2-trifluoroethanol (6.40 mL, 89.0 mmol) and sodium hydride (5.33 g, 133.0 mmol, 60% in oil) in N,N-dimethylacetamide (400 mL) is stirred at 90° C. for 21 hours. After cooling to room temperature, the reaction mixture is poured slowly into 2M hydrochloric acid (300 mL) and extracted with n-hexane/ethyl acetate (1:10, 500 mL). The organic layer is washed with 2M hydrochloric acid (300 mL×2) and dried over sodium sulfate. The organic solvent is concentrated under reduced pressure to give 7.64 g (78% yield) of the title compound as colorless oil. This material is used for the next reaction (Step-2) without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>C(#N)C>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH:15]1[CH2:16][CH2:17][N:12]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:13][CH2:14]1
Reactant: ClCc1nc2cccnc2s1
Reactant: c1ccc(C2CCNCC2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1ccc(C2CCN(Cc3nc4cccnc4s3)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Example 38A (50 mg, 0.11 mmol), 2-(4-piperidinyl)pyridine (25 mg, 0.13 mmol), and DIEA (340 μL, 2.1 mmol) were combined in acetonitrile (1 mL) and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was treated with hot methanol. The methanol was filtered and the filter cake washed with cold methanol to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.13 (m, 4H), 3.13 (m, 4H), 3.61 (m, 3H), 7.38 (d, J=4.75 Hz, 1H), 7.76 (dd, J=8.3 Hz, 4.6 Hz, 1H), 7.91 (m, 1H), 8.31 (m, 1H), 8.54 (m, 2H), 8.72 (dd, J=4.6 hz, 1.53 Hz, 1H); (ESI) m/z 311 (M+H)+.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])([CH3:5])([CH3:4])[CH3:3].O1CCOCC1.Cl[C:19]1[CH:24]=[C:23]([CH:25]([S:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[F:33])[C:22]([Cl:42])=[CH:21][N:20]=1>C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>[Cl:42][C:22]1[C:23]([CH:25]([S:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[F:33])=[CH:24][C:19]([NH:10][CH2:9][CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:11])=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)CCN
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CCNc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Temperature: 25 °C
Yield: 20.9 %

Procedure:
In a small amount of a saturated aqueous solution of potassium carbonate was dissolved β-alanine t-butyl ester hydrochloride (1.5 g), followed by extraction with methylene chloride. The extract was dried and concentrated into 720 mg of β-alanine t-butyl ester in the free form. The resulting ester and a 1,4-dioxane (2.0 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (300 mg, 0.72 mmol) obtained in Example 54 was stirred at 120° C. for 4 days under an argon atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate. The diluted mixture was washed with water and brine, dried and then concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to give the title compound (79 mg, 16%) as an oil.