Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[N:13]=NC1C=CC=CC=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[NH2:13]
Reactant: CCCOc1cc(C)c(N=Nc2ccccc2)c(C)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCCOc1cc(C)c(N)c(C)c1
Reaction time: 0.75 h

Procedure:
The yield of 2,6-dimethyl-4-propoxyazobenzene (20.2 g) from the previous step was dissolved in 95% alcohol (175 ml). Water was added (160 ml) and the mixture was heated to reflux. Sodium hydrosulfite (Na2S2O4) (44.8 g) was added to the boiling solution in small portions. After completion of this addition, reflux was continued for 30-60 min. The alcohol was removed by distillation at reduced pressure. The remaining heterogeneous residue was made alkaline and was extracted with ether. The ether extract was dried (Na2SO4), filtered, and evaporated. The residual oil was fractionated by distillation in vacuo. After a forerun of aniline, the desired product distilled at 101° C. (0.7 mmHg); nD25 =1.5393. The yield of 2,6-dimethyl-4-propoxyaniline was 6.86 g (51%).
Reaction SMILES: C1(OC)C=CC=CC=1.[F:9][C:10]1[CH:15]=[C:14]([S:16]CC2C=CC(OC)=CC=2)[CH:13]=[C:12]([O:26][CH3:27])[CH:11]=1>C(O)(C(F)(F)F)=O>[F:9][C:10]1[CH:15]=[C:14]([SH:16])[CH:13]=[C:12]([O:26][CH3:27])[CH:11]=1
Reactant: COc1ccc(CSc2cc(F)cc(OC)c2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(F)cc(S)c1
Yield: 65.3 %

Procedure:
A mixture of anisole (12.04 g), 1-fluoro-3-methoxy-5-((4-methoxybenzyl)sulfanyl)benzene (6.2 g) and TFA (20 mL) was refluxed for 1 h, then concentrated in vacuo. Water was added to the residue and the mixture was extracted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 and extracted with 2N NaOH (100 mL×3). The water layer was acidified with 6N HCl and extracted with EtOAc. The EtOAc extract was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo to give the title compound (2.30 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].[NH2:21][C:22]1[C:26]([C:27]#[N:28])=[CH:25][NH:24][N:23]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:23]3[N:24]=[CH:25][C:26]([C:27]#[N:28])=[C:22]3[N:21]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: N#Cc1c[nH]nc1N
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(F)c(C(F)(F)F)c1
Product: N#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(F)c(C(F)(F)F)c3)nc12
Yield: 38.5 %

Procedure:
Reaction of 1-(4-fluoro-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (302 mg, 1.0 mmol), prepared from commercially available 4-fluoro3-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as an off-white solid (144 mg, 38%). MS (ISP) 375.0 [(M+H)+]; mp 204° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:9]([O:11][C:12]1[C:13](=O)[C:14](=[O:19])[C:15]=1[O:16]CC)[CH3:10]>C(O)C>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:13]2[C:14](=[O:19])[C:15](=[O:16])[C:12]=2[O:11][CH2:9][CH3:10])=[CH:3][CH:4]=1
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: Nc1ccc(Cl)nc1
Solvent: CCO
Product: CCOc1c(Nc2ccc(Cl)nc2)c(=O)c1=O
Temperature: 80 °C
Yield: 43.5 %

Procedure:
5-Amino-2-chloropyridine (2.32 g, 18.0 mmol) in ethanol (50 mL) was added to a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione 3.07 g, 18.0 mmol) in ethanol (200 mL) at 70° C. over a period of 6 hours. The mixture was then heated at 80° C. for an additional 18 hours, filtered, and the solvents removed in vacuo. The crude product was suspended in 10% EtOH/EtOAc (30 mL) and adsorbed onto silica gel (15 g). Purification by flash chromatography on silica gel (eluted with 5% EtOH/EtOAc) provided 1.98 g of the desired product as a pale yellow powder.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8]([CH3:12])[CH2:7][C:6]=2[NH:5][C:4](=[O:13])[CH:3]=1.[N+:14]([O-])([OH:16])=[O:15].O>C(O)(=O)C>[OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8]([CH3:12])[CH2:7][C:6]=2[NH:5][C:4](=[O:13])[C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: CC1CCc2c(O)cc(=O)[nH]c2C1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CC1CCc2c([nH]c(=O)c([N+](=O)[O-])c2O)C1
Temperature: 100 °C

Procedure:
A suspension of 4-hydroxy-7-methyl-5,6,7,8-tetrahydrocarbostyril, (1.608 g; 0.009 mole) in glacial acetic acid (10 ml) was treated with concentrated nitric acid (2.5 ml; d 1.42) and the clear solution heated at 100° C until the exothermic reaction set in (ca 7 mins). After rapid cooling water (40 ml) was added and the yellow solid filtered off and recrystallised from ethanol; acetic acid, m.p. 238° (d).
Reaction SMILES: C=C[CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C@@H:17]1[O:21][C@H:20]([C@H:22]2[O:27][O:26][C@H:25]([CH2:28][C:29]([OH:31])=[O:30])[CH2:24][CH2:23]2)[CH2:19][CH2:18]1.[CH2:32]=CCCC/C=C/C=C\CCCCCCCC[C@@H]1O[C@H]([C@@H]2OO[C@H](CC(O)=O)CC2)CC1>CCOCC>[CH3:32][O:31][C:29]([CH2:28][C@H:25]1[O:26][O:27][C@H:22]([C@H:20]2[O:21][C@H:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH:8]=[CH:7]/[CH2:6][CH2:5][CH:4]=[CH2:3])[CH2:18][CH2:19]2)[CH2:23][CH2:24]1)=[O:30]
Reactant: C=CCCC/C=C/C=C\CCCCCCCC[C@H]1CC[C@@H]([C@H]2CC[C@@H](CC(=O)O)OO2)O1
Reactant: C=CCC/C=C\C=C/CCCCCCCC[C@H]1CC[C@@H]([C@@H]2CC[C@@H](CC(=O)O)OO2)O1
Solvent: CCOCC
Product: C=CCC/C=C\C=C/CCCCCC[C@@H]1CC[C@@H]([C@@H]2CC[C@@H](CC(=O)OC)OO2)O1
Reaction time: 1 h

Procedure:
Methylation of the mixture of stolonoxides A (1) and B (2): Excess of CH2N2 was added to a solution of the mixture of stolonoxide A (1) and B (2) (22 mg) in Et2O (2 mL) at room temperature. After 1 h, the solvent was removed under reduced pressure and the reaction crude subjected to HPLC chromatography yielding stolonoxide A methyl ester (1b, 18 mg) and stolonoxide B methyl ester (2b, 2 mg).
Reaction SMILES: Br[C:2]1[C:3]([C:19]#[N:20])=[CH:4][C:5]([F:18])=[C:6]([NH:8][CH:9]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:10]([NH2:12])=[O:11])[CH:7]=1.Cl.[NH2:22][C:23]1[S:27][N:26]=[C:25]([CH3:28])[CH:24]=1.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:19]([C:3]1[C:2]([NH:22][C:23]2[S:27][N:26]=[C:25]([CH3:28])[CH:24]=2)=[CH:7][C:6]([NH:8][CH:9]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:10]([NH2:12])=[O:11])=[C:5]([F:18])[CH:4]=1)#[N:20]
Reactant: N#Cc1cc(F)c(NC(CC(F)(F)F)C(N)=O)cc1Br
Reactant: Cc1cc(N)sn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(NC(CC(F)(F)F)C(N)=O)c(F)cc2C#N)sn1
Reaction time: 18 h
Yield: 99.6 %

Procedure:
A mixture of 2-(5-bromo-4-cyano-2-fluorophenylamino)-4,4,4-trifluorobutanamide (90 mg, 0.254 mmol), 5-amino-3-methylisothiazole hydrochloride (58 mg, 0.385 mmol), K2CO3 (200 mg, 1.45 mmol), BINAP (35 mg, 0.056 mmol) and Pd(OAc)2 (23 mg, 0.100 mmol) in dioxane (3 mL) was degassed with argon, then was stirred at 120 C for 18 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo to give 2-(4-cyano-2-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)-4,4,4-trifluorobutanamide (98 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[C:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=1.[H][H]>CO.CCOC(C)=O.[Pd]>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH2:13]2)[CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(N)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 83.7 %

Procedure:
A solution of tert-butyl 4-(2-methoxy-5-nitrophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate (1.30 g, 3.90 mmol) and 10% Pd/C (200.0 mg) in MeOH:EtOAc (1:4, 100 mL) was hydrogenated at room temperature for 72 h using the hydrogen balloon method. The reaction mixture was filtered through Celite and washed with ethanol (3×100 mL). The combined organic filtrates were concentrated in vacuo to afford tert-butyl 4-[5-amino-2-methoxyphenyl]-1-piperidinecarboxylate (1.00 g, 84%): ESMS m/e: 307.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH:21][CH:22]([CH3:24])[CH3:23])=[C:16]([NH2:25])[N:15]=2)=[N:6]1.C1N=CN([C:35](N2C=NC=C2)=[O:36])C=1.C(N(CC)CC)C>CN(C)C=O.O.C(OCC)(=O)C>[NH2:20][C:18]1[N:19]=[C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:26]=[CH:27][CH:28]=[CH:29][C:2]=3[F:1])[N:6]=2)[N:15]=[C:16]2[C:17]=1[N:21]([CH:22]([CH3:24])[CH3:23])[C:35](=[O:36])[NH:25]2
Reactant: CC(C)Nc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)n1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
520 mg (1.33 mmol) of the compound from example 61A were initially charged in dimethylformamide (5 ml), then 1.07 g (6.63 mmol) of N,N-carbonyldiimidazole and 2.31 ml (1.68 mmol) of triethylamine were added and the mixture was stirred at 100° C. overnight. The reaction mixture was then diluted with water and ethyl acetate, the phases were separated and the aqueous phase was extracted with ethyl acetate. The collected organic phases were dried over sodium sulfate, filtered and concentrated. The crude product (540 mg, 84% purity) was not purified any further.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([C:23]=1[N:24]([CH2:29][CH:30]1[CH2:32][CH2:31]1)[CH2:25][CH:26]1[CH2:28][CH2:27]1)=[CH:21][C:20]([CH3:33])=[CH:19][CH:18]=2)[C:8]1[N:9]=[N:10][NH:11][N:12]=1.[H-].[Na+].[CH3:45]I>CN(C=O)C.CCOC(C)=O>[F:38][C:37]([F:40])([F:39])[C:35]1[CH:34]=[C:5]([CH:4]=[C:3]([C:2]([F:41])([F:1])[F:42])[CH:36]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([C:23]=1[N:24]([CH2:29][CH:30]1[CH2:31][CH2:32]1)[CH2:25][CH:26]1[CH2:27][CH2:28]1)=[CH:21][C:20]([CH3:33])=[CH:19][CH:18]=2)[C:8]1[N:9]=[N:10][N:11]([CH3:45])[N:12]=1
Reactant: Cc1ccc2ncc(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nn[nH]n3)c(N(CC3CC3)CC3CC3)c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc2ncc(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c(N(CC3CC3)CC3CC3)c2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 28.63 %

Procedure:
A mixture of (3-{[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-methyl}-6-methyl-quinolin-4-yl)-bis-cyclopropylmethyl-amine (700 mg, 1.18 mmol) and sodium hydride (60%) (61 mg, 1.5 mmol) in DMF (25 mL) was stirred at 0° C. for 5 min. To this, methyl iodide (337 g, 2 mmol) was then added and stirring was continued for another 30 min. The reaction mixture was diluted with EtOAc (200 mL) and washed with water (200 mL×4) and finally with brine (100 mL). The organic layer was separated, dried over sodium sulphate and concentrated under vacuum. The crude product was purified by column chromatography (silica gel 230-400 mesh). Elution with 1.5% EtOAc in hexane afforded 0.205 gm of gummy mass (yield: 28.63%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH2:12])=[S:11].[C:13]([C:19](OC)=[O:20])#[C:14][C:15]([O:17][CH3:18])=[O:16]>CO>[CH3:18][O:17][C:15](=[O:16])[CH:14]=[C:13]1[S:11][C:10]([NH:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])=[N:12][C:19]1=[O:20]
Reactant: NC(=S)Nc1c(Cl)cccc1Cl
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Product: COC(=O)C=C1SC(Nc2c(Cl)cccc2Cl)=NC1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
2,6-Dichlorophenylthiourea (3.0 g, 13.6 mmol) was dissolved in 50 mL of dry methanol and dimethyl acetylenedicarboxylate (13.8 mmol, 1.7 mL) was added over a 10-minute period. The mixture was stirred at 25° C. for 40 minutes, then the mixture was heated at 55° C. for 3 hours. The solvent was removed by rotvap, and the crude product was recrystallized from methanol to yield the desired product.
Reaction SMILES: [CH3:1][C:2]12[CH2:33][CH:5]([C:6]3([CH3:32])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([CH:16]([OH:31])[C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[CH:23]=[C:22]([C:27]([O:29]C)=[O:28])[CH:21]=[CH:20]5)[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2.[OH-].[Na+].Cl>CO>[CH3:1][C:2]12[CH2:33][CH:5]([C:6]3([CH3:32])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([CH:16]([OH:31])[C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[CH:23]=[C:22]([C:27]([OH:29])=[O:28])[CH:21]=[CH:20]5)[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2
Reactant: COC(=O)c1ccc2cc(C(O)c3ccc4c(c3)C3(C)C5(C)CCC(C5)C3(C)O4)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC12CCC(C1)C1(C)Oc3ccc(C(O)c4ccc5cc(C(=O)O)ccc5c4)cc3C21C
Reaction time: 48 h
Yield: 109.3 %

Procedure:
898 mg (2.03 mmol) of the ester obtained in Example 6, in 25 ml of methanol, were treated with 2 g of sodium hydroxide. The reaction mixture was maintained under stirring for 48 hours. The reaction mixture was poured into ice-cold water, acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, filtered and evaporated to yield 951 mg (92%) of the expected compound, melting at 146°-148° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:33])[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]([OH:32])([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.FC1C=CC(C(=O)CCCC[N:47]2[CH2:52][CH2:51][CH:50](C(O)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:49][CH2:48]2)=CC=1.[I-].[K+]>N1CCCCC1>[OH:32][C:19]([CH:16]1[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][CH2:10][CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)=[CH:3][CH:4]=2)=[O:33])[CH2:14][CH2:15]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(CCCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1)c1ccc(F)cc1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: C1CCNCC1
Product: O=C(CCCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1)c1ccc(N2CCCCC2)cc1

Procedure:
A mixture of 15.6 g (0.35 mole) of 4'-fluoro-5-[4-(α-hydroxy-α-phenylbenzyl)piperidino]valerophenone, the free base of the compound of Example 2, and a small amount of potassium iodide in 100 ml of piperidine is refluxed for about 22 hours. The unreacted piperidine is removed under vacuum, and the remaining residue is triturated with water. The water is decanted and the residue is dissolved in methanol and then added to a large amount of water. The resulting precipitate is dissolved in a large volume of ether, dried over magnesium sulfate, and filtered. The filtrate is concentrated and cooled yielding a product which is recrystallized from ether to give 5-[4-(α-hydroxy-α-phenylbenzyl)piperidino]-4'-piperidinovalerophenone.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:25]C(=O)OC(C)(C)C)([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][C:11]=3[CH:12]=2)[CH2:4][O:3]1.ClC1C=C(C2ON=C(C3C=CC4OC(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)=CC=4C=3)N=2)C=CC=1OCCC>>[NH2:25][C:5]([C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][C:11]=2[CH:12]=1)([CH2:6][OH:7])[CH2:4][OH:3]
Reactant: CCCCCCCCc1ccc2oc(C3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2c1
Agent: CCCOc1ccc(-c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cc1Cl
Product: CCCCCCCCc1ccc2oc(C(N)(CO)CO)cc2c1
Yield: 51 %

Procedure:
When the product of Step B was substituted for tert-butyl 5-(5-(5-(3-chloro-4-propoxy phenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-yl-carbamate in Example 36, Step E, the similar procedure afforded the title compound in 51% yield, as off white solid. 1H NMR (DMSO-d6) 7.44 (d, 1H, J=1.98 Hz); 7.0 (dd, 1H, J=8.28, 1.98 Hz); 6.87 (d, 1H, J=8.22 Hz); 5.11 (s, 1H); 2.47 (t, 2H, J=7.5 Hz); 1.56-1.51 (m, 2H); 1.27-1.26 (m, 10H); 0.87 (t, 3H, J=6.45 Hz).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[C:11]([S:13][CH3:14])[CH:10]=[CH:9][C:8]=1[C:15](=[O:17])[CH3:16]>C(Cl)Cl>[OH:6][C:7]1[CH:12]=[C:11]([S:13][CH3:14])[CH:10]=[CH:9][C:8]=1[C:15](=[O:17])[CH3:16]
Reactant: COc1cc(SC)ccc1C(C)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CSc1ccc(C(C)=O)c(O)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 97.4 %

Procedure:
Boron tribromide (19 ml, 1 N in DCM, 19 mmol) was added to a mixture of crude 1-[2-methoxy-4-(methylthio)phenyl]ethanone (3.6 g, 16.9 mmol) and DCM (25 ml) at 0° C. The mixture was brought to room temperature and stirred for 3 h. Ice/water was added, the organic phase was separated and the water phase was extracted with EtOAc. The combined organic phases were filtered through a short plug of silica (EtOAc) and were concentrated to give the title compound (3.0 g) MS m/z (rel. intensity, 70 eV) 183 (6), 182 (M+, 53), 168 (10), 167 (bp), 152 (6).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.CO[C:12]([CH3:15])([CH3:14])[CH3:13]>[Cl-].[Zr+4].[Cl-].[Cl-].[Cl-]>[C:12]([C:7]1[C:2]([F:1])=[CH:3][C:4]([OH:9])=[CH:5][C:6]=1[F:8])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(C)(C)C
Reactant: Oc1cc(F)cc(F)c1
Agent: [Zr+4]
Agent: [Cl-]
Product: CC(C)(C)c1c(F)cc(O)cc1F
Temperature: 55 °C
Reaction time: 12 h
Yield: 54.2 %

Procedure:
A mixture of 3,5-difluorophenol (TCl, 14 g, 107 mmol), tert-butyl methyl ether (12.8 ml, 108 mmol) and zirconium(IV) chloride (25 g, 107 mmol) was stirred for 12 hours at 55 ° C., followed by addition of tert-butyl methyl ether (6.4 ml, 54 mmol). The additional injection of tert-butyl methyl ether (6.4 ml, 54 mmol), was repeated 8 times at intervals of 24 hours and then the reaction was quenched with saturated ammonium chloride aqueous solution and 2 M HCl aqueous solution. The whole was extracted with DCM, washed with brine, and dried over magnesium sulfate. The organic layer was evaporated to give a crude residue which was purified by silica gel column chromatography, eluting with gradually from hexane only to hexane/EtOAc (10:1), to give the title compound (10.8 g, 54%) as white solids.
Reaction SMILES: CON(C)[C:4](=[O:17])[CH2:5][CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[OH-:19].[Na+].Cl>CCO>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH:7]2[CH2:8][CH:6]2[CH2:5][C:4]([OH:17])=[O:19])=[CH:14][CH:13]=1
Reactant: [OH-]
Reactant: COc1ccc(C2CC2CC(=O)N(C)OC)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C2CC2CC(=O)O)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 96.1 %

Procedure:
The mixture of N-methoxy-2-(2-(4-methoxyphenyl)cyclopropyl)-N-methylacetamide (559) (1.8 g, 7.4 mmol), 2.5N NaOH (15 mL) and EtOH (15 mL) was stirred at 60° C. for 24 hours. The reaction mixture was acidified with HCl and extracted with EtOAc. The organic phase was washed with water, brine, dried over sodium sulfate and concentrated in vacuo to provide 2-(2-(4-methoxyphenyl)cyclopropyl)acetic acid (560) (1.5 g, 96.1%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]([OH:16])[C:14]#[CH:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]>CC(C)=O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13](=[O:16])[C:14]#[CH:15])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: C#CC(O)c1cc(OC)c(OC)c(OC)c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C#CC(=O)c1cc(OC)c(OC)c(OC)c1
Yield: 76.4 %

Procedure:
To a stirred solution of 1-(3,4,5-trimethoxyphenyl)prop-2-yn-1-ol (100 mg, 0.44 mmol) in acetone (10 mL), aqueous Jones reagent was added dropwise at 0° C. until the red color persisted. The reaction mixture was quenched by 2-propanol, and the precipitate was were removed by filtered through Celite. The filtrate was diluted with EtOAc, washed several times with a saturated aqueous NaHCO3 solution, water and brine, dried over MgSO4, and concentrated to give crude product, which was purified by flash chromatography eluting with EtOAc/n-hexane (1:4) to afford 1-(3,4,5-trimethoxyphenyl)prop-2-yn-1-one as a colorless oil (74 mg, 75%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]([C:12]1[N:17]=[C:16]([CH2:18][CH2:19][CH3:20])[C:15]([O:21][C:22]2[C:27](I)=[CH:26][N:25]=[C:24]([C:29](OC)=[O:30])[CH:23]=2)=[CH:14][CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[F:33][C:2]([F:1])([F:34])[C:3]([C:12]1[N:17]=[C:16]([CH2:18][CH2:19][CH3:20])[C:15]([O:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([CH2:29][OH:30])[CH:23]=2)=[CH:14][CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]
Reactant: CCCc1nc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1cc(C(=O)OC)ncc1I
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1nc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccnc(CO)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
To a solution of methyl 4-(6-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylpyridin-3-yloxy)-5-iodopicolinate (500 mg, 0.823 mmol) in tetrahydrofuran (8.2 mL), lithium aluminum hydride (63 mg, 1.65 mmol) was added under ice-cold conditions, and the resultant mixture was stirred at room temperature for 1 hour. After completion of the reaction, the resultant mixture was added with water under ice-cold conditions, and stirred at room temperature for 30 minutes. Then, the reaction solution was filtered using celite and extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified using column chromatography (hexane/acetone), and (4-(6-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylpyridin-3-yloxy) pyridin-2-yl)methanol (141 mg, yield 38%) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][CH2:8][C@H:7]([NH:16][C:17]([O:19]C(C)(C)C)=O)[C:6]1=[O:24].[CH2:26]([N:33]=[C:34]=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:34]([NH:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:35])[CH2:8][C@H:7]([NH:16][C:17](=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]1=[O:24]
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Reactant: O=C=NCc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)c2ccccc2)CN(C(=O)NCc2ccccc2)c2ccccc21
Temperature: 25 °C
Yield: 164.4 %

Procedure:
A solution of 600a/103 (400 mg, 1.1 mmol) and benzylisocyanate (166 mg, 1.2 mmol) in 10 ml of CH2Cl2 and 10 ml of DMF and heated at 80° C. for 3 days. The reaction was cooled to RT poured onto H2O and extracted with EtOAc (2×). The combined organic layers were washed with H2O (4×) and sat. aq. NaCl, dried over MgSO4 and concentrated in vacuo. Chromatography flash, SiO2, 50% to 80% EtOAc/hexane) gave 440 mg (80%) of 602p as a white solid.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=O)(C)(C)C.[ClH:22]>C(OCC)C>[ClH:22].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)NCCCCCCOc1cccnc1
Agent: Cl
Solvent: CCOCC
Product: NCCCCCCOc1cccnc1
Reaction time: 0.75 h

Procedure:
3-[6-(N-tert-Butoxycarbonylamino)-1-hexyl-oxy]-pyridine (180 mg) was treated with a large excess of hydrogen chloride in dietyl ether with stirring for 45 minutes followed by evaporation in vacuo. Trituration with diethyl ether, decantation and evaporation gave the title compound as a colourless powder.