Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[CH:4][C:3]=1[F:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([F:23])[CH:15]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[CH:4][C:3]=2[F:12])=[C:16]([F:23])[CH:15]=1
Reactant: COC(=O)c1cncc(F)c1Cl
Reactant: OB(O)c1ccc(Cl)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cncc(F)c1-c1ccc(Cl)cc1F
Temperature: 80 °C
Yield: 50.1 %

Procedure:
To a solution of methyl 4-chloro-5-fluoronicotinate (1.2 g, 6.33 mmol) in 1,4-dioxane (12 mL) and water (0.5 mL) was added (4-chloro-2-fluorophenyl)boronic acid (1.214 g, 6.96 mmol). The mixture was then purged with nitrogen gas for 5 min. Potassium phosphate, dibasic (2.205 g, 12.66 mmol) and PdCl2(dppf) (0.371 g, 0.506 mmol) were added and again the mixture was purged with N2 for 5 min. The reaction mixture was heated to 80° C. for 12 h. After cooling, water was added to and the mixture was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using hexane and ethyl acetate to afford methyl 4-(4-chloro-2-fluorophenyl)-5-fluoronicotinate (900 mg, 3.17 mmol, 50% yield) as a yellow solid. LC/MS (ESI) m/e 284.0 [(M+H)+, calcd for C13H9ClF2NO2 284.02]; LC/MS retention time (method D): tR=1.01 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[ClH:13].[NH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>ClCCl>[ClH:13].[C:15]1([NH:14][C:10]([N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=2)[CH3:12])=[NH:11])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CCc1cccc(N(C)C#N)c1
Reactant: Nc1cccc2ccccc12
Agent: Cl
Solvent: ClCCl
Product: CCc1cccc(N(C)C(=N)Nc2cccc3ccccc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.5 %

Procedure:
A mixture of m-ethylphenyl-N-methylcyanamide (520 mg, 3.25 mmol) and 1-aminonaphthalene hydrochloride (508 mg, 3.25 mmol) was placed in a pre-heated oil bath at 160° C. for 3 hours and then allowed to cool to room temperature. The resulting solid was taken into dichloromethane and washed with 10% NaOH solution. The organic layer was concentrated and the resulting residue was dissolved in abs. EtOH (2 ml) and treated with dil. HCl. It was concentrated and the solid was twice recrystallized from abs. EtOH-Et2O to give N-(1-naphthyl)-N'-(m-ethylphenyl)-N'-methylguanidine hydrochloride (403 mg, 37%) as off-white needles. mp 223°-25° C.
Reaction SMILES: [CH2:1]([CH:3]([C:9]([O-:11])=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[NH2:16].C1(N=C=NC2CCCCC2)CCCCC1>>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:9]([CH:3]([CH2:1][CH3:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:11])[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: CCOC(=O)C(CC)C(=O)[O-]
Reactant: Nc1cc(Cl)cc(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCOC(=O)C(CC)C(=O)Nc1cc(Cl)cc(Cl)c1
Yield: 10 %

Procedure:
Mono-ethyl ethylmalonate (5.0 grams, 0.03 mole), 3,5-dichloroaniline (5.06 grams, 0.03 mole) and 1,3-dicyclohexylcarbodiimide (6.44 grams, 0.03 mole) were reacted in a manner similar to that described in Example LVII to give 0.87 gram (0.003 mole) of ethyl 2-(3,5-dichlorophenylaminocarbonyl)butanoate having a melting point of 96.5° C.-98° C.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH2:26])[CH3:25].CC(O)=O.[BH3-]C#N.[Na+]>C(Cl)Cl>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:26][CH2:24][CH3:25])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCNCc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-((trans)-4-tert-butylcyclohexyloxy)-2-naphthaldehyde (200 mg, 0.64 mmol, 1 equiv), ethanamine (58 mg, 1.05 mmol, 2 equiv) and AcOH (62 mg, 1.05 mmol, 2 equiv) were dissolved in DCM (15 mL), and the mixture was stirred at r.t. for 2 h. Then NaBH3CN (101 mg, 1.9 mmol, 3 equiv) was added to the mixture and stirred for 16 h at r.t. The reaction mixture was washed by brine, dried over Na2SO4, and concentrated to give the title compound as a gray oil (250 mg, 100%). ESI-MS (M+1)+: 340.3. 1H NMR (400 MHz, CDCl3) δ: 7.73˜7.63 (m, 3H), 7.42˜7.31 (m, 1H), 7.16˜7.09 (m, 2H), 4.30˜4.21 (m, 1H), 3.91 (s, 2H), 2.73 (q, 2H), 2.31˜2.23 (m, 2H), 1.93˜1.83 (m, 2H), 1.49˜1.36 (m, 2H), 1.27˜1.18 (m, 2H), 1.15 (t, 3H), 1.12˜1.05 (m, 1H), 0.89 (s, 9H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]1[N:8]=[C:9]2[C:14](=[C:15]3[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]3)[CH:13]=[CH:12][CH:11]=[CH:10]2>CC(C)=O>[N:1]([CH2:6][C:7]1[N:8]=[C:9]2[C:14](=[C:15]3[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]3)[CH:13]=[CH:12][CH:11]=[CH:10]2)=[N+:2]=[N-:3]
Reactant: BrCc1nc2ccccc2c2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NCc1nc2ccccc2c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium azide (715 mg, 11.0 mmol) was added to a solution of the bromide 6 (301 mg, 1.10 mmol) in dry acetone (30 mL). The reaction mixture was stirred at ambient temperature for 1 hour, then heated to reflux for 2 hours. The reaction mixture was then allowed to cool to room temperature, the excess sodium azide was filtered off, and the solvent was removed under reduced pressure to yield the crude azide 7 as a light yellow crystalline solid, which was used immediately in the next step without further purification.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:18][CH:19]=[CH:20][C:21]=3[O:22][CH3:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C1C(=O)N([Br:31])C(=O)C1>C(Cl)Cl>[Br:31][C:19]1[S:18][C:17]([C:13]2[N:8]3[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]3=[N:15][C:14]=2[CH3:16])=[C:21]([O:22][CH3:23])[CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(CC)c1cc(C)nn2c(-c3sccc3OC)c(C)nc12
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3OC)c(C)nc12
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a solution of 8-(1-ethyl-propyl)-3-(3-methoxy-thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.78 g, 2.37 mmol) and CH2Cl2 (10 mL) is added NBS (0.44 g, 2.49 mmol). The solution is stirred for 1 hour, washed with water (3×10 mL), concentrated and purified by ISCO column chromatography (5%-15% EtOAc/hexane gradient) to furnish the title compound (0.87 g, 2.13 mmol, 90%). 1H NMR (CDCl3) δ 0.85 (t, J=7.5 Hz, 6H), 1.71-1.89 (m, 4H), 2.46 (s, 3H), 2.52 (s, 3H), 3.25-3.35 (m, 1H), 3.82 (s, 3H), 6.65 (s, 1H), 6.97 (s, 1H). LC/MS (m/z): calcd. for C18H22BrN3OS (M+H)+: 408.1; found: 408.3.
Reaction SMILES: [ClH:1].C(OC([NH:9][C@@H:10]([CH2:19][CH3:20])[CH2:11][NH:12][C:13](=[O:18])[C:14]([O:16][CH3:17])=[O:15])=O)(C)(C)C>O1CCOCC1>[ClH:1].[NH2:9][C@@H:10]([CH2:19][CH3:20])[CH2:11][NH:12][C:13](=[O:18])[C:14]([O:16][CH3:17])=[O:15]
Reactant: CC[C@@H](CNC(=O)C(=O)OC)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@H](N)CNC(=O)C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To an ice cold solution of 4M HCl in dioxane (20 mL) was added (S)-methyl 2-((2-((tert-butoxycarbonyl)amino)butyl)amino)-2-oxoacetate (1.3 g, 4.6 mmol). After 30 minutes, the reaction mixture was concentrated to provide a yellow foam (968 mg, 100%), which was used without further purification. MS (ESI): mass calcd. for C7H14N2O3, 174.1; m/z found, 175.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[N:9]([CH:13]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1)[CH2:8]2)#[N:2].Br.C(O)(=[O:28])C>>[O:12]=[C:10]1[C:11]2[C:3]([C:1]([NH2:2])=[O:28])=[CH:4][CH:5]=[CH:6][C:7]=2[CH2:8][N:9]1[CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2Cc3cccc(C#N)c3C2=O)C1
Reactant: CC(=O)O
Agent: Br
Product: NC(=O)c1cccc2c1C(=O)N(C1CCNC1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of EXAMPLE 13A (238 mg) in glacial acetic acid (2 mL) was added 33% hydrobromic acid in acetic acid (3 mL), and the mixture was stirred at ambient temperature for 2 hours and concentrated. The concentrate was purified by HPLC (Zorbax C-8, 0.1% trifluoroacetic acid/acetonitrile/water) and treated as described in EXAMPLE 7, Step B. 1H NMR (CD3OD) δ 2.34-2.44 (m, 1H), 2.45-2.56 (m, 1H), 3.37-3.47 (m, 1H), 3.57-3.66 (m, 1H), 3.67-3.78 (m, 2H), 4.66 (d, J=3.4 Hz, 2H), 4.71-4.78 (m, 1H), 7.78 (t, J=7.5 Hz, 1H), 7.87 (d, J=4.0 Hz, 1H), 7.89 (d, J=4.9 Hz, 1H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[C:10]1([O:16][CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>O.ClCCCl>[CH3:17][O:16][C:10]1[CH:15]=[CH:14][C:13]([C:5](=[O:8])[CH2:6][CH3:7])=[CH:12][CH:11]=1
Reactant: COc1ccccc1
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: CCC(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 66.5 %

Procedure:
525 ml of 1,2-dichloroethane and 209 g of aluminium chloride are added to a round flask which is fitted with a stirrer, thermometer, condenser and dropping funnel. The mixture is cooled to 0° C. and 127 g of propionic acid chloride are allowed to drop in at 0°-5° C. within 75 minutes. After the addition, the temperature is allowed to rise to 18° C. and then 141.6 g of anisole are added within 2 hours and at 20° C. The mixture is left to stand for 12 hours and then the product is poured into a mixture of 800 g of ice, 130 ml of water and 130 ml of concentrated hydrochloric acid. The aqueous phase is separated and extracted with two 250 ml portions of 1,2-dichloroethane. The combined organic phases are washed with three 200 ml portions of 2% sodium hydroxide and with 250 ml of water. The solvent is removed by evaporation under a vacuum and the residue (198 g) is distilled over a 25 cm column. There are obtained 143 g of p-methoxy-propiophenone (yield: 66.4% of theory). B.p.=90° C./0.4 mmHg; melting point 26° C.; nD20 =1.5451; d420 =0.9645.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:14])[CH:12]=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(O)(=[O:17])C.CC1C=CC=C(C)N=1.C(OO)(=O)C>C(OCC)(=O)C>[OH:13][C:12]([CH:11]([C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][CH:9]=1)[CH3:14])=[O:17]
Reactant: CC(=O)O
Reactant: CC(C)Cc1ccc(C(C)C=O)cc1
Agent: CC(=O)OO
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Yield: 92.2 %

Procedure:
To a stirred solution of 109 g (573 mmol) of 2-(4-isobutylphenyl)-propionaldehyde (ibuprofen aldehyde) in ethyl acetate (5 12 mL) cooled in a wet-ice bath (ca. 2° C.) was added concurrently 34.4 g (573 mmol) of glacial acetic acid and 61.4 g (573 mmol) of 2,6-dimethyl pyridine (2,6-lutidine). To this solution was then added slowly dropwise 276 mL (859 mmol) of a 23.7 weight percent solution of peracetic acid in ethyl acetate, at a rate slow enough such that the reaction temperature did not exceed 7° C. (ca. 1 h 40 min). After the initial exotherm, the temperature returned to 2° C,, and the reaction was maintained at this temperature for an additional 2 hours. Conversion of aldehyde at this time was ca. 99%, as monitored by GC (DB-1 column). The cold reaction solution was then transferred into a separatory funnel, was diluted with ethyl acetate (650 mL), and was washed with a 7% aqueous solution of sodium thiosulfate (Na2S2O3, 500 mL). The ethyl acetate layer was further washed with two portions of water (750 mL each), and the combined water washes were back-extracted with ethyl acetate (300 mL). The combined ethyl acetate layers were extracted with three portions of a 5% aqueous solution of sodium hydroxide (NaOH, 750 mL twice, then 500 mL). The combined NaOH solutions were acidified to pH=1 with a 10% aqueous solution of hydrochloric acid. The resulting solution was extracted with three portions of dichloromethane (500 mL twice, then 300 mL), and the extract was dried over anhydrous Na2SO4. The extract was filtered and concentrated in vacuo to give 109 g (92.2%) of ibuprofen as an off-white solid. HPLC analysis of this material indicated an `S` acid content of 83%, the same as the starting aldehyde as measured following KMnO4 oxidation.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][C:14]=2[F:23])[N:3]=1.[C:24](Cl)(=O)C(Cl)=O>ClCCl.CN(C=O)C>[CH3:24][O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([F:11])[C:2]([Cl:1])=[N:3][C:4]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Si:19]([CH3:20])([CH3:22])[CH3:21])=[CH:15][C:14]=1[F:23]
Reactant: C[Si](C)(C)c1ccc(Nc2nc(Cl)c(F)cc2C(=O)O)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)c(Cl)nc1Nc1ccc([Si](C)(C)C)cc1F
Temperature: 25 °C
Yield: 92.4 %

Procedure:
To a suspension of 6-chloro-5-fluoro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinic acid (7.6 g, 21.3 mmol) in dichloromethane (100 mL) and DMF (1 mL) was added oxalyl chloride (9.1 mL, 106.4 mmol) dropwise over 20 minutes. The reaction mixture was stirred at reflux for 18 hours and then concentrated in vacuo and the residue azeotroped with toluene. The resultant residue was taken up in cold (0° C.) methanol (100 mL). The resultant solution was heated at reflux for 1 hour, then cooled to room temperature and filtered. The precipitate was washed with cold methanol and dried under vacuum at 45° C. to give the title compound as a yellow solid (7.3 g, 92%). LCMS (method B): RT=5.38 min, [M+H]+=371.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH2:11]O)[CH:8]=[CH:7][C:5]=2[N:6]=1.Br.Cl.[NH2:15][CH2:16][CH2:17][SH:18]>>[NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH2:11][S:18][CH2:17][CH2:16][NH2:15])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1nc2ccc(CO)cc2[nH]1
Reactant: NCCS
Agent: Br
Agent: Cl
Product: NCCSCc1ccc2nc(N)[nH]c2c1

Procedure:
2-amino-5-hydroxymethylbenzimidazole (2.5 g) prepared according to the method described in Ger. offen. 2,528,846 (1976) and an aqueous 47% hydrobromic acid solution (25 ml) of cysteamine hydrochloride (1.3 g) were subjected to refluxing with heating for five hrs thereby to yield 2-amino-5-[(2-aminoethyl)thiomethyl]benzimidazole.3hydrobromate (melting point: 262°-265° C. (decomposition), 3 g).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].ClC1N=C(OC)N=C(OC)[N:32]=1.CN1CCOCC1.[NH4+].[OH-]>O1CCCC1>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH2:32])=[O:25])=[CH:22][CH:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: COc1nc(Cl)nc(OC)n1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc(C(=O)O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc(C(N)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzoic acid (12.0 g, 28.58 mmol) was suspended in tetrahydrofuran (100 mL). 2-Chloro-4,6-dimethoxy-1,3,5-triazine (6.02 g, 34.3 mmol) was added followed by 4-methylmorpholine (9.43 mL, 85.74 mmol). The resulting mixture was stirred at room temperature for 1.5 hours at which time NH4OH (50.0 mL) was added. The resulting mixture was stirred at room temperature for 1 hour and then partially concentrated. The precipitate was collected by filtration washing with H2O and diethyl ether to provide an off-white solid (12.11 g, >100%). 1H NMR (400 MHz, DMSO-d6) δ 7.91 (br s, 1H), 7.80 (d, J=8.3 Hz, 2H), 7.63 (app q, J=7.9 Hz, 1H), 7.31 (dt, J=2.6, 10.5 Hz, 1H), 7.17-7.12 (m, 1H), 7.13 (app d, J=8.3 Hz, 2H), 6.59 (s, 1H), 5.32 (s, 2H), 5.27 (s, 2H), 2.28 (s, 3H). ES-HRMS m/z 419.0968 (M+H calcd for C21H18ClF2N2O3 requires 419.0969).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[NH4+].[Cl-].I[CH2:15][C:16]([CH3:18])=[CH2:17]>C1COCC1.[Zn]>[Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([OH:5])[CH2:17][C:16]([CH3:18])=[CH2:15]
Reactant: O=C(CCCl)c1ccccc1
Reactant: C=C(C)CI
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: C=C(C)CC(O)(CCCl)c1ccccc1
Reaction time: 1 h
Yield: 75.6 %

Procedure:
A solution of 3-chloro-1-phenylpropan-1-one (16.8 g, 0.1 mol) in THF (50 mL) was added to a well-stirred suspension of zinc powder (13 g, 0.2 mol) in a mixture of satd aq NH4Cl solution (260 mL) and THF (65 mL). A solution of 3-iodo-2-methylprop -1-ene (36.4 g, 0.2 mol) in THF (50 mL) was added dropwise. The reaction was mildly exothermic, and the mixture began to reflux spontaneously. After refluxing had ceased, the mixture was stirred for 1 h. TLC showed the 3-chloro-1-phenylpropan-1-one had not reacted completely. A solution of 3-iodo-2-methylprop-1-ene (18.2 g, 0.1 mol) in THF (30 mL) was added, and the mixture was stirred at rt overnight. The mixture was extracted with EtOAc (2×500 mL). The combined organic layer was dried and concentrated. The residue was purified by column chromatography on silica gel eluted with petroleum ether/EtOAc 50:1→30:1→5:1, to give 1-chloro-5-methyl-3-phenylhex-5-en-3-ol (17 g, yield 76° A)) as an oil. 1H NMR (CDCl3): δ1.28 (s, 3H), 2.31 (m, 2H), 2.54 (m, 2H), 2.68 (d, 1H), 3.15 (m, 1H), 3.58 (m, 1H), 4.78 (m, 1H), 4.93 (m, 1H), 7.27 (t, 1H), 7.38 (m, 4H).
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][C:9]1[C:18]2[CH:19]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:16]3[C:17]=2[C:12]([C:13](=O)[CH2:14][CH2:15]3)=[CH:11][CH:10]=1>FC(F)(F)C(O)=O>[CH3:8][C:9]1[C:18]2[CH:19]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:16]3[C:17]=2[C:12]([CH2:13][CH2:14][CH2:15]3)=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1cc2c(C)ccc3c2n1CCC3=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2c(C)ccc3c2n1CCC3
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.1 %

Procedure:
Triethylsilane (3.07 g, 26.4 mmol) was added dropwise to a mixture of ethyl 5,6-dihydro-9-methyl-6-oxo-4H-pyrrolo[3,2,1-ij]quinoline-2-carboxylate (1.70 g, 6.61 mmol) and trifluoroacetic acid (20 ml) at room temperature. Then, the reaction mixture was stirred at room temperature for 3 hours and distilled under reduced pressure to remove the solvent. Ice water was added to the residue, followed by extraction with ethyl acetate (twice). The extract solution was washed with a 5% aqueous sodium hydrogencarbonate solution and then a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=3/97) to obtain 0.87 g of ethyl 5,6-dihydro-9-methyl-4H-pyrrolo[3,2,1-ij]quinoline-2-carboxylate. M.p. 51-52° C. (after recrystallization from n-hexane).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH2:23][OH:24])[CH:17]=2)=[C:11]([CH3:25])[CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:12]2[C:13]([CH3:15])=[CH:14][C:9]([OH:8])=[CH:10][C:11]=2[CH3:25])=[CH:17][C:18]=1[CH2:23][OH:24]
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1-c1ccc(F)c(CO)c1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(O)cc(C)c1-c1ccc(F)c(CO)c1
Reaction time: 12 h
Yield: 83.1 %

Procedure:
The crude (4′-(benzyloxy)-4-fluoro-2′,6′-dimethylbiphenyl-3-yl)methanol 18b (370 mg, 1.10 mmol) was dissolved in 5 mL of methanol, followed by addition of Pd/C (40 mg, 10%) under hydrogen atomosphere. The reaction mixture was stirred for 12 hours. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound 4′-fluoro-3′-(hydroxymethyl)-2,6-dimethylbiphenyl-4-ol 18c (225 mg, yield 83.3%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@@H:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([N:28]1[CH2:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29]1)(=[O:27])=[O:26].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@@H:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:31]4[CH2:32][CH2:33][N:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:29][CH:30]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2Cc3cc(Cl)ncc3O2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC([C@H]2Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1
Temperature: 170 °C
Reaction time: 1 h

Procedure:
A mixture of (R)-4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.40 g), 1-methanesulfonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,6-tetrahydro-pyridine (0.38 g), 2 M aqueous Na2CO3 solution (1.3 mL), and 1,4-dioxane (8 mL) is sparged with argon for 5 min. Tetrakis(triphenylphosphine)palladium(0) (0.10 g) is added and the mixture is stirred in a microwave oven at 170° C. for 1 h. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined extract is washed with brine, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 3:7→0:1) to give the title compound. Mass spectrum (ESI+): m/z=464 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[Cl:8][C:9]1[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[C:11]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:10]=1.[C:33]1([C@@H:39]([NH2:43])[CH2:40][CH2:41][NH2:42])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(O)C>[ClH:8].[NH2:43][C@H:39]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:40][CH2:41][NH:42][C:9]1[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[C:11]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:10]=1
Reactant: NCC[C@H](N)c1ccccc1
Reactant: Cn1c(Cl)nc(-c2ccncc2)c(-c2cccc(C(F)(F)F)c2)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cn1c(NCC[C@H](N)c2ccccc2)nc(-c2ccncc2)c(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Aqueous sat. sodium carbonate (2 ml) was added to a solution of 2-chloro-3-methyl-6-(4-pyridyl)-5-(3-trifluoromethylphenyl)-4(3H)-pyrimidinone hydrochloride (730 mg, 2 mmol) and (S)-1-phenyl-1,3-propanediamine (360 mg, 2.4 mmol) in ethanol (10 ml). The mixture was stirred for 4 h at room temperature. It was evaporated and the remainder partitioned between dichloromethane and water. The organic solution was dried and evaporated followed by column chromatography on silica gel (dichloromethane:methanol:conc. ammonium hydroxide=93:7:0.7). MS (m/z): 480 (M+H)+; C26H24F3N5O requir. 479.5 (free base).