Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:18]=[C:17]([NH:19][CH:20]([CH3:22])[CH3:21])[C:12]([C:13]([NH:15][NH2:16])=[O:14])=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1C=CC(S(O)(=O)=O)=CC=1>C(OC)(OC)(OC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:18]=[C:17]([NH:19][CH:20]([CH3:22])[CH3:21])[C:12]([C:13]3[O:14][C:23]([CH3:24])=[N:16][N:15]=3)=[CH:11][N:10]=2)=[CH:6][CH:7]=1
Reactant: CC(C)Nc1cc(Nc2ccc(F)cc2)ncc1C(=O)NN
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COC(C)(OC)OC
Product: Cc1nnc(-c2cnc(Nc3ccc(F)cc3)cc2NC(C)C)o1

Procedure:
A solution of 6-((4-fluorophenyl)amino)-4-(isopropylamino)nicotinohydrazide (91) (100 mg) and PTSA (10 mg) in trimethyl orthoacetate (5 mL) was heated at 100° C., overnight. The reaction mixture was concentrated, diluted with EtOAc. The organic layer was washed with sat. NaHCO3 solution, water and brine solution. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by prep. HPLC to afford N2-(4-fluorophenyl)-N4-isopropyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine-2,4-diamine (Example 149)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:26])[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][C:14]=2[Cl:25])[C:6]=1/[CH:7]=[CH:8]/[C:9]([OH:11])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Na].[CH:40](/[S:45]([NH2:48])(=[O:47])=[O:46])=[CH:41]\[CH2:42][CH2:43][CH3:44].Cl>CN(C)C=O.O>[Cl:1][C:2]1[N:3]=[C:4]([CH3:26])[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][C:14]=2[Cl:25])[C:6]=1/[CH:7]=[CH:8]/[C:9]([NH:48][S:45](/[CH:40]=[CH:41]/[CH2:42][CH2:43][CH3:44])(=[O:47])=[O:46])=[O:11]
Reactant: CCCCCOc1ccc(Cn2c(C)nc(Cl)c2/C=C/C(=O)O)c(Cl)c1
Reactant: CCC/C=C/S(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCC/C=C/S(=O)(=O)NC(=O)/C=C/c1c(Cl)nc(C)n1Cc1ccc(OCCCCC)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
(E)-3-(4-Chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methylimidazol-5-yl)-2-propenic acid (150 mg) was dissolved in N,N-dimethylformamide (1.5 ml) and carbonyldiimidazole was added. The mixture was stirred at room temperature for 3 hr. To the reaction mixture was added (E)-1-penten-1-ylsulfonamide sodium salt (97 mg), and the mixture was stirred at room temperature for 3 hr and left standing for one day. The reaction mixture was diluted with water (1.5 ml) and adjusted to pH 4 with 1N hydrochloric acid under ice-cooling. The precipitated powder was collected by filtration and washed with water. The resulting white powder was suspended in ethanol (0.75 ml) and heated. The mixture was stirred at room temperature for 30 min. The precipitate was collected by filtration, washed with ethanol and dissolved in N,N-dimethylformamide (0.75 ml) at 80° C. Water (0.25 ml) was added at the same temperature and the mixture was stirred at room temperature for 1 hr. The precipitated crystals were collected by filtration, washed with N,N-dimethylformamide—water (1:1) and then with water to give (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methylimidazol-5-yl)-N-((E)-1-penten-1-ylsulfonyl)-2-propenamide (160 mg) as colorless crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][C:12]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:11][C:10]=12)=[O:5])C.[OH-].[K+].O>C(O)(=O)C>[F:17][C:15]([F:16])([F:18])[C:14]1[N:9]2[CH:8]=[N:7][C:6]([C:4]([OH:5])=[O:3])=[C:10]2[N:11]=[C:12]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH:13]=1
Reactant: CCOC(=O)c1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 37 %

Procedure:
A mixture of 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine -8-carboxylic acid ethyl ester (5.6 g, 13.9 mmol), 2M potassium hydroxide solution (111 mL) and water (55 mL) was stirred at room temperature for 5 h, cooled (ice-water), and acetic acid (30 mL) was added. The mixture was evaporated, acetic acid (150 mL) was added and the stirred solution was heated under reflux conditions for 20 min. The reaction mixture was evaporated, water (150 mL) was added followed by extraction with ethyl acetate (2×300 mL). The combined organic layers were washed with brine (2×150 mL), dried (MgSO4) and evaporated. The crude product was further purified by cholumn chromatography on silica gel (ethyl acetate/heptane 1:1) to yield 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine-8-carboxylic acid (1.93 g, 37%) as a yellow solid. MS (ISN) 374.3 [(M−H)−]; mp 231° C.
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:24])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[CH:22]=O)/[N:7]([CH2:25][C@H:26]2[CH2:30][CH2:29][CH2:28][O:27]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:31]1[CH2:34][CH2:33][CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[N:31]1([CH2:22][C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:19])([F:20])[F:21])=[CH:17][C:12]=2[C:11](/[N:10]=[C:8]2\[S:9][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][N:7]\2[CH2:25][C@H:26]2[CH2:30][CH2:29][CH2:28][O:27]2)=[O:24])[CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2C=O)s1
Reactant: C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2CN2CCC2)s1
Reaction time: 2 h
Yield: 79 %

Procedure:
In a 20 mL vial, to a solution of Example 375C (52 mg, 0.118 mmol) in dichloromethane (2 mL) was added azetidine (20.22 mg, 0.354 mmol), followed by addition of acetic acid (7.09 mg, 0.118 mmol) and sodium triacetoxyborohydride (37.5 mg, 0.177 mmol) and the mixture was stirred for 2 hr. The reaction was quenched with saturated NaHCO3 and extracted with dichloromethane (3×5 mL). The organics were combined, dried, filtered, concentrated and the residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, gradient elution over 25 min with solvents A:B (100:0 to 10:90); solvent A=CH2Cl2; solvent B=7M NH3/MeOH (1):CH2Cl2 (9)) to afford the title compound in 79% yield. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.34 (s, 9H) 1.61-1.76 (m, 1H) 1.79-1.91 (m, 2H) 1.91-2.06 (m, 3H) 3.18 (t, J=6.94 Hz, 4H) 3.60-3.71 (m, 1H) 3.74-3.85 (m, 1H) 4.06 (s, 2H) 4.23-4.36 (m, 3H) 7.32 (s, 1H) 7.74-7.78 (m, 2H) 8.21-8.25 (m, 1H); MS (DCI/NH3) m/z 482 (M+H)+. Anal. calcd C25H32F3N3O2S.0.3 C6H6: C, 62.02; H, 6.56; N, 8.10. Found: C, 61.94; H, 6.43; N, 8.38.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1.C(N(CC)CC)C.Cl>C(#N)C>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:34]([NH:33][C:30]4[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=4)=[O:35])[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1ccc(F)cc1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccc(F)cc4)ccc3C2=O)C(=O)N1
Reaction time: 1 h
Yield: 69 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.50 g, 1.80 mmol) and 4-fluorophenylisocyanate (0.25 g, 1.80 mmol) in acetonitrile (20 mL), was added triethylamine (0.51 mL, 3.60 mmol) at room temperature under nitrogen. After 1 h, 1N aq. HCl (20 mL) was added and the mixture was stirred for 10 min. The product was isolated by filtration, washed with 1N aq. HCl (20 mL), acetonitrile (20 mL) and dried overnight in vacuo to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-(4-fluoro-phenyl)-urea as an off-white solid (0.51 g, 68% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.13 min (98.98%); mp: 262-264° C.; 1H NMR (DMSO-d6) δ 1.92-2.13 (m, 1H), 2.29-2.47 (m, 1H), 2.54-2.69 (m, 1H), 2.82-3.00 (m, 1H), 4.31 (d, J=17.4 Hz, 1H), 4.37-4.55 (m, 3H), 5.11 (dd, J=13.2, 5.1 Hz, 1H), 6.73 (t, J=5.9 Hz, 1H), 7.06 (t, J=8.9 Hz, 2H), 7.37-7.48 (m, 3H), 7.52 (s, 1H), 7.70 (d, J=7.9 Hz, 1H), 8.67 (s, 1H), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 22.5, 31.2, 42.8, 47.1, 51.6, 115.1 (d, J=22.0 Hz,), 119.4 (d, J=6.6 Hz), 121.9, 122.9, 126.9, 130.3, 136.8, 142.4, 144.9, 155.3 (d, J=4.4 Hz), 158.5, 168.0, 171.0, 172.9; LCMS: MH=411; Anal Calcd for C21H19FN4O4: C, 61.46; H, 4.67; N, 13.65. Found: C, 61.44; H, 4.53; N, 13.46.
Reaction SMILES: Cl[CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:17].[N-:18]=[N+:19]=[N-:20].[Na+]>CS(C)=O>[N:18]([CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:17])=[N+:19]=[N-:20]
Reactant: COC(=O)c1ccc2c(c1)CCC(Cl)C(=O)N2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(c1)CCC(N=[N+]=[N-])C(=O)N2
Temperature: 75 °C
Yield: 90.8 %

Procedure:
A solution of 3-chloro-7-carbomethoxy-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one 4 (3.50 g, 13.8 mmol) and NaN3 (1.08 g, 16.6 mmol) in DMSO (100 mL) was stirred at RT for 22 h, then heated at 75° C. for an additional 2 h. The resulting solution was poured into ice water (500 mL) and the resulting precipitate was filtered and dried under vacuum to give 5 (3.26 g, 91%). 1H NMR (250 MHz, CDCl3) δ 8.09 (1H, brs, H-1), 7.93 (2H, m, H-6,8), 7.10 (1H, d, j=6.5 Hz, H-9), 3.93 (3H, s, OCH3), 3.88 (1H, dd, j=8.0, 11.5 Hz, H-3), 3.01 (1H, ddd, j=8.0, 13.5, 13.5 Hz, H-5), 2.82 (1H, m, H-5), 2.59 (1H, m, H-4), 2.36 (1H , H-4).
Reaction SMILES: Cl[CH2:2][O:3][CH3:4].[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([I:17])[C:15]=1[OH:16])[CH:11]=[O:12])[CH3:6].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([I:17])[C:15]=1[O:16][CH2:2][O:3][CH3:4])[CH:11]=[O:12])[CH3:6]
Reactant: CCOc1cc(C=O)cc(I)c1O
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)cc(I)c1OCOC

Procedure:
Chloro(methoxy)methane (6.27 mL) was added to a mixture of 3-ethoxy-4-hydroxy-5-iodobenzaldehyde (16.1 g), potassium carbonate (15.2 g), and DMF (120 mL), and the resultant mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (12.1 g).
Reaction SMILES: [O:1]([CH2:8][C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>>[O:1]([CH2:8][C:9]([Cl:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)COc1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)COc1ccccc1

Procedure:
Phenoxyacetic acid shown by formula (26) is reacted with thionyl chloride by a conventional method to obtain phenoxyacetyl chloride shown by formula (27).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=2)[N:13]=1.I[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])=[CH:16][CH:15]=2)[N:13]=1
Reactant: C#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Reactant: FC(F)(F)c1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(C#Cc2ccccc2C(F)(F)F)cc1
Temperature: 110 °C
Reaction time: 5.5 h
Yield: 27.4 %

Procedure:
To a solution of 5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-2, 0.100 g, 0.319 mmol) in DMSO was added 1-iodo-2-(trifluoromethyl)benzene (0.13 g, 0.479 mmol), TBAF (0.301 g, 0.958 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.050 g, 0.071 mmol). The reaction mass was stirred at 110° C. for 5-6 h. The reaction mass was quenched in water and extracted with DCM and concentrated. The obtained product was purified with column chromatography on silica gel eluting with 2.0% EA:DCM to afford 0.040 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.50 (t, J=9.3 Hz, 1H), 7.57-7.73 (m, 6H), 7.82 (br s, 2H), 8.02 (d, J=8.7 Hz, 2H), 12.72 (br s, 1H). MS (m/z): 458.26 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:38][O:39][C:40]([C:42]1[C:50]2[N:49]=[C:48]([NH2:51])[NH:47][C:46]=2[CH:45]=[C:44]([CH2:52][CH2:53][CH3:54])[CH:43]=1)=[O:41]>>[CH3:38][O:39][C:40]([C:42]1[C:50]2[N:49]=[C:48]([NH:51][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])[NH:47][C:46]=2[CH:45]=[C:44]([CH2:52][CH2:53][CH3:54])[CH:43]=1)=[O:41]
Reactant: CCCc1cc(C(=O)OC)c2nc(N)[nH]c2c1
Reactant: O=C(O)c1cc2ccccc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCCc1cc(C(=O)OC)c2nc(NC(=O)c3cc4ccccc4cn3)[nH]c2c1
Yield: 75 %

Procedure:
0.4 g (75%) of 2-[(isoquinoline-3-carbonyl)-amino]-6-propyl-1H-benzoimidazole-4-carboxylic acid methyl ester was synthesized from 0.25 g (1.4 mmol) of isoquinoline-3-carboxylic acid, 0.6 g (1.6 mmol) of HBTU, and 0.3 g (1.3 mmol) of the above synthesized 2-Amino-6-propyl-1H-benzoimidazole-4-carboxylic acid methyl ester as described in general procedure A. LCMS: 389 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)#[N:2].C[Si](C#N)(C)C.[OH:19]C1C=CC=C2C=1C=CC=[N+]2[O-].C(N(CC)CC)C>CC#N>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:19])[N:4]=1)#[N:2]
Reactant: N#Cc1ccc2ccccc2n1
Reactant: [O-][n+]1cccc2c(O)cccc21
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ccc2c(O)cccc2n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Typical procedure to prepare 2-cyanoquinoline from N-oxide: Preparation of 2-cyano-5-hydroxyl-2-quinoline: Trimethylsilyl cyanide (12.4 ml) was added into a solution of 5-hydroxyl-quinoline N-oxide (5 g) with triethylamine (13 ml) in MeCN. After the reaction was stirred at room temperature for 12 hours, solvents were removed under vaccum to provide a residue which was then partitioned between saturated NaHCO3 solution (100 ml) and EtOAc (100 ml). The aqueous solution was then extracted with EtOAc (2×100 ml). And the combined organic layer was dried over anhydrous MgSO4, filtered and concentrated to afford a crude product which purified by silica gel column chromatography to provide 5.3 g of 2-cyano-5-hydroxylquinoline. MS m/z: (M+H)+ calcd for C10H7N2O 171.06, found 171.03. HPLC retention time: 1.22 minutes (column I).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[C:6]([CH2:8]Br)[CH:7]=1.[OH:17][CH2:18][C:19]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.[H-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:17][CH2:18][C:19]2([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:3]=1
Reactant: Fc1ccc(-c2cc(Br)cc(CBr)c2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(-c3ccc(F)cc3)c2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Bromo-5-(bromomethyl)-4′-fluorobiphenyl (398 mg, 1.16 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (280 mg, 0.96 mmol) were combined in dimethylformamide (5 mL) and cooled to 0° C. The reaction was treated with sodium hydride (46 mg, 1.92 mmol), stirred at 0° C. for 1 h, and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (20% ethyl acetate/hexanes) gave 470 mg (73%). 1H-NMR (CDCl3, 500 MHz) δ 7.51 (s, 1H), 7.28-7.42 (m, 6H), 7.19-7.23 (m, 2H), 7.06-7.14 (m, 3H), 4.34 (s, 2H), 3.69-3.74 (m, 2H), 3.40 (s, 2H), 2.98-3.06 (m, 2H), 2.14-2.19 (m, 2H), 1.81-1.90 (m, 2H), 1.41 (s, 9H). Mass spec.: 556.37 (MH)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([O:19][C@H:20]3[CH2:24][N:23]([C:25](=[O:35])[C@@H:26]([NH:31][C:32](=[O:34])O)[C:27]([CH3:30])([CH3:29])[CH3:28])[C@H:22]([C:36]([O:38][CH3:39])=[O:37])[CH2:21]3)=[CH:9][C:10]([N:14]3[CH:18]=[CH:17][CH:16]=[N:15]3)=[N:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:47]([N:51]=C=O)([CH3:50])([CH3:49])[CH3:48]>ClCCl>[CH3:39][O:38][C:36]([C@@H:22]1[CH2:21][C@@H:20]([O:19][C:8]2[C:7]3[C:12](=[CH:13][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[N:11]=[C:10]([N:14]3[CH:18]=[CH:17][CH:16]=[N:15]3)[CH:9]=2)[CH2:24][N:23]1[C:25](=[O:35])[C@@H:26]([NH:31][C:32]([NH:51][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:34])[C:27]([CH3:28])([CH3:29])[CH3:30])=[O:37]
Reactant: CC(C)(C)N=C=O
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2cc(-n3cccn3)nc3cc(OC)ccc23)CN1C(=O)[C@@H](NC(=O)O)C(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](Oc2cc(-n3cccn3)nc3cc(OC)ccc23)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-1-((2S,4R)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)-2-(methoxycarbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamic acid hydrochloride (0.165 mmol) in dichloromethane (3.0 mL) was added triethylamine (0.06 mL, 0.413 mmol) and tert-butylisocyanate (0.02 mL, 0.165 mmol) and the reaction mixture was stirred at room temperature. After 16 hours, the reaction mixture was diluted with dichloromethane and washed with 1N HCl, saturated sodium bicarbonate, and brine. The dichloromethane layer was then evaporated to dryness to give (2S,4R)-methyl-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)-pyrrolidine-2-carboxylate.
Reaction SMILES: [C:1]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[F:23])=[CH:12][CH:11]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>O>[CH2:1]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[F:23])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)c1ccc(-c2ccc(Br)cc2F)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCCCCCCc1ccc(-c2ccc(Br)cc2F)cc1
Temperature: 25 °C
Yield: 70.9 %

Procedure:
A reaction vessel was charged with 3.75 g of 4-octanoyl-2'-fluoro-4'-bromobiphenyl and 20 ml of trifluoroacetic acid. To the mixture was added dropwise 2.4 g of triethylsilane with stirring at room temperature. After stirring for 6 hours, the reaction liquid was poured into water and the mixture was extracted with benzene. The benzene extract was washed successively with water, an aqueous solution of sodium hydrogen carbonate and water, and then dried over Glauber's salt. The solvents were distilled off and the residue was distilled in a glass tube oven (GTO) to obtain 2.56 g (71.1%) of 4-octyl-2'-fluoro-4'-bromobiphenyl. GTO-set temperature: 150° C./0.2 mmHg.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.Cl.CN(C)CCCN=C=NCC.[N+:30]([C:33]1[CH:34]=[C:35]([CH:57]=[C:58]([N+:60]([O-:62])=[O:61])[CH:59]=1)[C:36]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][O:45][C:46](=[O:56])/[CH:47]=[CH:48]/[C:49]1[CH:54]=[CH:53][C:52](O)=[CH:51][CH:50]=1)=[O:37])([O-:32])=[O:31]>ClCCl.CN(C)C1C=CN=CC=1>[N+:30]([C:33]1[CH:34]=[C:35]([CH:57]=[C:58]([N+:60]([O-:62])=[O:61])[CH:59]=1)[C:36]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][O:45][C:46](=[O:56])/[CH:47]=[CH:48]/[C:49]1[CH:50]=[CH:51][C:52]([O:12][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][C:7]([O:6][CH2:5][CH2:4][CH2:3][C:2]([F:16])([F:17])[F:1])=[CH:8][CH:9]=2)=[CH:53][CH:54]=1)=[O:37])([O-:32])=[O:31]
Reactant: O=C(/C=C/c1ccc(O)cc1)OCCCCCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: O=C(O)c1ccc(OCCCC(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)F)cc2)cc1)OCCCCCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
8.61 g (0.0347 Mol) of 4-(4,4,4-trifluorobutoxy)benzoic acid are suspended in 100 ml of dichloromethane. 0.42 g (0.0035 Mol) of 4-Dimethylaminopyridine are added at room temperature. 7.98 g (0.04163 Mol) of N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC hydrochloride) are added at 0° C. The solution is stirred for 1 h at 0° C. 15.90 g (0.0347 Mol) of 6-[((2E)-{4-hydroxyphenyl}prop-2-enoyl)oxy]hexyl 3,5-dinitrobenzoate dissolved in 50 ml of dichloromethane are added dropwise to the solution at 0° C. and allowed to stir at room temperature overnight. After 22 hours at room temperature the reaction mixture is partitioned between dichloromethane and water. The mixture is acidified with HCl 25%. The organic phase is washed repeatedly with water, dried over sodium sulphate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 600 g silica gel using toluene:ethyl acetate (99:1) as eluant and crystallization from ethyl acetate/hexane (1:2) yielded 18.82 g (79%) of 6-{[((2E)-3-{4-[(4-(4,4,4-trifluorobutoxy)benzoyl)oxy]phenyl}prop-2-enoyl)oxy]}hexyl 3,5-dinitrobenzoate as white crystals.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[F:20][C:21]([F:32])([F:33])[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Product: O=C(O)c1cccc(COc2ccc(-c3ccccc3OC(F)(F)F)cc2)c1

Procedure:
3-(2′-Trifluoromethoxy-biphenyl-4-yloxymethyl)-benzoic acid was prepared using general procedure 1 from 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1) and 2-(trifluoromethoxy)benzeneboronic acid (ASDI Incorporated, Newark, Del.). Mass spectrum MH+=389.