Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>O1CCOCC1>[CH3:15][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][S:24]([C:21]2[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:28])[F:29])=[CH:23][CH:22]=2)(=[O:26])=[O:25])=[CH:12][CH:13]=1
Reactant: CN(C)CCCCOc1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: C1COCCO1
Product: CN(C)CCCCOc1ccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 84 %

Procedure:
A solution of 1.26 (6.03 mmol) of 4-(4-Dimethylamino-butoxy)-phenylamine in 15 ml dioxane was treated with 1.13 ml (6.1 mmol) Hünigsbase and 1.86 g (7.59 mmol) 4-(trifluoromethyl)benzenesulfonyl chloride. The reaction mixture was stirred over night at room temperature and extracted with aqueous saturated NaHCO3 solution/EtOAc (3×). The organic phase was dried over Na2SO4 and evaporated. The residue (partially disulfonamide) was dissolved in 20 ml dioxane, treated with 11.1 ml 1N NaOH and heated for 1 h at 100° C. The reaction mixture was neutralized (pH 7 with 1 N HCl) and extracted with EtOAc (2×). The organic phase was washed with aqueous saturated NaHCO3, dried over Na2SO4 and evaporated to yield 2.1 g (84%) of N-[4-(4-Dimethylamino-butoxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide, MS: 417 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[CH2:24]([OH:27])[C:25]#[CH:26]>C(N(CC)CC)C.C(OCC)(=O)C.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.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:21][C:20]([F:23])([F:22])[O:19][C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH:11]=[N:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:26]#[C:25][CH2:24][OH:27])=[CH:3][CH:4]=3)=[N:9]2)=[CH:14][CH:15]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(Br)cc3)n2)cc1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: OCC#Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 34.1 %

Procedure:
In a 1000 mL flask, 3-(4-bromophenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (25.0 g, 65.3 mmol) and propargyl alcohol (4.4 g, 78.36 mmol) were diluted with triethylamine (250 mL). Then bis(triphenylphosphine)palladium(II) chloride (0.915 g, 0.0200 mmol), copper(I) iodide (0.320 g, 0.169 mmol) and triphenylphosphine (0.102 g, 0.150 mmol) were added. The reaction was heated to 70° C. and stirred for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered through Celite®. A Brine solution was added to the filtrate and stirred for 15 minutes. The layers were separated and the aqueous layer further extracted with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by flash column chromatography using 15% ethyl acetate/petroleum ether as eluent to afford the title compound as yellow solid (8.00 g, 33%): mp 110-113° C.; 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.15 (d, J=8.4 Hz, 2H), 7.80 (d, J=9.0 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.39 (d J=8.4, 2H), 4.53 (d, J=4.8, 2H), 1.80-1.74 (brs, 1H); ES+API m/z 360 ([M+H]+).
Reaction SMILES: [CH:1]1[C:15](=[O:16])[N:14]=[C:13]2[N:3]([C@@H:4]3[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@@H:5]3[O:12]2)[CH:2]=1.C1C=CN=CC=1.[FH:23]>O1CCOCC1>[F:23][C@@H:5]1[C@H:6]([OH:11])[C@@H:7]([CH2:9][OH:10])[O:8][C@H:4]1[N:3]1[CH:2]=[CH:1][C:15](=[O:16])[NH:14][C:13]1=[O:12]
Reactant: O=c1ccn2c(n1)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Reactant: F
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Yield: 75 %

Procedure:
2,2′-Cyclouridine is treated with a solution of 70% hydrogen fluoride/pyridine in dioxane at 120° C. for ten hours to provide after solvent removal a 75% yield of 2′-deoxy-2′-fluorouridine. The 5′-DMT and 3′-cyanoethoxydiisopropyl-phosphoramidite derivitized nucleoside is obtained by standard literature procedures [Gait, Ed., Oligonucleotide Synthesis. A Practical Approach, IRL Press, Washington, D.C. (1984)], or according to the procedure of Example 4-a.
Reaction SMILES: C([N:5]([CH2:34][CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])[C:6](=[O:33])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[N:25]3)=[CH:20][CH:19]=2)[CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:15][CH:14]([CH3:16])[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([C:6]([NH:5][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:33])=[CH:8][CH:9]=1)[O:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[N:25]2)=[CH:22][CH:23]=1
Reactant: CC(C)C(Oc1ccc(-n2cc(C(F)(F)F)cn2)cc1)c1ccc(C(=O)N(CCC(=O)OC(C)(C)C)C(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(Oc1ccc(-n2cc(C(F)(F)F)cn2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24 %

Procedure:
To a room temperature solution of tert-butyl 3-(N-tert-butyl-4-(2-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)propyl)benzamido)propanoate (60 mg, 0.10 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (2.0 mL). The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and purification by HPLC gave (+/−)-3-(4-(2-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)propyl)benzamido)propanoic acid (11.4 mg, 24%). 1H NMR (400 MHz, CD3OD, δ): 8.53 (s, 1H), 7.89 (s, 1H), 7.76 (d, 2H), 7.55 (d, 2H), 7.45 (d, 2H), 6.97 (d, 2H), 5.06 (d, 1H), 3.61-3.58 (m, 2H), 2.62-2.59 (m, 2H), 2.21-2.11 (m, 1H), 1.08 (d, 3H), 0.93 (d, 3H). MS (M+1): 476.4.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]4[N:19]([C:20]5[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=5)[N:18]=[CH:17][CH:16]=4)[CH:13]=3)[C:8]([CH2:29][CH3:30])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]4[N:19]([C:20]5[CH:21]=[CH:22][C:23]([C:24]([N:33]([CH2:34][CH3:35])[CH2:31][CH3:32])=[O:26])=[CH:27][CH:28]=5)[N:18]=[CH:17][CH:16]=4)[CH:13]=3)[C:8]([CH2:29][CH3:30])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1nn(C2CCCC2)c2cc(-c3ccnn3-c3ccc(C(=O)O)cc3)ccc12
Reactant: CCNCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nn(C2CCCC2)c2cc(-c3ccnn3-c3ccc(C(=O)N(CC)CC)cc3)ccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 58 %

Procedure:
Into a 1-neck round-bottom flask was added 4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzoic acid (50.0 mg, 0.125 mmol), 2 mL of N,N-dimethylformamide, diethylamine (0.00913 g, 0.125 mmol), HATU (47.4 mg, 0.125 mmol) and N,N-diisopropylethylamine (43.5 uL, 0.250 mmol). The reaction was stirred for 3 days at room temperature, concentrated under reduced pressure, and purified by preparative HPLC (UV detection) to give 33 mg (0.0725 mmol, 58%) of 4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]-N,N-diethylbenzamide as a clear oil. LC/MS (EI) tR 5.26 (Method C), m/z 456.1 (M++1). 1H NMR (CDCl3 300 MHz) δ 1.0-1.2 (m, 5H); 1.3 (t, 3H); 1.7-1.9 (m, 5H); 2.0 (m, 4H); 3.0 (q, 2H); 3.1 (br s, 2H); 3.4 (br s, 2H); 4.8 (m, 1H); 6.6 (s, 1H); 6.9 (d, 1H); 7.2 (m, 5H); 7.5 (d, 1H); 7.7 (s, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[C:9]1([C@@H:15]([NH2:17])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[C:9]1([C@@H:15]([NH:17][C:6]([C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: O=C(Cl)c1ccc[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)c1ccc[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.5 %

Procedure:
To a solution of 1H-pyrrole-2-carbonyl chloride (1.3 g, 10 mmol) (from Example 30) in DCM (20 mL) was added (S)-1-phenyl-ethylamine (1.4 g, 11.55 mmol) (Aldrich, Milwaukee, Wis.), followed by triethylamine (1.5 mL). The reaction was stirred at room temperature for overnight. The reaction was washed with 1N NaOH, water, brine, dried and concentrated to give 867 mg (40%) of 1H-pyrrole-2-carboxylic acid ((S)-1-phenyl-ethyl)-amide.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([C:6](=[O:13])[C:7](=[O:12])[NH:8]2)=[CH:4][CH:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:15].[K+].[K+].S(=O)(=O)(O)O>>[CH3:11][C:10]1[C:9]2[NH:8][C:7](=[O:12])[C:6](=[O:13])[O:15][C:5]=2[CH:4]=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1ccc2c(c1C)NC(=O)C2=O
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1ccc2oc(=O)c(=O)[nH]c2c1C
Reaction time: 0.25 h

Procedure:
35 parts of 6,7-dimethylisatin are introduced into a solution of 60 parts of potassium peroxydisulfate in 400 parts of 98% strength sulfuric acid at from 5° C. to 10° C. The mixture is then stirred for 10-20 minutes, after which it is poured onto ice. The product is filtered off and dried, giving 34 parts of 5,6-dimethyl-2,3-dioxo-1,4-benzoxazine, of melting point 278°-284° C. (with decomposition).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]3)[CH:13]=[CH:12][N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>O1CCOCC1>[C:1]1([NH:7][C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:17][C:18](=[O:21])[C:19](=[CH:24][N:25]([CH3:27])[CH3:26])[CH2:20]3)[CH:13]=[CH:12][N:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(OC)N(C)C
Reactant: O=C1CCN(c2ccnc(C(=O)Nc3ccccc3)c2)C1
Solvent: C1COCCO1
Product: CN(C)C=C1CN(c2ccnc(C(=O)Nc3ccccc3)c2)CC1=O
Temperature: 100 °C
Yield: 60.9 %

Procedure:
A suspension of 4-(3-oxopyrrolidin-1-yl)-pyridine-2-carboxylic acid phenylamide (130 mg, 0.46 mmol) and dimethylformamide dimethylacetal (0.12 mL, 0.90 mmol) in 1,4-dioxane (2 ml) was heated under nitrogen at 100° C. for 4.5 h. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (25 g) eluted with dichloromethane:methanol 19:1 and gave the title compound (95 mg, 0.28 mmol, yield 61%).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([NH2:29])=[CH:28][C:23]=2[CH:22]=[CH:21]1>CC#N>[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([NH:29][C:8]3[C:9](=[O:10])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[S:6](=[O:19])(=[O:18])[C:7]=3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:28][C:23]=2[CH:22]=[CH:21]1
Reactant: Nc1ccc2occc2c1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Product: CCCCN1C(=O)C(Nc2ccc3occc3c2)=C(c2ccccc2)S1(=O)=O
Yield: 26.8 %

Procedure:
A solution of 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.047 g, 0.141 mmol) and 1-benzofuran-5-amine (0.046 g, 0.345 mmol) in MeCN (1.5 ml) was heated in a microwave reactor at 130° C. for 60 mins and at 140° C. for 45 mins. The reaction mixture was evaporated and the residue was purified by column chromatography using EtOAc:heptane (1:3) as eluant. Crystallisation from hexane and EtOH gave the title compound (0.015 g, 27%). 1H NMR (400 MHz, CD3CN): 7.80 (bs, 1H), 7.65 (d, 1H), 7.17-7.09 (m, 4H), 7.07-7.02 (m, 3H), 6.85 (dd, 1H), 6.60-6.58 (m, 1H), 3.76 (t, 2H), 1.87-1.78 (m, 2H), 1.54-1.43 (m, 2H), 1.01 (t, 3H); Mass Spectrum: M+H+ 397.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:19]=1[CH2:20][OH:21]>>[CH2:1]([N:5]1[C:9]2=[C:10]([O:21][CH2:20][C:19]3[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:18]=3[Cl:17])[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: OCc1c(F)cccc1Cl
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Product: CC=CCn1c(C)c(C)c2cnnc(OCc3c(F)cccc3Cl)c21
Yield: 57.6 %

Procedure:
The title compound (cis/trans=21/79) was prepared as a pale brown powder in 57.60% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=24/76) and 2-chloro-6-fluorobenzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([I:10])[CH:9]=1)[CH:5]=O.[F:12][C:13]([F:22])([F:21])/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([I:10])[CH:7]=[C:4]2[C:3]=1[O:11][CH:14]([C:13]([F:12])([F:22])[F:21])[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2
Reactant: O=Cc1cc(I)cc(Cl)c1O
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1=Cc2cc(I)cc(Cl)c2OC1C(F)(F)F
Temperature: 100 °C
Yield: 37.7 %

Procedure:
To 18 g (63.7 mmole) of 3-chloro-2-hydroxy-5-iodobenzaldehyde in 16 mL of DMF was added 14.3 mL (16.1 g, 95.6 mmole) of ethyl trifluorocrotonate and 9.69 g (70 mmole) of K2CO3. The mixture was heated to 100° C. for 2 h. The mixture was allowed to cool, treated with 300 mLs of H2O and extracted three times with Et2O. The combined extracts were washed with water and filtered through a silica plug (4.5×6 cm). The silica was washed with methylene chloride and combined filtrates concd to give 10.39 g of a yellow solid. Recystalization in hexanes gave 6.64 g (24.1%) of a crystalline, yellow solid: 1H NMR (CDCl3/400 MHz) 1.35 (t, 3H, J=7.1 Hz), 4.33 (m, 2H), 5.81 (q, 1H, J=6.6 Hz), 7.44 (d, 1H, J=2.0 Hz), 7.62 (s, 1H), 7.66 (d, 1H, J=2.0 Hz); 19F NMR (CDCl3/400 MHz) −79.0 (d, 3F, J=6.8 Hz); 13C NMR (CDCl3/100 MHz) 13.1, 60.8, 70.4 (q, J=33.7 Hz), 82.6 (C-I), 117.7, 121.2, 121.8, 121.9 (q, J=287.2 Hz), 133.6, 134.9, 139.9, 147.9, 162.0; MS (ESI+) 433 (M+1, 100); HRMS (EI) m/z calcd for (C13H9O3IClF3) 431.9237, found 431.9221.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH3:22]>CO>[CH3:21][O:20][C:17]1[N:16]=[CH:15][C:14]([N:12]([CH3:13])[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([NH2:22])[N:11]=2)=[CH:19][CH:18]=1
Reactant: N
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cn1
Solvent: CO
Product: COc1ccc(N(C)c2nc(N)nc3ccccc23)cn1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methylamine (10 mg, 0.030 mmol) and 7 M ammonia in methanol (1 mL) by a procedure similar to example 10 (3 mg, 30%). 1H NMR (CDCl3): 8.04 (dd, J=2.9, 0.6 Hz, 1H), 7.49-7.43 (m, 2H), 7.39 (dd, J=5.7 and 2.7 Hz, 1H), 6.92 (brd, J=8.4 Hz, 1H), 6.85-6.78 (m, 2H), 5.65 (s, 2H), 3.96 (s, 3H), 3.54 (s, 3H).
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4](OCCC)[N:3]=1.[CH3:15][C@H:16]([OH:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH3:15][C@H:16]([O:23][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCOc1nc(C)ccc1C(=O)O
Reactant: CCCCCC[C@H](C)O
Product: CCCCCC[C@H](C)Oc1ccc(C(=O)O)cn1

Procedure:
The same procedure followed for the methylpropyloxynicotinic acid was used employing 1(S)-methylheptanol as the starting alcohol. A quantitative yield of 6-(1(S)methylheptyloxy)nicotinic acid (2, where R2 is 1(S)-methylheptyl was obtained as a brownish solid. The material was used without further purification.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[K].[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>C(O)C>[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][O:22][C:19]2[CH:20]=[CH:21][C:16]([C:13]3[CH:12]=[CH:11][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][CH:14]=3)=[CH:17][CH:18]=2)=[CH:27][CH:26]=1
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1
Reactant: BrCc1ccc(Br)cc1
Agent: [K]
Solvent: CCO
Product: CCCCCCCCOc1ccc(-c2ccc(OCc3ccc(Br)cc3)cc2)cc1
Yield: 77.9 %

Procedure:
5 g of 4'-n-octyloxy-4-hydroxybiphenyl, 1.5 g of potassium hydrooxide, and 100 g of 95% ethanol were heated under reflux, and a solution wherein 4.2 g of p-bromobenzyl bromide was dissolved in 100 ml of ethanol was added thereto to effect reaction for 2 hours. The reaction liquid was treated in the ordinary method to obtain 6.1 g of 4'-n-octyloxy-4-biphenylyl p-bromobenzyl ether after recrystallization from ethyl acetate. The obtained product showed the following phase transition temperatures:
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[C:41](Cl)=[O:42].C(=O)(O)[O-].[Na+]>ClCCl>[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[C:41]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:8]2)=[CH:22][CH:23]=1)=[O:42]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CCOC(=O)Cc1nn(Cc2ccc(N)cc2)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc12
Yield: 46.9 %

Procedure:
The crude ethyl 2-[1-(4-aminobenzyl)-1H-indazol-3-yl]acetate (about 1.04 mmol) obtained in the last step and triethylamine (1.4 mL) were dissolved in dichloromethane (15 mL). In an ice bath, a dichloromethane solution (10 mL) of 2-naphthoyl chloride (210 mg, 1.1 mmol) was added dropwise slowly. Upon completion of the dropwise addition, it was reacted at room temperature for 16 hours. An aqueous solution of sodium bicarbonate was added to quench. It was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and filtered. The filtrate was removed under reduced pressure, and the resulting residue was chromatographed on a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain a white solid 226 mg, at a total yield over two steps of reactions of 46.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13](OCCCC(OCC)=O)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:30])[CH:3]=1.O.CO.Cl>[OH-].[Na+]>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:30])[CH:3]=1
Reactant: CCOC(=O)CCCOc1cc2ncnc(Nc3ccc(Cl)cc3F)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2ncnc(Nc3ccc(Cl)cc3F)c2c1
Temperature: 40 °C
Yield: 111.9 %

Procedure:
A mixture of 4-(4chloro-2-fluoroanilino)-7-(3-ethoxycarbonylpropoxy)-6-methoxyquinazoline (220 mg, 0.5 mmol) in aqueous sodium hydroxide solution (4 ml of a 2M solution, 8 mmol), water (2 ml) and methanol (0.5 ml) was stirred and heated at 40° C. for 3 hours. The mixture was allowed to cool and was then acidified with 2M hydrochloric acid. The resulting white precipitate was collected by filtration and washed with acetone and water to give 7-3-carboxypropoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (170 mg, 83%).
Reaction SMILES: Cl.[CH2:2]1[C:6]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH2:5][CH2:4][O:3]1>CO>[CH2:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][O:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCOC2)CC1
Agent: Cl
Solvent: CO
Product: C1CC2(CCN1)CCOC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.9 %

Procedure:
Methanolic hydrogen chloride (3M, 3 mL) was added to a stirred, cooled (0° C.) solution of 1,1-dimethylethyl 2-oxa-8-azaspiro[4.5]decane-8-carboxylate (Description 43, 150 mg, 0.62 mmol) in methanol and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in methanol and passed through Amberlyst 26 ion exchange resin, eluting with methanol. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane, dried (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound (77 mg, 88%). m/z (ES+) 142 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.C([Li])CCC.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>O1CCCC1.CCCCCC>[S:1]1[C:5]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][Br:15])=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: BrCCCCCCBr
Reactant: c1ccc2sccc2c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: BrCCCCCCc1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of benzo[b]thiophene (1.92 g., 14.3 mmol) in 90 ml anhydrous tetrahydrofuran at -10° to 0° under argon was added n-butyllithium (7.8 ml of a 1.86M solution in hexane). After two hours, this solution was transferred dropwise into a stirred, 0° solution of 1,6-dibromohexane (6.5 ml, 0.043 mol) in 250 ml tetrahydrofuran. The solution was warmed to room temperature, stirred for 15 hours, quenched with water and concentrated. The residue was acidified and partitioned between ethyl ether and water. The aqueous portion was extracted twice with ether, and the combined organic portions were washed with water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a brown oil. Excess benzo[b]thiophene and 1,6-dibromohexane were removed by bulb to bulb distillation (85° to 90°/0.1 mm) to leave a dark brown syrup. This material was purified by flash chromatography (silica, hexane to 5% ethyl ether/hexane) to give the desired alkyl halide.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([CH3:9])=[C:7]([C:10]#[CH:11])[N:6]=[C:5]2[CH3:12])[CH2:3][CH2:2]1.I[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=1>>[CH:1]1([N:4]2[C:8]([CH3:9])=[C:7]([C:10]#[C:11][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=3)[N:6]=[C:5]2[CH3:12])[CH2:3][CH2:2]1
Reactant: C#Cc1nc(C)n(C2CC2)c1C
Reactant: Cc1cc(I)ccn1
Product: Cc1cc(C#Cc2nc(C)n(C3CC3)c2C)ccn1

Procedure:
The title compound, MS: m/e=252.1 (M+H+), was prepared in accordance with the general method of example A, step 1 from 1-cyclopropyl-4-ethynyl-2,5-dimethyl-1H-imidazole and 4-iodo-2-methyl-pyridine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([N:25]2C(=O)C4C(=CC=CC=4)C2=O)=[N:20][CH:19]=[CH:18]3)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([NH2:25])=[N:20][CH:19]=[CH:18]3)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1c1nccc2cc(O[C@H]3CCCN(Cc4ccccc4)C3)ccc12
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1nccc2cc(O[C@H]3CCCN(Cc4ccccc4)C3)ccc12
Temperature: 50 °C

Procedure:
To a solution of the above (S)-2-[6-(1-benzylpiperidin-3-yloxy)isoquinolin-1-yl]-isoindole-1,3-dione (20 mg, 43 μmol) in ethanol (2 ml) was added hydrazine monohydrate (−3 μL, 65 μmol). The mixture was heated at 50° C. for 2 h then concentrated in vacuo to give a residue. The residue was purified by prep-HPLC to give (S)-6-(1-benzylpiperidine-3-yloxy)isoquinolin-1-yl amine El-MS: m/z=334.3 [M+H]+.