Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12](=[O:14])[NH2:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:15])[CH:3]=1.[CH:16](O)=O>>[OH:15][C:4]1[CH:3]=[C:2]2[C:11]([C:12](=[O:14])[NH:13][CH:16]=[N:1]2)=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(C(N)=O)c(N)cc1O
Reactant: O=CO
Product: COC(=O)c1cc2c(=O)[nH]cnc2cc1O

Procedure:
A mixture of methyl 4-amino-5-carbamoyl-2-hydroxybenzoate (5.4 g) and formic acid (50 ml) was heated to reflux for 1 hour. The mixture was evaporated. Toluene (75 ml) was added and the mixture was evaporated. The solid residue was washed with methanol and diethyl ether and dried to give methyl 7-hydroxy-4-oxo-3,4-dihydroquinazolin-6-carboxylate (5.2 g); NMR Spectrum: (DMSOd6) 4.9 (s, 3H), 7.09 (s, 1H), 7.39 (s, 1H), 8.5 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]([N+:17]([O-])=O)[CH:6]=[CH:5][CH:4]=1.[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.C(N(CC)CC)C.[H][H]>ClCCl.C(OCC)(=O)C.[Pd]>[NH2:17][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[CH2:9][N:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([Cl:20])=[CH:22][CH:23]=1
Reactant: [H][H]
Reactant: CCOC(=O)CNCc1c(OC)cccc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(Cc1c(N)cccc1OC)C(=O)c1ccc(Cl)cc1

Procedure:
5.6 g (21.3 mmol) of ethyl (6-methoxy-2-nitrobenzyl)aminoacetate was dissolved in 50 ml of dichloromethane. 3.3 ml (25.2 mmol) of 4-chlorobenzoyl chloride and 4.4 ml (32 mmol) of triethylamine were added to the obtained solution under cooling with ice, and they were stirred under cooling with ice for 2 hours. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the crude product was obtained. The crude product was dissolved in 50 ml of ethyl acetate. 520 mg of 10% palladium/carbon was added to the obtained solution and they were stirred in the presence of hydrogen at room temperature for 4 hours. The reaction mixture was filtered through Celite. The solvent was evaporated to obtain the crude product, which was then purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [C:1]1([CH3:9])[C:2]([C:7]#N)=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:10]([Mg]Br)[CH3:11].C1C[O:17]CC1>>[C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:17])[CH2:10][CH3:11]
Reactant: CC[Mg]Br
Reactant: Cc1ccccc1C#N
Reactant: C1CCOC1
Product: CCC(=O)c1ccccc1C
Temperature: 0 °C

Procedure:
To an oven dried 100 ml 3 neck flask equipped with septa, thermo probe and stirred bar was stirring a solution of o-tolunitrile (1 ml, 8.5 mmol) in 40 ml dry THF at 0° C. To this cold, well stirred solution was added a solution of ethylmagnesium bromide (17 ml, 17 mmol) in THF via syringe while keeping the temperature below 5° C. Removed ice bath and allowed the yellow solution to stir at ambient temperature for 24 h. The reaction was cooled to 0° C. and quenched with a solution of saturated NH4Cl (50 ml), extracted with 2× EtOAc and washed with H2O, brine, drying (MgSO4), filtration and removal of solvent in vacuo to give a crude oil. This material was chromatographed (Silica gel, 3% EtOAc/Hexane) to affort the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH:24]([OH:27])[CH2:25][CH3:26].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[C:24](=[O:27])[CH2:25][CH3:26]
Reactant: CCC(O)c1ccc(OC)cc1Oc1ccnc2cc(OC)c(OC)cc12
Solvent: O
Solvent: CS(C)=O
Product: CCC(=O)c1ccc(OC)cc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 0 °C
Reaction time: 18 h
Yield: 14 %

Procedure:
1-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-4-methoxyphenyl}-1-propanol was dissolved in anhydrous dimethylsulfoxide (1 ml). A sulfur trioxide trimethylamine complex (70 mg) was added thereto at 0° C., and the mixture was stirred at room temperature for 18 hr. Water (1 ml) was added dropwise to the reaction solution to stop the reaction. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give the title compound (25 mg, yield 14%).
Reaction SMILES: FC1C=CC(S)=CC=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.S([O-])(O)=O.[Na+:24]>>[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.[Na+:24]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Fc1ccc(S)cc1
Agent: O=S([O-])O
Agent: [Na+]
Product: O=S([O-])c1ccc(F)cc1

Procedure:
It has now been found that 4-fluorothiophenol can be prepared in an advantageous manner if 4-fluorobenzenesulphonyl chloride is first reacted with sodium hydrogen sulphite solution to give a solution of sodium 4-fluorobenzenesulphinate, then this solution is reduced with sulphur dioxide to give 4,4'-difluorodiphenyl disulphide and this is finally reacted with sodium borohydride in a water-miscible inert organic solvent to give 4-fluorothiophenol (sodium salt). 4-Fluorothiophenol can be isolated from this sodium salt solution after distilling off the solvent, for example by acidifying the solution, separating off the organic phase forming and if appropriate purifying still further.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][C:9]1([CH3:27])[CH2:14][C:13](=O)[CH2:12][CH2:11][CH:10]1[NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[CH3:8][C:9]1([CH3:27])[CH2:14][CH:13]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH2:12][CH2:11][CH:10]1[NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN1CCNCC1
Reactant: CC1(C)CC(=O)CCC1NC(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(C2CCC(NC(=O)OCc3ccccc3)C(C)(C)C2)CC1
Reaction time: 2 h
Yield: 44 %

Procedure:
N-Methylpiperazine (0.620 ml, 5.6 mmol, 2 eq) was added at 0° C. to a solution of benzyl 2,2-dimethyl-4-oxocyclohexylcarbamate (770 mg, 2.8 mmol, 1 eq) in dichloromethane (15 ml), and stirring was carried out for 2 h at RT. Na(OAc)3BH (1.78 g, 8.4 mmol, 3 eq) was added in portions at 0° C., and stirring was carried out for 18 h at RT. The reaction solution was diluted with dichloromethane (60 ml), washed with water (50 ml) and sat. NaCl solution (50 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (Alox neutral, 1% MeOH in dichloromethane), a white solid was obtained. Yield: 44% (440 mg, 1.225 mmol).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:7]([N:14]([CH2:16][CH2:17][O:18][CH2:19][C:20]1[NH:21][C:22]([CH3:42])=[C:23]([C:38]([O:40][CH3:41])=[O:39])[CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:37])[C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])C)C1C=CC=CC=1>CO.[Pd]>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH:24]1[C:23]([C:38]([O:40][CH3:41])=[O:39])=[C:22]([CH3:42])[NH:21][C:20]([CH2:19][O:18][CH2:17][CH2:16][NH:14][CH3:7])=[C:25]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C1=C(COCCN(C)Cc2ccccc2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CO
Product: CCOC(=O)C1=C(COCCNC)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Yield: 65.6 %

Procedure:
A solution of 2-[2-(N-benzyl-N-methylamino)ethoxymethyl]-4-[2-chlorophenyl]-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine, oxalate salt (4.3 g) in methanol (220 ml) was added to a suspension of 10% (by weight) palladium on charcoal (0.4 g) pre-hydrogenated in methanol (50 ml). Stirring under hydrogen at 50 p.s.i. and room temperature overnight resulted in complete removal of the benzyl group. After removal of the catalyst by filtration, the methanol was removed by evaporation and the residue crystallised from a little methanol to give the title compound (2.4 g), m.p. 211°.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:14]([NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:3][C:4](=[O:13])[O:5]CC1C=CC=CC=1.[CH2:32]([S:39](Cl)(=[O:41])=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(OCC)(=O)C.C(Cl)Cl>[C:33]1([CH2:32][S:39]([NH:1][C@H:2]([C:14]([NH:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:15])[CH2:3][C:4](=[O:13])[OH:5])(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)NCCc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(O)C[C@H](NS(=O)(=O)Cc1ccccc1)C(=O)NCCc1ccccc1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
The keto amide (8) (109 mg, 0.24 mmol) was dissolved in ethyl acetate (5 mL) and cooled in an ice bath. Dry HCl gas was bubbled through until the solution was saturated and then the solution was stirred at r.t. until the starting material had been consumed as indicated by tlc (˜30 min). The solvent was removed under reduced pressure. The residue (22) was dissolved in dry CH2Cl2 (5 mL) and triethylamine (61 mg, 84 μL) added. The solution was then added dropwise to a solution of benzyl sulfonyl chloride (46 mg, 0.24 mmol) in dry CH2Cl2 (5 mL) cooled in an ice bath. The resulting solution was allowed to stir at r.t. for 16 h. It was washed with 1M HCl, 5% sodium bicarbonate solution and saturated brine, then dried (MgSO4) and the solvent removed under reduced pressure to yield the product as a white solid (51 mg, 42%): mp 128-130° C. 1H NMR (CDCl3) δ2.61 & 2.99 (ABX, 2H, β-CH2), 2.86 (t, 2H, CH2Ph), 3.57 (m, 2H, NH—CH2), 4.74 (m, 1H, α-CH), 5.14 (2×s, 4H, benzyl CH2's), 6.53 & 6.74 (m, 2H, NH's), 7.29 (m, 15H, aromatic CH's); FABMS m/e 509 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([CH:40]=[CH:41][C:42]#[N:43])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:44][CH3:45])=[O:5])[CH3:2].[N-:46]=[N+:47]=[N-:48].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:37])([F:39])[F:38])[CH:27]=3)[C:22]([CH:40]=[CH:41][C:42]3[NH:48][N:47]=[N:46][N:43]=3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:44][CH3:45])=[O:5])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C=CC#N)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C=Cc3nnn[nH]3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 100 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
A mixture of (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-cyanovinyl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (385 mg), sodium azide (99 mg), ammonium chloride (81 mg) and N,N-dimethylformamide (5 ml) is stirred at 100°C. overnight. The mixture is partitioned by adding ethyl acetate and a saturated brine. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform to chloroform:methanol=5:1) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-{5-[2-(tetrazole-5-yl)vinyl]pyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (155 mg). MS (m/z): 678 [M+H]+
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[C:35]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][C:42]=1[F:43])#[N:36]>>[C:35]([C:37]1[CH:38]=[C:39]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:34])=[O:3])[CH:11]=[C:12]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)[CH:13]=2)[CH:40]=[CH:41][C:42]=1[F:43])#[N:36]
Reactant: N#Cc1cc(B(O)O)ccc1F
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(F)c(C#N)c2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 3-cyano-4-fluoro-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, MeOD) δ ppm 0.87 (dd, J=6.48, 2.81 Hz, 6H), 1.47 (dt, J=13.39, 6.63 Hz, 1H), 1.65 (ddd, J=13.63, 7.09, 6.91 Hz, 1H), 1.92-2.00 (m, 1H), 3.71-3.77 (m, 1H), 7.54 (td, J=7.70, 1.47 Hz, 1H), 7.59-7.61 (m, 1H), 7.65-7.72 (m, 3H), 7.77-7.81 (m, 2H), 7.86-7.89 (m, 1H), 7.96 (ddd, J=8.80, 5.14, 2.45 Hz, 1H), 8.02 (dd, J=5.99, 2.32 Hz, 1H); Calcd for C26H21F4NO2 (M+H) 456.44, Found 456.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].[C:17](O)(=[O:19])C>C=O>[CH2:1]([N:5]1[C:9]([CH2:17][OH:19])=[C:8]([CH3:10])[N:7]=[C:6]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cc(C)nc1-c1ccccc1
Reactant: CC(=O)O
Agent: C=O
Product: CCCCn1c(-c2ccccc2)nc(C)c1CO

Procedure:
A solution of 112 (1 g) in acetic acid (10 mL) and 40% aqueous formaldehyde (2 mL) is refluxed for 14 hours. The reaction is then concentrated and dried by repeated reconcentration with toluene. The residue is purified by column chromatography (10% MeOH/CHCl3). The fractions are assayed by GC and those fractions uncontaminated by the isomeric hydroxymethylimidazole combined. Concentration of the combined fractions provides compound 113 (320 mg) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.4–7.6 (m, 6H), 4.61 (s, 2H, CH2OH), 4.02 (t, J=7 Hz, 2H, NCH2), 2.22 (s, 3H, Me), 1.63 (m, 2H, 1.25 (m, 2H), 0.81 (t, J=7 Hz, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:14]([O:17][C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([C:27](=[O:39])[NH:28][C:29]3[CH:33]=[C:32]([C:34]5([CH2:37]O)[CH2:36][CH2:35]5)[O:31][N:30]=3)[CH:22]=[CH:21]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=O)(C)(C)C.C([N:42](CC)CC)C.N.CO.C(O)(C(F)(F)F)=O>C1COCC1.CN(C1C=CN=CC=1)C>[NH2:42][CH2:37][C:34]1([C:32]2[O:31][N:30]=[C:29]([NH:28][C:27]([N:23]3[C:24]4[C:20](=[CH:19][C:18]([O:17][C:14]5[C:15]6[CH2:16][NH:8][CH2:9][C:10]=6[N:11]=[CH:12][N:13]=5)=[CH:26][CH:25]=4)[CH:21]=[CH:22]3)=[O:39])[CH:33]=2)[CH2:36][CH2:35]1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1Cc2ncnc(Oc3ccc4c(ccn4C(=O)Nc4cc(C5(CO)CC5)on4)c3)c2C1
Agent: CN(C)c1ccncc1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: C1CCOC1
Product: NCC1(c2cc(NC(=O)n3ccc4cc(Oc5ncnc6c5CNC6)ccc43)no2)CC1
Reaction time: 2 h

Procedure:
To a solution of 4-{1-[5-(1-hydroxymethyl-cyclopropyl)-isoxazol-3-ylcarbamoyl]-1H-indol-5-yloxy}-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (500 mg, 0.939 mmol) in THF (10 mL), at 0° C., triethylamine (0.262 mL, 1.88 mmol) methanesulfonyl chloride (0.110 mL, 1.41 mmol) and DMAP (11.5 mg, 0.094 mmol) are added. After 2 h the reaction is complete and is quenched with water and the organics extracted with EtOAc. The crude product following concentration is then dissolved in THF (30 mL), and NH3 in MeOH (1.82 mL, 12.8 mmol) is added. The reaction is stirred for 36 h. At this point the volatiles are removed and the crude product is dissolved in DCM (10 mL) and then TFA (10 mL, 130 mmol) is added. After 10 minutes the volatiles are removed in vacuo. The product is dissolved in EtOAc and then NH4OH is added. The organics are removed and the crude product separated via FCC eluting with DCM:MeOH:NH4OH (100:0:0 to 92:7:1) to give the title compound. MS (ESI) m/z 432.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.55 (s, 1H) 8.35 (d, J=8.84 Hz, 1H) 8.15 (d, J=3.54 Hz, 1H) 7.44 (d, J=2.53 Hz, 1H) 7.11 (dd, J=9.09, 2.53 Hz, 1H) 6.77 (s, 1H) 6.70 (d, J=4.04 Hz, 1H) 4.09 (d, J=11.87 Hz, 4H) 2.94 (s, 2H) 1.05 (d, J=3.03 Hz, 4H).
Reaction SMILES: [OH:1][CH:2]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)[C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3([NH:24][C:25](=[O:27])[CH3:26])[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C1(C)C=CC([Bi](Cl)(Cl)(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.N12CCCN=C1CCCCC2.C(Cl)(Cl)Cl>C(Cl)Cl>[CH3:22][C:19]1([CH3:23])[O:18][CH2:17][C:16]([NH:24][C:25](=[O:27])[CH3:26])([CH2:15][CH2:14][C:11]2[CH:10]=[CH:9][C:8]([C:6]3[S:7][C:3]([C:2](=[O:1])[C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)=[CH:4][CH:5]=3)=[CH:13][CH:12]=2)[CH2:21][O:20]1
Reactant: CC(=O)NC1(CCc2ccc(-c3ccc(C(O)c4ccc(C)cc4)s3)cc2)COC(C)(C)OC1
Agent: Cc1ccc([Bi](Cl)(Cl)(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(=O)NC1(CCc2ccc(-c3ccc(C(=O)c4ccc(C)cc4)s3)cc2)COC(C)(C)OC1
Reaction time: 2 h
Yield: 63.1 %

Procedure:
To a solution of N-{5-[2-(4-{5-[hydroxy(4-methylphenyl)methyl]-2-thienyl}phenyl)ethyl]-2,2-dimethyl-1,3-dioxan-5-yl}acetamide (0.35 g) in methylene chloride (5 mL) were added tri(p-tolyl)bismuth dichloride (393 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (108 mg) at room temperature, and the mixture was stirred at the same temperature for 2 hr. Chloroform was added to the reaction mixture, and the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.22 g) as brown crystals.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:7]([CH2:8][CH2:9][OH:10])[C:6]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[CH:14][C:5]=2[N:4]=1.CCN(CC)CC.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([O:10][CH2:9][CH2:8][N:7]1[C:6]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[CH:14][C:5]=2[N:4]=[C:3]1[C:2]([F:1])([F:19])[F:20])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: OCCn1c(C(F)(F)F)nc2cc(C(F)(F)F)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCn1c(C(F)(F)F)nc2cc(C(F)(F)F)ccc21
Temperature: 0 °C

Procedure:
To a stirred solution of 2-[2,5-bis(trifluoromethyl)-1H-benzimidazol-1-yl]ethanol (5.36 g, 17 mmol) in CH2Cl2 (15 ml), Et3N (5.0 ml, 36 mmol) was added and cooled to 0° C. To the cooled solution, methanesulfonyl chloride (1.53 ml, 19.8 mmol) was added slowly.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([CH3:26])=[N:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].C(=O)([O-])[O-].[K+].[K+].[OH:35][CH:36]1[CH2:41][CH2:40][CH2:39][NH:38][CH2:37]1>CN(C)C=O>[CH3:28][O:27][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:3][CH2:2][N:38]1[CH2:39][CH2:40][CH2:41][CH:36]([OH:35])[CH2:37]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:15][C:16]1[C:17]([CH3:26])=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][N:20]=2
Reactant: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1OCCCl
Reactant: OC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1OCCN1CCCC(O)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
3-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine (compound 398) (42 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (44 mg) and 3-hydroxypiperidine (32 mg) were added to the solution, and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (29 mg, yield 56%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[O:13]([CH2:20][CH2:21][NH2:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:23]([NH2:25])[CH3:24]>>[CH2:23]([NH:25][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:22][CH2:21][CH2:20][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:11]=[CH:10]2)[CH3:24]
Reactant: CCN
Reactant: NCCOc1ccccc1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Product: CCNc1ccc2nc(NCCOc3ccccc3)ccc2c1

Procedure:
The title compound, MS: m/e=308.4 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-phenoxyethylamine and ethylamine (solution in tetrahydrofurane).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH:7]2[CH2:12][CH2:11][CH2:10][N:8]2[CH3:9])[CH:4]=[CH:3][CH:2]=1.OO.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:18]>>[N:1]1[CH:6]=[C:5]([CH:7]2[CH2:12][CH2:11][CH2:10][N+:8]2([O-:18])[CH3:9])[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CN1CCCC1c1cccnc1
Agent: OO
Product: C[N+]1([O-])CCCC1c1cccnc1
Temperature: 80 °C

Procedure:
500 g of nicotine (3.08 mol) are slowly added dropwise to an equimolar 30% hydrogen peroxide solution containing 5.9 g of citric acid (30.8 mmol), the temperature being maintained below 90° C. After the addition has ended, the mixture is heated at 80° C. for 5 hours.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([O:18]CC)=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[C:33]([CH2:35][CH3:36])[CH:32]=[CH:31][C:30]=2[N:37]2[CH:41]=[CH:40][C:39]([CH3:42])=[N:38]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1.[Li+].[OH-]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[C:33]([CH2:35][CH3:36])[CH:32]=[CH:31][C:30]=2[N:37]2[CH:41]=[CH:40][C:39]([CH3:42])=[N:38]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4cc(CC)ccc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1
Agent: [Li+]
Agent: [OH-]
Product: CCc1ccc(-n2ccc(C)n2)c([C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)c1

Procedure:
Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-1-(5-ethyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provided the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[C:5]([C:11]([OH:13])=O)[CH:4]=[N:3]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][CH:47]=1)[O:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([N:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[N:38]=2)[CH:35]=1>CN(C)C=O.CN(C)C(=O)C>[CH:42]1([C:40]([NH:39][C:37]2[N:38]=[C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:27]=[C:26]([NH:25][C:11]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[C:6]=5[C:7]([F:10])([F:9])[F:8])=[O:13])[CH:47]=[CH:46][CH:45]=4)=[CH:35][N:34]3[N:36]=2)=[O:41])[CH2:43][CH2:44]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: Cn1ncc(C(=O)O)c1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)c1C(F)(F)F
Yield: 64.7 %

Procedure:
In the same manner as in Example 18-4 and using 1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (175 mg, 0.904 mmol), tetrahydrofuran (8 mL), oxalyl chloride (118 μL, 1.36 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (70.0 mg, 0.226 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (71.0 mg, 65%) was obtained as a white solid.