Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li].Cl.Cl[CH2:16][CH:17]([N:19]([CH3:21])[CH3:20])[CH3:18].[Cl-].[NH4+]>C(Cl)Cl.CO.CCOCC>[CH3:16][CH:17]([N:19]([CH3:21])[CH3:20])[CH2:18][C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH2:4][CH:3]=[CH:2]1
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: CC(CCl)N(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Li]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: CC(CC1(c2ccccc2)C=CCC=C1)N(C)C
Temperature: -70 °C

Procedure:
46.1 g. of biphenyl in 400 ml. of absolute ether are added at about -33° C. while stirring to 600 ml. of dry, condensed ammonia. 4.2 g. of lithium wire (about 2 cm long pieces, de-greased with cyclohexane) are then added at about -50° C. within 15 minutes. The mixture is held at boiling temperature for 2 hours. It is then cooled to about -70° C. and 15.8 g. of racemic 2-chloro-N,N,1-trimethylethylamine hydrochloride are added portionwise over a period of 10 minutes. The mixture is again warmed to boiling temperature (about -33° C.) and stirred at this temperature for 2 hours. 32 g. of ammonium chloride are then added and the ammonia is distilled off. Subsequently, the mixture is worked-up aqueous: the ether solution is washed with water. The aqueous phase is adjusted to a pH greater than 12 with sodium hydroxide solution and extracted further twice with ether. The ether phases are combined and extracted twice with 2 N aqueous hydrochloric acid. The acid extracts are again made alkaline and extracted with ether. The ether phases are dried, filtered and concentrated. There is obtained an oily product which, after chromatography on a 20-fold amount of silica gel using methylene chloride/methanol (10:1) as the solvent, yields α,N,N-trimethyl-1-phenyl-2,5-cyclohexadien-1-ethylamine. This product is dissolved in ether and converted with hydrogen chloride into the hydrochloride which is recrystallized from methylene chloride/ether. The product has a melting point of 158°-159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH3:11]C1C2C(=CC=CC=2)NC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[CH:8]=[CH:7]2
Reactant: Cc1c[nH]c2ccccc12
Reactant: Clc1cccc2cc[nH]c12
Product: Cn1ccc2cccc(Cl)c21
Yield: 100 %

Procedure:
According to the procedure of Preparation 13 (a), except substituting 7-chloroindole for the 3-methylindole, the title compound (2.2 g, 100%) was obtained as a white solid: MS (ES) m/e 166.2 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[C:9]([C:15]([OH:17])=O)[NH:10]3)[CH2:3][CH2:2]1.Cl.Cl.Cl.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C@@H:29]([N:31]2[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]2)[CH3:30])[CH2:24][CH2:23]1>>[OH:37][CH:34]1[CH2:33][CH2:32][N:31]([C@@H:29]([CH3:30])[CH2:28][N:25]2[CH2:24][CH2:23][CH:22]([NH:21][C:15]([C:9]3[NH:10][C:11]4[C:7]([CH:8]=3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH:14]=[CH:13][CH:12]=4)=[O:17])[CH2:27][CH2:26]2)[CH2:36][CH2:35]1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Reactant: O=C(O)c1cc2c(OCC3CC3)cccc2[nH]1
Agent: Cl
Product: C[C@@H](CN1CCC(NC(=O)c2cc3c(OCC4CC4)cccc3[nH]2)CC1)N1CCC(O)CC1

Procedure:
This compound is synthesized analogously to example 1 from 4-cyclopropylmethoxy-1H-indole-2-carboxylic acid, 77 (see example 4) and amine 50.
Reaction SMILES: Cl.CN(C)[CH2:4][CH2:5]CN=C=NCC.[I:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][N:15]=1.C(O)C.CCOCC>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[I:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([O:20][CH2:4][CH3:5])=[O:19])=[CH:16][N:15]=1
Reactant: O=C(O)c1ccc(I)nc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(I)nc1
Temperature: 55 °C

Procedure:
A mixture of 16.230 g (84.5 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 90 ml of methylene chloride was cannulated into a mixture of 17.80 g (71.2 mmol) of 6-iodo-nicotinic acid in 30 ml of methylene chloride. The resulting mixture was stirred and 7.85 g (0.171 mmol) of ethanol, and then 0.826 g (6.8 mmol) of 4-dimethylaminopyridine was added and the resulting mixture refluxed at 55° C. for 20 hours and then stirred at room temperature for 12 hours. Ether and water were added and the layers separated. The aqueous layer was extracted with 2×40 ml of ether and the organic portions combined, washed with saturated NaCl, dried over Na2SO4, and concentrated yielding a white solid which was purified by flash chromatography (SiO2, 10% ethyl acetate in hexanes) to give the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH2:12][CH3:13])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[S:22][C:23]([CH2:26][NH:27][CH2:28][CH3:29])=[CH:24][N:25]=1.O>CN(C)C=O>[CH2:12]([O:11][C:4]1[N:3]=[C:2]([N:27]([CH2:26][C:23]2[S:22][C:21]([Cl:20])=[N:25][CH:24]=2)[CH2:28][CH3:29])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)[CH3:13]
Reactant: CCNCc1cnc(Cl)s1
Reactant: CCOc1ccc([N+](=O)[O-])c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc([N+](=O)[O-])c(N(CC)Cc2cnc(Cl)s2)n1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
1.36 g of 2-chloro-6-ethoxy-3-nitropyridine, 10 mL of N,N-dimethylformamide (DMF), and 2.00 g of potassium carbonate were added to a 100 mL single neck flask, under stirring at room temperature, 1.20 g of 2-chloro-5-ethylaminomethylthiazole prepared in the example 1 in 5.0 mL of DMF was added dropwise. After that, the reaction solution was heated to 40-80° C. and reacted for 3-6 hr. After cooling down, the resulting mixture was added to water (50 mL), then treated by the method according to the example 1 to obtain 1.01 g of 6-ethoxy-N-((2-chlorothiazole-5-yl)methyl)-N-ethyl-3-nitropyridin-2-amine, a viscous liquid, with 98.6% purity, a yield of 43.2%, and the structure was confirmed by GC-Mass and 1H NMR.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH2:9][OH:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[Li+].[Cl-].FC(F)(F)[C:16](O)=[O:17]>Cl[Pd]Cl>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]2[C:5](=[C:6]([F:8])[CH:7]=1)[C:16](=[O:17])[O:10][CH2:9]2
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1c(Br)cc(F)cc1CO
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Li+]
Product: Cc1c(Br)cc(F)c2c1COC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3-bromo-5-fluoro-2-methyl-phenyl)-methanol (1.7 g, 7.76 mmol) in trifluoroacetic acid (20 mL) was added Tl(CF3COO)3 (4.2 g, 7.76 mmol). The resulting mixture was stirred at room temperature overnight, then concentrated to dryness. The residue was dissolved in MeOH (50 mL). To the mixture was added PdCl2 (137 mg, 0.776 mmol), LiCl (652 mg, 15.5 mmol) and MgO (652 mg, 15.5 mmol). The resulting mixture was reacted under a CO (50 psi) atmosphere at room temperature overnight, and then filtered. The filtrate was concentrated and the residue was purified by column chromatography to give 5-bromo-7-fluoro-4-methyl-3H-isobenzofuran-1-one.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[O:29]1[C:33]2[CH:34]=[CH:35][C:36]([OH:38])=[CH:37][C:32]=2[O:31][CH2:30]1.[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[O:29]1[C:33]2[CH:34]=[CH:35][C:36]([O:38][C:2]3[C:7](=[O:8])[N:6]([CH2:9][C:10]4[CH:15]=[CH:14][C:13]([C:16]5[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=5)=[CH:12][CH:11]=4)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=3[CH2:27][CH3:28])=[CH:37][C:32]=2[O:31][CH2:30]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(Oc2ccc3c(c2)OCO3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 86.4 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.45 g), 1,3-benzodioxol-5-ol (0.21 g), 8 M potassium hydroxide solution (0.19 mL) and dimethyl sulfoxide (8 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.44 g, 86%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[NH2:27][C:28]1[CH:39]=[CH:38][C:31]([CH2:32][C:33]2[N:34]=[CH:35][NH:36][CH:37]=2)=[CH:30][CH:29]=1.N1CCCCC1.O>CN(C=O)C>[NH:36]1[CH:37]=[C:33]([CH2:32][C:31]2[CH:30]=[CH:29][C:28]([NH:27]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:39][CH:38]=2)[N:34]=[CH:35]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: Nc1ccc(Cc2c[nH]cn2)cc1
Solvent: C1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(Cc2c[nH]cn2)cc1)c1ccccc1

Procedure:
Prepared by reacting 1-acetyl-3-{1-ethoxy-1-phenylmethylidene}-5-nitro-2-indolinone with 1.45 equivalents of 4-(4-amino-benzyl)-1H-imidazole in DMF (100° C., for 2 hours), subsequent treatment with 5 equivalents of piperidine (20° C., 1 hour) and precipitation with water.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]3=[C:16]([OH:25])[C:15]=2[C:14]2[C:13]([C:26]([O:28]C)=O)=[CH:12][CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:30]#N.N>C1COCC1>[CH2:1]([N:8]1[C:20]2[CH:19]=[C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]3=[C:16]([OH:25])[C:15]=2[C:14]2[C:13]([C:26]([NH2:30])=[O:28])=[CH:12][CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#N
Reactant: COC(=O)c1cccc2c1c1c(O)c3ccccc3cc1n2Cc1ccccc1
Agent: N
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)c3ccccc3cc1n2Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
A solution of 5-benzyl-11-hydroxy-5H-benzo[b]carbazole-1-carboxylic acid, methyl ester, (0.229 g, 0.60 mM) in 8 mL THF was placed in an Ace Glass pressure tube (203 mm×38 mm) with a small stirring bar. A N2(g) stream was installed over the solution surface. The pressure tube and reaction solution were cooled to −78° C., and ˜8 mL NH3(l) was condensed into the reaction vessel by introduction of an NH3(g) stream. The pressure tube was sealed with a teflon O-ring screw cap, the resultant orange solution stirred at −78° C. for 10 minutes, then the cooling bath was removed and the reaction solution allowed to warm to ambient temperature behind a blast shield. After 48 h, the pressure tube was re-cooled to −78° C. and the internal NH3(g) pressure was released by careful removal of the Teflon™ cap. The reaction solution was allowed to slowly warm to room temperature while NH3(g) bubbled off, then the solution was concentrated in vacuo to afford 0.22 g (99%) of the title compound 5-benzyl-11-hydroxy-5H-benzo[b]carbazole-1-carboxylic acid amide as a yellowish-green solid (MW 366.42).
Reaction SMILES: [C:1]([N:5]([CH2:25][C:26]([O-:28])=[O:27])[C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:16][C:15]([F:18])([F:17])[CH2:14]2)=[C:9]([O:19][CH2:20][CH:21]2[CH2:23][CH2:22]2)[N:8]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C1COCC1.CO>O>[C:1]([N:5]([CH2:25][C:26]([OH:28])=[O:27])[C:6]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:14][C:15]([F:17])([F:18])[CH2:16]2)=[C:9]([O:19][CH2:20][CH:21]2[CH2:23][CH2:22]2)[N:8]=1)=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N(CC(=O)[O-])C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)N(CC(=O)O)C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.1 %

Procedure:
A solution of 2-(N-tert-butyl-6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinamido)acetate (Example 23, 58 mg, 136 μmol) in a mixture of 1N aqueous NaOH solution (164 μL, 164 μmol), THF (0.5 mL), MeOH (0.2 mL) and water (0.05 mL) was stirred at ambient temperature for 24 h and evaporated to dryness. The residue was partitioned between ice water/0.1N aqueous HCl solution (25 mL) and EtOAc (25 mL). The aqueous layer was extracted one more time with EtOAc (25 mL). The combined extracts were washed with ice/brine (25 mL), dried over Na2SO4 and brought to dryness to give the title compound (51 mg, 128 μmol, 94%) as light yellow solid; MS (EI): m/e=398.4 [MH+].
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]([F:27])([F:26])[C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=1)[O:18][CH:19]1[CH2:22][NH:21][CH2:20]1>>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([N:21]2[CH2:22][CH:19]([O:18][C:17]3[CH:23]=[CH:24][CH:25]=[C:15]([C:14]([F:13])([F:27])[F:26])[CH:16]=3)[CH2:20]2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Product: COC(=O)c1cc(Cl)cnc1N1CC(Oc2cccc(C(F)(F)F)c2)C1
Yield: 67.4 %

Procedure:
The title compound (D79) (110 mg) was prepared according to the experimental procedure described in Description 62 starting from Methyl 2,5-dichloronicotinate (87 mg, 0.422 mmol) and 3-(3-(trifluoromethyl)phenoxy)azetidine (D53) (110 mg, 0.506 mmol)
Reaction SMILES: C1CC1.Cl[CH2:5][C:6]([C:10]1[S:11][CH:12]=[CH:13][C:14]=1[CH3:15])=[C:7]([CH3:9])[CH3:8].C(Cl)(Cl)(Cl)[Cl:17]>>[Cl:17][C:6]1([C:10]2[S:11][CH:12]=[CH:13][C:14]=2[CH3:15])[CH2:5][C:7]1([CH3:9])[CH3:8]
Reactant: CC(C)=C(CCl)c1sccc1C
Reactant: ClC(Cl)(Cl)Cl
Agent: C1CC1
Product: Cc1ccsc1C1(Cl)CC1(C)C
Reaction time: 18 h

Procedure:
The cyclopropane produced in b) (0.40 g, 2.0 mmol) was stirred with gravity silica (0.15 g) in carbon tetrachloride (10 cm3) at 20° C. The silica developed a purple/black coloration within 30 min while the solution remained colourless. After 18 h at 20° C. no starting material remained. The silica was removed by filtration and the carbon tetrachloride evaporated to give a product characterised as 1-chloro-2-(3-methylthien-2-yl)-3-methylbut-2-ene (0.33 g, 82%) as the only product, which was pure by n.m.r. (Found: M+ +200.0417. C10H13SCl requires M, 200.0426) which showed νmax (film) 708 s, 1256 m, 1444 m, 1700 m and 29922 m cm-1 ; δH (CCl4) 1.65 (3H, s), 1.98 (3H, s), 2.06 (3H, s), 4.20 (2H, s), 6.72 (1H, d, J 5 Hz), 7.03 (1H, d, J 5 Hz); m/z 200 (M+), 165 (M+ -Cl).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[S:14](Cl)(=[O:17])(=[O:16])[NH2:15]>>[C:4]([C:3]1[CH:6]=[C:7]([C:10]([F:11])([F:12])[F:13])[CH:8]=[CH:9][C:2]=1[NH:1][S:14]([NH2:15])(=[O:17])=[O:16])#[N:5]
Reactant: NS(=O)(=O)Cl
Reactant: N#Cc1cc(C(F)(F)F)ccc1N
Product: N#Cc1cc(C(F)(F)F)ccc1NS(N)(=O)=O

Procedure:
Prepared as in Example 77a from 2-amino-5-(trifluoromethyl)benzonitrile (Example 86b) and sulfamoyl chloride. 1H NMR (400 MHz, DMSO-d6) δ 7.53 (s, 2H), 7.74-7.76 (d, J=8.4 Hz, 1H), 8.01-8.03 (dd, J=8.4 Hz, 1.6 Hz, 1H), 8.23-8.233 (d, J=1.2 Hz, 1H), 10.16 (b, 1H).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[CH3:14][NH2:15]>O>[CH3:14][NH:15][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: CN
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Solvent: O
Product: CNCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
2-Chloromethylquinoline hydrochloride (3.00 g, 14.01 mmol) was suspended in aqueous methylamine (40 mL, 40 wt % in H2O) at 10° C. under a N2 atmosphere. After 20 minutes, the reaction mixture was warmed to room temperature and stirred for 3 hours. The mixture was diluted with water and extracted with dichloromethane. The organic extracts were dried (MgSO4) and concentrated to afford 2.22 g (92%) of pure product as a brown oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22](=[O:48])[C:23]([CH3:47])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[C:35]([CH:39]=2)[C:36](O)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22](=[O:48])[C:23]([CH3:47])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[C:35]([CH:39]=2)[C:36]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(Oc3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(Oc3ccccc3)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.8 %

Procedure:
Morpholine (0.030 g, 0.343 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.099 g, 0.515 mmol) were added to a methylene chloride solution (5 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-phenoxybenzoic acid (0.070 g, 0.172 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.040 g, 0.0839 mmol, 49%).
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:29]([CH3:32])([CH3:31])[CH3:30])[S:8]/[C:9]/1=[N:10]\[C:11]([C:13]1[CH:14]=[C:15]([NH:21]C(=O)OC(C)(C)C)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])=[O:12])[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>>[NH2:21][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]([CH:14]=1)[C:11](/[N:10]=[C:9]1/[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:6][N:7]([C:29]([CH3:31])([CH3:32])[CH3:30])[S:8]/1)=[O:12]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(NC(=O)OC(C)(C)C)ccc1OC
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(N)ccc1OC
Yield: 94.1 %

Procedure:
The product from Example 55A (71 mg, 0.15 mmol) was treated with TFA (1 mL) at rt for 10 min, solvent removed and the mixture treated with saturated aqueous NaHCO3, and extracted with EtOAc (2×). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% Hexane in ethyl acetate) to afford 51 mg (92%) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 0.97 (t, J=7.32 Hz, 3 H) 1.36-1.47 (m, 2 H) 1.64 (s, 9 H) 1.67-1.77 (m, 2 H) 2.83 (dd, J=7.93 Hz, 2 H) 3.49 (brs, 2 H) 3.87 (s, 3 H) 6.76 (dd, J=8.54, 3.05 Hz, 1 H) 6.83 (d, J=8.54 Hz, 1 H) 7.54 (d, J=2.75 Hz, 1 H) 7.90 (s, 1 H); MS (DCI/NH4+) m/z 362 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH2:4][C:5](C)([C:24]([O:26][CH3:27])=[O:25])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]=[CH:19][Si](C)(C)C)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[CH:29](Cl)(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl>[CH3:29][C:4]1[C:5]2([C:24]([O:26][CH3:27])=[O:25])[CH:6]3[CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]([CH3:1])([CH2:19][CH:18]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=2)[N:3]=1
Reactant: ClC(Cl)Cl
Reactant: COC(=O)C1=C(C)NCC(C)(C(=O)OC)C1c1ccccc1C=C[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COC(=O)C1C2c3ccccc3C3CC1(C)N=C(C)C32C(=O)OC
Reaction time: 3 h

Procedure:
To the Compound 1b (1.0 mmol) in Chloroform (10 ml) was added titanium tetrachloride (1.1 mmol) under nitrogen at ambient temperature. After 3 hours, the solvent was removed in vacuo and the residue flash chromatographed on silica gel eluted with hexane:diethyl ether (1:2) to afford the desired product. The β-isomer was a white solid (Rf =0.4, m.p. 104.5°-105.5° C.). The α-isomer was a white solid (Rf =0.3, m.p. 160°-161.5° C.).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH2:4][CH2:3]1.Br[C:13]1[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:17][CH:18]=1>>[CH3:11][O:10][C:8]([CH:6]1[CH:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7]1)=[O:9]
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: COC(=O)C1=CCCN(C)C1
Product: COC(=O)C1CN(C)CCC1c1cccc(C(F)(F)F)c1

Procedure:
3-methoxycarbonyl-1-methyl-4-(3-trifluoromethylphenyl)piperidine was prepared as the cis/trans mixture from arecoline and 3-bromo-trifluoromethylbenzene as described (J.Org.Chem. 22 (1957) 261). The product was purified by vacuum distillation. B.p. 90°-110° C./0.7 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8](O)[CH3:9].CCN(CC)CC.CS(Cl)(=O)=O.Cl.[NH:24]1[C:30]2[CH:31]=[CH:32][S:33][C:29]=2[C:28](=[O:34])[NH:27][CH2:26][CH2:25]1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:24]1[C:30]2[CH:31]=[CH:32][S:33][C:29]=2[C:28](=[O:34])[NH:27][CH2:26][CH2:25]1)[CH3:9]
Reactant: CC(O)c1ccccc1Cl
Reactant: O=C1NCCNc2ccsc21
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(c1ccccc1Cl)N1CCNC(=O)c2sccc21
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 3.4 %

Procedure:
1-(2-Chloro-phenyl)-ethanol (1.0 g, 6.39 mmol, 3.6 Eq) and Et3N (1.16 mL, 8.30 mmol, 4.7 Eq) were dissolved in anhydrous DCM (20 mL) and cooled to 0° C. under nitrogen. MsCl (645 μL, 8.30 mmol, 4.7 Eq) was added portionwise. After 3.5 hours, the reaction was poured into 1M HCl (20 mL) and the layers separated. The aqueous layer was extracted with EtOAc (2×30 mL) and the combined organic extracts washed with brine (30 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in dioxane (6 mL) and 1,2,3,4-tetrahydro-thieno[3,2-e][1,4]diazepin-5-one (300 mg, 1.78 mmol, 1.0 Eq) was added and the reaction heated at reflux overnight. The reaction was cooled to ambient temperature and the solvent removed in vacuo. The residue was purified by column chromatography (ISCO™ Companion©, 40 g column, 0 to 10% MeOH/DCM) to give the title compound as an off-white solid (178 mg, 0.06 mmol, 33%); 1H NMR (DMSO D6) 1.50 (3H, d), 2.92-2.99 (1H, m), 3.13 (1H, m), 3.20-3.25 (2H, m), 5.32 (1H, dd), 6.91 (1H, d), 7.25-7.35 (2H, m), 7.36-7.41 (2H, m), 7.58 (1H, d), 7.61-7.63 (1H, m); LC/MS M+1 (obs.) 307.0.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.CC(C)([O-])C.[K+].C(=O)([O-])[O-].[K+].[K+].[CH2:21]([O:28][CH2:29][N:30]1[C:34]2=[N:35][CH:36]=[CH:37][C:38](Cl)=[C:33]2[CH:32]=[N:31]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN1C(=O)CCC1.O>[CH2:21]([O:28][CH2:29][N:30]1[C:34]2=[N:35][CH:36]=[CH:37][C:38]([O:8][C:3]3[CH:4]=[CH:5][C:6]([NH2:7])=[CH:1][CH:2]=3)=[C:33]2[CH:32]=[N:31]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1ccnc2c1cnn2COCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1ccc(Oc2ccnc3c2cnn3COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
P-Aminophenol (800 mg, 7.33 mmol) and potassium t-butoxide (820 mg, 7.31 mmol) were dissolved in NMP (10 mL), and potassium carbonate (510 mg, 3.69 mmol) was added thereto. The resulting mixture was stirred at room temperature for 1 hour, and 1-benzyloxymethyl-4-chloro-1H-pyrazolo[3,4-b]pyridine (860 mg, 5.62 mmol) was added thereto. The resulting mixture was stirred at 80° C. for 0.5 hours. The reaction container was cooled, and the content was diluted with water (100 mL) and extracted with ethyl acetate (100 mL) three times. The combined organic layer was washed with saturated brine (50 mL) twice, dried, and concentrated. The residue was purified by silica-gel column chromatography (Fuji Silysia, BW300, 30 g, n-hexane:EtOAc=1:1) to give 4-(1-benzyloxymethyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline as a light-yellow syrup (1105 mg, yield: quantitative).