Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([OH:16])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CO>CC(C)=O>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCCC(COCc2ccccc2)C1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CO
Product: O=C1CCCC(COCc2ccccc2)C1
Temperature: 0 °C

Procedure:
To a solution of the compound (10) (4.9 g; 22.2 mmol) in acetone (90 ml), Jones reagent (chromic anhydride acid-sulfuric acid) (0.07 mol) is dropwise added, and the resultant mixture is stirred at a temperature of 0° to 10° C. for 2 hours. Methanol is dropwise added to the reaction mixture, which is poured into ice-water and extracted with chloroform. The extract is washed with water, dried and concentrated under reduced pressure. The residue is chromatographed on a silica gel column to give 3-benzyloxymethylcyclohexanone (11).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([N:10]([CH3:22])[C:11]([CH:13]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Mg+2].[I-].[I-].[Cl-].[NH4+].O>C1(C)C=CC=CC=1>[OH:14][C@@H:13]1[C@@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:1][CH2:2][C@@H:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]([CH3:22])[C:11]1=[O:12]
Reactant: CN(C(=O)C1OC1c1ccccc1)[C@H](CO)c1ccccc1
Agent: [Cl-]
Agent: [I-]
Agent: [Mg+2]
Solvent: O
Solvent: Cc1ccccc1
Product: CN1C(=O)[C@H](O)[C@@H](c2ccccc2)OC[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 32 h

Procedure:
To a stirred solution of (2RS,3RS)—N-[(1S)-2-hydroxy-1-phenylethyl]-N-methyl-3-phenyloxirane-2-carboxamide (30a) (1.7 g, 5.72 mmol) in anhydrous toluene (120 mL) was added MgI2 (1.6 g, 5.72 mmol, 98% purity) and the mixture vigorously stirred at RT for 32 h. The mixture was treated with saturated ammonium chloride (50 mL) and water (50 mL) and stirred for 30 min. The separated organic layer was washed consecutively with saturated ammonium chloride and brine, dried, filtered and evaporated to an orange oil (1.6 g). Isocratic flash column chromatography (2:1 hexanes-ethyl acetate) separated the title compound (33b) (400 mg, 24%) as a white solid from the (3S,6S,7R) diastereomer (1.0 g, 59%). There was a significant NOE observed between proton 3 and proton 7. HPLC: 1.78 min (Method A).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.O1CCOCC1.[Pd]>[NH2:1][C:4]1[C:5]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1ccccc1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: Nc1cccnc1Nc1ccccc1
Yield: 70.7 %

Procedure:
A procedure similar to that described in Example 6 was repeated, except that 6.9 g of 3-nitro-2-phenylaminopyridine (prepared as described in Preparation 83) was hydrogenated in a mixture of 150 ml of ethanol and 50 ml of dioxane in the presence of 1.38 g of 10% w/w palladium-on-charcoal. After working up the product as described in Example 6, 4.2 g of the title compound, melting at 137°-140° C., were obtained.
Reaction SMILES: [H-].[Na+].[CH:3]1([SH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:11]1[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:12]=1[C:13]#[N:14].[NH4+].[Cl-]>CN(C=O)C.O>[CH:3]1([S:9][C:11]2[N:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[CH:15][C:12]=2[C:13]#[N:14])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: N#Cc1ccc(C(F)(F)F)nc1Cl
Reactant: SC1CCCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(F)(F)F)nc1SC1CCCCC1
Reaction time: 1.5 h
Yield: 94.6 %

Procedure:
1.3 equivalents of NaH (4.9 g, 0.124 mol) were dissolved in 50 mL DMF under a nitrogen atmosphere. After the addition of 1.2 equivalents of cyclohexanethiol (14.2 mL, 0.116 mol) stirring was performed at RT for 1.5 h. The resultant suspension was cooled to 10° C. and 1 equivalent of 2-chloro-6-(trifluoromethyl)nicotinonitrile (20 g, 0.096 mol) in 50 mL DMF was added dropwise and stirred for 2 h at RT. The reaction mixture was combined with sat. aq. NH4Cl soln., diluted with 1 L of water and extracted repeatedly with EA (3×200 mL). The combined organic phases were washed with a sat. aq. NaCl soln., dried over MgSO4 and evaporated under a vacuum. Purification performed by column chromatography (silica gel, 100-200 mesh, eluent: 2% EA in hexane) resulted in 26 g (93.8%) of product.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4](S)=[N:5][N:6]=1.Cl[CH2:9][C:10]#[N:11]>C(O)C>[NH2:1][C:2]1[S:3][C:4]([CH2:9][C:10]#[N:11])=[N:5][N:6]=1
Reactant: N#CCCl
Reactant: Nc1nnc(S)s1
Solvent: CCO
Product: N#CCc1nnc(N)s1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
A mixture of 2-amino-5-mercapto-1,3,4-thiadiazole (66.5 g, 0.50 mol.), and ethanol (500 ml) is heated to reflux and chloroacetonitrile (41.1 g, 0.55 mol.) is added dropwise at reflux. Heating is continued for four hours and then about 400 ml of distillate is removed using a Dean-Stark trap. The clear solution is cooled to about 75° C. and water (150 ml) is added, allowing the temperature to drop to about 50° C. After adjusting the pH to about seven by adding slowly a solution of Na2CO3, the mixture is cooled to room temperature and the gray product is collected by filtration and washed with water. The moist filter cake is recrystallized from 300 ml of ethanol to yield the desired product which melts at 163°-164° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4](=[O:14])[C:3]=1[C:15](Cl)=[O:16].C(N(C(C)C)CC)(C)C.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:43]=[CH:44][C:45]([NH2:48])=[N:46][CH:47]=1>ClCCl.CO>[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:43]=[CH:44][C:45]([NH:48][C:15]([C:3]2[C:4](=[O:14])[N:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[CH:7][C:2]=2[I:1])=[O:16])=[N:46][CH:47]=1
Reactant: COc1cc2nccc(Oc3ccc(N)nc3)c2cc1OC
Reactant: O=C(Cl)c1c(I)ccn(-c2ccccc2)c1=O
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4c(I)ccn(-c5ccccc5)c4=O)nc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
To a solution of 4-iodo-2-oxo-1-phenyl-1,2-dihydropyridine-3-carbonyl chloride (139 mg, 387 μmol) in dichloromethane (4 mL) at room temperature was added diisopropylethylamine (202 μl, 1160 μmol) followed by 5-(6,7-dimethoxyquinolin-4-yloxy)pyridin-2-amine (115 mg, 387 μmol). The reaction mixture was stirred at room temperature for 2 h. An aliquot was taken and analyzed by LCMS: reaction was done. The reaction mixture was diluted with methanol and directly adsorbed on silica. Purification by MPLC (CH2Cl2/MeOH: 100/0 to 96/4) afforded N-(5-(6,7-dimethoxyquinolin-4-yloxy)pyridin-2-yl)-4-iodo-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide (162 mg, 261 μmol, 68% yield for two steps). MS (ESI pos. ion) m/z: 621 (MH+). Calc'd exact mass for C28H20IN4O5: 620.
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[C:7]([Cl:9])[CH:8]=1)([O-])=O.C(OC(=O)C)(=O)C.Cl.CO>C(O)(=O)C.[Fe]>[ClH:9].[NH2:1][C:4]1[S:5][C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[C:7]([Cl:9])[CH:8]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(-c2ccc(Cl)cc2)s1
Agent: [Fe]
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Nc1cc(Cl)c(-c2ccc(Cl)cc2)s1

Procedure:
Following the procedure of Example 12, 2-nitro-4-chloro-5-(4-chlorophenyl)thiophene (2.3 g) is reacted with acetic anhydride (14 ml) and iron powder (2.3 g) in acetic acid (14 ml), followed by reacton with HCl and methanol (30 ml) to give 2-amino-4-chloro-5-(4-chlorophenyl)thiophene hydrochloric acid salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[NH2:12].Cl.[N:14]1([CH2:19][C:20](O)=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[NH:12][C:20](=[O:21])[CH2:19][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(O)CN1CCCC1
Reactant: COc1cc([N+](=O)[O-])ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc([N+](=O)[O-])ccc1NC(=O)CN1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.3 %

Procedure:
Dissolve 2-methoxy-4-nitro-phenylamine (1.0 g, 5.95 mmol), pyrrolidin-1-yl-acetic acid hydrochloride (0.99 g, 5.95 mmol) and N,N-diisopropylethylamine (1.08 mL, 6.55 mmol) in N,N-dimethylformamide (20 mL) and add O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.49 g, 6.55 mmol). Stir the mixture at room temperature for 16 h. Dilute the mixture with water (50 mL) and extract with dichloromethane (3×25 mL). Dry the combined organics (Na2SO4), filter, and concentrate in vacuo. Purify by chromatography (0% to 4% MeOH/CH2Cl2) to afford 0.77 g (46%) of the title compound. MS/ES m/z 280.0 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([C@H:19]([NH:21][C:22]([C:24]3([CH3:35])[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:34])[C@@H:31]([NH2:33])[CH3:32])[NH:25]3)=[O:23])[CH3:20])=[N:16]2)=[CH:11][CH:10]=1.[OH:36][C@@H:37]([CH:41]([CH3:43])[CH3:42])[C:38](O)=[O:39].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl>[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([C@H:19]([NH:21][C:22]([C:24]3([CH3:35])[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:34])[C@@H:31]([NH:33][C:38](=[O:39])[C@@H:37]([OH:36])[CH:41]([CH3:43])[CH3:42])[CH3:32])[NH:25]3)=[O:23])[CH3:20])=[N:16]2)=[CH:11][CH:10]=1
Reactant: C[C@H](N)C(=O)N1CCCC(C)(C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Reactant: CC(C)[C@H](O)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCCC(C)(C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.8 %

Procedure:
To a solution of ((S)-2-{3-[(R)-1-(7-bromo-quinolin-2-yl)-thylcarbamoyl]-3-methyl-tetrahydro-pyridazin-1-yl}-1-methyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (1.92 g, 3.5 mmol) in dichloromethane (15 mL) at 0° C. was added trifluoroacetic acid (3 mL). The reaction mixture was allowed to warm to room temperature and then stirred for 4 h. The reaction mixture was concentrated and the residue was co-evaporated with toluene (3×) to give 1-((S)-2-amino-propionyl)-3-methyl-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide trifluoroacetate salt (3.5 mmol) as a brown oil. LCMS (m/z) 448.0, 450.0 [M+H], Tr=1.22 min. 1-((S)-2-Amino-propionyl)-3-methyl-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide trifluoroacetate salt (3.5 mmol) was dissolved in dichloromethane (20 mL) and the solution was cooled to 0° C. (S)-2-Hydroxy-3-methyl-butyric acid (458 mg, 3.8 mmol), N,N-diisopropylethylamine (5 mL, 28.0 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino) phosphonium hexafluorophosphate (1.86 g, 4.2 mmol) were added. The reaction mixture was allowed to warm to room temperature and was stirred for 16 h. The solvent was evaporated and the residue was dissolved in ethyl acetate. The organic solution was washed with citric acid (10%), saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate/methanol 1:0 to 20:1 to afford the title compound (745 mg, 39% over 2 steps) as a white foam and as a 1:4 mixture of diastereoisomers. LCMS (m/z) 548.0, 550.0 [M+H], Tr=2.21 min.
Reaction SMILES: [CH3:1][SH:2].[Na].[CH2:4]([O:6][C:7](=[O:12])[C:8]([CH2:10]Br)=[CH2:9])[CH3:5]>C(O)C.O>[CH2:4]([O:6][C:7](=[O:12])[C:8]([CH2:10][S:2][CH3:1])=[CH2:9])[CH3:5]
Reactant: CS
Reactant: C=C(CBr)C(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: O
Product: C=C(CSC)C(=O)OCC
Reaction time: 2 h

Procedure:
A solution of methylmercaptan 4.8 g.) and sodium (2.3 g.) in absolute ethanol (75 ml.) is added dropwise to a solution of ethyl-2-bromomethylacrylate (19.3 g.) in ethanol (25 ml.). After two hours, it is diluted with water (400 ml.) and extracted with methylene chloride. The organic layer is dried and concentrated to dryness in vacuo to yield ethyl-2-methylthiomethylacrylate.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]([CH3:29])([CH3:28])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)C.C(O)C.[OH-].[Na+]>O>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH:11]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:29])([CH3:28])[C:4]([OH:30])=[O:3]
Reactant: CCOC(=O)C(C)(C)CCCCCC(c1ccccc1Cl)N1CCc2sccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(CCCCCC(c1ccccc1Cl)N1CCc2sccc2C1)C(=O)O
Yield: 43.4 %

Procedure:
8-(2-Chlorophenyl)-8-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2-dimethyloctanoic acid ethyl ester (0.86 g, 1.92 mmol) was added to a solution of ethanol (32 mL) and sodium hydroxide (0.53 g, 13.4 mmol) in water (10.4 mL). The mixture was heated to reflux for 6.5 hours. The solution was concentrated under reduced pressure and water (43 mL) was added to the residue. Any starting material was extracted with ethyl acetate/heptane (1/10, 43 mL). The heptane extract was discarded. The remaining aqueous solution was adjusted with 10 N hydrochloric acid solution to pH=6. The product was extracted with CH2Cl2 (3×40 mL), dried over Na2SO4, concentrated and purified by column chromatography (silica gel, ethyl acetate/heptane=1/10 to 1/3) to provide 8-(2-chlorophenyl)-8-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5yl)-2,2-dimethyloctanoic acid (Compound Im, 0.35 g, 43.8% yield, 99.6% purity by HPLC) as a yellow oil. 1H NMR (Field: 300 MHz, Solvent: CDCl3/TMS) δ (ppm): 10.43 (br, 1H), 7.52 (d, 1H, J=7.50 Hz), 7.39 (d, 1H, J=8.10 Hz), 7.28-7.15 (m, 2H), 7.03 (d, 1H, J=5.0 Hz), 6.69 (d, 1H, J=5.0 Hz), 4.24 dd, 1H, J=9.3, 4.2 Hz), 3.83 (d, 1H, J=14.40 Hz), 3.51 (d, 1H, J=14.40 Hz), 2.92-2.73 (m, 4H), 1.99-1.81 (m, 2H), 1.46-1.41 (m, 2H), 1.28-1.15 (m, 6H), 1.13 (s, 6H). (t, 3H, J=7.2 Hz), 1.15-1.08 (m, 2H), 1.07 (s, 6H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 184.02, 138.85, 135.16, 133.87, 133.42, 129.60, 129.17, 128.17, 126.92, 125.52, 122.74, 63.53, 50.54, 47.90, 42.29, 40.70, 32.95, 30.52, 25.75, 25.64, 25.26, 24.96. HRMS (FIA-ESI): Calculated for C23H30ClNO2S (M+H)+: 420.1759, found 420.1779. CHN analysis: Calculated; 65.77 C, 7.20 H, 3.33 N, found; 60.77 C, 6.68 H, 3.11 N. Best fit for CHN: C23H30ClNO2S+HCl
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([OH:20])=O)[CH2:11][CH2:10]1.[C@@H:27]12[NH:34][C@@H:31]([CH2:32][CH2:33]1)[CH2:30][CH2:29][CH2:28]2.[C@@H]12N(C)[C@@H](CC1)CCC2.CC(OC1C[C@H]2N(C)[C@H](CC2)C1)=O.Cl.CN(C)CCCN=C=NCC.[OH-].[Na+].Cl.O.Cl.Cl>C(Cl)Cl.CCOCC.C(N(CC)CC)C>[CH:31]12[N:34]([C:18](=[O:20])[CH:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:15][N:12]3[CH2:11][CH2:10][N:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:14][CH2:13]3)[CH:27]([CH2:33][CH2:32]1)[CH2:28][CH2:29][CH2:30]2
Reactant: C1C[C@@H]2CC[C@H](C1)N2
Reactant: COc1ccccc1N1CCN(CCC(C(=O)O)c2ccccc2)CC1
Agent: CC(=O)OC1C[C@H]2CC[C@@H](C1)N2C
Agent: CCN=C=NCCCN(C)C
Agent: CN1[C@@H]2CCC[C@H]1CC2
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCC(C(=O)N2C3CCCC2CC3)c2ccccc2)CC1

Procedure:
A mixture of 4-[4-(2-methoxyphenyl)piperazin-1-yl]-2-phenylbutanoic acid (4.0 g, 11.3 mmole), desmethyltropane (1.7 g, 15.3 mmole, prepared from tropane by the method used by R. A. Olofson et. al., J. Org. Chem., 1984, 49(11), 2081, for the conversion of O-acetyltropine to O-acetyldesmethyltropine), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.2 g, 11.3 mmole) and triethylamine (0.19.8 mmole) in methylene chloride (25 mL) was stirred at ambient temperature for 48 hr. The mixture was poured into 1 N sodium hydroxide (100 mL) and extracted with ethyl acetate (3×100 mL). The combined ethyl acetate layer was washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to give crude product. Purification of this material by column chromatoghaphy (silica gel with 1% ammonia in ethyl acetate as eluant) followed by the treatment with 1.1 equivalent of 1N hydrogen chloride in ether gave 2.5 g of the title compound as the hydrochloride hemihydrate, m.p. 225°-228° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=2)[CH2:6]1)=[O:4].C([O-])(=O)C.[Na+].Cl.[NH2:23][OH:24]>CO.O>[CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[N:23][OH:24])=[CH:11][CH:10]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CN(c2ccc(C=O)cc2)C1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C1CN(c2ccc(C=NO)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.9 %

Procedure:
To a stirred suspension of 1-(4-formyl-phenyl)-azetidine-3-carboxylic acid methyl ester (Preparation 9, 2.6 g, 11.87 mmol) in methanol (25 mL) and water (25 mL) was added sodium acetate (1.75 g, 21.36 mmol) followed by hydroxylamine hydrochloride (1.24 g, 17.80 mmol) at 0° C. Resulting reaction mixture was stirred at room temperature for 3 hours. After consumption of starting material, methanol was evaporated under reduced pressure and extracted with EtOAc (4×30 mL). Combined organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo to afford yellow colored solid (2.86 g, 99%). 1H NMR (400 MHz, CDCl3) δ: 3.55-3.59 (m, 1H), 3.75 (s, 3H), 4.05-4.13 (m, 4H), 6.42 (d, 2H, J=8.56 Hz), 7.41 (d, 2H, J=8.6 Hz), 8.03 (s, 1H); LC-MS (M+H): =235.00.
Reaction SMILES: Cl.Cl.[F:3][C@H:4]1[C@H:9]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:20]=2[N:19]=[CH:18][CH:17]=[CH:16]3)[CH2:8][CH2:7][NH:6][CH2:5]1.[C:21](Cl)(=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O.C(OCC)(=O)C>C(Cl)Cl>[F:3][C@H:4]1[C@H:9]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:20]=2[N:19]=[CH:18][CH:17]=[CH:16]3)[CH2:8][CH2:7][N:6]([C:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:30])[CH2:5]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: F[C@@H]1CNCC[C@H]1Oc1cccc2cccnc12
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CC[C@@H](Oc2cccc3cccnc23)[C@H](F)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
To a 0° C. solution of 8-((trans)-3-fluoropiperidin-4-yloxy)quinoline dihydrochloride (6.6 g, 26.8 mmol) and TEA (18.7 ml, 134.0 mmol) in 134 mL DCM was added benzyl carbonochloridate (4.4 ml, 29.5 mmol). The reaction mixture was stirred 15 minutes at 0° C., then warmed to ambient temperature and stirred another 16 hours. Water was added, and the mixture was extracted with DCM. The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel (Biotage 40M, loaded with 4:1hexanes:ethyl acetate and 500 mL flushed, then gradient to 1:1 hexanes:ethyl acetate) to give (trans)-benzyl 3-fluoro-4-(quinolin-8-yloxy)piperidine-1-carboxylate (5.2 g, 13.67 mmol, 51.01% yield) as an oil. MS APCI (+) m/z 381 (M+1) detected.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[F:21])=[CH:13][N:12]=[C:11]([C:22]([NH2:24])=[O:23])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1.[O:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>O1CCCC1.ClCCl.C(OCC)(=O)C>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]1[C:6]2[C:5]3[C:9](=[CH:10][C:2]([NH:1][CH:28]4[CH2:29][CH2:30][O:25][CH2:26][CH2:27]4)=[CH:3][CH:4]=3)[NH:8][C:7]=2[C:11]([C:22]([NH2:24])=[O:23])=[N:12][CH:13]=1
Reactant: O=C1CCOCC1
Reactant: NC(=O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(N)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(NC3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.9 %

Procedure:
A mixture of 7-amino-4-(2-fluorophenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (30.0 mg, 0.094 mmol), dihydro-2H-pyran-4(3H)-one (10.37 μL, 0.112 mmol), and sodium triacetoxyborohydride (39.7 mg, 0.187 mmol) in tetrahydrofuran (1 mL) and dichloromethane (1 mL) was stirred at rt for 16 hr. Additional dihydro-2H-pyran-4(3H)-one (10.37 μL, 0.112 mmol) and sodium triacetoxyborohydride (39.7 mg, 0.187 mmol) were added, and the mixture was stirred at room temperature for another 8 hr. To the reaction mixture was added water (2 mL), and the resulting mixture was stirred at room temperature for 20 min. It was diluted with ethyl acetate (50 mL), washed with saturated NaHCO3 solution (15 mL) and brine (15 mL), and dried over anhydrous MgSO4. Solvent was removed under vacuum, and the residue was subjected to prep. reverse phase HPLC purification. The correct fraction was concentrated under vacuum and basified with saturated NaHCO3 solution. The precipitating product (11.8 mg, 0.029 mmol, 30.8% yield) was collected as a yellow solid by suction filtration and dried at 50° C. under vacuum. LCMS (M+H)+=405.17. 1H NMR (500 MHz, DMSO-d6) δ: 11.30 (s, 1H), 8.23 (s, 1H), 8.11 (s, 1H), 7.70 (s, 1H), 7.65-7.61 (m, 2H), 7.49-7.42 (m, 2H), 6.98 (d, J=8.0 Hz, 1H), 6.94 (s, 1H), 6.46 (dd, J1=8.7 Hz, J2=1.5 Hz, 1H), 6.19 (br. s, 1H), 3.90 (m, 2H), 3.47 (m, 1H), 3.43 (m, 2H), 1.94 (m, 2H), 1.44 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[OH:11].[C:12]([N:16]1[CH2:19][CH:18]([OH:20])[CH2:17]1)([CH3:15])([CH3:14])[CH3:13].[OH-].[K+]>Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[O:11][CH2:17][CH:18]([OH:20])[CH2:19][NH:16][C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: COc1ccc(O)c(C)c1C
Reactant: CC(C)(C)N1CC(O)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(OCC(O)CNC(C)(C)C)c(C)c1C
Temperature: 140 °C
Yield: 72.5 %

Procedure:
A mixture of 9.1 parts of 2,3-dimethyl-4-methoxyphenol, 6.5 parts of 1-(tert.-butyl)-3-azetidinol and 0.3 part of potassium hydroxide was heated under nitrogen gas at 140° C. for 8 hours with agitation. The reaction product was dissolved in 100 parts of 2N-hydrochloric acid aqueous solution and washed twice with 100 parts of ether. The water layer was made alkaline with 4N-sodium hydroxide aqueous solution, and the resulting crystals were recovered by filtration and dried. Then the crystals were dissolved in 100 parts of ether and decolored. The decolored liquid was concentrated and allowed to cool. As a result 10.2 parts of 1-(2',3'-dimethyl-4'-methoxyphenoxy)-3-(tert.-butylamino)-2-propanol melting at 73° - 75° C were obtained. The yield was 72.5%. The results of infra-red spectrum analysis and nuclear magnetic resonance analysis of the product are as follows: