Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:6]=1[C:7]([NH:9][CH3:10])=[O:8])([CH3:3])[CH3:2].O.C(O)(=O)C>C(O)C.[Fe]>[NH2:15][C:12]1[CH:13]=[CH:14][C:5]([S:4][CH:1]([CH3:3])[CH3:2])=[C:6]([CH:11]=1)[C:7]([NH:9][CH3:10])=[O:8]
Reactant: CNC(=O)c1cc([N+](=O)[O-])ccc1SC(C)C
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CNC(=O)c1cc(N)ccc1SC(C)C
Temperature: 115 °C
Yield: 93 %

Procedure:
A suspension of 16B (1.2 g, 4.7 mmol) in a mixture of ethanol (30 mL), water (5 mL), and acetic acid (3.3 mL, 5.8 mmol) was heated by a 115° C. oil bath. Iron powder (1.80 g, 32.2 mmol) was added portionwise over 1 h. The reaction mixture was cooled to rt, filtered, and washed with ethyl acetate. Sodium bicarbonate solution was added until it was basic. The reaction mixture was extracted with ethyl acetate (3×) and the combined organics were washed with saturated sodium bicarbonate and brine, dried (MgSO4), and concentrated in vacuo to give 16C (0.98 g, 93%) as a beige solid. MS (ESI) m/z 225.1 (M+H)+.
Reaction SMILES: OC1C=C(C=CC=1)C=O.[NH:10]1CC[CH2:13][CH2:12][CH2:11]1.[N:16]1([CH2:22][C:23]2[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.ClCCCN>>[N:16]1([CH2:22][C:23]2[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[NH2:10][CH2:11][CH2:12][CH2:13][O:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[CH2:22][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C1CCNCC1
Agent: NCCCCl
Agent: O=Cc1cccc(O)c1
Agent: Oc1cccc(CN2CCCCC2)c1
Product: NCCCOc1cccc(CN2CCCCC2)c1

Procedure:
First, 3-piperidinomethylphenol is synthesized from 3-hydroxybenzaldehyde and piperidine. The 3-piperidinomethylphenol is then reacted with 3-chloropropylamine to produce N-[3-(3-aminopropoxy)benzyl]piperidine, which is reacted with acetoxyacetyl chloride to obtain N-[3-(3-piperidinomethylphenoxy)propyl]hydroxyacetamide. Separately, tranexamic acid and carbobenzoxy chloride are reacted to produce N-carbobenzoxyaminomethylhexanecarboxy chloride. The two compounds thus obtained are then reacted first to afford N-{3-[3-(1-piperidinomethyl)phenoxy]propyl}-2-(N-carbobenzoxy-aminomethylhexanecarboxy)acetamide. This compound is then reduced into 2-(aminomethylcyclohexanecarboxy)-N-(3-[3-(piperidinomethyl)phenoxy]propyl}acetamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Li+].[OH-].O1CCOCC1.Cl>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCc1ccc2cnn(-c3ccc(F)cc3)c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCCc1ccc2cnn(-c3ccc(F)cc3)c2c1
Temperature: 80 °C
Yield: 96.7 %

Procedure:
A mixture of ethyl 4-(1-(4-fluorophenyl)-1H-indazol-6-yl)butanoate (2, R1=4-Fluorophenyl) (17.95 g, 55.0 mmol), LiOH (3.95 g, 165 mmol), 1,4-dioxane (150 mL) and water (30 mL) was warmed in an oil bath heated to about 80° C. for about 16 h. The mixture was cooled to rt then concentrated under reduced pressure to give a solid. The material was dissolved in water (200 mL) then the mixture was acidified to about pH 1 with hydrochloric acid (6 N) (30 mL, 180 mmol). The mixture was extracted twice with EtOAc (150 mL, then 50 mL) then the combined organic solutions were dried over MgSO4, filtered and the filtrate concentrated under reduced pressure to yield 4-(1-(4-fluorophenyl)-1H-indazol-6-yl)butanoic acid (3, R1=4-Fluorophenyl) (15.87 g, 97%); LC/MS, method 3, Rt=2.19 min, MS m/z 299 (M+H)+. 1H NMR (400 MHz, DMSO) δ 12.03 (s, 1H), 8.30 (d, J=0.9 Hz, 1H), 7.84-7.74 (m, 3H), 7.57 (s, 1H), 7.48-7.39 (m, 2H), 7.13 (dd, J=8.3, 1.2 Hz, 1H), 2.79-2.72 (m, 2H), 2.26-2.22 (m, 2H), 1.91-1.81 (m, 2H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[Cl:10][C:11]1[C:16](B(O)O)=[CH:15][CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[Na+].[Na+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[H+].[B-](F)(F)(F)F>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].O.O1CCOCC1>[Cl:10][C:11]1[C:16]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=2)=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: COc1cc(I)ccn1
Reactant: OB(O)c1cccnc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2cccnc2Cl)ccn1
Temperature: 100 °C

Procedure:
To 4-iodo-2-methoxypyridine (834 mg, 3.55 mmol), 2-chloropyridine-3-boronic acid (838 mg, 5.32 mmol), Na2CO3 (1.13 g, 10.7 mmol), Pd(OAc)2 (40 mg, 0.18 mmol) and P(tBu)3.HBF4 (104 mg, 0.36 mmol) was added dioxane (12 mL) and water (4 mL). The mixture was heated overnight at 100° C. in a sealed tube. The resulting mixture was diluted with EtOAc and extracted with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The resulting solid was triturated with MeOH and dried to yield the title compound. MS m/z=221 [M+1]+. Calc'd for C1lH9ClN2O: 220.66.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[OH:28][C@H:29]([CH2:34][CH3:35])[CH2:30][C:31](O)=[O:32]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][C@H:29]([OH:28])[CH2:34][CH3:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: CC[C@@H](O)CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: CC[C@@H](O)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (56 mg, 52%), MS (ISP) m/z=431.5 [(M+H)+], mp 146° C., was prepared in accordance with the general method of example 5 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and (R)-3-hydroxy-pentanoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][CH2:7][CH2:8][O:9][C:10]([C:12]1[N:13]=[C:14]([C:43]([F:46])([F:45])[F:44])[N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:42])[CH2:22][C@H:23]([NH:34]C(OC(C)(C)C)=O)[CH2:24][C:25]3[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=3[F:33])[CH2:17][C:16]=12)=[O:11])=[O:5])[CH3:2].[ClH:47]>C(OCC)(=O)C>[ClH:47].[CH2:1]([O:3][C:4]([O:6][CH2:7][CH2:8][O:9][C:10]([C:12]1[N:13]=[C:14]([C:43]([F:44])([F:45])[F:46])[N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:42])[CH2:22][C@H:23]([NH2:34])[CH2:24][C:25]3[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=3[F:33])[CH2:17][C:16]=12)=[O:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)OCCOC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)OCCOC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F)CC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid (1-ethoxycarbonyloxy)-ethyl ester 34a (0.26 g, 0.39 mmol) and 5 mL of ethyl acetate were added into the reaction flask. A solution of 6.5 N hydrochloric acid in 3 mL of ethyl acetate was then added to the flask. The reaction mixture was stirred at room temperature for 6 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid (1-ethoxycarbonyloxy)-ethyl ester hydrochloride 34 (0.2 g, yield 85%) as a white solid.
Reaction SMILES: Cl.[CH:2]([O:5][C:6]1[CH:7]=[C:8]([C@@H:12]([NH2:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1)([CH3:4])[CH3:3].[Cl:15][C:16]1[CH:36]=[CH:35][C:34]([O:37][C@@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])=[CH:33][C:17]=1[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28](O)=[O:29])=[CH:25][CH:26]=2)[C:21]([CH3:31])=[C:20]1[CH3:32]>>[CH:2]([O:5][C:6]1[CH:7]=[C:8]([C@@H:12]([NH:14][C:28]([C:24]2[CH:23]=[C:22]3[C:27](=[CH:26][CH:25]=2)[N:19]([CH2:18][C:17]2[CH:33]=[C:34]([CH:35]=[CH:36][C:16]=2[Cl:15])[O:37][C@@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])[C:20]([CH3:32])=[C:21]3[CH3:31])=[O:29])[CH3:13])[CH:9]=[CH:10][CH:11]=1)([CH3:4])[CH3:3]
Reactant: CC(C)Oc1cccc([C@H](C)N)c1
Reactant: COC(=O)[C@H](C)Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Agent: Cl
Product: COC(=O)[C@H](C)Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(OC(C)C)c4)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropoxyphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride the (S)-1-(2-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C(Cl)Cl.N1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:27]([O:29][CH2:30][CH3:31])[CH3:28]>>[CH2:27]([O:29][CH:30]([O:5][C:1](=[O:6])[C:2]([CH3:4])=[CH2:3])[CH3:31])[CH3:28]
Reactant: CCOCC
Reactant: C=C(C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C(C)C(=O)OC(C)OCC
Yield: 96 %

Procedure:
In a flask having four inlets, 15.1 grams (0.21 mols) of ethylvinylehter and 20 grams (0.23 mols) of methacrylic acid were dissolved into 200 ml of methylene chloride. Then, 0.53 grams (0.0021 mols) of p-toluenesulfonic acid pyridine salt was added to the mixture, and stirred for complete dissolution of p-toluenesulfonic acid pyridine salt into the mixture. The resultant solution was stood at room temperature for six hours. Then, 200 ml of diethylether was added into the solution. The resultant solution was washed three times with 2.5% aqueous sodium hydroxide, and further six times with water. Then, an ether layer was dehydrated with magnesium sulfate. After filtering magnesium sulfate out, a methylene chloride layer was evaporated. As a result, there was obtained 31.8 grams of 1-ethoxyethylmethacrylate. The yield was 96%. With respect to a structure of the target material, IR was measured with an analyzer, IR-470 model available from Shimazu Seisakusho, and 1H-NMR was measured with an analyzer, AMX-400 model available from Bruker Instruments.
Reaction SMILES: O1CCOCC1.Cl[C:8]1[CH:13]=[C:12]([CH:14]([S:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[C:11]([Cl:31])=[CH:10][N:9]=1.[NH2:32][CH2:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36]>CCCCCC>[Cl:31][C:11]1[C:12]([CH:14]([S:23][C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:13][C:8]([NH:32][CH2:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])=[N:9][CH:10]=1
Reactant: CC(C)(CN)CO
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Solvent: CCCCCC
Solvent: C1COCCO1
Product: CC(C)(CO)CNc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Temperature: 25 °C
Yield: 90 %

Procedure:
A dioxane (1.5 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine (191 mg, 0.458 mmol) obtained in Example 54 and 3-amino-2,2-dimethylpropan-1-ol (515 mg, 5.00 mmol) was heated at 120° C. for 3 days in a sealed tube. The reaction mixture was cooled to room temperature and then, concentrated under reduced pressure. Ethyl acetate was added to the residue. The resulting mixture was washed sequentially with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated under reduced pressure to give the title compound (199 mg, 0.412 mmol, 90%) as an amorphous substance.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([CH2:23][CH:24]=O)=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[N:4]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[N:3]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([CH2:23][CH2:24][N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[N:4]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[N:3]=1
Reactant: C1CCNC1
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(CC=O)ccn45)cccc32)n1
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(CCN6CCCC6)ccn45)cccc32)n1

Procedure:
Prepared according to procedure of Example 72 from N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-oxoethyl)imidazo[1,2-a]pyridine-3-carboxamide (Example 72, Steps A-B) and pyrrolidine. MS (ES+APCI) m/z=494 (M+H) detected.
Reaction SMILES: Br.C(O)(=O)C.C([O:13][C:14]1[C:32]([O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:31][C:17]([C:18]([NH:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=2)=[O:19])=[CH:16][C:15]=1[Cl:40])C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[Cl:40][C:15]1[CH:16]=[C:17]([CH:31]=[C:32]([O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[C:14]=1[OH:13])[C:18]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=1)=[O:19]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(OCc3ccccc3)c(OC3CCCCC3)c2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(O)c(OC3CCCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
45% hydrogen bromide in acetic acid (26 μL, 0.20 mmol) was added to a stirring mixture of methyl 4-(4-(benzyloxy)-3-chloro-5-(cyclohexyloxy)benzamido)benzoate (6) (20 mg, 40 μmol) in TFA (3 mL) and the mixture was stirred at RT for 1 h. The mixture was partitioned between water (15 mL) and EtOAc (15 mL) and the phases were separated. The organic solution was washed with water (10 mL), dried over MgSO4 and the solvent was removed in vacuo to give methyl 4-(3-chloro-5-(cyclohexyloxy)-4-hydroxybenzamido)benzoate (7) (16 mg, 92%): m/z 402 [M−H]− (ES−); 1H NMR (400-MHz, DMSO-d6) δ: 10.37 (1H, s), 7.94 (4H, m), 7.68 (1H, d), 7.54 (1H, d), 4.40 (1H, m), 3.84 (3H, s), 1.94 (2H, m), 1.83-1.73 (2H, m), 1.57-1.45 (3H, m), 1.40-1.20 (3H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([C:22]2[CH:23]=[C:24]([C:28]3[O:32][C:31]([C:33](=O)[CH3:34])=[CH:30][CH:29]=3)[CH:25]=[CH:26][CH:27]=2)=[O:21])[CH2:15][CH2:14]1.N1CCCCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[C:33](/[C:31]1[O:32][C:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([C:20]([N:16]3[CH2:17][CH2:18][CH2:19][N:13]([CH3:12])[CH2:14][CH2:15]3)=[O:21])[CH:23]=2)=[CH:29][CH:30]=1)\[CH3:34]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: CC(=O)c1ccc(-c2cccc(C(=O)N3CCCN(C)CC3)c2)o1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: C/C(=C1\C(=O)Nc2ccc(Cl)cc21)c1ccc(-c2cccc(C(=O)N3CCCN(C)CC3)c2)o1
Yield: 42 %

Procedure:
A solution of 5-chlorooxindole (668 mg, 4 mmol), 1-(5-(3-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)ethanone (1.7 g of oil) and piperidine (394 μL, 4 mmol) in toluene (15 mL) was heated at reflux with a Dean-Stark receiver for 24 hours. After evaporation of the solvent, purification by silica column chromatography (methanol gradient in dichloromethane, 0 to 5% vol) gave (E)-5-chloro-3-(1-(5-(3-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)ethylidene)indolin-2-one (800 mg) as a E:Z mixture. LCMS (ES): m/z 476 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([N:15]([CH2:20][CH2:21][CH3:22])[C:16](=[O:19])[CH2:17][CH3:18])[C:12]([C:23]#[N:24])=[CH:11][C:10]=1[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1.[H-].[Na+]>>[NH2:24][C:23]1[C:12]2[C:13](=[N:14][C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[C:10]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[CH:11]=2)[N:15]([CH2:20][CH2:21][CH3:22])[C:16](=[O:19])[C:17]=1[CH3:18]
Reactant: CCCN(C(=O)CC)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Agent: [H-]
Agent: [Na+]
Product: CCCn1c(=O)c(C)c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc21

Procedure:
Using the procedure described in EXAMPLE 40, the product of Step A was reacted with NaH to afford the title compound. HPLC/MS: 472.0 (M+1), 474.0 (M+3); Rt=4.43 min.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH:25]([OH:26])[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18]4=[O:27])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.CCN(CC)CC.[C:37](Cl)(=[O:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>>[F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:25](=[O:26])[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:18]4[O:27][C:37](=[O:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CCCCCCCCCC(=O)Cl
Reactant: O=C1c2ccccc2C(O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(=O)OC1c2ccccc2C(=O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of 2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl-2,3-dihydro-3-hydroxy-1H-isoindol-1-one Et3N (1.2 ml, 8.8 mmol) followed by decanoyl chloride at 0° C. under nitrogen. After stirring for 1 h in the cooling bath, the solvent was removed using a stream of nitrogen. The remaining residue was diluted with EtOAc and the precipitated triethylamine hydrochloride was filtered off. The filtrate was concentrated and the remaining oil was flushed through alumina with ether to give 1.6 g (83% of the desired product as a yellow oil.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:23][CH2:22]1.N>C(OCC)(=O)C.CO.C1CCCCC1>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH:30]2[CH2:31][CH2:32][N:33]([C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:34][CH2:35]2)[CH2:23][CH2:22]1
Reactant: CN1CCN(CCCC2CCNCC2)CC1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Agent: N
Solvent: CO
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CN1CCN(CCCC2CCN(C(=O)N3c4ccccc4C(=O)Nc4cccnc43)CC2)CC1
Yield: 17 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 4-[3-(4-methyl-1-piperazinyl)propyl]piperidine in a yield of 17% of theory. Colourless crystals, m.p. 213°-214° C.; Rf 0.25 (Merck DC ready-made TLC plates, silica gel 60 F254 ; eluant: ethyl acetate/methanol/cyclohexane/conc. ammonia 80/10/10/1 v/v/v/v).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]([F:27])([F:26])[F:25])[C:5]2[N:6]([N:9]=[C:10]([CH2:12][CH2:13][C:14]3[NH:18][N:17]=[C:16]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:15]=3)[N:11]=2)[C:7]=1[CH3:8].[CH:28]1(B(O)O)[CH2:30][CH2:29]1.N1C=CC=CC=1.C(N(CC)CC)C>O1CCCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]([F:25])([F:27])[F:26])[C:5]2[N:6]([N:9]=[C:10]([CH2:12][CH2:13][C:14]3[N:15]=[C:16]([N:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)[N:17]([CH:28]4[CH2:30][CH2:29]4)[N:18]=3)[N:11]=2)[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)cc(C(F)(F)F)c2nc(CCc3nc(N4CCCC4)n[nH]3)nn12
Reactant: OB(O)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(Cl)cc(C(F)(F)F)c2nc(CCc3nc(N4CCCC4)n(C4CC4)n3)nn12
Temperature: 100 °C
Yield: 14.5 %

Procedure:
A mixture of 6-chloro-5-methyl-2-(2-(3-(pyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl)ethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine (30 mg, 75.0 μmol, Eq: 1.00), cyclopropyl-boronic acid (19.3 mg, 225 μmol, Eq: 3), copper (II) acetate (27.3 mg, 150 μmol, Eq: 2), molecular sieves, pyridine (47.5 mg, 48.6 μl, 600 μmol, Eq: 8), triethylamine (38.0 mg, 52.3 μl, 375 μmol, Eq: 5) in tetrahydrofuran (4 ml) was heated under air in a sealed tube for 2 h at 100° C. The mixture was filtered and concentrated to an oil. Water was added and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and then concentrated. The mixture was separated by preparative HPLC to give the product (4.8 mg, 14.5%) as a colorless oil. MS: m/z=440.2 (M+H+)
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCCCCCC=O
Reactant: CCNCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCCCCN(CC)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
Dissolve 50.90 ml (0.5 moles) diethylamine and 57.10 g (0.5 mole) heptaldehyde in 500 ml methanol and stir at room temperature for one hour. Slowly add 31.42 g sodium cyanoborohydride in 500 ml methanol to the stirred reaction mixture. Add glacial acetic acid to the reaction mixture until pH=6. Stir at room temperature overnight. Concentrate reaction mixture volume to 300 ml and then add 500 ml distilled water. Add concentrated hydrochloric acid until pH=1. Extract with 5×250 ml methylene chloride. Evaporate organic solvent and then dissolve the residue in 400 ml 0.1N HCl. Wash aqueous solution with 3×200 ml diethyl ether and then add 2N NaOH until solution is basic (pH=12). Extract with 3×200 ml diethyl ether. Dry over MgSO4, filter and evaporate, the distill in vacuo to obtain 46.0 g (53.7%) title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:27]=[CH:28][CH:29]=2)[CH2:11][N:12]([CH2:25][CH3:26])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[CH:4][N:3]=1.[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[CH2:25]([N:12]([CH2:11][C:10]1[CH:27]=[CH:28][CH:29]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:30][CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)[N:7]=2)[CH:9]=1)[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:26]
Reactant: NCCc1ccc(O)cc1
Reactant: CCN(CCCNC(=O)c1ccccc1)Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CCN(CCCNC(=O)c1ccccc1)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 44 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 510.