Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12.[CH3:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=1>>[CH2:13]([O:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]3[CH:9]=[N:10][NH:11][C:3]=23)=[CH:19][CH:20]=1)[CH3:12]
Reactant: Cc1cc(Cl)c2[nH]ncc2n1
Reactant: CCOc1ccc(N)cc1
Product: CCOc1ccc(Nc2cc(C)nc3cn[nH]c23)cc1
Yield: 14 %

Procedure:
7-Chloro-5-methyl-1H-pyrazolo[4,3-b]pyridine (0.5 g, 0.003 mole) was heated at reflux temperature under nitrogen in p-phenetidine for 8 h. The mixture was left to stand at room temperature while a blue/black precipitate formed. This was collected, washed with water and ethyl acetate and the residue, a grey solid, was recrystallized from ethanol with charcoal present to give the required product as an off-white solid (0.11 g, 14%), m.p. 217° C.
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.[CH3:31][C:32]1[C:36](B(O)O)=[C:35]([CH3:40])[O:34][N:33]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:36]4[C:32]([CH3:31])=[N:33][O:34][C:35]=4[CH3:40])=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Reactant: Cc1noc(C)c1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COc1cccc(-c2c(-c3c(C)noc3C)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 110 °C
Yield: 18.4 %

Procedure:
N-{2-Bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (100 mg, 0.191 mmol) (Example 33), (3,5-dimethyl-4-isoxazolyl)boronic acid (40.4 mg, 0.286 mmol), palladium(II) acetate (4.29 mg, 0.019 mmol), xantphos (22.09 mg, 0.038 mmol) and Cs2CO3 (187 mg, 0.573 mmol) were weighed into a round bottom flask. Degassed toluene (2 mL) was added to the mixture which was then heated at 110° C. for 19 h. After cooling to RT, the mixture was filtered through celite and rinsed with ethyl acetate (30 mL) and the combined filtrate concentrated. Purification by chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate in isohexane, afforded the title compound (19 mg). LCMS (A) m/z: 540 [M+1]+, Rt 1.40 min (acidic), Rt 0.94 min (basic).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][C:31]=1[C:39]([O:41][CH2:42][CH3:43])=[O:40]>>[CH2:42]([O:41][C:39]([C:31]1[CH:32]=[C:33]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18]4[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=4[CH:26]=3)[C:10]([F:13])([F:11])[F:12])=[C:4]([Cl:28])[CH:3]=2)[CH:34]=[CH:35][C:30]=1[Cl:29])=[O:40])[CH3:43]
Reactant: CCOC(=O)c1cc(B(O)O)ccc1Cl
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Product: CCOC(=O)c1cc(-c2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)ccc1Cl

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 22, step 3) was reacted with 4-chloro-3-ethoxycarbonylphenylboronic acid to give the title compound as a colorless solid. MS (m/e)=582.3 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:14](=[O:18])[CH2:15][CH2:16]Cl)=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH2:9][CH2:8]2.[I-].[Na+].[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.CCOCC.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:14](=[O:18])[CH2:15][CH2:16][N:30]2[CH2:31][CH2:32][N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH2:9][CH2:8]2
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(C(=O)CCCl)c2c1NC(=O)CC2
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)CCN2CCN(c3ccccc3)CC2)c2c1NC(=O)CC2
Temperature: 40 °C
Reaction time: 1 h

Procedure:
26.8 Grams of 8-methoxy-5-(3-chloropropionyl)-3,4-dihydrocarbostyril and 16.5 g of sodium iodide were dissolved in 200 ml of dimethylformamide and the mixture was stirred at 40° C. for 1 hour. Then 11.1 g triethyl amine and 17.1 g of 4-phenylpiperazine were added to the mixture and stirred at 40° C. for 2 hours additionally. The reaction mixture was concentrted under a reduced pressure to obtain a residue. Then a 5%-sodium hydrogencarbonate aquous solution and ether were added to the residue to obtain crystalline presipitates. The precipitates were collected by filtration and were recrystallized from ethanol to obtain 8-methoxy-5-[1-oxo-3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydrocarbostyril.
Reaction SMILES: [C:1]([C:3](=[C:9]([CH3:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[CH2:17][Mg]Cl.COC1C=C(C=CC=1)CCl.[NH4+].[Cl-]>C1COCC1.CCOCC>[C:1]([CH:3]([C:9]([CH3:10])([CH3:11])[CH2:17][C:16]1[CH:20]=[CH:21][CH:22]=[C:14]([O:13][CH3:12])[CH:15]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: COc1cccc(C[Mg]Cl)c1
Reactant: CCOC(=O)C(C#N)=C(C)C
Agent: COc1cccc(CCl)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)C(C)(C)Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A solution of ethyl 2-cyano-3-methylcrotonate (10.8 g, 0.07 mol) in THF (100 mL) was added dropwise to a stirred ethereal solution of 3-methoxybenzylmagnesium chloride (prepared by adding a solution of 3-methoxybenzyl chloride (9.3 mL, 0.064 mol) in ether (48 mL) to a slurry of Mg (1.7 g, 0.07 mol) in ether (20 mL)). After addition the mixture was stirred at room temperature for a further 2 h then NH4Cl (sat., 50 mL) was added. The solution was partitioned between EtOAc (200 mL) and water (200 mL) and the organic layer separated and dried (MgSO4). The solvent was evaporated and the residue chromatographed on silica gel, eluting with petrol:EtOAc (5:1). The title compound (9.0 g, 51%) was isolated as a colourless oil. 1H NMR (360 MHz, CDCl3) δ 1.10 (3H, s), 1.20 (3H, s), 1.33 (3H, t, J=7.1 Hz), 2.74 (1H, d, J=13.5 Hz), 2.78 (1H, d, J=13.5 Hz), 3.33 (1H, s), 3.81 (3H, s), 4.26 (2H, q, J=7.1 Hz), 6.72-6.82 (3H, m), 7.22 (1H, t, J=7.8 Hz). MS (ES+) 276 (M+1).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([CH:7]([NH:15][CH3:16])[CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1.[CH3:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[CH3:34])[N:30]([CH2:35][C:36]([OH:38])=O)[C:29](=[O:39])[CH:28]=[CH:27]2.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:2]=[CH:3][C:4]([CH:7]([N:15]([CH3:16])[C:36](=[O:38])[CH2:35][N:30]2[C:31]3[C:26](=[CH:25][C:24]([CH3:23])=[C:33]([CH3:34])[CH:32]=3)[CH:27]=[CH:28][C:29]2=[O:39])[CH2:8][N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:5][CH:6]=1
Reactant: Cc1cc2ccc(=O)n(CC(=O)O)c2cc1C
Reactant: CNC(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2ccc(=O)n(CC(=O)N(C)C(CN3CCOCC3)c3ccc(-c4ccccc4)cc3)c2cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.6 %

Procedure:
[1-(4-biphenylyl)-2-(4-morpholinyl)ethyl]methylamine (150 mg, 0.52 mmol) was added to a solution of (6,7-dimethyl-2-oxo-1(2H)-quinolinyl)acetic acid (100 mg, 0.43 mmol), (benzotriazol-1-yloxy) tris(dimethylamino) phosphonium-hexafluorophosphate (BOP) (230 mg, 0.52 mmol) and diisopropylethylamine (280 mg, 2.15 mmol) in dimethylformamide (DMF) (5 mL). The reaction mixture was stirred at room temperature for 3 h, filtered and washed with DMF. The crude was purified by preparative HPLC (YMC CombiPrep ODS-A, 50×20 mm, 20 mL/min, A: acetonitrile B: water, A: 10 to 90% over 10 min, UV detection at 214 nm) to give the title compound (43 mg, 16%), MS (ES) m/e 510 [M+H]+.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])=[N+:2]=[N-:3].[CH3:14][C:15]1[C:20]([C:21]#[CH:22])=[CH:19][CH:18]=[CH:17][N:16]=1.CC1C=C(C=C(N2C=C(C3C=NC=CC=3)N=N2)C=1C)C(O)=O>>[CH3:13][C:12]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N:1]1[CH:22]=[C:21]([C:20]2[C:15]([CH3:14])=[N:16][CH:17]=[CH:18][CH:19]=2)[N:3]=[N:2]1
Reactant: Cc1ccc(C(=O)O)cc1N=[N+]=[N-]
Reactant: C#Cc1cccnc1C
Agent: Cc1cc(C(=O)O)cc(-n2cc(-c3cccnc3)nn2)c1C
Product: Cc1ccc(C(=O)O)cc1-n1cc(-c2cccnc2C)nn1

Procedure:
4-Methyl-3-[4-(2-methyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzoic acid (5:3 mixture with 4-methyl-3-[5-(2-methyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzoic acid) was prepared from 3-azido-4-methyl benzoic acid and 2-methyl-3-ethynyl pyridine in the same manner as 3,4-dimethyl-5-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzoic acid (Example 8).
Reaction SMILES: [CH3:1][C:2]([CH3:38])([CH3:37])[C@H:3]([NH:9][C:10]1[C:15]([F:16])=[CH:14][N:13]=[C:12]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([F:26])[CH:24]=3)[N:19](S(C3C=CC(C)=CC=3)(=O)=O)[CH:18]=2)[N:11]=1)[CH2:4][S:5]([CH3:8])(=[O:7])=[O:6].C[O-].[Na+].[NH4+].[Cl-]>C1COCC1>[CH3:1][C:2]([CH3:38])([CH3:37])[C@H:3]([NH:9][C:10]1[C:15]([F:16])=[CH:14][N:13]=[C:12]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([F:26])[CH:24]=3)[NH:19][CH:18]=2)[N:11]=1)[CH2:4][S:5]([CH3:8])(=[O:7])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H](CS(C)(=O)=O)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[C@@H](CS(C)(=O)=O)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (S)—N-(3,3-dimethyl-1-(methylsulfonyl)butan-2-yl)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-amine, 80a, (0.21 g, 0.37 mmol) in THF (10 mL) was added NaOMe (0.33 mL of 25% solution in MeOH, 1.45 mmol). The solution was stirred at room temperature for 10 minutes, then diluted into aqueous saturated NH4Cl solution. The solvent was removed under reduced pressure and the residue was dissolved in water (10 mL). The aqueous layer was extracted with EtOAc (3×10 mL), dried (MgSO4), filtered and concentrated in vacuo. The product was purified by silica gel chromatography (0-10% MeOH/CH2Cl2 gradient) to afford 109 mg of the desired product as a white solid: 1H NMR (400 MHz, CDCl3) δ 9.38 (s, 1H), 8.53 (d, J=6.9 Hz, 1H), 8.16 (m, 2H), 8.06 (s, 1H), 5.09-4.89 (m, 1H), 3.42-3.31 (m, 1H), 3.11 (m, 1H), 2.84 (s, 3H), 1.00 (s, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 410.19 (M+H) RT=2.03 minutes.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].[C:7]1(=[O:13])[O:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][CH2:11][CH2:10][CH2:9][CH2:8][C:7]([OH:13])=[O:12]
Reactant: Sc1cccs1
Reactant: O=C1CCCCO1
Product: O=C(O)CCCCSc1cccs1

Procedure:
Method in which thiophene-2-thiol is reacted with δ-valerolactone to obtain 5-(2-thienylsulfanyl) valeric acid represented by Chemical Formula [4].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][O:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1>CCOC(C)=O.CCO.CCCCCC.O=[Pt]=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][S:23]([CH3:26])(=[O:24])=[O:25])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCCC#Cc1ccc2c(ccn2-c2ccc(Br)cc2)c1
Agent: O=[Pt]=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CS(=O)(=O)OCCCCCc1ccc2c(ccn2-c2ccc(Br)cc2)c1
Yield: 95 %

Procedure:
432 mg (1 mmol) Methanesulfonic acid 5-[1-(4-bromo-phenyl)-1H-indol-5-yl]-pent-4-ynyl ester in 30 ml EtOAc/EtOH/hexane (1:1:1) was hydrogenated in the presence of 20 mg PtO2, the solution was filtered and evaporated. Column chromatography on silica gel with hexane/EtOAc 4:1 yielded (95%) Methanesulfonic acid 5-[1-(4-bromo-phenyl)-1H-indol-5-yl]-pentyl ester as colorless viscous oil, MS: 435 (M, 1Br).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1I.C[CH2:14][N:15](C(C)C)C(C)C.ClC(OCC1C=CC=CC=1)=O>C1COCC1>[C:14]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7])#[N:15]
Reactant: COC(=O)c1ccc(O)c(I)c1
Reactant: CCN(C(C)C)C(C)C
Agent: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(O)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of 2 (0.376 mol), DIEA (196 mL, 1.13 mol) and THF (200 mL) was added benzyl chloroformate (59.0 mL, 0.414 mol) dropwise. After the reaction solution was stirred at room temperature for 1 hr, the solution was concentrated on a rotovap. The residue was partitioned between sat. NaHCO3 (300 mL) and dichloromethane and the aqueous phase extracted with additional dichloromethane (100 mL×3). The combined dichloromethane layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give product 3 (0.376 mol).
Reaction SMILES: [CH:1]([NH2:3])=O.[NH2:4][C:5]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O>O>[N+:14]([C:11]1[CH:10]=[C:6]2[C:5](=[CH:13][CH:12]=1)[N:4]=[CH:1][NH:3][C:7]2=[O:9])([O-:16])=[O:15]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: NC=O
Solvent: O
Product: O=c1[nH]cnc2ccc([N+](=O)[O-])cc12
Temperature: 155 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
A mixture of formamide (14 g, 0.3 mol) and 2-amino-5-nitrobenzoic acid (9.1 g, 0.05 mol) was heated at 155° C. for 7 h, cooled to RT and stirred overnight. The mixture was diluted with H2O (30 mL) and filtered. The resultant brown solid was dissolved in i-PrOH (300 mL), warmed to reflux, cooled to RT and filtered and dried to yield 6-nitroquinazolin-4(3H)-one, (5.85 g, 61% yield). MS (ESI) m/e (M+H+) 192.0
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:20][CH3:21])[CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:23][CH2:24][C:25]1[C:26](=[O:35])[NH:27][C:28]([CH3:34])=[CH:29][C:30]=1[CH2:31][CH2:32][CH3:33].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:20][CH3:21])[CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:23][CH2:24][C:25]1[C:26](=[O:35])[NH:27][C:28]([CH3:34])=[CH:29][C:30]=1[CH2:31][CH2:32][CH3:33])=[O:9]
Reactant: CCN(c1cc(Cl)cc(C(=O)O)c1C)C1CCN(C)CC1
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Cl)cc(N(CC)C2CCN(C)CC2)c1C
Temperature: 23 °C
Reaction time: 16 h
Yield: 17.1 %

Procedure:
To a stirred solution of 5-chloro-3-[ethyl(1-methylpiperidin-4-yl)amino]-2-methylbenzoic acid (crude material, 1.80 g, 3.26 mmol) and 3-(aminomethyl)-6-methyl-4-propyl-1,2-dihydropyridin-2-one HCl salt (916 mg, 4.24 mmol) in DMSO (10 mL) was added PyBOP (3.10 g, 5.87 mmol) and hunig base (1.20 g, 9.78 mmol). The reaction mixture was stirred at 23° C. for 16 hours. The reaction mixture was quenched with water and resulting precipitate was collected. The solid was purified by silica gel column chromatography (NH—SiO2 Ethylacetate/MeOH=10/1) to give the titled compound as a white solid (264 mg, 17% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.20 (t, J=5.9 Hz, 1H), 7.06 (d, J=2.0 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 5.96 (s, 1H), 4.54 (d, J=5.9 Hz, 2H), 3.02 (q, J=7.0 Hz, 2H), 2.81 (m, 2H), 2.64-2.71 (m, 3H), 2.21-2.27 (s×3, 9H), 1.84-1.94 (m, 2H), 1.55-1.65 (m, 6H), 1.00 (t, J=7.4 Hz, 3H), 0.84 (t, J=7.0 Hz, 3H); MS (ES) [M+H] 473.1, [M+Na] 495.3; HPLC 94.7% purity.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]2=[O:14])[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.[Cl:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[CH:32]=[C:31]([S:36]([CH2:39][C@@H:40]([OH:44])[C:41](O)=[O:42])(=[O:38])=[O:37])[CH:30]=[CH:29]2.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[CH:32]=[C:31]([S:36]([CH2:39][C@@H:40]([OH:44])[C:41]([N:1]1[CH2:2][CH2:3][CH:4]([N:7]3[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]3=[O:14])[CH2:5][CH2:6]1)=[O:42])(=[O:37])=[O:38])[CH:30]=[CH:29]2
Reactant: O=C(O)[C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reactant: O=C1CCN(C2CCNCC2)C(=O)N1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C1CCN(C2CCN(C(=O)[C@H](O)CS(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)C(=O)N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 9.1 %

Procedure:
To a solution of 1-piperidin-4-yl-dihydropyrimidin-2,4(1H,3H)-dione (105 mg) obtained in Example 45e), HOBt (83 mg) and (2S)-3-[(6-chloro-2-naphthyl)sulfonyl]-2-hydroxypropionic acid (170 mg) in DMF (10 mL) was added WSC (105 mg) at room temperature. The mixture was stirred at room temperature for 3 days, and DMF was distilled off under reduced pressure. The residue was diluted with chloroform, washed with an aqueous saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=10/1), and recrystallized from ethanol to obtain the title compound (24 mg, 9%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH:10]=[O:11])=[C:8]([F:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[BH4-].[Na+].O>CO>[Cl:1][C:2]1[C:9]([CH2:10][OH:11])=[C:8]([F:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)c(C=O)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(F)c(CO)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To a solution (10 mL) of 2-chloro-4-fluoro-3-formylbenzonitrile (600 mg) in methanol was added sodium borohydride (136 mg) under ice-cooling, and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was crystallized from hexane-isopropyl ether to give the title compound as a pale-yellow solid (yield: 410 mg).
Reaction SMILES: C(OCC)(=O)C.C(OC(=O)[NH:16][C@H:17]([CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32]CC3C=CC=CC=3)=[CH:28][C:27]=2[O:40]CC2C=CC=CC=2)[CH2:22][CH2:21]1)=[O:19])C1C=CC=CC=1>CO.[Pd]>[NH2:16][C@H:17]([CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=2[OH:40])[CH2:22][CH2:21]1)=[O:19]
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: N[C@H](Cc1ccccc1)C(=O)N1CCC(c2ccc(O)cc2O)CC1
Reaction time: 18 h
Yield: 97.7 %

Procedure:
In a 25 ml round-bottomed flask, 1.23 g of {(R)-1-benzyl-2-[4-(2,4-bis(benzyloxy)phenyl)piperidin-1-yl]-2-oxoethyl}carbamic acid benzyl ester are dissolved in 15 ml of methanol and also 15 ml of ethyl acetate in the presence of 0.25 g of palladium-on-charcoal at 10%. The reaction mixture is stirred for 18 hours under a hydrogen atmosphere. The reaction mixture is filtered. The residue is chromatographed on silica gel (95/5 dichloromethane/methanol). 0.625 g of (R)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-3-phenylpropan-1-one is obtained. Yield=64%.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=C.N1C(C)=CC=CC=1C.C(Cl)Cl.[O:23]1CCOCC1>O.[Os](=O)(=O)(=O)=O>[O:23]=[CH:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: C=CCCCCC(=O)OCC
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Solvent: ClCCl
Solvent: O
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)CCCCC=O
Temperature: 25 °C
Reaction time: 13.5 h

Procedure:
A colorless solution of commercially available ethyl hept-6-enoate (7.000 g; 44.80 mmol) in dioxane (330 ml) and water (110 ml) was treated successively with 2,6-lutidine (9.603 g; 89.61 mmol), a solution of osmium tetroxide (2.5 wt. % in 2-methylpropan-2-ol; 0.56 ml), and NaIO4 (38.335 g; 179.23 mmol). The resulting beige heterogeneous reaction mixture was further stirred at rt, under nitrogen, for 13.5 h. The resulting milky mixture was treated with water (100 ml) and DCM (500 ml). The layers were separated, and the aq. layer was further extracted with DCM (200 ml/150 ml). The mixed slightly yellow organic layers were then washed with brine (200 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure to give crude ethyl 6-oxohexanoate as a dark-yellow/brown oil which was directly used for the next step without additional purification.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[C:7]1[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][CH:12]=1>[Pd].CCO.O1CCOCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]1[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1=COC(c2cccnc2Oc2ccc(Nc3ccccn3)cc2)CC1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: c1ccc(Nc2ccc(Oc3ncccc3C3CCCCO3)cc2)nc1
Reaction time: 24 h

Procedure:
A mixture of (±)-N-(4-(3-(3,4-dihydro-2H-pyran-2-yl)pyridin-2-yloxy)phenyl)pyridin-2-amine (233 mg, 0.675 mmol) and palladium on carbon (wet) (71.8 mg, 0.067 mmol) in EtOH/dioxane was placed under an atmosphere of hydrogen gas and stirred for 24 hours. The mixture was then filtered through a cake of celite, washing with MeOH. The filtrate was concentrated and purified by silica gel chromatography, 10-100% acetone/hexanes, to give the title compound as a racemic mixture. MS (ESI, pos. ion) m/z: 348.0 (M+1). IC50 (uM) 0.149.
Reaction SMILES: C[N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:13]([CH2:14][CH2:15][O:16][CH2:17][CH3:18])[C:12]3[CH:19]=[CH:20][CH:21]=[CH:22][C:11]=3[N:10]=2)[CH2:4][CH2:3]1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:27]([O:26][C:24]([N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:13]([CH2:14][CH2:15][O:16][CH2:17][CH3:18])[C:12]3[CH:19]=[CH:20][CH:21]=[CH:22][C:11]=3[N:10]=2)[CH2:4][CH2:3]1)=[O:25])[CH3:28]
Reactant: CCOC(=O)Cl
Reactant: CCOCCn1c(N2CCCN(C)CC2)nc2ccccc21
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOCCn1c(N2CCCN(C(=O)OCC)CC2)nc2ccccc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Combine 1-methyl-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (1.79 g, 5.9 mmol) and ethyl chloroformate (0.75 mL, 7.8 mmol) in toluene (20 mL). Heat to 80° C. After 2 hours, cool the reaction mixture and dilute with ethyl acetate. Extract with a saturated aqueous sodium bicarbonate solution, dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 1-ethoxycarbonyl-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf=0.87 (silica gel, dichloromethane/methanol, 90/10).