Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C([S:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])[CH2:8]/[C:7]/1=[CH:25]\[C:26]1[N:30]=[CH:29][N:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[N:27]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[ClH:1].[CH:15]1([C:13](=[O:14])[CH:12]([N:9]2[CH2:10][CH2:11][CH:6]([SH:5])/[C:7](=[CH:25]/[C:26]3[N:30]=[CH:29][N:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[N:27]=3)/[CH2:8]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH2:17][CH2:16]1
Reactant: COC(=O)Cn1cnc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2SC(C)=O)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cn1cnc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)n1
Yield: 74.3 %

Procedure:
Following a procedure similar to that described in Example 151, (E)-4-(acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-{[1-(methoxycarbonylmethyl)-1H-1,2,4-triazol-3-yl]methylidene}piperidine hydrochloride (820 mg) was treated with potassium carbonate and the crude product was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024N hydrochloric acid, 30/70, v/v) to afford the title compound (560 mg, yield: 74%) as a colourless amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](O)=[O:23]>>[CH2:10]([N:5]1[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:22]([C:18]2[S:17][CH:21]=[CH:20][CH:19]=2)=[O:23])[N:3]=[CH:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Reactant: O=C(O)c1cccs1
Product: NC(=O)c1c(NC(=O)c2cccs2)ncn1Cc1ccccc1
Yield: 60 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 17, using 2.14 g (9.99 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide prepared in the same manner as in Reference Example 2 and 2-thiophenecarboxylic acid instead of 3-pyridylacetic acid hydrochloride to obtain 1.97 g of 1-benzyl-4-(2-thienylcarbonylamino)-5-imidazolecarboxamide (yield 60%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:34][C:33](=[O:35])[NH:32][N:31]=2)=[CH:26][CH:25]=1.[H-].[Na+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:35][C:33]1[CH:34]=[C:30]([C:27]2[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=2)[NH:31][N:32]=1
Reactant: O=C1CC(c2ccncc2)=NN1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(-c4ccncc4)[nH]n3)ncnc2cc1OCCCN1CCOCC1
Yield: 47.6 %

Procedure:
Using an analogous procedure to that described for Example 9, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (200 mg, 0.59 mmol), (prepared as described for the starting material in Example 2), was reacted with 3-(4-pyridyl)-4,5-dihydro-1H-pyrazol-5-one (240 mg, 1.5 mmol) in the presence of sodium hydride (59 mg, 1.5 mmol, prewashed with THF) in DMF (3 ml) to give 6-methoxy-7-(3-morpholinopropoxy)-4-(5-(4-pyridyl)pyrazol-3-yloxy)quinazoline (130 mg, 48%).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1.[BH4-].[Na+].Cl>C1COCC1>[OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1
Reactant: COC(=O)C1CCC(=O)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1CCC(O)C1
Temperature: 23 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A solution of methyl 3-oxocyclopentanecarboxylate (9.58 g, 67.5 mmol) in THF (100 ml) was added to a slurry of sodium borohydride (3.8 g, 100 mmol) in THF (100 ml). The mixture was stirred at 23° C. for 2 h, cooled to 0° C. and acidified to pH 6 with 1M hydrochloric acid. The mixture was extracted with EtOAc (2×100 ml) and the organic extracts were washed with water and saturated sodium chloride (100 ml each). The extracts were dried and the solvent was evaporated in vacuo to give the title compound as a colorless liquid, 6.66 g (68% yield), (a mixture of two isomers); ir (liq.) νmax : 3450, 1725 cm-1 : 1Hmr (CDCl3) δ: 4.30 (m, 1H, H-3), 3.70-3.67 (2×s, 3H, OMe), 2.9 (m, 1H, H-1), 2.8 (s, 1H, OH) and 2.3-1.6 ppm (m, 6H, CH2).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][CH2:13]I)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[N:15]1([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=2[N:29]=[CH:28][CH:27]=[CH:26]3)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][CH2:13][N:18]3[CH2:19][CH2:20][N:15]([C:21]4[CH:22]=[CH:23][CH:24]=[C:25]5[C:30]=4[N:29]=[CH:28][CH:27]=[CH:26]5)[CH2:16][CH2:17]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: c1cnc2c(N3CCNCC3)cccc2c1
Reactant: COc1cccc2c(CCI)coc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1cccc2c(CCN3CCN(c4cccc5cccnc45)CC3)coc12

Procedure:
A mixture of 2-(7-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg. 1 mmol) (obtained by the above mentioned process) and 8-piperazino quinoline (213 mg, 1 mmol) was heated at 120° C. in DMSO in the presence of N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. Afterwards, the reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous MgSO4 and concentrated to dryness. The dark colored low melting solid was purified by silica-gel column chromatography by initially eluting it with 70% ethyl acetae:hexane and then with 5% methanol:ethyl acetate. 8-{4-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline was isolated as a dark brown low melting solid. Yield: (HCl salt) 90 mg (21%); (M+H): 388; 1H NMR: δ□11.9 (bs, 1H), 9.2 (d, 1H), 9.0 (bs 1H), 8.2 (m, 2H), 7.9 (s1H), 7.84 (m, 2H), 7.45 (d, 1H), 7.21 (t, 1H), 6.98 (d, 1H), 4.01 9s, 3H), 3.77 (m, 4H), 3.67 9m, 2H), 3.59 (m, 4H), 3.3 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([NH:16][C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=2)=[O:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][NH:19][C:17]([NH:16][C:7]2[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=2)=[O:18])=[CH:22][CH:23]=1
Reactant: CC(C)(C)c1cc(NC(=O)NCc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)c1cc(NC(=O)NCc2ccc(N)cc2)cc(C(C)(C)C)c1O
Yield: 60 %

Procedure:
In a 100 ml autoclave, 0.55 g (1.38 mmole) of N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)methyl]-urea is dissolved in a 2/1 mixture of ethanol and ethyl acetate, in the presence of 10% Pd/C. After hydrogenation for one and a half hours at 20° C., under 20 PSI, the mixture is filtered on celite and the filtrate is concentrated under vacuum. The evaporation residue is diluted in 20 ml of diethyl ether and the expected product crystallizes spontaneously. The crystals are filtered out and rinsed with 20 ml of diethyl ether. A white powder is obtained with a yield of 60% (0.31 g). Melting point: 194-195° C.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[C:9](O)(=[O:13])[C:10]([CH3:12])=[CH2:11]>>[CH3:11][CH:10]1[CH2:12][C:3]2[C:4](=[O:8])[CH2:5][CH2:6][CH2:7][C:2]=2[NH:1][C:9]1=[O:13]
Reactant: C=C(C)C(=O)O
Reactant: NC1=CC(=O)CCC1
Product: CC1CC2=C(CCCC2=O)NC1=O

Procedure:
Prepared analogously to Example G from 1-amino- cyclohexen-3-one and methacrylic acid in an autoclave for a period of one hour at 180° C. Recrystallisation is from methanol and subsequently from a mixture of ethyl acetate/ethanol (3:1).
Reaction SMILES: [C:1]([NH:14][O:15][C:16]([C:18]1[CH:43]=[CH:42][C:21]([CH2:22][N:23]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:20][CH:19]=1)=O)(=[NH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>N1C=CC=CC=1>[F:40][C:38]([F:41])([F:39])[C:35]1[CH:34]=[CH:33][C:32]([CH2:31][N:23]([CH2:22][C:21]2[CH:20]=[CH:19][C:18]([C:16]3[O:15][N:14]=[C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:13]=3)=[CH:43][CH:42]=2)[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:37][CH:36]=1
Reactant: CCCCCCCCCCCC(=N)NOC(=O)c1ccc(CN(Cc2ccc(C(F)(F)F)cc2)C(=O)OC(C)(C)C)cc1
Solvent: c1ccncc1
Product: CCCCCCCCCCCc1noc(-c2ccc(CN(Cc3ccc(C(F)(F)F)cc3)C(=O)OC(C)(C)C)cc2)n1
Yield: 71 %

Procedure:
A solution of tert-butyl 4-{[(dodecanimidoylamino)oxy]carbonyl}benzyl[4-(trifluoromethyl)benzyl]carbamate in pyridine was stirred under inert atmosphere at 120° C. for 4 h. The resulting brown solution was evaporated (under high vacuum) and the resulting oil was purified by column chromatography over silica gel (AcOEt/c-Hex 20/80) to give the title compound as a colorless oil (50 mg, 71%). 1H NMR (CDCl3, 300 MHz) δ 8.00 (d, J=8.1 Hz, 2H), 7.51 (d, J=8.1 Hz, 2H), 7.35-7.14 (m, 4H), 4.43 (s, 2H), 4.35 (s, 2H), 2.71 (t, J=7.5 Hz, 2H), 1.80-1.65 (m, 2H), 1.41 (s, 9H), 1.36-1.12 (m, 16H), 0.89 (t, J=7.0 Hz, 3H)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][OH:12])=[CH:7][C:6]=2[CH:13]=1.[C:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)#[N:15].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[OH:12][CH2:11][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([C:19]3[CH:20]=[CH:21][C:16]([C:14]#[N:15])=[CH:17][CH:18]=3)=[CH:13][C:6]=2[CH:7]=1
Reactant: OCCc1cc2cc(Br)ccc2o1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: N#Cc1ccc(-c2ccc3oc(CCO)cc3c2)cc1
Temperature: 25 °C
Yield: 74.8 %

Procedure:
The product from Example 4A (241 mg, 1.0 mmol), 4-cyanophenylboronic acid (221 mg, 1.5 mmol), tetrakis(triphenylphosphine) palladium (0) (57.5 mg, 0.05 mmol), 2-(dicyclohexyl phosphino)biphenyl (35.0 mg, 0.10 mmol), and sodium carbonate (160 mg, 1.5 mmol) were combined in 1,2-dimethoxyethane (16 mL) and water (6 mL) and heated at 80° C. overnight. The mixture was allowed to cool to room temperature and diluted with ethyl acetate (30 mL). The mixture was washed with 5% NaHCO3, 25% brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography to provide 197 mg (75%) of the title compound. An analytical sample was crystallized from diethyl ether; mp; MS-DCl-NH3: 281 (M+NH4)+; 1H-NMR (CDCl3) δ 7.68 (5H, m), 7.51 (1H, d, J=8.5Hz), 7.44 (1H, dd, J=8.5, 1.9 Hz), 6.57 (1H, s), 4.02 (2H, q, J=5.8 Hz), 3.07 (2H, t, J=5.8Hz) 1.70 (1H, t, J=5.8Hz), 13C-NMR (CDCl3) δ 156.9, 154.6, 145.8, 133.9, 132.2, 129.3, 127.6, 122.8, 119.0, 118.8, 111.2, 110.2, 103.7, 60.7, 32.3.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)[S:5][N:4]=1.[C:14](=O)([O-])[O-].[K+].[K+].Cl.Cl.CCO>C(O)=O.C=O.C(O)(C)C.ClCCl>[CH3:2][C:3]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([CH3:14])[CH2:9]2)[S:5][N:4]=1
Reactant: Cc1nsc(C2CCCNC2)n1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O=CO
Solvent: CC(C)O
Product: Cc1nsc(C2CCCN(C)C2)n1

Procedure:
A solution of 12a (400 mg, 1.82 mmol) in formic acid (3 mL) and 37% formaldehyde (3 mL) was heated to 85° C. for 30 minutes. The cooled mixture was slowly added to a rapidly stirred mixture of saturated potassium carbonate (15 mL) and dichloromethane (20 mL). The aqueous layer was extracted again (3×20 mL) with dichloromethane. The organic layer was concentrated and the residue chromatographed over silica gel (6 g) with 8% methanol in dichloromethane to provide 190 mg of clear, pale amber oil. The free base was converted to the HCl salt in isopropanol by the addition of excess HCl-EtOH. The resulting solution was concentrated and the residue was crystallized from isopropanol-ethyl acetate (1:3) to afford 13 (100 mg) as a white solid. An analytical sample was obtained by recrystallization twice more from isopropanol-ethyl acetate. MS (ESI) m/z 198 [M+1]+. 1H NMR (CDCl3) δ 1.55-1.70 (m, 1H), 1.90-2.05 (m, 2H), (bd, 1H), 2.58 (s, 3H), 2.77 (s, 3H), 2.95 (bs, 1H), 3.15-3.26 (m, 1H), 3.41-3.44 (d, 1H), 3.71-3.74 (d, 1H), 3.83 (t, 1H), 10.87 (bs, 1H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:18]=[CH:17]3)=[CH:10][C:9]=1[CH3:29].Cl[CH2:31][C:32]1[C:33]([C:40]2[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:47])=[N:34][O:35][C:36]=1[CH:37]([CH3:39])[CH3:38].O>CN(C)C=O>[Cl:46][C:45]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:47])[C:40]=1[C:33]1[C:32]([CH2:31][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:18]=[CH:17]4)=[CH:10][C:9]=2[CH3:29])=[C:36]([CH:37]([CH3:39])[CH3:38])[O:35][N:34]=1
Reactant: CCOC(=O)c1ccc2cc(-c3ccc(O)c(C)c3)ccc2n1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)c(C)c3)ccc2n1
Yield: 21.7 %

Procedure:
Cesium carbonate (54.9 mg, 168.6 μmol) was added to ethyl 6-(4-hydroxy-3-methylphenyl)-2-quinolinecarboxylate (47.1 mg, 153.3 μmol) and 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (51.3 mg, 168.6 μmol) in N,N-dimethylformamide (3.1 mL) at room temperature. The resulting suspension was stirred for twenty hours, then water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 3:7 ethyl acetate:hexanes to give 19.1 mg (22%) of ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-3-methylphenyl]-2-quinolinecarboxylate as an oil. 1H NMR (400 MHz, d6-DMSO): δ 8.56 (d, J=9 Hz, 1H), 8.28 (s, 1H), 8.19-8.09 (m, 3H), 7.66-7.59 (m, 4H), 7.55 (dd, J=9, 7 Hz, 1H), 7.09 (d, J=9 Hz, 1H), 4.91 (s, 2H), 4.42 (q, J=7 Hz, 2H), 3.52 (septet, J=7 Hz, 1H), 1.97 (s, 3H), 1.38 (t, J=7 Hz, 3H), 1.36 (d, J=7 Hz, 6H). ESI-LCMS m/z 575 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][CH:15]=[C:14]([F:24])[CH:13]=2)(C)(C)C.[ClH:32]>C(OCC)(=O)C>[ClH:32].[NH2:7][CH2:8][C:9]1[N:10]([CH2:26][C:27]([CH3:28])([CH3:30])[CH3:29])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][CH:15]=[C:14]([F:24])[CH:13]=2
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2cc(F)ccc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOc1c(CN)n(CC(C)(C)C)c(=O)c2cc(F)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
To a solution of tert-butyl(4-butoxy-7-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (1.74 g, 4 mmol) in ethyl acetate (5 ml) was added a solution of 4N hydrogen chloride in ethyl acetate(5 ml), and the obtained solution was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the precipitated crystals were, recrystallized from methanol-diisopropyl ether to give 3-(aminomethyl)-4butoxy-7-fluoro-2-neopentyl-1(2H)-isoquinolinone hydrochloride (1.42 g, 95.9%) as crystals.
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[CH2:10]([O:12][C:13](=[O:28])[C:14]([CH3:27])([CH3:26])[CH2:15][CH2:16][CH:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[CH3:11].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C1COCC1.CN(C1C=CN=CC=1)C>[CH2:10]([O:12][C:13](=[O:28])[C:14]([CH3:27])([CH3:26])[CH2:15][CH2:16][CH:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]1[CH2:7][CH2:8][C:9]2[S:1][CH:2]=[CH:3][C:4]=2[CH2:5]1)[CH3:11]
Reactant: CCOC(=O)C(C)(C)CCC(Br)c1ccccc1Cl
Reactant: c1cc2c(s1)CCNC2
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)CCC(c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 67 %

Procedure:
4,5,6,7-Tetrahydrothieno[3,2-c]pyridine (0.65 g, 4.61 mmol) and 5-bromo-5-(2-chlorophenyl)-2,2-dimethylpentanoic acid ethyl ester (1.42 g, 4.08 mmol) were dissolved in THF (5 mL) and triethylamine (3 mL) with a few crystals of DMAP. The solution was heated overnight to 85° C. using an oil bath. After 20 hours, the solution was cooled to room temperature and sodium bicarbonate solution (20 mL) was added. After mixing, the product was extracted with dichloromethane (2×25 mL). The combined dichloromethane fractions were dried over sodium sulfate, filtered, and concentrated. The remaining yellow oil was purified by MPLC on a Companion Chromatography station using silica gel (40 g), eluting with a gradient of 100% heptane to 10% ethyl acetate over 20 minutes followed by a second gradient to 100% ethyl acetate at 40 minutes. The second broad fraction was collected and concentrated to produce 5-(2-chlorophenyl)-5-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2-dimethylpentanoic acid ethyl ester (Compound Ib, 1.11 g, 67.2% yield) as a light, yellow oil. 1H NMR (300 MHz, CDCl3/TMS): δ=7.46 (dd, 1H, J=7.80, 1.5 Hz), 7.38 (dd, 1H, J=7.80, 1.5 Hz), 7.30-7.15 (m, 2H), 7.04 (d, 1H, J=5.1 Hz), 6.70 (d, 1H, J=5.1 Hz), 4.18 (dd, 1H, J=8.7, 4.5 Hz), 4.08 (q, 2H, J=7.2 Hz), 3.79 (d, 1H, J=14.4 Hz), 3.45 (d, 1H, J=14.4 Hz), 2.90-2.62 (m, 4H), 2.0-1.85 (m, 1H), 1.82-1.68 (m, 1H), 1.49 (dt, 1H, J=13.5, 4.2 Hz), 1.30 (dt, 1H, J=13.5, 4.5 Hz), 1.20 (t, 3H, J=7.2 Hz), 1.10 (s, 6H). 13C NMR (75 MHz, CDCl3/TMS): δ=177.59, 138.99, 134.95, 134.25, 133.59, 129.64, 129.11, 128.07, 126.73, 125.43, 122.61, 63.81, 60.38, 50.63, 47.95, 42.22, 36.43, 28.22, 26.17, 25.52, 25.38, 14.47. MS (MMI-TOF): Calculated for C22H28NO2ClS (MH+): 406.1602. found 406.1576.
Reaction SMILES: C(N(C(C)C)CC)(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.[F:37][C:38]1[CH:63]=[CH:62][C:41]([O:42][C:43]2[CH:48]=[CH:47][C:46]([S:49]([NH:52][C:53]3([C:59]([OH:61])=O)[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)(=[O:51])=[O:50])=[CH:45][CH:44]=2)=[CH:40][CH:39]=1.Cl.[CH2:65]([O:72][NH2:73])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>CN(C)C=O>[CH2:65]([O:72][NH:73][C:59]([C:53]1([NH:52][S:49]([C:46]2[CH:45]=[CH:44][C:43]([O:42][C:41]3[CH:62]=[CH:63][C:38]([F:37])=[CH:39][CH:40]=3)=[CH:48][CH:47]=2)(=[O:50])=[O:51])[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)=[O:61])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: O=C(O)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCOCC1
Reactant: NOCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NOCc1ccccc1)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Diisopropyl ethylamine (3.89 grams, 0.030 mole) and (benzotriazol-1-yloxy)tris-(dimethylamino)-phosphonium hexafluorophosphate (13.27 grams, 0.030 mole) were added sequentially to a solution of 4-[4-(4-fluorophenoxy)-benzenesulfonylamino] tetrahydropyran-4-carboxylic acid (11.22 grams, 0.028 mole) in anhydrous N,N-dimethylformamide (140 mL). The resulting solution was stirred at room temperature for 16 hours. Additional diisopropyl ethylamine (4.0 mL, 0.051 mole) and O-benzyl hydroxylamine hydrochloride (5.46 grams, 0.034 mole) were then added and the resulting mixture was stirred at 60° C. for 18 hours. After concentration under vacuum, the residue was treated with 0.5N aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic extract was washed with saturated aqueous sodium bicarbonate solution, water, and brine. The solution was dried over magnesium sulfate, filtered and concentrated to one fourth original volume. Addition of an equal volume of hexane precipitated 4-[4-(4-fluorophenoxy)benzenesulfonylamino]-tetrahydropyran-4-carboxylic acid N-benzyloxyamide (11.595 g, 81.6%) as a white crystalline solid (mp 175-176° C.).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([O:11][C:12]([N:14]([CH2:23][CH3:24])[C:15]([CH3:22])([CH3:21])[C:16](OCC)=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[CH2:23]([N:14]([C:15]([CH3:21])([CH3:22])[CH2:16][OH:17])[C:12](=[O:13])[O:11][C:7]([CH3:10])([CH3:8])[CH3:9])[CH3:24]
Reactant: CCOC(=O)C(C)(C)N(CC)C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)C(C)(C)CO
Temperature: 0 °C
Reaction time: 4 h
Yield: 46 %

Procedure:
To a suspension of LiAlH4 (760 mg, 20 mmol, 1.0 equiv) in THF (50 mL) was added ethyl 2-(tert-butoxycarbonyl(ethyl)amino)-2-methylpropanoate (5.18 g, 20 mmol, 1 equiv) at 0° C. under N2. The mixture was stirred for 4 h at 0° C. It was quenched with ice/water at 0° C., then extracted with ethyl acetate (50 mL×3). The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated. The residue was purified by a silica gel column (pet. ether/ethyl acetate=4/1) to give 2 g (45%) of tert-butyl ethyl(1-hydroxy-2-methylpropan-2-yl)carbamate as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][O:31][CH2:32][CH2:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36](=[O:37])[CH2:35][O:34][CH2:33][CH2:32][O:31][CH3:30])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: COCCOCC(=O)Cl
Product: COCCOCC(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cccc(OC)c1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine (50 mg, 0.13 mmol) and 2-(2-methoxyethoxy)acetyl chloride (0.039 mL, 0.38 mmol). Yield 52 mg (80%).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)=[CH:16][C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)C.O1CCCC1.CO.[OH-].[Li+]>O>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][CH:6]([CH2:5][C:4]([OH:34])=[O:3])[CH2:7][CH2:8]2)=[N:13][CH:14]=[C:15]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:16]=1)=[O:27]
Reactant: CCOC(=O)CC1CCN(c2ncc(-c3ccccc3)cc2NC(=O)c2cccc(Cl)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1CCN(c2ncc(-c3ccccc3)cc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83 %

Procedure:
To a solution of 0.115 g (0.241 mmol) of [3′-(3-chloro-benzoylamino)-5′-phenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid ethyl ester in a 5:2 mixture of tetrahydrofuran:methanol (7 mL) is added a solution of 0.028 g (1.2 mmol) of lithium hydroxide in water (1 mL). The reaction mixture is stirred at room temperature for 3 days and then concentrated under reduced pressure to remove volatile organics. The residue is diluted with water and the pH of the mixture is adjusted to approximately pH 2 by the addition of concentrated hydrochloric acid causing a solid to precipitate. The formed yellow solid is collected by filtration and dried under vacuum to provide 0.090 g (83%) of [3′-(3-chloro-benzoylamino)-5′-phenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid.