Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:15]1([C@H:19]([NH:27][C:28]([CH:30]([C:34]2[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:35]=2[C:36](O)=[O:37])[C:31](=O)[CH3:32])=[O:29])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[CH2:18][CH2:17][CH2:16]1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]1[C:31]([CH3:32])=[C:30]([C:28](=[O:29])[NH:27][C@@H:19]([CH:15]2[CH2:16][CH2:17][CH2:18]2)[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[C:34]2[C:35](=[C:39]([F:43])[CH:40]=[CH:41][CH:42]=2)[C:36]1=[O:37])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Reactant: CC(=O)C(C(=O)N[C@H](c1cccc(F)c1)C1CCC1)c1cccc(F)c1C(=O)O
Product: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c2cccc(F)c2c(=O)n1C[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
(S)-2-Aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (510 mg, 2.54 mmol) and 2-(1-{[(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-2-oxo-propyl)-6-fluoro-benzoic acid (851 mg, 2.12 mmol) were condensed analogously to the method described for example 4 to give (S)-2-(4-{[(S)-Cyclobutyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-8-fluoro-3-methyl-1-oxo-1H-isoquinolin-2-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester. The Boc-protection group was removed analogously to the method described for example 6 with trifluoroacetic acid in 1,2-dichloroethane to give the title compound. LC-MS (m/z) 466.3 (MH+); tR=0.96.
Reaction SMILES: [CH3:1][C:2]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][C:6]1=[O:21].CCC(C)[BH-](C(C)CC)C(C)CC.[K+]>O1CCCC1>[CH3:1][C:2]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:3]=1[O:4][C@H:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][C@H:6]1[OH:21]
Reactant: Cc1cccc(OC2CCN(C(=O)OCc3ccccc3)CC2=O)c1C
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cccc(O[C@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2O)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.3 %

Procedure:
A solution of benzyl 4-(2,3-dimethylphenoxy)-3-oxopiperidine-1-carboxylate (10.0 g, 28.0 mmol) in tetrahydrofuran (60 ml) was treated at room temperature with K-selectride (1.0M in tetrahydrofuran, 56 ml, 56.0 mmol). On completion of addition the mixture was stirred at room temperature for 18 h. The mixture was concentrated to dryness in vacuo and diluted carefully by addition of ice-water (100 ml). Extraction with dichloromethane (2×200 ml) was followed by washing the combined organics with aqueous hydrochloric acid (100 ml, 0.1N), water (100 ml) and brine (100 ml). The organics were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a dark oil which was purified by silica gel chromatography using isohexanes:ethyl acetate (5:1) as eluent to furnish cis-benzyl 4-(2,3-dimethylphenoxy)-3-hydroxypiperidine-1-carboxylate as a pale yellow syrup (5.01 g, 50%).
Reaction SMILES: C([NH:8][C@H:9]([C:13](O)=[O:14])[CH:10]([CH3:12])[CH3:11])(OC(C)(C)C)=O.[ClH:16].[NH2:17][N:18]1[C:24](=[O:25])[CH:23]([CH3:26])[C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=2[C:20]2[CH:31]=[CH:32][CH:33]=[CH:34][C:19]1=2>>[ClH:16].[NH2:8][C@H:9]([C:13]([NH:17][N:18]1[C:24](=[O:25])[CH:23]([CH3:26])[C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=2[C:20]2[CH:31]=[CH:32][CH:33]=[CH:34][C:19]1=2)=[O:14])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1C(=O)N(N)c2ccccc2-c2ccccc21
Agent: Cl
Product: CC1C(=O)N(NC(=O)[C@@H](N)C(C)C)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using N-Boc-L-valine (Aldrich) and 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 1), the title compound was prepared.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:11]3[CH:12]=[C:13]([CH2:16][OH:17])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:44][C:45]1[CH:53]=[CH:52][CH:51]=[CH:50][C:46]=1[C:47](O)=[O:48].N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH3:44][C:45]1[CH:53]=[CH:52][CH:51]=[CH:50][C:46]=1[C:47]([O:17][CH2:16][C:13]1[CH:14]=[CH:15][N:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:18]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)=[C:11]2[CH:12]=1)=[O:48]
Reactant: Cc1ccccc1C(=O)O
Reactant: OCc1ccn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)OCc1ccn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2c1
Temperature: 25 °C

Procedure:
2-(4-Fluorophenyl)-5-hydroxymethyl-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine (Example 6. 50 mg, 0.157 mmol), triphenyl phosphine (82 mg, 0.314 mmol) and 2-methylbenzoic acid (0.314 mmol) are dissolved in dry THF (3 mL). To the stirred solution is added diethyl azodicarboxylate (55 mg, 0.314 mmol) dropwise. The resulting solution is stirred at room temperature until reaction is complete as determined by TLC and then diluted with hexane/ethyl acetate (30 mL of a 1:1 mixture) and washed with water (×3). The organic phase is then shaken with dilute hydrochloric acid. In cases were the hydrochloride salt of the product deposits at this stage it is filtered off, washed with water and then hexane and dried. If no deposit is observed, the acidic phase is separated, washed once with hexane/ethyl acetate (15 mL of a 1:1 mixture) and basified with saturated sodium bicarbonate solution. This is then extracted with dichloromethane (15 mL) five times and the dichloromethane solution dried (MgSO4), filtered and concentrated to give the title compound. 1H NMR (d6-DMSO) δ 2.50 (s, 3H), 5.41 (s, 2H), 7.25–7.33 (m, 5H), 7.48 (t, J=7.4 Hz, 1H), 7.56 (dd, J=5.6, 8.5 Hz, 2H), 7.73 (d, J=5.8 Hz, 2H), 7.88 (d, J=7.9 Hz, 1H), 8.06 (s, 1H), 8.71 (d, J=6.2 Hz, 2H), 8.92 (d, J=7.1 Hz, 1H). APESI-MS m/z 438 (M+1)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.O>CN(C=O)C>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCC1CCOCC1
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCCOc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 39 h

Procedure:
2-Butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (0.5 g) was heated to 60° C. for 1 hour with anhydrous potassium carbonate (0.79 g) in dry DMF (10 mL) and allowed to cool to room temperature before adding 4-(bromomethyl)tetrahydro-2H-pyran (0.26 g). The reaction was stirred at room temperature for 39 hours and heated for 2 hours at 50° C. The reaction was poured into water and extracted into ethyl acetate (twice). The combined ethyl acetate extracts were dried through a hydrophobic frit, stripped to dryness and purified first by silica chromatography (ISCO) (40 g) eluting with 0-100% ethyl acetate:cyclohexane then 0-20% methanol:ethyl acetate and then by reverse phase chromatography (43 g, C-18) (ISCO) eluting 20-60% acetonitrile (0.05% formic acid): water (0.1% formic acid) to give the title compound as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]([NH:9][C:10]([C:12]1[CH:21]=[C:20]([Cl:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[O:23][CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]1)=[O:11])([CH3:8])[CH2:6][CH3:7])C.[OH-].[Na+]>C1COCC1.CO>[C:31]([N:28]1[CH2:27][CH2:26][CH:25]([CH2:24][O:23][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]([Cl:22])=[CH:21][C:12]=2[C:10]([NH:9][C:5]([CH3:8])([CH2:6][CH3:7])[C:4]([OH:34])=[O:3])=[O:11])[CH2:30][CH2:29]1)(=[O:33])[CH3:32]
Reactant: CCOC(=O)C(C)(CC)NC(=O)c1cc(Cl)c2ccccc2c1OCC1CCN(C(C)=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(C)(NC(=O)c1cc(Cl)c2ccccc2c1OCC1CCN(C(C)=O)CC1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.5 %

Procedure:
A solution of 70 mg of 2-{[1-(1-acetyl-piperidin-4-ylmethoxy)-4-chloro-naphthalene-2-carbonyl]-amino}-2-methyl-butyric acid ethyl ester in 4 mL THF and 1 mL MeOH was treated with 4 mL of 2 M aqueous sodium hydroxide. The reaction mixture was stirred at room temperature overnight. The organic solvent was removed in vacuo. The residue was taken up in 6 mL of water and washed with ethyl acetate. The aqueous phase was treated with 2 M hydrochloric acid to pH 4, then extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulphate and concentrated to give 30 mg of 2-{[1-(1-acetyl-piperidin-4-yl-methoxy)-4-chloro-naphthalene-2-carbonyl]-amino}-2-methyl-butyric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8].[S:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:29]3[CH2:30][CH2:31][S:26][CH2:27][CH2:28]3)[CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8]
Reactant: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCNCC2)nc1
Reactant: O=C1CCSCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCN(C3CCSCC3)CC2)nc1
Temperature: 50 °C
Reaction time: 96 h
Yield: 40.1 %

Procedure:
5-Chloro-N-(5-methylpyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 99-A (0.45 g, 1.25 mmol) was dissolved in 95:5 methanol-acetic acid (10 mL), followed by addition of tetrahydrothiopyran-4-one (1.46 g, 12.6 mmol) and sodium cyanoborohydride (5.0 mL of a 1 M solution in tetrahydrofuran, 6.0 mmol). After stirring at 50° C. for 96 h, the mixture was concentrated in vacuo; and the residue was directly subjected to silica gel chromatography. Elution with 9:1 dichloromethane-methanol provided 0.23 g (40%) of the title product as a yellow solid.
Reaction SMILES: [CH2:1]([O:17][CH:18]1[O:23][CH:22]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:27])[CH:20]=[CH:19]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[CH2:34]=O>CO>[CH2:1]([O:17][CH:18]1[O:23][CH:22]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:27])[C:20]([CH2:34][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:19]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOC1C=CC(=O)C(C(C)C)O1
Reactant: C=O
Reactant: C1CCNCC1
Solvent: CO
Product: CCCCCCCCCCCCCCCCOC1C=C(CN2CCCCC2)C(=O)C(C(C)C)O1
Yield: 96.9 %

Procedure:
In 50 ml of methanol was dissolved 3.8 g of 6-cetyloxy-2-isopropyl-2H-pyran-3(6H)-one with stirring. Into the solution were added 1.02 g of piperidine and 1.05 g of 37% formalin solution, and the mixture was stirred at 55 ° to 60° C. for 7 hours. After the removal of methanol, the residue was separated by a silica gel column (developer: benzene/ethyl acetate=5/1) to give 4.62 g of 6-cetyloxy-4-piperidinomethyl-2-isopropyl-2H-pyran-3(6H)-one [compound 3] in a yellowish brown viscous oily form.
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10](OC2C=CC=CC=2)=[O:11])C=CC=CC=1.[CH3:49][N:50]([CH3:56])[C@@H:51]1[CH2:55][CH2:54][NH:53][CH2:52]1>CN(C)C=O>[CH3:49][N:50]([CH3:56])[C@@H:51]1[CH2:55][CH2:54][N:53]([C:10]([NH:9][C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38]([NH:39][C:40]5[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=5)=[O:47])[CH2:37][CH2:36]4)=[O:34])=[CH:28][CH:27]=3)[CH:22]=[CH:21][N:20]=2)=[O:11])[CH2:52]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1
Solvent: CN(C)C=O
Product: CN(C)[C@@H]1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3)ccn2)C1
Reaction time: 3 h
Yield: 39 %

Procedure:
To a solution of [4-(4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (50 mg) in N,N-dimethylformamide (1.0 ml) was added (3R)-3-dimethylaminopyrrolidine (0.050 ml) at room temperature, followed by stirring for 3 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of ethyl acetate:heptane=1:5 to the resultant residue. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (16.3 mg, 39%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)[CH3:9].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:38][CH2:39][C:40]1[C:41]([OH:48])=[N:42][C:43]([CH3:47])=[CH:44][C:45]=1[CH3:46]>ClCCl>[OH:48][C:41]1[C:40]([CH2:39][NH:38][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([CH:8]([O:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH3:9])=[CH:18][CH:17]=2)=[C:45]([CH3:46])[CH:44]=[C:43]([CH3:47])[N:42]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(Oc1ccccn1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccccn3)cc2)c(O)n1
Temperature: 20 °C
Reaction time: 13 h
Yield: 20.1 %

Procedure:
To a solution of 4-(1-(pyridin-2-yloxy)ethyl)benzoic acid (160 mg, 0.66 mmol), 1-hydroxybenzotriozole (135 mg, 1.0 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (192 mg, 1.0 mmol), triethylamine (0.3 mL) in dichloromethane (15 mL) was added 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (100 mg, 0.66 mmol). The reaction mixture was stirred at 20° C. for 13 hours. The mixture was washed with water (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-(pyridin-2-yloxy)ethyl)benzamide as a white solid (50 mg, 40%). LRMS (M+H+) m/z: 377.17. found 377. HPLC Purity (214 nm): 98%. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.30 (d, J=4.8 Hz, 1H), 8.06-8.04 (m, 1H), 7.80-7.68 (m, 3H), 7.44-7.42 (m, 2H), 6.93-6.84 (m, 2H), 6.17 (q, J=6.6 Hz, 1H), 5.84 (s, 1H), 4.27 (d, J=4.8, 2H), 2.15 (s, 3H), 2.11 (s, 3H), 1.55 (d, J=6.6 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1([C:12]2[CH:21]=[CH:20][C:15]([C:16]([NH:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[CH2:4][CH2:3]1.C([O-])(O)=O.[Na+].C(OCC)(=O)C.CCCCCC>C1COCC1.Cl>[OH:1][C:2]1([C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)[CH2:11][CH2:10][C:5](=[O:6])[CH2:4][CH2:3]1
Reactant: CNC(=O)c1ccc(C2(O)CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(C2(O)CCC(=O)CC2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 118.4 %

Procedure:
4-(8-Hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)-N-methylbenzamide (410 mg, 1.4 mmol) was dissolved in the mixture solvent of 7 mL of THF and 7 mL of 1 N HCl aqueous solution at room temperature. The reaction mixture was then stirred at 60° C. for 1 h. The solution was cooled down to room temperature, adjusted to pH 7-8 with saturated NaHCO3 aqueous solution. The organic layer was separated, and the aqueous layer was extracted twice with EA (20 mL×2). The combined organic extracts were dried over MgSO4 and evaporated to give an oil residue. Chromatography on silica gel (flash chromatography grade) with 40% Ethyl acetate-hexane gave 410 mg (90%) of the desired product: 1H NMR (CDCl3) δ 7.78 (2 H, d, J=11.2 Hz), 7.51 (2 H, d, J=10.9 Hz), 4.10 (H, s), 3.37 (3 H, s), 2.79-2.74 (2 H, m), 2.63-2.49 (2 H, m), 1.95-1.89 (2 H, m), 1.67-1.59 (2 H, m); MS: 248 (M+1)+.
Reaction SMILES: Cl.[CH2:2]([N:4]1[C:8]([OH:9])=[CH:7][CH:6]=[N:5]1)[CH3:3].C(N(CC)CC)C.[O:17]1[CH2:21][CH2:20][C:19]([C:22]2[C:23]([CH3:35])=[C:24]([CH:28]=[CH:29][C:30]=2[S:31]([CH3:34])(=[O:33])=[O:32])[C:25](Cl)=[O:26])=[N:18]1.CC(C)(O)C#N>C(Cl)(Cl)Cl>[O:17]1[CH2:21][CH2:20][C:19]([C:22]2[C:23]([CH3:35])=[C:24]([CH:28]=[CH:29][C:30]=2[S:31]([CH3:34])(=[O:33])=[O:32])[C:25]([C:7]2[CH:6]=[N:5][N:4]([CH2:2][CH3:3])[C:8]=2[OH:9])=[O:26])=[N:18]1
Reactant: Cc1c(C(=O)Cl)ccc(S(C)(=O)=O)c1C1=NOCC1
Reactant: CCn1nccc1O
Agent: CC(C)(O)C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C3=NOCC3)c2C)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
To 2.75 g of 3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoic acid were added 30 ml of benzene, then 1.7 ml of thionyl chloride and a drop of pyridine to heat at reflux for 3 hours. The reaction solution was cooled down. The solvent was distilled out under reduced pressure to give 2.90 g of 3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoyl chloride. Separately 0.93 g of 1-ethyl-5-hydroxypyrazole hydrochloride was dissolved in 20 ml of chloroform, and 1.60 g of triethylamine was added, while cooling with ice. Into the obtained solution was added dropwise 10 ml of a chloroform solution containing 1.90 g of 3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoyl chloride to stir at room temperature for 30 minutes, and 0.76 g of triethylamine and 0.16 g of acetone cyanohydrin were added to further stir overnight. The reaction solution was washed with dilute hydrochloric acid, then with a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled out under reduced pressure. Methanol was added to the residue. The obtained crystals were separated by filtration to give 1.59 g of the title compound as white crystals. m.p. 183~184.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:15][C:14]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:12])[CH2:5]2.Cl[CH2:39][CH2:40][O:41][CH2:42][CH2:43]Cl.CCN(C(C)C)C(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN1C(=O)CCC1>[CH2:31]([O:30][C:14]1[CH:15]=[C:16]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:17]([CH:19]([CH3:21])[CH3:20])=[CH:18][C:13]=1[C:11]([N:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([N:1]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH:3]=2)[CH2:7]1)=[O:12])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)c1cc(C(=O)N2Cc3ccc(N)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: ClCCOCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)c1cc(C(=O)N2Cc3ccc(N4CCOCC4)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 150 °C

Procedure:
A mixture of (5-amino-1,3-dihydro-isoindol-2-yl)-(2,4-bis-benzyloxy-5-isopropyl-phenyl)-methanone (100 mg; 0.2 mmol), bis(2-chloroethyl)ether (30 μl; 1.1 equiv.), Hunigs base (125 μl; 3.5 equiv.) and tetrabutylammonium iodide (10 mg) in NMP (1 ml) was heated in a CEM microwave synthesiser at 150° C. for 30 minutes. A further 30 μl of Hunig's base and 125 μl of bis(2-chloroethyl)ether were added and heating repeated for the same time. The reaction mixture was partitioned between EtOAc and saturated NH4Cl solution, the EtOAc layer was separated, washed with more saturated NH4Cl solution, then brine, dried (MgSO4) and evaporated. Purification by flash column chromatography (1:2 then 1:1 then 2:1 EtOAc/P.E. as eluant) gave 60 mg of (2,4-bis-benzyloxy-5-isopropyl-phenyl)-(5-morpholin-4-yl-1,3-dihydro-isoindol-2-yl)-methanone. MS: [M+H]+ 563.
Reaction SMILES: [K+].Br[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O-:7])=[O:6].[I:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>COCCOCCOC.O>[I:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:3]2[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=2[C:5]([OH:7])=[O:6])=[CH:15][CH:14]=1
Reactant: Nc1ccc(I)cc1
Reactant: O=C([O-])c1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: O
Product: O=C(O)c1ccccc1Nc1ccc(I)cc1

Procedure:
A mixture of o-bromobenzoic acid potassium salt (47.8 g, 0.2 mol), 4-iodoaniline (43.8 g, 0.2 mol), K2CO3 (13.8 g, 0.1 mol), and cupric acetate (2.87 g, 6%) in diglyme (100 mL) was heated to reflux for 30 minutes. The reaction mixture was diluted with H2O (1.0 L) and filtered. The filtrate was acidified with diluted AcOH. The resulting precipitate was collected by filtration, washed with H2O and dried in a vacuum at 50° C. for 16 hours. Recrystallization from EtOAc gave the desired product, a solid (29.7 g, 0.087 mol, 44%). mp 205-206° C.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH2:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>C(O)(=O)C.O>[C:1]1([C:7]2[CH:11]=[C:10]([N:12]3[C:16](=[O:17])[C:15]4[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:13]3=[O:18])[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1c1cc(-c2ccccc2)n[nH]1
Temperature: 120 °C
Yield: 91 %

Procedure:
A mixture of 3-phenyl-1H-pyrazol-5-amine (6 g, 0.038 mol), phthalic anhydride (5.6 g, 0.038 mol) in acetic acid (60 mL) was heated at 100° C. for 2 h and at 120° C. for 2 h and cooled to room temperature. The reaction mixture was diluted with water and the suspension was filtered. The collected solid was washed with water, dried, yielding the title compound as a solid (10 g).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:8][CH:9]=2)[C:4]1=O)[CH3:2].Cl.O1CCOCC1>O>[CH2:1]([CH:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:6]=2)[CH2:11]1)[CH3:2]
Reactant: CCC1Cc2ccc(C(C)C(=O)O)cc2C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCC1Cc2ccc(C(C)C(=O)O)cc2C1

Procedure:
A mixture of 10.5g. of 2-(2ethyl-1-oxoindan-6-yl)propionic acid, 20g. of zinc amalgam, 30 ml. of conc. hydrochloric acid, 150 ml. of dioxane and 20 ml. of water was heated under reflux for 15 hours. After completion of the reaction, the reaction mixture was extracted with ether and the ether extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract and the residue was subjected to vacuum distillation to give 8.2g. of the desired product as a colorless oily substance of b.p. 165° - 166° C./1.5 mmHg.