Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][NH2:8])=[O:6].[CH2:13]([N:20]1[CH2:24][CH2:23][C@@H:22]([NH:25][C:26](=[O:39])[CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([CH:35]=O)=[C:31]([O:37][CH3:38])[CH:30]=2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][N:8]=[CH:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][CH2:27][C:26]([NH:25][C@@H:22]2[CH2:23][CH2:24][N:20]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:21]2)=[O:39])=[CH:30][C:31]=1[O:37][CH3:38])=[O:6]
Reactant: COc1cc(OCC(=O)N[C@@H]2CCN(Cc3ccccc3)C2)ccc1C=O
Reactant: NNC(=O)c1ccc(O)c(N)c1
Solvent: CC(C)O
Product: COc1cc(OCC(=O)N[C@@H]2CCN(Cc3ccccc3)C2)ccc1C=NNC(=O)c1ccc(O)c(N)c1
Yield: 70.2 %

Procedure:
The above 3-amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and the above (R)-N-(1-benzylpyrrolidin-3-yl)-2-(4-formyl-3-methoxyphenoxy)acetamide (110 mg, 0.3 mmol) were dissolved in 2-propanol (4 ml) and the mixture was heated at reflux temperature for 16 hours. The cooled mixture was filtered and the precipitate was washed with 2-propanol (2×3 ml) and dried by suction to afford 109 mg (70%) of the title compound as a solid. M.p.: 157-160° C.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][N:7]([CH:9]2[CH2:12][O:11][CH2:10]2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:25](=[O:26])[N:24]([CH3:27])[CH:23]=[C:22]([C:28]3[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([N:37]4[CH:49]=[CH:48][N:40]5[C:41]6[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=6[CH:47]=[C:39]5[C:38]4=[O:50])[C:29]=3[CH:30]=[O:31])[CH:21]=2)=[N:17][CH:18]=1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([C@H:3]1[CH2:8][N:7]([CH:9]2[CH2:10][O:11][CH2:12]2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:25](=[O:26])[N:24]([CH3:27])[CH:23]=[C:22]([C:28]3[C:29]([CH2:30][OH:31])=[C:32]([N:37]4[CH:49]=[CH:48][N:40]5[C:41]6[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=6[CH:47]=[C:39]5[C:38]4=[O:50])[CH:33]=[C:34]([F:36])[CH:35]=3)[CH:21]=2)=[N:17][CH:18]=1)[CH3:2]
Reactant: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(-n4ccn5c6c(cc5c4=O)CCCC6)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(-n4ccn5c6c(cc5c4=O)CCCC6)c3CO)cn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.4 %

Procedure:
A mixture of 122b (100 mg, 0.15 mmol), NaBH4 (22 mg, 0.60), and methanol (10 mL) was stirred at 25° C. for 1 h. It was then quenched with water (5 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (2×10 mL) and the combined organic layer was concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 122 (32 mg, 31%). MS: [M+H]+ 680.3. 1H NMR (500 MHz, CDCl3) δ 8.56 (s, 1H), 7.91 (s, 1H), 7.80 (s, 1H), 7.53 (s, 1H), 7.28-7.26 (m, 2H), 7.05 (s, 1H), 6.97-6.93 (m, 2H), 6.81 (d, J=8.5 Hz, 1H), 6.45 (d, J=5.5 Hz, 1H), 4.71-4.61 (m, 4H), 4.38 (d, J=12.0 Hz, 1H), 4.36 (d, J=11.5 Hz, 1H), 3.70 (s, 3H), 3.52 (bs, 1H), 3.31 (d, J=5.5 Hz, 1H), 3.13-3.10 (m, 2H), 2.75-2.70 (m, 4H), 2.56-2.43 (m, 4H), 1.98-1.96 (m, 2H), 1.85-1.84 (m, 2H), 1.39-1.36 (m, 2H), 0.82 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH3:28])[CH2:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][CH:17]3O)[N:9]=1)[CH3:2].[CH3:29][S:30]([CH2:33][CH2:34][NH2:35])(=[O:32])=[O:31]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH3:28])[CH2:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][CH:17]3[NH:35][CH2:34][CH2:33][S:30]([CH3:29])(=[O:32])=[O:31])[N:9]=1)[CH3:2]
Reactant: CCOc1ccc(Cc2nc(-c3cccc4c3CCC4O)no2)cc1OCC
Reactant: CS(=O)(=O)CCN
Product: CCOc1ccc(Cc2nc(-c3cccc4c3CCC4NCCS(C)(=O)=O)no2)cc1OCC

Procedure:
Prepared using General Procedure 14 from 4-(5-(3,4-diethoxybenzyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ol 60 and 2-(methylsulfonyl)ethanamine.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:21])=[C:4]([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[CH2:22]([OH:24])[CH3:23].O1CCCC1.[H-].[Na+]>CCOCC.O>[Br:1][C:2]1[C:3]([Cl:21])=[C:4]([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:5]([O:24][CH2:22][CH3:23])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CCO
Reactant: CC(C)(C)OC(=O)NCc1c(F)c([N+](=O)[O-])cc(Br)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCOc1c([N+](=O)[O-])cc(Br)c(Cl)c1CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a mixture of the compound (200 mg) obtained in Example 519c, ethanol (36 μl) and tetrahydrofuran (5 ml), sodium hydride (content, 60%; 25 mg) was added under ice cooling. The reaction mixture was stirred at 0° C. for 2 h and then water and ether were added. The organic layer was washed with water and a saturated aqueous sodium chloride solution sequentially, then dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:n-hexane=1:4) to give 197 mg of the titled compound (yield, 92%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[CH:12]1([Mg]Br)[CH2:14][CH2:13]1.[Cl-].[NH4+]>CCOCC>[CH:12]1([C:7]2([OH:11])[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[CH2:5][CH2:6]2)[CH2:14][CH2:13]1
Reactant: O=C1CCc2cc(F)ccc21
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: OC1(C2CC2)CCc2cc(F)ccc21
Reaction time: 8 h
Yield: 106.8 %

Procedure:
To a solution of 5-fluoroindanone (0.95 g, 6.33 mmol) in anhydrous ether (30 ml) under nitrogen at room temperature add cyclopropyl magnesium bromide (9.1 ml, 7.28 mmol, 1.15 equivalents, 0.80 M in tetrahydrofuran) dropwise while maintaining a gentle reflux. After stirring overnight, quench the reaction at room temperature via dropwise addition of 10% aqueous ammonium chloride. Dilute the reaction with ether, wash with water (2×), dry over anhydrous sodium sulfate, filter, and concentrate to give the title compound (1.30 g, ˜100%). NMR (CDCl3, 400 MHz): δ 0.26 (m, 1H), 0.36-0.51 (m, 3H), 1.21 (m, 1H), 2.13 (m, 1H), 2.28 (m, 1H), 2.80 (m, 1H), 2.95 (m, 1H), 6.88 (m, 2H), 7.29 (m, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11](=[O:29])[NH:12][C:13](=[O:28])[C:14]=2[C:15]2[C:23]3[C:18](=[CH:19][C:20]([N+:24]([O-:26])=[O:25])=[CH:21][CH:22]=3)[N:17]([CH3:27])[CH:16]=2)=[CH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:40](Cl)(=[O:42])[CH3:41]>C1COCC1>[C:40]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11](=[O:29])[NH:12][C:13](=[O:28])[C:14]=2[C:15]2[C:23]3[C:18](=[CH:19][C:20]([N+:24]([O-:26])=[O:25])=[CH:21][CH:22]=3)[N:17]([CH3:27])[CH:16]=2)=[CH:2]1)(=[O:42])[CH3:41]
Reactant: Cn1cc(C2=C(c3c[nH]c4ccccc34)C(=O)NC2=O)c2ccc([N+](=O)[O-])cc21
Reactant: CC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)n1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)c2ccccc21
Yield: 65 %

Procedure:
A solution of 3-(l H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione (51 mg, 0.13 mmol), prepared as described in U.S. Ser. No. 09/268,887, in THF (20 ml) and cooled to −70° C. To this solution was added lithium bis(trimethylsilyl)amide (0.5 mmol, 0.5 ml, 3.8 eq, 1.0 M in THF, followed by excess acetyl chloride (0.1 ml). The resulting solution was stirred until the temperature reached −45° C. The reaction was evaporated and purified by silica gel chromatography to give 33 mg of 3-(1-acetyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione. (Yield 65 %).
Reaction SMILES: C(OC([NH:11][C:12]1[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=1)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=O)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:11][C:12]1[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=1)[C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16]
Reactant: CC(C)(C)OC(=O)c1cccc(NC(=O)OCc2ccccc2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)c1cccc(N)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
tert-Butyl 3-(N-benzyloxycarbonylamino)benzoate (2.18 g) and ammonium formate (2.1 g) were dissolved in methanol (30 ml). Catalyst (1 g) of 10% palladium/carbon was added, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was filtered through Celite to remove catalyst and the filtrate was concentrated. The residue was partitioned between chloroform and water. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give tert-butyl 3-aminobenzoate. This compound was dissolved in tetrahydrofuran (30 ml). N,N'-Carbonyldiimidazole (1.05 g) was added, and the mixture was stirred at room temperature for 3 hours. Triethylamine (1.82 ml) and 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (4.82 g) were added to the reaction mixture, and the mixture was further stirred at room temperature for 3 hours. The reaction mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with a 5% aqueous citric acid solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated. The residue was purified by silica gel column chromatography using a mixed solvent of ethyl acetate and methanol (10:1) as an eluent, and crystallized from isopropyl ether to give 0.95 g of tert-butyl 3-(3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)ureido)benzoate.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[C:8]=1[O:15][CH2:16][CH3:17])C>CCO>[CH2:16]([O:15][C:8]1[C:9]([F:14])=[CH:10][C:11]([F:13])=[CH:12][C:7]=1[C:6]([OH:18])=[O:5])[CH3:17]
Reactant: CCOC(=O)c1cc(F)cc(F)c1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1c(F)cc(F)cc1C(=O)O
Temperature: 40 °C
Reaction time: 18 h
Yield: 176.7 %

Procedure:
A 5M solution of sodium hydroxide (3.2 mL; 16 mmol; 3.2 eq.) was added to a solution of 2-ethoxy-3,5-difluoro-benzoic acid ethyl ester (1.16 g; 5.04 mmol; 1 eq.) in EtOH (23 mL) and the resulting mixture was stirred at 40° C. for 18 hours then concentrated in vacuo. The residue was taken up in water and the pH made acidic with 5M HCl. The precipitate was filtered off, washed with water and dried to afford the title compound (1.8 g, 90%) as a white solid. 1H NMR (DMSO-d6) δ 13.44 (s, 1H), 7.61-7.52 (m, 1H), 7.35-7.28 (m, 1H), 4.04 (q, J=7.0 Hz, 2H), 1.28 (t, J=7.0 Hz, 3H). HPLC (max plot) 79.5%; Rt 3.13 min.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].[CH3:11][O-:12].[Na+].O>CN(C=O)C>[Br:1][C:2]1[C:3]([O:12][CH3:11])=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(C)c(Br)c(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(C)cc(C)c1Br

Procedure:
A mixture of 3-bromo-2-chloro-4,6-dimethylpyridine (2.97 g) and sodium methoxide (11.0 mL, 28% solution in methanol) was stirred in a DMF solvent (30 mL) at 80° C. for 36 hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 0% to 10%) to give the title compound (2.33 g).
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([CH3:10])([CH3:9])[CH2:4][C:5](=[O:8])[O:6]2.[CH:11]([OH:14])([CH3:13])[CH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH:11]([O:14][CH:7]1[O:6][C:5](=[O:8])[CH2:4][C:3]([CH3:10])([CH3:9])[CH:2]1[OH:1])([CH3:13])[CH3:12]
Reactant: CC1(C)CC(=O)OC2OC21
Reactant: CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC(C)OC1OC(=O)CC(C)(C)C1O
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A mixture of 7 g of 5,6-epoxy-4,4-dimethyl-tetrahydro-pyr-2-one, 35 ml of isopropanol and 350 mg of p-toluene sulfonic acid was stirred at room temperature for 23 hours and was diluted with water. The mixture was extracted with methylene chloride and the combined extracts were washed with aqueous saturated sodium bicarbonate solution, was dried and evaporated to dryness under reduced pressure. The 9.18 g of residue was chromatographed over silica and was eluted with a 1-1 mixture of hexane-ethyl acetate to obtain 2.597 g of dl 6-isopropoxy-5-hydroxy-4,4-dimethyl-tetrahydro-pyr-2-one melting at 50° C.
Reaction SMILES: [F:1][CH:2]([CH2:6][CH2:7][C:8]#[CH:9])[C:3]([OH:5])=O.[NH2:10][C:11]([CH3:15])([CH3:14])[CH2:12]O.O>C1(C)C(C)=CC=CC=1>[F:1][CH:2]([C:3]1[O:5][CH2:12][C:11]([CH3:15])([CH3:14])[N:10]=1)[CH2:6][CH2:7][C:8]#[CH:9]
Reactant: C#CCCC(F)C(=O)O
Reactant: CC(C)(N)CO
Solvent: Cc1ccccc1C
Solvent: O
Product: C#CCCC(F)C1=NC(C)(C)CO1
Yield: 56.8 %

Procedure:
A mixture of 2-fluoro-5-hexynoic acid (3.0 g, 23.05 mmol) and 2-amino-2-methyl-1-propanol (2.05 g, 23.05 mmol) in 150 ml of dry xylene was refluxed for 16 h. The water formed during the reaction was removed by Linde 3A molecular sieves (15 g) contained in a continuous extractor. The xylene was then distilled off at atmospheric pressure, and the resulting pot material was taken into ether (100 ml). The ethereal solution was washed with saturated sodium bicarbonate solution, water, and dried over MgSO4. Evaporation of ether at 35° C./~35 mm, and distillation of the resulting crude product gave 2.4 g (57%) of 2-(1-fluoro-4-pentynyl)-4,5-dihydro-4,4-dimethyloxazole as a colorless liquid, bp 62°-66° C./0.6 mmHg.
Reaction SMILES: C(O[C:4]([N:6]([CH3:29])[N:7]=[C:8]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:5])C.C(N(CC)CC)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[CH2:49]([O:51][C:52](=[O:54])C)[CH3:50]>C1(C)C=CC=CC=1>[CH2:49]([O:51][C:52](=[O:54])[CH2:29][N:6]1[N:7]=[C:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[N:16]([CH2:17][C:18]([CH3:21])([CH3:19])[CH3:20])[C:4]1=[O:5])[CH3:50]
Reactant: CCOC(=O)N(C)N=C(c1ccccc1Cl)c1cc(Cl)ccc1NCC(C)(C)C
Reactant: CCOC(C)=O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CN1N=C(c2ccccc2Cl)c2cc(Cl)ccc2N(CC(C)(C)C)C1=O
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of 2-neopentylamino-2',5-dichlorobenzophenone ethoxycarbonyl methyl hydrazone (0.16 g) and triethylamine (90 mg) in toluene (2 ml) was added triphosgene (54 mg). The mixture was stirred for one hour at 70° C., to which was added acetic acid ethyl ester (50 ml). The mixture was washed with water and, then dried over anhydrous sodium sulfate. The solvent was then distilled off. The residue was purified by means of a silica-gel column chromatography (hexane:acetic acid ethyl ester=3:1 v/v as an eluent) to give 0.16 g of an oily compound.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([OH:32])=[C:26]([S:28]([NH2:31])(=[O:30])=[O:29])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC.C(OCC)(=O)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:32][CH2:2][C:3]([N:5]2[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:7][C@H:6]2[CH3:20])=[O:4])=[C:26]([S:28]([NH2:31])(=[O:30])=[O:29])[CH:27]=1
Reactant: NS(=O)(=O)c1cc(Cl)ccc1O
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1S(N)(=O)=O
Yield: 70.9 %

Procedure:
To a solution of 2-chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.29 g, 0.96 mmol) in 2-butanone (10 mL) was added 5-chloro-2-hydroxy-benzenesulfonamide (0.20 g, 0.96 mmol), potassium carbonate (0.27 g, 1.92 mmol) and potassium iodide (0.16 g, 0.96 mmol). The reaction was refluxed for 4 hours, cooled diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.32 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:14])=[CH:4][C:3]=1[Cl:23].Cl[CH2:25][C:26]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:27]>>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:25][C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])[CH2:19][CH2:18]2)=[O:14])=[CH:4][C:3]=1[Cl:23]
Reactant: CCc1cn2c(N)c(Cl)cc(C(=O)NCC3CCNCC3)c2n1
Reactant: O=C(CCl)N1CCOCC1
Product: CCc1cn2c(N)c(Cl)cc(C(=O)NCC3CCN(CC(=O)N4CCOCC4)CC3)c2n1

Procedure:
The title compound was prepared according to the procedure described in the step 5 of Example 4 from 5-amino-6-chloro-2-ethyl-N-(piperidin-4-ylmethyl)imidazo[1,2-a]pyridine-8-carboxamide (Example 4, Step 4) and 4-(chloroacetyl)morpholine (B. G. Hazra; V. S. Pore; S. P. Maybhate, Org. Prep. Proced. Int., 1989, 21, 355-8).
Reaction SMILES: [Si:1]([O:8][CH:9]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10](OC)=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Si:1]([O:8][CH:9]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH:10]=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COC(=O)C(O[Si](C)(C)C(C)(C)C)c1ccc(OC)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(C(C=O)O[Si](C)(C)C(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
Methyl {[tert-butyl(dimethyl)silyl]oxy}(4-methoxyphenyl)acetate (0.5 g, 1.61 mmol) was dissolved in toluene (10 mL) and cooled to −78° C. under a nitrogen atmosphere. DIBAL (1.0M in toluene, 1.9 mL, 1.93 mmol) was added slowly and the mixture was stirred at −78° C. for 1 h. The reaction mixture was poured onto a mixture of ice (20 g) and CHCl3 (20 mL). The mixture was stirred at r.t. for 30 minutes. The layers were separated and the water phase extracted with CHCl3. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated, obtaining 99% (0.45 g) of the title compound. The product was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[CH2:23]O)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:27])=O.C(=O)([O-])O.[Na+]>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[CH2:23][Cl:27])[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCOc1c(CO)n(CC(C)(C)C)c(=O)c2ccc(F)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCOc1c(CCl)n(CC(C)(C)C)c(=O)c2ccc(F)cc12
Yield: 91.6 %

Procedure:
To a solution of 4-butoxy-6-fluoro-3-hydroxymethyl-2-neopentyl-1(2H)-isoquinolinone (from Example 1(3), 1.68 g, 5 mmol) in tetrahydrofuran (10 ml) and toluene (10 ml) was added thionylchloride (0.73 ml, 10 mmol), and the resulting mixture was refluxed under heating for 2 h. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-butoxy-6-fluoro-3-chloromethyl-2-neopentyl-1(2H)-isoquinolinone (1.62 g, 92.0%) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C@H:20]4[CH2:24][CH2:23][CH2:22][O:21]4)[CH:14]=3)[C:9]2=[O:25])=[CH:4][C:3]=1[F:26].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:79]([O:83][C:84](=[O:91])[NH:85][CH:86]1[CH2:90][CH2:89][NH:88][CH2:87]1)([CH3:82])([CH3:81])[CH3:80]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:79]([O:83][C:84](=[O:91])[NH:85][CH:86]1[CH2:90][CH2:89][N:88]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C@H:20]5[CH2:24][CH2:23][CH2:22][O:21]5)[CH:14]=4)[C:9]3=[O:25])=[CH:4][C:3]=2[F:26])[CH2:87]1)([CH3:82])([CH3:80])[CH3:81]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=c1c2ccc(OC[C@H]3CCCO3)cc2ccn1-c1ccc(Br)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(-n3ccc4cc(OC[C@H]5CCCO5)ccc4c3=O)cc2F)C1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(4-bromo-3-fluorophenyl)-6-[(R)-1-(tetrahydrofuran-2-yl)methoxy]-2H-isoquinolin-1-one (75 mg), palladium(II) acetate (3 mg), BINAP (14 mg), cesium carbonate (82 mg) and pyrrolidin-3-yl-carbamic acid tert-butyl ester (48 mg) in degassed toluene (2 mL) was stirred for 18 h at 100° C. The mixture was diluted with ethyl acetate, filtered and the filtrate was concentrated. The residue was purified by preparative HPLC. In this way the product was obtained with molecular weight 523.61 (C29H34FN3O5); MS (ESI): 524 (M+H+).
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]=[CH:24][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.C(N(CC)CC)C.[CH3:35][C:36]1[C:40]([S:41](Cl)(=[O:43])=[O:42])=[C:39]([CH3:45])[O:38][N:37]=1.O>ClCCl.CN(C1C=CN=CC=1)C>[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:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][S:41]([C:40]4[C:36]([CH3:35])=[N:37][O:38][C:39]=4[CH3:45])(=[O:43])=[O:42])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1S(=O)(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reaction time: 18 h

Procedure:
To (1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenylpropan-2-amine (1a, 60 mg, 0.14 mmol) 130 μmol) in dichloromethane (6 mL) was added triethylamine (55 μl), followed by 3,5-dimethylisooxazole-4-sulfonyl chloride (39 mg, 200 μmol) and DMAP (2 mg, 17 μmol). The stirring was continued for 18 hours at room temperature and the reaction mixture was poured into water and extracted with dichloromethane. The combined organic phases were washed with brine, died over sodium sulphate, the solvent was removed i.vac., and the product purified by chromatography on silica gel.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([O:14][CH:15]([CH3:17])[CH3:16])[CH:10]=[CH:9][CH:8]=2)=[O:4].[Li+].[OH-].O>C1COCC1>[CH:15]([O:14][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]=[C:5]([C:3]([OH:4])=[O:2])[NH:6]2)([CH3:17])[CH3:16]
Reactant: COC(=O)c1cc2c(OC(C)C)cccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1cccc2[nH]c(C(=O)O)cc12
Reaction time: 48 h

Procedure:
4-Isopropoxy-1H-indole-2-carboxylic acid methyl ester 76 (114 mg, 0.49 mmol) is dissolved in 5 ml of THF. A 2M-solution of LiOH in water (2.5 ml, 5 mmol) is added and the mixture is stirred for 48 hours. The solvent is then evaporated and the residue is partitioned between water and EtOAc. The water layer is acidified with HCl and extracted twice with EtOAc. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to give a yellow powder.