Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[C:10](=[C:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:1]1[C:11]2[C:10](=[C:12]3[CH2:17][CH2:16][N:15]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:14][CH2:13]3)[C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCBr
Reactant: c1ccc2c(c1)COc1ccccc1C2=C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCN1CCC(=C2c3ccccc3COc3ccccc32)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
A mixture of 3.61 g of 4-(dibenz[b,e]oxepin-11(6H)-ylidene)piperidine, 2.6 g of ethyl 3-bromopropionate, 1.8 g of potassium carbonate and 25 ml of N,N-dimethylformamide was stirred at 80° C. for 2 hrs. After cooling, water was added to the reaction mixture and extracted with ether. The ether layer was washed with water and extracted with hydrochloric acid. The aqueous layer was made alkaline with potassium carbonate and extracted with ether. The ether layer was washed with water, dried and concentrated to give 4.2 g of yellowish brown liquid, which was purified by column chromatography on silica gel (eluent: chloroform) to give 3.9 g of pale yellow liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O>COCCOC>[CH:22]([N:12]([C:10](=[O:11])[CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[O:32][CH3:31])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:24])[CH3:23]
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Reactant: COc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccccc1-c1ccccc1CCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 38.8 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 2-methoxy-phenylboronic acid (29 mg, 0.19 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (21 mg, 39%). LC-MS m/e 417.30 (M+H+)
Reaction SMILES: CS(C)=O.[CH2:5]([O:7][C:8](=[O:24])[CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:20](=[O:21])[CH2:19][CH2:18][CH2:17][C@@H:16]1[CH2:22][OH:23])[CH3:6].FC(F)(F)C([O-])=O.[NH+]1C=CC=CC=1>C1C=CC=CC=1>[CH2:5]([O:7][C:8](=[O:24])[CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:20](=[O:21])[CH2:19][CH2:18][CH2:17][C@@H:16]1[CH:22]=[O:23])[CH3:6]
Reactant: CCOC(=O)COCCCCN1C(=O)CCC[C@@H]1CO
Agent: O=C([O-])C(F)(F)F
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: CS(C)=O
Product: CCOC(=O)COCCCCN1C(=O)CCC[C@@H]1C=O
Temperature: 0 °C
Reaction time: 4.25 h

Procedure:
1-(3-(Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 505 mg, 2.63 mmol) and DMSO (0.25 mL, 3.52 mmol) were added sequentially to a solution of [4-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-butoxy]-acetic acid ethyl ester (252 mg, 0.88 mmol) in benzene (5 mL). The mixture was cooled to 0° C. and pyridinium trifluoroacetate (187 mg, 0.97 mmol) was added. The reaction was allowed to warm to rt and then was stirred at rt for 4.25 h. The solution was decanted from the oily residue and the residue was washed with benzene (3×5 mL). The combined benzene phases were concentrated in vacuo to afford crude 4-((R)-2-formyl-6-oxo-piperidin-1-yl)-butoxy]-acetic acid ethyl ester that was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1Br.[N+:16]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17].CO.C([O-])([O-])=O.[Na+].[Na+]>[Al].C(OCC)(=O)C.CCCCCC.C1C=CC=CC=1>[NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:16]([O-:18])=[O:17])[CH:24]=1
Reactant: Nc1ccc(Cc2ccncc2)cc1Br
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Al]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(Cc2ccncc2)cc1-c1cccc([N+](=O)[O-])c1
Yield: 85.3 %

Procedure:
4-(4-Amino-3-bromobenzyl)pyridine (1.0 gm), 3-nitrobenzene boronic acid (0.63 gm), palladium tetrakis triphenylphosphine (0.47 gm), methanol (6.5 mL), 2.0M Na2CO3 (1.9 mL) and benzene (32 mL) are combined in a reaction flask that is wrapped in aluminum foil (to prevent exposure of the reagents to light). The reaction mixture is heated to reflux for 6 hours. The progress of the reaction is monitored by thin-layer chromatography (9:1 hexane:ethyl acetate). When the starting material is converted, the reaction mixture is allowed to cool and the solvents are removed. Ethyl acetate is added to the residue, the resultant solution is filtered through a pad of Na2SO4, and concentrated. The product is isolated by preparative thin-layer chromatography (9:1 hexane:ethyl acetate) yielding 983 mg of 4-[4-amino-3-(3-nitrophenyl)benzyl]pyridine as an orange oil.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([CH3:19])=[C:12]2[C:3]=1[CH:4]=[CH:5][C:6]1[S:11][CH2:10][CH2:9][S:8][C:7]=12.[C:20](Cl)(=[O:24])[C:21](Cl)=O>O1CCCC1.CN(C)C=O>[CH3:1][C:2]1[CH:15]=[C:14]([C:16]([O:18][C:2]2[CH2:3][CH2:4][CH2:21][C:20](=[O:24])[CH:1]=2)=[O:17])[C:13]([CH3:19])=[C:12]2[C:3]=1[CH:4]=[CH:5][C:6]1[S:11][CH2:10][CH2:9][S:8][C:7]=12
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(C(=O)O)c(C)c2c3c(ccc12)SCCS3
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)OC2=CC(=O)CCC2)c(C)c2c3c(ccc12)SCCS3
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 0.40 g of the title compound of Step D in 25 mL of tetrahydrofuran was added 0.34 mL of oxalyl chloride (purchased from Aldrich Chemical Co.) and 2 drops of N,N-dimethylformamide. The mixture was refluxed for 2 h and was then concentrated under reduced pressure to dryness. To the resulting residue was added 25 mL of tetrahydrofuran and evaporated to dryness again. Another 25 mL of tetrahydrofuran was added to the residue and the solution was cooled to about 0° C. To this mixture was added 0.16 g of 1,3-cyclohexanedione (purchased from Aldrich Chemical Co.) followed by addition of 0.52 mL of triethylamine. The mixture was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous sodium bicarbonate and the mixture was extracted with methylene chloride. The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to dryness. Chromatography of the crude product on silica gel eluting with a mixture of hexanes:ethyl acetate (8:1 and then 4:1) yielded 0.21 g of the title compound of Step E as a yellow solid melting at 126°-130° C. 1H NMR (CDCl3): δ 2.18 (m, 2H), 2.49 (t, 2H), 2.64 (s, 3H), 2.72 (t, 2H), 2.90 (t, 2H), 3.06 (s, 3H), 3.52 (t, 2H), 6.07 (s, 1H), 7.50 (d, 1H), 7.62 (s, 1H), 7.70 (d, 1H).
Reaction SMILES: S1C2C=CC=CC=2N=C1N(COCC[Si](C)(C)C)C(C1C=CC=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1SC(CN3CCN(C4C=CC=CC=4)CC3)=C(C(OC)=O)N=1)[CH2:19][CH2:18]2)=O.C(C1SC(N2CCC3C(=C(C(=O)/N=C4/SC5C=CC=CC=5N/4COCC[Si](C)(C)C)C=CC=3)C2)=NC=1C(OC)=O)=O.[NH2:94][C:95]1[CH:100]=[CH:99][C:98]([OH:101])=[CH:97][CH:96]=1.CN1CCC(=O)CC1>>[CH3:23][N:20]1[CH2:21][CH2:22][CH:17]([NH:94][C:95]2[CH:100]=[CH:99][C:98]([OH:101])=[CH:97][CH:96]=2)[CH2:18][CH2:19]1
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CN1CCN(c2ccccc2)CC1
Reactant: Nc1ccc(O)cc1
Agent: CN1CCC(=O)CC1
Agent: COC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4/sc5ccccc5n4COCC[Si](C)(C)C)c3C2)sc1C=O
Product: CN1CCC(Nc2ccc(O)cc2)CC1

Procedure:
The compound 104A was prepared in a similar manner to the synthesis of compound 62A by substituting 1-phenylpiperazine and compound 45C with 4-aminophenol and 1-methylpiperidin-4-one, respectively: ESI (+)/LC/MS: 207 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[C:8]([NH2:21])[N:7]=1)[CH2:2][CH2:3][CH3:4].[Br:22]N1C(=O)CCC1=O>C(Cl)Cl>[Br:22][C:11]1[N:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:13]2[C:9]([N:10]=1)=[C:8]([NH2:21])[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=2
Reactant: CCCCOc1nc(N)c2ncn(C3CCCCO3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCCCOc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
The product from step (ii) (30 g) was dissolved in dry DCM (200 ml). The solution was stirred at rt whilst N-bromosuccinimide (27 g) was added portion wise. The mixture was stirred at rt overnight. 20% (w/v)-Sodium sulfate (200 ml) was added and the separated aqueous phase extracted with DCM. The combined organic phase was washed with saturated NaHCO3 solution and brine. After concentration in vacuo, the residue was dissolved in EtOAc, washed with water, brine and dried. The solution was filtered through silica gel. The filtrate was concentrated in vacuo and dissolved in a mixture of diethyl ether and isohexane (1/1, 200 ml) to give the subtitle compound (26 g). The solvent was removed to give a residue, which was purified by column chromatography (EtOAc/isohexane), which afforded 2.5 g. The solids were combined to give the subtitle compound as a yellow solid. Yield 28.5 g. Melting point: 148-150° C.
Reaction SMILES: Cl[C:2]1[N:12](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[N:3]=1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH:34]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:33]1>>[CH3:11][N:8]1[C:9](=[O:10])[C:4]2[NH:3][C:2]([N:32]3[CH2:37][CH2:36][CH2:35][CH:34]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:43])([CH3:42])[CH3:44])[CH2:33]3)=[N:12][C:5]=2[CH:6]=[N:7]1
Reactant: Cn1ncc2c(nc(Cl)n2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1=O
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Product: Cn1ncc2nc(N3CCCC(NC(=O)OC(C)(C)C)C3)[nH]c2c1=O
Temperature: 150 °C
Yield: 98 %

Procedure:
0.020 g of 2-chloro-5-methyl-1-trityl-1,5-dihydroimidazo[4,5-d]pyridazine-4-one and 0.040 g of t-butyl piperidin-3-ylcarbamate were combined together, and the mixture was heated under a nitrogen atmosphere at 150° C. for 1 hour. The reaction mixture was purified by silica gel column chromatography. Thus, 0.016 g of t-butyl [1-(6-methyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl)piperidin-3-yl]carbamate was obtained from the fraction eluted with ethyl acetate. 0.0080 g of this compound was dissolved in 0.6 ml of N,N-dimethylformamide, and then 0.0038 g of potassium carbonate and 0.003 ml of 2-butynyl bromide were added thereto. The mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between 1 ml of ethyl acetate and 1 ml of water, and the organic layer was concentrated. The residue was dissolved in 0.5 ml of dichloromethane, and then 0.5 ml of trifluoroacetic acid was added thereto. After 1 hour, the reaction solution was concentrated. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.0046 g of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1)C.ClC1C=CC2OC=CC=2C=1.NN.C(N)(C)C>>[CH3:1][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1
Reactant: CCc1ccc2occc2c1
Agent: Clc1ccc2occc2c1
Agent: NN
Solvent: CC(C)N
Product: Cc1ccc2occc2c1

Procedure:
5-ethylbenzofuran in the procedure of Example 29 for 5-chlorobenzofuran followed by the synthetic steps of hydrazine reduction, acylation, demethylation, epoxide formation and opening of the epoxide with isopropylamine as described therein gives, ultimately, the following substituted benzofurans:
Reaction SMILES: Br[C:2]1[CH:39]=[CH:38][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[CH:16]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=2)[CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[F:40][C:41]([F:52])([F:51])[C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:36]([C:33]1[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][CH:16](/[CH:15]=[CH:14]/[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:5]2[CH:38]=[CH:39][C:2]([C:45]3[CH:46]=[CH:47][C:42]([C:41]([F:52])([F:51])[F:40])=[CH:43][CH:44]=3)=[CH:3][CH:4]=2)[CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)=[CH:31][CH:32]=1)#[N:37]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccc(Br)cc2)CCc2ccc(C#N)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CCc2ccc(C#N)cc2)cc1
Yield: 57.4 %

Procedure:
270 mg (0.47 mmol) of methyl E-4-{4-[2-(4-bromobenzyloxy)phenyl]-2-[2-(4-cyanophenyl)ethyl]but-3-enyl}benzoate from Example 18A are dissolved in 3 ml of 1,2-dimethoxyethane and, under argon, 106 mg (0.56 mmol) of 4-trifluoromethylphenylboronic acid, 3.3 mg of bis(triphenylphosphine)palladium(II) chloride and 0.51 ml of a 2 M solution of sodium carbonate in water are added. The reaction mixture is then stirred under reflux for 12 hours. The mixture is subsequently cooled, filtered through 1 g of Extrelut, washed with dichloromethane and concentrated. The resulting crude product is purified by preparative HPLC. 175 mg (0.27 mmol, 58% yield) of a colorless solid are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][C@H:19]([F:22])[CH2:18]1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29].C(N(CC)CC)C>C1COCC1>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:23][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([F:24])[CH:26]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][C@H:19]([F:22])[CH2:18]1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCN1CC[C@H](F)C1
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1ncc(Br)c1-c1cc(NC(=O)c2cccc(F)c2)ccc1OCCN1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 39.6 %

Procedure:
A mixture of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-((S)-3-fluoro-pyrrolidin-1-yl)-ethoxy]-phenylamine (76 mg, 0.2 mmol), 3-fluorobenzoyl chloride (32 mg, 0.22 mmol), triethylamine (0.3 mL) in THF (2 mL) was stirred at r.t. for 20 min. The solvent was concentrated in vacuo and the crude was purified by HPLC to give the title compound (40 mg, 40%) as a yellow solid as TFA salt. 1H NMR (DMSO-d6, 400 MHz) δ 1.98-2.10 (m, 2H), 2.90-3.45 (m, 6H), 3.68 (s, 3H), 4.28-4.30 (m, 1H), 4.39-4.42 (m, 1H), 5.28-5.42 (m, 1H), 7.28-7.31 (m, 1H), 7.44-7.49 (m, 1H), 7.57-7.63 (m, 1H), 7.67 (d, 1H), 7.73-7.82 (m, 3H), 7.94 (dd, 1H), 10.4 (s, 2H). Exact mass calculated for C23H23BrF2N4O2 504.1, found 505.5/507.5 (MH+).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][O:10][N:11]=[C:12]1[C:16](=[O:17])[C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[O:13]1>CO>[OH:7][CH2:8][CH2:9][O:10][N:11]=[C:12]1[C:16](=[O:17])[C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[O:13]1
Reactant: O=C1C(=NOCCOC2CCCCO2)Oc2ccccc21
Solvent: CO
Product: O=C1C(=NOCCO)Oc2ccccc21
Yield: 81.6 %

Procedure:
2.07 g (0.01 mol) of benzofuran-2,3-dione 2-{O-[2-(tetrahydropyran-2-yloxy)-ethyl]-oxime} (XIV-2) are dissolved in 12 ml of methanol and stirred at room temperature with 100 mg of acidic ion exchanger resin for 16 hours. 40 ml of methanol are added to the reaction mixture which is then warmed until the crystals have dissolved. The acidic ion exchanger resin is filtered off, the filtrate is concentrated and the residue is recrystallized from 10 ml of toluene. 1.69 g (81.5% of theory) of crystalline benzofuran-2,3-dione 2-[O-(2-hydroxy-ethyl)-oxime] (VII-1) of melting point 110-111° C. are obtained.
Reaction SMILES: [CH2:1](Br)[CH3:2].[Mg].[CH2:5]([N:12]1[CH2:21][CH2:20][C:15]2([O:19][CH2:18][CH2:17][O:16]2)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCOCC.C1C=CC=CC=1>[CH2:5]([N:12]1[CH2:13][CH2:14][C:15]([CH2:1][CH3:2])([O:16][CH2:17][CH2:18][OH:19])[CH2:20][CH2:21]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: c1ccc(CN2CCC3(CC2)OCCO3)cc1
Reactant: CCBr
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCC1(OCCO)CCN(Cc2ccccc2)CC1
Yield: 71.5 %

Procedure:
87.5 g of ethyl bromide dissolved in 100 ml of ether were added dropwise over 30 minutes to 19.2 g of magnesium in 100 ml of ether refluxing in a flask and the resulting solution was cooled. A solution of 46.6 g of 8-benzyl-1,4-dioxa-8-aza-spiro [4,5] decane in 250 ml of benzene was added thereto and the ether was evaporated off. 250 ml. of benzene were added and the mixture was refluxed for 20 hours. The mixture was cooled and hydrolyzed with a saturated aqueous ammonium chloride solution. The benzene phase was decanted and the aqueous phase was extracted with methylene chloride. The methylene chloride phase was washed with water until neutral, dried over sodium sulfate and the solvent was distilled off under reduced pressure. The residue was distilled to obtain 37.6 g of 2-(1-benzyl-4-ethyl-4-piperidyloxy)-ethanol as a colorless oil boiling at 152°-156° C at 0.5 mm Hg which was used as is for the next step.
Reaction SMILES: [NH2:1][CH:2]([CH3:32])[CH:3]([C:14]1[C:15]([CH3:31])=[C:16]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:17]=[CH:18][CH:19]=1)[C:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O=[CH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C1(C)C=CC=CC=1.Cl>O1CCOCC1>[CH2:23]([O:22][C:21]([NH:20][C:16]1[C:15]([CH3:31])=[C:14]([CH:3]2[C:4]3[C:12]4[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=4)[NH:6][C:5]=3[CH:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[NH:1][CH:2]2[CH3:32])[CH:19]=[CH:18][CH:17]=1)=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)C=O
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1C(c1c[nH]c2cc(Br)ccc12)C(C)N
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)C1NC(C)C(c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a homogeneous solution of benzyl (3-(2-amino-1-(6-bromo-1H-indol-3-yl)propyl)-2-methylphenyl)carbamate (4.00 g, 8.12 mmol) in dioxane (200 mL) under nitrogen was added 50% ethyl 2-oxoacetate in toluene (3.22 mL, 16.3 mmol) followed by 4 M hydrochloric acid in 1,4-dioxane (4.06 mL, 16.3 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (150 mL), washed with saturated aqueous sodium bicarbonate (75 mL), and washed with brine (75 mL). The organic layer was collected, and the aqueous layers were sequentially extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give ethyl 4-(3-(((benzyloxy)carbonyl)amino)-2-methylphenyl)-7-bromo-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylate in a quantitative yield as a burgundy solid. The mixture was used in the next step without any further purification. LC/MS M+1=576.2 and 578.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([CH2:11][C:12](O)=[O:13])=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([O:15][CH2:16][C:17]2[N:21]([CH3:22])[N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH:3]=1.C1COCC1.C(Cl)(=O)C(Cl)=O.C[N:39](C=O)C>>[Cl:1][C:2]1[C:7]2[C:8]([CH2:11][C:12]([NH2:39])=[O:13])=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([O:15][CH2:16][C:17]2[N:21]([CH3:22])[N:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=2)[CH:3]=1
Reactant: Cn1nc(C(F)(F)F)cc1COc1cc(Cl)c2c(CC(=O)O)csc2c1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: Cn1nc(C(F)(F)F)cc1COc1cc(Cl)c2c(CC(N)=O)csc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of (4-chloro-6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methoxy)-1-benzothiophen-3-yl)acetic acid (365 mg) and THF (dry) (5 mL) were added oxalyl chloride (0.095 mL) and DMF (6.98 μl) at room temperature. The mixture was stirred at room temperature for 20 min. The mixture was concentrated under reduced pressure. The residue was dissolved in THF (5 mL), and the solution was poured into stirred 28% aqueous ammonium hydroxide (5 mL) at room temperature. After stirring at room temperature for 15 min, the mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The solid was crystallized from MeOH to give the title compound (320 mg).
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12]C(=O)C)[C@H:10]([O:16]C(=O)C)[C@@H:9]([O:20]C(=O)C)[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH2:44][N:45]4[CH2:50][C:49]5([CH2:55][CH2:54][N:53]([C:56](=[O:66])[CH2:57][NH:58][C:59](=[O:65])[NH:60][CH2:61][CH:62]([CH3:64])[CH3:63])[CH2:52][CH2:51]5)[CH2:48][CH2:47][CH2:46]4)=[CH:37][CH:36]=3)=[CH:25]2)[O:7]1)(=O)C.CO.C[O-].[Na+]>O>[CH2:61]([NH:60][C:59]([NH:58][CH2:57][C:56]([N:53]1[CH2:54][CH2:55][C:49]2([CH2:48][CH2:47][CH2:46][N:45]([CH2:44][CH2:43][CH2:42][O:41][C:38]3[CH:37]=[CH:36][C:35]([CH2:34][C:26]4[C:27]5[C:32](=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])[N:24]([C@H:8]5[C@H:9]([OH:20])[C@@H:10]([OH:16])[C@H:11]([OH:12])[C@@H:6]([CH2:5][OH:4])[O:7]5)[CH:25]=4)=[CH:40][CH:39]=3)[CH2:50]2)[CH2:51][CH2:52]1)=[O:66])=[O:65])[CH:62]([CH3:64])[CH3:63]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(OCCCN4CCCC5(CCN(C(=O)CNC(=O)NCC(C)C)CC5)C4)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cccc2c1c(Cc1ccc(OCCCN3CCCC4(CCN(C(=O)CNC(=O)NCC(C)C)CC4)C3)cc1)cn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 0.17 h
Yield: 89.4 %

Procedure:
Cool a mixture of [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[[4-[3-[9-[2-(isobutylcarbamoylamino)acetyl]-4,9-diazaspiro[5.5]undecan-4-yl]propoxy]phenyl]methyl]-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate (74.28 mmoles; 68.20 g) and methanol (341.00 mL) in an ice-bath. Add sodium methoxide (111.43 mmoles; 6.02 g). Stir the mixture for 10 minutes. Pour the mixture into water (3.5 L), then filter the mixture. Wash the solid with water, dry on the sinter, and further dry in a vacuum oven at 60° C. to give the title compound (49.8 g, 89% yield) mass spectrum (m/z): 750.6 (M+1).