Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:15]=[CH:14][N:13]=2)[CH:5]=1.[NH2:25][NH2:26]>CCO>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=3[CH3:10])[C:3]([NH:25][NH2:26])=[O:2])[N:17]=2)[CH:19]=1
Reactant: NN
Reactant: COC(=O)c1ccc(C)c(Nc2nccc(-c3cccnc3)n2)c1
Solvent: CCO
Product: Cc1ccc(C(=O)NN)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C

Procedure:
4-Methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzoic acid methyl ester 4 (3.2 g, 10 mmol) and hydrazine (6 mmol) are dissolved in dry EtOH (20 mL) and heated at reflux overnight. The mixture is cooled to room temperature. The solid is filtered, washed with water and dried under vacuum overnight to afford the product 6 as a light yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 9.68 (s, 1H), 9.26 (m, 1H), 9.06 (s, 1H), 8.69 (dd, J=4.7, 1.5H, 1H), 8.52 (d, J=5.1, 1.2 Hz, 1H), 8.43 (m, 1H), 8.1 (dd, J=5.8, 1.6 Hz, 1H), 7.56 (m, 2H), 7.46 (dd, J=5.1, 1.6 Hz, 1H), 7.3 (d, J=7.9 Hz, 1H), 4.45 (s, 1H), 3.33 (s, 3H), 3.31 (s, 1H). MS (m/z) (M+1)+: 321.1.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.[C:25]([O:29][C:30]([N-:32][S:33](N1C=CC(=[N+](C)C)C=C1)(=[O:35])=[O:34])=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(#N)C>[C:25]([O:29][C:30]([NH:32][S:33]([NH:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1)(=[O:35])=[O:34])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN)C1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NS(=O)(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 116.4 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (100 mg) in acetonitrile (2 mL) was added N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide (181 mg) prepared by the method described in Organic Letters, 2001, 3 (14), 2241-2243, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, distilled water was added to the residue, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (172 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:33])[C:14]2[O:20][C:19]3[C:21]([Cl:29])=[CH:22][C:23]([NH:25][CH2:26][CH2:27]Cl)=[CH:24][C:18]=3[CH2:17][S:16](=[O:31])(=[O:30])[C:15]=2[CH:32]=1)=[O:10]>CN(C=O)C>[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:33])[C:14]2[O:20][C:19]3[C:21]([Cl:29])=[CH:22][C:23]([NH:25][CH2:26][CH2:27][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:24][C:18]=3[CH2:17][S:16](=[O:30])(=[O:31])[C:15]=2[CH:32]=1)=[O:10]
Reactant: C1CCNCC1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCN3CCCCC3)cc(Cl)c1O2

Procedure:
Piperidine (0.184 g, 2.16 mmol) was added with stirring to a solution of Example 56k. (0.6 g, 1.4 mmol) in DMF (1 mL) in an inert atmosphere and heated at 90° C. for 4 h. The reaction mixture was concentrated, treated with water, and the solid that precipitated was filtered, washed with water and purified using flash chromatography (silica gel, 2% methanol/chloroform) to obtain the title compound. Yield: 0.330 g, (48%); 1H NMR (CDCl3): δ 1.18 (bs, 2H, CH2), 1.32 (t, 4H, 2CH2), 2.21 (s, 3H, CH3), 2.3 (t, 2H, CH2), 2.4 (t, 2H, CH2), 2.8 (m, 4H, 2CH2), 3.41 (s, 3H, OCH3), 4.28 (s, 2H, CH2), 5.39 (bs, 1H, NH), 6.15 (s, 2H, Ar), 7.6 (s, 1H, Ar), 7.82 (s, 1H, Ar); MS: m/e (ES+) 478 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:3]1.[CH2:23]([O:25][C:26]([CH:28]1[CH2:30][CH:29]1[CH:31]=O)=[O:27])[CH3:24].C(=O)CCC>>[CH2:23]([O:25][C:26]([CH:28]1[CH2:30][CH:29]1[CH2:31][N:19]1[CH2:18][CH2:17][N:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:4]2[CH2:3][C:2]([CH3:22])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]2)[CH2:21][CH2:20]1)=[O:27])[CH3:24]
Reactant: CCOC(=O)C1CC1C=O
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Solvent: CCCC=O
Product: CCOC(=O)C1CC1CN1CCN(c2ccccc2C2CC(C)(C)CC(C)(C)C2)CC1

Procedure:
1-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazine (2.1 g, 7 mmol) produced in Example (8b) was used as a starting material. Reaction was conducted in a manner similar to Example (4g), using 2-formyl-1-cyclopropanecarboxylic acid ethyl ester (cis/trans mixture, predominantly trans) instead of butyraldehyde, and similar treatment was carried out to give 2.4 g of 2-{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropanecarboxylic acid ethyl ester as a colorless oil.
Reaction SMILES: NC1SC2C3C(CC=2[C:3]=1[C:14](N)=[O:15])=CC=CC=3.[NH2:17][C:18]1[S:22][C:21]2[C:23]3[C:28]([CH2:29][CH2:30][C:20]=2[C:19]=1[C:33]([NH2:35])=[O:34])=[CH:27][C:26]([O:31][CH3:32])=[CH:25][CH:24]=3>>[C:14]([NH:17][C:18]1[S:22][C:21]2[C:23]3[C:28]([CH2:29][CH2:30][C:20]=2[C:19]=1[C:33]([NH2:35])=[O:34])=[CH:27][C:26]([O:31][CH3:32])=[CH:25][CH:24]=3)(=[O:15])[CH3:3]
Reactant: NC(=O)c1c(N)sc2c1Cc1ccccc1-2
Reactant: COc1ccc2c(c1)CCc1c-2sc(N)c1C(N)=O
Product: COc1ccc2c(c1)CCc1c-2sc(NC(C)=O)c1C(N)=O

Procedure:
The title compound was prepared by the same procedure as Example 3 except that 2-amino-4H-indeno[1,2-b]thiophene-3-carboxylic acid amide was replaced with 2-amino-7-methoxy-4,5-dihydro-naphtho[1,2-b]thiophene-3-carboxylic acid amide to give the above title compound as light grey solid. ESMS m/z: 317 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[C:7]([O:20][CH3:21])=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[C:7]([O:20][CH3:21])=[CH:6][C:3]=1[CH2:4][NH2:5]
Reactant: COc1ccc(COc2cc(F)c(C#N)cc2OC)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(COc2cc(F)c(CN)cc2OC)cn1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 58 %

Procedure:
To a 0° C. stirred solution of 2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzonitrile (3.25 g, 11.27 mmol) in tetrahydrofuran (50 mL) was added (in three portions) lithium aluminum hydride (0.86 g, 22.55 mmol). Mild gas evolution was noted upon each addition, and the color of the reaction mixture became olive-green. After 1.5 h, the mixture was quenched by the slow addition of water (1.0 mL), 15% sodium hydroxide solution (1.0 mL), and water (3.0 mL). The resulting off-white suspension was allowed to stir at 0° C. After 15 min, the mixture was filtered through Celite with the aid of ethyl acetate. The filtrate was concentrated to provide 1.91 g (58%) of (2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine as a crude oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:29][Si:30]([CH3:37])([CH3:36])[CH2:31][CH2:32][O:33][CH2:34]Cl>CN(C=O)C.C1COCC1>[CH3:29][Si:30]([CH3:37])([CH3:36])[CH2:31][CH2:32][O:33][CH2:34][N:11]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=[CH:10]1
Reactant: Fc1ccc(-c2nc[nH]c2-c2ccncc2)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazole (3) (1 g 4.18 mmol) is dissolved in DMF/THF (50 ml/20 ml) and cooled to −78° C. Potassium bis-(trimethylsilyl)-amide (15% in toluene; 6.7 ml 5 mmol) is introduced at −78° C., stirred for 30 min. then 2-(trimethylsilyl)ethoxymethylchloride is added and the reaction mixture warmed up to r.t., poured on water after 2 hrs. and extracted 3× with ethyl acetate. The combined organic phases are dried over Na2SO4, evaporated to dryness and chromatographed (SiO2 acetone/hexane 4/6 to 6/4) to give 1-(2-(trimethylsilyl)ethoxymethyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole, being eluted first as white crystals (218 mg 14%) followed by 4-(4-pyridyl)-5-(4-fluorophenyl)-1-(2-(trimethylsilyl)ethoxymethyl) imidazole as white crystals (590 mg 38%). The correct assignment of the structures was achieved by ROESY, HSQC and HMBC spectrometry.
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[C:26][Si](C)(C)C)=[CH:21][C:20]=3[CH3:31])=[C:16]([F:32])[C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1.O>[CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[CH:26])=[CH:21][C:20]=3[CH3:31])=[C:16]([F:32])[C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: Cc1cc(C#C[Si](C)(C)C)ccc1Nc1c(C(=O)NOCC2CC2)cc2[nH]cnc2c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(Nc2c(C(=O)NOCC3CC3)cc3[nH]cnc3c2F)c(C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
7-Fluoro-6-(2-methyl-4-trimethylsilanylethynyl-phenylamino)-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide 11bbb (0.020 g, 0.044 mmol) is dissolved in tetrahydrofuran (0.50 mL) and the reaction solution is cooled to 0° C. TBAF (50 uL, 0.050 mmol, 1 M solution in tetrahydrofuran) is added. The reaction mixture is warmed to room temperature and additional TBAF (25 uL, 0.025 mmol, 1 M solution in tetrahydrofuran) is added. The reaction mixture is stirred at 50° C. for 2 hours under N2. The reaction mixture is cooled to room temperature, a few drops of H2O are added and then it is concentrated under reduced pressure. The residue is purified by FCC (eluting with 20:1 methylene chloride:methanol) to yield 0.011 g (65%) of the pure desired product. MS APCI (−) m/z 377 (M−1) detected; 1H NMR (400 MHz, CDCl3) δ 10.56 (broad s, 1H), 8.12 (s, 1H), 7.99 (s, 1H), 7.28 (s, 1H), 7.11 (d, 1H), 6.42 (broad, 1H), 3.70 (br s, 2H), 2.96 (d, 1H), 2.37 (s, 3H), 0.85 (m, 2H), 0.22 (m, 2H).
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1.Br[CH2:21][CH:22]=[CH2:23]>CN(C)C=O.[Ag]=O>[CH2:23]([O:3][C@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C@@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1)[CH:22]=[CH2:21]
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: C=CCBr
Agent: O=[Ag]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCO[C@@H]1C[C@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
1.55 g (38.6 mmol) of sodium hydride are added in portions under nitrogen to the solution of 10.3 g (42 mmol) of 1-tert-butyl 2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate and 36.34 ml (420 mmol) of 3-bromo-1-propene in 100 ml of dimethylformamide (DMF), and the mixture is subsequently stirred at room temperature for 15 minutes. 9.73 g (42 mmol) of silver oxide are then added in portions to the reaction mixture, and the reaction mixture is left to stir at room temperature for a further 12 hours: The reaction mixture is then filtered, the filtrate is evaporated to dryness under reduced pressure, and the residue is taken up in 20 ml of saturated citric acid solution. After the precipitate has been filtered off, the filtrate is extracted twice with 20 ml of ethyl acetate each time. Drying of the combined organic phases over sodium sulfate and stripping-off of the solvent gives 11.6 g of 1-tert-butyl 2-methyl (2R,4R)-4-allyloxypyrrolidine-1,2-dicarboxylate as a red-brown oil; ESI 286.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[Br:21]Br>ClCCl>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Br:21])[CH:12]=2)=[CH:8][CH:9]=1
Reactant: BrBr
Reactant: COC(=O)c1ccc(C(=O)c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)c2ccc(OC)c(Br)c2)cc1
Temperature: 25 °C

Procedure:
To the solution of 4-(4-methoxy-benzoyl)-benzoic acid methyl ester (3.4 g, 12.6 mmol) in dichloromethane (10 mL) is added bromine (2.4 g, 15.1 mmol). The solution is stirred at room temperature till the starting material is gone. Then the mixture is diluted with dichlormethane, washed with 1N NaOH, water, brine, dried, and purified with column chromatography to give the titled compound as a yellow solid: 4.42 g (100%).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[C:5]([CH:20]=O)[CH:4]=1)#[N:2].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(O)(=O)C.C([BH3-])#N>CO.O>[OH:16][B:15]1[C:11]2[CH:10]=[CH:9][C:8]([O:7][C:6]3[CH:18]=[CH:19][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[CH2:20][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:17][C:12]=2[CH2:13][O:14]1
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)c(C=O)c1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)c(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.7 %

Procedure:
A mixture of 5-(4-Cyano-2-formylphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (D23) (0.400 g, 1.43 mmol), morpholine (0.375 mL, 4.29 mmol), and acetic acid (0.246 mL, 4.29 mmol) in methanol (10 mL) was stirred for five minutes under nitrogen at room temperature. Cyanoborohydride (0.270 g, 4.29 mmol) was added, and the mixture was stirred at room temperature under nitrogen for two hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (5:5 ethyl acetate:hexanes to 4:1 dichloromethane/methanol). The desired fractions were combined and the solvent was removed under reduced pressure. Water and toluene were added and removed under reduced pressure to give pure 4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-3-(morpholinomethyl)benzonitrile (0.399 g, 80%).
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[O:10][C:9]([CH3:14])([CH3:13])[O:8][C:7]=2[CH:15]=1.CC(C)=[O:19]>O.[N+]([O-])([O-])=O.[Ag+]>[CH3:13][C:9]1([CH3:14])[O:8][C:7]2[CH:15]=[C:3]([CH:2]=[O:19])[CH:4]=[CH:5][C:6]=2[C:11](=[O:12])[O:10]1
Reactant: CC1(C)OC(=O)c2ccc(C(Br)Br)cc2O1
Reactant: CC(C)=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: CC1(C)OC(=O)c2ccc(C=O)cc2O1
Temperature: 25 °C
Reaction time: 14 h
Yield: 57 %

Procedure:
To a solution of 7-(dibromomethyl)-2,2-dimethyl-4H-1,3-benzodioxin-4-one (6.0 g, 17 mmol) in acetone (20 mL) and water (40 mL) under nitrogen was added AgNO3 (6.0 g, 35 mmol). The reaction mixture was stirred at rt for 14 hours, then filtered through a pad of Celite. The solvents were removed under reduced pressure. The residue was purified by chromatography (pet ether/EtOAc 9/1) to give 2.0 g (57%) of the titled compound as a solid. TLC-Pet Ether/EtOAc (7/3): Rf=0.7.
Reaction SMILES: [CH:1]1([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][O:11][CH:12]([O:16][CH3:17])[CH2:13][CH2:14]Br>>[CH3:10][O:11][CH:12]([O:16][CH3:17])[CH2:13][CH2:14][C:1]1([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1CCCC1
Reactant: COC(CCBr)OC
Product: COC(=O)C1(CCC(OC)OC)CCCC1
Yield: 72 %

Procedure:
Prepared according to a procedure identical to Stage A of Example 6, starting from methyl cyclopentanecarboxylate and 3-bromopropionaldehyde dimethyl acetal, with a 72% yield.
Reaction SMILES: O.[PH2:2]([O-:4])=[O:3].[Na+].S(=O)(=O)(O)O.C=C.OO.[C:15]([O-])(=O)[CH3:16].[Al+3:19].[C:20]([O-])(=O)[CH3:21].[C:24]([O-])(=O)[CH3:25].[Al+3].C(P(CC)(=O)[O-])C.C(P(CC)(=O)[O-])C.C(P(CC)(=O)[O-])C>O>[Al+3:19].[CH2:15]([P:2]([O-:4])[O-:3])[CH3:16].[CH2:20]([P:2]([O-:4])[O-:3])[CH3:21].[CH2:24]([P:2]([O-:4])[O-:3])[CH3:25].[Al+3:19]
Reactant: CC(=O)[O-]
Reactant: O=[PH2][O-]
Agent: C=C
Agent: CCP(=O)([O-])CC
Agent: O=S(=O)(O)O
Solvent: O
Product: CCP([O-])[O-]
Temperature: 100 °C
Yield: 92.6 %

Procedure:
1500 g (14 mol) of sodium hypophosphite monohydrate and 35 g of concentrated sulfuric acid are dissolved in 7.5 kg of water and initially charged in a 16 l steel-enamel jacketed pressure reactor. After heating the reaction mixture to 100° C., a reducing valve set to 6 bar is used to introduce ethylene into the reactor up to saturation. While stirring constantly at an ethylene pressure of 3 bar and a temperature of about 100° C., a solution of 80 g (5 mol %) of hydrogen peroxide (33% by weight) in 300 g of water is metered in homogeneously. At a conversion of ethylene of 90%, the metered addition of hydrogen peroxide is stopped and the reactor is decompressed. After cooling to about 90° C., 746 g (4.67 mol of aluminum) of aluminum acetate in 2254 g of water are added within 60 minutes. Subsequently, the resulting solid is filtered off, washed with 2 l of hot water and dried at 130° C. under reduced pressure. The resulting mixture comprises diethylphosphinic acid aluminum(III) salt and ethylphosphonous acid aluminum(III) salt in a ratio of 88.6% by weight of diethylphosphinic acid aluminum(III) salt and 11.4% by weight of ethylphosphonous acid aluminum(III) salt (92.6% yield).
Reaction SMILES: [CH2:1]([OH:34])[C@H:2]1[O:7][C@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@@H:12]([O:17][C@H]3[C@H](O)[C@@H](O)[C@@H](O)O[C@@H]3CO)[O:11][C@@H:10]2[CH2:29][OH:30])[C@H:5]([OH:31])[C@@H:4]([OH:32])[C@@H:3]1[OH:33].C(O)[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O)O[C@@H]4CO)O[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O.C(O)[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O.C(O)[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)C(O)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O.C(O)[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)C(O)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O>>[CH2:1]([OH:34])[C@H:2]1[O:7][C@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([OH:17])[O:11][C@@H:10]2[CH2:29][OH:30])[C@H:5]([OH:31])[C@@H:4]([OH:32])[C@@H:3]1[OH:33]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)[C@@H](O)[C@@H](O)O[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O)O[C@@H]4CO)O[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)C(O)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Product: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
Maltotriose (G3), Maltotetraose (G4), Maltopentaose (G5), Maltohexaose (G6), Maltoheptaose (G7), and Amylose DP-17: manufactured by Hayashibara Biochemical Co.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:17][CH:16]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCCN4CCNCC4)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCCN4CCNCC4)cc3)cc12
Temperature: 70 °C
Reaction time: 24 h
Yield: 46.1 %

Procedure:
To a solution of methyl 6-chloro-5-{4-[3-(piperazin-1-yl)propoxy]phenyl}-1H-indole-3-carboxylate (90 mg, 0.22 mmol) in methanol (8 mL) was added 1.0M aqueous NaOH (2.0 mL, 2.0 mmol). The mixture was stirred at 70° C. for 24 hours. The mixture was adjusted to pH 7 and purified by reverse phase HPLC to give the title compound (42 mg, 47% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[C:25](O)(=[O:29])[CH:26]([CH3:28])[CH3:27]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@H]3CCCN3)c2c1N
Reactant: CC(C)C(=O)O
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H]3CCCN3C(=O)C(C)C)c2c1N

Procedure:
Prepared as in Example 24a from (R)-ethyl 4-amino-2-methyl-5-(pyrrolidin-2-ylmethoxy)quinoline-3-carboxylate (Example 92b) and isobutyric acid as brown solid (39%). MS 400 (MH+).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[C:13]([OH:20])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:20][C:13]1[C:14]([C:16]([O:18][CH3:19])=[O:17])=[N:15][C:10]([Br:9])=[CH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1nc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1nc(Br)ccc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
Benzyl bromide (3.87 g, 22.6 mmol), was added to a suspension of methyl 6-bromo-3-hydroxypicolinate (5.00 g, 21.6 mmol) and K2CO3 (5.96 g, 43.1 mmol) in anhydrous DMF (40 mL). The reaction mixture was heated at 60° C. for 18 hours, cooled to rt, and poured into an ice/water mixture. After stirring for 2.5 hours, the precipitate was collected by filtration, washed with water, and dried to provide the desired product methyl 3-(benzyloxy)-6-bromopicolinate (29A).