Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl.Cl.N1CCCCC1>>[CH:2]([C:3]1[CH:11]=[CH:10][C:8]([O:9][CH2:12][CH:14]2[O:16][CH2:15]2)=[C:5]([O:6][CH3:7])[CH:4]=1)=[O:1]
Reactant: ClCC1CO1
Reactant: COc1cc(C=O)ccc1O
Agent: Cl
Solvent: C1CCNCC1
Product: COc1cc(C=O)ccc1OCC1CO1
Reaction time: 4 h

Procedure:
A mixture of 50 g. of vanillin, 77 ml. of epichlorohydrin and 0.33 g. of piperidine hydrochloride is heated at 95°-100°C. for 4 hours. The excess epichlorohydrin is removed by evaporation under reduced pressure and the residue is distilled at 178°-183°C./0.6-0.7 mm. The distilled product is stirred rapidly with 400 ml. of aqueous N-sodium hydroxide solution for 4 hours, and the solid is extracted from the mixture with 400 ml. of chloroform. The chloroform solution is dried and evaporated to dryness and there is thus obtained as residue 1-(4-formyl-2-methoxyphenoxy)-2,3-epoxypropane, a pale yellow solid which is used without further purification. A solution of 5 g. of 1-(4-formyl-2-methoxyphenoxy)-2,3-epoxypropane and 50 ml. of isopropylamine in 50 ml. of chloroform is heated under reflux for 18 hours. The mixture is evaporated to dryness and the residue is crystallised from a mixture of benzene and petroleum ether (b.p. 60°-80°C.). There is thus obtained 1-[2-methoxy-4-(N-isopropyliminomethyl)phenoxy]-3-isopropylamino-2-propanol. A mixture of the above compound, 75 ml. of concentrated aqueous hydrochloric acid and 75 ml. of water is heated under reflux for 4 hours. The aqueous hydrochloric acid is removed by evaporation and the residue is partitioned between 100 ml. of chloroform and 100 ml. of aqueous 2N-hydrochloric acid. The aqueous acidic layer is separated, made alkaline with sodium carbonate and extracted twice with 100 ml. of chloroform each time. The combined extracts are dried and evaporated to dryness. The residual basic oil is converted to the oxalate thereof by conventional means, and the oxalate is crystallised from a mixture of methanol and water. The oxalate is reconverted to the free base by conventional means, and the base is crystallised from a mixture of ethyl acetate and petroleum ether (b.p. 60°-80°C.). There is thus obtained 3-isopropylamino-1-(4-formyl-2-methoxyphenoxy)-2-propanol, m.p. 56°-58°C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:9]([CH3:24])[NH:8][C:7]=1[CH:25]=[CH:26][N:27](C)C)=O)C.O>N.C(O)C>[CH2:22]([O:21][C:19]([C:10]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:6]2[C:4](=[O:3])[NH:27][CH:26]=[CH:25][C:7]=2[NH:8][C:9]=1[CH3:24])=[O:20])[CH3:23]
Reactant: CCOC(=O)C1=C(C)NC(C=CN(C)C)=C(C(=O)OCC)C1c1cccc(Cl)c1
Agent: N
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1cccc(Cl)c1

Procedure:
6.0 g (14.3 mmol) 1,4-dihydro-4-(3-chlorophenyl)-2-(2-dimethylamino ethenyl)-6-methyl pyridine-3,5-dicarboxylic acid diethyl ester are kept for six hours at boiling temperature in a mixture of 60 ml concentrated aqueous ammonia solution and 60 ml ethanol. After cooling, the solution is reduced to half the volume under vacuum. Water is added and the solution is extracted twice with chloroform. The chloroform solution is washed with a small amount of water and dried over sodium sulfate. The residue obtained after distilling off the solvent is chromatographed over silica gel with methylene chloride/methanol.ammonia (9:1, v/v) and recrystallized from methanol. There is obtained 1,4,5,6-tetrahydro-4-(3-chlorophenyl)-2-methyl-5-oxo-1,6-naphthyridine-3-carboxylic acid ethyl ester in form of beige crystals with a melting point of 152°-155° C. (decomposition).
Reaction SMILES: [Mg].BrCC.Br[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1.[C:20](OCC)(=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>O.C1COCC1>[O:26]=[C:20]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Brc1ccccc1COC1CCCCO1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCBr
Solvent: O
Product: CCOC(=O)C(=O)c1ccccc1COC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
Magnesium (2.67 g, 0.11 mol) and bromoethane (0.2 ml) were added to a mixed solution of 1-bromo-2-(2-tetrahydropyranyloxymethyl)benzene (27.11 g, 0.10 mol) and THF (50 ml) under an atmosphere of nitrogen gas. The mixture was stirred at room temperature for 1 hour to prepare a Grignard reagent. The Grignard reagent was added dropwise to a mixed solution of diethyl oxalate (29.23 g, 0.20 mol) and THF (100 ml) cooled to -78° C. The mixture was stirred at -78° C. for 1 hour, water (150 ml) was added, and the mixture was extracted with ether (200 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain ethyl 2-oxo-2-[2-(2-tetrahydropyranyloxymethyl)phenyl]acetate (22.60 g, Yield: 77.3%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([CH3:19])([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:8]=1)[CH3:5].Cl.[H][H]>CO.[Pt]>[CH3:1][O:2][C:3](=[O:20])[C:4]([CH3:5])([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)[CH:8]=1)[CH3:19]
Reactant: COC(=O)C(C)(C)Oc1cccc(-c2cccnc2)c1
Reactant: [H][H]
Agent: [Pt]
Agent: Cl
Solvent: CO
Product: COC(=O)C(C)(C)Oc1cccc(C2CCCNC2)c1
Yield: 88.9 %

Procedure:
2-Methyl-2-(3-pyridin-3-yl-phenoxy)-propionic acid methyl ester (4.07 g, 15.0 mmol) was dissolved in methanol (40 mL) and followed by the addition of 37% HCl (3.8 mL) and 10% Pt/C (0.41 g). The mixture was shaken with hydrogen under 50 psi at 50° C. in a Parr bottle for 2 h, filtered through a pad of Celite, and rinsed with methanol. After solvent removal, the residue was treated with saturated aqueous Na2CO3 (100 mL) and extracted with ethyl acetate (2×100 mL). The organic extract was washed with water, dried over sodium sulfate, and concentrated to give 3.70 g (89%) of 2-methyl-2-(3-piperidin-3-yl-phenoxy)-propionic acid methyl ester as a yellow oil: 1H NMR (CDCl3) δ 1.57 (br m, 1H), 1.60 (s, 6H), 1.78 (br, 1H), 1.86 (br, 1H), 1.97 (brd, 1H), 2.61 (m, 3H), 3.06–3.13 (m, 2H), 3.76 (s, 3H), 6.61 (dd, 1H), 6.70 (s, 1H), 6.83 (d, 1H), 7.14 (t, 1H); MS m/z (relative intensity) 277 (M+, 2), 218 (6), 176 (100).
Reaction SMILES: [N:1]([C:4]1([CH3:19])[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH:5]1[OH:18])=[N+]=[N-].CP(C)C>C1COCC1.O>[NH2:1][C:4]1([CH3:19])[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][CH2:6][CH:5]1[OH:18]
Reactant: CC1(N=[N+]=[N-])CCN(Cc2ccccc2)CCC1O
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC1(N)CCN(Cc2ccccc2)CCC1O
Temperature: 65 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
To a solution of 5-azido-1-benzyl-5-methylazepan-4-ol (1.5 g, 5.76 mmol) in THF (12 mL) and water (4 mL) was added slowly a solution of trimethylphosphine (1 M in toluene, 28 mL, 28.9 mmol) and the reaction was stirred at 65° C. for 18 hr. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was dissolved in 1 M HCl (30 mL) and extracted with EtOAc (2×25 mL). The aqueous layer was basified to pH14 with aqueous 6 M NaOH and extracted with DCM (3×30 mL). The combined organic layers were passed through a phase separation cartridge concentrated under reduced pressure. Purification via silica gel column chromatography (1-10% 7 M NH3 in MeOH/DCM) gave 5-amino-1-benzyl-5-methylazepan-4-ol as a viscous yellow oil (1.2 g, 89%). 1H NMR (400 MHz, CDCl3) δ 7.34-7.20 (m, 5H), 3.60-3.52 (m, 2H), 3.50-3.46 (m, 2H), 2.80-2.79 (m, 1H), 2.70-2.45 (m, 4H), 2.15-1.95 (m, 1H), 1.79-1.72 (m, 2H), 1.49-1.40 (m, 2H), 1.19 (s, 3H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:22](=[O:36])[CH2:23][N:24]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.Cl.[CH3:54][O:55][C:56](=[O:59])[CH2:57][NH2:58]>CN(C)C=O.O1CCCC1.C(N(CC)CC)C>[CH3:54][O:55][C:56](=[O:59])[CH2:57][NH:58][C:19]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[C:13]([C:22](=[O:36])[CH2:23][N:24]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:25]([CH3:26])([CH3:27])[CH3:28])[CH:12]=[CH:11][C:10]=2[O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:21]
Reactant: COC(=O)CN
Reactant: CC(C)(C)N(CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(C(=O)O)cc12)Cc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)c1cc2c(C(=O)CN(Cc3ccccc3)C(C)(C)C)ccc(OCc3ccccc3)c2[nH]1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
1.00 g of 7-benzyloxy-4-(N-benzyl-N-tert-butylaminoacetyl)-2-indolecarboxylic acid hydrochloride is combined with 4 ml of absolute dimethylformamide and 8 ml of absolute tetrahydrofuran, cooled to -10° C., and combined with 0.52 ml of N-ethylmorpholine and, 5 minutes later, with 0.28 ml of isobutyl chloroformate. The mixture is allowed to stand at -5° C. for 30 minutes, 376 mg of aminoacetic acid methyl ester hydrochloride, 0.39 ml of triethylamine--dissolved in 4 ml of absolute dimethylformamide and 6 ml of absolute tetrahydrofuran--are added thereto, the mixture is stirred for 16 hours at room temperature, concentrated, the residue is taken up in ethyl acetate/water, and the aqueous phase is acidified with 1N hydrochloric acid and once again extracted with ethyl acetate. The combined organic phases are dried, concentrated, and chromatographed over an aluminum oxide column (activity stage II; eluent: methanol/chloroform 1+4), thus obtaining 600 mg of N-[7-benzyloxy-4-(N-benzyl-N-tert-butylaminoacetyl)-2-indolylcarbonyl]aminoacetic acid methyl ester, mp 151.5°-152.5° C. (from methanol/diisopropyl ether).
Reaction SMILES: N#N.[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][C:12](=[CH2:15])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].B1C2CCCC1CCC2.Br[C:26]1[CH:36]=[CH:35][C:29]2[O:30][C:31]([F:34])([F:33])[O:32][C:28]=2[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(Cl)Cl>[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][CH:12]([CH2:15][C:36]2[CH:26]=[CH:27][C:28]3[O:32][C:31]([F:33])([F:34])[O:30][C:29]=3[CH:35]=2)[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: C=C1CCN(C(=O)OC(C)(C)C)C1
Reactant: FC1(F)Oc2ccc(Br)cc2O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc3c(c2)OC(F)(F)O3)C1
Temperature: 25 °C
Yield: 96.7 %

Procedure:
A stream of N2 was bubbled through neat 3-methylene pyrrolidine-1-carboxylic acid tert-butyl ester (792 mg, 4.33 mmol) for 15 min before charging the flask with 9-BBN (0.5 M in THF, 8.8 mL). The reaction mixture was heated at reflux for 2.5 h; then cooled to rt. The resultant mixture was then added, via cannula, to a preformed solution consisting of 5-bromo-2,2-difluoro-1,3-benzodioxole (1.01 g, 4.24 mmol), Pd(dppf)Cl2.CH2Cl2 (92 mg), and potassium carbonate (760 mg, 5.50 mmol) in DMF/H2O (10 mL/1 mL). The reaction mixture was heated at 60° C. for 18 h, cooled to rt and poured into water. The pH of the mixture was adjusted to 11 with NaOH (1 N), and extracted with EtOAc (3×). The organic layers were combined, dried (Na2SO4), and concentrated. The crude residue was purified (FCC) to give the title compound (1.4 g, 94%).
Reaction SMILES: [C:1]([C:5]1[C:6]([O:20][CH:21]([CH3:23])[CH3:22])=[C:7]([C:10]([CH3:19])=[C:11]([C:13]#[C:14][Si](C)(C)C)[CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O1CCCC1>[C:1]([C:5]1[C:6]([O:20][CH:21]([CH3:23])[CH3:22])=[C:7]([C:10]([CH3:19])=[C:11]([C:13]#[CH:14])[CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C#C[Si](C)(C)C)cc(C(C)(C)C)c(OC(C)C)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1cc(C(C)(C)C)c(OC(C)C)c(C=O)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
A solution of 3-tert-butyl-2-isopropoxy-6-methyl-5-trimethylsilanylethynyl-benzaldehyde (Intermediate 142, 0.45 g, 1.37 mmol) in methanol (5 mL) and tetrahydrofuran was treated with potassium carbonate (0.2 g, 1.45 mmol) and the resulting reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was evaporated in vacuo and the residue was extracted with diethyl ether and washed with water and brine. The organic phase was dried, filtered and evaporated in vacuo to afford the title compound (0.35 g, 90%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:2].[Mn]([O-])(=O)(=O)=[O:17].[K+].S(=O)(=O)(O)O.S([O-])(O)=O.[Na+]>O>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:17])[CH3:2]
Reactant: CCc1cccc(Cc2ccccc2)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Agent: [K+]
Solvent: O
Product: CCc1cccc(C(=O)c2ccccc2)c1
Reaction time: 10 h
Yield: 97 %

Procedure:
In 200 ml of water, 19.7 g of the fraction containing (3-ethylphenyl)phenylmethane obtained in the above alkylation was suspended. With stirring the suspension, 2 liter of an 1.6% aqueous solution of potassium permanganate was dropped. After the dropping, the stirring was continued for about 10 hours at room temperature. After this mixture was acidified with concentrated sulfuric acid, sodium hydrogensulfite powder was added until the reaction mixture became transparent from brown and it was extracted with benzene. After drying the benzene layer with anhydrous magnesium sulfate, 3-ethylbenzophenone was obtained in a yield of 97% by reduced pressure distillation.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:48])[C:29]2[CH:34]=[CH:33][C:32]([CH:35]([O:42][CH2:43][CH2:44][N:45]([CH3:47])[CH3:46])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:31][CH:30]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9](OC3C=CC=CC=3)[C:8]=2[N:22]=1)[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[NH4+:53].[OH-].[Na+]>O>[NH2:53][C:9]1[C:8]2[N:22]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:48])[C:29]3[CH:34]=[CH:33][C:32]([CH:35]([O:42][CH2:43][CH2:44][N:45]([CH3:46])[CH3:47])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:31][CH:30]=3)[C:7]=2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=1
Reactant: [NH4+]
Reactant: CCCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCCCNC(=O)c1ccc(C(OCCN(C)C)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCc1nc2c(N)nc(C)c(C)c2n1CCCCNC(=O)c1ccc(C(OCCN(C)C)c2ccccc2)cc1
Temperature: 150 °C
Yield: 15.3 %

Procedure:
N-[4-(2-Butyl-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-4-[[2-(dimethylamino)ethoxy](phenyl)methyl]benzamide (101 mg, 0.16 mmol) and ammonium acetate (1.1 g) were placed into a pressure tube along with a stir bar. The tube was sealed and heated at 150° C. for 16 hours. The reaction was cooled to room temperature and diluted with water. The resulting cloudy aqueous mixture was made basic with 10% aqueous sodium hydroxide and extracted with chloroform (3×25 mL). The combined organic fractions were washed with water followed by brine, dried (Na2SO4), decanted and evaporated to provide a yellow oil. Purification by flash column chromatography (silica gel, 95:5 dichloromethane/methanol gradient to 9:1 dichloromethane/methanol and finally 94:5:1 dichloromethane/methanol/triethylamine) provided 14 mg of N-[4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-4-[[2-(dimethylamino)ethoxy](phenyl)methyl]benzamide as a yellow oil.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[CH2:12][N:13]([CH2:24][C:25]1[C:30]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:29][CH:28]=[CH:27][N:26]=1)[CH:14]1[C:23]2[N:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(C(C(C([O-])=O)O)O)([O-])=O.C(Cl)Cl>C1COCC1>[C:35]([O:34][C:32](=[O:33])[NH:31][C:30]1[C:25]([CH2:24][N:13]([CH2:12][C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH2:11])=[CH:9][C:4]=2[CH2:3][OH:2])[CH:14]2[C:23]3[N:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:17][CH2:16][CH2:15]2)=[N:26][CH:27]=[CH:28][CH:29]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)c1cc(C#N)ccc1CN(Cc1ncccc1NC(=O)OC(C)(C)C)C1CCCc2cccnc21
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccnc1CN(Cc1ccc(CN)cc1CO)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 37.4 %

Procedure:
2-{[(3-tert-Butoxycarbonylamino-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-5-cyano-benzoic acid methyl ester (0.4532 g, 0.86 mmol) was dissolved in dry THF (5 mL) and flushed with Ar. At 0° C., 1.0 M LiAlH4 in THF (8.6 mL, 8.6 mmol) was added dropwise to the solution and was stirred at room temperature for 6 hours. The reaction was cooled to 0° C. and saturated aqueous KNa Tartrate (Rochelle's salt, 10 mL) was added slowly, and then CH2Cl2 (100 mL) was added. The phases were separated and the aqueous phase was extracted with CH2Cl2 (8×75 mL). The organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) provided 0.1620 g (37%) of (2-{[(4-aminomethyl-2-hydroxymethyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-pyridin-3-yl)-carbamic acid tert-butyl ester as a yellow solid. 1H NMR (CDCl3) δ 1.54 (s, 9H), 1.62 (s, 6H), 1.97-2.06 (m, 1H), 2.25-2.26 (m, 1H), 2.69-2.82 (m, 2H), 2.95-2.97 (m, 1H), 3.62-3.72 (m, 1H), 3.80 (s, 2H), 3.85-3.99 (m, 3H), 4.22-4.26 (m, 1H), 4.48-4.52 (m, 1H), 7.08-7.23 (m, 4H), 7.39-7.37 (m, 1H), 8.17-8.19 (m, 1H), 8.45-8.51 (m, 1H), 8.65-8.69 (m, 1H), 9.41-9.44 (m, 1H). Deprotection with TFA using General Procedure F gave COMPOUND 406 as a white solid. 1H NMR (CDCl3) δ 1.64-1.68 (m, 4H), 2.02-2.13 (m, 2H), 2.17-2.26 (m, 1H), 2.64-2.69 (m, 1H), 2.77-2.88 (m, 1H), 3.61-3.69 (m, 3H), 3.82-3.88 (m, 3H), 4.06 (d, 1H, J=12.9 Hz), 4.18 (d, 1H, J=11.1 Hz), 4.58 (d, 1H, J=11.4 Hz), 4.92 (s, 2H), 6.93-6.96 (m, 1H), 6.99-7.04 (m, 1H), 7.06-7.10 (m, 1H), 7.13-7.16 (m, 1H), 7.22-7.29 (m, 2H), 7.37 (d, 1H, J=7.5 Hz), 7.91 (d, 1H, J=3.9 Hz), 8.35 (d, 1H, J=3.9 Hz). 13C NMR (CDCl3) δ 19.54, 21.88, 29.55, 46.47, 54.64, 55.47, 58.18, 63.17, 122.36, 122.63, 124.08, 126.62, 130.67, 131.64, 135.21, 135.32, 137.99, 138.29, 142.08, 142.92, 143.78, 143.88, 146.91, 157.29. ES-MS m/z 404 (M+H). Anal. Calcd. for C24H29N5O.0.8H2O.0.1CH2Cl2: C, 67.88; H, 7.28; N, 16.42. Found: C, 67.85; H, 7.3; N, 16.27.
Reaction SMILES: O.[Cl:2][C:3]1[C:8]([CH2:9][OH:10])=[CH:7][N:6]=[C:5]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:4]=12>C1(C)C=CC=CC=1.O=[Mn]=O>[Cl:2][C:3]1[C:8]([CH:9]=[O:10])=[CH:7][N:6]=[C:5]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:4]=12
Reactant: CCn1ncc2c(Cl)c(CO)cnc21
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCn1ncc2c(Cl)c(C=O)cnc21
Reaction time: 6 h
Yield: 67.5 %

Procedure:
Wet MnO2 (110 g) was refluxed for 90 minutes in 1 L of toluene with a Dean-Stark trap for the separation of water. This suspension was then cooled and the 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-methanol (17.5 g, 82.7 mmole) was added in 50 ml of toluene. The reaction mixture was then stirred for 6 hours and filtered with the aid of a filter pad. The toluene was evaporated and the residue added again to 100 g of wet MnO2 freshly prepared in the above manner. After additional 4 hours the reaction was briefly warmed at 55° and then filtered again through a filter pad. The residue which remained after evaporation of the toluene was purified by preparative high performance liquid chromatography (10% ethyl acetate/hexane, 250 ml/min) to yield 11.70 g of 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxaldehyde, mp 89°-90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:30][C@@H:31]1[CH2:36][CH2:35][C@H:34]([C:37]([OH:39])=O)[CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:27][CH2:28]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12][CH:13]2[N:14]([CH3:15])[C:37]([C@H:34]2[CH2:33][CH2:32][C@@H:31]([OH:30])[CH2:36][CH2:35]2)=[O:39])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)[C@H]1CC[C@@H](O)CC1
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)[C@H]1CC[C@@H](O)CC1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound cis-4-hydroxy-cyclohexanecarboxylic acid {(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using cis-4-hydroxycyclohexanecarboxylic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown oil. MS m/e: 564.4 [M]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([OH:15])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].Cl[CH2:17][C:18]([O-:20])=[O:19].[Na+].[OH-].[Na+]>>[CH3:1][O:2][CH2:3][CH:4]([O:15][CH2:17][C:18]([OH:20])=[O:19])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C([O-])CCl
Reactant: CCCCCCCCCCC(O)COC
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCC(COC)OCC(=O)O

Procedure:
108 g (0.5 mole) 1-methoxy-2-dodecanol are reacted with sodium chloroacetate (58.3 g; 0.5 mole) and powdered sodium hydroxide (20 g; 0.5 mole) as in Example 1 to yield 2-(1-Methoxymethylundecyloxy)acetic acid as a colourless oil, bp. 162° C./0.26 mbar, yield 59.0 g (43%).