Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][O:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:18]([C:20]3[NH:24][N:23]=[C:22]([C:25](O)=[O:26])[CH:21]=3)=[O:19])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.B.C1COCC1>>[OH:26][CH2:25][C:22]1[CH:21]=[C:20]([C:18]([NH:17][CH2:16][CH:13]2[CH2:14][CH2:15][N:10]([C:8]([O:7][CH2:6][C:5]3[CH:28]=[CH:29][C:2]([CH3:1])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[O:19])[NH:24][N:23]=1
Reactant: Cc1ccc(COC(=O)N2CCC(CNC(=O)c3cc(C(=O)O)n[nH]3)CC2)cc1
Agent: B
Solvent: C1CCOC1
Product: Cc1ccc(COC(=O)N2CCC(CNC(=O)c3cc(CO)n[nH]3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5-({[(1-{[(4-methylbenzyl)oxy]carbonyl}piperidin-4-yl)methyl]amino}carbonyl)-1H-pyrazole-3-carboxylic acid (50 mg, 0.13 mmol) was added BH3-THF solution (2.5 mL, 2.5 mmol, 1.0M in THE). The solution was stirred at rt for 1 h, quenched with HCl (1M) and extracted with EtOAc. The organic layer was washed with H2O dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel (gradient elution, EtOAc to 10% MeOH/EtOAc) to give 4-methylbenzyl 4-[({[3-(hydroxymethyl)-1H-pyrazol-5-yl]carbonyl}amino)methyl]piperidine-1-carboxylate.
Reaction SMILES: Cl.[NH2:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[C:4]([OH:6])=[O:5].O.[CH3:15]COCC>C(N(CC)CC)C>[NH2:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[C:4]([O:6][CH3:15])=[O:5]
Reactant: CC(N)(C(=O)O)c1ccccc1
Reactant: CCOCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C(C)(N)c1ccccc1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4.3 g of methyl DL aminophenylpropanoate hydrochloride, 43 ml of demineralized water, 86 ml of ether and 3 ml of triethylamine was stirred at 20° C. for 10 minutes and the aqueous phase was extracted with ether. The combined ether phases were dried and evaporated to dryness under reduced pressure to obtain 8.3 g of methyl aminophenylpropanoate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(C3C=CC4OCCOC=4C=3OC2)C1=O.Cl.[F:46][CH:47]([F:56])[C:48]1[C:49]([CH2:54]O)=[N:50][CH:51]=[CH:52][CH:53]=1.Cl.FC(F)(F)C1C(CO)=NC=CC=1>>[F:46][CH:47]([F:56])[C:48]1[C:49]([CH2:54][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C@@:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])=[N:50][CH:51]=[CH:52][CH:53]=1
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: OCc1ncccc1C(F)F
Agent: Cl
Agent: O=C1Nc2ccccc2C12COc1c2ccc2c1OCCO2
Agent: OCc1ncccc1C(F)(F)F
Product: O=C1N(Cc2ncccc2C(F)F)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 11.78 and making non-critical variations using (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 2,3-dihydrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]-2′(1′H)-one, and 3-(difluoromethyl)pyridin-2-yl methanol hydrochloride to replace (3-(trifluoromethyl)pyridin-2-yl)methanol hydrochloride, (8S)-1′-{[3-(difluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (50%) as a colorless solid: mp 181-182° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J=4.9 Hz, 1H), 8.08 (d, J=7.7 Hz, 1H), 7.52-7.50 (m, 1H), 7.52-7.42 (m, 1H), 7.25-7.15 (m, 2H), 7.01 (dd, J=7.5, 7.5 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 6.51 (s, 1H), 6.42 (s, 1H), 5.18 (ABq, 2H), 4.72 (ABq, 2H), 4.19-4.12 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 177.4, 155.0, 152.9 (t, JC-F=4.3 Hz), 151.4, 144.6, 143.2, 138.2, 135.0 (t, JC-F=7.0 Hz), 132.5, 129.1, 128.0 (t, JC-F=22.6 Hz), 123.9, 123.5, 123.3, 122.0, 113.8 (t, JC-F=236.6 Hz), 112.3, 109.7, 99.1, 79.7, 64.7, 64.1, 57.8, 42.3; MS (ES+) m/z 436.9 (M+1).
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10]([NH:12][C@H:13]([C@H:28]([OH:47])[CH2:29][N:30]([S:35]([C:38]2[CH:46]=[CH:45][C:41]3[O:42][CH2:43][O:44][C:40]=3[CH:39]=2)(=[O:37])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:14][C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:17][CH:16]=2)=[O:11])[CH2:2]1.O.[OH-].[Li+]>O1CCCC1.O>[O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10]([NH:12][C@H:13]([C@H:28]([OH:47])[CH2:29][N:30]([S:35]([C:38]2[CH:46]=[CH:45][C:41]3[O:42][CH2:43][O:44][C:40]=3[CH:39]=2)(=[O:37])=[O:36])[CH2:31][CH:32]([CH3:33])[CH3:34])[CH2:14][C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][CH:16]=2)=[O:11])[CH2:2]1
Reactant: CCOC(=O)COc1ccc(C[C@H](NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H](O)CN(CC(C)C)S(=O)(=O)c2ccc3c(c2)OCO3)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCC(=O)O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To an ice cold solution of Ethyl (4-{(2S,3R)-2-({[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}amino)-4-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-3-hydroxybutyl}phenoxy)acetate (107 mg, 0.16 mmol) in tetrahydrofuran/water (4 mL, 3:1) was added lithium hydroxide monohydrate (21 mg, 0.48 mmol). The reaction was allowed to warm to ambient temperature and stir for 1 h. The tetrahydrofuran was evaporated and the residue diluted with water (30 mL). The aqueous was then extracted with ether (30 mL), cooled in an ice bath and acidified to pH ˜2 with 1.0 N hydrochloric acid. The resulting precipitate was extracted into ethyl acetate (30 mL), washed with water (20 mL), dried (magnesium sulfate) and concentrated in vacuo to a white solid. Triturated with 10% ether in hexane and filtered to afford the title compound (77 mg) as a 2:1 mixture with the compound derived from the loss of the bis-tetrahydrofuran alcohol and subsequent ring closure at the 2-hydroxy position. The mixture was confirmed by NMR, HPLC and mass spectra. Data for major product: 1H NMR (DMSO-d6): δ 0.78 (6H, dd), 1.17-1.45 (2H, m), 1.92 (1H, m), 2.35 (1H, t), 2.64-2.78 (3H, m), 2.88-3.02 (2H, m), 3.24-3.30 (1H, m), 3.40-3.60 (4H, m), 3.70 (1H, t), 3.78-3.82 (1H, m), 4.54 (2H, s), 4.82 (1H, q), 5.00 (1H, d), 5.46 (1H, d), 6.12 (2H, s), 6.71 (2H, d), 7.00-7.30 (6H, m), 12.85 (1H, broad); MS: 651 (MH+); C30H38N2O12S (by-product MS: 521 (MH+); C24H28N2O9S).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1)[C:3]([OH:5])=O.CCN=C=NCCCN(C)C.Cl.N1(O)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[N+:56]([C:59]1[CH:64]=[CH:63][C:62]([NH:65][CH:66]2[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]2)=[CH:61][C:60]=1[C:72]([F:75])([F:74])[F:73])([O-:58])=[O:57]>ClCCl>[CH3:1][CH:2]([CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:23]([F:25])([F:24])[F:26])[CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1)[C:3]([N:69]1[CH2:70][CH2:71][CH:66]([NH:65][C:62]2[CH:63]=[CH:64][C:59]([N+:56]([O-:58])=[O:57])=[C:60]([C:72]([F:73])([F:74])[F:75])[CH:61]=2)[CH2:67][CH2:68]1)=[O:5]
Reactant: CC(CN1CCN(c2ccc3cc(C(F)(F)F)ccc3n2)CC1)C(=O)O
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CN1CCN(c2ccc3cc(C(F)(F)F)ccc3n2)CC1)C(=O)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To a solution of 2-methyl-3-[4-[6-(trifluoromethyl) quinolin-2-yl]piperazin-1-yl]propanoic acid (100 mg, 0.27 mmol) in dichloromethane (20 ml) was added EDAC.HCl (79 mg, 0.41 mmol, 1.5 eq.), 1H-1,2,3-benzotriazol-1-ol (55.2 mg, 0.41 mmol, 1.5 eq.), triethylamine (82.6 mg, 0.82 mmol, 3 eq.) and N-[4-nitro-3-(trifluoromethyl)phenyl]piperidin-4-amine (94.5 mg, 0.33 mmol, 1.2 eq.). The resulting solution was stirred overnight at room temperature and then quenched by the addition of water (50 ml) and extracted with dichloromethane (3×30 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by Prep-TLC with 5% methanol in dichloromethane to afford of 2-methyl-1-(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]piperidin-1-yl)-3-[4-[6-(trifluoromethyl)quinolin-2-yl]piperazin-1-yl]propan-1-one as a yellow solid (111.2 mg, 64%). (ES, m/z): [M+H]+ 639.40; 1H NMR (300 MHz, CDCl3): δ 7.95-8.08 (m, 1H), 7.72 (overlapping m, 2H), 7.01 (d, J=9.3 Hz, 1H), 6.89 (m, 1H), 6.65 (m, 1H), 4.49-4.70 (m, 2H), 4.08 (m, 1H), 3.72-3.85 (br m, 5H), 3.65 (m, 1H), 3.08 (br s, 1H), 2.88 (br m, 2H), 2.68 (br s, 3H), 2.38 (m, 1H), 2.07-2.20 (overlapping m, 2H), 1.47 (m, 2H), 1.13 (br s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([CH3:15])[C:10](OCC)=[O:11].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([CH3:15])[CH2:10][OH:11]
Reactant: CCOC(=O)C(C)c1c(Cl)cccc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CC(CO)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 98.6 %

Procedure:
To a solution of ethyl 2-(2,6-dichlorophenyl)propanoate (0.66 g, 2.7 mmol) in THF (30 ml) at 0° C. was added diisobutylaluminium hydride (6.6 ml of a 1.0M solution in THF, 6.6 mmol) dropwise. The cooling bath was removed and the mixture stirred at room temperature for 45 min. More diisobutylaluminium hydride (3 ml of a 1.0M solution in THF, 3.0 mmol) was added and the solution stirred for a further 45 min. After this time more diisobutylaluminium hydride (3 ml of a 1.0M solution in THF, 3.0 mmol) was added and the solution stirred for 1 h. NH4Cl (sat., 10 ml) was added and the mixture stirred at room temperature for 1 h. The organic layer was decanted off and the gelatinous precipitate partitioned between ether (30 ml) and 1M HCl (30 ml). The organic layers were combined, dried (Na2SO4) and evaporated. The residue was chromatographed on silica, eluting with petrol:EtOAc (3:1), to afford the alcohol (546 mg, 100%) as a colourless oil. 1H NMR (250 MHz, CDCl3) δ 1.41 (3H, d, J=6.7 Hz), 3.94-4.01 (2H, m), 4.13-4.23 (1H, m), 7.08 (1H, t, J=7.9 Hz), 7.20-7.40 (2H, m).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:15]=[CH:14]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[N:13]1([CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:15]=[CH:14]1
Reactant: CC(C)(C)[Si](C)(C)OCCCCn1cnc2cnc3ccccc3c21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCCCCn1cnc2cnc3ccccc3c21
Reaction time: 1 h
Yield: 64.3 %

Procedure:
The 1-[4-(tert-butyldimethylsilanyloxy)butyl]-1H-imidazo[4,5-c]quinoline (46.0 g, 129 mmol) from the previous step and tetrabutylammonium fluoride (142 mL of a 1 M solution in THF) were dissolved in THF (400 mL) and stirred for 1 hour, then concentrated under reduced pressure to provide 4-(1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol (20.0 g) as a light brown solid after chromatography on silica gel (elution with 10% methanol in dichloromethane).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.Cl[C:18]1[CH:19]=[C:20]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[N:30]=1)[C:21]([O:23]C(C)(C)C)=[O:22]>O1CCCC1>[C:13]([O:12][C:10]([N:7]1[CH2:6][CH2:5][CH:4]([O:3][C:18]2[CH:19]=[C:20]([CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[N:30]=2)[C:21]([OH:23])=[O:22])[CH2:9][CH2:8]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(=O)O)cc(C(F)(F)F)n2)CC1
Reaction time: 1 h

Procedure:
To sodium hydride (60% in mineral oil, 0.36 g, 8.9 mmol) in tetrahydrofuran (15 mL) at 0° C. was added tert-butyl 4-hydroxypiperidine-1-carboxylate (1.8 g, 8.9 mmol, Aldrich). The reaction mixture was allowed to reach room temperature and stir for 1 hour. A solution of tert-butyl 2-chloro-6-(trifluoromethyl)isonicotinate (1.0 g, 3.6 mmol, from Step 1) in tetrahydrofuran (4.9 mL, 60. mmol) was introduced and the mixture was stirred at room temperature over five nights. The mixture was quenched by the careful addition of 1N NaOH (15 mL) and allowed to stir overnight. The reaction was diluted with additional water and the aqueous layer was washed with Et2O. The aqueous layer was then acidified by the addition of c.HCl to achieve pH˜3. The product was extracted with three portions of ethyl acetate. The combined EtOAc extracts were dried over sodium sulfate, filtered and concentrated. The product was used without further purification. LCMS (M-tBu+H)+: 335.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.O.[Zn]>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]2[O:14][N:13]=[C:12]([O:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:16]=2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc([N+](=O)[O-])cc2)on1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(N)cc2)on1
Reaction time: 2 h
Yield: 89.5 %

Procedure:
3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-(4-nitrophenyl)isoxazole (0.55 g) was dissolved in a mixture of acetic acid and water (9:1, 5.5 ml), and zinc powder (0.55 g) was added thereto at room temperature, followed by stirring of the resulting mixture at the same temperature for 2 hours. After the reaction, zinc powder was filtered off and the filtrate was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=2/1) to obtain the title compound (0.45 g, 90%) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:22]=1[C:23](Cl)=[O:24]>C1COCC1>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:22]=1[C:23](/[N:12]=[C:6]1\[S:7][C:8]([CH3:11])=[C:9]([CH3:10])[N:5]\1[CH2:4][CH2:3][O:2][CH3:1])=[O:24]
Reactant: COCCn1c(C)c(C)sc1=N
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1c(Cl)cccc1Cl
Yield: 29.1 %

Procedure:
The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.3 mL, 2.2 mmol) and 2,6-dichlorobenzoyl chloride (Aldrich, 0.2 mL, 1.4 mmol) in 25 mL THF were processed as in Example 132 to afford the title compound (0.12 g, 0.32 mmol, 30% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.28 (s, 6H), 3.27 (s, 3H), 3.74 (t, J=4.6 Hz, 2H), 4.34-4.44 (m, 2H), 7.19 (dd, J=8.8, 6.8 Hz, 1H), 7.28-7.34 (m, 2H); MS (DCI/NH3) m/z 359 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.C([Li])CCC.CCCCCC.CN(C)[CH:27]=[O:28].[Cl-].[Na+]>C1COCC1>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([CH:27]=[O:28])[CH:11]=[CH:10]2
Reactant: CN(C)C=O
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc2cc(C=O)ccc2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of 2-bromo-6-methoxynaphthalene (4.00 g, 16.87 mmol) in 100 mL of anhydrous THF under nitrogen atmosphere at -78° C. was added a 1.6M solution of n-butyllithium in hexane (10.6 mL, 16.96 mmol). The reaction mixture turned into a yellow suspension 5 minutes after the addition of butyllithium. The suspension was stirred at -78° C. for 1 hour and then warmed to -23° C. Anhydrous N,N-dimethylformamide (4.0 mL, 51.7 mmol) was added. The reaction mixture was stirred at -23° C. for 30 minutes. Saturated sodium chloride solution (50 mL) was added to quench the reaction. The organic layer was collected and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried with anhydrous magnesium sulphate, filtered, and concentrated under reduced pressure. The residue oil was chromatographed by 10% ethyl acetate in hexanes on silica gel to give 2.86 g (91%) of 6-methoxy-2-naphthaldehyde as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[N:19])[C:5]([OH:7])=O.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[N:19])[C:5]([NH:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57])=[O:7]
Reactant: N#Cc1ccccc1Oc1ccc(C(=O)O)cc1Cl
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(Oc3ccccc3C#N)c(Cl)c2)c(O)n1
Reaction time: 0.5 h
Yield: 22.5 %

Procedure:
A solution of 3-chloro-4-(2-cyanophenoxy)benzoic acid (100 mg, 0.37 mmol) in dichloromethane (20 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (91 mg, 0.48 mmol), N-hydroxybenzotriazole (65 mg, 0.48 mmol) and triethylamine (104 mg, 0.7 mmol), stirred for 30 minutes. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (56 mg, 0.37 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was washed with water (50 mL). The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to afford 3-chloro-4-(2-cyanophenoxy)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (34 mg, 58%) as white solid. LRMS (M+H+) m/z: calcd 407.1. found 407; 1H-NMR (300 MHz, CD3OD) δ 11.47 (s, 1H), 8.53 (m, 1H), 8.14 (d, J=2.1 Hz, 1H), 7.90 (m, 2H), 7.68 (m, 1H), 7.29 (m, 2H), 6.93 (d, J=0.9 Hz, 1H), 5.86 (s, 1H), 4.29 (d, 2H, J=4.8 Hz), 2.17 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1([CH3:24])[C:13]([CH3:15])([CH3:14])[O:12][B:11]([C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[CH:18]=O)[O:10]1.[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.[BH4-].[Na+]>CCOCC.C(O)=O>[CH3:8][C:9]1([CH3:24])[C:13]([CH3:15])([CH3:14])[O:12][B:11]([C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[CH2:18][NH:31][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[O:10]1
Reactant: NC1CCCCC1
Reactant: CC1(C)OB(c2ccccc2C=O)OC1(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O=CO
Product: CC1(C)OB(c2ccccc2CNC2CCCCC2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Toluene (250 mL) was added to 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (5.0 g, 21.54 mmol) followed by cyclohexylamine (2.37 g, 23.89 mmol) and formic acid (˜1.0 mL of 88%) to form a clear solution. The mixture was allowed to reflux using a Dean-Stark trap and the toluene/water mixture collected till clear. Upon completion, the mixture was cooled to room temperature and the solution evaporated to 100 mL. MeOH (200 mL) was then added to the reaction mixture followed by NaBH4 (1.63 g, 43.08 mmol) portion wise. The mixture was stirred for 20 min and quenched with water (5 mL). The solution was evaporated to 100 mL and EtOAc (50 mL) was added. The solution was dried with Na2SO4 and the solvent removed by reduced pressure, yielding a white solid. Et2O (200 mL) was then added dissolving half of the white solid. The remaining solid was collected and dried under reduced pressure offering compound 7. Yield: 6.3 g, 46.4%. 1H NMR (CD2Cl2): δ 7.52-7.50 (d, 1H), 7.28-7.27 (m, 2H), 7.15-7.13 (d, 1H), 4.02 (s, 2H), 3.42 (s, 1H), 3.15-3.07 (m, 1H), 1.74-1.61 (m, 5H), 1.29 (s, 12H), 1.19-1.05 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH:40]C(C3C4N=CC=NC=4C(C4C(Cl)=C(OC)C=C(OC)C=4Cl)=CC=3)=O)=[N:38][CH:39]=2)[CH2:29][CH2:28]1>C(Cl)Cl.CO>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH:40][C:23]([C:20]3[CH:21]=[CH:22][C:13]([C:3]4[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[Cl:1])=[C:14]4[C:19]=3[N:18]=[CH:17][CH:16]=[CH:15]4)=[O:24])=[N:38][CH:39]=2)[CH2:29][CH2:28]1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1Cl
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncccc23)c1Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3ncccc23)c1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step 159.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography), and stirring the reaction mixture for 20 h at rt. Title compound: ESI-MS: 566.1 [M+H]+; TLC: Rf=0.22 (DCM/MeOH, 9:1).
Reaction SMILES: [C:1]([O:9][C@H:10]([CH:25]=[CH2:26])[C@H:11]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@@H:12]([F:16])[CH:13]=[N:14][OH:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[C:1]([O:9][C@@H:10]1[C@@H:25]2[C@@H:13]([NH:14][O:15][CH2:26]2)[C@H:12]([F:16])[C@H:11]1[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C[C@@H](OC(=O)c1ccccc1)[C@H](OCc1ccccc1)[C@@H](F)C=NO
Solvent: Cc1ccccc1
Product: O=C(O[C@@H]1[C@H]2CON[C@H]2[C@H](F)[C@H]1OCc1ccccc1)c1ccccc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
The compound (1.31 g, 3.66 mmol) synthesized in Example 17 (17e) was dissolved in toluene (30 mL) and the mixture was stirred at 120° C. for 8 hours. The solvent was distilled off under reduced pressure and the residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 3:1, V/V) to obtain the desired title compound (965 mg, yield 74%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:16])=[C:4](/[CH:8]=[N:9]/[S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1.CC([S@](N)=O)(C)C.BrC1C(C)=C(C=O)C=NC=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[C:3]([CH3:16])=[C:4]([CH2:8][NH:9][S@@:10]([C:12]([CH3:14])([CH3:13])[CH3:15])=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: Cc1c(Br)cncc1/C=N/[S@](=O)C(C)(C)C
Agent: CC(C)(C)[S@](N)=O
Agent: Cc1c(Br)cncc1C=O
Agent: [BH4-]
Solvent: CO
Product: Cc1c(Br)cncc1CN[S@](=O)C(C)(C)C

Procedure:
(R)-2-Methyl-propane-2-sulfinic acid 1-(5-bromo-4-methyl-pyridin-3-yl)-meth-(E)-ylideneamide, prepared from (R)-2-methylpropane-2-sulfinamide and 5-bromo-4-methyl-pyridine-3-carbaldehyde in analogy to procedure described for the preparation of intermediate A-35 [A], has been reduced with NaBH4 in MeOH in analogy to the procedure described for the preparation of intermediate A-35 [B] to give the title compound as colorless solid. MS: 305.3 and 307.4 (M+H+).