Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([O:5][NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4].[H-].[Na+].[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[S:27](Cl)(=[O:29])=[O:28]>>[CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([O:5][N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[S:27]([C:19]1[O:18][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=1)(=[O:28])=[O:29])=[O:4]
Reactant: CC(C)(C)OC(=O)NOC(=O)C(C)(C)C
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(OC(=O)C(C)(C)C)S(=O)(=O)c1cc2ccccc2o1

Procedure:
N-[(tert-Butoxy)carbonyl]1-benzofuran-2-sulfonamido 2,2-dimethylpropanoate (104) is prepared from [(tert-butoxy)carbonyl]amino 2,2-dimethylpropanoate, sodium hydride and 1-benzofuran-2-sulfonyl chloride according to Scheme 2. δH (250 MHz, DMSO-d6) 8.06 (1H, d, 0.8 Hz), 7.92 (1H, d, 7.3 Hz), 7.81 (1H, dd, 8.5, 0.8 Hz), 7.64 (1H, ddd, 8.5, 7.2, 1.4 Hz), 7.42-7.53 (1H, m), 1.37 (9H, s), 1.28 (9H, s).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li]CCCC.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C1CCCCC1>[CH2:37]([CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: C1CCCCC1
Product: CCCCCCCCCCCCCCCCCCC1c2ccccc2-c2ccccc21
Yield: 87.9 %

Procedure:
Fluorene (7.0 g, 42.1 mmol), n-BuLi (17.35 ml, 43.4 mmol, 2.5 M in hexane), RX=1-bromooctadecane (14.53 g, 43.6 mmol). Following the usual workup 44 was isolated as a white solid (15.5 g, 88%), Rf 0.73 (cyclohexane).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[N:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:24])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:25][NH:26][CH2:27][CH2:28][C:3]1=2.[C:29]1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:41].Cl>>[ClH:41].[ClH:41].[CH3:29][N:26]1[CH2:27][CH2:28][C:3]2[N:2]([CH3:1])[C:10]3[CH:9]=[C:8]([N:11]4[CH:16]=[CH:15][C:14]([C:17]5[N:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=5)=[CH:13][C:12]4=[O:24])[CH:7]=[CH:6][C:5]=3[C:4]=2[CH2:25]1
Reactant: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCNC5)c(=O)c2)nn1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Product: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCN(C)C5)c(=O)c2)nn1
Yield: 74 %

Procedure:
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-methylpyridazin-3-yl)pyridin-2(1H)-one (77 mg, 0.21 mmol) was reacted according to the procedure of Example 47 to provide the free-base. Conversion to the dihydrochloride salt using the procedure of Example 30 (step g) provided the title compound (60 mg, 74%) as a yellow solid: mp 285-288° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.32 (d, J=8.8 Hz, 1H), 7.85 (d, J=7.2 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.64 (d, J=1.5 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.25 (d, J=1.7 Hz, 1H), 7.14-7.11 (m, 2H), 4.65 (d, J=12.1 Hz, 1H), 4.31 (dd, J=14.2, 7.5 Hz, 1H), 3.81-3.74 (m, 1H), 3.71 (s, 3H), 3.55-3.45 (m, 1H), 3.26-3.15 (m, 2H), 2.98 (s, 3H), 2.72 (s, 3H); ESI MS m/z 386 [M+H]+; HPLC (Method B)>99% (AUC), tR=9.4 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[CH:20]=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(OC(C)C)(C)C>CO.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[CH2:20][OH:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C=O)c2cccc(OCc3ccccc3)c2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Solvent: CO
Product: Cc1cc(CO)c2cccc(OCc3ccccc3)c2n1
Yield: 82.7 %

Procedure:
To a suspension of 8-benzyloxy-4-formyl-2-methylquinoline (300 mg) in a mixture of methanol (3 ml) and tetrahydrofuran (2 ml) was added sodium borohydride (20.6 mg) portionwise in an ice bath. The suspension was stirred for half an hour, then quenched with saturated sodium chloride. The mixture was extracted with chloroform and the organic layer was dried over anhydrous magnesium sulfate. After being concentrated in vacuo the residue was chromatographed on silica gel eluting with ethyl acetate-n-hexane to give an amorphous solid which was solidified with diisopropyl ether to afford 8-benzyloxy-4-hydroxymethyl-2-methylquinoline (250 mg) as a colorless solid.
Reaction SMILES: [CH3:1][NH2:2].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=O.[BH4-].[Na+].Cl>C(O)C.ClCCl.C1C=CC=CC=1>[CH3:1][NH:2][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1
Reactant: O=Cc1ccccn1
Reactant: CN
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: CNCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
Methylamine gas was bubbled through the benzene solution(60 ml) of 10.7 g(100 mmol) of 2-pyridinecarboxaldehyde for 2 hours. Benzene was distilledoff under a reduced pressure and the residue was taken up in 40 ml of ethanol. To the resulting solution was added 5.7 g of NaBH4 in three portions and the resulting mixture was stirred at room temperature for 8 hours. To the reaction mixture was added 0.5N hydrochloric acid with care not to allow the pH below 6. 300 ml of dichloromethane was added thereto and the resulting solution was washed three times with 1M NaHCO3 solution of pH 10. The organic layer was concentrated under a reduced pressure to give 10.4 g of the title compound(yield: 85%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.[Cl:7][C:8]1[CH:13]=[C:12]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([S:24](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:26])=[O:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[C:11]([O:39][CH3:40])=[CH:10][C:9]=1[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:7][C:8]1[CH:13]=[C:12]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([S:24]([NH:6][C:3]4[CH:4]=[CH:5][O:1][N:2]=4)(=[O:26])=[O:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[C:11]([O:39][CH3:40])=[CH:10][C:9]=1[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1
Reactant: Nc1ccon1
Reactant: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Nc3ccon3)ccc12
Reaction time: 0.67 h

Procedure:
A vial was charged with isoxazol-3-amine (6.09 microliters, 6.93 mg, 0.082 mmol) (from Aldrich Co.), perfluorophenyl 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)isoquinoline-6-sulfonate (INTERMEDIATE TTTT, 45.67 mg, 0.075 mmol) and THF (0.5 mL) to give a clear solution. The vial was cooled in an ice-water bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (65.9 μl, 0.065 mmol) was added. After 40 min, additional portions of amine (10 microliters) and LHMDS solution (0.05 mL) were added. LCMS after 10 min showed mainly the desired product. The mixture was purified directly on silica gel (12-g Redi-Sep Gold column, 0-5% MeOH/DCM) to give 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)isoquinoline-6-sulfonamide (23.72 mg, 0.047 mmol, 62.1% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=11.92 (br. s., 1H), 8.78-8.72 (m, 2H), 8.69 (d, J=1.7 Hz, 1H), 8.16 (d, J=5.5 Hz, 1H), 8.01-7.84 (m, 2H), 7.64-7.53 (m, 2H), 7.49-7.40 (m, 2H), 7.37-7.29 (m, 1H), 7.27 (s, 1H), 6.50 (d, J=1.9 Hz, 1H), 3.70 (s, 3H). m/z (ESI) 510.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:5]2[C:6](=[O:10])[C:7]=1[CH2:8][CH3:9]>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH2:14][CH2:13][CH2:12][CH:11]([CH3:15])[N:5]2[C:6](=[O:10])[C:7]=1[CH2:8][CH3:9]
Reactant: CCc1c(C)nc2cccc(C)n2c1=O
Solvent: CCO
Product: CCc1c(C)nc2n(c1=O)C(C)CCC2
Reaction time: 7 h
Yield: 99.5 %

Procedure:
4.04 g. of 2,6-dimethyl-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine are dissolved in 50 ml. of ethanol and the solution is hydrogenated in the presence of 2 g. of Raney-nickel catalyst, previously washed to anhydrous with ethanol. Hydrogenation is performed under atmospheric pressure. In about seven hours the calculated amount of hydrogen is used up and the hydrogen consumption drops rapidly to zero. The catalyst is filtered off and the ethanol solution is evaporated. 4.10 g. (99.5%) of 2,6-dimethyl-3-ethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine are obtained as a pale-yellow non-crystallizing oil, which can be distilled under a pressure of 25 mmHg of 190° C.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][N:11]([C:37](=[O:39])[CH3:38])[CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29]CC[Si](C)(C)C)=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.N1C(C)=CC=CC=1C>C(#N)C>[C:37]([N:11]([CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([OH:29])=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])[CH2:10][CH2:9][P:4](=[O:3])([OH:5])[OH:8])(=[O:39])[CH3:38]
Reactant: CCOP(=O)(CCN(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)C(C)=O)OCC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: COc1c(C)c2c(c(O)c1CC=C(C)CN(CCP(=O)(O)O)C(C)=O)C(=O)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
To a solution of [2-(acetyl-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-amino)-ethyl]-phosphonic acid diethyl ester (14 mg, 0.024 mmol) in acetonitrile (0.5 mL) was added TMSBr (31 μL, 0.24 mmol) and 2,6-lutidine (28 μL, 0.24 mmol). The solution was stirred at room temperature for 1 hour. The reaction was quenched by addition of methanol and aqueous 1N HCl. The product was extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The product was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 5.4 mg of the product (53%) as a white solid. The NMR data of this compound shows two rotamers. 1H NMR (300 MHz, CDCl3) δ 1.67 and 1.73 (s, 3H), 1.85-2.12 (m, 5H), 2.13 (s, 3H), 3.30-3.61 (m, 4H), 3.75 (s, 3H), 3.76 (br s, 2H), 5.17 (s, 2H), 5.31 (br s, 1H) ppm; 31P (121.4 MHz, CDCl3) δ 27.5 and 28.8 ppm; MS (m/z) 428.2 [M+H]+, 450.2 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]1([NH:17][C:18]([NH:20]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)=[S:19])[CH2:12][C@H:11]([O:13][CH3:14])[CH2:10][C@H:9]1[CH2:15]O>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:12][C@@H:11]([O:13][CH3:14])[CH2:10][C@H:9]1[CH2:15][S:19][C:18]([NH2:20])=[N:17]2
Reactant: CO[C@@H]1C[C@@H](CO)[C@](NC(=S)NC(=O)OCC2c3ccccc3-c3ccccc32)(c2ccccc2F)C1
Solvent: CO
Product: CO[C@H]1C[C@H]2CSC(N)=N[C@@]2(c2ccccc2F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A solution of 9H-fluoren-9-ylmethyl ({[(1S*,2R*,4R*)-1-(2-fluorophenyl)-2-(hydroxymethyl)-4-methoxycyclopentyl]amino}carbonothioyl)carbamate (340 mg) in methanol (20 mL)-concentrated hydrochloric acid (1 mL) was heated under reflux for three hours. The reaction solution was concentrated under reduced pressure. Acetonitrile (10 mL) and piperidine (2 mL) were added to the residue at room temperature, and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure. The crude product was purified by NH-silica gel column chromatography to obtain the title compound (130 mg).
Reaction SMILES: [NH:1]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>N1C=CC=CC=1.CC(OC)(C)C>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]([N:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:26])=[CH:19][CH:20]=1
Reactant: c1ccc(NCCc2ccccn2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: COC(C)(C)C
Product: COc1ccc(C(=O)N(CCc2ccccn2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a 25 ml round-bottom flask 0.085 p-anisoyl chloride and 0.04 mL of pyridine are dissolved in 3 ml of MTBE. To this solution was added 0.10 g of 2-(2-anilinoethyl)pyridine. The solution is stirred at room temperature for 24 h. To the solution was added 5 mL of water. The organic layer was separated and washed with 5 mL of water. The organic layer was dried over MgSO4. The solvent was evaporated to yield a brown oil. The oil was purified on silica gel to afford 0.15 g of an off-white solid with the following spectroscopic properties:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1.CCN(C(C)C)C(C)C.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][N:13]([C:25]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[O:32])[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)c2cccnc2)CC1
Yield: 85.9 %

Procedure:
To a solution of COMPOUND 249 (65 mg, 0.21 mmol) in THF (2 mL) was added nicotinoyl chloride hydrochloride (60 mg, 0.34 mmol) followed by DIPEA (0.10 mL, 0.57 mmol). The resultant mixture was stirred at room temperature for 40 minutes. The mixture was treated with 1.0 N NaOH (5 mL) and extracted with CH2Cl2 (4×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 20:1:1 CH2Cl2-MeOH—NH4OH) provided 75 mg (86%) of COMPOUND 265 as a white solid. 1H NMR (CDCl3) δ 1.61-1.75 (m, 2H), 1.90-1.99 (m, 2H), 2.09 (s, 6H), 2.55-3.00 (m, 3H), 3.75-3.90 (m, 5H), 4.75-4.80 (m, 1H), 7.09 (dd, 2H, J=7.5, 4.8 Hz), 7.34-7.39 (m, 3H), 7.75 (dt, 1H, J=6.0, 1.8 Hz), 8.35 (d, 2H, J=4.8 Hz), 8.65 (s, 2H); ES-MS m/z 416 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH:10]([O:20][CH2:21][CH3:22])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH3:19])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39](O)=[O:40])=[CH:34][CH:33]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(OC(=O)C(OCC)CC1C=CC(OC(=O)CC2N=C(C3C=CC=CC=3)OC=2C)=C(CC2C=CC=CC=2)C=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9](=[O:23])[CH:10]([O:20][CH2:21][CH3:22])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:39](=[O:40])[CH2:38][C:35]2[CH:34]=[CH:33][C:32]([NH:31][C:29]([O:28][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:30])=[CH:37][CH:36]=2)=[C:14]([CH3:19])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(=O)O)cc1
Reactant: CCOC(Cc1ccc(O)c(C)c1)C(=O)OCc1ccccc1
Agent: CCOC(Cc1ccc(OC(=O)Cc2nc(-c3ccccc3)oc2C)c(Cc2ccccc2)c1)C(=O)OCc1ccccc1
Product: CCOC(Cc1ccc(OC(=O)Cc2ccc(NC(=O)OC(C)(C)C)cc2)c(C)c1)C(=O)OCc1ccccc1

Procedure:
The title compound was prepared from 2-ethoxy-3-(4-hydroxy-3-methyl-phenyl)-propionic acid benzyl ester (38 mg, 0.15 mmol) and (4-tert-butoxycarbonylamino-phenyl)-acetic acid (47 mg, 0.15 mmol) in the same manner as described for 3-{3-benzyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-acetoxy]-phenyl}-2-ethoxy-propionic acid benzyl ester. The crude product was purified by column chromatography using n-heptane/EtOAc (2:3) as the eluent to afford the product as a solid (32 mg, 85%). 1H NMR (400 MHz, CDCl3): δ 7.26-7.38 (m, 9H), 6.99-7.02 (m, 2H), 6.83-6.86 (d, 1H), 6.49 (br s, 1H), 5.12 (s, 2H), 4.00-4.05 (t, 1H), 3.80 (s, 2H), 3.58-3.61 (m, 1H), 3.31-3.36 (m, 1H), 2.94-2.96 (d, 2H), 1.98 (s, 3H), 1.52 (s, 9H), 1.12-1.16 (t, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]2[N:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:3]1=[O:17].[H-].[Na+].[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23]Cl.CCOCC>C1(C)C(C)=CC=CC=1.O>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3](=[O:17])[C:4]2[CH:16]=[CH:15][CH:14]=[N:13][C:5]1=2
Reactant: CN(C)CCCl
Reactant: CN1C(=O)c2cccnc2Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCOCC
Solvent: O
Product: CN(C)CCN1c2ccccc2N(C)C(=O)c2cccnc21
Yield: 59.1 %

Procedure:
9.0 gm of 6,11-dihydro-6-methyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one were dissolved in 200 ml of hot absolute xylene, 2.1 gm of 50% sodium hydride in mineral oil were added to the solution, and the mixture was refluxed for 2 hours. Then, 5.3 gm of 2-dimethylamino-ethyl chloride were added dropwise, and the mixture was refluxed for 16 hours more. The cooled reaction mixture was shaken with a mixture of ether and water, and the organic phase was separated and extracted with dilute acetic acid. Then the acidic aqueous layer was made alkaline with concentrated ammonia, and the precipitated oil was extracted with ether. After evaporation of the ether extract, the residue was distilled, yielding 7.0 gm (59% of theory) of 11-(2'-dimethylamino-ethyl)-6,11-dihydro-6-methyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, b.p. 163°-164° C. at 0.01 mm Hg.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([CH:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH2:20])=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[C:31](Cl)=[O:32]>CN(C)C=O>[Cl:8][C:9]1[C:10]([CH:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH:20][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:28]([O:27][CH3:26])[CH:29]=2)=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:14]=1
Reactant: CCOC(=O)C(N)c1ncc(C(F)(F)F)cc1Cl
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(NC(=O)c1ccc(OC)c(OC)c1)c1ncc(C(F)(F)F)cc1Cl
Reaction time: 0.75 h

Procedure:
Triethylamine (0.28 ml) was added to a solution of ethyl 2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycinate (1 g; prepared in a similar manner to the starting material for Example 3) in dimethylformamide (10 ml) with stiring followed by 3,4-dimethoxybenzoyl chloride (0.70 g). the mixture was stirred for 45 minutes and evaporated. The residue was extracted with ethyl acetate and the extracts worked up to give the title product, m.p. 40-3° C. (Compound 601)
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH2:26][C:27]([OH:29])=[O:28]>>[CH2:16]([C:10]1[CH:9]=[C:8]2[C:13]([C:14]([OH:15])=[C:5]([C:3]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4])[N:6]=[C:7]2[C:23]#[N:24])=[CH:12][CH:11]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1nc(C#N)c2cc(Cc3ccccc3)ccc2c1O
Reactant: NCC(=O)O
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2ccc(Cc3ccccc3)cc12

Procedure:
The title compound was synthesized from 7-benzyl-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester and glycine in analogy to example 1b; MS-(−)-ion: M−1=360.5.
Reaction SMILES: [CH2:1]([C:8]1[N:12]([CH:13]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:14]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])[C:11]2[CH:29]=[C:30]([Cl:34])[C:31]([F:33])=[CH:32][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([CH:41]=[O:42])CCCCC1.C1C(C=O)=CC2[O:51][CH2:52][O:53]C=2C=1.ClC1C=C(CC(O)=O)C=CC=1.C1(C(OC)C(O)=O)CCCCC1>>[O:51]1[C:26]2[CH:25]=[CH:24][C:23]([CH:13]([N:12]3[C:11]4[CH:29]=[C:30]([Cl:34])[C:31]([F:33])=[CH:32][C:10]=4[N:9]=[C:8]3[CH:1]([CH:2]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)[O:42][CH3:41])[C:14]([NH:16][CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)=[O:15])=[CH:28][C:27]=2[O:53][CH2:52]1
Reactant: O=CC1CCCCC1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: O=C(NC1CCCCC1)C(C1CCCCC1)n1c(Cc2ccccc2)nc2cc(F)c(Cl)cc21
Agent: COC(C(=O)O)C1CCCCC1
Agent: O=C(O)Cc1cccc(Cl)c1
Product: COC(c1nc2cc(F)c(Cl)cc2n1C(C(=O)NC1CCCCC1)c1ccc2c(c1)OCO2)C1CCCCC1

Procedure:
The title compound was prepared in analogy to Example 1, replacing (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester with (2-amino-4-chloro-5-fluoro-phenyl)-carbamic acid tert-butyl ester (([CAS RN 579474-50-3]), Example 47), cyclohexanecarbaldehyde with piperonal ([CAS RN 120-57-0]) and (3-chloro-phenyl)-acetic acid with DL-cyclohexyl-methoxy-acetic acid ([CAS RN 15540-18-8]). MS (ISP): 556.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:27][CH2:26][NH:25][C@@H:24]([CH2:28][OH:29])[CH2:23]5)=[N:19][C:18]4=[O:30])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.C=O.F[C:40](F)(F)C1C=C(C(F)(F)F)C=CC=1CN1C2C(=CC(C=C3SC(N4CCN(C)[C@@H](CO)C4)=NC3=O)=CC=2)C=N1>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH3:40])[C@@H:24]([CH2:28][OH:29])[CH2:23]5)=[N:19][C:18]4=[O:30])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:34])([F:35])[F:36])[CH:3]=1
Reactant: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C[C@@H]1CO
Reactant: O=C1N=C(N2CCN[C@@H](CO)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Agent: C=O
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C[C@@H]1CO

Procedure:
5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(R)-(hydroxymethyl)-4-methylpiperazin-1-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one and formaldehyde following procedure used for compound of example 195.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:12])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[OH:4].Br[CH2:14][CH2:15][C:16]1[CH:30]=[CH:29][C:19]([O:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][C:17]=1[Cl:31].C(N(CC)C(C)C)(C)C.O>CN(C)C=O>[Cl:31][C:17]1[CH:18]=[C:19]([CH:29]=[CH:30][C:16]=1[CH2:15][CH2:14][NH:1][C@@H:2]([CH3:12])[C@H:3]([OH:4])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[O:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCBr)c(Cl)c1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN[C@@H](C)[C@H](O)c2ccc(O)cc2)c(Cl)c1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 53.7 %

Procedure:
(1R,2S)-2-Amino-1-(4-hydroxyphenyl)propan-1-ol (70 mg) and ethyl 2-[4-(2-bromoethyl)-3-chlorophenoxy]-2-methyl-propionate (147 mg) were dissolved in N,N-dimethylformamide (2 ml), N,N-diisopropylethylamine (118 μl) was added to the solution, and the mixture was stirred for 2.5 hours at 80° C. After the reaction mixture was cooled, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Purification of the residue by medium pressure liquid column chromatography on aminopropyl silica gel (eluent: ethyl acetate/ethanol=20/1) gave ethyl 2-[3-chloro-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]-2-methylpropionate (98 mg).