Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]4[N:18]=[CH:17][N:16]([C:19]5[CH:20]=[C:21]([NH2:33])[CH:22]=[C:23]([C:25]6[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=6[F:32])[CH:24]=5)[C:13]4=[N:14][CH:15]=3)[N:7]=[N:6]2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH2:40]([S:42](Cl)(=[O:44])=[O:43])[CH3:41]>C(Cl)Cl>[CH:1]1([CH2:4][N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]4[N:18]=[CH:17][N:16]([C:19]5[CH:20]=[C:21]([NH:33][S:42]([CH2:40][CH3:41])(=[O:44])=[O:43])[CH:22]=[C:23]([C:25]6[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=6[F:32])[CH:24]=5)[C:13]4=[N:14][CH:15]=3)[N:7]=[N:6]2)[CH2:2][CH2:3]1
Reactant: Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(CC5CC5)nn4)cnc32)c1
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(CC5CC5)nn4)cnc32)c1
Yield: 33 %

Procedure:
To a solution of 5-(6-(1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)-3H-imidazo-[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine (50 mg, 0.112 mmol) in DCM was added pyridine (26 mg, 0.33 mmol, 3.0 eq.) and ethanesulfonyl chloride (17 mg, 0.135 mmol, 1.2 eq.). After completion of the reaction the solvent was distilled off and the crude product was purified by preparative HPLC to give the product in 33% yield (20 mg). 1H NMR (300 MHz, DMSO): δ 10.3 (s, 1H) 9.02-8.99 (m, 2H), 8.81 (d, 1H), 8.63-8.61 (d, 1H) 7.95 (d, 1H), 7.77-7.69 (m, 2H), 7.49-7.42 (m, 2H), 7.31-7.25 (d, 1H), 4.33 (d, 2H), 3.42-3.26 (m, 2H), 1.34-1.24 (t, 3H), 0.63-0.60 (t, 2H), 0.49-0.48 (t, 2H); LC-MS (ESI): Calculated mass: 535.5; Observed mass: 535.8 [M+H]+ (rt: 0.1.33 min).
Reaction SMILES: I[C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][O:27][C:28]1[CH:33]=[C:32]([C:2]2[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[C:3]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Ic1sc2ccccc2c1Oc1ccc(OCc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cccc(-c2sc3ccccc3c2Oc2ccc(OCc3ccccc3)cc2)c1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
To a solution of 2-iodo-3-(4-benzyloxyphenoxy)benzo[b]thiophene (5.00 g, 11.0 mmol) in 50 mL of toluene under N2 were added 3-methoxyphenylboronic acid (2.00 g, 13.0 mmol), (Ph3P)4Pd (0.75 g, 0.66 mmol), and 18.0 mL of 2.0 N Na2CO3 solution. The resulting mixture was heated to reflux for 2 h. Upon cooling to room temperature, the reaction was diluted with EtOAc and extracted several times with 0.1 N NaOH. The organic was then dried (Na2SO4) and concentrated in vacuo to an oil. Chromatography (SiO2, 0-10% Et2O/hexanes) provided 4.8 g (99%) of 2-(3-methoxyphenyl)-3-(4-benzyloxyphenoxy)benzo[b]thiophene as a brown oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]([CH3:20])([CH3:19])[O:10][C:9]2=[O:21])[CH:5]=[CH:4][N:3]=1.[C:22]1([C@@H:28]([NH2:30])[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CS(C)=O.CCOC(C)=O>[CH3:19][C:11]1([CH3:20])[O:10][C:9](=[O:21])[N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:30][C@H:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:29])[N:7]=2)[C@H:12]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CC1(C)OC(=O)N(c2ccnc(Cl)n2)[C@H]1c1ccccc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C[C@H](Nc1nccc(N2C(=O)OC(C)(C)[C@@H]2c2ccccc2)n1)c1ccccc1
Yield: 85 %

Procedure:
A solution of (S)-3-(2-chloropyrimidin-4-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one (33.9 mg, 0.112 mmol) and (S)-(−)-1-phenylethanamine (0.15 mL, 1.2 mmol, 10 equiv) in DMSO (1 mL) was heated at 110° C. for 140 min. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3×8 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 50%) provided (S)-5,5-dimethyl-4-phenyl-3-(2-((S)-1-phenylethylamino)pyrimidin-4-yl) oxazolidin-2-one (37.0 mg, white solid) in 85% yield. 1H NMR (400 MHz, CD3OD) δ 8.06 (d, J=5.8 Hz, 1H), 7.43 (d, J=5.8 Hz, 1H), 7.31-7.24 (m, 3H), 7.19-7.11 (m, 5H), 7.01 (br s 2H), 5.48 (s, 1H), 4.86-4.80 (m, 1H), 1.65 (s, 3H), 1.43 (d, J=7.0 Hz, 3H), 0.98 (s, 3H); HRMS(B) m/z 389.1987 (M+H)+.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH3:23])[CH2:12][O:13][C:14]1[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[O:16][N:15]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1COCC1.CO>[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH3:23])[CH2:12][O:13][C:14]1[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[O:16][N:15]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)c1cc(OC[C@H](C)NC(=O)OC(C)(C)C)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](COc1cc(C(=O)O)on1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.8 %

Procedure:
2M Aqueous sodium hydroxide solution (20 mL) was added to a solution of methyl 3-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)isoxazole-5-carboxylate (4.0 g) in THF/methanol (20 mL/20 mL), and the mixture was stirred at room temperature for 15 hr. The solvent was evaporated under reduced pressure, and the residue was neutralized with 6M hydrochloric acid and extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.5 g).
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])C(=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=[C:4]([O:38][CH3:39])C=1.COC1C(B(O)O)=CC=C[N:43]=1>C(Cl)Cl.CO>[CH3:37][S:34]([CH2:33][CH2:32][NH:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:5]1[C:4]([O:38][CH3:39])=[N:43][CH:2]=[CH:7][CH:6]=1)(=[O:36])=[O:35]
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: COc1ncccc1B(O)O
Solvent: ClCCl
Solvent: CO
Product: COc1ncccc1-c1ccncc1NCCS(C)(=O)=O

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-(2-methanesulfonyl-ethyl)-amine (example 158, intermediate b) and 2-methoxypyridine-3-boronic acid (CAS RN 163105-90-6) and using a gradient of CH2Cl2:methanol (100:0 to 85:15) for the chromatographic purification. Brown solid (89%). MS (ESI): m/z=308.11 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:9]2[C:10]([NH2:14])=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][CH:6]=1)(OC)=[O:2].C[O-].[Na+].CO.Cl>C(#N)C>[NH:14]1[C:10]2[N:9]3[C:8](=[N:7][CH:6]=[C:5]3[C:1]1=[O:2])[CH:13]=[CH:12][CH:11]=2
Reactant: COC(=O)c1cnc2cccc(N)n12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: O=c1[nH]c2cccc3ncc1n32
Yield: 167.7 %

Procedure:
To a solution prepared by dissolving 1.44 g (7.0 mM) of 3-carbomethoxy-5-aminoimidazo[1,2-a]pyridine in 10 ml of acetonitrile followed by addition of 3.2 ml (14.0 mM) of 25% sodium methoxide-methanol and the mixture was refluxed for 1 hour. After completion of the reaction, 1.15 ml (14.0 mM) of 12N-hydrochloric acid was added to the reaction mixture under ice-cooling and the solvent was thoroughly distilled off under reduced pressure to provide 2.01 g (yield 100%) of a crude product as tan-colored solid.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[C:13]([C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=[CH:11][C:10]=1[OH:23])([CH3:8])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].N1C(C)=CC=CC=1C.Cl[Sn](Cl)(Cl)Cl.[CH2:37]=[O:38].Cl>C1(C)C=CC=CC=1>[CH3:8][C:2]([C:9]1[CH:14]=[C:13]([C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=[C:11]([CH:37]=[O:38])[C:10]=1[OH:23])([CH3:1])[CH2:3][C:4]([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(C(C)(C)CC(C)(C)C)c1
Reactant: C=O
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: CC(C)(C)CC(C)(C)c1cc(C=O)c(O)c(C(C)(C)CC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
2,4-bis(1,1,3,3-tetramethylbutyl)phenol (26.2 g, 82.4 mmol, synthesized by the method described in U.S. Pat. No. 3,373,210), toluene (200 ml) and 2,6-lutidine (14.4 g, 135 mmol) was placed in a stirred flask under a blanket of nitrogen and the mixture was cooled to 0° C. SnCl4 (8.57 g, 33 mmol) was then carefully added. The mixture was subsequently stirred at room temperature for 20 minutes, before paraformaldehyde (15.1 g, 502 mmol) was added. The mixture was then stirred at 100° C. for 12 hours. After cooling, hydrochloric acid (1 M, 272 ml) was added. The resulting suspension was filtered through Celite and the solid was washed with 100 ml of ethyl acetate. The organic phase of the filtrate was then separated off, washed twice with 100 ml of NaCl solution, dried over MgSO4 and evaporated at reduced pressure. A slightly yellowish oil was formed as product. According to GC/MS, this crude product contains only about 3% of starting material. Yield: 26.9 g (94%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH:11]3[CH2:14][CH2:13][CH2:12]3)[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.Br[CH2:16][C:17]1[CH:36]=[CH:35][C:20]2/[C:21](=[C:31](/[CH3:34])\[C:32]#[N:33])/[C:22]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=3[O:24][CH2:25][C:19]=2[CH:18]=1>>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH:11]3[CH2:14][CH2:13][CH2:12]3)[N:10]([CH2:16][C:17]3[CH:36]=[CH:35][C:20]4/[C:21](=[C:31](/[CH3:34])\[C:32]#[N:33])/[C:22]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=5[O:24][CH2:25][C:19]=4[CH:18]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc2[nH]c(C3CCC3)nc12
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(Cn3c(C4CCC4)nc4c(Cl)nccc43)cc2COc2cc(F)ccc21
Yield: 91.5 %

Procedure:
[step 3] Using 4-chloro-2-cyclobutyl-1H-imidazo[4,5-c]pyridine (41 mg, 0.196 mmol) obtained in step 2 and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (70 mg, 0.196 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (87 mg, 91%) was obtained.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)=[O:3].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>C1C=CC=CC=1>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[N:8][C:7]2[CH:9]=[CH:10][C:4]([S:2]([CH3:1])=[O:3])=[CH:5][CH:6]=2)=[CH:14][CH:13]=1
Reactant: CS(=O)c1ccc(N)cc1
Reactant: O=Cc1ccc(F)cc1
Solvent: c1ccccc1
Product: CS(=O)c1ccc(N=Cc2ccc(F)cc2)cc1

Procedure:
A mixture of 3.0 g (19 mmol) of 4-methylsulfinylaniline (obtained in reference example 3), 2 mL (19 mmol) of 4-fluorobenzaldehyde and 80 mL of benzene was refluxed in a Dean-Stark for 2 days. The solvent was removed and the crude product obtained was directly used in the next reaction.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21](O)=[O:22])[C:12]3=[O:24])[CH:9]=[CH:10][C:2]1=2.CN(C)C=O.C(Cl)(=O)C([Cl:33])=O>ClCCl>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]([Cl:33])=[O:22])[C:12]3=[O:24])[CH:9]=[CH:10][C:2]1=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1nc2ccccc2n(-c2ccc3c(c2)OCCO3)c1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1nc2ccccc2n(-c2ccc3c(c2)OCCO3)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.9 g (31 mmol) of 1-(2,3-dihydrobenzo[b] 1,4-dioxin-6-yl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid was dissolved in dichloromethane (100 mL), and to this solution, N,N-dimethylformamide (0.5 mL) and 4.7 g (37 mmol) of oxalyl chloride were added sequentially. The mixture was stirred for one hour at room temperature. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure to obtain 1-(2,3-dihydrobenzo[b]1,4-dioxin-6-yl)-2-oxo-1,2-dihydroquinoxaline-3-carbonyl chloride as yellow crystals (Compound No. of Production Intermediate: IX-75).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:10][C:11]([OH:13])=[O:12])=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[CH:23](O)([CH3:25])[CH3:24]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([F:16])([F:17])[F:18])[CH2:10][C:11]([O:13][CH:23]([CH3:25])[CH3:24])=[O:12])=[CH:5][C:4]=1[C:19]([F:21])([F:20])[F:22])#[N:2]
Reactant: CC(C)O
Reactant: N#Cc1ccc(N(CC(=O)O)CC(F)(F)F)cc1C(F)(F)F
Product: CC(C)OC(=O)CN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized according to example 3 N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2,2,2-trifluoroethyl)glycine and isopropanol: 1H NMR (300 MHz, CD3OD) δ 7.81-7.73 (m, 1H), 7.17-7.09 (m, 2H), 5.04 (sept, J=6.3 Hz, 1H), 4.38 (s, 2H, overlapped with 4.35), 4.35 (q, J=9.0 Hz, overlapped with 4.38, 2H), 1.23 (d, J=6.1 Hz, 6H).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])=[CH:10][CH:11]=2)[C:6]([OH:21])=[C:5]([C:22](OCCCC)=[O:23])[N:4]=1)#[N:2].OC(C(F)(F)F)=O.[NH2:36][CH2:37][C:38]([CH3:43])([CH3:42])[C:39]([OH:41])=[O:40].C[O-].[Na+]>CCO>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])=[CH:10][CH:11]=2)[C:6]([OH:21])=[C:5]([C:22]([NH:36][CH2:37][C:38]([CH3:43])([CH3:42])[C:39]([OH:41])=[O:40])=[O:23])[N:4]=1)#[N:2]
Reactant: CC(C)(CN)C(=O)O
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccccc3C)cc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1Oc1ccc2c(C#N)nc(C(=O)NCC(C)(C)C(=O)O)c(O)c2c1

Procedure:
Butyl 1-cyano-4-hydroxy-6-(o-tolyloxy)isoquinoline-3-carboxylate (11 mg, 0.03 mmol), 3-amino-2,2-dimethyl-propionic acid TFA salt (27.1 mg, 0.12 mmol) and NaOMe (12.3 mg, 0.23 mmol) in EtOH (3 mL) were heated at 150° C. in a microwave for 90 minutes. The solvent was removed in vacuo and the residue was dissolved in H2O (15 mL) and EtOAc (15 mL). To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-25% MeOH/CH2Cl2) to give the title compound in 7 mg. MS: (−) m/z 417.94 (M−1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]=[C:11]([C:21]([OH:23])=O)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][NH2:32])[CH2:26][CH2:25]1.[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37]>C(O)C>[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37].[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:21](=[O:23])[NH:32][CH2:31][CH2:30][N:27]3[CH2:28][CH2:29][O:24][CH2:25][CH2:26]3)[N:12]=[C:13]([CH3:20])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: NCCN1CCOCC1
Reactant: CCOC(=O)c1c(-c2cccc(C#N)c2)cc(C(=O)O)nc1C
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Product: CCOC(=O)c1c(-c2cccc(C#N)c2)cc(C(=O)NCCN2CCOCC2)nc1C
Yield: 52.1 %

Procedure:
Ethyl 4-(3-cyanophenyl)-2-methyl-6-(2-morpholinoethylcarbamoyl)-3-pyridinecarboxylate, which was obtained according to a similar manner to that of Example 18 from 4-(3-cyanophenyl)-5-ethoxycarbonyl-6-methyl-2-pyridinecarboxylic acid (0.93 g) and 2-morpholinoethylamine (0.39 g), was treated with a solution of fumaric acid (0.54 g) in ethanol (11 ml) to give ethyl 4-(3-cyanophenyl)-2-methyl-6-(2-morpholinoethylcarbamoyl)-3-pyridinecarboxylate fumarate (0.84 g).
Reaction SMILES: ClC1C=CC(C2(O)CCN(CCC=C3C4[C:22](=NC=CC=4)[O:21][C:20]4C=CC=C(O)[C:19]=4C3)CC2)=CC=1.[Cl:34][C:35]1[CH:36]=[C:37]2[C:65](=[CH:66][CH:67]=1)[C:40]1([CH2:45][CH2:44][N:43]([CH2:46][CH2:47][CH:48]=[C:49]3[C:59]4[C:54](=[N:55][CH:56]=[CH:57][CH:58]=4)[O:53][C:52]4[CH:60]=[CH:61][CH:62]=[C:63]([OH:64])[C:51]=4[CH2:50]3)[CH2:42][CH2:41]1)[O:39][CH2:38]2>>[Cl:34][C:35]1[CH:36]=[C:37]2[C:65](=[CH:66][CH:67]=1)[C:40]1([CH2:41][CH2:42][N:43]([CH2:46][CH2:47][CH:48]=[C:49]3[C:59]4[C:54](=[N:55][CH:56]=[CH:57][CH:58]=4)[O:53][C:52]4[CH:60]=[CH:61][CH:62]=[C:63]([O:64][CH2:19][CH2:20][O:21][CH3:22])[C:51]=4[CH2:50]3)[CH2:44][CH2:45]1)[O:39][CH2:38]2
Reactant: Oc1cccc2c1CC(=CCCN1CCC3(CC1)OCc1cc(Cl)ccc13)c1cccnc1O2
Reactant: Oc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Product: COCCOc1cccc2c1CC(=CCCN1CCC3(CC1)OCc1cc(Cl)ccc13)c1cccnc1O2

Procedure:
The titled compound was prepared by following the procedure of example 175, but replacing the product of example 44 with the product of example 196.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.[C:23]([NH:31][NH2:32])(=O)[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[NH:6][C:23]([C:24]5[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=5)=[N:31][N:32]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:21][CH:20]=1
Reactant: NNC(=O)c1ccncc1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: Cl
Product: Fc1ccc(-c2n[nH]c3ccc(-c4nnc(-c5ccncc5)[nH]4)cc23)cc1
Yield: 15.4 %

Procedure:
The procedure described in example 119 using ethoxy[3-(4-fluorophenyl)(1H-indazole-5-yl)]methanimine hydrochloride (200 mg, 0.62 mmol), triethylainine (0.25 mL, 1.86 mmol) and isonicotinic acid hydrazide (171.42 mg, 1.25 mmol) was followed to yield the title compound (34 mg, 15% yield). 1H NMR (DMSO-d6) δ 13.6 (s, 1H), 8.78–8.82 (m, 3H), 8.05–8.25 (m, 5H), 7.8 (d, 1H), 7.45 (t, 2H), ES-MS (m/z) 357 [M+1]+.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:58])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:45]2)[CH:7]([CH3:59])[CH2:6][CH2:5][C:4]1=[O:60])[CH3:2].C(N(CC)CC)C.[CH:68]1([C:71](Cl)=[O:72])[CH2:70][CH2:69]1>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:58])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][C:71]([CH:68]3[CH2:70][CH2:69]3)=[O:72])[CH:46]([O:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:45]2)[CH:7]([CH3:59])[CH2:6][CH2:5][C:4]1=[O:60])[CH3:2]
Reactant: O=C(Cl)C1CC1
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N)C(Oc4ccccc4)C3)C(C)CCC1=O)C(C)CC2OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(NC(=O)C4CC4)C(Oc4ccccc4)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 34 mg of 17-ethyl-1-hydroxy-12-[2'-(4"-amino-3"-phenoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in dry methylene chloride (0.4 ml) is cooled to 0° C. To this solution is added triethylamine (10 μl) followed by a solution of cyclopropane carbonyl chloride (5 mg) in methylene chloride (0.1 ml). The reaction mixture is stirred at 0° C. for 30 min. The reaction mixture is purified by preparative tlc on silica gel to give the title compound.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH:11]1([CH:17]=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([CH:17]2[NH:10][C:1](=[O:9])[C:2]3[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:4]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=CC1CCCCC1
Reactant: NC(=O)c1ccccc1N
Product: O=C1NC(C2CCCCC2)Nc2ccccc21

Procedure:
Anthranilamide was transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 172–174° C.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][C@@H:11]1[C:17]1[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[C:1]([O:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][C@@H:11]1[C:17]1[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1nccc1[C@H]1CC(=O)CC[C@@H]1OC(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1nccc1[C@H]1C[C@@H](O)CC[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.7 %

Procedure:
To a solution of the (1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)-4-oxocyclohexyl benzoate (430 mg, 1.44 mmol) prepared in Example 162c in ethanol (7.0 mL), sodium borohydride (164 mg, 4.34 mmol) was added, and the mixture was stirred at room temperature for 5 hours. To the reaction solution, water (10 mL) was added, followed by extraction with ethyl acetate (50 mL). The thus obtained organic layer was washed twice with water (50 mL) and dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with reverse phase chromatography (YMC HPLC COLUMN, YMC-Pack ODS-A; methanol/water=6:4) to yield the title compound (293 mg, 69%) as a colorless solid.
Reaction SMILES: C([O:8][C@H:9]([C@@H:19]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[OH:20])[C@H:10]([O:15][C:16](=[O:18])[CH3:17])[C@@H:11]([OH:14])[CH:12]=[O:13])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:16]([O:15][C@@H:10]([C@@H:9]([C@@H:19]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[OH:20])[OH:8])[C@@H:11]([OH:14])[CH:12]=[O:13])(=[O:18])[CH3:17]
Reactant: CC(=O)OC[C@@H](O)[C@@H](OCc1ccccc1)[C@H](OC(C)=O)[C@@H](O)C=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(=O)OC[C@@H](O)[C@@H](O)[C@H](OC(C)=O)[C@@H](O)C=O

Procedure:
Degussa 10% Pd/C (50% wet) (0.4 g) was added to the solution of 4-O-benzyl-3,6-di-O-acetyl-D-glucose (5 mmol) in ethanol (50 mL). Obtained mixture was hydrogenated at room temperature using Paar apparatus with hydrogen (45 psi) After 12 hr reaction was completed (TLC), catalyst was filtered off and the solvent was evaporated to give a crude product. Product was purified by column chromatography (SilicaGel 60 Merck), using hexanes:ethyl acetate as eluent.