Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.[NH2:19][C:20]1[C:29](Br)=[N:28][C:27]([Br:31])=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23].C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:19][C:20]1[C:29]([C:13]2[CH:14]=[CH:15][C:10]([S:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)(=[O:9])=[O:8])=[CH:11][CH:12]=2)=[N:28][C:27]([Br:31])=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)c1cc(Br)nc(Br)c1N
Reactant: O=S(=O)(c1ccc(B(O)O)cc1)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1cc(Br)nc(-c2ccc(S(=O)(=O)N3CCOCC3)cc2)c1N
Yield: 76 %

Procedure:
A flask containing mixture of 4-(morpholinosulfonyl)-phenylboronic acid (0.920 g, 3.39 mmol), methyl 3-amino-2,6-dibromoisonicotinate (0.877 g, 2.83 mmol), tetrakistriphenylphosphine palladium(0) (0.196 g, 0.170 mmol), sodium carbonate (0.719 g, 6.79 mmol) was flushed with nitrogen. Toluene (7 mL), and MeOH (2.4 mL) were added and the reaction was heated at reflux under nitrogen for 24 hr. The reaction was partitioned between EtOAc and water. The organic phase was washed with brine, dried with sodium sulfate, and the solvent removed. Radial silica gel chromatography (step gradient elution with DCM containing 0 to 20% EtOAc) afforded methyl 3-amino-6-bromo-2-(4-(morpholinosulfonyl)phenyl)isonicotinate (982 mg, 2.15 mmol, 76% yield) as a yellow solid. MS (ESI) m/z 457.9 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 7.80-7.91 (5H, m), 5.94 (2H, br. s.), 3.94 (3H, s), 3.68-3.79 (4H, m), 2.98-3.07 (4H, m).
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[S:9]([C:12]1[CH:27]=[CH:26][C:15]([C:16]([O:18]CC2C=CC=CC=2)=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[S:9]([C:12]1[CH:27]=[CH:26][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(Cc2ccccc2)S(=O)(=O)c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccccc2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Yield: 42.3 %

Procedure:
Benzyl 4-(N-benzyl-N-(4-methoxybenzyl)sulfamoyl)benzoate (Example 5-1a) (517 mg, 1 mmol) was stirred a 10/1/2 solution of 6N NaOH (aq)/THF/MeOH (27 mL) at ambient temperature for 6 hours. The solution was acidified with 3N HCl (aq) to a pH of ˜3 (ca. 50 mL), and the aqueous phase was extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate and concentrated on the rotovap. The residue was taken up in MeOH (15 mL) and purified by reverse phased HPLC (5-95% acetonitrile in H2O gradient:25 minutes) in three 5 mL aliquots. The pure fractions were combined and concentrated to a white solid. The product was dissolved in 15 mL of absolute ethanol and evaporated on the rotovap (4×) to provide pure 4-(N-benzyl-N-(4-methoxybenzyl)sulfamoyl)benzoic acid (174 mg, 42%) as a white solid. M.p 161-163° C. 1H NMR (CDCl3, 400 MHz): 3.78 (s, 3H), 4.32 (s, 2H), 4.36 (s, 2H), 6.78 (d, J=8.4 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H), 709-7.07 (m, 2H), 7.27-7.24 (m, 3H), 7.93 (d, J=8.8 Hz, 2H), 8.24 (d, J=8 Hz, 2H). MS 412 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:10]([O:14][C:15](=[O:25])[NH:16][C:17]1[C:18]([CH:23]=O)=[N:19][CH:20]=[CH:21][CH:22]=1)([CH3:13])([CH3:12])[CH3:11].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:10]([O:14][C:15](=[O:25])[NH:16][C:17]1[C:18]([CH2:23][NH:9][CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[N:19][CH:20]=[CH:21][CH:22]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1cccnc1CN
Reactant: CC(C)(C)OC(=O)Nc1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CNCc1ncccc1NC(=O)OC(C)(C)C

Procedure:
Using General Procedure B: Reaction of C-(3-methyl-pyridin-2-yl)-methylamine and (2-formyl-pyridin-3-yl)-carbamic acid tert-butyl ester with NaBH(OAc)3 in CH2Cl2 gave (2-{[(3-Methyl-pyridin-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-carbamic acid tert-butyl ester as a yellow oil.
Reaction SMILES: C([N:8]1[CH2:11][CH2:10][CH:9]1[C:12]([NH:14][C@H:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)[CH3:16])=[O:13])C1C=CC=CC=1.CCO.C([O-])=O.[NH4+]>[Pd]>[NH:8]1[CH2:11][CH2:10][CH:9]1[C:12]([NH:14][C@H:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)[CH3:16])=[O:13]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)C2CCN2Cc2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)c1ccc([C@H](C)NC(=O)C2CCN2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of methyl 4-((1S)-1-(1-benzylazetidine-2-carboxamido)ethyl)benzoate (D76) (98 mg, 0.278 mmol in EtOH (20 ml) Pd/C 10% (90 mg, 0.083 mmol) and ammonium formate (52 mg, 0.83 mmol) were added and the heterogeneous solution was left stirring at RT for 20 hrs. Further addition of Pd/C 10% (90 mg, 0.083 mmol) and ammonium formate (52 mg, 0.83 mmol) was done and the resulting mixture was stirred at RT for 5 hrs. Catalyst was filtered off and the solvent evaporated to afford the title compound (D109) (60 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[S:14][CH2:13][C:12]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[N:11]2[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:5]([CH2:24][CH3:25])[CH:4]=1)#N.CC(C[AlH]CC(C)C)C.CC[O:37]C(C)=O>C1(C)C=CC=CC=1>[CH2:24]([C:5]1[CH:4]=[C:3]([CH:1]=[O:37])[CH:8]=[CH:7][C:6]=1[N:9]=[C:10]1[S:14][CH2:13][C:12]2([CH2:18][CH2:17][CH2:16][CH2:15]2)[N:11]1[CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH3:25]
Reactant: CCOC(C)=O
Reactant: CCc1cc(C#N)ccc1N=C1SCC2(CCCC2)N1C1CCCC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CCc1cc(C=O)ccc1N=C1SCC2(CCCC2)N1C1CCCC1
Temperature: -78 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
2-(4-Cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane was prepared in a manner analogous to Method C2a and the thiazolidine was alkylated in a manner analogous to Method D2b to give 2-(4-cyano-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. To a solution of 2-(4-cyano-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane (0.21 g, 0.60 mmol) in anh. toluene (20 mL) at −78C. was added DIBAL (1.0M in toluene, 1.20 mL, 1.20 mmol). The reaction mixture was stirred at −78° C. for 3 h, then EtOAc (3 mL) was added at −78° C., stirring was continued for 0.5 h, and wet silica gel (5% water, 2 g) was added. The reaction mixture was warmed to room temp., stirred for 3 h, then filtered through a pad of through Celite®. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC (30% EtOAc/hex) to give 2-(2-ethyl-4-formylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane as a white solid (0.16 g, 75%): mp 104-105° C.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.[C:29]([C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1)#[N:30]>>[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9]([CH2:11][O:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:34]3[CH:35]=[CH:36][C:31]([C:29]#[N:30])=[N:32][CH:33]=3)=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: Brc1cnc(N2CCOCC2)c2nc(COc3ccc4ccccc4n3)cn12
Product: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1

Procedure:
Compound 54a was prepared from compound 31b and 2-cyanopyridine-5-boronic acid pinacol ester using the methods described in Example 1, Step G. Mass Spectrum (LCMS, ESI pos.) Calcd. for C26H21N7O2: 464.2 [M+H]. found 464.2.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([N+:21]([O-])=O)=[C:11]([CH:20]=2)[NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:3][CH2:2]1.[H][H]>C1COCC1.[Ni]>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:20]=[C:11]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:10]([NH2:21])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(C2=CCOCC2)cc1NCc1ccccn1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc(C2CCOCC2)cc1NCc1ccccn1

Procedure:
5-(3,6-dihydro-2H-pyran-4-yl)-2-nitro-N-(pyridin-2-ylmethyl)aniline E-1.9′ (82 mg; 0.26 mmol) is dissolved in THF (25 ml) and filled into a Büchi autoclave. RaNi is added and the reaction is hydrogenated with 5 bar hydrogen pressure overnight. The reaction mixture is filtered on a plug of celite. The filtrate is then concentrated under reduced pressure. The product is used in the next step without further purification.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:36])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([CH3:35])=[N:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:36][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([CH3:35])=[N:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: Cc1ncccc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO[Si](C)(C)C(C)(C)C)C4)CC2)cc1
Agent: Cl
Solvent: CO
Product: Cc1ncccc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO)C4)CC2)cc1
Yield: 66.9 %

Procedure:
A solution of the compound (388 mg, 0.75 mmol) obtained in Example 17-1) and 4 M hydrochloric acid (1,4-dioxane solution, 2 mL) in methanol (2 mL) was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (204 mg, 67%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[N:6]([CH3:7])[CH2:5][CH:4]2[C:8](=O)[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10](=O)[CH:3]12.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C:2]1([CH3:20])[C@@H:3]2[CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][C@@H:4]2[CH2:5][N:6]1[CH3:7]
Reactant: CN1CC2C(=O)N(Cc3ccccc3)C(=O)C2C1(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C[C@H]2CN(Cc3ccccc3)C[C@H]2C1(C)C
Temperature: 0 °C
Yield: 29.5 %

Procedure:
4,4,5-Trimethyl-2-(phenylmethyl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (5.39 g, 20 mmol) (Bull. Chem. Soc. Jpn., 1987, 60, 4079-4089) was dissolved in THF (50 mL) and cooled to 0° C. LiAlH4 (2.25 g, 59 mmol) was added portionwise and the resulting mixture was refluxed overnight. Upon cooling to 0° C., the reaction was quenched by the addition of water (2.25 mL), followed by 15% (w/w) NaOH (aq) (2.25 mL) and another portion of water (6.75 mL). The quenched reaction was stirred and then filtered through Celite, before being concentrated under reduced pressure. Purification by RP-HPLC yielded (rac)-cis-1,1,2-trimethyl-5-(phenylmethyl)octahydropyrrolo[3,4-c]pyrrole (1.44 g, 30%). LCMS: (M+H)+: 245.2.
Reaction SMILES: [C:1]([Cu])#N.C[Li].[Cl:6][C:7]1[CH:12]=[C:11]([C:13]2[N:18]([CH2:19][C:20]#[CH:21])[C:17](=[O:22])[C:16]([CH2:23][CH3:24])=[C:15](OS(C(F)(F)F)(=O)=O)[N:14]=2)[CH:10]=[C:9]([Cl:33])[N:8]=1>C1COCC1>[Cl:6][C:7]1[CH:12]=[C:11]([C:13]2[N:18]([CH2:19][C:20]#[CH:21])[C:17](=[O:22])[C:16]([CH2:23][CH3:24])=[C:15]([CH3:1])[N:14]=2)[CH:10]=[C:9]([Cl:33])[N:8]=1
Reactant: C#CCn1c(-c2cc(Cl)nc(Cl)c2)nc(OS(=O)(=O)C(F)(F)F)c(CC)c1=O
Reactant: N#C[Cu]
Agent: [Li]C
Solvent: C1CCOC1
Product: C#CCn1c(-c2cc(Cl)nc(Cl)c2)nc(C)c(CC)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
To a stirred, cold (-78° C.) solution of CuCN (1.91 g, 20 mmol) in 100 mL of THF was added methyllithium (30 mL, 42 mmol, 2.1 equiv, 1.4M in diethyl ether) over 10 min. After stirring for 15 min, this solution was added over 10 min via a canula to a cold (-78° C.) solution of 2-(2,6-dichloro-4-pyridyl)-5-ethyl-3-propargyl-6-trifluoromethanesulfonyloxy-4(3H)-pyrimidinone in 20 mL of THF. The reaction mixture was stirred for 30 min, quenched with 15 mL of 10% concentrated NH4OH/saturated NH4Cl, diluted with 200 mL of ethyl acetate and warmed to room temperature. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to give a semi oil. The crude product was purified by flash chromatography (silica gel, ethyl acetate/hexane, 2/8) to afford 2.29 g (71%) of 2-(2,6-dichloro-4-pyridyl)-5-ethyl-6-methyl-3-propargyl-4(3H)-pyrimidinone as a white solid: mp 143-144° C.; IR (KBr) 3220, 2125, 1668, 1584, 1541, 1515, 1367 cm-1 ; 1H NMR (270 MHz, CDCl3) δ1.16 (t, J=7.6 Hz, 3H), 2.35 (s, 3H), 2.43 (t, J=2.6 Hz, 1H), 2.62 (q, J=14.8 Hz, 2H), 4.56 (d, J=2.6 Hz, 2H), 7.60 (s, 2H).
Reaction SMILES: O[C:2]1[C:3]2[N:4]([N:12]=[CH:13][C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:2]1[C:3]2[N:4]([N:12]=[CH:13][C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnn2c1c(O)nc1ccccc12
Product: CCOC(=O)c1cnn2c1c(Cl)nc1ccccc12

Procedure:
50 g. of the product of Example 1, part b in 200 ml. of phosphorus oxychloride are refluxed for 3 hours. After distilling off the excess phosphorus oxychloride, 4-chloropyrazolo[1,5-a]quinoxaline-3-carboxylic acid, ethyl ester crystallizes. The distillation residue is stirred shortly with ice water and then the crude product is filtered off. The crude product is dried briefly over potassium hydroxide and recrystallized from acetone. The pure product is obtained as white needles; yield 39.5 g., m.p. 105°-106°.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:50])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:27][N:28]2[CH2:32][CH2:31][CH2:30][CH:29]2[CH2:33][O:34][C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][C:36]=2[N+:45]([O-])=O)=[O:26])=[CH:20][C:19]=1[O:48][CH3:49])C1C=CC=CC=1>CO.C1COCC1.[Pd]>[NH2:45][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:35]=1[O:34][CH2:33][CH:29]1[CH2:30][CH2:31][CH2:32][N:28]1[NH:27][C:25](=[O:26])[CH2:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:16]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[OH:8])=[O:50])=[C:19]([O:48][CH3:49])[CH:20]=1)[C:39]([O:41][CH3:42])=[O:40]
Reactant: COC(=O)c1ccc(OCC2CCCN2NC(=O)Cc2ccc(NC(=O)Nc3ccccc3OCc3ccccc3)c(OC)c2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCC2CCCN2NC(=O)Cc2ccc(NC(=O)Nc3ccccc3O)c(OC)c2)c(N)c1
Reaction time: 17 h
Yield: 87.5 %

Procedure:
A solution of methyl 4-[1-[4-[N′-(2-benzyloxyphenyl)ureido]-3-methoxyphenylacetamido]-2-pyrrolidinylmethoxy]-3-nitrobenzoate (1.52 g, 2.27 mmol) in MeOH (20 mL) and THF (5 mL) was hydrogenated over 5% Pd—C (wet, 52.2%; 1.21 g) under hydrogen atmosphere (4 kg/cm2) at room temperature After being stirred for 17 hr, the catalyst was filtered off and the filtrate was concentrated to dryness. Chromatography of the residue with EtOAc as eluent gave methyl 3-amino-4-[1-[4-[N′-(2-hydroxyphenyl)ureido]-3-methoxyphenylacetamido]-2-pyrrolidinylmethoxy]benzoate (1.12 g, 90%) as a brownish amorphous solid. 1H-NMR (CDCl3) δ 1.97–2.10 (m, 4H), 3.44 (s, 3H), 3.52–3.63 (m, 2H), 3.85 (s, 3H), 4.10–4.18 (m, 2H), 4.53 (m, 1H), 6.65–6.67 (m, 4H), 6.93–7.02 (m, 3H), 7.33 (d, J=2.2 Hz, 1H), 7.36 (dd, J=8.3, 2.2 Hz, 1H), 7.60 (s, 1H), 7.69 (d, J=8.3 Hz, 1H), 8.08 (s, 1H), 9.47 (broad s, 1H); FAB-MS m/z 549 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[C:8]([NH:16]C=O)=[N:7]1)=[O:5])[CH3:2]>C(O)=O>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[C:8]([NH2:16])=[N:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)n1nc(NC=O)c2ccc(Cl)cc21
Solvent: O=CO
Product: CCOC(=O)n1nc(N)c2ccc(Cl)cc21
Yield: 71 %

Procedure:
Analogously to Example 56, 0.085 mol of 3-amino-6-chloroindazole-1-carboxylic acid ethyl ester and 100 ml of formic acid produce 3-formylamino-6-chloroindazole-1-carboxylic acid ethyl ester in 3.5 hours at 100° C (melting point 227°-230° (decomposition), yield: 71% of theory).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[OH-].[Na+:11]>O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O-:9])=[O:8].[Na+:11]
Reactant: O=C(O)CCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CCCCCBr

Procedure:
To a well-mixed solution of 20 g of water and 14.6 g of 6-bromohexanoic acid (0.075 mole) at 20° C. was added a 5.0M NaOH solution to adjust the pH to 7.5 (˜0.075 mole). The water was removed under vacuum and the resulting solid was ground to a free-flowing white powder.
Reaction SMILES: [CH:1]1([N:7]([CH3:17])[C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[OH-].[OH-].[Pd+2]>[CH:1]1([N:7]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][N:9]=2)[CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(c1ccc([N+](=O)[O-])cn1)C1CCCCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CN(c1ccc(N)cn1)C1CCCCC1
Reaction time: 6 h

Procedure:
Cyclohexyl-methyl-(5-nitro-pyridin-2-yl)-amine (1.72 g, 7.3 mmol) was dissolved in ethanol (80 mL) and treated with 20% palladium hydroxide on carbon (Pearlman's catalyst, 0.5 g) and the mixture was shaken under a hydrogen atmosphere (50 psi) for 6 hours. The catalyst was removed by filtration through celite then the filtrate was concentrated in vacuo and the resultant oil was chromotographed on SiO2 using 1:1 ethyl acetate/hexanes as eluent. MS (m/z) 206 (M+H)•; C12H19N3 requires 205.3.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:29][CH2:30][CH2:31][C:32]1[N:33]=[CH:34][N:35](C(OC(C)(C)C)=O)[CH:36]=1)[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:29][CH2:30][CH2:31][C:32]1[N:33]=[CH:34][NH:35][CH:36]=1)[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)n1cnc(CCCN(Cc2nc3ccccc3n2C(=O)OC(C)(C)C)C2CCCc3cccnc32)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cnc2c(c1)CCCC2N(CCCc1c[nH]cn1)Cc1nc2ccccc2[nH]1
Yield: 94.1 %

Procedure:
A solution of 2-{[[3-(1-tert-butoxycarbonyl-1H-imidazol-4-yl)-propyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylic acid tert-butyl ester (39 mg, 0.066 mmol) in 3:1 TFA/CH2Cl2 (4 mL) was stirred at room temperature for 30 minutes then concentrated in vacuo. The residue was partitioned between CH2Cl2 (15 mL) and 1 N NaOH(aq) (10 mL), and the aqueous phase was extracted with CH2Cl2 (15 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford COMPOUND 38 as a yellow foam (24 mg, 80%). 1H NMR (CDCl3) δ 1.67 (m, 3H), 1.86 (m, 1H), 2.00 (m, 1H), 2.16 (m, 1H), 2.42-2.87 (m, 6H), 4.01 (m, 3H), 6.51 (s, 1H), 7.15 (m, 3H), 7.42 (m, 2H), 7.53 (m, 2H), 8.54 (d, 1H, J=3.6 Hz); 13C NMR (CDCl3) δ 21.66, 23.85, 24.01, 28.39, 29.50, 49.64, 50.78, 62.36, 115.22, 118.74, 122.23, 122.74, 134.47, 135.25, 135.58, 138.03, 139.02, 146.88, 156.37, 157.69. ES-MS m/z 387 (M+H). Anal. Calcd. for C23H26N6.0.4CH2Cl2.0.9CH4O: C, 64.96; H, 6.82; N, 18.70. Found: C, 65.13; H, 6.93; N, 18.91.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH3:54][O:55][C:56]1[CH:61]=[C:60]([CH3:62])[CH:59]=[CH:58][C:57]=1[S:63](Cl)(=[O:65])=[O:64]>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:63]([C:57]1[CH:58]=[CH:59][C:60]([CH3:62])=[CH:61][C:56]=1[O:55][CH3:54])(=[O:65])=[O:64])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: COc1cc(C)ccc1S(=O)(=O)Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1S(=O)(=O)c1ccc(C)cc1OC)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (25 mg) was reacted with 2-methoxy-4-methylbenzenesulfonyl chloride to afford (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(2-methoxy-4-methyl-benzenesulfonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid methyl ester according to General Procedure E. This product (20 mg) was hydrolyzed according to General Procedure B to give the title compound (16 mg). LCMS (m/z): 0.919.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:9][N:10]([CH2:18][C:19]([NH:21][C:22]([NH2:24])=[O:23])=[O:20])[CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:25]([CH3:33])[CH:26]([CH3:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:3]=1.[ClH:34].[CH3:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][N:37]1[CH2:42][CH2:43][CH:44]([CH3:48])[C:45](O)=[O:46].C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:34].[CH3:17][C:14]1([CH3:16])[C:13]2[CH2:12][CH2:11][N:10]([CH2:18][C:19]([NH:21][C:22]([NH2:24])=[O:23])=[O:20])[CH2:9][C:8]=2[C:7]2[C:2]([O:1][C:45](=[O:46])[CH:44]([CH3:48])[CH2:43][CH2:42][N:37]3[CH2:38][CH2:39][CH2:40][CH2:41][CH:36]3[CH3:35])=[CH:3][C:4]([CH:25]([CH3:33])[CH:26]([CH3:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:5][C:6]=2[O:15]1
Reactant: CC(CCN1CCCCC1C)C(=O)O
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)NC(N)=O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCCCC(C)C(C)c1cc(OC(=O)C(C)CCN2CCCCC2C)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)NC(N)=O)CC1

Procedure:
The above-titled compound was prepared according to the method of Example 8 by reacting equimolar quantities of {[10-hydroxy-5,5-dimethyl-8-(1,2-dimethylheptyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridin-2-yl]acetyl}urea and [4-(2-methylpiperidino)]-2-methylbutyric acid hydrochloride in the presence of dicyclohexylcarbodiimide.
Reaction SMILES: [CH2:1]([Br:4])[C:2]#[CH:3].[CH2:5]([O:7][CH:8](OCC)[O:9][CH2:10][CH3:11])[CH3:6]>[I-].[Zn+2].[I-]>[Br:4][CH2:1][C:2]#[C:3][CH:8]([O:9][CH2:10][CH3:11])[O:7][CH2:5][CH3:6]
Reactant: CCOC(OCC)OCC
Reactant: C#CCBr
Agent: [I-]
Agent: [Zn+2]
Product: CCOC(C#CCBr)OCC

Procedure:
4-Bromo-1,1-diethoxy-2-butyne (Reagent L) was prepared according to the procedure of R. Epsystein and S. Marszak, Bull. Soc. Chim. Fr., I, pp. 313-17 (1968). A total of 74.1 g. (0.40 mole) of propargyl bromine, 59.28 g. (0.40 mole) of triethylorthoformate, and 3.2 g. (0.010 mole) of zinc iodide were combined in a reaction flask fitted with a packed distillation column and a stillhead. The mixture was heated to 100°-110° C. and ethanol was removed by slow distillation over 2.5 hours. Hexane (96 ml.) was added as required to maintain the stillhead temperature below 80° C. The pot residue was diluted with 200 ml. methylene chloride, washed with water and brine, dried with magnesium sulfate, filtered, and then distilled. A forerun of ethylorthoformate was collected, followed by the acetal at 50°-77° C./5-10 mm.