Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][NH:7][C@@H:8]([CH3:16])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[CH:21]1[C:33]2[CH:32]([CH2:34][O:35][C:36]([NH:38][C@@H:39]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=3)[C:40](O)=[O:41])=[O:37])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1>>[S:1]1[CH:5]=[C:4]([CH2:6][N:7]([C@@H:8]([CH3:16])[CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])[C:40](=[O:41])[C@@H:39]([NH:38][C:36](=[O:37])[O:35][CH2:34][CH:32]2[C:33]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: CCOC(OCC)[C@H](C)NCc1csc2ccccc12
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 65 %

Procedure:
According to the procedure described in the synthesis method of Compound III-1, (S)—N-(benzo[b]thiophen-3-ylmethyl)-1,1-diethoxypropan-2-amine (Compound IX-6) 1.45 g (4.941 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid 2.50 g (5.44 mmol) and purified on Buch silica gel column chromatography (n-hexane:ethyl acetate=7:3) to obtain the title compound 2.36 g (59%).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[Cl:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.ClCCl>O1CCOCC1>[Cl:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])[CH2:15][CH2:14]1
Reactant: O=C1CCCC(=O)O1
Reactant: ClCCCN1CCNCC1
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)CCCC(=O)N1CCN(CCCCl)CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 103.5 %

Procedure:
1.5 g of glutaric anhydride and then 2.13 g of N-(chloropropyl)piperazine in solution in 5 cm3 of dioxane and 1 cm3 of dichloromethane are added to 15 cm3 of dioxane in a round-bottomed flask kept under an argon atmosphere. After stirring for 2 hours at 20° C., the solvent is evaporated under reduced pressure (2.7 kPa) at 20° C., to give 3.75 g of 5-[4-(3-chloropropyl)piperazin-1-yl]-5-oxopentanoic acid in the form of a yellow oil which is used as it is.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7](=[O:10])[CH2:8]Br)(=[O:3])[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([O:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7](=[O:10])[CH2:8][O:20][C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(C)(C)C(=O)CBr
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)OCC(C)(C)C(=O)COc1ccc(Cl)cc1
Yield: 74.6 %

Procedure:
170 g (0.72 mol) of 4-acetoxy-1-bromo-3,3-dimethylbutan-2-one in 200 ml of acetone were added dropwise, over the course of 100 minutes, to a suspension of 92.1 g (0.72 mol) of 4-chlorophenol and 108 g (0.72 mol) of potassium carbonate in 1,000 ml of acetone. After heating for 15 hours whilst stirring under reflux, the mixture was filtered and the filtrate was concentrated by distilling off the solvent in vacuo. The residue was taken up in 200 ml of methylene chloride and the solution was washed three times with 50 ml of water at a time, dried over sodium sulphate and concentrated. The oily residue was distilled. 153 g (72% of theory) of 4-acetoxy-1-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one of boiling point 140°-145° C./0.2 mm Hg was obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si](C(C)(C)C)(C)C)[CH2:9][C@H:8]1[CH2:20][CH2:21][N:22]1[C:26]([CH2:27][OH:28])=[CH:25][N:24]=[CH:23]1)=[O:6])[CH:2]=[CH2:3].[CH3:29]C(C)([O-])C.[K+].CI.Cl.C[O-].[Na+].CO>O1CCCC1.CO.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:20][CH2:21][N:22]1[C:26]([CH2:27][O:28][CH3:29])=[CH:25][N:24]=[CH:23]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCn1cncc1CO
Reactant: CC(C)(C)[O-]
Agent: C[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CO
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1CCn1cncc1COC
Reaction time: 8 h
Yield: 52.1 %

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-{2-(5-hydroxymethylimidazol-1-yl)ethyl}pyrrolidine (9.22 g) in tetrahydrofuran (100 ml) was added potassium t-butoxide (3.54 g) with stirring under ice-cooling and then added dropwise methyl iodide (2.80 ml) at the same condition. The mixture was stirred at the same temperature for 1 hour. Ethyl acetate (100 ml) was added to a reaction mixture. The solution was washed successively with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (200 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give a residue. To a solution of the residue (7.79 g) in methanol (100 ml) was added conc. hydrochloric acid (4.60 ml) with stirring at ambient temperature. The mixture was allowed to stand overnight. To the solution was added 28% sodium methoxide-methanol solution (10.6 ml) with stirring under ice-cooling. The resulting precipitates were filtered off and the filtrate was evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (200 g) eluting with a mixture of chloroform and methanol (9:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2R,4R)-1-allyloxycarbonyl-4-hydroxy-2-{2-(5-methoxymethylimidazol-1-yl) ethyl}pyrrolidine (3.63 g).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:16]([C:26]([O:28][CH3:29])=[O:27])[CH2:15]1)=[O:12])[CH2:6]2.[CH:30]([B-](F)(F)F)=[CH2:31].[K+]>CCO.OS([O-])(=O)=O.[K+]>[CH:30]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[C@H:16]([C:26]([O:28][CH3:29])=[O:27])[CH2:15]1)=[O:12])[CH2:6]2)=[CH2:31]
Reactant: C=C[B-](F)(F)F
Reactant: COC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(Br)c3C2)CN1C(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCO
Product: C=Cc1cccc2c1CN(C(=O)O[C@@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1)C2
Temperature: 25 °C

Procedure:
To a solution of 1-t-butyl 2-methyl (2S,4R)-4-{[(4-bromo-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate (10.0 g, 21.3 mmol) in EtOH (200 mL) was added potassium vinyltrifluoroborate (4.28 g, 32 mmol) and Et3OH (4.5 mL, 32 mmol) followed by dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium (II) chloride dichloromethane adduct (175 mg, 0.21 mmol). The reaction mixture was heated to reflux for 6 hours, cooled to RT, diluted with 10% aqueous KHSO4. The EtOH was removed by evaporation in vacuo. The aqueous residue was extracted with EtOAc, and the organic phase washed with brine, dried over Na2SO4. The solvent was evaporated, and the crude product was purified by chromatography on silica eluting with 40-60% EtOAc/hexane to give, after evaporation, the title compound (8.18 g). LRMS (ESI) m/z 417.2 [(M+H)+; calcd for C22H29N2O6: 417.2].
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1C=CC(S([O-])(=O)=O)=CC=1)(=O)C.[Na+].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: C1CCNCC1
Agent: CC(=O)c1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Product: CC(=O)c1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The damp 4-acetylbenzenesulfonyl chloride from 100 g. of sodium 4-acetylbenzenesulfonate is added to a stirred solution of 500 ml. of 50% aqueous piperidine. The mixture is stirred at room temperature for 16 hours, cooled, and the precipitated 1-(4-acetylbenzenesulfonyl)piperidine removed by filtration, washed with water and dried; m.p. 113°-114° C. after crystallization from 2-propanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]2[N:9]=[CH:10][NH:11][C:5]=2[CH:4]=1.Cl[C:13]1([C:19]([O:21][CH3:22])=[O:20])[C:17](=[O:18])[CH:16]=[CH:15][S:14]1>C(Cl)(Cl)Cl>[OH:18][C:17]1[CH:16]=[C:15]([N:9]2[C:6]3[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:11]=[CH:10]2)[S:14][C:13]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)C1(Cl)SC=CC1=O
Reactant: COc1cc2[nH]cnc2cn1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sc(-n2cnc3cc(OC)ncc32)cc1O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of 2.00 g of 6-methoxy-1H-imidazo[4,5-c]pyridine in 50 ml of chloroform were added 1.25 g of methyl 2-chloro-3-oxo-2,3-dihydrothiophene-2-carboxylate in portions and the reaction mixture was stirred for 120 h at room temperature. The reaction mixture was washed with water (3×50 ml) and the organic layer was dried and concentrated under vacuum. The residue was recrystallized from methanol to yield the title compounds as an isomeric mixture.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:11]2([C:28]([F:31])([F:30])[F:29])[CH2:15][C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C:21]3([CH2:27][NH:26][CH2:25]3)[O:20][CH2:19]4)=[N:13][CH2:12]2)[CH:6]=[C:7]([Cl:10])[C:8]=1[Cl:9].CCN(C(C)C)C(C)C.[CH3:41][S:42]([CH2:45][C:46](O)=[O:47])(=[O:44])=[O:43].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[CH3:41][S:42]([CH2:45][C:46]([N:26]1[CH2:25][C:21]2([C:22]3[C:18](=[CH:17][C:16]([C:14]4[CH2:15][C:11]([C:5]5[CH:4]=[C:3]([Cl:2])[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=5)([C:28]([F:30])([F:29])[F:31])[CH2:12][N:13]=4)=[CH:24][CH:23]=3)[CH2:19][O:20]2)[CH2:27]1)=[O:47])(=[O:44])=[O:43]
Reactant: CS(=O)(=O)CC(=O)O
Reactant: FC(F)(F)C1(c2cc(Cl)c(Cl)c(Cl)c2)CN=C(c2ccc3c(c2)COC32CNC2)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)CC(=O)N1CC2(C1)OCc1cc(C3=NCC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.5 %

Procedure:
To a stirred solution of 5′-(3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]hydrochloride (Preparation 5, 900 mg, 1.77 mmol) in THF (20 mL) was added DIPEA (3.01 mL, 17.65 mmol), methanesulfonyl acetic acid (488 mg, 3.53 mmol) followed by addition of T3P (5.12 mL, 8.82 mmol, 50% solution in ethyl acetate) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours. Reaction was monitored by TLC, after complete consumption of staring material reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3×25 mL). Combined organic layer was washed with NaHCO3 solution (30 mL) & brine (30 mL), dried over sodium sulphate and concentrated to get crude sticky solid 1 g. The crude was purified by column chromatography using 100-200 mesh silica gel. Desired compound was eluted in 0.5% MeOH in DCM to get desired compound as pale green solid 490 mg, 46.6%. 1H NMR (400 MHz, DMSO-d6) δ: 3.14 (s, 3H), 3.75 (d, J=18.04 Hz, 1H), 3.88 (d, J=18.52 Hz, 1H), 4.23 (d, J=10.36 Hz, 4H), 4.44 (d, J=17.6 Hz, 1H), 4.57 (s, 2H), 4.82 (d, J=17.4 Hz, 1H), 5.10 (s, 2H), 7.66 (d, J=7.96 Hz, 1H), 7.80 (s, 2H), 7.86 (s, 1H), 7.95 (d, J=7.96 Hz, 1H). LC-MS (m/z): 594.8 (M+H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][C@@H:6]1[C@H:12]([OH:13])[C@H:11]([CH3:14])[O:10][CH:8]([OH:9])[CH2:7]1)=[O:4].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C.Cl>C(Cl)Cl>[F:16][C:2]([F:1])([F:15])[C:3]([NH:5][C@@H:6]1[C@:12]([S:18]([CH3:17])(=[O:20])=[O:19])([OH:13])[C@H:11]([CH3:14])[O:10][CH:8]([OH:9])[CH2:7]1)=[O:4]
Reactant: C[C@@H]1OC(O)C[C@H](NC(=O)C(F)(F)F)[C@@H]1O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1OC(O)C[C@H](NC(=O)C(F)(F)F)[C@@]1(O)S(C)(=O)=O
Yield: 133.3 %

Procedure:
To a stirred solution of 1-t-butyl dimethylsilyloxy, 3-trifluoroacetamido-2,3,6-trideoxy-L-lyxohexopyranose (504 mg, 1.41 mmol) in CH2Cl2 (7 ml) at 0° C. were added methanesulfonyl chloride (218 μl, 2.82 mmol) and triethylamine (590 μl, 4.2 mmol). After 2 hours the reaction mixture was worked up with CH2Cl2 and HCl 0.1N. The organic layer was washed with a solution of NaHCO3 and brine then dried over MgSO4. The solvent was evaporated to give 1-t-butyl dimethyl silyloxy, 3-trifluoroacetamido-2,3,6 trideoxy-4 methanesulfonyl-L-lyxohexopyranose (604 mg, 98%).
Reaction SMILES: C(OC(=O)CC1C=NC(Cl)=C(C2C=CC(C(F)(F)F)=CC=2CN(C(=O)C)CC2C=CC=CC=2)C=1)C.C([O:38][C:39](=[O:70])[CH2:40][C:41]1[C:42]([Cl:69])=[N:43][CH:44]=[C:45]([C:47]2[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][C:48]=2[CH2:57][N:58]([C:66](=[O:68])[CH3:67])[CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:46]=1)C>>[C:66]([N:58]([CH2:57][C:48]1[CH:49]=[C:50]([C:53]([F:55])([F:54])[F:56])[CH:51]=[CH:52][C:47]=1[C:45]1[CH:46]=[C:41]([CH2:40][C:39]([OH:70])=[O:38])[C:42]([Cl:69])=[N:43][CH:44]=1)[CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)(=[O:68])[CH3:67]
Reactant: CCOC(=O)Cc1cc(-c2ccc(C(F)(F)F)cc2CN(Cc2ccccc2)C(C)=O)cnc1Cl
Agent: CCOC(=O)Cc1cnc(Cl)c(-c2ccc(C(F)(F)F)cc2CN(Cc2ccccc2)C(C)=O)c1
Product: CC(=O)N(Cc1ccccc1)Cc1cc(C(F)(F)F)ccc1-c1cnc(Cl)c(CC(=O)O)c1

Procedure:
Prepared according to the procedure described in Example 17, Step 5, using the following starting material: a mixture of (5-{2-[(N-acetyl-N-benzyl-amino)-methyl]-4-trifluoromethyl-phenyl}-6-chloro-pyridin-3-yl)-acetic acid ethyl ester and (5-{2-[(N-acetyl-N-benzyl-amino)-methyl]-4-trifluoromethyl-phenyl}-2-chloro-pyridin-3-yl)-acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[CH:17]([CH3:35])[C:18]([C:24]1[CH:25]=[CH:26][C:27]2[O:31][C:30](=[O:32])[N:29]([CH3:33])[C:28]=2[CH:34]=1)([OH:23])[C:19]([F:22])([F:21])[F:20].[CH2:36]([O:38][C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43](Br)[N:42]=1)=[O:40])[CH3:37]>>[CH2:36]([O:38][C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([C:6]2[CH:5]=[CH:4][C:3]([CH:17]([CH3:35])[C:18]([OH:23])([C:24]3[CH:25]=[CH:26][C:27]4[O:31][C:30](=[O:32])[N:29]([CH3:33])[C:28]=4[CH:34]=3)[C:19]([F:22])([F:20])[F:21])=[C:2]([Cl:1])[CH:7]=2)[N:42]=1)=[O:40])[CH3:37]
Reactant: CC(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Reactant: CCOC(=O)c1cccc(Br)n1
Product: CCOC(=O)c1cccc(-c2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)n1

Procedure:
The title compound was prepared in analogy to Example 186, step 2 from 5-{2-[2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1-hydroxy-1-trifluoromethyl-propyl}-3-methyl-3H-benzooxazol-2-one (obtained in Example 186, step 1) with ethyl-6-bromopyridine-2-carboxylate [CAS Reg. No. 21190-88-5]. MS (m/e)=535.2 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:34]=1[C:35](Cl)=[O:36]>CC#N>[C:1]([O:5][C:6]([CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:35](=[O:36])[C:34]3[C:33]([Cl:32])=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:42])=[CH:19][CH:20]=2)[CH2:10]1)=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(O)cc2)C1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(OC(=O)c3c(Cl)cccc3Cl)cc2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.6 %

Procedure:
To a solution of 3-[2-(4-hydroxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (0.39 g; 1.27 mmol) and N-ethyldiisopropylamine (0.65 mL, 3.81 mmol) in CH3CN (5 mL) was added 2,6-dichlorobenzoyl chloride (0.44 ml; 3.0 mmol), at 0° C. Subsequently, the mixture was allowed to warm to RT and was stirred for 2 days at room temperature. The resulting mixture was partitioned between Et2O and 5% aqueous NaHCO3 solution. The layers were separated and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O to afford 2,6-dichloro-benzoic acid 4-[4-(2-tert-butoxycarbonyl-ethyl)-morpholin-2-yl]-phenyl ester (0.51 g).
Reaction SMILES: [C:1]1(=[CH:5][CH2:6][C:7]2[C:8]([C:10]([CH3:17])=[C:11]([CH3:16])[C:12](=[O:15])[C:13]=2[CH3:14])=[O:9])[CH2:4][CH2:3][CH2:2]1>N1C=CC=CC=1>[CH3:14][C:13]1[C:12]([OH:15])=[C:11]([CH3:16])[C:10]([CH3:17])=[C:8]2[C:7]=1[CH:6]=[CH:5][C:1]1([O:9]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC1=C(C)C(=O)C(CC=C2CCC2)=C(C)C1=O
Solvent: c1ccncc1
Product: Cc1c(C)c2c(c(C)c1O)C=CC1(CCC1)O2

Procedure:
The above 2-(2-cyclobutylideneethyl)-3,5,6-trimethylbenzo-1,4-quinone was dissolved in pyridine and the mixture was heated to reflux for 15 h. The solvent was removed under reduced pressure and the residue was chromatographed to afford 5,7,8-trimethylspiro[chromene-2,1′-cyclobutan]-6-ol (420 mg). 1H-NMR (300. MHz, CDCl3) δ=6.59 (d, J=9.9 Hz, 1H), 6.07 (d, J=9.9 Hz, 1H), 4.39 (s, 1H), 2.47 (m, 2H), 2.26-2.17 (m, 11H), 1.90 (m, 1H), 1.75 (m, 1H) ppm. 13C-NMR (75 MHz, CDCl3) δ=145.6, 144.6, 128.9, 123.0, 122.3, 120.2, 118.5, 116.2, 37.0, 12.5, 12.3, 11.8, 11.0 ppm. MS m/z: 231 (M+H+).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:21]2[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:30]4[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=4)[CH:27]=3)[C:22]2=[O:36])[CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.NN>>[NH2:10][CH2:9][C@@H:8]([N:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:30]3[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=3)[CH:27]=2)[C:22]1=[O:36])[CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cn1nccc1-c1ccc2c(c1)CN([C@@H](CC1CCCCC1)CN1C(=O)c3ccccc3C1=O)C2=O
Agent: NN
Solvent: CO
Product: Cn1nccc1-c1ccc2c(c1)CN([C@H](CN)CC1CCCCC1)C2=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
A mixture of 2-{(2S)-3-cyclohexyl-2-[5-(1-methyl-1H-pyrazol-5-yl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]propyl}-1H-isoindole-1,3(2H)-dione (30 mg, 0.062 mmol) was dissolved in methanol (3 mL, 70 mmol) and hydrazine (0.3 mL, 10 mmol). The resulting mixture was stirred at 50° C. for 2 h. Direct purification on prep.—HPLC afforded 11 mg (50% yield) of the desired final product. LC-MS found: 353.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:16][C:17](=[O:35])[C@@H:18]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33])(=[O:25])=[O:24])[CH2:19][CH:20]=[CH2:21])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.Br[CH2:38][CH2:39]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:36])[C@@H:4]([N:16]1[CH2:39][CH2:38][N:22]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])(=[O:25])=[O:24])[C@@H:18]([CH2:19][CH:20]=[CH2:21])[C:17]1=[O:35])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: C=CC[C@H](NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)OC
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CC[C@H]1C(=O)N([C@@H](Cc2ccc3ccccc3c2)C(=O)OC)CCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
To a solution of (S,S)-3-naphthalen-2-yl-2-[2-(2-nitro-benzenesulfonylamino)-pent-4-enoylamino]-propionic acid methyl ester, 3, (3.6 g, 7.0 mmol) and 1,2-dibromoethane (13.2 g, 70.0 mmol) in DMF (40 mL) is added potassium carbonate (9.6 g, 70.0 mmol). The reaction suspension was stirred at 65° C. for 12 h, quenched with 10% aqueous HCl and extracted with EtOAc. The extract is dried over Na2SO4, concentrated and the residue purified over silica gel (hexanes/EtOAc,1:2) to afford 3.7 g (97% yield) of the desired product.
Reaction SMILES: ClC1C2C(=CC=C([C:12]3[N:17]4[N:18]=[C:19]([NH:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:20]=[C:16]4[CH:15]=[CH:14][CH:13]=3)C=2)C=CN=1.ClC1C2C(=CC=C(B(O)O)C=2)C=CN=1.BrC1N2N=C(NC3C=CC=CC=3)N=C2C=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O>[C:22]1([NH:21][C:19]2[N:20]=[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][N:17]3[N:18]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Clc1nccc2ccc(-c3cccc4nc(Nc5ccccc5)nn34)cc12
Agent: Brc1cccc2nc(Nc3ccccc3)nn12
Agent: O=P([O-])([O-])[O-]
Agent: OB(O)c1ccc2ccnc(Cl)c2c1
Solvent: CS(C)=O
Product: c1ccc(Nc2nc3ccccn3n2)cc1
Temperature: 90 °C
Yield: 38.7 %

Procedure:
5-(1-Chloroisoquinolin-7-yl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-amine. A degassed mixture of 1-chloroisoquinolin-7-ylboronic acid (288 mg, 1.38 mmol), 5-bromo-N-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-amine (400 mg, 1.38 mmol), potassium phosphate (296 mg, 2.76 mmol) and tetrakis (triphenylphosphine)palladium(0) (160 mg, 0.138 mmol) in dimethylsulfoxide (10 mL) was heated at 90° C. under nitrogen overnight. After being cooled down to room temperature, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product, which was washed with ethyl acetate to give 541-chloroisoquinolin-7-yl)-N-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-amine (200 mg, 38.7% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.68 (br s, 1H), 9.23 (s, 1H), 8.45 (d, J=8.4 Hz, 1H), 8.41 (d, J=5.2 Hz, 1H), 8.27 (d, J=8.8 Hz, 1H), 8.01 (d, J=5.6 Hz, 1H), 7.69 (m, 4H), 7.44 (d, J=6.0 Hz, 1H), 7.23 (t, J=7.6 Hz, 2H), 6.85 (t, J=7.2 Hz, 1H); MS (ESI) m/z: 372.1 [M+1].+
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7]C2C=CC(C(O)=O)=CC=2C(O)=O)[N:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.BrC1C(C(O)=O)=CC=CC=1C(O)=O>>[CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: Cc1cc(Nc2ccc(C(=O)O)cc2C(=O)O)n(-c2ccccn2)n1
Agent: O=C(O)c1cccc(C(=O)O)c1Br
Product: Cc1cc(N)n(-c2ccccn2)n1
Yield: 99 %

Procedure:
Following the procedure described in Reference Example 2-5, 4-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]isophthalic acid was prepared from bromoisophthalic acid and 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (99% yield). A solution of the compound (23.0 g, 68.0 mmol) in phosphorus oxychloride (108 g, 704 mmol) was heated under reflux for I hour. The reaction solution was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. To a stirred mixture of the residue in tetrahydrofuran (100 mL), methanol (10 mL) was added dropwise carefully, and the precipitate was collected by filtration. The precipitate was dissolved in a sodium hydroxide solution, and organic matter was extracted with chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform) to give the title compound (3.40 g, 14% yield).