Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[OH:19])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1>>[C:2]1([C:1]2[O:19][C:11]3[CH:12]=[C:13]([C:14]([OH:16])=[O:15])[CH:17]=[CH:18][C:10]=3[N:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(NC(=O)c2ccccc2)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(O)c1ccc2nc(-c3ccccc3)oc2c1
Temperature: 160 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a suspension of 4-benzamido-3-hydroxybenzoic acid (2.15 g, 8.4 mmol) in xylenes (12 mL) was added p-TsOH (1.6 g, 8.4 mmol, 1.0 eq) at room temperature then the mixture was heated to 160° C. and stirred overnight. The solvent was removed under reduced pressure then the reaction was quenched with saturated aqueous NaHCO3 and biphasic mixture was extracted by CH2Cl2 (4×80 mL). The solvent was concentrated to give the title compound (2.0 g) which was used in the next step without further purification. LC-MS 237.9 [M−H]−, 240.3 [M+H]+, RT 1.12 min.
Reaction SMILES: [CH3:1][N:2]([S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([F:29])([F:28])[F:27])(=[O:19])=[O:18])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14]CC)=[O:13])=[CH:8]2.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CO>[CH3:1][N:2]([S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([F:29])([F:27])[F:28])(=[O:18])=[O:19])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2
Reactant: CCOC(=O)c1cc2cccc(N(C)S(=O)(=O)c3ccccc3C(F)(F)F)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.1 %

Procedure:
Ethyl 7-(methyl{[2-(trifluoromethyl)phenyl]sulfonyl}amino)-1H-indole-2-carboxylate (3.7 g) was dissolved in a mixed solvent of tetrahydrofuran (25 ml)-methanol (25 mL). Aqueous potassium hydroxide solution (prepared by dissolving potassium hydroxide (1.5 g) in water (20 mL)) was added to this solution, and the mixture was stirred at room temperature for 2 days. The reaction solution was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained colorless crystals were washed with ethyl acetate-hexane to give the title compound (2.7 g, yield: 63%) as colorless crystals. MS: 399 (MH+). melting point: 211-212° C.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:13])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].I[CH2:21][CH2:22][CH3:23]>CN(C=O)C.O>[C:1]([C:5]1[C:6]([O:13][CH2:21][CH2:22][CH3:23])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(C=O)c1O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1c(C=O)cccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 100.6 %

Procedure:
To a solution of 3-tert-butyl-2-hydroxy-benzaldehyde (2.04 g, 11.5 mmol) and K2CO3 (7.91 g, 57.3 mmol) in anhydrous DMF (23 ml) was added 1-iodopropane (2.34 ml, 24.0 mmol). The reaction mixture was left to stir for 48 h at room temperature. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (3×50 ml). Combined organic layers were washed with water (50 ml) and brine (50 ml), dried over MgSO4, filtered and the solvent was removed in vacuo to give a yellow oil. Purification by column chromatography (silica gel, gradient elution of hexanes to 20% EtOAc/hexanes) gave 3-tert-butyl-2-propoxy-benzaldehyde (2.55 g, 99%) as a yellow oil: 1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 7.62 (s, 1H), 7.61 (s, 1H), 7.19 (t J=8.0, 1H), 3.89 (t, J=8.0 Hz, 2H), 1.91-1.82 (m, 2H), 1.37 (s, 9H), 1.03 (t, J=8.0 Hz, 3H).
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:11]1[CH:20]=[C:19]2[C:14]([C:15]([C:21]3[C:22]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=4)=[N:23][N:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=34)=[CH:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1>[Cl-].[Zn+2].[Cl-].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:11]1[CH:20]=[C:19]2[C:14]([C:15]([C:21]3[C:22]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=4)=[N:23][N:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=34)=[CH:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(-c2nn3ccccc3c2-c2ccnc3cc(Br)ccc23)n1
Reactant: Cl[Mg]Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Product: Cc1cccc(-c2nn3ccccc3c2-c2ccnc3cc(Cc4ccccc4)ccc23)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.1 %

Procedure:
Bubble nitrogen gas through 1 mL of THF for 10 minutes. Add benzyl magnesium chloride (2M in THF, 0.12 mL, 0.24 mmol), zinc chloride (1M in diethyl ether, 0.26 mL, 0.26 mmol). Bubble with nitrogen gas for 15 minutes. Add Pd(PPh3)2Cl2 (4 mg, 0.006 mmol), 7-bromo-4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline (0.05 g, 0.12 mmol). Stir at room temperature for 48 hours. Quench with aqueous saturated NH4Cl solution. Evaporate the solvent in vacuo. Add methylene chloride. Filter the mixture and concentrate the filtrate in vacuo. Chromatograph the residue on silica gel (elute with 50% ethyl acetate/hexanes then 100% ethyl acetate). Final purification by preparative HPLC affords the title compound 20 mg (40%) as a yellow foam.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][CH:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[Cl:21][C:22]1[CH:37]=[CH:36][C:25]2[N:26]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:27](=[O:29])[NH:28][C:24]=2[CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[F:13][C:10]1[CH:11]=[CH:12][C:7]([CH:6]([NH:5][CH2:4][CH2:3][N:33]2[CH2:32][CH2:31][CH:30]([N:26]3[C:25]4[CH:36]=[CH:37][C:22]([Cl:21])=[CH:23][C:24]=4[NH:28][C:27]3=[O:29])[CH2:35][CH2:34]2)[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][CH:9]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Reactant: Fc1ccc(C(NCCCl)c2ccc(F)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(CCNC(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
A mixture of 10 parts of N-(2-chloroethyl)-4-fluoro-α-(4-fluorophenyl)benzenemethanamine hydrochloride, 7.3 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 10.6 parts of sodium carbonate, 0.1 parts of potassium iodide and 80 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. Water is added to the reaction mixture. The precipitated product is filtered off and set aside. From the filtrate, the organic phase is separated, washed with water, dried, filtered and evaporated. The residue is stirred in 4-methyl-2-pentanone. The solid product is filtered off, combined with the precipitated product, obtained above, and crystallized from 4-methyl-2-pentanone. The product is filtered off and dried in vacuo at 95° C, yielding 5 parts of 1-{1-[2-{[bis(4-fluorophenyl)methyl]amino}ethyl]-4-piperidinyl}-5-chloro-1,3-dihydro-2H-benzimidazol-2-one; mp. 198.6° C.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:9][C:8]=2[CH2:18][O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:38][CH3:39])=[C:32]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:33]=1.N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:39][O:38][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][CH2:26][N:15]2[CH2:16][CH2:17][CH:12]([C:10]3[O:11][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[C:8]([CH2:18][O:19][CH2:20][C:21]([F:22])([F:23])[F:24])[N:9]=3)[CH2:13][CH2:14]2)=[CH:33][C:32]=1[S:34]([NH2:37])(=[O:36])=[O:35]
Reactant: FC(F)(F)COCc1nc(C2CCNCC2)oc1-c1ccccc1
Reactant: COc1ccc(CCCl)cc1S(N)(=O)=O
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CCN2CCC(c3nc(COCC(F)(F)F)c(-c4ccccc4)o3)CC2)cc1S(N)(=O)=O
Temperature: 100 °C

Procedure:
To 4-[5-phenyl-4-(2,2,2-trifluoro-ethoxymethyl)-oxazol-2-yl]-piperidine (0.750 g), prepared as in Intermediate 5, in dioxane is added 5-(2-chloro-ethyl)-2-methoxy-benzenesulfonamide (0.716 g), prepared as in Intermediate 1, Nal (0.429 g) and DIEA (1.15 ml). After heating at 100° C. for 18 hours, the reaction mixture is partitioned between EtOAc and dilute NaHCO3 solution. The organic phase is washed with saturated brine, dried (NaSO4) and concentrated. The residue is dissolved in CHCl3 (20 mL) and preadsorbed onto silica gel. Purification by flash chromatography on silica gel using a MeOH-EtOAc gradient (2-10%), followed by radial chromotography using a MeOH-CH2Cl2 gradient (1-5%) and crystallization from CH2Cl2 -EtOAc affords the title compound as a white solid.
Reaction SMILES: OCCCN1C=C(C2C=CC(NC3C(C(F)(F)F)=CN=C(NC4C=CC(CP(=O)(OCC)OCC)=CC=4OC)N=3)=C3C=2CN(C)C3=O)C=N1.[NH2:50][C:51]1[C:52]([C:58]([NH:60][CH3:61])=[O:59])=[N:53][C:54]([Br:57])=[CH:55][CH:56]=1.OP1(=O)CC2C=CC(=C(OC)C=2)NC2=NC(=C(C(F)(F)F)C=N2)NC2C=CC(=NC=2C(NC)=O)C2=CN(N=C2)CCCO1.Cl[C:106]1[C:111]([C:112]([F:115])([F:114])[F:113])=[CH:110][N:109]=[C:108]([NH:116][C:117]2[CH:131]=[CH:130][C:120]([CH2:121][CH2:122][CH2:123][CH2:124][PH:125](=[O:129])[O:126][CH2:127][CH3:128])=[CH:119][C:118]=2[O:132][CH3:133])[N:107]=1>>[Br:57][C:54]1[N:53]=[C:52]([C:58](=[O:59])[NH:60][CH3:61])[C:51]([NH:50][C:110]2[C:111]([C:112]([F:113])([F:115])[F:114])=[CH:106][N:107]=[C:108]([NH:116][C:117]3[CH:131]=[CH:130][C:120]([CH2:121][CH2:122][CH2:123][CH2:124][PH:125](=[O:129])[O:126][CH2:127][CH3:128])=[CH:119][C:118]=3[O:132][CH3:133])[N:109]=2)=[CH:56][CH:55]=1
Reactant: CNC(=O)c1nc(Br)ccc1N
Reactant: CCO[PH](=O)CCCCc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Agent: CNC(=O)c1nc2ccc1Nc1nc(ncc1C(F)(F)F)Nc1ccc(cc1OC)CP(=O)(O)OCCCn1cc-2cn1
Product: CCO[PH](=O)CCCCc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1

Procedure:
Prepared analogously to Compound 1B replacing Compound 1C with compound 6D and Compound 1 E with ethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)propylphosphinate (Compound 37C). 1H NMR (CDCl3, 400 MHz): δ 12.25 (s, 1H), 9.05 (d, J=8.8 Hz, 1H), 8.43 (s, 1H), 8.10 (d, J=4.8 Hz, 2H), 7.69 (br. s., 1H), 7.51 (d, J=8.8 Hz, 1H), 6.94 (t, J=1.8 Hz, 1H), 6.82 (td, J=1.8, 8.2 Hz, 1H), 3.98-4.13 (m, 2H), 3.92 (s, 3H), 3.13 (d, J=16.4 Hz, 2H), 3.05 (d, J=5.3 Hz, 3H), 1.62-1.68 (m, 4H), 1.31 (t, J=7.1 Hz, 3H), 0.98-1.04 (m, 3H). MS (ESI): m/z 645.62/647.56 [M+H]+. UPLC: tR=1.47 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [OH:1][CH:2]([C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18](=[O:34])[C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24](=[O:33])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.CS(C)=O.C1CCC(N=C=NC2CCCCC2)CC1>>[CH3:12][O:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18](=[O:34])[C@@H:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:1])=[CH:10][CH:9]=1
Reactant: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)CCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CS(C)=O
Product: COc1ccc(OCC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)CCc2ccccc2)cc1
Yield: 35.3 %

Procedure:
(2S)-2-[1-Hydroxy-2-(4-methoxyphenoxy)ethyl]-1-[N-(3-phenylpropionyl)-L-prolyl]pyrrolidine (128 mg) was subjected to DMSO-DCC oxidation as in Example 1-D) to give 45 mg of the title compound (See Table 6).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[N:9]1[S:10][CH:11]=[C:12]2[C:17](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=[CH:14][C:13]=12.O>CS(C)=O>[N:9]1[S:10][CH:11]=[C:12]2[C:17]([CH:18]3[CH2:4][CH:19]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=[CH:14][C:13]=12
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1cccc2nscc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1CC1c1cccc2nscc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
Under nitrogen atmosphere, to a suspension of sodium hydride (60%, 1.08 g, 24.7 mmol) in dimethyl sulfoxide (100 mL) was added a solution of trimethylsulfoxonium iodide (5.43 g, 24.7 mmol) in dimethyl sulfoxide (100 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl(2E)-3-(2,1-benzisothiazol-4-yl)acrylate (4.80 g, 20.6 mmol) in dimethyl sulfoxide (200 mL) at 0° C., and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80) to give the title compound (2.70 g, yield 53%).
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([C:15]4[CH:16]=[N:17][NH:18][CH:19]=4)=[CH:10][C:9]=3[C:8]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[F:27])=[N:7][C:6]=12.CN(C=O)C.C(N(C(C)C)CC)(C)C.[CH3:50][Si:51]([CH3:58])([CH3:57])[CH2:52][CH2:53][O:54][CH2:55]Cl>O>[Br:1][C:2]1[N:3]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([C:15]4[CH:16]=[N:17][N:18]([CH2:55][O:54][CH2:53][CH2:52][Si:51]([CH3:58])([CH3:57])[CH3:50])[CH:19]=4)=[CH:10][C:9]=3[C:8]([C:20]3[C:21]([F:27])=[CH:22][CH:23]=[CH:24][C:25]=3[F:26])=[N:7][C:6]=12
Reactant: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(-c4cn[nH]c4)ccc32)c1Br
Reactant: C[Si](C)(C)CCOCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(-c2ccc3c(c2)c(-c2c(F)cccc2F)nc2c(Br)n(COCC[Si](C)(C)C)nc23)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
115 mg of 3-bromo-5-(2,6-difluorophenyl)-7-(1H-pyrazol-4-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinoline are introduced into 2 ml of DMF, 0.26 ml of diisopropylethylamine and 77 μl of 2-(trimethylsilyl)ethoxymethyl chloride. The reaction mixture is stirred at RT for 18 h and then poured into water, extracted with AcOEt, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. The product is purified by chromatography on silica gel (20-45 μm), eluting with a mixture of DCM and methanol (98/02 by vol.), to give 116 mg of 3-bromo-5-(2,6-difluorophenyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-7-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)-2H-pyrazolo[4,3-c]isoquinoline (yellow powder). 1H NMR: −0.01 (d, J=5.9 Hz, 4 H) 0.82-1.00 (m, 1 H) 3.60 (t, J=7.8 Hz, 1 H) 3.77 (t, 1 H) 5.46 (s, 1 H) 5.92 (s, 1 H) 7.42 (t, 1 H) 7.71-7.83 (m, 1 H) 8.03 (s, 1 H) 8.28 (dd, 1 H) 8.43 (s, 1 H) 8.58 (d, J=8.3 Hz, 1 H).
Reaction SMILES: N([O-])=O.[Na+].N[C@@H:6]([C:14]([OH:16])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[BrH:17].O>>[Br:17][C@H:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]([OH:16])=[O:15]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@H](Br)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
Sodium nitrite (27 g in water) is added at 0° C. to a solution of D-phenylalanine (40 g) in a mixture of 48% hydrobromic acid/water (1:1 by volume). The mixture is stirred for 30 minutes at 0° C. and then for 2 hours 30 minutes at a temperature close to 20° C. The reaction mixture is extracted with ether. The organic extracts are washed with water and a saturated sodium chloride solution and then dried over sodium sulphate. After filtration and concentration to dryness, the obtained residue is purified by distillation. (R)-2-Bromo-3-phenylpropanoic acid (33 g) is obtained which has the following characteristics: B.p.1 kPa =154° C.; Rf =0.47 (methylene chloride/methanol). The yield is 60%.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C@H:8]([CH2:19][N:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[N:22][C:21]1=[O:27])[C@H:9]([O:11][Si](C(C)(C)C)(C)C)[CH3:10])(C)(C)C.CN(C=O)C.C(OC(=O)C)(=O)C>C(N(CC)CC)C>[NH2:26][C:23]1[CH:24]=[CH:25][N:20]([CH2:19][C@H:8]([C@H:9]([OH:11])[CH3:10])[CH2:7][OH:6])[C:21](=[O:27])[N:22]=1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)Cn1ccc(N)nc1=O
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](O)[C@H](CO)Cn1ccc(N)nc1=O
Reaction time: 24 h
Yield: 225.8 %

Procedure:
To a solution of 44 (1.2 g. 2.7 mmol) in 15 of anhydrous DMF was added triethylamine (0.45 ml) followed by 0.31 ml (3.3 mmol) of acetic anhydride. The reaction was kept at room temperature for 1 day, then 3 hrs at 50 C and concentrated. The oily residue was dried by co-evaporation with xylene and then re-dissolved in ethyl acetate. The solution was washed with saturated NaHCO3 (2×100 ml), saturated NaCl, dried over MgSO4. Concentration of the extract and drying in vacuo afforded 1.3 g (99%) of 45 as an off-white amorphous solid. 1H NMR (DMSO-d6): δ 10.79 (s, 1H), 7.94 (d, J=7 Hz, 1H), 7.12 (d, J=7 Hz, 1H), 4.01 (m, 1H), 3.87 (m, 1H), 3.69 (m, 1H), 3.56 (d, J=6 Hz, 2H), 2.14 (m, 1H), 2.08 (s, 3H), 1.14 (d, J=6 Hz, 3H), 0.84 (s, 9H), 0.82 (s, 9H), 0.02 (s, 6H), −0.02 (s, 3H), −0.03 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:31][CH2:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[C:38](=[O:42])[N:37]([CH:43]1[CH2:48][CH2:47][C:46](=[O:49])[NH:45][C:44]1=[O:50])[CH2:36]2>CN(C=O)C>[O:50]=[C:44]1[CH:43]([N:37]2[CH2:36][C:35]3[C:39](=[CH:40][CH:41]=[C:33]([CH2:32][NH:31][C:9](=[O:11])[C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:13][CH:12]=4)[CH:34]=3)[C:38]2=[O:42])[CH2:48][CH2:47][C:46](=[O:49])[NH:45]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
A mixture of 4-methylsulphonylbenzoic acid (0.28 g, 1.4 mmol) and CDI (0.24 g, 1.5 mmol) was stirred in DMF (30 mL) at 40° C. for 4 hours. 3-(5-Aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.50 g, 1.4 mmol) was added and the mixture was stirred at 40° C. for 2 h. The mixture was quenched with 4% aqueous HCl (30 mL) and the resulting precipitate was filtered, washed with water (30 mL) and dried in vacuo providing N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-methanesulfonyl-benzamide as a white solid, (0.44 g, 71% yield); mp 260-262° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 4.08 (98.31%); 1H NMR (DMSO-d6) δ 1.96-2.03 (m, 1H), 2.31-2.46 (m, 1H), 2.57-2.63 (m, 1H), 2.86-2.98 (m, 1H), 3.27 (s, 3H), 4.31 (d, 1H, J=17.4 Hz), 4.45 (d, 1H, J=17.4 Hz), 4.63 (d, 2H, J=5.7 Hz), 5.11 (dd, 1H, J=13.2 Hz, J=4.8 Hz), 7.48 (d, 1H, J=8.1 Hz), 7.56 (s, 1H), 7.71 (d, 1H, J=7.8 Hz), 8.05 (d, 2H, J=8.4 Hz), 8.14 (d, 2H, J=8.4 Hz), 9.42 (t, 1H, J=6.0 Hz), 10.99 (s, 1H). 13C NMR (DMSO-d6) δ 22.5, 31.2, 42.9, 43.3, 47.1, 51.6, 122.1, 123.0, 127.1, 128.3, 130.4, 138.6, 142.4, 143.0, 143.5, 165.0, 167.9, 171.0, 172.8; LCMS: MH=456; Anal. Calcd for C22H21N3O6S: C, 58.01; H, 4.65; N, 9.23. Found: C, 58.15; H, 4.52; N, 9.04.
Reaction SMILES: [CH3:1][C:2]12[O:38][CH2:37][CH2:36][N:35]1[C:33](=[O:34])[C:5]1[C:6]([OH:32])=[C:7]3[C:13]4[C:14]([C:16]5[C:27](=[O:28])[C:26]6[C:21](=[CH:22][C:23]([O:30][CH3:31])=[C:24]([OH:29])[CH:25]=6)[O:20][C:17]=5[C:18](=[O:19])[C:12]=4[CH:11]=[CH:10][C:8]3=[CH:9][C:4]=1[CH2:3]2)=[O:15].[CH:39]12CC(C=C1)C1C(OC(=O)C21)=O.NC1C=CC=CN=1.CN(C1C=CC=CN=1)C.CC1(O)C2CC3CC(CC1C3)C2>C(OCC)(=O)C.O.O1CCCC1>[CH3:1][C:2]12[O:38][CH2:37][CH2:36][N:35]1[C:33](=[O:34])[C:5]1[C:6]([OH:32])=[C:7]3[C:13]4[C:14]([C:16]5[C:27](=[O:28])[C:26]6[C:21](=[CH:22][C:23]([O:30][CH3:31])=[C:24]([O:29][CH3:39])[CH:25]=6)[O:20][C:17]=5[C:18](=[O:19])[C:12]=4[CH:11]=[CH:10][C:8]3=[CH:9][C:4]=1[CH2:3]2)=[O:15]
Reactant: COc1cc2oc3c(c(=O)c2cc1O)C(=O)c1c(ccc2cc4c(c(O)c12)C(=O)N1CCOC1(C)C4)C3=O
Reactant: O=C1OC(=O)C2C3C=CC(C3)C12
Agent: CC1(O)C2CC3CC(C2)CC1C3
Agent: CN(C)c1ccccn1
Agent: Nc1ccccn1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2oc3c(c(=O)c2cc1OC)C(=O)c1c(ccc2cc4c(c(O)c12)C(=O)N1CCOC1(C)C4)C3=O
Temperature: 23 °C

Procedure:
16.42 parts of the compound (II-167-a) (5-norbornene-2,3-dicarboxylic acid anhydride, Wako Pure Chemical Industries, Ltd.) and 53.29 parts of tetrahydrofuran were charged, stirred at 23° C. to dissolved. To the obtained mixture, 2.44 parts of amino pyridine was added at 23° C., and stirred. To the obtained mixture, 2.44 parts of dimethylamino pyridine was added at 23° C., and stirred for 30 minutes at 50° C. To the obtained mixture, a mixture of 16.63 parts of 2-methyl-2-adamantanol and 53.29 parts of tetrahydrofuran was added in the form of drops over 1 hour, and stirred for 10 hours at 50° C. To the obtained mixture, 30 parts of ion-exchanged water and 60 parts of ethyl acetate were added to wash, and separated to collect an organic layer. To the obtained organic layer, 30 parts of ion-exchanged was added to wash, and separated to collect an organic layer. This washing with water operation was repeated three times. The obtained organic layer was concentrated to obtain a concentrate. The concentrate was column-fractionated under the condition below, whereby giving 25.2 parts of the compound (II-167-b).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.[Cl:18][C:19]([Cl:26])([Cl:25])[C:20]([N:22]=[C:23]=[O:24])=[O:21]>ClCCl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:23]([NH:22][C:20](=[O:21])[C:19]([Cl:26])([Cl:25])[Cl:18])=[O:24])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Solvent: ClCCl
Product: CC1(C)Oc2cc3nonc3cc2C(NC(=O)NC(=O)C(Cl)(Cl)Cl)C1O
Reaction time: 5 h
Yield: 25 %

Procedure:
200 mg (0.850 mmol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazole and 20 ml of dichloromethane were stirred at room temperature, and 100 μl (0.935 mmol) of trichloroacetyl isocyanate were added thereto and stirred for 5 hours. The crystals precipitated were filtered off to obtain 90 mg of the intended compoundas colorless crystals. (yield: 25%)
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[N:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[N:3]=1.[CH3:29][NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(O)C.C(Cl)(Cl)Cl>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:4]2[N:3]=[C:2]([N:30]([CH3:29])[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:7]([CH3:8])[C:6](=[N:9][C:10]3[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[CH3:18])[CH:5]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: CNCc1ccccc1
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(Cl)n2)cc1OC
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(N(C)Cc3ccccc3)n2)cc1OC

Procedure:
To a suspension of 2-chloro-3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (1.5 g) in ethanol (15 ml) was added N-methylbenzylamine (1.47 ml). The mixture was refluxed for 5 hours. The resulting suspension was dissolved in chloroform, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The obtained syrup was triturated in diisopropyl ether and filtered to afford 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-2-(N-methyl-N-benzylamino)-4-(2,4,6-trimethylphenylimino)pyrimidine (1.18 g).