Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:22]([CH2:23][OH:24])=[C:21]([CH:25]([CH3:27])[CH3:26])[N:20]=[C:19]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])[N:18]=2)=[CH:13][CH:12]=1.CC1C=CN=C(N)C=1C.[P:43](Cl)([O:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([O:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:44]>ClCCl>[P:43]([O:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)([O:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)([O:24][CH2:23][C:22]1[C:17]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)=[N:18][C:19]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])=[N:20][C:21]=1[CH:25]([CH3:27])[CH3:26])=[O:44]
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CO
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: Cc1ccnc(N)c1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1COP(=O)(Oc1ccccc1)Oc1ccccc1
Reaction time: 0.5 h

Procedure:
Diisopropyl ethyl amine (84.12 g) was slowly added to a mixture of N-[4-(4-fluorophenyl)-5-(hydroxymethyl)-6-(propan-2-yl)pyrimidin-2-yl]-N-methylmethanesulfonamide (commercially available; 100 g) and dimethyl aminopyridine (5 g) and diphenyl chlorophosphate (123.2 g) in dichloromethane (500 mL) at 0° C. to 5° C. The reaction mixture was stirred for 30 minutes at the same temperature to give [4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-(propan-2-yl)pyrimidin-5-yl]methyl diphenyl phosphate. To this mixture was added 2-mercapto-5-methyl-1,3,4-thiadiazole (41 g) at 0° C. to 5° C. followed by slow addition of diisopropyl ethyl amine (36.5 g). The resultant mixture was stirred for 2 hours at 0° C. to 5° C. After completion of the reaction, the mixture was quenched with de-ionized water (500 mL) and acidified to pH 3.5 using hydrochloric acid (6N). The organic layer was separated and washed with sodium bicarbonate (5%) at room temperature. The organic layer was separated and dichloromethane was recovered at 45° C. to give oily residue. Methanol (300 mL) was added to resulting oily residue and the mixture was stirred at room temperature for one hour to give N-[4-(4-fluorophenyl)-5-{[(5-methyl-1,3,4-thiadiazol-2-yl)sulfanyl]methyl}-6-(propan-2-yl)pyrimidin-2-yl]-N-methylmethanesulfonamide, which was filtered, washed with methanol (100 mL) and dried at 45° C. for 2 hours.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH2:7][C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[C@H:17]1[C@@H:21]2[O:22][C:23]([CH3:26])([CH3:25])[O:24][C@@H:20]2[C@@H:19]([CH2:27][NH:28][CH:29]2[CH2:32][CH:31]([CH2:33][CH2:34][C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])[CH2:30]2)[O:18]1.I[CH:46]([CH3:48])[CH3:47]>CC#N.CCOC(C)=O>[NH2:7][C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[C@H:17]1[C@@H:21]2[O:22][C:23]([CH3:25])([CH3:26])[O:24][C@@H:20]2[C@@H:19]([CH2:27][N:28]([CH:46]([CH3:48])[CH3:47])[CH:29]2[CH2:32][CH:31]([CH2:33][CH2:34][C:35]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[O:36])[CH2:30]2)[O:18]1
Reactant: CC(C)I
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CNC1CC(CCC(=O)OCc3ccccc3)C1)O[C@H]2n1cnc2c(N)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)N(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)OCc2ccccc2)C1
Temperature: 95 °C
Reaction time: 18 h

Procedure:
K2CO3 (528.92 mg, 3.83 mmol) was added to a solution of benzyl 3-[3-({[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-2H-furo[3,4-d][1,3]dioxol-4-yl]methyl}amino)cyclobutyl]propanoate (1.00 g, 1.91 mmol) and 2-iodopropane (0.57 ml, 5.74 mmol) in MeCN and stirred at 95° C. in a sealed tube for 18 hours. The reaction mixture was diluted with EtOAc (20 ml), filtered and evaporated to dryness. Purification by silica gel chromatography, eluting with 7N NH3 in MeOH:DCM (1:99-5:95) gave the desired product as a colourless oil, 700 mg (65%); MS (ESI+) for C30H40N6O5 m/z 565.70 [M+H]+; HPLC purity 96% (ret. time, 1.48 min); 1H NMR (500 MHz, CHLOROFORM-d) δH ppm 8.35 (d, J=3.5 Hz, 1H), 7.88 (d, J=3.2 Hz, 1H), 7.44-7.29 (m, 5H), 6.03 (t, J=2.2 Hz, 1H), 5.62-5.42 (m, 3H), 5.10 (d, J=3.3 Hz, 2H), 5.06-4.92 (m, 1H), 4.26 (dt, J=9.9, 3.4 Hz, 1H), 3.46-2.84 (m, 2H), 2.88-2.61 (m, 1H), 2.51 (ddd, J=14.0, 9.1, 7.5 Hz, 1H), 2.33-2.15 (m, 2H), 2.50-2.13 (m, 2H), 2.16-1.74 (m, 4H), 1.60 (s, 3H), 1.43-1.35 (m, 4H), 0.96 (d, J=6.7 Hz, 3H), 0.79 (d, J=6.6 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13])([O-])=O.[H][H]>[Pd].CN(C=O)C>[CH:11]1[CH:10]=[C:9]2[C:8](=[O:13])[N:7]([CH:14]3[C:15](=[O:21])[NH:16][C:17](=[O:20])[CH2:18][CH2:19]3)[CH2:6][C:5]2=[C:4]([NH2:1])[CH:12]=1
Reactant: [H][H]
Reactant: O=C1CCC(N2Cc3c(cccc3[N+](=O)[O-])C2=O)C(=O)N1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Temperature: 62.5 °C

Procedure:
Into a 5.0 L 4 necked RB flask, charged 100.0 g of 3-(4-nitro-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione, 10.0 g of 10% Pd/C and 3200 ml of DMF under nitrogen atmosphere. Stirred the mass and raise the reaction mass temperature to 60-65° C. Started the hydrogen gas bubbling into reaction mass at temperature 60-65° C. for 6 hours. The progress of the reaction is monitored by TLC. Cooled the mass to temperature 25 to 30° C. Filtered the catalyst Pd/C under plant vacuum in the presence of nitrogen atmosphere and wash with dimethylformamide; wet Pd/C is transferred into a polyethene bag for recovery. Distilled off the above organic layer solvent completely under vacuum below 60° C. Charged ethyl acetate 800 ml (lot-I) to the mass and stirred for 60 min. Filtered the solid and wash with 200 mL of ethyl acetate (Lot-II). Dried the above wet material in a oven at temperature 65-75° C. for 120-180 min. Dried Weight of the compound is 78.0 g.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][CH2:19]3)[N:8]2C2CCCCO2)=[C:4]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[N:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:17][N:18]3[CH2:19][CH2:20][N:21]([S:24]([CH3:27])(=[O:25])=[O:26])[CH2:22][CH2:23]3)[NH:8]2)=[C:4]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3n2C2CCCCO2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CS(=O)(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3[nH]2)CC1

Procedure:
4-(2-chloro-8-((4-(methylsulfonyl)piperazin-1-yl)methyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (250 mg) was treated with para-toluenesulfonic acid via General Procedure D to give 4-(2-chloro-8-((4-(methylsulfonyl)piperazin-1-yl)methyl)-9H-purin-6-yl)morpholine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1.[CH2:26]([O:28][C:29](Cl)=[O:30])[CH3:27]>N1C=CC=CC=1>[CH2:26]([O:28][C:29]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1)=[O:30])[CH3:27]
Reactant: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)n1cc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of Compound 1 (1.69 g) obtained in Example 1, ethoxycarbonyl chloride (2.5 ml) and pyridine (5 ml) was stirred at room temperature for 16 hours. The reaction solution was subjected to partitioning between chloroform and a 10% aqueous solution of citric acid. The organic layer was concentrated under reduced pressure, and the residue was recrystallized from 2-propanol to give Compound 7 (1.83 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.N1C=CN=C1.[CH3:27][O:28][C:29](=[O:37])[CH2:30][O:31][CH2:32][C:33]#[C:34][CH2:35]O>C(Cl)Cl>[CH3:27][O:28][C:29](=[O:37])[CH2:30][O:31][CH2:32][C:33]#[C:34][CH2:35][I:20]
Reactant: II
Reactant: COC(=O)COCC#CCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)COCC#CCI
Reaction time: 1 h
Yield: 38.6 %

Procedure:
Triphenylphosphine (6.23 g, 23.8 mmol), iodine (6.03 g, 23.8 mmol) and imidazole (1.57 g, 23.8 mmol) were added sequentially to a solution of (4-hydroxy-but-2-ynyloxy)-acetic acid methyl ester (3.13 g, 19.8 mmol) in CH2Cl2 (30 mL). After 1 h at rt, the reaction was filtered through activity I basic alumina, washing with 20% EtOAc/Hexane. The filtrate was concentrated in vacuo then purified by flash column chromatography on silica gel (Hexane→20% EtOAc/Hexane, gradient) to afford 2.05 g (39%) of (4-iodo-but-2-ynyloxy)-acetic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([Cl:13])=[C:6]([N+:14]([O-])=O)[CH:5]=1.Cl[Sn]Cl>CO>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([Cl:13])=[C:6]([NH2:14])[CH:5]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CO
Product: COC(=O)c1cc(N)c(Cl)c(N)c1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
A mixture of 4-chloro-3,5-dinitro-benzoic acid methyl ester (D25a) (2.6 g, 10 mmol, 1 equiv) and SnCl2 (18.95 g, 100 mmol, 10 equiv) in MeOH (80 ml) was refluxed for 1 h, cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt and 2N aqueous NaOH solution. The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was triturated with 1:1 Et2O/iso-hexane to give 3,5-diamino-4-chloro-benzoic acid methyl ester (D27a) (1.56 g, 78%) as a light orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH2:9][C:10]([OH:12])=O)[N:7]=[N:8][C:4]=2[C:3]=1[O:15][C:16]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([Cl:24])[CH:17]=1.C(Cl)(=O)C(Cl)=O.[Cl:31][C:32]1[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=1[NH2:34]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH2:9][C:10]([NH:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[Cl:31])=[O:12])[N:7]=[N:8][C:4]=2[C:3]=1[O:15][C:16]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([Cl:24])[CH:17]=1
Reactant: Nc1ccccc1Cl
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3CC(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3CC(=O)Nc2ccccc2Cl)c1
Reaction time: 0.17 h

Procedure:
To a suspension of [5-chloro-4-(3-chloro-5-cyanophenoxy)-1H-1,2,3-benzotriazol-1-yl]acetic acid (15 mg, 0.041 mmol) (see step 2 in Example 16) in DCM (0.5 mL) was added oxalyl chloride (58 mg, 0.454 mmol). This was followed by addition of DMF (1 drop) and then, following bubbling cessation, by addition of 2-chloroaniline (158 mg, 1.239 mmol). After 10 minutes, the reaction mixture was concentrated, taken up in DMF/MeOH and purified by reverse phase chromatography, eluting with 30-95% MeCN/H2O+0.1% TFA. The product fraction was lyophilized to yield the title compound. 1H NMR (DMSO-d6) δ 10.2 (s, 1H), 7.90 (d, J=9.0 Hz, 1H), 7.83 (m, 2H), 7.75 (d, J=8.3 Hz, 1H), 7.55 (m, 3H), 7.34 (m, 1H), 7.24 (m, 1H), 5.85 (s, 2H). HRMS (M+1)=472.0152.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](Br)=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[Cu][C:20]#[N:21]>CN1CCCC1=O>[CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([C:20]#[N:21])=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)c1cc(Br)c(C(C)C)cc1OCC
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cc(C#N)c(C(C)C)cc1OCC
Yield: 40.3 %

Procedure:
Ethyl 2-ethoxy-4-iso-propyl-5-bromobenzoate (1.2 g, 3.8 mmol) was treated with copper (I) cyanide (682 mg, 7.6 mmol) in N-methyl-2-pyrrolidinone (40 ml) as described in Procedure 5 to give the title compound as an oil (400 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])/[C:4](/[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1)=[C:5](/[CH:10]([CH3:12])[CH3:11])\[C:6]([O:8][CH3:9])=[O:7].N.O1CCOCC1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)[N:35]=1.CCCCCC.C(OCC)(=O)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:23])/[C:4](/[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:21])[NH2:35])=[CH:16][CH:15]=1)=[C:5](/[CH:10]([CH3:12])[CH3:11])\[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)/C(Cc1ccc(C(=O)O)cc1)=C(\C(=O)OC)C(C)C
Reactant: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: N
Agent: [Cl-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COC(=O)/C(Cc1ccc(C(N)=O)cc1)=C(\C(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
To a solution of 2-(4-carboxybenzyl)-3-isopropylmaleic acid dimethyl ester (7.8 mg, 0.024 mmol) in tetrahydrofuran (400 μL) were added a 0.5 M ammonia-dioxane solution (600 μL) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (14.8 mg, 0.0535 mmol), and the mixture was stirred at room temperature for 4 h. The reaction mixture was directly concentrated under reduced pressure and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 1:4) to give 7.0 mg of the title compound as a solid (yield: 90%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:35])[C@@H:14]([NH:24][C:25](OCC1C=CC=CC=1)=[O:26])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:37]([O:44][C:45]([NH:47][C@H:48](C(O)=O)[CH2:49][C:50](=[O:52])[NH2:51])=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:36])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:35])[C@@H:14]([NH:24][C:25](=[O:26])[C@H:48]([CH2:49][C:50](=[O:52])[NH2:51])[NH:47][C:45]([O:44][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:46])[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)[C@H](O)CN2CCC[C@H]2C(=O)OC(C)(C)C)cc1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OCc2ccccc2)[C@H](O)CN2CCC[C@H]2C(=O)OC(C)(C)C)cc1
Yield: 10.5 %

Procedure:
A solution of 730 mg of N-[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-(4-methoxyphenyl)butyl]-L-proline tert.butyl ester in 20 ml of ethanol was hydrogenated over 50 mg of 10% palladium-on-carbon for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated to give an oil which was coupled with 340 mg of N-(benzyloxycarbonyl)-L-asparagine in a manner analogous to that described in Example 1. The crude product was chromatographed on a column of silica gel using 10% methanol in dichloromethane for the elution. There were obtained 82 mg of N-[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-(4-methoxyphenyl)butyl]-L-proline tert.butyl ester as a white solid; MS: m/e 613 [M+H]+.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1>>[F:23][C:19]1[C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(C(=O)c2cn(-c3cccc(-c4cccc(F)c4OC)c3)cn2)cc1

Procedure:
This compound is prepared by method C using compound 12h and 4-bromoanisole
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH:27]([C:28]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)C(Cc1ccc(OC)c(CO)c1)C(=O)OC
Product: COC(=O)C(Cc1ccc(OC)c(COC(=O)Nc2ccccc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)-4-methoxybenzyl]malonate and phenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: Cl.[CH2:2]([N:5]([CH2:9][C:10]1[CH:35]=[CH:34][C:13]([CH2:14][NH:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:28][C:29]2[NH:30][CH:31]=[CH:32][N:33]=2)[CH2:21][C:22]2[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=2)=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH3:8])[CH2:3][CH3:4].[CH:36](OC)(OC)OC.C=O.[BH4-].[Na+]>CO.C(N(CC)CC)C>[CH2:2]([N:5]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][N:15]([CH3:36])[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:28][C:29]2[NH:33][CH:32]=[CH:31][N:30]=2)[CH2:21][C:22]2[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=2)=[CH:34][CH:35]=1)[CH2:6][CH2:7][CH3:8])[CH2:3][CH3:4]
Reactant: COC(OC)OC
Reactant: CCCN(CCC)Cc1ccc(CNCCCCN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Agent: C=O
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCN(CCC)Cc1ccc(CN(C)CCCCN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The hydrochloride (39.4 mg) of the compound obtained in Example 117-5 was dissolved in methanol (1.0 ml) and added with triethylamine (0.050 ml), trimethyl orthoformate (0.040 ml), and a 36% formaldehyde solution (0.020 ml), followed by stirring at room temperature for 2 hours. The solution was gradually added with sodium borohydride (15.0 mg) after having been cooled to 0° C., and then warmed to room temperature, followed by stirring for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution, followed by extraction with chloroform. The organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. Then, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (28.2 mg) of the subject compound as a white solid.
Reaction SMILES: [OH-].[Na+:2].CO.[CH3:5][C:6]1[CH:7]=[N:8][C:9]([CH2:15][S+:16]([O-:28])[C:17]2[NH:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[CH:23][C:24]=3[N:25]=2)=[C:10]([CH3:14])[C:11]=1[O:12][CH3:13].ClCCl>C(#N)C>[CH3:5][C:6]1[CH:7]=[N:8][C:9]([CH2:15][S+:16]([O-:28])[C:17]2[N-:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[CH:23][C:24]=3[N:25]=2)=[C:10]([CH3:14])[C:11]=1[O:12][CH3:13].[Na+:2]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: CC#N
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 29 °C

Procedure:
3.47 g of sodium hydroxide and 105 ml of methanol were taken into a round bottom flask and stirred at 29° C. A solution of 30 g of esomeprazole in 150 ml of acetonitrile was added to the above methanolic sodium hydroxide solution and stirred for 1 hour at 26° C. The reaction mass was then distilled under a vacuum of 300 mm Hg at 38° C. The residue was then co-distilled with 450 ml of acetonitrile in three equal lots. To the residue obtained, 60 ml of dichloromethane was added and stirred at 29° C. for 1.5 hours. The separated solid was filtered and washed with 30 ml of acetonitrile to give 42.6 g of Form J of esomeprazole sodium.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[NH:10][CH:11]=O.P(Cl)(Cl)(Cl)=O.N1C(C)=CC=CC=1C>O1CCCC1>[C:19]1([CH3:22])[CH:18]=[CH:17][C:16]([S:13]([CH:9]([N+:10]#[C-:11])[C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])(=[O:15])=[O:14])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)C(NC=O)c2cc(F)ccc2F)cc1
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: [C-]#[N+]C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.3 %

Procedure:
A 5 L three-necked round-bottomed flask, equipped with a mechanical stirrer, an addition funnel and a thermometer, was charged with N-[(2,5-Difluoro-phenyl)-(toluene-4-sulfonyl)-methyl]-formamide (207.0 g, 0.636 moles) and tetrahydrofuran (J. T. Baker, low water, 1.5 L). Phosphorous oxychloride (118.6 ml, 1.27 moles) was quickly poured into the reaction mixture (less than 5 minutes). The mixture was stirred at room temperature for 10 minutes and then cooled to 4° C. using an ice/water bath. 2,6-Lutidine (445 ml, 3.82 moles) was added via the addition funnel over a period of 30 minutes. The cooling bath was then removed and the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into a stirred and ice-water cooled solution of 1.5 kg of ice and 1.1 L of saturated aqueous sodium bicarbonate (NaHCO3). The mixture was then extracted with ethyl acetate (2 L plus 1.5 L). The combined organic extracts were washed with 1N aqueous hydrochloric acid (3 L), saturated aqueous NaHCO3 (3 L) and brine (3 L); and then dried (MgSO4). After removing all solvents, isopropanol (1.8 L) was added to the residual brownish solid. The resulting slurry was stirred at room temperature for 2 hours. Water (0.9 L) was added and the slurry was stirred for additional 30 minutes at room temperature and then filtered. The cake was washed with 2:1 isopropanol-water (2×500 ml) and dried in a vacuum-oven (30° C.) for 48 hours. The product, [α-(p-Toluenesulfonyl)-2,5-difluorobenzyl]isonitrile (133.4 g, yield 68%,), was obtained as a brownish powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.[C:29]([NH:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:31])[CH3:30]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([NH:32][C:29](=[O:31])[CH3:30])[CH:38]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Product: CC(=O)Nc1cccc(-c2cccc3c2CN(Cc2ccc(C(=O)Nc4ccccc4N)cc2)C3=O)c1
Yield: 54 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 3-acetamidophenyl boronic acid instead of phenyl boronic acid, to obtain the title compound (54%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[Br-].[C:18]1([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH:24]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccccc1OC(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of dry ortho-nitrophenol (79 mmol) in 200 ml of acetone there are added 127 mmol of potassium carbonate and also 79 mmol of diphenylmethane bromide. The reaction mixture is heated at reflux for 6 hours and, after the temperature has been lowered to ambient temperature, is stirred further overnight. The reaction mixture is filtered and rinsed with acetone. The filtrate is evaporated and then taken up in diethyl ether and hydrolysed. The aqueous phase is extracted with diethyl ether; the organic phase is then dried over magnesium sulphate, filtered and concentrated. The residue obtained is taken up in petroleum ether, filtered, rinsed with petroleum ether and then dried in vacuo, allowing the expected product to be isolated.