Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1N=C(C#CC(C2CCNCC2)O)C=CC=1.[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]([OH:28])([C:26]#[CH:27])[CH3:25])[CH2:20][CH2:19]1.Cl[C:30]1[C:35]([N+:36]([O-:38])=[O:37])=[CH:34][CH:33]=[C:32]([CH3:39])[N:31]=1>>[CH3:39][C:32]1[N:31]=[C:30]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([OH:28])([C:26]#[CH:27])[CH3:25])[CH2:20][CH2:19]2)[C:35]([N+:36]([O-:38])=[O:37])=[CH:34][CH:33]=1
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: C#CC(C)(O)C1CCNCC1
Agent: Cc1cccc(C#CC(O)C2CCNCC2)n1
Product: C#CC(C)(O)C1CCN(c2nc(C)ccc2[N+](=O)[O-])CC1
Yield: 93 %

Procedure:
The title compound was prepared as described for the compound of Example 237 but starting from Compound 312b instead of Compound 237a and 2-chloro-6-methyl-3-nitropyridine instead of 2-bromo-3-nitropyridine. After the work-up, the residue was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with PE-EtOAc from PE:EtOAc 9:1 affording the title products as yellow oil. Yield: 93%.
Reaction SMILES: C([N:3](CC)CC)C.[N+:8]([C:11]1[CH:19]=[CH:18][C:14](C(Cl)=O)=C[CH:12]=1)([O-:10])=[O:9].[CH2:20]([O:22][C:23](=[O:33])[CH2:24][NH:25]C1C(N)=CC=CN=1)[CH3:21]>O1CCCC1.[Pd]>[CH2:20]([O:22][C:23](=[O:33])[CH2:24][NH:25][C:12]1[C:11]([N+:8]([O-:10])=[O:9])=[CH:19][CH:18]=[CH:14][N:3]=1)[CH3:21]
Reactant: CCOC(=O)CNc1ncccc1N
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CNc1ncccc1[N+](=O)[O-]

Procedure:
Under a nitrogen atmosphere, triethylamine (14.9 g, 0.148 mole) and 4-nitrobenzoyl chloride (27.5 g, 0.148 mole) in tetrahydrofuran (25 ml) were added simultaneously (dropwise) to a stirred and chilled (5°-10° C.) solution of freshly prepared N-(3-amino-2-pyridinyl)glycine ethyl ester (0.14 mole), obtained by 5% palladium on carbon hydrogenation of N-(3-nitro-2-pyridinyl) glycine ethyl ester at room temperature, in dry tetrahydrofuran (140 ml). The reaction mixture was stirred at room temperature under nitrogen overnight and the solvent was evaporated under reduced pressure. The resulting solid was triturated in water (200 ml) and saturated sodium bicarbonate solution (200 ml). The solid was filtered off, rinsed with water and dried under vacuum at 50° C. to give 50.5 g (95%) of yellow solid. A 2.0-g sample was recrystallized from isopropyl alcohol to give 1.5 g of yellow solid, mp. 151°-154° C.
Reaction SMILES: C[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[N:11]O.[CH3:13]O>[Pd]>[CH3:13][CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([NH2:11])[CH2:2]1
Reactant: CC1Cc2ccccc2C1=NO
Reactant: CO
Agent: [Pd]
Product: CC1CC(N)c2ccccc21
Reaction time: 8 h
Yield: 96 %

Procedure:
A mixture of-methylindan-1-one oxime (223 mg, 1.38 mmol) and 10% palladium on carbon (14.7 mg, 50% water wet) in MeOH (5.00 mL) was stirred under an atmosphere of hydrogen overnight. The mixture was then filtered through celite, washed through with MeOH and the combined filtrates were concentrated in vacuo to afford the title compound (195 mg, 96%). 1H NMR (CDCl3, 300 MHz) δ: 7.39-7.14 (m, 4H), 4.26 (dd, J=7.2, 9.4 Hz, 1H), 3.13-2.96 (m, 1H), 2.71 (ddd, J=6.9, 6.9, 12.5 Hz, 1H), 1.75 (bs, 2H), 1.35 (d, J=6.8 Hz, 3H), 1.25 (ddd, J=9.9, 9.9, 11.7 Hz, 1H) ppm.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH:15]=CN=[CH:12][C:11]=3[N:10]=[CH:9]2)=[N:6][CH:7]=1.Br[C:18]1C(F)=CC=C[N:19]=1>>[N:6]1[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=1[N:8]1[C:16]2[CH:15]=[N:19][CH:18]=[CH:12][C:11]=2[N:10]=[CH:9]1
Reactant: Fc1cccnc1Br
Reactant: Fc1ccc(-n2cnc3cnccc32)nc1
Product: c1ccc(-n2cnc3ccncc32)nc1

Procedure:
Intermediate 69 was prepared in a manner analogous to Intermediate 1, substituting 2-bromopyrimidine for 2-bromo-fluoropyridine. MS (ESI): mass calculated for C11H8N4, 196.07; m/z found 197.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[C:13](Br)=[CH:12][CH:11]=[C:10]([C:15]#[C:16][CH2:17][O:18][CH3:19])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:22]1([OH:30])[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1)#[CH:21].C(N(CC)CC)C.N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:21]#[C:20][C:22]2([OH:30])[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]2)=[CH:12][CH:11]=[C:10]([C:15]#[C:16][CH2:17][O:18][CH3:19])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: COCC#Cc1ccc(Br)c(Cc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCC#Cc1ccc(C#CC2(O)CN3CCC2CC3)c(Cc2ccccc2)n1
Reaction time: 2 h
Yield: 57.7 %

Procedure:
Next, a mixture of 170 mg of 2-benzyl-3-bromo-6-(3-methoxy-1-propinyl)pyridine, 90 mg of 3-ethynyl-3-quinuclidinol, 30 mg of tetrakis(triphenylphosphine)palladium(0), 1 mg of cuprous iodide, 0.22 ml of triethylamine and 1 ml of N,N-dimethylformamide was stirred for 2 hours in an oil bath kept at 85° C. in a nitrogen atmosphere. Ethyl acetate and aqueous dilute ammonia were added to the reaction solution to separate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography using NH-silica gel to elute with 20-100% ethyl acetate/hexane and then with 2.5% methanol/ethyl acetate, to give 120 mg of the target compound.
Reaction SMILES: [CH:1]1([N:4]([CH2:12][C:13]2[CH:18]=[C:17]([CH2:19][OH:20])[CH:16]=[C:15]([Cl:21])[C:14]=2[Cl:22])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl.CCOCC>[CH3:32][S:33]([O:20][CH2:19][C:17]1[CH:18]=[C:13]([CH2:12][N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]([O:6][C:7]([CH3:9])([CH3:10])[CH3:8])=[O:11])[C:14]([Cl:22])=[C:15]([Cl:21])[CH:16]=1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CO)cc(Cl)c1Cl)C1CC1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1cc(COS(C)(=O)=O)cc(Cl)c1Cl)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,1-dimethylethyl cyclopropyl{[2,3-dichloro-5-(hydroxymethyl)phenyl]methyl}carbamate (1 eq.) from the previous step in dichloromethane (0.1 M) was added sequentially at 0 Hunig's base (3 eq.) and methanesulfonyl chloride (1.1 eq.). The resulting solution was stirred at 0° C. for 30 min and then at RT for 15 min. The reaction mixture was then diluted with ether and carefully quenched with 1 N aq. HCl. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford the crude title compound as a colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28]Br.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCCCBr
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: C1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCN3CCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 20 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate, 1,3-dibromopropane and pyrrolidine.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[NH:39]1[CH2:43][CH2:42][C@H:41]([OH:44])[CH2:40]1.CS(C)(=O)=O>O1CCOCC1>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14]([N:39]3[CH2:43][CH2:42][C@@H:41]([OH:44])[CH2:40]3)[N:13]=2)[CH2:6]1)(=[O:3])=[O:4]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Reactant: O[C@H]1CCNC1
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CCC[C@H](Nc2nc(N3CC[C@@H](O)C3)ncc2-c2cnc3[nH]ccc3n2)C1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, (S)-pyrrolidin-3-ol was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76, to give (R)-1-[4-((S)-1-methanesulfonyl-piperidin-3-ylamino)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-2-yl]-pyrrolidin-3-ol. MS: (ES+): 459
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>[OH-].[K+]>[C:11]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Agent: [K+]
Agent: [OH-]
Product: CC(=O)Nc1ccc(C(C)=O)cc1
Temperature: 25 °C
Yield: 67.1 %

Procedure:
To 250 ml of KOH dried pyridine was added 50 g (0.37 mole) of p-aminoacetophenone and 39.6 g of acetic anhydride. After one and a half hours of stirring at room temperature, the solution had become a thick suspension of a white solid. Filtration and drying gave 44 g of p-acetamidoacetophenone. This solid (44 g, 0.25 mole) was then suspended in 500 ml methylene chloride and treated with 44 g Br2 (0.275 mole). The reaction was allowed to proceed overnight whereupon it was stripped and dried under high vacuum, then suspended in 200 ml absolute EtOH and treated with 60 g 2-amino-2-thiazoline (0.59 mole). The reaction was stirred for 2 days then stripped, taken up in water and extracted with methylene chloride. The organic phase was washed with water, brine and was dried with sodium sulfate. Flash column chromatography with 2% MeOH/98% CH2Cl2 gave 10.2 g (0.039 mole) of the Formula (III) compound, 6-acetamidophenyl-2,3-dihydroimidazo[2,1-b]thiazole.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]([CH:23]1[CH2:27][CH2:26][N:25]([CH2:28][C:29](O)=[O:30])[CH2:24]1)=[O:22].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH3:19][O:20][C:21]([CH:23]1[CH2:27][CH2:26][N:25]([CH2:28][C:29](=[O:30])[N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:12]=[CH:11][C:10]([C:13]4[N:14]=[CH:15][CH:16]=[CH:17][N:18]=4)=[CH:9][CH:8]=3)[CH2:2][CH2:3]2)[CH2:24]1)=[O:22]
Reactant: COC(=O)C1CCN(CC(=O)O)C1
Reactant: c1cnc(-c2ccc(N3CCNCC3)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Reaction time: 24 h
Yield: 83.1 %

Procedure:
2-(4-piperazin-1-yl-phenyl)-pyrimidine (compound 10 from Step 7, 14.7 mmol) and 1-Carboxymethyl-pyrrolidine-3-carboxylic acid methyl ester (compound 5 from Step 3, 17.6 mmol) were dissolved in 72 ml of DMF. Triethylamine (8 ml, 57 mmol), 1-hydroxybenztriazole (2.29 gm) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (3.43 gm, 18 mmol) were added and the reaction mixture stirred for 24 hrs. After washing with brine, extracting with dichloromethane, and drying over magnesium sulfate, the mixture was evaporated and chromatographed on silica gel to obtain 5.0 gm of title product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CC(C)=O>O>[CH2:15]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCC(c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(4-Hydroxyphenyl)cyclohexanone (4.98 g, 26.18 mmol), benzyl bromide (4.92 g, 28.79 mmol), K2CO3 (5.06 g, 36.65 mmol) and 75 mL of acetone were mixed in a reaction flask equipped with a reflux condenser. The mixture was heated to reflux and stirred overnight. The mixture was cooled to room temperature and water was added. The mixture was extracted with ethyl acetate three times. The combined organic layers were dried over Na2SO4, filtered and concentrated. The resulting solid was recrystallized in ethyl acetate to provide the titled compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.80-2.00 (m, 2 H), 2.13-2.26 (m, 2 H), 2.43-2.55 (m, 4 H), 2.91-3.05 (m, 1 H), 5.05 (s, 2 H), 6.94 (d, J=8.82 Hz, 2 H), 7.16 (d, J=8.82 Hz, 2 H), 7.28-7.48 (m, 5 H); MS (DCI) m/z 298 (M−NH4)+.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][N:8]1[C:12]([OH:13])=[C:11]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[C:10]([CH3:24])=[N:9]1.C(N(CC)CC)C.[C:32](Cl)(=[O:44])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>CCOCC>[CH3:7][N:8]1[C:12]([O:13][C:32](=[O:44])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[C:11]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[C:10]([CH3:24])=[N:9]1
Reactant: Cc1nn(C)c(O)c1C(=O)c1ccc(Cl)cc1Cl
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCCCCC(=O)Oc1c(C(=O)c2ccc(Cl)cc2Cl)c(C)nn1C
Temperature: 25 °C
Reaction time: 19 h
Yield: 98 %

Procedure:
In 10 ml. of benzene is dissolved 0.285 g. of 1,3-dimethyl-4-(2,4-dichlorobenzoyl)-5-hydroxypyrazole and then 0.2 ml. of triethylamine is added thereto. Under ice-cooling, a solution of 0.27 g. of lauroyl chloride in 5 ml. of benzene is added dropwise thereto. After completion of the dropwise addition, the resulting mixture is stirred at room temperature for 19 hours. After completion of the reaction, ether is added to the reaction mixture, which is then washed successively with water, 1N HCl, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride. Then, the reaction mixture is dried over anhydrous sodium sulfate and the solvent is distilled off from the reaction mixture. The resulting residue is recrystallized from n-hexane under cooling with dry-ice to give 0.46 g. of the desired product as white crystals melting at 56° C. Yield 98.0%.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.ON1C2C=CC=CC=2N=N1.[NH:28]1[CH2:34][CH2:33][CH2:32][C@H:29]1[CH2:30][OH:31].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C(Cl)Cl>[C:1]1([NH:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([N:28]2[CH2:34][CH2:33][CH2:32][C@H:29]2[CH2:30][OH:31])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(O)c1ccccc1Nc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccccc1Nc1ccccc1)N1CCC[C@H]1CO

Procedure:
2.13 g (10 mmol) of N-phenylanthranilic acid, 1.35 g (10 mmol) of 1-hydroxybenzotriazole hydrate, 1.0 ml (10 mmol) of L-prolinol and 2.06 g (10 mmol) of DCC in 50 ml 1:1/methylene chloride:DMF. The coupling was carried out as described in Example 25 for the coupling of the acid and S(+)-2-pyrrolidinemethanol. Clean product of the title compound was obtained in virtually quantitative yield as a brownish gum without chromatographic purification. TLC (90:10/CH2Cl2 :MeOH): Rf =0.75. 1H NMR (CDCl3) δ: 7.50(bs,1H); 6.75-7.36 (m,9H); 4.65-4.80(m,1H); 4.25-4.40 (m,1H); 3.38-3.85(m,4H); 1.55-2.15(m,4H).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[F:15][C:16]([F:26])([F:25])[O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C(N(CC)CC)C>CN(C=O)C>[N+:12]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[NH:22][C:21]1[CH:23]=[CH:24][C:18]([O:17][C:16]([F:15])([F:25])[F:26])=[CH:19][CH:20]=1)[C:6]([O:8][CH3:9])=[O:7])([O-:14])=[O:13]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Nc2ccc(OC(F)(F)F)cc2)c([N+](=O)[O-])c1

Procedure:
A stirred solution of methyl 4-fluoro-3-nitrobenzoate (853 mg, 4.28 mmol), 4-trifluoromethoxyaniline (759 mg, 4.28 mmol) and triethylamine (1.79 mL, 12.9 mmol) in DMF (5.00 mL) was heated to 70° C. for 24 h. The reaction mixture was concentrated in vacuo, and the resulting crude residue was purified by flash chromatography on silica gel (gradient elution; 0%-10% methanol/DCM as eluent) afforded the title compound i-3a. m/z (ES) 357 (MH)+. 1H NMR (500 MHz, CDCl3): δ 9.77 (s, 1H), 8.96 (s, 1H), 8.03 (d, 1H, J=8.5 Hz), 7.34 (m, 4H), 7.16 (d, 1H, J=8.5 Hz), 3.95 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[N:15]1([CH2:22][C:23]2[CH:31]=[C:30]([O:32]C)[CH:29]=[C:28]3[C:24]=2[CH:25]=[CH:26][N:27]3[S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.Br.C([O-])(O)=O.[Na+]>C(O)(=O)C>[N:15]1([CH2:22][C:23]2[CH:31]=[C:30]([OH:32])[CH:29]=[C:28]3[C:24]=2[CH:25]=[CH:26][N:27]3[S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: COc1cc(CN2CCCNCC2)c2ccn(S(=O)(=O)c3ccccc3)c2c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: O=S(=O)(c1ccccc1)n1ccc2c(CN3CCCNCC3)cc(O)cc21
Temperature: 125 °C
Yield: 82.1 %

Procedure:
To 4-(1,4-Diazepan-1-ylmethyl)-6-methoxy-1-(phenylsulfonyl)-1H-indole (0.12 g, 0.03 mmol; Example 58) was 33% HBr in acetic acid (2 mL) added and the mixture was refluxed in STEM-block at 125° C. for 20 h which gave 70% conversion to product. Additional HBr in acetic acid (1 mL) was added and the mixture was refluxed for additional 20 h which gave 90% conversion product. Additional HBr in acetic acid (1 mL) was added and the mixture was refluxed for additional 21 h. The mixture was cooled to rt and sat. NaHCO3-solution was added (foaming) until neutral pH. The mixture was extracted with 3*EtOAc/ethanol (10:1). The organic layers were dried (Na2SO4), filtrated and the solvent was evaporated yielding 9.5 mg (82%) of a brownish-red solid. MS (ESI+) for C20H23N3O3S m/z 386 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][C:31]([NH2:33])=O)([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:34])[CH3:16])=[CH:11][CH:10]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl.CCN(C(C)C)C(C)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][C:31]#[N:33])([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:34])[CH3:16])=[CH:11][CH:10]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CC(N)=O)(c2ccc(F)cc2)OC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CC#N)(c2ccc(F)cc2)OC1=O
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a solution of 2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)acetamide (60 mg, 0.128 mmol) in anhydrous CH2Cl2 (4 mL) and DIEA (0.3 mL) was added TFAA (55 mg, 0.256 mmol) at 0□. The mixture was stirred for 2 h. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC to afford 2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)acetonitrile (40 mg, 82%). LC-MS Method 3 tR=1.52, min, m/z=451, 473; 1H NMR (CDCl3): 1.56 (m, 3H), 2.40 (m, 2H), 2.54 (m, 1H), 2.82-2.98 (m, 2H), 3.04 (m, 1H), 5.64 (m, 1H), 6.83-6.94 (m, 5H), 7.09 (m, 2H), 7.21 (m, 1H), 7.28 (m, 1H), 7.37 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][N:6]=[C:7]([CH2:11][S+:12]([O-:26])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH:23]([F:25])[F:24])=[CH:19][C:20]=3[N:21]=2)[C:8]=1[O:9][CH3:10].[OH-:27].[Na+:28].C([O:33]C)(C)(C)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][N:6]=[C:7]([CH2:11][S:12]([C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH:23]([F:24])[F:25])=[CH:19][C:20]=3[N:21]=2)=[O:26])[C:8]=1[O:9][CH3:10].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][N:6]=[C:7]([CH2:11][S:12]([C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH:23]([F:24])[F:25])=[CH:19][C:20]=3[N:21]=2)=[O:26])[C:8]=1[O:9][CH3:10].[OH2:33].[OH2:27].[OH2:2].[Na+:28].[Na+:28]
Reactant: [OH-]
Reactant: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Reactant: COC(C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccnc(CS(=O)c2nc3cc(OC(F)F)ccc3[n-]2)c1OC
Product: O
Temperature: 45 °C

Procedure:
Pantoprazole freebase (25 grams) was dissolved in a solution of ethyl acetate (50 ml) and aqueous sodium hydroxide solution (2.7 grams in 5 ml of water) and stirred at a temperature of 40-50° C. till the clear solution results. Methyl tertiary butyl ether (250 ml) was added to the reaction mixture and stirred for about 3-4 hours to crystallize the solid mass. The separated solid mass was filtered, washed with methyl tertiary butyl ether (50 ml) and suck dried under vacuum. The wet solid was further dried at a temperature of 40-50° C. to afford crystalline Form-I of Pantoprazole sodium sesquihydrate.
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=O.C[O-].[Na+].[Na].C(Cl)(=O)C.[CH:14]([NH:16][CH2:17][C:18]#[CH:19])=[O:15]>CN(C)C(=O)C.CO>[CH:14]([NH:16][CH2:17][C:18]1[O:3][N:1]=[C:4]([CH3:5])[CH:19]=1)=[O:15]
Reactant: CC[N+](=O)[O-]
Reactant: C#CCNC=O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CC(=O)N(C)C
Solvent: CC(=O)Cl
Product: Cc1cc(CNC=O)on1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
A stirred solution of nitroethane (17.9 ml, 0.25 mol) in N,N-dimethylacetamide (DMA) (250 ml) was added dropwise at 25°-30° C. to a solution of sodium methoxide, prepared by dissolving sodium (5.75 g) in dry methanol. The reaction mixture was cooled to 5° C. and acetyl chloride (18.5 ml, 0.26 mol) was added at 5°-10° C. Then was added a solution of 3-formylaminopropyn (17 g, 0.20 mol) in DMA (15 ml), and stirring was continued at room temperature overnight. The solvent was removed in vacuo and the residue was extracted with ether (300 ml). The ether was evaporated leaving an oily residue from which the title compound was isolated by distillation (120°-140° C./0.3 mmHg); 1H-NMR (CDCl3) 2.21 (s,3H), 4.35 (d,2H), 5.97 (s,1H), 7-8 (br, 1H), 8.13 (s,1H). (Compound 15).
Reaction SMILES: [CH3:1][C:2]([N:7]=[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[I:17])[C:10](=[O:18])[O:9]1)([CH3:6])[CH2:3][S:4][CH3:5].[CH3:19][C:20]1[CH:21]=[C:22]([CH:37]=[CH:38][C:39]=1[NH2:40])[CH2:23][N:24]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][C:26]([C:33]([F:36])([F:35])[F:34])=[N:25]1>C(#N)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:36][C:33]([F:34])([F:35])[C:26]1[CH:27]=[C:28]([C:29]([F:32])([F:30])[F:31])[N:24]([CH2:23][C:22]2[CH:37]=[CH:38][C:39]([NH:40][C:10](=[O:18])[C:11]3[C:16](=[C:15]([I:17])[CH:14]=[CH:13][CH:12]=3)[C:8]([NH:7][C:2]([CH3:6])([CH3:1])[CH2:3][S:4][CH3:5])=[O:9])=[C:20]([CH3:19])[CH:21]=2)[N:25]=1
Reactant: Cc1cc(Cn2nc(C(F)(F)F)cc2C(F)(F)F)ccc1N
Reactant: CSCC(C)(C)N=C1OC(=O)c2cccc(I)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: CSCC(C)(C)NC(=O)c1c(I)cccc1C(=O)Nc1ccc(Cn2nc(C(F)(F)F)cc2C(F)(F)F)cc1C
Temperature: 60 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
3-(1,1-Dimethyl-2-methylsulfanyl-ethylimino)-4-iodo-3H-isobenzofuran-1-one (0.53 g) and 1-(3-methyl-4-aminobenzyl)-3,5-bis(trifluoromethyl)-1H-pyrazole (0.45 g) were dissolved in acetonitrile (15 ml), to which p-toluenesulfonic acid monohydrate (0.01 g) was added and the mixture was stirred at 60° C. for 3 hours. After finishing the reaction, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain N1-[4-(3,5-bistrifluoromethylpyrazol-1-ylmethyl)-2-methylphenyl]-N2-(1,1-dimethyl-2-methylsulfanylethyl)-3-iodophthalamide (0.91 g). mp. 83-87° C.