Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CN(C)C(=O)C.[CH:32]1([SH:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>O>[CH:32]1([S:38][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: SC1CCCCC1
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc(SC2CCCCC2)cc1
Temperature: 60 °C
Reaction time: 40 h

Procedure:
The N-[(4-flourophenyl)sulphonyl]glycine, 1,1-dimethylethyl ester from Example 5a (4.5 mmol, 1.30 g) was combined with dried 325 mesh K2CO3 (5.0 mmol, 0.69 g) and N,N-dimethylacetamide (4.5 mL). Cyclohexyl mercaptan (5 mmol, 0.61 mL) was added, and the mixture was stirred under argon at 60° C. for 40 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (125 mL). The organic phase was dried using magnesium sulphate, filtered through silica, and concentrated. The N-[[4-(cyclohexyl-thio)phenyl]sulfonyl]glycine, 1,1-dimethylethyl ester, a white solid (528 mg), was obtained following chromatography eluting with hexane:ethyl acetate (4:1). NMR indicated the presence of about 20% starting material after chromatography, but the mixture was used as is in the next step. The structure was confirmed spectroscopically.
Reaction SMILES: C[Si]([Br:5])(C)C.[CH2:6]([O:13][C:14]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16]O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)(Cl)Cl>[CH2:6]([O:13][C:14]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][Br:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)c1ccc(CO)c(OCc2ccccc2)c1
Reactant: C[Si](C)(C)Br
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc(CBr)c(OCc2ccccc2)c1
Reaction time: 1 h

Procedure:
2.9 ml of trimethylsilyl bromide are added to a solution, stirred at room temperature, of 4 g of 2-benzyloxy-4-tert-butyl-benzyl alcohol in 100 ml of chloroform. The reaction mixture is stirred for a further 1 hour and then partitioned between trichloromethane and water. The organic phases are dried with Na2SO4 and concentrated by evaporation, yielding the title compound: Rf (dichloromethane/hexane=8.2)=0.95.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[C:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:16]([C:26]#[CH:27])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[N:3]=1.[CH3:32][CH:33]([CH3:36])[CH2:34][OH:35].[H-].[Na+].Cl>CN(C=O)C.O>[C:26]([C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([F:20])[C:17]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:7]1[C:2]([O:35][CH2:34][CH:33]([CH3:36])[CH3:32])=[N:3][C:4]([C:28]([F:31])([F:30])[F:29])=[CH:5][CH:6]=1)#[CH:27]
Reactant: CC(C)CO
Reactant: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc(F)c1NS(C)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2OCC(C)C)cc(F)c1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.2 %

Procedure:
A mixture of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (50 mg, 0.11 mmol), 2-methyl-1-propanol (20 μl, 0.22 mmol) and 60% NaH (13 mg, 0.33 mmol) in DMF was stirred at ambient temperature for 4 hrs. The reaction mixture was diluted with water and then acidified with 2N HCl solution. The aqueous phase was extracted with EtOAc and the combined organic phase was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex EtOAc=1/2) to give the title compound (12 mg, 40%).
Reaction SMILES: [OH-:1].[K+].[NH2:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]#N)=[CH:14][C:13]=2[F:21])=[C:6]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:5]=1.C[OH:29]>>[NH2:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:29])=[O:1])=[CH:14][C:13]=2[F:21])=[C:6]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:5]=1
Reactant: [OH-]
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1F
Reactant: CO
Agent: [K+]
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1F
Temperature: 65 °C
Reaction time: 15 h

Procedure:
A 5M aqueous solution of potassium hydroxide (3.10 mL) was added to a solution of the product of step (vii) (0.53 g) in MeOH (6 mL). The mixture was stirred at 65° C. for 15 h and allowed to cool. The solvent was evaporated under reduced pressure and the resulting aqueous solution adjusted to pH ˜7 with conc. HCl. The aqueous phase was extracted with DCM and EtOAc, the combined organic phase was evaporated under reduced pressure to give the subtitle compound as a colourless solid 0.547 g.
Reaction SMILES: C1([Li])C=CC=CC=1.[N:8]([CH:11]([CH3:32])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]2[CH2:18][C:19]3[C:24]([C:14]1=2)=[CH:23][C:22](C(OS(C)(=O)=O)=O)=[CH:21][CH:20]=3)=[N+:9]=[N-:10].C([O:35]CC)C.[Cl-].[NH4+]>O.O1CCCC1>[N:8]([CH:11]([CH3:32])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]2[CH2:18][C:19]3[C:24]([C:14]1=2)=[CH:23][C:22]([OH:35])=[CH:21][CH:20]=3)=[N+:9]=[N-:10]
Reactant: CC(Cn1ccc2c1-c1cc(C(=O)OS(C)(=O)=O)ccc1C2)N=[N+]=[N-]
Reactant: CCOCC
Agent: [Cl-]
Agent: [Li]c1ccccc1
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(Cn1ccc2c1-c1cc(O)ccc1C2)N=[N+]=[N-]
Reaction time: 0.25 h
Yield: 99 %

Procedure:
A 2M phenyllithium solution was added dropwise over 5 minutes to a solution, cooled to 0°, of 3.55 g of (RS)-1-(2-azido-propyl)-7-mesyloxycarbonyl-1,4-dihydro-indeno[1,2-b]pyrrole, 90 ml of anhydrous diethyl ether and 90 ml of anhydrous tetrahydrofuran. After 15 minutes at this temperature, an additional 5.87 ml of the phenyllithium solution were added dropwise and the mixture was stirred for an additional 5 minutes. Subsequently, the reaction mixture was treated with 50 ml of a saturated ammonium chloride solution and 25 ml of water. The mixture was extracted once with 50 ml of ethyl acetate and the aqueous phase was made slightly acidic with 1N hydrochloric acid and extracted three times with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated in a vacuum. 2.7 g (99%) of (RS)-1-(2-azido-propyl)-7-hydroxy-1,4-dihydro-indeno[1,2-b]pyrrole were obtained as a brown oil.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:31])[C:16]=3[C@H:32]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]([O:35][CH3:36])=[O:34])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3].[CH2:42]([C:46]1[CH:47]=[C:48](B2OC(C)(C)C(C)(C)O2)[CH:49]=[CH:50][CH:51]=1)[CH2:43][CH:44]=[CH2:45].C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:25]=[C:26]([C:50]6[CH:49]=[CH:48][CH:47]=[C:46]([CH2:42][CH2:43][CH:44]=[CH2:45])[CH:51]=6)[CH:27]=[CH:28][CH:29]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:31])[C:16]=3[C@H:32]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]([O:35][CH3:36])=[O:34])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3]
Reactant: C=CCCc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: C=CCN1CCOc2ccc(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(Br)c5)nn34)c(Cl)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCc1cccc(-c2cccc(-c3cc4nc(C)c([C@H](OC(C)(C)C)C(=O)OC)c(-c5ccc6c(c5Cl)N(CC=C)CCO6)n4n3)c2)c1
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 61.5 %

Procedure:
A mixture of (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (75 mg, 0.117 mmol), 2-(3-(but-3-en-1-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (45.4 mg, 0.176 mmol) and 2N Na2CO3 (0.117 mL, 0.234 mmol) in DMF (1 mL) was degassed for 15 min. tetrakis(triphenylphosphine)pallafium(0) (9.48 mg, 8.20 μmol) was then added and the degassing was continue for another 5 min. The mixture was then heated at 90° C. for 16 h. After cooling to room temperature, water was added and the mixture was extracted with ether (2×25 mL), washed with brine (15 mL), dried (Na2SO4), filtered and concentrated. Crude was then purified by biotage (0-15% EtOAc/hexane) to afford (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3′-(but-3-en-1-yl)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (50 mg, 0.072 mmol, 61.7% yield) as light yellow solid. 1H NMR (500 MHz, CDCl3) δ: 8.05 (t, J=1.6 Hz, 1H), 7.85-7.82 (m, 1H), 7.57-7.54 (m, 1H), 7.45 (dd, J=4.6, 2.5 Hz, 3H), 7.41-7.35 (m, 1H), 7.21 (d, J=7.6 Hz, 1H), 7.00 (d, J=5.0 Hz, 2H), 6.95-6.93 (m, 1H), 6.11-6.00 (m, 1H), 5.91 (ddt, J=17.0, 10.3, 6.6 Hz, 1H), 5.35 (dd, J=17.2, 1.6 Hz, 1H), 5.26 (dd, J=10.2, 1.6 Hz, 1H), 5.12-5.07 (m, 2H), 5.04-5.00 (m, 1H), 4.27 (t, J=4.4 Hz, 2H), 3.79-3.72 (m, 1H), 3.67 (s, 3H), 3.63 (dd, J=15.1, 6.1 Hz, 1H), 3.28-3.17 (m, 2H), 2.86 (s, 3H), 2.83-2.78 (m, 2H), 2.49-2.41 (m, 2H), 1.20 (s, 9H). LCMS (M+H)=691.5.
Reaction SMILES: [CH:1]1([N:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][CH2:19]C(O)=O)(=[O:17])=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N[C@H]2CC[C@H]([O:43][CH2:44][CH2:45][CH3:46])CC2)CCCCC1.C1(N([C@H]2CC[C@H](OC)CC2)C(=O)NC2SC(S[CH2:61][C:62]([OH:64])=[O:63])=CN=2)CCCC1.O[C@H]1CC[C@H](C2C=CC=C3C=2C(=O)NC3=O)CC1.BrCCC.C1(=O)CCCCC1.C(OC(=O)CCNS(C1SC(N)=NC=1)(=O)=O)C>>[CH:1]1([N:7]([C@H:24]2[CH2:29][CH2:28][C@H:27]([O:43][CH2:44][CH2:45][CH3:46])[CH2:26][CH2:25]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][CH2:19][CH2:61][C:62]([OH:64])=[O:63])(=[O:16])=[O:17])=[CH:13][N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCCO[C@H]1CC[C@H](NC2CCCCC2)CC1
Reactant: O=C(O)CNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: CO[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Agent: CCOC(=O)CCNS(=O)(=O)c1cnc(N)s1
Agent: O=C1NC(=O)c2c1cccc2[C@H]1CC[C@H](O)CC1
Solvent: CCCBr
Solvent: O=C1CCCCC1
Product: CCCO[C@H]1CC[C@H](N(C(=O)Nc2ncc(S(=O)(=O)NCCC(=O)O)s2)C2CCCCC2)CC1

Procedure:
Prepared in a similar manner to [2-(3,3-dicyclohexyl-ureido)-thiazole-5-sulfonylamino]-acetic acid via cyclohexyl-(trans-4-propoxy-cyclohexyl)-amine (prepared according to the procedure described for the synthesis of {2-[3-cyclopentyl-3-(trans-4-methoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid (Step 1) using (trans-4-hydroxy-cyclohexyl)-isoindole-1,3-dione, 1-bromopropane and cyclohexanone) and 3-(2-amino-thiazole-5-sulfonylamino)-propionic acid ethyl ester to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:17]O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16].P(Br)(Br)[Br:20].C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:17][Br:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16]
Reactant: BrP(Br)Br
Reactant: OCc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(Oc2ccc(CBr)cc2Br)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
To a solution of Example 287b (3.70 g, 11.74 mmol) in dichloromethane (20 mL) was added phosphorus tribromide (1.11 mL, 11.7 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 3 hours, and poured into ice water. The pH was adjusted to basic by the careful addition of saturated aqueous sodium bicarbonate and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried with anhydrous sodium sulfate, filtered, and concentrated to provide the title compound (4.15 g, 93%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([C:15](=[O:18])[CH2:16]Br)[CH:8]=[CH:9][C:10]=1[O:11][C:12](=[O:14])[CH3:13])(=[O:3])[CH3:2].[CH2:19]([NH:26][CH2:27][CH2:28][NH:29][C:30](=[O:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([N:26]([CH2:16][C:15]([C:7]1[CH:8]=[CH:9][C:10]([O:11][C:12](=[O:14])[CH3:13])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=1)=[O:18])[CH2:27][CH2:28][NH:29][C:30](=[O:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Cc1ccccc1)NCCNCc1ccccc1
Reactant: CC(=O)Oc1ccc(C(=O)CBr)cc1OC(C)=O
Product: CC(=O)Oc1ccc(C(=O)CN(CCNC(=O)Cc2ccccc2)Cc2ccccc2)cc1OC(C)=O

Procedure:
3',4'-Bis(acetoxy)-2-bromoacetophenone was reacted with N-[2-(benzylamino)ethyl]-2-phenylacetamide using a similar procedure to that described in Example 1 for the analogous pivaloyloxy derivative to give 2-{N-benzyl-N-[2-(2-phenylacetamido)ethyl]amino}-3',4'-bis(acetoxy)acetophenone, which was isolated as its free base and converted to its hydrochloride salt with ethereal hydrogen chloride to give a solid, m.p. 140°-145° C. This hydrochloride salt was dissolved in methanol containing 2% v/v of hydrobromic acid, and the solution was heated under reflux for 2 hours. After cooling to room temperature, the solution was diluted with ether (100 ml.) and stored at 0°-5° C. to give 2-{N-benzyl-N-[2-(2-phenylacetamido)ethyl]amino}-3',4'-dihydroxyacetophenone hydrobromide as a white solid in 98% yield, m.p. 175°-177° C. (after recrystallisation from methanol/ether).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]=[C:10]1[NH:16][CH2:15][CH2:14][N:13]([CH3:17])[C:12]2[CH:18]=[C:19](Br)[CH:20]=[CH:21][C:11]1=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[S:23]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24]1.[F-].[Cs+]>O1CCOCC1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[CH2:1]([O:3][P:4]([CH:9]=[C:10]1[NH:16][CH2:15][CH2:14][N:13]([CH3:17])[C:12]2[CH:18]=[C:19]([C:25]3[CH:26]=[CH:27][S:23][CH:24]=3)[CH:20]=[CH:21][C:11]1=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: OB(O)c1ccsc1
Reactant: CCOP(=O)(C=C1NCCN(C)c2cc(Br)ccc21)OCC
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: CCOP(=O)(C=C1NCCN(C)c2cc(-c3ccsc3)ccc21)OCC
Temperature: 80 °C
Yield: 61.2 %

Procedure:
To 300 mg (0.77 mmol) of (8-bromo-1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester (prepared as described in Example 41) in 2 ml of dioxane was added 116 mg (0.81 mmol) of thiophene-3-boronic acid, 8 mg (0.028 mmol) of tricyclohexylphosphine, 10.8 mg 0.012 mmol) of tris-(dibenzylideneacetone)-palladium (0) and 140 mg of caesium fluoride. The mixture was heated at 80° C. for 6 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was evaporated and the product was purified by column chromatography (20 g IST pre-packed column) eluting with acetone—petroleum ether (40-60° C.) (1:3) to give 185 mg of (1-methyl-8-thiophen-3-yl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester as a yellow gum; MS: m/e 393 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[C:10]([N:14]3[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[NH:16][C:15]3=[O:25])[C:11]([F:13])=[CH:12][C:7]=2[N:6]=[C:5]1[C:26]([F:29])([F:28])[F:27])[C:2]#[CH:3].[C:30](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:30][N:16]1[C:17]([C:21]([F:22])([F:23])[F:24])=[CH:18][C:19](=[O:20])[N:14]([C:10]2[C:11]([F:13])=[CH:12][C:7]3[N:6]=[C:5]([C:26]([F:27])([F:28])[F:29])[N:4]([CH2:1][C:2]#[CH:3])[C:8]=3[CH:9]=2)[C:15]1=[O:25]
Reactant: O=C([O-])[O-]
Reactant: C#CCn1c(C(F)(F)F)nc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: C#CCn1c(C(F)(F)F)nc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Yield: 69.1 %

Procedure:
A solution of 0.6 gram (0.001 mole) of 3-[1-(2-propyn-1-yl)-2-trifluoromethyl-5-fluorobenzimidazol-6-yl]-6-trifluoromethyluracil, 0.4 gram (0.003 mole) of potassium carbonate, and 0.17 mL (0.003 mole) of methyl iodide in 30 mL of acetone was stirred at ambient temperature for about 18 hours, after which the reaction mixture was concentrated under reduced pressure to a residue. The residue was taken up in diethyl ether and washed with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to an oily residue, which was subjected to column chromatography on silica gel. Elution was accomplished using 1:3 ethyl acetate:hexane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.3 gram of 1-methyl-3-[1-(2-propyn-1-yl)-2-trifluoromethyl-5-fluorobenzimidazol-6-yl]-6-trifluoromethyluracil, mp 104°-105° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:12]#[N:13]>CCOCC>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=1[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: COc1ccc(C#N)cc1Br
Solvent: CCOCC
Product: COc1ccc(C#N)cc1Oc1ccccc1

Procedure:
Phenol and 3-bromo-4-methoxybenzonitrile were subjected to Ullman ether coupling according to the procedure described in synthetic method 9 to afford product as a white solid: 1H NMR (CDCl3) δ 7.43 (dd, J=8.6, 2.0 Hz, 1H), 7.40-7.32 (m, 2H), 7.19-7.11 (m, 2H), 7.03 (d, J=8.6 Hz, 1H), 7.01-6.94 (m, 2H), 3.93 (s, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Br:7]N1C(=O)CCC1=O.BrCC1SC=CC=1.[C:22]1([P:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)(Cl)(Cl)Cl.O1CCCC1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br-:7].[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[CH2:1][P+:28]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1cccs1
Agent: BrCc1cccs1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: [Br-]
Product: c1ccc([P+](Cc2cccs2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 724.2 %

Procedure:
A mixture of 2-methylthiophene (10 g, 0.10 mol) and N-bromosuccinimide (18 g, 0.10 mol) in carbon tetrachloride (100 ml) was heated to reflux under nitrogen. Benzoyl peroxide (50 mg) was added and the mixture was refluxed for 3 hours. After cooling to room temperature the reaction was filtered and concentrated to a dark oil. The crude 2-bromomethylthiophene and triphenylphosphine (29 g, 0.011 mol) were dissolved in tetrahydrofuran (170 ml) under nitrogen and heated to reflux for 4 hours and then cooled to room temperature for precipitation. The product was collected by filtration, washed with ethyl ether (4×15 ml) and dried to afford (2-thienyl)methyl triphenylphosphonium bromide (35 g, 80%). m.p. 250° C.
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(#N)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].[OH2:27].[OH2:2].[OH2:2].[Na+:28].[Na+:28]
Reactant: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Reactant: [OH-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccnc(CS(=O)c2nc3cc(OC(F)F)ccc3[n-]2)c1OC
Product: O
Temperature: 30 °C

Procedure:
Pantoprazole free base (25 grams) was dissolved in a solution of acetonitrile (175 ml) and aqueous sodium hydroxide solution (2.7 grams in 5 ml of water) and stirred at a temperature of 25-35° C. till the clear solution results. The reaction solution was filtered through hyflow and washed the bed with acetonitrile (25 ml). Isopropyl ether (225 ml) was added slowly to the filtrate over a period of about ½ hour and the filtrate was stirred for about 1-2 hours to crystallize the solid mass. The separated solid mass was cooled to a temperature of 5-10° C. and further stirred for 3-4 hours. The solid was filtered, washed with Isopropyl ether (25 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: [NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[N:4]([CH2:10][O:11][C:12]([CH3:15])(C)C)[C:3]1=[O:16].C(O)[C:18]1[CH:23]=[CH:22]C=[CH:20][CH:19]=1.S(Cl)([Cl:27])=O>>[ClH:27].[NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[N:4]([CH2:10][O:11][CH2:12][C:15]2[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=2)[C:3]1=[O:16]
Reactant: CC1CCCC(N)C(=O)N1COC(C)(C)C
Reactant: OCc1ccccc1
Reactant: O=S(Cl)Cl
Product: CC1CCCC(N)C(=O)N1COCc1ccccc1
Product: Cl

Procedure:
Reaction of the major isomer of 3-amino-1-t-butoxymethyl-7-methylperhydroazepin-2-one with benzyl alcohol and thionyl chloride yields 3-amino-1-benzyloxymethyl-7-methylperhydroazepin-2-one hydrochloride, which after treatment with base, yields the free amino ester. Reaction of this amino ester as described in Example 37 affords the products of Formula I (R3, R5, R6 =H; R2 =CH3 ; R=OH) listed in Table IV.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:25]([C:26](=[O:29])[CH2:27][CH3:28])=[C:24]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Br:36])[CH:22]=3)[C:17]2=[O:37])=[CH:11][CH:10]=1)(=[O:8])=[O:7].CO.[OH-].[Na+].Cl>C1COCC1>[Br:36][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:37])[N:16]([CH2:15][C:12]1[CH:13]=[CH:14][C:9]([S:6]([NH:5][CH2:4][C:3]([OH:38])=[O:2])(=[O:8])=[O:7])=[CH:10][CH:11]=1)[C:25]([C:26](=[O:29])[CH2:27][CH3:28])=[C:24]2[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(=O)(=O)NCC(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(=O)(=O)NCC(=O)O)cc1
Yield: 48.3 %

Procedure:
To a mixture of [4-(6-bromo-1-oxo-4-phenyl-3-propionyl-1H-isoquinolin-2-ylmethyl)benzenesulfonylamino]acetic acid methyl ester (70 mg), methanol (2.0 ml) and THF (2.0 ml) was added 1N sodium hydroxide (0.23 ml) at room temperature with stirring, and the mixture was stirred at the same temperature for 18 hrs. The reaction mixture was neutralized with 1N hydrochloric acid and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (33 mg) in beige crystals. 1H NMR (CDCl3) δ: 0.52 (3H, t, J=6.9 Hz), 1.78 (2H, q, J=6.9 Hz), 3.82 (2H, d, J=6.0 Hz), 5.25-5.36 (3H, m), 7.23-7.31 (2H, m), 7.33 (2H, d, J=8.4 Hz), 7.44-7.55 (4H, m), 7.70 (1H, dd, J=1.8, 8.4 Hz), 7.80 (2H, d, J=8.4 Hz), 8.37 (1H, d, J=8.4 Hz). HPLC analysis: purity 95.2% (retention time: 4.38 min). MS (ESI+): 583 (M+H), 585.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.O=[C:17]([CH2:24][CH2:25][CH3:26])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([CH2:24][CH2:25][CH3:26])[NH:10][C:11]2=[N:12][NH:13][CH:14]=[C:15]12
Reactant: CCCC(=O)CC(=O)OCC
Reactant: O=Cc1ccccc1F
Reactant: Nc1cc[nH]n1
Product: CCCC1=C(C(=O)OCC)C(c2ccccc2F)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2-fluorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.