Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][N:12]=[CH:11]2)=[CH:5][CH:4]=1)#[N:2].[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1>C(#N)C>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:9]([N:10]2[CH:11]=[N:12][N:13]=[CH:14]2)[C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:18][CH:17]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Solvent: CC#N
Product: N#Cc1ccc(N(Cc2ccc(Br)cc2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
40 Milliliters of acetonitrile was added to 3.15 g of 4-[N-(4-cyanophenyl)amino]-4H-1,2,4-triazole, 4.25 g of 4-bromobenzyl bromide and 3.52 g of anhydride potassium carbonate and the mixture was stirred for 2 hours at room temperature. The solvent was removed by distillation under reduced pressure, and water was added to the residue formed, which was then extracted with chloroform. The chloroform layer separated was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography to give crude crystals from the chloroform/methanol (100/1) eluate. The crude crystals were recrystallized from ethanol to give 3.92 g of 4-[N-(4-bromobenzyl)-N-(4-cyanophenyl)amino]-4H-1,2,4-triazole.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH:3]=[O:4].[CH2:7]([Mg]Br)[CH:8]=[CH2:9]>C(OCC)C>[CH3:1][C:2]([CH3:6])([CH:3]([OH:4])[CH2:9][CH:8]=[CH2:7])[CH3:5]
Reactant: CC(C)(C)C=O
Reactant: C=CC[Mg]Br
Solvent: CCOCC
Product: C=CCC(O)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of trimethylacetaldehyde (10.2 mL, 90.9 mmol) in diethyl ether (200 mL) at 0° C. was added allylmagnesium bromide (100 mL, 1M in ether). The reaction mixture was stirred at 0° C. for 1 hour. The resulting mixture was quenched with saturated ammonium chloride and extracted with diethyl ether. The organic extracts were washed with brine, dried over Na2SO4 and filtered. The solvent was carefully removed under reduced pressure to afford the title compound;
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.Cl[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29]>CC(=O)CC.[I-].[K+]>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CC(C)(C)CCCCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)CCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Potassium carbonate (0.56 g, 4.8 mmol) was added to a solution of 4-bromo-4′-hydroxybiphenyl (0.80 g, 3.2 mmol) in butanone (50 ml) with potassium iodide (0.1 g) as catalyst. This mixture was left stirring at room temperature for 10 min and a solution of 1-chloro-7,7-dimethyloctance from step 6 (0.50 g, 2.8 mmol) in butanone (10 ml) was added dropwise. The reaction mixture was heated under reflux for 44 h. The mixture was filtered and butanone was removed from the filtrate under reduced pressure. The product was extracted into ether (2×75 ml) and the combined ethereal extracts were washed successively with water, 5% sodium hydroxide and water, and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by column chromatography [DCM] to give a white powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH2:11]([N:13]1[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[C:17](=[O:23])[N:16]([CH3:24])[C:15]2[CH:25]=[C:26]([CH2:29][N:30]([CH2:44][C:45]3[CH:52]=[CH:51][CH:50]=[CH:49][C:46]=3[CH:47]=O)[CH2:31][CH2:32][N:33]3[CH:38]=[CH:37][C:36]4[O:39][C:40]([CH3:42])=[CH:41][C:35]=4[C:34]3=[O:43])[CH:27]=[CH:28][C:14]1=2)[CH3:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O.ClCCCl>[CH2:11]([N:13]1[C:19](=[O:20])[C:18]([CH3:21])([CH3:22])[C:17](=[O:23])[N:16]([CH3:24])[C:15]2[CH:25]=[C:26]([CH2:29][N:30]([CH2:31][CH2:32][N:33]3[CH:38]=[CH:37][C:36]4[O:39][C:40]([CH3:42])=[CH:41][C:35]=4[C:34]3=[O:43])[CH2:44][C:45]3[CH:52]=[CH:51][CH:50]=[CH:49][C:46]=3[CH2:47][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:27]=[CH:28][C:14]1=2)[CH3:12]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3ccccc3C=O)ccc21
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CC(=O)O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3ccccc3CN3CCOCC3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Morpholine (0.06 ml) and acetic acid (0.1 ml) were added to a 1,2-dichloroethane solution (7 ml) of 2-({N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)benzaldehyde (0.35 g), and the mixture was stirred for 30 minutes at room temperature. Sodium triacetoxy borohydride (0.20 g) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction liquid, followed by extraction by dichloromethane. The organic layer was dried by anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:hexane=3:2). The purified product was condensed under reduced pressure to give the title compound (0.30 g) as a white amorphous solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]3[C:15]([C:18]([OH:20])=O)=[CH:16][N:17]=[C:11]3[CH:10]=2)[CH2:4][O:3]1.C(Cl)(=O)C(Cl)=O.[CH3:28][C:29]1[C:37]2[C:36]([NH2:38])=[CH:35][CH:34]=[CH:33][C:32]=2[N:31]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[N:41]=2)[N:30]=1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C=O>[CH3:21][C:2]1([CH3:1])[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]3[C:15]([C:18]([NH:38][C:36]4[CH:35]=[CH:34][CH:33]=[C:32]5[C:37]=4[C:29]([CH3:28])=[N:30][N:31]5[CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[N:41]=4)=[O:20])=[CH:16][N:17]=[C:11]3[CH:10]=2)[CH2:4][O:3]1
Reactant: CC1(C)OCC(COc2ccn3c(C(=O)O)cnc3c2)O1
Reactant: Cc1cccc(Cn2nc(C)c3c(N)cccc32)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(OCC6COC(C)(C)O6)ccn45)cccc32)n1
Reaction time: 8 h
Yield: 9.9 %

Procedure:
7-((2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (66 mg, 0.23 mmol) was dissolved in dichloromethane (1 mL) and 2 M oxalyl chloride in dichloromethane (0.12 mL, 0.25 mmol) was added with a drop of dimethylformamide. The mixture was stirred at ambient temperature for 1 hour before addition of 3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (57 mg, 0.23 mmol) and diisopropylethylamine (0.08 mL, 0.46 mmol), and then the mixture was stirred overnight. The crude mixture was purified using preparative thin layer chromatography (silica, 20×20 cm, 1 mm) developed in a chamber with 10% methanol/dichloromethane to give 7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (12 mg).
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([CH:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]3[N:22]=[C:21]([N:23]4[C:31]5[C:26](=[C:27]([O:32][CH2:33][CH2:34][CH2:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24]4)[CH:20]=[CH:19][N:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[C:40]([O:44][C:45](=[O:54])[NH:46][CH2:47]C1CCNCC1)([CH3:43])([CH3:42])[CH3:41].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C1COCC1>[C:40]([O:44][C:45](=[O:54])[NH:46][CH2:47][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([CH:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17]3[N:22]=[C:21]([N:23]4[C:31]5[C:26](=[C:27]([O:32][CH2:33][CH2:34][CH2:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24]4)[CH:20]=[CH:19][N:18]=3)[CH2:14][CH2:15]2)=[O:9])[CH2:4][CH2:3]1)([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: CS(=O)(=O)CCCOc1cccc2c1ccn2-c1ccnc(NC2CCC(C(=O)N3CCC(O)CC3)CC2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1CCN(C(=O)C2CCC(Nc3nccc(-n4ccc5c(OCCCS(C)(=O)=O)cccc54)n3)CC2)CC1

Procedure:
(4-hydroxy-piperidin-1-yl)-(4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanone (0.855 g, 2.116 mM) and piperidin-4-ylmethyl-carbamic acid t-butyl ester (0.907 g, 4.232 mM) were mixed in THF (40 mL) for approximately 2 h with diisopropylethylamine (1.47 mL, 8.464 mM) and BOP (1.87 g, 4.23 mM) to yield a fine solid that was purified on an alumina column with 1-3% MeOH/CH2Cl2, dried and extracted into EtOAc to yield [1-(4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarbonyl)-piperidin-4-ylmethyl]-carbamic acid t-butyl ester as a white powder upon drying in vacuo (0.856 g).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]3[CH2:16][CH2:15]3)[C:7]=12.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]3[CH2:16][CH2:15]3)[C:7]=12)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1c(C)n(CC2CC2)c2c(Cl)nncc12
Reactant: OCc1ccccc1
Product: Cc1c(C)n(CC2CC2)c2c(OCc3ccccc3)nncc12
Yield: 69.2 %

Procedure:
The title compound was prepared as a white powder in 69.2% yield in a similar procedure to that described in Example 1 by using 7-chloro-1-cyclopropylmethyl-2,3-dimethylpyrrolo[2,3-d]pyridazine and benzyl alcohol.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.CN(C)[CH:30]=[O:31]>O1CCCC1>[Cl:21][C:22]1[C:27]([CH:30]=[O:31])=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: CN(C)C=O
Reactant: Clc1ccccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1cccnc1Cl
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
Form a solution of lithium diisopropylamide by the adding n-butyl lithium (37.5 mL, 0.06 mol, 1.6 M in hexanes) to diisopropylamine (8.39 mL, 0.06 mol) in tetrahydrofuran (200 mL) at −10 to −20° C. under a nitrogen atmosphere. After stirring for 20 min., cool the mixture to −70° C. and add 2-chloropyridine (4.96 mL, 0.05 mol) dropwise via syringe and stir the mixture for 1 hour at this temperature. Add N,N-dimethylformamide (7.73 mL, 0.10 mol) dropwise via syringe and stir for 1 hour near −70° C. after which time remove the cooling bath and add a solution of aqueous 5N hydrochloric acid/tetrahydrofuran (5 ml125 mL) in a dropwise manner. Add water (200 mL) and warm the mixture to −10° C. Extract with ethyl acetate. Dry the combined extracts over sodium sulfate and concentrate in vacuo. Elute the resulting residue over silica gel using 10% ethyl acetate/hexanes allowing for isolation of the desired aldehyde (2.86 g, 40%) as a solid. MS(EI): (M)+ 140.2, 141.3, 143.3 m/z.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.IC1C=CC=CC=1.I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24]>>[CH3:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(C)cc(O)c1
Reactant: Cc1ccccc1I
Solvent: Ic1ccccc1
Product: Cc1cc(C)cc(Oc2ccccc2C)c1

Procedure:
Example 3.1 was repeated, replacing the phenol with 244 mg of 3,5-dimethylphenol (2 mmoles) and the iodobenzene with 383 μl of 2-iodotoluene (3 mmoles), and taking the reaction time to 118 hours.
Reaction SMILES: [C-]#[C-].[Na+].[Na+].COC1C=CC([C:13]2C=CS[C:14]=2[C:18]([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=O)=CC=1.CS(C)=[O:35]>>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([C:20]2[S:21][CH:13]=[CH:14][CH:18]=2)([OH:35])[C:23]#[CH:22])=[CH:30][CH:29]=1
Reactant: COc1ccc(-c2ccsc2C(=O)c2sccc2-c2ccc(OC)cc2)cc1
Reactant: CS(C)=O
Agent: [C-]#[C-]
Agent: [Na+]
Product: C#CC(O)(c1ccc(OC)cc1)c1cccs1

Procedure:
Sodium acetylide (1.37 g, 33.5 mmol) suspended in dry DMSO (25 ml) was added to p-methoxyphenyl-thiophene-2-yl-ketone (4.8 g, 22 mmol) in portions with stirring under water bath cooling while bubbling acetylene gas. After addition, the reaction mixture was stirred at room temperature for 2 hours, poured onto crushed ice, acidified with 4 M hydrochloric acid until the pH was approximately 6. After extraction with methylene chloride (20 ml, then 2×10 ml), the mixture was dried over anhydrous sodium sulfate and filtered. Evaporation of the solvent gave an oil that was purified by flush chromatography on neutral alumina (activity III) using hexane/methylene chloride (2:1) as eluent. De-coloration with a small amount of charcoal followed by removal of solvent afforded the relatively clean 1-(4methoxyphenyl)-1-(thiophene-2-yl)prop-2-yn-1-ol as yellow-brown oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:7]1[N:8]=[C:9]([O:33][CH3:34])[C:10]([N:13](COCC[Si](C)(C)C)[S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[Cl:24])(=[O:16])=[O:15])=[N:11][CH:12]=1>>[Cl:24][C:18]1[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=1[S:14]([NH:13][C:10]1[C:9]([O:33][CH3:34])=[N:8][C:7]([C:2]2[CH2:3][CH2:4][CH2:5][N:1]=2)=[CH:12][N:11]=1)(=[O:16])=[O:15]
Reactant: C1CCNC1
Reactant: COc1nc(Br)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Product: COc1nc(C2=NCCC2)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 55 using pyrrolidine (0.4 g) and N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (0.3 g). Yield 0.045 g.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:14]=1.[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>C1COCC1>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](=[O:31])[CH:19]([C:16]2[CH:15]=[CH:14][C:13]([S:12][CH3:11])=[CH:18][CH:17]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:28][CH:27]=1
Reactant: CCOC(=O)Cc1ccc(SC)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)c1ccc(F)cc1)c1ccc(SC)cc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
1 N Lithium bis(trimethylsilyl)amide (25 mL, 25 mmol) was added dropwise to a solution of ethyl 2-(4-(methylthio)phenyl)acetate (5.05 g, 24 mmol), prepared according to the method of Example 73A, in THF (20 mL) maintained at −78° C. After 15 minutes the mixture was treated dropwise with a solution of 4-fluorobenzoyl chloride (2.85 mL, 24 mmol) in THF (50 mL), and the resulting mixture was stirred at −78° C. for 90 minutes. The mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The acetate layer was washed with water, brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was triturated with hexanes:ether, 15:1, to provide the desired product (yield: 7.25 g; 90%). MS (DCI-NH3) m/z 333 (M+H)+, 350 (M+NH4)+; 1H NMR (300 MHz, DMSO) δ1.18 (m, 3H), 2.45 (s, 3H), 4.15 (m, 2H), 6.15 (s, 1H), 7.23 (m, 2H), 7.35 (m, 4H), 7.85 (d, J=9 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:16]=[N:15][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[Cl-].[Li+].CCN(C(C)C)C(C)C.C([Sn](CCCC)(CCCC)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)CCC.[F-].[K+]>CN(C=O)C.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>[N:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:2]1[CH:16]=[N:15][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: N#Cc1cc2c(cn1)[nH]c1ncc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cc2c(cn1)[nH]c1ncc(-c3ccccn3)cc12
Temperature: 165 °C
Yield: 6 %

Procedure:
A solution of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (150 mg, 0.549 mmol) and lithium chloride (69.9 mg, 1.65 mmol) in DMF (0.94 mL) was treated with DIPEA (239 μL, 1.37 mmol) and 2-(tributylstannyl)pyridine (607 μL, 1.65 mmol), and then degassed by the bubbling of nitrogen for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (31.7 mg, 27.5 μmol, 5.0 mol %) was added and the mixture heated at 165° C. for 15 h. The mixture was allowed to cool and treated with saturated aqueous potassium fluoride at ambient temperature. The resulting solids were removed by filtration and washed with 20% methanol in DCM and water. The filtrate was filtered through a pad of celite, washing with 20% methanol in DCM. The layers were separated, the aqueous phase extracted into 20% methanol in DCM, and the combined organic phases concentrated in vacuo to afford a solid residue. This solid was purified by preparative HPLC (0-30% MeCN/water modified with 0.1% formic acid) to afford an off-white solid powder (8.9 mg, 6.0%). 1H NMR (DMSO-D6, 400 MHz): 13.01 (s, 1H), 9.49 (d, J=2.2 Hz, 1H), 9.43 (d, J=2.2 Hz, 1H), 9.04 (dd, J=11.6, 0.8 Hz, 2H), 8.75 (d, J=4.0 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.98 (td, J=7.8, 1.8 Hz, 1H), 7.43 (dd, J=6.7, 4.9 Hz, 1H). LCMS (Method D): RT=7.26 min, M+H+=272.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:14][CH2:13][O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1C(O)=O.N1C2C(=CC=CC=2)C=CC=1>CCOCC>[CH2:13]1[O:14][C:8]2[CH:7]=[C:6]3[C:11]([C:2]([OH:1])=[CH:3][CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12]1
Reactant: O=C(O)c1cnc2cc3c(cc2c1O)OCO3
Solvent: c1ccc2ncccc2c1
Solvent: CCOCC
Product: Oc1ccnc2cc3c(cc12)OCO3
Temperature: 25 °C

Procedure:
A suspension of 50 g. of 4-hydroxy-6,7-methylenedioxyquinoline-3-carboxylic acid in 500 ml. of freshly distilled quinoline was heated at 200° until the evolution of gas ceased. The reaction mixture was cooled to room temperature, diluted with an equal amount of ether and kept cool overnight. The precipitated brown solid (51.4 g., m.p. 254°-267°) was collected by filtration and dissolved in refluxing ethanol. The insoluble material was removed and the ethanol solution was reduced to one-third of its volume. The solution was diluted with an equal amount of ether. On cooling, 31.1 g. of 6,7-methylenedioxy-4-quinolinol separated, m.p. 280°-282°. Recrystallization (2x) from hot water yielded analytically pure 6,7-methylenedioxy-4-quinolinol as a pale yellow solid, m.p. 288°-289° .
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[Cl:33][C:34]1[CH:35]=[C:36]([CH:66]=[CH:67][CH:68]=1)[C:37]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:54]=[C:53]3[C:49]([CH2:50][N:51]([CH:56]4[CH2:61][CH2:60][CH2:59][CH:58]([C:62]([O:64]C)=[O:63])[CH2:57]4)[C:52]3=[O:55])=[CH:48][CH:47]=2)=[CH:42][CH:41]=1)=[O:38]>>[Cl:33][C:34]1[CH:35]=[C:36]([CH:66]=[CH:67][CH:68]=1)[C:37]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:54]=[C:53]3[C:49]([CH2:50][N:51]([CH:56]4[CH2:61][CH2:60][CH2:59][CH:58]([C:62]([OH:64])=[O:63])[CH2:57]4)[C:52]3=[O:55])=[CH:48][CH:47]=2)=[CH:42][CH:41]=1)=[O:38]
Reactant: COC(=O)C1CCCC(N2Cc3ccc(-c4ccc(NC(=O)c5cccc(Cl)c5)cc4)cc3C2=O)C1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: O=C(Nc1ccc(-c2ccc3c(c2)C(=O)N(C2CCCC(C(=O)O)C2)C3)cc1)c1cccc(Cl)c1
Yield: 82 %

Procedure:
The compound of example 547 was prepared analogous to compound of example 98 by hydrolysis of compound of example 546.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[N:11]([CH2:32][CH3:33])[C:12](=[O:31])[CH2:13][C:14]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:17]=2[S:16](=[O:30])(=[O:29])[N:15]=1)=O)C.[O-]CC.[Na+]>C(O)C>[CH2:32]([N:11]1[C@@H:7]2[C@@H:6]([CH2:10][CH2:9][CH2:8]2)[C:4]([OH:3])=[C:13]([C:14]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:17]=3[S:16](=[O:29])(=[O:30])[N:15]=2)[C:12]1=[O:31])[CH3:33]
Reactant: CCOC(=O)C1CCCC1N(CC)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCN1C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)[C@@H]2CCC[C@@H]21
Temperature: 60 °C
Reaction time: 16 h
Yield: 23.9 %

Procedure:
A solution of the crude 2-{ethyl-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid ethyl ester in ethanol (20 mL) was treated with a 21% w/w solution of sodium ethoxide in ethanol (0.648 g) and stirred for 16 h at 60° C. Upon cooling, the reaction mixture was then quenched with 1.0 M aqueous hydrochloric acid solution (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered, and dried in vacuo. The residue was purified by prep-HPLC [Column ODS-A 5μ 100 Å, 150×21.2 mm, 5 micron, 50%-100% in 13.5 min @ 22 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, cis-N-[3-(1-ethyl-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl]-methanesulfonamide (54.3 mg, 0.120 mmol, 23.9% over two steps), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.08-1.30 (3H, m), 1.48-1.70 (4H, m), 1.99-2.24 (3H, m), 3.05 (3H, s), 3.64 (1H, bs), 3.87-4.45 (2H, m), 7.49-7.60 (3H, m), 10.16 (1H, s). LC-MS (ESI) calcd for C18H22N4O6S2 454.10, found 455.2 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].C1(C(C2C=CC=CC=2)(O)[C@H](C2C=CC=CC=2)O)C=CC=CC=1>C(C(C)=O)C(C)C>[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S@@:12]([C:13]2[NH:21][C:20]3[CH:19]=[C:18]([O:22][CH3:23])[CH:17]=[CH:16][C:15]=3[N:14]=2)=[O:24])=[N:4][CH:3]=1
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: O[C@@H](c1ccccc1)C(O)(c1ccccc1)c1ccccc1
Solvent: CC(=O)CC(C)C
Product: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of omeprazole (250 mg, 0.72 mmol) and (S)-1,1,2-triphenyl-1,2-ethanediol (315 mg, 1.08 mmol) was dissolved in a minimum volume of methyl isobutyl ketone (8 ml) at 90° C. On dissolution, the solution was cooled to ambient temperature slowly with vigorous stirring, and on reaching this temperature was stirred for a further 1 h. The precipitate was filtered, was washed with methyl isobutyl ketone (2×2 ml) and was dried in vacuo to afford (S)-omeprazole.2[(S)-1,1,2-triphenyl-1,2-ethanediol] inclusion complex (253 mg, 76%, 94% e.e.) as an off-white powder.