Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][CH3:9])=[N:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[C:4]([CH2:18][CH3:19])[N:3]=1.[CH2:20]([N:23]1[CH:27]=[CH:26][N:25]=[C:24]1[NH2:28])[CH2:21][CH3:22].C1(C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>O1CCOCC1.C([O-])(O)=O.[Na+].[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[C:5]1[N:6]=[C:7]([CH2:8][CH3:9])[C:2]([NH:28][C:24]2[N:23]([CH2:20][CH2:21][CH3:22])[CH:27]=[CH:26][N:25]=2)=[N:3][C:4]=1[CH2:18][CH3:19]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1Br
Reactant: CCCn1ccnc1N
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCCn1ccnc1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Temperature: 110 °C
Yield: 27.2 %

Procedure:
A mixture of 2-bromo-5-(2,4-dichlorophenyl)-3,6-diethylpyrazine (0.25 g, 0.69 mmol), 1-propyl-1H-imidazol-2-amine (0.15 g, 1.2 mmol), tris(dibenzylideneacetone) dipalladium (0.032 g, 0.032 mmol), 2-dicyclohexylphosphino)biphenyl (0.037 g, 0.12 mmol), and sodium tert-butoxide (0.093 g, 0.97 mmol) in dioxane (2.0 mL) was heated at 110° C. for 21 h. After cooling to rt, the reaction was diluted with saturated aqueous NaHCO3 and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40M) with (Biotage, 40S) with heptanes/EtOAc (3:1) to give 0.076 g (27%) of dark yellow oil: 1H NMR (400 MHz, CDCl3) δ 12.86, 7.47, 7.31, 6.70, 6.55, 3.94, 2.97, 2.48, 2.97, 2.48, 1.84, 1.30, 1.21, 0.98; IR (liq.) 2968, 2934, 1599, 1556, 1549, 1509, 1460, 1422, 1402, 1384, 1373, 1302, 1174, 1102, 712 cm−1; HRMS (FAB) calcd for C20H23Cl2N5+H 404.1408, found 404.1416.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:17]=[CH:16][C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:7][CH:6]=1.[OH-].[Li+]>O.C1COCC1>[C:12]([O:11][C:9]([C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:18])=[O:2])=[CH:17][CH:16]=1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)Cc1ccc(C(=O)OC(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
A solution of 4.2 g (16.78 mmol) of tert-butyl 4-(2-methoxy-2-oxoethyl)benzoate in 50 ml of water and 50 ml of THF is mixed with 0.8 g (33.6 mmol) of lithium hydroxide and stirred at room temperature for 1 hour. The phases are separated and the aqueous phase is adjusted to pH 3 with 2 M hydrochloric acid. It is extracted with ethyl acetate. The organic phase is then washed with sodium chloride solution, dried over sodium sulphate and evaporated. 3.6 g (15.2 mmol, 87% yield) of the title compound are obtained.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([N:37]([CH3:45])[CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])=[O:36])=[CH:31][CH:30]=1>>[CH:1]1([CH:7]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]([N:37]([CH3:45])[CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:36])=[CH:33][CH:34]=2)[C:9]2[C:10]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC(c1cn(-c2ccccc2)nc1CCc1ccccc1)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: CN(CCC(=O)O)C(=O)c1ccc(NC(c2cn(-c3ccccc3)nc2CCc2ccccc2)C2CCCCC2)cc1
Yield: 47.2 %

Procedure:
Using cyclohexyl[1-phenyl-3-(2-phenylethyl)-1H-pyrazol-4-yl]methanol (0.50 g) synthesized in Example 15(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.35 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.37 g, 47%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].Cl.[Cl:13][CH2:14][C:15](=N)OCC>C(O)C>[Cl:13][CH2:14][C:15]1[O:11][C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[N:1]=1
Reactant: CCOC(=N)CCl
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])c1ccc2oc(CCl)nc2c1

Procedure:
2-Amino-4-nitrophenol (10 g, 65 mmole) and ethyl chloroacetimidate hydrochloride (15.4 g, 97.5 mmole) were heated at reflux temperature in ethanol (100 ml) for 18 hours. The solvent was then removed by evaporation in vacuo and the residue recrystallised from ethanol to give the title compound, yield 9.0 g, m.p. 216°-217°.
Reaction SMILES: Cl[O-:2].[Na+:3].[OH-].[Na+].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[C:22]([O:25][CH:26]([F:28])[F:27])[CH:23]=[CH:24][C:18]=3[N:17]=2)[C:9]=1[O:29][CH3:30]>>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S+:15]([O-:2])[C:16]2[N-:17][C:18]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:27])[F:28])=[CH:21][C:19]=3[N:20]=2)[C:9]=1[O:29][CH3:30].[Na+:3]
Reactant: COc1ccnc(CSc2nc3ccc(OC(F)F)cc3[nH]2)c1OC
Reactant: [O-]Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[n-]2)c1OC

Procedure:
The intermediates (V) pantoprazole sulfide and pantoprazole base as shown in the scheme were not isolated during the process of the present invention. In particular, they were not subjected to any purification. Further, the pantoprazole sulfide obtained in situ was oxidized using aqueous sodium hypohalite solution preferably an aqueous solution of sodium hypochlorite with a strength from 2-14%, and having a sodium hydroxide content from 0.5 to 10%, more preferably from 1.0 to 3.0%. We prefer that the sodium hydroxide content is at least 2%. Most preferably, the sodium hydroxide content is from 2.0 to 2.3%. The oxidation of the pantoprazole sulfide is preferably carried out at a temperature ranging from 0° C. to ambient temperature, more preferably 5-8° C. The resulting reaction mass was cooled to afford pantoprazole sodium.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11]O.P(Br)(Br)[Br:14].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Br:14][CH2:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cc([N+](=O)[O-])ccc1CO
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])ccc1CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
To a solution of (2-methyl-4-nitrophenyl)methanol (2 g, 12 mmol) in DCM (25 ml) in an ice-water bath under nitrogen was added a solution of phosphorous tribromide (1.13 ml, 12 mmol, Aldrich) in DCM (20 ml). The resulting solution was allowed to warm to ambient temperature and stirred for 2 h. The reaction mixture was poured onto ice-water (70 ml) and saturated sodium hydrogen carbonate (30 ml). The mixture was diluted with DCM (50 ml) and the phases separated. The aqueous extract was washed with DCM (20 ml). The combined organic extracts were washed with water (50 ml), dried (MgSO4), filtered and the solvent removed in vacuo to leave 1-(bromomethyl)-2-methyl-4-nitrobenzene as a yellow solid (1.5 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8][CH:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH:14]=[CH:15][CH:16]=2)[CH3:10])[CH:5]=[CH:4][C:3]=1[O:27][CH2:28][C:29]([O:31]CC)=[O:30].[OH-].[Na+]>O1CCOCC1>[CH3:1][C:2]1[CH:7]=[C:6]([S:8][CH:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=3)[CH:14]=[CH:15][CH:16]=2)[CH3:10])[CH:5]=[CH:4][C:3]=1[O:27][CH2:28][C:29]([OH:31])=[O:30]
Reactant: CCOC(=O)COc1ccc(SC(C)c2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(SC(C)c2cccc(-c3ccc(C(F)(F)F)cc3)c2)ccc1OCC(=O)O
Yield: 98.5 %

Procedure:
A mixture of ethyl {[2-methyl-4-({1-[4′-(trifluoromethyl)-3-biphenylyl]ethyl}thio)phenyl]oxy}acetate (235 mg, 0.50 mmol) in dioxane (6 mL) was treated with aqueous NaOH (0.5N, 2.0 mL, 1.00 mmol) and the mixture heated at reflux for 1 hour. The resulting mixture was then cooled and treated with Dowex 50WX2 (pre-washed with dioxan), filtered and washed with more dioxan and reduced to give the title compound as a colourless gum (220 mg).
Reaction SMILES: N1CCCCC1.[OH:7][C:8]1[CH:17]=[CH:16][C:11]([CH:12]=[CH:13][CH:14]=O)=[CH:10][C:9]=1[O:18][CH3:19].[C:20]([CH2:22][C:23]([N-:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])#[N:21]>C(O)C>[CH2:26]([NH:25][C:23](/[C:22](=[CH:14]/[CH:13]=[CH:12]/[C:11]1[CH:16]=[CH:17][C:8]([OH:7])=[C:9]([O:18][CH3:19])[CH:10]=1)/[C:20]#[N:21])=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N#CCC(=O)[N-]Cc1ccccc1
Reactant: COc1cc(C=CC=O)ccc1O
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(/C=C/C=C(\C#N)C(=O)NCc2ccccc2)ccc1O

Procedure:
The compound was prepared as described in Example 37 by adding piperidine to a solution of 4-hydroxy-3-methoxycinnamaldehyde (35 mg, 0.2 mmol) and N-(cyanoacetyl)benzylamide (34 mg, 0.2 mmol) in ethanol. After recrystallization from ethanol-water a yellow solid was obtained (50 mg, 75%). The product gave the following analytical data:
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][C:22]1[N:23]=[C:24]([CH3:27])[O:25][CH:26]=1>CN(C=O)C.O>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:21][C:22]2[N:23]=[C:24]([CH3:27])[O:25][CH:26]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(Br)c12
Reactant: Cc1nc(CBr)co1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)co1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.6 %

Procedure:
A suspension of 3-bromo-4-nitro-1H-indazole (Preparation B; 500 mg, 2.07 mmol) and K2CO3 (1.14 g, 8.26 mmol) in anhydrous DMF (3 mL) was treated at ambient temperature, under a nitrogen atmosphere, with a solution of 4-(bromomethyl)-2-methyloxazole (727 mg, 2.07 mmol) (Org. Biom. Chem., 2003, 1, 4173-4208) in anhydrous DMF (2 mL). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with excess water and extracted multiple times with DCM and EtOAc. The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product (0.5 g). The material was purified by preparative thin-layer chromatography (silica, 5% MeOH-DCM as eluent) to afford the product (304 mg) as a solid.
Reaction SMILES: [NH3:1].[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]=[C:10]=[S:11])#[N:3]>O1CCOCC1>[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH2:1])=[S:11])#[N:3]
Reactant: N#CCCCCCN=C=S
Reactant: N
Solvent: C1COCCO1
Product: N#CCCCCCNC(N)=S
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0.5M solution of ammonia in dioxane (80 ml) at 10° C. was added 5-cyanopentyl isothiocyanate (5 g) and the solution was stirred at room temperature overnight. TLC of the reaction mixture still showed the presence of some starting material. Additional ammonia in dioxane (40 ml) was added and the solution was stirred for a further 6 hours. At this stage, the reaction was found to be complete as judged by TLC analysis. The solvent was then removed on a rotary evaporator and to the residue was added methyl tert-butyl ether (40 ml). The mixture was then heated on steam bath briefly (the solid did not dissolve) then cooled to give the required product as a colorless crystalline material (5 g), m.p. 69-71° C.
Reaction SMILES: O[CH2:2][C:3]1[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[C:6]([O:14][CH3:15])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O.[SH:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>C(Cl)Cl.O>[CH3:15][O:14][C:6]1[C:7]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:8]=2[C:3]([CH2:2][S:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:4][CH:5]=1
Reactant: Sc1ccncc1
Reactant: COc1ccc(CO)c2c1OC(C)(C)C2
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CSc2ccncc2)c2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
Compound 48a (2.0 g) obtained in Step A was dissolved in methylene chloride (100 ml), and then diisopropylethylamine (5.0 ml) and methanesulfonyl chloride (0.8 ml) were added thereto, followed by stirring at room temperature for one hour. At the same temperature, 4-mercaptopyridine (1.4 g) was added to the reaction solution, and the mixture was stirred for 30 minutes. Water was added to the reaction solution and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=30/1) to give Compound 48 (1.4 g, 48.3%) as colorless crystals.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:14])=[CH:5]1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH-:24].[Na+]>C1COCC1.C(OCC)C>[OH:24][CH2:3][CH2:2][CH2:1][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:14])=[CH:5]1
Reactant: [OH-]
Reactant: C=CCn1cc(C=O)c2ccccc21
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1cn(CCCO)c2ccccc12

Procedure:
In a 10 mL round-bottom flask, 1-Allyl-1H-indole-3-carbaldehyde (169 mg, 0.91 mmol) is dissolved in 0.5 mL of anhydrous THF. To this solution is added 0.5 M of 9-BBN in THF (2 mL, 1.0 mmol). The reaction is allowed to stir at room temperature for 1 hr, whereupon a 1M solution of NaOH (2.5 mL) is added. The organic layer is diluted with 10 mL of diethyl ether and the aqueous layer is removed. The organic layer is washed 3×10 mL with 1M NaOH, followed by 2×10 mL water and 2×10 mL saturated NaCl solutions. The organic layer is then dried over Na2SO4 and the solvent is removed under reduced pressure to afford 1-(3-hydroxy-propyl)-1H-indole-3-carbaldehyde.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH:14]=[C:15]([C:18]([O:20]CC)=[O:19])[C:16]([OH:17])=[C:10]2[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(C(F)(F)F)=O>C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16]([OH:17])=[C:10]2[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn2c(c1O)C(=O)N(Cc1ccccc1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: O=C(O)c1cn2c(c1O)C(=O)N(Cc1ccccc1)CC2
Temperature: 100 °C

Procedure:
A mixture of ethyl 2-benzyl-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo-[1,2-α]pyrazine-7-carboxylate (0.30 g; see Example 1) and aqueous sodium hydroxide (1 M, 2 mL) in ethanol (20 mL) was heated in a sealed tube at 100° C. overnight. The product mixture was acidified with addition of TFA and concentrated under vacuum. The residue was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: I[CH:2]([CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[C:3]([OH:5])=[O:4].CCN(CC)CC>C(Cl)Cl.Cl>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([S:7]([CH:6]=[CH:2][C:3]([OH:5])=[O:4])(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: COc1ccc(S(=O)(=O)CC(I)C(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)C=CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.3 %

Procedure:
2-Iodo-3-(4-methoxyphenylsulfonyl)propionic acid (4.23 grams, 11.43 mmol) and Et3N (3.22 ml, 2.34 grams, 23.09 mmol) were combined in methylene chloride (150 ml) and stirred overnight at room temperature. The reaction mixture was diluted with 1N hydrochloric acid(aq) (100 ml). The separated aqueous layer was extracted with Et2O (2×). The dried (MgSO4) combined organics were then filtered and concentrated in vacuo to give 2.58 grams of crude product. This was filtered, the filtrate concentrated and the residue taken up in methanol, filtered and the filtrate concentrated to give 1.87 grams of crude product. This was taken up in hot methylene chloride. Fine crystals crashed out. Decanted filtrate. Washed crystals methylene chloride (2×1 ml) (decanted washings). Dried crystals on high vac to give 0.396 grams of 3-(4-Methoxyphenylsulfonyl)propenoic acid as a pale yellow solid (m.p.: 123°-128.5° C.). The filtrate was concentrated to give 1.42 grams of yellow solid which was flash chromatographed (60% EtOAc/hexane/2%/HOAc/0.5% methanol) to give 1.42 grams of 3-(4-Methoxyphenylsulfonyl)propenoic acid. A second chromatography (40% EtOAc/hexane/2%/HOAc/0.5% methanol) gave 0.568 grams of pure 3-(4-Methoxyphenylsulfonyl)propenoic acid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5]([CH3:10])[N:4]=1.[CH3:11]OS(OC)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[CH3:11][O:9][C:8]1[C:3]([CH2:2][OH:1])=[N:4][C:5]([CH3:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(O)c(CO)n1
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COc1ccc(C)nc1CO
Yield: 84.9 %

Procedure:
To a solution of 2-(hydroxymethyl)-6-methylpyridin-3-ol (1.23 g, 8.84 mmol) in acetone (25 mL) was added Me2SO4 (1 mL, 10.6 mmol), followed by Cs2CO3 (3.6 g, 11.05 mmol). The reaction was refluxed for 2 h. The reaction was filtered and concentrated to give a red oil which was purified by column chromatography on ISCO (40 g) with 0-80% ethyl acetate in hexanes over 25 minutes to yield (3-methoxy-6-methylpyridin-2-yl)methanol(1.15 g, 85% yield) as a off-white solid. HPLC retention time (Method B)=0.17 min. 1H NMR (CDCl3, 400 MHz) δ ppm 2.49 (s, 3H), 3.83 (s, 3H), 4.45 (s, 1H), 4.70 (s, 2H), 7.03 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH:15][CH3:16])[C:12]([N+:17]([O-])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>CO.[Zn]>[NH2:17][C:12]1[C:13]([NH:15][CH3:16])=[N:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1
Reactant: CNc1nc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: CNc1nc(OCc2ccccc2)ccc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
21.4 g of zinc were added to a solution of 8.50 of 6-benzyloxy-2-methylamino-3-nitropyridine (prepared as described in Preparation 92) in 360 ml of methanol, and then 8.5 ml of acetic acid were added dropwise. The resulting mixture was then stirred at room temperature for one hour. At the end of this time, the reaction mixture was filtered to remove insoluble material. The filtrate was freed from the solvent by distillation under reduced pressure, and the resulting residue was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure, to give 7.50 g of the title compound having Rf=0.63 (on silica gel thin layer chromatography using ethyl acetate as the developing solvent).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:4][OH:5].N1C=CN=C1.[C:21]([Si:25](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl>[Si:25]([O:5][CH2:4][CH:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:11])([CH3:10])[CH3:12])[C:2]([F:14])([F:15])[F:1])([C:21]([CH3:24])([CH3:23])[CH3:22])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC(CO)C(F)(F)F
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(F)(F)F
Yield: 94 %

Procedure:
To a stirred solution of 340 (240 mg, 1.047 mmol) in DCM (3 mL) at 0° C. under nitrogen was added solid imidazole (71.29 mg, 1.047 mmol) followed by tert-butylchlorodiphenylsilane (272.3 μL, 1.047 mmol) neat by syringe. After 4 h the reaction was diluted to 30 mL with DCM and was washed 2N HCl (2×30 mL) and satd. aq. NaHCO3 (2×30 mL). The organic phase was isolated, dried (MgSO4), filtered and concentrated to afford 460 mg (94%) of tert-butyl 3-(tert-butyldiphenylsilyloxy)-1,1,1-trifluoropropan-2-ylcarbamate a white solid (342).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]2[NH:12][CH:13]=[C:14]([NH:15][C:16]([C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)=[O:17])[C:3]=12.[NH:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]1>CCCCO>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[C:16]([NH:15][C:14]1[C:3]2[C:4](=[N:5][CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]=2[N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:25]2)[NH:12][CH:13]=1)=[O:17]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=C(Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12)c1cnccn1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(C(F)(F)F)cnc3[nH]cc(NC(=O)c4cnccn4)c23)C1
Temperature: 155 °C
Yield: 35.3 %

Procedure:
N-(4-Chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazine-2-carboxamide (0.230 g, 0.673 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (0.404 g, 2.02 mmol) were placed in n-BuOH (3 mL) and heated to 155° C. for 18 hours in a sealed tube. The reaction was then cooled to room temperature and concentrated to dryness. The resulting residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 5-75% CH3CN/water gradient; 25 CV) to give (R)-tert-butyl 1-(3-(pyrazine-2-carboxamido)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.120 g, 35% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])[C:5]([Cl:23])=[CH:4][N:3]=1.[NH2:24][C:25]1[C:26]([O:38][CH3:39])=[CH:27][C:28]2[N:34]([CH3:35])[C:33](=[O:36])[O:32][CH2:31][CH2:30][C:29]=2[CH:37]=1>>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])=[N:7][C:2]([NH:24][C:25]2[C:26]([O:38][CH3:39])=[CH:27][C:28]3[N:34]([CH3:35])[C:33](=[O:36])[O:32][CH2:31][CH2:30][C:29]=3[CH:37]=2)=[N:3][CH:4]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCOC(=O)N2C
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCOCC4)cc3OC)n1)CCOC(=O)N2C
Yield: 49 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine and 2-Amino-3-methoxy-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one. Product isolated as an off-white powder (45 mg, 49%). mp: 242-245° C., MS (ESI+): 541 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.24 (s, 1H), 8.04 (s, 1H), 7.73 (s, 1H), 7.66 (s, 1H), 7.38 (d, J=8 Hz, 1H), 6.96 (s, 1H), 6.69 (s, 1H), 6.50 (s, 1H), 4.25 (t, 2H), 3.84 (s, 3H), 3.76 (br s, 8H), 3.26 (s, 3H), 3.14 (br s, 4H), 2.60 (t, 2H).