Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20]([OH:22])=[O:21])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:32]O>>[CH3:32][O:21][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=1[NH:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=2)=[CH:12][CH:13]=1
Reactant: Nc1ccc(CCCc2ccc(Nc3ccccc3C(=O)O)cc2)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1Nc1ccc(CCCc2ccc(N)cc2)cc1

Procedure:
To a solution of 2-{4-[3-(4-aminophenyl)propyl]phenylamino}benzoic acid (Example 159) (2.34 g, 6.75 mmol) in MeOH (50 mL) was added concentrated H2SO4 (1.0 mL) at room temperature. The mixture was stirred under reflux for 3.0 days. The reaction was quenched with Et3N (10 mL) at 5° C., and the solvent was removed under reduced pressure. The residue was diluted with water (20 mL) and extracted with Et2O (20 mL, 4 times). The combined ether layer was washed with water (10 mL) and brine (10 mL), and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and purification by column chromatography afforded crude title compound as a yellow amorphous material (2.59 g). This material was used without further purification.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[CH:6][C:5]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])=[N:4]1.[F:15][C:16]([F:25])([F:24])[CH2:17][CH2:18][CH:19]([C:22]#[N:23])[C:20]#[N:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:13][C:8]([F:14])([C:5]1[CH:6]=[CH:7][N:3]([CH2:2][C:19]([CH2:18][CH2:17][C:16]([F:15])([F:24])[F:25])([C:20]#[N:21])[C:22]#[N:23])[N:4]=1)[C:9]([F:12])([F:11])[F:10]
Reactant: FC(F)(F)C(F)(F)c1ccn(CCl)n1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1ccc(C(F)(F)C(F)(F)F)n1
Yield: 42.4 %

Procedure:
2.01 g of 1-(chloromethyl)-3-(pentafluoroethyl)-1H-pyrazole and 1.39 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 25 ml of N,N-dimethylformamide. 2.38 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.31 g of {[3-(pentafluoroethyl)-1H-pyrazole-1-yl]methyl}(3,3, 3-trifluoropropyl)malononitrile (referred as the compound of the present invention (36), hereinafter) shown by below formula.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CN(OC)[C:9](=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH:11]=1>O1CCCC1>[CH2:20]([NH:19][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[N+:16]([O-:18])=[O:17])[CH:9]=[O:24])[CH:21]([CH3:23])[CH3:22]
Reactant: CON(C)C(=O)c1ccc([N+](=O)[O-])c(NCC(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CNc1cc(C=O)ccc1[N+](=O)[O-]
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
Add lithium aluminum hydride (4.4 mL, 1 M in tetrahydrofuran) dropwise to a solution of N-[methyl]-N-[methoxy]-3-(isobutylamino)-4-nitrobenzamide (1.18 g, 4.2 mmol) in 20 mL of dry tetrahydrofuran at −78° C. Warm the mixture to −30° C. over 2 hours, and then to 0° C. over 30 minutes. Cool to −70° C. and carefully quench with 30 mL 5% aqueous potassium hydrogensulfate, warm to 0° C., and dilute with ethyl acetate. Separate the phases, dry the organic phase over magnesium sulfate and concentrate under reduced pressure to provide the desired benzaldehyde (70%).
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)[CH2:8]1)(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+]>CC(N(C)C)=O.C(OCC)(=O)C>[N:20]([CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)[CH2:8]1)=[N+:21]=[N-:22]
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)cc2)C(=O)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(I)cc2)C(=O)O1
Temperature: 80 °C
Yield: 81.2 %

Procedure:
[(5R)-3-(4-Iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl methanesulfonate (27 g, 68 mmol) was dissolved in dimethylacetamide (300 ml). Sodium azide (13.1 g, 202 mmol) was carefully added, and the solution was heated to 80° C. for 3 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (500 ml), washed with water (2×), brine, and dried over sodium sulfate. Flash chromatography with 0-1% methanol in dichloromethane as eluent gave the desired product (19 g).
Reaction SMILES: Cl[CH:2]([C:12]1[CH:17]=[C:16]([CH:18]2[C@H:23]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:22]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@H:21]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C@@H:20]([CH2:48][O:49][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[O:19]2)[CH:15]=[CH:14][C:13]=1[Cl:57])[C:3]1[N:4]=[N:5][C:6]([O:9][CH2:10][CH3:11])=[CH:7][CH:8]=1.CC(N=NC(C#N)(C)C)(C#N)C.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:57][C:13]1[CH:14]=[CH:15][C:16]([CH:18]2[C@H:23]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:22]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@H:21]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C@@H:20]([CH2:48][O:49][CH2:50][C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[O:19]2)=[CH:17][C:12]=1[CH2:2][C:3]1[N:4]=[N:5][C:6]([O:9][CH2:10][CH3:11])=[CH:7][CH:8]=1
Reactant: CCOc1ccc(C(Cl)c2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)nn1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCOc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)nn1
Temperature: 80 °C

Procedure:
To a solution of 3-(chloro(2-chloro-5-((3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)phenyl)methyl)-6-ethoxypyridazine (589 mg; 0.73 mmol) in anhydrous toluene (10 mL) was added catalytic amounts of AIBN and tributyltin hydride (0.3 mL; 1.10 mmol) at room temperature under nitrogen gas. The reaction solution was then heated at 80° C. until reaction was completed. The solution was coded to room temperature and toluene was removed on evaporator. The crude α/β mixture was purified by silica gel column chromatography with KF pad (eluent: hexane/EtOAc mixture (60/40; v/v)). The purified α/β mixture was separated by using Gilson prep HPLC system and then obtained α configured product (123 mg; 0.16 mmol) and β configured product (105 mg; 0.14 mmol) as colorless oil.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[NH2:8].[CH2:10]([NH2:13])[CH2:11][CH3:12]>>[Cl:9][C:6]1[C:7]([NH2:8])=[C:2]([NH:13][CH2:10][CH2:11][CH3:12])[N:3]=[N:4][CH:5]=1
Reactant: CCCN
Reactant: Nc1c(Cl)cnnc1Cl
Product: CCCNc1nncc(Cl)c1N
Temperature: 125 °C
Yield: 35 %

Procedure:
A mixture of 3,5-dichloro-4-aminopyridazine (Preparation 4, 2 g, 12.3 mmol) and 70% aqueous propylamine (8 mL) was heated at 125° C. in an autoclave vessel for 5 hours. The reaction mixture was cooled to room temperature and evaporated to dryness. The crude residue was purified by silica gel column chromatography eluting with CH2Cl2:MeOH 98:2 to afford the title compound as a brown solid in 35% yield, 800 mg.
Reaction SMILES: [CH3:1][C@@H:2]1[N:5]([P:6](=[O:10])([O-:9])[O:7][CH3:8])[C:4](=[O:11])[C@H:3]1[NH:12]C(OC(C)(C)C)=O.[K].[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C1(OC)C=CC=CC=1>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[NH2:12][C@H:3]1[C@H:2]([CH3:1])[N:5]([P:6](=[O:9])([OH:10])[O:7][CH3:8])[C:4]1=[O:11]
Reactant: COP(=O)([O-])N1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]1C
Agent: [K]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COP(=O)(O)N1C(=O)[C@@H](N)[C@@H]1C
Reaction time: 1.25 h

Procedure:
(3S-trans)-[4-Methyl-2-oxo-3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-azetidinyl]phosphonic aicd, methyl ester, potassium salt (300 mg) suspended in dry anisole (0.3 ml), under a nitrogen atmosphere, was cooled to 0°-5° C. and trifluoracetic acid (3 ml) was added while stirring. After 1.25 hours, trifluoroacetic acid was removed in vacuo without heating and residual acid was chased under reduced pressure with toluene. The residual oil was solidified and triturated with ether yielding a powder.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]1([CH:32]=O)[CH2:31][CH2:30]1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][CH:29]3[CH2:31][CH2:30]3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=CC1CC1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCC4CC4)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and cyclopropanecarbaldehyde. MS (ESI) m/z 433.
Reaction SMILES: Cl[CH:2]1[C:11]2[C:6](=[C:7]([O:12][C:13]3[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=3)[CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.[S-:23][C:24]#[N:25].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[CH3:22][O:21][C:15]1[CH:16]=[C:17]([O:19][CH3:20])[N:18]=[C:13]([O:12][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[C:4](=[O:5])[O:3][CH:2]3[S:23][C:24]#[N:25])[N:14]=1
Reactant: N#C[S-]
Reactant: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3Cl)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3SC#N)n1

Procedure:
A mixture of 1.4 g of 3-chloro-7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-phthalide (see Example 85) and 0.46 g of potassium thiocyanate is heated in the presence of a spatula tip of 18-crown-6 in 15 ml of acetonitrile for 4 hours. The mixture is then filtered through Celite®, concentrated by evaporation and chromatographed with 30% ethyl acetate/n-hexane to yield 7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-3-thiocyano-phthalide in the form of light-yellow crystals, m.p. 161°-163° C.
Reaction SMILES: [O-]CC.[Na+].[Na].[F:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.Br[CH2:15][CH:16]([CH3:19])[CH2:17][Cl:18]>C(O)C>[Cl:18][CH2:17][CH:16]([CH3:19])[CH2:15][O:13][C:10]1[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=1
Reactant: CC(CCl)CBr
Reactant: Oc1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CC(CCl)COc1ccc(F)cc1
Reaction time: 0.25 h

Procedure:
To a stirred sodium ethoxide solution, prepared starting from 3.5 parts of sodium in 24 parts of ethanol, were added 16.8 parts of 4-fluorophenol. After stirring for 15 minutes, there was added dropwise a solution of 77 parts of 1-bromo-3-chloro-2-methylpropane in 72 parts of ethanol at room temperature. Upon completion, stirring was continued for 20 hours at reflux temperature. The reaction mixture was filtered and the filtrate was evaporated. The residue was taken up in 2,2'-oxybispropane. The organic phase was washed with water and with alkaline water 5%, dried, filtered and evaporated. The residue was distilled, yielding 11.6 parts of 1-(3-chloro-2-methylpropoxy)-4-fluorobenzene; bp. 126° C. (water-jet) (intermediate 82).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[O-]CC.[Na+].[O:20]=[C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:22]=[CH2:23].Cl>C(O)C.O>[O:20]=[C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:22][CH2:23][CH:6]([C:4](=[O:5])[C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[Cl:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: C=CC(=O)CCCCCCC
Reactant: CCOC(=O)CC(=O)c1ccccc1Cl
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCCC(=O)CCC(C(=O)OCC)C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
To a stirred solution of 0.91 g of ethyl 2-chlorobenzoylacetate in 10 cc of ethanol was added 0.27 g of sodium ethoxide at room temperature, and the mixture was stirred at room temperature for 10 minutes. Then, 0.62 g of 3-oxo-1-decene in 10 cc of ethanol was added and the resulting mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the aqueous layer was acidified with 1N HCl and extracted three times with ethyl acetate. The combined organic layer was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the crude product thus obtained was purified by a silica gel column chromatography (eluent: ethyl acetate/hexane =1/9) to obtain 0.90 g of compound I. Yield: 59.1%.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:11])=[N:8][C:9]=1[CH3:10].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:11][S:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:12])([F:24])[F:25])[CH:15]=2)(=[O:22])=[O:21])=[N:8][C:9]=1[CH3:10]
Reactant: COCc1ccc(N)nc1C
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: COCc1ccc(NS(=O)(=O)c2cccc(C(F)(F)F)c2)nc1C

Procedure:
This material was prepared in analogy to example 1 from 5-methoxymethyl-6-methyl-pyridin-2-ylamine (0.058 g) and 3-(trifluoromethyl)-benzenesulfonyl chloride (0.103 g) as a light yellow gum (0.1 g). MS (ESI−): 359.0 ([M−H]−)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[C:4]([N+:10]([O-])=O)[C:3]=1[O:13][CH3:14]>CO>[Cl:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([NH2:10])[C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1
Reactant: COc1c(Cl)cc(C)c(C)c1[N+](=O)[O-]
Solvent: CO
Product: COc1c(Cl)cc(C)c(C)c1N
Reaction time: 15 h

Procedure:
1-Chloro-2-methoxy-4,5-dimethyl-3-nitro-benzene (10.0 g, 46.4 mmol; Stachel et. al., J. Org. Chem. 1997, 46, 4756) is dissolved in MeOH (200 mL) in a 500 mL round bottom flask. The flask is purged with N2 and 10% Pd on Carbon (0.7 g) is added and the reaction is again purged with N2. The reaction is purged with H2 and rapidly stirred for 15 h. The major product is the desired product from partial reduction. The reaction is filtered on celite and washed with MeOH and concentrated. Overreduction (des-chloro) product is filtered off as a solid from partially dissolving the crude reaction mixture in EtOH and MeOH to provide 3-chloro-2-methoxy-5,6-dimethyl-phenylamine which is used without further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[C:10]([C:20]3[CH:21]=[C:22]4[CH:28]=[CH:27][NH:26][C:23]4=[N:24][CH:25]=3)=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[CH:13]=2)[CH:6]=[CH:5][N:4]=1.[H-].[Na+].[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C>[C:31]1([S:37]([N:26]2[C:23]3=[N:24][CH:25]=[C:20]([C:10]4[C:9]([C:7]5[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=5)=[CH:13][N:12]([CH:14]5[CH2:19][CH2:18][CH2:17][CH2:16][O:15]5)[N:11]=4)[CH:21]=[C:22]3[CH:28]=[CH:27]2)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CSc1nccc(-c2cn(C3CCCCO3)nc2-c2cnc3[nH]ccc3c2)n1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nccc(-c2cn(C3CCCCO3)nc2-c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)n1
Temperature: 25 °C

Procedure:
To a solution of the 5-[4-(2-Methylsulfanyl-pyrimidin-4-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-1H-pyrrolo[2,3-b]pyridine (C-1-1) (870 mg, 2.22 mmol) in DMF (10 mL) at 25° C. was added Sodium Hydride (60% dispersion in oil, 133 mg, 3.32 mmol). The resulting suspension was stirred at ambient temperature for a few minutes until gas evolution ceased. Benzenesulfonyl chloride (0.4 mL, 3.13 mmol) was added and the mixture became cloudy. After stirring at ambient temperature for 15 minutes, LCMS showed complete conversion to desired product. The mixture was added slowly to 150 ml of saturated aqueous NaCl. The resulting precipitate was filtered, washed with water, and air dried. The solids were dissolved in dichloromethane, dried over MgSO4 and reduced to minimum volume. The residue was purified on a short column of silica gel using a gradient of 0-20% ethyl acetate in dichloromethane as eluent to give 1-Benzenesulfonyl-5-[4-(2-methylsulfanyl-pyrimidin-4-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-1H-pyrrolo[2,3-b]pyridine (C-1-2) (0.83 g, 70%) as a yellow foam. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.77 (s, 1H), 8.47 (d, J=5.31 Hz, 1H), 8.43 (d, J=2.02 Hz, 1H), 8.16 (d, J=2.02 Hz, 1H), 8.09-8.15 (m, 2H), 7.95 (d, J=4.04 Hz, 1H), 7.68-7.77 (m, 1H), 7.57-7.67 (m, 2H), 7.29 (d, J=5.05 Hz, 1H), 6.86 (d, J=4.04 Hz, 1H), 5.52 (dd, J=9.85, 2.27 Hz, 1H), 3.98 (br. d, J=11.87 Hz, 1H), 3.62-3.74 (m, 1H), 2.07-2.23 (br. m, 1H), 1.90-2.05 (br. m, 2H), 1.66-1.77 (br. m, 1H), 1.65 (s, 3H), 1.50-1.61 (br. m, 2H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:14]12[CH2:24][CH:17]([CH:18]([O:20][CH2:21][CH2:22][OH:23])[CH2:19]1)[CH2:16][NH:15]2.C(N(CC)CC)C.C(O)C>>[CH:11]([C:10]1[C:3]2[C:2]([N:15]3[CH2:16][CH:17]4[CH2:24][CH:14]3[CH2:19][CH:18]4[O:20][CH2:21][CH2:22][OH:23])=[N:7][CH:6]=[N:5][C:4]=2[S:8][CH:9]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1csc2ncnc(Cl)c12
Reactant: OCCOC1CC2CC1CN2
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)c1csc2ncnc(N3CC4CC3CC4OCCO)c12
Temperature: 50 °C

Procedure:
4-Chloro-5-isopropyl-thieno[2,3-d]pyrimidine (0.35 g, 1.6 mmol), 2-(2-azabicyclo[2.2.1]heptan-5-yloxy)ethanol (0.39 g, 2.5 mmol), triethylamine (0.50 g, 0.70 mL, 4.9 mmol) and ethanol (3.95 g, 5 mL, 85.6 mmol) were combined and heated to 50° C. overnight. The reaction mixture was concentrated in vacuo. The resulting residue was taken up in DCM, washed with water, dried over Na2SO4 and concentrated in vacuo to afford
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH3:30])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH3:30])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2cc(OC(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a pale yellow solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (33.4 mg, 61.3 μmol) in dichloromethane (1.44 mL) was added TFA (426 mg, 288 μL, 3.74 mmol, 61 equiv.). The reaction mixture turned orange and was stirred at 25° C. overnight then concentrated. The residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 3 h, then evaporated to a light yellow solid, dissolved in dichloromethane (containing a few drops of MeOH) and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product dissolved in dichloromethane/MeOH and dichloromethane evaporated to allow solid formation, the solid was separated by filtration and dried to give N-tert-butyl-2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (23 mg, 55.5 μmol, 90.5%) as an off-white solid. MS (M+H)+=415; 1H NMR (DMSO-d6) δ: 12.80 (br. s., 1H), 9.06 (s, 1H), 8.37 (s, 1H), 8.20 (d, J=1.9 Hz, 1H), 7.85 (d, J=8.7 Hz, 2H), 7.40 (dd, J=8.9, 2.1 Hz, 1H), 7.19 (t, J=74.4 Hz, 1H), 4.19 (s, 3H), 1.49 (s, 9H).
Reaction SMILES: C([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]3[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)[CH2:16][C@:14]2([C:26]2[CH:27]=[C:28]([NH:33][C:34]([C:36]3[C:41]([F:42])=[CH:40][C:39]([F:43])=[CH:38][N:37]=3)=[O:35])[CH:29]=[CH:30][C:31]=2[F:32])[N:15]=1)(=O)C1C=CC=CC=1.[ClH:44].CON.N1C=CC=CC=1>C1COCC1.CO.C(O)C>[ClH:44].[NH2:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]3[N:20]=[CH:21][C:22]([F:25])=[CH:23][N:24]=3)[CH2:16][C@:14]2([C:26]2[CH:27]=[C:28]([NH:33][C:34]([C:36]3[C:41]([F:42])=[CH:40][C:39]([F:43])=[CH:38][N:37]=3)=[O:35])[CH:29]=[CH:30][C:31]=2[F:32])[N:15]=1
Reactant: O=C(NC1=N[C@@]2(c3cc(NC(=O)c4ncc(F)cc4F)ccc3F)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Agent: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: CCO
Product: NC1=N[C@@]2(c3cc(NC(=O)c4ncc(F)cc4F)ccc3F)CN(c3ncc(F)cn3)C[C@H]2CS1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
N-[3-[(4aR,7aS)-2-benzamido-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-3,5-difluoro-pyridine-2-carboxamide (190 mg, 0.31 mmol, isomer 1) is dissolved in THF (1 mL) and diluted with methanol (3 mL) and ethanol (3 mL). O-Methylhydroxylamine hydrochloride (267 mg, 3.1 mmol) and pyridine (253 μL, 3.1 mmol) are added and the reaction is warmed to 50° C. and stirred overnight. The reaction is purified on an SCX column using 3:1 dichloromethane:methanol and then 2:1 dichloromethane:7 N ammonia in methanol. The material is purified a final time over silica gel with a 0% to 10% gradient of 7 N ammonia methanol in dichloromethane to give the free base of the title compound. This material is dissolved in dichloromethane (5 mL) and 1 M hydrogen chloride in diethyl ether (0.20 mL, 200 μmol) is added. The solvent is removed in vacuo to give the title compound (101 mg, 60%). ES/MS (m/e): 504 (M+H).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[C:4]([O:8]/[N:9]=[C:10](\[C:19]1[C:24]([CH2:25][O:26][CH3:27])=[CH:23][CH:22]=[CH:21][N:20]=1)/[C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1[OH:18])([CH3:7])([CH3:6])[CH3:5]>C(O)CC>[C:4]([O:8]/[N:9]=[C:10](\[C:19]1[C:24]([CH2:25][O:26][CH3:27])=[CH:23][CH:22]=[CH:21][N:20]=1)/[C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1[OH:18])([CH3:7])([CH3:6])[CH3:5].[Br:17][C:15]1[CH:14]=[CH:13][C:12]([OH:18])=[C:2]([CH:16]=1)[C:1]([C:19]1[C:24]([CH2:25][O:26][CH3:27])=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:3]
Reactant: CCO
Agent: COCc1cccnc1/C(=N\OC(C)(C)C)c1cc(Br)ccc1O
Solvent: CCCO
Product: COCc1cccnc1C(=O)c1cc(Br)ccc1O

Procedure:
Using ethanol, in place of n-propanol in Example 17, (Z)-2-(5-bromo-2-hydroxybenzoyl)-3-methoxymethylpyridine O-t-butyloxime (60 mg) (Compound 180) was produced from 2-(5-bromo-2-hydroxybenzoyl)-3-methoxymethylpyridine (80 mg).