Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]#[C:2]Br.[CH2:4]([C:8]1[CH:19]=[CH:18][C:11]([O:12][CH2:13][CH:14]([OH:17])[CH2:15][NH2:16])=[CH:10][CH:9]=1)[C:5]([CH3:7])=[O:6].C([O-])(=O)C.[Na+]>CO.Cl>[NH2:1][C:2]1[O:17][CH:14]([CH2:13][O:12][C:11]2[CH:18]=[CH:19][C:8]([CH2:4][C:5]([CH3:7])=[O:6])=[CH:9][CH:10]=2)[CH2:15][N:16]=1
Reactant: N#CBr
Reactant: CC(=O)Cc1ccc(OCC(O)CN)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(=O)Cc1ccc(OCC2CN=C(N)O2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of cyanogen bromide (0.88 g) in methanol (100 ml) was added, dropwise, to a stirred solution of (4-acetonylphenoxy)-3-amino propan-2-ol), ethylene ketal (3.62 g) and sodium acetate (1.46 g) in methanol (30 ml). The reaction mixture was stirred at ambient temperature for 20 hr. evaporated, cooled in ice, diluted with 2N sodium hydroxide solution and extrated into chloroform. The organic layer was dried (MgSO4) and evaporated to an oil which was purified by column chromatography on silica gel. Elution with acetonitrile/methanol/ammonia (15:2:1) gave a low-melting solid which was dissolved in a mixture of methanol (30 ml) and 2N hydrochloric acid (30 ml) and stirred at ambient temperature for 4 hr. The methanol was evaporated and the aqueous residue was basified by addition of 2N sodium hydroxide solution, extracted into chloroform, dried (MgSO4) and evaporated to give 2-amino-5-(4-acetonylphenoxymethyl]-4,5-dihydrooxazole.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[C:10]([O:14][CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[CH:9]=[C:8](F)[CH:7]=2)#[N:2].[N:22]1([CH2:28][CH2:29][CH2:30][OH:31])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.CC(C)([O-])C.[K+].C(O)(=O)C>CS(C)=O.O>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[C:10]([O:14][CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[CH:9]=[C:8]([O:31][CH2:30][CH2:29][CH2:28][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:7]=2)#[N:2]
Reactant: OCCCN1CCOCC1
Reactant: N#Cc1cnc2cc(F)cc(OC3CCOCC3)c2c1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cnc2cc(OCCCN3CCOCC3)cc(OC3CCOCC3)c2c1O
Temperature: 60 °C
Yield: 43.6 %

Procedure:
A mixture of 3-cyano-7-fluoro-4-hydroxy-5-(tetrahydro-2H-pyran-4-yloxy)quinoline (864 mg), 3-morpholin-4-ylpropan-1-ol (876 mg) and potassium tert-butoxide (1.0M solution in tetrahydrofuran; 9.0 ml) in anhydrous dimethyl sulphoxide (30 ml) was heated at 60° C. for 8 hours. The solution was cooled and then diluted with water (120 ml). Acetic acid was added until pH5 was reached. The solution was pumped onto a cation exchange cartridge (Waters Oasis MCX 6.0 g) and washed on with water. The column was flushed successively with water (200 ml), methanol/water (1:1; 200 ml) and methanol (200 ml). The product was eluted off the column with methanol containing triethylamine (1%). The fractions containing the product were combined and evaporated. The residue was further purified by chromatography on a Redisep silica cartridge (40 g) eluting with a gradient of methanol in dichloromethane (5–20%). This gave the title compound as an white solid (540 mg, 44%); NMR spectrum: (DMSOd6; 373° K) 1.73 (m, 2H), 1.91 (m, 4H), 2.39 (m, 4H), 2.45 (t, 2H), 3.49 (m, 2H), 3.58 (m, 4H), 3.95 (m, 2H), 4.10 (t, 2H), 4.64 (m, 1H), 6.46 (d, 1H), 6.60 (d, 1H), 8.24 (s, 1H); Mass spectrum: M+H+ 414.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N+:12]=[N-:13].[CH2:14]([OH:17])[C:15]#[CH:16]>CCOCC.C(O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:11])[N:12]3[N:13]=[C:15]([CH2:14][OH:17])[CH:16]=[C:5]3[C:4]=2[CH:3]=1
Reactant: [N-]=[N+]=C1C(=O)Nc2ccc(F)cc21
Reactant: C#CCO
Solvent: CCO
Solvent: CCOCC
Product: O=c1[nH]c2ccc(F)cc2c2cc(CO)nn12
Reaction time: 0.25 h

Procedure:
2.0 g (0.0113 mole) of 5- fluoro-3-diazooxindole (part B9 and 13.1 g (0.226 mole of 20 equivalents) of 97% propargyl alcohol are refluxed under argon for 4 hours. The reaction mixture is cooled, diluted with ether (200 ml) and stirred for 15 minutes. The beige-colored precipitates are filtered off and dried in vacuo overnight. Yield: 2.3 g, mp 295°-297°, 87.5% crude yield. The crude produce is taken up in absolute ethanol (500 ml), treated with activated carbon, filtered through a Celite pad, the pad is washed with 50 ml of hot ethanol. The clear filtrate is concentrated down to a volume of 100 ml and cooled. The white precipitates are filtered off and dried in vacuo at 60° to yield the product (title compound) 1.16 g, mp 303°-304°.
Reaction SMILES: [C:1](O)(=O)[CH3:2].[CH:5]([NH2:7])=[NH:6].[C:8]([OH:15])(=[O:14])/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12]>CCO.CC(C)=O.C(O)(C)C>[C:8]([OH:15])(=[O:14])/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12].[NH:7]1[CH2:2][CH2:1][N:6]=[CH:5]1
Reactant: CC(=O)O
Reactant: N=CN
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Solvent: CCO
Product: C1=NCCN1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Formamidine acetate (654 mg, 6.3 mmol) is added to a solution of the compound obtained in Step 7 (1.5 g, 6.3 mmol) in EtOH (100 ml). After stirring for 14 hours at ambient temperature, the ethanol is evaporated off and the white solid is taken up in acetone (75 ml) and isopropanol (10 ml). The solution is filtered and fumaric acid (694 mg, 6.3 mmol), previously dissolved, with warming, in acetone (25 ml) and isopropanol (10 ml), is added. The title compound is obtained in the form of a solid, which is filtered off and dried in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH2:10])=[O:4].[N:17]1([CH:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)[CH:21]=[N:20][CH:19]=[N:18]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH:10][CH:25]1[CH2:26][CH2:27][CH:22]([N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[CH2:23][CH2:24]1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N
Reactant: O=C1CCC(n2cncn2)CC1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CCC(n2cncn2)CC1

Procedure:
Reductive amination of 3-amino-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (0.237 g, 1.0 mmol) and 4-[1,2,4]triazol-1-yl-cyclohexanone (0.170 g, 1.0 mmol) is performed under the same conditions previously described using dibutyltin dichloride and phenylsilane to give 5-(3,3-dimethyl-but-1-ynyl)-3-(4-[1,2,4]triazol-1-yl-cyclohexylamino)-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][CH:11]([F:41])[C:12]1[N:16]([C:17]2[N:22]=[C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:20]=[C:19]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:18]=2)[C:15]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:14]=2[N:13]=1.[Cl-].Cl[S:44]([CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][NH+:52]=[CH:51][CH:50]=1)(=[O:46])=[O:45].O>C(Cl)Cl>[F:41][CH:11]([F:10])[C:12]1[N:16]([C:17]2[N:22]=[C:21]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:20]=[C:19]([N:29]3[CH2:34][CH2:33][N:32]([S:44]([CH2:47][CH2:48][C:49]4[CH:50]=[CH:51][N:52]=[CH:53][CH:54]=4)(=[O:45])=[O:46])[CH2:31][CH2:30]3)[N:18]=2)[C:15]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:14]=2[N:13]=1
Reactant: O=S(=O)(Cl)CCc1cc[nH+]cc1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCc3ccncc3)CC2)n1
Reaction time: 3 h
Yield: 64.8 %

Procedure:
DIPEA (0.29 mL, 1.66 mmol) was added to a suspension of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (Example 2) (150 mg, 0.336 mmol) and 4-[2-(chlorosulfonyl)ethyl]pyridinium chloride (122 mg, 0.504 mmol) in CH2Cl2 (10 mL) at room temperature under nitrogen, and the mixture was stirred for 3 hrs. Additional 4-[2-(chlorosulfonyl)ethyl]pyridinium chloride (41 mg, 0.169 mmol) was added and the mixture stirred for another 21 hrs. Water was added and the phases were separated. The aqueous phase was extracted with CH2Cl2 (1×), the combined organic extracts were dried (Na2SO4), and the solvent was removed under vacuum. Chromatography on silica eluting with CH2Cl2/MeOH (100:0 to 98:2) followed by recrystallization from CH2Cl2/MeOH gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(4-pyridinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (134 mg, 65%).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:55]=[C:54]([NH2:56])[CH:53]=[C:52]3[C:48]=2[CH:49]=[CH:50][NH:51]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:56][C:54]1[CH:53]=[C:52]2[C:48]([CH:49]=[CH:50][NH:51]2)=[C:47]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:55]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cc(N)cc3[nH]ccc23)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(N)cc5[nH]ccc35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 61.9 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (125 mg, 0.21 mmol) was treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-amine (110 mg, 0.43 mmol), sodium carbonate (55 mg, 0.52 mmols) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (52 mg, 0.06 mmol) in 1,2-dimethoxyethane (5.0 ml) and water (0.125 ml) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 50%, hexane-ethyl acetate) to give 84 mg (56% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]2[C:10](=O)[CH2:11][O:12][C:8]=2[CH:7]=1.C([O-])(=O)C.[Na+].Cl.[CH3:27][O:28][NH2:29]>CO>[Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]2[C:10](=[N:29][O:28][CH3:27])[CH2:11][O:12][C:8]=2[CH:7]=1
Reactant: CON
Reactant: O=C1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CON=C1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Yield: 56.7 %

Procedure:
To a mixture of 6-(2,4-dichlorobenzyloxy)benzofuran-3(2H)-one (2.0 g) in MeOH (20 mL) were added sodium acetate (0.531 g) and O-methylhydroxylamine hydrochloride (0.540 g). The mixture was refluxed overnight. After cooling, the mixture was concentrated. The residue was washed with water and EtOAc to give the title compound (1.24 g).
Reaction SMILES: C[O:2][P:3]([O:6][CH3:7])[O:4][CH3:5].Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=[O:10]>>[C:15]1([CH3:18])[CH:16]=[CH:17][C:12]([O:11][C:9]([P:3](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[O:10])=[CH:13][CH:14]=1
Reactant: COP(OC)OC
Reactant: Cc1ccc(OC(=O)Cl)cc1
Product: COP(=O)(OC)C(=O)Oc1ccc(C)cc1
Yield: 93 %

Procedure:
From 10.3 g (85 mmole) of trimethylphosphite and 10.3 g (60 mmole) of p-tolyl chloroformate (prepared according to M. J. Zabik and R. D. Scheutz J. Org. Chem. 32 (1967) 300). (100°, 2 hours) yield 93%. B.p.0.2 131°, nD20 1.4972. Analysis for C10H13O5P. Found (calculated): C 49.37 (49.18). H 5.53 (5.36), P 11.71 (12.69). NMR (CDCl3)δ: 2.40 (CH3), 3.92 and 4.12 (CH3O), 6.97-7.37 (aromatic protons).
Reaction SMILES: CN.[NH2:3][C:4]1[C:5]([F:28])=[CH:6][C:7]([F:27])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17](F)[C:18]=3[Cl:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[CH:9]=1.[N:29]1C=CC=[CH:31][CH:30]=1>>[NH2:3][C:4]1[C:5]([F:28])=[CH:6][C:7]([F:27])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17]([NH:29][CH2:30][CH3:31])[C:18]=3[Cl:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[CH:9]=1
Reactant: c1ccncc1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: CN
Product: CCNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
Pyridine (200 mg) and a 40% aqueous solution (250 mg) of methylamine were added to 1-(5-amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg), and the mixture was heated and stirred overnight at 70° C. The solvent was distilled off under reduced pressure, ethanol (2 ml) was added to the residue, and solids were collected by filtration to obtain the title compound (87 mg) as an orange powder.
Reaction SMILES: [H][H].[F:3][CH:4]([CH:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[CH:5]([F:7])[F:6].[NH3:15]>[Rh]>[F:3][CH:4]([CH:8]1[CH2:13][CH2:12][CH:11]([NH2:15])[CH2:10][CH2:9]1)[CH:5]([F:7])[F:6]
Reactant: O=C1CCC(C(F)C(F)F)CC1
Reactant: N
Reactant: [H][H]
Agent: [Rh]
Product: NC1CCC(C(F)C(F)F)CC1

Procedure:
At 50° C. and 20 bar hydrogen pressure, 4.7 g of 4-(1,2,2-trifluoroethyl)cyclohexanone were reductively aminated in 100 ml of ammonia-saturated methanol in an autoclave using rhodium on carbon as catalyst. The catalyst was filtered off and the reaction solution was concentrated, giving the title product as a brown oil which was reacted further without any purification.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH:8]=[O:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH2:11](O)[CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1.CCOCC>[CH3:1][C:2]([CH3:10])([CH:8]1[O:13][CH2:12][CH2:11][O:9]1)[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(C)(C)C=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)CC(C)(C)C1OCCO1
Yield: 94 %

Procedure:
Methyl 3,3-dimethyl-4-oxobutanoate (10 g, 70 mmol), prepared according to the procedure of Hudlicky et al., Synth. Commun., 16 169 (1986), was dissolved in 40 mL of benzene, followed by addition of ethylene glycol (20 mL), and p-toluenesulfonic acid monohydrate (1.3 g). The reaction was refluxed with azeotropic removal of water for 1 hour. The reaction was poured into 200 mL of ether, washed with saturated sodium bicarbonate, water and brine, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give 12.4 g (94%) of the title compound.
Reaction SMILES: Br[C:2]1[N:12]([CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([CH3:20])[CH2:16][CH2:15]2)[C:5]2[C:6]([Cl:11])=[N:7][C:8]([Cl:10])=[CH:9][C:4]=2[N:3]=1.[C:21]1([C@@H:27]2[CH2:32][O:31][CH2:30][CH2:29][NH:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[F-].[K+].C(N(CC)C(C)C)(C)C>C(OCC)(=O)C.CS(C)=O>[Cl:11][C:6]1[C:5]2[N:12]([CH2:13][C@H:14]3[CH2:19][CH2:18][C@H:17]([CH3:20])[CH2:16][CH2:15]3)[C:2]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][C@H:27]3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:3][C:4]=2[CH:9]=[C:8]([Cl:10])[N:7]=1
Reactant: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(Cl)nc(Cl)c32)CC1
Reactant: c1ccc([C@@H]2COCCN2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(Cl)nc(Cl)c32)CC1
Temperature: 100 °C

Procedure:
To a vial were added 2-bromo-4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (3.13 g, 8.30 mmol), (R)-3-phenylmorpholine (purchased from Beyond Pharmatech) (2.71 g, 16.6 mmol), potassium fluoride (2.41 g, 41.5 mmol), DMSO (25.5 mL), and N,N-diisopropylethylamine (7.25 mL, 41.5 mmol). The vial was sealed and heated to 100° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-60% ethyl acetate/hexanes, linear gradient) to afford 4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine. MS ESI calc'd. for C24H28Cl2N4O [M+H]+ 459. found 459.
Reaction SMILES: [F:1][C:2]([F:10])([C:6]([F:9])([F:8])[F:7])[C:3](=[NH:5])[NH2:4].C(O/[CH:14]=[C:15](/[C:21](=O)[CH:22]([F:24])[F:23])\[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.C[O-].[Na+]>C(O)C>[F:23][CH:22]([F:24])[C:21]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:4]=[C:3]([C:2]([F:10])([F:1])[C:6]([F:9])([F:8])[F:7])[N:5]=1
Reactant: CCO/C=C(\C(=O)OCC)C(=O)C(F)F
Reactant: N=C(N)C(F)(F)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc(C(F)(F)C(F)(F)F)nc1C(F)F
Yield: 39.5 %

Procedure:
A mixture of 1.620 g (10 mmol) of 2,2,3,3,3-pentafluoropropanimidamide (commercially available) and 2.222 g (10 mmol) of ethyl (2Z)-2-(ethoxymethylidene)-4,4-difluoro-3-oxobutanoate (for preparation see WO 2005/123690) in 10 ml of absolute ethanol is stirred under reflux for 4 days after adding 0.680 g (10 mmol) of sodium methylate. The mixture is then concentrated by evaporation in vacuo and the residue is taken up in 10 ml of water and extracted twice with 10 ml of ethyl acetate. The organic phases are washed successively with 5 ml of water and 5 ml of saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated by evaporation in vacuo. Chromatographic purification with a mixture of cyclohexane and ethyl acetate gives 1.264 g (3.95 mM, 39.5% of theory) of ethyl 4-(difluoromethyl)-2-(pentafluoroethyl)pyrimidine-5-carboxylate as a white solid.
Reaction SMILES: [NH2:1][C:2]([CH3:23])([CH3:22])[CH2:3][O:4][C:5](=[O:21])[C@H:6]([CH:18]([CH3:20])[CH3:19])[NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].N1C=CC=CC=1.Cl[C:31]([O:33][CH2:34][Cl:35])=[O:32]>ClCCl>[Cl:35][CH2:34][O:33][C:31]([NH:1][C:2]([CH3:23])([CH3:22])[CH2:3][O:4][C:5](=[O:21])[C@H:6]([CH:18]([CH3:19])[CH3:20])[NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:32]
Reactant: O=C(Cl)OCCl
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)NC(=O)OCCl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-amino-2-methyl-1-(N-benzyloxycarbonyl-L-valyloxy)-propane (2.9 g, 9 mmole) and pyridine (2 ml) in dichloromethane (50 ml) was added chloromethyl chloroformate(1.55 g, 12 mmole) and the mixture was stirred for 3 hours at room temperature. The mixture was evaporated under reduced pressure and ethyl acetate was added. The organic phase was washed with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with hexane/ethyl acetate. Yield: 1.1 g=29%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2C(OC(C)(C)C)=O.[Cl:18][C:19]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=[CH:21][N:20]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O.O>O1CCOCC1.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>[Cl:18][C:19]1[C:24]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[CH:5]3)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: CC(C)(C)OC(=O)c1n[nH]c2ccc(Br)cc12
Reactant: CC1(C)OB(c2cccnc2Cl)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Clc1ncccc1-c1ccc2[nH]ncc2c1
Temperature: 100 °C
Yield: 48.7 %

Procedure:
A single necked round bottom flask (250 mL) equipped with a magnetic stir bar was charged with tert-butyl 5-bromo-1H-indazole-carboxylate (4.0 g, 13.4 mmol) dissolved in 1,4-dioxane (130 mL), 2-chloro-3-pyridine boronic acid pinacol ester (4 g, 16.7 mmol), Pd(PPh3)4 (1.5 g, 1.3 mmol) and 2M aq.Na2CO3 (20 mL, 40 mmol) under nitrogen atmosphere. The rubber septum was replaced with reflux condenser containing three-way stopcock equipped with argon filled balloon. The reaction contents were stirred and air was removed from the closed reaction system by vacuum and back filled with argon. Following three cycles of degassing, the reaction mixture was heated at 100° C. (oil-bath) under argon. Inflated argon balloon was emptied, refilled with argon and remounted in the course of reaction. The initial pale yellow heterogeneous reaction mixture turned to clear biphasic off-brown solution. After 18 h with no additional change in the proportion of the product (62%) as analyzed by LC/MS, the reaction mixture was cooled to room temperature. Upon concentration of the reaction mixture, EtOAc/water (200 mL/75 mL) was transferred to the concentrate and stirred for 30 min. The organic layer was separated and the aqueous layer extracted with EtOAc (100 mL×2). MgSO4 (20g) and Celite® (20g) were added to combined organic layers and the contents suction filtered after stirring for 1 h. The filter cake was washed with EtOAc (300 mL) and the combined filtrates concentrated by rotary evaporator under vacuum. The crude concentrate was dissolved in 1% MeOH/CH2Cl2 and absorbed on silica gel (20g) by evaporating the solvent followed by drying. Subsequent purification by flash silica gel column purification of the dry powder (Combiflash® companion System® with RediSep® silica gel column 120 g, 30-70% EtOAC/hexanes eluting solvent) provided 5-(2-chloropyridin-3-yl)-1H-indazole (1.5 g, 47%) as a white crystalline solid after concentration of the desired product fractions. 1H NMR (DMSO-d6): δ 13.2 (s, 1H), 8.41 (dd, 1H, J=1.8 and 4.7 Hz), 8.13 (s, 1H), 7.90 (dd, 1H, J=1.7 and 4.7 Hz), 7.84 (s, 1H), 7.62 (d, 1H, J=8.8 Hz), 7.51 (dd, 1H, J=4.7 and 7.3 Hz), 7.42 (dd, 1H, J=1.4 and 8.5 Hz). LCMS: 95%, MS (m/e) 230 (MH+).
Reaction SMILES: [CH2:1]1[C:6]2[CH:7]=[C:8]([N:11]3[CH2:15][C@H:14]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[O:13][C:12]3=[O:21])[CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][S:2]1.[OH2:22]>CO.[Cl-].[Na+].O>[O:22]=[S:2]1[CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:15][C@H:14]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[O:13][C:12]3=[O:21])=[CH:7][C:6]=2[CH2:1]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CSCC3)C(=O)O1
Reactant: O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CS(=O)CC3)C(=O)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
A solution of NaIO4 (220 mg, 1.03 mmol) in H2O (4.1 mL) is treated with a solution of (−)-N-[[(5S)-3-(3,4-dihydro-1H-2-benzothiopyran-7-yl)-2-oxo-5-oxazolidinyl]methyl]acetamide (Example 14, 300 mg, 0.979 mmol) in MeOH (20 mL) over approximately 1 min, and the resulting mixture is stirred at ambient temperature for 18 hrs. The mixture is then diluted with brine (25 mL) and extracted with 10% MeOH/CH2Cl2 (4×25 mL), and the combined organic phase is dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue is chromatographed on a Flash 40S silica gel (40 g, 32-63 μm) cartridge, eluting with a gradient of MeOH/CH2Cl2 (2/98-8/92), and those fractions with an Rf=0.20 by TLC (MeOH/CHCl3, 10/90) are pooled and concentrated to give 293 mg (93%) of the title compound (mixture of diastereomers) as an amorphous, white solid.