Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[C:13](Cl)(=[O:16])[CH:14]=[CH2:15].[OH-].[K+]>CO.O.C1COCC1>[C:13]([NH:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4])(=[O:16])[CH:14]=[CH2:15]
Reactant: NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: C=CC(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Yield: 56 %

Procedure:
1-Amino-1-deoxy-D-sorbitol (D-glucamine) 10 (5.0 g, 28 mmol) was dissolved in a mixture of CH3OH (120 mL) and H2O (15 mL) and cooled in an ice bath. Acryloyl chloride (30 mL of a 2.35 M solution in THF, 71 mmol) was added dropwise to. the above solution, while the pH of the reaction mixture was maintained between 8 and 9 by periodic addition of 2M aqueous KOH. After an additional 1-h period on ice, the volatiles were evaporated under reduced pressure and the residue was subjected to silica gel chromatography with a gradient of 5-15% CH2Cl2 in MeOH to give 3.6 g (56%) compound 3 as a white solid; mp 122-123° C.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1.C([Li])CCC.CN(C)[C:18](=[O:20])[CH3:19].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][C:18](=[O:20])[CH3:19])[CH:4]=1
Reactant: CC(=O)N(C)C
Reactant: Cc1cc(N(C)C)ccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)Cc1cc(N(C)C)ccn1
Temperature: 0 °C

Procedure:
To a stirred solution of 4-dimethylamino-2-methylpyridine (1.30 g) in tetrahydrofuran (13 ml) was added a solution of n-butyllithium in n-hexane (1.56M, 7.34 ml) dropwise at −50° C. under a nitrogen atmosphere, and the mixture was warmed to 0° C. The mixture was cooled to −50° C., and N,N-dimethylacetamide (1.15 ml) was added dropwise. Then the mixture was warmed to room temperature, poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 ml×3). The combined organic layer was washed with brine, dried over sodium sulfate and-evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 50 g, 20% methanol in dichloromethane) to give 1-(4-dimethylaminopyridin-2-yl)propan-2-one (1.29 g).
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14].[S:18]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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>[CH:9]1([C:7]2[O:8][C:4]3[C:5](=[C:12]([C:15]#[N:16])[C:13]([CH3:14])=[C:2]([C:20]4[CH:21]=[CH:22][S:18][CH:19]=4)[C:3]=3[F:17])[N:6]=2)[CH2:11][CH2:10]1
Reactant: OB(O)c1ccsc1
Reactant: Cc1c(Br)c(F)c2oc(C3CC3)nc2c1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1c(-c2ccsc2)c(F)c2oc(C3CC3)nc2c1C#N
Temperature: 95 °C
Reaction time: 61 h
Yield: 48.8 %

Procedure:
6-Bromo-2-cyclopropyl-7-fluoro-5-methylbenzoxazole-4-carbonitrile (I-77) (200 mg, 0.68 mmol), 3-thiopheneboronic acid (347 mg, 2.71 mmol) and tripotassium phosphate (288 mg, 1.36 mmol) were suspended in 1,4-dioxane (8 ml), and at room temperature, tetrakis(triphenylphosphine)palladium(0) (157 mg, 0.14 mmol) was added. The mixture liquid was stirred under nitrogen atmosphere at 95° C. for 61 hours, then cooled to room temperature. The insoluble matter was separated by filtration with washing with ethyl acetate, and the filtrate was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=19:1, v/v) to obtain the entitled compound (99 mg, 49%) as a white solid.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:15]([CH:17]1[O:19][CH2:18]1)[Cl:16]>CO>[ClH:16].[C:9]1([CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:1]2[CH2:18][CH:17]([OH:19])[CH2:15]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClCC1CO1
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CO
Product: Cl
Product: OC1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 45 %

Procedure:
Aminodiphenylmethane (55 g; 0.3 mol) and epichlorhydrin (23.5 ml; 0.3 mol) are mixed in methanol (200 ml). The mixture is heated under reflux for 5 days. The methanol is then evaporated off in order to produce a beige solid. The latter is filtered and washed with ether in order to produce a white solid with a yield of 45%. Melting point: 186.0-186.4° C.
Reaction SMILES: [C:1]([C:3]1[C:4](Cl)=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[N:10]1[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[S:12][C:11]=1[NH2:19].Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([OH:31])[CH:29]=2)[N:24]=[CH:23][N:22]=1>>[C:1]([C:3]1[C:4]([O:31][C:28]2[CH:29]=[C:30]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][N:22]=[C:21]3[NH:19][C:11]2[S:12][C:13]3[C:18]([N:10]=2)=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: Nc1nc2cccnc2s1
Reactant: N#Cc1cccnc1Cl
Product: N#Cc1cccnc1Oc1ccc2ncnc(Nc3nc4cccnc4s3)c2c1

Procedure:
The compound of Example 80 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 3-cyano-2-chloropyridine, thiazolo[5,4-b]pyridin-2-yl-amine and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[C:33](=[O:42])[N:34]([CH3:41])[C:35]2=[O:40]>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][C:31]3[CH:39]=[CH:38][CH:37]=[C:36]4[C:32]=3[C:33](=[O:42])[N:34]([CH3:41])[C:35]4=[O:40])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH3:29])[CH:15]=1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CN1C(=O)c2cccc(N)c2C1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4c3C(=O)N(C)C4=O)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared using the procedure for Example 102 with diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and the commercially available 4-amino-2-methyl-1H-isoindole-1,3(2H)-dione. MS (ES+): m/z 594.34 (100) [MH+]; HPLC: tR=1.17 min (UPLC, purity).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)[CH3:10].C(O)(=[O:20])C.B.C(C1C=CC(C)=NC=1)C>>[CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([OH:20])[CH2:9][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccccc1
Reactant: CC(=O)O
Reactant: O=Cc1ccccc1
Agent: B
Agent: CCc1ccc(C)nc1
Product: OCCc1ccccc1
Product: OCc1ccccc1

Procedure:
Benzaldehyde (1.6 g, 15 mmol), acetophenone (1.8 g, 15% mmol) and acetic acid (0.3 g, 5 mmol) were combined in a flask under nitrogen. 5-Ethyl-2-methylpyridine borane (0.7 g, 5 mmol) was added via syringe over 5 minutes at room temperature. At the end of the addition the temperature of the reaction mixture reached 70° C. An ice water bath was applied immediately to bring the temperature down. The 1H NMR spectrum indicated that the reaction was complete, giving a 91:9 ratio of benzyl alcohol to phenethylalcohol. Of the combined carbonyl substrates, 37% were reduced and 63% remained unreduced. The 11B NMR spectrum indicated 77% borate (reduced carbonyl products) and 22% (combined species between 0 and 2 ppm) of amine coordinated to borate products.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.Cl[C:13]1[N:22]=[C:21]([NH2:23])[C:20]2[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=2)[N:14]=1>>[NH2:23][C:21]1[C:20]2[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=2)[N:14]=[C:13]([N:9]2[CH2:10][CH2:11][N:6]([C:4]([CH:1]3[CH2:2][CH2:3]3)=[O:5])[CH2:7][CH2:8]2)[N:22]=1
Reactant: O=C(C1CC1)N1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Product: COc1cc2nc(N3CCN(C(=O)C4CC4)CC3)nc(N)c2cc1OC

Procedure:
N-(Cyclopropylcarbonyl)piperazine (3.08 g., 0.02 mole) and 2-chloro-4-amino-6,7-dimethoxyquinazoline (4.74 g., 0.02 mole) are reacted according to the procedure of Example 1(a). The crude product crystallized from ethanol affords analytically pure 4-amino-2-[4-(cyclopropylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline, m.p. 283.5°-285.5° C. (corr.).
Reaction SMILES: [CH3:1][O-].[Na+].Cl[CH2:5][CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[C:19]([NH2:25])=[N:20][C:21](N)=[N:22][CH:23]=2)[C:14]([CH:26]([CH3:28])[CH3:27])=[CH:13][C:12]=1[O:29][CH3:30])=[O:9]>CO>[NH2:25][C:19]1[C:18]([O:17][C:15]2[C:14]([CH:26]([CH3:28])[CH3:27])=[CH:13][C:12]([O:29][CH3:30])=[C:11]([N:10]3[CH2:5][CH2:6][CH2:7][C:8]3=[O:9])[CH:16]=2)=[CH:23][N:22]=[C:21]([CH3:1])[N:20]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1NC(=O)CCCCl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(C)C)c(Oc2cnc(C)nc2N)cc1N1CCCC1=O
Yield: 47 %

Procedure:
To a solution of 5 ml 1.9 M NaOMe in MeOH was added 4-Chloro-N-[5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-butyramide (0.495 g, 1.3 mmol). After 6 h the solution was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with H2O, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 1-[5-(4-amino-2-methyl-pyrimidin-5-yloxy)4-isopropyl-2-methoxy-phenyl]-pyrrolidin-2-one (0.230 g, 47%) as white solid; [MH]+=358; mp (HCl salt)>300° C.
Reaction SMILES: [CH2:1]1C2[C:4](=[CH:5][CH:6]=CC=2)[CH:3]=[CH:2]1.[CH3:10][C:11]([CH3:13])=[O:12].C[N+]1([O-])CC[O:18]CC1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O.C(Cl)(Cl)(Cl)Cl.[Os](=O)(=O)(=O)=O.C(O)(C)(C)C>[OH:12][CH:11]1[C:13]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:1][CH:10]1[OH:18]
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)=O
Reactant: C1=Cc2ccccc2C1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: OC1Cc2ccccc2C1O
Reaction time: 72 h
Yield: 97 %

Procedure:
To a stirred solution of indene (0.5 g, 4.3 m mol), in a mixture of water (2.5 cm3 acetone (5 cm3) and tert-butanol (1.5 cm3), was added 4-methylmorpholine-N-oxide (0.6 g, 5.9 mmol) and a solution of osmium tetroxide in carbon tetrachloride (0.005 g/0.5 cm3). After stirring the reaction mixture for three days, at ambient temperature, a saturated aqueous solution of sodium metabisulphite (0.5 cm3) was added and the stirring was continued for another hour. The reaction mixture was diluted with water (50 cm3), extracted with ethyl acetate (2×50 cm3) and dried (Na2SO4). Distillation of the solvent, from the organic extract, under reduced pressure, gave crude racemic (1R:2S/1S:2R) 1,2-dihydroxy-1,2-dihydroindene as off-white fluffy crystals (0.63 g, 97%) m.pt. 98°-100° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])=[CH:18][CH:17]=1)#[N:2].[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>C(O)C.O1CCCC1.[C].[Pd]>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:24])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4)cc3)c2cc1C#N
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4)cc3)c2cc1CN
Reaction time: 8 h

Procedure:
After dissolving the N-[4-(6-cyano-7-methoxyquinolin-4-yloxy)phenyl]-N′-phenylurea (100 mg) synthesized in Example 37 in an ethanol (5 ml) and tetrahydrofuran (5 ml) mixed solvent, there were added trifluoroacetic acid (0.5 ml) and 50% palladium-carbon (50 mg), and the mixture was stirred overnight under a hydrogen stream. After filtering off the palladium carbon, the filtrate was concentrated. The obtained residue was washed with tetrahydrofuran to obtain the title compound (70 mg).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][C:22]([NH:25][C:26](=[O:28])[CH3:27])([CH3:24])[CH3:23])[C:14]([CH3:29])=[C:13]([CH3:30])[N:12]=1.CCOC(C)=O>C(COC)OC>[CH3:30][C:13]1[C:14]([CH3:29])=[C:15]([NH:20][CH2:21][C:22]([NH:25][C:26](=[O:28])[CH3:27])([CH3:24])[CH3:23])[C:16]([N+:17]([O-:19])=[O:18])=[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: CC(=O)NC(C)(C)CNc1c(C)c(C)nc(Cl)c1[N+](=O)[O-]
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(=O)NC(C)(C)CNc1c(C)c(C)nc(Oc2ccccc2)c1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 72.5 %

Procedure:
A 250 mL-round bottom flask was charged with NaH (60% oil dispersion, 534 mg, 13.3 mmol) under N2. The NaH was washed with three portions of hexanes and dried under a stream of N2. Dimethoxyethane (10 mL) was then added to the flask followed by phenol (1.25 g, 13.3 mmol). After stirring for 10 min, a solution of N-{2-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]-1,1-dimethylethyl}acetamide (2.80 g, 8.89 mmol) in 15 mL of dimethoxyethane was added to the reaction mixture, dropwise, via cannula. The reaction mixture was then heated to reflux for 24 h. The cooled solution was then treated with 100 mL of EtOAc and washed successively with H2O, 1% Na2CO3 solution (2×), H2O and brine. The organic portion was dried with Na2SO4 and concentrated to give a brown oil. Column chromatography (SiO2, 50% EtOAc/hexanes) gave N-{2-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]-1,1-dimethylethyl}acetamide (2.40 g) as a yellow oil.
Reaction SMILES: C(C1C=C2C(=CC=1)C(NC(=O)C1C=CC=CC=1)=NC=C2)=O.C([NH:29][C:30]1[C:39]2[C:34](=[CH:35][C:36]([CH:40]=[CH:41][C:42]([OH:44])=O)=[CH:37][CH:38]=2)[CH:33]=[CH:32][N:31]=1)C1C=CC=CC=1.NC1C2C(=CC(C=CC(O)=O)=CC=2)C=CN=1.Cl.[CH3:62][O:63][C:64](=[O:76])[CH2:65][C:66]([N:68]1[CH2:73][CH2:72][CH:71]([NH:74][CH3:75])[CH2:70][CH2:69]1)=[O:67]>>[CH3:62][O:63][C:64](=[O:76])[CH2:65][C:66]([N:68]1[CH2:69][CH2:70][CH:71]([N:74]([C:42](=[O:44])[CH:41]=[CH:40][C:36]2[CH:35]=[C:34]3[C:39](=[CH:38][CH:37]=2)[C:30]([NH2:29])=[N:31][CH:32]=[CH:33]3)[CH3:75])[CH2:72][CH2:73]1)=[O:67]
Reactant: O=C(O)C=Cc1ccc2c(NCc3ccccc3)nccc2c1
Reactant: CNC1CCN(C(=O)CC(=O)OC)CC1
Agent: Cl
Agent: Nc1nccc2cc(C=CC(=O)O)ccc12
Agent: O=Cc1ccc2c(NC(=O)c3ccccc3)nccc2c1
Product: COC(=O)CC(=O)N1CCC(N(C)C(=O)C=Cc2ccc3c(N)nccc3c2)CC1

Procedure:
Using the method described in example 81a N-(6-formyl-1-isoquinolinyl)benzamide (1f) was transformed into 3-(1-(benzylamino)-6-isoquinolinyl)acrylic acid. This compound was used to prepare 3-(1-amino-6-isoquinolinyl)acrylic acid according to the procedure described in example 81b. Reaction of 3-(1-amino-6-isoquinolinyl)acrylic acid with 3-(4-(methylamino)piperidin-1-yl)-3-oxopropionic acid methyl ester hydrochloride according to the procedures described in example 81e yielded the title compound. NMR (CDCl3) δ: 1.8 (4H, m), 2.7 (1H, m), 3.0 (3H, s), 3.2 (1H, m), 3.5 (2H, d), 3.7 (3H, s), 3.9 (1H, br d), 4.8 (2H, m), 4.9 (2H, br s), 7.0 (1H, d), 7.5 (1H, d), 7.65 (1H, d), 7.8 (3H, m), 8.0 (1H, d).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27](=O)[CH2:28][C@@H:29]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([S:45]([NH2:48])(=[O:47])=[O:46])=[CH:41][C:40]=2[S:49]([C:52]([F:55])([F:54])[F:53])(=[O:51])=[O:50])[CH2:30][S:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:23][CH2:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1>C1COCC1.N.CO>[Si:1]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C@@H:29]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([S:45]([NH2:48])(=[O:46])=[O:47])=[CH:41][C:40]=2[S:49]([C:52]([F:54])([F:53])[F:55])(=[O:50])=[O:51])[CH2:30][S:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:23][CH2:22]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OCCN1CCN(C(=O)C[C@H](CSc2ccccc2)Nc2ccc(S(N)(=O)=O)cc2S(=O)(=O)C(F)(F)F)CC1)(c1ccccc1)c1ccccc1
Agent: B
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)[Si](OCCN1CCN(CC[C@H](CSc2ccccc2)Nc2ccc(S(N)(=O)=O)cc2S(=O)(=O)C(F)(F)F)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.5 %

Procedure:
(R)-4-(4-(4-(2-(tert-Butyldiphenylsilyloxy)ethyl)piperazin-1-yl)-4-oxo-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 21, 0.98 g, 1.15 mmol) was dissolved in THF (4.6 ml), under a nitrogen atmosphere, and a solution of borane-THF complex (1M in THF; 6.93 ml, 6.93 mmol) was added. The mixture was diluted with NH3 in MeOH (7N, 20 ml) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (75 ml), washed with water (40 ml), and dried (Na2SO4). Evaporation of the volatiles under reduced pressure afforded a concentrate, which was purified by column chromatography (ISCO, 40 g silica gel column, eluting with 0→100% EtOAc/hexanes) to provide the title compound (245 mg, yield: 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:15])[C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][C:18]=1[C:27]([F:30])([F:29])[F:28]>N1C=CC=CC=1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:15][C:4]2[C:5]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:24])=[O:25])=[CH:19][C:18]=1[C:27]([F:30])([F:28])[F:29]
Reactant: Nc1cc(Cl)cnc1Oc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)cnc1Oc1ccccc1)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 5-chloro-2-phenoxy-pyridin-3-ylamine (60 mg, 0.27 mmol) in anhydrous pyridine (0.5 mL) was added drop wise a solution of 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (76 mg, 0.27 mmol) in pyridine (0.5 mL). The resulting mixture was stirred at room temperature for 5 h. The reaction mixture was separated by preparative HPLC using acetonitrile-water solvent mixture and pure product fractions were lyophilized to provide pure product as a solid. 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1 H), 7.89-7.87 (m, 2 H), 7.81 (m, 1 H), 7.59 (d, J=8.0 Hz, 1 H), 7.35 (t, J=8.4 Hz, 1 H), 7.25-7.19 (m, 2 H), 6.76 (d, J=8.0 Hz, 2 H). MS m/z: 463.0 (M+H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:13][C:14]1[C:15]([C:20]([OH:22])=O)=[N:16][CH:17]=[CH:18][N:19]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>CN(C)C=O.C(OCC)C>[NH2:13][C:14]1[C:15]([C:20]([NH:23][CH2:24][CH2:25][CH2:26][N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)=[O:22])=[N:16][CH:17]=[CH:18][N:19]=1
Reactant: Nc1nccnc1C(=O)O
Reactant: NCCCn1ccnc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Nc1nccnc1C(=O)NCCCn1ccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
A solution of 19.09 g (0.0776 mol) of 1,1'-carbonyldiimidazole in approximately 200 ml of dimethylformamide was added slowly to a cold (0° C.) solution of 15.78 g (0.1135 mol) of 3-aminopyrazine-2-carboxylic acid in 150 ml of dimethylformamide. The resulting solution was gradually warmed to 25° C. and stirred for about two hours. A solution of 14.75 g (0.118 mol) of N-(3-aminopropyl)imidazole in approximately 40 ml of dimethylformamide was added and the resulting solution was allowed to react for four hours. After four hours, the reaction solution was reduced to dryness under reduced pressure. The resultant semi-solid was suspended in diethyl ether and the portion which did not dissolve was recovered by filtration. The recovered solid was then suspended in diethyl ether containing a small amount of ethyl acetate and the resulting mixture was stirred for about 48 hours. After stirring for 48 hours, the undissolved solid was isolated by filtration. This solid was purified by filtration through silica gel using 4% methanol in dichloromethane. The resultant purified material was recrystallized from a 1:4 dichloromethane/diethyl ether solution to provide 24.4 g of the desired subtitled intermediate (m.p. 118°-120° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:5]2[N:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[C:9]([CH3:10])[N:4]2[N:3]=1.O[N:16]=[C:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1.N>>[CH3:1][C:2]1[CH:14]=[C:5]2[N:6]=[CH:7][C:8]([C:11]3[O:13][N:24]=[C:17]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:16]=3)=[C:9]([CH3:10])[N:4]2[N:3]=1
Reactant: Cc1cc2ncc(C(=O)O)c(C)n2n1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Cc1cc2ncc(-c3nc(-c4cccnc4)no3)c(C)n2n1

Procedure:
The title compound was prepared according Method C using 2,7-dimethylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (Maybridge) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ2.52 (s, 3H), 3.27 (s, 3H), 6.77 (s, 1H), 7.67 (ddd, J=8.0, 4.9, 0.7 Hz, 1H), 8.48 (dt, J=8.6, 1.9 Hz, 1H), 8.84 (dd, J=4.7, 1.7 Hz, 1H), 9.06 (s, 1H), 9.30 (dd, J=2.2, 0.8 Hz, 1H), 9.30 (d, J=1.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 293 (M+H)+.
Reaction SMILES: C[O-].[Na+].Cl.[CH3:5][O:6][CH2:7][C:8]([NH2:10])=[NH:9].[Cl:11][CH2:12][C:13](=O)[CH2:14][C:15](OCC)=[O:16].Cl>CO.O.CCOCC>[Cl:11][CH2:12][C:13]1[N:10]=[C:8]([CH2:7][O:6][CH3:5])[N:9]=[C:15]([OH:16])[CH:14]=1
Reactant: COCC(=N)N
Reactant: CCOC(=O)CC(=O)CCl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: COCc1nc(O)cc(CCl)n1
Reaction time: 3 h
Yield: 94.4 %

Procedure:
Sodium methylate (11.90 g, 0.22 mole) was added to a solution of methoxyacetamidine hydrochloride (12.45 g, 0.1 mole) and ethyl 4-chloroacetoacetate (16.50 g, 0.1 mole) in methanol (50 ml) at 5° to 10° C. with stirring. The resulting orange reaction mixture was stirred at 5° to 10° C. for 2 hours and then at 20° C. for 3 hours, and neutralized with conc. hydrochloric acid. The precipitate was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue which was then dissolved in water (300 ml). The aqueous solution was extracted with chloroform, and the chloroform extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crystalline residue. The residue was suspended in ether and then filtered to obtain 17.8 g of 6-(chloromethyl)-4-hydroxy-2-(methoxymethyl)pyrimidine as pale brown needle-like crystals (m.p. 124.0°-125.5° C.).