Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[C:12]([CH2:13][CH3:14])=[C:11]([C:15]([OH:17])=[O:16])[N:10]=[N:9]1)C1C=CC=CC=1.N.[Na].C(=O)([O-])[O-].[NH4+].[NH4+]>>[CH2:13]([C:12]1[NH:8][N:9]=[N:10][C:11]=1[C:15]([OH:17])=[O:16])[CH3:14]
Reactant: CCc1c(C(=O)O)nnn1Cc1ccccc1
Agent: N
Agent: O=C([O-])[O-]
Agent: [NH4+]
Product: CCc1[nH]nnc1C(=O)O

Procedure:
To a mixture of 24 g (104 mmoles) of 1(2 or 3)-benzyl-5-ethyl-1H-1,2,3-triazole-4-carboxylic acid in 250 ml of liquid ammonia at -78° C., 7.2 g (312 mmoles) of sodium pellets were added, in portions, until the solution maintained a dark blue color. The reaction was then quenched with 10 g (128 mmoles) of ammonium carbonate. The resulting yellow mixture was allowed to warm to room temperture and the ammonia evaporated. The solid residue was dissolved in 70 ml of water and extracted with ether. The aqueous phase was then adjusted to pH 1 with 12 molar hydrochloric acid and 14.0 g (95%) of 5-ethyl-1H-1,2,3-triazole-4-carboxylic acid was precipitated as a yellow solid. The stucture was confirmed by n.m.r. and I.R.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[C:9]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:8][O:7][N:6]=1)N.N([O-])=O.[Na+].[ClH:20]>O>[OH:1][N:2]=[C:3]([Cl:20])[C:5]1[C:9]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:8][O:7][N:6]=1
Reactant: NC(=NO)c1nonc1N1CCOCC1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: ON=C(Cl)c1nonc1N1CCOCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
A solution of N′-hydroxy-4-morpholin-4-yl-1,2,5-oxadiazole-3-carboximidamide (66 mg, 0.3 mmol) in 6.0 M HCl (0.62 mL) at 5-10° C. was treated with a solution of sodium nitrite (32 mg, 0.47 mmol) in water (0.5 mL) dropwise and stirred for 2 h at 0° C. The suspension was filtered and the solid washed with ice water to give desired product (22 mg, 30%). The filtrate was extracted with ethyl acetate (30 mL) which was washed with brine (10 mL), filtered and concentrated to give additional product (23 mg, 32%) that contained minor impurities. The combined material was used immediately in the next step.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:34](=[O:35])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:16]([CH3:20])([CH3:19])[S:17](=[O:18])[C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:36]N(C)S(C1C=CC(C)=CC=1)(=O)=O>>[CH3:19][C:16](=[CH2:20])[CH:15]([N:14]1[C:34](=[O:35])[CH:12]([NH:11][C:9](=[O:10])[CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]1[S:17]([Cl:36])=[O:18])[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22]
Reactant: Cc1ccc(S(=O)(=O)N(C)Cl)cc1
Reactant: CC1(C)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2S1=O
Product: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1S(=O)Cl
Temperature: 25 °C

Procedure:
To 150 ml. of distilled and molecular sieve-dried toluene were added 3.0 g. (6 mmol.) of p-nitrobenzyl 6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide and 1.3 g. (6 mmol.) of N-chloro-N-methyl-p-toluenesulfonamide. The mixture was heated at reflux for 60 minutes. The resulting reaction mixture then was cooled to room temperature. An aliquot (15 ml.) was separated, washed with water, and brine, dried over magnesium sulfate, and evaporated to dryness in vacuo. The nmr spectrum of the residue was consistent for the title compound contaminated with some N-methyl-p-toluenesulfonamide.
Reaction SMILES: C(#N)CC#N.[CH2:6]1[N:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1.[Cl-:14].[Li+]>O1CCCC1>[CH2:6]1[N:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1.[ClH:14]
Reactant: [Cl-]
Agent: C1CN2CCN1CC2
Agent: [Li+]
Solvent: C1CCOC1
Solvent: N#CCC#N
Product: Cl
Reaction time: 2 h

Procedure:
In 100 ml of anhydrous tetrahydrofurane under argon at 0° C., 20.27 g (100 mmoles) of 4-styrenesulfonyl chloride CH2═CHC6H4SO2Cl (commercially available from Monomer-Polymer & Dajac Laboratories), 10.42 g (100 mmoles) of malononitrile and 22.44 g (200 mmoles) of DABCO were reacted. After 2 hours at 0° C. and 48 hours at room temperature, the solution was filtered to remove the DABCO hydrochloride formed, and it was treated with 4.24 g of anhydrous lithium chloride (100 mmoles), stored and weighed in a glove box. There is immediately formed a precipitate of DABCO hydrochloride and the reaction mixture was then again filtered after stirring for 6 hours. After evaporation and drying under vacuum during 24 hours at room temperature, 31.16 g of the lithium salt of 4-styrenesulfonylmalononitrile were recovered, with a purity characterized by a proton and carbon RMN higher than 97%.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[CH2:30]([N:34]=[C:35]=[O:36])[CH2:31][CH2:32][CH3:33]>C(#N)C>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH3:20])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:21]=[CH:22][C:2]([NH:1][C:35]([NH:34][CH2:30][CH2:31][CH2:32][CH3:33])=[O:36])=[CH:3][CH:4]=1)#[N:18]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Reactant: CCCCN=C=O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CCCCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C#N)cc23)cc1
Yield: 55 %

Procedure:
4-(4-Aminophenoxy)-6-cyano-7-methoxyquinoline (150 mg) was added to 2.5 ml of toluene and 2.5 ml of acetonitrile, and the mixture was heated to reflux. After then adding n-butyl isocyanate (0.12 ml), the mixture was further heated to reflux for 1 hour. After cooling, the precipitated solid was filtered out and washed with ethyl acetate/toluene=1/1 to obtain 110 mg of the title compound as light brown crystals (55% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][C:21](=[O:37])[NH:22][CH2:23][CH2:24][CH2:25][C@H:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][NH2:28])([CH3:19])([CH3:18])[CH3:17].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][C:13]([NH:28][CH2:27][C@@H:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24][CH2:23][NH:22][C:21]([O:20][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:37])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CN)NC(=O)OC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Preparation takes place in analogy to Example 79A from 92 mg (0.44 mmol) of N-[(benzyloxy)carbonyl]glycine and 181 mg (0.57 mmol) of tert-butyl{(4S)-5-amino-4-[(tert-butoxycarbonyl)amino]pentyl}carbamate (Example 86A) in 6 ml of dimethylformamide with the addition of 110 mg (0.57 mmol) of EDC and 18 mg (0.13 mmol) of HOBt. The product is purified by preparative RP-HPLC (mobile phase water/acetonitrile gradient: 90:10→5:95).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(OC)[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:31]=[CH:30][C:25]2[O:26][CH2:27][CH2:28][O:29][C:24]=2[CH:23]=1.C([SiH](CC)CC)C.B(F)(F)F>C(#N)C.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:31]=[CH:30][C:25]2[O:26][CH2:27][CH2:28][O:29][C:24]=2[CH:23]=1
Reactant: COC1(c2ccc(Br)c(Cc3ccc4c(c3)OCCO4)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CC#N
Product: OC[C@H]1OC(c2ccc(Br)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 10 °C
Reaction time: 4 h
Yield: 106.4 %

Procedure:
To a stirred solution of (3R,4S,5S,6R)-2-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol (28.4 g, 57.1 mmol) in acetonitrile-dichloromethane 1:1 (250 mL) was added triethylsilane (36.5 mL, 228.4 mmol) and boron trifluoride diethyletharate complex (14.1 mL, 114.2 mmol) at 10° C. After stirring for 4 h at 10° C., the reaction was quenched with saturated aqueous sodium bicarbonate (˜100 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×150 mL). The organic layers were combined and dried over sodium sulfate, concentrated to furnish (3R,4R,5S,6R)-2-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (28.4 g). Crude product was used for next reaction without purification.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:10]([N:12]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]2)=[O:11])[CH:7]=[CH:8][CH:9]=1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]2[N:26]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=3)[N:27]=[CH:28][C:21]=12>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([C:10]([N:12]2[CH2:13][CH2:14][CH:15]([O:18][C:20]3[N:25]=[CH:24][N:23]=[C:22]4[N:26]([C:29]5[CH:30]=[CH:31][C:32]([S:35]([CH3:38])(=[O:36])=[O:37])=[CH:33][CH:34]=5)[N:27]=[CH:28][C:21]=34)[CH2:16][CH2:17]2)=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(c1cccc(F)c1)N1CCC(O)CC1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCN(C(=O)c5cccc(F)c5)CC4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 16 mL reaction vial was placed sodium hydride (48 mg, 60% in oil, 1.2 mmol) and 5 mL of THF. (3-Fluoro-phenyl)-(4-hydroxy-piperidin-1-yl)-methanone (66 mg, 0.3 mmol) was added to the suspension and the mixture was stirred 60 min under N2 at room temperature, followed by the addition of 4-chloro-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (60 mg, 0.2 mmol). After stir another 2 hrs under N2 at room temperature, all of the starting chloropyrozolepyrimidines was completely converted as indicated by LCMS. The reaction mixture was then filtered through a syringe filter and purified HPLC to give Compound A8. 1H NMR (CDCl3, 400 MHz) δ 1.95 (m, 2H), 2.21 (m, 2H), 3.11 (s, 3H), 3.45 (m, 1H), 3.68 (m, 1H), 3.75 (m, 1H), 4.20 (s, 1H), 5.72 (m, 1H), 7.12 (m, 1H), 7.16 (m, 1H), 7.22 (m, 1H), 7.41 (m, 1H), 8.11 (d, 2H), 8.27 (s, 1H), 8.62 (d, 2H), 8.67 (s, 1H). Exact mass calculated for C24H22FN5O4S 495.14, found 496.3 (MH+)
Reaction SMILES: C(#N)C.[NH2:4][C:5]1[CH:6]=[C:7]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:24])=[C:20](Cl)[N:21]=3)[C:16](=[O:25])[C:15]([C:26]([OH:28])=[O:27])=[CH:14]2)[C:8]([F:12])=[CH:9][C:10]=1[F:11].Cl.Cl.[NH2:31][CH:32]1[CH2:35][NH:34][CH2:33]1>C(N(CC)CC)C>[NH2:31][CH:32]1[CH2:35][N:34]([C:20]2[N:21]=[C:22]3[C:17]([C:16](=[O:25])[C:15]([C:26]([OH:28])=[O:27])=[CH:14][N:13]3[C:7]3[C:8]([F:12])=[CH:9][C:10]([F:11])=[C:5]([NH2:4])[CH:6]=3)=[CH:18][C:19]=2[F:24])[CH2:33]1
Reactant: NC1CNC1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(Cl)nc32)c(F)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)nc32)c(F)cc1F
Temperature: 80 °C
Reaction time: 15 h
Yield: 91.2 %

Procedure:
To 200 ml of acetonitrile were added 3.7 g of 1-(3-amino-4,6-difluorophenyl)-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 2.18 g of 3-aminoazetidine dihydrochloride, and 6.06 g of triethylamine. The solution was stirred at 80° C. for 15 hours. The reaction solution was cooled whereupon the precipitated solid was collected by filtration and washed with ethanol and isopropyl ether to give 3.7 g of the title compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:29])[C:11]2[CH:16]=[C:15]([O:17][CH2:18][CH2:19][C:20]3[CH:24]=[CH:23][S:22][CH:21]=3)[CH:14]=[C:13]([O:25][CH:26]([CH3:28])[CH3:27])[CH:12]=2)=[N:7][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:50]>C1COCC1.C(OCC)C>[Br:50][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:29])[C:11]2[CH:16]=[C:15]([O:17][CH2:18][CH2:19][C:20]3[CH:24]=[CH:23][S:22][CH:21]=3)[CH:14]=[C:13]([O:25][CH:26]([CH3:28])[CH3:27])[CH:12]=2)=[N:7][CH:8]=1
Reactant: CC(C)Oc1cc(OCCc2ccsc2)cc(C(=O)Nc2ccc(CO)cn2)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)Oc1cc(OCCc2ccsc2)cc(C(=O)Nc2ccc(CBr)cn2)c1
Reaction time: 16 h
Yield: 100.8 %

Procedure:
N-(5-Hydroxymethyl-pyridin-2-yl)-3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzamide (0.79 g, 1.92 mmol) in THF (10 mL) was added to a solution of triphenylphosphine (1.03 g, 3.84 mmol) and carbon tetrabromide (1.27 g, 3.84 mmol) in diethyl ether (10 mL). After 16 hours, the reaction mixture was concentrated under reduced pressure and partitioned in EtOAc (30 mL) and water (30 mL). The organic layer was rinsed with water (20 mL), and then a saturated sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and concentrated to yellow oil. After chromatography on silica gel with a gradient from 5-100% ethyl acetate-hexanes, N-(5-bromomethyl-pyridin-2-yl)-3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzamide (0.92 g, 101.3% yield) was obtained, including some impurity, but was used as-is. 1H NMR (300 MHz, DMSO-d6): δ 10.85 (s, 1H), 8.45 (s, 1H), 8.15 (d, J=6.0 Hz, 1H), 7.90 (d, J=6.0 Hz, 1H), 7.45 (d, J=3.0 Hz, 1H), 7.30 (s, 1H), 7.20 (s, 1H), 7.15 (s, 1H), 7.10 (d, J=3.0 Hz, 1H), 6.65 (s, 1H), 4.75 (s, 2H), 4.70 (m, 1H), 4.25 (t, 2H), 3.05 (t, 2H), 1.25 (s, 6H); LCMS (m/z): 477.1 [C22H23BrN2O3S+H]+.
Reaction SMILES: [CH:1]([C:3]1[S:7]/[C:6](=[N:8]\[CH3:9])/[N:5]([CH3:10])[C:4]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>ClCCCl.C(O)(=O)C>[CH3:10][N:5]1[C:4]([CH2:11][N:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17]2)=[C:3]([CH2:1][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[S:7]/[C:6]/1=[N:8]\[CH3:9]
Reactant: C1COCCN1
Reactant: C/N=c1\sc(C=O)c(CN2CCN(C(=O)OC(C)(C)C)CC2)n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C/N=c1\sc(CN2CCOCC2)c(CN2CCN(C(=O)OC(C)(C)C)CC2)n1C

Procedure:
tert-Butyl 4-(((2Z)-5-formyl-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-1-carboxylate (1.0 g) obtained in Example 35a) and morpholine (0.36 mL) were dissolved in a mixed solution of 1,2-dichloroethane (50 mL) and acetic acid (0.18 mL). Triacetoxy sodium borohydride (0.84 g) was added thereto at 0° C., and the mixture was mixed at room temperature overnight. The reaction solution was basified with an aqueous potassium carbonate solution, then extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off to give the title compound (1.2 g) as pale brown crystals.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:9]=[CH:10][CH:11]=1)#[N:2].CO>CN1CCCC1=O.[C].[Pd]>[NH2:23][C:21]1[CH:20]=[CH:19][C:4]([O:5][C:6]2[CH:7]=[C:8]([NH:12][C:13](=[O:18])[C:14]([F:15])([F:16])[F:17])[CH:9]=[CH:10][CH:11]=2)=[C:3]([C:1]#[N:2])[CH:22]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Oc1cccc(NC(=O)C(F)(F)F)c1
Agent: [Pd]
Solvent: CN1CCCC1=O
Solvent: CO
Product: N#Cc1cc(N)ccc1Oc1cccc(NC(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.4 %

Procedure:
To a solution of N-[3-(2-cyano-4-nitrophenoxy)phenyl]-2,2,2-trifluoroacetamide (2.81 g, 8.01 mmol) in 1-methylpyrrolidin-2-one (20 mL)/methanol (80 ml) was added 10% palladium-carbon (300 mg), and the mixture was stirred at room temperature for 6 hr under a hydrogen atmosphere (1 atm). Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (200 ml), washed successively with water (100 mL×2) and saturated brine (100 mL×2), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=50/50→80/20), and the fraction containing the object product was concentrated under reduced pressure to give the title compound (2.48 g, 97%) as a pale-yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4]([C:7]2[N:8](S(C3C=CC=CC=3)(=O)=O)[C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=3)=[CH:3][CH2:2]1.[OH-].[K+].C(=O)([O-])O.[Na+]>CO>[O:1]1[CH2:6][CH2:5][C:4]([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=3)=[CH:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc2c(c1)cc(C1=CCOCC1)n2S(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)c1ccc2[nH]c(C3=CCOCC3)cc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a solution of the compound obtained in Example 14 (3) (28.8 mg) in methanol (3 ml), a 1N aqueous potassium hydroxide solution (0.69 ml) was added and the mixture was stirred at 100° C. for 1 hour. The reaction solution was then poured into a saturated aqueous sodium hydrogencarbonate solution, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 16.5 mg of the desired product as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][C@H:33]1[CH2:37][CH2:36][CH2:35][C@H:34]1[C:38]([NH2:40])=[O:39]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:32][CH:33]3[CH2:37][CH2:36][CH2:35][CH:34]3[C:38]([NH2:40])=[O:39])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: NC(=O)[C@@H]1CCC[C@@H]1N
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1cc(F)ccc1-c1nc(NC2CCCC2C(N)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
Following the general procedure outlined in Example 225, the product of Example 48 (150 mg, 0.34 mmol) and cis-2-amino-1-cyclopentanecarboxamide (139 mg, 1.02 mmol) were reacted to give the crude material. Purification by flash chromatography eluting with EtOAc/hexane/triethylamine (50/50/2, v/v/v), followed by recrystallization from dichloromethane and hexane, afforded the desired product, 87 mg (52%). LC-MS: 494.0 (MEI+, m/z), 2.00 (Rt, min).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([O:14][CH3:15])[N:11]=[C:10]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:27]([N:29]=[C:30]=[O:31])[CH3:28]>N1C=CC=CC=1>[CH2:27]([NH:29][C:30]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:9]=[C:10]([NH:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[N:11]=[C:12]([O:14][CH3:15])[N:13]=2)[CH:3]=1)=[O:31])[CH3:28]
Reactant: CCN=C=O
Reactant: COc1ccc(CCNc2cc(-c3cccc(N)c3)nc(OC)n2)cc1
Solvent: c1ccncc1
Product: CCNC(=O)Nc1cccc(-c2cc(NCCc3ccc(OC)cc3)nc(OC)n2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.8 %

Procedure:
To a solution of [6-(3-amino-phenyl)-2-methoxy-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine (184 mg, 0.45 mmol, Example 2) in pyridine (1.5 mL) is added ethyl isocyanate (43 μL, 0.54 mmol). The reaction mixture is stirred for 18 hours at ambient temperature, quenched with the addition of water (25 mL), and extracted four times with EtOAc (25 mL). The combined extracts and washed four times with aqueous copper sulfate solution (25 mL), with water (25 mL), with brine (25 mL), dried over magnesium sulfate, filtered and concentrated by rotary evaporator. The resulting solid is subjected to flash column chromatography on silica (4.5 g) eluting with 20 to 40% EtOAc in heptane to afford 1-ethyl-3-(3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-urea [98.3 mg, 52%, Example 41]. LCMS: RT=2.68 minutes, MS: 422 (M+H). 1H NMR (300 MHz, CDCl3) δ 8.11 (1H, d, J=0.17 Hz), 7.88 (2H, s), 7.62 (1H, d, J=0.026 Hz), 7.49 (1H, d, J=0.026 Hz), 7.18 (4H, m), 6.81 (2H, m), 6.22 (1H, d, J=0.08 Hz), 5.83 (1H, s), 5.35 (1H, s), 3.93 (3H, d, J=0.04 Hz), 3.73 (3H, d, J=0.012 Hz), 3.55 (2H, m), 3.19 (2H, q, J=0.022 Hz), 2.81 (2H, m), 2.13 (1H, s), 1.04 (2H, t, J=0.022 Hz). IC50=7.6 nM
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][C:23]([C:25]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)=[N:22][C:21]=3[C:34]([OH:36])=[O:35])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][C:23]([C:25]4[CH:26]=[C:30]5[C:31]([CH:27]=[CH:28][NH:29]5)=[CH:32][CH:33]=4)=[N:22][C:21]=3[C:34]([OH:36])=[O:35])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3oc(-c4cccc5[nH]ccc45)nc3C(=O)O)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3oc(-c4ccc5cc[nH]c5c4)nc3C(=O)O)cc2)CC1

Procedure:
5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-2-(1H-indol-6-yl)oxazole-4-carboxylic acid was prepared according to the method described for the synthesis of 5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-2-(1H-indol-4-yl)oxazole-4-carboxylic acid in example M-12, except that during the NaOH mediated hydrolysis the reaction was worked up by acidifying the aqueous phase and extracting the product in DCM.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>C(#N)C>[F:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cc(F)ccc1O
Solvent: CC#N
Product: O=C(O)c1cc(F)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
6.24 g (40 mmol) of 5-fluoro-salicylic acid is dissolved in 62.4 ml of acetonitrile with warming, the solution is cooled to 0° C. and, with this temperature being maintained a solution of 2.96 ml (44 mmol) of 65% HNO3 in 14.8 ml of acetonitrile is instilled. The reaction mixture is stirred for 24 hours at 0° C., then filtered over 7.5 g of silica gel 60 and evaporated to dryness 6.1 g =75.8% of the theoretical yield is obtained of the crude product, which is used in the next reaction without purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[O:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33]>>[Cl:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:30]4[CH2:31][CH2:32][O:28][C:29]4=[O:33])=[CH:3][C:4]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([Cl:23])[CH:20]=1
Reactant: O=C1NCCO1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)N1CCN(c2ncc(Cl)cc2Cl)CC1
Product: CS(=O)(=O)c1cc(N2CCOC2=O)ccc1C(=O)N1CCN(c2ncc(Cl)cc2Cl)CC1
Yield: 84.7 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dichloropyridin-2-yl)piperazin-1-yl]methanone (0.5 g) described in Preparation Example 74 and oxazolidin-2-one (130 mg), the title compound (429 mg) was obtained.