Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]1[C:4]2([CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:6][NH:5]2)[CH2:3]1.[F:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:5]2[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C:4]32[CH2:3][CH2:2]3)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCNC2(CC2)C1
Reactant: Fc1ccc(I)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(F)cc2)C2(CC2)C1
Yield: 94.2 %

Procedure:
To a toluene solution (2.0 mL) of tert-butyl 4,7-diazaspiro[2.5]octane-7-carboxylate hydrochloride (100 mg, 0.402 mmol), 1-fluoro-4-iodobenzene (446 mg, 2.01 mmol), sodium tert-butoxide (77.3 mg, 0.804 mmol), and bis(tri-tert-butylphosphine)palladium (0) (41.1 mg, 0.0804 mmol) were added and the resultant mixture was stirred at 110° C. for 1 hour and 30 minutes. After completion of the reaction, the reaction solution was purified by silica gel column chromatography (hexane/ethyl acetate=1/0→4/1) to obtain the title compound (116 mg, yield 94%).
Reaction SMILES: [S-2:1].[Li+:2].[Li+:3].[P:4]12([S:16][P:14]3([S:17][P:7]([S:9][P:10]([S:13]3)([S:12]1)=[S:11])(=[S:8])[S:6]2)=[S:15])=[S:5]>>[S:1]([Li:3])[Li:2].[P:4]12([S:6][P:7]3([S:9][P:10]([S:13][P:14]([S:17]3)([S:16]1)=[S:15])(=[S:11])[S:12]2)=[S:8])=[S:5]
Reactant: [S-2]
Reactant: [Li+]
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: [Li]S[Li]

Procedure:
Lithium sulfide (Li2S) and phosphorus pentasulfide (P2S5) were used as a starting material. These powders were weighed in a glove box under an Ar atmosphere (dew point: −70° C.) so as to become a molar ratio of 73.5Li2S.26.5P2S5, and mixed by an agate mortar to obtain a raw material composition of 1 g (Li2S=0.3644 g, P2S5=0.6356 g). Next, 1 g of the obtained raw material composition was projected into a 45-ml zirconia pot, and zirconia ball (φ=10 mm, 10 pieces) was further projected thereinto to hermetically seal the pot completely (Ar atmosphere). This pot was mounted on a planetary ball milling machine (P7™ manufactured by FRITSCH JAPAN CO., LTD.) to perform mechanical milling for 40 hours at the number of rotating table revolutions of 370 rpm and then obtain a sulfide solid electrolyte glass.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[N:17][C:18]=3[NH:28][NH2:29])[N:13]=2)=[CH:8][CH:7]=1.O.[C:31]1(C)C(S(O)(=O)=O)=CC=CC=1.C1(C)C=CC=CC=1.C(OC)(OC)OC>CO>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:18]4=[N:28][N:29]=[CH:31][N:17]4[CH:16]=[CH:15][C:14]=3[N:13]=2)=[CH:8][CH:7]=1
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: NNc1nccc2nc(-c3ccc(C4OCCO4)cc3)c(-c3ccccc3)cc12
Solvent: Cc1ccccc1
Solvent: COC(OC)OC
Solvent: CO
Product: c1ccc(-c2cc3c(ccn4cnnc34)nc2-c2ccc(C3OCCO3)cc2)cc1
Temperature: 100 °C

Procedure:
To a solution of [2-(4-[1,3]dioxolan-2-yl-phenyl)-3-phenyl-[1,6]naphthyridin-5-yl]-hydrazine (3-4, 1.6 g, 4.2 mmol) and toluenesulfonic acid monohydrate (79 mg, 0.4 mmol) in 3:1 toluene:MeOH (16 mL) was added trimethyl orthoformate (0.58 mL, 12.5 mmol). The mixture was heated to 100° C. in a microwave reactor for 1 hr. The reaction mixture was then concentrated in vacuo. The solid was collected and dried with toluene azeotropically to give the title compound which was used for next step without further purification. LRMS m/z (M+1) Calcd: 395.1. Found 395.2.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([N+:22]([O-:24])=[O:23])[C:16]=1Cl)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[OH2:28]>>[CH2:1]([O:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([N+:22]([O-:24])=[O:23])[C:16]=1[OH:28])(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCCOCc2ccccc2)c1Cl
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCCOCc2ccccc2)c1O
Yield: 77 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-(2-benzyloxyethyl)-2,6-dichloro-3-nitrobenzenesulfonamide (2.31 g, 5.71 mmol), 60% NaH (683 mg, 17.1mmol) and water (103 μ, 5.72mmol) were reacted to form the desired product (1.70 g, 77%). LC-MS (m/z) 387.5(M+).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH3:4].[C:6]([O:10][C:11](=[O:29])[CH2:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:16][C:15]=1[NH2:28])([CH3:9])([CH3:8])[CH3:7]>C(O)(=O)C.CCO>[C:6]([O:10][C:11](=[O:29])[CH2:12][N:13]1[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:16][C:15]=2[N:28]=[C:1]1[CH2:2][CH2:3][CH3:4])([CH3:8])([CH3:7])[CH3:9]
Reactant: CCCC=O
Reactant: CC(C)(C)OC(=O)CNc1ccc(NC(=O)OC(C)(C)C)cc1N
Solvent: CC(=O)O
Solvent: CCO
Product: CCCc1nc2cc(NC(=O)OC(C)(C)C)ccc2n1CC(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Butyraldehyde (0.65 mL, 9.0 mmol) and acetic acid (7 drops) were added to a solution of (2-amino-4-tert-butoxycarbonylamino-phenylamino)-acetic acid tert-butyl ester (2.2 g, 6.5 mmol) in EtOH (100 mL), and stirred overnight at 70° C. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to give the crude sub-title compound that was used without further purification. MS calculated for C21H31N3O4+H: 390, observed: 390.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1)=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:12]([O:11][C:9]1[CH:10]=[C:5]([CH2:4][NH2:1])[CH:6]=[N:7][CH:8]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: [N-]=[N+]=NCc1cncc(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1cncc(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
To a stirring solution of 181 mg of 3-(azidomethyl)-5-(benzyloxy)pyridine in 6 mL of THF at 0° C. was added 80.6 mg (2.12 mmol) of LiAlH4. The ice bath was removed and stirring was continued with warming to r.t. After 30 min. the reaction was quenched by adding successively 160 μL of H2O, 160 μL of 15% aqueous NaOH, and 480 μL of brine. The mixture was filtered through Celite and concentrated. The crude product was used for the next reaction without further purification.
Reaction SMILES: C(=O)([O-])O.[Na+].Cl.[NH2:7][CH:8]([C:13](=[O:16])[CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10].O.[C:18](Cl)(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C>[C:18]([NH:7][CH:8]([C:13](=[O:16])[CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCC(=O)C(N)C(=O)OC
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(=O)C(NC(=O)C=Cc1ccccc1)C(=O)OC

Procedure:
Sodium hydrogen carbonate (10.0 g) was added to a mixture of methyl 2-amino-3-oxovalerate hydrochloride (9.1 g), ethyl acetate (50 ml) and water (40 ml) with ice-cooling and stirring followed by dropwise addition of a solution of cinnamoyl chloride (8.3 g) in ethyl acetate (10 ml). The whole mixture was stirred under ice-cooling for 2 hours and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate. The ethyl acetate layers were combined, washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and isopropyl ether was added to the residue to give methyl 2-cinnamoylamino-3-oxovalerate as crystals; yield 8.8 g (63.8%). Recrystallization from ethanol gave colorless needles melting at 119°-120° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:4][CH:3]=1.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22]1[C:23]([NH2:37])=[N:24][CH:25]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>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.COCCOC.O>[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22]1[C:23]([NH2:37])=[N:24][CH:25]=[C:26]([C:2]2[S:6][C:5]([N:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[N:4][CH:3]=2)[CH:27]=1
Reactant: CC1(C)OB(c2cnc(N)c(-c3nc4ccccc4s3)c2)OC1(C)C
Reactant: Brc1cnc(N2CCOCC2)s1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncc(-c2cnc(N3CCOCC3)s2)cc1-c1nc2ccccc2s1
Temperature: 100 °C

Procedure:
A solution of 4-(5-bromothiazol-2-yl)-morpholine (0.0600 g, 0.241 mmol), 3-benzothiazol-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-ylamine (BB8) (0.110 g, 0.313 mmol), potassium carbonate (0.106 g, 0.771 mmol), and Pd(PPh3)4 (0.02 g, 0.02 mmol) in previously degassed DME/Water (4:1) (2.7 mL) was placed in a microwave tube and evacuated and charged with N2 (2×). The reaction mixture was heated in the microwave reactor at 100° C. for 45 min. The reaction mixture was partitioned between CHCl3 and H2O and the layers were separated. The aqueous layer was re-extracted with CHCl3 (3×), and the combined organic extracts were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The crude material was submitted for MDP for purification. The pure fractions were combined and the organic was concentrated in vacuo then diluted with CHCl3 and neutralized with sat. NaHCO3. The layers were separated, and the aqueous layer was re-extracted with CHCl3 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo, giving the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=3.44 (d, J=5.1 Hz, 4H), 3.73 (d, J=5.1 Hz, 4H), 7.49 (t, J=7.7 Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 7.61 (s, 1H), 8.00 (d, J=2.2 Hz, 1H), 8.03 (br. s., 2H), 8.10 (d, J=7.7 Hz, 1H), 8.15 (d, J=7.3 Hz, 1H), 8.36 (d, J=2.2 Hz, 1H). MS (ES+): m/z=396.07 (100) [MH+]. HPLC: tR=3.57 min (ZQ2, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:30])[N:4]([C:19]2[CH:24]=[C:23]([C:25](=O)[C:26]#[CH:27])[CH:22]=[CH:21][C:20]=2[CH3:29])[C:5]([CH3:18])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1.Cl.[OH:32][C:33]([CH3:38])([CH3:37])[C:34]([NH2:36])=[NH:35].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3](=[O:30])[N:4]([C:19]2[CH:24]=[C:23]([C:25]3[CH:26]=[CH:27][N:36]=[C:34]([C:33]([OH:32])([CH3:38])[CH3:37])[N:35]=3)[CH:22]=[CH:21][C:20]=2[CH3:29])[C:5]([CH3:18])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1
Reactant: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(OC)c3)c(Cl)c2=O)c1
Reactant: CC(C)(O)C(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(COc2nc(C)n(-c3cc(-c4ccnc(C(C)(C)O)n4)ccc3C)c(=O)c2Cl)c1
Temperature: 85 °C
Yield: 35.5 %

Procedure:
To a solution of 5-chloro-6-(3-methoxy-benzyloxy)-2-methyl-3-(2-methyl-5-propynoyl-phenyl) -3H-pyrimidin-4-one from Example 6, Step E (32.5 mg, 0.08 mmol) in acetonitrile (1 mL) was added 2-hydroxy-2-methylpropionamidine HCl (16 mg, 0.12 mmol) and potassium carbonate (32 mg, 0.23 mmol) and the slurry was heated at 85° C. for eighteen hours. The reaction was returned to ambient temperature and filtered to remove excess salts. The filtrate was concentrated and purified via normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a white solid (14.4 mg, 37% yield). MS (M+H): 507; 1H NMR (400 MHz, chloroform-d) δ ppm, 1.64 (s, 6H), 2.17 (s, 3H), 2.21 (s, 3H), 3.85 (s, 3H), 5.49-5.58 (m, 2H), 6.90 (d, J=7.43, 1H), 7.07 (s, 1H), 7.09 (s, 1H), 7.31-7.35 (m, 1H), 7.54-7.58 (m, 2H), 7.93 (s, 1H), 8.13 (d, J=6.65 Hz, 1H), 8.77 (d, J=5.09, 1H).
Reaction SMILES: [C:1]1([S:7]([Cl:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C=CC(N2CCCN(C(OC(C)(C)C)=O)CC2)=CC=1N.N1C=CC=CC=1.[NH2:39][C:40]1[CH:45]=[C:44]([N:46]2[CH2:52][CH2:51][CH2:50][N:49](C(OC(C)(C)C)=O)[CH2:48][CH2:47]2)[CH:43]=[CH:42][C:41]=1[NH:60][S:61]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)(=[O:63])=[O:62].Cl.CCOCC>C(Cl)Cl.CO>[ClH:10].[N:46]1([C:44]2[CH:43]=[CH:42][C:41]([NH:60][S:61]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)(=[O:63])=[O:62])=[C:40]([NH:39][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:45]=2)[CH2:52][CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(NS(=O)(=O)c3ccccc3)c(N)c2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(N)c2)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: O=S(=O)(Nc1ccc(N2CCCNCC2)cc1NS(=O)(=O)c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
Benzenesulfonyl chloride (0.088 g, 0.50 mmol) was added to a solution of 2-amino-5-(4-t-butyloxycarbonyl-homopiperazin-1-yl)aniline (0.153 g, 0.50 mmol) and pyridine (514 mL, 6.39 mmol) in DCM. After 1 h at r.t. the mixture was washed with NaHCO3 (10%) dried (MgSO4) and the solvent was removed. Purification by column chromatography (CH2Cl2/MeOH/heptane, 4:1:15) gave a mixture of N-{2-amino-4-[4-t-butyloxycarbonyl-homopiperazin-1-yl-]phenyl}benzenesulfonamide and of the bis-sulphonylated N-{4-[4-t-butyloxycarbonyl]homopiperazinyl)-2-[(phenylsulfonyl)amino]phenyl}benzenesulfonamide (0.150 g, 86%). Boc-deprotection was achieved by dissolving the mixture in MeOH and adding HCl/ether. The mixture was let at r.t. for 0.5 h. Purification by preparative HPLC gave N-{4-(homopiperazinyl)-2-[(phenylsulfonyl)amino]phenyl}benzenesulfonamide hydrochloride; Anal. (C23H27ClN4O4S2) C, H, N, S; M+487.4 Calcd 486.14. And N-{4-(homopiperazinyl)-2-[(phenylsulfonyl)amino]phenyl}benzenesulfonamide hydrochloride; Anal. (C17H23ClN4O2S) C, H, N, S ; M+347.5 Calcd 346.15.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][N:15]1[CH2:19][C@@H:18]([OH:20])[C@@H:17]([CH2:21][NH:22]C(=O)C(F)(F)F)[CH2:16]1)=[N:10][C:9]([O:29][CH3:30])=[CH:8][CH:7]=2)#[N:2]>CO>[NH2:22][CH2:21][C@@H:17]1[C@H:18]([OH:20])[CH2:19][N:15]([CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:29][CH3:30])[N:10]=3)[N:5]=[CH:4][C:3]=2[C:1]#[N:2])[CH2:16]1
Reactant: COc1ccc2ncc(C#N)c(CCN3C[C@H](CNC(=O)C(F)(F)F)[C@H](O)C3)c2n1
Solvent: CO
Product: COc1ccc2ncc(C#N)c(CCN3C[C@H](CN)[C@H](O)C3)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-[((3S,4S)-1-{2-[3-cyano-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]-2,2,2-trifluoroacetamide (0.110 g, 0.26 mmol) was dissolved in methanol (5 mL). 10% aqueous K CO was added to the original solution and it was stirred at ambient temperature for 2 hours. The solution was extracted 3× with chloroform and washed with brine. The solvent was removed under reduced pressure. (0.076 g, 89%) LCMS: m/z 328.6 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:46][C:47]1[CH:52]=[CH:51][C:50]([Br:53])=[CH:49][N:48]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Br:53][C:50]1[CH:51]=[CH:52][C:47]([NH:46][C:35](=[O:37])[C@@H:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[CH2:33][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)=[N:48][CH:49]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc(Br)cn1)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 96.5 %

Procedure:
A solution of triphenylphosphine (411 mg, 1.57 mmol) in methylene chloride (15 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (316 mg, 1.78 mmol). The reaction mixture was stirred at 0° C. until it was completely dissolved and became light purple in color. The reaction mixture was then treated with 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionic acid (prepared in Example 54, 300 mg, 1.05 mmol). The reaction mixture was stirred at 0° C. for 20 min and then warmed to 25° C. where it was stirred for 30 min. After such time, the reaction mixture was treated with 2-amino-5-bromopyridine (271 mg, 1.57 mmol) and pyridine (0.15 mL, 1.88 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (10 mL) and extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionamide (448 mg, 97%) as a white solid: mp 107.3-109.9° C.; [α]23589=66.7° (c=0.084, chloroform); EI-HRMS m/e calcd for C19H19BrCl2N2O(M+) 440.0058, found 440.0056.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[CH:19]1([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([O:25][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: OC1CCCCC1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(OC2CCCCC2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, cyclohexanol and DBU in DME. ES-MS m/e (%): 285 (M+H+, 75), 203 ([M—C6H10]+, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][C:12]([O:14]CC)=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:19]O.[OH-].[Na+].O>CO>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([OH:14])[O:13][N:19]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2cc(O)on2)cc1

Procedure:
According to method of U.S. Pat. No. 3,781,438, 2 g of ethyl 3-(4-nitrophenyl)-3-oxopropanoate was dissolved in methanol, slightly excessive hydroxylamine hydrochloride and equivalent amount of sodium hydroxide were added, the mixture was heated to reflux. 3 hr later, the reaction was traced by Thin-Layer Chromatography, water was added to the reaction mixture, extracted with ethyl acetate, dried and concentrated to obtain 3-(4-nitrophenyl)isoxazol-5-ol as solid.
Reaction SMILES: N[C:2]1[CH:7]=CC(OC)=[CH:4][C:3]=1S(N)(=O)=O.[NH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([O:22]C)=[CH:17][C:16]=1[S:24]([NH2:27])(=[O:26])=[O:25]>>[O:25]=[S:24]1(=[O:26])[C:16]2[CH:17]=[C:18]([OH:22])[C:19]([F:21])=[CH:20][C:15]=2[N:14]2[CH2:7][CH2:2][CH2:3][CH:4]2[NH:27]1
Reactant: COc1ccc(N)c(S(N)(=O)=O)c1
Reactant: COc1cc(S(N)(=O)=O)c(N)cc1F
Product: O=S1(=O)NC2CCCN2c2cc(F)c(O)cc21

Procedure:
In Step A, 2-amino-5-methoxybenzenesulphonamide is replaced by 2-amino-4-fluoro-5-methoxybenzenesulphonamide.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:29][CH2:30][CH:31]([N:34]6[CH2:35][CH2:36][O:37][CH2:38][CH2:39]6)[CH2:32][CH2:33]5)=[CH:24][CH:23]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: Brc1ccc(N2CCC(N3CCOCC3)CC2)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc(N5CCC(N6CCOCC6)CC5)cc4)nc23)cc1

Procedure:
A round bottom flask equipped with a drying tube was charged with 4-piperidin-4-yl-morpholine (0.21 g, 1.2 mmol), cupric acetate (0.34 g, 1.9 mmol), 4-bromobenzeneboronic acid (0.50 g, 2.5 mmol), pyridine (0.20 mL, 2.5 mmol) and dichloromethane (5 mL, 80 mmol). The blue suspension was stirred open to the air for 6 days at room temperature. Water (25 mL) was added to the green-brown suspension and stirred for 10 minutes. The mixture was extracted with ethyl acetate (3×25 mL). The combined organic layer was washed with saturated aqueous sodium chloride (25 mL), dried over magnesium sulfate, filtered and evaporated. The residue was purified via chromatography using silica gel column (40 g) and 0%→8% methanol: dichloromethane solvent gradient. 4-[1-(4-Bromo-phenyl)-piperidin-4-yl]-morpholine was isolated as a tan solid (0.168 g, 41%). MP=146-149° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.32 (d, J=7.5 Hz, 2H), 6.79 (d, J=7.8 Hz, 2H), 3.76-3.71 (m, 4H), 3.68 (d, J=12.8 Hz, 2H), 2.71 (t, J=12.3 Hz, 2H), 2.60-2.54 (m, 4H), 2.37-2.27 (m, 1H), 1.93 (d, J=11.3 Hz, 2H), 1.69-1.58 (m, 2H). MS=325, 327 (MH)+. 49b) [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (50.0 mg, 0.173 mmol) and 4-[1-(4-bromo-phenyl)-piperidin-4-yl]-morpholine (65.0 mg, 0.200 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (20.0 mg, 0.0366 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow solid (0.044 g, 48%). MP=253-254° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.47 (d, J=6.3 Hz, 1H), 8.23 (d, J=7.5 Hz, 2H), 8.08 (d, J=8.2 Hz, 2H), 7.63 (d, J=7.3 Hz, 1H), 7.47 (d, J=7.1 Hz, 2H), 7.01-6.95 (m, 3H), 6.68 (s, 1H), 3.77-3.72 (m, 4H), 3.69-3.62 (m, 2H), 3.10 (s, 3H), 2.74-2.65 (m, 2H), 2.62-2.57 (m, 4H), 2.36-2.28 (m, 1H), 1.98-1.92 (m, 2H), 1.75-1.63 (m, 2H). MS=533 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH:12]C(C)=O)[C:9]([S:16]([CH2:18][CH3:19])=[O:17])=[CH:8][C:4]=1[C:5]([OH:7])=O.CC(C)=O.ClC(OCC(C)C)=O.[CH:32]1([CH2:38][N:39]2[CH2:43][CH2:42][CH:41]([NH2:44])[CH2:40]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>O.C(N(CC)CC)C>[CH:32]1([CH2:38][N:39]2[CH2:43][CH2:42][CH:41]([NH:44][C:5](=[O:7])[C:4]3[CH:8]=[C:9]([S:16]([CH2:18][CH3:19])=[O:17])[C:10]([NH2:12])=[CH:11][C:3]=3[O:2][CH3:1])[CH2:40]2)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: NC1CCN(CC2CCCCC2)C1
Reactant: CCS(=O)c1cc(C(=O)O)c(OC)cc1NC(C)=O
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCS(=O)c1cc(C(=O)NC2CCN(CC3CCCCC3)C2)c(OC)cc1N
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
8.5 g of 2-methoxy-4-acetamino-5-ethylsulphinyl benzoic acid, 70 ml of acetone, 10 ml of water and 3 g of triethylamine are placed in a 250 ml flask fitted with an agitator, a thermometer and a dropping funnel. The solution is cooled to about 0° C., after which 4.2 g of isobutyl chloroformate is poured in drop by drop. It is agitated for 45 minutes at 0° C. then 6 g of 1-cyclohexylmethyl-3-amino-pyrrolidine is dripped in. It is reacted for 2 hours at room temperature, 50 ml of water is added and the acetone is evaporated under vacuum. 10 ml of soda and 50 ml of water are added to the aqueous residue and it is heated to reflux for 5 hours then cooled. The suspension is extracted twice with 50 ml of methylene chloride, and the organic phase is dried over magnesium sulphate and filtered. The filtrate is evaporated dry under vacuum, and the residue is dissolved in 70 ml of hot ethyl acetate. The product is re-crystallised by cooling and filtered. It is washed with a little ether and dried in an oven at 50° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[CH:11](=O)C>>[CH3:11][NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: CC=O
Reactant: NCCCN1CCOCC1
Product: CNCCCN1CCOCC1

Procedure:
By using N-(3-aminopropyl)morpholine (1.0 g) as a starting material, the title compound (57 mg) was obtained in the same manners as those of Reference Example 51, (1), Reference Example 8, (2) and Reference Example 19, (3).