Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]([NH:13][C@H:14]([C:22]([CH2:24][Cl:25])=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO.C(Cl)(Cl)Cl>O1CCCC1>[CH2:3]([O:10][C:11]([NH:13][C@@H:14]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C@H:22]([OH:23])[CH2:24][Cl:25])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)CCl)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CCl)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
3.5 g of sodium borohydride were added to an ice-cooled stirred solution of 21 g of [N-(benzyloxycarbonyl)-L-phenylalanyl]methyl chloride in 500 ml of aqueous tetrahydrofuran. Stirring was continued for 0.5 hour and the solvent was removed by evaporation. The residue was partitioned between dichloromethane and water and then carefully acidified with concentrated hydrochloric acid. After working-up the organic phase gave a white solid which ran as two spots: Rf 0.4 and 0.5 (5% methanol/chloroform). The solids were extracted with boiling hexane until all of the higher running component had been extracted. The combined n-hexane extracts were evaporated and the residue was re-extracted with boiling n-hexane to remove a small amount (0.5 g) of the lower running component. In this manner there were obtained 11.5 g of 3(S)-(benzyloxyformamido)-1-chloro-4-phenyl-2(S)-butanol of melting point 151°-153° C. (from ethyl acetate/n-hexane).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH3:18])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[C:23]([F:31])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.C1(C)C=CC(S([C:46]#[N:47])(=O)=O)=CC=1.[NH4+].[Cl-]>C1COCC1.CCOCC.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH3:18])=[N:15][C:16]([C:46]#[N:47])=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[C:23]([F:31])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)c(F)c1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1nc(C#N)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)c(F)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A cooled (−78° C.) solution of 8-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-1-iodo-3-methyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (0.666 g; 1.204 mmol) in anhydrous THF (20 ml) was treated dropwise with 1.6M n-BuLi in hexanes (0.76 ml; 1.204 mmol). The resulting reaction mixture was further stirred at −78° C., under nitrogen, for 15 min., and a solution of para-toluenesulfonyl cyanide (0.379 g; 1.987 mmol) in anhydrous THF (5 ml) was then added dropwise. Stirring at −78° C. was continued for 20 min. before aq. sat. NH4Cl (2 ml) was added. The resulting mixture was allowed to warm-up to rt, and water (50 ml), followed by ether (50 ml) were added. The organic layer was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH, 50/1) afforded 1-cyano-8-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-3-methyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a pale yellow solid (0.271 g; 50%). LC-MS: tR=0.96 min.; [M+H]+=453.31 g/mol.
Reaction SMILES: I[C:2]1[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19](C(F)(F)F)[CH:18]=4)[CH:15]=3)=[N:8][C:9]=2[N:10]=1.C1COCC1.[F:36][C:37](I)([F:39])[F:38]>[Zn].CN(P(N(C)C)(N(C)C)=O)C>[CH2:28]([N:3]1[C:4](=[O:27])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:37]([F:39])([F:38])[F:36])[CH:18]=4)[CH:15]=3)=[N:8][C:9]=2[N:10]=[C:2]1[C:37]([F:39])([F:38])[F:36])[CH2:29][CH3:30]
Reactant: FC(F)(F)I
Reactant: CCCn1c(I)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCn1c(C(F)(F)F)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
A mixture of 2-Iodo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (36 mg, 0.068 mmol), Zn dust (10 mg, 0.136 mmol) and THF (2 ml) was stirred for 2 hours at room temperature. Trifluoromethyl iodide gas was passed through the reaction mixture and HMPA (2 ml) was added and heated at 120° C. for 18 hours. The reaction mixture was cooled to room temperature, organic volatile solvent was evaporated and the residue was extracted with DCM (2×10 ml). The organic layer was washed with brine (10 ml), dried over Na2SO4, evaporated and purified by preparative HPLC to get 1-Propyl-2-trifluoromethyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one as pale yellow solid (4.5 mg, 14%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:9]=[C:10]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:11]([Cl:14])=[N:12][CH:13]=2)=[C:5]([CH3:7])[N:6]=1.N1C=CC=CC=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>C1COCC1.CN(C=O)C>[C:30]1([O:29][C:27](=[O:28])[NH:1][C:2]2[S:3][C:4]([C:8]3[CH:13]=[N:12][C:11]([Cl:14])=[C:10]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:9]=3)=[C:5]([CH3:7])[N:6]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1nc(N)sc1-c1cnc(Cl)c(NS(C)(=O)=O)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1nc(NC(=O)Oc2ccccc2)sc1-c1cnc(Cl)c(NS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-[5-(2-Amino-4-methyl-1,3-thiazol-5-yl)-2-chloropyridin-3-yl]methanesulfonamide (63 mg, purity 88%, 0.17 mmol) was dissolved in a mixture of THF (1 mL) and DMF (1 mL) and cooled to 0° C. Pyridine (0.103 mL, 1.27 mmol) was added followed by phenyl chloroformate (0.027 mL, 0.2 mmol). The stirring was continued for 25 minutes at 0° C. and at room temperature for 1 hour. Additional phenyl chloroformate (0.013 mL, 0.1 mmol) was added and the stirring was continued for 45 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic phase was washed with saturated aqueous sodium hydrogen carbonate, twice with water and finally with brine. Evaporation of the organic solvent at reduced pressure gave N-[5-(6-chloro-5-methanesulfonylaminopyridin-3-yl)-4-methyl-1,3-thiazol-2-yl]carbamic acid phenyl ester which was used without purification; Mass Spectrum: M+H+ 439 and 441.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:9]=[O:10])C.[C:11]1([C:17]2[N:24]3[C:20]([S:21][CH:22]=[CH:23]3)=[CH:19][N:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:11]1([C:17]2[N:24]3[C:20]([S:21][CH:22]=[CH:23]3)=[C:19]([CH:9]=[O:10])[N:18]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc(-c2ncc3sccn23)cc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1nc(-c2ccccc2)n2ccsc12
Reaction time: 8 h

Procedure:
Phosphorus oxychloride (0.6 mL, 6.44 mmol) was added to DMF (2.5 mL) over 5 minutes with cooling in an ice-bath. 5-Phenylimidazo-[5,1-b]-thiazole (500 mg, 2.5 mmol) was added, and the mixture was kept overnight at room temperature. The thick solid that had formed was slurried in methylene chloride and stirred for 30 minutes with 10% aqueous sodium carbonate solution. The organic layer was separated, washed with saturated brine solution and evaporated. The title compound was obtained after flash chromatography eluting with 20% acetone in hexane.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].[C:27]1(=O)[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([NH:1][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[NH:8][C:9](=[O:26])[C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:21])([F:22])[F:23])=[CH:12][C:11]=2[O:24][CH3:25])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Reactant: O=C1CCCC1
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1CCCCC1NC1CCCC1

Procedure:
The title compound, off-white foam, MS: m/e=453.2 [(M+H)+], was prepared in accordance with the general method of example 11 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and cyclopentanone.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15]C(=O)C)=[N:13][CH:14]=2)[CH:5]=[C:4]([CH3:19])[N:3]=1.Cl.O>O1CCOCC1.CO>[NH2:15][C:12]1[N:13]=[CH:14][C:9]([NH:8][C:6]2[CH:5]=[C:4]([CH3:19])[N:3]=[C:2]([NH2:1])[N:7]=2)=[CH:10][CH:11]=1
Reactant: CC(=O)Nc1ccc(Nc2cc(C)nc(N)n2)cn1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(Nc2ccc(N)nc2)nc(N)n1
Yield: 98.9 %

Procedure:
A suspension of 4 (1.53 g, 5.19 mmol), in 1,4-dioxane/MeOH (1:1, 100 mL) and 2 N HCl [10 mL, H2O mL+c.HCl 2 mL)] was refluxed 24 h. The solvents were evaporated to dryness and the residue was basified with aq NH3. The resulting solution was extracted with EtOAc (110×50 mL), dried (Na2SO4) and evaporation of the solvent gave 5 (1.11 g, 99%). A small sample was recrystallized from DCM/Pet.ether; mp (DCM/Pet.ether) 183-186° C.; 1H NMR [(CD3)2SO] δ 8.41 (s, 1 H, NH), 8.01 (d, J=2.5 Hz, 1 H, H-2′), 7.56 (dd, J=8.7, ′), 6.42 (d, 2.6 Hz, 1 H, H-4 J=8.8 Hz, 1 H, H-5′), 5.90 (s, 2 H, NH2), 5.67 (s, 1 H, H-5), 5.59 (s, 2 H, NH2H, CH), 2.03 (s, 33) HRMS (EI+) calc. for C10H12N6 (M+) m/z 216.1123, found 216.1124; Anal. Calc. for C10H12N6.0.25H2O: C, 54.4; H, 5.7; N, 38.1; found, C, 54.4; H, 5.7; N, 37.9%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=1[C:21]([F:24])([F:23])[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-]>CO.[Zn]>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=1[C:21]([F:22])([F:23])[F:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(OCCOCc2ccccc2)c(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1ccc(OCCOCc2ccccc2)c(C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
To a mixture of 1-(2-(benzyloxy)ethoxy)-4-nitro-2-(trifluoromethyl)benzene (8.1 g, 23.73 mmol) in MeOH (100 mL) was added zinc (15.52 g, 237 mmol) and NH4Cl (12.70 g, 237 mmol). The mixture was stirred at 20° C. for 3 h. LCMS showed the reaction was finished. The mixture was filtered, and the filtrate was concentrated to give crude product, which was purified by silica gel column (PE/EA=5:1, Rf=0.4) to obtain 4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)aniline (5.1 g, 14.40 mmol, 60.7% yield). 1H NMR (400 MHz, CDCl3) 7.35-7.24 (m, 5H), 6.81 (t, J=8.4 Hz, 2H), 6.78 (d, J=2.8 Hz, 1H), 4.63 (s, 2H), 4.13 (t, J=4.8 Hz, 2H), 3.83 (t, J=3.6 Hz, 2H); ES-LCMS m/z 312(M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18]Br.[CH:20]([NH2:23])([CH3:22])[CH3:21]>>[CH3:21][CH:20]([NH:23][CH2:17][CH2:18][O:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2])[CH3:22]
Reactant: CC(C)N
Reactant: BrCCBr
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)NCCOc1cccc(C#N)c1

Procedure:
Following the procedure of Preparation 46, 3-cyanophenol, potassium carbonate and excess 1,2-dibromoethane are reacted and the product thereof is reacted with isopropylamine to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[C:7]([CH3:13])[C:6]=2[C:14]=1[O:15][CH3:16].C(Cl)(=O)C(Cl)=O.[CH3:23][O:24][C:25](=[O:47])[C@@H:26]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH:27]([CH3:29])[CH3:28]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:23][O:24][C:25](=[O:47])[C@@H:26]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:41]=[CH:42][C:43]([NH:46][C:10]([C:8]3[O:9][C:5]4[CH:4]=[CH:3][C:2]([Br:1])=[C:14]([O:15][CH3:16])[C:6]=4[C:7]=3[CH3:13])=[O:12])=[CH:44][CH:45]=2)=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH:27]([CH3:29])[CH3:28]
Reactant: COc1c(Br)ccc2oc(C(=O)O)c(C)c12
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4ccc(Br)c(OC)c4c3C)cc2)cc1)C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
To 40 mg (0.14 mmol) of 5-bromo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid was added 0.5 mL of oxalyl chloride and the mixture was refluxed for 2 h, then the excess oxalyl chloride was removed by vacuum. The residue was dissolved in 0.5 mL of dichloromethane and was added to a mixture of 92 mg (0.25 mmol) of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester, 34 mg (0.28 mmol) of 4-(dimethylamino)pyridine and 1 mL of dichloromethane in an ice/water bath. The mixture was stirred at 0° C. for overnight. The mixture was diluted with dichloromethane and was washed with 2N HCl, and water. Removal of the solvent from the organic solution gave 20 mg (23% yield) of (S)-2-{4′-[(5-bromo-4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2.O>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc2cccnc12)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.4 %

Procedure:
4-Chlorobenzenesulfonyl chloride (300 mg, 1.38 mmol) was added to a stirred solution of 8-aminoquinoline (200 mg, 1.38 mmol) in pyridine (2 ml). DMAP (cat.) was added and the reaction was stirred at room temperature for 4 h. After no further progress of the reaction was observed (monitored by TLC and LCMS), water was added and the mixture was extracted with DCM. The organic phase was washed with a sat. KHSO4 solution, dried (Na2SO4) and concentrated in vacuo. The crude residue was triturated with n-hexane to give the title compound (270 mg, 61%).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])[N:5]=1)([O-])=O>C1COCC1.[Pd]>[NH2:1][C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])[N:5]=1
Reactant: N#CCCCCn1ccc([N+](=O)[O-])n1
Agent: [Pd]
Solvent: C1CCOC1
Product: N#CCCCCn1ccc(N)n1

Procedure:
To a solution of 5-(3-nitropyrazol-1-yl)valeronitrile (9.16 g.) in dry THF (200 ml.) was added 5% w/w palladium on carbon (1.8 g.). The mixture was stirred at 20° under an atmosphere of hydrogen. 3.2 Liters of hydrogen were absorbed over 4 hours. The catalyst was filtered off and the filtrate was evaporated in vacuo to give 5-(3-aminopyrazol-1-yl)valeronitrile as an oil.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:10]=3)[C@:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)CCC.O1CCOCC1>CS(C)=O.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>[CH2:17]([O:16][C:8]1[CH:9]=[CH:10][C:11]2[O:12][C:13]3[C:4](=[CH:3][C:2]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)=[CH:15][CH:14]=3)[C@@:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:6]=2[CH:7]=1)[C:18]([CH3:19])([CH3:20])[CH3:21]
Reactant: CC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(Br)ccc1O2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: CC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3ccccn3)ccc1O2
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A vial was charged with (R)-2′-bromo-7′-(neopentyloxy)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (0.050 g, 0.120 mmol), tetrakis(triphenylphosphine)palladium (0) (0.014 g, 0.012 mmol), 2-(tributylstannyl)pyridine (0.132 g, 0.359 mmol), and dioxane (0.6 mL). The reaction was stirred overnight at 100° C. The mixture was diluted with DMSO and filtered through a syringe filter, which was flushed with additional DMSO. The material was purified via Gilson HPLC (10-90% MeCN:H2O). The clean product fractions were partitioned between DCM and saturated sodium bicarbonate solution. The aqueous layer was extracted with DCM, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated to afford (S)-2′-(neopentyloxy)-7′-(pyridin-2-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as a white solid. MS MH+ 416.4
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH:25]1([S:31](Cl)(=[O:33])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>N1C=CC=CC=1>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:31]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)(=[O:33])=[O:32])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Solvent: c1ccncc1
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)C3CCCCC3)cc2)c2ccc3ccccc3c2N1
Yield: 34.1 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and cyclohexanesulfonyl chloride (69 μL, 0.47 mmol) were treated by heating in pyridine (3 mL). A post-treatment was performed in a conventional manner to give the title compound (15 mg, yield 34%) as brown amorphous.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[OH:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:30][C:31]#[N:32].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:30][C:31]#[N:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCc2ccccc2C1c1cc(Cl)ccc1O
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CCOc1ccc(Cl)cc1C1c2ccccc2CCN1C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of (±)-1-(5-chloro-2-hydroxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (1.9 g, 5.00 mmol, 1.00 eq.) and chloroacetonitrile (0.34 mL, 5.19 mmol, 1.04 eq.) in DMSO (1.5 mL) was added to a suspension of potassium carbonate (980 mg, 7.09 mmol, 1.42 eq.) in DMSO (1.5 mL) (exothermic). The mixture was heated up to 80° C. and stirred at that temperature for 1 hour. The reaction mixture was poured onto ice. After the ice melted, the mixture was filtered and the filter cake was rinsed with water. The resulting yellow gum was dried under hv The product was used without further purification.
Reaction SMILES: C(O)(=O)C(O)=O.[SH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:12]=1.[H-].[Na+].[CH2:21]([O:23][CH2:24][CH2:25]Cl)[CH3:22]>CN(C)C=O.C(Cl)(Cl)Cl>[CH2:21]([O:23][CH2:24][CH2:25][S:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:12]=1)[CH3:22]
Reactant: CCOCCCl
Reactant: Sc1nc(-c2cccnc2)cs1
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOCCSc1nc(-c2cccnc2)cs1
Temperature: 25 °C
Yield: 9281.9 %

Procedure:
Dissolved in 2.5 ml of N,N-dimethylformamide were 0.50 g of 2-mercapto-4-(3-pyridyl)-thiazole oxalate (1.82 mmol), and 0.10 g (4.17 mmol) of sodium hydride were added to the solution, which was stirred at room temperature. One hour later, 0.40 ml (3.65 mmol) of 2-chloroethyl ethyl ether were added to the suspension, which was then stirred for 2 hours at 80° C. The reaction solution was diluted with 50 ml of chloroform, followed by addition of 50 ml of a 5% saline solution and washing. After separation of the chloroform layer, the organic layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residues were then purified by silica gel chromatography to obtain 45 g of the title compound as an yellow oily form (93% yield).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[N+:8]([O-:12])[C:7]=1[NH2:13]>C(O)C>[NH2:13][C:7]1[N+:8]([O-:12])=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]([OH:14])=[O:4]
Reactant: COC(=O)c1ccc[n+]([O-])c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(C(=O)O)ccc[n+]1[O-]

Procedure:
1N sodium hydroxide (0.5 ml) was added to a solution of 2-aminonicotinic acid methyl ester N-oxide (80 mg, 0.48 mmol) in ethanol (5 ml) and the reaction mixture was stirred under reflux for 10 h. The solvent was evaporated under vacuum and the residue was taken up with water and extracted with methylene chloride. After addition of 1N hydrochloric acid to the aqueous solution, the resulting precipitate was filtered, rinsed with water and dried under vacuum, thus obtaining 2-aminonicotinic acid N-oxide (I1) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:17])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:27][C:28]([C:30]1([C:33](O)=[O:34])[CH2:32][CH2:31]1)=[O:29].[CH2:36]([NH2:41])[C:37]([CH3:40])([CH3:39])[CH3:38].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:38][C:37]([CH3:40])([CH3:39])[CH2:36][NH:41][C:33]([C:30]1([C:28]([NH:27][C:3]2[CH:4]=[CH:5][C:6]([O:8][C:9]3[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]4[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]4)=[O:17])[CH:10]=3)=[CH:7][C:2]=2[F:1])=[O:29])[CH2:32][CH2:31]1)=[O:34]
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)O)CC4)c(F)c3)ccn2)CC1
Reactant: CC(C)(C)CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)NCC(C)(C)C)CC4)c(F)c3)ccn2)CC1
Reaction time: 22 h
Yield: 51 %

Procedure:
To a solution of 1-(2-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)carbamoylcyclopropanecarboxylic acid (40 mg) in N,N-dimethylformamide (1.0 ml) were added neopentylamine (0.0194 ml), triethylamine (0.023 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (72.9 mg) at room temperature, followed by stirring for 22 hr. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=97:3). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (23.2 mg, 51%).