Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[N:7][C:8](SC)=[N:9][CH:10]=2)[N:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C@H:22]([OH:24])[CH3:23])[N:17]=1)[CH:2]=[CH2:3].[CH3:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[N:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)[NH2:29]>>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[N:7][C:8]([NH:29][C:28]3[CH:30]=[CH:31][C:32]([N:33]4[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]4)=[C:26]([CH3:25])[CH:27]=3)=[N:9][CH:10]=2)[N:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([OH:24])[CH3:23])[N:17]=1)[CH:2]=[CH2:3]
Reactant: Cc1cc(N)ccc1N1CCN(C)CC1
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1cccc([C@@H](C)O)n1
Product: C=CCn1c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)c(C)c3)nc2n1-c1cccc(C(C)O)n1

Procedure:
83.2 mg of the entitled compound was obtained as a white solid in the same manner as in Example 86-1 to 86-3, for which, however, a racemic starting material thereof was used in place of the chiral starting material of 2-allyl-1-{6-[(1R*)-1-hydroxyethyl]pyridin-2-yl}-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one used in Example 86-2, and 3-methyl-4-(4-methylpiperazin-1-yl)aniline was used in place of 4-(4-methylpiperazin-1-yl)aniline used in Example 86-3.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:37]([O:39][CH3:40])=[O:38]>C(Cl)Cl>[C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:37]([O:39][CH3:40])=[O:38])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cl
Reactant: CSc1nc(-c2cccc(O)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Oc1cccc(-c2nc(SC)nc3sc(C(=O)NC(C)(C)C)c(N)c23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 5-amino-2-methylthio-4-(3-hydroxyphenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 1f, 100 mg) was dissolved in dry CH2Cl2 (5 ml). DIPEA (500 μl ) and methyl chloroformate (199 μl ) were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with H2O. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: CH3CN/H2O=10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.
Reaction SMILES: Cl[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[Cl:9][C:10]1[CH:11]=[C:12]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[O:13][C:14]1[C:15]([CH3:23])=[N:16][N:17]([CH2:20][CH2:21][OH:22])[C:18]=1[CH3:19].N1C=CN=C1.O>CN(C)C=O>[Si:2]([O:22][CH2:21][CH2:20][N:17]1[C:18]([CH3:19])=[C:14]([O:13][C:12]2[CH:24]=[C:25]([Cl:27])[CH:26]=[C:10]([Cl:9])[CH:11]=2)[C:15]([CH3:23])=[N:16]1)([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: Cc1nn(CCO)c(C)c1Oc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(CCO[Si](C)(C)C(C)(C)C)c(C)c1Oc1cc(Cl)cc(Cl)c1
Reaction time: 48 h
Yield: 100 %

Procedure:
Chloro-t-butyldimethylsilane (1.93 g, 12.8 mmol) was added in one portion to a stirred solution of the pyrazole of Example 1 (3.50 g, 11.6 mmol) and imidazole (1.03 g, 15.1 mmol) in N,N-dimethylformamide (23 ml) at room temperature under nitrogen. The reaction was stirred for 2 days and water (200 ml) was added. The aqueous phase was extracted with diethyl ether (3×200 ml) and the combined organic phases were washed with water (2×50 ml) and brine (2×50 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with pentane:ethyl acetate (80:20, by volume) to provide the title compound (4.82 g) as a colourless oil.
Reaction SMILES: [CH3:1][C:2]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].BrC1C=CC(C(C)(C)C(OCC)=O)=CC=1>>[CH3:8][C:2]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)c1cccs1
Agent: CCOC(=O)C(C)(C)c1ccc(Br)cc1
Product: CC(C)(C(=O)O)c1cccs1

Procedure:
The title compound was prepared according to the method of Example 22B, substituting the product of Example 23A for the product of Example 22A.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28]O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][O:16][C:13]2[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:5])=[O:18])=[O:17])=[CH:15][CH:14]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(O)cc1
Reactant: OCCCCc1ccccc1
Product: O=C(O)CNC(=O)c1ccc(OCCCCc2ccccc2)cc1
Yield: 62.6 %

Procedure:
The same reaction as in Example 1 (1b) was conducted using N-(4-hydroxybenzoyl)glycine tert-butyl ester (249 mg, 0.991 mmol) prepared in Example 1 (1a) and 4-phenylbutan-1-ol (200 μL, 1.30 mmol) to give 203 mg of the title compound (white powder, yield: 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH:23]([CH3:25])[NH:22][CH2:21][CH2:20]2>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:21][CH2:20][C:19]4[C:24](=[C:15]([F:14])[CH:16]=[CH:17][CH:18]=4)[CH:23]3[CH3:25])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2cccc(F)c21
Product: CC1c2c(F)cccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-fluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:12][C:13]1[CH:18]=[C:17]([CH:16]=[CH:15][CH:14]=1)[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1ccc(O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 4-hydroxybenzoate (0.400 g; 2.63 mmol), 3-fluorobenzene boronic acid (0.735 g; 5.26 mmol), copper acetate (0.955 g; 5.26 mmol) and pyridine (0.425 mL; 5.26 mmol) in dichloromethane (15 mL) was stirred at room temperature overnight. The reaction mixture was filtered and concentrated under reduced pressure.
Reaction SMILES: I[C:2]1[C-:3]([N:7]([CH3:9])[CH3:8])[CH:4]=[CH:5][CH:6]=1.[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>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.C(COC)OC>[C:16]1([C:2]2[C-:3]([N:7]([CH3:9])[CH3:8])[CH:4]=[CH:5][CH:6]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15]
Reactant: OB(O)c1ccccc1
Reactant: CN(C)[c-]1cccc1I
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: COCCOC
Product: CN(C)[c-]1cccc1-c1ccccc1
Temperature: 55 °C
Yield: 79.9 %

Procedure:
Racemic iodide 12i (89 mg, 0.25 mmol), PhB(OH)2 (34 mg, 0.28 mmol) and Pd(PPh3)4 (29 mg, 2.51×10−2 mmol) were added to a dry Schlenk flask, followed by dimethoxyethane (DME, 2 mL) and an aqueous solution of 3 M NaOH (0.17 mL, 0.50 mmol). Argon was bubbled through the resulting mixture for 10 minutes, and the system was heated at 55° C. for 14 h. The reaction was allowed to cool to room temperature, diluted with Et2O, washed with water (1×5 mL), brine (1×5 mL), dried over Na2SO4, filtered, and all volatiles were removed in vacuo. Flash column chromatography (silica gel, 98:2 hexane/EtOAc) afforded 55 (61 mg, 80%) as an orange oil: Rf 0.45 (90:10 hex/EtOAc); IR (KBr, CHCl3) vmax 3091, 2941, 2852, 2779, 1601, 1491, 1444, 1416 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.80-7.74 (m, 2H), 7.36-7.19 (m, 3H), 4.28-4.25 (m, 1H), 4.18 (s, 5H), 4.15-4.11 (m, 1H), 4.05 (t, 1H, J=2.7 Hz), 2.53 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 139.1, 128.4, 127.8, 125.9, 112.5, 78.1, 69.2, 66.5, 62.4, 58.0, 44.6; EIMS [m/z (%)] 305 (M+, 100); HRMS (EI) calcd for C18H19N56Fe: 305.0867. Found 305.0864.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][CH:25]=3)[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)C(C)C)C.[NH2:62][C@H:63]([CH2:67][S:68][S:69][C:70]([CH3:73])([CH3:72])[CH3:71])[C:64]([OH:66])=[O:65]>C(Cl)Cl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][CH:25]=3)[C:20]([NH:62][C@H:63]([CH2:67][S:68][S:69][C:70]([CH3:73])([CH3:72])[CH3:71])[C:64]([OH:66])=[O:65])=[O:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)SSC[C@@H](N)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)SSC[C@@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-indol-3-yl)propanoic acid (Fmoc-Trp-OH) (1.26 g, 2.96 mmol) and N-hydroxysuccinimide (341 mg, 2.96 mmol) in methylene chloride (5.9 mL) were mixed with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCI.HCl) (568 mg, 2.96 mmol) at 0° C., and the reaction solution was stirred at room temperature for 16 hours. N-Ethyl-N-isopropyl propane 2-amine (DIPEA, 517 μL, 2.96 mmol) and (S)-2-amino-3-(tert-butyldisulfanyl)propanoic acid (H-D-Cys(StBu)-0H) (Compound SP641) (620 mg, 2.96 mmol) were then mixed at 0° C., and the reaction solution was stirred at room temperature for 5 hours. After washing with 1 N hydrochloric acid, the organic layer was extracted with ethyl acetate, and the resulting organic layer was washed with a saturated aqueous sodium chloride solution and then dried over sodium sulfate. Following concentration under reduced pressure, the resulting residue was crude purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-indol-3-yl)propanamido)-3-(tert-butyldisulfanyl)propanoic acid (Fmoc-Trp-D-Cys(StBu)-OH) (Compound SP642).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[F:5][C:6]([F:15])([F:14])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.N1C=CC=CC=1>ClCCl>[N:13]([C:10]1[CH:11]=[CH:12][C:7]([C:6]([F:5])([F:14])[F:15])=[CH:8][CH:9]=1)=[C:1]=[S:2]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: S=C(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(N=C=S)cc1

Procedure:
Thiophosgene (5 mL) was added portion wise to a stirred solution of 4-trifluoromethyl-phenylamine (10 grams) and pyridine (12.5 mL) in dichloromethane (2 Liters) at 0° C. The reaction was maintained at the same temperature for 30 minutes. The reaction mixture was then diluted with dichloromethane and washed several times with a saturated solution of copper sulfate, followed by water, drying over sodium sulfate and evaporating to give the crude product which was further purified by passing through a column of silica gel, to yield the pure product (11 grams).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:22][C:23]([F:45])([O:28][C:29]([F:44])([F:43])[C:30]([F:42])([F:41])[O:31][C:32]([F:40])([F:39])[CH2:33][O:34][CH2:35][CH2:36][CH2:37]Br)[C:24]([F:27])([F:26])[F:25].BrCCCBr.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:37][CH2:36][CH2:35][O:34][CH2:33][C:32]([O:31][C:30]([F:41])([F:42])[C:29]([F:43])([F:44])[O:28][C:23]([F:22])([F:45])[C:24]([F:26])([F:27])[F:25])([F:40])[F:39])=[CH:17][CH:16]=2)=[N:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(F)(COCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F
Agent: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-octyl-2-(4-hydroxyphenyl)pyrimidine (2.0 g, 7.3 mmol), 3-(2-(2-(pentafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-bromopropane (3.38 g, 7.47 mmol; prepared by combining 1,3-dibromopropane with 3-(2-(2-(pentafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethanol), and potassium carbonate (1.16 g, 8.43 mmol) in acetonitrile (20 mL) and refluxing the resulting mixture under nitrogen overnight. The mixture was cooled and filtered, and the resulting solids were washed with toluene (50 mL). The toluene was then removed under reduced pressure, and the resulting waxy solid was dissolved in toluene (50 mL) and washed with three 30 mL aliquots of perfluorohexane. After removing the toluene under reduced pressure, the resulting crude product was further purified by silica gel chromatography, eluting with 20 volume percent ethyl acetate/hexane, to yield 3.60 g of purified product.
Reaction SMILES: [CH2:1]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][N:17]=3)[CH:13]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.NN>>[CH2:1]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][N:17]=3)[CH:13]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCC1Cc2ccc(-c3ccc([N+](=O)[O-])cn3)cc2C1
Agent: NN
Solvent: O
Product: CCCCCCC1Cc2ccc(-c3ccc(N)cn3)cc2C1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
Subsequently, 1.01 g (3.11 mM) of 2-hexyl-5-(5-nitropyridine-2-yl)indan, 0.19 g of activated carbon and 0.02 g ferric chloride hexahydrate were mixed and stirred at room temperature. To the mixture, 0.96 ml of 80%-hydrazine hydrate (density: 1.03) was added dropwise, followed by stirring for 40 minutes at 70°-71.5° C. The resultant insoluble matter was removed by filtration and the filtrate was concentrated under reduced pressure, followed by addition of methanol and cooling in a refrigerator to obtain an insoluble matter. The insoluble matter was recovered by filtration to obtain 0.71 g of 2-hexyl-5-(5-aminopyridine-2-yl)indan (Yield: 77.5%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:31]=CC=C[CH:27]=1.C(O)(C)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([O:25][CH:26]([CH3:31])[CH3:27])[CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1ccc(O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COC(=O)c1ccc(OC(C)C)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 81.7 %

Procedure:
To a solution of methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-hydroxy-benzoate (0.735 g, 2.1 mmol), triphenylphosphine (0.551 g, 2.1 mmol), and isopropanol (0.158 mL, 2 mmol) in tetrahydrofuran was added diisopropyl azodicarboxylate (0.433 mL, 2.2 mmol) dropwise. The solution was sonicated for 30 minutes. The reaction mixture was purified without workup by RPLC (EtOAc/Hexane 3:7) to give 0.675 g (86%) of pure product.
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][OH:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)Cl>[C:19]([O:11][CH2:10][CH2:9][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CN(CCO)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCN(C)c1ccccc1

Procedure:
A 1 L flask was charged with 2-(N-methylanilino)ethanol (8) (151.3 g, 1 mole), methylene chloride (250 mL), and triethylamine (151 g, 1.48 mole). Acetic anhydride (153.35 g, 1.5 mole) was added to the solution at room temperature through an addition funnel. The product (7) was collected by vacuum distillation (122 g, bp 110° C. at 400 micron Hg).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[CH2:20]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC#N>[CH2:20]([N:27]1[CH2:28][CH2:29][N:30]([C:33]2[CH:34]=[CH:35][C:36]([NH:39][C:8]3[C:9](=[O:10])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[S:6](=[O:19])(=[O:18])[C:7]=3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:37][CH:38]=2)[CH2:31][CH2:32]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Solvent: CC#N
Product: CCCCN1C(=O)C(Nc2ccc(N3CCN(Cc4ccccc4)CC3)cc2)=C(c2ccccc2)S1(=O)=O
Temperature: 180 °C
Yield: 101.8 %

Procedure:
A mixture of 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.400 g, 1.334 mmol), [4-(4-benzylpiperazin-1-yl)phenyl]amine (0.357 g, 1.334 mmol) and TEA (0.190 ml, 1.334 mmol) in MeCN (5 ml) was heated in a microwave reactor at 120° C. for 35 mins, 160° C. for 20 mins and 180° C. for 20 mins. The reaction mixture was evaporated and the residue was purified by flash chromatography (Horizons Biotage) using 35-65% EtOAc in petroleum ether 40-60° C. as eluent to give the title compound (0.721 g, 78%). 1H NMR (500 MHz CDCl3); δ 7.40-7.32 (m, 3H), 7.30-7.24 (m, 2H), 7.22-7.18 (m, 1H), 7.16-7.08 (m, 4H), 6.60 (d, 2H), 6.52 (d, 2H), 3.78 (t, 2H), 3.57 (d, 2H), 3.05 (t, 4H), 2.57 (t, 4H), 1.92-1.84 (m, 2), 1.54-1.46 (m, 2H), 1.01 (t, 3H); 13C NMR (125 MHz CDCl3).: 159.7, 149.4, 138.1, 131.5, 129.5, 129.4, 128.9, 128.5, 128.1, 127.9, 127.4, 125.1, 123.6, 118.8, 109.4, 63.3, 53.1, 49.5, 40.4, 30.5, 20.3, 13.8; Mass Spectrum: M+H+ 531.
Reaction SMILES: [N:1](=[C:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:4]#[N:5])[OH:2].[CH3:11][N:12]=[C:13]=[O:14]>C(N(CC)CC)C.CCOCC>[CH3:11][NH:12][C:13]([O:2][N:1]=[C:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:4]#[N:5])=[O:14]
Reactant: N#CC(=NO)c1cccs1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CNC(=O)ON=C(C#N)c1cccs1

Procedure:
To a solution of 3.04 g. (0.02 mole) of alphaoximino-2-thienylacetonitrile and 2 drops of triethylamine in 50 ml. of ether was added 1.14 g. (0.02 mole) of methylisocyanate in 10 ml. of ether. After 1 hour the solid was filtered and crystallized from benzene to give 3.8 g. of product melting at 154°-155° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([OH:21])=O)=[CH:5]2.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.[NH2:52][C:53]1[CH:54]=[C:55]2[N:61]=[C:60]([CH3:62])[N:59]([CH3:63])[C:56]2=[N:57][CH:58]=1>CN(C=O)C>[CH3:62][C:60]1[N:59]([CH3:63])[C:56]2=[N:57][CH:58]=[C:53]([NH:52][C:19]([C:6]3[N:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=4)[C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)=[O:21])[CH:54]=[C:55]2[N:61]=1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: Cc1nc2cc(N)cnc2n1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc2cc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)cnc2n1C
Temperature: 20 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a solution, stirred at 20° C., of 0.25 g (0.87 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid prepared in step 1.1, 183 mg (0.96 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) and 129 mg (0.96 mmol) of 1-hydroxybenzotriazole (HOBT) in 8 mL of DMF are added 130 microliters (0.96 mol) of triethylamine and then 224 mg (1.13 mmol) of 6-amino-2,3-dimethyl-3H-imidazo[4,5-b]pyridine hydrochloride (Ukrainskii Khimicheskii Zhurnal 1981, 47, 867). The reaction mixture is stirred for 8 hours at 20° C. and then concentrated under reduced pressure. The resulting product is taken up in 100 mL of water, and a precipitate is collected by filtration and is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol. The fractions containing the product are combined and evaporated to a quarter of their volume. 50 mL of n-heptane are added to the solution, and a solid is collected by filtration and dried under reduced pressure. 150 mg of the expected product are thus isolated.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CC(C)([O-])C.[K+].Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]([O:26]C)=[O:25])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]([OH:26])=[O:25])[CH:19]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1cc(Cl)ccn1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cc(Oc2cccc([N+](=O)[O-])c2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.6 %

Procedure:
A mixture of 3-nitrophenol (3.65 g, 26.2 mmol), potassium tert-butoxide (3.23 g, 28.8 mmol) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 30 min. After stirring, methyl 4-chloropyridine-2-carboxylate (3.00 g, 17.5 mmol) and potassium carbonate (10.9 g, 78.6 mmol) were added, and the mixture was stirred at 120° C. for 3 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, ethanol (20 mL) and 8N aqueous sodium hydroxide solution (3 mL) were added to the residue, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and the precipitated solid was collected by filtration and washed with water to give 4-(3-nitrophenoxy)pyridine-2-carboxylic acid (345 mg, 8.0%) as a white solid. A mixture of 4-(3-nitrophenoxy)pyridine-2-carboxylic acid (339 mg, 1.24 mmol) thus-obtained, diphenylphosphoryl azide (333 μL, 1.55 mmol), triethylamine (215 μL, 1.55 mmol), N,N-dimethylformamide (5 mL) and water (5 mL) was stirred at 100° C. for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure. The residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (253 mg, 8.8%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.Br[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[CH3:22][C:7]1([CH3:21])[C:8]2[NH:9][C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=3)[C:16]=2[C:17](=[O:18])[C:5]2[CH:4]=[CH:3][C:2]([O:1][C:25]3[N:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:23][C:6]1=2
Reactant: Brc1ncccn1
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(Oc3ncccn3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A6 and 2-bromopyrimidine.