Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:2]([C:12]([OH:14])=O)[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH2:46]([O:48][C:49]([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)=[O:50])[CH3:47].C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1.CC(=O)OCC>[CH2:46]([O:48][C:49]([N:51]1[CH2:52][CH2:53][N:54]([C:12](=[O:14])[C@@H:2]([NH:1][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3][CH2:4][C:5]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:11])[CH2:55][CH2:56]1)=[O:50])[CH3:47]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.9 %

Procedure:
To a solution of Z-(L)Glu(OtBu)-OH (5 g) in DCM/THF (1:1, 42 ml) were added at RT HOBT (2.5 g) and EDCI (3.1 g). After 15 min stirring at RT, 1-ethoxycarbonylpiperazine (2.6 g) was added and the stirring was continued at RT overnight. 150 ml of EA and 60 ml of a NaHCO3 solution were added to the reaction mixture and the phases were separated. The org. phase was washed with an aq. NaHSO4 (1M) solution and with brine, dried over Na2SO4 and evaporated off. After HV drying, 7 g of the desired compound were obtained.
Reaction SMILES: [OH:1][C:2]([C:22]([F:25])([F:24])[F:23])([CH3:21])[CH:3]=[CH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][C@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH3:20].C(Cl)Cl>[Pd].O>[OH:1][C:2]([C:22]([F:25])([F:24])[F:23])([CH3:21])[CH2:3][CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][C@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH3:20]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(C=CC(C)(O)C(F)(F)F)cc12
Agent: [Pd]
Solvent: O
Solvent: ClCCl
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(CCC(C)(O)C(F)(F)F)cc12

Procedure:
Obtained from the title compound of Example 96 by a procedure similar to that described in Example 2, but using 10% palladium on charcoal as catalyst, as a foam. Rf 0.40 (SS 7). Found: C,59.55; H,6.86; N,7.10. C19H25F3N2O; 0.17 CH2Cl2 ; H2O requires C,59.55; H,7.13; N,7.25%. LRMS: m/z 355.0 (M+1)+.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[F:9][C:10]([F:22])([F:21])[O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1/[CH:14]=[N:15]/[OH:16]>CN(C)C=O.O>[F:9][C:10]([F:21])([F:22])[O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1/[C:14](=[N:15]/[OH:16])/[Cl:8]
Reactant: O/N=C/c1ccccc1OC(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: O/N=C(\Cl)c1ccccc1OC(F)(F)F

Procedure:
NCS (22 g, 166.04 mmol, 1.12 equiv) was slowly added to a stirred solution of (E)-2-(trifluoromethoxy)benzaldehyde oxime (30 g, 146.27 mmol, 1.00 equiv) in N,N-dimethylformamide (300 mL) keeping the internal temperature below 25°C. The reaction mixture was stirred fo(1 h at room temperature. The resulting solution was diluted with water (300 mL) and extracted with ethyl acetate (2×500 mL). The organic layers were combined, washed with brine (5×300 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give (Z)-2-(trifluoromethoxy)benzoyl chloride oxime as a light yellow crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[C:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]([CH3:29])([CH3:28])[CH:21]=1>[Pt](=O)=O.CCOC(C)=O.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]([CH3:29])([CH3:28])[CH2:21]1
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2=CC(C)(C)CC(C)(C)C2)c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2CC(C)(C)CC(C)(C)C2)c1
Reaction time: 8 h
Yield: 59.3 %

Procedure:
A screw-cap pressure tube was charged with 69.31B (0.22 g, 0.55 mmol), 1:1 EtOAc/MeOH (10 mL), and platinum(IV) oxide (0.025 g, 0.11 mmol). The tube was purged three times with H2 at 50 psi and sealed, and the contents were stirred overnight. The mixture was diluted with EtOAc, filtered through silica gel (EtOAc), and concentrated. The crude product was purified by silica gel flash chromatography (0-8% EtOAc/hexane) to afford 69.32A (0.13 g, 59% yield) as a colorless oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][OH:6])=[NH:4].[CH3:7][C:8]1([C:11](Cl)=O)[CH2:10][CH2:9]1.C(N(CC)CC)C.[Cl-].[Na+]>CN(C)C=O>[Cl:1][CH2:2][C:3]1[N:4]=[C:7]([C:8]2([CH3:11])[CH2:10][CH2:9]2)[O:6][N:5]=1
Reactant: CC1(C(=O)Cl)CC1
Reactant: N=C(CCl)NO
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(c2nc(CCl)no2)CC1
Temperature: 130 °C
Reaction time: 6 h
Yield: 22.2 %

Procedure:
2.75 g of 2-chloro-N-hydroxyacetoamidine and 3.0 g of 1-methylcyclopropanecarbonyl chloride were dissolved in 50 ml of N,N-dimethylformamide, and 2.8 g of triethylamine was added dropwise under ice-cooling. After completion of the addition, the mixture was heated to 130° C., stirred for 6 hours and then cooled to room temperature. After aqueous saturated sodium chloride was added, the reaction mixture was extracted with methyl-t-butyl ether. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.97 g of 3-(chloromethyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole.
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.[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>COCCOC>[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]([NH:29][CH2:28][CH2:27][CH2:26][CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCCCCc1ccccc1
Solvent: COCCOC
Product: N#Cc1c(NCCCCc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and 4-phenylbutylamine in DME. ES-MS m/e (%): 334 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[N:11]2[CH:12]=[N:13][N:14]=[C:10]2[C:9]2[CH:8]=[C:7]([O:15][CH3:16])[C:6]([O:17][CH3:18])=[CH:5][C:4]=2[N:3]=1.C(O)(=[O:21])C>>[CH3:18][O:17][C:6]1[C:7]([O:15][CH3:16])=[CH:8][C:9]2[C:4]([CH:5]=1)=[N:3][C:2](=[O:21])[N:14]1[NH:13][CH:12]=[N:11][C:10]=21
Reactant: COc1cc2nc(Cl)n3cnnc3c2cc1OC
Reactant: CC(=O)O
Product: COc1cc2nc(=O)n3[nH]cnc3c2cc1OC

Procedure:
500 mg of 5-chloro-8,9-Dimethoxy-1,2,4-triazolo-[4,3-c]quinazoline is refluxed with 50 ml glacial acetic acid for 1 hour. The mixture is then evaporated in vacuo to dryness. The residue is treated with water/methylene chloride/diethyl ether and the solid material which is, 8,9-Dimethoxy-1,2,4-triazolo-[1,5-c]quinazoline-5-one is filtered off, washed well with water, then diethyl ether and dried, m.p. 320°-325° C.
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.[C:38]([N:42]([CH3:47])[C:43](=O)[CH2:44]Cl)([CH3:41])([CH3:40])[CH3:39]>>[C:38]([N:42]([CH3:47])[CH2:43][CH2:44][O:10][C:8]1[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[CH:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:6][CH:7]=1)([CH3:41])([CH3:40])[CH3:39]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(C(=O)CCl)C(C)(C)C
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN(C)C(C)(C)C)cc2)c1
Yield: 145.6 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and N-tert-butyl-2-chloro-N-methylacetamide (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (15 mg) was obtained.
Reaction SMILES: CNC(C1C=CC(CCC(O)=O)=CC=1)=O.NCC(N(C1C=CC(Cl)=C(COC2C3N=C(OC)N(CC4C=CC=CN=4)C=3C=CC=2)C=1Cl)C)=O.[Cl:50][C:51]1[C:56]([CH2:57][O:58][C:59]2[C:67]3[N:66]=[C:65]([O:68][CH3:69])[N:64]([CH2:70][C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][N:72]=4)[C:63]=3[CH:62]=[CH:61][CH:60]=2)=[C:55]([Cl:77])[CH:54]=[CH:53][C:52]=1[N:78]([CH3:100])[C:79](=[O:99])[CH2:80][NH:81][C:82](=[O:98])[CH2:83][CH2:84][C:85]1[CH:97]=[CH:96][C:88]([C:89]([NH:91][CH2:92]COC)=[O:90])=[CH:87][CH:86]=1>>[Cl:50][C:51]1[C:56]([CH2:57][O:58][C:59]2[C:67]3[N:66]=[C:65]([O:68][CH3:69])[N:64]([CH2:70][C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][N:72]=4)[C:63]=3[CH:62]=[CH:61][CH:60]=2)=[C:55]([Cl:77])[CH:54]=[CH:53][C:52]=1[N:78]([CH3:100])[C:79](=[O:99])[CH2:80][NH:81][C:82](=[O:98])[CH2:83][CH2:84][C:85]1[CH:86]=[CH:87][C:88]([C:89]([NH:91][CH3:92])=[O:90])=[CH:96][CH:97]=1
Reactant: COCCNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)cc1
Agent: CNC(=O)c1ccc(CCC(=O)O)cc1
Agent: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Product: CNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)cc1

Procedure:
Compound 33 is prepared from 3-(4-(methylcarbamoyl)phenyl)propanoic acid and 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide as described for compound 1. MS (ESI) 689 (M+) 1HNMR (CDCl3), 2.42-2.58 (m, 2H), 2.80-2.90 (m, 5H), 3.18 (s, 3H), 3.3-3.5 (m, 1H), 3.65-3.72 (m, 1H), 4.14 (s, 3H), 5.25 (s, 2H), 5.5-5.7 (m, 2H), 6.4-6.6 (m, 2H), 6.75-6.82 (m, 2H), 6.85-6.91 (m, 1H), 6.95-7.10 (m, 3H), 7.38-7.45 (m, 1H), 7.52-7.62 (m, 1H), 6.8-6.72 (m, 2H), 8.52-8.60 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[O:9])[NH2:8])=[C:4]([NH:10][C:11]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=O)[CH:3]=1.[OH-].[Na+].Cl>COCCOC>[Br:1][C:2]1[S:6][C:5]2[C:7](=[O:9])[NH:8][C:11]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: NC(=O)c1sc(Br)cc1NC(=O)c1nccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: O=c1[nH]c(-c2nccs2)nc2cc(Br)sc12
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a mixture of 3-amino-5-bromothiophene-2-carboxamide (200 mg) produced in Example 1, step D, triethylamine (0.19 mL) and tetrahydrofuran (4.0 μL) was added 1,3-thiazole-2-carbonyl chloride (0.22 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. Water was poured into the reaction system, and the precipitate was collected by filtration to give N-(5-bromo-2-carbamoylthiophen-3-yl)-1,3-thiazole-2-carboxamide (290 mg) as a pale-yellow solid. To N-(5-bromo-2-carbamoylthiophen-3-yl)-1,3-thiazole-2-carboxamide produced above were added 2M aqueous sodium hydroxide solution (1.75 mL) and 1,2-dimethoxyethane (4.0 mL), and the mixture was stirred at 100° C. for 18 hr. The reaction system was neutralized with 1M hydrochloric acid at 0° C. The precipitate was collected by filtration to give the title compound (236 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]([S:21][CH3:22])[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:31](=[O:40])[C:32]2[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=2[NH2:39])=[N:28][CH:29]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]([S:21][CH3:22])[CH:18]=[CH:17][C:13]=1[C:14]([NH:39][C:33]1[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:32]=1[C:31]([NH:30][C:27]1[CH:26]=[CH:25][C:24]([Cl:23])=[CH:29][N:28]=1)=[O:40])=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Reactant: CSc1ccc(C(=O)O)c(OCCNC(=O)OC(C)(C)C)c1
Product: CSc1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)c(OCCNC(=O)OC(C)(C)C)c1

Procedure:
2-[2-[2-(tert-Butoxycarbonylamino)ethoxy]-4-(methylthio)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide was prepared by methods described in example 4-E from 2-[2-(tert-butoxycarbonylamino)ethoxy]-4-(methylthio)benzoic acid and N-(5-chloropyridin-2-yl)-2-amino-5-chlorobenzamide (3 g, 92%). IR (CHCl3): 1665, 1500, 1375, 1296 cm−1.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][CH:4]([C:16]([O:18]CC)=O)[C:3]1=O.[C:22]1([CH2:28][C:29]([NH2:31])=[NH:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:28]([C:29]1[NH:31][C:16](=[O:18])[C:4]2[CH2:5][CH2:6][N:7]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:8][CH:2]([CH3:1])[C:3]=2[N:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC(C)C1=O
Reactant: N=C(N)Cc1ccccc1
Product: CC1CN(C(=O)OC(C)(C)C)CCc2c1nc(Cc1ccccc1)[nH]c2=O
Yield: 70 %

Procedure:
The title compound was prepared by a similar method to that of Preparation 1, Step A, starting from 1-tert-butyl 4-ethyl 6-methyl-5-oxoazepane-1,4-dicarboxylate and 2-phenyl-acetamidine, yielding 70% of title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]([CH3:23])[C:20]([NH2:22])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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]>[CH3:18][N:19]([CH3:23])[C:20]([NH:22][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1)=[O:21]
Reactant: CN(C)C(N)=O
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN(C)C(=O)Nc1cc(Oc2ccc([N+](=O)[O-])nc2)ccn1
Temperature: 100 °C
Yield: 86.2 %

Procedure:
A mixture of Example A1 (6 g, 23.8 mmol) in dioxane (100 mL) was sparged with Ar under sonication for 20 min, then treated with N,N-dimethyl urea (10.50 g, 119 mmol), Cs2CO3 (1.942 g, 5.96 mmol), and XANTPHOS (2.76 g, 4.77 mmol), and again sparged with Ar under sonication for 15 min. Pd2(dba)3 (2.18 g, 2.38 mmol) was added and the mixture was again sparged with Ar for 15 min under sonication. The reaction was then heated to 100° C. for 3 h. The mixture was cooled to RT, diluted with EtOAc and the solids removed via filtration through diatomaceous earth. The filtrate was concentrated to dryness and purified by silica gel chromatography (MeOH/DCM) to afford 1,1-dimethyl-3-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)urea (6.22 g, 81%). MS (ESI) m/z: 304.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9]C(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[N:14]1([CH2:19][CH2:20][CH2:21][NH2:22])[CH:18]=[N:17][CH:16]=[N:15]1>>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][C:6]=1[C:7]([NH:22][CH2:21][CH2:20][CH2:19][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)=[O:9]
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: NCCCn1cncn1
Product: Nc1ccc(Cl)cc1C(=O)NCCCn1cncn1

Procedure:
When 5-chloroisatoic anhydride was reacted with 3-(1H-1,2,4-triazol-1-yl)propylamine by the procedure of Example 14, this compound, mp 116°-118° C., was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[N+:17]([C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:27]([NH:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=2)=[O:28])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2cccc([N+](=O)[O-])c2)cc1-c1c(Br)cnn1C
Yield: 69.2 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.036 g, 0.13 mmol) was treated with 3-nitrophenyl isocyanate (0.023 g, 0.13 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 15 (0.040 g, 0.09 mmol, 70%) as a yellow solid. LCMS m/z (%)=446 (M+H79Br, 100), 448 (M+H81Br, 89). 1H NMR (400 MHz, acetone-d6) δ: 8.63 (s, 1H), 8.58 (s, 1H), 8.28 (s, 1H), 7.80-7.86 (m, 2H), 7.72 (dd, J=2.7, 9.0 Hz, 1H), 7.55 (t, J=8.2 Hz, 1H), 7.50 (s, 1H), 7.45 (d, J=2.7 Hz, 1H), 7.16 (d, J=9.0 Hz, 1H), 3.83 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: [C:1]([O:8]C)(=[O:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].B1C2CCCC1CCC2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:28]1[CH:33]=[C:32]([N:34](COCC[Si](C)(C)C)COCC[Si](C)(C)C)[N:31]2[N:51]=[CH:52][C:53]([C:54]3[CH:55]=[N:56][C:57]4[C:62]([CH:63]=3)=[CH:61][CH:60]=[CH:59][CH:58]=4)=[C:30]2[N:29]=1>C1COCC1.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:34][C:32]1[N:31]2[N:51]=[CH:52][C:53]([C:54]3[CH:55]=[N:56][C:57]4[C:62]([CH:63]=3)=[CH:61][CH:60]=[CH:59][CH:58]=4)=[C:30]2[N:29]=[C:28]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:7])[CH:33]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: C=CCCCC(=O)OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Nc1cc(CCCCCC(=O)O)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.3 %

Procedure:
To a solution of methyl hex-5-enoate (12 mg, 0.1 mmol) in THF (0.5 ml) under argon at 0° C. was added 9-BBN (0.2 mmol, 0.4 ml of 0.5 M solution in THF). The mixture was warmed to room temperature and stirred for 16 h. Potassium phosphate (3 M in H2O, 0.2 mmol) was added followed by the addition of 5-chloro-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (50 mg, 0.09 mmol) in DMF (0.5 ml) and Pd(dppf)Cl2—CH2Cl2 (5 mg, 0.005 mmol). The reaction mixture was heated at 90° C. for 16 h under argon. The solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 2:1 THF: MeOH (3 mL) and was treated with 2N NaOH(aq) (0.25 mL). The resulting solution was stirred at room temperature for 4 hours followed by the addition of 2N hydrochloride solution (1.0 ml). The solution was heated at 65° C. for 2 h, cooled to room temperature, concentrated in vacuo and purified by prep-LC to afford the title compound (8.2 mg): LC/MS RT=2.74 min. Mass calculated for, M+H 376.17, observed 376.17.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[CH:9]=[C:10]([CH3:15])[C:11]([OH:14])=[CH:12][CH:13]=1.Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].O>CN(C=O)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH3:15])[CH:9]=1)[CH3:22]
Reactant: Cc1cc(N)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CNc1ccc(O)c(C)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Potassium carbonate (5.04 g, 36.5 mmol) was added at room temperature to a solution of 4-amino-o-cresol (3.00 g, 24.4 mmol) and ethyl bromoacetate (2.70 mL, 24.4 mmol) in DMF (30 mL). The resulting solution was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby yield 5.10 g of the title compound.
Reaction SMILES: [CH:1]12[CH2:14][CH:11]([CH2:12][CH2:13]1)[C:10]1[CH:9]=[C:8]3[N:3]([CH2:4][CH2:5][NH:6][C:7]3=[O:15])[C:2]2=1.[C:16]([O:19][CH2:20][C:21]1[C:26]([Br:27])=[CH:25][C:24]([F:28])=[CH:23][C:22]=1Br)(=[O:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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]>[C:16]([O:19][CH2:20][C:21]1[C:22]([N:6]2[C:7](=[O:15])[C:8]3[N:3]([C:2]4[CH:1]5[CH2:14][CH:11]([C:10]=4[CH:9]=3)[CH2:12][CH2:13]5)[CH2:4][CH2:5]2)=[CH:23][C:24]([F:28])=[CH:25][C:26]=1[Br:27])(=[O:18])[CH3:17]
Reactant: O=C1NCCn2c1cc1c2C2CCC1C2
Reactant: CC(=O)OCc1c(Br)cc(F)cc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)OCc1c(Br)cc(F)cc1N1CCn2c(cc3c2C2CCC3C2)C1=O
Temperature: 100 °C
Yield: 72.7 %

Procedure:
Into a sealed tube was charged with 334f (800 mg, 4 mmol) and 197c (3.8 g, 12 mmol) in dioxane (25 mL), and cesium carbonate (2.6 g, 8 mmol). After bubbling nitrogen through the resulting solution for 30 min, XantPhos (230 mg, 0.4 mmol) and tris(dibenzylideneacetone)-dipalladium(0) (362 mg, 0.4 mmol) were added, and the reaction mixture was heated at 100° C. for 4 h. After this time the reaction was cooled to room temperature, and partitioned between ethyl acetate (100 mL) and water (100 mL). The aqueous layer was separated and extracted with ethyl acetate (50 mL×3). The organic layers were combined, washed with brine (20 mL×3), and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with 1:5 ethyl acetate/petroleum ether to give 334g as a brown solid (1.3 g, 72%). MS: [M+H]+ 447.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N[C:6]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:7]=1[CH:8]=O>O>[OH:3][C:2]1[N:4]=[CH:8][C:7]2[C:10](=[CH:11][C:12]([Cl:14])=[CH:13][CH:6]=2)[N:1]=1
Reactant: NC(N)=O
Reactant: Nc1cc(Cl)ccc1C=O
Solvent: O
Product: Oc1ncc2ccc(Cl)cc2n1
Temperature: 160 °C
Reaction time: 0.25 h

Procedure:
Urea (115 g, 1915 mmol) was melted in a 500 mL 3 neck flask under nitrogen and heated at 160° C. The crude aminobenzaldehyde from step 1 (8.4 g) was added, one of the necks of the flask was opened to the atmosphere and the temperature of the oil bath raised to 190° C. When the bath temperature reached 175° C., a white precipitate was observed. The mixture was cooled and water (400 mL) was added. It was stirred for 15 minutes then filtered through a sintered glass frit. The collected solids were dried by azeotroping with toluene at reduced pressure (3×300 mL) then further dried under high vacuum at 70° C. The crude material was used without further purification.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.C(Br)(Br)(Br)[Br:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:40][CH2:2][CH2:3][CH2:4][S@:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCO)c3ccccc3)c2)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@](=O)(CCCBr)c3ccccc3)c2)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
N-[(3-hydroxypropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide (1.71 g, 3.24 mmol) was dissolved in anhydrous CH2Cl2 (5 mL) and the resulting solution was cooled to 0° C. A solution of carbon tetrabromide (1.565 g ) in CH2Cl2 (3 mL) was added dropwise followed by a dropwise addition of a solution of triphenylphosphine (1.24 g) in CH2Cl2 (3 mL). The reaction was stirred at room temperature for 1.5 hours and then partitioned between saturated aqueous NaHCO3 and dichloromethane. The organic layer was separated, washed with brine (1×), dried with anhydrous Na2SO4, and concentrated with silica gel under reduced pressure. A gradient column chromatography (acetone-hex: from 1:10 to 1:4) rendered title compound as white solid in amount of 1.56 g (82%).