Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[NH2:16][C:17]1(N)[CH2:22][CH:21]=[CH:20][CH:19]=[C:18]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:6]
Reactant: NC1(N)CC=CC=C1c1ccccc1
Reactant: Nc1cccc(Cl)c1C(=O)O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Nc1cccc(Cl)c1C(=O)Nc1ccccc1-c1ccccc1
Yield: 57.2 %

Procedure:
Prepared according to Procedure A using 2-amino-6-chlorobenzoic acid (2.0 g, 11.7 mmol) and SOCl2 (2.1 mL, 29.3 mmol) in benzene (60 mL), followed by 2-aminobiphenylamine (4.15 g, 24.5 mmol) and CHCl3 (60 mL). The product was chromatographed in CH2Cl2 to provide 2.16 g of a foamy dark-amber residue (57%). 1H NMR (CDCl3) δ: 8.48 (d, J=8.2 Hz, 1H); 7.79 (br s, 1H); 7.34-7.46 (m, 6H); 7.20-7.30 (m, 2H); 7.00 (t, J=8.1 Hz, 1H); 6.63 (dd, J=0.6, 7.9 Hz, 1H); 6.54 (d, J=8.3 Hz, 1H); 4.58 (br s, 2H). MS (ES): m/z 323.1 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:19]2[C:14]([CH:15]=[N:16][C:17](S(C)=O)=[N:18]2)=[CH:13][CH:12]=1.Cl.[OH-:24].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:19]2[C:14]([CH:15]=[N:16][C:17]([OH:24])=[N:18]2)=[CH:13][CH:12]=1
Reactant: [OH-]
Reactant: COc1ccc(-c2ccc3cnc(S(C)=O)nn23)c(OC)c1
Agent: Cl
Agent: [Na+]
Product: COc1ccc(-c2ccc3cnc(O)nn23)c(OC)c1
Temperature: 80 °C

Procedure:
7-(2,4-Dimethoxy-phenyl)-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine (605 mg) was suspended in 5M NaOH (20 ml) and heated to 80° C. for 3 hours. Cooled to room temperature and acidified with concentrated HCl. Extracted with dichloromethane. Dried over magnesium sulfate. Concentrated to afford 7-(2,4-dimethoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol as a brown solid (245 mg) that was used without further purification.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=[CH:3][CH:2]=1.C(#N)C.C(N(CC)CC)C.[CH3:24][C:25]([CH3:30])([CH3:29])[C:26](Cl)=[O:27]>O>[CH3:24][C:25]([CH3:30])([CH3:29])[C:26]([N:7]([C:5]1[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][N:13]=1)=[O:27]
Reactant: CC(C)(C)C(=O)Cl
Reactant: c1ccc(Nc2ccccn2)nc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CC(C)(C)C(=O)N(c1ccccn1)c1ccccn1
Reaction time: 1 h
Yield: 60.3 %

Procedure:
To a flask were added 2.0 g of 2,2′-dipyridylamine and 35 ml of acetonitrile. The solution was stirred under nitrogen and cooled to 5 C, when 1.5 g of triethylamine were added, followed by 1.5 g of trimethylacetyl chloride and the mixture was allowed to warm to 22 C. After 1 hour, 50 ml of water were added and the acetonitrile was removed. The product was extracted with ethyl acetate and washed with water. Following solvent removal, the product was purified by silica gel chromatography using 50% ethyl acetate in hexane, resulting in 1.8 g of an oil that solidified on standing.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.B(Br)(Br)[Br:18].O>C(Cl)Cl>[Br:18][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: BrB(Br)Br
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: O
Solvent: ClCCl
Product: Clc1ccc(C(Br)c2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 15.14 g (59.3 mmol) of bis(4-chlorophenyl)methanol in 100 mL of methylene chloride was added slowly a solution of 71.2 mL of BBr3 (71.2 mmol, 1M in CH2Cl2). The solution was stirred for at 0° C. for 1 h. Then 60 mL of water was added to quench the reaction and the reaction mixture was poured into 200 mL of methylene chloride. The water layer was extracted with methylene chloride (60 mL×2) and the combined organic layer was dried over Na2SO4 and concentrated to give the title compound; 1NMR(CDCl3) δ 6.24 (s, 1H), 7.36 (d, 4H, J=8.7 Hz), 7.41 (d, 2H, J=8.7 Hz).
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([OH:9])[CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3]1.ClCC(O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[F:1][C@H:2]1[C@@H:8]([OH:9])[CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H](F)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C(O)CCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@@H](O)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
trans-tert-butyl 4-fluoro-5-hydroxyazepane-1-carboxylate (25.00 g, 107.2 mmol) was dissolved in THF (1100 mL). To this solution was added 2-chloroacetic acid (15.19 g, 160.8 mmol) and PPh3 (42.16 g, 160.8 mmol). The solution was cooled to 0° C. and DEAD (25.31 mL, 160.8 mmol) was added as a THF solution (250 mL). The reaction mixture was protected from light and stirred overnight as it slowly increased to ambient temperature. The THF was removed in vacuo and replaced with EtOAc. The solution was washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated. The crude product was dissolved in dioxane (500 mL), and water was added (250 mL). A 1N NaOH solution was added until the pH reached ˜10 (200 mL). The mixture was stirred for 1 hour and then quenched with 1N KHSO4 (250 mL). The mixture was extracted with EtOAc (3×250 mL) and the combined organic phases were washed with saturated aqueous NaHCO3, dried over Na2CO3, filtered and concentrated to a white paste. The paste was then slurried in 50% Et2O/hexanes (200 mL) and filtered through qualitative paper. The resulting white solid was washed with 50% Et2O/hexanes (3×200 mL) and the filtrate was concentrated. The crude residue was purified by column chromatography (10 to 40% Acetone/hexanes) to provide the product (22.4 g, 89%) as a thick colorless oil.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:3]1.O[C@@H:21]1[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1>>[F:19][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[C:8]([O:10][C@@H:21]2[CH2:25][CH2:24][NH:23][CH2:22]2)=[O:9])[CH2:3]1
Reactant: O=C(O)[C@](O)(c1ccc(F)cc1)[C@@H]1CCC(F)(F)C1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Product: O=C(O[C@@H]1CCNC1)[C@](O)(c1ccc(F)cc1)[C@@H]1CCC(F)(F)C1

Procedure:
Using (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-fluorophenyl)acetic acid and t-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate, the title compound was prepared by a method similar to Steps 2 and 3 of Referential Example 12.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)=[C:19]=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:19]([NH:18][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[O:20])[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: Cc1ccc(CN=C=O)cc1
Product: Cc1ccc(CNC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)cc1

Procedure:
Example 3 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-(isocyanatomethyl)-4-methylbenzene (19.1 μl) to give the title compound (0.0318 g). LC-MS (System A): Rt 2.33 mins, Mass Spectrum m/z 422 [MH+].
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([F:12])[C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=1.[C-:13]#[N:14].[Na+].O>CS(C)=O>[F:12][C:5]1[C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=[C:3]([CH2:2][C:13]#[N:14])[CH:4]=1
Reactant: [C-]#N
Reactant: Fc1cc(CCl)cc2c1OCO2
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1cc(F)c2c(c1)OCO2
Temperature: 30 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
A mixture of 6-chloromethyl-4-fluoro-benzo[1,3]dioxole (0.80 g, 4.3 mmol) and NaCN (417 mg, 8.51 mmol) in DMSO (20 mL) was stirred at 30° C. for 1 h and was then poured into water. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4 and evaporated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/E.A.=10/1) to afford 2-(7-fluorobenzo[d][1,3]dioxol-5-yl)acetonitrile (530 mg, 70%). 1H NMR (300 MHz, CDCl3) 6.68-6.64 (m, 2H), 6.05 (s, 2H), 3.65 (s, 2H). 13C-NMR δ151.1, 146.2, 134.1, 124.2, 117.5, 110.4, 104.8, 102.8, 23.3.
Reaction SMILES: [NH2:1][N:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([F:11])([F:10])[F:9])[C:3]1=[O:12].[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2([C:36]([F:39])([F:38])[F:37])[O:25][N:24]=[C:23]([C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([CH3:35])[CH:27]=3)[CH2:22]2)[CH:17]=[C:18]([Cl:20])[CH:19]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2([C:36]([F:38])([F:37])[F:39])[O:25][N:24]=[C:23]([C:26]3[CH:34]=[CH:33][C:29]([C:30]([NH:1][N:2]4[CH2:6][CH2:5][N:4]([CH2:7][C:8]([F:9])([F:11])[F:10])[C:3]4=[O:12])=[O:31])=[C:28]([CH3:35])[CH:27]=3)[CH2:22]2)[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: NN1CCN(CC(F)(F)F)C1=O
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NN1CCN(CC(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 30 h

Procedure:
Into a 25-mL round-bottom flask, was placed 1-amino-3-(2,2,2-trifluoroethyl)imidazolidin-2-one (90 mg, 0.49 mmol, 1.00 equiv), 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylbenzoic acid (200 mg, 0.48 mmol, 0.97 equiv), EDCI (192 mg, 1.00 mmol, 2.04 equiv), HOBT (135 mg, 1.00 mmol, 2.03 equiv), triethylamine (303 mg, 2.99 mmol, 6.09 equiv), dichloromethane (10 mL). The resulting solution was stirred for 30 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 39 mg (13%) of 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methyl-N-[2-oxo-3-(2,2,2-trifluoroethyl)imidazolidin-1-yl]benzamide as a white solid. (ES, m/z): 583 [M−H]−; 1H NMR (300 MHz, CDCl3) δ 7.89 (s, 1H), 7.43-7.62 (m, 6H), 4.06-4.12 (m, 1H), 3.54-3.89 (m, 7H), 2.47 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:33][CH2:34][CH3:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:33]([CH2:34][CH3:35])[C:23](=[O:24])[CH2:22][N:14]([S:11]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][CH:7]=1)(=[O:12])=[O:13])[C:15]1[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCNCc1ccccc1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1
Product: CCN(Cc1ccccc1)C(=O)CN(c1ccc(C)nc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(6-methyl-pyridin-3-yl)-amino]-acetic acid with benzyl-ethyl-amine
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:35]([CH2:37][CH2:38][C:39]([N:41]([CH3:49])[C:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=1)=[O:40])[CH3:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]([CH2:37][CH2:38][C:39]([N:41]([C:42]1[CH:43]=[CH:44][C:45]([NH:48]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:46][CH:47]=1)[CH3:49])=[O:40])[CH3:36])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CN(CCC(=O)N(C)c1ccc(N)cc1)Cc1ccccc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C)C(=O)CCN(C)Cc2ccccc2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-((2-(N-benzyl-N-methyl-amino)-ethyl)-carbonyl)-N-methyl-p-phenylenediamine Rf value: 0.4 (silica gel, methylene chloride/methanol=10:1) C35H34N4O4
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]([O:16]CC2C=CC(OC)=CC=2)=[CH:12][C:11]=1[CH:26](O)[CH2:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30]>CO.[C].[Pd]>[CH3:30][C:29]([CH3:32])([CH3:31])[CH2:28][CH2:27][CH2:26][C:11]1[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(O)CCC(C)(C)C)c2)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(O)cc2CCCC(C)(C)C)c1
Yield: 92.9 %

Procedure:
A solution (8.7 mL) of 1-(2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)-[1,1′-biphenyl]-2-yl)-4,4-dimethylpentan-1-ol (394 mg) and 10% palladium-carbon (168 mg) in methanol was stirred under a hydrogen balloon atmosphere at room temperature for 9 hr. The reaction mixture was filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (256 mg) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[N:11]2[N:12]=[C:13]([C:15]([OH:17])=O)[CH:14]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[Na].C(Cl)(=O)C([Cl:22])=O>C1C=CC=CC=1>[O:1]=[C:2]1[N:11]2[N:12]=[C:13]([C:15]([Cl:22])=[O:17])[CH:14]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc2c3ccccc3[nH]c(=O)n2n1
Agent: [Na]
Solvent: c1ccccc1
Product: O=C(Cl)c1cc2c3ccccc3[nH]c(=O)n2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4.8 g (0.019 mole) of 5,6-dihydro-5-oxopyrazolo[1,5-c]-quinazoline-2-carboxylic acid, sodium salt is added to a solution of 3.27 g (0.026 mole) of oxalyl chloride in 200 ml of benzene. The suspension is stirred at room temperature for 20 minutes and then refluxed under nitrogen for 2 hours. The solvent is stripped to give the product.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[N+:32]([C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)([O-:34])=[O:33]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:41]([C:38]4[CH:37]=[CH:36][C:35]([N+:32]([O-:34])=[O:33])=[CH:40][CH:39]=4)(=[O:42])=[O:43])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc([N+](=O)[O-])cc4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 4-nitro-benzenesulfonyl chloride. Purity (ELSD, based on MW=606.6)=98%.
Reaction SMILES: O[CH2:2][C:3]1[S:7][CH:6]=[N:5][CH:4]=1.Cl.[NH2:9][CH2:10][CH2:11][SH:12].[BrH:13]>>[BrH:13].[BrH:13].[NH2:9][CH2:10][CH2:11][S:12][CH2:2][C:3]1[S:7][CH:6]=[N:5][CH:4]=1
Reactant: NCCS
Reactant: OCc1cncs1
Agent: Br
Agent: Cl
Product: NCCSCc1cncs1

Procedure:
The reaction of 5-hydroxymethylthiazole (2.01 g) with cysteamine hydrochloride (1.99 g) in aqueous hydrobromic acid by the method described in Example 58 gave 5-((2-aminoethyl)thiomethyl)thiazole dihydrobromide (4.85 g) m.p. 191°-4° (from methanol).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([F:32])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.C(=O)([O-])[O-].[K+].[K+].[CH3:39][C:40]1[CH:44]=[CH:43][NH:42][N:41]=1.CO>CN1CCCC1=O.[Cu]>[F:32][C:5]1[CH:4]=[N:3][C:2]([N:42]2[CH:43]=[CH:44][C:40]([CH3:39])=[N:41]2)=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])[C:6]=12
Reactant: O=C(C(=O)N1CCN(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(Br)ncc(F)c12
Reactant: Cc1cc[nH]n1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cc1ccn(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)n1
Temperature: 160 °C
Yield: 13.8 %

Procedure:
A mixture of 1-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (50 mg, 0.1 mmol), potassium carbonate (13 mg, 0.1 mmol), copper (6.0 mg, 0.1 mmol) and 3-methylpyrazole (32 uL, 0.4 mmol) in N-methylpyrrolidinone (0.5 mL) was heated at 160° C. for 6 h. MeOH (3 mL) was added and the solution was filtered through Celite. Solvent was removed in vacuum and residue was dissolved in DMF and purified using reverse phase prep HPLC to afford 1-(4-fluoro-7-(3-methyl-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (6.9 mg) as a white solid; 1HNMR (500 MHz, CDCl3) δ 8.46 (d, J=2 Hz, 1H), 8.19 (s, 1H), 8.93 (d, J=2.0 Hz, 1H), 7.55-7.50 (m, 5H), 6.25 (d, J=2.0 Hz, 1H), 3.78 (m, 2H), 3.56 (m, 2H), 3.35 (m, 2H), 3.25 (m, 2H), 2.36 (s, 3H). LCMS: m/e 501 (M+H)+, ret time 2.34 min (method 2) and 1-(4-fluoro-7-(5-methyl-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (13.7 mg); 1HNMR (500 MHz, CDCl3) δ 8.25 (m, 1H), 8.08 (bs, 1H), 7.65 (m, 1H), 7.60 (m, 5H), 6.27 (m, 1H), 3.87 (m, 2H), 3.66 (m, 2H), 3.46 (m, 2H), 3.36 (m, 2H), 2.83 (s, 3H). LCMS: m/e 501 (M+H)+, ret time 2.34 min (method 2).
Reaction SMILES: [CH3:1][C:2]1([C:17]([O-:19])=[O:18])[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[CH3:20][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI.[Cl-].[NH4+]>C1COCC1>[CH3:1][C:2]1([C:17]([O:19][CH3:20])=[O:18])[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1
Reactant: CC1(C(=O)[O-])CCN(C(=O)OCc2ccccc2)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.9 %

Procedure:
To 1-benzyl 3-methylpyrrolidine-1,3-dicarboxylate (3.45 g, 13.1 mmol) in THF (20 mL) was added lithium bis(trimethylsilyl)amide (16.4 mL, 16.4 mmol) in THF at −78° C., and the reaction was stirred at this temperature for 20 minutes. MeI (1.10 mL, 17.7 mmol) was added, and the reaction was warmed to room temperature. After 2 hours at room temperature, the mixture was poured onto saturated ammonium chloride (20 mL) and extracted with ether, washed with brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by chromatography (hexane:ethyl acetate 4:1) to give 1-benzyl 3-methyl 3-methylpyrrolidine-1,3-dicarboxylate (2.72 g, 75% yield) as an oil.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][CH:6]1Cl)(=[O:3])[CH3:2].[K].[Cl:26][C:27]1[CH:28]=[N:29][C:30](=[O:33])[NH:31][CH:32]=1>CN(C)C=O>[C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][CH:6]1[N:31]1[CH:32]=[C:27]([Cl:26])[CH:28]=[N:29][C:30]1=[O:33])(=[O:3])[CH3:2]
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: CC(=O)N[C@H]1C(Cl)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [K]
Solvent: CN(C)C=O
Product: CC(=O)N[C@H]1C(n2cc(Cl)cnc2=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 80 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
2-Desoxy-2-acetylamino-3,4,6-tri-O-actyl-D-glucopyranosylchloride (0.01 mol) and the potassium salt of 5-chloropyrimid-2-one (0.008 mol) were heated together in dimethylformamide (60 ml) with stirring at 80° C. for 24 hours. The solvent was then evaporated at reduced pressure (1 mm Hg) and the residue was extracted with chloroform (120 ml). The chloroform solution was washed with aqueous 1 N NaOH (2×3 ml) and water (3 ml) before drying (Mg SO4). Evaporation left the title compound which was further purified by trituration with ether and recrystallization from a small volume of methanol; yield 50%, m.p. 165°-167° C. when the sample is heated rapidly. (Found: C, 47.00; H, 4.82. Calc. for C18H22ClN3O9: : C, 47.02; H, 4.82)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH:12]=[C:13]([C:19]#[N:20])[C:14]([O:16]CC)=O)=[CH:7][CH:6]=1)[CH3:2]>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[NH:11][CH:12]=[C:13]([C:19]#[N:20])[C:14]2=[O:16])=[O:21])[CH3:2]
Reactant: CCOC(=O)C(C#N)=CNc1ccc(C(=O)OCC)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1ccc2[nH]cc(C#N)c(=O)c2c1
Temperature: 40 °C
Yield: 84.7 %

Procedure:
The mixture of 4-(2-cyano-2-ethoxycarbonyl-vinylamino)-benzoic acid ethyl ester (55 g, 0.19 mol) in diphenyl ether (300 mL) was stirred under reflux for 4 h. HPLC showed all the starting material disappeared. After cooling to 40° C., the solution was poured into petroleum ether (1000 mL). The solid was filtered, washed with petroleum ether, ethyl acetate and dried to give 3-cyano-4-oxo-1,4-dihydro-quinoline-6-carboxylic acid ethyl ester as a brown solid (39 g, 85%). HPLC showed 90% purity. LC-MS m/e 243 (MH+)
Reaction SMILES: [Br-].Br[CH2:3][C:4]([C:6]1[CH:7]=[NH+:8][CH:9]=[CH:10][CH:11]=1)=O.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:19]=[CH:18][N:17]2[C:20]([C:23](=[S:25])[NH2:24])=[CH:21][N:22]=[C:16]2[N:15]=1>CN(C=O)C>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:4]2[N:24]=[C:23]([C:20]3[N:17]4[CH:18]=[CH:19][C:14]([C:13]([F:27])([F:26])[F:12])=[N:15][C:16]4=[N:22][CH:21]=3)[S:25][CH:3]=2)[CH:7]=1
Reactant: NC(=S)c1cnc2nc(C(F)(F)F)ccn12
Reactant: O=C(CBr)c1ccc[nH+]c1
Agent: [Br-]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccn2c(-c3nc(-c4cccnc4)cs3)cnc2n1
Temperature: 60 °C
Yield: 95 %

Procedure:
3-(Bromoacetyl)pyridinium bromide (41 mg, 0.14 mmol) was added to a stirred solution of the foregoing thioamide (24 mg, 0.1 mmol) in DMF (1 ml) at room temperature under N2. The reaction was warmed to 60° C. for 1 h and then concentrated under reduced pressure while azeotroping with xylene (20 ml). The crude residue was taken up in EtOAc (50 ml), washed with saturated sodium hydrogencarbonate solution (20 ml) and concentrated under reduced pressure while dry loading onto silica. Subsequent purification by column chromatography on silica using 70% EtOAc in hexanes containing 1% Et3N and 1% MeOH as the eluent gave 3-[4-(pyridin-3-yl)thiazol-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine (33 mg, 97%): δH (400 MHz, d6-DMSO) 7.52-7.60 (1H, m), 7.80 (1H, d, J 7.1), 8.43 (1H, s), 8.50 (1H, dt, J 7.8 and 2.0), 8.62 (1H, m), 8.83 (1H, s), 9.39 (1H, s), 10.33 (1H, d, J 7.1); m/z (ES+) 347 (M+).