Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]([N:14]2[CH2:18][CH:17]([S:19][CH:20]([CH:36]([CH:38]3[CH:41]([CH:42]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH3:43])[C:40](=[O:52])[NH:39]3)[CH3:37])C(=O)C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:16][CH:15]2[C:53]([N:55]([CH3:57])[CH3:56])=[O:54])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:58]([O:61][CH2:62][CH3:63])(=[O:60])[CH3:59]>ClCCl.O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:63]([CH2:62][O:61][C:58]([C:59]2[N:39]3[CH:38]([CH:36]([CH3:37])[C:20]=2[S:19][CH:17]2[CH2:16][CH:15]([C:53]([N:55]([CH3:57])[CH3:56])=[O:54])[N:14]([C:12]([O:11][CH2:10][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=4)=[O:13])[CH2:18]2)[CH:41]([CH:42]([O:44][Si:45]([C:48]([CH3:49])([CH3:51])[CH3:50])([CH3:46])[CH3:47])[CH3:43])[C:40]3=[O:52])=[O:60])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(O[Si](C)(C)C(C)(C)C)C1C(=O)NC1C(C)C(SC1CC(C(=O)N(C)C)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)C(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(C)=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(O[Si](C)(C)C(C)(C)C)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CC(C(=O)N(C)C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C(C)C12

Procedure:
Titanium tetrachloride (3.12 ml of a 1.0M solution in dichloromethane) is added to 1.5 ml of dry tetrahydrofuran under argon at .room temperature. To this mixture is added [2S-[2Alpha,4alpha[R*(or S*)-[1S*,1[2R*,3R*, -3(S*)]]]]]-2-[(dimethylamino)carbonyl]-4-[[1-[1-[3-[1-[[(1,1-di-methylethyl)dimethylsilyl]oxy]ethyl]-4-oxo-2-azetidinyl]ethyl]-3-[(4-nitrophenyl)methoxy]-2,3-dioxopropyl]thio]-1-pyrrolidinecarboxylic acid (4-nitrophenyl)methyl ester (0.392 g) in 2.5 ml of tetrahydrofuran. After 30 minutes the reaction mixture is treated with ice-cold saturated sodium bicarbonate solution and ethyl acetate. The aqueous layer is extracted with ethyl acetate. The combined organic layer is washed with three portions of brine, dried over anhydrous sodium sulfate and by anhydrous magnesium sulfate. Filtration and concentration affords the crude carbapenem which is purified via silica gel chromatography (80% ethyl acetate hexanes). The title compound is obtained as a pale yellow oil (0.295 g) 77%.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH:22]2[CH2:24][CH2:23]2)=[N:5][C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:7][C:8]=1[CH2:9][O:10][CH3:11].[CH2:25]([O:27][C:28](=[O:40])[C:29]([O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)([CH3:31])[CH3:30])[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH2:25]([O:27][C:28](=[O:40])[C:29]([O:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:2][C:3]2[C:4]([CH:22]3[CH2:24][CH2:23]3)=[N:5][C:6]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[N:7][C:8]=2[CH2:9][O:10][CH3:11])=[CH:37][CH:38]=1)([CH3:31])[CH3:30])[CH3:26]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Reactant: COCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C2CC2)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(COC)nc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1
Yield: 73.1 %

Procedure:
A solution of 200 mg (0.56 mmol) 5-chloromethyl-4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 113H]), 125 mg (0.56 mmol) 2-(4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester [Newman, Melvin S.; Cella, James A. Monoalkylation of hydroquinone. Journal of Organic Chemistry (1974), 39(2), p 214–15] and 237 mg (0.73 mmol) cesium carbonate in 3 ml DMF was stirred for 3 h at RT. The reaction mixture was taken up in ether and washed with 1N HCl and water. After purification of the crude product by chromatography over silica gel with AcOEt/heptane 1:3, 223 mg of pure 2-{4-[4-Cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-phenoxy}-2-methyl-propionic acid ethyl ester was isolated.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH2:13])[N:10]=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14]N1C(=O)CCC1=O>>[Cl:14][C:12]1[N:11]=[N:10][C:9]([NH2:13])=[N:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1nncc(-c2ccccc2)n1
Product: Nc1nnc(Cl)c(-c2ccccc2)n1
Yield: 92.4 %

Procedure:
6-Chloro-5-phenyl-1,2,4-triazin-3-amine (0.38 g, 65%) was prepared from 5-phenyl-1,2,4-triazin-3-amine (0.50 g, 1.99 mmol) and N-chlorosuccinimide (0.50 g, 3.7 mmol) according to the general procedure of Preparation 3.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)(N1C=CN=C1)=[O:2].Cl.[OH:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[CH:26](Cl)(Cl)Cl>CN(C)CCN.O1CCCC1>[CH:20]1([CH2:19][CH2:18][N:17]([CH2:16][CH2:15][OH:14])[C:1]([NH:8][CH2:12][CH2:11][N:10]([CH3:9])[CH3:26])=[O:2])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: ClC(Cl)Cl
Reactant: OCCNCCC1CCCCC1
Agent: CN(C)CCN
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)N(CCO)CCC1CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1,1′-Carbonyldiimidazole (0.43 g) was dissolved in a solution of 2-(dimethylamino) ethylamine (0.19 g) in anhydrous tetrahydrofuran (11 ml) in the nitrogen gas atmosphere and the resulting solution was stirred at room temperature for 20 minutes. To the reaction solution, there was added N-(2-hydroxyethyl)-2-cyclohexyl ethylamine hydrochloride (0.50 g) and the mixture was refluxed with heating for 3 hours. Chloroform was added to the reaction solution with ice cooling, followed by washing the mixture with saturated sodium hydrogen carbonate aqueous solution and then with saturated sodium chloride aqueous solution, drying over anhydrous magnesium sulfate and concentrating under reduced pressure. The resulting oily product was purified through the silica gel column chromatography to thus give the title compound (Compound 1-1, 0.68 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3=[CH:14][CH2:15][CH2:16][CH2:17][C:12]3([CH2:18][C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[NH:11][C:10]2=[O:27])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].[C:30]([O:37][CH2:38][CH3:39])(=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>CN(C=O)C>[CH2:38]([O:37][C:30](=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:13]12[CH2:14][CH2:15][CH2:16][CH2:17][C:12]1([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=1)[NH:11][C:10](=[O:27])[N:9]2[C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:39]
Reactant: CCCCCC(=O)OCC
Reactant: N#Cc1ccc(CC23CCCC=C2N(c2cc(Cl)cc(Cl)c2)C(=O)N3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCC12CCCCC1(Cc1ccc(C#N)cc1)NC(=O)N2c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[1-(3,5-Dichlorophenyl)-2-oxo-1,2,3,4,5,6-hexahydro-benzimidazol-3a-ylmethyl]benzonitrile (500 mg) (1.25 mmol) in DMF (20 ml) was carefully dropped on a suspension of NaH 60% (65 mg) (1.3 eq) in DMF (10 ml) at RT. The reaction mixture was stirred 1 h at RT, then ethyl hexanoate (0.27 ml) (1.2 eq) was added. After 3 h, the reaction mixture was poured on water and extracted with tBuOMe. The organic layer was washed with water, dried over Na2SO4 and concentrated. The residue was purified on SiO2 chromatography (eluent EtOAc/cyclohexane—2/8) to give 6-[7a-(4-Cyano-benzyl)-3-(3,5-Dichlorophenyl)-2-oxo-2,3,5,6,7,7a-hexahydro-benzimidazol-3a-yl]-hexanoic acid ethyl ester (200 mg) as an oil. 1H NMR (CDCl3): 7.55 (2H, d), 7.25 (2H, d), 7.1 (1H, m), 6.75 (2H, m), 4.95 (1H, m), 4.15 (2H, q), 3.7 (1H, m), 3.1 (1H, m), 3.0 (2H, s), 2.35 (2H, m), 2.2-1.3 (12H, m), 1.23 (3H, t).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[Cu][C:13]#[N:14]>CC(N(C)C)=O>[C:13]([C:2]1[CH:3]=[N:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)#[N:14]
Reactant: N#C[Cu]
Reactant: COC(=O)c1ncc(Br)cn1
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ncc(C#N)cn1
Temperature: 110 °C
Yield: 47.9 %

Procedure:
To a mixture of methyl 5-bromopyrimidine-2-carboxylate (2.30 g, 10.6 mmol) and copper (I) cyanide (1.92 g, 21.4 mmol) in a 100 mL round bottom flask was added DMA (21 mL). The reaction mixture was degassed by bubbling nitrogen through the solution for 5 min. The reaction mixture was heated to 110° C. for 2 d and cooled to room temperature. The reaction mixture was diluted with EtOAc and water and filtered through a glass frit (medium). The filtrate was transferred to a separatory funnel. The aqueous phase was extracted with EtOAc (4×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, concentrated to give a yellow oil. Purification by flash column chromatography on silica gel (80 g, 5% to 50% EtOAc in heptane) gave methyl 5-cyanopyrimidine-2-carboxylate (0.83 g, 5.08 mmol, 48% yield) as a white solid. LC/MS (ESI+) m/z=164.0 (M+H). Calculated for C7H5N3O2 163.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]=[CH:7][NH:6][C:5]2=[O:13].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[N:8]=[CH:7][NH:6][C:5]2=[O:13]
Reactant: C1COCCN1
Reactant: O=c1[nH]cnc2cc(F)c(F)cc12
Product: O=c1[nH]cnc2cc(N3CCOCC3)c(F)cc12
Temperature: 80 °C
Reaction time: 16 h
Yield: 74.8 %

Procedure:
37.2 g (0.20 mol) of 6,7-difluoro-3H-quinazolin-4-one were suspended in 70 ml (0.80 mol) of morpholine and stirred at an internal temperature of 80° C. for 16 h. Conventional work-up gave 37.3 g (Y=74%) of 6-fluoro-7-morpholin-4-yl-3H-quinazolin-4-one.
Reaction SMILES: N[C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C([O:26][C:27]([N:29]1CCC(OC2C=CC(C(O)=O)=CC=2)CC1)=O)(C)(C)C.[CH2:45]([O:52][C:53]([N:55]1[CH2:58][CH:57](C(O)=O)[CH2:56]1)=[O:54])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH2:45]([O:52][C:53]([N:55]1[CH2:56][CH:57]([NH:29][C:27]([C:2]2[CH:21]=[CH:20][C:5]([O:6][CH:7]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]3)=[CH:4][CH:3]=2)=[O:26])[CH2:58]1)=[O:54])[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)O)cc2)CC1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)NC3CN(C(=O)OCc4ccccc4)C3)cc2)CC1

Procedure:
The title compound was prepared as described in Example 1A, substituting benzyl 3-aminoazetidine-1-carboxylate for tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate and 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)benzoic acid for 1-(benzyloxycarbonyl)azetidine-3-carboxylic acid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=O)[C:11]([C:17]([CH3:21])([CH3:20])[CH:18]=[O:19])=[CH:10][C:9]2=[O:22])[CH2:2][CH2:3][CH3:4].[NH2:23][OH:24]>CO.O>[CH2:1]([O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:12]3[C:11]([C:17]([CH3:21])([CH3:20])[CH:18]([OH:19])[N+:23]=3[O-:24])=[CH:10][C:9](=[O:22])[C:8]=2[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc2c(c1)C(=O)C=C(C(C)(C)C=O)C2=O
Reactant: NO
Solvent: O
Solvent: CO
Product: CCCCOc1ccc2c(c1)C(=O)C=C1C2=[N+]([O-])C(O)C1(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(6-Butoxy-1,4-dioxo-1,4-dihydro-2-naphthalenyl)-2-methylpropanal (compound 5 prepared in step (I) above) (53 mg, 0.18 mmol) in MeOH (5 mL) and water (0.5 mL), 50% NH2OH in water solution (17 μL, 0.28 mmol) was added. The mixture was stirred 3 h at room temp and the solvent was evaporated. The crude product was fairly pure and was taken into the next step without further purification. Yield: 52 mg (92%). 1H NMR (400 MHz, CDCl3) δ 0.99 (tr., 3H), 1.38 (s, 3H), 1.52 (s, 3 H), 1.55 (m, 2 H), 1.84 (quint., 2H), 4.13 (tr., 2H), 5.31 (s, 1 H), 6.43 (s, 1H), 7.24 (d, 1 H), 7.73 (d, 1 H), 9.07 (d, 1 H).
Reaction SMILES: CC1(C)C[O:5][C:4]([C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[N:28]([CH2:29][CH2:30][O:31][CH2:32][CH3:33])[C:27]5[CH:34]=[CH:35][CH:36]=[CH:37][C:26]=5[N:25]=4)[CH2:20][CH2:19]3)=[CH:12][CH:11]=2)([CH3:9])[CH3:8])=N1.Cl.[OH-].[Na+].C([O:44]C(=O)C)C>C(O)CCC>[CH2:32]([O:31][CH2:30][CH2:29][N:28]1[C:27]2[CH:34]=[CH:35][CH:36]=[CH:37][C:26]=2[N:25]=[C:24]1[CH:21]1[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][C:13]2[CH:12]=[CH:11][C:10]([C:7]([CH3:9])([CH3:8])[C:4]([OH:44])=[O:5])=[CH:15][CH:14]=2)[CH2:23][CH2:22]1)[CH3:33]
Reactant: CCOC(C)=O
Reactant: CCOCCn1c(C2CCN(CCc3ccc(C(C)(C)C4=NC(C)(C)CO4)cc3)CC2)nc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: CCOCCn1c(C2CCN(CCc3ccc(C(C)(C)C(=O)O)cc3)CC2)nc2ccccc21
Yield: 87 %

Procedure:
In a reaction vessel, 2-[1-(2-{4-[1-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-1-methyl-ethyl]-phenyl}-ethyl)-piperidin-4-yl]-1-(2-ethoxy-ethyl)-1H-benzoimidazole (4.4 g) prepared in the Example 18 and hydrochloric acid aqueous solution (50 mL) were introduced, and the mixture was stirred with reflux. After the reaction was completed, sodium hydroxide solution was added to control the pH to 7. Ethylacetate (50 mL) was added to separate a layer, and the organic layer was condensed under reduced pressure. And, butanol (9 mL) was added and dissolved by heating. And then, it was cooled to precipitate crystals, and the crystals were filtered under reduced pressure to obtain 2-[4-(2-{4-[1-(2-ethoxy-ethyl)-1H-benzoimidazol-2-yl]-piperidin-1-yl}-ethyl)-phenyl]-2-methyl-propionic acid (3.43 g, yield 87%, HPLC purity 99% or more).
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:3]=1[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:31]=[CH:30][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]CCCC)=[O:22])=[CH:16][C:15]=2[C:28]#[N:29])=[CH:11][CH:10]=1)=[O:8].C(O)(C(F)(F)F)=O>ClCCl>[C:28]([C:15]1[CH:16]=[C:17]([CH2:20][C:21]([OH:23])=[O:22])[CH:18]=[CH:19][C:14]=1[O:13][C:12]1[CH:30]=[CH:31][C:9]([C:7](=[O:8])[NH:6][CH2:5][CH2:4][C:3]2[C:2]([Cl:1])=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:36])=[CH:10][CH:11]=1)#[N:29]
Reactant: CCCCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3c(Cl)cccc3Cl)cc2)c(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(CC(=O)O)ccc1Oc1ccc(C(=O)NCCc2c(Cl)cccc2Cl)cc1
Reaction time: 0.75 h
Yield: 111.5 %

Procedure:
tent-Butyl 2-(4-(4-((2,6-dichlorophenethyl)carbamoyl)phenoxy)-3-cyanophenyl)acetate (34 mg, 0.065 mmol) was dissolved in dichloromethane (1 ml) and TFA (1 ml) was added. After stirring for 45 minutes, the mixture was concentrated under reduced pressure to give 2-(3-cyano-4-(4-(2,6-dichlorophenethylcarbamoyl)phenoxy)phenyl)acetic acid (0.034 g).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[NH:31][C:13]4=[N:14][C:15]([N:18]5[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([N:26]6[CH2:30][CH2:29][CH2:28][CH2:27]6)=[O:25])[CH2:19]5)=[CH:16][CH:17]=[C:12]4[N:11]=3)[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.[B-](F)(F)(F)[F:33].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CN(C)C=O>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[NH:31][C:13]4=[N:14][C:15]([N:18]5[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([N:26]6[CH2:27][CH2:28][CH2:29][CH2:30]6)=[O:25])[CH2:19]5)=[C:16]([F:33])[CH:17]=[C:12]4[N:11]=3)[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: F[B-](F)(F)F
Reactant: O=C([C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1)N1CCCC1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CN(C)C=O
Product: O=C([C@@H]1CCCN(c2nc3[nH]c(-c4ccnc(C5CC5)n4)nc3cc2F)C1)N1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(R)-(1-(2-(2-Cyclopropylpyrimidin-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (Example 95, 100 mg, 0.2 mmol) was dissolved in N,N-dimethylformamide. The solution was cooled to 0° C. and Selectfluor (87 mg, 0.2 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 18 h. The reaction mixture was partitioned between ethyl acetate and water. The organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via HPLC to afford the title compound. MS (ESI+) (M+H) 436.2; HPLC retention time 2.72 min (Method A).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.Cl[C:11]1[O:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[C:4]([F:9])[CH:3]=1
Reactant: Clc1nc2ccccc2o1
Reactant: Nc1ccc(Br)cc1F
Product: Fc1cc(Br)ccc1Nc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 17 h
Yield: 91.6 %

Procedure:
To a solution of 4-bromo-2-fluoroaniline 1.00 g, 5.26 mmol) in toluence (25 mL) was added 2-chlorobenzoxazole (0.66 mL, 5.79 mmol, 1.1 equiv). The purple solution was heated at reflux for 30 min. and then at 100° C. for 17 hours. The resulting white suspension/purple solution was cooled to room temperature and the precipitate was filtered. The filter cake was washed with five 2-mL portion of heptane to afford N2-(4-bromo-2-fluorophenyl)-1,3-benzoxazol-2-amine (1.480 g, 92%) as a light purple powder. RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 minutes at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=12.87 min., 97%; and m/z 306.7(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([NH2:13])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23](=O)[CH2:24][C:25](OCC)=[O:26])=[CH:22][C:17]=2[N:16]=[N:15]1.CC1C=CC(S(O)(=O)=O)=CC=1>CCCCO>[NH:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3[NH:13][C:11]4[N:10]([N:9]=[C:8]([C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=5)[N:12]=4)[C:25](=[O:26])[CH:24]=3)=[CH:22][C:17]=2[N:16]=[N:15]1
Reactant: CCOC(=O)CC(=O)c1ccc2[nH]nnc2c1
Reactant: Nc1nc(-c2cccc(Cl)c2)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: O=c1cc(-c2ccc3[nH]nnc3c2)[nH]c2nc(-c3cccc(Cl)c3)nn12
Temperature: 130 °C
Reaction time: 5 h
Yield: 32.4 %

Procedure:
To a solution of 3-(3-chlorophenyl)-1H-1,2,4-triazol-5-amine (120 mg, 0.62 mmol) in n-BuOH (1 mL) was added ethyl 3-(1H-benzo[d][1,2,3]triazol-5-yl)-3-oxopropanoate (214 mg, 0.92 mmol) and TsOH (5.3 mg, 0.03 mmol), and the resulting mixture was stirred for 5 h at 130° C. The solids were collected by filtration, washed with MeOH (3×1 mL) to afford 5-(1H-benzo[d][1,2,3]triazol-5-yl)-2-(3-chlorophenyl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a off-white solid (73 mg, 33%).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH2:7]([N:14]1[C@H:18]([C:19](=[O:28])[NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16][C@@H:15]1[C:29]([OH:31])=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[ClH:4].[CH2:21]([N:20]1[C:29](=[O:31])[CH:15]2[N:14]([CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:18]([CH2:17][CH2:16]2)[C:19]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)[C@H]1CC[C@@H](C(=O)NCc2ccccc2)N1Cc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cl
Product: O=C1C2CCC(C(=O)N1Cc1ccccc1)N2Cc1ccccc1
Temperature: 25 °C
Yield: 79.1 %

Procedure:
Oxalyl chloride (18.5 g, 0.14 mol) was added dropwise to an ice cold suspension of cis-1-benzyl-5-(N-benzylcarbamoyl)-pyrrolidine-2-carboxylic acid (49.5 g, 0.14 mol; from step (b) above) in CH2Cl2 (500 mL) at such a rate that the reaction temperature did not exceed 8° C. The reaction slowly warmed to room temperature overnight with stirring. The reaction mixture was then concentrated in vacuo. The residue was slurried with 2-propanol and filtered to afford 39.5 g (84%) of the sub-title compound as a light tan solid.
Reaction SMILES: OS(C(F)(F)F)(=O)=O.[CH2:9]([N:16]([CH3:30])[C:17]1[N:18]=[C:19]([Cl:29])[C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([O:27][CH3:28])=[CH:22][CH:21]=2)[C:10]1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:29][C:19]1[C:20]2[C:25](=[CH:24][C:23]([O:27][CH3:28])=[CH:22][CH:21]=2)[CH:26]=[C:17]([N:16]([CH2:9][CH3:10])[CH3:30])[N:18]=1.[Cl:29][C:19]1[C:20]2[C:25](=[CH:24][C:23]([O:27][CH3:28])=[CH:22][CH:21]=2)[CH:26]=[C:17]([NH:16][CH3:9])[N:18]=1
Reactant: COc1ccc2c(Cl)nc(N(C)Cc3ccccc3)cc2c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: CCN(C)c1cc2cc(OC)ccc2c(Cl)n1
Product: CNc1cc2cc(OC)ccc2c(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 119.1 %

Procedure:
Triflic acid (4.09 mL, 46.0 mmol) was added to a solution of N-benzyl-1-chloro-6-methoxy-N-methylisoquinolin-3-amine (1.44 g, 4.60 mmol) in DCM (20 mL) at RT and stirred for 1 hr at RT before reverse adding to a solution of sat. sodium bicarbonate. The organic layer was diluted with DCM and separated. The organic layer was dried over MgSO4, filtered and evaporated. The crude material was purified via silica gel chromatography (90 g column, 0-30% EtOAc:Hex) to give the expected product 1-chloro-6-methoxy-N-methylisoquinolin-3-amine (610 mg, 2.74 mmol, 59.5% yield) as an orange solid. MS: MS m/z 223.15(M++1).
Reaction SMILES: FC(F)(F)C(O)=O.O.[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([S:20]([N:23]([CH2:30][CH:31](OCC)[O:32]CC)[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])(=[O:22])=[O:21])[CH:14]=[CH:13]2.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([S:20]([N:23]([CH2:30][CH:31]=[O:32])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])(=[O:22])=[O:21])[CH:14]=[CH:13]2
Reactant: CCOC(=O)CN(CC(OCC)OCC)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN(CC=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 51.4 %

Procedure:
To a mixed solution of trifluoroacetic acid (5 ml), chloroform (1.5 ml) and water (2.5 ml) was added a solution of the compound obtained in Step 2 (560 mg) in chloroform (1 ml) under cooling with ice water. After stirring for 1.5 hours under cooling with ice water, the reaction mixture was adjusted to pH 8 with saturated aqueous solution of sodium hydrogencarbonate and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and thereafter the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=5:1–2:1) to obtain the title compound (240 mg).
Reaction SMILES: C(O[C:4]([C:6]1([OH:14])[CH2:11][CH:10]([CH3:12])[CH2:9][CH:8]([CH3:13])[CH2:7]1)=[O:5])C.Cl.[NH2:16][C:17](N)=[NH:18].[OH-].[K+].C(O)(=O)C>C(O)C.O>[NH2:18][C:17]1[O:14][C:6]2([CH2:7][CH:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH2:11]2)[C:4](=[O:5])[N:16]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C1(O)CC(C)CC(C)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CC1CC(C)CC2(C1)OC(N)=NC2=O
Reaction time: 3 h
Yield: 35.6 %

Procedure:
A mixture of 9.43 grams of 1-hydroxy-3,5-dimethylcyclohexane carboxylic acid ethyl ester with 4.38 grams of guanidine hydrochloride and 2.59 grams of potassium hydroxide pellets in 52 ml of ethanol is refluxed for 1 hour. The solution is cooled, diluted with 172 ml of water and brought to pH 7 with glacial acetic acid resulting in a white precipitate being formed. After refrigeration at 5° C for 3 hours, the crystals are filtered, washed with water and ether, and dried yielding 3.20 grams of 2-amino-7,9-dimethyl-1-oxa-3-aza-spiro[4,5]dec-2-en-4-one, having a melting point of 276°-81° C.