Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(OO)(=[O:16])C.O>C(Cl)Cl>[CH:3]12[O:16][CH:4]1[CH2:5][CH2:6][CH:1]([C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:2]2
Reactant: CC(=O)OO
Reactant: CCCCCC(=O)C1CC=CCC1
Solvent: ClCCl
Solvent: O
Product: CCCCCC(=O)C1CCC2OC2C1

Procedure:
A 500 mL round bottom flask equipped with a stirrer bar was charged with 8.42 g (0.0668 mol) 1-(3-cyclohexen-1-yl)-1-hexanone, and 80 mL of methylene chloride. Peracetic acid (14.5 g, 35 wt. % in acetic acid; 0.0668 mol) in methylene chloride (60 mL) was added dropwise to above mixture over 20 min. in an ice bath. After the above mixture was reacted at room temperature overnight, 200 mL of water was added to above reaction mixture, the water layer was extracted with methylene chloride (2×100 mL), the organic layer was combined, and washed with saturated sodium carbonate solution (2×100 mL), then with water (2×100 mL), dried with sodium sulfate. The solvent was evaporated and the residue distilled to give pure product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[C:18](=[O:19])[NH:17][C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[C:10]=2[O:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:32](I)[CH3:33]>C(#N)C>[Cl:1][C:2]1[C:3]([C:9]2[C:18](=[O:19])[N:17]([CH2:32][CH3:33])[C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[C:10]=2[O:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)C(=O)Oc1c(-c2ncc(Cl)cc2Cl)c(=O)[nH]c2nccnc12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCn1c(=O)c(-c2ncc(Cl)cc2Cl)c(OC(=O)C(C)C)c2nccnc21
Temperature: 100 °C

Procedure:
Isobutyric acid 7-(3,5-dichloro-pyrid-2-yl)-6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazin-8-yl ester (Example 1.3) (0.250 g) was dissolved in acetonitrile (2 ml) and potassium carbonate (0.138 g) and ethyl iodide (0.1 ml) were added successively. The reaction mixture was heated in a microwave at 100° C. for 11 minutes, cooled to ambient temperature and concentrated. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate 1:1) to give Compound No. A6 of Table A as a yellow gum which solidified on standing (0.101 g).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([C:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=4)[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.FC(F)(F)S(OC1CCN(C(OC(C)(C)C)=O)CC=1)(=O)=O>CO.[Pd]>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([CH:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:19]4)[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3nc(-c4ccc(C(F)(F)F)cc4)oc3c2)CC1
Agent: [Pd]
Agent: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3nc(-c4ccc(C(F)(F)F)cc4)oc3c2)CC1
Reaction time: 12 h
Yield: 57.4 %

Procedure:
Following the general procedure, tert-butyl 4-[2-(4-(trifluoromethyl)phenyl]benzo[d]oxazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (260 mg) was prepared from intermediate 55 (420 mg, 1.08 mmol) and tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (358 mg, 1.08 mmol). tert-butyl 4-[2-(4-(trifluoromethyl)phenyl]benzo[d]oxazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (260 mg, 0.58 mmol) was dissolved in methanol (8 ml) and added Pd/C (5%) (520 mg). This mixture was stirred under H2 pressure (6.5 kg) for 12 h. Combined methanol fractions were evaporated on rotavapour to obtain the crude. Crude was purified on combiflash using a gradient mixture of EtOAc and Petether (1:9) as eluent to afford the titled compound (150 mg) as a white solid. M. P.: 174-179° C. MS (m/z): 446.46 [M+H]+.
Reaction SMILES: [Na:1].CC1(C)COC(CO[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18]([C:20]3[NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[N:21]=3)=[O:19])[C:12]=2[CH3:29])OC1.ClC1C=C[N+]([O-])=C(C)C=1C.[F:41][C:42]1([F:50])[CH2:47][O:46][CH:45]([CH2:48][OH:49])[O:44][CH2:43]1>>[Na:1].[F:41][C:42]1([F:50])[CH2:47][O:46][CH:45]([CH2:48][O:49][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18]([C:20]3[NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[N:21]=3)=[O:19])[C:12]=2[CH3:29])[O:44][CH2:43]1
Reactant: Cc1c(OCC2OCC(C)(C)CO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: OCC1OCC(F)(F)CO1
Agent: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [Na]
Product: Cc1c(OCC2OCC(F)(F)CO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 22.7 %

Procedure:
The same procedure as in the steps (1c) to (1g) of Example 1 was repeated using 4-chloro-2,3-dimethylpyridine 1-oxide and (5,5-difluoro-1,3-dioxan-2-yl)methanol to obtain the title compound (375 mg, 5 steps: 22.7%) as a white powder.
Reaction SMILES: [Cl-].[CH:2](=[N:9][N+:10]1[CH:14]=[CH:13][N:12](N=CC2C=CC=CC=2)[C:11]=1[CH3:23])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C-]#N.[K+]>CO.O>[CH:2](=[N:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[CH3:23])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1n(N=Cc2ccccc2)cc[n+]1N=Cc1ccccc1
Agent: [C-]#N
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1nccn1N=Cc1ccccc1
Reaction time: 0.25 h

Procedure:
3.24 g of 1,3-bis(benzylideneamino)-2-methylimidazolium chloride are dissolved in 50 ml of methanol. The solution is cooled to 0° (internal temperature) and treated while stirring with a solution of 2.6 g of potassium cyanide in 8 ml of water, whereby the temperature is not allowed to rise substantially. After 15 minutes, the methanol is removed by evaporation in a vacuum at the lowest possible temperature. The residue is diluted with 30 ml of water, whereupon the mixture is extracted three times with chloroform. The dried chloroform extract is evaporated and there is obtained 1-benzylideneamino-2-methylimidazole of m.p. 125°.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:4]=1[C:5](OC)=[O:6].[N:17]#[C:18][NH2:19]>C(#N)C>[NH2:19][C:18]1[N:2]=[C:3]2[CH:4]([C:5](=[O:6])[N:17]=1)[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12]2
Reactant: N#CN
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Agent: Cl
Solvent: CC#N
Product: COC(=O)C1=CC2=NC(N)=NC(=O)C2C=C1
Temperature: 80 °C
Yield: 78.7 %

Procedure:
Concentrated hydrogen chloride aqueous solution (800 μl, 26.1 mmol) was added to a solution of dimethyl 2-aminoterephthalate (1.82 g, 8.69 mmol), and cyanamide (658 mg, 15.6 mmol) in acetonitrile (20 mL). After the HCl addition, the reaction mixture became slurry and it was heated at 80° C. overnight. The reaction mixture was allowed to cool to room temperature and became thick slurry; then the solids were filtered, washed with ethyl ether, and dried to give the crude product (1.50 g, 78.7%) as a white solid. 1H NMR (300 MHz, DMSO): δ 3.9 (s, 3H), 7.84 (dd, 1H), 7.99 (d, 1H), 8.09 (d, 1H), 8.55 (b, 2H); Analytic LCMS (M+H)+: m/z=220.1.
Reaction SMILES: [CH2:1]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[CH2:3][CH2:2]1.[C:13](N)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:4]12([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH2:12][CH2:1][CH2:2][CH2:3]1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:13](=[O:20])[O:5]2
Reactant: NC(=O)c1ccccc1
Reactant: O=C1CCCCc2ccccc21
Product: O=C1OC2(CCCCc3ccccc32)c2ccccc21

Procedure:
Using a procedure similar to that described in Example 1a except adding 1-benzosuberone to the solution of dilithiated benzamide, the title compound was obtained as a white crystalline solid (46%), mp 150°-151° C. Analysis for C18H16O2 : Calculated: C, 81.79; H, 6.10. Found: C, 81.97; H, 6.08.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].S(OCC)(O[CH2:13][CH3:14])(=O)=O>[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:13][CH3:14]
Reactant: CCOS(=O)(=O)OCC
Reactant: Oc1ccccc1Br
Agent: [Na+]
Agent: [OH-]
Product: CCOc1ccccc1Br
Temperature: 25 °C

Procedure:
A mixture of 17.5 g of 2-bromophenol, 66 ml of diethyl sulfate and 170 ml of 10% NaOH solution is refluxed for 2 hours. After cooling the reaction mixture to RT, it is extracted with EtOAc, the organic phase is washed with 2N NaOH solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. 19.6 g of the expected product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[C:18]([O:22][C:23]([N:25]([CH2:43][CH:44]=O)[CH2:26][C@H:27]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH2:44][CH2:43][N:25]([CH2:26][C@@H:27]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)[O:35][Si:36]([C:39]([CH3:40])([CH3:41])[CH3:42])([CH3:38])[CH3:37])[C:23]([O:22][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:24])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N(CC=O)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Reactant: COC(=O)c1cccc(-c2cccc(N)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cccc(-c2cccc(NCCN(C[C@H](O[Si](C)(C)C(C)(C)C)c3cccc(Cl)c3)C(=O)OC(C)(C)C)c2)c1
Yield: 66.6 %

Procedure:
To a stirred solution of 3′-amino-[1,1′-biphenyl]-3-carboxylic acid methyl ester (3.0 g) and (R)-[(tert-butoxycarbonyl)-[2-(tertbutyidimethylsilanyloxy)-2-(3-chlorophenyl)ethyl]amino}acetaldehyde (8.2 g) in anhydrous dichloromethane (65 mL) was added acetic acid (8 drops). After stirring for twenty-five minutes, sodium triacetoxyborohydride (5.6 g) was added and the reaction stirred overnight. The reaction was quenched with saturated aqueous sodium bicarbonate and more dichloromethane was added. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure to yield a white foam. The residue was purified by silica gel chromatography and eluted with 9:1 hexane:ethyl acetate to provide the title compound as a white foam (5.62 g).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C:7]2[N:8]=[C:9]([O:29][CH2:30][CH2:31][CH3:32])[C:10]3[N:15]=[C:14]([C:16]4[CH:26]=[C:25]([CH3:27])[C:19]([O:20][CH2:21][C:22](Cl)=[O:23])=[C:18]([CH3:28])[CH:17]=4)[O:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.Cl.[C:36]([O:40][C:41](=[O:44])[CH2:42][NH2:43])([CH3:39])([CH3:38])[CH3:37].C(N(CC)CC)C>ClCCl>[C:36]([O:40][C:41](=[O:44])[CH2:42][NH:43][C:22](=[O:23])[CH2:21][O:20][C:19]1[C:18]([CH3:28])=[CH:17][C:16]([C:14]2[O:13][C:11]3[N:12]=[C:7]([CH2:6][C:5]4[CH:33]=[CH:34][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]=[C:9]([O:29][CH2:30][CH2:31][CH3:32])[C:10]=3[N:15]=2)=[CH:26][C:25]=1[CH3:27])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC(=O)Cl)c(C)c3)nc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC(=O)NCC(=O)OC(C)(C)C)c(C)c3)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.3 %

Procedure:
200 mg of {4-[5-(4-chloro-benzyl)-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenoxy}-acetyl chloride were dissolved in 2 ml of dichloromethane, and the solution was slowly added to a solution of 67 mg of glycine tert-butyl ester hydrochloride and 121 mg of triethylamine in 3 ml of dichloromethane. The mixture was stirred for 18 h at room temperature. Then the solvent was distilled off in vacuo and the product was isolated via preparative HPLC (method HPLC2) to yield 53 mg of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([O:11]C(=O)C2C=CC=CC=2)=[C:9]([OH:20])[N:8]=[C:7]([C:21]2([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:6]=1)=O.[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[C:38]([S:44]([CH3:47])(=[O:46])=[O:45])[CH:37]=1>CO>[C:31]([O:30][C:28](=[O:29])[NH:27][C:21]1([C:7]2[N:6]=[C:5]([C:3]([NH:41][CH2:40][C:39]3[CH:42]=[CH:43][C:36]([F:35])=[CH:37][C:38]=3[S:44]([CH3:47])(=[O:46])=[O:45])=[O:2])[C:10]([OH:11])=[C:9]([OH:20])[N:8]=2)[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)([CH3:33])([CH3:32])[CH3:34]
Reactant: COC(=O)c1nc(C2(NC(=O)OC(C)(C)C)CCOCC2)nc(O)c1OC(=O)c1ccccc1
Reactant: CS(=O)(=O)c1cc(F)ccc1CN
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(c2nc(O)c(O)c(C(=O)NCc3ccc(F)cc3S(C)(=O)=O)n2)CCOCC1

Procedure:
Methyl-5-(benzoyloxy)-2-{4[(tert-butoxycarbonyl)amino]tetrahydro-2H-pyran-4-yl}-6-hydroxypyrimidine-4-carboxylate (C-30) in dry MeOH was treated with 4-fluoro-2-(methylsulfonyl)benzylamine (2.5 eq.) at reflux for 2 hours. Solvent was removed in vacuo and the residue was taken up in ethyl acetate, washed with HCl 1N, brine, dried over Na2SO4. The filtrate was concentrated in vacuo and triturated with ethyl ether to obtain the crude title compound (C-31).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([S:11]([N:14]2[CH:27]([CH3:28])[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([F:29])[CH:25]=3)[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]2=3)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9]C.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[F:29][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:14]([S:11]([C:5]1[CH:4]=[C:3]([OH:2])[C:8]([OH:9])=[CH:7][CH:6]=1)(=[O:13])=[O:12])[CH:27]2[CH3:28]
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(F)cc3C2C)cc1OC
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)c(O)c1
Yield: 49.7 %

Procedure:
The title compound was prepared from 5-[(3,4-dimethoxyphenyl)sulfonyl]-8-fluoro-6-methyl-5,6-dihydrophenanthridine (0.50 g, 1.2 mmol), cyclohexene (4.4 mL, 44 mmol), and 1 M boron tribromide in dichloromethane (14.5 mL, 14.5 mmol) according to the procedure and in the same manner as described in Example 47, Step b. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:1 to 7:3 gradient), followed by re-crystallization from a mixture of dichloromethane-hexane (2×), to yield 4-[(8-fluoro-6-methylphenanthridin-5(6H)-yl)sulfonyl]benzene-1,2-diol as a homogeneous solid (0.23 g, 50%), m.p. 165-170° C.;
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:13][OH:14].C([O-])([O-])=O.[K+].[K+].C(O)C>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8](=[N:13][OH:14])[NH2:9])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: NC(=NO)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 29.6 g. (0.20 mole) of p-nitrobenzonitrile, 13.9 g. (0.20 mole) of hydroxylamine HCl, 13.8 g. (0.10 mole) of K2CO3 in 700 ml. of ethanol and 70 ml. of water is refluxed for 20 hours, cooled and diluted with 200 ml. of water. After removal of the ethanol by distillation in vacuo, the product is collected by filtration, washed with water and dried to yield 21.6 g. (60%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:30]=[C:31]([CH:33]1[CH2:35][CH2:34]1)[NH2:32]>>[CH:33]1([C:31]2[N:32]=[C:26]([CH:12]3[CH2:13][CH:14]([C:16]4[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=4)[CH2:15][N:10]([C:8]([N:5]4[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]4)=[O:9])[CH2:11]3)[O:27][N:30]=2)[CH2:35][CH2:34]1
Reactant: NC(=NO)C1CC1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1

Procedure:
100 mg (0.250 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 99A) and 27.5 mg (0.275 mmol) of N′-hydroxycyclopropanecarboximidamide (Example 78A) were reacted according to the General Method 1. Yield: 51.8 mg (45% of theory).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][C:27]=1[CH3:34]>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:30][C:29]3[CH:32]=[CH:33][C:26]([F:25])=[C:27]([CH3:34])[CH:28]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: Cc1cc(CBr)ccc1F
Product: Cc1cc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)ccc1F
Yield: 1.9 %

Procedure:
The title compound (0.002 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C; 0.1 g) using 4-fluoro-3-methylbenzyl bromide (0.09 g) in place of benzyl chloride. MS (ESI): exact mass calculated for C21H21ClFN3, 369.14; found, m/z 370.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.49-7.47 (m, 2H), 7.45-7.42 (m, 2H), 7.07-7.01 (m, 1H), 7.00-6.95 (m, 1H), 6.95-6.90 (m, 1H), 5.31 (s, 2H), 2.97-2.91 (m, 4H), 2.89-2.84 (m, 2H), 2.82-2.77 (m, 2H), 2.22 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15]CC2C=CC(OC)=CC=2OC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.FC(F)(F)C(O)=O>ClCCl>[NH2:15][C:4]1[C:3]([O:2][CH3:1])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:13][CH3:14])[CH:10]=2)[N:5]=1
Reactant: COc1ccc(CNc2nc3ccc(OC)cc3nc2OC)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2nc(N)c(OC)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
To 3,6-dimethoxy-2-(2,4-dimethoxybenzylamino)quinoxaline (4.45 g, 12.8 mmol), 70 ml of 50% trifluoroacetic acid in dichloromethane was added at room temperature. The resulting mixture was stirred at room temperature for 18 hours and concentrated under the reduced pressure to remove the solvent. The residue was neutralized with saturated sodium bicarbonate solution and then NaCl solution was added thereto. The product was extracted with dichloromethane and the organic layer was dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate mixture and concentration gave 2.50 g of the titled compound (yield, 95%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[N:5][C:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)[NH:3]1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[N:5][C:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)[N:3]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CC1CCc2cc(-c3ccccc3)c(-c3ccccc3)nc2N1
Reactant: CCOC(=O)CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCCCCCN1c2nc(-c3ccccc3)c(-c3ccccc3)cc2CCC1C
Reaction time: 2 h

Procedure:
To a microwave vial was added 2-methyl-6,7-diphenyl-1,2,3,4-tetrahydro-1,8-naphthyridine (step 2) (345 mg, 1.148 mmol) in NMP (1 ml) followed by ethyl 7-bromoheptanoate (0.671 ml, 3.45 mmol) and cesium carbonate (748 mg, 2.297 mmol). The resulting mixture was heated using microwave radiation at 160° C. for 2 h. Ethyl-7-bromoheptanoate (0.671 ml, 3.45 mmol) was added and heating continued for a further 2 h. The reaction mixture was partitioned between EtOAc and water and the organic portion was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-20% EtOAc in iso-hexane afforded a yellow oil which was loaded onto a Isolute™ SCX-2 cartridge and eluted with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions were concentrated in vacuo to afford racemate ethyl 7-(2-methyl-6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1(2H)-yl)heptanoate. Chiral separation of the mixture using Supercritical Fluid Chromatography afforded the individual enantiomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](/[CH:18]=[N:19]/[S:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])=[CH:11][C:12]2[N:13]([CH:15]=[CH:16][N:17]=2)[CH:14]=1.[CH3:26][Mg]Br.[NH4+].[Cl-]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([CH:18]([NH:19][S:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])[CH3:26])=[CH:11][C:12]2[N:13]([CH:15]=[CH:16][N:17]=2)[CH:14]=1
Reactant: CC(C)(C)S(=O)/N=C/c1cc2nccn2cc1-c1ccc(Cl)cc1Cl
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(NS(=O)C(C)(C)C)c1cc2nccn2cc1-c1ccc(Cl)cc1Cl

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid 1-[6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-7-yl]-meth-(E)-ylideneamide (20 mg, 0.045 mmol) in anhydrous THF (0.5 mL) was added methylmagnesium bromide (3 M solution in Et2O, 0.045 mL, 0.14 mmol) at RT. The reaction mixture was stirred for 3 h30 then poured into a saturated solution of NH4Cl in water and extracted with AcOEt. The organic layer was dried over Na2SO4, filtered and evaporated to dryness to give the crude 2-methyl-propane-2-sulfinic acid {1-[6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-7-yl]-ethyl}-amide intermediate.
Reaction SMILES: [CH2:1]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[OH:25])[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[C:26](O)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.C1(C)C(S(Cl)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[C:26]([O:25][C:15]1[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)c1ccccc1
Reactant: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2OC(=O)c2ccccc2)c(O)c(C(C)(C)C)c1
Yield: 96 %

Procedure:
To the same flask as used in Example 1 were added 340.51 g (1.0 mole) of 2,2'-methylenebis(6-tert-butyl-4-methylphenol), 122.12 g (1.0 mole) of benzoic acid, 500 g of toluene and 242.86 g (2.4 moles) of triethylamine. After replacing the air in the container with nitrogen, 229.15 g (1.2 moles) of o-toluenesulfonyl chloride was added dropwise with stirring. After completion of the dropwise addition, temperature maintenance and after-treatment were carried out in the same manner as in Example 3 to obtain 426.83 g of a white crystalline 2,2'-methylenebis(6-tert-butyl-4-methylphenol) monobenzoate having a melting point of 149° to 151° C. Yield, 96%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])[CH:5]=[C:4]([NH:14][CH3:15])[N:3]=1.C1C(=O)N([Br:23])C(=O)C1>CC#N>[Br:23][C:5]1[C:6]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])=[N:7][C:2]([Cl:1])=[N:3][C:4]=1[NH:14][CH3:15]
Reactant: CNc1cc(C(=O)N(C)OC)nc(Cl)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CNc1nc(Cl)nc(C(=O)N(C)OC)c1Br
Temperature: 60 °C
Yield: 85.5 %

Procedure:
To a solution of 2-chloro-N-methoxy-N-methyl-6-(methylamino)pyrimidine-4-carboxamide (959 mg) in MeCN (21 mL) was added NBS (814 mg), and the reaction mixture was heated at 60° C. for 8 h. The solvent was removed, and the residue was purified by Biotage eluting with 50%-70 EtOAc/Hexanes (1.2 L) to give the title compound as a white solid (1.1 g). LC-MS (M+H)+=310.95.