Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([C:10](=O)[CH3:11])[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[O:20][CH3:21])[CH:2]=[CH2:3].C([BH3-])#[N:23].[Na+].C([O-])(=O)C>>[CH2:1]([C:4]1[CH:9]=[C:8]([CH:10]([NH2:23])[CH3:11])[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[O:20][CH3:21])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C(C)=O)ccc1-c1cc(F)ccc1OC
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [Na+]
Product: C=CCc1cc(C(C)N)ccc1-c1cc(F)ccc1OC

Procedure:
A mixture of 3′-allyl-4′-hydroxyacetophenone (0.352 g, 2.0 mmol), N-phenyl-bis(trifluoromethane) sulfonimide) (0.710 g, 2.0 mmol) and potassium carbonate (0.830 g, 6.0 mmol) in tetrahydrofuran (3.0 ml) was heated in a microwave oven at 120° C. for 10 min. The resultant mixture was treated with 5-fluoro-2-methoxyphenyl boronic acid (0.680 g, 0.4 mmol), tetrakis(triphenylphosphine)palladium (0) (0.060 g, 0.05 mmol) and dimethylformamide (1.0 ml) and heated in a microwave oven at 120° C. for 10 min. The mixture was partitioned between ethyl acetate and dilute aqueous sodium carbonate solution. The organic phase was dried over anhydrous sodium sulfate, the solvent evaporated and the residue purified by flash chromatography over silica gel eluting with 9:1 heptane/ethyl acetate. Evaporation of solvent under reduced pressure gave 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethanone. A solution of 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethanone (0.319 g, 1.1 mmol), sodium cyanoborohydride (0.140 g, 2.2 mmol) and ammomium acetate (1.7 g, 22 mmol) was stirred under nitrogen at ambient temperature for 72 h, evaporated to dryness under reduced pressure and partitioned between dichloromethane and brine. The organic phase was dried over anhydrous sodium sulfate, the solvent evaporated and the residue purified by flash chromatography over silica gel eluting with 98:2 ethyl acetate/2M ammonia in methanol. Evaporation of solvent under reduced pressure gave 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine. To a solution of 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (19.0 mg, 0.07 mmol) in dichloromethane (1 ml) was added triethylamine (6.7 mg, 0.07 mmol) and 3,4-di-fluorophenyl sulfonyl chloride (14.2 mg, 0.06 mmol). The solution was stirred overnight and the solvent evaporated. The residue was purified by flash chromatography over silica gel eluting with dichloromethane. Evaporation of solvent under reduced pressure gave the title compound. 1H NMR (400 MHz, CDCl3): δ 7.52-7.42 (m, 2H), 7.13 (q, 1H), 7.04-6.90 (m, 4H), 6.88-6.83 (m, 1H), 6.77 (q, 1H), 5.67 (dt, 1H), 4.99-4.82 (m, 3H), 4.57 (dq, 1H), 3.71 (s, 3H), 3.09 (br s, 2H), 1.51 (d, 3H) ppm; MS (ESI) m/z: value [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:20])=[C:4]([C:9]2[C:10]([NH2:19])=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16]N=[CH:14][CH:13]=3)[C:5]([Cl:8])=[CH:6][CH:7]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27].Cl[CH2:35]Cl>CCOC(C)=O>[NH2:19][C:10]1[C:9]([C:4]2[C:3]([Cl:20])=[C:2]([NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:22]([F:33])([F:32])[F:21])[CH:24]=3)[CH:7]=[CH:6][C:5]=2[Cl:8])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:35][CH:16]=2)[N:11]=1
Reactant: ClCCl
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(Cl)c(-c2cc3cnccc3nc2N)c1Cl
Solvent: CCOC(C)=O
Product: Nc1nc2ccccc2cc1-c1c(Cl)ccc(NC(=O)c2cccc(C(F)(F)F)c2)c1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-(3-amino-2,6-dichloro-phenyl)-[1,6]naphthyridin-2-ylamine (2.0 g, 6.554 mmol) in the dichloromethane (400.0 mL) is added 3-(trifluoromethyl)benzoyl chloride (4.78 g, 22.94 mmol). After the mixture is stirred for 24 hours at room temperature, it is diluted with EtOAc and washed with saturated K2CO3, brine and water. The organic layer is dried, filtered and concentrated to give crude product, which is purified by flash silica gel column eluting with CH2Cl2 (100%) gradient to CH2Cl2/MeOH (NH3, 2N) (95/5) to give the product as a solid: 1H NMR 400 MHz (CDCl3) δ 8.97 (s, 1H), 8.61 (d, 1H), 8.57 (d, 1H), 8.52 (s, 1H), 8.20 (s, 1H), 8.06 (d, 1H), 7.86 (d, 1H), 7.85 (s, 1H), 7.68 (t, 1H), 7.58 (d, 1H), 7.51 (d, 3H), 5.25 (s, 2H); MS m/z 478.10 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]2([C:25]([O:27]CC)=[O:26])[CH2:24][CH2:23][CH2:22]2)[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]2([C:25]([OH:27])=[O:26])[CH2:22][CH2:23][CH2:24]2)[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C)cc3)c2)CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2cc(C3(C(=O)O)CCC3)cc(Cl)c2OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.3 %

Procedure:
A mixture of ethyl 1-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylate (300 mg, 0.70 mmol) and lithium hydroxide monohydrate (280 mg, 11.6 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10/ml) was stirred for 3 h at room temperature. After completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water, dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Flash Column Chromatography to give 1-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid (185 mg, 66%) as white solid. 1HNMR (CDCl3): 7.42 (m, 2H); 7.32 (s, 1H), 7.23 (d, 2H), 7.18 (s, 1H), 3.87 (q, 2H); 2.85 (m, 2H), 2.54 (m, 2H), 2.39 (s, 3H), 2.12 (m, 1H); 1.83 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](=[O:7])[CH2:5]Cl.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](=[O:7])[CH2:5][N:16]1[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)c2ccc(Cl)cc2Cl)CC1

Procedure:
1 mmol of 2,4-dichlorophenacyl chloride in DMF was added drop wise to 1. mmol of tert-butyl piperazinecarboxylate and 1.2 mmol Cs2CO3 in DMF at room temperature for fourteen hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate, and purified by column chromatography eluting with 50% ethylacetate and 50% hexane to obtain tert-butyl 4-[2-(2,4-dichlorophenyl)-2-oxoethyl]piperazinecarboxylate.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:12]1[CH:17]=[C:16]([C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[CH:21]=[C:20]([CH2:32][OH:33])[C:19]=2[CH2:34][OH:35])[CH:15]=[CH:14][N:13]=1.[H-].[Na+].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].[C:45]([O:48][CH2:49][CH3:50])(=[O:47])[CH3:46]>CN(C)C=O.O>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:12]1[CH:17]=[C:16]([C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[CH:21]=[C:20]([CH2:32][OH:33])[C:19]=2[CH2:34][O:35][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:15]=[CH:14][N:13]=1.[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:12]1[CH:17]=[C:16]([C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[CH:21]=[C:20]([CH2:32][O:33][CH2:46][C:45]([O:48][CH2:49][CH3:50])=[O:47])[C:19]=2[CH2:34][OH:35])[CH:15]=[CH:14][N:13]=1
Reactant: CCOC(C)=O
Reactant: CCOC(=O)CBr
Reactant: COc1cc2cc(CO)c(CO)c(-c3ccnc(-n4c(=O)ccc5ccccc54)c3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COCc1c(CO)cc2cc(OC)c(OC)cc2c1-c1ccnc(-n2c(=O)ccc3ccccc32)c1
Product: CCOC(=O)COCc1cc2cc(OC)c(OC)cc2c(-c2ccnc(-n3c(=O)ccc4ccccc43)c2)c1CO
Reaction time: 0.5 h

Procedure:
To a solution of 1-[2-(2-oxo-1,2-dihydroquinolin-1-yl)-4-pyridyl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (468 mg) in dimethylformamide (5 ml) is added sodium hydride (60 mg), and the mixture is stirred for 30 minutes. The mixture is cooled with ice, and thereto is added dropwise ethyl bromo-acetate (0.17 ml), and the mixture is stirred overnight. To the residue are added ethyl acetate and water, and the ethyl acetate layer is separated, washed, dried and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform:acetone=5: 1) to give 1-[2-(2-oxo-1,2-dihydroquinolin-1-yl)-4-pyridyl]-2-ethoxycarbonylmethoxymethyl-3-hydroxymethyl-6,7-dimethoxynaphthalene (70 mg, Example 96) and 1-[2-(2-oxo-1,2-dihydroquinolin-1-yl)-4-pyridyl]-2-hydroxymethyl-3-ethoxycarbonylmethoxymethyl-6,7-dimethoxynaphthalene (120 mg, Example 97), which are listed in Table 8.
Reaction SMILES: S(Cl)(Cl)=O.CN(C=O)C.[C:10]1([N:16]2[C:28]([CH2:29][CH2:30][CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[C:27]3[C:18]([C:19](=O)[NH:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=43)=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:38]CCl>C(#N)C>[Cl:38][C:19]1[C:18]2=[N:17][N:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:28]([CH2:29][CH2:30][CH:31]3[CH2:32][CH2:33][NH:34][CH2:35][CH2:36]3)=[C:27]2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: O=c1[nH]c2ccccc2c2c(CCC3CCNCC3)n(-c3ccccc3)nc12
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: Clc1nc2ccccc2c2c(CCC3CCNCC3)n(-c3ccccc3)nc12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Thionyl chloride (1.0 mL) and DMF (1.0 mL) were combined and added dropwise to a mixture of 2-phenyl-1-(2-piperidin-4-ylethyl)-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one (200 mg, 0.537 mmol) and dichloromethane (10 mL) at 0° C. The resulting suspension was stirred 5 minutes at 0° C. before warming to ambient temperature and stirring 55 minutes. The suspension was concentrated under reduced pressure to afford a light yellow oil that was stirred in acetonitrile and filtered to obtain a white solid. The solid was combined with additional acetonitrile and concentrated under reduced pressure to afford 100 mg of 4-chloro-2-phenyl-1-(2-piperidin-4-ylethyl)-2H-pyrazolo[3,4-c]quinoline.HCl as a white powder, mp 194° C. MS (APCI) m/z 391 (M+H)+; Anal. calcd for C23H23ClN4.1.0H2O.1.0HCl: C, 62.02; H, 5.88; N, 12.58. Found: C, 61.91; H, 5.67; N, 12.48.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:24][C:23]([C:25]([O:27]C)=[O:26])=[CH:22][C:9]=3[N:10]([CH2:18][C:19](O)=[O:20])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.B(Br)(Br)Br>CN(C=O)C.C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[S:24][C:23]([C:25]([OH:27])=[O:26])=[CH:22][C:9]=3[N:10]([CH2:18][C:19]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:20])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccccc1)n2CC(=O)O
Agent: BrB(Br)Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccccc1)n2CC(=O)N1CCOCC1
Reaction time: 0.07 h
Yield: 43 %

Procedure:
Following the procedure described above for 6-cyclohexyl-4-[2-(dimethylamino)-2-oxoethyl]-5-phenyl-4N-thieno[3,2-b]pyrrole-2-carboxylic acid (step 3), treatment of a solution (0.08 M) of [6-cyclohexyl-2-(methoxycarbonyl)-5-phenyl-4H-thieno[3,2-b]pyrrol-4-yl]acetic acid in DMF with morpholine (1.1 eq.), DIEA (3 eq.) and HATU (1.1 eq.) followed by treatment of a solution (0.1 M) of the resulting residue in DCM with BBr3 (1 M solution in DCM, 3 eq.) gave a residue that was purified by RP-HPLC (Conditions: Waters X-TERRA MS C18, 5 micron, 19×150 mm; flow: 17 mL/min; Gradient: A: H2O+0.05% TFA; B: MeCN+0.05% TFA; 60% A isocratic for 4 min, linear to 50% A in 2 min, linear to 40% in 2 min then isocratic for 2 min, linear to 35% A in 2 min isocratic for 1 min then linear to 30% A isocratic for 1 min then linear to 0% A in 3 min) to afford the title compound (43%) as a solid.
Reaction SMILES: O[C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][O:30][C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:24][CH2:23]2)=[O:21])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC([O:67][CH2:68][CH3:69])=O.[SH:75]CC(O)=O>O1CCCC1>[C:68]([S:75][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][O:30][C:31]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=3)=[O:32])[CH2:24][CH2:23]2)=[O:21])[CH2:3]1)(=[O:67])[CH3:69]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: O=C(O)CS
Reactant: O=C(OCCN1CCN(C(=O)[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)S[C@H]1C[C@@H](C(=O)N2CCN(CCOC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.17 h
Yield: 77.6 %

Procedure:
105 g of (2S,4R)-4-hydroxy-2-{4-[2-(4-nitrobenzyloxycarbonyl)oxyethyl]-1-piperazinylcarbonyl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 15) and 55 g of triphenylphosphine were dissolved in 700 ml of tetrahydrofuran, and a solution of 36.5 g of diethyl azodicarboxylate in 100 ml of tetrahydrofuran was added dropwise to it, whilst ice-cooling. The resulting mixture was then stirred at the same temperature for 10 minutes. At the end of this time, a solution of 15.9 g of mercaptoacetic acid in 100 ml of tetrahydrofuran was added dropwise to the mixture, and the resulting mixture was stirred at room temperature for 1 hour. The mixture was then concentrated by evaporation under reduced pressure. The concentrate was dissolved in 1.5 liters of ethyl acetate and washed with water and with an aqueous solution of sodium chloride, in that order. The organic layer was dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The resulting residue was mixed with 400 ml of diisopropyl ether and a soluble material was removed. This procedure was repeated four times in all. The residue was subjected to column chromatography through 3 kg of silica gel using mixtures of ethyl acetate and methanol ranging from 1:0 to 20:1 by volume as the eluent. Those fractions containing the title compound were collected and concentrated by evaporation under reduced pressure, to afford 88.4 g of the title compound as a colorless powder.
Reaction SMILES: Cl.[CH:2]([NH:5][OH:6])([CH3:4])[CH3:3].CC(C)([O-])C.[K+].[CH3:13][C:14]([C:17]1[CH:18]=[C:19]([CH:28]=[C:29]2[S:33][C:32](SC)=[N:31][C:30]2=[O:36])[CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])([CH3:16])[CH3:15]>C(O)C>[CH3:16][C:14]([C:17]1[CH:18]=[C:19]([CH:28]=[C:29]2[S:33][C:32]([N:5]([OH:6])[CH:2]([CH3:4])[CH3:3])=[N:31][C:30]2=[O:36])[CH:20]=[C:21]([C:24]([CH3:25])([CH3:26])[CH3:27])[C:22]=1[OH:23])([CH3:13])[CH3:15]
Reactant: CC(C)NO
Reactant: CSC1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)S1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CC(C)N(O)C1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)S1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
A mixture of N-isopropylhydroxylamine hydrochloride (5.5 g, 0.049 mole), potassium-t-butoxide (4.83 g, 0.043 mole), and ethanol (500 mL) is stirred at room temperature for 15 minutes. 5-[(3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene]-2-(methylthio)-4(5H)-thiazolone (7.27 g, 0.02 mole) is then added and the mixture is refluxed with stirring for six hours. After removal of the solvent under reduced pressure, the cooled reaction mixture is poured into a mixture of ice-water containing 1N hydrochloric acid and extracted with ether. The organic layer is washed with water, dried, and the solvent is evaporated to give 7.7 g of a residue. The residue is flash chromatographed on silica gel (202 g), eluting first with methylene chloride and then with methylene chloride-methanol (9:1) to give 7.0 g purified product. It is recrystallized from methylene chloride-ethyl acetate-ether to give 4.2 g (54%) of pure 5-[[3,5-Bis-(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2-[hydroxy(1-methylethyl)amino]-4(5H)-thiazolidinone, (Z)-, mp 208° C. (dec).
Reaction SMILES: [C:1]([O-:4])([O-])=O.[Cs+].[Cs+].[CH2:7]([O:14][C:15]1[CH:16]=[C:17](O)[C:18]2[C:19](=[O:31])[C:20]3[C:25]([O:26][C:27]=2[CH:28]=1)=[C:24]([O:29][CH3:30])[CH:23]=[CH:22][CH:21]=3)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CI.CCO>CN(C=O)C>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([O:4][CH3:1])[C:18]2[C:19](=[O:31])[C:20]3[C:25]([O:26][C:27]=2[CH:28]=1)=[C:24]([O:29][CH3:30])[CH:23]=[CH:22][CH:21]=3)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cccc2c(=O)c3c(O)cc(OCc4ccccc4)cc3oc12
Agent: [Cs+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccc2c(=O)c3c(OC)cc(OCc4ccccc4)cc3oc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.1 %

Procedure:
Cs2CO3 (27.0 g, 83 mmol) was added in portions to phenol (102) (14.5 g, 42 mmol) and MeI (8.0 mL, 125 mmol) in DMF (400 mL) at rt. After 3 h at 50° C., the reaction was decanted and washed with CH2Cl2 into an erlenmeyer which had been placed in an ice cooled bath. With stirring, 2M HCl was added slowly until acidic by pH paper. After warming to rt, the reaction was diluted with CH2Cl2 (800 mL) and H2O (400 mL). The layers are separated and the aqueous layer was reextracted with CH2Cl2 (300 mL). The organic layers were combined, washed with brine (400 mL), dried (Na2SO4) and concentrated under reduced pressure to provide a red sludge which could be tritrated with EtOH and filtered to afford (9.3 g, 66%) of (103) as a pink solid. Analytically pure material can be obtained at this point by column chromatography with 50% EtOH/hexane. (LH-63-5) 1H NMR (250 MHz, CDCl3) δ 7.84 (d, 1H, J=6.0Hz), 7.42−7.31 (complex, 5H), 7.20−7.07 (complex, 2 H), 6.63 (s, 1H), 6.37 (s, 1H), 5.08 (s, 2H), 3.92 (s, 3H), 3.88 (s, 3H); 13C NMR (62.5 MHz) δ 175.2, 163.8, 161.7, 159.4, 147.8, 144.5, 135.6, 128.6, 128.3, 127.5, 123.9, 123.1, 117.5, 114.3, 106.1, 95.9, 93.6, 70.4, 56.3, 56.2; mass spectrum (CI) m/z+1 363.1242 [C22H19O5 (M+1) requires 363.1232] 363 (base), 339.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[NH:10][NH2:11]>CCCCCC>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=[N:11][NH:10][C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC1CCC(=O)CC1
Solvent: CCCCCC
Product: CC1CCC(=NNC(=O)OC(C)(C)C)CC1
Yield: 89.1 %

Procedure:
To a 230 ml hexane solution of 23.6 ml (192 mmol) of 4-methylcyclohexanone, 25.5 g (192 mg) of t-butyl carbazate was added, followed by heating the mixture under reflux for 20 minutes. Then, the reaction mixture was brought to room temperature, and precipitated solids were collected by filtration to obtain 38.7 g (89%) of the captioned compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[NH:15])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[C:17]1([CH:23]([CH3:30])[C:24](=O)[CH2:25][C:26](=O)[CH3:27])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[O-]CC.[Na+]>C(O)C>[CH3:27][C:26]1[CH:25]=[C:24]([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:30])[N:16]=[C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([N:3]3[CH:4]=[CH:5][N:6]=[C:2]3[CH3:1])=[CH:12][CH:11]=2)[N:15]=1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Reactant: CC(=O)CC(=O)C(C)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(C)c2ccccc2)nc(Nc2ccc(-n3ccnc3C)cc2)n1
Yield: 1.4 %

Procedure:
1-(4-(2-Methyl-1H-imidazol-1-yl)phenyl)guanidine (953 mg, 4.43 mmol, example 9e), 5-phenylhexane-2,4-dione (842 mg, 4.43 mmol) and sodium ethoxide (301 mg, 4.43 mmol) in ethanol (5 mL) were heated in a microwave reactor at 100° C. for 15 minutes. The mixture was allowed to reach room temperature and the crude was purified by HPLC yielding 4-methyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-6-(1-phenylethyl)pyrimidin-2-amine (23.00 mg, 1.313%). MS (ES+) m/z 370.2 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([O:10][CH3:9])[CH:16]=2)=[CH:4][N:3]=1
Reactant: Nc1cnc(Br)cn1
Reactant: COc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(-c2cnc(N)cn2)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 102.5 %

Procedure:
To a solution of 2-amino-5-bromopyrazine (642 mg) in dimethoxyethane (40 mL) was added 3-methoxyphenylboronic acid (560 mg), 1.5N aqueous sodium carbonate solution (4 mL) and tetrakis(triphenylphosphine)palladium (0) (86 mg). The mixture was stirred at 80° C. for 6 hours. To the reaction mixture was added water (20 mL) and the whole was extracted with ethyl acetate (50 mL×3). The extract was washed with saturated saline solution and then dried over anhydrous Na2SO4. The concentration of the solvent left a crystal residue, which was washed with ethyl ether (10 mL) to give the subject compound (760 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[C:11](Br)[CH:10]=1>CCCCC.C([Li])(C)(C)C.O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]1[CH:12]=[C:13]([Br:15])[CH:14]=[C:9]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:10]=1
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: Brc1cc(-c2ccccn2)cc(-c2ccccn2)c1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 66 %

Procedure:
In a stream of argon, 89 mL of a 1.57M tert-butyllithium pentane solution was dissolved in 32 mL of tetrahydrofuran, and the solution was cooled to −78° C. 10.0 g of 2-bromopyridine was added dropwise to the solution, and the mixture was stirred for 1.5 hours. 42.5 g of dichloro(tetramethylethylenediamine)zinc was added to the mixture, and the temperature of the resultant mixture was elevated to room temperature, and the mixture was further stirred for 1 hour. To the resultant mixture, a suspension of 10.0 g of 1,3,5-tribromobenzene and 734 mg of tetrakis(triphenylphosphine)palladium in 64 mL of tetrahydrofuran was added. The obtained mixture was heated under reflux for 17 hours while being stirred. Then the obtained reaction mixture was cooled to room temperature, and was then distilled under a reduced pressure to remove all volatile materials. Water and chloroform were added to the concentrate, and the organic phase was separated and distilled to remove the solvent. The thus-obtained crude product was purified by silica gel chromatography using an ethyl acetate/hexane (2:8-1:1) mixed solvent to give 6.5 g of the target 3,5-di(2-pyridyl)bromobenzene as a yellow solid (yield: 66%).