Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[NH:13][C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1.Br.Br[CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[N:13]([CH2:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)[C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1
Reactant: BrCc1ccncc1
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1ccncc1
Reaction time: 0.17 h

Procedure:
Sodium hydride (13 mg, 0.32 mmol, 60% in mineral oil) was added to a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (20 mg, 0.1 mmol, from Example 2, Step 5) in DMF (3.0 mL). After stirring for 10 minutes, a solution of 4-(bromomethyl)pyridine hydrobromide (0.027 g, 0.11 mmol, Aldrich) in DMF (0.8 mL) was added. The mixture was stirred for 45 minutes and then quenched by the addition of water, diluted to 5 mL with MeCN, filtered and purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (1.0 mg, 3%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=4)[CH2:21][CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:30]([O:32]C)=[O:31])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].CC(O)=O>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=4)[CH2:21][CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:30]([OH:32])=[O:31])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4ccc(OC)cc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(c1)N(c1nc3cc(C(=O)O)ccc3nc1-c1ccc(F)cc1)CCC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.7 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(7-methoxy-1,2,3,4-tetrahydroquinolin-1-yl)quinoxaline-6-carboxylate (88 mg, 0.20 mmol) in methanol (30 ml) was added sodium hydroxide (32 mg, 0.80 mmol) and water (2 ml). The reaction was stirred for 2 days at room temperature. The resulting solution was diluted with water (15 ml), adjusted to pH 5 with AcOH, extracted with ethyl acetate (2×20 ml) and the organic layers were combined and concentrated in vacuo to afford 2-(4-fluorophenyl)-3-(7-methoxy-1,2,3,4-tetrahydroquinolin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid (59 mg, 69%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]2[N:9]=[N:10][N:11]([CH2:12][CH3:13])[C:7]=2[CH:6]=1)=O.[BH4-].[Li+].[Cl-].[NH4+]>O1CCCC1.CO>[CH2:12]([N:11]1[C:7]2[CH:6]=[C:5]([CH2:3][OH:2])[CH:15]=[CH:14][C:8]=2[N:9]=[N:10]1)[CH3:13]
Reactant: CCn1nnc2ccc(C(=O)OC)cc21
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CCn1nnc2ccc(CO)cc21
Reaction time: 0.5 h
Yield: 105.3 %

Procedure:
3-Ethyl-3H-benzotriazole-5-carboxylic acid methyl ester (0.143 g) was diluted with tetrahydrofuran (2 mL) and methanol (0.06 mL). Lithium borohydride (0.023 g) was added and the solution was allowed to stand at 23° C. for 30 minutes. The reaction was then poured onto saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried with sodium sulfate and concentrated to give (3-Ethyl-3H-benzotriazol-5-yl)-methanol (0.13 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[N:6][CH:5]=1.O1CCCC1.O.C(=O)([O-])[O-].[Na+].[Na+].[I:24]I>>[OH:10][C:8]1[C:7]([I:24])=[N:6][CH:5]=[C:4]([CH:9]=1)[C:3]([O:2][CH3:1])=[O:11]
Reactant: COC(=O)c1cncc(O)c1
Reactant: II
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cnc(I)c(O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.2 %

Procedure:
To solution of 5-hydroxy-nicotinic acid methyl ester (2.50 g, 16.3 mmol) in tetrahydrofuran (50.0 mL, 616 mmol)/water (50.0 mL, 2780 mmol) was added sodium carbonate (5.19 g, 49.0 mmol) and iodine (10.4 g, 40.8 mmol). The reaction mixture was stirred at room temperature 4h. The aqueous layer containing product was separated and wash with hexane. The organic layer was neutralized to pH 7 with HCl, extracted EtOAc 4×. The combined organic layers was dried Na2SO4, concentrated. The crude product was purified by flash chromatography (EtOAc/DCM) (eluted at 40 EtOAc) to give methyl 5-hydroxy-6-iodonicotinate (81.2%) MS: (ESI+) 280.0
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=12.C([O-])(=O)C.[Na+].[Br-:15].[K+].BrBr>CO>[Br:15][C:3]1[N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: c1cn2ccnc2cn1
Reactant: [Br-]
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Product: Brc1cnc2cnccn12
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
Imidazo[1,2-a]pyrazine (1.191 g, 10 mmol, Intermediate 1) and sodium acetate (0.984 g, 12.00 mmol) were suspended in methanol (10 ml) saturated with potassium bromide (excess) and cooled to −10° C. Bromine (0.515 mL, 10.00 mmol) was added dropwise and the mixture stirred at −10° C. for 10 min. The solution was quenched by the addition of 1N sodium sulfite solution (10 ml) and concentrated in vacuo. The residue was partitioned between ethyl acetate (100 ml) and 50% saturated sodium bicarbonate solution (100 ml). The aqueous phase was extracted with ethyl acetate (2×100 ml), combined, washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated to give crude 3-bromoimidazo[1,2-a]pyrazine (1.66 g, 8.38 mmol, 84% yield) that was used in subsequent steps without further purification 3-bromoimidazo[1,2-a]pyrazine (1.66 g, 8.38 mmol, 84% yield).
Reaction SMILES: Cl[C:2]1[C:3]([C:13]([NH2:15])=[O:14])=[N:4][C:5]([C:9]([OH:12])([CH3:11])[CH3:10])=[C:6]([Cl:8])[N:7]=1.[NH2:16][C:17]1[CH:18]=[N:19][N:20]([CH2:22][CH2:23][OH:24])[CH:21]=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>O1CCOCC1>[Cl:8][C:6]1[N:7]=[C:2]([NH:16][C:17]2[CH:18]=[N:19][N:20]([CH2:22][CH2:23][OH:24])[CH:21]=2)[C:3]([C:13]([NH2:15])=[O:14])=[N:4][C:5]=1[C:9]([OH:12])([CH3:11])[CH3:10]
Reactant: CC(C)(O)c1nc(C(N)=O)c(Cl)nc1Cl
Reactant: Nc1cnn(CCO)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(O)c1nc(C(N)=O)c(Nc2cnn(CCO)c2)nc1Cl
Yield: 62 %

Procedure:
A mixture of 3,5-dichloro-6-(2-hydroxypropan-2-yl)pyrazine-2-carboxamide (2.0 g), 2-(4-amino-1H-pyrazol-1-yl)ethan-1-ol (1.12 g), diisopropylethylamine (2.79 mL), and dioxane (20 mL) was heated and refluxed for 2 hours. The reactant was cooled, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with a mixture of chloroform:methanol (10:1). The organic phase was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=99:1-90:10) to obtain 5-chloro-3-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}-6-(2-hydroxypropan-2-yl)pyrazine-2-carboxamide (1.69 g) as a yellow solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.C1(C)C=CC=C(C)C=1.S(Cl)([Cl:24])=O>CCOC(C)=O.C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([Cl:24])=[O:13]
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: O=S(Cl)Cl
Solvent: Cc1cccc(C)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Cl)c1ccc2ccccc2c1
Yield: 100 %

Procedure:
In a flame dried rbf charged with nitrogen, a mixture of 2-naphthoic acid (0.516 g, 3 mmol), anhydrous m-xylene (14.83 mL) and thionyl chloride (11 mL) were refluxed for 2 hours. Rf=TLC (SiO2, 5% EtOAc/CH2Cl2) showed reaction was complete. The solvent was removed in vacuo resulting in 0.604 g of creamy white crystals of 2-naphthoyl chloride (100% yield). Fresh anhydrous m-xylene (5 mL) was added to 2-naphthoyl chloride (0.416 g, 2 mmol) and allowed to stir for 5 minutes, then a mixture of 2-amino-3-hydroxy-benzoic acid methyl ester (0.334 g, 2 mmol), triethylamine (3 mL) were added. The mixture was allowed to stir at room temperature for 4 hours, then the reaction mixture was heated to reflux and allowed to stir at refluxed temperature for 12 hours. The cooled mixture diluted with 100 mL of EtOAc and transferred to a separatory funnel, washed with of 0.1 M HCl (1×50 mL), H2O (1×50 mL) saturated NaHCO3 (1×50 mL), H2O (1×50 mL), and saturated NaCl (1×50 mL), respectively. The product was dried over Na2SO4; solvent was removed under pressure and concentrated in vacuo. The resulting 0.578 g of reddish-brown product was placed in a flame-dried rbf under N2 (g), then anhydrous m-xylene (14.4 mL), and PPTS (0.904 g, 3.6 mmol) were added. The reaction mixture refluxed for 4 hours. The cooled mixture was diluted with 100 mL EtOAc and transferred to a separatory funnel, washed with saturated NaHCO3 (1×50 mL), H2O (4×50 mL), and saturated NaCl (1×50 mL), dried over Na2SO4; solvent was removed under pressure and concentrated in vacuo using a coldfinger. The mixture was purified using flash chromatography Yield: 0.173 g tan solid (28% yield, 4 steps). Rf=0.40 (SiO2, 3% EtOAc/CH2Cl2). 1H NMR (400 MHz, CDCl3) δ 4.09 (s, 3H), δ 7.44 (t, J=7.8, 1H), δ 7.58-7.60 (m, 2H), δ 7.82 (dd, J=9.2 Hz, 1 Hz, 2H), δ 7.90 (d, J=7.3 Hz, 1H), δ 7.98-8.06 (m, 3H), δ 8.41 (dd, J=8.7 Hz, 1.8 Hz, 1H), δ 8.89 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[C:4]([CH:10]=[CH:11][C:12]([CH3:16])([OH:15])[CH:13]=[CH2:14])=[C:3]1[CH3:17].C(N(CC)CC)C.[CH3:25][Si:26]([CH3:29])([CH3:28])Cl.C(=O)([O-])O.[Na+]>CN(C)C=O.CCCCCC>[CH3:25][Si:26]([CH3:29])([CH3:28])[O:15][C:12]([CH3:16])([CH:13]=[CH2:14])[CH:11]=[CH:10][C:4]1[C:5]([CH3:8])([CH3:9])[CH2:6][CH:7]=[C:2]([O:1][Si:26]([CH3:29])([CH3:28])[CH3:25])[C:3]=1[CH3:17]
Reactant: C=CC(C)(O)C=CC1=C(C)C(=O)CCC1(C)C
Reactant: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C=CC(C)(C=CC1=C(C)C(O[Si](C)(C)C)=CCC1(C)C)O[Si](C)(C)C
Temperature: 120 °C

Procedure:
A solution of 23.1 g of 96.5% 1-(3-oxo-2,6,6-trimethyl-1-cyclohexen-1-yl)-3-methyl-1,4-pentadien-3-ol in 85 ml of dimethylformamide in a four-necked flask equipped with a stirrer and reflux condenser was treated with 80 ml of triethylamine and 73 ml of trimethylchlorosilane. The mixture was heated to reflux (heating bath temperature 120° C.) for 2 hours while stirring and under a light argon stream. The mixture was subsequently cooled to about 0° C. with an ice-bath and treated while stirring with 400 ml of hexane and 200 ml of semi-saturated sodium hydrogen carbonate solution. The phases were separated and the aqueous phase was extracted with 200 ml of hexane. The combined organic phases were washed once with 100 ml of saturated sodium chloride solution, dried over sodium sulphate and concentrated at 40° C. in a rotary evaporator. Distillation of the resulting brown oil (39.5 g) at 102°-107° C./0.1 Torr gave 35.0 g of trimethyl[[1-methyl-3-[2,6,6-trimethyl-3-(trimethylsiloxy)-1,3-cyclohexadien-1-yl]-1-vinylallyl]oxy]silane as a pale yellowish oil; purity about 77%.
Reaction SMILES: C(C1CC(=O)C2C(=CC=CC=2)N=1)C.C1(C(C2NN=NN=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.NC1C=CC=CC=1.C(CC(OC)=O)(=O)CC.[CH2:54]([C:57]1[CH:66]=[C:65]([O:67][CH2:68][C:69]2[CH:74]=[CH:73][C:72]([C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=3[C:81]3N=NN(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:85]=3)=[CH:71][CH:70]=2)[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[N:58]=1)[CH2:55]C.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[CH2:54]([C:57]1[CH:66]=[C:65]([O:67][CH2:68][C:69]2[CH:74]=[CH:73][C:72]([C:75]3[C:76]([C:81]#[N:85])=[CH:77][CH:78]=[CH:79][CH:80]=3)=[CH:71][CH:70]=2)[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[N:58]=1)[CH3:55]
Reactant: CCCc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2ccccc2n1
Agent: CCC(=O)CC(=O)OC
Agent: CCC1=Nc2ccccc2C(=O)C1
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: Nc1ccccc1
Product: CCc1cc(OCc2ccc(-c3ccccc3C#N)cc2)c2ccccc2n1
Reaction time: 0.5 h
Yield: 111.6 %

Procedure:
A mixture of 2-ethyl-4-quinolone (1.73 g), (prepared by a similar method to that described in Org. Syn., Coll. Vol. III, p.374 and p.593 from aniline and methyl propionylacetate), 4'-bromomethylbiphenyl-2-carbonitrile (A) (3.1 g) and solid potassium carbonate (1.81 g) in N-methylpyrrolidone (40 ml) were stirred for 36 hours under nitrogen. The mixture was then added dropwise to water (100 ml) at 15°-25° C. and stirred for 30 minutes. The suspended solid was collected by filtration, washed with water, and dried at 60° C. under vacuum. The solid was recrystallised from tert-butyl methyl ether to give 4'-[(2-ethylquinolin-4-yloxy)methyl]-biphenyl-2-carbonitrile as a solid (1.9 g), m.p. 151°-153° C.; NMR(CDCl3): 1.4(t, 3H), 2.97(q,2H), 5.35(s,2H), 6.76(s,1H), 7.4-7.6(m, 3H), 7.6-7.8(m, 6H), 8.0(d, 1H), 8.25(d, 1H).
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:17]=1[C:18]([N:20]([CH2:30][CH3:31])[CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:19])[C:8]1[N:13]=[CH:12][C:11](Br)=[CH:10][N:9]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].[NH:76]1[CH2:81][CH2:80][O:79][CH2:78][CH2:77]1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:17]=1[C:18]([N:20]([CH2:30][CH3:31])[CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:19])[C:8]1[N:13]=[CH:12][C:11]([N:76]2[CH2:81][CH2:80][O:79][CH2:78][CH2:77]2)=[CH:10][N:9]=1
Reactant: C1COCCN1
Reactant: CCN(CCC(=O)OC(C)(C)C)C(=O)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCN(CCC(=O)OC(C)(C)C)C(=O)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tert-butyl 3-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-benzoyl)-ethyl-amino]-propionate (300 mg) is dissolved in toluene (5 ml), and thereto are added tris(dibenzylideneacetone)dipalladium (36 mg), 2-(di-tert-butylphosphino)biphenyl (47 mg), sodium tert-butoxide (57 mg) and morpholine (52 μl), and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=17:3→7:3) and further by silica gel column chromatography (hexane:ethyl acetate=4:1→3:2) to give tert-butyl 3-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-benzoyl)-ethyl-amino]-propionate (13.3 mg). MS (m/z): 764 [M+H]+
Reaction SMILES: [C:1]([N:4]([CH2:17][C:18]1[CH:19]=[C:20]([C:24]2[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:31])[CH:21]=[CH:22][CH:23]=1)[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15]C)=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[C:1]([N:4]([CH2:17][C:18]1[CH:19]=[C:20]([C:24]2[C:25]([CH3:31])=[CH:26][CH:27]=[CH:28][C:29]=2[CH3:30])[CH:21]=[CH:22][CH:23]=1)[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)CCc1ccc(N(Cc2cccc(-c3c(C)cccc3C)c2)C(C)=O)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(=O)N(Cc1cccc(-c2c(C)cccc2C)c1)c1ccc(CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.1 %

Procedure:
To a solution of methyl 3-(4-{acetyl[(2′,6′-dimethylbiphenyl-3-yl)methyl]amino}phenyl)propanoate (0.644 g, 1.55 mmol) in a mixture of methanol (8 mL) and tetrahydrofuran (8 mL) was added 2 M aqueous sodium hydroxide solution (2.5 mL), and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was weakly acidified with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (0.430 g, yield 69%) as colorless prism crystals.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([C@@H:14]1[O:16][CH2:15]1)Cl.CC(C)([O-])C.[K+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(O)(C)C>[CH2:12]([C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6])[C@H:14]1[O:16][CH2:15]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClC[C@H]1CO1
Agent: CC(C)(C)[O-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: CC(C)O
Product: O=C1NC(=O)c2c(C[C@@H]3CO3)cccc21
Temperature: 40 °C
Reaction time: 24 h
Yield: 88.7 %

Procedure:
To a reaction vessel were added phthalimide 4.00 g (27.2 mmol), (R)-epichlorohydrin 4.52 g (49.0 mmol), benzyl trimethylammonium chloride 126 mg (0.68 mmol) and isopropanol 25 mL, and the mixture was stirred at 40° C. for 24 hours. To this mixture were dropped a mixture of potassium tert-butoxide 3.66 g (32.6 mmol) and isopropanol 15 mL and the mixture was stirred at 20° C. for 3 hours. After evaporation of the solvent, the condensed residue was dissolved in ethyl acetate and washed with water. The organic layer was taken and recrystallized to give (R)-glycidylphthalimide 4.90 g (Yield 89%, chemical purity 96%) as a white crystal.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>C1COCC1>[Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][O:23]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: Brc1cccc2[nH]cnc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: Brc1cccc2c1ncn2C1CCCCO1
Yield: 81.3 %

Procedure:
A mixture of 4-bromo-1H-benzo[d]imidazole (1.5 g, 7 mmol), TsOH.H2O (0.1 g, 0.7 mmol), and 3,4-dihydro-2H-pyran (2.9 g, 35 mmol) in THF (10 mL) was heated at reflux overnight. The reaction mixture was concentrated in vacuo. To the residue was added water and the mixture was extracted with EtOAc. The combined extracts were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by SiO2 chromatography using a petroleum ether/EtOAc gradient (10:1 to 3:1) to afford 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole as a gray solid (1.6 g, 75%). MS (ESI): m/z=281 [M+1]+.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH2:16])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[F:17][CH:18]([F:35])[C:19]1[N:27]=[CH:26][C:25]([CH2:28][NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])=[CH:24][C:20]=1[C:21](O)=[O:22].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH:16][C:21](=[O:22])[C:20]3[CH:24]=[C:25]([CH2:28][NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[N:27][C:19]=3[CH:18]([F:35])[F:17])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Nc1ncnc2c(N)cccc12
Reactant: CC(C)C(=O)NCc1cnc(C(F)F)c(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C(=O)NCc1cnc(C(F)F)c(C(=O)Nc2cccc3c(NC(C)(C)C)ncnc23)c1
Yield: 5.5 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(tert-butyl)quinazoline-4,8-diamine (Intermediate-55, 100 mg, 0.46 mmol), 2-(difluoromethyl)-5-(isobutyramidomethyl)nicotinic acid (Intermediate-66, 150 mg, 0.55 mmol), oxalyl chloride (104 mg, 0.83 mmol), DMF (1 drop) and DIPEA (178 mg, 1.38 mmol) in CH2Cl2 (2 mL) to afford 12 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.32 (s, 1H), 8.71 (s, 1H), 8.63 (m, 1H), 8.49 (m, 2H), 8.16 (d, 1H), 8.05 (m, 1H), 7.46 (m, 2H), 7.22 (t, J=54 Hz, 1H), 4.42 (d, 2H), 1.55 (s, 9H), 1.05 (d, J=6.6 Hz, 6H); MS [M+H]+: 471.49.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.[NH:31]1[CH:35]=[CH:34][CH:33]=[N:32]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC>CS(C)=O.[Cu]I>[OH:29][C@@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@H:23]1[N:13]1[C:12](=[O:30])[C:11]2[C:16](=[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([N:31]4[CH:35]=[CH:34][CH:33]=[N:32]4)=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: c1cn[nH]c1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@@H]1CCCC[C@H]1O
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: O=c1c2cc(Cc3ccc(-n4cccn4)nc3)c3ccccc3c2ncn1[C@@H]1CCCC[C@H]1O
Temperature: 130 °C

Procedure:
To a solution of rac-6-[(6-chloropyridin-3-yl)methyl]-3-[trans-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one (0.050 g, 0.12 mmol) and pyrazole (0.024 g, 0.36 mmol) in 2 mL of DMSO under an atmosphere of nitrogen was added cesium carbonate (0.24 mL, 1 N aqueous, 0.24 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (1.7 mg, 0.012 mmol), and copper(I) iodide (2.3 mg, 0.012 mmol). The mixture was heated at 130° C. for 24 h, cooled to rt, and purified via preparative reverse phase HPLC. The appropriate fractions were concentrated in vacuo. The residue was taken up in saturated aqueous sodium bicarbonate and extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 452.0 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 9.01-8.99 (m, 1H), 8.50 (s, 1H), 8.32-8.30 (m, 2H), 8.02 (s, 1H), 7.93-7.91 (m, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.69-7.64 (m, 3H), 7.56 (d, J=8.4 Hz, 1H), 6.43 (s, 2H), 4.63 (br s, 1H), 4.09 (br s, 1H), 2.28-2.22 (m, 1H), 2.14-2.00 (m, 1H), 1.94-1.84 (m, 3H), 1.60-1.40 (m, 3H), 1.18-1.10 (m, 1H).