Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cu][C:2]#[N:3].[CH2:4]([NH:11][C:12]([C:14]1[S:18][C:17](I)=[N:16][C:15]=1[CH3:20])=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CN(C)C=O.O>[CH2:4]([NH:11][C:12]([C:14]1[S:18][C:17]([C:2]#[N:3])=[N:16][C:15]=1[CH3:20])=[O:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: N#C[Cu]
Reactant: Cc1nc(I)sc1C(=O)NCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(C#N)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.6 %

Procedure:
To a stirred mixture of copper(I) cyanide (0.19 g, 2.10 mmol) in anhydrous N,N-dimethylformamide (6 mL) at 150° C. was added N-benzyl-2-iodo-4-methylthiazole-5-carboxamide (0.30 g, 0.84 mmol). The resulting reaction mixture was stirred at same temperature for 10 minutes, and then allowed to cool to ambient temperature and diluted with water (50 mL). The resulting precipitate was filtered, washed with water (50 mL) and ethyl acetate (100 mL). The organic filtrate was washed with water (2×50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (0-20% ethyl acetate in hexanes) to afford the title compound as a clear oil (0.09 g, 39%): 1H NMR (300 MHz, CDCl3) δ 7.42-7.30 (m, 5H), 6.17 (br s, 1H), 4.63 (d, J=5.6 Hz, 2H), 2.73 (s, 3H); MS (ES−) m/z 256.2 (M−1).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8]/[CH:9]=[CH:10]/[C:11]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[C:14]2=[N:22][NH:23][C:24](=[O:25])[N:13]2[CH:12]=1)(C)(C)C>CC#N.C(O)(C(F)(F)F)=O>[NH2:7][CH2:8]/[CH:9]=[CH:10]/[C:11]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[C:14]2=[N:22][NH:23][C:24](=[O:25])[N:13]2[CH:12]=1
Reactant: CC(C)(C)OC(=O)NC/C=C/c1cn2c(=O)[nH]nc2c2cc(Cl)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: NC/C=C/c1cn2c(=O)[nH]nc2c2cc(Cl)ccc12

Procedure:
tert-butyl[(2E)-3-(9-chloro-3-oxo-2,3-dihydro[1,2,4]triazolo[3,4-a]isoquinolin-6-yl)prop-2-en-1-yl]carbamate (3-10) was dissolved in CH3CN (10 mL) with 0.1% TFA present. The resulted solution was irradiated in microwave at 150° C. for 5 minutes. LCMS showed only product. The crude mixture was purified with reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA) to afford the desired product 3-11. 1H NMR (500 MHz, CD3OD) δ 8.29 (d, 1H, J=2.9 Hz), 7.90 (d, 1H, J=8.5 Hz), 7.78-7.64 (m, 2H), 7.14 (d, 1H, J=16.5 Hz), 6.30 (dt, 1H, J=16.5 , 7.0 Hz), 3.83 (d, 2H, J=7.0 Hz). LRMS m/z (M+H) 275.1 found, 275.1 required.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[C:5]1[C:6]2[N:7]([CH:11]=[C:12]([CH3:14])[N:13]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:2].[CH2:18]([CH:20]([C:23]1[C:24]2[N:25]([C:30](I)=[C:31]([CH3:33])[N:32]=2)[N:26]=[C:27]([CH3:29])[CH:28]=1)[CH2:21][CH3:22])[CH3:19]>>[CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[C:5]1[C:6]2[N:7]([C:11]([C:30]3[N:25]4[N:26]=[C:27]([CH3:29])[CH:28]=[C:23]([CH:20]([CH2:18][CH3:19])[CH2:21][CH3:22])[C:24]4=[N:32][C:31]=3[CH3:33])=[C:12]([CH3:14])[N:13]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: CCOC(OCC)c1cccn2cc(C)nc12
Product: CCOC(OCC)c1cccn2c(-c3c(C)nc4c(C(CC)CC)cc(C)nn34)c(C)nc12
Yield: 71.8 %

Procedure:
Using a procedure analogous to Example 16B, 8-diethoxymethyl-2-methyl-imidazo[1,2-a]pyridine (1.70 g, 7.26 mmol) and 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (2.49 g, 7.26 mmol) give the title compound (2.34 g, 5.21 mmol, 72%). 1H NMR (CDCl3): δ. 0.92 (t, J=7.5 Hz, 3H), 0.93 (t, J=7.5 Hz, 3H), 1.31 (t, J=7.1 Hz, 3H), 1.33 (t, J=7.1 Hz, 3H), 1.79-1.93 (m, 4H), 2.14 (s, 3H), 2.44 (s, 6H), 3.34-3.42 (m, 1H), 3.67-3.94 (m, 4H), 6.26 (s, 1H), 6.73 (s, 1H), 6.73-6.80 (m, 1H), 7.44-7.54 (m, 2H) ppm. ES-MS (m/z): calcd for C26H35N5O2 (M+H)+: 450.6. found: 450.3.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([CH3:19])=[C:11](Cl)[C:12]([F:17])=[CH:13]2)=[C:8]([CH:20]2[CH2:22][CH2:21]2)[CH:7]=1)=[O:5])C.[N:23]1([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(#N)C>[N:23]1([CH:29]2[CH2:34][CH2:33][N:32]([C:11]3[C:12]([F:17])=[CH:13][N:14]4[C:9]([C:10]=3[CH3:19])=[C:8]([CH:20]3[CH2:22][CH2:21]3)[CH:7]=[C:6]([C:4]([OH:3])=[O:5])[C:15]4=[O:16])[CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CC#N
Product: Cc1c(N2CCC(N3CCCCC3)CC2)c(F)cn2c(=O)c(C(=O)O)cc(C3CC3)c12

Procedure:
A 70 mg sample of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 2 mL of anhydrous acetonitrile, reacted with 4-(1-piperidyl)piperidine (70 mg, 0.4 mmol, Aldrich Chem. Co.), and carried forward as described in Example 253j-k to give the title product. MS 428 (M+H)+ ; 1H NMR (CDCl3) ∂: 0.69 (m, 2H), 1.02 (m, 2H), 1.18 (m, 4H), 2.27 (n, 1H), 2.78 (s, 3H), 2.72 (m, 1H), 3.35 (m, 3H), 3.55 (m, 1H), 3.75 (m, 1H), 8.36 (s, 1H), 9.20 (d, 1H). Anal. Calcd for C24H30 N3O3F.1.5 H2O: C, 63.42; H, 7.32; N, 9.24; Found: C, 62.99; H, 7.04; N, 8.78.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:15])=[N:11][C:12]=2Cl)[N:7]=[C:6]1[N:16]1[CH2:21][CH2:20][CH2:19][CH:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1)[C:2]#[C:3][CH3:4].C([O-])(=[O:32])C.[Na+]>CS(C)=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:32])[NH:11][C:10]([Cl:15])=[N:9][C:8]=2[N:7]=[C:6]1[N:16]1[CH2:21][CH2:20][CH2:19][CH:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2nc(Cl)nc(Cl)c21
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2nc(Cl)[nH]c(=O)c21
Temperature: 120 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
A mixture consisting of 1.79 g of t-butyl [1-[7-(2-butynyl)-2,6-dichloro-7H-purin-8-yl]piperidin-3-yl]carbamate, 1.0 g of sodium acetate and 18 ml of dimethyl sulfoxide was stirred in an oil bath at 120° C. for three hours. The mixture was removed from the oil bath, and 18 ml of water was added to the reaction solution. The mixture was cooled to room temperature. The crystals were collected by filtration, and washed with water and then with t-butyl methyl ether. The crystals were then dried to give 1.59 g of the title compound.
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH:18]1(B(O)O)[CH2:20][CH2:19]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:5]1[CH:4]=[C:3]([Cl:9])[C:2]([CH:18]2[CH2:20][CH2:19]2)=[CH:7][N:6]=1
Reactant: Clc1cc(Cl)c(Br)cn1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1cc(Cl)c(C2CC2)cn1
Temperature: 100 °C
Reaction time: 12 h
Yield: 60.3 %

Procedure:
A mixture of 5-bromo-2,4-dichloro-pyridine (CAN 849937-4, 4 g, 17.63 mmol), potassium phosphate tribasic (11.21 g, 52.89 mmol), cyclopropylboronic acid (5.2 g, 35.84 mmol) in toluene (45 ml) and water (5 ml) was degassed with argon for 15 minutes. To this reaction mixture was added palladium (II) acetate (80 mg, 0.35 mmol) and tricyclohexylphosphine (0.487 g, 1.74 mmol) at 25° C. and reaction mixture was again purged with argon for 5 minutes. The reaction mixture was then stirred at 100° C. for 12 hours. The reaction mixture was cooled to 25° C. and the catalyst was filtered off through a pad of celite and the filter pad was washed with ethyl acetate (3×50 ml). The filtrate was washed with brine, dried over sodium sulfate and evaporated to dryness. The crude material was purified by flash chromatography on silica eluting with a gradient of heptane and ethyl acetate to yield the title compound (2 g, 61%) as a light yellow oil. MS (ESI, m/z): 188.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])#[N:2].[CH3:12][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO.CCCCCC>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:8][CH3:12])=[O:7])#[N:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: N#Cc1cccc(C(=O)O)c1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
100 mg (0.68 mmol) of 3-cyanobenzoic acid are initially charged in 4 ml of toluene and 3.5 ml of methanol, and 0.51 ml (1.02 mnmol) of a 2 M solution of trimethylsilyldiazomethane in n-hexane is added at RT. The reaction mixture is stirred at RT for 1.5 h. After removal of the solvent on a rotary evaporator the residue is dried under reduced pressure. The product is obtained in pure form and is directly reacted further.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([C:24]([OH:26])=O)[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:28][O:29][C:30](=[O:33])[CH2:31][NH2:32].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.C(OC(N1CCCN(C2C=CC([N+]([O-])=O)=C(C(NCC(O)=O)=O)C=2)CC1)=O)(C)(C)C>C(Cl)Cl.Cl.COC(=O)CN>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([C:24]([NH:32][CH2:31][C:30]([O:29][CH3:28])=[O:33])=[O:26])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc([N+](=O)[O-])c(C(=O)O)c2)CC1
Reactant: COC(=O)CN
Agent: CC(C)(C)OC(=O)N1CCCN(c2ccc([N+](=O)[O-])c(C(=O)NCC(=O)O)c2)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CNC(=O)c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
4-(3-Carboxy-4-nitro-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (37.27 g, 102 mmol) and 107.1 mmol of glycine methyl ester hydrochloride salt were suspended in methylene chloride. To this suspension was added 102 mmol of N-hydroxybenzotriazole and the mixture was cooled with an ice-water bath. Triethylamine (214 mmol) was added, effecting a solution. At this time 1.1 equivalents of 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride was added. This mixture was stirred at 0° C. for 1 hour and then at room temperature for 3 days. At this time, thin layer chromatography indicated the presence of 4-[3-(carboxymethyl-aminocarbonyl)-4-nitro-phenyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester. An additional 5.1 mmol each of glycine methyl ester hydrochloride salt and N-hydroxybenzotriazole as well as 10.3 mmol of triethylamine were added. The reaction mixture was stirred at room temperature for another 24 hour. At this time, the reaction mixture was diluted with methylene chloride, washed with water, with 10% (wt/vol) KHSO4 solution, with water again, with saturated sodium bicarbonate aqueous solution, with water again, and finally with brine. The methylene chloride solution was concentrated to dryness in vacuo, resulting in a dark brown oil. The oil was purified by flash column chromatography: the column was loaded with a methylene chloride solution, followed by elution with ethyl acetate:hexane (7:3), and then finally with ethyl acetate. In this manner, fractions were collected and concentrated in vacuo to provide 42.05 g (94.4%) of 4-[3-(methoxycarbonylmethyl-aminocarbonyl)-4-nitro-phenyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[N:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](O)=[O:21])[CH:15]=1)[C:7]2=[O:23].ClC1C=CC=C2C=1NC(=O)N(CC1C=CC=C(C(OC)=O)C=1)C2=O.[OH-].[Na+].C(C1C=C(C=CC=1)CN1C2C(=CC=CC=2)C(=O)NC1=O)(O)=O.[N:72]1([C:78]2[N:83]=[CH:82][CH:81]=[CH:80][N:79]=2)[CH2:77][CH2:76][NH:75][CH2:74][CH2:73]1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[N:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([N:75]3[CH2:76][CH2:77][N:72]([C:78]4[N:79]=[CH:80][CH:81]=[CH:82][N:83]=4)[CH2:73][CH2:74]3)=[O:21])[CH:15]=1)[C:7]2=[O:23]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C(O)c1cccc(Cn2c(=O)[nH]c3c(Cl)cccc3c2=O)c1
Agent: COC(=O)c1cccc(Cn2c(=O)[nH]c3c(Cl)cccc3c2=O)c1
Agent: O=C(O)c1cccc(Cn2c(=O)[nH]c(=O)c3ccccc32)c1
Agent: [Na+]
Product: O=C(c1cccc(Cn2c(=O)[nH]c3c(Cl)cccc3c2=O)c1)N1CCN(c2ncccn2)CC1

Procedure:
The compound was prepared from 8-chloro-3-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione (prepared from 8-chloro-3-(3-methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione and NaOH using a procedure similar to those of compound of Example 2), and 2-(piperazin-1-yl)pyrimidine using a procedure similar to those described for the synthesis of compound of Example 3. 1H NMR (DMSO-d6): 11.15 (s, 1H), 8.38 (d, J=4.8 Hz, 2H), 7.95 (d, J=7.8 Hz, 1H), 7.82 (d, J=7.5 Hz, 1H), 7.50-7.30 (m, 4H), 7.23 (t, J=7.8 Hz, 1H), 6.67 (t, J=4.8 Hz, 1H), 5.14 (s, 2H), 3.90-3.55 (m, 8H). MS: m/z 477.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[C:5](=[O:13])[CH2:4][CH2:3]1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16].N1C=CN=C1.C([O-])(O)=O.[Na+]>CN(C)C=O>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([O:12][Si:19]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:21])[CH3:20])=[CH:9][CH:10]=2)[C:5](=[O:13])[CH2:4][CH2:3]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1(C)CCC(=O)c2cc(O)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC1(C)CCC(=O)c2cc(O[Si](C)(C)C(C)(C)C)ccc21
Reaction time: 5 h

Procedure:
To a solution of compound XIV (2.00 g, 10.5 mmol) in dimethylformamide (16 mL) was added tertbutyldimethylsilyl chloride (1.90 g, 12.6 mmol) and imidazole (1.79 g, 26.3 mmol) at room temperature. After 5 hours, 5% NaHCO3 (50 mL) was added and the mixture was extracted with hexane (2×75 mL). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated in vacuo to give 3.22 g (Y: 99%) of the title compound; 1H-NMR (CDCl3): δ7.44 (d, J=2.8 Hz, 1H), 7.29 (d, J=8.7 Hz, 1H), 7.01 (dd, J=8.7, 2.8 Hz, 1H), 2.71 (t, J=7.0 Hz, 2H), 1.99 (t, J=7.0 Hz, 2H), 1.36 (s, 6H), 0.98 (s, 9H), 0.20 (s, 6H); MS (DCI) m/e: 305 (MH+).
Reaction SMILES: [CH2:1]([NH:7][CH2:8][C:9]#[N:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH:11]S(O)(=O)=O>C(O)C>[CH2:1]([NH:7][CH2:8][C:9]([NH2:10])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=S(=O)(O)O
Reactant: CCCCCCNCC#N
Solvent: CCO
Product: CCCCCCNCC(N)=O
Temperature: 100 °C

Procedure:
11.2 gr of hexylaminoacetonitrile (0.081 mol) were dropwise added to 31 ml of H2SO4 diluted in 30 ml of ice-cooled ethanol. After the addition was completed, ethanol was evaporated and 40 ml of H2SO4 were added to the white solid as obtained. This solution was heated for 1 hour at 100° C., then cooled and dropwise added to 200 ml of ice-cooled ethanol. The white precipitate which formed was filtered and washed with 50 ml of ethanol.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:8]=[CH:9][CH:10]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>COCCOC>[CH3:1][N:2]([CH3:17])[CH2:3][C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CN(C)C(=O)c1ccccc1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Product: CN(C)Cc1ccccc1-c1ccccc1
Temperature: 25 °C
Yield: 106.9 %

Procedure:
Under a dry nitrogen atmosphere, 6.1 g (0.027 mole) of N,N-dimethyl-[1,1'-biphenyl]-2-carboxamide was dissolved with stirring in 250 ml of dry 1,2-dimethoxyethane. To this solution was added portionwise 1.3 g (0.034 mole) of lithium aluminum hydride. Upon complete addition, the reaction mixture was heated at reflux temperature for 18 hours. The reaction mixture was then cooled to room temperature, and 1.22 ml (0.068 mole) of water was added dropwise. The reaction mixture was filtered, and the filtrate concentrated under reduced pressure to give 6.1 g (100% yield) of N,N-dimethyl-[1,1'-biphenyl]-2-methanamine as a yellow liquid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8])([CH3:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1.O>[CH:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:6]=1[C:7]([OH:9])=[O:8])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1OC(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
Methyl 2-isopropoxy-5-nitrobenzoate (6.92 g, 28.95 mmol) was taken up in THF/H2O (35 ml of each) and LiOH (1.39 g, 57.9 mmol) was added. The mixture was stirred at RT overnight then the pH was lowered to 1 by the addition of concentrated HCl and the product extracted in ethyl acetate (50 ml). The organic layer was dried (MgSO4) and evaporated to give 2-isopropoxy-5-nitrobenzoic acid (6.02 g, 92.5%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9](=[O:18])[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[CH:5]=[CH:6][CH:7]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:30]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>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.CN(C=O)C>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:30]=1[C:2]1[CH:3]=[C:4]([N:8]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9](=[O:18])[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(OC)c1B(O)O
Reactant: CC(C)(C)OC(=O)CN(C(=O)c1c(F)cccc1F)c1cccc(Br)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: CN(C)C=O
Product: COc1cccc(OC)c1-c1cccc(N(CC(=O)OC(C)(C)C)C(=O)c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl 2-(N-(3-bromophenyl)-2,6-difluorobenzamido)acetate (0.55 mmol) is mixed with 2,6-dimethoxyphenyl boronic acid (6.13 mmol) and Pd(Ph3P)4 (0.024 mmol). To the solid mixture under nitrogen, Na2CO3 2M (0.83 mL) is added followed by DMF (5.6 mL). The reaction mixture is stirred at room temperature for 1 hour and then heated at 85° C. for 12 hours. The reaction mixture is purified by automated column chromatography (gradient of hexanes and ethyl acetate) to give tert-butyl 2-(N-(3-(2,6-dimethoxyphenyl)phenyl)-2,6-difluorobenzamido)acetate: 1H NMR (400 MHz, CDCl3) δ7.19 (m, 6H), 6.69 (t, J=7.2 Hz, 2H), 6.58 (d. J=8.4 Hz, 2H), 4.46 (s, 2H), 3.64 (s, 6H), 1.48 (s, 9H); MS: (ES+) 484.1 (M+23)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]#[N:21]>>[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1/[C:19](=[CH:11]/[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][CH:3]=1)/[C:20]#[N:21]
Reactant: N#CCc1ccccn1
Reactant: O=Cc1ccnc2ccccc12
Product: N#C/C(=C\c1ccnc2ccccc12)c1ccccn1
Yield: 53.7 %

Procedure:
4-Quinolinecarboxaldehyde (157 mg) was condensed with 2-pyridineacetonitrile (118 mg) through Method B (production step 3), to thereby yield the target product (yield: 138 mg, 54%).
Reaction SMILES: CN(C)[CH:3]=[O:4].Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])[CH:8]=1.C([O-])=O.[Na+]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:19][C:18]1[O:17][C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[N:15][C:14]=1[CH2:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[CH:3]=[O:4]
Reactant: CN(C)C=O
Reactant: Cc1ccc(-c2nc(Cc3cccc(Br)c3)c(C)o2)cc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(-c2nc(Cc3cccc(C=O)c3)c(C)o2)cc1
Temperature: 110 °C
Reaction time: 9 h

Procedure:
N,N-Dimethylformamide (30 ml) was added to 9.48 g of 1-bromo-3-{[5-methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzene, 2.83 g of sodium formate and 0.97 g of bis(triphenylphosphine)palladium (II) dichloride, and the mixture was stirred for 9 hours at 110° C. under bubbling carbon monoxide. To the reaction solution was added water, and extracted with ethyl acetate, filtered to remove insolubles, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane: ethyl acetate=4:1) to provide 3.58 g of the objective compound as colorless crystals. M.p. 98-99° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][CH:7]=1)(=O)C.[OH-].[K+]>C(O)C.O>[C:12]([C:9]1[CH:8]=[CH:7][C:6]([CH2:5][OH:4])=[CH:11][CH:10]=1)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(=O)OCc1ccc(C(=O)C(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)C(=O)c1ccc(CO)cc1

Procedure:
A mixture of 15 grams (0.064 mole) of α-acetoxy-p-pivaloyl-toluene and 15 grams (0.278 mole) of potassium hydroxide in 150 milliliter of ethanol and 50 milliliters of water is refluxed for 4 hours. The solvent is removed in vacuo, and the residue is treated with ether and water. The ether is separated and the water is again extracted with ether. The ether layers are combined, decolorized with charcoal, dried over magnesium sulfate, filtered and evaporated. The resulting yellow oil is distilled in vacuo to give p-pivaloyl benzyl alcohol (b.p. 100° to 105° C./0.1 milliliters).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[N:18][CH:19]=[C:20](Br)[CH:21]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:21]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cncc(Br)c1)N2
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cncc(N3CCOCC3)c1)N2
Temperature: 120 °C
Reaction time: 16 h
Yield: 40.3 %

Procedure:
A mixture of 2-(5-bromo-pyridin-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (8.5 g, 21.94 mmol), morpholine (19.1 mL, 219.3 mmol), copper(I) iodide (1.7 g, 8.8 mmol), N,N-dimethylglycine hydrochloride (2.5 g, 17.5 mmol) and potassium carbonate (9.1 g, 65.8 mmol) in dimethyl sulfoxide (35 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 3,3-dimethyl-2-(5-morpholin-4-yl-pyridin-3-yl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.5 g, 40.4%) as a white solid which was used for next step without further purification: LC/MS m/e calcd for C23H29N3O3 (M+H)+: 396.53, observed: 396.1.