Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2I.[CH3:18][S:19][C:20]1[N:25]=[C:24]([Sn](CCCC)(CCCC)CCCC)[CH:23]=[CH:22][N:21]=1>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.[Cu]I.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:22]1[CH:23]=[CH:24][N:25]=[C:20]([S:19][CH3:18])[N:21]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Reactant: Brc1ccc2c(c1)c(I)nn2C1CCCCO1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CSc1nccc(-c2nn(C3CCCCO3)c3ccc(Br)cc23)n1
Temperature: 100 °C
Yield: 42.1 %

Procedure:
A glass microwave reaction vessel was charged with 5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2.04 g, 5.01 mmol), Pd(PPh3)4 (0.555 g, 0.480 mmol), CuI (0.130 g, 0.683 mmol) and 2-(methylthio)-4-(tributylstannyl)pyrimidine (2.23 g, 5.37 mmol, Frontier Scientific). DMF (6 mL) was added and the reaction mixture was sealed under argon and heated thermally at 100° C. for 6.5 h. The solvent was removed in vacuo and the residue was dissolved in MeOH, evaporated onto silica gel and purified by flash chromatography (Isco, (80 gram)) eluting with 2M NH3 in MeOH:DCM (0:1→1:19) to give 855 mg of a tan amorphous solid. m/z: 405.0 [M+1].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH:18]([C:20]3[NH:29][C:28](=[O:30])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[CH3:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH:31]1(I)[CH2:35][CH2:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+].CC#N>CN(C=O)C>[CH:31]1([O:30][C:28]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[C:20]([CH:18]([CH:15]3[CH2:16][CH2:17][N:12]([S:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)(=[O:10])=[O:11])[CH2:13][CH2:14]3)[CH3:19])[N:29]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: IC1CCCC1
Reactant: COc1ccc(S(=O)(=O)N2CCC(C(C)c3nc4ccccc4c(=O)[nH]3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N2CCC(C(C)c3nc(OC4CCCC4)c4ccccc4n3)CC2)cc1
Temperature: 70 °C

Procedure:
A mixture of 2-{1-[1-(4-Methoxy-benzenesulfonyl)-piperidin-4-yl]-ethyl}-3H-quinazolin-4-one (34 mg, 0.08 mmol), cyclopentyl iodide (18 μL, 0.16 mmol), and potassium carbonate (55 mg, 0.4 mmol) in DMF (1 mL) was heated to 70° C. for 1 day. The reaction mixture was partitioned between dichloromethane and water. The organic layer was concentrated in vacuo and the residue was purified by HPLC (in the absence of TFA) to yield the product. 1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J=7.6 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.75 (t, J=7.0 Hz, 1H), 7.67 (d, J=8.9 Hz, 2H), 7.46 (t, J=7.5 Hz, 1H), 6.97 (d, J=8.9 Hz, 2H), 5.63 (m, 1H), 3.68 (s, 3H), 3.80 (d, J=11.6 Hz, 1H), 3.67 (dd, J=11.2, 1.6 Hz, 1H), 2.81 (quintet, J=7.3 Hz, 1H), 2.28 (t, J=11.8 Hz, 1H), 2.17 (m, 1H), 1.93 (m, 10H), 1.44 (m, 3H), 1.29 (d, J=6.9 Hz, 3H); HPLC ret. time 3.24 min, 10-99% CH3CN, 5 min run; ESI-MS m/z 496.3 (M+1)+
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[N:41]1([S:47]([CH2:50][CH2:51][CH2:52][O:53][C:54]2[CH:55]=[CH:56][C:57]3[C:58]4[N:59]([CH2:65][CH2:66][N:67]=4)[C:60]([NH2:64])=[N:61][C:62]=3[CH:63]=2)(=[O:49])=[O:48])[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>CN(C=O)C.CCOC(C)=O>[N:41]1([S:47]([CH2:50][CH2:51][CH2:52][O:53][C:54]2[CH:55]=[CH:56][C:57]3[C:58]4[N:59]([CH2:65][CH2:66][N:67]=4)[C:60]([NH:64][C:7]([C:5]4[CH:4]=[N:3][CH:2]=[N:1][CH:6]=4)=[O:9])=[N:61][C:62]=3[CH:63]=2)(=[O:48])=[O:49])[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1
Reactant: NC1=Nc2cc(OCCCS(=O)(=O)N3CCOCC3)ccc2C2=NCCN12
Reactant: O=C(O)c1cncnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NC1=Nc2cc(OCCCS(=O)(=O)N3CCOCC3)ccc2C2=NCCN12)c1cncnc1
Reaction time: 0.08 h
Yield: 61 %

Procedure:
To pyrimidine-5-carboxylic acid (95.0 mg, 0.77 mmol) in DMF (1 ml) was added HATU (342 mg, 0.9 mmol) and 4-methylmorpholine (91 mg, 0.9 mmol). The mixture was stirred for 5 min then 8-[3-(morpholin-4-ylsulfonyl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Step 1, 250 mg, 0.64 mmol) in DMF (2 mL) was added. The resulting solution was allowed to stir at rt for 16 h. It was diluted with EtOAc and filtered rinsing with EtOAc and MeOH to give the title compound (195 mg, 61%). TLC Rf=0.68 in 10% MeOH/CH2Cl2, HPLC MS RT=1.13 min, MH+=500.4; 1H NMR (DMSO-d6) δ: 2.25 (2H, m), 3.21 (4H, m), 3.30 (2H, m), 3.67 (4H, m), 4.23 (2H, t), 4.31 (2H, t), 4.60 (2H, t), 7.25 (1H, d), 7.78 (1H, s), 8.16 (1H, d), 9.44 (1H, s), 9.50 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH:26]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([NH:34][CH:26]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:17])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Reactant: NC1CCCCCCC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NC3CCCCCCC3)c2c1N

Procedure:
Prepared as in Example 24a from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and cyclooctanamine as a brown solid (46%). MS 456 (MH+).
Reaction SMILES: S(Cl)(Cl)=O.O[CH2:6][CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1>CCOCC>[OH:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]2[O:17][CH2:6][CH2:7][N:8]=2)=[CH:15][CH:14]=1
Reactant: O=C(NCCO)c1ccc(O)cc1
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: Oc1ccc(C2=NCCO2)cc1
Yield: 118 %

Procedure:
Thionyl chloride (160 ml) was added to 40 g of N-(2-hydroxyethyl)-4-hydroxybenzamide with evolution of gas. The reaction mixture was ultrasonicated for 1.75 hours, then cooled and diluted with ether. The resulting solid product was collected by filtration, washed with ether and dried overnight in a vacuum oven at 40° C. to give 42.5 g of 4,5-dihydro-2-(4-hydroxyphenyl)oxazole in the form of its hydrochloride salt, m.p. 162°-163° C.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.C(O)C>C(O)CC>[CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[C:4]1(=[O:5])[O:6][CH2:1][CH2:2][CH2:3]1
Reactant: O=C1C=CC(=O)O1
Solvent: CCCO
Solvent: CCO
Product: O=C1CCCO1
Product: OCCCCO

Procedure:
In the case when the C4+ hydrogenation feedstock is the crude maleic anhydride stream, then the light impurities are also hydrogenated in the hydrogenation step and result in light hydrogenation products including ethanol and propanol, which can be removed from the hydrogenation product as an overhead product by distillation. Heavy impurities and heavy impurity hydrogenation products can be separated by conventional distillation techniques as a bottom product from the crude hydrogenation product. Maleic anhydride derivatives, such as maleic acid and fumaric acid, are hydrogenated to form a corresponding additional amount of butane-1,4-diol, γ-butyrolactone, and tetrahydrofuran.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[CH:10][C:9]=1O.CI.O>CN(C)C=O>[Br:7][C:8]1[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[CH:10][C:9]=1[O:4][CH3:1]
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)c1ccc(O)c(Br)c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(S(C)(=O)=O)cc1Br
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
Potassium carbonate (2.31 g, 16.8 mmol) was added to a solution of 2-bromo-4-(methanesulfonyl)phenol (Description 27; 3.5 g, 14 mmol) in dimethylformamide (50 ml). The resulting solution was stirred for 30 min. and methyl iodide (1.04 ml, 16.8 mmol). After stirring for 1 h. the solution was poured into water (200 ml) and extracted with ethyl acetate (2×100 ml). The combined organics were washed with water and dried over sodium sulphate. Removal of the solvent in vacuo gave a white solid which was crystallised from diethyl ether to give the title compound (2.02 g). 1H NMR (250 MHz, CDCl3) δ8.12-8.11 (1H, d, J 2.2 Hz), 7.90-7.86 (1H, dd, J 8.7, 2.2 Hz), 7.04-7.00 (1H, d, J 8.7 Hz), and 3.99 (3H, s), and 3.05 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:23]#[N:24])[CH:5]=[CH:6][C:7]=1[Br:8].O.O.Cl[Sn]Cl>>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]([C:23]#[N:24])=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([Br:8])=[C:2]([Br:1])[CH:3]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(Br)c(Br)c1
Agent: Cl[Sn]Cl
Solvent: O
Product: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(Br)c(Br)c1
Yield: 27.3 %

Procedure:
Prepared from 4.90 g of 4-(3,4-dibromophenylamino)-6-nitroquinoline-3-carbonitrile and 12.4 g of SnCl2.2H2O in the same manner as EXAMPLE 378. There was obtained 1.25 g of 6-amino-4-(3,4-dibromophenylamino)quinoline-3-carbonitrile as a brown solid: mass spectrum (electrospray, m/e): M+H 416.9, 418.9.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=O)=[C:4]([CH2:11]Br)[CH:3]=1.[NH2:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:8])[N:13]([CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[CH2:11]2
Reactant: O=C([O-])c1ccc(Br)cc1CBr
Reactant: NC1CCOCC1
Product: O=C1c2ccc(Br)cc2CN1C1CCOCC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 6 starting from 4-bromo-2-(bromomethyl)benzoate (AstaTech Cat. No. 27012) and 4-aminotetrahydropyran (Aldrich Cat No. 711357). LCMS (M+H)+=296.0/298.0.
Reaction SMILES: [Se](=O)=O.[Br:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[C:10]2[CH3:15].[OH-:16].[Na+]>O1CCOCC1.O>[Br:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[C:10]2[CH:15]=[O:16]
Reactant: [OH-]
Reactant: Cc1ccnc2c(Br)cccc12
Agent: O=[Se]=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1ccnc2c(Br)cccc12
Temperature: 77 °C

Procedure:
As shown in step 9-iii of Scheme 9, selenium dioxide (764.7 g, 6.754 mol) was taken up in 3.25 L of dioxane and 500 mL of water. The stirred solution was heated to 77° C. and 8-bromo-4-methylquinoline (compound 2030, 500 g, 2.251 mol) was added in one portion. The reaction mixture was stirred at reflux for 30 minutes and then cooled with a water bath to about 45° C., at which temperature a precipitate was observed. The suspension was filtered through diatomaceous earth which was subsequently washed with the hot THF to dissolve any residual solids. The filtrate was concentrated to a minimum volume under reduced pressure and 2M NaOH (2.81 L, 5.63 mol) was added to achieve a pH of 8 to 9. The reaction mixture was stirred at this pH for 30 minutes. A precipitate resulted which was collected by filtration and air-dried overnight to produce 8-bromoquinoline-4-carbaldehyde (compound 2031) as an yellowish solid: MS=236.16 (M+H); 1H NMR (300 MHz, CDCl3) δ 10.52 (s, 1H), 9.34 (d, J=4.2 Hz, 1H), 9.05 (dd, J=8.5, 1.2 Hz, 1H), 8.18 (dd, J=7.5, 1.3 Hz, 1H), 7.88 (d, J=4.2 Hz, 1H), 7.60 (dd, J=8.5, 7.5 Hz, 1H). This material was used as is in subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.CN(C)[CH2:16][CH2:17]O.C([Zn]CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH2:16][CH3:17])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1
Reactant: CN(C)CCO
Reactant: COC(=O)c1cc(Cl)c(Cl)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[Zn]CC
Solvent: C1CCOC1
Product: CCc1nc(C(=O)OC)cc(Cl)c1Cl
Reaction time: 0.33 h

Procedure:
A 100 mL three-neck flask equipped with a reflux condenser and nitrogen inlet was charged with methyl 4,5,6-trichloropicolinate (2.40 g, 9.98 mmol). Anhydrous THF (50 mL) was added followed by N,N-dimethylethanolamine (0.20 g). The reaction mixture was sparged with nitrogen for 15 min. Solid Pd(PPh3)2Cl2 (140 mg, 0.2 mmol) was added. The reaction mixture was stirred under nitrogen for 20 min. Diethylzinc (1 M solution in hexanes; 10 mL, 10 mmol) was added in 2 mL portions. When starting material was no longer observed through analysis by GC, the reaction mixture was quenched with water and extracted into EtOAc. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure to a white solid (2.34 g). Analysis by GC-MS showed the solid contained 11% starting methyl 4,5,6-trichloropicolinate. 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H, pyridine H), 4.01 (s, 3H, CO2Me), 3.10 (q, J=8 Hz, 2H, CH2), 1.33 (t, J=8 Hz, 3H, CH2CH3); 13C{1H} NMR (101 MHz, CDCl3) δ 164.4, 162.8, 145.4, 143.3, 132.9, 124.5 (C3), 53.1 (CO2Me), 30.0 (CH2), 12.3 (CH2CH3).
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:5][CH:4]=1)=[CH2:2].B1C2CCCC1CCC2.[OH-:30].[Na+].OO>C1COCC1.O>[OH:30][CH2:2][CH2:1][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:5][CH:4]=1
Reactant: [OH-]
Reactant: C=Cc1ccc(NC(=O)OC(C)(C)C)c2ccccc12
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(CCO)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.2 %

Procedure:
To a solution of tert-butyl 4-vinylnaphthalen-1-ylcarbamate (31) (0.83 g, 3.08 mmol) in THF (10 mL) was added 9-BBN (0.5M in THF, 9.9 mL, 4.95 mmol) dropwise under nitrogen at 0° C. The mixture was warmed to RT and stirred for 16 hr. Water (1 mL), aqueous NaOH solution (3M, 10.0 mL, 30 mmol) and hydrogen peroxide (35% in water, 8.0 mL) were added. The reaction mixture was warmed to 50° C. and stirred for 2 hr and was then extracted with ethyl acetate. The ethyl acetate extract was washed with water and brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 10-60% ethyl acetate in isohexane, gradient elution) to afford the title compound (32) (0.763 g, 86%); m/z 288 (M+H)+, (ES+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8](Br)[CH:9]=[CH2:10].FC(F)(F)C(NC1C=CC=CC=1)=O>>[CH2:10]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:9]=[CH2:8]
Reactant: Nc1ccccc1
Reactant: C=CCBr
Agent: O=C(Nc1ccccc1)C(F)(F)F
Product: C=CCNc1ccccc1

Procedure:
N-Allylaniline [NMR (200 MHz, DMSO-d6): δ3.68 (t, J=5.2 Hz, 2H); 5.10 (d, J=10.2 Hz, 1H); 5.23 (d, J=17.2 Hz, 1H); 5.78 (br s, 1H); 5.75-5.97 (m, 1H); 6.52 (t, J=7.3 Hz, 2H); 6.56 (d, J=7.8 Hz, 2H); 7.06 (t, J=7.3 Hz, 2H)] was prepared from aniline and allyl bromide via trifluoroacetanilide using the general method described by Hodge (Harland, P.A.; Hodge, P; Maughan, W.; Wildsmith, E. Synthesis, 1984, 941).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>[Cu].CN(C=O)C>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:17][CH:16]=1
Reactant: Brc1ccc(I)cc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc(-n2c3ccccc3c3ccccc32)cc1
Temperature: 130 °C
Yield: 96.3 %

Procedure:
Compound 4 was prepared as follows: a mixture of carbazole (6.30 g, 37.7 mmol), 1-bromo-4-iodobenzene (15.99 g, 56.52 mmol), copper powder (4.79 g, 75.4 mmol), K2CO3 (20.83 g, 150.7 mmol) and anhydrous DMF (100 mL) was degassed with argon for about 1 h while stirring. The stirring reaction mixture was then maintained under argon at about 130° C. for about 42 h. Upon confirming consumption of the starting material by TLC (SiO2, 4:1 hexanes-dichloromethane), the mixture was cooled to RT, filtered, the filtrant washed copiously with EtOAc (ca. 200 mL) and the resulting filtrate concentrated in vacuo. Purification of the crude product by flash chromatography (SiO2, hexanes) afforded compound 4 (11.7 g, 96% yield) as a pale yellow solid. (See Xu, H.; Yin, K.; Huang, W. Chem. Eur. J., 2007, 13(36), 10281-10293.)
Reaction SMILES: [C@H:1]1([NH:11][C:12]([C@@H:14]2[CH2:23][C:22]3[C:17](=[CH:18][C:19](OS(C(F)(F)F)(=O)=O)=[CH:20][CH:21]=3)[CH2:16][N:15]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.CS(C)=O.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>[C@H:1]1([NH:11][C:12]([C@@H:14]2[CH2:23][C:22]3[C:17](=[CH:18][C:19]([C:32]([O:34][CH3:35])=[O:33])=[CH:20][CH:21]=3)[CH2:16][N:15]2[C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(OS(=O)(=O)C(F)(F)F)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)CN(C(=O)OC(C)(C)C)[C@H](C(=O)N[C@@H]1CCCc3ccccc31)C2
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 182.4 %

Procedure:
A 20 mL scintillation vial with a septum top was charged sequentially with (S)-tert-butyl 3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-7-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.39 g, 2.50 mmol), Pd(OAc)2 (0.028 g, 0.12 mmol), and 1,3-bis(diphenylphosphino)propane (0.052 g, 0.12 mmol). DMSO (3.7 mL), MeOH (2.5 mL), and Et3N (0.77 mL, 5.50 mmol) were then added, and the reaction mixture was stirred for 5 min. A CO balloon was then used to purge the reaction vial, turning the solution black. The reaction was topped with the CO balloon and heated to 70° C. for 12 h. The reaction mixture was then filtered through an ACRODISC®, and the filtrate was poured into a separatory funnel containing EtOAc and sat. aq. NH4Cl solution. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with sat. NaCl (2×), dried over MgSO4, filtered and concentrated in vacuo. The crude oil was purified by flash column chromatography (gradient elution from 0 to 50% EtOAc/hexanes) to afford the title compound (1.06 g, 2.28 mmol, 91%) as a light yellow solid. MS (ESI+) m/z 465.2 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([O:22][CH3:23])[O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[C:17][Si](C)(C)C)=[CH:9]2.[OH-].[Na+].C(OCC)(=O)C.O>C(O)C>[C:16]([C:10]1[CH:11]=[N:12][C:13]2[C:8]([CH:9]=1)=[CH:7][C:6]([O:5][CH:4]([O:22][CH3:23])[C:3]([OH:24])=[O:2])=[CH:15][CH:14]=2)#[CH:17]
Reactant: COC(=O)C(OC)Oc1ccc2ncc(C#C[Si](C)(C)C)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: C#Cc1cnc2ccc(OC(OC)C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
To a solution of methoxy-(3-trimethylsilanylethynyl-quinolin-6-yloxy)-acetic acid methyl ester (1.99 g) in ethanol (14 mL) was added a solution of sodium hydroxide 2N (4 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were added. The mixture was stirred. The two layers were separated. The aqueous layer was acidified at pH 1 with HCl 2N. Then it was extracted with ethyl acetate (twice). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to give (3-ethynyl-quinolin-6-yloxy)-metoxy-acetic acid (1.15 g) as an orange solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([N:18]2[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]2)[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH2:27]([NH:34][C:24]([CH:21]1[CH2:20][CH2:19][N:18]([C:11]2[CH:12]=[CH:13][C:14]([N+:15]([O-:17])=[O:16])=[C:9]([NH:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[CH2:23][CH2:22]1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)C1CCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)C1CCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 84.4 %

Procedure:
To a solution of 1-(3-(benzylamino)-4-nitrophenyl)piperidine-4-carboxylic acid (0.2 g, 0.56 mmol) and benzylamine (0.06 mL, 0.56 mmol) in DMF (5 mL) was added diisopropylethylamine (0.198 mL, 1.12 mmol) under argon. The mixture cooled to 0° C., HATU (0.212 g, 0.56 mmol) was added at that temperature and then stirred at room temperature for 4 h. After completion of reaction (by TLC), H2O (5 mL) was added drop by drop. The resulting yellow precipitate was filtered, washed with 2 mL of water, dried (high vacuum, 14 h) to furnish N-benzyl-1-(3-(benzylamino)-4-nitrophenyl)piperidine-4-carboxamide (0.21 g), 84% yield. 1H NMR (500 MHz, DMSO): δ 1.51 (m, 2H), 1.74 (m, 2H), 2.48 (m, 1H), 2.96 (m, 2H), 3.93 (m, 2H), 4.26 (d, J=5.9 Hz, 2H), 4.59 (d, J=5.8 Hz, 2H), 5.95 (d, J=2.45 Hz, 1H), 6.42 (dd, J=2.5 Hz, 1H), 7.24 (m, 4H) 7.37 (m, 4H), 7.42 (m, 2H), 7.91 (d, J=9.7 Hz, 1H), 8.35 (m, 1H), 8.84 (m, 1H). HRMS (ESI) calculated for C26H28N4NaO3: 467.2054, Found: 467.2054.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.Cl[C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:26][CH:27]=2)[CH:20]=[CH:21][CH:22]=1.[CH:34]([N:37](C(C)C)CC)(C)C.O>CS(C)=O>[C:34]([C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:8]([NH:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:30][CH2:29]3)[S:26][CH:27]=2)[CH:20]=[CH:21][CH:22]=1)#[N:37]
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Reactant: Clc1cccc(-c2csc(N3CCNCC3)n2)c1
Reactant: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cccc(-c2csc(N3CCN(C(=O)Nc4cccnc4)CC3)n2)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 26.5 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (219 mg, 0.814 mmol), 1-[4-(3-chlorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.740 mmol) and diisopropylethylamine (0.258 ml, 1.48 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 76.6 mg (26.5%) of the desired product as a solid.
Reaction SMILES: C[NH:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1.[CH2:16]([SiH](CC)CC)C>CO.[Pd]>[NH2:12][C:8]1[CH:7]=[C:6]([CH2:5][CH:4]([CH3:16])[C:3]([NH2:2])=[O:15])[CH:11]=[CH:10][CH:9]=1
Reactant: CNC(=O)C=Cc1cccc([N+](=O)[O-])c1
Reactant: CC[SiH](CC)CC
Agent: [Pd]
Solvent: CO
Product: CC(Cc1cccc(N)c1)C(N)=O
Yield: 72.3 %

Procedure:
To a stirred solution of N-methyl-3-(3-nitrophenyl)acrylamide (4 g, 19.40 mmol) and Pd—C (10%, 200 mg) in MeOH (30.0 ml) was added triethylsilane (31 ml, 194 mmol) dropwise at room temperature over a period of 1 hr. Reaction progress was monitored by TLC. After completion of reaction, reaction mixture was filtered through celite bed. The filtrate was concentrated under vacuum to give the title compound (2.5 gm).