Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:16]=[CH:17]/[C:18](OCC)=[O:19])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.[H-].C([Al+]CC(C)C)C(C)C.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:16]=[CH:17]/[CH2:18][OH:19])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)/C=C/c1ccc(Oc2cccnc2)c(OC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(/C=C/CO)ccc1Oc1cccnc1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
2.99 g of ethyl (E)-3-[3-methoxy-4-(3-pyridyloxy)phenyl]acrylate was dissolved in 30 ml of anhydrous toluene. To the solution was dropwise added 22.0 ml of a 1M toluene solution of diisobutylaluminum hydride at -50° C. in a nitrogen atmosphere. The mixture was stirred for 30 minutes at the same temperature. To the reaction mixture was dropwise added 1.6 ml of water. The mixture was stirred for 1 hour at room temperature. The resulting insolubles were removed by filtration. The filtrate was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 2.57 g of colorless oily (E)-3-[3-methoxy-4-(3-pyridyloxy)phenyl]allyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=O>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[O:7])[CH:10]=[CH:11][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: O=Cc1ccc(Cl)cc1
Product: O=C(C=Cc1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-chlorobenzaldehyde and 4-chloroacetophenone, 1,3-bis(4-chlorophenyl)-prop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: OO.[OH:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[O:12][CH3:13].[OH-].[K+].S([O-])([O-])=[O:17].[Na+].[Na+]>>[OH:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]([NH2:9])=[O:17])=[CH:6][C:5]=1[O:12][CH3:13]
Reactant: COc1cc(C#N)ccc1O
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [K+]
Agent: [Na+]
Product: COc1cc(C(N)=O)ccc1O
Reaction time: 16 h
Yield: 76.2 %

Procedure:
A 3% aqueous solution of hydrogen peroxide (155 mL, 0.151 mol) was added to a flask containing 4-hydroxy-3-methoxybenzonitrile (5.00 g, 33.52 mmol) at rt. Solid KOH (9.78 g, 174.33 mmol) was added slowly. Gas was evolved and the temperature of the rose. The solution was stirred for 16 h, and excess sodium sulfite was added. The mixture was then filtered and the solution was acidified to pH 2 with 2N HCl. The aqueous solution was extracted with dichloromethane. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the product as a pale yellow solid (4.27 g, 76.2%). 1H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 7.75 (s, 1H), 7.42 (d, 1H), 7.34 (dd, 1H), 7.096 (s, 1H), 6.76 (d, 1H), 3.78 (s, 3H).
Reaction SMILES: N[C:2]1C=CC(C)=CC=1.COC1C=CC(N)=CC=1.[Br-].[CH2:19]([Br:28])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH2:19]([Br:28])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([CH3:2])[CH3:27]
Reactant: CCCCCCCCCBr
Reactant: Cc1ccc(N)cc1
Agent: [Br-]
Solvent: COc1ccc(N)cc1
Product: CC(C)CCCCCCCBr

Procedure:
By the general procedure described in Example 1 using as appropriate p-toluidine, p-anisidine, or 3- or 4-chloroaniline and isoctyl bromide, nonyl bromide or isodecylbromide (complex mixture of isomers) there were obtained:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:17])=[C:5]([CH3:16])[C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:8].C(N(CC)CC)C.[Br:25][C:26]([CH3:31])([CH3:30])[C:27](Br)=[O:28]>ClCCl>[Br:25][C:26]([CH3:31])([CH3:30])[C:27]([NH:1][C:2]1[S:3][C:4]([CH3:17])=[C:5]([CH3:16])[C:6]=1[C:7](=[O:8])[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:28]
Reactant: CC(C)(Br)C(=O)Br
Reactant: Cc1sc(N)c(C(=O)c2ccc(Cl)cc2)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1sc(NC(=O)C(C)(C)Br)c(C(=O)c2ccc(Cl)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A round bottomed flask was charged with (2-amino-4,5-dimethylthiophen-3-yl)(4-chlorophenyl)methanone (2 g, 7.53 mmol) and a stirbar. Dichloromethane (75 mL, 0.1 M) was added, followed by triethylamine (1.573 ml, 11.29 mmol, 1.5 equiv). The solution was cooled to 0° C. for the addition of 2-bromo-2-methylpropanoyl bromide (1.163 ml, 9.41 mmol). The solution was stirred at room temperature 1 h, at which point LC/MS analysis showed complete conversion of the starting material. The solution was washed successively with water and brine before being dried with sodium sulfate and concentrated to give a quantitative yield of 2-bromo-N-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-2-methylpropanamide as a yellow amorphous solid (m/z=414/416), which was used crude in the subsequent reaction.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([OH:30])=[C:26]([N+:27]([O-:29])=[O:28])[C:20]=4[S:19](=[O:32])(=[O:31])[N:18]=3)[C:7]2=[O:33])[CH2:3][CH2:2]1.Br[CH2:35][C:36]#[N:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([O:30][CH2:35][C:36]#[N:37])=[C:26]([N+:27]([O-:29])=[O:28])[C:20]=4[S:19](=[O:32])(=[O:31])[N:18]=3)[C:7]2=[O:33])[CH2:2][CH2:3]1
Reactant: O=c1c(C2=NS(=O)(=O)c3c(ccc(O)c3[N+](=O)[O-])N2)c(O)c2ccccc2n1NCC1CC1
Reactant: N#CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: N#CCOc1ccc2c(c1[N+](=O)[O-])S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Yield: 60.6 %

Procedure:
The product of Example 381 (20 mg, 0.042 mmol) in N,N-dimethylformamide (2 mL) was reacted with 2-bromoacetonitrile (6 μl, 0.086 mmol), potassium carbonate (54.7 mg, 0.168 mmol) and tetrabutylammonium iodide (catalytic) at 25° C. for 18 hours. The solution was evaporated under reduced pressure and the residue was triturated with ethyl acetate, filtered and washed with water to give the title compound (13 mg, 60%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27]1[O:31][N:30]=[C:29]([CH:32]=O)[CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[F:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:21])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:32][C:29]3[CH:28]=[C:27]([C:23]4[S:22][CH:26]=[CH:25][CH:24]=4)[O:31][N:30]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: O=Cc1cc(-c2cccs2)on1
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=c1cnc2ccc(F)cc2n1CCN1CCC(NCc2cc(-c3cccs3)on2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.5 %

Procedure:
To 10 mL of a chloroform solution containing 407 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one and 275 mg of 5-(2-thienyl)-3-isoxazolecarbaldehyde, 80 μL of acetic acid were added, and stirred at room temperature for 1 hour. To the reaction mixture, 468 mg of sodium triacetoxyborohydride was added, and stirred overnight. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate:hexane=2:1], to give 232 mg of 7-fluoro-1-(2-(4-((5-(thiophen-2-yl)isoxazol-3-yl)methylamino)piperidin-1-yl)ethyl)quinoxalin-2(1H)-one as pale yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])=[CH:8][C:7]=2[N+:18]([O-])=O)[CH2:3][CH2:2]1>CO.C(OCC)(=O)C.[C].[Pd]>[NH2:18][C:7]1[CH:8]=[C:9]([S:12]([CH:15]([CH3:17])[CH3:16])(=[O:13])=[O:14])[CH:10]=[CH:11][C:6]=1[NH:5][CH2:4][CH:1]1[CH2:3][CH2:2]1
Reactant: CC(C)S(=O)(=O)c1ccc(NCC2CC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)c1ccc(NCC2CC2)c(N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
A mixture of N-(cyclopropylmethyl)-4-(isopropylsulfonyl)-2-nitroaniline (Step D, 521 mg, 1.8 mmol) and 10% palladium carbon (52 mg) in methanol (10 mL) and ethyl acetate (10 mL) was stirred at room temperature for 2 h under hydrogen. The mixture was filtered through a pad of celite and the filtrate was concentrated to afford the title compound (462 mg, 98%) as red brown amorphous.
Reaction SMILES: Br.[Br:2][C:3]1[C:26]([F:27])=[CH:25][C:6]2[O:7][C:8]3[CH:24]=[CH:23][CH:22]=[CH:21][C:9]=3[C@H:10]3[C@H:15]([NH:16]C(=O)OC)[CH2:14][CH2:13][CH2:12][N:11]3[C:5]=2[CH:4]=1.[OH-].[Na+]>C(O)(=O)C>[Br:2][C:3]1[C:26]([F:27])=[CH:25][C:6]2[O:7][C:8]3[CH:24]=[CH:23][CH:22]=[CH:21][C:9]=3[C@H:10]3[C@H:15]([NH2:16])[CH2:14][CH2:13][CH2:12][N:11]3[C:5]=2[CH:4]=1
Reactant: COC(=O)N[C@@H]1CCCN2c3cc(Br)c(F)cc3Oc3ccccc3[C@@H]12
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: N[C@@H]1CCCN2c3cc(Br)c(F)cc3Oc3ccccc3[C@@H]12
Temperature: 100 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
A mixture of acetic acid (40 mL) and hydrogen bromide (48%, 20 mL) was added to methyl (±)-(cis)-(7-bromo-8-fluoro-1,3,4,14b-tetrahydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamate (20.2 g, 48 mmol) and stirred overnight at 100° C. After cooling down the reaction mixture was poured into a cold 1M NaOH solution. It was extracted with CH2Cl2 and the organic layer was washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure to yield the crude title compound (15.9 g, 91%) which was used without further purification. (m/z)=363+365 (M+H)+.
Reaction SMILES: Br.C(O)(=O)CC.C1(O)C=CC=CC=1.[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[CH2:20][N:19](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:18]2>>[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[CH2:20][NH:19][CH2:18]2
Reactant: Cc1ccc(S(=O)(=O)N2Cc3ccc(Br)cc3C2)cc1
Agent: Br
Solvent: CCC(=O)O
Solvent: Oc1ccccc1
Product: Brc1ccc2c(c1)CNC2

Procedure:
To a solution of aqueous hydrobromic acid (16 mL, 48% solution in water), propionic acid (2.8 mL) and phenol (2 g) was added 5-bromo-2-(p-tolylsulfonyl)isoindoline (2.4 g, 6.8 mmol).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[OH-].[K+].[CH2:17]([CH:19]1[O:21][CH2:20]1)Br>O>[CH:1]1([CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:17][CH:19]3[O:21][CH2:20]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: BrCC1CO1
Reactant: Oc1ccc(OCCCC2CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: c1cc(OCC2CO2)ccc1OCCCC1CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
A mixture of 9 g of 4-cyclopropylpropoxy-phenol, 150 ml of water, 3 g of KOH and 7.7 g of epibromohydrin is stirred for 15 hours at ambient temperature. The reaction mixture is extracted with ether and the extract is washed with N NaOH and then with water. The ether is evaporated and the excess epibromohydrin is removed by entrainment with xylene (distillation at 15 mm Hg). 1-(4-Cyclopropylpropoxy-phenoxy)-2,3-epoxy-propane is obtained in a yield of 100%.
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[C:7]([CH3:14])[CH:6]=1)=[O:4].[CH3:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([CH:2]([CH3:15])[C:3]([C:5]3[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[C:7]([CH3:14])[CH:6]=3)=[O:4])[CH2:24][CH2:23]2)=[CH:28][CH:29]=1
Reactant: Cc1ccc(CC2CCNCC2)cc1
Reactant: COc1c(C)cc(C(=O)C(C)Br)cc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1c(C)cc(C(=O)C(C)N2CCC(Cc3ccc(C)cc3)CC2)cc1C

Procedure:
5.9 g (0.022 mol) of 2-bromo-4'-methoxy-3',5'-dimethylpropiophenone are dissolved in 30 ml of ethanol, 4.2 g (0.022 mol) of 4-(4-methylbenzyl)-piperidine and then 2.12 g (0.02 mol) of sodium carbonate are added and the mixture is heated under reflux for 2 hours. It is left to cool, the inorganic precipitate is filtered off and the filtrate is evaporated. The residual oil is purified by chromatography on silica using acetone as the eluant. This gives 8 g of a product, which is used as such.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:21]=3[OH:32])=[O:18])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)([O-])=O.CO.Cl.O1CCOCC1.C>ClCCl.[C].[Pd].O1CCOCC1>[ClH:1].[ClH:1].[NH2:2][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([C:28]([CH3:30])([CH3:29])[CH3:31])[C:21]=3[OH:32])=[O:18])[CH2:15][CH2:16]2)=[CH:7][CH:6]=1
Reactant: COc1cc(NC(=O)N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)c(O)c(C(C)(C)C)c1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(NC(=O)N2CCN(c3ccc(N)cc3)CC2)c(O)c(C(C)(C)C)c1
Reaction time: 4 h
Yield: 60.9 %

Procedure:
To a mixture of 680 mg of 2-{[4-(4-nitrophenyl)piperazin-1-yl]carbonylamino}-4-methoxy-6-tert-butylphenol hydrochloride, 30 ml of methanol and 30 ml of dioxane was added 100 mg of 10% palladium-carbon (Pd-C). The mixture was subjected to catalytic reduction for 4 hours by using a Parr's reduction apparatus. After removing the catalyst by filtration, the filtrate was condensed. The residue was dissolved in 10 ml of dichloromethane, and after adding 1 ml of 4N hydrogen chloride-dioxane solution, the mixture was treated with an activated charcoal. The treated mixture was evaporated to dryness under reduced pressure to give 210 mg of 2-{[4-(4-aminophenyl)piperazin-1-yl]carbonylamino}-4-methoxy-6-tert-butylphenol dihydrochloride as powder.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]([S:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)=[O:6].[I-:15].[Na+]>C(#N)C>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([S:7][C:5]([O:4][CH2:3][CH2:2][I:15])=[O:6])=[CH:9][CH:10]=1
Reactant: Cc1ccc(SC(=O)OCCCl)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(SC(=O)OCCI)cc1
Temperature: 50 °C

Procedure:
A 50 mL, three-neck, round-bottomed flask equipped with a magnetic stir bar, a reflux condenser, an internal thermometer, and a nitrogen inlet was charged with chloro-ester D1 (2 g, 8 mmol) and sodium iodide (1.8 g, 12 mmol) in acetonitrile (10 mL). The resulting slurry was warmed to 50° C. for 36 hours. The reaction mixture was cooled to room temperature and inorganic solids were removed by filtration. The clear organic phase was concentrated to give a viscous oil. The crude product was purified by column chromatography using ethyl acetate and hexane to give the title compound E4b as a viscous-oil (1 g, ˜30% yield). 1H NMR (CDCl3, 400 MHz): δ 2.31 (d, J=5.6 Hz, 3H), 2.47 (s, 3H), 6.80 (q, J=6 Hz, 1H), 7.11 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.8 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)[N:14]([CH3:16])[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[OH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([N:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]4=[O:24])=[CH:19][CH:18]=3)[N:14]([CH3:16])[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: Cn1cc(CNC(=O)c2ccc(Cl)s2)nc1-c1ccc(I)cc1
Reactant: Oc1ccccn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1cc(CNC(=O)c2ccc(Cl)s2)nc1-c1ccc(-n2ccccc2=O)cc1
Temperature: 130 °C

Procedure:
A mixture of 5-chloro-N-((2-(4-iodophenyl)-1-methyl-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide prepared above (14 mg, 0.031 mmol), 2-hydroxypyridine (14 mg, 0.15 mmol), 8-hydroxyquinoline (14 mg, 0.097 mmol) and K2CO3 (30 mg, 0.22 mmol) in DMSO (0.5 mL) was degassed with Argon before being charged with CuI (9 mg, 0.047 mmol). The mixture in a sealed tube was heated at 130° C. overnight. It was then purified by HPLC to give the titled compound (2 mg). MS 425.1 and 427.1 (M+H, Cl pattern).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]#[N:10])[C:3]=1[CH3:11].[CH2:12]([O:14][C:15]1[CH:16]=[CH:17][C:18]([F:24])=[C:19](B(O)O)[CH:20]=1)[CH3:13].C(=O)([O-])[O-].[Na+].[Na+]>CC#N.O.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>[CH2:12]([O:14][C:15]1[CH:16]=[CH:17][C:18]([F:24])=[C:19]([C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]#[N:10])[C:3]=2[CH3:11])[CH:20]=1)[CH3:13]
Reactant: Cc1cc(Br)c(C)c(C#N)n1
Reactant: CCOc1ccc(F)c(B(O)O)c1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOc1ccc(F)c(-c2cc(C)nc(C#N)c2C)c1
Temperature: 100 °C
Yield: 97.3 %

Procedure:
To a solution of 4-bromo-3,6-dimethyl-pyridine-2-carbonitrile (which may be prepared as described in Description 137) (3.82 g, 18.099 mmol) in MeCN (45 mL) and water (5 mL) in a Smith microwave vessel was added (5-ethoxy-2-fluoro-phenyl)boronic acid (3.6627 g, 19.909 mmol), bis(triphenylphosphine)palladium (II) dichloride (0.3811 g, 0.5430 mmol) and sodium carbonate (3.8367 g, 36.198 mmol). The reaction vessel was sealed and purged with nitrogen. The reaction mixture was heated by microwave at 100° C. for 25 min. The reaction mixture was treated with water and was extracted with DCM twice and the organic layers were collected by passing down a PhaseSep cartridge The solvent was removed by evaporation and the residue was purified by silica gel chromatography (100 g SiO2) eluting with ethyl acetate in iso-hexane (10-60%). Evaporation of desired fractions gave 4-(5-ethoxy-2-fluoro-phenyl)-3,6-dimethyl-pyridine-2-carbonitrile (D138) (4.76 g, 17.61 mmol, 97.3% yield);
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[C:20]#[N:21])=[O:5])C.O.[OH-].[Li+].CO>O>[C:20]([C:14]1[C:13]2[C:17](=[CH:18][CH:19]=[C:11]([C@@H:7]3[CH2:8][CH2:9][CH2:10][C@H:6]3[C:4]([OH:5])=[O:3])[CH:12]=2)[NH:16][CH:15]=1)#[N:21]
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1c1ccc2[nH]cc(C#N)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1c[nH]c2ccc([C@@H]3CCC[C@H]3C(=O)O)cc12

Procedure:
A solution of cis-2-(3-Cyano-1H-indol-5-yl)-cyclopentanecarboxylic acid ethyl ester (0.95 g, 3.36 mMol), lithium hydroxide monohydrate (0.71 g, 16.8 mMol), methanol (20 mL), and water (5 mL) was heated at reflux for 6 h. The solution was concentrated in vacuo and the residue dissolved in water and washed once with dichloromethane. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3×20 mL). The pooled organic extracts were washed once with brine, dried over sodium sulfate, and concentrated in vacuo to give the product as a light brown oil which solidified upon standing (0.66 g, 77%). LC-MS: 1.33 min (2 min gradient); 277.07 (MNa)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([C:25]#[C:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31](NC(OC(C)(C)C)=O)[CH3:32])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1)=[O:11].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([C:25]#[C:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][CH3:32])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1)=[O:11]
Reactant: COc1cc2c(NC(=O)Nc3c(Cl)cccc3Cl)ncnc2cc1C#CCCCCN(C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCCCC#Cc1cc2ncnc(NC(=O)Nc3c(Cl)cccc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1-(2,6-dichlorophenyl)-3-{7-[6-(N-tert-butoxycarbonylamino-N-methylamino)-1-hexynyl]-6-methoxyquinazolin-4-yl}urea (0.1 g), trifluoroacetic acid (1 ml) and methylene chloride (1 ml) was stirred at ambient temperature for 1.5 hours. The mixture was evaporated and a solution of hydrogen chloride gas in ethyl acetate was added. Toluene was added and the mixture was evaporated. The residue was triturated under diethyl ether and the resultant solid was isolated. There was thus obtained the title compound as the hydrochloride salt (0.095 g); NMR Spectrum: (DMSOd6) 1.65 (m, 2H), 1.78 (m, 2H), 2.55 (m, 5H), 2.95 (m, 2H), 4.0 (s, 3H), 7.38 (t, 1H), 7.6 (d, 2H), 7.89 (s, 1H), 8.16 (s, 1H), 8.7 (m, 3H), 10.9 (br, 1H), 11.8 (s, 1H); Mass Spectrum: M+H+ 472 and 474.
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[CH2:6]([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1)[CH3:7]>CO>[CH2:6]([O:8][C:9]1[N:10]=[N:11][CH:12]=[CH:13][C:14]=1[S:5][CH2:2][CH:3]=[CH2:4])[CH3:7]
Reactant: CCOc1ccc(Cl)nn1
Reactant: C=CCS
Agent: [Na]
Solvent: CO
Product: C=CCSc1ccnnc1OCC

Procedure:
0.57 g(0.025 mol) of metallic sodium was dissolved in 40 ml of absolute methanol and then mixed with 2.49 ml(0.025 mol) of allylmercaptan. To this mixture was added 3.96 g(0.025 mol) of 3-ethoxy-6-chloropyridazine. The reaction solution was refluxed for 24 hours and then treated according to the same manner as Example 1 to obtain the title compound as a freezing pale white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:9]=2[CH2:20][N:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)=[CH:4][CH:3]=1.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:9]=2[CH2:20][N:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)=[CH:4][CH:3]=1.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]
Reactant: CN(C)CCOc1cccc(-c2ccc(Cl)cc2)c1CN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCOc1cccc(-c2ccc(Cl)cc2)c1CN1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of EXAMPLE 199B (2 g) in dichloromethane (10 ml) was added trifluoroacetic acid (10 ml) at 0° C. The reaction mixture was stirred at room temperature for 30 minutes and concentrated. The residue was loaded onto a C18 column, and eluted with 0-50% 0.1% trifluoroacetic acid/water in acetonitrile. The title compound was obtained as a trifluoroacetic acid salt.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[N:21]([CH:22]=2)[CH2:20][CH2:19][O:18][C:17]2[C:12]3=[CH:13][C:14]([CH2:23][OH:24])=[CH:15][CH:16]=2)=[N:7][CH:6]=[N:5]1)[CH3:3].IC1C=CC=CC=1C(O)=O>CCOC(C)=O>[CH3:3][CH:2]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[N:21]([CH:22]=2)[CH2:20][CH2:19][O:18][C:17]2[C:12]3=[CH:13][C:14]([CH:23]=[O:24])=[CH:15][CH:16]=2)=[N:7][CH:6]=[N:5]1)[CH3:1]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(CO)ccc1OCC2
Agent: O=C(O)c1ccccc1I
Solvent: CCOC(C)=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(C=O)ccc1OCC2
Temperature: 80 °C
Yield: 61.9 %

Procedure:
To a solution of {4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-13-yl}methanol (1.30 g, 4.00 mmol) in EtOAc (100 mL) was added 2-iodobenzoic acid (4.48 g, 16.0 mmol). The mixture was heated at 80° C. overnight. The solid was filtered, the filtrate was concentrated and purified by column chromatography on silica gel eluting with a 20% gradient of EtOAc in petroleum ether to afford 4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene-13-carbaldehyde (800 mg, 62% yield) as yellow solid. LCMS (ESI) m/z: 324.2 [M+H+].