Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10].[CH3:12][N:13]([CH3:25])[C:14](=[O:24])[C:15]([CH3:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16]>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH3:25][N:13]([CH3:12])[C:14](=[O:24])[C:15]([C:17]1[CH:18]=[CH:19][C:20]([C:9](=[O:10])[CH2:8][CH2:7][CH2:6][Cl:5])=[CH:21][CH:22]=1)([CH3:23])[CH3:16]
Reactant: O=C(Cl)CCCCl
Reactant: CN(C)C(=O)C(C)(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CN(C)C(=O)C(C)(C)c1ccc(C(=O)CCCCl)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 72.4 %

Procedure:
Add AlCl3 (1.129, 8.40 mmol) to carbon tetrachloride (6 mL) under a nitrogen atmosphere at room temperature. Add 4-chlorobutyryl chloride (0.49 mL, 4.37 mmol), stir for 15 minutes and add, by dropwise addition over 3 minutes, a solution of 2-methyl-2-phenyl-propionic acid, dimethylamide (0.64 g, 3.36 mmol) in carbon tetrachloride (6 mL). Stir at room temperature for 17 hours, dilute with methylene chloride (10 mL), pour into ice water (50 mL) and separate the layers. Wash the aqueous layer with methylene chloride (2×70 mL), 51 aqueous sodium hydrogen carbonate, combine the organic layers and dry (Na2SO4). Filter, evaporate the filtrate in vacuo and purify by silica gel chromatography (5:2 hexane/ethyl acetate) to give the title compound (0.72 g, 72%) as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[NH:7][N:6]=[CH:5]2>C(O)C.O.N>[NH2:11][C:10]1[CH:9]=[C:8]2[C:4]([CH:5]=[N:6][NH:7]2)=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc2cn[nH]c2cc1[N+](=O)[O-]
Agent: N
Solvent: CCO
Solvent: O
Product: Cc1cc2cn[nH]c2cc1N
Yield: 72.2 %

Procedure:
8 g (45.2 mmol) of 5-methyl-6-nitro-indazole (formula 51), obtained according to E. Noelting, Ber. Dtsch. Chem. Ges. 37 (1904) 2556, are dissolved in 640 ml of 50% aqueous ethanol. A mixture of 80 g of ferrous sulphate in 400 ml of water and 80 ml of aqueous ammonia were added. The reaction mixture was refluxed for 20 hours and filtered while still hot. Removal of the ethanol and purification of the precipitated product with charcoal yielded 4.80 g (72%) of the target compound, m.p. 241°-242° C.
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.Cl.[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1>>[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:18][C:5](=[O:9])[CH2:6][CH2:7][CH:8]2[CH2:1][CH2:2][C:3](=[O:10])[NH:4]2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(CO)cc1
Reactant: O=C1CCC2CCC(=O)N12
Agent: Cl
Product: Cc1ccc(COC(=O)CCC2CCC(=O)N2)cc1
Temperature: 100 °C

Procedure:
Five grams of dihydro-1H-pyrrolizine-3,5(2H,6H)-dione (III) are dissolved in 27 g of p-methylbenzyl alcohol and 0.2 ml of concentrated hydrochloric acid is added. The solution is heated at 100° C. for 48 hours. The mixture is cooled and chromatographed over silica gel in dichloromethane. The starting p-methylbenzyl alcohol is eluted with dichloromethane and the product is eluted with 1.0% methanol in dichloromethane. The eluate containing the product is concentrated at reduced pressure and the residual oil solidifies upon standing. The solid is recrystallized from toluene-diethyl ether to yield 5-oxo-2-pyrrolidinepropanoic acid p-methylbenzyl ester with a melting point of 71°-72° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:14][CH:13]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30]([O:34][CH3:35])(=[O:33])[CH2:31][SH:32]>ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([S:32][CH2:31][C:30]([O:34][CH3:35])=[O:33])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CS
Reactant: OC(CCCc1ccccc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Solvent: ClCCl
Product: COC(=O)CSC(CCCc1ccccc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 1 h

Procedure:
To a mixture of the alcohol (1.56 g) (Step II) and methyl thioglycolate (414 μL) in dichloromethane (20 mL) at 0° was added BF3 ·OEt2 (1.10 mL) dropwise. The mixture was stirred at 0° for 1 h and poured onto buffer (pH 7), extracted with dichloromethane and the organic phase was dried and evaporated. Flash chromatography using 20% ethyl acetate/hexane afforded the title compound as a syrup.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)[CH3:2].[NH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1.C(#N)C>O>[CH3:25][O:24][C:18]1[N:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14]([NH:13][C:8](=[O:10])[C:7]3[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:12][CH:11]=3)=[N:15]2)=[CH:20][CH:19]=1
Reactant: COc1ccc2ccc(N)nc2n1
Reactant: CCOc1ccc(C(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: CCOc1ccc(C(=O)Nc2ccc3ccc(OC)nc3n2)cc1
Temperature: 4 °C
Yield: 67.7 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-ethoxybenzoic acid (8 g), N,N'-carbonyldiimidazole (7.8 g) and 2-amino-7-methoxy-1,8-naphthyridine (5.6 g). The product produced by precipitation in water (9.4 g; m.p. 74° C.) is dissolved in boiling acetonitrile (94 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (3×20 cc) and dried at 30° C. under reduced pressure (0.067 kPa). N-(7-methoxy-1,8-naphthyridin-2-yl)-4-ethoxybenzamide (7 g) is produced, m.p. 145° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][C:22]#[C:23][C:24]([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22]#[C:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: CC(C)(C)C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)C#CCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Yield: 23.1 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (10.5 g) is alkylated using 1-bromo-4,4-dimethyl-pent-2-yne (7 g; 40 mmol) and K2CO3 (5.52 g; 40 mmol) at 40° C. for 16 h. After aqueous work-up and purification by RP chromatography the pure material (3.9 g) is de-acetylated in MeOH (250 ml) using DBU (3.58 g) at reflux. After aqueous work-up 5-amino-1-(4,4-dimethyl-pent-2-ynyl)-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (2.9 g) is obtained and used without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[OH-].[K+].I[CH2:14][CH3:15]>CS(C)=O>[CH2:14]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1])[CH3:15]
Reactant: CCI
Reactant: Cc1cc2ccccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCn1c(C)cc2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.6 %

Procedure:
To a mixture of 0.20 g (1.52 mmol) of 2-methylindole, 0.38 g (6.89 mmol) of KOH in DMSO (6 mL) was added 0.24 mL (3.04 mmol) of iodoethane. The mixture was stirred at room temperature for 12 hours, quenched by the addition of 15 mL of H2O, and extracted with ethyl acetate (2×15 mL). The combined organic extracts were washed with water (10 mL), brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography (ether/petroleum ether 0.5:9.5) to give 0.20 g (83%) of the desired product as a red oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:6][CH:5]=[C:4]([Cl:13])[N:3]=1.C1(=O)O[CH2:17][CH2:16][O:15]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:13][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:9]([CH:10]=[CH:11][N:12]=3)[CH2:17][CH2:16][O:15][C:2]=2[N:3]=1
Reactant: O=C1OCCO1
Reactant: Clc1ccc(-c2ncc[nH]2)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Clc1ccc2c(n1)OCCn1ccnc1-2
Temperature: 90 °C

Procedure:
A mixture of 0.856 g (4.00 mmol) of 2,6-dichloro-3-(1H-imidazol-2-yl)pyridine, 704 mg (8.00 mmol) of ethylene carbonate and 2930 mg (9.00 mmol) of cesium carbonate was heated in 25.0 ml of N,N-dimethylformamidefor 13 hours at 90° C. The mixture was filtered, the filtrate concentrated in high vacuum, the residue purified on 10 g of silica column eluting with 80% of ethyl acetate in heptane to give 9-chloro-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine. Yield 0.359 g (41%). M/z 222.0, calc. 221.04. 1H NMR (500 MHz, CDCl3) δ 8.84 (d, J=8.2, 1H), 7.18 (s, 1H), 7.15 (d, J=8.2, 1H), 7.02 (s, 1H), 4.63-4.57 (m, 2H), 4.47-4.41 (m, 2H)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:15]([C:17]1[CH:27]=[C:26]([CH3:28])[C:20]([O:21][CH2:22][C:23]([NH2:25])=[O:24])=[C:19]([CH3:29])[CH:18]=1)=O.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[CH3:14][O:13][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[O:11][CH3:12])[N:1]=[C:15]([C:17]1[CH:27]=[C:26]([CH3:28])[C:20]([O:21][CH2:22][C:23]([NH2:25])=[O:24])=[C:19]([CH3:29])[CH:18]=1)[NH:6][C:4]2=[O:5]
Reactant: COc1cc(N)c(C(N)=O)cc1OC
Reactant: Cc1cc(C=O)cc(C)c1OCC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc2nc(-c3cc(C)c(OCC(N)=O)c(C)c3)[nH]c(=O)c2cc1OC
Temperature: 25 °C
Yield: 76.8 %

Procedure:
A solution of 4-hydroxy-3,5-dimethoxybenzaldehyde (1.0 g, 6.66 mmol) in DMF (10 mL) was cooled to 0° C. under nitrogen. NaH (0.4 g, 10 mmol, 60% in oil) was added portion-wise. The reaction was stirred for 30 min, then 2-bromoacetamide (0.918 g, 6.66 mmol) was added and stirring was continued for 36 h at room temperature. The DMF was removed under reduced pressure and water (50 mL) was added. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with an aqueous solution of NaOH (50 mL, 10%), washed with water (50 mL) and brine solution (50 mL) and dried over MgSO4 and concentrated to give 0.6 g of crude intermediate, which was purified by flash column chromatography to provide the desired intermediate (366 mg, 26%), as a white solid. A mixture of 2-amino-4,5-dimethoxybenzamide (0.2 g, 1.019 mmol), 2-(4-formyl-2,6-dimethyl-phenoxy acetamide (0.211 g, 1.019 mmol), sodium hydrogensulfite (0.116 g, 1.121 mmol) and p-toluenesulfonic acid (20 mg) in N,N-dimethyl acetamide (5 mL) was stirred at 150° C. for 16 h under nitrogen. The reaction mixture was cooled to room temperature and water (50 mL) was added. The white precipitate was filtered off and washed with cold water (30 mL×2) and dried under high vacuum to provide 2-(4-(6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)acetamide (300 mg, 76%) as a off white solid. Selected data: MS (ES) m/z: 384.1 (M+1); MP 354-356° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[CH:13]=[CH:12]2)=[O:10])=[C:4]([Cl:20])[CH:3]=1.[CH3:21][O:22][C:23](Cl)=[O:24].ClC1C=CC=C(Cl)C=1C(N1C2C=CN=C(NC(=O)OC)C=2C=C1)=O>>[Cl:8][C:6]1[CH:7]=[C:2]([NH:1][C:23](=[O:24])[O:22][CH3:21])[CH:3]=[C:4]([Cl:20])[C:5]=1[C:9]([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH:13]=[CH:12]1)=[O:10]
Reactant: Nc1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1
Reactant: COC(=O)Cl
Agent: COC(=O)Nc1nccc2c1ccn2C(=O)c1c(Cl)cccc1Cl
Product: COC(=O)Nc1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1

Procedure:
Methyl [3,5-dichloro-4-(1H-pyrrolo[3,2-c]pyridin-1-ylcarbonyl)phenyl]carbamate (Compound No. 79) was prepared by treating (4-amino-2,6-dichlorophenyl)(1H-pyrrolo[3,2-c]pyridin-1-yl)methanone with methylchloroformate following a procedure similar to the one used for methyl [1-(2,6-dichlorobenzoyl)-1H-pyrrolo[3,2-c]pyridin-4-yl]carbamate (Compound No. 74).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:22](=[O:29])[C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccncc2)CC1
Reaction time: 2 h
Yield: 76 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with isonicotinoyl chloride hydrochloride (0.028 g, 0.16 mmol) and triethylamine (0.058 mL, 0.41 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hrs. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (30 mg, 73%). LCMS calculated for C21H20ClN4O2 (M+H)+: m/z=395.1; Found: 395.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([Br:17])[N:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:7]=1[CH2:25]Br)=[O:5])[CH3:2].[CH2:27]([O:29][C:30](=[O:40])[CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH3:28]>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([Br:17])[N:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:7]=1[CH2:25][N:32]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:31][C:30]([O:29][CH2:27][CH3:28])=[O:40])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1c(-c2ccccc2)c(Br)n(-c2ccc(F)cc2)c1CBr
Product: CCOC(=O)CN(Cc1c(C(=O)OCC)c(-c2ccccc2)c(Br)n1-c1ccc(F)cc1)C(=O)OC(C)(C)C

Procedure:
Prepared in analogy to that of Example 1(c) from 5-bromo-2-bromomethyl-1-(4-fluoro-phenyl)-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester and tert-butoxycarbonylamino-acetic acid ethyl ester. The title compound, ESI MS (m/z): 625 (M+Na+).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=2[F:16])[CH2:5][N:4]([CH2:17][CH3:18])[C:3]1=[O:19].C(N(CC)C(C)C)(C)C.[CH:29]1[CH:34]=[CH:33][C:32]([O:35][C:36](OC2C=CC=CC=2)=[N:37][C:38]#[N:39])=[CH:31][CH:30]=1>ClCCl>[C:38]([N:37]=[C:36]([O:35][C:32]1[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=1)[NH:1][C@@H:2]1[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=2[F:16])[CH2:5][N:4]([CH2:17][CH3:18])[C:3]1=[O:19])#[N:39]
Reactant: CCN1C[C@H](c2cccc(F)c2F)CC[C@@H](N)C1=O
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=NC#N)Oc2ccccc2)C1=O
Reaction time: 5 h
Yield: 80 %

Procedure:
A solution of (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-ethylazepan-2-one (135 mg, 0.503 mmol) in dichloromethane was treated N,N-diisopropylethylamine (65 mg, 0.503 mmol) and diphenyl N-cyanocarbonimidate (204 mg, 0.855 mmol). After 5 h, the reaction was quenched with 0.5N NaOH and the organic layer washed with water and brine. The combined aqueous layers were extracted with EtOAc. The combined organics were dried, filtered and concentrated. Purification by silica gel chromatography (EtOAc/hexanes) gave the title compound (166 mg). MS 413.3 (M+1).
Reaction SMILES: I[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[S:8][CH:9]=[CH:10][C:11]=1I.[CH3:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[C:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(N(CCCC)CCCC)CCC>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[CH2:23]([C:22]1[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[C:21]=1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCC#CCCCCCCCC
Reactant: Ic1ccsc1-c1sccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: CCCCCCCCc1c(CCCCCCCC)c2ccsc2c2sccc12
Temperature: 130 °C
Yield: 84.8 %

Procedure:
To a two-necked RB flask under nitrogen was added 1.39 g (3.3 mmol) of 3,3′-diiodo-2,2′-bithiophene, 222 mg (0.33 mmol) of Pd(OAc)2, 2.5 g (10 mmol) of 9-octadecyne, tributyl amine 1.85 g (10 mmol), and 10 mL of anhydrous DMF. The mixture was heated at 130° C. for 4 hours. After cooling down to room temperature, 50 mL of ether ethyl was. The organic phase was washed with water several times, dried by MgSO4, concentrated under reduced pressure. The residue was further purified by flash chromatography on silica gel (hexane as eluent) to afford the pure product as a colorless liquid (1.16 g, yield: 85%). 1H NMR (300 MHz, CDCl3) δ 7.46 (d, 2H, J=5.43 Hz), 7.37 (d, 2H, J=5.42 Hz), 3.01 (t, 4H, J=7.89 Hz), 1.68 (m, 4H), 1.51 (m, 4H), 1.30 (m, 16H), 0.89 (t, 6H, J=6.7 Hz). 13C NMR (400 MHz, CDCl3) δ 137.47, 131.58, 131.32, 123.55, 123.38, 31.87, 31.52, 30.43, 30.16, 29.48, 29.27, 22.63, 14.04. MS: m/z=414.7 [M]+ (Calcd.: 414.7).
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[N:20]=[N:21][NH:22][CH:23]=3)=[C:9]([OH:24])[C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27].C1(N2C=CC(CCCC3N=NNC=3)=C(O)C2=S)C=CC=CC=1>>[C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[N:20]=[N:21][NH:22][CH:23]=3)=[C:9]([OH:24])[C:8]2=[S:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1c(O)c(CCCCCCc2c[nH]nn2)ccn1-c1ccccc1
Agent: Oc1c(CCCc2c[nH]nn2)ccn(-c2ccccc2)c1=S
Product: Oc1c(CCCCCCc2c[nH]nn2)ccn(-c2ccccc2)c1=S
Yield: 84.8 %

Procedure:
Reaction of 159e (0.18 g, 0.532 mmol) and P4S10 (0.118 g, 0.266 mmol) under neat conditions as described for synthesis of 162b gave compound 162e (0.080 g, 42%) as a olive green semi-solid. 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 7.83 (d, J=7.5 Hz, 2H), 7.76 (s, 1H), 7.41 (t, J=7.5 Hz, 2H), 7.32 (m, 2H), 6.94 (m, 1H), 6.72 (m, 1H), 4.49 (m, 2H), 4.40 (t, J=6.9 Hz, 2H), 1.97 (m, 4H), 1.36 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 164.38, 162.90, 147.70, 130.54, 128.76, 128.03, 126.64, 125.61, 119.51, 118.75, 118.29, 59.74, 50.10, 29.91, 27.99, 25.82, 25.65. HRMS (ESI) calcd for C19H23N4OS [M+H]+ 355.158. found 355.1632.
Reaction SMILES: [CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([C:29]4[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=4[F:37])=[C:22]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH:23]=3)[CH:11]=2)[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([C:29]4[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=4[F:37])=[C:22]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH:23]=3)[CH:11]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: COC(=O)CC(c1cccc(OCc2cnc(-c3cc(OC)ccc3F)c(OCC(C)C)c2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ncc(COc3cccc(C(CC(=O)O)C4CC4)c3)cc2OCC(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
To a solution of methyl 3-cyclopropyl-3-(3-((6-(2-fluoro-5-methoxyphenyl)-5-isobutoxypyridin-3-yl)methoxy)phenyl)propanoate (132 mg) in THF (2.0 mL) and methanol (1.0 mL) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at room temperature for 4 hr. 1N Hydrochloric acid (2.0 mL) was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (114 mg) as a white amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([OH:10])=O.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:32][N:33]([CH3:44])[CH2:34][CH2:35][NH:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([CH3:43])[CH2:39][CH2:38]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:32][N:33]([CH3:44])[CH2:34][CH2:35][N:36]([C@H:37]1[CH2:38][CH2:39][C@H:40]([CH3:43])[CH2:41][CH2:42]1)[C:8](=[O:10])[CH:7]=[CH:6][C:5]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C=CC(=O)N(CCN(C)C)[C@H]2CC[C@H](C)CC2)cc1OC

Procedure:
Using 2.7 g of 3,4-dimethoxycinnamic acid, 2.8 ml of diethyl chlorophosphate, 2.7 ml of triethylamine, 100 ml of methylene chloride, 3.0 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.5 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 81 was carried out. As a result, 1.53 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-3,4-dimethoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([F:30])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1.C(N(C(C)C)CC)(C)C.[CH3:40][O:41][CH2:42][CH2:43][O:44][CH2:45][C:46](Cl)=[O:47]>C(Cl)Cl>[Cl:3][C:4]1[C:5]([F:30])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH:24]4[CH2:29][CH2:28][N:27]([C:46](=[O:47])[CH2:45][O:44][CH2:43][CH2:42][O:41][CH3:40])[CH2:26][CH2:25]4)=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COCCOCC(=O)Cl
Reactant: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCC(=O)N1CCC(Oc2cc3ncnc(Nc4cccc(Cl)c4F)c3cc2OC)CC1
Yield: 33.6 %

Procedure:
N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and 2-(2-methoxyethoxy)acetyl chloride (0.105 g) were stirred in methylene chloride (9 ml) for 2.5 hours. Methylene chloride (20 ml) was added and the organic layer was washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The resulting product was purified by flash column chromatography eluting with methanol (3%) and methylene chloride (97%) gave a foam. This was re-precipitated by stirring in diethyl ether (20 ml) to give the title product as a white solid (0.110 g); 1H NMR Spectrum: (DMSO d6 373K) 1.73 (m, 2H), 2.02 (m, 2H), 3.29 (s, 3H), 3.42 (m, 2H), 3.51 (t, J=7 Hz, 2H), 3.60 (t, J=9 Hz, 2H), 3.78 (m, 2H), 3.96 (s, 3H), 4.17 (s, 2H), 4.87 (m, 1H), 7.27 (m, 1H), 7.33 (s, 1H), 7.42 (m, 1H), 7.58 (m, 1H), 7.85 (s, 1H), 8.39 (s, 1H), 9.29 (br s, 1H); Mass Spectrum: (M+H)+ 519; melting point 110 to 111° C.