Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:32]=[CH:33][C:34]=2[CH3:35])[CH2:25][CH2:24]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:36][C:37](=[O:41])[CH:38]([CH3:39])[CH3:40])[CH:32]=[CH:33][C:34]=3[CH3:35])[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1

Procedure:
Example 52 was prepared from bis(4-chlorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.62 (d, 1H, J=2.4 Hz), 7.53 (t, 1H, J=4.8 Hz), 7.28–7.22 (m, 8H), 7.12 (dd, 1H, J=2.0, 8.4 Hz), 7.03 (d, 1H, J=8.0 Hz), 4.80 (s, 1H), 3.36 (dd, 2H, J=6.0, 11.6 Hz), 2.91 (d, 2H, J=14.0 Hz), 2.64 (m, 1H), 2.47 (m, 1H), 2.38 (t, 2H, J=5.6 Hz), 2.24 (s, 3H), 2.00–1.93 (m, 2H), 1.70–1.56 (m, 6H), 1.16 (d, 6H, J=7.2 Hz); ESMS m/e: 580.3 (M+H)+.
Reaction SMILES: [S:1]1[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3][S:2]1.Cl.[CH3:10][O:11][C:12](=[O:16])[CH2:13][CH2:14][NH2:15].P(C#N)(OCC)(OCC)=O>CN(C)C=O.O1CCCC1>[S:1]1[CH2:5][CH:4]([C:6]([NH:15][CH2:14][CH2:13][C:12]([O:11][CH3:10])=[O:16])=[O:8])[CH2:3][S:2]1
Reactant: O=C(O)C1CSSC1
Reactant: COC(=O)CCN
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)CCNC(=O)C1CSSC1
Yield: 9.4 %

Procedure:
The reaction was carried out as described in Example 97, but using 5 ml of a solution of 3.3 mmol of 1,2-dithiolane-4-carboxylic acid (prepared as described in Example 96) in anhydrous dimethylformamide, 5 ml of anhydrous tetrahydrofuran, 1.01 ml of torethylamine, 502 mg of β-alanine methyl ester hydrochloride and 0.55 ml of diethyl cyanophosphate. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using a 2:1 by volume mixture of ethyl acetate and hexane as the eluent. The solvent was removed from the eluate solution by evaporation under reduced pressure, and the residue was recrystallized from a 2:2 by volume mixture of ethyl acetate and hexane, to obtain 73 mg of the title compound as pale yellow crystals having an Rf value of 0.41 (silica gel thin layer chromatography; using a 2:1 by volume mixture of ethyl acetate and hexane as developing solvent).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=3)[NH:9][CH:8]=2)[CH2:2]1.[C:18](=[O:21])([O-])[OH:19].[K+]>CC(=O)CC>[C:16]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:6][CH:3]1[CH2:4][CH2:5][N:1]([CH2:3][CH2:2][NH:1][C:18](=[O:21])[O:19][C:7]([CH3:15])([CH3:8])[CH3:6])[CH2:2]1)#[N:17]
Reactant: O=C([O-])O
Reactant: N#Cc1ccc2[nH]cc(CC3CCNC3)c2c1
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)NCCN1CCC(Cc2c[nH]c3ccc(C#N)cc23)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Under an inert atmosphere, 47.3 mmol (10 g) of 3-[(3-pyrrolidinyl)methyl]-1H-indole-5-carbonitrile, 47.3 mmol (9.95 g) of the product described in Preparation B and 1.55 ml of 2-butanone are mixed together and then 47.3 mmol (4.45 g) of potassium hydrogen carbonate are added. The mixture is stirred at 80° C. for 2 hours. After hydrolysis and separating off, the organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. Purification is carried out by chromatography on silica, using a mixture of dichloromethane/methanol/ammonia 97/3/0.3 as eluant, to yield the expected product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([F:13])([F:12])[CH2:6][NH:7][CH:8]1[CH2:11][CH2:10][CH2:9]1)[CH3:2].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:14])[C:5]([F:13])([F:12])[CH2:6][N:7]([C:18]1[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=1)[CH:8]1[CH2:11][CH2:10][CH2:9]1)[CH3:2]
Reactant: CCOC(=O)C(F)(F)CNC1CCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
A solution of 17.76 g (0.086 mole) 3-cyclobutylamino-2,2-difluoropropionic acid ethyl ester in 10 mL of ethyl acetate was added dropwise to a mixture of 16.6 g (0.086 mole) of 2,4-dichloro-5-nitro-pyrimidine, 28.9 g (0.344 mole) of sodium bicarbonate and 100 mL of ethyl acetate at 0 degrees. The cooling bath was removed and the reaction was stirred at room temperature for 18 h. Activated charcoal was added, and the mixture was filtered through a pad of Celite, washing the filter pad with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue purified by silica gel chromatography (elution with hexanes-ethyl acetate, gradient 100:0-50:50), to give 11.6 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclobutyl-amino]-2,2-difluoro-prop ionic acid ethyl ester (IV-1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12]C(C#N)=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:19]([OH:22])(=[O:21])[CH3:20].O.S(=O)(=O)(O)O>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][C:20]([C:19]([OH:22])=[O:21])=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: N#Cc1ccc2c(-c3cccc(F)c3)n[nH]c2c1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc2c(-c3cccc(F)c3)n[nH]c2c1
Temperature: 110 °C
Reaction time: 6 h

Procedure:
To 92 mg of 3-(3-fluorophenyl)-1H-6-indazolecarbonitrile were sequentially added 1 ml of glacial acetic acid, 0.5 ml of water and 0.4 ml of concentrated sulfuric acid, and the mixture was stirred at 110° C. for 6 hours. After standing to cool, 35 ml of ethyl acetate was added to the reaction mixture. The mixture was sequentially washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 94 mg of the title compound as bright yellow crystals.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[N:12]=1)(=O)=O.[NH2:34][C:35]1[CH:36]=[C:37]([CH2:41][OH:42])[CH:38]=[CH:39][CH:40]=1>CS(C)=O>[OH:42][CH2:41][C:37]1[CH:36]=[C:35]([NH:34][C:7]2[C:8]3[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[O:24][CH:23]=[N:22][CH:21]=4)=[CH:18][CH:19]=3)[N:12]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: Nc1cccc(CO)c1
Solvent: CS(C)=O
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(Nc3cccc(CO)c3)c2C1
Reaction time: 8 h
Yield: 22.5 %

Procedure:
6-Acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (35 mg, 0.07 mmol, Example 26a) in DMSO (1 mL) was dispensed in a library plate. (3-aminophenyl)methanol (8.62 mg, 0.07 mmol) was added to the funnel and the plate was left to shake overnight at 80° C. before it was filtered and purified by preparative HPLC to give 1-(4-(3-(hydroxymethyl)phenylamino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (7.2 mg, 22%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([F:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[Na+].[I-:12].C(Cl)(=O)C>C(#N)C>[F:10][CH:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([I:12])[CH:7]=1)[CH3:9]
Reactant: [I-]
Reactant: CC(F)c1ccnc(Cl)c1
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CC#N
Product: CC(F)c1ccnc(I)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Chloro-4-(1-fluoroethyl)pyridine (70 g, 439 mmol, 1.00 equiv), NaI (661 g, 4.41 mol, 10.00 equiv), ACN (700 mL) and acetyl chloride (56 g, 713 mmol, 1.60 equiv) were combined in a 2000-mL 4-necked round-bottom flask. The resulting solution was stirred overnight at 80° C. in an oil bath and then cooled to r.t, diluted with ice aqueous saturated sodium carbonate (500 mL) and extracted with dichloromethane (3×500 mL). The combined organic layer was washed with NaS2O3 (10%, 3×300 mL) and the aqueous phase was extracted with dichloromethane (2×200 mL). The combined organic layer was washed with brine (2×500 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel column (1:10 ethyl acetate/petroleum ether) to afford 4-(1-fluoroethyl)-2-iodopyridine as yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[C:12]4[CH:25]=[CH:24][S:23][C:13]=4[C:14](=[O:22])[NH:15][C:16]=3[CH:17]=[CH:18][C:19]=2[O:20]C)=[CH:6][CH:5]=1>BrB(Br)Br>[NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]3[C:12]4[CH:25]=[CH:24][S:23][C:13]=4[C:14](=[O:22])[NH:15][C:16]=3[CH:17]=[CH:18][C:19]=2[OH:20])=[CH:8][CH:9]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CCN)cc1
Agent: BrB(Br)Br
Product: NCCc1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Yield: 85.9 %

Procedure:
Following General Procedure F, 9-[4-(2-aminoethyl)phenyl]-8-methoxythieno[2,3-c]quinolin-4(5H)-one (800 mg, 1.8 mmol) was reacted with tribromoborane (10 mL) to afford the desired product (520 mg, 88%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 11.78 (s, 1H), 9.20 (s, 1H), 7.88 (br s, 2H), 7.69 (d, J=5.4 Hz, 1H), 7.41-7.36 (m, 3H), 7.22 (d, J=8.1 Hz, 2H), 7.15 (d, J=8.9 Hz, 1H), 5.88 (d, J=5.4 Hz, 1H), 3.21-3.14 (m, 2H), 3.01-2.98 (m, 2H); ESI MS m/z 337 [C19H16N2O2S+H]+; HPLC >99% (AUC), tR=7.72 min.
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH:8]=[CH:9][NH:10][C:6]=2[C:5]([Br:11])=[CH:4][N:3]=1.IC.[C:14](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH3:14])[C:6]=2[C:5]([Br:11])=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1ncc(Br)c2[nH]ccc12
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1ccc2c(Br)ncc(Br)c21
Yield: 69.8 %

Procedure:
A mixture of 4,7-dibromo-1H-pyrrolo[3,2-c]pyridine (1.35 g), iodomethane (609 ul) and anhydrous potassium carbonate (1.35 g) in dry acetone (90 ml) was refluxed overnight. The mixture was evaporated and the residue added to ethyl acetate (60 ml) and water (60 ml). The organic layer was washed with water then brine, dried (MgSO4) and evaporated. Purification of the residue by chromatography on silica gel, eluting with dichloromethane, gave the title compound (0.99 g)
Reaction SMILES: [ClH:1].N[C:3]1[N:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[N:4]=1.N([O-])=O.[Na+].[OH-].[Na+]>O>[Cl:1][C:3]1[N:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[N:4]=1
Reactant: Cl
Reactant: COc1cc(OC)nc(N)n1
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(OC)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1,260 ml of 36% hydrochloric acid were charged in a 5-l four-necked flask and then cooled to 0° C. After 180 g (1.16 moles) of 2-amino-4,6-dimethoxypyrimidine were added in small portions into the flask, the resulting mixture was stirred for about 1 hour until the reaction mixture changed into a syrupy form. After the reaction mixture was cooled to -15° C., 260 ml of 159 g (2.3 moles) of NaNO2 in H2O were added dropwise over about 1 hour under vigorous stirring. After completion of the dropwise addition, the resulting mixture was stirred at -15° to -10° C. for additional 1 hour so that the reaction was brought to completion. While the reaction mixture was retained at -5° C., 1.5 l of a 30% aqueous solution of NaOH were charged dropwise so that the reaction mixture was neutralized to pH 7. By filtration under reduced pressure, a clay-like material of a purple color was collected. The target compound was extracted from the clay-like material using 3 l of ethyl acetate. Through the procedure of washing with water, drying over anhydrous sodium sulfate and removal of the solvent, 63 g of bluish crude crystals were obtained. They were crystallized further by silica get chromatography to obtain 60.8 g of white crystals (yield: 29.9%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12](S(C2C=NC=CC=2)(=O)=O)[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=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>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:30]2[CH:29]=[CH:28][C:27]([F:26])=[CH:32][C:31]=2[F:33])[NH:12][CH:11]=1)[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
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+]
Product: CN(Cc1c[nH]c(-c2ccc(F)cc2F)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2,4-difluorophenyl)boronic acid (198 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (220 mg), the title compound was obtained as a colorless oil (yield 113 mg, 50%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1)#[N:26].[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:39][C:40]1[C:41]([C:50]([F:52])([F:51])[F:53])=[N:42][N:43]([CH2:46][C:47]([N:36]2[CH2:37][CH2:38][N:33]([C:30]3[CH:29]=[CH:28][C:27]([C:25]#[N:26])=[CH:32][CH:31]=3)[CH2:34][CH2:35]2)=[O:48])[C:44]=1[CH3:45]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(C#N)cc2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Cyanophenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (CDCl3, 400 MHz) 7.44 (d, 2H), 6.77 (d, 2H), 4.90 (s, 2H), 3.67 (m, 4H), 3.29 (m, 4H), 2.22 (s, 3H) ppm; MS (ES) M+Na expected=434.0, found 434.0.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].I[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[CH3:17][C:3]1([C:1]#[C:2][C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: Ic1cccs1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1cccs1)O2
Reaction time: 4 h
Yield: 56 %

Procedure:
A mixture of 4.6 g (20 mmol) of rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran -6ol, 6.3 g (30 mmol) of 2-iodothiophene, 0.8 g of triphenylphosphine, 0.19 g of cuprous iodide, 6 ml of triethylamine and 200 ml of acetonitrile was stirred and degassed with argon for 15 minutes. Palladium acetate, 220 mg, was then added and stirring under argon was continued for 4 hours. The solvent was removed under reduced pressure and the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried and evaporated. The residue was chromato graphed over 200 g of silica gel (Merck 70-230 mesh) using methylene chloride. Crystallization of the combined clean fractions from ether/hexane yielded 3.5 g (56 %) of rac-3,4-dihydro-2,5,7,8-tetramethyl-2-[(2-thienyl) ethynyl]-2H-1-benzopyran-6ol with m.p. 112-114° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([OH:20])=[O:19])[CH:8]=[C:7]2[N:21]([CH3:23])[CH3:22])(=[O:3])[CH3:2].[CH2:24](O)[CH3:25]>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20][CH2:24][CH3:25])=[O:19])[CH:8]=[C:7]2[N:21]([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CCCc1c(O)c(C(C)=O)cc2c(N(C)C)cc(C(=O)O)nc12
Reactant: CCO
Product: CCCc1c(O)c(C(C)=O)cc2c(N(C)C)cc(C(=O)OCC)nc12
Yield: 76 %

Procedure:
The product of step (a) (2 g; 6.3291 mmole) was dissolved in ethanol and hydrogen chloride was bubbled through the solution. When the heat of soluation subsided, the solution was heated to reflux on a steambath for 2 hours. The mixture was cooled, treated with water and concentrated, followed by basification with NH3 solution (pH about 6). The solution was extracted into chloroform and this was washed with water, dried and evaporated to give a brown solid (1.6 g, 76%). NMR and mass spectra were consistent with required structure.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:23])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4].[CH:24](=O)[CH2:25][CH:26]([CH3:28])[CH3:27]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:23]=[CH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1N
Reactant: CC(C)CC=O
Product: COC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1N=CCC(C)C

Procedure:
The present compound was synthesized by a method similar to that in Example 210 and using 2-amino-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (210 mg) and isovaleraldehyde. A colorless powder (95 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]1([CH2:13][CH2:14]O)[CH2:12][CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:10]1([CH2:13][CH2:14][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:12][CH2:11]1
Reactant: OCCC1CC1
Reactant: O=Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1ccc(OCCC2CC2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 75.6 %

Procedure:
To a mixture of 4-hydroxybenzaldehyde (2.84 g), 2-cyclopropylethanol (2.00 g), triphenylphosphine (6.09 g) and tetrahydrofuran (100 mL), diethyl azodicarboxylate (2.2 mol/L, solution in toluene, 10.5 mL) was added and the mixture was stirred at room temperature for 4 days. After concentrating the reaction mixture under reduced pressure, ethyl acetate (7.50 mL) and n-hexane (143 mL) were added and the mixture was stirred at room temperature for 15 minutes. The precipitate was removed by filtration through Celite (registered trademark). The filtrate was concentrated under reduced pressure and, thereafter, the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-50:50) to give the titled compound as a yellow oil (3.34 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].C([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])(C)(C)C>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:19]1[CH2:20][CH2:21][N:16]([C:14]([OH:15])=[O:13])[CH2:17][CH2:18]1)=[O:7]
Reactant: O=C(Cl)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(O)N1CCN(C(=O)c2cccs2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.7 %

Procedure:
2-Thiophenecarbonylchloride (2.04 g, 1.49 mL) was added to a solution of tert-butyl-1-piperazinecarboxylate (2.5 g, 13.4 mmol) and DMAP (20 mg) in pyridine (15 mL) at 0° C. under N2 atmosphere and stirred at room temperature for overnight. The mixture was poured into ice water, the precipitate was filtered, washed several times with water, and dried to yield white solids (3.5 g, 88%). Mp 76° C. 1H NMR (DMSO-d6): δ 1.42 (s, 12H), 3.40 (m, 4H), 3.61 (m, 4H), 7.12 (m, 1H), 7.43 (d, J=4.1 Hz, 1H), 7.77 (d, J=4.8 Hz, 1H). EIMS m/z 297 (M+1), 319 (M+23). Anal. (C14H20N2O3S) C, H, N.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=1.NO.[OH-].[K+].CO>C1COCC1>[CH3:18][N:16]([CH3:17])[C:13]1[CH:12]=[CH:11][C:10]([S:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:19])=[O:2])=[CH:15][CH:14]=1
Reactant: COC(=O)CCCCCSc1ccc(N(C)C)cc1
Agent: NO
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)c1ccc(SCCCCCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(4-dimethylamino-phenylsulfanyl)-hexanoic acid methyl ester (722 mg, 2.6 mmol) in distilled THF (20 mL) containing 50% aqueous hydroxylamine (1.7 mL, 25.7 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (1M, 4.4 mL, 4.4 mmol) in a dropwise manner. After stirring at 0° C. for 1 h, distilled water (20 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The aqueous solution was extracted with ethyl acetate (2×40 mL) and the combined extracts were washed with brine (80 mL), dried over anhydrous MgSO4, filtered and evaporated to dryness. The title compound was obtained as a colourless oil (377 mg, 52%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([CH2:7][CH3:8])[CH3:6].O>C(O)(=O)C>[N+:1]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH:5]([CH2:7][CH3:8])[CH3:6])[C:10]=1[OH:15])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCC(C)c1ccccc1O
Solvent: CC(=O)O
Solvent: O
Product: CCC(C)c1cccc([N+](=O)[O-])c1O
Temperature: 0 °C
Yield: 48.1 %

Procedure:
A mixture comprising 290.6 g of 65% nitric acid and 800 g of glacial acetic acid is cooled to 0° C., and at 0° to 4° C. there is added in the course of 11/2 hours, with thorough stirring and with cooling, a solution of 375.6 g of sec-butylphenol in 375 g of glacial acetic acid. There results a dark solution which is stirred at 0° to 4° C. for a further one hour. The reaction mixture is subsequently stirred into 5000 ml of water and ice. The nitrating mixture is obtained as a dark oil which is extracted with 1500 ml of chloroform. The chloroform is distilled off, and steam is passed into the dark oil obtained. As distillate is obtained 235 g of 2-nitro-6-sec-butylphenol in the form of light-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[C:10]#[CH:11])=[CH:4][CH:3]=1.I[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:12])[C:10]#[C:11][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:19]=2)=[CH:6][CH:7]=1
Reactant: Ic1ccc(CCN2CCCC2)cc1
Reactant: C#CC(=O)Nc1ccc(Cl)cc1
Product: O=C(C#Cc1ccc(CCN2CCCC2)cc1)Nc1ccc(Cl)cc1

Procedure:
Prepared analogously to Example 2.1.e. from propynoic acid-(4-chlorophenyl)amide and 1-[2-(4-iodophenyl)ethyl]pyrrolidine. Yield: 80 mg (34.1% of theory); melting point: 153° C.-154° C.; C21H21ClN2O (M=352.86); calc.: molecular ion peak (M+H)+: 353/355; found: molecular ion peak (M+H)+: 353/355.