Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]3[CH2:16][NH:15][CH2:14][CH2:13][N:12]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:9][C:4]=2[O:3][CH2:2]1.Cl[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[CH:28]=[CH:27][N:26]=1.C(N(CC)CC)C.O>C(O)CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]3[CH2:16][N:15]([C:25]4[C:34]5[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=5)[CH:28]=[CH:27][N:26]=4)[CH2:14][CH2:13][N:12]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc2ccnc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1Cc1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: OCCO
Solvent: O
Product: COc1ccc2ccnc(N3CCN(C(=O)OC(C)(C)C)C(Cc4ccc5c(c4)OCO5)C3)c2c1
Yield: 44 %

Procedure:
A mixture of 320 mg of 2-benzo[1,3]dioxol-5-ylmethyl-1-tert-butoxycarbonylpiperazine as synthesized in the above step, 200 mg of 1-chloro-7-methoxyisoquinoline and 100 mg of triethylamine was stirred in 2 ml of ethylene glycol at 150° C. for 18 hours. After addition of water, the solution was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified on silica gel column chromatography (ethyl acetate:n-hexane=1:1) to provide 210 mg (44%) of 1-(2-benzo[1,3]dioxol-5-ylmethyl-1-tert-butoxycarbonylpiperazin-4-yl)-7-methoxyisoquinoline.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([N:27]5[C:39]6[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=6[C:33]6[C:28]5=[CH:29][CH:30]=[CH:31][CH:32]=6)[CH:22]=4)[CH:17]=[CH:18][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.I[C:41]1[CH:42]=[C:43]([N:47]2[C:59]3[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=3[C:53]3[C:48]2=[CH:49][CH:50]=[CH:51][CH:52]=3)[CH:44]=[CH:45][CH:46]=1.CC(C)([O-])C.[Na+].C(P)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH:10]1[C:11]2[N:12]([C:14]3[CH:15]=[C:16]([N:20]([C:45]4[CH:46]=[CH:41][CH:42]=[C:43]([N:47]5[C:48]6[CH:49]=[CH:50][CH:51]=[CH:52][C:53]=6[C:54]6[C:59]5=[CH:58][CH:57]=[CH:56][CH:55]=6)[CH:44]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([N:27]5[C:39]6[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=6[C:33]6[C:28]5=[CH:29][CH:30]=[CH:31][CH:32]=6)[CH:22]=4)[CH:17]=[CH:18][CH:19]=3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: c1cc(Nc2cccc(-n3c4ccccc4c4ccccc43)c2)cc(-n2c3ccccc3c3ccccc32)c1
Reactant: Ic1cccc(-n2c3ccccc3c3ccccc32)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P
Solvent: Cc1ccccc1
Product: c1cc(N(c2cccc(-n3c4ccccc4c4ccccc43)c2)c2cccc(-n3c4ccccc4c4ccccc43)c2)cc(-n2c3ccccc3c3ccccc32)c1
Yield: 56 %

Procedure:
5.5 g of bis[3-(carbazol-9-yl)phenyl]amine, 4.9 g of 9-(3-iodophenyl)carbazole, 2.1 g of sodium tert-butoxide, 0.1 g of palladium acetate, and 50 ml of anhydrous toluene were added in a flask under a nitrogen atmosphere. At an inner temperature of 71° C., 0.4 g of tert-butylphosphine was added by using a syringe. After 10 hours of reaction at 100° C., 300 ml of toluene was added to extract the objective substance, followed by filtration. The filtrate was concentrated to dryness to obtain a crude product. The dried crude product was purified by column chromatography to obtain 5.3 g (yield 56%) of mTCTA (Compound 2). The product was identified by 1H-NMR analysis (see FIG. 1). The following 36 hydrogen atoms were detected upon 1H-NMR (CDCl3) analysis. δ (ppm): 8.083-8.130 ppm (6H), 7.468-7.565 ppm (6H), 7.128-7.390 ppm (24H).
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[OH:6][CH2:7][C@@H:8]1[CH2:13][N:12]2[N:14]=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[C:11]2[C:10](=[O:25])[NH:9]1.Cl>C(#N)C>[O:18]([CH2:17][C:15]1[CH:16]=[C:11]2[C:10](=[O:25])[NH:9][C@H:8]([CH2:7][O:6][Si:2]([CH3:5])([CH3:4])[CH3:3])[CH2:13][N:12]2[N:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C[Si](C)(C)Cl
Reactant: O=C1N[C@H](CO)Cn2nc(COc3ccccc3)cc21
Agent: Cl
Solvent: CC#N
Product: C[Si](C)(C)OC[C@@H]1Cn2nc(COc3ccccc3)cc2C(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
Chlorotrimethylsilane (0.30 mL, 2.41 mmol) was added to a solution of (S)-6-hydroxymethyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (0.33 g, 2.4 mmol) and TEA (0.33 mL, 2.4 mmol) in ACN (6 mL) at 0° C. The reaction was stirred for 30 minutes at room temperature. Then a 1N solution of HCl was added and the mixture extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo to yield (S)-2-phenoxymethyl-6-trimethylsilanyloxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (0.375 g, 90% yield) as an off-white solid that was used in the next step without further purification.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[N+:7]([C:10]1[S:14]C(C(O)=O)=[N:12][CH:11]=1)([O-:9])=[O:8].CN(C)C=O>C(Cl)Cl>[N+:7]([C:10]1[S:14][C:1]([C:2]([Cl:4])=[O:3])=[N:12][CH:11]=1)([O-:9])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ncc([N+](=O)[O-])s1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ncc([N+](=O)[O-])s1
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (13 ml) was added dropwise to a stirred suspension of 5-nitrothiazole-2-carboxylic acid (12.9 g; Chem. Ber. 1973, 106, 722) in a mixture of methylene chloride (80 ml and dimethylformamide (20 ml). The mixture was stirred at laboratory temperature for 30 minutes and evaporated to dryness to give 5-nitrothiazole-2-carbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27](O)[CH:28]=[CH:29][CH:30]=1.C(P(CCCC)CCCC)CCC.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][O:16][C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([O:24][CH3:23])[CH:30]=2)=[CH:6][CH:7]=1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCO)o1
Reactant: COc1cccc(O)c1
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cccc(OCCCc2oc(-n3ccnc3C)nc2-c2ccc(Cl)cc2)c1
Reaction time: 3 h
Yield: 70.5 %

Procedure:
To a mixture of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol (500 mg), 3-methoxyphenol (390 mg), tributylphosphine (640 mg) and tetrahydrofuran (20 ml) was added dropwise a toluene solution of diethyl azodicarboxylate (40%, 1.37 g) at room temperature, and the resulting mixture was stirred for 3 hours. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-5-[3-(3-methoxylphenoxy)propyl]-2-(2-methyl-1-imidazolyl)oxazole (470 mg, 70%) was obtained as an oil from an ethyl acetate-hexane (2:3, v/v)-eluted fraction.
Reaction SMILES: [CH3:1][N:2]([S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]([F:35])([F:34])[F:33])(=[O:25])=[O:24])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([O:20]CC)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CO>[CH3:1][N:2]([S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]([F:35])([F:34])[F:33])(=[O:25])=[O:24])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=[O:19])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4ccccc4C(F)(F)F)c3[nH]2)S1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.5 %

Procedure:
Ethyl {2-[7-(methyl{[2-(trifluoromethyl)phenyl]sulfonyl}amino)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (0.55 g) was dissolved in a mixed solvent of tetrahydrofuran (6 mL)-methanol (6 mL). Aqueous potassium hydroxide solution (prepared by dissolving potassium hydroxide (0.30 g) in water (5 mL)) was added to this solution, and the mixture was stirred at room temperature for 6 hr. The reaction solution was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained pale-yellow oil was crystallized from ethyl acetate-hexane to give the title compound (372 mg, yield: 72%) as pale-yellow crystals. MS: 498 (MH+). melting point 170-172° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[N:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH2:39])=[CH:33][CH:32]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:39][CH2:38][CH2:37][C:34]3[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: NCCc1ccncc1
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccncc3)n2)c1

Procedure:
Intermediate 4 was coupled with 2-pyridin-4-yl-ethylamine following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 441. 1H NMR (Varian 300 MHz, CDCl3—CD3OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.6 (m, 2H) 8.3 (m, 1H) 8.1 (m, 3H) 7.9 (m, 1H) 7.6 (m, 1H) 7.5 (m, 1H) 7.3 (m, 1H) 4.4 (m, 2H) 4.0 (m, 2H) 3.3 (m, 2H) 2.9 (m, 4H) 1.8 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8](=[O:19])[C:7]=1[C:20](O)=O)=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.[BH3-]C#N.[Na+].P([O-])([O-])([O-])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:58]>C(Cl)Cl.CN(C=O)C.C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8](=[O:19])[C:7]=1[CH2:20][Br:58])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccn(Cc2ccccc2)c(=O)c1C(=O)O
Reactant: BrC(Br)(Br)Br
Agent: O=C(Cl)C(=O)Cl
Agent: O=P([O-])([O-])[O-]
Agent: [BH3-]C#N
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)c1ccn(Cc2ccccc2)c(=O)c1CBr
Reaction time: 2.5 h
Yield: 39.9 %

Procedure:
1-Benzyl-2-oxo-1,2-dihydro-pyridine-3,4-dicarboxylic acid 4-ethyl ester (581 mg, 1.93 mmol) was dissolved in 15 mL of CH2Cl2. Oxalyl chloride (1.7 mL, 19.3 mmol) and DMF (2 drops) were added, and the mixture was stirred for 2.5 h. Solvent and excess oxalyl chloride were removed by evaporation in vacuo, and to the residue was added a solution of NaCNBH3 (250 mg, 3.86 mmol) in THF (15 mL). The resulting suspension was stirred at r.t. for 16 h. The reaction mixture was cooled in an ice bath, and then poured into a pre-cooled, vigorously stirring pH 4.9 phosphate buffer (100 mL). The resulting mixture was extracted several times with benzene, and the combined organic layer was washed with ice-cold water and dried over MgSO4. Evaporation of the solvent at reduced pressure gave a viscous oil, which was dissolved in 10 mL of CH2Cl2. The solution was cooled in at ice bath, and triphenylphosphine (759 mg, 2.90 mmol) and carbon tetrabromide (960 mg, 2.90 mmol) were added. The mixture was then stirred at r.t. for 16 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (0-40% EtOAc/hexanes) to give 270 mg of the title compound as a yellow oil. 1H NMR (CDCl3, 200 MHz): δ=7.15-7.42 (m, 6H), 6.51 (d, 1H, J=7.2 Hz), 5.18 (s, 2H), 4.90 (s, 2H), 4.41 (q, 2H, J=7.0 Hz), 1.43 (t, 3H, J=7.0 Hz).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][O:10][C:9]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]2[CH2:7]1)=[O:4].[F:18][C:19]([F:34])([F:33])[O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[N+:15]([C:13]1[N:12]=[C:9]2[N:8]([CH:14]=1)[CH2:7][C@H:6]([NH:5][C:3](=[O:4])[CH2:2][N:30]1[CH2:31][CH2:32][CH:27]([C:24]3[CH:25]=[CH:26][C:21]([O:20][C:19]([F:18])([F:33])[F:34])=[CH:22][CH:23]=3)[CH2:28][CH2:29]1)[CH2:11][O:10]2)([O-:17])=[O:16]
Reactant: FC(F)(F)Oc1ccc(C2CCNCC2)cc1
Reactant: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Product: O=C(CN1CCC(c2ccc(OC(F)(F)F)cc2)CC1)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Yield: 59.6 %

Procedure:
Similar to the manipulation of example 1, with (S)-2-chloro-N-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)acetamide (130 mg, 0.50 mmol) and 4-(4-(trifluoromethoxy)phenyl)piperidine (245 mg, 1.0 mmol) as crude materials, 140 mg title compound was generated and yield was 60%.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:3].[CH2:15]([CH:18]1[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1)[C:16]#[CH:17]>>[CH2:15]([CH:18]1[CH2:23][CH2:22][N:21]([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)=[O:3])[CH2:20][CH2:19]1)[C:16]#[CH:17]
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Product: C#CCC1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1

Procedure:
4-(nitro)benzyl chloroformate (5.00 g, 23.2 mmol) was added to a solution of tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (3.98 g, 17.4 mmol) according to general procedure 1. Yield=4.66 g, 86%. m/z MH+=302.98. HPLC rt=12.3 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([S:8][CH3:9])=[CH:4][N:3]=1.N1C=CC=CC=1.[Br:16]Br>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:7]([Br:16])=[N:6][C:5]([S:8][CH3:9])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: CSc1cnc(N)cn1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CSc1cnc(N)c(Br)n1
Reaction time: 0.5 h
Yield: 71967.6 %

Procedure:
To a solution of the compound obtained in Example 34 (1) (100 mg) in chloroform (18 ml), pyridine (56.0 mg) was added and then a solution of bromine (113 mg) in chloroform (18 ml) was added dropwise at 15 to 30° C. over 1 hour under light-shielding and the mixture was stirred at the same temperature for 30 minutes. After completion of the reaction, the reaction solution was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was separated using silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 112 g (72%) of the desired product as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]#[C:6][C:7]([O:9][CH3:10])=[O:8])=[O:4].[CH3:11][Si:12]([CH3:24])([CH3:23])[O:13][C:14]([C:16]([O:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH2:17])=[CH2:15]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH2:17][C:16]([O:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[C:14]([O:13][Si:12]([CH3:23])([CH3:11])[CH3:24])[CH2:15][C:6]=1[C:7]([O:9][CH3:10])=[O:8])=[O:4]
Reactant: COC(=O)C#CC(=O)OC
Reactant: C=C(O[Si](C)(C)C)C(=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C(=O)OC)CC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1

Procedure:
Under argon, a solution of 7.1 g (50 mmol) of acetylenedicarboxylic acid dimethyl ester in 30 ml of toluene is added dropwise to 12.5 g (50 mmol) of 2,3-bis(trimethylsilyloxy)-1,3-butadiene (95%) and then boiled under reflux for 19 hours. The reaction mixture is cooled, the solvent is evaporated off and the residue is distilled under a high vacuum (0.1 mbar,124°-127°), yielding the title compound in the form of a yellow, highly viscous oil, 1H-NMR (CDCl3): δ=0.18 (s, 18H), 3.09 (s, 4H), 3.78 (s, 6H).
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:15]3[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=3)=[CH:9][C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:2].[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C1COCC1.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)I>[CH2:1]([N:3]([CH2:22][CH3:23])[C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:31]#[C:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:17][CH:16]=3)=[CH:9][C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: C#Cc1ccccc1
Reactant: CCN(CC)c1ccc2c(-c3ccc(Br)cc3)cc(=O)oc2c1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc2c(-c3ccc(C#Cc4ccccc4)cc3)cc(=O)oc2c1

Procedure:
After charging 7.4 parts of 7-diethylamino-4-[(p-bromphenyl)]coumarin synthesized by a known method, 2.4 parts of phenylacetylene, 0.46 parts of tetrakis(triphenylphosphine)palladium(0), 0.038 parts of copper iodide and 20 ml of triethylamine in 40 ml of THF, the mixture was refluxed for 9 hours. The reaction mixture was filtered and washed with THF, and the obtained filtrate was concentrated and then diluted with water and filtered. The obtained cake was recrystallized from methanol. Upon drying under reduced pressure there was obtained 2.2 parts of 7-diethylamino-4-[4-(phenylethynyl)phenyl]coumarin having a melting point of 136-138° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:49][O:50][C:51](=[O:65])[C@H:52]([CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([C:63]#[N:64])[CH:58]=1)[C@H:53]([NH2:55])[CH3:54]>CN(C=O)C.CCOC(C)=O>[CH3:49][O:50][C:51](=[O:65])[C@H:52]([CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([C:63]#[N:64])[CH:58]=1)[C@H:53]([NH:55][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:17][CH:16]=1)[CH3:54]
Reactant: COC(=O)[C@H](Cc1cccc(C#N)c1)[C@@H](C)N
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1cccc(C#N)c1)[C@@H](C)NC(=O)c1ccc(-c2ccc(OC)nc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a stirred solution of 4-(6-methoxy-pyridin-3-yl)-benzoic acid (0.67 g, 2.54 mmol) in DMF (5 mL) is added DIPEA (0.44 mL, 2.54 mmol), TBTU (0.91 g, 2.54 mmol) and 2(R)-(3-Cyano-benzyl)-3(R)-amino-butyric acid methyl ester (0.59 g, 2.54 mmol). The solution is stirred overnight at room temperature. The reaction is diluted with EtOAc and washed with saturated sodium bicarbonate (3×), brine, dried over MgSO4, filtered and concentrated. The crude product is purified by flash chromatography (50% EtOAc/hexane to 60% EtOAc/hexane) to give the product as a white solid (0.83 g, 1.87 mmol). 1H NMR (CDCl3, 300 MHz) δ8.43 (d, 1H), 7.92 (d, 2H), 7.83 (dd, 1H), 7.63 (d, 1H), 7.30-7.55 (m, 4H), 6.87 (d, 1H), 4.42-4.53 (m, 1H), 3.98 (s, 3H), 3.66 (s, 3H), 2.85-3.08 (m, 3H), 1.28 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=O.[F:22][C:23]([F:31])([F:30])[C:24](=[O:29])[CH2:25][C:26](=O)[CH3:27].C(O)(C)C>CCCCCCC.C(OCC)(=O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([O:8][C:9]([F:12])([F:11])[F:10])[CH:4]=3)[N:1]=[C:26]([CH3:27])[C:25]=2[C:24](=[O:29])[C:23]([F:31])([F:30])[F:22])=[CH:16][CH:17]=1
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)c1ccc(Cl)cc1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1nc2ccc(OC(F)(F)F)cc2c(-c2ccc(Cl)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 34 %

Procedure:
The title compound was prepared from (2-Amino-5-trifluoromethoxy-phenyl)-(4-chloro-phenyl)-methanone [example A3] and 1,1,1-trifluoro-2,4-pentanedione according to the procedure of example 1, except that the solvent was isopropanol, the reaction time was of 16 h and heptane/ethyl acetate (1:2) was used. Yield: 34%; MS: m/z=433 (M).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].O>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21](=[O:22])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[O:9][C:10]([F:11])([F:12])[F:13])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(Br)cc1OC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Nc1ccc(Br)cc1OC(F)(F)F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 76 %

Procedure:
4-Bromo-2-(trifluoromethoxy)aniline (1.0 g, 3.9 mmol) was dissolved in dry toluene (25 mL), sodium carbonate (0.621 g, 5.86 mmol) and benzyl chloroformate (0.669 mL, 4.69 mmol) was added and the mixture stirred under nitrogen at room temperature for 22 hours. The reaction was then heated to 80° C. and stirred at this. temperature for 17 hours and then heated further to reflux and stirred for 22 hours. Water (100 mL) was added to the coiled mixture, the aqueous phase separated and washed with ethyl acetate (2×100 mL). The combined organic extracts were washed with 0.5 M aq. citric acid (70 mL), water (70 mL), brine (70 mL), dried (MgSO4), filtered and concentrated in vacuo to give a pink solid. The crude material was purified by silica gel chromatography (40 g Si cartridge, 0-20% EtOAc in 40-60° C. petroleum benzine) to give the title compound (I46) (1.153 g, 76% yield) as a white solid; 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J=8.7 Hz, 1H), 7.44-7.36 (m, 7H), 6.95 (s, 1H), 5.22 (s, 2H). LCMS Method C: rt 6.67 min; m/z 389.9 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([OH:21])[CH:14]=2)=[CH:4][C:3]=1[O:22][CH3:23].C(=O)(O)[O-].[Na+].[I-].[K+].Cl[CH2:32][CH:33]1[CH2:35][CH2:34]1>C(O)C>[CH:33]1([CH2:32][N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([OH:1])=[C:3]([O:22][CH3:23])[CH:4]=3)[CH:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([OH:21])[CH:14]=2)[CH2:35][CH2:34]1
Reactant: ClCC1CC1
Reactant: COc1ccc(CC2NCCc3cc(OC)c(O)cc32)cc1O
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(CC2c3cc(O)c(OC)cc3CCN2CC2CC2)cc1O

Procedure:
16.2 g. (48.9 mmol) (-)-7-Hydroxy-1-(3-hydroxy-4-methoxybenzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline, 8.2 g. (100 mmol) sodium bicarbonate and 500 mg. potassium iodide are dissolved in 200 ml. anhydrous ethanol and mixed with 4.5 ml. (4.44 g., 49 mmol) chloromethylcyclopropane. The reaction mixture is boiled under reflux for 40 hours in an inert gas atmosphere. The usual working up and chromatographic separation of unreacted starting material on silica gel with chloroform as elution agent gives (+)-2-cyclopropylmethyl-7-hydroxy-1-(3-hydroxy-4-methoxybenzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline; m.p. 70°-81° C. (recrystallised from methanol/diethyl ether/hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:19][CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([F:31])[CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:19][CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([F:31])[CH:22]=1)=[O:9]
Reactant: COC(=O)c1ccc(CN)cc1F
Reactant: O=C(O)c1cc(Cl)ccc1Oc1ccc(F)cc1
Product: COC(=O)c1ccc(CNC(=O)c2cc(Cl)ccc2Oc2ccc(F)cc2)cc1F

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-(4-fluorophenoxy)benzoic acid (step 2 of Example 67) and methyl 4-(aminomethyl)-2-fluorobenzoate: 1H-NMR (CDCl3) δ 8.22 (1H, d, J=2.6 Hz), 8.06–7.98 (1H, m), 7.86 (1H, t, J=7.7 Hz), 7.35 (1H, dd, J=8.9, 2.6 Hz), 7.13–6.98 (6H, m), 6.75 (1H, d, J=8.9 Hz), 4.69 (2H, d, J=5.9 Hz), 3.91 (3H, s); MS (ESI) m/z 432 (M+H)+, 430 (M−H)−.