Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[K+]>C1(C)C=CC=CC=1>[CH2:9]([O:16][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1ccccc1
Reactant: Brc1ccc(Br)nc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Brc1ccc(OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2,5-dibromopyridine (1.0 eq.), benzyl alcohol (1.3 eq.), KOH (2.4 eq.) and DB-18—C-6 (0.0 Seq.) in toluene (0.3M) was refluxed for 3 h, then stirred overnight at rt. The mixture was concentrated, poured in water and extracted with Tol (2×). The combined organic extracts were dried over MgSO4, filtered and concentrated. Recrystallization in Hex:Et2O afforded the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[CH:3]=1.[H-].[Na+].[F:10][C:11]([F:22])([F:21])[C:12]1[C:17]([C:18](Cl)=[O:19])=[CH:16][N:15]=[CH:14][CH:13]=1.C(OCC)(=O)C.CCCCCC>CN(C)C=O>[CH3:7][C:4]1[CH:3]=[C:2]([NH:1][C:18](=[O:19])[C:17]2[C:12]([C:11]([F:22])([F:10])[F:21])=[CH:13][CH:14]=[N:15][CH:16]=2)[O:6][N:5]=1
Reactant: O=C(Cl)c1cnccc1C(F)(F)F
Reactant: Cc1cc(N)on1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1cc(NC(=O)c2cnccc2C(F)(F)F)on1
Temperature: 80 °C
Yield: 44.5 %

Procedure:
5-Amino-3-methylisoxazole (147 mg, 1.5 mmol) was dissolved in dimethylformamide (5 ml), sodium hydride (60% dispersion in mineral oil, 72 mg, 1.8 mmol) was added and subsequently, 4-trifluoromethylnicotinic acid chloride (314 mg, 1.5 mmol) was added under ice-cooling. The mixture was stirred under heating at 80° C. for 2 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by thin layer chromatography (a developing solvent: ethyl acetate/hexane=1/1) to obtain the title compound (181 mg, yield 44%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1.C[O:14][CH:15](OC)[CH:16](N(CC1C=CC=C(Cl)C=1)C(=O)C)Cl>>[C:15]([N:8]1[CH:7]=[CH:6][C:5]2[C:10](=[C:11]([Cl:12])[C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:9]1)(=[O:14])[CH3:16]
Reactant: COC(OC)C(Cl)N(Cc1cccc(Cl)c1)C(C)=O
Reactant: Clc1ccc2c(c1Cl)CNCC2
Product: CC(=O)N1C=Cc2ccc(Cl)c(Cl)c2C1

Procedure:
The method of preparing 7,8-dichloro-1,2,3,4-tetrahydroisoquinoline, which comprises the steps of reacting N-acetyl-2,3-dichlorobenzylaminoacetaldehyde dimethyl acetal with a Lewis acid to form N-acetyl 7,8-dichloro-1,2-dihydroisoquinoline, catalytically hydrogenating said dihydroisoquinoline to N-acetyl-7,8-dichloro-1,2,3,4-tetrahydroisoquinoline, and hydrolyzing said tetrahydroisoquinoline to 7,8-dichloro-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:5]=2[CH:4]2[O:14][CH:3]12.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[ClH:22]>C(O)C>[ClH:22].[CH3:1][C:2]1([CH3:15])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:5]=2[C@@H:4]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C@@H:3]1[OH:14]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: C1CCNCC1
Agent: Cl
Solvent: CCO
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCCCC2)[C@@H]1O

Procedure:
Treatment of 2,2-dimethyl-3,4-epoxy-6-cyano-3,4-dihydro-2H-benzo[b]pyran (2.09 g) with piperidine (0.86 g) in refluxing ethanol (60 ml) for 24 hours followed by evaporation of solvent gave a yellow oil which was dissolved in the minimum quantity of ethanol and treated with ethereal hydrogen chloride to give crystals of trans-2,2-dimethyl-4-piperidino-6-cyano-3,4-dihydro-2H-benzo[b]pyran-3-ol hydrochloride on standing (2.06 g) of m.p. 253°-257° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:6][CH:5]=1.[CH:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CCCCCCC>[C:23]([C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:9][CH:8]=1)#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(OC(F)(F)F)cc2)cc1
Reactant: C#CCCCCC
Solvent: CCCCCCC
Product: CCCCCC#Cc1ccc(OC(F)(F)F)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-trifluoromethoxy-phenyl ester and 1-heptyne following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane; yield (100 mg, 78%); 1H NMR δ (CDCl3): 7.41 (d, J=8.55 Hz, 2H), 7.21 (d, J=8.56 Hz, 2H), 2.43 (t, J=7.21 Hz, 2H), 1.62 (p, J=7.16 Hz, 2H), 1.48-1.3 (m, 4H), 0.93 (t, J=7.22 Hz, 3H); LCMS m/z: 256.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][CH:11]([NH:14][CH2:15][CH2:16][N:17]1[CH2:22][C:21]([CH3:24])([CH3:23])[NH:20][C:19]([CH3:26])([CH3:25])[C:18]1=[O:27])[CH2:12][CH3:13].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:14]([CH:11]([CH3:10])[CH2:12][CH3:13])[CH2:15][CH2:16][N:17]2[CH2:22][C:21]([CH3:23])([CH3:24])[NH:20][C:19]([CH3:25])([CH3:26])[C:18]2=[O:27])[N:7]=1
Reactant: CCC(C)NCCN1CC(C)(C)NC(C)(C)C1=O
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCC(C)N(CCN1CC(C)(C)NC(C)(C)C1=O)c1nc(Cl)nc(Cl)n1
Reaction time: 0.5 h

Procedure:
In a 1 liter three-necked flask were placed 300 ml of water which was cooled to 1° C. 46.1 g (0.25 mole) of cyanuric chloride was dissolved in 240 ml acetone and added to the water in the flask. A white slurry formed which was stirred while adding to it dropwise, 63.9 g (0.25 mole) of 1-[2-(2-butylamino)ethyl]-3,3,5,5-tetramethyl-2-piperazinone in 60 ml acetone and 13.3 g of sodium carbonate in 60 ml water. The addition took about 30 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:24][CH:25]=[CH2:26])[C:21]([OH:27])=[C:20]([C:28]([OH:30])=[O:29])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[H][H]>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:24][CH2:25][CH3:26])[C:21]([OH:27])=[C:20]([C:28]([OH:30])=[O:29])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: [H][H]
Reactant: C=CCc1cc(-c2csc(-c3ccc(OCC)c(OCC)c3)n2)cc(C(=O)O)c1O
Solvent: CO
Product: CCCc1cc(-c2csc(-c3ccc(OCC)c(OCC)c3)n2)cc(C(=O)O)c1O
Yield: 76.8 %

Procedure:
A catalytic amount of 5% Pd--C was added to a solution of 250 mg of 2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-hydroxy-5-allylphenyl)thiazole in 10 ml of methanol. The mixture was stirred in a hydrogen atmosphere at room temperature for 6 hours. After the completion of a reaction, the reaction mixture was filtered. The filtrate was concentrated. The residue was recrystallized from ethanol to obtain 193 mg of 2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-hydroxy-5-propylphenyl)thiazole.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:18])[C:3]=1[C@H:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21].C(O[C:29]([CH3:32])([CH3:31])[CH3:30])(=O)C.Cl(O)(=O)(=O)=O>C(Cl)Cl>[C:29]([O:24][C@@H:19]([C:3]1[C:4]([CH3:18])=[N:5][C:6]2[N:7]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[CH:10]=2)[C:2]=1[Cl:1])[C:20]([O:22][CH3:23])=[O:21])([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1Cl
Reactant: CC(=O)OC(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
To a solution of (S)-methyl 2-(7-chloro-2-(3-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (1.0 g, 2.73 mmol) in CH2Cl2 (100 mL) at room temperature was added tert-butyl acetate (20 mL) followed by perchloric acid (0.282 mL, 3.28 mmol). The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was quenched with water and diluted with ethyl acetate. The organic phase was washed with saturated NaHCO3 and dried over sodium sulfate. The solvent was evaporated. Purification by silica gel chromatography provided the title compound (520 mg, 50%). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.07-8.00 (m, 1H), 7.89 (dt, J=6.7, 1.9 Hz, 1H), 7.48-7.37 (m, 2H), 6.93 (s, 1H), 5.68 (s, 1H), 3.75 (s, 3H), 2.69 (s, 3H), 1.29 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:14]([C:16]3[C:17]([O:35][CH2:36][CH3:37])=[C:18]([CH:24]4[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)[C:19]([F:23])=[C:20]([Cl:22])[CH:21]=3)[CH3:15])[N:9]=[C:10]([CH:11]([F:13])[F:12])[C:3]=12.[ClH:38].O1CCOCC1>ClCCl>[ClH:22].[ClH:38].[NH:26]1[CH2:27][CH:24]([C:18]2[C:17]([O:35][CH2:36][CH3:37])=[C:16]([CH:14]([N:8]3[C:4]4=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]4[C:10]([CH:11]([F:13])[F:12])=[N:9]3)[CH3:15])[CH:21]=[C:20]([Cl:22])[C:19]=2[F:23])[CH2:25]1
Reactant: CCOc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 3-(3-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-fluorophenyl)azetidine-1-carboxylate (0.64 g, 1.2 mmol) in dichloromethane (5 mL) was added 4.0 M hydrogen chloride in dioxane (2.4 mL, 9.5 mmol). The reaction solution was stirred at room temperature for 6 h. The solvent was removed to give the desired product as a white solid (0.61 g, 100%). LCMS calculated for C19H21ClF3N6O (M+H)+: m/z=441.1; Found:441.1.
Reaction SMILES: [BrH:1].[C:2]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C>[Br:1][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br
Reactant: OCCCCCc1ccccc1
Solvent: CCOC(C)=O
Product: BrCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 416.7 ml (1.83 mol) 48% strength hydrobromic acid is mixed with 50 g (0.304 mol) of 5-phenylpentan-1-ol at 0° C. and stirred at 0° C. for 30 min. The reaction solution is then stirred at 100° C. for 12 hours. After reaction is complete, the mixture is cooled to room temperature and 200 ml of ethyl acetate are added. After extraction, the organic phase is separated off, washed with saturated sodium bicarbonate solution and dried over sodium sulfate. After filtration, the filtrate is is concentrated to dryness. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane). 59.4 g (0.26 mol, 86% of theory) of a colorless liquid are obtained.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9](=[O:18])[C:8]2=[CH:19][CH:20]=[CH:21][N:7]2[N:6]=1)[CH2:3][CH3:4].[C:22]([O:26][C:27](=[O:33])[NH:28][CH2:29][CH2:30][CH:31]=O)([CH3:25])([CH3:24])[CH3:23].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[C:22]([O:26][C:27](=[O:33])[NH:28][CH2:29][CH2:30][CH2:31][NH:1][CH:2]([C:5]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:9](=[O:18])[C:8]2=[CH:19][CH:20]=[CH:21][N:7]2[N:6]=1)[CH2:3][CH3:4])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCC(N)c1nn2cccc2c(=O)n1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CCC(NCCCNC(=O)OC(C)(C)C)c1nn2cccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
2-(1-Amino-propyl)-3-benzyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 26, 300 mg, 0.94 mmol) and (3-oxo-propyl)-carbamic acid tert-butyl ester (J. Med. Chem. 1985, 28, 317–323, 982 mg, 5.64 mmol) were dissolved in CH3OH (20 mL) and stirred for 1 h at 25° C. The mixture was then treated with NaBH(OAc)3 (1.19 g, 5.64 mmol) and stirred for 18 h. The reaction mixture was concentrated under vacuum and purified by preparative HPLC using a YMC S10 ODS 30×250 mm column affording the desired compound (300 mg, 73%) as a colorless film: 13C NMR (CD3OD, 100 MHz) δ 160.8, 160.49, 154.89, 144.86, 136.06, 129.09, 128.04, 126.52, 121.79, 117.72, 115.16, 111.60, 109.53, 79.20, 57.97, 44.32, 27.38, 26.55, 25.5, 7.58; LC/MS (ESI+) 440 (M++H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([NH:13][CH2:14][C:15]3[C:16]([OH:23])=[N:17][C:18]([CH3:22])=[CH:19][C:20]=3[CH3:21])=[O:12])=[C:9]([CH3:24])[N:8]([C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[C:6]=2[N:7]=1>CO.[C].[Pd]>[OH:23][C:16]1[C:15]([CH2:14][NH:13][C:11]([C:10]2[C:5]3[CH:4]=[N:3][CH:2]=[N:7][C:6]=3[N:8]([C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[C:9]=2[CH3:24])=[O:12])=[C:20]([CH3:21])[CH:19]=[C:18]([CH3:22])[N:17]=1
Reactant: Cc1cc(C)c(CNC(=O)c2c(C)n([C@H](C)c3ccccc3)c3nc(Cl)ncc23)c(O)n1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2c(C)n([C@H](C)c3ccccc3)c3ncncc23)c(O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.6 %

Procedure:
To a solution of (R)-2-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (140 mg, 0.30 mmol) in MeOH (10 mL). Palladium-carbon catalyst (10%, 20 mg) was added, the mixture solution was stirred at 25° C. for 12 hours under hydrogen atmosphere (4 bar). The mixture was filtered and concentrated in vacuo and purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to afford (R)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (93 mg, 72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](OB(O)O)=[CH:5][CH:4]=1.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]3[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30](OS(C(F)(F)F)(=O)=O)[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[O:23]3)=[CH:21][C:16]=2[O:15][CH2:14]1>>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]3[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[O:23]3)=[CH:21][C:16]=2[O:15][CH2:14]1
Reactant: COc1ccc(OB(O)O)cc1
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)c2ccccc2OC1c1ccc2c(c1)OCO2
Product: COC(=O)C1=C(c2ccc(OC)cc2)c2ccccc2OC1c1ccc2c(c1)OCO2

Procedure:
4-Methoxyphenyl boric acid and methyl 2-(benzo[1,3]dioxol-5-yl)-4-(trifluoromethanesulfonyloxy)-2H-chromen-3-carboxylate (III-5) synthesized from the compound (II-3) by a similar method as described in Reference Example 2 were reacted in a similar manner as described in Example 18 to give methyl 2-(benzo[1,3]dioxol-5-yl)-4-(4-methoxy-phenyl)-2H-chromen-3-carboxylate (Ia-4).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N:26]4[C:34]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[C:28]5[CH:35]=[N:36][CH:37]=[CH:38][C:27]4=5)[N:21]=3)[CH:9]=2)=[CH:4][CH:3]=1.[C:39]1(B(O)O)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(Cl)(Cl)Cl.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(O)C>[C:2]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N:26]4[C:34]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[C:28]5[CH:35]=[N:36][CH:37]=[CH:38][C:27]4=5)[N:21]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(-n4c5ccccc5c5cnccc54)n3)c2)cc1
Reactant: OB(O)c1ccccc1
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: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc(-c3cc(-c4ccccn4)nc(-c4cccc(-n5c6ccccc6c6cnccc65)n4)c3)cc2)cc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 58.3 %

Procedure:
To 5.1 g of the resulting 4′-(4-bromophenyl)-6-(5H-pyrido[4,3-b]indol-5-yl)-[2,2′;6′,2″]terpyridine were added 1.1 g of phenylboronic acid, 0.5 g of tetrakis(triphenylphosphine)palladium, 23 mL of a 2 M aqueous potassium carbonate solution, 72 mL of toluene, and 18 mL of ethanol, followed by heating with reflux while stirring for 5.5 hours. After cooling to room temperature, a precipitate was collected by filtration. To the precipitate, 200 mL of chloroform was added and insoluble matter was removed by filtration. The filtrate was concentrated under a reduced pressure to obtain a concentrate. The concentrate was dissolved in chloroform and subjected to adsorptive purification with NH silica gel. Thereafter, the filtrate was concentrated under a reduced pressure to obtain a crude product. The crude product was washed with methanol to obtain 2.9 g (yield, 57%) of 4′-(biphenyl-4-yl)-6-(5H-pyrido[4,3-b]indol-5-yl)-[2,2′;6′,2″]terpyridine (Compound 133) as a white powder.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]#[C:17][C:18]3[CH:19]=[CH:20][C:21]([O:28][CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[C:22]([CH:27]=3)[C:23]([O:25]C)=[O:24])=[N:14][CH:15]=2)=[CH:6][CH:5]=1.Cl>CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]#[C:17][C:18]3[CH:19]=[CH:20][C:21]([O:28][CH2:29][CH2:30][N:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)=[C:22]([CH:27]=3)[C:23]([OH:25])=[O:24])=[N:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Temperature: 70 °C

Procedure:
1.6 mL aqueous 1 M NaOH are added to a solution of 369 mg (0.8 mmol) methyl 5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-benzoate (Example 3.4) in 20 mL MeOH and the reaction mixture is heated to 70° C. for 3 h. It is combined with 1.6 mL 1 M HCl, evaporated down i.vac. and the residue is coevaporated twice with in each case 20 mL MeOH. The residue is triturated with EtOH with heating and suction filtered.
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[NH+:8]([O-:13])[C:7]([CH3:15])([CH3:14])[CH2:6]1)[CH2:2][CH3:3].[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C1(C)C=CC=CC=1.O.[Pt]>[CH3:18][C:17]([CH3:20])([CH3:19])[C:16]([O:13][N:8]1[C:7]([CH3:14])([CH3:15])[CH2:6][CH:5]([O:4][CH2:1][CH2:2][CH3:3])[CH2:10][C:9]1([CH3:12])[CH3:11])=[O:21]
Reactant: CCCOC1CC(C)(C)[NH+]([O-])C(C)(C)C1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Pt]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCOC1CC(C)(C)N(OC(=O)C(C)(C)C)C(C)(C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
21.4 g (0.1 mol) of 4-propoxy-2,2,6,6-tetramethylpiperidine N-oxide (for preparation, see DE-A4 219 459) are hydrogenated to saturation at 4 bar in 20 ml of toluene using 0.05 g of platinum (10% on carbon). The catalyst is filtered off and 13 g (0.108 mol) of pivaloyl chloride are slowly added dropwise to the colourless filtrate under nitrogen. After the slightly exothermic reaction has abated, the mixture is stirred for another 1 hour at room temperature and diluted with 20 ml of water. The organic phase is washed with 4% NaOH solution, dried over MgSO4 and freed of the toluene on a rotary evaporator. This gives 13.5 g (45%) of the compound 110 which is in the form of a colourless oil.
Reaction SMILES: [BrH:1].CC1C=CC=CC=1O[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[CH:22][CH3:23])[C:18]([O:20][CH3:21])=[O:19]>C(Cl)Cl.C1CCCCC1>[Br:1][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[CH:22][CH3:23])[C:18]([O:20][CH3:21])=[O:19]
Reactant: CC=C(C(=O)OC)c1ccccc1COc1ccccc1C
Reactant: Br
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC=C(C(=O)OC)c1ccccc1CBr

Procedure:
Hydrogen bromide was passed at -5° C. into a solution of 14.8 g of methyl α-[2-(2-methylphenyloxymethyl)phenyl]but-2-enoate in 250 ml of methylene chloride until it was saturated (about 18 g of HBr). After termination of the reaction (about 2 h at 25° C.), the solvent was distilled off under reduced pressure. The residue thus obtained was taken up in 300 ml of cyclohexane. The solution was washed with 5% strength sodium hydroxide solution and then with water. After drying and concentrating the organic phase, 8 g of the title compound were obtained (m.p.: 64°-66° C.).
Reaction SMILES: C(N(CCCC)CCCC)CCC.[F:14][C:15]([F:27])([F:26])[CH:16]([C:22]([F:25])([F:24])[F:23])[C:17](OCCl)=O>>[F:14][C:15]([F:27])([F:26])[C:16]([C:22]([F:25])([F:24])[F:23])=[CH2:17]
Reactant: O=C(OCCl)C(C(F)(F)F)C(F)(F)F
Solvent: CCCCN(CCCC)CCCC
Product: C=C(C(F)(F)F)C(F)(F)F
Temperature: 65 °C
Yield: 75.9 %

Procedure:
In a four necked 100 ml flask equipped with a condenser, a dropping funnel and a thermometer, tributylamine (20.0 g, 108 mmoles) was charged and warmed to 65° C. Monochloromethyl 2-trifluoromethyl-3,3,3-trifluoropropanoate (4.88 g, 20 mmol) was dropwise added thereto while stirring. The reaction was continued at the same temperature as above for 3 hours while stirring. The gas evolved from a top of the condenser was washed with an alkaline solution, dried with alumina and cooled. The resultant liquid was distilled to give 2-trifluoromethyl-3,3,3-trifluoropropene (2.49 g). Yield, 76 %.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:28]([N+:29]([O-])=O)=[CH:27][C:7]([C:8]([N:10]([CH:24]([CH3:26])[CH3:25])[C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)=[O:9])=[C:6]([C:32]([F:35])([F:34])[F:33])[CH:5]=1)[CH3:2]>O1CCCC1.[C].[Pd]>[NH2:29][C:28]1[C:4]([NH:3][CH2:1][CH3:2])=[CH:5][C:6]([C:32]([F:33])([F:34])[F:35])=[C:7]([CH:27]=1)[C:8]([N:10]([CH:24]([CH3:25])[CH3:26])[C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:12]1)=[O:9]
Reactant: CCNc1cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCNc1cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)cc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.9 %

Procedure:
To a solution of tert-butyl (3R)-3-[[4-(ethylamino)-5-nitro-2-(trifluoromethyl)benzoyl]-(isopropyl)amino]piperidine-1-carboxylate (610 mg) in tetrahydrofuran (10 ml) was added 10% palladium-carbon (600 mg, 50% wet.), and the mixture was stirred at room temperature under hydrogen atmosphere for 3 hours. The reaction solution was filtered on celite, washed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure to give the title compound (550 mg).
Reaction SMILES: [CH3:1][SH:2].C(N(CC)CC)C.[NH2:10][C:11]1[C:16]([C:17]#[N:18])=[N:15][C:14]([Cl:19])=[C:13](Cl)[N:12]=1>CN(C)C=O>[NH2:10][C:11]1[C:16]([C:17]#[N:18])=[N:15][C:14]([Cl:19])=[C:13]([S:2][CH3:1])[N:12]=1
Reactant: N#Cc1nc(Cl)c(Cl)nc1N
Reactant: CS
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1nc(N)c(C#N)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In dimethylformamide (1.5 ml) there was dissolved 2-amino-3-cyano-5,6-dichloropyrazine (200 mmg, 1 mM) and then cooled in an ice bath. Through the solution there was then bubbled methanethiol gas for 5-10 minutes. The reaction mixture was then stirred overnight at room temperature. Triethylamine (0.14 ml) was added, followed by stirring at room temperature for 1 hour. The reaction mixture was then placed under a nitrogen atmosphere to remove solvent and excess methanethiol. The product was passed through a silica gel column, eluting with dichloromethane. The product was recrystallized from hexane/ether (139 mg). Elemental Analysis for C6H5N4ClS: :