Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:24])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[C:8]([N+:25]([O-])=O)[CH:7]=1>[Pd].CCO>[NH2:25][C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH2:3][CH:2]([CH3:28])[CH3:1])[CH:11]=[CH:10][C:9]=1[NH:12][C:13](=[O:24])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1
Reactant: COc1cccc(OCC(=O)Nc2ccc(OCCC(C)C)cc2[N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(OCC(=O)Nc2ccc(OCCC(C)C)cc2N)c1
Yield: 94 %

Procedure:
A 350 mL hydrogenation vessel was charge with nitroarene 48b (15.0 g, 38.6 mmol) and EtOH (150 mL). To the resultant suspension was added 10% Pd/C (1.4 g). The mixture was hydrogenated on a Parr shaker at 58 psi overnight. The reduction was incomplete as analyzed by HPLC and contained a large amount of ppt mixed with the catalyst. The catalyst was filtered on glass fiber paper and rinsed with EtOAc (100 mL). The filtrate was concentrated in vacuo to a yellow solid and taken up in EtOAc (150 mL). To the resultant solution was added 10% Pd/C (0.5 g). The mixture was further hydrogenated at 55 psi overnight. The catalyst was filtered off on glass fiber paper and rinsed with EtOAc (75 mL). The filtrate was concentrated in vacuo to give 13.0 g of 49b as an off-white solid (98%). 1H NMR (300 MHz, CDCl3): δ 7.99 (s, 1H), 7.32-7.23 (m, 1H), 7.10 (d, 1H), 6.67-6.55 (m, 3H), 6.43-6.35 (m, 2H), 4.65 (s, 2H), 3.96 (t, 2H), 3.83 (s, 3H), 3.83 (bs, 2H), 1.83 (nonet, 1H), 1.67 (qt, 2H), 0.96 (d, 6H) ppm. HPLC analysis (10:10:80 H2O:A1:MeOH) showed a purity of 98% with a retention time of 4.8 min.
Reaction SMILES: O[C:2](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5]CC)=[O:4].[OH-].[K+].S([O:27][CH2:28][C:29]1([CH2:33][CH3:34])[CH2:32][O:31][CH2:30]1)(C1C=CC(C)=CC=1)(=O)=O>C(O)C>[CH2:33]([C:29]1([CH2:28][O:27][C:12]2[CH:11]=[CH:10][C:9]([CH:8]=[CH:2][C:3]([OH:5])=[O:4])=[CH:14][CH:13]=2)[CH2:32][O:31][CH2:30]1)[CH3:34]
Reactant: CCOC(=O)C(O)=Cc1ccccc1
Reactant: CCC1(COS(=O)(=O)c2ccc(C)cc2)COC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCC1(COc2ccc(C=CC(=O)O)cc2)COC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 19.3 %

Procedure:
19 g of ethyl hydroxycinnamate and 7.3 g of potassium hydroxide were added to 150 ml of ethanol, and stirred at 50° C. for 1 hour. This was cooled to 40° C., and 35 g of 3-[(tosyloxy)methyl]-3-ethyloxetane was dropwise added to it. Then, this was refluxed for 3 hours. Ethanol was evaporated away, and water and toluene were added to it for liquid-liquid separation. The toluene layer was washed with 3% hydrochloric acid, saturated sodium hydrogencarbonate and water, and then toluene was evaporated away. To the resulting residue, added were 20 g of sodium hydroxide, 100 ml of ethanol and 50 ml of water, and this was refluxed for 2 hours. Ethanol was evaporated away, and the resulting residue was poured into 500 ml of 5% hydrochloric acid, and a crystal was thus formed. The crystal taken out through filtration was recrystallized from a mixed solvent of ethanol and water, and 5 g of 4-(3-ethyloxetan-3-ylmethoxy)cinnamic acid (OX6) was obtained. Its melting point was 127.5° C.
Reaction SMILES: B(Br)(Br)Br.[CH3:5][NH:6][S:7]([C:10]1[S:11][C:12]2[CH:18]=[C:17]([O:19]CC)[CH:16]=[CH:15][C:13]=2[N:14]=1)(=[O:9])=[O:8].C(=O)=O>C(Cl)Cl>[OH:19][C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:10]([S:7]([NH:6][CH3:5])(=[O:8])=[O:9])[S:11][C:12]=2[CH:18]=1
Reactant: CCOc1ccc2nc(S(=O)(=O)NC)sc2c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Product: CNS(=O)(=O)c1nc2ccc(O)cc2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
A one molar solution of boron tribromide in CH2Cl2 (21 mL) was cooled to -76° C. in a dry ice/acetone bath. N-Methyl-6-ethoxy-2-benzothiazole-sulfonamide (1, og.; 0.0037 mol) was added and the reaction stirred in the dry ice bath for four hours. The reaction was removed, stirred at room temperature for 18 hours, poured into a mixture of 25 mL of crushed ice/25 mL water and stirred for 30 minutes. The crude material was collected and purified by dissolving in 10% Na2CO3, filtered, anc precipitated with dilute acetic acid (1:1) to give 0.75g (83.0% yield) of pure product, m.p. 189°-190° C.; NMR(DMSO-d ) delta 8.5-8.0(m, 3H); 7.6(d, lH); 7.4-7.2 (q, lH).
Reaction SMILES: [Cl:1][C:2]([F:6])=[C:3]([F:5])[F:4].[Cl:7][C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[N:12][C:13]=1[Cl:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][CH:2]([F:6])[C:3]([F:5])([F:4])[O:15][C:10]1[CH:11]=[N:12][C:13]([Cl:14])=[C:8]([Cl:7])[CH:9]=1
Reactant: FC(F)=C(F)Cl
Reactant: Oc1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(Cl)C(F)(F)Oc1cnc(Cl)c(Cl)c1

Procedure:
Chlorotrifluoroethylene was passed into a mixture of 16.4 g (0.1 mol) of 5,6-dichloro-3-pyridinol I/29 and 20 g (0.145 mol) of anhydrous potassium carbonate in 100 ml of absolute acetonitrile at 35° C. until starting material was no longer present. The solid was filtered off under suction, the solvent was removed by distillation, and the residue was taken up in ether and washed until neutral. After drying over MgSO4 and removal of the ether by distillation, the residue was distilled in a high vacuum.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([CH3:20])[C:10]=1[CH:21]([OH:26])[C:22]([O:24][CH3:25])=[O:23].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.I[CH2:38][CH3:39]>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([CH3:20])[C:10]=1[CH:21]([O:26][CH2:38][CH3:39])[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C(O)c1c(-c2ccc(C)cc2C)c2ccccc2c(=O)n1C
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(C(=O)OC)c1c(-c2ccc(C)cc2C)c2ccccc2c(=O)n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 2-(4-(2,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-2-hydroxyacetate (50 mg, 0.142 mmol) in Tetrahydrofuran (THF) (1 mL) was treated with LiHMDS (0.213 mL, 0.213 mmol) and iodoethane (0.069 mL, 0.854 mmol) at 0° C. The mixture was stirred at room temperature for 1 hour and then quenched with saturated NH4Cl solution. The mixture was extracted with ethyl acetate, washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated. The residue was used crude in the next step without further purification (44 mg, 82%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.47-8.55 (m, 1 H) 7.46-7.55 (m, 2 H) 7.06-7.21 (m, 3 H) 6.85-6.96 (m, 1 H) 4.87-4.98 (m, 1 H) 3.65-3.68 (m, 2 H) 3.66 (s, 3 H) 2.86-3.00 (m, 3 H) 2.42 (s, 3 H) 2.02 (s, 3 H) 1.10-1.24 (m, 3 H). LC/MS (m/z) ES+=380 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]2[CH:8]3[CH2:14][CH2:13][CH:12]([CH:15]=[CH:16][CH3:17])[CH2:11][CH:9]3[O:10][C:6]=2[C:5]=1[F:20])[CH3:2].[H][H]>C1COCC1.[Pd]>[CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]2[CH:8]3[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH:9]3[O:10][C:6]=2[C:5]=1[F:20])[CH3:2]
Reactant: [H][H]
Reactant: CC=CC1CCC2c3ccc(OCC)c(F)c3OC2C1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCC1CCC2c3ccc(OCC)c(F)c3OC2C1

Procedure:
3.50 g (12.7 mmol) of (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-3-propenyl-1,2,3,4,4a,9b-hexahydrodibenzofuran in THF are hydrogenated for 23 h in a hydrogen atmosphere with addition of 1.8 g of Pd/C. After completion of the uptake of hydrogen, the reaction solution is filtered and concentrated to dryness. The residue is filtered adsorptively (SiO2, toluene:n-heptane=1:1), and the beige solid obtained is recrystallised repeatedly from isopropanol at room temperature, giving (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-3-propyl-1,2,3,4,4a,9b-hexahydrodibenzofuran as colourless solid (melting point 128° C.).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][CH2:17]3)=[CH:12][N:11]=2)=[CH:5][C:4]([C:26]2[C:31]([CH:32]=[O:33])=[C:30]([N:34]3[CH2:46][CH2:45][C:44]4[N:43]5[C:38]([CH2:39][CH2:40][CH2:41][CH2:42]5)=[CH:37][C:36]=4[C:35]3=[O:47])[N:29]=[CH:28][CH:27]=2)=[CH:3]1.[BH4-].[Na+]>CO>[OH:33][CH2:32][C:31]1[C:30]([N:34]2[CH2:46][CH2:45][C:44]3[N:43]4[C:38]([CH2:39][CH2:40][CH2:41][CH2:42]4)=[CH:37][C:36]=3[C:35]2=[O:47])=[N:29][CH:28]=[CH:27][C:26]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:17][CH2:18][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:20][CH2:21]3)=[CH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: Cn1cc(-c2ccnc(N3CCc4c(cc5n4CCCC5)C3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2ccnc(N3CCc4c(cc5n4CCCC5)C3=O)c2CO)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A mixture of 139b (95 mg, 0.15 mmol), NaBH4 (17 mg, 0.45), and CH3OH (10 mL) was stirred at 25° C. for 1 h. The mixture was extracted with CH2Cl2 (10 mL×2). The combined CH2Cl2 extract was concentrated under reduced pressure. The residue was purified with reverse-phase prep-HPLC to afford 139 (60 mg, 63%). LCMS: [M+H]+ 637. 1H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J=2.0, 1H), 8.47 (d, J=5.5, 1H), 8.42 (s, 1H), 7.85 (d, J=2.5, 1H), 7.49 (d, J=2.0, 1H), 7.37-7.39 (m, 1H), 7.30 (d, J=5.0, 1H), 7.24 (d, J=9.0, 1H), 6.05 (s, 1H), 4.47-4.57 (m, 2H), 4.41-4.47 (m, 2H), 4.39-4.41 (m, 1H), 4.33-4.35 (m, 1H), 4.11-4.16 (m, 1H), 3.93-3.96 (m, 1H), 3.76-3.82 (m, 2H), 3.59 (s, 3H), 3.41-3.45 (m, 2H), 3.06-3.08 (m, 4H), 2.98-3.01 (m, 1H), 2.92-2.95 (m, 1H), 2.71-2.72 (m, 2H), 2.36-2.39 (m, 4H), 1.91-1.93 (m, 2H), 1.72-1.78 (m, 2H)
Reaction SMILES: [Si:1]([O:18][CH2:19][CH:20]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:21][CH:22]=[CH2:23])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:41](Br)[CH:42]=[CH2:43]>CN(C=O)C.O>[CH2:43]([N:24]([CH:20]([CH2:21][CH:22]=[CH2:23])[CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[S:25]([C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1)(=[O:27])=[O:26])[CH:42]=[CH2:41]
Reactant: C=CCBr
Reactant: C=CCC(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCC(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N(CC=C)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
To a solution of N-(1-((tert-butyldiphenylsilyl)oxy)pent-4-en-2-yl)-4-methylbenzenesulfonamide (D9) (13 g, 26.33 mmol) in DMF (80 ml), Cs2CO3 (12.86 g, 39.49 mmol) and allyl bromide (1.8 ml, 21.06 mmol) were added and the mixture was stirred at RT for 4 hrs. The reaction mixture was diluted with water (40 ml) and extracted with EtOAc (3×60 ml). The combined organic phases were evaporated and the resulting residue was was purified by Biotage SNAP-Si (100 g) cartridge eluting with a mixture cycloexane/EtOAc from 100/0 to 90/10. Collected fractions after solvent evaporation afforded the title compound (D10) (10.7 g).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:11][C:12]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([N+]([O-])=O)[CH:16]=1>O1CCCC1>[CH2:1]([S:8][C:17]1[CH:16]=[C:15]([O:14][C:13]2[CH:27]=[CH:28][C:29]([C:31]([F:34])([F:32])[F:33])=[CH:30][C:12]=2[Cl:11])[CH:20]=[CH:19][C:18]=1[N+:21]([O-:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1SCc1ccccc1

Procedure:
1.7 g of benzyl mercaptan was dissolved in dry tetrahydrofuran and 0.5 g of sodium hydride added with stirring under dry nitrogen. The reaction mixture was stirred under reflux for 30 minutes, and a solution of 5 g of 1A dissolved in 25 ml of dry tetrahydrofuran was added dropwise. Reaction occurred rapidly, and the product was chromatographically purified to give 2-benzylthio-4-(2-chloro-4-trifluoromethylphenoxy)nitrobenzene (1B) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([N:15]([CH:25]3[CH2:27][CH2:26]3)CC3C=CC(OC)=CC=3)[C:12]3=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:11]3[N:10]=2)=[CH:6][C:5]([C:33]#[N:34])=[CH:4][C:3]=1[N:35]1[CH2:40][CH2:39][O:38][CH:37]([CH2:41][N:42](CC2C=CC(OC)=CC=2)[S:43]([CH3:46])(=[O:45])=[O:44])[CH2:36]1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH:25]3[CH2:26][CH2:27]3)[C:12]3=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:11]3[N:10]=2)=[CH:6][C:5]([C:33]#[N:34])=[CH:4][C:3]=1[N:35]1[CH2:40][CH2:39][O:38][CH:37]([CH2:41][NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH2:36]1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCOC(CN(Cc5ccc(OC)cc5)S(C)(=O)=O)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)NCC1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CCO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 13.1 %

Procedure:
To a round bottom flask charged with (+/−)-N-((4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)morpholin-2-yl)methyl)-N-(4-methoxybenzyl)methanesulfonamide (43.1 mg, 0.055 mmol) in dichloromethane (220 μl) was added anisole (30.0 μl, 0.275 mmol), followed by trifluoroacetic acid (169 μl, 2.200 mmol). The reaction mixture was stirred at room temperature ON. Excess TFA was removed by concentration in vacuo. The crude residue was taken up in methanol and free based on a 1 g Phenomenex Strata SCX column. The column was flushed with 3 column volumes MeOH and 1 column volume 7 N NH3/MeOH. The ammonia containing fraction was concentrated in vacuo. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 10-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. (+/−)-N-((4-(2-Chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)morpholin-2-yl)methyl)methanesulfonamide (3.9 mg) was isolated.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([CH:17]=O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.CCCCCC.[C:25]([O:28][CH2:29][CH3:30])(=[O:27])[CH3:26]>O1CCCC1>[CH2:29]([O:28][C:25](=[O:27])[CH:26]=[CH:17][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH3:30]
Reactant: O=Cc1cccc2ccccc12
Reactant: CCOC(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1cccc2ccccc12
Reaction time: 8 h
Yield: 90 %

Procedure:
22.4 g(0.10 mol) of triethylphosphonoacetate was dissolved in 500 ml of tetrahydrofuran and 12.4 g(1.1 mol) of potassium t-butoxide was slowly added thereto. To this solution was slowly added 15.6 g(0.10 mol) of 1-naphthaldehyde dissolved in 20 ml of tetrahydrofuran, then the resulting solution was stirred for 8 hours. The organic solvent was eliminated by distillation under reduced pressure, and the residue was dissolved in ethyl acetate, washed twice with water, dried over magnesium sulfate and concentrated. The concentrate was subjected to silica gel column chromatography(eluent: n-hexane/ethyl acetate=95/5, v/v) to obtain 20.3 g(0.090 mol, Yield 90%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=2[C:16]2[C:17]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([CH3:33])=[C:22]([C:34](O)=[O:35])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:3][CH2:2]1.[NH2:37][C@H:38]1[CH2:43][CH2:42][C@H:41]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:40][CH2:39]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:15])[F:14])=[CH:8][C:7]=2[C:16]2[C:17]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([CH3:33])=[C:22]([C:34]([NH:37][C@H:38]4[CH2:43][CH2:42][C@H:41]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:49])([CH3:48])[CH3:50])[CH2:40][CH2:39]4)=[O:35])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3cc(C(F)(F)F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c2ncnc(-c3cc(C(F)(F)F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c8) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as colorless foam.
Reaction SMILES: [F:1][C:2]([F:25])([C:21]([F:24])([F:23])[F:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]OS(C1C=CC(C)=CC=1)(=O)=O.[CH3:26][NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C@H:33]1[CH2:50][C@@:48]2([CH3:49])[C@@H:44]([CH2:45][CH2:46][C@@H:47]2[OH:51])[C@@:43]2([CH:52]=[CH2:53])[C@H:34]1[C:35]1[CH:36]=[CH:37][C:38]([OH:54])=[CH:39][C:40]=1[CH2:41][CH2:42]2>>[CH3:26][N:27]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:25])[C:21]([F:22])([F:23])[F:24])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C@H:33]1[CH2:50][C@@:48]2([CH3:49])[C@@H:44]([CH2:45][CH2:46][C@@H:47]2[OH:51])[C@@:43]2([CH:52]=[CH2:53])[C@H:34]1[C:35]1[CH:36]=[CH:37][C:38]([OH:54])=[CH:39][C:40]=1[CH2:41][CH2:42]2
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCCC(F)(F)C(F)(F)F)cc1
Reactant: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCNC)C[C@@]1(C)[C@H]2CC[C@@H]1O
Product: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCN(C)CCCCCCCC(F)(F)C(F)(F)F)C[C@@]1(C)[C@H]2CC[C@@H]1O

Procedure:
In the reaction with 8,8,9,9,9-pentafluorononyltosylate analogously to instructions 22.1, 32 mg of amine 31a yields 16 mg of amine 36a as colorless crystals (GC-MS: m/z theor.: 613, pract.: 613).
Reaction SMILES: Cl.[F:2][C:3]([F:28])([F:27])[C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[CH:6]([O:18][CH:19]1[CH2:22][NH:21][CH2:20]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1.[N-:29]=[C:30]=[O:31]>>[F:28][C:3]([F:27])([F:2])[C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[CH:6]([O:18][CH:19]1[CH2:22][N:21]([C:30]([NH:29][CH:4]([CH2:5][CH3:6])[CH3:3])=[O:31])[CH2:20]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1
Reactant: FC(F)(F)Oc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Reactant: [N-]=C=O
Agent: Cl
Product: CCC(C)NC(=O)N1CC(OC(c2ccc(OC(F)(F)F)cc2)c2ccccc2C(F)(F)F)C1

Procedure:
This material was prepared from 3-[2-(trifluoromethyl)-4′-(trifluoro-methoxy)benzyloxy]azetidine hydrochloride (141) and the corresponding isocyanate using the procedure described for compound (10).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][N:4]2[N:8]=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=[C:3]12.[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][N:16]=1>>[Cl:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([CH:7]2[CH2:6][CH2:5][N:4]3[N:8]=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=[C:3]3[C:2]2=[O:1])=[O:20])=[CH:22][CH:23]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: O=C(O)c1cc2n(n1)CCCC2=O
Product: O=C(O)c1cc2n(n1)CCC(C(=O)c1ccc(Cl)nc1)C2=O

Procedure:
A-07 is prepared using general procedure A2 starting from 4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridine-2-carboxylic acid (5.00 g, 27.8 mmol) and 6-chloro-nicotinoyl chloride (7.33 g, 41.6 mmol). Yield: 7.37 g. HPLC-MS: Rt=1.94 min, (M+H)+=320/322.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([F:21])[C:18](Cl)=[N:19][C:12]=2[N:11]([CH2:22][CH3:23])[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>ClCCl>[CH2:1]([O:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([F:21])[C:18]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)=[N:19][C:12]=2[N:11]([CH2:22][CH3:23])[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(Cl)nc21
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCN(C)CC3)nc21
Yield: 84.6 %

Procedure:
Following the procedure of Example X-2, the reaction of 3-benzyloxy-7-chloro-1-ethyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example N-2, 200 mg, 0.572 mmol) with 4-methylpiperazine (0.152 mL, 1.37 mmol) in dichloromethane (3 mL) afforded 200 mg of the title compound as a solid, mp 178-179° C.
Reaction SMILES: [CH2:1]([CH2:7][C@@H:8]([SH:12])[CH2:9][CH2:10][SH:11])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].O.[OH-].[Na+].OS(O)(=O)=O>C1(C)C=CC=CC=1>[CH2:9]1[C@@H:8]([CH2:7][CH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])[S:12][S:11][CH2:10]1
Reactant: O=C(O)CCCC[C@@H](S)CCS
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)CCCC[C@@H]1CCSS1

Procedure:
125.5 g of the dihydrolipoic acid solution are stirred in 5 l of completely deionized water in a 10 l round-bottomed flask, and the solution is adjusted to pH 8.5 using dilute sodium hydroxide solution and treated with catalytic amounts of Fe(III) sulfate solution. Air is introduced until the color lightens. After addition of 600 ml of toluene, the mixture is adjusted to pH 2 using H2SO4. The phases are separated and the water phase is extracted once with toluene. The combined toluene phases are concentrated to about 25% of the volume. The residue is treated with 600 ml of heptane, stirred under nitrogen and then forced through a filter loaded with silica gel. The filter is washed with toluene/heptane mixture.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=1>O>[Cl:14][C:13]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1CNCCN1
Reactant: Clc1cccnc1Cl
Solvent: O
Product: Clc1cccnc1N1CCNCC1
Temperature: 140 °C
Reaction time: 2 h
Yield: 102.5 %

Procedure:
Piperazine (20.0 g) was melted by heating at 140° C. and 2,3-dichloropyridine (3.42 g) was added thereto. The mixture was stirred at 120° C. for 2 hr. Water was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with brine, dried and concentrated under reduced pressure to give 1-(3-chloro-2-pyridyl)piperazine (4.68 g) as a dark-brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[N:18]([S:22]([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:17]1[CH:16]=[N:15][C:14]([C:32](=O)[CH2:33]Br)=[C:13]([CH2:36][O:37][CH3:38])[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]([NH2:42])(=[S:41])[CH3:40]>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[N:18]([S:22]([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:23])=[O:24])[C:17]1[CH:16]=[N:15][C:14]([C:32]3[N:42]=[C:39]([CH3:40])[S:41][CH:33]=3)=[C:13]([CH2:36][O:37][CH3:38])[C:12]2=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(N)=S
Reactant: COCc1c(C(=O)CBr)ncc2c1c1cc(OCc3ccccc3)ccc1n2S(=O)(=O)c1ccc(C)cc1
Solvent: CCO
Product: COCc1c(-c2csc(C)n2)ncc2c1c1cc(OCc3ccccc3)ccc1n2S(=O)(=O)c1ccc(C)cc1
Yield: 51105.6 %

Procedure:
0.530 g of 6-benzyloxy-3-bromoacetyl-4-methoxymethyl-9-tosyl-β-carboline is refluxed for 3 hours in 50 ml of ethanol with 0.07 g of thioacetamide. After concentration by evaporation the residue is chromatographed on silica gel with cyclohexane and ethyl acetate=1+1 as eluant. 0,260 g of 6-benzyloxy-4-methoxymethyl-3-(2-methyl-4-thiazolyl)-9-tosyl-β-carboline of a melting point 181°-182° C. is obtained.