Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[Br:18]Br>O>[Br:18][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=1
Reactant: c1ccc2c(c1)oc1ccccc12
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc2oc3ccccc3c2c1
Reaction time: 20 h
Yield: 30.3 %

Procedure:
150 grams (892 mmol) of dibenzofuran and 1 L of acetic acid were loaded into a flask. The air in the flask was replaced with nitrogen, and then the contents were dissolved under heat. 188 grams (1.18 mol) of bromine were dropped to the solution while the flask was sometimes cooled with water. After that, the mixture was stirred for 20 hours under air cooling. The precipitated crystal was separated by filtration, and was then sequentially washed with acetic acid and water. The washed crystal was dried under reduced pressure. The resultant crystal was purified by distillation under reduced pressure, and was then repeatedly recrystallized with methanol several times. Thus, 66.8 g of 2-bromodibenzofuran were obtained (in 31% yield). The resultant was identified as Intermediate 2-3 by FD-MS analysis.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH:7]1([Mg]Cl)[CH:11]=[CH:10][CH:9]=[CH:8]1>>[CH2:2]([C:11]1[CH2:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: Cl[Mg]C1C=CC=C1
Reactant: C=CCCCBr
Product: C=CCCCC1=CC=CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 5-bromo-1-pentene (100 g of 95 wt %, 0.637 mol) was added cyclopentadienyl magnesium chloride (700 mL of 1 M solution in THF, 0.7 mol) at 0° C. in an hour. After stirring for an additional 30 minutes at 0° C., the mixture was warmed to room temperature. After stirring overnight, the reaction was quenched with a mixture of ice and water. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum at room temperature gave a yellow-brown liquid (98 g, crude pent-4-enylcyclopentadiene). To the crude pent-4-enylcyclopentadiene (89 g) dissolved in THF (500 mL) was added n-BuLi (60 mL of 10 M in hexanes, 0.6 mol) at −78° C. The mixture was warmed up to room temperature and stirred overnight. The anion solution was added to benzophenone (110 g, 0.604 mol) dissolved in THF (500 mL) at 0° C. in 25 minutes. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched with a mixture of ice and 10% HCl aqueous solution. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum at 40° C. gave a dark red viscous oil. The oil was dissolved in heptane and filtered through silica gel. The product was collected by washing the silica gel with 5-10% CH2Cl2 in heptane. Removal of the solvent gave the desired product (145 g, 84% yield based on 5-bromo-1-pentene) as a dark red viscous oil. 1H NMR (300 MHz, CDCl3) δ 7.41-7.48 (m, 10H), 6.59-6.62 (dd, J=5.1 Hz, 1.4 Hz, 1H), 6.40-6.42 (dd, J=5.1 Hz, 1.4 Hz, 1H), 6.12-6.15 (m, 1H), 5.86-6.02 (m, 1H), 5.08-5.20 (m, 2H), 2.55-2.60 (t, J=7.2 Hz, 2H), 2.22-2.30 (m, 2H), 1.76-1.88 (quin, J=7.2 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 148.28, 148.13, 143.28, 140.85, 140.76, 138.01, 133.51, 131.34, 131.29, 127.76, 127.74, 127.13, 127.08, 124.74, 118.24, 114.24, 33.95, 30.13, 28.46.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:24][CH:25]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:26]([F:29])([F:28])[F:27])=[C:13]([CH:23]=1)[CH2:14][NH:15]C(=O)OC(C)(C)C>C(Cl)Cl>[NH2:15][CH2:14][C:13]1[CH:23]=[C:9]([Cl:8])[CH:10]=[CH:11][C:12]=1[CH2:24][CH:25]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[C:26]([F:29])([F:28])[F:27]
Reactant: COc1ccc(NC(Cc2ccc(Cl)cc2CNC(=O)OC(C)(C)C)C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(NC(Cc2ccc(Cl)cc2CN)C(F)(F)F)cc1

Procedure:
TFA (1 mL) was added to a stirred solution of tert-butyl 5-chloro-2-{2-[(4-methoxyphenyl)amino]-3,3,3-trifluoropropyl}benzylcarbamate (0.205 g, 0.447 mmol) in CH2Cl2 (2 mL). After 1 h the solvent was evaporated in vacuo and the residue was partitioned between EtOAc and saturated aqueous Na2CO3. The organic layer was dried (Na2SO4) and evaporated in vacuo to give N-{1-[2-(aminomethyl)-4-chlorobenzyl]-2,2,2-trifluoroethyl}-N-(4-methoxyphenyl)amine (0.182 a solid; 1H NMR (CDCl3, 400 MHz) δ 3.02 (dd, J=10.9 and 14.2 Hz, 1H), 3.11 (dd, J=3.4 and 14.2 Hz, 1H), 3.69 (s, 3H), 3.86 (d, J=12.9 Hz, 1H), 3.97 (d, J=12.9 Hz, 1H), 3.98 (obscured m, 1H), 6.44 (d, J=8.8 Hz, 2H), 6.66 (d, J=8.8 Hz, 2H), 7.19 (s, 2H), 7.22 (s, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:30]>O1CCCC1>[CH3:30][O:26][C:20]1([C:11]2[CH:12]=[CH:13][C:14]([C:16]([F:17])([F:18])[F:19])=[CH:15][C:10]=2[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(C(F)(F)F)ccc1C1(O)CCCCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2ccc(C(F)(F)F)cc2CO[Si](C)(C)C(C)(C)C)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
To a solution of 1-(2-((tert-butyldimethylsilyloxy)methyl)-4-(trifluoromethyl)phenyl)cyclohexanol (108 mg; 0.278 mmol) in tetrahydrofuran (2 mL) at 0° C. was added sodium hydride (22 mg; 0.55 mmol). The reaction was stirred at 0° C. for 30 minutes. Then iodomethane (50 uL; 0.80 mmol) was added. The reaction was stirred at 0° C. for 30 minutes and then at room temperature for 16 hours. More iodomethane (20 uL; 0.32 mmol) was added and stirred for 4 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The crude was purified over a 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-15% ethyl acetate in heptane) to give 63 mg (55%) the title compound as a colorless oil. MS-GC (El): Calc: 402.5, Found: 383 (M−F). 1H NMR (400 MHz, CDCl3) δ ppm 7.51 (d, J=7.88 Hz, 1H), 7.46 (d, J=7.47 Hz, 1H), 7.35 (d, J=8.30 Hz, 1H), 5.05 (s, 2H), 2.94 (s, 3H), 2.16 (d, J=12.45 Hz, 2H), 1.8-1.56 (m, 8H), 0.98 (s, 9H), 0.13 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N:9]([OH:11])[OH:10])=[CH:4][N:3]=1.[NH2:12][CH2:13][C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:5]([N:9]([OH:11])[OH:10])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Reactant: ON(O)c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1nc(Cl)ncc1N(O)O
Reaction time: 1 h
Yield: 71.3 %

Procedure:
2,4-Dichloro-5-(dihydroxyamino)pyrimidine (2.5 g, 12.75 mmol), 1,1-dimethylethyl (2S)-2-(aminomethyl)-1-pyrrolidinecarboxylate (1.277 g, 6.38 mmol), and DIEA (1.114 mL, 6.38 mmol) were dissolved in DCM (75 mL). The mixture was stirred for 1 h, and when the reaction was complete as determined by LCMS, the solution was concentrated in vacuo. This crude product was purified by flash chromatography (Combiflash, 0-100% ethyl acetate/hexanes) to provide 1,1-dimethylethyl (2S)-2-({[2-chloro-5-(dihydroxyamino)-4-pyrimidinyl]amino}methyl)-1-pyrrolidinecarboxylate (1.6362 g, 71%). LCMS: (M+H)+: 357.8.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:11]([O:18][C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][C@@H:25]2[CH2:27][O:26]2)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]([O:23][CH2:24][C@@H:25]([OH:26])[CH2:27][NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=2)=[CH:28][CH:29]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(COc2ccc(OC[C@@H]3CO3)cc2)cc1
Reactant: NCCc1ccc(O)cc1
Product: Oc1ccc(CCNC[C@H](O)COc2ccc(OCc3ccccc3)cc2)cc1

Procedure:
The title compound was prepared from tyramine and (S)-2-(4-benzyloxyphenoxymethyl)oxirane according to the method described in Procedure 13.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:23]=[CH:24][C:25]3[C:37](=[O:38])[C:36]4[C:35]5[C:30](=[CH:31][C:32]([C:39]#[N:40])=[CH:33][CH:34]=5)[NH:29][C:28]=4[C:27]([CH3:42])([CH3:41])[C:26]=3[CH:43]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C1COCC1>[CH3:41][C:27]1([CH3:42])[C:28]2[NH:29][C:30]3[C:35](=[CH:34][CH:33]=[C:32]([C:39]#[N:40])[CH:31]=3)[C:36]=2[C:37](=[O:38])[C:25]2[CH:24]=[CH:23][C:22]([O:21][CH:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]3)=[CH:43][C:26]1=2
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC1(C)c2cc(OC3CCNCC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 25 °C
Yield: 133.3 %

Procedure:
THF (0.5 mL) and TFA (0.5 mL) were added to 4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (Compound A7-1, 35 mg, 0.072 mmol), and the mixture was stirred at room temperature until Compound A7-1 disappears. The reaction solution was concentrated under reduced pressure and the residue was desalinated by using anion exchanger PL StratoSpheres (trademark) PL-HCO3 MP to obtain the title compound (37 mg, 76%).
Reaction SMILES: [N+:1]([CH:4]([CH3:15])[CH:5]([OH:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)Cl>[N+:1]([CH:4]([CH3:15])[CH:5]([O:14][C:21](=[O:23])[CH3:22])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C(O)CCc1ccccc1)[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(=O)OC(CCc1ccccc1)C(C)[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Crude 4-Nitro-1-phenyl-pentan-3-ol (179) from above was dissolved in CH2Cl2 (60 mL) and cooled in an ice bath under nitrogen. Concentrated sulfuric acid (0.76 mL, 14.2 mmol) then acetic anhydride (13.83 mL, 146.2 mmol) were added slowly, and the reaction was allowed to warm to room temperature, and was stirred until judged complete by HPLC (3 h, 40 min). (Note: The reaction turned black soon after the addition of the acetic anhydride). The reaction was quenched by pouring slowly into water, then the organic layer was removed, washed with aq. NaHCO3, dried, filtered, and concentrated. The crude product was purified by purified by silica gel chromatography (Combiflash column, 95:5 Hexanes:EtOAc) to achieve pure 180 (21.4447 g, 65.5%, 2 steps). HPLC: 10.45 min.
Reaction SMILES: [CH3:1]O.S(Cl)(Cl)=O.[N+:7]([C:10]1[CH:28]=[CH:27][C:13]([CH2:14][O:15][C:16]([N:18]2[CH2:26][C@H:24]([OH:25])[CH2:23][C@H:19]2[C:20]([OH:22])=[O:21])=[O:17])=[CH:12][CH:11]=1)([O-:9])=[O:8]>ClCCl>[OH:25][C@H:24]1[CH2:26][N:18]([C:16]([O:15][CH2:14][C:13]2[CH:27]=[CH:28][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=2)=[O:17])[C@H:19]([C:20]([O:22][CH3:1])=[O:21])[CH2:23]1
Reactant: CO
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methanol (94.5 ml) and dichloromethane (945 ml) under ice cooling are dropwise added thionyl chloride (18.7 ml) and after 5 minutes stirring N-p-nitrobenzyloxycarbonyl-L-hydroxyproline (1: 72.4 g), and the mixture is stirred overnight at room temperature. The reaction mixture is concentrated in vacuum to give crude (2S,4R)-4-hydroxy-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (86.5 g) as pale yellow oil. This product can be used in the next step without further purification. IR ν (CHCl3) cm-1 : 3450, 1742, 1703, 1605. 1HNMR δ (CDCl3) ppm: 1.77(1H, s), 2.05 to 2.45(2H, m), 3.55 to 3.8(2H, m), 3.66, 3.76(3H, 2s), 4.49 to 4.62(2H, m), 5.06 to 5.35(2H, m), 7.43 to 7.56(2H, m), 8.22(2H, d, J=8.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[C:18]([OH:24])=[CH:19][CH:20]=[C:21]([F:23])[CH:22]=2)[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C:11]1([CH3:16])[CH3:15])=[O:9].CC1C=CC(S(O[C@H:36]([CH3:41])[C:37]([O:39][CH3:40])=[O:38])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][C@@H:36]([CH3:41])[C:37]([O:39][CH3:40])=[O:38])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C:11]1([CH3:16])[CH3:15])=[O:9]
Reactant: COC(=O)[C@@H](C)OS(=O)(=O)c1ccc(C)cc1
Reactant: CC1(C)CCCN1C(=O)c1ccc(-c2cc(F)ccc2O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@H](C)Oc1ccc(F)cc1-c1ccc(C(=O)N2CCCC2(C)C)c(Cl)c1
Temperature: 65 °C

Procedure:
The intermediate from step d) (2.83 g) was dissolved in MeCN (30 mL). The product from step e) (2.11 g) and potassium carbonate (2.25 g) were added and the mixture was heated to 65° C. for 16 h. The mixture was cooled to rt and extracted with diethyl ether (×2), dried (MgSO4) and concentrated under reduced pressure to give an oil. The oil was purified by flash column chromatography on silica using isohexane 3:1 ethyl acetate as eluent to give the sub titled product as a colourless oil (2.29 g).
Reaction SMILES: [OH:1][P:2]([CH:16]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH2:4][CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6](O)=[O:7])=[O:3].[NH2:35][C@H:36]([C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[OH:3][P:2]([CH2:4][CH:5]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:6]([NH:35][C@H:36]([C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:7])([CH:16]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:1]
Reactant: O=C(NC(Cc1ccccc1)P(=O)(O)CC(Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC(Cc1ccccc1)P(=O)(O)CC(Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Yield: 70.3 %

Procedure:
To 200 mg (0.42 mmol) of 3-[hydroxy[2-phenyl-1-[[(phenylmethoxy)carbonyl]amino]ethyl]phosphinyl]-2-(phenylmethyl)propanoic acid, 178 mg (0.42 mmol) of phenylmethyl L-phenylalaninate in the form of the p-toluenesulphonic acid salt and 384 mg (0.87 mmol) of BOP in 0.8 ml of dimethylformamide is added, with stirring at a temperature in the region of 20° C., 0.7 ml of diisopropylethylamine. After reaction for 30 minutes at this temperature, the dimethylformamide is evaporated off under reduced pressure and 12 ml of 1N hydrochloric acid are added to the oily residue obtained. The precipitate is filtered off, washed with water and dried. 210 mg of product are recovered (yield=70.3%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[N:30]([CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)=[C:31]=[O:32]>C(Cl)Cl>[CH:33]1([NH:30][C:31]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=2)=[O:32])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C=NC1CCCCC1
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCCCC1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.36 mmol, example 9 (step 3) and DIEA (63 pt, 0.36 mmol) in DCM (2 mL) was added isocyanatocyclohexane (46 μL, 0.36 mmol). The resulting mixture was reacted under the same conditions as described for example 10 give the title compound as a white solid. MS (ESI, positive ion) m/z: 403 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[OH:30][C:27]([CH:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:35]3[CH:36]=[N:37][C:32]([CH3:31])=[CH:33][CH:34]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1)([CH3:29])[CH3:28]
Reactant: Cc1ccc(B(O)O)cn1
Reactant: CC(C)(O)C1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CCC(C(C)(C)O)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 113 using 5-bromo-6-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 113.1) and (6-methylpyridin-3-yl)boronic acid to afford an off-white amorphous solid. HPLC (Condition 4) tR=4.38 min, UPLC-MS (Condition 7) m/z=501.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.00 (d, J=16.03 Hz, 6H) 1.55-1.80 (m, 2H) 1.95-2.12 (m, 1H) 2.48 (s, 3H) 2.99-3.20 (m, 3H) 3.22-3.35 (m, 1H) 4.26 (s, 1H) 7.32 (dd, J=8.21, 5.86 Hz, 3H) 7.67 (dd, J=7.82, 2.35 Hz, 1H) 7.78-7.89 (m, 2H) 7.96 (d, J=2.35 Hz, 1H) 8.47 (d, J=2.35 Hz, 1H) 8.72 (d, J=2.35 Hz, 1H) 10.13 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[OH:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([OH:27])[CH:26]=1)[CH:22]=[O:23]>>[CH2:2]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:27][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2])[CH:26]=1)[CH:22]=[O:23])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=Cc1cc(O)cc(O)c1
Reactant: CCCCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCCCCOc1cc(C=O)cc(OCCCCCCCCCCCCCCCC)c1

Procedure:
The title compound was prepared according to the method described in Example 9 above from 1-bromohexadecane and 3,5-dihydroxy-benzaldehyde. The solid reaction product was collected by filtration and washed with methyl ethyl ketone (Soxhlet). The filtrate was evaporated under reduced pressure to give the title compound as a red oil which was crystallised from acetone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](O)=[O:19])[CH2:11][CH2:10]1.C(N(CC)CC)C.O=C1N(N(N2CCOC2=O)P(Cl)(Cl)=O)CCO1.[CH3:51][CH2:52][C:53]([NH2:58])([C:56]#[CH:57])[CH2:54][CH3:55]>C(Cl)Cl>[CH2:54]([C:53]([NH:58][C:18](=[O:19])[CH:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1)([CH2:56][CH3:57])[C:52]#[CH:51])[CH3:55]
Reactant: C#CC(N)(CC)CC
Reactant: COc1ccccc1N1CCN(CCC(C(=O)O)c2ccccc2)CC1
Agent: O=C1OCCN1N(N1CCOC1=O)P(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CC(CC)(CC)NC(=O)C(CCN1CCN(c2ccccc2OC)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.8 %

Procedure:
A mixture of 4-[4-(2-methoxyphenyl)piperazin-1-yl]-2-phenylbutanoic acid (1.772 g, 5 mmole), triethylamine (1.518 g, 15 mmole), and N,N-bis(2-oxo-3-oxazolidinyl)phosphoramidic chloride (1.527 g, 6 mmole) was stirred in methylene chloride (80 mL) under exclusion of moisture at ambient temperature for 30 minutes, after which 1,1-diethylpropargylamine (0.668 g, 6 mmole) was added at once at 0° C. The reaction mixture was stirred at room temperature overnight, washed with water (2×100 mL), dried over magnesium sulfate, filtered, and evaporated to dryness in vacuo. Chromatography on silica gel with methanol/chloroform as eluant, followed by trituration from diethyl ether with addition of ethanolic hydrochloric acid gave 0.6 g of the title compound as the trihydrochloride hemihydrate, m.p. 110°-12° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[CH:17]=[C:18]([Br:22])[N:19]=[C:20](Br)[C:15]4=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[NH2:24][CH2:25][CH2:26][CH2:27][OH:28].C1(C)C=CC=CC=1>CN(C)C=O>[Br:22][C:18]1[N:19]=[C:20]([NH:24][CH2:25][CH2:26][CH2:27][OH:28])[C:15]2[N:16]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([C:5]([NH:4][CH:1]4[CH2:2][CH2:3]4)=[O:23])=[CH:7][CH:8]=3)=[CH:13][N:14]=2)[CH:17]=1
Reactant: NCCCO
Reactant: O=C(NC1CC1)c1ccc(-c2cnc3c(Br)nc(Br)cn23)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(-c2cnc3c(NCCCO)nc(Br)cn23)cc1
Temperature: 40 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
To a solution of 500 mg (1.15 mmol) N-cyclopropyl-4-(6,8-dibromoimidazo[1,2-a]pyrazin-3-yl)benzamide which was prepared according to intermediate example 1b in 15 mL N,N-dimethylformamide were added 261 μL 3-aminopropan-1-ol and the mixture was stirred at 40° C. for 6 hours. Toluene was added and the solvents removed. The residue was purified by chromatography to give 453 mg (92%) of the title compound.
Reaction SMILES: [C:1]([N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Br:19])N=CC)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1C=CC=CC=1NN=CC.[CH2:31]1[CH:37]([C:38]([OH:40])=[O:39])[CH2:36][CH2:35][C:33](=O)[CH2:32]1.C(=O)C.Cl>O.C(O)(=O)C>[C:1]([N:9]1[C:33]2[CH2:32][CH2:31][CH:37]([C:38]([OH:40])=[O:39])[CH2:36][C:35]=2[C:18]2[C:13]1=[C:14]([Br:19])[CH:15]=[CH:16][CH:17]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC=NN(C(=O)c1ccccc1)c1ccccc1Br
Reactant: O=C1CCC(C(=O)O)CC1
Agent: CC=NNc1ccccc1Br
Agent: CC=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C1CCc2c(c3cccc(Br)c3n2C(=O)c2ccccc2)C1
Reaction time: 0.5 h

Procedure:
A solution of acetaldehyde 1-benzoyl-1-(2-bromophenyl)hydrazone, prepared from 11 g. of acetaldehyde 2-bromophenyl hydrazone (see below), and 9.16 g. of cyclohexanone-4-carboxylic acid in 25 ml. glacial acetic acid was heated on a hot plate until evolution of acetaldehyde was no longer detected (about two hours), 25 ml. glacial acetic acid saturated with hydrogen chloride was added and heating was continued for 30 minutes. The mixture was cooled and cautiously diluted with water, and the resulting solid was collected by filtration and washed with water to give 2.24 g. of the title compound; m.p. 196°-198°C. (chloroform-heptane).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH:7]([NH2:10])([CH3:9])[CH3:8]>>[CH:7]([NH:10][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6])([CH3:9])[CH3:8]
Reactant: CC(C)N
Reactant: C=CCCCBr
Product: C=CCCCNC(C)C
Temperature: 60 °C
Reaction time: 48 h
Yield: 40 %

Procedure:
5-Bromo-1-pentene (42.3 mmol) was added to isopropylamine (423 mmol), and the mixture was stirred at 60° C. for 48 h in the dark in a sealed tube. Then the volatiles were evaporated at reduced pressure and the crude residue was dissolved in 50 mL of diethyl ether and washed twice with water. The organic phase was dried over Na2SO4. Evaporation of the solvent gave N-isopropylpent-4-en-1-amine as brownish oil (40%) which was used without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.[CH2:13]([N:15]([CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH:19]([NH2:21])[CH3:20])[CH3:14]>>[CH3:14][CH2:13][N:15]([CH2:16][CH2:17][CH2:18][CH:19]([NH:21][C:6]1[CH:7]=[CH:8][N:9]=[C:10]2[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=12)[CH3:20])[CH2:22][CH3:23]
Reactant: O=C1CCNc2cc(Cl)ccc21
Reactant: CCN(CC)CCCC(C)N
Product: CCN(CC)CCCC(C)Nc1ccnc2cc(Cl)ccc12
Yield: 94.9 %

Procedure:
19.116 millimols, i.e. a yield of 94.9% relative to the 7-chloro-1,2,3,4-tetrahydroquinolin-4-one converted, and a yield of 97.5% relative to the 1-diethylamino-4-amino-pentane converted, and