Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[N:18]=2)=[CH:4][C:5]([NH:8][C@@H:9]2[CH2:13][CH2:12][C@H:11]([C:14](O)=[O:15])[CH2:10]2)=[N:6][CH:7]=1.[CH3:32][NH:33][CH3:34].C1COCC1.Cl.C(N=C=NCCCN(C)C)C.N1C2C(=NC=CC=2)N(O)N=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[N:18]=2)=[CH:4][C:5]([NH:8][C@@H:9]2[CH2:13][CH2:12][C@H:11]([C:14]([N:33]([CH3:34])[CH3:32])=[O:15])[CH2:10]2)=[N:6][CH:7]=1
Reactant: CNC
Reactant: O=C(O)[C@H]1CC[C@@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)C(=O)[C@H]1CC[C@@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To (1S,3R)-3-(5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridin-2′-yl-amino)cyclopentanecarboxylic acid U-31332-EXP080 (10 mg, 0.023 mmol), 2M dimethyl amine in THF (0.011 ml, 0.023 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (8.70 mg, 0.045 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (4.32 mg, 0.032 mmol) were added then dimethylformamide (1 ml) and diisopropyl ethylamine (0.016 ml, 0.091 mmol) were added, and the reaction mixture was stirred at ambient temperature for 18 hr and the progress followed by LCMS. The crude reaction mixture was filtered and purified by preparative LC. The product fractions were combined, 50 mL of 1M NaOH and 50 mL of ethyl acetate were added. The organic layer was removed, washed with 50 mL 1M NaOH, 50 mL saturated salt solution, dried over sodium sulfate, and reduced to constant mass. 3 mg of the desired compound was obtained. LCMS (m/z): 468.1 (MH+), retention time=0.72 min., 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.77-2.16 (m, 6H) 2.96 (s, 3H) 3.07 (s, 3H) 3.10-3.25 (m, 1H) 4.29 (m, 1H) 4.56 (d, J=5.27 Hz, 2H) 5.12 (br. s., 1H) 5.87 (br. s., 1H) 6.38 (d, J=8.50 Hz, 1H) 6.58 (s, 1H) 6.91-7.01 (m, 1H) 7.06-7.20 (m, 1H) 7.26-7.37 (m, 2H) 7.44-7.53 (m, 1H) 8.09 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[C:4]([C:12]2[C:13](=[O:29])[NH:14][C:15](=[O:28])[C:16]=2[C:17]2[C:25]3[C:20](=[CH:21][C:22]([NH2:26])=[CH:23][CH:24]=3)[N:19]([CH3:27])[CH:18]=2)=[CH:3]1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38].[O:41]1CC[CH2:43][CH2:42]1>>[C:37]([NH:26][C:22]1[CH:21]=[C:20]2[C:25]([C:17]([C:16]3[C:15](=[O:28])[NH:14][C:13](=[O:29])[C:12]=3[C:4]3[C:5]4[C:10](=[CH:9][C:8]([NH:11][C:42](=[O:41])[CH3:43])=[CH:7][CH:6]=4)[N:2]([CH3:1])[CH:3]=3)=[CH:18][N:19]2[CH3:27])=[CH:24][CH:23]=1)(=[O:39])[CH3:38]
Reactant: C1CCOC1
Reactant: CC(=O)Cl
Reactant: Cn1cc(C2=C(c3cn(C)c4cc(N)ccc34)C(=O)NC2=O)c2ccc(N)cc21
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2c(C3=C(c4cn(C)c5cc(NC(C)=O)ccc45)C(=O)NC3=O)cn(C)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
3,4-Bis-(1-methyl-6-amino-1H-indol-3-yl)-pyrrole-2,5-dione (50 mg, 0.13 mmole) was dissolved in tetrahydrofuran (2.5 mL) and cooled to 0° C. Triethylamine (38.5 μl, 0.27 mm) was added followed by acetyl chloride (19.4 pl, 0.27 mmole). The reaction was stirred for 30 min, then concentrated. The reaction mixture was dissolved in chloroform, washed with 0.1 N hydrochloric acid and the organic was dried over magnesiun sulfate, filtered and concentrated. The product was purified by column chromatography in 5% methanol/ethyl acetate to give N-{3-[4-(6-acetylamino-1-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-1-methyl-1H-indol-6-yl}-acetamide (14 mg, 23%).
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[N:13][C:12]=1[CH3:23])=[O:10].[N:24]1([C:30]2[N:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[N:24]1([C:30]2[N:35]=[CH:34][C:33]([NH:36][C:9]([C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[CH3:22])=[N:13][C:12]=3[CH3:23])=[O:10])=[CH:32][CH:31]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: Cc1ccccc1-c1nc(C)c(C(=O)ON2C(=O)CCC2=O)o1
Reactant: Nc1ccc(N2CCOCC2)nc1
Product: Cc1ccccc1-c1nc(C)c(C(=O)Nc2ccc(N3CCOCC3)nc2)o1

Procedure:
With a procedure similar to example 50 above, 4-methyl-2-o-tolyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 4-methyl-2-o-tolyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C21H22N4O3 (m/e) 378, obsd 379 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10](Cl)[CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([OH:15])[C:6]([OH:14])=[N:7]2.[CH3:16][C:17](=O)[CH2:18][C:19](=O)[CH3:20]>C(O)(=O)C>[OH:15][C:5]1[C:6]([OH:14])=[N:7][C:8]2[CH:9]=[CH:10][C:11]3[NH:12][C:17]([CH3:16])=[CH:18][C:19]([CH3:20])=[N:1][C:2]=3[C:3]=2[N:4]=1
Reactant: Nc1c(Cl)cc2nc(O)c(O)nc2c1N
Reactant: CC(=O)CC(C)=O
Solvent: CC(=O)O
Product: CC1=CC(C)=Nc2c(ccc3nc(O)c(O)nc23)N1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.9 %

Procedure:
A mixture of 0,5 g (2,24 mmol) 5,6-diamino-7-chloro-2,3-dihydroxyquinoxaline and 1,0 g (10 mmol) 2,4-pentanedione in 15 ml glacial acetic acid was stirred at 25° C. for 20 h. The precipitate was filtered off and washed with ethanol and ether to give 0,43 g (67%) 2,3-dihydroxy-8,10-dimethyl-7H-pyrazino(2,3-g)(1,5)benzodiazepine, m.p. >300° C. NMR (DMSO-D6): 7.07 (2H,s), 2.33 (3H,s), 2.27(3H,s).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][CH:9]=[C:8]2[O:17][C:18]1[C:19]([F:29])=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([NH2:28])[CH:22]=[CH:21]2.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35](O)=[O:36].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][CH:9]=[C:8]2[O:17][C:18]1[C:19]([F:29])=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([NH:28][C:35]([C:31]1[S:30][CH:34]=[CH:33][CH:32]=1)=[O:36])[CH:22]=[CH:21]2
Reactant: O=C(O)c1cccs1
Reactant: COc1cc2nccc(Oc3ccc4cc(N)ccc4c3F)c2cc1OC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(Oc3ccc4cc(NC(=O)c5cccs5)ccc4c3F)c2cc1OC
Reaction time: 16 h

Procedure:
To a solution of 6-(6,7-dimethoxy-4-quinolyloxy)-5-fluoro-2-naphthylamine 2HCl (Step c, 200 mg, 0.46 mmol), thiophene-2-carboxylic acid (120 mg, 0.91 mmol, Aldrich) and DIEA (353 mg, 2.74 mmol, Aldrich) in dry DMF was added PyBOP (476 mg, 0.91 mmol, Fluka) at RT. The reaction was stirred for 16 h. It was diluted with 40 mL of EtOAc and washed with saturated aqueous NaHCO3, followed by brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc) to give the title compound as a yellow solid. MS (ESI, pos. ion) m/z: 475.0 (M+1). Mass Calc'd for C26H19FN2O4S: 474.10.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]([O:16]C)=[O:15])=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:20][CH:19]=3)[C:9]=2[CH3:28])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]([OH:16])=[O:15])=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:20][CH:19]=3)[C:9]=2[CH3:28])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(-c2ccc(S(N)(=O)=O)cc2)c(C)c(-c2ccc(Cl)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(-c2ccc(S(N)(=O)=O)cc2)c(C(=O)O)n(C)c1-c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 84.1 %

Procedure:
Methyl 5-(4-chlorophenyl)-1,4-dimethyl-3-(4-sulfamoylphenyl)-1H-pyrrole-2-carboxylate (compound 49γ, 1.6 g, 3.82 mmol) was suspended in ethanol (100 ml) and treated with solution of NaOH (0.76 g 19.13 mmol) in water (20 ml) at 0° C. The reaction mixture was then heated at 80° C. under stirring for 15 h. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The reaction mixture was then treated with dilute HCl to bring pH of the mixture to between 6 and 7. The obtained mixture was then extracted with ethyl acetate (2×100 ml). The combined organic layer was then dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain the title compound (1.3 g, 84.4%).
Reaction SMILES: Cl[C:2]1[C:3]2[C:4](=[CH:13][S:14][CH:15]=2)[S:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[C:23]([O-:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([O-:28])=[O:27]>C1(C)C=CC=CC=1>[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27].[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:2]2[C:3]3[C:4](=[CH:13][S:14][CH:15]=3)[S:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=2)[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: ClC1=Nc2ccccc2Sc2cscc21
Solvent: Cc1ccccc1
Product: CN1CCN(C2=Nc3ccccc3Sc3cscc32)CC1
Product: O=C(O)/C=C/C(=O)O

Procedure:
10-Chloro-thieno[3,4-b][1,5]benzothiazepine (Example 14) is reacted with N-methylpiperazine in toluene giving the base compound, which is then converted to the fumarate, m.p. 186°-188° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:2]=1.[OH-].[K+].[C:14]([O:17][CH2:18][C:19]([CH3:23])([CH3:22])[CH2:20]Br)(=[O:16])[CH3:15].O>CS(C)=O.C(Cl)(Cl)Cl>[C:14]([O:17][CH2:18][C:19]([CH3:23])([CH3:22])[CH2:20][N:10]1[CH:11]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:8]=[CH:9]1)(=[O:16])[CH3:15]
Reactant: CC(=O)OCC(C)(C)CBr
Reactant: c1cncc(-c2c[nH]cn2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)OCC(C)(C)Cn1cnc(-c2cccnc2)c1
Temperature: 70 °C

Procedure:
To a solution of 4-pyridin-3-yl-imidazole (50 mg) in DMSO (1.7 mL) was added powered KOH (57 mg) and 3-bromo-2,2-dimethylpropyl acetate and the resulting suspension was heated at 70° C. for 48 hours. Water was added followed by CHCl3, the aqueous layer was extracted with CHCl3, the combined organic layers were washed with brine, dired over Na2SO4 and evaporated in vacuo. The residue was purified by preparative TLC (10% MeOH-90% CH2Cl2) the title compound as slightly yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([NH:13][CH3:14])[C:5]([C:6](OCC)=[O:7])=[CH:4][N:3]=1.[BH4-].[Li+]>C1COCC1.CO>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[C:11]([NH:13][CH3:14])[CH:12]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1NC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CNc1cc(Cl)ncc1CO
Temperature: 55 °C
Yield: 111.1 %

Procedure:
To a solution of ethyl 6-chloro-4-(methylamino)nicotinate (4.7 g, 21.9 mmol) in THF (30 mL) and methanol (30 mL) was added lithium borohydride (2.4 g, 109.8 mmol), and the reaction mixture was heated at 55° C. overnight. LCMS showed the reaction was completed. The reaction was cooled to RT, quenched with water (1 mL) and filtered. The filtrate was concentrated to afford the title compound (4.2 g, crude) as a white solid, which was directly used in the next step without further purification. MS (ES+) C7H9ClN2O requires: 172, 174. found: 173, 175 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[CH:24]=[C:23]([CH3:25])[S:22][CH:21]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:26])[N:3]=1.B([C:30]1[CH:41]=[CH:40][C:33]([CH2:34][C@@H:35]([C:37]([OH:39])=[O:38])[NH2:36])=[CH:32][CH:31]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:36][C@@H:35]([CH2:34][C:33]1[CH:40]=[CH:41][C:30]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[CH:24]=[C:23]([CH3:25])[S:22][CH:21]=3)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:26])[N:3]=2)=[CH:31][CH:32]=1)[C:37]([OH:39])=[O:38]
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Reactant: Cc1cc(-c2ccccc2C(Oc2cc(Cl)nc(N)n2)C(F)(F)F)cs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(-c2ccccc2C(Oc2cc(-c3ccc(C[C@H](N)C(=O)O)cc3)nc(N)n2)C(F)(F)F)cs1
Temperature: 150 °C
Yield: 25.5 %

Procedure:
In a microwave vial, 4-chloro-6-{2,2,2-trifluoro-1-[2-(5-methyl-thiophen-3-yl)-phenyl]-ethoxy}-pyrimidin-2-ylamine (30 mg, 0.075 mmol), 4-borono-L-phenylalanine (19 mg, 0.09 mmol), 1 ml of actonitrile and 0.7 ml of water were mixed. 0.3 ml of 1N aqueous sodium carbonate was added to the mixture, followed by 5 mole percent of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and then was purified by Prep-LC to give 10.1 mg of (S)-2-Amino-3-(4-{2-amino-6-[2,2,2-trifluro-1-(2-(5-methyl-thiophen-3-yl)-phenyl]-ethoxy}-pyrimidin-4-yl}-phenyl)-propionic acid. 1H NMR (400 MHz, CD3OD) δ (ppm) 7.83(d, J=8.4 Hz, 2H), 7.63(d, J=7.2 Hz, 1H), 7.34(m, 4H), 7.26(m, 1H), 7.12(d, J=1.2 Hz, 1H), 6.92(q, J=6.8, 1H), 6.82(d, J=1.2 Hz, 1H), 6.64(s, 1H), 4.21(t, J=5.6 Hz, 1H), 3.29(m, 1H), 3.20(m, 1H), 2.47(s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=1)=[CH:13][C:12]([C:27]#[N:28])=[CH:11][CH:10]=2)=[O:5])C.C1COCC1.[OH-].[Na+].Cl>C(O)C.CO>[Cl:26][C:20]1[CH:19]=[C:18]([CH2:17][NH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:27]#[N:28])[CH:13]=3)[N:8]=[CH:7][C:6]=2[C:4]([OH:5])=[O:3])[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: CCOC(=O)c1cnc2ccc(C#N)cc2c1NCc1ccc(OC)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(CNc2c(C(=O)O)cnc3ccc(C#N)cc23)cc1Cl
Reaction time: 1 h
Yield: 100 %

Procedure:
To 8.0 g (20 mmol) 4-(3-Chloro-4-methoxyphenylmethylamino)-6-cyanoquinoline-3-carboxylic acid ethyl ester was added 100 mL THF, 100 mL MeOH and 100 mL 1M NaOH, and the resulting mixture was stirred well. The solids gradually dissolved as the reaction progressed. After 1 h, the THF and most of the MeOH was evaporated under reduced pressure to leave an aqueous slurry of a white solid. The slurry was acidified to pH 1.5 with HCl, stirred well for 1 h, and then filtered and washed well with water to give 7.5 g (20 mmol, ˜100% yield) of a white chalky solid. Codistilling twice to dryness with absolute ethanol afforded the title compound: LC/MS: M/Z 368 (M+H) observed, 90+% purity; mp: decomposed 255-260° C. LC 2.93′.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)=[O:28].[CH3:37][NH:38][CH2:39][CH2:40][CH3:41]>>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][C:27](=[O:28])[N:2]([CH3:1])[C@H:3]2[CH2:4][CH2:5][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:38]([CH3:37])[CH2:39][CH2:40][CH3:41])[CH2:7][CH2:8]2)=[CH:31][CH:32]=1
Reactant: CCCNC
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CN[C@H]1CC[C@H](CCCCCOS(C)(=O)=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C)CCCCC[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1

Procedure:
In analogy to examples 29.10 and 29.11, trans-Methansulfonic acid 5-(4-methyl amino-cyclohexyl)-pentyl ester.Trifluoroacetic acid salt and 4-chlorophenyl chloroformate were reacted, followed by treatment with methyl-propyl-amine to give trans-Methyl-{4-[5-(methyl-propyl-amino)-pentyl]-cyclohexyl}-carbamic acid 4-chloro-phenyl ester, MS: 409 (MH+, 1Cl).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([C:8](=[S:10])[NH2:9])[CH:7]=1.Br[CH2:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18].C(OCC)(=O)C.CCCCCC>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([C:8]2[S:10][CH2:15][C:16]([C:17]([F:20])([F:19])[F:18])([OH:21])[N:9]=2)[CH:7]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: Cc1ccc([N+](=O)[O-])c(C(N)=S)c1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: Cc1ccc([N+](=O)[O-])c(C2=NC(O)(C(F)(F)F)CS2)c1
Temperature: 25 °C

Procedure:
The product from Step B (5.5 g, 0.028 mol) was dissolved in ethyl alcohol (100 mL). 3-bromo-1,1,1-trifluoroacetone (5.3 g, 0.028 mol) was added and the resulting solution refluxed for 3 h. After cooling to room temperature, the reaction mixture was evaporated to dryness. The residue was partitioned between ethyl acetate and 10% aqueous sodium carbonate (200 mL each). The organic layer was separated, dried (MgSO4) and then concentrated to give an oil. Flash chromatography of this oil on silica gel eluting with 20% ethyl acetate/hexane afforded a solid which was further purified by recrystallization from chlorobutane/hexane. Yield: 4.4 g (51%) of the title compound as a white solid melting at 148°-151° C. 1H NMR (300 MHz, CDCl3) δ 7.96-7.98 (m,1H), 7.42-7.44 (m,2H), 3.86-3.89 (m,1H), 3.34 (s,1H), 2.49 (s,3H).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([CH3:3])[CH3:2].[N:11]([O-])=O.[Na+]>O.Cl>[CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][NH2:11])([CH3:3])[CH3:2]
Reactant: O=N[O-]
Reactant: CC(C)c1ccccc1N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)c1ccccc1NN
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of the substituted aniline, 2-isopropylaniline (27g, 0.2 mole), concentrated hydrochloric acid (150 ml) and water (160 ml) is stirred mechanically for 30 minutes at room temperature. After cooling to 0° C, the mixture is diazotized by adding dropwise a solution of sodium nitrite (14 g, 0.203 mole) in water (140 ml) over a period of 20 minutes. Stirring is continued for an additional one hour at 0° C. The diazo solution is reduced by adding dropwise a solution of stannous chloride dihydrate (112 g, 0.497 mole) in concentrated hydrochloric acid (90 ml) over a period of 30 minutes at -10° C to -15° C. The reaction mixture is stirred for an additional 1.5 hour at -10° C to -15° C. The precipitate is collected by filtration to give the hydrochloric acid addition salt of the title compound. The salt is purified further by dissolving it in ethanol, concentrating the solution and adding a saturated solution of hydrochloric acid in either to give the hydrochloride salt with mp 206° - 210° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.C([O-])([O-])=O.[Cs+].[Cs+].[OH:19][CH2:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([C:30]=1[C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1)=[CH:28][CH:27]=[CH:26][C:25]=2[C:38]([F:41])([F:40])[F:39].Cl>C(OCC)(=O)C.C(Cl)Cl>[OH:19][CH2:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([C:30]=1[C:31]1[CH:32]=[C:33]([CH:34]=[CH:35][CH:36]=1)[O:37][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=[CH:28][CH:27]=[CH:26][C:25]=2[C:38]([F:41])([F:39])[F:40]
Reactant: O=C(O)Cc1ccc(CBr)cc1
Reactant: OCc1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccc(COc2cccc(-c3c(CO)cnc4c(C(F)(F)F)cccc34)c2)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
4-Bromomethylphenylacetic acid (1.86 g, 8.13 mmol) is taken into CH2Cl2 (80 mL) and to this is added Cs2CO3 (9.63 g, 29.56 mmol) and the mixture is stirred for 1 hour. Next, 3-[3-(hydroxymethyl)-8-(trifluoromethyl)quinolin-4-yl]phenol (2.36 g, 7.39 mmol) is added and the reaction is stirred overnight. The reaction is not complete, therefore an additional 3 g of 4-bromomethylphenylacetic acid and 2 g of Cs2CO3 is added and stirring is continued for another overnight period. The reaction is neutralized with HCl and then the solvent is removed. The resulting material is taken up into THF/MeOH/2N NaOH and heated at 70° C. for 45 minutes. The reaction is neutralized with HCl then the organics are removed and the aqueous layer is extracted with ethyl acetate. The combined organics is washed with water and brine and finally dried over Na2SO4. The resulting material is purified via column chromatography using 50% ethyl acetate in hexanes as the eluent to yield a white solid, which still contained an impurity. This material is dissolved into ethyl acetate and washed with saturated sodium bicarbonate. The ethyl acetate layer is concentrated to yield the desired product. HRMS: calcd for C26H20F3NO4+H, 468.14227; found (ESI, [M+H]+), 468.1428.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[NH:15][CH:14]=[CH:13]3)[CH2:5][CH2:4]1.C=O.[C:23](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(#N)C>[CH3:1][N:2]([CH3:23])[C@H:3]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[NH:15][CH:14]=[CH:13]3)[CH2:5][CH2:4]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CN[C@H]1CC[C@H](Oc2ccc3c(=O)[nH]ccc3c2)CC1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN(C)[C@H]1CC[C@H](Oc2ccc3c(=O)[nH]ccc3c2)CC1
Reaction time: 0.33 h

Procedure:
A couple of drops of glacial acetic acid were added to a solution of trans-6(4-methylaminocyclohexyloxy)-2H-isoquinolin-1-one (Example 12; 25 mg, 92 μmol) and formaldehyde (40 μL) in acetonitrile (1 ml). The mixture was stirred for 20 minutes and then sodium triacetoxyborohydride (100 mg) was added. The mixture was stirred at ambient temperature for 16 hours then concentrated in vacuo. The residue was partitioned between chloroform/isopropanol (3:1) and aqueous sodium hydrogen carbonate. The organic layer was separated then concentrated to give a residue that was purified by prep-HPLC to give trans-6(4-dimethylaminocyclohexyloxy)-2H-isoquinolin-1-one, EI-MS: m/z=287.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH2:16])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CCO>C(OCC)(=O)C>[Cl:8][C:7]1[C:2]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH2:16])[CH2:11][CH2:10]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: NCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)CCO
Solvent: CCOC(C)=O
Product: NCC1CCN(c2ncccc2Cl)CC1
Temperature: 95 °C
Yield: 72.8 %

Procedure:
A stirred mixture of 2,3-dichloropyridine (20 g), 1-(piperid-4-yl)methylamine (30 g), sodium carbonate (30 g) and 3-methyl-1-butanol (100 ml) was heated at 95° C. for 16 hours, then cooled to ambient temperature, diluted with ethyl acetate (200 ml), and filtered. The solvents were removed in vacua, and the residual oil distilled to give 1-[1-(3-chloropyrid-2-yl)piperid-4-yl]methylamine as a colourless oil (22.2 g), b.p. 115°-140° C. at 0.13 mbar.