Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[NH:23][C:24]([C:27](=[O:31])[N:28]([CH3:30])[CH3:29])=[CH:25][CH:26]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:32]1[CH2:36][CH2:35][C@@H:34]([OH:37])[CH2:33]1.CCN(C(C)C)C(C)C>CC(O)C>[Cl:19][C:16]([F:17])([F:18])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:23][C:24]([C:27](=[O:31])[N:28]([CH3:30])[CH3:29])=[CH:25][CH:26]=3)[C:2]([N:32]3[CH2:36][CH2:35][C@@H:34]([OH:37])[CH2:33]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: CN(C)C(=O)c1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2Cl)[nH]1
Reactant: O[C@@H]1CCNC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2N2CC[C@@H](O)C2)[nH]1

Procedure:
A mixture of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(5-(dimethylcarbamoyl)-1H-pyrrol-2-yl)nicotinamide (Stage 73.1, 60 mg, 0.102 mmol), (R)-pyrrolidin-3-ol (17.82 mg, 0.205 mmol), DIPEA (71.5 μL, 0.409 mmol) and iPrOH (205 μL) in a sealed vial was subjected to MW irradiation at 140° C. for 1 h. The RM was purified by preparative SFC (Column NH2, isocratic 24% in 6 min.) to yield the title compound as a white solid. UPLC-MS (Condition 3) tR=1.03 min, m/z=520.1 [M+H]+, m/z=564.2 [M+FA−H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.69-1.78 (m, 1H) 1.78-1.89 (m, 1H) 2.96 (d, J=11.74 Hz, 1H) 3.13 (br. s, 6H) 3.25-3.31 (m, 2H) 3.38-3.51 (m, 1H) 4.20 (br. s, 1H) 4.86 (d, J=2.57 Hz, 1H) 6.11-6.21 (m, 1H) 6.57-6.66 (m, 1H) 7.33 (d, J=9.17 Hz, 2H) 7.82-7.92 (m, 2H) 8.04 (d, J=2.45 Hz, 1H) 8.71 (d, J=2.45 Hz, 1H) 10.15 (s, 1H) 11.66 (br. s, 1H).
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[N:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]2=[N:10][C:9]=1[CH:19]=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]([Mg]Br)=[CH2:22]>C1COCC1>[CH2:1]([C:8]1[C:13](=[O:14])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]2=[N:10][C:9]=1[CH:19]([OH:20])[CH:21]=[CH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1nc2ccccn2c(=O)c1Cc1ccccc1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)c1nc2n(c(=O)c1Cc1ccccc1)CCCC2
Temperature: -78 °C
Reaction time: 3 h
Yield: 104.8 %

Procedure:
A mixture of 2.5 g (9.5 mmol) of the product from Step 6 (16) in 35 mL THF was cooled to −78° C. To the resulting solution was added dropwise 11.4 mL (11.4 mmol) of vinyl magnesium bromide and stirred at −78° C. for 3 hours. The reaction was quenched with saturated NH4Cl and extracted with ethyl acetate (4×). The combined organic layers were dried over MgSO4 and the solvent was removed in vacuo yielding 2.95 g of 3-benzyl-2-(1-hydroxyprop-2-enyl)-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (23) as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[NH2:9][NH2:10]>N1C=CC=CC=1>[NH:9]([C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1)[NH2:10]
Reactant: Clc1ccc(I)cn1
Reactant: NN
Solvent: c1ccncc1
Product: NNc1ccc(I)cn1
Temperature: 25 °C
Yield: 27.5 %

Procedure:
The solution of 2-chloro-5-iodopyridine (2.0 g, 20.9 mmol), anhydrous hydrazine (3.3 mL, 105 mmol) in pyridine (40 mL) was heated at reflux overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue was added 1 N sodium hydroxide solution and it was extracted with EtOAc. The organic layer was separated, dried (sodium sulfate) and concentrated under reduced pressure. To the residue was added hexanes, and the precipitate was collected and dried in vacuo to afford the title compound (1.35 g, 69% yield) as off-white crystals. MS (ES+, m/z): 236.2 (M++1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[C:20]([C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1)#[N:21]>CCCCCC.C(OCC)(=O)C>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[CH:23][CH:24]=3)[N:3]=2)[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2ccc(C#N)cc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 40 %

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 4-cyanophenylboronic acid pinacol ester with reaction time of 15 h. Chromatography (hexane/ethyl acetate 1:1) gave the 40% of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:6][NH:5][C@@H:4]([C:7]([NH:9][C:10]2([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[O:8])[CH2:3]1.[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:1][C:2]1([CH3:23])[CH2:6][N:5]([CH2:30][C:29]2[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:34])[F:35])=[CH:33][CH:32]=2)[C@@H:4]([C:7]([NH:9][C:10]2([C:13]3[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=3)[CH2:12][CH2:11]2)=[O:8])[CH2:3]1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CC(C)(C)CN3)CC2)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CC(C)(C)CN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1

Procedure:
The title compound (D151) (100 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from (R)-methyl 4-(1-(4,4-dimethylpyrrolidine-2-carboxamido)cyclopropyl)benzoate (D108) (70 mg) and 4-(trifluoromethyl)-benzylbromide (0.041 ml). (Cs2CO3: 1.5 eq; reaction time: 20 hrs, RT)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=O)[CH:6]=[CH:7][CH:8]=1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+].O>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[N:17][OH:18])[CH:6]=[CH:7][CH:8]=1
Reactant: NO
Reactant: COc1cccc(C2CCCCC2=O)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cccc(C2CCCCC2=NO)c1

Procedure:
2-(3-Methoxyphenyl)-cyclohexanone, as described in Step A above, (0.61 g, 3 mmol), hydroxylamine hydrochloride (0.40 g, 6 mmol) and sodium acetate (0.80, 6.2 mmol) were combined in EtOH (4 mL): H2O (2 mL) and heated at reflux for 3 h. The reaction mixture was concentrated, then partitioned between EtOAc (100 mL) and H2O (100 mL), the organic layer separated, washed with H2O, brine, and dried (MgSO4). Filtration and concentration to dryness gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40]N)=[CH:36][CH:35]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:40][C:37]3[C:38]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(F)c3)CC2)c1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3cccc(F)c3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methylphenylhydrazine hydrochloride: ESMS m/e: 512.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:45]=[CH:44][C:7]([CH2:8][O:9][C:10]([CH:12]([N:16]2[CH:19]([S:20][N:21]3[C:25](=[O:26])[C:24]4=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]4[C:22]3=[O:31])[CH:18]([NH:32][C:33](=[O:42])[CH2:34][O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:17]2=[O:43])[C:13]([CH3:15])=[CH2:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:46]N1C(=O)CCC1=O>ClCCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([CH:12]([N:16]2[CH:19]([S:20][N:21]3[C:22](=[O:31])[C:23]4=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]4[C:25]3=[O:26])[CH:18]([NH:32][C:33](=[O:42])[CH2:34][O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:17]2=[O:43])[C:13]([CH2:15][Br:46])=[CH2:14])=[O:11])=[CH:44][CH:45]=1)([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Solvent: ClCCCl
Product: C=C(CBr)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Temperature: 70 °C
Yield: 25 %

Procedure:
A mixture of 1.26 g (2 mmoles) of 1-(1-p-nitro-benzyloxycarbonyl-2-methylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothio-azetidin-2-one, 0.71 g (4mmoles) of N-bromosuccinimide, 50 mg (0.3 mmole) of azoisobutyronitrile and 80 ml of 1,2-dichloroethane was heated in the dark under nitrogen at 70° C for 3 hours. After washing twice with a sodium metabisulfite solution and with water, the reaction mixture was dried and concentrated to a small volume. After treating the residue with hexane, 1.2 g of crude material was isolated which was purified with column chromatography [sillica gel, 10:1 (v/v) methylene chloride ethyl acetate] to obtain 0.33 g o (0.5 mmole; 23% yield) of 1-(1-p-nitrobenzyloxycarbony-2-bromomethylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothioazetidin-2-one.
Reaction SMILES: Cl.[CH:2]1([NH:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C1C=CC=CC=1.[CH3:16][C:17]1[O:18][C:19]([CH3:25])=[CH:20][C:21]=1[C:22](Cl)=[O:23]>C(N(CC)CC)C>[CH:2]1([N:8]([C:22]([C:21]2[CH:20]=[C:19]([CH3:25])[O:18][C:17]=2[CH3:16])=[O:23])[OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: ONC1CCCCC1
Reactant: Cc1cc(C(=O)Cl)c(C)o1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N(O)C2CCCCC2)c(C)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
16.6 Parts of N-cyclohexylhydroxylamine hydrochloride is added to 300 parts of benzene; 20.2 parts of triethylamine is then introduced into the mixture. After stirring the mixture for 1 hour at room temperature, 15.9 parts of 2,5-dimethylfuran-3-carboxylic chloride is dripped in. The mixture is then stirred for a further hour and the precipitate is suction filtered, washed with water and then with petroleum ether, and dried. There is obtained 18.2 parts of N-cyclohexyl-2,5-dimethylfuran- 3-hydroxamic acid; m.p.: 135° - 137° C. ##SPC7##
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=1[O:7][CH2:8][CH:9]([OH:25])[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:13][CH2:12]1)(=[O:3])[NH2:2].[C:30](OC(=O)C)(=[O:32])[CH3:31].[OH-].[Na+]>N1C=CC=CC=1>[C:1]([CH2:4][C:5]1[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=1[O:7][CH2:8][CH:9]([O:25][C:30](=[O:32])[CH3:31])[CH2:10][N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:15][CH2:16]1)(=[O:3])[NH2:2]
Reactant: COc1ccccc1N1CCN(CC(O)COc2ccccc2CC(N)=O)CC1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COc1ccccc1N1CCN(CC(COc2ccccc2CC(N)=O)OC(C)=O)CC1
Temperature: 0 °C

Procedure:
Two grams of 1-(2-carbamoylmethylphenoxy)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-2-ol are added to 20 ml. of anhydrous pyridine, followed by the immediate addition of 8.0 g. of acetic anhydride with stirring. The resulting solution is refluxed for a period of 5 minutes, cooled and subsequently poured into 50 ml. of ice water, basified with 2N aqueous sodium hydroxide solution and extracted with chloroform. The organic phase is then washed with water, dried over anhydrous sodium sulfate and evaporated to yield the crude product. After recrystallization from ethanol, there is obtained pure 1-(2-carbamoylmethylphenoxy)-3-[4-(2-methoxyphenyl)piperazin-1-yl]-2-acetoxypropane as final product.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]([CH2:15][CH3:16])[C:13]#[N:14].[CH2:17](N)[CH2:18][NH2:19]>>[F:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]([C:13]1[NH:19][CH2:18][CH2:17][N:14]=1)[CH2:15][CH3:16]
Reactant: NCCN
Reactant: CCC(C#N)c1cccc(C(F)(F)F)c1F
Product: CCC(C1=NCCN1)c1cccc(C(F)(F)F)c1F

Procedure:
rac-2-[1-(2-Fluoro-3-trifluoromethyl-phenyl)-propyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(2-fluoro-3-trifluoromethyl-phenyl)-butyronitrile and ethylene diamine in analogy to Example 19 b): colourless powder; MS (ISP): 275.0 ((M+H)+.).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:15]=1[O:16][C:17]1[CH:29]=[CH:28][C:20]([C:21]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>>[Cl:34][C:32]1[CH:31]=[CH:30][C:15]([O:16][C:17]2[CH:29]=[CH:28][C:20]([C:21]([N:23]([CH2:24][CH3:25])[CH2:26][CH3:27])=[O:22])=[CH:19][CH:18]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:33]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CCN(CC)C(=O)c1ccc(Oc2ccc(Cl)cc2N)cc1
Product: CCN(CC)C(=O)c1ccc(Oc2ccc(Cl)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (111 mg, 0.62 mmol) was reacted with the product from Example 129b (199 mg, 0.62 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (49.2 mg, 14%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.01 (s, 6H) 2.73 (s, 3H) 3.35 (s, 1 H) 3.53-3.81 (m, 4 H) 6.70 (d, J=7.35 Hz, 1 H) 6.93 (d, J=8.46 Hz, 2 H) 7.22 (d, J=8.82 Hz, 2 H) 7.34 (d, J=8.82 Hz, 1 H) 7.62 (dd, J=8.82, 2.57 Hz, 1 H) 7.73 (d, J=6.25 Hz, 1 H) 7.75 (s, 1 H) 8.53 (d, J=6.99 Hz, 1 H) 8.82 (d, J=8.82 Hz, 1 H) 10.92 (s, 1 H) 14.55 (s, 1 H); MS (ESI+) m/z 461 (M+H−TFA)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][C:12](OC)=[O:13])[C:6]=1[N+:16]([O-])=O.[H][H]>O1CCCC1.CO.[Pd]>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[NH:16][C:12](=[O:13])[CH2:11]2
Reactant: COC(=O)Cc1cccc(CC(=O)OC)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)Cc1cccc2c1NC(=O)C2

Procedure:
A solution of 2-nitro-1,3-benzenediacetic acid dimethyl ester (5.98 g, 0.022 mole) in tetrahydrofuran and methanol (2:1, 100 ml) is treated with hydrogen gas in the presence of 20% Pd/C for 18 hours. The mixture is filtered and concentrated at reduced pressure to yield 2,3-dihydro-2-oxo-1H-indole-7-acetic acid methyl ester. Final purification is accomplished using flash chromatography on silica (elution with 1:19 methanol:dichloromethane) and results in pure 2,3-dihydro-2-oxo-1H-indole-7-acetic acid methyl ester, mp 156°-157° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.N1C=CC=CC=1.[CH2:31]([S:33](Cl)(=[O:35])=[O:34])[CH3:32]>ClCCl>[CH2:31]([S:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:22][CH2:23]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1)(=[O:35])=[O:34])[CH3:32]
Reactant: CCS(=O)(=O)Cl
Reactant: Cc1ccc(N)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc(C)c(-c2ccc3cc(NC(=O)C4CC4)ncc3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
To a solution of N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide (56.2 mg, 0.177 mmol) in methylene chloride (2.0 mL, 31 mmol) was added pyridine (0.20 mL, 2.5 mmol) and ethanesulfonyl chloride (23.0 uL, 0.243 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into dichloromethane, washed with water, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 39.5 mg (54%) of N-(7-(5-(ethylsulfonamido)-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (min)=4.534, M+H=410.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.73 (s, 1H), 9.18 (s, 1H), 8.49 (s, 1H), 7.98 (s, 1H), 7.92 (d, J=8.6 Hz, 1H), 7.66 (dd, J=8.5, 1.6 Hz, 1H), 7.29 (d, J=8.2 Hz, 1H), 7.18 (dd, J=8.1, 2.3 Hz, 1H), 7.15 (d, J=2.2 Hz, 1H), 3.10 (q, J=7.3 Hz, 2H), 2.21 (s, 3H), 2.12-2.04 (m, 1H), 1.21 (t, J=7.3 Hz, 3H), 0.84 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:5]2[N:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1.[O-:20][CH2:21][CH3:22].[Na+]>C(O)C>[CH2:21]([O:20][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:5]2[N:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1)[CH3:22]
Reactant: CC[O-]
Reactant: Cc1ccc(-n2c(=O)c(Cl)nc3cccnc32)cc1
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc2cccnc2n(-c2ccc(C)cc2)c1=O

Procedure:
Preparation as in Example 26 but using 2-chloro-3,4-dihydro-4-(4-methylphenyl)-3-oxopyrido[2,3-b]pyrazine and sodium ethoxide in ethanol gave the title compound which was identified by NMR Delta 1.50 (t) 3H, delta 2.43 (s) 3H, delta 4.59 (q) 2H, delta 7.05-7.45 (m) 5H, delta 7.91 (q) 1H, delta 8.27 (q) 1H.
Reaction SMILES: [C:1]1([NH2:9])(N)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[NH2:7].[C:10](OC)(=O)[C:11](OC)=O>>[N:7]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=[CH:11][CH:10]=1
Reactant: NC1CCCCC1(N)N
Reactant: COC(=O)C(=O)OC
Product: c1ccc2nccnc2c1

Procedure:
By the reaction of the cyclohexanetriamine with dimethyl oxalate to give a quinoxaline derivative in step d) of the process according to the invention, a racemate comprising two enantiomers is formed.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[Cl:12][C:13]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:14]=1[C:15]([N:17]=[C:18]=[O:19])=[O:16]>>[Cl:12][C:13]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:14]=1[C:15]([NH:17][C:18]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:8][N:7]=1)=[O:19])=[O:16]
Reactant: O=C=NC(=O)c1c(F)cccc1Cl
Reactant: Nc1ccc(C(F)(F)F)cn1
Product: O=C(NC(=O)c1c(F)cccc1Cl)Nc1ccc(C(F)(F)F)cn1

Procedure:
A portion of 5-trifluoromethyl-2-aminopyridine is reacted with 2-chloro-6-fluorobenzoyl isocyanate as described in Example 1. The reaction mixture is evaporated under vacuum and the product is recrystallized to obtain the product named above.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:14]2[N:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:36][O:37][CH3:38])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][N:40]1[CH:44]=[CH:43][C:42](B2OC(C)(C)C(C)(C)O2)=[N:41]1.C(=O)([O-])O.[Na+].O>COCCOC.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:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:14]2[N:19]=[CH:18][C:17]([C:43]3[CH:42]=[N:41][N:40]([CH3:39])[CH:44]=3)=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:36][O:37][CH3:38])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(Br)cn2)CN1C(=O)OC(C)(C)C
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1C(=O)OC(C)(C)C
Temperature: 95 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
A mixture of ((2S,4S)-4-(5-bromo-pyrimidin-2-ylamino)-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.84 mmol; 1.1 g), 3,5-bis(trifluoromethyl)benzyl bromide (4.3 mmol; 0.78 mL) and sodium hydride (60% dispersion in mineral oil, 4.3 mmol; 0.17 g) in DMF (9 mL) is stirred for 1 hour at room temperature under nitrogen. The reaction mixture is quenched with water then saturated ammonium chloride solution. The product is extracted twice with EtOAc. The combined organic layer is washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue is passed though silica pad (eluent: n-hexane/EtOAc) to give (2S,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester. To a mixture of (2S,4S)-4-[(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester, 1-methylpyrazol-3-yl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (7.1 mmol, 1.48 g), tetrakis(triphenylphosphine)palladium(0) (0.43 mmol, 490 mg) and 2M aqueous sodium hydrogen carbonate (3.6 mL) in 1,2-dimethoxy-ethane (4 mL) is allowed to warm to 95° C. and stirred for 3 hours. The mixture is cooled to room temperature and then added water. The mixture is extracted with CH2Cl2, and the combined organic layer is dried over Na2SO4, filtrated, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc) to give (2S,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.3 g, 74% overall yield for 2 steps); ESI-MS m/z: 615 [M+1]+, Retention time 2.12 min (condition A).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH3:10])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1.[BH4-].[Na+].[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25]>C(O)C.CCOCC>[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:12][CH2:13][CH2:14][CH2:15][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: NCCCn1ccnc1
Reactant: CCC(=O)c1ccc(Cl)cc1
Agent: O=C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CCC(NCCCn1ccnc1)c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
In a similar manner to Example 1, a mixture of 4'-chloropropiophenone (8.4 g) and 1-(3-aminopropyl)imidazole (6.3 g) was heated at 120° C. for 9 hours. The cooled mixture was dissolved in absolute ethanol (100 ml), treated with sodium borohydride (3.9 g) and boiled under reflux for 16 hours. The oil obtained after work-up was dissolved in ether and treated with ethereal oxalic acid until the mixture was just acidic. The solid was filtered off and recrystallised from ethanol to give N-[1-(4-chlorophenyl)propyl]-3-(imidazol-1-yl)propylamine oxalate, m.p. 189°-190° C.