Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH3:33][C:34]1([CH3:37])[CH2:36][O:35]1>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:33][C:34]([OH:35])([CH3:37])[CH3:36])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC1(C)CO1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(CC(C)(C)O)CC4)cn3)nc2n1C1CCCC1
Yield: 29.2 %

Procedure:
Following General Procedure E, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (50 mg, 0.115 mmol) and 2,2-dimethyloxirane (72 mg, 0.805 mmol) gave 7-cyclopentyl-2-{5-[4-(2-hydroxy-2-methyl-propyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (17 mg, 29%). MS (ESI) m/z 507.3 (M+H)|
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].O[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[C:29]=1[C:36](=[O:38])[CH3:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:36]([C:29]1[C:30]([O:34][CH3:35])=[CH:31][CH:32]=[CH:33][C:28]=1[O:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])(=[O:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: COc1cccc(O)c1C(C)=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc(OCCCNC(=O)OC(C)(C)C)c1C(C)=O
Reaction time: 18 h
Yield: 42.3 %

Procedure:
Diisopropyl azodicarboxylate (2.82 g, 14.0 mmol) is added to a stirred solution of tert-butyl 3-hydroxypropylcarbamate (2.45 g, 14.0 mmol), 1-(2-hydroxy-6-methoxyphenyl)ethanone (1.94 g, 11.7 mmol) and triphenylphosphine (3.66 g, 14.0 mmol) in THF (50 mL) at room temperature. After stirring for 18 h, the solvent is removed under reduced pressure and the crude product is chromatographed (hexane-ethyl acetate: 0-60% gradient) to afford 1.60 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[N:20]3)=[C:15](OS(C(F)(F)F)(=O)=O)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH2:31][CH2:32][C@H:33]1[CH2:37][NH:36][C:35](=[O:38])[CH2:34]1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O.O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[N:20]3)=[C:15]([NH:31][CH2:32][C@H:33]3[CH2:37][NH:36][C:35](=[O:38])[CH2:34]3)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: NC[C@H]1CNC(=O)C1
Reactant: COc1cc(-c2cc3ncccc3c(OS(=O)(=O)C(F)(F)F)n2)cc(OC)c1OC
Solvent: CC(=O)N(C)C
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2cc3ncccc3c(NC[C@H]3CNC(=O)C3)n2)cc(OC)c1OC
Temperature: 70 °C

Procedure:
100 mg 6.1 and 30 mg of (S)-4-(aminomethyl)pyrrolidin-2-one (2.2) were dissolved in dimethylacetamide. 0.175 mL of diisopropylethylamine was added and the mixture was heated at 70° C. overnight. The mixture was diluted with water and methanol and purified via chromatography (RP-HPLC) and the corresponding fractions were freeze-dried.
Reaction SMILES: [CH2:1]([N:8]([CH2:39][CH3:40])[C:9](=O)[CH:10]([O:35][CH2:36][CH3:37])[CH2:11][C:12]1[CH:34]=[CH:33][C:15]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=O)OC(C)(C)C)=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CSC.B.C(OC(=O)C)C.CCCCCCC>C1COCC1>[CH2:1]([N:8]([CH2:39][CH3:40])[CH2:9][CH:10]([O:35][CH2:36][CH3:37])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([NH:25][CH3:26])=[CH:23][CH:24]=2)=[CH:33][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)C(=O)N(CC)Cc1ccccc1
Agent: B
Solvent: CCOC(C)=O
Solvent: CSC
Solvent: CCCCCCC
Product: CCOC(Cc1ccc(OCCc2ccc(NC)cc2)cc1)CN(CC)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
tert-Butyl 4-[2-(4-{3-[benzyl(ethyl)amino]-2-ethoxy-3-oxopropyl}phenoxy)ethyl]phenylcarbamate (5.2 g, 9.5 mmole) was dissolved in dry THF and cooled to 0° C. Borane methylsulfide (2 M, 11.9 ml, 23.8 mmole) was added dropwise. The reaction mixture was stirred at 0° C. for 0.5 hours after which it was allowed to reach room temperature and then refluxed for 5 hours. The reaction was quenched with water, extracted three times with ethyl acetate dried with magnesium sulfate and evaporated. The residue was redissolved in ethylacetate and chromatography on silica using a gradient system of ethylacetate:heptane (0-100%) gave 2.55 g (49% yield) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([NH2:14])=[CH:12][CH:11]=[N:10]1.[CH3:15][C:16](OC(C)=O)=[O:17].CCN(CC)CC.[OH-].[K+].Cl>ClCCCl.CN(C1C=CN=CC=1)C.C(Cl)Cl.CCO.CC(O)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([NH:14][C:16](=[O:17])[CH3:15])=[CH:12][CH:11]=[N:10]1
Reactant: Nc1ccnn1-c1ccc(F)cc1F
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [K+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)Nc1ccnn1-c1ccc(F)cc1F
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A solution of 1-(2,4-difluorophenyl)-1H-pyrazol-5-amine (5.00 g, 26 mmol), in 80 mL of 1,2-DCE was added DMAP (0.94 g, 7.7 mmol), Ac2O (12 mL, 128 mmol) and Et3N (18 mL, 128 mmol). The dark brown reaction mixture was heated at 80° C. in an oil bath for 18 h. After cooling to RT, it was diluted with 20 mL of DCM and washed with saturated aqueous solution of sodium bicarbonate, and brine. The resulting organic solution was then dried over magnesium sulfate and concentrated under reduced pressure to give viscous brown oil which contains the bis-acylated product along with residual amount of Ac2O and AcOH. The viscous brown oil was dissolved in 50 mL of EtOH and treated with KOH (5.0 g 129 mmol). After the reaction mixture was stirred at RT for 4 h, it was acidified with 2 N HCl to pH 4. The volatile portion was removed on the rotovap. The residue was diluted with 150 mL of EtOAc, washed with saturated aqueous solution of sodium bicarbonate, and brine. The resulting organic solution was then dried over magnesium sulfate and concentrated under reduced pressure. Purification of the crude material on an ISCO 80 g column (60-100% EtOAc in hexanes) afforded N-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)acetamide as an off-white solid. MS (ES+): 238.1 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[C:25]([NH:27][C:28]4[CH:32]=[C:31]([CH3:33])N(C)[N:29]=4)[C:24](=[O:35])[N:23]([CH3:36])[CH:22]=3)[C:16]=1[CH2:37][OH:38])[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[C:39](OCC1C(B2OC(C)(C)C(C)(C)O2)=CC=CC=1N1CC2C(=CC=C(C(C)(C)C)C=2)C1=O)(=O)C.BrC1C=C(NC2C=CC=CN=2)C(=O)N(C)C=1>>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[C:25]([NH:27][C:28]4[CH:32]=[CH:31][CH:33]=[CH:39][N:29]=4)[C:24](=[O:35])[N:23]([CH3:36])[CH:22]=3)[C:16]=1[CH2:37][OH:38])[CH2:8]2)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Reactant: Cc1cc(Nc2cc(-c3cccc(N4Cc5cc(C(C)(C)C)ccc5C4=O)c3CO)cn(C)c2=O)nn1C
Agent: Cn1cc(Br)cc(Nc2ccccn2)c1=O
Product: Cn1cc(-c2cccc(N3Cc4cc(C(C)(C)C)ccc4C3=O)c2CO)cc(Nc2ccccn2)c1=O
Yield: 34 %

Procedure:
Using the same general procedure as described for the preparation of 105, reaction 103f (298 mg, 0.643 mmol) with 113a (150 mg, 0.536 mmol) gave a 34% yield (90 mg) of 113 as a white solid: mp 138-139° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.68 (d, 1H, J=2.0 Hz), 8.58 (s, 1H), 8.17 (m, 1H), 7.73-7.71 (m, 2H), 7.62-7.56 (m, 2H), 7.50 (t, 1H, J=7.5 Hz), 7.44 (d, 1H, J=7.5 Hz), 7.39-7.37 (m, 2H), 7.28 (d, 1H, J=7.5 Hz), 6.78 (dd, 1H, J=6.5, 5.0 Hz), 4.94 (s, 2H), 4.89 (t, 1H, J=4.5 Hz), 4.34 (d, 2H, J=4.5 Hz), 3.60 (s, 3H), 1.65 (s, 9H); MS (ESI+) m/z 495.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]([CH3:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])=[O:5].[Li+].CC([N-]C(C)C)C.CCCCCCC.C1C[O:38][CH2:37]C1.C(C1C=CC=CC=1)C.CN(C=O)C.O>C1COCC1>[Br:1][C:2]1[C:3]2[C:4](=[O:5])[N:6]([C:7]([CH3:15])([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:8])[CH:37]([OH:38])[C:16]=2[CH:17]=[CH:18][N:19]=1
Reactant: CC(C)(NC(=O)c1cccnc1Br)c1ccccc1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: CC(C)(c1ccccc1)N1C(=O)c2c(ccnc2Br)C1O
Reaction time: 1.6 h
Yield: 25.3 %

Procedure:
2-Bromo-N-(1-methyl-1-phenylethyl)nicotinamide (500 mg, 1.57 mmol) was dissolved in THF (20 mL), and the solution was added with LDA-heptane/THF/ethylbenzene solution (2.0 mol/L, 3.5 mL, 7.1 mmol) by drops at −78° C. for 25 minutes under argon atmosphere, followed by stirring at the same temperature for 1.6 hours. Then, the mixture was added with DMF (0.267 mL, 3.45 mmol) and warmed from −78° C. to room temperature over 1 hour. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (chloroform/methanol=100/1 to 97/3) to obtain 4-bromo-1-hydroxy-2-(1-methyl-1-phenylethyl)-1,2-dihydropyrrolo[3,4-c]pyridine-3-one (138 mg, yield 25%).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>C(O)C>[F:8][C:7]1[C:2]([NH:10][NH2:11])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1cccnc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1ncccc1F
Temperature: 60 °C
Reaction time: 72 h

Procedure:
To a solution of 9.59 g of 2-chloro-3-fluoropyridine in 6 ml of ethanol there was added 6 ml of hydrazine monohydrate, and the mixture was stirred at 60° C. for 3 days. The solution was adsorbed onto 50 g of NH silica gel and purified by NH silica gel column chromatography (ethyl acetate-heptane) to give the title compound (403 mg) as a yellow solid.
Reaction SMILES: Br[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[C:11]1(=[O:24])[C:16]2=[CH:17][C:18]3[CH2:19][CH2:20][CH2:21][CH2:22][C:23]=3[N:15]2[CH:14]=[CH:13][NH:12]1.C(=O)([O-])[O-].[Cs+].[Cs+].COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1>[Cu]I.O1CCOCC1>[Cl:10][C:6]1[C:3]([CH:4]=[O:5])=[C:2]([N:12]2[CH:13]=[CH:14][N:15]3[C:23]4[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=4[CH:17]=[C:16]3[C:11]2=[O:24])[N:9]=[CH:8][CH:7]=1
Reactant: O=c1[nH]ccn2c3c(cc12)CCCC3
Reactant: O=Cc1c(Cl)ccnc1Br
Agent: [Cu]I
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=Cc1c(Cl)ccnc1-n1ccn2c3c(cc2c1=O)CCCC3
Temperature: 80 °C
Yield: 64.2 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (15 mL), 2-bromo-4-chloronicotinaldehyde 103a (503 mg, 2.28 mmol), 195e (142 mg, 0.76 mmol), cesium carbonate (490 mg, 1.5 mmol), CuI (143 mg, 0.76 mmol), and 4,7-dimethoxy-1,10-phenanthroline (127 mg, 0.52 mmol). After three cycles of vacuum/argon flush, the mixture was heated at 80° C. for 10 hrs. It was then cooled to room temperature and filtered. The filtrate was washed with brine and concentrated under reduced pressure. The resulting residue was purified with silica-gel column chromatography eluting with 1:4 ethyl acetate/petroleum ether to afford 195f (160 mg, 65%) as a yellow solid. MS-ESI: [M+H]+ 328.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12](Cl)(=[O:14])=[O:13])[N:11]=[C:4]2[N:3]=1.[CH3:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:18]=1[NH2:19].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12]([NH:19][C:18]3[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:17]=3[CH3:16])(=[O:14])=[O:13])[N:11]=[C:4]2[N:3]=1
Reactant: Cc1cc(C)n2nc(S(=O)(=O)Cl)nc2n1
Reactant: Cc1cccc(C)c1N
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C)n2nc(S(=O)(=O)Nc3c(C)cccc3C)nc2n1
Yield: 97.7 %

Procedure:
A solution of 2.2. g (8.9 mmol) of 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonyl chloride, 1.01 ml (8.4 mmol) of 2,6-dimethylaniline, 0.7 ml (8.4 mmol) of dry pyridine and 4 mg of DMAP in 20 ml of CH2Cl2 was stirred at room temperature for 17 hours. The solvent was removed by evaporation and the residue was taken up in 0.5M NaOH. The solution was extracted with diethyl ether and the aqueous phase was acidified with 3N HCl to precipitate a solid. The solid was collected by filtration and dried in vacuo to yield 2.72 g (97 percent) of the desired product as a white solid, m.p. 263°-266° C. (decomp.): 1H NMR (DMSO--d6)δ10.4 (1H, broad S), 7.55 (1H, s), 7.2 (3H, s), 2.7 and 2.8 (3H each, s) and 2.1 (6H, s); IR (KBr) 3100, 2980-2780, 1628, 1540 and 1355 cm-1
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.C(Cl)(=O)C([Cl:24])=O>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([Cl:24])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cl)CNC(=O)OCc1ccccc1

Procedure:
To a mixture of N-[(benzyloxy)carbonyl]glycine (0.78 g, 3.8 mmol), N,N-dimethylformamide (0.1 ml) and tetrahydrofuran (20 ml) was added dropwise oxalyl chloride (0.33 ml, 3.7 mmol) under ice-cooling. The mixture was stirred under ice-cooling for 1 hr. to give a crude product of N-[(benzyloxy)carbonyl]glycyl chloride. To a mixture of tert-butyl N-[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]glycinate (0.40 g, 0.75 mmol), pyridine (0.3 ml, 3.7 mmol) and tetrahydrofuran (100 ml) was added dropwise the crude product. The obtained mixture was stirred for 1 hr. and 4-dimethylaminopyridine (0.01 g, 0.82 mmol) was added, and the mixture was stirred at room temperature for 2 days. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give tert-butyl N-[(benzyloxy)carbonyl]glycyl-N-[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]glycinate (0.47 g, yield 87%) as a white powder.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.CC(C)([O-])C.[K+].[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Cl>CN(C)C=O>[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][O:9][CH:6]1[CH2:7][CH2:8][C:3]([N:2]([CH3:16])[CH3:1])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH2:5]1
Reactant: CN(C)C1(c2ccccc2)CCC(O)CC1
Reactant: Fc1ccccc1CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C1(c2ccccc2)CCC(OCc2ccccc2F)CC1
Temperature: 0 °C
Yield: 14.1 %

Procedure:
2.75 g of 4-dimethylamino-4-phenylcyclohexanol were dissolved in 20 ml of dimethylformamide; 1.55 g of potassium tert.-butoxide were added and stirring was carried out for 45 minutes, before 2.0 g of 2-fluorobenzyl chloride were added dropwise in the course of 30 minutes. After stirring overnight, the mixture was added to 25 ml of ice-water and extracted repeatedly with ethyl acetate. The combined extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The resulting crude product (3.41 g) was separated on silica gel with methanol/ethyl acetate (V:V=1:1). 580 mg of [4-(2-fluoro-benzyloxy)-1-phenylcyclohexyl]dimethylamine were obtained in the form of a white solid which, as described for Example 1, was converted into 370 mg of the corresponding hydrochloride using chlorotrimethylsilane and water in 2-butanone.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:9]2[C:8](=[O:14])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C.O>C(O)C>[CH:15]1([NH:21][C:2]2[C:11]([C:12]#[N:13])=[CH:10][C:9]3[C:8](=[O:14])[CH2:7][CH2:6][CH2:5][C:4]=3[N:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCCC1
Reactant: N#Cc1cc2c(nc1Cl)CCCC2=O
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1cc2c(nc1NC1CCCCC1)CCCC2=O
Yield: 59.4 %

Procedure:
A solution of 2-chloro-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbonitrile (0.154 g, 0.75 mmol), cyclohexylamine (0.15 g, 1.5 mmol) and triethylamine (0.115 ml, 0.083 g, 0.82 mmol) in ethyl alcohol (3 ml) was heated at reflux for 3 h. Then water (10 ml) was added and the precipitated solid was filtered off and recrystallized from ethyl alcohol to give the title compound (0.12 g, 59%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][N:16]2[C:21](=[O:22])[NH:20][C:19]3[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:18]=3[S:17]2(=[O:30])=[O:29])[CH2:9][CH2:8]1.[H-].[Na+].[CH3:33]I>CN(C=O)C>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]2[C:21](=[O:22])[N:20]([CH3:33])[C:19]3[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:18]=3[S:17]2(=[O:29])=[O:30])[CH2:11][CH2:12]1
Reactant: CI
Reactant: COc1ccc2c(c1)S(=O)(=O)N(CCCN1CCN(c3ncccn3)CC1)C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)S(=O)(=O)N(CCCN1CCN(c3ncccn3)CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.028 mol of 2-(3-(4-(2-pyrimidinyl)-1-piperazinyl)propyl)-7-methoxy-1,2,4-benzothiadiazin-3(4H)one 1,1-dioxide is dissolved in 150 ml of absolute DMF, and 0.028 mol of sodium hydride is added to the solution and the mixture is stirred at room temperature for 0.25 hour. Then 0.028 mol of methyl iodide is added and the mixture is stirred at 25° C. for a further 2 hours. The product is precipitated as crystals by dropwise addition of a total of 18 ml of water. It is purified by crystallisation from isopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]3([CH2:20][NH2:21])[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[N:12]=2)=[CH:4][CH:3]=1.[F:22][C:23]([F:39])([F:38])[C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32](O)=[O:33])[N:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]3([CH2:20][NH:21][C:32](=[O:33])[C:31]4[CH:35]=[CH:36][CH:37]=[C:29]([C:26]5[N:25]=[C:24]([C:23]([F:39])([F:38])[F:22])[O:28][N:27]=5)[CH:30]=4)[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: CN1CCC(CN)(c2csc(-c3ccc(Cl)cc3)n2)CC1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: CN1CCC(CNC(=O)c2cccc(-c3noc(C(F)(F)F)n3)c2)(c2csc(-c3ccc(Cl)cc3)n2)CC1
Yield: 23 %

Procedure:
This compound was synthesized from (4-(2-(4-chlorophenyl)thiazol-4-yl)-1-methylpiperidin-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (50 mg, yield 23%). 1H NMR (400 MHz, DMSO-d6) δ 8.54-8.51 (m, 1H), 8.39 (m, 1H), 8.18-8.16 (d, J=7.6 Hz, 1H), 8.04-8.02 (d, J=7.6 Hz, 1H), 7.91-7.89 (d, J=8.2 Hz, 2H), 7.69-7.65 (t, J=7.8 Hz, 1H), 7.52-7.49 (m, 3H), 3.49-3.48 (m, 2H), 2.66-2.63 (m, 2H), 2.31-2.28 (m, 2H), 2.12-2.04 (m, 5H), 1.90-1.84 (m, 2H). MS (ESI) m/z: Calculated for C26H23ClF3N6O2S: 561.12. found: 562.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([N+:13]([O-])=O)=[C:11]([C:16]([OH:18])=[O:17])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:19]([F:22])([F:21])[F:20])=[N:8]2>C(O)C.[Ni]>[NH2:13][C:12]1[C:3]([O:2][CH3:1])=[C:4]2[C:9](=[CH:10][C:11]=1[C:16]([OH:18])=[O:17])[N:8]=[C:7]([C:19]([F:20])([F:21])[F:22])[CH:6]=[CH:5]2
Reactant: COc1c([N+](=O)[O-])c(C(=O)O)cc2nc(C(F)(F)F)ccc12
Agent: [Ni]
Solvent: CCO
Product: COc1c(N)c(C(=O)O)cc2nc(C(F)(F)F)ccc12

Procedure:
A sample of 5-Methoxy-6-nitro-2-trifluoromethyl-quinoline-7-carboxylic acid is hydrogenated in ethanol in the presence of Raney-Ni analogously to the procedure described for example H-18, step g). This gives the title product as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:5]=1.[CH2:28](Br)[CH:29]=[CH2:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([N:16]([CH2:30][CH:29]=[CH2:28])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:5]=1
Reactant: COC(=O)c1cc(NC(=O)OCc2ccccc2)cc(N2CCCC2=O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN(C(=O)OCc1ccccc1)c1cc(C(=O)OC)cc(N2CCCC2=O)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A suspension of 3.69 g (8.1 mmol) 3-benzyloxycarbonylamino-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester, 1.37 ml (16.2 mmol) allyl bromide, 2.24 g (16.2 mmol) potassium carbonate in 8 ml DMF is stirred at 50° C. for 4 h. The mixture is diluted with water and extracted with EtOAc. The organic phase is washed with water and dried over sodium sulfate. The product is purified by chromatography on silica gel (EtOAc/hexanes 1:4, 1:2, 1:1, 2:1). The title compound is isolated as a yellow resin.
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[S:14][CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=2)=O)=[C:8]([CH3:21])[C:7]([O:22][CH3:23])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1N=C(C2C=C(O)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[CH:18]([C:16]1[N:17]=[C:13]([C:11]2[CH:2]=[C:1]([OH:3])[C:4]3[C:9](=[C:8]([CH3:21])[C:7]([O:22][CH3:23])=[CH:6][CH:5]=3)[N:10]=2)[S:14][CH:15]=1)([CH3:20])[CH3:19]
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1C
Agent: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1C
Yield: 60 %

Procedure:
Compound 218b was synthesized from compound 217b as a yellow solid in 60% yield, according to the procedure as described for compound 218a. MS (ESI, EI+): m/z=315 (MH+).
Reaction SMILES: S=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]2[CH2:4][NH:3]1.[CH3:21][O:22][CH:23]([O:26][CH3:27])[CH2:24][NH2:25]>O>[CH3:21][O:22][CH:23]([O:26][CH3:27])[CH2:24][NH:25][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]2[CH2:4][N:3]=1
Reactant: COC(CN)OC
Reactant: CCOC(=O)c1ncn2c1CNC(=S)c1ccccc1-2
Solvent: O
Product: CCOC(=O)c1ncn2c1CN=C(NCC(OC)OC)c1ccccc1-2

Procedure:
2.1. 6.0 g of ethyl 5,6-dihydro-6-thioxo-4H-imidazo-[1,5-a][1,4]benzodiazepine-3-carboxylate in 40 ml of amino-acetaldehyde dimethyl acetal are stirred at 85° C. for 48 h. The mixture is diluted with 150 ml of water and extracted four times with ethyl acetate. The organic extracts are washed with saturated aqueous sodium chloride solution and evaporated in a vacuum. The residue is chromatographed over silica gel. Elution is carried out with dichloromethane/ethanol 99:1, 98:2 and 97:3. The crude eluate is recrystallized from ethyl acetate/diisopropyl ether. There are obtained 4.3 g of pure ethyl 6-[(2,2-dimethoxy-ethyl)amino]-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxylate of m.p. 121°-122° C.