Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a white solid (399 mg).
Reaction SMILES: Cl.Cl.[CH2:3]([CH:5]1[C:13]2[C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:11][CH:10]=[N:9][C:8]=2[CH2:7][S:6]1)[CH3:4].[C:20]([O:24][C:25]([NH:27][C@H:28]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([F:40])[CH:34]=1)[C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(N(CC)CC)C>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][C@@H:28]([NH:27][C:25](=[O:26])[O:24][C:20]([CH3:21])([CH3:22])[CH3:23])[C:29]([N:17]2[CH2:16][CH2:15][N:14]([C:12]3[C:13]4[CH:5]([CH2:3][CH3:4])[S:6][CH2:7][C:8]=4[N:9]=[CH:10][N:11]=3)[CH2:19][CH2:18]2)=[O:30])=[CH:34][C:35]=1[F:40]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)c(F)c1)C(=O)O
Reactant: CCC1SCc2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1SCc2ncnc(N3CCN(C(=O)[C@@H](Cc4ccc(Cl)c(F)c4)NC(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of 5-ethyl-4-(piperazin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine dihydrochloride (50 mg, 0.15 mmol) and (R)-2-(tert-butoxycarbonylamino)-3-(4-chloro-3-fluorophenyl)propanoic acid (49 mg, 0.15 mmol) in DCM (10 mL) and triethylamine (1 mL) was added HBTU (59 mg, 0.15 mmol). The mixture was stirred at room temperature for 3 hours. The solvent was removed and the residue was purified by silica gel chromatography, eluting with DCM/ethyl acetate (1:1) to give tert-butyl (R)-3-(4-chloro-3-fluorophenyl)-1-(4-(5-ethyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (80 mg, 90%). 1H NMR (CDCl3, 400 MHz) δ 8.54 (s, 1H), 7.40-6.90 (m, 3H), 5.36 (m, 1H), 4.82 (m, 1H), 4.65 (m, 1H), 4.12 (m, 1H), 3.90-3.18 (m, 8H), 3.04-2.89 (m, 2H). 1.95 (m, 1H), 1.57 (m, 1H), 1.42 (s, 9H), 0.94 (m, 3H). MS (APCI+) [M+H]+ 551.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:13][C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[N:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(OCC)C>CO.[Pd]>[CH3:27][N:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:12]3[O:13][C:9]([C:5]4[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=4)=[CH:10][N:11]=3)=[CH:16][CH:17]=2)[CH2:26][CH2:25]1
Reactant: COc1cccc(-c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)o2)c1
Agent: [Pd]
Solvent: CCOCC
Solvent: CO
Product: CN1CCN(c2ccc(Nc3ncc(-c4cccc(O)c4)o3)cc2)CC1
Reaction time: 12 h
Yield: 101.5 %

Procedure:
To a stirred solution of the title compound of Example 4 (0.20 g, 0.45 mmol) in methanol (50 mL) was added palladium on carbon (10% w/w, 0.1 g) and was hydrogenated at 50 psi for 12 h. The catalyst was removed by filtration and the solvent was evaporated from the filtrate to leave a tan solid. Trituration with diethyl ether afforded a solid that was collected by filtration and dried under vacuum to leave the title compound (0.16 g, 96%). 1H NMR (400 MHz, d6-DMSO): δ 2.20 (s, 3H), 2.43 (m, 4H), 3.03 (m, 4H), 6.62 (d, J=9.16, 1H), 6.90 (m, 3H), 6.95 (d, J=7.69, 1H), 7.17 (t, J=7.87, 1H), 7.29 (s, 1H), 7.46 (d, J=8.61, 2H), 9.95 (s, 1H). MS (APCI, m/z)=336 (m+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:11][C:10]=2[CH:21]=1.[NH:22]1[CH2:25][CH2:24][CH2:23]1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:22]4[CH2:25][CH2:24][CH2:23]4)=[CH:21][C:10]=3[S:11][CH:12]=2)=[CH:15][CH:16]=1
Reactant: Fc1ccc(-c2csc3cc(OCCCBr)ccc23)cc1
Reactant: C1CNC1
Product: Fc1ccc(-c2csc3cc(OCCCN4CCC4)ccc23)cc1

Procedure:
In analogy to example 3.1, 6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and azetidine were converted to yield 1-{3-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-azetidine as colorless oil, MS: 342 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13]C)=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[ClH:15].[NH2:16][C:17]([NH2:19])=[NH:18].C[O-].[Na+]>CO>[ClH:15].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:18][C:17]([NH2:19])=[NH:16])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: COC(=O)c1ccc2c(ccn2C)c1
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cn1ccc2cc(C(=O)NC(=N)N)ccc21
Yield: 68.8 %

Procedure:
The reaction was carried out in a manner similar to Example 1 except for using 1.00 g (5.29 mmol) of methyl 1-methyl-5-indolecarboxylate, 5.05 g (52.9 mmol) of guanidine hydrochloride and 50 ml of a methanol solution of 2.85 g (52.9 mmol) of sodium methoxide. Thus 0.92 g (68.9%) of 1-methyl-5-indoloylguanidine hydrochloride was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][OH:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][C:22]=1[C:28]([F:31])([F:30])[F:29].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][O:19][C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(CO)ccc2C1
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(COc3ccc(Cl)c(C(F)(F)F)c3)ccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of 6-hydroxymethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (85 mg, 0.323 mmol) in CH2Cl2 (1.5 mL) is added a solution of 4-chloro-3-trifluoromethyl-phenol (76 mg, 1.23 eq.) in CH2Cl2 (0.5 mL), PPh3 (127 mg, 1.5 eq.), and 1,1′-(azodicarbonyl)-dipiperidine (122 mg, 1.5 eq.). The mixture is stirred at room temperature overnight. All the solvent is removed under reduced pressure and the mixture is purified by column chromatography (silica gel, EtOAc/Hexane, gradient) to give 70 mg of 6-(4-chloro-3-trifluoromethyl-phenoxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[C:19]([CH2:20][CH2:21]O)=[CH:18][N:17]=[CH:16]2)=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:25][CH2:21][CH2:20][C:19]1[N:15]([CH2:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:16]=[N:17][CH:18]=1
Reactant: OCCc1cncn1Cc1ccccc1-c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Fc1ccc(-c2ccccc2Cn2cncc2CCCl)cc1

Procedure:
To a solution of 2-[3-(4′-fluorobiphenyl-2-ylmethyl)-3H-imidazol-4-yl]ethanol (0.341 g, 1.15 mmol) in CH2Cl2 (10 mL) is added, thionyl chloride (0.11 mL, 1.50 mmol) at 0° C. The mixture is then heated to reflux for 3 h before the solvent is removed and the residue dried under reduced pressure to give 5-(2-chloroethyl)-1-(4′-fluorobiphenyl-2-ylmethyl)-1H-imidazole. The residue is taken up in THF (60 mL). TMEDA (0.71 ml, 4.72 mmol) is added, followed by a hexane/THF solution of LDA (2.62 mL, 1.8 M) at −78° C. The resulting mixture is stirred at −78° C. for 5 h. The excess LDA is then quenched by the addition of saturated NH4Cl. The mixture is then diluted with CH2Cl2 and water. The organic layer is separated and washed with water, brine and dried over Na2SO4. After concentration, the residue is purified by flash chromatography (CH2Cl2/MeOH) to give 5-(4′-fluorobiphenyl-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole. MS (ESI), m/z 279.1 (M+H). Resolution of the (R) and (S) enantiomers of the title compound is achieved by chiral HPLC using ChiralPak AD column and 13% IPA:hexane to give enantiomer A (tr=9.6 min) and enantiomer B (tr=12.6 min). For enantiomer B: 1H NMR (400 MHz, CDCl3) (HCl salt) δ ppm 2.68-2.79 (m, 1H), 2.95-3.06 (m, 2H), 3.13-3.22 (m, 1H), 5.55 (app t, J=7.6 Hz, 1H), 6.96 (dd, J=7.6, 1.5 Hz, 1H), 7.13 (s, 1H), 7.18 (app t, J=8.6 Hz, 2H), 7.27-7.32 (m, 2H), 7.33-7.38 (m, 1H), 7.40-7.49 (m, 2H), 8.01 (s, 1H).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[C:8]([O:12][C:13]([N:15]1[CH2:21][CH2:20][CH2:19][C@H:16]1[CH:17]=[O:18])=[O:14])([CH3:11])([CH3:10])[CH3:9]>CS(C)=O.C1COCC1>[C:8]([O:12][C:13]([N:15]1[CH2:21][CH2:20][CH2:19][C@H:16]1[CH:17]1[O:18][CH2:4]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C1CO1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
DMSO (20 ml) was added to sodium hydride (1.55 g, NaH content 60%), and the mixture was stirred at 70° C. for 1 hour. The reaction mixture was cooled to room temperature and THF (20 ml) was added. The mixture was cooled to -5° C., and thereto was dropwise added a solution of trimethylsulfonium iodide (7.90 g) in DMSO (30 ml) over 3 minutes. After stirring for 1 minute, a solution of tert-butoxycarbonyl-L-prolinal (5.13 g) in THF (15 ml) was added quickly, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into ice-water (300 ml), and extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluate: hexane-ethyl acetate) to give two diastereomers of the title compound, 3.12 g of its less polar compound and 1.28 g of its more polar compound. (Configuration of the epoxy moiety of the both has not been identified.) The less polar compound was used in the following reactions.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(CC2CCCCC2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, (bromomethyl)cyclohexane (0.70 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with 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 the title compound as a colorless solid (0.38 g, 30%).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Br)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[SH:11][C:12]1[NH:13][CH:14]=[CH:15][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:11][C:12]2[NH:13][CH:14]=[CH:15][N:16]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: Sc1ncc[nH]1
Reactant: CC(=O)Nc1ncc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2ncc[nH]2)s1
Temperature: 90 °C
Yield: 87.2 %

Procedure:
A mixture of 2-acetylamino-5-bromothiazole (1.9 g), 2-mercaptoimidazole (0.9 g) and potassium carbonate (1.5 g) in N,N-dimethylformamide (30 ml) was heated at 90° C. for 2.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was extracted with methanol. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 150 g) and eluted with a mixture of chloroform and methanol (10:1). The fraction containing the objective compound were combined and concentrated under reduced pressure to give 2-acetylamino-5-(2-imidazolylthio)thiazole (1.8 g, yield: 87.4%). mp: 230°-235° C. (dec.) IR (Nujol): 3150, 3100, 1710, 1550, 1290 cm-1
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[NH:8][C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([F:29])=[CH:11][N:10]=2)=[O:5])[CH3:2].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[N:8]([CH2:35][C:34]2[CH:37]=[CH:38][CH:39]=[C:32]([F:31])[CH:33]=2)[C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([F:29])=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: Fc1cccc(CBr)c1
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)cnc2[nH]c1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)cnc2n(Cc2cccc(F)c2)c1=O

Procedure:
This compound was prepared from 6-fluoro-2-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (80) and 3-fluorobenzyl bromide according to General Procedure B. Yield 113 mg (8%), MP 113° C.; 1H-NMR (DMSO-d6): δ 1.29 (t, J=7.2 Hz, 3H), 3.15 (m, 4H), 3.90 (m, 4H), 4.33 (q, J=7.2 Hz, 2H), 5.55 (s, 2H), 7.08 (m, 3H), 7.15 (dd, J=3.6, 5.2 Hz, 1H), 7.34 (m, 1H), 7.46 (dd, J=1.2, 3.6 Hz, 1H), 7.80 (dd, J=1.2, 5.2 Hz, 1H), 8.17 (dd, J=2.8, 8.8 Hz, 1H), 8.74 (d, J=2.8 Hz, 1H); EIMS: 539 (M+1). Anal. (C27H24F2N4O4S) C, H, N.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[N:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]3=[CH:24][N:23]=2)=[O:21])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].O>ClCCl>[NH2:9][C:10]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[N:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]3=[C:24]([Br:1])[N:23]=2)=[O:21])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(C(=O)c2ncc3ccccn23)ccc1N
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc(C(=O)c2nc(Br)c3ccccn23)ccc1N
Yield: 85.7 %

Procedure:
0.42 g (2.4 mmol) of N-bromosuccinimide is added, under a nitrogen atmosphere at ambient temperature, to a solution of 0.67 g (2.4 mmol) of methyl 2-amino-5-(imidazo[1,5-a]pyridin-3-ylcarbonyl)benzoate in 20 ml of dichloromethane. After stirring for 2 h 30, water is added. The precipitate formed is filtered off, rinsed with water, and dried overnight at 40° C. under reduced pressure. 0.77 g of a yellow solid is obtained.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[NH2:21][CH:22]1[CH2:25][NH:24][CH2:23]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:24]4[CH2:25][CH:22]([NH2:21])[CH2:23]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: NC1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Yield: 57.7 %

Procedure:
A mixture of 1.2 g (4.53 mmoles) of 1-cyclopropyl 6,7-difluoro-1,4-dihydro-4oxo-3-quinolinecarboxylic acid, 1.3 g (9.05 mmoles) of 3-aminoazetidine hydrochloride and 0.5 ml of triethylamine heated in 15 ml of pyridine for 2 hours. The mixture is filtrated and washed with water and ethanol to obtain 0.83 g (58%) of 1-cyclopropyl-6-fluoro-7-(3-amino-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid melting at 246°-7° C.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:23]>CC(O)C>[F:20][C:19]([F:22])([F:21])[O:18][C:14]1[CH:13]=[C:12]([C:10]2[CH:9]=[CH:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:23])[C:3]=3[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)Oc1cccc(-c2ccc3ncnc(Cl)c3n2)c1
Reactant: N
Solvent: CC(C)O
Product: Nc1ncnc2ccc(-c3cccc(OC(F)(F)F)c3)nc12
Temperature: 35 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
The brown solid 4-chloro-6-(3-(trifluoromethoxy)phenyl)pyrido[3,2-d]pyrimidine obtained from step 2 was added to a solution of NH3 in propan-2-ol (50 mL, 12%), and stirred at 35° C. overnight. The reaction was concentrated under reduce pressure and the residue was purified by silica gel column chromatography (66% Ethyl acetate in Pentane) to afford 6-(3-(trifluoromethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine (0.2 g, 17% yield) as a brown solid.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](OC)=[O:23])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:32]([NH2:37])[CH2:33][CH:34]([CH3:36])[CH3:35]>>[CH:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH:37][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])=[O:23])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)CCN
Reactant: COC(=O)CCCCCOc1ccc2nc(-c3ccccc3)n(C3CCCCC3)c2c1
Product: CC(C)CCNC(=O)CCCCCOc1ccc2nc(-c3ccccc3)n(C3CCCCC3)c2c1

Procedure:
1-Cyclohexyl-6-[(5-(methoxycarbonyl)pentyl)oxy]-2-phenyl-benzimidazole is reacted according to general operating instructions 7 with isoamylamine. 1-Cyclohexyl-6-[(5-((3-methyl-butyl)aminocarbonyl)pentyl)oxy]-2-phenyl-benzimidazole is obtained as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([OH:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br.Br[CH2:37][C:38]1[CH:47]=[C:46]2[C:41]([CH:42]=[CH:43][CH:44]=[N:45]2)=[CH:40][CH:39]=1.[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:37][C:38]2[CH:47]=[C:46]3[C:41]([CH:42]=[CH:43][CH:44]=[N:45]3)=[CH:40][CH:39]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: BrCc1ccc2cccnc2c1
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2O)cc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3cccnc3c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.5 %

Procedure:
3.40 g (7.20 mmol) of (3R,4R)-3-hydroxy-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butylester and 2.18 g (7.20 mmol) of 7-bromomethyl-quinoline hydrobromide (1:1) [J. Am. Chem. Soc. 77, 1054(1955)], were dissolved in 50 ml of absolute dimethylformamide under argon and then 0.83 g (19.0 mmol) of sodium hydride dispersion (55% in mineral oil) was added at room temperature in small portions. Subsequently, the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured onto ice-water, the product was extracted 3 times with ethyl acetate, the combined organic phases were washed twice with distilled water, then dried over magnesium sulphate, filtered and concentrated. The crude product (5.2 g, yellow oil) was chromatographed on silica gel with ethyl acetate/hexane 2:1 to yield 3.77 g (85.4% of theory) of (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(quinolin-7-yl-methoxy)-piperidine-1-carboxylic acid tert-butylester as a colourless oil; MS: 613 (M+H)+.
Reaction SMILES: [CH3:1]O.C(Cl)(Cl)Cl.[O:7]=[C:8]1[CH:11]([N:12]2C(=O)C3=CC=CC=C3C2=O)[CH2:10][N:9]1[CH:23]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)[C:24]([O-:26])=[O:25]>C(OCC)(=O)C>[NH2:12][CH:11]1[CH2:10][N:9]([CH:23]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[C:24]([O:26][CH3:1])=[O:25])[C:8]1=[O:7]
Reactant: CO
Reactant: O=C([O-])C(c1cccs1)N1CC(N2C(=O)c3ccccc3C2=O)C1=O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)C(c1cccs1)N1CC(N)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Dimethqyl-1,3-propanediamine (1.32 g.) was added to a mixture of methanol (30 ml.) and chloroform (18 ml.) containing 2-(2-oxo-3-phthalimido-1-azetidinyl)-2-(2-thienyl)-acetate (2.22 g.), whereafter the mixture was stirred at ambient temperature overnight. After the reaction, the reaction mixture was evaporated to dryness under reduced pressure to give a residue, which was dissolved in ethyl acetate. The solution was extracted with three portions of an aqueous solution consisting of 1N hydrochloric acid (6.4 ml.) and water (10 ml.). The combined aqueous extracts were adjusted to pH 8 with sodium bicarbonate and then saturated with sodium chloride. The solution was extracted with ethyl acetate and the extract was washed with a saturated aqueous sodium chloride and then dried over magnesium sulfate. The solution was evaporated to dryness under reduced pressure to give a residue (1.57 g.), which was subjected to column chromatography on silica gel (25 g.). Elution was carried out with chloroform and the fractions containing a desired compound were collected. The solvent was removed by distillation from the solution under reduced pressure to give methyl 2-(3-amino-2-oxo-1-azetidinyl)-2-(2-thienyl)acetate (0.96 g.).
Reaction SMILES: [OH-].[Na+].Cl.[Cl:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1.Br[CH2:18][CH2:19][CH2:20][Cl:21]>CC(C)=O>[ClH:4].[Cl:21][CH2:20][CH2:19][CH2:18][N:14]1[CH2:15][CH2:16][N:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([Cl:4])[CH:6]=2)[CH2:12][CH2:13]1
Reactant: ClCCCBr
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: ClCCCN1CCN(c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 111 %

Procedure:
A 25% NaOH solution (320 ml, 2.0 mol) is added dropwise to a stirred solution of 1-(3-chlorophenyl)-piperazine hydrochloride (196.5 g, 1.0 mol) and 1-bromo-3-chloropropane (99.0 ml, 1.0 mol) in acetone (200 ml) while maintaining temperature of 0°-10° C. After the addition is completed, the mixture is allowed to warm to room temperature and is stirred for 18 hours. The upper organic phase is then separated and concentrated under reduced pressure. The residual oil is taken up in 250 ml acetone and filtered. The filtrate is concentrated under reduced pressure and the oily residue is dissolved in 1 l of 15% boiling HCl solution. A viscous oil is separated from the cooled mixture and poured into 1 l of ice-H2O with vigorous stirring, forming white precipitates. Recrystallization of the solid from boiling water gave 171.8 g (55.6% yield) of 1-(3-Chloropropyl)-4-(3-chlorophenyl)piperazine hydrochloride; m.p 199.5-200.5° C. 1H nmr (d-DMSO) δ 11.55 (bs, 1H, HCl), 7.29 (t, 1H, J=8.1 Hz, phenyl H), 7.08 (t, 1H, J=2.0 Hz, phenyl H), 6.99 (dd, 1H, J=2.1, 8.3 Hz, phenyl H), 6.89 (dd, 1H, J=1.5, 7.7 Hz, phenyl H), 3.90 (d, 2H, J=12.8 Hz, CH2), 3.80 (t, 2H. J=6.4 Hz, CH2), 3.58 (d, 2H, J=11.4 Hz, CH2), 3.09-3.41 (overlapping 8H, CH2), 2.30 (m, 2H, CH2); 13C nmr (d-DMSO) δ 150.8, 134.0, 130.7, 119.2, 115.3, 114.2, 53.3, 50.5, 44.8, 42.5, 26.2.