Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([NH:34][CH2:35][CH2:36][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: NCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(NCCN4CCOCC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 4-(2-aminoethyl)-morpholine. ES-MS m/e (%): 499 (M+H+, 100).
Reaction SMILES: O=[C:2]([CH3:8])[CH2:3][CH2:4][CH2:5][C:6]#[N:7].[NH2:9][C:10]1[C:15]([CH:16]=O)=[CH:14][CH:13]=[CH:12][N:11]=1>C(O)C>[CH3:8][C:2]1[C:3]([CH2:4][CH2:5][C:6]#[N:7])=[CH:16][C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: CC(=O)CCCC#N
Reactant: Nc1ncccc1C=O
Solvent: CCO
Product: Cc1nc2ncccc2cc1CCC#N

Procedure:
A mixture of 5-oxo-hexanenitrile (5 mL, TCI-US), 2-amino-3-formylpyridine (7 g, J. Org. Chem. 1983, vol. 48, p 3401) and ethanol (100 mL) was heated to reflux for 12 hours. Following evaporation of the solvent, the residue was chromatographed (silica gel, ethyl acetate) to give 4-[1,8]naphthyridin-2-yl-butyronitirile and the title product as colorless solids. 1H (CDCl3) δ 2.29 (3H, s); 2.83 (2H, t); 3.18 (2H, t); 7.48 (1H, dd); 8.04 (1H, s); 8.20 (1H, dd); 9.03 (1H, dd).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH:5]([O:8][CH3:9])[CH2:6][OH:7].Cl[C:11]1[N:16]=[C:15]([O:17][CH2:18][CH3:19])[CH:14]=[CH:13][N:12]=1.CC(O)=O>CN(C=O)C>[CH3:3][O:4][CH:5]([O:8][CH3:9])[CH2:6][O:7][C:11]1[N:16]=[C:15]([O:17][CH2:18][CH3:19])[CH:14]=[CH:13][N:12]=1
Reactant: COC(CO)OC
Reactant: CCOc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOc1ccnc(OCC(OC)OC)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a suspension of 60% NaH/mineral oil (2.55 g, 63.96 mmol) in anhydrous DMF (70 mL) at 0° C. under nitrogen atmosphere was slowly added glycolaldehyde dimethyl acetal (Aldrich, 5.65 g, 53.3 mmol). The mixture was stirred at ambient temperature for 1 hour and then transferred to a solution of the product from step (a) (8.05 g, 50.76 mmol) in anhydrous DMF (70 mL) at -55° C. over 15 minutes. The mixture was allowed to warm to -20° C. over 2 hours and then neutralized with AcOH. Solvent was evaporated in vacuo and the residue partitioned between H2O and CH2Cl2. The aqueous phase was extracted with CH2Cl2 and the combined organic phase was dried (Na2SO4) and evaporated in vacuo. The residue was flash chromatographed (EtOAc/hexanes, 1:4) to give the desired product (7.92 g, 69%) as a colourless oil: 1H NMR (CDCl3): δ1.37 (t, J=7.0 Hz, 3H), 3.44 (s, 6H), 4.36-4.43 (m, 4H), 4.78 (t, J=5.0 Hz, 1H), 6.34 (d, J=6.0 Hz, 1H), 8.15 (d, J=6.0 Hz, 1H); MS m/z 229 (M=1, 13%), 197 (100%). Anal Calcd. for C10H16N2O4 : C, 52.62; H, 7.07; N, 12.27. Found: C, 52.45; H, 7.01; N, 12.26.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH2:11][CH3:12])[C:6]([C:13]2[O:17][C:16](=[O:18])[NH:15][N:14]=2)=[CH:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[Br:50][CH2:51][CH2:52]O>O.C1COCC1>[Br:50][CH2:51][CH2:52][N:15]1[N:14]=[C:13]([C:6]2[C:7]([NH:9][CH2:10][CH2:11][CH3:12])=[N:8][C:3]([S:2][CH3:1])=[N:4][CH:5]=2)[O:17][C:16]1=[O:18]
Reactant: OCCBr
Reactant: CCCNc1nc(SC)ncc1-c1n[nH]c(=O)o1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCNc1nc(SC)ncc1-c1nn(CCBr)c(=O)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To 5.0 mL of THF, 5-(2-methylthio-4-propylaminopyrimidin-5-yl)-3H-[1,3,4]oxadiazol-2-one (200 mg) obtained in Step 1 of Example 17 was dissolved, then triphenylphosphine (588 mg), DEAD (40% toluene solution, 1.02 mL, 2.34 mmol) and 2-bromoethanol (280 mg) were added thereto, followed by stirring at room temperature for 1 hour. After completion of the reaction was confirmed by thin-layer chromatography, the reaction mixture was added with water and was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to give 3-bromoethyl-5-(2-methylthio-4-propylaminopyrimidin-5-yl)-3H-[1,3,4]oxadiazol-2-one [Compound (P) in which R1 represents n-propylamino, R8A represents 2-bromoethyl] (210 mg, yield 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10]C)=[O:9])=[C:4]([NH:14][C:15](OCC)=O)[CH:3]=1.Br.BrC[C:23]([C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=1)=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6]([CH2:7][C:8]([OH:10])=[O:9])=[C:15]([C:23]([C:25]3[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=3)=[O:24])[NH:14]2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)OC
Reactant: Cc1ccnc(C(=O)CBr)c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)O)c1
Yield: 20 %

Procedure:
A mixture of methyl trans-4-chloro-2-(ethoxycarbonylamino)cinnamate (step 1, 1.5 g, 5.3 mmol), 2-bromoacetyl-4-methylpyridine hydrobromide*, potassium carbonate (7.3 g, 53 mmol) and acetonitrile (50 ml) was heated at reflux temperature for 17 h. The mixture was then cooled and concentrated. The residue was diluted in ethyl acetate (200 ml) and washed with water (200 ml) and brine (200 ml). After drying (MgSO4) and removal of solvent, the crude product was purified by flash column chromatography eluting with ethyl acetate/hexane (1:5) to afford 433 mg (20%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:12][NH2:13])[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:14]1[N:19]=[C:18](Cl)[C:17]2[N:21]=[CH:22][N:23]([C@@H:24]3[O:28][C@H:27]([CH2:29][OH:30])[C@@H:26]([OH:31])[C@H:25]3[OH:32])[C:16]=2[N:15]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:12][NH:13][C:18]3[C:17]4[N:21]=[CH:22][N:23]([C:16]=4[N:15]=[CH:14][N:19]=3)[C@@H:24]3[O:28][C@H:27]([CH2:29][OH:30])[C@@H:26]([OH:31])[C@H:25]3[OH:32])[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCC1(c2cccc(Cl)c2)CCC1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC4(c5cccc(Cl)c5)CCC4)ncnc32)[C@H](O)[C@@H]1O
Yield: 82.1 %

Procedure:
The above amine (1.96 g, 10 mmol) is reacted with 6-chloropurine riboside (2.87 g, 10 mmol) and purified as described in Examples 1 and 7 above. N6-((1-(3-chlorophenyl)cyclobutyl)methyl)adenosine (3.66 g, 82%) as a pale yellow solid foam is obtained m.p. 92°-8° C. Found: C, 56.11; H, 5.33; N, 15.44; Cl, 8.99%. C21H24ClN5O4 calculated requires: C, 56.57; H, 5.39; N, 15.71; Cl, 7.97%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)=[C:7]([F:24])[C:6]=1F)[CH3:2].[CH:27]1([NH2:30])[CH2:29][CH2:28]1>CN(C)C(=O)C>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)=[C:7]([F:24])[C:6]=1[NH:30][CH:27]1[CH2:29][CH2:28]1)[CH3:2]
Reactant: NC1CC1
Reactant: CCOC(=O)c1ccc(N2CCC(NC(=O)OC(C)(C)C)C2)c(F)c1F
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(N2CCC(NC(=O)OC(C)(C)C)C2)c(F)c1NC1CC1
Yield: 76.9 %

Procedure:
A solution of 4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2,3-difluorobenzoic acid ethyl ester (Example 2h, 1.85 g, 5.01 mmol) and cyclopropylamine (14.0 mL, 201 mmol) in N,N-dimethylacetamide (5 mL) is heated in a sealed glass tube for 48 hours at 100° C. The solution is then concentrated under high vacuum and purified by column chromatography (1:9 ethyl acetate/hexanes) to afford the title compound (1.57 g). 1H NMR (CDCl3): δ 7.59 (bs, 1H), 7.57 (dd, 1H), 6.00 (dd, 1H), 4.82–4.68 (bd, 1H), 4.39–4.18 (m, 3H), 3.80–3.49 (m, 3H), 3.41–3.30 (m, 1H), 3.00–2.88 (m, 1H), 2.31–2.11 (m, 1H), 2.00–1.85 (m, 1H), 1.45 (s, 9H), 1.37 (t, 3H), 0.73–0.50 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH:7]([CH:10]1[CH2:12][CH2:11]1)[CH2:8][NH2:9])([CH3:4])([CH3:3])[CH3:2].C[O:15][C:16]([C:18]1[N:19]=[C:20]([C:37]#[N:38])[C:21]2[C:26]([C:27]=1[OH:28])=[CH:25][CH:24]=[C:23]([O:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH:22]=2)=O.C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O>[C:1]([O:5][C:6](=[O:13])[CH:7]([CH:10]1[CH2:12][CH2:11]1)[CH2:8][NH:9][C:16]([C:18]1[N:19]=[C:20]([C:37]#[N:38])[C:21]2[C:26]([C:27]=1[OH:28])=[CH:25][CH:24]=[C:23]([O:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH:22]=2)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(CN)C1CC1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3)ccc2c1O
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)C(CNC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3)ccc2c1O)C1CC1
Temperature: 150 °C
Yield: 45.9 %

Procedure:
A mixture of 3-amino-2-cyclopropyl-propionic acid tert-butyl ester (20 mg), 1-cyano-7-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (15 mg) and DBU (10 mg) in DMA (0.3 mL) was heated in an oil bath (150° C.) for 1 h. The reaction mixture was then partitioned between EtOAc and diluted HCl solution, EtOAc phase was separated and washed with water, diluted NaCl solution and dried over anhydrous sodium sulfate solution, filtered, concentrated and silica gel column purified to give desired product as brown solid (10 mg). LC-MS ESI+: 492 (M+1)+.
Reaction SMILES: C([N:5]1[C:9]2=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]2[C:7]([CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16]2)=[N:6]1)(C)(C)C>C(O)=O.Cl>[CH2:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:23][CH2:24][CH:15]1[C:7]1[C:8]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH2:14])[NH:5][N:6]=1
Reactant: CC(C)(C)n1nc(C2CCc3ccccc3C2)c2c(N)ncnc21
Agent: Cl
Solvent: O=CO
Product: Nc1ncnc2[nH]nc(C3CCc4ccccc4C3)c12
Reaction time: 0.5 h

Procedure:
1-tert-butyl-3-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (9 mg, 0.029 mmol) was dissolved in a solution of formic acid (1 mL) and conc. HCl (0.1 mL) and heated to reflux. The reaction was allowed to proceed 30 min., then concentrated in vacuo and the products purified by RP-HPLC (MeCN:H2O:0.1% TFA). ESI-MS (M+H)+ m/z calcd 266.1, found 266.4.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[CH:26][C:27]=1[Cl:28].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][C:27]([Cl:28])=[C:22]([Cl:21])[CH:23]=3)[CH2:34][CH2:33]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(F)cc1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(c3ccc(Cl)c(Cl)c3)CC2)cc1-c1ccc(F)cc1

Procedure:
162 mg (85%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propanal (100 mg, 0.365 mmol), 1-(3,4-dichlorophenyl)piperazine (84 mg, 0.365 mmol), DIPEA (0.1 mL, 0.548 mmol) and NaBH(OAc)3 (232 mg, 1.095 mmol).
Reaction SMILES: Cl.Cl.[CH2:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[N:21]=1>>[CH2:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][CH:4]1[N:12]1[CH2:13][CH2:14][N:15]([C:28]([C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([C:22]3[N:21]=[C:20]([C:19]([F:34])([F:18])[F:35])[O:24][N:23]=3)[CH:26]=2)=[O:29])[CH2:16][CH2:17]1
Reactant: c1ccc2c(c1)CC(N1CCNCC1)C2
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Agent: Cl
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCN(C2Cc3ccccc3C2)CC1
Yield: 39 %

Procedure:
This compound was synthesized from 1-(2,3-dihydro-1H-inden-2-yl)piperazine dihydrochloride and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (100 mg, yield 39%). 1H NMR (400 MHz, MeOD) δ 8.27-8.24 (m, 1H), 8.18 (m, 1H), 7.72-7.71 (m, 2H), 7.20-7.16 (m, 2H), 7.14-7.11 (m, 2H), 3.87 (m, 2H), 3.55 (m, 2H), 3.26-3.20 (m, 1H), 3.17-3.12 (m, 2H), 2.93-2.87 (dd, J=15.1 Hz, 8.5 Hz, 2H), 2.73 (m, 2H), 2.60 (m, 2H). MS (ESI) m/z: Calculated for C23H21F3N4O2: 442.16. found: 443.2 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C@H:7]([CH2:10][NH2:11])[CH2:8][O:9][C:4]=2[CH:3]=1.Cl[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][C:25](=[O:29])[O:26]2)=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN(C=O)C>[OH:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C@H:7]([CH2:10][NH:11][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[CH:23]=[CH:24][C:25](=[O:29])[O:26][C:27]=4[CH:28]=3)[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Reactant: NC[C@@H]1COc2cc(O)ccc2O1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=c1ccc2ccc(OCCCNC[C@@H]3COc4cc(O)ccc4O3)cc2o1
Temperature: 94 °C

Procedure:
(R)-2,3-Dihydro-6-hydroxy-1,4-benzodioxin-2-methanamine (2.58 g, 14.2 mmole), 7-(3-chloropropoxy)coumarin (3.08 g, 12.9 mmole), diisopropylethylamine (10 ml, 57 mmole) and sodium iodide (1.98 g, 13.2 mmole) were combined in 175 ml of DMF and heated at 94° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed in vacuum. The residue was twice column chromatographed on silica gel using 1% methanol/dichloromethane as eluant. The product-containing fractions (Rf=0.45 on silica gel with 5% methanol/dichloromethane) were combined and concentrated in vacuum and the pure free base redissolved in methanol and boiled on a hot plate, the methanol gradually being replaced with isopropanol. 4N HCL/isopropanol was added and the title compound was collected by filtration. After two additional recrystallizations from isopropanol, 0.35 g of white solid, monohydrochloride, m.p. 236°-242° C., was obtained.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[O:24]=[C:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH2:30][CH2:31][CH2:32][NH:33][C:34]1[CH2:38][S:37][C:36](=[O:39])[N:35]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:38]2/[C:34]([NH:33][CH2:32][CH2:31][CH2:30][N:26]3[CH2:27][CH2:28][CH2:29][C:25]3=[O:24])=[N:35][C:36](=[O:39])[S:37]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: O=C1N=C(NCCCN2CCCC2=O)CS1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(NCCCN2CCCC2=O)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 60 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (500 mg) in 2-propanol (10 mL) were added 4-([3-(2-oxopyrrolidin-1-yl)propyl]amino)thiazol-2(5H)-one (866 mg) and piperidinium acetate (107 mg). The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (439 mg).
Reaction SMILES: [N:1]1[CH:7]=[CH:6][C:5](=[O:8])[N:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C(Cl)Cl>[O:8]=[C:5]1[CH:6]=[CH:7][N:1]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:2][CH:3]=[N:4]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=c1ccnccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1C=CN(C(=O)OCc2ccccc2)CC=N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4.8 g (42.0 mmol) [1,4]diazepin-5-one are dissolved in 60 ml DCM and at ice bath temperature successively combined with 11.0 ml (83.9 mmol) triethylamine and 6.8 ml (46.2 mmol) benzyl chloroformate. The mixture is heated to RT and kept for three hours at this temperature. Then the mixture is concentrated and combined with water. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac. The crude product is [purified] by column chromatography on silica gel (eluant DCM/MeOH 95:5→90:10).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:11]([O-:14])(=[O:13])=[O:12].[Na+:15].[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[O:22]([C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:11]([O-:14])(=[O:13])=[O:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na+:15]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)[O-])c(Cl)c1
Reactant: Oc1ccccc1
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)[O-])c(Oc2ccccc2)c1

Procedure:
The synthesis of (A) was carried out as follows. First, sodium 2-chloro-4-nitrobenzenesulfonate and phenol were reacted in water in the presence of a base, to obtain sodium 2-phenoxy-4-nitrobenzenesulfonate. This was reacted with POCl3 /DMAC to produce the sulfonyl chloride form, and then the sulfonyl chloride was reacted with the ethyl ester of glycine, to obtain the carboxylic acid ethyl form of (A). Then it was hydrolyzed followed by reaction with SOCl2 in benzene, and then the benzene was distilled off, so that (A) was obtained in the form of crystals.
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[N:33]=[C:32]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1>>[C:35]([NH:34][C:32]1[N:33]=[C:28]([CH:25]2[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][NH:18][C:8](=[O:10])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:11])[CH2:23][CH2:24]2)[CH:29]=[CH:30][CH:31]=1)(=[O:39])[CH:36]([CH3:38])[CH3:37]
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)(c3ccccc3)c3ccccc3)CC2)n1

Procedure:
Example 83 was prepared from 2,2-diphenylpropanoic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.05 (d, 1H, J=8.0 Hz), 7.80 (s, 1H), 7.63 (t, 1H, J=7.6 Hz), 7.35–7.24 (m, 10H), 6.85 (d, 1H, J=8.0 Hz), 6.26 (t, 1H, J=4.8 Hz), 3.38 (dd, 2H, J=6.4, 12.4 Hz), 2.92–2.89 (m, 2H), 2.55–2.48 (m, 2H), 2.32 (t, 2H, J=6.8 Hz), 2.00 (s, 3H), 1.96 (t, 2H, J=11.2 Hz), 1.79 (d, 2H, J=11.6 Hz), 1.72–1.61 (m, 4H), 1.27 (d, 6H, 6.8 Hz); ESMS m/e: 513.3 (M+H)+.
Reaction SMILES: CCN=C=NCCCN(C)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[N:22]=[C:21]([C:31](O)=[O:32])[C:20]=2[CH2:34][C:35]#[N:36])=[CH:15][CH:14]=1.C1C=CC2N(O)N=NC=2C=1.[Br:47][C:48]1[CH:53]=[CH:52][C:51]([CH:54]([NH2:56])[CH3:55])=[CH:50][CH:49]=1>ClCCl>[Br:47][C:48]1[CH:53]=[CH:52][C:51]([CH:54]([NH:56][C:31]([C:21]2[C:20]([CH2:34][C:35]#[N:36])=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=3)[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[N:22]=2)=[O:32])[CH3:55])=[CH:50][CH:49]=1
Reactant: CC(N)c1ccc(Br)cc1
Reactant: N#CCc1c(C(=O)O)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(NC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1CC#N)c1ccc(Br)cc1
Reaction time: 16 h
Yield: 88 %

Procedure:
EDAC (386 mg, 2.00 mmol) was added to a stirred solution of [B1] (500 mg, 1.34 mmol) and HOBT (236 mg, 1.75 mmol) in dichloromethane (80 ml) at room temperature under argon. After 15 minutes 1-(4-bromo-phenyl)-ethylamine (322 mg, 1.61 mmol) was added and stirring continued for 16 hours. The mixture was washed with saturated aqueous sodium bicarbonate solution (3×) then with brine, dried over magnesium sulphate, filtered and evaporated in vacuo to give the title compound [C1] (655 mg, 1.18 mmol, 88%) as a foam.
Reaction SMILES: Cl.[CH2:2]([NH2:7])[CH:3]([NH2:6])[CH2:4][CH3:5].C(N(C(C)C)CC)(C)C.O=[C:18]([C:24](OCC)=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C>[CH2:4]([C:3]1[N:6]=[C:24]([OH:25])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:7][CH:2]=1)[CH3:5]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: CCC(N)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1ncc(CC)nc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25.2 %

Procedure:
To a suspension of butane-1,2-diamine hydrochloride (6.40 g, 39.7 mmol) in ethanol (60 mL) was added diisopropylethylamine (14 mL, 80.4 mmol), and the mixture was stirred at room temperature for 10 min. To this solution was added dropwise diethyl ketomalonate (6 mL, 39.3 mmol) at 0° C., and the mixture was stirred at room temperature for 1.5 hr with heating under reflux for 20 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a small amount of ethanol. The solution was passed through silica gel (100 g, eluent, hexane:ethyl acetate=1:1→ethyl acetate). The eluate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=2:1→ethyl acetate) to give the title compound (1.94 g, 25%) as a pale-yellow powder.
Reaction SMILES: C1C2C(COC([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][C:26]4[S:30][C:29]([C:31]([O:33]CC)=[O:32])=[CH:28][C:27]=4[NH:36][C:37]4[C:38]5[CH:46]=[CH:45][C:44]([CH:47]([CH3:49])[CH3:48])=[N:43][C:39]=5[N:40]=[CH:41][N:42]=4)=[CH:21][CH:20]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.O.[OH-].[Li+].Cl>O1CCOCC1.O>[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][C:26]2[S:30][C:29]([C:31]([OH:33])=[O:32])=[CH:28][C:27]=2[NH:36][C:37]2[C:38]3[CH:46]=[CH:45][C:44]([CH:47]([CH3:49])[CH3:48])=[N:43][C:39]=3[N:40]=[CH:41][N:42]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cc(Nc2ncnc3nc(C(C)C)ccc23)c(Sc2ccc(NC(=O)OCC3c4ccccc4-c4ccccc43)cc2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)O)sc3Sc3ccc(N)cc3)ncnc2n1
Yield: 72.5 %

Procedure:
The product of Example 90E (0.245 g, 0.356 mmol) in 1,4-dioxane (3 mL), was treated with a solution of lithium hydroxide monohydrate (0.0747 g, 1.78 mmol) in water (1.5 mL) at room temperature, the resulting mixture was heated at 60° for 25 minutes. The reaction mixture was cooled, diluted with water (10 mL), adjusted the pH to 3 with 1N aqueous HCl, and the resulting precipitate was collected by vacuum filtration. Washing of the crude product with small volumes of 1,4-dioxane afforded the title compound (0.113 g, 0.258 mmol, 72%). MS (ESI+) m/z 438 (M+H)+, MS (ESI−) m/z 436 (M−H)−.