Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:10]=[CH:9][C:8]=2[CH2:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#N)=[CH:26][CH:25]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:32].[OH-:33].[K+]>C(O)C>[CH:1]1([C:7]2[N:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:20])([F:21])[F:22])=[CH:16][CH:17]=3)[N:10]=[CH:9][C:8]=2[CH2:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]([OH:33])=[O:32])=[CH:26][CH:25]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O
Reactant: [OH-]
Reactant: N#Cc1ccc(Cc2cnn(-c3ccc(OC(F)(F)F)cc3)c2C2CCCCC2)cc1
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1ccc(Cc2cnn(-c3ccc(OC(F)(F)F)cc3)c2C2CCCCC2)cc1

Procedure:
To a hot solution of 0.73 g 4-({5-cyclohexyl-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}methyl)benzonitrile From Step E above in 15 mL ethanol and 6 mL water was added 1.11 g potassium hydroxide. The resulting solution was refluxed under nitrogen over night. The solvents were removed under reduced pressure. The residue was re-suspended in 10 mL water and acidified with 9.0 mL 2 N HCl. The resulting solid was filtered, washed with water, and dried to give the title compound as a white solid. 1H NMR (CD3OD, 500 MHz) δ 7.95 (d, J=8.2 Hz, 2H), 7.48˜7.50 (m, 2H), 7.45 (d, J=8.6 Hz, 2H), 7.36 (s, 1H), 7.32 (d, J=8.2 Hz, 2H), 4.06 (s, 2H), 2.66 (tt, J=3.0 & 12.7 Hz, 1H), 1.69˜1.73 (m, 4H), 1.53˜1.64 (m, 3H), 1.09˜1.19 (m, 3). LC-MS: 2.29 min. (M+H=445.2).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[OH:12])=[O:5])[CH3:2].N12CCCN=C1CCCCC2.[CH3:24][N:25]([CH3:29])[C:26](Cl)=[S:27]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[O:12][C:26](=[S:27])[N:25]([CH3:29])[CH3:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(C)nc1O
Reactant: CN(C)C(=S)Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1sc(C)nc1OC(=S)N(C)C
Temperature: 60 °C
Reaction time: 3 h
Yield: 55.3 %

Procedure:
To a mixture of 4-hydroxy-2-methyl-thiazole-5-carboxylic acid ethyl ester (7.2 g, 37.4 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (11.2 ml, 74.8 mmol) in DMF (50 ml) is added N,N-dimethyl-carbamothioyl chloride (6.94 g, 56.1 mmol). The mixture is stirred at RT for 14 h and at 60° C. for 3 h, poured onto water (100 ml) and extracted with EtOAc (3×50 ml). The combined organic layers are washed with water (2×50 ml), dried over sodium sulfate and concentrated. The residue is chromatographed (silica gel, 10% EtOAc/hexane) to give 4-(dimethyl-carbamothioyl)oxy-2-methyl-thiazole-5-carboxylic acid ethyl ester (5.7 g, 20.7 mmol, 55%).
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][C:5]=1[C:6]([NH:8][C:9]1[CH:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:10]=1)=[O:7])([O-])=O>CO.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][C:5]=1[C:6]([NH:8][C:9]1[CH:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:15]=2)[N:10]=1)=[O:7]
Reactant: O=C(Nc1ccn(-c2cccc(C(F)(F)F)c2)n1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 2-nitro-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide (900 mg, 1.96 mmol, 1.00 equiv) in methanol (15 mL) and ethyl acetate (15 mL). The mixture was treated with Pd/C (500 mg) stirred under a hydrogen atmosphere for 1 h at room temperature in an oil bath. The reaction progress was monitored by LCMS. The solids were filtered out. The resulting mixture was concentrated under vacuum to give 600 mg (71%) of product as a brown solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)[C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C([S-])C.[Na+].O.Cl>CN(C)C=O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]([C:25]3[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=3)[C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=Cc2ccc(N(c3ccc(C)cc3)c3ccc(C)cc3)cc2)cc1
Agent: CC[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=Cc3ccc(O)cc3)cc2)cc1

Procedure:
The above-prepared 4-methoxy-4′-(di-p-tolylamino)stilbene and twice equimolar amount of sodium ethanethiolate are dissolved in N,N-dimethylformamide, and reacted for 5 hours at 130° C. The mixture is cooled down, and then poured into water and neutralized with hydrochloric acid. The objective material is extracted therefrom using acetic acid. The extracted liquid is washed with water, and then dried. The crude objective material is prepared by removing the solvent (i.e., N,N-dimethylformamide) therefrom. Further, the crude objective material is purified with a column chromatography using silica gel. Thus, 4-hydroxy-4′-(di-p-tolylamino)stilbene (i.e., objective material) is prepared.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][Cl:10])=[CH:4][C:3]=1[S:12](=[O:15])(=[O:14])[NH2:13].[CH2:16]([NH:18][C:19]([NH:21][CH2:22][CH3:23])=[S:20])[CH3:17]>>[ClH:10].[CH2:22]([N:21]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:4]=2)([OH:11])[CH2:9][S:20][C:19]1=[N:18][CH2:16][CH3:17])[CH3:23]
Reactant: CCNC(=S)NCC
Reactant: NS(=O)(=O)c1cc(C(=O)CCl)ccc1Br
Product: CCN=C1SCC(O)(c2ccc(Br)c(S(N)(=O)=O)c2)N1CC
Product: Cl

Procedure:
4.6 g of 4'-bromo-3'-sulfamoyl-2-chloroacetophenone and 1.8 g of ground 1,3-diethylthiourea were reacted and worked up according to the prescription given in Example 12. Colorless solid body, decomposition beginning at 103° C., C=N 1615 cm-1.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)(=[O:4])=[O:3].O[CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].C(Cl)CCl>C(Cl)Cl.C(Cl)Cl.CO.CN(C1C=CN=CC=1)C>[CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:13][CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:12])=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: O=C(CO)OCc1ccccc1
Reactant: CS(=O)(=O)NCc1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCCl
Solvent: ClCCl
Product: CS(=O)(=O)NCc1ccc(C(=O)OCC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
To a solution of 4-(methylsulfonamidomethyl)benzoic acid (0.4 g, 1.745 mmol) and benzyl 2-hydroxyacetate (0.290 g, 1.745 mmol) in a mixture of DCM and THF 1/1 (50 ml), EDC (0.334 g, 1.745 mmol) and DMAP (0.256 g, 2.094 mmol) were added in one portion. The reaction was stirred at RT for 3 hours. The solvent was removed under vacuum and the resulting crude was portioned between EtOAc and HCl 2N. The organic phase was separated, washed with brine and dried over Na2SO4. The solvent was removed under vacuum affording 2-(benzyloxy)-2-oxoethyl 4-(methylsulfonamido-methyl)benzoate (0.4 g, 1.060 mmol, 60.7% yield, MS/ESI+ 377.9 [MH]+). This product was employed in the following step without any further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1CO)[C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[S:5]2.[H-].[Na+].[CH3:18][O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].CN(C)C=[O:32]>>[CH3:18][O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([O:32][C:9]1[N:8]2[C:4]([S:5][C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=32)=[N:3][C:2]=1[CH3:1])=[O:23]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CN(C)C=O
Reactant: Cc1nc2sc3ccccc3n2c1CO
Agent: [H-]
Agent: [Na+]
Product: COc1ccccc1C(=O)Oc1c(C)nc2sc3ccccc3n12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In 50 ml of dry dimethylformamide was suspended 3.00 g of 2-methylimidazo[2,1-b]benzothiazole-3-methanol. Then, 1.12 g of 60% sodium hydride was added to the suspension. After stirring for 30 minutes, 3.00 g of o-methoxybenzoyl chloride was added to the mixture followed by stirring at room temperature for 3 hours. Ice water was added to the reaction solution and the system extracted with chloroform. After the chloroform was removed, 2.60 g of the title compound was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[OH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[C:24]([C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH:6]([CH2:5][CH2:4][CH2:3][CH3:2])[C:7]([O:9][CH3:10])=[O:8])=[CH:13][CH:14]=2)=[CH:23][CH:22]=1)#[N:25]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: COC(=O)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(Oc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.7 %

Procedure:
8.80 g (42 mmole) of methyl 6-bromohexanoate, 8.20 g (42 mmole) of 4-hydroxy-4'-cyanobiphenyl, 20 ml dimethyl formamide and 5.8 g (42 mmole) potassium carbonate were placed in a 100 ml flask equipped with a calcium chloride drying tube, and stirred at room temperature for 24 hours, after which time the mixture was poured into water and the suspended solids filtered out and washed with water. The resultant product was dried in a vacuum desiccator for 48 hours to yield 11.50 g (85%) of the ester which was recrystallized from aqueous ethanol to yield a product with a melting point of 80° C.-81° C.
Reaction SMILES: [NH2:1][C:2]1[C:13]([Br:14])=[CH:12][C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][C:3]=1[CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7].[C:20](Cl)(=[O:24])[CH2:21][CH2:22][CH3:23]>C1C=CC=CC=1>[Br:14][C:13]1[C:2]([NH:1][C:20](=[O:24])[CH2:21][CH2:22][CH3:23])=[C:3]([CH:10]=[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=1)[CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7]
Reactant: CCOC(=O)c1cc(Br)c(N)c(CN(CC)CC)c1
Reactant: CCCC(=O)Cl
Solvent: c1ccccc1
Product: CCCC(=O)Nc1c(Br)cc(C(=O)OCC)cc1CN(CC)CC

Procedure:
3 gm of 2-Amino-3-bromo-5-carbethoxy-N,N-diethyl-benzylamine were dissolved in 30 ml of benzene, and the solution was heated for 30 minutes with 3 ml of butyric acid chloride at 50°C. Thereafter, the mixture was evaporated to dryness in vacuo, and the residue was purified by chromatography on silicagel (eluant: benzene/ethyl acetate = 6:1), yielding 3-bromo-2-butyrylamino-5-carbethoxy-N,N-diethyl-benzylamine, which was converted into its hydrochloride, m. p. 134°C, with ethanolic hydrochloric acid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.CN(C=O)C.[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1F)[CH:21]=[O:22]>C(OCC)(=O)C.O>[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)[CH:21]=[O:22]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-n2ccnc2)c(F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
Potassium carbonate (1.71 g) and imidazole (847 mg) were added to a DMF (20 mL) solution of 3,4-difluorobenzaldehyde (2.0 g). The reaction solution was agitated at 100° C. overnight, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane:ethyl acetate=1:1→ethyl acetate), and 1.11 g of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](N1C=CN=C1)=[O:11])[CH2:2]2.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[OH:25]>>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]([O:25][C:10](=[O:11])[O:9][C@@H:3]1[CH:4]2[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]2)[CH2:2]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32]
Reactant: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Reactant: OC(c1ccccc1Cl)c1ccccc1Cl
Product: O=C(OC(c1ccccc1Cl)c1ccccc1Cl)O[C@H]1CN2CCC1CC2

Procedure:
The desired product was prepared by reacting imidazole-1-carboxylic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester with bis(2-chlorophenyl)methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[N:38]1([CH2:44][CH2:45][OH:46])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:41]3[CH2:42][CH2:43][N:38]([CH2:44][CH2:45][OH:46])[CH2:39][CH2:40]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:31])[CH3:32])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: OCCN1CCNCC1
Product: CCOc1cc(C(C)(C)O)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCO)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-ethanol (Chemical Dynamics) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C35H43N4O4Cl2 [(M+H)+] 653.2656, observed 653.2657.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:7]2[N:18]=[CH:19][C:20]([C:21]#[N:22])=[C:6]12)=[O:4].[CH2:23]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C1(C)C=CC=CC=1.C(O)C.CCOCC>[ClH:1].[CH3:17][C:13]1[CH:12]=[C:11]([C:8]2[N:7]3[N:18]=[CH:19][C:20]([C:21]#[N:22])=[C:6]3[N:5]([C:3](=[O:4])[CH2:2][N:33]3[CH2:34][CH2:35][N:30]([CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:31][CH2:32]3)[CH2:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cccc(C2=CCN(C(=O)CCl)c3c(C#N)cnn32)c1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOCC
Product: Cc1cccc(C2=CCN(C(=O)CN3CCN(Cc4ccccc4)CC3)c3c(C#N)cnn32)c1

Procedure:
A mixture of 3.3 g of 4-(chloroacetyl)-4,5-dihydro-7-(3-methylphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile, 1.9 ml of 1-benzylpiperazine and 1.3 g of sodium carbonate in 130 ml of toluene was reacted as described in Example 146, giving 2.7 g of the neutral base form of the product. A 1.0 g portion of this base was warmed to solution in 20 ml of ethanol and then treated with 3 ml of 2.44N ethanolic hydrochloric acid and an excess of ether, giving 900 mg of the desired product, mp 205°-207° C.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[NH3:11]>>[NH2:11][CH2:3][C@@H:2]([OH:1])[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: C1CN(C[C@H]2CO2)CCO1
Reactant: N
Product: NC[C@@H](O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.6 %

Procedure:
(S)-4-oxiranylmethyl-morpholine 78b (5.52 g, 38.6 mmol) was added slowly with 395 ml of aqueous ammonia (25%, 5.8 mol) in an ice-water bath while maintaining the temperature below 0° C. Upon the completion of the addition, the reaction mixture was naturally warmed to room temperature, and stirred for another 18 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction was stopped. The reaction solution was concentrated under reduced pressure to remove the reaction solvent and to obtain the title compound (R)-1-Amino-3-morpholin-4-yl-propan-2-ol 78c (6.1 g, yield 99%) as a light yellow oil.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:24]([CH3:26])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[CH:36]1([NH2:39])[CH2:38][CH2:37]1>ClCCl.CN(C=O)C>[CH:36]1([NH:39][CH2:2][C:3]2[N:7]([C:8]3[CH:9]=[C:10]([C:14]4[CH2:20][C:19](=[O:21])[NH:18][C:17]5[CH:22]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:24]([CH3:26])=[CH:25][C:16]=5[N:15]=4)[CH:11]=[CH:12][CH:13]=3)[N:6]=[N:5][CH:4]=2)[CH2:38][CH2:37]1
Reactant: NC1CC1
Reactant: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CNC3CC3)c1)=N2
Yield: 68 %

Procedure:
Prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 68) (208 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with cyclopropylamine in DMF according to the method described in Example 47. Obtained as a light yellow solid (155 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:8]2=[O:20])=[C:4]([F:23])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:31][C:32]#[N:33]>C(#N)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:8](=[O:20])[CH:9]=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:31][C:32]#[N:33])=[CH:15][CH:14]=3)=[CH:12]2)=[C:4]([F:23])[CH:3]=1
Reactant: N#CCBr
Reactant: O=c1ccc(-c2ccc(O)cc2)cn1Cc1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCOc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)cc1
Temperature: 180 °C
Yield: 42.1 %

Procedure:
According to Scheme 14 Method A: A suspension of 1-(4-chloro-2-fluorobenzyl)-5-(4-hydroxyphenyl)pyridin-2(1H)-one (1 eq, 1.21 mmol, 0.40 g), K2CO3 (10 eq, 12.1 mmol, 1.68 g) and 2-bromoacetonitrile (1 eq, 1.21 mmol, 0.15 g) in acetonitrile (10 mL) was heated in a microwave at 180° C. during 5 min. The reaction mixture was filtered, the filtrate was concentrated and the resulting crude residue was dissolved in CH2Cl2. The organic phase washed with water, dried over MgSO4, filtered and evaporated. The crude oil was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/MeOH 98/2 as eluent followed by trituration in acetonitrile to afford 2-(4-(1-(4-chloro-2-fluorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)phenoxy)acetonitrile (0.51 mmol, 0.19 g, 42%) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25]Cl)=[CH:15][CH:16]=3)[CH2:11][C:10]=2[CH:9]=1)=[O:7].[CH3:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:28][CH:29]1[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]2[CH:20]=[CH:19][C:18]3[C:17]4[C:12](=[CH:13][C:14]([C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][N:32]5[CH2:33][CH2:34][CH:29]([CH3:28])[CH2:30][CH2:31]5)=[CH:15][CH:16]=4)[CH2:11][C:10]=3[CH:9]=2)=[O:7])[CH2:31][CH2:30]1
Reactant: CC1CCNCC1
Reactant: O=C(CCCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCCl)ccc1-2
Product: CC1CCN(CCCCC(=O)c2ccc3c(c2)Cc2cc(C(=O)CCCCN4CCC(C)CC4)ccc2-3)CC1

Procedure:
Following the procedure of Example 7, 20.2g (0.05 mole) of 2,7-bis(5-chlorovaleryl)fluorene, prepared in Example 2, and 39.6g (0.4 mole) of 4-methylpiperidine were reacted to give the desired product which was recrystallized three times from chloroform-acetone. M.P. 143°-144.5° C, λmaxCHCl3 329, E1cm1% 731.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1.Br[CH2:30][O:31][C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[C:40](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:30][O:31][C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:40][NH:1][C:2]2[CH:22]=[C:21]([C:23]3[N:27]=[C:26]([CH3:28])[O:25][N:24]=3)[CH:20]=[CH:19][C:3]=2[CH2:4][NH:5][C:6](=[O:18])[C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=2)[CH:34]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N)cc(OC)c1C
Reactant: O=C(OCBr)c1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(CNc2cc(-c3noc(C)n3)ccc2CNC(=O)c2cc(OC)c(C)c(OC)c2)c1
Temperature: 80 °C

Procedure:
A suspension of compound 1g (76 mg, 0.20 mmol), methyl-3-(bromomethylbenzoate (56 mg, 0.24 mmol) and potassium carbonate (55 mg, 0.40 mmol) in DMF (1 mL) was sealed in a pressure tube and heated at 80° C. overnight. The reaction mixture was diluted with water, and the resulting solid precipitate was recovered by filtration to give compound 16a. ESI-MS m/e 531.4 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH4-].[Na+]>CN(C=O)C.CC#N>[CH2:13]([N:10]1[CH2:11][CH:12]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:8][CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(-c2ccncc2)nc1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: C1=C(c2ccccn2)CCN(Cc2ccccc2)C1
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A Solution of 2 g (12.8 mmol) of 4-(2-pyridyl)pyridine (Aldrich) and 2.18 g (12.8 mmol) of benzylbromide in 15 mL of DMF and 15 mL of CH3CN was stirred at 95° C. for 4 h. The reaction mixture was then concentrated and redissolved in 20 mL of methanol. To the reaction mixture at 0° C. was added 0.95 g, (25.6 mmol) of NaBH4 and the reaction mixture was stirred for 1 h. The reaction was quenched with 6N HCl, and was partitioned between CH2Cl2 and 1N NaOH. The aqueous layer was extracted 3 times with CH2Cl2, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified chomatography [silica, CH2Cl2:ethyl acetate:(2M NH3 in MeOH), 100:100:2] to give 3.2 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:13][CH2:14][OH:15])[C:7]2=[O:12].[OH-].[K+].I[CH2:19][CH3:20].C(OCC)C>CS(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:13][CH2:14][O:15][CH2:19][CH3:20])[C:7]2=[O:12]
Reactant: CCI
Reactant: O=C1c2cccc(Br)c2CCN1CCO
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCOCCN1CCc2c(Br)cccc2C1=O
Reaction time: 0.5 h

Procedure:
0.363 g of 5-bromo-2-(2-hydroxyethyl)-3,4-dihydroisoquinolin-1(2H)-one is dissolved under an inert atmosphere in 3 cm3 of dimethylsulfoxide at a temperature close to 20° C. 98 mg of finely ground potassium hydroxide are added. The reaction mixture is stirred for 30 min at a temperature close to 20° C., then 0.131 cm3 of iodoethane is introduced. The stirring is continued for 20 h at a temperature close to 20° C. 50 cm3 of a water/ice mixture and 80 cm3 of ethyl ether are added. After decanting, the organic phase is washed with 3 times with 10 cm3 of water, 30 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated using a rotary evaporator under reduced pressure (5 kPa). 356 mg of 5-bromo-2-(2-ethoxyethyl)-3,4-dihydroisoquinolin-1(2H)-one are obtained in the form of a colorless oil.