Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:36])[NH:10][C@@H:11]([CH2:30][C:31]2[N:32]=[CH:33][S:34][CH:35]=2)[C:12]([NH:14][CH2:15][C:16]2[N:17]=[N:18][N:19]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[CH3:29])[CH:20]=2)=[O:13])[O:7]1)=[O:5])C.[Li+].[OH-]>>[C:22]1([CH3:29])[CH:23]=[C:24]([CH3:28])[CH:25]=[C:26]([CH3:27])[C:21]=1[N:19]1[CH:20]=[C:16]([CH2:15][NH:14][C:12](=[O:13])[C@@H:11]([NH:10][C:9]([C@H:8]2[O:7][C@@H:6]2[C:4]([OH:5])=[O:3])=[O:36])[CH2:30][C:31]2[N:32]=[CH:33][S:34][CH:35]=2)[N:17]=[N:18]1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cscn1)C(=O)NCc1cn(-c2c(C)cc(C)cc2C)nn1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(C)c(-n2cc(CNC(=O)[C@H](Cc3cscn3)NC(=O)[C@H]3O[C@@H]3C(=O)O)nn2)c(C)c1
Yield: 61.9 %

Procedure:
Followed general procedure using: the corresponding peptidomimetic epoxide ethyl ester 47 (24 mg, 0.05 mmol); LiOH (1.1 mg, 0.05 mmol); after extraction afforded the desired product as a white solid (15 mg, 66.1%). 1H NMR (DMSO-d6, 400 MHz): δ 8.98-8.97 (d, 1H, J=1.87 Hz); 8.72-8.70 (t, 1H, J=11.2 Hz); 8.55-8.53 (d, 1H, J=8.23 Hz); 7.93 (s, 1H): 7.34 (s, 1H); 7.08 (s, 1H); 4.68-4.63 (m, 1H); 4.42-4.40 (d, 2H, J=5.50 Hz); 3.61-3.50 (m, 4H); 2.32 (s, 3H); 1.86 (s, 6H). 13C NMR (DMSO-d6, 100 MHz): 170.29, 165.60, 153.65, 152.98, 144.93, 139.46, 134.51, 133.50, 128.90, 124.69, 115.78, 52.79, 52.58, 48.66, 34, 54, 33.10, 20.69, 16.89. HRMS-ESI: m/z [M+H+] calculated for C22H24N6O5S: 485.5343, observed: m/z 485.1622 (M+H+): m/z 483.1600 (M−H+); HPLC Method 2: Rt=23.6 min; 97.4%.
Reaction SMILES: [CH:1]([C:3]1[N:7]([CH3:8])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][C:4]=1[CH3:14])=[O:2].CO.[BH4-].[Na+].[Cl-].[NH4+]>C(OCC)(=O)C.O>[OH:2][CH2:1][C:3]1[N:7]([CH3:8])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][C:4]=1[CH3:14]
Reactant: CCOC(=O)c1cc(C)c(C=O)n1C
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CCOC(=O)c1cc(C)c(CO)n1C
Reaction time: 0.08 h
Yield: 66 %

Procedure:
To a mixture of ethyl 5-formyl-1,4-dimethyl-1H-pyrrole-2-carboxylate (0.99 g) and methanol (10 ml) was added sodium borohydride (0.38 g) under ice-cooling, followed by stirring for 5 minutes under ice-cooling. To a reaction mixture was added a saturated aqueous ammonium chloride solution under ice-cooling, followed by stirring at room temperature for 0.5 hour. To the reaction mixture were added water and ethyl acetate, and the aqueous layer was separated and extracted with ethyl acetate. The organic layer was combined, washed with a saturated sodium bicarbonate solution and saturated brine in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4:1) to obtain ethyl 5-hydroxymethyl-1,4-dimethyl-1H-pyrrole-2-carboxylate (0.66 g).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:5]([N:14]2[C:18]([CH3:19])=[C:17]([C:20]([NH:22][C:23]3[CH:24]=[N:25][C:26]([CH:30]4[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]4)=[C:27]([CH3:29])[CH:28]=3)=[O:21])[CH:16]=[N:15]2)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.O>CO>[F:3][C:4]1[C:5]([N:14]2[C:18]([CH3:19])=[C:17]([C:20]([NH:22][C:23]3[CH:24]=[N:25][C:26]([C@H:30]4[CH2:31][CH2:32][C@H:33]([OH:36])[CH2:34][CH2:35]4)=[C:27]([CH3:29])[CH:28]=3)=[O:21])[CH:16]=[N:15]2)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: Cc1cc(NC(=O)c2cnn(-c3ncc(C(F)(F)F)cc3F)c2C)cnc1C1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cc(NC(=O)c2cnn(-c3ncc(C(F)(F)F)cc3F)c2C)cnc1[C@H]1CC[C@H](O)CC1
Reaction time: 0.5 h

Procedure:
Sodium borohydride (116.8 mg) was added under ice-cooling to a solution of 1-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]-5-methyl-N-[5-methyl-6-(4-oxocyclohexan-1-yl)pyridin-3-yl]-1H-pyrazole-4-carboxamide (211 mg) described in Example F34 in methanol (3 ml) and stirred at the same temperature for 30 minutes. After the reaction, water was added and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was fractionated with HPLC (water-acetonitrile:containing 0.05% trifluoroacetic acid). The obtained fraction was neutralized by the addition of 10% sodium carbonate, and the precipitates was filtered and dried at 60° C. under current of air to give the titled compound (92 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:20]=[C:19]3[N:10]([C:11](=[O:21])[NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=43)[N:9]=2)=[CH:4][CH:3]=1.[CH3:22][O-].[Na+].CI>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:20]=[C:19]3[N:10]([C:11](=[O:21])[N:12]([CH3:22])[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=43)[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]c2ccccc2c2nc(-c3ccc(Cl)cc3)nn12
Reactant: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CI
Product: Cn1c(=O)n2nc(-c3ccc(Cl)cc3)nc2c2ccccc21
Temperature: 0 °C

Procedure:
To a mixture of 2-(4-chlorophenyl)-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)one (6 g) in dry dimethylsulphoxide (150 ml) is added sodium methoxide (1.3 g). The mixture is heated under nitrogen for one hour at 85° and methyl iodide (1.3 ml) in dimethyl sulphoxide (10 ml) added. A white solid forms rapidly. The reaction mixture is heated three hours longer, cooled and poured into ice water (800 ml). The precipitated white solid is washed with water, air dried (7.2 g) and recrystallized from dimethylacetamide twice to afford pure 2-(4-chlorophenyl)6-methyl-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)one, mp 323°-325°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.ClC1C=CC(C([NH:19][C:20]2[CH:21]=[N:22][C:23]([OH:26])=[CH:24][CH:25]=2)=O)=CC=1>>[OH:26][C:23]1[N:22]=[CH:21][C:20]([NH:19][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:25][CH:24]=1
Reactant: O=C(Nc1ccc(O)nc1)c1ccc(Cl)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Nc2ccc(O)nc2)cc1

Procedure:
Starting from 4-methoxybenzoyl chloride (1.71 g, 10.0 mmol) and using the procedure as described for the preparation of 4-Chloro-N-(6-hydroxy-pyridin-3-yl)-benzamide yielded the title compound, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12](OS(C(F)(F)F)(=O)=O)[C:11]=1[N+:24]([O-:26])=[O:25].Cl.[CH:28]1([CH:31]([NH2:34])[CH2:32][CH3:33])[CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:34][CH:31]([CH:28]2[CH2:30][CH2:29]2)[CH2:32][CH3:33])[C:11]=1[N+:24]([O-:26])=[O:25]
Reactant: CCC(N)C1CC1
Reactant: COc1ccc(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])c(Cl)c1
Agent: Cl
Product: CCC(Nc1nccc(-c2ccc(OC)cc2Cl)c1[N+](=O)[O-])C1CC1
Yield: 70.4 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl ester (0.91 g, 2.20 mmol), prepared substantially as described in Part C of Example 19a, and 1-cyclopropyl-propylamine HCl (0.56 g, 4.41 mmol) were treated substantially as described in Part C of Example 19a to produce 0.56 g (72%) of [4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine: MS (AP) m/z 361.8 [(M+H)+, 100].
Reaction SMILES: [C:1]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[F:26][C:27]([F:37])([F:36])[C:28]1[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][CH:29]=1>C(Cl)Cl>[F:26][C:27]([F:37])([F:36])[C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:6]/[C:1]([O:3][CH2:4][CH3:5])=[O:2])=[CH:30][CH:29]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1ccc(C(F)(F)F)cc1
Yield: 71.1 %

Procedure:
To a solution of (carbethoxymethylene)triphenylphosphorane (55.3 g, 159 mmol) in 150 mL DCM, alpha,alpha,alpha-trifluoro-p-tolualdehyde (25.00 g, 144 mmol) in 75 mL DCM was added. The reaction is exothermic. The mixture was heated at reflux for 90 minutes. After removing the solvent, hexane was added to the resulting residue. A precipitate appeared and was filtered through filter paper. The collected solid was subjected to a silica gel chromatography with 100% hexane as the eluant to afford a white solid ((E)-ethyl 3-(4-(trifluoromethyl)phenyl)acrylate(25.0 g, yield=71%). LCMS (API-ES) m/z (%): 245.1 (100%, M++H); 1H NMR (400 MHz, CD3OD) δ ppm 1.35 (t, J=7.14 Hz, 3H) 4.28 (q, J=7.04 Hz, 2H) 6.68 (d, J=1 6.04 Hz, 1H) 7.70-7.77 (m, 3H) 7.80-7.84 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[N:14]([CH:21]([CH2:26][CH2:27][CH3:28])[CH2:22][C:23]([OH:25])=O)[C:13]3=[O:29])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>C1COCC1.O>[CH2:30]([NH:37][C:23](=[O:25])[CH2:22][CH:21]([N:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:12]([CH2:11][C:9]2[C:10]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=3[S:7][CH:8]=2)[C:13]1=[O:29])[CH2:26][CH2:27][CH3:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCCC(CC(=O)O)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CCCC(CC(=O)NCc1ccccc1)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Reaction time: 16 h
Yield: 94.3 %

Procedure:
To the suspension of 3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid (20 mg, 0.049 mmol) in THF (1.0 mL) at room temperature are added benzyl amine (0.027 mL, 0.245 mmol) and 1-hydroxybenzotriazole (32 mg, 0.24 mmol). Then N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (40 mg, 0.21 mmol) is added and the reaction mixture is stirred for 16 hr. Water (5 mL) is added and the mixture is extracted with EtOAc (3×10 mL). The organic layers are combined, dried over MgSO4 and concentrated to give crude product. The crude is filtered through a short path of silica gel eluting first with CH2Cl2 then with 50% EtOAc in hexanes to give 23 mg (95%) of 3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid benzylamide. LCMS (ESMS): m/z 498.22 (M+H+).
Reaction SMILES: [CH3:1][CH2:2][O:3][P:4]([O:10][CH2:11][CH3:12])([C:6](Br)([F:8])[F:7])=[O:5].I[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.CCOCC>CN(C=O)C.Cl[Cu]>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([C:6]([P:4](=[O:5])([O:10][CH2:11][CH3:12])[O:3][CH2:2][CH3:1])([F:8])[F:7])=[CH:15][CH:16]=1)([O-:22])=[O:21]
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: Cl[Cu]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(F)(F)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
Under N2, a mixture of bromodifluoromethyl diethylphosphonate (0.427 g, 1.6 mmol) and Cd powder (180 mg, 1.6 mmol) in DMF (0.5 mL) was stirred at room temperature for 2 h. Most of Cd disappeared. 4-Iodo-1-nitrobenzene (249 mg, 1.00 mmol) and CuCl (115 mg, 1.16 mmol) were then added. The mixture was again stirred at room temperature for 3 h. Ether (20 mL) was added to the reaction mixture and the precipitated solids were filtered off and washed with 10 mL of ether. The combined ether layers were washed with NH4Cl (aq), dried over MgSO4, and evaporated to give the title product (267 mg, yield: 86%). 1H NMR (CD3OD, 400 MHz): δ=1.33 (t, J=7.2 Hz, 6 H), 4.20-4.28 (m, 4 H), 7.86 (d, J=8.4 Hz, 2 H), 8.39 (d, J=8.4 Hz, 2 H). MS (ES+): m/z 310.06 [MH+]. HPLC: tR=3.92 min (ZQ3, polar—5 min).
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6]([C:8]1[C:13](=[O:14])[CH:12]=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:9]=1)=O)C.[C:25]1([NH:31]N)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)(=O)C>[C:25]1([N:31]2[C:6]([C:8]3[C:13](=[O:14])[CH:12]=[CH:11][N:10]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=4)[N:9]=3)=[N:5][CH:4]=[N:2]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NNc1ccccc1
Reactant: CN(C)C=NC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Solvent: CC(=O)O
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ncnn1-c1ccccc1
Temperature: 120 °C
Yield: 93.9 %

Procedure:
A solution of N-[(dimethylamino)methylidene]-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxamide (0.119 g, 0.35 mmol) in acetic acid (5.0 mL) was treated with phenyl hydrazine (0.070 mL, 0.71 mmol). The resulting solution was heated under microwave heating conditions at 120° C. for 10 min. After that time the reaction was cooled to room temperature and the crude product purified by flash column chromatography (silica gel, ethyl acetate to 85:15 ethyl acetate/methanol) to give a colorless solid that was recrystallized from ethyl acetate/hexanes to give 0.126 g (46%) of 3-(1-phenyl-1H-1,2,4-triazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:11]2[CH:16]=[CH:15][C:14]([CH2:17]Br)=[CH:13][N:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:19]([O:21][C:22]([C:24]1[NH:25][C:26]([CH2:30][CH2:31][CH2:32][CH3:33])=[N:27][C:28]=1[Cl:29])=[O:23])[CH3:20]>>[CH2:19]([O:21][C:22]([C:24]1[N:25]([CH2:17][C:14]2[CH:13]=[N:12][C:11]([C:6]3([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][CH2:9][CH2:8][CH2:7]3)=[CH:16][CH:15]=2)[C:26]([CH2:30][CH2:31][CH2:32][CH3:33])=[N:27][C:28]=1[Cl:29])=[O:23])[CH3:20]
Reactant: CCCCc1nc(Cl)c(C(=O)OCC)[nH]1
Reactant: CCOC(=O)C1(c2ccc(CBr)cn2)CCCC1
Product: CCCCc1nc(Cl)c(C(=O)OCC)n1Cc1ccc(C2(C(=O)OCC)CCCC2)nc1

Procedure:
Alkylation was carried out on 1-(5-bromomethylpyridin-2-yl)cyclopentane-carboxlic acid ethyl ester (45) as described in Example 1, Step 5, using 2-butyl-5-chloro-3H-imidazole-4-carboxylic acid ethyl ester (69) to produce the title compound (82).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[Cl:15][C:16]1[CH:21]=[N:20][CH:19]=[C:18](Cl)[N:17]=1>CS(C)=O>[CH2:1]([O:8][C:18]1[CH:19]=[N:20][CH:21]=[C:16]([Cl:15])[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Clc1cncc(OCc2ccccc2)n1

Procedure:
Benzylalcohol (500 μL, 7.83 mmol) and potassium tert-butoxide (222.4 mg, 1.82 mmol) in anhydrous DMSO (1 mL) were reacted with 2,6-dichloropyrazine (149.7 mg, 1.00 mmol) as described in Example 19B to afford the title compound. MS (DCI/NH3) m/z 221 (M+H)+.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[F:27][C:28]1([F:34])[CH2:30][CH:29]1[C:31](O)=[O:32]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:31]([CH:29]5[CH2:30][C:28]5([F:34])[F:27])=[O:32])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)C1CC1(F)F
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)C1CC1(F)F

Procedure:
The title compound, light yellow solid (79 mg, 73%), MS (ISP) m/z=433.4 [(M+H)+], mp 199° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 2,2-difluoro-cyclopropane-carboxylic acid.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[N:8][CH:9]=1.Cl.[C@@H:16]12[N:23]([CH2:24][C@@H:25]([C:27]3[C:28]([CH3:37])=[C:29]4[C:33](=[CH:34][CH:35]=3)[C:32](=[O:36])[O:31][CH2:30]4)[OH:26])[C@@H:20](CC1)[CH2:19][NH:18][CH2:17]2>C(O)C>[OH:26][C@H:25]([C:27]1[C:28]([CH3:37])=[C:29]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[O:31][CH2:30]2)[CH2:24][N:23]1[CH2:16][CH2:17][N:18]([CH2:3][CH:2]([OH:1])[C:4]2[CH:9]=[N:8][C:7]([N:10]3[CH:14]=[N:13][N:12]=[N:11]3)=[CH:6][CH:5]=2)[CH2:19][CH2:20]1
Reactant: Cc1c([C@@H](O)CN2[C@@H]3CC[C@H]2CNC3)ccc2c1COC2=O
Reactant: c1cc(-n2cnnn2)ncc1C1CO1
Agent: Cl
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCN(CC(O)c3ccc(-n4cnnn4)nc3)CC2)ccc2c1COC2=O
Temperature: 150 °C

Procedure:
To a microwave tube were added 5-(oxiran-2-yl)-2-(1H-tetrazol-1-yl)pyridine (INTERMEDIATE 32) (100 mg, 0.53 mmol), (R)-5-(1-hydroxy-2-(piperazin-1-yl)ethyl)-4-methylisobenzofuran-1(3H)-one (INTERMEDIATE 12) (175 mg, 0.63 mmol), and ethanol (3.0 mL). The mixture was heated in the microwave for 1 hour at 150° C. The solvent was evaporated and the crude product was purified by Mass Directed Reverse-Phase HPLC Chromatography to give 5-[(1R)-1-hydroxy-2-[4-[2-hydroxy-2-[6-(tetrazol-1-yl)-3-pyridyl]ethyl]piperazin-1-yl]ethyl]-4-methyl-3H-isobenzofuran-1-one.
Reaction SMILES: C([O:3][C:4]([CH:6]1[O:20][C:9]2=[C:10]3[C:15](=[C:16]([CH3:18])[CH:17]=[C:8]2[CH2:7]1)[NH:14][C:13](=[O:19])[CH2:12][CH2:11]3)=O)C.[NH3:21].CO>C(Cl)(Cl)Cl>[NH2:21][C:4]([CH:6]1[O:20][C:9]2=[C:10]3[C:15](=[C:16]([CH3:18])[CH:17]=[C:8]2[CH2:7]1)[NH:14][C:13](=[O:19])[CH2:12][CH2:11]3)=[O:3]
Reactant: N
Reactant: CCOC(=O)C1Cc2cc(C)c3c(c2O1)CCC(=O)N3
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1cc2c(c3c1NC(=O)CC3)OC(C(N)=O)C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The compound obtained in Example 258 (1 g, 3.63 mmol) was dissolved in chloroform (20 ml). To the solution, saturated ammonia--methanol solution (50 ml) was added. The vessel containing the mixture was sealed, and the content was stirred at room temperature for 24 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. 0.88 g of the title compound was obtained as a white solid (99%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH:16]=O)[CH:5]=1)[CH3:2].Cl.Cl.[CH:20]1([NH:23][C:24](=[O:38])[C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[C:27]([CH3:37])[CH:26]=2)[CH2:22][CH2:21]1>>[CH:20]1([NH:23][C:24](=[O:38])[C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:32][CH2:33][N:34]([CH2:16][C:6]4[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:9]5[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=5[CH:7]=4)[CH2:35][CH2:36]3)=[C:27]([CH3:37])[CH:26]=2)[CH2:22][CH2:21]1
Reactant: Cc1cc(C(=O)NC2CC2)ccc1N1CCNCC1
Reactant: CCOc1cc(C=O)cc2c1OC(C)C(=O)N2
Agent: Cl
Product: CCOc1cc(CN2CCN(c3ccc(C(=O)NC4CC4)cc3C)CC2)cc2c1OC(C)C(=O)N2

Procedure:
Using 398B and N-cyclopropyl-3-methyl-4-(piperazin-1-yl)benzamide-2HCl in the general procedure for reductive aminations, the title compound was obtained as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.51-0.57 (m, 2H) 0.63-0.70 (m, 2H) 1.33 (t, J=7.07 Hz, 3H) 1.41 (d, J=6.82 Hz, 3H) 2.25 (s, 3 H) 2.52-2.60 (m, 4H) 2.81 (td, J=7.26, 3.92 Hz, 1H) 2.89 (br. s., 4H) 3.42 (s, 2H) 3.98-4.10 (m, 2H) 4.54-4.66 (m, 1H) 6.51 (d, J=1.52 Hz, 1H) 6.63 (d, J=1.77 Hz, 1H) 7.01 (d, J=8.08 Hz, 1H) 7.55-7.66 (m, 2H) 8.23 (d, J=4.04 Hz, 1H) 10.57 (s, 1H). ESI-MS: m/z 479.5 (M+H)+. mp 223.4-223.5° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](=[O:11])[NH:8][C:7]=2[CH:12]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CC(C)=O>[O:11]=[C:9]1[N:8]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:7]2[CH:12]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=[CH:5][C:6]=2[O:10]1
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2o1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)Cn1c(=O)oc2ccc(C(F)(F)F)cc21

Procedure:
To a mixture of 5-trifluoromethyl-1,3-benzoxazol-2(3H)-one (999 mg) and acetone (25 mL) were added K2CO3 (1.02 g) and ethyl bromoacetate (708 μL) at room temperature, followed by heating to reflux for 4 hours. The reaction mixture was filtered while hot, and washed with acetone. The filtrate and the washed solution were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: Hex/EtOAc=100/0-75/25) to obtain ethyl [2-oxo-5-(trifluoromethyl)-1,3-benzoxazol-3(2H)-yl]acetate (1.33 g).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Ba+2].[OH-].[Cl-].[Na+]>C1(C)C=CC=CC=1.O.O1CCOCC1>[C:16]1([C:2]2[CH:14]=[CH:13][C:12]3[C:11]4[C:6](=[CH:7][C:8]([C:2]5[CH:14]=[CH:13][CH:12]=[CH:4][CH:3]=5)=[CH:9][CH:10]=4)[CH2:5][C:4]=3[CH:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: OB(O)c1ccccc1
Agent: [Ba+2]
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(-c2ccc3c(c2)Cc2cc(-c4ccccc4)ccc2-3)cc1
Temperature: 80 °C
Yield: 161.6 %

Procedure:
There were mixed 10.00 g (30.86 mmol) of 2,7-dibromofluorene, 15.05 g (123.45 mmol) of phenylboronic acid, 29.21 g (92.59 mmol) of barium hydroxide (Ba(OH)2.8H2O) and 0.71 g (0.62 mmol) of tetrakis(priphenylphosphine) palladium in an atmosphere of nitrogen. To the mixture, 200 mL of 1,4-dioxane and 33 mL of water were added at a room temperature. Temperature of the resultant mixture was raised up to 80° C., and the mixture was heated at 80° C. for 6 hours. Temperature of the mixture was cooled down to a room temperature, and 200 mL of toluene and 100 mL of a saturated solution of sodium chloride were added to the mixture. The obtained mixture was filtered, thereby obtaining a white solid. There was extracted 2,7-diphenyfluorene from the white solid with each 400 mL of hot THF three times. THF contained in the extract was distilled away, and the resultant solid was dried under a reduced pressure, thereby obtaining 7.94 g (yield: 80%) of 2,7-diphenyfluorene as a white solid.
Reaction SMILES: CO.[ClH:3].[NH:4]1[CH2:9][CH2:8][CH:7](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1.[H][H]>[C].[Pd].O>[ClH:3].[NH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH2:18])=[O:17])=[CH:19][CH:20]=2)[CH2:6][CH2:5]1
Reactant: [H][H]
Reactant: NC(=O)c1ccc(/C=C/C2CCNCC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(=O)c1ccc(CCC2CCNCC2)cc1
Yield: 56 %

Procedure:
10% Palladium-carbon (catalytic amount) was added to a methanol (15 ml)/water (5 ml) solution containing 4-[(E)-2-piperidin-4-ylvinyl]benzamide hydrochloride (800 mg), followed by stirring in a hydrogen gas atmosphere at room temperature under normal pressure for 4 hours. The catalyst was removed by filtration, and the resulting filtrate was concentrated under reduced pressure. The resulting solid was recrystallized from ethanol/acetonitrile to obtain 4-(2-piperidin-4-ylethyl)benzamide hydrochloride (451 mg) (Reference Example 58).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[C:23]1[C:24]2[CH:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[NH:29][C:25]=2[N:26]=[CH:27][N:28]=1>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:23]2[C:24]3[CH:31]=[C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[NH:29][C:25]=3[N:26]=[CH:27][N:28]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Clc1ncnc2[nH]c(-c3ccccc3)cc12
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ncnc3[nH]c(-c4ccccc4)cc23)cc1
Reaction time: 15 h
Yield: 68.5 %

Procedure:
After adding 123 mg of 4-nitrophenol, 136 mg of potassium carbonate and 1.5 ml of dimethylformamide to 113 mg of the 4-chloro-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine described in WO97/02266 and PCT/EP96/02728, and stirring the mixture for 15 hours at 130–135° C., and additional 60 mg of 4-nitrophenol and 75 mg of potassium carbonate were added and the mixture was stirred for 6 hours. After returning the mixture to room temperature, water was added, liquid separation and extraction were performed with an ethyl acetate-tetrahydrofuran mixed solvent, and the solid obtained by concentration to dryness was washed with ether to obtain 112 mg of the title compound.