Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([OH:4])=O.COC1CCC(OC)O1.FC(F)(F)C(O)=O.[C:21]1([CH:27]2[N:31](C3C=CC(OC(F)(F)F)=CC=3)C(=O)C(NC3C=CC(OC(F)(F)F)=CC=3)=[CH:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OC(C)C)(=O)C.C[C@@H](N)C1C=CC=CC=1.C1([C@H]2NC(=O)C=C2)C=CC=CC=1.FC(F)(F)OC1C=CC(N2[C@@H](C3C=CC=CC=3)C=C(N[C@@H](C3C=CC=CC=3)C)C2=O)=CC=1>C1COCC1.C(O)(C)C.C1(C)C=CC=CC=1.O>[C:21]1([C@@H:27]2[NH:31][C:2](=[O:4])[CH:1]=[CH:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)O
Reactant: O=C1C(Nc2ccc(OC(F)(F)F)cc2)=CC(c2ccccc2)N1c1ccc(OC(F)(F)F)cc1
Agent: COC1CCC(OC)O1
Agent: C[C@@H](N)c1ccccc1
Agent: C[C@@H](NC1=C[C@H](c2ccccc2)N(c2ccc(OC(F)(F)F)cc2)C1=O)c1ccccc1
Solvent: CC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=C1C=C[C@H](c2ccccc2)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.4 %

Procedure:
Add HOAc (464 mL, 8.09 mol), 2,5-dimethoxytetrahydrofuran (393 mL, 3.03 mol), water (2.27 L), and trifluoroacetic acid (153 mL, 2.02 mol) sequentially to a solution of (±)-5-phenyl-1-(4-trifluoromethoxy-phenyl)-3-(4-trifluoromethoxy-phenylamino)-1,5-dihydro-pyrrol-2-one (1000 g, 2.02 mol) in THF (8.43 L). Stir the reaction mixture at ambient temperature for 18 hours. Add toluene (4.0 L) and isopropyl acetate (2.0 L). Wash the mixture with water (8.0 L) and saturated sodium hydrogencarbonate solution (6.0 L). Discard the aqueous layer. To the organic layer, add (R)-(+)-α-methyl benzylamine (390 mL, 3.03 mol). Stir the solution at ambient temperature for 3 hours. Concentrate the reaction mixture to obtain a mixture of 1-(4-trifluoromethoxy-phenyl)-3-(R)-1-phenyl-ethylamino)-5(S)-phenyl-1,5-dihydro-pyrrol-2-one and 1-(4-trifluoromethoxy-phenyl)-3-((R)-1-phenyl-ethylamino)-5(R)-phenyl-1,5-dihydro-pyrrol-2-one as a black oil. Dissolve the mixture (888 g, 2.02 mol) in isopropanol (2.0 L) and cool to −7° C. Filter the precipitate and wash with cold isopropanol. Dry under vacuum for 12 hours to give 1-(4-trifluoromethoxy-phenyl)-3-(R)-1-phenyl-ethylamino)-5(R)-phenyl-1,5-dihydro-pyrrol-2-one (130 g, 29%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.64 (d, J=8 Hz, 2H), 7.34 (d, J=8 Hz, 2H), 7.24 (m, 4H), 7.11 (m, 4H), 6.98 (d, J=4 Hz, 2H), 5.78 (m, 2H), 5.13 (s, 1H), 4.30 (m, 1H), 1.44 (d, J=4 Hz 3H). LC-MS ESI m/z: 439 (M+H)+, Tr=6.30 min., method 1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH2:14][CH2:13]2)(=[O:9])=[O:8].C(N(CC)CC)C.[Cl:26][CH2:27][C:28](Cl)=[O:29].CC#N>CN(C=O)C>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:28](=[O:29])[CH2:27][Cl:26])[CH2:14][CH2:13]2)(=[O:9])=[O:8]
Reactant: O=S(=O)(Nc1nccs1)c1ccc2c(c1)CCN2
Reactant: O=C(Cl)CCl
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: -75 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a stirring solution of 2,3-dihydro-1H-indole-5-sulfonic acid thiazol-2-ylamide (2.35 g, 8.36 mmol) in DMF (10 mL), at −75° C., was added triethylamine (1.16 mL, 8.36 mmol) followed by chloroacetyl chloride (1.88 g, 16.7 mmol). The mixture was stirred at −75° C. for 1 h. The reaction showed product formation by LC/MS (10-99% CH3CN). After quenching with MeOH and allowing the mixture to warm to room temperature, the solvents were removed in vacuo. The mixture was purified via column chromatography (2% MeOH in CH2Cl2) to obtain the desired amide (1.95 g, 5.9 mmol, 70% yield). LC/MS (10-99% CH3CN), M/Z: M+1 obs=359.3; tR=2.46 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:28][CH:29]([F:33])[C:30](Cl)=[O:31]>>[Cl:28][CH:29]([F:33])[C:30]([NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:31]
Reactant: O=C(Cl)C(F)Cl
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Product: C[C@H](NC(=O)C(F)Cl)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and chlorofluoroacetyl chloride (19 mg, 150 μmol). Yield 16 mg (70%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[N:16]=2)[CH2:9]1)=O)(C)(C)C.Cl>CO.O1CCOCC1>[NH:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[N:16]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nc(-c3ccccc3O)nc3ccccc23)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Oc1ccccc1-c1nc(N[C@@H]2CCCNC2)c2ccccc2n1
Reaction time: 24 h
Yield: 39.6 %

Procedure:
Crude (R)-3-[2-(2-hydroxy-phenyl)-quinazolin-4-yl-amino]-piperidine-1-carboxylic acid tert-butyl ester (˜1.0 mmol) was dissolved in methanol (4 mL) and 4M HCl in dioxane (10 mL) was added. After stirring for 24 hours the solution was concentrated and purified by ion exchange chromatography on SCX-2 Isolute acidic resin (5 g), eluting with methanol and then 1 M ammonia in methanol. Further purification by silica column chromatography, eluting with 20% methanol in dichloromethane, gave the title compound as a yellow solid (0.127 g, 40%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][CH:12]=[CH:11][C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[O:29])[CH3:28])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][CH:12]=[CH:11][C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[O:31][CH3:30])([OH:29])[CH3:28])[CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1[Mg]Br
Reactant: CC(=O)c1cccc(-c2cccc(-c3ccccc3)c2OCc2ccccc2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1C(C)(O)c1cccc(-c2cccc(-c3ccccc3)c2OCc2ccccc2)c1
Reaction time: 3 h

Procedure:
A solution of 32 (1.5 g, 3.96 mmol) in anhydrous tetrahydrofuran (16 mL) was stirred under nitrogen at room temperature and 1M ortho-methoxyphenyl magnesium bromide in tetrahydrofuran (6 mL, 1.5 equiv.) was slowly added. Stirring was continued at room temperature for 30 min and at 60° C. for 3 hr. After cooling, the reaction mixture was poured on saturated ammonium chloride (100 mL) and extracted with ethyl acetate (150 mL). The organic extract was washed with water (2×100 mL), dried over sodium sulfate and filtered. The solvent was removed in a rotary evaporator and the crude 33 thus obtained was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[CH:26]=[CH:27][C:28]=1[Cl:29]>>[Cl:22][C:23]1[CH:24]=[C:25]([S:30]([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)(=[O:31])=[O:32])[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(S(=O)(=O)c3ccc(Cl)c(Cl)c3)CC1)O2

Procedure:
Compound 76 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3,4-dichlorobenzenesulfonyl chloride and conditions outlined in procedure P. M.p.=275-276° C.; 400 1H NMR (DMSO-d6) δ: 8.00-7.95 (m, 2H), 7.86-7.83 (m, 1H), 7.78-7.74 (m, 1H), 7.55-7.49 (m, 1H), 7.45-7.40 (m, 1H), 7.15-7.11 (m, 1H), 3.62-3.53 (m, 2H), 3.09 (s, 2H), 2.66-2.57 (m, 2H), 2.13-2.03 (m, 2H), 1.94-1.84 (m, 2H) LCMS: 510 [M+H].
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][O:23][C:24]3[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=3[C:26]([O-:28])=[O:27])[CH2:17][CH2:16]2)=[CH:7]1)[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][O:23][C:24]3[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=3[C:26]([OH:28])=[O:27])[CH2:17][CH2:16]2)=[CH:7]1)[CH3:2]
Reactant: CCOCCn1cc(C2CCN(CCOc3ccccc3C(=O)[O-])CC2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOCCn1cc(C2CCN(CCOc3ccccc3C(=O)O)CC2)c2ccccc21
Temperature: 60 °C

Procedure:
1.05 g (2.33 mmol) of 2-(2-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoate was dissolved in 30 ml of ethanol. A solution of 0.19 g (4.66 mmol) of sodium hydroxide in 30 ml of water was added to the previous one and the whole mixture was heated at 60° C. for 2 h. After dilution with water and neutralisation with HCl 6N, the aqueous phase was extracted three times with chloroform. The organic solution was washed with brine, dried with sodium sulphate, filtered and evaporated to dryness. The 4.06 g of crude material was recrystallised in acetonitrile affording 2.54 g (64% of yield)of 2-(2-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([N+:31]([O-:33])=[O:32])[CH:23]=1>>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:2][CH2:3][C:4](=[O:5])[NH:6][CH:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:27])=[C:24]([N+:31]([O-:33])=[O:32])[CH:23]=1
Reactant: O=C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccc(Cl)cc1[N+](=O)[O-])NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-chloro-2-nitrobenzoic acid.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1.[P:25]([O:32]CC)([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28].C(OCC)C.C(Cl)Cl>C(OCC)C.O1CCCC1>[CH2:27]([O:26][P:25]([CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1)(=[O:32])[O:29][CH2:30][CH3:31])[CH3:28]
Reactant: CCOP(OCC)OCC
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CBr)c3c2)c1=O
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12)OCC
Temperature: 10 °C
Reaction time: 1.5 h
Yield: 81.2 %

Procedure:
A mixture of 3-[3-(bromomethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (1.00 g, 0.00240 mol) in diethyl ether is cooled to 10° C., treated dropwise with triethyl phosphite (0.580 mL, 0.00340 mol), stirred at 10° C. for 90 minutes, diluted with 10 mL of tetrahydrofuran, stirred at room temperature overnight, refluxed for 1 day, cooled, partially concentrated in vacuo and diluted with methylene chloride. The resultant organic solution is washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a yellow solid. Flash column chromatography of the solid using silica gel and a diethyl ether/methylene chloride solution (1:1) gives the title product as a white solid (0.930 g, mp 142-144° C.).
Reaction SMILES: O1C=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:15])=[O:7].[O:16]1C=CC(C(O)=O)=[CH:17]1>>[O:16]1[CH:4]=[CH:3][C:2]([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])=[O:7])=[CH:17]1
Reactant: O=C(O)c1ccoc1
Reactant: O=C1CCCCCN1C(=O)c1ccco1
Product: O=C1CCCCCN1C(=O)c1ccoc1

Procedure:
Synthesized as for N-(2-furoyl)caprolactam (Example X) using 3-furoic acid in place of 2-furoic acid.
Reaction SMILES: C([N:3](CC)CC)C.ClC(OCC(C)C)=O.[S:16]1[CH:20]=[CH:19][C:18]2[C:21]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][O:34][C:35]4[C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:38]=[C:37]([C:45](O)=[O:46])[CH:36]=4)[CH2:27][CH2:26]3)=[CH:22][CH:23]=[CH:24][C:17]1=2.N>C(#N)C.C(OCC)(=O)C>[S:16]1[CH:20]=[CH:19][C:18]2[C:21]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][O:34][C:35]4[C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:38]=[C:37]([C:45]([NH2:3])=[O:46])[CH:36]=4)[CH2:27][CH2:26]3)=[CH:22][CH:23]=[CH:24][C:17]1=2
Reactant: O=C(O)c1cc(OCCCN2CCN(c3cccc4sccc34)CC2)c2ccccc2n1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: CC#N
Product: NC(=O)c1cc(OCCCN2CCN(c3cccc4sccc34)CC2)c2ccccc2n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 14.7 %

Procedure:
Triethylamine (0.25 ml, 1.8 mmol) and isobutyl chloroformate (0.19 ml, 1.4 mmol) were added to a solution (10 ml) of 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]quinolin-2-carboxylic acid (0.53 g, 1.2 mmol) in acetonitrile with cooling in an ice-bath, followed by stirring at 0° C. for 3 hours. 28% Aqueous ammonia (0.15 ml) was added thereto and the reaction mixture was stirred at room temperature for 5 minutes. Ethyl acetate was further added thereto, then the reaction mixture was washed with water and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=3:1), and concentrated under reduced pressure. The residue (0.2 g) was dissolved and recrystallized from the mixed solvent of ethyl acetate and isopropyl ether to obtain 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-quinolin-2-carboxamide (79 mg, yield: 16%) as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([C:14]([O:16]CC)=O)[S:11][N:10]=2)=[CH:5][CH:4]=1.[C:19]1([C@@H:25]([NH2:27])[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[C:19]1([C@@H:25]([NH:27][C:14]([C:12]2[S:11][N:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[N:13]=2)=[O:16])[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CCOC(=O)c1nc(-c2ccc(OC)cc2)ns1
Solvent: ClCCl
Product: COc1ccc(-c2nsc(C(=O)N[C@@H](C)c3ccccc3)n2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 117.9 %

Procedure:
A mixture of (S)-1-phenylethyl)amine (1.21 g, 10 mmol) and ethyl 3-(4-methoxyphenyl)-[1,2,4]thiadiazole-5-carboxylate (1.32 g, 5 mmol) is stirred at 80° C. for 2 hours. A further portion of (S)-1-phenyl-ethylamine (0.5 g, 4 mmol) is added and the mixture is stirred for at 80° C. for a further 1.5 hours. The mixture is then cooled and dissolved in dichloromethane. The solution is washed with dilute sulphuric acid followed by water, and the organic phase is dried over magnesium sulphate. The solvent is evaporated in vacuo to give (S)-3-(4-methoxyphenyl)-[1,2,4]thiadiazole-5-carboxylic acid (1-phenylethyl)-amide (1.6 g, 94%) as colourless crystals, m.p. 143°-145° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[N:20]=[N:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[N:26]1([NH:25][C:21]([C:18]2[N:19]=[N:20][C:15]([O:14][CH2:13][C:12]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[N:10][C:11]=3[CH3:24])=[CH:16][CH:17]=2)=[O:23])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)nn1
Reactant: NN1CCOCC1
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)NN2CCOCC2)nn1
Yield: 71 %

Procedure:
As described for example 75b, 6-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (85 mg, 0.26 mmol), was converted, using 4-aminomorpholine instead of isopropylamine, to the title compound (76 mg, 71%) which was obtained as a white solid. MS: m/e=414.3 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.[NH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([NH:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)O)cc2)cc1
Reactant: CC(C)(C)OC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)NCC(=O)OC(C)(C)C)cc2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanoic acid (40 mg, 0.119 mmol), tert-butyl 2-aminoacetate (18.66 mg, 0.142 mmol), and TEA (0.033 mL, 0.237 mmol) in DMF (1 mL) was added HATU (54.1 mg, 0.142 mmol). The reaction was stirred at 60° C. for 2 h. The mixture was added 1M HCl (1 mL) and purified by HPLC to give the title compound. LCMS m/z=451.4 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.27 (d, J=6.9 Hz, 0.4H), 1.45 (s, 9H), 1.47 (d, J=6.5 Hz, 2.6H), 1.71-1.83 (m, 1H), 2.02-2.12 (m, 2H), 2.23-2.33 (m, 1H), 2.55 (t, J=7.5 Hz, 2H), 2.96 (t, J=7.8 Hz, 2H), 3.06-3.21 (m, 4H), 3.37-3.47 (m, 1H), 3.50-3.63 (m, 1H), 3.72-3.84 (m, 1H), 6.63 (s, 1H), 7.35 (d, J=8.2 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 7.58 (d, J=8.2 Hz, 2H), 7.64 (d, J=8.2 Hz, 2H).
Reaction SMILES: C([N:8]([CH2:32][CH2:33][O:34]C(C)(C)C)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]([CH3:22])[C:20](=[O:23])[CH2:19][N:18]=[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:16]=2[CH:31]=1)=[O:10])C1C=CC=CC=1.C(=O)(O)[O-].[Na+].CO>Br>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:17]1[C:16]2[CH:31]=[C:12]([NH:11][C:9]([NH:8][CH2:32][CH2:33][OH:34])=[O:10])[CH:13]=[CH:14][C:15]=2[N:21]([CH3:22])[C:20](=[O:23])[CH2:19][N:18]=1
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(NC(=O)N(CCOC(C)(C)C)Cc3ccccc3)ccc21
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CN1C(=O)CN=C(c2ccccc2F)c2cc(NC(=O)NCCO)ccc21

Procedure:
1.5 g (0.003 M) of 1-benzyl-1-(2-tert.butoxyethyl)-3-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]urea are dissolved in 15 ml of 48% aqueous hydrogen bromide solution, the mixture is heated on a steam-bath for 10 minutes, made alkaline with sodium bicarbonate, treated with a small amount of methanol and extracted three times with methylene chloride. The extracts are combined, dried over sodium sulphate, filtered and concentrated. The residue is purified in a pressure column (0.2-0.4 atmospheres of nitrogen) on 300 g of silica gel (particle size 0.04-0.06 mm) using acetone as the eluting agent and crystallised from acetone/ether. There is obtained 1-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-(2-hydroxyethyl)urea which, according to the IR spectrum, is identical with a sample of this substance prepared in another manner (see Example 7).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][N:7]=1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1.O>[CH2:18]([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[O:8][N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2OCc2ccccc2)on1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(-c2ccccc2OCc2ccccc2)on1
Reaction time: 2 h
Yield: 98.1 %

Procedure:
To a stirred solution of 4-(2-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester (3.75 g, 0.01149 mole) in acetic acid (20 mL) was added hydroxylamine hydrochloride (0.878 g, 0.0126 mole) and the resulting mixture was heated to reflux for 3 hours. Volatiles were removed and the resulting residue was diluted with water, basified with sodium bicarbonate solution and extracted with ethyl acetate, washed the ethyl acetate with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 3.42 g (92%) of 5-(2-benzyloxy-phenyl)-isoxazole-3-carboxylic acid ethyl ester. LCMS: 324.12 (M+1)+, 78.58%. To a stirred solution of 5-(2-benzyloxy-phenyl)-isoxazole-3-carboxylic acid ethyl ester (1.75 g, 0.00542 mol) in a mixture of THF (30 mL), methanol (15 mL) and H2O (15 mL) was added NaOH (0.651 g, 0.01628 mol) and the resulting mixture was stirred for 2 hours. The reaction mixture was then diluted with cold water. Volatiles were removed by evaporation and the residue was diluted with water acidified with concentrated HCl. The resulting precipitate was isolated by filtration and dried to afford 1.57 g (98%) of 5-(2-benzyloxy-phenyl)-isoxazole-3-carboxylic acid. LCMS: 296.08 (M+1)+, 84.73%
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:41]([N:45]1[C:50]2=[N:51][NH:52][C:53]([NH:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[C:49]2[C:48](=[O:61])[N:47]([CH3:62])[C:46]1=[O:63])[CH:42]([CH3:44])[CH3:43].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:41]([N:45]1[C:50]2=[N:51][N:52]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH:9]4[CH2:14][CH2:13][CH2:12][CH2:11][N:10]4[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:5][CH:4]=3)[C:53]([NH:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)=[C:49]2[C:48](=[O:61])[N:47]([CH3:62])[C:46]1=[O:63])[CH:42]([CH3:44])[CH3:43]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Nc3ccccc3)[nH]nc21
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1ccc(CO)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Nc3ccccc3)n(Cc3ccc(C4CCCCN4C(=O)OC(C)(C)C)cc3)nc21
Temperature: -78 °C
Yield: 81 %

Procedure:
tert-butyl 2-(4-(hydroxymethyl)phenyl)piperidine-1-carboxylate (47 mg, 0.16 mmol) is dissolved in 1 mL of anhydrous THF, and then triphenylphosphine (42 mg, 0.16 mmol) is added, followed by 7-isobutyl-5-methyl-3-(phenylamino)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (50 mg, 0.16 mmol). The mixture is cooled to −78° C., and then DIAD (95%, 50 μL) is added slowly. After the reaction is complete, the mixture is purified on a basic alumina column to give 76 mg of product (yield: 81%). MS (ESI) m/z 587.3 [M+H]+.