Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:21][C:20]=2[F:33])[C:7]1=[O:34].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH2:16]([C:14]1[S:15][C:9]2[N:8]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][C:20]=3[F:33])[C:7](=[O:34])[NH:6][C:11](=[O:12])[C:10]=2[CH:13]=1)[CH3:17]
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3F)c2s1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3F)c2s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
A mixture of 4′-{[3-(2,4-dimethoxybenzyl)-6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (1.3 g) and trifluoroacetic acid (20 mL) was stirred at 50° C. for 2 hr. To the reaction mixture was added toluene (20 mL), and the mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate (10 mL), and the mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.95 g, 100%).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]1[N:16]([C:20]([C:22]2[C:23](Cl)=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:21])[CH2:17][CH2:18][N:19]=1>C(O)(C)(C)C>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[C:23]2[N:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:20](=[O:21])[N:16]2[CH2:17][CH2:18][NH:19][C:15]=12
Reactant: O=C(c1cccnc1Cl)N1CCN=C1Cc1ccccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=c1c2cccnc2c(-c2ccccc2Cl)c2n1CCN2

Procedure:
Add potassium tert.-butoxide (0.928g) to 2-[(2-chlorophenyl)methyl]-1-[(2-chloro-3-pyridinyl)carbonyl]-4,5-dihydro-1H-imidazole (2.57g) suspended in tert.-butanol (25 ml). Reflux the reaction mixture under nitrogen for 5 hours, cool the resulting suspension, and evaporate the solvent Partition the residue between chloroform and water, separate and dry the chloroform solution over sodium sulfate. Filter the dried solution, evaporate the solvent, and crystallize the residue from methanol to give 10-(2-chlorophenyl)-2,3-dihydro-imidazo [1,2-g][1,6]naphthyridin-5(1H)-one, mp 295°-297° C. (d).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[CH3:23][C:24]1[N:25]([C:29]2[CH:30]=[C:31]([CH:35]=[C:36]([S:38]([F:43])([F:42])([F:41])([F:40])[F:39])[CH:37]=2)[C:32](O)=[O:33])[CH:26]=[CH:27][N:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[OH-].[Na+]>CN(C=O)C>[CH3:23][C:24]1[N:25]([C:29]2[CH:30]=[C:31]([CH:35]=[C:36]([S:38]([F:42])([F:39])([F:40])([F:43])[F:41])[CH:37]=2)[C:32]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]3[C:16]4[N:12]([N:13]=[C:14]([C:17]5[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=5)[CH:15]=4)[CH:11]=[CH:10]3)[CH:4]=2)=[O:33])[CH:26]=[CH:27][N:28]=1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Reactant: Cc1nccn1-c1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cc(-n3ccnc3C)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
50 mg (0.17 mmol) of the compound of Example 6A, 57 mg (0.17 mmol) of the compound of Example 26A and 79 mg (0.207 mmol) of HATU were initially charged in 0.6 ml of DMF, 36 μl (0.207 mmol) of N,N-diisopropylethylamine were added and the mixture was stirred at RT for 16 h. The reaction was then stirred into 10 ml of 0.1 M aqueous sodium hydroxide solution. After a further 10 min of stirring at RT, the precipitate formed was filtered off, washed with water and dried. This gave 66 mg (62% of theory) of the title compound.
Reaction SMILES: [CH:1]1([N:4]([CH3:27])[C:5]2[C:6](OS(C(F)(F)F)(=O)=O)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1.[O:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH:30]=[C:29]1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH:30]=[C:29]1[C:6]1[C:5]([N:4]([CH:1]2[CH2:3][CH2:2]2)[CH3:27])=[N:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=2)[N:7]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N(C)C3CC3)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cc4ccccc4o3)c(N(C)C3CC3)nc2c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(cyclopropyl(methyl)amino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (180.0 mg, crude) in dioxane (6 mL) was added benzofuran-2-ylboronic acid (149.0 mg, 0.92 mmol), K3PO4 (195.0 mg, 0.92 mmol), Pd(PPh3)4 (30.0 mg, 0.03 mmol) and water (3 drops). The resulting solution was stirred for 1 h at 90° C. and then concentrated under vacuum to give a residue, which was purified by a silica gel column with 5%-20% ethyl acetate in petroleum ether to afford methyl 2-(benzofuran-2-yl)-3-(cyclopropyl(methyl)amino)quinoxaline-6-carboxylate as a yellow solid (95.0 mg, 39% 2 steps).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:14]([CH:16]1[O:18][CH2:17]1)Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:18]1[CH2:17][CH:16]1[CH2:14][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(CC2CO2)CC1
Yield: 76.9 %

Procedure:
A mixture of tert-butyl piperazine-1-carboxylate (6.2 g, 33.29 mmol), epibromohydrin (5.4 g, 39.42 mmol) and potassium carbonate (5.5 g, 39.79 mmol) in acetonitrile (70 ml) was heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with methylene chloride. The extract was washed with brine, dried over sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to afford tert-butyl 4-oxiranylmethylpiperazine-1-carboxylate (6.2 g, yield 77%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([OH:10])[CH3:9].O.O.[I-:13].[Na+]>[Cu]I.CNCCNC.O1CCOCC1>[I:13][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([OH:10])[CH3:9]
Reactant: C[C@H](O)c1ccccc1Br
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](O)c1ccccc1I
Temperature: 150 °C
Reaction time: 16 h
Yield: 240.4 %

Procedure:
To each of three identical Emrys microwave reaction vessels was added (S)-1-(2-bromophenyl)ethanol (1.67 g, 8.3 mmol), CuI (189 mg, 1.0 mmol), 1,4-dioxane (12.4 ml), N,N′-dimethylethylenediamine (0.18 ml, 1.7 mmol) and sodium iodide dihydrate (3.1 g, 16.6 mmol). Each vessel was sealed and heated in an Emrys microwave reactor to 150° C. for 2 h. On cooling, the mixtures were combined and partitioned between water (20 ml) and EtOAc (20 ml). The organic phase was washed with brine (20 ml), dried (MgSO4), filtered, and concentrated in vacuo. The crude product was taken up in isohexane (50 ml) and the solution held at −15° C. for 16 h to afford (S)-1-(2-iodophenyl)ethanol as a white crystalline solid (4.95 g).
Reaction SMILES: [Cl-].[Cl-].[Ca+2].[CH3:4][S:5]([C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([C:20](OC)=[O:21])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[BH4-].[Na+]>CCO.C1COCC1>[CH3:4][S:5]([C:8]1[CH:9]=[CH:10][C:11]([CH2:20][OH:21])=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1)(=[O:6])=[O:7]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)cc1-c1ccccc1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(CO)c(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of CaCl2 (1.52 g, 13.78 mmol) in EtOH (50 mL) at RT was added methyl 5-(methylsulfonyl)-[1,1′-biphenyl]-2-carboxylate (2 g, 6.9 mmol) in THF (50 mL) followed by the addition of NaBH4 (1.0 g, 27.6 mmol). The reaction was stirred at RT for 24 h, then concentrated in vacuo and extracted with ethyl acetate, 5% HCl, and brine. Purification on normal phase silica gel provided (5-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)methanol as a white solid.
Reaction SMILES: [CH2:1]1[C@@H:3]2[C:4](=[O:22])[CH:5]=[C:6]3[C@:19]([CH3:20])([CH:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH2:8][CH2:7]3.[Br:23]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:23][C@H:7]1[C:6]2[C@:19]([CH3:20])([CH:2]3[CH2:1][C@@H:3]3[C:4](=[O:22])[CH:5]=2)[C@@H:18]2[C@H:9]([C@H:10]3[C@@:14]([CH2:16][CH2:17]2)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]3)[CH2:8]1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: C[C@]12CC[C@H]3[C@@H](C[C@@H](Br)C4=CC(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Temperature: 25 °C
Yield: 70 %

Procedure:
A mixture of 1,2β-methylenandrost-4-ene-3,17-dione (2.44 g), N-bromosuccinimide (2.33 g), benzoyl peroxide (0.060 g), and carbon tetrachloride (200 ml) are heated to reflux for 4 hours. After cooling to room temperature the precipitate is filtered off, the residue washed with carbon tetrachloride and the combined filtrates evaporated in vacuo. The residue is chromatographed on silica gel using benzene/ethyl ether to give pure 6β-bromo-1,2β-methylenandrost-4-ene-3,17-dione (2.16 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.[CH3:14][N:15]1[CH:19]=[C:18]([CH2:20][NH2:21])[CH:17]=[N:16]1.CCN(C(C)C)C(C)C>CC#N>[Cl:1][C:2]1[N:7]=[C:6]([NH:21][CH2:20][C:18]2[CH:17]=[N:16][N:15]([CH3:14])[CH:19]=2)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(Cl)nc1Cl
Reactant: Cn1cc(CN)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(Cl)nc1NCc1cnn(C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl 2,4-dichloropyrimidine-5-carboxylate (896 mg, 4 mmol) and (1-methyl-1H-pyrazol-4-yl)methanamine (445 mg, 4 mmol) in CH3CN (6 mL) at room temperature, DIEA (0.783 mL, 4.4 mmol) was added. The mixture was stirred at room temperature for 24 h, and was concentrated to give ethyl 2-chloro-4-((1-methyl-1H-pyrazol-4-yl)methylamino)pyrimidine-5-carboxylate as crude oil.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=3)=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=2)[CH2:4][CH2:3][CH2:2]1.[F:23][C:24]([F:33])([F:32])[C:25]1[N:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=1>>[CH:1]1([O:5][C:6]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=3)=[CH:13][C:9]([C:10]([NH:31][CH2:30][C:28]3[O:27][N:26]=[C:25]([C:24]([F:33])([F:32])[F:23])[N:29]=3)=[O:12])=[CH:8][N:7]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: O=C(O)c1cnc(OC2CCC2)c(-c2ccc(F)c(F)c2)c1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OC2CCC2)c(-c2ccc(F)c(F)c2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 6-cyclobutoxy-5-(3,4-difluorophenyl)nicotinic acid (example BZ) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 98.0%, 455.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[S:14](Cl)(=[O:16])=[O:15])[CH2:6]1)=[O:4].[Br:18][C:19]1[CH:20]=[C:21]([N:26]2[CH2:31][C@H:30]([CH3:32])[NH:29][C@H:28]([CH3:33])[CH2:27]2)[CH:22]=[CH:23][C:24]=1[Cl:25].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[Br:18][C:19]1[CH:20]=[C:21]([N:26]2[CH2:27][C@@H:28]([CH3:33])[N:29]([S:14]([C:11]3[CH:10]=[CH:9][CH:8]=[C:7]4[C:12]=3[CH2:13][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]4)(=[O:16])=[O:15])[C@@H:30]([CH3:32])[CH2:31]2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: COC(=O)C1Cc2cccc(S(=O)(=O)Cl)c2C1
Reactant: C[C@@H]1CN(c2ccc(Cl)c(Br)c2)C[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C1Cc2cccc(S(=O)(=O)N3[C@H](C)CN(c4ccc(Cl)c(Br)c4)C[C@@H]3C)c2C1
Temperature: 55 °C

Procedure:
4-Chlorosulfonyl-indan-2(R,S)-carboxylic acid methyl ester (225 mg, 0.82 mmol) was added to a mixture of 1-(3-bromo-4-chlorophenyl)-cis-3,5-dimethylpiperazine (569 mg, 1.87 mmol), potassium carbonate (500 mg, 3.6 mmol), and acetonitrile (8 mL) at rt under nitrogen, and the reaction was heated at 55° C. for 3 h. After allowing the reaction to cool to rt, it was poured into water (40 mL) and extracted with dichloromethane (40 mL×2). The combined organic extracts were dried, filtered, concentrated, and purified by silica gel chromatography (9:1→3:1; hexanes:ethyl acetate) to give methyl 4-(4-(3-bromo-4-chlorophenyl)-cis-2,6-dimethylpiperazin-1-ylsulfonyl)-2,3-dihydro-1H-indene-2(R,S)-carboxylate: MS (ESI): 541.2 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH:16]1([O:20][C:21]2[N:26]=[CH:25][C:24]([CH:27]([NH2:29])[CH3:28])=[CH:23][C:22]=2[CH3:30])[CH2:19][CH2:18][CH2:17]1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:29]([CH:27]([C:24]3[CH:25]=[N:26][C:21]([O:20][CH:16]4[CH2:19][CH2:18][CH2:17]4)=[C:22]([CH3:30])[CH:23]=3)[CH3:28])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)cnc1OC1CCC1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OC1CCC1
Yield: 59 %

Procedure:
The title compound is prepared in 59% yield (431 mg, pale yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (574 mg, 2.06 mmol, Step-1 of Intermediate-1) and 1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethanamine hydrochloride (500 mg, 2.06 mmol, Amine-75, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([N:7]1[CH:13]([CH3:14])[CH2:12][C:11]2[CH:15]=[C:16]3[O:21][CH2:20][O:19][C:17]3=[CH:18][C:10]=2[C:9]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[N:8]1)=[O:6].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].CN(C)C=O>O>[O:6]1[CH2:2][CH2:3][N:4]=[C:5]1[N:7]1[CH:13]([CH3:14])[CH2:12][C:11]2[CH:15]=[C:16]3[O:21][CH2:20][O:19][C:17]3=[CH:18][C:10]=2[C:9]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[N:8]1
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(=O)NCCCl)OCO3
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C1=NCCO1)OCO3
Temperature: 105 °C
Reaction time: 4 h
Yield: 76.4 %

Procedure:
A mixture of 1.43 g (3.32 mmol) of the starting material XXV, 1.38 g (9.98 mmol) of anhydrous potassium carbonate, 0.24 g (1.60 mmol) of sodium iodide and 24 ml of dimethylformamide was stirred at 100-110° C. for 4 h. Then the mixture was diluted with water and the precipitated crude product was recrystallized from ethanol to yield 1.00 g (76%) of the title compound; Mp.: 194-196° C.
Reaction SMILES: C(O)=O.C(N(CC)CC)C.CC1(C)[O:19][C:17](=[O:18])[CH2:16][C:14](=O)O1.C(=O)[C:22]1[CH:31]=[CH:30][C:27]([O:28][CH3:29])=[C:24]([O:25][CH3:26])[CH:23]=1>CN(C)C=O>[CH3:26][O:25][C:24]1[CH:23]=[C:22]([CH2:14][CH2:16][C:17]([OH:19])=[O:18])[CH:31]=[CH:30][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: O=CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CCC(=O)O)cc1OC
Temperature: 110 °C

Procedure:
After adding 6.25 ml of the mixture of formic acid and triethylamine prepared as described in Example 1 to 15 ml of dimethylformamide, 3.60 g (0.025 mol) of Meldrum's acid and 4.15 g (0.025 mol) of veratraldehyde were added to the above mixture, which was then heated to 110° C. during 1 hour and reacted at the same temperature for 3 hours. The product was separated from the reaction mixture by the method as described in Example 1.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]#[N:11])[CH2:5][CH2:4]1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:11][CH2:10][CH2:9][CH:6]1[CH2:5][CH2:4][C:3]([N:2]([CH3:1])[CH3:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1
Reactant: CN(C)C1(c2ccccc2)CCC(=CC#N)CC1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCC(CCN)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(4-Dimethylamino-4-phenylcyclohexylidene)acetonitrile (1.16 g, 4.8 mmole) was dissolved in methanol (30 ml). Nickel(II) chloride hexahydrate (2.28 g, 9.6 mmole) was added to this solution. NaBH4 (1.82 mg, 48 mmole) was then added in portions with stirring and ice water cooling. Once addition was complete, stirring was continued at RT for 1 h. The resultant black nickel boride was removed by suction filtration after addition of 2M hydrochloric acid (15 ml) and washed with 2M hydrochloric acid (3×10 ml). The hydrochloric, aqueous-methanolic solution was reduced to half its volume in order to remove the methanol. The remaining aqueous phase was extracted with ether (3×10 ml) to remove neutral substances. The aqueous phase was then alkalised by addition of conc. aqueous ammonia solution and again extracted with ether (3×20 ml). The combined extracts were washed with saturated NaCl-solution (30 ml), dried over Na2SO4 and then evaporated. The resultant crude product could be purified by column chromatography [silica gel 60 (100 g); MeOH (1000 ml)]. However, this did not result in separation of the diastereoisomers. [4-(2-Aminoethyl)-1-phenylcyclohexyl]dimethylamine was obtained as a colorless oil in a yield of 643 mg (54%).
Reaction SMILES: [NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:9]([OH:11])=O)[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[NH2:22][C@H:23]([C:30]([NH:32][C@H:33]([C:38]([NH:40][C@H:41]([C:45]([NH:47][C@H:48]([C:53]([NH:55][C@H:56]([C:63]([NH2:65])=[O:64])[CH2:57][C:58]1[N:62]=[CH:61][NH:60][CH:59]=1)=[O:54])[C@H:49]([CH2:51][CH3:52])[CH3:50])=[O:46])[CH:42]([CH3:44])[CH3:43])=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:31])[CH2:24][C:25]1[N:29]=[CH:28][NH:27][CH:26]=1.Cl.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CO.O>[NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:9]([NH:22][C@H:23]([C:30]([NH:32][C@H:33]([C:38]([NH:40][C@H:41]([C:45]([NH:47][C@H:48]([C:53]([NH:55][C@H:56]([C:63]([NH2:65])=[O:64])[CH2:57][C:58]1[N:62]=[CH:61][NH:60][CH:59]=1)=[O:54])[C@H:49]([CH2:51][CH3:52])[CH3:50])=[O:46])[CH:42]([CH3:43])[CH3:44])=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:31])[CH2:24][C:25]1[N:29]=[CH:28][NH:27][CH:26]=1)=[O:11])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1
Reactant: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1)C(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(N)=O

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 23 mg of Z-His-OH, 50 mg of H-His-Leu-Val-Ile-His-NH2.2HCl, 11 mg of HOBt, 24,6 μl of ethyldiisopropylamine and 21 mg of DCCI, the title compound is obtained in the form of a grey resin after flash chromatography (32 g of silica gel 60, 40-63 μm, eluant system methylene chloride/methanol/water/glacial acetic acid 280:160:40:2). Rf (B13)=0.40.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1)#[N:2].[NH2:13][CH2:14][CH2:15][C:16]([NH:18][C@H:19]([C:28]([NH:30][C@H:31]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:29])[CH2:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:17]>>[C:42]([O:41][C:39](=[O:40])[C@H:31]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[NH:30][C:28](=[O:29])[C@H:19]([CH2:20][C:21]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:27])[NH:18][C:16](=[O:17])[CH2:15][CH2:14][NH:13][C:10](=[O:12])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)([CH3:43])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)CCN)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(CC(=O)O)cc1
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)CCNC(=O)Cc1ccc(C#N)cc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Yield: 51.5 %

Procedure:
142 mg of 4-cyanophenylacetic acid were coupled with 371 mg of H-β-Ala-Asp(O-tBu)-Phe-O-tBu (Example 1b) in the manner described in Example 1a), yielding 250 mg of N-[N-[N-(p-cyanophenylacetyl)-β-alanyl]-3-t-butoxycarbonyl-L-alanyl]-3-phenyl-L-alanine t-butyl ester, m.p. 93°-94° C., after chromatography on silica gel using ethyl acetate/methanol.
Reaction SMILES: COC1C=CC([C@@H](NCCC2(O)CCC3(OCC(C)(C)CO3)CC2)CC)=CC=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[CH3:41][O:42][C:43]1[CH:48]=[CH:47][C:46]([C@@H:49]([N:52]2[CH2:57][CH2:56][C:55]3([CH2:69][CH2:68][C:60]4(OCC(C)(C)C[O:61]4)[CH2:59][CH2:58]3)[O:54][C:53]2=[O:70])[CH2:50][CH3:51])=[CH:45][CH:44]=1>>[CH3:41][O:42][C:43]1[CH:48]=[CH:47][C:46]([C@@H:49]([N:52]2[CH2:57][CH2:56][C:55]3([CH2:69][CH2:68][C:60](=[O:61])[CH2:59][CH2:58]3)[O:54][C:53]2=[O:70])[CH2:50][CH3:51])=[CH:45][CH:44]=1
Reactant: CC[C@@H](c1ccc(OC)cc1)N1CCC2(CCC3(CC2)OCC(C)(C)CO3)OC1=O
Agent: CC[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(OC)cc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: CC[C@@H](c1ccc(OC)cc1)N1CCC2(CCC(=O)CC2)OC1=O

Procedure:
The title compound is prepared from 9-{2-[(S)-1-(4-methoxy-phenyl)-propylamino]-ethyl}-3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-9-ol and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 2; the crude product, a mixture of the title compound and 3-[(S)-1-(4-methoxy-phenyl)-propyl]-12,12-dimethyl-1,10,14-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one, obtained after that is treated as described in Step 10 of Intermediate 2 to convert the intermediate to the title compound as well. Yield: 62% of theory; LC (method 6): tR=1.33 min; Mass spectrum (ESI+): m/z=332 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[C:11]2[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:8][C:7]=2[C:6]([O:18]C)=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1>[C:12]1([C:9]2[NH:10][C:11]3[C:3]([OH:2])=[CH:4][CH:5]=[C:6]([OH:18])[C:7]=3[N:8]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(OC)c2[nH]c(-c3ccccc3)nc12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Oc1ccc(O)c2[nH]c(-c3ccccc3)nc12
Reaction time: 0.5 h

Procedure:
A 2.54 g portion of 4,7-dimethoxy-2-phenyl-1H-benzimidazole and 3.96 g of aluminum chloride in 125 ml of toluene were refluxed for 2 hours, then cooled and poured over cold dilute hydrochloric acid in ice. This mixture was stirred 0.5 hour, then the solid was collected, washed with water and dried, giving 2.0 g of the desired product, mp>280° C. (dec.).