Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:11][N:12]2[C:18](=[O:19])[CH:17]3[CH2:20][CH2:21][CH2:22][C:16]3=[N:15][C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]2=3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C.CCCCCC>[C:1]1([CH2:11][N:12]2[C:18](=[O:19])[C@H:17]3[CH2:20][CH2:21][CH2:22][C@H:16]3[NH:15][C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]2=3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C2CCCC2=Nc2ccccc2N1Cc1cccc2ccccc12
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1[C@H]2CCC[C@H]2Nc2ccccc2N1Cc1cccc2ccccc12
Yield: 67 %

Procedure:
Using 9-(1-naphthylmethyl)-2,3,9,10a-tetrahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one, the titled compound was synthesized in substantially the same manner as in Working Example 24 in a yield of 67%, m.p. 126°-128° C. (ethyl acetate-hexane).
Reaction SMILES: C[CH2:2][CH2:3][C:4](Cl)=[S:5].[C:7]1([CH2:13][CH2:14][NH2:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH3:7][S:5][CH2:4][CH2:3][CH3:2].[C:7]1([CH2:13][CH2:14][NH-:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCCc1ccccc1
Reactant: CCCC(=S)Cl
Product: CCCSC
Product: [NH-]CCc1ccccc1

Procedure:
Prepared from 3-methylthiopropionyl chloride (2.76 g) and 2-phenylethylamine (5.04 g) by the method used in Example 10(a). The solid product (3.79 g) was pure by t.l.c. A sample crystallised from aqueous methanol as needles m.p. 56°-59°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:11][C:10]=1[CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)c(C2CCCC2)c1
Solvent: ClCCl
Product: CCOC(=O)C=Cc1ccc(OCc2ccccc2)c(C2CCCC2)c1
Temperature: 25 °C
Yield: 73.8 %

Procedure:
A mixture of 4-benzyloxy-3-cyclopentyl-benzaldehyde (1.3 g, 4.64 mmol) and ethyl 2-triphenylphosphoranylideneacetate (1.6 g, 4.64 mmol) in dichloromethane (12 mL) was heated at reflux for 24 h. The reaction was cooled to room temperature and concentrated in vacuo. Purification by silica gel chromatography (0-10% ethyl acetate/hexanes) yielded ethyl 3-(4-benzyloxy-3-cyclopentyl-phenyl)prop-2-enoate (1.2 g, 81% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.61-7.57 (m, 2H), 7.52 (dd, J=2.1, 8.5 Hz, 1H), 7.46-7.39 (m, 4H), 7.33 (t, J=7.1 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 6.49 (d, J=16 Hz, 1H), 5.18 (s, 2H), 4.16 (q, J=7.1 Hz, 2H), 3.32-3.27 (m, 1H), 1.99-1.92 (m, 2H), 1.74-1.67 (m, 2H), 1.65-1.58 (m, 4H), 1.24 (t, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:9]=1[OH:10])[CH3:3].Cl[C:15](=[O:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].O>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[OH:10][C:9]1[C:4]([CH:2]([CH3:1])[CH3:3])=[CH:5][C:6]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:7][C:8]=1[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: COC(=O)CCC(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCC(=O)c1cc(C(C)C)c(O)c(C(C)C)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
Propofol 5 (1.78 g, 10.0 mmol) and methyl 4-chloro-4-oxobutyrate (4.5 g, 25 mmol) were dissolved in methylene chloride (350 mL), the reaction mixture was cooled to −78° C. and titanium (IV) chloride (5.7 g, 30 mmol) was added drop-wise. The reaction mixture was stirred for 2 h at −78° C., allowed to warm up to room temperature and stirred overnight. The reaction mixture was then poured into water (300 mL), the organic phase was washed sequentially with saturated sodium bicarbonate solution, water and brine, and the solution dried over anhydrous magnesium sulfate. The product was purified by column chromatography on silica gel using hexane and hexane-ethyl acetate (4:1) step-gradient as an eluent to produce pure 6 (1.14 g, 39%) as a slightly yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.75 (s, 2H), 5.84 (s, 1H), 3.72 (s, 3H), 3.32 (t, J=6.8 Hz, 2H), 3.20 (septet, J=6.9 Hz, 2H), 2.76 (t, J=6.8 Hz, 2H), 1.28 (d, J=6.9 Hz, 12H). 13C NMR (100.61 MHz, CDCl3): δ 196.81, 173.35, 154.40, 133.27, 129.05, 123.97, 51.41, 32.59, 27.82, 26.79, 22.18. HRMS (m/z): [M+H]+ calcd. for C17H24O5 293.1747. found 293.1759.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH:13]1([CH2:19][N:20]=[C:21]=S)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[S:9](=[O:11])(=[O:10])[N:12]=[C:21]([NH:20][CH2:19][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)ccc1S(N)(=O)=O
Reactant: S=C=NCC1CCCCC1
Solvent: CCOC(C)=O
Product: O=S1(=O)N=C(NCC2CCCCC2)Nc2cc(Cl)ccc21
Temperature: 150 °C
Yield: 26 %

Procedure:
A mixture of 2-amino-4-chlorobenzenesulfonamide (2.1 g, 10.16 mmol) and cyclohexylmethyl isothiocyanate (6.31 g, 40.6 mmol) was heated at 150° C. for 4 h. The mixture was allowed to cool and then stirred with 25 ml of ethyl acetate for 1 h. The precipitate was isolated by filtration and recrystallised from ethanol to give 867 mg (26%) of the title compound; m.p. 317-323° C.; 1H-NMR (DMSO-d6): δ 0.8-1.8 (m, 11H, cyclohexyl), 3.08 (t, 2H, CH2), 7.78 (m, 3H, ArH+NH), 7.68 (d, 1H, ArH), 10.52 (br.s, 1H, NH); MS: m/e 327/329 (M+); (C14H18N3Cl1O2S1) calc. C, 51.29; H, 5.53; N, 12.82; found C, 51.21; H, 5.72; N, 12.81.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:17]2[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]=2[CH:11]=1.CN(C)[CH:26]=[O:27].[Cl-].[NH4+]>CCCCCC.C(OCC)C>[CH:26]([C:19]1[C:10]([O:9][CH2:8][O:7][CH3:6])=[CH:11][C:12]2[C:13]([CH3:23])([CH3:22])[CH2:14][CH2:15][C:16]([CH3:21])([CH3:20])[C:17]=2[CH:18]=1)=[O:27]
Reactant: CN(C)C=O
Reactant: COCOc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: COCOc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.2 %

Procedure:
22 ml of a 1.56M solution of n-butyllithium in hexane was dropwise added to 40 ml of a solution of 5.7 g of 5,6,7,8-tetrahydro-2-methoxymethoxy-5,5,8,8-tetramethylnaphthalene in anhydrous diethyl ether at -78° C. The temperature of the mixture was gradually raised to room temperature (in 10 minutes). The resulting mixture was stirred for 5 hours and cooled to -78° C., followed by the dropwise addition thereto of 5 ml of a solution of 2.6 g of N,N-dimethylformamide in diethyl ether. The temperature of the obtained mixture was gradually raised to room temperature (in 10 minutes). The resulting mixture was stirred for 3 hours, followed by the addition thereto of 30 ml of a saturated aqueous solution of ammonium chloride. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel chromatography (developer: 10% ethyl acetate/n-hexane) to give 4.2 g of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[NH:7])[CH3:2].Cl[C:14]1[C:19]([C:20](OCC)=[O:21])=[CH:18][N:17]=[C:16]([S:25][CH3:26])[N:15]=1.C(N(CC)CC)C>C(#N)C>[CH3:26][S:25][C:16]1[N:17]=[C:18]2[N:7]=[C:6]([C:5]3[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=3[O:3][CH2:1][CH3:2])[NH:8][C:20](=[O:21])[C:19]2=[CH:14][N:15]=1
Reactant: CCOc1ccccc1C(=N)N
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Temperature: 2 °C
Reaction time: 1 h

Procedure:
2-Ethoxybenzamidine (from sodium, 0.08 g, in ethanol, 10 ml, and 2-ethoxybenzamidine hydrochloride, 0.70 g) was dissolved in acetonitrile (10 ml) and the resulting cooled (2° C.) solution was added to a cooled (2° C.) suspension of ethyl 4-chloro-2-methylthio-5-pyrimidine carboxylate (0.81 g) in acetonitrile (10 ml). The reaction mixture was stirred at 2° C. for one hour. Triethylamine (0.35 g) was added and the reaction mixture was stirred at ambient temperature for 21 hours to yield a white precipitate, 0.22 g, which was collected by filtration. The filtrate was reduced in volume under reduced pressure to yield a second crop of solid, 0.41 g. The products were combined and recrystallised from ethanol to yield the title compound, 0.30 g, m.p. 224.5°-225.5° C.
Reaction SMILES: [C:1]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH:15][CH:16]([CH3:19])[CH2:17]Br>C(C#N)(C)=O>[C:4]([O:3][C:1](=[O:2])[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:17][CH:16]([OH:15])[CH3:19])[CH2:11][CH2:10]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC(O)CBr
Agent: CC(=O)C#N
Product: CC(O)CN1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Yield: 58.8 %

Procedure:
A mixture of 4-(N-Boc-amino)-piperidine (1.0 g, 5.0 mmol), 2-hydroxybromopropane (1.0 g; 7.5 mmol) and TEA (0.76 g, 7.5 mmol) in AcCN (20 mL) was heated at 60° C. for 4 days. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4 concentrated under reduced pressure. Purification of the residue by column chromatography on silica (0-5% 2M ammonia-MeOH in DCM) afforded [1-(2-hydroxy-propyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.76 g, 59%) as an oil. LCMS (Method G; ESI): RT=0.49 min, m+1=259.3.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH2:26]([NH2:30])[CH2:27][CH2:28][NH2:29]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:29][CH2:28][CH2:27][CH2:26][NH2:30])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCCCN
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCN)c2c1

Procedure:
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and propane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 7.96 (dd, J=7.83, 1.01 Hz, 1 H), 7.81 (d, J=7.07 Hz, 1 H), 7.64-7.54 (m, 2 H), 7.47-7.35 (m, 2 H), 7.26 (dd, J=8.59, 1.77 Hz, 1 H), 5.98 (s, 1 H), 5.12 (s, 2 H), 3.56 (t, J=4.93 Hz, 2 H), 3.39 (t, J=6.82 Hz, 2 H), 2.82 (t, J=6.95 Hz, 2 H), 2.39 (s, 3 H), 1.89 (t, J=6.95 Hz, 2 H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[NH:10][C:9]=2[C:8]([OH:22])=[CH:7][CH:6]=1)=[O:4].O[Li].O>C1COCC1.CO.O>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:11]1[NH:10][C:9]2[C:8]([OH:22])=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=2[N:12]=1
Reactant: COC(=O)c1ccc(O)c2[nH]c(-c3ccc(Cl)cc3Cl)nc12
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(O)c2[nH]c(-c3ccc(Cl)cc3Cl)nc12
Temperature: 25 °C
Yield: 89.4 %

Procedure:
Wang resin-supported 2-(2,4-dichloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester (570 mg, 0.47 mmol) obtained in step 5 was dissolved in THF, LiOH.H2O (99 mg, 2.35 mmol) in MeOH—H2O (2:1) was added thereto and the resulting mixture was refluxed for 5 hours. The resulting solution was cooled to room temperature and filtered. The filtrate was washed with MeOH and CH2Cl2, and dried to obtain the title compound (551 mg, 0.42 mmol) in a yield of 90%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21]([O:23]C)=[O:22])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:27]=[CH:28][C:29]2[O:33][C:32](S(C)(=O)=O)=[N:31][C:30]=2[CH:38]=1.[OH-].[Na+].Cl>ClC(Cl)C.CO>[F:25][C:26]1[CH:27]=[CH:28][C:29]2[O:33][C:32]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([CH:16]5[CH2:20][CH2:19][CH2:18][CH:17]5[C:21]([OH:23])=[O:22])=[O:15])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)=[N:31][C:30]=2[CH:38]=1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: CS(=O)(=O)c1nc2cc(F)ccc2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(Cl)Cl
Product: O=C(O)C1CCCC1C(=O)c1ccc(-c2ccc(Nc3nc4cc(F)ccc4o3)cc2)cc1
Temperature: 85 °C
Yield: 31.7 %

Procedure:
To a solution of methyl trans-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclopentane-carboxylate (100 mg, 0.31 mmol) in dichloroethane (3 mL), 5-fluoro-2-(methylsulfonyl)-1,3-benzoxazole (80 mg, 0.37 mmol) was added and the mixture was heated at 85° C. overnight. The solvent was removed by rotary evaporation, and the residue was redissolved in DMF (5 mL). A solution of 1 N aqueous NaOH (0.93 mL, 0.93 mmol) was added and the mixture was heated at 65° C. overnight. A solution of 1 N aqueous HCl (0.31 mL, 0.31 mmol) and methanol (5 mL) were added to the reaction mixture, and the crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford 2-({4′-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid as a white solid (43.7 mg, 31.4%). 1H NMR (300 MHz, DMSO-d6) δ 8.05 (d, 2 H), 7.90-7.80 (m, 6 H), 7.50 (m, 1 H), 7.30 (m, 1 H), 6.95 (m, 1 H), 4.05 (m, 1 H), 3.20 (m, 1 H), 2.20 (m, 1 H), 1.95 (m, 1 H), 1.80-1.60 (m, 4 H); LC-MS ret. time 3.66 min (method 2), m/z 445.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.C([O:15][C:16](=[O:21])[C@H:17]([CH2:19][SH:20])N)C>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[S:20][CH2:19][CH:17]([C:16]([OH:21])=[O:15])[N:11]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)[C@@H](N)CS
Reactant: N#CCc1cc(F)cc(F)c1
Agent: Cl
Product: O=C(O)C1CSC(Cc2cc(F)cc(F)c2)=N1

Procedure:
Following General Procedure G and using 3,5-difluorophenylacetonitrile and L-cysteine ethyl ester hydrochloride (Aldrich), the title compound was prepared.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[N:9][C:10]([C:13]([OH:15])=O)=[CH:11][N:12]=2)=[CH:3][CH:2]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28])=[CH:21]2.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[ClH:17].[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([S:27]([N:30]1[CH2:35][CH2:34][N:33]([C:13]([C:10]3[N:9]=[N:8][C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[N:12][CH:11]=3)=[O:15])[CH2:32][CH2:31]1)(=[O:29])=[O:28])=[CH:21]2
Reactant: O=S(=O)(c1cc2cc(Cl)ccc2[nH]1)N1CCNCC1
Reactant: O=C(O)c1cnc(-c2ccncc2)nn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(c1cnc(-c2ccncc2)nn1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Reaction time: 8 h

Procedure:
In N,N-dimethylformamide (10 ml) were suspended 3-(pyridin-4-yl)-1,2,4-triazine-6-carboxylic acid and 1-[(5-chloroindol-2-yl)sulfonyl]piperazine hydrochloride (292 mg) at room temperature. To the reaction mixture were successively added 1-hydroxybenzotriazole (117 mg), N-methylmorpholine (191 μl) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (250 mg), followed by stirring overnight. After completion of the reaction, the solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the residue to separate into layers. The organic layer was dried over magnesium sulfate and the filtrate was concentrated. Ethanol was added to the residue. Yellow crystals thus precipitated were collected by filtration and dried, whereby the free form (282 mg) of the title compound was obtained. The free form was suspended in ethanol and the resulting suspension was made acidic by the addition of 1N hydrochloric acid (in ethanol) and a small amount of water. After concentration of the resulting solution, ethanol and ethyl acetate were added and the resulting mixture was concentrated again. Crystals thus precipitated were collected by filtration and dried, whereby the title compound was obtained.
Reaction SMILES: Cl[CH:2]([C:8]([CH3:10])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N)(=S)C.[CH3:15][C:16]1[S:17][CH:18](C(OCC)=O)[CH:19](C)[N:20]=1.[C:27]1([CH3:39])[CH:32]=[CH:31][C:30]([S:33]([O:36]CC)(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[C:27]1([CH3:39])[CH:28]=[CH:29][C:30]([S:33]([O-:36])(=[O:34])=[O:35])=[CH:31][CH:32]=1.[CH3:15][C:16]1[S:17][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([CH3:10])[N+:20]=1[CH2:19][CH3:18]
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C1SC(C)=NC1C
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: CC(N)=S
Product: CCOC(=O)c1sc(C)[n+](CC)c1C
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
Ethyl 2-chloro-acetoacetate is condensed with thioacetamide to 2,4-dimethyl-5-ethoxycarbonyl-thiazoline which is reacted, analogously to Preparation Example 1 A, with ethyl p-toluenesulfonate to give the p-toluenesulfonate of the quaternary ammonium base.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>C(Cl)Cl>[C:9]([NH:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccnc1N
Solvent: ClCCl
Product: CC(=O)Nc1cccnc1N
Yield: 56.6 %

Procedure:
2,3-Diaminopyridine (28 g, 0.256 mole) and acetic anhydride (30 mL, 0.38 mole) were stirred at room temp in methylene chloride (770 mL) for 30 min. The mixture was concentrated in vacuo to a brown solid. Recrystallization from methylene chloride/hexane (10/1) gave off-white crystals (21.9 g, 57%) of 3-acetamido-2-aminopyridine. This acetamide was combined with 3-chloro-2,4-pentanedione (20 g, 0.146 mole) in abs. ethanol (350 mL) and stirred under reflux for 20 hrs. After cooling, the mixture was diluted with methylene chloride (300 mL) and washed with water (3×300 mL). The organic phase was dried over magnesium sulfate and concentrated to a green solid. Recrystallization from methylene chloride/hexane (1/1) gave the title compound as green crystals (7.3 g, 21%. m.p. 173°-175° C.).
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].[C:49]([O:53][C:54]([CH2:56][CH2:57][CH2:58][CH2:59][NH-:60])=[O:55])([CH3:52])([CH3:51])[CH3:50].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:37])[CH3:38])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:49]([O:53][C:54]([CH2:56][CH2:57][CH2:58][CH2:59][NH-:60])=[O:55])([CH3:52])([CH3:51])[CH3:50]
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C(=O)O)C(C)C
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)OC(=O)CCCC[NH-]
Agent: On1nnc2ccccc21
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)C

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 144 mg of Z-Phe-His-OH, 138 mg of H-Leu-Val-4-tert.-butoxycarbonylbutyl amide, 51 mg of HOBt and 89 mg of DCCI, the title compound is obtained after flash chromatography (180 g of silica gel 60, 40-63 μm, system N10). Rf (B2)=0.40, Rf (N8)=0.41.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:16]([CH3:20])[CH:17]=[CH:18][N:19]=2)[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:36]=[CH:35][C:26]2[NH:27][C:28](=[O:34])[CH2:29][CH2:30][C:31]([CH3:33])([CH3:32])[C:25]=2[CH:24]=1.Cl>O1CCOCC1.COCCO>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:16]([CH3:20])[CH:17]=[CH:18][N:19]=2)=[N:7][C:2]([NH:22][C:23]2[CH:36]=[CH:35][C:26]3[NH:27][C:28](=[O:34])[CH2:29][CH2:30][C:31]([CH3:33])([CH3:32])[C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: Cn1ccnc1-c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: Cn1ccnc1-c1ccccc1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl
Yield: 82.5 %

Procedure:
Combined (2,5-Dichloro-pyrimidin-4-yl)-[2-(1-methyl-1H-imidazol-2-yl)-phenyl]-amine (82 mg, 0.256 mmol), 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (63 mg, 0.308 mmol), 4 N HCl in dioxane (80 ul) and 2-methoxyethanol (4 mL). Heated reaction to 120° C. for 6 hours. Evaporated off solvent and purified with normal phase chromatography to yield a light brown solid, 7-{5-Chloro-4-[2-(1-methyl-1H-imidazol-2-yl)-phenylamino]-pyrimidin-2-ylamino}-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (103 mg, 82%). mp 227° C.; LCMS: m/z=488.23 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.20 (m, 1H), 7.95 (s, 1H), 7.54 (dd, 1H, J=8.5, 2.4 Hz), 7.39 (m, 4H), 7.24 (m, 2H), 7.01 (d, 1H, J=1.3 Hz), 6.81 (d, 1H, J=8.6 Hz), 6.71 (m, 1H), 6.53 (dd, 1H, J=8.2, 2.7 Hz), 3.67 (s, 3H), 2.30 (m, 2H), 2.03 (m, 2H), 1.29 (s, 6H).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H].Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:16]([CH3:32])=[C:15]([CH3:33])[N:14]=1>COCCOCCOC>[CH3:33][C:15]1[C:16]([CH3:32])=[C:17]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:18]([N+:19]([O-:21])=[O:20])=[C:13]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:14]=1
Reactant: [H][H]
Reactant: Oc1ccccc1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCOc2ccccc2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCOc2ccccc2)c1C
Temperature: 0 °C

Procedure:
2-Methoxyethyl ether (diglyme) (3 ml) and sodium hydride (60% in oil) (0.56 g) were combined and cooled to 0° C. Phenol (1.24 g) was added slowly in portions to allow for controlled release of hydrogen gas. A solution of 2-chloro-5,6-dimethyl-3-nitro-N-(2-phenoxyethyl)pyridin-4-amine (4.00 g) and diglyme (37 ml) was then added and the reaction mixture was heated to 150° C. for 16 hours. At this time, the reaction stalled at 85% completion. The reaction mixture was allowed to cool and the solvent was removed under reduced pressure. The oil was dissolved in ethyl acetate, washed with water, dried with magnesium sulfate, and concentrated under reduced pressure. The product was run through a column using 20/80 ethyl acetate/hexane as the eluant. HPLC analysis of the resulting orange solid indicated sufficient purity for use in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24][NH:25][C:26](=[N:29][C:30]#[N:31])SC)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][NH2:33].CCO>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24][NH:25][C:26]([NH:33][CH3:32])=[N:29][C:30]#[N:31])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: CSC(=NC#N)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: CCO
Product: CNC(=NC#N)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h

Procedure:
A 100 mL flask was charged with (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-((cyanoimino)(methylthio)methylamino)ethoxy)methyl)piperidine-1-carboxylate (2.2 g, 4.72 mmol) dissolved in 50 mL MeNH2/EtOH solution and stirred overnight. The mixture was concentrated in vacuo and used without any further purification.