Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12]/[N:13]=[C:14]2\[NH:15][C:16](=[O:28])[C:17]3[NH:18][CH:19]=[N:20][C:21]=3[N:22]\2[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=O)=[CH:5][CH:4]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[N:15]3[C:16](=[O:28])[C:17]4[NH:18][CH:19]=[N:20][C:21]=4[N:22]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:14]3=[N:13][N:12]=2)=[CH:5][CH:4]=1
Reactant: CCCCCn1/c(=N/NC(=O)Cc2ccc(OC)cc2)[nH]c(=O)c2[nH]cnc21
Solvent: Cc1ccccc1
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(Cc3ccc(OC)cc3)nnc12
Yield: 95.5 %

Procedure:
The mixture of 2-(4-methoxyphenyl)-N′-[(2E)-6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene]acetohydrazide (0.66 g, 1.4 mmol) in toluene (30 mL) was refluxed overnight. The reaction mixture was concentrated to give the crude product as a solid. The solid was washed with ethyl acetate and dried to yield the desired product (490 mg, 92%). LCMS calculated for C19H23N6O2(M+H): 367.2; found: 367.2.
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[CH:8]=[C:9]([CH:18]=[C:19]([F:21])[CH:20]=1)[O:10][Si](C(C)(C)C)(C)C.[CH3:22][N:23]([CH2:25][CH:26]1[CH2:32][CH2:31][CH:30]2[CH:28]([CH2:29]2)[C:27]1=[O:33])[CH3:24].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(Cl)Cl>[CH3:24][N:23]([CH2:25][CH:26]1[CH2:32][CH2:31][CH:30]2[CH:28]([CH2:29]2)[C:27]1([C:7]1[CH:8]=[C:9]([OH:10])[CH:18]=[C:19]([F:21])[CH:20]=1)[OH:33])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(F)cc(Br)c1
Reactant: CN(C)CC1CCC2CC2C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)CC1CCC2CC2C1(O)c1cc(O)cc(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 13.9 %

Procedure:
Add a solution of t-BuLi (19.4 mL, 25.2 mmol) via syringe to a solution of (3-bromo-5-fluoro-phenoxy)-tert-butyl-dimethyl-silane (6.99 g, 22.9 mmol) in THF (100 mL) at −78° C. under N2. After being stirred at −78° C. for 1 hour, add dropwise a solution of 3-dimethylaminomethyl-bicyclo[4.1.0]heptan-2-one (2.55 g, 15.3 mmol) to the reaction mixture and stir the reaction mixture at −78° C. for additional 2 hours. Quench the reaction with saturated NH4Cl solution (30 mL). Extract the resultant aqueous mixture with EtOAc (100 mL×3). The combined organic layers are washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Treat the residue with TBAF (6.00 g, 22.9 mmol) in CH2Cl2 (80 mL) at ambient temperature for 4 hours. Concentrate the mixture, and purify the residue by preparative HPLC to give 3-dimethylaminomethyl-2-(3-fluoro-5-hydroxy-phenyl)-bicyclo[4.1.0]heptan-2-ol as white solid (592 mg, yield: 13.9%). MS (m/z): 280 (M+1).
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH:20][C:21]3[CH:22]=[CH:23][C:24]4[N:25]([CH:27]=[C:28]([C:30]5([C:35]([O:37]C(C)C)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]5)[N:29]=4)[N:26]=3)[CH2:13][CH2:12]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C>[C:41]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:10][CH:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][NH:20][C:21]3[CH:22]=[CH:23][C:24]4[N:25]([CH:27]=[C:28]([C:30]5([C:35]([OH:37])=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]5)[N:29]=4)[N:26]=3)[CH2:15][CH2:16]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)OC(=O)C1(c2cn3nc(NCCCN4CCC(OC(c5ccccc5)c5ccccc5)CC4)ccc3n2)CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1(c2cn3nc(NCCCN4CCC(OC(c5ccccc5)c5ccccc5)CC4)ccc3n2)CCCC1
Yield: 70.5 %

Procedure:
598 mg of isopropyl 1-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]imidazo[1,2-b]pyridazin-2-yl]cyclopentanecarboxylate dihydrochloride was dissolved in 3 ml of ethanol; 2.24 ml of a 2 N aqueous solution of sodium hydroxide was added, followed by thermal refluxing for 7 hours. After cooling, the mixture was concentrated under reduced pressure; the residue was diluted with water, washed with ethyl acetate and ajusted to pH 4.5 by the addition of 1 N hydrochloric acid. The mixture was saturated with sodium chloride and extracted with ethyl acetate-tetrahydrofuran (1:2); the extract was dried with magnesium sulfate. The dry product was concentrated under reduced pressure, powdered by the addition of ethyl acetate-ethyl ether (1:1), washed with ethyl ether and dried to yield 349 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH2:37]([S:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:41])=[O:40])[CH3:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:45]3[CH2:44][CH2:43][N:42]([S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])[CH2:47][CH2:46]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:31])([CH3:30])[C:32]#[N:33])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCS(=O)(=O)N1CCNCC1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(S(=O)(=O)CC)CC1

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-(4-ethanesulfonyl-piperazine-1-carbonyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-phenyl}-2-methyl-propionitrile was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12j) and 1-ethanesulfonyl-piperazine (example 14) in an analogous manner as described in example 25. LR-MS: 682.3 [(M+H)+]
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH3:14]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:13]([CH3:14])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A cooled (0° C.) solution of 4-fluorobenzenesulfonyl chloride (2.00 g; 10.3 mmol) in THF (40 ml) is treated with a 2 M solution of dimethylamine in THF (11.3 ml; 22.6 mmol) and stirred at 0° C. for 30 minutes. The solvents were removed under reduced pressure, the residue taken up in EtOAc, the organic phase was washed with a saturated solution of NH4Cl twice and with water. The organic phase was dried on MgSO4, filtered and the solvent removed under reduced pressure to afford the title compound (1.80 g, 86%).
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([CH2:12][CH2:13][CH3:14])[C:9]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:17][C:8]=2[C:7]=1[OH:24])=[O:5])C.[NH2:25][CH2:26][C:27]([OH:29])=[O:28]>C[O-].[Na+].CO>[OH:24][C:7]1[C:8]2[S:17][C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:15][C:9]=2[C:10]([CH2:12][CH2:13][CH3:14])=[N:11][C:6]=1[C:4]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5]
Reactant: CCCc1nc(C(=O)OCC)c(O)c2sc(-c3ccccc3)nc12
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCc1nc(C(=O)NCC(=O)O)c(O)c2sc(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 81.9 %

Procedure:
A mixture of 7-hydroxy-2-phenyl-4-propyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (78 mg, 0.23 mmol) and glycine (343 mg, 4.57 mmol) in 0.5 M sodium methoxide/methanol (8.6 mL) was refluxed for three days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (30 mL) and extracted three times with methyl t-butyl ether. The remaining aqueous layer was acidified to pH=3 with 1N HCl (6 mL). The solid precipitate was filtered, washed with water and dried in vacuo to give the title compound as a white solid (70 mg): 1H NMR (DMSO-d6, 200 MHz): δ=13.02 (br s, 1H), 9.21 (br s, 1H), 8.17 (m, 2H), 7.65 (m, 3H), 4.06 (d, J=6.2 Hz, 2H), 3.33 (m, 2H), 1.92 (m, 2H), 1.04 (t, J=7.0 Hz, 3H); MS: (+) m/z 371.93 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([C:19]#[N:20])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1.[C:28](C1C2C=CC=CC=2ONC1=O)#[N:29].CN>O1CCCC1>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:10]([C:11]([NH:29][CH3:28])=[O:13])=[CH:14][C:15]([C:19]#[N:20])=[CH:16][C:17]=2[CH3:18])=[O:12])[N:4]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1
Reactant: N#CC1C(=O)NOc2ccccc21
Reactant: Cc1cc(C#N)cc2c(=O)oc(-c3cc(Cl)nn3-c3ncccc3Cl)nc12
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cc(C#N)cc(C)c1NC(=O)c1cc(Cl)nn1-c1ncccc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of 2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-benzoxazin-4-one (e.g. the cyanobenzoxazinone product of Step F) (100 mg, 0.25 mmol) in tetrahydrofuran (5 mL) was added dropwise methylamine (2.0 M solution in THF, 0.5 mL, 1.0 mmol) and the reaction mixture was stirred for 5 minutes, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford the title compound, a compound of the present invention, as a white solid (52 mg), which decomposed in the melting apparatus above 140° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([N:24]1[CH2:25][CH2:26][N:21]([C@H:18]2[CH2:19][CH2:20][N:15]([C:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:33])([F:1])[F:34])[CH:4]=3)=[O:14])[CH2:16][C@H:17]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:23]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Reactant: BrCc1ccccc1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(Cc3ccccc3)CC2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=576.1 (M+H+), was prepared in accordance with the general method of example 35 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone and benzyl bromide.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]([CH3:19])([CH3:18])[C:14]([F:17])([F:16])[F:15])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>C(Cl)Cl>[C:1]1([N:7]2[C:11]([NH:12][C:27](=[O:28])[O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:10][C:9]([C:13]([CH3:19])([CH3:18])[C:14]([F:16])([F:17])[F:15])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(c1cc(N)n(-c2ccccc2)n1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a solution of 1-phenyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-amine (590 mg, 2.2 mmol) and potassium carbonate (304 mg, 2.85 mmol) in anhydrous DCM (5.2 ml) was added dropwise phenyl chloroformate (0.30 ml, 2.4 mmol) as a solution in DCM (2.5 ml). The reaction mixture was stirred at rt overnight, then filtered and concentrated under reduced pressure. The crude was purified by silica gel chromatography (hexane/ethyl acetate 35%) to afford phenyl 1-phenyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-ylcarbamate (748 mg, 87%) as a solid. 1H NMR (300 MHz, CDCl3) δ 1.60 (s, 6H), 6.65 (brs, 1H), 7.02-7.55 (m, 11H); LC-MS (ESI) m/z 390 (M+H)+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][C@:14]([OH:64])([CH3:63])[C:15](=[O:62])[C@@H:16]([NH:21][C:22](=[O:61])[C@@H:23]([NH:31][C:32](=[O:60])[C@@H:33]([NH:38][C:39](=[O:59])[C@@H:40]([NH:49][C:50](=[O:58])[CH2:51][N:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1)[CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:17][CH:18]([CH3:20])[CH3:19]>>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:12][CH2:13][C@:14]([OH:64])([CH3:63])[C:15](=[O:62])[C@H:16]([CH2:17][CH:18]([CH3:19])[CH3:20])[NH:21][C:22](=[O:61])[C@H:23]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:31][C:32](=[O:60])[C@H:33]([CH2:34][CH:35]([CH3:37])[CH3:36])[NH:38][C:39](=[O:59])[C@H:40]([CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[NH:49][C:50](=[O:58])[CH2:51][N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)C[C@H](NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)[C@](C)(O)CO
Product: Cc1ccc(S(=O)(=O)OC[C@@](C)(O)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc2ccccc2)NC(=O)CN2CCOCC2)cc1

Procedure:
Prepared according to procedures described above, by reacting p-toluenesulfonyl chloride with (S)—N—((S)-1-(((2R,4S)-1,2-dihydroxy-2,6-dimethyl-3-oxoheptan-4-yl)amino)-1-oxo-3-phenylpropan-2-yl)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide. MS for C47H65N5O10S m/z: 892 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14]/[C:15](=[CH:20]\[CH2:21][CH2:22]/[C:23](/[CH3:33])=[CH:24]/[CH2:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)/[CH2:16][CH2:17][CH:18]=[O:19]>C1COCC1.CCCCCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:18]([OH:19])[CH2:17][CH2:16]/[C:15](/[CH3:14])=[CH:20]/[CH2:21][CH2:22]/[C:23](/[CH3:33])=[CH:24]/[CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)=[CH:3][CH:4]=1
Reactant: C/C(=C\CC/C(C)=C/COC1CCCCO1)CCC=O
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C/C(=C\COC1CCCCO1)CC/C=C(\C)CCC(O)c1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
A solution of 10.7 g of 1,4-dibromobenzene in 80 ml of absolute THF is cooled to −78° C. and treated within 30 min. with 25.6 ml of 1.6M butyllithium in hexane. After 30 min. 6.08 g of (4E,8E)-(RS)-4,8-dimethyl-10-(tetrahydro-pyran-2-yloxy)-deca4,8-dienal in 20 ml of THF are added dropwise. After 1 hr. at −78° C. the bath is removed until the suspension has dissolved and subsequently 7.2 ml of acetic acid in 10 ml of ether are added dropwise at −78° C. The solution is poured into saturated ammonium chloride solution/ethyl acetate. The organic phase is washed with saturated sodium bicarbonate solution and 10% sodium chloride solution, dried and evaporated. After silica gel chromatography with hexane/ethyl acetate 95:5 there are obtained 4.3 g of (4E,8E)-1-(4-bromo-phenyl)-4,8-dimethyl-10-(tetrahydro-pyran-2-yloxy)-deca-4,8-dien-1-ol.
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([NH:23]N)=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].N(OCCC(C)C)=O.N[CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44].Cl>CN(C=O)C>[NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([NH:23][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)NN
Reactant: CCOC(=O)CCN
Agent: CC(C)CCON=O
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 87.8 %

Procedure:
To a solution of Boc-Leu-DTrp-NHNH2 (39 mg) obtained in Example 1-(2) in DMF (0.5 ml ) was added 3.1 M HCl/14,-dioxane (81 μl) at -60° C. The temperature of the solution was raised to -20° C. and isoamyl nitrite (15 μl) was added. The reaction mixture was stirred at -20° C. to -15° C. for 1.5 h and cooled at -60° C. A solution of βAla-OEt.HCl (17 mg) in DMF (0.5 ml) and TEA (50 μl) were added. The reaction mixture was stirred at 5° C. overnight and concentrated under reduced pressure. The residue was partitioned between water and dichloromethane. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (Merck, Kieselgel 60 F254) with chloroform/methanol=30/1 for development to give the product (41 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([OH:13])=[CH:10]2)=[CH:5][CH:4]=1.[Cl-].[CH3:15][O:16][C:17]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:18]=1[CH:19]=[N+:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH3:15][O:16][C:17]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:18]=1[CH:19]([N:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1)[C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[CH:8][C:9]=1[OH:13]
Reactant: COc1ccc2ccc(O)cc2c1
Reactant: COc1cccc(C=[N+]2CCOCC2)c1OC
Agent: [Cl-]
Product: COc1ccc2ccc(O)c(C(c3cccc(OC)c3OC)N3CCOCC3)c2c1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 7-methoxy-2-naphthol and 4-(2,3-dimethoxy-benzylidene)-morpholin-4-ium chloride, which had been prepared in accordance with example 21.
Reaction SMILES: C([O:9][C:10]([C:12]1[NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:24](=[O:25])[NH:23][CH2:22][CH2:21][C:20]=1[C:19]=23)=[O:11])CCCCCCC.[OH-].[Li+].CO>O>[O:25]=[C:24]1[C:18]2[C:19]3[C:20](=[C:12]([C:10]([OH:11])=[O:9])[NH:13][C:14]=3[CH:15]=[CH:16][CH:17]=2)[CH2:21][CH2:22][NH:23]1
Reactant: CCCCCCCCOC(=O)c1[nH]c2cccc3c2c1CCNC3=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1[nH]c2cccc3c2c1CCNC3=O

Procedure:
6-Oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic acid octyl ester (Example FFF) (350 mg, 1.02 mmol) and lithium hydroxide (122 mg, 5.11 mmol) were dissolved in 10 mL 2:1 methanol:water and stirred at room temperature for 24 h. The reaction mixture was diluted with water then washed twice with dichloromethane. The aqueous solution was acidified to ca. pH 2 with conc. HCl. The white precipitate was collected by filtration, washed with water, and dried in vacuo to yield 6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic acid, 235 mg (99%) as a white solid: m.p. 298-299° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ3.17 (m, 2H), 3.41 (m, 2H), 7.35 (t, J=7.8 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.73 (d, J=7.5 Hz, 1H), 8.14 (br t, 1H), 11.77 (br s, 1H), 13.14 (br s, 1H). MS (electrospray, MH+): 231. Anal. (C12H10N2O3.1.0 H2O)C, H, N.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:9]=1[C:10](OC)=[O:11].O>C1COCC1>[F:7][C:8]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:9]=1[CH2:10][OH:11]
Reactant: COC(=O)c1ccc(OC)cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CO)c(F)c1
Reaction time: 0.5 h
Yield: 104 %

Procedure:
To a suspension of LiAlH4 (71.6 mg, 1.89 mmol) in THF (3 ml) was added dropwise a solution of methyl 2-fluoro-4-methoxybenzoate (273.3 mg, 1.48 mmol) in THF (3 ml). The mixture was stirred for 0.5 hours. To the mixture was added dropwise aqueous THF followed by water. The mixture was extracted three times with ethyl acetate and dried over MgSO4. The solvent was evaporated to give the crude title compound (240.4 mg; >99%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17](OC)=[O:18])[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][OH:18])[CH:14]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(c1)CN(Cc1ccccc1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)CN(Cc1ccccc1)C2
Yield: 99 %

Procedure:
Methyl 2-benzyl-2,3-dihydro-1H-isoindole-5-carboxylate (from above) was dissolved in anhydrous tetrahydrofuran (75 ml) and added dropwise over 15 minutes to a rapidly stirred suspension of lithium aluminum hydride (1.71 g, 45.0 mmol) in anhydrous tetrahydrofuran (75 ml). The mixture was stirred at room temperature for 2 hours whereupon excess lithium aluminum hydride was destroyed by the slow dropwise addition of 1M sodium sulphate solution (12 ml). The solids were removed by filtration, rinsed with ethyl acetate (2×50 ml) and sucked dry. The solvent was removed in vacuo to afford (2-benzyl-2,3-dihydro-1H-isoindol-5-yl)-methanol (7.15 g, 99%) as a tan solid. 1H NMR (DMSO-d6) 7.40-7.30 (4H, m), 7.28 (1H, m), 7.17-7.10 (3H, m), 5.10 (1H, t), 4.47 (2H, d), 3.85 (2H, s), 3.82 (2H, s), 3.80 (2H, s). MS: [M+H]+ 240.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:21](O)=[O:22])[S:5][C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:9]=1.[NH2:24][CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:26][OH:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[OH:27][CH2:26][CH:25]([NH:24][C:21]([C:4]1[S:5][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[CH:9]=2)=[C:2]([CH3:1])[N:3]=1)=[O:22])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NC(CO)c1ccccc1
Reactant: Cc1nc(C(=O)O)sc1Cc1cccc(N2CCN(C)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C(=O)NC(CO)c2ccccc2)sc1Cc1cccc(N2CCN(C)CC2)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 48.1 %

Procedure:
To a mixture of 4-methyl-5-(3-(4-methylpiperazin-1-yl)benzyl)thiazole-2-carboxylic acid (200 mg, 0.6 mmol), 2-amino-2-phenylethanol (99 mg, 0.7 mmol) and TEA (0.3 mL, 1.8 mmol) in DMF (2 mL), EDCI.HCl (175 mg, 0.9 mmol) and HOBT (95 mg, 0.7 mmol) were added. The mixture was stirred at 50° C. overnight, then cooled to RT, diluted with H2O (50 mL) and extracted with DCM/MeOH (10/1, 4×30 mL). The combined organic layers were washed with a saturated aqueous solution of LiCl (3×20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product, which was purified by Combiflash reverse phase chromatography (50%˜60% MeCN/H2O containing 10 mM NH4HCO3) to afford N-(2-hydroxy-1-phenylethyl)-4-methyl-5-(3-(4-methylpiperazin-1-yl)benzyl)thiazole-2-carboxamide as a colorless oil (130 mg, 48%). MS (ES+) C25H30N4O2S requires: 450, found: 451 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][CH2:7][C:8]2[C:9]([C:30]([O:32]C)=[O:31])=[N:10][C:11]([O:14][CH:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:16][C:17]3[N:21]([CH3:22])[CH:20]=[N:19][CH:18]=3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[F:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][CH2:7][C:8]2[C:9]([C:30]([OH:32])=[O:31])=[N:10][C:11]([O:14][CH:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:16][C:17]3[N:21]([CH3:22])[CH:20]=[N:19][CH:18]=3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(OC(Cc2cncn2C)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1cncc1CC(Oc1ccc(CCc2ccc(F)cc2)c(C(=O)O)n1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
A mixture of methyl 3-(4-fluorophenethyl)-6-[1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethoxy]pyridin-2-carboxylate (1.56 g), sodium hydroxide (0.65 g), water (12 ml) and methanol (80 ml) was heated at reflux for 16 hours and then cooled to ambient temperature. The mixture was concentrated under reduced pressure, 1M citric acid (17 ml) added and the mixture extracted with 10% methanol/dichloromethane (1×50 ml, 2×30 ml). The extracts were dried and concentrated under reduced pressure to give 3-(4-fluorophenethyl)-6-[1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethoxy]pyridin-2-carboxylic acid as a pale yellow foam (1.22 g).