Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([Si](C(C)C)(C(C)C)C(C)C)[CH:17]=2)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(NCc3ccccc3)nc2)c2cccnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(CNc2ccc(Cc3c[nH]c4ncccc34)cn2)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
Into a round bottom flask was added compound 10 (400.0 mg, 0.85 mmol), tetrahydrofuran (20.0 mL) and tetra-n-butylammonium fluoride (240 mg, 0.93 mmol). The reaction mixture was stirred at 20 Celsius for 30 min. TLC indicated no starting material. The reaction mixture was poured into water, extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with biotage (methylene chloride/methanol 1:10) to give product 9 (Table 1 Cmpd 1-1) (220 mg, Yield=82.4%) as a white solid (M+1=315).
Reaction SMILES: [OH:1][C:2]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:8]([CH3:18])[C:7](=[O:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:26][CH2:27][CH2:28][CH2:29][CH2:30]Br.O>CN(C)C=O>[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][O:1][C:2]1[C:11]2[O:10][C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:8]([CH3:18])[C:7](=[O:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(-c2ccccc2)oc2c(O)cccc2c1=O
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccccc2)oc2c(OCCCCBr)cccc2c1=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A mixture of 5 g of 8-hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 4.2 g of anhydrous potassium carbonate and 43.6 g of 1,4-dibromobutane in 45 ml of dimethylformamide was stirred at 75° C. for 2 hours. The mixture was cooled to 20°-25° C., poured into 100 ml of water and extracted with dichloromethane. The organic solution was washed with aqueous sodium chloride solution and dried on anhydrous sodium sulfate. The solvents and excess 1,4-dibromobutane were evaporated off in vacuo. The residue was rinsed with 55 ml of petroleum ether:diethyl ether (7:4) and collected by suction filtration to yield 5.6 g of the title compound, m.p. 91°-92° C.
Reaction SMILES: [OH-].[K+].[NH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH3:8][O:9][CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1>C(O)C>[CH3:8][O:9][CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]([OH:17])[C@@H:4]([C:5]([OH:7])=[O:6])[NH2:3])=[CH:14][CH:13]=1
Reactant: COCOc1ccc(C=O)cc1
Reactant: NCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COCOc1ccc(C(O)[C@H](N)C(=O)O)cc1
Reaction time: 19 h
Yield: 19.6 %

Procedure:
To a solution of potassium hydroxide (26.8 g) in ethanol (500 ml) was added glycine (14.6 g) and 4-methoxymethoxybenzaldehyde (48.5 g) at room temperature. After stirring for 19 hours, the solvent was removed in vacuo. The residue was dissolved in water and acidified with hydrochloric acid. The solution was washed with ethyl acetate and adjusted to pH 6.0 with sodium bicarbonate. White solid was precipitated and collected to give O-methoxymethyl-β-hydroxytyrosine (9.2 g).
Reaction SMILES: C([N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][N:29]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:32](=[O:33])[C:30]2=[O:31])[CH2:22][CH2:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:40]>O1CCCC1>[ClH:40].[ClH:40].[N:23]1([CH2:26][CH2:27][CH2:28][N:29]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:32](=[O:33])[C:30]2=[O:31])[CH2:24][CH2:25][NH:20][CH2:21][CH2:22]1
Reactant: O=C1C(=O)N(CCCN2CCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)c2ccccc21
Agent: Cl
Solvent: C1CCOC1
Product: O=C1C(=O)N(CCCN2CCNCC2)c2ccccc21

Procedure:
To a solution of 1-[3-(4-trityl-1-piperazinyl)propyl]isatin (5.0 g) in tetrahydrofuran (100 ml) was added all at once concentrated hydrochloric acid (5 ml) and the mixture was vigorously stirred for half an hour. The resultant precipitates were collected by filtration and washed with tetrahydrofuran to give 1-[3-(1-piperazinyl)propyl]isatin dihydrochloride (2.96 g).
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([F:20])[CH:13]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29].S.[OH-].[Na+]>O.C(O)C.C1(C)C(C)=CC=CC=1>[C:1]1([C:7]2[S:29][C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([F:20])[CH:13]=3)=[CH:9][C:8]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C(=O)CC(C(=O)c2ccccc2)c2ccccc2)cc1F
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: S
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cc(-c3ccccc3)c(-c3ccccc3)s2)cc1F

Procedure:
In a 1-liter autoclave were place 30 g (82.8 mmoles) of 1,2-diphenyl-4-(3-fluoro-4-methoxyphenyl)butane-1,4-dione, 100 ml of xylene, 18.4 g (41.4 mmoles) of phosphorus pentasulfide and 130 g of hydrogen sulfide. The vessel was heated 205 minutes at 155°-163` C. (1145-1235 psig.). The reactor was cooled and the hydrogen sulfide vented into a solution of 200 g of sodium hydroxide in 2 l of water. The semisolid residue was stirred with 150 ml of absolute ethanol. Filtration gave a first crop of 14.7 g (49.3%) m.p. 122°-125° C. Chilling the filtrate and refiltration gave a second crop of 10.5 g (35.2%), m.p. 118°-122° C. The two crops were combined and recrystallized from a mixture of 30 ml of dioxane and 70 ml of absolute ethanol to give 21.5 g (72.0%) of colorless plates, m.p. 123°-125° C.
Reaction SMILES: [OH-].[Na+].[C:3]([C:11]1[CH:12]=[C:13](/[C:17](=[N:23]/[O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[N:35]=[C:36]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[O:37][C:38]=3[CH3:39])=[CH:28][CH:27]=2)/[C:18]([O:20]CC)=[O:19])[CH:14]=[CH:15][CH:16]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO.Cl>O1CCCC1>[C:3]([C:11]1[CH:12]=[C:13](/[C:17](=[N:23]/[O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[N:35]=[C:36]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[O:37][C:38]=3[CH3:39])=[CH:28][CH:27]=2)/[C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1cccc(C(=O)c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\C(=O)O)c2cccc(C(=O)c3ccccc3)c2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (7 ml) was added to a solution of ethyl Z-2-(3-benzoylphenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate (800 mg) in tetrahydrofuran (14 ml)-methanol (7 ml) and stirred at 40° C. for 1 hour. 1N hydrochloric acid (7.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain Z-2(3-benzoylphenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetic acid (608 mg, yield 80%) as orange crystals. m.p. 185-186° C. (decomposition)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]1([CH2:17][CH2:18][C:19](N2C3C=CC=CC=3N=N2)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:19](=[O:20])[CH2:18][CH2:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: O=C(CCc1ccccc1)n1nnc2ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(CCc1ccccc1)c1c[nH]c2ccc(Br)cc12
Temperature: 0 °C
Yield: 73 %

Procedure:
To a solution of 5-bromoindole (1.0 g) in methylene chloride (10 ml), 1-(3-phenylpropanoyl)-1H-1,2,3-benzotriazole (1.28 g) was added. While stirring under ice cooling, a solution of titanium(IV) chloride (1.11 ml) in methylene chloride (5.0 ml) was added and the mixture was stirred at room temperature for 5 days. To the reaction solution, ice water (50 ml) was added, the mixture was stirred for a while, then the organic layer was separated and successively washed with water and brine and dried over anhydrous sodium sulfate. The solvent was distilled off in vacuo and the residue obtained was purified by silica gel column chromatography (methylene chloride:methanol=19:1 to 4:1) to afford the above-identified compound (1.22 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:47][C:48]([F:57])([F:56])[C:49]1[CH:50]=[C:51]([CH:53]=[CH:54][CH:55]=1)[NH2:52]>C(OCC)(=O)C.CN(C)C=O>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:52][C:51]2[CH:53]=[CH:54][CH:55]=[C:49]([C:48]([F:47])([F:56])[F:57])[CH:50]=2)=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 74 %

Procedure:
4-Methyl-3-nitrobenzoic acid (14.6 g, 81.0 mmol) was stirred in a solvent of dimethyl formamide (40 mL). The reaction solution was added with HATU (47.2 g, 124 mmol), DIPEA (32.5 mL, 186 mmol) and 3-(trifluoromethyl)aniline (7.72 mL, 62.1 mmol), followed by stirring for about 12 hours at room temperature. The reaction mixture was diluted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated solid was added with ethyl acetate, and stirred for 2 hours or more. The resulting solid was filtered under reduced pressure, and washed with ethyl acetate and methanol. The filtered solid was dried with warm wind in an oven (40° C.) for 3 hours or more to obtain the title compound (14.9 g, 74%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CN(C)C=O.Br[CH:11]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][NH:13][C:12]1=[O:24]>C(OCC)(=O)C>[N:1]([C@@H:11]1[CH2:17][CH2:16][C@@H:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:14][NH:13][C:12]1=[O:24])=[N+:2]=[N-:3]
Reactant: O=C1NCC(c2ccccc2)CCC1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@@H]1CC[C@@H](c2ccccc2)CNC1=O
Temperature: 60 °C
Reaction time: 6 h

Procedure:
2.0 g of sodium azide were added to 20 ml of dimethylformamide containing 1.6 g of 3-bromo-6-phenylperhydroazepin-2-one (Isomer A) [prepared as described in step (e) above]. The mixture was stirred for 6 hours at 60° C. and then diluted with ethyl acetate, washed with water three times and dried over anhydrous magnesium sulfate. The solvent was then distilled off. The crystalline residue was triturated in a 1:1 by volume mixture of methylene chloride and diisopropyl ether and then collected by filtration, to give 1.14 g of the title compound melting at 150°-152° C. (with decomposition).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:27]2([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17](CC3C=CC=CC=3)[CH2:16][CH2:15]2)=[CH:7][CH:6]=1>C(O)C.[Pd]>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:27]2([OH:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1
Reactant: COc1ccc(C(=CCN2CCN(Cc3ccccc3)CC2)C2(O)CCCCC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc(C(CCN2CCNCC2)C2(O)CCCCC2)cc1

Procedure:
A solution of 1-[1-(4-methoxyphenyl)-3-[4-(phenylmethyl)-1-piperazinyl]-1-propenyl]cyclohexanol, dihydrochloride (14.6 g, 29.6 mmole) in ethanol (250 mL) was hydrogenated in a Parr apparatus over 10% Pd/C for 65 hours. The catalyst was filtered and the filtrate evaporated. The residue was partitioned between ethyl acetate (120 mL) and N sodium hydroxide (65 mL). The layers were separated. The aqueous phase was extracted with ethyl acetate. The combined organic solution was washed with brine, dried over magnesium sulfate and evaporated to obtain the title compound as an oil. Wt. 7.8 g. Mass spectral analysis: Molecular weight by C.I.M.S.: M+1 334.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=CC2C=CC=CC=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.CC1C=CC=C(C)N=1.I([O-])(=O)(=O)=[O:27].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[O:27])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: Cn1nc(Cl)cc(C=Cc2ccccc2)c1=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: C1COCCO1
Product: Cn1nc(Cl)cc(C=O)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.7 %

Procedure:
A mixture of 6-chloro-2-methyl-4-styrylpyridazin-3(2H)-one (6 g, 24.32 mmol, Preparation #29), 4% aqueous osmium(VIII) oxide (0.1 mL, 1.216 mmol, Alfa-Aeser), 2,6-dimethylpyridine (5.21 g, 48.6 mmol, Aldrich) and sodium periodate (20.81 g, 97 mmol, Spectrochem) in aqueous dioxane (75%, 80 mL) was stirred at RT for about 3 h. The reaction mixture was diluted with water and the product extracted with EtOAc (5×60 mL). The combined organic layers were dried over sodium sulphate and evaporated under reduced pressure. The residue obtained was purified by silica gel (60-120) column chromatography by eluting with 30-50% EtOAc in hexane to afford 6-chloro-2-methyl-3-oxo-2,3-dihydropyridazine-4-carbaldehyde 2 g (47.7%) as pale yellow solid; 1H NMR (400 MHz, CDCl3) δ 10.359 (s, 1H), 7.658 (s, 1H), 3.846 (s, 3H); MS m/z: 170.9 (M−H)−
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:6]=1[C:7]#[N:8])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CCO.[Pd]>[C:1]([C:5]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:6]=1[C:7]#[N:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1C#N
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)c1ccc(N)cc1C#N
Temperature: 25 °C
Yield: 90.4 %

Procedure:
To a refluxing solution of 2-tert-butyl-5-nitrobenzonitrile (816 mg, 4.0 mmol) in EtOH (20 mL) was added ammonium formate (816 mg, 12.6 mmol), followed by 10% Pd—C (570 mg). The reaction mixture was refluxed for additional 90 min, cooled to room temperature and filtered through Celite. The filtrate was concentrated to give 2-tert-butyl-5-aminobenzonitrile (E-2) (630 mg, 91%), which was used without further purification. HPLC ret. time 2.66 min, 10-99% CH3CN, 5 min run; ESI-MS 175.2 m/z (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[S:8][C:7]=2[CH:19]=1.C1C(=O)N([Br:27])C(=O)C1>C1COCC1>[Br:27][C:10]1[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][C:7]=2[S:8][C:9]=1[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a 500 mL round bottom flask containing 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (22 g, 81 mmol) in THF (250 mL) at 0° C. was added NBS (15 g, 84 mmol). The reaction mixture was stirred at 0° C. for 60 min and then allowed to warm to room temperature and stirred for an additional 2 h. Upon completion the reaction mixture was concentrated to 50% volume and quenched with sat. aq. sodium thiosulfate solution. The resulting solution was extracted with diethyether 3× and the combined organic solvent was dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford 3-bromo-6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophene (27.5 g, 79 mmol, 97% yield). 1H NMR (400 MHz, CDCl3) δ ppm=7.63 (d, J=9.1 Hz, 1 H), 7.55-7.61 (m, 2 H), 7.19 (d, J=2.5 Hz, 1 H), 6.96-7.02 (m, 1 H), 6.87-6.95 (m, 2 H), 3.81 (s, 3 H), 3.79 (s, 3 H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([OH:22])=O)[CH2:3][CH2:2]1.O.[NH:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:24]2[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]2)=[O:22])[CH2:3][CH2:2]1
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)O
Reactant: O=C1CCNCC1
Solvent: O
Product: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(=O)CC1

Procedure:
The title compound was prepared analogously to intermediate 15 from 5-cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid and 4-piperidone hydrate. MS: 392.2 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][C@@H:8]([CH2:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])=[O:22])[NH:9]C(OCC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:30])[CH2:7][C@@H:8]([CH2:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])=[O:22])[NH2:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C[C@@H](CS(=O)(=O)c1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C[C@H](N)CS(=O)(=O)c1ccccc1
Yield: 98.7 %

Procedure:
A mixture of N-(benzyloxycarbonyl)-3(S)-phenylsulfonylmethy-β-alanine tert-butyl ester (0.44 g) and 10% Pd—C (0.1 g, 50% wet) in acetic acid (5 ml) was hydrogenated at 1 atmospheric pressure of hydrogen for 1 hour. The catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated aqueous NaHCO3 solution. The organic layer was dried over MgSO4 and evaporated in vacuo to give 3(S)-phenylsulfonylmethy-βalanine tert-butyl ester (0.3 g) as a colorless oil.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[NH2:8][CH:9]1[CH:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]2[CH:16]=[C:15]([CH2:26][NH:27][S:28]([CH2:31][CH2:32][CH3:33])(=[O:30])=[O:29])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1.C(Cl)(=O)C.C(N(C(C)C)C(C)C)C>ClCCl>[CH2:19]([CH:18]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:26][NH:27][S:28]([CH2:31][CH2:32][CH3:33])(=[O:30])=[O:29])[CH:16]=2)[CH2:11][CH2:10][CH:9]1[NH:8][C:3](=[O:5])[CH3:2])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CCCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccccc1)C(N)CC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CCCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccccc1)C(NC(C)=O)CC2

Procedure:
N-{[7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}propane-1-sulfonamide (cf. example 42) was acetylated in dichloromethane with acetyl chloride in the presence of ethyldiisopropylamine at room temperature.
Reaction SMILES: [F:1][C:2]1[CH:33]=[C:32]([N+:34]([O-])=O)[CH:31]=[CH:30][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][N:17]([CH2:19][CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=3)[S:13][C:6]=12.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:34][C:32]1[CH:31]=[CH:30][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[N:15]=[CH:16][N:17]([CH2:19][CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH:18]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:33]=1
Reactant: CN(CCn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1)C(=O)OC(C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CN(CCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 107 %

Procedure:
To a suspension of 99 (30 mg, 0.058 mmol) in EtOH (1.6 ml) and water (0.6 ml) was added ammonium chloride (3 mg, 0.9 eq, 0.053 mmol) and Fe (28 mg, 8.5 eq, 0.49 mmol) and the reaction mixture was heated to reflux for 45 min. The reaction mixture was cooled to RT, filtered through celite then concentrated to afford title compound 100 (30 mg, 100% yield). MS (m/z): 484.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.CC(C)([O-])C.[K+].[Br:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br.N1CCNCC1>O1CCCC1>[Br:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][CH:7]1[C:6](=[O:9])[N:5]([CH3:10])[C:4]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:3]=2[C:2]([Cl:1])=[N:8]1
Reactant: BrCc1ccccc1Br
Reactant: CN1C(=O)CN=C(Cl)c2cc(Cl)ccc21
Agent: C1CNCCN1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1C(=O)C(Cc2ccccc2Br)N=C(Cl)c2cc(Cl)ccc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 64.7 %

Procedure:
(E)-5,7-Dichloro-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one (400 mg, 1.65 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) under a nitrogen atmosphere, cooled to −78° C., then a 1 M solution of potassium tert-butoxide in tetrahydrofuran (1.7 mL, 1.7 mmol) was added dropwise. The reaction mixture was stirred for 10 minutes before a solution of the 2-bromobenzyl bromide (411 mg, 1.65 mmol) in tetrahydrofuran (2 mL) was added dropwise. The mixture was stirred at −78° C. for 20 minutes then the cooling bath removed and the mixture was allowed to warm to ambient temperature and stirred at ambient temperature for 18 hours. Piperazine (283 mg, 3.29 mmol) was added to remove excess 2-bromobenzyl bromide and the mixture was stirred at ambient temperature for 30 minutes, diluted with ethyl acetate, and washed with cold 1 M aqueous hydrogen chloride (2×40 mL). The organic layers were dried with sodium sulfate, decanted and concentrated in vacuo to approximately 20 mL of a red liquid. The product was purified on a short pad of silica gel eluting with 100 mL of ethyl acetate:hexanes (1:2) to yield (E)-3-(2-bromobenzyl)-5,7-dichloro-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one (0.44 g, 65%). 1H NMR (300 MHz, CDCl3) δ 3.40 (s, 3H) 3.75 (m, 2H), 4.15 (m, 1H), 7.05-7.55 (m, 7H).
Reaction SMILES: [CH2:1]([C:3]1[C:10]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=3)=[N:13][CH:12]=2)=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O)[CH3:2].C(O)(=O)C.C([O-])(=O)C.[Na+].[NH:39]1[CH2:44][CH2:43][CH:42]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:41][CH2:40]1>CO>[CH2:1]([C:3]1[C:10]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[C:18]([C:26]([F:28])([F:29])[F:27])[CH:17]=3)=[N:13][CH:12]=2)=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][N:39]1[CH2:44][CH2:43][CH:42]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:41][CH2:40]1)[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCc1c(C=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(Cc2cccc(-c3cnc(-c4ccc(OC(C)C)c(C(F)(F)F)c4)s3)c2CC)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 187 %

Procedure:
To a solution of 2-ethyl-3-{2-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}benzaldehyde (D72) (64 mg), acetic acid (0.044 mL) and sodium acetate (62.6 mg) in methanol (10.00 mL) stirred under nitrogen at room temperature was added ethyl 4-piperidinecarboxylate (120 mg) in one charge. The reaction mixture was stirred at room temperature for 1 h, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) (10 mL), sodium triacetoxyborohydride (97 mg) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (30 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product ethyl 1-[(2-ethyl-3-{2-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}phenyl)methyl]-4-piperidinecarboxylate (D81) (160 mg). The crude product was used for next step without further purification. MS (ES): C30H35F3N2O3S requires 560. found 561.3 (M+H+).