Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]=[CH2:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18](=[O:32])[C@@H:19]([NH2:31])[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.CN(C)CCCN=C=NCC>CN(C=O)C>[CH3:16][O:17][C:18](=[O:32])[C@@H:19]([NH:31][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH:14]=[CH2:15])[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc2ccccc2c1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)OC
Reaction time: 3 h
Yield: 83.4 %

Procedure:
To a solution of 2-(S)-tert-butoxycarbonylamino-pent-4-enoic acid (3.8 g, 18.0 mmol) and 2-(S)-amino-3-naphthalen-2-yl-propionic acid methyl ester (4.1 g, 18.0 mmol) in DMF (40 mL) are added 1-hydroxybenzotriazole (3.1 g, 23.4 mmol), N-methylmorpholine (9.1 g, 90.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (4.5 g, 23.4 mmol) consecutively and the reaction mixture is stirred for 3 hours. The reaction is quenched with aqueous NH4Cl and extracted with ethyl acetate. The extract is dried over Na2SO4, filtered and concentrated in vacuo and the residue purified over silica gel (hexanes/ethyl acetate, 1:1) to afford 6.4 g (84% yield) of the desired product.
Reaction SMILES: [CH:1]1([S:6][C:7]2[CH:8]=[C:9]([CH:41]=[CH:42][CH:43]=2)[CH2:10][O:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]3[CH2:27][C@@H:26]([C:28]4[CH:39]=[CH:38][C:31]5[O:32][C:33]([CH3:37])([CH3:36])[O:34][CH2:35][C:30]=5[CH:29]=4)[O:25][C:24]3=[O:40])=[CH:17][CH:16]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:45].[Na+]>CCO.O>[CH:1]1([S:6]([C:7]2[CH:8]=[C:9]([CH:41]=[CH:42][CH:43]=2)[CH2:10][O:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]3[CH2:27][C@@H:26]([C:28]4[CH:39]=[CH:38][C:31]5[O:32][C:33]([CH3:37])([CH3:36])[O:34][CH2:35][C:30]=5[CH:29]=4)[O:25][C:24]3=[O:40])=[CH:17][CH:16]=2)=[O:45])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(SC6CCCC6)c5)cc4)C(=O)O3)ccc2O1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(S(=O)C6CCCC6)c5)cc4)C(=O)O3)ccc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
A solution of (5R)-3-{2-[4-(2-{[3-(cyclopentylthio)benzyl]oxy}ethoxy)phenyl]ethyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (276 mg) in EtOH (15 ml) and water (5 ml) was treated with sodium periodate (391 mg) and stirred at room temperature under nitrogen for 3 h. The solution was concentrated in vacuo before pouring into water and extracting with EtOAc. The combined organic layers were washed with water, dried (MgSO4) and concentrated in vacuo to give the title compound (278 mg). LCMS RT=3.42 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CC(O)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(C(C)(C)C)cc21
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCc2ccc(C(C)(C)C)cc21

Procedure:
6-tert-Butyl indole-1-carboxylic acid tert-butyl ester (prepared in Example GG; 13.0 g, 48 mmol) was taken up in 500 mL of AcOH. 20% Pd/C (2 g) was added, and the mixture was shaken under a hydrogen atmosphere of 50 psi. The catalyst was filtered, and the filtrate was concentrated. The residue was dissolved in EtOAc, washed with saturated NaHCO3 solution and brine, and dried (MgSO4). Concentration gave the title compound which was used without purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[N+:11]([O-])([OH:13])=[O:12].[OH-].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1ccc2nccn2n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cnc2ccc(Cl)nn12
Reaction time: 4.5 h
Yield: 90.8 %

Procedure:
6-Chloroimidazo[1,2-b]pyridazine (4.95 g, 31.6 mmol) [purchased from Combi-Blocks] was dissolved in 60 mL concentrated sulfuric acid, cooled in an ice bath, and nitric acid (9.9 mL, 158 mmol) was added dropwise while stirring. The reaction was stirred at 0° C. for 30 minutes, then at ambient temperature for 4.5 hours to reach completion. The reaction was poured onto ice, and the resulting aqueous mixture was neutralized with 50% NaOH aqueous solution and then extracted with EtOAc (3×400 mL). The organic layers were combined and washed with water (2×400 mL) and brine (400 mL), dried (Na2SO4), filtered and concentrated to yield the product as a yellowish powder (5.7 g, 91% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:5][NH:6][NH2:7].C([O:14][C:15](=O)[CH:16]=[C:17]([NH2:21])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:21][C:17]1[NH:7][N:6]([CH2:5][C:4]2[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([CH3:1])[CH:3]=2)[C:15](=[O:14])[CH:16]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: Cc1cc(CNN)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1cc(Cn2[nH]c(N)cc2=O)ccc1Cl
Reaction time: 8 h

Procedure:
20.5 g of 3-methyl-4-chlorbenzylhydrazine were added dropwise, under nitrogen, to a solution of 19.1 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1.5 g of p-toluenesulphonic acid in 200 ml of ethanol. The reaction solution was stirred overnight and the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 131°, 10 g (35%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[CH2:7][C:6]=2[NH:5][C:4](=[O:18])[CH:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].C(OCCO)C.Cl>>[ClH:24].[NH:22]([N:23]=[C:10]1[CH2:9][CH:8]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH2:7][C:6]2[NH:5][C:4](=[O:18])[CH:3]=[C:2]([CH3:1])[C:11]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: N=C(N)NN
Reactant: Cc1cc(=O)[nH]c2c1C(=O)CC(c1ccsc1)C2
Agent: Cl
Solvent: CCOCCO
Product: Cc1cc(=O)[nH]c2c1C(=NNC(=N)N)CC(c1ccsc1)C2
Temperature: 125 °C
Reaction time: 13 h
Yield: 44.2 %

Procedure:
To a mixture of 4-methyl-7-(thiophen-3-yl)-1,2,5,6,7,8-hexahydroquinoline-2,5-dione (0.155 g) and aminoguanidine hydrochloride (73 mg) were added 2-ethoxyethanol (2 ml) and 2N hydrochloric acid (0.3 ml), and the mixture was stirred at 125° C. for 13 hours and cooled. Precipitated crystals were filtered, washed with ethanol and dried to give 5-guanidinoimino-4-methyl-7-(thiophen-3-yl)-1,2,5,6,7,8-hexahydroquinolin-2-one hydrochloride (Compound 138) (0.093 g) as colorless crystals.
Reaction SMILES: Br[C:2]1[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[O:9]1[CH2:14][CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[O:9]1[CH2:10][CH:11]=[C:12]([C:2]2[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:14]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Fc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Fc1ncccc1C1=CCOCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a round bottomed flask was added 3-bromo-2-fluoropyridine (5.2201 g, 29.7 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.79 g, 37.1 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (1.666 g, 2.373 mmol), and sodium carbonate (15.72 g, 148 mmol) in DME (47.5 mL) and Water (11.86 mL) to stir at 80° C. overnight. Reaction was allowed to cool to room temperature. The reaction mixture was diluted with water and extracted with DCM. The organic extract was washed with water, brine, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40M), eluting with a gradient of 10% to 100% EtOAc in hexane, to provide 3-(3,6-dihydro-2H-pyran-4-yl)-2-fluoropyridine. MS (ESI, pos. ion) m/z: 180.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[BH4-].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[OH:6])[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(c1ccccc1)c1cccc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC(c1ccccc1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 12.5 h
Yield: 76 %

Procedure:
To a solution of 3-bromobenzophenone (1.00 g, 4 mmol) in MeOH (15 mL) was added sodium borohydride (0.3 mL, 8 mmol) portionwise at rt and the suspension was stirred at rt for 1-24 h. The reaction was diluted slowly with water and extracted with CH2Cl2. The organic layer was washed successively with water, brine, dried over Na2SO4, and concentrated to give the title compound as oil (0.8 g, 79%), which was used in the next reaction without further purification. MS (ESI, pos. ion) m/z: 247.1 (M-OH).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>N1C=CC=CC=1>[CH:1]1([O:6][C:19]([C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:16][CH:17]=2)=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: OC1CCCC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(OC1CCCC1)c1ccc(OCc2ccccc2)cc1

Procedure:
Cyclopentanol (2.58g.; 0.03 m) was dissolved in pyridine (50 ml), 4-benzyloxybenzoyl chloride (6.76g; 0.03 m) was added and the mixture was boiled under reflux 6 hours. The resulting mixture was added to iced-water, extracted with ether, the organic extract washed with 2×100 ml. of 2N hydrochloric acid, 2×100 ml. saturated sodium bicarbonate solution and 1×100 ml. of water, dried (MgSO4) and evaporated. The ester was purified by elution from a column of silica in toluene.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16](=[N:23][O:24][CH3:25])[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.CC1[N:32]=C(C#CC2CC3(C4C(=CC=CC=4)C(=O)C3)ON=2)C=CC=1>>[CH3:25][O:24][N:23]=[C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]2([O:12][N:11]=[C:10]([C:9]#[C:8][C:4]3[CH:3]=[CH:2][CH:7]=[C:6]([CH3:5])[N:32]=3)[CH2:14]2)[CH2:15]1
Reactant: CON=C1CC2(CC(C#Cc3cccc(Cl)c3)=NO2)c2ccccc21
Reactant: Cc1cccc(C#CC2=NOC3(CC(=O)c4ccccc43)C2)n1
Product: CON=C1CC2(CC(C#Cc3cccc(C)n3)=NO2)c2ccccc21
Yield: 82 %

Procedure:
The title product was obtained the method described for the compound of Example 84 starting from the Compound of example 93 instead of the compound of Example 83. After the usual work-up procedure, the residue was purified by means of automated flash chromatography (SP01®TM-Biotage; gradient Petroleum Ether-EtOAc from 95:5 to 1:1) to give the title compound as a yellowish oil. Yield: 82%.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]([N+:27]([O-])=O)[C:21]=1[CH3:30])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].O>C(O)C.[Fe]>[NH2:27][C:22]1[C:21]([CH3:30])=[C:20]([CH2:19][O:18][Si:1]([C:14]([CH3:16])([CH3:15])[CH3:17])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:25]([CH3:26])=[CH:24][CH:23]=1
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(N)c(C)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 109.7 %

Procedure:
To a suspension of 1-(tert-butyldiphenylsilyloxymethyl)-2,6-dimethyl-3-nitrobenzene (42 g) and ammonium chloride (4.2 g) in ethanol (378 ml)-water (42 ml) was added iron (7.0 g), and the mixture was refluxed for 6 hours, during which iron (7.0 g) was added thereto twice. Insoluble materials were filtered off, and the filtrate was concentrated. To the residue was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated to give 3-amino-1-(tert-butyldiphenylsilyloxymethyl)-2,6-dimethylbenzene (42.8 g) as pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]=[C:9]=[S:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:11][C:12]1[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=1>CN(C=O)C>[Br:11][C:12]1[C:13]([NH:18][C:9]2[S:10][C:2]3[C:7]([N:8]=2)=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: S=C=Nc1cccnc1Cl
Reactant: Nc1ncccc1Br
Solvent: CN(C)C=O
Product: Brc1cccnc1Nc1nc2cccnc2s1
Temperature: 120 °C
Yield: 36.8 %

Procedure:
Heated a mixture of 2-chloro-3-isothiocyanatopyridine (0.986 g, 5.78 mmol) and 3-bromopyridin-2-amine (1.00 g, 5.78 mmol) in DMF (4 mL) at 80° C. for 3 hours. Heated at 120° C. overnight. Cooled, partitioned between ethyl acetate and water, washed with 2N NaOH, water, brine, dried, and concentrated. Crystallized from dichloromethane:hexanes (1:10, 110 mL) and filtered. The filtered material was further purified by dissolving in dichloromethane (10 mL), and subjecting to MPLC (Biotage) eluting with 3:2 hexane:ethyl acetate. The higher Rf component was concentrated to afford the title compound (0.654 g, 36.8% yield) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:16][CH:17]1[CH2:21][CH2:20]S[CH2:18]1.ClC1C=C(C=CC=1)C(OO)=O.[S:33]([O-:36])([O-])=[O:34].[Na+].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:16][CH:17]1[CH2:21][CH2:20][S:33](=[O:36])(=[O:34])[CH2:18]1
Reactant: O=S([O-])[O-]
Reactant: CCOC(=O)c1cc(Br)cc2c(CC3CCSC3)c[nH]c12
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)cc2c(CC3CCS(=O)(=O)C3)c[nH]c12
Reaction time: 5 h
Yield: 42.56 %

Procedure:
To a solution of ethyl 5-bromo-3-(tetrahydro-3-thienylmethyl)-1H-indole-7-carboxylate (7.61 g, 20.73 mmol) in dichloromethane (150 mL) was added portionwise 3-chlorobenzoperoxoic acid (10.69 g, 62.19 mmol) at room temperature. The resulting solution was stirred for 5 h. Sodium sulfite was added, and the mixture was washed with water, extracted with DCM (3×100 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by column on sillal gel (petroleum:ethyl acetate=10:1 to 5:1 to 2:1), giving 3.52 g (42.56%) of the title compound.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH2:9]([N:16]=[C:17]=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:9]([NH:16][C:17]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C=NCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)[C@@H]1CCCN1C(=O)NCc1ccccc1

Procedure:
L-Proline (23.3 g), benzyl isocyanate (22.9 g) and triethylamine (20.5 g) were stirred at room temperature for 1 hour in DMF (250 ml) to give a solution of N-(benzylaminocarbonyl)-L-proline. Thereto were added HOBt (29.7 g), water-soluble carbodiimide hydrochloride (42.13 g), L-proline benzyl ester hydrochloride (48.3 g) and triethylamine (27.9 ml) under ice-cooling, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with 10% potassium hydrogensulfate, a saturated aqueous solution of sodium bicarbonate and water in order, dried over anhydrous sodium sulfate, and concentrated to give the title compound (73.6 g).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH:13]1([C:19]2[C:20]3[CH:21]=[CH:22][C:23]([C:39](O)=[O:40])=[CH:24][C:25]=3[N:26]3[CH2:32][C@H:31]([OH:33])[C@H:30]([OH:34])[C:29]4[CH:35]=[CH:36][CH:37]=[CH:38][C:28]=4[C:27]=23)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:42][N:43]([CH3:48])[S:44]([NH2:47])(=[O:46])=[O:45]>CN(C1C=CN=CC=1)C.CN(C=O)C.C(Cl)Cl>[CH:13]1([C:19]2[C:20]3[CH:21]=[CH:22][C:23]([C:39]([NH:47][S:44]([N:43]([CH3:48])[CH3:42])(=[O:46])=[O:45])=[O:40])=[CH:24][C:25]=3[N:26]3[CH2:32][C@H:31]([OH:33])[C@H:30]([OH:34])[C:29]4[CH:35]=[CH:36][CH:37]=[CH:38][C:28]=4[C:27]=23)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](O)[C@H](O)c1ccccc1-3
Reactant: CN(C)S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](O)[C@H](O)c1ccccc1-3
Temperature: 22 °C
Reaction time: 18 h

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (12.6 mg, 0.066 mmol) was added to a solution of 13-cyclohexyl-6,7-dihydro-(5R,6S)-rel-5,6-dihydroxy-5H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (8.7 mg, 0.022 mmol) and DMAP (8.1 mg, 0.066 mmol) in DMF (0.3 mL) and CH2Cl2 (0.3 mL) at 22° C. The vial was shaken for a minute at 22° C. then N,N-dimethylsulfamide (5.5 mg, 0.044 mmol) was added. Stirring was continued for 18 hr. The solution was then filtered and purified by Prep. reverse phase chromatography. The product containing fraction was concentrated on a Speed Vac® to leave the title compound as a white film (1.2 mg, 11%). ESI-MS m/z 498 (MH+) 1H NMR (500 MHz, MeOD) δ 1.23-1.33 (m, 1 H) 1.39-1.54 (m, 2 H) 1.62 (m, 1 H) 1.77-1.87 (m, 2 H) 1.93-2.18 (m, 4 H) 2.99 (d, J=11.29 Hz, 1 H) 3.04 (s, 6 H) 3.35 (m, 1 H) 4.42 (d, J=4.58 Hz, 1 H) 4.56 (m, 1 H) 4.75 (dd, J=14.50, 7.17 Hz, 1 H) 7.47 (m, 2 H) 7.54 (m, 1 H) 7.61 (dd, J=8.55, 1.53 Hz, 1 H) 7.80 (d, J=7.63 Hz, 1 H) 7.94 (d, J=8.85 Hz, 1 H) 8.13 (s, 1 H).
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[NH2:25][CH2:26][CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([NH:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[N:3][C:4]=2[CH3:24])=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: NCCN1CCCC1
Solvent: CCCCO
Product: Cc1nc(NCCN2CCCC2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 100 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 70 μL of 1-(2-aminoethyl)pyrrolidine in 1 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(2-(pyrrolidin-1-yl)ethylamino)nicotinamide. MS (Q1) 436.0 (M)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:20][C:21]([F:27])([F:26])[CH2:22][C:23](O)=[O:24]>C(OCC)(=O)C.CCCCCC>[C:12]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][C:23](=[O:24])[CH2:22][C:21]([F:27])([F:26])[F:20])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)CC(F)(F)F
Reactant: Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(CC(F)(F)F)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 114 employing 3-amino-2-benzoyl-6-chloroindole (Example 1) and 3,3,3-trifluoropropionic acid. m.p.: 201-204° C. (ethyl acetate/hexane)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[S-:11][C:12]#[N:13].[NH4+].C(O)(=O)C.BrBr>O>[NH2:13][C:12]1[S:11][C:3]2[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=[CH:10][C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(C(=O)O)cc1
Agent: BrBr
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc2ccc(C(=O)O)cc2s1
Temperature: 15 °C
Reaction time: 8 h

Procedure:
220 parts of the β-acetoxyethyl ester of p-aminobenzoic acid and 333 parts of ammonium thiocyanate are suspended in 1000 parts of acetic acid. The suspension is cooled to 15° C. and then a solution of 176 parts of bromine in 300 parts of acetic acid is gradually added in a period of two hours, without allowing the temperature to exceed 15° C. The mixture is stirred for an hour at 15° C. and then allowed to stand overnight and is subsequently run into 2500 parts of water containing 15 parts of 19° Be hydrochloric acid. Then it is heated to 95° C., filtered at 95° C., and the cooled filtrate is neutralised by the addition of 700 parts of sodium carbonate, filtered again, and the precipitate is washed with 2000 parts of water, drained and dried at 60° C. 215 parts of β-acetoxyethyl ester of 2-amino-benzothiazole-6-carboxylic acid, m.p. 191°-192° C, are thus obtained.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:11][S:10][C:9]([NH:12]C(=O)OC(C)(C)C)=[N:8]2)[CH:5]=[N:4][CH:3]=[N:2]1.[ClH:20]>O1CCOCC1>[ClH:20].[ClH:20].[N:1]1([CH2:6][CH:7]2[CH2:11][S:10][C:9]([NH2:12])=[N:8]2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)NC1=NC(Cn2cncn2)CS1
Agent: Cl
Solvent: C1COCCO1
Product: NC1=NC(Cn2cncn2)CS1

Procedure:
a solution of 0.3 g of tert-butyl N-[(4RS)-4-(1,2,4-triazol-1-yl-methyl)-4,5-dihydro-2-thiazolyl]carbamate in 10 cm3 of 4N hydrochloric acid in dioxane is stirred at a temperature in the region of 20° C. for 34 hours. The reaction medium is filtered and then washed with 3 times 5 cm3 of diethyl ether and dried in a desiccator. 0.14 g of (4RS)-4-(1,2,4-triazol-1-ylmethyl)-4,5-dihydro-2-thiazolylamine dihydrochloride is obtained in the form of a white foam [mass spectrum: EI m/z=184 MH+ m/z=183 M+ m/z=114 C4H6N2+M/z=101 C3H5N2S+ base peak m/z=36 HCl DCI m/z=184 MH+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1>CN(C=O)C>[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:11][CH2:10][N:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=3)[C:8]2=[O:12])=[CH:5][CH:6]=1
Reactant: O=C1NCCN1c1ccncc1
Reactant: FC(F)(F)c1ccc(OCCCCCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(CCCCCCOc2ccc(C(F)(F)F)cc2)CCN1c1ccncc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 1-(4-pyridyl)-2-imidazolidinone (0.10 g, 0.61 mmol) and sodium hydride (75% dispersion in mineral oil, 0.02 g, 0.67 mmol) in anhydrous DMF (7 mL) was cooled in an ice bath and stirred at 0° C. for 30 minutes, followed by addition of a solution of 1-bromo-6-[4-(trifluoromethyl)-phenoxy]hexane (0.20 g, 0.61 mmol) in anhydrous DMF (3 mL). After 5 minutes, the ice bath was removed and the reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched with a saturated aqueous ammonium chloride solution followed by extraction with a mixture of diethyl ether and ethyl acetate (3:1, 100 mL×3). The organic layers were combined and washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude mixture thus obtained was purified with gradient chromatography [100% ethyl acetate, and, subsequently, a mixture of ethyl acetate and methanol (4:1)] to yield the product (i.e., Compound 1) as a white solid (0.18 g, 73%).