Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:25])[CH2:8][CH:9]([C:13]2[CH:22]=[C:21]([CH3:23])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH3:24])[CH2:10][C:11]=1[OH:12])(=O)[CH2:2][CH2:3][CH3:4].Cl.[CH2:27]([O:29][NH2:30])[CH3:28].O.O.O.C([O-])(=O)C.[Na+]>C(O)C>[CH3:24][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]([CH3:23])=[CH:22][C:13]=1[CH:9]1[CH2:10][C:11](=[O:12])[C:6]([C:1](=[N:30][O:29][CH2:27][CH3:28])[CH2:2][CH2:3][CH3:4])=[C:7]([OH:25])[CH2:8]1
Reactant: CCON
Reactant: CCCC(=O)C1=C(O)CC(c2cc(C)c3ccccc3c2C)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCC(=NOCC)C1=C(O)CC(c2cc(C)c3ccccc3c2C)CC1=O

Procedure:
A mixture of 2-butyryl-5-(1,4-dimethylnaphth-2-yl)-3-hydroxycyclohex-2-en-1-one (0.25 g), ethoxyamine hydrochloride (1.3 equiv) and sodium acetate trihydrate (1.3 equiv) were stirred in ethanol (30 ml) at room temperature for 4 hr. The mixture was then immediately extracted with ether. The dried (MgSO4) organic extract was evaporated to give 5-(1,4-dimethylnaphth-2-yl)-2-[1-(ethoxyimino)butyl]-3-hydroxycyclohex-2-en-1-one as a pale yellow oil. The product was characterized by proton nuclear magnetic resonance spectroscopy and the spectroscopic data is recorded in Table 4, Example 10.
Reaction SMILES: [CH3:1][C:2]1[NH:19][C:18]2[C:20]3[C:3]=1[CH2:4][C@@H:5]1[C:13]([C:14]=3[CH:15]=[CH:16][CH:17]=2)=[CH:12][C@@H:8]([C:9](=[O:11])[OH:10])[CH2:7][N:6]1[CH3:21].Cl.CO.[CH3:25]COCC.CCCCCC>CO>[CH3:25][O:11][C:9]([C@@H:8]1[CH:12]=[C:13]2[C@@H:5]([CH2:4][C:3]3[C:20]4[C:18](=[CH:17][CH:16]=[CH:15][C:14]2=4)[NH:19][C:2]=3[CH3:1])[N:6]([CH3:21])[CH2:7]1)=[O:10]
Reactant: CCOCC
Reactant: Cc1[nH]c2cccc3c2c1C[C@@H]1C3=C[C@@H](C(=O)O)CN1C
Agent: Cl
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)[C@@H]1C=C2c3cccc4[nH]c(C)c(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of 25 g 2-methyl-lysergic acid in 500 ml CH3OH are added 253 ml 3.5N HCl/CH3OH. The reaction mixture is then stirred at room temperature for 15 hours, then diluted with 500 ml CH3OH and stirred 2 days. The mixture is evaporated and partitioned between ethyl acetate and 5% K2CO3 solution. After drying and evaporating the heading compound is obtained as crystals, which are then rubbed with ether/hexane (1:1), m.p. 154° (sintering 150°).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[CH:6]([N:15]3[CH2:20][CH2:19][N:18]([C:21](SC)=[N:22][C:23]#[N:24])[CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3.[NH2:29][CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>C(#N)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[CH:6]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[N:29][CH2:30][C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)[NH:22][C:23]#[N:24])[CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3
Reactant: CSC(=NC#N)N1CCN(C2c3ccc(Cl)cc3SCc3cccnc32)CC1
Reactant: NCc1ccncc1
Solvent: CC#N
Product: N#CNC(=NCc1ccncc1)N1CCN(C2c3ccc(Cl)cc3SCc3cccnc32)CC1
Yield: 84.7 %

Procedure:
Methyl 4-(8-chloro-5,11-dihydro-[1]benzothiepino[4,3-b]pyridin-11-yl)-N-cyano-1-piperazinecarboximidothioate (200 mg, 0.465 mmol) was dissolved in acetonitrile (1 ml) in a 25 ml flask, and 4-aminomethylpyridine (0.94 ml, 9.30 mmol) was added. The mixture was refluxed for 1.6 hours. The reaction mixture was cooled and then acetonitrile was distilled off. The resulting tar was dissolved in water and CH2Cl2. The layers were separated; the aqueous layer was extracted three times with CH2Cl2. The combined organic layers were washed with brine, dried (MgSO4), filtered through `Celite` and concentrated. The residue was partially purified by flash chromatography, and the product (228 mg) was purified by further chromatography to afford the pure product (193 mg, 87%); MS (CI, M+H)=490.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([C:14]2[C@@H:23]3[C@@H:18]([CH2:19][CH:20]=[CH:21][CH2:22]3)[C:17](=[O:24])[N:16]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([N:33]4[CH2:38][CH2:37][N:36]([C:39]5C=CC=CC=5)[CH2:35][CH2:34]4)=[O:32])=[CH:27][CH:26]=3)[N:15]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH3:13])[CH3:3].C([O:47]CC)C>>[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([C:14]2[C@@H:23]3[C@@H:18]([CH2:19][CH:20]=[CH:21][CH2:22]3)[C:17](=[O:24])[N:16]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([N:33]4[CH2:38][CH2:37][N:36]([CH:39]=[O:47])[CH2:35][CH2:34]4)=[O:32])=[CH:29][CH:30]=3)[N:15]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH3:13])[CH3:3]
Reactant: CCOCC
Reactant: CCOc1ccc(C2=NN(c3ccc(C(=O)N4CCN(c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC
Agent: Cl
Product: CCOc1ccc(C2=NN(c3ccc(C(=O)N4CCN(C=O)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC

Procedure:
Prepared from intermediate product A1 and piperazinylcarbaldehyde as described for compound 1. Cystallised from diethyl ether as the free base. M.p. 143–144° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH2:6].[N+](=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N-]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]2[CH2:6][CH:12]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[CH:8][CH:9]=1
Reactant: C=Cc1cccc(F)c1
Reactant: CCOC(=O)C=[N+]=[N-]
Product: CCOC(=O)C1CC1c1cccc(F)c1
Yield: 54.9 %

Procedure:
3-Fluorostyrene (9.7 mL, 82 mmol) and ethyl diazoacetate (8.6 mL, 82 mmol) were reacted by the method reported in Org. Syn. Coll. Vol. VI, 1988, 913. The product was purified on silica. 9.4 g of ethyl 2-(3-fluorophenyl)cyclopropane carboxylate (45 mmol, 55%) was obtained. MS (GC/MS, EI) 208 (M+). (b) The trans ester was selectively hydrolyzed from the cis/trans mixture by the method reported in Org. Syn. Coll. Vol. VI, 1988, 913. Recrystallize from hexane to yield 2.5 g (13.9 mmol, 89% of the trans) of trans-2-(3-fluorophenyl)cyclopropane carboxylic acid. (c) The trans-2-(3-fluorophenyl)cyclopropane carboxylic acid (400 mg, 2.2 mmol) and (R)-3-methoxyphenyl ethylamine (280 mg, 1.9 mmol) were converted to the diastereomeric amides by the method reported in Aust. J. Chem. 1984, 37, 1709. 446 mg (1.4 mmol, 75%) of trans-2-(3-fluorophenyl)-N-(1(R))-(3-methoxyphenyl)ethyl)cyclopropane carboxamide was obtained. MS (GC/MS, EI) 313 (M+). (d) The mixture of diastereomeric amides (550 mg, 1.8 mmol) were reduced to the amines with BH3.THF (7 mL, 7.0 mmol) in 10 mL THF. Upon complete addition, the solution was heated to reflux, overnight. The solution was cooled to 0° C. and 7 mL of 6 N HCl was carefully added. This was stirred open to air for two hours, THF was removed in vacuo. The aqueous residue was basified to pH 9 with Na2CO3 solution and extracted with 3×20 mL CH2Cl2. The combined extracts were washed with 20 mL water and 20 mL of 1:1 water/brine. The organics were dried (Na2SO4), filtered, and solvent was removed. 520 mg of N-(trans-2-(3-fluorophenyl)cyclopropanylmethyl)-1-(R)-(3-methoxyphenyl)ethylamine (1.8 mmol, 99%) was obtained as an oil. MS (CI) m/z 300 (MH+).
Reaction SMILES: [CH3:1][C:2](=[N:5][OH:6])[CH2:3][CH3:4].[N:7]([CH2:10][Si:11]([O:16][CH3:17])([O:14][CH3:15])[O:12][CH3:13])=[C:8]=[O:9]>>[CH2:3]([C:2](=[N:5][OH:6])[CH2:1][C:8](=[O:9])[NH:7][CH2:10][Si:11]([O:14][CH3:15])([O:16][CH3:17])[O:12][CH3:13])[CH3:4]
Reactant: CCC(C)=NO
Reactant: CO[Si](CN=C=O)(OC)OC
Product: CCC(CC(=O)NC[Si](OC)(OC)OC)=NO
Reaction time: 1 h

Procedure:
A stirred mixture conditioned at a temperature of 80° C. of 86.1 g of 2-butanone oxime and 120 mg of “Borchi catalyst” (catalyst VP 0244 from Borchers GmbH, Langenfeld) was admixed over the course of 60 min with 150 g of (isocyanatomethyl)trimethoxysilane. After the end of the addition the mixture was stirred at the temperature stated for a further 60 min and excess 2-butanone oxime was removed by distillation. This gave N-[(trimethoxysilyl)methyl]carbamoylmethyl ethyl ketone oxime in quantitative yield with a purity of >95% (analysis by 29Si and 1H NMR).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:22]([N:25](CC2C=CC(OC)=CC=2OC)[C:26]2[S:30][N:29]=[CH:28][N:27]=2)(=[O:24])=[O:23])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=1I)#[N:2].[CH3:42][N:43]1[C:47](B2OC(C)(C)C(C)(C)O2)=[CH:46][CH:45]=[N:44]1>>[C:1]([C:3]1[CH:4]=[C:5]([S:22]([NH:25][C:26]2[S:30][N:29]=[CH:28][N:27]=2)(=[O:23])=[O:24])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:12][C:11]=1[C:47]1[N:43]([CH3:42])[N:44]=[CH:45][CH:46]=1)#[N:2]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(OC(F)(F)F)cc3I)c(C#N)c2)c(OC)c1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Product: Cn1nccc1-c1cc(OC(F)(F)F)ccc1Oc1ccc(S(=O)(=O)Nc2ncns2)cc1C#N

Procedure:
The title compound was prepared from 3-cyano-N-(2,4-dimethoxybenzyl)-4-[2-iodo-4-(trifluoromethoxy)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 497) and 1-methyl-1H-pyrazole-5-boronic acid pinacol ester using Method E above. Purification afforded the title compound.
Reaction SMILES: C1N=C[N:3]([C:6](N2C=NC=C2)=[S:7])C=1.[NH2:13][C:14]1[NH:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.C([O-])(=O)C.[NH4+]>C(#N)C>[NH:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=[C:14]1[NH:13][C:6]([NH2:3])=[S:7]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC#N
Product: NC(=S)Nc1nc2ccccc2[nH]1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
0.535 g (3.0 mmol) N,N′-thiocarbonyldiimidazole was dissolved in 5 ml acetonitrile, and to this yellow solution was added drop-wise 0.40 g (3.0 mmol) 2-aminobenzimidazole, suspended in 5 ml acetonitrile, at room temperature. After 30 minutes, a precipitate formed, and the mixture was stirred another 12 hours. After 0.474 g (6.0 mmol) ammonium acetate in substance (German: “in Substanz”) was added to this mixture, the mixture was heated in the microwave (at 100 Watt) 30 minutes long at 90° C. The solvent was removed under vacuum, water was added to the residue and an extraction with dichloromethane (3×30 ml) followed. The combined organic phase was washed once again with water and, after drying over MgSO4, the solvent was removed under vacuum. The product was purified by means of preparative HPLC (Merck: Chromolith RP-18E, 100-25; eluent wasser/acetonitrile/0.1 molar acetic acid). In this single pot procedure, 0.27 g of the N-1H-benzimidazole-2-ylthiourea was directly recovered without isolation of the intermediate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.[CH3:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Br)=[O:32])=[CH:29][CH:28]=1>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:12]1[CH2:11][C:10]2[C:14](=[CH:15][CH:16]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][C:27]([CH3:26])=[CH:28][CH:29]=4)=[CH:3][CH:4]=3)[CH:9]=2)[C:13]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Reactant: Cc1ccc(C(=O)Br)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)c4ccc(C)cc4)cc3)ccc2C1=O

Procedure:
The compound of example 318 was prepared analogous to compound of example 304 by reaction of compound of example 223 with 4-methyl benzoyl bromide. The compound of example 318 was used directly without isolation, for the preparation of compound of example 319.
Reaction SMILES: C([O:3][C:4]1[C:5](=O)[CH:6]([C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:8][CH:9]=1)C.O.[NH2:19][NH2:20]>C(O)C>[O:3]=[C:4]1[C:5]2[NH:20][N:19]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]=2[CH2:7][CH2:8][CH2:9]1
Reactant: CCOC(=O)C(=O)C1CCC=C(OCC)C1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1n[nH]c2c1CCCC2=O
Yield: 70 %

Procedure:
1 g (4.2 mmol) of ethyl (3-ethoxy-2-oxocyclohex-3-en-1-yl)(oxo)acetate were dissolved in mL of ethanol, 0.21 mL of hydrazine hydrate were added and the solution stirred at reflux for a day. The solvent was then evaporated and the residue redissolved with dichloromethane. The organic layer was washed with water, dried over Na2SO4 and concentrated. The crude was triturated with diethyl ether and filtered to give (70% yield) the title compound.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[O:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=O)[CH2:13][CH2:12]1>>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:14]1[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[O:11][CH2:12][C:13]2=1
Reactant: NNc1ccc(Br)cc1
Reactant: O=C1CCOc2ccccc21
Agent: Cl
Product: Brc1ccc2[nH]c3c(c2c1)COc1ccccc1-3

Procedure:
Following the procedure described in Example 4, using (4-bromo-phenyl)-hydrazine hydrochloride salt and chroman-4-one (3.0 g, 20 mmol) as the starting material, the title compound was prepared as a brown solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:12][C:13]([CH3:25])([CH3:24])[CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:25][C:13]([NH:12][C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])([CH3:24])[CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22]
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(C)(N)CCNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])c(NC(C)(C)CCNC(=O)OC(C)(C)C)c1

Procedure:
2.0 g (12.9 mmol) 3-fluoro-4-nitro-toluene, 2.6 g (13.0 mmol) tert-butyl (3-amino-3-methyl-butyl)-carbamate and 2.3 g (16.8 mmol) potassium carbonate are stirred overnight at ambient temperature in 20 mL DMF. The solvent is distilled off and the residue is combined with ethyl acetate. The mixture is washed repeatedly with water, dried with sodium sulphate and the solvent is eliminated. 4.8 g yellow oil. Mass spectroscopy: [M+H]+=338.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][N:17]([CH2:20][C:21](O)=[O:22])[C:16]3=[O:24])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Br.[N:28]1[N:29]=[C:30]([NH2:36])[N:31]2[CH2:35][CH2:34][S:33][C:32]=12.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[N:28]1[N:29]=[C:30]([NH:36][C:21](=[O:22])[CH2:20][N:17]2[CH2:18][CH2:19][CH:15]([N:12]3[CH2:13][CH2:14][CH:9]([C:7](=[O:8])[C:6]4[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:10][CH2:11]3)[C:16]2=[O:24])[N:31]2[CH2:35][CH2:34][S:33][C:32]=12
Reactant: COc1ccc(C(=O)C2CCN(C3CCN(CC(=O)O)C3=O)CC2)cc1
Reactant: Nc1nnc2n1CCS2
Agent: Br
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: ClCCl
Product: COc1ccc(C(=O)C2CCN(C3CCN(CC(=O)Nc4nnc5n4CCS5)C3=O)CC2)cc1
Temperature: 25 °C
Reaction time: 45 h
Yield: 34.4 %

Procedure:
A mixture of 500 mg of 76.5% pure 2-(3-(4-(4-methoxybenzoyl)piperidin-1-yl)-2-oxopyrrolidin-1-yl)acetic acid (382 mg, 1.061 mmol) and 5,6-dihydrothiazolo[2,3-c][1,2,4]triazol-3-amine hydrobromide (237 mg, 1.061 mmol) was stirred in diisopropylethylamine (0.741 mL, 549 mg, 4.25 mmol) and dichloromethane (10 mL) before addition of HATU reagent (444 mg, 1.161 mmol). The reaction was stirred over 45 hours at room temperature. A small amount of off-white solid was removed by filtration. The filtrate was eluted through a silica gel column with 0 to 15% methanol/dichloromethane, then 15% to 30%, followed by 30%. The fractions containing contaminated product were concentrated down and eluted through a second silica gel column with 5% to 12% methanol/dichloromethane gradient followed by 12% to afford the title compound (177 mg) as a white solid. Calculated mass for C23H28N6O4S=484.57. HR-MS [m/z, (M+H)+]=485.1956. HPLC retention time=2.73 minutes (Agilent 1100 HPLC system; 3.0×100 nm 3 um C18 column; flow rate of 1.0 mL/min; gradient of 5-95% acetonitrile/water with 0.1% formic acid over 10 minutes). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.06 (br s, 1H), 7.94 (d, J=9.09 Hz, 2H), 7.03 (d, J=8.59 Hz, 2H), 3.92-4.21 (m, 6H), 3.83 (s, 3H), 3.39-3.51 (m, 1H), 3.21-3.37 (m, 3H), 2.99 (d, J=13.14 Hz, 1H), 2.64-2.84 (m, 2H), 2.28-2.42 (m, 1H), 2.03-2.18 (m, 1H), 1.85-2.02 (m, 1H), 1.65-1.78 (m, 2H), 1.44-1.60 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=[N:19]2)=[CH:14][CH:13]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:25]([O:24][C:22]([C:17]1[CH:18]=[N:19][C:20]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([NH:11][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Br:1])[CH:21]=2)=[O:23])[CH3:26]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: CCOC(=O)c1cnc2cc(N)ccc2c1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1cnc2cc(NC(=O)c3ccccc3Br)ccc2c1
Temperature: 25 °C
Yield: 50 %

Procedure:
A solution of 2-bromobenzoyl chloride (5.38 g, 24.5 mmol) in 100 ml chloroform was added dropwise at room temperature to a solution of ethyl 7-aminoquinoline-3-carboxylate (2.65 g, 12.25 mmol), 4-N,N-dimethylaminopyridine (150 mg, 1.23 mmol) and pyridine (3.96 ml, 49 mmol) in 100 ml chloroform. The resulting solution was heated under reflux for 4 hr, then cooled to room temperature. The chloroform solution was then washed sequentially with dilute aqueous hydrochloric acid solution, water and brine, dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue was chromatographed on silica gel, eluting with 60:40 hexane/ethyl acetate to yield the title product as a solid foam (2.45 g 50% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]([C:23]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=O)[CH2:14][CH:13]2[C:31](OC)=[O:32])(=[O:11])=[O:10])=[CH:5][CH:4]=1>O1CCCC1.CO>[OH:32][CH2:31][CH:13]1[N:12]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[N:15]([CH2:23][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:14]1
Reactant: COC(=O)C1CN(C(=O)c2cccnc2)c2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)N2Cc3ccccc3N(Cc3cccnc3)CC2CO)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 65.6 %

Procedure:
A mixture of 0.100 g (0.208 mmol) of methyl 4-(4-methoxybenzenesulfonyl)-1-(3-pyridinylcarbonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate and 3 ml of borane-tetrahydroforan complex in tetrahydrofuran (1.0 M) was refluxed overnight. The solution was cooled to room temperature, diluted with methanol and the solvent removed. Methanol was added several times and, after each addition. the solvent was removed. To the residue was added 1N NaHCO3. The mixture was stirred for 45 minutes and then extracted with ethyl acetate. The extract was concentrated and then washed with H2O, brine and dried with Na2SO4. The solvent was removed under vacuum and the residue chromatographed on thick layer silica gel plates with 10% methanol in ethyl acetate as solvent to give 60 mg of solid (RF 0.26). Crystallization from ethyl acetate gave 30 mg of white crystals. Anal. for C23H25N3O4S: Calc'd: C,62.8; H,5.7; N,9.6; S,7.3; Found: C,61.1; H,5.6; N,9.2; S,7.3; Mass spectrum (ES) 440.2 (M+H).
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:13])[CH2:4][C@H:5]([NH:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:6]O.[C:14](=[S:16])=[S:15].C([O-])([O-])=O.[Cs+].[Cs+]>CC(=O)CC>[CH2:9]([N:8]1[C@@H:5]([CH2:4][CH:3]([CH3:13])[CH3:2])[CH2:6][S:16][C:14]1=[S:15])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)CN[C@H](CO)CC(C)C
Reactant: S=C=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: CC(C)C[C@H]1CSC(=S)N1CC(C)C
Yield: 47.5 %

Procedure:
To a mixture of (2S)4-methyl-2-(isobutylamino)pentan-1-ol HCl salt (Method B4c; 0.21 g, 1.0 mmol) and CS2 (0.30 mL, 5.0 mmol, 5.0 equiv.) in 2-butanone (20 mL) was added Cs2CO3 (0.72 g, 2.20 mmol, 2.2 equiv.) and the resulting mixture was heated at the reflux temp. overnight. The resulting orange solution was concentrated under reduced pressure and the residue was triturated with EtOAc (25 mL). The remaining solids were washed with EtOAc (25 mL), and the combined EtOAc phases were concentrated under reduced pressure. The residue was absorbed onto SiO2 and purified by MPLC (Biotage 40 S silica gel column; 5% EtOAc/hex) to give (4S)-3,4diisobutyl 1,3-thiazolidin-2-thione as a yellow oil (0.11 g, 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][CH2:34][CH2:35][CH:36]1[CH2:40][CH2:39][CH2:38][N:37]1[CH3:41]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:33][CH2:34][CH2:35][CH:36]3[CH2:40][CH2:39][CH2:38][N:37]3[CH3:41])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CN1CCCC1CCN
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN1CCCC1CCNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole), 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for two hours with nitrogen bubbling through it. A solution of 2-(2-aminoethyl)-1-methylpyrrolidine (5.6 g, 0.0435 mole) in tetrahydrofuran (6 ml) was added and the reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere. The solvents were removed under reduced pressure. The resulting solid was triturated in water (200 ml), collected by filtration, rinsed twice with water, twice with 5% potassium hydroxide solution and twice again with water. The solid was dissolved in hot isopropyl alcohol, filtered hot, and water was added. Upon cooling, a solid precipitated. The solid was collected by filtration and air dried to give 4.46 g (64%) of solid. A 0.5-g sample was dried under high vacuum to give 0.40 g of title compound, mp 170°-172° C.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.FC(F)(F)C([O-])=O.[N+:52]([C:55]1[CH:60]=[CH:59][C:58]([S:61](Cl)(=[O:63])=[O:62])=[CH:57][CH:56]=1)([O-:54])=[O:53]>>[N+:52]([C:55]1[CH:60]=[CH:59][C:58]([S:61]([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])(=[O:63])=[O:62])=[CH:57][CH:56]=1)([O-:54])=[O:53]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCCC[C@H](NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 51 %

Procedure:
Nα-tert-butoxycarbonyl-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine was deprotected at the α position by treatment with TFA/CH2Cl2 as described in the procedure outlined in example 24 and the resulting trifluoroacetate salt was alkylated with 4-nitrobenzenesulfonyl chloride as described in example 2, affording the title compound in 51% yield.