Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH2:10][CH3:11])=[CH:4][C:5](Cl)=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1>CN(C=O)C>[Br:1][C:2]1[C:3]([O:9][CH2:10][CH3:11])=[CH:4][C:5]([O:27][CH2:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[N:6][CH:7]=1
Reactant: CCOc1cc(Cl)ncc1Br
Reactant: COc1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1cc(OCc2ccc(OC)cc2)ncc1Br
Temperature: 120 °C
Reaction time: 12 h
Yield: 37.2 %

Procedure:
A mixture of 5-bromo-2-chloro-4-ethoxypyridine (8 g, 33.8 mmol), Cs2CO3 (33.1 g, 101 mmol) and (4-methoxyphenyl)methanol (5.37 g, 38.9 mmol) in DMF (100 mL) was stirred at 120° C. for 12 h. The mixture was then concentrated. The residue was added to DCM (150 mL). The mixture was filtered and the filtrate was concentrated. The crude material was purified by silica column chromatography (PE/EA=8:1). All fractions found to contain product by TLC (PE/EA=5:1, Rf=0.4) were combined and concentrated to yield a yellow solid of 5-bromo-4-ethoxy-2-((4-methoxybenzyl)oxy)pyridine (5 g, 12.57 mmol, 37% yield): 1H NMR (400 MHz, CDCl3) δ: 8.05 (s, 1H), 7.32 (d, J=8.8 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.17 (s, 1H), 5.18 (s, 2H), 4.02 (q, J=6.8 Hz, 2H), 3.74 (s, 3H), 1.40 (t, J=7.2 Hz, 3H); ES-LCMS m/z 338 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=O)=[CH:4][CH:3]=1>ClC1C=CC=CC=1>[CH:6]1[C:5]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:11])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=S(=O)(O)c1ccc(Cl)cc1
Solvent: Clc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
In this improved process, p-chlorobenzene sulfonic acid is partially converted in a counter-current reaction system with monochlorobenzene to form 4,4'-dichlorodiphenyl sulfone. The unconverted sulfonic acid is separated from the crude sulfone product with a minor amount of water and the aqueous acid is dehydrated and then returned to the reaction zone to form additional 4,4'-dichlorodiphenyl sulfone.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:16][CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[Cl:18][C:19]1[CH:20]=[C:21]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:22]=[CH:23][C:24]=1[CH3:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3([CH2:16][CH3:17])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]3=[O:15])[CH2:28][CH2:27]2)[CH:22]=[CH:23][C:24]=1[CH3:25]
Reactant: CCC1(CCCCCl)C(=O)Nc2ccccc21
Reactant: Cc1ccc(N2CCNCC2)cc1Cl
Product: CCC1(CCCCN2CCN(c3ccc(C)c(Cl)c3)CC2)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(3-chloro-4-methyl-phenyl)-piperazine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=O)=[CH:7][CH:6]=1.[CH3:20][C:21]1([CH3:30])[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23](=O)[CH2:22]1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[C:23]2[CH2:24][C:25]([CH3:28])([CH3:27])[CH2:26][C:21]([CH3:30])([CH3:20])[CH2:22]2)[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCO)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(OCCO)cc2)CC(C)(C)C1
Temperature: 25 °C
Yield: 41.5 %

Procedure:
To a stirred suspension of Zn (0.50 g, 7.59 mmol) in THF (10 mL) was added TiCl4 (0.42 mL, 3.79 mmol) dropwise. The mixture was refluxed under nitrogen for 2.5 h. Cooled to room temperature, a solution of 96 (0.245 g, 0.95 mmol) and 3,3,5,5-tetramethylcyclohexanone (0.45 g, 2.85 mmol) in THF (15 mL) was added at once. The reaction mixture was refluxed for another 2.5 h. Cooled to room temperature, the reaction was quenched with 10% K2CO3 (20 mL). The quenched reaction mixture was filtered through a pad of Celite and the pad washed with EtOAc (100 mL). The filtrate was transferred to a separatory funnel, the layers were separated and the aqueous phase was extracted with EtOAc (50 mL). The organic extracts were combined, washed with brine and dried (Na2SO4). Concentration yielded a pale brown oil which was further purified by chromatography on a silica gel column eluted with a gradient from hexanes to 45% EtOAc:hexanes to give a light yellow solid, Crystallization from 7:1 hexanes:EtOAc yielded 97 as colorless needles (0.15 g, 42%). mp 154-155° C. 1H NMR (400 MHz, CD3OD): δ 0.91 (s, 6H), 0.92 (s, 6H), 1.28 (s, 2H), 1.96 (s, 2H), 1.98 (s, 2H), 3.80-3.90 (m, 2H), 4.00-4.10 (m, 2H), 6.67 (d, J=8.5 Hz, 2H), 6.84 (d, J=8.6 Hz, 2H), 6.94 (d, J=8.6 Hz, 2H), 7.03 (d, J=8.6 Hz, 2H). LRMS (ESI): m/z 381 (M+H)+, 379 (M−H)−. The sample was silated prior to EI analysis. HRMS (EI) Calcd for C31H48O3Si2: 524.3142 (M+). Found: 524.3128.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][NH:5]1)#[N:2].C([O-])(O)=O.[Na+].BrBr.C(=O)=O.[C:28]([S-:30])#[N:29].[K+]>CO>[C:1]([C:3]1[S:30][C:28](=[NH:29])[N:5]2[CH2:6][CH2:7][C:8]3[C:13](=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=3)[C:4]=12)#[N:2]
Reactant: COc1cc2c(cc1OC)C(=CC#N)NCC2
Reactant: N#C[S-]
Agent: BrBr
Agent: O=C([O-])O
Agent: O=C=O
Solvent: CO
Product: COc1cc2c(cc1OC)-c1c(C#N)sc(=N)n1CC2
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 86.8 %

Procedure:
57.5 g. (0.25 moles) of 1-cyanomethylene-1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinoline, 21.5 g. (0.255 moles) of sodium hydrocarbonate and 375 ml. of methanol are introduced into a 2 l. flask equipped with a stirrer, reflux condenser, thermometer and addition funnel. The mixture is heated to boiling with stirring, thereafter it is cooled to 60°C, and 40 g. (0.25 moles) of bromine are added dropwise to the solution within 20 minutes. During the addition carbon dioxide evolves and leaves the system. Thereafter the solution is boiled, and a solution of 40 g. (about 0.4 moles) of potassium rhodanide in 300 ml. of methanol is added. The separated precipitate temporarily dissolves, thereafter a loose, voluminous precipitate separates. The mixture is boiled for 1.5 hours, thereafter left to stand in a refrigerator overnight. The precipitate is filtered off, suspended in 500 ml. of water, and 20 ml. of 1 n sodium hydroxide solution are added to the suspension. The precipitate is filtered again, and washed with 3×100 ml. of water. 62.3 g. (86.8 %) of 1-cyano-3-imino-3,4,5,6-tetrahydro-8,9-dimethoxy-1,3-thiazolo[4,3-a]isoquinoline are obtained; m.p.: 229°-230°C (under decomposition).
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([S:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:37].C(=O)([O-])[O-].[NH4+:42].[NH4+]>C(O)C>[ClH:37].[C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([S:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:42])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(SCc1ccc(C#N)cc1)n2C)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(SCc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 78 %

Procedure:
1.5 g (3.0 mMol) of 1-methyl-2-[(4-cyanophenyl)methylthio]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide were stirred in 80 ml of ethanol saturated with hydrogen chloride for 6.5 hours first at 0° C., then at room temperature, until no more starting material could be detected by thin layer chromatography. Then the solvent was distilled off at a maximum bath temperature of 30° C., the oily residue taken up in 80 ml of absolute ethanol and mixed with 1.0 g (10.5 mMol) of ammonium carbonate. After 18 hours the solvent was distilled off in vacuo and the crude product obtained was purified by flash chromatography (silica gel; methylene chloride/ethanol=19:1 to 10:1). Yield: 78% of theory of light beige solid, C28H29N5O3S (515.63) Rf value: 0.19 (silica gel; methylene chloride/ethanol=4:1) ##EQU92##
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[N:12][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N-:26]=[N+:27]=[N-:28].[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>CN(C)C=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[N:12][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:26]=[N+:27]=[N-:28])=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(CCc3ccc(CCl)cc3)nc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(c2ccc(CCc3ccc(CN=[N+]=[N-])cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
To a solution of 1-acetyl-4-(6-{2-[4-(chloromethyl)phenyl]ethyl}pyridin-3-yl)piperazine (234.8 mg, 0.656 mmol) in anhydrous N,N-dimethylformamide (5 ml) was added sodium azide (426.5 mg, 6.561 mmol), and the mixture was stirred at room temperature for 16 hrs. Aqueous sodium carbonate solution and ethyl acetate were added to the reaction mixture. The mixture was stirred, stood still and partitioned. The organic layer was dried over anhydrous magnesium sulfate, and concentrated to dryness to give 1-acetyl-4-(6-{2-[4-(azidomethyl)phenyl]ethyl}pyridin-3-yl)piperazine (226.8 mg, yield 94.9%) as a slightly yellow solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[CH2:6][C:7](=[NH:9])[NH2:8])[CH3:3].C([O-])C.[Na+].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=O>C(O)C>[NH2:9][C:7]1[NH:8][C:17]([C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[CH:16][C:6]=1[C:5]([O:4][CH2:2][CH3:3])=[O:10]
Reactant: CCOC(=O)CC(=N)N
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)[nH]c1N
Reaction time: 48 h

Procedure:
In a dry three-necked flask, under argon, 75 ml of abs. ethanol and 6.5 g (390 mmol) of 2-amidino-acetic acid ethyl ester hydrochloride [for preparation see: Liebigs Ann. Chem., 1895 (1977)] are cooled to 0-5° C. and 2.65 g (390 mmol) of sodium ethanolate are added thereto. Then 5 g (195 mmol) of 2-bromo-1-(4-nitro-phenyl)-ethan-1-one are added and the reaction mixture is allowed to come to RT and then stirred for 48 hours. The reaction mixture is then partitioned between water and ethyl acetate. The ethyl acetate phase is washed three times with water and once with saturated NaCl solution, dried and filtered and the filtrate is concentrated by evaporation. The red-brown residue is suspended in hexane and the title compound precipitates in the form of the crude product (purity 93%), which is used for the next step without further purification; MS: (M)+ =275.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)([O-])=O.O.[NH2:17]N>C(O)C.[Pd].C(OCC)(=O)C>[N:10]1([C:5]2[CH:6]=[CH:7][C:8]([NH2:17])=[CH:9][CH:4]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: NN
Reactant: O=[N+]([O-])c1ccccc1N1CCOCC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(N2CCOCC2)cc1
Reaction time: 12 h

Procedure:
To a stirred solution of Intermediate 4 (3.2 g) in ethanol (60 ml) were added hydrazine hydrate (3.71 ml) and palladium on charcoal (5%, 0.1 g). The reaction was stirred for 12 h, before being diluted with ethyl acetate (60 ml). The reaction was extracted with aqueous citric acid (5%, 4×15 ml), and the combined aqueous extracts neutralised with sodium bicarbonate. The aqueous was extracted with ethyl acetate (3 ×15 ml), and the combined organic extracts washed with brine (50 ml), dried over magnesium sulphate (2 g) and the solvent removed in vacuo to yield the title compound as a light brown oil (1.16 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:22]([N:29]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[C:35](=O)[O:34][CH2:33]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(COC)OC.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:35]1[C:36]2[C:32](=[CH:31][C:30]([N:29]([CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:38][CH:37]=2)[CH2:33][O:34]1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: O=C1OCc2cc(N(Cc3ccccc3)Cc3ccccc3)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C1=C1OCc2cc(N(Cc3ccccc3)Cc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.5 %

Procedure:
To a solution of 5-chlorooxindole (63 mg, 0.371 mmol) in dimethoxyethane (2.0 ml) at room temperature was added 1.0M LiHMDS in THF (742 μl). After the mixture was stirred for 10 minutes at room temperature, 5-dibenzylamino-3H-isobenzofuran-1-one (110 mg, 0.334 mmol) was added, and the reaction was rapidly stirred at room temperature for 1.5 hours. The mixture was quenched into 4% HCl (20 ml), and then stirred with EtOAc. The mixture was basified with saturated NaHCO3 aqueous solution. The organic layer was diluted with MeOH, followed by addition of HCl in MeOH to give a yellow precipitant. The yellow precipitant was separated, and rinsed with MeOH and 20% EtOAc/hexane to yield 5-chloro-3-(5-dibenzylamino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one as a yellow solid (36 mg, 23%).
Reaction SMILES: C([C@H]1C2=NC=C(C(O)=O)C=C2CN1CC1C=CC(C(F)(F)F)=CC=1)(C)C.[CH:27]([C@H:30]1[C:34]2=[N:35][CH:36]=[C:37]([C:39]([NH:41][CH2:42][C:43]3[CH:52]=[CH:51][C:46]([C:47]([O:49]C)=[O:48])=[CH:45][CH:44]=3)=[O:40])[CH:38]=[C:33]2[CH2:32][N:31]1[CH2:53][C:54]1[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:56][CH:55]=1)([CH3:29])[CH3:28]>>[CH:27]([C@H:30]1[C:34]2=[N:35][CH:36]=[C:37]([C:39]([NH:41][CH2:42][C:43]3[CH:52]=[CH:51][C:46]([C:47]([OH:49])=[O:48])=[CH:45][CH:44]=3)=[O:40])[CH:38]=[C:33]2[CH2:32][N:31]1[CH2:53][C:54]1[CH:55]=[CH:56][C:57]([C:60]([F:62])([F:63])[F:61])=[CH:58][CH:59]=1)([CH3:29])[CH3:28]
Reactant: COC(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(Cc2ccc(C(F)(F)F)cc2)[C@H]3C(C)C)cc1
Agent: CC(C)[C@H]1c2ncc(C(=O)O)cc2CN1Cc1ccc(C(F)(F)F)cc1
Product: CC(C)[C@H]1c2ncc(C(=O)NCc3ccc(C(=O)O)cc3)cc2CN1Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.03 h

Procedure:
Procedure same as that for (S)-7-isopropyl-6-(4-(trifluoromethyl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylic acid, using methyl(S)-4-((7-isopropyl-6-(4-(trifluoromethyl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamido)methyl)benzoate as a starting material. LC-MS tR=1.20 min in 2 min chromatography, MS (ESI) m/z 498 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[S-:10][C:11]#[N:12].[Na+].BrBr.C(=O)(O)[O-].[Na+]>CO>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([S:10][C:11]#[N:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#C[S-]
Reactant: N#Cc1ccccc1N
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N#CSc1ccc(N)c(C#N)c1
Yield: 70.9 %

Procedure:
To a solution of 2-aminobenzonitrile (4.00 g (33.9 mmol)) and sodium thiocyanate (3.00 g (37.0 mmol)) in methanol (20 ml), a solution of bromine (5.50 g (34.4 mmol)) in methanol (5.0 ml) was added dropwise over a period of 40 minutes under cooling with ice and with stirring. The mixture was then stirred under cooling with ice for 30 mitutes, and then neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography with chloroform as eluent to give 4.21 g (71%) of 2-amino-5-thiocyanobenzonitrile as pale yellow-white crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C@@H:12]1([NH2:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH:22][C@@H:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1)([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: N[C@H]1CCCc2ccccc21
Product: O=[N+]([O-])c1cccc(CN[C@H]2CCCc3ccccc32)c1

Procedure:
3-Nitrobenzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].[CH3:29][C:30]1([CH3:38])[O:34][C@@H:33]([CH2:35][O:36][NH2:37])[CH2:32][O:31]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([NH:37][O:36][CH2:35][C@H:33]1[CH2:32][O:31][C:30]([CH3:38])([CH3:29])[O:34]1)=[O:21]
Reactant: Cn1c(Nc2ccc(I)cc2Cl)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Reactant: CC1(C)OC[C@H](CON)O1
Solvent: C1CCOC1
Product: Cn1c(Nc2ccc(I)cc2Cl)c(C(=O)NOC[C@H]2COC(C)(C)O2)c(=O)n(C)c1=O
Yield: 42.2 %

Procedure:
Phenyl 6-(2-chloro-4-iodophenylamino)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 23, 300 mg, 0.588 mmol, 1 eq) and (R)-O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (260 mg, 1.826 mmol, 3 eq) were mixed in anhydrous THF (1.5 ml). The mixture was subjected to microwave irradiation at 100° C. for 50 minutes. The intended product was isolated by HPLC purification to give 140 mg of white solid (42%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (s, 3 H) 1.46 (s, 3 H) 3.04 (s, 3H) 3.38 (s, 3H) 3.85-3.8758 (m, J=8 Hz, 1 H) 4.03-4.05 (d, J=8 Hz, 2 H) 4.10-4.11 (t, J=4 Hz, 1 H) 6.70-6.72 (d, J=8 Hz, 1H) 7.56-7.58 (d, J=8 Hz,1 H) 7.82 (s, 1 H) 12.07 (s, 1 H) 12.79 (s, 1 H) [M+H] calc'd for C19H22ClIN4O6, 565; found, 565.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[C:8]1([SH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:15][C:16]1[CH:21]=[C:20](Cl)[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24]>O>[NH2:15][C:16]1[CH:21]=[C:20]([S:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Sc2ccccc2)ccc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
2.53 G. 57% sodium hydride in oil suspension in 20 ml. dimethylformamide is treated with 6.2 ml. thiophenol under nitrogen. 5.0 G. 2-amino-4-chloro-1-nitrobenzene is added and the mixture stirred for three hours. Water is added and the product filtered off and washed with water and hexane. Recrystallization from methanol gives pure 2-amino-4-phenylthio-1-nitrobenzene.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH2:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([C@H:23]([CH2:27][CH3:28])[C:24](O)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:24](=[O:25])[C@@H:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:27][CH3:28])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](C(=O)O)c1ccccc1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Product: CC[C@@H](C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 33 for (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine and substituting (R)-2-phenylbutanoic acid for (S)-2-phenylbutanoic acid in Step F of the procedure used to prepare Example 16: 1H NMR (500 MHz, CDCl3) δ ppm 7.38-7.21 (m, 10H), 5.29 (d, J=6.9, 1H), 4.04-3.90 (m, 1H), 3.65 (d, J=12.9, 1H), 3.52 (d, J=12.9, 1H), 3.15 (t, J=7.6, 1H), 2.68 (t, J=8.6, 1H), 2.64-2.48 (m, J=8.5, 3H), 2.30-2.22 (m, J=3.7, 8.3, 1.5H), 2.14 (ddd, J=7.4, 13.9, 19.9, 1.5H), 1.93 (dt, J=6.2, 12.5, 1H), 1.84-1.62 (m, J=7.6, 14.5, 20.6, 2H), 1.45-1.27 (m, 2H), 0.95-0.80 (m, 4H); MS (ESI+) m/z 363 (M+H)+.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][C:17]2([O:24][CH2:23][CH2:22][O:21]2)[C@@:16]1([CH3:31])[CH2:25][CH2:26][CH2:27][CH:28]([OH:30])[CH3:29])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl.CCOCC.[O-2].[O-2].[O-2].[Cr+6]>[CH2:7]([O:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][C:17]2([O:21][CH2:22][CH2:23][O:24]2)[C@@:16]1([CH3:31])[CH2:25][CH2:26][CH2:27][C:28](=[O:30])[CH3:29])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(O)CCC[C@@]1(C)[C@H](OCc2ccccc2)CCCC12OCCO2
Agent: [Cr+6]
Agent: [O-2]
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)CCC[C@@]1(C)[C@H](OCc2ccccc2)CCCC12OCCO2
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 61.2 %

Procedure:
A solution of pyridine (70.3 g, 0.89 mol) and chromium trioxide (44.5 g, 0.445 mol) in methylene chloride (1.8 l) in a nitrogen atmosphere is stirred for 45 minutes. Celite (180 g) is added followed by (2S*,3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-hydroxypentyl)-cyclohexane (25.8 g, 0.074 mol) in methylene chloride (100 ml). The mixture is stirred for 90 minutes at 23° C. The mixture is then filtered and the celite cake is washed with methylene chloride (10×200 ml). The filtrate and washings are combined and the solvents are removed under reduced pressure to give a dark oil, which is diluted with ether (750 ml) and filtered. The ether phase is dried (MgSO4) and the solvents are removed at reduced pressure. The crude product (21 g) is chromatographed on SilicAR CC-7 (300 g, Mallinckrodt) in hexane. Elution with 6% ethyl acetate/hexane gives (2S*,3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-oxopentyl)-cyclohexane as a clear colorless oil (15.7 g, 61%): ir (neat) 1712 cm-1 (CO); nmr (CDCl3)δ1.106 (s, 3H, -CH3), 2.04 ##STR30## 2.30 (m, 2H, -CH2 -CO), 3.50 ##STR31## 3.98 (s, 4H, ketal), 4.55 (d of d, J=10 Hz, 2H, -O-CH2Ph), 7.20 (s, 5H, aromatic).
Reaction SMILES: [C:1]([CH2:4][NH:5][C:6]([NH:8][CH2:9][C:10]1[CH:28]=[CH:27][C:13]([C:14]([N:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:12][C:11]=1[CH3:29])=[O:7])([OH:3])=[O:2].[CH3:30]N(C=O)C.C(Cl)(=O)C(Cl)=O>ClCCl>[CH3:30][O:2][C:1](=[O:3])[CH2:4][NH:5][C:6]([NH:8][CH2:9][C:10]1[CH:28]=[CH:27][C:13]([C:14]([N:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:12][C:11]=1[CH3:29])=[O:7]
Reactant: CN(C)C=O
Reactant: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)NCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)CNC(=O)NCc1ccc(C(=O)N2CCCCc3ccccc32)cc1C
Reaction time: 2 h

Procedure:
To a solution of the carboxylic acid from Example 33 (0.080 g, 0.20 mmol) under a nitrogen atmosphere in dichloromethane (25 ml) at 0° C. were added DMF (20 □l) and oxalyl chloride (31 mg, 0.24 mmol). The mixture was stirred at 0° C. to room temperature for 2 h and then concentrated in vacuo. The residue was dissolved in methanol (4 ml) and dichloromethane (16 ml) and the mixture stirred at room temperature for 16 h. The mixture was then washed with 1M KHSO4 (3 times), saturated sodium bicarbonate solution (3 times) and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant dichloromethane:methanol 96:4) to give a white solid; yield 0.049 g (60%).