Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=7)=[C:24]([C:34]([NH:36][CH3:37])=[O:35])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.[C:45]([O:49][CH2:50][CH3:51])(=[O:48])[CH:46]=[O:47]>>[F:1][C:2]1[C:3]2[C:4]([CH:46]([OH:47])[C:45]([O:49][CH2:50][CH3:51])=[O:48])=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=7)=[C:24]([C:34](=[O:35])[NH:36][CH3:37])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Reactant: CCOC(=O)C=O
Product: CCOC(=O)C(O)c1c2n(c3cccc(F)c13)COc1ccc(-c3cc4c(C(=O)NC)c(-c5ccc(F)cc5)oc4cc3N(C)S(C)(=O)=O)nc1-2
Temperature: 115 °C

Procedure:
A mixture of 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (500 mg, 0.814 mmol) and ethyl glyoxalate (323 μl, 1.627 mmol) was heated at 115° C. for 3 hours in a sealed tube. The reaction mixture was cooled to room temperature, concentrated under vacuum then applied onto 2-EP column (30 mm×250 mm) eluted with 30% IPA/CO2. This resulted in 108 mg (18.5%) of ethyl 2-(11-fluoro-2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-12-yl)-2-hydroxyacetate (Compound 206) as a white solid. LC-MS (ES, m/z) C36H30F2N4O8S: 716. Found: 717 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:16]([OH:18])=O)=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][N:25]=1>>[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[N:25]=[CH:26][C:27]([NH:30][C:16]([C:9]2[O:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:11][C:10]=2[C:12]([F:13])([F:14])[F:15])=[O:18])=[CH:28][CH:29]=1
Reactant: COCCN(C)c1ccc(N)cn1
Reactant: O=C(O)c1oc(-c2ccccc2)nc1C(F)(F)F
Product: COCCN(C)c1ccc(NC(=O)c2oc(-c3ccccc3)nc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 1 above, 2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C20H19F3N4O3 (m/e) 420, obsd 421 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][CH2:7][CH2:6]2.[Br:15][CH2:16][C:17](Cl)=[O:18].C([O-])([O-])=O.[K+].[K+].O>C(Cl)Cl>[Br:15][CH2:16][C:17]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:6][CH2:7]1)=[O:18]
Reactant: O=C(Cl)CBr
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CBr)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
A solution of 5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (33.6 g, 173 mmol) in CH.2Cl2 (150 mL) was added dropwise to a mixture of bromoacetylchloride (54.5 g, 346 mmol) and K2CO3 (53.0 g, 381 mmol) in CH2Cl2 (150 mL). The resulting solution was stirred at 0° C. for 1 hour, then warmed up RT for 4 hours. Water (150 mL) was added and the mixture was extracted with CH2Cl2 (2×100 mL). The organic phase was dried over Na2SO4, the solvent was removed to yield the 1-(bromoacetyl)-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (54.2 g, 99%). 1HNMR (400 MHz, DMSO) δ ppm 2.47(s, 2H), 3.25 (m, 2 H), 3.87 (s, 3 H), 4.21 (m, 2 H), 7.34 (s, 1 H), 8.42 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=O.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[N:18]1([C:11]2[C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: C1CNCCN1
Reactant: Nc1ccccc1Sc1ccccc1C(=O)O
Product: c1ccc2c(c1)N=C(N1CCNCC1)c1ccccc1S2

Procedure:
Next, 2-(2-aminophenylthio)benzoic acid which is expressed by the above Formula 7 is simultaneously subjected to cyclization and chlorination reactions in the presence of a equivalent amount of halogenating agent and base in an organic solvent, and then reacted with piperazine without separation, to produce 11-piperazinyl-dibenzo[b,f][1,4]thiazepine expressed by the above Formula 4.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH:14]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C@@H:19]1([NH2:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH2:14][NH:29][C@@H:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21][CH2:20]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccc(Sc2ccc([N+](=O)[O-])cc2)c1
Reactant: N[C@H]1CCCc2ccccc21
Product: O=[N+]([O-])c1ccc(Sc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
The product from Example 73A and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][N:16]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36])[C:17]([CH:19]1[C:24](=O)[C@:23]2([CH3:29])[C:26]([CH3:28])([CH3:27])[C@H:20]1[CH2:21][CH2:22]2)=[O:18])=O)(C)(C)C>ClCCl>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[N:16]1[C:17](=[O:18])[C:19]2[C@H:20]3[C:26]([CH3:28])([CH3:27])[C@:23]([CH3:29])([CH2:22][CH2:21]3)[C:24]=2[NH:15]1
Reactant: CC(C)(C)OC(=O)NN(C(=O)C1C(=O)[C@@]2(C)CC[C@@H]1C2(C)C)c1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccccc3Cl)c(=O)c12
Temperature: 25 °C
Reaction time: 19 h
Yield: 87 %

Procedure:
Trifluoroacetic acid (5 mL) was added slowly to a solution of N′-(2-chloro-phenyl)-N′-((1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (1.26 g, 3.0 mmol) in dichloromethane (5 mL), and the resulting solution was stirred at room temperature for 19 h. The solvent was evaporated and dichloromethane (100 mL) was added. The solution was washed with water (2×50 mL) and brine (50 mL), dried (sodium sulfate), filtered, and evaporated to give a light yellow solid. The solid was stored in the freezer over the weekend, and then triturated with 50% hexanes/diethyl ether (10 mL) and the mixture sonicated. The solid was collected by filtration, washed with ether, an air-dried to give (4R,7S)-2-(2-chloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (790 mg, 86%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[Cl-].O[NH3+:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:13]
Reactant: [NH3+]O
Reactant: O=Cc1ccc(O)c(Cl)c1
Agent: [Cl-]
Product: N#Cc1ccc(O)c(Cl)c1

Procedure:
The title compound was prepared from 3-chloro-4-hydroxybenzaldehyde and hydroxyl ammonium chloride, using the same method as that described for preparation 70. The title compound was purified by column chromatography on silica gel, eluting with pentane:ethyl acetate, 100:0 to 90:10, to afford the title compound as a white solid in 76% yield.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[N:2].Cl[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]>C(O)C>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: N#Cc1ccc(N)cc1
Solvent: CCO
Product: N#Cc1ccc(Nc2ccncc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.6 %

Procedure:
According to the method of J.C.S. Perkin Trans. I, 1979, 135, p-cyanoaniIine (6 894 g, 58.4 mmol) was added to a solution of 4-chloro-3-nitropyridine (9.26 g, 58.4 mmol) in ethanol (200 ml) and the mixture was stirred at room temperature for 18 hours. The resulting yellow suspension was poured into 500 ml of ice-cold dilute ammonia and filtered The solid was treated with 150 ml of boiling ethanol, cooled in ice, and filtered to give the title compound as a bright yellow powder, (12.15 g), m.p. 210°-211° C.
Reaction SMILES: [CH:1]1([C:4]2[C:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[CH:24][CH:23]=[N:22]4)=[CH:17][CH:16]=3)=[C:12]([CH3:26])[C:11]3[C:10]([OH:27])=[CH:9][CH:8]=[C:7]([F:28])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH2:41][C:42]([O:44][CH3:45])=[O:43]>O>[CH3:45][O:44][C:42](=[O:43])[CH2:41][O:27][C:10]1[CH:9]=[CH:8][C:7]([F:28])=[C:6]2[C:11]=1[C:12]([CH3:26])=[C:13]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=1)[C:4]([CH:1]1[CH2:2][CH2:3]1)=[N:5]2
Reactant: COC(=O)CBr
Reactant: Cc1c(Cc2ccc(-n3cccn3)cc2)c(C2CC2)nc2c(F)ccc(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(F)c2nc(C3CC3)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-cyclopropyl-8-fluoro-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-ol (0.040 g), potassium carbonate (0.044 g) and N,N-dimethylformamide (0.21 mL) was treated with methyl bromoacetate (0.011 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (30 mL), extracted with ethyl acetate (3×10 mL), and the combined extracts were dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 3:2 by volume) to afford the title compound as a yellow oil (0.034 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([N+:19]([O-])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:10]([NH2:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccccc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: NC1CN(Cc2ccccc2)CC1c1ccccc1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
To a stirred solution of rac-(3S,4R)-1-benzyl-3-nitro-4-phenyl-pyrrolidine (1.0 g, 3.54 mmol) in EtOAc (50 ml) was added in one portion SnCl2.2H2O (3.99 g, 17.70 mmol). The reaction mixture was then heated at reflux for 2 hours, cooled down to RT and a saturated aqueous solution of NaHCO3 (100 ml) was added. The salts were filtered off and the product extracted with EtOAc. The organic phases were then dried over Na2SO4, and concentration under vacuum gave 0.72 g (80%) of rac-(3S,4R)-1-benzyl-4-phenyl-pyrrolidin-3-ylamine as a light yellow oil. The product was then used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:39])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[C:42]1[CH:43]=[CH:44][C:45]([N+:48]([O-:50])=[O:49])=[N:46][CH:47]=1>>[C:1]([O:5][C:6](=[O:40])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:39])[C:16]2[CH:17]=[C:18]([O:23][C:24]3[CH:25]=[CH:26][C:27]([CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:28][CH:29]=3)[CH:19]=[C:20]([O:22][C:42]3[CH:47]=[N:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=3)[CH:21]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Oc2cc(O)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)cc1
Product: CC(C)(C)OC(=O)NCc1ccc(Oc2cc(Oc3ccc([N+](=O)[O-])nc3)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)cc1
Yield: 61.5 %

Procedure:
Following the procedure of Example 69(b) (4-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-hydroxy-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester 0.4 g (0.72 mmol) and 5-bromo-2-nitro-pyridine (0.17 g, 0.86 mmol) were used to afford 0.3 g of the required product. 1H NMR (DMSO-d6): δ 1.31 (18H, d), 1.8 (4H, d), 3.20 (2H, m), 3.8 (2H, m), 4.1 (2H, d), 7.35 (3H, d), 7.4 (3H, m), 7.9 (1H, d), 8.35 (2H, d), 8.5 (1H, s).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:6][CH:5]=1.I[CH2:21][CH2:22][CH2:23][CH3:24].Cl>CN(C=O)C>[CH2:21]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[C:11]1[CH2:10][C:7]1[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][CH:6]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCI
Reactant: Brc1ccc(Cc2cc3ccccc3[nH]2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1c(Cc2ccc(Br)cc2)cc2ccccc21
Reaction time: 0.17 h

Procedure:
A mixture of sodium hydride (0.32 g) in DMF (50 ml) was cooled in an ice bath. A solution of 2-(p-bromophenylmethyl)-indole (2.0 g), prepared, e.g., as described in Preparation 3, in DMF, was added, and the mixture stirred for 10 minutes. 1-Iodobutane (0.9 ml) in DMF was added dropwise, and the mixture stirred for 30 minutes. It was then poured into cold dilute HCl and extracted with ether. The extract was washed three times with cold water, dried over magnesium sulphate, and the solvent evaporated to afford an orange-red oil, 1-(n-butyl)-2-(p-bromophenylmethyl)indole (2.5 g), a compound of Formula (H).
Reaction SMILES: [CH:1]([C:3]1[C:9](=[O:10])[C:8]([OH:11])=[CH:7][C:6]([CH:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1)=[O:2].[CH2:15]([Li])[CH2:16][CH2:17]C>O1CCCC1.CCCCCC>[OH:2][CH:1]([C:3]1[C:9](=[O:10])[C:8]([OH:11])=[CH:7][C:6]([CH:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1)[CH2:15][CH2:16][CH3:17]
Reactant: [Li]CCCC
Reactant: CC(C)c1ccc(C=O)c(=O)c(O)c1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(C(C)C)cc(O)c1=O
Temperature: -78 °C

Procedure:
7-formyl-4-isopropyl-2-hydroxy-2,4,6-cycloheptatrien-1-one (1.95 g, 10 mmol) was dissolved in tetrahydrofuran (30 ml) and the resultant was cooled to -78° C. in a dry ice/acetone bath. A solution of n-butyllithium in hexane (1.6M, 14 ml) was added dropwise to the solution, then, the dry ice/acetone bath was removed and the resultant was stirred until insoluble matter was dissolved. An aqueous saturated ammonium chloride was added to the reaction mixture and the resultant was extracted with methylene chloride. The methylene chloride layer was washed with water, then dried over anhydrous sodium sulfate. Solvent was distilled off to give 2.72 g of 7-(α-hydroxybutyl)-4-isopropyl-2-hydroxy-2,4,6-cycloheptatrien-1-one as a reddish brown oil (yield: quantitative).
Reaction SMILES: C([NH:4][C:5]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH:13]=2)[N:8]([CH3:30])[C:7](=[O:31])[C:6]=1[C:32]([O:34]C)=O)(=O)C.[NH3:36]>C1COCC1.CO>[NH2:4][C:5]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])=[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[CH:13]=2)[N:8]([CH3:30])[C:7](=[O:31])[C:6]=1[C:32]([NH2:36])=[O:34]
Reactant: COC(=O)c1c(NC(C)=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(=O)c(C(N)=O)c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To the product of EXAMPLE 91 (30 mg) in THF (1 mL) was added 3 mL of NH3 in methanol (7 M). The reaction stirred for about 15 hours at room temperature before it was concentrated. The residue was dissolved in CH2Cl2 and washed with water. The solution was dried (Na2SO4) and concentrated. The concentrated residue was purified by preparative TLC on silica gel eluted with 100% EtOAc affording the title compound. HPLC/MS: 473.0 (M+1), 475.0 (M+3); Rt=4.19 min.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([N+:19]([O-])=O)=[C:14]([CH:18]=2)[C:15]([NH2:17])=[O:16])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])=O.[NH4+]>C(O)C.O.[Pd]>[NH2:19][C:13]1[CH:12]=[CH:11][C:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])=[CH:18][C:14]=1[C:15]([NH2:17])=[O:16]
Reactant: NC(=O)c1cc(S(=O)(=O)c2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: NC(=O)c1cc(S(=O)(=O)c2ccccc2)ccc1N
Temperature: 25 °C
Yield: 66 %

Procedure:
5-Benzenesulfonyl-2-nitro-benzamide (3.13 g, 10.23 mmol) was suspended in absolute ethanol (200 mL), treated with 10% Pd/C (1.5 g) and then with ammonium formate (9.7 g, 153 mmol). The mixture was stirred at reflux. After a couple of hours the reaction was complete. After cooling to room temperature the reaction was filtered over celite and the panel was washed with EtOH. Evaporation of the filtrate left the crude product that was taken up with a small amount of methanol and added dropwise to 400 mL of iced water kept under stirring. The solid thus formed was filtered and washed with water affording 1.87 g of title compound (66% yield).
Reaction SMILES: C(N[C:4]([NH:9][CH2:10][C:11]#C)=[N:5][CH2:6][CH2:7]S)#N.[C:13]([NH:15][C:16]([NH:21][CH2:22][C:23]#[C:24][CH3:25])=[N:17][CH2:18][CH2:19][SH:20])#[N:14]>>[C:13]([NH:15][C:16]([NH:17][CH2:18][CH2:19][S:20][CH2:11][C:10]1[NH:9][CH:4]=[N:5][C:6]=1[CH3:7])=[N:21][CH2:22][C:23]#[C:24][CH3:25])#[N:14]
Reactant: CC#CCNC(=NCCS)NC#N
Reactant: C#CCNC(=NCCS)NC#N
Product: CC#CCN=C(NC#N)NCCSCc1[nH]cnc1C

Procedure:
The general procedure of Example 1C is repeated except that the N-cyano-N'-propargyl-N"-(2-mercaptoethyl)guanidine utilized therein is replaced by an equimolar amount of N-cyano-N'-(2-butyn-1-yl)-N"-(2-mercaptoethyl)guanidine, and the title product is thereby produced.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[C:5]([CH:6]=[O:7])=[C:4]([OH:11])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>CN(C=O)C>[Cl:10][C:8]1[CH:9]=[C:2]([Cl:1])[CH:3]=[C:4]([O:11][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([F:18])=[CH:20][CH:21]=2)[C:5]=1[CH:6]=[O:7]
Reactant: Fc1ccc(CBr)cc1
Reactant: O=Cc1c(O)cc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1c(Cl)cc(Cl)cc1OCc1ccc(F)cc1
Temperature: 70 °C
Reaction time: 3.5 h

Procedure:
A solution of 13.77 g (72.5 mmol) of 4,6-dichloro-2-hydroxybenzaldehyde in 100 ml of DMF was stirred and 12.02 g (87 mmol) of K2CO3 was added. This mixture was heated to ~70° C. for 60 minutes, then 11.7 ml of 4-fluorobenzyl bromide was added. The resulting solution was stirred at 70° C. for 3.5 hours, then this was poured onto ice H2O (1.5 1), filtered and washed with H2O, and recrystallized from Et2O/petroleum ether. Yield: 17.88 g (83%) of off-white crystals, m.p. 107°-108° C.
Reaction SMILES: [F:1][CH2:2][C@H:3]1[CH2:7][N:6]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[C:5](=[O:16])[C@@:4]1([CH3:22])[C:17]([O:19]CC)=[O:18].[OH-].[Na+].O>C(O)C>[F:1][CH2:2][C@H:3]1[CH2:7][N:6]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[C:5](=[O:16])[C@@:4]1([CH3:22])[C:17]([OH:19])=[O:18]
Reactant: CCOC(=O)[C@]1(C)C(=O)N([C@H](C)c2ccccc2)C[C@@H]1CF
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@H](c1ccccc1)N1C[C@H](CF)[C@](C)(C(=O)O)C1=O
Reaction time: 0.5 h

Procedure:
To a solution of ethyl (3S,4R)-4-fluoromethyl-3-methyl-2-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (20.0 g, 65.1 mmol) in ethanol (400 mL), 10 mol/l aqueous solution of sodium hydroxide (65.1 mL, 651 mmol) was added dropwise, and the mixture was stirred for 30 minutes. Water (400 mL) was added to the reaction mixture in an ice bath, and the aqueous solution was washed with diethylether (500 mL). Concentrated hydrochloric acid was added to the aqueous layer in an ice bath to pH 2 to 3, and the mixture was extracted with chloroform (500 mL×3). The organic layer was dried with anhydrous sodium sulfate, and after filtration, the filtrate was concentrated under reduced pressure. The concentrate was azeotropically distilled by adding toluene (20 mL), and dried under reduced pressure to obtain 19.16 g (quantitative) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:7][O:6][C:5]([CH2:15][S:16][CH2:17][C:18]([O:20]CC)=[O:19])([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[O:4][CH2:3]1.[Li+].[OH-]>C1COCC1.O>[CH3:1][C:2]1([CH3:23])[CH2:7][O:6][C:5]([CH2:15][S:16][CH2:17][C:18]([OH:20])=[O:19])([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[O:4][CH2:3]1
Reactant: CCOC(=O)CSCC1(c2ccc(C)cc2)OCC(C)(C)CO1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C2(CSCC(=O)O)OCC(C)(C)CO2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
Ethyl ({[5,5-dimethyl-2-(4-methylphenyl)-1,3-dioxan-2-yl]methyl}thio)acetate (10.1 g, 29.8 mmol) was dissolved in THF (150 ml) and cooled to 0° C. LiOH (3.76 g, 89.5 mmol) in water (50 ml) was added and the mixture was stirred for two hours at room temperature. The mixture was concentrated under reduced pressure. Water was added and the mixture was extracted with diethyl ether. The aqueous layer was acidified using 2M HCl to pH 3 and extracted twice with CH2Cl2. The combined CH2Cl2 layers were dried (Na2SO4) and concentrated under reduced pressure to afford 8.7 g (94%) of the title compound as a white solid. 1H-NMR(CDCl3, 200 MHz): δ 0.6 (s, 3H), 1.2 (s, 3H), 2.4 (s, 3H), 3.0 (s, 2H), 3.4 (s, 2H), 3.4 (s, 4H), 7.2-7.4 (m. 4H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:43]=[CH:42][C:16]([CH2:17][N:18]([C:33](=[O:41])[CH2:34][CH2:35][CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:19]3[C:28]4[CH:27]=[C:26]([C:29]([O:31]C)=[O:30])[CH:25]=[CH:24][C:23]=4[CH2:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].O[Li].O>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:43]=[CH:42][C:16]([CH2:17][N:18]([C:33](=[O:41])[CH2:34][CH2:35][CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:19]3[C:28]4[CH:27]=[C:26]([C:29]([OH:31])=[O:30])[CH:25]=[CH:24][C:23]=4[CH2:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(C(=O)CCC3CCCC3)C3CCCc4ccc(C(=O)OC)cc43)cc2)cc1
Agent: [Li]O
Solvent: O
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)CCC3CCCC3)C3CCCc4ccc(C(=O)O)cc43)cc2)cc1

Procedure:
The titled compound was prepared following the procedure F using methyl 8-[{4-[(4-butylphenyl)ethynyl]benzyl}(3-cyclopentylpropanoyl)amino]-5,6,7,8-tetrahydro-2-naphthalenecarboxylate and LiOH.H2O, as a white solid (94%). 1H NMR (MeOD, 300 MHz) δ 7.80 (m, 1H), 7.71 (d, J=5.5 Hz. 1H), 7.47 (d, J=7.5 Hz, 1H), 7.38 (m, 3H), 7.18 (m, 5H), 5.94 (m, 0.5H), 5.30 (m, 0.5H), 4.80 (m, 1H), 4.63 (d, J=18.3 Hz, 0.5H), 4.21 (d, J=18.3 Hz, 0.5H), 2.81 (m, 2H), 2.62 (m, 2H), 2.45 (m, 1H), 2.27 (m, 1H), 2.10-1.06 (m, 19H), 0.93 (t, J=7.2 Hz, 3H). M− (ESI): 560.3; M+ (ESI): 562.2. HPLC, Rt: 5.97 min (Purity: 99.2%).