Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([C:9]([NH:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17]([OH:19])=[O:18])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[C:1]([C:5]1[CH:21]=[CH:20][C:8]([C:9]2[O:18][C:17](=[O:19])[C:13]3[S:14][CH:15]=[CH:16][C:12]=3[N:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccsc2C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2nc3ccsc3c(=O)o2)cc1
Reaction time: 2 h
Yield: 96.6 %

Procedure:
A solution of 3-(4-tert-butylbenzoyl)amino-2-thiophenecarboxylic acid (8.1 g, 27 mmol) in methylene chloride (135 mL) was treated with oxalyl chloride (11.8 mL, 135 mmol). The mixture was slowly heated to afford a homogeneous solution. After 2 h, the mixture was concentrated in vacuo and the residue dissolved in methylene chloride (135 mL) and treated with pyridine (2.2 mL). After 1 hr, the mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was washed four times with water, once with saturated sodium chloride solution, dried (magnesium sulfate), and filtered. Concentration and purification of the residue by flash chromatography (silica gel, hexanes/ethyl acetate) yielded 7.44 g (96%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[CH:13]=[CH2:14])([O-:3])=[O:2].C(O)C.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+]>O>[N+:1]([C:4]1[C:5]([CH:13]=[CH2:14])=[C:6]([CH:7]=[CH:8][CH:9]=1)[NH2:10])([O-:3])=[O:2]
Reactant: C=Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [S-2]
Solvent: CCO
Solvent: O
Product: C=Cc1c(N)cccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 24.2 %

Procedure:
The product from Example 44A (0.669 g, 3.45 mmoles) in 3:1 ethanol:water (40 mL) was treated with sodium sulfide nonahydrate (1.66 g, 6.90 mmoles) and heated at reflux for 30 minutes. The mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was mixed with water and extracted with chloroform (2×). The chloroform extracts were combined, washed with brine, dried with sodium sulfate and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 25% ethyl acetate/hexanes) to provide the title compound (0.137 g, 24%). MS (DCI) m/z 165 (M+H)+.
Reaction SMILES: BrC1C=CC(CCCC(O)=O)=C(C)C=1.[C:15]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:19])[CH2:16][CH:17]=[CH2:18].[Br:28][C:29]1[CH:34]=[CH:33][C:32](I)=[C:31]([CH2:36][CH3:37])[CH:30]=1>>[Br:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:18][CH2:17][CH2:16][C:15]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])=[C:31]([CH2:36][CH3:37])[CH:30]=1
Reactant: CCc1cc(Br)ccc1I
Reactant: C=CCC(=O)OCc1ccccc1
Agent: Cc1cc(Br)ccc1CCCC(=O)O
Product: CCc1cc(Br)ccc1CCCC(=O)OCc1ccccc1
Yield: 21 %

Procedure:
Using a procedure analogous to that used to prepare 8A, benzyl but-3-enoate (3.63 g, 0.020 mmol, reference for preparation: Cardillo, G.; De Simone, A.; Mingardi, A.; Tomasini, C. Synlett 1995, 11, 1131-2) was reacted with 4-bromo-2-ethyl-iodobenzene (6.23 g, 0.020 mmol) to give 21A (1.5 g, 21%). 1H NMR (400 MHz, CDCl3) δ ppm 1.18 (t, J=7.69 Hz, 3 H) 1.84-1.94 (m, 2 H) 2.41 (t, J=7.25 Hz, 2 H) 2.55-2.62 (m, 4 H) 5.12 (s, 1 H) 6.96 (d, J=7.91 Hz, 1 H) 7.22 (dd, J=7.91, 2.20 Hz, 1 H) 7.29 (d, J=2.20 Hz, 1 H) 7.30-7.40 (m, 5 H).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.[Li]CCCC.[N+:15]([C:18]1[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=1[C:20](OC)=[O:21])([O-:17])=[O:16]>C1COCC1>[N+:15]([C:18]1[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=1[C:20]([C:5]1[S:4][C:3]([Si:2]([CH3:9])([CH3:8])[CH3:1])=[N:7][CH:6]=1)=[O:21])([O-:17])=[O:16]
Reactant: COC(=O)c1ccccc1[N+](=O)[O-]
Reactant: C[Si](C)(C)c1nccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ncc(C(=O)c2ccccc2[N+](=O)[O-])s1
Reaction time: 0.5 h

Procedure:
To a solution of 2-trimethylsilylthiazole (2.0 g, 12.7 mmol) in THF at −78 C was added BuLi (5.08 mL, 2.5 M, 12.7 mmol). The reaction was stirred at −78 C for 0.5 hr and methyl 2-nitrobenzoate (2.69 mL, 19.1 mmol) was added. The suspension was stirred at room temperature for 2 hr and quenched with ammonium chloride solution. The mixture was extracted with ethyl acetate and the combined organic layer was dried over sodium sulfate, concentrated and purified by column chromatography to give 2H (680 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:14].[C:15](=[O:18])([O-])[O-:16].[K+].[K+]>CN(C)C=O>[NH2:14][C:3]1[CH:4]=[CH:5][C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:15]([O:16][C:6]([CH3:8])([CH3:7])[CH3:5])=[O:18])[CH2:10][CH2:9]2)=[CH:7][C:2]=1[Cl:1]
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(C2CCNCC2)cc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(Cl)c2)CC1
Temperature: 25 °C

Procedure:
A mixture of the product of Example 60D (77 mg, 0.36 mmol), di-tert-butyl bicarbonate (80 mg, 0.37 mmol) and potassium carbonate (117 mg, 0.85 mmol) in N,N-dimethylformamide (4 mL) was stirred at ambient temperature until TLC indicated no starting material remained. The mixture was concentrated and the residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 8/1 petroleum/ethyl acetate to provide the title compound. MS: 310 (M+H+).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH:6]1[CH2:19][S:18][C:9]2[N:10]([CH3:17])[C:11]3[C:16]([C:8]=2[C:7]1=[O:20])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:4].N1CC[CH2:23][CH2:22]1>O>[N:3]1([CH2:5][CH:6]2[CH2:19][S:18][C:9]3[N:10]([CH3:17])[C:11]4[C:16]([C:8]=3[C:7]2=[O:20])=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:2][CH2:23][CH2:22][CH2:4]1
Reactant: C1CCNC1
Reactant: CN(C)CC1CSc2c(c3ccccc3n2C)C1=O
Agent: Cl
Solvent: O
Product: Cn1c2c(c3ccccc31)C(=O)C(CN1CCCC1)CS2

Procedure:
A mixture of 2.50 g (0.008 mol) of 3-[(dimethylamino)methyl]-4-oxo-9-methyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole hydrochloride obtained in Example 1, stage E and 1.78 g (0.025 mol) of pyrrolidine in 40 ml of water is heated to reflux for 10 hours. After the mixture is cooled, the precipitate formed is drained, washed with water, dried and dissolved in 40 ml of tetrahydrofuran and the solution is treated with an ethereal solution of hydrochloric acid. The precipitate formed is drained, washed with ether and recrystallized in ethanol.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:22])=[C:4]([Cl:21])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=1)=[CH:7][C:6]=2[Cl:20].B(Br)(Br)Br>>[Br:1][C:2]1[C:3]([OH:22])=[C:4]([Cl:21])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1)=[CH:7][C:6]=2[Cl:20]
Reactant: COc1ccc(-c2cc(Cl)c3c(Cl)c(O)c(Br)cc3c2)cc1
Agent: BrB(Br)Br
Product: Oc1ccc(-c2cc(Cl)c3c(Cl)c(O)c(Br)cc3c2)cc1

Procedure:
The title compound was prepared by reacting 3-bromo-1,8-dichloro-6-(4-methoxyphenyl)-2-naphthol (0.18 g, 0.45 mmol) with boron tribromide (0.9 mL of 1N solution, 0.9 mmol) according to method D to yield 0.12 g (69%) of a light brown solid. The product was further purified by reverse phase preparative HPLC to yield the title compound as a white solid: mp 184–188° C.; 1H NMR (DMSO-d6): δ 6.89 (2H, d, J=8.59 Hz), 7.65 (2H, d, J=8.61 Hz), 7.95 (1H, d, J=1.78 Hz), 8.13 (1H, d, J=1.75 Hz), 8.37 (1H, s), 9.74 (1H, s), 10.50 (1H, s); MS (ESI) m/z 381/383/385 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[C:3](I)=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[C:3]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1cc(I)c(Br)cn1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Clc1ccc(-c2cc(Cl)ncc2Br)cc1
Temperature: 20 °C
Yield: 70.7 %

Procedure:
To a degassed solution of 5-bromo-2-chloro-4-iodopyridine (Ref. Cottet, F. and Schlosser, M. Tetrahedron 60, 11896-11874 (2004)) (2.0 g, 6.3 mmol), 4-chlorophenylboronic acid (1.1 g, 6.9 mmol) and K2CO3 (1.7 g, 12.6 mmol) in 1,2-dimethoxyethane (24 mL) and H2O (8.0 mL) was added Pd(PPh3)4 (0.727 g, 0.63 mmol) under argon at 20° C. The reaction mixture was refluxed for 15 h under argon, then allowed to cool to 20° C. The reaction was quenched by addition of H2O (30 mL) and extracted with EtOAc (50 mL×3). The combined organic was washed with saturated aqueous NaHCO3 (50 mL) and saturated aqueous NaCl (50 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was crystallized in EtOH to afford 1.35 g of the title compound as a light beige solid as the first crop. The second crop of the title product (0.44 g) was also isolated by concentrating the mother liquid followed by recrystallization in EtOH. LC/MS (method B): retention time=2.03 min, [M+H]+=301.9.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:18]=[C:17]([NH:19][NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:21]([NH:20][NH:19][C:17]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([S:6](=[O:7])(=[O:8])[NH2:5])[CH:18]=1)(=[O:25])[CH:22]([CH3:24])[CH3:23]
Reactant: COC(=O)c1ccc(NNC(=O)C(C)C)cc1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(NNC(=O)C(C)C)cc1S(N)(=O)=O
Yield: 94 %

Procedure:
1.0 g (2.7 mmol) of methyl 2-(N-tert-butylsulfamoyl)-4-(2-isobutyrylhydrazino)benzoate is stirred in 10 ml of trifluoroacetic acid at 25° C. for 2 hours. The mixture is evaporated and the residue is triturated with diethyl ether. Filtration with suction and drying gives 0.8 g (94% of theory) of methyl 4-(2-isobutyrylhydrazino)-2-sulfamoylbenzoate of melting point 198°-200° C.
Reaction SMILES: C1([C@H](N[C@@H:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C@H:11]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])C)C=CC=CC=1.CC[O-:30].[Na+]>CCO>[O:30]=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CC[O-]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N[C@H](C)c1ccccc1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
A mixture of 252D (460 mg, 1.22 mmol) and NaOEt (1.25 mL, 21% wt in EtOH) in EtOH (10 ml) was stirred at 50° C. for 3 hrs, then at RT for about 48 hours. The reaction mixture was concentrated in vacuo, followed by the addition of water. The mixture was acidified with 1N HCl to pH 4-5 and the solid was collected by filtration, washed with water and dried to give 300 mg (yield: 71%) of 252A. It had an analytical HPLC retention time=2.065 min. (Chromolith SpeedROD column 4.5×50 mm, 10-90% aqueous methanol containing 0.1% TFA over 4 min, 4 mL/min, monitoring at 220 nm). Mass (M+1)+=349.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]1[NH:27][C@H:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25][S:24]1.[C:35]([O:39][C:40]([NH:42][CH2:43][C:44](O)=[O:45])=[O:41])([CH3:38])([CH3:37])[CH3:36]>C(#N)C>[C:35]([O:39][C:40]([NH:42][CH2:43][C:44]([N:27]1[C@H:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25][S:24][C@@H:23]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[F:16])=[O:45])=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)[C@@H]1CSC(c2ccccc2F)N1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCC(=O)N1[C@@H](c2ccccc2F)SC[C@H]1C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 64.3 %

Procedure:
(2R,4R)-tert-Butyl 3-(2-tert-butoxycarbonylamino)-2-(2-fluorophenyl)-thiazolidine-4-carboxylate can be prepared in the following manner: a solution of 18.2 g of N,N'-dicyclohexylcarbodiimide in 75 cm3 of anhydrous acetonitrile is added over 30 minutes to a solution of 25.0 g of (2RS,4R)-tert-butyl 2-(2-fluorophenyl)thiazolidine-4-carboxylate and of 15.5 g of 2-tert-butoxycarbonylaminoacetic acid in 150 cm3 of anhydrous acetonitrile, maintained at a temperature close to 0° C. The reaction mixture is stirred for 16 hours at a temperature close to 25° C. The insoluble product is separated off by filtration, washed with 3 times 20 cm3 of acetonitrile, and the filtrate is concentrated to dryness at reduced pressure at 40° C. The crude product obtained is purified by chromatography on silica [eluent: ethyl acetatecyclohexane (30-70 by volume)]. The fractions containing the expected product are combined and concentrated to dryness at reduced pressure at 40° C. 25.0 g of (2R,4R)-tert-butyl 3-(2-tert-butoxycarbonylaminoacetyl)-2-(2-fluorophenyl)thiazolidine-4-carboxylate are thus obtained in the form of an oil, which is employed as it is in the subsequent syntheses.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C(NB)(C)(C)C.[CH2:11]([N:18]1[CH2:26][CH2:25][CH:24]2[CH:20]([C:21](=O)[C:22]3[S:29][CH:28]=[CH:27][C:23]=32)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Al+3].[Cl-].[Cl-].[Cl-].B.Cl.[OH-].[Na+]>C(Cl)Cl>[CH2:11]([N:18]1[CH2:26][CH2:25][CH:24]2[CH:20]([CH2:21][C:22]3[S:29][CH:28]=[CH:27][C:23]=32)[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1c2sccc2C2CCN(Cc3ccccc3)CC12
Agent: B
Agent: BNC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: c1ccc(CN2CCC3c4ccsc4CC3C2)cc1
Reaction time: 0.5 h
Yield: 73 %

Procedure:
A slurry of AlCl3 (571 mg, 4.29 mmol) in CH2Cl2 (4 ml) was treated with tert-butylaminoborane (746 mg, 8.58 mmol) at 0° C. and stirred for 30 minutes. Next, a solution of the product from step f) (406 mg, 1.43 mmol) in CH2Cl2 (3 ml) was added dropwise to the AlCl3/borane solution. After 2 hours at 0° C., the crude reaction mixture was poured into cold 10% HCl, treated with 2 M NaOH to pH 12 and extracted with CH2Cl2 (3×75 ml). The combined organic extracts were washed with brine (75 ml) and dried (MgSO4). The solvent was evaporated in vacuo and the crude product was purified by silica-gel chromatography using a ethyl acetate/hexanes gradient (0% to 75% ethyl acetate) to give 279 mg (73%) of the subtitle compound. MS calculated for C17H19NS+H 270, observed 270.
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH:11]=[C:10]([C:12]2[CH:35]=[CH:34][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH2:29][C:30]([F:33])([F:32])[F:31])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH:9]=[N:8]1)([CH3:6])[C:3](O)=[O:4].[CH2:36]([CH2:38][NH2:39])[OH:37]>>[OH:37][CH2:36][CH2:38][NH:39][C:3](=[O:4])[C:2]([N:7]1[CH:11]=[C:10]([C:12]2[CH:35]=[CH:34][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH2:29][C:30]([F:31])([F:33])[F:32])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH:9]=[N:8]1)([CH3:6])[CH3:1]
Reactant: NCCO
Reactant: CC(C)(C(=O)O)n1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Product: CC(C)(C(=O)NCCO)n1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1

Procedure:
Following the procedure for 453, 2-Methyl-2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-propionic acid was reacted with ethanolamine to give 324. MS (ESI+) 548.1. 1H NMR (400 MHz, DMSO) δ 8.46 (s, 1H), 8.30-8.25 (m, 2H), 8.07 (s, 1H), 7.52 (dd, J=8.3, 1.5, 1H), 7.41 (d, J=1.5, 1H), 7.20 (t, J=5.4, 1H), 5.86 (q, J=8.7, 2H), 4.59 (t, J=5.4, 1H), 4.40 (t, J=4.8, 2H), 3.47 (t, J=4.9, 2H), 3.36 (q, J=6.0, 2H), 3.12 (q, J=6.0, 2H), 1.75 (s, 6H)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:7]=[CH:6][C:5]=1[OH:18])([O-])=O>C(O)(=O)C.O.[Fe]>[NH2:1][C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:7]=[CH:6][C:5]=1[OH:18]
Reactant: CCCCCCCCc1ccc(O)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCc1ccc(O)c(N)c1
Reaction time: 0.75 h
Yield: 66.6 %

Procedure:
To 95.4 mg(0.38 mmole) of 2-nitro-4-octylphenol in 2 ml of 1:1 glacial acetic acid and water mixture at 85-90° C. was added 0.35 gm of activated iron in three portions over a 15 min period. The reaction was allowed to proceed at the same temperature for 45 min. The reaction mixture was diluted then with 5 ml of water and extracted pith 20 ml ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated by rotary evaporation. The crude product was flash chromatographed over silica gel using 30% ethyl acetate in hexane to yield 56 mg of 2-amino4octyl phenol, Structure (I-2), in 67% yield.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(Cl)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccc(Cl)cc2)n1
Yield: 59.5 %

Procedure:
Following the procedure in Example 118A, 3-tert-butyl-1-(4-chlorophenyl)-1H-pyrazol-5-amine (653 mg, 2.62 mmol) and phenyl chloroformate (1.0 mL, 7.85 mmol) were reacted to give phenyl 3-tert-butyl-1-(4-chlorophenyl)-1H-pyrazol-5-ylcarbamate (575 mg, 1.56 mmol, 59%). 1H NMR (300 MHz, DMSO-d6) δ 10.19 (br s, 1H), 7.63-7.60 (m, 4H), 7.39-7.36 (m, 2H), 7.23 (t, 1H), 7.06 (br s, 2H), 6.38 (s, 1H), 1.28 (s, 9H); LC-MS (ESI) m/z 370 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[N:6]=1)=[O:4]>[OH-].[Na+]>[CH3:19][C:16]([C:7]1[C:8]([OH:15])=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:10]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=1)([CH3:17])[CH3:18]
Reactant: COC(=O)c1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)c1nc(C(=O)O)nc(C(C)(C)C)c1O
Yield: 90.8 %

Procedure:
A solution of 4,6-bis (1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carboxylic acid methyl ester (500 mg) in 1N NaOH (50 mL) is heated at reflux for 1 hour. The reaction mixture is cooled, filtered, and acidified to pH 4 with 1N HCl. The resulting precipitate is collected by filtration and dried at room temperature under vacuum to give pure 4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carboxylic acid (430 mg); mp 200° C. dec.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[N:17]1([CH2:22][CH2:23][CH2:24][N:25]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:21][CH2:20][CH2:19][CH2:18]1>O>[N+:8]([C:3]1[CH:4]=[CH:5][C:6]([N:28]2[CH2:29][CH2:30][CH2:31][N:25]([CH2:24][CH2:23][CH2:22][N:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:26][CH2:27]2)=[CH:7][CH:2]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: C1CCN(CCCN2CCCNCC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCCN(CCCN3CCCC3)CC2)cc1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
Fluoronitrobenzene (5.56 g, 39.43 mmol) is dissolved in water, and then potassium carbonate (6.55 g, 47.31 mmol) and 1-(3-pyrrolidinopropyl)-homopiperazine (10 g, 47.31 mmol) are added. The medium is heated at 85° for 4 hours and then cooled to room temperature. The medium is filtered and a yellow solid is recovered after drying in a vacuum oven at 45° C. (12.5 g, yield=95.5%).
Reaction SMILES: [Na].CC[O-].[Na+].Cl.[NH2:7][OH:8].[C:9]1([N:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:16]([CH:18]([CH3:24])[C:19](OCC)=[O:20])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CO>[C:9]1([N:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:16]([CH:18]([CH3:24])[C:19]([NH:7][OH:8])=[O:20])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NO
Reactant: CCOC(=O)C(C)C(=O)N(c1ccccc1)c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C(=O)NO)C(=O)N(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 68 %

Procedure:
4.9 g (0.125 gram atom) of sodium in small pieces are added to 50 ml of anhydrous methanol and 2/3 of the sodium ethylate solution thus obtained is used to neutralise a solution of 5.25 g (0.075 mol) of hydroxylamine hydrochloride in 50 ml of anhydrous methanol; 15 g (0.05 mol) of ethyl 2-(N,N-diphenylcarbamoyl)-propionate are then added, after which the remaining one-third of the sodium ethylate solution is added in the cold. The reactants are left in contact overnight at 50° C., the mixture is evaporated to dryness in vacuo, the residue is taken up in ether and the sodium salt is filtered off, dissolved in water and acidified with concentrated HCl. CRL 40,438 is obtained by filtering off, drying and recrystallising from acetonitrile. Melting point: 171°-172° C. Yield: 68%.
Reaction SMILES: Cl[CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:10][CH:9]=1)[C:3](OC)=[O:4].[NH2:23][C:24]([NH2:26])=[S:25].C(=O)([O-])O.[Na+]>S1(CCCC1)(=O)=O>[NH:23]=[C:24]1[NH:26][C:3](=[O:4])[CH:2]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:10][CH:9]=2)[S:25]1
Reactant: COC(=O)C(Cl)Cc1ccc(OCCN2CCOCC2)cc1
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Product: N=C1NC(=O)C(Cc2ccc(OCCN3CCOCC3)cc2)S1
Yield: 40.1 %

Procedure:
A mixture of 10.0 g methyl 2-chloro-3-[4-(2-morpholinoethyloxy)phenyl]propionate and 4.64 g thiourea is heated in the presence of 100 ml of sulfolane at 120° C. for 4 hours. After cooling, a saturated aqueous solution of sodium hydrogen carbonate is added and the mixture is extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate and distilled to remove the ethyl acetate, whereupon 4.1 g (40.2%) of 2-imino-5-[4-(2-morpholinoethyloxy)benzyl]thiazolidin-4-one is obtained as crystals. These crystals are recrystallized from ethyl acetate-methanol. Colorless needles, m.p. 189°-190° C.
Reaction SMILES: [C:1]([S:4][C@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:7]([CH2:17]O)[CH2:6]1)(=[O:3])[CH3:2].[C:19]([O:23][C:24]([NH:26][S:27]([NH2:30])(=[O:29])=[O:28])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([NH:26][S:27]([NH2:30])(=[O:29])=[O:28])=[O:25])([CH3:22])([CH3:20])[CH3:21].[C:1]([S:4][C@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C@@H:7]([CH2:17][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[S:27](=[O:28])(=[O:29])[NH2:30])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)S[C@@H]1C[C@H](CO)N(C(=O)OC(C)(C)C)C1
Agent: CC(C)(C)OC(=O)NS(N)(=O)=O
Product: CC(=O)S[C@@H]1C[C@H](CN(C(=O)OC(C)(C)C)S(N)(=O)=O)N(C(=O)OC(C)(C)C)C1

Procedure:
N-t-butoxycarbonylsulfamide is prepared in the same manner as in the paragraph (a) of Step A-6 in preparative Example 7-A. (2R,4R)-4-acetylthio-1-t-butoxycarbonylpyrrolidine-2-methanol (i.e., a substrate) is allowed to react with the obtained N-t-butoxycarbonylsulfamide in the similar manner as in paragraph (b) of Step A-6 in Preparative Example 7-A under a condition for Step B-6 shown in Table 2 to give (2R,4R)-4-acetylthio-1-t-butoxycarbonyl-2-(N-t-butoxycarbonyl-N-sulfamoylamino)methylpyrrolidine.