Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[O:21])[CH2:3][NH:4]/[C:5](/[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])=[CH:6]\[C:7]([O:9]CC)=O.C(OCCCC)(=O)C.C[Si]([N:34]=[C:35]=[S:36])(C)C.[OH-].[Na+]>CO.O>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([O:19][CH3:20])=[C:12]([C:5]2[N:4]([CH2:3][C:2]([NH2:1])=[O:21])[C:35](=[S:36])[NH:34][C:7](=[O:9])[CH:6]=2)[CH:17]=1
Reactant: C[Si](C)(C)N=C=S
Reactant: CCOC(=O)/C=C(\NCC(N)=O)c1cc(Cl)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCOC(C)=O
Solvent: CO
Solvent: O
Product: COc1ccc(Cl)cc1-c1cc(=O)[nH]c(=S)n1CC(N)=O
Temperature: 30 °C
Reaction time: 15 h
Yield: 53.2 %

Procedure:
A reaction vessel equipped with an efficient stirrer was charged with (Z)-ethyl 3-((2-amino-2-oxoethyl)amino)-3-(5-chloro-2-methoxyphenyl)acrylate (15 g, 50.2 mmol), butyl acetate (150 mL) and trimethylsilyl isothiocyanate (160.7 mmole, 21.1 g, 22.7 mL) and the mixture was heated to reflux. After 15 hours, the mixture was cooled to 30° C. and treated with 1N aqueous sodium hydroxide (112.5 mL, 112.5 mmoles). After 30 min, the organic layer was separated and extracted with another portion of 1N sodium hydroxide (37.5 mL, 37.5 mmoles). The combined aqueous phases were extracted twice with dichloromethane (2×45 mL), filtered, and treated with 6N HCl until a pH of 2.5 was achieved. After stirring for 1 hour, the resulting solid was isolated by vacuum filtration, resuspended in 100 mL of a 1:1 methanol-water solution, heated with stirring at 50° C. for 2 hours, and cooled to room temperature before collecting the solid by vacuum filtration, pulling dry and drying in a vacuum oven (20 mm Hg, 50° C.) for 12 hours to afford 8.7 g of the desired product as a tan solid.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:23][C:22]([C:24]([OH:26])=[O:25])=[CH:21][C:9]=3[N:10]([CH2:18][O:19][CH3:20])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li]C(CC)C.CN(CCN(C)C)C.CN([CH:43]=[O:44])C>C1COCC1>[CH:1]1([C:7]2[C:8]3[S:23][C:22]([C:24]([OH:26])=[O:25])=[C:21]([CH:43]=[O:44])[C:9]=3[N:10]([CH2:18][O:19][CH3:20])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COCn1c(-c2ccccc2)c(C2CCCCC2)c2sc(C(=O)O)cc21
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COCn1c(-c2ccccc2)c(C2CCCCC2)c2sc(C(=O)O)c(C=O)c21
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 85 %

Procedure:
A solution (0.2 M) of 6-cyclohexyl-4-(methoxymethyl)-5-phenyl-4H-thieno[3,2-b]pyrrole-2-carboxylic acid in THF was added dropwise to a solution (0.6 M) of sec-BuLi (3 eq.) and TMEDA (3 eq.) in THF at −78° C. After 5 min at −78° C., the resulting solution was treated with DMF (10 eq.) then was allowed to warm up at −10° C. The mixture was quenched with water and poured into aqueous HCl (0.1 N) and extracted with AcOEt. The combined organic phase was dried and concentrated to give the title compound (85%) as a solid, that was used as such.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[N:7][N:8]([CH2:11][CH2:12][O:13][CH3:14])[C:9]=1[CH3:10])=[N+]=[N-].COCCN1C(C)=C(C(OCC)=O)C=N1>>[CH3:14][O:13][CH2:12][CH2:11][N:8]1[C:9]([CH3:10])=[C:5]([CH2:4][NH2:1])[CH:6]=[N:7]1
Reactant: COCCn1ncc(CN=[N+]=[N-])c1C
Agent: CCOC(=O)c1cnn(CCOC)c1C
Product: COCCn1ncc(CN)c1C

Procedure:
4-(azidomethyl)-1-(2-methoxyethyl)-5-methyl-1H-pyrazole was generated from ethyl 1-(2-methoxyethyl)-5-methyl-1H-pyrazole-4-carboxylate according to a procedure similar to that described for the 2,6 dimethyl 3,5-pyridyl derivative, then reduced to the crude primary amine, following procedures described herein.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1N1CCCC1
Agent: [Pd]
Product: CC(C)(C)c1ccc(N)cc1N1CCCC1
Reaction time: 8 h
Yield: 90.8 %

Procedure:
A flask charged with 1-(2-tert-butyl-5-nitrophenyl)pyrrolidine (150 mg, 0.60 mmol) and Pd/C (15 mg, 0.14 mmol) was flushed under N2 followed by evacuating under vacuum. Methanol (2 mL) was added under inert atmosphere followed by evacuating under vacuum. The reaction mixture was stirred overnight under an atmosphere of H2. The reaction mixture was filtered and the solvent was evaporated to give 4-tert-butyl-3-(pyrrolidin-1-yl)aniline (119 mg, 90%). LC/MS: m/z 218.5 (M+H)+ at 2 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: OC1C=CC(C)=CC=1N=NC1C=CC=CC=1[N+]([O-])=O.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][C:22]=1[N:31]=[N:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N+:39]([O-])=O>>[OH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][C:22]=1[N:31]1[N:39]=[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]2=[N:32]1
Reactant: CC(C)(C)c1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: Cc1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Product: CC(C)(C)c1ccc(O)c(-n2nc3ccccc3n2)c1

Procedure:
When in Example 13, the 2'-hydroxy-5'-methyl-2-nitroazobenzene was replaced by an equivalent amount of 2'-hydroxy-5'-tert-butyl-2-nitroazobenzene, the reduction reaction went rapidly to yield the product 2-(2-hydroxy-5-tert-butylphenyl)-2H-benzotriazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:15][O:16][C:17]1[C:22]([O:23][CH3:24])=[C:21]([O:25][CH3:26])[CH:20]=[CH:19][C:18]=1[CH2:27][C:28]#[N:29]>>[CH3:15][O:16][C:17]1[C:22]([O:23][CH3:24])=[C:21]([O:25][CH3:26])[CH:20]=[CH:19][C:18]=1[C:27](=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([O:13][CH3:14])=[C:10]([O:11][CH3:12])[C:3]=1[O:2][CH3:1])[C:28]#[N:29]
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: COc1ccc(CC#N)c(OC)c1OC
Product: COc1ccc(C=C(C#N)c2ccc(OC)c(OC)c2OC)c(OC)c1OC
Yield: 93.4 %

Procedure:
Following the Procedure A, the reaction was performed with 1.96 g of 2,3,4-trimethoxybenzaldehyde (10 mmol) and 2.07 g of 2,3,4-trimethoxyphenyl-acetonitrile (10 mmol), affording 2,3-bis-(2,3,4-trimethoxy-phenyl)-acrylonitrile as yellow powder (yield 3.6 g, 93%).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1.[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[N:18][N:19]2[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[C:15]([Sn](C)(C)C)[CH:14]=1>CN(C)C=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.[Cu]I>[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[N:18][N:19]2[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:23])=[O:24])=[C:15]([C:2]2[O:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=2)[CH:14]=1
Reactant: CCOC(=O)c1cnc(Cl)o1
Reactant: C[Sn](C)(C)c1cc(Cl)cc2c1cnn2S(=O)(=O)c1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(-c2cc(Cl)cc3c2cnn3S(=O)(=O)c2ccccc2)o1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 39.3 %

Procedure:
In 4 batches, tetrakis(triphenylphosphine)palladium(0) (3.37 g, 2.92 mmol), ethyl 2-chloro-1,3-oxazole-5-carboxylate (6.65 g, 37.9 mmol, available from Apollo Scientific) and copper(I) iodide (1.11 g, 5.83 mmol) were added to a solution of 6-chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole (13.28 g, 29.2 mmol) in N,N-dimethylformamide (52 ml). In 3 of the batches, tetrakis(triphenylphosphine)palladium(0) (1.03 g, 0.89 mmol), ethyl 2-chloro-1,3-oxazole-5-carboxylate (2.03 g, 11.59 mmol) and copper(I) iodide (0.34 g, 1.78 mmol) were added to a solution of 6-chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole (4.06 g, 8.91 mmol) in N,N-dimethylformamide (16 ml). In the fourth batch, tetrakis(triphenylphosphine)palladium(0) (0.28 g, 0.24 mmol), ethyl 2-chloro-1,3-oxazole-5-carboxylate (0.55 g, 3.14 mmol) and copper(I) iodide (0.09 g, 0.48 mmol) were added to a solution of 6-chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole (1.10 g, 2.42 mmol) in N,N-dimethylformamide (4 ml). Each batch was heated and stirred at 100° C. under microwave irradiation for 30 min. The mixtures were allowed to cool to RT and the combined precipitated product suspended in diethyl ether and collected by filtration, washing with further diethyl ether then drying in a vacuum oven for 72 h. Approximately 5.2 g of the resultant solid was dissolved in dichloromethane and passed through Celite, eluting with further dichloromethane. The solvent was evaporated in vacuo to give the title compound as a pale orange solid (4.95 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([CH3:21])[CH:13]=1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([N:4]2[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:2]([CH3:1])=[N:3]2)=[C:14]([CH3:21])[CH:13]=1
Reactant: COC(=O)c1c[nH]nc1C
Reactant: Cc1cc(F)ccc1B(O)O
Product: COC(=O)c1cn(-c2ccc(F)cc2C)nc1C
Yield: 67.7 %

Procedure:
Using methyl 3-methyl-1H-pyrazole-4-carboxylate (6.25 g) synthesized in Example 1(3) and 4-fluoro-2-methylphenylboronic acid (13.9 g) and in the same manner as in Example 17(1), the title object compound (7.5 g, 68%) was obtained as a white solid.
Reaction SMILES: Cl.C(Cl)Cl.[O:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=[N:22][OH:23])[C:19]([NH2:21])=[O:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>C1(C)C=CC=CC=1>[O:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1/[C:18](=[N:22]\[OH:23])/[C:19]([NH2:21])=[O:20])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NC(=O)C(=NO)c1ccccc1Oc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: NC(=O)/C(=N/O)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.8 %

Procedure:
Conc. hydrochloric acid (1 ml) and methylene chloride (12 ml) were added to 2-(2-phenoxyphenyl)-2-hydroxyiminoacetamide (Z=at least 98%) (1.79 g, 7.0 mmol), and the mixture was stirred at room temperature for 12 hours. After stirring, water (20 ml) and toluene (20 ml) were added. The resulting crystals were separated by filtration and dried to give (E)-2-(2-phenoxyphenyl)-2-hydroxyiminoacetamide (1.70 g, Yield: 95.0%) as colorless crystals.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.S1[CH2:17][CH:16]=[C:15]([C:18]2[CH:19]=[CH:20][C:21]([N+:31]([O-:33])=[O:32])=[C:22]([N:24]3[CH2:29][CH2:28][CH:27]([CH3:30])[CH2:26][CH2:25]3)[CH:23]=2)[CH2:14][CH2:13]1.[O-:34][S:35]([O-:37])=O.[Na+].[Na+].CCOC(C)=O>C(Cl)Cl.O>[O:34]=[S:35]1(=[O:37])[CH2:13][CH:14]=[C:15]([C:18]2[CH:19]=[CH:20][C:21]([N+:31]([O-:33])=[O:32])=[C:22]([N:24]3[CH2:29][CH2:28][CH:27]([CH3:30])[CH2:26][CH2:25]3)[CH:23]=2)[CH2:16][CH2:17]1
Reactant: CC1CCN(c2cc(C3=CCSCC3)ccc2[N+](=O)[O-])CC1
Reactant: O=S([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CC1CCN(c2cc(C3=CCS(=O)(=O)CC3)ccc2[N+](=O)[O-])CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A mixture of 3-chloroperoxybenzoic acid (77 mg, 0.35 mmol, 77%) in 2 mL of DCM was added slowly to a solution of 1-[5-(3,6-dihydro-2H-thiopyran-4-yl)-2-nitro-phenyl]-4-methyl-piperidine (as prepared in the previous step, 50 mg, 0.16 mmol) in 2 mL of DCM at −78° C. under Ar. The mixture was stirred at −78° C. for 0.5 h, and then Warmed to RT. Treated with 2 mL of 10% Na2SO3 solution, the mixture was stirred vigorously for 5 min. The mixture was treated with 30 mL of EtOAc and 10 mL of H2O. The aqueous layer was separated and the organic layer was washed with saturated aq NaHCO3 solution (10 mL), H2O (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (0-2% EtOAc/DCM) gave 35 mg (64%) of the title compound as a yellow oil: 1H-NMR (CDCl3; 400 MHz): δ 7.77 (d, 1H, J=8.6 Hz), 7.00 (d, 1H, J=1.9 Hz), 6.88 (dd, 1H, J=8.6, 1.9 Hz), 5.93 (m, 1H), 3.83 (br s, 2H), 3.24-3.30 (m, 4H), 3.11-3.17 (m, 2H), 2.83 (ddd, 2H, J=12.0, 12.0, 2.3 Hz), 1.72 (dd, 2H, J=12.6, 2.3 Hz), 1.53 (m, 1H), 1.35-1.47 (m, 2H), 1.00 (d, 3H, J=6.3 Hz). Mass spectrum (ESI, m/z): Calcd. for C17H22N2O4S, 351.1 (M+H), found 351.0.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][N:34]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C>ClCCl>[C:19]([O:23][C:24]([N:26]1[CH2:27][CH2:28][CH:29]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:35][N:34]=2)[CH2:30][CH2:31]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(N)cn2)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (0.67 g, 2.6 mmol), 4-(5-amino-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.76 g, 2.6 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrop, 1.45 g, 3.1 mmol), and diisopropylethylamine (0.9 mL, 5.2 mmol) in anhydrous dichloromethane (15 mL) was stirred at room temperature overnight. The reaction mixture was then concentrated and purified by flash chromatography (Merck silica gel 60, 230-400 mesh, eluted with ethyl acetate and hexane) to give 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-ylamino}-piperidine-1-carboxylic acid tert-butyl ester (0.78 g, 56%) as a white solid. LCMS calcd for C26H28F3N5O4 (m/e) 531, obsd 532 (M+H).
Reaction SMILES: [CH:1]1[C:18]2[CH:17]=[CH:16][C:15]3[C:6](=[CH:7][C:8]([CH2:19][NH:20][C:21]([CH3:26])([CH2:24][OH:25])[CH2:22][OH:23])=[C:9]4[C:14]=3[CH:13]=[CH:12][CH:11]=[CH:10]4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:27](O)(=[O:31])[CH:28]([CH3:30])[OH:29]>CO>[C:27]([O:25][CH2:24][C:21]([NH:20][CH2:19][C:8]1[CH:7]=[C:6]2[C:15](=[C:14]3[C:9]=1[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:16]=[CH:17][C:18]1[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=1)([CH3:26])[CH2:22][OH:23])(=[O:31])[CH:28]([CH3:30])[OH:29]
Reactant: CC(O)C(=O)O
Reactant: CC(CO)(CO)NCc1cc2c3ccccc3ccc2c2ccccc12
Solvent: CO
Product: CC(O)C(=O)OCC(C)(CO)NCc1cc2c3ccccc3ccc2c2ccccc12
Yield: 44.1 %

Procedure:
A mixture of 2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediol free base (1D) (3.45 g, 10 mmol) and lactic acid (Fisher Scientific Co., 711 Forbes Ave., Pittsburgh, PA, 15219, 85% liquid, 1.04 g, 10 mmol) in CH3OH (500 mL) was brought to reflux and filtered through a glass fritted funnel. The solvent was removed by rotary evaporation to give a crude white solid. This was crystallized (CH3OH/Et2O) 3x to give 1.84 g (42.2%) of 2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediol lactate mp 163°-164°. (C,H,N).
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([O:8][CH2:9][CH2:10][CH2:11][NH2:12])([O-:7])=[O:6].[O:13]=[C:14]1[NH:18][CH:17]([C:19](O)=[O:20])[CH2:16][S:15]1>>[N+:5]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:19]([CH:17]1[CH2:16][S:15][C:14](=[O:13])[NH:18]1)=[O:20])([O-:7])=[O:6]
Reactant: NCCCO[N+](=O)[O-]
Reactant: O=C1NC(C(=O)O)CS1
Solvent: O=[N+]([O-])O
Product: O=C1NC(C(=O)NCCCO[N+](=O)[O-])CS1
Yield: 35.4 %

Procedure:
A procedure similar to that described in Example 1 was repeated, but using 1.25 g of N-(3-nitrooxypropyl)-amine nitrate and 1.0 g of 2-oxothiazolidine-4-carboxylic acid, to obtain 0.60 g of the title compound as pale yellow crystals, melting at 83°-85° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1([CH2:14][N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[CH2:13][CH2:12]1)(C(C)(C)C)(C)C.Cl>C1COCC1.[NH4+].[Cl-]>[OH:8][CH2:9][CH2:10][C:11]1([CH2:14][N:15]2[C:16](=[O:25])[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]2=[O:24])[CH2:13][CH2:12]1
Reactant: CC(C)(C)[Si](C)(C)OCCC1(CN2C(=O)c3ccccc3C2=O)CC1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CC1(CCO)CC1
Yield: 87.5 %

Procedure:
To a solution of 2-{1-[2-(tert-butyldimethylsilyloxy)-ethyl]-cyclopropylmethyl}-isoindole-1,3-dione (0.24 g, 0.68 mmol) in THF (3 mL) was added 1.0 M HCl (3 mL). The resultant solution was stirred, at room temperature, for 3 hours. The mixture was diluted with saturated aqueous NH4Cl (10 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated. The crude material was purified by column chromatography on silica gel (2:1 hexanes-ethyl acetate) and provided 0.146 g (88%) of 2-[1-(2-hydroxy-ethyl)-cyclopropylmethyl]-isoindole-1,3-dione as a white solid. 1H NMR (CDCl3) δ 0.29-0.35 (m, 2H), 0.59-0.62 (m, 2H), 1.41 (t, 2H, J=6.6 Hz), 2.80 (br s, 1H), 3.53 (s, 2H), 3.76 (t, 2H, J=6.6 Hz), 7.59-7.63 (m, 2H), 7.69-7.74 (m, 2H);
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:16]([CH2:26][CH2:27][CH2:28]C2C=CC=CC=2)=[C:17]([CH3:25])C=[CH:19][C:20]=1S([O-])(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][C:36]12[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][CH:38]([CH2:39]3)[CH2:37]1)[CH2:43]2>C(#N)C>[C:36]12([NH:35][CH2:19][CH2:20][CH:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:16]3[CH:17]=[CH:25][CH:28]=[CH:27][CH:26]=3)[CH2:37][CH:38]3[CH2:44][CH:42]([CH2:41][CH:40]([CH2:39]3)[CH2:45]1)[CH2:43]2
Reactant: Cc1ccc(S(=O)(=O)[O-])c(-c2ccccc2OCc2ccccc2)c1CCCc1ccccc1
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: CC#N
Product: c1ccc(COc2ccccc2C(CCNC23CC4CC(CC(C4)C2)C3)c2ccccc2)cc1

Procedure:
This compound was similarly prepared from the toyslate (XXIX) of Example 4d) and 1-aminoadamantane. It was used as start material in Example 7q). The hydrochloridesemihydrate was prepared in acetonitrile and melted at 225° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1[N:31]=[C:32]([SH:35])[NH:33][CH:34]=1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1[N:31]=[C:32]([S:35][C:2]2[S:6][C:5]([NH:7][C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=3[C:18]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[O:9])=[N:4][CH:3]=2)[NH:33][CH:34]=1)=[O:29])[CH3:26]
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Reactant: CCOC(=O)c1c[nH]c(S)n1
Product: CCOC(=O)c1c[nH]c(Sc2cnc(NC(=O)Nc3ccc(C)cc3C(=O)C3CCCC3)s2)n1
Yield: 38 %

Procedure:
2-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-1H-imidazole-4-carboxylic acid ethyl ester (190 mg, 38%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 2-mercapto-1 H-imidazole-4-carboxylic acid ethyl ester (340 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1)[CH2:3][OH:4].C(N(CC)CC)C.[CH3:28][O:29][C@:30]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:34]([F:37])([F:36])[F:35])[C:31](Cl)=[O:32]>C(Cl)Cl>[CH3:28][O:29][C@@:30]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:34]([F:37])([F:36])[F:35])[C:31]([NH:1][CH:2]([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][CH:12]=1)[CH2:3][OH:4])=[O:32]
Reactant: CCCCCCCCc1ccc(CCC(N)CO)cc1
Reactant: CO[C@](C(=O)Cl)(c1ccccc1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCc1ccc(CCC(CO)NC(=O)[C@](OC)(c2ccccc2)C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
2-Amino-4-(4-octylphenyl)butanol (10 mg), N,N-dimethyl-p-aminopyridine (17.5 mg), anhydrous triethylamine (11.4 μl) and anhydrous methylene chloride (1 ml) were mixed and the mixture was stirred under a nitrogen atmosphere at room temperature. Thereto was added (R)-α-methoxy-α-trifluoromethylphenylacetyl chloride (16.8 μl) and the mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by thin layer chromatography (eluent; chloroform:methanol=9:1) to give the two diastereomer mixtures. Moreover, the mixture was purified by high performance liquid chromatography (eluent; methanol:water=88:12, flow rate; 8.0 ml /minute) to give the subject oily substance (9.8 mg) of 67.8 minutes at retention time and the subject oily substance (9.6 mg) of 71.6 minutes at retention time.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[Cl:11].S(Cl)(Cl)=O.[NH3:16].CCCCCCC>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:16])=[O:7])=[CH:4][C:3]=1[Cl:11]
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Reactant: N
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCCCCCC
Product: NC(=O)c1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 116.8 %

Procedure:
To a suspension of 4-bromo-3-chlorobenzoic acid (2.00 g, 8.49 mmol) in toluene (10 mL) at ambient temperature was added thionyl chloride (1.85 mL, 25.4 mmol). The reaction mixture was heated at reflux for 20.5 hours, then distilled for 1 hour, collecting 9 mL of distillate. Toluene (10 mL) was added and the reaction was distilled for 30 minutes, collecting 10 mL of distillate. The reaction mixture was cooled to ambient temperature resulting in a suspension. Toluene (10 mL) saturated with ammonia gas was added to the reaction mixture followed by bubbling ammonia gas through the reaction for 10 minutes. The reaction was stirred at ambient temperature for 1 hour. Heptane (10 mL) was added, and the reaction stirred at ambient temperature for 15 minutes, then 0° C. for 1 hour. The solids were collected by vacuum filtration, rinsed with excess heptane, and dried to afford 4-bromo-3-chlorobenzamide (2.327 g, 116.8%) as a white solid which was carried on without further purification.
Reaction SMILES: C(O[C:6]([N:8]([CH2:10][C:11]1[N:16]=[C:15]2[CH:17]=[CH:18][N:19](C(OC(C)(C)C)=O)[C:14]2=[CH:13][CH:12]=1)C)=O)(C)(C)C.[ClH:27].O1CCOCC1>CO.C(Cl)Cl>[ClH:27].[CH3:6][NH:8][CH2:10][C:11]1[N:16]=[C:15]2[CH:17]=[CH:18][NH:19][C:14]2=[CH:13][CH:12]=1
Reactant: CN(Cc1ccc2c(ccn2C(=O)OC(C)(C)C)n1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: CNCc1ccc2[nH]ccc2n1
Temperature: 50 °C
Reaction time: 7 h
Yield: 96.1 %

Procedure:
To a stirred solution of tert-butyl 5-((tert-butoxycarbonyl(methyl)amino)-methyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (140.0 mg, 0.387 mmol) in MeOH (2 mL) and DCM (2 mL) was added HCl in dioxane (2.3 mL, 9.05 mmol, 4M) and the reaction mixture was stirred at 50° C. under N2 for 7 h. The solvent was removed in vacuo and the crude product was pumped dry on high-vacuum line to afford 87.1 mg (96.1%) of the desired product as HCl salt: 1H NMR (400 MHz, DMSO-d6) δ 12.51 (br s, 1H), 9.74 (br s, 2H), 8.38 (d, J=7.9 Hz, 1H), 8.10 (s, 1H), 7.68 (d, J=8.0 Hz, 1H), 6.78 (s, 1H), 4.52 (s, 2H), 2.63 (s, 3H); MS (ESI) m/z: 162.3 [M+1]+.