Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[C:6]3[CH:11]=[CH:10][S:9][C:7]=3[S:8][C:4]=2[CH:3]=[C:2]1[C:12]([OH:14])=O.[Al+3].[Cl-].[Cl-].[Cl-].[C:19](Cl)(=O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]C.Cl>ClCCl>[C:12]([C:2]1[S:1][C:5]2[C:6]3[CH:11]=[CH:10][S:9][C:7]=3[S:8][C:4]=2[CH:3]=1)(=[O:14])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C(O)c1cc2sc3sccc3c2s1
Reactant: CCCCCCCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCC(=O)c1cc2sc3sccc3c2s1
Yield: 62.8 %

Procedure:
Dithienothiophene 2 (R1═R2═R3═R4═H) (765 mg, 3.90 mmol) was dissolved in dry dichloromethane (35 cm3) and the solution was ice-cooled before AlCl3 (790 mg, 5.92 mmol) was added in one portion yielding a dark mixture. A solution of octanoyl chloride (1.00 g, 6.02 mmol) in dichloromethane (20 cm3) was added dropwise over a 20 minute period and the mixture was then allowed to stand at room temperature for a further thirty minutes. It was then added to ice and the mixture was acidified with dilute hydrochloric acid (100 cm3). Additional dichloromethane (100 cm3) was added and the layers separated. The organic layer was washed with water, dried over MgSO4 and concentrated. Column Chromatography (hexane—30% dichloromethane/hexane) afforded 790 mg (63%) of the title compound. An analytical sample may be prepared by recrystallisation from a mixture of dichloromethane and methanol. Rf 0.31 (1:1 dichloromethane/hexane); m.p. 130-131° C.; 1H (250 MHz, CDCl3) δ 0.89 (3H, t, J6.5, CH2CH3); 1.25 (8H, br s, CH2CH2CH2); 1.78 (2H, m, CH2CH2CO); 2.93 (2H, t, J7.5, CH2CO); 7.32 (1H, d, J5.0, Dt-H); 7.52 (1H, d, J5.0, Dt-H); 7.91 (1H, s, Dt-H); 13C (100 MHz, CDCl3) δ 14.1; 22.6; 25.0; 29.1; 29.3; 30.9; 31.7; 39.0; 120.9; 125.5; 129.0; 141.4; 144.4; 144.9; 193.7; v (cm−1, KBr) 600, 702, 1191, 1364, 1466, 1493, 1644 (C═O), 2925; Calc. for C16H18S3O C, 59.6; H, 5.6. Found: C, 59.2; H, 5.6.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:8]=2[CH:9]=1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:22]1[S:23][C:24]2[C:25]([N:30]=1)=[N:26][CH:27]=[CH:28][CH:29]=2.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14][C:22]3[S:23][C:24]4[C:25]([N:30]=3)=[N:26][CH:27]=[CH:28][CH:29]=4)=[CH:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: Clc1nc2ncccc2s1
Reactant: COC(=O)c1cc2cc(O)ccc2o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2cc(Oc3nc4ncccc4s3)ccc2o1
Temperature: 50 °C
Yield: 102.1 %

Procedure:
To a solution of 5-hydroxy-benzofuran-2-carboxylic acid methyl ester (1.5 g, 7.8 mmol) in DMF (78 mL) was added Cs2CO3 (7.6 g, 26 mmol) and 2-chloro-thiazolo[4,5-b]pyridine (1.6 g, 7.8 mmol). The reaction mixture was heated (50° C., 10 h), cooled (rt) and water was added (50 mL). The resulting solid was filtered to provide the title compound as a colorless solid (2.6 g, 100%). MS (ESI): mass calcd. for C16H10N2O4S, 326.0; m/z found, 327.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.57 (dd, J=4.8, 1.6, 1H), 8.03 (dd, J=7.9, 1.6, 1H), 7.84 (d, J=2.4, 1H), 7.64 (d, J=9.0, 1H), 7.54 (d, J=0.9, 1H), 7.47 (dd, J=9.0, 2.5, 1H), 7.22 (dd, J=7.9, 4.8, 1H), 4.04-3.86 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH:10]([CH3:12])[CH3:11])[C:3]=1[CH3:13].[Li]CCCC.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[C:23]([CH3:29])[CH:22]=1>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:25]([C:24]2[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][C:23]=2[CH3:29])[OH:26])=[C:3]([CH3:13])[C:4]=1[CH:10]([CH3:12])[CH3:11]
Reactant: COc1ccc(Br)c(C)c1C(C)C
Reactant: COc1ccc(C=O)c(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccc(OC)c(C(C)C)c2C)c(C)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 116.1 %

Procedure:
To a stirring solution of 1-bromo-3-iso-propyl-4-methoxy-2-methyl-benzene (compound 7-16, step c; 0.7 g, 2.88 mmol) in THF (20 mL) at −78° C. was added n-BuLi (1.6 mL, 2.5 M in hexanes). The mixture was stirred at −78° C. for 1 hr and 4-methoxy-2-methyl-benzaldehyde (0.37 mL, 2.74 mmol) was added. The reaction mixture was stirred at −78° C. for 1 hr, allowed to warm to room temperature and stirred for 1 hr. The reaction mixture was quenched with saturated NH4Cl and diluted with diethyl ether. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude (4′-methoxy-3′-iso-propyl-2′-methylphenyl)-(4-methoxy-2-methylphenyl)-methanol as a light yellow oil (1.0 g, 100%). This crude oil was dissolved into EtOAc (25 mL) and AcOH (5 mL) and Pd/C (0.1 g) was added. After stirring at rt for 6 hours, the reaction mixture was filtered through the Celite and concentrated under reduced pressure to afford crude 4-(4′-methoxy-2′-methyl-3′-iso-propylbenzyl)-3-methyl-anisole as a yellow oil (0.8 g, 93%): 1H NMR (300 MHz, DMSO-d6): δ 6.88-6.80 (m, 5 H), 3.77 (s, 2 H), 3.74 (s, 3 H), 3.71 (s, 3 H), 3.34 (m, 1 H), 2.22 (s, 3 H), 2.14 (s, 3 H), 1.28 (d, J=6.9 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=8% ethyl acetate in hexanes; Rf=0.56.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]2[CH2:8][CH2:9][CH:10]([CH2:14][NH2:15])[CH2:11][CH:12](O)[C:6]=2[CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O>O1CCOCC1>[N+:1]([C:4]1[CH:17]=[CH:16][C:7]2[CH2:8][CH2:9][CH:10]([CH2:14][NH2:15])[CH:11]=[CH:12][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: NCC1CCc2ccc([N+](=O)[O-])cc2C(O)C1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: NCC1C=Cc2cc([N+](=O)[O-])ccc2CC1
Reaction time: 0.05 h
Yield: 108.3 %

Procedure:
A mixture of 10 g of the product of Step D in 100 ml of dioxane under nitrogen was heated to reflux and 20 ml of concentrated sulfuric acid were added thereto dropwise over 3 minutes. The mixture was stirred at reflux for 20 minutes and was then concentrated to 50 ml under reduced pressure. 300 ml of water were added and the neutral fraction was removed with ether. The aqueous phase was made alkaline at 10° C. with sodium hydroxide and was then extracted with methylene chloride. The organic extracts were dried and evaporated to dryness to obtain 10 g of 2-nitro-6,7-dihydro [5H] benzocycloheptene-7-methanamine in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:26][C@@H:27]([OH:30])[CH2:28][NH2:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:29][CH2:28][C@H:27]([OH:30])[CH3:26])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C[C@@H](O)CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Product: C[C@@H](O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and R-(−)-1-amino-2-propanol employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) tautomers are observed δ 11.81 (1H, t, J=5.7), 10.81 (1H, br s), 10.10 (1H, br s), 8.18 (0.58H, s), 8.15 (0.42H, s), 7.36-7.23 (3H, m), 7.15-7.08 (2H, m), 4,74 (1H, t, J=4.4 Hz), 3.98 (2H, s), 3.75-3.65 (1H, m), 3.26-3.15 (2H, m), 1.06 (3H, m); HRMS calcd for C19H18FN3O4+H+: 372.1360. Found 372.1367.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:16])[N:5]([C:8]2[CH:13]=[N:12][N:11]([CH3:14])[C:10](=[O:15])[CH:9]=2)[C:6]=1[CH3:7].[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)#[CH:18]>>[CH3:16][C:4]1[N:5]([C:8]2[CH:13]=[N:12][N:11]([CH3:14])[C:10](=[O:15])[CH:9]=2)[C:6]([CH3:7])=[C:2]([C:18]#[C:17][C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)[N:3]=1
Reactant: C#Cc1cccc(C)c1
Reactant: Cc1nc(I)c(C)n1-c1cnn(C)c(=O)c1
Product: Cc1cccc(C#Cc2nc(C)n(-c3cnn(C)c(=O)c3)c2C)c1

Procedure:
The title compound, light yellow cristalline solid, MS: m/e=319.1 (M+H+), was prepared in accordance with the general method of example 1c from 5-(4-iodo-2,5-dimethyl-imidazol-1-yl)-2-methyl-2H-pyridazin-3-one and 1-ethynyl-3-methyl-benzene.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:13]1[S:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[C:15]([CH3:22])[CH:14]=1)([CH3:12])([CH3:11])[CH3:10].CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:22][C:15]1[CH:14]=[C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])[S:17][C:16]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1sc(C(C)(C)C)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1sc(C(C)(C)C)cc1CBr
Temperature: 25 °C
Yield: 42 %

Procedure:
N-bromosuccinimide (18.5 g, 0.103 mol) was added to a solution of methyl 5-tert-butyl-3-methylthiophene-2-carboxylate (109b) (20 g, 0.09 mol) and AIBN (0.774 g, 0.0047 mol) in CCl4 (200 mL). The mixture was refluxed for 2 h, cooled to room temperature and filtered. The filtrate was concentrated under vacuum and the obtained residue was purified by flash column chromatography (silica, 95:5 hexanes-/dichloromethane) to afford methyl 3-(bromomethyl)-5-tert-butylthiophene-2-carboxylate (109c) (11 g, 40%) as a pale yellow liquid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Cl:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[N:14]=[CH:13][CH:12]=1>>[Cl:10][C:11]1[C:20]2[C:15](=[C:16]([N+:1]([O-:4])=[O:2])[C:17]([Cl:21])=[CH:18][CH:19]=2)[N:14]=[CH:13][CH:12]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(Cl)ccc2c(Cl)ccnc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
Fuming nitric acid (8 ml) and concentrated sulfuric acid (16 ml) were combined cautiously at −10° C. 4,7-dichloroquinoline (5 g, 25 mmol) was added portionwise at −10° C. and after complete addition the mixture was allowed to warm to room temperature and stirring continued for 18 h. The reaction mixture was poured onto ice and the resulting solid removed by filtration washed with water (100 ml) to give the title compound (5.7 g, 94%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([F:11])[CH:4]=1.[CH3:12][O:13][C:14]1[CH:34]=[CH:33][C:17]([CH2:18][NH:19][S:20]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[F:11][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[O:9][CH3:10])[CH2:2][N:19]([CH2:18][C:17]1[CH:33]=[CH:34][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)[S:20]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=1)(=[O:22])=[O:21]
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Reactant: COc1ccc(CBr)cc1F
Product: COc1ccc(CN(Cc2ccc(OC)c(F)c2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from 4-(bromomethyl)-2-fluoro-1-methoxybenzene and methyl 4-(N-(4-methoxybenzyl)sulfamoyl)benzoate (example 5-10b). MS (M−H, 458.10); NMR (400 MHz, CD3OD): δ, ppm: 3.73 (s, 3H), 3.80 (s, 3H), 4.24 (s, 2H), 4.28 (s, 2H), 6.75 (m, 4H), 6.88 (m, 1H), 6.97 (d, 2H, J=8.6 Hz), 7.88 (d, 2H, J=8.3 Hz), 8.14 (d, 2H, J=8.3 Hz).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31][CH2:32][CH3:33])=[CH2:30])CCC>CN(C=O)C.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>[CH2:32]([O:31][C:29]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1)=[CH2:30])[CH3:33]
Reactant: CC(c1cc2cnn(C)c2cc1F)c1cnc2ccc(Cl)nn12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
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: C=C(OCC)c1ccc2ncc(C(C)c3cc4cnn(C)c4cc3F)n2n1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 64.5 %

Procedure:
To a solution of 6-chloro-3-(1-(6-fluoro-1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazine (900 mg, 1.910 mmol) in DMF (8 mL) was added Pd(Ph3P)4 (221 mg, 0.191 mmol). The mixture was stirred for 20 min, and tributyl(1-ethoxyvinyl)stannane (784 mg, 2.102 mmol) was added. The resulting mixture was heated at 100° C. until LC-MS showed the reaction was complete. The reaction mixture was filtered through celite and the solid was washed with ether. The combined filtrate was washed with water, dried over Na2SO4, and concentrated. The residue was purified by column chromatography with gradient hexane:EtOAc to give 450 mg (52%) of the title compound.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[C:9]([F:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[CH:2]1[O:4][CH2:3]1.[NH:15]1[CH:20]=[CH:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1>>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[CH:7]=[CH:6][N:5]2[CH2:1][CH:2]([OH:4])[CH2:3][N:15]1[CH2:16][CH:17]=[C:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:19][CH2:20]1
Reactant: Fc1cccc2c1ccn2CC1CO1
Reactant: C1=CC(c2c[nH]c3ccccc23)CCN1
Product: OC(CN1CC=C(c2c[nH]c3ccccc23)CC1)Cn1ccc2c(F)cccc21
Yield: 52.2 %

Procedure:
A methanolic solution of 1-N-glycidyl-4-fluoroindole (0.52 g, 3.0 mmole) from example 3 and 3-(4-tetrahydropyridinyl)indole (0.59 g, 3.0 mmole) was refluxed under nitrogen for 15 hours. The reaction mixture was concentrated in vacuo and the product purified by flash silica gel chromatography (ethyl acetate) to afford the titled compound as a pale yellow colored solid (0.61 g, 53% yield). Treatment with a 0.25M ethanolic solution of fumaric acid (0.5 equivalents) gave the required product as a yellow colored solid. The product was recrystallized from ethanol.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:23]=1)[CH2:17][N:18]=[N+]=[N-])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CO.[H][H]>CCOCC>[CH2:25]([O:24][C:22]1[CH:21]=[C:16]([CH:15]=[C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:23]=1)[CH2:17][NH2:18])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCOc1cc(CN=[N+]=[N-])cc(OCCCCCCCCCCCC)c1
Solvent: CO
Solvent: CCOCC
Product: CCCCCCCCCCCCOc1cc(CN)cc(OCCCCCCCCCCCC)c1
Yield: 88 %

Procedure:
A thick walled bottle containing a stir bar was flushed out with nitrogen gas, and 5% Palladium on activated carbon (0.53 g, 10% by mass) was added along with a solution of 50% methanol and ether (approximately 10 mL). 3,5-didodecoxybenzyl azide (5.3 g, 12.6 mmol) was added using 50% methanol and ether (approximately 40 mL). The mixture was hydrogenated with hydrogen gas at 40 psi for approximately 1½ hour. The mixture was then filtered through celite with a controlled vacuum using 50% methanol and ether. The solvent was removed from the filtrate under reduced pressure and the trace solvent was removed with the high vacuum. This produced a 5.7 g yield or a 88% yield. The NMR characterization data for the derivative is as follows. 1NMR (300 MHz, CDCl3): 0.87 (t, J=6.6, 8H, CH2CH3), 1.15-1.6 (m, 36H, CH2(CH2)9), 1.76 (p, J=8.0, 4H, OCH2CH2), 3.79 (s, 2H, ArCH2), 3.92 (t, J=6.6, 4H, OCH2CH2), 6.33 (t, J=2.2, 1H, ArH), 6.40 (d, J=2.2, 2H, ArH).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].C([O-])([O-])=O.[Na+].[Na+].[CH:17]1[C:29]2[CH:28]([CH2:30][O:31][C:32](C3CC(=O)N(O)C3=O)=[O:33])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1>O1CCOCC1.C(Cl)Cl>[CH:17]1[C:29]2[CH:28]([CH2:30][O:31][C:32](=[O:33])[NH:7][CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([Br:2])[CH:4]=3)[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: NCc1cccc(Br)c1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)C1CC(=O)N(O)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(NCc1cccc(Br)c1)OCC1c2ccccc2-c2ccccc21
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To 3-bromobenzylamine hydrochloride (16.0 g, 71.9 mmol) was added aqueous 9% Na2CO3 (211 mL) followed by 9-fluorenylmethyloxycarbonyl-N-hydroxysuccinimide (25.5 g, 75.5 mmol) in dioxane (211 mL). This was stirred 30 minutes, then diluted with CH2Cl2 (200 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with 1 M HCl, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was purified by recrystallization (ethyl acetate/hexanes) to obtain a fluffy, white solid (24 g, 59 mmol, 82%). 1H NMR (400 MHz, d6-DMSO): δ 7.90 (t, 1H, J=6.2 Hz), 7.88 (d, 2H, J=7.5 Hz), 7.68 (d, 2H, J=7.5 Hz), 7.43 (m, 4H), 7.32 (dd, 2H, J=7.5 Hz, 7.5 Hz), 7.26 (d, 1H, J=7.7 Hz), 7.20 (d, 1H, J=7.3 Hz), 4.35 (d, 2H, J=6.6 Hz), 4.22 (t, 1H, J=6.6 Hz), 4.17 (d, 2H, J=6.2 Hz). ESI/MS: 408 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40]N)=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:40][C:37]3[C:38]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Cl)c3)CC2)c1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3cccc(Cl)c3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methylphenylhydrazine hydrochloride: ESMS m/e: 528.2 (M+H)+.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][C:9]=2[N+:18]([O-:20])=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:21]N1C(C)(C)C(=O)N(Br)C1=O.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[Br:21][C:13]1[CH:12]=[C:11]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:10]=[C:9]([N+:18]([O-:20])=[O:19])[C:8]=1[NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NS(=O)(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(Br)c(NC2CCCCC2)c([N+](=O)[O-])c1
Reaction time: 18 h

Procedure:
A room temperature solution of Example 3A (1.81 g, 6.0 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (950 mg, 3.3 mmol) in dichloromethane was treated with trifluoracetic acid (796 uL, 9.0 mmol), stirred in darkness for 18 hours, treated with saturated NaHCO3, and extracted with diethyl ether. The combined extracts were washed with brine, dried (Na2SO4), and concentrated. The concentrate was purified by flash column chromatography on silica gel with 15% ethyl acetate/hexanes to provide the desired product. MS (ESI(−)) m/e 376 (M−H)−.
Reaction SMILES: OO.F[C:4](F)(F)[C:5]([O:7][C:8](=O)[C:9](F)(F)F)=O.[CH2:16]([N:23]1CC=C(C)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:16]([N:23]1[CH2:24][CH2:25][C:8]2([CH3:9])[CH:5]([O:7]2)[CH2:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1=CCN(Cc2ccccc2)CC1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Product: CC12CCN(Cc3ccccc3)CC1O2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of a 30% hydrogen peroxide solution (3.6 mL) and DCM (120 mL) were added trifluoroacetic anhydride (6.0 mL) at 0° C., and a solution of 1-benzyl-4-methyl-1,2,3,6-tetrahydropyridine (2.9 g) in DCM (10 mL) was further added thereto, followed by stirring at room temperature for 12 hours and then stirring at 50° C. for additional 3 hours. To the reaction mixture was added an aqueous Na2SO3 solution, followed by stirring until peroxides disappeared, and then extracting with DCM. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column (chloroform/MeOH) to obtain 3-benzyl-6-methyl-7-oxa-3-azabicyclo[4.1.0]heptane (1.8 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([F:14])([F:13])[F:12])[C:5]=1[NH2:15])([O-])=O>CCO>[F:12][C:11]([F:13])([F:14])[O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([NH2:1])[C:5]=1[NH2:15]
Reactant: Nc1c(OC(F)(F)F)cccc1[N+](=O)[O-]
Solvent: CCO
Product: Nc1cccc(OC(F)(F)F)c1N
Reaction time: 5 h

Procedure:
3-Trifluoromethoxy-benzene-1,2-diamine was synthesized by dissolving 0.79 g of 2-nitro-6-trifluoromethoxy-phenylamine (J. Med. Chem. 1999, 42, 15, 2828-2843) in 20 mL EtOH, evacuating 3 times with N2 and adding 80 mg of 10 wt % Pd/C. The reaction mixture was stirred under a H2 atmosphere (balloon) for 5 h. Filtration over a pad of celite and washing with EtOH and EtOAc yielded after concentration in vacuo 0.55 g of 3-trifluoromethoxy-benzene-1,2-diamine as brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10]/[CH:11]=O)=[CH:5][CH:4]=1.[C:19]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH3:22])=[O:20]>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH3:22][O:21][C:19](=[O:20])/[CH:23]=[CH:11]/[CH:10]=[C:9](/[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)\[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(/C(=C/C=O)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)/C=C/C=C(\c1ccccc1)c1ccc(OC)cc1
Yield: 80 %

Procedure:
As described in Example 99, (E)-3-(4-methoxyphenyl)-3-phenyl-2-propenal (8.7 g) was reacted with (carbomethoxymethylene)triphenylphosphorane (14.2 g) in carbon tetrachloride (50 mL) and dichloromethane (5 mL) overnight at room temperature. The crude ester was isolated in the usual manner and was purified by HPLC (ether-hexane; 3:17) to yield 8.6 g of (E,E)-5-(4-methoxyphenyl)-5-phenyl-2,4-pentadienoic acid methyl ester. Crystallization of a portion from ethyl acetate-hexane gave the analytical specimen, mp 88°-89.5° C. Anal. Calcd. for C19H18O3 : C, 77.53; H, 6.19 Found: C, 77.40; H, 6.18.
Reaction SMILES: [Br-:1].[NH2:2][N+:3]1[CH:7]=[CH:6][N:5]([CH2:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[C:4]=1[CH2:15][CH3:16].[CH3:17][N:18]([CH3:27])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>C(O)(=O)C>[Br-:1].[CH3:17][N:18]([CH3:27])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[N:2][N+:3]2[CH:7]=[CH:6][N:5]([CH2:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:12])[CH3:13])[C:4]=2[CH2:15][CH3:16])=[CH:21][CH:20]=1
Reactant: CCc1n(CC(=O)C(C)(C)C)cc[n+]1N
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Br-]
Solvent: CC(=O)O
Product: CCc1n(CC(=O)C(C)(C)C)cc[n+]1N=Cc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2.38 g (8.2 mmol) of 1-amino-2-ethyl-3-(3,3-dimethyl-2-oxobutyl)imidazolium bromide are dissolved in 30 ml of glacial acetic acid, whereupon the solution is treated with 1.22 g (8.2 mmol) of p-dimethylaminobenzaldehyde. After stirring at room temperature 48 hours the product is recrystallized by the addition of ether, chromatographed on 20 g of silica gel (particle size 0.063-0.200 mm) while eluting with methylene chloride/methanol (19:1 v/v) and recrystallized from ethanol/ether. There is obtained 1-[[4-(dimethylamino)benzylidene]amino]-2-ethyl-3-(pivaloylmethyl)imidazolium bromide of melting point 188°-189°.