Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH:35]=[O:36])=[C:19]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]([C:32]([NH2:34])=[O:33])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.ClCCl.O.ClCCl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:35][OH:36])=[C:19]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]([C:32]([NH2:34])=[O:33])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c5ccccc54)c3C=O)ncc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c5ccccc54)c3CO)ncc2c1
Reaction time: 0.17 h
Yield: 69.4 %

Procedure:
To a cooled (ice bath) flask containing 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-formylphenyl)-1H-indole-3-carboxamide (51 mg, 0.11 mmol) dissolved in methanol/dichloromethane (1.35 ml, 2.9:1) was added a solution of sodium borohydride (20 mg, 0.53 mmol) in water (0.35 ml), via slow drop-wise addition. The mixture was stirred for 10 minutes and then taken up in dichloromethane (20 ml) and water (20 ml). The contents were poured into a separatory funnel and agitated. The organic phase was collected and washed with a solution of 50% diluted brine (20 ml). The dichloromethane layer was collected and the aqueous phases were back extracted with methylene chloride (2×20 mL). The organic phases were combined, dried over magnesium sulfate, filtered and stripped. The crude material was purified by filtration through a short column of silica gel, eluting with 7.5% methanol/dichloromethane. The desired fraction was collected and then the material was crystallized from a solution of hot dichloromethane/hexanes to provide white crystalline product as 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-1H-indole-3-carboxamide (37 mg). LC/MS calcd for C28H25FN4O3 (m/e) 484.54, obsd 485.0 (M+H, ES+): 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.44 (s, 9H) 4.03-4.37 (m, 2H) 5.49-6.00 (br. s, 2H) 7.18-7.38 (m, 3H) 7.49-7.71 (m, 5H) 8.13-8.28 (m, 2H) 8.32 (d, J=2.64 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: CO
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(F)c([N+](=O)[O-])c1

Procedure:
To a solution of 4-fluoro-3-nitro-benzoic acid (5.05 g, 27 mmol) in 50 mL methanol was added 1 mL of 99% sulphuric acid. The mixture was refluxed overnight, allowed to cool and then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was then dried over sodium sulphate and concentrated in vacuo to give the title product as a white solid (5.15 g, 26 mmol). 1H NMR (DMSO) δ 8.50 (1H, d), 8.30-8.27 (1H, m), 7.71 (1H, t), 3.90 (3H, s); LC-MS Rt 1.93 min.
Reaction SMILES: [CH:1]#[N:2].[Cl:3][C:4]([Cl:15])([Cl:14])[C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1.[C-]#N.[K+]>C(Cl)Cl.O.CN(C)CC1C=CC=CC=1>[Cl:3][C:4]([Cl:15])([Cl:14])[C:5]1[CH:13]=[CH:12][C:8]([C:9]([C:1]#[N:2])=[O:10])=[CH:7][CH:6]=1
Reactant: O=C(Cl)c1ccc(C(Cl)(Cl)Cl)cc1
Reactant: C#N
Agent: CN(C)Cc1ccccc1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: N#CC(=O)c1ccc(C(Cl)(Cl)Cl)cc1
Reaction time: 2 h
Yield: 48 %

Procedure:
50 ml of hydrogen cyanide, dissolved in 150 ml of methylene chloride, are added dropwise at -10° C. to -20° C. to a solution of 275 g of p-trichloromethylbenzoyl chloride and 2 g of dimethylbenzylamine in 1.5 l of methylene chloride. Subsequently, a solution of 60 g of potassium cyanide in 120 ml of water is slowly added dropwise at the same temperature and, finally, the mixture is stirred for a further two hours. The solids which have precipitated are filtered off with suction, the phases are separated and the organic phase is washed several times with water, dried over Na2SO4 and concentrated. A little ether is added to the remaining oily residue, whereupon 52 g (20%) of dimeric p-trichloromethylbenzoyl cyanide crystallize out, and the crystals are filtered off with suction. 127 g (48% of theoretical) of p-trichloromethylbenzoyl cyanide can be obtained from the filtrate by vacuum distillation.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH:13]([CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:21][CH2:20]1)[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.CO.[BH4-].[Na+]>O>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]([OH:16])[CH:13]([CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:21][CH2:20]1)[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Nc1c2c(nc3ccccc13)CCC(CCC1CCN(Cc3ccccc3)CC1)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1c2c(nc3ccccc13)CCC(CCC1CCN(Cc3ccccc3)CC1)C2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
0.41 gm of 9-amino-2-(2-(1-benzylpiperidin-4-yl)ethyl)-1,2,3,4-tetrahydroacridin-1-one was dissolved into 10 ml of methanol. To the solution was added 0.15 gm of sodium borohydride, and the mixture was stirred for 2 hours at room temperature. After the addition of 30 ml of water, the reaction mixture was extracted with chloroform. The extract was washed with saturated brine, dried, and evaporated under reduced pressure. 0.28 gm of 9-amino-2-(2-(1-benzylpiperidin-4-yl)ethyl)-1,2,3,4-tetrahydroacridin-1-ol (Compound (I) with R1 =R3 =H, R2 =-H2, A=>CH(CH2)n -, Y=>CHOH, m=2, and n=2) was obtained by recrystallizing the residue from ethyl acetate.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:29])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:28])[N:16]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[CH:10][CH:9]=1)[NH2:6].[Cl:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:32]=1[C:33](O)=[O:34].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:2][O:3][C:4](=[O:29])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:28])[N:16]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[CH:12][CH:13]=1)[NH:6][C:33]([C:32]1[C:36]([CH3:40])=[CH:37][CH:38]=[CH:39][C:31]=1[Cl:30])=[O:34]
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cc(Cl)cn(Cc3ccccc3)c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2cc(Cl)cn(Cc3ccccc3)c2=O)cc1)NC(=O)c1c(C)cccc1Cl
Yield: 58.6 %

Procedure:
A solution of 4-(1-benzyl-5-chloro-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride (100 mg, 0.23 mmol), 2-chloro-6-methylbenzoic acid (47 mg, 0.28 mmol), DIEA (200 μL, 1.2 mmol) and HBTU (133 mg, 0.35 mmol) in DMF (2 mL) was stirred at room temperature for 18 hr. The mixture was concentrated, the residue was dissolved in ethyl acetate (15 mL), was washed with 0.5 N HCl (1×5 mL), sat. NaHCO3 (1×5 mL), brine (1×5 mL) and was dried (MgSO4). The residue obtained upon evaporation was chromatographed on 25 g of silica gel, eluting with 45:55 ethyl acetate:hexane to give 4-(1-benzyl-5-chloro-2-oxo-3-pyridinyl)-N-[(2-chloro-6-methylphenyl)carbonyl]-L-phenylalanine methyl ester (74 mg, 58%). Obs. Mass 397.1313. Calcd. Mass 397.1320 (M+H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1[S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl.N1C=CC=CC=1>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([S:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][S:28]([C:20]2[O:19][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH:21]=2)(=[O:29])=[O:30])(=[O:11])=[O:10])=[CH:17][CH:16]=1
Reactant: Nc1ccccc1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccccc1NS(=O)(=O)c1cc2ccccc2o1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
To a solution of N-(2-aminophenyl)-4-chlorobenzenesulfonamide (0.5 mmol, prepared as in Example 11) in DCM (1 mL) and pyridine (1 mL), benzofuran-2-sulfonyl chloride (0.55 mmol), prepared as above, was added at RT and the reaction mixture was then allowed to stir at RT overnight or until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% aqueous HCl (5 mL), water (5 mL) and brine (5 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to afford 92 mg benzofuran-2-sulfonic acid [2-(4-chlorobenzenesulfonylamino)phenyl]-amide. LC: Tr 1.13 min, MS: 464.0 (M+1)+.
Reaction SMILES: O.O.O.O.O.O.O.O.O.O.[O-:11][P:12]([O:15][P:16]([O-:19])([O-:18])=[O:17])(=[O:14])[O-:13].[Na+].[Na+].[Na+].[Na+].[CH2:24]([N:28]([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27].N1C=CC=CC=1>O.CN(C)C=O>[O-:13][P:12]([O:15][P:16]([OH:19])([O-:18])=[O:17])(=[O:11])[O-:14].[CH2:33]([NH+:28]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:34][CH2:35][CH3:36].[CH2:33]([NH+:28]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:34][CH2:35][CH3:36].[CH2:33]([NH+:28]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:34][CH2:35][CH3:36]
Reactant: O=P([O-])([O-])OP(=O)([O-])[O-]
Reactant: CCCCN(CCCC)CCCC
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCC[NH+](CCCC)CCCC
Product: O=P([O-])([O-])OP(=O)([O-])O

Procedure:
Tetrasodium pyrophosphate decahydrate (4.46 g, 10 mmol) was dissolved in the minimum amount of water (about 50 mL) and passed through a column of AG50W X8 (100-200 mesh, 4×10 cm bed) poured in water. The column was eluted with water and the eluent was collected in an ice-cooled flask until pH of the eluent approached neutrality. Tri-n-butylamine (Aldrich Gold Label, 7.1 mL, 30 mmol) was added to the eluent and the two phases were stirred vigorously until all of the amine dissolved. The resulting solution was lyophilized. The residue was co-evaporated twice with dry pyridine and once with dry dimethylformamide. The residue was dissolved in dry dimethylforamide (10 mL) and the resulting 1.0M solution was stored (for as long as one month) at 0° under argon until used.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:8]([NH:9][CH2:10][CH3:11])=[CH:7][N:6]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:5]=1.C1OC1C.[Cl:22][CH2:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl>[Cl:22][CH2:23][CH2:24][C:25]([N:9]([C:8]1[C:4]([Cl:3])=[N:5][N:6]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=1)[CH2:10][CH3:11])=[O:26]
Reactant: O=C(Cl)CCCl
Reactant: CCNc1cn(-c2cccnc2)nc1Cl
Agent: CC1CO1
Agent: Cl
Solvent: ClCCl
Product: CCN(C(=O)CCCl)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
To a stirred solution of 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine dihydrochloride (1.00 g, 3.38 mmol) in CH2Cl2 (7 mL) was added propylene oxide (1.00 mL, 13.5 mmol) followed by 3-chloropropanoyl chloride (0.360 mL, 3.72 mmol). This was stirred at room temperature for 16 hours, and then the reaction mixture was then diluted with CH2Cl2 and washed with water. The phases were separated, the organic were dried, concentrated and purified by silica gel chromatography eluting with 0%-50% acetone/hexanes to afford a white solid (0.850 g, 80%): mp 85-86° C.; 1H NMR (400 MHz, CDCl3) δ 8.96 (d, J=2.6 Hz, 1H), 8.64 (dd, J=4.7, 1.4 Hz, 1H), 8.05 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.98 (s, 1H), 7.47 (ddd, J=8.4, 4.8, 0.6 Hz, 1H), 3.80 (t, J=6.7 Hz, 2H), 3.74 (q, J=7.1 Hz, 2H), 2.64 (t, J=6.7 Hz, 2H), 1.18 (t, J=7.2 Hz, 3H); ESIMS m/z 313 ([M+H]+).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([O:6][CH:7]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH3:8])[CH2:2]1.O.[OH-].[Li+].Cl>CO.O>[O:1]1[CH2:5][CH2:4][CH:3]([O:6][CH:7]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH3:8])[CH2:2]1
Reactant: COC(=O)c1ccc(C(C)OC2CCOC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(OC1CCOC1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.9 %

Procedure:
To the solution of methyl 4-(1-(tetrahydrofuran-3-yloxy)ethyl)benzoate (371 mg, 1.48 mmol) in methanol (15 mL) and water (5 mL) was added lithium hydroxide hydrate (100 mg, 2.4 mmol) were add ed. The mixture was stirred at room temperature for 12 hours. Then the reaction mixture was acidified by hydrochloric acid aqueous solution (1 N) to adjust pH=6 and extracted with dichloro methane (10 mL×3). The organic layers were combined and concentrated to give 4-(1-(tetrahydrofuran-3-yloxy)ethyl)benzoic acid (311 mg, 89%)
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])(=[O:3])[CH3:2].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH:8][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCCNc1cccc(NC(C)=O)c1

Procedure:
3-Acetylaminoaniline (15 parts) was reacted with n-octyl bromide (19.3 parts) at 90° to 100° C. for 4 hours in the presence of anhydrous potassium carbonate (6.9 parts) to obtain 3-acetylamino-N-octylaniline. Thereafter, reaction was further continued at 120° to 130° C. for 4 hours with addition of n-hexyl bromide (16.5 parts) and anhydrous potassium carbonate (6.9 parts) to obtain 3-acetylamino-N-n-octyl-N-n-hexylaniline (coupling component). In the same manner as in Example 1, 2-cyano-4-nitro-6-chloroaniline was diazotized and coupled with the above coupling component to obtain 45.9 parts of a dye (5).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][C:11]3[CH:15]=[C:16]([S:19](Cl)(=[O:21])=[O:20])[CH:17]=[CH:18][C:10]2=3)=[C:5]([O:23][CH3:24])[CH:4]=1)#[N:2].[F:25][C:26]1[C:31]([OH:32])=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:27]=1[F:36].C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][C:11]3[CH:15]=[C:16]([S:19]([O:32][C:31]4[C:30]([F:33])=[C:29]([F:34])[C:28]([F:35])=[C:27]([F:36])[C:26]=4[F:25])(=[O:21])=[O:20])[CH:17]=[CH:18][C:10]2=3)=[C:5]([O:23][CH3:24])[CH:4]=1)#[N:2]
Reactant: COc1cc(C#N)ccc1N1CCOc2cc(S(=O)(=O)Cl)ccc21
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C#N)ccc1N1CCOc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To a solution of 4-(4-cyano-2-methoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (220 mg, 0.603 mmol) in DCM (5 mL) was added pentafluorophenol (110 mg, 0.603 mmol) at 0° C. Triethylamine (0.12 mL, 0.904 mmol) was added at 0° C. and the reaction mixture was stirred at room temperature for 1 h. After completion, the reaction mixture was diluted with DCM (3 mL) and concentrated under reduced pressure. The crude mass thus obtained was purified by column chromatography (12 g column; elution: 5% ethyl acetate in hexane) to get perfluorophenyl 4-(4-cyano-2-methoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (180 mg, 58.4%) as a clear liquid. m/z (ESI) 512.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[CH:10]1[O:14][CH2:13][CH2:12][CH2:11]1>>[O:14]1[CH2:13][CH2:12][CH2:11][CH:10]1[CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(Br)cc1
Reactant: BrCC1CCCO1
Product: Brc1ccc(OCC2CCCO2)cc1

Procedure:
Prepared by the method of Example 42 (b) using 4-bromophenol and tetrahydrofurfuryl bromide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].CN(C)C=O.I[CH:15]([CH3:17])[CH3:16]>C(=O)([O-])O.[K+].O>[CH:15]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])([CH3:17])[CH3:16]
Reactant: Nc1ccccc1O
Reactant: CC(C)I
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Nc1ccccc1O

Procedure:
Into a 100 mL flask purged with nitrogen were added 12 g (109.92 mmol) of o-aminophenol and 60 mL of dimethylformamide (DMF), and the resultant mixture was stirred at room temperature and dissolved. Then, the obtained solution was mixed with 22.4 g (132 mmol) of 2-iodopropane such (molar ratio of 2-iodopropane to o-aminophenol: 1.2), and further with 11.4 g (114 mmol) of potassium hydrogencarbonate (KHCO3) as a catalyst, and the resultant mixture was stirred at room temperature for 5 h. After conducting the reaction for 5 h, 50 mL of water was added to the reaction solution to terminate the reaction.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[N+:18]([C:21]1[CH:22]=[C:23]([CH2:27]Br)[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19]>CC(C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:27][C:23]1[CH:22]=[C:21]([N+:18]([O-:20])=[O:19])[CH:26]=[CH:25][CH:24]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cccc(COc2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
A stirred solution of 3.8 grams (0.026 mole) of 2-naphthol and 3.6 grams (0.026 mole) of potassium carbonate in 200 mL of acetone was heated at reflux for about 30 minutes. The reaction mixture was then cooled to ambient temperature, and 5.0 grams (0.023 mole) of 3-nitrophenylmethyl bromide was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was then warmed to reflux where it stirred for about 18 hours. After this time the reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was partitioned between ethyl acetate and an aqueous solution saturated with sodium bicarbonate. The organic layer was separated and washed with three 50 mL portions of an aqueous solution saturated with sodium bicarbonate and then with one 50 mL portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to a residue. The residue was crystallized with hexane, yielding about 4.5 grams of 3-(naphth-2-yloxymethyl)nitrobenzene. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH3:10][C:11]([CH:13]=O)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[C:11]([CH3:13])[CH:10]=[N:9]2
Reactant: CC(=O)C=O
Reactant: Nc1ccc(Br)cc1N
Solvent: CC#N
Product: Cc1cnc2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from Example 61A (9.4 g, 50 mmol) in acetonitrile (100 mL) was treated with 40% aqueous pyruvic aldehyde (11.0 mL, 60 mmol) dropwise. After stirring at room temperature for 2 hours, the mixture was concentrated and the residue was suspended in IPAc (100 mL) and filtered. The filtrate was washed with 20% brine, dried with Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography eluting with heptane:EtOH:MeOH (8:2:1) to provide the title compounds. MS 224 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 8.72 (s, 1H), 8.23 (d, J=2.2 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 7.75-7.93 (m, 4H), 2.78 (s, 3H), 2.76 (s, 3H); 13C NMR (400 MHz, CDCl3) δ 154.32, 153.73, 146.34, 145.83, 142.28, 141.17, 140.45, 139.34, 133.17, 132.15, 131.15, 130.75, 130.16, 129.71, 123.66, 122.38, 22.89.
Reaction SMILES: C(NC(C)CNC(=S)SC)(=O)C.[C:13]([NH:16][CH2:17][CH:18]([NH:20][C:21](=[S:24])SC)[CH3:19])(=[O:15])[CH3:14].[N-:25]=[N+:26]=[N-:27].[Na+]>O1CCOCC1.O>[C:13]([NH:16][CH2:17][CH:18]([N:20]1[C:21]([SH:24])=[N:27][N:26]=[N:25]1)[CH3:19])(=[O:15])[CH3:14]
Reactant: CSC(=S)NC(C)CNC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: CSC(=S)NCC(C)NC(C)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)NCC(C)n1nnnc1S
Yield: 27 %

Procedure:
A mixture of methyl N-(2-acetamidopropyl)dithiocarbamate and methyl N-[1-(acetamidomethyl)ethyl]dithiocarbamate (100 g) in dioxane (300 ml) and a solution of sodium azide (41 g) in water (270 ml) were stirred for 4.5 hours under reflux. The reaction mixture was concentrated to half volume under reduced pressure, washed with diethyl ether and acidified with concentrated hydrochloric acid. The resulting precipitate was collected by filtration and washed with diethyl ether to give pale yellow powder of 1-[1-(acetamidomethyl)ethyl]-1H-tetrazole-5-thiol (26.32 g), mp 176° to 178° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=2[C:12](I)=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:25]C=C)[CH2:22]CC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[C:21]([C:12]1[C:13]2[C:18](=[O:19])[NH:17][N:16]=[CH:15][C:14]=2[N:10]([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:11]=1)(=[O:25])[CH3:22]
Reactant: C=COCCCC
Reactant: O=c1[nH]ncc2c1c(I)cn2COCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)c1cn(COCc2ccccc2)c2cn[nH]c(=O)c12
Temperature: 100 °C
Reaction time: 7.5 h
Yield: 40 %

Procedure:
To 43 ml of dehydrated N,N-dimethylformamide solution containing 6.48 g (17.0 mmol) of 1-benzyloxymethyl-3-iodo-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 21-(b) were added 0.19 g (0.46 mmol) of 1,3-bis(diphenylphosphino)propane, 94 mg (0.42 mmol) of palladium acetate and 8.4 g (83.9 mmol) of butyl-vinyl ether, and after degassing under reduced pressure, 4.7 ml of triethylamine was further added to the mixture under nitrogen atmosphere, and the mixture was stirred at 100° C. for 7.5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the obtained residue was applied to silica gel column chromatography (Eluent; toluene:ethyl acetate=7:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 2.02 g of the title compound as a pale yellowish solid. (Yield: 40%)
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][OH:13])[CH:6]=[CH:5]2.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[CH:28])=[N:25][CH:26]=2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[C:28][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[CH:8]=[C:7]([CH2:12][OH:13])[CH:6]=[CH:5]4)=[N:25][CH:26]=2)=[CH:19][CH:20]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: OCc1ccc2cc(I)ccc2c1
Product: OCc1ccc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc2c1

Procedure:
Prepared according to general working method I from (6-iodo-naphthalen-2-yl)-methanol (450 mg, 1.58 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (342 mg, 1.60 mmol).