Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:22])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][N:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:26][C:27]([O:29][CH3:30])=[O:28].N>CN(C=O)C>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[N:17]=[CH:16]4)[CH:7]=2)=[O:22])[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2[nH]ncc2c1
Reactant: COC(=O)CCl
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)ccc3C)ccc21
Reaction time: 2 h
Yield: 69.1 %

Procedure:
A solution of N-cyclopropyl-3-(1H-indazol-5-yl)-4-methylbenzamide (Example 17) (0.65 g) in dry DMF (26 ml) was treated with sodium hydride (60% oil dispersion, 0.134 g) under nitrogen. After 5 min methyl chloroacetate (0.29 g) was added and the mixture was stirred for 2 h. Aqueous ammonia (2M, 10 ml) was added and the solvent was removed under vacuum. The residue was purified by column chromatography on silica eluting with cyclohexane:ethyl acetate (2:1 to 1:1) to give the title compound (0.56 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([OH:23])[CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)[NH:7]C(OC(C)(C)C)=O.[CH3:25]CO.[ClH:28]>>[CH2:1]([O:2][C:3](=[O:24])[CH:4]([OH:23])[CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)[NH2:7])[CH3:25].[ClH:28]
Reactant: COC(=O)[C@H](O)CN(Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(O)CN(N)Cc1ccc(Br)cc1

Procedure:
A solution of (R)-3-[N-(4-bromobenzyl)-N′-t-butoxycarbonylhydrazino]-2-hydroxypropionic acid methyl ester (25 g, 62 mmol) in EtOH/HCl (310 mL, 1.0 M, 0.3 mol) was stirred overnight. The mixture was concentrated and the reside was washed with EtOAc (120 mL) and filtered to yield the title compound as a white solid HCl salt (15 g).
Reaction SMILES: [NH2:1][C:2](=[N:8][C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22](=[O:32])[CH2:23][NH:24]C(OC(C)(C)C)=O)[CH:15]=2)[N:13]=1)[NH:3][CH2:4][CH2:5][O:6][CH3:7].Cl.O1CCOCC1>CO>[NH2:1][C:2](=[N:8][C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22](=[O:32])[CH2:23][NH2:24])[CH:15]=2)[N:13]=1)[NH:3][CH2:4][CH2:5][O:6][CH3:7]
Reactant: COCCNC(N)=Nc1nc(-c2cccc(CNC(=O)CNC(=O)OC(C)(C)C)c2)cs1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COCCNC(N)=Nc1nc(-c2cccc(CNC(=O)CN)c2)cs1
Yield: 63.8 %

Procedure:
A solution of 2-[[(amino)(2-methoxyethylamino)methylene]amino]-4-(3-t-butoxycarbonylaminoacetylaminomethylphenyl)thiazole (1.6 g) and 4N-hydrogen chloride/dioxane (10 ml) in methanol (10 ml) was stirred at room temperature for 2.5 hours. The resulting precipitate was collected by filtration and then dissolved in water (50 ml). The mixture was alkalized to pH 10 with a 30% aqueous potassium carbonate solution. The resulting precipitate was collected by filtration. Recrystallization from a mixture of methanol and diisopropyl ether afforded 2-[[(amino)(2-methoxyethylamino)methylene]amino]-4-(3-aminoacetylaminomethylphenyl)thiazole (0.8 g).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[N:6][CH:5]=1.[CH3:12][C:13]([CH3:16])([O-:15])[CH3:14].[K+].C(O)(C)(C)C.Cl>C1COCC1>[C:13]([O:15][C:3](=[O:2])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[N:6][CH:5]=1)([CH3:16])([CH3:14])[CH3:12]
Reactant: COC(=O)c1cncc(O)c1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1cncc(O)c1
Yield: 34.2 %

Procedure:
5-Hydroxy-nicotinic acid methyl ester (1 g, 5.99 mmol) and potassium t-butoxide (4 g, 36 mmol) was stirred in THF (10 mL) and t-butanol (10 mL) at room temperature overnight. 1N HCl was added to adjust pH˜7 and the mixture was extracted with EtOAc (3×). The combined extracts were dried (Na2SO4), concentrated and purified by column chromatography to give the product (400 mg, 34%). MS (DCI) m/z 196 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[O:12][C:11]([NH:14][CH:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([O:29][CH2:30][CH3:31])[CH:23]=4)[CH2:17][CH2:16]3)=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-].O.Cl>C1COCC1.CO>[CH2:30]([O:29][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[CH3:28])[CH2:21][N:18]1[CH2:17][CH2:16][CH:15]([NH:14][C:11]2[O:12][C:13]3[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=[CH:8][C:9]=3[N:10]=2)[CH2:20][CH2:19]1)[CH3:31]
Reactant: CCOc1cc(CN2CCC(Nc3nc4cccc(C(=O)OC)c4o3)CC2)ccc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(CN2CCC(Nc3nc4cccc(C(=O)O)c4o3)CC2)ccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 0.1 %

Procedure:
To a solution of 2-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-benzooxazole-7-carboxylic acid methyl ester (22.0 mg, 52.0 mmol, 1.0 equiv; example 308/step 3) in a 1:1 mixture of THF/methanol (0.26 mL) was added a 1 M solution of LiOH in water (0.13 mL, 130.0 mmol, 2.5 equiv). After stirring for 18 h at rt, the pH of the reaction mixture was adjusted to 3.5 by addition of 1 M solution of HCl, the solution extracted with ethyl acetate (2×1 mL) and the combined organic phases washed with water (2×1 mL) and a conc. solution of sodium chloride (1 mL). The organic phase was dried over MgSO4, concentrated by evaporation under reduced pressure and the crude reaction product purified with column chromatography on silica eluting with ethyl acetate/acetone/acetic acid/water (6:2:1:1) providing 21.0 mg (96%) of the title compound. MS (ISP): 410.3 [M+H]+.
Reaction SMILES: [H-].[Na+].O=[C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1.O.[CH3:21]S(C)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:21]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CS(C)=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Solvent: O
Product: C=C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A sodium hydride (13.2 g) was added to an anhydrous dimethylsulfoxide (176 mL) and the mixture was heated for 2 hours at 60° C. After cooling, to a suspension of methyltriphenylphosphonium bromide (110.4 g) in dimethylsulfoxide (120 mL) was added the reaction mixture, and the mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added a solution of benzyl 4-oxo-1-piperidinecarboxylate (60 g) in dimethylsulfoxide (150 mL), the mixture was stirred for 1 hour at 50° C. After cooling, to the mixture was added water (2.5 L) and the mixture was extracted with ethyl acetate (1.5 L). The organic layer was washed with a saturated aqueous solution of ammonium chloride (0.5 L) and a saturated aqueous solution of sodium chloride (0.5 L), dried and then concentrated. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate:chloroform=9:1:1) to give the title compound (51.1 g) having the following physical data.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14](Br)=[CH:13][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:11]1[CH:21]=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[H][H]>[Pd].C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:11]1[CH:21]=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1cc(Br)n(COCc2ccccc2)c1C=O
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccn(COCc2ccccc2)c1C=O
Yield: 103 %

Procedure:
To 43 ml of toluene solution containing 3.66 g (10.0 mmol) of ethyl 1-benzyloxymethyl-5-bromo-2-formyl-1H-pyrrol-3-carboxylate obtained in Reference example 17-(c) were added 2.1 ml of N,N-diisopropylethylamine and 0.4 g of 5% palladium-active carbon, and the mixture was stirred under 1 atm hydrogen atmosphere at room temperature for 6 hours. After completion of the reaction, insoluble material was removed by filtration from the reaction mixture, ethyl acetate was added to the filtrate, and the filtrate was washed successively with water and a saturated aqueous solution of sodium chloride. The organic layer after separation was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 2.96 g the title compound as a pale yellowish solid substantially quantitatively.
Reaction SMILES: [C:1]([C@@H:3]([NH:12]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)#[N:2]>C(O)=O>[NH2:12][C@@H:3]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([I:11])=[CH:9][CH:10]=1)[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)N[C@H](C#N)Cc1ccc(I)cc1
Solvent: O=CO
Product: N#C[C@@H](N)Cc1ccc(I)cc1
Temperature: 50 °C
Yield: 87.9 %

Procedure:
(S)-tert-Butyl 1-cyano-2-(4-iodophenyl)ethylcarbamate (1.4 g) and formic acid (3 mL) were combined and heated at 50° C. for 10 min. Solvent was removed in vacuo and crude material was loaded onto an SCX cartridge. Non-basic impurities were washed off with methanol, then product was eluted with 10% ammonia in methanol. Solvent was removed in vacuo to give (S)-2-amino-3-(4-iodophenyl)propanenitrile (0.900 g).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18][CH2:19][CH2:20][CH3:21])[S:15][C:14]=3[S:22]([NH2:25])(=[O:24])=[O:23])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.N1(C2C=CC=CN=2)CCCC1.Cl[C:38]([O:40][CH2:41][CH2:42][CH2:43][CH3:44])=[O:39]>N1C=CC=CC=1>[CH2:41]([O:40][C:38]([NH:25][S:22]([C:14]1[S:15][C:16]([CH2:18][CH2:19][CH2:20][CH3:21])=[CH:17][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:8][CH:9]=1)(=[O:24])=[O:23])=[O:39])[CH2:42][CH2:43][CH3:44]
Reactant: CCCCOC(=O)Cl
Reactant: CCCCc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(N)(=O)=O)s1
Agent: c1ccc(N2CCCC2)nc1
Solvent: c1ccncc1
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CCCC)cc1-c1ccc(Cn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.9 %

Procedure:
3-(4Imidazol-1-ylmethylphenyl)-5-butylthiophene-2-sulfonamide (232 mg, 0.62 mmol; see step (d) above) was dissolved in pyridine (3 mL, dried over 4 Å molecular sieves). Pyrrolidinopyridine (91.6 mg, 0.618 mmol) and butyl chloroformate (785.7 μL, 0.618 mmol) were added to the mixture. The mixture was stirred overnight under a N2 atmosphere at room temperature. Evaporation and co-evaporation with acetonitrile to remove the solvents, followed by purification by column chromatography using 10% MeOH in chloroform as eluent, gave the title compound (29 mg, 0.061 mmol) in 10% yield.
Reaction SMILES: [C:1]([C@@H:5]([NH:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18]Cl)[CH:13]=1)[CH2:6][CH2:7][S:8][CH3:9])([O:3][CH3:4])=[O:2].[N-:21]=[N+:22]=[N-:23].[Li+]>CS(C)=O>[C:1]([C@@H:5]([NH:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:21]=[N+:22]=[N-:23])[CH:13]=1)[CH2:6][CH2:7][S:8][CH3:9])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1cccc(CCl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CS(C)=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1cccc(CN=[N+]=[N-])c1
Reaction time: 2 h

Procedure:
To a stirred solution of the product from Step A (13.52 g, 42.80 mmol) in 50 mL of dimethylsulfoxide under nitrogen was added lithium azide (2.3 g, 47.10 mmol). The solution was stirred for 2 h. The reaction mixture was then partitioned with 300 mL of ethyl acetate and 200 mL of water. The ethyl acetate layer was washed with 125 mL of saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as an oil. 1HNMR (300 MHz, CDCl3)δ7.75 (2H, m), 7.47 (2H, m), 7.02 (1H, d, J=8 Hz), 4.94 (1H, q, J=5 Hz), 4.41 (2H, s), 3.80 (3H, s), 2.60 (2H, t, J=6 Hz), 2.30 (1H, m), 2.15 (1H, m), 2.11 (3H, s).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][C:10]1([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=3)[CH:16]=[C:15]2[C:28]([O:30]CC)=O)[CH2:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+]>C(O)C>[O:30]=[C:28]1[C:15]2=[CH:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][C:22]=3[N:14]2[CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9][NH:8]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC3(CN)CC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1ccc2cc3n(c2c1)CC1(CC1)CNC3=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 35.5 %

Procedure:
Triethylamine (36.3 mL, 260.8 mmol) is added to the mixture of crude diethyl 1-{[1-(aminomethyl)cyclopropyl]methyl}-1H-indole-2,6-dicarboxylate (30 g, 86.9 mmol) and K2CO3 (36 g, 260.8 mmol) in ethanol (800 mL). The reaction mixture is heated at 80° C. for 2 h and it is cooled to room temperature and stirred for another 16 h. Solid K2CO3 is removed by filtration and the filtrate is concentrated to afford the crude compound which is purified by flash column chromatography using 3% methanol in CH2Cl2 to afford the title compound (9.2 g, 31% for 3 steps) as a white solid.
Reaction SMILES: O[C:2]1([C:13]([F:16])([F:15])[F:14])[C:10]2[C:5](=[CH:6][C:7]([O:11][CH3:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.P(Br)(Br)Br>O>[CH3:12][O:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([C:13]([F:14])([F:15])[F:16])=[CH:3][CH2:4]2)=[CH:9][CH:8]=1
Reactant: COc1ccc2c(c1)CCC2(O)C(F)(F)F
Agent: BrP(Br)Br
Solvent: O
Product: COc1ccc2c(c1)CC=C2C(F)(F)F
Temperature: 80 °C
Reaction time: 6 h
Yield: 92.7 %

Procedure:
To a stirred Compound 62(850 mg, 3.66 mmol) was added PBr3(9.90 g, 36.6 mmol) with ice-cooling. The reaction mixture was stirred at 80° C. for 6 h. The mixture was diluted with water with ice-cooling and extracted with CH2Cl2. The combined solution was washed with sat. NaHCO3 and brine, dried(MgSO4) and concentrated in vacuo to give crude product as a yellow oil. The crude product was purified by column chromatography on silica gel with hexane-ethyl acetate(50:1-40:1) to give Compound 63(727 mg, 93%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:35][C@@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH2:40][C@@H:36]([F:35])[CH2:37]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1
Reactant: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: F[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(N3CC[C@@H](F)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-1-hydroxycyclohexylmethyl)-amide, DIPEA and (R)-3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.56 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 442 [M+H]
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:20]([Cl:21])=[C:19]([O:22][CH3:23])[CH:18]=[CH:17][C:5]=1[C:6](=[N:15][OH:16])[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[F:14].N#N>CN(C=O)C>[Cl:21][C:20]1[C:4]2[O:16][N:15]=[C:6]([C:7]3[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=3[F:14])[C:5]=2[CH:17]=[CH:18][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(C(=NO)c2c(F)cccc2F)c(Cl)c1Cl
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(-c3c(F)cccc3F)noc2c1Cl
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 5 g of NaH in 200 ml of DMF, 48 g of 2,3-dichloro-4-methoxy-2',6'-difluorobenzophenone oxime in 250 ml of DMF is added dropwise in an atmosphere of N2 while the temperature is maintained at approximately 40° C. After the addition, the mixture is stirred 30 minutes and poured into ice water. A crude product, which is a mixture of isomers, is filtered off and chromatographed on silica gel with CHCl3 as eluant to yield 7-chloro-3-(2,6-difluorophenyl)-6-methoxy-1,2-benzisoxazole which is recrystallized from toluene for analysis, mp 175°-179° C.
Reaction SMILES: NC1C=CC(CCC[N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=CC=1.C(#N)C>C(O)(=O)C>[C:17]1([N:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(CCCN2CCN(c3ccccc3)CC2)cc1
Solvent: CC#N
Solvent: CC(=O)O
Product: c1ccc(N2CCNCC2)cc1

Procedure:
A mixture consisting of 29.5 gm (0.1 mol) of N-[γ-(p-amino-phenyl)-n-propyl]-N'-phenyl-piperazine (m.p. 102° C.), 5.8 gm (0.11 mol) of acetonitrile and 20 ml of glacial acetic acid was refluxed for 20 hours. Thereafter, the solvent was distilled off in vacuo, and the residue was recrystallized from dilute methanol, yielding 28.3 gm (81.3% of theory) of N-[γ-(p-β-cyanoethyl-amino]-phenyl)-n-propyl]-N'-phenyl-piperazine, m.p. 141°-143° C.
Reaction SMILES: Br[C:2]1[C:3](=[O:9])[CH2:4][CH2:5][C:6]=1[O:7][CH3:8].[C:10]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].ClCCl.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:3](=[O:9])[CH2:4][CH2:5][C:6]=2[O:7][CH3:8])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: COC1=C(Br)C(=O)CC1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: COC1=C(c2ccc(C(C)(C)C)cc2)C(=O)CC1
Yield: 79.1 %

Procedure:
A mixture of Example 7B (440 mg, 2.303 mmol), 4-tert-butylphenylboronic acid (492 mg, 2.76 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (188 mg, 0.230 mmol) and K2CO3 (637 mg, 4.61 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was stirred at 100° C. for 16 hours. The mixture was diluted with ethyl acetate (100 mL) and washed with brine (30 mL×4). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (on silica gel, eluted with petroleum ether/ethyl acetate=5:1, v/v) to afford the title compound (445 mg, 1.821 mmol, 79% yield) as a white solid. LC/MS (ESI) m/z 245 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[S:26][C:7]2[S:8][C:9]3([CH2:17][CH2:16][N:15](C(=O)C4C=CC=CC=4)[CH2:14][CH2:13]3)[CH2:10][C:11](=[O:12])[C:6]=2[CH:5]=1)([O-:3])=[O:2].[ClH:27]>CO>[ClH:27].[N+:1]([C:4]1[S:26][C:7]2[S:8][C:9]3([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[CH2:10][C:11](=[O:12])[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CC2(CCN(C(=O)c3ccccc3)CC2)Sc2sc([N+](=O)[O-])cc21
Agent: Cl
Solvent: CO
Product: O=C1CC2(CCNCC2)Sc2sc([N+](=O)[O-])cc21
Temperature: 25 °C
Yield: 73 %

Procedure:
A suspension of 1.1 g (2.9 mmol) of 2'-nitro-1-(benzoyl)spiro(piperidine-4,6'-(6H)thieno[2,3-b]thiopyran)-4'(5'H)-one in 25 mL methanol was treated with 25 ml of 6N HCl and heated to reflux for 3 days. The reaction was cooled to ambient temperature and the solid collected and dried in vacuo, to give 680 mg (73%) of the product, mp=262° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].[CH3:21][O:22][CH2:23][CH2:24]Br.[Cl-].[NH4+]>CN(C)C=O.O>[CH3:21][O:22][CH2:23][CH2:24][O:18][CH:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:13][CH2:14]1
Reactant: COCCBr
Reactant: COc1cc(N2CCC(O)CC2)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOC1CCN(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Yield: 29.8 %

Procedure:
To a solution of 1-(3-Methoxy-4-nitro-phenyl)-piperidin-4-ol (300 mg, 1.2 mmol) in N,N-dimethylformamide (3.0 mL), sodium hydride (1.52 g, 3.8 mmol) is added. After stirring, 2-bromoethyl methyl ether (150 μl, 1.6 mmol) is added and the mixture is further stirred at 70° C. for 15 hours. After addition of saturated aqueous ammonium chloride, the mixture is poured into water and extracted twice with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane-ethyl acetate gradient) to afford 4-(2-Methoxy-ethoxy)-1-(3-methoxy-4-nitro-phenyl)-piperidine (111 mg, 29%) as a yellow oil.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][N:8]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:9]=2)[C:5]([Br:17])=[CH:4][CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>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.C1(C)C=CC=CC=1.C(O)CCC>[Br:17][C:5]1[C:6]2=[N:7][N:8]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:9]=[C:10]2[C:2]([C:18]2[CH:23]=[CH:22][C:21]([C:2]3[C:10]4[C:6](=[N:7][N:8]([C:11]5[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=5)[N:9]=4)[C:5]([Br:17])=[CH:4][CH:3]=3)=[CH:20][CH:19]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)c2nn(-c3ccncc3)nc12
Reactant: OB(O)c1ccc(B(O)O)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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: Brc1ccc(-c2ccc(-c3ccc(Br)c4nn(-c5ccncc5)nc34)cc2)c2nn(-c3ccncc3)nc12
Temperature: 110 °C

Procedure:
A mixture of Intermediate A (90%, 2.40 g, 6.14 mmol), 1,4-benzenediboronic acid (248 mg, 1.5 mmol), sodium carbonate (530 g, 5 mmol) in water (4 mL), tetrakis(triphenylphosphine)palladium (0) (500 mg, 0.43 mmol), n-butanol (20 mL), and toluene (20 mL) was stirred and heated under argon at 110° C. for 68 hours. The reaction mixture was poured into water (300 mL), treated with 5N NaOH (50 mL), stirred for 1 hour, and extracted with dichloromethane (3×200 mL, low solubility in dichloromethane). The volatiles were removed under reduced pressure, and the residue was chromatographed (silica gel, chloroform/tetrahydrofuran 9:1). The obtained product was triturated with ethyl acetate (30 mL), filtered off and dried in a vacuum oven to give 1,4-bis(7-bromo-2-(pyridin-4-yl)-2H-benzo[d][1,2,3]triazol-4-yl)benzene (Intermediate G), yellow crystals, 610 mg (purity 80%, yield 65%). 1H NMR (400 MHz, CDCl3): δ 8.86 (m, 4H, pyridine), 8.39 (m, 4H, pyridine), 8.26 (s, 4H, benzotriazole), 7.79 (d, J=7.7 Hz, 2H, benzene), 7.62 (d, J=7.7 Hz, 2H, benzene).
Reaction SMILES: O.[H-].[Na+].[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH2:12][C:13]#[N:14].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24]Br)=[CH:18][CH:17]=1>CS(C)=O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH:12]([C:6]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]=2[Cl:4])[C:13]#[N:14])=[CH:18][CH:17]=1
Reactant: BrCCOc1ccc(Br)cc1
Reactant: N#CCc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC(CCOc1ccc(Br)cc1)c1ccc(Cl)cc1Cl
Reaction time: 0.5 h

Procedure:
To a stirred and cooled (water-bath) suspension of 7 parts of a sodium hydride dispersion 78% and 75 parts of dimethylsulfoxide is added dropwise, during a 30 minutes-period, a solution of 37 parts of 2,4-dichlorobenzeneacetonitrile in 100 parts of dimethylsulfoxide. The whole is stirred for 30 minutes while cooling in a water-bath. Then there is added dropwise, during a 30 minutes-period, a solution of 56 parts of 1-bromo-4-(2-bromoethoxy)benzene in 125 parts of dimethylsulfoxide and stirring is continued for another 30 minutes. The reaction mixture is poured onto water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed twice with water, dried, filtered and evaporated. The residue is triturated in petroleumether. The product is filtered off and crystallized from ethanol, yielding 38 parts of α-[2-(4-bromophenoxy)ethyl]-2,4-dichlorobenzeneacetonitrile; mp. 73.9° C.