Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.S1C=CC=C1[Li].[C:19](OCC)(=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1COCC1.CCCCCC>[CH2:23]([O:22][C:20](=[O:21])[C:19]([C:5]1[S:4][C:3]([O:2][CH3:1])=[CH:7][CH:6]=1)=[O:25])[CH3:24]
Reactant: CCOC(=O)C(=O)OCC
Reactant: COc1cccs1
Agent: [Li]CCCC
Agent: [Li]c1cccs1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(=O)c1ccc(OC)s1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-Methoxythiophene (15.4 g) is dissolved in 100 ml anhydrous THF and butyl lithium (0.135 moles) in hexane is added dropwise. The solution is stirred at room temperature 15 hr and then heated at reflux for 1 hr. After cooling, the clear solution is transferred to a dropping funnel by means of a siphon. The solution of thienyl lithium is added dropwise to a solution of diethyl oxalate (19.7 g) in 150 ml THF at -78° C. After stirring 2 hr at -78° C, the mixture is brought to -10° C and treated with saturated NH4C1 solution. The aqueous fraction is separated and extracted several times with ether. The combined ether extracts are washed with water and brine, dried (MgSO4) and concentrated. Chromatography on silica gel (eluant = benzene) gives 5-methoxy-2-thiopheneglyoxylic acid ethyl ester (2; X1 = CH3O, X2 and X3 = H and R10 = C 2 H5); mp 136 -137° C after recrystallization from benzene-hexane.
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:9][CH2:8][CH2:7][S:6]1)([O-:3])=[O:2].[CH3:10][NH2:11].Cl.[CH3:13][N:14]([CH2:16][C:17]1[O:21][C:20]([CH2:22]Cl)=[CH:19][CH:18]=1)[CH3:15]>C(#N)C>[CH3:13][N:14]([CH2:16][C:17]1[O:21][C:20]([CH2:22][S:6][CH2:7][CH2:8][NH:9][C:5]([NH:11][CH3:10])=[CH:4][N+:1]([O-:3])=[O:2])=[CH:19][CH:18]=1)[CH3:15]
Reactant: CN(C)Cc1ccc(CCl)o1
Reactant: O=[N+]([O-])C=C1NCCS1
Reactant: CN
Agent: Cl
Solvent: CC#N
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Combine 2-nitromethylene-thiazolidine (146 g, 1.0 mol) and acetonitrile (250 mL). Heat to 40° C. Add methylamine (90 g). After 30 minutes, cool to about -10° C. Add a solution of 5-[(dimethylamino)methyl]-2-(chloromethyl)-furan hydrochloride as obtained in Example 3.1, maintained at 50° C. to 60° C. to prevent crystallization (about 322 g of solution over 3 hours). Add methylamine (120 g). Warm to 40° C. while adding methylamine (65 g). After 30 minutes, cool to 0° C. Add the remainder of the solution of 5-[(dimethylamino)methyl]-2-(chloromethyl)-furan hydrochloride. After the addition is complete, evaporate in vacuo to give a residue. Partition the residue between methyl isobutyl ketone and aqueous 10% potassium carbonate solution. Separate the layers and extract the aqueous layer with methyl isobutyl ketone. Combine the organic layers extract with water. Evaporate the organic layer in vacuo to give a residue. Recrystallize the residue from methyl isobutyl ketone to give the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[C:8]([CH:11]=1)[C:9]#[N:10])(=[O:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH:21]=[C:22]([Cl:24])[CH:23]=1.C(N(CCCC)CCCC)CCC.Cl>O.C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:19]=[C:20]([C:25]([OH:30])([C:26]([F:27])([F:28])[F:29])[CH2:2][C:1]([C:4]2[CH:5]=[CH:6][C:7]([N:12]3[CH:16]=[N:15][CH:14]=[N:13]3)=[C:8]([CH:11]=2)[C:9]#[N:10])=[O:3])[CH:21]=[C:22]([Cl:24])[CH:23]=1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC(=O)c1ccc(-n2cncn2)c(C#N)c1
Agent: Cl
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Product: N#Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Temperature: 60 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
1.00 g (4.71 mmol) of 5-acetyl-2-(1H-1,2,4-triazol-1-yl)benzonitrile, 1.15 g (4.71 mmol) of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 2.30 g of toluene and 0.26 g (1.41 mmol) of tributylamine were fed and the mixture was stirred for 24 hours at 60° C. The mixture was cooled to room temperature, and a separation operation was performed by adding 20 ml of toluene and an aqueous solution prepared with 0.15 g (1.41 mmol) of 35% hydrochloric acid and 10 ml of water. The toluene phase was washed with 10 ml of water. After removing the solvent by distilling under reduced pressure, the residue was purified by silica gel column chromatography to obtain 1.20 g of 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile (yield 56.0%).
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([OH:9])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].N12CCN(CC1)CC2.C(N(C(C)C)CC)(C)C.Cl[C:28]1[N:33]2[N:34]=[C:35]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=3[Cl:50])[C:36]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)=[C:32]2[N:31]=[C:30]([CH3:51])[N:29]=1>O1CCCC1>[C:1]([N:5]1[CH2:8][CH:7]([O:9][C:28]2[N:33]3[N:34]=[C:35]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=4[Cl:50])[C:36]([C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=4)=[C:32]3[N:31]=[C:30]([CH3:51])[N:29]=2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1CC(O)C1
Reactant: Cc1nc(Cl)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(OC2CN(C(C)(C)C)C2)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Reaction time: 48 h

Procedure:
To a solution of 1-tert-butylazetidin-3-ol (19 mg, 0.15 mmol), 1,4-diazabicyclo[2.2.2]octane (11 mg, 0.10 mmol), and diisopropylethylamine (0.026 ml, 0.15 mmol) in tetrahydrofuran (1 ml) was added 4-chloro-7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazine (I-2A-1b; 39 mg, 0.10 mmol), portionwise. After stirring for 2 days, the reaction was concentrated, in vacuo, and the residue purified on a Biotage™ Flash 12S column using 20-40% ethyl acetate in hexanes to afford 11A-1 (25 mg, 52%) as a solid: +APcI MS (M+1) 482.3; 1H NMR (400 MHz, CD3OD) δ 7.52-7.42 (m, 4H), 7.39 (d, J=8.3 Hz, 2H), 7.24 (d, J=8.3 Hz, 2H), 5.58 (quintet, J=6.2 Hz, 1H), 3.80-3.75 (m, 2H), 3.63-3.58 (m, 2H), 2.60 (s, 3H), 1.04 (s, 9H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14]O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:16][C:17]([Cl:21])([Cl:20])[C:18]#[N:19].C1C2C(CCCC2)CCC1.C1C[O:35]CC1>O>[CH2:3]([O:10][CH2:11][CH:12]([NH:19][C:18](=[O:35])[C:17]([Cl:21])([Cl:20])[Cl:16])[CH:13]=[CH2:14])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#CC(Cl)(Cl)Cl
Reactant: C1CCOC1
Reactant: OC/C=C\COCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCC2CCCCC2C1
Product: C=CC(COCc1ccccc1)NC(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (53 mg, 2.4 mmol) was added to a solution of (2Z)-4-(benzyloxy)but-2-en-1-ol (2.0 g, 11 mmol) in THF (50 mL) at 0° C. 2,2,2-trichloroacetonitrile (1.63 g, 12 mmol) was added dropwise to the reaction mixture at 0° C. over a period of 30 minutes. The reaction mixture was stirred at room temperature for an additional 2 hours. The reaction mixture was concentrated under reduced pressure and then diluted with decahydronaphthalene (35.8 g, 259 mmol). The mixture was stirred and heated to 200° C. for 5 hours. The reaction mixture was cooled to ambient temperature, diluted with water, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give N-[1-(benzyloxy)but-3-en-2-yl]-2,2,2-trichloroacetamide. 1H NMR (400 MHz, CDCl3) δ 7.38-7.11 (m, 6H), 5.93-5.86 (m, 1H), 5.34-5.27 (m, 2H), 4.60-4.58 (m, 3H), 3.66-3.61 (m, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[Br:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][C:37]=1[O:44][CH2:45][CH2:46][CH2:47][O:48][CH3:49]>>[Br:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][O:1][CH:2]2[CH:7]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:10][CH:9]=3)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]2)=[CH:38][C:37]=1[O:44][CH2:45][CH2:46][CH2:47][O:48][CH3:49]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCOc1cc(CBr)ccc1Br
Product: COCCCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1Br

Procedure:
Analogously to Method D, 3:35 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 3.17 g of 1-bromo-4-bromomethyl-2-(3-methoxypropoxy)benzene (Example 79c) are used to obtain the title compound as a slightly yellowish oil. Rf=0.35 (1:1 EtOAc-heptane); Rt=6.42.
Reaction SMILES: Cl.N1C=CC=CC=1.[CH2:8]([N:11]([CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[O:31]C)[CH2:22]1)[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][CH3:10].[NH4+].[OH-]>O>[CH2:8]([N:11]([CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[OH:31])[CH2:22]1)[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][CH3:10]
Reactant: CCCN(CCOc1ccccc1)C1CCc2c(cccc2OC)C1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CCCN(CCOc1ccccc1)C1CCc2c(O)cccc2C1

Procedure:
A mixture of pyridine hydrochloride and the product of Example 1 was heated in an oil bath at 200° C. When the reaction was complete (TLC), it was cooled, diluted with H2O, made basic with NH4OH and extracted with ether. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to flash chromatography (Silica: 8:2 pet ether/EtOAc). The product was dissolved in ether and converted to a hydrochloride salt by the addition of dry ether-HCl. Anal. Calcd. for C21H27NO2 ·HCl: C, 69.69; H, 7.80; N, 3.87. Found: C, 69.54; H, 7.90; N, 3.87. NMR of the free base (300 MHz, CDCl3): δ 7.3-6.6(m, 8H), 4.0(t, 2H), 3.2-2.5(m, 9H), 2.1(m, 1H), 1.7-1.4(m, 3H), 0.9(t, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21]>>[N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:20](=[O:21])[N:19]([CH3:18])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(O)cc2)cc1
Product: CN(C(=O)Oc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-(4-nitro-phenoxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (71%, white crystals). HPLC-MS m/z=365.0 (M+1), Rt: 4.83 min. 4(300 MHz; CDCl3): 3.44 (s, 3H), 7.00 (d, 2H), 7.06 (d, 2H), 7.26-7.32 (m, 1H), 7.33-7.49 (m, 4H), 8.20 (dt, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:19]=1)[C:7]([NH:9][C:10]1[N:15]=[CH:14][C:13]([C:16](O)=[O:17])=[CH:12][CH:11]=1)=[O:8].S(Cl)([Cl:23])=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:19]=1)[C:7]([NH:9][C:10]1[N:15]=[CH:14][C:13]([C:16]([Cl:23])=[O:17])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)O)cn1
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1

Procedure:
A mixture of 6.2 g of 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carboxylic acid and 23 ml of thionyl chloride is refluxed for 1 hour. An additional 12 ml of thionyl chloride is added and the mixture refluxed for 0.5 hour. The mixture is concentrated to dryness under vacuum and 30 ml of toluene added to the residue. The toluene is removed under vacuum and the process (add toluene and remove) is repeated to give 7.7 g of crude product as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21](O)=[O:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:21](=[O:22])[CH2:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C(O)Cc1ccccn1
Reactant: COC(=O)c1cc(Br)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(Br)ccc1NC(=O)Cc1ccccn1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask was placed a solution of methyl 2-amino-5-bromobenzoate (5 g, 21.73 mmol), 2-(pyridin-2-yl)acetic acid hydrochloride (4.5 g, 25.92 mmol), HATU (10 g, 26.30 mmol) and DIEA (8.5 g, 65.77 mmol) in N,N-dimethylformamide (100 mL). The resulting solution was stirred overnight at 20° C. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3×100 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (1:50) to afford the title compound as a red solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:18][S:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].O.[O:28]1CCC[CH2:29]1>>[CH3:18][S:19][C:20]1[CH:21]=[C:22]([NH:23][C:29](=[O:28])[NH:1][CH2:2][C:3]([N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:4])[CH:24]=[CH:25][CH:26]=1
Reactant: C1CCOC1
Reactant: CSc1cccc(N)c1
Reactant: NCC(=O)N(c1ccccc1)c1ccccc1
Solvent: O
Product: CSc1cccc(NC(=O)NCC(=O)N(c2ccccc2)c2ccccc2)c1

Procedure:
N,N,'-Carbonyldiimidazole (0.72 g) is added to a solution of 2-amino-N,N-diphenylacetamide (1 g) in anhydrous tetrahydrofuran (15 cc). The solution is stirred for 2 hours at a temperature in the region of 25° C. and 3-methylthioaniline (1.2 g) is then added. The solution obtained is stirred under reflux for 12 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is taken up with distilled water (60 cc) and stirred for 30 minutes at a temperature in the region of 20° C. The insoluble product is separated by filtration, washed with distilled water and dried in the air. After recrystallization in acetonitrile, 2-[3-(3-methylthiophenyl)ureido]-N,N-diphenylacetamide (1 g), m.p. 182° C., is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[F:15].[Li]CCCC.CC([O:24][B:25](OC(C)C)[O:26]C(C)C)C>O1CCCC1>[F:15][C:3]1[CH:4]=[C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][C:2]=1[B:25]([OH:26])[OH:24]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1cc(Oc2ccccc2)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(Oc2ccccc2)cc1F
Temperature: -75 °C
Yield: 92.1 %

Procedure:
Into a 100 mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of 1-bromo-2-fluoro-4-phenoxybenzene (2 g, 7.49 mmol, 1.00 equiv) in tetrahydrofuran (20 mL). BuLi (1M, 8 mL) was added dropwise with stirring at −70 to −80° C. The resulting solution was stirred for 30 min at −70-−80° C. in a liquid nitrogen bath. Tris(propan-2-yl)borate (1.7 g, 9.04 mmol, 1.21 equiv) was added dropwise with stirring at −70 to −80° C. The resulting solution was allowed to react, with stirring, for an additional 2 b while the temperature was maintained at −70 to −80° C. The reaction was then quenched by the addition of 100 mL of water, extracted with ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20) to give 1.6 g of (2-fluoro-4-phenoxyphenyl)boronic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N+:11]([O-:13])=[O:12])[C:5]([NH2:10])=[N:6][C:7]=1[NH:8][NH2:9].[CH2:14](C(CC)(CC)C([O-])([O-])[O-])[CH3:15]>>[Cl:1][C:2]1[C:7]2[N:6]([C:14]([CH3:15])=[N:9][N:8]=2)[C:5]([NH2:10])=[C:4]([N+:11]([O-:13])=[O:12])[N:3]=1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: NNc1nc(N)c([N+](=O)[O-])nc1Cl
Product: Cc1nnc2c(Cl)nc([N+](=O)[O-])c(N)n12
Yield: 75 %

Procedure:
To 5.0 g (0.024 m) 5-chloro-6-hydrazino-3-nitropyrazinamine was added 50 ml of triethylorthoacetate and the resulting suspension was heated at 100° for 2.5 hours. The reaction mixture was cooled, filtered and the resulting dark brown solid washed with chloroform to give 4.1 g (75%) of the titled product as a brown solid, m.p. 220°; H' nmr (DMSO-d6): 9.60 (2H, broad singlet), 3.40 (3H, s); ms:m/e 228.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N:19]([CH:21]([CH3:23])[CH3:22])[CH3:20])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1[C:29]2N=CC=C[C:28]=2N=N1.Cl.N=C=N.C(O)C>CN(C)C1C=CN=CC=1.C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N:19]([CH:21]([CH3:23])[CH3:22])[CH3:20])[C:16]([O:18][CH2:28][CH3:29])=[O:17])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)N(C)C(C(=O)O)c1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: On1nnc2cccnc21
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: N=C=N
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(c1ccc(NC(=O)OC(C)(C)C)cc1)N(C)C(C)C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 25 (1.50 g, 4.66 mmol), THF (45 mL), 1-hydroxy-7-azabenzotriazole (1.27 g, 9.32 mmol) and 1-ethyl-3-[3-dimethyl amino)propyl]-carbodiimide hydrochloride (1.79 g, 9.32 mmol), and the reaction mixture was stirred for 15 min. Ethanol (429 mg, 9.32 mmol) and 4-dimethylamino pyridine (57 mg, 0.47 mmol) were added, and the reaction mixture was stirred at room temperature for a further 16 h. After this time, the reaction was partitioned between water (40 mL) and methylene chloride (50 mL). The layers were separated, and the aqueous phase was extracted with methylene chloride (2×30 mL). The organic extracts were combined and dried over sodium sulfate. The drying agent was removed by filtration, and the solvent was evaporated under reduced pressure. The resulting residue was dried to a constant weight under vacuum to afford 26 in 73% yield (1.20 g) as a white solid: mp 87-88° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.35 (s, 1H), 7.40 (d, 2H, J=7.5 Hz), 7.28 (d, 2H, J=7.5 Hz), 4.16 (s, 1H), 4.05 (m, 2H), 2.80 (septet, 1H, J=6.5 Hz), 2.02 (s, 3H), 1.47 (s, 9H), 1.11 (t, 3H, J=7.0 Hz), 0.94 (d, 3H, J=6.5 Hz), 0.88 (d, 3H, J=6.5 Hz); MS (ESI+) m/z 351 (M+H).
Reaction SMILES: CC1C=CC(S([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[CH:14][C:13]=2[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=O)=O)=CC=1.[OH-].[K+]>C(O)C.O>[CH2:22]([O:21][C:13]1[CH:14]=[C:15]([CH2:18][CH2:19][CH3:20])[CH:16]=[CH:17][C:12]=1[OH:11])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCc1ccc(OS(=O)(=O)c2ccc(C)cc2)c(OCc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCc1ccc(O)c(OCc2ccccc2)c1
Yield: 85.7 %

Procedure:
To a solution of 2-(benzyloxy)-4-propylphenyl 4-methylbenzenesulfonate (0.07 mmol; 28 mg) under argon, in a mixture of ethanol (0.2 mL) and water (0.1 mL), was added KOH (0.09 mmol; 5 mg). The reaction was refluxed for 1 hr, then hydrolysed with NH4Cl sat. (3 mL), and extracted with ethyl acetate (3*5 mL). Combined organic phases were washed with saturated NaHCO3 (3 mL), dried over MgSO4, concentrated. The residue was purified by preparative TLC (cyclohexane/dichlorométhane) to yield the title compound as a clear oil (16 mg; 0.06 mmol; 86%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N:16]4[CH:20]=[CH:19][C:18]([CH:21]5[CH2:26][CH2:25][CH2:24][N:23]([C:27](OC(C)(C)C)=O)[CH2:22]5)=[N:17]4)[CH:14]=3)[NH:9][N:8]=2)=[CH:3][CH:2]=1.[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:36]=1C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:36]=1[CH2:27][N:23]1[CH2:24][CH2:25][CH2:26][CH:21]([C:18]2[CH:19]=[CH:20][N:16]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[NH:9][N:8]=[C:7]4[C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[N:17]=2)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccn(-c3ccc4[nH]nc(-c5ccncc5)c4c3)n2)C1
Reactant: COc1cccc(F)c1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(F)c1CN1CCCC(c2ccn(-c3ccc4[nH]nc(-c5ccncc5)c4c3)n2)C1
Reaction time: 3 h
Yield: 85.2 %

Procedure:
To tert-butyl 3-(1-(3-(pyridin-4-yl)-1H-indazol-5-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylate (30 mg, 0.09 mmol) in THF (2 mL) were added 2-fluoro-6-methoxybenzaldehyde (20 mg, 0.13 mmol) and sodium triacetoxyborohydride (30 mg, 0.14 mmol). After 3 h, the reaction mixture was quenched with saturated NaHCO3 and extracted with EtOAc. After concentration, crude mixture was column purified with mixture of methanol, dichloromethane and ammonia to give 5-(3-(1-(2-fluoro-6-methoxybenzyl)piperidin-3-yl)-1H-pyrazol-1-yl)-3-(pyridin-4-yl)-1H-indazole (37 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Ca+2].[Cl-]>O.C(O)C.C(O)(=O)C.[Zn]>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Yield: 96.7 %

Procedure:
4-(4-Benzyl-1-piperazinyl)-1-nitrobenzene (2.6 g; 8.9 mmol) synthesized by the above process and zinc powder (3.2 g; 48 mmol) were added to a solution of calcium chloride (665 mg; 6.0 mmol) in water-ethanol-acetic acid (12 ml-55 ml-1.2 ml), and the mixture was stirred under reflux for 15 minutes in a bath controlled at 110° C. Insoluble substances were removed from the reaction mixture by suction filtration through Celite, and the filtrate was concentrated under reduced pressure. A saturated aqueous solution of sodium hydrogencarbonate was added to the resultant concentrated residue to conduct extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The thus-obtained crude crystals were recrystallized from benzene-n-hexane to obtain 2.3 g (yield: 96%) of 4-(4-benzyl-1-piperazinyl)aniline as pale brown needles (melting point: 137-138° C.).