Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:18][C:17]([CH:19]3[N:23]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=4[F:31])[N:22]=[C:21]([C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])[CH2:20]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[ClH:39]>C(OCC)(=O)C>[ClH:39].[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[N:23]1[CH:19]([C:17]2[S:18][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:15][CH:16]=2)[CH2:20][C:21]([C:32]([F:38])([F:37])[C:33]([F:34])([F:35])[F:36])=[N:22]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)s2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccc(N3CCNCC3)s2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-[5-(4-BOC-piperazin-1-yl)-thiophen-2-yl]-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (340.0 mg, 0.7 mmol) prepared in Example 202 was added to a saturated solution of hydrochloric acid in ethyl acetate (5.0 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give 300.0 mg of the titled compound as a brown liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[CH3:29].N1C=CC=CC=1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.[Cl-].[Na+].O.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:15]=[CH:16][C:17]([O:20][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=3[CH3:29])=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(O)cc2)C1
Reactant: Cc1cccc(I)c1C
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccc(Oc2ccc(C3CN(C(=O)OC(C)(C)C)CCO3)cc2)c1C
Temperature: 90 °C

Procedure:
To a degassed solution of 2-(4-hydroxy-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (10.23 g; 36.6 mmol), and 1-iodo-2,3-dimethyl-benzene (10.62 g; 45.8 mmol) in DMSO (50 mL), was added picolinic acid (0.90 g; 7.3 mmol), CuI (0.70 g; 3.7 mmol) and K3PO4 (15.55 g; 73.3 mmol). The resulting mixture was heated overnight, at 90° C. After cooling to RT, brine was added and the mixture extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2) to afford 2-[4-(2,3-dimethyl-phenoxy)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11]Cl)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.[Cl:14][C:15]1[CH:16]=[N:17][C:18](=[O:21])[NH:19][CH:20]=1.C(N(CC)CC)C.CC(C)=O>ClCCl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][N:19]2[CH:20]=[C:15]([Cl:14])[CH:16]=[N:17][C:18]2=[O:21])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(OCCl)cc1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(=O)c1ccc(OCn2cc(Cl)cnc2=O)cc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 6 by adding a solution of 4-acetyl-1-(chloromethoxy)benzene [see Preparation 7] (2.2 mmol) in dichloromethane (5 ml) to a solution of 5-chloropyrimidin-2-one hydrochloride (2.2 mmol) and triethylamine (4.4 mmol) in dichloromethane (20 ml). The product was the desired N-alkylated isomer; yield: 0.60 g (100%), m.p. 182° C. (acetone). (Found C56.38 H4.15 Calc. for C13H11ClN2O3 : C56.02; H3.99) 1H NMR (CDCl3): δ 2.50 (Me), 5.82 (CH2), 7.0 and 7.8 (H-4 and H-6, respectively, J 3 Hz). [70 eV, m/z, % rel. int.)]: 278 (7,M), 145 (31), 143 (100), 136 (18), 121 (33), 116 (22), 93 (15).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([N+:23]([O-])=O)=[C:16]2[N:15]=1.CO.C(Cl)Cl.[NH4+].[Cl-]>C(Cl)Cl.[Zn]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1
Reactant: O=[N+]([O-])c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: ClCCl
Solvent: CO
Product: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Yield: 99 %

Procedure:
To a yellowish solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-nitropyrazolo[1,5-a]pyrimidine (2.3 g, 6.66 mmol), in a 1:1 mixture of MeOH/DCM (30 mL/30 mL) was added Zn dust (4.36 g, 66.6 mmol) [<10 micron, Aldrich] while stirring. Saturated NH4Cl aqueous solution (30 mL) was added drop-wise to this suspension with rapid stirring. After NH4Cl addition was complete, the reaction mixture was allowed to cool to ambient temperature and stirred for another 15 minutes. The reaction was diluted with DCM (50 mL) and filtered through a GF/F paper, rinsing the wet cake with DCM. The organic layer of the filtrate was separated, and the aqueous layer was extracted with DCM (2×50 mL). The organic layers were combined, washed with brine (100 mL), dried over Na2SO4, and concentrated, to provide the basically pure product as a brownish foamy solid (2.08 g, 99% yield), which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(OC(=O)[C@H](CC1C=CC=CC=1)N)(C)(C)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]([OH:15])=[O:14])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccc(F)cc1
Agent: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Product: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc(F)cc1
Yield: 63.3 %

Procedure:
Following the 16a synthetic method, using B1 (110.65 mg, 0.5 mmol) instead of A1 gave 16b as a colorless oil (102.34 mg, 63.3%). [α]D25: +14.4 (c=0.34, CHCl3); 1H-NMR (300 MHz, CDCl3): δ 7.78-7.71 (m, 2H), 7.26-7.17 (m, 7H), 6.92 (d, J=9 Hz, 1H), 4.25-4.13 (m, 1H), 3.15-2.90 (m, 2H); 13C NMR (300 MHz, acetone-d6): δ 171.56, 166.28, 162.95, 137.52, 136.53, 129.74, 129.62, 129.39, 128.24, 126.68, 115.94, 115.63, 57.31, 38.48; HRMS (ESI): calcd for: C15H14FNO4S [M+Na]+=346.0520, obsd [M+Na]+=346.0523.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1>[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=3)[N:5]=2)[CH:3]=1
Reactant: Cc1ccncc1
Agent: [Pd]
Product: Cc1ccnc(-c2cc(C)cc(-c3cc(C)ccn3)n2)c1

Procedure:
4-Methyl-pyridine (900 mL, refluxed over and distilled fresh from KOH pellets) and palladium on charcoal (5%, 37 g) were heated on a bath at 170° C. as long as the chemical equilibrium is reached. The reaction mixture was filtered hot, the catalyst was washed with hot toluene and the filtrate left to crystallise. The 4,4′-dimethyl-2,2′-bipyridine crystals were filtered and washed with toluene. The mother liquors combined, concentrated to ⅓ of the volume and crystallised at 0° C. This second crop of bipyridine was treated as above, the mother liquor was evaporated to dryness under reduced pressure. The bipyridine and terpyridine components of the mother liquor were separated by careful multiple fractional sublimations at 0.02 mmHg, at bath temperatures 80-100° C. (depending on the geometry of the apparatus). Under these conditions, the 4,4′,4″-trimethyl-2,2′:6′,2″-terpyridine accumulates in the residue. The combined pure terpyridine fractions were sublimed twice at 0.02 mmHg at 120-140° C. yielding 15 g of off-white 4,4′,4″-trimethyl-2,2′:6′,2″-terpyridine. (For some fractions column chromatography on silicagel with dichloromethane as eluent was used to get the highly pure 4,4′,4″-trimethyl-2,2′:6′,2″-terpyridine.)
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6][C:7]=1[CH2:8][CH2:9][CH3:10].[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:11]1([C:5]2[O:6][C:7]([CH2:8][CH2:9][CH3:10])=[C:3]([CH2:2][O:17][C:18]3[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=3)[N:4]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1oc(-c2ccccc2)nc1COc1ccc(C=O)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
A mixture of 4-chloromethyl-2-phenyl-5-propyloxazole (2.26 g), 4-hydroxybenzaldehyde (1.33 g), anhydrous potassium carbonate (1.76 g) and N,N-dimethylformamide (50 mL) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water, and the precipitated solid was collected by filtration and dried with air to give crystals (2.75 g, 89%) of 4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]benzaldehyde. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 76-77° C.
Reaction SMILES: C[Al](C)C.[CH:5]([NH2:8])([CH3:7])[CH3:6].C[O:10][C:11]([C:13]1[O:17][N:16]=[C:15]([O:18][CH2:19][C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])[CH:14]=1)=O.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O1CCOCC1>[CH:5]([NH:8][C:11]([C:13]1[O:17][N:16]=[C:15]([O:18][CH2:19][C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])[CH:14]=1)=[O:10])([CH3:7])[CH3:6]
Reactant: CC(C)N
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)no1
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NC(C)C)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 1.27 mL, 2.6 mmol) was added dropwise (exothermic) to a solution of isopropyl amine (220 μL, 2.6 mmol) in dioxane (6 mL) and the resulting mixture was stirred at room temperature for 30 min. Then 3-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester (230 mg, 0.73 mmol) was added. The resulting mixture was then heated at 85-90° C. for 30 min and then cooled to room temperature and then poured into Seignette's salt and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (silica, heptane:ethyl acetate=4:1 to 0:1) afforded the title compound (184 mg, 74%) which was obtained as a white solid. MS: m/e=342.1 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=O)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C1C=CC(C2OC(CCCCCC([NH:49][OH:50])=O)=NC=2C2C=CC=CC=2)=CC=1)(C)C>>[OH:50][NH:49][C:24](=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:9]1[O:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: CC(C)(C)c1ccc(-c2oc(CCCCCC(=O)NO)nc2-c2ccccc2)cc1
Reactant: O=C(O)CCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Product: O=C(CCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1)NO

Procedure:
Using 4,5-diphenyl-2-oxazoleheptanoic acid (653 mg), a reaction and a treatment were carried out in the same manner as in the section (3) of example 1 to obtain the desired subject compound 24 (530 mg, Y=77.8%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:12][C:13](=[O:16])[CH2:14][Cl:15])([CH3:11])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C@@:8]([NH:12][C:13](=[O:16])[CH2:14][Cl:15])([CH3:11])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(CO)(NC(=O)CCl)c1cccc(Br)c1
Solvent: ClCCl
Product: C[C@](CO)(NC(=O)CCl)c1cccc(Br)c1

Procedure:
A solution of (RS)-N-[1-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide (8.0 g) in dichloromethane was divided in 200 mg aliquots which were separated on chiral HPLC (Reprosil Chiral NR 8 μm, 250×30 mm, Dr. Maisch GmbH) using a 80:20-mixture of heptane and isopropanol as the eluent. The first eluting enantiomer (retention time: 9.40 min), the (S)-(−)-N-[1-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide, was obtained as a viscous, colorless oil (3.30 g, 41% of theory), and the second eluting enantiomer (retention time: 14.14 min), the (R)-(+)-N-[1-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide, was also obtained as a viscous, colorless oil (3.62 g, 45% of theory), with
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[NH:25]([C:26]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)C(Cc1cccc(CO)c1)C(=O)OC
Reactant: O=C=Nc1ccccc1
Product: COC(=O)C(Cc1cccc(COC(=O)Nc2ccccc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)benzyl]malonate and phenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [C:1]([CH:9]1[CH2:16][C:12]2[S:13][CH:14]=[CH:15][C:11]=2[C:10]1=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:19][NH2:20].C(O)(=O)C>C(O)C>[C:2]1([C:1]2[C:9]3[CH2:16][C:12]4[S:13][CH:14]=[CH:15][C:11]=4[C:10]=3[NH:20][N:19]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccccc1)C1Cc2sccc2C1=O
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: c1ccc(-c2n[nH]c3c2Cc2sccc2-3)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
5-Benzoyl-5,6-dihydro-cyclopenta[b]thiophen-4-one (2.42 g, 10.0 mmol), hydrazine monohydrate (1.92 mL, 60 mmol), glacial acetic acid (2.7 mL) and ethanol (15 mL) was heated at 100° C. under nitrogen for 4 hr. The mixture was cooled to 25° C. and concentrated under reduced pressure to give a solid which was recrystallized from ethanol to provide the corresponding 6-Phenyl-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (2.4 g, 8.0 mmol) as white solid in 80% yield.
Reaction SMILES: O[C:2]1([C:18]2[C:19](=[O:25])[NH:20][C:21](=[O:24])[NH:22][CH:23]=2)[C:8]2[N:9]=[C:10]([CH3:12])[S:11][C:7]=2[CH2:6][CH2:5][C:4]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:3]1=2.[H-].[Na+].Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C)C=O.C(O)(=O)C>[CH3:12][C:10]1[S:11][C:7]2[CH:6]=[CH:5][C:4]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:3]=3[CH:2]([C:18]3[C:19](=[O:25])[NH:20][C:21](=[O:24])[N:22]([CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:23]=3)[C:8]=2[N:9]=1
Reactant: ClCCN1CCCC1
Reactant: Cc1ccc2c(c1)CCc1sc(C)nc1C2(O)c1c[nH]c(=O)[nH]c1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C=Cc1sc(C)nc1C2c1cn(CCN2CCCC2)c(=O)[nH]c1=O
Temperature: 50 °C

Procedure:
The product from example 18 step (ii) (1.44 g) was dissolved in dry N,N-dimethylformamide (20 ml) and treated cautiously with sodium hydride (60% dispersion by wt, 0.5 g) under nitrogen. After 10 min 1-(2-chloroethyl)pyrrolidine hydrochloride (0.8 g) was added and the whole heated at 50° C. for 16 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was collected, dried over magnesium sulphate and solvent evaporated under reduced pressure. Purification was by flash chromatography eluting with 9:1 dichloromethane/methanol. The product obtained was dissolved in acetic acid (10 ml) and heated at 100° C. for 2 h. The solvent was removed under reduced pressure. Purification was by flash chromatography eluting with dichloromethane/methanol mixtures to give the subtitle product as pale yellow foam.
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)[CH2:4][CH2:5][Cl:6])[CH3:2].[Sn](Cl)(Cl)(Cl)Cl>Cl>[ClH:6].[CH2:1]([N:3]([C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1)[CH2:4][CH2:5][Cl:6])[CH3:2]
Reactant: CCN(CCCl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Product: CCN(CCCl)c1ccc(N)cc1
Yield: 201.3 %

Procedure:
To a solution of 3.0 g (13.1 mmol) of 4-[N-ethyl,N-(2-chloroethyl)amino]nitrobenzene in 70 ml of a concentrated hydrochloric acid, 10 g of tin chloride were added. The resultant mixture was refluxed under heat for 3 hours, followed by treatment with aqueous ammonia and extraction with chloroform. The solvent was distilled out under reduced pressure. A solution of 4N hydrochloric acid/dioxane was added to the residue, followed by washing with IPA, whereby 3.1 g of the powder were obtained (yield: 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH:11]=O)=[C:9]([Br:13])[N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[N:7]=1)=[O:5])[CH3:2].[CH:21]([NH2:24])([CH3:23])[CH3:22].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][NH:24][CH:21]([CH3:23])[CH3:22])=[C:9]([Br:13])[N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[N:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)N
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(Br)c1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(-c2ccccc2Cl)c(Br)c1CNC(C)C
Reaction time: 18 h

Procedure:
To a stirred solution of 5-bromo-1-(2-chloro-phenyl)-4-formyl-1H-pyrazole-3-carboxylic acid ethyl ester (2 g), isopropylamine (0.95 ml) and acetic acid (0.4 ml) in 1,2-dichloroethane (16 ml) was added sodium triacetoxyborohydride (1.8 g) and the resulting slurry was stirred for 18 hours. The reaction was diluted into ethyl acetate, washed with saturated aqueous sodium bicarbonate, brine, dried (Na2SO4) and concentrated in vacuo to afford the title compound (I-1c) as a golden oil, 2.5 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:28]([O:30][CH3:31])=[O:29]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][N:9]2[C:28]([O:30][CH3:31])=[O:29])=[CH:4][CH:3]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2ccc(F)cc2)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Methyl 2-(4-fluorophenyl)piperidine-4-carboxylate (7.4 g, 31.19 mmol) was dissolved in DCM (100 mL) and DIPEA (6.52 mL, 37.43 mmol) added followed by methyl chloroformate (2.95 mL, 37.43 mmol) at 0° C. The solution was stirred at room temperature for 1 h. The reaction mixture washed with 0.1 M HCl and satd NaHCO3. The organic phase was passed through a phase separator and evaporated to yield dimethyl 2-(4-fluorophenyl)piperidine-1,4-dicarboxylate (8.07 g, 97%) as a brown oil. MS m/z 296 (M+H)+
Reaction SMILES: [C:1]([C:3]1[C:9]([C:10]#[N:11])=[C:8]([OH:12])[CH:7]=[CH:6][C:4]=1[OH:5])#[N:2].[OH-].[K+].CO.CS(O[CH2:22][CH:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:25][CH2:24]1)(=O)=O>O.CN(C)C=O>[C:1]([C:3]1[C:9]([C:10]#[N:11])=[C:8]([OH:12])[CH:7]=[CH:6][C:4]=1[O:5][CH2:22][CH:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:25][CH2:24]1)#[N:2]
Reactant: N#Cc1c(O)ccc(O)c1C#N
Reactant: CCCCCC1CCC(COS(C)(=O)=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCCC1CCC(COc2ccc(O)c(C#N)c2C#N)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 31.5 %

Procedure:
5.6 g of 2,3-dicyanohydroquinone and 4.6 g of 85%-potassium hydroxide were added to a mixture solvent of 15 ml of methanol and 60 ml of N,N-dimethylformamide, followed by heating to 50° C. to provide a solution. To the solution, 11.0 g of 4-n-pentylcyclohexylmethyl methanesulfonate was added, followed by stirring for 3 hours at 100° C. After the reaction, the reaction mixture was poured into cold water and washed with ether. The water layer was acidified with 6N-hydrochloric acid aqueous solution until a pH value of 1 was shown, and was subjected to extraction with ether. The organic layer was washed successively with 5%-sodium hydrogenecarbonate aqueous solution and water, followed by drying with anhydrous magnesium sulfate and distilling-off of the solvent to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: toluene/ethyl acetate) and treated with activated carbon, followed by recrystallization from methanol to obtain 3.6 g of 4-n-pentylcyclohexylmethyl 2,3-dicyano- 4-hydroxyphenyl ether.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])=[O:7].[C:17]1(=[O:23])[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18]1.Cl>C1(C)C=CC=CC=1>[C:9]([CH:8]([CH:19]1[CH2:20][CH2:21][CH2:22][C:17](=[O:23])[CH2:18]1)[C:6]([O:5][CH2:4][CH3:3])=[O:7])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: O=C1C=CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)c1ccccc1)C1CCCC(=O)C1
Reaction time: 36 h
Yield: 66.6 %

Procedure:
To a suspension of 60 mg (0.0025 mole) of sodium hydride in 7 ml of toluene was added 4.32 ml (0.025 mole) of ethyl benzoyl acetate. After several minutes a solution was obtained to which was added 2.41 ml (0.025 mole) of cyclohexenone. The reaction was stirred 36 hrs. at room temperature and then added to 25 ml 1 N hydrochloric acid--25 ml saturated sodium chloride--150 ml ether. The ether extract was dried over magnesium sulfate and evaporated to an oil. This crude oil was purified via column chromatography on 300 g of silica gel eluted with 50% ether--pentane to yield 4.8 g (67%) of the title compound as an oil.
Reaction SMILES: C(NC(C)C)(C)C.[Cl-].[Li+].C([Li])CCC.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.[CH:22]1([CH:25]=[O:26])[CH2:24][CH2:23]1>O1CCCC1>[CH:22]1([CH:25]([C:21]2[C:16]([F:15])=[N:17][CH:18]=[CH:19][CH:20]=2)[OH:26])[CH2:24][CH2:23]1
Reactant: O=CC1CC1
Reactant: Fc1ccccn1
Agent: [Cl-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OC(c1cccnc1F)C1CC1
Reaction time: 0.17 h
Yield: 42.7 %

Procedure:
Diisopropylamine (0.9 mL, 6.42 mmol) and lithium chloride (0.120 g, 2.83 mmol) were dissolved in dry tetrahydrofuran (1 mL) under nitrogen and cooled in a dry ice bath. A solution of butyllithium (2.5 M in hexanes, 2.6 mL, 6.50 mmol) was added slowly and the reaction stirred for 10 minutes. 2-Fluoropyridine (0.5 mL, 5.81 mmol) was added dropwise and the mixture stirred for 1 hour. Cyclopropanecarboxaldehyde (0.5 mL, 6.69 mmol) was added slowly. After 30 minutes, the mixture was quenched by addition of saturated ammonium chloride (5 mL). Water (200 mL) and ethyl acetate (300 mL) were added and the phases mixed and separated. The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to ethyl acetate gradient) gave cyclopropyl(2-fluoropyridin-3-yl)methanol (0.415 g, 2.482 mmol, 42.7% yield). The alcohol was dissolved in chloroform (150 mL) and treated with manganese (IV) oxide (3.0 g, 34.5 mmol). The suspension was heated at gentle reflux for 14 hours. The crude product was purified using silica chromatography (hexane to ethyl acetate gradient) to give cyclopropyl(2-fluoropyridin-3-yl)methanone (0.270 g, 1.635 mmol, 28.1% yield) as a clear oil.