Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)[C@H:9]([NH:20][CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[CH2:8][C@@H:7]1[CH2:36][CH3:37])=[O:5])[CH3:2].[C:38](OC(=O)C)(=[O:40])C.C([O-])=O.[Na+]>C(O)=O.O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:17])([F:18])[F:19])=[CH:13][CH:14]=2)[C@H:9]([N:20]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[C:24]([C:32]([F:35])([F:33])[F:34])[CH:23]=2)[CH:38]=[O:40])[CH2:8][C@@H:7]1[CH2:36][CH3:37])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1CC
Reactant: CC(=O)OC(C)=O
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](N(C=O)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1CC
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.4 %

Procedure:
A solution of cis-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 3E) (2.0 g, 3.65 mmol) in 20 mL of formic acid was treated with acetic anhydride (11.29 g, 111 mmol) and sodium formate (1.25 g, 18.5 mmol). After stirring for 24 h at room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude product, which was purified by silica gel chromatography using 10-15% ethyl acetate/hexanes as eluent to afford 1.8 g of the title product. MS m/z 571.2 (M+ +1); 1H NMR (~5:1 mixture of formamide rotamers, CDCl3) δ 0.75 (t, 3H), 1.28 (t, 3H), 1.42 (m, 1H), 1.6-1.75 (M, 2H), 2.3 (bm, 1H), 4.15-4.3 (m, 2H), 4.3-4.4 (m, 1H), 4.5-4.7 (bm, 1H), 4.8-5.8 (bm, 2H), 7.14 and 7.08 (s, 1H), 7.5-7.6 (m, 2H), 7.74 (s, 2H), 7.80 and 7.86 (s, 1H), 8.47 and 8.62 (s, 1H).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[CH3:11][S:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=O)(=[O:14])=[O:13].N>>[CH3:11][S:12]([C:15]1[CH:16]=[C:17]([C:18]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:21]=[CH:22][CH:23]=1)(=[O:13])=[O:14]
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: CS(=O)(=O)c1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-(methylsulfonyl)benzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 3.24 (s, 3H), 7.65 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 7.89-7.96 (m, 1H), 8.28 (ddd, J=8.0, 1.9, 1.0 Hz, 1H), 8.55-8.61 (m, 2H), 8.75 (dd, J=5.1, 1.7 Hz, 1H), 8.78 (t, J=1.5 Hz, 1H), 9.32 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 302 (M+H)+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[O:35][N:34]=[C:33]([CH3:36])[N:32]=2)[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:29]4[CH:30]=[CH:25][CH:26]=[C:27]([C:31]5[O:35][N:34]=[C:33]([CH3:36])[N:32]=5)[CH:28]=4)[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1noc(-c2cccc(I)c2)n1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCCC(=O)C1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3cccc(-c4nc(C)no4)c3)CCCC(=O)C2)cc1OC1CCCC1
Temperature: 80 °C

Procedure:
To a solution of the compound from Example 3 (0.125 g, 0.4 mmol) and 1-iodo-3-(3-methyl-[1,2,4]oxadiazol-5-yl)benzene (0.09 g, 0.32 mmol) in triethylamine (3 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)-palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C. for 0.2 h, was cooled to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, was dried (MgSO4) and was evaporated. The residue was purified by flash chromatography, eluting with 2:1 hexanes/ethyl acetate, followed by trituration from hexanes/ethyl acetate, to provide the title compound as a white solid, m.p. 122°-123° C.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:11][CH2:12][CH2:13][OH:14])=[C:4](O)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]2[C:3]=1[CH2:11][CH2:12][CH2:13][O:14]2
Reactant: COc1ccc(F)c(CCCO)c1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(F)c2c1OCCC2
Temperature: -74 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
After dissolving 4.78 g of 3-fluoro-2-(3-hydroxypropyl)-6-methoxyphenol and 9.4 g of triphenylphosphine in 70 ml of THF under a nitrogen atmosphere, the mixture was cooled to −74° C. Next, 7 ml of DIAD was added to the reaction mixture, which was then raised to room temperature and stirred overnight. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate-heptane system) to obtain the target compound (3.6 g) as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]2([CH:23](B(O)O)[CH2:22][CH2:21][CH2:20]2)[C:12]1=[O:27].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>COCCOC.O>[C:1]([C:3]1[CH:4]=[C:5]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[NH:11][C:12](=[O:27])[C:13]23[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2]
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: O=C1Nc2ccccc2C12CCCC2B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: N#Cc1cc(F)cc(-c2ccc3c(c2)C2(CCCC2)C(=O)N3)c1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
A solution of 3-cyano-5-fluoro-bromobenzene (0.5 g, 2.6 mmol), and tetrakis (triphenylphosphine)palladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 cm3) was stirred under N2 for 20 minutes. To this mixture was then added (spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (0.9 g, 3.9 mmol) and sodium carbonate (0.8 g, 7.8 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (×3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the subtitled compound (0.35 g, 44%) as white needles. mp: 235–237° C.; 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.1 (s, 1H), 8.0 (dt, 1H, J=1.7, 2.0, 7.0 Hz), 7.8–7.7 (m, 2H), 7.6 (dd, 1H, J=1.8, 6.4 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0–1.9 (m, 8H); MS (EI) M+ @ m/z 306.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:17])[C:14]=1[O:15][CH3:16])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.CCN=C=NCCCN(C)C.[CH3:29][C:30]1[N:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](O)=[O:33]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:17][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][CH:37]=[N:38][C:30]=3[CH3:29])[C:14]=1[O:15][CH3:16])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: COc1c(Cl)cc2c([nH]c3cnccc32)c1N
Reactant: Cc1ncccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: COc1c(Cl)cc2c([nH]c3cnccc32)c1NC(=O)c1cccnc1C
Temperature: 80 °C
Yield: 50 %

Procedure:
6-chloro-7-methoxy-9H-β-carbolin-8-ylamine (100 mg, 0.4 mmol), EDCI (125 mg, 0.64 mmol) and 2-methyl nicotinic acid (66 mg, 0.48 mmol) were taken in a round-bottom flask and suspended in pyridine (2 ml). The resulting mixture was heated at 80° C. overnight. The pyridine was then removed by rotary evaporation and 5% Na2CO3 solution was added. The resulting solid that precipitated out was collected by filtration. Chromatographic purification gave the desired product in 50-70% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH2:11](I)[CH3:12]>>[CH2:11]([O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[F:1])[CH3:12]
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: CCI
Product: CCOc1ccc(C=O)cc1F

Procedure:
Following a similar procedure to that described in reference example 3, but starting from 3-fluoro-4-hydroxybenzaldehyde instead of 4-hydroxybenzaldehyde and using ethyl iodide instead of 2-iodopropane, the title compound of the example was obtained as an oil (48% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]=[CH:25][CH:24]=[CH:23]4)=[CH:16][C:15]=2[CH2:30][NH:31][CH2:32][CH3:33])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]=[CH:25][CH:24]=[CH:23]4)=[CH:16][C:15]=2[CH2:30][N:31]([C:38]([CH:35]2[CH2:37][CH2:36]2)=[O:39])[CH2:32][CH3:33])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(-c2ccc3ncccc3c2)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)C1CC1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc4ncccc4c3)cc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-quinolin-6-yl-biphenyl-3-yl)-acetic acid ethyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: [CH:1]1[C:9]([NH2:10])=[CH:8][C:7]2[CH2:11][CH2:12][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=13.[C:18](Cl)(=[O:23])[CH2:19][CH:20]([CH3:22])[CH3:21]>ClC(Cl)C>[CH:1]1[C:9]([NH:10][C:18](=[O:23])[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:8][C:7]2[CH2:11][CH2:12][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=13
Reactant: CC(C)CC(=O)Cl
Reactant: Nc1cc2c3c(c1)c1c(n3CC2)CCCCC1
Solvent: CC(Cl)Cl
Product: CC(C)CC(=O)Nc1cc2c3c(c1)c1c(n3CC2)CCCCC1
Yield: 19.8 %

Procedure:
Following the procedure of Example 1, Step 4, 4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indole-2-amine (0.10 g, 0.44 mmol), isovaleryl chloride (0.054 mL, 0.44 mmol) and poly-(4-vinylpyridine) (600 mg) in dichloroethane (15 mL) provided N-4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indol-2-yl-3-methylbutanamide (27 mg). MS (ESI) m/z 311; HPLC purity 98.5% at 210-370 nm, 10.5 min.; 99.5% at 250 nm, 10.5 min. (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C20H26N2O+H+, 311.21179; found (ESI, [M+H]+), 311.2120.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH3:23]>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([O:12][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Cc1cc(O)c2ccccc2c1
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOc1cc(C)cc2ccccc12
Temperature: 90 °C
Reaction time: 3 h
Yield: 12 %

Procedure:
The crude product of 3-methylnaphthalen-1-ol, dimethylformamide (DMF, 20 ml), potassium carbonate (3 g, 21.7 mmol) and pentyl bromide (4.0 ml, 32.3 mmol) were mixed in a reaction vessel replaced with argon, and this solution was stirred at 90° C. for 3 hours. DMF was evaporated under reduced pressure, and water (20 ml) was added. The aqueous layer was extracted with ethyl acetate (20 ml) 3 times. The organic layer was washed with saturated brine (20 m1l) and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=100/0-50/1) to give 3-methyl-1-pentyloxynaphthalene (827 mg, 12% in 3 steps) as a colorless oil.
Reaction SMILES: [CH3:1]C1(CC(O)=O)C2NC3C(C=2CCO1)=CC=CC=3.[CH3:19][O:20][C:21](=[O:37])[CH2:22][C:23]1([CH3:36])[C:28]2[NH:29][C:30]3[C:35]([C:27]=2[CH2:26][CH2:25][S:24]1)=[CH:34][CH:33]=[CH:32][CH:31]=3>>[CH3:19][O:20][C:21](=[O:37])[CH2:22][C:23]1([CH3:36])[C:28]2[N:29]([CH3:1])[C:30]3[C:35]([C:27]=2[CH2:26][CH2:25][S:24]1)=[CH:34][CH:33]=[CH:32][CH:31]=3
Reactant: COC(=O)CC1(C)SCCc2c1[nH]c1ccccc21
Reactant: CC1(CC(=O)O)OCCc2c1[nH]c1ccccc21
Product: COC(=O)CC1(C)SCCc2c1n(C)c1ccccc21

Procedure:
Similarly, the replacement of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid by an equivalent amount of 1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid methyl ester, described in Example 3, affords 1,9-dimethyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid methyl ester.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:20])=[C:10]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]=2[F:13])[C:6](=[O:21])[C:5]([C:22]([OH:24])=[O:23])=[CH:4]1)[CH3:2].Br[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[O:28]>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:20])=[C:10]([N:14]3[CH2:15][CH2:16][N:17]([CH2:26][C:27]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=4)=[O:28])[CH2:18][CH2:19]3)[C:11]=2[F:13])[C:6](=[O:21])[C:5]([C:22]([OH:24])=[O:23])=[CH:4]1)[CH3:2]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)c(F)c21
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(=O)c4ccc(OC)cc4)CC3)c(F)c21

Procedure:
1-Ethyl-6,8-difluoro-7-{4-[2-(4-methoxyphenyl)-2-oxoethyl]-1-piperazinyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was prepared from 1-ethyl-6,8-difluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydroquinoline-3-carboxylic acid (0.50 g, 1.48 mmole) and 2-bromo-4′-methoxy-acetophenone (0.43 g, 1.86 mmole) by a method similar to that described for Example 4 (63% yield). Mp: 190° C. (dec). 1H NMR (DMSO-d6) δ 1.44 (t, 3H, J=7.0), 2.69 and 3.24 (two m, 8H), 3.84 (s, 3H), 3.87 (s, 2H), 4.58 (q, 2H, J=7.0), 7.05 (m, 2H), 7.85 (d, 1H), J=12.0), 8.01 (m, 2H), 8.92 (s, 1H), 14.92 (br s, 1H). Anal. Calcd. for C25H25F2N3O5•0.25 H2O: C, 61.28; H, 5.25; N, 8.58. Found: C, 61.25; H, 5.23; N, 8.67.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[OH:7][N:8]=[C:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11].CCO>C(Cl)Cl>[Cl:1][CH:2]([Cl:6])[C:3]([O:7][N:8]=[C:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:4]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: O=C(O)C(=NO)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCO
Product: O=C(O)C(=NOC(=O)C(Cl)Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of dichloroacetyl chloride (1.8 ml.) in methylene chloride (15 ml.) was added 2-hydroxyimino-(4-chlorophenyl)acetic acid (anti-isomer) (1.5 g.) and the suspension stirred for two hours at room temperature. During this time most of the material dissolved. The solid was removed, washed with petroleum (b.p. 40°-60°) and the washings and filtrate were combined, kept at 5° overnight and the resulting solid was collected and dried to give the title acid (2.0 g; 85%), m.p. 80°, λmax. (EtOH) 258 nm (ε 12,280), λmax. (Nujol) 1774 (ester), 1750 and 1722 cm.-1 (CO2H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:33](=[O:34])[CH:32]=[N:31][C:30]5[CH:35]=[CH:36][N:37]=[CH:38][C:29]4=5)[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1>ClCCl.FC(F)(F)C(O)=O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][N:28]4[C:33](=[O:34])[CH:32]=[N:31][C:30]5[CH:35]=[CH:36][N:37]=[CH:38][C:29]4=5)[CH2:24][CH2:25]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cnc3ccncc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1cnc2ccncc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Reaction time: 4 h
Yield: 24.8 %

Procedure:
To a solution of 10 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(3-oxopyrido(3,4-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)carbamate in 1 mL of dichloromethane, 1.0 mL of trifluoroacetic acid was added at room temperature. The mixture was stirred at the same temperature for 4 hours, and the solvent was distilled off under reduced pressure. The resultant residue was charged with chloroform and water and adjusted to pH 0.5 with 1 mol/L hydrochloric acid, and the aqueous layer was separated. Chloroform was added to the aqueous layer, and the aqueous layer was adjusted to pH 12 with a 1 mol/L aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 2 mg of 4-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)pyrido(3,4-b)pyrazin-3(4H)-one as a light brown oily substance.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[CH:5]=[C:4]([C:10]([CH3:12])=[O:11])[CH:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]([OH:11])[CH3:12])[CH:5]=[C:6]([CH3:9])[C:7]=1[O:8][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)c1cc(C)c(O)c(C)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1c(C)cc(C(C)O)cc1C

Procedure:
In the process for the production of 3,5-dimethyl-4-acetoxystyrene monomer, one may begin with commercially available 2,6-dimethyl phenol and esterify it with acetic anhydride to produce 2,6-dimethyl phenyl acetate. Then, via a Friedel-Crafts catalysis or Fries rearrangement this is converted to 3,5-dimethyl-4-hydroxy acetophenone. The 3,5-dimethyl-4-hydroxy acetophenone is then esterified with acetic anhydride. The latter is then hydrogenated to form 1-(3,5-dimethyl-4-acetoxyphenyl)ethanol. This is then dehydrated with an acid to form/3,5-dimethyl-4-acetoxystyrene monomer, copolymerized with/unsubstituted 4- acetoxystyrene, and hydrolyzed to produce poly (3,5,-dimethyl-4-hydroxystyrene-co-4-hydroxystyrene).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][N:11]=2)[S:7][CH:8]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][N:11]=2)[S:7][CH:8]=1
Reactant: O=c1[nH]nc(Cc2cc([N+](=O)[O-])cs2)c2ccccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1csc(Cc2n[nH]c(=O)c3ccccc23)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-(4-nitro-thiophen-2-ylmethyl)-2H-phthalazin-1-one (27) (0.90 g, 5.71 mmol) in ethanol (25 mL) under a nitrogen blanket was added dropwise a solution of ammonium chloride (0.31 g, 5.7 mmol) in water 18 mL). After stirring the resultant solution for 5 minutes, iron powder (0.64 g, 11.5 mmol) was added in one portion. The yellow mixture was stirred at 80° C. for 3 hours. The reaction mixture was filtered hot through celite which was washed with ethyl acetate (80 mL). The concentrated in vacuo and then diluted with ethyl acetate (20 mL) washed with brine (20 mL), dried over magnesium, sulphate and dried in vacuo to afford the title cpd as a bright yellow powder. Single peak in LC-MS analysis, (0.68 g, 84% purity and required no further purification; m/z (LC-MS, ESP), RT=2.94 (M+H) 258.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]([CH3:45])[CH3:44])=O>>[CH3:44][N:43]([CH3:45])[CH2:41][CH2:40][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=3[CH2:18]2)=[CH:37][CH:38]=1
Reactant: CN(C)C(=O)CCl
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN(C)C)cc2)C(C)C)c1
Yield: 45.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 2-chloro-N,N-dimethylacetamide (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (13 mg) was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[OH-].[Na+].[C:12](Cl)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>O>[CH2:15]([O:14][C:12]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 91.2 %

Procedure:
Piperidine-4-carboxylic acid (64.8 g, 0.5 mol) in H2O (50 mL) was treated with NaOH (44.0 g, 1.1 mol). The reaction mixture was cooled to 0° C. and treated with CbzCl (93.8 g, 0.55 mol). The reaction mixture was stirred at ambient temperature for 4 hours and the mixture was extracted with Et2O (3 150 mL). The aqueous phase was acidified with 6 N HCl (140 mL) and extracted with EtOAc (3 200 mL). The solution was dried over MgSO4, filtered, and concentrated to afford crude piperidine-1,4-dicarboxylic acid monobenzyl ester (120 g), which was used without further purification: MS (ESI) m/z 262 [M−H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]([CH2:16][S:17]([NH2:20])(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=1.O.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:11]=[C:12]([CH2:16][S:17]([NH2:20])(=[O:18])=[O:19])[CH:13]=[CH:14][CH:15]=2)[N:7]=1
Reactant: Nc1cccc(CS(N)(=O)=O)c1
Reactant: Clc1ncnc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2,4-dichloro-1,3,5-triazine (1.0 eq) in dry DMF (0.7 M) at 0° C. under N2 atmosphere was added a solution of (3-aminophenyl)-methanesulfonamide (1.0 eq) in dry DMF (0.7 M). The reaction mixture was stirred for 2.5 h at 0° C. Then water was added and the aqueous solution was neutralized with sat. aq. NaHCO3 solution. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4. Evaporation of solvent gave A1 as a white solid which was used in the next step without further purification. 1H NMR (400 MHz, d6-DMSO, 300K) δ 4.26 (s, 2H), 6.89 (s, 2H), 7.15 (d, J=7.4 Hz, 1H), 7.36 (d, J=7.4 Hz, 1H), 7.66 (d, J=7.4 Hz, 1H), 8.64 (s, 1H), 9.75 (br. s, 1H), 10.83 (s, 1H). MS (ES) C10H10ClN5O2S requires: 299. found: 300 (M+H)+.