Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([OH:10])[CH:3]=1.Cl[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])=[O:14].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[C:13]([C:12]1[O:10][C:4]2[CH:3]=[C:2]([I:1])[CH:9]=[CH:8][C:5]=2[CH:6]=1)=[O:14]
Reactant: O=Cc1ccc(I)cc1O
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1cc2ccc(I)cc2o1)c1ccc(Cl)cc1Cl
Reaction time: 48 h

Procedure:
To a solution of 4-iodo-2-hydroxy-benzaldehyde (5.4 g, 22 mmol) and 2-chloro-1-(2,4-dichlorophenyl)ethanone (11.2 g, 50.0 mmol) in anhydrous N,N-dimethylformamide (100 mL) was added K2CO3 (12.0 g, 86.9 mmol). The dark brown reaction mixture was stirred at 90 C for 48 h, then poured onto water (150 mL) and extracted with ethyl acetate. The solvent was removed under reduced pressure and the residue was purified by column chromatography, eluting with 50% hexanes in dichloromethane. The desired product was obtained as an orange solid (2.06 g, 23%). 1H-NMR (CDCl3) δ 7.98 (s, 1H), 7.70 (dd, J=8.3, 1.3 Hz, 1H), 7.54-7.21 (m, 5H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]([C:34]2[C:54]([O:55][CH2:56][CH:57]([F:59])[F:58])=[CH:53][C:37]3[N:38]([CH3:52])[C:39]([NH:41][C:42]4[C:47]([Cl:48])=[CH:46][CH:45]=[C:44]([CH2:49][NH2:50])[C:43]=4[Cl:51])=[N:40][C:36]=3[CH:35]=2)=[O:33])[CH:27]=[CH:28][C:29]=1[F:30].CCN(C(C)C)C(C)C.[F:69][C:70]([CH3:75])([CH3:74])[C:71](O)=[O:72]>CN(C=O)C>[Cl:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]([C:34]2[C:54]([O:55][CH2:56][CH:57]([F:58])[F:59])=[CH:53][C:37]3[N:38]([CH3:52])[C:39]([NH:41][C:42]4[C:47]([Cl:48])=[CH:46][CH:45]=[C:44]([CH2:49][NH:50][C:71](=[O:72])[C:70]([F:69])([CH3:75])[CH3:74])[C:43]=4[Cl:51])=[N:40][C:36]=3[CH:35]=2)=[O:33])[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: CC(C)(F)C(=O)O
Reactant: Cn1c(Nc2c(Cl)ccc(CN)c2Cl)nc2cc(C(=O)Nc3ccc(F)c(Cl)c3)c(OCC(F)F)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)F)c2Cl)nc2cc(C(=O)Nc3ccc(F)c(Cl)c3)c(OCC(F)F)cc21
Reaction time: 72 h

Procedure:
TBTU (1.0 mL of a 0.11 M solution in DMF) was added to a mixture of N-(3-chloro-4-fluoro-phenyl)-2-(2,6-dichloro-3-aminomethyl-phenylamino)-6-(2,2-difluoroethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid amide (1.0 mL of a 0.10 M solution in DMF), DIPEA (52 μl, 0.3 mmol) and 2-fluoro-2-methylpropionic acid (1.0 mL of a 0.13 M solution in DMF) and it was stirred for 3 d and the mixture was purified by prep. HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:12]#[CH:13])([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>[Pd]>[Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[C:4]([CH2:12][CH3:13])([OH:11])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C#CC(O)(c1ccccc1)c1ccc(Cl)cc1Cl
Agent: [Pd]
Product: CCC(O)(c1ccccc1)c1ccc(Cl)cc1Cl

Procedure:
0.48 g. of 10% palladium-on-carbon catalyst are added to a solution of 19.4 g. of 2,4-dichloro-α-ethynyl-benzhydrol in 200 ml. of benzene, and the mixture is hydrogenated until the absorption of the calculated amount of hydrogen (about 60 minutes). Thereafter the catalyst is removed by filtration, and the solvent is evaporated. The obtained 16.1 g. of crude product is distilled in vacuo, to yield pure 2,4-di-chloro-α-ethyl-benzhydrol, b.p.: 136°-138° C./0.1 mmHg.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:19]=[C:12]2[CH:13]=[C:14]([Br:18])[CH:15]=[C:16](Br)[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].C(#N)C.[C:26](O)(=[O:28])C>CO>[CH2:1]([S:8][C:9]1[N:19]=[C:12]2[CH:13]=[C:14]([Br:18])[CH:15]=[C:16]([O:28][CH3:26])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Brc1cc(Br)n2nc(SCc3ccccc3)nc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: COc1cc(Br)cc2nc(SCc3ccccc3)nn12

Procedure:
2-Benzylthio-5,7-dibromo[1,2,4]triazolo[1,5-a]pyridine (11.6 g, 0.029 mol) and 25 percent sodium methoxide in methanol (13.0 mL, 3.1 g, 0.057 mol) were combined with 300 mL of acetonitrile and the mixture was heated to reflux with stirring for an hour. An additional 26 mL of 25 percent sodium methoxide in methanol was then added. After a 15-min reaction period, the mixture was acidified with acetic acid and the volatiles were removed by evaporation under reduced pressure. The residue was chromatographed on silica gel eluting with 20 percent ethyl acetate in hexane to obtain 4.97 g (49 percent of theory) of the title compound as a tan powder melting at 80°-82° C.
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].CO[C:15](OC)([CH3:17])[CH3:16]>C(Cl)(Cl)Cl>[CH2:6]([C@@H:2]1[O:1][C:15]([CH3:17])([CH3:16])[O:4][C:3]1=[O:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(C)(C)OC
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(=O)[C@H](Cc2ccccc2)O1
Yield: 97.5 %

Procedure:
A solution of (S)-2-Hydroxy-3-phenyl-propionic acid (1.662 g, 10.0 mmol), 2,2-dimethoxypropane (8.328 g, 80.0 mmol) and PPTSA (1.257 g, 5.0 mmol) in chloroform was stirred at 70° C. for one hour, concentrated, dissolved in dichloromethane and purified on silica gel with 10% EtOAc-PE which gave the title compound (2.010 g, 97%) as a white solid.
Reaction SMILES: [C:1]([C:4]1([C:7]2[CH:40]=[CH:39][CH:38]=[CH:37][C:8]=2[CH2:9][CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]3[CH:20]=[N:21][N:22]([CH:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)[CH:23]=3)[N:12]=2)[CH2:6][CH2:5]1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:17][C:16]1[C:11]([CH2:10][CH2:9][C:8]2[CH:37]=[CH:38][CH:39]=[CH:40][C:7]=2[C:4]2([C:1]([NH2:2])=[O:3])[CH2:5][CH2:6]2)=[N:12][C:13]([NH:18][C:19]2[CH:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:23]=2)=[N:14][CH:15]=1
Reactant: Cc1cnc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)nc1CCc1ccccc1C1(C(N)=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(Nc2cnn(C3CCNCC3)c2)nc1CCc1ccccc1C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of tert-butyl 4-(4-((4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate A43 (0.113 g, 0.207 mmol) in DCM (10 mL) was treated with TFA (0.32 mL, 4.1 mmol) and stirred for 20 hours at room temperature. The volatiles were evaporated in vacuo and aq. NaOH (2 M, 40 mL) was added to the residue. The aqueous phase was extracted with EtOAc (3×40 mL) and the combined organics were washed with brine and dried over MgSO4. The solvent was removed in vacuo and the solid was suspended in DCM. Cyclohexane was added and the suspension was sonicated for 10 minutes. The solid was isolated by vacuum filtration to give the title compound A44 as an off-white solid (0.066 g, 72%). LCMS-D: rt 2.88 min; m/z 446 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[NH:11][N:10]=2)=[CH:4][C:3]=1[N:20]1[C:24](=[O:25])[CH:23]([CH3:26])[N:22]([CH2:27][C:28]([OH:30])=[O:29])[C:21]1=[O:31].S(=O)(=O)(O)O.[CH3:37]O>>[CH3:37][O:29][C:28](=[O:30])[CH2:27][N:22]1[CH:23]([CH3:26])[C:24](=[O:25])[N:20]([C:3]2[CH:4]=[C:5]([CH2:8][C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12](=[O:19])[NH:11][N:10]=3)[CH:6]=[CH:7][C:2]=2[F:1])[C:21]1=[O:31]
Reactant: CC1C(=O)N(c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)C(=O)N1CC(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CN1C(=O)N(c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)C(=O)C1C
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
To a solution of {3-[2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-phenyl]-5-methyl-2,4-dioxo-imidazolidin-1-yl}-acetic acid (36A)(0.04 g, 0.094 mmol) in methanol (4 ml) was added concentrated sulfuric acid (1 ml) and stirred at 70° C. for 90 minutes before being cooled to room temperature. The reaction mixture was then concentrated in vacuo, diluted with water (10 ml) an extracted with ethyl acetate (2×10 ml). The organic layer was then dried over sodium sulfate and concentrated in vacuo to afford a colourless oil. Single peak in LC-MS, (52 mg, 95% purity) and required no further purification; m/z (LC-MS, ESP), RT=3.24 mins (M+H) 439;
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](O)(=[O:10])[CH3:9]>>[CH3:9][C:8]([C:4]1[CH:3]=[CH:2][C:1]([OH:7])=[CH:6][CH:5]=1)=[O:10]
Reactant: Oc1ccccc1
Reactant: CC(=O)O
Product: CC(=O)c1ccc(O)cc1

Procedure:
The same type of reaction is disclosed in U.S. Pat. Nos. 4,560,789 and 4,568,763 in which phenol is reacted with acetic acid in HF to form 4-hydroxyacetophenone.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[NH:8][C:7]=2[CH:16]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>O1CCCC1.CO>[CH3:19][N:20]([CH3:22])[CH:21]=[N:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[NH:8][C:7]=2[CH:16]=1
Reactant: COC(OC)N(C)C
Reactant: NCc1ccc2c(c1)Nc1nccnc1S2
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C=NCc1ccc2c(c1)Nc1nccnc1S2
Temperature: 40 °C
Yield: 80.7 %

Procedure:
400 mg of 8-(aminomethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine was dissolved in tetrahydrofuran (5 ml)/methanol (5 ml). After adding 250 mg of N,N-dimethylformamide dimethyl acetal, the resulting mixture was heated to 40° C. for 1.5 hours. After distilling off the solvent under reduced pressure, the crystals thus precipitated were taken up by filtration and washed successively with diethyl ether and diisopropyl ether. Thus 400 mg of the title compound was obtained as yellow crystals.
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]([Cl:26])([Cl:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)C.[OH-].[K+].Cl>C(O)C>[Cl:26][C:5]([Cl:25])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:4]([OH:27])=[O:3]
Reactant: CCOC(=O)C(Cl)(Cl)CCCCCCSCCCCCc1ccc(Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(Cl)(Cl)CCCCCCSCCCCCc1ccc(Cl)cc1
Yield: 95.6 %

Procedure:
3.50 g (16.3 mmol) 89 was reacted analogously to example 27 with 5.2 g (16.3 mmol) of the ethyl ester of 7. 5.2 g (70%) 2,2-dichloro-8-[5-(4-chlorophenyl)-pentyl-sulfenyl]-octanoic acid ethyl ester 86 was obtained as a colourless oil after flash chromatography (heptanel toluene 2:1). 2.5 g (5.5 mmol) 86, 11 ml (11 mmol) 1 N KOH and 11 ml ethanol were stirred for 2 h at room temperature. It was acidified with 2 N HCl to pH 2 while cooling in an ice-bath, ethanol was removed by distillation, it was extracted with ether, washed with water, dried over Na2SO4 and, after removing the solvent, 2.24 g (96%) 34 was obtained as a colourless oil. 1.14 g (78%) of the sodium salt of 34 with a melting point of 154° C. was obtained from 1.41 g (3.29 mmol) 34 in 3 ml ethanol and 0.13 g (3.3 mmol) sodium hydroxide in 5 ml ethanol after mixing, admixing with ether, suction filtering and drying.
Reaction SMILES: I[CH2:2][CH3:3].[F:4][C:5]1[C:10]2[NH:11][C:12](=[O:14])[O:13][C:9]=2[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=1.N12CCCN=C1CCCCC2>CN(C=O)C>[CH2:2]([N:11]1[C:10]2[C:5]([F:4])=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[CH:8][C:9]=2[O:13][C:12]1=[O:14])[CH3:3]
Reactant: CCI
Reactant: O=c1[nH]c2c(F)cc([N+](=O)[O-])cc2o1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCn1c(=O)oc2cc([N+](=O)[O-])cc(F)c21

Procedure:
Prepared from iodoethane (0.61 ml, 7.57 mmol), 4-fluoro-6-nitro-1,3-benzoxazol-2(3H)-one (EXAMPLE 86, Step 5, 1.2 g, 6.06 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.13 ml, 7.57 mmol) in DMF (10 ml) according to the method of EXAMPLE 86, Step 6 (1.10 g, 80%); mp 121-2° C.
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=O.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH:21]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH3:31])[NH:24][C:23]([CH2:32][O:33][CH2:34][C:35](O)=[O:36])=[C:22]1[C:38]([O:40][CH2:41][CH3:42])=[O:39].N1C=CC=CC=1.CC1(C)OC(=O)CC(=O)O1>ClCCl>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH:21]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH3:31])[NH:24][C:23]([CH2:32][O:33][CH2:34][C:35]([CH3:1])=[O:36])=[C:22]1[C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CCOC(=O)C1=C(COCC(=O)O)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: CC1(C)OC(=O)CC(=O)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(COCC(C)=O)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.6 %

Procedure:
A solution of carbonyl diimidazole (8.00 g) and 2-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}acetic acid (20.00 g) (see European patent application publication No. 0100189) in dichloromethane (400 ml) was stirred at room temperature under nitrogen for 2 hours and then added to a solution of pyridine (3.60 g) and 2,2-dimethyl-1,3-dioxan-4,6-dione (6.50 g) in dichloromethane over 5 minutes. The mixture was stirred at room temperature for 2 days, washed successively with ice-cooled 2.5M hydrochloric acid and saturated brine, dried over magnesium sulphate and evaporated. The residue was dissolved in water (300 ml) and acetic acid (150 ml) and refluxed for 5 hours. The mixture was evaporated and partitioned between diethyl ether (800 ml) and 10% aqueous sodium carbonate. The ether solution was dried over magnesium sulphate and evaporated. The residue was chromatographed on silica (50 g) using 30% hexane in dichloromethane as the eluant. Fractions which contained the pure product were evaporated to give the title compound (6.5 g), m.p. 117°-119°.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC[N:16]=C=NCCCN(C)C.ON1C(=O)CCC1=O.[OH-].[NH4+]>O1CCCC1.CN(C)C=O>[NH2:16][C:11](=[O:13])[C@@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH3:10]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: O=C1CCC(=O)N1O
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.5 %

Procedure:
To a solution containing Boc-L-alanine (1.0 g, 5.29 mmol) in a mixture of tetrahydrofuran (25 mL) and N,N-dimethylformamide (5 mL) were added EDAC (1.5 g, 7.82 mmol) and N-hydroxysuccinimide (0.91 g, 7.91 mmol) and the mixture was stirred at room temperature for 16 hours. Aqueous ammonium hydroxide solution (15 mL, 28%) was added and the mixture was stirred for 0.5 hours at room temperature. The reaction was partitioned between ethyl acetate and water, and the organic was washed with brine and dried over MgSO4, filtered and evaporated to give the product (0.483 g, 49% yield), which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[C:4]([OH:12])[CH:3]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].Cl>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[C:4]([O:12][S:21]([CH3:20])(=[O:23])=[O:22])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(=O)c1ccc(Br)cc1O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)c1ccc(Br)cc1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
To a solution of 1-(4-bromo-2-hydroxy-phenyl)-propan-1-one (20.0 g, 87.3 mmol) in dichloromethane (100 mL) was added triethylamine (24.3 mL, 174 mmol). The resulting solution was cooled to 0° C. and methanesulfonyl chloride (8.10 mL, 105 mmol) was added dropwise. The reaction was stirred for 30 minutes, poured into 1N aqueous hydrochloric acid (100 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (50 mL), the organic layers were combined, dried over magnesium sulfate, filtered, and concentrated to an oil which crystallized upon standing. The solid was recrystallized from a 60/40 mixture of ethanol and water (40 mL) to provide methanesulfonic acid 5-bromo-2-propionyl-phenyl ester (21.8 g, 81% yield). 1H NMR (400 MHz, CDCl3) δ 1.17 (t, 3, J=7.3), 2.90 (q, 2, J=7.3), 3.24 (s, 3), 7.51-7.56 (m, 2), 7.59 (d, 1, J=1.3). 13C NMR (100 MHz, CDCl3) δ 8.04, 35.45, 38.51, 128.18, 127.08, 130.60, 130.69, 131.82, 146.15, 200.30. IR 3049, 2940, 1691, 1590, 1343, 959, 886 cm-1. Analysis calculated for C10H12BrO4S: C, 39.10; H, 3.61. Found: C, 38.90; H, 3.70.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CN(C)C=O>[CH2:17]([N:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[S:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCBr
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCN1c2ccccc2Sc2ccccc21
Yield: 81 %

Procedure:
Adding phenothiazine (5 g, 25 mmol), sodium hydride (1.8 g) into the N,N-dimethyl formamide (30 mL), stirring, and then dropping n-octyl bromide (5.4 g, 28 mmol) into the mixture. Cease reaction after 2 hours, putting the mixture into 300 mL distilled water for, extracting by n-hexane, rotary evaporation of the solvent, using n-hexane as eluent to elutriate the crude product, then separating by silica gel column chromatography to obtain a yellow sticky product, the yield was 81%.
Reaction SMILES: [Cl:1]C1C=CC(OCC2CCNCC2C2C=CC(F)=C(F)C=2)=NC=1.Cl.C(OC([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][O:39][C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][N:41]=2)[CH:34]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:33]1)=O)(C)(C)C>>[ClH:1].[Cl:46][C:43]1[CH:44]=[CH:45][C:40]([O:39][CH2:38][C@H:35]2[CH2:36][CH2:37][NH:32][CH2:33][C@@H:34]2[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[N:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(Cl)cn2)C(c2ccccc2)C1
Reactant: Fc1ccc(C2CNCCC2COc2ccc(Cl)cn2)cc1F
Agent: Cl
Product: Clc1ccc(OC[C@H]2CCNC[C@@H]2c2ccccc2)nc1

Procedure:
In analogy to the procedure described for the synthesis of 5-Chloro-2-[(3SR,4SR)-3-(3,4-difluoro-phenyl)-piperidin-4-ylmethoxy]-pyridine; hydrochloride the title compound was prepared from (3SR,4 SR)-4-(5-Chloro-pyridin-2-yloxymethyl)-3-phenyl-piperidine-1-carboxylic acid tert-butyl ester as off-white foam. MS (m/e): 303.3 [(M+H)+].
Reaction SMILES: Br.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-])=O.[Sn](Cl)Cl>C(O)C.Cl>[NH2:2][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1cccc(-c2csc(-c3cccnc3)n2)c1
Agent: Br
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cccc(-c2csc(-c3cccnc3)n2)c1
Temperature: 50 °C
Yield: 84.9 %

Procedure:
A suspension of 4-(3-nitrophenyl)-2-(3-pyridyl)-thiazole hydrobromide (3.6 g, 10 mmol) in ethanol (150 ml) was treated with a solution of tin (II) chloride (3.7 g, 30 mmol) in concentrated hydrochloric acid (12 ml). The mixture was heated at 50° C. for 16 h. A further portion of tin (II) chloride (2.9 g, 15 mmol) was added and the mixture heated at 50° C. for a further 4 hours before being evaporated to dryness. The residue was partitioned between ethyl acetate and 1M aqueous sodium hydroxide. The ethyl acetate extract was dried (Na2SO4) and filtered through a plug of silica. Evaporation afforded the title compound as a yellow solid (2.15 g, 85%).
Reaction SMILES: O=[C:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:3]([NH:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.C(O)(=O)C.[NH2:29][CH2:30][CH2:31][C@H:32]1[O:37]B(C2C=CC=CC=2)[O:35][C@@H:34]([CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:33]1>C(O)C>[C:12]1([C:11]2[N:29]([CH2:30][CH2:31][C@@H:32]([OH:37])[CH2:33][C@@H:34]([OH:35])[CH2:44][C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])[C:2]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:3]([C:4]3[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=3)[N:10]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OB(c2ccccc2)O1
Reactant: O=C(NC(C(=O)c1ccccc1)c1ccncc1)c1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@H](O)C[C@H](O)CCn1c(-c2ccccc2)nc(-c2ccncc2)c1-c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of N-(2-oxo-2-phenyl-1-(pyridin-4-yl)ethyl)benzamide, 67 (1.6 g) and acetic acid (1.5 mL) in ethanol (50 mL) is added tert-butyl 2-((4R,6R)-6-(2-aminoethyl)-2-phenyl-1,3,2-dioxaborinan-4-yl)acetate (7.9 g). Upon heating under reflux for 16 h, the solution is cooled to room temperature and the solvent is evaporated. The residue is partitioned between saturated aqueous sodium hydrogen carbonate and dichloromethane, the layers separated and the organic phase washed with brine, dried (magnesium sulfate), filtered and concentrated. Purification of the residue via chromatography affords the title compound, 68 (0.35 g).
Reaction SMILES: [CH3:1][S-:2].[Na+].[N+]([C:7]1[CH:14]=[C:13]([S:15]([F:20])([F:19])([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])([O-])=O>CC(C)=O>[CH3:1][S:2][C:7]1[CH:14]=[C:13]([S:15]([F:20])([F:19])([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10]
Reactant: C[S-]
Reactant: N#Cc1ccc(S(F)(F)(F)(F)F)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CSc1cc(S(F)(F)(F)(F)F)ccc1C#N
Temperature: 20 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
Sodium thiomethoxide (8.97 g) was added to a solution of 2-nitro-4-pentafluorosulphanylbenzonitrile (11.7 g) in acetone and stirred at 20° C. overnight, then evaporated and purified by column chromatography on silica gel eluting with ethyl acetate/hexane (3:97) to give 2-methylthio-4-pentafluorosulphanylbenzonitrile (4.65 g), m.p.101°-1020° C.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[N+:11]([O-])([OH:13])=[O:12]>C1CCCCC1>[C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[N+:11]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Agent: O=C(O)CCCCC(=O)O
Solvent: C1CCCCC1
Product: O=[N+]([O-])C1CCCCC1

Procedure:
Hereinafter, mainly, the methods of producing adipic acid directly from cyclohexane are mentioned. 1. Chemical Technology 1974(9) disclosed on page 555 - 559 that adipic acid was produced by oxidizing cyclohexane by molecular oxygen under a pressure, at a temperature about 80° - 90° C in the presence of catalyst and initiator in acetic acid. The selectivity rate of adipic acid was 72 - 74%, and conversion rate of cyclohexane was 82 - 88%. 2. Ullmann Encyclopaedia Der Technische Chemie Bd. 3 (1953) disclosed on page 95 that cyclohexane was oxidized by nitric acid under a pressure of 2 - 15 atm at a temperature of 90° - 120° C in about 12 hours to produce adipic acid in an yield about 34% with nitrocyclohexane in an yield about 16%.