Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([F:13])[C:3]=1C(O)=O.C(Cl)(C(Cl)=O)=O.[N-:20]=[N+]=[N-].[Na+]>C(Cl)Cl.CN(C=O)C.O>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([F:13])[C:3]=1[NH2:20]
Reactant: COc1ccc(F)c(C(=O)O)c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(F)c(N)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
To a solution of 2-chloro-6-fluoro-3-methoxy-benzoic acid (2.7 g, 13.2 mmol, 1.0 eq) in a mixture of DCM (20 mL) and DMF (3 drops) at 0° C. was added (COCl)2 (5.0 g, 39.6 mmol, 3.0 eq) dropwise. The reaction mixture was stirred at room temperature for 1 h, and then concentrated to dryness; the residue was dissolved in acetone (20 mL) and added dropwise to a solution of NaN3 (2.6 g, 39.6 mmol, 3.0 eq) in water (15 mL) at 0° C. The reaction was stirred 1 h at 0° C., water (50 mL) was added, then the reaction heated at 70° C. overnight. The acetone was removed by distillation and the aqueous residue extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give a residue, which was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:30) to give the title compound as a yellow oil (0.85 g, 37%).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1([CH3:21])[C@H:9]([CH:10]=[C:11](Br)Br)[C@H:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CCOCC.P(O)(O)([O-])=O.[Na+]>CCCCCC.O1CCCC1>[CH3:6][C:7]1([CH3:21])[C@H:9]([C:10]#[CH:11])[C@H:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@@H](C=C(Br)Br)C1(C)C
Agent: O=P([O-])(O)O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#C[C@@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Temperature: -80 °C
Reaction time: 1.5 h
Yield: 43.8 %

Procedure:
47 ml of a solution of 2.34M of butyllithium in hexane were slowly added at -100° C. to a solution of 38.7 g of tert.-butyl (1R,trans) 2,2-dimethyl-3-(2,2-dibromovinyl)-cyclopropane-carboxylate, 200 ml of ether and 200 ml of tetrahydrofuran and the mixture was stirred for 90 minutes at -80° C. and was poured into iced aqueous monosodium phosphate solution. The mixture was extracted with benzene and the organic phase was evaporated to dryness under reduced pressure. The residue was rectified under reduced pressure to obtain 9.3 g of tert.-butyl (1R,trans) 2,2-dimethyl-3-ethynyl-cyclopropane-carboxylate with a boiling point of 30° C. at 0.1 mm Hg.
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[C:2]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:15]2[CH2:16][CH2:17][C@H:18]([CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:19][CH2:20]2)=[CH:13][CH:14]=1)=[O:7]
Reactant: CCOC(=O)C(C)[C@H]1CC[C@H](c2ccc(N)cc2)CC1
Reactant: COC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(C)[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)OC)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl chlorooxoacetate (670 mg, 5.45 mmol) in DCM (3 mL) was added in one portion to a solution of trans-ethyl 2-[4-(4-aminophenyl)cyclohexyl]propanoate (1.0 g, 3.63 mmol) and pyridine (0.59 mL, 7.26 mmol) in DCM (22 mL) at 5° C. and the mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo and EtOAc (30 mL) was added. The layers were separated and the organic layer was washed with water (25 mL) and brine (25 mL). The organic layer was dried and concentrated in vacuo to give the title compound (1.3 g, 99%) as a solid; 1H NMR δ (CDCl3) 1.0-1.1.25 (2H, m), 1.1 (3H, d), 1.2 (3H, t), 1.3-1.47 (2H, m), 1.48-1.55 (2H, m), 1.68-1.79 (1H, m), 1.8-1.95 (2H, m), 2.18-2.28 (1H, m), 2.35-2.5 (1H, m), 3.9 (3H, t), 4.08 (2H, q), 7.12 (2H, d), 7.47 (2H, d); MS m/e (M−H)− 360.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:36])[CH:10]([CH3:35])[CH2:11][C:12]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:13](O)[CH2:14][CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(Cl)(Cl)(Cl)Cl.CC(C)=O.C(=O)=O.FC(F)(F)S(Cl)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:23]1([C:12]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH2:11][CH:10]([N:9]([CH3:36])[CH3:8])[CH3:35])[CH:13]=[CH:14][CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)C=CCC(O)C(CC(C)N(C)C)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=C=O
Agent: O=S(=O)(Cl)C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C=CC=CC(CC(C)N(C)C)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62.2 %

Procedure:
Triethylamine (2.49 ml, 17.88 mmol) was added to a stirred solution of ethyl 8-dimethylamino-6,6-diphenyl-5-hydroxynon-2-enoate (1.77 g, 4.47 mmol) in CH2Cl2 (30 ml) at -30° C. (CCl4 /acetone/CO2), and the solution was stirred for 5 min. Trifluoromethanesulfonyl chloride (0.38 ml, 4.91 mmol) was then added dropwise. The reaction mixture was stirred 15 min at -30° C., warmed to room temperature over 1 hour, and then stirred at room temperature for 2 hours. The mixture was diluted with CH2Cl2 (20 ml) and poured into 5% NaHCO3 (20 ml). The layers were separated, and the organic extracts were washed with brine (30 ml). The extracts were dried over Na2SO4 /trace K2CO3, filtered, and concentrated in vacuo on a rotary evaporator. The oily brown residue was applied to a column as described above, and eluted with 6% methanol in CHCl3 to yield 1.05 g of ethyl 6,6-diphenyl-8-dimethylaminonona-2,4-dienoate, as a clear light brown mobile oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[O:5][CH:6]([CH2:19][CH3:20])[C:7]([NH:9][C:10]([CH3:18])([CH3:17])[C:11]#[C:12][CH2:13][CH2:14][CH2:15]Cl)=[O:8].[C-:25]#[N:26].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[O:5][CH:6]([CH2:19][CH3:20])[C:7]([NH:9][C:10]([CH3:18])([CH3:17])[C:11]#[C:12][CH2:13][CH2:14][CH2:15][C:25]#[N:26])=[O:8]
Reactant: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)NC(C)(C)C#CCCCCl
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)NC(C)(C)C#CCCCC#N
Temperature: 95 °C
Reaction time: 18 h

Procedure:
A stirred solution of 2-(3,5-dichlorophenoxy)-N-(1-chloro-6-methylhept-4-yn-6-yl) butyramide (3.91) in dry N,N-dimethylformamide (35 ml) containing potassium cyanide (0.78 g) was heated to 95° C. for 6 hours, cooled to ambient temperature then stored for 18 hours. The mixture was poured into water, extracted with diethyl ether (three times) and the extracts were combined, washed with water (three times), dried over magnesium sulphate then evaporated under reduced pressure to give the required product as a yellow oil, 3.42 g. A portion of this material was fractionated by chromatography (silica; hexane/ethyl acetate 3:1 by volume) to give a pure sample of 2-(3,5-dichlorophenoxy)-N-(1-cyano-6-methylhept-4-yn-6-yl) butyramide as a yellow gum, 1H NMR (CDCl3) δ: 0.98-1.02(3H, t); 1.58(3H, s); 1.60(3H, s); 1.82-1.88(2H, m); 1.92-1.98(2H, m); 2.36-2.40(2H, t); 2.48-2.56(2H, m); 4.38-4.42(1H, t); 6.26(1H, s); 6.84(2H, s); 7.04(1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[C:13](=[O:14])[CH:12]=[C:11](/[N:15]=C/N(C)C)[N:10]([CH3:20])[C:9]2=[O:21])=[CH:5][CH:4]=1.[OH-].[NH4+]>CO>[NH2:15][C:11]1[N:10]([CH3:20])[C:9](=[O:21])[N:8]([CH2:7][C:6]2[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:13](=[O:14])[CH:12]=1
Reactant: COc1ccc(Cn2c(=O)cc(/N=C/N(C)C)n(C)c2=O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(Cn2c(=O)cc(N)n(C)c2=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.6 %

Procedure:
To a solution of (E)-N′-(1-(4-methoxybenzyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethylformimidamide (7.8 g, 24.7 mmol) in methanol (90 mL) was added ammonium hydroxide (155 mL, 28% wt/wt) and the mixture was stirred at room temperature for 48 h. The reaction was concentrated to give crude product which was purified by silica gel chromatography eluting with methanol/DCM (1:15) to give 6-amino-3-(4-methoxybenzyl)-1-methylpyrimidine-2,4(1H,3H)-dione (4.3 g, 66.6%) as yellow solid. LCMS retention time 0.445 min; LCMS MH+ 262.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:19])[CH:17]=[CH2:18]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:8][C:16](=[O:19])[CH:17]=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: C=CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 69.6 %

Procedure:
To a solution of benzyl alcohol (4.76 mL, 0.046 mol), 4-dimethylamino-pyridine (“DMAP,” 0.790 g, 0.0065 mol) and triethylamine (12.85 mL, 0.09297 mol) in dichloromethane (92 mL) was added a solution of acryloyl chloride (7.54 mL, 0.09297 mol) slowly at 0° C., and the mixture was stirred at 0° C. for 2.5 hours. The mixture was quenched with aqueous sodium bicarbonate, and the quenched mixture was extracted with dichloromethane (2×100 mL). The extracts were combined, dried (MgSO4), and rotary evaporated to give a yellow oil. The oil was purified by column chromatography, eluting with hexanes/ethyl acetate (95:5) to give 5.19 g (64%) of acrylic acid benzyl ester as a clear oil.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:20]([OH:23])(=[O:22])=[O:21]>C(Cl)(Cl)Cl>[N:14]1([C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:3]=[CH:4][C:5]([S:20]([OH:23])(=[O:22])=[O:21])=[CH:6][CH:7]=3)=[CH:9][CH:10]=2)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: c1ccc(Oc2ccc(-n3ccnc3)cc2)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(O)c1ccc(Oc2ccc(-n3ccnc3)cc2)cc1
Reaction time: 8 h

Procedure:
137 mmol of 1-(4-phenoxyphenyl)imidazole are dissolved in 250 ml of chloroform. 190 mmol of chlorosulphonic acid are then added dropwise. The whole is left at 45° C. overnight. After cooling and removal of the solvent by evaporation, the resulting oil is taken up in diethyl ether. The resulting solid is filtered off and dried to yield the expected product.
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.[C:6]([O:9][CH2:10][C@@H:11]1[CH2:16][CH:15]=[CH:14][CH2:13][C@@H:12]1CO)(=[O:8])[CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:6]([O:9][CH2:10][C@@H:11]1[CH2:12][CH:13]=[CH:14][CH2:15][C@@H:16]1[CH2:2][Br:5])(=[O:8])[CH3:7]
Reactant: CC(=O)OC[C@@H]1CC=CC[C@@H]1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=O)OC[C@@H]1CC=CC[C@@H]1CBr
Reaction time: 96 h

Procedure:
To a solution of dichloromethane (20 mL), tetrabromomethane (1.5 eq) and 1(R)-acetoxymethyl-2(S)-hydroxymethylcyclohex-4-ene (6.8 mmol) was added a solution of triphenylphosphine (1.2 eq) in dichloromethane (5 mL) and the reaction stirred in the dark for four days. The reaction was concentrated to a dark oil and triturated with ether. The solid was filtered and the filtrate concentrated and purified by silica gel chromatography to yield the desired compound as a colorless oil. 1HNMR (500 mHz), CDCl3): 5.64 ppm (dd, 2H), 4.09-4.0 (m, 2H); 3.48 (dd, 1H); 3.38 (t, 1H); 2.08 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14].[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24](B(O)O)[CH:25]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:21]=[C:20]([F:19])[CH:25]=[CH:24][C:23]=3[O:29][CH3:30])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14]
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(Br)cccc12
Reactant: COc1ccc(F)cc1B(O)O
Product: COc1ccc(F)cc1-c1cccc2c(N)c(C(=O)NC3CC3)nnc12
Yield: 75.5 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclopropyl-cinnoline-3-carboxamide (143 mg, 0.47 mmol) and 5-fluoro-2-methoxyphenylboronic acid (158 mg, 0.94 mmol) were reacted. After purification the title compound (125 mg, 76% yield) was obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.54 (bm, 1H), 7.87 (a dd, J=3.1, 6.6 Hz, 1H), 7.73 (m, 2H), 7.10(m, 2H), 6.95 (m, 1H), 3.66 (s, 3H), 2.96 (m, 1H), 0.86 (m, 2H), 0.64 (m, 2H). MS APCI, m/z=353.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])[CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([NH:13][C:14](=[O:24])[NH:15][CH2:16][CH2:17][O:18]C(=O)C(C)=C)[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5].[OH-].[Na+].C([O-])(O)=O.[Na+].O>CCO.CCOC(C)=O>[Cl:1][C:2]1[CH:28]=[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])[CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([NH:13][C:14]([NH:15][CH2:16][CH2:17][OH:18])=[O:24])[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5]
Reactant: C=C(C)C(=O)OCCNC(=O)Nc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(NC(=O)NCCO)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 25 °C

Procedure:
Compound 259 (0.05 g, 0.095 mmol) was dissolved in EtOH (2.5 mL). 2 N NaOH (0.25 mL) was added and the solution was heated to reflux for 3 h. The reaction mixture was cooled to room temperature and saturated aqueous NaHCO3 (2 mL) was added. H2O and EtOAc were added and the phases were separated. The water phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc as the eluent. This afforded the title compound as a slightly coloured solid. 13C NMR (CD3OD) δ
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=O)[NH:3][C:2]1=O.C([N:16]1C=C[N:18]=[C:17]1CCN)C1C=CC=CC=1>>[NH:1]1[CH:6]=[C:5]2[C:4]([N:16]=[CH:17][NH:18]2)=[N:3][CH2:2]1
Reactant: NCCc1nccn1Cc1ccccc1
Reactant: O=C1CCNC(=O)N1
Product: C1=c2[nH]cnc2=NCN1

Procedure:
Treatment of oxazole 1 with n-BuLi, followed by an alkylation reaction, and a deprotection reaction with TFA affords 2-(oxazol-2-yl)ethanamine 3. Amine 3 can be coupled with dihydropurine 4 to give compound 6.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1.[C:21]([OH:24])(=[O:23])[CH3:22]>C(OCC)(=O)C>[CH3:1][NH:2][C@@H:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1.[C:21]([O-:24])(=[O:23])[CH3:22]
Reactant: CC(=O)O
Agent: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Solvent: CCOC(C)=O
Product: CC(=O)[O-]
Reaction time: 5 h

Procedure:
Sertraline base (the compound of Preparation AA, 200.2 mg) was dissolved in ethyl acetate (200 μL) in a 5 ml reaction vial. Glacial acetic acid (41.2 μL) was added to the sertraline base solution with stirring. An additional 500 μL of ethyl acetate was added to facilitate stirring. The reaction mixture was allowed to granulate at room temperature for five hours. The solids were filtered, washed with 10 mL of ethyl acetate and then dried in a vacuum oven at 40° C. for 20 hour. The yield was determined to be 16%. mp 126° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH2:27][OH:28])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][C:2]1[NH:3][C:4]([CH2:27][O:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)NC(COC(=O)c2ccccc2)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
to a solution of diethyl 2-methyl-4-(2-nitrophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.95 g) in pyridine (25 ml) was dropwise added a solution of benzoyl chloride (2.0 g) in methylene chloride (5 ml) over 5 minutes at 5° to 6° C. with stirring. The resultant mixture was stirred for 15 minutes at the same temperature and then at room temperature for 2 hours, and followed by stirring at 50° C. for an hour and a half. After the reaction was over, the pyridine was distilled off and to the residue was added ethyl acetate and water. The ethyl acetate layer was separated, washed with dil. hydrochloric acid twice and then aqueous solution of sodium bicarbonate, and dried over magnesium sulfate. The solvent was removed and the residue was soon crystallized by treating with diethyl ether and collected by filtration. These crude crystals were washed with a mixture of diethyl ether and a small amount of ethyl acetate to give crystals, which was recrystallized from ethyl acetate (25 ml) to give powders of diethyl 2-methyl-4-(2-nitrophenyl)-6-benzoyloxymethyl-1,4-dihydropyridine-3,5-dicarboxylate, m.p. 156° to 157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:6][CH2:5]2
Reactant: C1CCNC1
Reactant: O=C1CCc2cc(Cl)ccc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccc2c(c1)CCC(N1CCCC1)=C2

Procedure:
1155 g (6.4 mol) of 6-chloro-3,4-dihydro-2(1H)-naphthalenone are dissolved in 5 l of toluene, 500 g (7.0 mol) of pyrrolidine and subsequently a solution of 26 g (0.14 mol) of p-toluenesulfonic acid monohydrate in toluene are added dropwise thereto and the mixture is boiled under reflux on a water separator. When about 120 ml of water have separated, 4 l of toluene are distilled and the mixture is left to cool slowly. A solid thereby crystallizes out. Filtration and washing with acetone gives 1-(6-chloro-3,4-dihydro-2-naphthyl)-pyrrolidine with melting point 117°-118°. Concentration of the mother liquor, suspension of the residue in ether, filtration and washing with acetone gives an additional portion of the above product with melting point 117°-118°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:23]2([C:27]([O:29]CC)=[O:28])[CH2:26][CH2:25][CH2:24]2)[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:23]2([C:27]([OH:29])=[O:28])[CH2:26][CH2:25][CH2:24]2)[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(C)C)cc3)c2)CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1ccc(-c2cc(C3(C(=O)O)CCC3)cc(Cl)c2OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.9 %

Procedure:
A mixture of ethyl 1-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylate (400 mg, 0.88 mmol) and lithium hydroxide monohydrate (215 mg, 5.1 mmol) in MeOH/THF/Water solvent mixture (10 ml/10 ml/10/ml) was stirred for 3 h at room temperature. After completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water, dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Flash Column Chromatography to give 1-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid (289 mg) as white solid. 1HNMR (CDCl3): 7.44 (d, 2H), 7.38 (s, 1H), 7.31 (d, 2H) 7.21 (s, 1H), 3.86 (q, 2H); 2.99 (m, 1H), 2.86 (m, 2H), 2.52 (m, 2H), 2.13 (m, 1H), 1.92 (m, 1H); 1.28 (d, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([Cl:15])[N:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[N:3]=1.[CH:25]([C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH2:37])(=[O:36])=[O:35])=[N:32][CH:33]=1)([CH3:27])[CH3:26].[K]>>[Cl:15][C:6]1[N:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[N:3]=[C:2]([NH:37][S:34]([C:31]2[CH:30]=[CH:29][C:28]([CH:25]([CH3:27])[CH3:26])=[CH:33][N:32]=2)(=[O:36])=[O:35])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc(Cc2nc(Cl)c(Oc3ccccc3)c(Cl)n2)c1
Reactant: CC(C)c1ccc(S(N)(=O)=O)nc1
Agent: [K]
Product: COc1cccc(Cc2nc(Cl)c(Oc3ccccc3)c(NS(=O)(=O)c3ccc(C(C)C)cn3)n2)c1

Procedure:
In analogy to Example 45, by reacting 4,6-dichloro-2-(3-methoxy-benzyl)-5-phenoxy-pyrimidine with potassium 5-isopropyl-pyridine-2-sulphonamide there was obtained 5-isopropyl-pyridine-2-sulphonic acid [6-chloro-2-(3-methoxy-benzyl)-5-phenoxy-pyrimidin-4-yl]-amide as a yellow foam. MS: 523 (M-H)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N+:3]=1[O-].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:13]>ClCCl>[OH:13][CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc[n+]([O-])c(C)c1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccnc(CO)c1
Reaction time: 8 h

Procedure:
A mixture of 2,4-dimethylpyridine N-oxide (10.9 g, 88.5 mmol) and trifluoroacetic anhydride (31 mL, 219 mmol) in dichloromethane (75 mL) was stirred at room temp. overnight. The product mixture was concentrated under vacuum. The residue was dissolved in a mixture of dichloromethane (75 mL) and aqueous sodium carbonate (225 mL, 2M), and stirred vigorously for 4 h. The resultant mixture was diluted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 1-2% methanol in chloroform gradient. Collection and concentration of appropriate fractions provided 2-hydroxymethyl-4-methylpyridine as clear oil.
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[Mg].[Cl-].[NH4+]>CO>[Cl:1][C:2]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: O=C(O)C=Cc1cccc(Cl)c1Cl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CO
Product: O=C(O)CCc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.4 %

Procedure:
To a solution of 2,3-dichlorocinnamic acid (1.0 g) in methanol (50 mL), magnesium (1.34 g) was added under ice-cooling and the resultant reaction mixture was stirred at room temperature for 3 days. To the reaction mixture, a saturated ammonium chloride aqueous solution was added and the resultant reaction mixture was extracted with dichloromethane. The organic phase was washed with a saturated saline and was dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure to obtain the subject compound (912 mg) as a white solid.