Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13](O)=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)O)C1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](CO)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.2 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)pyrrolidine-3(R)-carboxylic acid (800 mg, 3.72 mmol) in 20 mL of anhydrous THF was added dropwise BH3.THF complex (1M in THF, 7.4 mL, 2.0 equiv.) at 0° C. under N2. The resulting solution was stirred for 4 h at room temperature. The reaction was then quenched with water. The mixture was concentrated under vacuum and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was applied onto a silica gel column, which was eluted with EtOAc/petroleum ether 1:5 to give the title compound (720 mg, 96%) as a colorless oil. LC-MS (ESI) m/z 202 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[F:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:21]=[C:20]([CH:19]=[CH:18][CH:17]=1)[O:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Reactant: Oc1cccc(F)c1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc(F)c1
Yield: 86 %

Procedure:
The title compound (D42) (D021/047/1) (252.3 mg) was prepared according to the experimental procedure described in Description 40 starting from (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (D41) (200 mg, 0.993 mmol) and 3-Fluorophenol (0.089 ml, 0.993 mmol).
Reaction SMILES: C1(OC)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:13][O:14][C:15]([C@@H:17]1[O:21][C@H:20]([C:22]2[CH2:23][S:24][C@@H:25]3[C@H:41]([NH:42][C:43](=[O:54])/[C:44](/[C:48]4[N:49]=[C:50]([NH2:53])[S:51][CH:52]=4)=[N:45]\[O:46][CH3:47])[C:40](=[O:55])[N:26]3[C:27]=2[C:28]([O:30]CC2C=CC(OC)=CC=2)=[O:29])[CH2:19][CH2:18]1)=[O:16].C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Na+:69].[Na+].[Na+]>ClCCl>[NH2:53][C:50]1[S:51][CH:52]=[C:48](/[C:44](=[N:45]/[O:46][CH3:47])/[C:43]([NH:42][C@@H:41]2[C:40](=[O:55])[N:26]3[C:27]([C:28]([O-:30])=[O:29])=[C:22]([C@@H:20]4[CH2:19][CH2:18][C@H:17]([C:15]([O:14][CH3:13])=[O:16])[O:21]4)[CH2:23][S:24][C@H:25]23)=[O:54])[N:49]=1.[Na+:69]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C([C@@H]3CC[C@H](C(=O)OC)O3)CS[C@H]12)c1csc(N)n1
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C([C@@H]3CC[C@H](C(=O)OC)O3)CS[C@H]12)c1csc(N)n1
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of anisole (0.75ml) and dichloromethane (0.38ml) was cooled to -20° C. and aluminium chloride (19mg) was added. The mixture was stirred at the same temperature for 15min. and then cooled to -40° C., and then a solution of 4-methoxybenzyl (6R,7R)-3-[(2S,5R)-5-methoxycarbonyltetrahydrofuran-2-yl]-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]ceph-3-em-4-carboxylate (31mg) in dichloromethane (2.5ml) was added and the mixture stirred at the same temperature for 5min. Trisodium citrate (1.64ml of 0.5M solution) was then added and the mixture stirred for 10 min at room temperature. The aqueous phase was separated and washed twice with dichloromethane. The solution was evaporated and the product isolated by column chromatography of the residue (HP20SS, water with increasing proportions of acetone as eluent). Fractions containing product were combined, evaporated and the residue dissolved in water (3ml) and freeze dried to give the title compound (12mg); vmax (KBr) 1762, 1670 and 1604cm-1 ; δH [(CD3)2SO)]1.50-1.63 (1H, m), 1.90-2.26 (3H, m), 3.30-3.47 (2H, m), 3.65 (3H, s), 3.83 (3H, s), 4.39 (1H, dd, J 3.4, 8.7Hz), 4.98 (1H, d, J 4.8Hz), 5.0 (1H, dd, J 5.1, 9.8Hz), 5.52 (1H, dd, J 4.7, 8.2Hz), 6.75 (1H, s), 7.24 (2H, s) and 9.49 (1H, d, J 8.1Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[CH:10]=[S:11]([CH3:14])([CH3:13])=[O:12])=[CH:4][CH:3]=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[C:10](=[S:11]([CH3:13])([CH3:14])=[O:12])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: CS(C)(=O)=CC(=O)Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CC#N
Product: CCOC(=O)C(C(=O)Nc1ccc(Cl)cc1)=S(C)(C)=O
Temperature: 50 °C
Yield: 40 %

Procedure:
To a stirred solution of 7.72 grams (0.03 mole) of N-(4-chlorophenyl)-2-(dimethyloxosulfuranylidene)acetamide prepared in Part A of this Example, in 80 milliliters of anhydrous acetonitrile, was added 1.70 grams (0.02 mole) of ethyl chloroformate dropwise at room temperature and the resulting mixture then heated and stirred at 50° C. for an approximate 16-hour period. The hydrochloride by-product was filtered off and the filtrate vacuum evaporated to give a yellow solid. The latter was digested with cold 2N HCl to remove unreacted starting material and the undissolved solid was collected and recrystallized from methanol. Vacuum drying of the resulting solid gave 2.73 grams (0.008 mole) of ethyl 3-[(4-chlorophenyl)amino]-2-(dimethyloxosulfuranylidene)-3-oxopropanoate having a melting point of 162° C.-163° C.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@H:14]([CH2:15][P:16](=[O:21])([O:19][CH3:20])[O:17][CH3:18])[O:13][C@@H:12]([C:22]([F:25])([F:24])[F:23])[C@H:11]2[O:26]C(C)(C)[O:28][C@@H:10]12)(C(C)(C)C)(C)C.C(O)(C(F)(F)F)=O.O>CCOC(C)=O>[OH:8][C@H:9]1[C@H:10]([OH:28])[C@H:11]([OH:26])[C@H:12]([C:22]([F:24])([F:23])[F:25])[O:13][C@H:14]1[CH2:15][P:16](=[O:21])([O:17][CH3:18])[O:19][CH3:20]
Reactant: COP(=O)(C[C@@H]1O[C@@H](C(F)(F)F)[C@H]2OC(C)(C)O[C@H]2[C@@H]1O[Si](C)(C)C(C)(C)C)OC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COP(=O)(C[C@@H]1O[C@@H](C(F)(F)F)[C@@H](O)[C@@H](O)[C@@H]1O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 25 mL round bottom flask, dimethyl (((3aS,4R,6R,7S,7aR)-7-((tert-butyldimethylsilyl)oxy)-2,2-dimethyl-4-(trifluoromethyl)tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-6-yl)methyl)phosphonate (70 mg, 0.14 mmol) was taken up in a TFA-H2O mixture (2 mL, 9:1) at 0° C. The reaction mixture was gradually warmed to rt and stirred at rt for 3 h. Upon completion of the reaction (TLC, 50% EtOAc in hexanes, Rf 0.1), the reaction mixture was concentrated under reduced pressure. The residue obtained was washed with n-pentane (10 mL) to give dimethyl (((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(trifluoro methyl)tetrahydro-2H-pyran-2-yl)methyl)phosphonate that was used in next step without purification (40 mg, 88%): 1H NMR (400 MHz, CDCl3) δ 4.54-4.50 (m, 1H), 4.25-4.19 (m, 1H), 4.08-3.97 (m, 2H), 3.77 (d, J=6.0 Hz, 3H), 3.73 (d, J=6.0 Hz, 3H), 3.58-3.54 (m, 1H), 1.58 (s, 3H), 2.44-2.16 (m, 2H); 19F NMR (376.17 MHz, CDCl3) δ −74.36 ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH3:25][C:26]([CH:28]=[CH2:29])=[O:27].C(O)(=O)/C=C\C(O)=O>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:29][CH2:28][C:26](=[O:27])[CH3:25])[CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: C=CC(C)=O
Reactant: Fc1ccc(C(OCCN2CCNCC2)c2ccc(F)cc2)cc1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Product: CC(=O)CCN1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.7 g (2.1 mM) of 1-[2-(bis-(4-fluorophenyl) -methoxy)-ethyl]piperazine and 150 mg (2.1 mM) of freshly distilled methylvinyl-ketone was stirred at room temperature for 2 h. 30 ml of ethanol and 0.48 g of maleic acid were added, the precipitated salt was isolated by filtration and recrystallized from hot acetonitrile to yield the dimaleate salt of the title compound as colourless crystals melting at 159°-160° C. Analytical data were in accordance with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[C:12]2I.[CH3:29][O:30][C:31]1[CH:36]=[C:35]([Sn](C)(C)C)[N:34]=[C:33]([N:41]2[CH2:46][CH2:45][CH:44]([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:43][CH2:42]2)[N:32]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[C:12]2[C:35]1[CH:36]=[C:31]([O:30][CH3:29])[N:32]=[C:33]([N:41]2[CH2:46][CH2:45][CH:44]([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:52])([CH3:51])[CH3:53])[CH2:43][CH2:42]2)[N:34]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4c(F)cccc4F)ccc32)cc1
Reactant: COc1cc([Sn](C)(C)C)nc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(-c4c(F)cccc4F)cc23)nc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Temperature: 90 °C
Yield: 43.5 %

Procedure:
To a solution of 5-(2,6-difluorophenyl)-3-iodo-1-tosyl-1H-indole (0.107 g, 0.2 mmol) and tert-butyl (1-(4-methoxy-6-(trimethylstannyl)pyrimidin-2-yl)piperidin-4-yl)carbamate (0.1 g, 0.2 mmol) in DMF (2 mL) was added Pd(PPh3)4 (23 mg, 0.02 mmol) and CuI (42 mg, 0.22 mmol) and argon gas was bubbled for 15 min. The reaction was heated at 90° C. for 1 h then quenched with water. The suspension was extracted with EtOAc and the organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified with basic alumina chromatography (eluting with 50% EtOAc in petroleum ether) to give tert-butyl (1-(4-(5-(2,6-difluorophenyl)-1-tosyl-1H-indol-3-yl)-6-methoxypyrimidin-2-yl)piperidin-4-yl)carbamate (60 mg, 41%). MS (ESI, pos. ion) m/z: 690.2 (M+1); 1H-NMR (DMSO-d6, 300 MHz): δ ppm 8.71 (s, 1H), 8.61 (s, 1H), 8.10-8.20 (m, 3H), 7.42-7.52 (m, 4H), 7.20-7.25 (m, 3H), 6.76 (m, 1H), 4.56 (d, J=12.9 Hz, 2H), 3.87 (s, 3H), 3.32 (d, J=9 Hz, 3H), 3.03 (m, 2H) 2.33 (s, 3H), 1.74 (d, J=12.9 Hz, 2H), 1.3 (s, 9H).
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([CH:15]=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>CO>[CH3:18][C:16]1[N:17]=[C:10]2[C:9](=[O:8])[CH2:14][CH2:13][CH2:12][N:11]2[CH:15]=1
Reactant: [H][H]
Reactant: Cc1cn2cccc(OCc3ccccc3)c2n1
Solvent: CO
Product: Cc1cn2c(n1)C(=O)CCC2
Temperature: 25 °C
Reaction time: 22 h

Procedure:
60 g (251.8 mmol) of 8-benzyloxy-2-methylimidazo[1,2-a]pyridine (Kaminski et al, J. Med. Chem. 1985, 28, 876-892) are hydrogenated on Pd-carbon in 400 ml of methanol at a hydrogen pressure of 55 bar and 70° C. After completion of the hydrogenation, the catalyst is filtered off and the filtrate is concentrated. The residue (38 g) is taken up in dichloromethane and the solution is treated in portions at room temperature with manganese dioxide (109.5 g). The reaction mixture is stirred at room temperature for 22 h and then filtered through silica gel. The filtrate is concentrated to a residue and the crystallizate is dried in vacuo at 60° C. 25.13 g (66% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)(=[O:5])=[O:4].C1C(=O)N([Br:22])C(=O)C1>C(Cl)Cl>[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[C:12]([Br:22])[CH:13]=1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)CCc1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CNS(=O)(=O)CCc1ccc(N)c(Br)c1
Temperature: 0 °C
Yield: 85.6 %

Procedure:
A solution of 318 mg (1.48 mmol) of 2-(4-aminophenyl)-ethanesulfonic acid methylamide (as prepared in the previous step) in CH2Cl2 (20 mL) was cooled to 0° C. and treated with 251 mg (1.41 mmol) of NBS at that temperature for 1 h. The mixture was diluted with CH2Cl2 (30 mL) and washed with saturated aqueous NaHCO3 (1×30 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 25-g Varian MegaBond Elut SPE column with 50% EtOAc-hexane afforded 354 mg (81%) of the title compound as a white solid: 1H-NMR (CD3CN; 400 MHz): δ 7.34 (d, 1H, J=2.0 Hz), 7.03 (dd, 1H, J=8.0, 2.0 Hz), 6.77 (d, 1H, J=8.0 Hz), 5.06-4.97 (m, 1H), 4.48-4.40 (br s, 2H), 3.25-3.18 (m, 2H), 2.93-2.86 (m, 2H), 2.67 (d, 3H, J=5.2 Hz). Mass spectrum (ESI, m/z): Calcd. for C9H13N2O2SBr, 293.0/295.0 (M+H). found 293.0/295.0.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:4]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:18])=[N:15][CH:16]=1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][C:34]=1[I:35])[NH2:31].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:27][C:28]1[CH:29]=[C:30]([NH:31][CH2:2][C:3]2[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:4]=2[C:11]2[CH:12]=[CH:13][C:14]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:18])=[N:15][CH:16]=2)[CH:32]=[CH:33][C:34]=1[I:35]
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(F)c(F)cc2CBr)cn1
Reactant: Nc1ccc(I)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(F)c(F)cc2CNc2ccc(I)c(Cl)c2)cn1
Temperature: 25 °C

Procedure:
Ethyl 3-(5-(2-(bromomethyl)-4,5-difluorophenyl)picolinamido)propanoate (1.0 g, 2.3 mmol), 3-chloro-4-iodoaniline (1.2 g, 4.7 mmol), and K2CO3 (647 mg, 4.7 mmol) were diluted with DMF (2.4 mL) and the resulting mixture was stirred at room temperature. After 2 h the resulting mixture directly purified via column chromatography to yield the title compound.
Reaction SMILES: [CH:1](=[C:5]1[S:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][S:15][C:16]2[N:21]3[CH:22]=[CH:23][N:24]=[C:20]3[CH:19]=[CH:18][CH:17]=2)[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4].[Br:26]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)(Cl)Cl>[CH:1](=[C:5]1[S:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][S:15][C:16]2[N:21]3[C:22]([Br:26])=[CH:23][N:24]=[C:20]3[CH:19]=[CH:18][CH:17]=2)[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CCCC=C1SC(=O)N(CCCCSc2cccc3ncc(Br)n23)C1=O
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1.13 g (3.0 mmol) of 5-butylidene-3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione in 15 ml of carbon tetrachloride, 0.59 g (3.3 mmol) of N-bromosuccinimide was added at room temperature, followed by stirring at 80° C. for 90 minutes. After the reaction mixture was cooled, saturated aqueous sodium hydrogen carbonate was added. The organic layer was separated and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=2/1→1/4) to yield 1.11 g (81.4%, yellow oily substance) of the desired product.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].[OH-].[Na+]>CCO>[OH:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:19])=[O:2])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH:6]=1
Reactant: COC(=O)c1ccc(CO)cc1-c1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1-c1cc(CO)ccc1C(=O)O
Temperature: 80 °C

Procedure:
To a solution of 4-hydroxymethyl-2-(2-methylphenyl)benzoic acid methyl ester (73 g, 285 mmol), prepared as in example 1075D, in EtOH (300 mL) was added an aqueous 4N NaOH solution (350 mL, 1.4 mol), and mixture heated at 80° C. overnight. Reaction concentrated in vacuo, and residue mixed with water (300 mL). Aqueous mixture acidified to pH 6 using aqueous 3N HCl, and acid product extracted out with CHCl3 (3×200 mL). Organic extracts dried with Na2SO4, filtered, and concentrated in vacuo to produce a white solid (69 g, 100% crude yield). m/e (DCI) 243 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[CH:15]1([CH2:21][NH:22][CH2:23][CH3:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH:15]1([CH2:21][N:22]([C:2]2[C:11]([CH:12]=[O:13])=[CH:10][C:9]3[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=3)[N:3]=2)[CH2:23][CH3:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCNCC1CCCCC1
Reactant: O=Cc1cc2ccc(F)cc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(CC1CCCCC1)c1nc2cc(F)ccc2cc1C=O
Temperature: 25 °C

Procedure:
A suspension of 2-chloro-7-fluoroquinoline-3-carbaldehyde (200 mg, 0.95 mmol), N-(cyclohexylmethyl)-N-ethylamine (140 mg, 0.99 mmol) and potassium carbonate (140 mg, 1.0 mmol) in toluene (3 mL) is stirred and refluxed for 14 hours. The reaction mixture is cooled to room temperature and then diluted with water and ethyl acetate. The organic layer is washed with 1N HCl, brine, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by silica gel column chromatography to give 2-[N-(cyclohexylmethyl)-N-ethylamino]-7-fluoroquinoline-3-carbaldehyde.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH2:6][N:7]([CH3:14])[C:8](=[O:13])[C:9]([O:11]C)=[O:10])[CH3:4].[OH-].[Na+].Cl>O>[CH3:4][N:3]([CH2:5][CH2:6][N:7]([CH3:14])[C:8](=[O:13])[C:9]([OH:11])=[O:10])[CH3:2]
Reactant: COC(=O)C(=O)N(C)CCN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)CCN(C)C(=O)C(=O)O
Yield: 64.5 %

Procedure:
A solution of methyl N-dimethylaminoethyl-N-methyloxamate hydrochloride (500 mg) in water (20 ml) was cooled on an ice bath under stirring, and to the solution was added dropwise a solution of sodium hydroxide (356 mg) in water (10 ml). After the completion of the addition, the reaction solution was further stirred at room temperature for 2 hours and then adjusted the pH thereof to 4 with the addition of 1N aqueous HCl. After the removal of the solvent by distillation under a reduced pressure, methanol (20 ml) was added to the distillation residue and solid matters which remain undissolved were removed by filtration. The filtrate was concentrated and then purified by chromatography on a resin "Sephadex LH-20" using a 1:1 (by volume) mixture of methylene chloride-methanol as eluent, affording N-dimethylaminoethyl-N-methyloxamic acid (250 mg) as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[OH:14])[CH:2]=[CH2:3].Cl[Sn](Cl)(Cl)Cl.[I:20]I>ClCCl>[I:20][CH2:3][CH:2]1[CH2:1][C:4]2[CH:9]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:7]=[CH:6][C:5]=2[O:14]1
Reactant: II
Reactant: C=CCc1cc(C(F)(F)F)ccc1O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1ccc2c(c1)CC(CI)O2
Yield: 43.1 %

Procedure:
To a solution of 2-(prop-2-en-1-yl)-4-(trifluoromethyl)phenol (4 g, 20 mmol) in dichloromethane (50 ml) was added SnCl4 (2.6 g, 10.0 mmol, 0.5 eq) dropwise and iodine (5.03 g, 19.8 mmol, 1 eq) with stirring for 6 hours at room temperature. The reaction mixture was diluted with dichloromethane (200 ml) and quenched by the addition of water (100 ml). The organic layer was separated and the pH value of the aqueous layer was adjusted to ˜8 with aqueous sodium bicarbonate. The aqueous layer was extracted further with dichloromethane (3×100 ml). The organic layers were combined, washed with aqueous Na2S2O4 (5%, 100 ml) to remove remaining iodine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The crude material was purified by silica gel chromatography using 1% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford 2-(iodomethyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran as colorless oil (2.8 g, 43%); 1H NMR (300 MHz, CDCl3): δ 7.39 (d, J=5.7 Hz, 2H), 6.83 (d, J=8.7 Hz, 1H), 4.91-5.00 (m, 1H), 3.34-3.48 (m, 3H), 3.05-3.12 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([C:13]([F:12])([F:23])[F:24])[CH:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c([N+](=O)[O-])c1)c1cccc(C(F)(F)F)c1
Yield: 98.6 %

Procedure:
To a solution of 4-chloro-3-nitroaniline (1.72 g, 10.0 mmol) in 60 mL of anhydrous DCM was added crystalline DMAP (1.22 g, 10.0 mmol). The reaction mixture was stirred until all solids dissolved, then 3-trifluoromethylbenzoyl chloride (2.71 g, 13.0 mmol) was added dropwise. The reaction mixture was left to stir at ambient temperature for 6 hrs. The completion of the reaction was monitored by TLC and LC/MS. Then it was transferred into a separatory funnel and washed with water (3×100 mL), saturated NaHCO3 (2×100 mL), brine (1×100 mL), dried over anhydrous Na2SO4 and filtered through a short pad of silica gel. Solvent was removed in vacuo to give the title product as a light-brown solid (3.4 g, 100% yield).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH2:6]([N:13]([CH3:22])[CH2:14][CH2:15][C:16](N(OC)C)=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:6]([N:13]([CH3:22])[CH2:14][CH2:15][C:16](=[O:17])[CH2:1][CH2:2][CH2:3][CH3:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CON(C)C(=O)CCN(C)Cc1ccccc1
Reactant: [Li]CCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(=O)CCN(C)Cc1ccccc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Add butyllithium (12.3 ml (1.6 M solution in hexane), 19.6 mmol) to a stirred solution of 3-(benzyl-methyl-amino)-N-methoxy-N-methyl-propionamide and anhydrous tetrahydrofuran (70 ml) at −40° C. under N2. Stir for 1 hr at −40° C. Quench the reaction with saturated ammonium chloride (25 ml), allow the reaction to reach room temperature and add saturated sodium bicarbonate. Extract with ethyl acetate, wash with brine and dry over sodium sulfate. Filter off and concentrate to give the crude product. Purify the compound by flash chromatography, eluting with 2% ethanol/0.2% ammonium hydroxide/chloroform to yield 2.41 g (81%) of 1-(benzyl-methyl-amino)-heptan-3-one: mass spectrum (ion spray) m/z=234 (M+1); 1H NMR (CDCl3) δ 7.31-7.24 (m, 5H), 3.5 (s, 2H), 2.74-2.7 (m, 2H), 2.64-2.60 (m, 2H), 2.41 (t, 2H), 2.19 (s, 3), 1.59-1.51 (m, 2H), 1.35-1.28 (m, 2H), 0.91 (t, 3H).
Reaction SMILES: CC(C)([O-])C.[Na+:6].[C:7]1(=[O:14])[NH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[CH2:10]1[CH2:11][CH2:12][N:13]=[C:7]([O-:14])[CH2:8][CH2:9]1.[Na+:6]
Reactant: O=C1CCCCCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: [O-]C1=NCCCCC1
Temperature: 180 °C
Reaction time: 1 h

Procedure:
Sodium caprolactamate is prepared from sodium tert. butoxide and dissolved in caprolactam in the amount of 0.3 mol %. 0.3 Mol % of 2,2,4-trimethyl-3-oxopentanoyl-(4'-phenylazo)aniline is dissolved in the solution thus obtained. The polymerization product containing 89.5% of thecolored polyamide is obtained after heating to 180° C for 15 minutes; the polyamide contains 100% of the dye incorporated therein. Evenif the polymerization is carried out for 60 minutes, 96.5% of the polymer is formed which exhibits over 90% of the original color absorption. On thecontrary, if 2-benzoyl-2-(4'-dimethylaminophenylazo)-acetanilide is used (adye of the Hansa Yellow type), only 10-20% of the original color absorptionremains in the polymer under the same conditions.