Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:65][C:66]1[CH:71]=[CH:70][C:69]([C:72](=[O:82])[CH2:73][O:74][Si](C(C)(C)C)(C)C)=[CH:68][CH:67]=1>ClCCl.O>[OH:74][CH2:73][C:72]([C:69]1[CH:70]=[CH:71][C:66]([NH:65][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]2)=[O:30])=[CH:67][CH:68]=1)=[O:82]
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(=O)CO)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.8 %

Procedure:
To a solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.35 g, 0.749 mmol) in dichloromethane (25 ml) was added iPr2NEt (242 mg, 1.87 mmol) was added, followed by the addition of HATU (513 mg, 1.35 mmol) and 1-(4-aminophenyl)-2-(tert-butyldimethylsilyloxy)ethanone (398 mg, 1.5 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was poured into H2O (50 mL) and extracted with dichloromethane (3×25 mL). The organic layers were combined, washed with H2O (1×50 mL), brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was dissolved in THF (25 mL) and then an aqueous solution (1 N) of HCl (10 mL) was added. The reaction mixture was stirred at room temperature for 30 min. The mixture was concentrated in vacuo. The residue was poured into 20 mL saturated aqueous NaHCO3 and extracted with ethyl acetate (3×25 mL). The organic layers were combined, washed with H2O (25 mL), brine (25 mL), dried over MgSO4 and concentrated. The residue was purified by flash chromatography (silica gel, 40 g, 20% to 100% EtOAc in hexanes) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-hydroxy-acetyl)-phenyl]-amide as a light yellow solid (0.17 g, 38%).
Reaction SMILES: ClCCl.C[C:5]([O:7][CH2:8][C:9]1[CH2:18][S:17][C@@H:12]2[C@H:13]([NH2:16])[C:14](=[O:15])[N:11]2[C:10]=1[C:19]([OH:21])=[O:20])=O.S(=O)(=O)(O)O>CO>[NH2:16][CH:13]1[C:14](=[O:15])[N:11]2[C:10]([C:19]([OH:21])=[O:20])=[C:9]([CH2:8][O:7][CH3:5])[CH2:18][S:17][C@H:12]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CO
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reaction time: 1.75 h

Procedure:
To 10 ml of dichloromethane were added 1.41 g of 7-ACA, 2.1 ml of concentrated sulfuric acid and 1.05 ml of methanol. The reaction was conducted at 0° C. for 1.75 hours. After completion of the reaction, substantially the same procedure as in Example 1 was repeated, to thereby obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.27 g. The yield of the desired product was 21%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:12][CH2:11]3)=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]=2[CH:18]=1.[N+:19]([O-])([OH:21])=[O:20]>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:12][CH2:11]3)=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]=2[CH:18]=1
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1c(C2CC2)oc2ccc(Br)cc12
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(C2CC2)oc2cc([N+](=O)[O-])c(Br)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution of compound ethyl 5-bromo-2-cyclopropylbenzofuran-3-carboxylate (10 g, 34 mmol) in CHCl3 (60 mL), fuming HNO3 (12 mL, 95%) was added dropwise at −20° C. over 90 min and the mixture was stirred at 0° C. for 1 hour. The reaction mixture was added to ice water and extracted with CH2Cl2. The organic layer was washed with NaHCO3 (aq.) and brine. The solvent was removed by distillation to provide the crude product of ethyl 5-bromo-2-cyclopropyl-6-nitrobenzofuran-3-carboxylate (4.5 g, yield: 40%). 1H-NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.95 (s, 1H), 4.46 (q, J=7.2 Hz, 2H), 3.06˜3.10 (m, 1H), 1.46 (t, J=7.2 Hz, 3H), 1.34˜1.36 (m, 2H), 1.28˜1.32 (m, 2H). MS (M+H)+: 354/356.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N+:15]([O-])([OH:17])=[O:16]>CCOCC.C(O)(=O)C>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([CH2:11][C:12]([OH:14])=[O:13])=[C:6]([N+:15]([O-:17])=[O:16])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(CC(=O)O)cc1OC
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1cc(CC(=O)O)c([N+](=O)[O-])cc1OC
Temperature: 25 °C

Procedure:
3,4-Dimethoxyphenylacetic acid (7.84 g) was solubilised in ether (100 ml) and acetic acid (20 ml). Fuming nitric acid (1.68 ml) was added dropwise to the solution. Stirring was maintained at room temperature for 16 hours. The precipitate was collected by filtration, washed with ether and dried to give 4,5-dimethoxy-2-nitrophenylacetic acid (4.19 g); NMR (DMSO-d6) 3.88(s,3H); 3.80(s,3H); 3.97(s,2H); 7.15(s,1H); 7.70(s,1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[C:24]([F:29])[C:23]([F:30])=[C:22](F)[C:21]=1[F:32].C(=O)([O-])[O-].[K+].[K+]>C1(=O)OCCC1>[N+:26]([C:25]1[C:24]([F:29])=[C:23]([F:30])[C:22]([O:15][C:13]2[CH:12]=[CH:11][C:10]([N+:16]([O-:18])=[O:17])=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:14]=2)=[C:21]([F:32])[C:20]=1[F:19])([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccc(O)cc1OCc1ccccc1
Reactant: O=[N+]([O-])c1c(F)c(F)c(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C1CCCO1
Product: O=[N+]([O-])c1ccc(Oc2c(F)c(F)c([N+](=O)[O-])c(F)c2F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
24.5 g of 2-benzyloxy-4-hydroxynitrobenzene (0.1 mol) and 21.3 g of pentafluoronitrobenzene (0.1 mol) are dissolved in 300 ml of γ-butyrolactone in a three-neck flask fitted with stirrer. 30 g of potassium carbonate (0.22 mol) are then added in portions, and the mixture is stirred at room temperature for 24 hours. The reaction solution is then filtered via a fluted filter, and the crude product is extracted by shaking with 200 ml of ethyl acetate and 300 ml of water. The organic phase is washed three times with water, dried over sodium sulfate and evaporated to half in a rotary evaporator. The precipitated crude product is then recrystallized from a mixture of methylene chloride and petrol ether (volume ratio 1:1) and then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:20])OCC)=[CH:11][C:10]=2[N+:21]([O-:23])=[O:22])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:26][O:27][CH:28]([O:32][CH3:33])[CH2:29][NH:30][CH3:31]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:30]([CH2:29][CH:28]([O:32][CH3:33])[O:27][CH3:26])[CH3:31])=[O:20])=[CH:11][C:10]=2[N+:21]([O-:23])=[O:22])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CNCC(OC)OC
Reactant: CCOC(=O)Nc1ccc(Oc2ccc([N+](=O)[O-])cc2)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: COC(CN(C)C(=O)Nc1ccc(Oc2ccc([N+](=O)[O-])cc2)c([N+](=O)[O-])c1)OC

Procedure:
Ethyl [4-(4-nitrophenoxy)-3-nitrophenyl]carbamate (0.1 mole) and toluene (100 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer and condenser. N-(2,2-dimethoxyethyl)methanamine (0.15 mole) is added to the vessel and the mixture is refluxed for 16 hours. Solvent is then removed by mild warming under reduced pressure to yield the desired product N-[4-(4-nitrophenoxy)-3-nitrophenyl]-N'-(2,2-dimethoxyethyl)-N'-methylurea.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][C@@H:16]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4].Cl>O1CCOCC1>[CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][C@@H:16]3[CH2:20][CH2:19][NH:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(O[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c2ncccc2c1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1cc(O[C@@H]2CCNC2)c2ncccc2c1

Procedure:
This was prepared in an analogous manner to Intermediate 4, using 1,1-dimethylethyl (3R)-3-[(6-butyl-8-quinolinyl)oxy]-1-pyrrolidinecarboxylate (for example, as prepared for Intermediate 9) and 4 M hydrogen chloride in 1,4-dioxane instead of trifluoroacetic acid for 45 min. LCMS RT=2.46 min, ES+ve m/z 271 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[C:5]([NH:6][C:7]([CH3:18])([CH3:17])[C:8](=[O:16])[NH:9]2)=[CH:4][CH:3]=1.CI.[C:21](=O)([O-])[O-].C(OCC)(=O)C>CN(C)C=O.O>[Br:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[C:5]([NH:6][C:7]([CH3:18])([CH3:17])[C:8](=[O:16])[N:9]2[CH3:21])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(Br)ccc2c1NC(=O)C(C)(C)N2
Reactant: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CI
Product: COC(=O)c1c(Br)ccc2c1N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
A mixture of 7-bromo-8-methoxycarbonyl-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 1, 102 mg, 0.326 mmol), methyl iodide (100 μL, 1.60 mmol), and cessium carbonate (272 mg, 0.835 mmol) was suspended in anhydrous N,N-dimethylformamide (5 mL) and stirred at room temperature for 2 hours. Ethyl acetate (25 mL) and water (25 mL) were added to the reaction mixture and partitioned. The organic layer was washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (86.0 mg) as a pale yellow solid. (Yield 83%)
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C)(C)C.C([Li])CCC.CCCCCC.[OH:30][C:31]1[C:39]([CH2:40][CH:41]=[C:42]([CH3:48])[CH2:43][CH2:44][C:45](Cl)=[O:46])=[C:38]([O:49][CH3:50])[C:37]([CH3:51])=[C:36]2[C:32]=1[C:33](=[O:52])[O:34][CH2:35]2.Cl>O1CCCC1.C(OCC)(=O)C>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:45](=[O:46])[CH2:44][CH2:43]/[C:42](/[CH3:48])=[CH:41]/[CH2:40][C:39]1[C:31]([OH:30])=[C:32]2[C:36](=[C:37]([CH3:51])[C:38]=1[O:49][CH3:50])[CH2:35][O:34][C:33]2=[O:52])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(C)c2c(c(O)c1CC=C(C)CCC(=O)Cl)C(=O)OC2
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)N1C(=O)OCC1Cc1ccccc1)C(=O)OC2
Temperature: 0 °C

Procedure:
A solution of (S)-4-benzyl-2-oxazolidinone (177.4 g, 1 mol) and t-butyl alcohol (74.1 g , 1 mol) in anhydrous tetrahydrofuran (2L) was cooled to -78° C. A 1.6M solution of n-butyllithium in hexane (1280 mL, 2 mol) was added maintaining a temperature below -30° C. After recooling to -78° C. the (E) 6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl -3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoyl chloride solution (1 mol) was added and the mixture was allowed to warm to 0° C. over 2 hours. 2N Hydrochloric acid (1.5L) and ethyl acetate (1L) were added. The organic layer was washed sequentially with saturated aqueous sodium bicarbonate (0.5L), 2N hydrochloric acid (0.5L), and brine (1L). After drying over sodium sulfate, the organic layer was evaporated at reduced pressure to leave the crude imide as a tan solid. Recrystallization from ethyl acetate/hexane (2.5L/2.5L) gave (S) 4-benzyl-3-[(E) 6-(1,3-dihydro -4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoyl]-2-oxazolidinone as off-white, shiny plates, m.p. 112°-113° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:18]=1)=[N:7][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:9]([OH:11])[N:10]=2.O.[NH2:20][NH2:21].CCOC(C)=O.O>O1CCOCC1>[NH:20]([C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:18]=1)=[N:7][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:9]([OH:11])[N:10]=2)[NH2:21]
Reactant: NN
Reactant: Oc1nc2ccc(Cl)nc2nc1-c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: NNc1ccc2nc(O)c(-c3ccccc3)nc2n1

Procedure:
6-chloro-3-phenylpyrido[2,3-b]pyrazin-2-ol (3-2) (26.2 g, 102 mmol) and hydrazine hydrate (26.2 g, 102 mmol) in 1,4-dioxane (400 mL) was stirred at 100° C. for 3 days. To the mixture was added EtOAc and water. The resulting solid was collected by filtration to give 6-hydrazino-3-phenylpyrido[2,3-b]pyrazin-2-ol (3-3) as yellow powder.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([N+:19]([O-])=O)[CH:13]=3)[C:9](=[O:22])[N:8]([CH:23]([CH3:25])[CH3:24])[C:6]=2[N:7]=1>CCOC(C)=O.CO.[Pd]>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([NH2:19])[CH:13]=3)[C:9](=[O:22])[N:8]([CH:23]([CH3:25])[CH3:24])[C:6]=2[N:7]=1
Reactant: CC(C)n1c(=O)c(-c2ccc(F)c([N+](=O)[O-])c2)cc2cnc(N)nc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)n1c(=O)c(-c2ccc(F)c(N)c2)cc2cnc(N)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.3 %

Procedure:
To a solution of 2-amino-6-(4-fluoro-3-nitrophenyl)-8-isopropylpyrido[2,3-d]pyrimidin-7(8H)-one (0.52 g, 1.5 mmol) in EtOAc and methanol (5:1, 30 mL) was added palladium on carbon (50 mg of 10% mol) and mixture was stirred under a hydrogen atmosphere at RT for 16 h. The mixture was filtered over a Celite pad and the pad was washed with EtOAc (2×10 mL). The combined filtrate was concentrated in vacuo to provide crude product. Purification by silica gel chromatography afforded 2-amino-6-(3-ammo-4-fluorophenyl)-8-isopropylpyrido[2,3-d]pyrimidin-7(8H)-one as an off-white solid (0.34 g, 72% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.60 (s, 1H), 7.73 (s, 1H), 7.22 (s, 2H), 7.08 (dd, J=9.2 Hz, 1.2 Hz, 1H), 6.99 (dd, J=10.8 Hz, 8.4 Hz, 1H), 6.74-6.70 (m, 1H), 5.78-5.76 (m, 1H), 5.13 (s, 2H), 1.53 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 314.0 (M+H+).
Reaction SMILES: C(OP([CH2:9][P:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.C([Li])CCC.[CH2:23]([O:25][C:26]([N:28]1[CH2:32][CH2:31][C:30](=O)[CH:29]1[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:27])[CH3:24]>O1CCCC1>[CH2:23]([O:25][C:26]([N:28]1[CH2:32][CH:31]=[C:30]([CH2:9][P:10]([O:12][CH2:13][CH3:14])([O:15][CH2:16][CH3:17])=[O:11])[CH:29]1[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:27])[CH3:24]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: CCOC(=O)C1C(=O)CCN1C(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1C(CP(=O)(OCC)OCC)=CCN1C(=O)OCC
Temperature: 25 °C

Procedure:
A stirred solution of 5.3 ml of bis-(diethylphosphono)methane in 30 ml of anhydrous tetrahydrofuran (THF) under nitrogen is cooled to -78° and 8.5 ml of 2.5M butyl lithium is added dropwise. After stirring 5 minutes a solution of 4.64 g of ethyl 1-ethoxycarbonyl-3-oxopyrrolidine-2-carboxylate [J. Am. Chem. Soc. 86, 5297 (1964)]in 30 ml dry THF is added dropwise rapidly. The solution is heated at reflux for 18 hours, cooled to room temperature and concentrated; 40 ml of 1N hydrochloric acid is added and the mixture is extracted with 100 ml of methylene chloride. The organic fraction is washed with 25 ml water, dried over Na2SO4, filtered and concentrated. Purification by flash chromatography using ethyl acetate as solvent yields ethyl 1-ethoxycarbonyl-3-(diethylphosphonomethyl)-2,5-dihydropyrrole-2-carboxylate.
Reaction SMILES: [OH:1][CH:2]=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].S(OC)(O[CH3:17])(=O)=O>O>[CH3:17][O:1][CH:2]=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COS(=O)(=O)OC
Reactant: OC=CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC=CCc1ccccc1
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
25 g of o-hydroxyallylbenzene was dissolved in 100 ml of water and to the mixture was added 8g of sodium hydroxide. To the resulting mixture was added dropwise 25.2 g of dimethyl sulfate over a period of about 2 hours, while maintaining the temperature at 5° - 10° C. The thus obtained mixture was heated with stirring at 80°- 100° C for approximately 30 minutes, and then the oil layer was separated. This layer was distilled under reduced pressure, there was obtained 22.3 g (yield 81%) of o-methoxyallylbenzene having a boiling point of 51° C/2 mmHg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]([F:12])([F:11])[F:10])[C:3]=1[CH2:13]O.P(Br)(Br)[Br:16].C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]([F:12])([F:11])[F:10])[C:3]=1[CH2:13][Br:16]
Reactant: BrP(Br)Br
Reactant: OCc1c(Br)cccc1OC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)Oc1cccc(Br)c1CBr
Temperature: -10 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
To a stirred solution of 2-bromo-6-[(trifluoromethyl)oxy]benzoic acid (1.116 g, 3.92 mmol, Parkway Scientific), in THF (45 ml), under nitrogen, was added 1.0 M borane-tetrahydrofuran complex (12 ml, 12 mmol) carefully over about 2 minutes. The solution was then heated at gentle reflux for 24 h and allowed to cool. Methanol (20 ml) was added dropwise. The solution was heated at reflux for 30 min and allowed to cool. The solvent was evaporated in vacuo and acidified with dilute aqueous HCl. The mixture was extracted with chloroform and then filtered through a hydrophobic frit. The chloroform was evaporated in vacuo to give {2-bromo-6-[(trifluoromethyl)oxy]phenyl}methanol as a colourless oil (1.07 g). {2-bromo-6-[(trifluoromethyl)oxy]phenyl}methanol (1.06 g, 3.91 mmol) in dichloromethane (14 ml) under nitrogen was stirred and cooled to −10° C. A solution of phosphorus tribromide (0.37 ml, 3.91 mmol) in DCM (3.5 ml) was then added dropwise over about 12 min. The temperature was allowed to rise to ambient temperature over about 3 h then stirred for a further 2 h. Saturated aqueous sodium bicarbonate (12 ml) was then added in portions with stirring and the mixture left in a fridge over weekend. The mixture was extracted into chloroform three times. The combined chloroform extracts were filtered through a hydrophobic frit and the solvent was evaporated in vacuo to give 1-bromo-2-(bromomethyl)-3-[(trifluoromethyl)oxy]benzene as a colourless oil (0.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[Sn](Cl)Cl.[OH-].[Na+]>Cl>[NH2:12][C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]([CH:8]=1)[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: CNC(=O)c1cc(N)ccc1Cl
Reaction time: 20 h
Yield: 64.5 %

Procedure:
To a suspension of 2-chloro-N-methyl-5-nitro-benzamide (2.3 mmol) in concentrated hydrochloric acid (3 ml) was added a solution of tin dichloride (1.4 g, 7.2 mmol) in concentrated hydrochloric acid (4 ml). After stirring for 20 hours, the mixture was cooled in an ice bath and treated with 50% sodium hydroxide to basic pH. The mixture was extracted with ethyl acetate (3×25 ml). The combined extracts were dried over sodium sulfate and concentrated under reduced pressure to provide 5-amino-2-chloro-N-methylbenzamide (274 mg, 88% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:28]I>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][CH3:28])[CH2:10][C@H:9]1[CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](O)CN2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](OC)CN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.4 %

Procedure:
To a stirred solution of methyl 4-[(2S,4S)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinyl]methoxybenzoate (2.10 g, 5.98 mmol) in THF (60 ml) was added 60% oil NaH (359 mg, 8.97 mmol) at 0° C. After 15 minutes stirring, MeI (1.20 ml, 8.97 mmol) was added to the mixture was added at same temperature, and the resulting mixture was allowed to raise to room temperature for over 1 h. Then 60% oil NaH (359 mg, 8.97 mmol) and MeI (1.20 ml, 8.97 mmol) was added to the reaction mixture at room temperature and stirred for 14 h. The reaction mixture was poured into ice water and extracted with CHCl3. The combined extracts were washed with aq. NaHCO3 and brine. After dried over Na2SO4, the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [50 g, n-hexane/EtOAc(4/1)], to give methyl 4-[(2S,4S)-1-tert-butoxycarbonyl-4-methoxy-2-pyrrolidinyl]methoxybenzoate (1.32 g, 60%) as a colorless oil. 1H-NMR (CDCl3) δ 1.48 (s, 9H), 2.05 (m, 1H), 2.29 (d, J=14.2 Hz, 1H), 3.30 (s, 3H), 3.36–4.38 (m, 4H), 6.76 (br, 2H), 7.97 (d, J=8.8 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:4]=2[CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2.C(N(CC)CC)C.[CH2:31]([N:33]=[C:34]=[O:35])[CH3:32].C1(C)C=CC=CC=1>ClCCl>[CH2:31]([NH:33][C:34]([N:10]1[C:11]2[C:6](=[CH:5][C:4]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16][C:3]=3[C:2]=2[CH3:1])[CH2:7][CH2:8][CH2:9]1)=[O:35])[CH3:32]
Reactant: CCN=C=O
Reactant: Cc1c2c(cc3c1NCCC3)CCN(C(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCNC(=O)N1CCCc2cc3c(c(C)c21)CCN(C(=O)OC(C)(C)C)CC3
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 167 mg of t-butyl 11-methyl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in 2 ml of dichloromethane were added 0.221 ml of triethylamine and 0.062 ml of ethyl isocyanate, followed by stirring at room temperature for 15 hours. To the reaction mixture were added 3 ml of toluene and 0.062 ml of ethyl isocyanate, followed by heating to 60° C. and stirring for 15 hours. Then, the reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 200 mg of t-butyl 1-(ethylcarbamoyl)-11-methyl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate as a colorless viscous substance.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]#[C:15][C:16]2[CH:21]=[C:20]([C:22]#[C:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:19]=[C:18]([C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:17]=2)=[CH:8][C:7]=1[CH3:40]>C(O)C.[OH-].[Na+]>[N:25]1([CH2:24][C:23]#[C:22][C:20]2[CH:21]=[C:16]([C:15]#[C:14][CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:41])=[O:2])=[C:7]([CH3:40])[CH:8]=3)[CH:17]=[C:18]([C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:19]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(C#CCN3CCCCC3)cc(C#CCN3CCCCC3)c2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OCC#Cc2cc(C#CCN3CCCCC3)cc(C#CCN3CCCCC3)c2)ccc1OCC(=O)O

Procedure:
A solution of (4-{3-[3,5-bis-(3-piperidin-1-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester (126 mg, 0.247 mmol) in ethanol (5 ml) and 1N NaOH (0.5 ml) was stirred at 75° C. for 30 min. The reaction mixture was evaporated and the residue dissolved in water (2 ml). Aqueous 1N HCl (0.5 ml) was added and the mixture was extracted with methylene chloride (3×15 ml). The combined organic phases were dried and evaporated to give the title compound in 115 mg (93%) yield.