Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:16][CH2:17][CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]=1[CH2:16][CH2:17][CH3:18])[CH3:27]
Reactant: CCOC(=O)CBr
Reactant: CCCc1cc(OCc2ccccc2)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1cc(OCc2ccccc2)ccc1OCC(=O)OCC
Reaction time: 18 h
Yield: 97.3 %

Procedure:
A solution of 4-benzyloxy-2-propylphenol (0.50 g, 1.94 mmol) in dry DMF (7 mL) is cooled in an ice bath and treated with NaH (0.15 g, 3.8 mmol, 60% oil dispersion). The ice bath is removed, ethyl bromoacetate (0.43 mL, 3.9 mmol) is added, and the mixture is placed in an oil bath (T=85° C.). After 18 h, the reaction mixture is cooled and concentrated in vacuo. The residue is diluted with EtOAc, washed with brine (2×), dried (Na2SO4), and concentrated. The crude product is purified by radial chromatography using 10% ethyl acetate in hexanes to give a tan solid (0.62 g, 97%). 1H NMR (400 MHz, CDCl3) δ 7.44–7.31 (m, 5H), 6.82 (d, J=2.9 Hz, 1H), 6.72 (dd, J=8.8, 2.9 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 5.00 (s, 2H), 4.57 (s, 2H), 4.25 (q, J=7.0 Hz, 2H), 2.63 (t, J=7.6 Hz, 2H), 1.64 (q, J=7.5 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H); MS (FIA) m/e 329 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[Cl:12].[CH2:13]([Sn](CCCC)(CCCC)C=C)[CH2:14]CC>O1CCOCC1>[Cl:12][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:13]=[CH2:14])[CH:3]=2)[N:8]=[CH:7][CH:6]=1
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: C1COCCO1
Product: C=Cc1ccc2nccc(Cl)c2c1
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of 6-bromo-4-chloroquinoline (6.52 g, 26.88 mmol; see J. Med. Chem., 21, 268 (1978)), tributyl(vinyl)tin (8.95 g, 28.22 mmol), and tetrakistriphenylphosphine palladium(0) (0.62 g, 0.54 mmol) in 1,4-dioxane (150 mL) was refluxed for 2.0 h, cooled to room temperature, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-4% MeOH:CH2Cl2) to give the title compound (5.1 g) as a pale yellow solid. MS (ES)+ m/e 190 [M+H]+. This material was used directly in the next step.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].C1(C)C=CC=CC=1.[CH3:12][O:13][C:14]1[O:15][C:16]2[C:21]([C:22](=[O:24])[CH:23]=1)=[CH:20][CH:19]=[C:18]([O:25]C)[CH:17]=2>O>[OH:25][C:18]1[CH:17]=[C:16]2[C:21]([C:22](=[O:24])[CH:23]=[C:14]([O:13][CH3:12])[O:15]2)=[CH:20][CH:19]=1
Reactant: COc1ccc2c(=O)cc(OC)oc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(=O)c2ccc(O)cc2o1
Temperature: 90 °C
Reaction time: 4 h
Yield: 64.6 %

Procedure:
Under nitrogen atmosphere, 170 mg of aluminium trichloride was added to 5 ml solution of toluene with 103 mg of 2,7-dimethoxy-4H-chromen-4-one, and the mixture was stirred at 90° C. for 4 hours. Water was added to the reaction solution, the deposited white solid was filtered, separated and purified by preparative thin-layer chromatography (chloroform/methanol=9/1), to obtain 62 mg of the above compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH2:13]([O:20][C@H:21]([CH3:25])[C@H:22]([OH:24])[CH3:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+].[Cl-].[Na+]>C(OCC)C.C(#N)C>[CH2:13]([O:20][C@H:21]([CH3:25])[C@@H:22]([CH3:23])[O:24][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: C[C@@H](O)[C@@H](C)OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: C[C@@H](OCc1ccccc1)[C@@H](C)Oc1nc(Cl)ncc1C(F)(F)F
Temperature: 15 °C
Reaction time: 1.5 h

Procedure:
A solution of 5.00 g (23.0 mmol) of 2,4-dichloro-5-trifluoromethylpyrimidine and 5.40 g (30.0 mmol) of (2R,3R)-3-benzyloxybutan-2-ol in 60 ml of diethyl ether and 65 ml of acetonitrile were admixed at 0° C. with 1.21 g (27.7 mmol) of sodium hydride (55% strength), divided into 3 portions, and then stirred for 90 minutes at 15° C. The mixture was admixed with dilute sodium chloride solution and extracted (3×) with ethyl acetate. The combined organic phases were dried (Na2SO4), filtered and concentrated by evaporation. The resulting residue was purified chromatographically (hexane/ethyl acetate 95:5). This gave 1.60 g (4.4 mmol; yield: 19%) of the product.
Reaction SMILES: C(CC[O:5][C:6]([C:8]1[C@H:9]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:10]([C:16]([O:18][CH2:19][O:20][CH3:21])=[O:17])=[C:11]([CH3:15])[NH:12][C:13]=1[CH3:14])=[O:7])#N.[OH-].[Na+].O.Cl>O1CCOCC1.C(OCC)(=O)C>[CH3:14][C:13]1[NH:12][C:11]([CH3:15])=[C:10]([C:16]([O:18][CH2:19][O:20][CH3:21])=[O:17])[C@@H:9]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:8]=1[C:6]([OH:7])=[O:5]
Reactant: COCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCC#N)[C@@H]1c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COCOC(=O)C1=C(C)NC(C)=C(C(=O)O)[C@@H]1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
To a solution of 3.6 mg of methoxymethyl (4S)-5-(2-cyanoethoxy-carbonyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3-carboxylate in 0.25 ml of dioxane was added 0.1 ml of 1N aqueous sodium hydroxide solution. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with 5 ml of ethyl acetate, to which were added water and 0.1 ml of 1N aqueous hydrochloric acid. The resulting mixture was dried over anhydrous Glauber's salt (sodium sulfate), followed by distilling off the solvent under reduced pressure to obtain 2.6 mg of the objective compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.O>C(#N)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(F)cc2)cc1
Yield: 102 %

Procedure:
To a solution of 4-fluoroaniline (200.0 g (1.80 mol) in pyridine (155.0 g (1.96 mol)) and acetonitrile (155 ml), under cooling with ice and with stirring, p-toluenesulfonyl chloride (360.3 g (1.89 mol)) was added. After stirring for 20 hours at room temperature, water (1500 ml) was added to the reaction mixture to bring about separation of crystals. The crystals were filtered and washed with water to give 486.6 g (102%) of 4′-fluoro-p-toluenesulfonanilide as pale red crude crystals.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[O-:12][Mn](=O)(=O)=O.[K+].[OH2:18]>>[CH3:11][C:10]1[C:2]([C:1]([OH:12])=[O:18])=[CH:3][C:4]2[NH:8][CH:7]=[N:6][C:5]=2[CH:9]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1cc2nc[nH]c2cc1C
Reactant: O
Agent: [K+]
Product: Cc1cc2nc[nH]c2cc1C(=O)O
Reaction time: 0.5 h

Procedure:
A 1L three neck round bottom flask equiped with an addition funnel and condenser was charged with a solution of 5,6-dimethylbenzimidazole (2.00 g, 13.69 mmol) dissolved in water (400 mL). The mixture was warmed to reflux and KMnO4 (8.60 g, 54.4 mmol) dissolved in water (200 mL) was added over a 0.5 h period. The reaction stirred for 0.5 h at reflux and was filtered hot through a plug a celite, washed with water (2×100 mL), acidified to pH 1 with 3N HCl and concentrated to 50 mL volume. The solution was aged for 2 h, filtered, washed with cold water and the solid was dried overnight at 50° C. under 25 mm vacuum to provide a white solid:
Reaction SMILES: [CH:1]([N:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8])=[O:2].C(N(CC)CC)C.C[Si](C)(C)[Cl:18].CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)N2[C@H]1[C:41]([OH:43])=O>C1C=CC=CC=1>[CH:1]([N:3]1[CH2:7][CH2:6][N:5]([C:41]([Cl:18])=[O:43])[C:4]1=[O:8])=[O:2]
Reactant: O=CN1CCNC1=O
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=CN1CCN(C(=O)Cl)C1=O
Reaction time: 5 h

Procedure:
A mixture of N-formyl-imidazolidin-2-one (6.0 parts by weight), benzene (40 parts by volume) and triethylamine (11.8 parts by volume) was boiled under reflux and at the same time a solution of trimethylchlorosilane (8.5 parts by weight) in benzene (20 parts by volume) was added dropwise. Thereafter the mixture was boiled for a further 5 hours and then left to stand overnight at room temperature and the precipitate present was filtered off and washed with benzene. The combined benzene solutions, on standing overnight, formed further amounts of precipitate which were filtered off. A solution of phosgene (15.6 parts by weight) in dichloromethane (30 parts by volume) was then added dropwise to the filtrate and the mixture was subsequently left to stand overnight in a refrigerator. It was then completely evaporated to dryness in a rotary evaporator. The residue, a mass which did not crystallize throughout to give a solid, was used, as it was, for the reaction with ampicillin.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([O:36][CH2:37][CH3:38])[CH:35]=1)[CH:31]=O)[CH3:26]>ClC(Cl)C.ClCCl>[Br:2][C:1]([Br:5])=[CH:31][C:30]1[CH:33]=[C:34]([O:36][CH2:37][CH3:38])[CH:35]=[C:28]([O:27][CH2:25][CH3:26])[CH:29]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCOc1cc(C=O)cc(OCC)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCOc1cc(C=C(Br)Br)cc(OCC)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Carbon tetrabromide (4.78 g) was dissolved in dichloroethane (14 mL), and triphenylphosphine (7.56 g) was added thereto at 0° C. After stirring at 0° C. for 5 minutes, a solution of 3,5-diethoxybenzaldehyde (1.40 g) in dichloromethane (7 mL) was added thereto, followed by stirring for 20 minutes. Without performing further treatment, the reaction mixture was purified by silica gel chromatography (developing solvent: hexane/ethyl acetate) to obtain 1-(2,2-dibromovinyl)-3,5-diethoxybenzene. The obtained compound was used for the subsequent reaction without further purification. The compound obtained above was dissolved in THF (30 mL). A 1.63 M n-butyllithium solution in hexane (10.5 mL) was added thereto at −78° C. The resulting mixture was stirred at −78° C. for 30 minutes. After adding a saturated aqueous ammonium chloride solution, the reaction mixture was subjected to extraction using ethyl acetate. The resulting organic layer was washed with a saturated sodium chloride solution, and the organic layer was then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless, oily substance (1.31 g). Physical properties: m/z [M+H]+ 191.0
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]1OC2(CCCC2)[O:7][C@@H:6]([CH2:14][C:15]([OH:17])=[O:16])[CH2:5]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=O)[CH:26]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:27]([C:37](=O)[CH:38]([CH3:40])[CH3:39])[C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:29])=[CH:21][CH:20]=1.C(OCC)C.[Cl-].[NH4+]>CS(C)=O.O>[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:1]([CH2:2][CH2:3][C@H:4]3[CH2:5][C@H:6]([OH:7])[CH2:14][C:15](=[O:16])[O:17]3)[C:37]([CH:38]([CH3:40])[CH3:39])=[C:27]([C:28]([NH:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:29])[C:26]=2[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[CH:23][CH:24]=1
Reactant: NCC[C@@H]1C[C@H](CC(=O)O)OC2(CCCC2)O1
Reactant: CC(C)C(=O)C(C(=O)Nc1ccccc1)C(C(=O)c1ccc(F)cc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@H]1C[C@H](O)CC(=O)O1
Temperature: 105 °C
Reaction time: 3 h
Yield: 24.7 %

Procedure:
A solution of 0.295 g (1.21 mmol) of (±)-cis-9-(2aminoethyl)-6,10-dioxaspiro[4.5]decane-7-acetic acid and 0.504 g (1.20 mmol) of (±)-4-fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N,β-diphenylbenzenebutaneamide mixture of [R-(R*,R*)], [R-(R*,S*)], [S-(R*,R*)] and [S-(R*,S*)] isomers in 5 mL of dimethyl sulfoxide is heated at 105° C. for 15 hours. The solution is cooled and poured into 100 mL of diethyl ether and 50 mL of saturated ammonium chloride in water. The layers are separated and the organic layer washed with water (2×50 mL) and 5% sodium hydroxide solution (2×100 mL - to extract the intermediate protected acid from unreacted diketone). The aqueous layer is acidified with dilute hydrochloric acid solution, stirred for three hours and extracted with 30 mL of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution and allowed to stand 18 hours. The solution is concentrated in vacuo and the concentrate is redissolved in 30 mL of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred two hours, concentrated in vacuo, and dissolved in 6 mL of toluene Trans-(±)-5-(4-fiuorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide crystallizes and is isolated by filtration. A total of 0.16 g of trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]--1H-pyrrole-3-carboxamide is isolated in two crops.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[OH:16].C(N(C(C)C)CC)(C)C.[CH3:26][O:27][CH2:28]Cl>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].C(Cl)Cl>[CH3:26][O:27][CH2:28][O:16][C:3]1[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][C:6]([C:8]([CH3:9])([CH3:10])[CH3:11])=[CH:7][C:2]=1[Br:1]
Reactant: COCCl
Reactant: CC(C)(C)c1cc(Br)c(O)c(C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1c(Br)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 45 °C
Yield: 95.4 %

Procedure:
To a solution of 2-bromo-4,6-di-t-butylphenol (Compound D 2.54 g, 8.88 mmol) and catalytic amount of Bu4NI in 20 ml of dry CH2Cl2 at 0° C. was added diisopropylethylamine (9.51 ml, 53 mmol), followed by methoxymethyl chloride (2.02 ml, 26.6 mmol). The reaction mixture was heated to 45° C. for 12 hours. The reaction mixture was then washed with 10% citric acid, then NaHCO3 (sat.), brine, and dried over MgSO4. After filtration and removal of the solvent under reduced pressure, the residue was purified by column chromatography (pure hexane) to yield the title compound (2.79 g) as a colorless oil. 1H NMR δ 7.40 (d, J=2.44 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 5.22 (s, 2H), 3.70 (s, 3H), 1.43 (s, 9H), 1.29 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](O)=[O:23])=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:22](=[O:23])[CH2:21][C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: COc1ccc(CCN)cc1OC
Product: COc1ccc(CCNC(=O)Cc2ccc(F)cc2)cc1OC

Procedure:
prepared by reaction of 3,4-dimethoxyphenylethylamine and 4-fluorophenyl-acetic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([C:8]([O:10][C@H:11]([CH3:29])[C@@H:12]([NH:21]C(OC(C)(C)C)=O)[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][C@H:11]([CH3:29])[C@@H:12]([NH2:21])[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=2)=[O:9])=[CH:30][CH:31]=1)([O-:3])=[O:2]
Reactant: C[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)[C@@H](NC(=O)OC(C)(C)C)c1ccc(F)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)[C@@H](N)c1ccc(F)c(Cl)c1
Yield: 99.9 %

Procedure:
To a stirred solution of 332 (103 mg, 0.227 mmol) in DCM (2.2 mL) at RT under nitrogen was added TFA (1 mL). After 2 h the reaction was concentrated to dryness in a rotovap and high vacuum. The crude presumed TFA salt was redissolved in DCM (5 mL) and stirred rapidly with 10% aqueous Na2CO3 (5 mL). After 5 min the organics phase was separated, dried (MgSO4), filtered and concentrated to afford 80 mg (100%) of (1S,2R)-1-amino-1-(3-chloro-4-fluorophenyl)propan-2-yl 4-nitrobenzoate (334) as a yellow oil which was used without additional purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[CH:25]=O.C([O-])(=O)C.[NH4+]>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:25]([C:24]3[CH:27]=[CH:28][C:29]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[C:22]([Cl:21])[CH:23]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1ccc(N2CCOCC2)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4ccc(N5CCOCC5)c(Cl)c4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 77 %

Procedure:
In a similar fashion to Compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (100.00 mg, 0.29568 mmol), 3-Chloro-4-morpholin-4-yl-benzaldehyde (73.4 mg, 0.325 mmol), and Ammonium acetate (45.6 mg, 0.591 mmol) were reacted to produce 123.8 mg (77%) of the title compound. (300 MHz, DMSO-d6) 13.27 (s, 1H), 8.18 (s, 1H), 8.06 (d, J=8 Hz, 1H), 8.02 (s, 1H), 7.74 (s, 1H), 7.33 (s, 1H), 7.22 (s, 1H), 7.17 (d, J=9 Hz, 1H), 6.30 (s, 2H), 5.20 (t, J=17 Hz, 8.5 Hz, 1H), 3.77 (m, 4H), 3.07 (m, 4H), 2.90 (s, 1H), 2.78 (s, 1H), 2.63 (d, J=9 Hz, 1H), 2.24 (d, J=9 Hz, 1H), 1.39 (d, J=9 Hz, 1H). MS=545 (M+H), HPLC: 2.67 min. (G Method)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]1(=O)[O:17][C:15](=[O:16])[CH:14]=[CH:13]1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>CN(C=O)C>[C:12]1(=[O:17])[N:1]([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=2)[C:15](=[O:16])[CH:14]=[CH:13]1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: O=C1C=CC(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)Cc1ccc(N2C(=O)C=CC2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
According to the method of M. P. Cava, A. A. Deana, K. Muth and M. J. Mitchell (Org. Synth., Coll. Vol. 5, 944 (1973)), 40 ml of a solution of 10 g (66.2 mmols) of 4-aminophenylacetic acid in DMF was added to 15 ml of a solution of 7.14 g (72.8 mmols) of maleic anhydride in DMF at room temperature in argon atmosphere. The reaction mixture was stirred at room temperature for 3 hours and then diluted with 250 ml of ether-benzene (1:1). The resulting precipitate was filtered off, with which 2.87 g (35 mmols) of sodium acetate and 70 ml of acetic anhydride were admixed. The mixture was stirred at 100° C. for 1 hour in argon atmosphere and concentrated in a vacuum. The residue was diluted with 300 ml of ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride aqueous solution, dried over Na2SO4, concentrated and thereafter subjected to silica gel column chromatography (90:10:5 chloroform-ethyl acetate-acetic acid to 50:50:5 chloroform-ethyl acetate-acetic acid), giving 8.72 g (yield 57%) of (4-maleimidophenyl)acetic acid in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]=[C:7]2[CH2:12][CH2:11][CH2:10][CH:9]([CH3:13])[C:8]2=[O:14])=[CH:4][CH:3]=1.CI.[C:19](O)(CC)(C)C.[H-].[Na+]>O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[C:7]2[CH2:12][CH2:11][CH2:10][C:9]([CH3:19])([CH3:13])[C:8]2=[O:14])=[CH:15][CH:16]=1
Reactant: CCC(C)(C)O
Reactant: CC1CCCC(=Cc2ccc(Cl)cc2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: Cc1ccccc1
Product: CC1(C)CCCC(=Cc2ccc(Cl)cc2)C1=O
Temperature: 45 °C

Procedure:
2-(4-Chlorobenzylidene)-6-methylcyclohexanone (7.0 g), prepared above, and then methyl iodide (5.1 g) are added successively to a reaction medium prepared from toluene (25 cc), tert-amyl alcohol (3.6 cc) and sodium hydride (1.35 g of 60% strength dispersion in oil) and heated to 45° C. The mixture is brought to reflux (1 h), poured into water and extracted with ethyl acetate. After drying and concentration, the residue is recrystallized in methanol to give 2-(4-chlorobenzylidene)-6,6-dimethylcyclohexanone (4.7 g), m.p. 92°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1OS(C1C=CC(C)=CC=1)(=O)=O)=[O:4].[C:21]1([C:27]#[CH:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCCCCCC.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:28]#[C:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:4]
Reactant: COC(=O)c1sccc1OS(=O)(=O)c1ccc(C)cc1
Reactant: C#Cc1ccccc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: COC(=O)c1sccc1C#Cc1ccccc1

Procedure:
This product was prepared from 3-(toluene-4-sulfonyloxy)-thiophene-2-carboxylic acid methyl ester and phenylacetylene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 1:1; yield (91 mg, 75%); 1H NMR δ (CDCl3): 7.53 (m, 2H), 7.39 (d, J=5.02 Hz, 1H), 7.3 (m, 3H), 7.12 (d, J=5.10 Hz, 1H), 3.82 (s, 3H); LCMS m/z: 242.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[CH:19](Cl)[CH2:20][N:21]([CH3:23])[CH3:22].Cl.O1CCC[CH2:27]1>>[C:12]1([C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)([CH2:19][CH:20]([N:21]([CH3:23])[CH3:22])[CH3:27])[C:10]#[N:11])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Reactant: CC(Cl)CN(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CC(CC(C#N)(c1ccccc1)c1ccccc1)N(C)C

Procedure:
Sodium hydride (19.5 g of an 80% dispersion in oil, 0.65 mol) was added to a 1 L 3-neck round bottom flask and triturated twice with hexane (150 mL) to remove the oil). Tetrahydrofuran (THF)(150 mL) was added to the flask followed by a stir bar and the resulting suspension stirred under argon whilst adding a solution of diphenylacetonitrile (58 g, 0.3 mol) in THF (150 mL) dropwise via a dropping funnel over 40 minutes. It became necessary to cool the flask in a cold water bath during the addition due to the exotherm generated. After stirring a further 10 minutes at room temperature the flask was fitted with a reflux condenser and placed in an ice bath. The resulting green suspension was then treated with 2-dimethylaminoisopropyl chloride hydrochloride (54 g, 0.34 mol) portionwise, via an addition funnel, over 15 minutes with stirring.