Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=O.Cl.[CH3:13][O:14][NH2:15].C([O-])([O-])=O.[K+].[K+]>COCCOC>[CH3:13][O:14]/[N:15]=[CH:7]/[C:6]1[CH:9]=[C:2]([Br:1])[CH:3]=[C:4]([F:11])[C:5]=1[F:10]
Reactant: O=Cc1cc(Br)cc(F)c1F
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CO/N=C/c1cc(Br)cc(F)c1F
Temperature: 40 °C
Yield: 100 %

Procedure:
A mixture of 5-bromo-2,3-difluorobenzaldehyde (17.38 g, 78.6 mmol), O-methylhydroxylamine hydrochloride (7.23 g, 86.46 mmol), and K2CO3 (13 g, 94.32 mmol) in DME (80 mL) was heated at 40° C. for 14 h. Work-up: the reaction mixture was filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (0-2% EtOAc in petroleum ether), to give (E)-5-bromo-2,3-difluorobenzaldehyde O-methyl oxime (19.65 g). 1H NMR (CDCl3, 300 MHz): δ 8.20 (s, 1H), 7.76-7.73 (m, 1H), 7.35-7.29 (m, 1H), 4.01 (s, 3H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=1)[O:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].ClC1C=C([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([O:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH:39]=3)[CH:32]=2)C=CC=1>[Cu].C1(C)C=CC=CC=1>[O:37]([C:38]1[CH:39]=[C:40]([CH:41]=[CH:42][CH:43]=1)[O:44][C:45]1[CH:50]=[C:49]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][C:8]3[CH:21]=[CH:20][CH:19]=[C:10]([O:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:13]=4)[CH:9]=3)[CH:3]=2)[CH:48]=[CH:47][CH:46]=1)[C:33]1[CH:32]=[CH:31][CH:36]=[CH:35][CH:34]=1
Reactant: Clc1cccc(-c2cccc(Oc3cccc(Oc4ccccc4)c3)c2)c1
Reactant: Oc1cccc(Oc2cccc(Oc3ccccc3)c2)c1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: c1ccc(Oc2cccc(Oc3cccc(Oc4cccc(-c5cccc(Oc6cccc(Oc7ccccc7)c6)c5)c4)c3)c2)cc1

Procedure:
A 500 ml. reaction flask equipped with stirrer, condenser and Dean-Stark trap was charged with 59.8 g. (0.215 mole) of m-(m-phenoxyphenoxy)phenol, 50 ml. of toluene and 7.2 g. (0.129 mole) of potassium hydroxide. Water was azeotroped from the system and 100 ml. of diglyme added followed by dropwise addition of 20 g. (0.053 mole) of 3-chloro-3'-(m-phenoxyphenoxy)biphenyl over a 30 min. period. To this mixture 2.5 g. of cuprous chloride and 0.5 g. of copper powder was added. Diglyme was distilled from the system and the resulting mixture heated at 230°-240°C. for 18 hours. At the end of this time, 250 ml. of ether was added to the cooled mixture and the resulting slurry centrifuged to remove salts. The ethereal solution was washed thoroughly with aqueous base, water and then dried over anhydrous magnesium sulfate. The ether was removed under vacuum, and the resulting oil was distilled to give 24.4 g. of the desired product, bp 340°/ 0.05 mm., nD25 1.6510.
Reaction SMILES: C1(CC([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]23)=O)C=CC=CC=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO>[NH2:10][CH:11]1[C:37](=[O:38])[N:13]2[C:14]([C:21]([O:23][CH:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]12
Reactant: C/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: C/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Temperature: -40 °C
Reaction time: 0.08 h

Procedure:
6.4 (12.2 mmol) of benzhydryl 7-phenylacetamido-3-[(Z)-propen-1-yl]-3-cephem-4-carboxylate (Example 9) are dissolved in 64 ml of methylene chloride, the solution is cooled to -40° C. with a dry ice bath and 2.47 ml (30.5 mmol) of pyridine and 2.54 g (12.2 mmol) of phosphorus pentachloride are added in succession. After 5 minutes, the mixture is allowed to warm to -20° C., after which the temperature should rise to -10° C. in the course of 20 minutes and then rise to +10° C. The solution is now stirred at +10° C. to +15° C. for 1 hour. The mixture is subsequently cooled to -40° C., 100 ml of methanol (-30° C.) are added and the mixture is stirred at +10° C. for a further 30 minutes. The reaction solution is concentrated gently, the oil obtained is dissolved in 600 ml of methylene chloride, the solution is stirred into 800 ml of sodium bicarbonate solution and the mixture is stirred for 10 minutes. The methylene chloride phase is separated off, washed once with water and dried over sodium sulphate. The methylene chloride filtrate is chromatographed on 400 ml of silica gel (0.04-0.063 mm), elution being carried out first with methylene chloride and then with methylene chloride with the addition of methanol (gradient up to 10%). The eluate is investigated by means of analytical HPLC and TLC (thin layer chromatography) (methylene chloride/methanol=100:1).
Reaction SMILES: [N:1]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH2:5][N:4]([C:7](OC(Cl)(Cl)Cl)=[O:8])[CH2:3][CH2:2]1.O.[NH2:22][NH2:23].CCOC(C)=O>C1COCC1.[Cl-].[Na+]>[NH:22]([C:7]([N:4]1[CH2:5][CH2:6][N:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:2][CH2:3]1)=[O:8])[NH2:23]
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(Cl)(Cl)Cl)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)NN)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-tert-butyl 4-trichloromethyl piperazine-1,4-dicarboxylate (50 g, 0.145 mol) in THF (50 mL) was added dropwise over a 30 minute period to a solution of hydrazine hydrate (18 mL, 0.434 mol) in THF (150 mL). The reaction mixture was stirred at rt for 2 hrs, diluted with saturated sodium chloride (50 mL) and exacted with EtOAc (3×). The combined organic layer was washed with saturated sodium chloride (2×), dried with Na2SO4, and concentrated. The residue was purified by crystallization (3:1 petroleum ether/EtOAc) to obtain of tert-butyl 4-(hydrazinecarbonyl)piperazine-1-carboxylate, (13 g, 40% for two steps). ESI-MS (EI+, m/z): 245 [M+H]+. 1H-NMR (500 MHz, CDCl3): δ5.92 (s, 1H), 3.45-3.35 (m, 8H), 1.41 (s, 9H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C@:9]([CH3:26])([C:22]([F:25])([F:24])[F:23])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[N:16]=2)([CH3:14])[N:13]=1)(C)(C)C.C([O-])([O-])=O.[K+].[K+].[NH3:34]>C(O)CO.CNCCNC>[NH2:34][C:17]1[N:16]=[C:15]([C@:12]2([CH3:14])[CH2:11][O:10][C@@:9]([CH3:26])([C:22]([F:25])([F:24])[F:23])[C:8]([NH2:7])=[N:13]2)[CH:20]=[CH:19][CH:18]=1
Reactant: N
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cccc(Br)n2)CO[C@@]1(C)C(F)(F)F
Agent: CNCCNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Product: C[C@@]1(c2cccc(N)n2)CO[C@@](C)(C(F)(F)F)C(N)=N1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
To a suspension of (2R,5R)-5-(6-bromo-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine (6.0 g, 17.04 mmol, Example 8 step h), Cu2O (0.122 g, 0.852 mmol), K2CO3 (0.471 g, 3.41 mmol) and N,N′-dimethylethylenediamine (0.15 g, 1.704 mmol) were suspended in ethylene glycol (34 ml) were added 53 ml aq. NH3 (25% w). The flask was sealed and the suspension was stirred to 60° C. for 20 h. A green solution was obtained. It was occasionally necessary to shake the flask to make sure that all insoluble parts went in solution. The mixture was partitioned between water and EtOAc. The aq. phase was extracted with EtOAc, the combined org layers were washed with brine, dried with Na2SO4 and evaporated to give 5.11 g of a green resin, which was purified by chromatography on silica gel (DCM/1-4% (EtOH 25% aq NH3 9:1)) to give 2.77 g of the title compound as a colorless foam.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1(Cl)[N+:14]([O-])=O)[C:6]#[N:7])[CH3:2].O=P(Cl)(Cl)[Cl:21]>>[CH2:1]([O:3][C:4]([C:5]1[C:8]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[Cl:21])[NH:14][C:6]=1[NH2:7])=[O:18])[CH3:2]
Reactant: CCOC(=O)C(C#N)C1C=CC=CC1(Cl)[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(N)[nH]c2cccc(Cl)c12

Procedure:
The synthesis route used to prepare analogues is described in Scheme 3. (2-ethoxycarbonylmethyl-phenyl)-acetic acid ethyl ester 2 (71%) was obtained by hydrolysis of 1,2-phenylenediacetonitrile 1 with concentrated H2SO4. Compound 2 with sodium ethoxide in ethanol gave compound 3 (61%), which further reacted with guanidine in the presence of potassium t-butoxide under 150° C. in a microwave reaction to give compound 4 (34%). To access target compounds, first, compound 4 was tried to turn the 4-oxo to 4-chloro, which traditionally is adopted in synthesizing 4-anilino substituted analogues. However, because of the lower aromaticity of the ring, the chlorination did not run well under known reaction conditions. Compound 4 was decomposed when refluxed with POCl3. Thus, the 4-oxo was converted to 4-sulfonate, which is a good leaving group for SNi reaction. Compound 5 was obtained when treating compound 4 with the 4-nitrobenzensulfonyl chloride (36%). The target compound 6 with different substitution on the phenyl ring was obtained when refluxing compound 5 with corresponding aniline for 12-18 h.
Reaction SMILES: [F:1][C@H:2]1[C@@H:6]2[O:7][Si:8]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:9][Si:10]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[O:11][CH2:12][C@H:5]2[C:4](=[CH2:25])[C@H:3]1[OH:26].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+].[Cl-].[NH4+]>CO.C(O)(=O)C>[F:1][C@H:2]1[C@@H:6]2[O:7][Si:8]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:9][Si:10]([CH:16]([CH3:17])[CH3:18])([CH:13]([CH3:14])[CH3:15])[O:11][CH2:12][C@H:5]2[C:4](=[CH2:25])[C@@H:3]1[OH:26]
Reactant: C=C1[C@@H](O)[C@@H](F)[C@@H]2O[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)OC[C@@H]12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [BH4-]
Agent: [Ce+3]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: C=C1[C@H](O)[C@@H](F)[C@@H]2O[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)OC[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a stirred solution of allylic alcohol 14 (5 g, 12.3 mmol) the Dess-martin periodinane reagent (7.8 g, 18.5 mmol) was added at 0° C. The mixture was warm to ambient temperature and stirred for 1 h. Mixture was passed through celite bed and the filtrate was concentrated under reduced pressure to give a crude allylic ketone, which was proceeded as such in next step without further purification. The crude ketone (4.5 g, 11.1 mmol) was dissolved in anhydrous methanol, cooled the solution at −78° C., CeCl3.7H2O (5.5 g, 14.7 mmol) was added at −78° C., and then after 10 minutes stirring, NaBH4 (0.54 g, 14.3 mmol) was added at one portion. After 15 min stirring at −78° C., the reaction mixture was allowed to reach 0° C., saturated solution of ammonium chloride (30 mL) and 10% aqueous solution of acetic acid were added, and then the mixture was allowed for 1 hr while stirring. Organic solvent was removed under reduced pressure and the residue was extracted with DCM (200 ml×2). The combined DCM extracts were washed with brine (50 mL×2), dried (anhydrous Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (5% EtOAc/hexane) to give compound 15 (4.3 g, 86%) as oil. [α]26D −88.1° (c 0.5, MeOH); 1H NMR (500 MHz, CDCl3) δ 0.93-1.08 (m, 28H), 2.66 (s, 1H), 3.89 (dd, J=6.0, 11.5 Hz, 1H), 3.99 (dd, J=4.5, 12.0 Hz, 1H), 4.26-4.21 (m, 1H), 4.47 (dd, J=4.5, 13.5 Hz 1H), 4.65 (dt, J=8.0, 15.0 Hz, 1H), 5.16 (d, J=2.5 Hz, 1H), 5.35 (s, 1H); 19F NMR (500 MHz, CDCl3) δ −195.8 (m); 13C NMR (125 MHz, CDCl3) δ 12.5, 12.7, 13.3, 13.4, 16.9, 16.98, 17.07, 17.08, 17.4, 17.5, 49.1, 63.7, 73.7, 74.7, 102.3 (d, J=192.7 Hz), 111.5, 144.9, 150.0; HR-MS Calcd. For (C19H37FO4Si2+H)+ 405.2214. found 405.2202.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:5][OH:6].[O:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOC(C)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH:4]1[N:7]([C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[C:22]2([CH2:23][CH2:24][O:19][CH2:20][CH2:21]2)[O:6][CH2:5]1)=[O:18]
Reactant: COC(=O)C(CO)NC(=O)OCc1ccccc1
Reactant: O=C1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)C1COC2(CCOCC2)N1C(=O)OCc1ccccc1

Procedure:
2-Benzyloxycarbonylamino-3-hydroxy-propionic acid methyl ester (2.0 g, 7.9 mmol) was combined with tetrahydro-pyran-4-one (790 mg, 7.9 mmol). This mixture was dissolved in 120 mL of dry toluene. Catalytic amount (50 mg) of p-toluenesulfonic acid was then added to the reaction mixture which was heated under reflux overnight. It was brought to room temperature, diluted using EtOAc, and extracted using NaHCO3. Organic phase was isolated, dried over Na2SO4 and evaporated. The resulting clear oil was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22](O)=[O:23].[CH3:25][C:26]([NH2:34])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:27]>>[CH3:25][C:26]([NH:34][C:22]([C@H:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:15]([CH2:14][CH2:13][C@:11]12[CH3:12])[C@:16]1([CH3:21])[C:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]1)=[CH:4][CH2:5]3)=[O:23])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:27]
Reactant: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]12
Reactant: CC(C)(N)c1ccccc1
Product: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)NC(C)(C)c4ccccc4)[C@@]3(C)CC[C@@H]12
Yield: 70 %

Procedure:
The title compound was prepared in a yield of 70% in a similar manner to that described in Example 37 by reacting 4-methyl-3-oxo-4-azaandrost-5-ene-17β-carboxylic acid (prepared as described in Preparation 5) and 1-methyl-1-phenylethylamine.
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:20])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[N:10][C:11]=1[CH3:12].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([C:32]([F:35])([F:34])[F:33])=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:5][C:6]1[CH:7]=[C:8]([O:20][C:22]2[C:31]3[C:26](=[CH:27][C:28]([C:32]([F:35])([F:33])[F:34])=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[N:10][C:11]=1[CH3:12]
Reactant: Cc1ccc(-c2nc(C)c(C)cc2O)nc1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(-c2nc(C)c(C)cc2Oc2ccnc3cc(C(F)(F)F)ccc23)nc1
Temperature: 140 °C
Reaction time: 5 h
Yield: 75.4 %

Procedure:
Dimethyl sulfoxide (2 ml) was added to 5,6,5′-trimethyl-[2,2′]bipyridin-3-ol (50 mg), 4-chloro-7-trifluoromethylquinoline (162 mg), and cesium carbonate (228 mg), and the mixture was stirred at 140° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (72 mg, yield 75%).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)=[CH:8][N:7]=[CH:6]1.[H][H]>CO.[Pd]>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[C:9]([C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)=[CH:8][N:7]=[CH:6]1
Reactant: CN(C)CCn1cncc1-c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)CCn1cncc1-c1cccc(N)c1

Procedure:
A solution of dimethyl-{2-[5-(3-nitrophenyl)imidazol-1-yl]ethyl}amine (140 mg, 0.54 mmol) and 10% Pd/C (80 mg) in methanol (8 mL) was hydrogenated under 1 atm hydrogen pressure for 5 h. The reaction mixture was filtered through a Celite pad. The filtrate was concentrated to dryness to afford the desired amine, which was used directly in the next step without purification. 1H-NMR (CD3OD, 400 MHz): δ=2.15 (s, 6H), 2.49 (t, J=6.8 Hz, 2H), 4.18 (t, J=7.2 Hz, 2H), 6.69-6.77 (m, 3H), 6.91 (d, J=1.2 Hz, 1H), 7.18 (dt, J=1.2, 7.6 Hz, 1H), 7.44 (d, J=0.8 Hz, 1H). MS (ES+): m/z 231.29 [MH+]. HPLC: tR=0.39 min (ZQ2000, polar—5 min).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH:11]([NH:17]C(=O)OC(C)(C)C)[C:12]([N:14]([CH3:16])[CH3:15])=[O:13].O1CCOCC1.Cl>C(#N)C>[NH2:17][CH:11]([CH2:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)[C:12]([N:14]([CH3:15])[CH3:16])=[O:13]
Reactant: CN(C)C(=O)C(Cc1nc2ccccc2s1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: CN(C)C(=O)C(N)Cc1nc2ccccc2s1
Reaction time: 1 h

Procedure:
The tert-butyl 3-(benzo[d]thiazol-2-yl)-1-(dimethylamino)-1-oxopropan-2-ylcarbamate (0.13 g, 0.37 mmol) was taken up in a 4 M HCl dioxane solution (3 mL) at r.t. After stirring for 1 h. the reaction was concentrated under reduced pressure to give a residue. This was taken up in anhydrous acetonitrile and re-concentrated under reduced pressure 2 times, to finally 2-amino-3-(benzo[d]thiazol-2-yl)-N,N-dimethylpropanamide HCl salt (0.14 g, 100%) as a semisolid residue. Analytical LCMS (M+H)+: m/z=250.1.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:23])[C:13]([C:20]([OH:22])=[O:21])=[CH:14][N:15]3[CH2:18][CH3:19])=[CH:10][C:9]=2[F:24])[S:6][CH:7]=1.[CH3:25][NH2:26]>>[CH2:18]([N:15]1[C:16]2[C:11](=[CH:10][C:9]([F:24])=[C:8]([C:5]3[S:6][CH:7]=[C:3]([CH2:2][NH:26][CH3:25])[N:4]=3)[CH:17]=2)[C:12](=[O:23])[C:13]([C:20]([OH:22])=[O:21])=[CH:14]1)[CH3:19]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-c3nc(CCl)cs3)cc21
Reactant: CN
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-c3nc(CNC)cs3)cc21

Procedure:
A solution of 0.40 g 7-(4-chloromethyl-2-thiazolyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 100 ml 40% aqueous methylamine was stirred at room temperature overnight and evaporated to dryness. The resulting solid was crystallized from water to afford 0.33 g of the title compound, mp 216°-218° C. (dec). Analysis calculated for C17H16N3FO3S.0.2H2O: C, 55.94; H, 4.53; N, 11.51. Found: C, 55.92; H, 4.41; N, 11.18.
Reaction SMILES: [CH2:1]([P:3]([C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])[CH:10]=[CH:9][C:8]=1[N+:25]([O-:27])=[O:26])(=[O:6])[O:4]C)[CH3:2].O>Cl>[CH2:1]([P:3]([C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][C:15]=2[Cl:24])[CH:10]=[CH:9][C:8]=1[N+:25]([O-:27])=[O:26])(=[O:4])[OH:6])[CH3:2]
Reactant: CCP(=O)(OC)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Product: CCP(=O)(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
Methyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate (1 g) in 20 ml of 6N hydrochloric acid is heated under reflux overnight. The solution is then poured into water and extracted with methylene chloride. The combined solvent extracts are dried over magnesium sulfate and the solvent is then evaporated off to give P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][C:9]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1.OP([O-])([O-])=O.[K+].[K+].[C:25](S(Cl)(=O)=O)([F:28])([F:27])[F:26]>CCOC(C)=O.O.C1C=NC2C3N=CC=CC=3C=CC=2C=1.C1C=NC2C3N=CC=CC=3C=CC=2C=1.C1C=NC2C3N=CC=CC=3C=CC=2C=1.O.[Cl-].[Cl-].[Ru+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:25]([F:28])([F:27])[F:26])[NH:10][C:9]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CCOC(=O)c1[nH]ccc1-c1ccc(Cl)cc1
Agent: [Ru+2]
Agent: O=P([O-])([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c(C(F)(F)F)cc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 288.4 %

Procedure:
This reaction was carried out in 5 batches using the same procedure. To a mixture of ethyl 3-(4-chlorophenyl)-1H-pyrrole-2-carboxylate [for synthesis see ACI-01] (1.25 g, 5.01 mmol), K2HPO4 (2.62 g, 15 mmol) and dichlortris(1,10-phenanthroline)-ruthenium(II) hydrate (71 mg, 0.10 mmol) in argon degassed dry MeCN (35 mL) was added CF3SO2Cl (1.60 mL, 15 mmol). The reaction mixture was stirred for 16 h at room temperature adjacent to a fluorescent light bulb (E27-32W, 4000K, 65 mA). After 16 h, an additional amount of CF3SO2Cl (0.20 mL, 1.88 mmol) was added and the reaction mixture was stirred overnight at room temperature adjacent to a fluorescent light bulb. All reaction mixtures were combined and diluted with EtOAc (150 mL) and H2O was added. The aqueous layer was extracted with EtOAc (150 mL). The organic layers were combined and the solvent was evaporated to give an oil. The crude product was purified by flash chromatography (silica, gradient heptane/EtOAc, 1:0→1:1) to furnish the desired product (4.59 g, 58%).
Reaction SMILES: CC([O-])(C)C.[Na+].[NH2:7][C:8]1[CH2:9][N:10]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11][CH2:12][C:13]=1[C:14]([O:16]CC)=O.[CH3:26][O:27][CH:28]([O:34]C)[CH2:29][C:30](OC)=O>C1COCC1>[CH3:26][O:27][C:28]([C:29]1[CH:30]=[N:7][C:8]2[CH2:9][N:10]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:11][CH2:12][C:13]=2[C:14]=1[OH:16])=[O:34]
Reactant: CCOC(=O)C1=C(N)CN(Cc2ccccc2)CC1
Reactant: COC(=O)CC(OC)OC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cnc2c(c1O)CCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
To a suspension of NaOtBu (4.23 g, 34.57 mM) in THF (50 mL) was added a mixture of ethyl 3-amino-1-benzyl-1,2,5,6-tetrahydropyridine-4-carboxylate (3.0 g, 11.52 mM) and methyl 3,3-dimethoxypropanoate (5.12 g, 34.57 mM) in THF (20 mL) in one portion and the mixture was agitated at ambient temperature overnight. The mixture was concentrated to half the volume before being quenched with ice-cold water. The homogeneous solution was extracted ethyl ether and the aqueous layer was carefully acidified with HCl until acidic. The precipitate was filtered, washed with water, and dried under vacuum to obtain the title compound as an off-white solid (1.6 g, 47%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:11]([CH3:19])([CH2:13][CH2:14][C:15](Cl)([CH3:17])[CH3:16])[CH3:12].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:12][C:11]1([CH3:19])[C:7]2[C:6](=[CH:5][C:4]3[CH2:3][CH2:2][CH2:1][C:9]=3[CH:8]=2)[C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13]1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: c1ccc2c(c1)CCC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)CCC3
Yield: 76 %

Procedure:
A flame dried 3 L three neck round bottom flask fit with a magnetic stirrer, condenser, heating mantle, and nitrogen inlet was charged with indane (49 mL, 0.40 mol, Aldrich), anhydrous methylene chloride (800 mL, Aldrich), and 2,5-dichloro-2,5-dimethylhexane. The mixture was heated to reflux and the aluminum chloride (5.65 g, 0.042 mol). was added portionwise while refluxing the reaction. The reaction mixture was quenched in 1 L 5% HCl/ice, the layers separated, and the combined organics washed with water until neutral to pH paper. The organics were then dried over anhydrous magnesium sulfate, stripped of solvent by rotary evaporation and distilled to yield 5,5,8,8-tetramethyl-5,6,7,8-tetrahydrobenz(f)indane (32.1 g, 105-110° C./0.4-0.45 mm Hg, 76-89% pure by GC). 1HNMR (CDCl3, 500 MHz) δ7.19 (s, 2H); 2.86 (t, J=7.5 Hz, 4H); 2.04 (p, J=7.5 Hz, 2H); 1.67 (s, 4H); 1.28 (s, 12H).