Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]34[CH2:26][CH:25]3[CH2:24][CH:23](O)[CH2:22][CH2:21]4)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11]C(C)(C)C)=[O:10])[CH2:3][CH2:2]1.C(N(S(F)(F)[F:34])CC)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]34[CH2:26][CH:25]3[CH2:24][CH:23]([F:34])[CH2:22][CH2:21]4)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC23CCC(O)CC2C3)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cc(C2CC2)c(OCC23CCC(F)CC2C3)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.5 %

Procedure:
To a solution of tert-butyl 5-cyclopropyl-2-fluoro-4-((4-hydroxybicyclo-[4.1.0]heptan-1-yl)methoxy)benzoate (0.13 g, 0.41 mmol) in chloroform (2 mL) was added diethylaminosulfur trifluoride (0.11 mL, 0.89 mmol). The reaction solution was stirred at ambient temperature for 16 h and quenched with slow addition of aqueous saturated sodium hydrogencarbonate. The reaction mixture was extracted with dichloromethane. The solvent was concentrated in vacuo to dryness. The residue (0.10 g) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.15 g, 1.30 mmol) was added. The reaction mixture was stirred for 2 h and the solvent was concentrated in vacuo to obtain the title compound as a gum (0.080 g, 95%). The residue was carried forward without any further purification in next reaction: MS (ES−) m/z 321.1 (M−1).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[S:12][CH3:13].Br.O.C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[OH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[S:12][CH3:13]
Reactant: COc1ccc(C(=O)O)cc1SC
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CSc1cc(C(=O)O)ccc1O

Procedure:
A suspension of 7c (0.5 g; 2.5 mmol) in glacial acetic acid/48% strength hydrobromic acid (1+1, 7 ml) was stirred under reflux for 6 h. The reaction mixture was cooled, added to H2O (20 ml) and adjusted to pH 2 using 10% strength Na2CO3 solution. The aqueous solution was extracted with diethyl ether (4×20 ml). The combined organic extract was washed with saturated NaCl solution (2×), dried over Na2SO4 and concentrated. On standing at room temperature, the off-brown oily residue (7d) crystallized out. The crystals were triturated with H2O, filtered off and dried.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].OB(O)[C:23]1[CH:28]=[C:27]([F:29])[C:26]([O:30][C:31]([F:34])([F:33])[F:32])=[C:25]([F:35])[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].O>[F:29][C:27]1[CH:28]=[C:23]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][C@H:9]3[CH2:10][CH2:11][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]3)=[CH:15][CH:16]=2)[CH:24]=[C:25]([F:35])[C:26]=1[O:30][C:31]([F:32])([F:33])[F:34]
Reactant: CCCCC[C@H]1CC[C@H](COc2ccc(I)cc2)CC1
Reactant: OB(O)c1cc(F)c(OC(F)(F)F)c(F)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCC[C@H]1CC[C@H](COc2ccc(-c3cc(F)c(OC(F)(F)F)c(F)c3)cc2)CC1

Procedure:
A mixture of 5.0 g (13 mmol) of 4-(trans-4-pentylcyclohexyl) methoxyiodo benzene, 4.1 g (34 mmol) of dihydroxy (3,5-difluoro-4-trifluoromethoxyphenyl) borane, 3.0 g of 5% palladium on activated charcoal and 7.2 g (136 mmol) of sodium carbonate was refluxed in toluene/alcohol/water (1/1/1 v/v, 75 ml) under a nitrogen atmosphere for 3 days. After cooling, the reaction solution was added with water (100 ml) and extracted twice with toluene (100 ml). An organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent therein was distilled off under a reduced pressure. The residue thus obtained was purified by column chromatography (silica gel/heptane:toluene=5:1) and recrystallization (heptane-ethanol) to obtain colorless crystals of 2,6-difluoro-4-(4-(trans-4-pentylcyclohexyl) methoxyphenyl) trifluoromethoxybenzene.
Reaction SMILES: [Li]CCCC.Br[C:7]1[N:8]=[C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)[S:10][CH:11]=1.C(O[B:24]1[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]1)(C)C>CCOCC>[CH3:19][C:15]1[N:14]=[C:13]([O:12][C:9]2[S:10][CH:11]=[C:7]([B:24]3[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]3)[N:8]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cc1cccc(Oc2nc(Br)cs2)n1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1cccc(Oc2nc(B3OC(C)(C)C(C)(C)O3)cs2)n1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 29.2 %

Procedure:
According to Scheme 5, Step 3: At −78° C., under a nitrogen atmosphere, BuLi (3.69 mmol, 1.48 mL) was added dropwise to a solution of 2-(4-bromothiazol-2-yloxy)-6-methylpyridine (1.68 mmol, 455 mg) in Et2O (17 mL). After 5 minutes of stirring at −78° C., 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.69 mmol, 0.75 mL) was added and the resulting mixture was stirred at room temperature for 20 minutes. The reaction was quenched with a NH4Cl saturated aqueous solution and was extracted with EtOAc. The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography over silica gel using cyclohexane/EtOAc (70:30 to 30:70) as eluent to yield 2-(6-methylpyridin-2-yloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (0.49 mmol, 157 mg, 29%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[Cl:15][C:16]1[CH:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1>CN(C=O)C>[Cl:15][C:16]1[CH:21]=[C:20]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:19]=[CH:18][N:17]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1ccnc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccnc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
4-amino-phenol (8.9 g, 81.6 mmol) and potassium tert-butoxide (10.7 g, 95.2 mmol) were suspended in DMF (100 mL) and stirred at RT for 30 min. 2,4-Dichloro-pyridine (10 g, 68 mmol) was added and the resulting mixture was heated to 90° C. for 3 h. The solvent was removed under vacuum and the residue was extracted with DCM (2×100 mL). The combined organics were dried (MgSO4), concentrated in vacuo and purified by silica gel chromatography to afford 4-(2-chloro-pyridin-4-yloxy)-phenylamine (9.0 g, 60% yield). 1H NMR (DMSO-d6): δ 8.21 (d, J=5.6 Hz, 1 H), 6.85-6.82 (m, 4 H), 6.61 (d, J=6.6 Hz, 2 H), 5.17 (s, 2 H); MS (ESI) m/z: 221 (M+H+).
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[NH:28][CH:27]=[C:26]2[S:34](Cl)(=[O:36])=[O:35]>C1COCC1>[Br:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[NH:28][CH:27]=[C:26]2[S:34]([N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2][CH2:3]1)(=[O:36])=[O:35]
Reactant: O=c1[nH]cc(S(=O)(=O)Cl)c2cc(Br)ccc12
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2c[nH]c(=O)c3ccc(Br)cc23)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.8 %

Procedure:
To a solution of tert-butyl 1,4-diazepane-1-carboxylate (0.621 g) and triethylamine (0.864 mL) in THF (12 mL) was added dropwise a solution of 6-bromo-1-oxo-1,2-dihydroisoquinoline-4-sulfonyl chloride (Example 46a, 1 g) in THF (20 mL). The reaction was stirred at room temperature for 20 min. The resulting solution was concentrated under reduced pressure, acidified with 2 M HCl, and extracted into ethyl acetate. The combined organics were dried (MgSO4), filtered and evaporated under reduced pressure to give the subtitle compound (1.097 g) that was used without further purification.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[CH:17]=[CH:18][C:19]([N+:23]([O-:25])=[O:24])=[C:20]([CH:22]=1)[NH2:21].O>CN(C)C(=O)C>[CH3:1][C@H:2]1[CH2:3][N:4]([C:16]2[CH:17]=[CH:18][C:19]([N+:23]([O-:25])=[O:24])=[C:20]([CH:22]=2)[NH2:21])[CH2:5][C@@H:6]([CH3:8])[O:7]1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])c(N)c2)C[C@H](C)O1
Temperature: 120 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a solution of cis-2,6-dimethylmorpholine (4.15 g, 36.0 mmol, 1.8 eq) in dry N,N-dimethylacetamide (35 ml) was added potassium carbonate (2.94 g, 21.2 mmol, 1.05 eq) followed by 5-chloro-2-nitroaniline (3.44 g, 19.9 mmol) and the mixture heated in a 120° C. oil-bath under nitrogen for 46 h. The reaction mixture was then cooled to room temperature, poured into water (200 ml) and stirred for 1 h. The suspension was filtered and the collected solid washed carefully with water (3×30 ml), then diethyl ether (2×20 ml) before drying under vacuum over P2O5 to give 5-(cis-2′,6′-dimethylmorpholino)-2-nitroaniline (3.67 g, 73%) as a light ochre powder.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1>[Fe](Cl)(Cl)Cl>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:12]=1
Reactant: Cc1ccc(C)cc1
Reactant: ClCc1ccccc1
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Product: Cc1ccc(C)c(Cc2ccccc2)c1
Reaction time: 3 h

Procedure:
63.3 Parts of benzyl chloride at 20° are slowly added during 2 hours to a mixture of 1 part of iron (III) chloride and 531 parts of p-xylene held at a temperature of 115°-120° C. The rate of hydrogen chloride evolution is found to be directly proportional to the rate of benzyl chloride addition. After addition, the mixture is held at 120° C. for 3 hours then filtered to remove insoluble matter, and the unreacted p-xylene (406 parts) removed by atmospheric distillation at 135°-145° C. The residue is distilled under reduced pressure at 2-3 mm Hg and a further fraction of p-xylene (64 parts) is obtained at 30°-40° C. The total recovery of p-xylene is 470 parts (98% recovery). The product, 2,5-dimethyldiphenylmethane is obtained at 126°-134° C.: yield 80 parts (82% of theory). A residue of 10.1 parts of polymer remains after distillation.
Reaction SMILES: [N:1]1([C:6]2([C:10]#[N:11])[CH2:9][O:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12]1([Li])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+].[BH4-].[Na+]>O1CCCC1>[C:12]1([CH:10]([NH2:11])[C:6]2([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH2:9][O:8][CH2:7]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [Li]c1ccccc1
Reactant: N#CC1(N2CCCC2)COC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(c1ccccc1)C1(N2CCCC2)COC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-Pyrrolidin-1-yl-oxetane-3-carbonitrile (intermediate A, 1.6 g, 91% purity, 10 mmol) was dissolved in 10 mL tetrahydrofurane. Phenyllithium (2M in dibutylether, 9.8 mL, 20 mmol) was added dropwise at −5° C. The reaction mixture was stirred at room temperature for 1.5 hours and poured into cold saturated sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. The residue was dissolved in 35 mL methanol and sodiumborohydride (0.77 g, 20 mmol) was added portion-wise at 0° C. The reaction mixture was stirred at room temperature for 2 hours and quenched by addition of water. The solvent was evaporated off. The residue was taken up in water and ethyl acetate and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude product (brown oil, 2.26 g, 99%) was used for the next step without further purification, MS: m/e=216.3 [(M−NH2)+].
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)(=O)=O.[NH2:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1>CN(C)P(N(C)C)(N(C)C)=O>[CH:8]1([CH2:7][CH2:6][NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][CH:24]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)OCCC1CCCC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCC2CCCC2)cc1

Procedure:
A solution of 5 g. of 2-cyclopentylethyl methanesulfonate and 8.59 g. of ethyl p-aminobenzoate in 30 ml. of hexamethylphosphoramide is stirred at 110° C. under argon atmosphere for 18 hours. The cooled solution is diluted with 30 ml. of water and the resulting tan solid is collected by filtration. Recrystallization from ethanol-water furnishes ethyl p-[2-(cyclopentyl)ethyl]aminobenzoate as off-white crystals.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([NH:29][C:30]3[C:33](=O)[C:32](=[O:35])[C:31]=3[O:36]CC)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[N:10][CH:9]=2)[CH:2]([CH3:4])[CH3:3].[NH:39]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[CH2:1]([C:5]1[N:6]=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([NH:29][C:30]3[C:31](=[O:36])[C:32](=[O:35])[C:33]=3[N:39]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[N:10][CH:9]=2)[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)[C@H](Cc1ccc(Oc2nc(CC(C)C)cc3ccncc23)cc1)Nc1c(OCC)c(=O)c1=O
Reactant: C1CCCNCC1
Product: CCOC(=O)[C@H](Cc1ccc(Oc2nc(CC(C)C)cc3ccncc23)cc1)Nc1c(N2CCCCCC2)c(=O)c1=O

Procedure:
Prepared in a similar manner to the compound of Example 43 from the compound of Example 74 and azepane. δH (d6 DMSO) 9.56 (1H, s), 8.69 (1H, d, J 5.7 Hz), 7.79 (1H, d, J 9.2 Hz), 7.75 (1H, d, J 5.7 Hz), 7.31 (2H, d, J 8.5 Hz), 7.29 (1H, s), 7.20 (2H, d, J 8.5 Hz), 5.16 (1H, m), 4.13 (2H, q, J 7.0 Hz), 3.80-3.40 (4H, br m), 3.27 (1H, dd, J 13.9, 4.5 Hz), 3.06 (1H, dd, J 13.9, 10.7 Hz), 2.45 (2H, masked d), 1.88 (1H, septet, J 6.7 Hz), 1.68-1.50 (4H, m), 1.50-1.35(4H, m), 1.18(3H, t, J 7.1 Hz)and 0.77 (6H, d, J 6.7 Hz); m/z (ES+) 570 (MH+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10](O)[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[SH:15][CH2:16][C:17]([OH:19])=[O:18].C1C=CC=CC=1>CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.CCOCC>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([S:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)CS
Reactant: CCCC(O)c1ccc2c(c1)OCO2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCCC(SCC(=O)O)c1ccc2c(c1)OCO2
Yield: 89.3 %

Procedure:
A mixture of 103 g of 1-(1,3-benzodioxol-5-yl)-1-butanol, 73.3 g of mercaptoacetic acid, 0.1 g of D-10-camphorsulfonic acid and 500 ml of benzene was heated under reflux for 2 h. 2,000 ml of ether was added to the reaction mixture. After washing with water, the product was redissolved in 750 ml of 1NNaOH and then in 100 ml thereof. The solution thus obtained was washed with ether and then with chloroform, acidified with concentrated hydrochloric acid and extracted with 800 ml and then 400 ml of ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to obtain 132 g of the crude product. It was purified according to silica gel column chromatography (ethyl acetate/hexane/formic acid=100:900:1) to obtain 127 g of the intended compound in the form of a colorless oil. This oil was crystallized from n-hexane to obtain 115 g of the titled compound as a white crystalline powder. It was found to have a melting point of 59° to 61° C.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:17]=[CH:16][C:9]([CH2:10][C@@H:11]([C:13]([OH:15])=[O:14])[NH2:12])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH:27]1[C:39]2[CH:38]([CH2:40][O:41][C:42](Cl)=[O:43])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]=2[CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[NH:12]([C:42]([O:41][CH2:40][CH:38]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:39]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:43])[C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][C:9]1[CH:16]=[CH:17][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:7][CH:8]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)Oc1ccc(C[C@H](N)C(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Temperature: 25 °C

Procedure:
6.52 g (27.5 mmoles) of finely ground O-t-butyl-tyrosine (Chemical Dynamics Corp.) was placed in a 500 mL round bottom flask (oven dried) which was fitted with a condenser (oven dried). A nitrogen gas line was attached at the top of the condenser. The solid was suspended in 100 mL of dry dioxane and stirred vigorously. Diisopropylethylamine (9.04 mL, 80 mmoles) was added. Tms-Cl (6.98 mL, 55 mmoles) was added and let stir for 1 hour. Methylene chloride (200 mL) was added and the entire mixture was chilled in an ice bath. 9-Fluorenyl-methyloxycarbonyl chloride (6.47 g, 25 mmole) was added in one portion. The solution was stirred in ice for 20 minutes and warmed to room temperature for 1-1.5 hrs. The mixture was concentrated on a rotary evaporator and then distributed between 200 mL diethyl ether and 250 mL 2.5% sodium bicarbonate. The phases were separated and the aqueous layer was extracted with 2×50 mL diethyl ether. The ether layers were backwashed with 2×25 mL H2O. The combined aqueous layers were acidified to pH with 10% citric acid and extracted with 600 mL methylene chloride. The organic layers were dried over sodium sulfate, concentrated to an oil and dried by azeotroping with 2×30 mL acetonitrile. The oil solidified by pumping under high vacuum. Appropriate solvents were used to recrystallize the product. The product was found to be homogeneous (Table II).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH:13]([OH:16])[CH:14]=[CH2:15])=[CH2:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>O=[Mn]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13](=[O:16])[CH:14]=[CH2:15])=[CH2:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C=CC(O)C(=C)c1ccc(OC)c(OC)c1
Agent: O=[Mn]=O
Product: C=CC(=O)C(=C)c1ccc(OC)c(OC)c1
Yield: 56.6 %

Procedure:
According to the General Procedure B, MnO2 (1.81 g, 20.79 mmol) and 2-(3,4-dimethoxyphenyl)-1,4-pentadien-3-ol (220 mg, 0.99 mmol) are converted to give after workup and chromatography (SiO2, PE/EE 2:1, Rf=0.40) the title compound (122 mg, 0.56 mmol, 56%) as a yellow oil; C14H16O3 (218.25).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[CH3:26][NH:27][CH:28]1[CH2:31][NH:30][CH2:29]1>>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15]([N:30]5[CH2:31][CH:28]([NH:27][CH3:26])[CH2:29]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: CNC1CNC1
Agent: Cl
Product: CNC1CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C2CC2)C1
Temperature: 40 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
1-Cyclopropyl-7-fluoro-8-(3-methylamino-1-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid was prepared under the conditions of Example 11, but starting with 1.5 g of 1-cyclopropyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 1.13 g of 3-(methylamino)azetidine dihydrochloride. The reaction mixture is stirred for 1 hour at 40° C. 1 g of 1-cyclopropyl-7-fluoro-8-(3-methylamino-1-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid, which decomposes at 262° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccs1
Reactant: NC(=O)Nc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: NC(=O)Nc1cccc(-c2cccs2)c1
Temperature: 90 °C
Yield: 85.3 %

Procedure:
3-Bromopheylurea (10.40 g), 2-thiopheneboronic acid (8.20 g) and palladium tetrakistriphenylphosphine (2.63 g) were added to a flask containing 300 mL of dimethoxyethane and 100 mL of 2.0 M aqueous potassium carbonate under an atmosphere of dry N2. The reaction mixture was heated at 90° C. overnight. The reaction mixture was then cooled to room temperature and partitioned between EtOAc and water. The EtOAc layer was dried over MgSO4, filtered and concentrated under vacuum. The resulting residue was tritutrated with ethyl ether to give 9.00 g of 1-(3-(thiophen-2-yl)phenyl)urea.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH2:12][OH:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[C:17]([C:34]([F:37])([F:36])[F:35])[CH:16]=1.Cl[C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[CH2:12][O:13][C:39](=[O:41])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]5)=[C:17]([C:34]([F:37])([F:35])[F:36])[CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3c(CO)cnc4ccc(Cl)cc34)cc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C(=O)OCc4cnc5ccc(Cl)cc5c43)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
To a solution of tert-butyl 4-(4-(6-chloro-3-(hydroxymethyl)quinolin-4-ylamino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (407 mg, 0.75 mmol) in dichloromethane (10 mL) at 0° C. was added triphosgene (225 mg, 0.75 mmol) and Et3N (125 μL, 0.9 mmol). The resultant solution was allowed to warm up to room temperature and continued to stir for 4 h before being quenched with a satd. aqueous sodium bicarbonate (10 mL), extracted with EtOAc (3×20 mL), and dried over Na2SO4. After removal of the solvent in vacuo, the residue was purified by flash column chromatography to afford the title product (57%) as colorless oil. LC-MS: (M+H)=563.26
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C)C=O.O>[CH2:22]([CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:7]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC(C(=O)OCC)C(=O)OC(C)(C)C
Temperature: 70 °C

Procedure:
Potassium carbonate (28.0 g.) was added to a stirred solution of t-butyl ethyl malonate (37.6 g.) in dry N,N-dimethylformamide (DMF) (100 ml.). After 1 hour allyl bromide (34 ml.) was added. The mixture was heated at 70° C. for 66 hours, cooled to room temperature and diluted with water (900 ml.). The mixture obtained was extracted with ethyl acetate (3×200 ml.). The extracts were dried (MgSO4) and evaporated. The oil obtained was purified by flash column chromatography eluting with 1:15 v/v ethyl acetate/petroleum ether (b.p. 60°-80° C.) to give t-butyl ethyl 2-allylmalonate as a colourless oil (15.6 g.), b.p. 70°-72° C. at 0.2 mmHg; NMR: 1.21 (3H,t), 1.42 (9H,s), 2.66 (2H,m), 3.28 (1H,m), 4.16 (2H,q), 5.06 (2H,m) and 5.76 (1H,m) ppm.