Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[O:21][C:20]2[C:15](=[N:16][CH:17]=[C:18](Br)[CH:19]=2)[CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[Na+].[Na+].[C:29]1(C)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>[Pd]>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[O:21][C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:19]=2)[CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2ncc(Br)cc2o1
Reactant: Cc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2ncc(-c3ccccc3)cc2o1
Yield: 100 %

Procedure:
The 2-(1-BOC-2-(S)-pyrrolidinyl)-6-bromofuro[3,2-b]pyridine (0.2 g, 0.54 mmol) obtained from Example 46a above was dissolved in toluene (2 mL). Phenylbororic acid (0.19 g, 1.62 mmol), palladium (O) tetrakis(triphenyl phosphine) (40 mg) and 2 M Na2CO3 solution (1 mL) were then added to the toluene solution. The resultant mixture was heated under reflux for 16 h. The desired product was extracted with CH2Cl2, dried over MgSO4 and filtered. Solvent was then removed under reduced pressure and the residue was chromatographed (silica gel: Hexane/EtOAc, 5:1 to 2:1) to afford an oil (0.22 g, 100%). MS (CI/NH3) m/z: 365 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ 1.32, 1.50 (2s, 9H), 1.90-2.22 (m, 3H), 2.30 (m, 1H), 3.42-3.73 (m, 2H), 4.97-5.20 (m, 1H), 6.92-7.02 (m, 1H), 7.33-7.66 (m, 5H), 7.93 (s, 1H), 8.90 (s, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:19][C:20]([CH3:25])=[CH:21][C:22](Cl)=[O:23]>ClCCl>[C:1]([NH:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:7]([NH:8][C:22](=[O:23])[CH:21]=[C:20]([CH3:25])[CH3:19])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: CC(C)=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(NC(=O)C=C(C)C)c1

Procedure:
56.7 g. (0.42 mole) 3-acetamidoaniline in 400 ml. dichloromethane and 65 ml. (0.46 mol) triethylamine are mixed, while cooling with ice, with 59.0 g. (0.46 mole) 3,3-dimethylacryloyl chloride and stirred for 2 hours at ambient temperature. The solution is thereafter extracted with water and the separated organic phase is dried over anhydrous sodium sulphate, evaporated and the residue mixed with ethyl acetate. Upon standing in a refrigerator, crystals separate out. Yield 45.7 g. (47% of theory); m.p. 144°-148° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][P:16](Cl)(Cl)=[O:17]>>[CH3:15][P:16]1(=[O:17])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH2:1][N:8]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: CP(=O)(Cl)Cl
Product: CP1(=O)c2ccccc2CN1c1ccccc1
Yield: 1.75 %

Procedure:
The procedure of Example 1 was employed utilizing N-benzylaniline and methyl phosphonic dichloride. The crude product produced as a result of the chromatographic separation yielded without additional purification 1-methyl-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (0.4 g, 1.75% yield) as a brown glass.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[Si:16]([CH2:19]Cl)([CH3:18])[CH3:17])=[O:5])[CH3:2].[Na+].[I-:24]>C(#N)C.CCOCC>[CH2:1]([N:3]([CH2:21][CH3:22])[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[Si:16]([CH2:19][I:24])([CH3:18])[CH3:17])=[O:5])[CH3:2]
Reactant: [I-]
Reactant: CCN(CC)C(=O)c1c([Si](C)(C)CCl)ccc2ccccc12
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: CCN(CC)C(=O)c1c([Si](C)(C)CI)ccc2ccccc12
Yield: 98 %

Procedure:
A solution of this naphthalenecarboxamide (1.0 g, 3.0 mmol) and NaI (13.5 g, 90 mmol) in acetonitrile (90 mL) was refluxed overnight, then was diluted with ether and filtered through celite to remove most of the salts. The filtrate was then concentrated and eluted through a plug of silica gel with ethyl acetate. Concentration of the ethyl acetate afforded 1.25 g of the desired compound as a yellow oil, a 98% yield.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=1)=[N:5][CH:6]=[N:7]2.[H-].[Na+].F[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=1>CN(C=O)C.FC1C=CC(C(F)(F)F)=CN=1>[F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=3)=[C:18]([O:23][CH3:24])[CH:17]=1)=[N:5][CH:6]=[N:7]2
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: COc1cc(CCNc2ncnc3c(F)ccc(F)c23)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(CCNc2ncnc3c(F)ccc(F)c23)ccc1Oc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.1 %

Procedure:
To a solution of 4-[2-(5,8-difluoroquinazolin-4-ylamino)-ethyl]-2-methoxyphenol (3.73 g, 11.25 mmol) in DMF (25 mL) in a dry 250 mL round bottom flask equipped with a dry nitrogen line and a magnetic stir bar was added sodium hydride (324 mg, 13.5 mmol). After gas evolution had subsided, 2-fluoro-5-trifluoromethyl-pyridine (2.05 g, 12.3 mmol) was added, and the reaction mixture was stirred at 25° C. After 20 h, additional sodium hydride (50 mg, 2.1 mmol) and 2-fluoro-5-trifluoromethyl-pyridine (100 mg, 0.6 mmol) were added. After 20 min, the reaction mixture was quenched by addition of sat. aq. NH4Cl (30 mL) and concentrated in vacuo. The residue was suspended in water (50 mL) and stirred vigorously to break up chunks. The solid product was collected by suction filtration and washed on the filter with water. The filter cake again was suspended in water (50 mL) and stirred vigorously to break up chunks. The solid product was collected by suction filtration and washed with water. The filter cake was dried with suction on the filter overnight to provide 5.26 g (98% yield) of (5,8-difluoroquinazolin-4-yl)-{2-[3-methoxy-4-(5-trifluoromethylpyridin-2-yloxy)-phenyl]-ethyl}-amine as an off-white powder, M.P. 119-121° C. LC-MS: 477 (M++1); 1H NMR (CDCl3): δ 8.69 (s, 1H), 8.4 (m, 1H), 7.89 (dd, 1H), 7.36 (m, 1H), 7.12 (m, 1H), 7.01 (m, 2H), 6.93 (m, 2H), 6.78 (bd, 1H), 3.97 (m, 2H), 3.75 (s, 3H), 3.06 (m, 2H).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[CH3:8][C:7]1[C:2]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([O:14][C:13]([F:12])([F:24])[F:25])[CH:16]=2)=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: Cc1cc([N+](=O)[O-])cnc1Br
Product: Cc1cc([N+](=O)[O-])cnc1-c1cccc(OC(F)(F)F)c1
Yield: 91 %

Procedure:
Obtained (1.25 g, yield 91%) following the procedure described in Intermediate 27, starting with 2-bromo-3-methyl-5-nitropyridine (4.61 mmol, 1.0 g), 3-(trifluoromethoxy)phenyl boronic acid (4.61 mmol, 0.95 g).
Reaction SMILES: C([O:5][C:6](=[O:25])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:24])[CH:13]([CH3:23])[CH2:14][S:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[CH2:16]([S:15][CH2:14][CH:13]([CH3:23])[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:25])=[O:5])=[O:24])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(CSCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(CSCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
1-[3-(benzylthio)-2-methylpropanoyl]-L-proline tert.butyl ester (7.8 g.) is dissolved in a mixture of anisole (55 ml.) and trifluoroacetic acid (110 ml.). After one hour storage at room temperature, the solvent is removed in vacuo and the residue is dissolved in ether, washed several times with saturated sodium chloride, dried over magnesium sulfate and evaporated to dryness in vacuo to yield 1-[3-(benzylthio)-2-methylpropanoyl]-L-proline. Rf 0.5 (Silica gel, Benzene/acetic acid 3:1) Rf 0.5. (Silica gel, Methyl-ethylketone/acetic acid/pyridine/water 14:1:2:1).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[S:16][C:15]([C:18]([NH:20][C@@H:21]4[CH:26]5[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]5)[CH2:22]4)=[O:19])=[CH:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH:29]1([C:35]([Cl:37])=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[ClH:37].[N:23]12[CH2:24][CH2:25][CH:26]([CH2:27][CH2:28]1)[C@@H:21]([NH:20][C:18]([C:15]1[S:16][C:17]3[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([NH:2][C:35]([CH:29]5[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)=[O:36])[CH:4]=4)=[CH:10][CH:11]=[CH:12][C:13]=3[CH:14]=1)=[O:19])[CH2:22]2
Reactant: Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3cccc(NC(=O)C4CCCCC4)c3)c2s1

Procedure:
50 mg (0.12 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride (Example 21) and 35.4 mg (0.24 mmol) of cyclohexylcarbonyl chloride are reacted together by general method F. 9.8 mg (16.2% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1]CCCC1CCCCN1C(OCC1C=CC=CC=1)=O.O[CH2:22][CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH2:26]1>>[Br:1][CH2:22][CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH2:26]1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCCBr
Reactant: O=C(OCc1ccccc1)N1CCCC(CCCO)C1
Product: O=C(OCc1ccccc1)N1CCCC(CCCBr)C1

Procedure:
Prepared similarly to Intermediate 30 from phenylmethyl 3-(3-hydroxypropyl)-1-piperidinecarboxylate.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[NH2:7][CH:8]([CH2:11][CH:12]=[CH2:13])[CH2:9][OH:10].CCOC(C)=O.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>O.CCOC(C)=O.C1COCC1>[OH:10][CH2:9][CH:8]([NH:7][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27])[CH2:11][CH:12]=[CH2:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCC(N)CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C=CCC(CO)NS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 31.7 %

Procedure:
A solution of Na2CO3 (9.22 g, 86.92 mmol) in water (50 ml) was left under stirring at RT for 20 min prior addition of 2-aminopent-4-en-1-ol (D7) (8.3 g) and EtOAc (160 ml). After 30 minutes stirring, a solution of p-toluenesulfonyl chloride (12.9 g, 67.85 mmol) in EtOAc/THF (24/24 ml) was added over 15 minutes. The reaction mixture was stirred at RT for a weekend. Water (30 ml) and EtOAc (100 ml) were added to the reaction mixture, the phases were separated and the aqueous layer was extracted with EtOAc (2×80 ml). The combined organic phases were evaporated and the residue was purified by Biotage SNAP-Si (100 g) cartridge eluting with a mixture cHex/EtOAc from 80/20 to 50/50. Collected fractions after solvent evaporation afforded the title compound (D8) (5.5 g)
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([CH2:55][CH3:56])=[CH:51][CH:50]=2)=[CH:4][C:5]([CH:9]2[C@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:11]([CH2:39][O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:10]2)=[C:6]([OH:8])[CH:7]=1.[Br:57]Br>C(O)(=O)C>[Br:57][C:7]1[C:2]([Cl:1])=[C:3]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([CH2:55][CH3:56])=[CH:51][CH:50]=2)[CH:4]=[C:5]([CH:9]2[C@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:11]([CH2:39][O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[O:10]2)[C:6]=1[OH:8]
Reactant: BrBr
Reactant: CCc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)cc2Cl)cc1
Solvent: CC(=O)O
Product: CCc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)c(Br)c2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a mixture of 5-chloro-4-(4-ethylbenzyl)-2-((3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)phenol (3.0 g, 3.90 mmol) and TEA (1.63 mL) in acetic acid (20.1 mL) was added dropwise bromine (0.30 mL, 5.85 mmol) at 0° C. under nitrogen atmosphere. After stirring for 2 h at rt, the reaction mixture was quenched with saturated NH4Cl solution (50 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the compound 32 (2.99 g, 3.53 mmol, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17](=[O:18])[C:16]([CH3:19])=[C:15]([CH3:20])[C:14](=[O:21])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:32][C:33](OC(C)=O)=[O:34].[CH3:39][CH2:40][O:41]C(C)=O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:33]([O:21][C:14]1[C:11]2[C:12]([CH3:13])=[C:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=3)[O:9][C:10]=2[C:17]([O:18][C:40](=[O:41])[CH3:39])=[C:16]([CH3:19])[C:15]=1[CH3:20])(=[O:34])[CH3:32]
Reactant: COc1ccc(Cc2oc3c(c2C)C(=O)C(C)=C(C)C3=O)cc1
Reactant: CCOC(C)=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(Cc2oc3c(OC(C)=O)c(C)c(C)c(OC(C)=O)c3c2C)cc1

Procedure:
A solution of 2-(4-methoxybenzyl)-3,5,6-trimethyl-4,7-benzofurandione (from Preparation 3) (0.5 g) in EtOAc (50 mL) was stirred vigorously with a saturated aqueous solution of Na2S2O4 (50 mL) at 25° C. for 16h. The organic layer was separated, dried (MgSO4) and the solvent evaporated to give a white solid. The solid was dissolved in pyridine (10 mL) containing at catalytic amount of 4-(dimethylamino) pyridine and 3 equivalents of Ac2O were added.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[F:38])[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].FC1C=CC=C(F)C=1C[C@@H](C(O)=O)N.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[F:38][C:32]1[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:31]=1[CH2:30][C@H:17]([NH:16][C:7]([C:5]1[S:6][C:2]([CH3:1])=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=2)[CH:4]=1)=[O:9])[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29]
Reactant: N[C@@H](Cc1cc(F)ccc1F)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1sc(C(=O)O)cc1-c1ccnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: N[C@@H](Cc1c(F)cccc1F)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(C(=O)N[C@@H](Cc2cc(F)ccc2F)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a 50 mL round-bottomed flask was added 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (171 mg, 0.77 mmol) [prepared according to the procedure of Example 151], 2-[(2S)-2-amino-3-(2,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (270 mg, 0.77 mmol) [prepared according to the procedure of Preparation 18 except substituting 2,5-difluoro-L-phenylalanine (3.02 g, 15.0 mmol) for 2,6-difluoro-L-phenylalanine] and PyBrop (436 mg, 0.93 mmol) in chloroform (7.5 mL). DIEA (680 μL, 3.89 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (246 mg, 0.44 mmol, 52%): LC-MS (ES) m/z=521 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([C:16](O)=[O:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:19]=1.C1C2CCC3C=CC=CC=3SC=2C=C(C(O)=O)C=1>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([CH2:16][OH:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:19]=1
Reactant: O=C(O)c1ccc2c(c1)Sc1ccc(O)cc1C=C2
Agent: O=C(O)c1ccc2c(c1)Sc1ccccc1CC2
Product: OCc1ccc2c(c1)Sc1ccc(O)cc1C=C2

Procedure:
Repeat the process of Example 1, substituting an equivalent quantity of 8-hydroxy-dibenzo[b,f]thiepin-3-carboxylic acid for the 10,11-dihydro-dibenzo[b,f]thiepin-3-carboxylic acid, to obtain the title product.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:24])([CH3:23])[C:17]=3[CH:25]=2)=[CH:3][CH:2]=1.[OH:32]O>>[C:1]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:2]=[CH:3][C:4]([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:24])([CH3:23])[C:17]=3[CH:25]=2)=[O:32])=[CH:5][CH:6]=1
Reactant: OO
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(-c4ccccc4)cc3)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(-c4ccccc4)cc3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-biphenylylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH2:1]([C:3]1[C:12]([CH3:13])=[C:11]([OH:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:16])[C:9]=2[Cl:15])[N:4]=1)[CH3:2].[H-].[Na+].C(C1C(C)=[C:29]([O:32][C:33](C2CC2)=[O:34])C2C(=CC(F)=C(F)C=2)N=1)C.C(C1C(C)=C(OC(C2CC2)=O)C2C(=CC=C(F)C=2F)N=1)C>CN(C)C=O.O>[CH2:1]([C:3]1[C:12]([CH3:13])=[C:11]([O:14][C:33]([O:32][CH3:29])=[O:34])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:16])[C:9]=2[Cl:15])[N:4]=1)[CH3:2]
Reactant: CCc1nc2cc(F)c(F)cc2c(OC(=O)C2CC2)c1C
Reactant: CCc1nc2ccc(F)c(Cl)c2c(O)c1C
Agent: CCc1nc2ccc(F)c(F)c2c(OC(=O)C2CC2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc2ccc(F)c(Cl)c2c(OC(=O)OC)c1C
Reaction time: 1 h

Procedure:
2-Ethyl-3-methyl-4-cyclopropanecarbonyloxy-5-chloro-6-fluoroquinoline (1.5 g) prepared as described in Example 7 was dissolved in 70 ml of methanol. To this solution was added 30 ml of a 10% aqueous sodium hydroxide solution. The mixture was stirred at 50° C. for 1.5 hr. The reaction mixture was allowed to stand for cooling, was then poured into 50 ml of water, and was neutralized with 1 N hydrochloric acid, and the precipitate was then collected by filtration to give 1.17 g of 0.2-ethyl-3-methyl-4-hydroxy-5-chloro-6-fluoroquinoline. In 15 ml of dimethyl formamide was suspended 40.1 mg of 60% sodium hydride. Separately, 200 mg of 2-ethyl-3-methyl-4-hydroxy-5-chloro-6-fluoroquinoline (starting material 1) prepared above was suspended in 2 ml of dimethyl formamide, and this suspension was added dropwise to the above suspension under ice cooling. After stirring for one hr, 78.5 mg of methyl chloroformate (starting material 2) was added thereto, and the mixture was stirred at room temperature for 3 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated, brine and was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on Wako Gel C-200 (100 ml; elution solvent=n-hexane-ethyl acetate (10:1)) to give 218.8 mg of 2-ethyl-3-methyl-4-methoxycarbonyloxy-5-chloro-6-fluoroquinoline (compound 36). 1H-NMR data are shown in Table 3.
Reaction SMILES: C1(=O)[N:5]([CH:6]2[C:12](=[O:13])[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]([CH3:18])[CH2:7]2)C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH:6]1[C:12](=[O:13])[NH:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[N:8]([CH3:18])[CH2:7]1
Reactant: CN1CC(N2C(=O)c3ccccc3C2=O)C(=O)Nc2ccccc21
Agent: NN
Solvent: O
Solvent: CCO
Product: CN1CC(N)C(=O)Nc2ccccc21
Temperature: 25 °C

Procedure:
A suspension of 1.93 g of 3-phthalimido-5-methyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2-one in 60 ml of absolute ethanol is treated with 0.31 ml of hydrazine hydrate and the reaction mixture is heated to reflux for 1.5 hr. After cooling at room temperature, the solid is removed by filtration and the filtrate is concentrated in vacuo. The residue is dissolved in chloroform and filtered and concentrated again to afford 3-amino-5-methyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2-one.
Reaction SMILES: CC([NH:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[CH:8]=[CH:7][C:6]=1[N+:20]([O-:22])=[O:21])=O.C(O)C.[OH-].[Na+]>Cl>[N+:20]([C:6]1[CH:7]=[CH:8][C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])=[CH:10][C:5]=1[NH2:4])([O-:22])=[O:21]
Reactant: CC(=O)Nc1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
N-methylcarbonyl 2-nitro-5-(2,4-dichlorophenoxy)aniline (2.0 g, 5.9 mmol) in 50 ml of 10% hydrochloric acid is heated under reflux for 2 hours. The reaction is cooled to RT, 10 ml of ethanol is added, and the reaction is heated under reflux for another 4 hours. The reaction is cooled to RT, made slightly basic with 20% sodium hydroxide and extracted with ether. The combined extracts are washed with water, dried and stripped to give 2-nitro-5-(2,4-dichlorophenoxy)aniline.
Reaction SMILES: [OH:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[C:25]=1[P:32](Cl)(=[O:36])[O:33][CH2:34][CH3:35]>C(#N)C>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[C:25]=1[P:32](=[O:36])([O:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1)[O:33][CH2:34][CH3:35]
Reactant: CCOP(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: O=c1c2ccccc2oc2c(O)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOP(=O)(Oc1cccc2c(=O)c3ccccc3oc12)c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Hydroxyxanthen-9-one (0.01 mole), acetonitrile (25 ml) and potassium carbonate (0.01 mole) are charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer. O-Ethyl (2,4,6-trichlorophenyl)phosphonochloridate (0.01 mole) in acetonitrile (6 ml) is added dropwise, with stirring, at room temperature. The reaction mixture is stirred for a period of about 48 hours at a temperature of from about 35° C. to 50° C. It is then cooled to room temperature and filtered. Solvent is stripped from the filtrate using a rotary evaporator (70° C., 15 mm Hg). The devolatilized residue is redissolved in 1/1 v/v chloroform/cyclohexane (25 ml). This solution is then slurried with silica gel (2 grams) at room temperature for a period of about 2 hours, then filtered. Solvent is stripped from the filtrate using a rotary evaporator to yield the desired product O-ethyl O-(xanthen-9-one-4-yl) (2,4,6-trichlorophenyl)phosphonate.
Reaction SMILES: [CH:1]1([C:6]([OH:8])=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.S(Cl)(Cl)=O.[CH2:13](O)[CH3:14]>>[CH:1]1([C:6]([O:8][CH2:13][CH3:14])=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: O=C(O)C1CC=CC1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1CC=CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a stirred solution of cyclopent-3-enecarboxylic acid (10 g, 89.3 mmol) in anhydrous ethanol (30 mL) was added sulfurous dichloride (15.9 g, 134 mmol) at 0° C. The reaction mixture was stirred at room temperature overnight and then concentrated. The residue was poured into water. The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (2.5% ethyl acetate in petroleum ether) to give the desired product (6.7 g, 47.9 mmol, yield=54%) as a yellow oil which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 5.66 (s, 2H), 4.18-4.10 (m, 2H), 3.16-3.05 (m, 2.66 (s, 2H), 2.63 (s, 2H), 1.29-1.24 (t, J=9.4, 3H).