Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3]1.[CH2:10]([NH2:12])[CH3:11]>O>[CH2:10]([NH:12][C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:9])[CH3:11]
Reactant: CCN
Reactant: Cn1cc(C(=O)O)cn1
Solvent: O
Product: CCNC(=O)c1cnn(C)c1
Yield: 54.7 %

Procedure:
N-Ethyl-1-methyl-1H-pyrazole-4-carboxamide was prepared from 1-methyl-1H-pyrazole-4-carboxylic acid and 70% ethylamine in water using the methods of steps a and b of Example 248. The product was purified by flash chromatography with 10% ethyl acetate-hexane and recovered as a white solid in 54.7% yield. m.p. 103°-106° C.
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]([NH:15][C:16](=[O:47])[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2[N:29]=[C:28]([NH:30][C:31]3([C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=4)[CH2:33][CH2:32]3)[N:27]=[C:26]([O:41][CH2:42][C:43]([F:46])([F:45])[F:44])[N:25]=2)=[CH:19][CH:18]=1)[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][C@H:10]([NH:15][C:16](=[O:47])[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2[N:29]=[C:28]([NH:30][C:31]3([C:34]4[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=4)[CH2:32][CH2:33]3)[N:27]=[C:26]([O:41][CH2:42][C:43]([F:46])([F:45])[F:44])[N:25]=2)=[CH:19][CH:18]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CN)NC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.8 %

Procedure:
To a solution of (S)-methyl 3-(tert-butoxycarbonylamino)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoate (1 g) in CH2Cl2 (10 mL) was added TFA (3 mL). The mixture was stirred at room temperature for 16 hours. All the solvents were removed under vacuum to give (S)-methyl 3-amino-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoate (0.8 g).
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:27]=[CH:26][S:25][C:4]=2[N:5]([CH:22]([CH3:24])[CH3:23])[C:6](=[O:21])[C:7]=1[C:8]([NH:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17](C)[CH2:16][CH2:15]1)=[O:9].[CH2:28]([Li])CCC.CI>C1COCC1>[CH:22]([N:5]1[C:6](=[O:21])[C:7]([C:8]([NH:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[O:9])=[C:2]([O:1][CH3:28])[C:3]2[CH:27]=[CH:26][S:25][C:4]1=2)([CH3:24])[CH3:23]
Reactant: CC1CCN(CCCNC(=O)c2c(O)c3ccsc3n(C(C)C)c2=O)CC1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COc1c(C(=O)NCCCN2CCCCC2)c(=O)n(C(C)C)c2sccc12
Temperature: 0 °C
Reaction time: 4 h
Yield: 98.3 %

Procedure:
To a solution of 6,7-dihydro-4-hydroxy-7-isopropyl-N-(3-(4-methylpiperidin-1-yl)propyl)-6-oxothieno[2,3-b]pyridine-5-carboxamide (0.075 g, 0.20 mmol) in THF (2.5 mL) at −78° C. was added n-butyllithium (0.087 mL, 2.5 M in hexanes, 0.22 mmol). The reaction mixture was warmed to 0° C. for 30 min and re-cooled to −78° C.; then methyl iodide (0.037 mL, 0.40 mmol) was added. The mixture was warmed to room temperature, stirred for 4 h and concentrated. The residue was dissolved in dichloromethane; the resulting solution was washed with water, dried over anhydrous sodium sulfate and concentrated to afford the title compound as an off-white solid (0.077 g, 99%). 1H NMR (400 MHz, CD3OD): δ 7.35 (d, 1 H), 7.20 (d, 1 H), 3.55 (t, 2 H), 3.49-3.45 (m, 2 H), 3.40 (t, 4 H), 3.09 (s, 3 H), 2.17-2.09 (m, 2 H), 1.91 (m, 4 H), 1.76-1.62 (m, 2 H), 1.64 (d, 6 H); MS: m/e 392 (M+H+).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.[CH3:11][CH:12]([NH2:14])[CH3:13]>>[OH:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:8]([NH:14][CH:12]([CH3:13])[CH3:11])=[O:10])[CH2:6][CH2:7]1
Reactant: O=C(O)C1CCC(O)CC1
Reactant: CC(C)N
Product: CC(C)NC(=O)C1CCC(O)CC1

Procedure:
Prepared as in Example 24a from 4-hydroxycyclohexanecarboxylic acid and propan-2-amine as a colorless oil (68%). MS 186 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.[CH3:29][C@H:30]1[O:35][C@@H:34]([CH3:36])[CH2:33][NH:32][CH2:31]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:11]([C:4]2[C:5]([C:8]([N:32]3[CH2:31][C@H:30]([CH3:29])[O:35][C@H:34]([CH3:36])[CH2:33]3)=[O:9])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:12][O:13][CH3:14])(=[O:17])=[O:16])=[CH:19][C:20]=1[C:25]([F:28])([F:27])[F:26]
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: COCN(c1cc(Cl)cnc1C(=O)Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCN(c1cc(Cl)cnc1C(=O)N1C[C@@H](C)O[C@@H](C)C1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl chloride (50 mg, 0.11 mmol), cis-2,6-dimethylmorpholine (50 mg, 0.40 mmol) and di-isopropylethylamine (DIEA, 0.07 mL, 0.40 mmol) in CH2Cl2 (1.5 mL) was stirred at room temperature overnight. The mixture was concentrated to provide 4-chloro-N-[5-chloro-2-(cis-2,6-dimethyl-morpholine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide, which was directly used in the next step without any purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([CH3:13])=[C:5]2[N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20](I)[CH:21]=2)[C:16]([CH3:25])([CH3:24])[CH2:15]1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][NH:37][CH:38]=2)O1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([CH3:13])=[C:5]2[N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:34]3[CH:35]=[N:36][NH:37][CH:38]=3)[CH:21]=2)[C:16]([CH3:25])([CH3:24])[CH2:15]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Cc1nc2ccc(Cl)cc2c(N2CC(C)(C)c3ccc(I)cc32)c1C
Product: Cc1nc2ccc(Cl)cc2c(N2CC(C)(C)c3ccc(-c4cn[nH]c4)cc32)c1C

Procedure:
Prepared according to procedure W using 6-chloro-4-(6-iodo-3,3-dimethylindolin-1-yl)-2,3-dimethylquinoline (0.15 g, 0.32 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.084 g, 0.432 mmol) to give 6-chloro-4-(3,3-dimethyl-6-(1H-pyrazol-4-yl)-2,3-dihydro-1H-indol-1-yl)-2,3-dimethylquinoline as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ ppm 12.73 (1H, br. s.), 8.01 (1H, d, J=9.0 Hz), 7.91 (1H, br. s.), 7.75 (1H, d, J=2.4 Hz), 7.62-7.71 (2H, m), 7.19 (1H, d, J=7.6 Hz), 6.94 (1H, d, J=7.6 Hz), 6.07 (1H, s), 3.56-3.78 (2H, m), 2.68 (3H, s), 2.21 (3H, s), 1.48 (3H, s), 1.43 (3H, s); Mass Spectrum (ESI) m/e=403.1 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[N:20][CH:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:17])=[CH:19][N:20]=1
Reactant: CCOC(=O)C1(NC(=O)c2cncc3ccccc23)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cncc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
The mixture of 2-[(isoquinoline-4-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (51) (200 mg, 0.55 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate formed. The precipitate is filtered to give a pure product (52) as white solid (170 mg, 93%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH2:5]1.[CH:12](OCC)=[O:13].C(O)C>C(OCC)C.C(O)C>[OH:13]/[CH:12]=[C:7]1\[C:6](=[O:10])[CH2:5][C:4]([CH3:11])([CH3:3])[CH2:9][CH2:8]\1
Reactant: CC1(C)CCCC(=O)C1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CC1(C)CC/C(=C/O)C(=O)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89.4 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 475 mg, 11.9 mmol) in diethyl ether (25 mL) at 0° C. was added ethanol (0.06 ml, 1.03 mmol) dropwise. The grey suspension was stirred at 0° C. for 20 min. A solution of 3,3-dimethylcyclohexanone (1.50 g, 11.9 mmol) and ethyl formate (1.45 ml, 17.8 mmol) in diethyl ether (3 mL) was added dropwise over 10 min. The yellow heterogeneous reaction mixture was stirred at 0° C. for 1 h then warmed to room temperature and stirred for 2 h. Ethanol (1 mL) was added and the mixture was stirred at room temperature for 1 h then quenched with water (25 mL). The layers were separated and the aqueous phase was washed with diethyl ether. The aqueous layer was acidified with 1M HCl until pH=2 and then extracted with diethyl ether (2×). The combined organic layers were dried over MgSO4 and concentrated to afford 1.64 g (90%) of 2-[1-hydroxy-meth-(Z)-ylidene]-5,5-dimethyl-cyclohexanone as a light yellow oil. 1H NMR (CDCl3, 400 MHz): δ (ppm) 14.38 (br. s., 1H), 8.79 (s, 1H), 2.34-2.47 (m, 2H), 2.16 (s, 2H), 1.42-1.53 (m, 2H), 1.00 (s, 6H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][N:7]1[C:11]([I:12])=[C:10]([CH:13]=[O:14])[CH:9]=[C:8]1[C:15]([O:17][CH3:18])=[O:16].N1C2C(=CC=CC=2)C(CCCC[OH:35])=C1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:13]([C:10]1[CH:9]=[C:8]([C:15]([O:17][CH3:18])=[O:16])[N:7]([CH2:6][C:5]2[CH:19]=[CH:20][CH:21]=[C:3]([CH2:2][OH:35])[CH:4]=2)[C:11]=1[I:12])=[O:14]
Reactant: COC(=O)c1cc(C=O)c(I)n1Cc1cccc(CBr)c1
Reactant: OCCCCc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C=O)c(I)n1Cc1cccc(CO)c1
Temperature: 65 °C
Yield: 93.2 %

Procedure:
To a stirred solution of 1 (0.20 g, 0.43 mmol) in DMF (2.5 mL) was added 4-(1H-Indol-3-yl)butan-1-ol (82 mg, 0.43 mmol) and K2CO3 (60 mg, 0.43 mmol) at room temperature. The resulting mixture was heated at 65° C. for 18 hours. After cooling to room temperature water (3 mL) was added, extracted with EtOAc, washed with brine, dried over MgSO4, and then purified by MPLC (gradient: Hex to EtOAc) to give 0.16 g of the titled compound as an inseparable mixture with 4-(1H-Indol-3-yl)butan-1-ol. It was intended to obtain an ether, but the reaction converted the Br to OH; 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 7.54 (s, 1H), 7.27-7.2 (m, 2H), 7.04 (s, 1H), 6.87 (d, J=7.0 Hz, 1H), 5.79 (s, 2H), 4.65 (s, 2H), and 3.77 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:19]=[CH:18][C:13]3[O:14][CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)[C:5]([C:20]#[N:21])=[C:4](SC2C=CC=CC=2)[N:3]=1.CC(C)([O-])C.[K+].[CH3:35][C:36]1[S:37][CH:38]=[C:39]([CH2:41][OH:42])[N:40]=1>COCCOC>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:19]=[CH:18][C:13]3[O:14][CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([O:42][CH2:41][C:39]2[N:40]=[C:36]([CH3:35])[S:37][CH:38]=2)[N:3]=1
Reactant: Cc1nc(CO)cs1
Reactant: N#Cc1c(N)nc(Sc2ccccc2)c(C#N)c1-c1ccc2c(c1)OCCO2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1nc(COc2nc(N)c(C#N)c(-c3ccc4c(c3)OCCO4)c2C#N)cs1

Procedure:
100 mg (0.26 mmol) of 2-amino-4-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-(phenylsulfanyl)-3,5-pyridinedicarbonitrile [prepared analogously to Kambe et al., Synthesis, 531-533 (1981)] are, together with 44 mg (0.39 mmol) of potassium tert-butoxide and 334 mg (2.59 mmol) of (2-methyl-1,3-thiazol-4-yl)methyl alcohol, stirred in 5 ml of 1,2-dimethoxyethane at room temperature overnight. The reaction solution is concentrated under reduced pressure and the residue is then purified by preparative HPLC on reversed-phase silica gel.
Reaction SMILES: C([CH:8]([CH:10]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:12]=2[O:11]1)[NH2:9])C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.Cl[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]>>[CH2:38]([O:37][C:35](=[O:36])[NH:9][CH2:8][CH:10]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:12]=2[O:11]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: NC(Cc1ccccc1)C1Cc2cccc(-c3ccccc3)c2O1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3ccccc3)c2O1)OCc1ccccc1

Procedure:
Treatment of (±)-benzyl(7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine (1.5 g, 1.43 mmol) with diisopropylethylamine (0.277 g, 2.14 mmol) followed by benzyl chloroformate (0.268 g, 1.572 mmol) generally according to the procedure described for Intermediate 12 provided 1.64 (79%) of (±)-benzyl[7-phenyl-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a clear oil. Rf=0.68 (silica, ethyl acetate:hexanes 1:2); Anal. calcd. for C23H21NO3: C, 76.86; H, 5.89; N, 3.90. Found: C, 75.10H, 5.71; N, 3.90. Chiral HPLC separation of (±)-benzyl[7-phenyl-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralpak AD, ethanol:hexane 1:1) provided two fractions. Fraction 1 (Rt=10.746 min, Chiralpak AD, ethanol:hexane 1:1); Fraction 2 (Rt=13.433 min, Chiralpak AD ethanol:hexane 1:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][C:30]2([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[O:29][C@@H:28]([CH2:37][C:38]([O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:39])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][C:30]4([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[O:29][C@@H:28]([CH2:37][C:38]([O:40][C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)=[O:39])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: NCC[C@@H]1C[C@H](CC(=O)Oc2ccccc2)OC2(CCCCC2)O1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)Oc2ccccc2)OC2(CCCCC2)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and phenyl 2-((2R,4R)-4-(2-aminoethyl)-1,5-dioxaspiro[5.5]undecan-2-yl)acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][CH2:13][C:14](Cl)=[O:15].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Cl:12][CH2:13][C:14]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[Cl:1])[NH:8][C:7](=[O:11])[CH2:6]2)=[O:15]
Reactant: O=C(Cl)CCl
Reactant: O=C1Cc2ccc(Cl)cc2N1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1Cc2cc(C(=O)CCl)c(Cl)cc2N1
Temperature: 75 °C
Yield: 68 %

Procedure:
A mixture of 750 ml of dichloromethane, 150 g of 6-chlorooxindole, 161.6 g of chloroacetyl chloride and 477.2 g of aluminium chloride was refluxed for 9.5 hours. The reaction mass was quenched into a mixture of crushed ice and 135 ml of hydrochloric acid. The formed solid was filtered, and the wet compound was washed with water. The wet compound was dissolved in 3525 ml acetic acid by heating to 70 to 80° C., then carbon was added and the mixture was stirred briefly at the same temperature, and the carbon was removed by filtration and washed with 15 ml of acetic acid. The filtrate was allowed to cool to about 20° C. for solid formation. The solid was filtered, washed three times with 600 ml of water, and then dried to yield 148.5 g of the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][N:6]2[C:8](=[O:20])[C@@H:9]([NH:10][C:11](=[O:19])[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:5]2[S:4][CH2:3]1.O1CCCC1.Cl>C(Cl)Cl>[O:1]=[C:2]1[CH2:7][N:6]2[C:8](=[O:20])[C@@H:9]([NH:10][C:11](=[O:19])[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:5]2[S:4][CH2:3]1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C[C@@H](O)CS[C@H]12
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2C1
Reaction time: 1 h

Procedure:
A solution of (3R,6R,7R)-3-hydroxy-7-phenylacetamidocepham (0.5 g., 1.72 mmole) in anhydrous acid-free methylene chloride (15 ml.) containing anhydrous tetrahydrofuran (3 ml.) was treated with a solution of chromium trioxide/pyridine complex (1.3 g., 3 equivalents) in methylene chloride 30 ml.) at 21° for 1 hour. The reaction mixture was poured into excess dilute hydrochloric acid. After separation, the organic phase was washed with water, dried, and evaporated to an oil. Trituration with ethyl acetate and ether gave the title compound (0.095 g., 19% m.p. 174° to 177° (cap.) νmax. (bromoform, Unicam) 3430 (NH), 1770 (β-lactam), 1735 (ketone), 1678 and 1515 cm.- 1 (amide).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:18][CH3:19].Cl>CS(C)=O.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][O:11][CH2:18][CH3:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCBr
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 1 h

Procedure:
To a solution of N-(tert-butoxycarbonyl)serine (10.26 g, 50.00 mmol) in DMSO (500 mL) was added sodium hydride (2.0 g, 50 mmol) at room temperature. After 1 hour, bromoethane (5.45 g, 50.0 mmol) was added and then additional sodium hydride (2.0 g, 50 mmol) was added immediately. After 16 hours, hydrochloric acid (1.0 M in water, 50 mL, 50 mmol) and water (2 L) were added. The mixture was extracted with ethyl acetate, and the organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford N-(tert-butoxycarbonyl)-O-ethylserine which was used without further purification. MS ESI calc'd. for C10H20NO5 [M+H]+ 234. found 234.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:37]([CH2:39][NH2:40])[OH:38]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:40][CH2:39][CH2:37][OH:38])=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxohexahydro-1H-azepin-1-yl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.54 (d, J=5.05 Hz, 4 H), 1.60-1.75 (m, 4 H), 2.41 (d, J=11.16 Hz, 2 H), 3.34-3.42 (m, 4 H), 3.45 (t, J=5.58 Hz, 2 H), 3.53-3.63 (m, 2 H), 4.16-4.24 (m, 4 H), 4.93 (t, J=4.21 Hz, 1 H), 7.11-7.18 (m, 2 H), 7.37-7.45 (m, 2 H), 8.00 (s, 1 H), 8.56 (d, J=1.47 Hz, 1 H), 10.41 (t, J=6.00 Hz, 1 H), 17.20 (s, 1 H); ES+ MS: 511 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:16]([CH3:18])[CH3:17])=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[CH:8][CH:7]([CH3:15])[CH2:6]2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[CH3:14][O:13][C:12]1[C:3]([O:2][CH3:1])=[C:4]([CH:16]([CH3:17])[CH3:18])[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([CH3:15])[CH:6]=2)[CH:11]=1
Reactant: COc1cc2c(c(C(C)C)c1OC)CC(C)C=C2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: COc1cc2ccc(C)cc2c(C(C)C)c1OC
Reaction time: 3 h
Yield: 95.1 %

Procedure:
Compound 12 (3.00 g, 12.2 mmol) was dissolved in 25 mL of benzene and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2.80 g, 12.2 mmol) was added slowly with stirring and stirring was continued for 3 h. The reaction mixture was filtered through a short column of alumina which was washed with dichloromethane. The solvent was evaporated from the colorless eluant and the residual product was crystallized from petroleum ether to give 2.83 g (11.6 mmol, 95%) of 18 as colorless microcrystalline plates: mp 62-63° C.; 1H NMR: δ1.51 (d, J=7.2 Hz, 6H), 2.50 (s, 3H), 3.88 (s, 3H), 3.90 (sept, J=7.2 Hz, 1H), 3.94 (s, 3H), 7.01 (s, 1H), 7.20 (d, J=8.3 Hz, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.88 (s, 1H). Anal. (C16H20O2) C, H. 8-Deoxyhemigossypol dimethyl ether (19; 2,3-dimethoxy-6-methyl-4-(1-methylethyl)-1-naphthaldehyde. A reaction mixture consisting of 18 (2.5 g, 10.2 mmol) and dichloromethyl methyl ether (3 g, 2.4 ml, 26.5 mmol) in 20 mL of dichloromethane under nitrogen was cooled in an ice bath. Titanium tetrachloride (1.5 ml, 14 mmol) was added slowly with stirring. The mixture was stirred into 100 g of ice with 10 mL of 6 M HCl and the reaction mixture was extracted with ether. The ether layer was washed with water and brine and dried over magnesium sulfate. Petroleum ether was added, the solution was concentrated and the product was allowed to crystallize to give 2.28 g (8.36 mmol, 82%) of 19 as light yellow crystals: mp 103-104° C.; IR 16865 (aldehyde); 1H NMR δ1.52 (d, J=7.2 Hz, 6H), 2.50 (s, 3H), 3.91 (s, 3H), 3.99 (sept, J=7.2 Hz, 1H), 4.02 (s, 3H), 7.38 (d, J=8.7 Hz, 1H), 7.93 (br s, 1H), 9.16 (d, J=8.7 Hz, 1H), 10.75 (s, 1H). Anal. (C17H20O3) C, H.
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:30][N:31]([CH3:35])[C:32](Cl)=[O:33]>>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:32]([N:31]([CH3:35])[CH3:30])=[O:33])[CH2:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: CN(C)C(=O)Cl
Agent: Cl
Product: CN(C)C(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Yield: 80.3 %

Procedure:
The compound (0.15 g) obtained in Example 1 and N,N-dimethylcarbamic acid chloride (0.074 g) were reacted and treated in the same manner as in the method described in Example 6 to obtain the title compound as colorless oil (0.13 g, 80%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]([F:17])([F:16])[CH2:14][OH:15].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([O:15][CH2:14][C:13]([F:17])([F:16])[F:12])[CH:7]=1
Reactant: OCC(F)(F)F
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(F)cc1OCC(F)(F)F
Reaction time: 8 h
Yield: 66.5 %

Procedure:
A mixture of 2,4-difluoro-1-nitrobenzene (10 g, 62.9 mmol) and 2,2,2-trifluoroethanol (6.29 g, 62.9 mmol) in THF (100 mL) at 25° C. was treated with Cs2CO3 (20.5 g, 62.9 mmol) and stirred for 8 hours before being diluted with the addition of water and extracted with EtOAc. The organic extract was dried (Na2SO4), concentrated, and subjected to flash chromatography (3% EtOAc-petroleum ether) to give 4-fluoro-1-nitro-2-[(2,2,2-trifluoroethyl)oxy]benzene (10 g, 67%) as a yellow solid. MS (m/z) 240.0 (M+H+).