Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1.[CH2:59]([C:62]1[C:71]2[O:70][C:69](=O)[N:68](C)[C:67](=[O:74])[C:66]=2[CH:65]=[CH:64][C:63]=1[O:75][CH3:76])[CH:60]=[CH2:61].S([O-])([O-])=O.[Na+].[Na+].Cl>O.C(O)(C)(C)C>[CH2:59]([C:62]1[C:71]([OH:70])=[C:66]([CH:65]=[CH:64][C:63]=1[O:75][CH3:76])[C:67]([NH:68][CH3:69])=[O:74])[CH:60]=[CH2:61]
Reactant: C=CCc1c(OC)ccc2c(=O)n(C)c(=O)oc12
Agent: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: Cl
Agent: O=S([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: C=CCc1c(OC)ccc(C(=O)NC)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
3.94 g of AD-mix-β was added to a mixture consisting of 0.97 g of 8-allyl-7-methoxy-3-methyl-2H-1,3-benzoxazin-2,4(3H)-dione, 30 ml of tert-butanol, and 20 ml of water. The obtained mixture was stirred at room temperature overnight. Thereafter, 4.73 g of sodium sulfite was added to the reaction solution, and the obtained mixture was stirred for 50 minutes. The reaction solution was adjusted to be approximately pH 5 with addition of 1 N hydrochloric acid, and the reaction mixture was then extracted with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. 8 ml of methanol and 4 ml of tetrahydrofuran were added to the obtained residue, and then, 1.44 ml of a 5 N sodium hydroxide aqueous solution was added thereto. The reaction mixture was then stirred for 10 minutes. The reaction solution was cooled on ice, and then 1 N hydrochloric acid was added thereto, so as to adjust pH to be approximately 6. Ethyl acetate was added to the reaction solution for extraction. The obtained organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure, so as to obtain 0.81 g of the subject compound. It was observed as a mixture of two conformers in NMR. The ratio was approximately 2:1. The following measurement results are indicated with the number of hydrogen atoms such that the sum of conformers becomes a single molecule.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.O=P(Cl)(Cl)[Cl:9].O[C:13]1[CH:18]=[C:17]([CH3:19])[NH:16][C:15](=[O:20])[C:14]=1[C:21]#[N:22].[NH4+].[OH-]>C(Cl)(Cl)Cl>[Cl:9][C:13]1[CH:18]=[C:17]([CH3:19])[NH:16][C:15](=[O:20])[C:14]=1[C:21]#[N:22]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)c(C#N)c(=O)[nH]1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)c(C#N)c(=O)[nH]1
Reaction time: 0.08 h
Yield: 36 %

Procedure:
Using a 100 ml round bottom with reflux condenser, PCl5 (6.7 g, 32 mmol), POCl3 (3.0 mL, 32 mmol) and 30 ml CHCl3 (dry) were stirred for 5 min (see: Heterocycles, vol. 60, No. 6, 2003, 1461-1468). Added 4-hydroxy-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (4 g, 26.6 mmol) and stirred for 2 h at 80° C. Quenched reaction while hot and poured into 1 L beaker with 100 “g” ice, 24 mL NH4OH, pH by paper was 8-9. Stirred 5 min and filtered. Washed solid with water. Suspended solid in ethanol and filtered and washed with ethanol. Gave: 4-chloro-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (1.7 g, 9.58 mmol, 40% yield) 1H NMR (400 MHz, DMSO-d6) δ ppm 12.85 (br. s., 1H) 6.53 (s, 1H) 2.28 (s, 3H) MS(ES) [M+H]+ 168.9.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:4]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([NH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:4]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: NCc1cc(CCC(=O)O)no1
Solvent: c1ccncc1
Product: CC(=O)NCc1cc(CCC(=O)O)no1

Procedure:
7 g (0.04313 mol) of the product from Example 12 are suspended in a solution of 70 ml of acetic anhydride in 140 ml of pyridine with intensive stirring, the starting material slowly going into solution. After completion of the reaction (TLC checking), the mixture is concentrated in vacuo and the product is crystallized from acetone. Yield: 5.5 g; melting point: 134° C.
Reaction SMILES: [Li+].[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([O-:21])=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[Cl:58][C:59]1[CH:64]=[CH:63][C:62]([NH:65][CH:66]2[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]2)=[CH:61][C:60]=1[C:72]([F:75])([F:74])[F:73]>CN(C)C=O.ClCCl.O1CCCC1>[Cl:58][C:59]1[CH:64]=[CH:63][C:62]([NH:65][CH:66]2[CH2:67][CH2:68][N:69]([C:19](=[O:21])[CH2:18][CH2:17][CH2:16][N:13]3[CH2:14][CH2:15][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([F:2])([F:22])[F:23])=[CH:5][CH:6]=4)[CH2:11][CH2:12]3)[CH2:70][CH2:71]2)=[CH:61][C:60]=1[C:72]([F:75])([F:73])[F:74]
Reactant: FC(F)(F)c1cc(NC2CCNCC2)ccc1Cl
Reactant: O=C([O-])CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1)N1CCC(Nc2ccc(Cl)c(C(F)(F)F)c2)CC1
Reaction time: 0.08 h

Procedure:
4-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-butyric acid lithium salt (40 mg; 0.12 mmol, prepared in accordance with Example 3), diisopropylethyl amine (45 μL; 0.26 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (48 mg; 0.12 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran 1.5 mL) and the resulting solution is stirred for 5 minutes. A solution of (4-chloro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (35 mg; 0.11 mmol, prepared in accordance with Example 84) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 4 hours at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (3×5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (44 mg; 0.08 mmol). The structure was confirmed using Protocol I-B. Calculated mass=577; observed mass=577; HPLC retention time=5.38 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]([C:14]([O:16]C)=[O:15])[CH2:11][CH2:10][N:9]2[C:18]([O:20][CH3:21])=[O:19])=[CH:4][CH:3]=1.C(#N)C.[Br-].[Li+].CCN(CC)CC>CC(OC)(C)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11][CH2:10][N:9]2[C:18]([O:20][CH3:21])=[O:19])=[CH:4][CH:3]=1
Reactant: COC(=O)C1CCN(C(=O)OC)C(c2ccc(Cl)cc2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(C(=O)O)CC1c1ccc(Cl)cc1
Yield: 92.1 %

Procedure:
Dimethyl 2-(4-chlorophenyl)piperidine-1,4-dicarboxylate (3.97 g, 12.73 mmol) was dissolved into acetonitrile (55 mL) and water (1.1 mL), then lithium bromide (8.85 g, 101.87 mmol) was added. Et3N (7.10 mL, 50.94 mmol) was added and the resulting yellow suspension was heated at reflux for 2 h. Water (100 mL) and MTBE (150 mL) were added. The phases were separated and the organic layer was extracted with water (2×). The pooled water layers were acidified to pH 1 with 3.8 M HCl and extracted with MTBE (2×). The combined organic layer was dried over Na2SO4, filtered and evaporated leaving 2-(4-chlorophenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (3.49 g, 92%) as a yellow semi-solid. MS m/z 298 (M+H)+
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C@@H:10]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C:3]=1[CH2:29][CH3:30].[NH:31]1[CH2:36][CH2:35][CH:34]([C:37]([O:39][CH3:40])=[O:38])[CH2:33][CH2:32]1.C(NCC)(C)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[CH2:29]([C:3]1[C:4]([NH:8][CH2:9][C@@H:10]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])=[N:5][CH:6]=[N:7][C:2]=1[N:31]1[CH2:36][CH2:35][CH:34]([C:37]([O:39][CH3:40])=[O:38])[CH2:33][CH2:32]1)[CH3:30]
Reactant: CCc1c(Cl)ncnc1NC[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reactant: COC(=O)C1CCNCC1
Agent: CCNC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1c(NC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)ncnc1N1CCC(C(=O)OC)CC1
Temperature: 25 °C
Yield: 17 %

Procedure:
A mixture of 1.2 g (2.8 mmoles) of (1,1-dimethylethyl) 3-[(6-chloro-5-ethyl-4-pyrimidinyl)amino]-N-[(phenyl methoxy)carbonyl]alaninate, 5 ml of methyl 4-piperidinylcarboxylate and 1 ml of isopropylethylamine is heated between 110 and 120° C. for 4 hours. After cooling down to ambient temperature, the reaction medium is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate then concentrated to dryness under vacuum. The residue is chromatographed on silicagel with a gradient of pure heptane to pure ethyl acetate. 260 mg (Yield=17%) of expected product is obtained in the form of an oil.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[F:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:27][C:26]4[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=4[F:24])=[O:2])([CH2:5][CH2:6]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1ccccc1F
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccccc3F)(CC1)CC2
Yield: 23.6 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-fluoroaniline (38.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(2-fluorophenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (15.2 mg).
Reaction SMILES: Cl.O1CCOCC1.C(OC([N:15]1[CH2:20][CH:19]=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:23][N:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.O.[OH-].[Na+]>C(Cl)Cl>[N:28]1[CH:29]=[CH:30][CH:31]=[N:32][C:27]=1[C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH:17]=2)=[N:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(-c3ncccn3)cn2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: C1=C(c2ccc(-c3ncccn3)cn2)CCNC1
Reaction time: 4 h
Yield: 116.2 %

Procedure:
Added 4M HCl/dioxane (5 ml) to solution of 5-Pyrimidin-2-yl-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (2Q) (110 mg, 0.325 mmol) in MeCl2 (5 ml) at room temperature, then stirred 4 hours. Evaporated solvent. Added MeCl2 (100 ml), H2O (50 ml) and 10% NaOH (3 ml). The organic layer was separated, dried over MgSO4, filtered and solvent evaporated yielding 3Q as a white solid (90 mg, 100%) ESMS (MH, 239) LCMS (MH, 239) Retention time=1.53 minutes.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[C:15]([O:17]CC)=[O:16])=[CH:10][CH:9]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:30].[K+]>[Cu].O>[I:30][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(O)c1ccc(-c2ccccc2N)cc1
Reactant: [I-]
Agent: [Cu]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)C(O)c1ccc(-c2ccccc2I)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To 0.05 moles of ethyl 2'-amino-4-biphenylylglycolate dissolved in a mixture of 50 g. of ice water and .06 moles of concentrated sulfuric acid at 0°c is added a solution of 0.05 moles of 95% sodium nitrite in 8 ml. of water. Stirring is continued for 1/2 hour and then 1.5 ml. of concentrated sulfuric acid is added. This solution is poured into an ice cold solution of .06 moles of potassium iodide in 10 ml. of water. To this is added 0.075 g. copper bronze with stirring and the solution is warmed slowly on a water bath to about 80°C for 2 hours. After cooling to room temperature the reaction mixture is extracted thrice with 15 ml. portions of chloroform. This is then washed with dilute thiosulfate solution, water, dried over sodium sulfate and evaporated in vacuo. The residue is crystallized to obtain 2'-iodo-4-biphenylylglycolic acid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:10])[C@H:7]([CH3:9])[NH2:8])([CH3:4])[CH3:3].[C:11](#[N:13])[CH3:12]>>[O:5]=[C:2]([NH:8][C@H:7]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:10])[CH3:9])[CH2:1][CH2:12][CH:11]1[CH2:9][CH2:7][C:6](=[O:10])[NH:13]1
Reactant: CC#N
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Product: C[C@H](NC(=O)CCC1CCC(=O)N1)C(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
A solution of 7.0 g (0.05 mol) of dihydro-1H-3,5(2H,6H) dioxopyrrolizidine in 150 ml of acetonitrile is treated with 14.5 g (0.1 mol) L-alanine 1,1-dimethylethyl ester. The mixture is refluxed 24 hours. The solution is concentrated at reduced pressure and the resulting oil is chromatographed over silica gel using elution with 2.5% methanol in dichloromethane. After concentration at reduced pressure the oil is rechromatographed over silica gel using 19:1 dichloromethane:methanol. The eluate is concentrated at reduced pressure and heated at 80° C. to yield N-[1-oxo-3-(5-oxo-2-pyrrolidinyl)propyl]-L-alanine, 1,1-dimethylethyl ester as an analytically pure oil with the following characteristic proton NMR spectrum: 1H-NMR(CDCL3) 1.35 (d, 3H), 1.5 (s, 9H), 1.5-2.4 (m, 9H), 3.5-3.8 (m, 1H), 4.4 (m, 1H), 6.6-6.8 (m, 1H), 7.4-7.6 (m, 1H).
Reaction SMILES: C(O[C:6](=O)[NH:7][C:8]1[C:9]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[CH3:26])=[C:10]2[CH:16]=[N:15][N:14]([CH2:17][CH3:18])[C:11]2=[N:12][CH:13]=1)(C)(C)C.[H-].[Na+].IC>CN(C=O)C>[CH2:17]([N:14]1[C:11]2=[N:12][CH:13]=[C:8]([NH:7][CH3:6])[C:9]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])=[C:10]2[CH:16]=[N:15]1)[CH3:18]
Reactant: CCn1ncc2c(-c3ccc(F)cc3C)c(NC(=O)OC(C)(C)C)cnc21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCn1ncc2c(-c3ccc(F)cc3C)c(NC)cnc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.7 %

Procedure:
To a solution of [1-ethyl-4-(4-fluoro-2-methyl-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-carbamic acid tert-butyl ester (2.6 g, 7.02 mmol) in DMF (50 mL) at 0° C. was added NaH (0.44 g, 50% purity, 9.12 mmol). After 20 minutes, iodomethane (1.49 g, 10.5 mmol) was added and the temperature raised to RT. The reaction was quenched by addition of H2O and the product extracted with EtOAc. The combined organic phases were dried over Na2SO4, and concentrated under vacuo to give a crude intermediate which was used directly in the next step without further purification. This residue as dissolved in CH2Cl2 (30 mL) and TFA (8 mL) was added. The reaction mixture was heated at 40° C. for 2 hours, diluted with CH2Cl2 (100 mL) and aqueous NaOH (1N) was added until pH reached 8. The organic phase was dried over Na2SO4, concentrated under vacuo to give the title product 1.95 g with high purity (no further purification needed) (99%) as a light yellow solid. ES-MS m/e: 285.1 (M+H+).
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:9][C:10]1[C:11](=[O:18])[C:12]([Cl:17])=[CH:13][C:14](=[O:16])[CH:15]=1.Cl.C(OCC)(=O)C>C1COCC1>[Cl:9][C:10]1[C:11](=[O:18])[C:12]([Cl:17])=[CH:13][C:14]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])([OH:16])[CH:15]=1
Reactant: O=C1C=C(Cl)C(=O)C(Cl)=C1
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)C=C(Cl)C(=O)C(Cl)=C1
Yield: 74 %

Procedure:
Under, nitrogen atmosphere, 6 mL of THF was added to 1.22 g (2 mmol, 0.6 equivalent) of (BrZnCH2COOEt.THF)2. A solution of 0.59 g (3.33 mmol) of 2,6-dichloro-p-benzoquinone in 3 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 1 hour. 5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 10 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, purification with silica gel column (developing solvent; ethyl acetate/n-hexane=1/3) afforded 0.76 g of the desired product (NMR yield 74%; internal standard trioxane). As a purified product, 0.48 g of the desired product was obtained (yield 54%). 1H NMR (CDCl3), (ppm): δ 1.31 (3H, t, J=7.2 Hz), 2.77 (2H, s), 4.21-4.29 (3H, m), 7.15 (2H, s).
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([O:23][CH3:24])[C:17]=2[Cl:25])=[C:10]([OH:27])[CH:9]=1)=[O:7])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[C:39](Cl)(=[O:44])[CH2:40][CH:41]([CH3:43])[CH3:42]>>[CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([O:23][CH3:24])[C:17]=2[Cl:25])=[C:10]([O:27][C:39](=[O:44])[CH2:40][CH:41]([CH3:43])[CH3:42])[CH:9]=1)=[O:7])([CH3:3])[CH3:2]
Reactant: CC(C)CC(=O)Cl
Reactant: COc1c(C)ccc(C(=O)Oc2ccc(C(=O)CNC(C)C)cc2O)c1Cl
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: COc1c(C)ccc(C(=O)Oc2ccc(C(=O)CNC(C)C)cc2OC(=O)CC(C)C)c1Cl

Procedure:
Following a procedure similar to that described in Example 2A above, when 3-hydroxy- 4-(2-chloro-3-methoxy-4-methylbenzoyloxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with isovaleryl chloride there is obtained 3-(isovaleryloxy)-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-(isovaleryloxy)-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[S:9])[C:7]2[CH:10]=[CH:11][CH:12]=[N:13][C:6]=2[O:5][CH:4]([CH2:14][CH2:15][NH:16][CH3:17])[CH2:3]1.C(N(C(C)C)CC)(C)C.[C:27]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Cl)=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28].[C:39]([OH:44])(=[O:43])[C:40]([OH:42])=[O:41]>C(O)(C)C.C(O)C>[C:39]([OH:44])(=[O:43])[C:40]([OH:42])=[O:41].[CH3:28][C:27]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35][N:16]([CH3:17])[CH2:15][CH2:14][CH:4]2[CH2:3][N:2]([CH3:1])[C:8](=[S:9])[C:7]3[CH:10]=[CH:11][CH:12]=[N:13][C:6]=3[O:5]2)=[CH:33][CH:32]=1)([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1ccc(CCl)cc1
Reactant: CNCCC1CN(C)C(=S)c2cccnc2O1
Agent: O=C(O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: CCO
Product: CN(CCC1CN(C)C(=S)c2cccnc2O1)Cc1ccc(C(C)(C)C)cc1

Procedure:
To 40 ml of absolute ethanol was added 6.6 g of 2,3-dihydro-4-methyl-2-[2-(methylamino)ethyl]pyrido[3,2-f]-1,4-oxazepine-5(4H)-thione and 3.35 g (0.026 mole) of diisopropylethylamine. While stirring, 4.75 g (0.026 mole) of p-(t-butyl)benzyl chloride was added at a rapid drop rate. The reaction solution was heated to reflux for 4 hr. After cooling, ethanol was removed by rotary evaporation. The residue was taken up in 100 ml of methylene chloride and the solution was washed with 2×50 ml of 1N potassium hydroxide and 50 ml of water, dried over sodium sulfate, and filtered. The methylene chloride was removed by rotary evaporation and ethylacetate was added to the residue which caused some precipitate to fall out (probably quaternary). After filtering off the precipitate, ethyl acetate was removed by rotary evaporation. The oily residue was heated with 2 equivalents of oxalic acid in isopropyl alcohol which yielded 4.3 g (31%) of yellow, analytically pure crystals, m.p. 175°-78° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[S:12]1[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>C(O)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:18][CH:15]2[CH2:16][CH2:17][S:12][CH2:13][CH2:14]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: NC1CCSCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(Cl)nc1NC1CCSCC1
Temperature: 80 °C
Yield: 50.8 %

Procedure:
2,6-Dichloro-3-nitropyridine (0.500 g, 2.59 mmol), tetrahydro-2H-thiopyran-4-amine (0.304 g, 2.59 mmol) and DIEA (0.91 mL, 5.19 mmol) were taken up in ethanol (2.0 mL) and heated to 80° C. for 18 h in a sealed tube. The reaction solution was chilled to form a precipitate. The precipitate was collected by vacuum filtration to give the title compound (0.360 g) LCMS m/z=274.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 1.70-1.85 (m, 2H), 2.20-2.35 (m, 2H), 2.60-2.90 (m, 4H), 3.90-4.10 (m, 1H), 5.84 (d, J=10.0 Hz, 1H), 8.24 (d, J=9.3 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10](OCC)=O)=[C:8]([NH:15][C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=3[NH2:23])[S:7][C:6]=2[CH:24]=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C1(OC)C=CC=CC=1>[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[C:10]([N:29]4[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]4)=[N:23][C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[NH:15][C:8]=3[S:7][C:6]=2[CH:24]=1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1c(Nc2cc(F)ccc2N)sc2cc(Br)ccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: CN1CCN(C2=Nc3ccc(F)cc3Nc3sc4cc(Br)ccc4c32)CC1

Procedure:
In the same manner as in Example 1 and using ethyl 6-bromo-2-(2-amino-5-fluoroanilino)benzo[b]thiophene-3-carboxylate (3.8 g), 1-methylpiperazine (16 ml), anisole (85 ml) and titanium tetrachloride (3.0 ml), 3-bromo-8-fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine (1.16 g) was obtained.
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][CH3:17])[CH2:11][C:10]2[C:5](=[C:6]([Cl:14])[C:7]([Cl:13])=[C:8]([OH:12])[CH:9]=2)[C:4]1=[O:15])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28]CC)=[O:27].[OH-].[Na+]>CN(C=O)C.O>[O:15]=[C:4]1[C:5]2[C:10](=[CH:9][C:8]([O:12][CH2:25][C:26]([OH:28])=[O:27])=[C:7]([Cl:13])[C:6]=2[Cl:14])[CH2:11][C:3]1([CH2:1][CH3:2])[CH2:16][CH3:17]
Reactant: CCC1(CC)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC1(CC)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 55 °C

Procedure:
A stirred mixture of 2,2-diethyl-5-hydroxy-6,7-dichloro-1-indanone (3.6 g., 0.013 mole), potassium carbonate (4.2 g.) and ethyl bromoacetate (5 g.) in DMF (40 ml.) is warmed in an inert atmosphere at 55° C. for one hour, then treated with water (40 ml.) and 10N sodium hydroxide (6 ml.) and heated on a steam bath for 1.5 hours. The reaction mixture is poured into ice water (200 ml.), acidified, then extracted with ether, washed with water and dried over magnesium sulfate. Following evaporation of the ether the residue is crystallized from butyl chloride affording 1.3 g. of (1-oxo-2,2-diethyl-6,7-dichloro-5-indanyloxy)acetic acid which melts at 111° C.