Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[OH:11][C@@H:12]([CH2:22][O:23][CH3:24])[C:13]([NH:15][C:16]1[S:20][N:19]=[C:18]([CH3:21])[N:17]=1)=[O:14].Cl[C:26]1[N:31]=[CH:30][N:29]=[C:28]2[N:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[Cl:41])[N:33]=[CH:34][C:27]=12>C1COCC1.CCOC(C)=O>[Cl:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[N:32]1[C:28]2=[N:29][CH:30]=[N:31][C:26]([O:11][C@@H:12]([CH2:22][O:23][CH3:24])[C:13]([NH:15][C:16]3[S:20][N:19]=[C:18]([CH3:21])[N:17]=3)=[O:14])=[C:27]2[CH:34]=[N:33]1
Reactant: COC[C@H](O)C(=O)Nc1nc(C)ns1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1nc(C)ns1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 11.5 %

Procedure:
A solution of lithium bis(trimethylsilyl)amide (0.947 mL, 0.95 mmol) was added dropwise to a stirred solution of (S)-2-hydroxy-3-methoxy-N-(3-methyl-1,2,4-thiadiazol-5-yl)propanamide (Intermediate E1) (187 mg, 0.86 mmol) in anhydrous THF (5 mL) over a period of 3 minutes under nitrogen. The resulting suspension was stirred at ambient temperature for 10 minutes and then a solution of 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) (228 mg, 0.86 mmol) in dry THF (1.5 mL) added dropwise over 1 minute and the reaction heated to 50° C. for 16 hours. Reaction was cooled, diluted with EtOAc (50 mL), washed with 1M citric acid (25 mL) and brine (25 mL), dried (MgSO4), and evaporated. The residue was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane to afford (2S)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-methoxy-N-(3-methyl-1,2,4-thiadiazol-5-yl)propanamide (44 mg, 11%) 1H NMR (400 MHz, CDCl3) δ 2.48 (3H, s), 3.41 (3H, s), 4.01 (2H, ddd), 6.13 (1H, t), 7.38-7.48 (3H, m), 7.56 (1H, dd), 8.34 (1H, s), 8.51 (1H, s), 9.90 (1H, s). m/z (ESI+) (M+H)+=446.08; HPLC tR=2.02 min.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([NH:11][C:12](=[O:14])[CH3:13])=[CH:9][C:8]([Cl:15])=[C:7]([NH2:16])[CH:6]=1)(=[O:3])[CH3:2].CO[CH:19]1[CH2:23][CH2:22][CH:21](OC)O1>C(O)(=O)C>[Cl:15][C:8]1[CH:9]=[C:10]([NH:11][C:12](=[O:14])[CH3:13])[C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][C:7]=1[N:16]1[CH:19]=[CH:23][CH:22]=[CH:21]1
Reactant: CC(=O)Nc1cc(N)c(Cl)cc1NC(C)=O
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(Cl)c(-n2cccc2)cc1NC(C)=O

Procedure:
3 g (12.4 mmol) of 4,5-diacetamido-2-amino-1-chlorobenzene and 1.6 g (12.4 mmol) of 2,5-dimethoxytetrahydrofuran in 150 ml of acetic acid were refluxed for 30 minutes. The reaction mixture was concentrated, the residue was washed with water and ethyl acetate, and the organic phase was worked up.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]([CH3:26])[CH:21]1[CH2:25][CH2:24][NH:23][CH2:22]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:23]3[CH2:24][CH2:25][CH:21]([N:20]([CH3:26])[CH3:19])[CH2:22]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN(C)C1CCNC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)C1
Yield: 61 %

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxaldehyde 10 was reacted with 3-(dimethylamino) pyrrolidine using standard reductive amination conditions. The resulting crude oil was triturated with diethyl ether and methanol to give [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-pyrrolidin-3-yl]dimethyl-amine as a solid (61% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with diethyl ether and methanol to give 341 as an off white solid (86% yield). NMR (CDCl3, 400 MHz), 1.76-1.82 (1H, m), 2.20-2.10 (1H, m), 2.23 (6H, s), 2.48 (2H, dd, J=7.4 and 8.5), 2.66-2.17 (2H, m), 2.81-2.95 (3H, m), 3.88-3.90 (4H, m), 3.90-3.99 (2H, m), 4.03-4.06 (4H, m), 5.23 (2H, br s), 7.28 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=441
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:7]=1.[CH3:12][N:13](C(OC(C)(C)C)=O)[C@H:14]([CH2:16][CH:17]=[CH2:18])[CH3:15].C([O-])([O-])=O.[K+].[K+].[OH:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CN(C=O)C>[OH:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=1.[CH3:12][NH:13][C@H:14]([CH2:16]/[CH:17]=[CH:18]/[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:7]=1)[CH3:15]
Reactant: C=CC[C@H](C)N(C)C(=O)OC(C)(C)C
Reactant: CC(C)Oc1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: CN[C@@H](C)C/C=C/c1cncc(OC(C)C)c1
Temperature: 130 °C
Reaction time: 3 h
Yield: 61.6 %

Procedure:
A mixture of 3-bromo-5-isopropoxypyridine (21.0 g, 97.2 mmol), (S)—N-Methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine (24.0 g, 120 mmol), DMF (53 mL), K2CO3 (22 g, 159 mmol), palladium(II) acetate (0.22 g, 0.98 mmol) and tri-o-tolylphosphine (0.57 g, 1.9 mmol) was degassed and placed under a nitrogen atmosphere. The stirred mixture was then heated at 130° C. for 2.5 h. To remove palladium salts, Smopex™ (20 g) and ethyl acetate (100 mL) were added. The stirred mixture was heated at 50° C. for 5 h and at ambient temperature for 16 h and then filtered. The filtrate was concentrated under reduced pressure, and the residue (83 g) was dissolved in methanol (25 mL), cooled in a cold water bath (<5° C.) and treated drop-wise with 6 M HCl (100 mL). This mixture was stirred 3 h at ambient temperature, and the methanol was removed by concentration under vacuum. The remaining aqueous mixture was washed with dichloromethane (100 mL), made basic by careful (with cooling) addition of 3 M NaOH, and extracted (2×200 mL) with dichloromethane. These latter extracts were washed with saturated aqueous NaCl and concentrated under vacuum. The residue was dissolved in acetone (150 mL), and p-hydroxybenzoic acid (14.0 g, 101 mmol) was added. After complete dissolution of the p-hydroxybenzoic acid, the solution was kept at ambient temperature, as a large amount of solid formed (several hours). After several hours of cooling at −15° C., the mixture was suction filtered. The resulting solid (24.8 g) was recrystallized from acetone (240 mL) to give 22.3 g (61.6%) of off-white crystals (97+% pure by GCMS and LCMS).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[C:8]([O:15][C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[C:6]=2[CH:7]=1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:59][C:60]1[CH:61]=[CH:62][C:63]([NH2:66])=[N:64][CH:65]=1>CN(C=O)C.O>[CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([NH:66][C:63]3[CH:62]=[CH:61][C:60]([CH3:59])=[CH:65][N:64]=3)=[O:14])[CH:9]=[C:8]([O:15][C:16]3[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=3)[C:6]=2[CH:7]=1)[CH3:2]
Reactant: Cc1ccc(N)nc1
Reactant: CCc1cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)O)cc2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)Nc3ccc(C)cn3)cc2o1
Reaction time: 8 h
Yield: 30.8 %

Procedure:
A solution of 2-ethyl-4-[4-(methylsulfonyl)phenoxy]-1-benzofuran-6-carboxylic acid (300 mg, 0.83 mmol), HATU (476 mg, 1.3 mmol) and DIPEA (162 mg, 1.3 mmol) in DMF (20 mL) was stirred for 1 h. After which 5-methylpyridin-2-amine (108 mg, 1.0 mmol) was added. The resulting mixture was stirred overnight. The reaction was monitored by TLC (petroleum ether/EtOAc 1:1). The mixture was poured into water (30 mL) and extracted with EtOAc (30 mL×3). The organic layer was washed with brine (20 mL×2), dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC to afford the desired product (115.0 mg, 31%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.52 (s, 1H), 8.18 (d, 1H), 8.04 (s, 1H), 7.86 (d, 3H), 7.52 (d, 1H), 7.42 (s, 1H), 7.06 (d, 2H), 6.20 (s, 1H), 3.00 (s, 3H), 2.74 (q, 2H), 2.24 (s, 3H), 1.26 (t, 3H); MS (ACPI, pos): 451.2.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[Cl-].[Ca+2].[Cl-].[Cl-].[Al+3].[Cl-].[Cl-].[C:21]1(C)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1C2C(CCCC2)CCC1>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:24]3[CH:23]=[CH:22][C:21]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[CH:26][CH:25]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCC2CCCCC2C1
Product: c1cc(N2CCOCC2)ccc1Nc1ccc(N2CCOCC2)cc1
Temperature: 0 °C
Yield: 58.4 %

Procedure:
In a 300-ml four-necked flask were charged 68 ml of decahydronaphthalene (boiling point: 190° C.) as a solvent and 17.8 g (0.50 mol) of 4-morpholinoaniline, followed by the addition of 15.4 g (0.138 mol) of anhydrous calcium chloride and 18.5 g (0.138 mol) of anhydrous aluminum chloride under stirring. The resulting mixture was reacted at 200 to 210° C. for 5 hours under a nitrogen atmosphere. After cooling, the reaction mixture was added with 76 ml of toluene, followed by charging in 96 g of ice water. The resulting mixture was stirred and allowed to stand, and then, the resulting water layer was separated out. The organic layer was washed successively with 90 ml of a 5% aqueous solution of hydrochloric acid, 60 ml of a 5% aqueous solution of sodium bicarbonate and 60 ml of water. After removal of the organic solvent by distillation under reduced pressure, 48 ml of isopropyl alcohol was added to the residue and the mixture was crystallized overnight at −3 to −8° C. The resulting crystals were collected by filtration, washed with 18 ml of isopropyl alcohol and then dried, whereby 44.9 g (yield: 58.4%) of the title compound was obtained as white crystals. As a result of HPLC. analysis (column: YMC-A-312, detection UV: 280 nm, flow rate: 1.0 ml/min, eluent: acetonitrile/water 7/3), the compound was found to have a purity of 99.7%.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14](I)[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[CH:31])=[N:28][CH:29]=2)=[CH:20][CH:19]=1>>[Br:1][C:2]1[CH:15]=[C:14]([C:31]#[C:30][C:27]2[CH:26]=[CH:25][C:24]([C:21]3[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=3)=[CH:29][N:28]=2)[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Brc1cc(I)ccc1OCCN1CCCC1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(OCCN4CCCC4)c(Br)c3)nc2)cc1

Procedure:
Prepared according to general working method I from 1-[2-(2-bromo-4-iodo-phenoxy)-ethyl]-pyrrolidine (278 mg, 0.34 mmol, 70%) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (110 mg, 0.52 mmol).
Reaction SMILES: S(=O)(=O)(O)O.CO.[NH2:8][C:9]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([O:24][CH3:25])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[C:26](=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[NH2:8][C:9]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([O:24][CH3:25])=[CH:14][C:10]=1[C:11]([O:13][CH3:26])=[O:12]
Reactant: COc1cc(C(=O)O)c(N)cc1-c1ccccc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(OC)c(-c2ccccc2)cc1N
Temperature: 25 °C

Procedure:
Under ice-cooling, concentrated sulfuric acid (1 mL) was added to a methanol (10 mL) suspension of the obtained 2-amino-5-methoxy-4-phenylbenzoic acid, followed by heating to reflux for 6 hours. The reaction mixture was cooled to room temperature and was adjusted to a pH of 8.0 with a saturated aqueous solution of sodium bicarbonate, and chloroform was added thereto. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Hexane was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.24 g of methyl 2-amino-5-methoxy-4-phenylbenzoate as a brown solid.
Reaction SMILES: C(O[C:6]([NH:8][NH:9][C@H:10]1[CH2:15][CH2:14][C@@H:13]([C:16]2[O:20][N:19]=[C:18]([CH:21]([CH3:23])[CH3:22])[N:17]=2)[CH2:12][CH2:11]1)=O)(C)(C)C.[Cl:24][C:25]1[C:30](C=O)=[C:29](Cl)[N:28]=[CH:27][N:26]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:24][C:25]1[N:26]=[CH:27][N:28]=[C:29]2[N:9]([C@H:10]3[CH2:11][CH2:12][C@H:13]([C:16]4[O:20][N:19]=[C:18]([CH:21]([CH3:22])[CH3:23])[N:17]=4)[CH2:14][CH2:15]3)[N:8]=[CH:6][C:30]=12
Reactant: CC(C)c1noc([C@H]2CC[C@@H](NNC(=O)OC(C)(C)C)CC2)n1
Reactant: O=Cc1c(Cl)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)c1noc([C@H]2CC[C@H](n3ncc4c(Cl)ncnc43)CC2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of N′-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-trans-cyclohexyl]-hydrazinecarboxylic acid tert-butyl ester (Intermediate 13; 691 mg, 2.03 mmol) in tetrahydrofuran (3 mL) was added to a cooled (0° C.) solution of 4,6-dichloro-pyrimidine-5-carbaldehyde (Intermediate 16; 361 mg, 2.03 mmol) and diisopropylethylamine (718 μL, 4.06 mmol) in anhydrous tetrahydrofuran (6 mL), and the mixture was stirred at 0° C. for 30 min and then at room temperature for 5 h. The mixture was filtered, and the filtrate was washed with brine. The aqueous layer was extracted with methyl tert-butyl ether and the organic extracts were combined, washed with brine, dried (sodium sulfate), filtered, evaporated, and held under high vacuum. Toluene (15 mL) was added and the mixture was held at 110° C. overnight. The solvent was evaporated and the residue was purified on a Supelco 50 g column, eluting with 0-3% methanol/dichloromethane to give 4-chloro-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-trans-cyclo-hexyl]-1H-pyrazolo[3,4-d]pyrimidine (489 mg, 69%). 1H NMR (300 MHz, DMSO-d6) δ 1.24 (d, 6H, J=6.9 Hz), 1.74-1.88 (m, 2H), 2.04-2.28 (m, 6H), 2.98-3.08 (m, 1H), 3.11-3.22 (m, 1H), 4.91-4.97 (m, 1H), 8.49 (s, 1H), 8.86 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[S:32][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][C:13]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:14]=3[O:15][CH:16]([CH3:26])[CH2:17][NH:18]C(=O)OC(C)(C)C)[C:6]=2[C:5]=1[CH3:33])(=[O:3])[NH2:2].[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[NH2:18][CH2:17][CH:16]([O:15][C:14]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:13]=1[NH:12][C:11]1[C:6]2[C:5]([CH3:33])=[C:4]([C:1]([NH2:2])=[O:3])[S:32][C:7]=2[N:8]=[CH:9][N:10]=1)[CH3:26]
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC(C)CNC(=O)OC(C)(C)C)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC(C)CN)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-(2-(6-carbamoyl-5-methylthieno[2,3-d]pyrimidin-4-ylamino)-5-fluorophenoxy)propylcarbamate (740 mg) was dissolved in dichloromethane (20 ml) and trifluoroacetic acid (4 ml) was added and the reaction was stirred at room temperature overnight. The reaction was concentrated in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH:3]([OH:5])[CH3:4].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[CH3:17][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:6][CH2:1][CH2:2][CH:3]([OH:5])[CH3:4])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: CC(O)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCC(C)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 110.6 %

Procedure:
To a solution of butane-1,3-diol (1 g, 11.1 mmol), TEA (4.6 mL, 33.2 mmol) and DMAP (30 mg, 0.25 mmol) in DCM (20 mL) was added p-toluenesulfonyl chloride (2.75 g, 14.4 mmol) at 0° C. The resulting mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give 3-hydroxybutyl 4-methylbenzenesulfonate (3 g, 100% yield) as yellow oil, which was used without purification. Product tlc [DCM/methanol (100:1) developed with potassium permanganate, Rf 0.4]
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:12]=2)[C:7]1=[O:25])[CH3:2].C1(C2[O:34]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C(Cl)Cl>[CH2:1]([S:3]([CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH:12]=2)[C:7]1=[O:25])=[O:34])[CH3:2]
Reactant: CCSCCN1C(=O)c2ccc(OCc3ccc(F)cc3)cc2C1=O
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Product: CCS(=O)CCN1C(=O)c2ccc(OCc3ccc(F)cc3)cc2C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.5 %

Procedure:
A mixture of 2-(2-ethylsulfanyl-ethyl)-5-(4-fluoro-benzyloxy)-isoindole-1,3-dione (96 mg, 0.27 mmol) and 3-phenyl-2-(phenylsulfonyl)oxaziridine (84 mg, 0.32 mmol) in CH2Cl2 (3 mL) was stirred at room temperature for 72 h. Then the mixture was evaporated and the residue was purified by chromatography (SiO2, CH2Cl2:2N NH3/MeOH 97:3 to 9:1) to afford the title compound (34 mg, 34%) as a white solid. MS: m/e=375.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15]S(C1C=CC(C)=CC=1)(=O)=O.[CH2:26]([O:28][C:29](=[O:41])[C:30]([O:33][C:34]1[CH:39]=[CH:38][C:37](O)=[CH:36][CH:35]=1)([CH3:32])[CH3:31])[CH3:27].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:26]([O:28][C:29](=[O:41])[C:30]([CH3:32])([O:33][C:34]1[CH:39]=[CH:38][C:37]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:36][CH:35]=1)[CH3:31])[CH3:27]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Yield: 78 %

Procedure:
A mixture of the toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester (See Japan Tobacco Inc International Application WO 9518125) (24 g, 66.9 mmol), 2-(4-hydroxyphenoxy)-2-methylpropanoic acid ethyl ester (See American Home Products U.S. Pat. No. 3,795,691) (12.5 g, 55.71 mmol) and Cs2CO3 (22.7 g, 69.6 mmol) was heated at 55° C. in DMF (45 mL) for 18 h. The reaction was partitioned between EtOAc (160 mL) and H2O (180 mL), and the aqueous phase extracted with EtOAc (150 mL). The combined organic phases were dried (MgSO4) and concentrated under reduced pressure to an oil which was purified by column chromatography (1500 mL SiO2, 10% EtOAc/hexanes to 20% EtOAc/hexanes) to provide 2-methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}propionic acid ethyl ester (17.8 g, 78%) as a colorless, viscous oil: Rf=0.48 in 35% EtOAc/hexanes; 1H NMR (400 MHz, CDCl3) δ 7.99-7.96 (m, 2H), 7.43-7.40 (m, 3H), 6.83-6.75 (m, 4H), 4.22 (q, J=9.2 Hz, 2H), 4.18 (t, J=8.8 Hz, 2H), 2.95 (t, J=8.8 Hz, 2H), 2.36 (s, 3H), 1.52 (s, 6H), 1.27 (t, J=9.2 Hz, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.C1CCCCC1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[S:28][C:27]3=[CH:29][N:30]([CH2:41]O)[C:31](=[O:40])[C:32]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)=[C:26]3[NH:25][C:24]=2[CH:43]=1>N1C=CC=CC=1>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[S:28][C:27]3=[CH:29][N:30]([CH2:41][O:4][C:3](=[O:5])[CH:2]([CH3:1])[CH:6]([CH3:8])[CH3:7])[C:31](=[O:40])[C:32]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)=[C:26]3[NH:25][C:24]=2[CH:43]=1
Reactant: CC(C)C(C)C(=O)O
Reactant: O=c1c(-c2ccc(Cl)cc2)c2c(cn1CO)Sc1ccc(Cl)cc1N2
Solvent: O=S(Cl)Cl
Solvent: C1CCCCC1
Solvent: c1ccncc1
Product: CC(C)C(C)C(=O)OCn1cc2c(c(-c3ccc(Cl)cc3)c1=O)Nc1cc(Cl)ccc1S2
Yield: 11 %

Procedure:
A mixture of 1.0 g. of 2,3-dimethylbutyric acid (8.6 mmol.) and 2.5 ml. of thionyl chloride (34.3 mmol.) in 10 ml. of cyclohexane was refluxed on a steam bath for 1.5 hours. The resulting solution was then concentrated under reduced pressure and the residue azeotroped with cyclohexane to yield a colorless oil. The oil was then added dropwise to a cold, stirred suspension containing 0.8 g. of 7-chloro-4-(4-chlorophenyl)-2-(hydroxymethyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one (2.0 mmol.) in 15 ml. of pyridine. After stirring for 35 minutes, the mixture was poured onto ice-water, resulting in the formation of a yellow precipitate which was filtered, washed with water and air-dried, then purified using flash chromatography on silica gel, employing a mixture of 5% ethyl acetate: 95% methylene chloride as the eluent. Fractions containing the product were combined and triturated with ether to yield 7-chloro-4-(4-chlorophenyl)-2-[(2,3-dimethyl-1-oxobutoxy)methyl]-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one as a yellow crystalline solid (110 mg; 11% yield) having the structural formula, ##STR20## a melting point in the range of 204°-205° C. and the following elemental analysis:
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].C(=O)(O)[O-].[Na+].[NH:15]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:16]([C:21](ON1C(=O)CCC1=O)=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19].Cl>CN(C=O)C.O>[NH:15]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[C@H:16]([C:21]([NH:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: CSCC[C@@H](N)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCC[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
D-Met-OH (1.4 g, 10 mM) and sodium bicarbonate (1.68 g, 20 mM) were added to a mixture of water (15 ml) and DMF (5 ml). Boc-Leu-OSu (3.28 g, 10 mM) in DMF (30 ml) was added thereto and the mixture was stirred overnight at room temperature. After cooling to 0° C., the pH was adjusted to pH 6.5 with 1 N-HCl and the solution was concentrated in vacuo. The residue was dissolved in ethyl acetate-1 N-HCl (50 ml-50 ml). The ethyl acetate layer was washed with water, dried by adding sodium sulfate and ethyl acetate was distilled off. The residue was charged on a column of silica gel (100 g) and eluted with benzene-ethyl acetate (1:1) to obtain Boc-Leu-D-Met-OH (1.6 g).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=O)[C:4]2=[CH:14][S:15][CH:16]=[C:3]12.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][CH2:5][C:4]2=[CH:14][S:15][CH:16]=[C:3]12
Reactant: CN1c2ccccc2NC(=O)c2cscc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1c2cscc2CNc2ccccc21
Reaction time: 10 h

Procedure:
A mixture comprising 4 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one [U.S. Pat. No. 3,953,430 (Example 2)] in 75 ml. of tetrahydrofuran is combined with 2 g. of lithium aluminum hydride in 50 ml. of tetrahydrofuran and refluxed under nitrogen with stirring for 10 hours. A 2 ml. portion of water is carefully added dropwise with cooling followed by 2 ml. of 15% sodium hydroxide and 6 ml. of water. The mixture is filtered and the precipitate is washed thoroughly with ether. The filtrate and washings are combined, dried over sodium sulfate, filtered and concentrated to a semi-crystalline brown oil. The product is triturated with hexane producing a tan crystalline solid. This solid is recovered, washed thoroughly with hexane and dried. This crystalline material is purified by column chromatography (alumina activity II), eluting with methylene chloride:hexane (50:50). Evaporation of the solvents yields a solid which is triturated with hexane and washed with ether, giving the desired product as pale blue crystals, mp. 125°-127° C.