Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([CH3:22])[C@H:2]([C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[C:23]([N:33]([CH3:41])[C@H:34]([C:38]([OH:40])=O)[CH:35]([CH3:37])[CH3:36])([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].O.Cl>C1COCC1>[C:23]([N:33]([CH3:41])[C@H:34]([C:38]([N:1]([CH3:22])[C@H:2]([C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:5]=1)=[O:40])[CH:35]([CH3:36])[CH3:37])([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24]
Reactant: CN[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(=O)NS(C)(=O)=O
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(=O)NS(C)(=O)=O)N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of the crude N-Me-Tyr(3-t-Bu)-NHSO2Me (0.51 g, 1.43 mmol), Z-N-Me-Val-OH 0.49 g, 1.86 mmol) and CMPI (0.51 g, 2.00 mmol) in THF (10 ml), TEA (0.60 ml, 4.29 mmol) was added under cooling with ice and stirred at room temperature overnight. The reaction mixture was mixed with water, rendered acidic by the addition of 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=2:3 containing 0.5% acetic acid) to give the titled compound (0.70 g, in 2 steps, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]#[CH:18].C1(C)C=CC=CC=1>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH2:18][C:17]#[CH:16]
Reactant: C#CCBr
Reactant: Oc1cc(Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: C#CCOc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,5-Dichlorophenol (8 g, 49 mmol) was mixed with potassium carbonate (13.6 g, 98 mmol) and 80% solution of propargyl bromide in toluene (11 ml, 98 mmol) in acetone (100 ml) and stirred overnight at room temperature. The precipitate was removed by filtration and washed with acetone. The acetone solution obtaind was concentrated by rotary evaporation and kept under vacuum for 5 h. The product was obtained as yellow oil with quantitative yield. It was used for futher transformations without additional purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([N+:12]([O-])=O)[CH:5]=[CH:4][CH:3]=1.[H][H]>[Ni].CO>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:12])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: [H][H]
Reactant: COC(=O)c1c(Cl)cccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: COC(=O)c1c(N)cccc1Cl

Procedure:
4.5 gm (0.212 mol) of methyl 6-chloro-2-nitro-benzoate were hydrogenated with Raney nickel in 1.8 liters of methanol until the calculated amount of hydrogen was absorbed. The filtered reaction mixture was evaporated in vacuo, and the residue was distilled in vacuo.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=2)[CH2:10][NH:11][C:12](=[O:15])[O:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:21][O:22][CH2:23]Br.O>O1CCCC1>[CH3:21][O:22][CH2:23][N:11]([CH2:10][C:9]1[CH:16]=[CH:17][CH:18]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1)[C:12](=[O:15])[O:13][CH3:14]
Reactant: COCBr
Reactant: COC(=O)NCc1cccc(-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCN(Cc1cccc(-c2ccccc2)c1)C(=O)OC
Reaction time: 8 h
Yield: 76.1 %

Procedure:
1.00 g of methyl N-(3-phenylbenzyl)carbamate in tetrahydrofuran (20 ml) was stirred together with 0.22 g of 60% sodium hydride at room temperature for 30 minutes. 0.78 g of methoxymethyl bromide was added dropwise at room temperature, and the resulting solution was stirred overnight. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure for removal of the solvent. The residue was purified by silica gel column chromatography to give 0.90 g of methyl N-methoxymethyl-N-(3-phenylbenzyl)carbamate as a pale yellow transparent viscous liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9](=O)[CH2:8][CH2:7][C:6]2([CH3:16])[CH3:15].[CH3:17]C[Mg+].[Br-]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10]([C:9]([CH3:17])=[CH:8][CH2:7][C:6]2([CH3:16])[CH3:15])=[CH:11][C:12]=1[CH3:13]
Reactant: CC[Mg+]
Reactant: COc1cc2c(cc1C)C(=O)CCC2(C)C
Agent: [Br-]
Product: COc1cc2c(cc1C)C(C)=CCC2(C)C
Yield: 42.2 %

Procedure:
Following General Procedure F, 6-methoxy-4,4,7-trimethyl-3,4-dihydro-2H-naphthalen-1-one (compound 30, 1.0 g, 4.6 mmol) was reacted with a solution of 3 M EtMgBr (8 mL, 23.0 mmol), and the crude product was purified by flash column (hexane:ethyl acetate=96:4) to give 0.42 g (40%) of the title compound as a clear oil. PNMR (300 MHz, CDCl3) δ 1.36 (t, 3 H, J=6.0 Hz), 1.46 (s, 6 H), 2.35 (d, 2 H, J=4.5 Hz), 2.42 (s, 3 H), 2.65 (q, 2 H, J=7.5 Hz), 4.03 (s, 3 H), 5.82 (t, 1 H, J=2.5 Hz), 7.02 (s, 1 H), 7.28 (s, 1 H).
Reaction SMILES: C([Li])CCC.C([O:10]O)(C)(C)C.[F:12][C:13]([F:27])([F:26])/[CH:14]=[C:15](/[S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18])\[CH3:16]>O1CCCC1.C(OCC)(=O)C>[C:20]1([S:17]([C:15]2([CH3:16])[CH:14]([C:13]([F:12])([F:26])[F:27])[O:10]2)(=[O:18])=[O:19])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OO
Reactant: C/C(=C\C(F)(F)F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(S(=O)(=O)c2ccccc2)OC1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 49 %

Procedure:
To a solution of 15.2 mmol n-butyllithium solution (1.6 M in hexane) in 20 ml tetrahydrofuran at −78° C. was added dropwise 15.2 mmol tert-butyl hydroperoxide solution (5.5 M in nonane) and the mixture was stirred at −78° C. for 10 min, then warmed to −50° C. and re-cooled to −78° C. A solution of 10.1 mmol ((E)-4,4,4-trifluoro-but-2-ene-2-sulfonyl)-benzene in 6 ml tetrahydrofuran was then added dropwise and stirring continued for a further 30 min at −78° C. and then the reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with ethyl acetate and washed sequentially with 1 M hydrochloric acid and with brine. The organic phase was then dried over sodium sulphate and concentrated in vacuo. The residue was purified by chromatography (SiO2, ethyl acetate/heptane) to afford the title compound as a colourless oil (yield 49%). EI-MS (m/e): 251.1 ([M−CH3]+, 6%), 250.1 ([M−O]+, 20%), 126.1 (PhSOH+, 61%), 125.0 ([M−PhSO2]+, 100%), 78.2 (PhH+, 21%), 77.2 (Ph+, 44%), 43.3 (CH3CHCH3+, 73%).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Br.CC(O)=[O:17]>>[OH:17][C:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)sc1ccccc12
Reactant: CC(=O)O
Agent: Br
Product: Oc1cccc2sc3ccccc3c12
Temperature: 130 °C

Procedure:
To a stirred solution of the dibenzothiophene (0.040 g, 0.19 mmoles) isolated from Step D in HOAc (2.5 mL) was added 40% HBr (0.65 mL, 5.6 mmoles) under N2. The reaction was heated to 130° C. for 20 hrs. The resulting green solution was partitioned between EtOAc and ice/brine. The organic layer was washed with sat. NaHCO3 (2×) and brine. The EtOAc extract was dried over Na2SO4 and concentrated in vacuo to give an off-white solid (0.0366 g). Purification by plate layer chromatography with 1:1 hexane/CH2Cl2 afforded the desired phenol as a white solid (0.0294 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][CH:2]=1.[CH3:7][C:8]([CH3:12])([CH3:11])[CH:9]=[O:10]>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[CH3:7]
Reactant: CC(C)(C)C=O
Reactant: c1cnccn1
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1cnccn1
Yield: 11 %

Procedure:
The reaction of pyrazine and trimethylacetaldehyde is conducted in the manner described in Example I on the same molar scale. Preparative thick layer chromatography (2000μ silica gel GF, developed with methylene chloride) of the crude reaction product provides an 11% yield of 1-pyrazinyl-2,2-dimethyl-1-propanone.
Reaction SMILES: [NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[Br:13].[CH3:14]/[C:15](/[NH2:19])=[CH:16]\[C:17]#[N:18].[CH2:20]([CH:23]1[CH2:28][C:27](=[O:29])[CH2:26][C:25](=O)[CH2:24]1)[CH2:21][CH3:22]>C(O)C>[NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]2[C:26]3[C:27](=[O:29])[CH2:28][CH:23]([CH2:20][CH2:21][CH3:22])[CH2:24][C:25]=3[NH:19][C:15]([CH3:14])=[C:16]2[C:17]#[N:18])=[CH:4][C:3]=1[Br:13]
Reactant: Nc1c(Br)cc(C=O)cc1[N+](=O)[O-]
Reactant: CCCC1CC(=O)CC(=O)C1
Reactant: C/C(N)=C\C#N
Solvent: CCO
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(N)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 4-amino-3-bromo-5-nitro-benzaldehyde (665 mg), 3-aminocrotonitrile (223 mg), 5-propylcyclohexane-1,3-dione (418 mg) in 50 ml of ethanol was stirred at 80° C. for 4 h, then at room temperature for 16 h. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/0→0/1 (v/v) as eluent.
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Cl:10][C:11]1[CH:26]=[CH:25][C:14]([CH2:15][CH:16]([C:22]([CH3:24])=O)[C:17](OCC)=[O:18])=[CH:13][CH:12]=1.Cl>C(O)C>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][C:16]2[C:17](=[O:18])[O:2][C:1]3[CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[C:3]=3[C:22]=2[CH3:24])=[CH:25][CH:26]=1
Reactant: CCOC(=O)C(Cc1ccc(Cl)cc1)C(C)=O
Reactant: Oc1cc(O)cc(O)c1
Agent: Cl
Solvent: CCO
Product: Cc1c(Cc2ccc(Cl)cc2)c(=O)oc2cc(O)cc(O)c12

Procedure:
A solution of phloroglucinol (1.57 g) and ethyl 2-(4-chlorobenzyl)acetoacetate (3.18 g) in ethanol (25 ml) was treated with dry HCl at 0° C. for 1.5 hours and the solution was kept at that temperature overnight. Solvent was evaporated and the precipitate triturated with water. Yield 3.87 g (98%). Melting point 270-278° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7]1.N1C=CC=CC=1.[C:28](OC(=O)C)(=[O:30])[CH3:29].O>C(Cl)Cl>[C:28]([NH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])[CH2:7]1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(Cc2cccc(N)c2)C1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1cccc(CN2CC[C@@H](NC(=O)OC(C)(C)C)C2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl [(3R)-1-(3-aminobenzyl)-3-pyrrolidinyl]carbamate (681 mg) in CH2Cl2 (6.8 mL) was added pyridine (28:4 uL), acetic anhydride (265 uL), and N,N-dimethylaminopyridine (14 mg), which was stirred at room temperature for 1.5 hours. To the resultant was added H2O. The mixture was extracted with CH2Cl2. The organic phase was washed by brine, dried over Na2SO4, filtered, and evaporated in vacuo to give tert-butyl {(3R)-1-[3-(acetylamino)benzyl]-3-pyrrolidinyl}carbamate (944 mg) as a off-white amorphous.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[CH:9]=[C:8]([CH3:20])[N:7]=1)=[O:5])C.[F:21][C:22]1[S:26][C:25]([NH2:27])=[N:24][CH:23]=1>>[F:21][C:22]1[S:26][C:25]([NH:27][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:20])[N:7]=2)=[O:5])=[N:24][CH:23]=1
Reactant: Nc1ncc(F)s1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(F)c2)cc(C)n1
Product: Cc1cc(-c2cc(F)cc(F)c2)cc(C(=O)Nc2ncc(F)s2)n1

Procedure:
The title compound, was prepared from 4-(3,5-Difluoro-phenyl)-6-methyl-pyridine-2-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 5-Fluoro-thiazol-2-ylamine (CAS: [64588-82-5], WO2006016178 instead of 3-Chloroaniline to yield the final compound as a light yellow crystalline solid, MS (ISP): m/e=350.2 (M+H)+.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:18])[C:8](=O)[CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=O)[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[C:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[NH:3][N:2]=1)=[O:18])[CH3:5]
Reactant: CCOC(=O)C(=O)C1CCCCCC1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1n[nH]c2c1CCCCC2
Yield: 72.3 %

Procedure:
Hydrazine hydrate (0.142 mL, 2.94 mmol) was added to a stirring room temperature solution of 13 (0.6229 g, 2.94 mmol) in EtOH (2.9 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by TLC (4.5 h): The reaction was concentrated and purified by silica gel chromatography (Combiflash column, 70:30:2 Hexanes:CH2Cl2:2N NH3 in EtOH): Only pure fractions were combined and concentrated to obtain 0.4428 g (72.3%) of 14. 1H (CDCl3, 400 MHz): δ 8.56 (1H, broad s), 4.30 (2H, q, J=7.1 Hz), 2.92-2.86 (2H, m), 2.73-2.78 (2H, m), 1.84-1.76 (2H, m), 1.65-1.57 (4H, m), 1.30 (3H, t, J=7.1 Hz) ppm. 13C (CDCl3, 100 MHz): δ 162.11, 150.70, 134.97, 124.58, 60.85, 32.33, 28.63, 28.32, 27.39, 24.42, 14.47 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 14.47; CH2 carbons: 60.85, 32.33, 28.63, 28.32, 27.39, 24.42; ppm. HPLC: 9.19 min.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C(N(CC)CC)C.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19].Cl>C(OCC)C>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:17](=[O:20])[CH:18]=[CH2:19]
Reactant: Cc1cccc(C)c1N
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2,6-dimethylaniline (8.68 g, 0.0718 mole) and triethylamine (15.3 ml) in ethyl ether (250 ml) was cooled to +5° C. A solution of acryloyl chloride (6.47 g, 0.0716 mole) in ethyl ether (25 ml) was added dropwise with stirring over a 20 minute period. The solution was allowed to warm to room temperature and stirred for 72 hours. 10 Percent hydrochloric acid (150 ml) was added and the layers separated. The acid layer was extracted with ethyl acetate (150 ml), combined, washed with water (150 ml), dried over sodium sulfate, filtered and the solvents evaporated. The solid was taken up in hot ethyl acetate and recrystallized from hexane to yield the title compound, m.p. ca. 143.5°-145.0° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:48]=[CH:47][C:12]([CH2:13][C@H:14]([NH:35][C:36](=[O:46])[O:37][C@H:38]2[C@H:45]3[C@H:41]([O:42][CH2:43][CH2:44]3)[O:40][CH2:39]2)[C@H:15]([OH:34])[CH2:16][N:17]([CH2:30][CH:31]([CH3:33])[CH3:32])[S:18]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:51](OC)([CH3:53])[CH3:52].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C@H:14]2[C@@H:15]([CH2:16][N:17]([CH2:30][CH:31]([CH3:33])[CH3:32])[S:18]([C:21]3[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=3)(=[O:19])=[O:20])[O:34][C:51]([CH3:53])([CH3:52])[N:35]2[C:36]([O:37][C@H:38]2[C@H:45]3[C@H:41]([O:42][CH2:43][CH2:44]3)[O:40][CH2:39]2)=[O:46])=[CH:47][CH:48]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(C)(C)OC
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)O[C@@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(OCc2ccccc2)cc1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 64.5 %

Procedure:
To a solution of (3S,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-{isobutyl[(4-nitrophenyl)sulfonyl]amino}propylcarbamate (1.00 g, 1.5 mmol) in 20 mL of dichloromethane was added 2,2-dimethoxypropane (1.5 g, 14.6 mmol) and p-toluenesulfonic acid (0.09 g, 0.5 mmol). The solution was refluxed for 12 hours, and the solvent was removed under reduced pressure. The residue was purified on silica gel using ethyl acetate-hexanes (3.5:6.5) as eluent to provide 0.70 g (70%) of the title compound.
Reaction SMILES: [CH2:1]([O:5][C@H:6]([CH3:10])[C@H:7]([OH:9])[CH3:8])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20].O>ClCCl>[CH3:18][S:19]([O:9][C@@H:7]([C@H:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH3:10])[CH3:8])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCO[C@H](C)[C@@H](C)O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCO[C@H](C)[C@@H](C)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
1.00 g of (2R,3R)-3-butoxy-2-butanol and 0.83 g of triethylamine were dissolved in 10 ml of dichloromethane. Thereto was dropwise added 0.94 g of methanesulfonyl chloride with ice-cooling. The mixture was stirred overnight at room temperature. The mixture was poured into water and extracted with dichloromethane. The organic layer was washed with dilute hydrochloric acid and an aqueous sodium bicarbonate solution in this order, and then dried and concentrated under reduced pressure. The residue was subjected to Kugel-rohr distillation (1 mmHg) to obtain 1.30 g of (2R,3R)-3-butoxy-2-butyl methanesulfonate.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[CH3:11][O:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12][CH3:11])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNC1
Reactant: COc1ccccc1C(=O)Cl
Product: CCOC(=O)C1CCN(C(=O)c2ccccc2OC)C1
Yield: 68 %

Procedure:
The title compound was prepared according to the method described for Preparation 2 using pyrrolidine-3-carboxylic acid ethyl ester (see Preparation 1) and 2-methoxy-benzoyl chloride to afford the title compound as a colourless oil (4.17 g, 68%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.C1C(=O)N([Br:20])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[CH:8]=1
Reactant: Cc1ccc2cc(F)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc2cc(CBr)ccc2c1

Procedure:
6-Fluoro-2-methylnaphthalene (20.5 g, 128 mmol, prepared by adaptation of the method of Wolinska-Mocydlarz et al2) and NBS (22.8 g, 128 mmol) were heated at reflux for 16 hr in CCl4 (210 mL) during which time, benzoyl peroxide (2.5 g) was added portionwise. The cooled solution was filtered and evaporated and the residue was extracted thoroughly with hexane (4×250 mL). The extracts were decanted from tarry material, combined and evaporated to give the product as a yellow solid, 29.8 g (97%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]([CH:12]=[CH2:13])[C:9]([NH2:11])=[S:10])[CH:5]=[CH:4][CH:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[CH2:20]=O>>[O:17]1[CH2:18][CH2:19][N:14]([CH2:20][NH:11][C:9](=[S:10])[CH:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)[CH:12]=[CH2:13])[CH2:15][CH2:16]1
Reactant: C1COCCN1
Reactant: C=O
Reactant: C=CC(C(N)=S)c1cccc(C)n1
Product: C=CC(C(=S)NCN1CCOCC1)c1cccc(C)n1

Procedure:
Reacting 2-(6-methyl-2-pyridyl)-3-thiobutenamide with morpholine and formalin by the procedure of Example 1 gives N-morpholinomethyl-2-(6-methyl-2-pyridyl)-3-thiobutenamide.
Reaction SMILES: CCCCCC.[S:7]1[CH:11]=[CH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]1=2.[Br:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][CH3:26])=[C:21]([CH:24]=1)[CH:22]=[O:23].[Cl-].[NH4+]>O1CCCC1>[S:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=[C:11]1[CH:22]([C:21]1[CH:24]=[C:17]([Br:16])[CH:18]=[CH:19][C:20]=1[O:25][CH3:26])[OH:23]
Reactant: c1ccc2sccc2c1
Reactant: COc1ccc(Br)cc1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(Br)cc1C(O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
1.6 M n-butylithium hexane solution (30.5 mL) was added to a mixture of benzo[b]thiophene (6.6 g, 0.049 mol) and tetrahydrofuran (66 mL) at −78° C. After stirred for 0.5 hours, the reaction mixture was added with a tetrahydrofuran (50 mL) solution of 5-bromo-2-methoxybenzaldehyde (10.0 g, 0.047 mol), further stirred for five minutes and warmed to room temperature. After the reaction mixture was added with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate, the organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=6:1) to obtain pale yellow crystal (1-benzothien-2-yl)(5-bromo-2-methoxyphenyl)methanol (11.3 g, 69%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([OH:16])=[CH:6][C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][C:8]=2[CH:15]=1)[CH3:2].[CH3:17]O.S(=O)(=O)(O)O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[C:5]([OH:16])=[CH:6][C:7]2[S:11][C:10]([C:12]([O:14][CH3:17])=[O:13])=[CH:9][C:8]=2[CH:15]=1)[CH3:2]
Reactant: CO
Reactant: CCOc1cc2cc(C(=O)O)sc2cc1O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOc1cc2cc(C(=O)OC)sc2cc1O

Procedure:
A solution of 0.71 g. of 5 -ethoxy-6-hydroxybenzothiophene-2-carboxylic acid, 0.29 g. of methanol, and a catalytic amount of sulfuric acid in methylene chloride was heated to reflux for 48 hours. The solution was diluted with ethyl acetate and was washed first with a 10% aqueous sodium bicarbonate solution and then with water. The organic solution was dried over sodium sulfate and evaporated to dryness providing the desired ester intermediate which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.C(N(CC)CC)C.[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH2:16]([O:23][C:24]([NH:1][C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ncc(C=O)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=Cc1cnc(NC(=O)OCc2ccccc2)s1
Yield: 63.5 %

Procedure:
1 g (7.8 mmol) of 2-amino-5-formyl-1,3-thiazole was dissolved in 25 ml of tetrahydrofuran and 1.35 ml (9.36mmol) of triethylamine and 1.33 ml (9.36 mmol) of benzylchloroformate were added at 0° C. under stirring. After 8 hours at room temperature the solvent was evaporated, the residue redissolved with methylene chloride and washed with saturated tartaric acid and then with water. The solvent was dried over anhydrous sodium sulfate and evaporated. The residue was purified by chromatography on silica gel using cyclohexane-ethylacetate as eluent to give 1.3 g (65% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32](O)=[O:33])=[CH:28][CH:27]=1>>[NH2:23][C:12]1[N:13]=[C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:32](=[O:33])[CH2:31][O:30][C:29]3[CH:35]=[CH:36][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)[CH2:21][CH2:22]2)[C:15]2[N:16]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[S:9][C:10]=2[N:11]=1
Reactant: COc1ccc(OCC(=O)O)cc1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3ccc(Cl)cc3)sc2n1
Product: COc1ccc(OCC(=O)N2CCN(c3nc(N)nc4sc(-c5ccc(Cl)cc5)nc34)CC2)cc1
Yield: 63 %

Procedure:
This compound was prepared from 2-(4-chlorophenyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-methoxyphenoxyacetic acid in a yield of 63%, according to the procedure for the synthesis of example 50.