Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1(/[C:6](/[N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21](COCC[Si](C)(C)C)[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)=[CH:7]/[C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH:1]1(/[C:6](/[N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)=[CH:7]/[C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(/C(=C\C#N)C4CCCC4)c3)ncnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#C/C=C(/C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A solution of (2Z)-3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]acrylonitrile (0.030 g, 0.069 mol) in DCM (3 mL) and TFA (2 mL) was stirred for 1 hour. The solvents were removed in vacuo and the product was stirred with THF (1.5 mL), sodium hydroxide, 50% aqueous solution (0.75 mL) and water (0.75 mL) for 2 hours. The reaction mixture was neutralized by the dropwise addition of conc. HCl. The product was extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by preparative-HPLC/MS (C18 column eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to afford the desired product (16 mg, 76%).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].N1C=CC=CC=1.[N:13]([CH2:16][CH2:17][CH2:18][OH:19])=[N+:14]=[N-:15]>C(Cl)Cl>[C:1]([O:19][CH2:18][CH2:17][CH2:16][N:13]=[N+:14]=[N-:15])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: [N-]=[N+]=NCCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCCN=[N+]=[N-]
Reaction time: 1 h

Procedure:
29 mL (0.3 mol) of methacryloyl chloride was added to a mixture of 100 mL methylene chloride and 50 mL of pyridine (both solvents had been dried over sodium sulfate overnight). The suspension was cooled in an ice-water bath and 18.6 mL (0.2 mol) of 3-azidopropanol was added over a period of 10 minutes. A clear solution was formed, which was kept in the cooling bath for another 1 hour and then at room temperature for 24 h. 50 mL of methylene chloride were then added, and the mixture was extracted with a solution of 50 mL HCl in 300 mL water followed by four 200-milliliter portions of water (NaCl had to be added to break the stable emulsion). The methylene chloride layer was dried over sodium sulfate (5 grams of sodium carbonate were added to react with the excess of methacrylic acid potentially present), and the solvent was removed under vacuum. The obtained liquid was distilled under reduced pressure (0.1 g of hydroquinone was added to prevent polymerization). The yield was 8.55 g (25%). The procedure needs to be optimized, but the monomer obtained by this procedure was very pure (NMR) and was used to study polymerization reactions.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH:7]=[C:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.[OH-].[K+:14].C(O)COCCOCCO>CO>[O:1]1[CH2:2][CH2:3][N:4]([CH:7]=[C:8]([CH3:12])[C:9]([O-:11])=[O:10])[CH2:5][CH2:6]1.[K+:14]
Reactant: CC(=CN1CCOCC1)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: OCCOCCOCCO
Product: CC(=CN1CCOCC1)C(=O)[O-]

Procedure:
To a small beaker was added 34.2 g (0.20 mole) of crude morpholinomethacrylic acid (Example II compound) and 60 ml methanol. The mixture was stirred until a clear solution resulted. Then, a solution of 12.3 g (0.20 mole) 91% potassium hydroxide in 50 ml methanol was added. The resulting solution was only slightly basic (pH = 8-9). Triethyleneglycol, 40 g, was added and the resulting solution was stripped on a rotary evaporator to remove methanol and water. A slightly viscous solution, that was 51% by weight of the title salt, was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[C:7]([CH:19]=O)[CH:6]=[CH:5][C:4]=2[N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27]>CO.ClCCl>[CH2:15]([N:14]1[C:10]2[C:9]3[CH:8]=[C:7]([CH2:19][NH:27][CH2:26][C:25]4[CH:28]=[CH:29][CH:30]=[C:23]([O:22][CH3:21])[CH:24]=4)[CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[CH:13]1)[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(C=O)cc3c21
Reactant: COc1cccc(CN)c1
Solvent: ClCCl
Solvent: CO
Product: COc1cccc(CNCc2ccc3nc(N)c4ncn(CC(C)C)c4c3c2)c1
Reaction time: 0.5 h
Yield: 9.7 %

Procedure:
4-Amino-1-isobutyl-1H-imidazo[4,5-c]quinoline-8-carbaldehyde (237 mg, 0.66 mmol) and 3-methoxybenzylamine (100 mg, 1.3 mmol) were combined in methanol (25 mL) and dichloromethane (1 mL). The solution was purged with nitrogen gas and a 1M solution of sodium cyanoborohydride in THF (2 mL) was added. The reaction was stirred for 30 minutes. Additional sodium cyanoborohydride in THF (1M, 1 mL) was added and the reaction was stirred for an additional 15 minutes. Aqueous sodium carbonate (1%, 0.25 mL) was added and the reaction was stirred for 7 days. The solvent was removed under reduced pressure and approximately equal portions of chloroform and water were added. The fractions were separated and the organic fraction was sequentially dried (MgSO4), filtered, and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient, 0-20% CMA). Recrystallization from acetonitrile provided 25 mg of 1-isobutyl-8-{[(3-methoxybenzyl)amino]methyl}-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid, mp 125-126° C.
Reaction SMILES: C1C2C(=CC=CC=2)CC1C(O)=O.[CH3:13][C@@H:14]1[NH:19][CH2:18][CH2:17][N:16]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)[CH2:15]1.C[O:32][C:33]([CH:35]1[CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2[S:44](Cl)(=[O:46])=[O:45])[CH2:36]1)=[O:34]>>[CH3:13][C@H:14]1[CH2:15][N:16]([C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]([F:30])([F:28])[F:29])=[CH:24][CH:25]=2)[CH2:17][CH2:18][N:19]1[S:44]([C:41]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:42]=1[CH2:43][CH:35]([C:33]([OH:34])=[O:32])[CH2:36]2)(=[O:46])=[O:45]
Reactant: COC(=O)C1Cc2cccc(S(=O)(=O)Cl)c2C1
Reactant: C[C@H]1CN(c2ccc(OC(F)(F)F)cc2)CCN1
Agent: O=C(O)C1Cc2ccccc2C1
Product: C[C@H]1CN(c2ccc(OC(F)(F)F)cc2)CCN1S(=O)(=O)c1cccc2c1CC(C(=O)O)C2

Procedure:
4-|2-(S)-Methyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl|-indan-2-carboxylic acid. The compound 4-[2-(S)-Methyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid was prepared from 3-(S)-methyl-1-(4-trifluoromethoxy-phenyl)-piperazine and 4-chlorosulfonyl-indan-2-carboxylic acid methyl ester following the procedure outlined in Example 79. 1H NMR (400 MHz, DMSO-d6): δ 7.65 (d, 1H), 7.53 (d, 1H), 7.38 (t, 1H), 7.18 (d, 2H), 6.98-6.92 (m, 2H), 4.15-4.00 (m, 1H), 3.60-3.12 (m, 9H), 2.83-2.75 (m, 1H), 2.64-2.50 (m, 1H), 1.18 (d, 3H); MS (ESI): 485.3 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]2[O:11][CH2:12][CH2:13][O:14][CH:7]2[CH2:6]1.[Cl:15][C:16]1[CH:17]=[C:18]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([OH:34])[CH:32]=3)[N:27]=[CH:26][N:25]=2)[CH:19]=[CH:20][C:21]=1[F:22].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([O:34][CH2:2][CH2:3][CH2:4][N:5]4[CH2:10][CH2:9][CH:8]5[O:11][CH2:12][CH2:13][O:14][CH:7]5[CH2:6]4)[CH:32]=3)[N:27]=[CH:26][N:25]=2)[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Reactant: ClCCCN1CCC2OCCOC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCC2OCCOC2C1
Temperature: 80 °C
Yield: 25.9 %

Procedure:
A mixture of 6-(3-chloropropyl)octahydro-[1,4]dioxino[2,3-c]pyridine (100 mg, 0.46 mmol, 1 eq), 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (145 mg, 0.46 mmol, 1 eq) and K2CO3 (128 mg, 0.92 mmol, 2 eq) in DMF (10 mL) was heated at 80° C. overnight under N2, and cooled to room temperature. To this, 100 mL of CH2Cl2 was added. The mixture was washed with brine (20 mL×3) and water (20 mL×2). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (20:1 (v/v) CH2Cl2/MeOH) to afford the title compound as a yellow solid (60 mg, 28.00%), HPLC: 95.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 503.1 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.04-2.10 (2H, m), 2.21-2.48 (3H, m), 2.60-2.63 (2H, m), 2.92-3.08 (2H, m), 3.56-3.62 (2H, m), 3.67-3.72 (1H, m), 3.76-3.82 (2H, m), 3.52-3.53 (1H, m), 3.97 (2H, s), 4.08-4.15 (2H, m), 7.10-7.15 (1H, m), 7.21 (1H, s), 7.31 (1H, s), 7.62-7.65 (1H, m), 7.93-7.94 (1H, m), 8.62 (1H, s) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4](I)[CH:3]=1.[CH2:10]([OH:14])[CH2:11][C:12]#[CH:13].C(NC(C)C)(C)C>C(OC(C)C)(=O)C.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:12]([CH2:11][CH2:10][OH:14])=[CH:13][C:4]=2[CH:3]=1
Reactant: C#CCCO
Reactant: Oc1ccc(Br)cc1I
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)OC(C)C
Solvent: CC(C)NC(C)C
Product: OCCc1cc2cc(Br)ccc2o1
Temperature: 60 °C
Yield: 72.2 %

Procedure:
The product from Example 3A (14.95 g, 50 mmol), palladium(ll) acetate (0.11 g, 0.5 mmol), triphenylphosphine (0.26 g, 1.0 mmol), and copper(I) iodide (0.19 g, 1.0 mmol) were combined in isopropyl acetate (100 mL). Nitrogen gas was bubbled through the reaction mixture for about 15 minutes. The mixture was treated with 3-butyn-1-ol (5.6 mL, 75.0 mmol) stirred briefly and then treated with diisopropylamine (42 mL, 300 mmol) slowly over about 10 minutes. After stirring for 2 hours at about 22° C., the mixture was heated at about 60° C. for about 6 hours and then cooled to about 22° C. The reaction mixture was filtered through a pad of Celite® (˜5 g) and the Celite® was washed with isopropyl acetate (˜30 mL). The filtrate was washed with saturated NaHCO3 solution (100 mL, 2×), 10% Na2S2O3 solution (100 mL, 2×), brine (50 mL), dried over Na2SO4, and distilled to dryness. The residue was purified by silica gel column chromatography to provide the title compound (8.7 g, 72% yield). MS DCl (M+NH4)+ m/z at 258,260; 1H NMR(CDCl3at 400 MHz) δ 3.03 (m, 2H), 3.98 (m, 2H), 6.45 (m, 1H), 7.25-7.32 (m, 2H), 7.60 (d, 1H); 13C NMR (CDCl3 at 100 MHz) δ 32.2, 60.6, 103.0, 112.1, 115.4, 122.8, 126.1, 130.4, 153.1, 157.0.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:13][O:14]C1C(OC)=CC(C(O)=O)=C([N+]([O-])=O)C=1>>[NH2:1][C:2]1[CH:10]=[C:9]([O:14][CH3:13])[C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: COc1ccc(N)c(C(N)=O)c1
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OC
Product: COc1cc(N)c(C(N)=O)cc1OC

Procedure:
According to the preparation of 10, 4,5-dimethoxy-2-nitrobenzoic acid (5) (1.0 g, 4.4 mmol) was used to afford 11 (0.8 g) as brown powder; MS m/z 196 (M+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]([C:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][C:16](Cl)=[C:17]([F:22])[CH:18]=2)[N:13]([CH2:24][CH3:25])[CH:12]=1)=[O:10]>N1C=CC=CC=1>[CH3:7][O:8][C:9]([C:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][C:16]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[C:17]([F:22])[CH:18]=2)[N:13]([CH2:24][CH3:25])[CH:12]=1)=[O:10]
Reactant: C1CNCCN1
Reactant: CCn1cc(C(=O)OC)c(=O)c2cc(F)c(Cl)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)OC)c(=O)c2cc(F)c(N3CCNCC3)cc21
Reaction time: 5 h
Yield: 94.2 %

Procedure:
A mixture of 1.7 g of anhydrous piperazine and 1.4 g of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid methyl ester in 3 ml of pyridine was refluxed with stirring for 5 hrs. The reaction mixture was cooled to give crude crystals. The crude crystals were recrystallized from a mixture of methylene chloride and methanol to give 1.55 g (77.5% yield) of 1-ethyl-6-fluoro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid methyl ester. mp: 179°-181° C.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].C(O)CO.CN(C)C=O.[N:39]1[CH:44]=[CH:43][C:42]([SH:45])=[CH:41][CH:40]=1>[Cu]I>[N:18]1([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([S:45][C:42]5[CH:43]=[CH:44][N:39]=[CH:40][CH:41]=5)[N:10]4[N:9]=3)=[CH:13][CH:14]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: Brc1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Reactant: Sc1ccncc1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: OCCO
Product: c1cc(Sc2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)ccn1
Temperature: 135 °C

Procedure:
Into a sealed tube, (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-(4-morpholin-4-yl-phenyl)-amine (0.174 g, 0.465 mmol), Sodium tert-butoxide (134 mg, 1.40 mmol), Copper(I) iodide (8.8 mg, 0.046 mmol), 1,2-Ethanediol (52.1 uL, 0.934 mmol), N,N-Dimethylformamide (6.5 mL, 84 mmol), and Pyridine-4-thiol (0.207 g, 1.86 mmol) were added. The reaction was heated at 135° C. for 2 days. The solvent was removed under vacuum. The reaction was partitioned with water and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum to give a yellow solid. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN as eluant (5 to 35% ACN). The collected fractions were lyophilized to give a yellow solid. (33 mg, 14%). LCMS (E/I+) 405.7 (M+H). NMR 1H (DMSO-d6)-9.25 (s, 1H), 9.10 (s, 1H), 8.56 (bs, 1H), 7.40 (d, 2H, J=6.68 Hz), 7.33 (d, 2H, J=8.91 Hz), 7.19 (d, 1H, J=4.45 Hz), 7.04 (d, 1H, J=4.45 Hz), 6.70 (d, 2H, J=9.65 Hz), 3.74 (t, 4H, J=5.08 Hz), 302 (t, 4H, J=5.08 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:27][O:28][C:29]1[N:30]=[CH:31][C:32]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=4[C:13]=3[CH3:22])(=[O:10])=[O:11])=[C:4]([C:23]([F:25])([F:26])[F:24])[CH:3]=2)=[CH:33][CH:34]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: COc1ccc(-c2ccc(NS(=O)(=O)c3sc4ccc(F)cc4c3C)c(C(F)(F)F)c2)cn1
Yield: 76.4 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.10 g) and 2-methoxy-5-pyridineboronic acid (0.065 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.32 ml) and 2 M aqueous sodium carbonate solution (0.8 ml) with tetrakis(triphenylphosphine)palladium (0.012 g) to obtain the title compound (0.081 g) as a colorless solid. MS (ISP): 497.3 (M+H)+
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[N+:10]([O-:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]1>>[CH3:11][N:10]1[C@H:9]([CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C@@H:14]2[C:13](=[O:19])[CH2:18][CH2:17][CH2:16][C@@H:15]2[O:12]1
Reactant: C[N+]([O-])=CCCc1ccccc1
Reactant: O=C1C=CCCC1
Product: CN1O[C@H]2CCCC(=O)[C@H]2[C@H]1CCc1ccccc1
Temperature: 25 °C
Yield: 89 %

Procedure:
N-(3-Phenylpropylidene)methylamine N-oxide (1.50 g, 9.19 mmol) and 2-cyclohexenone (5 ml) were heated at 80°-90° C. for 24 hours in a sealed tube under nitrogen. The solution was cooled to room temperature and the excess 2-cyclohexenone was removed under reduced pressure using Kugelrohr distillation to yield the crude product as a dark yellow oil (2.36 g, 99%). The crude product was purified by flash chromatography using 60:40 v/v light petroleum (fraction of bp 40°-60° C.):ethyl acetate as the solvent system to give the title compound as a colourless oil (2.11 g, 89%), vmax (film) 2941, 2872, 1710, 1454, 1235 cm-1 ; δH (250 MHz, CDCl3 --Me4Si) 1.70-2.0 (6H, br m), 2.25-2.55 (2H, m), 2.60-2.80 (2H, m), 2.70 (3H, s), 2.75 (1H, t), 3.25 (1H, br m), 4.45 (1H, br m), 7.10-7.30 (5H, br m); M/z 259 (M+ 100%) (Found: M+ 259.1572; C16H21NO2 requires M+ 259.1603).
Reaction SMILES: [N+]([O-])(OCCCCC)=O.[CH:10]([Br:13])(Br)Br.NC1[S:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:19]=1>>[Br:13][C:10]1[S:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:19]=1
Reactant: BrC(Br)Br
Reactant: COC(=O)c1cnc(N)s1
Agent: CCCCCO[N+](=O)[O-]
Product: COC(=O)c1cnc(Br)s1

Procedure:
A mixture containing 100 g. of amyl nitrate and 600 ml. of bromoform is warmed to 70° C and then a total of 100 g. of 2-amino-5-methoxycarbonylthiazole is added portionwise with rapid stirring while maintaining the temperature at about 95°-100° C. The mixture is then stirred for an additional ten minutes at this temperature and then the bromoform is distilled off under vacuum. The residue is chromatographed on silica gel yielding 2-bromo-5-methoxycarbonylthiazole.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([NH:16][C@H:17]([CH2:28][OH:29])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:8][C@H:9]([C:14]([NH:16][C@H:17]([CH2:28][OH:29])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CO)Cc1c[nH]c2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC[C@H](C)[C@H](N)C(=O)N[C@H](CO)Cc1c[nH]c2ccccc12
Reaction time: 4 h

Procedure:
To a solution, being ice cooled, of N-tert-butoxycarbonyl-(L)-isoleucyl-(L)-tryptophanol (1.0 g) in chloroform (10 ml), trifluoroacetic acid (5%, 0.5 g) was added, followed by stirring at the same temperature for 4 hours. After the reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue. The ethyl acetate layer was washed with water and dried (MgSO4), and the solvent was distilled off to yield (L)-isoleucyl-(L)-tryptophanol as an oily substance. This oily substance was dissolved in chloroform (20 ml), and p-toluenesulfonyl chloride (0.52 g) was added and then triethylamine (1.4 ml) was added at 0° C. After stirring at room temperature for 2 days, the reaction mixture was poured over water and extracted with chloroform. After the chloroform layer was dried (MgSO4), the solvent was distilled off, and the oily residue was recrystallized from ethyl acetate to yield N-(p-toluenesulfonyl)-(L)-isoleucyl-(L)-tryptophanol (0.32 g, 28%).
Reaction SMILES: N12CCN(CC1)CC2.[CH2:9]([N:11]=[C:12]=[S:13])[CH3:10].[F:14][C:15]1[CH:31]=[CH:30][C:18]([O:19][C:20]2[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26][OH:27])=[CH:22][CH:21]=2)=[CH:17][CH:16]=1>N1C=CC=CC=1>[F:14][C:15]1[CH:31]=[CH:30][C:18]([O:19][C:20]2[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26][O:27][C:12](=[S:13])[NH:11][CH2:9][CH3:10])=[CH:22][CH:21]=2)=[CH:17][CH:16]=1
Reactant: OCCOc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CCN=C=S
Agent: C1CN2CCN1CC2
Solvent: c1ccncc1
Product: CCNC(=S)OCCOc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
50 mg of 1,4-diazabicyclo(2,2,2)octane and 0.9 g of ethyl isothiocyanate are added to a solution of 2.3 g of 2-[p-(p-fluorophenoxy)phenoxy]-ethanol in 10 ml of pyridine. The mixture is then allowed to stir at 80° C. for 16 hours. The cooled mixture is poured into 50 ml of ice/water and extracted three times with 80 ml of ethyl acetate each time. The extracts are washed twice with 50 ml of water each time and with 50 ml of sodium chloride solution. The extracts are dried over anhydrous sodium sulfate and evaporated. The residue is purified chromatography on silica gel with n-hexane/ethyl acetate (2:1) to yield pure [2-[p-(p-fluorophenoxy)phenoxy]-ethyl]N-ethylthiocarbamate; m.p. 73°-75° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[O:10][N:9]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1)=[O:4].[CH2:15]([S:19]Cl)[CH2:16][CH2:17][CH3:18].C1C=CC=CC=1>N1C=CC=CC=1>[CH3:1][N:2]([S:19][CH2:15][CH2:16][CH2:17][CH3:18])[C:3]([NH:5][C:6]1[O:10][N:9]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1)=[O:4]
Reactant: CNC(=O)Nc1cc(C(C)(C)C)no1
Reactant: CCCCSCl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCSN(C)C(=O)Nc1cc(C(C)(C)C)no1
Temperature: 0 °C
Reaction time: 8 h
Yield: 2.2 %

Procedure:
To a solution of 1-methyl-3-(3-t-butyl-5-isoxazolyl)-urea (0.99 g) in pyridine (8 ml), butylsulfenyl chloride (0.67 g) is added dropwise at -30° to -40° C., and the resultant mixture is stirred at the same temperature for 6 hours. The reaction mixture is allowed to stand at room temperature overnight, poured into ice water and shaken with benzene. The organic layer is washed with 3% hydrochloric acid, 5% aqueous sodium bicarbonate solution and water in that order, dried over anhydrous sodium sulfate and evaporated to remove the solvent. The residue is chromatographed on a column of silica gel, whereby 1-methyl-1-butylthio-3-(3-t-butyl-5-isoxazolyl)urea (0.031 g) is obtained as an oil. IR: 1712, 1617 cm-1 (CC14).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21]Cl)[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH:30][CH2:31][CH:32]=[CH2:33])[CH:28]=[CH2:29]>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21][N:30]([CH2:31][CH:32]=[CH2:33])[CH2:27][CH:28]=[CH2:29])[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3nc(CCl)cs3)c2[C@@H]2CCCN12
Reactant: C=CCNCC=C
Solvent: C1CCOC1
Product: C=CCN(CC=C)Cc1csc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)n1
Reaction time: 8 h
Yield: 55.8 %

Procedure:
A solution of 0.81 g (0.002 mol) of (S)-8-chloro-1-(4-chloromethyl-thiazol-2-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in 5 ml of tetrahydrofuran was treated with 3 ml (0.024 mol) of diallylamine and stirred at 50° for 8 hrs. All volatiles were removed in a water-jet vacuum and the residue was chromatographed over silica gel with methylene chloride/methanol 98:2 as the eluent. After recrystallization from diethyl ether there was obtained 0.52 g (55%) of (S)-8-chloro-1-(4-diallylaminomethyl-thiazol-2-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in the form of white crystals; m.p. 186°-187° and [α]D20 =-67.5° (MeOH, c=1%).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:10]=1[C:11](Cl)=[O:12].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1)[NH2:24]>C1(C)C=CC=CC=1>[CH3:29][O:28][C:26]1[CH:25]=[C:23]([NH:24][C:11](=[O:12])[C:10]2[C:9]([F:8])=[CH:17][CH:16]=[CH:15][C:14]=2[F:18])[CH:22]=[C:21]([O:20][CH3:19])[CH:27]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc(NC(=O)c2c(F)cccc2F)cc(OC)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
5.5 ml (39.2 mmol; 1.2 equivalent) of triethylamine and 4.5 ml (35.9 mmol; 1.1 equivalent) of 2,6-difluorobenzoyl chloride are added to 5 g (32.6 mmol) of 3,5-dimethoxyaniline in solution in 100 ml of anhydrous toluene. The reaction medium is maintained under stirring at 70° C. for 1 hour 30 minutes, then, after returning to ambient temperature, washed with 3 times 50 ml of water. The resulting organic phase is dried over magnesium sulphate then the solvent is evaporated off under reduced pressure. The expected product is obtained in the form of a white powder (8.75 g; yield=97%) used in the following stage without other purification.