Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].O1CCC[CH2:14]1.[H-].[Na+].CI>CN(C)C=O.O>[CH3:14][N:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:11]#[N:12]
Reactant: N#CNc1cccc([N+](=O)[O-])c1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CN(C#N)c1cccc([N+](=O)[O-])c1
Temperature: -20 °C
Reaction time: 0.13 h

Procedure:
To a cooled (-20° C.) and stirred solution of 3-nitrophenyl cyanamide (1 g) in a mixture of anhydrous tetrahydrofuran and anhydrous dimethylformamide (3:1; 20 ml) was added sodium hydride (60% dispersion in oil; 294 mg) in one portion, under a nitrogen atmosphere. After 8 minutes of stirring at -20° C., methyl iodide (1.14 ml) was added and the red mixture was allowed to warm to room temperature and diluted with anhydrous dimethylformamide (5 ml). After a further 45 minutes of stirring, water (75 ml; CAUTION| hydrogen evolution) was added and products were extracted with ethyl acetate (2×100 ml). The combined organic phases were washed with brine (1×50 ml), dried (MgSO4) and concentrated. The remaining solid was dissolved in ethyl acetate (30 ml) and hexane (100 ml) was added to give the title compound (880 mg) as fine needles; δH (250 MHz, DMSO-d6) 7.98 (1H, m, Ar--H), 7.85 (1H,t, J=2.2 Hz, Ar--H), 7.73 (1H, t, J=7.7 Hz, Ar--H), 7.60 (1H, m, Ar--H), 3.45 (3H, s, --NMe);m/z (CI) 177 (M-).
Reaction SMILES: O=[C:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH:3]1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl.[NH2:21][OH:22]>N1C=CC=CC=1>[OH:22][N:21]=[C:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH:3]1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: NO
Reactant: CCOC(=O)CC1CN(c2ccccc2)C(=O)C1=O
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)CC1CN(c2ccccc2)C(=O)C1=NO
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of product of Example 62 in pyridine is treated with an excess of hydroxylamine hydrochloride and the reaction is stirred at room temperature for 2 d. The solution is concentrated in vacuo and the residue is chromatographed on silica gel to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]([CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:4].[C:17](Cl)(=[O:19])[CH3:18]>>[C:17]([N:6]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH2:5][C:3]([N:2]([CH3:16])[CH3:1])=[O:4])(=[O:19])[CH3:18]
Reactant: CN(C)C(=O)CNc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)Cl
Product: CC(=O)N(CC(=O)N(C)C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-[N-(dimethylaminocarbonylmethyl)-amino]-nitrobenzene and acetyl chloride
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4](Cl)=[O:5].[NH2:13][C:14]1[S:15][CH:16]=[C:17]([C:19](=[C:25]2[S:29][C:28](=[S:30])[N:27]([CH2:31][C:32]([OH:34])=[O:33])[C:26]2=[O:35])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:18]=1>O1CCCC1>[OH2:5].[CH2:23]([O:22][C:20]([C:19](=[C:25]1[S:29][C:28](=[S:30])[N:27]([CH2:31][C:32]([OH:34])=[O:33])[C:26]1=[O:35])[C:17]1[N:18]=[C:14]([N:13]2[C:4](=[O:5])[C:3]3=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]3[C:1]2=[O:11])[S:15][CH:16]=1)=[O:21])[CH3:24].[CH2:23]([O:22][C:20]([C:19](=[C:25]1[S:29][C:28](=[S:30])[N:27]([CH2:31][C:32]([OH:34])=[O:33])[C:26]1=[O:35])[C:17]1[N:18]=[C:14]([N:13]2[C:4](=[O:5])[C:3]3=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]3[C:1]2=[O:11])[S:15][CH:16]=1)=[O:21])[CH3:24]
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(N)n1
Solvent: C1CCOC1
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(N2C(=O)c3ccccc3C2=O)n1
Product: O
Temperature: 60 °C
Reaction time: 6 h

Procedure:
0.7 g of phthaloyl dichloride was added dropwise under ice-cooling to a solution of 1.19 g of 5-[1-(2-aminothiazol-4-yl)-1-ethoxycarbonylmethylene]rhodanine-3-acetic acid in 8 ml of tetrahydrofuran. The resulting mixture was stirred for 6 hours under ice-cooling and then heated at 60° C. for 4 hours. The crystals which precipitated out after cooling were collected by filtration and recrystallized from ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:10][C:9]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:8]=2[N:7]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:6][CH:5]1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].Br[CH2:31][C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33]>CN(C)C=O>[C:34]([C:32]([CH2:31][N:10]1[C:9]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:8]=2[N:7]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:6][CH:5]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:4]1=[O:3])=[O:33])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)C(=O)CBr
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(NC(=O)OC(C)(C)C)CN2C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
60% Sodium hydride (53 mg) was suspended in anhydrous N,N-dimethylformamide (5 ml), under ice-cooling 2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (410 mg) was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, bromomethyl-tert-butyl ketone (217 mg) was added to the mixture under ice-cooling, the mixture was stirred at room temperature for 30 minutes. Ice-water was added to the reaction mixture, extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, to thereby 517 mg of the title compound (Yield: 100%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:18]1.N1C=CC=CC=1>C1COCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:25]([O:24][C:22]([C:19]1[N:18]([C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)[N:17]=[CH:21][CH:20]=1)=[O:23])[CH3:26].[CH2:25]([O:24][C:22]([C:19]1[CH:20]=[CH:21][N:17]([C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)[N:18]=1)=[O:23])[CH3:26]
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)c1cc[nH]n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)c1ccn(-c2ccc(Oc3ccccc3)cc2)n1
Product: CCOC(=O)c1ccnn1-c1ccc(Oc2ccccc2)cc1
Temperature: 200 °C
Reaction time: 48 h
Yield: 10.3 %
Yield: 4.6 %

Procedure:
To a suspension of 4-phenoxyphenylboronic acid (1.70 g, 7.85 mmol), ethyl 3-pyrazolecarboxylate (0.55 g, 3.92 mmol), copper(II)acetate (1.1 g, 5.89 mmol) and 4 Å molecular sieves (powdered and heated at 200° C. for 2 h prior to use) in 30 mL of anhydrous THF was added 0.6 mL of pyridine. The reaction was stirred open to air at room temperature for 2 days and then filtered and the filtrate was concentrated to dryness. The crude product was purified by flash chromatography, eluting with 15% EtOAc/hexane, affording 5-ethoxycarbonyl-1-(4-phenoxyphenyl)-1H-pyrazole (Rf=0.6, 55 mg, 4.6%) and 3-ethoxycarbonyl-1-(4-phenoxyphenyl)-1H-pyrazole (Rf=0.5, 125 mg, 10.3%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3C(OCC3C=CC=CC=3)=O)=[N:9][C:10]=2Br)[CH:5]=[CH:6][N:7]=1.[S:27]1[C:31]2[CH2:32][CH2:33][CH2:34][CH2:35][C:30]=2[N:29]=[C:28]1[NH:36][C:37](=[O:53])[C:38]1[CH:43]=[CH:42][C:41](B2OC(C)(C)C(C)(C)O2)=[CH:40][CH:39]=1>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][NH:13]3)=[N:9][C:10]=2[C:41]2[CH:42]=[CH:43][C:38]([C:37]([NH:36][C:28]3[S:27][C:31]4[CH2:32][CH2:33][CH2:34][CH2:35][C:30]=4[N:29]=3)=[O:53])=[CH:39][CH:40]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCN3C(=O)OCc3ccccc3)nc(Br)c12
Reactant: CC1(C)OB(c2ccc(C(=O)Nc3nc4c(s3)CCCC4)cc2)OC1(C)C
Product: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4nc5c(s4)CCCC5)cc3)c12
Yield: 60 %

Procedure:
This intermediate was prepared, in an analogous manner as described for intermediate 2, from (S)-benzyl 2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Intermediate 1e) and N-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (intermediate 14b) to afford the title compound (260 mg, 60%).
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[CH:3]1[C:9]([OH:11])=[O:10].C(N(CC)CC)C.[C:19]([O:23][C:24](ON=C(C1C=CC=CC=1)C#N)=[O:25])([CH3:22])([CH3:21])[CH3:20]>O.O1CCOCC1>[C:19]([O:23][C:24]([NH:1][CH:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[CH:3]1[C:9]([OH:11])=[O:10])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NC1C2CCC(C2)C1C(=O)O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NC1C2CCC(C2)C1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.5 %

Procedure:
To a solution of 3-aminonorbornane-2-carboxylic acid (12.6 g.) in a mixture of water (100 ml.) and dioxane (100 ml.) were added triethylamine (12.2 g.) and 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (16.2 g.). The mixture was stirred for 5 hours at ambient temperature and washed with ethyl acetate at pH 10 (each 250 ml., 2 times). The aqueous layer was adjusted to pH 2 with 10% aqueous hydrochloric acid. The acidified solution was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was pulverized with isopropyl ether to give 3-(N-tert-butoxycarbonylamino)norbornane-2-carboxylic acid (10.5 g.).
Reaction SMILES: C([CH:4]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[C:12]2[C:11](=[O:22])[CH2:10][CH2:9][CH2:8][C:7]=2[NH:6][C:5]1([C:24]([F:27])([F:26])[F:25])O)(O)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:27][C:24]([F:25])([F:26])[C:5]1[NH:6][C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:22])[C:12]=2[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[CH:4]=1
Reactant: N#Cc1cccc(C2C3=C(CCCC3=O)NC(O)(C(F)(F)F)C2C(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1cccc(C2C=C(C(F)(F)F)NC3=C2C(=O)CCC3)c1
Yield: 55.2 %

Procedure:
A suspension of 3-carboxy-2-trifluoromethyl-2-hydroxy-4-(3-cyanophenyl)-4,6,7,8-tetrahydro-5(1H)-quinolone (2.25 g) in toluene (100 ml) was treated with p-toluene sulfonic acid monohydrate (0.33 g). The mixture was vigorously refluxed under Dean-Stark conditions for 1.5 hours and then partitioned between water and ethyl acetate. The organic portion was washed (water and brine) and evaporated. The residue was purified by chromatography (hexane/ethyl acetate, 1:1) to yield the title compound (1.04 g) as a white solid; m.p. 182°-183° C.; NMR: 1.80-2.00(m,2, CH2), 2.13-2.30(m,2,CH2), 2.50-2.67(m,2,CH2 4.68(d,1, CH, J=5.2), 5.61(d,1, CH, J=5.3), 7.51(m,2, Ar), 7.60(s,1, Ar), 7.64(m,1, Ar), 9.42(s,1, NH); MS: m/z =318(M); Analysis for C17H13F3N2O: Calculated: C, 64.15; H, 4.12; N, 8.80; Found: C, 64.15; H, 4.10; N, 8.63.
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH:30]1([C:36]2[CH:43]=[CH:42][C:39]([CH2:40][OH:41])=[CH:38][CH:37]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.CCOCC>C(Cl)(Cl)Cl>[CH:30]1([C:36]2[CH:37]=[CH:38][C:39]([CH:40]=[O:41])=[CH:42][CH:43]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: OCc1ccc(C2CCCCC2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(C2CCCCC2)cc1
Reaction time: 0.33 h

Procedure:
18-Crown-6 (Aldrich; 4 molar eq.) and pyridinium chlorochromate (Aldrich; 4 molar eq.) were added together in chloroform and stirred for 20 minutes. 4-Cyclohexylbenzylalcohol (from Example D22 below; 1 molar eq.) was added and stirring continued for 3 hours. Ether was added and the mixture filtered through a plug of silica eluting with ether. The solvent was removed via rotary evaporation. The residue was dissolved in ether and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+].[ClH:26]>CO.O>[ClH:26].[N:18]1([CH2:17][CH2:16][O:15][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)c1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Temperature: 25 °C
Yield: 70 %

Procedure:
A suspension of ester 12 (1.02 g, 3.20 mmol) in MeOH (8 mL) was treated with a solution of NaOH (150 mg, 3.75 mmol) in water (4 mL) and heated at reflux for 3 h. After cooling to room temperature, the solution was adjusted to pH 6 with 1 M HCl and the solvent was removed under reduced pressure. The residue was dissolved in MeOH, 1 M HCl was added dropwise and the formed precipitate was collected by filtration to give 13 (727 mg, 70%) as a brown solid. Purification of the residue obtained by evaporation of the mother liquor using column filtration on silica gel (MeOH, 1% conc. HCl) provided a second batch of 13 (232 mg, 22%). 1H NMR (300 MHz, DMSO-d6): δ=3.07-3.61 (m, 6 H, 2′-H2, 3″-H2, 5″-H2), 3.76-4.06 (m, 4 H, 2″-H2, 6″-H2), 4.43 (t, J=5.0 Hz, 2 H, 1′-H2), 6.98 (dd, J=8.9, 2.3 Hz, 1 H, 6-H), 7.01 (d, J=1.8 Hz, 1 H, 3-H), 7.20 (d, J=2.3 Hz, 1 H, 4-H), 7.37 (d, J=8.9 Hz, 1 H, 7-H), 11.39 (sbr, 1 H, NH+), 11.65 (s, 1 H, NH), 12.85 (sbr, 1 H, CO2H) ppm; 13C NMR (50.3 MHz, DMSO-d6): δ=51.6 (C-3″, C-5″), 54.9 (C-2′), 62.8 (C-1′), 63.1 (C-2″, C-6″), 103.9 (C-4), 106.9 (C-3), 113.5 (C-7), 115.9 (C-6), 127.0 (C-2), 129.0 (C-3a), 133.0 (C-7a), 152.0 (C-5), 162.6 (C═O) ppm; MS (70 eV, EI): m/z (%)=290 (6) [M-Cl]+, 100 (100) [CH2N(CH2)4O]+; C15H19ClN2O4 (326.78): calcd. C, 55.13; H, 5.86; found C, 54.96; H, 5.81.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[CH2:12]([N:14]1[C:18](=[O:19])[CH2:17][O:16][C:15]1=[O:20])[CH3:13].C1COCC1.[H-].[Na+]>O>[CH2:12]([N:14]1[C:18](=[O:19])[C:17](=[CH:7][C:6]2[CH:1]=[CH:2][C:3]3[O:11][CH2:10][O:9][C:4]=3[CH:5]=2)[O:16][C:15]1=[O:20])[CH3:13]
Reactant: CCN1C(=O)COC1=O
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCN1C(=O)OC(=Cc2ccc3c(c2)OCO3)C1=O
Yield: 16.8 %

Procedure:
1.16 g (7.73 mmol) of piperonal and 1.00 g (7.75 mmol) of N-ethyl-2,4-oxazolidinedione are introduced into a 50 ml of eggplant-shaped flask, and a spiral condenser and a drying tube are mounted thereon. The reaction vessel is internally charged with an atmosphere of nitrogen and about 10 ml of THF dried with molecular sieve is added, followed by dissolution by stirring with a magnetic stirrer. After dissolution, 0.36 g (9.0 mmol) of NaH (60 wt. %, oily) is added little by little under stirring with magnetic stirrer. After stirring at room temperature for 2 hours, the reaction mixture is poured into water. The oily substance formed is extracted with ethyl acetate, and after drying over magnesium sulfate, the solvent is removed under reduced pressure, followed by recrystallization from methanol to give 0.34 g (1.3 mmol) of N-ethyl-5-(3,4-methylenedioxy-benzylidene)-2,4-oxazolidinedione at a yield of 17 % (m.p.=135°-137 ° C.).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:28])=[C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[N:19][S:18][C:9]2=[C:10]([C:12]#[C:13][Si](C)(C)C)[N:11]=1)=[O:5])C.[NH2:29][CH2:30][C:31]([OH:33])=[O:32].C[O-].[Na+]>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]2[C:8]3[C:9](=[C:10]([C:12]#[CH:13])[N:11]=[C:6]([C:4]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:5])[C:7]=3[OH:28])[S:18][N:19]=2)=[CH:26][CH:25]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#C[Si](C)(C)C)c2snc(-c3ccc(Cl)cc3)c2c1O
Agent: C[O-]
Agent: [Na+]
Product: C#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(-c3ccc(Cl)cc3)nsc12
Yield: 86.7 %

Procedure:
A mixture of 3-(4-Chloro-phenyl)-4-hydroxy-7-trimethylsilanylethynyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (51.5 mg, 0.119 mmol), glycine (269.7 mg, 3.59 mmol) and NaOMe (5.98 mL, 2.99 mmol, 0.5 M solution in MeOH) was refluxed for 24 h before it was concentrated in vacuo. The residue was dissolved in water (50 mL). The solution was then washed with CH2Cl2 (2×20 mL) before it was acidified by addition on aqueous 1N HCl solution. The resulting precipitate was sucked off, washed with water, and dried in vacuo to give the title compound (40 mg) as white solid: MS (m/z) 388.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH:6]=[C:7]2[CH2:15][C:14]34O[CH:13]3[CH:12]=[CH:11][CH:10]=[C:9]4[C:8]2=O)=[CH:4][CH:3]=1.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][NH:29][NH2:30])[CH2:22][CH2:21]1.C(O)(=O)C.Cl>CCO.CC#N>[ClH:1].[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]2[N:29]([CH2:28][CH2:27][CH2:26][N:23]3[CH2:22][CH2:21][O:20][CH2:25][CH2:24]3)[N:30]=[C:8]3[C:9]4[C:14]([CH2:15][C:7]=23)=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:4][CH:3]=1
Reactant: O=C1C(=Cc2ccc(Cl)cc2)CC23OC2C=CC=C13
Reactant: NNCCCN1CCOCC1
Agent: Cl
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CCO
Product: Clc1ccc(-c2c3c(nn2CCCN2CCOCC2)-c2ccccc2C3)cc1
Yield: 134.7 %

Procedure:
Interaction of 16.1 g (0.059 mole) of 2-(p-chlorobenzylidene)-1-indanone oxide and 10.0 g (0.063 mole) of 3-morpholinopropylhydrazine in 285 ml of EtOH in the presence of 9.6 ml of glacial acetic acid as described in Example 1 yields 20.2 g of crude base as a yellow-orange viscous syrup. The latter is dissolved in 150 ml of warm MeCN, cooled, and treated with 9.3 ml of 5.5 N alcoholic HCl. After filtering a small amount of solid which has separated, the solution is diluted to 550 ml with ether. On rubbing, the crystalline HCl salt rapidly separates. After cooling overnight, the pale yellow solid weighs 20.1 g (78%); m.p. 174°-177° (s. 80°). Crystallization from 60 ml of MeCN gives 17.1 g of cream-colored material; m.p. 181°-183° (s. 140°). Following recrystallization from 60 ml of MeCN, the nearly colorless product weighs 13.7 g (53%); m.p. 181°-183°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](C)[S:8][C:9]=1[C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1)=[O:4].[NH2:18]C(N)=S.C(N)(=S)C>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH2:18])[S:8][C:9]=1[C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1)=[O:4]
Reactant: NC(N)=S
Reactant: COC(=O)c1nc(C)sc1-c1cccc(C)c1
Agent: CC(N)=S
Product: COC(=O)c1nc(N)sc1-c1cccc(C)c1

Procedure:
This compound was synthesised as 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid methyl ester but using thiourea instead thioacetamide.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[O:3]1.C(N(CC)CC)C.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>C1COCC1>[C:24]([O:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)[CH:10]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2cccc(OC(=O)c3ccccc3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.0 g), triethylamine (1.90 mL) and N,N-dimethylaminopyridine (56 mg) in THF (10 mL) was added benzoyl chloride (1.16 mL) at 0° C., and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.74 g).
Reaction SMILES: [C:1]1(=[N:7]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9](O)(CC)(C)[CH3:10].[CH:15]#[CH:16]>CS(C)=O>[CH:15]([N:7]1[C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=2[CH:10]=[CH:9]1)=[CH2:16]
Reactant: CCC(C)(C)O
Reactant: C#C
Reactant: ON=C1CCCCC1
Solvent: CS(C)=O
Product: C=Cn1ccc2c1CCCC2
Yield: 94.9 %

Procedure:
5 g of cyclohexanone oxime, 1 g of potassium tert.amylate, 125 ml of dimethylsulfoxide and 125 ml of tert-amyl alcohol are heated for a period of 3 hours at a temperature of 120° C in a one-liter rotary autoclave in the presence of a 4-fold excess of acetylene (with respect to the stoichiometric amount thereof). Maximal pressure is 29 atm. The reaction mixture is extracted with diethyl ether and distilled to give 5.6 g (94.9%) of 1-vinyl-4,5,6,7-tetrahydroindole.
Reaction SMILES: Cl[C:2](=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[NH2:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=1[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>C(Cl)Cl>[CH3:7][O:6][C:4](=[O:5])[CH2:3][C:2]([NH:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:8]
Reactant: Nc1c(Cl)cc(Cl)cc1C(=O)c1ccccc1
Reactant: COC(=O)CC(=O)Cl
Solvent: ClCCl
Product: COC(=O)CC(=O)Nc1c(Cl)cc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
Methyl 3-chloro-3-oxopropanoate (317 mg, 249 μl, 2.25 mmol, Eq: 1.2) was added dropwise to a yellow solution of (2-amino-3,5-dichloro-phenyl)-phenyl-methanone (500 mg, 1.88 mmol, Eq: 1.00) in DCM (5 ml) at 0° C. The yellow solution was then allowed to warm slowly to RT. After completion of the reaction the mixture was washed with sat. NaHCO3 solution and brine, dried with Na2SO4 and evaporated. The remaining light brown residue (603 mg) was used in the next reaction step without further purification. MS (ESI): 366.0 (M+H)+.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[OH:14][CH2:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].O>O1CCCC1.ClCCl>[Si:6]([O:14][CH2:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[CH2:19][N:20]1[C:21](=[O:30])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]1=[O:29])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: O=C1c2ccccc2C(=O)N1Cc1cccc(CO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under argon and at room temperature, imidazole (1.0 g, 15.0 mmol) and tert-butyldimethylsilyl chloride (1.7 g, 11.2 mmol) are added to a solution of 2-[3-(hydroxymethyl)benzyl]-1H-isoindole-1,3(2H)-dione (2.0 g, 7.5 mmol) in tetrahydrofuran (22.5 ml). The reaction mixture is stirred at room temperature for 16 h, and water is added. After addition of dichloromethane and phase separation, the aqueous phase is extracted with dichloromethane. The combined organic phases are dried (sodium sulfate), filtered and concentrated under reduced pressure. The desired product is purified by flash chromatography (petroleum ether/ethyl acetate mixtures). Yield: 2.7 g, 95% of theory.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH2:5][N:6](C(OC(C)(C)C)=O)[CH2:7][CH2:8][C:9]=2[N:10]=1.[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21]>ClCCl>[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21].[Br:1][C:2]1[S:3][C:4]2[CH2:5][NH:6][CH2:7][CH2:8][C:9]=2[N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Br)sc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1nc2c(s1)CNCC2
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
2-Bromo-5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (890 mg) was dissolved in dichloromethane (2 ml), and to the solution trifluoroacetic acid (15 ml) was added, and the mixture was stirred at room temperature for 1 minute. The reaction mixture was concentrated under reduced pressure, and diethyl ether was added to the residue. Precipitated solid materials were collected by filtration to obtain the title compound (867 mg) as a colorless solid.