Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:23]=1[NH2:24]>>[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:23]=1[NH:24][C:14]([C:12]1[S:13][C:9]([S:8][C:7]2[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=2[Cl:20])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=1)=[O:15]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: Nc1c(Cl)cccc1Cl
Product: O=C(Nc1c(Cl)cccc1Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 2,6-dichloro-aniline (63 mg, 0.39 mmol). The title compound was obtained as a solid (70 mg, 43% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.76 (1H, s), 8.99 (2H, s), 8.68 (1H, s), 7.60 (2H, m), 7.41 (1H, m). MS m/z: 492.00, 493.99, 495.96 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=3)[NH:12][CH:11]=2)[CH2:6][CH2:5]1.[CH:22]1([S:28](Cl)(=[O:30])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.O>CN(C)C=O>[CH:22]1([S:28]([N:12]2[C:13]3[C:18](=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)[C:10]([C:7]3[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH:8]=3)=[CH:11]2)(=[O:30])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Reactant: O=S(=O)(Cl)C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CC=C(c2cn(S(=O)(=O)C3CCCCC3)c3ccc([N+](=O)[O-])cc23)CC1
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
468 mg (9.8 mMol) of 50% sodium hydride in oil were added at 0° C. to a solution of 1.0 g (3.9 mMol) of 3-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)-5-nitro-1H-indole in 50 ml of anhydrous dimethylformamide, and the mixture was left to stir for 30 minutes. Then 2.14 g of cyclohexanesulfonyl chloride were added, and the stirring continued for 3 hours at room temperature. Water was added and evaporated to dryness. The resulting crude was treated with sodium bicarbonate and was extracted with chloroform. The organic phase was dried with anhydrous sodium sulfate and evaporated to dryness; the resulting solid was purified by chromatography, obtaining 900 mg (57%) of 1-cyclohexanesulfonyl-3-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)-5-nitro-1H-indole as a yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][F:36])=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)C)(C)(C)C>ClCCl>[F:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([CH:23]=[CH:22][C:19]2[CH:20]=[CH:21][C:16]([NH:14][CH3:13])=[CH:17][CH:18]=2)=[CH:25][CH:26]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C=Cc2ccc(OCCOCCF)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1ccc(C=Cc2ccc(OCCOCCF)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
Trifluoroacetic acid (0.5 ml) was added slowly to a solution of compound 11a (7.0 mg, 0.017 mmol) in dichloromethane (1 ml). The mixture was then stirred at room temperature for 1 hour. After standard workup with dichloromethane, the residue was purified by silica gel preparative TLC (1.0% methanol in dichloromethane) to afford 12a (3 mg, 56%): 1H NMR δ 7.37 (m, 4H), 6.90 (m, 4H), 6.65 (d, 2H, J=8.4 Hz), 4.60 (d, t, 2H, J1=46 Hz, J2=4.0 Hz), 4.17 (t, 2H), 3.90 (t, 3H), 3.76 (t, 1H), 2.88 (s, 3H). Anal. (C19H22FNO2) C. H. N.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH:10]=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][C:26]([OH:28])=[O:27].C(=O)([O-])[O-].[K+].[K+].C(OC(=O)C)(=O)C>O>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7](/[CH:10]=[C:25](/[C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)\[C:26]([OH:28])=[O:27])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)Cc1cccs1
Reactant: CCCCc1ncc(C=O)n1Cc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCCCc1ncc(/C=C(\C(=O)O)c2cccs2)n1Cc1ccccc1Cl
Temperature: 140 °C
Reaction time: 6 h

Procedure:
A mixture of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde (2 mmol), 2-thienylacetic acid (2.3 mmol), potassium carbonate (0.91 mmol), and acetic anhydride (1 mL) is heated gradually to 140° C. and held at this temperature for 6 hours. The cooled reaction is diluted with water and the solid is separated, triturated several times with ether, and the solid is crystallized to give (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)-2-propenoic acid. The title tetrazole compound is prepared from this acid by the procedure described in Example 1.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:18][CH2:19][O:20][C:21]1[CH:34]=[CH:33][C:24]([CH:25]=[C:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:23][CH:22]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCOCC1.[Pd]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:18][CH2:19][O:20][C:21]1[CH:34]=[CH:33][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:23][CH:22]=1)[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(OCCN(Cc3ccccc3)c3nc4ccccc4s3)cc2)S1
Agent: [Pd]
Solvent: C1COCCO1
Product: O=C1NC(=O)C(Cc2ccc(OCCN(Cc3ccccc3)c3nc4ccccc4s3)cc2)S1

Procedure:
5-(4-(2-(N-(2-Benzothiazolyl)-N-benzylamino)ethoxy)benzylidene)-2,4-thiazolidinedione (2.4 g) in dioxan (150 ml) was hydrogenated in the presence of 10% palladium-charcoal (4.8 g) for 3 h. at room temperature and atmospheric pressure. A further portion of catalyst (2.4 g) was added and the hydrogenation continued for a total of 20 h. The mixture was filtered through diatomaceous earth and the solvent was evaporated. The residue was chromatographed on silica gel with 3% methanol-dichloromethane as eluant to afford the title compound as a foam, which collapsed at 78° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[N:3]=1.[CH3:10][S-:11].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][S:11][CH3:10])[N:3]=1
Reactant: BrCc1cccc(Br)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSCc1cccc(Br)n1
Temperature: 80 °C

Procedure:
2-Bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (0.20 g, 0.80 mmol) and sodium thiomethoxide (0.072 g, 1.04 mmol) were taken up in DMF (12.1 mL) heated at 80° C. for 3 hours. The reaction was then cooled to ambient temperature, diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography to yield the title compound. 1H NMR (600 MHz, CDCl3): 7.53 (t, J=9.0 Hz, 1H), 7.37 (d, J=9.0 Hz, 1H), 7.36 (d, J=9.0 Hz, 1H), 3.77 (s, 2H), 2.08 (2, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20]Cl)[O:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH:30]([CH:32]1[CH2:36][CH2:35][CH2:34][NH:33]1)[OH:31]>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20][N:33]4[CH2:34][CH2:35][CH2:36][C@@H:32]4[C@H:30]([C:26]4[O:25][CH:29]=[CH:28][CH:27]=4)[OH:31])[O:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Reactant: OC(c1ccco1)C1CCCN1
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCC[C@@H]3[C@@H](O)c3ccco3)oc21

Procedure:
Analogous to the procedures described in Example 59, N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 2) is treated with 2-furyl(pyrrolidin-2-yl)methanol (Preparation 73) to afford the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:35])=[C:13]([C:15]2[CH2:19][C:18]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[O:17][N:16]=2)[CH:14]=1)C1C=CC=CC=1.[H][H]>[Pd].CO>[C:31]([O:30][C:28](=[O:29])[CH2:27][C:18]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[O:17][N:16]=[C:15]([C:13]2[CH:14]=[C:9]([OH:8])[CH:10]=[CH:11][C:12]=2[CH3:35])[CH2:19]1)([CH3:34])([CH3:33])[CH3:32]
Reactant: [H][H]
Reactant: Cc1ccc(OCc2ccccc2)cc1C1=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(O)cc1C1=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C1
Yield: 71.7 %

Procedure:
A mixture of tert-butyl 3-(5-(benzyloxy)-2-methylphenyl)-5-(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (3.93 g), 10% Pd/C (containing about 55% water, 400 mg), and methanol (40 mL) was stirred at room temperature for 75 minutes in a hydrogen atmosphere. The catalyst was filtered off, and then, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (2.29 g).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(#N)C.[CH2:25](Br)[CH:26]=[CH2:27]>C(N(CC)CC)C>[CH2:27]([N:12]1[CH2:11][CH2:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:15][CH2:14][CH2:13]1)[CH:26]=[CH2:25]
Reactant: Oc1ccc(C2(c3ccccc3)CCNCCO2)cc1
Reactant: C=CCBr
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=CCN1CCOC(c2ccccc2)(c2ccc(O)cc2)CC1

Procedure:
The mixture of 11.2 g of 7-(4-hydroxyphenyl)-7-phenylhexahydro-1,4-oxazepine hydrochloride, 110 ml of dry acetonitrile. 14.0 g of triethylamine and 5.05 g of allyl bromide is stirred at room temperature for 48 hours. It is evaporated and the residue partitioned between benzene and 2N aqueous sodium hydroxide. The aqueous layer is separated, combined with a further basic extraction of the benzene solution, and the combined aqueous solutions are adjusted to 9 pH of 4-6.3 with acetic acid. The solid which separates is collected, dried and converted to the hydrochloride in acetone (mp. 150°-153°). The free base is liberated again and crystalized from ethanol, to yield the 4-allyl-7-(4-hydroxyphenyl)-7-phenyl-hexahydro-1,4-oxazepine melting at 205°-207°.
Reaction SMILES: [CH2:1]([OH:8])[C:2]([NH2:7])([CH2:5][OH:6])[CH2:3][OH:4].Cl.CO[C:12](OC)([CH3:14])[CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CN(C=O)C>[NH2:7][C:2]1([CH2:5][OH:6])[CH2:3][O:4][C:12]([CH3:14])([CH3:13])[O:8][CH2:1]1
Reactant: NC(CO)(CO)CO
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)OCC(N)(CO)CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
Tris hydrochloride (51 g, 324 mmol) was suspended in dry DMF (100 ml) and 2,2-dimethoxypropane (39 g, 374 mmol) was added followed by para-toluenesulfonic acid (2.6 g, 13.5 mmol). The mixture was stirred in a sealed flask for 18 h at ambient temperature when a clear solution resulted. Triethylamine (2.5 ml) was added and solvent evaporated. The viscous crude was dissolved in triethylamine (40 ml) and ethyl acetate (750 ml) added and the white precipitate of ammonium salts was filtered off after stirring for 30 mins. The filtrate was evaporated to give the product as a colourless liquid in approx. 85% yield.
Reaction SMILES: [NH:1]([C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH3:12])=[C:5]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]=1)[NH2:2].[CH3:20][C:21](=O)[CH2:22][C:23](=O)[CH3:24]>>[CH3:20][C:21]1[CH:22]=[C:23]([CH3:24])[N:1]([C:3]2[N:11]=[C:10]3[C:6]([N:7]=[CH:8][N:9]3[CH3:12])=[C:5]([NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:4]=2)[N:2]=1
Reactant: Cn1cnc2c(Nc3ccccc3)nc(NN)nc21
Reactant: CC(=O)CC(C)=O
Product: Cc1cc(C)n(-c2nc(Nc3ccccc3)c3ncn(C)c3n2)n1

Procedure:
Was prepared according to Example 9 from (2-hydrazino-9-methyl-9H-purin-6-yl)-phenyl-amine and 2,4-pentanedione.
Reaction SMILES: [N:1]1([C:6]2[S:7][CH:8]=[C:9]([CH2:11][OH:12])[N:10]=2)[CH:5]=[N:4][CH:3]=[N:2]1>C(Cl)(Cl)Cl.CO.O=[Mn]=O>[N:1]1([C:6]2[S:7][CH:8]=[C:9]([CH:11]=[O:12])[N:10]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: OCc1csc(-n2cncn2)n1
Agent: O=[Mn]=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=Cc1csc(-n2cncn2)n1

Procedure:
MnO2 (5.3 g; 60.9 mmol) was added to a solution of (2-[1,2,4]triazol-1-ylthiazole-4-yl)methanol (0.32 g; 2.25 mmol), prepared as described in the above step, in chloroform (15 ml) and methanol (1.5 ml).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([CH2:21][OH:22])=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:29])[CH:17]=4)[C:12]3=[O:30])=[CH:9][C:4]=2[O:3][CH2:2]1.[N:31]1[CH:36]=[CH:35][C:34]([CH2:37]O)=[CH:33][CH:32]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([CH2:21][O:22][CH2:37][C:34]4[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=4)=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:29])[CH:17]=4)[C:12]3=[O:30])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OCc1ccncc1
Reactant: O=c1c2ccc(Br)cc2c(-c2ccccc2)c(CO)n1Cc1ccc2c(c1)OCO2
Product: O=c1c2ccc(Br)cc2c(-c2ccccc2)c(COCc2ccncc2)n1Cc1ccc2c(c1)OCO2

Procedure:
The present compound was synthesized by a method similar to that in Example 240 and using 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-3-hydroxymethyl-4-phenyl-2H-isoquinolin-1-one (250 mg) and pyridin-4-ylmethanol. Colorless crystals (59 mg).
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:1]([O:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C([O-])c1ccccc1
Product: O=C(OC(=O)c1ccccc1)c1ccccc1

Procedure:
Moreover, in the case of benzoyl chloride, the resulting mixed anhydride is more reactive than benzoyl chloride. Thus, the carboxylate ion of acrylic acid preferentially reacts with the mixed anhydride to give acrylic anhydride and the benzoate ion, which subsequently reacts with unreacted benzoyl chloride to give benzoic anhydride, according to reaction scheme I.
Reaction SMILES: COC([NH:5][C@H:6]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=1)[C:7]([OH:9])=[O:8])=O.[BrH:20]>C(O)(=O)C>[BrH:20].[OH:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][C@@H:6]([NH2:5])[C:7]([OH:9])=[O:8])=[CH:17][CH:16]=1
Reactant: COC(=O)N[C@H](CCc1ccc(OC)cc1)C(=O)O
Agent: Br
Solvent: CC(=O)O
Product: N[C@H](CCc1ccc(O)cc1)C(=O)O
Temperature: 25 °C

Procedure:
A solution of (2R)-2-[(methoxycarbonyl)amino]-4-(4-methoxyphenyl)-butanoic acid (5.0 g, 18.7 mmol) in 5 mL of 30% HBr in acetic acid was heated at 60° C. overnight. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure to give the title compound as an orange solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].[CH3:12][O:13][CH2:14][CH2:15]Br>>[CH3:10][O:9][C:5]1[C:4]([O:11][CH2:15][CH2:14][O:13][CH3:12])=[C:3]([CH2:2][OH:1])[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc(CO)c1O
Reactant: COCCBr
Product: COCCOc1c(CO)cccc1OC

Procedure:
Analogously to Method F, 2.44 g of 2-hydroxymethyl-6-methoxyphenol and 2.56 g of 2-bromoethyl methyl ether are reacted and the title compound is obtained as a colourless oil. Rf=0.22 (1:1 EtOAc-heptane); Rt=2.91.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5](=[O:10])[C:6]([CH3:9])([CH3:8])[N:7]=1.[K+].[CH2:12]([O:14][C:15]([S-:17])=[S:16])[CH3:13]>C(#N)C>[CH2:12]([O:14][C:15](=[S:16])[S:17][CH2:2][C:3]1[O:4][C:5](=[O:10])[C:6]([CH3:9])([CH3:8])[N:7]=1)[CH3:13]
Reactant: CCOC(=S)[S-]
Reactant: CC1(C)N=C(CCl)OC1=O
Agent: [K+]
Solvent: CC#N
Product: CCOC(=S)SCC1=NC(C)(C)C(=O)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-chloromethyl-4,4-dimethyl-4H-oxazol-5-one (15.67 g; 97 mmol) and 125 mL acetonitrile was added O-ethyl xanthic acid potassium salt (15.55 g; 97 mmol). The mixture was stirred under a nitrogen atmosphere at room temperature for 16 hours. The reaction mixture was filtered and the solid was washed with 50 mL acetonitrile. The combined filtrate was concentrated under reduced pressure to afford 21.79 g (91%) of AzTC as a yellow crystalline solid.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:11]1([C:17]2[CH:31]=[CH:30][C:20]3[NH:21][C:22]([CH2:24][C:25]([O:27]CC)=O)=[N:23][C:19]=3[CH:18]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[NH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][C:34]=1[C:39]#[N:40]>C1COCC1>[NH2:40][C:39]1[C:34]2[C:33](=[CH:38][CH:37]=[N:36][CH:35]=2)[NH:32][C:25](=[O:27])[C:24]=1[C:22]1[NH:21][C:20]2[CH:30]=[CH:31][C:17]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)=[CH:18][C:19]=2[N:23]=1
Reactant: CCOC(=O)Cc1nc2cc(N3CCOCC3)ccc2[nH]1
Reactant: N#Cc1cnccc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1c(-c2nc3cc(N4CCOCC4)ccc3[nH]2)c(=O)[nH]c2ccncc12
Reaction time: 8 h

Procedure:
LiHMDS (3.3 eq) was added to ethyl (5-morpholin-4-yl-1H-benzimidazol-2-yl)acetate (1.0 eq) and 4-aminopyridine-3-carbonitrile (see J. Chem. Soc. 1967, p 1558–1564; 1.0 eq) in THF at 0° C. The reaction was stirred overnight. The resulting mixture was quenched with an aqueous saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield a brown solid. The crude material was washed successively with CH2Cl2 and MeOH, and then was purified by reverse phase HPLC to provide the desired product. LC/MS m/z 363.2 (MH+), Rt 1.55 minutes.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:14]([Sn](CCCC)(CCCC)CCCC)[CH:15]=[CH2:16].[Cl-].[Li+]>CN(C=O)C.C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:16]([C:2]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH:15]=[CH2:14]
Reactant: COC(=O)c1cc(F)c(F)cc1Br
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: C=CCc1cc(F)c(F)cc1C(=O)OC
Temperature: 90 °C
Yield: 78.1 %

Procedure:
A mixture of methyl 2-bromo-4,5-difluorobenzoate (0.5 g, 1.992 mmol), allyltributylstannane (0.679 mL, 2.191 mmol), lithium chloride (0.169 g, 3.98 mmol) in DMF (1 mL), acetonitrile (10 mL) was added bis(triphenylphosphine)palladium(ii) dichloride (0.070 g, 0.100 mmol). It was then degassed for 2 min, then filled with N2. After heating at 90° C. for 16 h, it was quenched with NH4Cl, extracted with EtOAc. The organic layer was washed with KF solution for 5 times, then dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 10% EtOAc/hexane to isolate methyl 2-allyl-4,5-difluorobenzoate (330 mg, 1.555 mmol, 78% yield) as an oil. 1H NMR (400 MHz, CDCl3) 7.78 (dd, J=11.1, 8.2 Hz, 1H), 7.11 (dd, J=11.1, 7.7 Hz, 1H), 5.98 (ddt, J=16.9, 10.2, 6.5 Hz, 1H), 5.16-5.02 (m, 2H), 3.91 (s, 3H), 3.76 (d, J=6.6 Hz, 2H).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[F:16])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:24])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:24][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:7])=[O:8])=[C:10]([F:16])[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)NC(C)(C)C)c(F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)NS(=O)(=O)c1ccc(CBr)cc1F
Yield: 79.5 %

Procedure:
A mixture of N-tert-butyl-2-fluoro-4-methylbenzenesulfonamide (2 g), NBS (1.16 g) and AIBN (40 mg) in CCl4 (25 ml) was refluxed for 3 hours. The reaction mixture was cooled, filtered and concentrated to give a viscous syrup, which was purified by silica gel column chromatography to give 1.68 g 4-(bromomethyl)-N-tert-butyl-2-fluorobenzenesulfonamide as a colorless crystal solid.
Reaction SMILES: C([N:8]1[CH2:14][CH2:13][NH:12][CH:11]([CH3:15])[C:10]2[C:16](=[O:21])[N:17]([CH3:20])[N:18]=[CH:19][C:9]1=2)C1C=CC=CC=1.C1CCCCC=1>[Pd].C(O)C>[CH3:15][CH:11]1[NH:12][CH2:13][CH2:14][NH:8][C:9]2[CH:19]=[N:18][N:17]([CH3:20])[C:16](=[O:21])[C:10]1=2
Reactant: CC1NCCN(Cc2ccccc2)c2cnn(C)c(=O)c21
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CC1NCCNc2cnn(C)c(=O)c21

Procedure:
0.38 g (2 mmol) of 1-benzyl-5,7-dimethyl-2,3,4,5-tetrahydro-6(7H)-pyridazino[4,5-b][1,5]diazepinone, 10 ml of abs. ethanol, 2 ml of cyclohexene and 0.20 g of Pd/C are warmed for 2 hours at 80° C. After cooling the mixture is filtered. The filtrate is evaporated and the residue is taken up in 10 ml of water, then it is shaken with 4×10 ml of ethyl acetate. The ethyl acetate phase is dried with anhydrous sodium sulphate and evaporated. The crystalline material obtained is recrystallized from 2 ml of ethyl acetate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:30][C:31]([CH3:37])=[C:32]([CH2:34][CH2:35]O)[N:33]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:35][CH2:34][C:32]2[N:33]=[C:29]([C:26]3[CH:25]=[CH:24][C:23]([C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:28][CH:27]=3)[S:30][C:31]=2[CH3:37])=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: Cc1sc(-c2ccc(C(C)(C)C)cc2)nc1CCO
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(C(C)(C)C)cc3)sc2C)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with 2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethanol (example 12 b]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(4-{2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3-fluoro-phenyl)-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-3-(4-{2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3-fluoro-phenyl)-2-ethoxy-propionic acid as colorless solid.