Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[CH2:5][NH:6][CH:7]([CH3:10])[CH2:8][OH:9].O1[CH2:17][CH:16]1[CH2:18][N:19]1C(=O)C2C(=CC=CC=2)C1=O.S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[CH2:5][N:6]1[C@H:7]([CH3:10])[CH2:8][O:9][C@H:16]([CH2:18][NH2:19])[CH2:17]1
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Reactant: CC(CO)NCc1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: C[C@@H]1CO[C@H](CN)CN1Cc1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 42 h
Yield: 72.3 %

Procedure:
A mixture of Intermediate 4 (0.470 g) and 2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione (0.410 g) was heated at 80° C. under nitrogen for 5 h. The mixture was treated with concentrated sulphuric acid (0.6 ml) then stirred at 150° C. for 42 h. The mixture was treated with water (50 ml) then washed with ethyl acetate (2×50 ml). The dark aqueous phase was basified to ˜pH 11 using 5M aqueous sodium hydroxide then extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with water and brine, dried (Na2SO4) and concentrated under vacuum to give the title compound as a brown oil (0.42 g).
Reaction SMILES: [CH3:1][C:2](=[O:23])[C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C@H:10]([CH2:11][C:12](=[O:22])[CH2:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[CH3:24][Mg]Cl>O1CCCC1>[CH3:1][C:2]([C@@H:3]1[C@@:20]2([CH3:21])[CH2:19][CH2:18][C@@H:17]3[C@@:15]4([CH3:16])[CH2:14][CH2:13][C@:12]([OH:22])([CH3:24])[CH2:11][C@@H:10]4[CH2:9][CH2:8][C@H:7]3[C@@H:6]2[CH2:5][CH2:4]1)=[O:23]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@](C)(O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 6 h

Procedure:
5α-Pregnane 3,20-dione (10 g) is reacted with a reagent obtained by reacting FeCl3 (5.2 g) and MeMgCl (4 equiv, based on FeCl3) in anhydrous tetrahydrofuran (200 mL) at −25° C. for 3 h. The reaction is quenched with acetic acid (32 ml). The reaction mixture is concentrated in vacuo and the residue is stirred with 3N HCl for 6 h. The solid is collected by filtration, washed with water and dried at 50° C. under vacuum to obtain crude ganaxolone. The crude product is dissolved in THF (33 mL) at reflux and filtered hot. The filtrate is added with water (45 mL) to obtain a suspension, which is collected by filtration, washed with water and dried. The dried product is further slurried in ethyl acetate (50 mL) at 70° C. for 19 h. The suspension is cooled to 0° C. and filtered, washed with cold ethyl acetate and dried to obtain ganaxolone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:12]=[C:13]2[C:18](=[O:19])[NH:17][NH:16][CH:15]=[C:14]2[N:20]=1.[OH:21]O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:10])=[O:21])[CH:6]=[CH:5][C:4]=1[C:11]1[N:12]=[C:13]2[C:18](=[O:19])[NH:17][NH:16][CH:15]=[C:14]2[N:20]=1
Reactant: OO
Reactant: COc1cc(SC)ccc1-c1nc2c[nH][nH]c(=O)c-2n1
Solvent: CC(=O)O
Product: COc1cc(S(C)=O)ccc1-c1nc2c[nH][nH]c(=O)c-2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
An amount of 0.21 gm of 2-(2-methoxy-4-methylmercapto-phenyl)-5H-imidazo[4,5-d]pyridazin-4-one is suspended in 10 ml of glacial acetic acid and mixed with 0.08 ml of 30% hydrogen peroxide. The mixture is stirred for 24 hours at ambient temperature and poured onto 20 ml of ice water. It is then stirred until a precipitate has formed. This is subjected to suction filtration and purified by chromatography on silica gel [eluant: methylene chloride/ethanol (100:0 to 100:3)].
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:25])[CH2:7][C:8]1[N:9]=[N:10][N:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:12]=1)C>O.C(O)C>[CH2:13]([N:11]1[N:10]=[N:9][C:8]([CH2:7][C:6]([OH:25])=[O:5])=[N:12]1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCn1nnc(CC(=O)OCC)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCn1nnc(CC(=O)O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
A solution of KOH (4.21 g, 0.075 mol) in water (10 mL) was added to a solution of the 2-dodecyltetrazole acetic acid ethyl ester (23.2 g, 0.0715 mol) in ethanol (250 mL). The mixture was stirred at room temperature for 3 hours, concentrated in vacuo to ~50 mL, diluted with water (200 mL), and washed with ethyl acetate (100 mL). The aqueous layer was acidified with 1.0M HCl and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated to give 18.0 g, 85% of a white solid, mp 70°-73° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[O:22][CH3:23])=[CH:4][CH:3]=1.[CH2:24]([CH:26]([CH2:30][CH2:31][CH2:32][CH3:33])[C:27](Cl)=[O:28])[CH3:25]>>[CH2:24]([CH:26]([CH2:30][CH2:31][CH2:32][CH3:33])[C:27]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[O:22][CH3:23])=[CH:4][CH:3]=1)=[O:28])[CH3:25]
Reactant: CCCCC(CC)C(=O)Cl
Reactant: COC(=O)c1ccc(Cn2ncc3ccc(N)cc32)c(OC)c1
Product: CCCCC(CC)C(=O)Nc1ccc2cnn(Cc3ccc(C(=O)OC)cc3OC)c2c1
Yield: 68 %

Procedure:
Using an analogous procedure to that described in Example 1, but starting from methyl 4-(6-aminoindazol-1-ylmethyl)-3-methoxybenzoate and 2-ethylhexanoyl chloride, there was obtained methyl 4-[6-(2-ethylhexanamido)indazol-1-ylmethyl]-3-methoxybenzoate in 68% yield as a white solid, m.p. 135.5°-136.5° C.; microanalysis, found: C, 68.37; H, 7.10; N, 9.43%; C25H31,N3O4 requires: C, 68.64; H, 7.14; N, 9.60%.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])[O:7][C:8]=1[C:9]1[CH:28]=[CH:27][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)(=[O:3])[NH2:2].Cl.O1CCOCC1.C([O-])=O>C(Cl)Cl>[F:35][C:34]1[CH:33]=[CH:32][CH:31]=[C:30]([F:36])[C:29]=1[C:6]1[O:7][C:8]([C:9]2[CH:10]=[CH:11][C:12]([CH2:13][N:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)=[CH:27][CH:28]=2)=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3oc(-c4c(F)cccc4F)nc3C(N)=O)cc2)CC1
Agent: Cl
Agent: O=C[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(CN2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of tert-butyl 4-(4-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-yl)benzyl)piperazine-1-carboxylate (0.100 g, 0.2 mmol) in DCM (3 mL) was added 4M HCl in dioxane (2 mL, 8.0 mmol) and the resulting mixture stirred at room temperature overnight. The solvent was removed in vacuo. The residue was purified by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(4-(piperazin-1-ylmethyl)phenyl)oxazole-4-carboxamide (0.043 g, 0.1 mmol, 50%) as a white solid as the formate salt. 1H NMR (DMSO) 2.44 (4H, m), 2.88 (4H, m), 3.55 (2H, s), 7.40 (2H, t), 7.47 (2H, d), 7.75 (3H, m), 8.19 (2H, d), 8.32 (1H, s). LCMS (2) Rt: 2.63 min; m/z (ES+) 399.
Reaction SMILES: C(O[C:4](=[O:18])[CH2:5][CH2:6][C:7]1([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:10][CH2:9][CH2:8]1)C.[H-].[Na+].C(O)(=O)C>O1CCCC1>[O:18]=[C:4]1[CH2:5][CH2:6][C:7]2([CH2:8][CH2:9][CH2:10]2)[CH2:11][CH:12]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CCC1(CCC(=O)OCC)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C1CC2(CCC2)CCC1=O

Procedure:
20.6 mmol of 3-[1-(ethoxycarbonylethyl)cyclobutyl]propionic acid ethyl ester in solution in tetrahydrofuran are added at 0° C. to 22.7 mmol of 95% sodium hydride in suspension in 15 ml of tetrahydrofuran. The reaction mixture is refluxed for 4 hours and then 49 ml of acetic acid are added. The tetrahydrofuran is evaporated off and the residue obtained is extracted with ethyl acetate. The combined organic phases are washed, filtered, dried and evaporated to yield an oil, which is subjected to chromatography on silica (eluant: dichloromethane/ethyl acetate 95/5) to yield the expected product.
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O)C([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=CC=2)(=O)=O)C=CC=CC=1.[CH:28]12[N:35]([S:36]([CH2:39][C:40]3[C:45]([C:46]([O:48][CH3:49])=[O:47])=[C:44]([O:50][CH3:51])[C:43](Br)=[CH:42][CH:41]=3)(=[O:38])=[O:37])[CH:32]([CH2:33][CH2:34]1)[CH2:31][CH2:30][CH2:29]2>>[CH:28]12[N:35]([S:36]([CH2:39][C:40]3[C:45]([C:46]([O:48][CH3:49])=[O:47])=[C:44]([O:50][CH3:51])[C:43]([C:23]4[CH:27]=[CH:26][O:25][CH:24]=4)=[CH:42][CH:41]=3)(=[O:38])=[O:37])[CH:32]([CH2:33][CH2:34]1)[CH2:31][CH2:30][CH2:29]2
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Reactant: COC(=O)c1c(CS(=O)(=O)N2C3CCCC2CC3)ccc(Br)c1OC
Product: COC(=O)c1c(CS(=O)(=O)N2C3CCCC2CC3)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 6-(8-azabicyclo[3.2.1]octane-8-ylsulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 186) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[N:9]=[C:10]2[N:14]([CH:15]=1)[CH:13]=[C:12](Br)[S:11]2)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20](=[O:53])[NH:21][C@H:22]([C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C:33]1[NH:34][C:35]([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)=[CH:36][N:37]=1)=[O:27])[CH:23]([CH3:25])[CH3:24]>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[N:9]=[C:10]2[N:14]([CH:15]=1)[CH:13]=[C:12]([C:41]1[CH:42]=[CH:43][C:38]([C:35]3[NH:34][C:33]([C@@H:29]4[CH2:30][CH2:31][CH2:32][N:28]4[C:26](=[O:27])[C@@H:22]([NH:21][C:20]([O:19][CH3:18])=[O:53])[CH:23]([CH3:25])[CH3:24])=[N:37][CH:36]=3)=[CH:39][CH:40]=1)[S:11]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)Nc1cn2cc(Br)sc2n1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3cn4cc(NC(=O)OC(C)(C)C)nc4s3)cc2)[nH]1)C(C)C
Yield: 22 %

Procedure:
Compound A35 was synthesized from compound 10 (0.126 mmol) and compound 8 (0.164 mmol), following the procedure as described for compound A1, as a white lyophilized solid in 22% yield. MS (ESI, EI+) m/z=608.35 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=1.C1(=O)O[CH2:14][CH2:13][O:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:14][CH2:13][OH:12])[CH:3]=1
Reactant: O=C1OCCO1
Reactant: N#Cc1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Br)cc1OCCO
Temperature: 125 °C
Yield: 56.1 %

Procedure:
4-Bromo-2-hydroxybenzonitrile (1.00 g, 5.05 mmol), ethylene carbonate (467 mg, 5.30 mmol) and potassium carbonate (348 mg, 2.52 mmol) were suspended in DMF (2.00 mL) and heated to 125° C. for 4.5 h. The mixture was partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane to give the title compound (686 mg, 56%). 1H NMR (300 MHz, d4-MeOD): 3.92 (2H, t, J=4.7 Hz), 4.21 (2H, t, J=4.7 Hz), 7.26 (1H, dd, J=8.2, 1.7 Hz), 7.44 (1H, d, J=1.6 Hz), 7.53 (1H, d, J=8.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](I)=[CH:15][C:14]=3[O:22][CH3:23])=[O:9])=[CH:4][CH:3]=1.[CH2:26]([O:29][CH3:30])[C:27]#[CH:28].O>C(NCC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:28]#[C:27][CH2:26][O:29][CH3:30])=[CH:15][C:14]=3[O:22][CH3:23])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cc(I)cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Reactant: C#CCOC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCNCC
Product: COCC#Cc1cc(OC)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 46 %

Procedure:
N-(4-chlorobenzyl)-4-hydroxy-6-iodo-8-methoxy-3-quinolinecarboxamide (469 mg) from Example No. 117, copper (I) iodide (57 mg), and bis(triphenylphosphine)-palladium (II) chloride (35 mg) are suspended in diethylamine (15 mL). Methyl propargyl ether (101 μL) is added and the mixture is allowed to stir at rt for 64 h. The reaction mixture is poured into water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layer is washed with saturated aqueous ammonium chloride (3×10 mL) and brine (10 mL). The aqueous layer is back-extracted with ethyl acetate (20 mL). The combined organic layers are dried (MgSO4) and concentrated. The crude product is purified by column chromatography (heptane/2-propanol, 12/1; 10/1; 5/1) to afford 188 mg (46%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][CH:13]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]4[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:21]=4[N:22]=3)[CH2:14]2)[CH:6]=1.I[CH2:30][CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]([CH2:30][CH2:31][CH2:32][CH3:33])[CH:13]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]4[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:21]=4[N:22]=3)[CH2:14]2)[CH:6]=1
Reactant: CCCCI
Reactant: COC(=O)Cc1cccc(CNC2CCN(c3nc4ccc(Cl)cc4s3)C2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCN(Cc1cccc(CC(=O)OC)c1)C1CCN(c2nc3ccc(Cl)cc3s2)C1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 36 %

Procedure:
A mixture of [3-[[1-(6-chlorobenzothiazole-2-yl)pyrrolidine-3-ylamino]methyl]phenyl]acetic acid methyl ester (68 mg), 1-iodobutane (37 μL), potassium carbonate (45 mg) and dimethylformamide (1 mL) was stirred at 80° C. for 3.5 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The residue was purified by column chromatograph on silica gel to give the title compound (28 mg). Yield: 36%.
Reaction SMILES: [OH:1][C:2]1([C:15]([OH:17])=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.S(=O)(=O)(O)O.[C:23](=O)([O-])O.[Na+]>CO>[OH:1][C:2]1([C:15]([O:17][CH3:23])=[O:16])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: O=C([O-])O
Reactant: O=C(O)C1(O)c2ccccc2-c2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(O)c2ccccc2-c2ccccc21

Procedure:
50.4 g (0.223 mol) of 9-hydroxy-9-fluorenecarboxylic acid are dissolved in 500 mL of methanol, combined with 5 mL (0.089 mol) of concentrated sulfuric acid and refluxed for 1 hour. After cooling, 100 mL of sodium hydrogen carbonate solution (about pH 8) are added and the methanol is largely evaporated down. The mixture is extracted with dichloromethane and water, the organic phase is dried and evaporated to dryness. The product is purified by recrystallization from ethyl acetate. Yield: 50.0 g of white crystals (93% of theoretical yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([CH:10]=O)=[CH:7][CH:8]=[CH:9][C:2]1=2.O.[C:13]([O:16][CH2:17]C)(=O)C>O1CCCC1>[CH3:13][O:16][CH:17]=[CH:10][C:6]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=Cc1cccc2sccc12
Reactant: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC=Cc1cccc2sccc12
Temperature: -60 °C
Reaction time: 8 h

Procedure:
In an atmosphere of nitrogen, 4.85 g of (methoxymethyl)triphenylphosphonium chloride is suspended in 40 mL of tetrahydrofuran. Then, 1.5 mL of diisopropylamine is added to the suspension, and cooled to −60° C. After dropwise adding thereto 6.6 mL of 1.6 mol/L solution of n-butyllithium in hexane, the mixture thus obtained is stirred for 30 minutes at an ice-cooled temperature. Then, the reaction mixture is cooled to −60° C., a solution of 1.72 g of benzo[b]thiophene-4-carboaldehyde in 15 mL of tetrahydrofuran is dropwise added, and the resulting mixture is allowed to stand overnight at ambient temperature. The reaction mixture is introduced into a mixture of water and ethyl acetate, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, the residue is treated with diethyl ether, and the deposited crystal is filtered off. The solvent is distilled off from the filtrate under reduced pressure, and the residue thus obtained is purified by column chromatography (eluent: n-hexane:ethyl acetate=100:1 to 50:1) to obtain 1.04 g of 2-benzo[b]thiophen-4-yl-1-ethenyl methyl ether as an oily product.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=[O:13])[NH:8][C:7]=1[CH3:14])=[O:5])C.[OH-].[K+].O>CO>[CH:12]([C:9]1[NH:8][C:7]([CH3:14])=[C:6]([C:4]([OH:5])=[O:3])[C:10]=1[CH3:11])=[O:13]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1[nH]c(C=O)c(C)c1C(=O)O
Temperature: 8 °C
Yield: 93.5 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (806 g), potassium hydroxide (548 g), water (2400 mL) and methanol (300 mL) were refluxed for two hours with stirring and then cooled to 8° C. The mixture was extracted twice with dichloromethane. The aqueous layer was adjusted to pH 4 with 1000 mL of 10 N hydrochloric acid keeping the temperature under 15° C. Water was added to facilitate stirring. The solid was collected by vacuum filtration, washed three times with water and dried under vacuum at 50° C. to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic (645 g, 93.5% yield) acid as a yellow solid. NMR (DMSO-d6) δ2.40, 2.43 (2×s, 2×3H, 2×CH3), 9.57 (s, 1H, CHO), 12.07 (br s, 2H, NH+COOH). MS m/z 168 [M+1].
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[S:10][CH:11]=[C:12]([Sn](C)(C)C)[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][N:23]2[C:26](I)=[CH:27][N:28]=[C:22]2[CH:21]=1.[Li+].[Cl-]>O1CCOCC1.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>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[S:10][CH:11]=[C:12]([C:26]2[N:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][C:22]3=[N:28][CH:27]=2)[N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1nc([Sn](C)(C)C)cs1
Reactant: Clc1ccn2c(I)cnc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1nc(-c2cnc3cc(Cl)ccn23)cs1
Temperature: 90 °C
Yield: 38.8 %

Procedure:
To a solution of (4-trimethylstannyl-thiazol-2-ylmethyl)-carbamic acid tert-butyl ester (0.480 g, 1.27 mmol, 1.0 eq.) [prepared as in the PCT application WO2004046101, Jun. 3, 2004, filed Nov. 10, 2003] in anhydrous dioxane (4 mL), add 7-chloro-3-iodo-imidazo[1,2-a]pyridine (0.354 g, 1.27 mmol, 1.0 eq.) and LiCl (0.162 g, 3.0 eq.). Add Pd(PPh3)4 (0.102 g, 0.07 eq.). Deoxygenate the reaction mixture and fill with nitrogen. Stir at 90° C. over night, cool, then dilute with 5% MeOH/DCM (100 mL), wash with saturated aqueous saturated sodium chloride (2×20 mL), water (2×20 mL), dry, filter, and concentrate. Chromatograph on silica gel first with a 50%-100% EtOAc/DCM gradient then a 5% MeOH/DCM gradient to afford 0.180 g of the title compound, which is used in the next step without further purification: MS(ES), m/z 365 (M+1).
Reaction SMILES: [H-].[Na+:2].CN(C=O)C.[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]>CCCCCCC>[Na:2][CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:8]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: [Na+]
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: CCOC(=O)C([Na])C(=O)OCC
Reaction time: 0.5 h

Procedure:
Wash 29 g (2 equiv.) of NaH (60% dispersion in oil) with heptane (2×80 mL). Combine the washed Nail with 60 mL of DMF, then slowly add 11.0 g (68.8 mmol) of diethyl malonate while keeping the reaction temperature below 30° C. Stir the resulting mixture for 30 min to form a solution of diethyl sodiomalonate.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:28].[NH+]1C=CC=CC=1>C1COCC1>[Br:28][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)=[O:9]
Reactant: Br
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)Cc3ccccc3)cc2)CCC1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A mixture of tert-butyl {1-[4-(phenylacetyl)phenyl]cyclobutyl}carbamate (5.0 g, 13.68 mmol, 1.0 eq) and pyridinium hydrobromide perbromide (4.38 g, 13.68 mmol, 1.0 eq) in THF (78 mL) was stirred at 0° C. for 30 minutes. The mixture was partitioned between EtOAc and water, and the organic phase washed with an aqueous sodium thiosulfate solution and brine, dried, filtered through a silicone coated filter paper, and concentrated in vacuo to give the crude title compound (5.44 g, 93% purity by UPLC-MS) which was used without further purification.