Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:31][CH:30]([C:32]2[NH:33][CH:34]=[CH:35][N:36]=2)[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37]N(C=O)C.[H-].[Na+].CI>C1COCC1>[CH2:1]([N:8]1[CH2:31][CH:30]([C:32]2[N:36]([CH3:37])[CH:35]=[CH:34][N:33]=2)[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(c2ncc[nH]2)O3)ccc1OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(c2nccn2C)O3)ccc1OC(C)C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
[8-Benzyl-10-(1H-imidazol-2-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (233 mg, 0.48 mmol) was suspended in a mixture of anhydrous DMF (1.5 mL)/THF (0.1 mL) under an atmosphere of nitrogen at 0° C. NaH (19 mg, 0.48 mmol) was added and the reaction mixture was stirred for 30 minutes, then MeI (68 mg, 30 μL, 0.48 mmol) was added and the reaction mixture was stirred for 10 minutes. The reaction mixture was quenched with water and diluted with EtOAc, the layers were separated and the aqueous layer was extracted once more with EtOAc. The combined organics were washed with brine solution (2×5 mL), dried over Na2SO4, filtered and concentrated in vacuo to an oil. The residue was purified by silica gel column chromatography using 0-5% MeOH in DCM to yield [8-benzyl-10-(1-methylimidazol-2-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (205 mg, 86%) as a white foam. ESI-MS m/z calc. 502.3. Found 503.1 (M+1)+; Retention time: 1.51 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 7.38-7.30 (m, 4H), 7.25 (ddd, J=8.4, 5.9, 2.2 Hz, 1H), 7.19 (d, J=7.0 Hz, 2H), 7.10 (d, J=1.1 Hz, 1H), 6.96 (t, J=5.9 Hz, 1H), 6.75 (d, J=1.1 Hz, 1H), 4.96 (ddd, J=9.9, 6.7, 2.4 Hz, 1H), 4.68-4.59 (m, 1H), 3.70 (s, 3H), 3.53 (td, J=13.6, 9.0 Hz, 3H), 3.30-3.15 (m, 2H), 2.93 (dd, J=11.1, 0.7 Hz, 1H), 2.74-2.69 (m, 1H), 2.66-2.52 (m, 2H), 2.13 (s, 3H), 1.95-1.86 (m, 1H), 1.61-1.33 (m, 4H), 1.28 (d, J=6.9 Hz, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:13])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=O)([O-:3])=[O:2].[CH:14]([NH2:16])=O>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:7]([C:8](=[O:10])[NH:16][CH:14]=[N:13]2)=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: NC=O
Product: O=c1[nH]cnc2cc([N+](=O)[O-])ccc12
Temperature: 165 °C
Yield: 94.9 %

Procedure:
A mixture of 4-nitroanthranilic acid (2.17 g, 11.91 mmol) and formamide (1.5 mL, 38.43 mmol) was heated at 165° C. for 4 hours. The warm reaction mixture was poured into ice/water (30 mL) and the resulting precipitate was collected via filtration, to give an orange solid (2.16 g, 95% yield) which was dried over P2O5. This was used without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH2:13][CH2:14][CH:15]=[C:16]([CH3:23])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[C:5](=[O:12])[CH2:6][C:7](OCC)=O.Br[CH2:25][C:26](C)=[CH:27][CH2:28][CH2:29][C:30]([CH3:37])=[CH:31][CH2:32][O:33]C(=O)C>CCOCC>[CH3:37][C:30]([CH2:29][CH2:28][CH:27]=[C:26]([CH3:25])[CH2:7][CH2:6][C:5](=[O:12])[CH:4]([CH3:3])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:23])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:21])[CH3:22])=[CH:31][CH2:32][OH:33]
Reactant: CC(=O)OCC=C(C)CCC=C(C)CBr
Reactant: CCOC(=O)CC(=O)C(C)CCC=C(C)CCC=C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)=CCCC(C)=CCCC(C)C(=O)CCC(C)=CCCC(C)=CCO
Temperature: 0 °C
Yield: 96.2 %

Procedure:
To a suspension of sodium hydride (2.64 g) in ether (70 ml), a solution of ethyl 3,7,11-trimethyl-6,10-dodecadien-2-one-1-carboxylate (14.7 g) in ether (15 ml) is dropwise added, and then a solution of 1-bromo-8-acetoxy-2,6-dimethyl-2,6-octadiene (15 g) in ether (15 ml) is dropwise added thereto while cooling with ice. The reaction mixture is poured into ice water. The ether layer is washed with water, dried and evaporated. The residue (24.8 g) is added to a solution of potassium hydroxide (8.4 g) in ethanol (150 ml), and the resultant mixture is poured into water, followed by washing with petroleum ether, acidifying with 5% aqueous solution of sulfuric acid and extracting with ether. The ether layer is washed with water, dried and evaporated. The resulting product (23.5 g) is purified by chromatography on silica gel (235 g) using benzene to give 3,7,11,15,19-pentamethyl-2,6,14,18-eicosatetraen-10-on-1-ol (18 g). IR: 3400, 1000 cm-1 (OH): 1705 cm-1 (C=O); 1668 cm-1 (C=C). NMR (carbon tetrachloride): δ 1.04 (d), 1.59 (s), 1.66 (s), 2.01 (m), 2.7 (m), 4.1 (m), 5.05 (m).
Reaction SMILES: [CH2:1]([N:3]1[C:8]2=[N:9][C:10]([S:13][CH3:14])=[N:11][CH:12]=[C:7]2[CH2:6][N:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([N+:22]([O-])=O)[CH:16]=2)[C:4]1=[O:25])[CH3:2]>C(OCC)(=O)C.CO.[Pd]>[NH2:22][C:17]1[CH:16]=[C:15]([N:5]2[CH2:6][C:7]3[C:8](=[N:9][C:10]([S:13][CH3:14])=[N:11][CH:12]=3)[N:3]([CH2:1][CH3:2])[C:4]2=[O:25])[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: CCN1C(=O)N(c2ccc(F)c([N+](=O)[O-])c2)Cc2cnc(SC)nc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCN1C(=O)N(c2ccc(F)c(N)c2)Cc2cnc(SC)nc21
Yield: 30 %

Procedure:
To a solution of 1-ethyl-3-(4-fluoro-3-nitrophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (2.4 g, 6.5 mmol) in ethyl acetate and methanol (1:1, 40 mL) was added Pd/C (230 mg) and the mixture was hydrogenated (55 psi) in a Parr shaker for 2 days. The reaction mixture was filtered and the filter cake was washed with methanol. The combined filtrates were concentrated in vacuo. The residue was dissolved in THF and the solid was filtered. The filtrate was concentrated and purified by silica gel column chromatography to obtain 3-(3-amino-4-fluorophenyl)-1-ethyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.65 g, 30% yield). 1H-NMR (400 MHz, DMSO-d6): δ 8.20 (s, 1 H), 6.97 (m, 1 H), 6.70 (dd, J=8.0, 2.4 Hz, 1 H), 6.46 (m, 1 H), 5.21 (s, 2 H), 4.64 (s, 2 H), 3.94 (q, J=6.8 Hz, 2 H), 2.48 (s, 3 H), 1.15 (t, J=6.8 Hz, 3 H); MS (ESI) m/z: 334.1 (M+H+).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([C:25]([O:27][CH3:28])=[O:26])[CH:19]=2)[CH2:14][C@H:13]1[O:29][CH3:30])=O)C1C=CC=CC=1>[C].[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([C:25]([O:27][CH3:28])=[O:26])[CH:19]=2)[CH2:14][C@H:13]1[O:29][CH3:30]
Reactant: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)cc(C)n1
Agent: [Pd]
Product: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)cc(C)n1
Yield: 100.5 %

Procedure:
The same operation as in Example (160c) was performed using methyl cis(±)-4-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-6-methylpyridine-2-carboxylate obtained in Example (168a) (190 mg) and a 10% palladium-carbon catalyst (200 mg), to obtain 129 mg of the title compound as a colorless oily substance. The resulting compound was used for the next reaction without purification.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][C:18]([CH3:24])([CH3:23])[CH2:17][C:16]3([CH3:26])[CH3:25])=[CH:7][CH:6]=1.[OH-].[Na+]>CO>[CH3:23][C:18]1([CH3:24])[CH2:17][C:16]([CH3:25])([CH3:26])[C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:12]#[C:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:27])=[O:2])=[CH:10][CH:9]=3)[CH:14]=2)[O:19]1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CC(C)(C)c2cc(C#Cc3ccc(CC(=O)O)cc3)ccc2O1
Temperature: 55 °C
Yield: 75.1 %

Procedure:
A solution of [4-(2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)phenyl]acetic acid methyl ester (Compound 27, 0.047 g, 0.13 mmol) in 5 mL of methanol was treated with 1M sodium hydroxide solution (2 mL) and heated at 55° C. for 2 h. The volatiles were distilled off in vacuo and the residue was acidified with 10% hydrochloric acid and extracted with ethyl acetate (×2). The combined organic phase was washed with brine (×1), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which was purified by preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase to afford the title compound (0.034 g, 82%). 1H NMR (300 MHz, CDCl3): δ7.49-7.45 (m, 3H), 7.26-7.22 (m, 3H), 6.75 (d, 1H, J=8.2 Hz), 3.65 (s, 2H), 1.84 (s, 2H), 1.36 (s, 6H), 1.35 (s, 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:20]([O:19][C:17](=[O:18])[CH2:16][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
A mixture of ethyl 1H-indole-2-carboxylate (5.68 g, 30 mmol), tert-butyl 2-bromoacetate (6.44 g, 33 mmol), and potassium carbonate in 60 mL of DMF was heated to 80° C. for 2 days. The TLC showed that the reaction stopped at around 50% completion. The reaction was worked up by the addition of water and the aqueous phase was extracted with EtOAc (2×30 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by Combiflash (40 g silica gel cartridge, 0-30% EtOAc in hexane) to afford the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH3:38][Zn]C>C1(C)C=CC=CC=1>[F:36][C:30]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=1[S:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:38])[N:7]=2)[C:20]=1[F:37])(=[O:28])=[O:27]
Reactant: C[Zn]C
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Solvent: Cc1ccccc1
Product: Cc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 25 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (150 mg, 0.265 mmol) and 2N dimethylzinc in toluene ((0.265 mL, 0.529 mmol), the title compound was obtained as a solid (116 mg, 73% yield). MS (ESI): 547 [M+H]+.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][OH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:25]>C(OCC)(=O)C>[C:24](=[O:25])([O:12][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[O:26][C:27]1[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1CO
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1COC(=O)Oc1ccc([N+](=O)[O-])cc1
Yield: 91.2 %

Procedure:
The alcohol 29 (135 mg, 0.56 mmol) is dissolved in ethyl acetate (0.82 ml). Pyridine (0.081 ml) is then added, followed by 4-nitrophenyl chloroformate (275 mg, 2.4 eq.). After one night at room temperature, the solvent is evaporated off. Chromatography on silica gel gives the carbonate 30 (206 mg, 91%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11].[CH3:13]OC(OC)(C)C.S(=O)(=O)(O)O>CO>[C:10]([CH:2]1[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)([O:12][CH3:13])=[O:11]
Reactant: COC(C)(C)OC
Reactant: O=C(O)C1Cc2ccccc2C1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 144 h
Yield: 96.1 %

Procedure:
Dissolve 2-indancarboxylic acid (3.82 g, 23.5 mmol) in methanol (60 mL) and treat with dimethoxypropane (5.8 mL, 47 mmol) and sulfuric acid (0.8 mL). Stir at room temperature for 6 days. Evaporate the solvent in vacuo, dilute with methylene chloride (75 mL) and wash with saturated sodium hydrogen carbonate (35 mL). Extract the aqueous phase with methylene chloride (30 mL), wash combined organics with brine (30 mL) and dry (Na2SO4). Evaporate the solvent in vacuo and pass through a plug of silica gel to give 2-(carbomethoxy)indane as a yellow oil (3.98 g, 96%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:3]=1.[Li+].CC([N-]C(C)C)C.[CH3:26][S:27]SC>C1COCC1>[F:1][C:2]1[C:7]([S:27][CH3:26])=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][CH:9]=2)[N:3]=1
Reactant: Fc1cccc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: CSSC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ccc(-c2ccc(C(F)(F)F)cc2)nc1F
Temperature: -20 °C
Yield: 41.8 %

Procedure:
To a solution of 2-fluoro-6-(4'-trifluoromethyl-phenyl)pyridine (2.4 g, 10 mmol, prepared according to example 17) in dry THF (35 mL) is added dropwise a solution of 2M LDA in THF (7.5 mL, 15 mmol) at -70° C. After 2 hours at -70° C. dimethyl disulfide (1.41 g, 15 mmol) is added and the reaction mixture is allowed to warm at -20 ° C. The mixture is hydrolysed and extracted with diethylether. After separation the organic layer is dried with anhydrous magnesium sulphate. The solvents are removed and the crude product is purified by flash column chromatography (silica gel). Elution with hexane/ethyl acetate (20/1 v/v) gives the title compound (1.2 g, 42%) with mp 70°-73° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@H:27]([CH2:28][OH:29])[CH2:26][O:25][C:24]4=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].I[CH3:34].O>CN(C)C=O>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@H:27]([CH2:28][O:29][CH3:34])[CH2:26][O:25][C:24]4=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CI
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)cc3)CC2)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9 %

Procedure:
(R)-3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-4-hydroxymethyloxazolidin-2-one (205 mg) described in Example 72 was dissolved in N,N-dimethylformamide (1 mL), sodium hydride (32 mg) was added, and the mixture was stirred at room temperature for 30 min. Iodomethane (142 mg) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol) to give the title compound (19 mg).
Reaction SMILES: [N:1]1([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:5][CH2:4][CH:3]([C:6]([O:8]C(C)(C)C)=[O:7])[NH:2]1.Cl.CCOCC>ClCCl>[C:17]1([CH2:16][O:15][C:13]([N:1]2[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=[O:7])[NH:2]2)=[O:14])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)C1CCN(C(=O)OCc2ccccc2)N1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
At r.t., to a 50 mL round bottomed flask containing crude 3-(1,1-dimethylethyl) 1-(phenylmethyl) 1,3-pyrazolidinedicarboxylate (88 mg) in dichloromethane (DCM) (0.5 mL), was added HCl in ether (2M) (3.59 mL, 7.18 mmol), then the reaction vessel was equipped with a glass stopper. The reaction mixture was stirred at r.t. for 48 hr. The solid was filtered and washed with ether, providing the product as an off-white solid. (58.4 mg, 71% over two steps).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12](Cl)=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][OH:22])=[CH:19][CH:18]=1.CN(C)C.O>O1CCCC1>[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:22][C:12](=[O:13])[CH:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=2)[CH3:15])=[CH:19][CH:18]=1
Reactant: Cc1ccc(CO)cc1
Reactant: CC(C)Cc1ccc(C(C)C(=O)Cl)cc1
Agent: CN(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(COC(=O)C(C)c2ccc(CC(C)C)cc2)cc1
Yield: 84.5 %

Procedure:
To a solution of 5.4 g of 2-(4-isobutylphenyl)propionic acid chloride and 3.5 g of p-methylbenzyl alcohol in 30 ml of tetrahydrofuran was added 3.7 g of trimethylamine, dropwise under cooling, and reacted at room temperature for 2 hours. After the reaction was complete, the crystals produced were removed by filtration. The filtrate was freed of solvent by distillation to leave a residue, to which was added water. The resulting mixture was extracted with ether, and the extract was dehydrated and freed of solvent by distillation to give an oily residue. This residue was then distilled in vacuo to yield 6.3 g of 2-(4-isobutylphenyl)propionic acid-p-methylbenzyl ester as a colorless oil, boiling at 139°-140° C./0.1 mmHg. Mass spectrum: parent ion 310 m/e.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[C:14]([N+:22]([O-])=O)[CH:13]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])O.[K+].[H][H]>CO.O.[Pd]>[C:1]1([S:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[C:14]([NH2:22])[CH:13]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1N
Yield: 57.8 %

Procedure:
N-benzenesulfonyl-4-acetylamino-3-nitrobenzamide (12.67 g) was dissolved in 200 ml of methanol and 30 ml of water, and 7.59 g of potassium hydrogencarbonate were further added thereto. The mixture was hydrogenated in a hydrogen atmosphere using 2.53 g of 5% palladium on carbon as catalyst at 40° C. for 24 hours. The solid material was separated through filtration, and the filtrate was concentrated. The resulting residue was purified through silica-gel column chromatography (eluent: a mixture of ethyl acetate and methanol at a ratio of 4:1) to give 6.72 g of N-benzenesulfonyl-4-acetylamino-3-aminobenzamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[CH:19][C:11]3[NH:12][C:13](=[O:18])[O:14][C:15]([CH3:17])([CH3:16])[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:26]1[S:27][CH:28]=[CH:29][N:30]=1)CCC>CN(C=O)C>[CH3:16][C:15]1([CH3:17])[O:14][C:13](=[O:18])[NH:12][C:11]2[CH:19]=[CH:20][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:26]4[S:27][CH:28]=[CH:29][N:30]=4)[CH:3]=3)=[CH:9][C:10]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cccc(Br)c3)cc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(-c4nccs4)c3)cc21
Temperature: 90 °C
Yield: 23.8 %

Procedure:
A mixture of 6-(3-bromo-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.25 g, 0.75 mmol), tri-n-butyl-thiazol-2-yl tin (0.5 g, 1.3 mmol) in DMF (5 mL) was degassed to remove oxygen and then heated under nitrogen at 90° C. for 3 hours. The reaction mixture was cooled to rt and treated with ice-water (70 mL). Ethyl acetate (100 mL) was added and organic layer was separated, washed with brine, and dried (MgSO4). After removal of solvent, the residue was purified by a silica gel column (hexane:ethyl acetate/1:1) to give the title compound as a white solid (60 mg, 23%): mp 223-224° C.; 1H-NMR (DMSO-d6) δ10.4 (s, 1H), 9.13 (s, 1H), 8.45 (s, 1H), 7.94 (bs, 1H), 7.67-7.61 (m, 4H), 7.53 (t, 1H, J=7.68 Hz), 7.00 (d, 1H, J=8.81 Hz), 1.7 (s, 6H); MS (APCI) m/z 337([M+H]+, 100%), Anal. Calc. For C19H16N2O2S.0.25 H2O: C, 66.94; H, 4.88; N, 8.22. Found: C, 66.57; H, 4.65; N, 7.92.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=2[F:17])=[CH:4][CH:3]=1.Cl[C:19]1[CH:29]=[C:23]2[N:24]([CH3:28])[CH2:25][CH2:26][CH2:27][N:22]2[C:21](=[O:30])[N:20]=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:19]3[CH:29]=[C:23]4[N:24]([CH3:28])[CH2:25][CH2:26][CH2:27][N:22]4[C:21](=[O:30])[N:20]=3)=[CH:11][C:10]=2[F:17])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Oc2ccc(Cl)nc2)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(Cl)nc3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (4-((6-chloropyridin-3-yl)oxy)-3-fluorophenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=3)[C:9]3[C:14]([C:15]=2[NH:16][C:17]([NH2:19])=[O:18])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:28])[O:4][N:3]=1>I>[CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:20]3[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=3)[C:9]3[C:14]([C:15]=2[NH:16][C:17]([NH2:19])=[O:18])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: COc1ccc(-n2c(-c3c(C)noc3C)c(NC(N)=O)c3ccccc32)cc1
Agent: I
Product: Cc1noc(C)c1-c1c(NC(N)=O)c2ccccc2n1-c1ccc(O)cc1

Procedure:
1-(2-(3,5-Dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-1H-indol-3-yl)urea was heated neat in hydriodic acid (aq, 57%) at 100° C. for 3 hours. The reaction mixture was cooled and concentrated, and co-evaporated with DCM and EtOAc. The residue was subjected to reversed phase preparative HPLC. Appropriate fractions were combined and evaporated, and identified by 1H NMR. ES/MS m/z: 363.19 (M+H), 362.18 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.65 (m, 1H), 7.22-7.09 (m, 5H), 6.93 (m, 2H), 2.25 (s, 3H) and 1.94 (s, 3H).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH2:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[O-])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(#N)C>[CH2:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:5]#[N:6])[N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1ccccc1Cc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1cccc(Cc2ccccc2)n1
Temperature: 25 °C
Yield: 16.1 %

Procedure:
Trimethylsilyl cyanide (14.56 g, 19.6 ml, 0.147 moles) was added dropwise to a solution of 2-benzylpyridine-N-oxide (10.86 g, 0.059 moles) and triethylamine (8.91 g, 12.3 ml, 0.088 moles) in acetonitrile (40 ml) at 20° C. After complete addition the mixture was heated under reflux for 20 hours, cooled to room temperature and partitioned between methylene chloride and saturated sodium bicarbonate. The organic layer was washed with water and saturated sodium chloride, and then dried over anhydrous magnesium sulphate. Removal of the solvent gave an orange oil which was purified by column chromatography (silica gel eluted with hexane:ethyl acetate 9:1) to give 2-benzyl-6-cyanopyridine (1.84 g, 16%) as a pale yellow oil.