Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[CH3:15][O:16][C:17]([C:19]#[C:20][C:21](OC)=[O:22])=[O:18].C[O-].[Na+].[Na]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:21](=[O:22])[CH:20]=[C:19]([C:17]([O:16][CH3:15])=[O:18])[NH:14]1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: COC(=O)C#CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)c1cc(=O)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]1
Reaction time: 2.5 h
Yield: 65 %

Procedure:
To a solution of 30.1 g (0.123 mole) of 2,6-dichloro-4-trifluoromethylphenylhydrazine in 75 ml of methanol was added dropwise with stirring a solution of 18.5 g (0.13 mole) of dimethylacetylene dicarboxylate dissolved in 75 ml of methanol. The reaction mixture was stirred for 2.5 hrs. at 10°-20° C. The brown mixture was then added slowly, over a period of 50 min., to a stirred solution of sodium methoxide (made by dissolving 11.0 g (0.478 mole) of sodium in 400 ml of anhydrous methanol). After stirring for an additional period of 1.5 hr, the solution was concentrated under a partial vacuum and acidified with 100 ml of 4N hydrochloric acid. The precipitated solid was filtered, washed with water and air dried to afford 28.4 g (65 percent yield) of a tan colored solid, mp 245°-246° C., which was recrystallized from methanol to give a solid, mp 249°-250° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]3[C:17]([N:18]=[C:19]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]=24)=[CH:16][CH:15]=[N:14]3)=[CH:8][CH:7]=1.[CH3:26][CH:27]1[CH2:31][CH2:30][CH2:29][NH:28]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:26][CH:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]3[C:17]([N:18]=[C:19]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]=24)=[CH:16][CH:15]=[N:14]3)=[CH:8][CH:7]=1
Reactant: ClCCCOc1ccc(-c2c3c(nc4ccnn24)CCCCC3)cc1
Reactant: CC1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1CCCN1CCCOc1ccc(-c2c3c(nc4ccnn24)CCCCC3)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
A mixture of 10-[4-(3-chloro-propoxy)-phenyl]-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene (50 mg, 0.2 mmol), 2-methyl-pyrrolidine (71 mg, 1.0 mmol) and K2CO3 (45 mg, 0.3 mmol) in DMF (1 mL) was stirred at 80° C. overnight. The reaction was cooled, diluted with EtOAc (3 mL) and washed with H2O, brine, dried over MgSO4, and concentrated. The residue was purified by preparative LCMS to give 10-{4-[3-(2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene (33 mg, 66% yield).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:8][N:7]=[C:6]([C:9]([O:11]C)=O)[N:5]=1)=[O:2].[CH3:13][S:14][CH2:15][S:16]([CH3:18])=[O:17].[H-].[Na+].C(Cl)Cl>CN(C)C=O>[CH:1]([NH:3][C:4]1[S:8][N:7]=[C:6]([C:9](=[O:11])[CH:15]([S:14][CH3:13])[S:16]([CH3:18])=[O:17])[N:5]=1)=[O:2]
Reactant: CSCS(C)=O
Reactant: COC(=O)c1nsc(NC=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CSC(C(=O)c1nsc(NC=O)n1)S(C)=O
Temperature: 40 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
To a mixture of methyl 5-formamido-1,2,4-thiadiazole-3-carboxylate (9.2 g) and methyl methylthiomethyl sulfoxide (6.1 g) in N,N-dimethylformamide (100 ml) was added 50% sodium hydride (7.1 g) with cooling in an ice-bath. The mixture was stirred for an hour at ambient temperature and for an additional one hour at 40° C. After cooling to ambient temperature, methylene chloride (300 ml) was added to the reaction mixture, and the resulting precipitates were collected by filtration and washed with methylene chloride. The precipitates were added to a stirred mixture of hydrochloric acid (14.7 ml), ice-water (200 ml) and methylene chloride (200 ml). An insoluble material was filtered off and the methylene chloride layer was separated from the filtrate. The solution was dried over anhydrous magnesium sulfate, evaporated and the residue was triturated with diethyl ether to give the title compound (4.5 g), mp. 130° to 132° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[CH2:15][CH2:14][C:13]4[C:19]([C:23]([NH:25][C:26]5[C:31]([CH2:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=5[CH2:34][CH3:35])=[O:24])=[N:20][N:21]([CH3:22])[C:12]=4[C:11]=3[N:10]=2)=[C:4]([O:36][CH3:37])[CH:3]=1.O1[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]1.C(O)(C(F)(F)F)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[CH3:65][N+:66](C)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:34]([C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([CH2:32][CH3:33])[C:26]=1[NH:25][C:23]([C:19]1[C:13]2[CH2:14][CH2:15][C:16]3[CH:17]=[N:18][C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([NH:1][CH:41]5[CH2:42][CH2:43][N:66]([CH3:65])[CH2:39][CH2:40]5)=[CH:3][C:4]=4[O:36][CH3:37])=[N:10][C:11]=3[C:12]=2[N:21]([CH3:22])[N:20]=1)=[O:24])[CH3:35]
Reactant: O=C1CCOCC1
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccc(N)cc3OC)nc1-2
Reactant: C[N+](C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccc(NC4CCN(C)CC4)cc3OC)nc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a stirred solution of 8-[(4-amino-2-methoxyphenyl)amino]-N-(2,6-diethylphenyl)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (80 mg, 0.158 mmol) in 1.5 ml of CH2Cl2 under argon atmosphere, tetrahydro-4H-pyran-4-one (20 mg, 0.198 mmol), TFA (0.428 mmol; 2.7 eq) and tetramethylammonium triacetoxyborohydride (63 mg, 0.238 mmol) were added. The mixture was stirred at room temperature for 1 h. Saturated aqueous NaHCO3 was added and the organic layer separated, dried on anhydrous Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (97.5/2.5 CH2Cl2/CH3OH) giving the to desired product as a brown foam in a 34% yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][NH2:10].[O-]CC.[Na+].Cl[C:16]1[C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1.[OH-].[Na+]>O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][NH:10][C:16]1[C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: NCCSCc1nccs1
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cccnc1NCCSCc1nccs1

Procedure:
An intimate mixture of 2-(2-thiazolylmethylthio)ethylamine [prepared from 6.73 g; 0.02 moles of the dihydrobromide salt and sodium ethoxide (from 0.92 g; 0.040 g. atom of sodium in ethanol)] and 2-chloropyridine 3-carboxylic acid (3.15 g; 0.020 moles) was heated to 150° for 3 hours. The resulting brown residue was cooled, dissolved in a little water, and basified to pH5 by dropwise addition of 2N sodium hydroxide solution, to precipitate an oil. The latter was separated and dried, and chromatographed on a column of silica-gel using chloroform/ethyl acetate, (1:1). The crude product was then recrystallised from isopropanol to give 2-[2-(2-thiazolylmethylthio)ethyl]amino pyridine 3-carboxylic acid as a cream-coloured solid (0.36 g, m.p. 133°-4° (softening above 123°).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CCN([CH2:46][CH3:47])CC>C(Cl)Cl>[C:31]1([S:37]([N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[C:2]2[CH2:10][N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][NH:20][S:37]([C:47]3[CH:46]=[CH:33][CH:32]=[CH:31][CH:36]=3)(=[O:39])=[O:38])=[CH:17][CH:18]=2)[CH:21]2[C:30]3[N:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH2:24][CH2:23][CH2:22]2)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCN(CC)CC
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Product: O=S(=O)(NCc1ccc(CN(Cc2nc3ccccc3n2S(=O)(=O)c2ccccc2)C2CCCc3cccnc32)cc1)c1ccccc1

Procedure:
A solution of N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (302 mg, 0.760 mmol), benzenesulfonyl chloride (0.12 mL, 0.94 mmol), and Et3N (0.15 mL, 1.1 mmol) in CH2Cl2 (7.5 mL) was heated at reflux for 17 h, then concentrated in vacuo. The residue was partitioned between saturated NaHCO3(aq) (15 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (20 mL), and the combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. Purification of the crude material by column chromatography on silica gel (400:5:1 CH2Cl2/MeOH/NH4OH) afforded AMD9830 (229 mg, 71%) as a yellow foam. 1H NMR (CDCl3) δ 1.64-2.03 (m, 3H), 2.37 (m, 1H), 2.66-2.84 (m, 2H), 3.76-3.89 (m, 4H), 4.06 (m, 1H), 4.41 (dd, 1H, J=9.6, 6.0 Hz), 4.66 (d, 1H, J=15 Hz), 4.79 (d, 1H, J=15 Hz), 6.76 (d, 2H, J=8.1 Hz), 7.07 (m, 1H), 7.18 (d, 2H, J=8.1 Hz, 7.27 (m, 2H), 7.41 (m, 3H), 7.55 (m, 5H), 7.84 (m, 3H), 7.96 (m, 2H), 8.48 (m, 1H); 13C NMR (CDCl3) δ 20.15, 27.15, 27.55, 45.30, 51.78, 53.32, 61.49, 111.81, 118.60, 119.84, 122.59, 123.06, 125.43, 125.60, 127.06, 127.47, 127.76, 131.01, 131.24, 131.92, 132.55, 132.69, 134.81, 136.75, 138.13, 139.21, 140.14, 145.11, 151.74, 156.99. ES-MS m/z 678 (M+H). Anal. Calcd. for C37H35N5S2O4.0.5H2O: C, 64.70; H, 5.28; N, 10.20. Found: C, 64.65; H, 5.11; N, 10.08.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[CH:11]=2)[N:6]=[C:5]([CH2:14][CH2:15][CH3:16])[C:4]=1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].CCOC(C)=O.C(Cl)Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:25]([O:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[CH:11]=2)[N:6]=[C:5]([CH2:14][CH2:15][CH3:16])[C:4]=1[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([Br:24])=[CH:22][CH:23]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CCCc1nc2ccc(C)cc2c(CO)c1Cc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1nc2ccc(C)cc2c(CO[Si](C)(C)C(C)(C)C)c1Cc1ccc(Br)cc1
Temperature: 0 °C

Procedure:
To 50 mg (0.13 mmole) of 54 in 0.5 mL of CH2Cl2 containing 25 λ Et3N (17.5 mg; 0.17 mmole) and 10 mg DMAP (0.08 mmole) was added dropwise with stirring under a nitrogen atmosphere while cooling to 0° C., 25 mg (0.17 mmole) of t-butyldimethylsilyl chloride in 0.5 mL of CH2Cl2. After stirring overnight, the reaction mixture was washed with water, dried (MgSO4) and the product isolated by preparative tlc on silica gel GF using 5% EtOAc/CH2Cl2, giving clean 55.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[Li]CCCC.[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[N:26]1[C:30]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[C:29](/[CH:38]=[CH:39]/[CH:40]=[O:41])[C:28]([CH:42]([CH3:44])[CH3:43])=[N:27]1>C1COCC1>[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[N:26]1[C:30]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[C:29](/[CH:38]=[CH:39]/[CH:40]([OH:41])[CH2:7][C:5](=[O:6])[CH2:4][C:3]([O:9][CH2:10][CH3:11])=[O:8])[C:28]([CH:42]([CH3:44])[CH3:43])=[N:27]1
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)c1nn(-c2nc3ccccc3s2)c(-c2ccc(F)cc2)c1/C=C/C=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)/C=C/c1c(C(C)C)nn(-c2nc3ccccc3s2)c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To a hexane washed suspension of NaH (1.23 g, 30.7 mmol) in THF (20 ml) at 0° C. under an inert atmosphere, was added a solution of ethyl acetoacetate (3.66 ml, 28.7 mmol) in THF (20 ml). The resulting clear solution was stirred at 0° C. for 15 minutes before n-BuLi (13.1 ml, 28.7 mmol) was added dropwise. This orange solution was stirred at 0° C. for 15 minutes before it was cooled to -78° C. and a solution of the unsaturated aldehyde (7.50 g, 19.2 mmol, Step E) in THF (100 ml) was added dropwise. The reaction was stirred at -78° C. for one hour and then it was quenched by adding 4 ml glacial acetic acid and removing the cooling bath. The reaction mixture was partitioned between Et2O and saturated aqueous K2CO3 solution. The organic extracts were dried (MgSO4) and evaporated to give an orange solid. Recrystallization from hexanes gave 8.71 g (87%) of product as a pale yellow orange solid.
Reaction SMILES: Cl[C:2]([CH2:4][O:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])=[O:3].[CH3:11][C:12]1(C)[O:17]C(=O)[CH2:15][C:14](=O)[O:13]1.N1C=CC=CC=1>ClCCl>[CH3:10][O:9][C:7]([CH2:6][O:5][CH2:4][C:2](=[O:3])[CH2:11][C:12]([O:13][CH2:14][CH3:15])=[O:17])=[O:8]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COC(=O)COCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)COCC(=O)OC
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 12.3 %

Procedure:
Methyl 2-(chloroformylmethoxy)acetate (216.6 g) was added over 45 minutes to a stirred solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (173.9 g) and pyridine (189.6 g) in dichloromethane (1000 ml) keeping the temperature below 5° C. The mixture was stirred at 5° C. for 30 minutes, allowed to warm up to room temperature over one hour, washed with 2.4M hydrochloric acid and water, dried over magnesium sulphate and evaporated. The resulting brown oil was dissolved in ethanol (300 ml) and the solution heated under reflux for 2.5 hours and evaporated. The residual oil was distilled to give the title compound (32.5 g), b.p. 138°-140°/1 torr which was characterised by its N.m.r. spectrum in CDCl3, δ values: 4.27 (2H,s); 4.20 (2H, q, J 7 Hz); 4.16 (2H,s); 3.75 (3H, s); 3.54 (2H, s); 1.29 (3H, t, J 7 Hz).
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([CH3:13])[C:5]2[N:6]=[C:7]([NH2:10])[N:8]=[N:9][C:4]=2[CH:3]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2([C:24]#[N:25])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C1C=CC(P([C:39]2[C:48]([C:49]3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=[C:47]3[C:42]([CH:43]=CC=C3)=[CH:41][CH:40]=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1>[CH3:43][C:42]1[CH:41]=[CH:40][CH:39]=[C:48]([CH3:49])[C:47]=1[C:2]1[CH:12]=[C:11]([CH3:13])[C:5]2[N:6]=[C:7]([NH:10][C:15]3[CH:20]=[CH:19][C:18]([C:21]4([C:24]#[N:25])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:8]=[N:9][C:4]=2[CH:3]=1
Reactant: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Reactant: Cc1cc(Br)cc2nnc(N)nc12
Reactant: N#CC1(c2ccc(Br)cc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1-c1cc(C)c2nc(Nc3ccc(C4(C#N)CC4)cc3)nnc2c1
Reaction time: 24 h
Yield: 45.7 %

Procedure:
About 50 mg (0.2 mmol) of 7-bromo-5-methyl-benzo[1,2,4]triazin-3-ylamine and about 84 mg (0.38 mmol) of 1-(4-bromo-phenyl)-cyclopropanecarbonitrile were dissolved in about 10 ml of toluene. About 8 mg (0.009 mmol) of Pd(dba)3, about 17 mg (0.027 mmol) of BINAP, and about 50 mg (0.226 mmol) of KOt-Bu were added to the solution. The mixture was kept at about 100° C. for about 24 hours under argon. The crude product was purified by preparative HPLC. About 5 mg of 1-{4-[7-(2,6-dimethyl-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamino]-phenyl}-cyclopropanecarbonitrile (product having formula (X)) was isolated. ESI-MS: [M+H]+, 406.5; 1H NMR (DMSO-d6): δ 1.49 (q, 2 H, J=5.3 Hz), 1.72 (q, 2 H, J=5.3 Hz), 2.05 (s, 6 H), 2.67(s, 3 H), 7.18 (d, J=7.4 Hz, 2 H), 7.23 (m, 1H), 7.38 (d, J=6.85 Hz, 2 H), 7.63 (s, 1 H), 7.91 (s, 1 H), 8.06 (d, J=6.85 Hz, 2 H).
Reaction SMILES: [CH:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:11][C:12](=O)OC(C)(C)C)=O.CO/C=[CH:22]/[C:23]([O:25][CH3:26])=[O:24].Cl.C([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:1]=[C:22]([C:23]([O:25][CH3:26])=[O:24])[CH:12]=[N:11]2
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1C=O
Reactant: CO/C=C/C(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc2cccc(OC)c2c1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
To a solution of tert-butyl N-(2-formyl-3-methoxyphenyl)carbamate (7.8 g, 31 mmol) [described in Adv. Synth. Catal. 2003, 345, 743-765] and methyl trans-3-methoxyacrylate (7.4 mL, 68.4 mmol) dissolved in 150 ml of methanol, was added slowly 100 mL of an aqueous solution of hydrochloric acid 3M. The resulting mixture was stirred under reflux for 3 hours. The reaction mixture was then cooled to room temperature and neutralised by adding Na2CO3. The aqueous solution was extracted with CH2Cl2 (4×150 mL). The combined organic layers were dried over MgSO4, filtered and evaporated under vacuum. The crude product was then filtered on silica gel (AcOEt:cyclohexane/1:1) to afford 5.6 g of compound of molecular formula C12H11NO3. Aspect: yellow powder.
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[H-].[Na+].[CH3:7][NH:8][C:9]([N:11]1[C:15]([CH3:16])=[CH:14][C:13]([O:17][C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][N:19]=2)=[N:12]1)=[O:10].O>CN(C=O)C>[CH3:7][N:8]([CH2:3][O:2][CH3:1])[C:9]([N:11]1[C:15]([CH3:16])=[CH:14][C:13]([O:17][C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:27])([F:28])[F:26])=[CH:20][N:19]=2)=[N:12]1)=[O:10]
Reactant: COCCl
Reactant: CNC(=O)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCN(C)C(=O)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)cc1C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
Chloromethyl methyl ether (0.16 g, 2.0 mmol) was added to a solution of sodium hydride (60% in oil, 0.09 g, 2.2 mmol) and N-methyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole-1-carboxamide (0.67 g, 2.0 mmol) in DMF (10 ml) at 0° C., and while the mixture was allowed to have room temperature gradually, the mixture was stirred overnight. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant. The solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/5), to give a colorless viscous substance of N-methyl-N-methoxymethyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole-1-carboxamide (0.18 g, yield: 23.8%). 1H-NMR (CDCl3, TMS, ppm): δ 1.87 (s, 3H), 3.52 (s, 3H), 3.53 (s, 3H), 5.18 (s, 2H), 5.46 (s, 1H), 7.80-7.95 (m, 1H), 8.50-8.65 (m, 1H).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH3:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][NH2:19].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:19]([CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([CH3:14])[CH:16]=1)[CH2:11]2
Reactant: Cc1cccc(CN)c1
Reactant: COC(=O)c1c(I)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1cccc(CN2Cc3cccc(I)c3C2=O)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.107 g, 0.3 mmol), 3-methyl-benzylamine (0.063 mL, 0.5 mmol), and K2CO3 (0.138 g, 1.0 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-(3-methyl-benzyl)-2,3-dihydro-isoindol-1-one (0.037 g, 34%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.35 (s, 3H), 4.08 (s, 2H), 4.82 (s, 2H), 7.12-7.38 (m, 6H), 7.93 (d, 1H). GC-MS: m/z 363 (M)+.
Reaction SMILES: Cl[C:2]1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:56][CH3:57])[C:44]([NH:49][C@H:50]2[CH2:54][O:53][CH2:52][C@H:51]2[OH:55])=[N:45][C:46]=1[CH2:47][CH3:48].IC>>[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:56][CH3:57])[C:44]([NH:49][C@H:50]2[C@@H:51]([O:55][CH3:2])[CH2:52][O:53][CH2:54]2)=[N:45][C:46]=1[CH2:47][CH3:48]
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@H]1COC[C@H]1O
Solvent: CI
Product: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1COC[C@@H]1OC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting of cis-(+/−)-4-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}tetrahydrofuran-3-ol and iodomethane and making non-critical variations provided the title compound as a colorless semi-solid. IR (liq.) 2970, 2936, 2874, 1606, 1566, 1483, 1441, 1397, 1287, 1230, 1203, 1182, 1126, 1076, 1049 cm−1; OAMS supporting ions at: ESI+ 392.1; MS (EI) m/z 391 (M+); HRMS (FAB) calcd for C20H26CLN3O3+H1 392.1741, found 392.1758. Anal. Calcd for C20H26ClN3O3: C, 61.30; H, 6.69; N, 10.72. Found: C, 61.16; H, 6.47; N, 10.65.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:14][C:15]([C:17]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:18]=1[OH:24])=[O:16].O>N1C=CC=CC=1>[C:1]12([C:11]([O:23][C:21]3[CH:22]=[C:17]4[C:18](=[CH:19][CH:20]=3)[O:24][C:11]([C:1]35[CH2:10][CH:5]6[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]6)[CH2:8]3)[CH2:2]5)=[CH:14][C:15]4=[O:16])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: c1ccncc1
Solvent: O
Product: O=C(Oc1ccc2oc(C34CC5CC(CC(C5)C3)C4)cc(=O)c2c1)C12CC3CC(CC(C3)C1)C2
Reaction time: 18 h

Procedure:
4 g 1-adamantoyl chloride are added to a solution of 1.5 g 2,5-dihydroxyacetophenone in dry pyridine. The mixture is stirred for 18 hours at 40°, poured into water and extracted with ethyl acetate. The combined organic layers are washed 3 times with 1 N aqueous hydrochloric acid and subsequently with aqueous sodium carbonate solution, dried over magnesium sulfate and concentrated in vacuo. The crude product is dissolved in dry dimethylformamide and added dropwise at 5° to a suspension of 330 mg of sodium hydride (80% in mineral oil) in dry dimethylformamide. The cooling bath is removed, and the mixture is stirred for 4 hours at room temperature. Then 1.5 ml of acetic acid and 250 ml of water are added, followed by extraction with ethyl acetate. The combined extracts are dried over magnesium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 6/1) to remove starting materials and major by-products. Cyclisation of the resultant 1-[5-(1-adamantoyloxy)-2-hydroxyphenyl]-3-(1-adamantyl)-1,3-propandione is achieved by treatment with 20 ml of 32% aqueous hydrochloric acid in methanol/dioxane. 6-(1-adamantoyloxy)-2-(1-adamantyl)-4H-chromen-4-one is obtained: