Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][CH:6]=[CH:5][C@H:4]([O:8]C(C)=O)[C@H:3]1[O:12]C(C)=O.C[O-].[Na+].C(O)(=O)C>CO>[CH3:1][C@@H:2]1[O:7][CH:6]=[CH:5][C@H:4]([OH:8])[C@H:3]1[OH:12]
Reactant: CC(=O)O[C@H]1[C@H](C)OC=C[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H]1OC=C[C@H](O)[C@H]1O
Reaction time: 8 h

Procedure:
10 grams of 3,4-di-O-acetyl-L-rhamnal is dissolved in 100 milliliters of methanol, and the pH is adjusted to 8 to 9 by the dropwise addition of a freshly prepared solution of sodium methoxide in methanol. The flask is sealed and allowed to stand at 0°-5° C. overnight after which time deacetylation is complete. The solution is neutralized by the careful dropwise addition of glacial acetic acid, and then the solvent is removed under reduced pressure. The resulting clear syrup is co-evaporated several times with toluene to remove any excess acetic acid, and the syrup crystallizes during these evaporations to give L-rhamnal. The yield of this compound is 6 grams.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]O)=[CH:16][CH:15]=2)[N:3]=1.S(Cl)([Cl:25])=O>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:25][CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([N:4]2[C:5]([CH3:13])=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:2]([CH3:1])=[N:3]2)=[CH:15][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nn(-c2ccc(CCO)cc2)c(C)c1-c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1nn(-c2ccc(CCCl)cc2)c(C)c1-c1ccccc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethanol (step 1 of Example 2, 100 mg, 0.34 mmol) in toluene (3 mL) and chloroform (1 mL) was added thionyl chloride (50 μL, 0.68 mmol), and the resulting mixture was stirred at 80° C. for 3h. The reaction mixture was quenched by 2 M NaOH aq. and extracted with dichloromethane. Organic layer was dried (Na2SO4) and the solvent was evaporated to give the title compound as brown solids (quant.): MS (ESI) m/z 311 [M+H]+, 1H-NMR (CDCl3) δ 7.46-7.31 (9H, m), 3.74 (2H, t, J=7.3 Hz), 3.12 (2H, t, J=7.3 Hz), 2.34 (3H, s), 2.30 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=2)[N:13]=1.[Cl:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:29]=1I.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>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.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:29]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[Cl:23])=[CH:16][CH:15]=2)[N:13]=1
Reactant: C#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Reactant: Clc1cnccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(C#Cc2ccncc2Cl)cc1
Yield: 25.8 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-2, 0.100 g, 0.319 mmol), 3-chloro-4-iodopyridine (Intermediate-4, 0.114 g, 0.429 mmol), TBAF (0.201 g, 0.638 mmol), bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.028 mmol) and DMSO (3.0 mL). The obtained product was purified with column chromatography on silica gel eluting with 1.0% MeOH:DCM to afford 0.035 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.49 (t, J=8.7 Hz, 1H), 7.56 (d, J=11.7 Hz, 2H), 7.60-7.77 (m, 3H), 8.08 (d, J=8.4 Hz, 2H), 8.57 (d, J=5.1 Hz, 1H), 8.78 (s, 1H), 12.76 (br s, 1H). MS (m/z): 425.43 (M+).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:25]([O:29][C:30]([N:32]1[CH:36]=[CH:35][CH:34]=[C:33]1B(O)O)=[O:31])([CH3:28])([CH3:27])[CH3:26]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:33]4[N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH:36]=[CH:35][CH:34]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccn4C(=O)OC(C)(C)C)cc32)N=C1N
Temperature: 120 °C
Yield: 1.7 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (30 mg, 0.099 mmol) in 1,4-dioxane (1.2 mL), Cs2CO3 (2 N, 0.3 mL) and 1-(tert-butoxycarbonyl)-1H-pyrrol-2-ylboronic acid (30 mg, 0.142 mmol). The mixture was heated at 120° C. in a microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure tert-butyl 2-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-1H-pyrrole-1-carboxylate (0.8 mg, 2%). 1H-NMR (MeOD): 1.40 (s, 9H), 2.44 (m, 1H), 2.61 (m, 1H), 3.25 (s, 3H), 5.85 (d, 1H), 6.14 (m, 1H), 6.23 (m, 1H), 7.05 (m, 1H), 7.16 (m, 1H), 7.32 (m, 2H), 7.49 (m, 5H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[NH:32]1[C:40]2C(=CC=CC=2)[C:34](CCCC(O)=O)=[CH:33]1.C(OC(=O)CSC1SC(N)=NC=1)C>>[NH:32]1[C:33]2[C:2](=[CH:7][CH:6]=[CH:5][CH:34]=2)[C:3]([CH2:4][CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)=[CH:40]1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCCc2c[nH]c3ccccc23)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 4-(1H-indol-3-yl)-butyric acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][C@@H:19]1[CH2:31][CH:32]([OH:34])[CH3:33])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl.C(=O)(O)[O-].[Na+]>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][C@@H:19]1[CH2:31][C:32](=[O:34])[CH3:33])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(O)C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(=O)C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 87.3 %

Procedure:
Add oxalyl chloride (2.52 mL, 28.9 mmol) to a solution of dimethyl sulfoxide (3.42 mL, 48.2 mmol) in dichloromethane (130 mL) at −78° C. After 15 minutes at −78° C., add (S)-2-(2-hydroxypropyl)piperazine-1,4-dicarboxylic acid di-tert-butyl ester 6.64 g, 19.3 mmol) in dichloromethane (20 mL). Stir the mixture for 1 hour at −78° C., add triethylamine (13.4 mL, 96.4 mmol) and warm to room temperature overnight. Dilute the mixture with saturated aqueous sodium bicarbonate and extract three times with dichloromethane. Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure. Purify by flash chromatography, eluting with a step gradient (100% dichloromethane to 5% 2N ammonia-methanol in dichloromethane), to obtain (S)-2-(2-oxo-propyl)-piperazine-1,4-dicarboxylic acid di-tert-butyl ester (5.77 g, 87%): mass spectrum (APCI): m/z=143.1 (M+1-2BOC).
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8]N1C(=O)CCC1=O.[NH2:16][C:17]1[CH:43]=[CH:42][C:20]([C:21]([NH:23][C:24]2[C:29]([Cl:30])=[CH:28][C:27]([C:31]([F:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])=[CH:26][C:25]=2[Cl:41])=[O:22])=[CH:19][CH:18]=1>O>[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([NH:23][C:24]2[C:25]([Cl:41])=[CH:26][C:27]([C:31]([F:40])([C:36]([F:37])([F:38])[F:39])[C:32]([F:33])([F:34])[F:35])=[CH:28][C:29]=2[Cl:30])=[O:22])=[CH:42][C:43]=1[Cl:8]
Reactant: Nc1ccc(C(=O)Nc2c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Cl)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc(C(=O)Nc2c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Cl)cc1Cl
Temperature: 80 °C
Reaction time: 6 h
Yield: 67.3 %

Procedure:
To the toluene (30 ml) solution in which 4-amino-N-[2,6-dichloro-4-(1,1,1,2,3,3,3-heptafluoro propan-2-yl)phenyl]benzamide (2.80 g) is dissolved, N-chlorosuccinimide (0.87 g) was added. The reaction solution was stirred for 6 hours at 80° C. under heating. The solution was cooled to room temperature, diluted with water and extracted twice with ethyl acetate. The organic phases were combined, and then dried over magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography to give 4-amino-3-chloro-N-[2,6-dichloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)phenyl] benzamide (2.03 g, yield 67.3%).
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]1[CH2:22][CH:21]1[CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[S:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1>CCO>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:22][CH:21]([OH:20])[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[S:32][C:33]3[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=3[N:35]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(-c2nc3ccccc3s2)c(OCC2CO2)c1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CCO
Product: OC(COc1ccccc1-c1nc2ccccc2s1)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 42.7 %

Procedure:
A solution of 1-benzhydryl-piperazine (891 mg, 3.53 mmol) and 2-[2-(oxiran-2-yl-methoxy)phenyl]benzothiazole (1000 mg, 3.53 mmol) in EtOH (7 mL) were refluxed under N2 (g) for about 16 hours. The mixture was concentrated in vacuo to a white foam and flash chromatographed on silica (35% EtOAc/hexanes) to afford 807 mg (42%) of the free base of the product as a white solid. mp 152-155° C.; LSIMS m/z 536 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][CH:17]([O:19][CH3:20])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[O:22]=[S:23]1(=[O:31])[CH2:27][CH:26]([C:28]([NH2:30])=[O:29])[NH:25][CH2:24]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:25]3[CH:26]([C:28]([NH2:30])=[O:29])[CH2:27][S:23](=[O:31])(=[O:22])[CH2:24]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][CH:17]([O:19][CH3:20])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: COC1CN(c2ccc(C(=O)O)nc2OCC2CC2)C1
Reactant: NC(=O)C1CS(=O)(=O)CN1
Agent: Cl
Product: COC1CN(c2ccc(C(=O)N3CS(=O)(=O)CC3C(N)=O)nc2OCC2CC2)C1
Yield: 33 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxylic acid (Example 128 a, 30 mg, 108 μmol) was reacted with 1,1-dioxo-1,3-thiazolidine-4-carboxamide hydrochloride (Example 127 d, 26.0 mg, 129 μmol) to give the title compound (15 mg, 33%) as off-white solid, MS (EI): m/e=425.5 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([NH:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.S([O-])([O-])(=O)=O.[Mg+2]>>[Cl:1][C:2]1[C:11]([NH2:12])=[C:10]([NH:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[C@@H](Nc1c([N+](=O)[O-])c(Cl)nc2ccccc12)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: C[C@@H](Nc1c(N)c(Cl)nc2ccccc12)c1ccccc1
Reaction time: 1 h
Yield: 96.2 %

Procedure:
The method of Part B of Example 1 was used to hydrogenate 2-chloro-3-nitro-N-[(1R)-1-phenylethyl]quinolin-4-amine (24.35 g, 73.3 mmol) with the modifications that the reaction was stopped after one hour, and magnesium sulfate was added to the mixture before filtration. 2-Chloro-N4-[(1R)-1-phenylethyl]quinoline-3,4-diamine (21.0 g) was isolated as an amber oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH:13]1([N:19]2[C:23]([CH2:24][CH2:25][CH2:26][CH2:27]Cl)=[N:22][N:21]=[N:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>S([O-])([O-])=O.[Na+].[Na+].CO>[CH:11]1[C:2]([O:1][CH2:27][CH2:26][CH2:25][CH2:24][C:23]2[N:19]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[N:20]=[N:21][N:22]=2)=[CH:3][C:4]2[CH2:5][CH2:6][C:7]([NH:8][C:9]=2[CH:10]=1)=[O:12]
Reactant: O=C1CCc2cc(O)ccc2N1
Reactant: ClCCCCc1nnnn1C1CCCCC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C1CCc2cc(OCCCCc3nnnn3C3CCCCC3)ccc2N1
Temperature: 10 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
Into a flask having a capacity of 200 ml were introduced 6-hydroxy-3,4-dihydrocarbostyril (12 g, 0.07 mol), 1-cyclohexyl-5-(4-chlorobutyl)-1,2,3,4-tetrazole (19.64 g, 0.08 mol), potassium carbonate (22.36 g, 0.16 mol), sodium hydroxide (2.35 g, 0.05 mol), sodium sulfite (0.6 g, 0.004 mol), purified water (36 mL) and isopropanol (3.6 mL), and the reaction was conducted for about 6 hours under reflux. After the completion of the reaction, the reaction mixture was cooled to around 10° C., and the precipitated crystals were collected by filtration. The crystals obtained were introduced into a flask, and purified water (120 mL) was added thereto, then the crystals were washed with stirring at about 85° C. for about 15 minutes. The reaction mixture was cooled to around 50° C. and the precipitated crystals were collected by filtration. The crystals obtained were introduced into a flask again and methanol (84 mL) was added thereto, then the crystals were washed with stirring at about 25° C. for about 15 minutes. The reaction mixture was cooled to 10° C. or less, the precipitated crystalline product was collected by filtration and washed with methanol (24 mL), then dried at about 80° C. Thus, 24.31 g of cilostazol was obtained. Yield: 89.47%, Purity: 99.45%, m.p.: 158–159° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([O:9][CH3:10])=[O:8])=[C:3]1[CH2:11][C:12]([O:14][CH3:15])=[O:13].[H-].[Na+].[CH:18](OC)=[O:19].C(=O)=O>C1COCC1>[OH:19][CH:18]=[C:11]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][C:4]=1[C:7]([O:9][CH3:10])=[O:8])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC=O
Reactant: COC(=O)Cc1c(C(=O)OC)ccn1C
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(=CO)c1c(C(=O)OC)ccn1C
Temperature: 118 °C
Reaction time: 0.83 h

Procedure:
To a suspension of methyl 1-methyl-2-[2-(methyloxy)-2-oxoethyl]-1H-pyrrole-3-carboxylate (37.9 g) in THF (anhydrous, 300 ml), under argon, was added sodium hydride (60% dispersion in mineral oil, 37.9 g) portion-wise. After complete addition the reaction was stirred at 22° C. for 15 minutes before the drop-wise addition of methyl formate (16.6 ml). The reaction was stirred at 118° C. for 50 minutes. During this period the temperature increased to around 21.5° C. before a rapid rise in temperature with gas evolution. Cooling (solid carbon dioxide) was applied to the outside of the flask. The temperature reached a maximum of 30° C. before dropping to 20° C. The coolant was removed and the reaction stirred for a further 17 hours. The reaction mixture was cooled by an ice/water bath before the cautious addition of methanol (100 ml). The reaction mixture was then combined with the product of another second mixture prepared in a similar manner (starting weight of methyl 1-methyl-2-[2-(methyloxy)-2-oxoethyl]-1H-pyrrole-3-carboxylate was 35.5 g). The solution was concentrated in vacuo. The residue was treated with saturated ammonium chloride solution (600 ml) then acidified to pH1 by the cautious addition concentrated hydrochloric acid. Ice was added to cool the solution and it was then extracted with ethyl acetate (3×400 ml). The combined organics were dried (MgSO4) and the solvent removed to yield a black oily solid. Oil was decanted and the residue triturated with hexane (2×200 ml), diethyl ether (200 ml) and hexane (200 ml). This yielded the title compound as a brown solid (65.2 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][CH2:11][CH2:12][O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[NH:20]2)=[C:16]([NH2:25])[N:15]=1)[CH3:9].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][O:40][CH2:39]1)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[CH2:8]([O:10][CH2:11][CH2:12][O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][O:40][CH2:39]2)=[C:16]([NH2:25])[N:15]=1)[CH3:9]
Reactant: CS(=O)(=O)OCC1CCCOC1
Reactant: CCOCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOCCOc1nc(N)c2nc(OC)n(CC3CCCOC3)c2n1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-{[2-(ethyloxy)ethyl]oxy}-8-(methoxy)-9H-purin-6-amine trifluoroacetic acid salt (500 mg) in dry N,N-dimethylformamide (6.0 ml) at room temperature and under nitrogen was added potassium carbonate (0.75 g) in one go. The reaction was stirred at 60° C. for 1.5 hours. A solution of tetrahydro-2H-pyran-3-ylmethyl methanesulfonate (0.29 g) in dry N,N-dimethylformamide (1.0 ml) was added in one go and the reaction heated at 90° C. for 2 hours. The reaction was cooled to room temperature and then diluted with ethyl acetate (20 ml) and washed with water (10 ml). The organic layer was concentrated in vacuo. The product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (10-60%) to afford the title compound as a clear viscous oil that crystallises at room temperature (245 mg).
Reaction SMILES: [CH3:1][C:2]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]>CO.[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:2]([CH3:1])([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:14][CH:15]=1
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C(C)(C(=O)OCC)c1ccc(N)cc1
Reaction time: 3 h

Procedure:
To a solution of 4.98 g Diethyl 2-methyl-2-(4-nitrophenyl)malonate in 70 ml methanol are added 896 mg of 10% palladium on charcoal. The mixture is hydrogenated at 2 bar for 3 hours. After filtration the solvent is evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethylacetate 90:10 to 50:50).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][NH2:14].[O:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]([C:24]2[S:28][C:27](Cl)=[N:26][CH:25]=2)=[O:23])[CH2:17][CH2:16]1>CN(C=O)C>[O:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]([C:24]2[S:28][C:27]([NH:14][CH2:13][C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:26][CH:25]=2)=[O:23])[CH2:17][CH2:16]1
Reactant: Cc1onc(-c2ccccc2)c1CN
Reactant: O=C(NC1CCOCC1)c1cnc(Cl)s1
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1CNc1ncc(C(=O)NC2CCOCC2)s1
Yield: 5.7 %

Procedure:
A stirred solution of (5-methyl-3-phenyl-4-isoxazolyl)methylamine (100 mg, 0.53 mmol) and 2-chloro-thiazole-5-carboxylic acid (tetrahydro-pyran-4-yl)-amide (131 mg, 0.53 mmol) in DMF (3 mL) was heated at 150° C. under microwave irradiation for 1 h. The reaction mixture was cooled and concentrated in vacuo, then purified by chromatography (silica, 0 to 3% methanol in dichloromethane) to give the title compound (12 mg, 6%) as a white solid. MS: m/e=399.1 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])(Cl)[Cl:3].O1CCCC1.[CH3:11][C:12]1[CH:13]([Li])[C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2>CCCCCC>[CH3:1][Si:2]([Cl:3])([CH3:5])[CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[C:12]1[CH3:11]
Reactant: C[Si](C)(Cl)Cl
Reactant: [Li]C1C(C)=Cc2ccccc21
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1=Cc2ccccc2C1[Si](C)(C)Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
In a three-necked flask equipped with a mechanical stirrer were charged 44.5 g (345 mmol) of dimethyldichlorosilane, 300 ml of tetrahydrofuran and n-hexane, to which was added at -78° C. a 2-methylindenyllithium solution, followed by stirring at room temperature for 3 hours. After the solvent was distilled off under reduced pressure, 100 ml of hexane was added and insoluble matter was removed by centrifugation. After the solvent was distilled off under reduced pressure, distillation under reduced pressure (113° C./7mmHg) afforded 14.9 g (67 mmol, yield: 58%) of dimethyl(2-methylindenyl)silyl chloride as a pale yellow liquid.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=O.[OH-].[K+].C(O)(=O)C>CO.O>[OH:20][N:18]=[C:17]1[CH:16]=[CH:15][C:14](=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]#[N:9])[CH:13]=[C:12]1[O:11][CH3:10]
Reactant: N#CCc1ccccc1
Reactant: COc1ccccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: COC1=CC(=C(C#N)c2ccccc2)C=CC1=NO
Temperature: 55 °C
Reaction time: 6 h

Procedure:
21.0 g (0.18 mol) of phenylacetonitrile and 25 g (0.16 mol) of o-nitroanisole are added at 25° C. to a solution of 35.6 g KOH (0.54 mol, assay 85%) in 180 ml of methanol and the dark red reaction mixture is stirred at 55° C. for 6 hrs. After cooling, the mixture is diluted with 500 ml of water, and acidified by addition of 60 ml of acetic acid with cooling. The resulting orange precipitate is filtered, washed with water, methanol:water 1:1 (v/v), and dried at 80° C. under vacuum. The crude product (30.8 g, 75%) has a melting point of 180-182° C. (dec) (Lit: 187° C. dec; J. Org. Chem. 26, 4270, 1961) and is used in the next step without further purification. The 1H-NMR spectrum indicates the presence of two isomers in nearly 1:1 ratio.