Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH:13](N)[N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[CH:5][CH:4]=1.C(N(CC)C1C=CC=CC=1)C.Cl>CN1CCCC1=O>[C:18]1(=[O:19])[N:14]([CH2:13][CH2:12][CH2:11][C:10]2[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:27]=[CH:26][C:6]=3[O:7][CH2:8][CH:9]=2)[C:15](=[O:24])[C:16]2=[CH:23][CH:22]=[CH:21][CH:20]=[C:17]12
Reactant: COc1ccc(OCC#CCCC(N)N2C(=O)c3ccccc3C2=O)cc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)c1ccccc1
Product: COc1ccc2c(c1)C(CCCN1C(=O)c3ccccc3C1=O)=CCO2

Procedure:
A mixture of 40 g of 6-(4-methoxyphenoxy)-1-phthalimido-4-hexynylamine and 8.5 g of N,N-diethylaniline in 400 ml of N-methylpyrrolidinone is heated at 210° for 30 hours. After pouring onto water containing 57 ml of 1N hydrochloric acid the product is extracted with ether, dried, and the solvent is removed in vacuo. The residue is crystallized from isopropanol to afford 4-(3-phthalimidopropyl)-6-methoxy-2H-[1]-benzopyran, m.p. 78°-80°.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](I)[CH:8]=1.[C:14]([N:21]1[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>C1COCC1>[C:17]([O:16][C:14]([N:21]1[CH2:26][CH2:25][CH2:24][C:23]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([Br:6])[CH:8]=2)([OH:27])[CH2:22]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: Brc1cccc(I)c1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(O)(c2cccc(Br)c2)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 32.3 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 7.6 mL, 19.0 mmol) was added over 10 min to a solution of 1-bromo-3-iodobenzene (5.37 g, 19.0 mmol) in THF (100 mL) at −78° C. After 15 min, a solution of 1-boc-3-piperidone (3.44 g, 17.3 mmol) in THF (10 mL) was added and the resultant reaction mixture was left to stir at −78° C. for 1 h, then warmed to 0° C. and quenched by the addition of saturated aqueous ammonium chloride (50 mL). The mixture was allowed to warm to ambient temperature and partitioned between ethyl acetate (400 mL) and water (150 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The resultant residue was purified by flash chromatography (silica, 80 g column, ISCO, 0-100% ethyl acetate in cyclohexane) to afford the title compound as a colourless gum (1.99 g, 33%). 1H NMR (CDCl3, 300 MHz): 7.70-7.67 (m, 1H); 7.46-7.40 (m, 2H); 7.24-7.20 (m, 1H); 4.15-3.88 (m, 2H); 3.21-3.08 (m, 1H); 2.93-239 (m, 1H); 2.03-1.82 (m, 2H); 1.75-1.51 (m, 2H); 1.48 (s, 9H). LCMS (Method B): RT=3.88 min, M-[Boc-18]+238.
Reaction SMILES: C[O-].[Na+].C([O:7][C:8]1[CH:40]=[CH:39][C:11]([CH2:12][CH:13]2[S:17][C:16](=[O:18])[N:15]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]2=[O:38])=[CH:10][CH:9]=1)(=O)C.Cl>CO.C1(C)C=CC=CC=1>[OH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH:13]2[S:17][C:16](=[O:18])[N:15]([C:19]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:14]2=[O:38])=[CH:39][CH:40]=1
Reactant: CC(=O)Oc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.99 g of a 28% w/v methanolic solution of sodium methoxide in 10 ml of methanol was added dropwise, whilst ice-cooling, to a solution of 7.86 g of 5-(4-acetoxybenzyl)-3-triphenylmethyl-thiazolidine-2,4-dione [prepared as described in step (c) above] in 70 ml of toluene, and the resulting mixture Was stirred at room temperature for 1 hour, after which it was allowed to stand overnight at the same temperature. The pH of the reaction mixture was then adjusted to a value of 4 by the addition of 1N aqueous hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the crystals which appeared in the residue were collected, washed with hexane and dried, to give the title compound.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][CH:12]2[C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:6]=1)(=O)C.C([O-])(=O)C.[NH4+]>CO.O>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:13][CH:12]2[C:14]([O:16][CH3:17])=[O:15])=[CH:9][CH:10]=1
Reactant: COC(=O)C1CC1c1ccc(OC(C)=O)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COC(=O)C1CC1c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 96 %

Procedure:
Methyl 2-[4-(acetyloxy)phenyl]cyclopropanecarboxylate (2.26 g, 9.65 mmol) was dissolved in a mixed solvent of methanol (80 mL) and water (20 mL), and ammonium acetate (5.95 g, 77.2 mmol) was added. The mixture was stirred at room temperature for 10 hr and further stirred at 60° C. for 8 hr. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-40:60) to give the title compound (1.78 g, yield 96%) as colorless crystals.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:29][CH:30]([CH3:36])[CH2:31][C:32]([NH:34][NH2:35])=O>>[CH3:29][CH:30]([CH3:36])[CH2:31][C:32]1[O:28][C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[O:8])[CH2:10]2)=[N:35][N:34]=1
Reactant: CC(C)CC(=O)NN
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: CC(C)Cc1nnc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)o1
Yield: 36.6 %

Procedure:
100 mg (0.249 mmol) of the compound from Example 44A and 32 mg (0.273 mmol) of 3-methylbutanehydrazide were reacted according to the General Method 4. Diastereomer separation of the cis/trans isomer mixture according to Method 14C gave 44 mg of the title compound (cis isomer) and 12 mg of the trans isomer.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=2)=[CH:5][CH:4]=1)=[O:2].C([O-])([O-])=[O:23].[K+].[K+].OO.O>CS(C)=O>[CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]([NH2:19])=[O:23])=[CH:16][N:15]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: N#Cc1ccc(Oc2ccc(C=O)c3ccccc23)nc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(C=O)c3ccccc23)nc1
Temperature: 0 °C

Procedure:
To a solution of 6-(4-formylnaphthalen-1-yloxy)nicotinonitrile (Preparation 1) (3.83 g, 14.0 mmol) in DMSO (90 mL) was added K2CO3 (0.97 g, 7.0 mmol). The mixture was cooled to 0° C., H2O2 (27.5% w/v, 4.6 mL, 37.0 mmol) added dropwise and the reaction allowed to warm to rt. The mixture was poured into water (300 mL) and the resulting precipitate was filtered, washed with water and air dried to give the title compound which was used without further purification: RT=3.13 min; m/z (ES+)=292.9 [M+H]+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:12]3=[C:13]4[S:19][CH:18]=[CH:17][C:14]4=[N:15][CH:16]=[C:11]3[N:10]=[C:9]2[C@H:20]([OH:22])[CH3:21])[CH2:4][CH2:3]1.[C:23](#[N:26])[CH:24]=[CH2:25].N12CCCN=C1CCCCC2>C(#N)C>[OH:22][C@@H:20]([C:9]1[N:8]([CH:5]2[CH2:6][CH2:7][N:2]([CH2:25][CH2:24][C:23]#[N:26])[CH2:3][CH2:4]2)[C:12]2=[C:13]3[S:19][CH:18]=[CH:17][C:14]3=[N:15][CH:16]=[C:11]2[N:10]=1)[CH3:21]
Reactant: C=CC#N
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCNCC1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCN(CCC#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
To a solution of (1R)-1-(1-piperidin-4-yl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)ethanol hydrochloride (21.7 mg, 0.0640 mmol) (Example 15, Step 4) in acetonitrile (0.40 mL) was added 2-propenenitrile (8.4 μL, 0.13 mmol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (38 μL, 0.26 mmol). The resulting mixture was stirred at room temperature overnight. After evaporating to dryness, the residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (11 mg, 48%). LCMS calculated for C18H22N5OS (M+H)+: m/z=356.2. Found: 356.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:12][C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH:24]1([CH2:27]Br)[CH2:26][CH2:25]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH2:27][CH:24]3[CH2:26][CH2:25]3)[C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: BrCC1CC1
Reactant: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1CC1CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1.5 g (4.7 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 1, Step E) in 9.4 mL of DMF was added sodium hydride (60% suspension in mineral oil, 244 mg, 6.1 mmol) at 0° C. The reaction was stirred at 0° C. for 20 min and then treated with cyclopropylmethyl bromide (759 μl, 5621 μmol).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.F[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][C:2]1[N:3]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(-n2ccnc2C)cc1
Temperature: 120 °C
Yield: 34 %

Procedure:
A mixture of 2-methylimidazole (50 g, 0.6 mol), ethyl 4-fluorobenzoate (100 g, 0.6 mol) and potassium carbonate (415 g, 3 mol) in dry DMSO (1.5 l ) was heated at 120° C. for 66 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was poured into ice-cold water (1 l ), and extracted with Et2O (750 ml×2). The organic phase was washed with water (500 ml) and brine (500 ml), dried over MgSO4 and evaporated. The residual solid was recrystallized from ethyl acetate-hexane to give the titled compound (47 g, 33%) as yellow needles.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6]([OH:8])=[O:7].[Si:14]([O:21][C@H:22]1[CH2:31][C@H:30](O)[C@H:29]2[C:24]([CH:25]=[CH:26][C@H:27]([CH3:50])[C@@H:28]2[CH2:33][CH2:34][C@H:35]2[O:40][C:39](=[O:41])[CH2:38][C@H:37]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[CH2:36]2)=[CH:23]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>>[Si:14]([O:21][C@H:22]1[CH2:31][C@H:30]([O:7][C:6](=[O:8])[CH:5]([O:4][C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]=2[Cl:1])[CH3:9])[C@H:29]2[C:24]([CH:25]=[CH:26][C@H:27]([CH3:50])[C@@H:28]2[CH2:33][CH2:34][C@H:35]2[O:40][C:39](=[O:41])[CH2:38][C@H:37]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:44])[CH3:45])[CH2:36]2)=[CH:23]1)([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:16])[CH3:15]
Reactant: CC(Oc1ccccc1Cl)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CC(Oc1ccccc1Cl)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 96.9 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 0.72 g of (2RS)-2-(2-chlorophenoxy)propionic acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.29 g of the title compound as a colorless foam.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>C(#N)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: C1CCNC1
Solvent: CC#N
Product: CS(=O)(=O)c1cc(F)c2c(c1)OC(CN1CCCC1)CO2

Procedure:
Preparation according to Example 42 using [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), pyrrolidine (0.5 ml), ACN (2.5 ml). MS m/z (rel. intensity, 70 eV) 315 (M+, 0.7), 110 (3), 85 (6), 84 (bp), 55 (4).
Reaction SMILES: [C:1]1([N:7]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]([C:10]2[CH:31]=[CH:30][C:13]3[N:14]([CH3:29])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=4[CH2:27][CH3:28])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:39].C(=O)([O-])[O-].[NH4+:44].[NH4+]>C(O)C>[ClH:39].[C:1]1([N:7]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]([C:10]2[CH:31]=[CH:30][C:13]3[N:14]([CH3:29])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:44])[NH2:26])=[CH:21][C:20]=4[CH2:27][CH3:28])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1CC)n2C)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1CC)n2C)c1ccccc1

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyano-2-ethyl-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9](I)[N:8]([CH3:13])[C:7]=1[CH3:14])=[O:5])[CH3:2].[CH3:15][O:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:18]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].O>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>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([N+:23]([O-:25])=[O:24])[C:17]=2[O:16][CH3:15])[N:8]([CH3:13])[C:7]=1[CH3:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)c(I)n(C)c1C
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cccc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C)c(-c2cccc([N+](=O)[O-])c2OC)n(C)c1C
Temperature: 25 °C
Yield: 40.1 %

Procedure:
5-Iodo-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6e (2.88 g, 9.38 mmol) was dissolved in 25 mL of 1,4-dioxane followed by addition of 2-(2-methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane 6a (3.6 g, 10.3 mmol), tetrakis(triphenylphosphine)palladium (270 mg, 0.234 mmol), sodium carbonate (1.99 g, 18.77 mmol) and 10 mL of water. Upon completion of the addition, the reaction mixture was heated to reflux for 3 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was cooled to room temperature followed by addition of 30 mL of water and extracted with ethyl acetate (30 mL×3). The combined organic extracts were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain the title compound 5-(3-nitro-2-methoxy-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6f (1.25 g, yield 40.4%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:43][C:44]1[CH:49]=[CH:48][C:47]([CH:50]2[CH2:64][N:54]3[C:55](=[O:63])[NH:56][C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][C:62]=4[C:53]3=[N:52][CH2:51]2)=[CH:46][CH:45]=1>CN(C=O)C>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:43][C:44]1[CH:49]=[CH:48][C:47]([CH:50]2[CH2:64][N:54]3[C:55](=[O:63])[NH:56][C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][C:62]=4[C:53]3=[N:52][CH2:51]2)=[CH:46][CH:45]=1)=[O:9]
Reactant: Cc1ccoc1C(=O)O
Reactant: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccoc1C(=O)Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
A mixture of 3-methyl-furan-2-carboxylic acid (3.7 mg, 0.029 mmol), N,N-diisopropylethylamine (0.025 mL, 0.145 mmol), and HBTU (13.2 mg, 0.035 mmol) in 0.8 mL DMF was stirred at rt for 10 minutes, then 3-(4-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (7.6 mg, 0.026 mmol) added and the reaction continued at rt. After 40 min, a spatula tip of 3-methyl-furan-2-carboxylic acid and HBTU was added, the reaction briefly warmed to approximately 60° C. several times, then allowed to cool to rt. At 1.25 hours the reaction mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was chromatographed on a prep plate eluting with 15% MeOH/CHCl3. The obtained solid was then partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated to give the title compound as an off-white solid (7.6 mg, 86%). 1H NMR (CD3OD/CDCl3 mixture) δ: 8.03 (dd, J=7.9, 1.2 Hz, 1H), 7.65-7.71 (m, 2H), 7.43-7.52 (m, 2H), 7.26-7.32 (m, 2H), 7.14 (ddd, J=8.1, 7.2, 1.2 Hz, 1H), 7.00-7.05 (m, 1H), 6.45 (d, J=1.5 Hz, 1H), 4.45 (ddd, J=13.0, 4.4, 2.8 Hz, 1H), 3.83-3.91 (m, 1H), 3.59-3.70 (m, 2H), 3.04-3.16 (m, 1H), 2.42 (s, 3H)
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@@H:12]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@H:13]([OH:20])[CH2:14]OS(C)(=O)=O.[Cl-].[Na+].S(=O)(=O)(O)O>O1CCCC1>[C:22]1([CH2:21][C@@H:12]([C@H:13]2[CH2:14][O:20]2)[N:3]2[C:4](=[O:11])[C:5]3=[CH:6][CH:7]=[CH:8][CH:9]=[C:10]3[C:2]2=[O:1])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)OC[C@@H](O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@@H](Cc1ccccc1)[C@H]1CO1
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
A solution of 0.26 g of methanesulfonic acid (2S,3S)-3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-2-hydroxy-4-phenylbutyl ester in 1.6 ml of tetrahydrofuran is treated at -15° with a solution of 0.090 g of potassium tert.butylate in 0.5 ml of tetrahydrofuran and the mixture is stirred for 0.5 hours. The mixture is treated with 2.2 ml of semi-saturated sodium chloride solution and the pH value is adjusted to 6 with 0.1 ml of 1N sulphuric acid. Thereafter, the mixture is extracted with ethyl acetate. The extracts are dried and filtered, and the filtrate is evaporated to give 0.12 g (60%) of 2(S)-[2-phenyl-1(S)-phthalimidoethyl]oxirane, IR (KBr): 1773 m and 1709 s (C=O of imide).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:13][CH:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[O:30])=[CH:25][CH:24]=1
Reactant: OC1CCN(Cc2ccc(F)cc2)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccc(F)cc3)CC2)cc1
Yield: 45.4 %

Procedure:
0.5 g (0.00239 mol) of 1-(4-fluoro-benzyl)-piperidin-4-ol and 0.67 ml (0.00478 mol) of triethylamine were dissolved in 15 ml of toluene, treated with 0.632 ml (0.00478 mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.355 g (59%) of 1-(4-fluoro-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as a yellow oil. MS: me/e=328 (C2H23FNO2+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([S:17]([CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])(=[O:19])=[O:18])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][NH2:43])[CH:37]=1>>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([S:17]([CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:35]=[CH:34][C:30]([C:31]([NH:43][CH2:42][C:38]4[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=4)=[O:33])=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])(=[O:18])=[O:19])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1OC
Reactant: NCc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: COc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4cccnc4)cc3)oc2C)cc1OC
Yield: 74 %

Procedure:
Reaction of oxalyl chloride (92 λL, 1.06 mmol) and benzoic acid 41 (294 mg, 0.70 mmol) with subsequent coupling to 3-pyridinylmethylamine (78 λL, 0.77 mmol) gave benzamide 42 (263 mg, 74%) as a white powder: mp (EtOAc) 104-108° C.; 1H NMR δ 9.23 (t, J=5.9 Hz, 1H, CONH), 8.57 (d, J=1.6 Hz, 1H, H-2′), 8.46 (dd, J=4.7, 1.5 Hz, 1H, H-6′), 8.01 (d, J=8.5 Hz, 2H, H-2, H-6), 7.92 (d, J=8.5 Hz, 2H, H-3, H-5), 7.74 (br d, J=7.5 Hz, 1H, H-4′), 7.37 (dd, J=7.5, 4.8 Hz, 1H, H-5′), 7.33 (dd, J=8.5, 2.1 Hz, 1H, H-6″), 7.25 (d, J=2.1 Hz, 1H, H-2″), 7.14 (d, J=8.5 Hz, 1H, H-5″), 4.63 (s, 2H, CH2SO2), 4.51 (d, J=5.8 Hz, 2H, CH2N), 3.84 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 2.15 (s, 3H, CH3); 13C NMR δ 165.5, 157.9, 153.1, 149.9, 148.8, 148.6, 148.0, 135.3, 135.1, 134.8, 129.7, 128.8, 128.0 (2), 126.2, 125.3 (2), 123.4, 122.2, 111.2, 110.6, 55.9, 55.7, 52.9, 40.4, 9.6; MS m/z 508.7 (MH+, 100%). Anal. calcd for C26H25N3O6S.¾CH3OH: C, 60.44, 5.31; N, 7.90. Found: C, 60.58; H, 5.17; N, 7.63%.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]([CH2:7][CH2:8]C=O)[C:4](=[O:11])[CH:3]=1.[CH:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C(O)C>[CH2:20]([O:19][CH:12]([O:16][CH2:17][CH3:18])[CH2:8][CH2:7][N:5]1[C:4](=[O:11])[CH:3]=[C:2]([Cl:1])[S:6]1)[CH3:21]
Reactant: O=CCCn1sc(Cl)cc1=O
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(CCn1sc(Cl)cc1=O)OCC

Procedure:
A solution of compound 5 (2.5 g, 0.013 mole), triethyl orthoformate (3.87 g, 0.026 mole) in 20 ml ethanol and p-toluenesulfonic acid (35 mg) was refluxed for 18 hours. Upon cooling, the mixture was treated with 0.2 ml of triethylamine and extracted with diethyl ether. The extract was then washed successively with NaHCO3 solution, water and brine. After drying (MgSO4), the solvent was removed in vacuo. The residual brown oil was purified by column chromatography on silica gel, using diethyl ether/hexane (4/1) as eluant. The product was obtained as a light brown oil; 2.2 g; IR (neat) 1625 cm-1 ; NMR (CDCl3) δ6.3 (s, 1H); 4.6 (t, 1H); 3.85 (t, 2H); 3.4-3.8 (m, 4H); 2.0 (q, 2H); 1.2 (t, 6H).