Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2Br)[CH2:8][CH2:7][CH:6]1[O:22]C(=O)C)(=O)C.[CH2:26]([OH:28])C.[CH:29]1([NH2:32])[CH2:31][CH2:30]1.[OH-].[Na+]>O.CO.CO.C(Cl)(Cl)Cl>[Cl:19][C:17]1[C:16]([Cl:20])=[CH:15][C:14]2[N:10]([C@H:9]3[C@H:5]([OH:4])[C@H:6]([OH:22])[C@@H:7]([CH2:26][OH:28])[CH2:8]3)[C:11]([NH:32][CH:29]3[CH2:31][CH2:30]3)=[N:12][C:13]=2[CH:18]=1
Reactant: NC1CC1
Reactant: CCO
Reactant: CC(=O)OC1CCC(n2c(Br)nc3cc(Cl)c(Cl)cc32)C1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: OC[C@H]1C[C@@H](n2c(NC3CC3)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O

Procedure:
(1S, 2R, 3R, 5R)-3-Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1-H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (500 mg 0.958 mmole) was refluxed in water: ethanol/2:1 (7.5 mL) with cyclopropylamine (0.66 mL, 9.6 mmole) under nitrogen for 18 hours. TLC (silica gel, 10% methanol-chloroform) showed complete conversion to a single spot with lower Rf than starting material. 1 N sodium hydroxide (0.96 mL) was added and volatiles were evaporated. The residue was chromatographed on a silica gel flash column. Title compound was eluted with 10% methanol-chloroform as a colorless glass which solidified from water:ethanol/2:1 (5 mL) to give off-white powder (207 mg, 59%, m.p. 116-118° C. dec.; 1H-NMR(DMSO-d6)δ and mass spectrum: identical with those of enantiomer described in Example 74; [α]20589 -12.2°, [α]20578 -12.5°, [α]20546 -13.5° (c=0.312, methanol).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].O=[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1>CO>[NH:1]1[C:9]2=[CH:8][N:7]=[CH:6][CH:5]=[C:4]2[C:3]([C:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]=2)=[CH:2]1
Reactant: c1cc2cc[nH]c2cn1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3cnccc23)CC1
Temperature: 70 °C
Yield: 99.6 %

Procedure:
6-Azaindole (4.48 g, 37.9 mmol) was dissolved in MeOH (70 mL) and KOH (4.68 g, 83.4 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (8.31 g, 41.7 mmol) were added. The reaction mixture was heated at 70° C. for 18 h. The residue was partitioned between water (250 mL) and DCM (250 mL) and the aq phase was extracted with DCM (2×250 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo to give the title compound as a yellow foam (11.3 g, 99%). LCMS (ES+): 300.1 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([NH2:19])=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[NH:19][S:27]([C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)(=[O:29])=[O:28])[N:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CNc2ccc3c(N)cccc3n2)o1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: Cc1ccc(CNc2ccc3c(NS(=O)(=O)c4ccc(F)cc4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=412.4 (M+H+), was prepared in accordance with the general method of example 39 from N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,5-diamine and 4-fluorobenzenesulfonylchloride.
Reaction SMILES: C(OC(=O)[N:7]([C@H:12]1[CH2:16][C@@H:15]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([Cl:27])=[N:21][C:22]=3[Cl:26])[C@H:14]([OH:28])[C@@H:13]1[OH:29])[C:8](=[O:11])[CH2:9][CH3:10])(C)(C)C.[NH2:31][CH2:32][CH:33]([C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=1)[C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1.CCN(C(C)C)C(C)C>C1COCC1>[ClH:26].[OH:40][C:37]1[CH:38]=[CH:39][C:34]([CH:33]([C:41]2[CH:42]=[CH:43][C:44]([OH:47])=[CH:45][CH:46]=2)[CH2:32][NH:31][C:22]2[N:21]=[C:20]([Cl:27])[N:19]=[C:18]3[C:23]=2[N:24]=[CH:25][N:17]3[C@@H:15]2[CH2:16][C@H:12]([NH:7][C:8](=[O:11])[CH2:9][CH3:10])[C@@H:13]([OH:29])[C@H:14]2[OH:28])=[CH:35][CH:36]=1
Reactant: CCC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: NCC(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccc(O)cc4)c4ccc(O)cc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Product: Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A reaction mixture comprising [(1S,2R,3S,4R)-4-(2,6-dichloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionyl-carbamic acid tert-butyl ester (Intermediate G) (2.00 g, 4.35 mmol) and 4,4′-(2-aminoethylidene)bis-phenol (prepared by the procedure of R. M. Schelkun et al. Bioorg. Med. Chem. Lett. 9 (1999) 2447-2452.) (1.19 g, 5.20 mmol) in dry THF (40 ml) is treated with DIPEA (0.67 g, 5.20 mmol) and stirred at room temperature for 2 days. The solvent is removed in vacuo and the title compound is obtained after purification by reverse phase column chromatography (Isolute™ C18, 20-70% acetonitrile in water—0.1% HCl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH2:11][C:12](=O)[CH3:13])[N:4]=1.[CH3:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24]N.C1(C)C=CC=CC=1.O>[Cl-].[Zn+2].[Cl-].C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]2[C:20]3[C:19](=[C:18]([CH2:17][O:16][CH3:15])[CH:23]=[CH:22][CH:21]=3)[NH:24][C:12]=2[CH3:13])[N:4]=1
Reactant: COCc1ccccc1NN
Reactant: COc1cc(OC)nc(CC(C)=O)n1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COCc1cccc2c(-c3nc(OC)cc(OC)n3)c(C)[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
Into a reactor were fed 6.2 g (31.6 m moles) of 1-(4,6-dimethoxypyrimidine-2-yl)-2-propanone, 4.8 g (31.5 m moles) of 2-methoxymethylphenylhydrazine, 4.76 g (34.9 m moles) of zinc chloride and 60 ml of toluene. Refluxing was made for 2 hours with heating. After the completion of the reaction, the reaction mixture was cooled to room temperature. Water and ethyl acetate were added and phase separation was made. The ethyl acetate layer was concentrated. The resulting crystals were washed with diisopropyl ether to obtain 4.57 g (14.6 m moles) of 3-(4,6-dimethoxypyrimidine-2-yl)-2-methyl-7-metoxymethylindole. Yield: 46%,
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1F.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC>[C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:25]3[C:24]([Cl:23])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:30])=[CH:19][CH:20]=2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1c(Cl)cccc1Cl
Reactant: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(O)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(Oc3c(Cl)cccc3Cl)cc2)C1
Temperature: 25 °C

Procedure:
A mixture of 3-[2-(4-hydroxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (200 mg; 0.65 mmol), 2,6-dichlorofluorobenzene (107.35 mg; 0.65 mmol) and K2CO3 (134.9 mg; 0.98 mmol), in DMF (10 mL) was heated at 100° C., for 2 days. After cooling to RT the mixture was diluted with Et2O and washed with water (3 times). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (Et2O) to afford 3-{2-[4-(2,6-dichloro-phenoxy)-phenyl]-morpholin-4-yl}-propionic acid tert-butyl ester: (150.00 mg).
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].[H-].[Na+].F[C:8]1[C:9]([S:14]([NH2:17])(=[O:16])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1>O1CCCC1>[F:1][CH2:2][CH2:3][O:4][C:8]1[C:9]([S:14]([NH2:17])(=[O:16])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: OCCF
Reactant: NS(=O)(=O)c1ncccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ncccc1OCCF
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5.76 ml of 2-fluoroethanol are added dropwise, with cooling, to a suspension of 6.54 g of sodium hydride (55.6% NaH in oil) in 120 ml of tetrahydrofuran so that the temperature does not exceed 20° C. When the dropwise addition is complete, the reaction mixture is stirred at room temperature for 15 minutes and then a further solution of 10.56 g of 3-fluoro-pyrid-2-ylsulfonamide in 60 ml of tetrahydrofuran is added dropwise over a period of 10 minutes. The reaction solution is then stirred for 10 minutes at room temperature and for 2 hours at reflux before it is cooled and concentrated. For purification, the oil remaining is chromatographed on a silica gel column using ethyl acetate/hexane 4/1. Evaporation of the eluant yields a light-coloured oil which crystallises spontaneously, yielding 5.88 g of title product which melts at 122°-123° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH:37]1(O)[CH2:42][CH2:41]C[CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH:26]2[CH2:41][CH2:42][CH2:37][CH2:38][CH2:39]2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: OC1CCCCC1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC4CCCCC4)c(C)c3C)c2cc1OC
Yield: 61.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-cyclohexanol (47 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (85 mg, yield 56%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:7]=[C:6]1[CH3:22].[OH:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:31]([O:30][C:28](=[O:29])[C:27]1[CH:33]=[CH:34][C:24]([O:23][CH2:2][CH2:3][CH2:4][N:5]2[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:7]=[C:6]2[CH3:22])=[CH:25][CH:26]=1)[CH3:32]
Reactant: Cc1nc(-c2ccccc2)c(-c2ccccc2)n1CCCBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCCn2c(C)nc(-c3ccccc3)c2-c2ccccc2)cc1
Temperature: 55 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
(Scheme 2 (H)) To a solution of 1-(3-Bromo-propyl)-2-methyl-4,5-diphenyl-1H-imidazole (0.80 g, 2.2 mmol) and ethyl 4-hydroxybenzoate (1.20 g, 7.2 mmol) in DMF (30 mL) was added K2CO3 (0.40 g, 2.9 mmol). The resulting mixture was stirred at 55° C. for 1 hour, quenched by addition of water, extracted by EtOAc, washed by water, and then was dried over MgSO4. After filtration and concentration in vacuo, the residue was purified by flash chromatography (SiO2: EtOAc/Hexanes). This compound was obtained as a pale yellow gum (0.92 g, 2.0 mmol, 94% yield): 1H NMR (DMSO): δ1.32 (t, 3H), 1.85 (m, 2H), 2.402 (s, 3H), 3.87 (m, 4H), 4.28 (q, 2H), 6.89 (d, J=8.82 Hz, 2H), 7.143 (m, 3H), 7.36 (m, 4H), 7.46 (m, 3H), 7.82 (d, J=8.85 mHz, 2H). Mass spec: 441.28 (MH+).
Reaction SMILES: [CH:1]([OH:14])([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.[NH2:15][C:16]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:17]=1[O:18][C:19]1[CH:27]=[CH:26][C:25]([C:28]([CH3:32])([CH3:31])[CH2:29][CH3:30])=[CH:24][C:20]=1[C:21]([O-:23])=[O:22].[F:41][C:42]([F:57])([F:56])[C:43]1[CH:44]=[C:45]([N:53]=[C:54]=[O:55])[CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1>N1C=CC=CC=1>[CH:1]([OH:14])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:41][C:42]([F:56])([F:57])[C:43]1[CH:44]=[C:45]([NH:53][C:54](=[O:55])[NH:15][C:16]2[CH:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=[CH:33][C:17]=2[O:18][C:19]2[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:32])[CH2:29][CH3:30])=[CH:24][C:20]=2[C:21]([O-:23])=[O:22])[CH:46]=[C:47]([C:49]([F:52])([F:50])[F:51])[CH:48]=1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2N)c(C(=O)[O-])c1
Agent: OC(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CCC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2NC(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(C(=O)[O-])c1

Procedure:
Benzhydrol-2-(2-amino-4-trifluoromethylphenoxy)-5-(1,1-dimethylpropyl)benzoate (200 mg, 0.0004 mol) and 3,5-di(trifluoromethyl)phenyl isocyanate (300 μL 0.002 mol) were mixed in pyridine, under argon, at room temperature for 16 h. The solvent was evaporated and the residue flash chromatographed (silica gel, ethyl acetate/hexane) to yield the title compound. 1H NMR (250 MHz, CDCl3) δ8.69 (d, 2H), 7.97 (d, 1H), 7.59 (s, 2H), 7.48 (d, 2H), 7.20-7.39 (m, 9H), 7.08 (d, 1H), 6.95 (s, 1H), 6.82 (dd, 2H), 2.05 (d, 1H), 1.64 (dd, 2H), 1.32 (s, 6H), 0.99 (d, 1H), 0.72 (t, 3H).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:21]=[C:20]([C:22]#[N:23])[N:19]([CH3:24])[N:18]=3)=[CH:13][CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3].[CH:25]12CC(C=C1)C=[CH:26]2>O1CCOCC1>[CH3:24][N:19]1[C:20]([C:22]#[N:23])=[CH:21][C:17]([C:14]2[CH:15]=[CH:16][C:11]([N:7]3[CH2:6][C@H:5]([CH2:4][N:1]4[CH:26]=[CH:25][N:3]=[N:2]4)[O:9][C:8]3=[O:10])=[CH:12][CH:13]=2)=[N:18]1
Reactant: C1=CC2C=CC1C2
Reactant: Cn1nc(-c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2)cc1C#N
Solvent: C1COCCO1
Product: Cn1nc(-c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2)cc1C#N
Temperature: 90 °C
Yield: 50.8 %

Procedure:
3-{4-[(5R)-5-(Azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-1-methyl-1H-pyrazole-5-carbonitrile (Intermediate 14, 00 mg, 0.62 mmol), bicyclo[2.2.1]hepta-2,5-diene (0.70 ml, 6.50 mmol) and dioxane (5 ml) were combined and warmed to 90° C. for 8 hours. The mixture was evaporated and purified by chromatography on silica gel eluting with ethyl acetate to give the title compound as an off-white solid (110 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH:21](OC)OC)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:28])[CH:3]=1.C(O)(C(F)(F)F)=O.[CH:36]1([NH2:41])[CH2:40][CH2:39][CH2:38][CH2:37]1.C(O)(=O)C.C([BH3-])#N.[Na+]>O>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][NH:41][CH:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:28])[CH:3]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCC(OC)OC
Reactant: NC1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCNC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.7 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-(2,2-dimethoxyethoxy)-6-methoxyquinazoline (210 mg, 0.52 mmol), water (5 ml) and TFA (5 ml) was stirred at ambient temperature for 3 hours then heated at 60° C. for 1 hour. The solution was allowed to cool, then diluted with water and the resulting precipitate was collected by filtration and dried. The solid was dissolved in methanol (10 ml) and cyclopentylamine (0.057 ml, 0.57 mmol) and dried 3 Å molecular sieves (2.5g) were added. The mixture was stirred for 30 minutes, glacial acetic acid (0.20 ml, 3.2 mmol) and sodium cyanoborohydride (150 mg, 2.4 mmol) were added and the reaction stirred for 4 hours then left to stand for 18 homs. The insolubles were removed by filtration and the solvent was removed from the filtrate by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (1008/1). The purified product was triturated with ether/hexane, collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-7-(2-cyclopentylaminoethoxy)-6-methoxyquinazoline (80 mg, 36%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([N+:29]([O-:31])=[O:30])[CH:23]=2)([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=1[N+:32]([O-:34])=[O:33].Cl>N1C=CC=CC=1>[S:2]([O:28][C:25]1[CH:26]=[CH:27][C:22]([C:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][S:2]([CH3:1])(=[O:4])=[O:3])=[C:8]([N+:32]([O-:34])=[O:33])[CH:9]=2)([C:18]([F:21])([F:19])[F:20])[C:14]([F:16])([F:15])[F:17])=[CH:23][C:24]=1[N+:29]([O-:31])=[O:30])([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cc(C(c2ccc(O)c([N+](=O)[O-])c2)(C(F)(F)F)C(F)(F)F)ccc1O
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Oc1ccc(C(c2ccc(OS(C)(=O)=O)c([N+](=O)[O-])c2)(C(F)(F)F)C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 85 %

Procedure:
11.5 g (0.1 mol) of methanesulfonyl chloride are added dropwise, at a reaction temperature of 0-5° C., to a mixture of 21.3 g (0.05 mol) of 2,2-bis-(4-hydroxy-3-nitrophenyl)-hexafluoropropane and 100 ml of pyridine. Stirring is continued for 1 hour at 5° C. and overnight at room temperature. The reaction mixture is then acidified, first with dilute hydrochloric and then with half-concentrated hydrochloric acid; the precipitate which is deposited is filtered off with suction and washed with water until neutral. The crude product (29.3 g) is then recrystallized from toluene, resulting in 24.8 g of analytically pure 2,2-bis-(4-mesyloxy-3-nitrophenyl)-hexafluoropropane to be isolated. Yield 85%; m.p. 119-121° C.
Reaction SMILES: C([Mg]Cl)(C)C.[Cl-].[Li+].Br[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.[O:19]=[C:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:22][CH2:21]1>C1COCC1>[OH:19][C:20]1([C:9]2[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=2)[CH2:21][CH2:22][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:24][CH2:25]1
Reactant: FC(F)(F)c1cncc(Br)c1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(O)(c2cncc(C(F)(F)F)c2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
Isopropylmagnesium chloride-lithium chloride complex (1.0M in THF) (5.31 mL, 5.31 mmol) was added dropwise to 3-bromo-5-(trifluoromethyl)pyridine (1.20 g, 5.31 mmol) in THF (10 mL) cooled to 0° C. over a period of 10 minutes. The resulting solution was stirred at 0° C. for 1 hour then benzyl 4-oxo-1-piperidinecarboxylate (1.24 g, 5.31 mmol) in THF (5 mL) was added dropwise. The mixture was allowed to warm slowly to room temperature and stirred for a further 1 hour before quenching with aqueous ammonium chloride (25 mL). The mixture was then extracted with tert butyl methyl ether. The extract was washed with water followed by saturated brine, dried over MgSO4, concentrated by evaporation then purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford benzyl 4-hydroxy-4-[5-(trifluoromethyl)pyridin-3-yl]piperidine-1-carboxylate (1.32 g, 65%) as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[NH:7][C:8]1[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=1[C:10]([NH:12][CH2:13][CH:14]=[CH2:15])=[O:11])([O-:3])=[O:2].[H-].[Na+].ClC1C=C(N=[C:33]=[O:34])C=CC=1>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]2[C:8]3[C:9](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:10](=[O:11])[N:12]([CH2:13][CH:14]=[CH2:15])[C:33]2=[O:34])[CH:20]=[CH:21][CH:22]=1)([O-:3])=[O:2]
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: C=CCNC(=O)c1ccccc1Nc1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCn1c(=O)c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
3.0 g of 2-(m-nitroanilino)-N-allylbenzamide was dissolved in 20 ml of tetrahydrofuran. To the solution was added 1.0 g of approximately 50 % sodium hydride and stirring was performed for 30 minutes. To this was added dropwise under cooling 4.6 g of m-chlorophenyl isocyanate, and the mixture was stirred for one hour, and then refluxed for 5 hours. After the reaction was complete, the solvent was distilled off from the resulting mixture. The residue thus obtained was recrystallized from methanol to give 2.3 g of 1-(m-nitrophenyl)-3-allylquinazoline-2,4(1H, 3H)-dione as colorless needles, melting at 165°-166° C.
Reaction SMILES: C(#N)C=C.[C:5]([OH:16])(=[O:15])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14].[C:17]([O:28][CH3:29])(=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH2:26]>>[C:5]([OH:16])(=[O:15])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[C:17]([O:28][CH3:29])(=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C=CCCCCCCCC(=O)O
Reactant: C=CCCCCCCCC(=O)OC
Solvent: C=CC#N
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OC

Procedure:
The cross metathesis reaction of acrylonitrile is preferably carried out with a compound chosen from 9-decenoic acid or methyl 9-decenoate, which are obtained from the ethenolysis of oleic acid or of methyl oleate, or of a triglyceride containing oleic acid; 10-undecenoic acid or methyl 10-undecenoate, which are obtained from the cracking of ricinoleic acid or from methyl ricinoleate, oleic acid, or methyl oleate; 9-octadecenedioic acid or methyl 9-octadecenedioate, which are obtained from homometathesis or from the fermentation of oleic acid, erucic acid, and methyl erucate; 12-tridecenoic acid or methyl 12-tridecenoate, which are obtained from the thermal cracking of lesquerolic acid; 13-tetradecenoic acid or methyl 13-tetradecenoate, which are obtained from the ethenolysis of erucic acid, lesquerolic acid and methyl lesquerolate, gondoic acid or methyl gondoate; 11-dodecenoic acid or methyl 11-dodecenoate, which are obtained from the ethenolysis of lesquerolic acid or of gondoic acid.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[C:5]1([CH3:13])[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7][CH:6]=1.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15][C:16]([CH3:18])=O.C(O)(=O)C.B(F)(F)F.CCOCC>O1CCCC1.[Cu]Cl>[CH3:18][C:16]1[NH:4][C:2](=[O:3])[NH:1][CH:11]([C:8]2[CH:9]=[CH:10][C:5]([CH3:13])=[CH:6][CH:7]=2)[C:15]=1[C:14]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: NC(N)=O
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1ccc(C=O)cc1
Agent: Cl[Cu]
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C)NC(=O)NC1c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.5 %

Procedure:
A suspension of urea (2,70 g; 45 mmol), copper (I) chloride (0,297 g; 3 mmol), p-tolualdehyde (3,53 ml; 30 mmol), ethyl acetoacetate (3,81 ml; 30 mmol), acetic acid (0,172 ml; 3 mmol) and boron trifluoride etherate (4,90 ml; 39 mmol) in dry tetrahydrofuran (60 mL) was heated to reflux for 21 h. After cooling to room temperature, the reaction mixture was quenched by adding a saturated solution of sodium hydrogen carbonate and the aqueous solution was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, the residue was suspended in toluene and left standing at room temperature for 24 h. The formed solid was filtered, washed with toluene and dried under reduced pressure to afford 7,45 g (91%) of the title compound as a green solid.