Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4](=[O:12])[C:3]=1[C:13](=[O:28])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[C:18]([Cl:27])[CH:17]=1.[H-].[Na+].S(OC)(O[CH3:35])(=O)=O>CN(C)P(N(C)C)(N(C)C)=O>[CH3:35][O:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4](=[O:12])[C:3]=1[C:13](=[O:28])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[C:18]([Cl:27])[CH:17]=1
Reactant: O=C(C=Cc1ccc(OC(F)(F)F)c(Cl)c1)c1c(O)c2ccccc2oc1=O
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1c(C(=O)C=Cc2ccc(OC(F)(F)F)c(Cl)c2)c(=O)oc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 15 ml of hexamethylphosphoramide was dissolved 1.37 g of 4-hydroxy-3-[3-[3-chloro-4-(trifluoromethoxy)phenyl]1-oxo-2-propenyl]-2H-1-benzopyran-2-one, to this solution was added 0.17 g of sodium hydride (60% oily), and this was stirred at room temperature for 30 minutes. Then, 0.8 ml of dimethyl sulfate, and this was stirred at 65° C. for 2 hours. Thereafter, the reaction mixture was added to ice water, and this was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was washed with t-butyl methyl ether to obtain 0.38 g of 4-methoxy-3-[3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-oxo-2-propenyl]-2H-1-benzopyran-2-one [Compound No. (2c-17)] as a pale yellow crystal.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][S:13][C:14]2[N:19]=[C:18]([OH:20])[CH:17]=[C:16]([CH3:21])[N:15]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.O>CS(C)=O>[CH3:21][C:16]1[N:15]=[C:14]([S:13][CH2:12][C:11]2[C:2]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:19]=[C:18]([OH:20])[CH:17]=1
Reactant: C1CCNCC1
Reactant: Cc1cc(O)nc(SCc2cc3ccccc3nc2Cl)n1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(O)nc(SCc2cc3ccccc3nc2N2CCCCC2)n1
Temperature: 90 °C
Yield: 60.8 %

Procedure:
A mixture of 2-{[(2-chloroquinolin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (0.5 g, 1.57 mmol) and piperidine (1.33 g, 15.7 mmol) in DMSO was heated overnight at 90° C. Water was then added, and the product was extracted in dichloromethane and back washed with water. The organic layer was separated, dried, and evaporated to provide the titled product as a beige solid (0.35 g, 61% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.09 (s, 3H), 2.31 (s, 3H), 4.95 (s, 2H), 6.04 (bs, 1H), 7.87 (t, J=7.8, 15.0 Hz, 1H), 8.08 9m, 2H), 8.26 (d, J=8.1 Hz, 1H), 8.48 (d, J=8.2 Hz, 1H), 9.00 (d, J=8.2 Hz, 1H); M+366.5.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[CH2:11][C@:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=2)([CH2:14][CH2:15][CH3:16])[N:13]=1)(C)(C)C.[F:27][C:28]([F:36])([F:35])[C:29]1([C:32](O)=[O:33])[CH2:31][CH2:30]1>>[NH2:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[CH2:11][C@:12]([C:17]2[CH:18]=[C:19]([NH:23][C:32]([C:29]3([C:28]([F:36])([F:35])[F:27])[CH2:31][CH2:30]3)=[O:33])[CH:20]=[CH:21][CH:22]=2)([CH2:14][CH2:15][CH3:16])[N:13]=1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: CCC[C@@]1(c2cccc(N)c2)CC(=O)N(C)C(NC(=O)OC(C)(C)C)=N1
Product: CCC[C@@]1(c2cccc(NC(=O)C3(C(F)(F)F)CC3)c2)CC(=O)N(C)C(N)=N1

Procedure:
The coupling of [(S)-4-(3-amino-phenyl)-1-methyl-6-oxo-4-propyl-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F5) and 1-trifluoromethyl-cyclopropanecarboxylic acid followed by deprotection of the intermediate yielded the title compound as a white solid. MS (ESI): m/z=397.2 [M+H]+.
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].[OH-].[Na+].Cl[O:12]C(C)(C)C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1.[Br:75][C:76]1[CH:81]=[C:80](/[CH:82]=[CH:83]/[C:84]2[CH:89]=[CH:88][C:87]([F:90])=[CH:86][CH:85]=2)[C:79]([F:91])=[CH:78][N:77]=1>C(O)CC.O>[Br:75][C:76]1[CH:81]=[C:80]([C@@H:82]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[C@@H:83]([C:84]2[CH:89]=[CH:88][C:87]([F:90])=[CH:86][CH:85]=2)[OH:12])[C:79]([F:91])=[CH:78][N:77]=1
Reactant: CC(C)(C)OCl
Reactant: Fc1ccc(/C=C/c2cc(Br)ncc2F)cc1
Reactant: CC(C)(C)OC(N)=O
Agent: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](c1cc(Br)ncc1F)[C@H](O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a solution of tert-butyl carbamate (189 mg, 1.612 mmol) in propanol (4 mL) was added sodium hydroxide (54.1 mg, 1.352 mmol) in water (2 mL) followed by tert-butyl hypochlorite (172 mg, 1.586 mmol). After 5 min the solution was cooled to 0° C. and treated with a solution of (DHQD)2PHAL (20.26 mg, 0.026 mmol) in propanol (1 mL). To this solution was added a solution of (E)-2-bromo-5-fluoro-4-(4-fluorostyryl)pyridine (154 mg, 0.520 mmol) in propanol (7 mL). To this solution was added potassium osmate dihydrate (7.66 mg, 0.021 mmol) dissolved in water (3 mL) in one portion. The reaction turned light orange and was allowed to stir at 0° C. overnight. The reaction was complete the next morning after warming to room temperature. The reaction was then quenched with a 10% solution of sodium thiosulfate and stirred for 30 min. The reaction was then extracted with diethylether (3×). The combined organic extracts were combined washed with water, then brine. The organic layer was separated, dried over sodium sulfate and evaporated in vacuo. The crude residue was purified by silica gel chromatography 25% EtOAc/75% Hexanes to 50%/50% EtOAc/Hexanes to afford tert-butyl (1R,2R)-1-(2-bromo-5-fluoropyridin-4-yl)-2-(4-fluorophenyl)-2-hydroxyethylcarbamate (56 mg, 0.130 mmol, 62.7% yield) along with its regioisomer as an inseparable mixture. LC/Mass spec. (Analytical HPLC method 2): RT=2.09 min. Mass=431.05 (MH)+.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:8][C:9](N)=[O:10]>O>[CH:1]1([NH:7][C:9]([NH2:8])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: NC(N)=O
Solvent: O
Product: NC(=O)NC1CCCCC1
Yield: 91.7 %

Procedure:
730 ml of mother liquor from Example 3, 50 ml of water, 495 g (5 mols) of cyclohexylamine and 312 g (5.2 mols) of urea are reacted and worked up as in Example 3. 652 g of N-cyclohexylurea (92% of theory) are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[Cl:24][C:25]1[CH:40]=[CH:39][C:28]([O:29][C:30]2[N:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32](Cl)=[O:33])=[CH:27][CH:26]=1>C1COCC1.C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([O:29][C:30]2[N:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:13]=3)[CH2:10][CH2:11]2)=[O:33])=[CH:39][CH:40]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN)CC2)c1
Reactant: O=C(Cl)c1cccnc1Oc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCNC(=O)c3cccnc3Oc3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-{3-[1-(4-aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 2-(4-chlorophenoxy)nicotinoyl chloride: ESMS m/e: 549.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.S(C1C=CC(C)=CC=1)(O[CH2:17][C:18]([F:21])([F:20])[F:19])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:19][C:18]([F:21])([F:20])[CH2:17][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCCc2cc(OCC(F)(F)F)ccc21
Temperature: 100 °C
Yield: 85.3 %

Procedure:
To a solution of 6-hydroxy-3,4-dihydro-1(2H)-naphthalenone (200 mg, 1.2 mmol) and 2,2,2-trifluoroethyl tosylate (345 mg, 1.4 mmol) in DMF (10 mL) was added potassium carbonate (339 mg, 2.5 mmol) at rt. The solution was heated at 100° C. overnight. The reaction was cooled, diluted with water (20 mL), and extracted with EtOAc (20 mL×3). Organics were dried (Na2SO4) and concentrated to give 250 mg (83%) of the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 2.12-2.16 (2H, m), 2.64 (2H, t, J=6.3 Hz), 2.95 (2H, t, J=6.3 Hz), 4.34-4.46 (2H, m), 6.78 (1H, d, J=2.4 Hz), 6.87 (1H, dd, J=2.4, 8.7 Hz), 8.05 (1H, dd, J=8.7 Hz).
Reaction SMILES: Br[CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[CH:22]=[C:23]([C:31]([CH3:37])([S:33]([CH3:36])(=[O:35])=[O:34])[CH3:32])[CH:24]=[C:25]3[C:30]=2[N:29]=[CH:28][CH:27]=[CH:26]3)[CH:16]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.[Cl:38][C:39]1[CH:40]=[C:41]([C:45](=[S:47])[NH2:46])[CH:42]=[CH:43][CH:44]=1>CN(C=O)C.O.C([O-])(O)=O.[Na+].CCOCC>[Cl:38][C:39]1[CH:40]=[C:41]([C:45]2[S:47][C:2]([C:15]3[CH:16]=[C:17]([C:21]4[CH:22]=[C:23]([C:31]([CH3:37])([S:33]([CH3:36])(=[O:35])=[O:34])[CH3:32])[CH:24]=[C:25]5[C:30]=4[N:29]=[CH:28][CH:27]=[CH:26]5)[CH:18]=[CH:19][CH:20]=3)=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=3)[N:46]=2)[CH:42]=[CH:43][CH:44]=1
Reactant: NC(=S)c1cccc(Cl)c1
Reactant: CC(C)(c1cc(-c2cccc(C(Br)C(=O)c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(c1cc(-c2cccc(-c3sc(-c4cccc(Cl)c4)nc3-c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 80 °C

Procedure:
To a solution of the alpha-bromoketone from step 4 (1.0 eq) in DMF (0.1M) was added 3-chlorobenzenecarbothioamide (1.0 eq). The mixture was heated at 40-120° C. for 1-3 h, cooled, diluted with water, saturated NaHCO3 solution and ether. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (Hexane:EtOAc) to afforded the title compound.
Reaction SMILES: [C:1]([C:5]1[N:9]2[C:10]([CH2:14][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][CH2:17][CH2:18][NH:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][CH:6]=1)(OC)=[O:2].[BH4-].[Li+].Cl>C1COCC1.CO>[OH:2][CH2:1][C:5]1[N:9]2[C:10]([CH2:14][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][CH2:17][CH2:18][NH:19][S:20]([C:23]([F:25])([F:24])[F:26])(=[O:21])=[O:22])=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][CH:6]=1
Reactant: COC(=O)c1cnc2cccc(CN(CCCNS(=O)(=O)C(F)(F)F)C(=O)OC(C)(C)C)n12
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCCNS(=O)(=O)C(F)(F)F)Cc1cccc2ncc(CO)n12
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To a solution of 396 mg (0.80 mmol) of 3-carbomethoxy-5-[N-tert-butoxycarbonyl-N-(3-trifluoromethanesulfonamidopropan-1-yl)aminomethyl]imidazo[1,2-a]pyridine in a mixture of 5.0 ml of THF and 1.0 ml of methanol was added, at room temperature, 87.12 mg (4.00 mmol) of lithium borohydride with small portions. The mixture was heated for 30 minutes under reflux. The reaction mixture was cooled to room temperature, and poured into ice-water. The mixture was neutralized with 1N HCl, and extracted with 50 ml of chloroform. The organic layer was washed with 50 ml of a saturated aqueous saline solution, which was dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol=20:1) to afford 269 mg of the desired compound (72%, a pale yellow liquid).
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].[CH:15](=[O:20])[CH2:16][CH2:17][CH:18]=[CH2:19]>>[CH3:3][C@H:2]([C@@H:15]([OH:20])[CH2:16][CH2:17][CH:18]=[CH2:19])[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Reactant: C=CCCC=O
Product: C=CCC[C@H](O)[C@@H](C)C(=O)n1c(=O)oc2ccccc21

Procedure:
Was prepared according to the method of paragraph C by reaction of N-propionyl-2-benzoxazolinone with 4-pentenal. 13C-NMR (CDCl3, 100 MHz): δ 176.28, 151.07, 142.20, 137.96, 127.75, 125.50, 124.89, 116.26, 115.19, 109.89, 70.93, 43.76, 33.12, 30.16, 10.21.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[N:21]([C:27]1[CH:28]=[C:29]([CH:33]=O)[CH:30]=[N:31][CH:32]=1)[CH2:20][CH2:19]2.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CO>[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[N:21]([C:27]1[CH:32]=[N:31][CH:30]=[C:29]([CH2:33][NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:28]=1)[CH2:20][CH2:19]2
Reactant: Nc1ccccc1
Reactant: O=Cc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: O=C1c2ccc(Cl)cc2CCN1c1cncc(CNc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.8 %

Procedure:
NaBH(OAc)3 (84 mg, 0.4 mmol) was added to a solution of 5-(6-chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-pyridine-3-carbaldehyde (28.6 mg, 0.1 mmol, example 9) and aniline (9.3 mg 0.1 mmol) in MeOH (3 mL) and the resulting reaction mixture was stirred at RT overnight before it was poured into ice-water and extracted with EtOAc (2×10 mL). The organic layers were dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by prep-HPLC to give title compound (7.2 mg, 20%) as a white solid. MS: 364.2 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Cl[CH2:21][C:22]1[C:23]2[C:28]([CH:29]=[C:30]3[C:35]=1[CH:34]=[CH:33][CH:32]=[CH:31]3)=[CH:27][CH:26]=[CH:25][CH:24]=2>>[CH:24]1[C:23]2[C:28](=[CH:29][C:30]3[C:35]([C:22]=2[CH2:21][N:7]2[C:8]([S:9][C:10]4[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=4)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:27]=[CH:26][CH:25]=1
Reactant: ClCc1c2ccccc2cc2ccccc12
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2c3ccccc3cc3ccccc23)c(=O)[nH]c1=O
Yield: 41.8 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 9-chloromethyl anthracene were reacted by the same way with the example 1 to obtain the titled compound (195 mg, yield: 41.8%).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:16])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl:19][C:20]1[CH:25]=[C:24]([NH2:26])[CH:23]=[CH:22][C:21]=1[OH:27]>O1CCOCC1>[ClH:16].[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][C:24]1[CH:23]=[CH:22][C:21]([OH:27])=[C:20]([Cl:19])[CH:25]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccc(O)c(Cl)c1
Product: Cl
Yield: 34.4 %

Procedure:
3-Butyryl-4-chloro-8-methoxyquinoline (2.64 g, 10 mmol), 2-chloro-4-aminophenol (1.58 g, 11 mmol) and 1,4-dioxan (20 ml) were warmed briefly to reflux, cooled, and the solid filtered off. Recrystallisation from pyridine gave 3-butyryl-4-(3-chloro-4-hydroxyphenylamino)-8methoxyquinoline hydrochloride (1.40 g, 34%), m.p. 267°-269° (dec).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:14][C:13]2[CH:12]=CN=[CH:9][C:8]=2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][C:17]=1[F:23])=[O:5])[CH3:2].[I-:24].[Na+].CN[C@@H]1CCCC[C@H]1[NH:34][CH3:35]>O1CCOCC1.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[S:14][C:13]2=[CH:12][N:34]=[CH:35][CH:9]=[C:8]2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:24])=[CH:18][C:17]=1[F:23])=[O:5])[CH3:2]
Reactant: [I-]
Reactant: CCOC(=O)c1sc2ccncc2c1Nc1ccc(Br)cc1F
Reactant: CN[C@@H]1CCCC[C@H]1NC
Agent: [Cu]I
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1sc2cnccc2c1Nc1ccc(I)cc1F
Temperature: 105 °C
Reaction time: 24 h
Yield: 742.4 %

Procedure:
A mixture of 3-(4-bromo-2-fluoro-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acid ethyl ester (209 mg, 0.53 mmol), copper (1) iodide (5 mg, 0.026 mmol), sodium iodide (159 mg, 1.06 mmol) and trans-N,N′-dimethyl-1,2-cyclohexane diamine (8.5 g, 0.053 mmol) in 1,4-dioxane (1.0 ml) was heated at 105° C. for 24 hours under an argon atmosphere. Copper (1) iodide (5 mg, 0.026 mmol) and trans-N,N′-dimethyl-1,2-cyclohexane diamine (8.5 μl, 0.053 mmol) were added and heating continued for a further 24 h. Once the reaction was cooled to room temperature, the mixture was partitioned between ethyl acetate (30 ml) and 10% v/v 0.880 ammonia/water (20 ml). The layers were separated and the aqueous phase was extracted with DCM (30 ml). The combined organic layer was dried over sodium sulphate, filtered and evaporated then the residue was purified by flash chromatography a Si-SPE (eluting with pentane:diethyl ether, gradient 90:10 to 70:30) to afford the title compound as a yellow solid (174 mg, 74%). LCMS (method B): RT=3.97 min, M+H+=443.
Reaction SMILES: [CH:1]([Cl:4])([CH3:3])[CH3:2].[Mg:5].[CH3:6][C:7]1[CH2:12][CH2:11][CH:10]([CH:13]=[O:14])[CH2:9][CH:8]=1.S(=O)(=O)(O)O>CCOCC>[CH:7]([Mg:5][Cl:4])([CH3:12])[CH3:6].[CH:1]([CH:13]1[CH:10]2[CH2:11][CH2:12][C:7]([CH3:6])([CH2:8][CH2:9]2)[O:14]1)([CH3:3])[CH3:2]
Reactant: CC(C)Cl
Reactant: [Mg]
Reactant: CC1=CCC(C=O)CC1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CC(C)C1OC2(C)CCC1CC2
Product: CC(C)[Mg]Cl
Temperature: 0 °C
Yield: 89.7 %

Procedure:
A solution of isopropyl magnesium chloride in ether is prepared by dropwise adding a solution of 410 grams (3.45 moles) of isopropyl chloride in 700 ml of dry ether to a stirred slurry of 76.5 grams of magnesium (3.15 moles) in 600 ml of dry ether under nitrogen at reflux. The resulting solution is stirred at reflux for 30 minutes. A solution of 372 grams of 4-methyl-3-cyclohexenecarboxaldehyde (3.38 moles) in 200 ml of ether is then added to the reaction mixture over a period of 1 hour at reflux under nitrogen. The resulting slurry is heated at reflux for 30 minutes and then cooled to 0° C. 1200 grams of 20% sulfuric acid is slowly added with external cooling over a 30 minute period. After the addition is complete, two clear layers appear. A distillation head is placed on the flask and ether is distilled from the reaction mixture at atmospheric pressure to a pot temperature of 90° C. 500 ml of water and 300 ml of isopropyl alcohol is added to the reaction mixture. Sulfuric acid (200 grams) is added slowly and the resulting solution is heated to reflux for 9 hours. At the end of this period the reaction mass is cooled. 500 ml of water and 200 ml of toluene is added thereto with stirring. The phases are allowed to separate and the aqueous phase is discarded. The organic phase is washed twice with H2O, with sufficient sodium carbonate added to the second wash to adjust to pH to 7-8. Distillation of the organic layer affords 255 grams of 3-isopropyl-1-methyl-2-oxabicyclo[2.2.2]octane.
Reaction SMILES: [CH:1]12[N:9]([CH:10]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=3)[C:11]3[CH:23]=[CH:22][C:14]([C:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=3)[CH:6]([CH2:7][CH2:8]1)[CH:5]1[NH:32][CH:2]2[CH2:3][CH2:4]1.[CH2:33](Br)[CH:34]=[CH2:35].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:35]([N:32]1[CH:2]2[CH:1]3[N:9]([CH:10]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=4)[C:11]4[CH:23]=[CH:22][C:14]([C:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=4)[CH:6]([CH:5]1[CH2:4][CH2:3]2)[CH2:7][CH2:8]3)[CH:34]=[CH2:33]
Reactant: C=CCBr
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(OC)c2)N2C3CCC2C2CCC3N2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN1C2CCC1C1CCC2N1C(c1ccc(C(=O)N(CC)CC)cc1)c1cccc(OC)c1
Yield: 96 %

Procedure:
A mixture formed of the compound obtained in example 5.1 (0.98 mmoles), of allyl bromide (1.5 equivalents) and of anhydrous potassium carbonate (3 equivalents) in acetone (25 ml) is heated at reflux for 14 hours. At the end it is filtered and the filtrate is evaporated under vacuum. The compound 4-[(10-allyl-9,10-diazatricyclo[4.2.1.12,5]dec-9-yl)-(3-methoxyphenyl)methyl]-N,N-diethyl benzamide (light solid) is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:24])[CH:3]=1.[CH3:25][N:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:28]4[CH2:29][CH2:30][N:26]([CH3:25])[C:27]4=[O:31])=[CH:3][C:4]=3[CH3:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CN1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3C)CC2)c(C)c1
Yield: 83 %

Procedure:
Using (4-bromo-2-methylphenyl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (233 mg) described in Preparation Example 118 and 1-methylimidazolidin-2-one (90 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (203 mg) was obtained.
Reaction SMILES: O[C:2]1[C:3]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:4]([CH:8]=[CH:9][CH:10]=1)C(N)=O.[F:15][C:16]([F:29])([F:28])[S:17]([O:20]S(C(F)(F)F)(=O)=O)(=[O:19])=[O:18].[N:30]1C=CC=C[CH:31]=1>C(OCC)(=O)C>[F:15][C:16]([F:29])([F:28])[S:17]([O:20][C:9]1[CH:10]=[CH:2][C:3]([CH2:11][CH:12]([CH3:13])[CH3:14])=[CH:4][C:8]=1[C:31]#[N:30])(=[O:19])=[O:18]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: c1ccncc1
Reactant: CC(C)Cc1c(O)cccc1C(N)=O
Solvent: CCOC(C)=O
Product: CC(C)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
At 0° C., to a stirred solution of the hydroxy-isobutylbenzamide (3.72 g, 19.3 mmol) in pyridine (15 mL) under argon was added trifluoromethanesulfonic anhydride (10.2 ml, 57.8 mmol). The reaction mixture was eventually warmed up to room temperature and stirred overnight. The reaction was diluted with ethyl acetate, and washed with 1N HCl (×2), water (×1) and brine (×1), dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (5% ethyl acetate: hexane) to afford 2.66 g of the desired product as a clear oil (50% yield). 1H NMR (CDCl3) δ 7.56 (s, 1 H), 7.50 (d, J=8 Hz, 1 H), 7.43 (d, J=8 Hz, 1 H), 2.57 (d, J=8 Hz, 2 H), 1.92 (m, 1 H), 0.97 (d, J=4 Hz, 6 H).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH2:8][O:9][CH2:10][CH2:11][OH:12])[CH2:3][O:4][CH2:5][CH2:6][OH:7].[C:14]([OH:18])(=O)[CH:15]=[CH2:16]>>[C:3]([O:12][CH2:11][CH2:10][O:9][CH2:8][C:2]([CH3:13])([CH3:1])[CH2:3][O:4][CH2:5][CH2:6][O:7][C:14](=[O:18])[CH:15]=[CH2:16])(=[O:4])[CH:2]=[CH2:1]
Reactant: C=CC(=O)O
Reactant: CC(C)(COCCO)COCCO
Product: C=CC(=O)OCCOCC(C)(C)COCCOC(=O)C=C

Procedure:
One mole of neopentyl glycol (viz., 2,2-dimethylpropane-1,3-diol) is reacted with two moles ethylene oxide to produce 5,5-dimethyl-3,7-dioxanonane-1,9-diol. One mole of 5,5-dimethyl-3,7-dioxanonane-1,9-diol is reacted with two moles acrylic acid to produce 1,9-diacrylyloxy-5,5-dimethyl-3,7-dioxanonane.