Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]([Cl:19])([Cl:18])[CH:11](O)[NH:12][C:13](=[O:16])[CH2:14][Cl:15].S(=O)(=O)(O)[OH:21]>>[Cl:9][C:10]([Cl:18])([Cl:19])[CH:11]([NH:8][C:1](=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[NH:12][C:13](=[O:16])[CH2:14][Cl:15]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccccc1
Reactant: O=C(CCl)NC(O)C(Cl)(Cl)Cl
Product: O=C(CCl)NC(NC(=O)c1ccccc1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Benzonitrile (5.2g) was added dropwise to a solution of 1,1,1-trichloro-2-hydroxy-2-(chloroacetamido)ethane (12.05g) in concentrated sulphuric acid (50 ml). The temperature was kept at 0° during the addition. The mixture was stirred at room temperature for 4 hours, then left overnight. The reaction mixture was poured on to ice. The precipitated solid was collected, washed with water and dried (19.6g). Recrystallisation from nitromethane gave pure 1,1,1-trichloro-2-benzamido-2-(chloroacetamido)ethane (14.6g, m.p. 210°-12°)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:20]([NH:22][C:23]1[CH:24]=[N:25][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:28]=1)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:39]1[CH:43]=[C:42]([CH2:44]O)[CH:41]=[N:40]1)=O)(C)(C)C>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:20]([N:22]([C:23]1[CH:24]=[N:25][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:28]=1)[CH2:44][C:42]1[CH:43]=[N:39][NH:40][CH:41]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(OCc2ccccc2)c2c1C(C(=O)Nc1ccc(C(C)C)nc1)CCC2
Reactant: CC(C)(C)OC(=O)n1cc(CO)cn1
Product: Cc1ccc(OCc2ccccc2)c2c1C(C(=O)N(Cc1cn[nH]c1)c1ccc(C(C)C)nc1)CCC2
Yield: 58.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 82 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-8-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.75 g) and 1-(tert-butyloxycarbonyl)-4-(hydroxymethyl)pyrazole (0.84 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-8-methyl-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.22 g) was obtained.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]1[C:9](=[O:10])[CH2:8][NH:7][C:6]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)=[N:5]1.[H-].[Na+].Cl[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25]>O1CCCC1>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]1[C:9](=[O:10])[CH2:8][N:7]([C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])[C:6]([C:11]2[CH:12]=[C:13]([Cl:18])[CH:14]=[C:15]([Cl:17])[CH:16]=2)=[N:5]1
Reactant: C=CCOC(=O)Cl
Reactant: O=C1CNC(c2cc(Cl)cc(Cl)c2)=NN1CC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC(=O)N1CC(=O)N(CC(F)(F)F)N=C1c1cc(Cl)cc(Cl)c1
Reaction time: 0.08 h
Yield: 93.2 %

Procedure:
To a solution of 1-(2,2,2-trifluoroethyl)-3-(3,5-dichlorophenyl)-4,5-dihydro-1,2,4-triazin-6-one (110 mg, 0.34 mmol) in 5 mL tetrahydrofuran at was added sodium hydride (30 mg, 0.67 mmol). After the reaction stirred 5 min, the allyl chloroformate (0.07 mL, 0.67 mmol) was added dropwise. After the reaction was heated at reflux for 6 h, it was quenched with water and diluted with ethyl acetate. The two layers were separated and the aqueous phase was extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Flash column chromatography (100% hexanes-10% ethyl acetate/hexanes) afforded the acylated product 1-(2,2,2-trifluoroethyl)-3-(3,5-dichlorophenyl)-4-allyloxycarbonyl-4,5-dihydro-1,2,4-triazin-6-one (130 mg, 93%) as a yellow oil in 100% purity by gas chromatography (GC).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][NH:22]4)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].C1COCC1.C(C(O)=O)(F)(F)F>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][NH:22]4)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1OCC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCOc1ccc(-c2nc(-c3cccc4c3CCN4)no2)cc1OCC
Yield: 43 %

Procedure:
To a solution of the product of Step B (0.06 g; 0.172 mmol) in 1M BH3 in THF (0.35 ml; 0.35 mmol) CF3CO2H (0.4 ml) was added drop wise at 0° C. with stirring. After the addition was completed (˜5 min) the reaction was quenched with H2O (0.5 ml) and solvents were removed under reduced pressure. The residue was diluted to 10 ml with EtOAc and was washed with 10% NaOH (2×2 ml), brine and dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.026 g; 43%) as a creamy foam, which was used in the next step without further purification. 1H-NMR (CDCl3) 1.49 (m, 6H); 1.7 (broad s, 1H+H2O); 3.45 (tr, 2H, J=8.9 Hz); 3.65 (tr, 2H, J=8.9 Hz); 4.19 (m, 4H); 6.75 (d, 1H, J=7.7 Hz); 6.97 (d, 1H, J=8.5 Hz); 7.17 (tr, 1H, J=7.7); 7.52 (d, 1H, J=7.2 Hz); 7.68 (d, 1H, J=1.9 Hz); 7.78 (dd, 1H, J=1.9, 7.2 Hz).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:7]([S:12]([NH2:15])(=[O:14])=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([NH:26][C:27](=O)[O:28]C2C=CC=CC=2)[N:19]=1.N12CCCCC1C=NCCC2>C(#N)C>[CH2:1]([NH:5][C:6]1[C:7]([S:12]([NH:15][C:27]([NH:26][C:20]2[N:19]=[C:18]([O:17][CH3:16])[CH:23]=[C:22]([O:24][CH3:25])[N:21]=2)=[O:28])(=[O:14])=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: CCCCNc1cccnc1S(N)(=O)=O
Agent: C1=NCCCN2CCCCC12
Solvent: CC#N
Product: CCCCNc1cccnc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Reaction time: 0.5 h

Procedure:
The following are added in succession to a mixture of 2.75 g of 3-n-butylaminopyridin-2-ylsulfonamide in 40 ml of acetonitrile: 3.5 g of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate and 1.97 ml of 1,5-diazabicyclo[5.4.0]undec-5-ene. The reaction mixture is stirred for 30 minutes and evaporated, the oily residue is triturated with 10 ml of 2N hydrochloric acid and subsequently with 10 ml of ice/water and a little diethyl ether, and the mixture is filtered. The filter residue is subsequently washed with a little water and diethyl ether and dried. 4.39 g of N-(3-n-butylaminopyridin-2-ylsulfonyl)-N'-(4,6-dimethoxypyrimidin-2-yl)urea (compound No. 1.001) of a melting point of 118°-119° C. are obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:26](=[O:35])[C:27]2[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=2)([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:17]=2[CH3:24])[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[CH3:33][C:31]1[CH:32]=[C:27]([CH:28]=[C:29]([CH3:34])[CH:30]=1)[C:26]([C:11]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:17]=2[CH3:24])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:35]
Reactant: COc1cccc(C(=O)NC2(C(=O)c3cc(C)cc(C)c3)CCN(C(=O)OC(C)(C)C)CC2)c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(C(=O)NC2(C(=O)c3cc(C)cc(C)c3)CCNCC2)c1C

Procedure:
A solution of 4-(3,5-dimethyl-benzoyl)-4-(3-methoxy-2-methyl-benzoylamino)-piperidine-1-carboxylic acid tert-butyl ester in CH2Cl2 and trifluoroacetic acid (20 mL) was stirred at room temperature for 2 hours. The solvent was removed on a rotary evaporator, and the residue was partitioned between ether (150 mL) and saturated aqueous NaHCO3 (50 mL). Significant amounts of undissolved solid were present. The ether layer was dried over MgSO4 and evaporated to leave N-[4-(3,5-dimethyl-benzoyl)-piperidin-4-yl]-3-methoxy-2-methyl-benzamide (0.50 g) as a solid. Additional product (0.11 g) was obtained by extraction and concentration of the aqueous layer with CH2Cl2 (2×50 mL). 1H NMR (500 MHz, CDCl3) δ(ppm): 7.55 (s, 2H), 7.12 (m, 2H), 6.87 (d, 1H), 6.77 (d, 1H), 6.65 (br, 1H), 3.8 (s, 3H), 3.1 (br, 2H), 2.95 (br, 2H), 2.3 (s, 6H), 2.25 (br s, 4H), 1.94 (s, 3H).
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([Br:15])[C:13]=1[OH:14])[CH:9]=[O:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:14][C:13]1[C:6]([Br:5])=[CH:7][C:8]([CH:9]=[O:10])=[CH:11][C:12]=1[Br:15]
Reactant: BrCCBr
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)c(OCCBr)c(Br)c1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
1,2-Dibromoethane (62 mL, 0.72 moles) was added to a mixture of 3,5-dibromo-4-hydroxybenzaldehyde (10 g, 36 mmoles) and potassium carbonate (25 g, 180 mmoles) in DMF (100 ml) and the resulting mixture was stirred vigorously at 70° C. for 16 hours. After cooling, the mixture was poured into water (300 mL) and extracted with ethyl acetate (400 mL). Water (200 mL) was added to the aqueous phase and this was extracted with ethyl acetate (150 mL). The combined organic phases were washed with saturated sodium chloride (3×150 mL), dried over MgSO4 and evaporated in vacuo. The residue was dissolved in refluxing 96% ethanol (60 mL). Water (15 mL) was added and after cooling, filtration, washing with 60% ethanol and drying 10.7 g (77%) of 4-(2-bromoethoxy)-3,5-dibromobenzaldehyde was isolated in two crops. M.p. 84-85° C.
Reaction SMILES: [CH:1](=[N:8][C:9](=[CH:15][CH2:16][CH2:17][CH3:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CCN(CC)CC.C(Cl)(=[O:34])C1C=CC=CC=1>C1COCC1.C(Cl)Cl>[CH2:13]([O:12][C:10](=[O:11])[C:9]([NH:8][C:1](=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:15][CH2:16][CH2:17][CH3:18])[CH3:14]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCC=C(N=Cc1ccccc1)C(=O)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCC=C(NC(=O)c1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
Schiff base (6) (97.1 g, 0.4M) is dissolved in THF (250 ml) and shaken in a separatory funnel with 10% aqueous HCl (1 l) for 5 minutes. This mixture is washed with Et2O (3×250 ml), the aqueous phase separated, neutralized with solid NaHCO3 and extracted with CHCl3 (3×250 ml). The combined CHCl3 extracts are dried over anhydrous MgSO4, filtered and evaporated to yield a pale yellow liquid, 57.9 g (93% yield). 'H-N.M.R. (CDCl3 /TMS): δ=1.30 (t, 3H, --CH2CH3); 1.50 (s, 2H, --NH2); 1.47-2.38 (m, 4H, --CH2CH2 --); 3.43 (dd, 1H, >CH--CH2 --, J=6 and 8 Hz); 4.20 (q, 2H, --CH2CH3); 4.80-5.20 (m, 2H, --CH=CH2); 5.45-6.20 ppm (m, 1H, --CH=CH2). The latter is stirred in CH2Cl2 (600 ml) containing Et3N (51 ml, 0.37M) and cooled in an ice bath before benzoyl chloride (43 ml, 0.37M) in CH2Cl2 (100 ml) is added dropwise over a period of 1/2 hour. The reaction mixture is allowed to warm to room temperature and stirred overnight. The formed Et3N HCl is removed by filtration and the filtrate is evaporated to dryness. The residue is taken up in Et2O, filtered, washed with 5% aqueous HCl (3×100 ml), saturated aqueous NaHCO3 (3×100 ml), saturated aqueous NaCl (3×100 ml), dried over anhydrous MgSO4 and evaporated to dryness. The white solid thus obtained is recrystallized twice from Et2O/hexane to yield 64.3 g of the desired product (7) (67% yield) m.p. 68°-70° C. The two recrystallizations are required in order to remove an impurity which turned out to be the bis alkylated material (m.p. 46°-49° C.) that is carried along. 'H-N.M.R. (CDCl3 /TMS): δ=1.3 (t, 3H, --CH2CH3); 1.80-2.34 (m, 4H, --CH2CH2 --); 4.28 (q, 2H, --CH2CH3); 4.64-5.15 (m, 3H, >CH=CH2 and CHCO2Et); 5.53-6.0 (m, 1H, CHCH2); 6.70 (d, 1H, >NH); 7.30-7.85 ppm (m, 5H, Ph).
Reaction SMILES: CC1C=CC(C(O[C@H]([C@@H](OC(=O)C2C=CC(C)=CC=2)C(O)=O)C(O)=O)=O)=CC=1.[F:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:39]=1[N:38]=[C:37]([N:40]1[CH2:45][CH2:44][N:43]([C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH3:53])[CH:47]=3)[CH2:42][CH2:41]1)[N:36]([C:54]1[CH:59]=[C:58]([C:60]([F:63])([F:62])[F:61])[CH:57]=[CH:56][C:55]=1[O:64][CH3:65])[CH:35]2[CH2:66][C:67]([O:69]C)=[O:68].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:39]=1[N:38]=[C:37]([N:40]1[CH2:41][CH2:42][N:43]([C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH3:53])[CH:47]=3)[CH2:44][CH2:45]1)[N:36]([C:54]1[CH:59]=[C:58]([C:60]([F:63])([F:62])[F:61])[CH:57]=[CH:56][C:55]=1[O:64][CH3:65])[C@@H:35]2[CH2:66][C:67]([OH:69])=[O:68]
Reactant: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3cccc(OC)c3)CC2)N1c1cc(C(F)(F)F)ccc1OC
Agent: Cc1ccc(C(=O)O[C@@H](C(=O)O)[C@@H](OC(=O)c2ccc(C)cc2)C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cccc(N2CCN(C3=Nc4c(F)cccc4[C@@H](CC(=O)O)N3c3cc(C(F)(F)F)ccc3OC)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.6 %

Procedure:
(2R,3R)-2,3-Bis[(4-methylbenzoyl)oxy]succinic acid-methyl {8-fluoro-2-[4-(3-methoxyphenyl)-piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate (1:1 salt) (170 g) are suspended in ethyl acetate (850 ml) and shaken with saturated aqueous sodium bicarbonate solution (850 ml) until both phases are clear (ca. 5 min.). The phases are separated, and the solvent of the organic phase is replaced at normal pressure with 1,4-dioxane up to a final temperature of 99° C. (a total of 2.55 l of solvent is distilled off and 2.55 l of 1,4-dioxane are employed in portions). The mixture is cooled to room temperature and stirred at room temperature for 18 h with 1N sodium hydroxide solution (525 ml). Subsequently, the pH is adjusted to 7.5 using concentrated hydrochloric acid (ca. 35 ml), MIBK (850 ml) is added, then the pH is readjusted to 7.0 using concentrated hydrochloric acid (ca. 10 ml). The phases are separated, and the organic phase is dried over sodium sulphate and concentrated. The residue is dissolved in ethanol (350 ml) and concentrated, then again dissolved in ethanol (350 ml) and concentrated at 50° C. A total of 91.6 g of (R)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid are thus obtained as an amorphous solid, corresponding to 91.6% of theory.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[C:7](=[O:12])([O:10]C)[O:8][CH3:9].[C:13](=O)=O>CO>[CH3:9][O:8][C:7](=[O:10])[O-:12].[CH3:1][N+:2]1[CH:6]=[CH:5][N:4]([CH3:13])[CH:3]=1
Reactant: O=C=O
Reactant: COC(=O)OC
Reactant: Cn1ccnc1
Solvent: CO
Product: COC(=O)[O-]
Product: Cn1cc[n+](C)c1
Temperature: 130 °C
Reaction time: 60 h

Procedure:
82 parts of 1-methylimidazole, 135 parts of dimethyl carbonate and 192 parts of methanol were put into an autoclave made of a stainless steel equipped with a cooling condenser and mixed homogenously. After nitrogen substitution, the temperature was then raised to 130° C. while being sealed, so as to initiate a reaction. At the beginning, the pressure was approximately at 4.5 Kg/cm2, but it was gradually raised due to generation of carbon dioxide, so that the gasses were appropriately released from the upper part of the cooling condenser, adjusted at a pressure of about 7 Kg/cm2 or less. After 60 hours, they were cooled at 30° C., and the result of the reacted solution by means of 1H-NMR showed that 1-methylimidazole was disappeared and 1,3-dimethylimidazolium monomethyl carbonate was produced approximately under a quantitative theory. Into 401 parts of the resultant solution of 1,3-dimethylimidazolium monomethyl carbonate, methanol and dimethyl carbonate, 205 parts of an aqueous solution of fluoroboric acid at a concentration of 42 wt % were gradually put in drops with stirring at a room temperature over a period of about 30 minutes. As putting them in drops, bubbles of carbon dioxide were generated. Finishing the dropping and the generation of the bubbles, all the solvents were removed at a pressure of 20 Torr and at a temperature of 150° C., so as to obtain 180 parts of a white solid (6). The examinations of 1H-NMR, 9F-NMR, 13C-NMR and HPLC of the white solid (6) resulted in showing that 98 mol % of 1,3-diethyl imidazolium tetrafluoroborate (which is hereinafter shortened as “DMI.BF4”), 2 mol %, in total, of 1,3-dimethyl-4-carboxylate imidazolium and 1,3-dimethyl-4-carboxy-5-carboxylate imidazolium.
Reaction SMILES: [CH3:1][S:2]([Cl:5])(=[O:4])=[O:3].[OH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:35])/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([NH:27][O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)=[O:26])=[CH:19][CH:18]=2)=[CH:10][CH:9]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.O>[O:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH:29]1[O:28][NH:27][C:25](/[CH:24]=[CH:23]/[C:20]1[CH:21]=[CH:22][C:17](/[CH:16]=[CH:15]/[C:14]([C:11]2[CH:10]=[CH:9][C:8]([CH2:7][O:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=2)=[O:35])=[CH:18][CH:19]=1)=[O:26].[Cl:5][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:35])/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([NH:27][O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)=[O:26])=[CH:19][CH:18]=2)=[CH:10][CH:9]=1
Reactant: O=C(/C=C/c1ccc(/C=C/C(=O)c2ccc(CO)cc2)cc1)NOC1CCCCO1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)OCc1ccc(C(=O)/C=C/c2ccc(/C=C/C(=O)NOC3CCCCO3)cc2)cc1
Product: O=C(/C=C/c1ccc(/C=C/C(=O)c2ccc(CCl)cc2)cc1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (388 mg, 3.39 mmol) was added to a stirred solution of (E)-3-{4-[(E)-3-(4-hydroxymethyl-phenyl)-3-oxo-propenyl]-phenyl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (1.15 g, 2.82 mmol) and TEA (1.18 ml, 8.46 mmol) in DCM (20 ml) and DMF (20 ml). The mixture was stirred at room temperature for 1 h and then additional methanesulfonyl chloride (258 mg, 2.25 mmol) and TEA (0.393 ml, 2.82 mmol) were added. After stirring for additional 1 h the solution was diluted with water and brought to basic conditions with 5% NaHCO3. The resulting slurry was extracted with AcOEt and the organic phase was washed with water, dried over Na2SO4 and evaporated in vacuo. The crude reaction mixture was purified by column chromatography (eluent: petroleum ether/AcOEt 1:1) to give 277 mg of the title compound and 423 mg of (E)-3-{4-[(E)-3-(4-chloromethyl-phenyl)-3-oxo-propenyl]-phenyl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([CH3:9])[CH:8]=1)[CH3:2].C(O)C.Cl.[N:15]([O-])=[O:16].[Na+]>O>[CH2:1]([C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([CH3:9])[C:8]=1[N:15]=[O:16])[CH3:2]
Reactant: O=N[O-]
Reactant: CCc1cc(C)cc(O)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCc1cc(O)cc(C)c1N=O
Temperature: 0 °C

Procedure:
102 g (749 mmol) of 3-ethyl-5-methylphenol are introduced into 600 ml of ethanol. While stirring vigorously, 600 ml of concentrated hydrochloric acid are added dropwise, keeping the reaction vessel at room temperature by cooling. The reaction mixture is then cooled to 0° C. At this temperature, 77.5 g (1123.5 mmol) of sodium nitrite in 78 ml of deionised water are added dropwise. The resulting mixture is then stirred at 5° C. for 2 hours and subsequently poured into 3 liters of ice-water, when the title compound crystallises out. It is filtered off, washed several times with ice-water and recrystallised from methanol. Yield 88.7 g (71.8% of theory); melting point 138° C. (with decomposition).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13](I)=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C([Li])(C)(C)C.B(OC)(OC)OC.[CH3:30][CH2:31][CH2:32][CH2:33]CC.[CH2:36]1[CH2:40]O[CH2:38][CH2:37]1>C(OC(=O)C)C>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:7]3[N:8]([CH3:13])[C:37]4[CH:38]=[C:32]([CH3:33])[C:31]([CH3:30])=[CH:40][C:36]=4[N:15]=3)=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: CCCCCC
Reactant: C1CCOC1
Agent: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3nc4cc(C)c(C)cc4n3C)c(C)nc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In an oven dried nitrogen purged 3 neck 50 mL round bottom flask, 1.00 g (2.91 mmol) of 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine in 60 mL of dry THF is cooled to −78° C. 4.12 mL (7.00 mmol) of 1.7M t-butyllithium in hexanes is added and reaction is stirred at −78° C. for 1 h. 0.818 mL (7.30 mmol) of trimethyl borate is added and reaction is followed by MS and TLC (1:1 hexane:ethylacetate) See indication of the title compound by MS. Allow to stir for an additional hour, quench with 1N hydrochloric acid, dilute with ethyl acetate, separate layers, extract aqueous 3×100 mL ethyl acetate, dry (MgSO4), and concentrated. Triturate in hexanes and filter off solid to give the title compound 6.4 g (53%), MS, ES+=262.2 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9]CO1)C.[H-].[Na+].[CH3:14]N(C=O)C.C(Br)CCC>C1COCC1.C1(C)C=CC=CC=1>[CH2:6]([O:5][CH2:3][C@@H:2]([OH:1])[CH3:14])[CH2:11][CH2:10][CH3:9]
Reactant: C[C@@H](CO)OC1CCCCO1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCCCBr
Product: CCCCOC[C@H](C)O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
(S)-1-hydroxy-2-tetrahydropyranyloxypropane (120 g, 0.75 mol) was dropwise added to sodium hydride (44.8 g, 1.87 mol) in THF (400 ml), followed by adding DMF (200 ml), agitating the mixture for 2 hours, dropwise adding to the mixture, butyl bromide (112.4 g, 0.82 mol) at 30° C. or lower, agitating the mixture at room temperature for 6 hours, adding toluene, sufficiently agitating the mixture, washing the resulting organic layer with 2N-NaOH aqueous solution and then with water, drying it over anhydrous magnesium sulfate, distilling off toluene, adding to the resulting oily residue, pyridium p-toluenesulfonate (18 g) and ethanol (500 ml), heating the mixture at 70° C. for one hour, distilling off ethanol, adding toluene to the residue, sufficiently washing the mixture with water, distilling off toluene and distilling the residue to obtain (S)-1-butyloxy-2-hydroxypropane (79.3 g) (b.p. 87° C./35 mmHg) (αD24 =+3.6 (l=1.0 dm neat)).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:11][C:12]1[C:21]([Cl:22])=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]1)=[N:17]2>>[Cl:22][C:21]1[C:12]([NH:11][C:8](=[O:10])[CH2:7][CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([N:23]1[CH2:24][CH2:25][CH:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:27][CH2:28]1)[CH:15]=[CH:14]2
Reactant: O=C(O)CCC1CCCC1
Reactant: CCOC(=O)C1CCN(c2ccc3c(N)c(Cl)ccc3n2)CC1
Product: CCOC(=O)C1CCN(c2ccc3c(NC(=O)CCC4CCCC4)c(Cl)ccc3n2)CC1

Procedure:
Prepared according to the method of example 62(a), using cyclopentanepropanoic acid (256 mg) and 1-(5-amino-6-chloro-2-quinolinyl)-4-piperidinecarboxylic acid, ethyl ester Example 77(a)) (200 mg), to afford the sub-titled compound (240 mg).