Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[C:38](O)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.Cl.C(N=C=NCCCN(C)C)C.Cl>C(#N)C.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([S:34]([NH:37][C:38](=[O:45])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)(=[O:36])=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1c(-c2c(S(N)(=O)=O)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1c(-c2c(S(=O)(=O)NC(=O)c3ccccc3)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
(+)-1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide (prepared in Example 209) (46 mg) was dissolved in acetonitrile (1 ml) and thereto were added benzoic acid (13 mg), 4-dimethylaminopyridine (21 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (25 mg) and the resulting mixture was stirred for three hours at room temperature. To the reaction solution were added 1N hydrochloric acid (20 ml) and ethyl acetate (30 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with 1N hydrochloric acid (20 ml) and saturated saline (30 ml) successively, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford N-(1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-4-ylsulfonyl)benzamide (51 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.[C:16](O)(=[O:19])[CH:17]=[CH2:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>ClC(Cl)(Cl)C.C(C1CC(=CN(C)C)C=C(C(C)(C)C)C=1O)(C)(C)C>[C:16]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)(=[O:19])[CH:17]=[CH2:18]
Reactant: C=CC(=O)O
Reactant: O=C(O)c1ccc(OCCCCO)cc1
Agent: CN(C)C=C1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(Cl)(Cl)Cl
Product: C=CC(=O)OCCCCOc1ccc(C(=O)O)cc1
Yield: 63.2 %

Procedure:
276.6 g of 4-chlorobutyl acetate (1.8 mol) were added to a solution of 249 g of ethyl 4-hydroxybenzoate (1.5 mol), 3 g of potassium iodide (0.018 mol) and 248 g of potassium carbonate (1.8 mol) in 2 l of DMF, and the mixture was stirred at 90° C. for 11 hours. The reaction mixture was poured into 5 l of ice-water, and the precipitate was filtered off with suction and washed with 4 l of ice-water. The crude product was dissolved in 3 l of ethanol, potassium hydroxide (400 g) was added, and the mixture was refluxed for 3 hours. The reaction mixture was poured into 6 l of ice-water and acidified using concentrated hydrochloric acid, and the precipitate was filtered off. The precipitate was washed with water until neutral and then dried, giving 282.1 g of 4-(4′-hydroxybutoxy)benzoic acid (yield 89%). b) A solution of 282 g of 4-(4′-hydroxybutoxy)benzoic acid (1.34 mol), 230 ml of freshly distilled acrylic acid (3.35 mol), 0.3 g of 2,6-di-tert-butyl-4-(dimethylaminomethylene)phenol (Ethanox® 703) and 23.7 g of p-toluenesulfonic acid in 1.1 liter of 1,1,1-trichloroethane was refluxed for 10 hours on a water separator. The reaction mixture was cooled to 60° C.-70° C. and stirred into 2.5 l of petroleum ether, and the precipitate was filtered off. After washing with petroleum ether, the precipitate was dried for 24 hours at room temperature under reduced pressure, giving 223.7 g of 4-(4′-acryloxybutoxy)benzoic acid (yield 60%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7].Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[N:33]=[CH:32][CH:31]=[N:30]2)=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]2[CH2:18][CH2:19]2)=[CH:11][CH:10]=1)(=[O:7])=[O:8])[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[N:30]=[CH:31][CH:32]=[N:33]2)=[CH:27][CH:28]=1
Reactant: COC(=O)CNS(=O)(=O)c1ccc(OCC2CC2)cc1
Reactant: ClCc1ccc(-n2nccn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN(Cc1ccc(-n2nccn2)cc1)S(=O)(=O)c1ccc(OCC2CC2)cc1
Reaction time: 18 h

Procedure:
To a solution of 1 g (3.3 mmol) of the compound of Stage 3.7 in 10 ml of DMF, 0.8086 g (4.175 mmol) of 2-(4-chloromethyl-phenyl)-2H-[1,2,3]triazole, 0.0555 g (0.33 mmol) of KI and 0.646 g (4.68 mmol) of K2CO3 are added successively at r.t. After stirring for 18 h, the reaction is quenched with ice water and the mixture is extracted with AcOEt. The combined extracts are washed with H2O, brine, dried over MgSO4 and concentrated under reduced pressure to give a solid which is washed with diethylether and MeOH to give the title compound.
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[C:11]([I:12])=[CH:10][N:9]([C@@H:13]3[CH2:16][C@H:15]([CH2:17][OH:18])[CH2:14]3)[C:5]=2[N:6]=[CH:7][N:8]=1.C(=O)=O.CC(C)=O>O1CCOCC1.CC(O)C>[NH2:1][C:3]1[C:4]2[C:11]([I:12])=[CH:10][N:9]([C@@H:13]3[CH2:16][C@H:15]([CH2:17][OH:18])[CH2:14]3)[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: OC[C@H]1C[C@@H](n2cc(I)c3c(Cl)ncnc32)C1
Reactant: N
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Nc1ncnc2c1c(I)cn2[C@H]1C[C@@H](CO)C1
Temperature: 90 °C
Reaction time: 17 h

Procedure:
Gaseous ammonia (from a lecture bottle) was bubbled into a suspension of cis-[3-(4-chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutyl]-methanol (406.8 mg, 1.12 mmol) in dioxane (10 mL) and iPrOH (10 mL) in a Parr bomb, cooled by dry ice/acetone, for 5 min, then the vessel was sealed and heated to 90° C. overnight. LC/MS after 17 h indicated incomplete conversion. More ammonia was bubbled into the mixture, and heating to 90° C. was continued. After 1 d, conversion was complete. The solvents were evaporated, water was added to the residue, and the pale yellow solid was filtered off and dried in vacuo to give the title compound as a pale yellow solid. The compound was used in the next step without further purification. The aqueous filtrate was extracted with CH2Cl2 (3×20 mL), the combined extracts were dried over MgSO4, filtered and concentrated to give a yellow oil that slowly solidified. Purification by HPLC gave analytically pure material. 1H NMR (CDCl3, 400 MHz): δ=2.40-2.57 (m, 4H), 2.57-2.66 (m, 2H), 3.73 (d, J=4.4 Hz, 2H), 5.03 (quint, J=8.4 Hz, 1H), 5.62 (brs, 2H), 7.21 (s, 1H), 8.26 (s, 1H). 13C NMR (DMSO-d6, 100.6 MHz, DEPT135): b=29.96 (+), 32.70 (2C, −), 44.42 (+), 50.25 (Cquart), 64.16 (−), 102.98 (Cquart), 126.94 (+), 149.41 (Cquart), 151.72 (+), 157.13 (Cquart). MS (ES+): m/z 345.0 (100) [MH+]. HPLC: tR=1.7 min (OpenLynx, polar—5 min). C11H13lIN4O.⅔H2O: C: calc. 37.10, found 36.92; H: calc. 4.06, found 3.88; N: calc. 15.73, found 16.07.
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[N:7]([CH:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:6](=[O:27])[C@@H:5]1[C@H:28]([O:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH3:29])=[CH2:3].[Cl:41]Cl.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C.C(Cl)(Cl)(Cl)Cl>[Cl:41][CH2:3][C:2]([C@H:4]1[N:7]([CH:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:6](=[O:27])[C@@H:5]1[C@H:28]([O:30][C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[CH3:29])=[CH2:1]
Reactant: ClCl
Reactant: C=C(C)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(CCl)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Reaction time: 0.25 h

Procedure:
(3S,4S)-4-(1-Methylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (200 g) was dissolved in ethyl acetate (3 liters), and a solution of chlorine in carbon tetrachloride (3.85%, 870 g) was added dropwise thereto at room temperature over a period of 15 minutes, followed by stirring for 1 hour. Water (1 liter) and then 10% aqueous sodium thiosulfate solution (50 ml) were poured into the reaction mixture, which was stirred for 0.5 hour and allowed to stand. The organic layer was washed successively with a saturated sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo to give (3S,4S)-4-(1-chloromethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone. m.p., 84°-85° C.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([C:8]2[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=2[CH3:17])=[CH:5][CH:4]=1)=[O:2].P([O-])([O-])([O-])=[O:19].[Na+].[Na+].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.C1COCC1.O>[C:14]([NH:13][C:11]1[S:12][C:8]([C:6]2[O:7][C:3]([C:1]([OH:19])=[O:2])=[CH:4][CH:5]=2)=[C:9]([CH3:17])[N:10]=1)(=[O:16])[CH3:15]
Reactant: O=P([O-])([O-])[O-]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(C=O)o2)s1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2ccc(C(=O)O)o2)s1
Temperature: 0 °C

Procedure:
To a solution of 1.2 g of N-(5-(5-formylfuran-2-yl)-4-methylthiazol-2-yl)acetamide in 100 mL of tert-butanol was added 5 mL of water and 20 mL of 2N monobasic sodium phosphate. The resulting suspension was cooled to 0° C. while being stirred. To the chilled suspension was added 20 mL of a 2M solution of 2-methyl-2-butene in THF followed by 3 g of sodium chlorite in 10 mL of water. The reaction was allowed to warm to room temperature overnight and the upper organic layer was separated and dried over sodium sulfate and used as is in the subsequent reactions. LC/MS: 267.04 (M+H)/2.04 min.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])=[O:3].[CH:11](OCC)(OCC)OCC.C(OC(=O)C)(=O)C.[Br:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>>[Br:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][CH:11]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:31][CH:30]=1
Reactant: CCOC(=O)CS(C)(=O)=O
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccc(Br)cc1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=CNc1ccc(Br)cc1)S(C)(=O)=O
Temperature: 130 °C

Procedure:
A mixture of ethyl 2-(methylsulfonyl)acetate (1.9 g, 11.4 mmol), triethyl orthoformate (5.64 mL, 34.2 mmol), and acetic anhydride (5 mL) were heated at 130° C. for 5 h with a Dean Stark trap. The reaction was cooled, 4-bromoaniline (3.1 g, 18.0 mmol) was added and the reaction mixture was heated at 150° C. for 2 h. The reaction mixture was cooled, concentrated and the residue was purified by column chromatography to afford the desire product (1.08 g, 27% over 2 steps) as a tan solid: 1H NMR (300 MHz, CDCl3) δ 10.58 (d, J=13.5 Hz, 1H), 8.39 (d, J=13.7 Hz, 1H), 7.59-7.48 (m, 2H), 7.15-7.02 (m, 2H), 4.41 (q, 1=7.1 Hz, 2H), 3.19 (s, 3H), 1.43 (t, J=7.1 Hz, 3H).
Reaction SMILES: BrC1[S:18][C:5]2[C:6]3[S:14][C:13]4[C:12]5[S:15][CH:16]=[CH:17][C:11]=5[S:10][C:9]=4[C:7]=3[S:8][C:4]=2[C:3]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[CH:29]#[C:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].[CH2:39](N(CC)CC)C>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.[Cu]I>[C:30]([C:29]1[S:18][C:5]2[C:6]3[S:14][C:13]4[C:12]5[S:15][CH:16]=[CH:17][C:11]=5[S:10][C:9]=4[C:7]=3[S:8][C:4]=2[C:3]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])#[C:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCN(CC)CC
Reactant: CCCCCCCCCCc1c(Br)sc2c1sc1c2sc2c3sccc3sc21
Reactant: C#CCCCCCCCC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCCCC#Cc1sc2c(sc3c2sc2c4sccc4sc23)c1CCCCCCCCCC
Temperature: 130 °C
Yield: 90.2 %

Procedure:
2-Bromo-3-decanyldithieno[2,3-d:2′,3′-d′]thieno[3,2-b:4,5-b′]dithiophene (2.16 g, 4.6 mmol) (106) is mixed with 1-decyne (1.27 g, 9.2 mmol), tetrakis(triphenylphosphine)palladium (0.27 g, 0.23 mmol) and copper(I) iodide (0.087 g, 0.46 mmol) in triethylamine (50 mL). This mixture is bubbled with nitrogen for 5 minutes and then heated to 130° C. under argon for 16 hours. The triethylamine is evaporated and hexane (150 mL) is added. This mixture is filtered to remove solid salts. The organic layer is washed with 1M hydrochloric acid (50 mL) and brine (50 mL), then dried over MgSO4. The solvent is removed in vacuo, and the residue is purified by chromatography on silica gel eluted with hexane to produce the target compound (2.3 g, 90.2% yield). 1HNMR (CD2Cl2): δ 7.41 (d, 1H), 7.33 (d, 1H), 2.84 (t, 2H), 2.23 (t, 2H), 1.73-1.27 (m, 28H), 0.89 (m, 6H).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[C:2]([O:4]C)=O.C[O-].[Na+].CO.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=1.Cl>C(OCC)C.C(OCC)(=O)C>[CH3:8][O:7][C:1](=[O:6])[C:2](=[O:4])[CH2:22][C:21]([C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=1)=[O:23]
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)C(=O)CC(=O)c1ccc(Cl)cc1
Yield: 11.8 %

Procedure:
Dimethyl oxalate (23.6 g, 200 mmol) was placed in a 500 mL three-necked round bottom flask, and dissolved in diethyl ether (200 mL). To the stirred solution was added 25% sodium methoxide in methanol (48 mL, 210 mmol) via an addition funnel over a 2 minute period. Next, 4′-chloroacetophenone (25.91 g, 200 mmol) was dissolved in diethyl ether (50 mL), and added to the reaction dropwise over 3-minutes. After stirring overnight (18 hours), 1N HCl (400 mL) and ethyl acetate (750 mL) were added. The organic layer was collected, washed with brine (350 mL), dried over MgSO4, filtered, and concentrated in vacuo to give 5.7 g of a yellow solid. The solid was recrystallized from ethyl acetate and iso-octane to give 23 g (48%) of the dione: mp 108.5-110.5° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[CH:8][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:49][O:50][CH2:51][CH2:52][NH2:53]>C(Cl)Cl>[CH3:49][O:50][CH2:51][CH2:52][NH:53][C:13](=[O:15])[C:12]([C:9]1[CH:8]=[CH:7][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:11][CH:10]=1)([CH3:17])[CH3:16]
Reactant: CC(C)(C(=O)O)c1ccc(-c2ccco2)cc1
Reactant: COCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)C(C)(C)c1ccc(-c2ccco2)cc1
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a solution of 2-(4-(furan-2-yl)-phenyl)-2-methyl-propionic Acid (reference example 28) (344 mg, 1.5 mmol) in CH2Cl2 (4 mL) is added TBTU (528 mg, 1.65 mmol) followed by diisopropylethylamine (280 mL, 1.6 mmol). The resulting mixture is stirred for 2 h then a further portion of DIEA added (280 mL) along with 2-methoxy-ethylamine (225 mL, 2.6 mmol). The resulting solution is stirred for 90 minutes then concentrated. The residue is purified by flash chromatography (eluting with 10% CH2Cl2/50% ethyl acetate in hexanes) to give 380 mg of product as a white solid. 1H NMR (CD3OD) d 1.58 (s, 6H), 3.24 (s, 3H), 3.36 (m, 4H), 5.58 (bs, 1H), 6.47 (dd, J=3, 2 Hz, 1H), 6.65 (d, J=3 Hz, 1H), 7.41 (m, 2H), 7.49 (d, J=2 Hz, 1H), 7.65 (m, 2H). MS (EI) m/z 287 (M+).
Reaction SMILES: [CH3:1][CH:2]([C:4]([CH3:8])([OH:7])[CH2:5][CH3:6])[CH3:3].C[Li].Cl[C:12]([O:14][CH2:15][C:16](=[CH2:18])[CH3:17])=[O:13].O>O1CCCC1.C(OCC)C>[C:12](=[O:13])([O:14][CH2:15][C:16](=[CH2:17])[CH3:18])[O:7][C:4]([CH3:8])([CH2:5][CH3:6])[CH:2]([CH3:3])[CH3:1]
Reactant: C=C(C)COC(=O)Cl
Reactant: CCC(C)(O)C(C)C
Agent: [Li]C
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)COC(=O)OC(C)(CC)C(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 94.6 %

Procedure:
To a solution of 13.94 grams (0.12 mole) of 2,3-dimethylpentan-3-ol in 75 milliliters of anhydrous tetrahydrofuran at 0° C. under a nitrogen atmosphere was added with stirring one equivalent of methyllithium in diethyl ether. Then 19.31 grams (0.14 mole) of methallyl chloroformate in 25 milliliters of anhydrous tetrahydrofuran was added. During additions the temperature was maintained at 0° C. Cooling was discontinued and the reaction mixture was stirred for about 18 hours. The reaction mixture was poured into water, and then extracted with ether. The ether layer was separated and washed with water, and then dried over magnesium sulfate. Removal of solvent under reduced pressure yielded 24.32 grams (94.6%) of a yellow oil. A pure sample was obtained by vacuum distillation (Fraction 2).
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15]Br>>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][C:3]([CH2:9][CH3:10])([CH2:1][CH3:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(CC)CC
Reactant: BrCCCCBr
Product: CCOC(=O)C(CC)(CC)CCCCBr

Procedure:
Using ethyl 2-ethylbutyrate and 1,4-dibromobutane, the same reaction as in Reference Example 16 was conducted to produce the title compound. b.p. 125°-130° C./0.3 mmHg
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([C:16]1[CH:17]=[N:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[N:20][CH:21]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl>C(N(CC)CC)C>[CH2:7]([C:6]1[CH2:16][CH2:21][CH:4]([C:5]([O:28][C:25]2[CH:24]=[CH:23][C:22]([C:19]3[N:20]=[CH:21][C:16]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:17][N:18]=3)=[CH:27][CH:26]=2)=[O:1])[CH2:3][CH:2]=1)[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C1CCOC1
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCc1cnc(-c2ccc(OC(=O)C3CC=C(CCCCC)CC3)cc2)nc1
Reaction time: 1 h

Procedure:
2-{4'-[(4-pentyl-3-cyclohexenyl)-carbonyloxy]-phenyl}-5-decylpyrimidine is synthesized as follows. Tetrahydrofuran (35 carboxyl chloride (2.3 g) and 5-decyl-2-(4'-hydroxyphenyl)-pyrimidine (3.66 g). The reaction mixture is stirred until homogenous, then triethylamine (2.5 ml) is added. The reaction mixture immediately turns turbid. The turbid solution is stirred 1 hour, poured into a dilute (5%) hydrochloric acid solution, and extracted with ethyl acetate. The combined organic layers are then extracted with saturated sodium chloride, dried over sodium sulfate, and the solvent removed in vacuo. The product is purified by flash chromatography using 10% ethyl acetate in hexane as the eluent, and recrystallized from acetonitrile to produce the product, 2-{4'-[(4-pentyl-3-cyclohexenyl)-carbonyloxy]-phenyl)-5-decylpyrimidine.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.Cl[CH2:21][C:22](=O)[CH3:23]>>[NH3:6].[Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=2)[C:5]2[N:6]([CH:21]=[C:22]([CH3:23])[N:8]=2)[CH:7]=1
Reactant: Cc1c(Br)cnc(N)c1-c1cccc(C(F)(F)F)c1
Reactant: CC(=O)CCl
Product: Cc1cn2cc(Br)c(C)c(-c3cccc(C(F)(F)F)c3)c2n1
Product: N
Reaction time: 24 h
Yield: 163.2 %

Procedure:
5-Bromo-4-methyl-3-(3-trifluoromethyl-phenyl)-pyridin-2-ylamine (Int. 1, 500 mg, 1.51 mmol) and 1-chloropropan-2-one (144 μL, 1.81 mmol) were heated at reflux in IMS (3 mL) for 18 hrs then a further quantity of 1-chloropropan-2-one (144 μL) was added. Heating was continued for 24 hrs then the solvent was evaporated in vacuo and the residue was purified by flash chromatography eluting with a gradient of 0-50% EtOAc in cyclohexane then 0-10% (2N NH3 in MeOH) in DCM to give the title compound as a cream solid (455 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:10]([Br:13])[CH:11]=[CH2:12]>>[Br-:13].[CH2:12]([N+:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH:2]=1)[CH:11]=[CH2:10]
Reactant: c1ccc2scnc2c1
Reactant: C=CCBr
Product: C=CC[n+]1csc2ccccc21
Product: [Br-]

Procedure:
135 g of benzothiazole and 121 g of allylbromide were mixed and the mixture was heated for 2 hours on a steam bath to solidify by crystallization. After cooling, diethyl ether was added to wash the crystals. After filtration and drying, the crystals obtained were recrystallized from ethanol. Melting point: 145°-147°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[C:25]([N:29]1[C:33]([C:34](Cl)=[O:35])=[CH:32][C:31]([CH3:37])=[N:30]1)([CH3:28])([CH3:27])[CH3:26].C(OCC)(=O)C.O1CCCC1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[C:25]([N:29]1[C:33]([C:34]([NH:1][C:2]2[CH:3]=[C:4]([O:5][C:6]3[CH:7]=[CH:8][C:9]4[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]5[CH2:20][CH2:19]5)=[O:17])[N:14]=4)[N:11]=3)[CH:21]=[CH:22][C:23]=2[CH3:24])=[O:35])=[CH:32][C:31]([CH3:37])=[N:30]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cc1cc(C(=O)Cl)n(C(C)(C)C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)n(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4.4 %

Procedure:
To a solution of N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (210 mg, 0.65 mmol) in N,N-dimethylacetamide (5 mL) was added a solution of 1-tert-butyl-3-methyl-1H-pyrazole-5-carbonylchloride (160 mg, 0.78 mmol) in N,N-dimethylacetamide (1 mL), and the mixture was stirred at room temperature for 30 min. Ethyl acetate/tetrahydrofuran and saturated aqueous sodium hydrogencarbonate solution were added to the mixture, the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×4). Combined organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→90/10) to give the title compound (14 mg, 4%) as a white solid.
Reaction SMILES: Cl.[F:2][C:3]1([C:7]([OH:9])=[O:8])[CH2:6][NH:5][CH2:4]1.S(Cl)([Cl:12])=O.[CH3:14]O>>[ClH:12].[F:2][C:3]1([C:7]([O:9][CH3:14])=[O:8])[CH2:6][NH:5][CH2:4]1
Reactant: O=C(O)C1(F)CNC1
Reactant: CO
Reactant: O=S(Cl)Cl
Agent: Cl
Product: COC(=O)C1(F)CNC1
Temperature: 5 °C

Procedure:
3-Fluoroazetidine-3-carboxylic acid hydrochloride (0.10 g, 8.4 mmol) was dissolved in methanol (2 mL) and cooled to 5° C. Thionyl chloride (0.05 g, 4.2 mmol) was added dropwise. The reaction mixture was heated at 65° C. overnight and concentrated under reduced pressure to afford methyl 3-fluoroazetidine-3-carboxylate hydrochloride. The product was used in the next step without further purification.