Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([NH:13]S(C(C)(C)C)=O)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.Cl.O1CCOCC1>CO.C(=O)([O-])[O-].[K+].[K+]>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([NH2:13])[C:9]([F:10])([F:11])[F:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)S(=O)NC(c1ccc(Br)nc1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: NC(c1ccc(Br)nc1)C(F)(F)F

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid [1-(6-bromo-pyridin-3-yl)-2,2,2-trifluoro-ethyl]amide (1.17 g, 3.26 mmol) in methanol (15 mL) was added a 4 N solution of HCl in dioxane (2 mL, 8.0 mmol). The reaction was monitored by TLC (ethyl acetate-hexanes 3:7). The mixture was diluted with saturated aqueous potassium carbonate and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (3×15 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography eluting with ethyl acetate-hexanes (1:9, then 2:8) to afford the title compound as a clear oil.
Reaction SMILES: Cl.[C:2]([O:5][C@H:6]1[O:28][C@@H:27]([CH2:29][O:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:17]([O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:7]1[O:8]C(=O)C1C=CC=CC=1)(=[O:4])C.[C:39](Cl)(=O)[CH3:40]>ClCCl.C(OCC)(=O)C>[C:2]([O:5][C@@H:6]1[O:28][C@@H:27]([CH2:29][O:30][C:31](=[O:38])[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C@H:17]([O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:7]1[OH:8])(=[O:4])[C:40]1[CH:39]=[CH:27][CH:17]=[CH:7][CH:6]=1
Reactant: CC(=O)O[C@H]1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(OC[C@@H]1O[C@@H](OC(=O)c2ccccc2)[C@@H](O)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Reaction time: 12 h
Yield: 63.7 %

Procedure:
HCl (gas) was bubbled for 1.5 hours into a solution of 50 g (99.16 mole) of the compound (12) dissolved in 460 ml of anhydrous dichloromethane and 7.5 ml of acetyl chloride at 0° C. The resulting solution was kept in a refrigerator for 12 hours and then evaporated in vacuo. The residue was coevaporated with toluene (3×150 ml) at 45° C. and redissolved in 105 ml of acetonitrile. To this solution, 13 ml of water was added dropwise at 0° C. A white solid began to precipitate from the mixture after 30 minutes, after which the mixture was kept in a refrigerator for 2 hours to induce additional precipitation. After filtration of the resulting solid, the filter cake was. carefully washed with cold diethylether to remove the reaction by-product 1-hydroxy-isomer, which is indistinguishable by TLC from the compound (13). The white solid thereby obtained was dissolved in ethyl acetate. The solution was washed with saturated sodium bicarbonate to remove the remaining HCl, dried over MgSO4 and filtered. The solvent was removed from the filtrate to obtain 29.2 g (Yield: 63.7%) of the compound (13) in the form of a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=O)[C:5]=2[CH2:4][CH2:3]1.Cl.[CH3:15][NH:16][CH3:17].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:15][N:16]([CH3:17])[C:11]([C:6]1[C:5]2[CH2:4][CH2:3][C:2](=[O:1])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:13]
Reactant: CNC
Reactant: O=C(O)c1cccc2c1CCC2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cccc2c1CCC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 5 (300 mg, 1.70 mmol) in N,N-dimethylformamide (3 mL) was added dimethyl amine hydrochloride (139 mg, 1.70 mmol), 1-hydroxybenzotriazole hydrate (253 mg, 1.87 mmol), triethylamine (0.48 mL, 3.4 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (358 mg, 1.87 mmol). The reaction mixture was stirred at room temperature overnight, quenched by addition of saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel using dichloromethane/methanol (20:1) as the mobile phase to provide the desired product. MS (APCI): m/z 204 (M+H)+.
Reaction SMILES: BrC1C(C2CCNCC=2)=NC2N(N=CC=2C2C=NC3C(C=2)=CC=CC=3)C=1N.[Br:28][C:29]1[C:30]([C:65]2[CH2:70][CH2:69][CH:68]([C:71]3[CH:72]=[N:73][N:74](COCC[Si](C)(C)C)[CH:75]=3)[CH2:67][CH:66]=2)=[N:31][C:32]2[N:33]([N:52]=[CH:53][C:54]=2[C:55]2[CH:56]=[N:57][C:58]3[C:63]([CH:64]=2)=[CH:62][CH:61]=[CH:60][CH:59]=3)[C:34]=1[N:35](COCC[Si](C)(C)C)COCC[Si](C)(C)C.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC(C3C=NC4C(C=3)=CC=CC=4)=C2N=C(C2CCN(C(OC(C)(C)C)=O)CC=2)C=1>>[NH:73]1[CH:72]=[C:71]([CH:68]2[CH2:69][CH2:70][C:65]([C:30]3[C:29]([Br:28])=[C:34]([NH2:35])[N:33]4[N:52]=[CH:53][C:54]([C:55]5[CH:56]=[N:57][C:58]6[C:63]([CH:64]=5)=[CH:62][CH:61]=[CH:60][CH:59]=6)=[C:32]4[N:31]=3)=[CH:66][CH2:67]2)[CH:75]=[N:74]1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(Br)c(C2=CCC(c3cnn(COCC[Si](C)(C)C)c3)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Agent: CC(C)(C)OC(=O)N1CC=C(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)CC1
Agent: Nc1c(Br)c(C2=CCNCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Product: Nc1c(Br)c(C2=CCC(c3cn[nH]c3)CC2)nc2c(-c3cnc4ccccc4c3)cnn12

Procedure:
5-(4-(1H-pyrazol-4-yl)cyclohex-1-enyl)-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine was synthesized in a manner similar to the synthesis of 6-bromo-3-(quinolin-3-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine, but with 6-bromo-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)-5-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)cyclohex-1-enyl)pyrazolo[1,5-a]pyrimidin-7-amine substituted for tert-Butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate. The reaction mixture was purified via reverse-phase preparatory HPLC to yield 5-(4-(1′-1-pyrazol-4-yl)cyclohex-1-enyl)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine as yellow solid. (M+H=486.12, retention time=3.43 min.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:16]=[CH:15][S:14][C:9]=3[NH:10][C:11](=[O:13])[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH:19]1([CH2:22]Br)[CH2:21][CH2:20]1.O>CN(C)C=O>[CH:19]1([CH2:22][O:13][C:11]2[N:12]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[CH:16]=[CH:15][S:14][C:9]=3[N:10]=2)[CH2:21][CH2:20]1
Reactant: O=c1nc(-c2ccccc2)c2ccsc2[nH]1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-c2nc(OCC3CC3)nc3sccc23)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 500 mg of 4-phenyl-1,2 -dihydrothieno[2,3-d]pyrimidin-2-one in 10 ml of dimethylformamide is added 100 mg of 63 % sodium hydride. After stirring at 60°C for 1 hour, 590 mg of cyclopropylmethyl bromide is added dropwise thereto. The mixture is heated at 120°C for 4 hours, then cooled to room temperature. The reaction mixture is poured into water and extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure. The residue is chromatographed on silica gel, using chloroform as an eluent. From the first fraction, 2-(cyclopropylmethoxy)-4-phenylthieno[2,3-d]pyrimidine is obtained as crystals having a melting point of 86.5°- 87.5°C. From the second fraction 1-cyclopropylmethyl-4-phenyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one is obtained as crystals having a melting point of 191° - 191.5°C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:23])[CH:12]([CH3:22])[CH2:13][N:14]2[CH2:19][CH:18]([CH3:20])[O:17][CH:16]([CH3:21])[CH2:15]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Na+].[C:27](OC(=O)C)(=[O:29])[CH3:28]>>[C:27]([O:23][CH:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)[CH:12]([CH3:22])[CH2:13][N:14]1[CH2:15][CH:16]([CH3:21])[O:17][CH:18]([CH3:20])[CH2:19]1)(=[O:29])[CH3:28]
Reactant: CC1CN(CC(C)C(O)c2ccc(C(C)(C)C)cc2)CC(C)O1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)OC(c1ccc(C(C)(C)C)cc1)C(C)CN1CC(C)OC(C)C1
Yield: 73 %

Procedure:
7.2 g (0.02 mole) of 1-(p-tert.-butyl-phenyl)-2-methyl-3-(2,6-dimethylmorpholin-4-yl)-1-propanol (obtained according to Example 2) were stirred in 50 ml of acetic anhydride to room temperature for 3 hours. The reaction mixture was then introduced into 100 ml of water and the mixture was adjusted to a pH value of 7 with dilute sodium hydroxide solution and extracted with chloroform. The organic phase was dried over sodium sulphate and concentrated. The oily residue was taken up in ethyl acetate, the ethyl acetate mixture was shaken with active charcoal and filtered and the filtrate was concentrated. The resulting oil was digested with petroleium ether, a brown precipitate was separated off and the mixture was concentrated. 5.3 g (73% of theory) of 1-acetoxy-1-(p-tert.-butyl-phenyl)-2-methyl-3-(2,6-dimethylmorpholin-4-yl)-propane were obtained as a viscous oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][N:14]=1)[C:9]([OH:11])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:50]1[CH2:55][CH2:54][O:53][CH2:52][CH:51]1[C:56]1[C:64]2[S:63][C:62]([NH2:65])=[N:61][C:60]=2[C:59]([O:66][CH3:67])=[CH:58][CH:57]=1>C1COCC1.C(Cl)(Cl)Cl>[O:50]1[CH2:55][CH2:54][O:53][CH2:52][CH:51]1[C:56]1[C:64]2[S:63][C:62]([NH:65][C:9](=[O:11])[C:8]3[CH:12]=[CH:13][N:14]=[C:6]([CH2:5][O:4][CH2:3][C:2]([F:1])([F:16])[F:15])[CH:7]=3)=[N:61][C:60]=2[C:59]([O:66][CH3:67])=[CH:58][CH:57]=1
Reactant: O=C(O)c1ccnc(COCC(F)(F)F)c1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(COCC(F)(F)F)c3)nc12

Procedure:
From 2-(2,2,2-trifluoro-ethoxymethyl)-isonicotinic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+121.3° (c=1.05, CHCl3), ES-MS m/e (%): 484 (M+H+, 100).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:5]=1[OH:12])[CH:2]=[CH2:3].C(OO)(=[O:15])C.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.C([O-])(=O)C.[Na+]>[CH3:11][O:10][C:6]1[C:5]2[O:12][CH:2]([CH2:3][OH:15])[CH2:1][C:4]=2[CH:9]=[CH:8][CH:7]=1
Reactant: C=CCc1cccc(OC)c1O
Reactant: CC(=O)OO
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc2c1OC(CO)C2
Temperature: 15 °C
Reaction time: 48 h
Yield: 16 %

Procedure:
124 g of 2-allyl-6-methoxyphenol, dissolved in 80 ml of acetic acid, are added to a mixture, cooled to 15° C., containing 160 ml of 32% strength peracetic acid in acetic acid and 2.4 g of sodium acetate. The mixture is left at room temperature for 48 hours and then hydrolyzed with 2 1 of water containing 400 g of sodium carbonate. The mixture is extracted with ethyl ether and the organic phase is washed with sodium hydroxide. It is dried, the ether is evaporated off and the residue is distilled at 110° C. and at 0.02 mmHg to obtain 7-methoxy-2,3-dihydro-2-benzofuranylmethanol.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=3F)[N:7]=[N:6][N:5]=2)[CH2:3][CH2:2]1.[Si:19]([O:26][CH2:27][CH2:28][OH:29])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C.O>[Si:19]([O:26][CH2:27][CH2:28][O:29][C:10]1[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:9]=1[N:8]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][N:6]=[N:7]1)([C:22]([CH3:24])([CH3:25])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCCO
Reactant: O=[N+]([O-])c1ccc(F)c(-n2nnnc2C2CC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc([N+](=O)[O-])cc1-n1nnnc1C1CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 12.6 %

Procedure:
A mixture of 5-cyclopropyl-1-(2-fluoro-5-nitrophenyl)-1H-tetrazole (112 mg, 0.45 mmol), 2-((tert-butyldimethylsilyl)oxy)ethan-1-ol (159 mg, 0.9 mmol) and Cs2CO3 (325 mg, 1.0 mmol) in DMF (3 mL) was heated to 50° C. and stirred for 4 hr. The reaction was cooled and then poured in to EtOAc (30 mL) and H2O (20 mL). The aqueous and organic layers were partitioned and the aqueous was extracted with EtOAc (2×20 mL). The combined organic layers were dried (Na2SO4), filtered and the solvent removed under vacuum to leave a crude residue. The residue was dry-loaded on to silica gel and purified by column chromatography on silica gel using EtOAc/heptane (4:6 to 1:0) to give the desired product (23 mg, 13% yield), followed by the desired product as de-silylated material, 2-(2-(5-cyclopropyl-1H-tetrazol-1-yl)-4-nitrophenoxy)ethan-1-ol (82 mg, 63%). Both products were taken to the final desired compound.
Reaction SMILES: C(O)(=O)CCCCCCC/C=C\CCCCCCCC.C(O)[C@H]1O[C@H]([O:28][CH2:29][C@H:30]2[O:35][C@H:34]([O:36][C@:37]3([CH2:46][OH:47])[O:41][C@H:40]([CH2:42][OH:43])[C@@H:39]([OH:44])[C@@H:38]3[OH:45])[C@H:33]([OH:48])[C@@H:32]([OH:49])[C@@H:31]2[OH:50])[C@H](O)[C@@H](O)[C@H]1O.C(O)[C@H]1O[C@H](OC[C@H]2O[C@H](OC[C@H]3O[C@H](O[C@]4(CO)O[C@H](CO)[C@@H](O)[C@@H]4O)[C@H](O)[C@@H](O)[C@@H]3O)[C@H](O)[C@@H](O)[C@H]2O)[C@H](O)[C@@H](O)[C@H]1O>>[CH2:29]([OH:28])[C@H:30]1[O:35][C@H:34]([O:36][CH:37]2[C@@H:46]([OH:47])[C@H:42]([OH:43])[CH:40]([OH:41])[C@H:39]([OH:44])[C@@H:38]2[OH:45])[C@H:33]([OH:48])[C@@H:32]([OH:49])[C@H:31]1[OH:50]
Reactant: OC[C@H]1O[C@H](OC[C@H]2O[C@H](O[C@]3(CO)O[C@H](CO)[C@@H](O)[C@@H]3O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@H]1O
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: OC[C@H]1O[C@H](OC[C@H]2O[C@H](OC[C@H]3O[C@H](O[C@]4(CO)O[C@H](CO)[C@@H](O)[C@@H]4O)[C@H](O)[C@@H](O)[C@@H]3O)[C@H](O)[C@@H](O)[C@H]2O)[C@H](O)[C@@H](O)[C@H]1O
Product: OC[C@H]1O[C@H](OC2[C@@H](O)[C@H](O)C(O)[C@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@H]1O

Procedure:
T2 plants of events EAFS 4818.1.5 and EAFS 4871.6.10 that were homozygous for an YL DGAT1/YL DGAT2 event (Example 6) and a PGM/RFO ko event (Example 31), respectively were crossed. Resulting F1 seed were analyzed by GC and TLC as described above to monitor presence of the DGAT trait (elevated oleic acid) and PGM/RFO ko trait (reduced raffinose and stachyose). A total of 23 F1 seed with elevated oleic acid content and reduced raffinosaccharide levels were planted, resulting plants were grown to maturity. For every F1 plant a total of 48 F2 seed were subjected to the following analysis sequence. Seed oil content was measured non-destructively by NMR (Example 4). Seed were chipped and the resulting seed chip was extracted with heptane. Heptane extracts were subjected to GC analysis to determine the presence of the DGAT transgene (indicated by the altered fatty acid profile of the oil). The heptane-extracted residue was subjected to TLC analysis of raffinose and stachyose content (Example 29) to determine presence or absence of the EAFS 4871.6.10 transgene. In this manner 1104 seed were genotyped and the effect of transgene genotype on oil content was determined.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[S:16]([O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CO)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 3 h
Yield: 97.9 %

Procedure:
(S)-tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (3.5 g, 16.59 mmol) was dissolved in CH2Cl2 (60 ml), and then TsCl (3.8 g, 19.91 mmol), Et3N (3.47 ml, 24.87 mmol), and DMAP (0.21 g, 1.66 mmol) were added, followed by at room temperature for 3 hours. After the completion of the reaction, the reaction mixture was extracted with H2O, MC, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (EA:Hex=1:5), to give (S)-tert-butyl 3-((tosyloxy)methyl)piperidine-1-carboxylate (6 g, 97%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[Cl:28][S:29](O)(=[O:31])=[O:30]>ClCCl>[F:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][C:25]([S:29]([Cl:28])(=[O:31])=[O:30])=[CH:24][CH:23]=2)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)c1cn2c3c(c(-c4ccccc4)c(F)cc3c1=O)OCC2C
Solvent: ClCCl
Product: CCOC(=O)c1cn2c3c(c(-c4ccc(S(=O)(=O)Cl)cc4)c(F)cc3c1=O)OCC2C
Temperature: 0 °C

Procedure:
A suspension of ethyl 9-fluoro-10-phenyl-3-methyl-7-oxo-2,3-dihydro-(7H)-pyrido-(1,2,3-de)-1,4-benzoxazine-6-carboxylate (0.4 g, 1.2 mmol) in dichloromethane (15 ml) was cooled to 0° C. with stirring. Chlorosulfonic acid (5 ml) was added dropwise over 5 minutes. The dark solution was stirred at 0° C. for 15 minutes, then it was warmed gradually to room temperature over 1.5 hour. The reaction mixture was poured onto ice water with stirring. Three extractions with chloroform, drying the combined organic layers over magnesium sulfate, filtration and removal of solvent in vacuo gave a yellow oil (0.5 g) which was used without further purification.
Reaction SMILES: Br[C:2](Cl)([C:9]([F:12])([F:11])[F:10])[CH:3](O)[CH:4]=[C:5]([CH3:7])[CH3:6].C(OC)(OC)(OC)C.C(O)(=O)C(C)C>>[CH3:6][C:5](=[CH:4][CH2:3][CH2:2][C:9]([F:12])([F:11])[F:10])[CH3:7]
Reactant: CC(C)=CC(O)C(Cl)(Br)C(F)(F)F
Agent: COC(C)(OC)OC
Solvent: CC(C)C(=O)O
Product: CC(C)=CCCC(F)(F)F
Temperature: 111 °C

Procedure:
5-Bromo-5-chloro-4-hydroxy-2-methyl-6,6,6-trifluorohex-2ene (10.0 g), trimethyl orthoacetate (48.0 g) and isobutyric acid (0.29 g) were charged to a round-bottomed flask fitted with: nitrogen inlet/bubbler, thermometer and Dean and Stark received packed with 5A molecular seives. The mixture was heated with agitation to reflux and distillates collected until reaction mass temperature increased to 111° C. (ca. 1 hr). Once the reaction was complete, the residual trimethyl orthoacetate was removed by distillation under vacuum (ca. 50° C. ≃50 mmHg) to give the product, 5-bromo-5-chloro-4-1,1-dimethoxyethoxy)-2-methyl-6,6,6-trifluorohex-2-ene, as an orange oil (10.9 g, 85% yield).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[N:19]=[C:20]([CH2:23][CH2:24][CH2:25][CH3:26])[N:21]([CH3:22])[C:12]=3[C:11]=2[CH:10]=1)C1C=CC=CC=1.C(OC1C=CC2C3N(CC(C)C)C(CCC)=NC=3C(N)=NC=2C=1)C1C=CC=CC=1>>[CH2:23]([C:20]1[N:21]([CH3:22])[C:12]2[C:11]3[CH:10]=[C:9]([OH:8])[CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:19]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1C
Agent: CCCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Product: CCCCc1nc2cnc3ccc(O)cc3c2n1C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
A modification of the general method described in Part J of Example 1 was followed using 8-benzyloxy-2-butyl-1-methyl-1H-imidazo[4,5-c]quinoline (14.65 g, 42.4 mmol) in lieu of 7-benzyloxy-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine. The reaction was placed under hydrogen pressure for 3.5 hours. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to a small volume, and hexanes were added. A precipitate formed, and the mixture was stored overnight in a refrigerator. The solid was isolated by filtration, washed with hexanes (500 mL), and dried for three days under high vacuum to provide 9.40 g of 2-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-8-ol as a white solid, mp 219-220.2° C.
Reaction SMILES: [CH2:1]1[NH:6][C:4](=[O:5])[NH:3][CH2:2]1.[CH2:7]([Li])[CH2:8][CH2:9]C.CCCCCC.BrCC#C.S(=O)(=O)(O)[O-].[K+]>O1CCCC1>[CH2:9]([N:3]1[CH2:2][CH2:1][NH:6][C:4]1=[O:5])[C:8]#[CH:7]
Reactant: O=C1NCCN1
Reactant: [Li]CCCC
Agent: C#CCBr
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#CCN1CCNC1=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 23.7 %

Procedure:
To a suspension of ethylene urea (592 mg, 6.88 mmol) in tetrahydrofuran (15 mL) was added dropwise butyl lithium/hexane solution (2.7 mL, 13.6 mmol) at 0° C. under nitrogen. Thereto was added 3-bromopropyne (410 mg, 6.88 mmol), and the mixture was stirred at 60° C. for 3 hours. Thereto was added 5% aqueous potassium bisulfate solution, and the mixture was extracted with ethyl acetate, dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (ethyl acetate/hexane 1/1) to give the titled compound (202 mg, 24%).
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10]2[N:11]=[CH:12][C:13]3[CH:19]=[CH:18][C:17](=[O:20])[NH:16][C:14]=3[N:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:22][CH2:23][O:24][CH3:25]>CN(C)C=O>[CH3:25][O:24][CH2:23][CH2:22][N:16]1[C:14]2[N:15]=[C:10]([NH:9][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:11]=[CH:12][C:13]=2[CH:19]=[CH:18][C:17]1=[O:20]
Reactant: COCCBr
Reactant: O=c1ccc2cnc(Nc3ccccc3)nc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCn1c(=O)ccc2cnc(Nc3ccccc3)nc21
Temperature: 50 °C
Yield: 56.2 %

Procedure:
To a suspension of NaH (49 mg of a 60% suspension of NaH in mineral oil) in 6 mL of dimethylformamide was added 2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one (200 mg, 0.84 mmol). The reaction mixture was heated to 50° C. resulting in a yellow solution. The solution was cooled slightly, and 2-bromoethylmethyl ether (140 μL, 1.49 mmol) was added. The reaction mixture was heated at 50° C. for 10 minutes, then cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by flash chromatography eluting with a gradient of 2:1 hexane:ethyl acetate to all ethyl acetate gave 140 mg (56%) of 8-(2-methoxyethyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one, mp 179-180° C.
Reaction SMILES: C[O-].[Na+].Cl.[Cl:5][C:6]1[C:16]([Cl:17])=[C:15]([C:18](=O)[CH2:19][CH2:20]N(C)C)[CH:14]=[CH:13][C:7]=1[O:8][CH2:9][C:10]([OH:12])=[O:11].O=[C:26]([CH2:33]C)[CH2:27][C:28](OCC)=[O:29]>C(O)C>[Cl:5][C:6]1[C:16]([Cl:17])=[C:15]([C:18]2[CH2:33][CH2:26][CH2:27][C:28](=[O:29])[C:19]=2[CH3:20])[CH:14]=[CH:13][C:7]=1[O:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CN(C)CCC(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Reactant: CCOC(=O)CC(=O)CC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC1=C(c2ccc(OCC(=O)O)c(Cl)c2Cl)CCCC1=O

Procedure:
To a stirred solution of sodium methoxide (7.2 g, 0.133 mole) in ethanol (240 ml) and ethyl 3-oxopentanoate (13.5 ml) was added [2,3-dichloro-4-(3-dimethylamino-1-oxopropyl)phenoxy]acetic acid hydrochloride (15.0 g, 0.042 mole). The reaction mixture was heated at reflux for 3 hours, the solvent was distilled at reduced pressure, then the mixture was treated with 150 ml of 2.5% sodium hydroxide and heated on a steam bath for 21/2 hours. The mixture was diluted with water, acidified, extracted into ether, washed with water, brine, dried over magnesium sulfate and evaporated at reduced pressure to give 4.1 g of [2,3-dichloro-4-(2-methyl-3-oxo-1-cyclohexen-1-yl)phenoxy]acetic acid which melted at 143°-145° C. after recrystallization from butyl chloride.