Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([O:45][CH3:46])[C:42]=1[O:43][CH3:44])[C:37](Cl)=[O:38]>C1COCC1.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:10]=[C:11]([C:37]([C:36]3[CH:40]=[C:41]([O:45][CH3:46])[C:42]([O:43][CH3:44])=[C:34]([O:33][CH3:32])[CH:35]=3)=[O:38])[N:12]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: O=S(=O)(c1ccccc1)n1ccnc1-c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1cc(C(=O)c2cn(S(=O)(=O)c3ccccc3)c(-c3ccc(Cl)cc3)n2)cc(OC)c1OC
Reaction time: 0.17 h
Yield: 36.8 %

Procedure:
To a solution of 2-(4-chlorophenyl)-1-(phenylsulfonyl)-1H-imidazole (10f) (6.0 mmol) in anhydrous THF (30 mL) at −78° C. was added 1.7 M tert-butyllithium in pentane (5.3 mL, 9.0 mmol) and stirred for 10 min. 3,4,5-Trimethoxybenzoyl chloride (7.2 mmol) was added at −78° C. and stirred for overnight. The reaction mixture was diluted with 100 mL of saturated NaHCO3 solution (aqueous) and extracted by ethyl acetate (200 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (hexane:ethyl acetate 4:1) to give a white solid. Yield: 36.8%; 1H NMR (500 MHz, CDCl3) δ 8.05 (d, J=7.5 Hz, 2H), 7.77 (t, J=7.5 Hz, 1H), 7.62 (t, J=8.0 Hz, 2H), 7.48 (s, 1H), 7.44 (d, J=9.0 Hz, 2H), 7.39 (d, J=8.5 Hz, 2H), 7.37 (s, 2H). MS (ESI): calculated for C25H21ClN2O6S, 512.1. found 513.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][Br:9])[CH:5]=[CH:4][C:3]=1[CH2:10][OH:11]>CCO.CCOC(C)=O.O=[Mn]=O>[Br:9][CH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH:10]=[O:11])=[C:2]([Br:1])[CH:7]=1
Reactant: OCc1ccc(CBr)cc1Br
Agent: O=[Mn]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=Cc1ccc(CBr)cc1Br
Yield: 80.6 %

Procedure:
The compound of Step 2 (8 g, 29 mmol, 1 eq) was dissolved in 10% EtOH/EtOAc (300 ml) and 5 eq of MnO2 (12.4 g, 142 mmol) was added every hour for 6 hours. The mixture was filtered through Celite and the solvent was removed under vacuum to give 6.5 g (80%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=O.[C:14]1([CH3:23])[CH:19]=[CH:18][C:17]([S:20]([OH:22])=[O:21])=[CH:16][CH:15]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH:39]([NH2:41])=[O:40]>>[C:14]1([CH3:23])[CH:19]=[CH:18][C:17]([S:20]([CH:7]([C:6]2[CH:5]=[C:4]([O:10][CH3:11])[C:3]([O:12][CH3:13])=[C:2]([Cl:1])[CH:9]=2)[NH:41][CH:39]=[O:40])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: NC=O
Reactant: COc1cc(C=O)cc(Cl)c1OC
Reactant: Cc1ccc(S(=O)O)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Product: COc1cc(C(NC=O)S(=O)(=O)c2ccc(C)cc2)cc(Cl)c1OC
Temperature: 65 °C
Reaction time: 2 h

Procedure:
5-Chloroveratraldehyde (5.7 g, 23.4 mmol), para-toluenesulfinic acid (3.0 g, 19.3 mmol) and camphorsulfonic acid (110 mg, 0.47 mmol) were treated with formamide (10 mL). Upon heating to 65° C. the reaction mixture turned into a solution and after two hours the product began to precipitate. After stirring for 16 h the precipitate was filtered, washed with methanol and dried in vacuum.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:16](OC)=[O:17])[CH:9]=[CH:8]1>O1CCCC1>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:16][OH:17])[CH:9]=[CH:8]1
Reactant: COC(=O)c1cccc2cc[nH]c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc2cc[nH]c12
Reaction time: 2 h

Procedure:
Solid lithium aluminum hydride (1.0 g) was added in portions over 1 hour to a stirred solution of methyl 7-indolecarboxylate (6.7 g) in tetrahydrofuran (100 ml). The mixture was stirred for a further 2 hours then excess lithium aluminium hydride was destroyed by addition of acetic acid, the mixture was diluted with aqueous sodium hydroxide and extracted with ethyl acetate. The extract was dried and evaporated and the residue was chromatographed on silica in ethyl acetate-hexane (1:9 to 1:2) to give the product.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.O=S(Cl)[Cl:12].[CH2:14](O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].C(Cl)(=O)C1C=CC=NC=1>C(Cl)(Cl)Cl>[ClH:12].[C:1]([O:9][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCCCCCO
Reactant: O=C(O)c1cccnc1
Agent: O=C(Cl)c1cccnc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCCCCCCCCCCCOC(=O)c1cccnc1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
Commercial SOCl2 (>99.5) and nicotinic acid (>99.5) were used without any further purification. To a three-necked flask was added nicotinic acid (16.9 g, 0.137 mol) under dry nitrogen atmosphere, and commercial SOCl2 (50 ml, 0.685 mol) was added dropwise. The mixture was heated to reflux for 3 hours and SOCl2 was evaporated under dry nitrogen atmosphere. After cooling to room temperature, 1-octacosanol (23.45 g, 0.057 mol) and CHCl3 (300 ml, dried anhydrous Na2SO4) were added to the nicotinic chloride and the mixture was heated to reflux for 4 hours. After cooling to room temperature overnight, the mixture was filtered under reduced pressure. The precipitate was dissolved in warm CHCl3 (800 ml) and then saturated NaHCO3 (100 ml) was added slowly. After stirring at room temperature for 1 hour, the organic layer was separated, washed with deionized water, brine and then dried over anhydrous Na2SO4. After the removal of the organic solvent, the residue was dissolved in warm CHCl3 (150 ml) and concentrated HCl (5 ml) was added with vigorous stirring for 30 minutes. The mixture was filtered under reduced pressure and the precipitate was washed with deoinized water, 95% EtOH, to obtain the product octacosanyl nicotinate hydrochloride (28.4 g, 90.3% yield, mp: 58-60° C.) as a pale yellow solid, and then re-crystallized with CHCl3 to give 24.3 g of octacosanyl nicotinate hydrochloride in yield 77.3%, mp: 74-75° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:4]([NH2:6])=[O:5].Cl[C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([Si](C)(C)C)[C:17]=1[C:18](Cl)=O.[OH-].[NH4+].C(=O)C1C=CC=CC=1.[NH:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[N:40]1>C1(C)C=CC=CC=1>[N:39]1([CH:18]([C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:16]=2)[NH:6][C:4](=[O:5])[C:3]2[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[N:40]1
Reactant: C[Si](C)(C)c1cccc(Cl)c1C(=O)Cl
Reactant: c1ccc2[nH]nnc2c1
Reactant: C[Si](C)(C)c1cccc(Cl)c1C(N)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O=Cc1ccccc1
Product: C[Si](C)(C)c1cccc(Cl)c1C(=O)NC(c1ccccc1)n1nnc2ccccc21

Procedure:
A mixture of 2-chloro-6-trimethylsilylbenzamide (2.27 g, 10 mmol), which may be readily prepared by the reaction of the compound of Example b and ammonium hydroxide, benzaldehyde (1.1 g, 10 mmol), and benzotriazole (1.2 g, 10 mmol) was refluxed 5 days in toluene utilizing a Dean-Stark trap to remove water. The solvent was removed to yield an oil which crystallizes. Recrystallization from ethyl acetate yielded 0.5 g of the title compound. m.p. 184-186° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([OH:8])[C:5]([OH:7])=[O:6].Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(=O)([O-])[O-].[Na+].[Na+].O[N:27]1[C:31](=[O:32])[CH2:30][CH2:29][C:28]1=[O:33].C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[CH2:13]([O:12][C:10]([NH:1][CH2:2][CH2:3][C@H:4]([OH:8])[C:5]([O:7][N:27]1[C:31](=[O:32])[CH2:30][CH2:29][C:28]1=[O:33])=[O:6])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCC[C@H](O)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCC[C@H](O)C(=O)ON1C(=O)CCC1=O)OCc1ccccc1

Procedure:
A mixture of the N-Cbz protected (S)-4-amino-2-hydroxybutanoic acid (76 mg, 0.300 mmol, prepared from treatment of 1.0 eq. of the acid with 1.2 eq. of benzyl chloroformate in the presence of 2.1 equiv. of sodium carbonate at 0–5° C. overnight, [α]D25=−61°), N-hydroxysuccinimide (38 mg, 0.318 mmol), and DCC (63 mg, 0.300 mmol) in anhydrous THF (3.5 mL) was stirred at room temperature under an atmosphere of argon for 2 h. This solution was directly used for the syntheses of 29–31.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.Cl.NC1C=NC=CC=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([NH:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: Nc1cccnc1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Agent: Cl
Solvent: O
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3cccnc3)nc21
Temperature: 210 °C
Reaction time: 1 h

Procedure:
A mixture of 0.165 g (0.47 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one, 0.500 g (5.30 mmol) of 3-aminopyridine base, and 0.066 g (0.50 mmol) of 3-aminopyridine hydrochloride was heated with stirring in a 210° C. oil bath for 1 hour. Water (5 mL) was added to the cooled reaction mixture to precipitate a solid. The solid was filtered, washed well with water, and dried; wt 0.147 g. Purification was effected by silica gel chromatography by eluting with chloroform and then ethyl acetate. The ethyl acetate eluent containing the pure product was concentrated to 2 mL volume. The crystals that separated on inducement were filtered and washed with 0.5 mL of ethyl acetate and 1 mL of ether; wt 0.810 g; mp 247-248° C.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[CH3:16][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC.O>C1COCC1>[C:1]([C:3]1([CH3:16])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: CC1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of tert-butyl 4-cyanopiperidine-1-carboxylate (0.500 g, 2.38 mmol) in 15 mL of THF at −78° C. was added lithium bis(trimethylsilyl)amide (1 M solution in diethyl ether, 5.23 mL, 5.23 mmol). After 20 min, iodomethane (0.338 g, 2.38 mmol) was added dropwise, and the reaction was slowly warmed to rt. After 15 h, the mixture was cooled to 0° C., treated with water, and extracted 3× with ethyl acetate. The solution was extracted 3× with ethyl acetate, and the combined organic solution was washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide tert-butyl 4-cyano-4-methylpiperidine-1-carboxylate that gave a proton NMR spectra consistent with theory.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:11])=[O:10])=[CH:4][CH:3]=1.[CH:12]([NH2:15])([CH3:14])[CH3:13]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[S:9]([CH3:11])([NH:15][CH:12]([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: CS(=O)Nc1ccc(Br)cc1
Product: CC(C)NS(C)(=O)=Nc1ccc(Br)cc1

Procedure:
The title compound is prepared from N-(4-bromophenyl)methanesulfinamide and isopropylamine following a procedure analogous to that described for Intermediate 3 (Step 2). LC (method 1): tR=0.96 min; Mass spectrum (ESI+): m/z=291, 293 [M+H]+.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([CH2:17][N:18]4[CH2:22][CH:21]([CH2:23][CH2:24][CH3:25])[CH2:20][C:19]4=[O:26])=[C:11]3[N:10]=[CH:9]2)=CC=1.C1(OC)C=CC=CC=1.OS(O)(=O)=O.C([O-])(O)=O.[Na+]>FC(F)(F)C(O)=O.C(OCC)(=O)C>[N:10]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][C:16]=2[CH2:17][N:18]2[CH2:22][CH:21]([CH2:23][CH2:24][CH3:25])[CH2:20][C:19]2=[O:26])[NH:8][CH:9]=1
Reactant: CCCC1CC(=O)N(Cc2ccnc3c2ncn3Cc2ccc(OC)cc2)C1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCC1CC(=O)N(Cc2ccnc3[nH]cnc23)C1
Temperature: 20 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A solution containing 1-{[3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one x187 (0.6 g), anisole (0.4 ml) and concentrated H2SO4 (0.2 ml) in trifluoroacetic acid (4 ml) is stirred in a flow of argon at 20° C. for 2 h. The homogeneous reaction mixture is added dropwise at 0° C. to a mixture of a saturated aqueous solution of NaHCO3 (50 ml) and ethyl acetate (50 ml). The organic layer is separated. The aqueous one (pH˜8) is subjected to additional extraction with chloroform containing 10% of tert-butanol. The combined organic layers are dried with anhydrous sodium sulfate and evaporated. The residue is purified by chromatography on silicagel (chloroform/methanol) to afford 1-(3H-imidazo[4,5-b]pyridin-7-ylmethyl)-4-propylpyrrolidin-2-one 95 (0.34 g).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([N:12](CCO)[C:13]1C=CC=C[CH:14]=1)[CH3:11].C(N(CC)CC)C.[OH2:29]>C1COCC1>[C:1]([O:8][CH2:11][CH2:10][NH:12][CH2:13][CH3:14])(=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CCO)c1ccccc1
Reactant: O
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNCCOC(=O)c1ccccc1
Reaction time: 18 h
Yield: 96 %

Procedure:
Benzoyl chloride (7.8 mL, 66 mmol) was added dropwise to a stirring solution of (N-ethyl-N-(2-hydroxyethyl)aniline (10 g, 60 mmol) in THF (200 ML) containing triethyl amine (9.2 g, 66 mmol) at room temperature. The mixture formed a thick precipitate which was stirred for 18 hours and then poured into water (400 mL). The aqueous layer was extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed successively with 1 molar hydrochloric acid (100 mL), saturated sodium bicarbonate (100 mL), water (100 mL), saturated sodium chloride (100 mL), dried over magnesium sulfate and the solvent was removed under reduced pressure to yield the product (16.4 g, 96% yield) as a dark green oil.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.[C:11]1([C@@H:17]2[CH2:22][CH2:21][C@H:20]([NH2:23])[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:9]([C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:23][C@H:20]2[CH2:19][CH2:18][C@@H:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:22][CH2:21]2)[C:7]=1[I:8])[CH3:10]
Reactant: N[C@H]1CC[C@@H](c2ccccc2)CC1
Reactant: CCc1ncnc(Cl)c1I
Product: CCc1ncnc(N[C@H]2CC[C@@H](c3ccccc3)CC2)c1I

Procedure:
Prepared as in Example 1 from 4-chloro-5-iodo-6-ethylpyrimidine and cis-4-phenylcyclohexylamine.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[N:11]([NH:12][C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:20])[C:10](=[O:21])[NH:9][C:8](=[O:22])[CH:7]=1.[H+].[B-](F)(F)(F)[F:25]>O>[F:25][C:6]1[N:11]([NH:12][C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:20])[C:10](=[O:21])[NH:9][C:8](=[O:22])[CH:7]=1
Reactant: F[B-](F)(F)F
Reactant: Cc1cccc(C)c1Nn1c(N)cc(=O)[nH]c1=O
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Cc1cccc(C)c1Nn1c(F)cc(=O)[nH]c1=O

Procedure:
Sodium nitrite (1.1 mole) dissolved in water is slowly added to a cool (0°-5°) solution of 6-amino-1-(2,6-dimethylanilino)-2,4-pyrimidinedione (1 mole) in dilute fluoboric acid. The precipitate which forms is filtered off, washed with water, dried and pyrolyzed under nitrogen (only a small amount at a time) to give 6-fluoro-1-(2,6-dimethylanilino)-2,4-pyrimidinedione.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH3:15])[C:5]=2[CH2:16]O)[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:38]>ClCCl>[Br:38][CH2:16][C:5]1[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[N:7][O:8][C:4]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ccccc1-c1noc(C2CC2)c1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccccc1-c1noc(C2CC2)c1CBr

Procedure:
Into a 100 mL round bottom flask was placed (5-cyclopropyl-3-(o-tolyl)isoxazol-4-yl)methanol (1.86 g, 8.11 mmol), triphenylphosphine (3.50 g, 12.2 mmol, 1.5 equiv) and dichloromethane (50 mL). The mixture was stirred until completely dissolved, and then slowly cannulated dropwise into a stirring solution of carbon tetrabromide (4.00 g, 12.2 mmol, 1.5 eq) in dichloromethane (20 mL). The solution was stirred for one hour and the solvent was then evaporated in vacuo. The crude residue was purified by silica gel chromatography using a 0-50% gradient of ethyl acetate/hexanes. The desired product was obtained as a yellow oil. MS m/z 292.0/294.0 (M+1, Br79/Br81 isotope pattern).
Reaction SMILES: CC([O:4][C@@H:5]1[C@@H:14]2[O:15][C:16]3=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:11]4=[C:12]3[C@:13]32[CH2:22][CH2:23][N:24](C)[C@H:9]([CH2:10]4)[C@@H:8]3[CH:7]=[CH:6]1)=O.[Cl:26]C(OCCCl)=O.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C>C(Cl)Cl>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:11]2[CH2:10][C@H:9]3[NH:24][CH2:23][CH2:22][C@:13]45[C@H:14]([C@@H:5]([OH:4])[CH:6]=[CH:7][C@@H:8]34)[O:15][C:16]=1[C:12]=25.[ClH:26]
Reactant: COc1ccc2c3c1O[C@H]1[C@@H](OC(C)=O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Reactant: O=C(Cl)OCCCl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCl
Product: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)NCC[C@@]341
Product: Cl
Yield: 93.3 %

Procedure:
A solution of 6-acetylcodeine (10.0 g, 29.3 mmol), 1 chloroethyl chloroformate (5.56 g,38.1 mmol), and proton sponge (1.0 g) in methylene chloride (50 ml) was heated at reflux for 50 min. The reaction mixture was evaporated in vacuo to about 30 ml. Methanol (25 ml) and concentrated HCl (2 ml) were added. The solution was heated at reflux for 40 min. and evaporated in vacuo to almost dryness. The residue was added hexane and filtered to give norcodeine hydrochloride (8.8 g, 93% yield). IR (KBr), (ν, cm-1): 3540 (NH), 3380 (6-OH), 2800-2600 (broad) and 2480 (sharp) (NH·HCl); NMR (δH)(DMSO-d6): 9.66 (2, s (broad), 17-N+H2Cl-), 6.72 (1, d, J, 8.2, 2-H), 6.57 (1, d, J, 8.2, 1-H), 5.66 (1, dt, J, 9.9 & 3.0, 7-H), 5.28 (1, dt, J, 9.8 & 3.0, 8-H), 5.10 (1, s (broad), 6-OH), 4.82 (1, dd, J, 6.1 & 1.2, 5-H), 4.15 (2, m, 6-H & 9-H), 3.77 (3, s, 3-OCH3), 3.22 (1, d, J, 19.1, 10-Hβ), 3.21 (1, td, J, 13.2 & 4.1, 16-He), 3.06 (1, m, 14-H), 2.91 (1, dd, J, 18.5 & 6.3, 10-Hα), 2.79 (1, dd, J, 13.0 & 3.9, 16-Ha), 2.22 (1, td, J, 13.4 & 4.9, 15-Ha) and 1.89 (1, dd, J, 13.6 & 2.7, 15-He).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.I([O-])(=O)(=O)=[O:18].[Na+]>CO.O>[CH3:1][S:2]([CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)=[O:18]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSCCOc1ccc2c(c1)CCC(=O)N2
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)CCOc1ccc2c(c1)CCC(=O)N2
Reaction time: 1.5 h

Procedure:
1.42 gm (0.006 mol) of 6-(2-methylmercapto-ethoxy)-3,4-dihydro-carbostyril were suspended in 12 ml of methanol, and a solution of 1.71 gm (0.008 mol) of sodium metaperiodate in 8 ml of water was added. The reaction mixture was stirred for 1.5 hours; at the beginning a distinct warming of the reaction mixture was noted. Subsequently, the mixture was diluted with a little water and exhaustively extracted with chloroform. The evaporation residue of the chloroform extract was recrystallized from ethyl acetate by addition of a little ethanol.
Reaction SMILES: [N-:1]=[C:2]=[S:3].[NH4+].[Cl:5][C:6]1[CH:11]=[C:10]([C:12](Cl)=[O:13])[CH:9]=[C:8]([Cl:15])[N:7]=1.Cl.[F:17][C:18]1[C:23]([F:24])=[C:22]([F:25])[CH:21]=[CH:20][C:19]=1[NH2:26]>CC(C)=O>[Cl:5][C:6]1[CH:11]=[C:10]([C:12]([NH:1][C:2]([NH:26][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[C:23]([F:24])[C:18]=2[F:17])=[S:3])=[O:13])[CH:9]=[C:8]([Cl:15])[N:7]=1
Reactant: [N-]=C=S
Reactant: Nc1ccc(F)c(F)c1F
Reactant: O=C(Cl)c1cc(Cl)nc(Cl)c1
Agent: Cl
Agent: [NH4+]
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1ccc(F)c(F)c1F)c1cc(Cl)nc(Cl)c1
Reaction time: 0.5 h

Procedure:
Ammonium isothiocyanate (7.726 g, 0.1015 mol) was added to a solution of 2,6-dichloro-4-pyridinecarbonyl chloride (17.8 g, 0.0846 mol) in acetone (300 ml). The mixture was stirred for 30 minutes and subsequently 2,3,4-trifluorobenzenamine hydrochloric acid (.HCl) was added slowly. The reaction mixture was stirred at room temperature for 2 hours and was then quenched with H2O (100 ml). The mixture was extracted with CH2Cl2 (3×80 ml) and the combined organic layers were dried (MgSO4), filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography (eluent: heptane/EtOAc from 80/20 to 50/50). The desired fractions were collected and the solvent was evaporated in vacuo. Yield: 22.2 g of intermediate D9 (69%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([OH:12])[CH:11]=1)[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].C(#N)C.O.Cl[C:25]([F:35])([F:34])C(C1C=CC=CC=1)=O>>[F:34][CH:25]([F:35])[O:12][C:10]1[CH:11]=[C:2]([F:1])[CH:3]=[C:4]2[C:9]=1[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cc(F)cc(O)c2n1
Reactant: O=C(c1ccccc1)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc2cc(F)cc(OC(F)F)c2n1
Temperature: 80 °C

Procedure:
To a mixture of 6-fluoro-2-methylquinolin-8-ol (0.15 g, 0.85 mmol) and potassium carbonate (4.2 g, 30 mmol) in acetonitrile (3.4 mL, 0.85 mmol) and water (3.4 mL, 0.85 mmol) was added 2-chloro-2,2-difluoroacetophenone (0.62 mL, 4.2 mmol). The vessel was sealed and the mixture was heated at 80° C. for 4 hours. The cooled reaction mixture was extracted with diethyl ether (2×30 mL), and the combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure at ambient temperature The resulting residue was purified by reverse phase chromatography on a C18 column (0-100% acetonitrile/water). Aqueous fractions containing the product were combined and extracted with diethyl ether (2×100 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure at ambient temperature providing the title compound. Presence of water was noted and the material taken on as is assuming theoretical yield obtained (0.19 g, 100%).