Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([F:12])=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1C(O)=O.CN1C(=O)CCC1>O>[F:12][C:8]1[CH:9]=[C:10]([F:11])[C:2]([F:1])=[CH:3][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1c(F)cc(F)c(F)c1C(=O)O
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.8 %

Procedure:
A 250 mL single-neck flask equipped with a condenser and a magnetic stirrer was charged with 30.00 g of 3,4,6-trifluorophthalic acid, and 200 mL of NMP. The reaction mixture was then heated with stirring for 18 hr. at a bath temperature of 140° C., followed by 55 hr. at a bath temperature of 150° C. The flask was then allowed to cool to room temperature and the contents were poured into 500 mL of water, and extracted with 4×200 mL of ethyl acetate. The combined organic extracts were washed with water (2×200 mL), dried over magnesium sulfate, filtered, and the solvent removed on a rotary evaporator followed by drying at the pump overnight. The crude product (24.25 g) was then dissolved in 25 mL of ethyl acetate and introduced at the top of a silica column (4.5 cm ID×56 cm, flushed with hexane). The product was then eluted with 90:10 hexane:ethyl acetate under a slight nitrogen pressure, and the fractions (500 mL each) were monitored by gas chromatography. The fractions containing the product were combined, the solvent removed on a rotary evaporator, and then dried at the pump overnight to give 2,4,5-trifluorobenzoic acid as a light yellow solid (21.06 g, 98.97% pure, 87.8% yield). Recrystallization of the product from toluene (50 mL, ca. 60° C.) gave a white product (71.1% overall yield) mp 101°-102° C.
Reaction SMILES: [C:1]1([S:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[O-:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24].[C:30]1([I+]C2C=CC=CC=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCOCC>O.C([O-])(=O)C1C=CC=CC=1.[Cu+2].C([O-])(=O)C1C=CC=CC=1>[O-:25][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:24])=[O:22].[C:1]1([S+:11]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc([I+]c2ccccc2)cc1
Reactant: c1ccc2c(Sc3cccc4ccccc34)cccc2c1
Agent: [Cu+2]
Agent: O=C([O-])c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O
Solvent: CCOCC
Product: c1ccc([S+](c2cccc3ccccc23)c2cccc3ccccc23)cc1
Reaction time: 24 h
Yield: 90 %

Procedure:
Di(1-naphthyl)sulfide (3 g, 0.0104 mole), diphenyliodonium triflate (5.8 g, 0.0135 mole) and copper benzoate (0.08 g, 0.003 mole) are heated without solvent for 3 hours at 120-145° C. under a nitrogen atmosphere. After cooling down, 75 ml ether was added and the mixture vigorously stirred overnight to achive solidification. Filtration and washing with ether yielded a brown solid, which was dissolved in hot water, the solution filtered and the water removed in vacuo. The resulting white solid was stirred in 50 ml ethyl ether for 24 hours, the mixture filtered and the residue washed with ethyl ether, yielding 4.8 g (90%) of the title compound, di-(1-naphthyl)phenylsulfonium triflate. The structure was confirmed by 1H/13C NMR spectroscopy.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[CH3:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1>C1COCC1>[CH3:5][O:4][N:3]([CH3:2])[C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:7]([CH3:6])=[CH:8][CH:9]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CNOC
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 100.9 %

Procedure:
To a mixture of N,O-dimethylhydroxylamine hydrochloride (8.20 g) in THF (dry) (75 mL) was added TEA (23.4 mL) at 0° C. After being stirred at 0° C. for 20 min, 4-methylbenzoyl chloride (10 g) in THF (dry) (20 mL) was added to the reaction mixture. The mixture was stirred at room temperature for 2 days. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give N-methoxy-N,4-dimethylbenzamide (11.7 g) as a yellow oil. n-Butyllithium (1.6 M in hexane) (25.1 mL) was added dropwise to a mixture of 1,4-dibromobenzene (8.29 g) in THF (dry) (105 mL) at −78° C. for 10 min. The mixture was stirred at the same temperature under nitrogen for 30 min to form white precipitates. A solution of N-methoxy-N,4-dimethylbenzamide (6 g) in THF (dry) (20 mL) was added to the reaction mixture at −78° C. and the mixture was stirred at the same temperature under nitrogen for 30 min and then at room temperature under a dry atmosphere with anhydrous calcium chloride tube overnight. The mixture was quenched with sat. NH4Cl aq. at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (7.18 g) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.S(Cl)(Cl)=O.[CH3:16]O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)cc1O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Cl)cc1O
Yield: 95 %

Procedure:
To a solution of 4-chloro-2-hydroxybenzoic acid (20 g, 115.90 mmol) in methanol (500 mL) was added thionyl chloride (26 mL). After refluxing for 3 h, the reaction mixture was concentrated under vacuum, dissolved in petroleum ether (300 mL) and filtered to give methyl 4-chloro-2-hydroxybenzoate as a white solid (21 g, 95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:30].O.CCOCC.C[N:38]1CCCC1=O>>[NH2:38][C:16]1[N:17]=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[C:13]2[CH:12]=[CH:11][C:10](=[O:30])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1
Reactant: CS(=O)(=O)c1nc(-c2ccccc2F)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN1CCCC1=O
Solvent: O
Solvent: CCOCC
Product: Nc1nc(-c2ccccc2F)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 8-(2,6-difluoro-phenyl)-4-(2-fluoro-phenyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (432 mg, 1 mmol) in 1-methyl-2-pyrrolidinone (5 mL) was added NaNH2 (195 mg, 5 mmol, 5 eq) and the mixture was heated to 50°. After 1 h, H2O (20 mL) was added then Et2O (20 mL). The layers were separated. The organic layer was washed with satd aq NaCl, dried (MgSO4), filtered and solvent was removed in vacuo. The yellow residue was then purified by Flash chromatography to afford 2-amino-8-(2,6-difluoro-phenyl)-4-(2-fluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (100 mg, 53% yield). 1H-NMR (CDCl3) δ 5.51 (br s, 2H), 6.42 (d, 1H, J=9.8 Hz), 7.08 (m, 2H), 7.30 (m, 2H), 7.50 (m, 4H), LC MS (m/e)=369 (MH+). Rt=1.77 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].C1C(=O)N([Br:19])C(=O)C1>FC(F)(F)C1C=CC=CC=1.CC(N=NC(C#N)(C)C)(C#N)C>[Br:19][CH2:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: FC(F)(F)c1ccccc1
Product: O=[N+]([O-])c1ccc(F)c(CBr)c1
Temperature: 80 °C
Yield: 50.8 %

Procedure:
A mixture of 1-fluoro-2-methyl-4-nitrobenzene (2.5 g, 16.12 mmol) and NBS (3.16 g, 17.73 mmol) in trifluorotoluene (45 mL) was treated with AIBN (66 mg, 0.403 mmol) and heated at 80° C. overnight. The mixture was cooled to RT, the solids removed via filtration and the filtrate concentrated to dryness. The residue was dissolved in EtOAc, washed with water, then brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 2-(bromomethyl)-1-fluoro-4-nitrobenzene (1.915 g, 50% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.53-8.52 (m, 1H), 8.28 (ddd, J=9.1, 4.4, 3.0 Hz, 1H), 7.55 (t, J=9.2 Hz, 1H), 4.80 (s, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:2]1.CS(C)=[O:18].Cl.[N+](=C)=[N-]>>[O:18]=[C:2]1[CH:3]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1]1
Reactant: CS(C)=O
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Agent: C=[N+]=[N-]
Agent: Cl
Product: O=C(O)CCCC1C(=O)Nc2ccccc21
Yield: 89 %

Procedure:
Similar treatment of methyl 3-(3-indolinyl)propanoic [II: R1 =R3 =H, R2 =(CH2)2COOH] (0.93 g) with DMSO/HCl, followed by esterification with diazomethane and chromatography on silica gel, gave methyl 3-(2-oxo-3-indolyl)propanoate [III: R1 -R3 =H, R2 =(CH2)2COOMe] (0.89 g, 89%) as a yellow oil (Julian PL, Printy HC, J. Am. Chem. Soc. 1953;75:5301-5305 report mp 79°-80° C.).
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[N:11]([CH3:12])[C:10](=[O:13])[NH:9][C:8](=[O:14])[CH:7]=1.[N:15]([O-])=O.[Na+]>O>[NH2:15][C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[N:11]([CH3:12])[C:6]=1[NH2:5]
Reactant: Cn1c(N)cc(=O)[nH]c1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(N)c(N)c(=O)[nH]c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
Glacial acetic acid (4.5 ml, 75 mmol) was added to a suspension of 6-amino-1-methyluracil (5.66 g, 50 mmol) in hot water (100 ml). Sodium nitrite (4.14 g) was added in portions and the reaction mixture was stirred for 1 hour. The precipitate was collected by filtration, washed with water (75 ml) and then suspended in water (100 ml). The mixture was warmed to 50° C. and sodium dithionite (10 g) was added in portions keeping the temperature of the reaction between 50-55° C. The mixture was stirred at 50° C. for 1 hr and then cooled to room temperature and filtered. The solid was washed with water (2×25 ml), acetone (2×25 ml) and dried under vacuum to provide 5,6-diamino-1-methyluracil (5.6 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22])([OH:13])=[O:12].[O-]CCCC.[K+]>CC(N(C)C)=O>[C:11]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)([OH:13])=[O:12]
Reactant: O=C(O)COc1ccccc1O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CCCC[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)COc1ccccc1Oc1ccc([N+](=O)[O-])cc1

Procedure:
4-nitro-fluorobenzene and 2-(carboxymethoxy)phenol were reacted together in DMA in the presence of potassium butoxide for 2 hours at 150° C. to yield 4-(2-(carboxymethoxy)phenoxy)nitrobenzene.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH2:21]([O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][NH:31]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(#N)C>[C:4]([O:3][C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]([N:31]1[CH2:32][CH2:33][CH2:34][C@H:30]1[C:29]([O:28][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:35])=[O:19])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a suspension of N-Boc-L-phenylalanine (1.000 g, 3.77 mmol) in acetonitrile (25 ml) at room temperature was added L-proline benzyl ester HCl (1.002 g, 4.15 mmol), PyBOP (2.060 g, 3.96 mmol) followed by DIPEA (1.382 ml, 7.92 mmol). The reaction turned to clear and was stirred at room temperature for 1 hour. The reaction was quenched by brine and was extracted with EtOAc. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (silica gel, 30 to 50% EtOAc/HEP) and gave the title compound: 1.6 g (yield: 97%). LCMS (condition B): 453.4 (M+1); retention time=1.44 min.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:8]1[O:12][CH:11]([N:13]2[CH:18]=[CH:17][C:16]([N:19]=[CH:20][N:21]([CH3:23])[CH3:22])=[N:15][C:14]2=[O:24])[C:10]([OH:26])([CH3:25])[CH:9]1[OH:27])([CH3:4])([CH3:3])[CH3:2].[C:40]([NH:47][C@H:48]([C:52](O)=[O:53])[CH:49]([CH3:51])[CH3:50])([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([SiH2:5][O:6][C:7]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH:8]1[CH:9]([O:27][C:52](=[O:53])[CH:48]([NH:47][C:40]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:41])[CH:49]([CH3:51])[CH3:50])[C:10]([OH:26])([CH3:25])[CH:11]([N:13]2[CH:18]=[CH:17][C:16]([N:19]=[CH:20][N:21]([CH3:22])[CH3:23])=[N:15][C:14]2=[O:24])[O:12]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=Nc1ccn(C2OC(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)C(O)C2(C)O)c(=O)n1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OC1C(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(n2ccc(N=CN(C)C)nc2=O)C1(C)O

Procedure:
The next steps in this process comprise reacting (3) with Me2NCH(OMe)2 in DMF to form (4), N-[1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-N,N-dimethyl-formamidine, which is the amino-protected form of (3); reacting (4) with TBDPSCl and imidazole in DCM to provide the 5′-silyl-protected form of (4) as N′-{1-[5-(tert-butyl-diphenyl-silanyloxymethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yl]-2-oxo-1,2-dihydro-pyrimidin-4-yl}-N,N-dimethyl-formamidine (5), where the use of DCM provides the advantage of having greater control over disilyl by-product formation; reacting (5) with N-Boc-L-valine, EDC and DMAP in DCM at room temperature to form 2-tert-butoxycarbonylamino-3-methyl-butyric acid 2-(tert-butyl-diphenyl-silanyloxy-methyl)-5-[4-(dimethylamino-methyleneamino)-2-oxo-2H-pyrimidin-1-yl]-4-hydroxy-4-methyl-tetrahydro-furan-3-yl ester (6); removing the silyl and amino-protecting groups by reacting (6) with NH4F in MeOH in the presence of approximately 10 mole equivalents of ethyl acetate to prevent cleavage of the 3′-O-valinyl ester by liberated ammonia, and refluxing the mixture to provide 2-tert-butoxycarbonylamino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester to provide (7); and finally, reacting (7) with HCl in EtOH to provide 2-amino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester, dihydrochloride salt (8) as a final product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[Br:20]Br>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[Br:20])=[CH:5][CH:4]=1
Reactant: BrBr
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Br)cc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
To a solution of 2-(4-methoxyphenyl)-6-methoxybenzo[b]thiophene (27.0 g, 100 mmol)in 1.10 L of chloroform at 60° C. was added bromine (15.98 g, 100 mmol) dropwise dissolved in 200 mL of chloroform. After the addition was complete, the reaction was cooled to room temperature, and the solvent removed in vacuo to provide 34.2 g (100%) of 2-(4-methoxyphenyl)-3-bromo-6-methoxybenzo[b]thiophene as a white solid. mp 83-85° C. 1H NMR (DMSO-d6) δ7.70-7.62 (m, 4H), 7.17 (dd, J=8.6, 2.0 Hz, 1H), 7.09 (d, J=8.4 Hz, 2H). FD mass spec: 349, 350. Anal. Calcd. for C16H13BrO2S: C, 55.03; H, 3.75. Found: C, 54.79; H, 3.76.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7]O.P(Br)(Br)[Br:12].COC(C)(C)C>C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][Br:12]
Reactant: BrP(Br)Br
Reactant: OCc1cc(Br)ccc1Cl
Solvent: COC(C)(C)C
Solvent: CCOCC
Product: Clc1ccc(Br)cc1CBr
Temperature: 0 °C
Yield: 156.3 %

Procedure:
To a solution of 2.08 g (9.39 mol) of 5-bromo-2-chlorobenzylalcohol in 30 ml of dry diethyl ether was added dropwise 1.27 g (4.23 mmol) of phosphorous tribromide with ice-cooling. The mixture was stirred with ice-cooling for 3 hours and stirred at room temperature for 1.5 hours. To the reaction solution were added ice water and then tert-butyl methyl ether. The mixture was stirred for 30 minutes and separated. The organic layer was washed successively with an about 5% aqueous solution of sodium bicarbonate and water, then dried and concentrated. The solid residue (1.99 g) was subjected to silica gel column chromatography (eluted with n-hexane) to obtain 1.88 g of 5-bromo-2-chlorobenzylbromide as flocculent crystals.
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[BrH:13].N([O-])=O.[Na+]>C(#N)C.O>[Br:13][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: Br
Reactant: Nc1ccc2c(c1)C(=O)NCC2
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C1NCCc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution of 7-amino-3,4-dihydro-1(2H)-isoquinolinone, (0.77 g, 4.77 mmol)(for a synthesis see Girard, Yves; Atkinson, Joseph G.; Belanger, Patrice C.; Fuentes, Jose J.; Rokach, Joshua; Rooney, C. Stanley; Remy, David C.; Hunt, Cecilia A J. Org. Chem. (1983), 48(19), 3220) in acetonitrile (10 ml) at 0° C. was added 48% aqueous HBr (10 ml, precooled to 0° C.). The mixture was stirred at 0° C. for 0.5 h before addition of a solution of NaNO2 (0.379 g, 5.49 mmol) in water (2 ml) over 0.4 h. The reaction was then stirred at 0° C. for 0.5 h and then CuBr (0.822 g, 5.726 mmol) was added portionwise over 10 min. The reaction mixture was then warmed to room temperature, stirred at room temperature for 0.5 h and then at 70° C. for 1 h. The reaction mixture was then cooled to 0° C., water (60 ml) was added and the mixture stirred at 0° C. for 1 h before filtering and drying in vacuo. The residue was dissolved in 10% methanol/dichloromethane, dried with magnesium sulphate and evaporated to give the desired product (0.679 g, 63%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]([CH:11]([F:13])[F:12])=[N:9][CH:10]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>C(Cl)Cl>[F:12][CH:11]([F:13])[C:8]1[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][C:5]([CH2:4][NH:3][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[CH:10][N:9]=1
Reactant: CCOC(=O)c1cc(CN)cnc1C(F)F
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(CNC(=O)C(C)C)cnc1C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
Cool a mixture of ethyl 5-(aminomethyl)-2-(difluoromethyl)pyridine-3-carboxylate dihydrochloride (29.8 g, 111.8 mmol, 1.0 equiv), DCM (510 mL), and triethylamine (59.2 mL, 424.6 mmol, 3.8 equiv) to 0° C., then add a solution of isobutyryl chloride (15.3 mL, 145.3 mmol, 1.3 equiv) in DCM (23 mL) drop wise over 20 min. Stir overnight while allowing the mixture to warm to room temperature. Remove the solid precipitate by filtration, and rinse the filter with EtOAc (500 mL). Concentrate the filtrate under reduced pressure; filter the concentrate to remove the solids; and rinse the solids with EtOAc. Concentrate the filtrate under reduced pressure to give a yellow oil. Subject this crude material to silica gel chromatography eluting with a gradient of 40-90% EtOAc/hexanes gradient, to give the title compound as a light yellow crystalline solid (25.8 g, 77% yield). ES/MS (m/z) 301 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:17][C@@H:18]([CH2:21][CH3:22])[CH2:19]O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[CH3:17][CH:18]([CH2:21][CH3:22])[CH2:19][O:13][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][C:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CC[C@H](C)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCC(C)COC(=O)c1ccc(-c2ccc(O)cc2)cc1

Procedure:
Five grams of 4-(4'-hydroxyphenyl)benzoic acid, 5 g of (s)-2-methylbutylalcohol and 11 g of p-toluenesulfonic acid were dissolved with 50 ml of benzene. Occurred water in the mixture was removed by azotropic dehydration with refluxing for eight hours. After adding 50 ml of water to the residue, the organic phase was concentrated to obtain 4-(4'-hydroxyphenyl)benzoic acid-2-methylbutyl ester (BJ).
Reaction SMILES: Cl[CH:2]([CH:8]=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:10]([NH2:12])=[S:11]>>[C:3]([C:2]1[S:11][CH:10]=[N:12][CH:8]=1)([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(Cl)C=O
Reactant: NC=S
Product: CCOC(=O)c1cncs1
Yield: 33 %

Procedure:
According to the procedure of Mashraqui and Keehn (J. Am. Chem. Soc. 1982, 104, 4461), ethyl α-chloro-α-formylacetate was condensed with thioformamide and vacuum distilled to provide 5.65 g (33%) of the desired compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.[C:13](Cl)(=[O:15])[CH3:14].O.Cl>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CC(=O)Cl
Reactant: CC1(C)CCSc2ccccc21
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)c1ccc2c(c1)C(C)(C)CCS2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 14.3 g (80.21 mmol) of 4,4-dimethyl thiochroman (from Example 2) and 6.76 g (86.12 mmol) of acetyl chloride in 65 ml benzene was cooled in an ice bath and treated dropwise with 26.712 g (102.54 mmol) of stannic chloride. The mixture was stirred at room temperature for 12 hours, then treated with 65 ml water and 33 ml conc. hydrogen chloride and heated at reflux for 0.5 hours. After being cooled to room temperature, the organic layer was separated and the aqueous layer extracted with 5×50 ml benzene. The recovered organic fractions were combined and washed with 5% sodium carbonate solution, water, saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexanes) followed by kugelrohr distillation (150° C., 0.7 mm) to give the title compound as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1>[CH2:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(OCc2ccccc2)cc1
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
A mixture containing 325 g of 4-cyanophenol, 346 mL of benzyl chloride and 758 g of potassium carbonate in 1.2 L of NMP was heated at 95° C. with stirring for 1.5 hrs. The reaction mixture was cooled to room temperature and poured into 5L of cold water. The resulting white solid was collected, washed with water and hexanes and dried at 70° C. in vacuo giving 570.0 g of 4-benzyloxybenzonitrile.