Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=4)[S:15][C:8]=23)=[C:4]([F:27])[CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37]([N:39]=[C:40]=[S:41])=[O:38]>CCO.C1(C)C=CC=CC=1>[F:27][C:4]1[CH:3]=[C:2]([NH:1][C:40]([NH:39][C:37](=[O:38])[CH2:36][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[O:29][CH3:28])=[S:41])[CH:26]=[CH:25][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[S:15][C:8]=12
Reactant: COc1ccccc1CC(=O)N=C=S
Reactant: COc1cccc(Nc2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cccc(Nc2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5OC)cc4F)c3s2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.5 %

Procedure:
A solution of 449 (40 mg, 0.10 mmol) in 1:1 mixture of EtOH/toluene (2 mL) was treated with 2-(2-methoxyphenyl)acetyl isothiocyanate (394 mg, 2.22 mmol) and stirred at room temperature for 2 hours. The reaction mixture was then concentrated and purified by flash chromatography using the gradient 75-100% EtOAc in hexanes as an eluent, yielding 447 (15 mg, 24% yield). CDCl3 12.39 (s, 1H), 9.47 (s, 1H), 8.34 (d, J=5.7 Hz, 1H), 7.92 (dd, J=2.0, 11.8 Hz, 1H), 7.36 (m, 2H), 7.22 (m, 2H), 7.01 (m, 3H), 6.80 (s, 2H), 6.59 (d, J=7.4 Hz, 2H), 6.39 (d, J=5.6 Hz, 1H), 4.00 (s, 3H), 3.80 (s, 3H), 3.72 (s, 2H) LCMS: (M+H) 589.0
Reaction SMILES: C1COC2C=CC(NC3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=CC=2O1.[S:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([CH2:36][NH2:37])=[CH:28]1.[Cl:38][C:39]1[N:44]=[C:43](Cl)[C:42]([F:46])=[CH:41][N:40]=1>>[S:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([CH2:36][NH:37][C:41]2[C:42]([F:46])=[CH:43][N:44]=[C:39]([Cl:38])[N:40]=2)=[CH:28]1
Reactant: NCc1csc2ccccc12
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Product: Fc1cnc(Cl)nc1NCc1csc2ccccc12

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of benzothiophen-3-ylmethylamine (244 mg, 1.5 mmol) and 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) gave N4-(benzothiophen-3-ylmethyl)-2-chloro-5-fluoro-4-pyrimidineamine. The reaction of N4-(benzothiophen-3-ylmethyl)-2-chloro-5-fluoro-4-pyrimidineamine and 3-aminophenol (200 mg, 1.83 mmol) gave N4-(benzothiophen-3-ylmethyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. (40 mg, 36%). 1H NMR (CDCl3): δ 4.45 (br, 1H), 4.95 (dd, J=1.2 and 5.4 Hz, 2H), 5.33 (br, 1H), 6.40 (ddd, J=1.2, 2.4 and 8.1 Hz, 1H), 6.85 (ddd, J=0.9, 2.1 and 8.1 Hz, 1H), 6.91 (br, 1H), 7.05 (t, J=8.1 Hz, 1H), 7.26 (m, 1H), 7.39-7.47 (m, 3H), 7.81 (dd, J=1.2 and 5.1 Hz, 1H), 7.84 (d, J=3.3 Hz, 1H), 7.92 (m, 1H); 19F NMR (282 MHz, CDCl3): δ −168.89; LCMS: ret. time: 21.91 min.; purity: 99.34%; MS (m/e): 366.96 (MH+).
Reaction SMILES: CS[C:3]([S:13][CH3:14])=[C:4]([C:10](=O)[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=1[NH:24][NH2:25].O>C(O)C>[CH2:8]([O:7][C:5]([C:4]1[C:3]([S:13][CH3:14])=[N:25][N:24]([C:17]2[C:18]([Cl:23])=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=2[Cl:15])[C:10]=1[CH3:11])=[O:6])[CH3:9]
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Reactant: CCOC(=O)C(C(C)=O)=C(SC)SC
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(SC)nn(-c2c(Cl)cc(Cl)cc2Cl)c1C
Yield: 56.4 %

Procedure:
A mixture of 1.22 g (5.23 mmol) of ethyl 3,3-bismethylthio-2-acetylacrylate and 1.11 g (5.23 mmol) of 2,4,6-trichlorophenylhydrazine in 12 mL of ethanol was heated at reflux for 2 hours. The cooled reaction mixture was then poured into cold water and the product was extracted into ether. The ethereal extracts were dried and evaporated and the residues were chromatographed on silica gel using 6:1 hexane/ethyl acetate as eluent to give 1.12 g (56%) of the desired product as a crystalline solid, m.p. 95-98° C. 1H-NMR (CDCl3) δ1.38 (3H, t, J=7), 2.30 (3H, s), 2.49 (3H, s.), 4.31 (2H, q, J=7), 7.47 m(2H, s).
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([I:19])[C:3]=1[NH2:4].[Cl:20][C:21]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].O>CN1C(=O)N(C)CC1>[Cl:20][C:21]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:4][C:3]1[C:2]([I:1])=[CH:8][C:7]([C:9]([F:18])([C:10]([F:13])([F:12])[F:11])[C:14]([F:15])([F:16])[F:17])=[CH:6][C:5]=1[I:19])=[O:24]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1Cl
Reactant: Nc1c(I)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1I
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: O=C(Nc1c(I)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1I)c1cccc([N+](=O)[O-])c1Cl
Temperature: 135 °C
Reaction time: 3 h
Yield: 103.5 %

Procedure:
To a solution of 40.0 g (78.0 mmol) of 2,6-diiodo-4-(heptafluoropropan-2-yl)aniline in 100 ml of DMI was added 20.6 g (94.0 mmol) of 2-chloro-3-nitrobenzoyl chloride, followed by stirring at 135° C. for 3 hours. After cooling to room temperature, the reaction mixture was poured into 1000 ml of water. After extraction with the addition of 1000 ml of ethyl acetate, the organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was washed with hexane to prepare 56.2 g (yield 99%) of a target compound.
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][N:17]=1.Cl>C1COCC1>[F:15][C:16]1[N:17]=[CH:18][C:19]([CH:20]([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)[OH:21])=[CH:22][CH:23]=1
Reactant: O=Cc1ccc(F)nc1
Reactant: CSc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CSc1ccc(C(O)c2ccc(F)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
Magnesium turnings (0.214 g, 8.79 mmol) in a minimal amount of THF were treated with 1,2-dibromoethane (50 μL, cat.) and the mixture was allowed to stand until effervescence was observed (1 min) A solution of 4-bromothioanisole (Aldrich) (1.705 g, 8.39 mmol) in THF (20 mL) was added dropwise and the mixture stirred for 2 h, occasionally heating to gentle reflux with a heat gun, to give a cloudy pale yellow solution. The resulting Grignard solution was added dropwise over 10 min to a solution of 6-fluoronicotinaldehyde (Frontier Scientific) (1.000 g, 7.99 mmol) in THF (10 mL) cooled in a dry ice/acetone bath. The mixture was stirred at −78° C. for 30 min, and then quenched by dropwise addition of 2 N aqueous HCl (9.0 mL, 2 equiv.). The cooling bath was removed and the mixture was allowed to warm to ambient temperature. The mixture was extracted into EtOAc from water, dried (MgSO4) and concentrated to give (6-fluoropyridin-3-yl)(4-(methylthio)phenyl)methanol (1.856 g, 7.44 mmol, 93% yield) as a colorless oil. 1H NMR (400 MHz, d6-DMSO) δ 8.23 (s, 1H); 7.87 (t, J=8.22 Hz, 1H); 7.32 (d, J=8.02 Hz, 2H); 7.22 (d, J=7.82 Hz, 2H); 7.11 (d, J=8.41 Hz, 1H); 6.11 (br. s., 1H); 5.78 (s, 1H); 2.44 (s, 3H). m/z (ESI, +ve) 250.0 (M+H)+.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[N:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:16])[C:10]=2[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C1COCC1>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:16][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]=[CH:8][CH:7]=[N:6]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cccc2ncccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=P(Cl)(Cl)Oc1cccc2ncccc12
Temperature: 25 °C

Procedure:
Phosphorus oxychloride (0.385 mL, 4.14 mmol.) and quinolin-5-ol (Aldrich, 600 mg, 4.14 mmol.) were stirred in anhydrous THF (25 mL). Anhydrous triethylamine was added (0.576 mL, 4.14 mmol.) at −78° C. and the solution was allowed to warm to room temperature. The reaction mixture was monitored by 31PNMR for completion of phosphorus oxychloride (about 30 min) and this mixture was used directly.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[Br:13]N1C(=O)CCC1=O>CC#N.CCOC(C)=O>[NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([Br:13])=[C:6]([F:8])[CH:7]=1
Reactant: COC(=O)c1ncc(F)cc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(Br)c(F)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To a solution of methyl 3-amino-5-fluoropyridine-2-carboxylate (3.6 g, 21 mmol) in MeCN (60 mL), N-bromosuccinimide (4.1 g, 23 mmol) was added portionwise. After stirring at room temperature for 2 h, the reaction mixture was diluted with EtOAc (200 mL), washed with a saturated aq. NaHCO3 (200 mL) and brine (200 mL), then dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to afford the sub-title compound as a pale yellow solid (4.0 g, 76%) LCMS calc. for C7H7BrFN2O2 (M+H)+: m/z=249.0. found 249.0.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][C:10]([CH:12]1[C:28]2([CH3:29])[CH:15]([CH:16]3[CH:25]([CH2:26][CH2:27]2)[C:24]2([CH3:30])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][CH2:23]2)[CH2:18][CH2:17]3)[CH2:14][CH2:13]1)=[O:11])=[O:7].[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C)C=O>[N:32]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][C:10]([CH:12]1[C:28]2([CH3:29])[CH:15]([CH:16]3[CH:25]([CH2:26][CH2:27]2)[C:24]2([CH3:30])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][CH2:23]2)[CH2:18][CH2:17]3)[CH2:14][CH2:13]1)=[O:11])=[O:7])=[N+:33]=[N-:34]
Reactant: CC12CCC(=O)C=C1CCC1C2CCC2(C)C(C(=O)COC(=O)CCCCBr)CCC12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC12CCC(=O)C=C1CCC1C2CCC2(C)C(C(=O)COC(=O)CCCCN=[N+]=[N-])CCC12
Temperature: 65 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To a solution of 8 (325 mg, 0.639 mmol) in anhydrous N,N-dimethylformamide (7 mL) was added sodium azide (415 mg, 6.39 mmol). The reaction mixture was heated to 65° C. and stirred overnight. Excess sodium azide was filtered off and the solvent was removed by rotary evaporation. The crude residue was dissolved in ethyl acetate and washed with water three times. The organic layer was dried over sodium sulfate and concentrated followed by flash chromatography in hexanes/ethyl acetate (4:3) to give 10 (206 mg, 71%). 1H NMR (500 MHz, CD3CN) δ 5.62 (1H, s, 4-H), 4.72 (1H, d, J=17, COCH2O), 4.53 (1H, d, J=17, COCH2O), 3.31 (2H, t, J=6.5, CH2N3), 2.55-0.99 (complex, 26H), 1.17 (3H, s, CH3), 0.64 (3H, s, CH3); 13C NMR (125 MHz, CD3CN) δ 204.49, 199.18, 173.04, 171.81, 123.86, 69.81, 59.25, 56.55, 54.21, 51.43, 44.95, 39.12, 38.60, 36.20, 35.94, 34.28, 33.36, 32.96, 32.52, 28.46, 24.79, 23.62, 23.07, 21.46, 17.35, 13.20. ESI-MS m/z [M+Na]+ observed: 478.3, calculated: 478.3.
Reaction SMILES: C([O:14][NH:15][C:16]([CH:18]1[CH:24]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[S:34]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)(=[O:36])=[O:35])=[O:17])(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[OH:14][NH:15][C:16]([CH:18]1[CH:24]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[S:34]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)(=[O:36])=[O:35])=[O:17]
Reactant: COc1ccc(S(=O)(=O)N2CCCCC(COCc3ccccc3)C2C(=O)NOC(c2ccccc2)c2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N2CCCCC(COCc3ccccc3)C2C(=O)NO)cc1

Procedure:
To a solution of 3-Benzyloxymethyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid benzhydryloxy-amide (10 mg, 0.016 mmoL) in 0.25 mL of dichloromethane at 0° C. was added 0.25 mL of trifluoroacetic acid followed by triethyl silane (3.7 mg, 0.032 mmoL). After 50 minutes the solvent was removed under reduced pressure and the residue was azeotroped twice with toluene. The residue was then purified by column chromatography (silica: 1.5% to 3% methanol in dichloromethane) to yield 3-Benzyloxymethyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid hydroxyamide; MS: (M-H)- =447.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[Cl:9].[NH:10]1[C:18]2[C:13](=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[Cl:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[C:18]2[C:13](=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: Clc1cccc(I)c1Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3cccc(Cl)c3Cl)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1,2-dichloro-3-iodobenzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 520.2 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[OH:21])[CH:16]=[O:17])([O-:12])=[O:11].C(N(CC)CC)C>C(Cl)Cl>[N+:10]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:16]=[O:17])([O-:12])=[O:11]
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1ccc(OC(=O)c2ccccc2)c([N+](=O)[O-])c1

Procedure:
To a solution of benzoyl chloride (2.50 mL, 20.0 mmol) in methylene chloride (100 mL) cooled at 0° C. was added 3-nitro-4-hydroxybenzaldehyde (3.00 g, 19.0 mmol) and triethylamine (2.80 mL, 20.0 mmol). After 1 hour the mixture was washed with water and concentrated to an oil, in vacuo. The product was crystallized from ethyl acetate-hexane giving 1.70 g (33.0%); mp110.5-112° C. 1H NMR (CDCl3): 10.05 (s,1H,CHO), 8.59 (s,1H) 8.20 (m,3H), 7.62 (2,1H), 7.38 (m,3H). MS (DCl) 272 (MH+). C14H9NO5.
Reaction SMILES: BrNC(=O)CCC(N)=O.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[NH:18][C:19](=[O:25])/[CH:20]=[CH:21]/OCC.[NH2:26][C:27]([NH2:29])=[S:28].[OH-].[NH4+]>O1CCOCC1.O>[NH2:29][C:27]1[S:28][C:20]([C:19]([NH:18][C:12]2[C:13]([CH3:17])=[CH:14][CH:15]=[CH:16][C:11]=2[Cl:10])=[O:25])=[CH:21][N:26]=1
Reactant: NC(N)=S
Reactant: CCO/C=C/C(=O)Nc1c(C)cccc1Cl
Agent: NC(=O)CCC(=O)NBr
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(Cl)c1NC(=O)c1cnc(N)s1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
N-Bromosuccinamide was added to a mixture of (E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide in 1,4-dioxane and water at −10° C. to 0° C. to obtain a slurry which was warmed and stirred at 20° C. to 22° C. for 3 hours. Thiourea was added and the mixture was heated to 80° C. After 2 hours, the resulting solution was cooled to 20° C. to 22° C. and concentrated ammonium hydroxide was added dropwise. The resulting slurry was concentrated under vacuum to about half volume and cooled to 0° C. to 5° C. to obtain a solid which was collected by vacuum filtration, washed with cold water, and dried to obtain 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (Formula 1c).
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[Cl:11]Cl.O>C(O)(=O)C>[Cl:11][C:4]1[C:5]([OH:10])=[C:6]([CH:9]=[C:2]([I:1])[CH:3]=1)[CH:7]=[O:8]
Reactant: ClCl
Reactant: O=Cc1cc(I)ccc1O
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1cc(I)cc(Cl)c1O
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To 24 g (96.8 mmole) of 5-iodosalicylaldehyde in 320 mL of acetic acid was added an excess of gaseous chlorine. After addition of about 10 g of Cl2, a white solid appeared in the solution. The mixture was heated to 70° C. and allowed to stir for 3 h. The heated solution was homogeneous and remained so after cooling to rt. The mixture was added to 1200 mL of water and allowed to stir for 1 h. The resultant solid was collected by filtration, washed with water, filtered and allowed to air dry to afford 27.3 g of a yellow solid. The solid was recrystallized by dissolving the material in 250 mL of hot methanol and adding 80 mL of H2O. After standing overnight, the crystalline solid was collected and air-dried to afford 20.3 g (74.2%) of a yellow solid. The product contained a minor impurity (approx. 9% by 1H NMR) and was used in the next step without further purification: 1H NMR (CDCl3/400 MHz) 7.78 (d, 1H, J=2.1 Hz), 7.88 (d, 1H, J=1.8 Hz), 9.83 (s, 1H), 11.40 (s, 1H); 13C NMR (CDCl3/100 MHz) 79.5, 122.8, 123.7, 140.3, 144.4, 156.9, 194.8; MS (ESI+) 283 (M+1, 100); HRMS (El) m/z calcd for (C7H4O2ICl) 281.8945, found 281.8899.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]2[C:6]([N:7]=[CH:8][C:9](=O)[NH:10]2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:18])=O.CCCCCC>C(OCC)(=O)C>[Cl:18][C:9]1[CH:8]=[N:7][C:6]2[C:11](=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2ncc(=O)[nH]c2c1OC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc2ncc(Cl)nc2c1OC
Temperature: 25 °C
Yield: 77.1 %

Procedure:
A solution of 7,8-dimethoxy-quinoxalin-2-one (5.0 g, 24.25 mmol, 1.0 eq) in phosphorus oxychloride (25 mL, 268.21 mmol, 11.06 eq) is heated under reflux for 1 hour. Then the reaction mixture is cooled down to room temperature and the solvent is evaporated. The residue is poured into ice water, the resulting mixture is neutralized with saturated sodium hydrogen carbonate and extracted with ethyl acetate (3×50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: hexane:ethyl acetate, 2:1 to 1:1, v/v) to afford 2-chloro-7,8-dimethoxy-quinoxaline as a light yellow solid (4.2 g, 77% yield).
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:12]([C:11]1[C:2]([OH:1])=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1cccc(O)c1O
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(Oc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 96 h
Yield: 11.5 %

Procedure:
To a mixture of methyl 2,3-dihydroxybenzoate (1.50 g, 8.9 mmol), phenylboronic acid (1.08 g, 8.9 mmol) and copper acetate (1.62 g, 8.9 mmol) suspended in dichloromethane (100 ml) was added triethylamine (6.15 ml, 44.5 mmol) and the mixture was stirred at room temperature for 96 h. The solvent was removed and the product chromatographed through a silica column using a gradient of 0-10% methanol in dichloromethane. The product was obtained as a pale yellow oil (0.25 g).
Reaction SMILES: [CH3:1][S-:2].[Na+].[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1>C1COCC1>[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][S:2][CH3:1])=[CH:7][CH:6]=1
Reactant: C[S-]
Reactant: BrCc1ccc(Br)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CSCc1ccc(Br)cc1
Temperature: 60 °C

Procedure:
Sodium thiomethoxide (1.0 g, 14.3 mmol) and 4-bromobenzyl bromide (2.65 g, 10.6 mmol) were combined with anhyd THF (50 mL) and the reaction mixture was stirred at 60° C. After 3 h the reaction mixture was concentrated in vacuo and the residue was washed into a separatory funnel with EtOAc and water. The organic layer was separated, dried (anhyd MgSO4), and concentrated in vacuo to yield 1-bromo-4-methylthiomethyl-benzene. To a solution of this crude thioether in DCM (100 mL) was added 3-chloroperoxybenzoic acid (77%, 4.0 g) portionwise. After stirring overnight the reaction mixture was poured into a separatory funnel, washed with 1N NaOH, dried (Na2SO4), and concentrated in vacuo. The residue was crystallized from EtOAc-Hex to afford 1-bromo-4-methanesulfonylmethyl-benzene (2.02 g, 76%) as light tan needles:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13]([Si:15]([CH3:18])([CH3:17])[CH3:16])#[CH:14].C(NC(C)C)(C)C>C1COCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][Si:15]([C:13]#[C:14][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:18])[CH3:17]
Reactant: CCOC(=O)c1cccc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(C#C[Si](C)(C)C)c1
Yield: 90 %

Procedure:
A mixture of ethyl 3-bromobenzoate (1.0 g, 4.37 mmol), ethynyl trimethylsilane (644 mg, 6.56 mmol), diisopropylamine (929 mg, 9.20 mmol), cuprous iodide(I) (16.6 mg, 0.0872 mmol), and bis(triphenylphosphine) palladium(II) chloride (123 mg, 0.175 mmol) was heated at 45° C. for 5 h in dried THF (8 ml) under argon atmosphere. After cooling, the reaction was quenched by the addition of water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel flash column chromatography (eluent: hexane/ethyl acetate=50/1) to give ethyl 3-[(trimethylsilyl)-ethynyl]benzoate (90%)
Reaction SMILES: C[O:2][C:3]([C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=2)=[O:16])[C@@H:7]([CH3:24])[CH2:6]1)=[O:4].[CH3:25][O-:26].[Na+].CO.Cl>COCCOC>[CH3:25][O:26][C:20]1[N:19]=[CH:18][C:17]([C:15]([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:5]([C:3]([OH:2])=[O:4])[CH2:6][CH:7]2[CH3:24])=[O:16])=[CH:22][CH:21]=1
Reactant: COC(=O)[C@@H]1C[C@H](C)N(C(=O)c2ccc(Cl)nc2)c2ccccc21
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Product: COc1ccc(C(=O)N2c3ccccc3C(C(=O)O)CC2C)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 32 %

Procedure:
To a solution of cis-1-(6-chloro-pyridine-3-carbonyl)-2-methyl-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid methyl ester (620 mg, 1.8 mmol) in ethylene glycol dimethyl ether (6.00 mL) was added at 0° C. a 5M solution of sodium methoxide in methanol (3.3 mL, 16.2 mmol). The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was acidified to pH 1 by addition of aqueous 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to yield 1-(6-methoxy-pyridine-3-carbonyl)-2-methyl-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (190 mg, 32%).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]2[C:10](=[N:11][CH:12]=1)[N:9]=[CH:8][N:7]=[CH:6]2.[Br:13]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC(N(C)C)=O>[Br:13][CH2:2][C:3]1[N:4]=[C:5]2[C:10](=[N:11][CH:12]=1)[N:9]=[CH:8][N:7]=[CH:6]2
Reactant: OCc1cnc2ncncc2n1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: BrCc1cnc2ncncc2n1

Procedure:
Condensation of 2,4,5,6-tetraaminopyrimidine with dihydroxyacetone gave 6-hydroxymethylpteridine 1. Compound 1 was treated with bromine and triphenyl phosphine in dimethylacetamide to give the corresponding 6-bromomethylpteridine which was coupled in situ with 4-aminobenzoic acid to afford pteroylbenzoic acid 2. Purity of the crude product was about 85% as analyzed by HPLC. Due to the low solubility of this compound in most solvents, purification by recrystallization proved to be impractical. The corresponding sodium salt, however, was soluble in hot water and crystallized upon cooling. Although compound 2 decomposes in hot aqueous hydroxide, treatment of the crude product with dilute sodium bicarbonate gave the sodium salt without observable decomposition. Recrystallization of the salt from dilute aqueous bicarbonate raised product purity to 93% or above. The purified salt was then converted back to acid 2 by treatment with aqueous acetic acid.