Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([NH2:16])[C:3]=1[N+:17]([O-])=O.[NH4+].[Cl-]>CCO.O.[Fe]>[Cl:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([NH2:16])[C:3]=1[NH2:17]
Reactant: Nc1nc(SCc2ccccc2)nc(Cl)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1nc(SCc2ccccc2)nc(Cl)c1N
Temperature: 85 °C
Yield: 78.3 %

Procedure:
A suspension of the product from example 2, step (d) (980 mg), NH4Cl (1.61 g) and iron powder (559 mg) in EtOH (100 ml) and H2O (15 ml) was heated at 85° C. for 1.5 h. The mixture was filtered through celite and washed with hot MeOH (100 ml) before concentrating the filtrate onto silica under reduced pressure. Column chromatography using 1:1 isohexane/ethyl acetate as eluent provided the subtitled product as a yellow solid (0.69 g, 78%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1.[NH2:19][C:20]([NH2:22])=[S:21]>>[CH3:1][O:2][C:3]([C:4]1[N:19]=[C:20]([NH2:22])[S:21][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)=[O:18]
Reactant: COC(=O)C(=O)C(Cl)c1cccc(C(F)(F)F)c1
Reactant: NC(N)=S
Product: COC(=O)c1nc(N)sc1-c1cccc(C(F)(F)F)c1

Procedure:
prepared by reaction of 3-chloro-3-(3-trifluoromethyl-phenyl)-2-oxo-propionic acid methyl ester with thiourea. LC-MS: tR=0.86 min; [M+H]+=303.3.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10](/[C:13](=[CH:25]\[CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)/[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:36]>C(O)(=O)C.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10](/[C:13](/[C:14]3[NH:36][C:17]([C:19]4[S:20][CH:21]=[CH:22][N:23]=4)=[CH:16][CH:15]=3)=[CH:25]\[CH:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: O=C(CCC(=O)c1nccs1)/C(=C/C1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc(/C(=C\C2CCOCC2)c2ccc(-c3nccs3)[nH]2)cc1)C1CC1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 49.9 %

Procedure:
To a solution of (5E)-5-[4-(cyclopropylsulfonyl)phenyl]-6-(tetrahydro-2H-pyran-4-yl)-1-(1,3-thiazol-2-yl)hex-5-ene-1,4-dione (278 mg) in acetic acid (5 mL) was added ammonium acetate (750 mg), and the mixture was stirred at 110° C. for 45 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (133 mg, yield 50%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (3:2, volume ratio). MS: 441 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1/[CH:11]=[CH:12]/[N+:13]([O-:15])=[O:14].[CH3:16][C:17]1[N:21]([C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:20]=[N:19][N:18]=1.C(=O)=O.CC(C)=O.C([Li])CCC.CCCCCC>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH:11]([CH2:12][N+:13]([O-:15])=[O:14])[CH2:16][C:17]1[N:21]([C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:20]=[N:19][N:18]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1/C=C/[N+](=O)[O-]
Reactant: Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc([N+](=O)[O-])cc1C(Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1)C[N+](=O)[O-]

Procedure:
Adapting literature known protocols (Huff et al., Tetrahedron Lett., 1996, 37(12), 3655-3658; Baylis, Tetrahedron Lett., 1995, 36(51), 9385-9388; and Xu, et al., U.S. Pat. No. 8,344,028 (2013)), 5-[2-(2-methyl-5-nitro-phenyl)-3-nitro-propyl]-1-trityl-tetrazole (20b) is prepared from 1-methyl-4-nitro-2-[(E)-2-nitrovinyl]benzene (19a) through 1,4-conjugate addition of lithiated 5-methyl-1-trityl-tetrazole (Huff et al., Tetrahedron Lett., 1996, 37(12), 3655-3658). 5-Methyl-1-trityl-tetrazole (3.92 g, 12.0 mmol) in anhydrous tetrahydrofuran (THF) (15 mL) is lithiated under a nitrogen atmosphere and at a temperature of about −78° C. (dry ice/acetone bath) with n-butyllithium (nBuLi) in hexane (12.0 mL, 12.0 mmol) and added via a cannula to a cooled solution (−78° C.; dry ice/acetone bath, nitrogen atmosphere) of (19a) (2.08 g, 10.0 mmol) in anhydrous tetrahydrofuran (THF) (15 mL). Aqueous work-up and purification by silica gel column chromatography using ethyl acetate (EtOAc) and hexanes mixtures afford the title compound (20b).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:40]3[S:44][C:43]([O:45][CH2:46][CH2:47][O:48][Si](C(C)(C)C)(C)C)=[N:42][CH:41]=3)=[C:13]2[C:24](=[O:39])[N:25]([CH:36]2[CH2:38][CH2:37]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=2[CH3:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH:10]([CH2:11][C:12]([C:40]3[S:44][C:43]([O:45][CH2:46][CH2:47][OH:48])=[N:42][CH:41]=3)=[C:13]2[C:24](=[O:39])[N:25]([CH:36]2[CH2:37][CH2:38]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=2[CH3:35])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cccc(CN(C(=O)C2=C(c3cnc(OCCO[Si](C)(C)C(C)(C)C)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(CN(C(=O)C2=C(c3cnc(OCCO)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A sol. of compound E7 (3.55 mmol; 2.84 g) in MeOH (35.5 mL) was treated with para-toluenesulfonic acid (3.91 mmol; 0.74 g), and the mixture was stirred at rt for 30 min. 10% aq. Na2CO3 (20 mL) was added, and the solvents were partially removed under reduced pressure. The resulting suspension was extracted with EtOAc (200 mL), washed with 10% aq. Na2CO3 (100 mL), sat. aq. NaHCO3 (100 mL), and brine (100 mL). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The product (2.46 g; 99%) was used for the next step without purification. LC-MS: tR=1.07 min; ES+: 685.50.
Reaction SMILES: [NH2:1][O:2][CH2:3][CH2:4][OH:5].[F:6][C:7]1[C:8]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=2)=[C:9]([CH:13]=[CH:14][C:15]=1[F:16])[C:10](O)=[O:11].C1N=CN(C(N2C=NC=C2)=O)C=1>C1COCC1>[F:6][C:7]1[C:15]([F:16])=[CH:14][CH:13]=[C:9]([C:10]([NH:1][O:2][CH2:3][CH2:4][OH:5])=[O:11])[C:8]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=1
Reactant: NOCCO
Reactant: COC(=O)c1ccc(Nc2c(C(=O)O)ccc(F)c2F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
This material was then coupled directly with 2-(aminooxy)ethanol as follows: The crude 3,4-difluoro-2-[[4-(methoxycarbonyl)-phenyl]amino]benzoic acid was dissolved in dry THF (20 mL) to which was added CDI (1.63 g, 10.0 mmol). This reaction mixture was stirred at room temperature for 2 hours, then a solution of 2-(aminooxy)ethanol (1.55 g, 20.1 mmol) in dry THF (10 mL) was added and the reaction allowed to stir at room temperature overnight. The reaction solvent was removed under reduced pressure and the resulting oil dissolved in EtOAc (200 mL) which was washed sequentially with 1 M HCl (100 mL), water (100 mL), and brine (100 mL). The solution was dried (Na2SO4), the solvent removed under reduced pressure and the crude oil purified by chromatography on flash silica (10% EtOAc as eluant) to give methyl 4-[[2,3-difluoro-6-[[(2-hydroxyethoxy)amino]carbonyl]phenyl]amino]benzoate (0.889 g, 48%) as a white solid; mp (EtOAc/hexanes) 158-160° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.64 (br s, 1 H), 8.76 (br s, 1 H), 7.78 (d, J=8.8 Hz, 2 H), 7.41-7.27 (m, 2 H), 6.80 (dd, J=8.8, 1.8 Hz, 2 H), 4.67 (br s, 1 H), 3.78 (s, 3 H), 3.76 (t, J=4.8 Hz, 2 H), 3.50 (t, J=4.6 Hz, 2 H). Anal Calcd for C17H16F2N2O5: C, 55.7; H, 4.4; N, 7.7. Found C, 55.7; H, 4.4; N, 7.6.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[C:11]1[C:10]([OH:17])=[CH:9][C:8]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:7][C:6]=1[O:5]2.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][OH:31])[CH:25]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>CS(C)=O>[OH:17][C:10]1[C:11]2[C:12](=[O:16])[C:13]3[C:4](=[CH:3][C:2]([O:31][CH2:30][C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)=[CH:15][CH:14]=3)[O:5][C:6]=2[CH:7]=[C:8]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:9]=1
Reactant: OCc1cccnc1
Reactant: O=c1c2ccc(F)cc2oc2cc(N3CCOCC3)cc(O)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1c2ccc(OCc3cccnc3)cc2oc2cc(N3CCOCC3)cc(O)c12
Temperature: 80 °C
Reaction time: 60 h
Yield: 33.6 %

Procedure:
6-Fluoro-1-hydroxy-3-morpholin-4-yl-xanthen-9-one (16 mg. 0.05 mmol) and 3-pyridylmethanol (8 mg, 0.07 mmol) were dissolved in DMSO (0.25 mL), and KHMDS (0.5 M in toluene, 0.24 mL) was added. The reaction mixture was heated to 80° C. for 16 hours, then stirred at room temperature for 60 hours. The reaction was quenched with sat. NH4Cl/water (1:1, 2 mL) and the solids were filtered. The crude solid was purified via flash chromatography eluting with CH2Cl2/MeOH (98:2) to yield 6.8 mg (34%) of product. 1H NMR (CDCl3, 400 MHz) δ: 12.80 (s, 1H), 8.73 (s, 1H), 8.64 (d, 1H), 8.15 (d, 1H), 7.80 (d, 1H), 7.36 (dd, 1H), 6.97 (dd, 1H) 6.85 (s, 1H), 6.27 (s, 1H), 6.24 (s, 1H), 5.19 (s, 2H), 3.86-3.83 (m, 4H), 3.37-3.35 (m, 4H). LRMS (APCI, positive): Da/e 405.1 (m+1).
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][Si](C(C)(C)C)(C)C.[NH:18]1[CH2:21][CH:20]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH2:19]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.[Cl-].[NH4+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)(Cl)Cl.C1COCC1.CCOC(C)=O.C1(C)C=CC=CC=1>[F:17][C:3]1[C:2]([N:18]2[CH2:21][CH:20]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH2:19]2)=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][OH:6]
Reactant: c1cc(OC2CNC2)ccn1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Br)c1F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: OCc1cccc(N2CC(Oc3ccncc3)C2)c1F
Temperature: 90 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
Under argon atmosphere, [(3-bromo-2-fluorobenzyl)oxy](tert-butyl)dimethylsilane (800 mg) and 4-(azetidin-3-yloxy)pyridine (268 mg) were mixed with toluene (6 ml), and Pd2(dba)3 (80 mg), BINAP (160 mg), and sodium tert-butoxide (300 mg) were added thereto, followed by stirring at 90° C. for 3 hours. The reaction mixture was cooled to room temperature, and EtOAc was added thereto, followed by carrying out filtration using Celite as a filtration adjuvant. The filtrate was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus obtained was mixed with THF (6 ml), and a 1M TBAF/THF solution (3 ml) was added thereto, followed by stirring at room temperature for 1 hour. To the reaction mixture were added a saturated aqueous ammonium chloride solution and CHCl3, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain {2-fluoro-3-[3-(pyridin-4-yloxy)azetidin-1-yl]phenyl}methanol (335 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:6]=2[N:19]=1.I[CH3:21].[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:21])[C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:6]=2[N:19]=1
Reactant: CC(C)CCN1CC(C)C(=O)Nc2cnc(Cl)nc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CCN1CC(C)C(=O)N(C)c2cnc(Cl)nc21
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
To a mixture of 0.61 g, (0.00216 mole) of (rac)-2-chloro-7-methyl-9-(3-methyl-butyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-27), 0.2 mL (0.00324 mole) of iodomethane and 7 mL of N,N-dimethyl-formamide at 0 degrees, was added 0.13 g (0.00324 mole) of sodium hydride, 60% dispersion in mineral oil. The mixture was stirred at 0 degree for 1.5 hours, and then partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-60:40), to give 0.61 g of (rac)-2-chloro-5,7-dimethyl-9-(3-methyl-butyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-27). HRMS (ES+) m/z Calcd for C14H21ClN4O+H [(M+H)+]: 297.1477. Found: 297.1476.
Reaction SMILES: [C:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1)(=O)[NH2:2].N1C=CN=C1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1)#[N:2]
Reactant: COC(=O)[C@H]1CC[C@H](C(N)=O)CC1
Agent: c1c[nH]cn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)[C@H]1CC[C@H](C#N)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the compound prepared in Example 21 (0.84 g, 4.6 mmol) in pyridine (20 mL) was added imidazole (1.0 g, 4.6 mmol) and phosphorusoxychloride (1.0 mL) in one portion at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 4 h whereupon the reaction was quenched with water and extracted with ethyl acetate. The organic extract was washed with 2 M hydrochloric acid, dried and concentrated to give the title compound (0.76 g, 99%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)[C:3]=1[C:21](=[CH:26]N(C)C)[C:22]([O:24][CH3:25])=[O:23].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:41](=O)(O)[O-:42].[K+].C(=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>C(OCC)C.O.CN(C)C=O>[CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:10]=2)[C:3]=1[C:21](=[CH:26][O:42][CH3:41])[C:22]([O:24][CH3:25])=[O:23]
Reactant: O=C([O-])O
Reactant: COC(=O)C(=CN(C)C)c1c(C)ncnc1Oc1cccc(-c2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COC=C(C(=O)OC)c1c(C)ncnc1Oc1cccc(-c2ccccc2)c1
Reaction time: 16 h
Yield: 81.5 %

Procedure:
Methyl α-[6-methyl-4-(3-phenylphenoxy)-5-pyrimidinyl]-β-dimethylaminoacrylate (60 g, 0.15 mol) is dissolved in diethylether (300 ml) and a solution of p-toluene sulfonic acid (44 g, 0.23 mol) in water (200 ml) is added at room temperature with stirring. After 16 hours the mixture is partially neutralized by adding solid potassium bicarbonate (28 g). Extraction of the product with diethylether, drying of the organic phase (MgSO4) and evaporation of the solvent gives the crude enol (52 g, 93%). The product is dissolved in dimethylformamide (100 ml) and potassium carbonate (33 g, 0.24 mol) and dimethyl sulfate (18.9 g, 0.15 mol) is added with cooling. After stirring the reaction mixture at room temperature for 3 hours, diethylether is added and the mixture is washed repeatedly with bring. Drying and chromatography on silicagel (eluant:hexane/ethyl acetate 1:1) gives the pure methyl α-[6-methyl-4(3-phenylphenoxy)-5-pyrimidinyl]-β-methoxyacrylate as a yellowish oil (46 g, 85%). 1H-NMR (CDCl3):8.60 (s, 1H); 7.66 (s, 1H); 7.60-7.02 (m, 9H); 3.92 (s, 3H); 2.42 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[Br-:10].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>O.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([Br:10])[C:5]([CH3:8])=[CH:4][C:3]=1[OH:9]
Reactant: [Br-]
Reactant: Cc1ccc(C)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(Br)c(C)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a stirred suspension of 2,5-dimethyl phenol (5.0 g, 40.9 mmol) in H2O (150 mL), at room temperature was added tetrabutylammonium tribromide (19.9 g, 41.39 mmol) in CHCl3 (150 mL). The reaction mixture was stirred for 2 h at rt, the organic layer was separated and dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane-ethyl acetate (1:5) to afford 2,5-dimethyl-4-bromophenol as a brown solid (6.2 g, 76%); 1H NMR (300 MHz, DMSO-d6): δ 9.47 (s, 1H), 7.24 (s, 1H), 6.74 (s, 1H), 2.21 (s, 3H), 2.07 (s, 3H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-ethyl acetate (9:1); Rf=0.52.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH:8]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:6][N:5]2[CH:15]=1.CN(C)[C:18]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[O:19]>>[C:20]1([C:18]([C:15]2[N:5]3[CH2:6][CH2:7][CH:8]([C:9]([O:11][CH:12]([CH3:13])[CH3:14])=[O:10])[C:4]3=[CH:3][C:2]=2[CH3:1])=[O:19])[S:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cc2n(c1)CCC2C(=O)OC(C)C
Reactant: CN(C)C(=O)c1cccs1
Product: Cc1cc2n(c1C(=O)c1cccs1)CCC2C(=O)OC(C)C

Procedure:
In accordance with the method of Example 9, isopropyl 1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate is condensed with N,N-dimethylthiophene-2-carboxamide to produce isopropyl 5-(2-thenoyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (XI, R = CH3, R1 = H, R2 = iC3H7, X = S), having a melting point of 102.5° C.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:15]=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:21]O>>[Cl:6][C:7]1[CH:15]=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:13]=[CH:12][C:8]=1[C:9]([O:11][CH3:21])=[O:10]
Reactant: CO
Reactant: CS(=O)(=O)Nc1ccc(C(=O)O)c(Cl)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(NS(C)(=O)=O)cc1Cl

Procedure:
Concentrated sulphuric acid (20 ml) was added to a suspension of 2-chloro-4-(N-methylsulphonylamino)benzoic acid (10.3 g) in methanol and the mixture was stirred and heated at reflux for 22 hours. It was cooled, evaporated to dryness and diluted with water, extracted with ethyl acetate, washed with aqueous sodium bicarbonate solution, water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give methyl 2-chloro-4(N-methylsulphonylamino)benzoate(10.0 g) as an off-white solid, NMR (DMSO-d6) 3.15(s,3H) 3.85(s,3H) 7.2(d,1H) 7.3(s,1H) 7.85(d,1H) 10.5(s,1H).
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[C:6]2[O:13][CH:12]=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC#N>[CH3:1][S:2][C:5]1[C:6]2[O:13][CH:12]=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: Clc1ncnc2ccoc12
Reactant: C[S-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CSc1ncnc2ccoc12
Temperature: 90 °C
Yield: 85.2 %

Procedure:
Sodium thiomethoxide (1.2 g) was added to a solution of 4-chlorofuro[3,2-d]pyrimidine (Intermediate 84) (1.32 g) in MeCN (100 mL). The mixture was heated to 90° C. for 60 minutes, cooled, and added to 50% sodium carbonate solution (100 ml). The resulting mixture was extracted into EtOAc (3×100 mL). The combined organics were dried (MgSO4) and the solvent removed to afford the title compound as a pale orange solid (1.21 g, 85%);
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH:12]1[CH2:14][CH2:13]1)[CH:5]=[O:6].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:12]1([CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: O=Cc1ccc(OCC2CC2)c(Br)c1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc(C=O)ccc2OCC2CC2)cc1
Yield: 89.7 %

Procedure:
To a degassed solution of 3-bromo-4-cyclopropylmethoxybenzaldehyde (1.53 g, 6 mmol), 4-methoxybenzeneboronic acid (1.22 g, 8 mmol) and potassium carbonate (2.74 g, 20 mmol) in toluene/ethanol 2/1 (40 mL), Pd(PPh3)4 (100 mg) was added and the mixture was degassed for further 5 minutes. The mixture was then refluxed for 12 hours. The solid is filtered off, and the solvent partitioned between ethyl acetate and water and extracted. The organic solvent was removed under reduced pressure, dried over sodium sulphate and purified by column chromatography on silica (hexane/ethyl acetate 8/2) to afford 1.52 g of product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][N:3]=1.[CH:13]1(B(O)O)[CH2:15][CH2:14]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[N:7]=[C:6]([CH:13]2[CH2:15][CH2:14]2)[C:5]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][N:3]=1
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1cnc(Cl)nc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: COC(=O)c1cnc(Cl)nc1C1CC1
Temperature: 25 °C
Yield: 25.9 %

Procedure:
To a solution of methyl 2,4-dichloropyrimidine-5-carboxylate (852 mg, 4 mmol) and cyclopropylboronic acid (344 mg, 4 mmol) in THF (10 mL) was added K3PO4 (3.1 g, 12 mmol) followed by Pd(dppf)Cl2 (292 mg, 0.4 mmol) under N2. The mixture was refluxed for 4 h until the material was disappeared. The reaction mixture was cooled to rt. THF was removed under vacuum. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL×3). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford methyl 2-chloro-4-cyclopropylpyrimidine-5-carboxylate (220 mg, 26% yield) as a white solid.