Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:18]1(=[O:30])[CH2:23][CH2:22][CH:21]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:20][CH2:19]1>CO>[CH:1]([C:4]1[CH:9]=[C:8]([C:24]2([C:21]3[CH:22]=[CH:23][C:18]([OH:30])=[C:19]([CH:7]([CH3:8])[CH3:6])[CH:20]=3)[CH2:29][CH2:28][C:27]([C:27]3[CH2:28][CH2:29][C:24]([C:21]4[CH:22]=[CH:23][C:18]([OH:30])=[C:19]([CH:4]([CH3:9])[CH3:5])[CH:20]=4)([C:14]4[CH:15]=[CH:16][C:11]([OH:17])=[C:12]([CH:1]([CH3:3])[CH3:2])[CH:13]=4)[CH2:25][CH:26]=3)=[CH:26][CH2:25]2)[CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2]
Reactant: Oc1ccccc1
Reactant: CC(C)c1ccccc1O
Reactant: O=C1CCC(C2CCCCC2)CC1
Solvent: CO
Product: CC(C)c1cc(C2(c3ccc(O)c(C(C)C)c3)CC=C(C3=CCC(c4ccc(O)c(C(C)C)c4)(c4ccc(O)c(C(C)C)c4)CC3)CC2)ccc1O
Yield: 232.7 %

Procedure:
The same method as specified in Reference Example 1 was used, except that 236.8 g of 0-isopropyl phenol and 23.7 g of methanol were used instead of 209.4 g of phenol and 18.9 g of methanol, and that a solution made of 39.0 g of 4,4′-bicyclohexanon and 39.0 g of 0-isopropyl phenol dissolved in 15.8 g of methanol was used instead of a solution made of 24.2 g of 4,4′-bicyclohexanon and 24.2 g of phenol dissolved in 24.2 g of methanol, to achieve reaction, neutralization, crystallization and filtering to obtain 175.9 g of 4,4,4′4′-tetra(3-isopropyl-4-hydroxyphenyl)bicyclohexene as white solid (still wet with the solution).
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20](=O)[CH2:21][CH:22]1[CH2:24][CH2:23]1)(=O)OC.O.[NH2:27][NH2:28]>>[CH:22]1([CH2:21][C:20]2[N:27]=[N:28][C:3]3[C@:2]4([CH3:1])[C:8]([CH3:10])([CH3:9])[C@H:5]([C:4]=3[CH:19]=2)[CH2:6][CH2:7]4)[CH2:24][CH2:23]1
Reactant: NN
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Reactant: COP(=O)(CC(=O)CC1CC1)OC
Solvent: O
Product: CC1(C)[C@H]2CC[C@]1(C)c1nnc(CC3CC3)cc12

Procedure:
Yellow solid. MS (ESI): 243.2 (MH+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione, [(3-cyclopropyl-2-oxo-propyl)-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][C:12]1=[O:17].[Cl:18][C:19]1[S:23][C:22]([CH:24]=[CH:25][S:26](Cl)(=[O:28])=[O:27])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[S:23][C:22]([CH:24]=[CH:25][S:26]([N:14]2[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][NH:8][C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[CH3:1])[C:12](=[O:17])[CH2:13]2)(=[O:28])=[O:27])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)s1
Reactant: Cc1cnccc1NCCN1CCNCC1=O
Product: Cc1cnccc1NCCN1CCN(S(=O)(=O)C=Cc2ccc(Cl)s2)CC1=O
Yield: 32.5 %

Procedure:
1-[2-(3-Methylpyridin-4-yl-amino)-ethyl]-piperazin-2-one (38 mg, 0.16 mmol), EXAMPLE 94, is reacted with 2-(5-chloro-thiophen-2-yl)-ethenesulfonyl chloride (40 mg, 0.16 mmol), EXAMPLE 3, using the same procedure as described in EXAMPLE 719. Reverse phase HPLC purification gives the title compound (29 mg, 0.052 mmol) as a white solid. MS m/z 441, 443 (M+H); 1H NMR (CD3OD, 300 MHz) δ8.08 (d, 1H), 7.98 (s, 1H), 7.56 (d, 1H), 7.30 (d, 1H), 7.02 (s, 1H), 7.00 (d. 1H), 6.78 (d, 1H), 3.87 (s, 2H), 3.70-3.50 (m, 8H), 2.15 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@:3]1([C:19]1[N:23]2[CH:24]=[C:25]([O:28][C@H:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C@@H:32]([NH2:39])[CH2:31][CH2:30]3)[CH:26]=[CH:27][C:22]2=[N:21][N:20]=1)[CH2:7][O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11].ClC(Cl)(Cl)C[O:43][C:44](=O)[NH:45][C:46]1[N:47]([C:55]2[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=2)[N:48]=[C:49]([C:51]([CH3:54])([CH3:53])[CH3:52])[CH:50]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:51]([C:49]1[CH:50]=[C:46]([NH:45][C:44]([NH:39][C@@H:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@H:29]([O:28][C:25]3[CH:26]=[CH:27][C:22]4[N:23]([C:19]([C@:3]5([CH2:7][O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:14])[CH3:15])[CH:10]([CH3:11])[CH3:12])[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])=[N:20][N:21]=4)[CH:24]=3)[CH2:30][CH2:31]2)=[O:43])[N:47]([C:55]2[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=2)[N:48]=1)([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)[Si](OC[C@@]1(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CCCN1C)(C(C)C)C(C)C
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@]5(CO[Si](C(C)C)(C(C)C)C(C)C)CCCN5C)n4c3)c3ccccc32)cc1
Yield: 48 %

Procedure:
A solution of Intermediate 85j (230 mg, 0.418 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009. which is incorporated herein by reference in its entirety; 253 mg, 0.628 mmol) and DIPEA (215 mg, 1.67 mmol) in DMF (4 mL) was stirred at 50° C. for 1 h. The mixture was diluted with EtOAc, washed with water (2×), brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound as a white foam (250 mg, 48%). LCMS (Method 3): Rt 3.70 min, m/z 805 [MH+].
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:13])[CH:6]=[CH:7][C:8]=2[Cl:12])[N:3]=1.IC.[C:16](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([O:13][CH3:16])[CH:6]=[CH:7][C:8]=2[Cl:12])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Cl)c2cnc(Cl)nc12
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(Cl)c2cnc(Cl)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,5-dichloroquinazolin-8-ol (1 eq) (See example 32 for synthesis) in DMF was added iodomethane (3 eq) and potassium carbonate (3 eq). The reaction mixture was stirred at room temperature for overnight. Diluted with ethyl acetate and washed with water and brine and dried over sodium sulfate. Filtered, evaporated and dried to provide product as a yellow solid in quantitative yield. ES/MS m/z 229.0 (MH+). Proceed for next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[N+:24]([O-])=O)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1.[Cl-].[NH4+].C(O)C.O1CCCC1>O>[NH2:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[CH:11]=2)=[CH:3][C:2]=1[Cl:1]
Reactant: O=C(Nc1cn2cc(Oc3ccc([N+](=O)[O-])c(Cl)c3)ccc2n1)C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1Cl
Yield: 60.2 %

Procedure:
Using N-[6-(3-chloro-4-nitrophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (300 mg, 0.805 mmol), reduced iron (237 mg, 4.02 mmol), ammonium chloride (430 mg, 8.05 mmol), ethanol (2 mL), tetrahydrofuran (2 mL) and water (0.5 mL), and in the same manner as in Reference Example 105, the title compound (166 mg, 60%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1.CCN(C(C)C)C(C)C.[NH2:35][CH:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH2:40][CH:36]([NH2:35])[CH2:37]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1
Reactant: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: NC1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: NC1CCN(c2ccc3c(C(=O)NCC4(O)CCCC(F)(F)C4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-1-hydroxycyclohexylmethyl)-amide, DIPEA and 3-aminopyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.61 (s, 1H), 4.01 (m, 2H), 3.80 (m, 2H), 3.45 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 439 [M+H]
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Cl:8][C:9]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=1>CO.C(Cl)Cl>[Cl:8][C:9]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:12]([C:13]([O:15][CH3:1])=[O:14])=[CH:11][N:10]=1
Reactant: O=C(O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1

Procedure:
(Trimethylsilyl)diazomethane (8.25 mL of a 2.00 M solution in hexanes, 16.5 mmol) was added in three portions to a stirred solution of 6-chloro-5-nitronicotinic acid (1.00 g, 4.95 mmol) in methanol (12.0 mL) and DCM (24.0 mL) at 0° C. The reaction mixture was quenched with TPA and concentrated in vacuo to afford the title compound i-2a. m/z (ES) 217 (MH)+. 1H NMR (500 MHz, CDCl3): δ 9.20 (d, 1H, J=2.1 Hz), 8.79 (d, 1H, J=2.1 Hz), 4.05 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.C([NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[N:39][O:40][CH3:41])[C:17]([NH:19][C@@H:20]2[C:37](=[O:38])[N:22]3[C:23]([C:34]([O-:36])=[O:35])=[C:24]([CH2:27][N+:28]4[N:29]([CH3:33])[CH:30]=[CH:31][CH:32]=4)[CH2:25][S:26][C@H:21]23)=[O:18])[N:15]=1)=O.Cl.C(OCC)C>CO>[NH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[N:39][O:40][CH3:41])[C:17]([NH:19][C@@H:20]2[C:37](=[O:38])[N:22]3[C:23]([C:34]([O-:36])=[O:35])=[C:24]([CH2:27][N+:28]4[N:29]([CH3:33])[CH:30]=[CH:31][CH:32]=4)[CH2:25][S:26][C@H:21]23)=[O:18])[N:15]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3cccn3C)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3cccn3C)CS[C@H]12)c1csc(N)n1
Reaction time: 2 h
Yield: 37.5 %

Procedure:
To a solution of trifluoroacetic acid salt of 7β-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (syn isomer, 2.2 g) in methanol (11 ml) was added conc. hydrochloric acid (0.78 ml) at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was added to diethyl ether (300 ml), and the precipitates were collected by filtration. The precipitates were dissolved in water (20 ml) and the solution was adjusted to pH 5 with saturated aqueous solution of sodium bicarbonate. The solution was subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" and eluted with 15% aqueous solution of isopropyl alcohol The fractions containing the object compound were collected and evaporated in vacuo to remove isopropyl alcohol. The solution was lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (syn isomer, 0.78 g).
Reaction SMILES: [C:1]1([C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][Cl:16])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][N:32]([CH3:34])[CH3:33].C(O)C>>[Cl-:16].[CH3:31][N+:32]([CH2:15][C:14]1[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:13]=1)([CH3:34])[CH3:33]
Reactant: ClCc1ccc(OCCC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CN(C)C
Solvent: CCO
Product: C[N+](C)(C)Cc1ccc(OCCC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Cl-]
Temperature: 80 °C

Procedure:
A suspension of 4-(3,3,3-triphenylpropoxy)benzyl chloride, prepared in example 28, (413 mg, 1.0 mmol) in commercial 33% trimethylamine-ethanol solution was sealed in a screw-topped culture tube and was heated to 80° C. for 24 hr. The mixture was cooled and the solvent evaporated, and the residue recrystallized from isopropanolethyl acetate to provide the title compound as a hydrate, a white powder, mp 224°-225° C. (dec). 1H NMR (CDCl3) δ 7.43 (d, J=8.7 Hz, 2H) 7.15-7.35 (m, 15H), 6.71 (d, J=8.7 Hz, 2H), 4.82 (s, 2H), 3.73 (t, J=7.7 Hz, 2H), 3.31 (s, 9H), 3.13 (t, J=7.7 Hz, 2H). Anal. calcd. for C31H34NO.Cl.1.5H2O: C, 74.60; H, 7.47; N, 2.81; Cl, 7.10. Found: C, 74.99; H, 7.49; N, 2.83; Cl, 7.07.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].O1CCCC1>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])c1cc(CO)cc(C(F)(F)F)c1
Temperature: 0 °C

Procedure:
3-Nitro-5-(trifluoromethyl)benzoic acid (5.0 g, 21.2 mmol) was combined with tetrahydrofuran (43 mL) and cooled to 0° C. To this solution was added a 1 M borane tetrahydrofuran complex (42 mL, 42 mmol) cautiously over 15 min and the reaction mixture allowed to warm to room temperature overnight. The mixture was cooled to 0° C., treated with excess methanol and concentrated in vacuo to afford 4.0 g (85%) which was used without further purification. 1H-NMR (CDCl3, 300 MHz) δ 8.39 (s, 1H), 8.35 (s, 1H), 7.94 (s, 1H), 4.87 (s, 2H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].B(F)(F)F.CCOCC.[C:18](O)(=[O:22])[CH:19]([CH3:21])[CH3:20].CC([O-])=O.[Na+]>>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:18](=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: Oc1cccc(O)c1
Reactant: CC(C)C(=O)O
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)C(=O)c1ccc(O)cc1O
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Resorcinol (1 eq) was taken up in BF3.OEt2 (6 eq) and isobutyric acid (1 eq) added. The solution was heated for 1.5 hours at 90° C. than allowed to cool to room temperature. The solution was added drop wise to 10% NaOAc (aq) and allowed to stand for 4 hours, before being extracted in to EtOAc. The organic phases were combined and washed with sat. NaHCO3 (aq), then dried over magnesium sulfate, filtered and concentrated in vacuo to give 1-(2,4-dihydroxy-phenyl)-2-methyl-propan-1-one as a red oil which was used without additional purification
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH:9][CH2:10][CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[CH:4][N:3]=1.Cl.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH:18]1[C:23](O)=[O:24].CCN(C(C)C)C(C)C>CS(C)=O.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:9]([CH2:10][CH:11]3[CH2:15][CH2:14][O:13][CH2:12]3)[C:23](=[O:24])[CH:18]3[CH2:19][O:20][CH2:21][CH2:22][N:17]3[C:6]=2[N:7]=1
Reactant: O=C(O)C1COCCN1
Reactant: Clc1ncc(NCC2CCOC2)c(Cl)n1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1C2COCCN2c2nc(Cl)ncc2N1CC1CCOC1
Temperature: 100 °C
Yield: 408.9 %

Procedure:
2,4-Dichloro-N-((tetrahydrofuran-3-yl)methyl)pyrimidin-5-amine (7 g, 28.2 mmol), morpholine-3-carboxylic acid hydrochloride (832 mg, 4.97 mmol), and DIPEA (2.67 ml, 15.28 mmol) were combined in DMSO (8 ml). The reaction mixture was heated overnight at 100° C. Upon cooling the solution was diluted with water then extracted twice with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered, and evaporated in vacuo to give 6.6 g of 2-chloro-5-((tetrahydrofuran-3-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one as a brown oil which was used without further purification. [M+H] found 325.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:6]([C:8]1[CH:13]=[CH:12]N=CC=1)=[O:7].[C:19]([C:21]1C=CC=CN=1)#[N:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:6]([C:8]1[CH:13]=[CH:12][CH:21]=[CH:19][N:20]=1)=[O:7]
Reactant: N#Cc1ccccn1
Reactant: COc1ccc(C(=O)c2ccncc2)cc1OC
Product: COc1ccc(C(=O)c2ccccn2)cc1OC

Procedure:
2-(3,4-Dimethoxybenzoyl)pyridine was prepared analogously to 4-(3,4-dimethoxy-benzoyl)pyridine using 2-cyanopyridine. The crude mixture was purified by flash column chromatography (silica gel, 1% methanol/methylene chloride) to afford after drying in vacuo (60° C., 1 mm) 1.67 g (34%) of the product: mp 91.5-93° C.; 1H NMR (CDCl3) δ 8.76-8.70 (m, 1 H), 8.05-7.71 (m, 4 H), 7.55-7.45 (m, 1 H), 7.00-6.89 (m, 1 H), 3.96 (s, 3 H), 3.96 (s, 3 H); 13C NMR (CDCl3) δ 192.1, 155.7, 153.3, 148.7, 148.2, 136.9, 128.9, 126.7, 125.7, 124.4, 112.6, 109.8, 56.0, 55.9; Anal. Calcd for C14H13NO3. Theoretical: C, 69.12; H, 5.39; N, 5.76. Found: C, 68.96; H, 5.47; N, 5.66.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10](Cl)(Cl)Cl)=[CH:6][CH:5]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22].Cl>>[C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:22][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]=2)=[CH:6][CH:5]=1)([O:2][CH3:1])=[O:14]
Reactant: Nc1ccccc1O
Reactant: COC(=O)c1ccc(C(Cl)(Cl)Cl)cc1
Agent: Cl
Product: COC(=O)c1ccc(-c2nc3ccccc3o2)cc1
Reaction time: 4 h

Procedure:
In the apparatus described in Example 1, 25.4 g of 4-trichloromethylbenzoic acid methyl ester (0.1 mol) and 10.9 g of 2-aminophenol (0.1 mol) were mixed and slowly heated up to 200° C, so that the stream of HCl that commences at 130° C would not become too strong. The total reaction time was about 4 hours. The ground reaction product was washed thrice with 100 ml of hot benzene and the combined and concentrated benzene phases where chromatographed through an Al2O3 : 8.9 g of raw product XVI, melting point 190°-191° C (35% of the theory), becoming 193°-194° C after recrystallization from benzene.
Reaction SMILES: C(OCCOC)(=O)CC(C)=O.[CH3:12][C:13]1([CH3:21])[O:18][C:17](=[O:19])[CH:16]=[C:15]([CH3:20])O1.[NH3:22].C(OC(C)C)(=O)CC(C)=O>CC(O)C.COCCO>[NH2:22]/[C:15](/[CH3:20])=[CH:16]\[C:17]([O:18][CH:13]([CH3:21])[CH3:12])=[O:19]
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: N
Agent: CC(=O)CC(=O)OC(C)C
Agent: COCCOC(=O)CC(C)=O
Solvent: CC(C)O
Solvent: COCCO
Product: C/C(N)=C/C(=O)OC(C)C

Procedure:
The ester, 2-methoxyethyl acetoacetate (51), was prepared by the reaction of 2-methoxyethanol with 2,2,6-trimethyl-4H-1,3-dioxin-4-one (53) (eq. 28). (Hyatt, J. A. J. Org. Chem. 1984, 49, 5102. Hyatt, J. A.; Feldman, P. L.; Clemens, R. J. Ibid. 1984, 49, 5105. Kato, T.; Sato, M.; Kanuma, N. Chem. Pharm. Bull. 1982, 30, 1315). The enamine, 1-methylethyl 3-aminocrotonate (52) was prepared by the reaction of ammonia with 1-methylethyl acetoacetate (54) (eq. 29) (Iwanami, J. et al. Chem. Pharm. Bull. 27, 1426 (1979)) which was obtained by the reaction of 2-propanol with 53 (eq. 30) as shown in Schemes IIa, IIb and IIc. ##STR13##
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:61])([CH3:60])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[CH3:58])[C:47]1=[O:59])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:61])([CH3:60])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[CH3:58])[C:47]1=[O:59])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: Cc1ccccc1CN1CCN([C@H](C(=O)O)C(C)(C)C)C1=O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2C)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
A solution containing the product from Example 1H (0.020 g, 0.038 mmol)in THF (0.4 mL) was treated with the product from Example 65A (0.023 g, 0.076 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.033 mL, 0.189 mmol) and the mixture was stirred at 25° C. for 2 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The product was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was washed brine, dried over MgSO4, filtered and concentrated to give the title compound (0.013 g, 42% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80 (s, 9 H), 0.89 (m, 9 H), 1.46 (m, 2 H), 2.29 (s, 3 H), 2.38 (m, 1 H), 2.76 (m, 5 H), 3.22 (m, 2 H), 3.53 (m, 4 H), 3.84 (d, J=9.93 Hz, 1 H), 3.95 (m, 1 H), 4.02 (s, 1 H), 4.18 (m, 2 H), 4.41 (m, 2 H), 6.88 (d, J=9.56 Hz, 1 H), 7.04 (m, 5 H), 7.21 (m, 6 H), 7.32 (m, 1 H), 7.53 (d, J=9.56 Hz, 1 H), 7.89 (m, 5 H), 8.65 (d, J=4.04 Hz, 1 H).
Reaction SMILES: CO.[CH3:3][S:4][C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=1)([CH3:10])[C:6]([O:8]C)=[O:7].[OH-].[Na+]>O>[CH3:3][S:4][C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=1)([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(C)(SC)c1cccc(Oc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSC(C)(C(=O)O)c1cccc(Oc2ccccc2)c1
Yield: 99.3 %

Procedure:
Methanol (4 ml) and 2 ml of water were added to 663 mg of methyl α-methylthio-α-(m-phenoxyphenyl)propionate, and then 300 mg of sodium hydroxide was added. The mixture was heated under reflux for 2 hours. The mixture was diluted with 30 ml of water, and extracted with 10 ml of diethyl ether. The aqueous layer was acidified with about 1 ml of conc. hydrochloric acid, and extracted three times with 20 ml of diethyl ether. The organic layer was washed with 10 ml of water, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 628 mg of α-methylthio-α-(m-phenoxyphenyl)propionic acid as an oil in a yield of 99%. This product crystallized on standing at room temperature. Recrystallization from hexane/carbon tetrachloride afforded colorless crystals having a melting point of 87° to 88° C.
Reaction SMILES: [Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][C:5]2[N:6]=[C:7]([S:10][CH3:11])[N:8]([CH3:9])[C:4]=2[CH:3]=1.[C:15]1([CH3:26])[CH:20]=[CH:19][C:18]([S:21]([O:24]C)(=[O:23])=[O:22])=[CH:17][CH:16]=1>CC(C)=O>[C:15]1([CH3:26])[CH:16]=[CH:17][C:18]([S:21]([O-:24])(=[O:22])=[O:23])=[CH:19][CH:20]=1.[Cl:14][C:13]1[C:2]([Cl:1])=[CH:3][C:4]2[N+:8]([CH3:9])=[C:7]([S:10][CH3:11])[N:6]([CH3:15])[C:5]=2[CH:12]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CSc1nc2cc(Cl)c(Cl)cc2n1C
Solvent: CC(C)=O
Product: CSc1n(C)c2cc(Cl)c(Cl)cc2[n+]1C
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 60 °C

Procedure:
5,6-Dichloro-3-methyl-2-(methylthio)benzimidazole (Int-k) (5.58 g, 0.022 mol) and 4.22 g methyl p-toluenesulfonate were mixed with 10 ml xylenes and heated to 124°-136° C. for 5 hrs. Upon cooling to 60° C., acetone was added to cover and slurry. The product was collected by filtration and reslurried in acetone. Filtration and drying yielded 3.14 g, mp 152°-156° C. The product was again slurried with acetone overnight to give 2.38 g, mp 152°-155° C., which NMR indicated was contaminated with some unreacted starting material.