Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]4[O:18][CH:17]([CH2:19][OH:20])[CH2:16][C:15]=4[C:10]=3[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.S(=O)(=O)(O)[OH:23]>CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]4[O:18][CH:17]([C:19]([OH:23])=[O:20])[CH2:16][C:15]=4[C:10]=3[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCC1Cc2c(ccc3c(-c4ccccc4)noc23)O1
Reactant: O=S(=O)(O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)C1Cc2c(ccc3c(-c4ccccc4)noc23)O1
Reaction time: 8 h
Yield: 43.2 %

Procedure:
A portion (5.5 g) of the 7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-methanol prepared in Example 1 was dissolved in 200 ml of acetone. To the stirred solution, a mixture of chromium (VI) oxide (10 g), water (20 ml) and concentrated sulfuric acid (16 g) was added dropwise over time, and the solution was left to stand overnight. The insolubles were filtered off by suction. After distilling off the acetone, water was added to the residue and the mixture was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried, followed by distilling off the solvent. The residue was recrystallized with acetonitrile to yield 2.5 g of 7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-carboxlic acid. m.p. 219°-220° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 281.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[O:8][CH2:9][CH2:10][O:11][C:5]2=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1>C(Cl)Cl>[CH3:1][C:2]1[N+:7]([O-:20])=[C:6]2[O:8][CH2:9][CH2:10][O:11][C:5]2=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc2c(n1)OCCO2
Solvent: ClCCl
Product: Cc1ccc2c([n+]1[O-])OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To a 0° C. solution of 6-methyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (19 g, 0.12 mol) in anhydrous CH2Cl2 (250 mL) was added m-CPBA (32 g, 0.15 mol) portionwise. The mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was purified via column chromatography (silica gel, EtOAc/petroleum ether 1:1) to yield 6-methyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine 5-oxide (15.0 g, 72%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:21][C:20]3[C:11](=[CH:12][C:13]4[CH2:14][C@@H:15]([C:31](O)=[O:32])[N:16]([C@H:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:23][CH3:24])[CH2:17][C:18]=4[CH:19]=3)[N:10]([CH3:34])[C:9]2=[O:35])=[CH:4][CH:3]=1.Cl.[CH3:37][O:38][C:39](=[O:56])[C@@H:40]([NH2:55])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1>>[CH3:37][O:38][C:39](=[O:56])[C@@H:40]([NH:55][C:31]([C@@H:15]1[CH2:14][C:13]2[CH:12]=[C:11]3[C:20]([O:21][C@@H:8]([C:5]4[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=4)[C:9](=[O:35])[N:10]3[CH3:34])=[CH:19][C:18]=2[CH2:17][N:16]1[C@H:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:23][CH3:24])=[O:32])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)N(C)C(=O)[C@H](c1ccc(O)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(F)cc2)cc1
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(F)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(O)cc1)O3

Procedure:
(S)-3-(4′-Fluoro-biphenyl-4-yl)-2-{[(3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (57 mg, LC/MS: m/z 729) was prepared from (3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (70 mg) and (S)-2-amino-3-(4′-fluoro-biphenyl-4-yl)-propionic acid methyl ester hydrochloride using general procedure A.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=3)=[CH:10][C:9]=2[CH3:22])=[O:7])=[CH:4][CH:3]=1.CC1C=C[C:29]([C:32](C2N(C)C(CC(OC)=O)=CC=2)=[O:33])=CC=1.C(OC(=O)C)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:32](=[O:33])[CH3:29])=[CH:17][N:16]=3)=[CH:10][C:9]=2[CH3:22])=[O:7])=[CH:23][CH:24]=1
Reactant: Cc1cc(Cc2ccc(N)cn2)n(C)c1C(=O)c1ccc(Cl)cc1
Reactant: COC(=O)Cc1ccc(C(=O)c2ccc(C)cc2)n1C
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Cc2cc(C)c(C(=O)c3ccc(Cl)cc3)n2C)nc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A solution of N-{2-[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]pyridin-5-yl}amine (0.3 g, 0.88 mmol) [prepared by the method described in Example 5, but substituting zomepirac methyl ester for tolmetin methyl ester in Step (a)] and acetic anhydride (0.375 ml, 3.96 mmol) in THF was stirred at 60° C. for 4 h. The solvents were removed under reduced pressure and the residue was crystallized from hexane-chloroform to give N-{2-[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]pyridin-5-yl}-acetamide (295 mg, 88%) as a solid, mp 194-195° C.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]2=[C:4]([C:11]([NH2:13])=[O:12])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1.[O:21]([CH2:39][C:40]([CH3:56])([CH3:55])[CH2:41][NH:42][C:43](=O)[O:44]C1C=CC([N+]([O-])=O)=CC=1)[Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>C(#N)C>[O:21]([CH2:39][C:40]([CH3:56])([CH3:55])[CH2:41][NH:42][C:43]([N:9]1[CH2:8][CH2:7][N:6]2[C:2]([Cl:1])=[C:3]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[C:4]([C:11]([NH2:13])=[O:12])=[C:5]2[CH2:10]1)=[O:44])[Si:22]([C:35]([CH3:38])([CH3:36])[CH3:37])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NC(=O)c1c(-c2cccc(F)c2)c(Cl)n2c1CNCC2
Reactant: CC(C)(CNC(=O)Oc1ccc([N+](=O)[O-])cc1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)(CNC(=O)N1CCn2c(Cl)c(-c3cccc(F)c3)c(C(N)=O)c2C1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 65 °C

Procedure:
A suspension of 0.250 (0.85 mmol) of 6-chloro-7-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide, 0.518 g (1.02 mmol) of 4-nitrophenyl 3-(tert-butyldiphenylsilanoxy)-2,2-dimethylpropylcarbamate and 0.235 g (1.70 mmol) of sodium carbonate in 3 ml of acetonitrile is heated at 65° C. for 1 hour 30 minutes. After cooling, the mixture is poured into aqueous 1N sodium hydroxide solution and the product is extracted with dichloromethane. After drying over sodium sulfate and filtering, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a mixture of 35 to 65% ethyl acetate in cyclohexane, to give 0.44 g of N2-(3-(tert-butyldiphenylsilanoxy)-2,2-dimethylpropyl)-6-chloro-7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide in the form of a pale yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.O.[OH-].[Na+].[N+:15]([O-])([OH:17])=[O:16]>C(Cl)(Cl)Cl.S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:15]([O-:17])=[O:16])=[C:5]([CH2:9][CH2:10][NH2:11])[CH:4]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cccc(CCN)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(CCN)c1
Reaction time: 3 h
Yield: 21 %

Procedure:
To a solution of 2-(3-methoxyphenyl)ethylamine (1.51 g) in chloroform (30 ml), fuming nitric acid (specific gravity=1.52; 0.84 ml) and sulfuric acid (1.07 ml) were successively added dropwise under ice cooling and stirred under ice cooling for 3 h. Water and 2 N aqueous sodium hydroxide solution were added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform:methanol=9:1) to give 400 mg of the titled compound (yield, 21%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[C:15](=[O:25])[CH2:14][CH2:13][CH2:12]1.Br[CH:27]([CH3:29])[CH3:28]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:27]([CH3:29])[CH3:28])=[CH:20][CH:19]=2)[C:15](=[O:25])[CH2:14][CH2:13][CH2:12]1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(O)cc1
Reactant: CC(C)Br
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(OC(C)C)cc1

Procedure:
Prepared according to the described general procedure 7 (GP7) by O-alkylation of 6-(2,6-dimethoxyphenyl)-1-(4-hydroxybenzyl)piperidin-2-one with commercially available 2-bromopropane. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.77 min.; [M+H]+: 384.28 g/mol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](Cl)[CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].O.[ClH:13]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:13])=[C:6]([CH2:7][OH:8])[CH:10]=1
Reactant: Cl
Reactant: O=C(O)c1cc(Cl)cc(Br)c1
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
10 g (42.5 mmol) of 5-bromo-3-chlorobenzoic acid are dissolved in 135 ml of THF. At 0° C., 4.2 g (55.2 mmol, 5.24 ml) of borane-dimethyl sulfide complex are added dropwise. The mixture is then stirred at RT for 25 min and under reflux for 30 min. 40 ml of water and 15 ml of 2N hydrochloric acid are successively added dropwise while cooling in ice, followed by stirring at RT for 45 min. After a renewed addition of 15 ml of 2N hydrochloric acid the mixture is extracted several times with diethyl ether. The combined organic phase is washed successively with 1N hydrochloric acid, water, a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The solid is dried under high vacuum to constant weight.
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[N:15](COCC)[CH:14]=[N:13][C:12]=2[N:11]([CH3:23])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:24]>>[ClH:24].[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[NH:15][CH:14]=[N:13][C:12]=2[N:11]([CH3:23])[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCn1cnc2c1c(=O)n(Cc1ccccc1)c(=O)n2C
Agent: Cl
Product: Cn1c(=O)n(Cc2ccccc2)c(=O)c2[nH]cnc21
Temperature: 60 °C
Reaction time: 6 h

Procedure:
The unpurified 1-benzyl-7-ethoxymethyl-3-methylxanthine was treated with 1000 ml of 5N hydrochloric acid and stirred at 60° C. for 6 hours. The precipitated solid was filtered off with suction, washed with ethanol and dried under reduced pressure (164 g). It was possible from the mother liquor, after concentrating to approximately 50%, to isolate a further 35 g of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:21]=[CH:20][C:12]3[O:13][C:14]([CH3:19])([CH3:18])[C:15]([CH3:17])=[CH:16][C:11]=3[CH:10]=2)=[CH:4][CH:3]=1.N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C)C=O>[Si:27]([O:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[CH:21]=[CH:20][C:12]3[O:13][C:14]([CH3:18])([CH3:19])[C:15]([CH3:17])=[CH:16][C:11]=3[CH:10]=2)=[CH:6][CH:7]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1=Cc2cc(Sc3ccc(O)cc3)ccc2OC1(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC1=Cc2cc(Sc3ccc(O[Si](C)(C)C(C)(C)C)cc3)ccc2OC1(C)C
Temperature: 40 °C
Reaction time: 18 h
Yield: 83.5 %

Procedure:
6-(4-Hydroxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (5.799 g) (see Preparation 8) was dissolved in dry dimethylformamide (12 ml) and imidazole (2.768 g) and tert-butyidimethylsilyl chloride (2.923 g) were added. The flask was fitted with a calcium chloride drying tube and the mixture was stirred at 40° C. for 18 hours. The solvent was then removed under reduced pressure and the residue was partitioned between aqueous sodium bicarbonate solution and dichloromethane. The organic layer was dried (anhydrous sodium sulphate), the solvent removed under reduced pressure and the crude product chromatographed on silica using 1:1 hexane: dichloromethane as the eluent to yield 6-(4-tert-butyldimethylsilyloxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (6.681 g) as an oil. LRMS m/z=413 (m+1)+.
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Cl.[F:26][C:27]([F:40])([F:39])[S:28]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>>[F:39][C:27]([F:26])([F:40])[S:28]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH:36][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)[CH:18]=2)=[CH:33][CH:32]=1)(=[O:29])=[O:30]
Reactant: CCCCCCCCCCCc1noc(-c2cccc(C=O)c2)n1
Reactant: NCc1ccc(S(=O)(=O)C(F)(F)F)cc1
Agent: Cl
Product: CCCCCCCCCCCc1noc(-c2cccc(CNCc3ccc(S(=O)(=O)C(F)(F)F)cc3)c2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 3-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 4-[(trifluoromethyl)sulfonyl]benzylamine hydrochloride gave the title compound as an oil. M+(LC/MS(ESI)): 552.5. HPLC (Condition A), Rt: 4.85 min (HPLC purity: 62.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[C:12]([F:13])=[CH:11][C:10]([S:14]([N:17](CC3C=CC(OC)=CC=3OC)[C:18]3[S:22][N:21]=[CH:20][N:19]=3)(=[O:16])=[O:15])=[C:9]([F:34])[CH:8]=2)=[C:4]([C:37]2[N:41]3[CH:42]=[CH:43][N:44]=[CH:45][C:40]3=[CH:39][N:38]=2)[CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[C:12]([F:13])=[CH:11][C:10]([S:14]([NH:17][C:18]3[S:22][N:21]=[CH:20][N:19]=3)(=[O:15])=[O:16])=[C:9]([F:34])[CH:8]=2)=[C:4]([C:37]2[N:41]3[CH:42]=[CH:43][N:44]=[CH:45][C:40]3=[CH:39][N:38]=2)[CH:3]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ncc4cnccn34)cc2F)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1ncns1)c1cc(F)c(Oc2ccc(Cl)cc2-c2ncc3cnccn23)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a solution of 4-(4-chloro-2-(imidazo[1,5-a]pyrazin-3-yl)phenoxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.110 g, 0.16 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (0.4 mL). The mixture was stirred for 16 h at ambient temperature and concentrated in vacuo. Methanol (1 mL) was added to the residue. The mixture was concentrated in vacuo and the residue triturated in diethyl ether. The resultant solid was dissolved in a mixture of methanol and acetonitrile (1:1), filtered through a 0.2 μm filter and concentrated in vacuo. The residue was triturated in hexanes to afford 4-(4-chloro-2-(imidazo[1,5-a]pyrazin-3-yl)phenoxy)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as a yellow solid in 90% yield (0.075 g): 1H NMR (300 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.52 (s, 1H), 8.10 (d, J=4.6 Hz, 1H), 8.02 (s, 1H), 7.80 (s, 1H), 7.71-7.56 (m, 3H), 7.35 (d, J=8.9 Hz, 1H), 7.29 (dd, J=10.3, 6.2 Hz, 1H); MS (ES+) m/z 520.7 (M+1), 522.7 (M+1).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH2:10])[CH3:2].[C:11]([CH2:13][C:14](OCC)=O)#[N:12]>>[CH2:1]([N:3]1[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=[C:14]1[CH2:13][C:11]#[N:12])[CH3:2]
Reactant: CCOC(=O)CC#N
Reactant: CCNc1ccncc1N
Product: CCn1c(CC#N)nc2cnccc21
Temperature: 25 °C
Yield: 37.3 %

Procedure:
The product from Step 2 (500 mg, 3.6 mmole) and ethyl cyanoacetate (620 mg, 5.5 mmol) were heated together at 190° C. for 20 minutes. After cooling to room temperature, the residue was purified by column chromatography eluting with 10% methanol in ethyl acetate to afford the title compound (250 mg, 37%); MS (ES+) m/e 187 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:6]=1[C:7]#[N:8])(=O)C.C[O-].[Na+].Cl>CO>[OH:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: COC(=O)c1ccc(OC(C)=O)c(C#N)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(O)c(C#N)c1

Procedure:
A suspension of 70.6 g (0.32 mol) of the compound from Example XXXVIII and 3.48 g (0.06 mol) of sodium methylate in 0.5 1 of methanol is heated under reflux for 3 hours, the pH is brought to 6.5 with 1N hydrochloric acid at 25° C., the mixture is concentrated in vacuo, the residue is taken up in methylene chloride, the mixture is washed with saturated sodium chloride solution, the organic phase is dried over sodium sulphate and concentrated and the residue is crystallised from diethyl ether/petroleum ether mixtures.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8](Cl)[N:7]=[C:6]([CH3:14])[N:5]=1>CCCCCC>[NH2:2][C:1]1[N:7]([CH3:8])[CH:6]([CH3:14])[N:5]=[C:4]([Cl:3])[C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: CN
Solvent: CCCCCC
Product: CC1N=C(Cl)C([N+](=O)[O-])=C(N)N1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Methylamine (15.4 mL 1M in THF, diluted with 10 mL of hexane) is added dropwise to a solution of 4,6-Dichloro-2-methyl-5-nitropyrimidine (3.2 g, 15.4 mmol) in Hexane (30 mL). After addition, the reaction mixture is stirred at room temperature for one hour, and concentrated in vacuo to a solid. After the solid is dissolved in 50 mL of CH2Cl2, the resultant solution is washed with 0.1 N HCl (20 mL) and water (20 mL), dried over Na2SO4 and concentrated to a yellow solid. 1H NMR (CDCl3): δ 7.7 (bs, 1H), 3.10 (d, 3H), 2.55 (s, 5H).
Reaction SMILES: C([CH:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5])#N.C(=O)([O-])O.[Na+]>Br>[C:12]1([CH2:3][C:4]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[O:5])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#CC(C(=O)c1cccnc1)c1ccccc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(Cc1ccccc1)c1cccnc1
Temperature: 140 °C
Reaction time: 5 h
Yield: 87.9 %

Procedure:
2-Cyano-2-phenyl-1-(3-pyridyl)ethanone (5.0 g) was dissolved in 48% hydrobromic acid (50 mL) and the solution was stirred at 140° C. for 5 h. After the mixture was cooled, the mixture was neutralized with an aqueous saturated solution of sodium hydrogen carbonate and the product was extracted with ethyl acetate. The extracts were washed with water, dried, and the solvent was evaporated. The crystalline residue was recrystallized from isopropyl ether to obtain the title compound (3.9 g, yield 88%).
Reaction SMILES: O[N:2]=[C:3]1[C:11]2[C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4]1>Cl.C(O)(=O)C.[Zn]>[NH2:2][CH:3]1[C:11]2[C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)c1cccc2c1C(=NO)CC2
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: NC1CCc2cccc(C(=O)O)c21
Temperature: 90 °C
Yield: 34.1 %

Procedure:
A mixture of the 3-hydroxyimino-indan-4-carboxylic acid (0.45 g, 2.35 mmol), zinc powder (0.72 g) in 1M HCl (10 ml) and glacial acetic acid (3 ml) was heated to 90° C. for 18 hours. The mixture was cooled to room temperature, the solid filtered off and the solvent removed by evaporation under reduced pressure. The residue was diluted with water (5 ml) and extracted with dichloromethane (3×10 ml) and ethyl acetate (5 ml). The aqueous fraction was purified by ion-exchange column (DOWEX™ 50WX2-100) eluting with a solvent gradient of ammonia: water (5:95) to give the title compound (0.142 g, 34%) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH:18]2[CH2:22][N:21]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=3)[C:20](=[O:34])[N:19]2[CH3:35])=[CH:11][C:10]=1[CH3:36])([CH3:7])[CH3:6])C>CO>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:21]2[CH2:22][CH:18]([CH2:17][CH2:16][CH2:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:37])=[O:3])=[C:10]([CH3:36])[CH:11]=3)[N:19]([CH3:35])[C:20]2=[O:34])=[CH:25][CH:26]=1)([CH3:31])([CH3:32])[CH3:33]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)cc1C
Solvent: CO
Product: Cc1cc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)ccc1OC(C)(C)C(=O)O
Temperature: 0 °C
Yield: 97.5 %

Procedure:
2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (0.065 g, 0.128 mmole) is treated with 3:1 MeOH/5.0N NaOH (4 mL) at room temperature overnight, and then concentrated. The resulting residue is diluted with water (2 mL), cooled down to 0° C., acidified to pH=2 by adding concentrated HCl dropwise. The aqueous suspension is loaded on a Chem elut tube and eluted with DCM (50 mL). Evaporation of methylene chloride gives the titled compound as an oil (0.060 g, 98%). Mass [EI+] 481 (M+H)+, [EI−] 479 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([N+:17]([O-])=O)[C:11]=1[OH:20])(=[O:9])=[O:8])[CH3:2].[H][H]>[Pd]>[CH2:1]([O:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=1[OH:20])(=[O:9])=[O:8])[CH3:2]
Reactant: CCOCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Reactant: [H][H]
Agent: [Pd]
Product: CCOCCNS(=O)(=O)c1c(Cl)ccc(N)c1O

Procedure:
Following the general hydrogenation procedure outlined in example 15, crude N-(2-ethoxyethyl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (0.98 g) was reduced with hydrogen and Pd/C (250 mg). The crude product (1.01 g) was carried onto the next step without purification. 1H NMR (MeOD-d4): δ 6.88 (m, 2H), 3.40 (t, 2H), 3.36 (m, 2H), 3.13 (t, 2H), 1.08 (t, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[NH:3]1.N([O-])=O.[Na+]>>[CH3:1][C:2]1[NH:3][N:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:5](=[O:7])[CH:6]=1
Reactant: Cc1ccc(N2NC(C)CC2=O)cc1
Agent: O=N[O-]
Agent: [Na+]
Product: Cc1ccc(-n2[nH]c(C)cc2=O)cc1
Yield: 88 %

Procedure:
7 parts of 3-methyl-1-(4'-methylphenyl)-5-pyrazolidone are treated in a similar manner to that described in Example 1. The actual weight yield is 6.3 g of strength 91.3% (determined by titration with sodium nitrite solution which represents a yield of 88% of 3-methyl-1-(4'-methylphenyl)-5-pyrazolone.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=1.[O:16]1[CH2:22][C@@H:21]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH2:20][NH:19][CH2:18][CH2:17]1.C(N(CC)CC)C>>[CH3:8][N:7]1[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=[C:2]1[N:19]1[CH2:20][C@H:21]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH2:22][O:16][CH2:17][CH2:18]1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: N#Cc1ccc([C@H]2CNCCOC2)cc1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCOC[C@@H](c3ccc(C#N)cc3)C2)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.2 %

Procedure:
To a solution of 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (73.4 mg, 0.330 mmol) and (S)-4-([1,4]oxazepan-6-yl)benzonitrile (70.0 mg, 0.346 mmol) was added triethylamine (100 mg, 0.989 mmol) at room temperature. The mixture was stirred at room temperature for 5 hours and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/9) to afford (S)-4-(4-(1,6-dihydro-1-methyl-6-oxo-4-(pyrimidin-4-yl)pyrimidin-2-yl)-[1,4]oxazepan-6-yl)benzonitrile (A076) as white solid (93.8 mg, 70%).