Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH3:22])[N:21]=2)=[N:11][CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23](/B(O)O)=[CH:24]\[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH3:22])[N:21]=2)=[N:11][CH:12]=[C:13](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: Cc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1csc(Nc2ncc(/C=C/c3ccccc3)cc2OCc2ccccc2)n1
Temperature: 80 °C
Yield: 98.6 %

Procedure:
3-(Benzyloxy)-5-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine (0.300 g, 0.797 mmol), (E)-styrylboronic acid (0.142 g, 0.957 mmol), Pd(PPh3)4 (0.0461 g, 0.0399 mmol), and sodium carbonate (0.254 g, 2.39 mmol) were added to DME (10 mL) and water (5 mL) and heated at 80° C. for 18 hours. An additional 0.5 eq of (E)-styrylboronic acid, Pd(PPh3)4, and 2M sodium carbonate were added and the reaction was heated at 80° C. for an additional 6 hrs. The reaction mixture was cooled and partitioned between water and dichloromethane. The layers were separated, dried, filtered, and concentrated to provide the title compound (0.314 g, 98.6% yield). 1H NMR (CDCl3) δ 8.03 (d, 1H), 7.63 (d, 2H), 7.49 (m, 2H), 7.39 (m, 5H), 7.32 (m, 2H), 6.98 (s, 2H), 6.39 (s, 1H), 5.42 (s, 2H), 2.46 (s, 3H). Mass spectrum (apci) m/z=400.0 (M+H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[C:7]([C:22](=[S:24])[NH2:23])[N:6]=1)([CH3:4])[CH3:3].[NH2:25]N.[C:27](=[S:29])=S>CO.O>[CH3:19][C:18]([C:9]1[C:10]([O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[N:6]=[C:7]([C:22]2[S:24][C:27](=[S:29])[NH:25][N:23]=2)[N:8]=1)([CH3:21])[CH3:20]
Reactant: NN
Reactant: S=C=S
Reactant: COCCOCOc1c(C(C)(C)C)nc(C(N)=S)nc1C(C)(C)C
Solvent: CO
Solvent: O
Product: COCCOCOc1c(C(C)(C)C)nc(-c2n[nH]c(=S)s2)nc1C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
4,6-Bis(1,1-dimethylethyl)-5-[(2-methoxyethoxy)-methoxy]-2-pyrimidinecarbothioamide (0.22 g, 0.6 mmoles) is dissolved in 5 mL of methanol and added dropwise to 10 mL of 5% hydrazine in methanol at 0° C.. The reaction mixture is stirred at 0° C. for 1 hour, and then diluted with 20 mL of water. The methanol is evaporated under reduced pressure, and the organics are extracted into 50 mL of ethyl acetate. The ethyl acetate extract is washed with brine (4×50 mL) and dried over magnesium sulfate. The solvent is evaporated and the crude amidrazone is dissolved in 10 mL of methanol. Carbon disulfide (0.23 g, 3.1 moles) is added at room temperature. After 10 minutes, the methanol is evaporated and the remaining oil is adsorbed onto a silica gel pad. The pad is eluted with 50% ether/hexane. Evaporation of the eluant gives 0.18 g (73%) of 5-[4,6-bis (1,1-dimethylethyl) -5-[(2-methoxyethoxy) methoxy]-2-pyrimidinyl]-1,3,4-thiadiazole-2 (3H)-thione as an oil. This product is used without further purification in the deprotection reaction.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]([OH:48])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=1[CH2:17][CH2:18][C@@H:19]([S:39][CH2:40][C:41]1([CH2:44][C:45]([OH:47])=[O:46])[CH2:43][CH2:42]1)[C:20]1[CH:21]=[CH:22][CH:23]=[C:24](/[CH:26]=[CH:27]/[C:28]2[CH:29]=[CH:30][C:31]3[CH:32]=[CH:33][C:34]([Cl:38])=[CH:35][C:36]=3[N:37]=2)[CH:25]=1)[CH3:10].[OH-].[Na+:50].CCCCCCC>CO>[CH3:10][C:9]([OH:48])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=1[CH2:17][CH2:18][C@@H:19]([S:39][CH2:40][C:41]1([CH2:44][C:45]([O-:47])=[O:46])[CH2:42][CH2:43]1)[C:20]1[CH:21]=[CH:22][CH:23]=[C:24](/[CH:26]=[CH:27]/[C:28]2[CH:29]=[CH:30][C:31]3[CH:32]=[CH:33][C:34]([Cl:38])=[CH:35][C:36]=3[N:37]=2)[CH:25]=1)[CH3:8].[Na+:50]
Reactant: CC(C)(O)c1ccccc1CC[C@@H](SCC1(CC(=O)O)CC1)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(O)c1ccccc1CC[C@@H](SCC1(CC(=O)[O-])CC1)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
1.15 L of toluene were added to 115.2 g of Montelukast acid (e.e.: 99.9%). The mixture was cooled between 2 and 10° C. and 313.3 ml of 0.5M NaOH solution in methanol were added over 15 minutes. Then, the mixture was warmed to room temperature and stirred for 30 minutes. After this period of time, 1.5 L of the solvent were distilled off under reduced pressure at 30° C. Then, 2.4 L of toluene were charged to the crude and the distillation was resumed to obtain a final volume of 300 ml. The solution of crude obtained was added over 1 hour to 1 L of heptane under stirring at room temperature. 18 hours after the addition, an off white solid was filtered off under a nitrogen atmosphere and washed with 500 ml of heptane. The wet product was dried under vacuum at 75° C. for 3 days to yield 120 g of Montelukast sodium. Yield: 100%. e.e.: 99.9%.
Reaction SMILES: O=[C:2]1[C:10]2([CH:12]([C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)O2)[CH2:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.O.[NH2:23][NH2:24]>C(O)(=O)C.CO>[NH:23]1[C:2]2[C:3]3[C:8]([CH2:9][C:10]=2[C:12]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)=[N:24]1)=[CH:7][CH:6]=[CH:5][CH:4]=3
Reactant: O=C(O)c1ccc(C2OC23Cc2ccccc2C3=O)cc1
Reactant: NN
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1

Procedure:
4-(1-Oxospiro[indan-2,2′-oxiran]-3′-yl)benzoic acid from Example 7b (780 mg), methanol (50 ml), hydrazine hydrate (0.18 ml) and glacial acetic acid (6 drops) were boiled under reflux for 24 hours. The mixture was cooled in ice and filtered to give 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzoic acid, m.p. >320° C.
Reaction SMILES: CN(C)[C:3](Cl)=[O:4].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]([NH:24][NH2:25])=[O:23])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)([O-:9])=[O:8]>N1C=CC=CC=1>[N+:7]([C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:17][CH2:18][CH:19]([C:22]3[O:23][C:3](=[O:4])[NH:25][N:24]=3)[CH2:20][CH2:21]2)=[CH:14][CH:15]=1)([O-:9])=[O:8]
Reactant: NNC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Product: O=c1[nH]nc(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)o1
Temperature: 85 °C
Yield: 39.9 %

Procedure:
To a stirred solution of 4-fluoro nitrobenzene (1a, 3.1 g, 22 mmol) and methyl 4-piperidine carboxylate (2, 3.15 g, 22 mmol) in DMF solvent and K2CO3 (7.6 g, 55 mmol) as base and heated at 80° C. for 10 h, after completion of the reaction, reaction is poured into ice water and extracted into ethyl acetate finally purification by column chromatography to afford pure compound methyl 1-(4-nitrophenyl)-4-piperidinecarboxy-late (3a, 4.93 g, 85%). To a stirred solution of ester (3a, 4.75 g, 18 mmol) in ethanol, NH2NH2. H2O (2.25 g, 45 mmol) is added and refluxed for 24 h. After completion of the reaction ethanol is evaporated under vacuum and water is added and extracted into ethyl acetate finally purification by column chromatography to afford pure compound 1-(4-nitrophenyl)-4-piperidinecarbohydrazide (4a, 3.99 g, 84%). Addition N,N-dimethyl carbamyl chloride (1.29 g, 12 mmol) to hydrazide (4a, 3.17 g, 12 mmol) in pyridine at room temperature (27° C.) and followed by reflux at temperature 85° C. for 2.5 h. After completion of the reaction, the reaction mixture is cooled and filtered. The residue is recrystallized from water to get 5-[1-(4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5a, 1.39 g, 40%). Nitro compound (5a, 1.16 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (7a, 884 mg, 85%). To a stirred solution of 5-nitro2-furanoic acid (0.16 g, 1 mmol) in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide)) (0.19 g, 1 mmol) and amine compound (7a, 0.26 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-4-[4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8a, 323 mg, 81%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=O)=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[ClH:22]>CC(N(C)C)=O>[N+:12]([C:3]1[CH:4]=[C:5]([S:8]([Cl:22])(=[O:10])=[O:11])[CH:6]=[CH:7][C:2]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([O-:14])=[O:13]
Reactant: Cl
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)O)ccc1Cl
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Nc1ccccc1

Procedure:
A mixture composed of 23.8 g (0.1 mol) of 4-chloro-3-nitrobenzenesulfonic acid, 28 g of aniline and 30 ml of dimethylacetamide was heated to 90° to 100° C. for 3 hours. After being allowed to cool, the reaction solution was poured into cold diluted hydrochloric acid, and the resulting yellow crystals were filtered off. The resulting salt of 3-nitro-4-phenylaminobenzenesulfonic acid was chlorinated under the same condition as in (1-b) to obtain 3-nitro-4-phenylaminobenzenesulfonyl chloride (3-b).
Reaction SMILES: [Cl-].[Cl-].C([Al+2])C.[C:6]([O:10][CH3:11])(=[O:9])[C:7]#[CH:8].[C:12]([O:15][C@@H:16]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@H:18]([CH2:19][CH2:20][C@@H:21]3[C:31]2=[CH:30][CH2:29][C@@:28]2([CH3:36])[C@H:22]3[CH2:23][CH2:24]/[C:25]/2=[CH:26]/[CH3:27])[CH2:17]1)(=[O:14])[CH3:13].O>C(Cl)Cl>[C:12]([O:15][C@@H:16]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@H:18]([CH2:19][CH2:20][C@@H:21]3[C:31]2=[CH:30][CH2:29][C@@:28]2([CH3:36])[C@H:22]3[CH2:23][CH:24]=[C:25]2[C@H:26]([CH3:27])/[CH:8]=[CH:7]/[C:6]([O:10][CH3:11])=[O:9])[CH2:17]1)(=[O:14])[CH3:13]
Reactant: C#CC(=O)OC
Reactant: C/C=C1/CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)C3=CC[C@]12C
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)/C=C/[C@@H](C)C1=CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)C3=CC[C@]12C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.8 %

Procedure:
Ethyl aluminum dichloride (104.5 mL, 192 mmol, 1.8 M in toluene) was added to a solution of methyl propiolate (13.58 mL, 153 mmol) in DCM (100 mL) at 0° C. under inert atmosphere. The resulting solution was stirred for 15 min and then compound 1.6a (22 g, 64.3 mmol) was added. After stirring for an additional 20 min at 0° C., the temperature was raised to 25° C. and held there for a further 18 h. At this point the reaction was determined to be complete by TLC, and the mixture was poured into cold (0° C.) water (200 mL). The phases were separated and the aqueous layer was extracted with DCM (150 mL). The organic layers were combined and washed sequentially with water (200 mL) and saturated brine solution (100 mL). It was then dried over anhydrous Na2SO4 (40 g) and filtered. The filtrate was concentrated under vacuum and the resulting solid was purified by slurring in methanol (280 mL) to provide compound 1.7a (17.5 g 68%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.[C:31]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)(=[O:33])[CH3:32].C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:31]([C:34]1[CH:39]=[CH:38][C:37]([O:1][C:2]2[CH:3]=[C:4]([C:14]3[N:15]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[C:16]([C:19]4[S:20][CH:21]=[CH:22][N:23]=4)=[CH:17][CH:18]=3)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=2)=[CH:36][CH:35]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(C)=O)cc2)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.2 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (92 mg, 0.214 mmol) synthesized in Example (38d) was dissolved in dichloromethane (10 mL), and 4-acetylphenylboronic acid (70 mg, 0.427 mmol), copper (II) acetate (60 mg, 0.330 mmol), triethylamine (0.15 mL, 1.08 mmol) and molecular sieves 4A (90 mg) were added, followed by stirring at room temperature for 1 day under nitrogen atmosphere. The deposit of this reaction solution was Celite filtered. This mother liquor was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=15%-25%) to afford the desired compound (73 mg, yield 62%) as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1)([OH:3])=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[CH3:41][NH:42][C@H:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46][CH2:45][CH2:44]1>ClCCl>[CH3:41][N:42]([C@H:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46][CH2:45][CH2:44]1)[C:1]([C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1)=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Reactant: CN[C@@H]1CCCc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1)[C@@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1-(1,1-dimethylethyl) 4-[4-carboxy-2-thiazolyl]-1-piperidinecarboxylate (i.e. the product of Example 1, Step B) (3.84 g, 12.29 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.36 g, 12.29 mmol) and triethylamine (2.3 mL, 16.76 mmol) in 50 mL dichloromethane was stirred for 15 minutes at room temperature. (1R)-1,2,3,4-Tetrahydro-N-methyl-1-naphthalenamine (i.e. the product of Example 6, Step A) (2.18 g, 13.5 mmol) was added and the reaction mixture was stirred for 16 h. The reaction mixture was diluted with 20 mL of dichloromethane, washed with 1 N aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate solution, water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 20% to 100% of ethyl acetate in hexanes to give 2.4 g of the title compound as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:14][F:15])([CH2:12][F:13])[CH:9]=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:7]=2[CH:22]=1)#[N:2].ClC1C=CC=C(C(OO)=[O:31])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:14][F:15])([CH2:12][F:13])[CH:9]=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N+:17]=3[O-:31])[C:7]=2[CH:22]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)C(c1ccccn1)=CC(CF)(CF)O2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)C(c1cccc[n+]1[O-])=CC(CF)(CF)O2
Yield: 35.6 %

Procedure:
In 3 ml of methylene chloride was dissolved 80 mg of 6-cyano-2,2-bisfluoromethyl-4-(2-pyridyl)-2H-1-benzopyran and 75.7 mg of m-chloroperbenzoic acid (70%) was added thereto with stirring under ice-cooling. The mixture was stirred at room temperature for 15 hours. After addition of 28 mg of m-chloroperbenzoic acid (70%), the mixture was further stirred for 19 hours. Sodium bicarbonate solution was added thereto and the mixture was extracted with methylene chloride. After the organic layer was washed with water and dried, the solvent was distilled off. The resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 30 mg of 2-(6-cyano-2,2-bisfluoromethyl-2H-1-benzopyran-4-yl)pyridine N-oxide represented by the following formula having a melting point of 204°-207° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])C(C(F)(F)F)=[CH:10][C:9]=1[NH:23][C:24](=[O:40])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[N:37][CH:36]=[CH:35][N:34]=2)[CH:28]=1)(C)(C)C.[C:42](O)([C:44]([F:47])([F:46])[F:45])=O>C(Cl)Cl>[CH3:18][N:14]([CH2:15][CH2:16][CH3:17])[C:12]1[C:42]([C:44]([F:47])([F:46])[F:45])=[CH:10][C:9]2[NH:23][C:24](=[O:40])[CH2:25][C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[CH:38]=[N:37][CH:36]=[CH:35][N:34]=4)[CH:28]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cnccn3)c2)cc1C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cnccn3)c1)=N2

Procedure:
The title compound was prepared from {5-(methyl-propyl-amino)-2-[3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M93) (0.34 g, 0.59 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (176 mg, 65%).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[OH:20].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN1C(=O)CCC1>[Br:1][C:2]1[C:3]([O:20][C:14]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=2[F:12])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1cnc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 60 °C
Yield: 60.4 %

Procedure:
A solution of 3-bromo-2-chloro-5-nitropyridine (2.4 g, 10 mmol) and 2,4-difluorophenol (1 mL, 11 mmol) in NMP (20 ml) was treated with cesium carbonate (3.9 g, 12 mmol). The resulting mixture was heated to 60° C. for 12 h. The mixture was treated with water (100 ml) and extracted with EtOAc (3×50 ml); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow solid. The solid was purified by silica gel column chromatography (gradient of 5 to 30% EtOAc in hexanes) to afford the free base of the title compound (2 g, 59%) as a yellow solid. LCMS (M+H)+=332.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.ON1C(=O)CCC1=O.[C:16]([OH:20])([CH3:19])([CH3:18])[CH3:17]>CN(C)C1C=CN=CC=1>[C:16]([O:20][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)O
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Agent: O=C1CCC(=O)N1O
Product: CC(C)(C)OC(=O)CCC(=O)O

Procedure:
Sodium 2,2-d2-4-hydroxybutyrate is prepared in the following manner: treatment of succinic anhydride with tert-butanol, N-hydroxysuccinimide, and 4-dimethylaminopyridine (4-DMAP) according to the procedure of Yao, Z-J., et al, J. Org. Chem. 2003, 68, 6679-6684 affords the succinic acid mono-tert-butyl ester. In accordance with Yao, reduction of the succinic acid with borane-dimethyl sulfide complex gives the 4-hydroxybutanoic acid tert-butyl ester. Subjecting the ester to hydrogen/deuterium exchange by treatment with potassium carbonate in d1-methanol affords the 2,2-d2-4-hydroxybutanoic acid tert-butyl ester. Finally, saponification of the tert-butyl ester with sodium hydroxide in d1-methanol in a manner analogous to the procedure of Goto, G., et al, Chem. Pharm. Bull. 1985, 33, 4422-4431 affords the desired sodium 2,2-d2-4-hydroxybutyrate.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][C:7](O)=O)[N:3]=[CH:2]1.[NH2:10][C:11]1[C:12](=[O:33])[N:13]([CH2:30][CH2:31][CH3:32])[C:14](=[O:29])[N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[C:16]=1[NH2:17]>>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:15]2[C:16]3[N:17]=[C:7]([CH2:6][C:4]4[N:3]=[CH:2][S:1][CH:5]=4)[NH:10][C:11]=3[C:12](=[O:33])[N:13]([CH2:30][CH2:31][CH3:32])[C:14]2=[O:29])=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: CCCn1c(=O)c(N)c(N)n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: O=C(O)Cc1cscn1
Product: CCCn1c(=O)c2[nH]c(Cc3cscn3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O

Procedure:
By the method of Example 2, 4-thiazolylacetic acid is reacted with 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(4-thiazolyl)methyl]xanthine. By the method of Example 3, this substance is alkylated with a mixture of 1,2-dichloroethane, sodium carbonate and 2-(ethylamino)ethanol to yield 7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(4-thiazolyl)methyl]xanthine. By the method of Example 4 this substance is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(4-thiazolyl)methyl]xanthine free base. The corresponding hydrochloride salt is then made on exposure to an excess of hydrogen chloride in solution.
Reaction SMILES: C(=O)CCC.C=O.[CH2:8]([C:10]([CH2:15][OH:16])([CH2:13][CH3:14])[CH:11]=[O:12])[OH:9]>C(O)=O>[CH2:8]([C:10]([CH2:15][OH:16])([CH2:11][OH:12])[CH2:13][CH3:14])[OH:9]
Reactant: CCC(C=O)(CO)CO
Agent: C=O
Solvent: CCCC=O
Solvent: O=CO
Product: CCC(CO)(CO)CO

Procedure:
In the Cannizzaro process, butyraldehyde is reacted with formaldehyde in the presence of a stoichiometric amount of base. This initially forms 2,2-dimethylolbutanal which then reacts with a further molecule of formaldehyde in a cross-Cannizzaro reaction to form formic acid and trimethylolpropane. The disadvantage of this method is that one molar equivalent of formate is formed as coproduct. This has to be worked up and increases the consumption of formaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:15][C:14](=[O:16])[O:13][C:11](=[O:12])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:22][NH2:23].[CH2:33](N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][C:11]([N:23]([CH2:22][C:21]2[CH:20]=[C:19]([C:18]([F:31])([F:32])[F:17])[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=2)[CH3:33])=[O:12])[CH2:15][C:14]([OH:13])=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)CC(=O)O1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(3,4-Dichlorophenyl)glutaric anhydride (3.1 g, Example 1, Step C) in CH2Cl2 (50 mL) at 0° C. was treated sequentially with 3,5-bis-(trifluoromethyl)benzylamine (3.4 g), triethylamine (1.83 mL) and N,N-dimethylaminopyridine (150 mg). The mixture was stirred at 0° C. for two hours then allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was diluted with CH2Cl2 (200 mL) and washed with 1N HCl (1×100 mL) and water (1×100 mL). The organic layers were dried over MgSO4, filtered and concentrated to afford the title compound (6.1 g).