Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6]CC)=O.[CH3:13][N:14]1[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17](=O)[O:16]C1=O.Cl>O.C(O)C>[OH:16][C:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[N:14]([CH3:13])[C:4](=[O:6])[C:3]=1[C:2]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: Cn1c(=O)oc(=O)c2cccnc21
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(O)c2cccnc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 0.345 g. (0.15 g. atom) of sodium in 30 ml. of ethanol was added 4.8 g. of diethyl malonate. The mixture was stirred at room temperature for 5 minutes and then was evaporated in a rotary evaporator. The residue was dissolved in 30 ml. of N,N-dimethylformamide and 2.67 g. (0.015 mole) of 1-methyl-1H-4H-pyrido[2,3-d][1,3]-oxazine-2,4-dione was added. The mixture was heated under reflux for 10 minutes and the thick mixture was dissolved in 100 ml. of water. The solution was acidified with conc. hydrochloric acid and the precipitate which formed was collected, air dried, and a small amount of this 1.7 g. was recrystallized from ethanol to give the analytical sample of 4-hydroxy-1,2-dihydro-1-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, m.p. 158°-160° C.
Reaction SMILES: [CH3:1][C:2]1[S:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1>CN(C=O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:6]2[C:5]3[S:12][C:2]([CH3:1])=[CH:3][C:4]=3[C:9](=[O:10])[O:8][C:7]2=[O:11])=[CH:16][CH:17]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1cc2c(=O)oc(=O)[nH]c2s1
Solvent: CN(C)C=O
Product: Cc1cc2c(=O)oc(=O)n(Cc3ccc(F)cc3)c2s1
Temperature: 0 °C
Yield: 41.2 %

Procedure:
step 3—Sodium hydride (1.5 g of a 60% dispersion in mineral oil, 37.5 mmol) was suspended in DMF (50 mL) in a 250 mL round-bottom flask equipped with a stir bar, and cooled to 0° C. and maintained under a nitrogen atmosphere. A solution of 61a (4.6 g, 25 mmol) dissolved in DMF (50 mL) was added dropwise through a septum. The flask was removed from the ice bath and the mixture was stirred at RT for 30 m. The reaction was cooled to 10° C. and 1-bromomethyl-4-fluoro-benzene (3.74 mL, 30 mmol) was added through the septum. The flask was removed from the ice bath and the mixture was stirred at RT for 2 h. The reaction was poured into ice and 1N HCl, extracted twice with EtOAc, dried (Na2SO4), filtered and concentrated. A solid was precipitated from the EtOAc by addition of Et2O and hexanes to afford 3.0 g (41%) of 1-(4-fluoro-benzyl)-6-methyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione (61b): ms 2[M+Na]=605.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[C:23]1([CH:30]=[CH:29][C:27]([OH:28])=[CH:26][CH:25]=1)[OH:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][O:24][C:23]4[CH:30]=[CH:29][C:27]([OH:28])=[CH:26][CH:25]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: Oc1ccc(O)cc1
Product: CCN1c2ncc(COc3ccc(O)cc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 67 %

Procedure:
Using a procedure analogous to that described in Example 104, the title compound, m.p. 199°-200° C., was prepared from 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and hydroquinone. The yield was 67% of theory.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2].[C:18](OC(=O)C)(=[O:20])[CH3:19].S(=O)(=O)(O)O.O>C(#N)C>[C:18]([O:17][C:6]1[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:20])[CH3:19]
Reactant: COc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Product: COc1cc(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.50 kg (6.35 mol) of 2,6-di-tert-butyl-4-methoxyphenol and 658 mL (6.98 mol) of acetic anhydride dissolved in 1.2 L of acetonitrile, 3 mL of conc. sulfuric acid was added and the mixture was stirred overnight at room temperature. To the mixture, a great excess of water was added and the resulting solids were filtered and dried. The obtained 4-acetoxy-3,5-di-tert-butylanisole was used in the next reaction without further purification.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[C:9](#[N:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C1(C)C=CC=CC=1>C(O)(C)C>[OH:3][NH:2][C:9](=[NH:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCC#N
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCCCCC(=N)NO
Reaction time: 0.21 h

Procedure:
To a solution of 0.107 g (15.4 mmol) of hydroxylamine hydrochloride in 11 mL of isopropyl alcohol, 1.90 g (22.64 mmol) of sodium bicarbonate was added. The resulting mixture was stirred at 25° C. to 30° C. for 10-15 min. 1.0 g (10.2 mmol) of hexanenitrile was added and stirred at 80° C. to 85° C. for 3-4 h. After the reaction period, the reaction mixtures was cooled to 25° C. to 30° C., filtered and washed with 2 mL of isopropyl alcohol. The filtrate was collected and distilled out completely to obtain a crude residue. The residue with chased with 5 mL of toluene, to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH:10]=O)=[CH:7][CH:6]=[CH:5][N:4]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=1)[CH2:16][NH:17][C:18](=[O:26])[CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.C(O)(=O)C>[F:12][C:13]1[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=1)[CH2:16][NH:17][C:18](=[O:26])[CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]1[CH2:10][CH2:9][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ncccc1CC=O
Reactant: O=C(CC1CCCCN1)NCc1cccc(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ncccc1CCN1CCCCC1CC(=O)NCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
200 mg of 2-(2-methoxy-3-pyridyl)acetaldehyde, 400 mg of N1-(3-fluorobenzyl)-2-(2-piperidyl)acetamide, 440 mg of sodium triacetoxyborohydride and 0.12 ml of acetic acid were suspended in THF, followed by stirring at room temperature for 1 hour. An aqueous sodium bicarbonate was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate. After filtering off the drying agent, the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=8:1, subsequently 4:1), to give 370 mg of a yellow oil.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.N1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:31]([C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42]CO)=[CH:36][CH:35]=1)([O-:33])=[O:32]>C(Cl)Cl>[N+:31]([C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42][CH2:1][Br:5])=[CH:36][CH:35]=1)([O-:33])=[O:32]
Reactant: BrC(Br)(Br)Br
Reactant: O=[N+]([O-])c1ccc(CCCCO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(CCCCBr)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
Part A.Carbon tetrabromide (34.01 gm, 102.55 mmol), pyridine (8.3 mL, 102.55 mmol) and triphenylphosphine (25.52 gm, 112.55 mmole) were added sequentially to a solution of 4-(4-nitrophenyl) butanol (20.0 gm, 102.55 mmol) in 400 mL of CH2Cl2 (precooled to 0° C.) and was allowed to stir overnight with warming to room temperature. The volatiles were removed under vacuum and the residue dissolved in ethyl acetate, filtered through a plug of silica and concentrated to dryness. The resulting oil was purified by flash chromatography eluting hexane:ethyl acetate(v:v, 4:1) to give 4-(4-nitrophenyl)butyl bromide as an oil 23.51 gm (88%). 1H NMR (CDCl3) 1.95-1.81 (m, 4H), 2.78 (t, 2H), 3.45 (t, 2H), 7.37 (d, 2H), 8.15 (d, 2H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][NH:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].C(=O)(O)[O-].[Na+].C1COCC1.F[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=1[N+:36]([O-:38])=[O:37]>O>[N+:36]([C:27]1[CH:28]=[C:29]([C:32]([F:33])([F:34])[F:35])[CH:30]=[CH:31][C:26]=1[N:13]1[CH2:12][CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:14]1)([O-:38])=[O:37]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a 200-mL RBF was added (s)-3-n-boc-amino piperidine (10.9 g, 54.4 mmol), Sodium bicarbonate (11.4 g, 136 mmol), THF, and 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (7.62 ml, 54.4 mmol). The yellow mixture was heated to 70° C. with a water-cooled reflux condenser. The orange mixture was allowed to stir for 14 h, and was then cooled to ambient temperature, and filtered through a glass frit, rinsing with EtOAc. Concentration in vacuo afforded an orange oil, which crystallized on standing to an orange solid. The material was treated with 250 mL hexanes and heated on the rotovap (no vacuum) to 60° C. Small amounts of EtOAc were added until all solid dissolved, total volume of EtOAc was approx 10 mL. The solution was allowed to cool overnight, resulting in the formation of orange crystals. The liquid was decanted and the crystals rinsed twice with 50 mL hexanes. The crystals were collected to give (S)-tert-butyl 1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ylcarbamate as orange crystals. The filtrate was concentrated to an orange solid. This material was treated with 150 mL hexanes and was heated to 65° C. Almost all of the material had dissolved. The hot liquid was decanted into a flask and allowed to cool overnight, resulting in an orange solid. The liquid was discarded, and additional crystals of (S)-tert-butyl 1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ylcarbamate were collected. MS m/z=390 [M+H]+. Calc'd for C17H20F3N3: 389.
Reaction SMILES: [OH-].[Ca+2].[OH-].[CH2:4]([O:7][C:8]([N:10]1[CH2:14][C@H:13](OS(C)(=O)=O)[CH2:12][C@H:11]1[CH2:20][N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)=[O:9])[CH:5]=[CH2:6].[C:26]([SH:29])(=[O:28])[CH3:27]>CC(C)CC(=O)C>[C:26]([S:29][C@@H:13]1[CH2:14][N:10]([C:8]([O:7][CH2:4][CH:5]=[CH2:6])=[O:9])[C@H:11]([CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH2:12]1)(=[O:28])[CH3:27]
Reactant: CC(=O)S
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1Cn1ccnc1
Agent: [Ca+2]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1Cn1ccnc1

Procedure:
To a solution of calcium hydroxide (2.25 g) and (2S,4R)-1-allyloxycarbonyl-2-(imidazol-1-yl)methyl-4-methanesulfonyloxypyrrolidine (10 g) in 4-methyl-2-pentanone (60 ml) was added dropwise thioacetic S-acid (4.38 ml) with stirring below 45° C. The solvent (18 ml) of the mixture was removed under reduced pressure at 40°-45° C. The resulting suspension was heated at 80°-85° C. for 2 hours. After cooling, water (20 ml) and ethyl acetate (20 ml) was added to the reaction mixture The insoluble material was filtered off and washed with ethyl acetate (30 ml). The filtrate and washing were combined. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(imidazol-1-yl)methylpyrrolidine (7.94 g).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][OH:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:12][C:13]1[N:14]=[C:15]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:16]([C:23]2[CH:24]=[CH:25][C:26](=[O:32])[N:27]([CH:29]([CH3:31])[CH3:30])[N:28]=2)=[N:17][C:18]=1S(C)(=O)=O.Cl>C(Cl)(Cl)Cl>[NH2:12][C:13]1[N:14]=[C:15]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:16]([C:23]2[CH:24]=[CH:25][C:26](=[O:32])[N:27]([CH:29]([CH3:31])[CH3:30])[N:28]=2)=[N:17][C:18]=1[O:11][CH2:10][CH2:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCCc1ccccc1
Reactant: CC(C)n1nc(-c2nc(S(C)(=O)=O)c(N)nc2-c2ccccc2)ccc1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)n1nc(-c2nc(OCCc3ccccc3)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 27.5 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60% in oil suspension) (31.1 mg) in 1,2-dimethyl-2-imidazolidinone (0.6 ml) was added 2-phenylethanol (0.094 ml) and the mixture was stirred at 25-30° C. for 30 minutes. 6-[5-Amino-6-(methylsulfonyl)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (150 mg) was added and the mixture was heated at 100-105° C. for 15 hours. To the mixture was added 0.1N HCl (3 ml) and an aqueous layer was removed by decantation to give a residue. The residue was dissolved in CHCl3, dried over MgSO4, concentrated under reduced pressure and purified by column chromatography on silica gel. By elution with a mixture of n-hexane and EtOAc (60:40 v/v) was obtained 6-[5-amino-3-phenyl-6-(2-phenylethoxy)-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone as a solid (9 mg). By elution with a mixture of MeOH and EtOAc (1:99 v/v) was obtained 6-(5-amino-6-oxo-3-phenyl-1,6-dihydro-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone as a solid (89 mg).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][OH:12])[N:10]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1.[C:19]([N:26]1[CH2:31][CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[OH:12][CH2:11][C:9]1[N:10]=[C:6]2[C:5]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:4][CH:3]=[C:2]([C:29]3[CH2:30][CH2:31][N:26]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:27][CH:28]=3)[N:7]2[CH:8]=1
Reactant: OCc1cn2c(Br)cnc(N3CCOCC3)c2n1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: CC(C)(C)OC(=O)N1CC=C(c2cnc(N3CCOCC3)c3nc(CO)cn23)CC1

Procedure:
Compound 1e was subjected to Suzuki coupling reaction conditions with N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester using the method described in Example 1, Step G to obtain compound 26a. Mass Spectrum (LCMS, ESI pos.) Calcd. for C21H29N5O4: 416.2 (M+H). Found 416.3.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:10]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:35]([S:38](Cl)(=[O:40])=[O:39])[CH2:36][CH3:37]>ClCCl>[CH2:13]([CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][S:38]([CH2:35][CH2:36][CH3:37])(=[O:40])=[O:39])[CH:12]=2)[CH2:7][CH2:8][CH:9]1[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(CN)cc2C1Cc1ccccc1
Reactant: CCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccccc1)C(NC(=O)OC(C)(C)C)CC2
Reaction time: 0.58 h
Yield: 81.2 %

Procedure:
tert-Butyl 7-(aminomethyl)-1-benzyl-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (0.600 g, 1.637 mmol) was suspended in dichloromethane (5 mL) and triethylamine (0.228 mL, 1.637 mmol) and cooled to 0° C. 1-Propanesulfonyl chloride (0.184 mL, 1.64 mmol) was added. The solid immediately dissolved. The mixture was stirred 35 minutes, and then it was diluted with dichloromethane and washed with brine (1×50 mL). The organic phase was collected, dried on MgSO4 and the volatiles were evaporated under reduced pressure, yielding the product as a pale yellow solid (628.3 mg, 1.33 mmol, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[NH:16]C(C)=[N:14][C:13]=3[C:12](=[O:19])[N:11]3[CH2:20][C:21](C)(C)[N:22]=[C:10]23)=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]([NH2:16])=[C:13]([NH2:14])[C:12](=[O:19])[N:11]3[CH:20]=[CH:21][N:22]=[C:10]23)=[CH:4][CH:3]=1
Reactant: Cc1nc2c([nH]1)N(Cc1ccc(Cl)cc1)C1=NC(C)(C)CN1C2=O
Solvent: CC(=O)OC(C)=O
Product: Nc1c(N)n(Cc2ccc(Cl)cc2)c2nccn2c1=O
Yield: 70 %

Procedure:
4-[(4-CHLOROPHENYL)METHYL]-6,7-DIHYDRO-2,6,6-TRIMETHYL-3H-IMIDAZO[1,2-a]PURIN-9(4H)-ONE. The nitroso compound of Procedure 103 was catalytically hydrogenated to the diamino compound and then treated with acetic anhydride according to the method of Procedure 63. There resulted from this process the mono N-acetyl derivative of 8-[(4-chlorophenyl)methyl]-6,7-diaminoimidazo[1,2-a]pyrimidin-5-one, m.p. 155°-159° after recrystallization from isopropanol and drying under vacuum.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([C:20]#[N:21])[N:3]=1.[CH3:22][O-:23].[Na+]>CN(C=O)C>[CH3:22][O:23][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([C:20]#[N:21])[N:3]=1
Reactant: C[O-]
Reactant: COc1ccc2c(Cl)nc(C#N)c(-c3ccccc3)c2c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(OC)nc(C#N)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-chloro-6-methoxy-4-phenylisoquinoline-3-carbonitrile (50 mg) in 1 mL of DMF was added NaOMe (3 equivalents). The reaction was stirred at room temp overnight, then concentrated and purified by flash chromatography (30% EtOAc/hexanes). Trituration (ether/hexanes) of the concentrated material gave the titled compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH:21]1([C:24]([CH3:32])([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[NH2:25])[CH2:23][CH2:22]1>>[CH:21]1([C:24]([NH:25][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH3:32])[CH2:23][CH2:22]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: Cc1nc(C(C)(N)C2CC2)no1
Product: Cc1nc(C(C)(NC(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and α-cyclopropyl-α,5-dimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1155536-64-3) as starting materials. MS (EI): m/e=434.5 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[O:9].[C:10]1([C:16]2[C:18](=[O:19])[C:17]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18](=[O:19])[O:9]1
Reactant: O=Nc1ccccc1Cl
Reactant: O=c1c(-c2ccccc2)c1-c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C1ON(c2ccccc2Cl)C(c2ccccc2)C1c1ccccc1

Procedure:
4.6 Parts of o-chloronitrosobenzene and 6.7 parts of diphenylcyclopropenone is refluxed in 60 parts of chloroform for 72 hours. The solvent is removed under reduced pressure and the residue remaining is triturated with ethyl ether. Recrystallization from ethyl acetate then affords as tan crystals, pure 2-(o-chlorophenyl)-3,4-diphenylisoxazolin-5-one, melting at about 178°-180°. That compound is represented structurally by the following formula. ##STR7##
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[N:13]1[C:18](=[O:19])[C:17]([CH3:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[N:15]=[CH:14]1.O>S(=O)(=O)(O)O>[F:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N+:1]([O-:4])=[O:2])=[CH:8][C:7]=1[N:13]1[C:18](=[O:19])[C:17]([CH3:20])=[C:16]([C:21]([F:23])([F:24])[F:22])[N:15]=[CH:14]1
Reactant: Cc1c(C(F)(F)F)ncn(-c2ccc(F)cc2F)c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(C(F)(F)F)ncn(-c2cc([N+](=O)[O-])c(F)cc2F)c1=O
Yield: 73.9 %

Procedure:
Fuming nitric acid (1.63 g) was added to a solution of 3-(2,4-difluorophenyl)-5-methyl-6-trifluoromethylpyrimidin-4-one (7.5 g) in conc. sulfuric acid (50 g) at 10° C. The reaction mixture was poured into water, and the resultant mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diethyl ether to give 3-(2,4-difluoro-5-nitrophenyl)-5-methyl-6-trifluoromethylpyrimidine-4-one (6.4 g), m.p. 156.7° C.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:7])[N:4]([CH3:6])[CH3:5].[H-].[Na+].C(O[C:13](=O)[CH2:14][S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)C>C1COCC1>[CH3:5][N:4]([CH3:6])[C:3]1[N:7]=[C:13]([CH2:14][S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:1][N:2]=1
Reactant: CN(C)C(=N)NO
Reactant: CCOC(=O)CSc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)c1noc(CSc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a stirred suspension of 14 g (0.129 mol, 1.4 eq) of 3-hydroxy-1,1-dimethyl-guanidine in 300 mL dry THF at 0° C. was added portionwise 6.191 g (0.155 mol, 1.2 eq) of NaH (60% in oil). The resulting heavy suspension was stirred at RT for 1 hour 30 minutes. Then, 28.126 g (0.129 mol) phenylsulfanyl-acetic acid ethyl ester were slowly added. The reaction mixture was stirred at RT for 2 hours and then at 65° C. for 1 hour. The reaction was quenched by addition of a saturated aqueous solution of NH4Cl and the product extracted with EtOAc. The combined organic phase was dried on Na2SO4, filtered and evaporated. Column chromatography on silica gel (EtOAc/heptane, 1:9 to 1:2) yielded 19.370 g (64%) dimethyl-(5-phenylsulfanylmethyl-[1,2,4]oxadiazol-3-yl)-amine as a colorless oil, MS: 236 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11][CH3:12])[CH:9]=2)[CH:4]=[CH:3]1.[C:13](Cl)(=[O:17])[C:14]([Cl:16])=[O:15]>CCOCC>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11][CH3:12])[CH:9]=2)[C:4]([C:13](=[O:17])[C:14]([Cl:16])=[O:15])=[CH:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CSc1ccc2ccn(C)c2c1
Solvent: CCOCC
Product: CSc1ccc2c(C(=O)C(=O)Cl)cn(C)c2c1
Reaction time: 3 h
Yield: 82.5 %

Procedure:
To a solution of 1-methyl-6-methylsulfanyl-1H-indole (658 mg, 3.71 mmol) in Et2O(7 ml) at 0° C., was added oxalyl chloride (0.55 ml, 6.31 mmol). After stirring for 3 hours, the orange solid was collected, washed with Et2O, and dried to afford (1-methyl-6-methylsulfanyl-1H-indol-3-yl)-oxo-acetyl chloride (819 mg, 66%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:18])[CH:12]([OH:17])[C:13]([OH:16])([CH3:15])[CH3:14])(=O)[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH2:5]([NH:10][CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:18])[CH:12]([OH:17])[C:13]([OH:16])([CH3:15])[CH3:14])[CH3:2])[CH:4]=[CH2:1]
Reactant: CC(=O)c1ccccc1NC(=O)C(O)C(C)(C)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=CCNC(C)c1ccccc1NC(=O)C(O)C(C)(C)O

Procedure:
Prepared analogously to Example 11, starting with the product of Example 13 in 29% isolated yield (mixture of diastereomers), from flash column chromatography in ethyl acetate-hexane (3:2 to 4:1). 1H NMR (250 MHz, CDCl3) δ 8.35-8.18 (m, 1H), 7.30-7.19 (m, 1H), 7.15-6.98 (m, 2H), 5.99-5.77 (m, 1H), 5.23-5.03 (m, 2H), 4.06-3.91 (m, 2H), 3.13 (d, J=5.6 Hz, 2H), 1.42 (d, J=6.7 Hz, 3H), 1.31 (s, 3H), 1.29 (d, J=2.5 Hz, 3H).