Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+].[F:17][C:18]1[CH:19]=[CH:20][C:21]([OH:51])=[C:22](/[CH:24]=[CH:25]/[CH:26]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([O:49][CH3:50])=[O:48])=[CH:43][CH:42]=2)[CH2:27][CH2:28][C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[CH:23]=1>CN(C=O)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([O:51][CH2:2][CH2:3][CH2:4][N:5]2[CH2:9][CH2:8][CH2:7][C:6]2=[O:10])=[C:22](/[CH:24]=[CH:25]/[CH:26]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([O:49][CH3:50])=[O:48])=[CH:43][CH:42]=2)[CH2:27][CH2:28][C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[CH:23]=1
Reactant: COC(=O)c1ccc(CCC(/C=C/c2cc(F)ccc2O)CCc2ccc(C(=O)OC)cc2)cc1
Reactant: O=C1CCCN1CCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCC(/C=C/c2cc(F)ccc2OCCCN2CCCC2=O)CCc2ccc(C(=O)OC)cc2)cc1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
146 mg (0.91 mmol) of 1-(3-chloropropyl)pyrrolidin-2-one [CAS Reg. No. 91152-30-6] and 295 mg (0.91 mmol) of anhydrous cesium carbonate are added to a solution of 215 mg (0.45 mmol) of methyl 4-[(4E)-5-(5-fluoro-2-hydroxyphenyl)-3-{2-[4-(methoxycarbonyl)phenyl]ethyl}pent-4-en-1-yl]benzoate in 5 ml of dry DMF, and the mixture is then stirred at 60° C. for 12 h. The mixture is then filtered, and the filtrate is evaporated to dryness. The residue is purified by preparative HPLC. This gives 165 mg (purity 93%, 0.25 mmol, 56% of theory) of a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[O:5][C:4]([CH:8]=[CH2:9])=[N:3]1.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH2:15]>COC(C)(C)C>[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH:15][C:6]([C:2]([NH:3][C:4](=[O:5])[CH:8]=[CH2:9])([CH3:10])[CH3:1])=[O:7]
Reactant: C=CC1=NC(C)(C)C(=O)O1
Reactant: COC(CN)OC
Solvent: COC(C)(C)C
Product: C=CC(=O)NC(C)(C)C(=O)NCC(OC)OC

Procedure:
62.62 g (0.45 mol) of 4,4-dimethyl-2-vinyl-4H-oxazol-5-one (azalactone) are introduced into 275 g of tert-butyl methyl ether. 47.34 g (0.45 mol) of aminoacetaldehyde dimethyl acetal are slowly added with stirring. The product is formed as a white precipitate, which is filtered off, washed with tert-butyl methyl ether and dried, giving 106 g (96.5% of theory) of a white product of melting point 80-82° C.
Reaction SMILES: CON(C)[C:4](=[O:21])[CH:5]([C:13]1[CH:17]=[C:16]([S:18][CH3:19])[N:15]([CH3:20])[N:14]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH:23]([Mg]Br)=[CH2:24].Cl>O1CCCC1>[CH3:20][N:15]1[C:16]([S:18][CH3:19])=[CH:17][C:13]([CH:5]([CH2:6][CH:7]2[CH2:8][CH2:9][O:10][CH2:11][CH2:12]2)[C:4](=[O:21])[CH:23]=[CH2:24])=[N:14]1
Reactant: CON(C)C(=O)C(CC1CCOCC1)c1cc(SC)n(C)n1
Reactant: C=C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)C(CC1CCOCC1)c1cc(SC)n(C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of N-methoxy-N-methyl-2-[1-methyl-5-(methylsulfanyl)-1H-pyrazol-3-yl]-3-(tetrahydro-2H-pyran-4-yl)propanamide (0.80 g) in tetrahydrofuran (30 mL) was slowly added vinylmagnesium bromide (1.0M tetrahydrofuran solution: 7.3 ml) at room temperature under a nitrogen atmosphere, and the mixture was stirred for 30 min. The reaction mixture was poured into an ice-cooled 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (0.60 g, yield 83%) as a colorless oil from the fraction eluted with ethyl acetate-hexane (4:1, volume ratio). MS: 295 (MH+).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]1[CH2:8][CH2:7]1)[CH2:2][CH3:3].C[Al](C)C.CCCCCCC.CO[C:22]([C:24]1[N:25]([CH3:41])[N:26]=[C:27]2[C:32]=1[CH:31]=[CH:30][CH:29]=[C:28]2[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[Cl:40])=[O:23].[OH-].[Na+]>C1C=CC=CC=1>[CH:6]1([CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[C:22]([C:24]2[N:25]([CH3:41])[N:26]=[C:27]3[C:32]=2[CH:31]=[CH:30][CH:29]=[C:28]3[C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=2[Cl:40])=[O:23])[CH2:8][CH2:7]1
Reactant: CCCNCC1CC1
Reactant: COC(=O)c1c2cccc(-c3ccc(Cl)cc3Cl)c2nn1C
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: c1ccccc1
Product: CCCN(CC1CC1)C(=O)c1c2cccc(-c3ccc(Cl)cc3Cl)c2nn1C
Temperature: 79 °C
Yield: 47.1 %

Procedure:
To a solution of N-propylcyclopropanemethyl amine (0.69 mL, 4.8 mmol) in 12 mL of benzene was slowly added a 2M solution of trimethylaluminum in heptane (2.4 mL, 4.8 mmol), and the solution was stirred for 75 m. The solution was transferred with a pipette to a solution of 35b (0.200 g, 0.597 mmol) in 10 mL of benzene. The solution was heated to 79° C., stirred for 2 d, then cooled to 0-5° C. A 2 M aqueous NaOH solution (20 mL) was slowly added, and the mixture was extracted with three 20 mL portions of dichloromethane. The combined organic layers were washed with 40 mL of a saturated NaCl solution, dried over MgSO4, filtered, and concentrated to a brown oil. Column chromatography (0→20% EtOAc/hexanes) afforded 7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole-3-carboxylic acid cyclopropylmethyl-propyl-amide (35c: 0.117 g; 47%) as an oil.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]([CH3:43])([CH3:42])[C:37]([O:39]CC)=[O:38])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:44][CH2:45][NH:46][S:47]([CH2:50][C:51]1[CH:56]=[CH:55][C:54]([Cl:57])=[C:53]([Cl:58])[CH:52]=1)(=[O:49])=[O:48])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>CO>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]([CH3:43])([CH3:42])[C:37]([OH:39])=[O:38])=[CH:31][CH:30]=2)(=[O:27])=[O:28])=[C:15]1[CH2:44][CH2:45][NH:46][S:47]([CH2:50][C:51]1[CH:56]=[CH:55][C:54]([Cl:57])=[C:53]([Cl:58])[CH:52]=1)(=[O:49])=[O:48])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(C)(C)Cc1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(Cc1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1)C(=O)O
Yield: 93.9 %

Procedure:
Ethyl 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino)-ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]-2,2-dimethylpropanoate (0.04 g, 0.05 mmol), THF (0.5 mL), MeOH (0.5 mL), and 1N NaOH (0.5 mL) were stirred together overnight. Solvents were removed and the resulting residue was taken up in water. The solution was acidified with 1N HCl and extracted with ethyl acetate. The extract was dried over sodium sulfate, and evaporated. The resulting residue was triturated with a mixture of ether and hexanes to give 0.04 g of 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]-2,2-dimethylpropanoic acid as a white solid; mp 207-208° C.; MS (ESI) m/z 849.1 (M−H); HRMS: calcd for C43H41Cl3N2O6S2, 850.1472; found (ESI+), 851.1545.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:5]=[C:6]([OH:12])[C:7](=[CH:10][CH:11]=1)[CH:8]=O)[CH3:2].[CH3:15][O:16][C:17]([CH2:19][C:20]([CH2:22][C:23](OC)=[O:24])=[O:21])=[O:18]>>[CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:5]=[C:6]2[C:7]([CH:8]=[C:22]([C:20]([CH2:19][C:17]([O:16][CH3:15])=[O:18])=[O:21])[C:23](=[O:24])[O:12]2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Reactant: COC(=O)CC(=O)CC(=O)OC
Product: CCN(CC)c1ccc2cc(C(=O)CC(=O)OC)c(=O)oc2c1

Procedure:
A solution of 1.93 g 4-diethylaminosalicylaldehyde, 1.80 g. dimethyl 1,3-acetone dicarboxylate in 10 ml. alcohol containing 10 drops piperidine was heated under reflux on a steam bath for 2 hours. After chilling in the freezer, the product was collected and recrystallized from a mixture of alcohol and acetonitrile. Yield 2.6 g (82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][NH:21][CH2:22][C:17]=4[O:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:24][N:25]([CH3:32])[CH2:26]/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21]([C:29](=[O:30])/[CH:28]=[CH:27]/[CH2:26][N:25]([CH3:32])[CH3:24])[CH2:22][C:17]=4[O:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: Clc1ccc(Nc2ncnc3oc4c(c23)CCNC4)cc1Cl
Agent: Cl
Product: CN(C)C/C=C/C(=O)N1CCc2c(oc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1

Procedure:
In analogy to Example 89, the title compound was prepared from N-(3,4-dichlorophenyl)-5,6,7,8-tetrahydropyrido[4′,3′:4,5]furo[2,3-d]pyrimidin-4-amine from Example 41A (100 mg, 0.30 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (69 mg, 0.42 mmol) to yield 75 mg (56%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[NH:13][C:12]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:27][N:28]([CH2:31][CH2:32]Cl)[CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[ClH:25].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[N:13]([CH2:30][CH2:29][N:28]([CH3:27])[CH2:31][CH3:32])[C:12]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2OC(C)=O)cc1
Reactant: CCN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(C)CCN1C(=O)[C@H](OC(C)=O)[C@H](c2ccc(OC)cc2)Sc2cc(Cl)ccc21
Yield: 155.8 %

Procedure:
A mixture of 1 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 0.5 g of 2-(N-methyl-N-ethylamino)ethyl chloride hydrochloride, 0.95 g of potassium carbonate and 20 ml of acetone is treated in the same manner as described in Example 1. The product thus obtained is converted into its hydrochloride and recrystallized from a mixture of chloroform, ethanol and ether. 1.03 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-methyl-N-ethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride are thereby obtained.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C@@H:15]2[CH2:19][S:18][C:17]([C:20]3[NH:21][C:22]4[C:27]([CH:28]=3)=[CH:26][C:25]([Cl:29])=[CH:24][C:23]=4[NH:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[N:16]2)[CH2:9]1)(C)(C)C.O1CCOCC1.Cl>ClCCl>[NH2:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C@@H:15]2[CH2:19][S:18][C:17]([C:20]3[NH:21][C:22]4[C:27]([CH:28]=3)=[CH:26][C:25]([Cl:29])=[CH:24][C:23]=4[NH:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[N:16]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCOCC5)c4[nH]3)=N2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@H]1CCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCOCC5)c4[nH]3)=N2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.1 %

Procedure:
[(S)-1-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-pyrrolidin-3-yl]-carbamic acid t-butyl ester (150 mg, 0.27 mmol) prepared in Example 169 was dissolved in dichloromethane (30 mL). 4N hydrochloric acid dioxane solution (0.34 mL, 1.35 mmol) was added thereto, and the mixture was stirred for 4 h at room temperature. After completion of the reaction, the solvent was removed under reduced pressure. The residue was recrystallized from DCM/ethylether to give the title compound (92 mg, Yield 75%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([CH3:10])[CH:9]=1)([CH3:3])[CH3:2].[F:12][CH2:13][N:14]([CH2:18][F:19])[C:15](F)=[O:16].C(N(CC)CC)C>C(Cl)Cl>[F:12][CH2:13][N:14]([CH2:18][F:19])[C:15](=[O:16])[O:11][C:6]1[CH:7]=[C:8]([CH3:10])[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1
Reactant: O=C(F)N(CF)CF
Reactant: Cc1cc(O)cc(C(C)C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(OC(=O)N(CF)CF)cc(C(C)C)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
16 parts of 80 percent strength by weight 3-isopropyl-5-methyl-phenol in 30 parts of methylene chloride are added to 12.7 parts of N,N-bis-fluoromethyl-carbamic acid fluoride (from Example 2) in 50 parts of methylene chloride. 10.1 parts of triethylamine in 20 parts of methylene chloride are then added. The reaction mixture is stirred for one hour at 40° C. and when it has cooled it is extracted by shaking with 10 percent strength by weight sodium hydroxide solution and water, dried and distilled to dryness under reduced pressure. 24.1 parts (95% of theory) of O-3-isopropyl-5-methyl-phenyl N,N-bis-fluoromethyl-carbamate of boiling point 120° C./0.05 mm Hg are obtained.
Reaction SMILES: Cl.Cl.C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)C=CC=CC=1.CC(C)([O-])C.[K+].C[O:36][C:37]1[C:42]([CH2:43][N:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH:45]2[CH2:50][CH:51]=O)=[CH:41][CH:40]=[CH:39][N:38]=1.O>CN(C=O)C>[O:36]=[C:37]1[C:42]([CH2:43][N:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH:45]2[CH2:50][CH2:51][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:41][CH:40]=[CH:39][NH:38]1
Reactant: COc1ncccc1CN1CCCCC1CC=O
Reactant: c1ccc([P+](Cc2ccccn2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]cccc1CN1CCCCC1CCCc1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20.3 %

Procedure:
In DMF was dissolved 2.1 g of triphenyl(2-pyridylmethyl)phosphonium dihydrochloride, followed by adding 1.4 g of potassium tert-butoxide thereto at room temperature under stirring. After 15 minutes, a solution of 1.25 g of 2-[1-[(2-methoxy-3-pyridyl)methyl]-2-piperidyl]acetaldehyde dissolved in DMF was added dropwise into the above-mentioned solution at room temperature under stirring, and the mixture was left overnight. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1, subsequently ethyl acetate, and subsequently ethyl acetate:methanol=4:1). 760 mg of the resulting brown oil, 0.56 ml of thionyl chloride and 10 ml of ethanol were stirred under reflux for 30 minutes. The reaction solution was cooled to room temperature, a 2N aqueous sodium hydroxide was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1, subsequently ethyl acetate, and subsequently ethyl acetate:methanol=4:1). The resulting yellow oil (350 mg) was dissolved in 10 ml of ethanol, 100 mg of 10% palladium-carbon (water-containing product) was added thereto, and the mixture was catalytically hydrogenated at normal pressure under stirring for 1.5 hours. The catalyst was filtered off and the solvent was evaporated. The residue was purified by NH-silica gel chromatography (ethyl acetate, subsequently ethyl acetate:methanol=4:1), to give 310 mg of an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[CH:3]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:26]=[O:27]>O>[NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[C:3]=1[CH:26]=[O:27]
Reactant: CN(C)C=O
Reactant: Cn1c(=O)cc(N)n(-c2ccccc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c(=O)c(C=O)c(N)n(-c2ccccc2)c1=O
Yield: 75 %

Procedure:
6-Amino-3-methyl-1-phenyl-2,4 (1H, 3H)-pyrimidinedione (5.00 g, 23 mmol) was suspended in dimethylformamide (77 ml). To the resultant suspension was added phosphorus oxychloride (2.57mL,27.6 mmol), and the resultant mixture was reacted at 60° C. for 3 h. The reaction mixture was diluted with water, and adjusted to ca. pH 12 with sodium hydroxide. The precipitates formed in the reaction mixture was filtered to give a crude product. The crude product was recrystallized from a mixture of ethanol, ethyl acetate and water to give an aldehyde, 6-amino-5-formyl-3-methyl-1-phenyl-2,4 (1H, 3H)-pyrimidinedione (yield 75%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:16](=[O:17])[CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([Mg]Br)[CH:26]=[CH2:27]>C1COCC1>[CH2:27]([C:16]1([OH:17])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:13][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1)[CH:26]=[CH2:25]
Reactant: CC(C)(C)OC(=O)N1CC(=O)[C@@H](NC(=O)OCc2ccccc2)C1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCC1(O)CN(C(=O)OC(C)(C)C)C[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.44 g of the ketone of step B in 20 mL of anhydrous THF cooled at 0° C. was added a solution of 6.2 mL of 1 M allyl magnesium bromide. The color turned dark right away. After being stirred at room temperature overnight, the reaction mixture was quenched with 50/50 mL of EtOAc/water. Water phase was extracted twice with EtOAc. The combined organic phase was dried over Na2SO4 and concentrated under vacuum. Column chromatography on silica gel using 3:1˜2:1 hexane/EtOAc as eluent provided 0.85 g of the title compound. MS (M+H)+377.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[CH:9]=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)([OH:14])N.Cl([O-])=O.[Na+].S([O-])(O)=O.[Na+]>C(Cl)CCl.O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:11])[C:9]([OH:14])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C=O)c1ccc(I)cc1
Reactant: NS(=O)(=O)O
Agent: O=S([O-])O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: ClCCCl
Solvent: O
Product: CC(C(=O)O)c1ccc(I)cc1
Reaction time: 0.17 h
Yield: 94.2 %

Procedure:
To a solution of 34 g of 2-(4-iodophenyl)propionaldehyde in 100 ml of ethylene chloride was added a solution of 16.5 g of sulfamic acid in 85 ml of water. To the mixture was added dropwise with stirring a solution of 15.2 g of sodium chlorite in 22 ml of water, while maintaining the temperature at 10° to 15° C. After stirring for 10 minutes, about 15 g of sodium hydrogensulfite was added in small portions to the mixture. The organic layer was separated, washed with water, and mixed with 150 ml of 1 N sodium hydroxide solution. The aqueous layer was separated and adjusted to pH 3.0 with 6 N hydrochloric acid to precipitate white crystals. The crystals were collected by filtration, washed with water, and dried to obtain 34 g (94% yield) of 2-(4-iodophenyl)propionic acid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>C(#N)C>[N:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:24][CH2:25][N:26]([CH2:2][C:3]([C:5]3[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:27][CH2:28]2)=[CH:19][CH:18]=1
Reactant: COC(=O)COc1ccc(C(=O)CBr)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CC#N
Product: COC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 1.5 h

Procedure:
A solution of methyl 4-bromoacetylphenoxyacetate (4.3 g) in acetonitrile (50 ml) was added dropwise over 40 minutes to a stirred solution of 1-(4-pyridyl)piperazine (4.9 g) in acetonitrile (100 ml). Stirring was continued for a further 1.5 hours, then the solution was filtered and the filtrate evaporated in vacuo. The solid residue was triturated with water (50 ml), then dried and suspended in methylene chloride (50 ml). The suspension was then filtered and the filtrate concentrated to a small volume. Purification by flash chromatography on neutral alumina eluting first with dichloromethane, then 0.5% v/v methanol/dichloromethane and finally 1% v/v methanol/dichloromethane gave the title compound, 1.93 g, as a solid: m.p. 150°-152° C.; NMR(d6DMSO) δ 8.14(2H,d), 7.98(2H,d), 7.03(2H,d), 6.78(2H,d), 4.90(2H,s), 3.83(2H,s), 3.72(3H,s), 3.34(4H,bt), 2.65(4H,bt); m/e 370 (M+H)+ ; calculated for C20H23N3O4 : C, 65.0; H, 6.3; N, 11.4. found: C, 65.2; H, 6.4; N, 11.3%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)=[CH:23][C:22]=1[CH2:35]O.[Br:37]C(Br)(Br)Br.CCCCC>ClCCl>[Br:37][CH2:35][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][C:21]=1[F:20])[CH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1
Reactant: OCc1cc(COC2CCCCO2)ccc1F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: ClCCl
Product: Fc1ccc(COC2CCCCO2)cc1CBr
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
4.44 g (16.94 mmol) triphenylphosphine in 10 ml dichloromethane is added in drops to an ice-cold solution of 3 g (12.49 mmol) [2-fluoro-5-(tetrahydropyrane-2-yloxymethyl)-phenyl]methanol and (15.61 mmol) tetrabromomethane in 30 ml anhydrous dichloromethane and stirred for another 45 minutes at 0° C. The reaction solution is mixed with pentane, the precipitation is suctioned off and washed with dichloromethane. The filtrate is washed with 5% sodium hydrogen carbonate solution, water and sodium chloride solution and dried over magnesium sulfate. After removing the solvent, the residue is purified by way of column chromatography on silica gel using diethyl ether/petrol ether 1:10.
Reaction SMILES: [CH:1]([NH2:3])=[O:2].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][CH:6]=1>>[CH:1]([NH:3][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([Cl:4])=[CH:6][CH:7]=1)[CH3:12])=[O:2]
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: NC=O
Product: CC(NC=O)c1ccc(Cl)cc1
Yield: 99.7 %

Procedure:
In the same manner as in Example 1 except that 110.7 g of formamide was used in place of ammonium formate and 126.7 g of 4'-chloroacetophenone was used in place of acetophenone, the reaction and post treatment were carried out to obtain 150 g of crude N-formyl-1-(4-chlorophenyl)ethylamine; the purity: 87.4%.
Reaction SMILES: C1(CC[C@H](OC2CCCCO2)/C=C/[C@@H:12]2[C@@H:19]3[C@@H:15]([O:16][C:17](=[O:20])[CH2:18]3)[CH2:14][C@H:13]2OC2CCCCO2)C=CC=CC=1>CCOC(C)=O.[Pd].[C]>[O:16]1[C:17](=[O:20])[CH:18]=[C:19]2[CH:12]=[CH:13][CH:14]=[C:15]12
Reactant: O=C1C[C@@H]2[C@@H](/C=C/[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1C=C2C=CC=C2O1
Yield: 403.9 %

Procedure:
A solution of the lactone 6 (6.44 g, 13.4 mmol) in 50 mL of EtOAc was hydrogenated in the presence of 10% Pd/carbon (0.15 g) at 40 psi in a Parr hydrogenation apparatus for 4 h. The reaction mixture was filtered through Celite and the filtrate was concentrated to afford 7 (6.5 g, 99% yield) as a colorless oil. 1H-NMR (CDCl3) δ (characteristic peaks only) 7.22 (m, 5H), 5.00 (m, 1H), 4.76 (m, 2H), 3.52 (m, 2H).
Reaction SMILES: [CH:1]([CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[C:5]1=[O:14])=[O:2].S(=O)(O)[O-].[Na+].[C-:20]#[N:21].[Na+]>O.CCOCC>[C:20]([CH:1]([OH:2])[CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[C:5]1=[O:14])#[N:21]
Reactant: CN1C(=O)C(CC=O)c2ccccc21
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CN1C(=O)C(CC(O)C#N)c2ccccc21
Temperature: 25 °C

Procedure:
89 Grams of 3-formylmethyl-1-methyloxindole and 54 g of sodium bisulfite was dissolved in a mixed solvent of 75 ml of water with 150 ml of ether, then to the resultant mixture was added dropwise a solution of 28 g of sodium cyanide with 60 ml of water, under stirring at a room temperature. The reaction mixture was stirred for 1 hour, then water was added to the reaction mixture until the crystals formed were dissolved, the whole reaction mixture was further stirred for 1 hour. The crystals formed were collected by filtration, washed with water, dried and recrystallized from benzene to obtain 30 g of 3-(2-cyano2-hydroxyethyl)-1-methyloxindole in the form of white powdery substance. Melting point: 136°-138°C.)