Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C@@H:5]1[NH:29][C:27](=[O:28])[C@@H:26]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH3:39])=[CH:35][CH:36]=2)[NH:25][C:23](=[O:24])[CH2:22][CH2:21][S:20][S:19][CH2:18][C@@H:17]([C:40]([N:42]2[C@H:46]([C:47]([NH:49][C@H:50]([C:55]([NH:57][CH2:58][C:59]([NH2:61])=[O:60])=[O:56])[CH2:51][CH2:52][CH2:53][NH2:54])=[O:48])[CH2:45][CH2:44][CH2:43]2)=[O:41])[NH:16][C:14](=[O:15])[C@H:13]([CH2:62][C:63]([NH2:65])=[O:64])[NH:12][C:10](=[O:11])[C@H:9]([C@H:66]([OH:68])[CH3:67])[NH:8][C:6]1=[O:7])[CH3:4].O.N.OO>C(#N)C>[CH3:1][CH2:2][C@@H:3]([C@@H:5]1[NH:29][C:27](=[O:28])[C@@H:26]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH3:39])=[CH:35][CH:36]=2)[NH:25][C:23](=[O:24])[CH2:22][CH2:21][S:20][S:19][CH2:18][C@@H:17]([C:40]([N:42]2[C@H:46]([C:47]([NH:49][C@H:50]([C:55]([NH:57][CH2:58][C:59]([NH2:61])=[O:60])=[O:56])[CH2:51][CH2:52][CH2:53][NH2:54])=[O:48])[CH2:45][CH2:44][CH2:43]2)=[O:41])[NH:16][C:14](=[O:15])[C@H:13]([CH2:62][C:63]([NH2:65])=[O:64])[NH:12][C:10](=[O:11])[CH:9]([C@H:66]([OH:68])[CH3:67])[NH:8][C:6]1=[O:7])[CH3:4]
Reactant: CCOc1ccc(C[C@H]2NC(=O)CCSSC[C@@H](C(=O)N3CCC[C@H]3C(=O)N[C@@H](CCCN)C(=O)NCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H]([C@@H](C)CC)NC2=O)cc1
Agent: N
Agent: OO
Solvent: CC#N
Solvent: O
Product: CCOc1ccc(C[C@H]2NC(=O)CCSSC[C@@H](C(=O)N3CCC[C@H]3C(=O)N[C@@H](CCCN)C(=O)NCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)C([C@@H](C)O)NC(=O)[C@H]([C@@H](C)CC)NC2=O)cc1
Reaction time: 0.17 h

Procedure:
2.85 g of atosiban acetate is prepared by dissolving the linear atosiban obtained from Example 2 in 250 ml of 5% acetonitrile aqueous solution, adjusting the pH value to 8 to 9 with 30% ammonia water, adding 0.60 g of H2O2, reacting for 10 min at 25° C., monitoring with HPLC (HPLC: 75.6%), filtering after reaction, purifying filtrate by preparative RP-HPLC (column C18 or C8), transferring salt, and freeze-drying, MS: 994.5, HPLC: 99.4%.
Reaction SMILES: [Br-:1].[CH3:2][N+:3]1([CH3:22])[C:12]2[C:7](=[C:8]([N:14]=NC3C=CC=CC=3)[CH:9]=[CH:10][C:11]=2[OH:13])[CH2:6][CH2:5][CH2:4]1.CO.[H][H]>[Pd].O>[Br-:1].[CH3:2][N+:3]1([CH3:22])[C:12]2[C:7](=[C:8]([NH2:14])[CH:9]=[CH:10][C:11]=2[OH:13])[CH2:6][CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: C[N+]1(C)CCCc2c(N=Nc3ccccc3)ccc(O)c21
Agent: [Pd]
Agent: [Br-]
Solvent: CO
Solvent: O
Product: C[N+]1(C)CCCc2c(N)ccc(O)c21

Procedure:
Into a stainless steel autoclave, one introduces 36.2 g of N,N-dimethyl-1,2,3,4-tetrahydro-5-phenylazo-8-hydroxyquinolinium bromide (i.e. 0.1 mole), 200 ml of methanol and 3 g of 5% palladium on charcoal. The reduction is carried out at a pressure of 3-5 kg/cm2 of hydrogen and a temperature of 50°-60°C. After cooling, one adds a sufficient quantity of water to dissolve the entire mass, then one filters off the catalyst. One evaporates the filtrate to the dry state. The residue is extracted by means of ether so as to remove the aniline. One washes, with acetone, the clear brown compound that is obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1.[C:22](O)(=[O:24])[CH3:23].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[C:22]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1)(=[O:24])[CH3:23]
Reactant: NCc1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)NCc1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Reaction time: 1 h
Yield: 89.8 %

Procedure:
6-(5-Aminomethyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (38 mg, 0.13 mmol), acetic acid (0.015 mL, 0.27 mmol) and triethyl amine (0.056 mL, 0.40 mmol) are mixed in 2.5 mL of acetonitrile. Then TBTU (52 mg, 0.16 mmol) is added and the mixture is stirred for 1 hrs. All the solvents are removed and the residue is first purified by flash column chromatography and then filtered through a StratoSpheres SPE cartridge (PL-HCO3 MP SPE) to remove the HOBt. The filtrate is concentrated and dried to give 38 mg of the titled product.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]([OH:23])=O)[C:17]=3[CH:24]=2)[C:3]1=[O:25].C(Cl)(=O)C(Cl)=O.Cl.[CH3:33][O:34][NH2:35].C(N(CC)CC)C>CN(C)C=O.O1CCCC1.C(Cl)Cl>[CH3:1][N:2]1[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]([NH:35][O:34][CH3:33])=[O:23])[C:17]=3[CH:24]=2)[C:3]1=[O:25]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(=O)O)c3c2)c1=O
Reactant: CON
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CONC(=O)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 0 °C
Yield: 5.6 %

Procedure:
To a mixture of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxylic acid (4.00 g, 0.0108 mol), methylene chloride and tetrahydrofuran on an ice bath is added N,N-dimethylformamide (5 drops) followed by oxalyl chloride (13.5 ml, 0.0269 mol). The resultant mixture is stirred 90 minutes at ambient temperature and concentrated in vacuo. The residue is taken up in tetrahydrofuran and 25% of the solution is added to a mixture of O-methyl hydroxylamine hydrochloride (0.900 g, 0.0108 mol), tetrahydrofuran and triethylamine (2.25 ml, 0.0162 mol). The resultant mixture is stirred overnight at room temperature, poured into ice water, and extracted with methylene chloride. The organic layers are dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue is chromatographed on silica gel with methylene chloride to give the title compound as a light yellow solid (0.240 g, 22.3%, mp 125-127° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:18]([O:20][CH3:21])=[O:19])=[C:11]([CH2:13][O:14]COC)[N:12]=2)=[CH:4][CH:3]=1.Cl>CO.Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([C:18]([O:20][CH3:21])=[O:19])=[C:11]([CH2:13][OH:14])[N:12]=2)=[CH:6][CH:7]=1
Reactant: COCOCc1nc(-c2ccc(Cl)cc2)oc1C(=O)OC
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)c1oc(-c2ccc(Cl)cc2)nc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
144 mg (0.52 mmol) of the compound from Example 43A are initially charged in 0.5 ml of methanol, and 0.13 ml of 4 N hydrochloric acid are added. 3 drops of conc. hydrochloric acid are then added. The reaction mixture is stirred at RT for 8 h. The mixture is then diluted with about 5 ml of water and extracted three times with in each case 10 ml of diethyl ether. The combined organic phases are dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The product obtained is used without further purification in the subsequent reaction.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)=[C:9]([CH3:23])[CH:8]=1.[CH3:24]C(C)([O-])C.[K+].IC.CCOCC>CN(C=O)C.C(OCC)(=O)C.ClCCl>[CH3:24][N:6]1[CH2:5][CH2:4][N:3]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:18]=3)=[C:9]([CH3:23])[CH:8]=2)[C:2]1=[O:1]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1ccc(-c2ccc(N3CCNC3=O)cc2C)cc1
Agent: [K+]
Solvent: ClCCl
Solvent: CI
Solvent: CCOCC
Product: COC(=O)c1ccc(-c2ccc(N3CCN(C)C3=O)cc2C)cc1
Reaction time: 1 h
Yield: 94.3 %

Procedure:
Methyl 4'-(4,5-dihydro-2-oxoimidazol-1-yl)-2'-methylbiphenyl-4-carboxylate (D18) (0.208 g, 0.67 mmol) was stirred in dry DMF (5 ml). Potassium t-butoxide (0.10 g, 0.82 mmol) and iodomethane (0.065 ml, 1.0 mmol) were added. The mixture was stirred for 1 h, diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated to give a gum. Chromatography on silica eluting with 50% ether in dichloromethane gave the title compound (0.205 g, 94%) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[N:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[ClH:31]>ClCCl.O1CCOCC1>[ClH:31].[N+:21]([C:18]1[N:17]=[CH:16][C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:20][CH:19]=1)([O-:23])=[O:22].[ClH:31]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc([N+](=O)[O-])nc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(NC2CCNCC2)cn1
Reaction time: 0.5 h

Procedure:
4-(6-nitro-pyridin-3-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (200 mg; 0.62 mmol, prepared in accordance with Example 93) is dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) is added under stirring. After 30 minutes, the reaction mixture is concentrated under reduced pressure and the residue obtained is co-evaporated with dichloromethane (2×10 mL). The product is then diluted in dioxane (3 mL) and a 4N solution of hydrochloric acid in dioxane (3 mL) is added. The precipitate formed is filtered and dried under high vacuum at 40° C. to afford the desired product as hydrochloride (159 mg; 0.61 mmol).
Reaction SMILES: Cl.O1CCN(C2C=C3C(=CC=2)C(=O)CCC3)CC1.Cl.C(N1CCNCC1)(C1C=CC=CC=1)C1C=CC=CC=1.C=O.C(=O)([O-])O.[Na+].[CH:46]([N:59]1[CH2:64][CH2:63][N:62]([CH2:65][CH:66]2[CH2:75][CH2:74][C:73]3[C:68](=[CH:69][CH:70]=[C:71]([N:76]4[CH2:81][CH2:80][O:79][CH2:78][CH2:77]4)[CH:72]=3)[C:67]2=[O:82])[CH2:61][CH2:60]1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.[BH4-].[Na+]>CO.C(O)C>[CH:46]([N:59]1[CH2:60][CH2:61][N:62]([CH2:65][CH:66]2[CH2:75][CH2:74][C:73]3[C:68](=[CH:69][CH:70]=[C:71]([N:76]4[CH2:81][CH2:80][O:79][CH2:78][CH2:77]4)[CH:72]=3)[CH:67]2[OH:82])[CH2:63][CH2:64]1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=C1c2ccc(N3CCOCC3)cc2CCC1CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Solvent: CO
Product: OC1c2ccc(N3CCOCC3)cc2CCC1CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 240 h

Procedure:
In 50 ml. of ethanol was dissolved a mixture of 2 g. of 6-morpholino-3,4-dihydro-1(2H)-naphthalenone hydrochloride, 4 g. of 1-benzhydrylpiperazine hydrochloride and 4 g. of a 37% aqueous solution of formalin. The solution was allowed to stand at room temperature for 10 days, after which it was neutralized with an aqueous solution of sodium hydrogen carbonate and extracted with 100 ml. of chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. By the above procedure there was obtained 5 g. of 2-[(4-benzhydryl-1-piperazinyl)methyl]-6-morpholino-3,4-dihydro-1(2H)-naphthalenone as colorless oil. IRνc=o neat 1665 cm-1. This oil was dissolved in 50 ml. of methanol and stirred with 3 g. of sodium borohydride at room temperature for 30 minutes. The reaction mixture was diluted with 500 ml. of water and extracted with 150 ml. of chloroform. The extract was dried and distilled under reduced pressure to remove the solvent, whereupon 4.5 g. of 2-[(4-benzhydryl-1-piperazinyl)methyl]-6-morpholino-1,2,3,4-tetrahydro-1-naphthalenol was obtained as an oil. A portion of this oil was purified by chromatography on a column of silica gel and lead to its fumarate melting at 184°-187° C.(decomposition).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:27].[C:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:39])[CH3:38]>O>[C:37]([N:40]1[CH2:45][CH2:44][N:43]([C:16]2[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]3[C:8](=[O:27])[N:7]([CH2:6][C:5]4[CH:4]=[C:3]([C:2]([F:36])([F:35])[F:1])[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=4)[CH2:14][CH2:13][CH2:12][O:11][C:10]=3[N:15]=2)[CH2:42][CH2:41]1)(=[O:39])[CH3:38]
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1ccccc1-c1cc(Cl)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Solvent: O
Product: CC(=O)N1CCN(c2cc(-c3ccccc3C)c3c(n2)OCCCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C3=O)CC1
Temperature: 150 °C
Reaction time: 5 h
Yield: 38 %

Procedure:
A mixture of 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (compound of Reference Example 17; 100 mg) and 1-acetylpiperazine (73.0 mg) was stirred at 150° C. for 5 hours. To the resulting residue, water was added, and then the mixture was subjected to extraction with ethyl acetate. The resulting extract was dried on anhydrous sodium sulfate. The solvent was removed by distillation to obtain a residue, and then the residue was purified on silica gel column chromatography (ethyl acetate: methanol=10:1) to obtain 9-(4-acetylpiperazine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (44.6 mg, 38%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:40])=[C:9]([CH2:11][O:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][N:18]3[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[C:20](OS(C(F)(F)F)(=O)=O)=[N:19]3)=[CH:15][CH:14]=2)[N:10]=1.[F:41][C:42]([F:53])([F:52])[C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+].Cl>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.O1CCCC1.C(O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:40])=[C:9]([CH2:11][O:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][N:18]3[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C:20]([C:46]4[CH:47]=[CH:48][C:43]([C:42]([F:53])([F:52])[F:41])=[CH:44][CH:45]=4)=[N:19]3)=[CH:15][CH:14]=2)[N:10]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccco2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(-c3ccc(C(F)(F)F)cc3)n2)cc1
Yield: 28.8 %

Procedure:
Tetrakis(triphenylphosphine)palladium (990 mg) was added to a mixture of ethyl 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy)benzyl]-3-trifluoromethanesulfonyloxy-1H-pyrazol-4-yl]propionate (2.50 g), 4-trifluoromethylphenylboronic acid (1.23 g), 2N aqueous sodium carbonate solution (6.5 ml), ethanol (7 ml), and toluene (100 ml). This mixture was refluxed under an argon atmosphere for 13 hours. Ethyl acetate was added to this reaction mixture, which was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio). A mixture of the oily substance obtained, 1N aqueous sodium hydroxide solution (5 ml), ethanol (5 ml), and tetrahydrofuran (5 ml) was stirred at room temperature for 2 hours. The reaction mixture was acidified with dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy)benzyl]-3-(4-trifluoromethylphenyl)-1H-pyrazol-4-yl]propionic acid (680 mg, yield: 29%). This was recrystallized from ethyl acetate-hexane. Melting point: 92–93° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]2[C:5](=[O:23])[N:4]([CH3:24])[C:3]1=[O:25].O.[Li+].[OH-]>C1COCC1.CCOC(C)=O>[CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]2[C:5](=[O:23])[N:4]([CH3:24])[C:3]1=[O:25]
Reactant: COC(=O)CCn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)c2c(-c3ccccc3)n(CCC(=O)O)cc2n(C)c1=O
Temperature: 50 °C

Procedure:
A mixture of methyl 3-(1,3-dimethyl-2,4-dioxo-5-phenyl-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)propanoate (step 2) (3.24 g, 9.49 mmol) in THF (33.9 mL)/water (33.9 mL) and LiOH (2.273 g, 95 mmol) was heated to 50° C. for 1 hr. The reaction mixture was diluted with EtOAc (50 ml) and the layers separated. The organics were then washed with water (3×50 ml). The aqueous extracts were combined and the pH adjusted to approx. pH3 with 5M HCl. The resulting precipitate was isolated using suction filtration.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C([O-])([O-])=O.[K+].[K+].[I-].[K+].[OH:15][C:16]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:17]=1[CH2:18]Br.Cl>CS(C)=O.O>[OH:15][C:16]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:17]=1[CH2:18][N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6]
Reactant: O=[N+]([O-])c1ccc(O)c(CBr)c1
Reactant: O=C1NCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CS(C)=O
Product: O=C1NCCN1Cc1cc([N+](=O)[O-])ccc1O
Reaction time: 1.6 h

Procedure:
A 7.9 g (0.092 mole) portion of 2-imidazolidinone in 92 ml of dimethylsulfoxide was treated with 12.7 g (0.092 mole) of K2CO3, 7.4 g (0.045 mole) of potassium iodide and 20.0 g (0.092 mole) of 2-hydroxy-5-nitrobenzyl bromide. The reaction mixture was heated to 105° over 0.3 hours and held at 105° for 1.6 hours. The reaction mixture was poured with stirring into 550 ml of water. The aqueous mixture was acidified with 9 ml of concentrated HCl and extracted with 480 ml of chloroform. The chloroform extract was washed with 60 ml of H2O, dried over MgSO4 overnight and filtered. The filtrate was concentrated under reduced pressure to give 18 g of a yellow semi-solid. The crude product was crystallized using 65 ml of benzene and filtered, washing with ether to give 9.7 g (44%) of a light yellow semi-solid. Recrystallization from acetonitrile gave an analytical sample, m.p. 222°-224° dec.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[CH:30]=[CH2:31]>O>[CH2:31]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:2][CH2:3]1)[CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN1CCN(c2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.3 %

Procedure:
To a mixture of 1 g of 6-(1-piperazinyl)-3,4-dihydrocarbostyril, 15 ml of DMF and 1.82 g of potassium carbonate was added 500 mg of allyl bromide and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into a large amount of water and extracted with chloroform. After washing with water, the extract was dried over anhydrous sodium sulfate. Then, chloroform was distilled off and the residue was purified through silica gel column chromatography and recrystallized from chloroform-ether to give 0.43 g of 6-(4-allyl-1-piperazinyl)-3,4-dihydrocarbostyril, m.p. 175°-176° C., colorless scales.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCOC(C)=O.FC(F)(F)C(O)=O.[N:32]1([C:41](=[O:48])/[CH:42]=[CH:43]/[C@@H:44]([NH2:47])[CH2:45][CH3:46])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1.[C:49]([O:53][C:54]([NH:56][C:57]1([C:63](O)=[O:64])[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1)=[O:55])([CH3:52])([CH3:51])[CH3:50].CCN(CC)CC>C(Cl)Cl>[N:32]1([C:41](=[O:48])/[CH:42]=[CH:43]/[C@@H:44]([NH:47][C:63]([C:57]2([NH:56][C:54](=[O:55])[O:53][C:49]([CH3:51])([CH3:50])[CH3:52])[CH2:58][CH2:59][O:60][CH2:61][CH2:62]2)=[O:64])[CH2:45][CH3:46])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCOCC1
Reactant: CC[C@H](N)/C=C/C(=O)N1CCc2ccccc21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H](/C=C/C(=O)N1CCc2ccccc21)NC(=O)C1(NC(=O)OC(C)(C)C)CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37.8 %

Procedure:
A solution of 50 wt % ®T3P in EtOAc (1.3 mL, 2.184 mmol) was added dropwise to a solution of [(1S,2E)-4-(2,3-dihydro-1H-indol-1-yl)-1-ethyl-4-oxo-2-buten-1-yl]amine trifluoroacetate (500 mg, 1.452 mmol), 4-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-carboxylic acid (356 mg, 1.452 mmol), and Et3N (1 mL, 7.21 mmol) in CH2Cl2 (5 mL) at 0° C. (bath temp). The ice bath was removed, and the reaction was stirred at RT. After 1 h 20 min, the reaction mixture was washed with saturated aq. NaHCO3 (1×5 mL) and 10% citric acid (1×5 mL). The organic layer was concentrated under a stream of nitrogen, and the residue was purified by flash column chromatography, giving 251 mg (38%) of the title compound. LC-MS m/z 458 (M+H)+, 0.96 (ret time).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:5]=2[N:6]=1.[Cl-].[CH2:13]([O:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][NH2+:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:11][C:8]1[CH:9]=[CH:10][C:4]2[O:3][C:2]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][C@H:23]3[C:21]([O:20][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:22])=[N:6][C:5]=2[CH:7]=1
Reactant: Cc1ccc2oc(Cl)nc2c1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCC[NH2+]1
Agent: [Cl-]
Product: Cc1ccc2oc(N3CCCC[C@H]3C(=O)OCc3ccccc3)nc2c1

Procedure:
The title compound was prepared by a similar method to Preparation 2 from 2-chloro-5-methyl-1,3-benzoxazole [see J.Med.Chem, 1988, 31, 1719-1728] and (2S)-2-[(benzyloxy)carbonyl]piperidinium chloride [see EP 530167 A1 930303]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 90:10 changing to 70:30, by volume, hexane:ethyl acetate to afford benzyl(2S)-1-(5-methyl-1,3-benzoxazol-2-yl)-2-piperidinecarboxylate as an oil.
Reaction SMILES: [C:1]1(C(C2(O)CCCCC2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]([CH3:45])[C:18]=1[C:19]([P:21](=[O:39])(C(=O)C1C(C)=CC(C)=CC=1C)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20].COC(C1C=CC=CC=1)C(C1C=CC=CC=1OC)=O.C(C(N(C)C)(CC)C(C1C=CC(N2CCOCC2)=CC=1)=O)C1C=CC=CC=1.COC1C=CC=C(OC)C=1C(P(=O)(C(=O)C1C(OC)=CC=CC=1OC)CC(C)CC(C)(C)C)=O.OC1(C2C=CC=CC=2C(C2C=CC=CC=2C2(O)CCCCC2)=O)CCCCC1>>[C:22]1([P:21](=[O:39])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:19](=[O:20])[C:18]2[C:40]([CH3:45])=[CH:41][C:42]([CH3:44])=[CH:43][C:17]=2[CH3:16])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(c1ccccc1)C1(O)CCCCC1
Reactant: Cc1cc(C)c(C(=O)P(=O)(C(=O)c2c(C)cc(C)cc2C)c2ccccc2)c(C)c1
Agent: CCC(Cc1ccccc1)(C(=O)c1ccc(N2CCOCC2)cc1)N(C)C
Agent: COc1cccc(OC)c1C(=O)P(=O)(CC(C)CC(C)(C)C)C(=O)c1c(OC)cccc1OC
Agent: COc1ccccc1C(=O)C(OC)c1ccccc1
Product: Cc1cc(C)c(C(=O)P(=O)(c2ccccc2)c2ccccc2)c(C)c1

Procedure:
1-hydroxycyclohexyl phenyl ketone; bis (2,4,6-trimethylbenzoyl)-phenylphosphine oxide such as Irgacure 819 from BASF; 2,2′-dimethoxy-2-phenylacetophenone; 2-benzyl-2-(dimethylamino)-1-[4-(4-morpholinyl)phenyl]-1-butanone; 2-methyl-1-(4(methylthio)phenyl)-2-moropholino-1-propane; bis (2,6-dimethoxybenzoyl)-2,4,4-trimethyl pentyl phosphine oxide; and 1-hydroxy-cyclohexyl-phenyl-ketone (a blend of 25:75 of the latter two components may be employed).