Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH2:4]1.[C:27](OC(=O)C)(=[O:29])[CH3:28].O>CN(C)C(=O)C>[CH3:26][N:17]([S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:20])=[O:19])[C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[NH:9][C:8]([C:6]1[S:7][CH:3]([CH2:2][NH:1][C:27](=[O:29])[CH3:28])[CH2:4][N:5]=1)=[CH:16]2
Reactant: CC(=O)OC(C)=O
Reactant: CN(c1cccc2cc(C3=NCC(CN)S3)[nH]c12)S(=O)(=O)c1cccs1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)NCC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a solution of N-{2-[5-(aminomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (0.27 g) in N,N-dimethylacetamide (6 mL) was added acetic anhydride (0.10 mL) at 0° C., and the, mixture was stirred for 30 min. Water was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water, and dried. The obtained solid was subjected to silica gel column chromatography to give the title compound. (0.20 g, yield 68%) as pale-yellow crystals from a fraction eluted with ethyl acetate-hexane (95:5, volume ratio). melting point 212-213° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH2:7])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([NH:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])(=[O:18])=[O:17]
Reactant: CC(=O)NCCN
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCNS(C)(=O)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
N-Acetylethylenediamine (10.2 g, 100 mmol) and triethylamine (15 ml, 10.9 g, 108 mmol) were dissolved in dichloromethane (300 ml) and the solution cooled to 0° C. Methanesulphonyl chloride (8 ml, 11.8 g, 103 mmol) was dissolved in dichloromethane (10 ml) and added dropwise, and stirring was continued at 0° C. for 3 hours. The dichloromethane was removed in vacuo, and the residue was suspended in a mixture of ether and acetone, removing the insoluble material by filtration. The filtrate was concentrated in vacuo to give the title compound as a pale brown gum (14.5 g, 88.3 mmol, 88%); δH [2H6]DMSO 7.93 (1H,br t), 7.05 (1H,t), 3.11 (2H,t), 2.97 (2H,t), 2.89 (3H,s), 2.09 (3H,s).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11].[C:19](O)(=[O:24])[CH2:20][C:21](O)=[O:22]>C(O)(=O)C>[CH3:8][N:9]1[C:21](=[O:22])[CH2:20][C:19](=[O:24])[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]1=[O:11]
Reactant: CNC(=O)Nc1ccccc1
Reactant: O=C(O)CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CN1C(=O)CC(=O)N(c2ccccc2)C1=O
Temperature: 90 °C

Procedure:
Acetic anhydride (16 ml, 0.17 mole) was added dropwise over three hours to a solution of 1-methyl-3-phenylurea (6 g, 0.04 mole) and malonic acid (4.6 g, 0.04 mole) in acetic acid (40 ml) at 60° C. After the addition was completed, the temperature was raised to 90° C. and maintained for four hours. The solvent was evaporated and the resulting residue treated with 0.1N NaOH (50 ml). After filtration, the solution was acidified with 0.2N HCl (120 ml). The solution was evaporated to dryness under reduced pressure, leaving solid 1-methyl-3-phenyl-2,4,6-(1H,3H,5H)- pyrimidinetrione upon cooling. It was recrystallized from ethanol to yield colorless crystals, m.p. 122.5°-123° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:19]([O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)([CH3:21])[CH3:20].O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:18][O:17][C:11]1[CH:10]=[C:9]([CH2:8][CH:2]([NH:1][C:27]([C:26]2[CH:30]=[CH:31][C:23]([O:22][CH:19]([CH3:21])[CH3:20])=[CH:24][CH:25]=2)=[O:28])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)C(N)Cc1ccc(OC)c(OC)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(OC)c(OC)c1)NC(=O)c1ccc(OC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-amino-3-(3,4-dimethoxyphenyl)propionate (the compound obtained in Example 1-(1)) (15.2 g), 4-isopropyloxybenzoic acid (10.8 g), and 1-hydroxybenzotriazole monohydrate (9.2 g) are dissolved in methylene chloride (120 ml), and thereto is added 1,3-dicyclohexylcarbodiimide (12.4 g) under ice-cooling, and the mixture is stirred at room temperature overnight. The insoluble materials are removed by filtration, and the filtrate is washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals are collected by filtration with diethyl ether to give ethyl 3-(3,4-dimethoxyphenyl)-2-{[4-(isopropyloxy)phenyl]carbonylamino}propionate (24.2 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH:7]([CH2:11][C:12]1([C:17](=[O:33])[NH:18][CH:19]([C:29](=[O:32])[NH:30][CH3:31])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:8][CH2:9]O)([CH3:4])([CH3:3])[CH3:2].[O:35]=[C:36]1[C:44]2[CH:43]=[C:42]3[CH:45]=[CH:46][CH:47]=[CH:48][C:41]3=[CH:40][C:39]=2[C:38](=[O:49])[NH:37]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:1]([O:5][C:6](=[O:34])[CH:7]([CH2:11][C:12]1([C:17](=[O:33])[NH:18][CH:19]([C:29](=[O:32])[NH:30][CH3:31])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:13][CH2:14][CH2:15][CH2:16]1)[CH2:8][CH2:9][N:37]1[C:38](=[O:49])[C:39]2[CH:40]=[C:41]3[CH:48]=[CH:47][CH:46]=[CH:45][C:42]3=[CH:43][C:44]=2[C:36]1=[O:35])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)C(Cc1ccc(OC)cc1)NC(=O)C1(CC(CCO)C(=O)OC(C)(C)C)CCCC1
Reactant: O=C1NC(=O)c2cc3ccccc3cc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CNC(=O)C(Cc1ccc(OC)cc1)NC(=O)C1(CC(CCN2C(=O)c3cc4ccccc4cc3C2=O)C(=O)OC(C)(C)C)CCCC1
Reaction time: 240 h

Procedure:
To a solution of 4-hydroxy-2-{1-[2-(4-methoxyphenyl)-1-(methylcarbamoyl)ethylcarbamoyl]cyclopentylmethyl}butyric acid tert-butyl ester (500 mg, 1.05 mmol) in dry tetrahydrofuran (20 mL) was added 1,3-dioxo-1,3-dihydrobenzo[f]isoindole (414 mg, 2.1 mmol), triphenylphosphine (550 mg, 2.1 mmol) and diethylazodicarboxylate (0.33 mL, 2.1 mmol) and the resulting mixture was stirred for 10 days. The solvent was evaporated under vacuum and the residue was chromatographed on silica gel eluting with 30% ethyl acetate in hexane. Fractions containing the two diastereomeric products were combined and evaporated to leave a solid which was recrystallized from ethyl acetate to afford 4-(1,3-dioxo-1,3-dihydrobenzo[f]isoindol-2-yl)-2-{1-[2-(4-methoxyphenyl)-1-(methylcarbamoyl)ethylcarbamoyl]cyclopentylmethyl}butyric acid tert-butyl ester (diastereomer A) as a white solid, 45 mg (7%). The mother liquor from the recrystallization was concentrated under vacuum to afford an oil which was taken up in 25% ethyl acetate in hexane and allowed to stand overnight. A small amount of solid was removed by filtration and the solvent was evaporated to give an oil highly enriched in diastereomer B, 60 mg (9%).
Reaction SMILES: CS[C:3]([N:7]1[CH2:11][CH:10]([CH2:12][CH3:13])[CH:9]=[N:8]1)=[N:4][CH2:5][CH3:6].[C:14]1(/[CH:20]=[CH:21]/[S:22]([NH2:25])(=[O:24])=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[CH2:5]([NH:4][C:3]([N:7]1[CH2:11][CH:10]([CH2:12][CH3:13])[CH:9]=[N:8]1)=[N:25][S:22](/[CH:21]=[CH:20]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:23])=[O:24])[CH3:6]
Reactant: CCN=C(SC)N1CC(CC)C=N1
Reactant: NS(=O)(=O)/C=C/c1ccccc1
Solvent: CC#N
Product: CCNC(=NS(=O)(=O)/C=C/c1ccccc1)N1CC(CC)C=N1
Yield: 0.3 %

Procedure:
0.70 g (1 mol equiv.) 4,N-Diethyl-4,5-dihydro-pyrazole-1-carboximidothioic acid methyl ester and 0.68 g (1.05 mol equiv.) trans-2-phenyl-ethenesulfonic acid amide were added to 7 mL acetonitrile, and the reaction mixture was refluxed overnight. Volatiles were removed under reduced pressure, and the residue was taken up in ethyl acetate and extracted with 2N NaOH. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Purification by flash chromatography on silica gel (Et2O:PA=2:1) afforded 1.00 g (81%) trans-2-phenyl-ethenesulfonic acid ethylamino-(4-ethyl-4,5-dihydro-pyrazol-1-yl)-methyleneamide. 1H NMR (400 MHz, CDCl3) δ 0.98 (t, J=7.5 Hz, 3H), 1.21 (t, J=7.2 Hz, 3H), 1.46-1.70 (m, 2H), 3.06-3.16 (m, 1H), 3.51-3.59 (m, 2H), 3.74 (dd, J=11.3, 7.5 Hz, 1H), 4.13 (t, J=11.3 Hz, 1H), 6.70-6.92 (m, 1H), 6.92 (d, J=1.3 Hz, 1H), 6.97 (d, J=15.4 Hz, 1H), 7.35-7.41 (m, 3H), 7.44 (d, J=15.4 Hz, 1H), 7.46-7.50 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=O)[NH:4][C:3]1=[O:13].C(N(CCC)CCC)CC.P(Cl)(Cl)([Cl:26])=O.[OH-].[Na+]>C(N(CCC)CCC)CC.C(Cl)(Cl)Cl>[Cl:26][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:2]([CH3:1])[C:3](=[O:13])[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(=O)[nH]c(=O)c2ccccc21
Agent: CCCN(CCC)CCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)nc(Cl)c2ccccc21
Reaction time: 1 h

Procedure:
A mixture of 1-methylquinazoline-2,4-dione (8.8 g), tri-n-propylamine (8.6 g) and phosphorus oxychloride (80 ml) was stirred for 1 hour at 110°-120° C. The resultant mixture was cooled to ambient temperature and concentrated under reduced pressure to give a residue, which was dissolved in 2% tri-n-propylamine-chloroform solution. The solution was added dropwise to a mixture of 2 N sodium hydroxide aqueous solution and ice at alkaline pH. The aqueous layer was separated and extracted twice with chloroform. The combined chloroform layer was washed with water and with aqueous solution saturated with sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crystalline 4-chloro-1-methyl-1H-quinazoline-2-one.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH3:7][N:8]([CH3:20])[CH2:9][CH2:10][S:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1>O.CO>[CH3:7][N:8]([CH3:20])[CH2:9][CH2:10][S:11]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1)=[O:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CN(C)CCSc1ccc(C=O)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(C)CCS(=O)c1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 7 h
Yield: 53 %

Procedure:
Sodium periodate (512 mg, 2.39 mmol) was dissolved in water (10 ml) and cooled to 0° C. 4-(2-Dimethylaminoethylthio)benzaldehyde (0.5 g, 2.39 mmol), prepared as described in Reference Example 2, was then added in methanol (2 ml) and the reaction mixture stirred at room temperature and then later warmed to 35° C. After 7 hours the reaction mixture was basified using sodium carbonate and exhaustively extracted with dichloromethane, dried over magnesium sulphate and the solvent removed in vacuo to yield the title compound as an oil in a yield of 53%.
Reaction SMILES: [CH2:1]1[CH:7](O)[NH:6][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[O:3][CH2:2]1.[OH:16][NH:17][C:18]([NH2:20])=[O:19].ClC(Cl)(Cl)C(O)=O>CN(C=O)C.C(OCC)(=O)C>[OH:16][N:17]([CH:7]1[CH2:1][CH2:2][O:3][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[NH:6]1)[C:18]([NH2:20])=[O:19]
Reactant: O=P1(N(CCCl)CCCl)NC(O)CCO1
Reactant: NC(=O)NO
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)N(O)C1CCOP(=O)(N(CCCl)CCCl)N1
Reaction time: 20 h

Procedure:
15 g (54 mmol) of 4-hydroxycyclophosphamide (that is to say 2-[bis-(2-chloroethyl)-amino]-4-hydroxytetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide) and 4.4 g (58 mmol) of hydroxyurea were dissolved in 70 ml of DMF, acidified with trichloroacetic acid (pH 3-4) and left for 20 hours at 0° C. in a refrigerator. The resultant crystal sludge was diluted with 70 ml of ethyl acetate and after 2 hours was drawn off by suction, washed, dried and recrystallized from methanol.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:15]([C:16]#[N:17])=[CH:14][CH:13]=[CH:12][N:11]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:8][C:10]1[N:11]=[CH:12][CH:13]=[CH:14][C:15]=1[C:16]#[N:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccnc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.1 %

Procedure:
To a mixture of benzyl alcohol (32.0 g), 2-chloro-3-cyanopyridine (37.3 g) and N,N-dimethylformamide (200 mL) was added sodium hydride (60%, oil, 12.92 g) under ice-cooling. The reaction mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give 2-(benzyloxy)nicotinonitrile as an oil (39.13 g, 69%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[C:5]([CH3:17])([CH3:16])[C:4]=2[CH:3]=1.B(OC(C)C)(OC(C)C)[O:19]C(C)C.C([Li])CCC.Cl>C1COCC1.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:11]3[CH:10]=[CH:9][C:8]([OH:19])=[CH:7][C:6]=3[C:5]2([CH3:17])[CH3:16])=[CH:13][CH:14]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC1(C)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)c2cc(O)ccc2-c2ccc(Br)cc21
Reaction time: 2 h

Procedure:
21.2 g (58.6 mmol) of 2,7-dibromo-9,9-dimethyl-9H-fluorene (CAS No. 28320-32-3) and 19.0 ml (82.8 mmol) of triisopropyl borate are dissolved in 500 ml of THF, and 56 ml (89 mmol) of a 15 percent solution of n-butyllithium in n-hexane are added at −70° C. After 2 h, 200 ml of 2 M hydrochloric acid are added, and the batch is allowed to thaw at room temp. and extracted three times with MTB ether. The combined org. phases are dried over sodium sulfate, the solvent is removed in vacuo, and the residue is taken up in 400 ml of toluene. After addition of 85 ml of 2 M sodium hydroxide solution, 15.5 ml of 30 percent hydrogen peroxide are added with vigorous stirring at such a rate that the temp. does not exceed 40° C. When the addition is complete, the batch is stirred for a further 30 min, added to 500 ml of water and acidified using 2 M hydrochloric acid. The aqueous phase is separated off and extracted three times with ethyl acetate. The combined org. phases are washed with dil. ammonium iron(II) sulfate soln. and water, dried over sodium sulfate and evaporated. Filtration of the crude product through silica gel with toluene/ethyl acetate (9:1) gives 7-bromo-9,9-dimethyl-9H-fluoren-2-ol as colourless solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[NH:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)(O)[O-].[Na+].Br[CH2:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28]>C(O)(C)C>[OH:31][C:26]1([C:27]([F:30])([F:29])[F:28])[CH2:25][N:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[N:13]1
Reactant: O=C(CBr)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2cccs2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2cccs2)cc1
Temperature: 82.5 °C
Yield: 39.7 %

Procedure:
To a mixture of the amidine of step 1 (2.0 g, 7.1 mmol) and sodium bicarbonate (1.2 g, 14.3 mmol) in isopropanol (200 ml), 3-bromo-1,1, 1-trifluoroacetone 1.1 ml, 10.7 mmol) was added. After heating at 80-85° C. for 16 hours, the reaction mixture was cooled and filtered. The residue was washed with methylene chloride and the combined organic fractions were dried over sodium sulfate, filtered and concentrated. The crude mixture (25.7 g) was purified by chromatography (silica gel, ethyl acetate/hexane 55/45) to give the 4,5-dihydro-imidazole (1.1 g, 38%) as a white solid: mp (DSC) 214° C. Anal. Calc'd. for C15H13N2S2O3F3: C, 46.15, H, 3.36, N, 7.18, S, 16.43. Found: C, 46.09, H, 3.26, N, 7.07, S, 16.71.
Reaction SMILES: C12(C)C(C)(C)C(CC1)CC2C(Cl)=O.N[CH:15]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:16]1=[O:17].C(OC1C=CC=CC=1C([NH:31]C1CCC(=O)NC1=O)=O)(=O)C>C(Cl)(Cl)Cl>[NH2:31][N:18]1[C:19](=[O:22])[CH2:20][CH2:21][CH2:15][C:16]1=[O:17]
Reactant: CC(=O)Oc1ccccc1C(=O)NC1CCC(=O)NC1=O
Reactant: NC1CCC(=O)NC1=O
Agent: CC1(C)C2CCC1(C)C(C(=O)Cl)C2
Solvent: ClC(Cl)Cl
Product: NN1C(=O)CCCC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
A mixture of (+)-camphanic chloride (19 mg, 00868 mmol), aminoglutarimide (21 mg, 0.0868 mmol) and Et3N (24) in CHCl3 (1 ml) was stirred at room temperature for 16 hours. The solution was diluted with CHCl3, washed with saturated aqueous solution of NaHCO3, dried over Na2SO4, concentrated and purified by chromatography (silica gel, CH2Cl2; EtOAc=10:1) to give product (16 mg, 60.0% yield) as a colorless gel: 13CNMR (CDCl3) δ 172.6, 169.4, 168.6, 165.5, 90.3, 58.3, 53.3, 48.2, 47.6, 29.2, 28.2, 26.9, 22.7, 14.6, 7.6; MS (CI/CH4) m/z 308 (M+). This compound exhibited angiogenic activity in the assay of Example 13.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].[OH-].[Na+].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1ccccc1O
Reactant: BrCCCCBr
Agent: [Na+]
Agent: [OH-]
Product: CCc1ccccc1OCCCCBr

Procedure:
The solution of 19.04 ml of 2-ethylphenol in 24 ml of 1,4-dibromobutane is heated to 100° C. with stirring and admixed slowly with 99.2 ml of 1.6M NaOH. The emulsion is stirred at 100° C. over 20 h. The reaction mixture is cooled and extracted with tertbutyl methyl ether (2×150 ml). The organic phases are washed successively with 2M NaOH (1×150 ml), water (1×150 ml) and brine (1×150 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of distillation. b.p. 132° C. (1.1 mbar); Rt=5.75.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)Br.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30][C:31]([OH:33])=O.[NH2:34][C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[C:37]([CH3:42])[N:36]=1>O1CCCC1>[CH3:41][C:39]1[CH:38]=[C:37]([CH3:42])[N:36]=[C:35]([NH:34][C:31](=[O:33])[CH2:30][C:26]2[S:25][CH:29]=[CH:28][CH:27]=2)[CH:40]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: O=C(O)Cc1cccs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Br
Product: Cc1cc(C)nc(NC(=O)Cc2cccs2)c1

Procedure:
9.22 g of triphenylphosphine, 6.93 ml of trichlorobromomethane, 5 g of 2-thienylacetic acid and 8.50 g of 2-amino-4,6-dimethylpyridine are dissolved in 120 ml of tetrahydrofuran. The mixture is brought to reflux and filtered, and the filtrate is concentrated; the residue is chromatographed on silica gel, eluting with dichloromethane, and the product obtained is recrystallized from isopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[P:49]([O:61][CH2:62]Cl)([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50]>CN(C)C=O>[C:52]([O:51][P:49]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])([O:61][CH2:62][O:36][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)=[O:50])([CH3:55])([CH3:54])[CH3:53]
Reactant: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OCOP(=O)(OC(C)(C)C)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reaction time: 3 h
Yield: 70.7 %

Procedure:
To a solution of chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 200.0 mg, 0.324 mmol) in dimethylformamide (8 mL) was added cesium carbonate (529 mg, 1.62 mmol). The mixture was stirred for ˜20 min before di-tert-butyl chloromethyl phosphate (TCI, 236 mg, 0.9912 mmol) in dimethylformamide (1 mL) was added. The reaction mixture was allowed to stirr at room temperature for 3 h before it was partitioned between ethyl acetate and water, washed with water and dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography (hexane/ethyl acetate, 85/15 to 5/95) to give chiral 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid di-tert-butoxy-phosphoryloxymethyl ester as a white solid (192 mg, 70% yield). LCMS (ES+) m/z calcd. for C40H49Cl2F2N3O8P [(M+H)+]: 838, found: 838.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:11])=[N:8][C:9]=1[CH3:10].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:11][S:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:12])([F:24])[F:25])[CH:15]=2)(=[O:22])=[O:21])=[N:8][C:9]=1[CH3:10]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: COCc1ccc(N)nc1C
Product: COCc1ccc(NS(=O)(=O)c2cccc(C(F)(F)F)c2)nc1C

Procedure:
This material was prepared in analogy to example 1 from 5-methoxymethyl-6-methyl-pyridin-2-ylamine (0.058 g) and 3-(trifluoromethyl)-benzenesulfonyl chloride (0.103 g) as a light yellow gum (0.1 g). MS (ESI−): 359.0 ([M−H]−)
Reaction SMILES: [Br:1]Br.[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9]2)([O-:5])=[O:4]>C(Cl)(Cl)Cl.CO>[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH:10]([Br:1])[CH2:9]2)([O-:5])=[O:4]
Reactant: BrBr
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc21
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C1c2ccc([N+](=O)[O-])cc2CC1Br
Temperature: 25 °C

Procedure:
Bromine (1.79 ml) in chloroform (125 ml) was added dropwise over 15 minutes to a stirred solution of 5-nitroindan-1-one (6.17 g) in chloroform (200 ml) at 5° C. The stirred solution was allowed to warm to room temperature and after one hour, when the bromine colour had discharged, the solution was washed with water and dried. Evaporation of the filtered solution under reduced pressure afforded an oil which was diluted with methanol and crystallised (with seeding) to give 5-nitro-2-bromoindan-1-one, m.p. 88.5°-90.5° C. (recrystallised from methanol).