Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].O[CH2:36][CH2:37][C:38]1[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:36][CH2:37][C:38]3[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:24])([CH3:25])[CH2:22][CH2:23]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Reactant: N#Cc1ccc(CCO)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCCc3ccc(C#N)cc3)cc2)c1N1CCC(C)(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (0.04 g, 0.085 mmol), 4-(2-hydroxyethyl)benzonitrile (0.063 g, 0.427 mmol) and Ph3P (0.067 g, 0.256 mmol) in THF (5 mL) was added DEAD (0.041 ml, 0.256 mmol) at 0° C. After 1 h, the cold bath was removed and stirred for 16 h at rt. Then, the reaction mixture was concentrated and the residue purified by prep-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(5-(4-(4-cyanophenethoxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetate (0.0327 g, 0.055 mmol, 64.1% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.65 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H), 7.17 (dd, J=8.5, 2.0 Hz, 1H), 7.08 (dd, J=8.5, 2.0 Hz, 1H), 6.96 (qd, J=4.2, 2.4 Hz, 2H), 6.07 (s, 1H), 4.31-4.24 (m, 3H), 4.18 (dq, J=10.8, 7.1 Hz, 1H), 3.22 (t, J=6.5 Hz, 2H), 3.18 (br. s., 1H), 2.86 (t, J=12.2 Hz, 1H), 2.61 (s, 3H), 2.28 (d, J=11.3 Hz, 1H), 2.19 (s, 3H), 2.05 (t, J=11.6 Hz, 1H), 1.54 (br. s., 1H), 1.42-1.33 (m, 1H), 1.26 (t, J=7.1 Hz, 3H), 1.21 (s, 9H), 1.20-1.16 (m, 1H), 1.07 (d, J=10.7 Hz, 1H), 0.91 (s, 3H), 0.65 (s, 3H). LCMS (M+H)=598.4.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([O:4][C:5]([NH:7][C@H:8]1[CH2:14][CH2:13][CH2:12][C@@H:11]([CH3:15])[NH:10][C:9]1=[O:16])=[O:6])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCCC1>[CH3:3][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]1[CH2:14][CH2:13][CH2:12][C@@H:11]([CH3:15])[N:10]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:9]1=[O:16])=[O:6])[CH3:17]
Reactant: C[C@@H]1CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@H]1C
Reaction time: 0.5 h

Procedure:
A solution of (3S-cis)-hexahydro-3-[[(1,1-dimethylethoxy)carbonyl]amino]-7-methyl-2H-azepin-2-one [prepared as described in Example 64(f), 500 mg., 2.06 mmol.] in tetrahydrofuran (13 ml.) at room temperature under argon was treated dropwise with 1.0M lithium bis(trimethylsilyl)amide in tetrahydrofuran (2.7 ml., 2.7 mmol.) immediately followed by the dropwise addition of ethyl bromoacetate (0.47 ml., 4.21 mmol.). The resulting mixture was stirred for 30 minutes, quenched with aqueous ammonium chloride, diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried (sodium sulfate), filtered and concentrated to a yellow oil. Following flash chromatography (E Merck silica gel) eluting with 2:1 hexane/ethyl acetate, 750 mg. of title product was obtained as a light yellow oil; TLC (1:1 ethyl acetate:hexane) Rf =0.52.
Reaction SMILES: [NH2:1][NH2:2].[CH3:3][CH:4]([CH3:11])[CH2:5][CH2:6][C:7](OC)=[O:8]>CO>[CH3:3][CH:4]([CH3:11])[CH2:5][CH2:6][C:7]([NH:1][NH2:2])=[O:8]
Reactant: COC(=O)CCC(C)C
Reactant: NN
Solvent: CO
Product: CC(C)CCC(=O)NN
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
Under nitrogen, a solution of 53.8 g (1.68 mol) of anhydrous hydrazine in 300 mL of methanol was cooled to 0° C. and treated with 186 g (1.4 mol) of methyl 4-methylvalerate. The reaction was allowed to warm to ambient temperature and stir overnight prior to stirring at reflux for 4 h. The reaction was concentrated in vacuo giving 166 g (93%) of 4-methylvaleric acid hydrazide as a colorless solid: 49–51° C.; NMR (CDCl3) δ 0.89 (d, J=7 Hz, 6H), 1.48–1.64 (m, 3H), 2.15 (t, J=7 Hz, 2H), 3.91 (br s, 2H), 6.94 (br s, 1H). A 7.86 g (60 mmol) sample of the hydrazide was dissolved in 50 mL of methanol and treated with 7.8 g (60 mmol) of ethyl iminovalerate under nitrogen. The reaction was stirred at reflux overnight and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (40:60) gave 9.6 g (82.%) of 3-butyl-5-isopentyl-1H-1,2,4-triazole as a colorless solid which melts close to ambient temperature: NMR (CDCl3) δ 0.81–0.90 (m, 9H), 1.25–1.40 (m, 2H), 1.47–1.74 (m, 5H), 2.70 (t, J=7 Hz, 4H); MS (FAB) m/e (rel intensity) 196 (100); HRMS. Calcd for M+H: 196.1814. Found: 196.1832.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.C1(C)C=CC(S([N:26]=[N+:27]=[N-])(=O)=O)=CC=1>CC#N>[CH3:6][O:5][C:3](=[O:4])[C:2](=[N+:26]=[N-:27])[C:1]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CC(=O)OC
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C(=[N+]=[N-])C(=O)OC
Temperature: 39 °C
Reaction time: 0.25 h

Procedure:
9.9 g. (0.075 mole) of dimethyl malonate, 50 ml of anhydrous acetonitrile, and 7.6 g (0.075 mole) of triethylamine (b.p. 88.5-90.5° C.) were added to a 300 ml double-jacketed flask with a dropping funnel, reflux condenser and mechanical stirrer (Rushton). The temperature of the mixture was adjusted to 20° C., and 14.8 g (0.075 mole) of p-toluenesulfonyl azide in 50 ml of CH3CN is added dropwise with vigorous stirring over 15 minutes. The addition caused the reaction mixture to warm to 38-40° C. and assume a yellow colour. After the mixture had been stirred at room temperature for 2.5 hours, the solvent was evaporated at 35° C. (12 mm). The partially crystalline residue was triturated with 100 ml of ether, and the mixture, including the insoluble residue, was placed in a 500 ml separatory funnel. The mixture was washed successively with a 50 ml solution of potassium hydroxide (2N) and a 50 ml solution of potassium hydroxide (0.5N) solution. The yellow-orange ethereal phase was dried over anhydrous sodium sulfate, and the solvent evaporated at 35° (15 mm) until the residue had attained a constant weight. The yellow-orange diazo ester weighed 5 g. The product was checked by 1HNMR spectroscopy and found to be ca. 90% pure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH:17]=1>CC(N(C)C)=O.CCOC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([O:8][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH:17]=2)=[CH:6][CH:7]=1
Reactant: CC(C)NC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)c1cc(Oc2ccc(N)nc2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
A solution of 2-amino-5-hydroxypyridine (0.446 g, 4.05 mmol) in DMA (6.75 mL) was treated with potassium tert-butoxide (0.511 g, 4.55 mmol), stirred at RT for 1 h, treated with DMA (2 mL) and a solution of 4-chloro-N-isopropylpicolinamide (0.67 g, 3.37 mmol) in DMA (6.75 mL) and stirred at RT overnight under Ar. The mixture was diluted with EtOAc, washed with 1N NaOH, then brine and the organic layer was dried over Na2SO4, concentrated to dryness and purified by silica gel chromatography (MeOH/EtOAc) to afford 4-((6-aminopyridin-3-yl)oxy)-N-isopropylpicolinamide (0.523 g, 57%). 1H NMR (400 MHz, DMSO-d6): δ 8.46 (t, J=5.6 Hz, 2H), 7.82 (d, J=2.9 Hz, 1H), 7.33 (d, J=2.6 Hz, 1H), 7.30 (dd, J=8.9, 3.0 Hz, 1H), 7.12 (dd, J=5.6, 2.6 Hz, 1H), 6.53 (d, J=8.9 Hz, 1H), 6.08 (s, 2H), 4.05-4.04 (m, 1H), 1.14 (d, J=6.6 Hz, 6H); MS (ESI) m/z: 273.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH:5]=1.Cl>CO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OCC2CC2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(N)c(OCC2CC2)c1
Reaction time: 5 h
Yield: 95.7 %

Procedure:
3-Cyclopropylmethoxy-4-nitro-benzoic acid methyl ester (12.7 g) was dissolved in MeOH (100 ml) and EtOAc (100 ml); 10% Pd/C (1.0 g, suspended in 20 ml of water) was added, and the mixture is hydrogenated in a Parr apparatus (H2: 20 psi) for 5 hours. 37% HCl was added (10 ml), and hydrogenation was continued for additional 2 hours to obtain complete conversion. The catalyst was filtered over a celite pad, the mixture was diluted with EtOAc (200 ml) and washed with an aqueous saturated solution of NaHCO3 (2×100 ml). The organic layer was dried over Na2SO4 and the solvent was removed by evaporation to yield 10.7 g of the desired intermediate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[I:22][C:23]1[N:24]=[CH:25][NH:26][C:27]=1[CH3:28]>>[I:22][C:23]1[N:24]=[CH:25][N:26]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[C:27]=1[CH3:28]
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Reactant: Cc1[nH]cnc1I
Product: Cc1c(I)ncn1-c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example A.2) (0.33 g, 1.0 mmol) and commercially available 4-iodo-5-methyl-imidazole (0.25 g, 1.2 mmol) according to the general procedure IVa. Obtained as an off-white solid (0.43 g, 85%). MS (ISP) 498.8 [(M+H)+]; mp 202° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:17][CH:16]3[NH:18][CH:12]([CH2:13][CH2:14][CH2:15]3)[CH2:11]2)=[CH:6][CH:5]=1.[CH3:21][O:22][C:23]([CH:25]1[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[S:34](Cl)(=[O:36])=[O:35])[CH2:26]1)=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:21][O:22][C:23]([CH:25]1[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[S:34]([N:18]2[CH:16]3[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:11][N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:19])[F:20])=[CH:5][CH:6]=2)[CH2:17]3)(=[O:36])=[O:35])[CH2:26]1)=[O:24]
Reactant: FC(F)(F)Oc1ccc(N2CC3CCCC(C2)N3)cc1
Reactant: COC(=O)C1Cc2cccc(S(=O)(=O)Cl)c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C1Cc2cccc(S(=O)(=O)N3C4CCCC3CN(c3ccc(OC(F)(F)F)cc3)C4)c2C1
Temperature: 50 °C

Procedure:
A mixture of 3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane (60 mg, 0.21 mmol), 4-chlorosulfonyl-indan-2(R,S)-carboxylic acid methyl ester (120 mg, 0.44 mmol), potassium carbonate (200 mg, 1.4 mmol), and acetonitrile (3 mL) were heated at 50° C. for 2 h. The mixture was filtered through Celite, concentrated, and purified by silica gel chromatography (9:1→4:1; hexanes:ethyl acetate) to give 4-[3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-9-sulfonyl]-indan-2-carboxylic acid methyl ester: MS (ESI): 525.5 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2.[CH3:24][O:25][CH2:26][C:27](Cl)=[O:28]>>[CH3:24][O:25][CH2:26][C:27]([NH:23][C:21]1[CH:20]=[CH:19][C:17]2[N:18]=[C:13]([NH:12][CH:10]3[C:11]4[C:7](=[CH:6][CH:5]=[CH:4][C:3]=4[O:2][CH3:1])[CH2:8][CH2:9]3)[O:14][CH2:15][C:16]=2[CH:22]=1)=[O:28]
Reactant: COCC(=O)Cl
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CC2
Product: COCC(=O)Nc1ccc2c(c1)COC(NC1CCc3cccc(OC)c31)=N2
Yield: 60.9 %

Procedure:
Prepared from rac-N2-(7-methoxy-indan-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 10) (100 mg, 0.323 mmol) and methoxyacetyl chloride (32 ul, 0.356 mmol) according to the procedure described for Example 17. Obtained the title compound as a white solid (75 mg, 61%), MS (ISP) m/e=382.2 [(M+H)+].
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[O-]S([O-])(=O)=O.[Mg+2].[CH2:11]([O:18][C:19]([NH:21][C:22]([CH3:29])([CH:27]=O)[C:23]([O:25][CH3:26])=[O:24])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[CH2:1]([NH:4][CH2:29][C:22]([NH:21][C:19]([O:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:20])([CH3:27])[C:23]([O:25][CH3:26])=[O:24])[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: COC(=O)C(C)(C=O)NC(=O)OCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: C=CCNCC(C)(NC(=O)OCc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.4 %

Procedure:
1.237 ml (16.5 mmol) of allylamine and 0.9 g (7.48 mmol) of MgSO4 are added to a solution of 0.874 g (3.3 mmol) of methyl 2-benzyloxycarbonylamino-2-methyl-3-oxopropionate in 15 ml of DCM. The mixture is stirred at room temperature overnight. The reaction mixture was then filtered and concentrated in vacuo. 50 ml of anhydrous MeOH, 6 ml of NaCNBH3 (1.0M in THF) and 1.8 ml of acetic acid are added to the crude product. This mixture is stirred at RT for 2 h. The reaction solution is concentrated in vacuo, and then EtOAc and water are added. The organic phase is separated off and dried over MgSO4, and the solvent is removed in vacuo. Purification takes place by chromatography (25 g of SiO2, eluent MeOH/DCM (gradient 0-10%). 1.035 g of the desired product are obtained as an oil. MW=306 (calculated, monoisotopic), measured value: (M+H)+307.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[O:4][N:3]=1.[N+](=[CH2:11])=[N-]>CCOCC>[CH3:11][N:3]1[C:2](=[O:1])[C:6]([CH3:7])=[C:5]([CH3:8])[O:4]1
Reactant: C=[N+]=[N-]
Reactant: Cc1onc(O)c1C
Solvent: CCOCC
Product: Cc1on(C)c(=O)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-hydroxy-4,5-dimethylisoxazole (7 g, 62 mmol) in ether (50 mL) was added diazomethane until a persistent yellow colour was obtained. The reaction was stirred for another 30 min at room temperature. The ether was evaporated off and the residue purified by column chromatography on silica gel suing either as eluent. 4 g of the desired material was obtained.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[NH:17]1[C:25](=[O:26])[C:23](=[O:24])[C:21](=[O:22])[NH:20][C:18]1=[O:19].Cl>CCCCCC.O1CCCC1>[OH:24][C:23]1([C:9]2[O:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:11][CH:10]=2)[C:21](=[O:22])[NH:20][C:18](=[O:19])[NH:17][C:25]1=[O:26]
Reactant: c1ccc(-c2ccco2)cc1
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1NC(=O)C(O)(c2ccc(-c3ccccc3)o2)C(=O)N1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
2-Phenylfuran (5.76 g., 40 mmoles) was combined with 100 ml. of tetrahydrofuran and cooled to -30° C. Butyl lithium in hexane (2.3 M, 19.1 ml.) was added dropwise over 5 minutes, keeping the temperature between -20° and -30° C. The reaction mixture was allowed to warm to room temperature and then recooled to -30° C. Sublimed alloxan (5.96 g., 42 mmoles) in 40 ml. of tetrahydrofuran was added over 5 minutes, again keeping the temperature -20° to -30° C. The reaction mixture was again allowed to warm to room temperature, then recooled to 0° C. and 50 ml. of 1 N hydrochloric acid added portionwise over 2-3 minutes. The quenched reaction mixture was extracted with 100 ml. of ethyl acetate. The extract was filtered through a bed of anhydrous magnesium sulfate, and evaporated to yield 5-hydroxy-5-(5 -phenyl-2-furyl)-2,4,6(1H,3H,5H)pyrimidinetrione [9.4 g., gummy solid, Rf 0.75 (1:1 hexane ethyl acetate/5% acetic acid)] contaminated with starting material (Rf 0.45).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:18]=[CH:17][N:16]([C:19]3[N:24]=[C:23](SC#N)[C:22]([N+:28]([O-:30])=[O:29])=[CH:21][N:20]=3)[C:15]=2[CH:31]=1.Cl.[C:33]([O:37][C:38](=[O:42])[C@@H:39]([CH3:41])[NH2:40])([CH3:36])([CH3:35])[CH3:34]>C1COCC1>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:18]=[CH:17][N:16]([C:19]3[N:24]=[C:23]([NH:40][C@H:39]([CH3:41])[C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:42])[C:22]([N+:28]([O-:30])=[O:29])=[CH:21][N:20]=3)[C:15]=2[CH:31]=1
Reactant: N#CSc1nc(-n2cnc3ccc(Cl)cc32)ncc1[N+](=O)[O-]
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1nc(-n2cnc3ccc(Cl)cc32)ncc1[N+](=O)[O-])C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
Diisopropylethylamine (2.6 mL) was added to a mixture of 6-chloro-1-(5-nitro-4-thiocyanatopyrimidin-2-yl)-1H-benzo[d]imidazole (1.66 g, 5 mmol) and D-alanine t-butyl ester hydrochloride (1.1 g, Chem-Impex Int.) in THF (50 mL). The combined mixture was stirred at RT overnight, partitioned between ethyl acetate and water then separated. The aqueous layer was extracted once again with ethyl acetate and the combined organics were concentrated and purified by column chromatography. Elution with DCM and 0.5% MeOH in DCM provided the above compound (0.58 g), MH+=419, 421.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[CH2:14]([NH:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16]>Cl>[CH2:14]([N:17]([CH2:18][CH2:19][CH3:20])[CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2)[CH2:15][CH3:16]
Reactant: O=C1Cc2c(CCBr)cccc2N1
Reactant: CCCNCCC
Agent: Cl
Product: CCCN(CCC)CCc1cccc2c1CC(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6 %

Procedure:
Under an atmosphere of nitrogen, a suspension of 4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (245 mg, 102 mmol) was prepared by the addition of di-n-propylamine (1.00 g, 10 mmol, 1.35 ml) which has previously been degassed with a stream of nitrogen. After stirring for 30 minutes, degassed acetonitrile (5 ml) was added to give a pale yellow solution. After an additional hour the solution was heated, and maintained at reflux for 5 hours. After cooling to ambient temperature, the solution was poured into IN hydrochloric acid (35 ml) and extracted with ether (50 ml). The aqueous layer was made neutral to pH 7-7.5 with solid sodium bicarbonate and extracted with dichloromethane (50 ml). After drying separately, the ether layer was evaporated to give 4-vinyl-indol-2-one (60 mg, 37.7%) Evaporation of the dichloromethane layer gave 4-[2-(dipropylamino)ethyl]-1.3-dihydro-2H-indol-2-one (155 mg. 58.5%) as free-base which was then taken up in absolute ethanol (5 ml) and saturated with gaseous hydrogen chloride. The solvent was removed in vaccuo to give the crude hydrochloride salt (170 mg) as a light yellow solid. Recrystallisation from absolute ethanol (2 ml) gave light yellow crystals (110 mg 63% from the free-base) of 4-[2-(dipropylamino)ethyl]-1,3- dihydro-2H-indol-2-one hydrochloride m.p. 242-244° C.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[I:21])[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[C:7]([O:6][C:5]([NH:4][CH2:3][CH2:2][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[I:21])[C:16]#[N:17])=[O:11])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: N#Cc1ccc(I)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCOc1cc(C#N)ccc1I
Temperature: 75 °C
Reaction time: 3 h

Procedure:
18.5 g (82.6 mmol) of t-butyl (2-bromoethyl)carbamate was dissolved in 200 ml of DMF. 10.1 g (41.3 mmol) of 3-hydroxy-4-iodobenzonitrile and 5.7 g (41.3 mmol) of potassium carbonate were added to the obtained solution, and they were stirred at 75° C. for 3 hours. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the title compound was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][Cl:6].C(=O)([O-])[O-].[K+].[K+].[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][C:20](=[O:24])[NH:21]2)=[CH:16][CH:15]=1.CC(C)=O>CCCCCC>[Cl:6][CH2:5][CH2:4][CH2:3][CH2:2][O:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][C:20](=[O:24])[NH:21]2)=[CH:16][CH:15]=1
Reactant: ClCCCCBr
Reactant: O=C1CCc2ccc(O)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: O=C1CCc2ccc(OCCCCCl)cc2N1
Yield: 78 %

Procedure:
1-bromo-4-chloro-butane (3.4 g, 20 mmol), anhydrous potassium carbonate powder (4.14 g, 30 mmol) and 7-hydroxy-3,4-dihydro-2(1H)-quinolinone (1.63 g, 10 mmol) are added to 10 ml of acetone and reflux for 24 hours. The reaction solution is evaporated to dryness and dispersed with 20 ml of dichloromethane and 20 ml of water respectively. The organic layer is extracted with water (20 ml×2) and saturated saline (20 ml) successively, dried over anhydrous magnesium sulfate, and evaporated to dryness to obtain a light yellow powder. The powder is slurried with n-hexane (20 ml×3), filtered, and dried to obtain 1.98 g of 7-(4-chlorobutoxy)-3,4-dihydro-2(1H)-quinolinone, with a yield of 78%.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@@H:5]([CH2:7][CH2:8][OH:9])[CH2:4][O:3]1.[H-].[Na+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18](CCl)=[CH:17][CH:16]=1>C1COCC1>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([O:9][CH2:8][CH2:7][C@H:5]2[CH2:4][O:3][C:2]([CH3:10])([CH3:1])[O:6]2)=[CH:17][CH:16]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC1(C)OC[C@H](CCO)O1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(OCC[C@H]2COC(C)(C)O2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanol (Aldrich, 5 g, 34.2 mmol) in THF was added sodium hydride 60% (1.504 g, 37.6 mmol, 1.1 eq) portionwise and the mixture stirred for 1 h (cloudy solution). The mixture was cooled to 0° C. and to it was added 4-methoxybenzyl chloride (5.89 g, 37.6 mmol, 1.1 equivalent (eq.)) in one portion and the mixture stirred at the temperature for 30 min and heated to 65–70° C. overnight. After cooling to rt and quenching with saturated NH4Cl/water, the mixture was extracted with ethyl acetate (2×) and the organic extracts were washed with water, brine and dried over MgSO4. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography (15% ethyl acetate/hexanes) to give desired product as a colorless oil. 1H NMR (400 MHz, Acetone-d6): δ7.28 (2 H, d), 6.93–6.91 (2 H, m), 4.43 (2 H, s), 4.20–4.14 (1 H, m), 4.04–3.98 (1 H, m), 3.80 (3H, s), 3.56–3.50 (3H, m), 1.88–1.76 (2H, m), 1.31 (3H, s), 1.28 (3 H, s).