Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[OH:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([NH:34][NH2:35])=[O:33])=[CH:28][CH:27]=2)=[O:24])[CH:17]=[CH:18][C:19]=1[OH:20]>C(O)(=O)C>[OH:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([NH:34][N:35]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=4)[NH:7][C:6]3=[O:11])=[O:33])=[CH:28][CH:27]=2)=[O:24])[CH:17]=[CH:18][C:19]=1[OH:20]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1ccc(NC(=O)CCc2ccc(O)c(O)c2)cc1
Solvent: CC(=O)O
Product: O=C(CCc1ccc(O)c(O)c1)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 87 %

Procedure:
Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 3-(3,4-dihydroxyphenyl)-N-[4-(hydrazinocarbonyl)phenyl]propanamide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 161 mg of the title compound (87%) as a yellow solid in 96% purity by HPLC (Rt: 3.56, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].Cl[CH:14]([CH3:18])[C:15](Cl)=[O:16].[Cl-:19].[Cl-].[Cl-].[Al+3].Cl>C(Cl)(Cl)Cl>[Cl:19][CH2:18][CH2:14][C:15]([C:10]1[C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][C:7]=2[S:8][CH:9]=1)=[O:16]
Reactant: [Cl-]
Reactant: O=[N+]([O-])c1ccc2sccc2c1
Reactant: CC(Cl)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Solvent: ClC(Cl)Cl
Product: O=C(CCCl)c1csc2ccc([N+](=O)[O-])cc12
Yield: 30 %

Procedure:
A solution of 1 g (5.58×10−3 moles) of 5-nitrobenzo[b]thiophene and 0.65 ml (6.64×10−3 moles) of 2-chloropropionyl chloride dissolved in 40 ml of dry chloroform was added dropwise over 650 mg of aluminum trichloride, dissolved in 20 ml dry chloroform under a nitrogen atmosphere. The mixture was left to react for 24 hours at room temperature and an additional amount of 650 mg of aluminum trichloride and 0.65 ml of 2-chloropropionyl chloride was added. After 48 hours reaction 100 ml of HCl 1.5N were added, followed by decantation and the organic phase was subsequently washed with a dilute solution of NaHCO3, with H2O and with a saturated solution of NaCl. It was dried with Na2SO4, the solvent was removed and it was purified in a silica column using hexane/toluene (25:75) as mobile phase. Yield: 30%.
Reaction SMILES: [Mg].II.ClC(C)C.[CH3:8][O:9][Si](OC)(OC)OC.CO.C([Si:22]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[O:23][CH3:24])(C)C>COC(C)(C)C>[CH:25]([Si:22]([CH:28]([CH3:30])[CH3:29])([O:9][CH3:8])[O:23][CH3:24])([CH3:27])[CH3:26]
Reactant: CO[Si](C(C)C)(C(C)C)C(C)C
Reactant: CO[Si](OC)(OC)OC
Agent: CC(C)Cl
Agent: II
Agent: [Mg]
Solvent: COC(C)(C)C
Solvent: CO
Product: CO[Si](OC)(C(C)C)C(C)C

Procedure:
Under an inert gas, 24.2 g magnesium chips (1.0 mol) were combined with about 20 ml methyl-tert-butylether, an iodine crystal and 3.1 g 2-chloropropane (0.04 mol). To start the reaction a solution of 61.9 g tetramethoxysilane (0.41 mol) and 75.4 g 2-chloropropane (0.96 mol) in 140 ml methyl-tert-butylether was added dropwise, with stirring, to the first mixture at a rate to maintain a moderate reflux. After addition of the solution, the reaction was allowed to reflux for six more hours. After cooling the reaction mixture, 6.0 g methanol (0.19 mol) was added, the mixture was stirred for a few minutes and then the resulting precipitate was removed by filtration. After washing the filter cake with several portions of methyl-tert-butylether, the solvent was distilled from the combined filtrates. The remaining residue consisted of 70.5 g diisopropyldimethoxysilane (98% of the theoretical yield) which had a purity of 98% according to GC. Triisopropylmethoxysilane was not detected by GC.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[F:5][C:6]([F:25])([F:24])[C:7]1[CH:8]=[C:9]([CH:21]=[CH:22][CH:23]=1)[O:10][C:11]1[C:16]([C:17](OC)=[O:18])=[N:15][CH:14]=[CH:13][N:12]=1>C1(C)C=CC=CC=1>[CH:1]1([NH:4][C:17]([C:16]2[C:11]([O:10][C:9]3[CH:21]=[CH:22][CH:23]=[C:7]([C:6]([F:24])([F:5])[F:25])[CH:8]=3)=[N:12][CH:13]=[CH:14][N:15]=2)=[O:18])[CH2:3][CH2:2]1
Reactant: COC(=O)c1nccnc1Oc1cccc(C(F)(F)F)c1
Reactant: NC1CC1
Solvent: Cc1ccccc1
Product: O=C(NC1CC1)c1nccnc1Oc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
0.11 g (2.0 mmol) of cyclopropylamine is added to a suspension of 3.0 g (10 mmol) of methyl 2-(3-trifluoromethylphenoxy)-3-pyrazinecarboxylate, 20 g of 3 Å molecular sieve and 20 g of 5 Å molecular sieve in 240 ml of dry toluene at room temperature. The reaction mixture is refluxed for 6 hours. After the mixture has cooled to room temperature, solid components are filtered off. The filtrate is extracted with 10% strength, aqueous hydrochloric acid, washed with distilled water, dried over magnesium sulfate, filtered and freed from the solvent under reduced pressure. 2.8 g (81%) of a colorless, crystalline solid of melting point 74-77° C. are obtained.
Reaction SMILES: C[C@@H](N)C1C=CC=CC=1.[CH3:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH:18]([C:22]([OH:24])=[O:23])[CH2:19]2)=[CH:14][CH:13]=1.Cl>CC(C)=O.O>[CH3:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][C@H:18]([C:22]([OH:24])=[O:23])[CH2:19]2)=[CH:14][CH:13]=1
Reactant: COc1ccc2c(c1)CC(C(=O)O)CC2
Agent: C[C@@H](N)c1ccccc1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc2c(c1)C[C@@H](C(=O)O)CC2

Procedure:
(R)-(+)-α-methylbenzylamine (25.8 ml, 0.2 mol) is added to a solution of 7-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid racemate (41 g, 0.2 mol) in acetone (800 ml) and after 2 hours at room temperature the obtained salt is recovered by filtration (45.2 g) and crystallized twelve times from acetone until a product with constant [α] of -20.5° (c=1.4%, CHCl3) is obtained. This product is then taken up in water (30 ml) and the obtained solution is made acidic by the addition of concentrated HCl and extracted with ethyl ether. The organic phase is dried and evaporated to dryness and the obtained residue is crystallised from benzene (20 ml) affording 0.9 g of 7-methoxy-1,2,3,4-tetrahydronaphthalen-2(S)-carboxylic acid; m.p. 133°-135° C.; [α]=-45.1° (c=1.4%, CHCl3). To determine its absolute configuration, the thus obtained product is converted into the corresponding 2-amino-7-methoxy-1,2,3,4 -tetrahydronaphthalene by the Curtius reaction.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([CH3:14])([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])[CH3:3].C(N(C(C)C)C(C)C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:46]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[O:54][C:55]1[N:60]=[CH:59][C:58]([NH2:61])=[CH:57][CH:56]=1)[CH3:47]>CN(C)C=O>[CH2:46]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[O:54][C:55]1[N:60]=[CH:59][C:58]([NH:61][C:11](=[O:13])[C:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:10])[CH3:14])=[CH:57][CH:56]=1)[CH3:47]
Reactant: CCc1ccccc1Oc1ccc(N)cn1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1ccccc1Oc1ccc(NC(=O)C(C)(C)NC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21.7 %

Procedure:
In a 8 mL vial N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-methylalanine (208 mg, 1.022 mmol) was dissolved in N,N-dimethylformamide (4 mL) to give a colourless solution. N-ethyl-N-(1-methylethyl)-2-propanamine (0.223 mL, 1.277 mmol) and N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylidene]-N-methylmethanaminium tetrafluoroborate (328 mg, 1.022 mmol) were added. The reaction mixture was stirred at room temperature for 15 min. 6-[(2-ethylphenyl)oxy]-3-pyridinamine (Intermediate 46, 228 mg) was added and the reaction mixture was warmed to 60° C. After 24 hours, additional 150 mg of N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylidene]-N-methylmethanaminium tetrafluoroborate were added. After additional 8 hours, the solvent was evaporated under vacuum using the Genevac affording a dark brown oil which was purified by silica gel chromatography (Biotage system, 25 g SNAP column) with as eluent a gradient Cyclohexane/EtOAc from 3:1 to 1:1 in 10 CV, then 1:1 for 5 CV. The collected fractions afforded the title compound as a pale orange solid (88.6 mg).
Reaction SMILES: I[C:2]1[C:3](=[O:10])[CH2:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH:7]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1>O1CCCC1.O.[Ag]=O.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([C:2]2[C:3](=[O:10])[CH2:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: CC1(C)C=C(I)C(=O)CC1
Agent: Cl[Pd]Cl
Agent: O=[Ag]
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: N#Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C2=CC(C)(C)CCC2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
Dissolve 2-iodo-4,4-dimethyl-cyclohex-2-enone(Tetrahedron Letters (1994), 35(37), 6787-90) (11 g, 44 mmol) in tetrahydrofuran (200 ml). Add 3-methoxyphenyl boronic acid (10 g, 65.8 mmol), triphenyl arsine (808 mg, 2.64 mmol), silver oxide (15.3 g, 66 mmol) in water (25 ml), bis(benzonitrile)dichloropalladium(II) (506 mg, 1.32 mmol). Stir at room temperature for 1 h. Quench with saturated aqueous ammonium chloride (200 ml), and stir 1 h. Filter reaction mixture through a bed of celite rinsing celite with ether (200 ml). Separate filtrate layers and extract the aqueous layer with additional ether (200 ml), combine organic extracts, and wash with water 2×(200 ml), brine (100 ml), dry, and concentrate. Chromatograph residue on a Biotage eluting with 10% ethyl acetate in hexanes to give (10.1 g, 99%) of the title compound as a yellow oil: 1H NMR (CDCl3) δ 7.26-7.23 (m, 1H), 6.88-6.84 (m, 3H), 6.69 (s, 1H), 3.81 (s, 3H), 2.62 (t, 2H), 1.96 (t, 2H), 1.25 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[NH:7][CH2:6][N:5]([CH2:13][CH3:14])[C:4]=2[CH:3]=1.[N-:15]=[C:16]=[O:17].[CH2:18](N(CC)CC)[CH3:19]>CC#N>[Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]([C:16]([NH:15][CH2:18][CH3:19])=[O:17])[CH2:6][N:5]([CH2:13][CH3:14])[C:4]=2[CH:3]=1
Reactant: CCN1CNS(=O)(=O)c2sc(Cl)cc21
Reactant: CCN(CC)CC
Reactant: [N-]=C=O
Solvent: CC#N
Product: CCNC(=O)N1CN(CC)c2cc(Cl)sc2S1(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
200 mg of the compound of Example 3 are dissolved in 1.5 ml of CH3CN. 1 ml of ethyl to isocyanate and 0.2 ml of triethylamine are then added to the solution. The reaction mixture is stirred at ambient temperature for 2 hours At the end of that period, the solvents are removed in vacuo. The residue is dissolved in a minimum of acetone. The product is then precipitated by gradual addition of water. The product is quickly collected by filtration, washed with water and then dried.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.[CH3:15][C:16]1[C:20]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[C:19]([CH3:33])[O:18][N:17]=1.N1C=CC=CC=1>ClCCl>[CH3:15][C:16]1[C:20]([CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([S:29]([NH:8][C:7]3[C:2]([CH3:1])=[N:3][C:4]([N:9]4[CH2:14][CH2:13][O:12][CH2:11][CH2:10]4)=[CH:5][CH:6]=3)(=[O:31])=[O:30])=[CH:27][CH:28]=2)=[C:19]([CH3:33])[O:18][N:17]=1
Reactant: Cc1nc(N2CCOCC2)ccc1N
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc(N2CCOCC2)ccc1NS(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Temperature: 65 °C
Yield: 67.2 %

Procedure:
A mixture of 2-methyl-6-(4-morpholinyl)-3-pyridinamine (170 mg, 0.880 mmol) and 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (265 mg, 0.880 mmol) in dichloromethane (4 mL) and pyridine (0.142 mL, 1.759 mmol) was heated at 65° C. for 2 hours. The reaction mixture was allowed to cool and separated between dichloromethane and saturated sodium bicarbonate solution. The organic phase was passed through a hydrophobic frit and evaporated in vacuo. The crude was purified by flash silica (Si) chromatography (0-100% ethyl acetate-cyclohexane gradient) to give the title compound (271 mg) as an off-white solid. LCMS (2 min, formic) Rt 0.82 min, m/z (ES+) 459 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH:12]([CH2:18][NH2:19])[CH2:11]2)=[CH:4][CH:3]=1.C1([O:26][C:27](=O)[NH:28][C:29]2[CH:34]=[C:33]([C:35]3[N:39]([CH3:40])[N:38]=[N:37][N:36]=3)[CH:32]=[C:31]([CH2:41][CH3:42])[CH:30]=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH2:41]([C:31]1[CH:30]=[C:29]([NH:28][C:27]([NH:19][CH2:18][CH:12]2[C:13]([CH3:17])([CH3:16])[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:11]2)=[O:26])[CH:34]=[C:33]([C:35]2[N:39]([CH3:40])[N:38]=[N:37][N:36]=2)[CH:32]=1)[CH3:42]
Reactant: CC1(C)CCN(CCc2ccc(F)cc2)CC1CN
Reactant: CCc1cc(NC(=O)Oc2ccccc2)cc(-c2nnnn2C)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cc(NC(=O)NCC2CN(CCc3ccc(F)cc3)CCC2(C)C)cc(-c2nnnn2C)c1
Reaction time: 18 h
Yield: 50.9 %

Procedure:
A solution of 1-[2-(4-fluorophenyl)ethyl]-4,4-dimethyl-piperidin-3-ylmethylamine (53 mg, 199 μmol) and [3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-carbamic acid phenyl ester (50 mg, 199 μmol) in N,N-dimethylformamide (1.0 mL) was treated with triethylamine (55 μL, 398 μmol). After 18 hours, the mixture was concentrated under vacuum. The residue was purified by flash chromatography, eluting with 5% methanol in dichloromethane containing 0.5% aqueous ammonium hydroxide, providing an amorphous solid (50 mg, 50%). 1H NMR (300 MHz, CDCl3) δ8.45 (s, 1H), 7.66 (s, 1H), 7.62 (s, 1H), 7.09 (m, 2H), 7.07 (s, 1H), 6.91 (t, J=9 Hz, 2H), 6.23 (m, 1H), 4.13 (s, 3H), 3.38 (m, 1H), 3.10 (m, 2H), 2.85 (m, 3H), 2.74 (m, 2H), 2.62 (q, J=7 Hz, 2H), 2.45 (m, 1H), 2.32 (m, 1H), 1.8-1.6 (m, 2H), 1.46 (m, 1H), 1.21 (t, J=7 Hz, 3H), 1.02 (s, 3H), 0.88 (s, 3H). Mass spec (ES+) m/z 494.3 (M+H+, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:25][CH3:26])[C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[CH2:14][C@H:13]1[C:22](O)=[O:23])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:28][C:29]([F:33])([F:32])[CH2:30][NH2:31].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl.C(OCC)(=O)C>[F:28][C:29]([F:33])([F:32])[CH2:30][NH:31][C:22]([C@@H:13]1[CH2:14][C:15]2[C:20](=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[N:12]1[C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:25][CH3:26])=[O:23]
Reactant: NCC(F)(F)F
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(Cl)cc2C[C@H]1C(=O)O
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(Cl)cc2C[C@H]1C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-(N-t-Butoxycarbonyl-2(S)-aminobutyryl)-5-chloroindoline-2(S)-carboxylic acid (0.192 g, 0.5 mmol) and 2,2,2-trifluoroethylamine hydrochloride (0.205 g, 1.5 mmol) were dissolved in dried dichloromethane (5 ml) under nitrogen at 0° C., and triethylamine (0.63 ml, 4.5 mmol) was added followed by bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.382 g, 1.5 mmol). The temperature was allowed to rise to room temperature and the mixture was stirred at room temperature for 24 hours, then filtered. The filtrate was concentrated under vacuum to give a brown solid which was columned on silica gel using 7:3 petroleum spirit: ethyl acetate as eluent to provide a white solid.
Reaction SMILES: N([C:8]1[C:9](=[O:21])[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13]([CH3:19])=[C:12]([CH3:20])[CH:11]=2)C1C=CC=CC=1.S(=O)(=O)(O)[OH:23]>O>[CH3:19][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[CH3:20])[C:9](=[O:21])[C:8]([OH:23])=[CH:17][C:16]2=[O:18]
Reactant: Cc1cc2c(cc1C)C(=O)C(Nc1ccccc1)=CC2=O
Reactant: O=S(=O)(O)O
Solvent: O
Product: Cc1cc2c(cc1C)C(=O)C(O)=CC2=O

Procedure:
A solution of 2-anilino-6,7-dimethyl-1,4naphthoquinone (3.1; 0.014 mole) in concentrated sulphuric acid (70ml) was diluted with an equal volume of water and refluxed for 1 minute. After pouring into cold water the precipitated hydroxy derivative was filtered off and extracted into petrol ether (b.p. 100°-102° C). After treatment of the extract with charcoal the title compound separated as a yellow solid, 1.29g (55%), m.p. 175°-177° C (d). (Found; C, 71.29; H, 5.07 C12H10O3 requires; C, 71.28; H, 4.98%)
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([C:23]=1[N:24]([CH2:29][CH:30]1[CH2:32][CH2:31]1)[CH2:25][CH:26]1[CH2:28][CH2:27]1)=[CH:21][C:20]([CH3:33])=[CH:19][CH:18]=2)[C:8]1[N:9]=[N:10][NH:11][N:12]=1.[H-].[Na+].[CH3:45]I>CN(C=O)C.CCOC(C)=O>[F:38][C:37]([F:40])([F:39])[C:35]1[CH:34]=[C:5]([CH:4]=[C:3]([C:2]([F:41])([F:1])[F:42])[CH:36]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([C:23]=1[N:24]([CH2:29][CH:30]1[CH2:31][CH2:32]1)[CH2:25][CH:26]1[CH2:27][CH2:28]1)=[CH:21][C:20]([CH3:33])=[CH:19][CH:18]=2)[C:8]1[N:9]=[N:10][N:11]([CH3:45])[N:12]=1
Reactant: CI
Reactant: Cc1ccc2ncc(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nn[nH]n3)c(N(CC3CC3)CC3CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc2ncc(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c(N(CC3CC3)CC3CC3)c2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 28.63 %

Procedure:
A mixture of (3-{[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-methyl}-6-methyl-quinolin-4-yl)-bis-cyclopropylmethyl-amine (700 mg, 1.18 mmol) and sodium hydride (60%) (61 mg, 1.5 mmol) in DMF (25 mL) was stirred at 0° C. for 5 min. To this, methyl iodide (337 g, 2 mmol) was then added and stirring was continued for another 30 min. The reaction mixture was diluted with EtOAc (200 mL) and washed with water (200 mL×4) and finally with brine (100 mL). The organic layer was separated, dried over sodium sulphate and concentrated under vacuum. The crude product was purified by column chromatography (silica gel 230-400 mesh). Elution with 1.5% EtOAc in hexane afforded 0.205 gm of gummy mass (yield: 28.63%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH:18]1[CH2:20][CH2:19]1)[CH:8]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:21]([O-])=[O:22].[Na+]>>[Cl:1][CH2:2][CH2:3][N:4]([N:21]=[O:22])[C:5]([N:7]([CH2:17][CH:18]1[CH2:20][CH2:19]1)[CH:8]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=C(NCCCl)N(CC1CC1)C1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Product: O=NN(CCCl)C(=O)N(CC1CC1)C1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 47.2 %

Procedure:
3.1 g of 1-(2-chloroethyl)-3-cyclopropylmethyl-3-(D-ribofuranosyl)urea and 1.5 g of sodium nitrite are treated in the same manner as described in Example 41. 1.6 g of 1-(2-chloroethyl)-1-nitroso-3-cyclopropylmethyl-3-(D-ribofuranosyl)-urea are thereby obtained as yellow liquid.
Reaction SMILES: [CH2:1]([CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:2][CH3:3].[H-].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O.O>[CH2:1]([C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:2][CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CCCC(C(=O)OCC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(CC(=O)OCC)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Yield: 97.2 %

Procedure:
Diethyl prop-1-ylmalonate (70.23 g) was added dropwise to a stirred suspension of sodium hydride (8.35 g) in dimethylformamide (400 ml) under an atmosphere of nitrogen at 10° to 15° C. Following the addition, the mixture was allowed to stir at room temperature until effervescence ceased. The resulting clear solution was cooled again and ethyl bromoacetate (58.06 g) was added. The mixture was heated at 70° C. for 2 hours then allowed to cool, diluted with water, and extracted with ether. The extracts were washed with water, dried over magnesium sulphate, and concentrated to give almost pure diethyl 2-prop-1-yl-2-ethoxycarbonylsuccinate (97.35 g, 97%) as a pale yellow liquid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1([CH3:49])[CH2:18][C:17]2[CH:19]=[C:20]([C:23]3[C:28](=[O:29])[N:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=5)=[CH:33][CH:32]=4)[C:26]([CH2:45][CH2:46][CH3:47])=[N:25][C:24]=3[CH3:48])[CH:21]=[CH:22][C:16]=2[O:15]1>O>[CH3:13][C:14]1([CH3:49])[CH2:18][C:17]2[CH:19]=[C:20]([C:23]3[C:28](=[O:29])[N:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]5[NH:3][C:4](=[O:7])[O:5][N:44]=5)=[CH:33][CH:32]=4)[C:26]([CH2:45][CH2:46][CH3:47])=[N:25][C:24]=3[CH3:48])[CH:21]=[CH:22][C:16]=2[O:15]1
Reactant: CCCc1nc(C)c(-c2ccc3c(c2)CC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCc1nc(C)c(-c2ccc3c(c2)CC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 15.6 %

Procedure:
A mixture of hydroxylammonium chloride (2.49 g), sodium hydrogen carbonate (3.54 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-{[5-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (1.03 g) was added, and the mixture was stirred at 90° C. for 5 hr. The mixture was allowed to cool to room temperature. Water was added to the reaction mixture, and the precipitate was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.51 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.47 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.18 g, 16%).
Reaction SMILES: [C:1]1([C:7]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1[CH:21]=[CH:20]N=C1)=O.[Cl-].[Mg+2].[Cl-].C(O)(=O)[CH2:31][C:32]([OH:34])=[O:33].C([K])C.C(N(CC)CC)C>>[CH2:20]([O:34][C:32](=[O:33])[CH2:31][C:12](=[O:14])[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][CH2:10][CH2:11]1)[CH3:21]
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CC(=O)O
Agent: CC[K]
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)C1(c2ccccc2)CCCC1

Procedure:
The title compound was prepared from 1-phenyl-1-cyclopentanecarboxylic acid (50.0 g, 0.220 mol), 1,1'-carbonyldiimidazole (43.0 g, 0.265 mol), magnesium chloride (40.0 g, 0.418 mol), ethyl potassium malonate (60.0 g, 0.352 mol), and triethylamine (48.9 g, 0.484 mol) using the procedure described in Example 3, Step A.