Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C@H]1P(CCP2[C@H](C)CC[C@H]2C)[C@H](C)CC1.[OH:17][C:18]1[CH:31]=[CH:30][C:21]2[C:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:23][O:24][C:20]=2[CH:19]=1.[H][H]>CO>[OH:17][C:18]1[CH:31]=[CH:30][C:21]2[CH:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:23][O:24][C:20]=2[CH:19]=1
Reactant: [H][H]
Reactant: COC(=O)Cc1coc2cc(O)ccc12
Agent: C[C@@H]1CC[C@@H](C)P1CCP1[C@H](C)CC[C@H]1C
Solvent: CO
Product: COC(=O)CC1COc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.5 %

Procedure:
To a mixture of (1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (12 mg) and (R,R)-Me-BPE (6.5 mg) was added methanol (2.5 mL) sufficiently substituted with argon gas, and the mixture was stirred at room temperature for 15 min. This was added to methyl (6-hydroxy-1-benzofuran-3-yl)acetate (51 mg), and the mixture was stirred at 70° C. for 3 hr under 0.7 MPa hydrogen atmosphere. The reaction mixture was quantified by HPLC. As a result, the enantiomeric excess was 47.9%, and the yield was 41.5%.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:34])[N:24]([CH2:30][CH2:31][C:32]#[N:33])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=[C:19]([Cl:35])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[C:32]([CH2:31][CH2:30][N:24]([CH2:25][C:26]([CH3:27])([CH3:29])[CH3:28])[C:23](=[O:34])[C:21]1[CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:18]=[C:19]([Cl:35])[CH:20]=1)(=[O:40])[NH2:33]
Reactant: CC(C)(C)CN(CCC#N)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CN(CCC(N)=O)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Reaction time: 18 h

Procedure:
A solution of (2-{3-chloro-5-[(2-cyano-ethyl)-(2,2-dimethyl-propyl)-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.052 g) in a mixture of dichloromethane (5 ml) and trifluoroacetic acid (2 ml) was stored at room temperature for 18 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.02 g) was obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11]([C:13]1[CH:17]=[N:16][N:15](C2CCN(C(OC(C)(C)C)=O)CC2)[N:14]=1)=[O:12])[CH3:9].C(OC(C1N([CH:41]2[CH2:46][CH2:45][N:44](C(OC(C)(C)C)=O)[CH2:43][CH2:42]2)N=NC=1)=O)C>>[N:44]1([C:13]2([C:11]([O:10][CH2:8][CH3:9])=[O:12])[CH:17]=[N:16][NH:15][NH:14]2)[CH2:45][CH2:46][CH2:41][CH2:42][CH2:43]1
Reactant: CCOC(=O)c1cnn(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Reactant: CCOC(=O)c1cnnn1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(N2CCCCC2)C=NNN1
Reaction time: 0.75 h

Procedure:
Trifluoroacetic acid (3 mL) was added to 1,1-dimethylethyl 4-[4-(ethoxycarbonyl)-2H-1,2,3-triazol-2-yl]-1-piperidinecarboxylate (0.41 g, 1.3 mmol) (i.e. the product of Example 32, Step A). The reaction mixture was stirred for 45 minutes. The reaction mixture was then concentrated in vacuo. The resulting mixture was treated with saturated aqueous sodium bicarbonate and the aqueous layer was extracted three times with dichloromethane. The solvent was removed with a rotary evaporator to afford 0.23 g of ethyl 4-piperidinyl-2H-1,2,3-triazole-4-carboxylate as an oil. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2>>[CH3:13][C:10]1[CH:11]=[CH:12][C:2]([NH:1][C:15]2[CH:16]=[N:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:3]([CH:9]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: Brc1cnc2ccccc2c1
Reactant: CCOC(=O)c1cc(C)ccc1N
Product: CCOC(=O)c1cc(C)ccc1Nc1cnc2ccccc2c1

Procedure:
Obtained (0.845 g, 97% of yield) following the procedure described in Example 14 (step B) starting from ethyl 2-amino-5-methylbenzoate (0.395 g, 2.20 mmol) and 3-bromoquinoline (0.46 g, 2.20 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14]2[N:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[N:17]=[C:16]([C:25](O)=[O:26])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1)#[N:2].ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[O:54]=[C:52]1[CH2:53][N:49]([C:25]([C:16]2[CH:15]=[C:14]([C:5]3[CH:4]=[C:3]([CH:8]=[C:7]([O:9][C:10]([F:11])([F:13])[F:12])[CH:6]=3)[C:1]#[N:2])[N:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[N:17]=2)=[O:26])[CH2:50][NH:51]1
Reactant: N#Cc1cc(OC(F)(F)F)cc(-c2cc(C(=O)O)nn2-c2cccnc2)c1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: N#Cc1cc(OC(F)(F)F)cc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccnc2)c1

Procedure:
98 mg (0.26 mmol) of the compound of Example 58A is reacted analogously to the synthesis of the compound of Example 1 with 35 mg (0.29 mmol) of 4-imidazolinone-hydrochloride. 80 mg (69% of theory) of the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][OH:11])[CH2:7][C:6]=2[CH:12]=1.CC1(C)N([O])C(C)(C)CCC1.[O-:24]Cl.[Na+].Cl>O.CC#N>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([OH:24])=[O:11])[CH2:7][C:6]=2[CH:12]=1
Reactant: [O-]Cl
Reactant: OCC1Cc2cc(Cl)ccc2O1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(O)C1Cc2cc(Cl)ccc2O1
Temperature: 0 °C
Yield: 74 %

Procedure:
To a solution of (5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanol (2 g, 11 mmol), KHCO3 (4.32 g, 43 mmol, 4 eq) and TEMPO (20 mg, 0.13 mmol, 0.1 eq) in water (8 ml) and CH3CN (18 ml) was added NaOCl (20 ml, aq. 15%, ˜4 eq) dropwise with stirring at 0° C. and stirred for 1 hour. The mixture was diluted with water (200 ml) and adjusted to pH˜4 with hydrogen chloride (2N). After extraction with ethyl acetate (3×200 ml), the organic layers were combined, washed with brine (200 ml), dried over anhydrous sodium sulfate, filtered, and then concentrated under vacuum. The crude material was purified by silica gel chromatography using 1% methanol in dichloromethane to elute. The product-containing fractions were combined and concentrated under vacuum to afford 5-chloro-2,3-dihydro-1-benzofuran-2-carboxylic acid as a yellow solid (1.6 g, 74%). 1H NMR (300 MHz, CDCl3): δ 7.05-7.22 (m, 2H), 6.83 (d, J=8.4 Hz, 1H), 5.20-5.30 (m, 1H), 3.56-3.65 (m, 1H), 3.33-3.45 (m, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[C:12]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=1[C:14]#[N:15].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:12]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=2[C:14]#[N:15])=[CH:4][CH:3]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Sc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])ccc1Sc1ccc(Cl)cc1
Temperature: 60 °C
Yield: 99.1 %

Procedure:
To a solution of 15.2 g (0.105 moles) of 4-chlorothiophenol dissolved in 150 ml of DMSO was added 4.2 g (0.105 moles) of NaOH. The mixture was heated to 60° C. and 18.3 g (0.100 moles) of 2-chloro-5-nitrobenzonitrile was added and the mixture heated at 60° C. for 21/2 hrs. The mixture was cooled and poured into a solution of 100 ml of 2 N aqueous NaOH and 600 ml of water. The product was collected by filtration, washed well with water and dried to obtain 28.8 g of product (99% yield). Recrystallization from ethanol afforded purified 2-((4-chlorophenyl)thio)-5-nitrobenzonitrile, mp 162°-164.5° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:18][CH:17]([CH2:19][N:20]([CH3:25])[CH:21]2[CH2:24][O:23][CH2:22]2)[CH2:16]1)=O)(C)(C)C>ClCCl>[NH:15]1[CH2:16][CH:17]([CH2:19][N:20]([CH3:25])[CH:21]2[CH2:22][O:23][CH2:24]2)[CH2:18]1
Reactant: CN(CC1CN(C(=O)OC(C)(C)C)C1)C1COC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CC1CNC1)C1COC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.3 %

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of 3-[(methyl(oxetan-3-yl)amino)methyl]azetidine-1-carboxylic acid tert-butyl ester (330 mg, 1.29 mmol) in dichloromethane (12 mL) The resulting reaction mixture was stirred at RT for 1.5 h. The solvents were reduced in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge (5 g). The cartridge was washed with DCM/MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM to afford (Azetidin-3-ylmethyl)methyl(oxetan-3-yl)amine as colourless oil (180 mg, 90%). 1H NMR (400 MHz, CDCl3): δ 4.64 (2 H, t, J=6.59 Hz), 4.57 (2 H, t, J=6.31 Hz), 3.72 (2 H, t, J=7.87 Hz), 3.58-3.49 (1 H, m), 3.37 (2 H, t, J=7.22 Hz), 2.92-2.82 (1 H, m), 2.44 (3 H, m), 2.06 (3 H, s)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[I-:13].[Na+]>C(O)CCC.[Cu]I.CNCCNC>[I:13][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)cc1C(F)(F)F
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: CCCCO
Product: Nc1ncc(I)cc1C(F)(F)F
Temperature: 23 °C
Yield: 101.8 %

Procedure:
A mixture of 5-bromo-3-trifluoromethyl-pyridin-2-ylamine (example C.18 step 3) (723 mg, 3 mmol), sodium iodide (900 mg, 6 mmol), copper (I) iodide (29 mg, 5 mol %) and N,N′-dimethylethylendiamine (26 mg, 10 mol %) in n-butanol (6 mL) was stirred at reflux under argon atmosphere for 18 h. The reaction mixture was cooled to 23° C., extracted with ethyl acetate and water, the organic layers were dried over MgSO4, filtered and evaporated to leave the title compound as a brown solid (880 mg, 102%), which was used without further purification. MS (ISN) 287.0 [(M−H)−].
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][C:11]=2[N:10]=[C:9]1[CH:18](Br)[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>CCO.CCOC(C)=O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][C:11]=2[N:10]=[C:9]1[CH:18]([NH:26][CH2:25][CH2:24][N:23]([CH3:27])[CH3:22])[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: CCC(Br)c1nc2c(c(=O)n1Cc1ccccc1)CCC2
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC(NCCN(C)C)c1nc2c(c(=O)n1Cc1ccccc1)CCC2
Temperature: 80 °C

Procedure:
3-benzyl-2-(1-bromopropyl)-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one (1-3, 0.080 g, 0.23 mmol) was dissolved in EtOH (2.0 mL) and treated with N,N-dimethyl ethylenediamine (0.05 mL, 0.46 mmol). The reaction was heated to 80° C. for 24 hours. The reaction was diluted with EtOAc (10 mL), washed with 5% NH4Cl, and dried over MgSO4. The organics were concentrated under reduced pressure to provide 3-benzyl-2-(1-{[2-(dimethylamino)-ethyl]amino}propyl)-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one (1-4). MS 355.1 found 354.5 required.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[CH3:23][CH:24]([CH3:28])[CH2:25][CH2:26][NH2:27]>ClCCl.C(=O)(O)[O-].[Na+]>[CH2:26]([NH:27][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])[CH2:25][CH:24]([CH3:28])[CH3:23]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
4-Nitrobenzene-1-sulfonyl chloride (1.5 g, 6.57 mmol) was dissolved in dichloromethane (30 ml) and cooled to 0° C. followed by addition of diisopropylethylamine (2.293 ml, 13.13 mmol). 3-Methylbutan-1-amine (0.926 ml, 7.88 mmol) was dissolved in 5 ml dichloromethane and added via syringe. After the addition, the mixture was allowed to warm to room temperature for 3 hours. The solution was diluted with aqueous sodium bicarbonate and extracted twice with dichloromethane. The organics were combined, dried over magnesium sulfate, filtered and concentrated. Chromatography provided the title compound.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:15][C:16]#[N:17])=[CH:3][CH:2]=1.CCCCC.[H-].[Na+].Cl.Cl[CH2:27][C:28]1[N:29]=[C:30]([CH3:33])[S:31][CH:32]=1>CN(C=O)C>[CH3:33][C:30]1[S:31][CH:32]=[C:28]([CH2:27][N:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[C:4]([O:14][CH2:15][C:16]#[N:17])[C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:29]=1
Reactant: N#CCOc1cccc2[nH]c3ccccc3c12
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: Cc1nc(Cn2c3ccccc3c3c(OCC#N)cccc32)cs1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75.9 %

Procedure:
2-(9H-Carbazol-4-yloxy)acetonitrile (0.143 g, 0.64 mmol)) is added to a slurry of pentane-washed NaH (0.0825 g, 0.0021 mol) in DMF (1 mL) and allowed to stir for 20 min at room temperature. 4-Chloromethyl-2-methylthiazole hydrochloride (0163 g, 0.89 mmol) is added and after stirring for 2 h the mixture is partitioned between ethyl acetate and water. The combined organic layers are dried over magnesium sulfate and concentrated to an oil. The oil is chromatographed on silica gel (75 mL) using ethyl acetate/hexane (20/80 and 40/60) and solids are crystallized from dichloromethane/ether to give 0.162 g (76%) of the title compound; MS (ESI+) for C19H15N3OS m/z 334.2 (M+H)+; IR (drift) 1581, 1459, 1440, 1341, 1333, 1275, 1228, 1215, 1182, 1157, 1151, 1113, 782, 754, 718 cm−1; 1H NMR (CDCl3) δ2.74, 5.09, 5.62, 6.38, 6.78, 7.19, 7.31, 7.44, 8.32. Anal. Calcd for C19H15N3OS: C, 68.45; H, 4.53; N, 12.60. Found: C, 68.27; H, 4.53; N, 12.33.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)CC)C.[NH2:17][C:18]1[CH:40]=[CH:39][C:21]([C:22]([N:24]2[CH2:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[CH2:27][C:26]3[CH:35]=[CH:36][CH:37]=[CH:38][C:25]2=3)=[O:23])=[CH:20][CH:19]=1>C(Cl)Cl>[CH:35]1[C:26]2[CH2:27][C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[CH2:30][N:24]([C:22]([C:21]3[CH:20]=[CH:19][C:18]([NH:17][C:7]([CH:1]4[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]4)=[O:8])=[CH:40][CH:39]=3)=[O:23])[C:25]=2[CH:38]=[CH:37][CH:36]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: O=C(Cl)C1CC=CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)C1CC=CCC1
Reaction time: 18 h
Yield: 67.1 %

Procedure:
A mixture of 208 mg of 3-cyclohexene-1-carbonyl chloride (prepared from 3-cyclohexene-1-carboxylic acid and thionyl chloride) and 145 mg of triethylamine in 3 ml of methylene chloride is added to a solution of 377 mg of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine in 7 ml of methylene chloride. The mixture is stirred for 18 hours, washed with water, 1N HCl, water, 1M NaHCO3 and brine then dried with Na2 SO4. The organic layer is passed through a short column of hydrous magnesium silicate and hexane added to the filtrate at the boil to give 340 mg of the desired product as a crystalline solid, m.p. 234°-236° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)=[O:4].S(Cl)([Cl:16])=O>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Product: COC(=O)c1ccc(C(=O)Cl)cc1
Temperature: 40 °C

Procedure:
A suspension of 5 g of the acid, prepared in section (a) above, in 50 cm3 of thionyl chloride is heated for 3 hours at 40° C. At the end of the reaction, the reaction medium is homogenized and the solution is concentrated under reduced pressure. The expected acid chloride crystallizes in the form of pink flakes. The yield is quantitative. This solid is employed directly for the condensation reaction.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[OH-].[K+].Cl[CH2:12][CH:13]=O.Cl>CO>[O:7]1[C:3]2[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[C:2]=2[CH:13]=[CH:12]1
Reactant: O=C1CCCC(=O)C1
Reactant: O=CCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCCc2occc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
In methanol (40 mL) was dissolved 11.2 g (0.100 mol) of 1,3-cyclohexanedione, an aqueous solution (8 mL) containing 6.60 g (0.100 mol) of 85% potassium hydroxide was added dropwise to the solution, and the resulting mixture was stirred at room temperature for 30 minutes. This mixture was cooled in an ice bath, 21.6 g (0.110 mol) of 40% chloroacetaldehyde aqueous solution was added to the mixture with stirring and the resulting mixture was stirred at room temperature overnight. To the reaction mixture was added dropwise 2 mol/L hydrochloric acid aqueous solution, and the resulting mixture was stirred at room temperature for 30 minutes and extracted with ether. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 8.63 g (0.0635 mol, Yield: 63.5%) of 6,7-dihydro-1-benzofuran-4(5H)-one.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[CH2:14][C@@H:13]1[C@H:4]([CH2:5][CH2:6][C@H:7]3[C@@:12]1([CH3:20])[CH2:11][CH2:10][C@H:9]([OH:21])[CH2:8]3)[CH2:3]2.[I-].[CH3:23][S+](C)C.CC(C)([O-])C.[K+].O>CS(C)=O>[CH3:1][C@@:2]12[C@:18]3([CH2:23][O:19]3)[CH2:17][CH2:16][C@H:15]1[CH2:14][C@@H:13]1[C@H:4]([CH2:5][CH2:6][C@H:7]3[C@@:12]1([CH3:20])[CH2:11][CH2:10][C@H:9]([OH:21])[CH2:8]3)[CH2:3]2
Reactant: C[C@@]12CC[C@H](O)C[C@H]1CC[C@@H]1C[C@]3(C)C(=O)CC[C@H]3C[C@H]12
Reactant: C[S+](C)C
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@@]12CC[C@H](O)C[C@H]1CC[C@@H]1C[C@@]3(C)[C@@H](CC[C@@]34CO4)C[C@H]12
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of compound 22 (35 mg, 0.12 mmol) in DMSO (3 mL) was added trimethylsulfonium iodide (204 mg, 1.0 mmol) and potassium tert-butoxide (112 mg, 1.0 mmol) at room temperature. After 3 h, water (20 mL) was added and the product extracted into EtOAc (50 mL×3). The combined extracts were dried, filtered and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 20% EtOAc in hexanes) to afford compound 23 (23 mg, 63%): mp 138-140° C.; [α]D20 −16.7 (c 0.15, CHCl3); 1H NMR (CDCl3) δ 4.06 (s, br, 1H), 2.90 (d, J=5.1 Hz, 1H), 2.61 (d, J=5.1 Hz, 1H), 0.86 (s, 3H), 0.79 (s, 3H); 13C NMR (CDCl3) δ 70.5, 66.6, 54.6, 53.6, 47.1, 42.6, 40.2, 39.2, 36.4, 35.8, 35.1, 32.0, 31.8, 29.1, 28.9, 28.8, 25.9, 24.4, 14.4, 11.2; IR νmax 3435, 1007, 758 cm−1. Anal. Calcd for (C20H32O2): C, 78.90; H, 10.59. Found: C, 78.83; H, 10.77.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:8]1[O:16][CH2:15][C@@H:13]([OH:14])[C@@H:11]([OH:12])[C@@H:9]1[OH:10])=[O:6].[N+:22]([O-])([N+]([O-])=O)=[O:23]>>[Cl:1][CH2:2][CH2:3][N:4]([N:22]=[O:23])[C:5]([N:7]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:8]1[O:16][CH2:15][C@@H:13]([OH:14])[C@@H:11]([OH:12])[C@@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: COCCCN(C(=O)NCCCl)C1OC[C@@H](O)[C@@H](O)[C@@H]1O
Product: COCCCN(C(=O)N(CCCl)N=O)C1OC[C@@H](O)[C@@H](O)[C@@H]1O
Yield: 55.7 %

Procedure:
3.3 g of 1-(2-chloroethyl)-3-(3-methoxy-n-propyl)-3-(D-arabinopyranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 10-(2). 2.0 g of 1-(2-chloroethyl)-1-nitroso-3-(3-methoxy-n-propyl)-3-(D-arabinopyranosyl)urea are thereby obtained as pale yellow powder.
Reaction SMILES: C(OC(=O)NC1CC(=O)OC1OCC)C=C.NC1C=CC(C(NC(C)C(N2CCCC2C(O)=O)=O)=O)=CC=1Cl.[O:40]=[C:41]1[O:45][CH:44]([O:46][CH2:47][CH2:48]C2C=CC=CC=2)[CH:43]([NH:55][C:56]([CH:58]2[CH2:62][CH2:61][CH2:60][N:59]2[C:63](=[O:77])[CH:64]([NH:66][C:67](=[O:76])[C:68]2[CH:73]=[CH:72][C:71]([NH2:74])=[C:70]([Cl:75])[CH:69]=2)[CH3:65])=[O:57])[CH2:42]1>>[CH2:47]([O:46][CH:44]1[CH:43]([NH:55][C:56]([CH:58]2[CH2:62][CH2:61][CH2:60][N:59]2[C:63](=[O:77])[CH:64]([NH:66][C:67](=[O:76])[C:68]2[CH:73]=[CH:72][C:71]([NH2:74])=[C:70]([Cl:75])[CH:69]=2)[CH3:65])=[O:57])[CH2:42][C:41](=[O:40])[O:45]1)[CH3:48]
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Agent: C=CCOC(=O)NC1CC(=O)OC1OCC
Agent: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)O
Product: CCOC1OC(=O)CC1NC(=O)C1CCCN1C(=O)C(C)NC(=O)c1ccc(N)c(Cl)c1

Procedure:
Prepared from (2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester and 97a following the method used for 98a. The title compound was isolated as a white solid (195 mg, 82% yield). 1H-NMR (500 MHz, CD3OD) δ 1.32-1.55 (m, 3H), 1.58-1.77 (m, 3H), 1.98-2.54 (m, 4H), 2.68-2.76 (d, 0.3H), 2.79-2.89 (m, 0.7H) 2.96-3.10 (m, 0.7H), 3.18-3.27 (dd, 0.3H), 3.72-4.18 (m, 4H), 4.46-5.12 (m, 3H), 5.60 (s, 0.4H), 5.74-5.84 (m, 0.6H), 7.03 (d, 0.8H), 7.75-7.86 (m, 1H), 8.01 (d, 0.7H), 8.35 (d, 0.3H), 8.74 (d, 0.2H). Analytical HPLC 8.31 min. LC-MS (ES+) m/e=467.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[C@@H:12]1[CH2:14][C@H:13]1[CH2:15]O.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:48]1(=[O:58])[NH:52][C:51](=[O:53])[C:50]2=[CH:54][CH:55]=[CH:56][CH:57]=[C:49]12>O1CCCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[C@@H:12]1[CH2:14][C@H:13]1[CH2:15][N:52]1[C:48](=[O:58])[C:49]2[C:50](=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:51]1=[O:53]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cn1cc2c([C@@H]3C[C@H]3CO)c(F)ccc2n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cn1cc2c([C@@H]3C[C@H]3CN3C(=O)c4ccccc4C3=O)c(F)ccc2n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of trans-[2-(5-fluoro-2-methyl-2H-indazol-4-yl)cyclopropyl]methanol (500 mg, 2.27 mmol) in tetrahydrofuran (22 mL) were added a solution (40%, 1.24 mL, 2.72 mmol) of diethyl azodicarboxylate in toluene, triphenylphosphine (774 mg, 2.95 mmol) and phthalimide (434 mg, 2.95 mmol), and the mixture was stirred under nitrogen atmosphere at room temperature for 1.5 hr. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane=10/90→40/60) to give trans-2-{[2-(5-fluoro-2-methyl-2H-indazol-4-yl)cyclopropyl]methyl}-1H-isoindole-1,3(2H)-dione as a crudely purified product (893 mg).
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:18][N:19]2[CH2:23][C:22](=[O:24])[NH:21][C:20]2=[O:25])[CH2:3]1.N1C=CC(=[O:32])NC1=O>>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:18][N+:19]2([O-:32])[CH2:23][C:22](=[O:24])[NH:21][C:20]2=[O:25])[CH2:3]1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: CN1C[C@H](CN2CC(=O)NC2=O)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Product: CN1C[C@H](C[N+]2([O-])CC(=O)NC2=O)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Yield: 63 %

Procedure:
Repeating Example 1 but using 1-[(6-methylergolin -8β- yl)methyl]-2,4-imidazolidinedione instead of 1-[(6-methyl -Δ- 9,10-ergolen -8β- methyl]-2,4-(1H,3H)-pyrimidinedione the title compound was obtained in 63% yield, m.p. 163-165° C.