Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[C:7]([O:13][CH3:14])(=O)[CH2:8][CH2:9][CH2:10][CH3:11]>[Pd]>[CH2:7]([O:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4])[CH2:8][CH2:9][CH2:10][CH3:11].[CH3:2][CH2:14][O:13][CH2:7][CH3:8]
Reactant: CCCCC(=O)OC
Reactant: OCC(O)CO
Agent: [Pd]
Product: CCCCCOCC(O)CO
Product: CCOCC
Temperature: 140 °C
Yield: 58 %

Procedure:
A stirred autoclave was charged, at room temperature, with 65.76 g(714 mmol) of glycerol, 2.15 g (17.6 mmol) of methyl valerate, 0.23 g (10 wt %) of camphosulfonic acid and 0.40 g (1.0 mol %) of Pd/C at 5%. The autoclave was then pressurized at 50 bar of dihydrogen gas H2, and then it was heated at 140° C. for 16 h, stirring vigorously. After 16 h of reaction, the reaction mixture was brought back to room temperature. The catalyst was filtered on a MILLIPORE® filter (a membrane filter) (0.45 μm) and was rinsed with absolute ethanol. The solvents were evaporated and the organic products were extracted from the glycerol phase by extraction with CH2Cl2 (3×50 ml). The organic phase was washed with water (2×30 ml) and the CH2Cl2 was then evaporated at reduced pressure. The crude reaction product was purified on a flash silica column (eluent: cyclohexane/ethyl acetate=4:1˜1:1). 1-O-pentyl-glycerol ether was obtained at an isolated yield of 58%.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:12]([CH2:18]OC)[CH2:13][Si](C)(C)C)([CH3:11])([CH3:10])[CH3:9].[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1/[CH:29]=[CH:30]/[C:31]([O:33]C)=[O:32].C(=O)(O)[O-].[Na+].C(Cl)[Cl:41]>>[ClH:41].[C:8]([N:12]1[CH2:13][C@@H:29]([C:23]2[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=2[F:21])[C@H:30]([C:31]([OH:33])=[O:32])[CH2:18]1)([CH3:9])([CH3:10])[CH3:11]
Reactant: COC(=O)/C=C/c1ccc(F)cc1F
Reactant: ClCCl
Reactant: COCN(C[Si](C)(C)C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)N1C[C@@H](C(=O)O)[C@H](c2ccc(F)cc2F)C1
Product: Cl
Reaction time: 18 h

Procedure:
Trifluoroacetic acid (116 μL, 1.51 mmol) was added to a solution of N-tert-butyl-N-(methoxymethyl)-N-(trimethylsilylmethyl)amine from Step B (3.07 g, 15.1 mmol) and methyl (2E)-3-(2,4-difluorophenyl)prop-2-enoate (2.99 g, 15.1 mmol) in methylene chloride (60 mL) at ambient temperature. After 18 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with methlene chloride. The combined organic extracs were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification of the residue by normal phase medium pressure liquid chromatography on silica gel (gradient elution; 0-9% methanol (containing 10% v/v ammonium hydroxide)/methylene chloride as eluent) gave the racemic title compound as a colorless liquid. The racemic titled compound was resolved into its enantiomeric components using preparative chiral high pressure liquid chromatography on CHIRALPAK AD Phase (5% isopropanol/heptanes as eluent) to give in order of elution: methyl (3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylate enantiomer of the titled compound as a colorless oil followed by the methyl (3R,4S)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylate enantiomer of the title compound as a colorless oil.
Reaction SMILES: O[CH2:2][C@@H:3]([NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:9])[CH2:4][CH2:5][CH3:6].CC(C)([O-])C.[K+].O>C1COCC1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]2[CH2:2][C@H:3]([CH2:4][CH2:5][CH3:6])[NH:7][C:8]2=[O:9])=[CH:12][CH:13]=1
Reactant: CCC[C@@H](CO)NC(=O)Nc1ccc(OC)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@H]1CN(c2ccc(OC)cc2)C(=O)N1
Reaction time: 1 h
Yield: 6.7 %

Procedure:
A solution of 1-[(2S)-1-hydroxypentan-2-yl]-3-(4-methoxyphenyl)urea (550 mg) and potasium tert-butoxide (593 mg) in THF (25 mL) was cooled in ice under nitrogen atomosphere, and a solution of p-toluenesulfonylchrolide (672 mg) in THF (10 mL) was added dropwise thereto. After the mixture was stirred for 1 hr while cooling in ice, water was added thereto, and the resulting mixture was extracted with chloroform. The organic layer was separated out by phase-separation cartridge, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate=88:12-0:100), and further recrystallized from chloroform/hexane. The solid was collected by filtration to afford (4S)-1-(4-methoxyphenyl)-4-propylimidazolidin-2-one (34 mg). In addition, the filtrate was concentrated under reduced pressure to afford (4S)-1-(4-methoxyphenyl)-4-propylimidazolidin-2-one (254 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1.[CH3:27][CH:28]1[CH2:32][C:31]2[CH:33]=[CH:34][CH:35]=[C:36]([NH2:37])[C:30]=2[O:29]1>>[F:15][C:16]1[CH:17]=[C:18]([S:23]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([NH:37][C:36]2[C:30]4[O:29][CH:28]([CH3:27])[CH2:32][C:31]=4[CH:33]=[CH:34][CH:35]=2)=[N:9]3)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: CC1Cc2cccc(N)c2O1
Product: CC1Cc2cccc(Nc3ccc4c(NS(=O)(=O)c5cc(F)cc(F)c5)cccc4n3)c2O1

Procedure:
The title compound, MS: m/e=468.3 (M+H+), was prepared in accordance with the general method of example 89 from 5-nitro-2-chloroquinoline, 3,5-difluorobenzenesulfonylchloride and 2,3-dihydro-2-methyl-7-benzofuranamine (CAS 26210-74-2).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][C@H:7]1[C:15]2[C:14](O)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9][CH2:8]1>ClCCCl>[Cl:3][C:14]1[C:15]2[C@H:7]([CH3:6])[CH2:8][CH2:9][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: C[C@@H]1CCc2ncnc(O)c21
Solvent: ClCCCl
Product: C[C@@H]1CCc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 61.1 %

Procedure:
Neat POCl3 (463.9 mL, 5067 mmol) was added slowly by addition funnel to a 0° C. solution of (R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (152.2 g, 1013 mmol) in DCE (1.2 L). After addition was complete, the reaction mixture was warmed to room temperature and then heated to reflux while being stirred at reflux for 70 minutes, after which the reaction was complete by HPLC. The reaction mixture was cooled to room temperature, and the excess POCl3 was quenched in 4 portions. The reaction mixture was transferred to a separatory funnel and dripped into a beaker containing ice and saturated NaHCO3 solution cooled in an ice bath. Once the addition of each portion of the reaction mixture was complete, the quenched mixture is stirred for 30 minutes to ensure complete destruction of POCl3 prior to transferring it to a separatory funnel. The mixture was transferred to a separatory funnel and extracted with DCM (2×). The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel (1 kg silica gel slurried in 9:1 hex:ethyl acetate onto a 3 L fritted funnel, silica settled under vacuum, topped with sand). The crude was loaded with a DCM/hexane mixture, and compound was eluted using 1 L sidearm flasks with vacuum. High Rf byproducts eluted first, then (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (104.4 g, 61.09% yield) as a brown oil. Triethylamine (93.0 mL, 534 mmol) and tert-butyl piperazine-1-carboxylate (34.8 g, 187 mmol) were added to a solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (30.0 g, 178 mmol) in n-BuOH (250 mL). The reaction mixture was heated to reflux under nitrogen and stirred overnight (17 hours). The reaction mixture was concentrated on a rotavap. The resulting oil was dissolved in DCM, washed with H2O, dried (Na2SO4), filtered, and concentrated. The resulting brown oil was purified on silica gel eluting first with 2:1 hexanes:ethyl acetate until product eluting cleanly, then gradient 1:1 to 1:5 DCM:ethyl acetate to give (R)-tertbutyl 4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (42.0 g, 74.1% yield) as a beige powder. LC/MS (APCI+) m/z 319.1 [M+H]+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:21]1([O:27][CH2:28][CH2:29][CH2:30][Br:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[Br-:31].[OH:10][C:9]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:30][CH2:29][CH2:28][O:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([CH2:8][CH2:7]1)[CH2:2][CH2:3]2
Reactant: OC(c1cccs1)(c1cccs1)C12CCN(CC1)CC2
Reactant: BrCCCOc1ccccc1
Solvent: ClC(Cl)Cl
Product: OC(c1cccs1)(c1cccs1)C12CC[N+](CCCOc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 45.5 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct-4-yl(di-2-thienyl)methanol (0.0578 g, 0.189 mmol) and 3-bromopropyl phenyl ether (0.033 mL, 0.209 mmol) in 1MeOH/1 CHCl3 (4.0 mL) were reacted to give the desired product (0.0448 g, 45.4%). EI-MS m/z 440 (M+) Rt (1.94 min).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:11])[CH2:7][C:8](=O)[CH3:9].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C(OCC)(=O)C>[N:12]1([C:8]([CH3:9])=[CH:7][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:11])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNC1
Reactant: CC(=O)CC(=O)c1cccs1
Solvent: CCOC(C)=O
Product: CC(=CC(=O)c1cccs1)N1CCCC1

Procedure:
A mixture of 0.01 mole of 1-(2-thienyl)butan-1,3-dione was reacted with pyrrolidine in ethyl acetate to give 3-(1-pyrrolidinyl)-1-(2-thienyl)-2-buten-1-one, mp 154°-156° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[CH:7]([NH2:12])[CH2:6][CH2:5]2.[C:13]([O:17][C:18]([NH:20][C:21]1([C:24](O)=[O:25])[CH2:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18](=[O:19])[NH:20][C:21]1([C:24](=[O:25])[NH:12][CH:7]2[C:8]3[C:4](=[CH:3][C:2]([Br:1])=[CH:10][C:9]=3[F:11])[CH2:5][CH2:6]2)[CH2:22][CH2:23]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: NC1CCc2cc(Br)cc(F)c21
Product: CC(C)(C)OC(=O)NC1(C(=O)NC2CCc3cc(Br)cc(F)c32)CC1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B] and for the preparation of example 12, (rac)-5-bromo-7-fluoro-indan-1-ylamine (intermediate A-7 [C]) has been coupled with 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid to give [1-((rac)-5-bromo-7-fluoro-indan-1-ylcarbamoyl)-cyclopropyl]-carbamic acid tert-butyl ester, which was then reacted with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) and (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) and subsequently with 3-(2-bromo-4-chloro-6-fluoro-phenyl)-5-methyl-[1,2,4]oxadiazole (intermediate B-2) to give the title compound as light brown solid. MS: 545.2 (MH+, 1Cl).
Reaction SMILES: [CH2:1]([NH:13][C:14]([C:16]1[CH:17]=[C:18]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[C:19]([O:23][CH2:24][CH2:25][NH2:26])=[C:20]([Br:22])[CH:21]=1)=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.Cl[C:45]([O:47][CH3:48])=[O:46]>C1COCC1>[CH3:48][O:47][C:45](=[O:46])[NH:26][CH2:25][CH2:24][O:23][C:19]1[C:20]([Br:22])=[CH:21][C:16]([C:14](=[O:15])[NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:17][C:18]=1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=1
Reactant: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCN)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCNC(=O)OC)c(-c2cccc(C(F)(F)F)c2)c1
Reaction time: 0.25 h
Yield: 861.4 %

Procedure:
To a solution of 6-(amino-ethoxy)-5-bromo-3′-trifluoromethyl-biphenyl-3 carboxylic acid dodecylamide (0.273 g, 0.48 mmol, 1 eq) in THF (6 mL) at 0° C. was added triethylamine (0.150 mL, 1.08 mmol, 2.25 eq) followed by methyl chloroformate (0.040 mL, 0.052 mmol, 1.11 eq). The reaction was stirred for 15 min, then poured into pH 7 buffer and extracted with Et2O. The combined organics were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (30% EtOAc:hexane ) to afford the title compound (0.282 g, 93%) as a white solid. mp 79.6-80.5° C. 1H NMR (DMSO-d6) δ 8.56 (bt, 1H); 8.12 (d, 1H); 7.88 (m, 3H); 7.79 (d, 1H); 7.70 (t, 1H); 7.02 (t, 1H); 3.54 (dd, 2H); 3.44 (s, 3H); 3.24 (dd, 2H); 3.08 (ddd, 2H); 1.48 (dd, 2H); 1.23 (m, 18H); 0.83 (t, 3H); IR (KBr) 3330, 2950, 2840, 1695, 1640, 1540, 1340, 1180, 1110, 920, 805 cm−1; mass spectrum [(+)MAT900], rm/z 629/631 (M+H)+; Anal. Calcd. for C30H40BrF3N2O4: C, 57.23; H, 6.40; N, 4.45, Found: C, 56.12; H, 6.29; N, 4.29.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH:17]1([N:23]2[C:31]3[C:26](=[CH:27][C:28](/[C:32](/[CH3:37])=[CH:33]/[C:34](O)=[O:35])=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([N:23]2[C:31]3[C:26](=[CH:27][C:28](/[C:32](/[CH3:37])=[CH:33]/[C:34]([NH:1][C:2]4[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=4[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:35])=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C2CCCCC2)c1
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2C2CCCCC2)c1

Procedure:
0.22 g of compound 24 was obtained in a similar manner to those described in the Examples 1 to 2 using 0.47 g of ethyl 4-(2-aminophenoxy)butyrate and 0.30 g of 3-(1-cyclohexylindol-5-yl)isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]([CH:10]1[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH:11]1[N:17]1[C:21](=[O:22])[CH2:20][CH:19]([C:23]([OH:25])=O)[CH2:18]1)([CH3:9])[CH3:8].C(N(CC)C(C)C)(C)C.[CH2:35]([NH2:39])[CH:36]([CH3:38])[CH3:37].Cl>ClCCl.CN(C)C=O>[CH2:35]([NH:39][C:23]([CH:19]1[CH2:20][C:21](=[O:22])[N:17]([CH:11]2[CH2:12][CH:13]([CH3:16])[CH2:14][CH2:15][CH:10]2[CH:7]([CH3:8])[CH3:9])[CH2:18]1)=[O:25])[CH:36]([CH3:38])[CH3:37]
Reactant: CC1CCC(C(C)C)C(N2CC(C(=O)O)CC2=O)C1
Reactant: CC(C)CN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)CNC(=O)C1CC(=O)N(C2CC(C)CCC2C(C)C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.2 %

Procedure:
Oxalyl chloride ((COCl)2) (350 mg, 2.8 mmol, 240 mL) and dimethylformamide (DMF; (CH3)2NC(O)H catalytic) (20 μL) were carefully added to 1-(2-isopropyl-5-methyl-cyclohexyl)-5-oxo-pyrrolidine-3-carboxylic acid (obtained as in EXAMPLE II, 500 mg, 1.87 mmol) suspended in anhydrous dichloromethane (CH2Cl2) (10 mL). The reaction mixture slowly turned into a homogeneous solution over about 3 hours, which was then concentrated in vacuo to remove (COCl)2. The resulted raw oil was dissolved in anhydrous CH2Cl2 and subsequently added dropwise to a mixture of N,N-diisopropylethylamine (DIEA; (CH3CH2)3N) (290 mg, 2.24 mmol) and isobutylamine (H2NCH2CH(CH3)2) (160 mg, 2.24 mmol) at 0° C. with stirring. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was poured into HCl (1 N) and extracted with CH2Cl2. The organic phases were collected, washed with brine, dried, and evaporated. Column chromatography with ethyl:acetate (50:50) provided 1-(2-isopropyl-5-methyl-cyclohexyl)-5-oxo-pyrrolidine-3-carboxylic acid isobutyl-amide (390 mg, 1.2 mmol).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:5]=1[O:18][CH3:19].C1(C)C=CC(S(O[CH2:30][CH2:31][CH:32](O)[CH2:33][CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)(=O)=O)=CC=1.CN(C)C=[O:46]>>[CH3:19][O:18][C:5]1[CH:6]=[C:7](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:8]=[CH:9][C:4]=1[O:3][CH2:30][CH:31]([OH:46])[CH2:32][CH2:33][CH2:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)OCCC(O)CCc2cccnc2)cc1
Reactant: COc1cc(/C=C/c2ccccc2)ccc1O
Agent: [H-]
Agent: [Na+]
Product: COc1cc(/C=C/c2ccccc2)ccc1OCC(O)CCCc1cccnc1

Procedure:
Prepared according to the method described in Example 96d) from sodium hydride (60% dispersion in mineral oil, 55 mg), trans-4-hydroxy-3-methoxystilbene (0.314 g) and (±)-3-hydroxy-5-(3-pyridyl)-1-pentyl para-toluenesulfonate (310 mg) in anhydrous dimethylformamide (6 ml). The crude product was purified by column chromatography over silica eluting with methanol:dichloromethane (1:19) to give the title compound (0.197 g) as a solid which was recrystallised from ethyl acetate:hexane.
Reaction SMILES: [CH3:1][N:2]([CH:7]1[CH:19]2[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][C:4](O)=O.[CH:20]([OH:22])=[O:21].C(OC(=O)C)(=[O:25])C>O>[CH3:4][CH:3]([C:20]([OH:22])=[O:21])[N:2]([CH:1]=[O:25])[CH:7]1[CH:19]2[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: CC(=O)OC(C)=O
Reactant: CN(CC(=O)O)C1c2ccccc2C2CCCCC21
Reactant: O=CO
Solvent: O
Product: CC(C(=O)O)N(C=O)C1c2ccccc2C2CCCCC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
A mixture of 16.6 parts of methyl N-(1,2,3,4,4a,9a-hexahydro-9H-fluoren-9-yl)glycine, 44 parts of formic acid and 11.9 parts of acetic acid anhydride was stirred overnight at room temperature. The reaction mixture was poured into water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated, yielding 15.9 parts (86.4%) of methyl N-formyl-N-(1,2,3,4,4a,9a-hexahydro-9H-fluoren-9-yl)glycine as a residue (int. 2).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1Cl.[CH2:11]([NH:18][CH2:19][CH2:20][CH2:21][OH:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>O>[CH2:11]([N:18]([C:7]1[CH:6]=[N:5][N:4]([CH3:9])[C:3](=[O:10])[C:2]=1[Cl:1])[CH2:19][CH2:20][CH2:21][OH:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCCNCc1ccccc1
Reactant: Cn1ncc(Cl)c(Cl)c1=O
Agent: Cl
Solvent: O
Product: Cn1ncc(N(CCCO)Cc2ccccc2)c(Cl)c1=O
Reaction time: 8 h
Yield: 53.7 %

Procedure:
A solution of 11.48 g (64,1 mmol) of 4,5-dichloro-2-methyl-3(2H)-pyridazinone and 31.84 g (193.0 mmol) of 3-(N-benzylamino)propanol in 250 ml of water is boiled for 25 hours while stirring. The mixture is cooled, its pH is set with concentrated hydrochloric acid to 3 and it is extracted with 2×400 ml of ethyl acetate. The organic phase is dried and evaporated, 10 ml of ethyl acetate are added to the evaporation residue, then it is left to stand overnight at −10° C. The precipitated crystals are filtered and washed with ethyl acetate and then with diethyl ether. In this way 10.60 g (54%) of the title compound are obtained with a melting point of 94-95° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([C:11]2([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:19].C(N(CC)CC)C.[C:40]1([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[C:1]1([CH2:7][O:8][C:9]([C:11]2([NH:17][C:18]([N:49]3[CH2:50][CH2:51][N:46]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH2:47][CH2:48]3)=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: NC1(C(=O)OCc2ccccc2)CCCCC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
A solution of 366 mg (3 mmol) of N,N-dimethylaminopyridine and 6.99 g (30 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester in methylene chloride was added to a solution of 6.55 g (30 mmol) of di-t-butyl dicarbonate in 150 ml of methylene chloride, and the mixture was stirred at room temperature for 30 minutes. Thereafter, a solution of 6.07 g (60 mmol) of triethylamine and 5.11 g (33 mmol) of 1-phenylpiperazine in methylene chloride was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, ethyl acetate was added thereto, and the mixture was successively washed with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained crystal was washed with diethyl ether to obtain 8.88 g (70%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1)(=[O:12])=[O:11])([O-:3])=[O:2].[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][C:34]=2[CH2:39][O:40][C:41]2[CH:46]=[CH:45][C:44]([CH2:47]O)=[CH:43][CH:42]=2)=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[F:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][C:34]=2[CH2:39][O:40][C:41]2[CH:42]=[CH:43][C:44]([CH2:47][N:13]([S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=3)=[CH:45][CH:46]=2)=[CH:31][CH:32]=1
Reactant: Cn1ncc(COc2ccc(CO)cc2)c1-c1ccc(F)cc1
Reactant: COC(=O)CCc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)CCc1ccc(N(Cc2ccc(OCc3cnn(C)c3-c3ccc(F)cc3)cc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(4-{[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (182 mg, 0.5 mmol), (4-{[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]methoxy}phenyl)methanol (156 mg, 0.5 mmol) and triphenylphosphine (262 mg, 1.0 mmol) in dichloromethane (5 mL) was added diethyl azodicarboxylate (40% toluene solution, 435 mg, 1.0 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was purified by silica gel column chromatography (10%-80% ethyl acetate/hexane) to give a yellow oil containing the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.S([O-])(O)(=O)=O.I[CH2:17][CH3:18].[OH-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:17][CH3:18])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: N#CCc1cccc(Br)c1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCC(C#N)c1cccc(Br)c1
Reaction time: 4 h

Procedure:
A solution of 3-bromophenylacetonitrile (8.12 g) in dichloromethane (150 mL) at room temperature was treated sequentially with tetrabutylammonuim hydrogen sulfate (14.1 g), iodoethane (10 mL), and 15% NaOH (35 mL), stirred for 4 hours, and separated. The aqueous phase was extracted with dichloromethane, and the combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50% dichloromethanehexanes to provide the desired product.