Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15](=[O:19])[NH:16]2)=[C:11]([CH:20]([OH:43])[CH2:21][NH:22][C:23]([CH3:42])([CH3:41])[CH2:24][CH2:25][N:26]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[C:29]([CH2:38][CH3:39])([CH2:36][CH3:37])[O:28][C:27]2=[O:40])[CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:38]([C:29]1([CH2:36][CH3:37])[O:28][C:27](=[O:40])[N:26]([CH2:25][CH2:24][C:23]([NH:22][CH2:21][CH:20]([OH:43])[C:11]2[CH:10]=[C:9]([OH:8])[CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][C:15](=[O:19])[NH:16]3)([CH3:41])[CH3:42])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]1=2)[CH3:39]
Reactant: [H][H]
Reactant: CCC1(CC)OC(=O)N(CCC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3[nH]c(=O)ccc23)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CCC1(CC)OC(=O)N(CCC(C)(C)NCC(O)c2cc(O)cc3[nH]c(=O)ccc23)c2ccccc21

Procedure:
A suspension of 1-{3-[2-(7-benzyloxy-2-oxo-1,2-dihydroquinolin-5-yl)-2-hydroxyethylamino]-3-methylbutyl}-4,4-diethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one (152 mg, 0.338 mmol) and Pd/C (10%) (40 mg) in MeOH (12 mL) is hydrogenated at room temperature (RT) and 1 bar hydrogen pressure for 4 hours. The catalyst is filtered off through CELITE® filter aid and washed with MeOH (5 mL). The organic phase is evaporated down, the residue is triturated with EtOAc and the precipitate formed is filtered off and dried in vacuo. Yield: 76 mg (46%); Rf=0.3 (silica gel, dichloromethane/MeOH/saturated aqueous ammonia 90:10:0.5); ESI-MS: [M+H]+=494.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[O:13])[S:9][CH:10]=1)[CH3:2].[Cl:30]N1C(=O)CCC1=O>C(#N)C.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[O:13])[S:9][C:10]=1[Cl:30])[CH3:2]
Reactant: CCOC(=O)Cc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)Cc1nc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)sc1Cl
Reaction time: 1.5 h
Yield: 148.2 %

Procedure:
To a solution of {2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester (0.05 g, 0.12 mmol) in 2 ml of acetonitrile was added N-chlorosuccinimide (0.018 g, 0.13 mmol). The reaction mixture was stirred under nitrogen in a pressure bottle excluded from light for 1.5 hour at 80° C. The mixture was diluted with 15 ml of DCM, washed (1N HCl, saturated NaHCO3, water), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by preparative HPLC to afford the title compound (0.08 g, 15%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C@@H:8]([CH2:14]N)[CH2:7]2.C([N:18](CC)CC)C.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>ClCCl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C@H:8]([CH2:14][C:23]1([C:26]([NH2:18])=[O:27])[CH2:25][CH2:24]1)[CH2:7]2
Reactant: COc1cc2c(cc1OC)[C@@H](CN)C2
Reactant: O=C(Cl)C1CC1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Product: COc1cc2c(cc1OC)[C@H](CC1(C(N)=O)CC1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 4.6 g (20 mmol) of {[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}amine hydrochloride in 60 mL of dichloromethane, at ambient temperature, there are added, all at once, 6.1 mL (44 mmol/2.2 eq.) of triethylamine and stirring is carried out for about 30 minutes. There are then added dropwise, over 40 minutes, 2 mL (22 mmol/1.1 eq.) of cyclopropanecarboxylic acid chloride. The mixture is then stirred at ambient temperature for 1 hour 30 minutes and is then transferred to a separating funnel; 60 mL of dichloromethane are added and successive washing with 40 mL of water, two 40 mL quantities of 1N hydrochloric acid, two 40 mL quantities of saturated aqueous sodium hydrogen carbonate solution and 40 mL of water are carried out. After drying over magnesium sulphate, filtration and concentration, the desired product is collected.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][N:11]=[C:10]3[NH:15][CH:16]=[CH:17][C:9]=23)[C:5]([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)=[N:4]1)[CH3:2].[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26]>>[CH2:25]([NH:27][C:28]([NH:22][C:21]1[CH:23]=[CH:24][C:18]([C:5]2[C:6]([C:8]3[C:13]([CH3:14])=[CH:12][N:11]=[C:10]4[NH:15][CH:16]=[CH:17][C:9]=34)=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=2)=[CH:19][CH:20]=1)=[O:29])[CH3:26]
Reactant: CCn1cc(-c2c(C)cnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Reactant: CCN=C=O
Product: CCNC(=O)Nc1ccc(-c2nn(CC)cc2-c2c(C)cnc3[nH]ccc23)cc1

Procedure:
Following the procedure described in Example 1 with 4-[1-ethyl-4-(5-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and ethyl isocyanate afforded the title compound. ESMS [M+H]+: 389.2
Reaction SMILES: [Br-].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:3]1.C1CCN2C(=NCCC2)CC1.[CH3:42][S:43][C:44]1[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=1[CH:46]=O>CO>[CH3:42][S:43][C:44]1[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=1/[CH:46]=[CH:11]/[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:2][N:3]=1
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Reactant: CSc1ccccc1C=O
Agent: [Br-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CSc1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
A solution of (1H-indazol-3-ylmethyl)triphenylphosphonium bromide (0.10 g, 0.21 mmol) in methanol (0.60 mL) was added with DBU (0.047 mL, 0.32 mmol) and 2-methylsulfanylbenzaldehyde (0.035 g, 0.23 mmol) obtained in Step 2 was further added, followed by stirring at room temperature for 2.0 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 95/5). The obtained compound was washed with hydrogen chloride-ethyl acetate solution and the precipitated solid was filtered. Then the solid was added with saturated aqueous sodium hydrogencarbonate solution and ethyl acetate to separate the mixture into organic layer and aqueous layer. The organic layer was concentrated under reduced pressure and the residue was washed with ethyl acetate/hexane (2/1, 1.0 mL) to obtain Compound 146 (0.016 g, 28%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:33]([CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)[S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:9][CH:10]=1)(=[O:3])=[O:4])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COC(=O)Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCc1ccccc1
Product: COc1ccc(CN(Cc2ccccc2)S(=O)(=O)c2ccc(CC(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-27 from Methyl 2-(4-(chlorosulfonyl)phenyl)acetate (example 5-47a), 4-methoxybenzaldehyde and benzylamine. MS (M−H, 424.10); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.66 (s, 3H), 3.72 (s, 2H), 4.18 (s, 2H), 4.22 (s, 2H), 6.73 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.4 Hz, 2H), 7.02 (m, 2H), 7.19 (m, 3H), 7.49 (d, J=8.4 Hz, 2H), 7.80 (d, J=8 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[OH:10][C:11]1[C:16]2[CH:17]=[CH:18][S:19][C:15]=2[CH:14]=[CH:13][C:12]=1[C:20](OC)=[O:21]>C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:20]([C:12]2[CH:13]=[CH:14][C:15]3[S:19][CH:18]=[CH:17][C:16]=3[C:11]=2[OH:10])=[O:21])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2sccc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(NCc1ccc(Cl)cc1)c1ccc2sccc2c1O
Temperature: 120 °C
Yield: 68 %

Procedure:
A mixture of 4-chlorobenzylamine (1 mL) and methyl 4-hydroxy-1-benzothiophene-5-carboxylate (Preparation 13, 0.50 g) is heated to 120° C. under an atmosphere of nitrogen for 4 hours. After cooling, the residue is diluted with ethyl acetate and methanol (1:1) and absorbed onto silica gel. Chromatography on a Biotage column eluting with 500 mL of toluene gave 520 mg (68%) of the title compound as a white solid. Physical characteristics: Mp 168-169° C.; MS (ESI−) m/z 316.1 (M−H)−. Anal. Found: C, 60.82; H, 3.87; N, 4.33.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)#[N:2].[CH3:15][NH:16][CH3:17]>CO>[C:1]([CH2:3][C:4]1([N:16]([CH3:17])[CH3:15])[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Reactant: CNC
Solvent: CO
Product: CN(C)C1(CC#N)CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
1.20 g (6,18 mmol) of tert-butyl 3-cyanomethyleneazetidine-1-carboxylate (WO 2009/064 835) are dissolved in 15 mL of methanol in a sealed tube. 6.18 mL (12.36 mmol) of a solution of dimethylamine in methanol are added and the reaction medium is stirred at 80° C. for 3 hours.
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1[C:8]([N+:14]([O-:16])=[O:15])=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:24][C:25]([F:28])([F:27])[F:26]>CCOCC.O>[N+:14]([C:8]1[C:9]([O:13][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:10][CH:11]=[CH:12][C:7]=1[CH3:6])([O-:16])=[O:15]
Reactant: Cc1cccc(O)c1[N+](=O)[O-]
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: Cc1cccc(OCC(F)(F)F)c1[N+](=O)[O-]

Procedure:
To 50 ml of dimethylformamide containing 7.65 g (50 mmol) of 3-methyl-2-nitrophenol, 13.6 g (100 mmol) of potassium carbonate and 12.6 g (60 mmol) of 1-iodo-2,2,2-trifluoroethane were added, and the mixture was heated at 120° to 130° C. under agitation for 2 hours. Water and ether were added to the reaction mixture, and thereafter, the ether layer was concentrated to obtain 11.2 g of 2-nitro-3-(2,2,2-trifluoroethoxy)toluene as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.C[N:24](C)C=O>>[NH2:24][C:2]([CH3:7])([CH3:1])[CH2:3][C:4]([O:6][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:5]
Reactant: BrCc1ccccc1
Reactant: CC(C)=CC(=O)O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(N)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 3,3-dimethylacrylic acid (1.3 g) and potassium carbonate (2.07 g) in N,N-dimethylformamide (15 mL) was added benzyl bromide (1.19 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in 2-propanol (20 mL). An ammonia gas was bubbled into the solution at −15° C. until saturation, and the mixture was stirred at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=15/1-7/1) to give the title compound (0.31 g).
Reaction SMILES: C1(C(=[N:14][C:15]([CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30])([CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C2C=CC=CC=2)C=CC=CC=1.Cl.[CH:32]1[C:44]2[CH:43]([CH2:45]OC(ON3C(=O)CCC3=O)=O)[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]=2[CH:35]=[CH:34][CH:33]=1.[C:57](=[O:60])([O-:59])[O-].[Na+].[Na+]>C(OCC)C.CC(C)=O.O>[CH:41]1[C:42]2[CH:43]([CH2:45][O:59][C:57]([NH:14][C:15]([CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25])([CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:60])[C:44]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:37]=2[CH:38]=[CH:39][CH:40]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: C=CCCCC(CCCC=C)(N=C(c1ccccc1)c1ccccc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CC(C)=O
Product: C=CCCCC(CCCC=C)(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCC
Reaction time: 0.25 h

Procedure:
To a stirred solution of crude ethyl 2-(diphenylmethyleneamino)-2-(pent-4-enyl)hept-6-enoate 11 (18.2 g, 45.1 mmol) in ethyl ether (200 mL) was added a 6N solution of hydrochloric acid (45 mL) at 0° C. over 45 min and the resulting mixture was stirred for another 15 min. The organics were extracted in ethyl ether (2×100 mL), and the combined etherial layer was concentrated. The residue was dissolved in acetone (75 mL), to which a solution of N-(9-fluorenylmethoxycarbonyloxy)succinimide (16 g, 47.5 mmol, 1.05 equiv.) in acetone (75 mL) and a solution of sodium carbonate (19.1 g, 180.4 mmol, 4.0 equiv.) in water (150 mL) were consecutively added. The resulting mixture was stirred at room temperature for 16 h. The product was extracted with ethyl acetate (2×150 mL) and the combined organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting with 7% ethyl acetate in n-hexanes) to give 12 as a white solid: 1H-NMR (400 MHz, CDCl3) δ 7.77 (d, J=7.2 Hz, 2H), 7.62 (d, J=8.0 Hz, 2H), 7.40 (t, J=7.2 Hz, 2H), 7.32 (dt, J=7.2, 0.8 Hz, 2H), 5.90 (br s, 1H), 5.75 (m, 2H), 4.99 (d, J=17.6 Hz, 2H), 4.95 (d, J=11.2 Hz, 2H), 4.39 (d, J=6.8 Hz, 2H), 4.25 (m, 3H), 2.35 (dt, J=12.8, 4.0 Hz, 2H), 2.02 (m, 4H), 1.76 (dt, J=12.8, 4.0 Hz, 2H) 1.39 (m, 2H), 1.30 (t, J=7.2 Hz, 3H), 1.06 (m, 2H); 13C-NMR (100 MHz, CDCl3) δ 174.2, 154.0, 144.2, 141.6, 138.5, 127.9, 127.3, 125.3, 120.2, 115.1, 66.3, 64.2, 62.1, 47.6, 35.3, 33.6, 23.6, 14.5; HRMS (ESI) m/z for C29H36NO4 [M+H]+ calcd 462.2644. found 462.2637.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17](C(O)=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[C:25](=[O:28])([O-])[O-].[K+].[K+].CN([CH:34]=[O:35])C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]2[CH:15]=[CH:16][C:17]([O:35][CH3:34])=[CH:18][C:19]2=[C:25]=[O:28])[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COC1=CC(=C=O)C(C2CCN(C(=O)OC(C)(C)C)CC2)C=C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(4-carboxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (828 mg, 2.71 mmol) in DMF (5 ml) are added iodomethane (577 mg, 4.07 μl) and potassium carbonate (375 mg, 2.71 mmol) and the reaction mixture is stirred for 4 hours at room temperature. The reaction mixture is evaporated and the residue is treated with dichloromethane. The solids are filtered off and the filtrate is evaporated to dryness to afford 4-(4-methoxy-carbonyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester as yellow solid; HPLC/MS 2.21 min (A), [M-tBu] 264.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:23].[C:24]1(=[O:30])[O:29][C:27](=[O:28])[CH2:26][CH2:25]1.C(N(CC)CC)C.C(Cl)(Cl)Cl>O>[O:30]=[C:24]([NH:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:23])[CH2:25][CH2:26][C:27]([OH:29])=[O:28]
Reactant: O=C1CCC(=O)O1
Reactant: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1CCNC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
1-(2-Aminoethyl)-5-(benzoxazol-2-yl)-2-methylbenzimidazole hydrochloride (see Working Example 56) (0.20 g, 0.6 mmol), succinic anhydride (0.06 g, 0.6 mmol), triethylamine (0.22 g, 2.2 mmol) and CHCl3 (2 mL) were added together, and after stirring for 1 hour at room temperature this was heated to reflux with stirring for 1 hour. After cooling, water was added and back-extraction was carried out. The aqueous layer obtained was concentrated, and the residue was reslurried in methanol. After the precipitated crystals were filtered, they were dried to yield the title compound (0.13 g, 69% yield) as white crystals.
Reaction SMILES: [NH:1]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:19][C:20]([CH3:26])([CH2:24][CH3:25])[C:21](Cl)=[O:22]>>[CH3:19][C:20]([CH3:26])([CH2:24][CH3:25])[C:21]([N:1]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:22]
Reactant: CCC(C)(C)C(=O)Cl
Reactant: C1COCCOCCOCCOCCOCCN1
Product: CCC(C)(C)C(=O)N1CCOCCOCCOCCOCCOCC1

Procedure:
Analogously to Example 14 from 1-aza-4,7,10,13,16-pentaoxacyclooctadecane and 2,2-dimethylbutyryl chloride.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]=[C:5]([CH3:7])[CH3:6].[C:8]1([P:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(#N)C>[Br-:1].[CH3:6][C:5]([CH3:7])=[CH:4][CH2:3][CH2:2][P+:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)=CCCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)=CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 95 °C
Reaction time: 20 h
Yield: 70.9 %

Procedure:
A mixture of 5-bromo-2-methyl-2-pentene (489.2 mg, 3 mmole) and triphenylphosphine (787 mg, 3 mmole) in 6 ml of acetonitrile was stirred at 95° C. (oil bath temperature) under nitrogen for 20 hours. The solvent was evaporated by a stream of nitrogen. The residue was dried in vacuo at room temperature to give a foam. This was rinsed with ethyl ether to give a white solid which was filtered, washed with ethyl ether and dried in vacuo at 100° C. for 4 hours to afford 905 mg of (4-methyl-3-pentenyl)triphenylphosphonium bromide.
Reaction SMILES: [C:1]1([N:7]2[C:11](=O)[CH2+:10]=[CH:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:15])=O>CCOCC>[Cl-:15].[C:1]1([N+:7]2[S:8][CH:9]=[CH:10][C:11]=2[Cl:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1[CH2+]=CSN1c1ccccc1
Solvent: CCOCC
Product: Clc1ccs[n+]1-c1ccccc1
Product: [Cl-]
Temperature: 60 °C

Procedure:
2-Phenyl-4-isothiazolium-3-one (J. Het. Chem., 8, 571 (1971) (1 g.) is stirred at room temperature with phosphorous oxychloride (3-5 ml.); the progress of the reaction was monitored by TLC for disappearance of starting material. The reaction can be speeded up by warming to 60° C. Ether is added to precipitate a white gum. The residue was flushed once more with ether and decanted. The material is used as such in the next step.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[CH3:13][C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1>ClC1C=CC=CC=1Cl>[Br-:1].[C:10]([CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N+:18]2[C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][C:14]=2[CH3:13])=[CH:4][CH:5]=1)([OH:12])=[O:11]
Reactant: Cc1nc2ccccc2o1
Reactant: O=C(O)Cc1ccc(CBr)cc1
Solvent: Clc1ccccc1Cl
Product: Cc1oc2ccccc2[n+]1Cc1ccc(CC(=O)O)cc1
Product: [Br-]
Temperature: 80 °C
Yield: 63.3 %

Procedure:
2-Methylbenzoxazole (yellow) was distilled under vacuum to give a colourless liquid (33 ml). 4-(Bromomethyl)phenylacetic acid (20 g, 87.3 mmol) and 2-methylbenzoxazole (distilled, 33 ml, 278 mmol) were dissolved in 1,2-dichlorobenzene (70 ml). The reaction mixture was heated at 80° C. for 2.5 days to produce a thick yellow precipitate. The reaction mixture was then cooled to room temperature, the precipitate collected via filtration and washed with 1,2-dichlorobenzene (3×100 ml) and diethyl ether (4×200 ml). The cream solid collected was dried in vacuo to give 3-(4-(carboxymethyl) benzyl]-2-methyl-1,3-benzoxazol-3-ium bromide (20 g, 55.3 mmol, 63% yield). UV (methanol): λmax=277 nm. MS: m/z=282 (C17H16NO3=282.32). Normal phase TLC (ether) indicated that the starting 2-methylbenzoxazole had an Rf=0.9±0.05 and the product an Rf=0. 1H NMR (200 MHz-DMSO-d6): δ1.75 (s, 2H); 3.2 (s, 3H); 5.85 (s, 2H); 7.31 (d, 2H, J=6.8 Hz); 7.53 (d, 2H, J=6.8 Hz); 7.72 (m, 2H, J=6.3 Hz); 7.89 (d, 1H, J=8.3 Hz); 8.17 (d, 1H, J=7.3 Hz); 9.8 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].Cl.[CH3:12][NH:13][O:14][CH3:15].CN(C)CCCN=C=NCC.N1C=CC=CC=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([N:13]([O:14][CH3:15])[CH3:12])=[O:6]
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 82.4 %

Procedure:
In a round-bottomed flask, 2.0 g of 2-bromoisonicotinic acid, 1.1 g of N,O-dimethylhydroxylamine hydrochloride, 3.8 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 3.2 ml of pyridine are placed in 50 ml of tetrahydrofuran. The mixture is stirred at ambient temperature for 40 h. The mixture is concentrated, and the residue is taken up in 50 ml of ethyl acetate and 50 ml of water. The organic phase is washed with 50 ml of a 1N solution of sodium hydroxide and 50 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and then concentrated under reduced pressure. 2.0 g of compound are obtained.
Reaction SMILES: [CH2:1]([C@@H:3]1[C:8]([CH3:10])([CH3:9])[C@H:7]([CH:11]=O)[C:6]([CH3:13])=[CH:5][CH2:4]1)[CH3:2].[CH3:14][C:15]([CH3:17])=[O:16].CO[Na].CC(=O)C=C>C(O)C.CO>[CH2:1]([C@H:3]1[C:8]([CH3:10])([CH3:9])[C:7](/[CH:11]=[CH:14]/[C:15](=[O:16])[CH3:17])=[C:6]([CH3:13])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CC(C)=O
Reactant: CC[C@H]1CC=C(C)[C@@H](C=O)C1(C)C
Agent: C=CC(C)=O
Agent: CO[Na]
Solvent: CO
Solvent: CCO
Product: CC[C@@H]1CCC(C)=C(/C=C/C(C)=O)C1(C)C
Reaction time: 65 h

Procedure:
This compound was prepared by aldol condensation of 2 g (0.011 mol) of (+)-(1R,5S)-5-ethyl-2,6,6-trimethyl-2-cyclohexen-1-carbaldehyde (obtained according to example 4i.) with 2 ml (0.03 mol) of acetone, in 10 ml of ethanol. After adding 0.1 ml of a 30% solution of CH3ONa in methanol, the reaction was allowed to proceed for about 65 h. Following the usual treatment, 1.3 g of 95% pure mixture were obtained, containing 83% of the above-mentioned butenone, 13% of its α-trans isomer and 4% of its α-cis isomer.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH2:37](O)[CH2:38][CH2:39][CH2:40][CH2:41]C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: CCCCCCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCCCOC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C)c1C
Yield: 76 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-hexanol (48 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (106 mg, yield 72%).