Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[CH2:47]1[C:49]2([CH2:54][CH2:53][CH:52]([CH2:55][OH:56])[CH2:51][CH2:50]2)[CH2:48]1>>[Cl:17][C:18]1[C:19]([O:56][CH2:55][CH:52]2[CH2:53][CH2:54][C:49]3([CH2:47][CH2:48]3)[CH2:50][CH2:51]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCC1CCC2(CC1)CC2
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCC2CCC3(CC2)CC3)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with spiro[2.5]octan-6-ylmethanol, the title compound was obtained as a colorless solid (0.17 g, 40%): 1H NMR (300 MHz, CDCl3) δ 8.65-8.59 (m, 1H), 8.06 (d, J=8.1 Hz, 1H), 6.67 (d, J=13.8 Hz, 1H), 3.88 (d, J=6.3 Hz, 2H), 3.01 (s, 6H), 1.95-1.72 (m, 5H), 1.34-1.21 (m, 2H), 0.96-0.90 (m, 2H), 0.33-0.26 (m, 2H), 0.22-0.16 (m, 2H); MS (ES−) m/z: 417.2, 419.2 (M−1).
Reaction SMILES: BrCCCCCCCCOC1C=CC([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)=CC=1.O.C(OCC)(=O)C.[ClH:33]>CC1OC(C)CNC1>[ClH:33].[C:21]([OH:23])(=[O:22])[C:20]1[CH:24]=[CH:25][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)c1ccc(-c2ccc(OCCCCCCCCBr)cc2)cc1
Agent: CC1CNCC(C)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccccc1

Procedure:
A suspension of 4-[4-(8-bromooctyloxy)phenyl]benzoic acid (1 g) in 2,6-dimethylmorpholine (3.06 ml) was refluxed for 30 minutes. The reaction mixture was added to mixture of water and ethyl acetate and adjusted to pH 2.0 with conc. HCl. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 4-[4-[8-2,6-dimethylmorpholin-4-yl)octyloxy]phenyl]benzoic acid hydrochloride (0.95 g).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[S:37][C:30]4=[N:31][C:32]([CH3:36])=[CH:33][C:34](=[O:35])[N:29]4[N:28]=2)[C@H:20]([NH:38][C:39](=[O:73])/[C:40](/[C:48]2[N:49]=[C:50]([NH:53][C:54]([C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)([C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)[C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)[S:51][CH:52]=2)=[N:41]\[O:42]C(OC)(C)C)[C:19]3=[O:74])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(OCC)(=O)C>CC(C)=O>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[S:37][C:30]4=[N:31][C:32]([CH3:36])=[CH:33][C:34](=[O:35])[N:29]4[N:28]=2)[C@H:20]([NH:38][C:39](=[O:73])/[C:40](/[C:48]2[N:49]=[C:50]([NH:53][C:54]([C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)([C:61]4[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=4)[C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=4)[S:51][CH:52]=2)=[N:41]\[OH:42])[C:19]3=[O:74])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(C)(C)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nn4c(=O)cc(C)nc4s3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(=O)n2nc(SCC3=C(C(=O)OC(c4ccccc4)c4ccccc4)N4C(=O)[C@@H](NC(=O)/C(=N\O)c5csc(NC(c6ccccc6)(c6ccccc6)c6ccccc6)n5)[C@H]4SC3)sc2n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 75.8 %

Procedure:
To a solution of the product obtained in Step 3 (1.5 g) in acetone (12 ml) was added 1N hydrochloric acid (2.6 ml), and the resulting solution was stirred at room temperature for 3.5 hours. Ethyl acetate was added to the solution, and the organic layer was washed with water, 5% sodium bicarbonate solution and brine in that order, and dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, giving 1.06 g of the objective compound as milky white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([CH2:13][NH2:14])[OH:12].C(N(CC)CC)C.Cl>C(Cl)Cl>[OH:12][CH2:11][CH2:13][NH:14][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: NCCO
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCO)c1ccc(Cl)cc1
Yield: 77.6 %

Procedure:
2.6 ml (0.02 mol) of 4-chlorobenzoyl chloride are added dropwise at 0° to a solution of 1.2 ml (0.02 mol) of ethanolamine and 3 ml (about 0.02 mol) of triethylamine in 30 ml of methylene chloride. The mixture is then poured into dilute hydrochloric acid and extracted twice with methylene chloride. The methylene chloride extracts are dried over magnesium sulfate and concentrated. After purification on silica gel using chloroform and chloroform/methanol 9:1) as the eluting agent, there are obtained 3.1 g of N-(2-hydroxyethyl)-4-chlorobenzamide.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][N:11]([CH3:19])[C:12]([CH:14]1[CH2:17][C:16](=O)[CH2:15]1)=[O:13].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[CH2:1]([NH:8][CH:16]1[CH2:17][CH:14]([C:12]([N:11]([O:10][CH3:9])[CH3:19])=[O:13])[CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CON(C)C(=O)C1CC(=O)C1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CON(C)C(=O)C1CC(NCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.1 %

Procedure:
Benzylamine (751 mg, 7.02 mmol), N-methoxy-N-methyl-3-oxocyclobutanecarboxamide (423 mg, 2.70 mmol), and sodium cyanoborohydride (237 mg, 3.78 mmol) were dissolved in 25 mL of anhydrous methanol. The pH of the solution was brought to 5 by addition of acetic acid, and the reaction was stirred for 24 hours at room temperature. The pH of the solution then was brought to 8 by addition of 1 M aqueous sodium bicarbonate. The solvents were removed under reduced pressure. The crude product was partitioned between ethyl acetate (80 mL) and water (25 mL). The organic layer was washed with water and brine and dried, purified using flash column chromatography with hexanes/ethyl acetate (2:1) as an eluant to give 3-(benzylamino)-N-methoxy-N-methylcyclobutanecarboxamide (498 mg, 2.00 mmol, 75% yield) as an oil.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][O:14][C:15]([C:17]1[S:18][CH:19]=[CH:20][C:21]=1[N:22]([C:36]([C@H:38]1[CH2:43][CH2:42][C@H:41]([CH3:44])[CH2:40][CH2:39]1)=[O:37])[C@H:23]1[CH2:28][CH2:27][C@H:26]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[CH2:25][CH2:24]1)=[O:16].[C:45]1(=[O:51])[CH2:50][CH2:49][CH2:48][CH:47]=[CH:46]1.[NH4+].[Cl-]>C1COCC1>[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:45]2([OH:51])[CH2:50][CH2:49][CH2:48][CH:47]=[CH:46]2)=[CH:20][C:21]=1[N:22]([C:36]([C@H:38]1[CH2:39][CH2:40][C@H:41]([CH3:44])[CH2:42][CH2:43]1)=[O:37])[C@H:23]1[CH2:24][CH2:25][C@H:26]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[CH2:27][CH2:28]1)=[O:16]
Reactant: O=C1C=CCCC1
Reactant: COC(=O)c1sccc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC2CCCCO2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1sc(C2(O)C=CCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC2CCCCO2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a mixture of THF (0.5 mL) and diisopropylamine (31 μl, 0.22 mmol) cooled to −40° C. n-BuLi (1.3 M, 165 μl, 0.21 mmol) was added dropwise. After stirring at this temperature for 30 min it was cooled to −78° C. and 3-{(trans-4-methyl-cyclohexanecarbonyl)-[trans-4-(tetrahydro-pyran-2-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid methyl ester (82 mg, 0.18 mmol) in THF (0.5 mL) was added dropwise. The mixture was stirred at this temperature for 30 min. Cyclohex-2-enone (20 μl, 0.21 mmol) was added quickly and it was stirred for 20 min at −78° C. Saturated NH4Cl solution was added and the mixture was allowed to come to room temperature. It was extracted with EtOAc. The extract was washed with brine, dried (MgSO4) and evaporated. Pure 5-(1-hydroxy-cyclohex-2-enyl)-3-{(trans-4-methyl-cyclohexanecarbonyl)-[trans-4-(tetrahydro-pyran-2-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid methyl ester was obtained after chromatography over silica gel (hexane:EtOAc—80:20 as eluent) (48 mg, 48%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]34[C:12](=[CH:13][C:14](=[O:15])[C:5]=2[NH:4][CH:3]=1)[N:11]([C:16]([C:18]1[NH:26][C:25]2[C:20](=[C:21]5[CH2:32][CH2:31][N:30]([C:33]([C:35]6[NH:43][C:42]7[C:37](=[C:38]8[CH2:49][CH2:48][N:47]([C:50]([NH2:52])=[O:51])[C:39]8=[C:40]([OH:46])[C:41]=7[O:44][CH3:45])[CH:36]=6)=[O:34])[C:22]5=[C:23]([OH:29])[C:24]=2[O:27][CH3:28])[CH:19]=1)=[O:17])[CH2:10][CH:9]3[CH2:8]4.[C:53]([OH:56])(=[O:55])[CH3:54]>>[C:53]([O:56][CH2:8][CH:9]1[CH2:10][N:11]([C:16]([C:18]2[NH:26][C:25]3[C:24]([O:27][CH3:28])=[C:23]([OH:29])[C:22]4[N:30]([C:33]([C:35]5[NH:43][C:42]6[C:41]([O:44][CH3:45])=[C:40]([OH:46])[C:39]7[N:47]([C:50]([NH2:52])=[O:51])[CH2:48][CH2:49][C:38]=7[C:37]=6[CH:36]=5)=[O:34])[CH2:31][CH2:32][C:21]=4[C:20]=3[CH:19]=2)=[O:17])[C:12]2[CH:13]=[C:14]([OH:15])[C:5]3[NH:4][CH:3]=[C:2]([CH3:1])[C:6]=3[C:7]1=2)(=[O:55])[CH3:54]
Reactant: CC(=O)O
Reactant: COc1c(O)c2c(c3cc(C(=O)N4CCc5c4c(O)c(OC)c4[nH]c(C(=O)N6CC7CC78C6=CC(=O)c6[nH]cc(C)c68)cc54)[nH]c13)CCN2C(N)=O
Product: COc1c(O)c2c(c3cc(C(=O)N4CCc5c4c(O)c(OC)c4[nH]c(C(=O)N6CC(COC(C)=O)c7c6cc(O)c6[nH]cc(C)c76)cc54)[nH]c13)CCN2C(N)=O

Procedure:
In The Journal of Antibiotics, 1985, 38, 746, D. G. Martin et al reported that acetic acid adds across the spirocyclopropylcyclohexadienyl (SCPCH) system of CC-1065 to produce the phenolic, acetic acid product (AAP), 7-[[7-[[1-[(acetyloxy)methyl]-1,6-dihydro-5-hydroxy-8-methylbenzo[1,2-b:4,3-b']dipyrrol-3(2H)-yl]carbonyl]-1,6-dihydro-4-hydroxy-5-methoxybenzo[1,2-b:4,3-b']-dipyrrol-3(2H)-yl]carbonyl]-1,6-dihydro-4-hydroxy-5-methoxybenzo[1,2-b:4,3-b']dipyrrole-3(2H)-carboxamide. AAP was tested in vitro and in vivo and found to be less potent than CC-1065 by a factor of 103 to 104 depending upon the particular test system and therefore tended to divert attention from adducts of the SCPCH system as useful antitumor agents or as prodrugs to CC-1065 analogs.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][CH:10]([C:11]([O:13][CH3:14])=[O:12])[N:5]2[C:4](=[O:15])[NH:3]1.Br[CH2:17][CH2:18][Cl:19]>>[Cl:19][CH2:18][CH2:17][N:3]1[C:2](=[O:1])[N:6]2[CH2:7][CH2:8][CH2:9][CH:10]([C:11]([O:13][CH3:14])=[O:12])[N:5]2[C:4]1=[O:15]
Reactant: COC(=O)C1CCCn2c(=O)[nH]c(=O)n21
Reactant: ClCCBr
Product: COC(=O)C1CCCn2c(=O)n(CCCl)c(=O)n21

Procedure:
Alkylation of methyl hexahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylate with 1-bromo-2-chloroethane in a manner analogous to that described in the preceding paragraph gave methyl 2-(2-chloroethyl)-2,3,5,6,7,8-hexahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylate of melting point 94°-95° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH2:14][NH:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[O:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)(=O)C.CO>[C:26]1([C:11]2([CH2:14][NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[O:17])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1ccccc1C(=O)NCC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccccc1C(=O)NCC1(c2ccccc2)CCNCC1

Procedure:
A mixture of 1.3 g (3.1 mmol) of 1-N-Benzyl-4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)piperidine (Example 1), 100 mg of Pearlman's catalyst (palladium hydroxide on carbon, purchased from Aldrich Chemical Co., Milwaukee, Wis.) and 3 drops of acetic acid in 20 mL of methanol was stirred in a hydrogen atmosphere (50 psi) for 18 hr. The reaction mixture was filtered and the filtrate was concentrated to afford the title compound.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:12][C:13]#[C:14][C@@H:15]([O:21][C:22](=[O:24])[CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CN(C)C=O.O>[CH2:1]([O:8][CH2:12][C:13]#[C:14][C@@H:15]([O:21][C:22](=[O:24])[CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC[C@@H](C#CCBr)OC(C)=O
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC[C@@H](C#CCOCc1ccccc1)OC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl alcohol (1 molar equivalent) is added dropwise to a stirred suspension of sodium hydride (1 molar equivalent) in dry dimethylformamide maintained at 0° to 5° C. throughout the addition. The reaction mixture is allowed to warm to and then is maintained at room temperature for 1/2 hour. After cooling to 0° to 5° C., the reaction mixture is treated with 1-bromo-4(S)-acetyloxy-2-nonyne (1 molar equivalent) added dropwise over 1/2 hour. The resulting reaction mixture is stirred at ambient temperature for 2 hours and then diluted with water providing a turbid mixture which is extracted with ether. The organic extract is washed with water and saturated aqueous brine, dried over sodium sulfate and filtered. Evaporation (in vacuo at 40° to 50° C.) of the filtrate leaves an oily residue which is distilled to provide the pure title compound.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:34]([OH:36])=[O:35])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26]CC4C=CC=CC=4)=[CH:22][CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:37]=[CH:38][CH:39]=[CH:40][C:4]=2[NH:3]1.C(N(CC)CC)C>CO.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:34]([OH:36])=[O:35])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:37]=[CH:38][CH:39]=[CH:40][C:4]=2[NH:3]1
Reactant: O=C(O)[C@@H](Cc1ccc(OCc2ccccc2)cc1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)[C@@H](Cc1ccc(O)cc1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Reaction time: 24 h

Procedure:
220 mg 10% Pd/C were added to a solution of 2.2 g (4.1 mmol) of (R)-1-carboxy-2-(4-benzyloxy-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 450 mg (4.4 mmol) triethylamine in 90 mL MeOH and the reaction mixture was hydrogenated at 3 bar H2 for 24 h. The catalyst was filtered, washed twice with MeOH and the filtrate was evaporated down i.vac. The residue was taken up in 20 mL water and adjusted to pH 2-3 with 10% HCl. The precipitate formed was filtered, washed with a little water and dried at 50° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH2:12])[CH2:4][CH2:3]1.[CH3:13][N:14]=[C:15]=[O:16]>>[CH3:13][NH:14][C:15]([NH:12][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:1])[CH2:3][CH2:4]1)=[O:16]
Reactant: NC1CCC(=O)c2ccccc21
Reactant: CN=C=O
Product: CNC(=O)NC1CCC(=O)c2ccccc21

Procedure:
In the manner described in Example 19, 1,2,3,4-tetrahydro-4-oxo-1-naphthylamine is allowed to react with methyl isocyanate to afford the title compound, m.p. 220° C. to 223° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](Cl)(=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].O>N1C=CC=CC=1>[C:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: Oc1ccc(Br)cc1
Reactant: CCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCC(=O)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-bromophenol (20 g) in dry pyridine (75 ml) was cooled to 0° C. and heptanoyl chloride (18.79 ml) was added dropwise. The mixture was stirred at room temperature for 21/2 hours. Water (10 ml) was added to dissolve the precipitate and the mixture then evaporated under reduced pressure. The residue was dissolved in diethyl ether, washed with water, hydrochloric acid, water, aqueous saturated sodium hydrogen carbonate, water, dried and evaporated under reduced pressure to give 4-bromophenyl heptanoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([NH2:10])[S:9][C:5]=2[CH:4]=1.Br[CH2:14][C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]3[CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:10]=[C:8]3[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(N)sc2c1
Reactant: CCOC(=O)C(=O)CBr
Product: CCOC(=O)c1cn2c(n1)sc1cc(OC)ccc12
Yield: 57.9 %

Procedure:
Ethyl 7-methoxyimidazo[2,1-b]-benzthiazole-2-carboxylate was prepared according to the procedure as outlined in Example 1, (Step 1). Starting from 6-methoxy-2-amino benzothiazole (27 g, 0.15 mol) and ethyl bromopyruvate (39.9 g, 0.2 mol), 24 g (43% Yield) of ethyl 7-methoxyimidazo[2,1-b]-benzthiazole-2-carboxylate was isolated as a brown solid. (M+H) 277.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[CH:4][CH:3]=1
Reactant: OCCCCCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCCCCOc1ccc(Br)cc1
Temperature: 52.5 °C
Reaction time: 5 h
Yield: 76.4 %

Procedure:
In a flask equipped with a stirrer and a thermometer, 4.29 g (24.8 mmol) of 4-bromophenol was dissolved in 40 ml of dry dimethylformamide (abbreviated as DMF hereinbelow) under a nitrogen atmosphere, and 5.0 g (29.9 mmol) of 5-bromopentanol and 4.14 g (29.9 mmol) of potassium carbonate were added at room temperature, followed by stirring at 50 to 55° C. for 5 hours under incubation. After the completion of the reaction, water was added, and the mixture was subjected to extraction with ethyl acetate. The resulting organic phase was washed with NaCl saturated water, dried over anhydrous sodium sulfate, filtered, and concentrated, to thereby obtain 7.8 g of a crude product in the form of a yellow oil. The crude product was then purified by silica gel column chromatography using hexane/ethyl acetate as an eluting solvent to obtain 4.91 g of 5-(4-bromophenoxy)pentanol in the form of a light yellow oil in a 76% yield.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:16]([O:8][C:7]([C@@H:2]1[CH2:3][CH2:4][C:5](=[O:6])[NH:1]1)=[O:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CC[C@@H](C(=O)OCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 387 g of L-pyro-glutamic acid in 300 mL of dimethylformamide is treated with 103.6 g of potassium carbonate at room temperature. Benzyl bromide (35.6 mL) is added and the suspension stirred room temperature for 4 hours. The suspension is filtered and the solid washed with 300 mL of acetone. The filtrate is evaporated at 50° C. to give an oil. The oil is dissolved in 300 mL of ethyl acetate and washed with 300 mL of water. The aqueous phase is re-extracted with 150 mL of ethyl acetate and the organic layers combined, dried and the solvent removed to give (S)-5-oxo-pyrrolidine-2-carboxylic acid benzyl ester as an oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.[CH3:13][N:14](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:13]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1)#[N:14]
Reactant: COC(=O)c1ccc(Br)cc1C
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1ccc(C#N)cc1C
Temperature: 140 °C
Yield: 26 %

Procedure:
A mixture of methyl 4-bromo-2-methylbenzoate (1 g, 4.4 mmol), zinc cyanide (0.7 g, 6.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.086 mmol) in N,N-dimethylformamide was heated to 140° C. under nitrogen atmosphere. And then the mixture stirred under reflux condition for 12 hours. The mixture was cooled to room temperature, and partitioned between dichloromethane (20 mL*3) and brine (60 mL). The organic layer was concentrated to dryness and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=15:1) to give methyl 4-cyano-2-methylbenzoate as a white solid (200 mg, 26%). LRMS (M+H+) m/z: calcd 175.06. found 175. 1H NMR (300 MHz, CDCl3): δ 7.97 (d, J=8.7 Hz, 1H), 7.57-7.53 (m, 2H), 3.93 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([N:7]1[CH2:11][C:10]2[CH2:12][N:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[CH2:14][C:9]=2[CH2:8]1)=[O:6].[CH:30]1([CH2:33][NH2:34])[CH2:32][CH2:31]1>>[CH:30]1([CH2:33][NH:34][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([N:13]3[CH2:12][C:10]4[CH2:11][N:7]([C:5](=[O:6])[C:4]5[CH:24]=[CH:25][CH:26]=[CH:27][C:3]=5[C:2]([F:1])([F:28])[F:29])[CH2:8][C:9]=4[CH2:14]3)=[N:16][CH:17]=2)[CH2:32][CH2:31]1
Reactant: NCC1CC1
Reactant: O=C(O)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Product: O=C(NCC1CC1)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Yield: 77 %

Procedure:
6-[5-(2-Trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]nicotinic acid (54 mg, 0.134 mmol) was reacted with C-cyclopropylmethylamine analogously to example 3d. Yield: 77%, M+H+: 457.26.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][OH:11].Cl.C([O-])([O-])=O.[Na+].[Na+]>CO>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:10][OH:11])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: ON=Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.6 %

Procedure:
To a solution of 4-fluorobenzaldehyde (3.0 g, 24.1 mmol) in MeOH (15 mL) was added NH2OH.HCl (2.0 g, 29.1 mmol) and Na2CO3 (1.53 g, 14.4 mmol) and the reaction stirred for 4 hours at room temperature. The reaction was concentrated under reduced pressure, extracted with DCM (2×100 mL), and the organic layer washed with water (2×50 mL) followed by brine solution (2×25 mL). The organic layer was concentrated under reduced pressure to obtain 4-fluorobenzaldehyde oxime [Brain, J. Am. Chem. Soc., 133:949-957 (2011)] as white solid (2 g, 61% yield). 1H NMR (400 MHz, CDCl3): δ 8.12 (s, 1H), 7.55 (dd, 2H), 7.06 (t, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]([O:12][CH2:13][C@@H:14]2[CH2:19][N:18]([CH3:20])[C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[O:15]2)[CH:9]=[C:8]([CH3:25])[C:4]=1[C:5](O)=[O:6])[CH3:2].C(Cl)(=O)C([Cl:29])=O>COCCOC.CN(C)C=O>[CH2:1]([C:3]1[CH:11]=[C:10]([O:12][CH2:13][C@@H:14]2[CH2:19][N:18]([CH3:20])[C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[O:15]2)[CH:9]=[C:8]([CH3:25])[C:4]=1[C:5]([Cl:29])=[O:6])[CH3:2]
Reactant: CCc1cc(OC[C@@H]2CN(C)c3ccccc3O2)cc(C)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: COCCOC
Solvent: CN(C)C=O
Product: CCc1cc(OC[C@@H]2CN(C)c3ccccc3O2)cc(C)c1C(=O)Cl
Temperature: 40 °C

Procedure:
Under an argon atmosphere, the compound prepared in Example 18 (79 g) was dissolved in 1,2-dimethoxyethane (500 mL). The reaction mixture was added with anhydrous N,N-dimethylformamide (3 drops) and oxalyl chloride (24 mL), and stirred at 40° C. for an hour. The reaction mixture was concentrated to obtain the title compound.