Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34]OS(C)(=O)=O)[CH:28]=3)[C:15](=[O:26])[N:16]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:40]1(=[O:50])[NH:44][C:43](=[O:45])[C:42]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:41]12.[K]>CN(C)C=O>[NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][N:44]4[C:40](=[O:50])[C:41]5=[CH:49][CH:48]=[CH:47][CH:46]=[C:42]5[C:43]4=[O:45])[CH:28]=3)[C:15](=[O:26])[N:16]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1cccc(Cl)c1N1Cc2cnc(Nc3ccccc3)nc2N(c2cccc(CCOS(C)(=O)=O)c2)C1=O
Agent: [K]
Solvent: CN(C)C=O
Product: Cc1cccc(Cl)c1N1Cc2cnc(Nc3ccccc3)nc2N(c2cccc(CCN3C(=O)c4ccccc4C3=O)c2)C1=O
Temperature: 90 °C
Yield: 99.1 %

Procedure:
A solution of 233 mg (0.41 mmol) of 7-anilino-3-(2-chloro-6-methylphenyl)-3,4-dihydro-1-[3-(2-methanesulfonyloxyethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one in 10 ml of dimethylformamide was treated with 100 mg (0.54 mmol) of potassium phthalimide and the mixture heated at 90° C. for 3 hours. The mixture was cooled and evaporated. The residue was partitioned between 50 ml of ethyl acetate and 50 ml of water. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 250 mg (99%) of 7-anilino-3-(2-chloro-6-methylphenyl)-3,4-dihydro-1-[3-(2-phthalimidoethyl)phenyl]-pyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid. [Mass spectrum (ESI) MH+ =615].
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][CH2:7][CH:6]([Se]C2C=CC=CC=2)[C:5]1=[O:16])[CH:2]=[CH2:3].[Cl-].[NH4+].OO>ClCCl>[CH2:1]([CH:4]1[C:5](=[O:16])[CH:6]=[CH:7][CH2:8]1)[CH:2]=[CH2:3]
Reactant: C=CCC1CCC([Se]c2ccccc2)C1=O
Agent: OO
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: C=CCC1CC=CC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred, ice cold (3° C.) solution of 2-allyl-5-(phenylselanyl)cyclopentanone, mixture of isomers (12.0 g, 43 mmol) in dichloromethane (200 mL) in a 1 L round bottomed-flask equipped for boil-over containment was treated with saturated aqueous ammonium chloride (45 mL), then dropwise with 30% aqueous hydrogen peroxide (22 mL), and slowly carefully warmed to room temperature. At approximately 20° C. a vigorous exotherm started, and the ice bath was re-applied. The mixture was cooled to room temperature and stirred for 1 h, then the solution was washed with water (100 mL), stirred with 10% aqueous sodium thiosulfate pentahydrate (75 mL) for 10 min, and separated. The organic solution was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride (75 mL each), dried (Na2SO4), and concentrated to 30 mL volume. The solution was added to a silica gel column (˜400 cc) and eluted with dichloromethane to afford (after very gentle concentration of appropriate fractions) 5-allylcyclopent-2-enone (3.95 g, 75%) as a very pale yellow oil. NMR (CDCl3): δ 7.61 (m, 1 H), 6.12 (m, 1 H), 5.60-5.75 (m, 1 H), 4.90-5.05 (m, 2 H), 2.70-2.80 (m, 1H), 2.45-2.55 (m, 1 H), 2.30-2.40 (m, 2 H), 2.05-2.15 (m, 1 H).
Reaction SMILES: [C:1]([N:9]1[CH2:27][CH2:26][C:12]2[N:13]([CH2:20][C:21]([O:23]CC)=[O:22])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.O>[C:2]1([C:1]([N:9]2[CH2:27][CH2:26][C:12]3[N:13]([CH2:20][C:21]([OH:23])=[O:22])[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:11]=3[CH2:10]2)=[O:8])[C:7]2[C:6](=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CN(C(=O)c1ccccc1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cn1c2c(c3ccccc31)CN(C(=O)c1cccc3ccccc13)CC2

Procedure:
Step b): A solution of crude ethyl (2-benzoyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-acetate (0.085 mmol) in THF (0.5 ml) is treated with 0.2 N aqueous NaOH solution (0.64 ml) at rt for 15 min. Then, the yellow reaction mixture is diluted with water (2 ml), washed with diethyl ether (2 ml), acidified with conc. HCl to pH 1 and extracted with dichloromethane. The combined organic phases are washed with water, then dried over Na2SO4, filtered and the solvent evaporated. The crude product is recrystallized from diisopropyl ether to give pure title compound as yellow solid: tR (LC-1) 2.95 min; ESI-MS positive ion): m/z 335.17 [M+H]+ (calcd 334.37 for C20H18N2O3).
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:13][C:12]=1[CH2:22][CH2:23][CH3:24])=[O:10].[CH3:25][O:26][CH2:27][CH2:28][N:29]([CH3:37])[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][N:31]=1>>[CH3:25][O:26][CH2:27][CH2:28][N:29]([CH3:37])[C:30]1[N:31]=[CH:32][C:33]([NH:36][C:9]([C:11]2[O:15][C:14]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)=[N:13][C:12]=2[CH2:22][CH2:23][CH3:24])=[O:10])=[CH:34][CH:35]=1
Reactant: CCCc1nc(C2CCCCC2)oc1C(=O)ON1C(=O)CCC1=O
Reactant: COCCN(C)c1ccc(N)cn1
Product: CCCc1nc(C2CCCCC2)oc1C(=O)Nc1ccc(N(C)CCOC)nc1

Procedure:
With a procedure similar to example 50 above, 2-cyclohexyl-4-propyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-cyclohexyl-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C22H32N4O3 (m/e) 400, obsd 401 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:28][CH:29]([CH3:31])[CH3:30])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:15][C:14]=1F)(=[O:12])=[O:11].[CH3:32][O-:33].[Na+]>CO.ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:28][CH:29]([CH3:31])[CH3:30])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:15][C:14]=1[O:33][CH3:32])(=[O:12])=[O:11]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)cc2F)c(C)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OCC2CCOCC2)ccc1S(=O)(=O)N(CC(C)C)c1ccc(C)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N-(2,4-dimethylphenyl)-2-fluoro-N-isobutyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide (358 mg, 0.478 mmol) in methanol (1 mL) at room temperature was added 25% sodium methoxide in methanol (109 uL, 0.478 mmol). The reaction mixture was stirred at room temperature for 2 hours, then heated to reflux for 1 hour. The reaction was quenched with water (1 mL) and the solvents removed in vacuo to give a yellow solid. The crude residue was dissolved in dichloromethane (DCM) (10 mL) and the organics washed with water (3×10 mL). The organics were passed through a hydrophobic frit and the filtrate evaporated to dryness to give a yellow oil. The crude was purified by mass directed autoprep (ammonium carbonate modifier). The solvent was evaporated under a stream of nitrogen to give the required product, 129 mg. LCMS [LCMS2] Rt 1.47 min, m/z (ES+) 462 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5]>CO.[Pd]>[NH2:11][C:7]1[C:8]([F:10])=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])c(F)cc1F
Agent: [Pd]
Solvent: CO
Product: N#Cc1cc(N)c(F)cc1F
Yield: 70.5 %

Procedure:
A suspension of 2,4-difluoro-5-nitrobenzonitrile (1.0 g, 5.43 mmol) and Pd/C 10% (0.1 g, 0.94 mmol) in MeOH (20 mL) was hydrogenated (balloon) for 5 hr. This was filtered and the solvent was removed. Flash chromatography on silica gel eluting with hexane containing 20% EtOAc gave 5-amino-2,4-difluorobenzonitrile (0.59 g) as a light yellow solid.
Reaction SMILES: [CH2:1]=[C:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:16]([NH2:18])[CH3:17]>C(O)C>[CH2:16]([NH:18][CH2:1][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:17]
Reactant: C=C(CCc1ccccc1)C(=O)OCC
Reactant: CCN
Solvent: CCO
Product: CCNCC(CCc1ccccc1)C(=O)OCC
Temperature: 105 °C

Procedure:
17 g of ethyl 2-methylene-4-phenylbutyrate (Example 1.4) and 3.6 g of ethylamine were dissolved in 50 ml of absolute ethanol and heated under 40 atmospheres of nitrogen at 105° C. for 20 hours. After the solvent had been removed, the residue was taken up in 5 normal hydrochloric acid, extracted with ether and the aqueous solution was adjusted to pH 9.5 with potassium carbonate, again extracted with ether, and this was dried with potassium carbonate and evaporated.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[CH2:18][CH2:17]2)=[O:15])=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30].C(=O)(O)[O-].[Na+]>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.COCCOC>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:38]=[CH:39][C:40]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C:14]([N:16]4[CH2:21][CH2:20][N:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[CH3:28])[CH2:18][CH2:17]4)=[O:15])=[CH:6][CH:7]=3)=[CH:41][CH:42]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1ccccc1N1CCN(C(=O)c2c(C)noc2-c2ccc(Br)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(=O)N4CCN(c5ccccc5C)CC4)cc3)cc2)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-(4-o-tolyl-piperazin-1-yl)-methanone (0.156 g, 0.36 mmol), 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester (0.168 g, 0.53 mmol), tetrakis(triphenylphosphine)palladium(0) (0.042 g, 0.04 mmol), and sodium bicarbonate (0.076 g, 0.90 mmol) were combined in 3:1 DME:H2O, and the mixture was purged with N2 (g). The reaction was stirred at 80° C. for 1 hour and then cooled and concentrated. The crude material was purified by silica gel chromatography (0-40% EtOAc in hexanes) to give the title compound.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:5]([CH3:16])=[N:6][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]=1[NH2:9].[NH3:17]>O.C(O)C>[NH2:9][C:8]1[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=[C:5]([CH3:16])[C:4]=1[N:3]=[C:4]1[C:8](=[NH:7])[NH:9][N:17]=[C:5]1[CH3:16]
Reactant: N
Reactant: Cc1nn(-c2ccccc2)c(N)c1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC1=NNC(=N)C1=Nc1c(C)nn(-c2ccccc2)c1N
Reaction time: 17 h

Procedure:
2.6 g 4,5-diamino-3-methyl-1-phenyl-1H-pyrazole dihydrochloride were dissolved in a mixture of 30 ml water and 30 ml ethanol. The pH of the resulting solution was then adjusted to 9 with concentrated ammonia. Subsequently the reaction mixture was stirred for 17 hours with a gasifying stirrer. The precipitated dye compounds was separated by filtration, washed with water and dried. The yield amounted to 1.2 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][C@@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][C@H:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)[CH3:21]>>[CH3:29][O:28][C:26]([C:25]1[CH:30]=[CH:31][C:22]([C@@H:20]([NH:19][C:15]([C@H:9]2[CH2:10][C:11](=[O:14])[CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:17])[CH3:21])=[CH:23][CH:24]=1)=[O:27]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C[C@@H]1C(=O)O
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(=O)CCN2C(=O)OC(C)(C)C)cc1

Procedure:
The title compound (D60) (300 mg) was prepared according to the general procedure for amides preparation (Method C) starting from (R)-1-(tert-butoxycarbonyl)-4-oxopiperidine-2-carboxylic acid (200 mg; available from Aldrich#701130) and (S)-methyl 4-(1-aminoethyl)benzoate hydrochloride (195 mg). Reaction time: 1 h
Reaction SMILES: Cl[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH2:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)[CH3:17]>>[CH2:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:2]2[C:3]3[C:8]([N:9]=[C:10]4[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:20][CH2:19]1)[CH3:17]
Reactant: Clc1c2ccccc2nc2ccccc12
Reactant: CCN1CCC(N)CC1
Product: CCN1CCC(Nc2c3ccccc3nc3ccccc23)CC1

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 9-chloroacridine and 1-ethylpiperidin-4-amine, the title compound was obtained; MS (Found M+1=306).
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=[C:13]([C:14]([O:16]CC)=[O:15])[C:8]=2[C:7]([CH3:23])=[N:6]1)([CH3:4])[CH3:3].[OH-].[Na+]>CCO>[CH3:4][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:8]=2[C:7]([CH3:23])=[N:6]1)([CH3:1])[CH3:3]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nc2c1c(C)nn2C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(C(C)(C)C)c2nc(C(C)(C)C)cc(C(=O)O)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an EtOH solution (8 mL) of ethyl 1,6-bis(1,1-dimethylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (528 mg, 1.663 mmol) was added sodium hydroxide (2.77 mL, 8.32 mmol), and the mixture was stirred for at room temperature for 2 h. The volatiles were removed under reduced pressure and the aqueous phase was acidified using 1H HCl to ˜pH 3. The precipitate was filtered, washed with water, and dried under high vacuum to give the product as 445 mg (92%). LCMS E-S (M+H)=289.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.49 (s, 9H), 1.76 (s, 9H), 2.51 (s, 3H), 7.51 (s, 1H).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl.C([BH3-])#N.[Na+].O[CH:11]1[NH:16][C:15](=[O:17])[C:14]2([C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]1>C(#N)C>[C:15]([C:14]1([CH2:13][CH2:12][CH2:11][NH:4][CH:1]([CH3:3])[CH3:2])[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:17])[NH2:16]
Reactant: CC(C)N
Reactant: O=C1NC(O)CCC12c1ccccc1-c1ccccc12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Product: CC(C)NCCCC1(C(N)=O)c2ccccc2-c2ccccc21
Temperature: 25 °C
Yield: 70 %

Procedure:
The pH of a cold (10° C.) solution of 12.0 ml of isopropylamine in 500 ml of acetonitrile was adjusted to 8.0 by addition of gaseous hydrogen chloride. While the reaction mixture was stirred there were added sequentially 2.0 g of sodium cyanoborohydride and 5.4 g of 6'-hydroxyspiro(9H-fluorene-9,3'-piperidine)-2'-one (the cyclic carbinol and its tautomer prepared as described in Examples 1 and 2). The reaction mixture was heated at reflux for six hours, cooled to 25° C. and then diluted by addition of 100 ml of 1N hydrochloric acid. The organic solvent was removed by evaporation under reduced pressure. The aqueous solution was washed several times with dichloromethane, made alkaline by addition of ammonium hydroxide, and the product was extracted into fresh dichloromethane. The organic extracts were combined, washed with water, dried and concentrated to dryness to give 70% yield of 9-carbamoyl-9-(3-isopropylaminopropyl)fluorene, the identity of which was confirmed by thin layer chromatographic comparison with an authenic sample (silica gel, ethyl acetate:methanol, 80:20 v/v).
Reaction SMILES: C([Mg]Br)C.[CH:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH3:15][O:16][CH:17](OC)[O:18][CH3:19]>C(OCC)C>[CH3:15][O:16][CH:17]([O:18][CH3:19])[C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: COC(OC)OC
Reactant: C#CCCCCCCCC
Agent: CC[Mg]Br
Solvent: CCOCC
Product: CCCCCCCCC#CC(OC)OC

Procedure:
To freshly prepared ethyl magnesium bromide (from 61 mmoles bromoethane and 63 mmoles magnesium) was added 1-decyne (50 mmoles) in diethyl ether (10 ml) dropwise at ambient temperature. The reaction mixture was then heated at reflux for 2 hours. After cooling the reaction mixture, trimethylorthoformate (75 mmoles) in diethyl ether (10 ml) was added and the resultant mixture heated to distill off the diethyl ether. The resultant paste was taken up in anhydrous toluene (50 ml) and heated at reflux for 1 hour. The reaction mixture was poured into saturated ammonium chloride (50 ml) and then extracted with diethyl ether (3×50 ml). The organic phase was washed with water (3×20 ml) and dried over anhydrous magnesium sulfate. Evaporation of the organic phase afforded the desired product as an oil.
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]([CH3:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]O>>[C:1]([O:12][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:14]([CH3:22])[CH3:13])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CN(C)CCCCCCO
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)OCCCCCCN(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 6-dimethylamino-1-hexanol as starting materials to give the aimed compound.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:9]1[C:10](=[O:28])[CH2:11][CH:12]([C:16]2[C:17]([O:26][CH3:27])=[N:18][C:19]([S:24][CH3:25])=[N:20][C:21]=2[O:22][CH3:23])[CH2:13][C:14]=1[OH:15])[CH2:6][CH2:7][CH3:8])[CH3:2].Cl.[Cl:30][CH:31]=CCON>>[Cl:30][CH:31]=[CH:2][CH2:1][O:3][N:4]=[C:5]([C:9]1[C:10](=[O:28])[CH2:11][CH:12]([C:16]2[C:21]([O:22][CH3:23])=[N:20][C:19]([S:24][CH3:25])=[N:18][C:17]=2[O:26][CH3:27])[CH2:13][C:14]=1[OH:15])[CH2:6][CH2:7][CH3:8]
Reactant: NOCC=CCl
Reactant: CCCC(=NOCC)C1=C(O)CC(c2c(OC)nc(SC)nc2OC)CC1=O
Agent: Cl
Product: CCCC(=NOCC=CCl)C1=C(O)CC(c2c(OC)nc(SC)nc2OC)CC1=O

Procedure:
2-[1-(3-Chloroallyloxyimino)butyl]-3-hydroxy-5-(4,6-dimethoxy-2-methylthio-5-pyrimidyl)cyclohex-2-en-1-one (6) was prepared from 2-butyryl-3-hydroxy-5-[5-(4,6-dimethoxy-2-methylthiopyrimidyl]cyclohex-2-en-1-one (see Example 3) and 3-chloroallyloxyamine hydrochloride following essentially the same procedure as that described in Example 1, part (iv). The product was obtained as a nearly colourless oil and was characterized by nuclear resonance spectroscopy.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:12])[C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:13]([N:9]1[CH2:8][CH2:7][CH:6]([C:4]([N:3]([O:2][CH3:1])[CH3:12])=[O:5])[CH2:11][CH2:10]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CON(C)C(=O)C1CCNCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CON(C)C(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 80 °C

Procedure:
To the solution of N-methoxy-N-methylpiperidine-4-carboxamide (40 g, 232 mmol) in acetone (400 mL) was added benzyl bromide (42 mL, 349 mmol) and K2CO3 (64 g, 465 mmol) and the reaction mixture was stirred at 80° C. under reflux for 16 h. After completion of the reaction, the reaction mixture was filtered and acetone was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 50% ethyl acetate in hexane) to afford 1-benzyl-N-methoxy-N-methylpiperidine-4-carboxamide product. [M+1]=263.15
Reaction SMILES: [CH3:1][C@:2]([OH:17])([CH2:15][CH3:16])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[OH:4].BrBr>C(Cl)Cl.[F-].[K+].CCOCC>[OH:17][C@@:2]([CH3:1])([CH2:15][CH3:16])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][CH:10]=1)=[O:4]
Reactant: CC[C@](C)(O)[C@H](O)c1ccc(S(C)(=O)=O)cc1
Agent: BrBr
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC[C@](C)(O)C(=O)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of the crude product from Step 7 (7 g) and (Bu3 Sn)2O (30 mL) in 150 mL of CH2Cl2 cooled at 10° C. was added a solution of Br2 (9.3 g in 30 mL of CH2Cl2). After stirring at r.t. for 30 min. the mixture was diluted with a solution of KF (500 mL, 3N) and 500 mL of Et2O. The solid generated was removed by filtration and the filtrate was separated. The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography eluted with 1:1 hexane/EtOAc to give 5 g of the title compound as a yellow oil.
Reaction SMILES: C(O)CCCC.[CH3:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl.CS[C:17]1[N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[CH2:21][C:20]2[CH:27]=[CH:28][CH:29]=[CH:30][C:19]=2[N:18]=1.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]\[C:34]([OH:36])=[O:35]>C(O)(C)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]\[C:34]([OH:36])=[O:35].[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([C:17]2[N:23]3[CH:24]=[CH:25][N:26]=[C:22]3[CH2:21][C:20]3[CH:27]=[CH:28][CH:29]=[CH:30][C:19]=3[N:18]=2)[CH2:10][CH2:9]1
Reactant: CSC1=Nc2ccccc2Cc2nccn21
Reactant: CN1CCNCC1
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCCCCO
Solvent: CC(C)O
Product: CN1CCN(C2=Nc3ccccc3Cc3nccn32)CC1

Procedure:
Amyl alcohol (5100 ml) and 918.35 g (9.17 moles) of N-methylpiperazine were charged into a 12 liter 3-necked reaction flask fitted with a Dean-Stark adapter. The solution was stirred under nitrogen atmosphere and 989 ml of 10N ethanolic hydrogen chloride solution were added rapidly. The reaction mixture was heated to reflux and the distillate was collected in the Dean-Stark adapter. When the temperature of the reaction mixture reached 131° the Dean-Stark adapter was removed and an additional 918.35 g (9.17 moles) of N-methylpiperazine followed by 1045.0 g (4.56 moles) of 5-methylthio-11H-imidazo[1,2-c][1,3]benzodiazepine were added. The mixture was heated at reflux under nitrogen atmosphere for 20 hours. Amyl alcohol was then removed under reduced pressure at a water bath temperature of 80°. The viscous residual oil was dissolved in 10,000 ml of dichloromethane, washed with 3×4,000 ml of 4N sodium hydroxide and 6×4,000 ml of water. The dichloromethane solution was then extracted with 3×2,000 ml of 6N hydrochloric acid. The aqueous solution was back washed with 2×2,000 ml of dichloromethane, treated with 100 g of activated carbon and filtered. The clear filtrate was adjusted to pH 9-10 with 1,500 ml of ammonium hydroxide solution (29%). The oil which separated was extracted with 3×4,000 ml of dichloromethane, the extracts were dried over 1,000 g of sodium sulfate and the solvent removed at reduced pressure with a water bath temperature of 60°. An oil was obtained which rapidly solidified and after drying further (5 mm Hg/40°) yielded crude product, m.p. 113°-120°. The crude product was dissolved in 8,000 ml of hot (60°-70°) isopropanol. The solution was decolorized with 200 g of activated carbon and filtered. To this solution was added a solution of 760.7 g (8.28 moles) of maleic acid in 2,500 ml of warm (30°) isopropanol and the maleate salt began to precipitate. The suspension was stirred overnight at ambient temperature to complete crystallization and the solid was collected by filtration. The product was washed with 3×500 ml of cold isopropanol and dried (0.5 mm/50°). This was recrystallized from ethanol, the resulting product was washed first with ethanol and then with ether and then dried to give 5-(4-methyl-1-piperazinyl)-11H-imidazo[1,2-c][1,3]benzodiazepine monomaleate, m.p. 204°-205° (dec).