Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Br:9][CH:10]1[C:15]([CH3:16])=[C:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[N:13]2[C:24](=[O:36])[CH:25]([NH:26][C:27](=[O:35])[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:12]2[S:11]1=[O:37]>ClCCl>[Br:9][CH:10]1[C:15]([CH2:16][Br:1])=[C:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[N:13]2[C:24](=[O:36])[CH:25]([NH:26][C:27](=[O:35])[CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C@H:12]2[S:11]1=[O:37]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1Br
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1=C(CBr)C(Br)S(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
3.05 g of N-bromosuccinimide were added portionwise over 1.75 hours to an ice-cold solution of 4.6 g of t-butyl 2-bromo-3-methyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide in 350 ml of dichloromethane under the exposure to light of a tungsten lamp of 150 W. After the addition of N-bromosuccinimide was complete, the exposure was continued for one hour and the orange colored solution was evaporated to dryness under vacuo at low temperature. The residue was chromatographed over silica gel, using as initial eluent a 72:1 mixture of methylene chloride and acetone and then a 49:1 mixture of the same components to obtain 1.4 g of t-butyl 2-bromo-3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide by evaporation to dryness of the suitable fractions.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:12]=[CH2:13])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=C[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N-].[Si:22]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Si:22]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])([C:25]([CH3:27])([CH3:28])[CH3:26])([CH3:24])[CH3:23].[C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:23][CH2:13]1)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=C[C@H](CO)NC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C
Solvent: CCOCC
Product: CCOC(=O)C1([C@H](CO)NC(=O)OC(C)(C)C)CC1
Yield: 87.9 %

Procedure:
Palladium(II) acetate (168 mg, 0.75 mmol) was dissolved in an ether solution (50 ml) of t-butyldimethylsilyl ether of (2R)-N-t-butoxycarbonyl-2-amino-3-butenol (3) (4.34 g, 15.0 mmol) and to this was added an ether solution (100 ml) of ethyl diazoacetate (17.1 g, 150 mmol) and palladium(II) acetate (168 mg, 0.75 mmol) over 3 hours. The insoluble material in the reaction mixture was filtered off and the filtrate was concentrated under reduced pressure to give an oily product. Purification of the product by column chromatography over silica gel (20% ether/hexane) afforded t-butyldimethylsilyl ether of (2R)-N-t-butoxycarbonyl-2-(ethoxycarbonylcyclopropyl)glycinol (4) as an oil (4.00 g, 87.9%). Compound (4) thus obtained was dissolved in ethanol (70 ml) and CSA (10 mg) was added to this solution then the mixture was stirred for 16 hours at room temperature. The solvent was removed under reduced pressure and the residue was subjected to medium pressure column chromatography over silica gel (50% ether/hexane) 932 mg of (2R,3S,4S)-N-t-butoxycarbonyl-2-(ethoxycarbonylcyclopropyl)glycinol (5), 175 mg of its stereoisomer (6) and 560 mg of a mixture of inseparable stereoisomer.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]([C:19]1[C:24]([O:25][CH3:26])=[N:23][C:22]([CH3:27])=[CH:21][N:20]=1)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1I)(=[O:11])=[O:10])=[O:7])[CH:2]([CH3:4])[CH3:3].[C:28]1([CH3:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O)C.C(=O)([O-])[O-].[Na+].[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.O>[CH2:1]([O:5][C:6]([N:8]([C:19]1[C:24]([O:25][CH3:26])=[N:23][C:22]([CH3:27])=[CH:21][N:20]=1)[S:9]([C:12]1[C:13]([C:31]2[CH:32]=[CH:33][C:28]([CH3:34])=[CH:29][CH:30]=2)=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:11])=[O:10])=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1ccccc1
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1ccccc1I
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: O
Solvent: CCO
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1ccccc1-c1ccc(C)cc1

Procedure:
A mixture of N-(isobutoxycarbonyl)-N-(3-methoxy-5-methyl-2-pyrazinyl)-2-iodobenzenesulphonamide (0.252 g) 4-methylbenzeneboronic acid (0.068 g), tetrakis(triphenylphosphine)palladium(0) (0.0115 g), toluene (2.5 ml), ethanol (1.25 ml) and 2H sodium carbonate solution (3.75 ml) was stirred vigorously and heated under reflux for 2 hours under an atmosphere of argon. Water (10 ml) was added and the mixture was extracted with ethyl acetate (2×10 ml). The combined extracts were washed with saturated sodium chloride solution (25 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:4 v/v), to give N-(isobutoxycarbonyl)-N-(3-methoxy-5-methyl-2-pyrazinyl)-4'-methyl-2-biphenylsulphonamide (0.182 g); 1H NMR (DMSO-d6): 0.6 (d,6H), 1.55-1.75 (m,1H), 2.35 (s,3H), 2.5 (s,3H), 3.85 (d,2H), 3.95 (s,3H), 7.15-7.25 (m,4H), 7.35-7.45 (m,1H), 7.7-7.8 (m,2H), 8.15 (s,1H), 8.45-8.55 (m,1H); mass spectrum (+ve FAB, methanol/NBA): 470 (M+H)+.
Reaction SMILES: [CH2:1]([C@:4]12[CH2:12][CH2:11][C:10]3[C:13]4[CH:14]=[CH:15][C:16]([O:21][CH3:22])=[CH:17][C:18]=4[CH2:19][CH2:20][C:9]=3[C@@H:8]1[CH2:7][CH2:6][C@@H:5]2[OH:23])[CH2:2][CH3:3].[Li]>O1CCCC1.NC1C=CC=CC=1.N>[CH2:1]([C@:4]12[CH2:12][CH2:11][C@@H:10]3[C:13]4[CH:14]=[CH:15][C:16]([O:21][CH3:22])=[CH:17][C:18]=4[CH2:19][CH2:20][C@H:9]3[C@@H:8]1[CH2:7][CH2:6][C@@H:5]2[OH:23])[CH2:2][CH3:3]
Reactant: CCC[C@]12CCC3=C(CCc4cc(OC)ccc43)[C@@H]1CC[C@@H]2O
Agent: N
Agent: [Li]
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Product: CCC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reaction time: 3 h
Yield: 99.4 %

Procedure:
Add 13β-n-propyl-3-methoxy-gona-1,3,5(10), 8-tetraen-17β-ol (3.1 g.) dissolved in a mixture of tetrahydrofuran (10 cc.) and freshly distilled aniline (60 cc.) to liquid ammonia (160 cc.) and add lithium metal (1.5 g.) in small pieces. Stir the reaction mixture for 3 hours, then quench with solid ammonium chloride (12.5 g.) and take up in water. Ether-extract the product and evaporate the washed and dried extracts to obtain a semisolid residue of crude 13β-n-propyl-3-methoxy-gona-1,3,5(10) -trien-17β-ol (3.1 g.); ultraviolet absorption peak at 279 mμ (ε1,800).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[O:8])=[CH:5][CH:4]=1.C(O)C.[C:23]1([N:29]=[C:30]=[S:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])(=O)C.[Na+]>O>[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:30]([NH:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[S:31])=[CH:13][CH:12]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: Nc1ccc(NNC(=O)c2ccc(Cl)cc2)cc1
Reactant: S=C=Nc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(NNc1ccc(NC(=S)Nc2ccccc2)cc1)c1ccc(Cl)cc1

Procedure:
1-(4-Chlorobenzoyl)-2-(4-aminophenyl)hydrazine hydrochloride (2.0 g, 0.0067 mole) was mixed with ethanol (125 ml) and water (25ml). Phenyl isothiocyanate (1.1 g, 0.01 mole) was added to the mixture along with sodium acetate (0.82 g, 0.1 mole) in water (10 ml). The reaction mixture was stirred and refluxed for 5 minutes, then was stirred at room temperature for 11/2 hours. The mixture was chilled in ice and then filtered. The product was washed with ethanol and dried to give an off-white solid. Yield 1.9 g (71%), m.p. 197.5°-199° C.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13](=[O:21])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:22])[N:6]=1)[CH2:3][CH3:4].Cl[C:24]1[CH:29]=[CH:28][N:27]=[C:26]2[NH:30][CH:31]=[CH:32][C:25]=12.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[NH:30]1[C:26]2=[N:27][CH:28]=[CH:29][C:24]([NH:1][C@H:2]([C:5]3[N:14]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:13](=[O:21])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[F:22])[N:6]=3)[CH2:3][CH3:4])=[C:25]2[CH:32]=[CH:31]1
Reactant: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1ccccc1
Reactant: Clc1ccnc2[nH]ccc12
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ccnc2[nH]ccc12)c1nc2cccc(F)c2c(=O)n1-c1ccccc1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
Under nitrogen, to (S)-2-(1-aminopropyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (27 mg, 0.091 mmol, 1.0 equiv) in t-BuOH (0.5 mL) at 23° C. is added 4-chloro-1H-pyrrolo[2,3-b]pyridine (21 mg, 0.14 mmol, 1.5 equiv) and diisopropylethylamine (63 μL, 0.36 mmol, 4.0 equiv). After stirring for 48 hr at 120° C. in a sealed tube, the reaction mixture is concentrated in vacuo and the residue is purified by preparative TLC eluting with CH2Cl2/MeOH to afford the title compound (Compound 5A).
Reaction SMILES: S=C1[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:20])[CH3:19])=[C:13]([O:21][CH3:22])[CH:12]=2)=[O:8])[CH2:5][CH2:4]S1.C(N)[C:24]1[CH:29]=[CH:28]C=[CH:26][CH:25]=1>C1COCC1.C(OCC)C>[C:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:7](=[O:8])[NH:6][CH2:5][C:4]2[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=2)=[CH:12][C:13]=1[O:21][CH3:22])(=[O:20])[CH3:19]
Reactant: NCc1ccccc1
Reactant: COc1cc(COC(=O)N2CCSC2=S)ccc1OC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(COC(=O)NCc2ccccc2)ccc1OC(C)=O
Reaction time: 8 h
Yield: 7 %

Procedure:
Compound VII (339 mg, 0.993 mmol) was dissolved in anhydrous THF (5 mL). To the stirred, yellow solution was added at room temperature a solution of benzylamine (160 mg, 163 pt, 1.5×0.993 mmol) in anhydrous THF (5 mL), After being stirred overnight, the reaction solution was diluted with diethyl ether and extracted with 1N HCl, water and saturated NaCl. The organic phase was dried over anhydrous MgSO4, filtered and concentrated. Purification by column chromatography on silica gel eluting with hexanes/ethyl acetate (7:3-1:1, v/v) afforded 23 mg (7%) of 8 as a clear oil: Rf=0.30 (hexanes/ethyl acetate, 1:1, v/v); 1HNMR (CDCl3) δ 7.34-7.25 (m, 5H), 6.99 (d, 3J=8.0 Hz, 1H), 6.96 (s, 1H), 6.92 (d, 3J=8.1 Hz, 1H), 5.09 (s, 2H), 5.04 (bs, 1H, NH), 4.38 (d, 3J=6 Hz, 2H), 3.81 (s, 3H) and 2.29 (s, 3H). While the synthesis proceeded in excellent yield, product isolation was compromised by decomposition during work-up.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]([CH2:16][CH2:17][O:18]C(=O)C)[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)(=O)C.[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31]C(O)=O)=[CH:27][CH:26]=1)([O-:24])=[O:23].N1CCCCC1>CN(C)C=O>[OH:18][CH2:17][CH2:16][N:7]([CH2:6][CH2:5][OH:4])[C:8]1[CH:9]=[CH:10][C:11]([CH:12]=[CH:31][C:28]2[CH:29]=[CH:30][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)=[CH:14][CH:15]=1
Reactant: CC(=O)OCCN(CCOC(C)=O)c1ccc(C=O)cc1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(N(CCO)CCO)cc2)cc1
Temperature: 0 °C

Procedure:
A mixture of the crude reaction product of the previous step, viz. 4-di(2-acetyloxyethyl)aminobenzaldehyde, 270 g of 4-nitrophenyl acetic acid, 2 l of dimethyl formamide, and 100 ml of piperdine was stirred for 4 days at 20°-25° C. Next, the reaction mixture was concentrated by evaporation at 70° C. to a thick red oil, which was titrated three times, each time with 1 l of n-hexane. The residue was dissolved in 2.5 l of dimethyl formamide. Then there was added a solution of 320 g of sodium hydroxide in 800 ml of water. The resulting reaction mixture was then heated for 16 hours to 100° C. and subsequently poured into 10 l of ice water. The precipitated product was filtered off and thoroughly after-washed three times, each time with 1 l of water. After drying the crude reaction product was crystallized from 250 ml of dimethyl formamide and 500 ml of dichloromethane. The resulting yield of 4-di(2-hydroxy-ethyl) amino-4'-nitrostilbene was 190 g with a melting point of 184°-185° C. Calculated on N,N-di(2-hydroxyethyl)aniline this is 58% of theory.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:16]=[C:15]([Cl:25])[C:14]=1[OH:26].O>CN(C)C=O>[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:16]=[C:15]([Cl:25])[C:14]=1[O:26][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: BrCCCBr
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.7 %

Procedure:
A reaction vessel was charged with 10.6 g of 1,3-dibromopropane, 5.53 g of potassium carbonate and 100 ml of N,N-dimethylformamide, to which a solution of 30.5 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol dissolved in 40 ml of N,N-dimethylformamide was slowly added dropwise. After stirring at room temperature for 24 hours, the reaction mixture was poured into water, and extracted twice with 150 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 11.1 g of 3,5-dichloro-4-(3-bromopropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (77% yield), nD24.0 1.5693.
Reaction SMILES: C[O-].[Na+].[NH:4]([CH2:11][CH2:12][C:13]#[N:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O[CH:16]([C:22]1[CH:32]=[C:31]([O:33][CH3:34])[C:25]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])=[C:24]([O:35][CH3:36])[CH:23]=1)CS(C)(=O)=O.CS(C)=O>O>[NH:4]([CH:11]=[C:12]([C:13]#[N:14])[CH2:16][C:22]1[CH:32]=[C:31]([O:33][CH3:34])[C:25]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])=[C:24]([O:35][CH3:36])[CH:23]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#CCCNc1ccccc1
Reactant: COc1cc(C(O)CS(C)(=O)=O)cc(OC)c1N(C)C(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(CC(C#N)=CNc2ccccc2)cc(OC)c1N(C)C(C)=O

Procedure:
A mixture of 3.24 g. of sodium methylate, 8.75 g. of β-anilino-propionitrile and 14.9 g. of 4'-[1-hydroxy-2-(methylsulfonyl)-ethyl]-2',6'-dimethoxy-N-methylacetanilide in 60 ml. of absolute dimethylsulfoxide was stirred at 50° C. for 4 hours with the exclusion of moisture. The solution was poured into 600 ml. of water. The resulting emulsion was extracted with two 400 ml. portions of ethyl acetate. Thereafter, the ethyl acetate extracts were washed with two 150 ml. portions of water, combined, dried over magnesium sulfate and evaporated under vacuum. Recrystallization of the residue from ethyl acetate gave 4'-(3-anilino-2-cyano-allyl)-2',6'-dimethoxy-N-methyl-acetanilide having a melting point of 202°-204° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:20][NH:21][C:22]1[C:23](=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:15][CH2:14][CH2:13][CH:9]1[C:10]([N:21]([CH3:20])[C:22]1[C:23](=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CCCN1Cc1ccccc1
Reactant: CCOC(=O)c1ccccc1NC
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccccc1N(C)C(=O)C1CCCN1Cc1ccccc1

Procedure:
A mixture of 21 g. of N-benzylproline and 300 ml. of benzene is stirred and 12 g. of thionyl chloride is added dropwise. The reaction mixture is heated on the steam bath for 2 hours, and 18 g. of ethyl N-methylanthranilate are added. The mixture is heated at reflux temperature for 6 hours, washed with dilute sodium hydroxide and concentrated. The residue is purified by partition chromatography and ethyl N-(N-benzyl-2-pyrrolidinylcarbonyl)-N-methylanthranilate is obtained.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:10])([CH3:9])[CH2:7][OH:8].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:10])([CH3:9])[CH2:7][O:8][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: C1=COCCC1
Reactant: CC(C)(CO)CCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(CCCCBr)COC1CCCCO1
Yield: 82.6 %

Procedure:
According to the procedure for the preparation of 207d, (Ackerley, N. et al. J. Med. Chem. 1995, 38, 1608-1628; Manley, P. W. et al. J. Med. Chem. 1987, 30, 1812-1818) 206c (521.0 g, 2.49 mol) was reacted with 3,4-dihydro-2H-pyran (278.0 g, 3.30 mol) and p-toluenesulfonic acid hydrate (3.13 g, 16 mmol) in CH2Cl2 (2.2 L) to yield 207c (603.0 g, 83%) as a pale-yellow oil, which was used without further purification. 1H NMR (CDCl3): δ 4.55 (t, 1H, J=3.3), 3.84 (m, 1H), 3.50 (m, 1H), 3.47 (d, 1 H , J=9.0), 3.42 (t, 2H, J=6.7), 2.99 (d, 1H, J=9.0), 1.88 (m, 2H), 1.75-1.33 (m, 10H), 0.91 (s, 3H), 0.90 (s, 3H). 13C NMR (CDCl3): δ 99.37, 76.58, 62.17, 38.56, 34.43, 34.19, 33.90, 30.88, 25.79, 24.80, 24.71, 22.89, 19.67. HRMS (LSIMS, nba): Calcd for C13H25BrO2 (MH+): 293.1116, found: 293.1128.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[N:5]=[C:4]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH:3]=1.[CH:23]([Mg]Br)=[CH2:24].O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH:23]=[CH2:24])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH:3]=1
Reactant: C=C[Mg]Br
Reactant: CS(=O)(=O)c1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Reaction time: 0.5 h

Procedure:
A solution of (6-chloro-2-methanesulfonyl-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine (821 mg, 2.16 mmol) in THF (15 mL) is cooled to 0° C. A 1 M solution of vinyl magnesium bromide in THF (5.4 mL, 5.4 mmol) is added and the mixture is stirred for 30 minutes before adding water (30 mL) and extracted thrice with EtOAc (50 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and evaporated. The residue is subjected to chromatography on silica gel eluting with 30% ethyl acetate:heptane to afford (6-chloro-2-vinyl-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine (600 mg) as a solid.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH:15]2[CH2:16][CH2:17][CH2:18][CH:11]1[CH2:12][CH:13]([CH2:19][C:20]([O:22]CC)=[O:21])[CH2:14]2)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1COCC1.[Cl-].[Na+].O>[C:3]([O:7][C:8]([N:10]1[CH:15]2[CH2:16][CH2:17][CH2:18][CH:11]1[CH2:12][CH:13]([CH2:19][C:20]([OH:22])=[O:21])[CH2:14]2)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)CC1CC2CCCC(C1)N2C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CCCC1CC(CC(=O)O)C2
Temperature: 25 °C

Procedure:
10 ml of 1M aqueous NaOH are added to a solution of 3-ethoxycarbonylmethyl-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester in 20 ml of THF and the mixture obtained is stirred at RT. To the mixture obtained 10 ml of brine and 70 ml of EtAc are added, and the mixture obtained is washed with 1M aqueous HCl. The organic layer obtained is dried and solvent is evaporated. 3-Carboxymethyl-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester in the form of an oil is obtained. 13C-NMR: 178.47, 177.28, 155.61, 154.50, 79.70, 79.63, 47.39, 45.88, 43.39, 40.31, 36.92, 32.22, 31.98, 31.37, 30.99, 30.74, 30.64, 30.08, 29.59, 29.20, 21.15, 20.60, 14.05.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:5]1.[H-].[Na+].[Cl:19][C:20]1[CH:25]=[C:24](F)[CH:23]=[CH:22][N:21]=1.C([O-])(O)=O.[Na+]>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[C:24]([O:1][CH2:2][CH2:3][N:4]2[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:5]2)[CH:23]=[CH:22][N:21]=1
Reactant: O=c1ccc(-c2ccccc2)nn1CCO
Reactant: Fc1ccnc(Cl)c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccc(-c2ccccc2)nn1CCOc1ccnc(Cl)c1
Reaction time: 0.08 h
Yield: 79.6 %

Procedure:
To a 15 mL round-bottomed flask was added 2-(2-hydroxyethyl)-6-phenylpyridazin-3(2H)-one (0.20 g, 0.92 mmol) and N,N-dimethylformamide (5 mL). To the mixture at 25° C. was added sodium hydride (0.039 g, 1.0 mmol, 60% dispersion in mineral oil). The solution was stirred for 5 min and then 2-chloro-4-fluoropyridine (0.17 g, 1.3 mmol) was added. After stirring for 2 hours the mixture was poured into aq. NaHCO3 (100 mL) and then extracted with 50% EtOAc/hexane (3×75 mL). The combined extracts were washed with H2O (3×75 mL) and brine (75 mL), dried (Na2SO4), and concentrated onto silica. Purification by silica gel chromatography (40 to 90% EtOAc/hexane) afforded the title compound as a white solid (0.24 g, 78% yield). MS (ESI, pos. ion.) m/z: 328 (MH+). Calc'd exact mass for C17H14ClN3O2: 327. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.53 (t, J=5.0 Hz, 2 H), 4.61 (t, J=5.1 Hz, 2 H), 7.00 (dd, J=5.9, 2.3 Hz, 1 H), 7.08 (d, J=9.8 Hz, 1 H), 7.14 (d, J=2.2 Hz, 1 H), 7.44-7.51 (m, 3 H), 7.85-7.87 (m, 2 H), 8.06 (d, J=9.8 Hz, 1 H), 8.18 (d, J=5.9 Hz, 1 H).
Reaction SMILES: [CH3:1][C@:2]12[N:18]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:25]4[C:26]5[CH2:31][NH:30][C:28](=[O:29])[C:27]=5[C:15]5=[C:16]([C:17]=43)[N:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=35)[C@H:6]([O:7]1)[CH2:5][C@@H:4]([NH:32][CH3:33])[C@H:3]2[O:34][CH3:35].C[C@H](N)CC1C=CC=CC=1.C[C@H](N)CC1C=CC=CC=1.[OH:56]S(O)(=O)=O>CS(C)=O.[OH-].[Na+].C(OCC)(=O)C>[CH3:1][C@:2]12[N:18]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:25]4[C:26]5[C@H:31]([OH:56])[NH:30][C:28](=[O:29])[C:27]=5[C:15]5=[C:16]([C:17]=43)[N:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=35)[C@H:6]([O:7]1)[CH2:5][C@@H:4]([NH:32][CH3:33])[C@H:3]2[O:34][CH3:35]
Reactant: O=S(=O)(O)O
Reactant: CN[C@@H]1C[C@H]2O[C@@](C)([C@@H]1OC)n1c3ccccc3c3c4c(c5c6ccccc6n2c5c31)C(=O)NC4
Agent: C[C@H](N)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN[C@@H]1C[C@H]2O[C@@](C)([C@@H]1OC)n1c3ccccc3c3c4c(c5c6ccccc6n2c5c31)C(=O)N[C@H]4O
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
100 mg (0.21 mmol) of staurosporine (commercially available from Kyowa Medex Co., Ltd., Japan) was dissolved in a mixture of 4 ml of DMSO and 1 ml of 2N sodium hydroxide. The solution was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed with water and brine in order, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography using the elution with 0%, 4%, 6%, and 10% acetone-containing chloroform in order to obtain 60 mg (yield: 59%) of UCN-01.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]3[CH2:20][CH2:21][CH2:22][CH2:23][C@H:16]3[CH2:15]2)=[O:13])=[CH:5][CH:4]=1.[F:24][C:25]([F:36])([F:35])C1C=C(CCO)C=CC=1>>[F:24][C:25]([F:36])([F:35])[C:4]1[CH:5]=[C:6]([CH2:9][CH2:10][O:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]3[CH2:20][CH2:21][CH2:22][CH2:23][C@@H:16]3[CH2:15]2)=[O:13])[CH:7]=[CH:8][CH:3]=1
Reactant: COc1ccc(CCOC(=O)N2CCN3CCCC[C@H]3C2)cc1
Reactant: OCCc1cccc(C(F)(F)F)c1
Product: O=C(OCCc1cccc(C(F)(F)F)c1)N1CCN2CCCC[C@@H]2C1

Procedure:
48 mg of the title compound was prepared as described for (S)-octahydropyrido[1,2-a]pyrazine-2-carboxylic acid 2-(4-methoxyphenyl)ethyl ester, using 2-(3-(trifluoromethyl)-phenyl)ethanol instead of 2-(4-methoxyphenyl)ethanol.