Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17](=[O:27])[CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[CH:31][C:32]([O:38][CH3:39])=[C:33](B(O)O)[CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][C@H:9]([NH:16][C:17](=[O:27])[CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:31]2[CH:30]=[C:29]([F:28])[CH:34]=[CH:33][C:32]=2[O:38][CH3:39])=[CH:3][CH:4]=1)[CH3:15]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: CCOC(=O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)CCC(=O)OC(C)(C)C
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: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(F)ccc2OC)cc1)NC(=O)CCC(=O)OC(C)(C)C
Temperature: 95 °C
Reaction time: 18 h

Procedure:
To a solution of (R)-tert-butyl 4-(1-(4-bromophenyl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoate, intermediate 9, (100 mg, 0.23 mmol) and 5-fluoro-2-methoxyphenylboronic acid (57.6 mg, 0.34 mmol) in toluene (1 mL) and EtOH (0.1 mL) is added Pd(PPh3)4 (26.1 mg, 0.023 mmol) and Na2CO3 (47.9 mg, 0.45 mmol). After stirring at 95° C. under nitrogen for 18 hours, the solution is cooled to ambient temperature and then quenched with aqueous 1 M HCl. The crude is diluted with ethyl acetate, the organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on silica gel (eluent: heptane/EtOAc=100:0 to 30:70) to give (R)-tert-butyl 4-(4-ethoxy-1-(5′-fluoro-2′-methoxybiphenyl-4-yl)-4-oxobutan-2-ylamino)-4-oxobutanoate (65 mg). HPLC retention time=1.44 minutes (condition B); MS (m+1)=488.3; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.32 (t, J=7.1 Hz, 3H) 1.48 (s, 9H) 2.41-2.48 (m, 2H) 2.51-2.63 (m, 4H) 2.90 (dd, J=13.6, 6 Hz, 1H) 3.02 (dd, J=13.6, 6 Hz, 1H) 3.81 (s, 3H) 4.14-4.29 (m, 2H) 4.49-4.63 (m, 1H) 6.44 (d, J=8.6 Hz, 1H) 6.89-6.97 (m, 1H) 6.98-7.05 (m, 1H) 7.05-7.11 (m, 1H) 7.27 (d, J=8.1 Hz, 2H) 7.49 (d, J=8.1 Hz, 2H).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][CH2:13][NH:14][C:15]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[O:16])=[CH:7][CH:6]=1.[OH-].[Na+]>O1CCCC1.CO>[CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[C:15]([NH:14][CH2:13][C:12]#[C:11][C:8]1[CH:7]=[CH:6][C:5]([C:4](=[O:27])[C:3]([OH:28])=[O:2])=[CH:10][CH:9]=1)=[O:16]
Reactant: COC(=O)C(=O)c1ccc(C#CCNC(=O)c2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1ccc(C#CCNC(=O)c2ccc3ccccc3c2)cc1
Reaction time: 0.08 h
Yield: 92.4 %

Procedure:
A solution of 4-[3-[[(2-naphthalenyl)carbonyl]amino]-1-propynyl]-alpha-oxobenzeneacetic acid methyl ester (0.225 g) in tetrahydrofuran (2 mL) and methanol (1 mL) was treated with 1N sodium hydroxide (1 mL). After five minutes, the reaction mixture was concentrated and the resulting white suspension partitioned between dichloromethane (10 mL) and 1N hydrochloric acid (2 mL). The aqueous layer was diluted with saturated sodium chloride and was extracted with tetrahydrofuran (2×10 mL). The combined extracts were dried (MgSO4) and concentrated to give 0.2 g of a white solid, mp 153°-155° C. Crystallization from dichloromethane-ethyl acetate-hexane gave 0.15 g of 4-[[(2-naphthalenyl)carbonyl]amino]-1-propynyl]-alpha-oxobenzeneacetic acid, mp 156-°158° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:14]O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:14])=[O:8]
Reactant: O=C(O)CCCCCBr
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCCCCBr
Reaction time: 48 h

Procedure:
For protecting thiol groups, take 2-thioethylamine hydrochloride and triphenylmethanol as reactants and boron trifluoride-diethyl ether complex is used as a catalyst to get 2-[(triphenylmethyl)thio]ethylamine. The reaction temperature is 72 degrees Celsius and the reaction time is 4 hours. Step (2): Use 2-[(Triphenylmethyl)thio]ethylamine and chloroacetyl chloride to carry out the amidation reaction in trichloromethane solution so as to produce N-[2-((Triphenylmethyl)thio)ethyl]-chloroacetamide. Step (3): Take 2-[(Triphenylmethyl)thio]ethylamine, N-[2-((Triphenylmethyl)thio)ethyl]-chloroacetamide and use triethylamine used as a reagent to carry out the substitution reaction in dichloromethane solution. Thus an amine-amide-thiol ligand is produced. The reaction temperature of the substitution reaction is 55° C. and the reaction time is 48 hours. Step (4): Dissolve 6-bromohexanoic acid and thionyl chloride in absolute methanol solution to carry out the esterification reaction and get methyl 6-bromohexanoate. The reaction temperature of the esterification reaction is 25° C. and the reaction time is 24 hours. Step (5): Take the amine-amide-thiol ligand and methyl 6-bromohexanoate and use sodium hydroxide (NaOH) as a reagent to carry out the substitution reaction in acetonitrile solution and get methyl 7,10-diaza-9-oxo-7-[2-((triphenylmethyl)thio)-ethyl]-12-[(triphenylmethyl)thio]dodecanoate. The reaction temperature of the substitution reaction is 85° C. and the reaction time is 24 hours. Step (6): Hydrolyze methyl 7,10-diaza-9-oxo-7-[2-((triphenylmethyl)thio)-ethyl]-12-[(triphenylmethyl)thio]dodecanoate in alkaline methanol solution to get 7,10-diaza-9-oxo-7-[2-((triphenylmethyl)thio)-ethyl]-12-[(triphenyl-methyl)thio]dodecanoic acid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.CCCCCC.[CH3:17][C:18]([CH3:28])([CH3:27])/[CH:19]=[N:20]/[S:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22]>C1COCC1>[CH3:17][C:18]([CH3:28])([CH3:27])[CH:19]([NH:20][S:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[C:2]1[S:1][CH:5]=[CH:4][N:3]=1
Reactant: c1cscn1
Reactant: CC(C)(C)/C=N/S(=O)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)C(NS(=O)C(C)(C)C)c1nccs1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
To a solution of thiazole (247 mg, 206 μl, 2.91 mmol) in 10 mL dry THF under argon at −73° C. was slowly added a 1.6M solution of BuLi in hexane (1.82 ml, 2.91 mmol). The resulting reaction mixture was stirred at −75° C. for 30 min and a solution of (E)-N-(2,2-dimethylpropylidene)-2-methylpropane-2-sulfinamide (Example 306a) (500 mg, 2.64 mmol) in 5 mL dry THF was added. The reaction mixture was stirred at −75° C. for 30 min, then cooling bath was removed and reaction stirred at r.t for 1 h. The reaction was quenched by the addition of few drops of water, the reaction mixture poured into ethyl acetate, and the solution was then extracted with aqueous NaHCO3 1M. The organic phase was collected, dried over Na2SO4 and evaporated down to dryness to give the title compound (666 mg, 92%) as crude dark orange oil. The crude was used without any further purification, MS (EI): m/e=275.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27]>CC(C)=O>[C:12]1([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][N:7]=3)[C:2]([O:1][CH2:27][CH:26]=[CH2:25])=[CH:3][C:4]2=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=c1cc(O)c2cccnc2n1-c1ccccc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(=O)n(-c2ccccc2)c2ncccc12

Procedure:
To a mixture of 62 g. of 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one, 39.6 g. of anhydrous potassium carbonate and 1,800 ml of acetone, there is added dropwise, with stirring, 37.5 g. of allyl bromide. The reaction mixture is refluxed for 22 hours, concentrated in vacuo, and the residue extracted with 600 ml. of chloroform. The organic extract is washed with water, 1N sodium hydroxide solution and again with water, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude solid is triturated with 3×400 ml of boiling isopropyl ether and filtered, yielding the insoluble product, wt. 38.5 g., m.p. 171°-174°. Recrystallization from methanol produces the product as a colorless solid, m.p. 176°-177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[C:16]([CH:17]=O)=[CH:15][CH:14]=[CH:13][N:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:19][O:20][C:21](=[O:34])[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=2)[CH:25]=[C:24]1[CH3:33]>>[CH3:19][O:20][C:21](=[O:34])[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=2)[C:25]([CH2:17][C:16]2[C:11]([S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:9])=[O:10])=[N:12][CH:13]=[CH:14][CH:15]=2)=[C:24]1[CH3:33]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1cccnc1S(=O)(=O)c1cccc(Cl)c1
Product: COC(=O)Cn1c(C)c(Cc2cccnc2S(=O)(=O)c2cccc(Cl)c2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using 2-(3-chlorobenzenesulfonyl)pyridine-3-carbaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][C:12](=[O:15])[NH:11][C:10]=2[CH:16]=1)=[O:4].[Cl:19]N1C(=O)CCC1=O>CN(C=O)C>[Cl:19][C:8]1[C:9]2[O:14][CH2:13][C:12](=[O:15])[NH:11][C:10]=2[CH:16]=[C:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:17])[F:18])[CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C1COc2ccc(NC(=O)C(F)(F)F)cc2N1
Solvent: CN(C)C=O
Product: O=C1COc2c(Cl)cc(NC(=O)C(F)(F)F)cc2N1

Procedure:
2,2,2-Trifluoro-N-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)acetamide was treated with N-chlorosuccinimide in DMF to obtain N-(8-chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-2,2,2-trifluoroacetamide.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:21][C:22]1([CH2:25][OH:26])[CH2:24][CH2:23]1>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][C:22]2([CH2:25][OH:26])[CH2:24][CH2:23]2)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: NC1(CO)CC1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: OCC1(Nc2nc(Cl)nc3c2SCC3)CC1
Temperature: 160 °C

Procedure:
1.4 g (II) are placed in 10 ml dioxane, then 3.6 ml diisopropylethylamine are added followed by 1 g 1-aminocyclopropanmethanol (cf. 2.2). The reaction mixture is heated to 160° C. until there is no further reaction, then cooled and evaporated down. The residue is treated with cyclohexane/ethyl acetate (4:1) in the ultrasound bath, the solid is suction filtered and dried. 1.24 g (III-2) are obtained in the form of a solid. Analytical HPLC-MS (method A): RT=1.01 min.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[CH:8]1([N:11]2[C:20]3[C:15](=[C:16]([CH3:23])[C:17]([F:22])=[C:18](F)[CH:19]=3)[C:14](=[O:24])[C:13]([C:25]([OH:27])=[O:26])=[CH:12]2)[CH2:10][CH2:9]1>CN1CCCC1=O>[CH:8]1([N:11]2[C:20]3[C:15](=[C:16]([CH3:23])[C:17]([F:22])=[C:18]([N:6]4[CH2:5][CH2:4][NH:3][CH:2]([CH3:1])[CH2:7]4)[CH:19]=3)[C:14](=[O:24])[C:13]([C:25]([OH:27])=[O:26])=[CH:12]2)[CH2:9][CH2:10]1
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC1CNCCN1
Solvent: CN1CCCC1=O
Product: Cc1c(F)c(N2CCNC(C)C2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 90 °C
Yield: 37.4 %

Procedure:
0.65 g of 2-methylpiperazine was added to a solution of 0.48 g of 1-cyclopropyl-6,7-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid in 5 ml of N-methyl-2-pyrrolidone, followed by heating at 90° C. for 20 minutes. After distilling off the solvent under reduced pressure, the residue was added with ethanol. The resulting crystals were filtered and recrystallized from ethyl acetate-ethanol to give 231 mg of 1-cyclopropyl-6-fluoro-7-(3-methyl-1-piperazinyl)-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[CH3:13][C:14]1[NH:18][N:17]=[C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([CH3:29])[CH:21]=2)[CH:15]=1.Cl>C(OCC)(=O)C>[CH2:8]([NH:10][C:11]([N:18]1[C:14]([CH3:13])=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([CH3:29])[CH:21]=2)=[N:17]1)=[O:12])[CH3:9]
Reactant: Cc1cc(Oc2ccc([N+](=O)[O-])c(C)c2)n[nH]1
Reactant: CCN=C=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCNC(=O)n1nc(Oc2ccc([N+](=O)[O-])c(C)c2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
Triethylamine (0.18 g, 1.8 mmol) and ethyl isocyanate (0.13 g, 1.8 mmol) were added to a solution of 5-methyl-3-(3-methyl-4-nitrophenyloxy)pyrazole (0.35 g, 1.5 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature for 8 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/7), to give a white solid of N-ethyl-5-methyl-3-(3-methyl-4-nitrophenyloxy)pyrazole-1-carboxamide (0.27 g, yield: 59.2%). mp: 67-69° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.24 (t, J=7.3 Hz, 3H), 2.63 (s, 6H), 3.40 (dq, J=5.9 and 7.3 Hz, 2H), 5.79 (q, J=0.8 Hz, 1H), 6.85-7.00 (m, 1H), 7.00-7.15 (m, 2H), 8.07 (d, J=8.6 Hz, 1H).
Reaction SMILES: C(OOC(C)(C)C)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:18]OC(C)(C)C)(=[O:17])[CH3:16]>>[C:15]([O:18][CH:2]1[CH2:3][CH2:4][CH2:5][CH:6]=[CH:7]1)(=[O:17])[CH3:16]
Reactant: CC(C)(C)OOC(=O)c1ccccc1
Reactant: CC(=O)OOC(C)(C)C
Product: CC(=O)OC1C=CCCC1

Procedure:
In Example 5, the t-butyl peroxybenzoate was replaced by 5 ml of t-butyl peroxyacetate (30% solution), whereby 0.60 g of 2-cyclohexenyl acetate was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([CH3:19])=[CH:4][N:3]=1.[CH2:20]([N:22]1[CH2:28][CH2:27][C:26]2[CH:29]=[C:30]([NH2:33])[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1)[CH3:21].Cl>O1CCOCC1.C(O)(C)C>[CH2:20]([N:22]1[CH2:28][CH2:27][C:26]2[CH:29]=[C:30]([NH:33][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=4[C:11]([NH:13][CH3:14])=[O:12])[C:5]([CH3:19])=[CH:4][N:3]=3)[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1)[CH3:21]
Reactant: CCN1CCc2ccc(N)cc2CC1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CCN1CCc2ccc(Nc3ncc(C)c(Nc4ccccc4C(=O)NC)n3)cc2CC1
Yield: 38.7 %

Procedure:
2-(2-Chloro-5-methyl-pyrimidin-4-ylamino)-N-methyl-benzamide (32 mg, 0.12 mmol) and 3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (24 mg, 0.13 mmol) were combined with 1 drop of a solution of 4N hydrochloric acid in dioxane and 2 mL isopropanol and subjected to microwave irradiation (CEP) at 170° C. for 150 minutes. The reaction mixture was concentrated and the organics were partitioned between dichloromethane and saturated sodium bicarbonate solution (100 mL each). The dichloromethane extract was separated, dried (sodium sulfate), and concentrated to afford a material which was purified on silica gel (methanol:dichloromethane gradient elution) to afford 20 mg (39%) of a white foam -2-[2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-5-methyl-pyrimidin-4-ylamino]-N-methyl-benzamide. MS: 431.20 (M+H); 1H NMR (d6-dmso): δ 11.20 (s, 1H), δ 8.99 (s, 1H), δ 8.86 (d, J=8 Hz, 1H), δ 8.74 (d, J=4 Hz, 1H), δ 7.97 (s, 1H), δ 7.75 (d, J=8 Hz, 1H), δ 7.49 (s, 1H), δ 7.45 (t, J=8 Hz, 1H), δ 7.38 (d, J=8 Hz, 1H), δ 7.08 (t, J=8 Hz, 1H), δ 6.97 (d, J=8 Hz, 1H), δ 2.82 (d, J=6 Hz, 3H), δ 2.80 (m, 2H), δ 2.70-2.40 (m, 8H), δ 2.10 (s, 3H), δ 1.01 (t, J=8 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C1(C)C=CC(S(O[CH2:21][CH2:22][Cl:23])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:23][CH2:22][CH2:21][O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6]
Reactant: NC(=O)c1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: NC(=O)c1cccc(OCCCl)c1
Yield: 70.6 %

Procedure:
To a solution of 3-hydroxybenzamide (21.6 g) in methyl ethyl ketone ("MEK") was added 2-chloroethyl p-toluenesulphonate (55.46 g) and potassium carbonate (16.0 g). After stirring at reflux for 6 hours, the resultant mixture was poured onto water and a colourless solid filtered off. Crystallisation from ethanol gave the title compound, (22.2 g), m.p. 125°-126°.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[C:12]([CH3:23])=[N:13][O:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:19]3[CH:20]=[CH:21][C:16]([C:15]4[O:14][N:13]=[C:12]([CH3:23])[C:11]=4[NH:10][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:24])=[CH:17][CH:18]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)OCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid benzyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[N:11]1([C:17](=[O:19])[CH3:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:14]2[CH2:15][CH2:16][N:11]([C:17](=[O:19])[CH3:18])[CH2:12][CH2:13]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 100.5 %

Procedure:
A solution of 1-fluoro-4-nitrobenzene (6.7 g, 47.5 mmol), 1-piperazin-1-yl-ethanone (6.7 g, 52.3 mmol) and K2CO3 (6.6 g, 47.5 mmol) in DMSO (60 mL) was heated at 100° C. for 18 h. After cooling, the mixture was poured into H2O (0.5 L). The resulting yellow precipitate was filtered and washed with H2O to afford of 1-[4-(4-nitro-phenyl)-piperazin-1-yl]-ethanone (11.9 g). This was partially dissolved in EtOH (100 mL) and AcOH (50 mL). The mixture was warmed to ca. 65° C. and iron powder (−325 mesh, 12.0 g, 215 mmol) was added in 1-g portions. The mixture was heated at reflux for 2 hr and filtered through a pad of Celite. The filtrate was evaporated to leave a black oil, which was basified by addition of 2 M aq NaOH and was extracted with EtOAc. The combined organics were washed with brine, dried on MgSO4, filtered, and evaporated in vacuo to afford 1-[4-(4-amino-phenyl)-piperazin-1-yl]-ethanone (6.7 g) as a yellow solid. An aliquot of this material (2.0 g, 9.12 mmol) was dissolved in EtOH (5 mL) and HNO3 was added (69% aq soln., 1.26 mL, 19.61 mmol), followed by cyanamide (50% w/v aq soln., 2.48 mL, 31.92 mmol). The resulting mixture was heated at reflux for 18 h. It was cooled to room temperature and poured into Et2O (100 mL). The ethereal layer was separated and concentrated. The resulting precipitate was filtered and washed with iPrOH/Et2O, then neat Et2O. The light brown solid was dried to afford N-[4-(4-acetyl-piperazin-1-yl)-phenyl]-guanidine nitrate (1.2 g). This material (1.1 g, 2.84 mmol) was dissolved in 2-methoxyethanol (14 mL) and K2CO3 (0.79 g, 5.68 mmol) was added, followed by 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone (0.60 g, 2.84 mmol). The resulting mixture was heated at 115° C. for 18 h. It was cooled and concentrated. The residue was purified by SiO2 chromatography (9:1 EtOAc/2 M NH3 in MeOH) and recrystallisation from iPr2O/MeOH to afford the title compound (930 mg) as a light brown solid. 1H-NMR (CDCl3) δ: 2.15 (s, 3H, CH3), 2.69 (s, 3H, CH3), 2.71 (s, 3H, CH3), 3.12 (t, 2H, J=5.4 Hz, CH2), 3.15 (t, 2H, J=5.4 Hz, CH2), 3.63 (t, 2H, J=5.4 Hz, CH2), 3.79 (t, 2H, J=5.4 Hz, CH2), 6.90 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 6.96 (m, 2H, Ph-H), 6.98 (br. s, 1H, NH), 7.54 (m, 2H, Ph-H), 8.39 (d, 1H, J=5.4 Hz, pyrimidinyl-H). MS (ESI+) m/z 409.6 (C21H24N6OS requires 408.5).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH3:18])=[CH:4][CH:3]=1.ClC(Cl)C(O)=O.[CH2:27]([C@@H:34]1N[C@H](C(C)(C)C)N(C)[C:35]1=[O:44])[C:28]1C=CC=CC=1.C(=O)/C=C/C>C(O)(C)C.C(Cl)Cl>[Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([C@H:27]([CH3:28])[CH2:34][CH:35]=[O:44])=[C:8]2[CH3:18])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)cc(C)n2Cc1ccc(Br)cc1
Reactant: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Agent: C/C=C/C=O
Agent: O=C(O)C(Cl)Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1ccc2c(c1)c([C@H](C)CC=O)c(C)n2Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 420.1 %

Procedure:
To 1-(4-bromo-benzyl)-5-methoxy-2-methyl-1H-indole (110 mg, 0.333 mmol) in a 2-dram amber vial was added CH2Cl2 (0.60 mL), isopropanol (0.066 mL), dichloroacetic acid (5.5 μL, 0.066 mmol) and (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-imidazolidin-4-one (16.4 mg, 0.066 mmol). This solution was stirred for 10 min at room temperature, then placed in a −70° C. bath for an additional 10 min. At this time, crotonaldehyde (82 μL, 1.0 mmol) was added and the reaction was stirred at −70° C. for 9 h. The reaction mixture was then transferred cold through a silica plug into a flask and concentrated to provide, after silica gel chromatography (20:80 EtOAc/hexanes), the title compound as a colorless oil (111 mg, 84% yield, 87% ee). IR (film) 2930, 2823, 2730, 1722, 1618, 1581, 1530, 1483, 1452, 1405, 1229, 1156, 1073, 1037, 1011, 902, 798, 476 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.69 (dd, J=1.8, 1.8 Hz, 1H, CHO), 7.38 (dt, J=2.4, 9.0 Hz, 2H, ArH), 7.12 (d, J=2.1 Hz, 1H, ArH), 7.05 (d, J=9.0, 1H, ArH), 6.79-6.75 (m, 3H, ArH), 5.19 (s, 2H NCH2), 3.88 (s, 3H, OCH3), 3.66 (dt, J=7.2, 22.2 Hz, 1H ArCH), 3.02 (ddd, J=1.8, 8.1, 16.5 Hz, 1H, CH2CO); 2.85 (ddd, J=2.1, 6.6, 16.5 Hz, 1H, CH2CO); 2.30 (s, 3H, ArCH3) 1.48 (d, J=7.2 Hz, 3H, CHCH3); 13C NMR (75 MHz, CDCl3) δ 202.5, 153.6, 137.0, 132.7, 132.0, 131.9, 127.6, 126.6, 121.1, 114.5, 110.0, 109.8, 102.3, 56.2, 50.6, 46.2, 26.4, 21.4, 10.9; HRMS (CI) exact mass calcd for (C21H22BrNO2) requires m/z 399.0834, found m/z 399.0833. [α]D=−20.8 (c=1.0, CHCl3). The enantiomeric ratio was determined by HPLC analysis of the alcohol, obtained by NaBH4 reduction of the aldehyde, using a Chiracel OD-H and OD guard column (4:96 ethanol/hexanes, 1 mL/min); S isomer tr=45.1 min and R isomer tr=35.9 min.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N:8]2[C:12]([CH3:13])=[C:11]([I:14])[N:10]=[C:9]2[CH3:15])[N:5]=[CH:4][N:3]=1.[OH-:16].[K+]>C(O)(C)(C)C>[I:14][C:11]1[N:10]=[C:9]([CH3:15])[N:8]([C:6]2[N:5]=[CH:4][NH:3][C:2](=[O:16])[CH:7]=2)[C:12]=1[CH3:13]
Reactant: Cc1nc(I)c(C)n1-c1cc(F)ncn1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1nc(I)c(C)n1-c1cc(=O)[nH]cn1

Procedure:
The title compound, light yellow crystalline solid, MS: m/e=316.9 (M+H+), was prepared in accordance with the general method of example 1a by treatment of 4-fluoro-6-(4-iodo-2,5-dimethyl-imidazol-1-yl)-pyrimidine with 50% KOH in tert-butanol.