Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[CH:18]([N:21]([CH2:25][CH3:26])[CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19].O1CCCC1.C([S:35][CH2:36][CH2:37][CH2:38][C:39]#[N:40])(=O)C>C(#N)C>[CH:18]([N:21]([CH2:25][CH3:26])[CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19].[SH:35][CH2:36][CH2:37][CH2:38][C:39]#[N:40]
Reactant: CC(=O)SCCCC#N
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#CCCCS

Procedure:
A solution of allyl (4R,5R,6S)-4-(2"-azidoethyl)-6-[(1'R)-1'-tert-butyldimethylsilyloxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0heptane-2-carboxylate (6.46 mmol, prepared by cyclization of 3.0 g, 6.46 mmol of the diazo precursor prepared in Example 2, Step E) in dry acetonitrile (50 mL) was treated at -15° C. and under Argon with diphenyl chlorophosphate (1.4 mL, 6.75 mmol) and N,N-diisopropylethylamine (1.2 mL, 6.9 mmol) added simultaneously over 5 min. A small crystal of 4-N,N-dimethylaminopyridine was then added and the temperature of the mixture was slowly warmed to 0°-5° C. over 30 min. N,N-Diisopropylethylamine (1.2 mL, 6.9 mmol) and 4-mercaptobutyronitrile (1.31 g, 13.0 mmol) [obtained from basic hydrolysis of an aqueous tetrahydrofuran solution of 4-acetylmercaptobutyronitrile (U.S. Pat. No. 3,223,585)] were added and the mixture was stirred at 0°-5° C. for 4 h and overnight at -15° C. The reaction mixture was then diluted with EtOAc (300 mL), washed with water, 1M NaHSO3, saturated NaHCO3, brine and dried (MgSO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel (5×15 cm). Elution with a mixture of EtOAc and toluene (1:9) gave 2.62 g (78%) of the title compound as a brown oil:
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:20])[NH:10][C:11]3[C:16]=2[CH:15]=[C:14]2[CH:17]=[CH:18][CH:19]=[C:13]2[CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:28][CH3:29].O>CN(C=O)C>[CH2:28]([O:20][C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[CH2:15][C:14]3=[CH:17][CH:18]=[CH:19][C:13]3=[CH:12][C:11]=2[N:10]=1)[CH3:29]
Reactant: O=c1[nH]c(-c2ccccc2)c2cc3cccc3cc2[nH]1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nc2c(c(-c3ccccc3)n1)CC1=CC=CC1=C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.8 %

Procedure:
To a suspension of 4-phenylcyclopenta[g]quinazolin-2(1H)-one (120 mg, 0.46 mmol) and K2CO3 (76 mg, 0.55 mmol) in 4 mL of DMF was added iodoethane (44 μL, 0.55 mmol) and stirred at rt overnight. Water was then added and the resulting suspension extracted with 2×20 mL of EtOAc. The extract was washed with water twice and brine, then dried over MgSO4 and concentrated in vacuo. The crude solid was then subjected to flash column chromatography eluting with acetone/hexane to give the title compound 2-ethoxy-4-phenyl-cyclopenta[g]quinazoline (25 mg, 19%) followed by the title compound 1-ethyl-4-phenylcyclopenta[g]quinazolin-2(1H)-one (66 mg, 50%). 1H NMR (CDCl3): 7.7 (d, 2H), 7.63 (s, 1H), 7.53 (m, 3H),. 7.29 (s, 1H)., 4.38 (q, 2H), 3.09 (t, 2H), 2.93 (t, 2H), 2.16 (p, 2H), 1.45 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C1C(=O)N([Br:16])C(=O)C1>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:16])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)cc1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
A 300-ml flask was charged with 16.6 g of 4-fluorotoluene, 30.0 g of NBS, 0.5 g of benzoyl peroxide and 150 ml of carbon tetrachloride, and the mixture was refluxed for 2.0 hours. The reaction mixture was cooled to room temperature, and the formed precipitate was removed by filtration and the residual CCl4 solution was washed with dilute alkali and then with water, dried over Na2SO4, and evaporated under reduced pressure to give 28.8 g of crude 4-fluorobenzyl bromide.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]([CH3:14])([CH3:13])[C:8]([O:10]CC)=[O:9])=[C:4]([CH3:17])[CH:3]=1.[OH-].[Na+]>O1CCCC1.CO.O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]([CH3:14])([CH3:13])[C:8]([OH:10])=[O:9])=[C:4]([CH3:17])[CH:3]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(F)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1OC(C)(C)C(=O)O
Reaction time: 8 h

Procedure:
A solution of 4-fluoro-2-methylphenol (10 g, 79.28 mmol), ethyl 2-bromoisobutyrate (23.2 mL, 158.6 mmol), potassium carbonate (21.9 g, 158.6 mmol), and DMSO (80 mL) was stirred at room temperature for 72 hours. Water and ethyl acetate were added and the layers were separated. The aqueous phase was extracted with ethyl acetate (3×50 mL) and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (20%) to afford ethyl 2-(4-fluoro-2-methylphenoxy)-2-methylpropanoate. To a solution of ethyl 2-(4-fluoro-2-methylphenoxy)-2-methylpropanoate (13.3 g, 55.44 mmol) in tetrahydrofuran (40 mL) and methanol (10 mL) was added NaOH (6.66 g, 166.32 mmol) in water (14 mL) and stirred overnight. The volatiles were removed in vacuo and acidified with concentrated HCl. The milky white solution was extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated in vacuo to give 2-(4-fluoro-2-methylphenoxy)-2-methylpropanoic acid (658) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]([C:13]1[C:14]([CH3:20])=[N:15][N:16]([CH3:19])[C:17]=1[F:18])=[O:12].[CH3:21][O:22][N:23]=[CH:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:9][C:4]1[C:3]([NH:10][C:11]([C:13]2[C:14]([CH3:20])=[N:15][N:16]([CH3:19])[C:17]=2[F:18])=[O:12])=[C:2]([C:28]2[CH:29]=[CH:30][C:25]([CH:24]=[N:23][O:22][CH3:21])=[CH:26][CH:27]=2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: CON=Cc1ccc(B(O)O)cc1
Reactant: Cc1nn(C)c(F)c1C(=O)Nc1c(F)cc(F)cc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CON=Cc1ccc(-c2cc(F)cc(F)c2NC(=O)c2c(C)nn(C)c2F)cc1
Reaction time: 15 h
Yield: 49.7 %

Procedure:
At room temperature, a mixture of 0.35 g (0.001 mol) of N-(2-bromo-4,6-difluorophenyl)-5-fluoro-1,3-dimethyl-1H-pyrazole-4-carboxamide, 0.06 g (0.00005 mol) of tetrakis-(triphenylphosphine)-palladium, 0.32 g (0.0018 mol) of 4-[(methoxyimino)methyl]phenylboronic acid and 10 ml of 1,2-dimethoxyethane is admixed with a solution of 0.5 g (0.0047 mol) of sodium carbonate in 3 ml of water. The reaction mixture is then heated to reflux temperature and kept at this temperature for 15 h. For work-up, the reaction mixture is stirred into 200 ml of water. The resulting precipitate is filtered off with suction and dried. The residue that remains is chromatographed on silica gel using the mobile phase cyclohexane:ethyl acetate=1:1. Concentration of the eluate gives 0.20 g (48% of theory) of N-{3,5-difluoro-4′-[(methoxyimino)methyl]-1,1′-biphenyl-2-yl}-5-fluoro-1,3-dimethyl-1H-pyrazole-4-carboxamide in the form of a solid of melting point 164 to 167° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(#N)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:20]2[CH2:19][CH2:18][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:22][CH2:21]2)=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)cc2)CC1
Temperature: 80 °C
Yield: 23.4 %

Procedure:
A mixture of 4-fluorobenzonitrile (3.6 g) and N-tert-butyloxycarbonylpiperazine (5.58 g) in acetonitrile (60 mL) was heated at 80° C. for 72 hours. The reaction mixture was then cooled to room temperature and then treated with a mixture of sodium bicarbonate solution and ethyl acetate (300 mL, 1:1, v/v). The organic phase was separated and then evaporated. The residue was subjected to chromatography on silica gel eluting with a mixtures of heptane and ethyl acetate (from 3:7 to 1:1, v/v) to give the title compound (2 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)(O)[CH:9]=[CH2:10])=[CH:4][CH:3]=1.[OH-:18].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:9][CH2:10][OH:18])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: C=CC(O)(c1ccc(Cl)cc1)c1cccnc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: OCC=C(c1ccc(Cl)cc1)c1cccnc1

Procedure:
1-(4-Chlorophenyl)-1-(3-pyridyl)-2-propen-1-ol (0.33 g) was stirred in 25 ml 2 M sulfuric acid overnight at 50° C. The reaction mixture was made alkaline with 45% sodium hydroxide and extracted with ether. The ethereal layer was dried (MgSO4) and evaporated to give 0.30 g of the title compound as an oil. 1H NMR (CDCl3) revealed an approximate Z/E ratio of 60/40:δ3.8 (Br, OH), 4.20 and 4.25 (two doublets, allyl), 6.37 and 6.30 (two triplets, vinyl), 6.9-7.6 (aromatic) and 8.3-8.6 (multiplet, 2,6-pyridyl). This crude product was used directly in the oxidation step according to Example K.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([OH:15])[CH:11]=[CH:12][C:13]=2[CH3:14])[CH:5]=[C:4]([Cl:16])[N:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])(=O)=O>ClCCl>[Si:31]([O:15][C:10]1[CH:11]=[CH:12][C:13]([CH3:14])=[C:8]([C:6]2[CH:5]=[C:4]([Cl:16])[N:3]=[C:2]([NH2:1])[N:7]=2)[CH:9]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Cc1ccc(O)cc1-c1cc(Cl)nc(N)n1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1-c1cc(Cl)nc(N)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
3-(2-amino-6-chloropyrimidin-4-yl)-4-methylphenol (2.12 g, 9.00 mmol) obtained in Step 4 above was placed in a reaction vessel, and then dichloromethane (60 ml) was added thereto. The mixture was cooled to 0° C. 2,6-Lutidine (1.25 ml, 10.7 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (2.27 ml, 9.88 mmol) were sequentially added to the solution. The mixture was stirred at 0° C. for 1 hour and then at room temperature for 30 minutes. The resulting reaction solution was diluted with dichloromethane (150 ml), and sequentially washed with a saturated aqueous sodium bicarbonate solution (150 ml), water (150 ml), and a saturated aqueous sodium chloride solution (150 ml). The dichloromethane solution was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=9:1 to 6:1) to yield 4-[5-(tert-butyldimethylsilanyloxy)-2-methylphenyl]-6-chloropyrimidin-2-ylamine (Compound 1-5) (2.41 g, 77%).
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([C:10]2[O:14][C:13]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[OH:24][CH:21]([CH2:20][O:19][C:18]1[C:25]([CH3:27])=[CH:26][C:15]([C:13]2[O:14][C:10]([C:8]3[S:9][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=3)=[N:11][N:12]=2)=[CH:16][C:17]=1[CH3:28])[CH2:22][O:23][S:39]([CH3:38])(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(-c2nnc(-c3ccc(CC(C)C)s3)o2)cc(C)c1OCC(O)CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nnc(-c3ccc(CC(C)C)s3)o2)cc(C)c1OCC(O)COS(C)(=O)=O
Reaction time: 1 h
Yield: 29.3 %

Procedure:
To a solution of 3-{4-[5-(5-isobutyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol (627 mg, 1.56 mmol) and DIPEA (311 mg, 2.41 mmol) in DCM (10 mL), methanesulfonyl chloride (207 mg, 1.81 mmol) is added. The mixture is stirred at rt before another portion of DIPEA (40 mg, 0.31 mmol) and methanesulfonyl chloride (36 mg, 0.31 mmol) is added. Stirring is continued for 1 h before the reaction is quenched by adding water. The mixture is extracted with DCM. The org. extract is washed with water, dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give methanesulfonic acid 2-hydroxy-3-{4-[5-(5-isobutyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenoxy}-propyl ester (220 mg) as a colourless oil; LC-MS: tR=1.08 min, [M+1]+=481.09.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[CH2:6][C:7]3([O:18][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:10][N:9](C)[CH2:8]3.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23].CCCCCC>ClCCl>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[CH2:6][C:7]3([O:18][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:10][N:9]([C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23])[CH2:8]3
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1Cc2ccccc2C2(Cc3ccc(Cl)cc3O2)C1
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(Oc1ccccc1)N1Cc2ccccc2C2(Cc3ccc(Cl)cc3O2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To an ice cold solution of 6-chloro-2'-methylspiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (5.0 g) in dichloromethane (150 ml) is slowly added dropwise phenyl chloroformate (3.7 g) in dichloromethane (20 ml). The mixture is stirred at ambient temperature overnight. Removal of the solvent in vacuo yields an orange oil which solidifies upon trituration with hexane. An analytical sample is twice recrystallized from hexane to yield product as a solid (6.6 g, 99%), mp 138°-140°.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][S:19][C:15]=3[CH2:14][N:13]3[CH:20]=[CH:21][CH:22]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C>C(O)C.[Pd]>[NH2:1][C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][S:19][C:15]=3[CH2:14][N:13]3[CH:20]=[CH:21][CH:22]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2cccn2Cc2sccc21
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)N2Cc3cccn3Cc3sccc32)cc1
Reaction time: 5 h

Procedure:
A mixture of 5 mmol of 4,10-dihydro-4-(4-nitrobenzoyl)-5H-pyrrolo-[1,2-a]thieno[3,2-e][1,4)-diazepine in 25 ml of ethyl alcohol and 25 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to a solid which is purified by flash chromatography on silica gel to give the desired product.
Reaction SMILES: C(O)CCCCCCCO.FC1C=C(C(F)(F)F)C=CC=1CBr.[F:24][C:25]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:26]=1[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37].FC1C=C(C(F)(F)F)C=CC=1COCCCCCCCC(O)=O.Cl.Cl.[CH2:71]([O:78][C:79](=[O:87])[CH2:80][C@@H:81]([NH2:86])[CH2:82][N:83]([CH3:85])[CH3:84])[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1>>[CH2:71]([O:78][C:79](=[O:87])[CH2:80][C@@H:81]([NH:86][C:36](=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:28][CH2:27][C:26]1[CH:38]=[CH:39][C:40]([C:42]([F:43])([F:44])[F:45])=[CH:41][C:25]=1[F:24])[CH2:82][N:83]([CH3:84])[CH3:85])[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1
Reactant: OCCCCCCCCOCc1ccc(C(F)(F)F)cc1F
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: Cl
Agent: Fc1cc(C(F)(F)F)ccc1CBr
Agent: O=C(O)CCCCCCCOCc1ccc(C(F)(F)F)cc1F
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCOCc1ccc(C(F)(F)F)cc1F

Procedure:
The title compound, m/e=463.1 ([M−H]−), was produced in analogy with intermediate 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated in step 1 with 2-fluoro-4-trifluoromethyl-benzyl bromide, leading to 8-(2-fluoro-4-trifluoromethyl-benzyloxy)-octan-1-ol, which was oxidized in step 2 to 8-(2-fluoro-4-trifluoromethyl-benzyloxy)-octanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-3-[8-(2-fluoro-4-trifluoromethyl-benzyloxy)-octanoylamino]-4-dimethylamino-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[F:21][C:22]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:22]=3[F:21])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1cccc(F)c1F
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cccc(F)c1F

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-2,3-difluoro-benzamide was prepared starting from intermediate D and 2,3-difluoro-benzoyl chloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (s, 1H) 8.28 (d, J=8.66 Hz, 1H) 8.00 (s, 1H) 7.15-7.80 (m, 9H) 6.92 (d, J=1.81 Hz, 1H) 0.39 (d, J=5.64 Hz, 2H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([O:14][C:15]([NH:17][C@@:18]1([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:23][C:22](=O)[C@@H:21]2[C@H:19]1[C@H:20]2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[CH2:7]([O:14][C:15]([NH:17][C@@:18]1([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:23][C:22](=[CH2:1])[C@@H:21]2[C@H:19]1[C@H:20]2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)[C@H]1[C@@H]2C(=O)C[C@@](NC(=O)OCc3ccccc3)(C(=O)OCC)[C@@H]21
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C1C[C@@](NC(=O)OCc2ccccc2)(C(=O)OCC)[C@H]2[C@@H]1[C@@H]2C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, combine methyl-triphenylphosphonium bromide (67.4 g, 184.9 mmol) and tetrahydrofuran (300 mL) with agitation. Add a solution of potassium tert-butoxide (1M) in tetrahydrofuran, 184.9 mL, 184.9 mmol) to the reaction mixture over 15 minutes and stir the resulting slurry at ambient temperature for 3 hours. Dissolve diethyl (1S,2S,5R,6R)-2-benzyloxycarbonylamino-4-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylate (12.3 kg, 31.6 mol) in tetrahydrofuran (120 mL) and add to the reaction mixture over 1 hour, maintaining the reaction temperature below 30° C. Stir the resulting slurry overnight at ambient temperature, then dilute with ethyl acetate (600 mL) and quench with water (300 mL). After stirring the biphasic mixture for 30 minutes, separate the layers and wash the organics with water (300 mL) followed by 0.25M HCl (300 mL). Dry the organics over Na2SO4, filter, and concentrate in vacuo (45° C.) to afford the crude product as a dark oil (111.0 g). Purify the material by silica gel plug chromatography (1 Kg Kieselgel-60, 4 L 15% EtOAc in heptanes, then 10 L 30% EtOAc in heptanes) to afford the title compound as a clear oil (37.3 g, 87.9% potency, 54.9%). MS (m/z): 388 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[N:10][C:11]=1[N:12]([CH3:14])[CH3:13])[N:8]=[C:7]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:6]=[C:5]2[N:21]([CH3:23])[CH3:22].[CH2:24]([SH:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([S:31][C:2]1[N:3]=[C:4]2[C:9](=[N:10][C:11]=1[N:12]([CH3:14])[CH3:13])[N:8]=[C:7]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:6]=[C:5]2[N:21]([CH3:23])[CH3:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: SCc1ccccc1
Reactant: CN(C)c1nc2nc(N3CCNCC3)nc(N(C)C)c2nc1Cl
Product: CN(C)c1nc2nc(N3CCNCC3)nc(N(C)C)c2nc1SCc1ccccc1

Procedure:
This compound was prepared analogous to Example 2 from 6-chloro-4,7-bis-(dimethylamino)-2-piperazino-pteridine and benzylmercaptan.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][C@@H:33]1[CH2:36][C@H:35]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:34]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[C:40]([O:39][C:38](=[O:44])[NH:37][C@H:35]1[CH2:36][C@@H:33]([NH:32][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[CH:19]=2)=[O:23])[CH2:34]1)([CH3:43])([CH3:41])[CH3:42]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2C[C@@H](NC(=O)OC(C)(C)C)C2)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
A round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (110 mg, 0.25 mmol) and cis-tert-butyl 3-aminocyclobutylcarbamate (65 mg, 0.35 mmol). Then DMF (1.2 ml) was added followed by N,N-diisopropylethylamine (0.12 ml, 0.69 mmol) and HATU (104 mg, 0.27 mmol). The yellow reaction mixture was stirred at room temperature overnight then water and petroleum ether were added. The suspension was filtered and the solids were washed with water and a little petroleum ether. The product collected was dried under high vacuum to afford 145 mg (95%) of (cis-3-{[2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-cyclobutyl)-carbamic acid tert-butyl ester as an off-white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C(OP([CH2:18]/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])(OCC)=O)C.[H-].[Na+].CN(C)C=O>O1CCCC1.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:18]/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22]
Reactant: O=Cc1ccccc1Cl
Reactant: CCOP(=O)(C/C=C/C(=O)OC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)/C=C/C=C/c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
To a solution of 500 mg of o-chlorobenzaldehyde and 840 mg of methyl 4-diethylphosphonocrotonate dissolved in 5 ml of tetrahydrofuran, 142 mg of sodium hydride (60% oily dispersion) was added under ice-cooling. Imeediately, 2 ml of dimethylformamide was added and the mixture was stirred at room temperature for 2 hours. The mixture was poured into water and extracted twice with ether. The organic layer was washed twice with water, dried and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (solvent: hexane-ethyl acetate=20:1) to give 650 mg of methyl (2E, 4E)-5-(2-chlorophenyl)-2,4-pentadienoate as an oily substance.