Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[C:39]([F:40])[C:32]=3[F:31])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1cccc(CBr)c1F
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: Cc1nc2c(ccn2Cc2cccc(F)c2F)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2,3-difluorobenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.49-7.43 (m, 1 H), 7.20-7.04 (m, 5 H), 6.94 (dd, J=4.9, 8.4 Hz, 1 H), 6.32 (dd, J=3.5, 11.1 Hz, 1 H), 5.75-5.53 (m, 3 H), 4.33-4.26 (m, 2 H), 3.00-2.81 (m, 2 H), 2.79 (s, 3 H), 2.17-2.07 (m, 2 H), 0.97 (s, 9 H); LC/MS (m/z) ES+=521.33 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:17]([O:19]CC)=[O:18])[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:5])[CH3:2].[OH-].[Na+].Cl>CCO.O>[CH2:1]([O:3][C:4]([C:6]1([C:17]([OH:19])=[O:18])[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1(C(=O)O)CN(C(=O)OC(C)(C)C)C1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Azetidine-1,3,3-tricarboxylic acid 1-tert-butyl ester 3,3-diethyl ester (1.2 g; 0.4 mmol) in EtOH (12 ml) is cooled to 5° C. under stirring and combined with NaOH (60 mg; 0.04 mmol) in water (4 ml). The reaction mixture is left at room temperature for 1 hour, heated to 50° C. for 5 minutes, poured on brine, acidified with 2N HCl and extracted with TBME three times. The reaction mixture is extracted with TBME three times, the organic phases are combined, dried over Na2SO4 and evaporated to dryness, yielding the desired product as colorless crystals. 1H-NMR (400 MHz; DMSO-d6: 13.58 (bs, 1H); 4.20 (q, 2H); 4.12 (bs, 4H); 1.39 (s, 9H); 1.21 (t, 3H). MS (m/z) ES+: 274 (30; MH+); 174 (100).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11](=[O:12])[C:10]2[N:9]([C@@H:13]([CH3:17])[C:14]([OH:16])=O)[CH:8]=[N:7][C:6]=2[N:5]([CH3:18])[C:4]1=[O:19].[CH3:20][C@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:26]1[N:31]=[CH:30][C:29]([C:32]2[N:37]=[C:36]([NH2:38])[CH:35]=[N:34][CH:33]=2)=[CH:28][N:27]=1.C1C=NC2N(O)N=NC=2C=1.N1C=CC=CC=1.CC(C)N=C=NC(C)C>C(Cl)Cl>[CH3:2][N:3]1[C:11](=[O:12])[C:10]2[N:9]([C@@H:13]([CH3:17])[C:14]([NH:38][C:36]3[CH:35]=[N:34][CH:33]=[C:32]([C:29]4[CH:28]=[N:27][C:26]([N:22]5[CH2:23][CH2:24][CH2:25][C@@H:21]5[CH3:20])=[N:31][CH:30]=4)[N:37]=3)=[O:16])[CH:8]=[N:7][C:6]=2[N:5]([CH3:18])[C:4]1=[O:19]
Reactant: C[C@H]1CCCN1c1ncc(-c2cncc(N)n2)cn1
Reactant: C[C@@H](C(=O)O)n1cnc2c1c(=O)n(C)c(=O)n2C
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H]1CCCN1c1ncc(-c2cncc(NC(=O)[C@H](C)n3cnc4c3c(=O)n(C)c(=O)n4C)n2)cn1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 47 %

Procedure:
A flask was charged with (S)-2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanoic acid hydrochloride (Intermediate 8) (8.96 g, 31.0 mmol), (S)-6-(2-(2-methylpyrrolidin-1-yl)pyrimidin-5-yl)pyrazin-2-amine (7.23 g, 28.2 mmol), HOAt (3.84 g, 28.2 mmol), nitrogen, DCM (141 ml) and stirred at room temperature. The suspension was cooled to 0° C. followed by addition of pyridine (4.60 ml, 56.4 mmol), then DIC (6.59 ml, 42.3 mmol). The reaction was removed from ice bath immediately after addition of DIC was complete. The reaction was complete after 7.5 hours. The reaction mixture was diluted with 100 mL DCM. The organic layer was washed with 0.5 M HCl aq. (2×20 mL). The resulting organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated. The resulting DCM filtrate was slowly added dropwise to 300 mL of stirred hexanes at room temperature. The resulting solids were collected via vacuum filtration with aide of hexanes and dried on on frit filter overnight to afford off-white solids (6.5 g, 13.25 mmol, 47.0% yield, 93% ee). ESI-MS (EI+, m/z): 491.33, 1H NMR (DMSO-d6) δ: 11.35 (s, 1H), 9.10 (s, 1H), 9.05 (s, 2H), 8.91 (s, 1H), 8.36 (s, 1H), 5.85 (d, J=7.2 Hz, 1H), 4.30 (s, 1H), 3.59 (d, J=27.6 Hz, 2H), 3.46 (s, 3H), 3.19 (s, 3H), 2.08 (s, 3H), 1.95 (s, 1H), 1.88 (d, J=7.3 Hz, 3H), 1.72 (s, 1H), 1.24 (d, J=6.3 Hz, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][C:7]2(C#N)[C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=1.[CH3:24][O-:25].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][C:7]2([O:25][CH3:24])[C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=1
Reactant: C[O-]
Reactant: COc1cc(OC)nc(C2(C#N)OC(=O)c3c(Cl)cccc32)n1
Agent: [Na+]
Solvent: CO
Product: COc1cc(OC)nc(C2(OC)OC(=O)c3c(Cl)cccc32)n1
Reaction time: 0.17 h

Procedure:
1.0 g of 7-chloro-3-cyano-3-(4,6-dimethoxy-2-pyrimidinyl)phthalide is slurried in 20 ml of methanol and the solution cooled with ice and 0.6 ml of sodium methoxide added dropwise. After stirring for 10 min a further 1 ml of sodium methoxide is added and stirring continued for 10 min and the mixture is then quenched with 2N H2SO4. Methanol is removed on a rotovaporator and the residue partitioned between water and ethyl acetate. The organic phase is dried over Na2SO4 and concentrated. Flash chromatography of the residue over silica gel using 25% ethyl acetate/hexane yields a white solid m.p. 180°14 183° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.I[CH2:15][CH2:16][CH2:17][CH3:18].[H-].[Na+]>O1CCCC1>[CH2:15]([CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCI
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC1CCc2cc(OC)ccc2C1=O
Temperature: 25 °C
Reaction time: 15.5 h

Procedure:
A mixture of 6-methoxy-3,4-dihydro-1(2H)-naphthalenone (400 mg, 2.27 mmol), iodobutane (0.284 mL, 2.5 mmol), NaH (98 mg of a 61.1% dispersion in mineral oil, 2.5 mmol), and anhydrous tetrahydrofuran (THF, 1 mL) was placed under a N2 atmosphere and stirred at room temperature for 15.5 hours. The mixture was partitioned between EtOAc (20 mL) and water (30 mL) containing 2N HCl (3 mL). The organic phase was washed with brine (20 mL), dried over MgSO4, filtered, and evaporated under vacuum to afford an oil. The crude product was purified by preparative layer chromatography on five 0.1×20×20 cm silica gel GF plates (Analtech, Newark, Del.), developing with CH2Cl2. The UV visible product band was eluted with EtOAc and the eluant evaporated under vacuum to provide 2-butyl-6-methoxy-3,4-dihydro-1(2H)-naphthalenone as a clear oil.
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1C=CC=C[CH:5]=1.[C:11]([C:16]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:20]([CH3:22])(C)[CH2:19][CH2:18][NH:17]1)([O:13][CH2:14][CH3:15])=[O:12]>>[CH2:26]([O:25][C:23]([C:16]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:20]([C:22]2[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH2:19][CH2:18][NH:17]1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C1(C(=O)OCC)NCCC1(C)C
Reactant: O=CC=Cc1ccccc1
Product: CCOC(=O)C1(C(=O)OCC)NCCC1c1ccccc1

Procedure:
Diethyl-3-phenylpyrrolidine-2,2-dicarboxylate was prepared from cinnamaldehyde (1.22 mL, 9.70 mmol) essentially according to the procedure described in U.S. Pat. No. 4,060,603 for the preparation of 2,2-dicarboethoxy-3,3-dimethyl-pyrrolidine. The resulting yellow oil was used in the next step without purification. LCMS RT=1.26 min. LCMS (M+H)=292.1.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10](=O)[CH:11]=1)=[CH:8][C:7]([CH3:13])=[CH:6][CH:5]=2.[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=[C:2]([CH3:1])[CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2[nH]c(C)cc(=O)c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc2nc(C)cc(Cl)c2c1
Temperature: 80 °C
Yield: 65 %

Procedure:
A mixture of 2,6-dimethyl-1H-quinolin-4-one (17.3 g, 100 mmol) and phosphorus oxychloride (30 mL) was heated at 80° C. for 3 h. After cooling down to room temperature, the reaction mixture was poured onto ice. The resulting solution was carefully alkalinized to pH 8–9 with 0.5 N NaOH and saturated Na2CO3. The solution was extracted with CH2Cl2 (200 mL×3). The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (10% ethyl acetate in n-hexane) to give 4-chloro-2,6-dimethyl-quinoline (12.4 g, 65% yield).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[C:7]([C:9]1[N:14]=[CH:13][C:12]([C:15]2[C:27]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([C:28]4[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[C:30](F)[CH:29]=4)[C:19]=3[CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)#[N:8]>CS(C)=O.O>[C:7]([C:9]1[N:14]=[CH:13][C:12]([C:15]2[C:27]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([C:28]4[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[C:30]([NH:20][C@H:19]5[CH2:27][CH2:26][C@H:1]([OH:4])[CH2:17][CH2:18]5)[CH:29]=4)[C:19]=3[CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)#[N:8]
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1N[C@H]1CC[C@H](O)CC1
Temperature: 90 °C

Procedure:
0.3 g of potassium carbonate and 1.68 g of 4-trans-aminocyclohexanol are successively added to a solution of 0.34 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-fluorobenzoate in 6 ml of dimethyl sulphoxide. The reaction mixture is heated at 90° C. for 2 hours in a microwave, and then diluted with distilled water. The aqueous phase is extracted twice with ethyl acetate and the combined organic phases are washed with water and a saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a mixture of cyclohexane and ethyl acetate (75/25 by volume), so as to give 0.15 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(trans-4-hydroxycyclohexyl)amino]benzoate in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([C:30]4[C:35]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:33]=[CH:32][N:31]=4)=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH:16]=[CH:15][C:14]=1[C:40]([CH3:43])([CH3:42])[CH3:41])=[O:4].[OH-].[Na+]>CO>[C:40]([C:14]1[CH:15]=[CH:16][C:17]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([C:30]4[C:35]([C:36]([F:39])([F:37])[F:38])=[CH:34][CH:33]=[CH:32][N:31]=4)=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)=[CH:18][C:13]=1[O:12][CH2:11][CH2:10][N:6]1[CH2:7][CH2:8][CH2:9][CH:5]1[C:3]([OH:4])=[O:2])([CH3:43])([CH3:41])[CH3:42]
Reactant: COC(=O)C1CCCN1CCOc1cc(Nc2ncnc3cc(-c4ncccc4C(F)(F)F)ccc23)ccc1C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1ccc(Nc2ncnc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1OCCN1CCCC1C(=O)O
Reaction time: 12 h

Procedure:
To a solution of 1-(2-{2-tert-butyl-5-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-ylamino]-phenoxy}-ethyl)-pyrrolidine-2-carboxylic acid methyl ester (59 mg, 0.1 mmol) in methanol (5 ml) add sodium hydroxide (12 mg, 0.3 mmol). Stir the mixture for 12 hours and evaporate to dryness. Add water (2 ml) and 1M hydrochloric acid (until pH=7.0) and extract with ethyl acetate. Wash the combined extracts with brine, dry (MgSO4) and concentrate under reduced pressure to give the title compound. MS 580 (M+1).
Reaction SMILES: C(ON=O)(C)(C)C.N[C:9]1[N:13]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:12]=[C:11]([C:26]#[N:27])[C:10]=1[S:28]([C:31]([F:34])([F:33])[F:32])(=[O:30])=[O:29].C(Br)(Br)[Br:36]>>[Br:36][C:9]1[N:13]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:12]=[C:11]([C:26]#[N:27])[C:10]=1[S:28]([C:31]([F:34])([F:33])[F:32])(=[O:30])=[O:29]
Reactant: BrC(Br)Br
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)(=O)C(F)(F)F
Agent: CC(C)(C)ON=O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Br)c1S(=O)(=O)C(F)(F)F
Temperature: 65 °C
Reaction time: 2.5 h
Yield: 79 %

Procedure:
t-Butylnitrite (84 ml, 0.662 mol) was added to a suspension of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfonylpyrazole (100 g, 0.221 mol) in bromoform (320 ml). The resulting mixture was heated to 60-70° C. for 3 hours. Another portion of t-butylnitrite (84 ml, 0.662 mol) was added and the mixture stirred at 60-70° C. for a further 2.5 hours. It was then cooled, washed with hexane, hexane-toluene, and then filtered. The solid was washed with pentane and vacuum dried to give 5-bromo-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfonylpyrazole as a yellow solid (96.69 g, 79% yield), mp 142° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)[C:5]([C:15]#[N:16])=[C:4]([SH:17])[N:3]=1.Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[O:23][CH:24]=1.C(=O)(O)[O-].[Na+].O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[O:23][CH:24]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1cncs1
Reactant: ClCc1coc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(N)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cncs1

Procedure:
250 mg (0.964 mmol) of 2-amino-6-sulfanyl-4-(1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile, together with 242 mg (1.060 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-oxazole and 243 mg (2.892 mmol) of sodium bicarbonate, were stirred in 5 ml DMF at room temperature for 1 h. The reaction mixture was added to water, and the resulting precipitate was filtered off and washed with diethyl ether. Drying under reduced pressure gave 53 mg (12% of theory) of the target compound.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>>[N:17]1([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:16]3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(N3CCCC3)cc2C1
Agent: Cl
Product: c1cc2c(cc1N1CCCC1)CNC2

Procedure:
Prepared in analogy to Example A3(e) from 5-Pyrrolidin-1-yl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and HCl. Brown oil. MS (m/e): 189.6 (M+H+, 100%).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[C:19](=[O:20])[CH2:18][C:17]3[C:12](=[CH:13][C:14]([O:23][CH:24]([CH3:26])[CH3:25])=[C:15]([O:21][CH3:22])[CH:16]=3)[CH:11]2[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:34][Mg]Br>C1COCC1>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:11]2[C:12]3[C:17](=[CH:16][C:15]([O:21][CH3:22])=[C:14]([O:23][CH:24]([CH3:26])[CH3:25])[CH:13]=3)[CH2:18][C:19](=[O:20])[N:10]2[CH:7]2[CH2:6][CH2:5][CH:4]([C:1]([OH:3])([CH3:34])[CH3:2])[CH2:9][CH2:8]2)=[CH:32][CH:31]=1
Reactant: COc1cc2c(cc1OC(C)C)C(c1ccc(Cl)cc1)N(C1CCC(C(C)=O)CC1)C(=O)C2
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC(C)C)C(c1ccc(Cl)cc1)N(C1CCC(C(C)(C)O)CC1)C(=O)C2
Reaction time: 2 h
Yield: 16.6 %

Procedure:
To the stirred solution of Example 15 (100 mg, 0.211 mmol) in THF (1.05 ml) was added methylmagnesium bromide (3M in diethyl ether) (0.126 ml, 0.329 mmol) during 2 min at −15° C. Stirring was continued for 2 h at RT and then quenched with 1M NH4Cl. The mixture was extracted with EtOAc (2×). The organic phases were washed with brine and dried over Na2SO4, filtered and evaporated to dryness. The resulting crude material was purified by reverse phase prep-HPLC (Waters system) to yield the title compound as a beige foam (17 mg, 0.035 mmol, 17%). HPLC: BtRet=5.71; LC-MS: m/z 486.3 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:13](=[O:35])[C:14]([F:34])([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:22]=3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.O>CO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH:13]([OH:35])[C:14]([F:34])([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:22]=3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(F)(Cc1cccc(Oc2ccccc2)c1)C(=O)C1(c2ccc(Cl)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)C(F)(Cc1cccc(Oc2ccccc2)c1)C(O)C1(c2ccc(Cl)cc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 103.8 %

Procedure:
Sodium borohydride (20 mg, 0.53 mmol) is added to a solution of ethyl 1-(p-chlorophenyl)-α-fluoro-β-oxo-α-(m-phenoxybenzyl)cyclopropanepropionate (214 mg, 0.46 mmol) in methanol at 0° C. The reaction mixture is stirred at 0° C. for 20 minutes, treated with water (2 mL), and concentrated in vacuo to obtain a residue. A solution of the residue in ethyl acetate is washed sequentially with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a colorless gum (224 mg, 100%) which is found to have a 9:1 [R,S and S,R] to [R,R and S,S] ratio by NMR spectral analyses.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[NH:11][C:10]([CH2:12][O:13][CH3:14])=[N:9][C:8]=1[C:15]([O:18][CH3:19])([CH3:17])[CH3:16])=O.Cl.[NH2:22][C:23]([NH2:25])=[NH:24].C[O-].[Na+]>C(O)CCC>[NH2:24][C:23]1[N:25]=[C:5]([C:7]2[NH:11][C:10]([CH2:12][O:13][CH3:14])=[N:9][C:8]=2[C:15]([O:18][CH3:19])([CH3:17])[CH3:16])[CH:4]=[CH:3][N:22]=1
Reactant: COCc1nc(C(C)(C)OC)c(C(=O)C=CN(C)C)[nH]1
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: COCc1nc(C(C)(C)OC)c(-c2ccnc(N)n2)[nH]1
Yield: 60.4 %

Procedure:
5-(3-Dimethylaminoprop-2-en-1-oyl)-1-methoxyisopropyl-2-methoxymethylimidazole (Method 56; 3.13, 11.1 mmol) and guanidine hydrochloride (2.65 g, 27.8 mmol) were suspended in 1-butanol (20 ml). Sodium methoxide (2.4 g, 44 mmol) was added in one portion and the mixture heated under reflux, under an atmosphere of nitrogen, for 18 hours. The volatiles were removed by evaporation. Water (50 ml) was added and extracted EtOAc (3×50 ml). The organic layers were combined and dried with Chemelut CE1010 and the solvent evaporated in vacuo. The residue was purified by flash silica chromatography eluting with DCM:MeOH (100:0 increasing in polarity to 95:5) to give the title compound as an orange solid (1.86 g, 60%). NMR: 1.43 (d, 3H), 3.16 (s, 3H), 3.24 (s, 3H), 3.63 (m, 1H), 3.89 (m, 1H), 4.50 (q, 2H), 5.26 (m, 1H), 6.57 (s, 2H), 6.80 (d, 1H), 7.40 (s, 1H), 8.21 (d, 1H); m/z 278.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][O:13][CH3:14])=[C:5]2[C:15]([O:17][CH3:18])=[O:16].[H-].[Na+].[CH3:21]I.O>CN(C)C=O>[CH3:21][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][O:13][CH3:14])=[C:5]2[C:15]([O:17][CH3:18])=[O:16]
Reactant: CI
Reactant: COCc1c(C(=O)OC)c2cc(O)ccc2n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1c(C(=O)OC)c2cc(OC)ccc2n1C
Temperature: 50 °C
Yield: 89.6 %

Procedure:
14.9 g of 5-hydroxy-3-methoxycarbonyl-2-methoxymethyl-1-methylindole (59.8 mmol) obtained in Example 1 was dissolved in 150 ml of anhydrous dimethylformamide, and the solution was stirred in a stream of nitrogen under ice cooling. To this were added 2.63 g (65.8 mmol) of sodium hydride (60% oil dispersion) and 4.1 ml (65.9 mmol) of methyl iodide in that order. After 2 hours of heating at 50° C., the resulting reaction mixture was cooled down, mixed with water and then extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was filtered off and the solvent was distilled off under reduced pressure, the resulting residue was purified by a silica gel column chromatography (eluent: hexane-ethyl acetate, 3:1) to obtain 14.1 g of the title compound with a yield of 89%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>CN(C=O)C>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:9]3)=[CH:4][CH:3]=2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cnc2cc(O)ccc2c1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2cc(OCc3ccc(Cl)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
To a solution of ethyl 7-hydroxyquinoline-3-carboxylate (Intermediate 1, 50 mg, 0.23 mmol) in DMF (1.15 mL) was added Cs2CO3 (150 mg, 0.46 mmol) and 4-chlorobenzyl chloride (41 mg, 0.25 mmol). The reaction was stirred overnight at ambient temperature. The reaction mixture was loaded directly onto a column and purification (FCC, SiO2, EtOAc/hexanes, 0-20%) afforded the title compound as a white solid (50 mg, 63%). 1H NMR (400 MHz, CDCl3) δ 9.37 (d, J=2.3 Hz, 1H), 8.74 (d, J=2.0 Hz, 1H), 7.83 (d, J=9.0 Hz, 1H), 7.50 (d, J=2.3 Hz, 1H), 7.45-7.35 (m, 4H), 7.34-7.29 (m, 1H), 5.20 (s, 2H), 4.45 (q, J=7.3 Hz, 2H), 1.44 (t, J=7.0 Hz, 3H). [M+H]=342.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C:20]4([S:25][CH3:26])[CH2:24][CH2:23][NH:22][CH2:21]4)=[O:19])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([C:43]3[N:48]=[CH:47][CH:46]=[CH:45][N:44]=3)=[C:39]([F:49])[CH:38]=2)[CH2:33][CH2:32]1)=[O:30].C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C:20]4([S:25][CH3:26])[CH2:24][CH2:23][N:22]([CH2:28][C:29]([N:31]5[CH2:36][CH2:35][N:34]([C:37]6[CH:42]=[CH:41][C:40]([C:43]7[N:44]=[CH:45][CH:46]=[CH:47][N:48]=7)=[C:39]([F:49])[CH:38]=6)[CH2:33][CH2:32]5)=[O:30])[CH2:21]4)=[O:19])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCl)N1CCN(c2ccc(-c3ncccn3)c(F)c2)CC1
Reactant: CSC1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCNC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSC1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)c(F)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methylsulfanyl-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1H-indazol-5-yl]-amide (12AB) (40 mg, 0.09 mmol, 1 equiv) and 2-Chloro-1-[4-(3-fluoro-4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethanone (7AB) (37 mg, 0.11 mmol, 1.2 equiv) were weighed out in a flask, and to it was added N,N-dimethylformamide (3 mL) and diisopropylethylamine (23 mg, 32 uL, 0.18 mmol, 2 equiv). The reaction content was stirred at room temperature overnight.