Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[O:11][CH:10]([CH3:13])[CH2:9][C:8]=2[C:7]([CH3:14])=[C:6]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:5]=1[CH3:21])[CH3:2].Br[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=1>>[CH2:30]([O:29][C:26]1[CH:27]=[CH:28][C:23]([N:18]2[CH2:19][CH2:20][N:15]([C:6]3[C:5]([CH3:21])=[C:4]([O:3][CH2:1][CH3:2])[C:12]4[O:11][CH:10]([CH3:13])[CH2:9][C:8]=4[C:7]=3[CH3:14])[CH2:16][CH2:17]2)=[CH:24][CH:25]=1)[CH3:31]
Reactant: CCOc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)C2
Reactant: CCOc1ccc(Br)cc1
Product: CCOc1ccc(N2CCN(c3c(C)c4c(c(OCC)c3C)OC(C)C4)CC2)cc1
Yield: 64.8 %

Procedure:
By using 1-(7-ethoxy-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (580 mg, 2.0 mmol) synthesized in Reference example 89 and 1-bromo-4-ethoxybenzene (804 mg, 4.0 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 532 mg (yield 65%). Melting point was 121 to 122° C. (ethanol-water).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[S:17]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18]1.C([O-])([O-])=O.[Na+].[Na+]>C(O)CC.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>[CH3:16][C:10]1[O:9][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:19]3[CH:20]=[CH:21][S:17][CH:18]=3)[CH:3]=2)=[N:12][C:11]=1[CH2:13][CH2:14][OH:15]
Reactant: OB(O)c1ccsc1
Reactant: Cc1oc(-c2cccc(Br)c2)nc1CCO
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: CCCO
Product: Cc1oc(-c2cccc(-c3ccsc3)c2)nc1CCO
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
2-[2-(3-Bromo-phenyl)-5-methyloxazol-4-yl]ethanol (1.0 g, 3.54 mmol) (see Ex. 2, Part D) and 3-thiophene boronic acid (5.32 mmol) were stirred in n-PrOH (10 mL) under nitrogen, to which 2M Na2CO3 (3.54 mL) was added. The mixture was heated at 85° C., and after Pd(PPh3)4 (41 mg, 0.0354 mmol) was added, the reaction proceeded for 0.5 h. Once the reaction mixture had cooled to room temperature, it was concentrated and taken up in CH2Cl2 (20 mL), then washed with 0.5M NaOH (20 mL). The aqueous layer was back-extracted with CH2Cl2 (10 mL), combined organics were washed with 1M NaOH (10 mL), followed by H2O (10 mL), then dried over Na2SO4, and concentrated to a crude solid. Recrystallized from ethyl acetate:hexanes (1:1) and vacuum oven-dried at 50° C. to yield a tan solid. 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.57 (s, 1H), 7.48 (t, J=8.0 Hz, 1H) 7.46(m, 1H), 7.41 (m, 1H), 3.95 (t, J=5.6 Hz, 2H), 2.74 (t, J=5.6 Hz, 1H), 2.36 (s, 3H); MS (EI) 286.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[C:11]([Cl:16])[C:10]=1[F:17])([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][CH2:21][CH2:22][NH:23][CH3:24].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([N:23]([CH2:22][CH2:21][O:20][CH3:19])[CH3:24])[CH:12]=[C:11]([Cl:16])[C:10]=1[F:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCCOC
Reactant: CC(C)(C)OC(=O)NCc1cc(Br)cc(Cl)c1F
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCCN(C)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Temperature: 140 °C

Procedure:
A suspension of (5-bromo-3-chloro-2-fluoro-benzyl)-carbamic acid tert-butyl ester (250 mg, 0.7 mmol), N-methoxyethyl-methylamine (99 mg, 1.1 mmol), sodium tert-butoxide (142 mg, 1.5 mmol) and di-μ-bromobis(tri-tert-butylphosphino)dipalladium (I) [CAS 185812-86-6] (29 mg, 0.04 mmol) in toluene (5 mL) was sealed in a microwave vial and heated for 30 min at 140° C. (Emrys Optimizer; personal chemistry). The reaction mixture was quenched by addition of saturated aqueous NaHCO3, extracted with EtOAc, dried (Na2SO4) and evaporated in vacuo. The crude product was purified by RP-preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min) to give the title compound after lyophilization. MS (LC/MS): 347.0 [M]+. tR (HPLC conditions c): 5.23 min.
Reaction SMILES: [C:1]12([C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH:4]=[CH:3][CH2:2]2.C(=O)(O)[O-:18].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[O:18]1[CH:4]2[CH:3]1[CH2:2][C:1]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11]1)[C:10]1[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1NC(=O)C2(CC=Cc3ccccc32)N1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C1NC(=O)C2(CC3OC3c3ccccc32)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To a slurry of 2.7 g. (0.013 mole) of spiro[imidazolidine-4,1'(2'H)-naphthalene]-2,5-dione in 50 ml. of chloroform and 125 ml. of a 5% sodium bicarbonate solution was added 3.4 g. (0.016 mole) of m-chloroperbenzoic acid and the reaction mixture allowed to stir at room temperature for 3 hours. The reaction mixture was poured into 100 ml. of a 5% sodium bicarbonate solution and the product extracted with chloroform (2×75 ml.) and ethylacetate (2×75 ml.). The combined extracts were washed with a sodium bicarbonate solution and a brine solution, dried over sodium sulfate and concentrated to a yellow solid. Trituration with diethyl ether gave 1.6 g. (55% yield) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Cl:13].[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[Cl:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:21]([NH:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:22]
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2)c(Cl)c1
Reaction time: 15 h
Yield: 85.6 %

Procedure:
To a mixture of methyl 4-amino-3-chlorophenylacetate (1.31 g, 6.56 mmol) and phenyl isocyanate (0.71 ml, 6.56 mmol) in THF (20 ml) was added Et3 N (0.19 ml, 1.33 mmol) at room temperature. After 15 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 3-chloro-4-(N′-phenylureido)phenylacetate (1.79 g, 86%) as a pale brown solid. 1H-NMR (CDCl3) δ 3.56 (s, 2H), 3.70 (s, 3H), 6.70 (m, 1H), 7.06 (s, 1H), 7.14–7.18 (m, 2H), 7.26 (dd, J=7.8, 1.9 Hz, 1H), 7.33–7.38 (m, 4H), 8.14 (dd, J=8.3, 3.0 Hz, 1H); MS (ESI) m/z 319 (M++1), 321 (M++3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>>[CH:13]1([NH:16][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: COc1ccc(C=O)cc1OC
Product: COc1ccc(CNC2CC2)cc1OC

Procedure:
Synthesized according to typical procedure J from 3,4-dimethoxybenzaldehyde and cyclopropylamine.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(O)c(-c2cccc(-c3cccc(Br)n3)n2)c1
Reactant: OB(O)c1ccccc1O
Product: COc1ccc(O)c(-c2cccc(-c3cccc(-c4ccccc4O)n3)n2)c1
Yield: 66 %

Procedure:
6-(2-Hydroxyphenyl)-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine and 2-hydroxyphenylboronic acid in 66% yield using method F; δH [2H6]-DMSO 13.55,(1H, s), 12.57,(1H, s), 8.35,(2H, m), 8.27-8.10,(5H, m), 7.65,(1H, s), 7.37,(1H, t), 7.03-6.93,(4H, m), 3.83,(3H, s); MS 371 (MH)+; HPLC retention time (system 1) 4.08 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:15]([CH2:16][OH:17])=[N:14][N:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:12](=[O:24])[C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1>ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:15]([CH:16]=[O:17])=[N:14][N:13]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:12](=[O:24])[C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1
Reactant: Cn1c2cc(Cl)ccc2c2c(CO)nn(-c3ccccc3)c(=O)c21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cn1c2cc(Cl)ccc2c2c(C=O)nn(-c3ccccc3)c(=O)c21
Reaction time: 24 h

Procedure:
5.7 g (65.6 mmol) of manganese dioxide are added to a solution of 3.3 g (9.7 mmol) of 7-chloro-1-(hydroxymethyl)-5-methyl-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indol-4-one in 300 ml of dichloromethane and the reaction mixture is stirred for 24 h under reflux.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([O:26][CH3:27])[CH:17]=2)=[S:14])=[O:11])[CH:7]=[C:6]([CH3:28])[N:5]=1.[CH3:29]I>C1COCC1>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([NH:12][C:13](=[N:15][C:16]2[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[C:18]([O:26][CH3:27])[CH:17]=2)[S:14][CH3:29])=[O:11])[CH:7]=[C:6]([CH3:28])[N:5]=1
Reactant: COc1cc(NC(=S)NC(=O)c2cc(C)nc(Cl)c2)cc(C(F)(F)F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(N=C(NC(=O)c2cc(C)nc(Cl)c2)SC)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73.5 %

Procedure:
(Reaction performed under N2 atmosphere) NaH (1.267 g, 0.05279 mol) was added portionwise to an ice-cooled solution of intermediate D5 (21.32 g, 0.05279 mol) in THF (480 ml) and the resulting mixture was stirred for 15 minutes at 0° C. Subsequently, a solution of CH3I (7.493 g, 0.05279 mol) in THF (40 ml) was added dropwise and the mixture was stirred for 2 hours at room temperature. Then the reaction mixture was quenched with H2O and extracted with CH2Cl2 (3×500 ml). The organic layers were separated, combined, washed with brine, dried (MgSO4), filtered and the solvent was evaporated in vacuo. The crude product was triturated with DIPE/heptane. The off-white solid was filtered off and dried to yield 16.203 g of intermediate D6 (73.5%). Heptane and H2O were added to the filtrate and this mixture was stirred overnight at room temperature. The off-white precipitate was filtered off and dried to yield more (1.957 g) of intermediate D6 (9%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[CH:14][C:13]=1[F:23])=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1>>[Cl:31][C:28]1[CH:27]=[N:26][C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[C:17]([N:18]3[N:19]=[CH:20][CH:21]=[N:22]3)=[CH:16][CH:15]=[CH:14][C:13]=2[F:23])=[O:11])=[N:30][CH:29]=1
Reactant: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-n2nccn2)[C@@H]1CN
Reactant: Clc1cnc(Cl)nc1
Product: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-n2nccn2)[C@@H]1CNc1ncc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 430 [M+1]+.
Reaction SMILES: O.NN.[CH2:4]([CH:6]1[C:10]2[C:11]([O:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][N:17]=3)=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][O:7]1)[CH3:5]>C(O)C.[Pd]>[CH2:4]([CH:6]1[C:10]2[C:11]([O:15][C:16]3[N:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=3)=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][O:7]1)[CH3:5]
Reactant: CCC1OCc2cccc(Oc3ccc([N+](=O)[O-])cn3)c21
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CCC1OCc2cccc(Oc3ccc(N)cn3)c21
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
In a 50 ml round-bottomed flask 2-[(3-ethyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-5-nitropyridine (Intermediate 107, 97.6 mg) was dissolved in ethanol (10 ml) to give a pale yellow solution. Pd/C (26.1 mg, 0.245 mmol) and hydrazine hydrate (12.29 mg, 0.245 mmol) were added. The reaction mixture was stirred at 90° C. After 45 minutes, the reaction was completed. The reaction mixture was filtered and the organic phase was evaporated under vacuum affording the crude product which was charged on a 2 g SCX cartridge. It was then flushed with 15 ml of methanol followed by 15 ml of a 2M solution of ammonia in methanol. The ammonia eluate was evaporated under vacuum affording nothing. The methanol eluate was then evaporated under vacuum to afford the title compound as a colourless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH3:12][O:13][C:14](=[O:37])[CH2:15][CH2:16][CH2:17][N:18]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:19]([C:21]1([CH3:28])[CH2:24][CH2:23][N:22]1[C:25](Cl)=[O:26])=[O:20]>C1COCC1>[CH3:12][O:13][C:14](=[O:37])[CH2:15][CH2:16][CH2:17][N:18]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[C:19]([C:21]1([CH3:28])[CH2:24][CH2:23][N:22]1[C:25]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)=[O:26])=[O:20]
Reactant: COC(=O)CCCN(Cc1ccc(Cl)cc1)C(=O)C1(C)CCN1C(=O)Cl
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CCCN(Cc1ccc(Cl)cc1)C(=O)C1(C)CCN1C(=O)n1ccc2ccccc21
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of indole (1 eq.) in THF is added NaH (1.5 eq., 60% in oil) and the mixture is stirred at 20° C. for 1 h. A solution of 4-[(4-Chloro-benzyl)-(1-chlorocarbonyl-2-methyl-azetidine-2-carbonyl)-amino]-butyric acid methyl ester in THF in added dropwise and the mixture is stirred at 20° C. for 16 h. The mixture was concentrated and the residue dissolved in EtOAc, washed with aqueous HCl (0.1N), a saturated aqueous solution of NaHCO3 and brine. The organic layer is dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue is used as such in next step.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2)=[C:4]([CH2:16][CH2:17][CH2:18]O)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C([Br:35])C=C.C(OCC)C>C(#N)C>[Br:35][CH2:18][CH2:17][CH2:16][C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[C:10]2[C:5]=1[N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2
Reactant: COc1nc2cc(Cl)cc(CCCO)c2nc1OC
Reactant: C=CCBr
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOCC
Solvent: CC#N
Product: COc1nc2cc(Cl)cc(CCCBr)c2nc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
0.5 g (1.77 mmol) of 3-(7-chloro-2,3-dimethoxy-quinoxalin-5-yl)-propan-1-ol and 0.287 g (1.77 mmol) of 1,1'-carbonyidiimidazole are placed in 5 ml of acetonitrile under N2. 0.75 ml of allyl bromide is added, and the mixture is then stirred at room temperature for 30 minutes and at reflux for 2 hours. The reaction mixture is cooled to room temperature, diethyl ether is added and extraction is carried out with water, 0.1N hydrochloric acid, saturated sodium hydrogen carbonate solution and brine. The aqueous phases are then washed with diethyl ether. The organic phases are combined, dried over sodium sulfate, filtered over a layer of silica gel and concentrated. 0.438 g (79.9%) of 5-(3-bromopropyl)-7-chloro-2,3-dimethoxy-quinoxaline is obtained in the form of a yellow oil which is used further without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCCl>[N:11]1([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: N#Cc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: N#Cc1ccc(CN2CCOCC2)cc1
Yield: 79.2 %

Procedure:
Dissolve 4-cyanobenzaldehyde (5 g, 38.1 mmol), morpholine (4.15 g, 47.7 mmol) and acetic acid (2.2 mL, 38.1 mmol) in DCE (100 mL). Add sodium cyanoborohydride (3.59 g, 57.2 mmol), and stir the mixture overnight. Add water (100 mL), separate the layers and extract the aqueous layer with DCM (3×50 mL). Wash the combined organic extracts with brine, dry over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (80 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 1:2 over 1.25 h, 80 mL/min) to obtain the desired intermediate as a colorless oil (6.1 g, 79%). MS (APCI+) m/z: 203 (M+H)+.
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].ClC1C=CC=C(C(OO)=[O:16])C=1.[N:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:26]>C(Cl)Cl>[N+:19]1([O-:16])[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:26]
Reactant: Cc1cccc(C)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccc(C)[n+]1[O-]
Reaction time: 18 h

Procedure:
Sodium sulphate (6 g) and a solution of m-chloroperbenzoic acid (40 g) in DCM (140 ml) was added to a solution of 2,6-lutidine (5 ml) in dry DCM (60 ml). The mixture was stirred at 23° and under a nitrogen atmosphere for 18 h; then it was quenched with a saturated aqueous sodium bicarbonate solution (200 ml). Then a solution of potassium carbonate was added and the aqueous phase was saturated with NaCl and then it was extract with DCM (3×100 ml). The organic extract was dried and concentrated in vacuo to a yellow oil which was purified by flash chromatography (eluting in gradient from EA to EA-MeOH 9:1) to give the title compound as a yellow oil (4.7 g).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:18]([OH:22])[CH:19]([CH3:20])[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)c1cc2cc(Cl)ccc2n1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)C(O)c1cc2cc(Cl)ccc2n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
To a solution of 1-(1-benzyl-5-chloro-1H-indole-2-yl)-2-methylpropan-1-one (0.6 mmol) in 5 mL of MeOH, was added NaBH4 (1.8 mmol) at 0° C. The mixture was stirred for additional 30 min. The solution was poured into ice water, and extracted with EtOAc (×3). The organic layers were combined, washed with H2O (×3), brine (×3), dried over Na2SO4, filtered, and the filtrate was concentrated to yield 182 mg of 1-(1-benzyl-5-chloro-1H-indole-2-yl)-2-methylpropan-1-ol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:13](=[O:14])[CH:12]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:11][C:10]2=[O:22])=[C:4]([CH3:23])[CH:3]=1.Cl[C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([Cl:35])[CH:31]=2)[N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:35][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([O:1][C:2]1[CH:3]=[C:4]([CH3:23])[C:5]([CH:9]3[C:13](=[O:14])[CH:12]([CH2:15][CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH2:11][C:10]3=[O:22])=[C:6]([CH3:8])[CH:7]=1)[CH:34]=[CH:33]2
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: Cc1cc(O)cc(C)c1C1C(=O)CC(CC2CCOCC2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc3cc(Cl)ccc3n2)cc(C)c1C1C(=O)CC(CC2CCOCC2)C1=O
Temperature: 140 °C

Procedure:
A suspension of 2-(4-hydroxy-2,6-dimethylphenyl)-4-(tetrahydropyran-4-ylmethyl)cyclopentane-1,3-dione (0.104 g, 0.00033 mol), 2,6-dichloroquinoline (0.065 g, 0.00033 mol) and potassium carbonate (0.140 g, 0.00101 mol) in anhydrous N,N-dimethylformamide (3 ml) is heated at 140° C. for 40 minutes under microwave irradiation. After cooling to room temperature the reaction mixture was quenched with 2M hydrochloric acid and extracted with ethyl acetate. The organic phase is separated, washed with distilled water then dried over anhydrous magnesium sulfate. The mixture is filtered, the filtrate is evaporated in vacuo and the residue is purified by preparative reverse phase HPLC to afford 2-[4-(6-chloroquinolin-2-yloxy)-2,6-dimethylphenyl]-4-(tetrahydropyran-4-ylmethyl)cyclopentane-1,3-dione.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][CH:10]([C:13]3[S:14][C:15]([C:18]([O:20]CC)=[O:19])=[CH:16][N:17]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+:23].[OH-]>O1CCCC1.CO>[C:1]1([N:7]2[CH2:12][CH2:11][CH:10]([C:13]3[S:14][C:15]([C:18]([O-:20])=[O:19])=[CH:16][N:17]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+:23]
Reactant: CCOC(=O)c1cnc(C2CCN(c3ccccc3)CC2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C([O-])c1cnc(C2CCN(c3ccccc3)CC2)s1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A solution of ethyl 2-(1-phenylpiperidin-4-yl)thiazole-5-carboxylate (31 mg, 0.098 mmol) in 1 ml of 1:1 tetrahydrofuran/methanol was treated with 1M LiOH (0.11 ml, 0.11 mol) and stirred at 65° C. for 3 hours. The mixture was taken to dryness and used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[CH2:18][C:19]([O:21][CH3:22])=[O:20].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:33]1[CH2:37]OC[CH2:34]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]([CH3:17])([CH3:15])[CH3:16])[C:3]=1[CH:18]([CH2:34][CH2:33][CH3:37])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1C(C)(C)C)CCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1C(C)(C)C)CCC3
Yield: 46.1 %

Procedure:
This compound was prepared according to the procedure C from Methyl [2-methyl-4-(tert-butyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate (0.067 g; 0.211 mmol), LHMDS 1N in THF (0.232 mL; 0.232 mmol), 1-iodopropane (0.031 mL; 0.317 mmol) in DMF (0.85 mL) for 3 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 0.035 g (46%) of the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.C[Al](C)C.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@@:25]([OH:51])([CH2:45][N:46]1[CH:50]=[N:49][CH:48]=[N:47]1)[C@H:26]([S:28][C@@H:29]1[CH2:34][O:33][C@@H:32]([C:35]2[CH:44]=[CH:43][C:38]([C:39](OC)=[O:40])=[CH:37][CH:36]=2)[O:31][CH2:30]1)[CH3:27]>>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@@:25]([OH:51])([CH2:45][N:46]1[CH:50]=[N:49][CH:48]=[N:47]1)[C@H:26]([S:28][C@@H:29]1[CH2:34][O:33][C@@H:32]([C:35]2[CH:36]=[CH:37][C:38]([C:39]([NH:8][C:7]3[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=3)=[O:40])=[CH:43][CH:44]=2)[O:31][CH2:30]1)[CH3:27]
Reactant: COC(=O)c1ccc([C@H]2OC[C@H](S[C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CO2)cc1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: C[Al](C)C
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(4), a reaction was carried out using commercially available 4-(trifluoromethoxy)aniline (123 mg, 0.69 mmol), trimethylaluminium (0.64 ml, 1.07M n-hexane solution, 0.69 mmol) and methyl 4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzoate (100 mg, 0.20 mmol), obtained in Example 12(1), and the reaction mixture was treated using a similar procedure to that described in Example 3(4) to afford the title compound (122 mg, yield 95%) as white solid which was recrystallized from ethyl acetate-hexane to give white powdery crystals.