Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[N:19]=[C:20]([C:23]6[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=6)[CH:21]=[N:22][C:17]5=[N:16][N:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][NH2:39].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CO>[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][NH:39][C:27](=[O:29])[C:26]1[CH:25]=[CH:24][C:23]([C:20]2[CH:21]=[N:22][C:17]3[N:18]([C:14]([C:11]4([C:7]5[CH:6]=[C:5]6[C:10](=[CH:9][CH:8]=5)[N:1]=[CH:2][CH:3]=[CH:4]6)[CH2:12][CH2:13]4)=[N:15][N:16]=3)[N:19]=2)=[CH:31][CH:30]=1
Reactant: NCc1ccccn1
Reactant: O=C(O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C(NCc1ccccn1)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoic acid (10 mg, 0.00002 mol), 2-pyridinemethanamine (2.9 mg, 0.000027 mol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (12 mg, 0.000027 mol), N,N-diisopropylethylamine (11 μL, 0.000061 mol) in DMF (0.4 mL) was stirred at RT for 2 h. The mixture was diluted with methanol and purified by RP-HPLC (pH=10) to afford the desired product. Analytical LCMS: (M+H)+=499.1.
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)[O:7][CH2:6][CH2:5]2.N#N.[CH3:29][N:30](C=O)C>CCOC(C)=O.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.[C-]#N.[C-]#N.[Zn+2]>[C:29]([C:3]1[C:2]([F:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][O:7][CH:8]2[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)#[N:30]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCN(CC2OCCc3c2ccc(F)c3I)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: [C-]#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CC2OCCc3c2ccc(F)c3C#N)CC1
Temperature: 25 °C

Procedure:
A solution of tert-butyl 4-[(6-fluoro-5-iodo-3,4-dihydro-1H-isochromen-1-yl)methyl]piperazine-1-carboxylate (200 mg, 0.42 mmol), Pd(PPh3)4 (200 mg) and Zn(CN)2 (300 mg, 2.6 mmol) in 20 mL of anhydrous DMF was to 110° C. at N2 atmosphere for 2 hours. The reaction was cooled to room temperature, diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified with prep-TLC to afford tert-butyl 4-[(5-cyano-6-fluoro-3,4-dihydro-1H-isochromen-1-yl)methyl]piperazine-1-carboxylate.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[CH:5]([CH2:7][OH:8])[NH2:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:34][CH:35]([CH3:39])[C:36](O)=[O:37].C(N(CC)CC)C>O.C(Cl)Cl>[F:34][CH:35]([CH3:39])[C:36]([NH:6][CH:5]([CH2:7][OH:8])[C:4]([O:3][CH3:2])=[O:9])=[O:37]
Reactant: CC(F)C(=O)O
Reactant: COC(=O)C(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(CO)NC(=O)C(C)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
A rbf was charged with DL-serine methyl ester hydrochloride (1.49 g, 9.57 mmol, Sigma-Aldrich Chemical Company, Inc.), HATU (4.37 g, 11.49 mmol, Sigma-Aldrich Chemical Company, Inc.) and DCM (22 mL). 2-Fluoropropionic acid (0.75 ml, 9.57 mmol, Alfa Aesar, A Johnson Matthey Company) and triethylamine (3.3 ml, 23.93 mmol, Sigma-Aldrich Chemical Company, Inc.) were added and the reaction mixture was allowed to stir at rt overnight. The reaction mixture was diluted with water and extracted with DCM. The organic extract was washed with water, aqueous saturated NaHCO3 solution, brine, and dried over MgSO4. The solution was concentrated in vacuo and the crude product was purified by silica gel chromatography, eluting with a gradient of 1% to 10% MeOH in DCM, to provide methyl 2-(2-fluoropropanamido)-3-hydroxypropanoate (0.69 g, 3.60 mmol, 38% yield).
Reaction SMILES: C(O[C:9]([NH:11][C@H:12]([C:14]([N:16]1[CH2:29][CH2:28][CH2:27][C@H:17]1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])=[O:15])[CH3:13])=[O:10])C1C=CC=CC=1.[CH3:30][CH2:31]OCC.C(OC(=O)CC)(=O)CC>Br.C(O)(=O)C>[C:9]([NH:11][C@H:12]([C:14]([N:16]1[CH2:29][CH2:28][CH2:27][C@H:17]1[C:18]([NH:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:19])=[O:15])[CH3:13])(=[O:10])[CH2:30][CH3:31]
Reactant: CCOCC
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Agent: Br
Agent: CCC(=O)OC(=O)CC
Solvent: CC(=O)O
Product: CCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8.7 g (0.022 mol) of N-benzyloxycarbonyl-L-alanyl-L-proline anilide were dissolved in 40 ml of 4-N hydrogen bromide in acetic acid and the solution was stirred at room temperature for 1 hour. Upon addition of 300 ml of dry ether a white solid separated. It was allowed to settle. The solution was decanted off and the solid washed with two 150 ml portions of ether, dried on a rotary evaporator and dissolved in 120 ml of dry pyridine. 5.73 ml (0.044 mol) of propionic anhydride were added and the mixture was stirred at room temperature for 1 hour and then evaporated. The residue was dissolved in 250 ml of chloroform and the solution washed with 100 ml of 1-N hydrochloric acid, 100 ml of water and 100 ml of 5% sodium bicarbonate solution, dried over magnesium sulphate and evaporated to an oil. This oil crystallised from ethyl acetate/ether to yield 3.5 g of N-propionyl-L-alanyl-L-proline anilide. A second crop (1.5 g) was obtained from the mother liquor on allowing same to stand. The two crops were combined and chromatographed on 200 g of silica gel. 2% methanol/chloroform was used for the elution and 15 ml fractions were collected. Fractions 35-90 were combined and evaporated. The residue was recrystallised from ethyl acetate/petroleum ether to give 3.24 g (46%) of N-propionyl-L-alanyl-L-proline anilide of melting point 156°-157° C.; [α]D20 =-188.7° (c=1.034% in methanol).
Reaction SMILES: [N+:1]([CH2:4][CH:5]1[CH2:13][C:8]2(OCC[O:9]2)[CH:7]([CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:6]1[CH:23]=[CH:24][C:25]([OH:37])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([O-:3])=[O:2].O1CCCC1.Cl>O>[OH:37][C:25]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:24]=[CH:23][CH:6]1[CH:5]([CH2:4][N+:1]([O-:3])=[O:2])[CH2:13][C:8](=[O:9])[CH:7]1[CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: CCCCCC(O)(C=CC1C(C[N+](=O)[O-])CC2(OCCO2)C1CC=CCCCC(=O)O)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC(O)(C=CC1C(C[N+](=O)[O-])CC(=O)C1CC=CCCCC(=O)O)c1ccccc1

Procedure:
A solution of 0.3 g. of 7-[8-nitromethyl-7-(3-hydroxy-3-phenyl-1-octenyl)-1,4-dioxaspiro[4.4]-non-6-yl]-5-heptenoic acid in 6 ml. of dry tetrahydrofuran was treated at 0° C. with 0.6 ml. of concentrated hydrochloric acid and stirred at 0° C. for 1.5 hours. The reaction mixture was added to water and extracted with ether. After washing with water and drying over magnesium sulfate, the extract was evaporated and the residue chromatographed on silica. Elution with 33% ethyl acetate in hexane gave 0.08 g. of the title product as an oil, λmaxfilm 3.00 (shoulder), 3.40, 5.75, 6.40, 7.20, 10.20, 13.20, 14.18 μ. NMR: δ 4.45 (m, 2, --CH2NO2), 5.40 (m, 2, 5 and 6-H), 5.85 (m, 2, 13 and 14-H), 5.90 (s, 2, OH), 7.40 (s, 5, aromatic -H) ppm. Mass spectrum: M+ at m/e 471 (theory 471), M+ -H2O at m/e 453 (theory 453).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[Cl:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][N:20]2[CH2:24][CH2:23][CH:22]([CH2:25][NH:26][C:27](=[O:30])[CH2:28][NH2:29])[CH2:21]2)=[CH:17][CH:16]=1.CO>ClCCl.C(Cl)(Cl)Cl>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:29][CH2:28][C:27]([NH:26][CH2:25][CH:22]1[CH2:23][CH2:24][N:20]([CH2:19][C:18]2[CH:31]=[CH:32][C:15]([Cl:14])=[CH:16][CH:17]=2)[CH2:21]1)=[O:30])=[O:7]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)C1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 3-(trifluoromethyl)benzoyl chloride (0.058 mmol) in dichloromethane (0.2 mL) was added to a mixture of 1-(4-chlorobenzyl)-3-{(glycylamino)methyl}pyrrolidine (0.050 mmol) and peperidinomethylpolystyrene (60 mg) in chloroform (0.2 mL) and dichloromethane (1 mL). After the reaction mixture was stirred at room temperature for 2.5 h, methanol (0.30 mL) was added and the mixture was stirred at room temperature for 1 h. The reaction mixture was loaded onto Varian™ SCX column, and washed with CH3OH (15 mL). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated to afford (3-[{N-(3-trifluoromethylbenzoyl)glycyl}aminomethyl]-1-(4-chlorobenzyl)pyrrolidine (Compound No. 1463) (22.4 mg, 99%): The purity was determined by RPLC/MS (97%); ESIJMS m/e 454.2 (M++H, C22H23ClF3N3O2).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[Br:20]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Br:20][C:6]1[C:5]2[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[N:8]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:7]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2ccc(F)cc21
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1cc(Br)c2ccc(F)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To a solution of 6-fluoro-1-(phenylsulfonyl)-1H-indole (Intermediate 1; 1.0 g; 3.6 mmol) in DCM (20 mL) at 0° C. was added a solution of bromine (0.64 g; 4.0 mmol) in DCM (20 mL) dropwise. The mixture was stirred at 0° C. for 0.5 h, then added saturated aqueous Na2S2O3 (10 mL), and stirred at r.t. for 10 minute. The organic layer was separated and the aqueous layer was extracted with DCM (10 mL×2). The combined organic layers were washed with saturated aqueous NaHCO3 (20 mL×2), water (20 mL×2), brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford 1.26 g (99%) of the title compound as a pink solid.
Reaction SMILES: [CH3:1][O:2][N:3]=C1C2C=CN=NC=2OC1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[O:21][CH2:22][C:23](=O)[C:16]=12>>[CH3:1][O:2][N:3]=[C:23]1[C:16]2[C:17](=[N:18][CH:19]=[CH:20][C:15]=2[O:14][CH3:13])[O:21][CH2:22]1
Reactant: COc1ccnc2c1C(=O)CO2
Reactant: CON=C1COc2nnccc21
Product: CON=C1COc2nccc(OC)c21

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime (A.2.3.3), 4-methoxyfuro[2,3-b]pyridin-3(2H)-one replacing furo[2,3-c]pyridazin-5(6H)-one. Purification by (KP-SIL™ from Biotage) using Hept/EtOAc (1/1) gives the desired product as white solid;
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([N:20]3[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]3)[CH:11]=2)=[CH:4][C:3]=1[NH:27][C:28]([N:30]1[C:34]2[N:35]=[CH:36][N:37]=[C:38](Cl)[C:33]=2[CH:32]=[CH:31]1)=[O:29].Cl.Cl.[CH3:42][N:43]([CH3:51])[C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([NH2:50])[CH:45]=1.C(Cl)(=O)C.NC1C=CC=CC=1>C(O)CCC>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([N:20]3[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]3)[CH:11]=2)=[CH:4][C:3]=1[NH:27][C:28]([N:30]1[C:34]2[N:35]=[CH:36][N:37]=[C:38]([NH:50][C:46]3[CH:47]=[CH:48][CH:49]=[C:44]([N:43]([CH3:51])[CH3:42])[CH:45]=3)[C:33]=2[CH:32]=[CH:31]1)=[O:29]
Reactant: CN(C)c1cccc(N)c1
Reactant: Cc1cn(-c2cc(C(=O)Nc3ccc(C)c(NC(=O)n4ccc5c(Cl)ncnc54)c3)cc(C(F)(F)F)c2)cn1
Agent: Cl
Solvent: Nc1ccccc1
Solvent: CC(=O)Cl
Solvent: CCCCO
Product: Cc1cn(-c2cc(C(=O)Nc3ccc(C)c(NC(=O)n4ccc5c(Nc6cccc(N(C)C)c6)ncnc54)c3)cc(C(F)(F)F)c2)cn1
Temperature: 80 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
4-Chloro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-methyl-5-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzoylamino]-phenyl}-amide resin (50 mg, 0.05 mmol), prepared as in reference 3, in n-butanol (2 mL) is mixed with N,N-dimethyl-1,3-phenylenediamine dihydrochloride (52.3 mg, 0.25 mmol) or mixed with acetyl chloride (17.8 μL, 0.25 mmol) and aniline and shaken at 80° C. for 24 hours. The resulting mixture is filtered and the resin is treated with TFA/CH2Cl2/H2O (45/50/5) (600 μL) for 30 minutes before filtering and washing with CH2Cl2 (3×2 mL), MeOH (3×2 mL). The washes are then combined together and concentrated. The residue is purified by preparative HPLC-MS to give 4-(3-dimethylamino-phenylamino)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-methyl-5-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzoylamino]-phenyl}-amide (23.2 mg, yield 71%); 1H NMR (400 MHz, DMSO-d6) δ 11.60 (s, 1H), 10.65 (s, 1H), 9.68 (s, 1H), 9.61 (s, 1H), 8.60 (s, 1H), 8.54 (s, 1H), 8.53 (s, 1H), 8.46 (s, 1H), 8.41 (s, 1H), 8.16 (s, 1H), 7.82 (d, J=3.9 Hz, 1H), 7.60 (d, J=8.2 Hz, 1H), 7.32 (d, J=3.6 Hz, 1H), 6.54 (d, J=8.4 Hz, 1H), 2.92 (s, 6H), 2.45 (s, 3H), 2.35 (s, 3H); ESIMS m/z 654.2 (M++1).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])O1.[OH-].[Na+].[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21]([NH:27][C:28]([C:30]1[O:31][C:32]3[C:38](Br)=[CH:37][CH:36]=[CH:35][C:33]=3[CH:34]=1)=[O:29])[CH2:20]2>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:38]1[C:32]2[O:31][C:30]([C:28]([NH:27][C@@H:21]3[CH:22]4[CH2:23][CH2:24][N:19]([CH2:26][CH2:25]4)[CH2:20]3)=[O:29])=[CH:34][C:33]=2[CH:35]=[CH:36][CH:37]=1
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccccc1-c1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)oc12
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
752 mg (3.44 mmol) of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine and 11.45 ml of 1N sodium hydroxide solution are added to a mixture of 1.0 g (2.86 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide (Example 30A) and 234 mg (0.29 mmol) of PdCl2(dppf) in 15 ml of DMF. The reaction mixture is heated at 95° C. overnight and then filtered through kieselguhr. The solvent is then removed under reduced pressure, and the residue is taken up in 100 ml of ethyl acetate and 100 ml of 1N sodium hydroxide solution. The organic phase is washed twice with 1N sodium hydroxide solution and once with saturated sodium chloride solution. The combined organic phases are dried over magnesium sulphate, and the solvent is removed in a rotary evaporator under reduced pressure. The crude product is taken up in methanol and shaken together with acidic ion exchanger (Dowex® WX2-200) for about 30 min. The loaded ion exchanger is washed three times with 30 ml of methanol each time and then with DMF. It is washed successively with methanol, dichloromethane, methanol, water, methanol, dichloromethane, methanol, THF and finally once again with methanol. The product is eluted with methanol/triethylamine 95:5. The solvent is removed in a rotary evaporator under reduced pressure. Drying under high vacuum results in 601 mg (48% of theory) of the title compound in sufficient purity for further reactions.
Reaction SMILES: C(O[C:4]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6](=[O:11])[CH:5]=1)C.[CH2:12]([Mg]Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.OS(O)(=O)=O>C1COCC1>[CH2:12]([C:4]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6](=[O:11])[CH:5]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC1=CC(=O)CCCC1
Reactant: Cl[Mg]Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=C1C=C(Cc2ccccc2)CCCC1
Reaction time: 6 h
Yield: 65 %

Procedure:
A solution of 3-ethoxy-2-cyclohepten-1-one(5 g, 0.89 mol) in THF (70 mL) was added at room temperature to a solution of 2M benzyl magnesium chloride (800 ml) under N2 and stirred for 6 h. The resulting mixture was poured into a solution of 30% H2SO4 and stirred for 5 h. The resulting organic layer was separated, and the aqueous layer was extracted with several portions of ether. The combined organic layer was dried (MgSO4), and concentrated in vacuo to give 3-benzyl-2-cyclohepten-1-one (3.1 g, 65%) as a colorless oil. NMR (CDCl3); 3.45(s,2H1benzylic protons), 5.97 (bs, 1H, olefinic proton), 7.22 (m, 5H, aromatic protons).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:23]([O:25]CC)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:28][CH2:29][CH:30]1[CH2:32][CH2:31]1.[Li+].[OH-]>CO.C1COCC1.O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)=[CH:6][C:5]([C:18]2([C:23]([OH:25])=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22]2)=[CH:4][C:3]=1[O:28][CH2:29][CH:30]1[CH2:32][CH2:31]1
Reactant: CCOC(=O)C1(c2cc(OCC3CC3)c(Cl)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(c2cc(OCC3CC3)c(Cl)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.8 %

Procedure:
Ethyl 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate (80 mg) dissolved in 10 mL of MeOH/THF/H2O (10 mL/10 mL/5 mL) and 57 mg LiOH added. The reaction mixture was stirred at room temperature for 5 h and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography over silica gel (hexane/EtOAc 9:1) gave 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentane carboxylic acid (45 mg) as a white solid. 1H-NMR (500 MHz, CDCl3): 7.68 (d, 2H), 7.55 (d, 2H), 6.99 (s, 1H), 6.97 (s, 1H), 3.97 (d, 2H), 2.64 (m, 2H), 1.95 (m, 2H), 1.77 (m, 4H), 1.21 (m, 1H), 0.45 (m, 2H), 0.18 (m, 2H);
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[NH:21]1[CH2:24][CH:23]([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:22]1.C(OC)(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:21]3[CH2:24][CH:23]([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:22]3)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(C)(O)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: COC(OC)OC
Product: Cn1c(CCN2CC(C(C)(C)O)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 22.6 %

Procedure:
To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (300 mg, 1.01 mmol) in DCE (20 mL) was added 2-azetidin-3-ylpropan-2-ol (118 mg, 1.02 mmol), trimethyl orthoformate (1.11 mL, 10.14 mmol) and acetic acid (0.06 mL, 1.01 mmol). The reaction mixture was stirred at room temperature for 6 h, sodium triacetoxyborohydride (323 mg, 1.52 mmol) was added and the resulting mixture stirred for a further 18 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, the cartridge was washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si—PCC, 0-10% MeOH in DCM) to give the title compound as a pale yellow oil (90 mg, 23%). LCMS (Method A): RT=2.37 min, [M+H]+ 395.2
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:26][CH2:27][CH2:28][O:29][CH2:30][CH3:31])=[O:25])[C:6]1=[O:32].[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[C:33]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:26][CH2:27][CH2:28][O:29][CH2:30][CH3:31])=[O:25])[C:6]1=[O:32])(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN)c1=O
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCNC(C)=O)c1=O

Procedure:
This compound was prepared from 1-(3-aminopropyl)-N-[2-(ethyloxy)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide and acetic anhydride employing methods similar to those described in Step 2 of Example 373 and was obtained as a white solid: ES+ MS: 485 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:14])([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[CH:15]1([C:18]2[CH:19]=[CH:20][C:21]3[N:22]([C:24]([C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[C:30](O)[CH:31]=[CH:32][CH:33]=5)[N:28]=4)=[N:25][N:26]=3)[CH:23]=2)[CH2:17][CH2:16]1>>[CH:15]1([C:18]2[CH:19]=[CH:20][C:21]3[N:22]([C:24]([C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[C:30]([O:1][CH2:2][C:3]([CH3:14])([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH:31]=[CH:32][CH:33]=5)[N:28]=4)=[N:25][N:26]=3)[CH:23]=2)[CH2:17][CH2:16]1
Reactant: CC(C)(CO)CNC(=O)OC(C)(C)C
Reactant: Oc1cccc2ccc(-c3nnc4ccc(C5CC5)cn34)nc12
Product: CC(C)(CNC(=O)OC(C)(C)C)COc1cccc2ccc(-c3nnc4ccc(C5CC5)cn34)nc12

Procedure:
Prepared as described in Example 9, Step A, using tert-butyl 3-hydroxy-2,2-dimethylpropylcarbamate in place of tert-butyl-4-hydroxypiperidine-1-carboxylate and 2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol in place of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol.