Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([CH3:33])[CH:27]=2)[O:23][C:24]=1[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([CH3:33])[CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:8][C:7]=1[CH3:13]
Reactant: Cc1cc(-c2nc(CCl)c(C)o2)ccc1F
Reactant: CCO[C@@H](Cc1ccc(O)cc1C)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccc(F)c(C)c3)oc2C)cc1C)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (2S)-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (example 1 d]) was reacted with 4-chloromethyl-2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazole in the presence of cesium carbonate and potassium iodide to yield (S)-2-ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid methyl ester as colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([C:11](F)=[CH2:12])=[C:9]([NH2:14])[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[C:16]=2F)[N:6]=1)=[O:4].C([Sn](CCCC)(CCCC)C([F:32])=C)CCC.ClC1C=CC(B2OC(C)(C)C(C)(C)O2)=C(F)C=1C(F)C>>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH:11]=[CH2:12])=[C:9]([NH2:14])[N:8]=[C:7]([C:15]2[CH:16]=[C:17]([O:22][CH3:23])[C:18]([Cl:21])=[CH:19][C:20]=2[F:32])[N:6]=1)=[O:4]
Reactant: C=C(F)[Sn](CCCC)(CCCC)CCCC
Reactant: C=C(F)c1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OC
Agent: CC(F)c1c(Cl)ccc(B2OC(C)(C)C(C)(C)O2)c1F
Product: C=Cc1c(N)nc(-c2cc(OC)c(Cl)cc2F)nc1C(=O)OC

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-(1-fluorovinyl)pyrimidine-4-carboxylic acid methyl ester (utilized tributyl-(1-fluorovinyl)stannane prepared according to the procedures found in Bull. Chem. Soc. Jpn. 2002, 75(11), 2497-2502) (Compound 9): 1H NMR (CDCl3) δ 7.67 (dd, 1H), 7.22 (dd, 1H), 5.52 (br s, 2H), 5.23 (dd, 1H), 4.9 (dd, 1H), 3.99 (d, 3H), 3.95 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:32]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.Cl.C([O-])(O)=O.[Na+]>>[CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH2:32])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)[C@@H](N)Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-{(S)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-propionic acid methyl ester was treated with HCl according to General Procedure C and followed by aqueous NaHCO3 wash to give (S)-2-amino-3-{(S)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-propionic acid methyl ester. This was subjected to alkylation with (1-bromo-propyl)-benzene according to General Procedure P. Resulting product was purified on silica gel to give (S)-3-{(S)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-((R)-1-phenyl-propylamino)-propionic acid methyl ester (slower moving diastereomer). LCMS (m/z): 606. 1H NMR (400 MHz, Acetone-d6) 7.72 (d, 1H), 7.62 (d, 1H), 7.48 (m, 1H) 7.44 (d, 2H), 7.3 (m, 4H), 7.22 (m, 1H) 7.10 (d, 1H) 6.8 (d, 1H) 6.74 (d, 1H) 6.68 (m, 1H) 5.2 (s, 2H) 5.1 (m, 1H) 4.35 (m, 1H) 4.0 (m. 1H) 3.56 (t, 1H) 3.45 (s, 3H) 3.40 (t, 1H) 3.15 (s, 3H) 2.9 (m, 2H) 1.74 (m, 1H) 1.56 (m, 1H) 0.75 (t, 3H).
Reaction SMILES: C[CH:2]([C:6]1[O:10][N:9]=[C:8]([CH3:11])[N:7]=1)[C:3]([OH:5])=O.[CH:12]1([O:16][C:17]2[CH:18]=[C:19]([N:25]3[CH2:30][CH2:29][NH:28][C@@H:27]([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:26]3)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:15][CH2:14][CH2:13]1>>[CH:12]1([O:16][C:17]2[CH:18]=[C:19]([N:25]3[CH2:30][CH2:29][N:28]([C:3](=[O:5])[CH2:2][C:6]4[O:10][N:9]=[C:8]([CH3:11])[N:7]=4)[C@@H:27]([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:26]3)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:13][CH2:14][CH2:15]1
Reactant: Cc1noc(C(C)C(=O)O)n1
Reactant: COc1ccc(N2CCN[C@@H](CC(C)C)C2)cc1OC1CCC1
Product: COc1ccc(N2CCN(C(=O)Cc3nc(C)no3)[C@@H](CC(C)C)C2)cc1OC1CCC1
Yield: 4 %

Procedure:
Prepared by the method outlined for Example 275 using methyl-(3-methyl-1,2,4-oxadiazol-5-yl)acetic acid and (S)-1-(3-cyclobutlyoxy-4-methoxy-phenyl)-3-isobutyl-piperazine as starting materials. Product was obtained as an off-white solid (4%). LC/MS (Method B) 3.8 min, [M+1]+ 443.
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[C:12]([CH3:14])[C:11]([C:15]([O:17]CC)=[O:16])=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([C:8]1[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=[O:16])=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc(Cc2ccccc2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(Cc2ccccc2)ncc1C(=O)O
Temperature: 25 °C
Reaction time: 15 h
Yield: 91 %

Procedure:
To 40 ml of ethanol, 10.0 g (39 mmol) of ethyl 2-benzyl-4-methylpyrimidine-5-carboxylate was dissolved, followed by adding 12.5 g (78 mmol) of 25% sodium hydroxide aqueous solution and stirring at room temperature for 15 hours. Ethanol was then removed, and the residue was dissolved in 100 ml of water, and 10% hydrochloric acid was added to make acidic. Crystal precipitated was filtered, washed with water and dried to obtain 8.10 g (yield: 91%) of 2-benzyl-4-methylpyrimidine-5-carboxylic acid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[N:25](COCC[Si](C)(C)C)[CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CCO.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:14][CH2:15][S:16](=[O:19])(=[O:20])[CH2:17][CH2:18]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[NH:25][CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CCS(=O)(=O)CC2)cc1C1=CCCCC1
Solvent: CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCS(=O)(=O)CC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-phenyl]-amide (as prepared in the previous step, 145 mg, 0.261 mmol) in 6 mL of DCM was added 0.20 mL of EtOH followed by 2 mL of TFA. The resulting solution was stirred at RT for 3 h. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (20-25% EtOAc/DCM) gave 83 mg (90%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 12.34 (s, 1H), 9.60 (s, 1H), 8.35 (d, 1H, J=8.4 Hz), 7.75 (s, 1H), 7.30 (dd, 1H, J=8.4, 2.2 Hz), 7.08 (d, 1H, J=2.2 Hz), 5.86 (m, 1H), 3.11-3.23 (m, 4H), 2.80 (dddd, 1H, J=12.2, 12.2, 2.8, 2.8 Hz), 2.40-2.57 (m, 2H), 2.17-2.35 (m, 6H), 1.74-1.91 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C22H24N4O3S, 425.2 (M+H), found 425.6.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:21]([N:24](CC2C=CC(OC)=CC=2OC)[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][N:26]=2)(=[O:23])=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][C@H:10]1[CH2:14][CH2:13][CH2:12][C@@H:11]1[C:15]1[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=1)#[N:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([S:21]([NH:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][N:26]=2)(=[O:23])=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][C@H:10]1[CH2:14][CH2:13][CH2:12][C@@H:11]1[C:15]1[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=1)#[N:2]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCC[C@@H]3c3ccnn3C)c(C#N)c2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)cc1C#N
Yield: 78.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using 3-cyano-N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (91.0 mg, 0.16 mmol) prepared in Example 26b, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (53.3 mg, 79%) as a colorless solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]2)OCC1.[H-].[Na+].[CH3:15]I.O>O1CCCC1>[CH3:15][O:12][CH2:11][CH:8]1[CH2:7][CH2:6][C:5](=[O:1])[CH2:10][CH2:9]1
Reactant: OCC1CCC2(CC1)OCCO2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCC1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To (1,4-dioxa-spiro[4.5]dec-8-yl)-methanol (10 g) in tetrahydrofuran (300 mL) in an ice bath was added sodium hydride (3.6 g of 60% in mineral oil) and the mixture stirred for 30 min. Methyl iodide 7.8 mL in THF (20 mL) was added dropwise and the reaction was allowed to warm slowly to room temperature overnight. Water (20 mL) was added and the reaction mixture partially concentrated, then partitioned between water (100 mL) and diethyl ether (300 mL). The organic phase was isolated, dried and concentrated in vacuo. The crude was then taken up in tetrahydrofuran (250 mL) and 40 mL of 3N aqueous HCl was added. The reaction was stirred for 2 h at room temperature, partially concentrated and then the crude product was extracted with diethyl ether, dried, concentrated and purified by flash chromatography (4 hexane: 1 ethyl acetate) to give 4-methoxymethyl-cyclohexanone 4.9 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.N1(C2C=C[C:24]([CH:25]=[O:26])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][C:8]1[CH:15]=[CH:14][C:11](/[CH:12]=[CH:24]/[CH:25]=[O:26])=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(Oc2ncccn2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1ccc(Oc2ncccn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(2-pyrimidinyloxy)benzaldehyde (prepared as described in Reference Example 9) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 227 (M+H)+.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])#[N:2]>CO.O=[Pt]=O>[NH2:2][CH2:1][CH:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCOCC1C#N
Agent: O=[Pt]=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOCC1CN

Procedure:
To a solution (0.3 M) of tert-butyl 3-cyano-4-morpholinecarboxylate (prepared as described in the J. Med. Chem. 2007, 50, 4953-4975) in MeOH was added PtO2 (0.1 eq) and the mixture was stirred O/N under an H2 atmosphere at 50 psi. The reaction mixture was filtered and concentrated under reduced pressure to afford the title compound RR1. MS (ES) C10H20N2O3 required: 216, found: 217 (M+H)+.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:8][C:9]([F:24])([F:23])[C:10]1[CH:11]=[C:12]([N:20]=[C:21]=[O:22])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1>ClCCl>[CH:1]1([NH:7][C:21]([NH:20][C:12]2[CH:13]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:15]=[C:10]([C:9]([F:8])([F:23])[F:24])[CH:11]=2)=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NC1CCCCC1
Solvent: ClCCl
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC1CCCCC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
Cyclohexylamine 4.98 g (49.3 mmol) was added to 120 ml of anhydrous dichloromethane in a 500 ml round bottomed flask. This stirred solution was cooled to 0° C. using an ice water bath. 3,5-Bis(trifluoromethyl)phenyl isocyanate 12.33 g (48.3 mmol) was added drop wise over a period of 15 minutes. The reaction mixture was allowed to warm to room temperature and stirred at ambient temperatures for 18 hours. During this time a heavy precipitate was formed. This solid was collected by filtration on a Buchner funnel, and was re-suspended in 250 ml of dichloromethane. After approximately 30 minutes of stirring, the solid was again filtered on a Buchner funnel and then placed under vacuum at 40° C. to dry for a period of 24 hours to give 15.4 g of a white solid (90% yield). 1H NMR (400 MHz DMSO) δ 9.10 (s 1H) 8.10 (s 2H) 7.53 (s 1H) 6.43 (d 1H) 3.49 (m 1H) 1.81 (t 2H) 1.68 (m 2H) 1.54 (m 1H) 1.25 (m 5H). MS: m/z 355 (M+1).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH3:16][O:17][C:18]([C:20]1[S:24][C:23]2[CH:25]=[C:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:27]=[CH:28][C:22]=2[C:21]=1O)=[O:19].O.CCOC(C)=O>C(Cl)Cl.CCN(CC)CC>[CH3:16][O:17][C:18]([C:20]1[S:24][C:23]2[CH:25]=[C:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:27]=[CH:28][C:22]=2[C:21]=1[O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[O:19]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1sc2cc(C(=O)OC(C)(C)C)ccc2c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1sc2cc(C(=O)OC(C)(C)C)ccc2c1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
Trifluoromethanesulfonic anhydride (4.6 ml 27 mmol, 1.5 equiv) was dropwise added to a 0° C. solution of 3-hydroxy-benzo[b]thiophene-2,6-dicarboxylic acid 6-tert-butyl ester 2-methyl ester (5.56 g, 18 mmol) in DCM (50 ml) and Et3N (50 ml). The reaction mixture was warmed to RT and stirred for 30 min. After adding water and EtOAc the crude reaction mixture was washed with sat. NaHCO3 then dried over MgSO4. Filtration, evaporation, and purification by column chromatography yielded 4.56 g (57%) of 3-trifluoromethanesulfonyloxy-benzo[b]thiophene-2,6-dicarboxylic acid 6-tert-butyl ester 2-methy ester. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.64 (s, 9H) 4.01 (s, 3H) 7.87 (d, J=8.59 Hz, 1H) 8.12 (dd, J=8.59, 1.52 Hz, 1H) 8.50 (s, 1H). HRMS (ESI+, m/z) calcd for [M+NA]1+, 463.01035, found 463.01013.
Reaction SMILES: C([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:10][C:9]=1[C:21](O)([C:27]([F:30])([F:29])[F:28])[C:22]#[C:23][CH:24]1[CH2:26][CH2:25]1)(C)(C)C.C([Li])CCC>C1(C)C=CC=CC=1>[CH:24]1([C:23]#[C:22][C:21]2([C:27]([F:30])([F:28])[F:29])[O:5][C:6](=[O:32])[NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:10][C:9]2=3)[CH2:26][CH2:25]1
Reactant: COCCOCOc1ccc(NC(=O)OC(C)(C)C)c(C(O)(C#CC2CC2)C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: COCCOCOc1ccc2c(c1)C(C#CC1CC1)(C(F)(F)F)OC(=O)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.2 %

Procedure:
To 1.2 g (2.6 mmol) of 7 was added 15 mL of toluene, and the reaction mixture was cooled to 0° to −4° C. under argon atmosphere. To the reaction mixture 1.4 mL (3.5 mmol) of n-butyl lithium (2.5M in hexane) was added, and the resulting reaction mixture was allowed to stir at 0° to −4° C. for 10 minutes, warmed up to room temperature, and allowed to reflux for 1 hour. The reaction mixture was concentrated. Then 20 mL of water was added and the aqueous layer was extracted with 4×20 mL of dichloromethane. Organic layers were combined, dried (Na2SO4), and concentrated. The residue was purified by silica gel flash column chromatography using 20% ethyl acetate in hexane to give 965 mg (2.5 mmol, 96%) of 8 as a light brown oil [LC-MS; M+H 386.1].
Reaction SMILES: [OH:1][C:2]1([C:6]2[S:7][C:8]([C:11]3[CH:12]=[C:13]([NH:20][C:21]4[N:26]=[C:25]([O:27][CH:28]5[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]5)[CH:24]=[CH:23][N:22]=4)[CH:14]=[C:15]([N+:17]([O-])=O)[CH:16]=3)=[CH:9][N:10]=2)[CH2:5][CH2:4][CH2:3]1>CO.[Pt]>[NH2:17][C:15]1[CH:14]=[C:13]([NH:20][C:21]2[N:26]=[C:25]([O:27][CH:28]3[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]3)[CH:24]=[CH:23][N:22]=2)[CH:12]=[C:11]([C:8]2[S:7][C:6]([C:2]3([OH:1])[CH2:5][CH2:4][CH2:3]3)=[N:10][CH:9]=2)[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Nc3cc(-c4cnc(C5(O)CCC5)s4)cc([N+](=O)[O-])c3)n2)CC1
Agent: [Pt]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Nc3cc(N)cc(-c4cnc(C5(O)CCC5)s4)c3)n2)CC1
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To the product from Step 2 (320 mg, 0.563 mmol) in MeOH (2.8 mL) was added Pt/C doped with V (3% wt, 110 mg, 0.017 mmol) and the mixture was stirred under H2 balloon for 2 h. The mixture was passed through a silica gel pack and washed with DCM/MeOH. Solvent was removed in vacuo and the residue was purified using column chromatography on silica gel (0-100%, ethyl acetate: 10:1 methanol in DCM) to afford 250 mg (0.46 mmol, 82%) of tert-butyl 4-{[2-({3-amino-5-[2-(1-hydroxycyclobutyl)-1,3-thiazol-5-yl]phenyl}amino)pyrimidin-4-yl]-oxy}piperidine-1-carboxylate as yellow solid. MS ESI: [M+H]+ m/z 539.3.
Reaction SMILES: Cl.Cl.[CH3:3][Si:4]([CH3:31])([CH3:30])[CH2:5][CH2:6][O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C:23]4([CH2:27][C:28]#[N:29])[CH2:26][NH:25][CH2:24]4)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1.[OH:32][CH2:33][CH2:34][C:35]1[N:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[N:38]=[C:37]([O:45][CH:46]2[CH2:51][CH2:50][C:49](=O)[CH2:48][CH2:47]2)[CH:36]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[OH:32][CH2:33][CH2:34][C:35]1[N:40]=[C:39]([C:41]([F:44])([F:42])[F:43])[N:38]=[C:37]([O:45][CH:46]2[CH2:51][CH2:50][CH:49]([N:25]3[CH2:24][C:23]([CH2:27][C:28]#[N:29])([N:21]4[CH:22]=[C:18]([C:17]5[C:12]6[CH:11]=[CH:10][N:9]([CH2:8][O:7][CH2:6][CH2:5][Si:4]([CH3:30])([CH3:3])[CH3:31])[C:13]=6[N:14]=[CH:15][N:16]=5)[CH:19]=[N:20]4)[CH2:26]3)[CH2:48][CH2:47]2)[CH:36]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Reactant: O=C1CCC(Oc2cc(CCO)nc(C(F)(F)F)n2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCC(Oc6cc(CCO)nc(C(F)(F)F)n6)CC5)C4)c3)ncnc21
Temperature: 20 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
{3-[4-(7-{[2-(Trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (1.9 g, 3.9 mmol), and 4-{[6-(2-hydroxyethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexanone (1.3 g, 4.3 mmol), in dry tetrahydrofuran (36 mL) were stirred for 15 min under nitrogen. Sodium triacetoxyborohydride (1.7 g, 8.2 mmol) was then added. The mixture was stirred at 20° C. for 16 hours. HPLC and LCMS analysis showed clean conversion to the trans and cis products (M+H 698; 1:1 ratio). The reaction was quenched with water, concentrated, stirred with 20% KHCO3 and extracted with ethyl acetate, dried (Na2SO4), filtered, and evaporated to give 2.8 g. The isomeric products were separated by prep LCMS using a Waters instrument and a 30 mm×100 mm Xbridge C18 column; 60 mL/min; 55% CH3CN—H2O (0.1% NH4OH); 0.5 min; 4.5 gradient to 72%; 24 runs; retention time trans isomer, 4.6 min; cis isomer, 5.4 min. The isolated cis isomer contained <1% residual trans isomer. Yield 1.00 g cis isomer, 37% yield. 1H NMR (500 MHz, CDCl3; also COSY, HSQC, and HMBC): δ8.83 (s, 1H); 8.40 (s, 1H); 8.28 (s, 1H); 7.40 (m, 1H); 6.80 (m, 1H); 6.67 (s, 1H); 5.64 (s, 2H, SEM); 5.17 (m, 111, OCH); 4.01 (t, 211, OCH2); 3.74 (s, 2H, NCH); 3.59 (m, 2H, NCH); 3.55 (t, 2H, SEM); 3.38 (s, 2H, CH2CN); 2.95 (t, 211, CH2); 2.30 (m, 1H, NCH); 2.15 (m, 2H); 1.84 (m, 2H); 1.50 (m, 2H); 1.30 (m, 2H); 0.90 (t, 2H, SEM); −0.92 (s, 9H, SEM).
Reaction SMILES: [Br:1]Br.[CH2:3]([C:10]1[CH:31]=[C:30]([O:32][CH3:33])[C:13]2[N:14]([CH2:26][CH2:27][O:28][CH3:29])[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)=[N:16][C:12]=2[CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CCOC(C)=O>C(O)(=O)C>[CH2:3]([C:10]1[CH:31]=[C:30]([O:32][CH3:33])[C:13]2[N:14]([CH2:26][CH2:27][O:28][CH3:29])[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)=[N:16][C:12]=2[C:11]=1[Br:1])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: BrBr
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(Cc3ccccc3)cc(OC)c21
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(Cc3ccccc3)cc(OC)c21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.9 %

Procedure:
6 μl (0.122 mmol) bromine are added to a solution of 48 mg (0.116 mmol) 5-benzyl-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole in 6 ml glacial acetic acid. The reaction mixture is stirred at room temperature for 10 min. 25 ml EtOAc are added and this solution is washed 4N NaOH (2×), water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is recrystallized from dichloromethane/diethyl ether/hexane to afford 40 mg of the title compound as colorless crystals.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:27]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:32]=[CH:31][C:30]([CH2:33][C:34]([OH:36])=[O:35])=[CH:29][CH:28]=1.CI>O1CCCC1.O>[C:27]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:28]=[CH:29][C:30]([CH:33]([CH3:1])[C:34]([OH:36])=[O:35])=[CH:31][CH:32]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CC(C(=O)O)c1ccc(-c2ccccc2)cc1
Reaction time: 4 h
Yield: 93 %

Procedure:
In usual manner, lithium diisopropylamide in tetrahydrofuran was prepared with diisopropylamine (3.2 ml, 22.6 mmol) and 1.6 M n-butyllithium in hexane (14.2 ml, 22.6 mmol). ("Reagents for Organic Synthesis", 2, p. 249) To this lithium diisopropylamide in tetrahydrofuran was added dropwise 4-biphenylyl acetic acid (2.40 g, 11.3 mmol) in tetrahydrofuran at from -50° C. to -30° C. After the mixture was reacted at from -40° C. to -10° C. for 2 h, to the mixture was added dropwise methyliodide (1.77 g, 12.4 mmol) in tetrahydrofuran, then the temperature was rised at from -30° C. to room temperature in nature. After the mixture was stirred for 4 h, was added water and was adjusted at pH 2 with 3 N sulfonic acid, then extracted with ether. After the ether extract was dried over, then the extract was evaporated under reduced pressure to a residue, which was chromatographed to afford 2-(4-biphenylyl)propionic acid (2.38 g, 93% yield) as white crystalline material: mp 144°-145° C.