Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([C:11]([CH3:16])([CH3:15])[CH2:12][O:13][CH3:14])[CH:3]=1.[Br:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([CH:29]=1)[C:23](N(OC)C)=[O:24]>>[Br:17][C:18]1[CH:29]=[C:22]([C:23]([C:2]2[C:10]3[CH:9]=[N:8][CH:7]=[N:6][C:5]=3[N:4]([C:11]([CH3:16])([CH3:15])[CH2:12][O:13][CH3:14])[CH:3]=2)=[O:24])[CH:21]=[N:20][CH:19]=1
Reactant: COCC(C)(C)n1cc(I)c2cncnc21
Reactant: CON(C)C(=O)c1cncc(Br)c1
Product: COCC(C)(C)n1cc(C(=O)c2cncc(Br)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Preparation 64 using 5-Iodo-7-(2-methoxy-1,1-dimethyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine (Preparation 262) and 5-Bromo-N-methoxy-N-methyl-nicotinamide to afford the title compound as light brown gum in 51% yield, 3 g.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](B(O)O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[C:14]1[CH:15]=[C:16]([CH:20]=[O:21])[CH:17]=[N:18][CH:19]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+].O>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].O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:14]3[CH:15]=[C:16]([CH:20]=[O:21])[CH:17]=[N:18][CH:19]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=Cc1cncc(Br)c1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=Cc1cncc(-c2ccc3[nH]ccc3c2)c1
Temperature: 100 °C
Yield: 62.6 %

Procedure:
Indole-5-boronic acid (1 g 6.25 mmol), 5-bromopyridine-3-carboxaldehyde (1.3 g, 6.9 mmol) and PdCl2(dppf).DCM (2.2 g, 2.7 mmol) and 15 ml of dioxane were evenly distributed amongst five 5 mL microwave vessels (Smith Personal Chemistry). The mixtures were degassed (evacuate in vacuo and pressurize with nitrogen). Sodium carbonate in water (2M, 9.38 mL, 18.7 mmol) was evenly distributed amongst the reaction vessels and the mixtures degassed two more times as described above. The mixture was heated to 100° C. for 12 min in a Smith synthesizer. The samples were cooled, combined and washed with water. The aqueous phase was extracted with dichloromethane and the combined organic phases were dried over MgSO4, filtered and evaporated to give crude product. Chromatography (elution with ethyl acetate/cyclohexane) provided 870 mg of product.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[C:12]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=O)[CH:13]([CH3:15])[CH3:14].C([O-])(=O)C.[Na+]>O>[CH2:21]([O:20][C:18]([C:17]1[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:3][NH:2][C:12]=1[CH:13]([CH3:15])[CH3:14])=[O:19])[CH3:22]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: NCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1c(-c2ccccc2)c[nH]c1C(C)C
Temperature: 100 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
A mixture of 2-aminoacetophenone hydrochloride (1 equiv.), ethyl isobutyrylacetate (1.2 equiv.) and sodium acetate (2.4 equiv.) in H2O was stirred at 100° C. for 18 hours and then cooled to room temperature. The aqueous layer was decanted off and the oil was dissolved in ethyl acetate. It was then washed with water and brine and then dried to give (93%) of 2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester as a red brown oil.
Reaction SMILES: [Cl-].[CH3:2][C:3]1([CH3:10])[O:7][C@@H:6]([CH2:8][NH3+:9])[CH2:5][CH2:4]1.[Br:11][C:12]1[CH:17]=[CH:16][N:15]2[C:18]([C:21]([NH:23][C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=3[F:33])[C:27](O)=[O:28])=[O:22])=[CH:19][N:20]=[C:14]2[CH:13]=1>>[Br:11][C:12]1[CH:17]=[CH:16][N:15]2[C:18]([C:21]([NH:23][C:24]3[CH:25]=[C:26]([C:27](=[O:28])[NH:9][CH2:8][C@@H:6]4[CH2:5][CH2:4][C:3]([CH3:10])([CH3:2])[O:7]4)[CH:30]=[CH:31][C:32]=3[F:33])=[O:22])=[CH:19][N:20]=[C:14]2[CH:13]=1
Reactant: CC1(C)CC[C@H](C[NH3+])O1
Reactant: O=C(O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Agent: [Cl-]
Product: CC1(C)CC[C@@H](CNC(=O)c2ccc(F)c(NC(=O)c3cnc4cc(Br)ccn34)c2)O1

Procedure:
The title compound was prepared from (R)-(5,5-dimethyltetrahydrofuran-2-yl)methanaminium chloride (Intermediate 9B) and 3-(7-Bromoimidazo[1,2-a]pyridine-3-carboxamido)-4-fluoro benzoic acid (prepared by hydrolysis of methyl 3-(7-bromoimidazo[1,2-a]pyridine-3-carboxamido)-4-fluorobenzoate (Intermediate 1A) using NaOH) analogously to Example 7.4 step 1;
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][C@@H:15]3[CH2:17][C@H:12]2[CH2:13][N:14]3[CH3:18])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:19](OC)(OC)OC.C([O-])(=O)C.[NH4+]>CO>[CH3:18][N:14]1[CH2:13][C@@H:12]2[CH2:17][C@H:15]1[CH2:16][N:11]2[C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:19][NH:6][C:4]2=[O:5]
Reactant: CN1C[C@@H]2C[C@H]1CN2c1ccc(N)c(C(N)=O)c1
Reactant: COC(OC)OC
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Product: CN1C[C@@H]2C[C@H]1CN2c1ccc2nc[nH]c(=O)c2c1
Temperature: 120 °C
Yield: 60.8 %

Procedure:
To a solution 2-amino-5-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzamide (Intermediate 31D) (1 g, 3.83 mmol) in methanol (15 ml) was added trimethyl orthoformate (812 mg, 7.66 mmol) and ammonium acetate (0.60 g, 7.66 mmol). The vessel was sealed and the reaction heated at 120° C. for 4 hours. The methanol was then removed and the product chromatographed on silica elueting with 5% methanol in dichloromethane to afford 6-((1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)quinazolin-4(3H)-one (0.60 g, 2.33 mmol) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:24])[N:5]([CH:12]1[CH2:17][CH:16]([O:18][C:19](=[O:21])[CH3:20])[C:15](=[O:22])[NH:14][C:13]1=[O:23])[C:6]2=[O:11].[CH3:25][O:26][CH2:27][C:28](Cl)=[O:29]>O1CCCC1>[CH3:25][O:26][CH2:27][C:28]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:24])[N:5]([CH:12]1[CH2:17][CH:16]([O:18][C:19](=[O:21])[CH3:20])[C:15](=[O:22])[NH:14][C:13]1=[O:23])[C:6]2=[O:11])=[O:29]
Reactant: CC(=O)OC1CC(N2C(=O)c3cccc(N)c3C2=O)C(=O)NC1=O
Reactant: COCC(=O)Cl
Solvent: C1CCOC1
Product: COCC(=O)Nc1cccc2c1C(=O)N(C1CC(OC(C)=O)C(=O)NC1=O)C2=O

Procedure:
A solution of 3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxo-5-acetoxypiperidine (1 g, 3.5 mmol) and methoxyacetyl chloride (0.38 g, 3.5 mmol) in tetrahydrofuran (20 mL) is heated at reflux for 1 hour. The solvent is removed in vacuo to give 3-[4-(2-methoxyacetylamino)-1,3-dioxoisoindolin-2-yl]-2,6-dioxo-5-acetoxypiperidine which is further purified by column chromatography.
Reaction SMILES: S1C=CC=C1.C([Li])CCC.Cl[Si:12]([CH2:15][Cl:16])([CH3:14])[CH3:13].[NH4+].[Cl-].[CH2:19]([O:21][CH2:22][CH3:23])[CH3:20]>>[Cl:16][CH2:15][Si:12]([CH3:14])([CH3:13])[C:19]1[O:21][CH:22]=[CH:23][CH:20]=1
Reactant: C[Si](C)(Cl)CCl
Reactant: CCOCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: c1ccsc1
Product: C[Si](C)(CCl)c1ccco1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Dissolve thiophene (4.76 g, 56.5 mmol) in dry diethyl ether. Add n-butyl lithium (62.2 mmol) at room temperature and stir overnight under nitrogen. Cool the mixture to 0° C., add chloro(chloromethyl)dimethylsilane (8.1 g, 56.5 mmol, in 2.5 mL diethyl ether) slowly and stir overnight under nitrogen. Add saturated NH4Cl solution to the reaction mixture. Drain off the aqueous phase and wash the organic phase with brine. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Distill the residue in a kugelrohr to afford chloromethyl(dimethyl)furylsilane (4.4 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=O)[CH3:11].[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][C:22](O)=[O:23])=[CH:17][CH:16]=1>>[CH3:9][O:8][C:6]1[CH:7]=[C:2]2[C:3]([C:10]([CH3:11])=[C:21]([C:18]3[CH:19]=[N:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)[C:22](=[O:23])[O:1]2)=[CH:4][CH:5]=1
Reactant: COc1ccc(CC(=O)O)cn1
Reactant: COc1ccc(C(C)=O)c(O)c1
Product: COc1ccc2c(C)c(-c3ccc(OC)nc3)c(=O)oc2c1

Procedure:
The title product was prepared as a white solid according to the procedure described in Example 9 using 1-(2-hydroxy-4-methoxy-phenyl)-ethanone and (6-methoxy-pyridin-3-yl)-acetic acid as the starting material.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[F:11][C:12]([F:18])([F:17])[C:13]1([NH2:16])[CH2:15][CH2:14]1.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)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:16][C:13]2([C:12]([F:18])([F:17])[F:11])[CH2:15][CH2:14]2)=[O:10])=[N:6][CH:7]=1
Reactant: NC1(C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(Br)cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1(C(F)(F)F)CC1)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
A mixture of 5-bromopyridine-2-carboxylic acid (150 mg, 0.74 mmol), 1-(trifluoromethyl)cyclopropanamine (93 mg, 0.74 mmol) (Oakwood, Cat. #: 038175), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (345 mg, 0.780 mmol) and triethylamine (310 μL, 2.2 mmol) in methylene chloride (1 mL) was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in dichloromethylene (0-5%) to afford the desired product (124 mg). LCMS (M+H)+: m/z=309.0.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[N:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)CCCOc1ccccc1C=O
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)CCCOc1ccccc1C=Nc1ccccc1
Yield: 45.4 %

Procedure:
A solution of 32.5 g (0.156 mole) of 2-(3-dimethylaminopropoxy)benzaldehyde and 14.6 g (0.157 mole) of aniline in 150 ml of toluene is refluxed for 9 hours. Water which is formed very slowly is collected in a Dean-Stark trap. The bulk of solvent is removed on a rotary evaporator and the oily residue is fractionated to give 20.0 g of product; boiling point 165°-170° C/0.2 mm of Hg.
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][CH:4]=[CH:5][C:6](=[O:8])[CH3:7].[CH2:10]([Mg]Br)[C:11]#[CH:12]>>[CH3:7][C:6]([OH:8])([CH2:5][CH2:4][CH:3]=[C:2]([CH3:9])[CH3:1])[CH2:12][C:11]#[CH:10]
Reactant: C#CC[Mg]Br
Reactant: CC(=O)C=CC=C(C)C
Product: C#CCC(C)(O)CCC=C(C)C

Procedure:
Reaction of this ketone with propargyl magnesium bromide provides 4,8-dimethyl-4-hydroxy non-7-ene-1-yne. This alcohol is protected with trimethylsilyl chloride and converted to trans vinyl tin derivative 4,7-dimethyl-4-trimethylsiloxy-non-8-ene-1-yne which is converted to the corresponding prostaglandin by the methods described in U.S. Pat. Nos. 4,322,543 and 4,271,314 to provide methyl 7-[3α-hydroxy-2β-(4-hydroxy-4,8-dimethyl-1,5,7-trans,trans,trans-nonatrienyl)-5-oxocyclopentane]-1α-hept-4-cis-enoate having the formula ##STR14##
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([O:20][CH3:21])[CH:12]=2)[CH2:4][CH2:3]1>CO.[Pd]>[CH3:21][O:20][C:13]1[CH:12]=[C:11]([O:10][CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)[CH:16]=[CH:15][C:14]=1[NH2:17]
Reactant: COc1cc(OCCN2CCN(C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1cc(OCCN2CCN(C)CC2)ccc1N
Yield: 85.1 %

Procedure:
1-methyl-4-(2-{[3-(methyloxy)-4-nitrophenyl]oxy}ethyl)piperazine (1.7 g, 5.76 mmol) was dissolved in methanol (75 mL) and cycled through the H-Cube using a Pd/C cartridge. After an hour of cycling through the system the solvent was removed under reduced pressure to afford 2-(methyloxy)-4-{[2-(4-methyl-1-piperazinyl)ethyl]oxy}aniline as a purple sticky solid (1.3 g, 4.9 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.14 (s, 3 H) 2.18-2.48 (m, 8 H) 2.61 (t, J=5.96 Hz, 2 H), 3.73 (s, 3 H) 3.93 (t, J=5.91 Hz, 2 H) 4.23 (br. s., 2 H) 6.28 (dd, J=8.43, 2.57 Hz, 1) 6.45 (d, J=2.57 Hz, 1 H) 6.49-6.57 (m, 1 H).
Reaction SMILES: [C:1]([N:4]([CH2:15][CH:16]([O:37]C(=O)C)[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)[C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:1]([N:4]([CH2:15][CH:16]([OH:37])[CH2:17][N:18]1[CH2:19][CH2:20][N:21]([CH:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:22][CH2:23]1)[C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(CN1CCN(C(c2ccccc2)c2ccccc2)CC1)CN(C(C)=O)c1cccc2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)N(CC(O)CN1CCN(C(c2ccccc2)c2ccccc2)CC1)c1cccc2ncccc12
Reaction time: 8 h
Yield: 98.6 %

Procedure:
In a mixed solvent of 10 ml of methanol and 5 ml of water were dissolved 0.55 g of 5-[N-acetyl-(2-acetoxy-3-(4-diphenylmethylpiperazine-1-yl)propylamino)]quinoline and 0.5 g of potassium carbonate, and the liquid was allowed to stand at room temperature overnight. The liquid was extracted with methylene chloride, and the extract was then dried with anhydrous magnesium sulfate and was concentrated to obtain 0.5 g of the desired compound.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([CH3:36])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([NH:26][C@H:27]([C:29]([O:31]C(C)(C)C)=[O:30])[CH3:28])=[O:25])=[CH:18][CH:17]=3)[NH:8][C:7]=2[N:6]([CH2:37][CH2:38][CH3:39])[C:5]1=[O:40])[CH2:2][CH3:3].O1CCOCC1>Cl>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([CH3:36])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([NH:26][C@H:27]([C:29]([OH:31])=[O:30])[CH3:28])=[O:25])=[CH:18][CH:17]=3)[NH:8][C:7]=2[N:6]([CH2:37][CH2:38][CH3:39])[C:5]1=[O:40])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)c2nc(C(C)Cc3ccc(OCC(=O)N[C@@H](C)C(=O)OC(C)(C)C)cc3)[nH]c2n(CCC)c1=O
Agent: Cl
Solvent: C1COCCO1
Product: CCCn1c(=O)c2nc(C(C)Cc3ccc(OCC(=O)N[C@@H](C)C(=O)O)cc3)[nH]c2n(CCC)c1=O

Procedure:
Dissolve (-)-N-[[[4-[2-(2,3,6,9-tetrahydro-1,3-dipropyl-2,6-dioxo-1H-purin-8-yl)propy]phenyl]oxy]acetyl]-L-alanine, t-butyl ester (5.55 g, 10 mmol) in 4N hydrochloric acid in dioxane (25 mL, 100 mmol) and stir for several hours. Evaporate the solvent in vacuo and purify by ion-exchange chromatography to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.CC1(C)COB([C:23]2[CH:24]=[CH:25][C:26]([F:37])=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=3)[CH:28]=2)OC1>>[F:37][C:26]1[CH:25]=[CH:24][C:23]([C:2]2[C:3]3[C:8](=[N:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[CH:28][C:27]=1[C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=1
Reactant: CC1(C)COB(c2ccc(F)c(-c3ccc(C#N)cc3)c2)OC1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Product: N#Cc1ccc(-c2cc(-c3ccnc4nc(C(F)(F)F)ccc34)ccc2F)cc1
Yield: 24.3 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 5′-(5,5-dimethyl[1,3,2]dioxaborinan-2-yl)-2′-fluorobiphenyl-4-carbonitrile (87 mg, 0.28 mmol) as described in Example 7 part g), affording 2′-fluoro-5′-(7-trifluoromethyl[1,8]naphthyridin-4-yl)biphenyl-4-carbonitrile (21 mg, 25%). δH (360 MHz, CDCl3) 7.41-7.46 (1H, m), 7.52-7.60 (3H, m), 7.71-7.82 (4H, m), 7.85 (1H, d, J 8.4), 8.52 (1H, d, J 8.8), 9.30 (1H, d, J 4.6). m/z (ES+) 394 [MH]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH:13]2[CH2:25]O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[K+]>C(Cl)(Cl)(Cl)Cl.O>[Cl:3][CH2:25][CH:13]1[CH2:14][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:16][CH2:17][N:12]1[CH2:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1

Procedure:
To a solution of 10.1 ml of thionyl chloride in 50 ml of carbon tetrachloride was added, with stirring, a solution of 22.15 g of 1,4-bis(phenylmethyl)-2-piperazinemethanol in 120 ml of carbon tetrachloride. This mixture was stirred in an oil bath at 70° C. for one hour, then cooled in an ice bath and a solution of 17.1 g of potassium hydroxide in 50 ml of water was added. The mixture was extracted several times with dichloromethane. The extracts were combined, filtered through hydrous magnesium silicate and evaporated. The residual gum was dissolved in warm heptane, filtered and evaporated to an oil which crystallized on standing, giving 17.94 g of 2-chloromethyl-1,4-bis(phenylmethyl)piperazine, mp 54°-56° C.
Reaction SMILES: [Na].[Br:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5](F)[CH:4]=1.[CH2:15]([OH:17])[CH3:16]>>[CH2:10]([O:9][C:7](=[O:8])[C:6]1[CH:12]=[CH:13][C:3]([Br:2])=[CH:4][C:5]=1[O:17][CH2:15][CH3:16])[CH3:11]
Reactant: CCOC(=O)c1ccc(Br)cc1F
Reactant: CCO
Agent: [Na]
Product: CCOC(=O)c1ccc(Br)cc1OCC
Temperature: 0 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
Sodium (1.815 g, 78.9 mmol, Aldrich) was cut into small pieces and added to ethanol (100 mL). After all the pieces were dissolved, the clear solution was added to a solution of ethyl 4-bromo-2-fluoro-benzoate (13 g, 52.6 mmol) in ethanol (20 mL) cooled to 0° C. The ice bath was then removed and the mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated in vacuo, and the residue was taken in water and 20% ethyl acetate-hexane. The organic layer was washed with saturated solution of sodium bicarbonate, brine, and dried over anhydrous sodium sulfate. The solids were filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (120 g of silica gel, eluting with 10-15% ethyl acetate in hexane) gave 4-bromo-2-ethoxy-benzoic acid ethyl ester as white solids (11.020 g, 77%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH:13]=[C:12]([C:14]([OH:16])=O)[N:11]=[CH:10]2)[CH:4]=1.[NH:19]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20]1.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)CC)C>CN(C=O)C>[F:17][C:2]([F:1])([F:18])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH:13]=[C:12]([C:14]([N:19]3[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:20]3)=[O:16])[N:11]=[CH:10]2)[CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=C(O)c1cn(-c2cc(C(F)(F)F)ccn2)cn1
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(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)c2cn(-c3cc(C(F)(F)F)ccn3)cn2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[4-(trifluoromethyl)pyridin-2-yl]-1H-imidazole-4-carboxylic acid (120 mg, 0.47 mmol) and tert-butyl (3S)-pyrrolidin-3-ylcarbamate (87 mg, 0.47 mmol) in DMF (3 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (210 mg, 0.47 mmol) followed by triethylamine (0.20 mL, 1.4 mmol). The reaction was stirred at room temperature overnight and purified by HPLC to give the title compound. MS (M+H) 426.3.
Reaction SMILES: CN(C=O)C.[Br:6][C:7]1[C:15]2[N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[NH:12][C:11]=2[CH:10]=[C:9]([N+:19]([O-:21])=[O:20])[CH:8]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:25]=1[CH3:34].C(=O)([O-])[O-].[K+].[K+]>O>[Br:6][C:7]1[C:15]2[N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[C:25]=3[CH3:34])[C:11]=2[CH:10]=[C:9]([N+:19]([O-:21])=[O:20])[CH:8]=1
Reactant: CC(C)c1nc2c(Br)cc([N+](=O)[O-])cc2[nH]1
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Cn2c(C(C)C)nc3c(Br)cc([N+](=O)[O-])cc32)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.8 %

Procedure:
To a 100 mL round bottomed flask containing DMF (50 mL) was added 4-bromo-2-isopropyl-6-nitro-1H-benzo[d]imidazole (4.1 g, 14.43 mmol), 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (3.6 mL, 21.34 mmol) and potassium carbonate (5.98 g, 43.3 mmol). The resultant suspension was heated to 50° C. and after stirring for 30 minutes the mixture was allowed to cool to rt and diluted with 100 mL H2O. The mixture was stirred overnight and the next day a black filterable solid was isolated by filtration providing crude 4-bromo-2-isopropyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-nitro-1H-benzo[d]imidazole (7.1 g, 15.56 mmol, 108% yield). MS (ES+) m/e: 455.1, 455.9 [M+H]+
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CS([C:11]1[N:12]=[C:13]([O:27][CH2:28][CH2:29][CH3:30])[C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[O:17][C:15]=2[N:16]=1)(=O)=O.[CH:31]1([OH:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>CN(C=O)C>[CH:31]1([O:37][C:11]2[N:12]=[C:13]([O:27][CH2:28][CH2:29][CH3:30])[C:14]3[N:19]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=4)[O:17][C:15]=3[N:16]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: OC1CCCCC1
Reactant: CCCOc1nc(S(C)(=O)=O)nc2oc(-c3cccc(C)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCOc1nc(OC2CCCCC2)nc2oc(-c3cccc(C)c3)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.5 %

Procedure:
113 mg of cesium carbonate and 100 mg of 5-methanesulfonyl-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine were added to a solution of 29 mg of cyclohexanol in 3 ml of DMF. The mixture was stirred at room temperature for 18 h. After filtration, the solvent was distilled off in vacuo, and the product was isolated via preparative HPLC to yield 10 mg of the title compound.
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][C@H:6]([N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])[C:7]([O:9]CC1C=CC=CC=1)=[O:8])=[O:2]>C(OCC)(=O)C.[H][H].[Pd]>[CH:1]([CH2:3][CH2:4][CH2:5][C@H:6]([N:17]1[C:18](=[O:27])[C:19]2=[CH:26][CH:25]=[CH:24][CH:23]=[C:20]2[C:21]1=[O:22])[C:7]([OH:9])=[O:8])=[O:2]
Reactant: [H][H]
Reactant: O=CCCC[C@@H](C(=O)OCc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=CCCC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Yield: 102.4 %

Procedure:
Benzyl 5-formyl-2(S)-phthalimidopentanoate (4.72 g) was dissolved in 230 ml of ethyl acetate and hydrogenated at 5 psig of hydrogen over 0.82 g of 10% palladium on carbon. After the uptake of 1 equivalent of hydrogen, catalyst was removed by filtration. Removal of solvent afforded 3.64 g of 5-formyl-2(S)-phthalimidopentanoic acid.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24]1[N:25]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([Cl:36])[CH:31]=2)[N:26]=[C:27]([CH3:29])[CH:28]=1)=[O:4].[OH-].[Li+]>>[Cl:36][C:32]1[CH:31]=[C:30]([N:25]2[C:24]([N:6]3[CH2:7][C@H:8]([S:10]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=4[C:20]([F:21])([F:22])[F:23])(=[O:11])=[O:12])[CH2:9][C@H:5]3[C:3]([OH:4])=[O:2])=[CH:28][C:27]([CH3:29])=[N:26]2)[CH:35]=[CH:34][N:33]=1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1c1cc(C)nn1-c1ccnc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)O)n(-c2ccnc(Cl)c2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-1-[2-(2-chloro-pyridin-4-yl)-5-methyl-2H-pyrazol-3-yl]-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as yellow solid. MS (ESI): m/z=533.1 [M+H]+.