Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.Cl.[N:34]1[CH:39]=[CH:38][C:37]([C:40]2([NH2:43])[CH2:42][CH2:41]2)=[N:36][CH:35]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:43][C:40]5([C:37]6[CH:38]=[CH:39][N:34]=[CH:35][N:36]=6)[CH2:42][CH2:41]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: NC1(c2ccncn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccncn5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.096 g, 0.221 mmol, 1.0 eq), 1-(pyrimidin-4-yl)cyclopropanamine HCl (0.03 g, 0.221 mmol, 1.0 eq) in DMF at 0° C. was added TEA (0.12 g, 1.188 mmol, 5.0 eq) and BOP reagent (0.146 g, 0.330 mmol, 1.5 eq). The reaction mixture was stirred as RT overnight. The reaction mixture was diluted with water, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel (60-120) column chromatography using 3% MeOH/CHCl3 as eluent. Yield: 0.070 g (57.33%). 1H NMR (400 MHz, CD3OD): δ 8.99 (d, J=1.0 Hz, 1H), 8.61 (d, J=5.6 Hz, 1H), 7.99-7.93 (m, 2H), 7.79 (s, 1H), 7.69-7.54 (m, 3H), 7.39-7.23 (m, 3H), 7.16 (s, 1H), 4.08 (s, 3H), 2.96 (s, 3H), 2.34 (s, 3H), 1.85-1.82 (m, 2H), 1.61-1.49 (m, 2H). LCMS: (ES+) m/z=551.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-])=O)[CH2:9][N:8]([CH:16]([CH3:19])[CH2:17][CH3:18])[CH2:7][CH2:6]2.[H][H]>C(OCC)(=O)C.[Pd].CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[NH2:13])[CH2:9][N:8]([CH:16]([CH3:19])[CH2:17][CH3:18])[CH2:7][CH2:6]2
Reactant: [H][H]
Reactant: CCC(C)N1CCc2cc(OC)c([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(C)N1CCc2cc(OC)c(N)cc2C1
Yield: 96.1 %

Procedure:
6-(methyloxy)-2-(1-methylpropyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline (0.23 g, 0.87 mmol) was dissolved in ethyl acetate (5 mL), treated with 10% palladium on carbon (50 mg, Aldrich), and then diluted with methanol (10 mL). The mixture was stirred under 60 psi of hydrogen pressure for 16 h in a Fischer-Porter apparatus. The pressure was released, the reaction vessel evacuated, and back-filled with nitrogen twice. The mixture was filtered through celite and the filtrate was concentrated to provide 6-(methyloxy)-2-(1-methylpropyl)-1,2,3,4-tetrahydro-7-isoquinolinamine (196 mg, 96%). 1H NMR (400 MHz, CDCl3) δ ppm 0.90 (t, J=7.4 Hz, 3 H), 1.02 (d, J=6.6 Hz, 3 H), 1.28-1.40 (m, 1 H), 1.59-1.69 (m, 1 H), 2.56-2.75 (m, 5 H), 3.48-3.67 (m, 4 H), 3.77 (s, 3 H), 6.35 (s, 1 H), 6.47 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH2:13]/[CH:14]=[CH:15]/[CH3:16])[C:3]([O:5]CC1C=CC=CC=1)=[O:4]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH2:13][CH2:14][CH2:15][CH3:16])[C:3]([OH:5])=[O:4]
Reactant: C/C=C/CC(C)(C(=O)OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCC(C)(C(=O)O)c1ccccc1
Reaction time: 72 h
Yield: 99.6 %

Procedure:
A solution of Example 27A (2.45 g, 8.32 mmol) in ethyl acetate (20 mL) was treated with 10% palladium on carbon (0.245 g, 10 weight percent) and stirred under a hydrogen balloon for 72 hours. The vessel was purged with nitrogen gas and the mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give the title compound (1.71 g, 99%). 1H NMR (300 MHz, CDCl3): δ ppm 0.87 (m, 3 H) 1.24 (m, 4 H) 1.57 (m, 3H) 1.98 (m, 2 H) 7.32 (m, 5 H). MS (DCI NH3+) m/z 224 (M+NH4)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])[C:5]([Cl:23])=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:40]=[CH:39][C:28]2[N:29]([CH2:37][CH3:38])[C:30](=[O:36])[CH2:31][CH2:32][C:33]([CH3:35])([CH3:34])[C:27]=2[CH:26]=1.Cl>O1CCOCC1.COCCO>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])=[N:7][C:2]([NH:24][C:25]2[CH:40]=[CH:39][C:28]3[N:29]([CH2:37][CH3:38])[C:30](=[O:36])[CH2:31][CH2:32][C:33]([CH3:34])([CH3:35])[C:27]=3[CH:26]=2)=[N:3][CH:4]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCC(C)(C)c2cc(N)ccc21
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: CCN1C(=O)CCC(C)(C)c2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OC)n3)ccc21
Yield: 92.3 %

Procedure:
Combined (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (113 mg, 0.3185 mmol), 7-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (74 mg, 0.3185 mmol), 4 N HCl in dioxane (100 ul) and 2-methoxyethanol (4 mL). Heated reaction to 120° C. for 3 hours. Evaporated off solvent and purified with normal phase chromatography to yield a yellow solid, 7-[5-Chloro-4-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-2-ylamino]-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (162 mg, 92%). LCMS: m/z=551.00 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.21 (d, 1H, J=9.4 Hz), 8.04 (s, 1H), 7.69 (d, 1H, J=9.4 Hz), 7.60 (s, 1H), 7.34 (s, 1H), 7.19 (d, 1H, J=8.1 Hz), 6.92 (s, 1H), 6.56 (s, 1H), 6.49 (d, 1H, J=8.6 Hz), 3.94 (s, 3H), 3.90 (m, 4H), 3.82 (m, 2H), 3.16 (m, 4H), 2.32 (m, 2H), 2.06 (m, 2H), 1.33 (m, 9H).
Reaction SMILES: Cl.[I:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[CH3:11][C:12]([O:15][C:16]([NH:18][C@H:19]([C:26](O)=[O:27])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:17])([CH3:14])[CH3:13].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:12]([O:15][C:16]([NH:18][C@H:19]([C:26]([NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([I:2])=[CH:4][CH:5]=1)=[O:27])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:17])([CH3:13])([CH3:11])[CH3:14]
Reactant: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCc1ccc(I)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.7 %

Procedure:
A solution of 4-iodobenzylamine hydrochloride (2.965 g, 11.0 mmol), Boc-Glu(OMe)-OH.DCHA (4.426 g, 10.0 mmol), EDCI (2.301 g, 10.0 mmol), HOBt (1.351 g, 10.0 mmol) in DCM (100 mL) containing DIPEA (5.23 mL) was stirred at room temperature under nitrogen for 20 h. The reaction mixture was diluted with DCM, washed with 1N HCl, sat. NaHCO3 solution, and brine. The solvent was evaporated under reduced pressure to give a crude product, which was purified by flash chromatography eluting with hexane/ethyl acetate (3:1) to give (S)-methyl 4-(tert-butoxycarbonylamino)-5-(4-iodobenzylamino)-5-oxopentanoate (3.653 g, 77%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 6.65 (s, 1H), 5.24 (brs, 1H), 4.39 (t, J=5.4 Hz, 2H), 4.15 (m, 1H), 3.70 (s, 3H), 2.57-2.37 (m, 2H), 2.20-2.11 (m, 1H), 1.99-1.90 (m, 1H), 1.44 (s, 9H); MS (ESI), 499 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:27][CH3:28])[C:9]3[CH:14]=[C:13]([CH2:15][C:16]4[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=4)[C:19]([O:21]C)=[O:20])[N:12]=[CH:11][C:10]=3[N:26]=2)=[N:4][O:5][N:6]=1.[Li+].[OH-]>CO.O>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:27][CH3:28])[C:9]3[CH:14]=[C:13]([CH2:15][C:16]4[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=4)[C:19]([OH:21])=[O:20])[N:12]=[CH:11][C:10]=3[N:26]=2)=[N:4][O:5][N:6]=1
Reactant: CCn1c(-c2nonc2N)nc2cnc(Cc3cccc(C(=O)OC)c3)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCn1c(-c2nonc2N)nc2cnc(Cc3cccc(C(=O)O)c3)cc21
Temperature: 80 °C
Yield: 83.6 %

Procedure:
To a solution of the product from Step 1 (85 mg, 0.22 mmol) in MeOH (12 ml) and water (4 ml), was added LiOH (40 mg, 0.95 mmol). This mixture was then heated to 80° C. for 2 h. Reaction mixture was concentrated, dissolved in 10 ml water, acidified with 1 N HCl to pH=5, then filtered and washed with water to afford a pale yellow solid (67 mg, 82%). MS (ES+) m/e 365 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.IC.[C:12](=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5](=[O:8])[N:6]([CH3:12])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(=O)[nH]cc1Br
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: Cc1cc(=O)n(C)cc1Br
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-4-methylpyridin-2(1H)-one (164 mg, 0.872 mmol) and iodomethane (124 mg, 0.872 mmol) in DMSO (3 mL) was added potassium carbonate (121 mg, 0.872 mmol). The mixture was stirred at 60° C. overnight, filtered, and purified via preparative HPLC, eluting with a gradient of 20-70% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA) to give the title compound.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:14])([CH3:13])[C@@H:8]1[CH2:12][CH2:11][CH2:10][NH:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([CH2:22]Cl)[CH:21]=1.[H-].[Na+]>>[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([CH2:22][N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[C:7]([CH3:14])([CH3:13])[O:6][SiH2:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:21]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1CCCN1
Reactant: ClCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1CCCN1Cc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediates A-12 [B], (S)-2-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidine (intermediate A-3 [A]) was reacted with 3-bromo-5-chloromethyl-pyridine (intermediate A-12 [A]) in presence of NaH to give the title compound as a yellow solid. MS: 385.2, 387.2 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=2[S:5][CH:4]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]2[S:5][CH:4]=[C:3]([CH2:2][N:23]3[CH2:22][CH2:21][N:20]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[F:13])[CH2:25][CH2:24]3)[C:7]=2[CH:8]=1
Reactant: Clc1ccc2scc(CBr)c2c1
Reactant: Fc1ccccc1N1CCNCC1
Product: Fc1ccccc1N1CCN(Cc2csc3ccc(Cl)cc23)CC1

Procedure:
3-(Bromomethyl)-5-chloro-1-benzothiophene and 1-(2-fluorophenyl)piperazine were processed as described in Example 2 to provide the title compound. 1H NMR (d6-DMSO, 300 MHz) δ 2.65 (m, 2H), 3.02 (m, 6H), 3.78 (s, 2H), 6.92-7.10 (m, 4H), 7.40 (dd, 1H, J=8.7, 1.5), 7.67 (s, 1H), 7.78 (d, 1H, J=8.7 Hz), 8.06 (d, 1H, J=1.5 Hz). MS (DCI/NH3) m/z 361.0 (M+H)+. Anal. Calcd for C19H18N2SClF: C, 63.24;H, 5.03; N, 7.76. Found: C, 63.17;H, 4.90; N, 7.67.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][CH:18]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:27].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][Br:27])=[CH:19][CH:18]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: O=c1cc(OCc2ccccc2)ncn1CCc1ccc(CO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1cc(OCc2ccccc2)ncn1CCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 200 mg (0.60 mmol) 6-benzyloxy-3-[2-(4-hydroxymethyl-phenyl)-ethyl]-3H-pyrimidin-4-one (example 20.1a) in 2.0 mL of DCM is added at 0° C. 29 μL (0.30 mmol) phosphorus tribromide. The mixture is stirred 2 h at RT and is then added to 5% aqueous NaHCO3-solution. The layers are separated, the aqueous phase is extracted with DCM and the organic phase is washed with water. The combined organic phase is dried over MgSO4, filtered and the solvent is evaporated to afford the product.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:30]1([CH3:39])[C:31]([C:36](Cl)=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=1>ClCCl>[CH:17]1([N:8]([C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([NH:1][C:36](=[O:37])[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH3:39])=[CH:3][CH:4]=2)[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: COc1ccc(N(C(=O)c2ccc(N)cc2)C2CCCC2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(N(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.4 %

Procedure:
To a solution of N-(4-aminobenzoyl)-N-cyclopentyl-p-anisidine (870 mg) and pyridine (443 mg) in dichloromethane (20 ml) was added o-toluoyl chloride (868 mg) at 0° C. Then the mixture was stirred for 3 hours at ambient temperature. The reaction mixture was concentrated and diluted with ethyl acetate and the solution was washed with water, IN-hydrochloric acid and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (SiO2 20 g, ethyl acetate:n-hexane=1:2). The eluent was concentrated and triturated with diethyl ether to give N-cyclopentyl-N-[4-(2-methylbenzoylamino)benzoyl]-p-anisidine (750 mg).
Reaction SMILES: Cl[C:2]1[C:3]([C:24]([NH:26]C2C=CC=CC=2)=O)=[CH:4][C:5]2[N:6](C(CC3CCC(F)(F)CC3)=C(C(F)(F)F)[N:10]=2)[CH:7]=1.[Cl:33]C1C(C(O)=O)=CC2N(C(CC3CCC(F)(F)CC3)=C(C(F)(F)F)N=2)C=1.NC1C=CC=CC=1>>[NH2:10][C:5]1[C:4]([Cl:33])=[C:3]([C:24]#[N:26])[CH:2]=[CH:7][N:6]=1
Reactant: O=C(Nc1ccccc1)c1cc2nc(C(F)(F)F)c(CC3CCC(F)(F)CC3)n2cc1Cl
Reactant: O=C(O)c1cc2nc(C(F)(F)F)c(CC3CCC(F)(F)CC3)n2cc1Cl
Solvent: Nc1ccccc1
Product: N#Cc1ccnc(N)c1Cl

Procedure:
Compound 107 (40.9 mg, yield 69%) was obtained in the same manner as in step 4 of Example 21, using 6-chloro-3-(4,4-difluorocyclohexylmethyl)-2-trifluoromethylimidazo[1,2-a]pyridine-7-carboxylic acid obtained in step 3, and aniline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1.[Cl:27][C:28]1[N:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C1COCC1>[Cl:19][C:6]1[CH:5]=[C:4]([NH:20][S:34]([C:31]2[CH:32]=[N:33][C:28]([Cl:27])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1)c1ccc(Cl)nc1
Yield: 55.8 %

Procedure:
The title compound was prepared using the method of example 94, starting with 3,5-dichloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (90) (150 mg, 0.47 mmol), pyridine (Aldrich, 0.19 mL, 2.34 mmol) and 6-chloro-pyridine-3-sulfonyl chloride (Qorpark, 109 mg, 0.52 mmol) in THF. 130 mg (56%) of 96 was obtained as a pale yellow solid.
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[CH2:3][C:4]1[C:9]([CH2:10]2)=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:5]=1[O:14][CH3:15].[F:16][C:17]([F:31])([F:30])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1.C(O)C>C1(C)C(C)=CC=CC=1>[CH3:15][O:14][C:5]1[CH:6]=[CH:7][C:8]([O:12][CH3:13])=[C:9]2[C:4]=1[CH2:3][C@@H:2]([N:27]1[CH2:26][CH2:25][N:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:30])([F:31])[F:16])[CH:19]=3)[CH2:29][CH2:28]1)[C@H:11]([OH:1])[CH2:10]2
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: COc1ccc(OC)c2c1CC1OC1C2
Solvent: Cc1ccccc1C
Solvent: CCO
Product: COc1ccc(OC)c2c1C[C@@H](O)[C@H](N1CCN(c3cccc(C(F)(F)F)c3)CC1)C2
Yield: 36.7 %

Procedure:
A solution of 10.3 g of 2,3-epoxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene, 11.5 g of N-(α,α,α-trifluoro-m-tolyl)piperazine, and 2 ml of absolute ethanol in 100 ml of xylene is refluxed for 7 days. The reaction mixture is concentrated in vacuo, and the residue is triturated with ether to give 11.9 g of crude product. Recrystallization from ethyl acetate gives 8.0 g of the title compound, melting point 184°-187° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[Pd].CO>[Si:19]([O:18][CH2:17][CH:13]1[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)OCC1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCC1CCCNC1
Yield: 95.6 %

Procedure:
10% palladium on activated carbon (1.32 g) was added to 1-(benzyloxycarbonyl)-3-(tert-butyldimethylsilyloxymethyl)piperidine (13.2 g, 36.3 mmol) in methanol (130 mL). The mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. Subsequently, the mixture was filtered through Celite, followed by evaporation of the solvent to give 7.96 g (96%) of the desired compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][CH:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH3:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]([N:24]2[CH2:25][CH2:26][N:21]([CH:19]([CH3:20])[CH3:18])[CH2:22][CH2:23]2)=[O:17])[CH2:13][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3 g (12 mmol) 4-tert-butoxycarbonylamino-trans-cyclohexane carboxylic acid (commercially available), 1.74 g (14 mmol) 1-(2-propyl)-piperazine (commercially available), 4.75 g (15 mmol) TBTU and 3.64 g (36 mmol) NEt3 in 10 ml DMF was stirred for 3 h at room temperature. After evaporation the residue was washed with 1N NaHCO3 solution, extracted with DCM and the combined organic layers dried with MgSO4 and evaporated to dryness to yield 4.56 g (94%) of the title compound. MS (m/e): 354.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19](O)=[O:20])=[CH:12][N:11]3[C:25]=2[C:26](=[O:29])[NH:27][CH3:28])=[CH:4][CH:3]=1.CN(C=O)C.[CH3:35][C:36]([NH2:39])([CH3:38])[CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CO>[C:36]([NH:39][C:19]([C:18]1[CH:17]=[C:16]([C:13]2[CH:14]=[CH:15][C:10]3[N:11]([C:25]([C:26]([NH:27][CH3:28])=[O:29])=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:9]=3)[CH:12]=2)[CH:24]=[CH:23][CH:22]=1)=[O:20])([CH3:38])([CH3:37])[CH3:35]
Reactant: CC(C)(C)N
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)nc2ccc(-c3cccc(C(=O)O)c3)cn12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)nc2ccc(-c3cccc(C(=O)NC(C)(C)C)c3)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
3-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)imidazo[1,2-a]pyridin-6-yl)benzoic acid (40 mg, 0.10 mmol) was slurried into DMF (0.7 mL) and TEA (0.1 mL). To this slurry was added 2-methylpropan-2-amine (11.27 mg, 0.154 mmol) and then HATU (59 mg, 0.15 mmol) (solution became yellow). The reaction was stirred at rt overnight (complete by LCMS). The reaction was diluted with MeOH (0.7 mL), filtered and purified by prep HPLC (acetonitrile/water, with 10 mM ammoniun acetate buffer) to yield 6-(3-(tert-butylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide (19.6 mg, 0.042 mmol, 41% yield) as a white solid. 1H NMR (500 MHz, CD3OD) δ ppm 9.25 (br s, 1H), 8.08 (t, J=1.8 Hz, 1H), 7.90 (dd, J=9.2, 1.8 Hz, 1H), 7.88-7.85 (m, 1H), 7.84-7.82 (m, 1H), 7.81-7.78 (m, 2H), 7.77 (br d, J=9.2 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.29 (t, J=8.9 Hz, 2H), 2.69 (s, 3H), 1.52 (s, 9H). LC-MS retention time 1.39 min; m/z 443 (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[C:9]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[O:19]=[C:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][CH:30]=O)=[CH:28][C:23]=2[CH2:22][O:21]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][S:2][C:3]1[CH:10]=[C:9]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][N:16]([CH2:30][CH2:29][C:27]3[CH:26]=[CH:25][C:24]4[C:20](=[O:19])[O:21][CH2:22][C:23]=4[CH:28]=3)[CH2:17][CH2:18]2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: O=CCc1ccc2c(c1)COC2=O
Reactant: CSc1cc(CCN2CCNCC2)ccc1C#N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CSc1cc(CCN2CCN(CCc3ccc4c(c3)COC4=O)CC2)ccc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(methylthio)-4-(2-piperazin-1-ylethyl)benzonitrile (0.69 mmol) in 20 mL of DCM was added (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (180 mg, 1.03 mmol) and NaBH(OAc)3 (580 mg, 2.8 mmol), and the mixture was stirred at room temperature overnight. The reaction was diluted with DCM, and washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to give 2-(methylthio)-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H-NMR (400 MHz, CDCl3) δ ppm 7.82 (d, J=8.6 Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.33˜7.37 (m, 2H), 7.16 (s, 1H), 7.02˜7.05 (m, 1H), 5.27 (s, 2H), 2.49˜3.01 (m, 19H). (0.55 μM)
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:4]([F:16])[CH:3]=1.CS([O-])(=O)=O.[C:22]([O:27][CH3:28])(=[O:26])[CH:23]([CH3:25])O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH:23]([CH3:25])[C:22]([O:27][CH3:28])=[O:26])=[CH:11][CH:12]=2)=[C:4]([F:16])[CH:3]=1
Reactant: Oc1ccc(Oc2ccc(Br)cc2F)cc1
Reactant: COC(=O)C(C)O
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C(C)Oc1ccc(Oc2ccc(Br)cc2F)cc1
Yield: 189.6 %

Procedure:
A mixture of the 4-(4-bromo-2-fluorophenoxy)phenol (2.83 g, 0.01 mole), the methanesulfonate of S methyl lactate (18.2 g, 0.01 mole), and potassium carbonate (1.67 g, 0.012 mole) in DMSO (70 ml) was stirred at room temperature for 40 hours, then poured into water (700 ml). The mixture was extracted with ether (2×200 ml). Pentane (100 ml) was added to the combined ether extracts and the resulting solution washed with water (300 ml). The organic phase was dried (MgSO4) and the solvent evaporated to give a light yellow oil (~7 g). This oil was purified via prep HPLC (8:2 hexane-acetone) with the first peak desired product enriched in the "R" enantiomer; Optical rotation=+20.34°@25° C. R.I.=1.5614@25° C.; NMR (CDCl3) was identical with that obtained in Example 4. No attempt was made to determine the optical purity of this material.