Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:18][N:17]([C:19]([C:21]4[CH:32]=[CH:31][C:24]([O:25][C@H:26]5[CH2:30][CH2:29][NH:28][CH2:27]5)=[CH:23][CH:22]=4)=[O:20])[CH2:16]3)[CH2:11][CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[CH3:40][N:41]([CH3:46])[S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[CH3:40][N:41]([CH3:46])[S:42]([N:28]1[CH2:29][CH2:30][C@H:26]([O:25][C:24]2[CH:31]=[CH:32][C:21]([C:19]([N:17]3[CH2:16][CH:15]([N:12]4[CH2:11][CH2:10][N:9]([C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[O:8])[CH2:14][CH2:13]4)[CH2:18]3)=[O:20])=[CH:22][CH:23]=2)[CH2:27]1)(=[O:44])=[O:43]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: O=C(c1ccccc1)N1CCN(C2CN(C(=O)c3ccc(O[C@H]4CCNC4)cc3)C2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)N1CC[C@H](Oc2ccc(C(=O)N3CC(N4CCN(C(=O)c5ccccc5)CC4)C3)cc2)C1
Reaction time: 3 h
Yield: 58 %

Procedure:
A solution of compound 33a (0.164 mmol) and Et3N (0.5 mL) in CH2Cl2 (2 mL) was treated with N,N-dimethylsulfamoyl chloride (26 μL, 0.246 mmol) at room temperature. The resulting mixture was stirred for 3 h, and the solvent was then removed under reduced pressure. The resultant residue was directly loaded onto a silica gel column and was purified by silica gel flash column chromatography, eluting with 5% MeOH/CH2Cl2 to give compound 439 (51.5 mg). 1H NMR (CDCl3): δ 7.61 (d, J=8.21 Hz, 2H), 7.36-7.46 (m, 5H), 6.86 (d, J=8.6 Hz, 2H), 4.98 (m, 1H), 4.31 (br. s., 1H), 4.11-4.26 (m, 2H), 4.05 (br. s., 1H), 3.87-3.96 (m, 1H), 3.84 (m, 1H), 3.70-3.79 (m, 1H), 3.66 (dd, J=11.4, 4.8 Hz, 1H), 3.39-3.58 (m, 4H), 3.21-3.26 (m, 1H), 2.82 (s, 6H), 2.42 (br. s., 4H), 2.19-2.29 (m, 2H); MS m/z (M+H+) 542.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:18].COC(=O)C(OC)C(C1C=CC=C(OCC2C=CC=CC=2)C=1)O>>[CH2:24]([O:23][C:21](=[O:22])[CH:20]([O:19][CH2:17][CH3:18])[CH:12]([C:11]1[CH:14]=[CH:15][CH:16]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)[OH:13])[CH3:25]
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Reactant: CCOCC(=O)OCC
Agent: COC(=O)C(OC)C(O)c1cccc(OCc2ccccc2)c1
Product: CCOC(=O)C(OCC)C(O)c1cccc(OCc2ccccc2)c1

Procedure:
The title compound was prepared from 3-benzyloxy-benzaldehyde and ethyl ethoxyacetate via the same procedure used for the preparation of 3-(3-benzyloxy-phenyl)-3-hydroxy-2-methoxy-propionic acid methyl ester (Example 291, Step 1) to afford the title compound as a colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:26])[NH:23][CH2:24][CH3:25])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=C(C=CC=2)C(NCC)=O)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:28]1([CH2:27][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:26])[NH:23][CH2:24][CH3:25])[CH:17]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:8][N:9]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCNC(=O)c1cccc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)OCC)s2)c1
Agent: CCNC(=O)c1cccc(NCC2CCCC2)c1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: CCNC(=O)c1cccc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)c1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-ethylcarbamoyl-phenyl)ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 3-(cyclopentylmethyl-amino)-N-ethyl-benzamide and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][N:6]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9](=[O:15])[N:8]([OH:16])[C:7]1=[O:17].[NH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)=[O:23]>>[OH:16][N:8]1[C:9](=[O:15])[C:10]2[S:14][CH:13]=[CH:12][C:11]=2[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([C:27]3[CH:28]=[CH:29][C:24]([C:22]([NH2:21])=[O:23])=[CH:25][CH:26]=3)[CH:20]=[CH:19][CH:18]=2)[C:7]1=[O:17]
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: O=c1c2sccc2n(Cc2cccc(Br)c2)c(=O)n1O
Product: NC(=O)c1ccc(-c2cccc(Cn3c(=O)n(O)c(=O)c4sccc43)c2)cc1

Procedure:
The title compound was prepared from 1-(3-Bromo-benzyl)-3-hydroxy-1H-thieno[3,2-d]pyrimidine-2,4-dione (from previous example) and 4-aminocarbonyl-phenyl boronic acid via general procedure C. The crude product was purified by mass-triggered preparative HPLC. 1H NMR (DMSO-d6) δ 10.87 (bs, 1H), 8.11 (d, 1H, J=5.4 Hz), 7.96 (d, 2H, J=8.4 Hz), 7.74 (s, 1H), 7.71 (d, 2H, J=7.8 Hz), 7.63 (d, 1H, J=7.8 Hz), 7.45 (t, 1H, J=7.8 Hz), 7.36 (d, 1H, J=5.4 Hz), 7.28 (d, 1H, J=7.5 Hz), 5.35 (s, 2H); Electrospray MS: 394 (M+H); retention time: 1.96 min.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].ON1C2C=CC=CC=2N=N1.[C:44]([NH:51][CH2:52][CH2:53][C:54](O)=[O:55])([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45].Cl.CN(C)CCCN=C=NCC>CC#N>[C:47]([O:46][C:44]([NH:51][CH2:52][CH2:53][C:54]([NH:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24])=[O:55])=[O:45])([CH3:50])([CH3:49])[CH3:48]
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 67.2 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.7 g, 4.62 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, 1-hydroxybenzotriazole (0.3 g, 2.22 mmol), N—BOC-b-alanine (0.42 g, 2.22 mol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodimide hydrochloride 0.53 g, 2.78 mmol) were added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N citric acid (30 ml), H2O (2×30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2: CH3OH 100:2) to give 3-[(tert-butoxy)carbonylamino]-N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}propanamide (0.57 g, 67%) as a white solid:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=O.[NH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C.C(O)(=O)C>[C:11]([O:10][C:8](=[O:9])[CH2:7][O:6][C:5]1[CH:4]=[C:3]([CH:17]=[CH:16][CH:15]=1)[CH2:1][NH:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)COc1cccc(C=O)c1
Reactant: CC(C)(C)OC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)CNCc1cccc(OCC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.9 %

Procedure:
To a solution of tert-butyl (3-formylphenoxy)acetate (1.50 g) in dichloroethane (20.0 mL) were added tert-butyl glycinate (874 mg) and acetic acid (1.09 mL), and then sodium triacetoxyborohydride (2.69 g) was added thereto under ice-cooling. The reaction suspension was stirred at room temperature for 16 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain tert-butyl N-[3-(2-tert-butoxy-2-oxoethoxy)benzyl]glycinate (1.18 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]=NC(C)C)=[C:4]([CH3:19])[CH:3]=1.[OH:20]S(O)(=O)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:14]=[O:20])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:4]([CH3:19])[CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(F)ccc1-c1ccccc1C=NC(C)C
Product: Cc1cc(F)ccc1-c1ccccc1C=O
Temperature: 25 °C

Procedure:
A solution of 20.36 g (79.8 mmol) (4′-fluro-2′-methyl-biphenyl-2-ylmethylene)-isopropyl-amine in 110 ml 4N H2SO4 was heated at reflux for 6 h. After cooling to RT, the solution was extracted twice with 150 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/hexane 1:1) to give 4′-fluoro-2′-methyl-biphenyl-2-carbaldehyde as a pale yellow oil.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49][NH2:50]>C1COCC1>[C:1]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:50][CH2:49][CH2:48][N:47]([CH3:51])[CH3:46])=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: CN(C)CCN
Reactant: O=C(O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
To a solution of 4-(4-biphenylylmethoxy)phenylacetic acid (0.6 g) in THF (30 ml) were added WSC (0.4 g) and HOBt (0.3 g). N,N-Dimethylethylenediamine (0.2 g) was added to the reaction mixture. After stirring at room temperature for 18 hr, the reaction mixture was poured onto water and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated in vacuo. The residue was recrystallized from ethyl acetate/ethanol to obtain the titled compound (0.3 g).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].CC(C)([O-])C.[K+].Cl[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1>C1COCC1>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1
Reactant: CN(C)CCO
Reactant: Clc1cnccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)CCOc1cnccn1
Reaction time: 0.08 h

Procedure:
A solution of 2-dimethylaminoethanol (1 mL) in THF (20 mL) was treated with potassium tert-butoxide (1.2 g). After 5 min, chloropyrazine (2 g) was added and the reaction stirred 2 h. The solvent was evaporated, the residue suspended in cold water, the mixture acidified, and the mixture extracted with ether. The aqueous fraction was made basic and extracted with EtOAc. The extracts were dried, the solvent evaporated, and the residue purified by radial chromatography eluting with 10%-EtOH-1%-NH4OH-CHCl3 to give 2-(2-dimethylaminoethoxy)pyrazine (1.3 g). The HCl salt crystallized from 2-propanol as a white solid, m.p. 151-153° C. (Compound 26).
Reaction SMILES: CS(C)=O.[I-].[CH3:6][S+](C)(C)=O.[H-].[Na+].[CH3:13][C:14]([CH3:24])([CH3:23])[C:15]([C:17]1[CH:18]=[N:19][CH:20]=[N:21][CH:22]=1)=[O:16]>O1CCCC1>[C:14]([C:15]1([C:17]2[CH:22]=[N:21][CH:20]=[N:19][CH:18]=2)[CH2:6][O:16]1)([CH3:24])([CH3:23])[CH3:13]
Reactant: C[S+](C)(C)=O
Reactant: CC(C)(C)C(=O)c1cncnc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)C1(c2cncnc2)CO1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under an atmosphere of argon, 10 ml of dimethyl sulphoxide are slowly added dropwise to 0.96 g (4.3 mmol) of trimethylsulphoxonium iodide and 0.17 g of sodium hydride (60%, 4.3 mmol). The reaction mixture is then stirred at room temperature for 15 min, and 0.65 g (3.9 mmol) of 2,2-dimethyl-1-(5-pyrimidinyl)-1-propanone, dissolved in 2 ml of tetrahydrofuran, is added. The reaction mixture is stirred at 50° C. for 90 min. The reaction mixture is then concentrated under reduced pressure, and saturated aqueous sodium chloride solution and ethyl acetate are added to the residue. The organic phase is separated off dried over sodium sulphate, filtered and concentrated. This gives 0.70 g (99%) of the desired product, which is reacted without further purification.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[NH:13][C:12]3[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=3[N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:19][N:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]1=[O:35].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:24]2[CH:23]=[CH:22][C:21](=[O:35])[N:20]([CH3:19])[CH:25]=2)=[N:3][C:4]=1[C:9]1[NH:13][C:12]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=2[N:10]=1
Reactant: Cc1ccc2nc(-c3nc(Br)cnc3N)[nH]c2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc2nc(-c3nc(-c4ccc(=O)n(C)c4)cnc3N)[nH]c2c1
Temperature: 110 °C
Yield: 43.4 %

Procedure:
A mixture of 5-bromo-3-(6-methyl-1H-benzimidazol-2-yl)pyrazin-2-amine (100 mg, 0.3288 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (154.6 mg, 0.6578 mmol), potassium carbonate (136.4 mg, 0.9867 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (26.86 mg, 0.03289 mmol) in DMF (3 mL) were heated to 110° C. for 2 hours. The mixture was diluted with EtOAc, washed with water, and the organic layer concentrated in vacuo. The resulting residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound (47.4 mg, 40% Yield). MS (ES+) 333
Reaction SMILES: C([O-])(=O)C.[NH4+].[CH2:6]([N:13]1[CH2:18][CH2:17][C:16](=O)[C:15]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([BH3-])#[N:25].[Na+]>CO>[NH2:25][CH:16]1[CH2:17][CH2:18][N:13]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:14][C:15]1([CH2:22][CH3:23])[CH2:20][CH3:21]
Reactant: CCC1(CC)CN(Cc2ccccc2)CCC1=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC1(CC)CN(Cc2ccccc2)CCC1N
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ammonium acetate (7.85 g, 102 mmol) was added to the stirred solution of 1-benzyl-3,3-diethyl piperidin-4-one (5.0 g, 20.40 mmol) in methanol (100 ml) and stirring was continued for 3 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (1.3 g, 20.40 mmol) was added to it. Cooling was removed after 10 min. and resulting mixture was stirred for 6 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 4-amino-1-benzyl-3,3-diethyl piperidine. Yield 8.2 (82%), C16H26N2, m/z 247 (M+1), PMR (CDCl3): 0.84 (s, 3H), 0.98 (s, 3H), 1.48 (bs, 2H, D2O exchangeable), 1.66 (m, 2H), 2.04 (m, 2H), 2.42 (m, 2H), 2.86 (m, 1H), 3.46 (dd, 2H), 7.32 (m, 5H).
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1)(=[O:5])=[O:4])[CH3:2].C1(=O)O[CH2:26][CH2:25][O:24]1>CN(C)C=O>[CH2:1]([S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:26][CH2:25][OH:24])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Reactant: O=C1OCCO1
Solvent: CN(C)C=O
Product: CCS(=O)(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3CCO)c2c1
Temperature: 120 °C

Procedure:
To a stirred solution of 5-(2-ethylsulphonylethyl)-3-(2(R)-pyrrolidinylmethyl)-1H-indole (Preparation 5; 350 mg, 1.1 mmol) in dry dimethylformamide (10 ml) at room temperature under nitrogen was added ethylene carbonate (160 mg, 1.8 mmol). The mixture was heated at 120° C. for 18 hours, allowed to cool, then partitioned between ethyl acetate and water. The organic phase was separated, washed with water (3×), dried (Na2SO4) and evaporated under reduced pressure to give a foam. Purification by column chromatography on silica gel, eluting initially with dichloromethane followed by a gradient of 0.880 aqueous ammonia:ethanol: dichloromethane (0:10:90 to 0.5:10:90), afforded the title compound as gum. Rf 0.35 (SS 4). Found: C,62.29; H,7.73; N,7.23. C19H28N2O3S; 0.05 CH2Cl2 requires C,62.04; H,7.68; N,7.60%. δ(CDCl3): 1.35(3H,t), 1.50-1.90(5H,m), 2.30(1H,m), 2.50(1H,m), 2.70(1H,m), 2.80-3.35(10H,m), 3.60-3.75(2H,m), 5.30(0.10H,s,CH2Cl2), 7.00(1H,d), 7.05(1H,s), 7.25(1H,d), 7.40(1H,s), 8.25(1H,br s).
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]([C:11](Cl)=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23][CH2:22]2)=[N:19][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[O:3][C:4]([C:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:22][CH2:23][CH:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:25][CH2:26]3)=[N:19][CH:20]=2)=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1
Reactant: O=C(Cl)c1oc(Br)nc1C(F)(F)F
Reactant: Nc1ccc(N2CCC(c3ccccc3)CC2)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCC(c3ccccc3)CC2)nc1)c1oc(Br)nc1C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 38.4 %

Procedure:
A solution of 2-bromo-4-trifluoromethyloxazole-5-carbonyl chloride (A-39) (0.34 g, 1.2 mmol) and 1-(5-aminopyridin-2-yl)-4-phenylpiperidine (B-6) (0.25 g, 1.0 mmol) in CH2Cl2 (10 mL) was cooled to −78° C. then triethyl amine (0.16 mL, 1.2 mmol) was added. The reaction mixture was stirred for 2 h while the temperature was warmed slowly up to 0° C. The solvent was concentrated, and the residue was purified by chromatography on a silica-gel column (eluant: 0-50% EtOAc/hexane gradient) to yield 1-(5-(2-bromo-4-(trifluoromethyl)oxazole-5-carboxamido)pyridin-2-yl)-4-phenylpiperidine (A-40) (0.19 g, 35% yield) as a yellow solid. Note: the product A-40 contains compound with the bromine atom exchanged for a chlorine atom. 1H NMR (500 MHz, CDCl3) δ 9.58 (br s, 1H), 8.59 (br s, 1H), 8.34 (dd, 1H, J=9.5, 1.8 Hz), 7.35 (m, 2H), 7.30-7.22 (m, 3H), 6.89 (d, 1H, J=9.4 Hz), 4.42 (d, 2H, J=13.3 Hz), 3.17 (t, 2H, J=12.7 Hz), 2.85 (m, 1H), 2.05 (m, 2H), 1.84 (m, 2H); LCMS (ESI) calcd for [M+1]+ for chloride 451.1. found 451.4.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([C@@H:11]([CH3:43])[C:12]([NH:14][C@H:15]1[CH2:21][O:20][C:19]2[C:22]([C:26]([F:29])([F:28])[F:27])=[CH:23][CH:24]=[CH:25][C:18]=2[N:17]([CH2:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][C:32]=2[CH3:41])[C:16]1=[O:42])=[O:13])C(=O)OC(C)(C)C>CCOCC.CO>[ClH:1].[CH3:2][NH:3][C@@H:11]([CH3:43])[C:12]([NH:14][C@H:15]1[CH2:21][O:20][C:19]2[C:22]([C:26]([F:29])([F:28])[F:27])=[CH:23][CH:24]=[CH:25][C:18]=2[N:17]([CH2:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][C:32]=2[CH3:41])[C:16]1=[O:42])=[O:13]
Reactant: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc2c1cccc2C(F)(F)F
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CN[C@@H](C)C(=O)N[C@H]1COc2c(cccc2C(F)(F)F)N(Cc2c(C)ccc3ccccc23)C1=O
Yield: 82 %

Procedure:
2 M solution of HCl in Et2O (1.26 mL) was added to a solution of tert-butyl methyl((S)-1-((S)-5-((2-methylnaphthalen-1-yl)methyl)-4-oxo-9-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxopropan-2-yl)carbamate (66 mg, 113 μmol) in MeOH (400 μL) After 2.5 h the mixture was concentrated, MeCN was added to the residue and the mixture concentrated. The residue was lyophilized from MeCN/H2O to afford the title compound (48 mg, 82%) as a white powder. MS m/z 486 (MH)+
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:22][N:23]([CH3:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:28]([C:27]3[CH:30]=[CH:31][C:24]([N:23]([CH3:32])[CH3:22])=[CH:25][CH:26]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)CN1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)CN1CCN(c2c(Br)cnc3[nH]c(-c4ccc(N(C)C)cc4)nc23)CC1
Temperature: 70 °C

Procedure:
To a mixture of 5-bromo-4-(4-isobutylpiperazin-1-yl)-3-nitropyridin-2-amine (0.039 g, 0.11 mmol), ethanol (4 ml), and 4-dimethylaminobenzaldehyde (0.021 g, 0.14 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was heated at 70° C. for 5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 1 to 2.5% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a yellow solid after trituration with diethyl ether (0.013 g, 26%); 1H-NMR (500 MHz, DMSO-d6) 0.91 (d, J=6.55 Hz, 6H, CH(CH3)2), 1.82 (m, 1H, CH(CH3)2), 2.12 (d, J=7.35 Hz, 2H, N—CH2), 2.56 (br s, 4H, piperazine N(CH2)2), 3.00 (s, 6H, N(CH3)2), 3.63 (br s, 4H, piperazine N(CH2)2), 6.82 (d, J=9.01 Hz, 2H) and 8.02 (d, J=8.87 Hz, 2H) (3,5-C6H4NMe2 and 2,6-C6H4—NMe2), 8.14 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.17 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[C:10]([F:20])=[C:11]([CH:15]=[C:16]([F:19])[C:17]=1[F:18])[C:12]([OH:14])=[O:13].[ClH:21]>C(#N)C>[Cl:21][C:9]1[C:10]([F:20])=[C:11]([CH:15]=[C:16]([F:19])[C:17]=1[F:18])[C:12]([OH:14])=[O:13]
Reactant: Nc1c(F)c(F)cc(C(=O)O)c1F
Reactant: Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: O=C(O)c1cc(F)c(F)c(Cl)c1F
Temperature: 60 °C

Procedure:
9.3 g of anhydrous cuprous chloride and 8.8 g of tert-butyl nitrite were added to 150 ml of acetonitrile and under stirring and heating at 60° C., 11 g of 3-amino-2,4,5-trifluorobenzoic acid 26 (a commercial product) was added. The mixture was stirred for 20 minutes. After cooling, 500 ml of 15% hydrochloric acid was added and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was then removed under reduced pressure. Finally the residue was subjected to silica gel (100 g) column chromatography using chloroform as an eluent. The procedure gave 8.4 g of 3-chloro-2,4,5-trifluorobenzoic acid 27 as colorless needles.