Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)O.N1C=CC=CC=1.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1>[Cl:22][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[C:2]([F:13])([F:12])[F:1]
Reactant: O=S(Cl)Cl
Reactant: Oc1ccc(C(O)C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Oc1ccc(C(Cl)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled (ice bath) mixture of 4-(2,2,2-trifluoro-1-hydroxyethyl)phenol (4.3 g, 22 mmol) and anhydrous pyridine (1.8 ml, 22 mmol) in toluene was added thionyl chloride (SOCl2) (2.3 ml, 31 mmol) drop wise via a syringe. After stirred for 1 h at 0° C., the reaction was heated at 70° C. for 2 h. At this point, reaction did not go completion, indicated by LCMS. Heating was continued for 16 h. Reaction was quenched with ice water. The resulted mixture was diluted with EtOAc. The organic layer was washed with saturated Na2CO3, water and brine. After dried over Na2 SO4, the solution was filtered and concentrated. The residue was purified on a silica gel column (5-10% EtOAc/hexane) giving the title compound as a light yellow oil. MS m/z: 211 (M+1).
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[N:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[NH2:16])=[N:8][CH:9]=1.[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[C:21]=1[C:22](O)=[O:23].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.CN1CCOCC1>CN(C=O)C.CO>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[C:21]=1[C:22]([NH:16][C@H:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[NH:10][C:7]1[CH:6]=[N:5][C:4]([C:3]([F:2])([F:17])[F:18])=[CH:9][N:8]=1)=[O:23]
Reactant: COc1cccc(F)c1C(=O)O
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CO
Product: COc1cccc(F)c1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1

Procedure:
A solution of (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 14 mg, 0.05 mmol), 2-fluoro-6-methoxybenzoic acid (CAS number 137654-21-8; 8.5 mg, 0.05 mmol), TOTU (20 mg, 0.06 mmol) and 4-methylmorpholine (0.008 ml, 0.075 mmol) in DMF (0.25 ml) was stirred at room temperature for 1 hour. The reaction was then diluted with methanol and concentrated in vacuo. The resulting residue was purified by reverse phase preparative HPLC (eluted with acetonitrile/water with 0.1% ammonia) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([OH:15])=O)=[CH:4][C:3]=1[Cl:16].[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.CCOC(OC(OCC)=O)=O.C(N(C(C)C)CC)(C)C>CN(C)C=O>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[O:15])=[CH:4][C:3]=1[Cl:16]
Reactant: CCc1cn2c(N)c(Cl)cc(C(=O)O)c2n1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: CCOC(=O)OC(=O)OCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cn2c(N)c(Cl)cc(C(=O)NCC3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Yield: 90 %

Procedure:
A mixture of 5-amino-6-chloro-2-ethylimidazo[1,2-a]pyridine-8-carboxylic acid (Example 4, Step 2, 10.00 g, 41.72 mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (J. Prugh, L. A. Birchenough and M. S. Egbertson, Synth. Commun., 1992, 22, 2357-60, 15.20 g, 70.93 mmol), DEPC (10.76 mL, 70.93 mmol) and diisopropylethylamine (18.17 mL, 104.4 mmol) in N,N-dimethylformamide (267 mL) was stirred at room temperature for 43 h. The solvent was removed by evaporation. The residue was basified with aqueous sodium bicarbonate (40 mL), and extracted with dichloromethane (5×100 mL). The combined extract was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. Flash chromatography of the residue eluting with dichloromethane/methanol (100:1 to 20:1) afforded 19.08 g (90%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3](=[O:31])[CH2:4][N:5]([C@@H:25]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1)[C:6]1[C:7]2[CH:14]=[CH:13][N:12]([S:15]([C:18]3[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:8]=2[N:9]=[CH:10][N:11]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:54][C:55]1[CH:56]=[C:57]([NH:62][CH2:63][C:64](O)=[O:65])[CH:58]=[C:59]([Cl:61])[CH:60]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:54][C:55]1[CH:56]=[C:57]([NH:62][CH2:63][C:64]([N:27]2[CH2:28][CH2:29][CH2:30][C@@H:25]([N:5]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([S:15]([C:18]5[CH:19]=[CH:20][C:21]([CH3:22])=[CH:23][CH:24]=5)(=[O:17])=[O:16])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH2:4][C:3]([N:2]([CH3:1])[CH3:32])=[O:31])[CH2:26]2)=[O:65])[CH:58]=[C:59]([Cl:61])[CH:60]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N(CC(=O)N(C)C)[C@@H]4CCCNC4)ncnc32)cc1
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N(CC(=O)N(C)C)[C@@H]4CCCN(C(=O)CNc5cc(Cl)cc(Cl)c5)C4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
To a solution of (R)—N, N-dimethyl-2-(piperidin-3-yl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino) acetamide (100 mg, 0.24 mmol) in DMF (7 mL) was added EDCI (54 mg, 0.3 mmol), HOBt (39 mg, 0.3 mmol), 2-(3,5-dichlorophenylamino)acetic acid (53 mg, 0.24 mmol) and DIEA (0.50 mL, 0.36 mmol) at 0° C. The solution was stirred at rt overnight and the reaction mixture was diluted with water (50 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to give a residue which was purified by column chromatography (silica gel, gradient 0-2% methanol in chloroform) to afford the titled compound (50 mg, 31%). LCMS [M+1]: 675.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26](OS(C)(=O)=O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.O>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:9][C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: Oc1cc(F)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2F)CC1
Temperature: 80 °C
Yield: 63 %

Procedure:
To a stirred solution of 2,5-difluorophenol (1.0 g, 0.0076 mole) in DMF (20 mL) was added cesium carbonate (12.4 g, 0.038 mole) followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (2.1 g, 0.076 mole). The reaction mixture was heated at 80° C. overnight. The reaction mixture was then diluted with water and the product extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate, and concentrated. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (10% ethyl acetate in hexane) to afford 1.5 g (63.0%) of 4-(2,5-Difluoro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 356.08 (M+1)+, 85%. 1H NMR (CDCl3): δ 7.0 (m, 1H), 6.6 (m, 1H), 6.5 (m, 1H), 4.5 (m, 1H), 3.7 (m, 2H), 3.4 (m, 4H), 2 (m, 2H), 1.9 (m, 2H). 1.5 (s, 9H). A solution of 4-(2,5-difluoro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 0.0047 mole) in dioxane.HCl (2 mL) was stirred at ambient temperature for 1 hour. Ether was then added, and the resulting precipitate was isolated by filtration and dried to afford 0.65 g (65%) of 4-(2,5-difluoro-phenoxy)-piperidine hydrochloride. LCMS: 214.1 (M+1)+, 100%. 1H NMR (CDCl3): δ 9.2 (bs, 2H), 7.4 (m, 2H), 6.9 (m, 1H), 4.8 (m, 1H), 3.2 (m, 2), 3.0 (m, 2H), 2.2 (m, 2H), 1.9 (m, 2H).
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=[O:2].[NH2:8][CH2:9][CH2:10][CH2:11][C@:12]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[OH:13].C(N(CC)CC)C.C(OC(=O)C)(=O)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([NH:8][CH2:9][CH2:10][CH2:11][C@:12]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[OH:13])(=[O:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](O)(CCCN)c2cccc(Cl)c2)C1
Reactant: O=C(O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)NCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
To a 100 mL, round bottom flask were added TFA salt of (R)-tert-butyl 3-((S)-4-amino-1-(3-chlorophenyl)-1-hydroxybutyl)piperidine-1-carboxylate (0.374 g, 0.75 mmol, 1.0 equiv), DMAP (0.1615 g), CH2Cl2 (10 mL), and triethylamine (3 mL). The mixture was cooled in an ice bath and a solution of acetic anhydride (0.280 g, 2.74 mmol, 3.6 equiv) in CH2Cl2 (10 mL) was added. The reaction mixture was allowed to slowly warm to rt while stirring overnight (16 h). After the solvents were removed in vacuo, the residue was purified by reversed-phase HPLC (Phenomenex® Luna 5μ C18(2) 100A, 250×21.20 mm, 5 micron, 70%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 1.5 min, flow rate 25 mL/min) to give 0.2589 g (81%) of (R)-tert-butyl 3-((S)-4-acetamido-1-(3-chlorophenyl)-1-hydroxybutyl)-piperidine-1-carboxylate. LC-MS (3 min) tR=1.72 min, m/z 447, 449 (MNa+), 425 (MH+), 325, 327; 1H NMR (400 MHz, CDCl3) □ 7.38-7.37 (m, 1H), 7.28-7.18 (m, 3H), 6.06 (br s, 1H), 4.36-4.34 (m, 1H), 3.97-3.95 (m, 1H), 3.35-3.26 (m, 1H), 3.13-3.05 (m, 1H), 2.99 (br s, 2H), 2.55-2.49 (m, 2H), 1.97 (s, 3H), 1.44 (s, 9H), 1.95-1.15 (m, 6H); 13C NMR (100 MHz, CDCl3) □ 171.41, 155.17, 146.75, 134.24, 129.33, 126.63, 126.01, 123.83, 79.68, 77.60, 46.34, 44.69, 39.71, 35.91, 28.43, 25.40, 25.23, 24.15, 22.99.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.C(OC([NH:51][C@H:52]([CH3:56])[C:53](O)=[O:54])=O)(C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:51][C@@H:52]([C:53]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1)=[O:54])[CH3:56]
Reactant: N[C@H]1CC[C@H](Nc2cc(Nc3ccccn3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](N)C(=O)N[C@H]1CC[C@H](Nc2cc(Nc3ccccn3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-((trans)-4-aminocyclohexylamino)-N-(3-fluoropyridin-4-yl)-8-(pyridin-2-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (0.020 g, 0.043 mmol) in DMF (1 mL) at room temperature was added DIEA (0.038 mL, 0.217 mmol), (R)-2-(tert-butoxycarbonylamino)propanoic acid (0.016 g, 0.087 mmol), and BOP (0.058 g, 0.130 mmol). The resulting clear, colorless solution was stirred at room temperature for 30 minutes. Volatiles were removed in vacuo and the crude material was suspended in dichloromethane (0.5 mL) and TFA (0.5 mL). The resulting suspension was stirred vigorously at room temperature for 1.5 h. Volatiles were removed via a stream of nitrogen, and the crude material was diluted with 1 mL MeOH and purified via preparatory HPLC using a YMC ODS C-18 column (30×250 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 60 min, flow rate 25 mL/min. Rt=49.547 min. 6-((trans-4-(D-alanylamino)cyclohexyl)amino)-N-(3-fluoro-4-pyridinyl)-8-(2-pyridinylamino)imidazo[1,2-b]pyridazine-3-carboxamide (0.006 g, 18.20% yield) was obtained as a white solid. LC/MS, m/z 533.2 (M+1). HPLC Rt=3.616 min. YMC S5 ODS-A column (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.2% H3PO4). Solvent A: (10% MeOH, 90% H2O, 0.2% H3PO4). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% 1 min, flow rate 4 mL/min. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.27 (1H, d, J=1.76 Hz), 9.85 (1H, s), 8.67 (1H, d, J=2.77 Hz), 8.48-8.55 (1H, m), 8.44 (1H, d, J=5.54 Hz), 8.34 (1H, dd, J=4.91, 1.38 Hz), 8.28 (1H, d, J=7.55 Hz), 8.13 (1H, s), 8.04 (2H, d, J=4.53 Hz), 7.98 (1H, s), 7.71-7.78 (1H, m), 7.51 (1H, d, J=8.31 Hz), 7.28 (1H, d, J=8.31 Hz), 7.02 (1H, dd, J=7.05, 5.79 Hz), 3.87 (1H, s), 3.73-3.81 (1H, m), 3.58 (1H, s), 2.07 (2H, d, J=3.78 Hz), 1.86 (2H, s), 1.34 (3H, d, J=6.80 Hz), 1.28-1.44 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][C:32]=1[O:40][CH3:41]>>[Cl:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([N:14]([CH:13]2[CH:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12]2)[CH3:15])=[O:37])=[CH:33][C:32]=1[O:40][CH3:41]
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: COc1cc(C(=O)O)ccc1Cl
Product: COc1cc(C(=O)N(C)C2CN(C(=O)C3CCN(C(=O)C4(C)CC4)CC3)CC2c2ccc(Cl)c(Cl)c2)ccc1Cl

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound 4-chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-3-methoxy-N-methyl-benzamide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 4-chloro-3-methoxybenzoic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown foam. MS m/e: 608.1 [M+H]+.
Reaction SMILES: [C@@H:1]12[C:9](=[O:10])[NH:8][C:7](=[O:11])[C@@H:2]1[CH2:3][CH:4]=[CH:5][CH2:6]2.[N:12]#[C:13]Br.CC(C)=O.C(N(CC)CC)C>C(OCC)(=O)C>[C:13]([N:8]1[C:7](=[O:11])[C@@H:2]2[CH2:3][CH:4]=[CH:5][CH2:6][C@@H:1]2[C:9]1=[O:10])#[N:12]
Reactant: O=C1NC(=O)[C@@H]2CC=CC[C@H]12
Reactant: N#CBr
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: N#CN1C(=O)[C@H]2CC=CC[C@H]2C1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Using a 250 mL round-bottomed flask equipped with a magnetic stir bar and an ice/salt bath, a suspension of cis-4-cyclohexene-1,2-dicarboximide (15.1 g, 100 mmol), cyanogen bromide (11.7 g, 110 mmol), and 100 mL of acetone was cooled to 0° C. Triethylamine (16.0 mL, 115 mmol) was added via syringe over a 12 minute period. The resulting peach slurry was allowed to stir for 15 minutes. The mixture was diluted with ethyl acetate and filtered to remove solid triethylamine hydrobromide. The filter cake was rinsed with ethyl acetate and the filtrate was concentrated using a rotary evaporator. The crude paste was partitioned between water and a 2:1 mixture of ethyl acetate/hexanes. The organic phase was washed with brine, dried (MgSO4), and concentrated to give a light brown solid. The crude product was purified by recrystallization using ethyl acetate/pet ether or ethyl acetate/hexanes to afford 11.5 g (65%) of a glossy off white solid, mp 136°-138° C.: IR (nujol) 2256 (nitrile), 1749 (carbonyl) cm-1 ; 1H NMR (200 MHz, CDCl3) δ 2.30 (ddd, 2, J=15, 4.4, 2.75 Hz), 2.64 (ddd, 2, J=15, 3.8, 2.75 Hz), 3.35 (dd, 2, J=3.5, 2.75 Hz), 5.98 (ddd, 2, J= 3.9, 1.7, 1.5 Hz); 13C NMR (50 MHz, CDCl3) δ 173.48, 127.52, 100.72, 40.08, 23.26; GC/MS m/e (relative intensity) 176 (29.5), 147 (11.1), 107 (20.0), 105 (23.3), 80 (44.0), 79 (100), 78 (35.1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C@H:12]4[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:14][C@H:13]4[N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:11]=1.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[Cl:32]>>[Cl:25][C:26]1[CH:27]=[C:28]([C:2]2[CH:3]=[C:4]3[C:9]4=[C:10]([C@H:12]5[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:15][CH2:14][C@H:13]5[N:8]4[CH2:7][CH2:6][CH2:5]3)[CH:11]=2)[CH:29]=[CH:30][C:31]=1[Cl:32]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(Br)cc3c1N2CCC3
Product: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(-c3ccc(Cl)c(Cl)c3)cc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 109 from tert-butyl(±)-cis-2-bromo-5,6,8,9,11,11a-hexahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (101.7 mg, 0.26 mmol) and 3,4-dichlorophenylboronic acid (97 mg, 0.52 mmol), after chromatographic purification (91.6 mg, 77%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 7.57 (d, 1H, J=1.8 Hz), 7.42 (d, 1H, J=8.4 Hz), 7.31 (dd, 1H, J=2.2, 8.4 Hz), 7.12 (bs, 1H), 7.07 (bs, 1H), 3.62–3.75 (m, 1H), 3.48–60 (m, 1H), 3.15–3.35 (m, 4H), 2.65–2.80 (m, 4H), 2.10–2.20 (m, 2H), 1.85–2.00 (m, 2H), 1.46 (s, 9H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])[C:9]([OH:11])=O.[S:23]1[CH2:27][CH2:26][N:25]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)=[O:29])[CH2:24]1.C(Cl)CCl>CN(C=O)C>[S:23]1[CH2:27][CH2:26][N:25]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:9](=[O:11])[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[NH:12][C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[O:14])=[CH:32][CH:31]=2)=[O:29])[CH2:24]1
Reactant: Nc1ccc(C(=O)N2CCSC2)cc1
Reactant: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)Nc1ccc(C(=O)N2CCSC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
To a solution of 2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (46 mg, 0.14 mmol) and 4-(thiazolidin-3-ylcarbonyl)phenylamine (30 mg, 0.14 mmol) in DMF (2 mL), EDC (54 mg, 0.28 mmol) was added. The reaction mixture was stirred at room temperature overnight. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a white powder (15 mg). MS 509.2 and 511.2 (M+H, Cl pattern).
Reaction SMILES: [OH:1][C@H:2]([CH2:6][C:7]1[CH:15]=[C:14]([CH3:16])[C:13]2[C:9](=[CH:10][N:11]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:12]=2)[CH:8]=1)[C:3]([OH:5])=O.C(N(C(C)C)CC)(C)C.[N:34]1([CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O.ClCCl>[OH:1][C@H:2]([CH2:6][C:7]1[CH:15]=[C:14]([CH3:16])[C:13]2[C:9](=[CH:10][N:11]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:23])([CH3:22])[CH3:24])[N:12]=2)[CH:8]=1)[C:3]([N:43]1[CH2:44][CH2:45][CH:40]([N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:41][CH2:42]1)=[O:5]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](O)C(=O)O)cc2cn(COCC[Si](C)(C)C)nc12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C[C@@H](O)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of the (R)-2-hydroxy-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)propanoic acid (610 mg, 1.74 mmol), diisopropylethylamine (0.61 mL, 3.48 mmol), and 4-piperidinopiperidine (585.76 mg, 2.0 equiv) in dimethylformamide (20 mL) and dichloromethane (20 mL) at 0° C. was added PyBOP® (951 mg, 1.83 mmol). The reaction was stirred at 0° C. for 2 h. The reaction was concentrated, diluted with ethyl acetate, washed with water, then brine, dried over magnesium sulfate, and concentrated. The product was purified by column chromatography (4:96:1 methanol/dichloromethane/triethylamine) to give 795 mg (91%). Mass spec.: 501.40 (MH)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)(=[O:12])=[O:11].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: Cc1ccnc(Cl)c1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccnc(-c2ccc(S(C)(=O)=O)cc2)c1
Temperature: 120 °C
Yield: 73.8 %

Procedure:
To a mixture of 2-chloro-4-methylpyridine (3 g, 23.5 mmol), 4-(methylsulfonyl)phenylboronic acid (5.64 g, 28.2 mmol), potassium phosphate (12.0 g, 56.4 mmol) and DMF (50 mL) under an atmosphere of nitrogen was added palladium tetrakistriphenylphosphine (1.36 g, 1.18 mmol). After heating at 120° C. for 14 hours, the reaction was cooled and the DMF removed in vacuo. The residue was partitioned between ethyl acetate (100 mL) and water (100 mL), separated and the organic layer dried over sodium sulfate and concentrated in vacuo. Purification by silica chromatography eluting with a gradient of ethyl acetate in cyclohexane gave the title compound (4.29 g, 74%) TLC RF 0.19 (1:1 ethyl acetate:cyclohexane) LC retention time 2.36 mins, MS m/z 248 (MH+)
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[N:11]=2)=[CH:6][CH:5]=1.C1COCC1.CO.[OH-].[Na+].Cl>O>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][N:12]1[C:13](=[O:16])[CH:14]=[CH:15][C:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:22])=[O:2])=[CH:9][CH:8]=2)=[N:11]1
Reactant: COC(=O)c1ccc(-c2ccc(=O)n(CCN(C)C)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CCn1nc(-c2ccc(C(=O)O)cc2)ccc1=O
Reaction time: 1.5 h
Yield: 94.2 %

Procedure:
To a solution of 4-[1-(2-dimethylamino-ethyl)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzoic acid methyl ester (542 mg, 1.8 mmol, reference example 62a) in 1:1 THF/methanol (6 mL) is added 10N NaOH (1.8 mL, 18 mmol) followed by H2O (0.5 mL). The resulting solution is stirred for 1.5 hours then cooled to 0°-5° C., adjusted to pH 6 with 2N HCl and concentrated. The residue is purified by reverse phase HPLC (eluting with 15%-40% acetonitrile(0.1%TFA)/H2O(0.1%TFA) over 20 min) to give 487 mg of title compound. 1H NMR (DMSO) δ 2.89 (s, 6H), 3.59 (m, 2H), 4.52 (bt, 2H), 7.14 (d, J=10 Hz, 1H), 8.04 (s, 4H), 8.16 (d, J=10 Hz, 1H), 9.63 (bs, 1H). MS (ion spray) m/z 288 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CC(C)=O>[Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[O:12][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(C=O)cc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1c(Cl)cc(C=O)cc1OC
Reaction time: 1 h
Yield: 44.8 %

Procedure:
To a solution of 5-chlorovanilline (505 mg, 2.7 mmol) in acetone (25 mL) was added cesium carbonate (1.16 g, 3.56 mmol), followed by ethyl bromoacetate (0.45 mL, 4.05 mmol). The mixture was refluxed in acetone under stirring for 1 hour. After evaporation of acetone under reduced pressure, 100 mL of water were added and the mixture was extracted with dichloromethane (200 mL). The organic phase was washed with brine (100 mL), dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography over silica gel (eluent: dichloromethane) to give 330 mg of an oil (45% yield). 1H NMR (250 MHz, CD3COCD3): δ 1.27 (t, J=7.2 Hz, 3H), 3.98 (s, 3H), 4.22 (q, J=7.2 Hz, 2H), 4.87 (s, 2H), 7.50 (s, 1H), 7.58 (s, 1H), 9.90 (s, 1H). 13C NMR (126 MHz, CD3COCD3): δ 15.1, 57.5, 62.1, 70.5, 112.3, 125.8, 128.9, 134.0, 149.7, 154.5, 169.5, 191.2.