Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([OH:14])[CH:7]=1)[CH3:2].[Br:16][C:17]1[CH:18]=[CH:19][C:20](F)=[C:21]([CH:24]=1)[CH:22]=[O:23].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:20]2[CH:19]=[CH:18][C:17]([Br:16])=[CH:24][C:21]=2[CH:22]=[O:23])[CH:7]=1)[CH3:2]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CCOC(=O)Cc1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2C=O)c1
Temperature: 90 °C

Procedure:
(3-Hydroxy-4-methoxy-phenyl)-acetic acid ethyl ester (2.0 g, 9.5 mmol), 5-bromo-2-fluorobenzaldehyde (2.0 g, 9.5 mmol), and potassium carbonate (2.0 g, 14.3 mmol) were combined in 1,4-dioxane and heated to 90° C. overnight. After work-up, the crude material was purified by silica gel chromatography (0-25% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][NH:24][CH2:25][CH2:26][OH:27]>>[OH:27][CH2:26][CH2:25][N:24]([CH3:23])[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:5]=[N:1][NH:2][CH:3]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:19]
Reactant: CNCCO
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CN(CCO)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 2-(methylamino)ethanol (1.2 equiv) to give 154 (10.4 mg, M+1 371.1)
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=2[CH:5]=[C:4]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:3]=1.Cl[CH:19]1[C:28]2[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=2)[O:22][CH2:21][CH2:20]1>>[F:29][C:25]1[CH:24]=[C:23]2[C:28]([CH:19]([O:1][C:2]3[C:10]4[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=4[CH:5]=[C:4]([C:13]([N:15]([CH3:16])[CH3:17])=[O:14])[CH:3]=3)[CH2:20][CH2:21][O:22]2)=[CH:27][CH:26]=1
Reactant: Fc1ccc2c(c1)OCCC2Cl
Reactant: Cc1nc2c(O)cc(C(=O)N(C)C)cc2n1C
Product: Cc1nc2c(OC3CCOc4cc(F)ccc43)cc(C(=O)N(C)C)cc2n1C
Yield: 45 %

Procedure:
The title compound was prepared as a white solid in 45% yield (0.96 g) from 4-hydroxy-N,N,1,2-tetramethyl-1H-benzimidazole-6-carboxamide (1.3 g, 5.5 mmol, WO 2004054984) and 4-chloro-7-fluorochromane (2.0 g, 11 mmol, STEP 2) by the same manner in STEP 1 of Example 1:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:5][C@H:6]2[O:12][C@H:11]([CH2:13]O)[C@@H:10]([OH:15])[C@H:9]([OH:16])[C@H:7]2[N:8]=1)[CH3:2].[Cl:17]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O>[Cl:17][CH2:13][C@H:11]1[O:12][C@H:6]2[C@H:7]([N:8]=[C:4]([NH:3][CH2:1][CH3:2])[S:5]2)[C@@H:9]([OH:16])[C@@H:10]1[OH:15]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CCl)O[C@@H]2S1
Temperature: 50 °C
Reaction time: 2 h
Yield: 16.9 %

Procedure:
In a 5 mL seal vial equipped with a stir bar was added (3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol (30.00 mg; 0.12 mmol; 1.00 eq.) and 1-chloropyrrolidine-2,5-dione (24.20 mg; 0.18 mmol; 1.50 eq.) in N,N-dimethylformamide (1.00 ml) followed by triphenylphosphine (63.38 mg; 0.24 mmol; 2.00 eq.). After the clear solution was stirred at 50° C. for 2 h, color became wine red. The reaction was stirred for overnight before it is concentrated and dissolved in 2 mL MeOH. Yamazen HPLC Channel1 (acidic condition, 220 nm, 55 g Interchim column, product efflux at H2O/ACN=75/25) was used to isolate 5.4 mg (12%) of the title compound as a white solid once lyophilized.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].CN1CCOCC1.ClC(OCC(C)C)=O.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36]1[C:37]([NH2:42])=[N:38][CH:39]=[CH:40][CH:41]=1.[NH4+].[Cl-]>C(Cl)Cl>[O:6]=[C:4]([NH:42][C:37]1[C:36]([NH:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)=[CH:41][CH:40]=[CH:39][N:38]=1)[C@@H:2]([NH:1][C:7](=[O:8])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:3]
Reactant: Nc1ncccc1Nc1ccccn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ncccc1Nc1ccccn1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a −10° C. solution (NaCl-ice bath) of Boc-L-Ala-OH (1.214 g, 6.42 mmol) and N-methylmorpholine (0.741 mL, 6.74 mmol) in DCM (16.04 mL) was added isobutyl chloroformate (0.839 mL, 6.42 mmol). The resulting cloudy light yellow mixture was stirred at −10° C. After 15 min at −10° C., to the mixture was then added a solution of N3-(pyridin-2-yl)pyridine-2,3-diamine (0.5974 g, 3.21 mmol) in DCM (16 mL) at −10° C. with stirring. The resulting mixture was allowed to warm to rt with stirring. After 15.5 h at rt, to the mixture was added satd. NH4Cl (50 mL). The organic layer was separated. The aqueous mixture was extracted with DCM (50 mL×1). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 14 min, then 50% isocratic of EtOAC in hexane for 14 min, then 50 to 100% gradient of EtOAc in hexane over 14 min, and then 100% isocratic of EtOAC for 30 min as eluent to give (S)-tert-butyl 1-oxo-1-(3-(pyridin-2-ylamino)pyridin-2-ylamino)propan-2-ylcarbamate as a light pink foamy solid: LC-MS (ESI) m/z 358.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=O)[CH:11]([C:15](=O)[CH2:16][CH3:17])[C:10](=[O:19])[CH2:9]1.O.[NH2:21][NH2:22].O.NN>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12]2[NH:22][N:21]=[C:15]([CH2:16][CH3:17])[C:11]=2[C:10](=[O:19])[CH2:9]1
Reactant: CCC(=O)C1C(=O)CC(c2ccccc2Cl)CC1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCc1n[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Yield: 142.7 %

Procedure:
A solution of 5-(2-chlorophenyl)-2-propionylcyclohexane-1,3-dione (0.6 g) and hydrazine hydrate hydrazine hydrate (0.12 g) in ethanol (20 ml) was refluxed for 2 hours. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethyl acetate-hexane to give colorless crystals of 6-(2-chlorophenyl)-3-ethyl-4,5,6,7-tetrahydroindazol-4-one (0.47 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][CH2:18][C@@H:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=2)=[CH:12][CH:11]=1.[H][H]>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[NH:20][C@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1
Reactant: [H][H]
Reactant: COC(=O)[C@@H]1CCC(c2ccc(NCc3ccccc3F)cc2)=N1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CC[C@H](c2ccc(NCc3ccccc3F)cc2)N1
Yield: 92.1 %

Procedure:
A solution of methyl (2S)-5-(4-{[(2-fluorophenyl)methyl]amino}phenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (D67, 39 mg, 0.119 mmol) and Pt 5% on carbon in ethyl acetate (10 ml) was stirred under 1 atm of hydrogen for 4.5 h, filtrated over celite and evaporated to afford the title compound (36 mg, 92%). MS: (ES/+) m/z: 329 [MH]+, —C19H21FN2O2 requires 328.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C(Cl)Cl>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:1][CH2:2][CH2:3][CH:4]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)CCCCC(CCN)Cc1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCCC(CCNS(=O)(=O)c1ccc(Cl)cc1)Cc1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 8-amino-6-(3-pyridylmethyl)-octanoate (0.5 g) is dissolved in 50 ml of methylene chloride and 3 ml of triethylamine is added. To this solution is added dropwise a solution of 0.5 g of p-chlorophenylsulfonyl chloride in 10 ml of methylene chloride. The reaction mixture is stirred at room temperature for 1 h, the solvent is evaporated and the residue thus obtained purified by chromatography over silica gel, using methylene chloride as eluent to obtain methyl 8-(p-chlorophenylsulfonamido)-6-(3-pyridylmethyl)-octanoate as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:19]3=[O:29])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:36][C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][N:38]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:36][C:37]1[N:38]=[CH:39][C:40]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]4[CH2:22][CH2:21][N:20]([CH:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[C:19]4=[O:29])=[O:17])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)=[CH:41][CH:42]=1
Reactant: O=C(Nc1ccc(Oc2ccnc(Cl)c2)cn1)N1CCN(C2CCOCC2)C1=O
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCOCC5)C4=O)nc3)ccn2)cn1
Temperature: 95 °C
Yield: 51.9 %

Procedure:
A mixture of Example C1 (0.200 g, 0.479 mmol), K2CO3 (0.132 g, 0.957 mmol) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.126 g, 0.574 mmol) in dioxane (8 mL) and water (2 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.055 g, 0.048 mmol), sparged again with Ar and heated at 95° C. overnight. The mixture was cooled to RT, treated with satd. NaHCO3 and extracted with EtOAc (4×). The combined organics were dried over Na2SO4, concentrated to dryness, suspended in MeCN and sonicated. The resulting solid was collected via filtration and dried to afford N-(5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (118 mg, 52%). 1H NMR (400 MHz, DMSO-d6): δ 10.97 (s, 1 H), 9.09 (d, J=2.3 Hz, 1 H), 8.54 (d, J=5.7 Hz, 1 H), 8.29-8.24 (m, 2 H), 8.07 (d, J=9.0 Hz, 1 H), 7.75 (dd, J=9.0, 2.9 Hz, 1 H), 7.63 (d, J=2.4 Hz, 1 H), 7.33 (d, J=8.2 Hz, 1 H), 6.87 (dd, J=5.7, 2.4 Hz, 1 H), 3.92-3.77 (m, 5 H), 3.48-3.34 (m, 4 H), 2.50 (s, 3 H), 1.77-1.65 (m, 2 H), 1.62-1.55 (m, 2H); MS (ESI) m/z: 475.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24]([O:26]C)=O.Cl.[OH-].[NH4+:30]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:30]
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1c(F)cccc1F
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1c(F)cccc1F
Yield: 70 %

Procedure:
A solution of the 9-[(2,6-difluorophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (514 mg, 1.4 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was stirred at room temperature for 64 hours. The pH was adjusted to 10.5 with 5 N HCl. The resultant precipitate was collected by filtration, resuspended in H2O, adjusted the pH to 11.7 with concentrated ammonium hydroxide. The resultant precipitate was collected by filtration. The precipitate was dissolved in ethyl acetate, washed three times with 5 N NaOH, H2O, and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated to afford 310 mg (70%) of the 9-[(2,6-difluorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a yellow solid. 1H NMR (DMSO-d6) δ 10.4 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (d, 1H, J=8 Hz), 7.6-7.0 (m, 7H), 6.6 (d, 1H, J=8 Hz), and 5.7 (s, 2H). IR (KBr, cm−1) 3404, 3113, 1626, and 1587. MS (ES) m/e 351, 353.
Reaction SMILES: C(O[C:4](=[O:21])[CH:5]([N:7]1[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH2:8]1)[CH3:6])C.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]2=[O:35])=[CH:25][C:24]=1[F:36]>>[F:36][C:24]1[CH:25]=[C:26]([N:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]2=[O:35])[CH:27]=[CH:28][C:23]=1[NH:22][C:4]([CH:5]([N:7]1[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH2:8]1)[CH3:6])=[O:21]
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Reactant: CCOC(=O)C(C)N1CC[C@@H](NC(=O)c2ccc(Cl)s2)C1
Product: CC(C(=O)Nc1ccc(-n2ccccc2=O)cc1F)N1CC[C@@H](NC(=O)c2ccc(Cl)s2)C1

Procedure:
6.4 Using general procedure F 2-{(R)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidin-1-yl}-propionic acid ethyl ester was reacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (CAS 536747-52-1, prepared according to WO 2003045912) to give 5-chloro-thiophene-2-carboxylic acid ((R)-1-{1-[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-ethyl}-pyrrolidin-3-yl)-amide. Yellow solid. MS 487.4 ([M−H]−)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:7]2[C:3]=1[CH2:4][N:5]([CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH3:35])[CH:24]=1)[CH2:19][C:20]([OH:22])=O)[C:6]2=[O:17].C1N=C[N:38](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-]>C1COCC1>[C:20]([CH2:19][CH:18]([N:5]1[C:6](=[O:17])[C:7]2[C:3](=[C:2]([Cl:1])[CH:10]=[CH:9][C:8]=2[NH:11][C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])[CH2:4]1)[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:31])[F:32])=[C:25]([O:33][CH2:34][CH3:35])[CH:24]=1)(=[O:22])[NH2:38]
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(N)=O)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Yield: 17.9 %

Procedure:
Cyclopropanecarboxylic acid {2-[2-carbamoyl-1-(4-difluoromethoxy-3-ethoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl }-amide was prepared by the procedure of Example 6 from 3-[4-chloro-7-(cyclopropanecarbonylamino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.55 g, 1.1 mmol), CDI (0.26 g, 1.6 mmol) and NH4OH (0.35 ml, 3.3 mmol) in THF (15 ml) to give cyclopropanecarboxylic acid {2-[2-carbamoyl-1-(4-difluoromethoxy-3-ethoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (0.10 g, 20%): mp 198–200° C.; 1HNMR (CDCl3): δ 0.89–0.93 (m, 2H, c-CH2), 1.10–1.20 (m, 2H, c-CH2), 1.44 (t, J=7.5 Hz, 3H, OCH2CH3), 1.66–1.68 (m, 1H, c-CH), 2.98 (dd, J=5, 15 Hz, 1H, CH2), 3.43 (dd, J=10, 15 Hz, 1H, CH2), 4.09 (q, J=7.5 Hz, 2H, OCH2CH3), 4.18 (d, J=17.5 Hz, 1H, CHHN), 4.37 (d, J=17.5 Hz, 1H, CHHN), 5.48 (br, 1H, NHH), 5.57–5.53 (m, 1H, CHN), 5.92 (br, 1H, NHH), 6.86 (t, JH-F=75 Hz, 1H, CF2H), 6.94–7.02 (m, 3H, Ar), 7.16(d, J=10 Hz, 1H, Ar), 7.38 (t, J=8 Hz, 1H, Ar), 8.45 (d, J=8 Hz, 1H, Ar), 10.40 (s, 1H, NHCO). 13CNMR (CDCl3): δ 8.5, 14.6, 16.2, 38.6, 47.9, 54.1, 64.9, 101.57, 102.3, 113.2, 116.0, 119.2, 119.8, 121.8, 123.0, 133.2, 136.8, 137.1, 139.1, 150.9, 169.4, 171.1, 172.6; Anal Calcd for C24H26ClF2N3O5: C, 56.75; H, 4.76; N, 8.27. Found: C, 56.68; H, 4.63; N, 8.04.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH:34]1[CH2:39][CH2:38][CH:37]([O:40][C:41]2[N:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[CH2:36][CH2:35]1>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:34]4[CH2:35][CH2:36][CH:37]([O:40][C:41]5[N:42]=[CH:43][CH:44]=[CH:45][N:46]=5)[CH2:38][CH2:39]4)(=[O:22])=[O:21])[CH:15]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: c1cnc(OC2CCNCC2)nc1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N4CCC(Oc5ncccn5)CC4)c3)n2)n1
Yield: 54.2 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available 2-(piperidin-4-yloxy)-pyrimidine [CAS-no. 499240-48-1] (0.367 g, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.140 g, 54%) as a white foam. MS (ISP) 632.3 [(M+H)+]; mp 134° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[C:12]([Cu])#[N:13].O>CN(C)C=O.Cl.[Fe](Cl)(Cl)Cl>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: N#C[Cu]
Reactant: O=C1CCc2cc(Br)ccc21
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)CCC2=O

Procedure:
9.5 g of 5-bromoindan-1-one and 4.93 g of CuCN are suspended in 10 ml of dimethylformamide and the mixture is refluxed for 4 hours. A solution of 18 g of iron(III) chloride in 5 ml of conc. hydrochloric acid with 30 ml of water is added dropwise with stirring to the cooled, dark-brown, viscous suspension and the mixture is then stirred at 70° C. for 30 minutes. The reaction mixture is extracted three times by shaking with 50 ml of toluene, and the combined organic phases are extracted by shaking with 50 ml of 2N hydrochloric acid and 50 ml of 2N sodium hydroxide solution and then washed with water until neutral. The toluene extract is dried over magnesium sulfate and concentrated in vacuo, and the residue is recrystallized from n-heptane. 1-Oxoindan-5-carbonitrile of melting point 123-125° C. is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:16]1[CH2:20][CH2:19][C:18](=O)[CH2:17]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH3:15])[CH:18]2[CH2:19][CH2:20][O:16][CH2:17]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCOC1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C1CCN(C(=O)OC(C)(C)C)CC1)C1CCOC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.9 %

Procedure:
A mixture of 4-(methylamino)piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.93 mmol), dihydrofuran-3-one (145 μl, 161 mg, 1.87 mmol), 4 Å powdered molecular sieves (550 mg) and DIPEA (323 μl, 241 mg, 1.87 mmol) in DCM (10 mL) was stirred at room temperature for 30 min before the addition of sodium triacetoxyborohydride (396 mg, 1.87 mmol). The reaction mixture was stirred at room temperature for 16 h then diluted with DCM and washed with H2O. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording the title compound as an oil (132 mg, 50%). 1H NMR (CDCl3, 300 MHz): δ 4.33-4.05 (m, 2 H); 4.01-3.91 (m, 1 H); 3.90-3.73 (m, 2 H); 3.68-3.48 (m, 1 H); 3.47-3.23 (m, 1 H); 2.72-2.56 (m, 2 H); 2.21 (s, 3 H); 2.11-1.94 (m, 1 H); 1.93-1.78 (m, 1 H); 1.76-1.63 (m, 2 H); 1.76-1.63 (m, 1 H); 1.54-1.46 (m, 2 H); 1.46 (s, 9 H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:13](=[O:31])[CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[C:27]([O:26][C:24]([N:21]1[CH2:20][CH2:19][CH:18]([NH:17][N:14]2[CH2:15][CH2:16][NH:11][CH2:12][C:13]2=[O:31])[CH2:23][CH2:22]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(NN2CCN(C(=O)OCc3ccccc3)CC2=O)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(NN2CCNCC2=O)CC1

Procedure:
A solution of 4-benzyloxycarbonyl-1-[1-(tert-butoxycarbonyl)-4-piperidinylamino]-2-piperazinone (3.7 g) and 10% Pd/C (800 mg) in methanol (150 ml) was stirred at room temperature for 15 hours under a hydrogen atmosphere. The catalyst was filtered off and the reaction mixture was concentrated to obtain 1-[1-(tert-butoxycarbonyl)-4-piperidinylamino]-2-piperazinone.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[C:10]([CH2:13][CH:14]([C:18]([OH:20])=[O:19])C(O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[Cl-].[Na+].[CH3:24]N(C=O)C>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[C:10]([CH2:13][CH2:14][C:18]([O:20][CH3:24])=[O:19])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CC=C(CC(C(=O)O)C(=O)O)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(=O)CCC1=CCN(C(=O)OC(C)(C)C)C1
Temperature: 150 °C
Yield: 92 %

Procedure:
To a solution of 4.52 g (14.4 mmol) 2-(1-tert.-butoxycarbonyl-2,5-dihydro-1H-pyrrol-3-yl-methyl)-malonic acid idimethylester n 140 ml DMF were added 1.94 g (108 mmol) water and 1.26 g( 21.6 mmol) sodium chloride. The mixture was degassed and heated to 150° C. for 30 h under an atmosphere of argon. After this period of time no starting material could be detected by TLC. The mixture was cooled to room temperature, diluted with 200 ml ether and washed three times with water, then with brine. The organic layer was dried over MgSO4 and evaporated. Purification by bulb-to-bulb distillation gave 3.38 g (92%) of 3-(2-methoxycarbonyl-ethyl)-2,5-dihydropyrrole-1-carboxylic acid tert. butylester as a colorless oil, b.p. 130° C. (0.2 mbar).
Reaction SMILES: CC([Si](C)(C)[O:6]C1CC(CCC2C3C(=CC(C)CC3O)C=CC2C)OC(=O)C1)(C)C.[Cl:31][C:32]1[CH:44]=[CH:43][C:35]([O:36][C:37]([CH3:42])([CH3:41])[C:38](Cl)=[O:39])=[CH:34][CH:33]=1>N1C=CC=CC=1>[Cl:31][C:32]1[CH:44]=[CH:43][C:35]([O:36][C:37]([CH3:42])([CH3:41])[C:38]([OH:6])=[O:39])=[CH:34][CH:33]=1
Reactant: CC1C=C2C=CC(C)C(CCC3CC(O[Si](C)(C)C(C)(C)C)CC(=O)O3)C2C(O)C1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of [1S-[1α(4R*,6R*),2α,6β,8β,8aα]]-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6-[2-(1,2,6,7,8,8a-hexahydro-8-hydroxy-2,6-dimethyl-1-naphthalenyl)ethyl]tetrahydro-2H-pyran-2-one in an amount of 1.00 g (2.29 mmol), 18.6 ml of dry pyridine, 1.40 g (1.15 mmol) 4-N,N-dimethylaminopyridine and 5.34 g (22.9 mmol) of 2-(4-chlorophenoxy)-2-methylpropionyl chloride was heated at 50° C. for 63/4hour, then stirred overnight at room temperature. Ice chips were then added, and after 30 min the mixture was poured into ice water and extracted four times with diethylether. The combined ether layers were washed with water, then washed with 0.1M H2SO4 and then dried over a conventional drying agent, preferably anhydrous sodium sulfate. The mixture was filtered and volatiles removed under reduced pressure (i.e. below atmospheric pressure, preferably around 30 mm). The residue was dissolved in diethylether, washed with saturated sodium bicarbonate solution and dried over anhydrous sodium sulfate. The mixture was filtered and volatiles removed under reduced pressure to leave 1.6 of 2-(4-chlorophenoxy)-2-methylpropionic acid-[1S-[1α,3α,7β,8β(2R*,4R*),8aβ]]-8-[2[tetrahydro-4-[ [(1,1-dimethylethyl)dimethylsilyl]oxy]6-oxo-2H-pyran-2-yl]ethyl]-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-1-naphthalenyl ester as a brown oil which was used directly without further purification.