Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([CH:7]=O)[N:4]([CH3:9])[N:3]=1.[Cl-].[CH3:11][C:12]1[N:17]2[N:18]=[C:19]([CH2:21][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:20]=[C:16]2[C:15]([CH3:41])=[CH:14][N:13]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[Br:1][C:2]1[N:6]=[C:5](/[CH:7]=[CH:21]/[C:19]2[N:20]=[C:16]3[N:17]([C:12]([CH3:11])=[N:13][CH:14]=[C:15]3[CH3:41])[N:18]=2)[N:4]([CH3:9])[N:3]=1
Reactant: Cc1cnc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Reactant: Cn1nc(Br)nc1C=O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cnc(C)n2nc(/C=C/c3nc(Br)nn3C)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.9 %

Procedure:
To a solution of 3-bromo-1-methyl-1H-1,2,4-triazole-5-carbaldehyde (120 mg, 632 μmol, Eq: 1.00) in tetrahydrofuran (25 ml) were added ((5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methyl)triphenylphosphonium chloride (290 mg, 632 μmol, Eq: 1.00) (prepared as described in WO2011150156, pp 123-125, Expl. 24 g) and DBU (106 mg, 105 μl, 695 μmol, Eq: 1.1). The resulting solution was stirred for 18 hours at 25° C. The crude material was applied on silica gel and purified by flash chromatography over a 20 g silica gel column using ethyl acetate methanol 0-10% as eluent affording 2-[(E)-2-(5-bromo-2-methyl-2H-[1,2,4]triazol-3-yl)-vinyl]-5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidine (154 mg, 73%) as a white solid. MS: m/z=336.63537 (M+H+)
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH:19]1([NH2:22])[CH2:21][CH2:20]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH2:4]([O:3][C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13](=[O:15])[NH:22][CH:19]1[CH2:21][CH2:20]1)=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: NC1CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NC1CC1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.6 %

Procedure:
A mixture of carbobenzyloxy-L-proline (994 mg, 3.99 mmol), cyclopropylamine (0.41 mL, 5.9 mmol), HOBt (807 mg, 6 mmol), EDC (1.12 g, 5.9 mmol) and TEA (1.1 mL) in DMF (11 mL) was stirred at room temperature for 48 hours. The reaction was quenched with saturated sodium bicarbonate and extracted with dichloromethane. The organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was column chromatographed to give 985 mg (81%) of (S)-2-cyclopropylcarbamoyl-pyrrolidine-1-carboxylic acid benzyl ester.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[CH:10]([C:19]([OH:21])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:25])=O>C(Cl)Cl.CN(C=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[CH:10]([C:19]([Cl:25])=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CN(Cc2ccccc2)CCC1c1ccsc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1CN(Cc2ccccc2)CCC1c1ccsc1

Procedure:
A solution of the product from step d) (4.68 g, 13.8 mmol) in CH2Cl2 (77 ml) was treated with DMF (3-4 drops) and oxalyl chloride (2.72 ml, 31 mmol) at 22° C. for 1 hour. Next, the solvent was evaporated providing the subtitle compound (4.38 g) that was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]3[CH2:20][CH:19]4[CH:21](C(O)=O)[CH:16]([CH2:17][CH2:18]4)[CH:15]=3)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].C([O-])(O)=[O:30].[Na+]>C1COCC1>[O:30]=[C:21]1[CH:16]2[CH2:17][CH2:18][CH:19]1[CH2:20][CH:14]([C:7]1[NH:6][C:5]3[C:4](=[O:25])[N:3]([CH2:26][CH2:27][CH3:28])[C:2](=[O:1])[N:10]([CH2:11][CH2:12][CH3:13])[C:9]=3[N:8]=1)[CH2:15]2
Reactant: O=C([O-])O
Reactant: CCCn1c(=O)c2[nH]c(C3=CC4CCC(C3)C4C(=O)O)nc2n(CCC)c1=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C3CC4CCC(C3)C4=O)nc2n(CCC)c1=O
Temperature: 25 °C

Procedure:
The product (390 mg) from Example 35, was taken in THF (10 ml) 6N HCl (3 ml) and heated to reflux overnight. The next day, after cooling to room temperature, poured over ice, neutralized with NaHCO3, extracted with ethyl acetate, washed with brine and dried over MgSO4. Filtered, concentrated, and purified on silica. Yield (321 mg). Mass (ES+ 359).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C(N(C(C)C)CC)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:8][C:5]1[N:6]=[CH:7][C:2](/[CH:11]=[CH:10]/[C:9]([O:13][CH2:14][CH3:15])=[O:12])=[N:3][CH:4]=1
Reactant: C=CC(=O)OCC
Reactant: Brc1cnc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnc(Br)cn1
Temperature: 115 °C
Yield: 8.6 %

Procedure:
A solution of 2,5-dibromopyrazine (238.0 mg, 1.0 mmol), ethyl acrylate (174.0 μL, 1.6 mmol), palladium(II) acetate (3.4 mg, 0.015 mmol), and tri(o-tolyl)phosphine (36.5 mg, 0.12 mmol) in DMF (1.4 mL) and diisopropylethylamine (0.7 mL) was heated at reflux (115° C. oil bath) for 4.4 h, cooled to room temperature, and then quenched with H2O. The suspension was extracted with EtOAc (300 mL). The extract was washed (brine) and dried. After solvent removal at reduced pressure, the residue was purified on silica gel (11% EtOAc/hexane) to give 22 mg (8.5%) of ethyl(E)-3-(5-bromo-2-pyrazinyl)-2-propenoate as a cream solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[F:26][C:27]([C:30]1[CH:34]=[C:33]([NH:35][C:36](=O)[O:37]C2C=CC=CC=2)[O:32][N:31]=1)([CH3:29])[CH3:28].COC1C=C2C(=CC=1OC)N=CN=C2OC1C=C(NC(NC2ON=C(C(C)C)C=2)=O)C=CC=1>>[F:26][C:27]([C:30]1[CH:34]=[C:33]([NH:35][C:36]([NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([O:18][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:20]=2)=[O:37])[O:32][N:31]=1)([CH3:28])[CH3:29]
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(F)c1cc(NC(=O)Oc2ccccc2)on1
Agent: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)F)no4)c3)c2cc1OC
Yield: 42.4 %

Procedure:
Prepared from 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (72 mg, 0.212 mmol) and phenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate from Example 42A (56 mg, 0.212 mmol) according to the method described for 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea in Example 122B to afford 1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea as a colorless solid (46 mg, 43%). 1H NMR (300 MHz, DMSO-d6) δ 10.45 (brs, 1H), 9.12 (brs, 1H), 8.56 (s, 1H), 7.57-7.58 (m, 2H), 7.39-7.45 (m, 2H), 7.32 (m, 1H), 7.00 (m, 1H), 6.14 (s, 1H), 4.32-4.35 (m, 2H), 3.99 (s, 3H), 3.75-3.78 (m, 2H), 3.35 (s, 3H), 1.67 (d, J=21 Hz, 6H); LC-MS (ESI) m/z 512 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:41][C:42]([OH:45])([CH3:44])[CH3:43])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([C:17](O)=[O:18])=[CH:12][C:11]=3[N:10]=[C:9]([NH:20][C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:8]=2[N:40]=1)[CH3:2].CN([C:49]([O:53][N:54]1N=NC2C=CC=C[C:55]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CNOC>CN(C=O)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:41][C:42]([OH:45])([CH3:43])[CH3:44])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([C:17]([N:54]([O:53][CH3:49])[CH3:55])=[O:18])=[CH:12][C:11]=3[N:10]=[C:9]([NH:20][C:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:8]=2[N:40]=1)[CH3:2]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCOCc1nc2c(NC(c3ccccc3)(c3ccccc3)c3ccccc3)nc3cc(C(=O)O)ccc3c2n1CC(C)(C)O
Agent: CNOC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOCc1nc2c(NC(c3ccccc3)(c3ccccc3)c3ccccc3)nc3cc(C(=O)N(C)OC)ccc3c2n1CC(C)(C)O
Yield: 111.1 %

Procedure:
To a solution of 2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinoline-7-carboxylic acid (484 mg, 741 μmol) in DMF (5.19 mL) in an inert atmosphere was added TBTU (357 mg, 1.11 mmol), DIEA (388 μL, 2.22 mmol) and N,O-dimethylhydroxylamine hydrochloride (108 mg, 1.11 mmol) with stirring. The reaction mixture was stirred for 1 h at room temperature and afterwards the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate (40 mL, 2×20 mL) and water (40 mL). The organic phases were washed with water (2×20 mL), combined, dried over MgSO4, concentrated in vacuo and purified by flash chromatography (silica gel, 50% to 100% ethyl acetate in heptane) to give the title compound (0.53 g, quant.) as white foam; LC-MS (UV peak area, ESI) 92%, 644.4 (MH+).
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)OCC)C.C(OP([CH:24](O)[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)(=O)OCC)C>O1CCCC1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:24]=[CH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:26][CH:27]=1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Reactant: CCOP(=O)(OCC)C(O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: Clc1ccc(C=Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
22.8 g (0.1 mol) of benzylphosphonic acid diethyl ester were added dropwise to a solution, cooled to 0° to 5° C., of 22.4 g (0.2 mol) of potassium tert.-butylate in 100 ml of tetrahydrofuran (dried over sodium) in the course of 15 minutes. The mixture was stirred for one hour; a solution of 28 g (0.1 mol) of α-hydroxy-4-chlorobenzylphosphonic acid diethyl ester in 50 ml of tetrahydrofuran was then added to the mixture, while cooling to 0° to 5° C., and the mixture was stirred at room temperature (about 20° C.) for a further 15 hours. It was then poured into 1 liter of ice-water, filtered off and dried. 18 g (84% of theory) of 1-(4-chlorophenyl)-2-phenyl-ethylene were thus obtained in the form of colorless crystals of melting point 130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][C:6]1[C:7]([CH2:13][CH3:14])=[N:8][NH:9][C:10]=1[CH2:11][CH3:12].[CH2:19]=[O:20]>O.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][C:6]1[C:10]([CH2:11][CH3:12])=[N:9][N:8]([CH2:19][OH:20])[C:7]=1[CH2:13][CH3:14]
Reactant: C=O
Reactant: CCc1n[nH]c(CC)c1Cc1cc(Cl)cc(Cl)c1
Solvent: CCO
Solvent: O
Product: CCc1nn(CO)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.7 %

Procedure:
A solution of the pyrazole of Example 11 (283 mg, 1.00 mmol) in water (1 ml) and ethanol (0.5 ml) was treated with 37% w/w aqueous formaldehyde solution (112 μL, 1.50 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The reaction was then stirred under reflux for 2 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organic extract was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with pentane:ethyl acetate (2:1, by volume) to afford the title compound (231 mg) as a white solid, m.p. 117-118° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[C:9]3=[CH:19][CH:20]=[CH:21][N:8]3[CH2:7][C:6]=2[CH:22]=1.[Br:23]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Br:23][C:21]1[N:8]2[C:9]([CH:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[O:11][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][C:6]=3[CH2:7]2)=[CH:19][CH:20]=1
Reactant: CN1CCC(C2Oc3ccc(Cl)cc3Cn3cccc32)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCC(C2Oc3ccc(Cl)cc3Cn3c(Br)ccc32)CC1

Procedure:
A solution of 7-chloro-11-[(1-methyl)piperidin-4-yl]-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (5.5 g; 0.017 mole) and N-bromosuccinimide (3.7 g; 0.021 mole) in 150 ml of tetrahydrofuran was stirred for 20 hours at ambient temperature. The reaction mixture was then diluted with ethyl acetate and washed twice with a dilute Na2SO3 solution and once with water and dried (saturated NaCl solution, anhydrous MgSO4).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][N:12]=2)[CH:4]=1)[CH3:2].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:13][N:12]=2)[CH:4]=1)[CH3:2]
Reactant: C1CCNC1
Reactant: CCc1cc(-c2ccc(C(=O)O)cn2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(C(=O)N3CCCC3)cn2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-5-carboxylic acid and pyrrolidine to afford the title compound. MS: m/e=312 (M+H).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]1[C:34](O)=[O:35].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][C:34]([C:26]2[NH:25][C:33]3[C:28]([CH:27]=2)=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:35])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1)c1cc2ccccc2[nH]1

Procedure:
200 mg (0.550 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reacted in analogy to Example 4a with 106 mg (0.661 mmol) of indole-2-carboxylic acid, 168 mg (0.661 mmol) of bis(2-oxo-3-oxazolidinyl)phosphinic chloride and 169 μl (1.21 mmol) of triethylamine. The title compound ##STR87## is obtained (89 mg, 32%) as white crystals with melting point 254° C. TLC: methylene chloride/methanol/conc. ammonia (2000:50:1) Rf =0.56, FD-MS: M+ =505, 507; IR: 3430, 3290, 1625 cm-1.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]/[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[N:10]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:9]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33].[O:37]=[C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40](=[O:47])[N-:39]1.[K+]>CN(C)C=O.C(OCC)(=O)C>[O:37]=[C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40](=[O:47])[N:39]1[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]/[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[N:10]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:9]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)c1c(/C=C/CCCCCl)c2cc(F)ccc2n1CCCOc1cccc2ccccc12
Reactant: O=C1[N-]C(=O)c2ccccc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(/C=C/CCCCN2C(=O)c3ccccc3C2=O)c2cc(F)ccc2n1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 160A (531 mg) and potassium 1,3-dioxoisoindolin-2-ide (213 mg) in N,N-dimethylformamide (10 ml) was heated at 80° C. for 8 hours. The reaction was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and was concentrated. The residue was purified by flash chromatography, eluting with 0-100% ethyl acetate in dichloromethane to give (E)-ethyl 3-(6-(1,3-dioxoisoindolin-2-yl)hex-1-enyl)-5-fluoro-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate. This ester was dissolved in a mixture of tetrahydrofuran and methanol and 5 equivalents of aqueous NaOH (10%) was added. The mixture was heated at 50° C. for 5 hours. The reaction mixture was concentrated and the residue was dissolved in dimethyl sulfoxide and trifluoroacetic acid-methanol (3:1), and purified by RPHPLC to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 13.06 (s, 2H), 8.25 (t, J=5.52 Hz, 1H), 8.19 (dd, J=7.83, 1.38 Hz, 1H), 7.86 (dd, J=7.21, 1.99 Hz, 1H), 7.74 (dd, J=7.52, 1.38 Hz, 1H), 7.60-7.69 (m, 2H), 7.43-7.58 (m, 5H), 7.34-7.41 (m, 2H), 6.99-7.16 (m, 2H), 6.85 (d, J=7.36 Hz, 1H), 6.15-6.32 (m, 1H), 4.65-4.96 (m, 2H), 4.13 (t, J=5.68 Hz, 2H), 3.20-3.29 (m, 2H), 2.20-2.36 (m, 4H), 1.49-1.67 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8](O)=[O:9].[C:12]([C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:8]([C:7]2[CH:6]=[C:5]([Cl:11])[N:4]=[N:3][C:2]=2[Cl:1])=[O:9])=[CH:20][CH:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(NC(=O)c2cc(Cl)nnc2Cl)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3,6-Dichloro-pyridazine-4-carboxylic acid (1.93 g, 10 mmol), 4-tert-Butyl-phenylamine (1.49 g, 10 mmol), DIEA (3.5 mL, 20 mmol), and HATU (4.56 g, 12 mmol) were added to DMF (20 mL). The reaction was stirred at rt for 15 h. The resulting dark brown solution was extracted with DCM (2×10 mL), washed with H2O (2×10 mL), and dried over sodium sulfate. The curde product was further purified using Flash Chromatography (2% MeOH/DCM), affording the desired product as yellow solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23]Cl>CCO>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][S:15][C:13]1[O:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]3[NH:3][CH:2]=[N:1][C:5]=3[CH:6]=2)=[N:11][N:12]=1
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Reactant: ClCc1ccccn1
Agent: Cl
Solvent: CCO
Product: c1ccc(CSc2nnc(-c3ccc4[nH]cnc4c3)o2)nc1

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.418 mL, 3.0 mmol) and (pyridin-2-yl)methylchloride hydrochloride (0.246 g, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.C(=O)=O.CC(C)=O.O[C:18]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=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]1.ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][C:18]([F:7])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:19][CH2:20]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2)CC1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(F)(c2ccccc2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
A solution of diethylaminosulfur trifluoride (4 mL, 32.7 mmol) in dichloromethane (10 mL) was added to a cold (−78° C.; dry ice/acetone bath) solution of tert-butyl 4-hydroxy-4-phenylpiperidine-1-carboxylate (8.05 g, 29.0 mmol) in dichloromethane (100 mL) under nitrogen. The reaction was stirred at −78° C. for ˜1 hour. The reaction was removed from the bath and warmed to ambient temperature then stirred another 30 minutes. The reaction was quenched with saturated aqueous NaHCO3 (100 mL). The organic fraction was washed with brine (˜50 mL). Then 3-chloroperoxybenzoic acid (1.0995 g, 6.37 mmol) was added to the reaction and stirred at ambient temperature for 30 minutes. This step was quenched with saturated aqueous NaHCO3 (100 mL). The organic fraction was washed with saturated aqueous NaHCO3 (1×100 mL), water (1×100 mL), and brine (1×100 mL), dried (MgSO4), tested for peroxide (3-10 ppm) and concentrated to light yellow oil. The oil was dried under vacuum to afford 8.27 g (100%) of the titled compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (d, J=5.7, 9H), 1.96-1.85 (m, 3.5H), 2.03 (ddd, J=5.2, 13.3, 17.8, 1.5H), 3.06 (s, 2H), 3.98 (d, J=12.0, 2H), 7.33 (d, J=7.1, 1H), 7.46-7.36 (m, 4H); MS (DCI) m/z 280 (M+H+, 60%), 297 (M+NH4+, 100%).
Reaction SMILES: [C:1]1(=[O:30])[N:5]([CH2:6][CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19])[CH:15]=3)[NH:10][CH:9]=2)[C:4](=[O:25])[C:3]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:2]12.[H-].[Na+].[C:33]1([CH3:43])[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>C(#N)C>[C:4]1(=[O:25])[N:5]([CH2:6][CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][S:18]([C:21]([F:24])([F:22])[F:23])(=[O:20])=[O:19])[CH:15]=3)[N:10]([S:39]([C:36]3[CH:37]=[CH:38][C:33]([CH3:43])=[CH:34][CH:35]=3)(=[O:41])=[O:40])[CH:9]=2)[C:1](=[O:30])[C:2]2=[CH:29][CH:28]=[CH:27][CH:26]=[C:3]12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc(OS(=O)(=O)C(F)(F)F)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(CCN3C(=O)c4ccccc4C3=O)c3cc(OS(=O)(=O)C(F)(F)F)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60.1 %

Procedure:
To a solution of 3-(2-phthalimidoethyl)-5-trifluoromethanesulfonyloxy-1H-indole (Example 10) (0.640 g, 1.46 mmol) in anhydrous acetonitrile (15 mL) was added sodium hydride (60% dispersion in mineral oil, 0.335 g, 23.3 mmol) and the resulting mixture was stirred at room temperature under argon for 5 minutes. p-Toluenesulfonyl chloride (0.333 g, 1.75 mmol) was then added and the mixture stirred at room temperature for 2 hours. After quenching with water (20 mL), the mixture was extracted with ethyl acetate (2×20 mL) and the organic phase dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica gel using hexane/ethyl acetate (4:1 and 2:1) to provide the title compound (0.520 g, 60%) as a white solid. 1H NMR (CDCl3, 300 MHz) δ: 8.03 (d, J=9.0 Hz, 1H), 7.86-7.83 (A2 of A2B2 system, 2H), 7.75-7.72 (B2 of A2B2 system and A2' of A2'B2' system, 4H), 7.58 (s, 1H), 7.51 (d, J=2.4 Hz, 1H), 7.26-7.21 (B2' of A2'B2' system, 2H), 7.20 (dd, J=2.4 and 9.0 Hz, 1H), 3.97 (t, J=7.3 Hz, 2H), 3.05 (t, J-7.3 Hz, 2H), 2.36 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH2:14][C@H:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]#[N:25])[CH:22]=2)[CH2:17][C:16]1([CH3:27])[CH3:26].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:24]([C:21]1[CH:22]=[C:23]2[C:18]([CH2:17][C:16]([CH3:27])([CH3:26])[C@H:15]2[NH:14][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)=[O:13])=[CH:19][CH:20]=1)#[N:25]
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Reactant: CC1(C)Cc2ccc(C#N)cc2[C@@H]1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC1(C)Cc2ccc(C#N)cc2[C@@H]1NC(=O)c1cc2cc(F)ccc2[nH]1
Temperature: 50 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
A mixture of 5-fluoro-1H-indole-2-carboxylic acid (56.0 mg, 0.312 mmol), (R)-3-amino-2,2-dimethyl-2,3-dihydro-1H-indene-5-carbonitrile (39.0 mg, 0.209 mmol), BOP reagent (180 mg, 0.407 mmol), N-methylmorpholine (0.13 mL, 1.18 mmol) in DMF (0.5 mL) was stirred at 50° C. for 2 hr. The desired title product (55.6 mg, 76% yield) was isolated as a white solid by prep. HPLC. LCMS (M+H)+=348.33. 1H NMR (500 MHz, DMSO-d6) δ: 11.7 (s, 1H), 8.58 (d, J=8.8 Hz, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.62 (s, 1H), 7.46 (d, J=7.7 Hz, 1H), 7.44 (dd, J=8.8, 5.0 Hz, 1H), 7.39 (d, J=9.9 Hz, 1H), 7.28 (s, 1H), 7.04 (t, J=9.35 Hz, 1H), 5.37 (d, J=9.35 Hz, 1H), 2.87 (dd, J=22.0, 16.5 Hz, 2H), 1.21 (s, 3H), 0.94 (s, 3H).