Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CCN(CC)CC.[Cl:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([S:33](Cl)(=[O:35])=[O:34])[CH:31]=2)[C:26]([Cl:37])=[CH:25][N:24]=1>C(Cl)Cl>[Cl:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([S:33]([NH:1][C@@H:2]3[CH2:3][CH2:4][C@H:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)(=[O:35])=[O:34])[CH:31]=2)[C:26]([Cl:37])=[CH:25][N:24]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CC[C@@H](N)CC1
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)cnc(Cl)c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@H]1CC[C@@H](NS(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of t-butyl cis-4-aminocyclohexanecarboxylate (282 mg, 1.20 mmol), NEt3 (0.33 mL, 2.37 mmol) and 1,4-dichloro-7-isoquinolinesulphonyl chloride (296 mg, 1.00 mmol) in CH2Cl2 (10 mL) was stirred at 0° C. for 1 h. The mixture was diluted with CH2Cl2 (150 mL), was washed with dilute HCl (30 mL, 1 M), water, dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using pentane-EtOAc (100:0 to 75:25) to give t-butyl cis-4-{[(1,4-dichloro-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylate (360 mg, 0.78 mmol) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[S:3]([C:6]1[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:8]=2[CH:7]=1)(=[O:5])=[O:4].S(C1C=CC([N+]([O-])=O)=CC=1)(OC[C@H:23]1[O:25][CH2:24]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][N:2]([CH3:17])[S:3]([C:6]1[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH2:16][C@H:24]3[O:25][CH2:23]3)[C:8]=2[CH:7]=1)(=[O:5])=[O:4]
Reactant: COc1cccc2oc(S(=O)(=O)N(C)C)cc12
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C)S(=O)(=O)c1cc2c(OC[C@@H]3CO3)cccc2o1

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 2-(N,N-dimethylsulfamoyl)-4-methoxybenzo(b)furan (1.10 g), (S)-glycidyl nosylate (1.30 g) and potassium carbonate (1.89 g), a crude product of the title compound was quantitatively obtained as a pale-yellow oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH:24]([O:27][C:28]1[C:29]([CH2:43][OH:44])=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)([CH3:26])[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][C:29]([CH2:43][OH:44])=[C:28]([O:27][CH:24]([CH3:26])[CH3:25])[CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CC(C)Oc1cc(B2OC(C)(C)C(C)(C)O2)cnc1CO
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc(CO)c(OC(C)C)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and [3-isopropoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-methanol (Stage 190.1.1) to give the title compound as a white solid. (HPLC: tR 2.19 min (Method A); M+H=459 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.27-8.23 (m, 1H), 8.15-8.10 (m, 2H), 8.03-7.98 (m, 1H), 7.62-7.59 (m, 1H), 7.40-7.37 (m, 1H), 4.84 (br, 1H), 4.76 (hp, 1H), 4.55 (s, 2H), 3.88 (s, 3H), 3.58 (s, 3H), 1.97 (s, 3H), 1.36-1.31 (m, 6H))
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:33])[C:5]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]4[CH2:30][CH2:29][CH2:28][C:27](=[O:31])[NH:26][C:25]=4[CH:32]=3)[N:14]=2)=[C:6]([CH:11]=1)[C:7]([NH:9][CH3:10])=[O:8].C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[C:50]([C:52]1[CH:57]=[CH:56][C:55](B(O)O)=[CH:54][CH:53]=1)#[N:51]>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>[CH3:10][NH:9][C:7]([C:6]1[CH:11]=[C:2]([C:55]2[CH:56]=[CH:57][C:52]([C:50]#[N:51])=[CH:53][CH:54]=2)[CH:3]=[C:4]([F:33])[C:5]=1[NH:12][C:13]1[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]2[CH:22]=[CH:23][C:24]3[CH2:30][CH2:29][CH2:28][C:27](=[O:31])[NH:26][C:25]=3[CH:32]=2)[N:14]=1)=[O:8]
Reactant: CNC(=O)c1cc(Br)cc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3)ncc1Cl
Reactant: N#Cc1ccc(B(O)O)cc1
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: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CNC(=O)c1cc(-c2ccc(C#N)cc2)cc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3)ncc1Cl
Temperature: 90 °C
Yield: 43.7 %

Procedure:
5-Bromo-2-[5-chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide (55.0 mg, 0.103 mmol) was dissolved in toluene (4.00 mL, 37.6 mmol) and ethanol (4.00 mL, 68.5 mmol). Tetrakis(triphenylphosphine)palladium(0) (11.9 mg, 0.0103 mol) was added followed by 1.00 M sodium carbonate in water (412 uL) and 4-cyanophenylboronic acid (21.2 mg, 0.144 mmol). The reaction was heated at 90° C. overnight and then concentrated under reduced pressure. The residue was taken up in DCM (10 mL) and washed with 1 M Na2CO3 (10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by prep-HPLC using a gradient of 20-45% AcN/water containing 0.1% TFA as the eluting solvent to obtain 4-[5-chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-4′-cyano-5-fluoro-biphenyl-3-carboxylic acid methylamide as a white foam (25 mg, 44%). LCMS (m/e) 556 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.54 (s, 1H), 9.40-9.30 (m, 2H), 8.80-8.71 (m, 1H), 8.21 (s, 1H), 8.08-7.98 (m, 4H), 7.95 (d, 1H, J=12.1 Hz), 7.89 (s, 1H), 7.27 (d, 1H, J=8.1 Hz), 7.16-7.10 (m, 1H), 6.93 (d, 1H, J=8.1 Hz), 2.77 (d, 3H, J=4.2 Hz), 2.60-2.43 (m, 2H), 2.02-1.94 (m, 4H); 19F-NMR (d6-DMSO, 400 MHz) δ −75.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:28][CH2:27][C:13]3([C:18]4=[CH:19][CH:20]=[CH:21][N:17]4[C:16]4[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:15]=4[O:14]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[O:29][CH3:30].C[Si](C)(C)[O:33][CH:34]=[CH2:35]>CN(C=O)C.F[Zn]F>[Cl:26][C:24]1[CH:23]=[CH:22][C:16]2[N:17]3[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]3([CH2:27][CH2:28][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([CH2:35][CH:34]=[O:33])=[C:3]([O:29][CH3:30])[CH:4]=4)=[O:9])[CH2:11][CH2:12]3)[O:14][C:15]=2[CH:25]=1
Reactant: C=CO[Si](C)(C)C
Reactant: COc1cc(C(=O)N2CCC3(CC2)Oc2cc(Cl)ccc2-n2cccc23)ccc1Br
Agent: F[Zn]F
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2cc(Cl)ccc2-n2cccc23)ccc1CC=O
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a microwave vial was added Pd(tBu3P)2 (128 mg, 0.250 mmol) and difluorozinc (259 mg, 2.50 mmol). The vial was capped and purged with nitrogen for 10 minutes. DMF (1 mL) was added and the mixture was stirred for 10 minutes. A solution of (4-bromo-3-methoxy-phenyl)-(7′-chlorospiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl)methanone (244 mg, 0.500 mmol) in DMF (1.5 mL) was added followed by trimethyl(vinyloxy)silane (581 mg, 5.00 mmol). The reaction mixture was heated at 80° C. for 1 h before it was quenched with brine and extracted with EtOAc (3×). The combined organic layers were dried over sodium sulfate and the solvent was removed. The crude reaction was purified by silica gel chromatography (5%-80% ethyl acetate/hexanes) to give 2-(4-(7-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-ylcarbon-yl)-2-methoxyphenyl)acetaldehyde.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[CH:7]=[C:6]2[C:14]2[N:18]([CH3:19])[C:17]3[C:20](OC)=[CH:21][C:22]([C:24]([O:26][CH3:27])=[O:25])=[CH:23][C:16]=3[N:15]=2)[CH2:3][CH2:2]1.CNC1C=CC(C(OC)=O)=CC=1[N+]([O-])=O.C1(CN2C3=NC=CC=C3C=C2C=O)CC1>>[CH:1]1([CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[CH:7]=[C:6]2[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][C:22]([C:24]([O:26][CH3:27])=[O:25])=[CH:23][C:16]=3[N:15]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(OC)c2c(c1)nc(-c1cc3cccnc3n1CC1CC1)n2C
Agent: CNc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: O=Cc1cc2cccnc2n1CC1CC1
Product: COC(=O)c1ccc2c(c1)nc(-c1cc3cccnc3n1CC1CC1)n2C

Procedure:
Prepared in a similar manner to Intermediate 44 using methyl 4-(methylamino)-3-nitrobenzoate (89 mg, 0.424 mmol) and 1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (85 mg, 0.424 mmol).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18](I)[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH2:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.[CH2:21]([OH:24])[C:22]#[CH:23]>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:19]=[C:18]([C:23]#[C:22][CH2:21][OH:24])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH2:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: C#CCO
Reactant: Cn1cc(C(N)=O)c(Nc2ccc(I)cc2F)cc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: Cn1cc(C(N)=O)c(Nc2ccc(C#CCO)cc2F)cc1=O
Yield: 89 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide was reacted with propargyl alcohol in the presence of CuI, (Ph3P)2PdCl2 and TEA in DMF as for example 2. The residue resulting from removal of the reaction solvents under reduced pressure was purified by column chromatography on silica gel (5% MeOH/CH2Cl2 as eluant) to give 4-[2-fluoro-4-(3-hydroxy-1-propynyl)anilino]-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide as an off-white solid (89%). 1H NMR [(CD3)2SO, 400 MHz] δ 10.57 (s, 1 H), 8.35 (s, 1H), 7.90 (br s, 1H), 7.50 (t, J=8.5 Hz, 1H), 7.48 (br s, 1H), 7.39 (dd, J=11.4, 1.8 Hz, 1H), 7.28 (dd, J=8.3, 1.5 Hz, 1H), 5.69 (s, 1H), 5.36 (t, J=6.0 Hz, 1H), 4.30 (d, J=5.9 Hz, 2H), 3.37 (s, 3H). LCMS (APCI+) calcd for C16H15FN3O3 316 (MH+), found 316.
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][NH:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[C:19]([NH:26][CH2:27][CH:28]=O)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:23][C:22]([O:21][C:19]([NH:26][CH2:27][CH2:28][N:4]1[CH2:5][CH2:6][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:2][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:20])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(1,1-dimethylethyl) 3-ethyl 1,3-piperazinedicarboxylate [EP1486498, 2004] (2.023 g, 8.28 mmol) in 10 mL of dichloroethane was added a solution of N-boc-2-aminoacetaldehyde (1.87 g, 12.42 mmol) in 20 mL of dichloroethane. The solution was stirred at room temperature and under nitrogen atmosphere for 30 min. Sodium triacetoxyborohydride (3.32 g, 16.56 mmol) was then added and the reaction kept at room temperature overnight. The product was isolated on a SCX cartridge. 2.492 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH:11]=[CH:10][NH:9][C:8]2=S)=[CH:3][CH:2]=1>[Ni].[OH-].[NH4+]>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH:11]=[CH:10][N:9]=[CH:8]2)=[CH:3][CH:2]=1
Reactant: S=c1[nH]ccn1-c1ccncc1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Product: c1cc(-n2ccnc2)ccn1

Procedure:
An ethanolic solution of 5.9 g (0.028 mol) 1,3-dihydro-1-(4-pyridyl)-2H-imidazole-2-thione prepared in Example 8 is charged with 23.0 g Raney nickel and 10 ml concentrated ammonium hydroxide. The black slurry is refluxed for 2 hours, then filtered to remove the nickel catalyst. The ethanol is removed under vacuum and the product is extracted into CH2Cl2 (2×100 ml). Drying (NaSO4) and concentration gives the 1-(4-pyridyl)-1H-imidazole.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3([NH:24]C(=O)C)[CH2:21][O:20]C(C)(C)[O:18][CH2:17]3)=[CH:10][CH:9]=2)=[C:4]([F:28])[CH:3]=1.[CH3:29][C:30]1[S:34][C:33]([SH:35])=[CH:32][CH:31]=1.C(N(C(C)C)CC)(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O>[NH2:24][C:16]([CH2:15][CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([S:35][C:33]3[S:34][C:30]([CH3:29])=[CH:31][CH:32]=3)=[CH:3][C:4]=2[F:28])=[CH:13][CH:12]=1)([CH2:21][OH:20])[CH2:17][OH:18]
Reactant: Cc1ccc(S)s1
Reactant: CC(=O)NC1(CCc2ccc(-c3ccc(Br)cc3F)cc2)COC(C)(C)OC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(Sc2ccc(-c3ccc(CCC(N)(CO)CO)cc3)c(F)c2)s1
Temperature: 80 °C
Reaction time: 4 h
Yield: 24.5 %

Procedure:
A solution of N-{5-[2-(4′-bromo-2′-fluorobiphenyl-4-yl)ethyl]-2,2-dimethyl-1,3-dioxan-5-yl}acetamide (225 mg) of Reference Example 10, 5-methylthiophene-2-thiol (65 mg), diisopropylethylamine (129 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (12.9 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (14.9 mg) in 1,4-dioxane (2 mL) was heated under reflux for 6 hr under a nitrogen atmosphere. Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (12.9 mg) and Xantphos (14.9 mg) were added to the reaction mixture, and the mixture was further heated under reflux for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in ethanol (4 mL). Concentrated hydrochloric acid (2 mL) was added, and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was concentrated, aqueous potassium carbonate solution was added to the residue, and the precipitated crystals were collected by filtration. The crude crystals were purified by preparative HPLC to give the title compound (51 mg) as brown crystals.
Reaction SMILES: [F:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][N:7]([CH3:40])[C:8]([C@@:10]2([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=3)[CH2:12][C@H:11]2/[CH:13]=[CH:14]/[CH2:15][N:16]2[CH2:21][CH2:20][C:19]([NH:28][C:29](=[O:31])[CH3:30])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1>ClCCl.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CC=CCCC=C1.C1C=CN=CC=1.F[P-](F)(F)(F)(F)F.[Ir]>[F:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][N:7]([CH3:40])[C:8]([C@@:10]2([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=3)[CH2:12][C@H:11]2[CH2:13][CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][C:19]([NH:28][C:29](=[O:31])[CH3:30])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:20][CH2:21]2)=[O:9])=[CH:4][CH:3]=1
Reactant: CC(=O)NC1(c2ccccc2)CCN(C/C=C/[C@@H]2C[C@@]2(C(=O)N(C)Cc2ccc(F)cc2)c2ccc(Cl)c(Cl)c2)CC1
Agent: [Ir]
Agent: C1=C\CC/C=C\CC/1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: c1ccncc1
Solvent: C1=CCCC=CCC1
Solvent: ClCCl
Product: CC(=O)NC1(c2ccccc2)CCN(CCC[C@@H]2C[C@@]2(C(=O)N(C)Cc2ccc(F)cc2)c2ccc(Cl)c(Cl)c2)CC1
Reaction time: 3 h

Procedure:
(1S,2S)-2-[(E)-3-(4-Acetylamino-4-phenyl-piperidin-1-yl)-propenyl]-1-(3,4-dichloro-phenyl)-cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide (65 mg, 0.11 mmol) is dissolved in dichloromethane (10 ml). N2 is bubbled through the solution for 15 minutes before adding Crabtree's catalyst (17.7 mg, 0.022 mmol, [(1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)iridium(I) hexafluorophosphate]). The reaction mixture is hydrogenated at a Parr apparatus (ambient temperature, 3 atm. H2) for 3 hours. The solvent is removed by evaporation and the residue is subjected to silica gel chromatography eluting with ethyl acetate:ethanol:triethylamine (95:0:5)-(85:10:5). Evaporation from heptane furnishes the title compound as a white solid. Yield 25 mg (38%).
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[CH:16][C:6]([C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:14]=2[OH:15])=O)=[CH:5][CH:4]=1)[CH3:2]>[OH-].[OH-].[Pd+2].CO>[CH2:1]([C:3]1[CH:17]=[CH:16][C:6]([CH2:7][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:14]=2[OH:15])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(=O)c2cnccc2O)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCc1ccc(Cc2cnccc2O)cc1
Reaction time: 18 h
Yield: 83 %

Procedure:
Next, a mixture of 3-(4-ethylbenzoyl)-4-hydroxypyridine (2.69 g, 0.0118 mol), 20% palladium hydroxide/carbon (530 mg) and methanol (60 mL) was stirred under a hydrogen atmosphere for 18 hours. Additional 20% palladium hydroxide/carbon (300 mg) was added and stirred for 6 hours, followed by further addition of 20% palladium hydroxide/carbon (340 mg) and stirring for 15 hours. After filtration to remove the insoluble materials, the filtrate was purified by silica gel column chromatography (chloroform:methanol=10:1) to give 3-(4-ethylbenzyl)-4-hydroxypyridine (2.09 g, 83%) as a colorless amorphous substance.
Reaction SMILES: [Br:1][C:2]1[S:9][C:8]2[C:7]([CH:10]=O)=[C:6]([C:12](OCC)=[O:13])[N:5]([CH3:17])[C:4]=2[CH:3]=1.O.[NH2:19][NH2:20].BrC1SC2C(C=O)=C(C(OCC)=O)NC=2C=1>C(OCCO)C>[CH3:17][N:5]1[C:6]2[C:12]([NH:19][N:20]=[CH:10][C:7]=2[C:8]2[S:9][C:2]([Br:1])=[CH:3][C:4]1=2)=[O:13]
Reactant: CCOC(=O)c1c(C=O)c2sc(Br)cc2n1C
Reactant: NN
Agent: CCOC(=O)c1[nH]c2cc(Br)sc2c1C=O
Solvent: CCOCCO
Solvent: O
Product: Cn1c2cc(Br)sc2c2cn[nH]c(=O)c21
Reaction time: 8 h
Yield: 93.7 %

Procedure:
The N-methylated product 63 (420 mg, 1.33 mmol) was dissolved in warm 2-ethoxyethanol (26 mL). To a refluxed solution of hydrazine monohydrate (1 mL, 31.9 mmol) and 2-ethoxyethanol (5 mL) under nitrogen was added prepared N-methylated product 62 solution dropwise over a 2 hr period and the solution continued to reflux for additional 1 hr. After cooling to room temperature, about half of the 2-ethoxyethanol was removed under reduced pressure and the remaining solution was refrigerated at −20° C. overnight. The precipitate was filtered and washed with 2-ethoxyethanol to give desired pyridazinone 64 (354 mg, 94%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([N+:23]([O-])=O)[CH:17]=1)[CH3:2]>[Pd].CCOC(C)=O>[NH2:23][C:18]1[CH:17]=[C:16]([C:4]2[N:3]([CH2:1][CH3:2])[C:11]3[C:6]([C:5]=2[C:14]#[N:15])=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:21]=[CH:20][C:19]=1[OH:22]
Reactant: CCn1c(-c2ccc(O)c([N+](=O)[O-])c2)c(C#N)c2ccc(OC)cc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCn1c(-c2ccc(O)c(N)c2)c(C#N)c2ccc(OC)cc21
Reaction time: 1 h
Yield: 90.8 %

Procedure:
1-Ethyl-2-(4-hydroxy-3-nitrophenyl)-6-methoxy-1H-indole-3-carbonitrile (369 mg, 1.1 mmol), prepared as in example 1Gd, is combined with EtOAc (20 mL) and Pd/C (150 mg, 10%). This mixture is hydrogenated at 30 p.s.i. for 1 h. This is filtered through celite. The filtrate is concentrated and triturated with ether to yield 2-(3-amino-4-hydroxyphenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (307 mg, 91%), compound 322, as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:49])[C@H:4]([CH:46]([CH3:48])[CH3:47])[NH:5][C:6](=[O:45])[C@H:7]([CH:42]([CH3:44])[CH3:43])[NH:8][C:9](=[O:41])[CH2:10][CH:11]1[CH2:17][CH2:16][C:15]([C@@H:18]([NH:20][C:21](=[O:32])[C@H:22]([CH3:31])[NH:23]C(OC(C)(C)C)=O)[CH3:19])=[CH:14][CH:13]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:12]1[OH:40].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:49])[C@H:4]([CH:46]([CH3:48])[CH3:47])[NH:5][C:6](=[O:45])[C@H:7]([CH:42]([CH3:43])[CH3:44])[NH:8][C:9](=[O:41])[CH2:10][CH:11]1[CH2:17][CH2:16][C:15]([C@@H:18]([NH:20][C:21](=[O:32])[C@H:22]([CH3:31])[NH2:23])[CH3:19])=[CH:14][CH:13]([CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:12]1[OH:40]
Reactant: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)CC1CCC([C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)=CC(Cc2ccccc2)C1O)C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)CC1CCC([C@H](C)NC(=O)[C@H](C)N)=CC(Cc2ccccc2)C1O)C(C)C)C(C)C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 30 mg of (40) in CH2Cl2 (1 mL) was added trifluoroacetic acid (10 mL). After stirring for 45 min the reaction was evaporated to dryness, triturated with ether, filtered and dried under vacuum to give the title compound (41) as a mixture of isomers (24rag, 75%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.C1(C)C=CC=CC=1.Br[CH2:21][C:22]([O:24]C)=[O:23]>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:3][C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][N:10]([CH2:21][C:22]([OH:24])=[O:23])[C:7]2=[N:8][CH:9]=1
Reactant: Clc1cnc2[nH]ccc2c1
Reactant: COC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)Cn1ccc2cc(Cl)cnc21
Temperature: 100 °C
Reaction time: 5 h
Yield: 97 %

Procedure:
To a solution of NaOH (5.19 g, 129.8 mmol) in water (10 mL) was added tetrabutylammonium bromide (0.35 g, 1.08 mmol), 5-chloro-1H-pyrrolo[2,3-b]pyridine (1.5 g, 9.83 mmol), toluene (60 mL) and methyl 2-bromoacetate (9 g, 59 mmol). The reaction was heated overnight at 100° C. The reaction was quenched with water, the layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated. 2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)acetate solution in THF was treated with NaOH and stirred at RT for 5 hours. The reaction mixture was then diluted with water and the pH was adjusted to 1 with 1N HCl to crash out the product. The reaction was then filtered, azeotroped with acetonitrile and dried to give 2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)acetic acid. (2 g, 97% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J=2.3 Hz, 1H), 8.05 (d, J=2.3 Hz, 1H), 7.57 (d, J=3.5 Hz, 1H), 6.42 (d, J=3.5 Hz, 1H), 4.74 (s, 2H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=211.1; tR=1.10 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[CH:14]=[CH:13][C:11](N)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.N([O-])=O.[Na+].[I:19]I>C(O)(=O)C.Cl.O>[I:19][C:11]1[CH:13]=[CH:14][C:8]([CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:9][CH:10]=1
Reactant: II
Reactant: Nc1ccc(Cc2ccncc2)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Ic1ccc(Cc2ccncc2)cc1
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
A solution of 4-(pyridin-4-ylmethyl)aniline (679 mg, 3.7 mmol) in acetic acid (1.84 mL) and concentrated hydrochloric acid (0.787 mL) was cooled to 0° C. NaNO2 (280 mg, 40.7 mmol) in water (1.23 mL) was added dropwise and the reaction mixture was allowed to stir for 30 min. A solution of KI (737 mg, 4.44 mmol) and iodine (563 mg, 2.22 mmole) in water (3.7 mL) was added dropwise to the above solution. The solution stirred for 30 min at 0° C. and for 1 h at rt. The reaction was quenched by the addition of aq. NaS2O4 and the solution was extracted with EtOAc. The combined organic solutions were washed with sat. NaHCO3, brine and 1% NaOH, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give the title compound (140 mg, 18%). LCMS: (FA) ES+ 296.1 (M+1).