Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:8][CH2:7][CH2:6][NH:5][C:4]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:3]1=2.N1C=CC=CC=1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>CN(C)C1C=CN=CC=1.ClCCCl>[Cl:23][CH2:24][C:25]([N:5]1[CH2:6][CH2:7][CH2:8][C:2]([CH3:16])([CH3:1])[C:3]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:4]1=2)=[O:26]
Reactant: CC1(C)CCCNc2cc([N+](=O)[O-])ccc21
Reactant: O=C(Cl)CCl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC1(C)CCCN(C(=O)CCl)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (0.837 g, 3.80 mmol), pyridine (0.408 mL, 5.04 mmol) and 4-dimethylaminopyridine (14.4 mg, 0.118 mmol) were dissolved in anhydrous 1,2-Dichloroethane (9.0 mL) before adding chloroacetyl chloride (0.403 mL, 5.07 mmol). The reaction was stirred at room temperature for 3 hours, washed sequentially with 1 N HCl, water, saturated sodium bicarbonate solution and brine. The organic phase was dried with magnesium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with ether (6 mL×2) to yield a crude brown solid, 2-Chloro-1-(5,5-dimethyl-8-nitro-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-ethanone. LCMS: m/z=297.42 (M+H+).
Reaction SMILES: [O:1]1[CH2:21][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:20])[C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][N:15]=2)=[CH:7][CH:6]=1.[CH2:22]([NH:29][CH2:30][CH2:31][O:32][C:33]1[CH:41]=[C:37]([C:38]([NH2:40])=[O:39])[C:36]([OH:42])=[CH:35][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(C)C>[CH2:22]([N:29]([CH2:30][CH2:31][O:32][C:33]1[CH:34]=[CH:35][C:36]([OH:42])=[C:37]([C:38](=[O:39])[NH2:40])[CH:41]=1)[CH2:21][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]([CH3:20])[C:13]([C:16]([F:17])([F:19])[F:18])=[CH:14][N:15]=2)=[CH:9][CH:10]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NC(=O)c1cc(OCCNCc2ccccc2)ccc1O
Reactant: Cn1c(C(F)(F)F)cnc1-c1ccc(OCC2CO2)cc1
Solvent: CC(C)O
Product: Cn1c(C(F)(F)F)cnc1-c1ccc(OCC(O)CN(CCOc2ccc(O)c(C(N)=O)c2)Cc2ccccc2)cc1

Procedure:
A solution of 5 g of the resulting 2-[4-(2,3-epoxypropoxy)-phenyl]-1-methyl-5-(trifluoromethyl)-1H-imidazole and 4.7 g of 5-[2-(benzylamino)-ethoxy]-salicylamide in 100 ml of isopropanol is heated under reflux for 15 hours and the solvent is subsequently removed in a rotary evaporator. The crude 1-[N-benzyl-2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-[1-methyl-5-(trifluoromethyl)-1H-imidazol-2-yl]-phenoxy]-2-propanol obtained in the form of an oil is further processed in that form.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)[CH:13]=[CH:12][C:11]=1[C:21]1[N:26]=[N:25][C:24]([O:27][CH:28]2[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]2)=[CH:23][CH:22]=1.[OH-].[Na+]>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)[CH:13]=[CH:12][C:11]=1[C:21]1[N:26]=[N:25][C:24]([O:27][CH:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)=[CH:23][CH:22]=1
Reactant: COc1cc(-n2cccn2)ccc1-c1ccc(OC2CCN(C(=O)OC(C)(C)C)C2)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-n2cccn2)ccc1-c1ccc(OC2CCNC2)nn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 103.7 %

Procedure:
Trifluoroacetic acid (1 mL) was added to tert-butyl 3-((6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazin-3-yl)oxy)pyrrolidine-1-carboxylate (0.18 g, 0.40 mmol) in DCM (3 mL) at 0° C. The reaction was stirred for 2 days at RT. The reaction mixture was added to an aqueous solution of NaOH (1 M) and the aqueous phase was extracted with chloroform/propan-2-ol (3:1). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 3-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-6-(pyrrolidin-3-yloxy)pyridazine (0.14 g, 100%) as a brown solid.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](Cl)=[N:19][OH:20])=[CH:13][CH:12]=1.[C:25]([C:27]1[C:28]([NH2:34])=[N:29][C:30]([NH2:33])=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[F:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[CH:26]=[C:25]([C:27]3[C:28]([NH2:34])=[N:29][C:30]([NH2:33])=[CH:31][CH:32]=3)[O:20][N:19]=2)=[CH:13][CH:12]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(Oc2cccc(F)c2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(Oc4cccc(F)c4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.2 %

Procedure:
To a tetrahydrofuran (5.00 mL) solution of (4-(3-fluoro-phenoxy)-phenyl)-acetohydroximoyl chloride (210 mg, 0.622 mmol) described in Manufacturing Example 81-1-2 and 3-ethynyl-pyridine-2,6-diamine (30.0 mg, 0.225 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (94.1 μL, 0.675 mmol) at room temperature, which was stirred for 30 minutes at room temperature. Water was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound (29.0 mg, 34.2%).
Reaction SMILES: [C:1]1(=[O:26])[C:5]2[C:6]3[C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[NH:18][C:7]=3[CH2:8][C:9]3[NH:10][C:11]4[C:16]([C:17]=3[C:4]=2[C:3](=[O:25])[NH:2]1)=[CH:15][CH:14]=[CH:13][CH:12]=4>Cl.O.CCO.C1(C)C=CC=CC=1.[Zn].Cl[Hg]Cl>[C:3]1(=[O:25])[CH:4]2[C:17]3[C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[NH:10][C:9]=3[CH2:8][C:7]3[NH:18][C:19]4[C:24]([C:6]=3[CH:5]2[C:1](=[O:26])[NH:2]1)=[CH:23][CH:22]=[CH:21][CH:20]=4
Reactant: O=C1NC(=O)C2=C1c1c([nH]c3ccccc13)Cc1[nH]c3ccccc3c12
Agent: Cl
Agent: Cl[Hg]Cl
Agent: [Zn]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C1NC(=O)C2c3c([nH]c4ccccc34)Cc3[nH]c4ccccc4c3C12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.20 g (18.4 mmol) of Zn granules are washed with 2×3 ml of 2 N HCl, then immediately added to 90 mg (0.33 mmol) of HgCl2 in 1.5 ml of H2O and 1.5 ml of conc. HCl and the mixture is shaken at room temp. for 10 min. The aq. phase is decanted and the zinc amalgam is additionally washed with 2×3 ml of dil. HCl before it is added to a solution of 60.0 mg (0.18 mmol) of 1,2,3,8,9,10-hexahydroindolo[3′,2′:5,6]pyrrolo-[3′,4′:3,4]cyclohepta[b]indole-1,3-dione in 1.5 ml of 5 N HCl, 1.5 ml of EtOH and 1.5 ml of toluene and heated under reflux. After 1 h, as soon as the reaction solution has cooled to room temp. H2O is added and the mixture is extracted with 2×10 ml of CH2Cl2. The org. extracts are dried over Na2SO4, concentrated in vacuo and purified by column chromatography (SiO2; CH2Cl2/ethyl acetate/MeOH 8:2:0.5): colourless wax, yield 14 mg (23%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH:8]1([CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:32]=[CH:33][CH:34]=2)[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28](=[O:31])(=[O:30])[NH2:29])=[O:20])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>CN(C)C1C=CN=CC=1.O1CCCC1>[CH:8]1([CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:32]=[CH:33][CH:34]=2)[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([NH:29][C:1](=[O:3])[CH3:2])(=[O:31])=[O:30])=[O:20])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(=O)OC(C)=O
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCC2CCCCC2)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
In a stream of nitrogen and at 0° C., 0.11 ml (1.10 mmol) of acetic anhydride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 400 mg (1.00 mmol) of 3-cyclohexylmethoxy-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 7 and 237 mg (1.90 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 430 mg (yield: 96.9%) of the title compound.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:34])=[C:23]([CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:38][N:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[CH2:44][NH2:45].CS(C)=O.C(N(CC)CC)C>C(#N)C.ClCCl.C(OCC)(=O)C>[CH3:38][N:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[CH2:44][NH:45][C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[C:28]([CH3:34])=[CH:29][CH:30]=[CH:31][C:32]=4[CH3:33])=[C:23]([CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: Cn1cccc1CN
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1c(C)cccc1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)NCc4cccn4C)n3Cc3ccccc32)ccc1-c1c(C)cccc1C

Procedure:
The title compound was prepared according to procedure of Example 2 starting from 2,2,2-trichloro-1-{10-[(2,2′,6′-trimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 3 (1.4 g, 2.5 mmole), (1-methyl-1H-pyrrol-2-yl)methylamine (0.234 g, 2.1 mmole), dimethylsulfoxide (0.822 g, 10.5 mmole) and triethyl amine (0.470 g, 4.6 mmole) in 15 mL of acetonitrile, Flash chromatography of the residue on silica gel Merck-60 (0-25% ethyl acetate in dichloromethane) gave a foam (0.924 g) which solidified upon treatment with ethyl acetate/hexane/dichloromethane, mp. 222-224° C.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[N+:5]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[CH:16]=[C:15]([OH:18])[CH:14]=[CH:13]2)([O-:7])=[O:6].FC(F)(F)S(O)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[C:2]([O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH:11]=[CH:10][CH:9]=[C:8]2[N+:5]([O-:7])=[O:6])=[CH:13][CH:14]=1)([CH3:3])([CH3:1])[CH3:4]
Reactant: C=C(C)C
Reactant: O=[N+]([O-])c1cccc2ccc(O)cc12
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)Oc1ccc2cccc([N+](=O)[O-])c2c1
Temperature: -20 °C

Procedure:
Isobutylene (150 mL) was condensed into a stirred mixture of 8-nitro-2-naphthol, as described above in Step C, (4.35 g, 23.0 mmol) in CH2Cl2 (200 mL) at −78° C. Trifluoromethanesulfonic acid (0.203 mL, 2.30 mmol) was added and the mixture was allowed to slowly warm to −20° C. over about 4 hours. Triethylamine (2.56 mL, 18.4 mmol) was added and the mixture was allowed to warm to ambient temperature, then concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica, eluting with hexane—5% EtOAc to yield the titled product.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[N:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:26][CH:25]=3)[C:21]([C:22]#[N:23])=[C:17]2[N:16]=[CH:15][CH:14]=1>CO.O1CCOCC1.O.NN>[NH2:3][CH2:12][C:13]1[N:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:26][CH:25]=3)[C:21]([C:22]#[N:23])=[C:17]2[N:16]=[CH:15][CH:14]=1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c(CN3C(=O)c4ccccc4C3=O)ccnc12
Agent: NN
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c(CN)ccnc12
Temperature: 60 °C
Yield: 70.9 %

Procedure:
To a solution of 7-((1,3-dioxoisoindolin-2-yl)methyl)-2-(4-phenoxyphenyl) pyrazolo[1,5-a]pyrimidine-3-carbonitrile (290 mg, 0.62 mmol) in 5 mL of MeOH and 5 mL of dioxane was added 12 drops of hydrazine hydrate. The reaction mixture was stirred and heated to 60° C. for 3 hr. The mixture was concentrated and suspended in 20 mL of solvent (DCM/MeOH=10/1). The mixture was filtered and the filtrate was concentrated and purified by the flash chromatography eluting with EA followed by DCM/MeOH (10/1) to give 150 mg (71%) of 7-(aminomethyl)-2-(4-phenoxyphenyl) pyrazolo[1,5-a]pyrimidine-3-carbonitrile as a solid. MS (ESI) m/e [M+1]+ 342.1.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7](Br)[CH:8]=[CH2:9].[OH:11][C:12]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]>CN(C=O)C>[CH3:17][O:16][C:14](=[O:15])[C:13]1[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:12]=1[O:11][CH2:9][CH:8]=[CH2:7]
Reactant: C=CCBr
Reactant: COC(=O)c1cc(OC)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(OC)cc1C(=O)OC
Temperature: 60 °C
Yield: 82.2 %

Procedure:
K2CO3 (4.64 g, 33.6 mmol) and allyl bromide (1.56 mL, 18.5 mmol) were added to a solution of methyl 2-hydroxy-5-methoxybenzoate (2.5 mL, 16.8 mmol) in DMF (10 mL). The reaction mixture was heated to 60° C. for 1 h, and then quenched with H2O (80 mL) and extracted with EtOAc (2×80 mL). The organic layers were washed with H2O (150 mL), dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 5-10% EtOAc/hexane to give a colorless oil (3.07 g, 82%). 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=3.28 Hz, 1 H) 6.98-7.03 (m, 1H) 6.90-6.94 (m, 1 H) 6.01-6.11 (m, 1 H) 5.44-5.51 (m, 1 H) 5.25-5.31 (m, 1 H) 4.57 (td, J=3.28, 1.52 Hz, 2 H) 3.91 (s, 3 H) 3.80 (s, 3 H).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15]/[CH:16]=[CH:17]/[CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1.Br[CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1>>[CH:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:43]=[CH:44][C:35]=1[CH2:34][O:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15]/[CH:16]=[CH:17]/[CH2:18][O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OC/C=C/COc3ccccc3)cc2)C(O)C1
Reactant: BrCc1ccc2ccccc2c1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OC/C=C/COc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (E)-(3RS,4RS)-3-hydroxy-4-[4-(4-phenoxy-but-2-enyloxy)-phenyl]-piperidine-1-carboxylate [Example 123(k)] with 2-bromomethyl-naphthalene there was obtained tert-butyl (E)-(3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(4-phenoxy-but-2-enyloxy)-phenyl]-piperidine-1-carboxylate as a colourless solid; MS: 580 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([C:17]#[N:18])=[CH:4][C:5]([F:16])=[C:6]([NH:8][C@H:9]([CH2:13][O:14][CH3:15])[C:10]([NH2:12])=[O:11])[CH:7]=1.Cl.[NH2:20][C:21]1[S:25][N:24]=[C:23]([CH3:26])[CH:22]=1.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:17]([C:3]1[C:2]([NH:20][C:21]2[S:25][N:24]=[C:23]([CH3:26])[CH:22]=2)=[CH:7][C:6]([NH:8][C@H:9]([CH2:13][O:14][CH3:15])[C:10]([NH2:12])=[O:11])=[C:5]([F:16])[CH:4]=1)#[N:18]
Reactant: Cc1cc(N)sn1
Reactant: COC[C@@H](Nc1cc(Br)c(C#N)cc1F)C(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: COC[C@@H](Nc1cc(Nc2cc(C)ns2)c(C#N)cc1F)C(N)=O
Reaction time: 18 h
Yield: 27.9 %

Procedure:
A mixture of (R)-2-(5-bromo-4-cyano-2-fluorophenylamino)-3-methoxypropanamide (52 mg, 0.164 mmol), 5-amino-3-methylisothiazole hydrochloride (40 mg, 0.265 mmol), K2CO3 (110 mg, 0.797 mmol), BINAP (30 mg, 0.048 mmol) and Pd(OAc)2 (25 mg, 0.111 mmol) in dioxane (2 mL) was degassed with argon, then was stirred at 120 C for 18 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(4-cyano-2-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)-3-methoxypropanamide (16 mg).
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:28])[NH:15][C:16]2[CH:21]=[C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[CH:19]=[CH:18][C:17]=2[NH2:27])=[CH:10][CH:9]=1)(=[O:6])[O:4]C.[OH-].[Na+].C(O)(C(F)(F)F)=O>O1CCOCC1.CN(C=O)C>[CH3:1][O:2][P:3]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14](=[O:28])[NH:15][C:16]2[CH:21]=[C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[CH:19]=[CH:18][C:17]=2[NH2:27])=[CH:12][CH:13]=1)(=[O:4])[OH:6]
Reactant: COP(=O)(Cc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COP(=O)(O)Cc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
[4-(2-Amino-5-thiophen-2-yl-phenylcarbamoyl)-benzyl]-phosphonic acid dimethyl ester (35 mg, 0.066 mmol) was made 0.25 M in dioxane and to this stirring solution was added 5N aqueous sodium hydroxide (26 μL, 0.132 mmol). The resulting solution was stirred at 80° C. overnight then diluted with DMF, acidified with TFA, and purified by HPLC (0-60% MeCN in water w/0.025% TFA) to afford the title compound: 1H NMR (DMSO-d6, 600 MHz) δ9.80 (s, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.48-7.50 (m, 1H), 7.31-7.42 (m, 4H), 7.26-7.28 (m, 1H), 7.04-7.06 (m, 1H), 6.88 (d, J=8.4 Hz, 1H), 3.52 (d, J=11.4 Hz, 3H), 3.18 (d, J=21.6 Hz, 2H). MS: cal'd 403 (MH+), exp 403 (MH+)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[N:18]=[CH:17]3)[CH2:10][C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])(CC)C.Br[CH2:40][CH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.O>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([Si:23]([CH:27]([CH3:29])[CH3:28])([CH:30]([CH3:32])[CH3:31])[CH:24]([CH3:25])[CH3:26])[N:18]=[CH:17]3)[CH:10]([CH2:40][CH:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCC1CCOCC1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ncc2cc(N3CCN(Cc4ccccc4)C(=O)C3)ccc21
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ncc2cc(N3CCN(Cc4ccccc4)C(=O)C3CC3CCOCC3)ccc21
Temperature: 25 °C
Yield: 57.7 %

Procedure:
To a solution of 1-benzyl-4-(1-triisopropylsilanyl-1H-indazol-5-yl)-piperazin-2-one (0.78 g, 1.7 mmol) in 8.5 mL THF at −78° C. was added sec-butyllitium (1.3 mL, 1.9 mmol) drop-wise over 5 minutes. After 30 minutes 4-bromomethyl-tetrahydropyran (0.36 g, 2.0 mmol) was added in one portion and mixture was warmed to room temperature. After 18 hours H2O was added and the mixture was extracted with ethyl acetate. The combined organic layerss were washed with H2O, brine, dried over NaSO4, filtered and concentrated in vacuo. Purification via flash chromatography afforded 1-benzyl-3-(tetrahydro-pyran-4-ylmethyl)-4-(1-triisopropylsilanyl-1H-indazol-5-yl)-piperazin-2-one (0.55g, 90%) as a white foam.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[C:10]([NH:12]C(OCC)=O)[N:9]=[C:8]2[NH:18][CH:19]=[N:20][C:7]=12.[OH-].[K+].[Cl-].[NH4+]>C(O)C>[NH2:12][C:10]1[N:9]=[C:8]2[NH:18][CH:19]=[N:20][C:7]2=[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:11]=1
Reactant: CCOC(=O)Nc1cc(-c2cccs2)c2nc[nH]c2n1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCO
Product: Nc1cc(-c2cccs2)c2nc[nH]c2n1
Yield: 108.1 %

Procedure:
To a solution of 7-(2-thienyl)-5-ethoxycarbonylamino-3H-imidazo[4,5-b]pyridine (1.21 g, 3.72 mmol) in ethanol (130 ml), potassium hydroxide (7.29 g) was added and heated under reflux for 4 hours. To this solution, an aqueous ammonium chloride solution (7.65 g/26 ml) was added, followed by evaporation under reduced pressure to remove the solvent. The product was isolated by silica gel column chromatography (methylene chloride:ethanol=9:1 to 7:3) to give 5-amino-7-(2-thienyl)-3H-imidazo[4,5-b]pyridine (870 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([CH2:10]O)[CH:7]=[C:6]([CH3:12])[C:5]=1[N:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15].C(Br)(Br)(Br)[Br:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([CH2:10][Br:34])[CH:7]=[C:6]([CH3:12])[C:5]=1[N:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)c1cc(CO)cc(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(CBr)cc(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 0.25 h
Yield: 89.5 %

Procedure:
To a 0° C. solution of 1.08 g (2.37 mmol) of the product of Example 278 and 983 mg (2.96 mmol) of carbon tetrabromide in 24 ml of dichloromethane was added 933 mg (3.55 mmol) of triphenyl phosphine. The resulting mixture was stirred for 15 min and then concentrated in vacu. The residue was chromatographed on silica gel using EtOAc:Hexane (1:6) as eluant to provide 1.1 g (96%) of the desired product as a white crystalline solid. Electrospray Mass Spec 520 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:39]1[CH2:43][CH2:42][O:41][CH2:40]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH3:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:7]=[C:2]([O:1][CH:39]3[CH2:43][CH2:42][O:41][CH2:40]3)[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=2)=[CH:13][CH:12]=1
Reactant: OC1CCOC1
Reactant: COC(=O)c1cc(O)cc(-c2ccc(C)cc2)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(OC2CCOC2)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 5-hydroxy-4′-methylbiphenyl-3-carboxylate (120 mg, 0.47 mmol), triphenylphosphine (120 mg, 0.47 mmol), 3-hydroxytetrahydrofuran (45 mg, 0.50 mmol) in CH2Cl2 (7 mL) at rt was slowly added a solution of diisopropyl azodicarboxylate (100 mg, 0.50 mmol) in CH2Cl2 (2 mL). The mixture was stirred at rt overnight, and then concentrated in vacuo. The residue was purified by flash chromatography to afford the title compound.
Reaction SMILES: ClC1C=CC=CC=1NC(=O)NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=NC=1.[F:35][C:36]1[CH:37]=[C:38]([NH:43][C:44](=[O:71])[NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([O:65]C)=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[CH:48][C:47]=2[F:70])[CH:39]=[CH:40][C:41]=1[F:42]>>[F:35][C:36]1[CH:37]=[C:38]([NH:43][C:44](=[O:71])[NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([OH:65])=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[CH:48][C:47]=2[F:70])[CH:39]=[CH:40][C:41]=1[F:42]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)c(F)c4)c(F)c3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cn3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)c(F)c4)c(F)c3)cc2C1=O
Yield: 93 %

Procedure:
The compound of example 440 was prepared analogous to the compound of example 394 by hydrolysis of the compound of example 439.