Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[C:7]2[CH:16]=[C:15]([CH2:17][CH3:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[C:8]=2[N:9]=[C:10](SC)[N:11]=1>C(O)C.[Ni]>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[C:7]2[CH:16]=[C:15]([CH2:17][CH3:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: CCc1cc2c(OCC(=O)OC)nc(SC)nc2n1Cc1cccc(F)c1
Agent: [Ni]
Solvent: CCO
Product: CCc1cc2c(OCC(=O)OC)ncnc2n1Cc1cccc(F)c1
Reaction time: 24 h
Yield: 75.4 %

Procedure:
A suspension of 211 mg (0.541 mmol) of [[2-(methylthio)-6-ethyl-7-[(3-fluorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester in 20 mL of ethanol was treated with 1.27 g of Raney Ni and heated to reflux. After 24 hours, the solids were removed by filtration through a filter aid and the reaction concentrated to provide 140 mg (75%) of [[6-ethyl-7-[(3-fluorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a solid. nmr (300 MHz, CDCl3) δ1.20 (t, 3H), 2.62 (q, 2H), 3.79 (s, 3H), 5.09 (s, 2H), 5.45 (s, 2H), 6.42 (s, 1H), 6.72 (d, 1H), 6.82 (d, 1H), 6.93 (dt, 1H), 7.26 (dt, 1H), 8.37 (s, 1H)
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[CH:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][N:19]=2)[C:15]#[N:16])O1.O.[NH2:21][NH2:22]>O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][N:19]=2)[C:15]#[N:16])=[N:22][NH:21]1
Reactant: N#Cc1ccnc(C=C2OC(=O)c3ccccc32)c1
Reactant: NN
Solvent: O
Product: N#Cc1ccnc(Cc2n[nH]c(=O)c3ccccc23)c1
Temperature: 90 °C

Procedure:
To crude 2-(3-oxo-3H-isobenzofuran-1-ylidenemethyl)-isonicotinonitrile (iii-int)(approx 4.0 mmol) suspended in water (30 mL) and hydrazine monohydrate (2 mL). The reaction mixture was then heated to 90° C. for 90 minutes and then cooled to room temperature. The resulting suspension was filtered and washed with methanol (5 mL), water (10 ml) and then ethyl ether (2×30 mL). A buff solid was isolated with single peak in LC-MS analysis. (0.61 g, 26.7% over 3 steps); m/z (LC-MS, ESP), RT=3.48 mins, (M+H)=263.0.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:11]=[C:10]([S:12][CH3:13])[C:9]([C:14]([NH2:16])=[O:15])=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].C1(C2[O:25]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1.C(OCC)(=O)C>C(Cl)(Cl)Cl>[C:1]([NH:5][C:6]1[N:11]=[C:10]([S:12]([CH3:13])=[O:25])[C:9]([C:14]([NH2:16])=[O:15])=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CSc1nc(NC(C)(C)C)ncc1C(N)=O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CS(=O)c1nc(NC(C)(C)C)ncc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a stirring solution of 2-(tert-butylamino)-4-(methylthio)pyrimidine-5-carboxamide (0.1 g, 0.416 mmol) in chloroform (12 mL) was added portion-wise 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (0.130 g, 0.499 mmol). The resulting pale yellow solution was stirred at ambient temperature overnight. The reaction solution was concentrated under reduced pressure to give the crude product as a white solid. Ethyl acetate (1 mL) was added and the slurry was stirred at room temp for 1 h. The solids were filtered, washed with ethyl acetate, and dried under vacuum to afford 2-(tert-butylamino)-4-(methylsulfinyl)pyrimidine-5-carboxamide (0.092 g, 0.359 mmol, 86% yield). MS (ESI) m/z 257.3 [M+1]+.
Reaction SMILES: [OH2:1].S([O-])(O)(=O)=O.[Na+].[CH3:8][C:9]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:11]([OH:12])[C:10]=1O>>[CH3:8][C:9]1[CH:10]=[C:11]([OH:12])[CH:13]=[C:14]([CH3:16])[C:15]=1[OH:1]
Reactant: Cc1cc(C)c(O)c(O)c1
Reactant: O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: Cc1cc(O)cc(C)c1O

Procedure:
By following the same manner as in Example 56 except that 0.013 g. of sodium hydrogen sulfate monohydrate (NaHSO4.H2O) was used, 3.42 g. (24.8 m.moles) of 3,5-dimethylcatechol and 1.66 g. (12.0 m.moles) of 2,6-dimethylhydroquinone were obtained. The yield of dihydric alkylphenols was 87.4%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([N+:13]([O-:15])=[O:14])=[C:10]([C:16]([NH2:18])=[O:17])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:19][N:20]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=[N:21]1>O1CCCC1.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>[CH3:19][N:20]1[C:24]([C:2]2[N:7]=[CH:6][C:5]([C:8]3[S:12][C:11]([N+:13]([O-:15])=[O:14])=[C:10]([C:16]([NH2:18])=[O:17])[CH:9]=3)=[CH:4][CH:3]=2)=[CH:23][CH:22]=[N:21]1
Reactant: NC(=O)c1cc(-c2ccc(Cl)nc2)sc1[N+](=O)[O-]
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1nccc1-c1ccc(-c2cc(C(N)=O)c([N+](=O)[O-])s2)cn1
Temperature: 150 °C

Procedure:
5-(6-Chloropyridin-3-yl)-2-nitrothiophene-3-carboxamide (300 mg, 1.06 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (352 mg, 1.69 mmol), and tetrakis(triphenylphosphine)palladium(0) (61.1 mg, 0.05 mmol) were dissolved in tetrahydrofuran (8.5 ml) and 2 M sodium carbonate (2.1 ml) and the mixture was bubbled with nitrogen for 5 min. The reaction was then heated in the microwave to 150° C. for 15 min. The mixture was poured into ethyl acetate and water and extracted with ethyl acetate (3×100 mL). The combined organic fractions were washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate/hexane to yield the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([C:17]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]=1[OH:31])[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[OH:16].C(N(CC)CC)C.Cl[C:40]1[C:41]([C:67]([CH3:70])([CH3:69])[CH3:68])=[CH:42][C:43]2[C:49]3[CH:50]=[C:51]([C:58]([CH3:61])([CH3:60])[CH3:59])[CH:52]=[C:53]([C:54]([CH3:57])([CH3:56])[CH3:55])[C:48]=3[O:47][PH:46][O:45][C:44]=2[C:62]=1[C:63]([CH3:66])([CH3:65])[CH3:64].C(#N)C>C1(C)C=CC=CC=1>[C:58]([C:51]1[CH:52]=[C:53]([C:54]([CH3:57])([CH3:56])[CH3:55])[C:48]2[O:47][P:46]([O:31][C:18]3[C:19]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:20][C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:22][C:17]=3[CH2:1][C:2]3[CH:7]=[C:6]([C:8]([CH3:11])([CH3:9])[CH3:10])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=3[OH:16])[O:45][C:44]3[C:62]([C:63]([CH3:65])([CH3:64])[CH3:66])=[CH:40][C:41]([C:67]([CH3:70])([CH3:69])[CH3:68])=[CH:42][C:43]=3[C:49]=2[CH:50]=1)([CH3:61])([CH3:60])[CH3:59]
Reactant: CC(C)(C)c1cc(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Reactant: CC(C)(C)c1cc(C(C)(C)C)c2o[pH]oc3c(C(C)(C)C)c(Cl)c(C(C)(C)C)cc3c2c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)c1cc(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2Op2oc3c(C(C)(C)C)cc(C(C)(C)C)cc3c3cc(C(C)(C)C)cc(C(C)(C)C)c3o2)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.9 %

Procedure:
Into a solution of 21.23 g (50 mmol) of 2,2'-methylenebis(4,6-di-tert-butylphenol) and 7 mL (50 mmol) of triethylamine in 200 mL of toluene is added dropwise a solution of 23.84 g (50 mmol) of 3-chloro-2,4,8,10-tetra-tert-butyl-dibenzo[d,f][1,3,2]dioxaphosphepin in 100 mL of toluene at ambient temperature. After 20 hours of stirring at ambient temperature, the reaction mass is filtered to remove triethylamine hydrochloride and the filtrate is concentrated in vacuo to give a brownish oil. Trituration of the crude oil with 200 mL of acetonitrile gives 36.65 g (85% yield) of a white solid: m.p.=195°-205° C.
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH:4]=1.[Br:12][C:13]1[C:14](Cl)=[N:15][C:16]([Cl:19])=[N:17][CH:18]=1.C(OCC)(=O)C>CN(C=O)C.O>[Br:12][C:13]1[C:14]([N:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=[CH:4]2)=[N:15][C:16]([Cl:19])=[N:17][CH:18]=1
Reactant: c1ccc2[nH]cnc2c1
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1ncc(Br)c(-n2cnc3ccccc32)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.6 %

Procedure:
Sodium hydride (60% dispersion in oil; 110 mg, 2.75 mmol) was added to a solution of benzimidazole (295 mg, 2.5 mmol) in DMF (6 ml) at 0° C. The mixture was stirred at 0° C. for 10 minutes and then added dropwise to a cold (0° C.) solution of 5-bromo-2,4-dichloropyrimidine (712 mg, 3.14 mmol) in DMF (6 ml). The mixture was stirred for at 0° C. for 2 hours and then ethyl acetate (20 ml) and water (20 ml) were added. The organic phase was separated and dried and volatile material was removed by evaporation. The residue was purified by column chromatography, eluting with 20% ethyl acetate/DCM, to give the product as a white solid (500 mg, 52%). NMR: 7.4 (m, 2H), 7.8 (m, 2H), 8.8 (s, 1H), 9.3 (s, 1H); MS (MH+): 309, 311.
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C@H:10]2[CH2:11][C@H:7]([C@@H:8]([C:19]([N:21]3[CH2:25][CH2:24][CH2:23][C@H:22]3[C:26]#[N:27])=[O:20])[N:9]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)[CH:2]=[CH2:3].CN(C)C=[O:31]>O.[Cu]Cl>[C:26]([C@@H:22]1[CH2:23][CH2:24][CH2:25][N:21]1[C:19]([C@@H:8]1[C@H:7]2[CH2:11][C@H:10]([C@H:5]([O:4][CH2:1][C:2](=[O:31])[CH3:3])[CH2:6]2)[N:9]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:20])#[N:27]
Reactant: C=CCO[C@@H]1C[C@@H]2C[C@H]1N(C(=O)OC(C)(C)C)[C@@H]2C(=O)N1CCC[C@H]1C#N
Reactant: CN(C)C=O
Agent: Cl[Cu]
Solvent: O
Product: CC(=O)CO[C@@H]1C[C@@H]2C[C@H]1N(C(=O)OC(C)(C)C)[C@@H]2C(=O)N1CCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (1R,3S,4S,6R)-6-allyloxy-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 16-1 (277 mg) in dimethylformamide (5.0 mL) and water (0.45 mL), were added palladium(2) chloride (105 mg) and copper(1) chloride (292 mg). The mixture was stirred vigorously in aerobic condition at room temperature for 3 hrs.
Reaction SMILES: [CH:1]1([C:7]([NH:9][C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]([CH:22]3[O:27][C:26]4[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=4[O:24][CH2:23]3)=[O:21])[CH2:15][CH2:14]2)=[O:11])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(NC(NC2CCNCC2)=O)=O)CCCCC1.BrCC(C1OC2C=CC=CC=2OC1)=O.[BH4-].[Na+]>CN(C=O)C.CCN(CC)CC.[OH-].[Na+]>[CH:1]1([C:7]([NH:9][C:10]([NH:12][CH:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH:20]([CH:22]3[O:27][C:26]4[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=4[O:24][CH2:23]3)[OH:21])[CH2:17][CH2:18]2)=[O:11])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC(=O)C1CCCCC1)NC1CCN(CC(=O)C2COc3ccccc3O2)CC1
Agent: O=C(CBr)C1COc2ccccc2O1
Agent: O=C(NC(=O)C1CCCCC1)NC1CCNCC1
Agent: [BH4-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC(=O)C1CCCCC1)NC1CCN(CC(O)C2COc3ccccc3O2)CC1

Procedure:
1-Cyclohexylcarbonyl-3-[1-(2-[1,4-benzodioxan-2-yl]-2-oxoethyl)piperid-4-yl]urea, prepared by reacting 1-cyclohexylcarbonyl-3-(piperid-4-yl)urea with 2 -bromoacetyl-1,4-benzodioxan in DMF/Et3N, may be reduced using sodium borohydride in 2 N sodium hydroxide to give the title compound.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:6][C:5]=1[C:20]#[N:21])=[N+]=[N-].[H][H]>[C].[Pd].CO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:6][C:5]=1[C:20]#[N:21]
Reactant: COC(=O)c1ccnc(-c2ccc(N=[N+]=[N-])c(C#N)c2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccnc(-c2ccc(N)c(C#N)c2)c1

Procedure:
Palladium-carbon was added to a methanol solution of methyl 2-(4-azido-3-cyanophenyl)isonicotinate, and the mixture was stirred in the presence of hydrogen gas at room temperature for 5 hours to obtain methyl 2-(4-amino-3-cyanophenyl)isonicotinate. AP: 254.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[C:14]([C:16]([OH:19])([CH3:18])[CH3:17])[N:15]=3)[S:10][C:3]=12.[CH:20]1([CH2:23][NH:24][C:25]([C:27]2[C:35]3[C:30](=[CH:31][C:32]([OH:36])=[CH:33][CH:34]=3)[N:29]([CH3:37])[C:28]=2[CH3:38])=[O:26])[CH2:22][CH2:21]1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH:20]1([CH2:23][NH:24][C:25]([C:27]2[C:35]3[C:30](=[CH:31][C:32]([O:36][C:2]4[CH:7]=[CH:6][N:5]=[C:4]5[CH:8]=[C:9]([C:11]6[S:12][CH:13]=[C:14]([C:16]([OH:19])([CH3:18])[CH3:17])[N:15]=6)[S:10][C:3]=45)=[CH:33][CH:34]=3)[N:29]([CH3:37])[C:28]=2[CH3:38])=[O:26])[CH2:22][CH2:21]1
Reactant: Cc1c(C(=O)NCC2CC2)c2ccc(O)cc2n1C
Reactant: CC(C)(O)c1csc(-c2cc3nccc(Cl)c3s2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1c(C(=O)NCC2CC2)c2ccc(Oc3ccnc4cc(-c5nc(C(C)(C)O)cs5)sc34)cc2n1C

Procedure:
This material was prepared by the reaction of 2-[2-(7-chlorothieno[3,2-b]pyridin-2-yl)-1,3-thiazol-4-yl]propan-2-ol 40a (0.102 g, 0.33 mmole) with N-(cyclopropylmethyl)-6-hydroxy-1,2-dimethyl-1H-indole-3-carboxamide 55b (0.085 g, 0.33 mmole) and Cs2CO3 (0.1089, 0.33 mmole) in a manner as previously described for example 1. 1H NMR (300 MHz, DMSO-d6) δ 8.50 (1H, d, J=5.5 Hz), 8.12 (1H, s), 7.83 (1H, d, J=8.6 Hz), 7.73 (1H, t, J=5.8 Hz), 7.58 (1H, s), 7.54 (1H, d, J=2.1 Hz), 7.05 (1H, dd, J=2.1, 8.6 Hz), 6.59 (1H, d, J=5.5 Hz), 3.68 (3H, s), 3.17 (2H, t, J=6.1 Hz), 2.61 (3H, s), 1.50 (6H, s), 1.08 (2H, m), 0.43 (2H, m), 0.25 (2H, m); ESIMS (MH+): 533.15.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][NH:14][C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[CH:20]3)=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=C[C:30]=1OCC1C=CC(CNC(C2C(N)=NC(N)=CN=2)=O)=CC=1.C=O.C(=O)(O)[O-].[Na+]>C(O)(=O)C.O1CCCC1>[CH2:1]([N:8]([CH3:30])[C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH:14][C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[CH:20]3)=[O:16])=[CH:27][CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccc(NCc2ccccc2)cc1)c1ccc2ncccc2c1
Reactant: Nc1cnc(C(=O)NCc2ccc(COc3ccccn3)cc2)c(N)n1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)c1ccc(CNC(=O)c2ccc3ncccc3c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 35 %

Procedure:
Quinoline-6-carboxylic acid 4-benzylamino-benzylamide described in Preparation Example E+-3 (30 mg, 82 μmol), formalin (9 μl, 115 μmol), triacetoxy sodium borohydride (25 mg, 115 μmol) and acetic acid (several drops) were suspended in tetrahydrofuran (1 mL), and the solution was stirred at room temperature for 4 hours. An aqueous solution of saturated sodium bicarbonate was added to the reaction suspension at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, purification was carried out using thin layer NH silica gel chromatography (hexane:ethyl acetate=1:1), and the title compound (11 mg, 28 μmol, 35%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH:22]3[C:26](=[O:27])[N:25]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35](=[O:38])[NH:36][CH3:37])[CH:30]=4)[C:24](=[O:39])[NH:23]3)[CH:19]=2)[NH:14][CH:13]=1)C)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:1][NH:8][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH:22]3[C:26](=[O:27])[N:25]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([NH:36][CH3:37])=[O:38])[CH:30]=4)[C:24](=[O:39])[NH:23]3)[CH:19]=2)[NH:14][CH:13]=1
Reactant: CNC(=O)c1cccc(CN2C(=O)NC(Cc3ccc4[nH]cc(CCN(C)Cc5ccccc5)c4c3)C2=O)c1
Agent: [Pd]
Solvent: CCO
Product: CNCCc1c[nH]c2ccc(CC3NC(=O)N(Cc4cccc(C(=O)NC)c4)C3=O)cc12
Reaction time: 6 h
Yield: 40.9 %

Procedure:
A mixture of the product from step (b) (257 mg) and 10% Pd/C (110 mg) in ethanol (16 ml) was hydrogenated at room temperature and atmospheric pressure for 6 hours (uptake 12 ml). The mixture was filtered through celite, the residue washed with ethanol and the filtrate evaporated in vacuo to give a colourless oil which was flash chromatographed through a silica column using DCM/ethanol/ammonia (50:8:1 v/v/v) to give the desired product as a colourless oil (87 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([OH:27])[CH:19]=3)=[CH:13][CH:12]=2)=[N:6][CH:7]=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>>[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([OH:27])[CH:19]=4)=[CH:13][CH:12]=3)=[N:6][CH:7]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(Cc1ccc(Oc2ccc([N+](=O)[O-])c(O)c2)cc1)Nc1ccc(Br)cn1
Product: O=C(Cc1ccc(Oc2ccc([N+](=O)[O-])c(O)c2)cc1)Nc1ccc(-c2cccc(C(F)(F)F)c2)cn1
Yield: 45 %

Procedure:
The resin-bound N-(5-bromo-pyridin-2-yl)-2-[4-(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetamide (120 mg, 0.1 mmol) was reacted with 3-trifluoromethyl-phenyl boronic acid (57 mg, 0.3 mmol) as described in example 208 to afford 22.9 mg (45%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]([CH3:26])[C@@H:18]([C:22]([O:24][CH3:25])=[O:23])[CH:19]([CH3:21])[CH3:20])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH:29]=[C:28]1[C:36](Cl)=[O:37].C(N(CC)C(C)C)(C)C>ClCCl>[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH:29]=[C:28]1[C:36]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([N:17]([CH3:26])[C@@H:18]([C:22]([O:24][CH3:25])=[O:23])[CH:19]([CH3:21])[CH3:20])(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1)=[O:37]
Reactant: COC(=O)[C@@H](C(C)C)N(C)S(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: O=C(Cl)c1cc2ccccc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H](C(C)C)N(C)S(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4ccccc4o3)cc2)cc1
Temperature: 25 °C
Yield: 85.5 %

Procedure:
To 0.11 g of methyl N-[(4′-amino-1,1′-biphenyl-4-yl)sulfonyl]-N-methyl-D-valinate in 4 mL dichloromethane cooled in ice bath, was added 0.058 g of 2-benzofurancarbonyl chloride, and N,N-diisopropylethylamine (0.15 mL) was dropped in. The reaction was stirred at room temperature overnightand then diluted with dichloromethane. The organic layer was washed with water, 5% HCl, and brine, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography eluting with hexane:ethyl acetate (2:1) to provide 0.13 g of methyl N-({4′-[(1-benzofuran-2-ylcarbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)-N-methyl-D-valinate. Yield 86.6%. m.p. 67-69° C. MS: 521.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:33])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])C)[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:34][C@@H:35]1[N:40]([CH3:41])[CH2:39][CH2:38][N:37]([CH2:42][CH2:43][OH:44])[CH2:36]1.C[C@H]1N(C)[C@@H](C)CN(CCO)C1>>[CH3:34][C@@H:35]1[N:40]([CH3:41])[CH2:39][CH2:38][N:37]([CH2:42][CH2:43][O:44][C:2]2[CH:7]=[CH:6][N:5]3[C:8]([C:11]([NH:13][C:14]4[CH:22]=[CH:21][CH:20]=[C:19]5[C:15]=4[C:16]([CH3:33])=[N:17][N:18]5[CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH3:32])[N:25]=4)=[O:12])=[CH:9][N:10]=[C:4]3[CH:3]=2)[CH2:36]1
Reactant: C[C@H]1CN(CCO)CCN1C
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(Cl)ccn34)c12
Agent: C[C@@H]1CN(CCO)C[C@H](C)N1C
Product: CCc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(OCCN6CCN(C)[C@@H](C)C6)ccn45)cccc32)n1
Yield: 27 %

Procedure:
Prepared according to Example 7, Step F, substituting 7-chloro-N-(1-((6-ethylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide for 7-chloro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol for 2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)ethanol to give the title compound (27%). MS (APCI), positive scan, m/z=567.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:27])=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][C:6]1[C:7]([O:22][CH3:23])=[CH:8][C:9]([O:20][CH3:21])=[C:10]([C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=1.CO[CH:30](OC)[N:31]([CH3:33])[CH3:32]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([F:27])=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][C:6]1[C:7]([O:22][CH3:23])=[CH:8][C:9]([O:20][CH3:21])=[C:10]([CH:11]=1)[C:12]([C:13](=[CH:30][N:31]([CH3:33])[CH3:32])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1cc(Cc2cccc(Cl)c2F)c(OC)cc1OC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Cc2cccc(Cl)c2F)c(OC)cc1OC
Temperature: 95 °C
Reaction time: 10 h

Procedure:
Under a nitrogen atmosphere, ethyl 3-(5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxyphenyl)-3-oxopropionate (2.76 g) and N,N-dimethylformamide dimethyl acetal (1.36 g) were dissolved in toluene. This solution was stirred at 95° C. for 10 hr, and the completion of the reaction was confirmed by HPLC. The reaction mixture was cooled to room temperature to give a solution of ethyl 2-(5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoyl)-3-dimethylaminoacrylate in toluene. The reaction mixture was directly used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[F:23][C:24]([Si](C)(C)C)([F:26])[F:25].[F-].[K+].Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)([OH:12])[C:24]([F:26])([F:25])[F:23])=[CH:9][N:10]=2)[N:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(c1ccc2ncccc2c1)(c1cnc2ccc(Cl)nn12)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-quinolin-6-yl-methanone (Stage 1.2, 50 mg, 0.162 mmol) was dissolved in DMF (5 mL) and (trifluoromethyl)trimethylsilane (1.294 mL, 8.10 mmol) and KF (4.70 mg, 0.081 mmol) were introduced. After 30 min at rt, 1 N HCl was added to the RM. It was stirred at rt for 20 h. the reaction was not completed. It was then heated at 150° C. under microwave irradiations for 5 min. It was extracted with EtOAc twice. Combined organic layers was washed with brine and dried over Na2SO4. It was filtered and the solvent was removed to afford as brown solid 1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-2,2,2-trifluoro-1-(quinolin-6-yl)ethanol (tR 0.8 min (conditions 2), MH+=379).