Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[CH:11]([NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)([CH3:13])[CH3:12].[ClH:26]>C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC.C(OCC)(=O)C>[ClH:26].[CH:11]([NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:21][CH:20]=1)([CH3:13])[CH3:12]
Reactant: CC(C)NCCCOc1ccc(Br)cc1
Reactant: Cc1ccccc1B(O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1ccccc1-c1ccc(OCCCNC(C)C)cc1
Temperature: 80 °C

Procedure:
2-Methylphenyl boronic acid (0.42 g) was added to a solution of N-isopropyl-3-(4-bromophenoxy)propylamine (1.0 g) and tetrakis triphenylphosphine palladium (100 mg) in aqueous 2M sodium carbonate (8.4 ml) and dimethoxyethane (5 ml). The mixture was heated at 80° C. for 18 hours, cooled to ambient temperature and diluted with ethyl acetate. The reaction mixture was washed with dilute sodium hydroxide solution, brine, dried (MgSO4) and evaporated. The residue was purified by dry flash column chromatography on silica gel (Merck 60H, Art No 7736) using a 5:95 v/v mixture of methanol and dichloromethane to give an oil. This oil was treated with ethereal hydrogen chloride to give a solid which was recrystallised from isopropyl alcohol to give N-isopropyl-3-[4-(2-methylphenyl)phenoxy]propylamine hydrogen chloride (0.38 g) as a solid, m.p. 157°-158° C.; microanalysis, found: C, 71.6; Hi 8.2; N, 4.4; Cl, 10.8%; C19H25NO. HCl requires: C, 71.3; H, 8.19; N, 4.38; Cl, 11.1%; NMR([CD3 ]2SO): 1.27(6H,d), 2.14(2H,m), 2.22(3H,s), 3.05(2H,t), 3.29(1H,m), 4.13(2H,t), 7.01(2H,d) and 7.12-7.30(6H,m); m/z 284(M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([C:14]2[S:21][C:20]([CH3:22])=[C:19]3[C:15]=2[CH2:16][C@H:17]2[C:23]([CH3:25])([CH3:24])[C@H:18]23)=[O:13])[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8].Br[CH2:27][CH2:28][OH:29]>C(O)(C)C.[OH-].[Na+]>[OH:29][CH2:28][CH2:27][O:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([CH2:10][CH2:11][C:12]([C:14]2[S:21][C:20]([CH3:22])=[C:19]3[C:15]=2[CH2:16][C@H:17]2[C:23]([CH3:25])([CH3:24])[C@H:18]23)=[O:13])=[CH:5][C:6]=1[CH3:9]
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1O
Reactant: OCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCCO
Temperature: 70 °C
Reaction time: 5.5 h
Yield: 46.6 %

Procedure:
A solution of 3-(3,5-dimethyl-4-hydroxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (3.00 g, 8.46 mmol, Intermediate 10) in isopropanol (80 mL) and 2 N aq. NaOH (30 mL) is treated with 2-bromoethanol (2.11 g, 16.9 mmol). The dark red reaction mixture is stirred at 70° C. for 5.5 h. The solvent is removed under reduced pressure and the residue is dissolved in EA and washed twice with water. The organic layer is dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 1:1 to give 3-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (1.57 g) as an orange oil; LC-MS: tR=1.09 min, [M+1]+=399.35.
Reaction SMILES: ClC1C=C(Cl)N2N=C(N3C(=O)C4C(=CC=CC=4)C3=O)C(CC3C=CC=C(C(F)(F)F)C=3C)=C2N=1.[OH-].[Na+].C(O)(=O)C.N1CCOCC1.NN.[NH2:49][C:50]1[C:65]([CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[C:69]([C:73]([F:76])([F:75])[F:74])[C:68]=2[CH3:77])=[C:53]2[NH:54][C:55]([N:59]3[CH2:64][CH2:63][O:62][CH2:61][CH2:60]3)=[CH:56][C:57](=[O:58])[N:52]2[N:51]=1.C1(=O)OC(=O)C2=CC=CC=C12>O1CCCC1.C(O)C.C(#N)C.CCOC(C)=O.O>[NH2:49][C:50]1[C:65]([CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[C:69]([C:73]([F:76])([F:75])[F:74])[C:68]=2[CH3:77])=[C:53]2[N:54]=[C:55]([N:59]3[CH2:64][CH2:63][O:62][CH2:61][CH2:60]3)[CH:56]=[C:57]([OH:58])[N:52]2[N:51]=1
Reactant: Cc1c(Cc2c(N)nn3c(=O)cc(N4CCOCC4)[nH]c23)cccc1C(F)(F)F
Agent: Cc1c(Cc2c(N3C(=O)c4ccccc4C3=O)nn3c(Cl)cc(Cl)nc23)cccc1C(F)(F)F
Agent: NN
Agent: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1c(Cc2c(N)nn3c(O)cc(N4CCOCC4)nc23)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(5,7-dichloro-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}pyrazolo[1,5-a]pyrimidin-2-yl)-1H-isoindole-1,3(2H)-dione (1.0 g, 1.979 mmol) in Tetrahydrofuran (THF) (30 mL) was added sodium hydroxide (1.187 mL, 5.94 mmol). The reaction mixture was stirred at rt for 18 h. Sodium hydroxide (1.187 mL, 5.94 mmol) was added to the reaction. The reaction mixture was stirred at rt for 3 h. Water (20 mL) and EtOAc (20 mL) was added in. The reaction mixture was acidified with acetic acid (0.680 mL, 11.87 mmol). The aqueous phase was extracted with EtOAc (30 mL). The combined organic phases were washed with brine (30 mL), dried (MgSO4) and concentrated. To the crude in Ethanol (5 mL) was added morpholine (1.035 mL, 11.87 mmol). The reaction was subjected to MW irradiation at 150° C. for 7 h. The reaction was concentrated. To the crude was added Ethanol (20 mL) and hydrazine (0.097 mL, 1.979 mmol). The reaction mixture was refluxed for 3 h. The reaction was concentrated and purified by reversed phase HPLC (20˜50% CH3CN (0.1% TFA)/Water (0.1% TFA)). NMR is not clean. To the solution of 2-amino-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-5-(4-morpholinyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (0.13 g, 0.319 mmol) in Acetonitrile (4 mL) was added phthalic anhydride (0.142 g, 0.957 mmol). The reaction mixture was stirred at 100° C. for 6 h. The reaction was concentrated. The residue was purified on a silica column (20˜60% EtOAc/Hexane) and then (0˜10% MeOH/DCM). To the purified material was added Ethanol (10 mL) and hydrazine (0.020 mL, 0.638 mmol). The reaction mixture was refluxed for 1 h. The reaction mixture was concentrated and purified by reverse phase HPLC (20˜50% CH3CN (0.1% TFA)/Water (0.1% TFA)). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.45 (s, 3H) 3.25 (m, 4H) 3.64 (m, 4H) 3.81 (s, 2H) 4.99 (s, 1H) 7.11-7.24 (m, 1H) 7.25-7.33 (m, 1H) 7.53 (m, 1H); LC/MS: MS (ES+) m/e 408.1 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[C:5](Br)=[CH:6][N:7]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:8]=2[CH:9]=[CH:10][CH:11]=1.[Li]C(C)(C)C.[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>CCOCC>[CH3:1][S:2][C:3]1[C:4]2[C:5]([CH2:33][C:32]3[CH:35]=[CH:36][C:29]([Cl:28])=[CH:30][CH:31]=3)=[CH:6][N:7]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CSc1cccc2c1c(Br)cn2[Si](C(C)C)(C(C)C)C(C)C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CSc1cccc2c1c(Cc1ccc(Cl)cc1)cn2[Si](C(C)C)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 71.3 %

Procedure:
To a solution of the indole of Step 4 (2.4 g, 6 mmol) in Et2O (50 mL) at −78° C. was added t-BuLi (7 mL, 12 mmol). The reaction mixture was stirred for 10 minutes at −78° C. and p-chlorobenzyl bromide (3.6 g, 18 mmol) was added. The reaction mixture was stirred for 2 hours at r.t. and was quenched with saturated aqueous NH4Cl. The phases were separated and the aqueous layer was extracted with Et2O. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 5% EtOAc in Hexanes to provide 1.9 g of the title compound as a pale yellow oil used as such.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5](=[O:8])[NH:6][N:7]=1.[NH2:9][S:10]([C:13]1[CH:14]=[C:15]([NH:20][C:21]2[N:26]=[C:25]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)[C:24]([F:35])=[CH:23][N:22]=2)[CH:16]=[CH:17][C:18]=1[F:19])(=[O:12])=[O:11].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[NH2:9][S:10]([C:13]1[CH:14]=[C:15]([NH:20][C:21]2[N:26]=[C:25]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:2][C:3]4[NH:4][C:5](=[O:8])[NH:6][N:7]=4)=[CH:30][CH:29]=3)[C:24]([F:35])=[CH:23][N:22]=2)[CH:16]=[CH:17][C:18]=1[F:19])(=[O:12])=[O:11]
Reactant: NS(=O)(=O)c1cc(Nc2ncc(F)c(Nc3ccc(O)cc3)n2)ccc1F
Reactant: O=c1[nH]nc(CCl)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: NS(=O)(=O)c1cc(Nc2ncc(F)c(Nc3ccc(OCc4n[nH]c(=O)[nH]4)cc3)n2)ccc1F
Yield: 20.4 %

Procedure:
To a solution of 5-chloromethyl-2,4-dihydro-1,2,4-triazol-3-one (35 mg, 0.26 mmol) in 2-butanone, were added N2-(3-aminosulfonyl-4-fluorophenyl)-5-fluoro-N4-(4-hydroxyphenyl)-2,4-pyrimidinediamine (100 mg, 0.25 mmol) and potassium carbonate (35 mg, 0.25 mmol). The resulting mixture was microwaved at 140° C. for 5 hours, and then additional of 5-chloromethyl-2,4-dihydro-1,2,4-triazol-3-one was added as needed The reaction solvent was removed under a reduced pressure, and the residual was purified by column chromatography (silica gel, dichloromethane:methanol 8:2 v/v) to give 25 mg of N2-(3-aminosulfonyl-4-fluorophenyl)-5-fluoro-N4-[4-(2,4-dihydro-3-oxo-1,2,4-triazol-5-yl)methoxyphenyl]-2,4-pyrimidinediamine (76) as a light yellow solid. 1H NMR (D2O): δ 7.90-7.89 (d, J=3 Hz, 1H), 7.60-7.58 (d, J=6 Hz, 1H), 7.34 (bs, 2H), 7.24-7.18 (m, 2H), 7.05-7.02 (d, J=9.0 Hz, 2H), 6.65-6.62 (d, J=9.0 Hz, 2H), 5.11 (br s, 2H); LCMS (m/z): 491.05 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([N:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:46][CH3:47])=[O:5])[CH3:2].I[CH2:49][CH2:50][OH:51].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[CH:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:27]=[C:28]([C:36]([F:39])([F:37])[F:38])[CH:29]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:31]=3)[C:22]([N:40]3[CH2:45][CH2:44][N:43]([CH2:49][CH2:50][OH:51])[CH2:42][CH2:41]3)=[CH:21][N:20]=2)[CH2:8][CH:7]1[CH2:46][CH3:47])=[O:5])[CH3:2]
Reactant: OCCI
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(N3CCNCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1c2ccc(OC)nc2C(Nc2ncc(N3CCN(CCO)CC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)CC1CC
Temperature: 50 °C
Reaction time: 5 h

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(piperazin-1-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (150 mg) is dissolved in N,N-dimethylformamide (1 ml), then thereto are added 2-iodoethanol (26 μl) and excess potassium carbonate, and the mixture is heated to 50° C. under nitrogen flow and stirred for 5 hours. After adding distilled water, the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform:methanol=19:1→9:1) to give (2R*,4-{[3,5-bis(trifluoromethyl)benzyl]-[5-[4-(2-hydroxyethyl)piperazin-1-yl]pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (128 mg). MS (m/z): 712 [M+H]+
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[N:11]=2)[CH:5]=1.[OH-].[Li+]>O1CCOCC1>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[N:11]=[C:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:22])=[O:2])[O:14][N:13]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1cccc(-c2nc(-c3ccc(F)cc3)no2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1cccc(-c2nc(-c3ccc(F)cc3)no2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a 25 ml flask, 0.93 g (3.1 mmol) of 3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-benzoic acid methyl ester are dissolved in 17 ml of dioxane. Then, 4.7 ml of an aqueous lithium hydroxide solution (1M, 4.7 mmol, 1.5 eq.) are added and the cloudy mixture is stirred for 6 h at room temperature. Now, the dioxane is removed in vacuo, 20 ml of water are added and the pH of the solution is adjusted to 2. The resulting precipitate is filtered and washed with water and CH2Cl2. This yields, after drying, the title compound. Mass spectrum: m/z (M−H)−: 283.0
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[C:12]([N+:15]([O-])=O)[CH:13]=[CH:14][C:7]2=[N:6][C:5]=1[CH3:18].[H][H]>[Pt]=O.CO>[NH2:15][C:12]1[CH:13]=[CH:14][C:7]2[N:8]([CH:11]=1)[C:9](=[O:10])[C:4]([CH2:3][CH2:2][Cl:1])=[C:5]([CH3:18])[N:6]=2
Reactant: Cc1nc2ccc([N+](=O)[O-])cn2c(=O)c1CCCl
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: Cc1nc2ccc(N)cn2c(=O)c1CCCl

Procedure:
A mixture of 40 parts of 3-(2-chloroethyl)-2-methyl-7-nitro-4H-pyrido[1,2-a]pyrimidin-4-one and 240 parts of methanol was hydrogenated at normal pressure and at room temperature with 0.5 parts of platinum oxide. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in acetonitrile and 2-propanol. The salt was filtered off and dissolved in water while heating. The solution was treated with activated charcoal. The latter was filtered off over Hyflo and the filter-cake was washed with water. The filtrate was stirred in a dilute ammonium hydroxide solution. The precipitated product was filtered off, washed with water and with petroleumether, and dried, yielding 19.4 parts of 7-amino-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 185° C. (intermediate 9).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](Br)[CH:9]=2)[NH:4][N:3]=1.[CH2:12]([O:14][C:15](=[O:35])[CH:16]=[C:17](C1C=CC=C2C=1C(C#N)=CN2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:35])[CH:16]=[C:17]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[CH3:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13]
Reactant: Cc1n[nH]c2ccc(Br)cc12
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CCOC(=O)C=C(c1ccccc1)c1ccc2[nH]nc(C)c2c1

Procedure:
3-(3-Methyl-1H-indazol-5-yl)-3-phenyl-acrylic acid ethyl ester CCXIX) was prepared from 3-methyl-5-bromo-1H-indazole using the procedure described for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (Example 14).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:44][C:45]1[CH:65]=[CH:64][C:48]([O:49][C:50]2[C:55]([C:56]3[CH:61]=[CH:60][N:59]=[C:58]([NH:62][CH3:63])[N:57]=3)=[CH:54][CH:53]=[CH:52][N:51]=2)=[CH:47][CH:46]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:44][C:45]1[CH:46]=[CH:47][C:48]([O:49][C:50]2[C:55]([C:56]3[CH:61]=[CH:60][N:59]=[C:58]([NH:62][CH3:63])[N:57]=3)=[CH:54][CH:53]=[CH:52][N:51]=2)=[CH:64][CH:65]=1)=[O:10]
Reactant: O=C(O)c1cccnc1F
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(N)cc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)c3cccnc3F)cc2)n1
Reaction time: 16 h

Procedure:
To a mixture of 2-fluoro-3-pyridinecarboxylic acid (1.06 g, 7.50 mmol) and HATU (3.11 g, 8.18 mmol) in CHCl3 at ambient temperature under nitrogen was added n,n-diisopropylethylamine (2.38 ml, 13.6 mmol) via syringe. The mixture was allowed to stir for 5 min. at which point 4-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (2.00 g, 6.82 mmol) was added. The reaction was allowed to stir 16 h, resulting in the formation of a fine precipitate. The reaction was filtered, rinsing with 2×dichloromethane and the solid dried in vacuo to give 2-fluoro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)nicotinamide as a tan solid. MS m/z=417 [M+1]+. Calc'd for C22H17FN6O2: 416.41.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:9]=[C:10]([C:17]2[C:18]([N+:37]([O-])=O)=[CH:19][C:20]3[O:24][C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[C:22]([C:32]([NH:34][CH3:35])=[O:33])[C:21]=3[CH:36]=2)[CH:11]=[C:12]([N+:14]([O-])=O)[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:37][C:18]1[C:17]([C:10]2[CH:9]=[C:8]([C:6](=[O:7])[NH:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:13]=[C:12]([NH2:14])[CH:11]=2)=[CH:36][C:21]2[C:22]([C:32]([NH:34][CH3:35])=[O:33])=[C:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[O:24][C:20]=2[CH:19]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3cc(C(=O)NC(C)(C)C)cc([N+](=O)[O-])c3)cc12
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3cc(N)cc(C(=O)NC(C)(C)C)c3)cc12
Reaction time: 16 h
Yield: 64.4 %

Procedure:
To a solution of 5-(3-(tert-butylcarbamoyl)-5-nitrophenyl)-2-(4-fluorophenyl)-N-methyl-6-nitrobenzofuran-3-carboxamide (350 mg) in MeOH (50 mL) was added palladium on carbon (69.7 mg). The mixture was stirred under hydrogen with a balloon for 16 hours. Pd/C was removed by filtration and the filtrate was concentrated to give 6-amino-5-(3-amino-5-(tert-butylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide 3 (200 mg).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[N:7][CH:8]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][C:24]=3[N:25]([CH3:28])[C:26]=2[CH:27]=1>>[CH3:28][N:25]1[C:26]2[CH:27]=[C:19]([N:12]3[CH:13]=[CH:14][C:9]([C:6]4[N:7]=[CH:8][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:4][N:5]=4)=[CH:10][C:11]3=[O:15])[CH:20]=[CH:21][C:22]=2[C:23]2[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][C:24]1=2
Reactant: O=c1cc(-c2ncc(C(F)(F)F)cn2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Product: Cn1c2c(c3ccc(-n4ccc(-c5ncc(C(F)(F)F)cn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 39.3 %

Procedure:
4-(5-(Trifluoromethyl)pyrimidin-2-yl)pyridin-2(1H)-one (100 mg, 0.34 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (124 mg, 0.339 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (70 mg, 39%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 9.11 (s, 2H), 7.86 (s, 1H), 7.59-7.53 (m, 2H), 7.38 (s, 1H), 7.28-7.26 (m, 1H), 7.08 (d, J=8.4 Hz, 1H), 4.89-4.63 (br m, 2H), 3.90-3.80 (br m, 2H), 3.65 (s, 3H), 2.88-2.79 (br m, 2H), 1.50 (s, 9H).
Reaction SMILES: [NH2:1][C:2]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH:7]([F:9])[F:8])[C:3](OC)=[O:4].[BH4-].[Li+].Cl>C1COCC1>[NH2:1][C:2]([CH:7]([F:8])[F:9])([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:3][OH:4]
Reactant: COC(=O)C(N)(Cc1ccccc1)C(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC(CO)(Cc1ccccc1)C(F)F
Temperature: 45 °C

Procedure:
To a solution of methyl 2-amino-2-benzyl-3,3-difluoropropanoate (0.11 g, 0.48 mmol) (for synthesis see: Bey et al, J. Org. Chem. 1979, 44, 2732-2742) in 6.8 mL THF was added lithium borohydride (2M in THF, 1.45 mL, 2.9 mmol) dropwise. The reaction was heated at reflux temperature for 2 h, quenched with MeOH and acetone and concentrated. Hydrochloric acid (1M, 14.5 mL, 14.5 mmol) was added, the mixture was heated to 45° C. for 1.5 h and concentrated. The reaction was made basic with saturated NaHCO3 and extracted with CHCl3. Drying and solvent evaporation gave 2-amino-2-(difluoromethyl)-3-phenylpropan-1-ol. 1H NMR (400 MHz, CDCl3) δ 7.35-7.24 (m, 5H), 5.67 (t, J=56.5 Hz, 1H), 3.56 (A of AB, d, J=11.0 Hz, 1H), 3.46 (B of AB, d, J=11.0 Hz, 1H), 2.89 (A of AB, d, J=13.6 Hz, 1H), 2.84 (B of AB, d, J=13.6, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1.[CH2:19]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[CH2:34]Br)[CH:20]=[CH2:21]>>[CH2:19]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[CH2:34][N:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9](=[O:11])[CH3:10])[CH:20]=[CH2:21]
Reactant: CC(=O)Nc1cc(F)ccc1Oc1ccccc1
Reactant: C=CCOCCOc1ccc(OC)cc1CBr
Product: C=CCOCCOc1ccc(OC)cc1CN(C(C)=O)c1cc(F)ccc1Oc1ccccc1
Yield: 49 %

Procedure:
The general procedure C was applied to N-(5-Fluoro-2-phenoxy-phenyl)-acetamide and 10b The desired product 10c was obtained in 49% yield (4.9 mmol; 2.28 g).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:25]4[O:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:24]=4[CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH:11]=[C:10]([N+:33]([O-])=O)[C:9]1=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.CN(C=O)C.O.C(OCC)(=O)C.[Pd]>[NH2:33][C:10]1[C:9](=[O:36])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:25]4[O:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:24]=4[CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH:11]=1
Reactant: O=c1c([N+](=O)[O-])cc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cn1Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1cc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cn(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-benzyl-5-(4-dibenzofuran-4-yl-phenyl)-3-nitro-1H-pyridin-2-one (100 mg, 0.212 mmol) was dissolved in hot 50% ethanol in DMF (8 mL) and cooled to room temperature. 10% Pd—C (10 mg) was added and the solution was shaken on a Parr hydrogenator with 60 psi H2 for 2 h. The resulting mixture was diluted with water (30 mL) and ethyl acetate (70 mL), separated and extracted with ethyl acetate (100 mL). The combined organic layers were washed with sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 3-amino-1-benzyl-5-(4-dibenzofuran-4-yl-phenyl)-1H-pyridin-2-one as a yellow sold that was used without further purification.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.F[C:13]1[C:14]([N+:23]([O-:25])=[O:24])=[CH:15][C:16]2[S:20][C:19]([CH3:21])=[N:18][C:17]=2[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[C:6]([S:11][C:13]3[C:14]([N+:23]([O-:25])=[O:24])=[CH:15][C:16]4[S:20][C:19]([CH3:21])=[N:18][C:17]=4[CH:22]=3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Cc1nc2cc(F)c([N+](=O)[O-])cc2s1
Reactant: Sc1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(Sc3cccc4cnccc34)c([N+](=O)[O-])cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
5-Isoquinolinethiol 250 mg (1.5 mmol) was dissolved in DMF 10 ml, 5-fluoro-2-methyl-6-nitrobenzothiazole 330 mg (1.5 mmol) and potassium carbonate 650 mg (4.7 mmol) were added, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure, the residue was crystallized from ether, and 5-(5-isoquinolylsulfanyl)-2-methyl-6-nitrobenzo[d][1,3]thiazole 180 mg (33.1%) was obtained.