Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]([N:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)=[N:40][CH:41]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[CH3:25][C:24]1[CH:23]=[C:22]([CH3:26])[NH:21][C:20](=[O:27])[C:19]=1[CH2:18][NH:17][C:15]([C:4]1[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:36]2[CH:41]=[N:40][C:39]([N:42]3[CH2:43][CH2:44][NH:45][CH2:46][CH2:47]3)=[CH:38][CH:37]=2)[CH:3]=1)=[O:16]
Reactant: CC1(C)OB(c2ccc(N3CCNCC3)nc2)OC1(C)C
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCNCC4)nc3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Reaction time: 0.17 h

Procedure:
6-Bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxamide (1.9 g, 4.42 mmol), 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (1.277 g, 4.42 mmol) and potassium phosphate (tribasic) (2.81 g, 13.25 mmol) were placed in a 150 mL pressure vessel followed by addition of 1,4-dioxane (40 mL) and water (10.00 mL). The suspension was stirred and degassed under N2 for 15 min. (emulsion). Next added in PdCl2(dppf)-CH2Cl2 adduct (0.361 g, 0.442 mmol) and degassed for 2 min. The reaction flask was sealed and the contents heated at reflux for 2 h. The suspension was filtered, and dioxane was removed in vacuo. The resultant oil was partitioned between 300 mL of ethyl acetate and 100 mL of water, and the layers were separated. Decolorizing carbon was added, and after 10 min, the organic layer was filtered through short pad of silica. 300 mL of 1M HCl was added and neutralized with NaOH (to pH ˜9). The contents were extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The product was suspended in diethyl ether and filtered. The title compound was isolated as a yellow solid (950 mg, 41% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.49 (br. s., 1H), 8.52 (d, J=2.27 Hz, 1H), 8.15 (t, J=5.05 Hz, 1H), 7.95 (dd, J=2.53, 8.84 Hz, 1H), 7.73 (d, J=1.26 Hz, 1H), 7.29 (s, 1H), 7.19 (d, J=1.52 Hz, 1H), 6.93 (d, J=9.09 Hz, 1H), 5.87 (s, 1H), 4.85 (quin, J=6.63 Hz, 1H), 4.35 (d, J=5.05 Hz, 2H), 3.49-3.63 (m, 4H), 2.81-3.02 (m, 4H), 2.24 (s, 3H), 2.16 (s, 3H), 2.11 (s, 3H), 1.43 (d, J=6.57 Hz, 6H); LCMS=513.3 (MH+).
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:50]1[CH:55]=[C:54]([O:56][CH:57]2[CH2:62][O:61][CH:60]([C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[O:59][CH2:58]2)[N:53]=[C:52]([S:69][CH2:70][C:71]2[CH:76]=[CH:75][CH:74]=[C:73]([F:77])[C:72]=2[F:78])[N:51]=1>O1CCOCC1.C(Cl)Cl.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.[Pd].[Pd]>[F:78][C:72]1[C:73]([F:77])=[CH:74][CH:75]=[CH:76][C:71]=1[CH2:70][S:69][C:52]1[N:51]=[C:50]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[CH:55]=[C:54]([O:56][CH:57]2[CH2:58][O:59][CH:60]([C:63]3[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=3)[O:61][CH2:62]2)[N:53]=1
Reactant: NS(=O)(=O)N1CCC1
Reactant: Fc1cccc(CSc2nc(Cl)cc(OC3COC(c4ccccc4)OC3)n2)c1F
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(OC2COC(c3ccccc3)OC2)nc(SCc2cccc(F)c2F)n1)N1CCC1
Temperature: 100 °C

Procedure:
A mixture of azetidine-1-sulphonamide (420 mg), tris(dibenzylideneacetone)dipalladium (0) (71 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (37 mg), cesium carbonate (380 mg) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2-phenyl-1,3-dioxan-5-yl)oxy]-pyrimidine (350 mg) in anhydrous dioxane (8 ml) was heated to reflux in a microwave at 100° C., 300 W, open vessel with cooling for 10 minutes. The reaction mixture was diluted with methylene chloride, filtered through arbocel and the filtrate evaporated. The residue was purified by column chromatography on silica using a 80:20 to 70:30 mixture of iso-hexane and ethyl acetate as eluent to give the sub-title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:23]2([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[Cl:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[Cl:37].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[Cl:30][C:31]1[CH:32]=[C:33]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([C:23]3([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:9][N:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:12][CH2:11]3)[CH:3]=2)[CH:34]=[CH:35][C:36]=1[Cl:37]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2cccc(Br)c2)C2(O)CCCCC2)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: COCCOC
Product: CC(C)(C)OC(=O)N1CCN(CC(c2cccc(-c3ccc(Cl)c(Cl)c3)c2)C2(O)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.5 %

Procedure:
A mixture of tert-butyl 4-[2-(3-bromophenyl)-2-(1-hydroxycyclohexyl)ethyl]piperazine-1-carboxylate (0.72 g, 1.55 mmol) and tetrakis(triphenylphosphine)palladium (37 mg, 0.032 mmol, 10 mol %) in 1,2-dimethoxyethane (30 mL) was stirred for 10 min at room temperature. To this mixture was added sequentially 3,4-dichlorophenyl boronic acid (0.44 g, 2.32 mmol) and a 2M aqueous solution of sodium carbonate (0.8 mL, 1.6 mmol, 5 equivalent), and the mixture was heated at reflux until all starting material was consumed and precipitation of black palladium occurred (3 h). After cooling, water was added and the reaction mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude solid, which was purified via flash column chromatography (silica, gradient from 0% ethyl acetate/hexane to 30% ethyl acetate/hexane) to yield 0.55 g (67%) of tert-butyl 4-[2-(3′,4′-dichloro-biphenyl-3-yl)-2-(1-hydroxycyclohexyl)ethyl]piperazine-1-carboxylate as a foam, which was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:12]([OH:21])[CH:11]=2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.I[CH2:30][CH3:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:12]([O:21][CH2:30][CH3:31])[CH:11]=2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: CCI
Reactant: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1O
Product: CCOc1cc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)ccc1CS(C)(=O)=O
Yield: 41.2 %

Procedure:
N-(4-Chloro-3-(pyridin-2-yl)phenyl)-3-hydroxy-4-(methylsulfonylmethyl)benzamide (50 mg, 0.12 mmol) was treated with iodoethane (10 μl, 0.12 mmol) via procedure U to yield 22 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-ethoxy-4-(methylsulfonylmethyl)benzamide. MS (Q1) 445 (M)+.
Reaction SMILES: C([C@@:8]([NH2:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][NH2:10])(OC(C)(C)C)=O.[C:18]1(=[O:28])[O:23][C:21](=O)[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12>C(Cl)(Cl)Cl>[CH2:21]([O:23][C:18]([NH:17][C@H:8]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][N:10]1[C:18](=[O:28])[C:19]2=[CH:27][CH:26]=[CH:25][CH:24]=[C:20]2[C:21]1=[O:23])=[O:28])[CH2:20][CH2:19][CH3:27]
Reactant: CC(C)(C)OC(=O)[C@](N)(CN)c1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: ClC(Cl)Cl
Product: CCCCOC(=O)N[C@@H](CN1C(=O)c2ccccc2C1=O)c1ccccc1

Procedure:
Boc-(R)-1,2 diamino-1-phenylethane (prepared by the method of O'Brien, P. et al. J. Med. Chem. 37 (1994) 12, 1810-1822) (0.3 g, 1.27 mmol.), phthalic anhydride (0.2 g., 1.4 mmol.) and TEA (0.1 ml) were dissolved in chloroform (20 ml.) and stirred under reflux for 2 days. The reaction mixture was then washed with 10% hydrochloric acid, 2M sodium hydroxide solution and brine, dried over magnesium sulphate, filtered and evaporated to give the product. The above product was further elaborated by Method 4 to the title compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[C:24]([OH:26])=O)[CH:21]=[CH:20][S:19]3)[CH2:3][CH2:2]1.[F:27][C:28]([F:36])([F:35])[C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[C:24]([NH:34][C:31]2[S:32][CH:33]=[C:29]([C:28]([F:36])([F:35])[F:27])[N:30]=2)=[O:26])[CH:21]=[CH:20][S:19]3)[CH2:2][CH2:3]1
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC1CC1
Reactant: Nc1nc(C(F)(F)F)cs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)Nc2nc(C(F)(F)F)cs2)c1OCC1CC1

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 1 (200 mg, 0.539 mmol) with 4-(trifluoromethyl)-1,3-thiazol-2-amine (100 mg, 0.593 mmol) in the presence of EDCI hydrochloride (206 mg, 1.079 mmol) and DMAP (99 mg, 0.809 mmol) in a mixture of DCM and DMF (4:1, 5 mL) to give 72 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.24-0.26 (m, 2H), 0.47-0.49 (m, 2H), 1.15-1.18 (m, 1H), 3.75 (d, J=6.9 Hz, 2H), 3.79 (s, 3H), 6.96-6.99 (m, 1H), 7.09 (t, J=7.8 Hz, 1H), 7.30-7.33 (m, 1H), 7.40-7.42 (m, 1H), 7.46 (d, J=15.6 Hz, 1H), 7.87 (d, J=15.6 Hz, 1H), 8.03 (s, 1H), 8.06 (d, J=4.2 Hz, 1H), 12.94 (s, 1H); ESI-MS (m/z) 521.34 (MH)+.
Reaction SMILES: C(OS([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)=O)CCCCCCCCCCC.[Na].Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1C=CC=CC=1>[C:25]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCCCCCCCCCCCOS(=O)(=O)c1ccccc1
Reactant: Brc1ccccc1
Agent: [Na]
Solvent: c1ccccc1
Product: c1ccc(-c2ccccc2)cc1

Procedure:
The procedure of Example 15 is repeated except that the 4 parts of sodium diisopropyl naphthalene sulphonate are replaced by 4 parts of sodium dodecylbenzene sulphonate. Again all the bromobenzene is reduced, but mainly to benzene, so that only 0.94 parts of biphenyl are isolated.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:21])[CH2:9][N:10]([CH2:18][CH2:19]O)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][C:3]=1[CH3:22].C(N(CC)CC)C.CS(Cl)(=O)=O>C1COCC1>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[O:21][CH2:19][CH2:18][N:10]([C:11]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:17])[CH2:9]2)=[CH:4][C:3]=1[CH3:22]
Reactant: Cc1cc(C(O)CN(CCO)C(=O)OC(C)(C)C)cnc1Br
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C2CN(C(=O)OC(C)(C)C)CCO2)cnc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.5 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-(6-bromo-5-methylpyridin-3-yl)-2-hydroxyethyl(2-hydroxyethyl)carbamate (2.57 g) and triethylamine (1.51 ml) in THF (30 ml) at 0-5° C. was added dropwise methanesulfonyl chloride (546 •1). The reaction mixture was then stirred at room temperature for 15 min to afford a white suspension. The reaction mixture was then filtered to remove triethylamine hydrochloride, washing the filter with THF (10 ml). The filtrate was cooled to 0-5° C. and potassium 2-methyl-2-butoxide (5.62 ml, 1.7 M solution in toluene) was added. The reaction mixture was stirred at room temperature for 10 min and then poured into EtOAc and washed sequentially with water and with saturated brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 70% EtOAc in hexanes) to afford tert-butyl (RS)-2-(6-bromo-5-methylpyridin-3-yl)morpholine-4-carboxylate (1.7 g, 73% over 3 steps) as a colourless oil. MS (ISP): 359.0 ([{81Br}M+H]+), 357.0 ([{79Br}M+H]+), 303.0 ([{81Br}M+H—C4H8]+), 301.0 ([{79Br}M+H—C4H8]+).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=2)[CH:29]=1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38](=[O:39])[C:37]5[CH:36]=[CH:35][C:34]([C:30]6[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=6)=[CH:42][CH:41]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc(-c2cccnc2)cc1

Procedure:
The title compound, white solid (110 mg, 86%), MS (ISP) m/z=512.5 [(M+H)+], mp 218° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 4-pyridin-3-yl-benzoic acid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1([OH:16])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11]C(C)(C)C)=O)[CH2:4]1.Cl.[Br:20][C:21]1[N:26]=[C:25](C(O)=O)[CH:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.C(#N)C.CO>[Br:20][C:21]1[N:26]=[C:25]([C:9]([N:5]2[CH2:6][CH2:7][CH2:8][C:3]([OH:16])([C:2]([F:1])([F:17])[F:18])[CH2:4]2)=[O:11])[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)(C(F)(F)F)C1
Reactant: O=C(O)c1cccc(Br)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(c1cccc(Br)n1)N1CCCC(O)(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
After tert-butyl 3-(trifluoromethyl)-3-hydroxypiperidine-1-carboxylate (709 mg, 2.63 mmol) was dissolved in THF (10 ml), followed by addition of HCl (2.0M solution in diethyl ether, 30 ml), and then the resulting mixture was stirred at room temperature for 2 hours. The resulting reaction liquid was concentrated under reduced pressure and dried under vacuum, and then the residue thus obtained was dissolved in acetonitrile (30 ml). 6-Bromopicolinic acid (638 mg, 3.16 mmol) was added thereto, and cooled to 0° C. N,N-Diisopropylethylamine (1.1 ml, 6.58 mmol) and HBTU (1.2 g, 3.16 mmol) were sequentially added thereto, and then the resulting mixture was stirred at room temperature under nitrogen stream for 20 hours. The resulting reaction liquid was concentrated under reduced pressure, followed by addition of MC (50 ml), and then washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (3% MeOH/MC), to obtain 800 mg of white solid (86%).
Reaction SMILES: C([S:4][CH2:5][C@H:6]([C:20]([F:23])([F:22])[F:21])[C:7]([NH:9][C@H:10]([C:15]1[NH:19][N:18]=[N:17][N:16]=1)[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])(=O)C.[NH4+].[OH-].C(OCC)(=O)C.CO>O>[F:22][C:20]([F:21])([F:23])[C@@H:6]([CH2:5][SH:4])[C:7]([NH:9][C@H:10]([C:15]1[NH:19][N:18]=[N:17][N:16]=1)[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:8]
Reactant: CC(=O)SC[C@@H](C(=O)N[C@@H](CC(C)C)c1nnn[nH]1)C(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](CS)C(F)(F)F)c1nnn[nH]1
Reaction time: 0.03 h

Procedure:
To a suspension of (S,S)-2-[(acetylthio) methyl]-3,3,3-trifluoro-N-[3-methyl-1-(1H -tetrazol-5-yl)butyl]propanamide [prepared in Example 39(e), 1.034 g., 2.95 mmol.] in 6 mL of degassed water at room temperature under argon was added a mixture of concentrated NH4OH (1.95 mL) and water (1.95 mL). After two minutes, the reaction was quenched with saturated potassium bisulfate (pH 1.5) and extracted with ethyl acetate. The organic extracts were dried and purified by flash chromatography (50 mm×6 inch, 1:1 hexanes:ethyl acetate +0.5% acetic acid) to give 0.76 g. of white solid product. This material was combined with 25 mg. from a previous experiment and recrystallized from ethyl acetate/hexanes to give 0.69 g. of the title (S,S) isomer product as a white solid, m.p. 183°-184° C., TLC Rf =0.14 (1:1, hexanes:ethyl acetate +0.5% acetic acid). [α]D =-39.8° (c=0.57, methanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([OH:34])[CH:32]=5)[N:27]=[CH:26][N:25]=4)=[C:19]([F:37])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N:57]1([CH2:63][CH2:64][CH2:65]O)[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([O:34][CH2:65][CH2:64][CH2:63][N:57]6[CH2:62][CH2:61][O:60][CH2:59][CH2:58]6)[CH:32]=5)[N:27]=[CH:26][N:25]=4)=[C:19]([F:37])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:6][CH:7]=1
Reactant: OCCCN1CCOCC1
Reactant: COc1cc2ncnc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 10.2 %

Procedure:
Crude cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(6-hydroxy-7-methoxy-quinazolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (333 mg, 0.66 mmol), PS—PPh3 resin, (loading=2.33 mmol/g, 797 mg, 1.86 mmol), 3-morpholin-4-yl-propan-1-ol (0.26 ml, 1.88 mmol), and DEAD (0.31 ml, 1.91 mmol) were combined in CH2Cl2 (10 ml) and stirred at room temperature for 1-2 hrs. The reaction mixture was filtered and the resin thoroughly washed with CH2Cl2. The filtrate was concentrated in vacuo and the resulting residue was dissolved in EtOAc and washed with H2O (4×) and sat'd NaCl (1×) and then extracted with 1N HCl (3×). The combined 1N HCl extractions were washed with EtOAc (2×). The acidic aqueous phase was then basified with 1N NaOH and extracted with EtOAc (3×). The combined EtOAc extractions were washed with H2O (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The resulting residue was purified by preparative reverse phase HPLC (25 mM NH4OAc/acetonitrile) and the pure fractions were lyophilized to give cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yloxy]-phenyl}-amide (4-fluoro-phenyl)-amide (42.6 mg, 10%). 1H NMR (400 MHz, DMSO-d6): δ 10.37 (br s, 1H), 10.05 (br s, 1H), 8.55 (s, 1H), 7.84 (m, 1H), 7.65 (m, 2H), 7.58 (s, 1H), 7.43 (m, 3H), 7.16 (t, 2H), 4.27 (m, 2H), 4.00 (s, 3H), 3.60 (m, 6H), 2.39 (m, 4H), 1.99 (m, 2H), 1.47 (m, 4H). LC/MS Calcd for [M+H]+ 634.2, found 634.1.
Reaction SMILES: [C:1]([C:3]1[CH:37]=[CH:36][C:6]2[NH:7][C:8]([C:10]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][N:21]4C(OC(C)(C)C)=O)([NH:15][CH3:16])[C:11]([F:14])([F:13])[F:12])=[N:9][C:5]=2[CH:4]=1)#[N:2].C([O-])([O-])=O.[Cs+].[Cs+]>CO>[F:14][C:11]([F:12])([F:13])[C:10]([C:8]1[NH:7][C:6]2[CH:36]=[CH:37][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[N:9]=1)([C:17]1[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]2[C:18]=1[CH:19]=[CH:20][NH:21]2)[NH:15][CH3:16]
Reactant: CNC(c1nc2cc(C#N)ccc2[nH]1)(c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: CNC(c1nc2cc(C#N)ccc2[nH]1)(c1c(OC)cc(C)c2[nH]ccc12)C(F)(F)F
Temperature: 60 °C

Procedure:
To a solution of (±)-tert-butyl 4-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(methylamino)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (0.87 g, 1.69 mmol) in MeOH (16.94 mL) at room temperature, Cs2CO3 (2.76 g, 8.47 mmol) was added and the reaction was stirred at 60° C. After 2.5 hours the reaction was cooled to room temperature, quenched with aq. NH4Cl. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6 with about 5 μL TFA) δ ppm 11.14 (br. s., 1H) 8.21 (br. s., 1H) 7.72 (d, J=8.46 Hz, 1H) 7.64 (dd, J=8.40, 1.45 Hz, 1H) 7.18 (t, J=2.84 Hz, 1H) 6.89 (s, 1H) 5.56 (br. s., 1H) 3.57 (br. s., 3H) 2.31 (s, 3H). HRMS calcd. for C21H18F3N5O (M+H)+ 414.1542. found 414.1542.
Reaction SMILES: COC1C=CC([CH2:7][N:8](C)[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:21]4[CH:26]=[C:25]([NH2:27])[C:24]([F:28])=[CH:23][C:22]=4[CH3:29])[C:15](=[O:20])[N:16]3[CH3:19])=[CH:11][N:10]=2)=CC=1.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>>[NH2:27][C:25]1[C:24]([F:28])=[CH:23][C:22]([CH3:29])=[C:21]([C:14]2[C:15](=[O:20])[N:16]([CH3:19])[C:17]3[C:12]([CH:13]=2)=[CH:11][N:10]=[C:9]([NH:8][CH3:7])[CH:18]=3)[CH:26]=1
Reactant: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2cc(N)c(F)cc2C)c(=O)n3C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CNc1cc2c(cn1)cc(-c1cc(N)c(F)cc1C)c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-4-fluoro-2-methylphenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (1.86 g, 4.3 mmol) and TFA (9.5 mL, 121 mmol) were combined and stirred at RT overnight. The mixture was treated slowly with 2M Na2CO3 until the mixture was just faintly basic, then stirred at RT for 1 h. The solids were collected by filtration, washed thoroughly with H2O, dried partially in the air and then under high vacuum at 65° C. The crude product was purified by flash column chromatography (THF/EtOAc) to afford 3-(5-amino-4-fluoro-2-methylphenyl)-1-methyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (0.86 g, 64% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.35 (s, 1H), 7.58 (s, 1H), 6.99 (q, J=4.8 Hz, 1H), 6.56 (d, J=12.0 Hz, 1H), 6.56 (d, J=9.2 Hz, 1H), 6.15 (s, 1H), 4.87 (br s, 2H), 3.48 (s, 3H), 2.84 (d, J=5.2 Hz, 3H), 1.94 (s, 3H); MS (ESI) m/z: 313.2 [M+H]+.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[Cl:16][CH2:17][CH2:18]O.N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:5][C:4]([F:7])([F:6])[S:1]([O:8][CH2:18][CH2:17][Cl:16])(=[O:3])=[O:2]
Reactant: OCCCl
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(OCCCl)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of triflic anhydride (2.0 mL, 11.9 mmol) in CCl4 (10 mL) at 0° C. was treated with a solution of 2-chloroethanol (0.8 mL, 11.9 mmol) and pyridine (0.96 mL, 11.9 mmol) in CCl4 (6.0 mL) which was pre-cooled to 0° C. The reaction mixture was stirred at 0° C. for 45 minutes and then filtered through a pad of Na2SO4. The filtrate was concentrated and used immediately in the next step.