Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([C@H:47]1[CH2:52][CH2:51][C@H:50]([C:53]([O:55]C)=[O:54])[CH2:49][CH2:48]1)[S:4]([C:7]1[CH:8]=[C:9]([CH:44]=[CH:45][CH:46]=1)[C:10]([NH:12][C:13]1[S:14][C:15]2[CH2:43][CH2:42][CH2:41][CH2:40][C:16]=2[C:17]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][CH:31]=2)=[CH:23][CH:22]=1)=[O:19])=[O:11])(=[O:6])=[O:5])[CH3:2].CO.[OH-].[Na+]>C1COCC1>[C:53]([C@H:50]1[CH2:51][CH2:52][C@H:47]([N:3]([CH2:1][CH3:2])[S:4]([C:7]2[CH:8]=[C:9]([CH:44]=[CH:45][CH:46]=2)[C:10]([NH:12][C:13]2[S:14][C:15]3[CH2:43][CH2:42][CH2:41][CH2:40][C:16]=3[C:17]=2[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:38][CH:39]=3)=[CH:23][CH:22]=2)=[O:19])=[O:11])(=[O:6])=[O:5])[CH2:48][CH2:49]1)([OH:55])=[O:54]
Reactant: CCN([C@H]1CC[C@H](C(=O)OC)CC1)S(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN([C@H]1CC[C@H](C(=O)O)CC1)S(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCCc4ccc(C(=O)O)cc4)cc2)CCCC3)c1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
To a mixture of 230 mg of methyl 4-(3-{4-[({2-[(3-{ethyl[trans-4-(methoxycarbonyl)cyclohexyl]sulfamoyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}propyl)benzoate, 2 mL of methanol, and 2 mL of THF was added 2 mL of a 1 M aqueous NaOH solution, followed by stirring at 60° C. for 2 days. The reaction mixture was cooled and then concentrated under reduced pressure. The obtained residue was diluted with water and then neutralized with 1 M hydrochloric acid. To the reaction mixture was added 0.5 mL of THF and the precipitate was collected by filtration. The obtained solid was suspended in 10 mL of ethanol, and then the precipitate was collected by filtration to obtain 147 mg of 4-{3-[4-({[2-({3-[(trans-4-carboxycyclohexyl)(ethyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]propyl}benzoic acid as a beige crystal.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[C:9]1[C:19]([NH2:20])=[N:18][C:12]2[N:13]=[C:14]([NH2:17])[N:15]=[CH:16][C:11]=2[CH:10]=1.[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[NH2:17][C:14]1[N:15]=[CH:16][C:11]2[CH:10]=[C:9]([C:3]3[C:2]([Br:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Br:8])[C:19]([NH:20][C:26]([NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])=[N:18][C:12]=2[N:13]=1
Reactant: Nc1ncc2cc(-c3c(Br)cccc3Br)c(N)nc2n1
Reactant: CC(C)(C)N=C=O
Product: CC(C)(C)NC(=O)Nc1nc2nc(N)ncc2cc1-c1c(Br)cccc1Br

Procedure:
The title compound was prepared from 0.25 g of 6-(2,6-dibromo-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 60 and 0.077 mL of tert-butyl isocyanate according to Example 2. The product was purified by MPLC eluting with a gradient of CHCl3 :EtOAc (1:1) to EtOAc to afford the pure product; mp >300° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[O:15][CH:14]([CH2:16][CH:17]([P:26](=[O:29])([OH:28])[OH:27])S(C2C=CC=CC=2)=O)[CH:13]([F:30])[CH:12]1[OH:31].C(N(CCCC)CCCC)CCC.C[Si](Cl)(C)C>CN(C=O)C>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[O:15][CH:14]([CH:16]=[CH:17][P:26](=[O:27])([OH:28])[OH:29])[CH:13]([F:30])[CH:12]1[OH:31]
Reactant: Nc1ncnc2c1ncn2C1OC(CC(S(=O)c2ccccc2)P(=O)(O)O)C(F)C1O
Agent: C[Si](C)(C)Cl
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2C1OC(C=CP(=O)(O)O)C(F)C1O
Temperature: 130 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
Compound 49.4 (147 mg, 0.31 mmol) was dissolved in anhydrous DMF, treated with tributylamine (1.49 mL, 6.24 mmol) and TMSCl (0.79 mL, 6.24 mmol). The mixture was heated to 130° C. for 4 h and then cooled to rt. The reaction was quenched with water and stirred at rt for another 2 h. The mixture was concentrated under reduced pressure and the residue was washed with acetonitrile. The acetonitrile washes were discarded and the residue was dissolved in water, subjected to a reverse phase HPLC to give compound 49.5 (34 mg, 24% yield). 1H NMR (D2O, 300 MHz): δ 4.91-5.17 (m, 3H), 5.92-5.95 (m, 1H), 6.07-6.59 (m, 2H), 8.37 (s, 1H). 31PNMR: 11.82 ppm. LRMS [M−H]− C11H13FN5O5P requires 344.1. Found 344.1.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[OH:9][C:10]1[CH:11]=[C:12]([C:16](=O)[CH3:17])[CH:13]=[CH:14][CH:15]=1>C(O)C.O.C(OCC)(=O)C>[OH:9][C:10]1[CH:11]=[C:12]([C:16](=[N:2][OH:3])[CH3:17])[CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=NO)c1cccc(O)c1
Temperature: 80 °C
Yield: 113.4 %

Procedure:
Hydroxylamine hydrochloride (1 g, 10 mmol) and sodium acetate (1 g, 10 mmol) were added to a solution of 1-(3-hydroxyphenyl)ethanone (Aldrich, Cat. #H18801) (1 g, 7 mmol) in ethanol (30 mL) and water (4 mL). The reaction was heated at 80° C. for 2 h. The reaction was allowed to cool to r.t. and taken up in ethyl acetate and washed with 1 N HCl. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give crude 1-(3-hydroxyphenyl)ethanone oxime (1.2 g, 100%) as yellow oil. Analytical LCMS (M+H)+: m/z=151.9.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)(=[O:25])=[O:24])=[C:16]([O:33][CH3:34])[CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:36]1C=C(S(Cl)(=O)=O)C=CC=1>>[CH3:36][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)(=[O:25])=[O:24])=[C:16]([O:33][CH3:34])[CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)c(Cl)c2)cc2c1CCN2S(=O)(=O)c1cccc(Cl)c1
Product: COC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(3-chloro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 521.1 (M+H+.), was prepared in analogy to example 21, steps 1 to 6. Step 5 was performed using 3-chloro-benzenesulfonyl chloride, yielding 2-chloro-4-{[1-(3-chloro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [CH3:1][CH:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3]1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][CH:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: COC(=O)c1ccc2c(c1)OCC2C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC1COc2cc(C(=O)O)ccc21
Yield: 78.6 %

Procedure:
To a reversible vial was added methyl 3-methyl-2,3-dihydrobenzofuran-6-carboxylate (384 mg, 2 mmol) in methanol (16 mL) was added triethylamine (900 mg, 9 mmol), palladium acetate (116 mg, 0.5 mmol) and 1,3-bis(diphenylphosphino) propane (480 mg, 1 mmol). Then the reaction mixture was charged with carbonate monoxide under 15 atm at 110° C. for 12 hours. The suspension was concentrated in vacuum and quenched with aqueous 1N hydrochloric acid (5 mL). The residue was taken up with water (50 mL) and extracted with dichloromethane (50 mL). The combined extract was dried over sodium sulphate, evaporated and purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give the product 3-methyl-2,3-dihydrobenzofuran-6-carboxylic acid (0.28 g, 78%) as colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:14][CH3:15])=[N:8][CH:9]=[CH:10][C:11]=1[CH2:12][CH3:13])=[O:5])[CH3:2].C1C=C([Cl:22])C=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:14][CH3:15])=[N:8][C:9]([Cl:22])=[CH:10][C:11]=1[CH2:12][CH3:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CC)ccnc1CC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(CC)cc(Cl)nc1CC
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.7 %

Procedure:
To a solution of 2.73 g (14.12 mmol) 2,4-diethyl-pyridine-3-carboxylic acid ethylester in chloroform (109 ml) was added 6.97 g, (70% pure, 28.29 mmol) mCPBA at 0° C. The reaction mixture was stirred at RT for 6 h and was then diluted with chloroform and washed with a sat. NaHCO3 sol and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in POCl3 (70 ml) and the reaction mixture was heated at 110° C. for 6.5 h. Then excess POCl3 was evaporated and cold water was added to the residue. The mixture was basified with a sat. NaHCO3 sol to pH˜10 and was extracted EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of this residue by CC (hexane/EtOAc 9:1) provided 1.6 g (7.02 mmol, 20%) 6-chloro-2,4-diethyl-pyridine-3-carboxylic acid ethylester.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[C:21](Cl)[N:20]=3)[CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=1.C(N(CC)CC)C.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O.O1CCOCC1>[Cl:25][C:24]1[CH:23]=[N:22][C:21]2[NH:3][C:4]3[N:5]=[CH:6][CH:7]=[C:8]([CH:9]=3)[CH2:10][CH2:11][C:12]3[CH:13]=[C:14]([NH:18][C:19]=1[N:20]=2)[CH:15]=[CH:16][CH:17]=3
Reactant: Nc1cc(CCc2cccc(Nc3nc(Cl)ncc3Cl)c2)ccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Clc1cnc2nc1Nc1cccc(c1)CCc1ccnc(c1)N2
Yield: 61.8 %

Procedure:
To a mixture of N-{3-[2-(2-aminopyridin-4-yl)ethyl]phenyl}-2,5-dichloropyrimidin-4-amine dihydrochloride (35.0 mg, 0.08 mmol) and triethylamine (0.034 mL, 0.24 mmol) in a mixed solvent of 1,4-dioxane (0.70 mL) and N,N-dimethylformamide (0.70 mL) at rt were added (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (5.6 mg, 0.010 mmol), palladium acetate (2.2 mg, 0.010 mmol) and cesium carbonate (52.6 mg, 0.16 mmol). The mixture was degassed by bubbling N2 through the solution. The sealed tube was then microwaved at 160° C. for 20 min. The reaction mixture was diluted with THF/MeOH, filtered and concentrated to give a residue, which was triturated with MeOH/EtOAc (1:1) to provide the desired product (16 mg, 61%) as a light brown powder. LCMS for C17H15ClN5 (M+H)+: m/z=324.0. 1H NMR (400 MHz, DMSO-d6): δ 9.44 (s, 1H), 9.22 (s, 1H), 8.18 (m, 1H), 8.06 (m, 1H), 7.86 (m, 1H), 7.68 (m, 1H), 7.40 (m, 1H), 7.28 (m, 1H), 7.05 (m, 1H), 6.28 (m, 1H), 3.05 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:14][CH2:15][CH2:16][O:17][CH:18]([CH3:20])[CH3:19])[N:3]=1.[B:21]1([OH:31])[C:25]2[CH:26]=[CH:27][C:28]([OH:30])=[CH:29][C:24]=2[CH2:23][O:22]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CS(C)=O>[OH:31][B:21]1[C:25]2[CH:26]=[CH:27][C:28]([O:30][C:2]3[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:14][CH2:15][CH2:16][O:17][CH:18]([CH3:20])[CH3:19])[N:3]=3)=[CH:29][C:24]=2[CH2:23][O:22]1
Reactant: CC(C)OCCOc1nc(Cl)c(C(F)(F)F)cc1C#N
Reactant: OB1OCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)OCCOc1nc(Oc2ccc3c(c2)COB3O)c(C(F)(F)F)cc1C#N
Temperature: 40 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
A mixture of 6-chloro-2-(2-isopropoxyethoxy)-5-(trifluoromethyl)nicotinonitrile (180 mg, 0.58 mmol), benzo[c][1,2]oxaborole-1,5(3H)-diol (87 mg, 0.58 mmol) and Cs2CO3 (228 mg, 0.7 mmol) in DMSO (20 mL) was stirred at 40° C. for 1 hr, the mixture was diluted by water, extracted by EtOAc, the organic layer was concentrated in vacuo and the residue was purified by prep. HPLC (column: Gemini 100×21.2 mm, 5μ; liquid phase: [A-H2O; B—CH3CN+0.4% NH4OH] B %: 45%-65%, 15 min).to afford 6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-2-(2-isopropoxyethoxy)-5-(trifluoromethyl)nicotinonitrile (170 mg, 69%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 9.24 (s, 1H), 8.73 (s, 1H), 7.79-7.77 (d, 1H), 7.31-7.31 (d, 1H), 7.23-7.21 (q, 1H), 4.97 (s, 2H), 4.14-4.11 (t, 2H), 3.47-3.45 (t, 2H), 3.43-3.37 (m, 1H), 0.98-0.96 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[CH:11]=[CH:10][CH:17]=[CH:16][C:13]=2[CH:14]=[O:15])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=Cc1ccc(F)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccccc1Oc1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A heterogeneous mixture of 4-chlorophenol (14.1 g, 0.11 mmol), 4-fluorobenzaldehyde 12.4 g, 0.1 mmol) and CS2CO3 (65.0 g, 0.20 mmol) in DMF (400 mL) was stirred at 90° C. for 6 h. The reaction mixture was poured into water (1.2 L) and extracted with ethyl acetate (2×200 mL). The organic phase was washed with water (2×100 mL), dried over magnesium sulfate and concentrated to give essentially pure 4-chlorophenoxybenzaldehyde, which was used directly in the next step.
Reaction SMILES: CN([CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=2[NH:7][CH:6]=1)C.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.P(CCCC)(CCCC)CCCC>CC#N>[F:14][C:11]1[CH:10]=[C:9]2[C:8](=[CH:13][CH:12]=1)[NH:7][CH:6]=[C:5]2[CH:4]=[CH:21][C:17]1[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1cccnc1
Reactant: CN(C)Cc1c[nH]c2ccc(F)cc12
Agent: CCCCP(CCCC)CCCC
Solvent: CC#N
Product: Fc1ccc2[nH]cc(C=Cc3cccnc3)c2c1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A solution of 5-fluorogramine (576 mg, 3 mmol) and pyridine-3-carboxaldehyde (531 mg, 3 mmol) in MeCN (6 mL) is treated with Bu3P (1.12 mL, 4.5 mmol) and stirred at 90° C. for 24 h. The mixture is concentrated, filtered through a pad of silica gel eluting with 30% EtOAc in heptane to afford 5-fluoro-3-(2-pyridin-3-yl-vinyl)-1H-indole as a mixture of olefin isomers, which is used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[F:31].[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:24]([O:23][CH2:22][C:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:36]5[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=5)=[C:3]([F:31])[CH:4]=4)[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)c(F)c4)CC3)n2CCS1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: Cn1cc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2F)cn1
Temperature: 25 °C
Yield: 121.1 %

Procedure:
A solution of the compound (300 mg, 0.59 mmol) obtained in Example 25-3), 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (130 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (66 mg, 0.06 mmol), and potassium carbonate (157 mg, 1.18 mmol) in 1,2-dimethoxyethane (3 mL) and water (1.5 mL) was stirred at 120° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature, water (3 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=70:30) to obtain the title compound (377 mg, quant.) in an orange oily form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:18][CH:19]=2)[N:14]=1.C(O)C>O>[F:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[O:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: Nc1ccc2ccc(Oc3cccc(F)c3)nc2n1
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)Nc2ccc3ccc(Oc4cccc(F)c4)nc3n2)cc1
Temperature: 4 °C
Yield: 60 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (6.1 g), N,N'-carbonyldiimidazole (6.5 g) and 2-amino-7-(3-fluorophenoxy)-1,8-naphthyridine (7.65 g). The product produced by precipitation in water (14 g) is dissolved in boiling ethanol (110 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (2×10 cc) and dried at 45° C. at reduced pressure (0.067 kPa). N-[7-(3-fluorophenoxy)-1,8-naphthyridin-2-yl]-4-methoxybenzamide (7 g) is produced, m.p. 151° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH2:10]1[CH2:16][S:13](=[O:15])(=[O:14])[O:12][CH2:11]1>C(#N)C>[N:1]1([CH2:11][CH2:10][CH2:16][S:13]([OH:15])(=[O:14])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=S1(=O)CCCO1
Reactant: c1ccc2c(c1)CCN2
Solvent: CC#N
Product: O=S(=O)(O)CCCN1CCc2ccccc21
Temperature: 25 °C

Procedure:
A mixture of dihydroindole (4.76 g, 40 mmole) and 1,3-propane sultone (4.88 g, 40 mmole) in 50 ml reagent grade acetonitrile was heated under a nitrogen atmosphere and refluxed overnight. After cooling to room temperature, then to ice bath temperature, the resulting white solid was filtered and washed with cold acetonitrile. The yield was 8.1 g (84%), and the product had a melting point of greater then 200° C. Nuclear magnetic resonance (NMR) and elemental analysis showed the product to be consistent with the assigned structure. NMR (D2O): 7.45 (s, 4H), 2.8-4.0 (m, 8H), 2.2 (t, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:30][C@H:31]([C:36]2[CH:41]=[C:40](Cl)[CH:39]=[CH:38][C:37]=2[C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([S:49]([CH3:52])(=[O:51])=[O:50])[CH:44]=2)[C:32]([F:35])([F:34])[F:33])[N:3]=1.[CH2:53]([Sn](CCCC)(CCCC)C=CC)[CH2:54][CH2:55]C.[F-].[Cs+]>CN(C=O)C.CC(P(C(C)(C)C)C(C)(C)C)(C)C.CC(P(C(C)(C)C)C(C)(C)C)(C)C.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:30][C@H:31]([C:36]2[CH:41]=[C:40]([CH:53]=[CH:54][CH3:55])[CH:39]=[CH:38][C:37]=2[C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([S:49]([CH3:52])(=[O:51])=[O:50])[CH:44]=2)[C:32]([F:35])([F:34])[F:33])[N:3]=1
Reactant: CC=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4cc(Cl)ccc4-c4cccc(S(C)(=O)=O)c4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC=Cc1ccc(-c2cccc(S(C)(=O)=O)c2)c([C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)OCC)N(C(=O)OC(C)(C)C)C4)nc(N)n2)C(F)(F)F)c1
Temperature: 130 °C

Procedure:
To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-1-(4-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (500 mg, 0.65 mmol) in DMF (10 mL) was added tributyl(prop-1-enyl)stannane (258 mg, 0.78 mmol), Pd(t-Bu3P)2 (33 mg, 0.065 mmol), and CsF (217 mg, 1.43 mmol). The reaction was heated to 130° C. in a sealed tube for 3 h, then cooled to RT. The reaction mixture was partitioned between water and CH2Cl2, and extracted. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-4-(prop-1-en-1-yl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: CC1(C)[O:7][C@@H:6]2[C@@H:8]([OH:13])[C@@H:9]([OH:12])[CH2:10][O:11][C@H:5]2[CH2:4][O:3]1.Cl>CO>[OH:3][CH2:4][C@H:5]1[C@H:6]([OH:7])[C@@H:8]([OH:13])[C@@H:9]([OH:12])[CH2:10][O:11]1
Reactant: CC1(C)OC[C@@H]2OC[C@H](O)[C@H](O)[C@H]2O1
Agent: Cl
Solvent: CO
Product: OC[C@@H]1OC[C@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C

Procedure:
To a solution of (+)-(4aS,7S,8S,8aR)-2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol (24 mg, 0.12 mmol) in MeOH (2 mL) was added a solution of methanolic HCl (0.4 mL, prepared from 0.5 mL conc. HCl in 30 mL of MeOH). The solution was stirred for 1 H at ambient temperature and concentrated in vacuo.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](F)[N:27]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[O:15][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[N:27]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1cccc(F)n1
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(Br)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(Oc2cccc(F)n2)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.7 %

Procedure:
To a solution of 4-[(4-bromo-phenyl)-hydroxy-methyl]-piperidine-1-carboxylic acid tert-butyl ester (1.36 g, 3.67 mmol) in DMF (18 mL) was added NaH (60% in mineral oil, 367 mg, 9.17 mmol) and the mixture was stirred at room temperature for 10 minutes. 2,6-Difluoropyridine (1.00 mL, 11.0 mmol) was added and the mixture was heated at 70° C. overnight. Work-up and purification gave 4-[(4-bromo-phenyl)-(6-fluoro-pyridin-2-yloxy)-methyl]-piperidine-1-carboxylic acid tert-butyl ester as an off-white solid (1.60 g, 94%).
Reaction SMILES: C[Si](Cl)(C)C.[I-].[Na+].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[C:21]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])(O)[CH2:22][CH2:23][C:19]=3[N:18]=[C:17]2[CH:31]([CH3:33])[CH3:32])=[CH:11][CH:10]=1>C(#N)C>[CH2:29]([O:28][C:26](=[O:27])[CH:25]=[C:21]1[C:20]2[N:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=3)[C:17]([CH:31]([CH3:33])[CH3:32])=[N:18][C:19]=2[CH2:23][CH2:22]1)[CH3:30]
Reactant: CCOC(=O)CC1(O)CCc2nc(C(C)C)n(Cc3ccc(Cl)cc3)c21
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)C=C1CCc2nc(C(C)C)n(Cc3ccc(Cl)cc3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A mixture of TMSCl (0.252 mL) and sodium iodide (296 mg) in Acetonitrile (3 ml) was added to a stirred suspension of Intermediate 26 (186 mg) in acetonitrile (3 ml). The RM was stirred at room temp under nitrogen overnight. The reaction mixture was partitioned between EtOAc (20 ml) and sat. NaHCO3 aq sol: water (1:1, 20 ml). The two phases were separated and the aqueous phase was extracted again with EtOAc (20 ml). The phases were separated, the organic extracts were combined, dried (hydrophobic frit) and concentrated under vacuum. The residue was purified on silica using a cyclohexane:ethyl acetate 0-100% gradient. The desired fractions were combined and concentrated under vacuum to give the title compound (170 mg). LC/MS MH+ 359, 369, Rt 1.01 min (2 minute run).