Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1N(C2C=CC(F)=CC=2)C(C2C=NC=CC=2)=CC=1C([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C@H:17]2[CH2:21][O:20]C(C)(C)[O:18]2)[CH:10]=1)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:48][OH:49]>O>[OH:18][C@@H:17]([CH2:21][OH:20])[CH2:16][O:15][C:11]1[CH:10]=[CH:9][CH:14]=[CH:13][C:12]=1[CH:48]=[O:49]
Reactant: CC1(C)OC[C@H](COc2cccc(C(=O)c3cc(-c4cccnc4)n(-c4ccc(F)cc4)c3N)c2)O1
Reactant: CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=Cc1ccccc1OC[C@@H](O)CO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 0.7 g (1.44 mmol) of [2-amino-1-(4-fluorophenyl)-5-pyridin-3-yl-1H-pyrrol-3-yl]-[3-(2,2-dimethyl-[1,3]dioxolan-4(S)-ylmethoxy)-phenyl]-methanone and 0.35 g of p-toluenesulfonic acid in 20 mL of methyl alcohol and 5 mL of water was heated to 50°. After 18 h, the reaction mixture was cooled to room temperature and the solvent was concentrated under reduced pressure. The residue was partitioned between aqueous sodium bicarbonate and ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The product was purified by flash chromatography (gradient elution: 100% ethyl acetate-10% methyl alcohol/ethyl acetate/0.4% ammonium hydroxide). The purified product was converted to a HCl salt by treatment of an ethyl acetate solution with HCl/ether. The salt was isolated by filtration and dried to give 0.4 g (56%) of 2-amino-1-(4-fluorophenyl)-5-pyridin-3-yl-1H-pyrrol-3-yl]-3-{[2(S), 3dihydroxypropoxy]phenyl}-methanone (MH+=448).
Reaction SMILES: [CH:1]1([N:6]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:15][CH2:16][C:17]4[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=4)[CH:12]=3)[C:7]2=[O:26])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[C:31]([OH:33])=[O:32].C([O-])([O-])=O.[K+].[K+].Cl>C1(C)C=CC=CC=1.CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]1([N:6]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:15][CH2:16][C:17]4[CH:18]=[C:19]([C:35]5[C:36]([O:37][CH3:38])=[CH:28][CH:29]=[C:30]([C:31]([OH:33])=[O:32])[CH:34]=5)[CH:20]=[CH:21][CH:22]=4)[CH:12]=3)[C:7]2=[O:26])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C(=O)O)cc1I
Reactant: O=C1c2ccc(OCc3cccc(B(O)O)c3)cc2CN1C1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(C(=O)O)cc1-c1cccc(COc2ccc3c(c2)CN(C2CCCC2)C3=O)c1
Temperature: 80 °C
Yield: 13.1 %

Procedure:
3-((2-Cyclopentyl-1-oxoisoindolin-5-yloxy)methyl)phenylboronic acid (30 mg, 0.08 mmol), 3-iodo-4-methoxybenzoic acid (19.7 mg, 0.07 mmol), K2CO3 (29 mg, 0.21 mmol) and PdCl2(PPh3)2 (6.2 mg, 0.009 mmol) were dissolved in a mixture of toluene-MeOH (1.1 mL:0.1 mL) and heated at 80° C. for 1.5 hours. The mixture was filtered through celite washed with water and solvent was removed was evaporated in vacuo. The resulted crude material was acidified with 2 M HCl, extracted into EtOAc and dried over anhyd. Na2SO4, evaporated solvent in vacuo to obtain the crude acid which was purified using automated prep-HPLC to yield the desired compound 4.2 mg, 13%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.93 (d, J=8.2 Hz, 1H), 7.82 (s, 1H), 7.55-7.42 (m, 5H), 7.21-7.18 (m, 2H), 7.10 (dd, J=8.7 Hz, J=2.3 Hz, 1H), 5.23 (s, 2H), 4.54-4.46 (m, 1H), 4.37 (s, 2H), 3.84 (s, 3H), 1.85-1.80 (m, 2H), 1.71-1.56 (m, 6H). LRMS calcd. for C28H27NO5 [M+H]+ 458 found: 458.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:18]2[N:19]=[CH:20][N:21]([CH2:22][CH2:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1.C(=O)([O-])[O-].[K+].[K+].[F:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1.[OH-].[Na+]>CN(C)C=O>[Cl:8][C:9]1[C:18]2[N:19]=[CH:20][N:21]([CH2:22][CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([S:43]([C:40]4[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=4)(=[O:45])=[O:44])[CH2:26][CH2:25]3)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: Clc1nc2ccccc2c2c1ncn2CCC1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(F)cc1)N1CCC(CCn2cnc3c(Cl)nc4ccccc4c32)CC1
Reaction time: 5 h
Yield: 63.5 %

Procedure:
To a suspension of 0.50 g of 4-chloro-1-[2-(4-piperidyl)ethyl]-1H-imidazo-[4,5-c]quinoline trifluoroacetate and 0.32 g of potassium carbonate in 2 ml of N,N-dimethylformamide, a solution of 0.23 g of p-fluorobenzenesulfonyl chloride in 3 ml of N,N-dimethylformamide was added dropwise at room temperature, and the mixture was stirred for 5 hours. The reaction mixture was adjusted to pH 10 with 10% aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried, and then the solvent was evaporated to give 0.35 g of a colorless solid. Recrystallization from a mixture of methanol, ethanol and water gave colorless crystals having the melting point of from 175 to 178.5° C.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C@H:8]([NH:11][S:12]([C:15]2[CH:23]=[CH:22][C:18]3[N:19]=[CH:20][S:21][C:17]=3[CH:16]=2)(=[O:14])=[O:13])[CH2:9][OH:10])=[CH:5][CH:4]=1)=[O:2].N1C=CN=C1.[CH3:29][C:30]([Si:33](Cl)([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C=O)C>[Si:33]([O:10][CH2:9][C@@H:8]([NH:11][S:12]([C:15]1[CH:23]=[CH:22][C:18]2[N:19]=[CH:20][S:21][C:17]=2[CH:16]=1)(=[O:14])=[O:13])[C:6]1[S:7][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1)([C:30]([CH3:32])([CH3:31])[CH3:29])([CH3:35])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1ccc([C@@H](CO)NS(=O)(=O)c2ccc3ncsc3c2)s1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H](NS(=O)(=O)c1ccc2ncsc2c1)c1ccc(C=O)s1
Reaction time: 8 h

Procedure:
To a solution of N-[(1R)-1-(5-formylthiophen-2-yl)-2-hydroxyethyl]-1,3-benzothiazole-6-sulfonamide (5.48 g, 14.9 mmol) and imidazole (1.27 g, 18.6 mmol) in DMF (75 mL) was added TBSCl (2.80 g, 18.6 mmol) and the reaction mixture was stirred overnight. The reaction was then quenched by the addition of water (400 mL) and ether (200 mL). The phases were separated and the aqueous layer was extracted with ether (3×250 mL). The combined organic layers were washed twice with brine solution (2×300 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude was purified on silica gel eluting with hexanes and ethyl acetate to afford the title compound.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)#[CH:11]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][C:4]1[N:3]=[C:2]([C:11]#[C:10][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:7]([NH2:8])=[CH:6][CH:5]=1
Reactant: Cc1ccc(N)c(Br)n1
Reactant: C#Cc1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(N)c(C#Cc2cccnc2)n1
Yield: 44.9 %

Procedure:
Following the same procedure as described in Example 1, (2-bromo-6-methyl-pyridin-3-yl)amine (200 mg, 1.07 mmol) reacted with (PPh3)2PdCl2 (37 mg, 0.05 mmol), Cul (10 mg, 0.05 mmol) and 3-ethynyl-pyridine (110 mg, 1.07 mmol) in triethylamine (1.6 ml). The crude residue was purified by flash chromatography (DCM-DCM/MeOH 97:3) to yield 100 mg (0.48 mmol, 49%) of (6-methyl-2-pyridin-3-ylethynyl-pyridin-3-yl)amine as a yellow powder. The hydrochloride of (6-methyl-2-pyridin-3-ylethynyl-pyridin-3-yl)amine was prepared as described in Example 1 to yield after trituration with pentane 145 mg (100%) of the title hydrochloride as a yellow solid.
Reaction SMILES: C1(C)C=CC(S(NN=[C:12]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)(=O)=O)=CC=1.C([Li])CCC.CN([CH:29]=[O:30])C.O>CCN(CCN(CC)CC)CC.CCCCCC>[C:12]1([CH:29]=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)NN=C2CCCCCCC2)cc1
Reactant: CN(C)C=O
Agent: CCN(CC)CCN(CC)CC
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: O=CC1=CCCCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To cyclooctanone p-toluenesulfonyl hydrazone (4.5 g) suspended in N,N,N′,N′-tetraethylenediamine (46 ml) was added dropwise at −55° C. a 1.6 M solution of n-butyllithium in hexane (38 ml). The resulting mixture was stirred at room temperature for 30 minutes under an argon atmosphere, was then cooled with ice, was mixed with DMF (5.9 ml) and was stirred at room temperature for one hour. The reaction mixture was poured into water and was extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid, water and an aqueous saturated solution of sodium chloride, and was then dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent. The residue was subjected to purification using a silica gel column (ethyl acetate:hexane=1:9) to obtain cyclooctene-1-carbaldehyde (1.5 g) as a light yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:3]=1.[CH2:17]([O:19][C:20]([C:22]1[C:23]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][C:24]=2[S:25][CH:26]=1)=[O:21])[CH3:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN1C(=O)CCC1.O>[CH2:17]([O:19][C:20]([C:22]1[C:23]2[CH:30]=[CH:29][C:28]([O:31][C:2]3[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:3]=3)=[CH:27][C:24]=2[S:25][CH:26]=1)=[O:21])[CH3:18]
Reactant: CCCCCC(=O)OCc1nccc(Cl)n1
Reactant: CCOC(=O)c1csc2cc(O)ccc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCCCC(=O)OCc1nccc(Oc2ccc3c(C(=O)OCC)csc3c2)n1
Temperature: 60 °C
Reaction time: 45 h

Procedure:
A suspension of 324 mg (1.33 mMol) hexanoic acid 4-chloro-pyrimidin-2-ylmethyl ester, 313 mg (1.41 mMol) 6-hydroxy-benzo[b]thiophene-3-carboxylic acid ethyl ester (Step 12.3) and 312 mg (1.47 mMol) K3PO4 in 5 ml NMP is stirred for 45 h at 60° C. The reaction mixture is dissolved in water and EtOAc, the aq. phase separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; CH2Cl2/ether 59:1→9:1) and crystallization from hexane gives the title compound: m.p.: 51° C.; MS: [M+1]+=429; TLC(CH2Cl2/ether 19:1): Rf=0.28.
Reaction SMILES: [Br:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:3]=1N.OS(O)(=O)=O.N([O-])=O.[Na+].[I-:22].[K+].II.[O-]S([O-])=O.[Na+].[Na+]>O>[Br:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:3]=1[I:22]
Reactant: [I-]
Reactant: Nc1cccc(C(F)(F)F)c1Br
Agent: II
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: FC(F)(F)c1cccc(I)c1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
2-Bromo-3-trifluoromethylaniline (8 g, 33.33 mmol) is suspended in water (90 mL) and cooled to 0° C. 96% H2SO4 (26.7 mL, 13.7 mmol) is added and the mixture stirred for 30 minutes. NaNO2 (2.41 g, 35 mmol) is dissolved in a small quantity of water and added dropwise at 0° C. The mixture is stirred for 30 minutes then potassium iodide (9.24 g, 55.66 mmol) and iodine (9.31 g, 36.66 mmol) in water are added dropwise with cooling. The mixture is stirred until gas evolution ceases then warmed to 40° C. and allowed to cool to room temperature. The mixture is shaken with excess aqueous Na2SO3 solution and extracted with ethyl acetate. The organic extracts are evaporated and the residue purified by flash chromatography (eluent: cyclohexane) to give the title compound (Yield 10.0 g)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[F:24][C:25]1[N:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[F:24][C:25]1[N:30]=[CH:29][C:28]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][C:11]4[S:10][C:9]([C:15]5[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=5)=[N:8][C:7]=4[C:6]=3[CH:23]=2)=[CH:27][CH:26]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3ccc(F)nc3)cc1-2
Yield: 30 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 6-fluoropyridin-3-ylboronic acid were reacted to give 495 (0.346 g, 30%). 1H NMR (500 MHz, DMSO) δ 8.68 (d, J=2.3, 1H), 8.55 (s, 1H), 8.28 (td, J=8.3, 2.5, 1H), 8.13 (s, 1H), 7.68 (dd, J=8.4, 2.3, 1H), 7.35 (dd, J=8.6, 2.7, 1H), 7.22 (d, J=8.4, 1H), 5.77 (dt, J=13.1, 6.6, 1H), 4.43 (t, J=4.9, 2H), 3.49 (t, J=4.9, 2H), 1.51 (dd, J=54.9, 6.6, 6H). MS (ESI(+)): m/z 408.1 (M+H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[C:3]=1[F:10].CC(C)([O-])C.[K+].[Cl:17][C:18]1[CH:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>>[Cl:17][C:18]1[CH:23]=[C:22]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([F:10])[C:4]=2[F:9])[CH:21]=[CH:20][N:19]=1
Reactant: Nc1ccc(O)c(F)c1F
Reactant: Clc1ccnc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1F
Yield: 65.9 %

Procedure:
Using a procedure analogous to Example A2, 4-amino-2,3-difluorophenol (6 g, 41.4 mmol), potassium tert-butoxide (4.9 g, 43.5 mmol) and 2,4-dichoropyridine (6.1 g, 41.4 mmol) were combined to afford 4-(2-chloro-pyridin-4-yloxy)-2,3-difluorophenylamine (7 g, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J=6.0 Hz, 1H), 7.05 (s, 1H), 6.95 (m, 1H), 6.92 (d, J=8.8 Hz, 1H), 6.62 (d, J=8.8 Hz, 1H), 5.60 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[N:18]=3)=[C:15]3[N:10]([C:11](SC)=[N:12][CH:13]=[CH:14]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:32]1[CH:33]=[C:34](C=CC=1)[C:35](OO)=[O:36].[Na].[O-:43]CCCC.[Na+:48]>ClCCl.C(OCC)(=O)C.C(O)CCC>[O-:36][CH2:35][CH2:34][CH2:33][CH3:32].[Na+:48].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[N:18]=3)=[C:15]3[N:10]([C:11]([OH:43])=[N:12][CH:13]=[CH:14]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3cccc(Cl)c3)nn12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CCCC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Oc1nccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3cccc(Cl)c3)nn12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 26 %

Procedure:
To a cold (0° C.) solution of 4-[2-(3-chlorophenyl)-7-(methylthio)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentylpyrimidin-2-amine (90 mg, 0.206 mmol) in dichloromethane (10 mL) was added m-chloroperoxybenzoic acid (54 mg, 0.313 mmol). The reaction mixture was stirred 1.5 hours at 0° C. then diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration provided a crude oil. In a separate flask, a solution of sodium butoxide was prepared by reacting sodium (35 mg, 1.52 mmol) with n-butanol (2 mL). The sodium butoxide solution was added to the crude oil and the resulting solution was heated in a sealed tube at 120° C. for 16 hours. The reaction mixture was cooled and concentrated in vacuo. The resulting oil was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration provided a crude oil which was diluted with ethyl acetate (˜5 mL). Upon standing 7 hours, a solid had precipitated, which was collected on a filter to provide 2-(3-chlorophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-c]pyrimidin-7-ol (22 mg, 26%) as a pale yellow solid. 1H NMR (CDCl3) δ 8.00 (d, 1H), 7.60 (s, 1H), 7.42 (d, 1H), 7.36 (d, 1H), 7.30 (d, 1H), 7.25 (s, 1H), 7.14 (d, 1H), 7.02 (d, 1H), 6.24 (d, 1H), 4.19 (m, 1H), 1.99 (m, 2H), 1.78–1.42 (m, 6H); MS m/z 407 (M+1).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[C:12]2[N:13]=[CH:14][N:15]([C:31]=2[N:32]=[C:33]([NH:35]C(=O)COC2C=CC=CC=2)[N:34]=1)[C@@H:16]1[O:30][C@H:27]([CH2:28][OH:29])[C@@H:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:17]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.Cl>CC#N>[CH2:3]([O:10][C:11]1[C:12]2[N:13]=[CH:14][N:15]([C:31]=2[N:32]=[C:33]([NH2:35])[N:34]=1)[C@@H:16]1[O:30][C@H:27]([CH2:28][OH:29])[C@@H:18]([O:19][Si:20]([C:23]([CH3:24])([CH3:26])[CH3:25])([CH3:22])[CH3:21])[CH2:17]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2cnc3c(OCc4ccccc4)nc(NC(=O)COc4ccccc4)nc32)O[C@@H]1CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2cnc3c(OCc4ccccc4)nc(N)nc32)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 21 h
Yield: 93.2 %

Procedure:
NaOH (2 M, 21 mL, 42.3 mmol) is added to a solution of 9 (2.56 g, 4.23 mmol) dissolved in CH3CN (13 mL) and stirred at room temperature for 21 h. Water (20 mL) is added to the reaction and the pH is adjusted to 7 with HCl. The solution is extracted with CH2Cl2 (2×30 mL), and the organic extracts are combined, dried over MgSO4, and filtered. The solvent is removed under reduced pressure to yield 10 as a white solid (1.86 g, 93.4%). 1H NMR (DMSO-d6) δ 8.11 (1H, s, H-8), 7.51-7.48 (2H, m, Bn Ar), 7.42-7.33 (3H, m, Bn Ar), 6.50 (211, br s, N2H2, exchanges with D2O), 6.21 (1H, dd, J=8.0, J=6.0, 11-1′), 5.50 (2H, s, CH2-Ph), 5.04 (1H, t, J=5.6, 5′-OH, exchanges with D2O), 4.53 (1H, ddd, J=5.2, J=2.4, J=2.4, H-3′), 3.82 (1H, ddd, J=4.4, J=4.4, J=2.4, H-4′), 3.55 (H-1, ddd, J=11.6, J=5.2, J=5.2, H-5′), 3.49 (1H, ddd, J=11.6, J=5.2, J=4.8, H-5′), 2.70 (1H, ddd, J=13.2, J=8.0, J=5.6, H-2′), 2.21 (1H, ddd, J=12.8, J=5.6, J=2.4, H-2′), 0.90 (9H, s, Si—C(CH3)3), 0.11 (6H, s, Si—(CH3)2). Anal. (C23H33N5O4Si) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]1(=O)[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[C:12](=[O:13])[C:11]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]3[C:9]2=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A stirring slurry of 3-bromoaniline (3.00 g, 17.44 mmol), phthalic anhydride (2.58 g, 17.44 mmol), and toluene (45 ml) was heated under reflux, using a Dean-Stark apparatus, at 140° C. (oil bath temperature) for 24 h. After cooling to ambient temperature, the solution was concentrated by rotary evaporation. The resulting off-white solid was purified by column chromatography on silica gel (150 g, Merck 70-230 mesh) eluting with CHCl3-acetone (9:1, v/v) to collect unreacted 3-bromoaniline (Rf 0.61) and phthalic anhydride (Rf 0.43). Elution with CHCl3-methanol (9:1, v/v) gave the product (Rf 0.38). Selected fractions containing the product were combined and concentrated by rotary evaporation to give 1.53 g of an off-white to light-beige solid. Impure fractions were combined and concentrated by rotary evaporation. The resulting white solid was dissolved in a mixture of CHCl3, acetone, and methanol and re-chromatographed on silica gel (150 g). Elution with CHCl3 removed impurities; the product was then eluted with CHCl3-acetone (4:1, v/v). Selected fractions were combined, concentrated by rotary evaporation, and vacuum dried for 16 h to give 1.41 g of an off-white to light-beige solid, mp 176-179° C., bringing the total yield to 2.94 g (55.8%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)([OH:12])=[O:11].C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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:1][C:2]1[N:7]=[C:6]([C:16]2[CH:17]=[CH:18][C:13]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Fc1cnc(Cl)nc1Cl
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: O=C(O)c1ccc(-c2nc(Cl)ncc2F)cc1
Temperature: 85 °C
Yield: 29 %

Procedure:
2,4-Dichloro-5-fluoropyrimidine (0.50 g, 3.0 mmol) and 4-carboxyphenyl boronic acid (0.5 g, 3.0 mmol) were dissolved in dimethoxyethane (20 mL) in a screw cap test tube and 6 mL 2M Na2CO3 was added followed by 80 mg (0.069 mmol) tetrakis(triphenylphosphine)palladium. Argon was bubbled through the reaction mixture for 5 minutes and then the reaction mixture was heated to 85° C. overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to a solid, which was purified by chromatography on silica (MeOH 5%/CH2Cl2) to give 0.22 g (0.87 mmol, 29% yield) of 4-(2-chloro-5-fluoropyrimidin-4-yl)-benzoic acid as a white solid. 1H NMR 500 MHz (MeOH-d4): 8.85 (m, 1H), 8.20 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:17][O:18][CH2:19]Cl>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:17][O:18][CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Product: COCOC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthesis Example 59 using N-(tert-butoxycarbonyl)-4-hydroxypiperidine, sodium hydride and methoxymethylchloride, N-(tert-butoxycarbonyl)-4-methoxymethoxypiperidine was obtained. This was treated with trifluoroacetic acid-chloroform to give 4-methoxymethoxypiperidine, which was subjected to the reaction and treatment in the same manner as in Starting Material Synthesis Example 40 using 4-fold equivalents of triethylamine to give the title compound.
Reaction SMILES: Cl[N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:9]2=[O:18])[CH2:4][CH2:3]1.O=O.[K+].C1OCCOCCOCCOCCOCCOC1.C[Si]([C:44]#[N:45])(C)C>CCOCC>[C:44]([CH:3]1[CH2:4][CH:5]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:9]2=[O:18])[CH2:6][CH2:7][NH:2]1)#[N:45]
Reactant: C[Si](C)(C)C#N
Reactant: O=C1OCc2ccccc2N1C1CCN(Cl)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=O
Agent: [K+]
Solvent: CCOCC
Product: N#CC1CC(N2C(=O)OCc3ccccc32)CCN1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(N-chloro-4-piperidyl)-3,1-benzoxazin-2-one from Step 1 above (230 mg, 0.86 mmol) was dissolved in warm ether (30 mL) and the solution was added dropwise to a suspension of potassium superoxide (135 mg, 1.9 mmol) and 18-crown-6 (10 mg, 0.04 mmol) in ether (10 mL). The mixture was stirred at ambient temperature for five days, with two additional lots of 135 mg each of potassium superoxide being added on the second and third days. The reaction was filtered and the filtrate was added dropwise to an ether solution of trimethylsilylcyanide (0.172 mL, 128 mg, 1.3 mmol). The mixture was stirred at ambient temperature for 18 hours, then evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with 4:96 MeOH:CH2Cl2. The combined product fractions were evaporated to dryness in vacuo, and the residue was evaporated twice from ether to give 1-(2-cyano-4-piperidyl)-3,1-benzoxazin-2-one: MS (FAB): M+H @ m/e=258.