Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH:3]1[CH2:11][C:12]#[C:13][CH2:14][CH3:15].N1C=CC=C[CH:17]=1>[Pd]>[CH3:15][CH2:14]/[CH:13]=[CH:12]\[CH2:11][C@H:3]1[C:2](=[O:1])[CH2:6][CH2:5][C@@H:4]1[CH2:7][C:8]([O:10][CH3:17])=[O:9]
Reactant: CCC#CCC1C(=O)CCC1CC(=O)O
Reactant: c1ccncc1
Agent: [Pd]
Product: CC/C=C\C[C@H]1C(=O)CC[C@@H]1CC(=O)OC
Yield: 98 %

Procedure:
Four hundred mg. of the methyl ester of 3-oxo-2-(2-pentynyl)-cyclopentaneacetic acid dissolved in 10 ml. of pyridine is added to 100 mg of 5% palladium on barium sulfate, and the resulting mixture is hydrogenated at room temperature and pressure. Forty-four milliliters of hydrogen is absorbed in 90 minutes, then the reaction stops completely. After filtering off the catalyst, the solvent is evaporated. The remaining oil is dissolved in ether-hexane 1:1 and washed with 1N HCl, aqueous saturated sodium bicarbonate and finally water. After drying (MgSO4), the solvent is evaporated and 392 mg. of methyl cis-jasmonate is obtained. Yield 98%. Spectral properties are in agreement with the above structure and published spectral data. The product shows one spot on thin layer chromatography. Methyl cis-jasmonate was also characterized as its semicarbazone, m.p. 118°-119° C (Lit. 115°-117° C).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[F:18])[CH:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=1.[Cl:23][C:24]1[CH:29]=[C:28](B(O)O)[CH:27]=[CH:26][N:25]=1>>[Cl:23][C:24]1[CH:29]=[C:28]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][C:9]=3[F:18])[CH:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=2)[CH:27]=[CH:26][N:25]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: Fc1cc(C(F)(F)F)ccc1-c1cc(C(F)(F)F)nc(Cl)n1
Product: Fc1cc(C(F)(F)F)ccc1-c1cc(C(F)(F)F)nc(-c2ccnc(Cl)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(2-fluoro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example A.61) (1.50 g, 4.35 mmol) and commercially available 2-chloro-pyridine-4-boronic acid (0.75 g, 4.8 mmol) according to the general procedure IVb. Obtained as a light red solid (0.64 g, 35%). MS (ISP) 422.0 [(M+H)+]; mp 146° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.[Cl:18][C:19]([Cl:26])([Cl:25])[C:20]([N:22]=[C:23]=[O:24])=[O:21]>ClCCl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:23]([NH:22][C:20](=[O:21])[C:19]([Cl:26])([Cl:25])[Cl:18])=[O:24])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1(C)Oc2cc3nonc3cc2C(NC(=O)NC(=O)C(Cl)(Cl)Cl)C1O
Reaction time: 5 h
Yield: 25 %

Procedure:
200 mg (0.850 mmol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazole and 20 ml of dichloromethane were stirred at room temperature, and 100 μl (0.935 mmol) of trichloroacetyl isocyanate were added thereto and stirred for 5 hours. The crystals precipitated were filtered off to obtain 90 mg of the intended compoundas colorless crystals. (yield: 25%)
Reaction SMILES: BrCC[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([OH:13])(=[O:12])=[O:11].[Br:14][CH2:15][CH2:16]C1C=C(S(O)(=O)=O)C=CC=1>>[Br:14][CH2:15][CH2:16][C:8]1[CH:9]=[CH:4][C:5]([S:10]([OH:13])(=[O:12])=[O:11])=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)c1cccc(CCBr)c1
Reactant: O=S(=O)(O)c1ccccc1CCBr
Product: O=S(=O)(O)c1ccc(CCBr)cc1

Procedure:
As a result, a mixture of 2-(2-bromoethyl)benzenesulfonic acid, 3-(2-bromoethyl)benzenesulfonic acid, and 4-(2-bromoethyl)benzenesulfonic acid was obtained, and the mixture was separated and purified with a silica gel column.
Reaction SMILES: C([C@H](NC(=O)C1C=C(C2C=CC=CC=2)C=C(N2CCCC2=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[O:44]=[C:45]1[CH2:49][CH2:48][CH2:47][N:46]1[C:50]1[CH:51]=[C:52]([CH:56]=[C:57]([N:59]2[CH2:63][CH2:62][CH2:61][C:60]2=[O:64])[CH:58]=1)[C:53](O)=[O:54].[CH:65]12[CH2:71][CH:68]([CH2:69][CH2:70]1)[CH2:67][CH:66]2[NH:72][C:73](=[O:88])[C@H:74]([CH3:87])[CH2:75][C@H:76]([OH:86])[C@@H:77]([NH2:85])[CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1>>[CH2:78]([C@H:77]([NH:85][C:53](=[O:54])[C:52]1[CH:51]=[C:50]([N:46]2[CH2:47][CH2:48][CH2:49][C:45]2=[O:44])[CH:58]=[C:57]([N:59]2[CH2:63][CH2:62][CH2:61][C:60]2=[O:64])[CH:56]=1)[C@@H:76]([OH:86])[CH2:75][C@H:74]([C:73](=[O:88])[NH:72][CH:66]1[CH2:67][CH:68]2[CH2:71][CH:65]1[CH2:70][CH2:69]2)[CH3:87])[C:79]1[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Reactant: O=C(O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1)C(=O)NC1CC2CCC1C2

Procedure:
Prepared in an analogous manner to E6, from 3,5-bis-(2-oxopyrrolidin-1-yl)benzoic acid (D8) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D29).
Reaction SMILES: Cl[C:2]1([CH2:7][Cl:8])[O:5][C:4](=O)[CH2:3]1.Cl.[NH2:10][C:11]([NH2:13])=[NH:12].Cl>O>[NH2:13][C:11]1[N:12]=[C:2]([CH2:7][Cl:8])[CH:3]=[C:4]([OH:5])[N:10]=1
Reactant: N=C(N)N
Reactant: O=C1CC(Cl)(CCl)O1
Agent: Cl
Solvent: O
Product: Nc1nc(O)cc(CCl)n1
Temperature: 120 °C

Procedure:
620 parts of 4-chloro-4-chloromethyloxetan-2-one and 440 parts of guanidine hydrochloride were charged to a reaction flask and the mixture was stirred and heated under nitrogen purge as the bath temperature was gradually raised to 120° C. When the bath temperature approached 100° C., reaction commenced accompanied by evolution of hydrogen chloride. When the initial reaction subsided after a few minutes the bath temperature was raised to 130° C. and held until the reaction ceased as indicated by cessation of gassing (about 1 hour). The reaction mixture was allowed to cool about 60° C. and 1750 parts of water was added to the syrup. The solution was extracted with 500 parts of ethyl acetate and the extract was discarded. The aqueous phase was treated with decolourising charcoal, filtered and the pH was adjusted to pH 8 by the addition of saturated aqueous sodium bicarbonate solution. The precipitated solid was filtered, washed with water and dried to constant weight at 80° C. in a vacuum oven to give 2-amino-4-chloromethyl-6-hydroxypyrimidine, m.p. 195°-197° C.
Reaction SMILES: [CH2:1]([CH:4]1[C:10]([Cl:12])([Cl:11])[CH2:9][CH2:8][CH:7]2[C:5]1(Cl)[O:6]2)[CH:2]=[CH2:3].N1C=CC=CC=1.[ClH:20]>>[CH2:1]([C:4]1([Cl:20])[C:10]([Cl:12])([Cl:11])[CH2:9][CH2:8][CH2:7][C:5]1=[O:6])[CH:2]=[CH2:3]
Reactant: Cl
Reactant: C=CCC1C(Cl)(Cl)CCC2OC21Cl
Solvent: c1ccncc1
Product: C=CCC1(Cl)C(=O)CCCC1(Cl)Cl

Procedure:
1.60 g (6.62 mmol) of epoxide 2j and 2 cm3 (25 mmol) of pyridine were heated to reflux for 24 h. After cooling, the mixture was acidified to pH=1 with 3N HCl, extracted with ether (3×30 cm3), dried over MgSO4, filtered and evaporated down. The crude product was purified by flash chromatography on silica (eluent: ether/petroleum ether=1/99). The following were isolated (in the order of elution): starting epoxide 2j, 0.40 g of transposition ketone 6a (Yld=40%), traces of 2-allyl-2,3-dichloro-3-cyclohexenone 7 (evidence based on GC/mass) and phenol 4f.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](SC)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][N:3]=1.ClC1C=C(C=CC=1)C(OO)=O.[CH:36]([NH2:39])([CH3:38])[CH3:37]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:39][CH:36]([CH3:38])[CH3:37])[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)N
Reactant: CSc1nccc(-c2c(-c3ccnc(F)c3)nn3ccccc23)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)Nc1nccc(-c2c(-c3ccnc(F)c3)nn3ccccc23)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
2-(2-Fluoro-4-pyridinyl)-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridine (0.18 g, 0.53 mmol) was dissolved in dichloromethane (10 mL) and the resulting solution cooled to 0° C. in an ice bath. To this solution was added dropwise 3-chloroperoxybenzoic acid (230 mg, 57–86%) in dichloromethane. This reaction mixture was stirred at 0° C. for 10 minutes. Additional dichloromethane was added and the reaction mixture was extracted with saturated aqueous potassium carbonate. The organic phase was dried over magnesium sulfate, filtered and concentrated to give a foam. This foam was dissolved in isopropylamine and heated to 50° C. for 2 hours. The resulting mixture was concentrated to a solid that was purified by by silica gel chromatography (1:1 ethyl acetate:hexane) give 90 mg (48%) of the title compound as a solid. 1H NMR (CDCl3): δ 8.56 (d, 1H), 8.31 (m, 2H), 8.19 (d, 1H), 7.52 (m, 1H), 7.40 (t, 1H), 7.33 (broad s, 1H), 7.02 (t, 1H), 6.45 (d, 1H), 5.20 (m, 1H), 4.20 (m, 1H), 1.31 (d, 5H); 19F NMR (CDCl3): 8–67.68; MS m/z 349 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([CH2:11][CH2:12][OH:13])=[CH:5]2.CSC.C(=O)(O)[O-].[Na+].[OH-].[NH4+:23]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8]([CH:7]=[C:6]([CH2:11][CH2:12][OH:13])[N:23]=[CH:5]2)=[CH:9][CH:10]=1
Reactant: OCCC1=Cc2cc(Br)ccc2C1
Reactant: [NH4+]
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CSC
Product: OCCc1cc2ccc(Br)cc2cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product from Example 52D (0.85 g, 3.5 mmol) in methanol (15 mL) at −70° C. was ozonated until a bluish color developed (˜10 minutes). The mixture was treated with dimethylsulfide (0.7 mL, excess) and sodium bicarbonate (0.2 g) and allowed to warm to room temperature. After stirring for 3 hours, the mixture was treated with aqueous ammonium hydroxide (7.4 mL, 28%). After stirring an additional 4 hours, the reaction mixture was concentrated under vacuum and then diluted with dichloromethane (20 mL). The organic layer was separated and evaporated to provide the title compound which was used without further purification in the next step. 1H NMR (CDCl3) δ 3.13 (t, J=5.6 Hz, 2H); 4.07 (t, J=5.6 Hz, 2H); 7.47 (s, 1H); 7.61 (d, J=8.7 Hz, 1H); 7.71 (dd, J=1.9, 8.7 Hz, 1H); 9.04 (s, 1H); Anal. Calcd. for C11H10BrNO: C, 52.41; H, 4.00; N, 5.56. Found: C, 52.51; H, 3.94; N, 5.42.
Reaction SMILES: FC(F)(F)S(O[Si:7]([CH3:18])([CH3:17])[CH:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH3:15])=[C:9]1[CH3:16])(=O)=O.[C:21]([C:25]1[CH:30]=[CH:29][C:28]([C-:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32]2)=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22].[Li+]>CCOCC>[C:21]([C:25]1[CH:26]=[CH:27][C:28]([C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]([Si:7]([CH3:17])([CH3:18])[CH:8]3[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH3:15])=[C:9]3[CH3:16])[CH:32]=2)=[CH:29][CH:30]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1ccc(-[c-]2ccc3ccccc32)cc1
Reactant: CC1=C(C)C([Si](C)(C)OS(=O)(=O)C(F)(F)F)C(C)=C1C
Agent: [Li+]
Solvent: CCOCC
Product: CC1=C(C)C([Si](C)(C)C2C=C(c3ccc(C(C)(C)C)cc3)c3ccccc32)C(C)=C1C
Reaction time: 18 h

Procedure:
To a solution of dimethyl(2,3,4,5-tetramethylcyclopenta-2,4-dien-1-yl)silyl trifluoromethanesulfonate (Compound C, 7.50 g, 22.8 mmol, 1.00 eq.) in ether (25 mL) at −35° C. was added lithium (1-(4-t-butylphenyl)indenide) (6.20 g, 24.4 mmol, 1.07 eq.). The reaction was stirred for 18 hours, and was then evaporated under vacuum. The residue was extracted with pentane (40 mL) and the extract was filtered. The resulting solution was evaporated under vacuum to give a thick oil. Yield 10.11 g (104%). 1H NMR(C6D6): δ 7.83 (d, 1H), 7.67 (d, 2H), 7.50 (d, 1H), 7.41 (d, 2H), 7.26 (m, 2H), 6.64 (s, 1H), 3.71, (s, 1H), 2.95 (br s, 1H), 1.95 (s, 3H), 1.93 (s, 3H), 1.84 (s, 3H), 1.82 (s, 3H), 1.30 (s, 9H), −0.06 (s, 3H), −0.36 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:13](=O)[C:14]([O:16]C)=O)=[CH:8][N:9]2[CH3:12])=[CH:5][CH:4]=1.[CH3:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:27]=2)[C:22]([CH2:34][C:35]([NH2:37])=[O:36])=[CH:21]1>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:13]3[C:14](=[O:16])[NH:37][C:35](=[O:36])[C:34]=3[C:22]3[C:23]4[C:28](=[CH:27][C:26]([N:29]5[CH2:30][CH2:31][CH2:32][CH2:33]5)=[CH:25][CH:24]=4)[N:20]([CH3:19])[CH:21]=3)=[CH:8][N:9]2[CH3:12])=[CH:5][CH:4]=1
Reactant: Cn1cc(CC(N)=O)c2ccc(N3CCCC3)cc21
Reactant: COC(=O)C(=O)c1cn(C)c2cc(OC)ccc12
Product: COc1ccc2c(C3=C(c4cn(C)c5cc(N6CCCC6)ccc45)C(=O)NC3=O)cn(C)c2c1
Yield: 57.6 %

Procedure:
3-(6-Methoxy-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)pyrrole-2,5-dione (55 mg, 58%) was prepared from methyl (6-methoxy-1methyl -1H-indol-3-yl)-glyoxylate (57mg, 0.23 mmol) and (1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)-acetamide (54 mg, 0.21 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:16][CH2:15]1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][CH2:28][CH2:29][NH2:30].C(N(CC)CC)C.[NH4+].[Cl-]>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:30][CH2:29][CH2:28][NH:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:16][CH2:15]1
Reactant: NCCNc1ccccn1
Reactant: Nc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1c(F)c(NCCNc2ccccn2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
A solution of 5-amino-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (300 mg, 1.07 mmol), N-2-pyridyl-1,2-ethanediamine (221 mg, 1.61 mmol) and triethylamine (0.224 mL, 1.61 mmol) in DMSO (5 mL) was stirred at 100° C. for 3 h. After the reaction mixture was cooled to room temperature, 10% aq. NH4Cl was added to neutralize and the suspension was stirred for 30 min. The resulting precipitate was collected by filtration in vacuo, washed with water and hot EtOH, dried to yield 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylic acid (385 mg, 91%) as a colorless solid.
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([C:11](=[O:15])[CH:12]=[N+]=[N-])[CH:8]=[CH:9][CH:10]=1)(=[O:4])(=[O:3])[NH2:2].[ClH:16].C(O)C>COCCOCCOC>[Cl:16][CH2:12][C:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([S:1](=[O:4])(=[O:3])[NH2:2])[CH:6]=1)=[O:15]
Reactant: [N-]=[N+]=CC(=O)c1cccc(S(N)(=O)=O)c1
Reactant: Cl
Solvent: CCO
Solvent: COCCOCCOC
Product: NS(=O)(=O)c1cccc(C(=O)CCl)c1

Procedure:
9.5 g of 3'-sulfamoyl-diazoacetophenone were reacted as prescribed in Example 66b) with 37% HCl in diethylene glycol dimethyl ether and worked up. Colorless crystals, melting point: 118° C (from a small amount of ethanol).
Reaction SMILES: [N:1]#[C:2]Br.[NH2:4][C:5]1[CH:6]=[C:7]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:8]=[CH:9][C:10]=1[OH:11].[OH-].[Na+]>O>[NH2:1][C:2]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:6][C:5]=2[N:4]=1
Reactant: CC(C(=O)O)c1ccc(O)c(N)c1
Reactant: N#CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)c1ccc2oc(N)nc2c1
Temperature: 25 °C
Reaction time: 41 h
Yield: 7.1 %

Procedure:
Cyanogen bromide (1.06 g., 0.1 mole.) was added to a stirred suspension of 2-(3-amino-4-hydroxyphenyl) propionic acid (1.8 g., 0.1 mole.) in water (100 ml.). The suspension was stirred at room temperature for a further 41 hours. The pH of the suspension was adjusted to 4 by the addition of 50% w/v sodium hydroxide solution. The suspension was filtered and the solid was washed (x2) with small volumes of water. Recrystallisation of the solid from 50% aqueous methanol gave 2-(2-amino-5-benzoxazolyl) propionic acid (1.46 g.), m.p. 225°-229°C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:25]3[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[CH:13][CH:12]=3)[C:3]=12.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.FC1C(F)=CC=CC=1OC1C=CC(C2C3C(=NC=NC=3N)N(C[C@H]3CCCN3)N=2)=CC=1>ClCCl>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([CH:25]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]3)[N:9]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4F)cc3)c3c(N)ncnc32)C1
Agent: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3F)cc1)nn2C[C@H]1CCCN1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3F)cc1)nn2C1CCCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
Into a 100 mL, round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of tert-butyl 3-[4-amino-3-[4-(2-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (200 mg, 0.40 mmol, 1.00 equiv) in dichloromethane (20 mL), and trifluoroacetic acid (10 g, 87.70 mmol, 221.25 equiv). The resulting solution was stirred overnight at room temperature and then concentrated under vacuum. The pH value of the solution was adjusted to 8-10 with 10% aqueous sodium carbonate. The solution was extracted with dichloromethane and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give 0.1 g (62%) of 3-[4-(2-fluorophenoxy)phenyl]-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH:23]1C=CC=CC=1>>[CH3:23][O:17][C:16](=[O:18])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: c1ccccc1
Reactant: O=C(O)Cc1ccc(Sc2ccc(Cl)cc2)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(Sc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 21 g of [p-(p-chlorophenylthio)phenyl]acetic acid and 11.9 g of thionyl chloride are stirred overnight at room temperature. To the resulting greenish yellow solution is added 20 ml of benzene and the solvent is evaporated at reduced pressure. This procedure is repeated once. The residue is added dropwise to 300 ml of methanol, maintained at 0° C., and the resulting solution is stirred overnight. The solvent is evaporated at reduced pressure and the mixture is dissolved in 200 ml of ether. The ether layer is washed with 100 ml of water, 100 ml of saturated NaHCO3, 100 ml of saturated brine and dried over MgSO4. Evaporation of the solvent and distillation of the residue affords the product as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.NC1C(C(C2C=C(F)C=CC=2OC)=O)=CN=C(S(CC)(=O)=O)N=1.[NH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:49][CH2:48]1>CN1CCCC1=O.O>[C:56]([O:55][C:53]([N:50]1[CH2:51][CH2:52][CH:47]([NH:46][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=3[O:17][CH3:18])=[CH:6][N:5]=2)[CH2:48][CH2:49]1)=[O:54])([CH3:59])([CH3:57])[CH3:58]
Reactant: CCS(=O)c1ncc(C(=O)c2cc(F)ccc2OC)c(N)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CCS(=O)(=O)c1ncc(C(=O)c2cc(F)ccc2OC)c(N)n1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc1N
Temperature: 70 °C
Yield: 95 %

Procedure:
A solution composed of a 9:1 mixture of (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone and (4-amino-2-ethanesulfonyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone (11.6 g, 36 mmol, Example 163) and 4-amino-1-N-Boc-piperidine (Astatech Inc.) (10.8 g, 54 mmol) in 1-methyl-2-pyrrolidinone (50 mL, Aldrich) was heated at 70° C. for 30 minutes. The reaction was diluted with water and extracted with ethyl acetate. The dried (Na2SO4) organic solution was evaporated and the residue was triturated with ethyl ether/hexane to give 95% yield of 4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester as a colorless solid, mp 122–124 dec. Mass Spectrum (LR-ES) M+: 445.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:2]1.CCN(CC)CC.[F:25][C:26]1[C:27]2[CH:37]=[C:36]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:35]=[CH:34][C:28]=2[S:29][C:30]=1[C:31](Cl)=[O:32]>C(Cl)Cl>[F:25][C:26]1[C:27]2[CH:37]=[C:36]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:35]=[CH:34][C:28]=2[S:29][C:30]=1[C:31]([N:1]1[CH2:2][CH:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)=[O:12])[CH2:9][CH2:10]2)[CH2:4]1)=[O:32]
Reactant: O=C(c1nccs1)N1CCN(C2CNC2)CC1
Reactant: O=C(Cl)c1sc2ccc(-c3ccccc3)cc2c1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1nccs1)N1CCN(C2CN(C(=O)c3sc4ccc(-c5ccccc5)cc4c3F)C2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
To a solution of compound 5e (42.7 mg, 0.131 mmol) and Et3N (0.07 mL, 0.5 mmol) in CH2Cl2 (2 mL) at 0° C. was slowly added a solution of compound 52e (36.3 mg, 0.125 mmol) in CH2Cl2 (1 mL). The reaction was stirred at 0° C. for 2 h, diluted with CH2Cl2, and washed with aqueous NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (silica gel, 2% MeOH/EtOAc) to give compound Cpd 1315 (16.7 mg). 1H NMR (400 MHz, CDCl3): δ 7.98 (d, J=1.2 Hz, 1H), 7.89 (d, J=3.2 Hz, 1H), 7.80-7.86 (m, 1H), 7.73 (dd, J=8.6, 1.7 Hz, 1H), 7.62-7.68 (m, 2H), 7.55 (d, J=3.2 Hz, 1H), 7.46-7.53 (m, 2H), 7.37-7.44 (m, 1H), 4.22-4.67 (m, 5H), 4.05-4.20 (m, 1H), 3.77-4.01 (m, 2H), 3.25-3.37 (m, 1H), 2.42-2.68 (m, 4H). MS m/z (M+H+) 507.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([C:7]([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]3=[O:31])[C@H:26]([OH:37])[C@@H:25]2[OH:38])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[C:50]([CH2:52][CH2:53][O:54][CH2:55]Cl)#[N:51].C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]3=[O:31])[C@H:26]([O:37][CH2:55][O:54][CH2:53][CH2:52][C:50]#[N:51])[C@@H:25]2[OH:38])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]2[CH:39]=[CH:40][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N#CCCOCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OCOCCC#N)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 31.3 %

Procedure:
5′-O-(4,4′-Dimethoxytrityl)uridine (546 mg, 1 mmol) was dissolved in 4 mL of 1,2-dichloroethane, and 452 mg of diisopropylethylamine (3.5 mmol) was added thereto, and 365 mg of dibutylstannyl dichloride (1.2 mmol) was further added thereto. The reaction was performed at room temperature for 1 hour. Subsequently, the reaction was performed at 80° C., and 155.4 mg of chloromethyl 2-cyanoethyl ether (1.3 mmol) was added dropwise, and the reaction solution was stirred for 30 minutes. After the reaction completed, the reaction solution was added into an aqueous saturated sodium bicarbonate solution, and was subjected to extraction with methylene chloride, and the extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained mixture was purified by 30 g of silica gel column chromatography to obtain 5′-O-(4,4′-dimethoxytrityl)-2′-O-(2-cyanoethoxymethyl)uridine (197 mg, yield 34%).