Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([C:10]3[NH:14][N:13]=[N:12][N:11]=3)[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25][CH2:26][C:27](O)=[O:28].[K+].[Br-]>>[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25][CH2:26][C:27]([NH:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([C:10]3[NH:11][N:12]=[N:13][N:14]=3)[C:6]([CH3:8])([CH3:9])[S:7][C@H:3]12)=[O:28]
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Reactant: NCc1ccccc1SCC(=O)O
Agent: [Br-]
Agent: [K+]
Product: CC1(C)S[C@@H]2C(NC(=O)CSc3ccccc3CN)C(=O)N2C1c1nnn[nH]1
Yield: 14 %

Procedure:
The title compound is prepared in 14% yield, as a colorless amorphous solid, by acylation of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam with 2-(2-[aminomethyl]phenylthio)acetic acid (U.S. Pat. No. 3,766,176), using the method of Example LXXVII. IR(KBr disc): 1780 and 1665 cm-1. NMR (DMSO-d6 /D2O): 7.50 ppm (m, 4H), 5.70 ppm (d, 1H), 5.43 ppm (d, 1H), 5.19 ppm (s, 1H), 4.35 ppm (s, 2H), 3.94 ppm (s, 2H), 1.60 ppm (s, 3H), and 1.00 ppm (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:19]1[CH2:20][O:21][C:22](=[O:24])[CH:23]=1.[Br:25]N1C(=O)CCC1=O>C(Cl)Cl>[Br:25][C:23]1[C:22](=[O:24])[O:21][CH2:20][C:19]=1[N:3]1[CH2:4][CH2:5][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:2]1=[O:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=CC(=O)OC1)C2=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=C(Br)C(=O)OC1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-butyl 1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (I-16, Step A) (2.73 g, 8.12 mmol) was dissolved in DCM (70 mL) and was treated with N-bromosuccinimide (1.73 g, 9.74 mmol) at 25° C. and the resulting mixture was stirred overnight at room temperature. The next day, the reaction mixture was diluted with DCM and was washed with water and brine then dried over Na2SO4. Removing solvent gave crude product that was purified by silica gel column chromatography (80 g RediSep Gold Column) using (25-80) % EtOAc/Hexanes as mobile phase to afford the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5]C(C#N)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:12]([OH:15])(=[O:14])[CH3:13].S(=O)(=O)(O)O>O>[NH:1]1[C:9]2[C:4](=[CH:5][C:13]([C:12]([OH:15])=[O:14])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: N#Cc1ccc2[nH]ncc2c1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc2[nH]ncc2c1
Temperature: 110 °C
Reaction time: 10 h

Procedure:
To 867 mg of 1H-5-indazolecarbonitrile used in Production Example I-14-a were added 8 ml of glacial acetic acid, 2.5 ml of water and 2 ml of concentrated sulfuric acid, and the mixture was stirred at 110° C. for 10 hours. After standing to cool, the mixture was added with 50 ml of water, and the resulting crystals were collected by filtration and dried in vacuo, to give 911 mg of the title compound as white crystals.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CO[C:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[N:17]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:16]=1[CH2:33][N:34]([CH2:45][C:46]#[N:47])S(C1C=CC(C)=CC=1)(=O)=O)=[O:14]>C1COCC1>[C:27]1([S:24]([N:17]2[C:16]3[CH:33]=[N:34][C:45]([C:46]#[N:47])=[C:13]([OH:14])[C:15]=3[C:23]3[CH:22]=[CH:21][CH:20]=[N:19][C:18]2=3)(=[O:25])=[O:26])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)c1c(CN(CC#N)S(=O)(=O)c2ccc(C)cc2)n(S(=O)(=O)c2ccccc2)c2ncccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ncc2c(c1O)c1cccnc1n2S(=O)(=O)c1ccccc1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
Lithium bis(trimethylsilyl)amide (9.6 mL, 1N solution in THF, 9.60 mmol) was added dropwise to a cooled (−78° C.) suspension of 1-benzenesulfonyl-2-{[cyanomethyl(toluene-4-sulfonyl)amino]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (1.72 g, 3.19 mmol) in dry THF (50 mL). The reaction mixture was allowed to warm to −30° C., stirred at −30° C. for 2 h, before warming to ambient temperature. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (30 mL) and water (50 mL). The aqueous phase was extracted with DCM (2×20 mL) and the combined organic phase was washed with brine and concentrated in vacuo. The resultant solid was triturated with THF (2×4 mL) to afford the title compound. The filtrate was purified by flash chromatography (silica, 5 g column, Si-SPE, ethyl acetate then 10-20% MeOH in DCM) to afford the remaining title compound. The two batches of material were combined to afford a yellow solid (1.03 g, 90%). LCMS (Method B): RT=3.26 min, M+H+=351.
Reaction SMILES: [ClH:1].[OH:2][C@@H:3]([CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][C:14]([O:16]CC)=[O:15]>Cl.CC(C)=O>[ClH:1].[OH:2][C@@H:3]([CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)CCc1ccccc1OC[C@@H](O)CNC(C)C
Agent: Cl
Solvent: CC(C)=O
Product: CC(C)NC[C@H](O)COc1ccccc1CCC(=O)O
Temperature: 25 °C
Yield: 67.2 %

Procedure:
(S)-Ethyl 3-[2-[2-hydroxy-3-(isopropylamino)propoxy]phenyl]propionate hydrochloride (10 g, 0.029 moles) was dissolved in 6 N hydrochloric acid (200 mL). This solution was refluxed for 16 h and evaporated to dryness to give a white solid. This solid was dissolved in 50 mL of acetone with warming. Trace insoluble solid was removed by filtration through a fluted filter paper and the solution was allowed to cool to room temperature. The white crystalline solid which separated was filtered, washed with ether (2×25 mL) and air dried to give 6.2 g (0.0195 moles, 67.2%) of crude (S)-(−) 3-[2-[2-hydroxy-3-(isopropylamino)propoxy]phenyl]propionic acid hydrochloride, m.p. 123-124° C. The crude acid (7.5 g, 0.023 moles) was dissolved in hot acetone (40 mL) and allowed to cool at room temperature. The white crystalline solid which separated was filtered, washed with ether (50 mL) and recrystallized three times as described above. The product was then dried in vacuo to give 2.5 g (0.00786 moles, 34.1%) of (S)-(−) 3-[2-[2-hydroxy-3-(isopropylamino)propoxy]phenyl]propionic acid hydrochloride as a white crystalline powder; m.p. 125.9° C., Mass spec. (MS/MS) M+1, m/z 282.42.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.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>[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31]([C:2]2[N:11]=[C:10]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:3]=2)=[CH:30][N:29]=1
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Reactant: COc1ncc(B(O)O)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: CN(C)C=O
Solvent: O
Product: COc1ncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)cn1
Temperature: 90 °C
Reaction time: 12 h
Yield: 56 %

Procedure:
To a solution of 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (300 mg, 0.87 mmol) in DMF (20 mL) and H2O (2 mL) under nitrogen was added 2-methoxypyrimidin-5-ylboronic acid (199 mg, 1.30 mmol) and potassium carbonate (239 mg, 1.73 mmol). The resulting mixture was degassed with nitrogen for 15 min and then tetrakis(triphenylphosphine)palladium (100 mg, 0.086 mmol) was added. Upon completion of addition, the reaction mixture was again degassed with nitrogen for 10 min. After this time, the reaction mixture was heated to 90° C. where it stirred for 12 h. After this time, the reaction mixture was allowed to cool to room temperature and then quenched by the addition of water. The reaction mixture was extracted with ethyl acetate and the organic layer was washed successively with water and brine. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting concentrate was purified by preparative HPLC to afford 2-(2-methoxypyrimidin-5-yl)-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (205 mg) as an off-white solid. Preparative HPLC Conditions: Column: Sunfire C18 (250×19 mm), Mobile Phase A: 0.1% TFA in H2O, Mobile Phase B: CH3CN, Gradient: 0 to 40% B over 35 min, 100% B for 10 min., Flow Rate: 14 mL/min., Retention time: 28 min. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.50 (s, 2H), 8.27 (d, J=4.7 Hz, 1H), 7.92 (d, J=3.6 Hz, 2H), 7.85-7.81 (t, J=8.0 Hz, 1H), 7.60-7.52 (m, 5H), 7.42-7.38 (m, 2H), 7.34-7.31 (m, 1H), 4.83 (d, J=4.2 Hz, 2H), 4.04 (s, 3H). LCMS Method O: retention time 1.45 min, [M+1]=421.2. HPLC Method B: purity 98.7%, retention time 5.53 min.
Reaction SMILES: [CH:1](O)([C:6]([F:9])([F:8])[F:7])[C:2]([F:5])([F:4])[F:3].[F:11]F>>[F:3][C:2]([F:5])([F:4])[CH:1]([F:11])[C:6]([F:9])([F:8])[F:7]
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: FF
Product: FC(C(F)(F)F)C(F)(F)F
Yield: 90 %

Procedure:
A vapor plug flow reactor ½″ diameter×3′ long Monel® pipe is fed with 1 g/min of the hexafluoro-2-propanol and 150 cc/min of elemental fluorine at ambient conditions to produce 1,1,1,2,3,3,3 heptafluoropropane in greater than 90% yield.
Reaction SMILES: [P:1]([O-:40])([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Br)([O:3][CH2:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:31])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:9][CH2:8][CH2:7][O:6]1)=[O:2].[OH:41][CH2:42][CH2:43][C:44]1[S:48][CH:47]=[N:46][C:45]=1[CH3:49]>C1(C)C=CC=CC=1>[P:1]([O-:40])([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:47]1[S:48][C:44]([CH2:43][CH2:42][OH:41])=[C:45]([CH3:49])[NH+:46]=1)([O:3][CH2:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:31])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:9][CH2:8][CH2:7][O:6]1)=[O:2]
Reactant: CCCCCCCCCCCCCCCCCNC(=O)O[C@@H]1CCCO[C@H]1COP(=O)([O-])OCCCCCCBr
Reactant: Cc1ncsc1CCO
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCNC(=O)O[C@@H]1CCCO[C@H]1COP(=O)([O-])OCCCCCCc1[nH+]c(C)c(CCO)s1
Temperature: 80 °C

Procedure:
0.88 g of dl-[trans-3-(N-heptadecylcarbamoyloxy)tetrahydropyran-2-yl]methyl 6-bromohexyl phosphate (prepared as described in the first step of Example 8f) was dissolved in 2.0 ml of toluene. The resulting solution was mixed with 2.88 ml of 5-(2-hydroxyethyl)-4-methylthiazole. The mixture was then heated on an oil bath at 80° C. for 90 hours, whilst stirring. It was then worked up as described in Example 1f, to give 0.460 g of the title compound as a powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21][C:22]([CH2:24][C:25]2[CH:32]=[CH:31][C:28]([CH2:29][OH:30])=[CH:27][CH:26]=2)=[O:23])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21][C:22]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([CH:29]=[O:30])=[CH:31][CH:32]=2)=[O:23])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(NC(=O)Cc2ccc(CO)cc2)c2ccccc2N2CCCCC2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Cc1ccc(C(NC(=O)Cc2ccc(C=O)cc2)c2ccccc2N2CCCCC2)cc1
Reaction time: 12 h

Procedure:
One-half gram (1.2 m mol) of 4-{N-[α-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl}-benzyl alcohol was added to a suspension of 0.4 gm (1.5 m mol) of pyridinium chlorochromate in 2 ml of chloroform. After 12 hours at ambient temperature, ether was added, the mixture was filtered, and the concentrated filtrate was purified by column chromatography on silica gel [eluant: toluene/ethyl acetate (5:1)].
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]([OH:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C@@:24]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:28]([F:31])([F:30])[F:29])[C:25](Cl)=[O:26]>>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@H:10]([O:21][C:25](=[O:26])[C@:24]([O:23][CH3:22])([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:28]([F:30])([F:31])[F:29])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@](C(=O)Cl)(c1ccccc1)C(F)(F)F
Reactant: OC1CN(Cc2ccccc2)CCC1Cc1ccccc1
Product: CO[C@@](C(=O)O[C@@H]1CN(Cc2ccccc2)CC[C@@H]1Cc1ccccc1)(c1ccccc1)C(F)(F)F
Yield: 29 %

Procedure:
The title compound was prepared from (3SR,4SR)-1,4-dibenzyl-piperidin-3-ol and (S)-(+) -alpha-methoxy-alpha-trifluoromethylphenylacetyl chloride in 29% yield as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:19])([CH3:18])[C:16]#[N:17])=[CH:11][CH:10]=2)[C:5]([C:20]#[C:21][CH2:22][OH:23])=[CH:4][N:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:20]=[C:21]([CH2:22][OH:23])[N:8]([C:9]3[CH:10]=[CH:11][C:12]([C:15]([CH3:19])([CH3:18])[C:16]#[N:17])=[CH:13][CH:14]=3)[C:6]=2[N:7]=1
Reactant: CC(C)(C#N)c1ccc(Nc2nc(Cl)ncc2C#CCO)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ccc(-n2c(CO)cc3cnc(Cl)nc32)cc1
Yield: 68 %

Procedure:
2-(4-(2-chloro-5-(3-hydroxyprop-1-ynyl)pyrimidin-4-ylamino)phenyl)-2-methylpropanenitrile was reacted with a solution of 1M tetrabutylammonium fluoride in THF (5.85 mL, 5.85 mmol) diluted to 10 mL with additional dry THF for 1.5 hr at 60° C. Analytical LC indicates the reaction is complete (minimal shift in retention time). Volatiles were removed and the residue taken up into ethyl acetate. Organics were washed with water, brine then dried over sodium sulfate. Volatiles were removed and the residue purified by NPLC (10-75% ethyl acetate in Heptane, Analogix) to yield the desired product (589 mg, 68%). MS 327.3 m/z (M+H)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([N:12]([CH2:14][C:15]2[S:23][C:22]3[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:20][C:19]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][CH2:38][O:39][Si](C(C)(C)C)(C)C)[CH:31]=4)=[N:18][C:17]=3[CH:16]=2)[CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([N:12]([CH2:14][C:15]2[S:23][C:22]3[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:20][C:19]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][CH2:38][OH:39])[CH:31]=4)=[N:18][C:17]=3[CH:16]=2)[CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(N(C)Cc2cc3nc(-c4cccc(OCCO[Si](C)(C)C(C)(C)C)c4)nc(N4CCOCC4)c3s2)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(N(C)Cc2cc3nc(-c4cccc(OCCO)c4)nc(N4CCOCC4)c3s2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
A mixture of 0602-289 (1.94 g, 5.1 mmol), 0504 (0.5079 g, 1.3 mmol) and NaHCO3 (0.323 g, 3.8 mmol) were taken into 10 ml toluene (10 mL), ethanol (6.4 mL) and water (2.8 mL) followed the addition of Pd(PPh3)2Cl2 (54 mg). The resulting mixture was heated at 120° C. overnight. TLC showed the reaction complete. The reaction mixture was filtered through celite and washed with dichloromethane. The crude product was purified by column chromatography eluted with hexanes/ethyl acetate to afford 2-[(2-{3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-phenyl}-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amino]-pyrimidine-5-carboxylic acid ethyl ester (0.71 g, 83%) as an off-white solid. LC-MS: 665 [M+1]+. 2-[(2-{3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-phenyl}-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amino]-pyrimidine-5-carboxylic acid ethyl ester (680 mg, 1.02 mmol) was taken into THF (20 mL) followed by the addition of tetrabutyl ammonium fluoride (533 mg, 2.04 mmol). The resulting mixture was stirred at room temperature for 30 min. TLC showed reaction complete. Reaction mixture was diluted with ethyl acetate, washed with water and dried with Na2SO4. The crude product was purified by column chromatography eluted with hexanes/ethyl acetate to afford titled compound as an off-white solid (540 mg, 96%). m.p.: 216-220° C. LC-MS: 551.3 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 1.38 (t, J=6.8 Hz, 3H), 3.31 (s, 3H), 3.86 (t, J=5.2 Hz, 4H), 3.99-4.02 (m, 6H), 4.20 (t, J=4.4 Hz, 2H), 4.37 (q, J=7.2 Hz, 2H), 5.19 (s, 2H). 7.01 (dd, J=8 Hz, 2 Hz, 1H), 7.35-7.39 (m, 2H). 8.01-8.05 (m, 2H), 8.92 (s, 2H).
Reaction SMILES: [ClH:1].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]([CH3:41])[N:14]([C:33]3[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=3)[C:15](=[O:32])[C:16]=2[C:17]([N:19]2[CH2:24][CH2:23][CH:22]([O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:21][CH2:20]2)=[O:18])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[NH4+:46].[NH4+]>C(O)C>[ClH:1].[C:39]([C:36]1[CH:35]=[CH:34][C:33]([N:14]2[C:15](=[O:32])[C:16]([C:17]([N:19]3[CH2:20][CH2:21][CH:22]([O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:24]3)=[O:18])=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([C:2]([CH3:3])([CH3:4])[CH3:5])=[CH:11][CH:10]=3)[N:13]2[CH3:41])=[CH:38][CH:37]=1)(=[NH:46])[NH2:40]
Reactant: [NH4+]
Reactant: CCOC(=O)COC1CCN(C(=O)c2c(-c3ccc(C(C)(C)C)cc3)n(C)n(-c3ccc(C#N)cc3)c2=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)COC1CCN(C(=O)c2c(-c3ccc(C(C)(C)C)cc3)n(C)n(-c3ccc(C(=N)N)cc3)c2=O)CC1

Procedure:
Dry hydrogen chloride was introduced into a mixture of 1.19 g of 3-(4-t-butylphenyl)-4-{[4-(ethoxycarbonylmethyloxy)-1-piperidinyl]carbonyl}-1-(4-cyanophenyl)-2-methyl-2H-pyrazol-5-one and 15 ml of absolute ethanol under cooling with ice for 2 hours, and the mixture was stirred under cooling with ice for another 15 hours. 38.5 g of ammonium carbonate was added to adjust the pH to 7-8, and the reaction solution was stirred at room temperature for 22 hours. The precipitated insolubles were filtered off, and hydrochloric acid in ethanol was added to the mother liquor to adjust the pH to 3. The precipitated crystals were filtered off, and the mother liquor was concentrated under reduced pressure. The residue was purified by C-18 reverse phase silica gel chromatography (water/methanol=2:1). The resulting crude crystals were recrystallized in methanol-chloroform-ethyl acetate to give 543 mg of the title compound as colorless crystals.
Reaction SMILES: [C:1]1([CH3:11])[C:2]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[CH:26]=[C:25]2[C:20]([C:21](=[N:28][OH:29])[CH:22]([CH3:27])[CH2:23][O:24]2)=[CH:19][CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[C:1]1([CH3:11])[C:2]([S:7]([O:29][N:28]=[C:21]2[C:20]3[C:25](=[CH:26][C:17]([C:13]4[O:12][CH:16]=[CH:15][CH:14]=4)=[CH:18][CH:19]=3)[O:24][CH2:23][CH:22]2[CH3:27])(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CC1COc2cc(-c3ccco3)ccc2C1=NO
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)ON=C1c2ccc(-c3ccco3)cc2OCC1C
Reaction time: 6 h
Yield: 57.1 %

Procedure:
Toluenesulfonyl chloride (397 mg, 2.08 mmol) was added to a 0° C. solution of 7-furyl-3-methyl-4-chromanone oxime (61) (461 mg, 1.89 mmol) and pyridine (0.5 mL) in CH2Cl2 (10 mL). After 6 hours, the mixture was diluted with CH2Cl2 (30 mL) and washed with 5% HCl (20 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified via flash chromatography using 5:1 hexanes:EtOAc as the eluent, to provide 7-furyl-3-methyl-4-chromanone O-(toluenesulfonyl)-oxime (62) (429 mg) as a pink solid, m.p. 163-164° C. (dec).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)[N:3]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: OB(O)c1ccc(F)cc1
Product: COc1ccc2c(-c3ccc(F)cc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-fluoro-phenylboronic acid to give [1-(4-fluoro-phenyl)-6-methoxy-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 335(MH+).
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[C:3]([C:10]([OH:12])=O)[CH:2]=1.[Br:13][C:14]1[C:15]([NH2:20])=[N:16][N:17]([CH3:19])[CH:18]=1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[Br:13][C:14]1[C:15]([NH:20][C:10]([C:3]2[CH:2]=[N:1][N:5]3[CH:6]=[CH:7][CH:8]=[N:9][C:4]=23)=[O:12])=[N:16][N:17]([CH3:19])[CH:18]=1
Reactant: Cn1cc(Br)c(N)n1
Reactant: O=C(O)c1cnn2cccnc12
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(Br)c(NC(=O)c2cnn3cccnc23)n1
Yield: 62.9 %

Procedure:
A solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (165.5 mg, 1.014 mmol, 1.01 eq), 4-bromo-1-methyl-1H-pyrazol-3-amine (177.4 mg, 1.008 mmol, 1.0 eq), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uranium hexafluorophosphate (497 mg, 1.31 mmol, 1.30 eq), N,N-diisopropylethylamine (0.25 mL, 1.4 mmol, 1.4 eq), and 4-dimethylaminopyridine (33.8 mg, 0.277 mmol, 0.27 eq) in 5 mL N,N-dimethylformamide was heated at 50° C. for 4 days. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel (20 to 80% ethyl acetate in dichloromethane (containing 5% methanol)) to yield 203.6 mg (63%) of N-(4-bromo-1-methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=321.1; 1H NMR (400 MHz, CD3OD) δ: 9.16 (d, 1H), 8.84 (d, 1H), 8.68 (s, 1H), 7.76 (s, 1H), 7.28 (d of d, 1H), 3.88 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C@:21]([F:26])([CH3:25])[C:22](O)=[O:23])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]([F:45])([C:41]([F:44])([F:43])[F:42])[CH2:38][CH2:39][NH2:40]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C@:21]([F:26])([CH3:25])[C:22]([NH:40][CH2:39][CH2:38][C:37]([F:45])([F:36])[C:41]([F:44])([F:43])[F:42])=[O:23])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCC(F)(F)C(F)(F)F
Reactant: C[C@](F)(C(=O)O)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Product: C[C@](F)(C(=O)NCCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (R)—N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2-fluoro-2-methyl-malonamic acid and 3,3,4,4,4-pentafluoro-butylamine, the title compound was prepared in the same manner as described for example 1c. White solid (68%). MS: m/e=622(M+H+).