Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][NH:11][CH2:12][C:13]([CH2:36][CH3:37])=[CH:14][CH2:15][C:16]1[C:17]([O:29]CC[Si](C)(C)C)=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[CH2:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C>CN(C=O)C.C(Cl)Cl>[CH2:36]([C:13](=[CH:14][CH2:15][C:16]1[C:17]([OH:29])=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[CH2:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])[CH2:12][NH:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])[CH3:37]
Reactant: CCOP(=O)(CCNCC(=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CC)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(=CCc1c(O)c2c(c(C)c1CC)COC2=O)CNCCP(=O)(O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 44.7 %

Procedure:
(2-{2-Ethyl-4-[6-ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enylamino}-ethyl)-phosphonic acid diethyl ester (24.9 mg, 0.045 mmol) was dissolved in DMF (0.5 mL) and DCM (0.5 mL). Trimethylsilyl bromide (68.7 mg, 0.449 mmol) was added and the reaction was stirred at room temperature. After 20 hours, the reaction was quenched with MeOH (0.15 mL). The solvents were evaporated in vacuo and the crude material was purified by RP-HPLC (eluent: water/MeCN). The product-containing fractions were combined and lyophilized to yield 8.0 mg of the free phosphonic acid [MS: 498 M++1].
Reaction SMILES: [O:1]1[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[O:4][CH2:3][C@@H:2]1[CH2:15][NH:16][CH2:17][CH2:18][CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=2)[NH:22][CH:21]=1)[N:11]=[CH:10][CH:9]=[CH:8]3.C=O.[C:32]([BH3-])#N.[Na+].C(O)(=O)C>CO>[O:1]1[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[O:4][CH2:3][CH:2]1[CH2:15][N:16]([CH2:17][CH2:18][CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=2)[NH:22][CH:21]=1)[CH3:32])[N:11]=[CH:10][CH:9]=[CH:8]3
Reactant: Fc1ccc2[nH]cc(CCCNC[C@H]3COc4ccc5ncccc5c4O3)c2c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(CCCc1c[nH]c2ccc(F)cc12)CC1COc2ccc3ncccc3c2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2S)-(2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-[3-(5-fluoro-1H-indol-3-yl)-propyl]-amine (0.13 g, 0.33 mmol) and formaldehyde (37 wt. % in water, 0.26 g, 3.3 mmol) in methanol (20 mL) was added sodium cyanoborohydride (0.038 g, 0.59 mmol) and acetic acid (0.03 g, 0.5 mmol) at room temperature. The mixture was stirred at room temperature under nitrogen overnight, then quenched with 1N NaOH (5 mL). The mixture was extracted with methylene chloride (3×50 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. The crude oil was column chromatographed on silica gel (5% methanol-methylene chloride). The product-containing fractions were concentrated in vacuum to give 0.1 g of the (S)-enantiomer of the title compound as a brown oil. The dihydrochloride salt was prepared in ethyl acetate as a yellow solid (decomposed at 78° C.).
Reaction SMILES: [OH-:1].[K+].[OH:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:14])[CH:10]=2)[CH:5]=1.C([O:17][P:18]([CH2:23][CH2:24][CH2:25][CH2:26]Br)(=[O:22])[O:19]CC)C>C(O)C>[P:18]([CH2:23][CH2:24][CH2:25][CH2:26][O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH2:26][CH2:25][CH2:24][CH2:23][P:18]([OH:17])([OH:19])=[O:22])[CH:10]=2)[CH:5]=1)([OH:19])([OH:17])=[O:1]
Reactant: [OH-]
Reactant: Oc1ccc2cc(O)ccc2c1
Reactant: CCOP(=O)(CCCCBr)OCC
Agent: [K+]
Solvent: CCO
Product: O=P(O)(O)CCCCOc1ccc2cc(OCCCCP(=O)(O)O)ccc2c1
Reaction time: 8 h

Procedure:
1.34 g of KOH in ethanol were added dropwise to a mixture of 2,6-dihydroxynaphthalene (1.6g, 10 mmol) and diethyl(4-bromobutyl)phosphonate (6.0 g, 22 mmol) in ethanol, the mixture was left at room temperature for over night. The product was extracted with CH2Cl2. The CH2Cl2 solution was dried, leaving a brownish solid. The ester was purified by column chromatography. The bisphosphonate ester was converted to the acid by overnight stirring with 4-fold excess of bromotrimethylsilane in dry dichloromethane followed by addition of water. The bisphosphonic acid derivative was washed with CH2Cl2, filtered and collected.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].CC1(C)C(C)(C)OB([C:32]2[O:33][C:34]([CH3:37])=[CH:35][CH:36]=2)O1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.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>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([C:32]4[O:33][C:34]([CH3:37])=[CH:35][CH:36]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)o1
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: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3ccc(C)o3)c(C)sc2n1
Temperature: 120 °C
Yield: 45 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 61) (90 mg, 0.208 mmol) was dissolved in 1,4-dioxane (1.5 mL) and water (0.7 mL). 4,4,5,5-Tetramethyl-2-(5-methyl-2-furanyl)-1,3,2-dioxaborolane (0.064 mL, 0.313 mmol), tetrakis(triphenylphosphine)palladium(0) (24.09 mg, 0.021 mmol) and potassium carbonate (86 mg, 0.625 mmol) were added and the mixture heated in a microwave at 120° C. for 10 min. Ethyl acetate (10 mL) was then added and the mixture washed with water (2×5 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-30% ethyl acetate in cyclohexane and further triturated with MeOH, to give the title compound (40.5 mg). LCMS (A) m/z: 433 [M+1]+, Rt 1.50 min (acidic).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](OC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:22][NH2:23]>CO>[NH:22]([C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:23]
Reactant: NN
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
To (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate (Aldrich, 300 mg, 1.07 mmol) in MeOH (5.4 mL) was added hydrazine hydrate (170 μL, 3.44 mmol). The resulting solution was stirred at room temperature overnight and then concentrated in vacuo. The residue was triturated with hexanes (2×) and then from a minimal amount of 2:3 hexanes/MeOH (2×) to give the title compound (195 mg, 65%) as a white solid. 1H NMR (CDCl3) δ 7.41-7.25 (m, 3H), 7.20 (d, J=6.8 Hz, 2H), 4.39-4.21 (m, 1H), 3.07 (d, J=7.0 Hz, 2H), 1.42 (s, 9H); MS (ESI+) m/z 280.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([NH2:17])=O)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][C:30]=1[NH:31][NH2:32])[C:23]([N:25]([CH3:27])[CH3:26])=[O:24].[C:33](O)(=O)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:31]([C:30]5[CH:29]=[CH:28][C:22]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[CH:21][C:20]=5[Cl:19])[N:32]=[CH:33][N:17]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:18]=1
Reactant: CC(=O)O
Reactant: NC(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Reactant: CN(C)C(=O)c1ccc(NN)c(Cl)c1
Product: CN(C)C(=O)c1ccc(-n2ncnc2-c2cc3c(s2)-c2ccc(Br)cc2OCC3)c(Cl)c1

Procedure:
Following the procedure from Example 235, 8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide was reacted with 3-chloro-4-hydrazinyl-N,N-dimethylbenzamide in acetic acid to give 342 as a colorless solid after purification by flash column chromatography (50-100% ethyl acetate in hexanes). MS: (ESI+) 531.0
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:10]([C:12]1[N:17]=[C:16]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)[N:15]=[C:14]([Cl:28])[CH:13]=1)[CH3:11]>CN(C)C=O>[ClH:28].[CH2:10]([C:12]1[N:17]=[C:16]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)[N:15]=[C:14]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=2[CH3:1])[CH:13]=1)[CH3:11]
Reactant: Cc1cc(F)ccc1N
Reactant: CCc1cc(Cl)nc(N2CCc3ccccc3C2)n1
Solvent: CN(C)C=O
Product: CCc1cc(Nc2ccc(F)cc2C)nc(N2CCc3ccccc3C2)n1
Product: Cl
Yield: 87.6 %

Procedure:
After 2-methyl-4-fluoroaniline(0.35 ml, 3.15 mmol) was added to a mixture solution of 6-ethyl-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)-4-chloropyrimidine(0.40 g, 1.46 mmol) and dimethylformamide(10 ml), 0.51 g of the titled compound was obtained in accordance with the same procedure as in Step 4 of Example 57.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([O:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:34](=[N:37]O)([CH3:36])[CH3:35].O>ClCCl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][N:37]=[C:34]([CH3:36])[CH3:35])=[O:9])[C:5]([O:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)=NO
Reactant: COc1cc(OC)nc(Oc2ccc(N)nc2C(=O)O)n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: COc1cc(OC)nc(Oc2ccc(N)nc2C(=O)ON=C(C)C)n1
Yield: 58.3 %

Procedure:
1.5 g (5 mmol) of 6-amino-3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinic acid, 0.8 g (5 mmol) of carbonyldiimidazole and 0.25 g (3 mmol) of N-isopropylidenehydroxylamine were stirred and refluxed in dichloromethane for 4 hours. After completion of the reaction, the reaction mixture was poured into water, and the dichloromethane layer was separated, washed with water and dried. Then, the solvent was distilled off under reduced pressure. The residual oily product was purified by column chromatography to obtain the desired product as colorless transparent crystals.
Reaction SMILES: [CH:1]1([CH2:5][C@H:6]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([CH3:20])[CH:11]=2)[C:7]([OH:9])=O)[CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[N:29]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:5][C@H:6]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([CH3:20])[CH:11]=2)[C:7]([NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH2:33][C:34]([OH:36])([CH3:35])[CH3:37])[N:29]=2)=[O:9])[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: Cc1cc([C@@H](CC2CCC2)C(=O)O)ccc1S(C)(=O)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc([C@@H](CC2CCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
In a flask (R)-3-cyclobutyl-2-(4-methanesulfonyl-3-methyl-phenyl)-propionic acid (88 mg, 0.30 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylformamide (two drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 160 μL, 0.32 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (2 mL) and added dropwise into a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 47 mg, 0.30 mmol), 2,6-lutidine (70 μL, 0.60 mmol) and methylene chloride (2 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was quenched with a small amount of methanol and diluted with ethyl acetate (20 mL). This was then washed with a 1 N aqueous hydrochloric acid solution (10 mL) and a saturated aqueous brine solution (10 mL). It was then dried over sodium sulfate, filtered and concentrated with silica gel (2 g) in vacuo and then purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes to 80% ethyl acetate) to afford (R)-3-cyclobutyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methanesulfonyl-3-methyl-phenyl)-propionamide (93 mg, 72%) as a white foam: [α]2958932 −14.7° (c=0.19, methylene chloride); ES-HRMS m/e calcd for C22H31N3O4S (M+H)+ 434.2108, observed 434.2108; 1H NMR (300 MHz, DMSO-d6) δ 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.49-2.21 (m, 9 H, CH and 4×CH2), 2.62 (s, 3H, ArCH3), 3.17 (s, 3H, SO2CH3), 3.73 (m, 1H, ArCHCO), 3.86 (s, 2H, NCH2), 4.64 (s, 1H, OH), 6.44 (d, J=2.2 Hz, 1H, Ar), 7.42 (m, 2H, Ar), 7.50 (d, J=2.2 Hz, 1H, Ar), 7.84 (d, Jo=8.6 Hz, 1H, Ar), 10.70 (s, 1H, NH).
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([CH:9](P(=O)([O-])[O-])[F:10])=[C:5](CC)[C:4]=1[Br:17])C.[Li+].CC([N-]C(C)C)C.[CH:26]([C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1)=O.O>C1COCC1>[Br:17][C:4]1[CH:5]=[C:6](/[C:9](/[F:10])=[CH:26]/[C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH:7]=[CH:8][CH:3]=1
Reactant: CCc1ccc(C(F)P(=O)([O-])[O-])c(CC)c1Br
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(/C=C(\F)c2cccc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
A solution of diethyl(3-bromophenyl)fluoromethylphosphonate (2.1 g, 6.5 mmol) in 50 mL of THF was added dropwise via syringe to a solution of LDA (5 mL, 10 mmol) in THF at −78° C. under N2 atmosphere. After 30 min at this temperature methyl 4-formylbenzoate (1.1 g, 6.5 mmol) in 50 mL of THF was added dropwise via syringe and then stirred at this temperature for 30 min and then allow warm to room temperature over 4 hours, and stirred overnight. The mixture was poured into H2O (300 mL) and then extracted with ethyl acetate (3×100 mL). The combined organic layer was concentrated and purified by silica gel chromatography (eluting with a mixture of petroleum ether and ethyl acetate=50:1) to give (Z)-methyl 4-(2-(3-bromophenyl)-2-fluorovinyl)benzoate (0.73 g, 33.6%) as a yellow oil.
Reaction SMILES: [CH:1]1([C:4]2[C:8]([CH2:9][S:10]([C:13]3[CH2:17][C:16]([CH3:19])([CH3:18])[O:15][N:14]=3)(=[O:12])=[O:11])=[C:7]([CH3:20])[O:6][N:5]=2)[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[Cl:27]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.O>[Cl:27][CH:9]([S:10]([C:13]1[CH2:17][C:16]([CH3:18])([CH3:19])[O:15][N:14]=1)(=[O:11])=[O:12])[C:8]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][O:6][C:7]=1[CH3:20]
Reactant: Cc1onc(C2CC2)c1CS(=O)(=O)C1=NOC(C)(C)C1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(C2CC2)c1C(Cl)S(=O)(=O)C1=NOC(C)(C)C1
Temperature: -78 °C
Yield: 44.2 %

Procedure:
3-Cyclopropyl-4-(5,5-dimethyl-4,5-dihydroisoxazol-3-ylsulfonylmethyl)-5-methyl-isoxazole (108 mg, 0.36 mmol) was dissolved in THF (5 ml) under nitrogen. The solution was cooled to −78° C. and potassium tert-butoxide (0.4 ml, 0.4 mmol) added, followed by hexachloroethane (90 mg, 0.4 mmol). The solution was allowed to warm to room temperature, diluted with water (20 ml) and extracted with ethyl acetate (3×15 ml). The combined organic phases were dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel (eluent: ethyl acetate/hexane) to give the product (Compound No. 3.07 of Table 29) as a white solid (53 mg, 44% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:9].[CH:10]([NH2:13])([CH3:12])[CH3:11]>CS(C)=O>[Cl:8][C:4]1[N+:3]([O-:9])=[C:2]([NH:13][CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][CH:5]=1
Reactant: [O-][n+]1c(Cl)cccc1Cl
Reactant: CC(C)N
Solvent: CS(C)=O
Product: CC(C)Nc1cccc(Cl)[n+]1[O-]
Temperature: 120 °C

Procedure:
To a solution consisting of 10 grams (0.06 mole) of 2,6-dichloropyridine-N-oxide in 50 milliliters of dimethylsulfoxide was slowly added 7.9 grams (0.134 mole) of isopropylamine. The temperature of the mixture was 90°C. at the start of the reaction and was allowed to increase to 120°C. After a total reaction time of ~50 minutes, 3/4 of the dimethylsulfoxide was removed by evaporation and the reaction mixture poured over ice. The solid precipitate which formed was removed by filtration and taken up in 500 milliliters of hot hexane. The 6-chloro-2-(isopropylamino)pyridine-N-oxide product melting at 150°-151°C. and was recovered by filtration in a yield of 5 grams. Upon analysis, the product was found to have carbon, hydrogen, chlorine and nitrogen contents of 51.47, 5.96, 19.01 and 15.01 percent, respectively, as compared with the theoretical contents of 51.46, 5.94, 18.99 and 14.99 percent, respectively, calculated for the above named compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=2)[CH:5]=1.[CH2:21]([NH2:23])[CH3:22].[BH4-].[Na+]>CO.ClCCl>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH2:18][NH:23][CH2:21][CH3:22])[CH:17]=2)[CH:5]=1
Reactant: CCN
Reactant: COC(=O)c1ccc(C#N)c(-c2cncc(C=O)c2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCNCc1cncc(-c2cc(C(=O)OC)ccc2C#N)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
4-Cyano-3-(5-formyl-pyridin-3-yl)-benzoic acid methyl ester (0.445 g, 1.67 mmol) was suspended in MeOH/dichloromethane (1:1; 8 mL) and a solution of ethylamine (2M in MeOH, 1.25 mL, 2.51 mmol) was added. The mixture was stirred for 16 hours at room temperature. The mixture was then was cooled to 0° C. and NaBH4 (76 mg, 2.01 mmol) was added in portions over 10 minutes. After allowing the mixture to warm to room temperature over 2 h, the reaction was quenched with 1 mL of water. The solution was concentrated in vacuo to ⅓ of its original volume and then it was partitioned between H2O and EtOAc. The aqueous phase was extracted with EtOAc (×2) and the combined organics were dried (Na2SO4) filtered and the solvent removed in vacuo to give 4-cyano-3-(5-ethylaminomethyl-pyridin-3-yl)benzoic acid methyl ester as a yellow oil (0.353 g, 72%). MS(ESI) m/z 296.0 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[C:8]=2[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:3][CH2:2]1.CC(O)=O.[OH-].[Na+].[CH3:34][C:35]([CH3:37])=O>>[CH3:34][CH:35]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:16][CH:17]=3)[C:8]=2[C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)[CH2:3][CH2:2]1)[CH3:37]
Reactant: CC(C)=O
Reactant: FC(F)(F)c1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)N1CCC(c2[nH]nc(-c3ccc(C(F)(F)F)cc3)c2-c2ccncc2)CC1
Reaction time: 120 h

Procedure:
To a solution of 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-(trifluoromethyl)phenyl]pyrazole (Example C-83) (300 mg, 0.7 mmol) in 50 mL of acetone was added 1 mL of AcOH and NaBH(OAc), (15 g, 70.8 mmol). The mixture was warmed to reflux and was stirred for 5 days, The reaction mixture was poured onto 100 mL of 2.5 N NaOH and was extracted with ethyl acetate (2×100 mL). The extracts were combined and washed with brine (1×100 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to afford the title compound: MS (M+H): 415 (base peak).
Reaction SMILES: C(O)(C(F)(F)F)=O.O.C([O:13][C:14](=[O:46])[CH2:15][CH:16]([C:29](=[O:45])[N:30]([C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:35][CH:34]=1)[CH2:31][CH3:32])[CH:17]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([OH:20])=[O:19])(C)(C)C>C(Cl)Cl>[C:36]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:35]=[CH:34][C:33]([N:30]([CH2:31][CH3:32])[C:29]([CH:16]([CH2:15][C:14]([OH:46])=[O:13])[CH:17]([CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:18]([OH:20])=[O:19])=[O:45])=[CH:38][CH:37]=1
Reactant: CCN(C(=O)C(CC(=O)OC(C)(C)C)C(CCc1ccccc1)C(=O)O)c1ccc(-c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(C(=O)C(CC(=O)O)C(CCc1ccccc1)C(=O)O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice cooled solution of TFA (30%) in DCM (5 mL) containing water (5%) was added the compound of Example 55. The reaction mixture was stirred for 2 h at room temperature, after which time, the solvent was removed. The residue was triturated with ether and evaporated. The residue was partitioned between sodium hydroxide (1N) and ether. Following separation, the alkaline phase was acidified to pH 1 using HCl (1N) and extracted with ethyl acetate. The recombined organic layer was dried over sodium sulfate, filtered and evaporated. FAB: 460.1(MH+), FAB(M−H+): 458.0.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([NH:9][CH:10]3[CH2:14][CH2:13][N:12]([C:15]([C:17]4[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=4[O:25][CH3:26])=[O:16])[CH2:11]3)[O:8][C:4]=2[CH:3]=1.CI.[C:31]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:9]([CH3:31])[C@@H:10]3[CH2:14][CH2:13][N:12]([C:15]([C:17]4[C:18]([O:25][CH3:26])=[CH:19][CH:20]=[CH:21][C:22]=4[O:23][CH3:24])=[O:16])[CH2:11]3)[O:8][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(OC)c1C(=O)N1CCC(Nc2nc3ccc(Cl)cc3o2)C1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc(OC)c1C(=O)N1CC[C@@H](N(C)c2nc3ccc(Cl)cc3o2)C1
Temperature: 75 °C
Yield: 46.2 %

Procedure:
A mixture of 20 mg (0.05 mmol) [3-(6-Chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(2,6-dimethoxy-phenyl)-methanone (example 1), 353 mg (2.48 mmol) methyliodid and 10 mg (0.075 mmol) K2CO3 in 0.5 mL DMF was stirred at 75° C. The mixture was concentrated, water and methanol was added and the mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated to yield 9.6 mg (461%) of the title compound as light yellow solid. (MH+) 418.1.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:10]=2[C:11]#[N:12])[CH:7]=1.[OH:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[OH:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[C:9]([C:13]4[CH:18]=[CH:17][C:16]([O:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:15][CH:14]=4)[C:10]=3[C:11]#[N:12])[CH:7]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2cc(Br)cnc12
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: O
Solvent: C1COCCO1
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2cc(-c3cccc(O)c3)cnc12
Temperature: 65 °C
Reaction time: 16 h
Yield: 61.8 %

Procedure:
To a solution of 6-bromo-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (782 mg, 2.0 mmol) in dioxane (10 mL) and H2O (10 mL) was added 3-hydroxyphenylboronic acid (276 mg, 2.0 mmol), Pd(PPh3)4 (240 mg, 0.2 mmol) and Na2CO3 (424 mg, 4.0 mmol). After stirring at 65° C. under N2 for 16 hr, the mixture was concentrated and 100 mL of DCM, 10 mL of CH3OH, 100 mL of H2O were added. Organic layers were separated from aqueous layers and dried over Na2SO4 and purified by chromatography column on silica gel eluting with DCM/CH3OH to afford 500 mg (62%) of 6-(3-hydroxyphenyl)-2-(4-phenoxyphenyl) pyrazolo[1,5-a]pyrimidine-3-carbonitrile as a yellow solid. MS (ESI) m/e [M+1]+ 404.9.