Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:31])=[C:6]([C@@H:14]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]C)=[O:21])[C:7]([O:12]C)=[C:8]([CH3:11])[C:9]=1[CH3:10])(=[O:3])[CH3:2].B(Br)(Br)Br>ClCCl>[C:1]([C:4]1[C:5]([CH3:31])=[C:6]([C@@H:14]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:7]([OH:12])=[C:8]([CH3:11])[C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: COC(=O)CCCCC[C@H](c1ccc(F)cc1)c1c(C)c(C(C)=O)c(C)c(C)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)c1c(C)c(C)c(O)c([C@H](CCCCCC(=O)O)c2ccc(F)cc2)c1C
Temperature: 0 °C
Reaction time: 6 h
Yield: 82.9 %

Procedure:
A solution of methyl (R)-7-(3-acetyl-6-methoxy-2,4,5-trimethylphenyl)-7-(4-fluorophenyl)heptanoate (2.0 g, 4.7 mmol) in dichloromethane (10 ml) was added dropwise to boron tribromide (2.0 ml, 5.3 g, 21.0 mmol) in dichloromethane (30 mi) at -78° C. The temperature of the reaction solution was elevated gradually to room temperature, and the reaction solution was stirred for 6 hours at the same temperature. To the reaction solution was was added ice-water at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous solution of sodium chloride in the order mentioned, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to a silica gel column chromatography to give (R)-7-(3-acetyl-6-hydroxy-2,4,5-trimethylphenyl)-7-(4-fluorophenyl)heptanoic acid (1.56 g). Physico-chemical properties and spectral data are shown in [Table 5].
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:13]([OH:15])=O)[CH2:10][O:11][CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=C2[N:22]=NN(O)C2=CC=1.O.C(Cl)CCl.[NH4+].[OH-]>CN(C=O)C.CCOC(C)=O.O>[NH2:22][C:13](=[O:15])[C@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][O:11][CH3:12]
Reactant: COC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@@H](NC(=O)OC(C)(C)C)C(N)=O
Reaction time: 18 h
Yield: 22.9 %

Procedure:
A solution of N-Boc-O-methyl-D-serine (438 mg, 2.00 mmol), HOBt monohydrate (364 mg, 2.38 mmol) and EDC (460 mg, 2.39 mmol) in DMF (9 mL) was stirred at room temperature for 2 h, conc. NH4OH (0.700 mL, ca. 9.80 mmol) was added. The mixture was stirred for 18 h. Water and EtOAc were added. The organic phase was washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give (R)-tert-butyl 1-amino-3-methoxy-1-oxopropan-2-ylcarbamate (100 mg). The aqueous phase was further extracted with nBuOH (30 mL). The nBuOH solution was washed with 5% NaHCO3, then was concentrated in vacuo to give another portion of (R)-tert-butyl 1-amino-3-methoxy-1-oxopropan-2-ylcarbamate (242 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[N:11]O)[CH3:10].CS(Cl)(=O)=O.N12CCCN=C1CCCCC2>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:9]([CH3:10])=[N:11]1
Reactant: CC(Cc1ccccc1Br)=NO
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC1=NC1c1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2-bromophenyl)propan-2-one oxime (1.36 g, 5.96 mmol) and TEA (722 mg, 7.15 mmol) in anhydrous THF (50 mL) at RT was added dropwise a solution of methanesulfonyl chloride (819 mg, 7.15 mmol) in anhydrous THF (5 mL). After stirring at RT for 1 h, 1,8-diazabicyclo[5.4.0]undec-7-ene (2.26 g, 14.9 mmol) was added and stirring continued at RT for 1 h. The reaction mixture was passed through a pad of SiO2, concentrated in vacuo, and purified by SiO2 chromatography eluting with petroleum ether/EtOAc (10:1) to afford 2-(2-bromophenyl)-3-methyl-2H-azirine as yellow oil (758 mg, yield, 60.5%). MS (ESI): m/z=242.1 [M+33]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10]/[C:11](=[CH:14]\[CH2:15][C:16]1[C:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][CH2:18][C:17]=1[CH3:24])/[CH2:12]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:12]/[C:11](=[CH:14]\[CH2:15][C:16]1[C:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][CH2:18][C:17]=1[CH3:24])/[CH2:10][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC1=C(C/C=C(\C)CO)C(C)(C)CCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC1=C(C/C=C(\C)COc2ccc(C=O)cc2)C(C)(C)CCC1
Yield: 51.8 %

Procedure:
By the method of example 13 above, 4-hydroxybenzaldehyde (12.0 g) and (2E)-2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-butenol (Chem. Abstr., 94, 65904h) (20.5 g) are coupled with triphenylphosphine and diethyl azodicarboxylate to provide 4-((2E)-2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-butenyloxy)benzaldehyde (15.9 g, 50%) as a colorless oil after chromatography. By the method of example 2 above, this is converted into the title compound, mp 136°-137° after recrystallization from hexane-dichloromethane.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:13]=3[CH:28]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].N[C:30]([CH3:34])([CH3:33])[CH2:31][OH:32]>C1(Cl)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH3:33][C:30]1([CH3:34])[CH2:31][O:32][C:1]([C:3]2[CH:4]=[C:5]([C:9]3[CH:10]=[CH:11][C:12]4[O:16][C:15]([C:17]5[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=5)=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:13]=4[CH:28]=3)[CH:6]=[CH:7][CH:8]=2)=[N:2]1
Reactant: CC(C)(N)CO
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C#N)c3)cc12
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C4=NC(C)(C)CO4)c3)cc12
Temperature: 200 °C
Reaction time: 168 h
Yield: 14.6 %

Procedure:
Zinc chloride (1 mg) was added to a stirring solution of 5-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (40 mg, 0.108 mmol) and 2-amino-2-methylpropan-1-ol (10 mg, 0.108 mmol) in PhCl (3 mL) at 130° C. It was allowed to stir for 7 days. ˜20% conversion was observed. Additional amounts of ZnCl (8 mg) and 2-amino-2-methylpropan-1-ol (50 mg) were added and the reaction was heated in the microwave for 1 hr at 200° C. The reaction had progressed ˜50%. The mixture was concentrated and purified on silica gel (Biotage, EtOAc/hexanes gradient, Rf ˜0.2 in 50% EtOAc/hexanes; fraction collection at λ=254 nm) followed by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (7 mg, 14%). 1H NMR (500 MHz, CD3OD) δ ppm 8.24 (1 H, s), 7.97 (2 H, dd, J=8.09, 5.65 Hz), 7.93 (1 H, s), 7.88 (2 H, dd, J=11.44, 8.39 Hz), 7.68 (2 H, s), 7.57 (1 H, t, J=7.78 Hz), 7.27 (2 H, t, J=8.55 Hz), 4.25 (2 H, s), 2.99 (3 H, s), 1.42 (6 H, s). LC-MS retention time 1.60 min; m/z (MH+): 443. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=12.24 min, purity=95%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 μm, Rt=10.02 min, purity=95%.
Reaction SMILES: [CH3:1][C:2]1([C:21]([OH:23])=O)[CH2:17][C:10]2([N+:18]([O-:20])=[O:19])[C:11]3[C:16]([CH:3]1[C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.CCN=C=NCCCN(C)C.[C:54]1([C:64]2[NH:68][N:67]=[C:66]([NH2:69])[N:65]=2)[C:63]2[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=2)[CH:57]=[CH:56][CH:55]=1>C(#N)C>[CH3:1][C:2]1([C:21]([N:67]2[C:66]([NH2:69])=[N:65][C:64]([C:54]3[C:63]4[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=4)[CH:57]=[CH:56][CH:55]=3)=[N:68]2)=[O:23])[CH2:17][C:10]2([N+:18]([O-:20])=[O:19])[C:11]3[C:16]([CH:3]1[C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3
Reactant: CC1(C(=O)O)CC2([N+](=O)[O-])c3ccccc3C1c1ccccc12
Reactant: Nc1n[nH]c(-c2cccc3ccccc23)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC1(C(=O)n2nc(-c3cccc4ccccc34)nc2N)CC2([N+](=O)[O-])c3ccccc3C1c1ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
To a stirred solution of 15-methyl-8-nitrotetracyclo[6.6.2.02,7.09,14]hexadeca-2,4,6,9,11,13-hexaene-15-carboxylic acid (22 mg, 0.07 mmol, prepared according to WO04009017), 1-hydroxybenzotriazole (14 mg, 0.11 mmol), and N-ethyl-N,N-diisopropylamine (0.25 mL) in anhydrous acetonitrile (2 mL) was added EDCI (34 mg, 0.18 mmol) at RT under argon. After the mixture was stirred at RT for 10 min, 5-(naphthalen-1-yl)-1H-1,2,4-triazol-3-amine (22 mg, 0.1 mmol) was added. The reaction mixture was stirred at RT overnight and at 80° C. for 1 h. After the solvents were removed, the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with methylene chloride. The combined organic solutions were dried (Na2SO4), concentrated and purified by silica gel chromatography to give 33 mg (94% yield) of the title compound as a white solid. (M+H)+=502.26.
Reaction SMILES: [CH3:1][C:2]1[CH:34]=[C:33]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[CH:32]=[C:31]([CH3:41])[C:3]=1[O:4][C:5]1[C:6]2[N:29]([CH3:30])[CH:28]=[CH:27][C:7]=2[N:8]=[C:9]([N:11]([C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)C(=O)OC(C)(C)C)[N:10]=1>C(O)(C(F)(F)F)=O>[CH3:1][C:2]1[CH:34]=[C:33]([C:35]2[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=2)[CH:32]=[C:31]([CH3:41])[C:3]=1[O:4][C:5]1[C:6]2[N:29]([CH3:30])[CH:28]=[CH:27][C:7]=2[N:8]=[C:9]([NH:11][C:19]2[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[CH:23][CH:24]=2)[N:10]=1
Reactant: Cc1cc(-c2ccncc2)cc(C)c1Oc1nc(N(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)nc2ccn(C)c12
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccncc2)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2ccn(C)c12
Yield: 100 %

Procedure:
tert-Butyl 4-(2,6-dimethyl-4-(pyridin-4-yl)phenoxy)-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-2-yl-4-cyanophenylcarbamate was treated with TFA (10 mL) at 25° C. for 2 h. TFA was evaporated, the obtained residue dissolved in EtOAc, and extracted with saturated aqueous NaHCO3 (×2). The organic layer was collected, concentrated, and the product purified by chromatography (SiO2, 1:4 hexanes/EtOAc) to give the title compound as a solid (277 mg, 100%). 1H NMR (400 MHz, CDCl3-CD3OD (5:1), 25° C.) δ 8.67 (bs, 2H), 7.63 (m, 3H), 7.50 (s, 2H), 7.43 (d, J=8.8 Hz, 2H), 7.32 (d, J=3.0 Hz, 1H), 7.26 (d, J=8.7 Hz, 2H), 6.43 (d, J=2.9 Hz, 1H), 4.16 (s, 3H), 2.27 (s, 6H).
Reaction SMILES: O=S1(=O)[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([CH:14]([CH3:16])[CH3:15])[CH2:4]O1.[F-:18].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:7]([NH:6][C@@H:5]([CH:14]([CH3:16])[CH3:15])[CH2:4][F:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)[C@H]1COS(=O)(=O)N1Cc1ccccc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CC(C)[C@@H](CF)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To an ice-cooled solution of (4S)-2,2-dioxo-3-benzyl-4-isopropyl-1,2,3-oxathiazolidine (1.9 g, 7.44 mmol) in THF (30 mL) was added a 1.0 M THF solution of tetrabutylammonium fluoride (14.88 mL, 14.88 mmol). The mixture was stirred for 1 h as ice bath melted and the reaction was gradually warmed to room temperature, then stirred overnight. The mixture was concentrated, and the remaining residue was treated with ether (25 mL) and 20% vol/vol aqueous sulfuric acid (25 mL). The reaction was stirred for 2 h at room temperature. The mixture was neutralized with 2 M NaOH (ca. 50 mL) and the layers were separated. The aqueous layer was extracted with ether (25 mL). The combined organic extracts were dried (MgSO4), filtered, then concentrated under vacuum to give the title compound (1.4 g) as a colorless oil. LCMS m/z=196.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 0.95 (d, J=6.8 Hz, 3H), 0.97 (d, J=6.8 Hz, 3H), 1.88 (oct, J=6.8 Hz, 1H), 2.57-2.66 (m, 1H), 3.80 (d, J=13.4 Hz, 1H), 3.88 (d, J=13.4 Hz, 1H), 4.34-4.59 (m, 2H), 7.22-7.36 (m, 5H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20](=[O:23])(=[O:22])[NH2:21])=[CH:16][CH:15]=2)[C:11]#N)=[CH:6][CH:5]=1)[CH3:2].O=[CH:25][C:26](=C)[CH3:27]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20](=[O:23])(=[O:22])[NH2:21])=[CH:16][CH:15]=3)[CH:25]=[C:26]([CH3:27])[CH:11]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1
Reactant: C=C(C)C=O
Product: CCOc1ccc(-c2cc(C)cn2-c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(4-ethoxyphenyl)-α-(4-sulfamoylanilino)acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as a brown powder (yield 3%), melting at 135-139° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@@H:13]([C:24]([O:26]CC)=[O:25])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[C@@H:13]([C:24]([OH:26])=[O:25])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@@H]1C(=O)O
Yield: 91.9 %

Procedure:
To a solution of ethyl (2R)-4-benzyloxycarbonyl-1-tert-butoxycarbonyl-2-piperazinecarboxylate (15.0 g) in dioxane (100 ml) was added 1N NaOH (76.4 ml) at ambient temperature for 4 hours, the reaction mixture was concentrated in vacuo to remove dioxane. The resulting solution was acidified with 3N HCl to be pH2 and extracted with AcOEt (300 ml). The organic layer was washed with saturated NaCl solution, dried over MgSO4 and evaporated in vacuo to give 12.8 g of (2R)-4-benzyloxycarbonyl-1-tert-butoxycarbonyl-2-piperazinecarboxylic acid as an amorphous powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[F:24][C:25]1[C:26]([O:35][CH3:36])=[CH:27][C:28]([CH3:34])=[C:29](B(O)O)[CH:30]=1>>[F:24][C:25]1[C:26]([O:35][CH3:36])=[CH:27][C:28]([CH3:34])=[C:29]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:16][C@@H:5]34)[CH:10]=2)[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: COc1cc(C)c(B(O)O)cc1F
Product: COc1cc(C)c(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CC3)cc1F

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl (6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and corresponding 5-fluoro-4-methoxy-2-methylphenyl boronic acid (184 mg, 1.0 mmol) to afford after chromatographic purification the title compound (130 mg, 60%). 1H NMR (CDCl3, 300 MHz) δ6.94 (d, 1H, J=12.5 Hz), 6.84 (s, 1H), 6.79-6.82 (m, 2H), 4.02-4.22 (m, 1H), 3.90 (s, 3H), 3.82-3.92 (m, 1H), 3.64-3.74 (m, 1H), 3.24-3.54 (m, 4H), 2.86-3.22 (m, 3H), 2.22 (s, 3H), 1.82-1.94 (m, 2H), 1.48 (s, 9H) ppm. MS-ApCI: 439 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([Cl:23])[C:5]2[O:6][C:7]3[C:16]([CH3:17])=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:8]=3[S:9](=[O:12])(=[O:11])[CH2:10][C:4]=2[CH:3]=1.[CH3:24][O-].[Na+].C=O.[BH4-].[Na+].[OH-].[K+]>CO>[Cl:23][C:21]1[C:5]2[O:6][C:7]3[C:16]([CH3:17])=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:8]=3[S:9](=[O:11])(=[O:12])[CH2:10][C:4]=2[CH:3]=[C:2]([NH:1][CH3:24])[CH:22]=1
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N)cc1CS2(=O)=O
Reactant: C[O-]
Agent: C=O
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: CNc1cc(Cl)c2c(c1)CS(=O)(=O)c1cc(C(=O)O)cc(C)c1O2
Temperature: 25 °C
Reaction time: 5 h
Yield: 38.46 %

Procedure:
Methyl ester of Example 35j (0.5 g, 1.36 mmol) was added to solution of sodium methoxide [Na (0.156 g, 6.78 mmol) in methanol (6 mL)], which in turn was added to a solution of paraformaldehyde (0.057 g, 1.90 mmol) in MeOH (5 mL). The reaction mixture was stirred for 5 h at room temperature, treated with sodium borohydride (0.051 g, 1.36 mmol), refluxed for 1 h, cooled, treated with 1M aqueous KOH (1.5 mL) and stirred for 15 mins. It was extracted with ethyl acetate and the aqueous portion was neutralized to pH 5 with 10% aqueous HCl to obtain the title compound (J. Chem. Soc. Chem. Commun, 1334, (1984)). Yield: 38.46%; 1H NMR (DMSO-d6): δ 2.60 (s, 3H, N—CH3), 2.70 (s, 3H, CH3), 5.10 (s, 2H, CH2), 6.30 (d, 1H, NH), 6.65 (d, 1H, Ar), 7.50 (d, 1H, Ar), 8.08 (s, 1H, Ar), 8.20 (s, 1H, Ar); MS: m/e (EI+) 367 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[CH3:10][NH:11][C:12]([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:10][N:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8][C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: CNC(C)(C)C
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(Cc1ccc(Cl)nc1)C(C)(C)C
Temperature: 80 °C
Yield: 56.1 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (570 mg, 3.52 mmole) in 7 mL of dry acetonitrile is 608 mg (7.04 mmol) of N-methyl-t-butylamine followed by 486 mg (3.52 mmol) of potassium carbonate. The reaction is heated at 80° C. for 12 h. After cooling, the reaction mixture is quenched with 5 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 420 mg (56% yield) of N-methyl-tert-Butyl-(6-chloro-pyridin-3-ylmethyl)-amine. Diagnostic 1H NMR (400 MHz, CDCl3) 1.14 (s, 9H), 2.06 (s, 3H), 3.48 (s, 2H), 7.26 (d, 1H, J=6.2 Hz), 7.68 (d, 1 h, J=6.6 Hz), 8.28 (d, 1H, J=2.5 Hz); MS 213.3 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=O.S(Cl)([Cl:13])=O>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([Cl:13])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccncc1Br
Product: O=C(Cl)c1ccncc1Br

Procedure:
3-Bromopyridine-4-carboxylic acid (5.0 g) was dissolved in thionyl chloride (50 ml) and the solution heated under reflux for 4 hours, cooled and evaporated in vacuo. Re-evaporation of added toluene gave 3-bromopyridine4-carbonyl chloride, m.p.151°-154° C. (dec.) (5.45 g) as a green solid.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[N:7][C:6]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:10]=2)=[N:5][C:4]=1O)[CH3:2].P(Cl)(Cl)(Cl)=O.[NH3:32]>C(#N)C>[CH2:1]([C:3]1[N:8]=[N:7][C:6]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:10]=2)=[N:5][C:4]=1[NH2:32])[CH3:2]
Reactant: CCc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1O
Reactant: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.800 g (5.138 mmol) of 6-ethyl-3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-1,2,4-triazin-5-ol were admixed with 25 ml of phosphoryl chloride and stirred overnight at RT. The reaction mixture was diluted with 100 ml of dry acetonitrile and, with ice-cooling, stirred into 375 ml of concentrated aqueous ammonia solution (25% strength). Stirring was carried out for 4 h at RT. Concentration on a rotary evaporator was carried out and the residue was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulphate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.1% TFA, gradient 30:70→95:5). This gave 157 mg (8% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([C:25](O)=[O:26])[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:43]([NH2:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1.C(OCC)(=O)C>[CH2:43]([NH:50][C:25](=[O:26])[C@@H:4]([CH2:3][O:2][CH3:1])[NH:5][C:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: NCc1ccccc1
Reactant: COC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of Example 2 product (i.e., O-methyl-N-trityl-D-serine, 50 g) in tetrahydrofuran (500 ml), N-methyl morpholine (20.9 g) was added at −15° C. in 5-10 minutes. The reaction mixture was stirred for 15 minutes and then isobutylchloroformate (18.8 g) diluted with tetrahydrofuran was added to it at −15° C. under nitrogen atmosphere in 15-20 minutes. The solution was stirred for 15 minutes and benzyl amine (14.7 g) was added to it at −15° C. in 15 minutes. The solution was allowed to cool to room temperature and stirred for 2 hours. The solvent was recovered from the solution. Dichloromethane (250 ml) was added to the crude product and stirred for 5 minutes to dissolve. The dichloromethane layer was washed or stirred for 5 minutes with water (250 ml). The layers were separated and the dichloromethane layer was again washed with 5% NaHCO3 (250 ml). The layers were separated and then the dichloromethane layer was sequentially washed with 5% citric acid solution (250 ml) and then with water (250 ml). The solvent was recovered at 40° C. to 45° C. to get oil. Ethyl acetate was added to the oil and the mixture was heated to 60° C. to 65° C. to dissolve. The clear solution so formed was cooled up to room temperature and then hexanes (350 ml) were added to it. It was stirred for 1 hour at room temperature, filtered and then dried to get compound of Formula Va. Yield=30 gm.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[NH:13]C(=O)C.[ClH:17]>>[ClH:17].[ClH:17].[ClH:17].[NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[NH2:13]
Reactant: CC(=O)Nc1cc(N)ccc1OCCCN
Agent: Cl
Product: NCCCOc1ccc(N)cc1N

Procedure:
0.00806 mol (1.8 g) of 2-acetylamino-4-aminophenyl γ-aminopropyl ether is heated in 4.5 cm3 of concentrated hydrochloric acid for one hour on a boiling waterbath. On cooling, the expected product precipitates. After being filtered off, washed with ethyl ether and dried in vacuo over KOH, it melts at 260° C. with decomposition. A potentiometric determination is carried out in water by means of N/10 NaOH and the following result is obtained:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:10]=[CH:9][C:6]([O:7]C)=[CH:5][CH:4]=1.[BrH:11]>C(O)(=O)C>[BrH:11].[CH3:1][NH:2][C:3]1[CH:10]=[CH:9][C:6]([OH:7])=[CH:5][CH:4]=1
Reactant: CNc1ccc(OC)cc1
Agent: Br
Solvent: CC(=O)O
Product: CNc1ccc(O)cc1
Temperature: 110 °C
Yield: 99 %

Procedure:
A solution of 30 g (219 mmol) N-methyl-p-anisidine was dissolved in 250 ml 62% aqueous HBr and 435 ml acetic acid. The reaction mixture was heated to 110° C. for 8 h, cooled and evaporated to yield 44.1 g (99%) of 4-Methylamino-phenol hydrobromide (1:1) as a brown solid, MS: 124 (MH+).