Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1.[CH2:32]([NH:34][CH2:35][CH2:36][CH3:37])[CH3:33]>>[CH2:32]([N:34]([CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1)[CH2:35][CH2:36][CH3:37])[CH3:33]
Reactant: CCCNCC
Reactant: CCOC(=O)c1c(CBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Product: CCCN(CC)Cc1nc2cc(OC)c(OC)cc2c(-c2ccc(OC)c(OC)c2)c1C(=O)OCC

Procedure:
According to the same manner as that described in Example 29, ethyl 2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate was reacted with N-ethyl-N-propylamine to give ethyl 2-(N-ethyl-N-propylaminomethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate. Colorless prisms, mp. 105°-106° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.O.[C:12]1(=[O:17])[CH2:16][CH2:15][CH:14]=[CH:13]1.CCN(CC)CC>O1CCOCC1.[B-](F)(F)(F)F.C1C2C=CC1C=C2.C1C2C=CC1C=C2.[Rh]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:14]2[CH2:15][CH2:16][C:12](=[O:17])[CH2:13]2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: O=C1C=CCC1
Agent: [Rh]
Agent: C1=CC2C=CC1C2
Agent: F[B-](F)(F)F
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C1CC[C@H](c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
A solution of 4-bromophenylboronic acid (20 g, 100 mmol) in 1,4-dioxane (120 mL) in a 500 ml flask was purged with nitrogen for 5 mins S-BINAP (0.992 g, 1.593 mmol) and bis(norbornadiene)rhodium (I) tetrafluoroborate (0.559 g, 1.494 mmol) were added sequentially to the solution under a positive pressure of nitrogen. After 2 hours of agitation at room temperature, water (20 mL) was added followed by cyclopent-2-enone (8.06 mL, 100 mmol) and Et3N (13.88 mL, 100 mmol). The mixture was allowed to stir at room temperature for 16 hours. The resulting dark solids were removed by filtration and the filtrate was poured into 250 ml of ethyl acetate. The solution was washed with water twice and the organic layer was concentrated. The residue was purified by flash column chromatography (split into two batches, each run on a 330 g silica column 0%-25% ethyl acetate in hexane) to afford 12.1 grams of (S)-3-(4-bromophenyl)cyclopentanone. HPLC purity was >98% and Chiral HPLC analysis indicated approximately 90% ee. The material was further purified under the Chiral SFC conditions described below. Experimental Details: Instrument: Berger SFC MGIII; Preparative Conditions Column: CHIRALPAK® AD-H 25×5 cm, 5 μm; Column Temperature: 40° C.; Flow rate: 200 mL/min; Mobile Phase: CO2/MeOH=80/20; Detector Wavelength: 225 nm; Injection Vol.: 1.0 mL; Sample Preparation: 12.1 g in; 210 mL MeOH (Conc. 60 mg/ml); Analytical Conditions: Column: CHIRALPAK® AD 25×0.46 cm, 10 μm; Column Temperature: 40° C.; Flow rate: 2.0 min; Mobile Phase: CO2/MeOH=70/30; Detector Wavelength: 220 nm; Injection Vol.: 5 μL.
Reaction SMILES: [CH:1]([Si:4]([C:11]#[CH:12])([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(N(CC)CC)C.O=O.[Br:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1>O1CCCC1.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:12]#[C:11][Si:4]([CH:5]([CH3:6])[CH3:7])([CH:1]([CH3:3])[CH3:2])[CH:8]([CH3:10])[CH3:9])=[CH:25][CH:24]=1
Reactant: Brc1ccc(I)cc1
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: O=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)[Si](C#Cc1ccc(Br)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
11.6 mL triisopropylsilylacetylen and 14.4 mL triethylamine followed by 0.2 g copper iodide and 0.73 g bis-(triphenylphosphine)-palladium dichloride are added under argon to an oxygen-free solution of 15.0 g 4-bromo-1-iodo-benzene in 150 mL dry tetrahydrofuran. The solution is stirred for 16 h at ambient temperature and then filtered through Celite and evaporated down. The residue is purified by chromatography on silica gel (cyclohexane).
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[CH:7][C:5]([NH2:6])=[C:4]([F:17])[CH:3]=1.Cl[C:19]([O:21][CH3:22])=[O:20].CN(C)C1C=CC=CC=1.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([F:17])[C:5]([NH:6][C:19]([O:21][CH3:22])=[O:20])=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16]
Reactant: COC(=O)Cl
Reactant: Nc1cc(Oc2ccccc2O)c(Cl)cc1F
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)Nc1cc(Oc2ccccc2O)c(Cl)cc1F
Temperature: 25 °C

Procedure:
Into a mixture of 4-chloro-2-fluoro-5-(2-hydroxyphenoxy)aniline [Intermediate Compound A3-4], methyl chloroformate and tetrahydrofuran is added dropwise N,N-dimethylaniline, and the mixture is stirred at room temperature. Dilute hydrochloric acid is added to the reaction solution, and this is extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated to obtain 2-(2-chloro-4-fluoro-5-methoxycarbonylaminophenoxy)phenol [Intermediate compound A9-4].
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].C(N(C(C)C)CC)(C)C.[CH2:23]([O:25][C@@H:26]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([NH:44][CH3:45])[N:39]=2)=[CH:34][CH:33]=1)[C:27]([O:29][CH3:30])=[O:28])[CH3:24].O>ClCCl>[CH2:23]([O:25][C@@H:26]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([N:44]([CH3:45])[C:2]([O:4][C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)=[O:3])[N:39]=2)=[CH:34][CH:33]=1)[C:27]([O:29][CH3:30])=[O:28])[CH3:24]
Reactant: CCO[C@@H](Cc1ccc(-c2cccc(NC)n2)cc1)C(=O)OC
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCO[C@@H](Cc1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)n2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 123.8 %

Procedure:
0.96 g (4.8 mmol) of 4-nitrophenyl chloroformate and then 0.85 ml (4.8 mmol) of diisopropylethylamine are added to a solution of 1 g (3.2 mmol) of methyl 2(S)-ethoxy-3-[4-(6-methylaminopyrid-2-yl)phenyl]propanoate in 25 ml of dichloromethane. The reaction medium is stirred at room temperature for 1 hour 30 minutes. After addition of water and extraction with dichloromethane, the organic phase is dried over magnesium sulfate, filtered and evaporated. 1.9 g (100%) of methyl 2(S)-ethoxy-3-(4-{6-[methyl-(4-nitrophenoxycarbonyl)amino]pyrid-2-yl}phenyl)propanoate are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Br:11]Br>C(OCC)C>[Br:11][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(F)cc1
Reactant: BrBr
Solvent: CCOCC
Product: O=C(CBr)c1ccc(F)cc1
Yield: 79 %

Procedure:
In 25 ml of diethyl ether was dissolved 5.00 g (36.2 mmol) of p-fluoroacetophenone and while stirring the solution on an ice bath, 5.8 g (36.2 mmol) of bromine was dropped. After dropping, the mixture was stirred for 5 minutes and then the solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform 100%). The results of NMR measurement revealed that it contained the target compound, and in addition, the raw materials and a dibromo form as a side product. Yield after adjustment was 6.21 g and % yield was 79.0%.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[OH:13].[CH:20]1([CH3:32])[CH2:25][CH2:24][CH:23]([CH:26]([CH3:28])[CH3:27])[CH:22]([C:29](Cl)=[O:30])[CH2:21]1.Cl>C(Cl)Cl>[OH:13][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][NH:10][C:29]([CH:22]1[CH2:21][CH:20]([CH3:32])[CH2:25][CH2:24][CH:23]1[CH:26]([CH3:28])[CH3:27])=[O:30]
Reactant: CC1CCC(C(C)C)C(C(=O)Cl)C1
Reactant: NCC(O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCC(C(C)C)C(C(=O)NCC(O)c2ccccc2)C1
Temperature: 0 °C
Yield: 84.9 %

Procedure:
A 500 mL round bottom flask equipped with stir bar was charged with CH2Cl2 (200 mL), DIEA (28 g, 0.219 mol), and 2-Amino-1-phenyl-ethanol (10 g, 0.073 mol) and cooled to 0° C. Menthoyl chloride (14.8 g, 0.073 mol) was added drop wise over a 15 min period. Once the addition was complete the reaction was allowed to warm to ambient temperature and stirred 2 h. CH2Cl2 (100 mL) and 1N HCl (100 mL) was added to the reaction mixture and stirred for an additional 20 min. The heterogeneous mixture was transferred to a separatory funnel where the aqueous phase was separated and re-extracted with CH2Cl2 (2×100 mL). The organic phases were combined and washed with 1N HCl (8×100 mL), H2O (1×100 mL), 1N NaOH (2×100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was eluted through a plug of silica gel (50% ethyl acetate/hexane for elution) provided the title compounds as colorless solid (18.8 g, 85%).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[Se:10][C:6]=2[N:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[O:17][C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][C:20]=1[C:21]#[N:22].[OH-].[Na+]>CN(C=O)C>[C:23]1([C:18]2[O:17][C:16]([NH:15][C:2]3[C:7]4[C:8]5[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=5[Se:10][C:6]=4[N:5]=[CH:4][N:3]=3)=[C:20]([C:21]#[N:22])[CH:19]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Clc1ncnc2[se]c3c(c12)CCCC3
Reactant: N#Cc1cc(-c2ccccc2)oc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ccccc2)oc1Nc1ncnc2[se]c3c(c12)CCCC3
Yield: 78 %

Procedure:
To a solution of 4-chloro-5,6,7,8-tetrahydrobenzo[1,2-b]pyrimidino[5,4-d]selenophene (250 mg, 0.917 mmol, from step b of example 1) in DMF (10 mL) was added sequentially 2-amino-5-phenylfuran-3-carbonitrile (160 mg, 0.917 mmol; Matsuda, T.; Yamagata, K.; Tomioka, Y.; Yamazaki, M. Chem. Pharm. Bull., 1985, 33, 937-943) and powdered NaOH (110 mg, 2.751 mmol) at rt. Work-up as described in example 2, gave the product as a yellow color solid (300 mg, 78%), mp 252-256° C. (decomp). 1H NMR (400 MHz, CDCl3): δ 9.82 (1H, s, H-2), 7.78-7.81 (2H, m, Ph), 7.41-7.45 (2H, m, Ph), 7.31-7.35 (1H, m, Ph), 7.16 (1H, br s, exchangeable with D2O, —NH), 7.01 (1H, s, H-4′), 3.35 (2H, br s, H-8), 2.98 (2H, br s, H-5), 1.93-1.95 (4H, m, H-6,7); 13C NMR (100 MHz, CDCl3): δ 162.3, 158.6, 153.7, 151.9, 145.3, 143.3, 137.0, 133.9, 129.5, 128.9, 128.4, 126.1, 124.3, 102.7, 100.1, 29.1, 28.4, 23.1, 22.5; LC-MS (positive ion mode): m/z 419, 421 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([O-:9])=O)[N:6]=1.[Na+].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:33][C@H:34]([CH:53]([CH3:55])[CH3:54])[C:35]([N:37]1[CH2:42][CH2:41][C@@:40]([C:44]2[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=2)([OH:43])[C:39]([CH3:52])([CH3:51])[CH2:38]1)=[O:36]>CN(C=O)C>[NH2:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([NH:33][C@H:34]([CH:53]([CH3:55])[CH3:54])[C:35]([N:37]2[CH2:42][CH2:41][C@@:40]([C:44]3[CH:45]=[CH:46][C:47]([Cl:50])=[CH:48][CH:49]=3)([OH:43])[C:39]([CH3:51])([CH3:52])[CH2:38]2)=[O:36])=[O:9])[N:6]=1
Reactant: CC(C)[C@@H](N)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Reactant: Nc1nc(C(=O)[O-])co1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)[C@@H](NC(=O)c1coc(N)n1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
Sodium 2-aminooxazole-4-carboxylate (75 mg, 0.500 mmol), HOBt (67.5 mg, 0.500 mmol) and EDCI (96 mg, 0.500 mmol) were dissolved in DMF (0.5 mL). The mixture was stirred at rt for 0.5 h, then was added (R)-2-amino-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methylbutan-1-one hydrochloride (188 mg, 0.500 mmol) and further stirred for 2 h. The reaction was quenched with water and stirred at rt for 2 h. The solids were filtered and rinsed with water to give 2-amino-N—((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)oxazole-4-carboxamide (169 mg, 0.376 mmol, 75% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=1[O:26][CH3:27]>CC(C)=O.CCCCCCC>[CH3:27][O:26][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:18]=1[O:17][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH:22]=[O:23]
Reactant: COc1cc(C=O)ccc1O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CC(C)=O
Product: COc1ccc(COc2ccc(C=O)cc2OC)cc1
Temperature: 55 °C
Reaction time: 28 h
Yield: 99 %

Procedure:
5 g (36.1 mmol) of potassium carbonate and then 4.9 ml (36.1 mmol) of 1-chloromethyl-4-methoxy-benzene are added to a solution of 5 g (33 mmol) of 4-hydroxy-3-methoxy-benzaldehyde in 100 ml of acetone. The reaction mixture is then stirred at 55° C. for 28 hours and then filtered. The filtrate is concentrated under vacuum. The residue obtained is taken up in heptane and filtered. 8.9 g (100%) of 3-methoxy-4-(4-methoxy-benzyloxy)-benzaldehyde is obtained in the form of a beige solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[N:5][C:6]2[C:7](=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=2)[N:8]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[N:15]1([CH2:2][C:3]2[N:4]=[N:5][C:6]3[C:7](=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=3)[N:8]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: Nc1nc(N)c2nc(CCl)nnc2n1
Reactant: C1COCCN1
Product: Nc1nc(N)c2nc(CN3CCOCC3)nnc2n1
Temperature: 80 °C

Procedure:
A mixture of 3-Chloromethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine 3 (200 mg; 0.95 mmol) and 2.0 mL of morpholine were heated to 80° C. in a sealed tube for 7 h. The mixture was then allowed to cool to room temperature and concentrated in vacuo. The crude product was purified by reverse phase HPLC (Rainin C18, 0% CH3CN to 30% CH3CN gradient, CH3CN/H2O, 0.1% TFA) and the bright yellow fractions containing the product were lyophilized after removal of CH3CN in vacuo to give 261 mg of yellow colored 3-Morpholin-4-ylmethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine as the trifluoroacetate salt.
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1>[O-2].[O-2].[O-2].[Cr+6].C(Cl)Cl>[CH:8]([CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)=[O:7]
Reactant: O=C1CCC=C1CCO
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=CCC1=CCCC1=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Chromium trioxide (0.6 mol) is added to a stirring solution of (1.2 mol) of anhydrous pyridine in 1500 ml. of anhydrous methylene chloride cooled in an ice bath. The deep red suspension is stirred for 15 minutes at 0° C. and 45 minutes at ambient temperature. A solution of 01.5 mol of 2-(2-hydroxyethyl)-cyclopent-2-en-1-one (Example 897) in 50 ml. of methylene chloride is added, all at once, to the suspension. A black tarry deposit is formed immediately. After stirring the mixture for 25 minutes at ambient temperature, the methylene chloride is decanted from the tarry precipitate which is then triturated several times with ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)=[CH:5][CH:4]=1>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ccc([N+](=O)[O-])cc2)c2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2ccc(N)cc2)c2ccccc12

Procedure:
The nitro intermediate (10 mmol) obtained above was dissolved in EtOAc (50 mL) and hydrogenated in the presence of 10% Pd/C (360 mg) until completion according to General Procedure H, as indicated by TLC or HPLC. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-(4-methoxy-naphthalen-1-yloxy)aniline, which was used directly for further transformation without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:10]([OH:19])[CH2:11][S:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:29]>ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:10]([OH:19])[CH2:11][S:12]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CC(NC(=O)OC(C)(C)C)C(O)CSC1CCCCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)CC(NC(=O)OC(C)(C)C)C(O)CS(=O)C1CCCCC1

Procedure:
Treating the resultant compound of Example 3 with 1.05 equivalents of 3-chloroperoxybenzoic acid in dichloromethane, gave the desired compound after chromatography. Mass spectrum: M+ =361.
Reaction SMILES: O[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)([CH3:5])[C:3]#[N:4].C(N(S(F)(F)[F:21])CC)C>C(Cl)Cl>[F:21][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)([CH3:5])[C:3]#[N:4]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(O)(C#N)c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Product: CC(F)(C#N)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a cooled solution (T=−60° C.) of 2-hydroxy-2-(3-nitrophenyl)propanenitrile (1.11 g, 5.8 mmol) in dry CH2Cl2 (60 ml), (diethylamino)sulfur trifluoride (0.8 mL, 6.0 mmol) was added under vigorous stirring. The resulting reaction mixture was left stirring at room temperature overnight. The reaction mixture was diluted with a buffer solution (pH=5.0) (10 ml), trasferred into a separator funnel and the two phases were debated and separated. The aqueous one was extracted with water (3×10 mL); the collected organic extracts were dried over Na2SO4 and evaporated under vacuum to give a crude which was purified by flash chromatography to afford pure 2-fluoro-2-(3-nitrophenyl)propanenitrile (0.9 g, yield 79%) as brown oil. 1H-NMR (CDCl3) δ 8.52 (s, 1H), 8.45 (d, 1H, J=3 Hz), 7.90 (m, 1H), 7.70 (t, 1H, J=7 Hz), 2.12 (d, 3H, J=23 Hz).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:19]=2)=[CH:16][C:15]([C@H:44]([N:46]2[CH2:51][CH2:50][N:49]([S:52]([CH3:55])(=[O:54])=[O:53])[CH2:48][CH2:47]2)[CH3:45])=[CH:14][N:13]=1.[F:56][C:57]1[CH:58]=[C:59]([NH2:65])[CH:60]=[N:61][C:62]=1[O:63][CH3:64]>C1COCC1>[F:56][C:57]1[CH:58]=[C:59]([NH:65][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=4)[CH2:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[N:19]=3)=[CH:16][C:15]([C@H:44]([N:46]3[CH2:47][CH2:48][N:49]([S:52]([CH3:55])(=[O:53])=[O:54])[CH2:50][CH2:51]3)[CH3:45])=[CH:14][N:13]=2)[CH:60]=[N:61][C:62]=1[O:63][CH3:64]
Reactant: COc1ncc(N)cc1F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.0 M in hexane; 31.9 mL, 31.9 mmol) was added (dropwise over 10 min) to a mixture of (R)-4-(2-fluoro-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 146, Step 6; 6.75 g, 10.62 mmol) and 5-fluoro-6-methoxypyridin-3-amine (Anichem, North Brunswick, N.J.; 2.264 g, 15.93 mmol) in THF (100 mL) at 0° C., and the resulting solution was stirred at 0° C. for 1 h. Excess LiHMDS was then quenched with saturated aqueous NH4Cl (140 mL) and the reaction mixture was partitioned between EtOAc (500 mL) and half-saturated aqueous NH4Cl (200 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×200 mL). The combined organic extracts were sequentially washed with brine (300 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 100% EtOAc/hexanes) furnished (R)-4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (7.25 g, 90% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 11.88 (1H, s), 8.72 (1H, d, J=2.0 Hz), 8.25 (1H, d, J=2.2 Hz), 8.06 (1H, dd, J=12.3, 1.6 Hz), 7.96 (1H, d, J=2.0 Hz), 7.21 (4H, t, J=8.2 Hz), 6.86 (4H, dd, J=14.1, 8.4 Hz), 4.70-4.96 (4H, m), 4.01 (3H, s), 3.81 (3H, s), 3.78 (3H, s), 3.55 (1H, q, J=6.7 Hz), 3.15 (4H, br s), 2.68 (3H, s), 2.59 (3H, s), 2.48-2.57 (4H, m), 1.38 (3H, d, J=6.7 Hz). 19F NMR (376 MHz, CDCl3) δ −139.13 (1F, d, J=13.0 Hz). m/z (ESI, +ve) 758.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]2[O:23][C:22]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][N:31](C)[C:32](=O)OC(C)(C)C)=[CH:26][CH:25]=3)=[N:21][N:20]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([C:17]#[N:18])([CH3:16])[CH3:15])[CH:9]=2)=[CH:6][N:7]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([CH3:16])([CH3:15])[C:17]#[N:18])[CH:9]=2)=[N:4][C:3]=1[C:19]1[O:23][C:22]([C:24]2[CH:25]=[CH:26][C:27]([CH2:30][NH:31][CH3:32])=[CH:28][CH:29]=2)=[N:21][N:20]=1
Reactant: CN(Cc1ccc(-c2nnc(-c3nc(-c4ccnc(C(C)(C)C#N)c4)cnc3N)o2)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1ccc(-c2nnc(-c3nc(-c4ccnc(C(C)(C)C#N)c4)cnc3N)o2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.32 %

Procedure:
tert-butyl N-[[4-[5-[3-amino-6-[2-(1-cyano-1-methyl-ethyl)-4-pyridyl]pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (199.3 mg, 0.3785 mmol) was dissolved in dichloromethane (5 mL) followed by the addition of trifluoroacetic acid (500 μL, excess). The mixture was stirred at ambient temperature for 2 hours and then concentrated in vacuo to an oil. Azeotroped with dichloromethane/methanol. Compound was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% trifluoroacetic acid in water; solvent B: acetonitrile) over 16 minutes at 25 mL/minutes], combined fractions were then freeze-dried to give 2-[4-[5-amino-6-[5-[4-(methylaminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-2-pyridyl]-2-methyl-propanenitrile Compound I-4 as a pale yellow powder (mono trifluoroacetic acid salt) (88.6 mg, 43.32% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 1.80 (s, 6H), 2.64 (t, J=5.0 Hz, 3H), 4.28 (t, J=5.4 Hz, 2H), 7.76 (d, J=8.3 Hz, 2H), 8.12 (dd, J=1.5, 5.3 Hz, 1H), 8.25 (d, J=8.3 Hz, 2H), 8.41 (s, 1H), 8.73 (d, J=5.2 Hz, 1H), 8.91 (s, 2H) and 9.18 (s, 1H) ppm; LC/MS m/z 427.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]CC)=[O:8])[CH3:2].[OH-].[Na+]>O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[CH3:2]
Reactant: CCOCCCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOCCCC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.7 %

Procedure:
To an ice cold stirred solution of ethyl 4-ethoxybutanoate (30) (˜1 g) in 10 mL of tetrahydrofuran (THF) was added aqueous NaOH solution (0.62 g in 7 ml of H2O) and stirred at room temperature for 12 h, while monitoring the reaction by TLC. Most of the solvent was evaporated under reduced pressure and the residue was diluted with water (10 mL). The aqueous layer was acidified with 1N HCl solution (PH˜2) and then extracted with ethyl acetate (15 mL×3). The combined organic extracts was dried over anhydrous Na2SO4 and concentrated under vacuum to yield 0.6 g (73.14) of 4-ethoxybutanoic acid as light yellow oil. 1HNMR (400 MHz, CDCl3): δ 1.20 (t, J=9.2 Hz, 3H); 1.87-1.95 (m, 2H); 2.47 (t, J=10 Hz; 2H); 3.48 (q, J=9.2 Hz, 4H).