Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([NH:13][C:14]([C:16]1[C:17]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:15])[CH:7]=2)=[O:2].P([O-])(O)(O)=[O:33].[K+].Cl([O-])=O.[Na+].S([O-])([O-])=O.[Na+].[Na+].Cl>C(#N)C>[F:30][C:28]([F:31])([F:29])[C:25]1[CH:24]=[CH:23][C:22]([C:17]2[C:16]([C:14]([NH:13][C:8]3[CH:7]=[C:6]4[C:11]([CH:12]=[C:3]([C:1]([OH:33])=[O:2])[CH:4]=[N:5]4)=[CH:10][CH:9]=3)=[O:15])=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:27][CH:26]=1
Reactant: O=P([O-])(O)O
Reactant: O=Cc1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.6 %

Procedure:
To a solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid (3-formyl-quinolin-7-yl)-amide (7.65 g, 18.2 mmol, 1 equiv) in acetonitrile (100 mL, 15 volumes) was added an aqueous solution of potassium dihydrogen phosphate (1.25 M, 72.8 mL, 91 mmol, 5 equiv), followed by sodium chlorite (6.17 g, 54.6 mmol, 3 equiv). The slurry was stirred at room temperature for 12 hours. An aqueous solution of sodium sulfite (1 M, 75 mL, 75 mmol, 4.1 equiv) was added and the resulting slurry was stirred at room temperature for 15 minutes. 1 N HCl (50 mL) was added to bring the pH to about 3 to 4. The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated to about 75 mL of ethyl acetate. Hexanes (about 75 mL) was added to the slurry and the resulting slurry was allowed to stir at room temperature for 2 hours. The precipitate was collected by filtration to provide 7-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (6.32 g, 80% over two steps) as a yellow powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=O)[CH:16]=2)[O:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:16]=2)[O:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCOc2ccc(C=O)cc21
Reactant: C1CCNCC1
Product: CC(C)(C)OC(=O)NC1CCOc2ccc(CN3CCCCC3)cc21

Procedure:
The reductive amination procedure in Example 1, Step H was used to react (6-formyl-chroman-4-yl)-carbamic acid tert-butyl ester (Step E) with piperidine to provide (6-piperidin-1-ylmethyl-chroman-4-yl)-carbamic acid tert-butyl ester. The Boc group was deprotected with TFA in CH2Cl2 to provide the amine salt. The coupling procedure described in the preparation of Example 1, Step F with 3-(naphthalen-2-yl-sulfonylamino)-3-phenylpropionic acid was used to provide the title compound as a mixture of diastereomers (ca. 1:1 by 1H NMR) isolated as the HCl salt. MS (ESI) 584 (M+H)+.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:6]2[N:5]=1)=O.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.CN1CCCC1=O>CO>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:36][C:33]4[CH:32]=[CH:31][C:30]([N:27]5[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]5)=[CH:35][CH:34]=4)=[N:5]3)=[CH:10][CH:11]=2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CS(=O)c1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Solvent: CO
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5ccc(S(C)(=O)=O)cc5)n4n3)cc2)CC1
Temperature: 150 °C

Procedure:
Into a 30 mL vial, 2-Methanesulfinyl-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (80 mg, 0.0002 mol), 4-(4-Methyl-piperazin-1-yl)-phenylamine (0.100 g, 0.000525 mol) and N-Methylpyrrolidinone (0.25 mL, 0.0026 mol) were added. The reaction mixture was heated at 150° C. for 90 minutes. The reaction was cool to room temperature. Methanol (15 mL) was added. The solid was filtered and washed with hot MeOH (10 mL) to afford [7-(4-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine as a light brown solid. MP 234-238° C. LCMS (E/I+) 373.18 (M+H). NMR 1H (DSMO-d6)-9.31 (s, 1H), 9.00 (s, 1H), 8.48 (d, 2H, J=8.48 Hz), 8.02 (d, 2H, J=8.16 Hz), 7.57 (d, 2H, J=8.79 Hz), 7.33 (d, 1H, J=4.77 Hz), 6.95 (d, 1H, J=4.76 Hz), 6.95-7.04 (m, 3H), 3.28 (s, 3H), 3.09 (bs, 4H), 2.40-2.56 (m, 4H), 2.22 (s, 3H).
Reaction SMILES: [H-].[Na+].[C:3]1([C@@H:9]([N:11]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:12][CH2:13][C:14]([O:16]CC)=O)[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1.O.CCOC(C)=O>[O:16]=[C:14]1[CH2:13][CH2:12][N:11]([C@H:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:10])[CH2:19][C@@H:20]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)CCN(CCC(=O)OCC)[C@@H](C)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CN([C@@H](C)c2ccccc2)CCC1=O
Temperature: 25 °C

Procedure:
A suspension of NaH (2.24 g, 93.4 mmol) in THF (20 mL) was cooled to 0° C. and as solution of (S)-diethyl 3,3′-((1-phenylethyl)azanediyl)dipropanoate (15 g, 46.7 mmol) in THF was then added dropwise. The reaction mixture was allowed to warm to rt and then warmed to 60° C. and heated for 3 h. The mixture was diluted with water and EtOAc and the organic layer was then separated, dried (Na2SO4), filtered and concentrated. The residue was purified by FCC (5-7% EtOAc/hexanes) to give (5)-ethyl 4-oxo-1-((S)-1-phenylethyl)piperidine-3-carboxylate.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:16][OH:17])/[CH:4]=[CH:5]/[P:6](=[O:15])([O:11][CH:12]([CH3:14])[CH3:13])[O:7][CH:8]([CH3:10])[CH3:9].[C:18](OC)(OC)([O:20]C)[CH3:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1.C(N(CC)CC)C>[C:18]([O:17][CH2:16][CH:3]([CH2:2][OH:1])/[CH:4]=[CH:5]/[P:6](=[O:15])([O:7][CH:8]([CH3:10])[CH3:9])[O:11][CH:12]([CH3:13])[CH3:14])(=[O:20])[CH3:19]
Reactant: CC(C)OP(=O)(/C=C/C(CO)CO)OC(C)C
Reactant: COC(C)(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OCC(/C=C/P(=O)(OC(C)C)OC(C)C)CO
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
A solution of diisopropyl (E)-4-hydroxy-3-hydroxymethylbut-1-enylphosphonate (5 g, 19 mmol), trimethyl orthoacetate (7 ml, 56 mmol) and p-toluenesulphonic acid (0.36 g, 1.9 mmol) in anhydrous THF (50 ml) was stirred at room temperature for 1.5 h. The solution was treated with water (5 ml), stirred for a further 30 min, then treated with triethylamine (0.1 ml). The solvent was removed in vacuo and the residue chromatographed on silica, eluting with chloroform-methanol (30:1) to give diisopropyl (E)-3-acetoxymethyl-4-hydroxybut-1-enylphosphonate as an oil (4.94 g, 85%);υmax (film) 3382, 2980, 2934, 2877, 2361, 2333, 1741, 1631, 1468,and 1455 cm-1 ; δH (CDCl3) 1.30 (6H, d, J 6.3 Hz, 2×CH3CH), 1.34 (6H, d, J 6 Hz, 2×CH3CH) 2.06 (3H, s, CH3CO), 2.40 (1H, br.s, D2O exchangeable OH), 3.68 (2H, m, CH2OH), 424 (2H, m, CH2), 4.64 [2H, m, 2×CH(CH3)2 ], 5.83 (1H, ddd, J 1, 17 and 19 Hz, PCH=CH), 6.67 (1H, ddd, J 8, 17 and 22 Hz, PCH=CH) (Found: C, 50.15; H, 8.46%; MH+ 309.1466. C13H17O6P.0.25 H2O requires: C, 49.95; H, 8.22%; MH+ 309.1467).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.C1C(=O)N([Br:20])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:1][O:2][C:3](=[O:12])[CH:4]([Br:20])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(F)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(F)cc1
Yield: 102.1 %

Procedure:
To a solution of methyl-4-fluorphenylacetate (10 g) in carbontetrachloride (80 mL) was added NBS (11.64 g) and AIBN (0.976 g) at RT. The reaction was then heated to reflux for 3 days. The reaction mixture was filtered and the solid washed with further carbontetrachloride. The filtrate was reduced in vacuo and the diluted with water (50 mL) and EtOAc (100 mL). The phases were separated and the aqueous phase was extracted with further EtOAc (100 mL). The combined organic phases were dried over sodium sulphate, filtered and evaporated in vacuo to afford the desired bromo-(4-fluoro-phenyl)-acetic acid methyl ester (15.0 g) as a yellow oil which was taken into the next step without further purification.
Reaction SMILES: [C:1]12([C:12]([O:14]C)=[O:13])[CH2:7][C:4]([C:8]([O:10]C)=[O:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[OH-].[K+].C(O)C.Cl>O>[C:1]12([C:12]([OH:14])=[O:13])[CH2:7][C:4]([C:8]([OH:10])=[O:9])([CH2:3][CH2:2]1)[CH2:5][CH2:6]2
Reactant: COC(=O)C12CCC(C(=O)OC)(CC1)C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C12CCC(C(=O)O)(CC1)C2
Temperature: 60 °C

Procedure:
A mixture of Example 117A (3.18 g, 15.0 mmol), solid potassium hydroxide (8.4 g, 150 mmol), and a mixture of ethanol (75 mL) and water (15 mL) was heated at about 60° C. overnight. After cooling, the pH of the mixture was adjusted to about 1 by addition of 1N aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (4×50 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporator to give a tan powder. The crude product was recrystallized from ethyl acetate/hexanes to give the title compound as a white solid that was used without further purification for the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[N:11]([N:15]=[CH:16][N:17]=2)[C:12](=O)[CH:13]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:12]1[N:11]2[N:15]=[CH:16][N:17]=[C:10]2[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2ccccc2F)[nH]c2ncnn12
Product: Fc1ccccc1-c1cc(Cl)n2ncnc2n1
Yield: 46 %

Procedure:
5-(2-Fluoro-phenyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one (840 mg, 3.64 mmole) was suspended in phosphorous oxychloride (5 ml) and heated to reflux for 45 min. The excess phosphorous oxychloride was removed under vacuum, the residue was treated with ice, the product was extracted with chloroform, then the chloroform was washed with 10% sodium bicarbonate, dried over sodium sulfate and the solvent was removed under vacuum to give 420 mg of product (yield 46%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]([N:19]([CH3:35])[C:20]([NH:22][C:23]2[C:28]([Cl:29])=[C:27]([O:30][CH3:31])[CH:26]=[C:25]([O:32][CH3:33])[C:24]=2[Cl:34])=[O:21])[CH:14]=1.[C:36](Cl)(=[O:39])[CH:37]=[CH2:38]>C1COCC1>[Cl:34][C:24]1[C:25]([O:32][CH3:33])=[CH:26][C:27]([O:30][CH3:31])=[C:28]([Cl:29])[C:23]=1[NH:22][C:20](=[O:21])[N:19]([C:15]1[N:16]=[CH:17][N:18]=[C:13]([NH:12][C:3]2[CH:4]=[CH:5][C:6]([CH2:8][N:9]([CH3:10])[CH3:11])=[CH:7][C:2]=2[NH:1][C:36](=[O:39])[CH:37]=[CH2:38])[CH:14]=1)[CH3:35]
Reactant: C=CC(=O)Cl
Reactant: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccc(CN(C)C)cc3N)ncn2)c1Cl
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cc(CN(C)C)ccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Temperature: -10 °C
Reaction time: 5 h
Yield: 9.5 %

Procedure:
To a stirred solution of 1-[6-(2-amino-4-dimethylaminomethyl-phenylamino)-pyrimidin-4-yl]-3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-methyl-urea (45 g, 0.11 mmol) in THF (40 mL) at −10° C. was added acryloyl chloride (30 g, 0.33 mmol) in THF (3 mL). The solution was stirred at −10° C. for 5 hours. LCMS showed major product peak. The reaction was quenched with MeOH (3 mL) and evaporated. The residue was purified by prep-HPLC (water/ACN in NH4HCO3 condition) to afford the title compound (6 mg, yield: 15%). 1H-NMR (400 MHz, MeOH-d4) δ 8.25 (s, 1H), 7.47 (d, 1H), 7.44 (s, 1H), 7.16 (dd, 1H), 6.70 (s, 1H), 6.33-6.20 (m, 3H), 5.67 (dd, 1H), 3.84 (s, 6H), 3.43 (s, 2H) 3.22 (s, 3H), 2.20 (s, 6H); MS (ESI): 574 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1([C:6]2[C:11]([O:12][CH2:13][O:14][CH3:15])=[CH:10][CH:9]=[CH:8][C:7]=2[OH:16])[CH2:5][CH2:4]1.O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[CH3:15][O:14][CH2:13][O:12][C:11]1[C:6]2[C:3]3([CH2:2][O:16][C:7]=2[CH:8]=[CH:9][CH:10]=1)[CH2:4][CH2:5]3
Reactant: COCOc1cccc(O)c1C1(CO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCOc1cccc2c1C1(CC1)CO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
To a solution of 2-[1-(hydroxymethyl)cyclopropyl]-3-{[(methyloxy)methyl]oxy}phenol (Reference Intermediate 212, 190 mg) in dry tetrahydrofuran (10 ml) triphenylphosphine (333 mg, 1.271 mmol) was added and the reaction mixture was stirred until complete dissolution of PPh3. DIAD (0.198 ml, 1.017 mmol) was then added dropwise and the reaction mixture was stirred for 30 minutes at room temperature The solvent was removed under reduced pressure. The residue was purified by flash chromatography (Biotage system) on silica gel using a 25 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 9:1 as eluents affording the title compound as a light yellow oil (120 mg).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:4].[CH3:18][O:19]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]([F:16])([F:17])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH:18]=[O:19])[CH:9]=1)=[O:4]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(CCNC(=O)C(F)(F)F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)C(F)(F)F)cc1C=O
Temperature: 25 °C
Yield: 87.2 %

Procedure:
The product from step (a) (24.7 g, 0.1 mole) was dissolved in dry dichloromethane (500 ml) and the solution cooled to -15°. A solution of titanium tetrachloride (57.0 g, 21.6 ml, 0.3 mole) in dry dichloromethane (200 ml) was added dropwise with stirring and cooling. To the yellow-orange solution was added -dichloromethyl methyl ether (27.9 g, 22.0 ml, 0.24 mole) in dry dichloromethane (200 ml). The solution was stirred at -15° for 0.5 hr and warmed to room temperature over a period of 2 hr. The reaction mixture was poured onto ice/2N hydrochloric acid (21/500 ml) and stirred vigorously. The dichloromethane layer was separated and the aqueous layer extracted with dichloromethane (2×200 ml). The combined organic extracts were washed with water, dried (Na2SO4) and evaporated. The crude product was recrystallised from 50% aqueous methanol to give an off-white solid (24.0 g) mp 105°-6°.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[NH:5][C:4](=[O:13])[CH:3]=1.[C:14]1([S:20]([CH2:22][CH2:23][CH2:24][CH2:25]Br)=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:25][CH2:24][CH2:23][CH2:22][S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:21])[CH:10]=2)[NH:5][C:4](=[O:13])[CH:3]=1
Reactant: O=S(CCCCBr)c1ccccc1
Reactant: Cc1cc(=O)[nH]c2ccc(O)cc12
Product: Cc1cc(=O)[nH]c2ccc(OCCCCS(=O)c3ccccc3)cc12

Procedure:
Prepared analogous to Example 140 from 4-methyl-6-hydroxy-carbostyril (m.p. 326°-330° C.) and 4-phenylsulfinyl-butyl bromide.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C@@H:15]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][N:16]2C(OC(C)(C)C)=O)=[O:14])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13]([C@@H:15]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][NH:16]2)=[O:14])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCc1ccc(NC(=O)[C@@H]2Cc3ccccc3CN2)cc1
Reaction time: 2.5 h
Yield: 86 %

Procedure:
The product of step 1 was dissolved in methylene chloride (40 mL) and treated with trifluoroacetic acid (20 mL). After stirring for 2.5 hours the reaction was concentrated and the residue was partitioned between methylene chloride and aqueous sodium bicarbonate solution. The organic layer was removed and the aqueous layer was further basified with concentrated ammonium hydroxide (ca., 20 mL) and extracted with additional methylene chloride. The combined organic layers were dried (sodium sulfate) and concentrated. The resulting tacky, golden solid was triturated with diethyl ether and vacuum oven dried to afford 8.34 g (86%) of product as colorless platelets: 1H NMR (CDCl3) δ 9.25 (s, 1H), 7.54-7.48 (m, 2H), 7.26-7.04 (m, 6H), 4.10-3.98 (m, 2H), 3.67 (dd, J=10.4, 5.5 Hz, 1H), 3.35 (dd, J=16.4, 5.5 Hz, 1H), 2.90 (dd, J=16.4, 10.4 Hz, 1H), 2.57 (t, J=7.6 Hz, 2H), 1.64-1.54 (m, 2H), 1.39-1.24 (m, 4H), 0.88 (t, J=6.8 Hz 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:11][C:10]=2[C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:28]=[N:29][NH:30][N:31]=3)=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.[C:32]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.CO.CC#N>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:11][C:10]=2[C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:28]=[N:29][N:30]([CH3:32])[N:31]=3)=[CH:23][CH:22]=2)=[CH:6][CH:7]=1
Reactant: Cn1c(-c2ccccn2)nc(-c2ccc(-c3nn[nH]n3)cc2)c1Sc1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Solvent: CI
Product: Cn1nnc(-c2ccc(-c3nc(-c4ccccn4)n(C)c3Sc3ccc(Cl)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the product of Step 1 in 1.5 mL of DMF was added K2CO3 (85 mg, 0.61 mmol). After stirring at rt for 30 min, MeI (0.05 mL, 0.82 mmol) was added and stirring continued for 1.5 h. The reaction mixture was diluted with MeOH/MeCN, and the precipitate was collected by filtration to give the title compound. 1H NMR (500 MHz, (CDCl3): 8.44 (d, 1H), 8.39 (d, 1H), 8.27 (d, 2H), 8.19 (d, 2H), 7.88 (t, 1H), 7.36 (dd, 1H), 7.26 (d, 2H), 7.07 (d, 2H), 4.42 (s, 3H), 4.15 (s, 3H). LCMS: m/z 460 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]([NH:13][CH2:14][CH:15]([OH:17])[CH3:16])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(#N)C.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]([NH:13][CH2:14][C:15](=[O:17])[CH3:16])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)CNC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: O
Product: CC(=O)CNC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
To a solution of N2-(tert-butoxycarbonyl)-N-(2-hydroxypropyl)-D-alaninamide (13 g, 53 mmol) in acetonitrile (800 ml) and water (320 ml), was added RuCl3 (300 mg, 1.06 mmol) and NaBrO3 (4 g, 26.5 mmol). The resulting mixture was stirred at room temperature overnight. After concentration to remove most of acetonitrile, the residue was departed between water and ethyl acetate. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated to give 8.5 g (65.9%) of N2-(tert-butoxycarbonyl)-N-(2-oxopropyl)-D-alaninamide as solid. 1H-NMR CDCl3 δ 6.86 (br, 1H), 5.08 (br, 1H), 4.13 (s, 2H), 5.09 (s, 2H), 2.19 (s, 3H), 1.43 (s, 9H), 1.37 (s, 3H). ES-MS [M+1]+: 244.90
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:3]=1.CCCCCC.[Li]CCCC.[C:33]1([N:39]=[C:40]=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(OCC)C>[C:33]1([NH:39][C:40]([C:2]2[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:3]=2)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CN(C)c1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Reactant: O=C=Nc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CN(C)c1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)Nc2ccccc2)c1
Reaction time: 0.17 h

Procedure:
0.8 g (0.0022 mol) of 2-bromo-4-dimethylamino-6-{3-(trifluoromethyl)phenoxy} pyridine was dissolved in about 15 ml of diethyl ether. While cooling the solution in a dry ice-acetone bath in an argon atmosphere, 1.5 ml of a 1.6M-hexane solution of BuLi (0.0022×1.1 mol) was added to the solution, followed by stirring the solution for about 10 minutes. After 0.60 g (0.0022×2.3 mol) of phenyl isocyanate dissolved in about 5 ml of diethyl ether was added to the reaction solution, the solution was removed from the bath and stirred at room temperature for about 30 minutes. The reaction solution was mixed with about 5 ml of a 1.2N-aqueous hydrochloric acid solution, and then distributed in ethyl acetate-water, followed by washing with saturated sodium bicarbonate water and saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography (eluting solution: ethyl acetate/hexane) to separate a main fraction therefrom. The fraction was concentrated and then precipitated with hexane, thereby obtaining an aimed product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1Cl.[NH2:10][NH2:11].C([O-])([O-])=O.[Na+].[Na+]>C1(O)CCCCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[NH:10][NH2:11]
Reactant: Fc1cncc(Br)c1Cl
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: OC1CCCCC1
Product: NNc1c(F)cncc1Br

Procedure:
3-bromo-4-chloro-5-fluoro-pyridine (500 mg, 2.376 mmol), hydrazine (761.4 mg, 745.7 μL, 23.76 mmol), Na2CO3 (503.7 mg, 4.752 mmol) in cyclohexanol was heated at 100 C overnight. The reaction mixture was filtered on celite and loaded on a SCX column, washed with DCM/MeOH mixtures and was eluted with a 2M solution of NH3 in MeOH. The filtrate was concentrated in vacuo and the 3/1 mixture of 3-bromo-5-fluoro-4-hydrazinylpyridine and 3-bromo-4-chloro-5-hydrazinylpyridine was used in next step without further purification. MS (ES+) 205.9.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]([C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[N:14]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:13]=[C:12]4B3OC(C)(C)C(C)(C)O3)=[N:7][N:8]=2)[CH2:3][CH2:2]1.Br[C:38]1[CH:43]=[N:42][CH:41]=[C:40]([CH:44]2[CH2:46][CH2:45]2)[N:39]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[CH:1]1([C:4]2[O:5][C:6]([C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[N:14]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:13]=[C:12]4[C:38]3[CH:43]=[N:42][CH:41]=[C:40]([CH:44]4[CH2:46][CH2:45]4)[N:39]=3)=[N:7][N:8]=2)[CH2:3][CH2:2]1
Reactant: Brc1cncc(C2CC2)n1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(C5CC5)o4)ccc32)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(C4CC4)n3)c3cc(-c4nnc(C5CC5)o4)ccc32)cc1
Temperature: 100 °C
Yield: 78.3 %

Procedure:
A brown mixture of 2-cyclopropyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazole (298.4 mg, 0.590 mmol), 2-bromo-6-cyclopropylpyrazine (CombiPhos Catalysts, Inc., Princeton, N.J.; 129 mg, 0.649 mmol), Pd2(dba)3 (16.22 mg, 0.018 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPhos; 16.89 mg, 0.035 mmol), and potassium phosphate (376 mg, 1.771 mmol) in a mixture of dioxane (5.0 mL) and water (0.500 mL) was sparged with argon then heated at 100° C. for 2 h. The reaction was then cooled to RT, diluted with DCM (20 mL), and concentrated onto silica gel. Chromatographic purification (silica gel, 0-100% EtOAc/Hex) furnished 2-cyclopropyl-5-(3-(6-cyclopropylpyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazole (230 mg, 0.462 mmol, 78%) as a light-yellow solid: MS (ESI, pos. ion) m/z: 498.6 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.99 (1H, s), 8.75 (1H, s), 8.43 (1H, s), 8.18 (1H, s), 8.12 (2H, s), 7.84 (2H, d, J=8.4 Hz), 7.28 (2H, s), 2.36 (3H, s), 2.24-2.32 (1H, m), 2.12-2.21 (1H, m), 1.25-1.31 (4H, m), 1.15-1.23 (4H, m).