Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([N+:25]([O-:27])=[O:26])[C:12]=1[N:13]([CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])C(=O)C(F)(F)F)[C:5]([O:7][CH2:8]C)=[O:6].C(O[Na])=O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:24][CH:22]([C:21]1[C:2]2[C:12](=[C:11]([N+:25]([O-:27])=[O:26])[CH:10]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2)[NH:13][CH:20]=1)[CH3:23]
Reactant: CCOC(=O)c1cc(Br)c(N(CC=C(C)C)C(=O)C(F)(F)F)c([N+](=O)[O-])c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])c2[nH]cc(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 135.1 %

Procedure:
To a solution of ethyl 3-bromo-4-[(3-methyl-2-buten-1-yl)(trifluoroacetyl)amino]-5-nitrobenzoate (D215) (12.9 g, 28.5 mmol, 1 equiv) in DMF (130 ml) were added HCOONa (1.94 g, 28.5 mmol, 1 equiv), Na2CO3 (7.54 g, 71.2 mmol, 2.5 equiv), Bu4NCI (8.7 g, 31.3 mmol, 1.1 equiv) and palladium (II) acetate (320 mg, 1.42 mmol, 0.05 equiv) and the resulting mixture was stirred under nitrogen for 1 h then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt and H2O and the two layers were separated. The insoluble material in the aqueous phase was filtered off through a pad of celite and the aqueous layer extracted twice with AcOEt. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to give methyl 3-(1-methylethyl)-7-nitro-1H-indole-5-carboxylate (D218) (10.1 g, 128%) as a black solid which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([C:21](O)=[O:22])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>O1CCCC1.O>[CH2:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C@H:11]([CH2:21][OH:22])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1CO
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
To a solution of (2S,4R)-4-(benzyloxy)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (5.00 g, 15.56 mmol) in tetrahydrofuran (50 mL) at −10° C. was added N-methylmorpholine (1.882 mL, 17.11 mmol). To this solution was added slowly isobutyl chloroformate (2.34 g, 2.25 mL, 17.11 mmol). The resulting mixture was stirred for 30 minutes and filtered, and the filtrate was added to a solution of sodium borohydride (1.18 g, 31.1 mmol) in water (1.5 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 minutes, and the reaction was quenched by the addition of a saturated solution of NH4Cl. The mixture was extracted with ethyl acetate, and the organic extract was washed with brine, dried with MgSO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-2% methanol in dichloromethane to give the title compound as a colorless oil (3.93 g, 82%). 1H NMR (400 MHz, pyridine-d5, 90° C.) δ ppm 7.36 (d, J=7.4 Hz, 2 H), 7.30 (t, J=7.3 Hz, 2 H), 7.23 (t, J=7.2 Hz, 1 H), 4.50 (s, 2 H), 4.20-4.29 (m, 2 H), 3.92-4.00 (m, 1 H), 3.80-3.87 (m, 2 H), 3.50-3.59 (m, 1 H), 2.16-2.30 (m, 2 H), 1.47 (s, 9 H).
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.CC(C)([O-])C.[K+].[CH3:21][O:22][C:23](=[O:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>CN(C=O)C.C(OCC)(=O)C.O.[I-].[K+]>[CH3:21][O:22][C:23](=[O:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:14][CH2:13][C:5]1=2
Reactant: CN1CCc2[nH]c3ccccc3c2C1
Reactant: COC(=O)CCCCCBr
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCn1c2c(c3ccccc31)CN(C)CC2
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 41.2 %

Procedure:
2-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (17) (0.50 g, 2.7 mmol) was placed under argon and dissolved in 5 mL of anhydrous DMF. Potassium tert-butoxide (0.32 g, 2.8 mmol) was dissolved in 3 mL of anhydrous DMF and added slowly to the reaction at room temperature. The reaction turned from orange to dark brown. After 15 min, 6-bromohexanoic acid methyl ester (0.56 g, 2.7 mmol) and 5 mg of potassium iodide were added to the reaction at room temperature. The reaction was heated to 80° C. for 2 h upon which a precipitate formed and the reaction turned from dark brown to dark orange. The reaction was then diluted with 30 mL of ethyl acetate and 30 mL of water. The organic layer was isolated and the aqueous layer extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with water (2×20 mL), brine (15 mL), dried (Na2SO4) and concentrated in vacuo. Purification by MPCC (0-80% gradient of ethyl acetate in hexane) afforded the title compound (0.35 g, 40%) as a yellow oil. 1H NMR (400 MHz, DMSO): δ 7.46 (m, 2H), 7.17 (m, 1H), 7.06 (m, 1H), 4.46 (m, 2H), 4.10 (t, 2H, J=7.0 Hz), 3.66 (m, 2H), 3.56 (s, 3H), 3.16 (m, 2H), 3.00 (s, 3H), 2.28 (t, 2H, J=7.4 Hz), 1.66 (m, 2H), 1.55 (m, 2H), 1.29 (m, 2H). 13C NMR (100 MHz, DMSO): δ 173.7, 136.7, 131.3, 124.7, 121.9, 119.7, 118.0, 110.3, 101.8, 51.6, 51.0, 50.5, 42.9, 42.2, 33.6, 29.8, 26.1, 24.6, 19.8. ESI-HRMS (m/z): [M+H]+ calcd. for C19H26N2O2, 315.1959. found, 315.1945.
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([C:12]2[N:13]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:35].C(N(CC)CC)C.[F:43][C:44]([F:50])([F:49])[S:45](Cl)(=[O:47])=[O:46]>ClCCl>[Cl:1][C:2]1[C:10]([O:11][S:45]([C:44]([F:50])([F:49])[F:43])(=[O:47])=[O:46])=[CH:9][C:8]([C:12]2[N:13]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:35]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(O)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 69.8 %

Procedure:
In a similar manner to Step 1 of Example 299, 4-chloro-5-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]Isoindolinone (550 mg, 1.12 mmol) was dissolved in dichloromethane (22 mL), and the solution was treated with triethylamine (0.78 ml, 5.56 mmol) and trifluoromethanesulfonyl chloride (0.356 mL, 3.34 mmol), followed by purification by flash chromatography (chloroform, chloroform/methanol=99/1, 95/1) to obtain 4-chloro-5-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (491 mg, yield 71%).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[CH:6]=[C:7]([CH3:9])[CH:8]=1.CCN(C(C)C)C(C)C.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>CC#N.[Cl-].[Na+].O>[CH3:9][C:7]1[CH:6]=[C:5]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[S:35]([C:32]2[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:34][CH:33]=2)(=[O:37])=[O:36])=[O:12])[CH:4]=[C:3]([CH3:2])[CH:8]=1
Reactant: Cc1cc(C)cc(NC(=O)[C@@H]2CCCN2)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)Nc2cc(C)cc(C)c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
(S)—N-(3,5-dimethylphenyl)pyrrolidine-2-carboxamide hydrochloride (18, 3.299 g; 10.7 mmol) is dissolved in MeCN (40 ml) at rt and DIPEA (4.4 g; 34 mmol) is slowly added over 10 minutes followed by the careful addition of commercially available 4-methoxybenzenesulfonyl chloride (19, 2.8 g; 13.6 mmol). The reaction mixture is stirred for 12 h at rt followed by the addition of brine (50 ml) and the extraction of the product with DCM (3×35 ml). The combined organic layers are dried over MgSO4, filtered and concentrated under reduced pressure to give 3.95 g (95%) of (S)—N-(3,5-dimethylphenyl)-1-((4-methoxyphenyl)sulfonyl)-pyrrolidine-2-carboxamide (Example 26) as amorphous solid. LC-MS: tR=0.83 min; [M+H]+=389.3.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[CH3:48][C:49]1[C:53]([C:54](O)=[O:55])=[CH:52][O:51][N:50]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:54]([C:53]2[C:49]([CH3:48])=[N:50][O:51][CH:52]=2)=[O:55])[CH2:42][CH2:41]1
Reactant: Cc1nocc1C(=O)O
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1nocc1C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 55 %

Procedure:
The desired compound was prepared according to the procedure of Example A27, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 3-methylisoxazole-4-carboxylic acid as starting materials in 55% yield. LCMS for C29H30ClN8O3 (M+H)+: m/z=573.2.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([N:9]2[C@@H:18]3[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:12][CH2:11][CH2:10]2)=[O:8])[CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][N:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:19][O:20][C:21]1[N:22]=[CH:23][C:24]([C:2]2[S:6][CH:5]=[C:4]([C:7]([N:9]3[CH:18]4[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]4)[CH2:12][CH2:11][CH2:10]3)=[O:8])[CH:3]=2)=[CH:25][CH:26]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=C(c1csc(Br)c1)N1CCC[C@@H]2CCCC[C@@H]21
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2cc(C(=O)N3CCCC4CCCCC43)cs2)cn1
Temperature: 140 °C

Procedure:
cis-(5-Bromo-thiophen-3-yl)-(octahydro-quinolin-1-yl)methanone (0.1 g, 0.30 mmol) was combined with 2-methoxypyridine-5-boronic acid (0.045 g, 0.3 mmol), caesium carbonate (0.142 g, 0.44 mmol), and palladium tetrakis(triphenylphosphine) (0.031 g, 0.03 mmol) in DME (6 mL), IMS (2 mL) and water (13 mL). The reaction mixture was heated by microwave irradiation to 140° C. for 20 minutes. The solution was partitioned between ethyl acetate and water and the phases separated then the organic phase was dried and evaporated to afford the title compound as a gum. The compound was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were evaporated to give the title compound as an oil (0.077 g). LCMS m/z 357.25 [M+H]+ R.T.=12.46 min (Analytical Method 2).
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[F:26][C:27]1[CH:28]=[C:29]([NH:33][CH:34]=[C:35]2[C:40](=[O:41])OC(C)(C)OC2=O)[CH:30]=[N:31][CH:32]=1.CCOC(C)=O>C(OCC)C>[F:26][C:27]1[CH:28]=[C:29]2[C:30]([C:40]([OH:41])=[CH:35][CH:34]=[N:33]2)=[N:31][CH:32]=1
Reactant: CC1(C)OC(=O)C(=CNc2cncc(F)c2)C(=O)O1
Solvent: CCOC(C)=O
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCOCC
Product: Oc1ccnc2cc(F)cnc12
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
To a stirred solution of Dowtherm A at 250° C., was added 5-(((5-fluoropyridin-3-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1 g, 0.003 mol) portionwise over a period of 10 minutes. The reaction was monitored by TLC (TLC eluent: 50% EtOAc in petroleum ether, uv active). After completion of reaction, the mixture was cooled to ambient temperature and treated with diethyl ether to obtain a grey precipitate. The precipitate was stirred for 5-10 minutes and filtered, washed with diethyl ether and dried under vacuum to obtain 7-fluoro-1,5-naphthyridin-4-ol as a tan colored solid, (0.4 g, 64.93%). 1H NMR (400 MHz, DMSO-d6): δ 12.68 (bs, 1H), 9.43 (s, 1H), 8.75 (t, J=6.4 Hz, 1H), 8.59 (d, J=8, 1H), 6.99 (d, J=17.2 Hz, 1H). m/z (ESI) 165.1 (M+H)+.
Reaction SMILES: N#N.Br[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[N:6]([CH3:15])[CH:5]=1.[CH3:16][N:17]1[CH:21]=[C:20](B(O)O)[CH:19]=[N:18]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:15][N:6]1[CH:5]=[C:4]([C:20]2[CH:19]=[N:18][N:17]([CH3:16])[CH:21]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:14]
Reactant: Cn1cc(B(O)O)cn1
Reactant: Cn1cc(Br)c2ccccc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: C1COCCO1
Product: Cn1cc(-c2cn(C)c(=O)c3ccccc23)cn1
Reaction time: 0.05 h
Yield: 52.2 %

Procedure:
For 3 min, N2 was bubbled through a mixture of 4-bromo-2-methylisoquinolin-1(2H)-one (54 mg, 0.23 mmol), (1-methylpyrazol-4-yl)boronic acid (31 mg, 0.25 mmol), aqueous 2M Na2CO3 (0.375 mL) and Pd(dppf)Cl2 (8 mg, 0.01 mmol) in 1,4-dioxane (1.5 mL) which was then microwaved at 120° C. for 1 h. Work up in a manner similar to Example 18, step 3, and two successive silica gel chromatographies, eluting with 15-80% EA in hexane over 6 min and continuing 80% isocratic EA followed by a second chromatography 15-100% EA in hexane over 6 min and continuing 100% isocratic EA gave the title compound (28 mg, 0.12 mmol) as a cream solid in 51% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.54 (s, 3H) 3.92 (s, 3H) 7.50 (s, 1H) 7.55 (ddd, J=8.02, 5.87, 2.27 Hz, 1H) 7.60-7.64 (m, 1H) 7.70-7.80 (m, 2H) 7.95 (s, 1H) 8.31 (d, J=7.83 Hz, 1H). LCMS (M+H)+ 240.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1.CO.C(Cl)Cl.CN(C=O)C>[Pd].CO.C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1
Reactant: Oc1cccc(-c2cnc3[nH]cc(C=Cc4ccccn4)c3c2)c1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Oc1cccc(-c2cnc3[nH]cc(CCc4ccccn4)c3c2)c1
Reaction time: 48 h
Yield: 59.5 %

Procedure:
A suspension of 3-[3-(2-pyridin-2-yl-vinyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenol (10 mg, 0.032 mmol) and 10 wt % Pd/C (1.7 mg, 0.0016 mmol) in 0.9 ml of a (1:1:1) mixture of MeOH/CH2Cl2/DMF was stirred for 2 days under H2 atmosphere. The mixture was adsorbed directly on silica gel. Purification on silica gel with a gradient, of MeOH/CH2Cl2 afforded 3-[3-(2-pyridin-2-yl-ethyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenol as a yellow solid (6 mg, 60% yield), 1H NMR (500 MHz, DMSO-d6) δ 3.22 (t, J=7.5 Hz, 2H), 3.37 (t, J=7.5 Hz, 2H), 6.77 (d, J=7.5 Hz, 1H), 7.07 (s, 1H), 7.11 (d, J=7.0 Hz, 1H), 7.27 (m, 2H), 7.82 (m, 1H), 7.93 (d, J=7.0 Hz, 1H), 8.21 (s, 1H), 8.43 (m, 2H), 8.79 (d, J=5.5 Hz, 1H), 9.54 (broad s, 1H), 11.53 (s, 1H). MS: m/z 316 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:16][C@@H:17]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:18][OH:19])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.O.I(O)(=O)(=O)=[O:26].P(O)([O-])([O-])=O.[Na+].[Na+]>C(#N)C.[Cr]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:16][C@@H:17]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:18]([OH:26])=[O:19])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CC(C)C[C@@H](CO)N[C@H](c1ccc(F)cc1)c1ccc(Br)cc1
Reactant: [O-][I+3]([O-])([O-])O
Agent: [Cr]
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)C[C@H](N[C@H](c1ccc(F)cc1)c1ccc(Br)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S)-2-{(R)-[(4-bromophenyl)-(4-fluorophenyl)-methyl]-amino}-4-methylpentan-1-ol (3.28 g, 8.65 mmol) in acetonitrile (50 mL) containing water (0.375 mL) at 0-5° C. was added, over 20 minutes, a solution of periodic acid and chromium [VI] oxide in acetonitrile (50 mL: prepared by dissolving 11.4 grams of H5IO6 and 23 mg of CrO3 in 100 mL of CH3CN and stirring for 2 hours at room temperature according to the procedure described in Tetrahedron Letters, 1998, vol. 39, p. 5323-5326). The reaction mixture was stirred overnight while warming to room temperature. Disodium phosphate (1.8 g/100 mL water) was added. The reaction mixture was extracted with toluene (150 mL), washed with 1:1 brine/water (50 mL), freshly prepared sodium bisulfite solution (2 g/50 mL water), brine (50 mL), dried over MgSO4, filtered, concentrated in vacuo, and purified on a short plug of silica gel (30% ethyl acetate/hexane elution to remove non-polar impurities, then 50% ethyl acetate/dichloromethane elution) to give (2S)-2-{(R)-[(4-bromophenyl)-(4-fluorophenyl)-methyl]-amino}-4-methylpentanoic acid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=3)[NH2:14])[CH:9]=2)[NH:4][CH:3]=1.[C:18](O)(=[O:23])/[CH:19]=[CH:20]/[CH2:21][CH3:22].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:14][C:18](=[O:23])/[CH:19]=[CH:20]/[CH2:21][CH3:22])[CH:15]=[CH:16][CH:17]=3)[CH:9]=2)[NH:4][CH:3]=1
Reactant: Cc1c[nH]c2ncc(-c3cccc(N)c3)cc12
Reactant: CC/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC/C=C/C(=O)Nc1cccc(-c2cnc3[nH]cc(C)c3c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 11.7 %

Procedure:
A solution of 24 (50 mg, 0.2242 mmol) and trans-2-pentenoic acid 25 (24.6 mg, 0.246 eq) in DMF was added EDC.HCl (33 mg, 0.2706 mmol) and HOBt (36.5 mg, 0.2706 mmol). DIPEA (57.9 mg, 0.448 eq) was added to the reaction, stirred 12 h at RT and check the TLC for completion of the reaction and quench the reaction mixture with dilute water. The organic layer was treated with ethyl acetate (25 mL) and was washed with brine solution (25 mL) and dried over sodium sulphate, filtered and concentrated to get the crude product. The resulting oil was purified through silica gel chromatography using a gradient of 4% Ethyl acetate:hexane to afford 8 mg of Compound 26. MS-ES+305.1 1H NMR (400 MHz, DMSO-D6-d6): 11.45 (s, 1H), 10.08 (s, 1H), 8.40 (s, 1H), 8.17 (s, 1H), 7.85 (d, 1H), 7.61 (m, 1H), 7.36 (m, 2H), 7.30 (d, 1H), 5.62 (m, 1H), 2.35 (s, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].C1(C)C=CC(S([CH2:16][N+:17]#[C-])(=O)=O)=CC=1.[CH2:20]([O:27][C:28]1[C:32]([CH:33]=O)=[CH:31][N:30]([CH3:35])[N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>C(COC)OC.CO>[CH2:20]([O:27][C:28]1[C:32]([CH2:33][C:16]#[N:17])=[CH:31][N:30]([CH3:35])[N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cn1cc(C=O)c(OCc2ccccc2)n1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: Cn1cc(CC#N)c(OCc2ccccc2)n1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 81.9 %

Procedure:
To a mixture of potassium t-butoxide (2.24 g) and dimethoxyethane (10 ml) was added a solution of p-toluenesulfonylmethyl isocyanide (2.05 g) in dimethoxyethane (10 ml) and the mixture was stirred at −78° C. for 5 min. Then a solution of 3-benzyloxy-1-methyl-1H-pyrazole-4-carbaldehyde (2.16 g) in dimethoxyethane (10 ml) was added. After stirring at said temperature for 1 hr, the mixture was stirred for 1 hr. while raising the temperature to room temperature. To the obtained mixture was added methanol (380 ml), and the mixture was refluxed for 1 hr. After cooling, the reaction solution was poured into saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-benzyloxy-1-methyl-1H-pyrazol-4-ylacetonitrile (1.86 g, yield 82%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][N:15]([CH3:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].Cl.C(=O)([O-])O.[Na+]>C(O)C.C(OCC)(=O)C>[Cl:3][C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][N:15]([CH3:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:9]=[CH:8][C:5]=1[CH2:6][OH:7]
Reactant: CN(CCOc1ccc(C=O)c(Cl)c1)c1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(CCOc1ccc(CO)c(Cl)c1)c1ccccn1
Reaction time: 2 h
Yield: 99.1 %

Procedure:
Sodium borohydride (58 mg) was added to a solution of 2-chloro-4-((2-(N-methyl-N-(2-pyridinyl)amino)ethyl)oxy)benzaldehyde (438 mg) in ethanol (3 ml) at room temperature and the mixture was stirred for 2 hr. 1N Hydrochloric acid (1.5 ml) was dropwise added to the reaction mixture to decompose the redundant reagent and the whole mixture was diluted with ethyl acetate. A saturated aqueous solution of sodium hydrogencarbonate was added to neutralize the mixture and the resulting product was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the objective compound (437 mg) as a colorless oil.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])#[N:7].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1C=CC=CC=1>[CH3:12][O:11][C:9](=[O:10])[C:8]([C:6]#[N:7])=[CH:1][CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C=O
Reactant: COC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(C#N)=CC(C)C
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of isobutyraldehyde (18.2 mL, 200 mmol) in dry benzene (20 mL) was added methyl cyanoacetate (18 mL, 200 mmol), ammonium acetate (2 g) and glacial acetic acid (4 mL). The reaction mixture was stirred at 60° C. for 30 minutes and allowed to cool to room temperature. Excess of solvents was removed in vacuo and the residue was dissolved in EtOAc (200 mL). The organic layer was washed with water, dried over sodium sulfate and evaporated to give 2-cyano-4-methyl-pent-2-enoic acid methyl ester as pale yellow oil. Further purification of the pale yellow oil by distillation (7 mm Hg) gave product 2 (27.4 g, 56%) as colorless oil: 1H NMR (300 MHz, CDCl3) δ 1.16 (d, J=6.6 Hz, 6H), 2.96–3.04 (m, 1H), 3.87 (s, 3H), 7.47 (d, J=10.5 Hz, 1H).
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6]3([CH2:12][O:11]3)[C:5]=2[CH:4]=[N:3][CH:2]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[OH:22].C(=O)([O-])[O-].[K+].[K+]>CC(O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][CH2:12][C:6]1([OH:11])[CH2:7][CH2:8][CH2:9][C:10]2[N:1]=[CH:2][N:3]=[CH:4][C:5]1=2
Reactant: c1ncc2c(n1)CCCC21CO1
Reactant: COc1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COc1ccc(Br)c(OCC2(O)CCCc3ncncc32)c1

Procedure:
A solution of 10 mmol of 7′,8′-dihydro-6′H-spiro[oxirane-2,5′-quinazoline] and 15 mmol of 2-bromo-5-methoxyphenol [63604-94-4] in 30 ml of 2-propanol is admixed with 20 mmol of finely powdered potassium carbonate. The mixture is heated at reflux for 12-18 hours, cooled and filtered over Hyflo. The filtrate is evaporated and from the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.