Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][O:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:31]4[CH2:32][CH2:33][CH:28]([O:27][CH3:26])[CH2:29][CH2:30]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: COC1CCNCC1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: COC1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)c(F)c4C)c3O)nc2)CC1

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 4-methoxypiperidine. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.49 (br. s., 2 H) 1.75-1.97 (m, 2 H) 2.33 (d, J=1.95 Hz, 3 H) 3.11-3.68 (m, 7 H) 3.92 (br. s., 1 H) 7.64 (br. s., 1 H) 7.70-7.79 (m, 1 H) 8.07 (d, J=7.81 Hz, 1 H) 8.12-8.65 (m, 3 H). ESI-MS m/z [M+H]+ 436.3.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:16][C@@H:15]([C:17]2[CH:28]=[CH:27][C:20]3[O:21][C:22]([CH3:26])([CH3:25])[O:23][CH2:24][C:19]=3[CH:18]=2)[O:14][C:13]1=[O:29])[CH2:2][C:3]#[CH:4].I[C:31]1[CH:32]=[C:33]([S:37]([NH2:40])(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>C(#N)C.C(N(CC)CC)C.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>[CH3:26][C:22]1([CH3:25])[O:21][C:20]2[CH:27]=[CH:28][C:17]([C@H:15]3[O:14][C:13](=[O:29])[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][C:3]#[C:4][C:31]4[CH:32]=[C:33]([S:37]([NH2:40])(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=4)[CH2:16]3)=[CH:18][C:19]=2[CH2:24][O:23]1
Reactant: C#CCCOCCCCCCN1C[C@@H](c2ccc3c(c2)COC(C)(C)O3)OC1=O
Reactant: NS(=O)(=O)c1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCC#Cc4cccc(S(N)(=O)=O)c4)C(=O)O3)ccc2O1
Reaction time: 17 h
Yield: 94.7 %

Procedure:
(5R)-3-[6-(But-3-ynyloxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazol idin-2-one (1.79 g) was stirred with 3-iodobenzene sulphonamide (1.4 g) in acetonitrile:triethylamine (1:1, 42 ml) under nitrogen for 10 min. Cuprous iodide (0.083 g) and dichlorobis(triphenylphosphine)palladium (0.192 g) were added and the mixture was stirred for 17 h under nitrogen at 21°. The mixture was evaporated to dryness and the residue was chromatographed on silica gel (250 g) in 30% ethyl acetate:petroleum ether (bp 40-60°), then 50%, then 75% and finally ethyl acetate to give the title compound (2.35 g), LCMS RT=3.44 min.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)=[C:2]=[O:3].OC(C(F)(F)F)=O.[Cl:21][C:22]1[CH:39]=[CH:38][C:25]([CH2:26][N:27]2[C:31]([C@H:32]3[CH2:36][CH2:35][CH2:34][NH:33]3)=[N:30][N:29]=[C:28]2[CH3:37])=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.[Cl-].[Na+].O>[Cl:21][C:22]1[CH:39]=[CH:38][C:25]([CH2:26][N:27]2[C:28]([CH3:37])=[N:29][N:30]=[C:31]2[C@H:32]2[CH2:36][CH2:35][CH2:34][N:33]2[C:2]([NH:1][C:4]2[CH:5]=[CH:6][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:8][CH:9]=2)=[O:3])=[CH:24][CH:23]=1
Reactant: Cc1nnc([C@H]2CCCN2)n1Cc1ccc(Cl)cc1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnc([C@H]2CCCN2C(=O)Nc2ccc(C(F)(F)F)cc2)n1Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a stirring solution of 1-isocyanato-4-(trifluoromethyl)benzene (48.6 mg, 0.26 mmol) in 8 mL of CH2Cl2 at 0° C. was slowly added a solution of the (R)-4-(4-chlorobenzyl)-3-methyl-5-(pyrrolidin-2-yl)-4H-1,2,4-triazole TFA salt (0.1237 g, 0.2 mmol) and N,N-diisopropylethylamine (0.108 mL, 0.620 mmol) in dichloromethane (2 mL). The resulting mixture was stirred 0° C. for 30 minutes, then at room temperature overnight. The reaction mixture was treated with sat. aqueous NaHCO3 (10 mL) and brine, dried over Na2SO4, and concentrated in vacuo. Flash chromatography purification (Hex/EtOAc gradient, 10-100% EtOAc with 10% of MeOH) afforded the desired product (49.2 mg, 53.0%).
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.[C:34](Cl)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>C(Cl)Cl>[C:34]([O:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([C:21]#[N:22])[CH:23]=4)[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4O)no2)cc1C#N
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4OC(=O)C(C)(C)C)no2)cc1C#N
Temperature: 25 °C
Reaction time: 96 h
Yield: 51.6 %

Procedure:
To a flask containing (R)-5-(3-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 5 (36 mg, 0.10 mmol) in DCM (1 mL) was added pyridine (24 μL, 0.3 mmol) and pivaloyl chloride (37 μL, 0.3 mmol). The reaction was stirred at room temperature for 4 days. The crude reaction mixture was washed with saturated sodium bicarbonate, dried over magnesium sulfate, and purified by chromatography (EA/hexane) to give 23 mg (52%) of (R)-4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl pivalate 14 as a white solid. LCMS-ESI (m/z) calculated for C26H27N3O4: 445.2, tR=4.7 min. 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J=2.2, 1H), 8.28 (dd, J=8.9, 2.2, 1H), 8.12-8.05 (m, 1H), 7.46 (d, J=7.4, 1H), 7.34 (t, J=7.6, 1H), 7.06 (d, J=9.0, 1H), 6.19 (dd, J=7.3, 4.6, 1H), 4.73 (hept, J=6.1, 1H), 3.44 (ddd, J=17.5, 8.7, 5.4, 1H), 3.24 (ddd, J=17.5, 8.6, 5.7, 1H), 2.56 (tdd, J=8.6, 7.4, 5.4, 1H), 2.12-1.99 (m, 1H), 1.41 (d, J=6.1, 6H), 1.14 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]([O:15][CH:16]([C:19]1[CH:20]=[N:21][C:22]([CH3:25])=[N:23][CH:24]=1)[CH2:17][NH2:18])([CH3:14])[CH3:13]>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][CH:16]([O:15][CH:12]([CH3:14])[CH3:13])[C:19]1[CH:20]=[N:21][C:22]([CH3:25])=[N:23][CH:24]=1)=[O:6]
Reactant: Cc1ncc(C(CN)OC(C)C)cn1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)OC(C)C)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-isopropoxy-2-(2-methylpyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=368.1, tR (minutes, Method D)=0.64
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([CH:17]=O)=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=1.CN(C)CC[O:31][NH2:32]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([CH:17]=[N:32][OH:31])=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N#Cc1ccccc1-c1cc(-c2cnc3nc(C=O)ccn23)ccc1F
Reactant: CN(C)CCON
Solvent: CCO
Product: N#Cc1ccccc1-c1cc(-c2cnc3nc(C=NO)ccn23)ccc1F
Temperature: 55 °C
Yield: 28.7 %

Procedure:
A mixture of 2′-fluoro-5′-(7-formylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile (100 mg) and O-(2-dimethylaminoethyl)hydroxylamine (150 mg) in ethanol (5 ml) was heated at 55° C. for 16 h then cooled to ambient temperature. The resulting solid was collected by filtration and washed with ice-cold ethanol to give 2′-fluoro-5′-[7-(hydroxyiminomethyl)imidazo[1,2-α]pyrimidin-3-yl]biphenyl-2-carbonitrile as a white solid (30 mg): δH (360 MHz, DMSO) 7.44 (1H, d, J 7), 7.62-7.73 (2H, m), 7.80 (1H, s), 7.89 (1H, dd, J 8 and 1), 7.90-7.93 (2H, m), 8.06 (1H, dd, J 8 and 1), 8.08 (1H, s), 8.13 (1H, s), 9.05 (1H, d, J 7), 12.25 (1H, s); m/z (ES+) 358 (M++H).
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[C:3](=[O:26])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:25].CN(C=O)C.[N-:34]=[N+:35]=[N-:36].[Na+].N(CC)(CC)CC.Cl>CCOC(C)=O>[CH2:13]([C:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:26])[C:2]([CH3:1])([CH3:27])[CH3:28])=[C:7]([CH3:25])[CH:8]=1)([C:17]1[CH:18]=[CH:19][C:20]([C:21]2[NH:36][N:35]=[N:34][N:22]=2)=[CH:23][CH:24]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: [N-]=[N+]=[N-]
Reactant: CCC(CC)(c1ccc(C#N)cc1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCC(CC)(c1ccc(-c2nnn[nH]2)cc1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Temperature: 110 °C
Yield: 66.7 %

Procedure:
To a mixture of 4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzonitrile (0.50 g, 1.32 mmol), and DMF (5 mL) is added NaN3 (0.26 g, 3.95 mmol) and Et3N.HCl (0.54 g, 3.95 mmol). The slurry is heated at 110° C. overnight. The slurry is diluted with EtOAc (50 mL), washed with 1M HCl (40 mL) water (40 mL), brine (40 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO (20%-40% [89% EtOAc: 10% MeOH: 1% AcOH] gradient) to furnish the title compound (0.37 g, 0.88 mmol, 66%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][CH:8]2[CH:4]([CH2:5][N:6](C(OCC)=O)[CH2:7]2)[NH:3]1>Cl>[CH3:1][CH:2]1[CH2:9][CH:8]2[CH:4]([CH2:5][NH:6][CH2:7]2)[NH:3]1
Reactant: CCOC(=O)N1CC2CC(C)NC2C1
Agent: Cl
Product: CC1CC2CNCC2N1

Procedure:
17 g (85.7 mmol) of ethyl 3-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate together with 100 ml of concentrated hydrochloric acid are refluxed overnight. The mixture is concentrated, the concentrate is taken up in 50 ml of water, and the mixture is rendered alkaline using potassium carbonate and extracted ten times using 50 ml portions of chloroform. The extracts are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=O)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([CH:16]=[C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([CH3:29])([CH3:28])[NH2:27])=[CH:21][CH:20]=1)[CH3:18])([O:14][CH3:15])=[O:13]>>[C:12]([CH:16]=[C:17]([C:19]1[CH:20]=[CH:21][C:22]([CH2:25][C:26]([NH:27][CH2:10][CH:8]([OH:9])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([CH3:29])[CH3:28])=[CH:23][CH:24]=1)[CH3:18])([O:14][CH3:15])=[O:13]
Reactant: O=CC(=O)c1ccccc1
Reactant: COC(=O)C=C(C)c1ccc(CC(C)(C)N)cc1
Solvent: O
Product: COC(=O)C=C(C)c1ccc(CC(C)(C)NCC(O)c2ccccc2)cc1
Yield: 55.8 %

Procedure:
This was prepared in an identical manner to the compound described in Example 13 using phenylglyoxal monohydrate (1.5 g) and 2{4-(2-carbomethoxy-1-methylethenyl)phenyl}-1, 1-dimethylethanamine (2.47 g). The title compound (2.02 g) m.p. 98°-103° C. (benzene/hexane) was obtained after chromatography on Kieselgel 60 eluting with 1% methanolchloroform. τ(CDCl3) 8.9 (6H, s), 7.55 (3H, d, J=1.5 Hz), 7.35 (2H, s), 6.8-7.6 (4H, m) 6.3 (3H, s), 5.4 (1H, dd) 3.85 (1H, q, J=1.5 Hz), 3.0-2.2 (9H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([CH3:18])[CH3:17])[CH:11]=2)[C:5]([C:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([CH3:18])[CH3:17])[CH:11]=2)[C:5]([C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1
Reactant: CC(C)c1cccc(OCc2cc(Br)ccc2C(=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)c1cccc(OCc2cc(Br)ccc2C(=O)O)c1
Reaction time: 8 h

Procedure:
Add 23.79 gm. (0.0655 mole) of 5-bromo-α-(3-isopropylphenoxy)-o-toluate to a solution of 5.24 gm. (0.1310 mole) of sodium hydroxide in 35 ml. of water and 315 ml. of methanol. Heat at reflux for 3 hours. Remove the methanol under vacuum and dilute the residual solution with 300 ml. of water. Extract with ether. Separate the aqueous layer and acidify with concentrated hydrochloric acid to the Congo Red end point. Extract the resulting oil into ether, wash with water and dry over magnesium sulfate. Remove the solvent under vacuum and allow the resulting oil (21.33 gm.) to stand overnight. Wash the solids formed with petroleum ether to obtain the title compound [yield 10.94 gm., m.p. 103°-122° C., pmr (CDCl3) 1.20(6H,d,(CH3)2CH--), 2.82(1H,m, (CH3)2CH--), 5.47(2H,s,CH2O--), 9.18 (1H, broad s, COOH)].
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[CH2:31][CH2:32][CH2:33][NH2:34]>CCCCO>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[CH2:31][CH2:32][CH2:33][NH:34][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COc1ccc(Br)c(CCCN)c1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Solvent: CCCCO
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(NCCCc3cc(OC)ccc3Br)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (200 mg, 0.58 mmol, 1.00 equiv), 3-(2-bromo-5-methoxyphenyl)propan-1-amine (1.14 g, 2.35 mmol, 4.00 equiv, 50%), n-BuOH (3 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). This resulted in 245 mg (83%) of methyl 3-(3-(2-bromo-5-methoxyphenyl)propylamino)-2-phenylquinoxaline-6-carboxylate as a yellow semi-solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](O)[C:5]2[N:13]3[C:8]([C:9]([C:14]4[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=4[CH3:22])=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[N:23]=1.OC1C2N3C(C=CC=C3)=C(C3C(C)=CC(C)=CC=3C)C=2N=C(C)C=1.P(Cl)(Cl)([Cl:51])=O>>[Cl:51][C:4]1[C:5]2[N:13]3[C:8]([C:9]([C:14]4[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=4[CH3:22])=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[N:23]=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(C)c(-c2cccn3c2cc2nc(C)cc(O)c23)c(C)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cc1cc(C)c(-c2c3nc(C)cc(O)c3n3ccccc23)c(C)c1
Product: Cc1cc(C)c(-c2cccn3c2cc2nc(C)cc(Cl)c23)c(C)c1
Temperature: 25 °C

Procedure:
Heat at 100° C. for 1 h a solution of 4-hydroxy-2-methyl-10-(2,4,6-trimethylphenyl)pyridino-[2,3-b]indolizine 2-methyl-9-(2,4,6-trimethylphenyl)pyrido[2,3-b]-indolizin-4-ol (10.1 g; 32 mmol) in phosphorus oxychloride (60 mL), cool to ambient temperature, and concentrate in vacuo. Partition the residue into ice water and CH2Cl2. Separate the aqueous phase, extract twice with CH2Cl2, and wash the combined organic extracts with a 1 N aqueous sodium hydroxide solution and then with water. Dry the solution over Na2SO4, filter, and concentrate in vacuo. Filter the dark residue through a short pad of silica gel and wash with 25% EtOAc in hexane. Concentrate the filtrate in vacuo to obtain the title compound as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 2.00 (s, 6H), 2.37 (s, 3H), 2.64 (s, 3H), 6.58 (t, 1H), 6.95 (dd, 1H), 7.00 (s, 2H), 7.07 (s, 1H), 7.08 (d, 1H), 9.26 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6](OS(C(F)(F)F)(=O)=O)[N:5]=[C:4]2[N:21]([CH3:24])[N:22]=[CH:23][C:3]=12.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[C:30]([Cl:32])[CH:31]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CCOC(C)=O.[Pd].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>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:28]2[CH:27]=[C:26]([Cl:25])[CH:31]=[C:30]([Cl:32])[CH:29]=2)[N:5]=[C:4]2[N:21]([CH3:24])[N:22]=[CH:23][C:3]=12
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2c(cnn2C)c1Cl
Agent: [Pd]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2cc(Cl)cc(Cl)c2)nc2c(cnn2C)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33 %

Procedure:
A solution of ethyl 4-chloro-1-methyl-6-trifluoromethanesulfonyloxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (387 mg, 1 mmol) in THF is treated with tetrakis(triphenyl phosphine) palladium (115 mg, 10 mol %), stirred for 20 min at room temperature, treated sequentially with 3,5-dichlorobenzeneboronic acid (285 mg, 1.5 mmol), 2N K2CO3 (0.7 mL) and benzyl triethyl ammonium chloride (319 mg, 1.4 mmol), heated at reflux temperature for 4 h, cooled to room temperature and diluted with EtOAc. The phases are separated and the organic phase is washed sequentially with water and brine, dried over Na2SO4 and concentrated in vacuo. The resultant residue is chromatographed (silica gel, hexanes:EtOAc, 5:1) to afford the title product as a white solid, 127 mg (33% yield), identified by HNMR analysis.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH2:8])=[O:7].[Cl:9][CH2:10][C:11]([CH2:13]Cl)=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:9][CH2:10][C:11]1[N:8]=[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[O:7][CH:13]=1
Reactant: NC(=O)c1cccs1
Reactant: O=C(CCl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: ClCc1coc(-c2cccs2)n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
A mixture of 2-thiophenecarboxamide (5.09 g) and 1,3-dichloroacetone (457 g) was stirred at 120° C. for 2 hours. The reaction mixture was poured into water, nautralized with potassium carbonate, and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography. From the fraction eluted with diethyl ether-hexane (1:9, v/v), 4-chloromethyl-2-(2-thienyl)oxazole (4.09 g, 57%) was obtained. Recrystallization from isopropylether gave colorless needles, mp 59-59° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:16][CH:15]2[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[N:9]1[C:17](=[O:44])[CH:18]([NH:23][C:24](=[O:43])[CH:25]([NH:32]C(OCC1C=CC=CC=1)=O)[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:19]([CH3:22])([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([CH:8]1[CH2:16][CH:15]2[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[N:9]1[C:17](=[O:44])[CH:18]([NH:23][C:24](=[O:43])[CH:25]([NH2:32])[CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)[C:19]([CH3:22])([CH3:21])[CH3:20])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C1CC2CCCCC2N1C(=O)C(NC(=O)C(NC(=O)OCc1ccccc1)C1CCCCC1)C(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)C1CC2CCCCC2N1C(=O)C(NC(=O)C(N)C1CCCCC1)C(C)(C)C
Yield: 100 %

Procedure:
CBz ester 15b (3.0 g, 4.9 mmol) was stirred in EtOH (25 mL) and charged with 300 mg 10%Pd(OH)2/C. H2 gas was bubbled into the suspension until the reaction was complete. Catalyst was removed by filtration and the filtrate concentrated in vacuo to give 1-[2-(2-amino-2-cyclohexyl-acetylamino)-3,3-dimethyl-butyryl]-octahydro-indole-2-carboxylic acid tert-butyl ester 16b (2.34 g, 4.9 mmol, 100%) which was used as is in the next step without further purification.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li+].CCC[CH2-].CCCCCC.[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=1.IC>C1COCC1>[Br:19][C:20]1[N:21]=[C:22]([F:26])[C:23]([CH3:1])=[CH:24][CH:25]=1
Reactant: Fc1cccc(Br)n1
Reactant: CC(C)NC(C)C
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCCCC
Product: Cc1ccc(Br)nc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
To Diisopropylamine (22.001 mmol; 2240 mg; 3.13 mL) in THF (40 mL) at 0° C. was added N-Butyllithium (2.5 mol/L) in Hexane (24.001 mmol; 9.6 mL). The reaction was stirred at 0° C. for 0.5 h, and then cooled to −78° C. 2-bromo-6-fluoro-pyridine (20.001 mmol; 3520.0 mg) in THF (10 mL) was added dropwise. The mixture was stirred at −78° C. for 3 h. Iodomethane (22.001 mmol; 3122.8 mg; 1.37 mL) was added slowly. The mixture was allowed to warm to room temperature with stirring for 1 hour. The reaction was quenched with water (˜50 mL) and stirred overnight. The layers were separated. The organic layer was concentrated, and the residue was purified on silica eluted with 0 to 5% EtOAc in Heptane to afford 6-bromo-2-fluoro-3-methyl-pyridine as a white solid (2.08 g, 55%).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[C:21]([CH3:30])=[N:22][C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:31][CH3:32])C1C=CC=CC=1.CS(O)(=O)=O>FC(F)(F)C(O)=O>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[C:21]([CH3:30])=[N:22][C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:31][CH3:32]
Reactant: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1OCc1ccccc1
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1O
Temperature: 70 °C
Reaction time: 1 h
Yield: 105.1 %

Procedure:
3-(7-Benzyloxy-6-methoxy-quinolin-4-yloxy)-2-methyl-[1,8]naphthyridine (compound 397) (730 mg) was dissolved in trifluoroacetic acid (7 ml) to prepare a solution. Methanesulfonic acid (0.7 ml) was added to the solution, and the mixture was stirred at 70° C. for one hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. An aqueous sodium hydrogencarbonate solution was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give 3-[7-hydroxy-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine (604 mg, yield 100%).
Reaction SMILES: C1(COC(=O)[NH:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])C=CC=CC=1.C1CC=CCC=1>[Pd].C(O)C>[CH2:22]([O:21][P:16]([CH2:15][CH2:14][NH:13][CH2:12][CH2:11][NH2:10])(=[O:17])[O:18][CH2:19][CH3:20])[CH3:23]
Reactant: CCOP(=O)(CCNCCNC(=O)OCc1ccccc1)OCC
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: CCOP(=O)(CCNCCN)OCC
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a flask containing 10% palladium on carbon (3.79 g) under nitrogen was added [2-[[2-(diethoxyphosphinyl)ethyl]amino]ethyl]carbamic acid phenylmethyl ester (3.79 g, 10 mmol) in ethanol (50 mL), followed by 1,4-cyclohexadiene (10.4 mL, 110 mmol). After stirring the suspension overnight, it was filtered through Celite®, preadsorbed onto silica gel, and purified by flash chromatography (7 cm diameter, elution with dried (MgSO4) 5/10/85 ammonium hydroxide/methanol/dichloromethane) to afford [2-[(2-aminoethyl)amino]ethyl]phosphonic acid diethyl ester as a yellow oil (1.98 g, 88%); MS (+FAB): 225 (MH+, 9), 194 (100), 166 (34), 138 (71), 120 (38), 57 (39), 44 (32); 1H NMR (CDCl3, 400 MHz): δ 4.18-4.04 (m, 4H), 2.91 (d of t, J=15 and 7 Hz, 2H), 2.80 (t, J=5.5 Hz, 2H), 2.68 (t, J=5.5 Hz, 2H), 1.98 (d of t, J=18 and 7 Hz, 2H), 1.68 (br s, 3 NH), 1.33 (t, J=7 Hz, 6H).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[CH2:17][CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([C:43]#[N:44])=[N:41][CH:42]=2)O1>>[O:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[N:6]([C:2]([C:37]4[CH:38]=[CH:39][C:40]([C:43]#[N:44])=[N:41][CH:42]=4)=[C:3]([CH2:17][CH2:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)[N:4]=3)[N:7]=[CH:8][CH:9]=2)[CH2:12][CH2:13]1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: Brc1c(CCc2ccc3ccccc3n2)nc2c(N3CCOCC3)ccnn12
Product: N#Cc1ccc(-c2c(CCc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1

Procedure:
Compound 46a (0.5 g, 1.1 mmol) was subjected to Suzuki coupling conditions with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile as described in Example 38, Step A, to obtain compound 46b as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C27H23N7O: 462.2 (M+H). Found: 462.2.