Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>C(O)C.O.[Pd]>[N:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cccc(NCCN2CCOCC2)c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: Nc1cccc(NCCN2CCOCC2)c1
Reaction time: 12 h
Yield: 74.9 %

Procedure:
20 g N-2-(morpholin4-yl)ethyl-3-nitroaniline was dissolved in 270 ml ethanol and 30 ml water, and 0.3 Pd/C (5%) was added. After purging with nitrogen, hydrogenation was performed for 12 h at 50° C. under 50 bar of hydrogen pressure. After cooling, nitrogen purging was repeated, the catalyst was filtered off, and the filtrate was reduced on a rotary evaporator. 13.2 g of black oil was obtained; this was distilled twice in a ball tube (180–206° C., 0.06–0.08 mbar). The product obtained was a viscous orange oil (middle fraction).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.O1CCCC1.O[Li].O>CO.O>[F:43][C:40]1[CH:41]=[CH:42][C:37]([C:34]2[S:33][C:32]([CH2:31][C:26]3[CH:25]=[C:24]([C@@H:6]4[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]4[OH:4])[CH:29]=[CH:28][C:27]=3[CH3:30])=[CH:36][CH:35]=2)=[CH:38][CH:39]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(-c4ccc(F)cc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 19 h
Yield: 80.8 %

Procedure:
(1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(3-{[5-(4-fluorophenyl)-2-thienyl]methyl}-4-methylphenyl)-D-glucitol (5 g) was dissolved in methanol (35 mL) and tetrahydrofuran (25 mL) at room temperature. A solution of LiOH hydrate (192 mg) in water (10 mL) was added dropwise to the mixture for 30 minutes at 20-24° C. After the mixture was stirred for 19 hours at room temperature, the solvent was evaporated in vacuo. The residue was partitioned to ethyl acetate (50 mL) and water (25 mL), stirred for 15 minutes, then the layers were separated. The organic layer was washed with water. The organic layer was dried over Na2SO4, filtered using activated carbon pre-coated filter and evaporated. The resulting residue was dissolved in ethyl acetate (11.1 mL) at 40° C., water (241 mL) was added to the mixture at the same temperature. n-Heptane (5.6 mL) was added to the mixture at 40° C., then the mixture was seeded with a slight amount of (1S)-1,5-anhydro-1-(3-{[5-(4-fluorophenyl)-2-thienyl]methyl}-4-methylphenyl)-D-glucitol at same temperature. After stirred for 1 hour at 35° C., n-heptane (2.6 mL) was added slowly to the mixture. The resulting mixture was cooled. The precipitate was filtered and washed with ethyl acetate/n-heptane, then dried to give hemihydrate of (1S)-1,5-anhydro-1-(3-{[5-(4-fluorophenyl)-2-thienyl]methyl}-4-methylphenyl)-D-glucitol (2.93 g) as white crystals.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:7][CH:6]([C:8]([OH:10])=[O:9])[N:5]=[CH:4]1.[CH3:11]O>>[CH3:2][N:3]1[CH2:7][CH:6]([C:8]([O:10][CH3:11])=[O:9])[N:5]=[CH:4]1
Reactant: CN1C=NC(C(=O)O)C1
Reactant: CO
Agent: Cl
Product: COC(=O)C1CN(C)C=N1

Procedure:
17.0 g of 38C was dissolved in 203 ml of anhydrous methanol and dry hydrogen chloride was bubbled rapidly into the mixture while it was heated to and at reflux for 2 hours. the mixture was cooled, stripped of volatiles, mixed with 300 ml of water, neutralized with solid sodium bicarbonate, made basic to pH=9 with 3N aqueous sodium carbonate solution. The aqueous phase was extracted with methylene chloride, the extract was dried (MgSO4), filtered and stripped of solvent, to give methyl 1-methylimidazoline-4-carboxylate (38D), as a brown oil.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:17](=O)[C:16](=O)[N:15]3[C@H:10]([CH2:11][O:12][CH2:13][CH2:14]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]1([CH2:7][N:8]2[CH2:17][CH2:16][N:15]3[C@H:10]([CH2:11][O:12][CH2:13][CH2:14]3)[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C(=O)N2CCOC[C@@H]2CN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CN2CCN3CCOC[C@@H]3C2)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To (9aS)-8-(phenylmethyl)hexahydropyrazino[2,1-c][1,4]oxazine-6,7-dione (2.06 g, 7.90 mmol) in THF (20 mL) at 0° C. was added LAH (30.0 mL, 29.6 mmol, 1M in THF) dropwise. The solution was heated overnight at 45° C. and a subsequent 5 days at 65° C. The reaction was cooled to 0° C., quenched slowly with EtOAc (15 mL), H2O (1.2 mL), NaOH (1.20 mL, 15% w/w in H2O) and H2O (3.60 mL). The resultant mixture was stirred for 1 h, diluted with EtOAc and filtered. The filter cake was taken up in 1N NaOH, extracted with diethyl ether and dried over MgSO4 to afford the title compound of step F (1.80 g, 7.70 mmol, 98%). 1H NMR (400 MHz, CD3OD) δ ppm 1.79 (t, J=10.8 Hz, 1H), 2.27-2.39 (m, 3H), 2.66 (tt, J=10.6, 2.1 Hz, 1H), 2.74 (ddd, J=10.8, 2.6, 2.4 Hz, 1H), 2.83 (dq, J=10.8, 2.2 Hz, 1H), 3.14-3.23 (m, 1H), 3.30 (dt, J=3.3, 1.6 Hz, 2H), 3.47-3.52 (m, 1H), 3.52-3.57 (m, 1H), 3.57-3.67 (m, 2H), 3.80 (dd, J=11.5, 3.5 Hz, 1H), 7.23-7.33 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:5][CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:9][CH:8]=1.[CH2:32]=O.Cl>C(O)=O>[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[N:5]([CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:9][CH:8]=1)[CH3:32]
Reactant: CCCCc1ncc(CN[C@@H](Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Reactant: C=O
Agent: Cl
Solvent: O=CO
Product: CCCCc1ncc(CN(C)[C@@H](Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Yield: 70.4 %

Procedure:
N-[{1-[(2-Chlorophenyl)methyl]-2-n-butyl-1H-imidazol-5-yl}methyl]phenylalanine methyl ester (prepared in Example 3(i) method B) (o.52 g, 1.18 mmol), 88% formic acid (0.31 g), and 37% aqueous formaldehyde (o.44 g) were heated over a steam bath for 18 hours. The reaction mixture was poured into 10% hydrochloric acid solution and then extracted with diethyl ether. The aqueous layer was basified to pH 10 with 10% sodium hydroxide solution and then the product was extracted into ethyl acetate. The organic extract was dried with anhydrous magnesium sulfate and the solvent was removed in vacuo. The crude product was chromatographed on silica gel with 50% ethyl acetate in hexane to give 0.377 g (70%) of N-[{1-[(2-chlorophenyl)methyl]-2-n-butyl-1H-imidazol -5-yl}methyl]-N-methylphenylalanine methyl ester. Hydrolysis of the ester following the procedure of Example 2(ii) gave the title compound as a foam (0.265 g, 77%); mp 59°-61° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](O)=[O:28].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CO.CN(C)C=O>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][CH:32]=[C:24]([C:23]([F:22])([F:33])[F:34])[CH:25]=3)[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)c1cccc(C(F)(F)F)c1
Yield: 60.8 %

Procedure:
Preparation of example 43 from the title compound of Example 7 (0.03 g, 0.11 mmol), 3-Trifluoromethyl-benzoic acid (0.031 g, 0.16 mmol), triethylamine (0.078 mL, 0.43 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.062 g, 0.11 mmol) and N,N-dimethylformamide (0.05 M, 2.0 mL) was carried out analogously to Example 11. Silica gel chromatography (95:5 CH2Cl2/methanol) afforded the title compound (0.030 g) as a yellow powder in 61% yield.
Reaction SMILES: C(Cl)(Cl)Cl.C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:15][CH2:16][CH2:17][N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=2)[C:21]([Cl:29])=[CH:20][C:19]1=[O:30]>O.C(N(CC)CC)C>[Cl:29][C:21]1[C:22]2[C:27](=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:18]([CH2:17][CH:16]=[O:15])[C:19](=[O:30])[CH:20]=1
Reactant: O=c1cc(Cl)c2ccc(Cl)cc2n1CCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=CCn1c(=O)cc(Cl)c2ccc(Cl)cc21
Reaction time: 0.25 h

Procedure:
To 2 mL of a chloroform solution containing 54 mg of oxalyl chloride, 64 mg of dimethyl sulfoxide was added dropwise at −60° C., and the mixture was stirred for 15 minutes. Thereto was added dropwise 2 mL of a chloroform solution containing 85 mg of 1-(2-hydroxyethyl)-4,7-dichloroquinolin-2(1H)-one at the same temperature, and the reaction mixture was stirred for 15 minutes. Thereto was added 133 mg of triethylamine at the same temperature, then the mixture was stirred at room temperature for 45 minutes, and water was added thereto. The organic layer was separated, washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [silica gel; Silica gel 60N manufactured by Kanto Chemical Co., Inc., eluent; chloroform:methanol=10:1] to obtain 69 mg of a brown oily substance, (4,7-dichloro-2-oxoquinolin-1(2H)-yl)acetaldehyde.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.C1(C)C=CC(S([N:22]=[N+:23]=[N-])(=O)=O)=CC=1>C1COCC1.CN>[N+:22](=[C:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]1=[O:12])=[N-:23]
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: CN
Solvent: C1CCOC1
Product: [N-]=[N+]=C1C(=O)Oc2ccccc2C1=O
Yield: 70.6 %

Procedure:
To a 100 mL round-bottom flask fitted with a mechanical stirrer, nitrogen inlet and bubbler was charged 4-hydroxycoumarin (3.1 g, 18.8 mmol) dissolved in dry THF (21.6 g) and Methylamine (1.8 g). A solution of p-toluenesulfonyl azide (5.3 g, 28.3 mmol) in dry THF (14.4 g) was then added to this solution dropwise over a period of 15 minutes. The reaction was continued until all of 4-hydroxycoumarin had reacted as monitored by HPLC (ca. 2.0 hours). The precipitated reaction product was filtered on a small Buchner funnel and the filtrate was packed in powdered dry ice to produce a second crop of crystals which were also isolated by filtration. The combined filtercakes were dried overnight under vacuum at 60° C. to obtain orange colored crystals of 3-diazo-4-oxo-3,4-dihydrocoumarin; yield 2.5 g (70.6% yield). The crude product was further purified by dissolving it in 75.0 g of acetone and precipitating by pouting into 150.0 g ice-water yielding pale yellow crystals. The product was characterized by 13C NMR, and DSC. A sample recrystallized from acetone-water melted at 159.5° C.; 13C-NMR in DMSO-d6 solvent showed 9 singlet lines at the following chemical shifts, in ppm: 173.748, 157.754, 153,316, 136.239, 125.231, 125.063, 118.696, 117.741, 77.022.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:29]2[CH2:33][C@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])[O:31][C:30]2=[O:39])[CH:5]=[CH:6][C:7]=1[C:8]1[C:9](OC)=[N:10][C:11]([O:14][C@@H:15]2[CH2:20][O:19][C:18]3=[N:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][N:17]3[CH2:16]2)=[N:12][CH:13]=1.BrC1[C:42](N(C)C)=[N:43][C:44](O[C@@H]2COC3=NC([N+]([O-])=O)=CN3C2)=NC=1>>[CH3:42][N:43]([CH3:44])[C:9]1[C:8]([C:7]2[CH:6]=[CH:5][C:4]([N:29]3[CH2:33][C@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])[O:31][C:30]3=[O:39])=[CH:3][C:2]=2[F:1])=[CH:13][N:12]=[C:11]([O:14][C@@H:15]2[CH2:20][O:19][C:18]3=[N:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][N:17]3[CH2:16]2)[N:10]=1
Reactant: CN(C)c1nc(O[C@@H]2COc3nc([N+](=O)[O-])cn3C2)ncc1Br
Reactant: COc1nc(O[C@@H]2COc3nc([N+](=O)[O-])cn3C2)ncc1-c1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3cnc(O[C@@H]4COc5nc([N+](=O)[O-])cn5C4)nc3N(C)C)c(F)c2)C(=O)O1

Procedure:
(S,S)—N-(3-{3-Fluoro-4-[4-methoxy-2-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxy)-pyrimidin-5-yl]-phenyl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide. The title compound was prepared by following the same procedure as described in the preparation of Example 7, except [5-bromo-2-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6(S)-yloxy)-pyrimidin-4-yl]-dimethyl-amine was used in place of 6-(5-bromo-pyridin-2-yloxy)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine. ESI MS m/z 557.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:20][CH2:21][C:22]([F:24])([F:23])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:19])=[N:16][NH:17][CH:18]=1)[CH2:9][CH2:8]3.C(=O)([O-])[O-].[K+].[K+].I[C:32]1[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[CH:34][N:33]=1.CN[C@@H]1CCCC[C@H]1NC>[Cu]I.C1(C)C=CC=CC=1>[Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:20][CH2:21][C:22]([F:23])([F:24])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:19])=[N:16][N:17]([C:32]2[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:18]=1)[CH2:9][CH2:8]3
Reactant: COc1cccnc1I
Reactant: Cc1n[nH]cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1cccnc1-n1cc(CN2CCC3(CC2)OCC(F)(F)c2cc(Cl)sc23)c(C)n1
Reaction time: 24 h
Yield: 54.1 %

Procedure:
To a screw-cap test tube are added copper(I) iodide (23.74 mg, 0.125 mmol), 2-chloro-4,4-difluoro-1′-[(3-methyl-1H-pyrazol-4-yl)methyl]spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine] (233.00 mg, 0.623 mmol), potassium carbonate (182.71 mg, 1.31 mmol), toluene (2 mL) (previously bubbled with nitrogen for 20 min) and a stir bar. The reaction mixture is bubbled with nitrogen for 20 minutes and then 2-iodo-3-methoxypyridine (302.01 mg, 1.25 mmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (39.31 mL, 0.25 mmol) are added. The reaction tube is quickly sealed (caution: build-up of pressure possible; use a safety shield) and immersed in a preheated oil bath at 110° C. for 24 hours with the aid of a magnetic stirrer. Then, the mixture is poured on SCX column (25 g) and eluted with methanol and then 2N solution of ammonia in methanol. The basic fraction is concentrated and the resulting residue is purified by basic-HPLC to give 162 mg of the title compound. MS (m/z): 481 (M+1).
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([OH:17])[O:11][C@@H:10]2[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].P([O-])([O-])([O-])=O.[Ca+2].P([O-])([O-])([O-])=O.[Ca+2].[Ca+2]>>[OH:17][CH:12]1[O:11][C@H:10]([CH2:18][OH:19])[C@@H:9]([O:8][C@@H:6]2[O:7][C@H:2]([CH2:1][OH:23])[C@H:3]([OH:22])[C@H:4]([OH:21])[C@H:5]2[OH:20])[C@H:14]([OH:15])[C@H:13]1[OH:16]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: [Ca+2]
Product: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O

Procedure:
The equivalents of 10.0 wt % vitamin E, 6.6 wt % maltose, and 1.6 wt % calcium phosphate were mixed using a mixer to produce a preliminary mixture powder. This powder was thoroughly mixed with 20.9 wt % Panax notoginseng extract powder obtained in a manner similar to that of Example 2, 10 wt % starch, and 45 wt % lactose-powder cellulose, followed by sieve analysis. The mixture was placed into a mixer, and 5 wt % sucrose fatty ester, 0.9 wt % calcium phosphate, and 5 wt % lactose-powder cellulose was added to the mixture, followed by mixing. The resultant powder was tableted, followed by shellac coating and polishing, to produce a prototype edible composition tablet.
Reaction SMILES: ClC1C(Cl)=C(Cl)N=C(C(Cl)=O)C=1.[F-].[Cs+].C1OCCOCCOCCOCCOCCOC1.[CH3:33][CH:34]([OH:36])[CH3:35].C(N(CC)CC)C.[F:44][C:45]1[C:50]([F:51])=[C:49]([F:52])[N:48]=[C:47]([C:53](F)=[O:54])[CH:46]=1>C(#N)C>[F:44][C:45]1[C:50]([F:51])=[C:49]([F:52])[N:48]=[C:47]([C:53]([O:36][CH:34]([CH3:35])[CH3:33])=[O:54])[CH:46]=1
Reactant: O=C(F)c1cc(F)c(F)c(F)n1
Reactant: CC(C)O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C(Cl)c1cc(Cl)c(Cl)c(Cl)n1
Agent: [Cs+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)OC(=O)c1cc(F)c(F)c(F)n1
Reaction time: 22 h
Yield: 84 %

Procedure:
Into a 250 mL 3-necked flask equipped with a mechanical stirrer and a condenser was added 4,5,6-trichloropicolinoyl chloride (23.3 g, 95 mmol), CsF (72.2 g, 475 mmol), 18-crown-6 (2.5 g, 9.5 mmol) and anhydrous acetonitrile (150 mL). The reaction was blanketed with nitrogen, and the mixture was heated at reflux with vigorous stirring for 22 hours. A sample was taken and analyzed by GC. The results showed that the reaction was not complete, therefore additional CsF (14.43 g, 95 mmol) was added, and the mixture was heated at reflux for an additional 24 hours at which time the reaction was deemed complete. Then 6.28 g (104.5 mmol) of anhydrous 2-propanol and 9.61 g (95 mmol) of anhydrous triethyl amine were added to the flask dropwise at 6° C. The mixture was stirred for 5-6 hours at room temperature. The reaction was stopped when GC showed no starting 4,5,6-trifluoropicolinoyl fluoride was left in the mixture. The salts were removed by filtration and washed with some acetonitrile. After removing acetonitrile with a rotary evaporator, the wet product paste was re-dissolved in ethyl ether. The mixture was washed with water and dried over MgSO4. Most of ethyl ether was removed with a rotary evaporator. The concentrated crude product mixture in ethyl ether was filtered through a bed of silica gel, and eluted with some ethyl ether. After stripping away the solvent on a rotary evaporator, 17.52 g (84% yield, 94% HPLC purity) of isopropyl 4,5,6-trifluoropicolinate was obtained 1H NMR (CDCl3, 300 MHz) δ 7.90 (ddd, 1H, J=9 Hz, 5 Hz, 1 Hz), 5.30 (m, 1H, J=6 Hz), 1.41 (d, 6H, J=6 Hz); 13C NMR (CDCl3, 75 MHz, 1H decoupled) δ 161.2 (d, J=4 Hz), 157.2 (ddd, J=265 Hz, 9 Hz, 6 Hz), 152.1 (ddd, J=241 Hz, 12 Hz, 5 Hz), 140.9 (m), 136.8 (ddd, J=269 Hz, 30 Hz, 13 Hz), 113.6 (m), 70.4 (s), 21.3 (s).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]2[C:22]3[C:17](=[C:18]([NH:23][C:24]([C:26]4[N:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]5=[N:28][CH:27]=4)=[O:25])[CH:19]=[CH:20][CH:21]=3)[C:16]([CH2:35][CH3:36])=[N:15]2)[N:8]=1)(=O)=O.[NH:39]1[CH2:44][CH2:43][CH:42]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:41][CH2:40]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH2:35]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([C:26]2[N:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]3=[N:28][CH:27]=2)=[O:25])[N:14]([CH2:13][C:9]2[N:8]=[C:7]([N:39]3[CH2:40][CH2:41][CH:42]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:50])([CH3:49])[CH3:51])[CH2:43][CH2:44]3)[CH:12]=[CH:11][CH:10]=2)[N:15]=1)[CH3:36]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CCc1nn(Cc2cccc(OS(=O)(=O)C(F)(F)F)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCc1nn(Cc2cccc(N3CCC(NC(=O)OC(C)(C)C)CC3)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 90 °C
Yield: 44.6 %

Procedure:
To a reaction vial was added 6-((3-ethyl-4-(imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)pyridin-2-yl trifluoromethanesulfonate (30 mg, 0.0551 mmol; prepared according to Example 24, Step A), tert-butyl piperidin-4-ylcarbamate (22.1 mg, 0.110 mmol) and cesium carbonate (53.9 mg, 0.165 mmol). Toluene (2 mL) was added and argon was bubbled through the mixture for 10 minutes. To this mixture was added rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6.86 mg, 0.0110 mmol) and tris(dibenzylideneacetonyl)bis-palladium (5.05 mg, 0.00551 mmol). The reaction mixture was heated at 90° C. for 4 hours. The mixture was filtered through Celite®, washing with dichloromethane and methanol. The solution was concentrated under a stream of nitrogen and the residue was purified by preparative thin layer chromatography on silica, eluting with 10% methanol in dichloromethane containing 0.5% ammonium hydroxide solution to give tert-butyl 1-(6-((3-ethyl-4-(imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)pyridin-2-yl)piperidin-4-ylcarbamate (14.6 mg).
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([O:14]C)=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[CH3:16][N:17]([CH2:19][CH2:20][CH2:21][NH2:22])[CH3:18]>C1(C)C=CC=CC=1>[CH3:16][N:17]([CH3:18])[CH2:19][CH2:20][CH2:21][NH:22][C:12]([C:11]1[C:2]([OH:1])=[CH:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=1)=[O:14]
Reactant: CN(C)CCCN
Reactant: COC(=O)c1cc2ccccc2cc1O
Solvent: Cc1ccccc1
Product: CN(C)CCCNC(=O)c1cc2ccccc2cc1O

Procedure:
The coupling component used in this Example was obtained by reacting methyl 2-hydroxy-3-naphthoate with dimethylamino propylamine in toluene to obtain N,N-dimethyl-N-3-(3-hydroxy-2-naphthamido)propylamine, and converting the amide compound isolated by filtration, with dimethylsufuric acid in methanol, to a quaternary ammonium form. Further, the amide compound may also be readily prepared via 2-hydroxy-3-napthoic acid chloride.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.FC(F)(F)S([C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]=[CH:31][NH:32]2)(=O)=O.[CH3:39][O:40][N:41]([CH3:46])[C:42](=[O:45])[CH:43]=[CH2:44].C(N(CC)CC)C>CN(C=O)C.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[NH:32]1[C:33]2[C:29](=[CH:28][CH:36]=[C:35]([CH:44]=[CH:43][C:42]([N:41]([O:40][CH3:39])[CH3:46])=[O:45])[CH:34]=2)[CH:30]=[CH:31]1
Reactant: C=CC(=O)N(C)OC
Reactant: O=S(=O)(c1cccc2[nH]ccc12)C(F)(F)F
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)C=Cc1ccc2cc[nH]c2c1
Temperature: 120 °C
Yield: 39 %

Procedure:
Tris(dibenzylideneacetone) dipalladium (45 mg, 0.05 mmol) and tri-o-tolylphosphine (120 mg, 0.20 mmol) were stirred in DMF at room temperature for 30 min. The 4-trifluoromethanesulfonyl-1H-indole, N-methoxy-N-methyl acrylamide (1.26 g, 11.00 mmol), and triethylamine (2.20 g, 22.00 mmol) were added and the reaction was heated to 120° C. for 4 h. The reaction was allowed to cool and the solvent removed in vacuo. The residue was taken up in methylene chloride, washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give a brown solid. The solid was purified by flash chromatography (EtOAc, hexanes) to give 3-(1H-indol-6-yl)-N-methoxy-N-methyl-acrylamide (0.90 g, 39% yield for the three reactions). 1H NMR (CDCl3): δ8.385 (bs, 1H), 7.86 (d, J=18.6 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.57 (s, 1H), 7.25 (d, J=8.5 Hz, 1H), 7.25 (m, 1H), 7.03 (d, J=18.6 Hz, 1H), 6.55 (m, 1H), 3.78 (s, 3H), 3.32 (s, 3H).