Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]1[CH2:6][O:5][C:4](=[O:7])[O:3]1.[C:8]([NH:11][C:12]1[C:13]([I:28])=[C:14]([N:23]([C:25](=[O:27])[CH3:26])[CH3:24])[C:15]([I:22])=[C:16]([C:19]([O-:21])=[O:20])[C:17]=1[I:18])(=[O:10])[CH3:9].[K+].[I-].[Na+]>CN(C=O)C>[C:8]([NH:11][C:12]1[C:13]([I:28])=[C:14]([N:23]([C:25](=[O:27])[CH3:26])[CH3:24])[C:15]([I:22])=[C:16]([C:19]([O:21][CH:2]2[CH2:6][O:5][C:4](=[O:7])[O:3]2)=[O:20])[C:17]=1[I:18])(=[O:10])[CH3:9]
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Reactant: O=C1OCC(Cl)O1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OC2COC(=O)O2)c(I)c(N(C)C(C)=O)c1I
Temperature: 50 °C
Reaction time: 96 h

Procedure:
4-Chloro-1,3-dioxolan-2-one (1.35 g, 11 mmol) was added at room temperature to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (6.66 g, 10 retool) and sodium iodide (0.15 g, 1 retool) in dry DMF (50 ml). After stirring at 50° C. for 6 hours and at room temperature for 4 days the solvent was removed at reduced pressure. The residue was dissolved in chloroform (100 ml) and washed four times with a saturated sodium hydrogen carbonate solution and finally twice with water. After treatment with magnesium sulfate the solution was finally evaporated to dryness. Yield: 5.6 g. Purity by HPLC: 93%. 1H-NMR (DMSO-d6): delta=1.67 (N(CH3)COCH3); 2.05(NCOCH3); 2.96 (NCH3); 4.7; 4.9(CH2); 7.02(CH); 10.14 ppm (NH).
Reaction SMILES: C([O:5][C:6](=[O:20])[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:9]1=[O:19])(C)(C)C.[O:21]=[C:22]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH2:30][CH2:29]1)[CH2:23][CH2:24][C:25](O)=[O:26].Cl.C(N=C=NCCCN(C)C)C>C(#N)C>[CH3:18][O:17][C:15]([CH2:14][C@@H:10]1[N:11]([C:25](=[O:26])[CH2:24][CH2:23][C:22](=[O:21])[N:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[CH2:30][CH2:29]2)[CH2:12][CH2:13][N:8]([CH2:7][C:6]([OH:5])=[O:20])[C:9]1=[O:19])=[O:16]
Reactant: COC(=O)C[C@@H]1NCCN(CC(=O)OC(C)(C)C)C1=O
Reactant: O=C(O)CCC(=O)N1CCN(c2ccccn2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Product: COC(=O)C[C@H]1C(=O)N(CC(=O)O)CCN1C(=O)CCC(=O)N1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
To suspension of (S)-(3-methoxycarbonylmethyl-2-oxopiperazin-1-yl)acetic acid tert-butyl ester (0.64 g) and 4-oxo-4-(4-pyridin-2-ylpiperazin-1-yl)butanoic acid (0.65 g) produced in Reference Example 3 in acetonitrile (20 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.52 g) and the suspension was stirred for 5 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the concentrate was purified by means of a silica gel column chromatography (acetonitrile/methanol=9/1). To the produced ester derivative was added trifluoroacetic acid (10 ml) and the solution was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the concentrate was purified by means of CHP-20 column chromatography (H2O→10% acetonitrile aqueous solution). The objected fraction was concentrated and subjected to lyophilization to give the titled compound (0.84 g) as a white amorphous powdery product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[N:11]=[N:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:14]=1[OH:24])([O-])=O.C(N)CCC.[H][H]>[Pt].C1(C)C(C)=CC=CC=1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]2=[N:1][N:12]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:14]=3[OH:24])[N:11]=[C:5]2[CH:6]=1
Reactant: Cc1cc(N=Nc2cc(Cl)ccc2[N+](=O)[O-])c(O)c(C(C)(C)C)c1
Reactant: [H][H]
Agent: [Pt]
Solvent: Cc1ccccc1C
Solvent: CCCCN
Product: Cc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Reaction time: 1.5 h

Procedure:
60 g of 2-nitro-5-chloro-2'-hydroxy-3'-tert-butyl-5'-methylazobenzene (purity 86%), 40 g of xylene, 60 g of n-butylamine and 1 g of 1% Pt on activated carbon are put into a 300 ml hydrogenation reactor at room temperature under argon. Argon is then replaced by hydrogen. After the injection of 10 bar hydrogen, the hydrogenation is carried out at 35°-37° C. with intensive stirring. The heat released is removed by cooling. The end of the hydrogenation reaction is easily detectable by the hydrogen absorption ceasing after 2 mol equivalents of hydrogen, relative to the azobenzene starting product. The total hydrogenation time is about 1.5 hours.
Reaction SMILES: C(OC([NH:8][CH:9]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][F:24])[CH:16]=1)[CH2:10][C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH:9]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][F:24])[CH:16]=1)[CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CC(NC(=O)OC(C)(C)C)c1cccc(OCCF)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CC(N)c1cccc(OCCF)c1
Reaction time: 20 h
Yield: 101.6 %

Procedure:
To methyl 3-[(tert-butoxycarbonyl)amino]-3-[3-(2-fluoroethoxy)phenyl)propanoate (5.0 g, 20 mmol) in dichloromethane was added trifluoro acetic acid (5.64 mL, 73 mmol). After stirring for 24 hours at room temperature additional trifluoro acetic acid (1.13 mL) was added and stirring was continued for 20 hours. The mixture was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (methanol in dichloromethane 0% to 40%)) to yield 4.9 g methyl 3-amino-3-[3-(2-fluoroethoxy)phenyl]propanoate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([O:24]C)=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2]>C(#N)C.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccnc(-n2nccc2OCc2ccc(C#N)cc2)c1
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(COc2ccnn2-c2cc(C(=O)O)ccn2)cc1

Procedure:
The title compound was prepared from methyl 2-[5-[(4-cyanophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate (EXAMPLE 98) according to the procedure for the preparation of Example 97, part B. 1H NMR (400 MHz, DMSO-d6): δ 5.41 (2H, s), 6.00 (1H, d, J=2.0 Hz), 7.61 (1H, d, J=1.6 Hz), 7.67-7.69 (2H, m), 7.77 (1H, dd, J=0.8 Hz, J=4.8 Hz), 7.87-7.89 (2H, m), 8.10 (1H, s), 8.70 (1H, d, J=5.2 Hz), 13.92 (1H, s). LCMS (mobile phase: 10%-95% Acetonitrile-Water-0.02% NH4Ac): purity is >95%, Rt=2.104 min. [M+H] Calc'd for C17H12N4O3, 321; Found, 321.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:12])[CH:8]=2)[N:3]=1.[CH:13]1[CH:18]=[C:17]([CH:19]=[O:20])[CH:16]=[C:15]([CH:21]=O)[CH:14]=1.C(OC(=O)C)(=O)C>C1(C)C(C)=CC=CC=1>[F:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2](/[CH:1]=[CH:21]/[C:15]1[CH:16]=[C:17]([CH:18]=[CH:13][CH:14]=1)[CH:19]=[O:20])[CH:11]=[CH:10]2
Reactant: Cc1ccc2cc(F)ccc2n1
Reactant: O=Cc1cccc(C=O)c1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1C
Product: O=Cc1cccc(/C=C/c2ccc3cc(F)ccc3n2)c1
Yield: 50.7 %

Procedure:
Using the procedure of Preparation I1, 5.04 g of 2-methyl-6-fluoroquinoline, 4.20 g of isophthaldehyde and 8.86 ml of acetic anhydride in 100 ml of xylene gave 4.40 g of the titled product as a pale yellow solid, m.p. 110°-111° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH:3]=1.[C:20]([O:24][C:25](=[O:34])[NH:26][C:27]1[N:32]=[C:31]([NH2:33])[CH:30]=[CH:29][N:28]=1)([CH3:23])([CH3:22])[CH3:21].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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]>[C:20]([O:24][C:25](=[O:34])[NH:26][C:27]1[N:32]=[C:31]([NH:33][C:2]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=3[F:19])[CH:3]=2)[CH:30]=[CH:29][N:28]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: Fc1ccc(Cl)cc1-c1cc(Cl)c2cccnc2n1
Reactant: CC(C)(C)OC(=O)Nc1nccc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1nccc(Nc2cc(-c3cc(Cl)ccc3F)nc3ncccc23)n1
Yield: 27.7 %

Procedure:
200 mg 4-chloro-2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine (cf. EXAMPLE 1) and 143 mg (4-amino-pyrimidin-2-yl)-carbamic acid tert-butyl ester in 8 ml dioxane containing 444 mg Cs2CO3, 13 mg Pd2(dba)3 and 16 mg xantphos were incubated under argon gas at 80° C. for 16 hrs. After evaporation to dryness the crude sample was flashed on SiO2 with a MeOH gradient in DCM. A pooled fraction was dried down and digested with ether to give 88 mg product {4-[2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-ylamino]-pyrimidin-2-yl}-carbamic acid tert-butyl ester as a white powder with Rt˜1.80 min and correct mass found M+H˜467.
Reaction SMILES: [C:1]1([C:7]([CH3:18])([CH2:13][CH2:14][CH2:15][C:16]#[N:17])[CH2:8][CH2:9][CH2:10][C:11]#[N:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.N.[H][H]>[Ni]>[C:1]1([C:7]([CH3:18])([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(CCCC#N)(CCCC#N)c1ccccc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(CCCCN)(CCCCN)c1ccccc1
Temperature: 125 °C
Yield: 172.5 %

Procedure:
An autoclave was charged with 0.42 mole 100 g 5-phenyl-5-methylnonanedinitrile, 10 g Raney nickel, and 9.86 mole 400 ml methanol. The reaction mixture was flushed with nitrogen and then charged with 8.9 mole 150 g ammonia. The reactor was then pressurized to 1500 psig with hydrogen and heated at 125° C. for two hours. The reactor was cooled, vented and the controls filtered and the filtrate concentrated in a rotary evaporator. Another hydrogenation run was made under essentially the same conditions described above except that 0.46 mole 110 g of 5-phenyl-5-methylnonanedinitrile was employed. The product of this run was concentrated as described above. Analysis of these concentrates by NMR and GLC indicated that complete hydrogenation of the nitrile groups to amino groups had been accomplished. The concentrates were then fractionally distilled under vacuum to give 180 g of 5-phenyl-5-methyl-1,9-nonanediamine for an 84 mole percent yielf based on the 5-phenyl-5-methylnonanedinitrile.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:19][CH2:20][CH3:21])[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:9]2[OH:12])=[CH:4][C:3]=1[O:22][CH3:23].F[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:19][CH2:20][CH3:21])[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:9]2[O:12][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=2)=[CH:4][C:3]=1[O:22][CH3:23]
Reactant: CCCc1cc2cc(OC)c(F)cc2c(O)c1-c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cc2cc(OC)c(F)cc2c(Oc2ccc(C=O)cc2)c1-c1ccccc1
Temperature: 100 °C
Yield: 68.4 %

Procedure:
7-Fluoro-6-(methyloxy)-2-phenyl-3-propyl-1-naphthalenol (137) (0.42 g, 1.34 mmol) was dissolved in DMF (5 mL). To this solution was added 4-fluorobenzaldehyde (0.34 g, 2.68 mmol) followed by Cs2CO3 (0.57 g, 1.74 mmol). The mixture was heated at 100° C. for 36 h, poured into water (50 mL) and extracted with EtOAc (2×75 mL). The combined organic extract was washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as reddish brown oil. The crude product was purified by flash chromatography over SiO2 eluted with a gradient from hexanes to 15% EtOAc in hexanes to give 0.38 g (69%) of the title compound (138) as a yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ 0.81 (t, J=7.4 Hz, 3H), 1.40-1.60 (m, 2H), 2.53 (t, J=7.8 Hz, 2H), 4.02 (s, 3H), 6.66 (d, J=8.8 Hz, 2H), 7.06-7.12 (m, 2H), 7.18-7.25 (m, 4H), 7.40 (d, J=12.1 Hz, 1H), 7.56-7.64 (m, 3H), 9.80 (s, 1H). LCMS (ESI): m/z 415 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([CH3:10])[C:4]=1[N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[Cl:18][C:19]1[CH:32]=[CH:31][C:22]2[S:23][C:24]([S:27](Cl)(=[O:29])=[O:28])=[C:25]([CH3:26])[C:21]=2[CH:20]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:27]([C:24]2[S:23][C:22]3[CH:31]=[CH:32][C:19]([Cl:18])=[CH:20][C:21]=3[C:25]=2[CH3:26])(=[O:29])=[O:28])=[C:5]([CH3:10])[C:4]=1[N:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1
Reactant: COc1ccc(N)c(C)c1N1CCN(C)CC1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Product: COc1ccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c(C)c1N1CCN(C)CC1

Procedure:
The title compound (E125) was prepared from 4-methoxy-2-methyl-3-(4-methylpiperazin-1-yl)phenylamine (D33) (58 mg, 0.247 mmol) and 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (70 mg, 0.247 mmol) using the method of Example 1 (103 mg, 81%). MH+=480/482.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[OH:22])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].CN(C)C.[C:27]([O:34][CH:35]([CH3:39])[C:36](Cl)=[O:37])(=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(=O)([O-])O.[Na+]>ClCCl.C(OCC)(=O)C>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:36](=[O:37])[CH:35]([O:34][C:27](=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH3:39])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1O
Reactant: CCCCCC(=O)OC(C)C(=O)Cl
Agent: CN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCC(=O)OC(C)C(=O)O[C@H]1[C@@H](CC)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C

Procedure:
In 15 ml of dichloromethane are dissolved 0.75 g of 16β-ethyl-17β-hydroxy-4-estren-3-one and 0.5 ml of trimethylamine, and 0.5 ml of 2-(n-hexanoyloxy)propionyl chloride is added to the solution. The mixture is refluxed for 2 hours. After cooling, the reaction mixture is poured into a mixture of 100 ml of ethyl acetate and 30 ml of saturated aqueous sodium hydrogen carbonate solution. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue dissolved in a small amount of diisopropyl ether. The solution is subjected to silica gel column chromatography. After serial passage of diisopropyl ether-n-hexane mixtures (2:8, 100 ml and 1:6, 300 ml), elution is carried out with 500 ml of a 1:1 mixture of the same solvents. The eluate is evaporated under reduced pressure to remove the solvent, giving 0.48 g of the above-identified compound as a light-yellow viscous oil.
Reaction SMILES: [CH3:1][Si:2]([CH3:42])([CH3:41])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([C:17]2[CH2:24][CH:23]3[N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:19]([CH2:20][O:21][CH2:22]3)[CH:18]=2)[CH:9]=1.[H][H]>CCOC(C)=O.[Pd]>[CH3:40][Si:37]([CH3:38])([CH3:39])[CH2:36][CH2:35][O:34][CH2:33][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:42])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:18][CH:19]3[N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:23]([CH2:22][O:21][CH2:20]3)[CH2:24]2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1C2C=C(c3cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n4nccc4n3)CC1COC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C2COCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n1)C2
Yield: 86.1 %

Procedure:
tert-butyl 7-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-9-azabicyclo[3.3.1]non-6-ene-9-carboxylate (1.27 g, 2.06 mmol) in EtOAc (50 mL) was hydrogenated at 50° C. using 10% Pd/C catalyst (200 mg) and 1 atmospheric hydrogen pressure for 16 h. After filtering off the catalyst, the solvent was evaporated off under reduced pressure and crude material was purified by column chromatography (0-40% hexane-ethyl acetate) to give product tert-butyl 7-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (1.1 g) as syn- and anti-mixture. HPLC-MS tR=3.15 min (UV254 nm). Mass calculated for formula C30H53N5O5Si2 619.3; observed MH+ (LCMS) 620.2 (m/z).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:11][CH2:12]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O-:26])(=[O:25])[CH3:24].[Na+]>CN(C)C=O>[C:23]([O:26][CH2:12][O:11][CH:10]([CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)[O-]
Reactant: ClCOC(COCc1ccccc1)COCc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCOC(COCc1ccccc1)COCc1ccccc1
Temperature: 21 °C
Reaction time: 15 h

Procedure:
To a solution of 1,3-di-O-benzyl-2-O-chloromethylglycerol from Preparation II (17.5 g, 55 mmol) in 400 ml of dimethylformamide at 0° C. under a drying tube was added sodium acetate (6 g). The solution was then warmed to 21° C. and magnetically stirred for 15 hours. The solvent was removed by evaporation at reduced pressure and the oily residue dissolved in 1 pound of diethylether. The ether solution was washed once with 750 ml of water, two times with 250 ml of water, and once with 250 ml of brine, dried over sodium sulfate and concentrated to give 19 g of 2-O-acetoxymethyl-1,3-di-O-benzylglycerol as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[N:5][CH:6]=[N:7]2.[I:13]Cl>Cl>[Cl:1][C:2]1[CH:11]=[C:10]([I:13])[C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[N:5][CH:6]=[N:7]2
Reactant: ClI
Reactant: Oc1ccc(Cl)c2cncnc12
Agent: Cl
Product: Oc1c(I)cc(Cl)c2cncnc12

Procedure:
5-Chloro-8-hydroxy-quinazoline (10 mmol) was added to a stirred solution of ICl (12 mmol) in concentrated HCl (10 mL).8 After 5 min, the precipitate was isolated via filtration, washed successively with H2O, saturated sodium thiosulfate and H2O, and dried. This provided 5-chloro-8-hydroxy-7-iodo-quinazoline (A53) as a solid.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:6][C:5]([CH:24]=[CH2:25])=[CH:4][N:3]=1.[NH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[N:31][CH:32]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O>C1COCC1>[CH3:34][O:33][C:30]1[N:31]=[CH:32][C:27]([NH:26][C:2]2[C:7]([C:8]3[N:16]=[C:15]([CH3:17])[N:14]=[C:13]4[C:9]=3[N:10]=[CH:11][N:12]4[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[CH:6][C:5]([CH:24]=[CH2:25])=[CH:4][N:3]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(N)cn1
Reactant: C=Cc1cnc(F)c(-c2nc(C)nc3c2ncn3C2CCCCO2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc3c2ncn3C2CCCCO2)c1
Reaction time: 0.58 h
Yield: 31.2 %

Procedure:
6-(2-Fluoro-5-vinylpyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (1.007 g, 2.967 mmol) and 5-amino-2-methoxypyridine (0.369 g, 2.97 mmol) were dissolved in THF (25 mL) and the reaction flask was cooled in an ice water bath. Then, LiHMDS (Aldrich, St. Louis, Mo., 1.0 M in THF, 9.0 mL, 9.0 mmol) was added via syringe, and the reaction was stirred under nitrogen for 35 minutes. Then, it was poured into water (50 mL), and the layers were separated. The aqueous phase was extracted with DCM, and the organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (40:1 DCM/2 N ammonia in MeOH to 30:1 DCM/2 N ammonia in MeOH) to give N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-vinylpyridin-2-amine (410.3 mg, 85% purity, 20% yield over 2 steps). MS (ESI pos. ion) m/z 444 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:15])=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCCl>[CH3:1][C:2]1[C:6]2[C:7]([OH:15])=[C:8]([C:11]([CH3:14])([CH3:12])[CH3:13])[CH:9]=[C:10]([C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:5]=2[O:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)c1oc2ccc(C(C)(C)C)c(O)c2c1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)c1oc2c(C(=O)c3ccccc3)cc(C(C)(C)C)c(O)c2c1C

Procedure:
To a solution of ethyl 3-methyl-4-hydroxy-5-tert-butylbenzofuran-2-carboxylate, compound 12a (1.00 g, 3.62 mmol) and benzoyl chloride (0.763 g, 5.43 mmol) in 1,2-dichloroethane (40 mL) at 0° C. was added aluminum chloride (0.720 g, 5.43 mmol) and the resulting mixture warmed to reflux for 3.5 hours. The reaction was allowed to cool, poured into 2N HCl (100 mL) and extracted with methylene chloride (4×25 mL). The combined extracts were washed with 5% NaHCO3 (25 mL), dried (Na2SO4), and concentrated. Flash chromatography using 25% ethyl acetate in hexane as eluant afforded ethyl 3-methyl-4-hydroxy-5-tert-butyl-7-benzoylbenzofuran-2-carboxylate, compound 15 as an oil sufficiently pure for further chemistry. 1H NMR d 1.34 (3H, t, J=6 Hz), 1.51 (9H, s), 2.89 (3H, s), 4.35 (2H, q, J=6 Hz), 7.56 (3H, m), 7.86 (3H, m).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([O:14]CC)=[O:13])=[CH:10][N:11]=2)[CH:8]=1)#[N:2].[CH3:17][O:18][CH2:19][C:20]([NH:22][NH2:23])=O.C[O-].[Na+]>C(OCCO)C>[CH3:17][O:18][CH2:19][C:20]1[N:2]=[C:1]([C:3]2[CH:4]=[CH:5][C:6]3[N:7]([C:9]([C:12]([OH:14])=[O:13])=[CH:10][N:11]=3)[CH:8]=2)[NH:23][N:22]=1
Reactant: COCC(=O)NN
Reactant: CCOC(=O)c1cnc2ccc(C#N)cn12
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCCO
Product: COCc1n[nH]c(-c2ccc3ncc(C(=O)O)n3c2)n1
Temperature: 110 °C

Procedure:
To a solution of ethyl 6-cyanoimidazo[1,2-a]pyridine-3-carboxylate (24q) (265 mg, 1.23 mmol) and 2-methoxyacetohydrazide (193 mg, 1.85 mmol) in 2-ethoxyethanol (5 mL) was added NaOMe (0.5 M in MeOH, 3.7 mL). The mixture was heated at 110° C. in a sealed vial overnight. The reaction mixture was purified by HPLC to give 6-(3-(methoxymethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (99). MS m/z 274.1 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=O.[N:20]([O-])=O.[Na+].[OH-].[Na+]>Cl.O>[N+:17]([C:14]1[CH:13]=[C:3]2[C:2](=[CH:16][CH:15]=1)[NH:1][N:20]=[C:4]2[CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)([O-:19])=[O:18]
Reactant: CN1CCC(C(=O)c2cc([N+](=O)[O-])ccc2N)CC1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCC(c2n[nH]c3ccc([N+](=O)[O-])cc23)CC1
Temperature: -3 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
To a −5° C. solution of 4-(2-amino-5-nitrobenzoyl)-1-methylpiperidine (570 mg, 2.2 mmol) in 9.6N aqueous hydrochloric acid (10 mL) was added dropwise a solution of sodium nitrite (164 mg, 2.4 mmol) in water (3 mL). This resulting diazonium salt solution was stirred 10 minutes at −5° C. then added dropwise to a −5° C. solution of stannous chloride dihydrate (1.95 g, 8.6 mmol) in 12N aqueous hydrochloric acid (6 mL). The resulting solution was stirred 2 hours at −3° C., basified with 1N aqueous sodium hydroxide (190 mL) and extracted exhaustively with ethyl acetate and methylene chloride. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give 420 mg of a brown residue. Purification by radial chromatography (silica gel, 2000 micron rotor, methylene chloride:methanol:ammonium hydroxide, 100:10:1) gave 177 mg (31.4%) of the title compound. The product was crystallized as the hydrochloride salt. EA calculated for C13H17ClN4O2: C, 52.62; H, 5.77; N, 18.88. Found: C, 52.39; H, 5.96; N, 18.77.