Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][OH:2].[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[C:6](F)[N:5]=1.C[O-].[Na+].CO>C(Cl)(Cl)Cl>[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[C:6]([O:2][CH3:1])[N:5]=1
Reactant: Nc1nc(F)c(F)cc1F
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1nc(N)c(F)cc1F
Temperature: 70 °C

Procedure:
To 1 ml of methanol were added 500 mg of 2-amino-3,5,6-trifluoropyridine together with 800 mg of 28% sodium methoxide/methanol solution, and the mixture was stirred at 70° C. for 3 and half hours, and allowed to cool. After adding 25 ml of chloroform, the mixture was washed with 5 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title product.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[C:13]1[CH:14]=[CH:15][C:16]([N+:28]([O-:30])=[O:29])=[C:17]([N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=1.[H-].[Na+]>CN(C)C=O>[CH3:27][N:19]([C:17]1[CH:18]=[C:13]([O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=2)[CH:14]=[CH:15][C:16]=1[N+:28]([O-:30])=[O:29])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:23])[CH3:24]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2)ccc1[N+](=O)[O-]
Yield: 20.4 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 4-trifluoromethylphenol (3.0 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (4.3 g), sodium hydride (55 wt. %, 1.1 g) and anhydrous N,N-dimethylformamide (70 ml) and the reaction mixture was purified to give the title compound (1.26 g)
Reaction SMILES: [Na].[C:2]([O:9][CH2:10][CH3:11])(=[O:8])[C:3]([O:5]CC)=O.[CH3:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]>C(O)C>[N+:19]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[CH2:12][C:3](=[O:5])[C:2]([O:9][CH2:10][CH3:11])=[O:8])([O-:21])=[O:20]
Reactant: Cc1ccncc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1ccncc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
To a solution of 930 mg of sodium in 50 mL of absolute ethanol are rapidly added 26 mL of diethyl oxalate. The reaction medium is stirred for 15 minutes at 20° C. A solution of 3.8 g of 4-methyl-3-nitropyridine in 50 mL of absolute ethanol is then added dropwise over 1 hour. The reaction medium is stirred for 4 hours at a temperature in the region of 20° C. and then concentrated under reduced pressure. The residue is taken up in 100 mL of ethyl ether and then filtered. The solid is stirred with 40 mL of 5N hydrochloric acid and then filtered, washed with water and dried under vacuum at 40° C. to give 6.2 g of ethyl 3-(3-nitro-4-pyridyl)-2-oxopropionate having the following characteristics:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CC(O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1
Yield: 103.4 %

Procedure:
1-Fluoro-4-nitrobenzene (3.00 mL, 28.3 mmol) was combined in a flask with anhydrous 2-propanol (28 mL), triethylamine (4.34 mL, 31.1 mmol), and morpholine (2.47 mL, 28.3 mmol). The mixture was refluxed for 3.5 h before adding additional morpholine (2.47 mL, 28.3 mmol) and refluxing for 20 h. The mixture was then cooled and concentrated under reduced pressure. Purification by silica gel flash chromatography provided 161-a (6.09 g, 98%) as a 95% pure solid. MS: APCI (AP−): 207.1 (M)−.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=5)[S:20][C:13]=34)[CH:9]=[CH:10][C:4]=2[C:3]=1[C:27]([OH:29])=O.C([N:33](CC)[CH:34]([CH3:36])[CH3:35])(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:34]1([NH:33][C:27]([C:3]2[C:4]3[CH:10]=[CH:9][C:8]([O:11][C:12]4[CH:17]=[CH:16][N:15]=[C:14]5[CH:18]=[C:19]([C:21]6[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=6)[S:20][C:13]=45)=[CH:7][C:5]=3[S:6][C:2]=2[CH3:1])=[O:29])[CH2:36][CH2:35]1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1sc2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc2c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1sc2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc2c1C(=O)NC1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of 2-methyl-6-{[2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yl]oxy}benzo[b]thiophene-3-carboxylic acid 117b (75 mg, 0.18 mmole) in DMF (1.5 mL) at 0° C. were added N,N-diisopropylethylamine (68 μL, 0.39 mmole) and HBTU (100 mg, 0.27 mmole). The reaction mixture was stirred 30 min at 0° C. then warmed to room temperature and stirred 18 hr. The mixture was poured onto H2O (25 mL) and the precipitate was collected by vacuum filtration. The filter paper was extracted with a mixture of CH2Cl2 (10 mL) and MeOH (10 mL). The solution was concentrated and the crude mixture was purified by silica gel chromatography (5% MeOH/EtOAc) to afford a pale yellow solid (58 mg, 71%). 1H NMR (DMSO-d6, 300 MHz) δ 8.52 (1H, d, J=5.46 Hz), 8.46 (1H, d, J=4.33 Hz), 7.95 (1H, d, J=2.26 Hz), 7.88 (1H, s), 7.80 (1H, d, J=8.67 Hz), 7.40 (1H, s), 7.32 (1H, dd, J=2.26, 8.85 Hz), 7.02 (1H, s), 6.70 (1H, d, J=5.46 Hz), 3.98 (3H, s), 2.90 (1H, m), 2.57 (3H, s); 0.73 (2H, m), 0.57 (2H, m);
Reaction SMILES: Br[C:2]1[S:3][C:4]([Sn](C)(C)C)=[CH:5][C:6]=1[CH2:7][CH2:8][C:9]1[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cu]=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CN(C=O)C>[CH3:14][C:12]1([CH3:15])[CH2:11][O:10][C:9]([CH2:8][CH2:7][C:6]2[CH:5]=[CH:4][S:3][CH:2]=2)=[N:13]1
Reactant: CC1(C)COC(CCc2cc([Sn](C)(C)C)sc2Br)=N1
Agent: O=[Cu]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CC1(C)COC(CCc2ccsc2)=N1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
2-(2-(2-bromo-5-(trimethylstannyl)thiophen-3-yl)ethyl)-4,5-dihydro-4,4-dimethyloxazol (7.0 g, 15.5 mmol) was weighed in 100 mL Schlenk flask followed by the addition of 30 mL dry DMF then purged with nitrogen for 15 min. To this mixture, copper (II) oxide (1.24 g, 15.5 mmol, 1 eq.), triphenylphosphine (814 mg, 0.031 mmol, 0.20 eq.) and bis(dibenzylidene acetone)palladium(0) (446 mg, 0.776 mmol, 0.05 eq) was added all at once. The greenish-brown suspension solution was purged with nitrogen for 15 min then heated to 100° C. and stirred for 18 hrs under argon atmosphere. The reaction mixture was filtered thru celite and the purple precipitate was extracted with chloroform. The chloroform extract was concentrated and the resulting solid was soxhlet-extracted with hexanes then extracted with chloroform. The solvent was removed to afford a purple solid (2.1 g, 66% S5 yield). 1H NMR (300 MHz, CDCl3): δ=7.06 (s, 1H), 3.94 (s, 2H), 3.14 (d, 2H), 2.66 (d, 2H), 1.28 (s, 6H); 13C NMR (75 MHz, CDCl3): δ=166.7, 138.4, 134.4, 132.4, 129.8, 80.0, 68.0, 29.6, 29.2, 26.4. CDCl3
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:8][NH:9]C(=O)C1C=CC(OCCCCCl)=CC=1)([CH3:4])([CH3:3])[CH3:2].N1CCOCC1.CN(C=O)C>CCOC(C)=O>[C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:8][NH2:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(OCCCCCl)cc1)NS(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1COCCN1
Product: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1

Procedure:
A stirring solution of 24-4 (500 mg, 1.0 mmol), morpholine (437 gL, 5.0 mmol), and DMF (5 mL) was heated at 80° C. for 20 hours. The cooled reaction mixture was diluted with EtOAc and then washed with H2O and brine, dried (MgSO4) and concentrated. Flash chromatography (silica, EtOAc) gave 24-5 as a yellow solid. TLC Rf 0.14 (silica, EtOAc);
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@:3]1([CH2:19][F:20])[C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[F:18]>C(O)C.[Pd]>[NH2:15][C:13]1[CH:12]=[CH:11][C:10]([F:18])=[C:9]([C@:3]2([CH2:19][F:20])[C:2]([F:21])([F:1])[CH2:7][O:6][C:5]([NH2:8])=[N:4]2)[CH:14]=1
Reactant: NC1=N[C@](CF)(c2cc([N+](=O)[O-])ccc2F)C(F)(F)CO1
Agent: [Pd]
Solvent: CCO
Product: NC1=N[C@](CF)(c2cc(N)ccc2F)C(F)(F)CO1
Yield: 108.2 %

Procedure:
A solution of (S)-5,5-difluoro-4-fluoromethyl-4-(2-fluoro-5-nitro-phenyl)-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate F7.1) (38.2 mg, 120 μmol) in ethanol (2 ml) was hydrogenated at atmospheric pressure using palladium (10% on carbon) (6.4 mg, 6 μmol) as the catalyst during 15 hours at room temperature. The reaction mixture was filtrated over a layer of Dicalite®, which was washed with ethanol (2×10 ml). The combined solutions of ethanol were evaporated at reduced pressure. The (S)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-fluoromethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (36 mg, quantitative yield) was obtained as a light red solid and was engaged in the following step without further purification. MS (ISP): m/z=278.2 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[N:3]=1.[O-]Cl.[Na+].[NH4+:17].[OH-]>[OH-].[Na+].O>[F:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[N:3]=[C:2]([S:1][NH2:17])[S:6][N:5]=1
Reactant: [NH4+]
Reactant: Fc1ccccc1-c1nsc(S)n1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Product: NSc1nc(-c2ccccc2F)ns1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 29.5 g of 5-mercapto-3-(2-fluorophenyl)-1,2,4-thiadiazole in 550 ml of 4.5% NaOH and a solution prepared by diluting 180 ml of 10% NaOCl to 550 ml with water were added dropwise simultaneously to 1450 ml of NH4OH solution maintained at 0° C. with an ice/methanol bath. The resulting mixture was stirred for 30 minutes and the solids were collected, washed with water and dried under high vacuum (P2O5) to give 19.0 g of solid, mp 151°-2° dec.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][CH2:10][OH:11])=[N:6][C:5]([S:12][CH3:13])=[CH:4][N:3]=1.[H-].[Na+].[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.[Cl-].[NH4+]>CN(C)C=O>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:1]2[C:2]3=[N:3][CH:4]=[C:5]([S:12][CH3:13])[N:6]=[C:7]3[CH:8]=[C:9]2[CH:10]=[O:11])=[CH:19][CH:18]=1
Reactant: CSc1cnc(N)c(C#CCO)n1
Reactant: Fc1ccc(CBr)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CSc1cnc2c(cc(C=O)n2Cc2ccc(F)cc2)n1
Reaction time: 0.33 h
Yield: 97.2 %

Procedure:
To a solution of the compound obtained in Example 34 (5) (10 mg) in N,N-dimethylformamide (0.5 ml), 60% sodium hydride (3 mg) was added at 0° C. and the mixture was stirred for 20 minutes. To the resulting mixture was added dropwise 4-fluorobenzyl bromide (15 mg) and the mixture was stirred at 15 to 30° C. for 30 minutes. The reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with chloroform, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (hexane:ethyl acetate=5:1) to obtain 15 mg (99.6%) of the desired product as an orange powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[OH:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Reactant: Oc1ccncc1
Product: COc1ccc(-c2cc(Oc3ccncc3)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (200 mg, 0.613 mmol) and 4-hydroxypyridine were reacted as starting materials at 150° C. for 22 hours and post-treatment was then conducted, whereby the title compound was obtained as a pale yellow crystalline powder (201.6 mg, 85.2%). Melting point: 186.8-188.8° C. (hexane).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([C@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][N:25]3C(OC(C)(C)C)=O)=[O:23])[CH2:18][CH2:17]2)=[CH:12][C:11]=1[NH:37][C@@H:38]([C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=1[Cl:47])[CH3:39])#[N:9]>ClCCl>[Cl:47][C:41]1[CH:42]=[C:43]([Cl:46])[CH:44]=[CH:45][C:40]=1[C@H:38]([NH:37][C:11]1[CH:12]=[C:13]([N:16]2[CH2:17][CH2:18][N:19]([C:22]([C@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]3)=[O:23])[CH2:20][CH2:21]2)[CH:14]=[CH:15][C:10]=1[C:8]#[N:9])[CH3:39]
Reactant: C[C@@H](Nc1cc(N2CCN(C(=O)[C@H]3CCCCN3C(=O)OC(C)(C)C)CC2)ccc1C#N)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Nc1cc(N2CCN(C(=O)[C@H]3CCCCN3)CC2)ccc1C#N)c1ccc(Cl)cc1Cl
Reaction time: 1 h
Yield: 75 %

Procedure:
Trifluoroacetic acid (0.3 mL) was added to a solution of (R)-t-butyl 2-(4-(4-cyano-3-((R)-1-(2,4-dichlorophenyl)ethylamino)phenyl)piperazine-1-carbonyl)piperidine-1-carboxylate (0.095 g, 0.16 mmol) in dichloromethane (1 mL) at room temperature, and the solution was stirred for 1 h. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane. The organic layer was neutralized with aqueous saturated sodium bicarbonate solution, and the aqueous layer was further extracted with dichloromethane. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound as a white solid (0.060 g, 0.12 mmol, 75%). 1H NMR (400 MHz, DMSO-d6) δ 9.0 (br, 1H), 8.62-8.52 (m, 1H), 7.62-7.50 (m, 2H), 7.37 (dd, J=2.2, 8.4 Hz, 1H), 7.05 (d, J=8.8 Hz, 1H), 6.19 (dd, J=2.5, 8.8 Hz, 1H), 5.82 (d, J=2.6 Hz, 1H), 5.68 (br, 1H), 4.86 (br, 1H), 3.70-2.80 (m, 9H), 1.98-1.92 (m, 1H), 1.78-1.58 (m, 4H), 1.50-1.40 (m, 5H); MS: (ES) m/z calculated for C25H30Cl2N5O [M+H]+ 486.2. found 486.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH2:19])[NH:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].CS(O[C@@H:31]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32]1)(=O)=O>CN(C=O)C>[NH2:19][C:17]1[N:16]=[CH:15][N:14]=[C:13]2[N:12]([C@H:35]3[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34]3)[N:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[C:18]=12
Reactant: Nc1ncnc2[nH]nc(-c3ccc([N+](=O)[O-])cc3)c12
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H](n2nc(-c3ccc([N+](=O)[O-])cc3)c3c(N)ncnc32)C1
Reaction time: 6 h
Yield: 51.8 %

Procedure:
A solution of 3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.5 g, 1.95 mmol), K2CO3 (1.08 g, 7.8 mmol), and (R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl methanesulfonate (0.62 g, 2.34 mmol) in DMF (20 mL) was brought to 80° C. under an argon atmosphere. The reaction mixture was left stirring for 6 hours, then cooled and filtered. The filtrate was concentrated in vacuo, but not to dryness. 20 mL of 0.1 sodium citrate was added causing a solid to form, which was collected by filtration to afford (S)-tert-butyl 3-(4-amino-3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate (0.43 g, 52% yield). ESI-MS m/z [M+H]+ found 426.7, calculated 426.2.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1.[ClH:18].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:18].[CH3:1][O:2][CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]1
Reactant: COCC[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: COCC[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (S)-3-(2-methoxyethyl)piperidine-1-carboxylate (64 g, 263 mmol) in ethyl acetate (100 ml) was added 4N HCl-ethyl acetate solution (320 ml), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure to give (S)-3-(2-methoxyethyl)piperidine hydrochloride as a crude product (46.7 g, yield 98%). The obtained crude product was used for Step 4 without further purification.
Reaction SMILES: [C:1](OC)([O:5][CH3:6])([O:3]C)[CH3:2].[C:9]1([CH:15](O)[C:16]([CH3:18])=[CH2:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)(=O)CC>CO>[CH3:17]/[C:16](=[CH:15]\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)/[CH2:18][CH2:2][C:1]([O:5][CH3:6])=[O:3]
Reactant: C=C(C)C(O)c1ccccc1
Reactant: COC(C)(OC)OC
Solvent: CO
Solvent: CCC(=O)O
Product: COC(=O)CC/C(C)=C/c1ccccc1
Yield: 20.9 %

Procedure:
Trimethyl orthoacetate (186 g, 1.52 mol) and 1-phenyl-2-methyl-2-propen-1-ol (90% pure from Alfa Aesar, 25 g, 0.152 mol) were heated in the presence of propionic acid (0.2 ml) in an oil bath at 145° C. for 4 hours. The methanol formed during the reaction was distilled. The excess orthoacetate was then removed under vacuum and the residue was purified by column chromatography on silica gel (eluent: heptanes/ethyl acetate 25:1 to 8:1) followed by bulb-to-bulb distillation (67° C./0.001 mbar). 6.5 g (yield=21%) of the desired product were obtained.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.C[O:19][C:20]([C:22]1[C:23]([C:30]2[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:37])=[N:24][O:25][C:26]=1[CH:27]1[CH2:29][CH2:28]1)=O.CO>C1COCC1.CCOC(C)=O.O>[CH:27]1([C:26]2[O:25][N:24]=[C:23]([C:30]3[C:31]([Cl:37])=[CH:32][CH:33]=[CH:34][C:35]=3[Cl:36])[C:22]=2[CH2:20][OH:19])[CH2:29][CH2:28]1
Reactant: COC(=O)c1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: Cc1ccccc1
Product: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
Diisobutylaluminium hydride 1M/toluene (4.62 L, 4.62 mol) is added dropwise to a stirred solution of 5-Cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole-4-carboxylic acid methyl ester (687.14 g, 2.20 mol) in THF (4.4 L) at 0° C. The reaction is stirred at room temperature for 2 hours. Methanol (150 mL) is added over the mixture at 0° C. and stirred for 10 min. Then, water (2.2 L) and EtOAc (4.3 L) is added. The precipitate formed is filtered through celite and all the solvents are removed in vacuum. The solid is triturated in 1 L of hexane and dried under vacuum filtration to obtain title compound (534.7 g, 85% yield) as a white solid. MS (m/e): 312 (M+1)
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1)[CH2:2][CH3:3].[Br:14]Br.N.CO.C(Cl)Cl>CC(O)=O>[CH2:1]([N:4]1[C:8]2[C:9]([Br:14])=[C:10]([NH2:13])[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1)[CH2:2][CH3:3]
Reactant: BrBr
Reactant: CCCn1cnc2ccc(N)cc21
Agent: N
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CCCn1cnc2ccc(N)c(Br)c21
Yield: 37 %

Procedure:
To a solution of 3-propyl-5-aminobenzimidazole (0.71 g, 4.3 mmol) in 10 ml of AcOH was added solution of Br2 in AcOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CH2Cl2) to provide 0.40 g (1.6 mmol, 37%) of the product.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH:14]([OH:16])[CH2:15][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])[CH3:3].C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].Br[CH2:42][C:43]1[C:44]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[CH3:57])=[N:45][O:46][C:47]=1[CH:48]1[CH2:50][CH2:49]1>O1CCCC1.O.C(OCC)(=O)C>[CH:48]1([C:47]2[O:46][N:45]=[C:44]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=3[CH3:57])[C:43]=2[CH2:42][O:16][CH:14]2[CH2:15][CH:9]3[N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH:12]([CH2:11][CH2:10]3)[CH2:13]2)[CH2:50][CH2:49]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)C2
Reactant: Cc1ccccc1-c1noc(C2CC2)c1CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1-c1noc(C2CC2)c1COC1CC2CCC(C1)N2C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
A flask was purged with nitrogen and then charged with N-Boc-nortropine (1.64 g, 7.20 mmol), 18-crown-6 (1.59 g, 6.00 mmol), and anhydrous tetrahydrofuran (60 mL). Potassium tert-butoxide (1.34 g, 12.0 mmol) was added portion-wise, and the mixture was stirred vigorously under nitrogen for 1 hour. 4-(Bromomethyl)-5-cyclopropyl-3-(o-tolyl)isoxazole (1.75 g, 6.00 mmol) in tetrahydrofuran (20 mL, anhydrous) was added dropwise, and the reaction mixture was stirred for 1 hour under nitrogen. The solvent was reduced in vacuo and the mixture diluted with water (100 mL) and ethyl acetate (100 mL). The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The crude residue was purified by silica gel chromatography using a gradient of 0-100% ethyl acetate/hexanes to yield the desired product as a yellow oil. MS m/z 439.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:33](COCC[Si](C)(C)C)[C:16]4=[N:17][CH:18]=[C:19]([N:21]([CH2:29][C:30](=O)[CH3:31])C(=O)OC(C)(C)C)[N:20]=[C:15]4[CH:14]=3)=[CH:9][CH:8]=2)OCC[O:3]1.C(O)(C(F)(F)F)=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>>[CH3:31][C:30]1[N:20]2[C:15]3[CH:14]=[C:13]([C:10]4[CH:9]=[CH:8][C:7]([C:2](=[O:3])[CH3:1])=[CH:12][CH:11]=4)[NH:33][C:16]=3[N:17]=[CH:18][C:19]2=[N:21][CH:29]=1
Reactant: CC(=O)CN(C(=O)OC(C)(C)C)c1cnc2c(cc(-c3ccc(C4(C)OCCO4)cc3)n2COCC[Si](C)(C)C)n1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1ccc(-c2cc3c(ncc4ncc(C)n43)[nH]2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.2 %

Procedure:
tert-Butyl 6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl(2-oxopropyl)carbamate (0.425 g, 0.729 mmol) was stirred in TFA (4.0 mL, 52 mmol). To the mixture was added TFAA (4 mL, 28.3 mmol) and the reaction stirred for about 20 h at rt. The solvents were removed under vacuum and 1,4-dioxane (12 mL) was added along with concentrated NH4OH (8 mL). The mixture was stirred for about 3 h. The resulting solid was collected by vacuum filtration washed with water and dried under vacuum at about 50° C. in the presence of P2O5 to a constant weight give 1-(4-(8-methyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-2-yl)phenyl)ethanone (0.121 g, 57%): LC/MS (Table 2, Method h) Rt=1.06 min.; MS m/z: 291 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]#[C:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[CH3:2].[C:14]([O:18][C:19]([N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH2:31][CH2:32][O:33][C:34]3[CH:35]=[C:36]4[C:40](=[CH:41][CH:42]=3)[NH:39][CH:38]=[CH:37]4)[N:29]=2)[CH2:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH2:31][CH2:32][O:33][C:34]3[CH:35]=[C:36]4[C:40](=[CH:41][CH:42]=3)[N:39]([C:6]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:13])[CH:38]=[CH:37]4)[N:29]=2)[CH2:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)C#Cc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Product: CCOC(=O)C=C(c1ccncc1)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 64 %

Procedure:
The title compound is prepared from pyridin-4-yl-propynoic acid ethyl ester and 7-[2-(1H-Indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 17, step (a), in 64% yield as an E/Z mixture. The mixture is used for the next reaction without further separation.