Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([S:4][C@@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:7]([C:8](=[O:25])[CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)(=O)C.C([S-])CC.[Na+].Cl.O>CO>[SH:4][C@@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:7]([C:8](=[O:25])[CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1
Reactant: CC(=O)S[C@@H]1CC[C@@]2(C)C(C1)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: CCC[S-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@@H](S)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99.7 %

Procedure:
To a suspension of 3α-acetylthioandrostane-6,17-dione (1.07 g) in MeOH (30 mL), sodium propanethiolate (0.28 g) was added and the reaction stirred for 20 minutes at room temperature. The mixture was neutralized with 1N HCl. Water was added and the mixture extracted with EtOAc. The organic layer was separated, washed with brine, and dried over Na2SO4 and evaporated to dryness to give 3α-mercaptoandrostane-6,17-dione (943 mg, 100%), used without further purification. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 3.54 (1H, m), 2.77 (1H, m), 2.54 (1H, d), 2.45-1.10 (19H, m), 0.78 (3H, s), 0.66 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([OH:18])=[C:7]3[C:15](=[O:16])[NH:14][NH:13][C:12](=[O:17])[C:8]3=[N:9][C:10]=2[CH:11]=1.[C:19](Cl)(=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([OH:18])=[C:7]3[C:15]([O:16][C:19](=[O:28])[CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:14][NH:13][C:12](=[O:17])[C:8]3=[N:9][C:10]=2[CH:11]=1
Reactant: O=c1[nH][nH]c(=O)c2c(O)c3ccc(Cl)cc3nc12
Reactant: O=C(Cl)CCc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(CCc1ccccc1)Oc1n[nH]c(=O)c2nc3cc(Cl)ccc3c(O)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 7-chloro-2,3-dihydro-10-hydroxypyridazino-[4,5-b]quinoline-1,4-dione (0.60 g, 2.3 mM), as prepared in Example 2, and hydrocinnamoyl chloride (1.15 g, 6.84 mM) in pyridine (9 mL) was refluxed for 1 hr. Upon cooling to room temperature, the solution solidified. After 2 hr at room temperature, the mixture was diluted with water (60 mL) and the solids broken up with a glass rod to provide a free-flowing aqueous suspension which was stirred for 1 hr. The solids were collected, washed with water (10 mL), and resuspended in 50% aqueous methanol (60 mL). After stirring for 15 minutes, this suspension was filtered and the collected solids were washed with 50% aqueous methanol (10 mL) and then sucked dry under a stream of nitrogen to provide a tan solid. This material was dried for 2.5 days in vacuo (50 mTorr) at 100° C. and then was recrystallized from dimethylsulfoxide/methanol. The title compound was obtained (0.40 g, 44%), after drying 24 hr in vacuo (50 mTorr) at 100° C, as an off-white powder, mp >300° C.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([CH:12]3[CH2:14][CH2:13]3)[O:11][C:7]=2[C:6]([CH:15](C(OC)=O)[C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:4]=1[CH3:30])#[N:2].[Cl-].[Mg+2].[Cl-]>CS(C)=O.O>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([CH:12]3[CH2:14][CH2:13]3)[O:11][C:7]=2[C:6]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:4]=1[CH3:30])#[N:2]
Reactant: COC(=O)C(C(=O)OC)c1c(-c2ccccc2)c(C)c(C#N)c2nc(C3CC3)oc12
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)Cc1c(-c2ccccc2)c(C)c(C#N)c2nc(C3CC3)oc12
Temperature: 90 °C
Reaction time: 23 h
Yield: 90 %

Procedure:
Dimethyl 2-(4-cyano-2-cyclopropyl-5-methyl-6-phenyl-1,3-benzoxazol-7-yl)malonate (I-294) (2.887 g, 7.11 mmol) was dissolved in dimethyl sulfoxide (50 ml) and water (5 ml), then at room temperature, magnesium chloride (2.03 g, 21.34 mmol) was added. The solution was stirred at 90° C. for 23 hours, then cooled to room temperature. The solvent was evaporated away under reduced pressure, the residue was fractionated with ethyl acetate and saturated brine. The aqueous layer was separated, extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=3:1, v/v) to obtain the entitled compound (2.216 g, 90%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([C@@:4]1([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20](=[O:25])[NH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[H-].[Na+].I[CH3:36]>CN(C=O)C>[CH2:1]([C@@:4]1([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:20](=[O:25])[N:21]([CH3:36])[CH:22]=[CH:23][CH:24]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc[nH]c3=O)cc2)C(=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3cccn(C)c3=O)cc2)C(=O)O1
Reaction time: 0.33 h
Yield: 83 %

Procedure:
A solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(2-oxo-1,2-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (15.5 mg, 0.036 mmol) in dry DMF (1 mL) was cooled to 0° C. Sodium hydride (60% in mineral oil, 3 mg, 2 equiv) was added. After 20 min, iodomethane (4.5 μL, 2 equiv) was added. The mixture was stirred another 20 min before being warmed to it slowly and stirred for 2 h. LC-MS found the reaction completed. The mixture was quenched with satd aq NH4Cl (1 mL) and purified by prep HPLC to afford (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (13.3 mg, 83% yield). LC-MS Method 1 tR=1.63 min, m/z 447 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(N(CC)CC)C.[CH3:19][O:20][CH2:21][CH2:22][CH2:23][NH2:24]>ClCCl>[Cl:11][C:4]1[N:3]=[C:2]([NH:24][CH2:23][CH2:22][CH2:21][O:20][CH3:19])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COCCCN
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCNc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 91.5 %

Procedure:
2,6-Dichloro-3-nitropyridine (3.29 mmol, 0.635 g) was added to an oven dried 50 mL round-bottomed flask equipped for stirring under nitrogen. Dichlormethane (12 mL) and triethylamine (3.62 mmol, 0.504 mL) were added and the resultant solution was cooled to −15° C. with an acetone/ice bath. 3-methoxypropan-1-amine (3.29 mmol, 0.337 mL) was then added drop-wise via syringe and the resultant solution was stirred at −15° C. for 0.5 hr. The acetone/ice bath was removed and the reaction was allowed to warm to room temperature and stir for 0.5 hr. The reaction solution was poured into water and extracted twice with dichloromethane (50 mL). The organic layer was collected and subsequently dried with anhydrous Na2SO4 and filtered. This filtrate was collected, concentrated, and dried in-vacuo affording an orange oil. This material was then purified by chromatography on silica gel (20% ethyl acetate/hexanes) to afford 6-chloro-N-(3-methoxypropyl)-3-nitropyridin-2-amine (33A) as a yellow solid (3.01 mmol, 0.740 g, 92% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.79-1.89 (m, 2H) 3.00 (s, 3H) 3.43 (t, J=6.06 Hz, 2H) 3.53-3.61 (m, 2H) 6.77 (d, J=8.59 Hz, 1H) 8.42 (d, J=8.08 Hz, 1H). ESI-MS: m/z 246.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:25]=[C:26]([C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=1[Cl:36])[CH3:27]>CN(C=O)C.[Cu]I>[Cl:36][C:29]1[CH:30]=[C:31]([F:35])[C:32]([F:34])=[CH:33][C:28]=1/[C:26](/[CH3:27])=[CH:25]\[N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]1=2
Reactant: CC(=CBr)c1cc(F)c(F)cc1Cl
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C(=C/n1c2c(c3cc(C)ccc31)CN(C)CC2)c1cc(F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was dissolved in DMF. Copper (I) iodide (19 mg, 0.1 mmol) L-proline (23 mg, 0.2 mmol) and potassium phosphate (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-2-chloro-4,5-difluorobenzene (321 mg, 1.2 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-5% MeOH-DCM. The product was further purified by HPLC. Yield: 10 mg as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.30 (m, 1H), 7.18 (s, 1H), 7.10 (m, 2H), 6.95 (d, 1H), 6.90 (s, 1H), 4.40 (d, 1H), 4.22 (d, 1H), 3.80 (m, 1H), 3.45 (m, 1H), 3.10 (m, 2H), 3.0 (s, 3H), 2.38 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]([OH:14])=O)=[CH:3]1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]([NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=2)=[O:14])=[CH:3]1
Reactant: Cn1cc(CC(=O)O)c2ccccc21
Reactant: Nc1cccc(C(F)(F)F)c1
Product: Cn1cc(CC(=O)Nc2cccc(C(F)(F)F)c2)c2ccccc21
Yield: 62 %

Procedure:
The title compound was synthesized in 62% yield (41.1 mg) according to a procedure described in Example 107 starting from (1-methyl-1H-indol-3-yl)-acetic acid and 3-trifluoromethyl-aniline. Calculated for C16H23N3O m/z: 332.11, found 332.89 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.74 (s, 2H), 3.75 (s, 3H), 7.01 (m, 1H), 7.14 (m, 1H), 7.25 (s, 1H), 7.38 (t, J=8.1 Hz, 2H), 7.53 (t, J=7.8 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H), 8.10 (s, 1H), 10.43 (s, 1H).
Reaction SMILES: [Na].[CH3:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=O.[CH:12](OCC)=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[N:19]=1.[OH-].[Na+]>>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]2[C:20](=[N:24][C:3]([C:5]3[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=3)=[CH:2][CH:12]=2)[N:19]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: CCOC=O
Reactant: Nc1cccc(N)n1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Product: Nc1ccc2ccc(-c3ccc(Cl)cc3)nc2n1
Yield: 88.2 %

Procedure:
The procedure is analogous to that described in Example 11, but starting with sodium (2.3 g), 4-chloroacetophenone (15.5 g) and ethyl formate (11 g). The solid obtained (20.4 g) is then added to 2,6-diaminopyridine (11.6 g). The product obtained after hydrolysis and neutralization with sodium hydroxide is separated by filtration, washed with distilled water (6×100 cc) at a temperature in the vicinity of 50° C., and then air-dried. 2-Amino-7-(4-chlorophenyl)-1,8-naphthyridine (22.6 g), m.p. approximately 130° C., is thus obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([CH3:20])[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)=[CH:6][CH:5]=1.[N:21]#[C:22][NH2:23]>C(O)C>[NH2:23][C:22]1[N:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=2)[C:11]([CH3:20])=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:21]=1
Reactant: CC(Nc1ccc(CCO)cc1)C(=O)c1ccccc1
Reactant: N#CN
Solvent: CCO
Product: Cc1c(-c2ccccc2)nc(N)n1-c1ccc(CCO)cc1
Yield: 33.4 %

Procedure:
A mixture of 2-{[4-(2-hydroxyethyl)phenyl]amino}-1-phenyl-1-propanone (1.3 g, 5.0 mmol) and cyanamide (420 mg, 10 mmol) in ethanol (60 mL) was refluxed for 16 h. After removal of solvent, the residue was diluted with dichloromethane. The organic layer was washed with water, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/ethanol (10:1) to give 490 mg (33%) of the title compound as yellow solids: 1H-NMR (CDCl3) δ 2.16 (3H, s), 2.96 (2H, t, J=5.6 Hz), 3.96 (2H, t, J=5.6 Hz), 4.24 (1H, br), 7.29-7.21 (2H, m), 7.46-7.38 (4H, m), 7.66-7.63 (2H, m).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+].Cl.C(OCC)(=O)C>O1CCCC1.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:3]([OH:24])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid methyl ester (1.17 g, 3.29 mmol) in tetrahydrofuran (6 mL) was treated with a 0.8M aqueous lithium hydroxide solution (6.17 mL, 4.94 mmol). The reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was then diluted with water (50 mL), a 1N aqueous hydrochloric acid solution. (10 mL), and ethyl acetate (50 mL). The layers were separated, and the aqueous layer was back-extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (993 mg, 88%) as a yellow foam which contained a small impurity. A small amount of the yellow foam (50 mg) was re-purified using Biotage chromatography (FLASH 40S, Silica, 3/1 then 1/1 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid as a white foam: mp 114-118° C. (foam to gel); FAB-HRMS m/e calcd for C15H19NO6S (M+H)+ 342.1011, found 342.1014.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:14])[C:10]=1[C:11](Cl)=[O:12])=[O:5])[CH3:2].[Br:15][C:16]1[C:17]([NH2:31])=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)[CH:21]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:14])[C:10]=1[C:11](=[O:12])[NH:31][C:17]1[C:16]([Br:15])=[CH:21][N:20]2[CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=[C:19]2[CH:18]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Cl
Reactant: Nc1cc2nc(-c3ccccc3)cn2cc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.2 %

Procedure:
A solution of 5-chlorocarbonyl-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (as prepared in Example 14, Step 2, 2.35 g, 10.8 mmol) in dichloromethane (5 ml) was added dropwise over 20 min to a cooled (0° C.) solution of 6-bromo-2-phenyl-imidazo[1,2-a]pyridin-7-ylamine (1.56 g, 5.4 mmol) and triethylamine (877 mg) in dichloromethane (20 ml); the mixture was then stirred for at r.t. (30 min). The mixture was washed (water), and the organic layer was dried (Na2SO4), and evaporated. The title compound (460 mg, 23%) was isolated by filtration over a column of silica gel with dichloromethane as an eluent, and was used without further purification in the next step. MS (m/e)=470.1 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CC(C)=O>[CH2:20]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N+:9]([O-:11])=[O:10])[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1c(O)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cccc(Cl)c1[N+](=O)[O-]
Yield: 84.5 %

Procedure:
4.7g of 3-chloro-2-nitrophenol in 30ml of acetone were treated with 3.7g potassium carbonate and then reacted with 3.25g allylbromide under reflux for 8 hours. The reaction mixture was cooled and filtered and the residue extracted into chloroform, washed once with water, dried using sodium sulphate and 6.5g of an oily residue obtained The crude product was then purified by flash chromatography to give 4.85g of 3-chloro-2-nitrophenyl allyl ether as a colourless oil (yield 84%).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[N:10][CH:11]=1)=[O:5].[CH3:26][Mg]Br>C1COCC1>[OH:5][CH:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[N:10][CH:11]=1)[CH3:26]
Reactant: CON(C)C(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl 4-(5-(methoxy(methyl)carbamoyl)pyridin-2-yl)piperazine-1-carboxylate (1.45 g, 4.1 mmol) was taken into THF (20 mL) and the solution cooled to 0° C. under a nitrogen atmosphere. Methyl magnesium bromide (3.0M in ethyl ether, 3.5 mL) was added in portions and the mixture was allowed to stir 10 minutes followed by addition of another 1.5 mL aliquot then the mixture was warmed to room temperature. The solution was then partitioned with ethyl ether and water and the organic phase washed with brine then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was taken into methanol (25 mL) followed by portion-wise addition of sodium borohydride solid (250 mg) over 10 minutes. The mixture was allowed to stir at room temperature another 10 minutes then concentrated. The residue was partitioned with ethyl ether and water and the aqueous phase extracted ethyl ethyl ether (2×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl 4-(5-(1-hydroxyethyl)pyridin-2-yl)piperazine-1-carboxylate (1.48 g) which was carried forward without further purification.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:7]([Li])[CH2:8][CH2:9][CH3:10].[OH:12][CH:13]1CCCO1>[Cl-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:3]1(/[CH:10]=[CH:9]/[CH2:8][CH2:7][CH2:13][OH:12])[CH:2]=[CH:1][CH:6]=[CH:5][CH:4]=1
Reactant: [Li]CCCC
Reactant: CCCCCC
Reactant: OC1CCCO1
Agent: [Cl-]
Agent: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: OCCC/C=C/c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4 g of benzyltriphenylphosphonium chloride in 20 ml of tetrahydrofuran was added 7.07 ml of 1.6M hexane solution of n-butyl lithium under cooling at 0° C. After stirring at room temperature for 30 minutes, 1 g of 2-hydroxytetrahydrofuran was added, followed by stirring at room temperature for 16 hours. Subsequently, after refluxing for 2 hours, insolubles were filtered off and the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent: hexane-ethyl acetate=2:1) to give 2 g of (E)-5-phenyl-4-penten-1-ol as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[N:21]=3)=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.O.O.[Sn](Cl)Cl>C(O)C>[NH2:17][C:13]1[CH:12]=[C:11]([C:9]2[N:10]=[C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]3[C:8]=2[C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[N:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc3c(Cl)cccn3c2-c2ccnc(NC3CCCC3)n2)c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cccc(-c2nc3c(Cl)cccn3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 80 °C
Yield: 99.7 %

Procedure:
To a solution of N-{4-[8-chloro-2-(3-nitrophenyl)imidazo[1,2-α]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopentylamine (744 mg, 1.71 mmol) in ethanol (25 mL) was added tin(II) chloride dihydrate (1.62 g, 8.57 mmol). The mixture was heated at 80° C. for 4 hours. The solution was cooled to room temperature and quenched by the dropwise addition of saturated aqueous sodium bicarbonate. Dichloromethane was added and the organic layer was washed with brine. The aqueous layer was extracted with dichloromethane and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (1:1 to 1:2 hexanes:ethyl acetate) provided 4-[2-(3-aminophenyl)-8-chloroimidazo[1,2-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (690 mg, 99%) as a foam. 1H NMR (CDCl3): δ 9.54 (broad, 1H), 8.10 (d, 1H), 7.39 (d, 1H), 7.16 (t, 1H), 7.05 (m, 1H), 6.97 (d, 1H), 6.84 (t, 1H), 6.72 (m, 1H), 6.51 (d, 1H), 5.18 (d, 1H), 4.33 (m, 1H), 3.72 (broad, 2H), 2.14–2.06 (m, 2H), 1.82–1.54 (m, 6H); MS m/z 405 (M+1).
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:18])([C:7]([F:17])([F:16])[C:8]([F:15])([F:14])[C:9]([F:13])([F:12])[CH2:10][OH:11])[CH2:5][OH:6].[CH2:19](I)[CH3:20]>O>[CH2:19]([O:11][CH2:10][C:9]([F:12])([F:13])[C:8]([F:15])([F:14])[C:7]([F:16])([F:17])[C:4]([F:18])([F:3])[CH2:5][OH:6])[CH3:20]
Reactant: CCI
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOCC(F)(F)C(F)(F)C(F)(F)C(F)(F)CO
Temperature: 90 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
15.4 g potassium hydroxide was dissolved in 200 ml of deionized water, 62 g of 2,2,3,3,4,4,5,5-octafluorohexane-1,6-diol [prepared essentially as described by I.L. Knunyants, L. Chih-yan and V. V. Shokina, Advances in Chem. (Uspekhi Khimi) 32, Original 1502, Eng. Trans. 461-476 (1963); Translation RSIC-165 (Redstone Information Center)] was added, and the mixture was heated to 90° C. Over a period of one hour, 35.7 g of ethyl iodide was added with rapid stirring to the flask via an addition funnel. The reaction mixture was then heated to reflux for two hours. The reaction mixture was cooled to room temperature, and the bottom product phase (54 g crude product) was split away from the aqueous layer. The crude product was distilled at 92°-100° C. at 5.5 mm Hg (5.5 torr) to give 29.1 g of 6-ethoxy-2,2,3,3,4,4,5,5-octafluorohexanol.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([O:20][CH3:21])(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH2:14].C(N(CC)CC)C.C(N1C(=O)C2C(=CC=CC=2)NC1=O)C1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH2:1]([NH:8][C:9]([NH:14][C:13]1[C:12](=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([O:20][CH3:21])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1N
Reactant: O=C=NCc1ccccc1
Agent: O=c1[nH]c2ccccc2c(=O)n1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: COC(=O)c1ccccc1NC(=O)NCc1ccccc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
A solution of benzyl isocyanate (13.3 g, 0.10 mol) in xylene (40 ml) is metered, at room temperature, into a solution of methyl anthranilate (15.1 g, 0.10 mol) in xylene (80 ml). After the addition has ended, the batch is stirred at 110° C. for 2 hours. Triethylamine (1.4 ml, 1.01 g, 0,010 mol) is added. The mixture is stirred at 90° C. for a further 2 hours. The desired cyclization product 3-(benzyl)-2,4(1H,3H)-quinazolinedione cannot be detected in the reaction solution by thin-layer chromatography. After cooling, the precipitate is filtered off with suction, washed with 3×25 ml of xylene and dried. 23.1 g of methyl N-(benzylcarbamoyl)anthranilate (yield: 81.3% of theory) of melting point 140° to 141° C. (lit. 139° to 140° C.) are obtained.