Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:27][O:28][CH3:29])[N:21]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[C:17]=2[C:16]2[CH:15]=[CH:14][C:13]([CH:30]=[CH:31][C:32]#[N:33])=[CH:12][C:11]=2[N:10]=1>[Pd].CO>[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:27][O:28][CH3:29])[N:21]([CH2:22][C:23]([CH3:24])([OH:26])[CH3:25])[C:17]=2[C:16]2[CH:15]=[CH:14][C:13]([CH2:30][CH2:31][CH2:32][NH2:33])=[CH:12][C:11]=2[N:10]=1
Reactant: COCc1nc2c(N)nc3cc(C=CC#N)ccc3c2n1CC(C)(C)O
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COCc1nc2c(N)nc3cc(CCCN)ccc3c2n1CC(C)(C)O
Reaction time: 18 h
Yield: 90.7 %

Procedure:
A glass Parr vessel was charged with 10% palladium on carbon (1.0 g), methanol (200 mL), trifluoroacetic acid (5.4 mL, 72.5 mmol) and 3-[4-amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enenitrile (5.1 g, 14.5 mmol). The vessel was evacuated and charged with hydrogen gas (40 psi, 2.8×105 Pa). The mixture was shaken for approximately 18 hours and then filtered through a 0.2 micron PTFE membrane filter and concentrated under reduced pressure. The resulting yellow oil was dissolved in 10% aqueous hydrochloric acid (100 mL) and stirred for 30 minutes. The solution was made basic (pH 10) by the slow addition of potassium carbonate. Potassium hydroxide was added until pH equaled 13. The solution was then concentrated under reduced pressure. The resulting off-white solid was slurried in hot methanol (300 mL) and filtered. The hot methanol slurry procedure was repeated. The combined filtrates were concentrated and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient; 0-30% CMA) to provide 4.7 g of 1-[4-amino-7-(3-aminopropyl)-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as an off-white foam. MS (APCI) m/z 358 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH2:15][S:16][CH3:17])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]2)[CH2:26][O:25]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH2:15][S:16][CH3:17])[C:11]([NH:35][C:32]2[CH:33]=[CH:34][N:30]([CH2:29][C@@H:27]3[CH2:26][O:25][C:24]([CH3:36])([CH3:23])[O:28]3)[N:31]=2)=[O:13])[C:7](=[O:18])[CH:6]=1
Reactant: CSCC[C@@H](C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSCC[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 46.4 %

Procedure:
In a round bottom flask under argon was placed (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methylsulfanyl-butyric acid (171 mg, 0.50 mmol) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 118 mg, 0.60 mmol) in N,N-dimethylformamide (4 mL). To this mixture was added N,N-diisopropyethylamine (250 μL, 1.5 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (331 mg, 0.75 mmol) and the mixture was stirred for 3.5 h at 25° C. After this time, the mixture was diluted with ethyl acetate (30 mL) and washed with a saturated aqueous solution of ammonium chloride (25 mL), saturated aqueous solution of sodium bicarbonate (25 mL) and a saturated aqueous solution of sodium chloride (25 mL) dried over sodium sulfate and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (Aspire 40 g column, 100% ethyl acetate) afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-4-methylsulfanyl-butyramide (121 mg, 46%) as a white foam: HR-ES-MS m/z calculated for C24H29N4O5ClS [M+H]+ 521.1620, observed 521.1622.
Reaction SMILES: [ClH:1].[N:2]([CH2:10][CH:11]([C:13](=[NH:15])N)[CH3:12])=NCC(C(=N)N)C.[CH3:16][C:17]([CH3:19])=O>>[ClH:1].[CH2:10]([NH2:2])[CH:11]=[CH2:12].[ClH:1].[CH2:19]([NH:15][CH2:13][CH:11]=[CH2:12])[CH:17]=[CH2:16]
Reactant: CC(CN=NCC(C)C(=N)N)C(=N)N
Reactant: CC(C)=O
Agent: Cl
Product: C=CCN
Product: C=CCNCC=C
Temperature: 60 °C
Reaction time: 24 h

Procedure:
The monomers prepared above were mixed together at a molar ratio shown in Table 1. After heating the monomer mixture to 60° C., 2.5% by weight (based on the monomer mixture) of azobis(2-amidinopropane) hydrochloride was added, and polymerization was carried out for 24 hours. After the reaction, the solution was added into acetone to form a precipitate, and the precipitate was collected by filtration with a glass filter and dried under reduced pressure. Thus, a copolymer of monoallylamine hydrochloride and diallylamine hydrochloride was obtained.
Reaction SMILES: FC(F)(F)S(OC)(=O)=O.[F:10][C:11]1[CH:22]=[CH:21][C:14]([CH2:15]N(C)C(=S)C)=[CH:13][CH:12]=1.[NH2:23][C:24]1[CH:33]=[C:32]2[C:27]([CH2:28][CH2:29][CH:30]([OH:49])[CH:31]2[NH:34][C:35]([C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:39][CH:38]=2)=[O:36])=[CH:26][CH:25]=1.[N:50]1[CH:55]=CC=[CH:52][CH:51]=1>C(Cl)Cl>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][CH2:55][NH:50][C:51](=[N:23][C:24]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][C@@H:30]([OH:49])[C@@H:31]3[NH:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)=[CH:39][CH:38]=3)=[O:36])=[CH:26][CH:25]=2)[CH3:52])=[CH:21][CH:22]=1
Reactant: Nc1ccc2c(c1)C(NC(=O)c1ccc(-c3ccccc3)cc1)C(O)CC2
Reactant: c1ccncc1
Reactant: CC(=S)N(C)Cc1ccc(F)cc1
Agent: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CC(=Nc1ccc2c(c1)[C@@H](NC(=O)c1ccc(-c3ccccc3)cc1)[C@H](O)CC2)NCCc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 2.6 %

Procedure:
Add methyl trifluoromethanesulfonate (0.150 g, 0.915 mmol) to a solution of N-4-fluorobenzyl-N-methylthioacetamide (0.145 g, 0.736 mmol) in 10 mL of CH2Cl2 at room temperature. Stir the mixture for 30 minutes and remove the solvent under reduced pressure. Then add biphenyl-4-carboxylic acid (7-amino-2-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (0.22 g, 0.61 mmol) followed by 5 mL of pyridine. Stir the resulting mixture for 12 h. After evaporate pyridine, purify the residue by column chromatography (silica gel, 5% MeOH in CH2Cl2) to give 10 mg of the title compound in 2.6% yield as a light yellow solid: 1H NMR (CDCl3) δ 7.89 (2H, d, J=8.0 Hz), 8.66 (2H, d, J=8.4 Hz), 7.61 (2H, d, J=7.2 Hz), 7.47 (2H, t, J=7.6 Hz), 7.39 (1H, t, J=7.6 Hz), 7.21 (1H, dd, J=6.0, 8.8 Hz), 6.98-7.05 (3 B, m), 6.72 (1H, s), 6.62 (1H, dd, J=2.0, 8.4 Hz), 6.56 (1H, d, J=7.2 Hz), 5.22 (1H, t, J=7.6 Hz), 4.60 (2H, s), 3.98-4.04 (2H, m), 3.41 (11H, t, J=6.0 Hz), 2.96 (3H, s), 2.85 (2H, t, J=4.8 Hz), 2.15-2.21 (2H, m), 1.87-1.95 (1H, m), 1.92 (3H, s), 1.60-1.64 (1H, m); MS 522 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])[CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[SH2:32]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][N:2]([CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23](=[S:32])[NH2:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])[CH2:3][CH2:4][CH3:5]
Reactant: CCCN(C)CC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: S
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCCN(C)CC(C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of 10-[(2RS)-1-(N-methyl-N-propylamino)-2-propyl]-2-phenothiazinecarbonitrile (4.3 g) and triethylamine (1.77 cc) in pyridine (86 cc) is treated with hydrogen sulphide and left stirred for 16 hours at a temperature in the region of 20° C. The green solution obtained is diluted with ethyl acetate (200 cc), washed with distilled water (5×40 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual oil (5.4 g) is purified by chromatography on a column (height: 30 cm; diameter: 5.5 cm) of silica gel (0.04-0.063 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with a mixture (97.5:2.5 by volume) (5 liters) of methylene chloride and methanol and collecting 100-cc fractions. The combined fractions 13 to 44 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual yellow oil (4.37 g) is dissolved in ethanol (12 cc) under reflux and treated, with stirring, with a solution of fumaric acid (1.4 g) in ethanol (15 cc) under reflux. After 2 hours, stirring at a temperature in the region of 5° C., the solid formed is drained, washed with ethanol (5 cc) and dried under reduced pressure (5 mm Hg; 0.68 kPa) at 40° C. 10-[(2RS)-1-(N-Methyl-N-propylamino)-2-propyl]-2-phenothiazinecarbothioamide acid fumarate (4.35 g) is thereby obtained in the form of yellow crystals, m.p. 204° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:12][N:11]=1.C([O-])([O-])=[O:27].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([NH2:7])=[O:27])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:12][N:11]=1
Reactant: N#Cc1ccc(Cl)c(-c2ccc(CNCCC3CCCCC3)cn2)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Cl)c(-c2ccc(CNCCC3CCCCC3)cn2)c1

Procedure:
To a solution of 4-chloro-3-{5-[(2-cyclohexylethylamino)methyl]pyridin-2-yl}benzonitrile (170 mg, 0.48 mmol) in DMSO (4 mL) was added K2CO3 (66 mg, 0.48 mmol) and 70% hydrogen peroxide (0.5 mL, 4.8 mmol). The mixture was stirred at rt for 5 h before water (5 mL) was added and the mixture partitioned between EtOAc (20 mL) and water (20 mL). The organic phase was washed with water (3×20 mL), brine (20 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography (0.4% NH3: 4% MeOH: DCM) to give the title compound: RT=2.57 min; m/z (ES+)=372.2 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:29])=[C:16]([C:24](OCC)=[O:25])[C:17](=[O:23])[C:18]2([CH3:22])[CH3:21])=[CH:13][CH:12]=1.Cl.[C:31]([O:35][C:36](=[O:39])[CH2:37][NH2:38])([CH3:34])([CH3:33])[CH3:32]>O1CCOCC1.CCOCC>[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:29])=[C:16]([C:24]([NH:38][CH2:37][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:39])=[O:25])[C:17](=[O:23])[C:18]2([CH3:22])[CH3:21])=[CH:13][CH:12]=1
Reactant: CCOC(=O)C1=C(O)c2ccc(Br)cc2C(C)(C)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(Br)cc2C(C)(C)C1=O
Temperature: 85 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
DIPEA (3.86 mL, 22.2 mmol, 1.2 eq) was added to a mixture of ethyl 7-bromo-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (6.27 g, 18.5 mmol) and glycine tert-butyl ester hydrochloride (3.72 g, 22.2 mmol) in dioxane (30 mL). The reaction mixture was stirred at 85° C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a light yellow solid. The crude solid was suspended in ether, filtered, and washed with water to give the desired ester as a white solid (6.53 g). MS (m/e)=368.1 (M+H-tBu)+.
Reaction SMILES: CO[C:3]([C:5]1[C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4].[C:14]1([C:20]2[N:21]=[C:22]3[N:27]=[C:26]([NH2:28])[CH:25]=[CH:24][N:23]3[CH:29]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([N:32]([CH2:35][CH3:36])[CH2:33]C)C>ClCCl>[N:32]1([C:3]([C:5]2[N:6]=[CH:7][CH:8]=[CH:9][C:10]=2[C:11]([NH:28][C:26]2[CH:25]=[CH:24][N:23]3[CH:29]=[C:20]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:21]=[C:22]3[N:27]=2)=[O:12])=[O:4])[CH2:33][CH2:36][CH2:35]1
Reactant: COC(=O)c1ncccc1C(=O)Cl
Reactant: CCN(CC)CC
Reactant: Nc1ccn2cc(-c3ccccc3)nc2n1
Solvent: ClCCl
Product: O=C(Nc1ccn2cc(-c3ccccc3)nc2n1)c1cccnc1C(=O)N1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
3-Chlorocarbonyl-pyridine-2-carboxylic acid methyl ester (620 mg, 3.1 mmol) was added slowly to a solution of 2-phenyl-imidazo[1,2-a]pyrimidin-7-ylamine (step 1, example 1, 470 mg, 2.2 mmol) and triethylamine (566 mg) in dichloromethane (7 ml), and the mixture was stirred overnight at RT. The mixture was diluted with additional dichloromethane, and washed with water. The combined organic layers were dried (Na2SO4), the solvent was evaporated, and the title compound (490 mg, 49%) was obtained from the residue by column chromatography (silica gel, dichloromethane:methanol=50:50-0:100). MS (m/e)=374.2 [M+H+].
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].C(N(CC)CC)C.[C:16]1([CH3:25])[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][CH:17]=1.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O>C(OCC)(=O)C.C(OC)(C)(C)C>[C:6]1(=[O:7])[N:2]([O:1][C:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:25])=[CH:17][CH:18]=2)=[O:23])[C:3](=[O:8])[CH2:4][CH2:5]1
Reactant: O=C1CCC(=O)N1O
Reactant: Cc1ccc(C(=O)O)cc1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: Cc1ccc(C(=O)ON2C(=O)CCC2=O)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
2.42 g (0.021 mol) of N-hydroxysuccinimide and 5.06 g (0.050 mol) of triethylamine were initially introduced into 5 ml of ethyl acetate and the suspension was stirred at room temperature. 2.72 g (0.020 mol) of solid 4-toluic acid were added to this suspension in the course of 5 min. and then a solution of 5.64 g (0.21 mol) of diphenyl chlorophosphate was added dropwise in the course of 20 min., the reaction mixture warming to about 35° C. The mixture was stirred at room temperature for 1 hour until the reaction was complete. The reaction mixture was then diluted with 100 ml of ethyl acetate and the organic phase was washed with 50 ml each of water, 2N hydrochloric acid and 10% strength aqueous sodium hydrogencarbonate solution and then evaporated. 4.65 g of crude product were isolated, which was then stirred at room temperature for 30 minutes with 20 ml of methyl tert-butyl ether. The white crystalline solid was filtered off and dried at 50° C. and 10 mbar. 4.28 g (94%) of 4-toluic acid succinimidyl ester were isolated.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH:16]1([CH2:20][S:21](Cl)(=[O:23])=[O:22])[CH2:19][CH2:18][CH2:17]1.[CH:25]([O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)([CH3:27])[CH3:26]>>[CH:16]1([CH2:20][S:21]([N:9]2[CH2:8][CH2:7][C:6]3([C:4](=[O:5])[N:33]([C:32]4[CH:31]=[CH:30][C:29]([O:28][CH:25]([CH3:27])[CH3:26])=[CH:35][CH:34]=4)[CH2:13][CH2:12]3)[CH2:11][CH2:10]2)(=[O:23])=[O:22])[CH2:19][CH2:18][CH2:17]1
Reactant: O=S(=O)(Cl)CC1CCC1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: CC(C)Oc1ccc(N)cc1
Product: CC(C)Oc1ccc(N2CCC3(CCN(S(=O)(=O)CC4CCC4)CC3)C2=O)cc1

Procedure:
Light brown solid. MS (ESI): 421.21 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), cyclobutyl-methanesulfonyl chloride, 4-isopropoxy-aniline.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:15][CH:16]([CH2:21][O:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:18][CH2:19][OH:20])(=[O:14])[CH3:13].O>N1C=CC=CC=1.CCOCC>[S:7]([O:20][CH2:19][CH2:18][CH2:17][CH:16]([O:15][C:12](=[O:14])[CH3:13])[CH2:21][O:22][CH2:23][CH2:24][CH3:25])([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCOCC(CCCO)OC(C)=O
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: CCCOCC(CCCOS(=O)(=O)c1ccc(C)cc1)OC(C)=O
Temperature: 20 °C
Reaction time: 0.67 h

Procedure:
A solution of p-toluenesulfonyl chloride (42.0 g., 0.22 mole) in pyridine (100 ml.) is cooled in an ice bath while 4-acetoxy-5-propoxy-1-pentanol (36.8 g., 0.193 mole) is added dropwise with stirring during 40 minutes. The ice bath is replaced by a cool (20° C.) water bath and stirring is continued for 2 hours. The mixture is then poured into 500 ml. of water. The oily product is taken up in ether, washed with 2 N hydrochloric acid and water, and dried over sodium sulfate. The solvent is distilled in vacuo to leave the crude title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:13]([O:17][C:18](ON=C(C1C=CC=CC=1)C#N)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>CO.Cl.[Pd].ClCCl>[C:13]([O:17][C:18](=[O:19])[NH:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:2]=1[F:1])([CH3:16])([CH3:15])[CH3:14]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1F
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1ccc(N)cc1F
Reaction time: 16 h

Procedure:
A solution of 2-fluoro-4-nitrobenzonitrile (0.541 g, 2.43 mmol) in methanol (20 mL) and hydrochloric acid (3 mL, 6 N) was hydrogenated (55 psi) over 10% palladium on carbon (164 mg) overnight. The reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL) and treated with 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (0.517 mg, 2.10 mmol) and triethylamine (0.6 mL, 4.3 mmol). After 16 h at rt, the reaction mixture was diluted with dichloromethane and washed with sodium bicarbonate solution and brine, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient from 0 to 50% ethyl acetate in hexanes) to give 1-63A-(0.287 g, 60%) as a colorless oil which solidified on standing.
Reaction SMILES: [CH:1]1([CH:4]([OH:8])[CH2:5][CH:6]=[CH2:7])[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:12][CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>O1CCCC1>[CH2:15]([O:14][CH:13]([O:17][CH2:18][CH3:19])[CH2:12][O:8][CH:4]([CH:1]1[CH2:3][CH2:2]1)[CH2:5][CH:6]=[CH2:7])[CH3:16]
Reactant: C=CCC(O)C1CC1
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(OCC(OCC)OCC)C1CC1
Temperature: 25 °C

Procedure:
1-Cyclopropylbut-3-en-1-ol (C14, see C. Tahtaoui et al., J. Org. Chem. 2010, 75, 3781-3785) (92%, 8.1 g, 66 mmol) was added to a 0° C. suspension of sodium hydride (60% in mineral oil, 8.25 g, 206 mmol) in tetrahydrofuran (105 mL). The cooling bath was removed and the suspension was stirred until the internal temperature reached 21° C. The reaction mixture was then cooled in an ice bath, and 2-bromo-1,1-diethoxyethane (97%, 18.5 mL, 119 mmol) was added drop-wise at a rate that maintained the internal temperature below 5° C. After warming to room temperature, the reaction mixture was heated to 58° C. for 27 hours. Sodium hydride (60% in mineral oil, 3.3 g, 83 mmol) and 2-bromo-1,1-diethoxyethane (97%, 10 mL, 64 mmol) were added again, and the reaction mixture was heated at mild reflux for 14 hours. It was then cooled to 0° C., slowly quenched with water (100 mL) and extracted with diethyl ether (3×200 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo; purification via silica gel chromatography (Gradient: 0% to 10% ethyl acetate in heptane) afforded the product as a colorless oil. Yield: 12.1 g, 53.0 mmol, 80%. 1H NMR (400 MHz, CDCl3) δ 5.87-5.98 (m, 1H), 5.05-5.11 (m, 1H), 5.00-5.04 (m, 1H), 4.61 (t, J=5.3 Hz, 1H), 3.66-3.75 (m, 3H), 3.54-3.62 (m, 2H), 3.47 (dd, J=10.3, 5.5 Hz, 1H), 2.70 (dt, J=8.4, 6.0 Hz, 1H), 2.36-2.41 (m, 2H), 1.22 (t, J=7.0 Hz, 3H), 1.22 (t, J=7.0 Hz, 3H), 0.80-0.90 (m, 1H), 0.54-0.62 (m, 1H), 0.35-0.50 (m, 2H), 0.07-0.14 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:19])/[C:5](=[CH:7]\[C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][CH:12]=2)/N=1.Cl.C([OH:23])C>>[OH:23]/[C:5](=[CH:7]\[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:12]=1)/[C:4]([O:3][CH2:2][CH3:1])=[O:19]
Reactant: CCO
Reactant: CC1=N/C(=C/c2ccc(-c3ccccc3)o2)C(=O)O1
Agent: Cl
Product: CCOC(=O)/C(O)=C/c1ccc(-c2ccccc2)o1
Yield: 55 %

Procedure:
To an ethanol (10 mL) suspension of (E)-2-methyl-4-((5-phenylfuran-2-yl)methylene)oxazol-5(4H)-one 47 (253 mg, 1.0 mmol) was added 12M HCl (5 mL). The reaction mixture was refluxed for 5 h, then the excess solvent was removed in vacuo. The residue was diluted with ethyl acetate (100 mL), then washed with water (2×30 mL). The organic layer was dried with brine and MgSO4, then concentrated in vacuo. Flash column chromatography on silica gel (n-hexanes:ethyl acetate=10:1) of the residue afforded the desired product 48 in 55% yield (142 mg, yellow solid). 1H NMR (400 MHz, CDCl3): 7.70 (d, J=7.2 Hz, 2H), 7.39 (t, J=7.2 Hz, 2H), 7.27 (t, J=7.2 Hz, 1H), 6.97 (d, J=3.6 Hz, 1H), 6.78 (d, J=3.6 Hz, 1H), 6.65 (d, J=1.6 Hz, 1H), 6.43 (d, J=1.6 Hz, 1H), 4.37 (q, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: COC(=O)CC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CC(=O)c1ccc(O)cc1
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer were charged ethyl acetate (15 mL), to that stirred solvent was added methyl 3-[4-(benzyloxy)phenyl]-3-oxopropanoate (0.3 g, 1.05 mmol), and palladium carbon 10% (80 mg) was added. After addition, the hydrogen balloon was fixed to the reaction mixture and stirred at room temperature for 1 h. After 3 h, the reaction mixture was filtered through celite. Then the organic layer was concentrated and dried. The product was obtained as colourless liquid (0.2 g, Yield: 98%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([NH2:28])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[O:29]1[CH2:32][C:31](=O)[CH2:30]1>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([NH:28][CH:31]5[CH2:32][O:29][CH2:30]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: Nc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Reactant: O=C1COC1
Solvent: C1CCOC1
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(NC4COC4)ccc2OCC3)c(F)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
Compound 134 (200 mg, 0.5 mmol) was dissolved in THF, and oxetan-3-one (252 mg, 0.35 mmol) was added at 0° C. The mixture was warmed to 80° C. and stirred for 0.5 h at this temperature. It was cooled to 0° C., NaBH(CN)3 (67 mg, 0.6 mmol) was added. Then the mixture was warmed to 80° C. and stirred for further 0.5 h at this temperature. The reaction mixture was filtered to gather the solution. Then water was added into the solution. It was extracted by DCM (20 mL×3). The combined organics were dried over Na2SO4, concentrated in vacuo, and separated by prep TLC (EtOAc/hexanes=4:1) to give 434 (115 mg, yield: 50%). 1H NMR (DMSO-d6, 400 MHz): δ9.42 (s, 1 H), 8.42 (s, 1 H), 8.00-7.49 (m, 4 H), 7.12 (s, 1 H), 7.04 (d, J=9.6 Hz, 1H), 4.85-4.83 (m, 1 H), 4.58-4.38 (m, 4 H), 3.65 (t, J=6.4 Hz, 2 H), 2. 93 (t, J=6.4 Hz, 2 H). LC-MS (ESI): m/z=454 [M+H]+