Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C([Li])CCC.[F:25][C:26]1[CH:27]=[C:28](Br)[CH:29]=[CH:30][C:31]=1[O:32][C:33]([F:36])([F:35])[F:34].O>C1COCC1.CCCCCC.[Cl-].[Zn+2].[Cl-]>[F:25][C:26]1[CH:27]=[C:28]([C:7]2[C:2]([F:1])=[CH:3][C:4]([C:9]3[N:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:13][N:14]=3)=[CH:5][C:6]=2[F:8])[CH:29]=[CH:30][C:31]=1[O:32][C:33]([F:34])([F:35])[F:36]
Reactant: CCCCCc1cnc(-c2cc(F)cc(F)c2)nc1
Reactant: Fc1cc(Br)ccc1OC(F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCc1cnc(-c2cc(F)c(-c3ccc(OC(F)(F)F)c(F)c3)c(F)c2)nc1
Temperature: -60 °C
Reaction time: 1 h
Yield: 0.7 %

Procedure:
In 80 ml of THF was dissolved 8.0 g (30 mmol) of the 2-(3,5-difluorophenyl)-5-pentylpyrimidine described above, and cooled down to −60° C. under nitrogen gas atmosphere. To this solution was added dropwise 20 ml of 1.60 M solution of n-butyl lithium (32 mmol) in hexane while maintaining the condition that the temperature of the solution did not exceed −50° C., and then stirred at the same temperature for 1 hour. Subsequently, 64 ml of 0.5 M solution of zinc chloride (32 mmol) in THF was added dropwise to the reaction solution while maintaining the condition that the temperature of the solution did not exceed −50° C., warmed up to room temperature, and then stirred for 30 min. To this solution were added 0.5 g of tetrakistriphenylphosphine palladium and 8.3 g of 3-fluoro-4-trifluoromethoxybromobenzene, and heated to reflux for 3 hours. To the reaction solution was added 100 ml of water, and the product was extracted with toluene. The extract was washed with 3N-hydrochloric acid, saturated aqueous solution of sodium bicarbonate, and saturated aqueous solution of sodium chloride in turn, and dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: heptane/toluene=1/1), and then recrystallized twice from heptane/ethyl acetate=1/1 to obtain 0.09 g (0.2 mmol) of 2-(4-(3-fluoro-4-trifluoromethoxyphenyl)-3,5-difluorophenyl)-5-pentylpyrimidine. Yield of this product from 2-(3,5-difluorophenyl)-5-pentylpyrimidine was 0.7%.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[CH2:6]([O:8][C:9]([C:11](=[CH:16][C:17]1[CH:21]=[C:20]([CH3:22])[O:19][CH:18]=1)[CH2:12][C:13](O)=O)=[O:10])[CH3:7]>C(OC(=O)C)(=O)C.ClCCl>[C:1]([O:4][C:13]1[C:18]2[O:19][C:20]([CH3:22])=[CH:21][C:17]=2[CH:16]=[C:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=Cc1coc(C)c1)CC(=O)O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(OC(C)=O)c2oc(C)cc2c1
Yield: 81 %

Procedure:
Sodium acetate (15 g, 0.18 mol) was added under vigorous stirring to a solution of 3-(ethoxycarbonyl)-4-(5-methyl-3-furyl)but-3-enoic acid (14 g, 58 mmol) in 150 mL of acetic anhydride. The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 70° C. until the solvent distillation ceased. The obtained crude product was suspended in 300 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 250 mL of dichloromethane. The combined solutions were washed by 350 mL of a saturated aqueous solution of NaHCO3 and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (250×150 mm) with hexane/ethyl acetate mixture (3:1) as eluent to give the desired product 12.5 g (47 mmol, 81%) as a solid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:17]([O:27][C@@H:28]2[O:57][C@H:56]([CH2:58][OH:59])[C@@H:47]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C@H:38]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@H:29]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:16]([CH2:60][O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[O:15][CH:10]1[O:11][CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:69]1(C)[CH:74]=[CH:73][C:72]([S:75](Cl)(=[O:77])=[O:76])=[CH:71][CH:70]=1.N1C=CC=C[CH:81]=1>CN(C)C1C=CN=CC=1>[CH2:1]([O:8][C@@H:9]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@H:17]([O:27][C@@H:28]2[O:57][C@H:56]([CH:58]([S:75]([C:72]3[C:73]([CH3:81])=[CH:74][CH:69]=[CH:70][CH:71]=3)(=[O:76])=[O:77])[OH:59])[C@@H:47]([O:48][CH2:49][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[C@H:38]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C@H:29]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:16]([CH2:60][O:61][CH2:62][C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[O:15][CH:10]1[O:11][CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: C=CCOC1O[C@H](COCc2ccccc2)[C@@H](O[C@@H]2O[C@H](CO)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Product: C=CCOC1O[C@H](COCc2ccccc2)[C@@H](O[C@@H]2O[C@H](C(O)S(=O)(=O)c3ccccc3C)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 74 %

Procedure:
The compound (37.8 g, 41.0 mmol) synthesized in Example 2 (2c) was dissolved in pyridine (300 mL) and p-toluenesulfonyl chloride (15.6 g, 82.0 mmol) and 4-dimethylaminopyridine (1.0 g, 0.82 mmol) were added thereto, followed by stirring of the mixture at room temperature for 13 hours. After the solvent was distilled off under reduced pressure, the residue was poured to 10% aqueous hydrochloric acid solution (50 mL) and ethyl acetate (200 mL) and the organic layer was washed with 10% aqueous hydrochloric acid solution (50 mL), saturated aqueous sodium hydrogencarbonate solution (20 mL) and saturated brine (20 mL) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 5:1-3:1, V/V) to obtain the desired title compound (32.6 g, yield 74%) as a yellow oil.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[C:12]1(/[C:18](/[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C-:32]#[N:33].[Na+].O>CS(C)=O>[C:32]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]/[CH:19]=[C:18](\[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)/[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)#[N:33]
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Reactant: [C-]#N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCCCCC/C=C(\c1ccccc1)c1cccnc1
Reaction time: 18 h
Yield: 75.4 %

Procedure:
p-Toluensulfonate of (E)-7-phenyl-7-(3-pyridyl)-6-hepten-1-ol (1.0 g, 2.4 mmoles) was dissolved in dimethyl sulfoxide (10 ml), and sodium cyanide (0.3 g, 6 mmoles) was added, followed by stirring for 18 hours. To the reaction mixture was added water (100 ml) and the product was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using ethyl acetate-isopropyl ether (1:1) as the developing solvent to give (E)-1-cyano-7-phenyl-7-(3-pyridyl)-6-heptene (0.5 g, 76%).
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([N:10]1[C:14](=O)[CH2:13][O:12][C:11]1=[S:16])[CH3:9].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C(OCC)(=O)C>[CH2:8]([N:10]1[C:14](=[S:26])[CH2:13][O:12][C:11]1=[S:16])[CH3:9]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCN1C(=O)COC1=S
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCN1C(=S)COC1=S
Yield: 94 %

Procedure:
A toluene (10 mL) solution of 3-ethyl-2-thioxooxazolidin-4-one 3 (145 mg, 1.0 mmol) and Lawesson's reagent (607 mg, 1.5 mmol) was refluxed overnight. The solution was cooled and diluted with ethyl acetate (100 mL), then washed with water (2×20 mL). The organic layer was dried with brine and MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (hexane:ethyl acetate=10:1), and the desired product 6 was obtained in 94% yield (152 mg, orange oil). 1H NMR (400 MHz, CDCl3): δ 5.12 (s, 2H), 4.21 (q, J=7.2 Hz, 2H), 1.29 (t, J=7.2 Hz, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:4]=1[Cl:11].[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([SH:20])[N:14]=1.C(N(CC)CC)C>C(O)C>[CH3:19][C:17]1[N:16]=[C:15]([S:20][CH2:2][C:3]2[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([Cl:10])[C:8]=2[Cl:9])[N:14]=[C:13]([NH2:12])[CH:18]=1
Reactant: Cc1cc(N)nc(S)n1
Reactant: Clc1ccc(Cl)c(CBr)c1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(N)nc(SCc2c(Cl)ccc(Cl)c2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
In a 100 mL round bottom flask, 2-(bromomethyl)-1,3,4-trichlorobenzene (550 mg, 2.0 mmol), 4-amino-6-methylpyrimidine-2-thiol (282 mg, 2.0 mmol), and triethylamine (0.28 mL, 2.0 mmol) were mixed in ethanol (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated. To the crude solid, water (50 mL) was added. The suspension was filtered and washed with water and ethyl acetate to provide a white solid (530 mg, 95% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.18 (s, 3H), 4.65 (s, 2H), 6.03 (s, 1H), 6.90 (br, 1H), 7.55 (d, 1H), 7.64 (d, 1H); M+334, 336.
Reaction SMILES: [C:1]1([CH2:7][O:8][C@H:9]2[C@H:16]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@@H:15]([CH2:25][O:26]CC3C=CC=CC=3)[O:14][C@H:10]2[CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C[O:41][CH2:42][C@H:43]2[O:63][C@H:62]([CH2:64][CH2:65][OH:66])[C@@H:53]([O:54][CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C@@H:44]2[O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)C=CC=CC=1.B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>C(OC(=O)C)(=O)C>[C:1]1([CH2:7][O:8][C@H:9]2[C@H:16]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@@H:15]([CH2:25][OH:26])[O:14][C@H:10]2[CH2:11][CH2:12][OH:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:56]1([CH2:55][O:54][C@H:53]2[C@H:44]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C@@H:43]([CH2:42][OH:41])[O:63][C@@H:62]2[CH2:64][CH2:65][OH:66])[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1
Reactant: OCC[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: OCC[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: OCC[C@@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Product: OCC[C@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cold (0°-5° C.) solution of 12.2 g of a mixture of 3,6-anhydro-2-deoxy-4,5,7-tris-O-(phenylmethyl)-D-gluco-heptitol and 2,5-anhydro-6-deoxy-1,3,4-tris-O-(phenylmethyl)-D-manno-heptitol in 64 ml of acetic anhydride was treated with 370 μl of borontrifluoride etherate under argon. After 13/4 hours, 53 ml of saturated aqueous sodium bicarbonate was added, the mixture was stirred at 0° C. for 15 minutes, then at ambient temperature for 15 minutes and the volatiles removed. The residue was taken up in ether/water. The organic layer was separated, dried and evaporated. The residue was taken up in 74 ml of methanol, a solution of 15.4 g of potassium carbonate in 90 ml of water added and this mixture stirred at reflux for 45 minutes. The volatiles were removed, the residue taken up in ether/water and the organic layer separated and evaporated. The 12 g of residue was purified by high pressure liquid chromatography on silica gel, eluting first with hexane:ethyl acetate (1:1), and then with hexane:ethyl acetate (1:3), giving 3,6-anhydro-2-deoxy-4,5-bis-O-(phenylmethyl)-D-gluco-heptitol in 20% yield and 3,6-anhydro-2-deoxy-4,5-bis-O-(phenylmethyl)-D-manno-heptitol in 65% yield.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([N+:19]([O-])=O)[CH:13]=2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[NH2:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[CH3:18])[C:11]([NH:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1)=[O:22]
Reactant: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To N-(3-isopropyl-phenyl)-4-methyl-3-nitro-benzamide (3.0 g, 0.010 mol) dissolved in EtOAc (60 mL) in a 100 mL RBF was added Pd/C (10%, 250 mg). The flask was capped with a rubber septum and flushed with H2 gas through a balloon/needle. Positive H2 pressure was applied through the balloon/needle and reaction was stirred vigorously at room temperature for 3 days. TLC indicated clean conversion of starting material. The reaction was filtered through a pad of sand/celite. After concentration, the mixture was purified by silica gel chromatography to afford a light orange oil. Trituration with a mixture of hexanes and EtOAc afforded 3-amino-N-(3-isopropyl-phenyl)-4-methyl-benzamide as an off-white solid. MS m/z 269=[M+H]+. Calc'd for C17H20N2O: 268.36.
Reaction SMILES: [OH-:1].[Na+].O.[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1[O:10][C:11](=[O:26])/[C:12](=[CH:14]/[C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)/[N:13]=1.CO>CC(C)=O>[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([NH:13]/[C:12](=[CH:14]\[C:15]1[O:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:18][CH:19]=1)/[C:11]([OH:10])=[O:26])=[O:1]
Reactant: [OH-]
Reactant: O=C1OC(c2ccco2)=N/C1=C\c1ccc(-c2ccccc2)o1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Solvent: O
Product: O=C(O)/C(=C/c1ccc(-c2ccccc2)o1)NC(=O)c1ccco1
Temperature: 75 °C

Procedure:
1N NaOH (100 μL) and H2O (500 μL) is added to a solution of (4Z)-2-(2-furyl)-4-[(5-phenyl-2-furyl)methylene]-1,3-oxazol-5(4H)-one (10 mg, 0.0327 mmol), prepared as described above, in acetone (1 mL). The reaction mixture is heated to 75° C. for one hour and then cooled to 25° C. The crude mixture is loaded onto a QAX column, which was pre-treated with MeOH. After 2 minutes the column is washed with MeOH and the product is eluted with 3% HCl/MeOH. Subsequently, the column is washed with MeOH (2 mL) and the combined washings are concentrated under reduced pressure to provide 9.5 mg of (2Z)-2-(2-furoylamino)-3-(5-phenyl-2-furyl)prop-2-enoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH2:10][C:11](O)([C:13]([F:16])([F:15])[F:14])[N:12]=2)[N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH:10]=[C:11]([C:13]([F:15])([F:16])[F:14])[N:12]=2)[N:3]=1
Reactant: Cc1cccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2nc(C(F)(F)F)cn2-c2ccc(S(C)(=O)=O)cc2)n1
Yield: 38.6 %

Procedure:
A mixture of the 4,5-dihydro-imidazole of step 2 (1.3 g, 3.26 mmol) and p-toluenesulfonic acid monohydrate (0.26 g, 1.36 mmol) in toluene (200 ml) was heated to reflux for 24 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude mixture (1.56 g) was purified by chromatography on silica gel using ethyl acetate/acetone (98/2) to give pure 2-methyl-6-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine (0.48 g, 38%) as a white solid: mp (DSC) 205° C. Anal. Calc'd. for C17H14N3SO2F30.25H2O: C, 52.91; H, 3.79; N, 10.89; S, 8.31. Found: C, 52.67; H, 3.55; N, 10.64; S, 8.68.
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.C[O:8][C:9](=O)[CH:10]([CH3:25])[CH2:11][NH:12][C:13]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:24][O:23][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([NH:12][CH2:11][CH:10]([CH3:25])[C:9]([NH2:2])=[O:8])[CH:22]=1
Reactant: COC(=O)C(C)CNc1cc(OC)c2ccccc2n1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(NCC(C)C(N)=O)nc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
A slurry of ammonium chloride (0.38 g, 7.11 mmol) in dry methylene chloride (20 mL) at 0° C. was treated with trimethylaluminum (1 eq, 7.11 mmol, 3.6 mL of a 2M solution in toluene). The mixture was allowed to warm to room temperature over a period of two hours, at which time a solution of 3-(4-methoxy-quinolin-2-ylamino)-2-methyl-propionic acid methyl ester (0.33 eq, 2.37 mmol, 0.65 g) in dry methylene chloride (5 mL) was added. The solution stirred at room temperature for two hours, then was quenched slowly by addition of concentrated HCl (1 mL). After stirring for an additional 30 minutes, the mixture was diluted with 10% NaOH (30 mL) and brine (20 mL) and extracted into methylene chloride. The organic extracts were dried over Na2SO4, filtered and concentrated to an oil. Purification via column chromatography on silica (95:5 methylene chloride/methanolic ammonia) provided the product (0.29 g, 48%) as a white solid. [M+H]+ 260.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]=[C:15]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:27]=2[NH:28]C(=O)C(Cl)(Cl)Cl)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:27]=2[NH2:28])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]=[C:15]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:27]=2[NH2:28])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccncc1C(=NC1CCN(Cc2ccccc2)CC1)c1ccccc1)C(Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccncc1C(=NC1CCN(Cc2ccccc2)CC1)c1ccccc1
Product: Nc1ccncc1C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 18.0 g (34.9 mmol) of 3-[α-{(1-benzylpiperidin-4-yl)imino}benzyl]-4-trichloroacetylaminopyridine in 150 mL of ethanol was added 2.65 g (70 mmol) of sodium borohydride under ice-cooling and the mixture was stirred for 5 hours at ambient temperature. The reaction mixture was poured into water, and the ethanol was evaporated in vacuo. The residue was extracted with ethyl acetate. The organic layer separated was washed with water and then with brine, dried on anhydrous sodium sulfate and then concentrated in vacuo. Purification by means of column chromatography (silica gel, 1:9 methanol:chloroform) gave 4.82 g (12.9 mmol) of the title compound and 6.65 g (17.9 mmol) of 3-[α-{(1-benzyl-piperidin-4-yl)imino}benzyl]-4-aminopyridine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6](=[O:9])[CH2:7][CH3:8])[CH3:2].[CH3:11][CH2:12][O-].[Na+].C(I)C>CCO>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH2:11][CH3:12])[C:6](=[O:9])[CH2:7][CH3:8])[CH3:2]
Reactant: CCOC(=O)CC(=O)CC
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCI
Solvent: CCO
Product: CCOC(=O)C(CC)C(=O)CC
Temperature: 80 °C
Reaction time: 16 h
Yield: 70.6 %

Procedure:
To a solution of 3-oxo-pentanoic acid ethyl ester (5.19 g, 36 mmol) in anhydrous EtOH (40 mL) was added NaOEt (21% wt. in EtOH, 11.7 mL, 36 mmol). he reaction mixture was heated to 80° C. Ethyl iodide (6.18 g, 39.6 mmol) was added dropwise at 80° C. Stirring was continued at 80° C. for 16 hours. The reaction mixture was concentrated and loaded onto a silica gel column and eluted with 1-2% EtOAc/heptane to give 4.38 g of the title compound.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=O)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:30])=[N:5]1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([O:23][C:24]([CH3:29])([CH3:28])[C:25]([N:44]5[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]5)=[O:27])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][C:6]([CH3:30])=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)(C)C(=O)O)cc2OCC3)n(C(C)C)n1
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)(C)C(=O)N4CCN(C)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
To a suspension of 2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-2-methylpropionic acid from Example 45 (0.0922 mmol) in DMF (2 mL) were added DIPEA (47 ul, 0.277 mmol), 1-methylpiperazine (31 uL, 0.277 mmol), HOBt (19 mg, 0.138 mmol) and EDCI (27 mg, 0.138 mmol) and the reaction mixture was stirred at RT for 2 h. Additional EDCI (50 mg) was added and the reaction mixture was stirred at RT for 18 h. The mixture was then partitioned between EtOAc and water. The aqueous layer was further extracted with EtOAc and the combined organic layers were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-8% MeOH in DCM) affording 250 as a white solid (28 mg, 60% over three steps). LCMS: RT 2.92 min [M+H]+ 494.1. 1H NMR (DMSO, 400 MHz): δ 8.29 (1H, d, J=8.97 Hz), 7.83 (1H, s), 6.64 (1H, dd, J=8.98, 2.60 Hz), 6.42 (1H, d, J=2.57 Hz), 5.88-5.76 (1H, m), 4.47 (4H, s), 3.75-3.44 (4H, m), 2.24 (3H, s), 2.19 (2H, s), 2.06-1.94 (5H, m), 1.58 (6H, s), 1.44 (6H, d, J=6.59 Hz)
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:12][CH:11]=2)[CH2:8][CH2:7][N:6]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:5]1.Br[CH2:45][C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=1>CN(C)C=O>[CH:47]1[C:48]2[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:54]=[CH:55][C:46]=1[CH2:45][O:3][CH:4]1[CH:9]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][O:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:14][CH:15]=2)[CH2:8][CH2:7][N:6]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(COC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)C(O)C1
Reactant: BrCc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(COC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
290 mg (6.05 mmol) of sodium hydride (50% dispersion in refined oil) were added to a solution of 2.08 g (3.78 mmol) of tert-butyl (3RS,4RS)-3-hydroxy-4-(4-trityloxymethyl-phenyl)-piperidine-1-carboxylate and 1.0 g (4.54 mmol) of 2-bromomethylnaphthalene in 30 ml of dimethylformamide and the reaction mixture was stirred at room temperature for 2 hours. For the working-up, the reaction mixture was evaporated in an oil pump vacuum, the residue was partitioned between 100 ml of saturated ammonium chloride solution and 100 ml of ethyl acetate and thereafter the separated aqueous phase was extracted twice with 50 ml of ethyl acetate each time. The combined ethyl acetate extracts were dried over sodium sulphate and evaporated under reduced pressure. For purification, the crude product was chromatographed on silica gel using a 4:1 mixture of methylene chloride and hexane as the eluent. There were obtained 2.27 g (87% of theory) of tert-butyl (3RS,4RS)-3-naphthalen-2-ylmethoxy-4-(4-trityloxymethyl-phenyl)-piperidine-1-carboxylate as a colourless solid; MS: 707 (M+NH4)+.