Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([OH:49])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].O.ON1C2C=CC=CC=2N=N1.[CH2:61](O)[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>C1COCC1>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)O)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Reactant: OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)OCc6ccccc6)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic acid (80 mg, 0.12 mmol) in THF (1 mL) was added polystyrene-carbodiimide (208 mg, 0.24 mmol), 1-hydroxybenzotriazole hydrate (32 mg, 0.24 mmol) and benzyl alcohol (0.5 mL). The reaction mixture was stirred at room temperature under nitrogen for 17 h. The reaction was filtered through a micro filter and concentrated. The crude material was purified by preparative HPLC (10:90 acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 10 min, then isocratic) to afford (6R,6aS,14aR)-benzyl 1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate as a mixture of diastereomers (14 mg, 20%) and as a dark red solid: 1H NMR (500 MHz, CDCl3) δ 14.26 (s, 0.3H), 14.17 (s, 0.7H), 12.09 (s, 0.3H), 12.08 (s, 0.7H), 8.32 (br s, 6H), 8.27 (s, 0.3H), 8.21 (s, 0.7H), 6.86 (d, J=8.0 Hz, 1H), 6.52 (s, 1H), 5.87 (s, 0.7H), 5.86 (s, 0.3H), 5.28 (s, 2H), 4.96 (d, J=8.0 Hz, 1H), 4.67 (d, J=8.0 Hz, 1H), 3.80 (s, 3H), 3.74-3.70 (m, 2H), 3.61 (s, 3H), 3.58-3.53 (m, 2H), 3.40 (s, 3H), 3.37-3.30 (m, 3H), 3.13 (t, J=9.0 Hz, 1H), 2.41 (s, 2H), 3.39 (s, 1H), 1.36 (d, J=6.5 Hz, 3H); MS (ESI+) m/z 774 (M+H); HPLC >99% (AUC), tR 15.52 min.
Reaction SMILES: [N:1]([C:12]1[NH:13][C:14]([C:19]#[N:20])=[C:15]([C:17]#[N:18])[N:16]=1)=[N:2][C:3]1[NH:4][C:5]([C:10]#[N:11])=[C:6]([C:8]#[N:9])[N:7]=1.N1C=CC=CC=1>[Zn].C(O)(=O)C>[NH:2]([C:3]1[NH:7][C:6]([C:8]#[N:9])=[C:5]([C:10]#[N:11])[N:4]=1)[NH:1][C:12]1[NH:13][C:14]([C:19]#[N:20])=[C:15]([C:17]#[N:18])[N:16]=1
Reactant: N#Cc1nc(N=Nc2nc(C#N)c(C#N)[nH]2)[nH]c1C#N
Agent: [Zn]
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: N#Cc1nc(NNc2nc(C#N)c(C#N)[nH]2)[nH]c1C#N

Procedure:
2.65 g of 2,2'-azobis(4,5-imidazoledicarbonitrile) was placed in a flask with 65 ml of pyridine and 25 ml of galcial acetic acid. The slurry was then purged and deoxygenated thoroughly with a stream of nitrogen. Then 3 equivalents (1.95 g) of zinc dust was added. An immediate green/black solution was formed characteristic of a radical anion species. This slowly faded to a pale green as the last of the intermediate reacted. The mixture was filtered under nitrogen to remove excess zinc salts. This gave a pale yellow solution of 2,2'-hydrazobis(4,5-imidazoledicarbonitrile). Exposure of an aliquot to the air caused immediate air oxidation back to the bright yellow azo compound which precipitated as the bis pyridinium salt.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:33]=[CH:32][C:13]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([NH2:31])[CH:29]=4)[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1>C(#N)C>[F:9][C:10]1[CH:33]=[CH:32][C:13]([CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([N:22]3[C:30]4[C:25](=[CH:26][C:27]([Cl:1])=[C:28]([NH2:31])[CH:29]=4)[CH2:24][CH2:23]3)[CH2:20][CH2:21]2)=[CH:12][CH:11]=1
Reactant: Nc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Nc1cc2c(cc1Cl)CCN2C1CCN(CCc2ccc(F)cc2)CC1
Yield: 34.5 %

Procedure:
N-Chlorosuccinimide (0.24 g) was added at room temperature to a solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminoindoline (0.5 g) in acetonitrile (50 ml) and the resultant mixture was stirred for 1 hr. Then the reaction mixture was filtered and concentrated under reduced pressure. Next, a 5 N aqueous solution of sodium hydroxide and ethyl acetate were added thereto and the layers were separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The resulting residue was purified by silica gel column chromatography (methylene chloride/ethanol system) to give the title compound (0.19 g) as a brown oil (yield: 34%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH:14]3[CH2:17][N:16]([C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:23])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[CH:34][C:35]3[O:39][CH:38]=[CH:37][C:36]=3[CH:40]=2)O1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O>[O:39]1[C:35]2[CH:34]=[CH:33][C:32]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[C:12]([CH2:13][CH:14]5[CH2:17][N:16]([C:18]([CH:20]6[CH2:22][CH2:21]6)=[O:19])[CH2:15]5)=[N:11][NH:10][C:9]4=[O:23])=[CH:4][CH:3]=3)=[CH:40][C:36]=2[CH:37]=[CH:38]1
Reactant: O=C(C1CC1)N1CC(Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Reactant: CC1(C)OB(c2ccc3occc3c2)OC1(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(C1CC1)N1CC(Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Temperature: 100 °C
Reaction time: 22 h
Yield: 40.6 %

Procedure:
In a microwave vial purged with nitrogen, a mixture of 4-(4-bromophenyl)-5-{[1-(cyclopropylcarbonyl)-3-azetidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (83 mg, 0.220 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (9 mg, 11 μmol), and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran (59 mg, 0.242 mmol) in 1,4-dioxane (2 mL) and 2M aq potassium carbonate (0.5 mL, 1.00 mmol) was stirred at 100° C. in an oil bath for 22 h. Additional 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran (59 mg, 0.242 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (9 mg, 11 μmmol) were added and the reaction mixture was heated at 100° C. in an oil bath for 20 h. The reaction was cooled to room temperature, poured into water (50 mL), and adjusted to pH˜4.5 with 1N aq HCl. The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (ethyl acetate, then 0-10% methanol/ethyl acetate) followed by a second purification by reverse phase HPLC (20-70% acetonitrile/water+0.1% NH4OH) provided the title compound as an ivory solid (37 mg, 38%). MS(ES)+ m/e 415.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]([NH:16]C(OCC1C=CC=CC=1)=O)=[CH:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][N:10]=[CH:9]2.FC(F)(F)C(O)=O>CO>[CH3:1][O:2][C:3](=[O:27])[CH:4]([NH2:16])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][N:10]=[CH:9]2
Reactant: COC(=O)C(=Cc1cc(Cl)c2[nH]ncc2c1)NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COC(=O)C(N)Cc1cc(Cl)c2[nH]ncc2c1
Reaction time: 96 h

Procedure:
A solution of 2-benzyloxycarbonylamino-3-(7-chloro-1H-indazol-5-yl)-acrylic acid methyl ester (300 mg, 0.78 mmol) in methanol (10 mL) was treated with trifluoroacetic acid (0.2 mL), flushed with nitrogen, and treated with 10% palladium on charcoal (30 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen. After 4 days, all starting material had been consumed. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography gave 78 mg (40%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH3:19])[N:13]=2)[CH:3]=1.[NH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>CN1CCCC1=O>[C:30]([O:29][C:28](=[O:34])[NH:27][C@H:22]1[CH2:23][CH2:24][CH2:25][CH2:26][C@H:21]1[NH:20][C:2]1[N:7]=[N:6][C:5]([C:8](=[O:9])[NH2:10])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH3:19])[N:13]=2)[CH:3]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CCc1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: CN1CCCC1=O
Product: CCc1cccc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)n1
Temperature: 150 °C
Reaction time: 16 h
Yield: 46.7 %

Procedure:
6-Chloro-4-(6-ethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide (218 mg, 0.785 mmol), and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (336 mg, 1.57 mmol) were dissolved in N-methylpyrrolidinone (4 mL) and heated at 150° C. for 40 h. Additional tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (168 mg, 0.78 mmol) was added and the heating continued for 16 h more. The reaction mixture was cooled and concentrated in vacuo, then diluted with water, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by chromatography (silica, 0 to 5% methanol in dichloromethane) gave {(1S,2R)-2-[6-carbamoyl-5-(6-ethyl-pyridin-2-ylamino)-pyridazin-3-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (167 mg, 46%) as a light brown amorphous residue. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 11.44 (s, 1H) 8.47 (s, 1H) 7.97-8.03 (m, 1H) 7.52 (t, J=7.6 Hz, 1H) 7.22-7.26 (m, 1H) 6.78 (d, J=7.2 Hz, 1H) 6.70 (d, J=7.9 Hz, 1H) 5.38-5.43 (m, 1H) 4.92-5.00 (m, 1H) 3.97-4.08 (m, 2H) 2.80 (q, J=7.6 Hz, 2H) 1.58-1.96 (m, 8H) 1.41 (s, 9H) 1.31-1.39 (m, 3H); LCMS (EI/CI) m/z: 456 [M+H].
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][NH:11][C:10]3=O)=[N:4][N:3]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:5]3[O:6][C:2]([CH3:1])=[N:3][N:4]=3)[CH:8]=2)[N:13]=[CH:12][N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nnc(-c2ccc3nc[nH]c(=O)c3c2)o1
Product: Cc1nnc(-c2ccc3ncnc(Cl)c3c2)o1

Procedure:
6-(5-Methyl-1,3,4-oxadiazol-2-yl)quinazolin-4-one (0.3 g) was treated with phosphorus oxychloride at reflux under N2 for 5 hours. The mixture was concentrated in vacuo and the residue azeotroped with toluene. This was then taken up in ethyl acetate and washed with 5% sodium bicarbonate and saturated brine, dried over magnesium sulphate and concentrated in vacuo to give the title compound (0.22 g) as a yellow solid; δH [2H6]DMSO 12.65 (1H, bs), 8.71(1H, d), 8.45 (1H, dd), 8.33 (1H, s), 7.95 (1H, s) 2.73 (3H, s).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([C:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[ClH:28]>C(Cl)Cl.CCOCC>[ClH:28].[F:27][C:2]([F:1])([F:26])[C:3]1[CH:4]=[C:5]([C:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH:14]=2)[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: FC(F)(F)c1cc(C2=CCNCC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
To a solution of tert-butyl 4-(3,5 bis(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (18, 0.891 g, 2.25 mmol) in CH2Cl2 (13.5 mL) in CH2Cl2 (11 mL) was added HCl (2.0 N solution in Et2O, 11.0 mL) and the mixture stirred at ambient temperature for 18 h. The reaction mixture was diluted with Et2O (30 mL), and the resulting precipitate was collected by filtration to provide 4-(3,5-bis(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine hydrochloride (19) as a white solid (0.452 g, 60%): 1H NMR (300 MHz, DMSO-d6) δ 9.34 (br s, 2H), 8.14-8.09 (m, 2H), 8.08-8.04 (m, 1H), 6.59-6.53 (m, 1H), 3.83-3.74 (m, 2H), 3.38-3.25 (m, 2H), 2.83-2.71 (m, 2H); ESI MS m/z 296 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1.[C:25]1(O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([O:19][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1
Reactant: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(Cl)cc12
Reactant: Oc1ccccc1
Product: Cc1c(S(=O)(=O)Nc2cccc(C(=O)Oc3ccccc3)c2)sc2ccc(Cl)cc12
Yield: 74 %

Procedure:
The product was prepared from 3-{[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoic acid (21 mg, 0.055 mmol) (Intermediate 19) and phenol (9.4 mg, 0.100 mmol) according to the General Procedure 7, described in Example 107. The title compound was obtained in 74% yield (18.7 mg). 1H NMR (500 MHz, CDCl3) δ ppm 2.50 (s, 3 H) 7.06 (s, 1 H) 7.10-7.15 (m, 2 H) 7.25-7.29 (m, 1 H) 7.39-7.44 (m, 2 H) 7.44 (dd, J=8.10, 7.70 Hz, 1 H) 7.44 (dd, J=8.65, 2.02 Hz, 1 H) 7.51 (ddd, J=8.10, 2.34, 1.15 Hz, 1 H) 7.72 (dd, J=8.65, 0.57 Hz, 1 H) 7.73 (dd, J=2.02, 0.57 Hz, 1 H) 7.86 (dd, J=2.34, 1.58 Hz, 1H) 7.99 (ddd, J=7.70, 1.58, 1.15 Hz, 1 H). MS (ESI+) m/z 458 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:20]1([OH:26])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[C:10]([O:12]CC1C=CC=CC=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([C:20]1([OH:26])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC(C(=O)OCc1ccccc1)C1(O)CCOCC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(C(=O)O)C1(O)CCOCC1
Yield: 87.8 %

Procedure:
N-(t-Butoxycarbonyl)-α-(4-hydroxy-2,3,5,6-tetrahydro-4-pyranyl)glycine, benzyl ester (10.34 g, 28.3 mmoles) and 10% palladium on charcoal (2.0 g) in 200 ml of absolute ethanol was treated with hydrogen at 1 atmosphere for 2 hours. The catalyst was filtered and the solvent removed in vacuo finally by co-evaporation with benzene. A small amount of ethyl acetate induced crystallization. The slurry was triturated with isopropyl ether, filtered and washed with isopropyl ether and hexane and dried in air to give 6.84 g of product as a white solid, melting point 140°-141° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH2:13]([N:20]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:21]1[C:26]([C:27]([O:29]CC)=O)=[C:25]([Cl:32])[N:24]=[C:23]([S:33][CH3:34])[N:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>O1CCCC1>[CH2:13]([N:20]1[C:21]2[N:22]=[C:23]([S:33][CH3:34])[N:24]=[C:25]([Cl:32])[C:26]=2[C:27](=[O:29])[CH:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:35]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CCN(Cc1ccccc1)c1nc(SC)nc(Cl)c1C(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1CN(Cc2ccccc2)c2nc(SC)nc(Cl)c2C1=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a cooled solution at 0° C. of diisopropylamine (51.0 mL, 0.361 mol) in tetrahydrofuran (600 mL) was added n-BuLi (221 mL, 0.353 mol, 1.6 M in hexane) dropwise and the mixture was stirred at the 0° C. for 45 min. The reaction mixture was then cooled to −78° C. and a solution of ethyl 4-(benzyl(3-ethoxy-3-oxopropyl)amino)-6-chloro-2-(methylthio)pyrimidine-5-carboxylate (50 g, 0.114 mol) in tetrahydrofuran (500 mL) was added drop wise over 45 min. The reaction mixture was stirred at -78° C. for 15 min before water (1 L) was added. The reaction mixture was then warmed to room temperature and the organic phase was separated from the aqueous layer. The aqueous layer was extracted with EtOAc (500 mL). The combined organic layers were washed with water (1 L), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude ethyl 8-benzyl-4-chloro-2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carboxylate that was used for next step directly.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])=O)C.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[Cl:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[C:7]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C:6]([CH2:4][OH:3])=[CH:15]2
Reactant: CCOC(=O)c1cc2cccc(Cl)c2nc1-c1cccnc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OCc1cc2cccc(Cl)c2nc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a suspension of 8-chloro-2-(pyridin-3-yl)quinoline-3-carboxylic acid ethyl ester (1.0 g, 3.2 mmol) in toluene at −78° C. was added a solution of DIBAL-H (10 mL, 1M in DCM) dropwise over 10 minutes. The mixture was stirred at this temperature for 2 h, then quenched by the addition of a saturated aqueous solution of Rochelle salt (5 mL). After warming to room temperature, extra Rochelle salt solution (5 mL) was added. The resulting solid was filtered, washed on the sinter with aqueous NaOH solution (2N) and water, and dried to give [8-chloro-2-(pyridin-3-yl)quinolin-3-yl]methanol (860 mg, quantitative) as a beige solid. δH (DMSO-d6) 8.92 (d, J 1.7 Hz, 1H), 8.73 (dd, J 4.8, 1.6 Hz, 1H), 8.61 (s, 1H), 8.17 (dt, J 7.9, 1.9 Hz, 1H), 8.09 (dd, J 8.2, 1.1 Hz, 1H), 7.97 (dd, J 7.5, 1.2 Hz, 1H), 7.63 (m, 1H), 7.58 (ddd, J 7.8, 4.8, 0.6 Hz, 1H), 5.76 (s, 1H), 5.62 (t, J 5.2 Hz, 1H), 4.68 (d, J 4.9 Hz, 2H). LCMS (ES+) 271.0 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[O:15]1[CH:17]2[CH2:18][CH2:19][CH2:20][CH:16]12.[OH-].[K+]>CCOCC.CCCCCC>[O:7]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:17]2[CH2:18][CH2:19][CH2:20][CH:16]2[OH:15])=[CH:10][CH:9]=1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: C1CC2OC2C1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOCC
Product: OC1CCCC1Oc1ccc(Oc2ccccc2)cc1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
A mixture of 52 g of 4-hydroxydiphenyl ether and 23.5 g of 1,2-epoxycyclopentane is heated to 150° C. To this melt are added in the course of 25 minutes 6.7 g of 90% potassium hydroxide powder and the mixture is stirred for one hour at 130° C. After cooling, the reaction mixture is taken up in ether/hexane (1:1) and the organic solution is washed 4 times with 10% potassium hydroxide solution and 3 times with saturated sodium chloride solution. The organic phase is dried over sodium sulphate and concentrated by rotary evaporation under reduced pressure. Distillation of the crude product yields 2-(4-phenoxyphenoxy)-cyclopentan-1-ol as a colourless oil with a boiling point of 181°-185° C./0.001 torr and a refractive index of nD20 =1.5812.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([OH:18])[CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.O.NN>CO>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([N:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([OH:18])[CH2:13]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(N2CCC[C@H](O)C2)ccc1[N+](=O)[O-]
Agent: NN
Solvent: O
Solvent: CO
Product: COc1cc(N2CCC[C@H](O)C2)ccc1N
Yield: 74.4 %

Procedure:
A solution of (3S)-1-[3-(methyloxy)-4-nitrophenyl]-3-piperidinol (3.90 g, 15.5 mmol), FeCl3 (0.630 g, 3.9 mmol), activated carbon (4.0 g), and hydrazine hydrate (3.9 mL, 124 mmol) was heated in MeOH (100 mL) for 3 h. Once the starting material was judged consumed by TLC, the mixture was filtered over celite and concentrated to afford the title compound of step B as a dark purple solid (2.56 g, 11.53 mmol, 74% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.62-1.72 (m, 2H), 1.75 (d, J=3.30 Hz, 1H), 1.93 (td, J=8.07, 4.40 Hz, 1H), 2.44 (s, 2H), 2.88 (s, 1H), 2.93 (d, J=9.53 Hz, 1H), 2.99 (dd, J=10.81, 6.05 Hz, 2H), 3.12 (d, J=10.63 Hz, 1H), 3.84 (s, 3H), 3.95 (s, 1H), 6.44 (d, J=8.07 Hz, 1H), 6.53 (s, 1H), 6.64 (d, J=8.07 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[S:8][C:9]([CH3:11])=[CH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].[I:15]N1C(=O)CCC1=O>B(F)(F)F.CCOCC.O>[I:15][C:10]1[C:6]2[C:5](=[O:12])[N:4]([CH3:13])[C:3](=[O:14])[N:2]([CH3:1])[C:7]=2[S:8][C:9]=1[CH3:11]
Reactant: Cc1cc2c(=O)n(C)c(=O)n(C)c2s1
Reactant: O=C1CCC(=O)N1I
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Product: Cc1sc2c(c1I)c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of Step 4 intermediate (12.5 g, 59.52 mmol) in boron trifluoride diethyl etherate (300 ml) was added N-iodosuccinimide (19.9 g, 89.28 mmol) and the mixture was stirred for 3 h at room temperature under nitrogen atmosphere. The reaction mixture was diluted with water (100 ml), extracted with ethyl acetate (3×200 ml) and the combined organic layers were washed with water (2×150 ml), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 2% ethyl acetate in chloroform to obtain 9.7 g of the product as a pale brown solid; 1H NMR (300 MHz, DMSO-d6) δ 2.37 (s, 3H), 3.21 (s, 3H), 3.42 (s, 3H); MS (m/z) 337.11 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([C@@H:18]([CH:22]([CH3:24])[CH3:23])[C:19]([OH:21])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6]([CH:8]([C@@H:18]([CH:22]([CH3:24])[CH3:23])[C:19]([OH:21])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)[C@@H](C(=O)O)C(C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)[C@@H](C(=O)O)C(CCCc1ccccc1)C(=O)OC(C)(C)C

Procedure:
A solution of (E)-2(R)-[1-(RS)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-3-methylbutyric acid in ethanol was shaken in a hydrogen atmosphere in the presence of 10% palladium on charcoal catalyst until the uptake of hydrogen had stopped. The catalyst was filtered off and the solvent was evaporated to give 2(R)-[1(RS)-(tert.-butoxycarbonyl)-4-phenylbutyl]-3-methylbutyric acid in the form of a pale yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:31])[CH:14]([P:23]([O:28][CH2:29][CH3:30])([O:25][CH2:26][CH3:27])=[O:24])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(C)(C)C>ClCCl>[CH2:29]([O:28][P:23]([CH:14]([CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:13]([OH:31])=[O:12])([O:25][CH2:26][CH3:27])=[O:24])[CH3:30]
Reactant: CCOP(=O)(OCC)C(CCc1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(OCC)C(CCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (4 mL) was added drop wise to a stirring solution of 2-(diethoxy-phosphoryl)-4-phenyl-butyric acid tert-butyl ester (1.00 g, 2.81 mmol) in anhydrous dichloromethane (16 ml). The mixture was stirred for 2 hours at room temperature followed by the removal of the solvent. The crude residue was purified by flash chromatography (100% dichloromethane-2.5% methanol in dichloromethane) to afford the desired compound as a yellowish oil. 1H NMR (CDCl3, 400 MHz) δ 11.21 (br s, 1H), 7.29-7.14 (m, 5H), 4.24-4.12 (m, 4H), 3.09-3.00 (m, 1H), 2.82-2.75 (m, 1H), 2.64-2.57 (m, 1H), 2.35-2.27 (m, 1H), 2.15-2.11 (m, 1H), 1.31-1.25 (m, 6H); 13C (CDCl3, 100 MHz) δ 170.4, 140.4, 128.4, 128.3, 126.1, 63.4, 63.2, 45.1, 43.8, 34.0, 28.5, 16.0; 31P (CDCl3, 400 MHz) δ 24.3; HRMS calcd. for C14H21O5P 300.1127, found 300.1129.