Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[S:10][C:9](=[O:11])[NH:8][C:6]=2[N:7]=1.C(O[CH:17]1[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])(=O)C>>[NH2:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:17]3[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]3[O:19][C:20](=[O:22])[CH3:21])[C:6]=2[N:7]=1
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Nc1nc2[nH]c(=O)sc2c(=O)[nH]1
Product: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
Compound 4 (10 g, 54.4 mmol) was glycosylated exactly as described for the synthesis of 6 except that the sugar used in this case was the 1,2,3,5-tetra-O-acetyl-D-ribofuranose (20.7 g, 65.1 mmol). After the usual workup the crude residue was flash chromatographed on silica gel using 10% methanol in dichloromethane. Yield of pure material 7.1 g (29%) as a dry foam or amorphous solid.
Reaction SMILES: [OH:1][C@H:2]([CH3:37])[C@H:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[N:20]([CH3:28])[N:19]=3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])[CH2:4][OH:5].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[OH:1][C@H:2]([CH3:37])[C@H:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[N:20]([CH3:28])[N:19]=3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])[CH2:4][OH:5]
Reactant: C[C@@H](O)[C@@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: C[C@@H](O)[C@@H](CO)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 39.6 %

Procedure:
In a 10 mL round-bottom flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((1R,2R)-2-hydroxy-1-hydroxymethyl-propyl)-amide (30 mg, 0.057 mmol) and TFA (0.3 ml, 3.9 mmol) were combined with dichloromethane (1 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2.5 h then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (1 mL) and ethylenediamine (0.10 ml, 1.5 mmol) was added. The reaction mixture was stirred at room temperature for 18 h then concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (hot dichloromethane/heptane) to afford 9 mg (40%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((1R,2R)-2-hydroxy-1-hydroxymethyl-propyl)-amide as a light yellow solid. MS: [M+H]+=399; 1H NMR (DMSO-d6) δ: 12.61 (br. s., 1H), 9.16 (s, 1H), 8.83 (dd, J=8.9, 5.5 Hz, 1H), 8.44 (s, 1H), 8.15 (d, J=9.4 Hz, 1H), 7.64 (dd, J=9.8, 1.9 Hz, 1H), 7.15 (td, J=9.3, 1.9 Hz, 1H), 5.07 (d, J=4.2 Hz, 1H), 4.85 (t, J=4.9 Hz, 1H), 4.15 (s, 3H), 3.98-4.24 (m, 2H), 3.54-3.71 (m, 2H), 1.13 (d, J=6.0 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:35]=[CH:34][C:29]([O:30][CH2:31][CH2:32]Br)=[CH:28][CH:27]=1>>[C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:32][CH2:31][O:30][C:29]2[CH:34]=[CH:35][C:26]([F:25])=[CH:27][CH:28]=2)[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(OCCBr)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(CCOc2ccc(F)cc2)c2ccccc2-c2ccccc21

Procedure:
Using ((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-carbamic acid tert-butyl ester and 4-fluorophenoxy-ethylbromide, the title product was prepared in the same manner as described for example 1a (84%). White solid. MS: m/e=463(M+H+).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25](O)=[O:26])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.[NH2:40][C:41]1[N:46]([CH2:47][CH2:48][CH2:49][CH3:50])[C:45](=[O:51])[N:44]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[F:59])[C:43](=[O:60])[C:42]=1[NH:61][C:62](=[O:71])[CH2:63][C:64]1[CH:69]=[CH:68][C:67]([NH2:70])=[CH:66][CH:65]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:40][C:41]1[N:46]([CH2:47][CH2:48][CH2:49][CH3:50])[C:45](=[O:51])[N:44]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[F:59])[C:43](=[O:60])[C:42]=1[NH:61][C:62]([CH2:63][C:64]1[CH:65]=[CH:66][C:67]([NH:70][C:25]([C:23]2[N:22]=[CH:21][N:20]([C:1]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:24]=2)=[O:26])=[CH:68][CH:69]=1)=[O:71]
Reactant: CCCCn1c(N)c(NC(=O)Cc2ccc(N)cc2)c(=O)n(Cc2ccccc2F)c1=O
Reactant: O=C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCn1c(N)c(NC(=O)Cc2ccc(NC(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)cc2)c(=O)n(Cc2ccccc2F)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 111.5 %

Procedure:
A solution of 1-trityl-1H-imidazole-4-carboxylic acid (67 mg, 0.19 mmol) in N,N-dimethylformamide (1.0 mL) at 25 ° C. was treated with 1-hydroxybenzotriazole hydrate (25.4 mg, 0.19 mmol) and O-benzotriazol-1-yl-N,N,N′N′-tetramethyluronium hexafluorophosphate (71 mg, 0.19 mmol). This solution was cooled to 0° C. and then was treated with N-[6-amino-1-butyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-2-(4-amino-phenyl)-acetamide hydrochloride salt (81.5 mg, 0.17 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.85 mmol). The reaction was stirred at 0° C. for 1 h and then at 25° C. for 4 h. At this time, the reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×25 mL). Some residual solids were then removed by filtration. The filtrate was washed with a saturated aqueous sodium chloride solution. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 1-trityl-1H-imidazole-4-carboxylic acid (4-{[6-amino-1-butyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl]-methyl}-phenyl)-amide (147 mg, quant.) as a pale yellow foam: LR-MS for C23H18N2O2 (M−H)+ at m/z=353.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:10][C:8](=[O:9])[NH:7][C:5]=2[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1>CN(C)C=O>[O:9]=[C:8]1[N:7]([CH2:18][CH2:19][O:20][C:21]2[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=2)[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=2[O:10]1
Reactant: O=c1[nH]c2ccccc2o1
Reactant: O=Cc1ccc(OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCn2c(=O)oc3ccccc32)cc1

Procedure:
Dissolve benzoxazolinone (0.024 mol) in dimethylformamide and add potassium carbonate (0.047 mol). Heat at reflux for 20 minutes and then add the compound obtained in Step A (0.021 mol). Stir magnetically at reflux for 80 minutes. Hydrolyse the reaction mixture in 150 ml of water, suction-filter off the resulting precipitate and recrystallise it from a 5/5 cyclohexane/toluene mixture.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:11]([NH2:12])[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].O>ClCCl>[CH2:1]([O:3][C:4]([C@H:6]1[C@H:11]([NH:12][C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1NC(=O)OCc1ccccc1
Reaction time: 22 h
Yield: 51.6 %

Procedure:
In a dry flask (3R,4R)-4-aminopiperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (3.07 g, 11.3 mmol) was dissolved in dichloromethane (100 mL) and triethylamine (2.1 mL, 15.1 mmol) and benzyl chloroformate (2.0 mL, 12.6 mmol) were added. The mixture was stirred for 22 hours. Water (30 mL) was added and the layers separated. The aqueous layer was extracted with dichloromethane (30 mL). The combined organic layers were dried with magnesium sulfate, filtered, and concentrated in vacuo to give a crude oil (4.91 g). Purification by flash column chromatography (40% ethyl acetate/hexanes) provided a colorless oil (2.37 g, 51%). 1H NMR (300 MHz, CDCl3), δ: 7.33 (m, 5H), 5.08 (s, 2H), 4.71 (s, 1H), 4.12 (m, 4H), 3.90 (m, 1H), 2.98 (bs, 1H), 2.85 (t, 1H, J=13), 2.37 (m, 1H), 2.06 (d, 1H, J=7), 1.45 (s, 9H), 1.37 (m, 1H), 1.20 (t, 3H, J=7).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:19]([O:26][C:27](=[O:32])[NH:28][CH2:29][CH2:30]Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.CCOCC>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][CH2:8][N:9]([CH2:30][CH2:29][NH:28][C:27]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:32])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=C(NCCBr)OCc1ccccc1
Reactant: CCOC(=O)C1(Cc2ccccc2)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccccc2)CCN(CCNC(=O)OCc2ccccc2)CC1
Temperature: 80 °C

Procedure:
4-Benzyl-piperidine-4-carboxylic acid ethyl ester (2.5 g, 10 mmol), (2-bromo-ethyl)-carbamic acid benzyl ester (2.58 g, 10 mmol) and DIPEA (1.7 mL, 10 mmol) are dissolved in THF (50 mL) and heated at 80° C. for 15 h. The mixture is poured into Et2O (200 mL) and washed with sat. Na2CO3 (50 mL). The ether phase is extracted with 1M aqueous HCl (3×50 mL), the aqueous extracts washed with ether (50 mL) and adjusted to pH 14 with cooled 33% aqueous NaOH. The aqueous phase is extracted with CH2Cl2 (4×50 mL). The organic extracts are dried (Na2SO4), filtered and evaporated to provide the title compound.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]1[C:10]([F:11])=[CH:9][C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:7]([CH3:17])[CH:6]=1)[CH3:4].[F:18][C:19]([F:37])([F:36])[C:20]([C:23]1[CH:32]=[CH:31][C:30]2[CH2:29][C@@H:28]([C:33](O)=[O:34])[CH2:27][CH2:26][C:25]=2[N:24]=1)([CH3:22])[CH3:21].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>CN1CCCC1=O>[F:11][C:10]1[CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]([CH3:17])=[CH:6][C:5]=1[C@H:3]([NH:2][C:33]([C@H:28]1[CH2:27][CH2:26][C:25]2[N:24]=[C:23]([C:20]([CH3:22])([CH3:21])[C:19]([F:37])([F:36])[F:18])[CH:32]=[CH:31][C:30]=2[CH2:29]1)=[O:34])[CH3:4]
Reactant: CC(C)(c1ccc2c(n1)CC[C@H](C(=O)O)C2)C(F)(F)F
Reactant: Cc1cc([C@@H](C)N)c(F)cc1NS(C)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc([C@@H](C)NC(=O)[C@H]2CCc3nc(C(C)(C)C(F)(F)F)ccc3C2)c(F)cc1NS(C)(=O)=O
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A 2 ml, vial was charged with (R)—N-(4-(1-aminoethyl)-5-fluoro-2-methylphenyl)methanesulfonamide hydrochloride (51 mg, 0.18 mmol), (S)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (47 mg, 0.16 mmol) and N,N-diisopropylethylamine (110 uL, 0.65 mmol) and N-methylpyrrolidinone (0.8 mL). A solution of N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (75 mg, 0.20 mmol) in N-methylpyrrolidinone (0.4 mL) was added and the resulting mixture was stirred at room temperature. After 30 min the mixture was filtered and purified by reverse-phase HPLC (10-75% MeCN in 10 mM Et2NH/H2O) to afford the amide as a solid (72 mg, 85%). The sample was dissolved in hot 2/3 IPA/hexane (5 mL). 1.2 mL injections were separated on a ChiralPak AD-H 5 um, 250×20 mm column, eluting with 85/15/0.03 hexane/IPA/Et2NH at 20 mL/min. Peaks eluted at 7.5 and 8.7 min, with UV monitoring at 254 and 230 nm. The major isomer, eluting at 8.7 min was concentrated to afford the amide as fine plates (47 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.41 (d, J=7.6 Hz, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 7.07 (d, J=11.6 Hz, 1H), 5.09 (app pentet, J=7.2 Hz, 1H), 3.01 (s, 3H), 2.92-2.78 (m, 4H), 2.71-2.61 (m, 1H), 2.26 (s, 3H), 2.06-1.97 (m, 1H), 1.82-1.69 (m, 1H), 1.53 (s, 3H), 1.35 (d, J=7.1 Hz, 3H); m/z=516.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:5]([O:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)=[NH:10])=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:8]=[C:9]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][CH:15]=[CH:14]4)[N:10]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(C(=O)ONC(=N)c2ccc3[nH]ccc3c2)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1Cl
Temperature: 25 °C
Yield: 92.6 %

Procedure:
A suspension of the product of Step D (0.4 g; 1.16 mmol) and 1M TBAF in THF (0.5 ml) in anhydrous toluene (10 ml) was refluxed for 3 h under N2, cooled to room temperature and solvents were removed under reduced pressure. The residue was washed with H2O (5 ml) and the solid was purified by FCC (SiO2; CH2Cl2) to give the title compound (0.35 g; 92%) as colourless solid. 1H-NMR (CDCl3) 4.0 (s, 3H); 6.66 (m, 1H); 7.05 (d, 1H, J=8.7 Hz); 7.27 (m, 1H); 7.49 (d, 1H, J=8.7 Hz); 7.97-8.01 (m, 1H); 8.1-8.13 (m, 1H); 8.27 (d, 1H, J=2.1 Hz); 8.3 (broad s, 1H); 8.48 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:4]([CH3:17])[N:3]=1.[F:18][C:19]([F:37])([F:36])[C:20]1[CH:21]=[C:22]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:23][NH:24][CH2:25][CH2:26][CH2:27][OH:28].ClC1C(C(O)=O)=C(C2C=CC=CC=2)C=CN=1.FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)CNCCO>>[F:18][C:19]([F:36])([F:37])[C:20]1[CH:21]=[C:22]([CH:29]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:31]=1)[CH2:23][N:24]([CH2:25][CH2:26][CH2:27][OH:28])[C:8]([C:7]1[C:2]([Cl:1])=[N:3][C:4]([CH3:17])=[CH:5][C:6]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: OCCCNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1cc(-c2ccccc2)c(C(=O)O)c(Cl)n1
Agent: O=C(O)c1c(-c2ccccc2)ccnc1Cl
Agent: OCCNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Cc1cc(-c2ccccc2)c(C(=O)N(CCCO)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(Cl)n1

Procedure:
The same process as in Step 2 in Reference Example 12 was repeated, except that 2-chloro-6-methyl-4-phenyl-3-pyridinecarboxylic acid was reacted with N-[3,5-bis(trifluoromethyl)benzyl]-N-(3-hydroxypropyl)amine in place of reacting 2-chloro-4-phenyl-3-pyridinecarboxylic acid with N-[3,5-bis(trifluoromethyl)benzyl]-N-(2-hydroxyethyl)amine, to obtain the entitled compound as a pale-yellow, oily substance. NMR(200 MHz, CDCl3) ppm: 1.15-1.65(2H,m), 2.59(3H,s), 2.75-3.20(2H,m), 4.06(1H×2/5,d,J=15.4 Hz), 4.31(1H×2/5,d,J=15.4 Hz), 4.65(1H×3/5,d,J=15.2 Hz), 4.74(1H×3/5,d,J=15.2 Hz), 7.16(1H,s), 7.20-7.60(5H,m), 7.72(2H,s), 7.78(1H,s)
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10](=[O:13])[CH2:11][CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6].S(Cl)([Cl:17])(=O)=O>C(O)(=O)C>[CH3:1][O:2][N:3]=[C:4]([C:10](=[O:13])[CH:11]([Cl:17])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=NOC)C(=O)CC
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOC)C(=O)C(C)Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.9 %

Procedure:
A mixture of ethyl 2-methoxyimino-2-propionylacetate (14.7 g.), sulfuryl chloride (10.9 g.) and acetic acid (14.7 ml.) was stirred at room temperature for an hour and then at 40° C. for 2.5 hrs. Ice-water was added to the reaction mixture, adjusted to pH 6.5 and extracted with methylene chloride. The extract was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and then filtered. The filtrate was evaporated in vacuo to give ethyl 2-methoxyimino-2-(2-chloropropionyl)acetate (16.0 g.).
Reaction SMILES: [CH3:1]OC[C@@]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)[C@@H](O)CC4)CCC1=C[C@@H](O)C[C@H]2C.[CH3:25]OC[C@@]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)[C@@H](O)CC4)C[C@H](C)C1=C[C@@H](O)CC2.[C:49]([O:52][C@H:53]1[CH2:70][CH2:69][C@@:68]2([CH2:71][O:72][CH3:73])[C:55]([CH2:56][CH2:57][C@@H:58]3[C@@H:67]2[CH2:66][CH2:65][C@@:63]2([CH3:64])[C@H:59]3[CH2:60][CH2:61][C@@H:62]2[O:74][C:75](=[O:77])[CH3:76])=[CH:54]1)(=[O:51])[CH3:50]>>[C:49]([O:52][C@H:53]1[CH2:70][C@@H:69]([CH3:1])[C@@:68]2([CH2:71][O:72][CH3:73])[C:55]([CH2:56][CH2:57][C@@H:58]3[C@@H:67]2[CH2:66][CH2:65][C@@:63]2([CH3:64])[C@H:59]3[CH2:60][CH2:61][C@@H:62]2[O:74][C:75](=[O:77])[CH3:76])=[CH:54]1)(=[O:51])[CH3:50].[C:49]([O:52][C@H:53]1[CH2:70][CH2:69][C@@:68]2([CH2:71][O:72][CH3:73])[C:55]([C@@H:56]([CH3:25])[CH2:57][C@@H:58]3[C@@H:67]2[CH2:66][CH2:65][C@@:63]2([CH3:64])[C@H:59]3[CH2:60][CH2:61][C@@H:62]2[O:74][C:75](=[O:77])[CH3:76])=[CH:54]1)(=[O:51])[CH3:50]
Reactant: COC[C@]12CC[C@H](O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Reactant: COC[C@@]12C(=C[C@@H](O)C[C@H]1C)CC[C@H]1[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]12
Reactant: COC[C@]12CC[C@H](OC(C)=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Product: COC[C@@]12C(=C[C@@H](OC(C)=O)C[C@H]1C)CC[C@H]1[C@@H]3CC[C@H](OC(C)=O)[C@@]3(C)CC[C@@H]12
Product: COC[C@]12CC[C@H](OC(C)=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12

Procedure:
Substituting 19-methoxy-1β-methyl-4-androstene-3β,17β-diol and 19-methoxy-6α-methyl-4-androstene-3β,17β-diol in lieu of the 19-methoxyandrost-4-ene-3β,17β-diol above results in the preparation of 19-methoxy-1β-methyl-4-androstene-3β,17β-diol diacetate and 19-methoxy-6α-methyl-4-androstene-3β,17β-diol diacetate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:12][O:13][CH2:14]OC.CN(C)C=O.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: COCOC
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COCOc1ccc([N+](=O)[O-])c(F)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
A solution of 3-fluoro-4-nitrophenol (10.0 g, 0.064 mol), dimethoxymethane (19.3 g, 0.255 mol) and N,N-dimethylformamide (6.0 g, 0.083 mol) in toluene is heated to 65° C., treated dropwise with phosphorus oxychloride (15.7 g, 0.102 mol), stirred at 90° C. for two hours, cooled to room temperature and poured into ice water which contains five mL of 50% sodium hydroxide solution. After the ice has melted, the mixture is extracted with ether. The organic extract is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product as a yellow liquid (4.0 g) which is identified by 1HNMR spectral analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[CH3:10][N:11]1[C:15]([CH3:16])=[C:14]([C:17]([OH:19])=O)[C:13](=[O:20])[N:12]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.[CH:38]1[CH:43]=[N:42][C:41]2[N:44](O)N=N[C:40]=2[CH:39]=1>C(Cl)Cl>[NH2:44][C:41]1[CH:40]=[C:39]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:17]([C:14]3[C:13](=[O:20])[N:12]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:11]([CH3:10])[C:15]=3[CH3:16])=[O:19])=[CH:3][C:4]=2[F:9])[CH:38]=[CH:43][N:42]=1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: On1nnc2cccnc21
Reactant: Nc1ccc(O)c(F)c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 45 °C
Reaction time: 12 h
Yield: 367.4 %

Procedure:
To a suspension of 4-amino-2-fluorophenol (2.54 g, 20 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (4.74 g, 20.4 mmol) in DCM (60 mL) were added EDCI (4.6 g, 24 mmol) and HOAT (0.54 g, 4 mmol). The reaction was stirred at 45° C. for 12 hours, then cool to rt, quenched with H2O (10 mL), and stirred for another 4 hours. The solid was obtained by filtration and washed with DCM (20 mL×3), then dried at 60° C. in vacuo for 12 hours to give the title compound as a pale yellow solid (6.37 g, 93.4%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18].[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>O.ClCCl.C(#N)C>[CH2:19]([N:21]([CH2:22][CH3:23])[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18])[CH3:20]
Reactant: CCNCC
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CCN(CC)CCCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Temperature: 65 °C
Reaction time: 18 h

Procedure:
1-(3-chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (100 mg, 0.359 mmol), diethylamine (263 uL, 3.59 mmol), potassium iodide (596 mg, 3.59 mmol) and potassium carbonate (496 mg, 3.59 mmol) were weighed into an argon purged vial fitted with a magnetic stirbar. Anhydrous acetonitrile (4 mL) was added, and the yellow suspension stirred in a heating block at a temperature of 65° C. for 18 hours. As starting material remained, the reaction was stirred at this temperature for an additional 3 days. After cooling to room temperature, the reaction was diluted with water (10 mL) and dichloromethane (15 mL) and transferred to a separatory funnel. The organic layer was collected, and the aqueous layer extracted twice more with dichloromethane (2×10 mL). The combined organic layers were washed with brine (15 mL) and dried over sodium sulphate. The solution was decanted and concentrated to afford a yellow oil. The product was purified using flash chromatography (2 M NH3 in MeOH:CH2Cl2, 2.5-5:95-97.5) to afford a yellow oil. Yield: 102 mg yellow oil (93%). 1H NMR (CDCl3) δ: 8.14 (dd, J=2.7, 9 Hz, 1H), 8.06 (d, J=2.4 Hz, 1H), 7.23 (d, J=9.0 Hz, 1H), 4.02 (t, J=7.5 Hz, 2H), 3.01 (t, J=7.2 Hz, 2H), 2.73-2.68 (m, 2H), 2.57-2.48 (m, 6H), 1.83-1.73 (m, 2H), 1.04 (t, J=7.2 Hz, 6H). MS (EI): 305 (M+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[CH3:15][C:16]([O:19][C:20]([O:22]N=C(C1C=CC=CC=1)C#N)=O)([CH3:18])[CH3:17]>O1CCOCC1>[C:20]([N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7])([O:19][C:16]([CH3:15])([CH3:17])[CH3:18])=[O:22]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: CNCCCCO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(CCCCO)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.7 %

Procedure:
To a 250 mL round bottom flask, charged with 3.00 g (28.5 mmol) of N-methyl-4-aminobutanol in 75 mL of dioxane, was added 5 mL of triethylamine (35.4 mmol) followed by 7.85 g (31.9 mmol) of BOC-ON, 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile. The mixture was stirred at room temperature for 20 h and then concentrated via rotary evaporation. The residue was chromatographed on silica gel, eluting first with 20% ethyl acetate/hexane, then with 40% ethyl acetate/hexane, and finally with 75% ethyl/hexane. The fractions containing product were combined and concentrated via rotary evaporation to afford 4.85 g of the product (32) as a near colorless oil (84%): 1H-NMR (CDCl3) d 3.65 (2H, t), 3.23 (2H, t), 2.81 (3H, s), 1.67-1.45 (4H, m), and 1.42 (9H, s) ppm.