Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K+].[Br-].[CH3:3][C:4]1[O:8][CH:7]=[C:6](/[CH:9]=[C:10](/[C@H:12]2[O:30][C:28](=[O:29])[CH2:27][C@H:26]([OH:31])[C:25]([CH3:33])([CH3:32])[C:23](=[O:24])[C@H:22]([CH3:34])[C@@H:21]([OH:35])[C@@H:20]([CH3:36])[CH2:19][CH2:18][CH2:17][C@@:15]3([CH3:37])O[C@H:14]3[CH2:13]2)\[CH3:11])[N:5]=1.CCC1SC=C(/C=C(/[C@H]2OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC[C@H]3O[C@H]3C2)\C)N=1.CC1SC=C(/C=C(/[C@H]2OC(=O)C[C@H](O)[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC[C@H]3O[C@H]3C2)\C)N=1.CC1OC=C(/C=C(/[C@H]2OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC[C@H]3O[C@H]3C2)\C)N=1>CO>[CH3:3][C:4]1[O:8][CH:7]=[C:6](/[CH:9]=[C:10](/[C@H:12]2[O:30][C:28](=[O:29])[CH2:27][C@H:26]([OH:31])[C:25]([CH3:33])([CH3:32])[C:23](=[O:24])[C@H:22]([CH3:34])[C@@H:21]([OH:35])[C@@H:20]([CH3:36])[CH2:19][CH2:18][CH2:17][C:15]([CH3:37])=[CH:14][CH2:13]2)\[CH3:11])[N:5]=1
Reactant: C/C(=C\c1coc(C)n1)[C@@H]1C[C@@H]2O[C@]2(C)CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Agent: C/C(=C\c1coc(C)n1)[C@@H]1C[C@@H]2O[C@@H]2CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Agent: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H]2O[C@@H]2CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)[C@H](C)[C@@H](O)CC(=O)O1
Agent: C/C1=C/C[C@@H](/C(C)=C/c2coc(C)n2)OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC1
Solvent: CO
Product: CC1=CC[C@@H](/C(C)=C/c2coc(C)n2)OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC1

Procedure:
colorless amorphous solid; [α]22D −44.4 (c 0.25, MeOH); UV (MeOH) λmax nm (ε) 203 (14500), 236 (12200); IR (KBr) νmax 3436, 2967, 2935, 2880, 1734, 1690, 1586, 1251, 1007 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.46 (1H, s, H-19), 6.30 (1H, bs, H-17), 5.23 (1H, dd, J=9.8, 2.1 Hz, H-15), 5.12 (1H, dd, J=10.1, 5.3 Hz, H-13), 4.20 (1H, ddd, J=10.8, 5.7, 2.9 Hz, H-3), 3.71 (1H, ddd, J=3.8, 2.6, 2.6 Hz, H-7),3.14 (1H, dq, J=2.6, 6.9 Hz, H-6), 2.93 (d, J=5.7 Hz, 3-OH), 2.90 (1H, bd, J=2.6 Hz, 7-OH), 2.62 (1H, ddd, J=15.1, 9.8, 9.8 Hz, H-14a), 2.46 (1H, dd, J=15.1, 10.8 Hz, H-2a), 2.43 (3H, s, H-21), 2.32 (1H, dd, J=15.1, 2.9 Hz, H-2b), 2.29 (1H, m, H-11a), 2.19 (1H, bd, J=15.1 Hz, H-14b), 1.97 (3H, d, J=1.3 Hz, H-27), 1.87 (1H, m, H-11b), 1.73 (1H, m, H-8), 1.67 (1H, m, H-10a), 1.65 (3H, bs, H-26), 1.32 (3H, s, H-23), 1.26 (2H, m, H-9), 1.24 (1H, m, H-10b), 1.18 (3H, d, J=6.9 Hz, H-24), 1.07 (3H, s, H-22), 1.00 (3H, d, J=7.0 Hz, H-25); 13C NMR (CDCl3, 100 MHz) δ 220.6 (s, C-5), 170.3 (s, C-1), 161.0 (s, C-20), 138.6 (s, C-12), 138.4 (s, C-16), 137.5 (s, C-18), 135.6 (d, C-19), 120.8 (d, C-13), 115.8 (d, C-17), 78.9 (d, C-15), 74.3 (d, C-7), 72.7 (d, C-3), 53.3 (s, C-4), 42.0 (d, C-6), 39.6 (t, C-2), 38.6 (d, C-8), 32.4 (t, C-14), 31.9 (t, C-9), 31.6 (t, C-11), 25.6 (t, C-10), 23.0 (q, C-26), 22.8 (q, C-23), 18.8 (q, C-22), 16.1 (q, C-27), 15.9 (q, C-25), 13.8 (q, C-21), 13.6 (q, C-24); EIMS m/z 475 [M]+ (11), 288 (9), 287 (5), 188(7), 171 (32), 152 (100), 111 (10); HREIMS m/z 475.2913 (calcd. for C27H41NO6, 475.2934).
Reaction SMILES: [CH2:1]([NH:3][C:4](=O)[CH2:5][CH2:6][C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=1)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1>[CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH:7]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][S:15]([CH3:18])(=[O:16])=[O:17])=[CH:12][CH:13]=1)[OH:19])[CH3:2]
Reactant: CCNC(=O)CCC(=O)c1ccc(NS(C)(=O)=O)cc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCNCCCC(O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 18.9 %

Procedure:
The product from Step I (3.0 g, 0.010 mol) was added in small portions, under nitrogen to a stirred, ice-cold mixture of LiAlH4 (1.15 g, 0.030 mol) in THF (75 ml). This mixture was kept in the ice bath for 1 hour and at ambient temperature for 2 hours. It was then mixed with an additional 100 ml of THF, refluxed for a few minutes and kept at ambient temperature for 18 hours. The mixture was treated carefully with 69 ml of a saturated sodium potassium tartrate solution and stirred for 1 hour. It was extracted with EtOAc. The extract was washed with a dilute sodium chloride solution. The aqueous layer contained the product; it was concentrated and finally freeze-dried. The resulting solid was extracted with MeOH. The methanol solution was concentrated and the residue extracted with CH2Cl2. The CH2Cl2 solution was concentrated to give 1.6 g of crude product that was purified by chromatography on silica gel with 1% NH4OH-10 to 20% MeOH--CHCl3. The product was crystallized from MeOH--EtOAc to give 540 mg of N-(4-(4-(ethylamino)-1-hydroxybutyl)phenyl)methanesulfonamide, mp 174°-176° C. The analytical sample was crystallized from MeOH and had mp 178.5°-180.5° C. Anal. calc'd for C13H22N2O3S: C, 54.52; H, 7.74; N, 9.78; S, 11.20. Found: C, 54.40; H, 7.84; N, 10.00; S, 11.02.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]>C1(C)C(C)=CC=CC=1>[C:2]1([NH:1][C:9]2[N:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1C
Product: O=C(O)c1cccnc1Nc1ccccc1

Procedure:
50 ml of distilled aniline and 43.2 g of 2-chloronicotinic acid are mixed in 126 ml of xylene. The mixture is brought to reflux for 4 hours. It is allowed to cool and the precipitate is filtered off and washed several times with water.
Reaction SMILES: C(OC(NC1(C(O)=O)CC1/C=C/C1C(C)(C)[C@H]2[C@](C)(CC=1)[C@@H]1[C@](C)([C@@]3(C)[C@H](CC1)[C@H]1[C@H](C(C)=C)CC[C@]1(NCCN1CCS(=O)(=O)CC1)CC3)CC2)=O)(C)(C)C.[F:57][C:58]1([C:107]([O:109]CC)=[O:108])[CH2:63][CH2:62][C:61](=[CH:64][C:65]2[C:66]([CH3:106])([CH3:105])[C@H:67]3[C@:80]([CH3:83])([CH2:81][CH:82]=2)[C@@H:79]2[C@:70]([CH3:104])([C@@:71]4([CH3:103])[C@H:76]([CH2:77][CH2:78]2)[C@H:75]2[C@H:84]([C:87]([CH3:89])=[CH2:88])[CH2:85][CH2:86][C@:74]2([NH:90][CH2:91][CH2:92][N:93]2[CH2:98][CH2:97][CH:96]([S:99]([CH3:102])(=[O:101])=[O:100])[CH2:95][CH2:94]2)[CH2:73][CH2:72]4)[CH2:69][CH2:68]3)[CH2:60][CH2:59]1>>[F:57][C:58]1([C:107]([OH:109])=[O:108])[CH2:59][CH2:60][C:61](=[CH:64][C:65]2[C:66]([CH3:106])([CH3:105])[C@H:67]3[C@:80]([CH3:83])([CH2:81][CH:82]=2)[C@@H:79]2[C@:70]([CH3:104])([C@@:71]4([CH3:103])[C@H:76]([CH2:77][CH2:78]2)[C@H:75]2[C@H:84]([C:87]([CH3:89])=[CH2:88])[CH2:85][CH2:86][C@:74]2([NH:90][CH2:91][CH2:92][N:93]2[CH2:94][CH2:95][CH:96]([S:99]([CH3:102])(=[O:100])=[O:101])[CH2:97][CH2:98]2)[CH2:73][CH2:72]4)[CH2:69][CH2:68]3)[CH2:62][CH2:63]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C=C6CCC(F)(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(/C=C/C6CC6(NC(=O)OC(C)(C)C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C=C6CCC(F)(C(=O)O)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
1-fluoro-4-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)methylene)cyclohexanecarboxylic acid was prepared following the method described above for the preparation of 1-((tert-butoxycarbonyl)amino)-2-((E)-2-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)vinyl)cyclopropanecarboxylic acid, using ethyl 1-fluoro-4-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)methylene)cyclohexanecarboxylate as the reactant in step 2. The reaction crude was purified by prep HPLC (method 4) to afford the title compound as a mixture of isomers in 20.7% of yield. MS: m/e 755.5 (M+H)+, 2.610 min (method 4). 1H NMR (400 MHz, METHANOL-d4) δ 5.95-5.35 (m, 1H), 5.32-5.12 (m, 1H), 4.79 (br. s., 1H), 4.71 (s, 1H), 3.25-3.04 (m, 5H), 2.96 (s, 3H), 2.90-1.81 (m, 24H), 1.76 (s, 3H), 1.73-1.27 (m, 15H), 1.22 (br. s., 3H), 1.13-1.08 (m, 3H), 1.07-0.91 (m, 6H), 0.90-0.83 (m, 3H); 19F NMR (376 MHz, METHANOL-d4) δ −154.27-167.89 (m, 1F).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]([CH2:17][OH:18])[CH:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.[H-].[Na+].[CH3:29]I>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]([CH2:17][O:18][CH3:29])[CH:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COc1ccc(C2C(CO)c3ccc(OC)cc3C3CCCCC32)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC1c2ccc(OC)cc2C2CCCCC2C1c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 216 %

Procedure:
Combine [6-methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthren-9-yl]-methanol (0.084 g, 0.24 mmol), NaH (0.014 mg, 0.29 mmol), and DMF (3.0 mL) and stir under nitrogen atmosphere at −10° C. After 1 hour, add MeI (50 uL, 0.072 mmol) and stir at room temperature for 18 hours. Concentrate reaction under vacuum then add ethyl acetate and water, separated the organic phase and wash 2× with brine. Dry the organic phase over anhydrous sodium sulfate. Concentrate the organic phase under vacuum and flash chromatograph using 0% to 25% ethyl acetate/hexanes to yield the titled compound (0.057 g, 65%) as a white solid. TLC Rf=0.40 in 3:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 7.58 (d, 1H, J=8.8 Hz), 7.25 (d, 2H, J=8.8 Hz), 6.93 (m, 3H), 6.81 (dd, 1H, J=8.4, 2.6 Hz), 3.85 (m, 6H), 3.66 (m, 1H), 3.38 (m, 2H), 3.23 (m, 4H), 3.11 (dd, 1H, J=11.9, 3.1 Hz), 2.48 (d, 1H, J=13.7 Hz), 1.92 (m, 1H), 1.42 (m, 2H), 1.18 (m, 3H), 1.77 (m, 2H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:15]#[N:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].Cl>O1CCCC1.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:15]#[N:16])([C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[C:18]([F:17])([F:28])[F:29])[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=1
Reactant: COC(=O)C(C#N)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C#N)(C(=O)c1ccccc1C(F)(F)F)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 58.9 %

Procedure:
0.10 g (2.6 mmols) of sodium hydride was suspended in 20 ml of tetrahydrofuran. To the suspension was added dropwise, while stirring and cooling, 5 ml of a tetrahydrofuran solution in which 0.42 g (2.0 mmols) of methyl 2-(4-chlorophenyl)cyanoacetate and 0.41 g (2.6 mmols) of 2-trifluoromethylbenzoyl chloride had been dissolved. The mixture was stirred at room temperature over night. The reaction mixture was poured into ice water. The water phase thereof was acidified by diluted hydrochloric acid and twice extracted with 30 ml of ethyl acetate. The ethyl acetate extraction solutions were mixed, washed with a saturated brine solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue thus-obtained was purified by silica gel column chromatography (n-hexane:benzene=1:1), giving 0.45 g of the desired product (yield 59%).
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]2([CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:9]1[C:10]2([CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]2)[CH2:11][NH:8]1
Reactant: CC(=O)N1CCC2(CC1)CN(C(=O)OC(C)(C)C)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1CCC2(CC1)CNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of 2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester (70 mg, 0.309 mmol) in DCM (3 mL) were added acetyl chloride (32 μL, 0.450 mmol) and triethylamine (54 μL, 0.526 mmol). The resulting mixture was stirred at RT for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, and washed with MeOH then eluted with 2 M NH3 in MeOH to give 7-acetyl-2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester. To a solution of 7-acetyl-2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester in DCM (3 mL) was added TFA (1 mL) and the resulting mixture was stirred at RT for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give the title compound as a colourless oil (41 mg, 79%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[OH:27][C:28]1[CH:36]=[CH:35][C:31]([CH2:32][CH2:33]O)=[CH:30][CH:29]=1.I.N1C=CN=C1>O.ClCCl>[I:25][CH2:33][CH2:32][C:31]1[CH:35]=[CH:36][C:28]([OH:27])=[CH:29][CH:30]=1
Reactant: OCCc1ccc(O)cc1
Reactant: II
Agent: I
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(CCI)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Triphenylphosphine (1.57 g, 0.006 mol) and imidazole (0.41 g, 0.006 mol) were added to dry dichloromethane (20 ml). When the imidazole was in solution iodine (1.52 g, 0.006 mol) was added. After precipitation of the imidazole hydroiodide (4-hydroxyphenethyl) alcohol (0.69 g, 0.005 mol) was added. The mixture was stirred at room temperature for 4 h. Then water was added and the mixture was extracted with dichloromethane. The extracts were washed with water, dried and concentrated in vacuo to give a raw product. Purification by flash chromatography (heptane/ethyl acetate as a gradient eluent 9:1-6:4) gave a pure product. 1H NMR (400 MHz, DMSO-d6): 2.99 (2H, t, 3J=7.6 Hz), 3.38 (2H, t, 3J=7.6 Hz), 6.68 (2H, d, 3J=8.5 Hz), 7.03 (2H, d, 3J=8.5 Hz), 9.24 (1H, s, —OH).
Reaction SMILES: C(O[C:4](=[O:13])[CH:5]=[C:6]([NH:11][CH3:12])[C:7]([F:10])([F:9])[F:8])C.[CH2:14]([O:17][C:18]([C:20]([O:23][C:24](=[O:35])[C:25]1[CH:30]=[C:29]([N:31]=[C:32]=[O:33])[CH:28]=[CH:27][C:26]=1[Cl:34])([CH3:22])[CH3:21])=[O:19])[CH:15]=[CH2:16]>CN(C)C=O>[CH2:14]([O:17][C:18]([C:20]([O:23][C:24](=[O:35])[C:25]1[CH:30]=[C:29]([N:31]2[C:4](=[O:13])[CH:5]=[C:6]([C:7]([F:8])([F:9])[F:10])[N:11]([CH3:12])[C:32]2=[O:33])[CH:28]=[CH:27][C:26]=1[Cl:34])([CH3:22])[CH3:21])=[O:19])[CH:15]=[CH2:16]
Reactant: C=CCOC(=O)C(C)(C)OC(=O)c1cc(N=C=O)ccc1Cl
Reactant: CCOC(=O)C=C(NC)C(F)(F)F
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(C)(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
0.347 g of potassium tert.butylate (content: 97%, 0.003 mols) are suspended in 30 g of anhydrous dimethylformamide (water content <0.01%), and heated to a temperature of 40° C. Subsequently, 1.97 g of 3-methylamino-4,4,4-trifluorobut-2-enoic acid ethyl ester (content: 99.5%, 0.01 mols) are added at a temperature of 40 to 45° C., and this temperature is maintained for a further 30 minutes, whereby a red-brown solution is produced. After cooling the reaction mixture to a temperature of 0° C., 3.51 g of 5-isocyanato-2-chloro-benzoic acid 1-allyloxycarbonyl-1-methyl-ethyl-ester (content: 97%, 0.0105 mols) are dispensed in over the course of 30 minutes, whereby the temperature is maintained at between 0 and 5° C. After removing the cooling bath, the resultant dark brown solution is stirred for a further 30 minutes, and the pH value of the now dark red solution is adjusted to pH 7 with 2.7 g of 1 M HCl [the content of 2-chloro-5-(3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1-(2H)pyrimidinyl)-benzoic acid 1-allyloxyoarbonyl-1-methyl-ethyl-ester in this solution is 11%, which corresponds to a yield of 89%]. The solvent is subsequently distilled off in a rotary evaporator, and the residue (5.6 g) is recrystallised in 12 g of isopropyl alcohol [the inorganic salts are removed by hot filtration]. After drying in a vacuum drying chamber (60° C. for 12 hours), 4.10 g (86.3% of theory) of 2-ohloro-5-(3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1-(2H)pyrimidinyl)-benzoic acid 1-allyloxycarbonyl-1-methyl-ethyl-ester are obtained in a content of 99%.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[O:7][C:8]1[N:9]([CH2:23][CH2:24][CH3:25])[C:10](=[O:22])[C:11]2[NH:12][C:13]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:14][C:15]=2[N:16]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C>[CH:17]1([C:13]2[NH:12][C:11]3[C:10](=[O:22])[N:9]([CH2:23][CH2:24][CH3:25])[C:8]([O:7][C:6]4[CH:26]=[CH:27][CH:28]=[C:4]([CH:1]([OH:3])[CH3:2])[CH:5]=4)=[N:16][C:15]=3[N:14]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCCn1c(Oc2cccc(C(C)=O)c2)nc2nc(C3CCCC3)[nH]c2c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCn1c(Oc2cccc(C(C)O)c2)nc2nc(C3CCCC3)[nH]c2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
2-(3-Acetyl-phenoxy)-8-cyclopentyl-1-propyl-1,7-dihydro-purin-6-one (0.05 g, 0.178 mmol) was taken in ethanol (2 ml). To this was added NaBH4 (0.02 mg, 0.525 mmol) at 0° C. and stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated NH4Cl and solvent was concentrated under reduced pressure. Aqueous layer was extracted with ethyl acetate and organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC using 1% methanol in dichloromethane as solvent system to give the product as off white solid (0.04 g) in 85% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:17]=[C:16](O)[N:15]([CH3:19])[N:14]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:17]=[C:16]([SH:29])[N:15]([CH3:19])[N:14]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cn1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1O
Solvent: Cc1ccccc1
Product: Cn1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1S
Reaction time: 3 h
Yield: 53 %

Procedure:
A suspension of 1.0 g of 3-(2,6-dichloro-4-trifluoromethylphenyl)-5-hydroxy-1-methylpyrazole (6) and 0.7 g of Lawesson's reagent in 10 ml of toluene were refluxed with stirring for 3 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/6), giving 0.3 g of the desired compound in the form of colorless crystals (yield 27.3%).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][C:18](=[O:20])[C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH:13]=[CH:12][CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl>[O:30]1[C@H:12]2[CH2:11][C@H:10]3[C@:15]([CH3:16])([CH2:14][C@@H:13]12)[C@@H:17]1[C@H:7]([C@H:6]2[C@@:2]([CH2:19][C:18]1=[O:20])([CH3:1])[C:3](=[O:21])[CH2:4][CH2:5]2)[CH2:8][CH2:9]3
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@]12CC=CC[C@@H]1CC[C@@H]1[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]12
Solvent: ClC(Cl)Cl
Product: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A mixture of 5α-androst-2-ene-11,17-dione (37.2 g), m-chloroperbenzoic acid (30 g) and chloroform (600 ml) was allowed to stand for 0.5 hour at room temperature before partitioning between chloroform and saturated aqueous NaHCO3 solution. The organic phase was isolated and washed with water, dried and evaporated to a low volume. Addition of petroleum ether (b.p. 60°-80° C.) followed by refrigeration overnight afforded crystalline material (27.5 g). Recrystallisation from ethyl acetate-petroleum ether (b.p. 60°-80° C.) afforded the title compound, m.p. 166°-167°, [α]D +126°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[NH2:12].C(N(CC)CC)C.Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>C1COCC1>[C:25]([O:24][C:22](=[O:23])[CH2:21][NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[NH2:12])([CH3:28])([CH3:27])[CH3:26]
Reactant: NCc1ccc([N+](=O)[O-])cc1N
Reactant: CC(C)(C)OC(=O)CBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNCc1ccc([N+](=O)[O-])cc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a solution of 2-aminomethyl-5-nitro-phenylamine (2.84 g, 17 mmol) in dry THF (150 mL) and triethylamine (12 mL, 85 mmol) was added tert-butyl bromoacetate (5 mL, 34 mmol). The mixture solution was stirred at room temperature for 16 hours and concentrated. Chromatography of the resulting residue on silica gel with methylene chloride and methanol (50:1) gave 2.15 g of (2-amino-4-nitro-benzylamino)-acetic acid tert-butyl ester (45%): 1H NMR (300 MHz, CDCl3) δ 7.58 (dd, 1H), 7.55 (5, 1H), 7.22 (d, 1H), 5.2 (br, 2H) 3.95 (s, 2H), 3.39 (s, 2H), 1.58 (s, 9H); MS (m/e): 282.3 (M+1).
Reaction SMILES: C1(CBr)CC1.Br[CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1.[CH3:14][C:15]1[N:16]=[C:17]([N:25]2[CH2:29][CH2:28][NH:27][C:26]2=[O:30])[S:18][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH3:14][C:15]1[N:16]=[C:17]([N:25]2[CH2:29][CH2:28][N:27]([CH2:7][CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][O:9]3)[C:26]2=[O:30])[S:18][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: BrCC1CCCCO1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: BrCC1CC1
Product: CCOC(=O)c1sc(N2CCN(CC3CCCCO3)C2=O)nc1C
Yield: 39 %

Procedure:
Following the procedure as described in Example 10, making variations as required to replace cyclopropylmethyl bromide with (bromomethyl) tetrahydro-2H-pyran to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 39% yield: 1H NMR (300 MHZ, CDCl3) δ 4.26 (q, J=7.2 Hz, 2H), 4.11-4.05 (m, 2H), 3.97-3.92 (m, 1H), 3.83-3.62 (m, 2H), 3.55-3.34 (m, 2H), 3.22-3.15 (m, 1H), 2.60 (s, 3H), 1.85-1.82 (m, 1H), 1.57-1.44 (m, 4H), 1.31-1.22 (m, 5H): MS (ES+) m/z 354.3 (M+1).
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@H:8]([CH3:19])[O:7][C@H:6]1[CH2:20][CH:21]=[CH2:22])(=O)C.O(C)[Na]>CO>[C@@H:6]1([CH2:20][CH:21]=[CH2:22])[O:7][C@@H:8]([CH3:19])[C@@H:9]([OH:15])[C@@H:10]([OH:11])[C@@H:5]1[OH:4]
Reactant: C=CC[C@@H]1O[C@@H](C)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CO[Na]
Solvent: CO
Product: C=CC[C@@H]1O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3-(2,3,4-tri-O-acetyl-α-L-fucopyranosyl)-1-propene (10.65 g, 33.9 mmol) in CH3OH (50 mL) was added NaOCH3 (183 mg, 3.4 mmol). After stirring at rt for 2 hr, the reaction mixture was neutralized with Amberlite IR120 (pre-washed with methanol 3×25 mL). The resin was filtered off and the filtrate was concentrated to give a white solid, which was recrystallized from EtOAc (˜200 mL) to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 1.22 (d, J=6.5, 3H), 2.41 (m, 1H), 2.47 (m, 1H), 3.73 (m, 2H), 3.85 (qd, J=6.5, 2.0, 1H), 3.90 (dd, J=8.9, 5.5, 1H), 3.99 (m, 1H), 5.07 (m, 1H), 5.15 (dq, J=17.2, 1.7, 1H), 5.85 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1.OCC1SC(B(O)O)=CC=1>>[CH:26]([C:25]1[CH:28]=[CH:29][C:22]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:23][CH:24]=1)=[O:27]
Reactant: COc1cccc(N(C)S(=O)(=O)c2ccc(Br)cc2)c1
Reactant: O=Cc1ccc(Br)cc1
Agent: OCc1ccc(B(O)O)s1
Product: COc1cccc(N(C)S(=O)(=O)c2ccc(-c3ccc(C=O)cc3)cc2)c1
Yield: 73 %

Procedure:
When the product of Step B and 4-carbaldehyde-boronic acid were substituted for 4-bromobenzaldehyde and 5-(hydroxymethyl)thiophen-2-ylboronic acid, respectively, in Example 22, Step A, the similar process afforded the title compound in 73% yield, as pale solid. 1H-NMR (CDCl3) 10.07 (s, 1H); 7.98 (d, 2H, J=6.56 Hz); 7.75 (d, 2H, J=8.24 Hz); 7.7 (d, 2H, J=8.82 Hz); 7.66 (d, 2H, J=8.75 Hz); 7.19 (t, 1H, J=8.13 Hz); 6.81 (dd, 1H, J=8.30, 2.45 Hz); 6.74 (t, 1H, J=2.17 Hz); 6.65 (dd, 1H, J=7.96, 1.24 Hz); 3.76 (s, 3H); 3.20 (s, 3H).