Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:12][O:13][CH2:14][CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[N:12][O:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:29][CH:30]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(Cl)c1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Product: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1cccc(Cl)c1

Procedure:
Following a procedure similar to that described in Example 40(f), 0.18 ml of 3'-chloroacetophenone was reacted with 400 mg of 5-[4-(2-aminooxyethoxy)benzyl]-thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)]. The reaction mixture was then concentrated by evaporation under reduced pressure, and the resulting residue was extracted with ethyl acetate. The extract was washed with water and the solvent was removed by distillation under reduced pressure. The residue was mixed with a mixture of diethyl ether, diisopropyl ether and hexane, and stirred. The resulting precipitate was collected by filtration, to give 290 mg of the title compound, melting at 82-84° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])[CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:23])[C:21]=1Cl.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:23])[C:21]=1[N:12]1[CH2:13][CH2:14][CH:9]([C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[O:8])[CH2:10][CH2:11]1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: O=C(C1CCNCC1)N1CCOCC1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=C(C1CCN(c2c(Cl)cncc2Cl)CC1)N1CCOCC1
Yield: 36.3 %

Procedure:
General procedure C was followed using morpholino(piperidin-4-yl)methanone (21 mg, 0.12 mmol), 3,4,5-trichloropyridine (23 mg, 0.12 mmol), triethylamine (32 μL, 0.23 mmol) and NMP (1 mL). The crude product was purified by flash column chromatography on silica gel (hexane/EtOAc, 1:1) to furnish the title compound as a white solid (15 mg, 35%), m.p. 172-174° C.; umax (CHCl3)/cm−1 3006, 2858, 1632, 1559, 1448, 1116, 1020; m/z (ESI) C15H20Cl2N3O2 requires 344.0927, found [M+H]+ 344.0929.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[CH3:12][NH:13][CH3:14]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:13]([CH3:14])[CH3:12])(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1ccccc1Cl
Temperature: 25 °C

Procedure:
A stirred solution of 63.3 g of 2-chlorobenzensulfonyl chloride in 500 mL of tetrahydrofuran was cooled to 0°-5° C. and treated with 46 mL of dimethylamine, added dropwise at a rate that maintained the temperature below 10° C. The resulting mixture was allowed to warm gradually to room temperature. The precipitate was removed by filtration, and was washed well with tetrahydrofuran. The combined filtrates were evaporated in vacuo and the resulting oil was dissolved in 400 mL of methylene chloride, washed with two 200-mL portions of water, and dried over MgSO4. Evaporation of the solvent in vacuo afforded an oil, which solidified upon standing. Trituration with hexanes afforded 58.6 g of 2-chloro-N,N-dimethylbenzenesulfonamide as a white solid, m.p. 49°-51° C.; NMR (CDCl3): δ2.9 (s, 6H), 7.3-7.7 and 7.9-8.2 (m, 4H); IR(KBr): 1340 and 1170 cm-1.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:19])=[O:29])=[CH:23][CH:22]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Nn1nc(-c2cccc(Cl)c2)c2ccccc2c1=O
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(-c2cccc(Cl)c2)c2ccccc2c1=O

Procedure:
The product of Example 125A and 2-(4-chlorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.74 (s, 1H), 8.39-8.42 (m, 1H), 7.90-8.05 (m, 2H), 7.68-7.74 (m, 1H), 7.55-7.67 (m, 4H), 7.35-7.46 (m, 4H), 3.71 (s, 2H); MS (ESI+) m/z 424 (M+H)+.
Reaction SMILES: C([O:9][C@@H:10]1[CH2:17][N:16]2[C@:12]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=3)([C:13]([CH2:27][CH3:28])=[C:14]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)[C:15]2=[O:18])[CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[Na+]>C1COCC1.CO>[Br:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][C@:12]23[C:13]([CH2:27][CH3:28])=[C:14]([C:19]4[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=4)[C:15](=[O:18])[N:16]2[CH2:17][C@@H:10]([OH:9])[CH2:11]3)=[CH:35][CH:34]=1
Reactant: CCC1=C(c2cc(Cl)cc(Cl)c2)C(=O)N2C[C@@H](OC(=O)c3ccccc3)C[C@@]12Cc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC1=C(c2cc(Cl)cc(Cl)c2)C(=O)N2C[C@@H](O)C[C@@]12Cc1ccc(Br)cc1
Reaction time: 5 h
Yield: 42 %

Procedure:
(2S,7aS)-7a-(4-Bromobenzyl)-6-(3,5-dichlorophenyl)-7-ethyl-5-oxo-2,3,5,7a-tetrahydro-1H-pyrrolizin-2-yl benzoate VIIb (5 mg, 0.01 mmol) was suspended in THF (1 mL) and treated with 1N aqueous NaOH (50 uL). The reaction was stirred for 5 h, diluted with MeOH (1 mL) and purified on preparative HPLC using MeOH, H2O, TFA(0.1%) as the eluant to give (6S, 7aS)-7a-(4-Bromobenzyl)-2-(3,5-dichlorophenyl)-1-ethyl-6-hydroxy-5,6,7,7a-tetrahydro-3H-pyrrolizin-3-one VIII, (2 mg, 42%) LCMS, (m/z) 480/482 (M++H), HPLC Retention Time/Condition 1: 2.03 min.
Reaction SMILES: [CH3:1][Si:2]([CH3:34])([CH3:33])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:8]1[N:13]2[N:14]=[CH:15][C:16](I)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[CH:9]=1.[C:35]1([C:41]2[CH:46]=[CH:45][C:44](B3OC(C)(C)C(C)(C)O3)=[CH:43][N:42]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:1][Si:2]([CH3:34])([CH3:33])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:44]3[CH:43]=[N:42][C:41]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:46][CH:45]=3)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[CH:9]=1
Reactant: CC1(C)OB(c2ccc(-c3ccccc3)nc2)OC1(C)C
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=O)CC2)nc2c(I)cnn12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=O)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Temperature: 90 °C
Yield: 81.8 %

Procedure:
A mixture of 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone (751 mg, 1.22 mmol), 2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (444 mg, 1.58 mmol), PdCl2(dppf)CH2Cl2 (99.6 mg, 0.122 mmol), and K3PO4 (777 mg, 3.66 mmol) in dioxane/H2O (7/0.7 mL) was degassed and then heated at 90° C. for 16 h. After cooling, the reaction mixture was diluted with EtOAc and washed with H2O and brine, dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-40% EtOAc/Hexanes, Rf=0.2 in 20% EtOAc/Hexanes) to afford 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone as a pale yellow solid (643 mg). HPLC-MS TR=3.12 min (UV 254 nm, 5 min method); mass calculated for formula C35H49N5O3Si2 643.3, observed LCMS m/z 644.2 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH:7]([NH:23][C:24](=[O:31])[CH:25]([NH2:30])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:40]([C:44]1[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1)([CH3:43])([CH3:42])[CH3:41].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:32])[C@@H:7]([NH:23][C:24](=[O:31])[C@@H:25]([NH:30][S:50]([C:47]1[CH:48]=[CH:49][C:44]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:45][CH:46]=1)(=[O:52])=[O:51])[CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)CC(N)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NS(=O)(=O)c1ccc(C(C)(C)C)cc1)C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 70 %

Procedure:
A solution of the product from Example AI ([S-(R*,R*)]-2-{2-amino-4-methyl-pentanoylamino}-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (0.20 g, 0.45 mmol) and triethylamine (0.13 mL, 0.90 mmol) in 5 mL of CHCl3 was cooled to 0° C. and treated with 4-tert-butylphenylsulfonyl chloride (0.10 g, 0.45 mmol). The reaction mixture was warmed to room temperature and treated with saturated aqueous NaHCO3. The organic phase was separated from the aqueous phase. The aqueous phase was extracted with additional CHCl3, and the combined organic extracts were dried MgSO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 1:1 heptane/ethyl acetate). The chromatography product was crystallized from hot heptane/ethyl acetate to give the title compound as a white solid 0.20 g 70%), mp=142-143° C.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C[O-].[Na+].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl>CO.O>[CH2:9]([CH2:2][C:1]([OH:4])=[S:3])[CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CC(O)=S
Reactant: CCCCCCC/C=C\CCCCCBr
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCC/C=C\CCCCCCC(O)=S
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.6 %

Procedure:
Thioacetic acid (35 mg, 0.38 mmol) in methanol (20 ml) was treated successively with sodium methoxide (50 mg, 0.9144 mmol) and bromide 8 (105 mg, 0.381 mmol) and stirred at r.t. for 2 d. The reaction mixture was diluted in water and acidified with cold conc. aq. HCl. The aqueous layer was extracted with hexanes, dried (MgSO4) and concentrated invacuo to afford a crude residue was purified by flash column chromatography (eluent gradient elution 65-75% EtOAc in Hexanes) to afford the pure 4 as a viscous oil (105 mg, 0.367 mmol, 96%); δH(270 MHz, CDCl3); 0.86 (3H, t, J 6.8), 1.35 (14H, m), 1.60 (2H, m), 2.00 (4H, m), 2.65 (21, t, J 7.4), 3.24 (2H, s), 5.34 (2H, m) and 10.0 (1H, br s); δC(67.5 MHz, CDCl3) 14.20, 22.76, 27.09, 27.31, 28.45, 28.89, 29.32, 29.35, 29.35, 29.83, 31.95, 32.82, 33.54, 129.44, 130.36 and 176.77; MS (CI) 304 (M+NH4)+; HRMS: Found [M+NH4]+ 304.230876. Calc. for C16H34NO2S: [M+NH4]+0304.231026.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][CH2:6]2.[Br-:13].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Br:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:10]=1[NH:9][CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCN2
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1cc(Br)c2c(c1)CCCN2
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.9 %

Procedure:
Part A: A solution of 6-methoxy-1,2,3,4-tetrahydroquinoline (6.19 g, 37.9 mmol) in CH2Cl2 (76 mL) was treated with pyridinium tribromide (25.42 g, 79.7 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with sat NaHSO3 (50 mL) and water (50 mL). The dichloromethane was separated, dried (Na2SO4) and concentrated. The residue was chromatographed on silica gel using 20% ethyl acetate/hexanes as eluent to give 8-bromo-6-methoxy-1,2,3,4-tetrahydroquinoline (2.93 g, 32% yield): 1H NMR (300 MHz, CDCl3): δ 6.88 (s 1 H), 6.55 (s, 1 H), 3.71 (s, 3H), 3.37-3.33 (t, J=6.6, 2 H), 2.78-2.74 (t, 2 H), 1.97-1.89 (m, 2 H); LRMS (AP+) for (M+H)+: for C10H12NOBr Calculated: 241.1 found: 241.0.
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[CH3:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:23])[F:24])(=[O:15])=[O:14])[CH2:10][N:9]1[C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:27]([CH3:26])=[CH:28][CH:29]=1)=[O:7])#[N:3]
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Agent: Cl
Product: Cc1ccc(C(=O)N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@H]2C(=O)NCC#N)cc1

Procedure:
(2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride from experiment K2 was coupled with 4-methyl-benzoic acid in analogy to experiment A1 to give (2S,4R)-1-(4-methyl-benzoyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a colorless oil. MS: 480.1 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][C@:6]12[CH2:44][CH2:43][C@@H:42]([C:45]([CH3:47])=[CH2:46])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:41])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.[O:48](C(OC(C)(C)C)=O)[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:52]([O:51][C:49]([N:4]([CH2:5][C@:6]12[CH2:44][CH2:43][C@@H:42]([C:45]([CH3:47])=[CH2:46])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:41])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:26])([CH3:27])[C:15]([C:28]2[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH2:3][CH2:2][OH:1])=[O:48])([CH3:55])([CH3:54])[CH3:53]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)[C@@H]1CC[C@]2(CN(CCO)C(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 0 °C
Reaction time: 6 h

Procedure:
tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-hydroxyethylamino)methyl)-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)benzoate (600 mg, 0.932 mmol) was dissolved in CH2Cl2 (10 mL), BOC2O (0.260 mL, 1.118 mmol) was added followed by Hunig's Base (0.163 mL, 0.932 mmol) to form a colorless solution that was stirred at 0° C. for 6 hrs. LCMS indicated formation of desired product (M+23=767). The solvent was removed in vacuo and the resultant white solid was used as is in the next step.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][O:36][CH2:35]1>CN(C=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH:34]2[CH2:38][CH2:37][O:36][CH2:35]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCCC1CCOC1
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCC3CCOC3)c2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt, (200 mg) and potassium carbonate (236 mg) in dry DMF (2 mL) were heated at 60° C. with stirring for 1 h. 3-(2-Bromoethyl)tetrahydrofuran, Intermediate 83 (123 mg) was added and the reaction was continued for 2 h at 60° C. The mixture was quenched with water and extracted with EtOAc (×3). The combined organics were washed with water and brine, dried using a hydrophobic frit and evaporated to an oil (261 mg). This material was purified by flash chromatography (silica, 5-20% methanol:ethyl acetate) and the appropriate fractions combined and evaporated to give the title compound, yield 181 mg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].Br[CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:2]([O:1][CH2:16][CH3:17])[CH:3]=1
Reactant: CCBr
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Temperature: 15 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 3-hydroxyl-4-nitrobenzoate (25.1 g, 125 mmol) and bromoethane (20 mL, 263 mmol) in 200 mL ACN is cooled to 15° C. Potassium carbonate (54.4 g, 390 mmol) is added and the reaction mixture is stirred overnight at 60° C. Additional bromoethane (10 mL, 131 mmol) is added and the reaction mixture is stirred overnight at 95° C. The reaction mixture is filtered and the filtrate is concentrated in vacuo. The residue is triturated with ACN and dried in vacuo. Yield: 26.5 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[OH:24][C:25]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:26][CH2:27][CH2:28][CH2:29][NH2:30]>C1COCC1>[OH:24][C:25]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:9](=[O:11])[CH:8]=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCC(O)(c1ccccc1)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(C=Cc1cccnc1)NCCCCC(O)(c1ccccc1)c1ccccc1

Procedure:
Batch size: 1.7 g (11.3 mmol) 3-(3-pyridyl)-acrylic acid, 1.7 g (10 mmol) CDI and 2.4 g (9.4 mmol) 5-hydroxy-5,5-diphenyl-pentylamine in 40 ml abs. THF.
Reaction SMILES: NC([CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C@@H:16]2[CH2:20][O:19][C:18]([CH3:22])([CH3:21])[O:17]2)=[CH:10][CH:9]=1)C#N.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:25].[OH-].[Na+]>C(Cl)Cl>[CH3:21][C:18]1([CH3:22])[O:17][C@H:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][CH:5]=[O:25])=[CH:9][CH:10]=2)[CH2:20][O:19]1
Reactant: CC1(C)OC[C@@H](COc2ccc(CCCC(N)C#N)cc2)O1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC1(C)OC[C@@H](COc2ccc(CCC=O)cc2)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To (3-[4-((R)-2,2-dimethyl-[1,3]-dioxolan-4-ylmethoxy)-phenyl]-propan-1-ol (Intermediate B, Step 2) (1.18 g, 4.42 mmol) in DCM (150 mL) is added Dess-Martin periodinane (1.88 g, 4.42 mmol). The reaction mixture is stirred at RT for 3 h then treated with 1 N NaOH solution (50 mL) and stirred at RT for 1 h. The organic layer is separated, dried (MgSO4), filtered and concentrated in vacuo to give a clear oil. Purification by flash column chromatography (SiO2, EtOAc:iso-hexane, gradient 17-25%) affords the title compound. [M+H]+ 265.
Reaction SMILES: Cl[C:2]1[C:11]([NH:12][C:13](=O)[CH2:14][O:15][CH3:16])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C(C)=CC=CC=1>[CH3:16][O:15][CH2:14][C:13]1[S:27][C:2]2[C:11]([N:12]=1)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COCC(=O)Nc1cc(C(=O)OC)cnc1Cl
Solvent: Cc1ccccc1C
Product: COCc1nc2cc(C(=O)OC)cnc2s1

Procedure:
A mixture of 0.53 g (2.05 mmol) of methyl 6-chloro-5-methoxyacetamidonicotinate and 0.42 g (1.0 mmol) of Lawesson's reagent was refluxed for 16 hours in 25 mL of xylene. After the solvent had been removed in vacuo, the crude product obtained was purified by flash chromatography (silica gel; methylene chloride/ethanol=100:1) and evaporated down again in vacuo. Yield: 0.33 g (67% of theory) of yellow amorphous solid; Rf value: 0.52 (silica gel; ethyl acetate/petroleum ether=1:4).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@@H:13]([CH2:17][N+:18]([O-:20])=[O:19])[CH2:14][CH2:15][OH:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:16][CH2:15][CH2:14][C@@H:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:17][N+:18]([O-:20])=[O:19])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@H](CCO)C[N+](=O)[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1[C@H](CCOS(C)(=O)=O)C[N+](=O)[O-]

Procedure:
A 3.5 g sample of the alcohol from step 471a above was dissolved in 25 mL of methylene chloride and treated with methanesulfonyl chloride an TEA at 0° C. for 2 hours. The reaction mixture was washed with NaHCO3 solution and water, and the solvent was removed. The residue was chromatographed on silica gel to give 3 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:26])=[C:5]([C:17]([O:24][CH3:25])=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].[CH3:27][Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH3:26])=[C:5]([C:17]([O:24][CH3:25])=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:16])=[C:11]([CH:15]=1)[C:12]([O:14][CH3:27])=[O:13]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1c(C)c(Cc2ccc(O)c(C(=O)O)c2)c(OC)c(OC)c1OC
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1O
Yield: 96.4 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzoic acid (0.800 g, 2.21 mmol) was dissolved in a mixed solvent of methanol (4 ml) and benzene (28 ml) and after adding thereto trimethylsilyldiazomethane (10% hexane solution) (0.303 g, 2.65 mmol), the solution was stirred at room temperature for 3 hours. The reaction solution was concentrated and the obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=3:1) to obtain the titled compound (0.800 g, 2.13 mmol, 96%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([CH2:13][CH2:14]O)[N:9]([C:16](=[O:27])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[C:8]=2[CH:28]=1)([O-:3])=[O:2].S(Cl)([Cl:31])=O.O>ClCCl>[Cl:31][CH2:14][CH2:13][CH:10]1[N:9]([C:16](=[O:27])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[C:8]2[CH:28]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[O:12][CH2:11]1
Reactant: O=S(Cl)Cl
Reactant: O=C(c1cccc(C(F)(F)F)c1)N1c2cc([N+](=O)[O-])ccc2OCC1CCO
Solvent: ClCCl
Solvent: O
Product: O=C(c1cccc(C(F)(F)F)c1)N1c2cc([N+](=O)[O-])ccc2OCC1CCCl

Procedure:
To 5.37 g (0.0135 mol) of (±)-6-nitro-4-[3-(trifluoromethyl)benzoyl]-3,4-dihydro-2H-1,4-benzoxazine-3-ethanol dissolved in 80 ml of dichloromethane are added dropwise 4.85 ml (0.0675 mol) of thionyl chloride and the mixture is stirred, while being kept warm in a bath of hot water, for 5 h 30.