Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[C@@H:7]([NH:20][C:21](=[O:40])[NH:22][C@@H:23]([CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:8][CH2:9][C:10](ON1C(=O)CCC1=O)=[O:11])([CH3:4])([CH3:3])[CH3:2].[NH2:42][C@@H:43]([CH2:47][CH2:48][CH2:49][CH2:50][N:51]([CH2:66][C:67]1[N:68]([CH2:72][C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[CH:69]=[CH:70][N:71]=1)[CH2:52][C:53]1[N:54]([CH2:58][C:59](=[O:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[CH:55]=[CH:56][N:57]=1)[C:44]([OH:46])=[O:45].CCN(C(C)C)C(C)C>CN(C=O)C>[C:61]([O:60][C:59](=[O:65])[CH2:58][N:54]1[CH:55]=[CH:56][N:57]=[C:53]1[CH2:52][N:51]([CH2:66][C:67]1[N:68]([CH2:72][C:73](=[O:74])[O:75][C:76]([CH3:79])([CH3:78])[CH3:77])[CH:69]=[CH:70][N:71]=1)[CH2:50][CH2:49][CH2:48][CH2:47][C@H:43]([NH:42][C:10](=[O:11])[CH2:9][CH2:8][C@@H:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:41])[NH:20][C:21](=[O:40])[NH:22][C@H:23]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:31][CH2:32][C:33](=[O:34])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:44]([OH:46])=[O:45])([CH3:62])([CH3:64])[CH3:63]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Cn1ccnc1CN(CCCC[C@H](N)C(=O)O)Cc1nccn1CC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCC(=O)N[C@@H](CCCCN(Cc1nccn1CC(=O)OC(C)(C)C)Cc1nccn1CC(=O)OC(C)(C)C)C(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 85.6 %

Procedure:
A solution of (S)-di-tert-butyl 2-(3-((S)-1-tert-butoxy-5-(2,5-dioxopyrrolidin-1-yloxy)-1,5-dioxopentan-2-yl)ureido)pentanedioate (138 mg, 0.236 mmol), (S)-2-amino-6-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)hexanoic acid (127 mg, 0.237 mmol) and DIPEA (0.50 mL) in DMF (1.0 mL) was stirred at rt for overnight. The Solvent was removed under reduced pressure to give a residue, which was purified by biotage eluting with 1% to 50% MeOH in DCM to afford (2S,7S,11S)-2-(4-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)butyl)-7,11-bis(tert-butoxycarbonyl)-16,16-dimethyl-4,9,14-trioxo-15-oxa-3,8,10-triazaheptadecan-1-oic acid (203 mg, 86%) as a white solid. 1H NMR (400 MHz, CDCl3) 7.40 (brs, 1H), 6.99 (s, 2H), 6.79 (s, 2H), 6.12 (brs, 1H), 5.62 (brs, 1H), 4.67-4.28 (m, 7H), 3.68 (d, J=14.0 Hz, 2H), 3.62 (d, J=14.0 Hz, 2H), 2.62-2.53 (m, 2H), 2.34-2.02 (m, 8H), 1.83-1.42 (m, 51H); MS (ESI), 503.5 (M/2+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:27][C:28]([NH2:30])=[S:29])[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:27][C:28]2[S:29][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:11][CH3:12])[N:30]=2)[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: COc1ccccc1C(=O)CBr
Product: COc1ccccc1-c1csc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
The title compound was prepared in analogy to example 1 step e) from 77 mg (0.33 mmol) 2-bromo-2′-methoxyacetophenon and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The crude product was purified through stirring with methylene chloride at room temperature yielding 104 mg (88%) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[4-(2-methoxy-phenyl)-thiazol-2-yl]-amine as a light yellow solid. MS ISP (m/e): 393.2 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.65 (s, 1H), 9.32 (s, 1H), 8.17 (d, 1H), 8.05 (s, 1H), 7.70 (s, 1H), 7.53 (d, 1H), 7.51 (s, 1H), 7.32-7.29 (m, 2H), 7.15 (d, 1H), 7.07 (t, 1H), 3.94 (s, 3H), 3.93 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[CH3:8][C:9]([CH3:27])([CH3:26])[C:10]([O:12][CH2:13][CH2:14][O:15][C:16](ON1C(=O)CCC1=O)=[O:17])=[O:11]>>[CH3:8][C:9]([CH3:27])([CH3:26])[C:10]([O:12][CH2:13][CH2:14][O:15][C:16]([NH:1][C@H:2]([CH2:3][OH:4])[C:5]([OH:7])=[O:6])=[O:17])=[O:11]
Reactant: N[C@H](CO)C(=O)O
Reactant: CC(C)(C)C(=O)OCCOC(=O)ON1C(=O)CCC1=O
Product: CC(C)(C)C(=O)OCCOC(=O)N[C@H](CO)C(=O)O
Yield: 27.5 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, D-serine (504 mg, 4.8 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl 2,2-dimethylpropanoate (1.1 g, 4.0 mmol) were reacted to provide 305 mg (28% yield) of the title compound (24) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=6.78 (m, 1H), 6.40 (br s, 1H), 6.11 (t, 1H), 4.41 (m, 1H), 4.04 (m, 1H), 3.93 (m, 1H), 1.44 (2d, 3H), 1.20 (s, 9H). MS (ESI) m/z 278.05 (M+H)+; 295.06 (M+NH4)+; 300.04 (M+Na)+; 276.04 (M−H)−.
Reaction SMILES: [CH2:1]([C:13]1[CH:17]=[C:16]([CH3:18])[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([Li])CCC.[C:24](=[O:26])=[O:25]>O1CCCC1>[CH2:1]([C:13]1[CH:17]=[C:16]([CH2:18][C:24]([OH:26])=[O:25])[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1cc(C)on1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1cc(CC(=O)O)on1
Temperature: -75 °C

Procedure:
To a cold (-75° C.), stirred suspension of 3-dodecyl-5-methylisoxazole (3.40 g, 0.0135 mol) in dry tetrahydrofuran (900 mL) was added in one portion a 1.6M solution (8.5 mL, 0.014 mol) of n-butyl lithium in hexanes, and the mixture was stirred for 1.5 hours. The mixture was poured onto freshly crushed dry ice and allowed to warm overnight. The mixture was rotoevaporated, and the residue was partitioned between petroleum ether and 0.5M NaOH. The aqueous layer was washed (petroleum ether), acidified with concentrated hydrochloric acid to pH ~1-2, and extracted (CHCl3). The extract was dried (MgSO4) and rotoevaporated to a waxy solid. The solid was recrystallized from toluene to give a white solid; yield 0.65 g (16%); mp 79°-80° C.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].N1C=CC=CC=1.[CH2:22]([C:29](O)([CH2:33][CH2:34][CH2:35][CH3:36])[C:30]([OH:32])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([C:29]([O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])([CH2:33][CH2:34][CH2:35][CH3:36])[C:30]([OH:32])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCCC(O)(Cc1ccccc1)C(=O)O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC(Cc1ccccc1)(OS(=O)(=O)C(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
Triflic anhydride (71 mmoles, 20 g) was added at -27° C. to a solution of pyridine (74 moles, 5.9 g) in 150 ml methylene chloride with vigorous stirring. The solution was warmed to room temperature. Benzyl 2-hydroxyhexanoic acid (57 moles, 12.65 g) in 15 ml methylene chloride was added over 2 minutes. The solution was stirred for 1 hour and filtered. The filtrate was concentrated, filtered through silica gel eluted with hexane, and evaporated to yield 17.0 g of benzyl 2-(trifluoromethanesulfonylhydroxy)hexanoic acid. (MS)
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:13][C:14]([F:23])([F:22])[C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1>>[Br:1][C:2]1[C:3]([O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:13])([F:22])[F:23])[CH:16]=2)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1cnc(Cl)c(Br)c1
Product: COC(=O)c1cnc(Oc2cccc(C(F)(F)F)c2)c(Br)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from methyl 5-bromo-6-chloronicotinate and 3-(trifluoromethyl)phenol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[F:18][C:19]1[C:20]([C@@H:26]([NH2:28])[CH3:27])=[N:21][CH:22]=[C:23]([F:25])[CH:24]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:17][C:5]1[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)=[N:7][C:2]([NH:28][C@H:26]([C:20]2[C:19]([F:18])=[CH:24][C:23]([F:25])=[CH:22][N:21]=2)[CH3:27])=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Reactant: C[C@H](N)c1ncc(F)cc1F
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1)c1ncc(F)cc1F
Temperature: 175 °C
Yield: 80.5 %

Procedure:
A mixture of 2,5-dichloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 7; 0.18 g, 0.666 mmol), (S)-1-(3,5-difluoropyridin-2-yl)ethanamine (Method 21; 0.132 g, 0.833 mmol), and DIEA (0.139 ml, 0.800 mmol) in n-BuOH (2 ml) was heated in a sealed tube at 175° C. for 17 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane:EtOAc=1.5:1) to give the title compound as a white solid (0.21 g, 80%). 1H NMR (400 MHz) δ 12.50 and 12.09 (s, 1H), 9.60 and 8.50 (s, 1H), 8.43 and 8.35 (s, 1H), 7.88-8.04 (m, 3H), 7.26 (br, 1H), 5.33 (m, 1H), 1.88 (m, 1H), 1.36 (d, J=6.8 Hz, 3H), 0.94 (m, 1H), 0.86 (m, 1H), 0.74 (m, 1H), 0.62 (m, 1H). MS: Calcd.: 391. Found: [M+H]+ 392.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[C:11]([C:21]2[CH:49]=[CH:48][C:24]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][N:32]4[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH:34]([C:45]([O-:47])=[O:46])[CH2:33]4)=[CH:27][CH:26]=3)=[CH:23][CH:22]=2)=[CH:10][CH:9]=1>ClCCl>[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[C:11]([C:21]2[CH:22]=[CH:23][C:24]([C:25]3[CH:26]=[CH:27][C:28]([CH2:31][N:32]4[CH2:37][CH2:36][NH:35][CH:34]([C:45]([OH:47])=[O:46])[CH2:33]4)=[CH:29][CH:30]=3)=[CH:48][CH:49]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3ccc(-c4cccc5c4oc4ccccc45)cc3)cc2)CC1C(=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CN(Cc2ccc(-c3ccc(-c4cccc5c4oc4ccccc45)cc3)cc2)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of 4-(4′-Dibenzofuran-4-ylbiphen-4-ylmethyl)-piperazine-1,2-dicarboxylic acid, 1-tert-butyl ester (80 mg) in anhydrous dichloromethane. The reaction was stirred at room temperature for 2 hours (TLC control). The resultant brown oil was reconstituted and concentrated from methanol (3×10 mL) and then from dichloromethane (2×10 mL) to give the title compound as a white solid (65 mg, 100%): Rf 0.25 (20% methanol in dichloromethane). 1H NMR (DMSO-d6, 300 MHz): δ 8.19 (1H, d, J=9 Hz, Ar—H), 8.16 (1H, d, J=9 Hz, Ar—H), 8.01 (2H, d, J=9 Hz, Ar—H), 7.86 (2H, d, J=9 Hz, Ar—H), 7.72 (4H, m, Ar—H), 7.53 (2H, q, J=8 Hz, Ar—H), 7.45 (3H, m, Ar—H), 4.22 (1H, m, CHN), 3.78 (2H, s), 3.35 (1H, m), 3.08 (2H, m), 2.86 (1H, m), 2.58 (2H, m); ESI-LCMS e/z calcd for C30H26N2O3 462.546, found 563 (M+H)+.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[C:11]([O:16]CC)(=[O:15])[C:12]([CH3:14])=[O:13].[Cl-].[NH4+]>CCCCCC.C(OCC)C>[OH:13][C:12]([C:7]1[S:6][CH:10]=[CH:9][CH:8]=1)([CH3:14])[C:11]([OH:16])=[O:15]
Reactant: CCOC(=O)C(C)=O
Reactant: c1ccsc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(O)(C(=O)O)c1cccs1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 1.6 molar solution of n-butyl-lithium in hexane (37 ml.) was added to a solution of thiophene (5 g.) in diethyl ether (50 ml.) which was maintained at 0° C., and the mixture was heated under reflux for 6 hours and then cooled to -78° C. A solution of ethyl pyruvate (5.9 g.) in diethyl ether (20 ml.) was added dropwise, the mixture was allowed to warm up to laboratory temperature and saturated aqueous ammonium chloride solution (20 ml.) was added. The mixture was extracted with ethyl acetate and the organic extract was washed with water and then with saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated to dryness. The residue was dissolved in ethanol (30 ml.), a solution of potassium hydroxide (1.4 g.) in water (5 ml.) was added and the mixture was stirred at laboratory temperature for 2 hours and then evaporated to dryness. The residue was washed with ethyl acetate, dilute aqueous hydrochloric acid was added and the mixture was extracted with ethyl acetate. The extract was washed with water and then saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated to dryness. There was thus obtained as residue 2-hydroxy-2-(thien-2-yl)propionic acid, which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=O)=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:18][CH:19]=1
Reactant: [H][H]
Reactant: COC(=O)c1cccc(C(=O)c2ccc(O)cc2)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cccc(Cc2ccc(O)cc2)c1

Procedure:
Methyl 3-(4-hydroxybenzoyl)benzoate (0.1 mol) in absolute ethanol (500 ml) is shaken under 50 psi of hydrogen in the presence of 10% palladium on carbon (2 g). After consumption of the starting material the suspension isfiltered and evaporated to give methyl 3-(4-hydroxybenzyl)benzoate
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([OH:15])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCOC(=O)c1cc2c(O)cccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Oc3ccccc3[N+](=O)[O-])cccc2[nH]1
Temperature: 25 °C

Procedure:
4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester (0.5 g, 2.436 mmol) and 2-fluoro-nitro-benzene (0.257 ml, 2.436 mmol) are dissolved in 10 ml of dimethylformamide. After addition of potassium carbonate (0.67 g, 4.87 mmol) the mixture is stirred over night at room temperature. Then the reaction mixture is evaporated under reduced pressure, dissolved with ethyl acetate and washed with water. The organic layers are dried over sodium sulfate and evaporated. The crude product is used in the next step without further purification.
Reaction SMILES: C(OC(N1CCN([CH2:14][CH2:15][NH:16][C@:17]23[CH2:51][CH2:50][C@@H:49]([C:52]([CH3:54])=[CH2:53])[C@@H:18]2[C@@H:19]2[C@@:32]([CH3:35])([CH2:33][CH2:34]3)[C@@:31]3([CH3:36])[C@@H:22]([C@:23]4([CH3:48])[C@@H:28]([CH2:29][CH2:30]3)[C:27]([CH3:38])([CH3:37])[C:26]([C:39]3[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][CH:40]=3)=[CH:25][CH2:24]4)[CH2:21][CH2:20]2)CC1)=O)(C)(C)C.[CH2:55]([S:57]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)(=[O:59])=[O:58])[CH3:56]>>[CH2:55]([S:57]([N:60]1[CH2:61][CH2:62][N:63]([CH2:14][CH2:15][NH:16][C@:17]23[CH2:51][CH2:50][C@@H:49]([C:52]([CH3:54])=[CH2:53])[C@@H:18]2[C@@H:19]2[C@@:32]([CH3:35])([CH2:33][CH2:34]3)[C@@:31]3([CH3:36])[C@@H:22]([C@:23]4([CH3:48])[C@@H:28]([CH2:29][CH2:30]3)[C:27]([CH3:37])([CH3:38])[C:26]([C:39]3[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][CH:40]=3)=[CH:25][CH2:24]4)[CH2:21][CH2:20]2)[CH2:64][CH2:65]1)(=[O:59])=[O:58])[CH3:56]
Reactant: CCS(=O)(=O)N1CCNCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)OC(C)(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(S(=O)(=O)CC)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described in above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(tert-butoxycarbonyl)piperazin-1-yl)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)benzoic acid using 1-(ethylsulfonyl)piperazine as the alkylating reagent in Step 3. The product was isolated as a white solid (11 mg, 53%). LCMS: m/e 734.56 (M+H)+, 2.28 min (method 11). 1H NMR (400 MHz, Acetic) δ 7.99 (d, J=8.5 Hz, 2H), 7.26 (d, J=8.3 Hz, 2H), 5.34 (d, J=4.5 Hz, 1H), 4.81 (s, 1H), 4.70 (s, 1H), 3.63-3.28 (m, 7H), 3.26-3.16 (m, 1H), 3.14-2.98 (m, 6H), 2.95-2.75 (m, 1H), 2.33-1.06 (m, 22H), 1.73 (s, 3H), 1.32 (t, J=7.4 Hz, 3H), 1.23 (s, 3H), 1.10 (s, 3H), 1.06 (s, 3H), 0.98 (s, 3H), 0.97 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1.N1C=CN=C1.[C:14]([Si:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)Cl)([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O.CN(C1C=CN=CC=1)C.O>[Si:18]([O:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1NC[C@@H](CO)O1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC[C@@H]1CNC(=O)O1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 79 %

Procedure:
(S)-5-(hydroxylmethyl)oxazolidin-2-one (1.61 g, 13.7 mmol) was dissolved in dried N,N-dimethyl formamide. Imidazole (1.87 g, 27.4 mmol) and DMAP (168 mg, 1.37 mmol) were added. The resulting mixture was cooled to 0° C., and then tert-butyldiphenylchlorosilane (5.66 g, 20.6 mmol) was added. The mixture was raised to room temperature to react for 4 hrs. The reaction was measured by TLC. After the reaction completed, the mixture was diluted with water, and extracted with ethyl acetate. The organic phase was combined, washed sequentially with water and saturated saline solution, dried over anhydrous sodium sulfate, and filtered. Column chromatography afforded 3.85 g of white solid (compound 25a), yield 83%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([F:21])[CH:15]=2)[C@H:10]2[CH2:22][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2].[CH3:23][S:24]([NH:27][C:28]1[CH:43]=[CH:42][C:31]2[NH:32][C:33]([CH2:38][C:39](O)=[O:40])=[N:34][S:35](=[O:37])(=[O:36])[C:30]=2[CH:29]=1)(=[O:26])=[O:25].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([F:21])[CH:15]=2)[C:39](=[O:40])[CH2:38][C:33]2[NH:32][C:31]3[CH:42]=[CH:43][C:28]([NH:27][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:29][C:30]=3[S:35](=[O:36])(=[O:37])[N:34]=2)[C@H:10]2[CH2:22][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(C)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(Cc1ccc(C)c(F)c1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (1S,2R,3S,4R)-3-(3-fluoro-4-methyl-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (92 mg, 0.30 mmol), (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 100 mg, 0.30 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (60 mg, 0.315 mmol) in N,N-dimethylformamide (4.0 mL) was added N-methylmorpholine (0.07 mL, 0.63 mmol). After stirring at 25° C. for 3 h, the mixture was poured into a 1.0 M aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with saturated aqueous brine solution, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, (1S,2R,3S,4R)-3-{(3-fluoro-4-methyl-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester, as an orange oil. The crude product was used in the next step without further purification. LC-MS (ESI) calcd for C28H33FN4O7S2 620.18, found 621.4 [M+H+].
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:6]=1[C:14]#[C:15][C@H:16]([OH:18])[CH3:17].[H][H]>[Pd].CO>[NH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:6]=1[CH2:14][CH2:15][C@H:16]([OH:18])[CH3:17]
Reactant: [H][H]
Reactant: COCOc1cccc([N+](=O)[O-])c1C#C[C@@H](C)O
Agent: [Pd]
Solvent: CO
Product: COCOc1cccc(N)c1CC[C@@H](C)O
Reaction time: 0.25 h
Yield: 100 %

Procedure:
A 400-mL Parr bottle charged with (R)-4-(2-(methoxymethoxy)-6-nitrophenyl)but-3-yn-2-ol (2.9 g, 11.54 mmol), methanol (58 mL), and 10% palladium on carbon (50% water, 1.228 g, 0.577 mmol) was pressurized to 39 psig with hydrogen and then shaken. Hydrogen was quickly consumed, and within 15 min, the pressure had dropped to 0 psig. The bottle was re-pressurized to 39 psig and shaking was continued. The pressure dropped to ca. 20 psig over the next 15 min and stabilized. The bottle was re-pressurized to 34 psig and held there with continued shaking for 2 h. The mixture was flushed with nitrogen, and then filtered through a pad of Celite. The bottle and catalyst were rinsed with methanol, and the filtrate concentrated under reduced pressure. Toluene was added and the mixture was concentrated to afford (R)-4-(2-amino-6-(methoxymethoxy)phenyl)butan-2-ol (2.60 g, 100%) as a dark yellow syrup which was used without further purification. MS (ESI, pos. ion) m/z 248 [M+23]+.
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[OH:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[N:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C1COCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:18]1([C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][CH2:7][O:6][C:5]3[CH:30]=[CH:31][C:2]([C:35]4[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=4)=[CH:3][CH:4]=3)[CH2:11][CH2:12]2)[OH:17])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1ccncc1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCN(CCCOc2ccc(Br)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1ccccc1)C1CCN(CCCOc2ccc(-c3ccncc3)cc2)CC1
Temperature: 90 °C
Yield: 41.8 %

Procedure:
Bromide intermediate (1-(3-(4-bromophenoxy)propyl)piperidin-4-yl)diphenylmethanol (A1) (75 mg, 0.15 mmol), Pd(dppf)Cl2 (15 mg), CsCO3 (150 mg), and pyridin-4-ylboronic acid (30 mg) was placed under an argon atmosphere in a microwave vial. Degassed THF (3 mL) and 0.1 mL of water was added via syringe and the mixture heated for 30 min. at 90° C. in a Biotage microwave reactor. The reaction was partitioned between EtOAc (10 mL) and water (3 mL) and the organic phase isolated. The organic phase was subsequently washed with brine, dried over Na2SO4, and concentrated to dryness. Purification by RP-HPLC afforded the title compound (30 mg, 41%): LC-MS (>98%) m/z=479.1 [M+H].