Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=[CH:8][CH:7]=1)([OH:3])=[O:2].B(C1C=CC(/C=C/C(O)=O)=CC=1)(O)O.B(O)O>>[C:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=[CH:8][CH:7]=1)([OH:3])=[O:2]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(CCC(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=C(O)/C=C/c1ccc(B(O)O)cc1
Agent: OBO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(/C=C/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 above for compound (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(2-carboxyethyl)phenyl)-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]chrysene-3a-carboxylic acid (example 4a) using (E)-3-(4-boronophenyl)acrylic acid as the reactant boronic acid. The product was isolated as a white solid (3.65 mg, 11%). LCMS: m/e 583.60 (M−H)−, 5.03 min (method 2). 1H NMR (599 MHz, DMSO-D6_CDCl3) δ ppm 0.94 (d, J=3.52 Hz, 6H), 1.00 (s, 6H), 1.02 (s, 3H), 1.03-1.76 (m, 17H), 1.71 (s, 3H), 1.88 (d, J=7.03 Hz, 2H), 2.08-2.16 (m, 1H), 2.20 (d, J=12.30 Hz, 1H), 2.30-2.40 (m, 1H), 3.02 (d, J=5.27 Hz, 1H), 4.61 (s., 1H), 4.74 (s, 1H), 5.28 (d, J=4.69 Hz, 1H), 6.49 (d, J=15.82 Hz, 1H), 7.17 (d, J=8.20 Hz, 2H), 7.54-7.71 (m, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:45](COCC[Si](C)(C)C)[C:25]4[N:26]=[CH:27][N:28]=[C:29]([O:30][C:31]5[CH:36]=[CH:35][C:34]([NH:37][C:38]([NH:40][CH:41]6[CH2:43][CH2:42]6)=[O:39])=[C:33]([Cl:44])[CH:32]=5)[C:24]=4[CH:23]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[Cl:44][C:33]1[CH:32]=[C:31]([O:30][C:29]2[C:24]3[CH:23]=[C:22]([C:19]4[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[CH:17][CH:18]=4)[NH:45][C:25]=3[N:26]=[CH:27][N:28]=2)[CH:36]=[CH:35][C:34]=1[NH:37][C:38]([NH:40][CH:41]1[CH2:42][CH2:43]1)=[O:39]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3cc4c(Oc5ccc(NC(=O)NC6CC6)c(Cl)c5)ncnc4n3COCC[Si](C)(C)C)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Oc2ncnc3[nH]c(-c4ccc(OCC5CCNCC5)cc4)cc23)cc1Cl)NC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
After dissolving 37 mg of 4-(4-(4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenoxymethyl)piperidine-1-carboxylic acid tert-butyl ester in 1 ml of trifluoroacetic acid, the mixture was stirred at room temperature for 2 hours. The reaction system was concentrated under reduced pressure, saturated bicarbonate water was added to alkalinity and liquid separation and extraction were performed with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to dryness to obtain the 25 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:16]2[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[C:18]([CH3:24])[N:17]=2)=[CH:10]3)=[CH:4][C:3]=1[O:25][CH3:26].C([Sn](CCCC)(CCCC)[C:32]([O:34][CH2:35][CH3:36])=[CH2:33])CCC.[Li+].[Cl-].[F-].[K+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:35]([O:34][C:32]([C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:16]2[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[C:18]([CH3:24])[N:17]=2)=[CH:10]3)=[CH:4][C:3]=1[O:25][CH3:26])=[CH2:33])[CH3:36]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cc2c(cc1Br)-c1nc(-c3nc(C)nn3C(C)C)cn1CCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: C=C(OCC)c1cc2c(cc1OC)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Temperature: 80 °C
Reaction time: 16 h
Yield: 130.9 %

Procedure:
A mixture of 13-bromo-12-methoxy-4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen (1.55 g, 3.73 mmol), tributyl(1-ethoxyvinyl)stannane (1.35 g, 3.74 mmol), LiCl (472 mg, 11.2 mmol), and Pd(PPh3)4 (130 mg, 0.120 mmol) in THF (30 mL) in a sealed tube was stirred at 80° C. for 16 hrs under N2 atmosphere. After cooling to room temperature, aq. KF (2.0 M, 50.0 mL) was added. The resulting mixture was stirred at room temperature for 1 h and then filtered. The filtrate was extracted with ethyl acetate (5×50 mL). The combined organic layers were washed with brine and dried over MgSO4. Removal of the solvent gave the desired product (2.0 g) as pale yellow oil. LCMS m/z [M+H]+ 410.3
Reaction SMILES: [N:1]1([C:7]2[S:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27].CCN(C(C)C)C(C)C>CN1CCCC1=O>[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[S:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:8]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccccc1CCl
Reactant: Cc1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2nsc(N3CCN(Cc4ccccc4C)CC3)n2)cc1
Temperature: 165 °C

Procedure:
A mixture of 5-(piperazin-1-yl)-3-p-tolyl-1,2,4-thiadiazole (17.3 mg, 66.4 μmol), 1-(chloromethyl)-2-methylbenzene (14.0 mg, 99.7 μmol) and DIPEA (42.9 mg, 58.0 μl) in 0.8 mL N-Methyl-2-pyrrolidinone was heated in the microwave oven 165° C. for 12.5 min. The resulting reaction mixture solution was purified by preparative HPLC on reversed phase eluting with a gradient formed from MeCN, water and NEt3 to yield after evaporation of the product containing fractions 17.5 mg (72%) of the title compound as yellow viscous oil. MS (m/e): 365.3 (MH+).
Reaction SMILES: BrC[CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].[CH:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([CH3:20])[CH3:19]>CN(C=O)C>[CH:18]([N:21]1[CH2:26][CH2:25][N:24]([CH2:3][C:4]2[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][CH:11]=2)[CH2:23][CH2:22]1)([CH3:20])[CH3:19]
Reactant: O=Cc1ccc(CCBr)cc1
Reactant: CC(C)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(Cc2ccc(C=O)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.4 %

Procedure:
To a mixture of 4-(bromoethyl)benzaldehyde (0.200 g, 1.0 mmol) and K2CO3 (0.277 g, 2.0 mmol) in DMF (5 mL) was added N-isopropylpiperazine (0.129 g, 1.0 mmol) and the reaction was stirred at room temperature for 5 hours, then concentrated in vacuo. The resulting mixture was diluted with H2O and extracted with EtOAc. The organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford 4-((4-Isopropylpiperazin-1-yl)methyl)benzaldehyde (0.240 g, 97%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:5][O:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:25][C:26]([F:49])([F:48])[CH2:27][CH2:28][C@@H:29](OS(C(F)(F)F)(=O)=O)[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:6]([C@H:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:29]([CH2:28][CH2:27][C:26]([F:25])([F:48])[F:49])[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[CH:5][O:4][N:3]=1
Reactant: O=C(OCc1ccccc1)[C@@H](CCC(F)(F)F)OS(=O)(=O)C(F)(F)F
Reactant: Cc1nocc1CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1nocc1[C@H](C(=O)OC(C)(C)C)[C@@H](CCC(F)(F)F)C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
In a 250 mL round-bottomed flask, a solution of tert-butyl 2-(3-methylisoxazol-4-yl)acetate (1.75 g, 8.87 mmol) in THF (56 mL) and toluene (27 mL) was cooled in a −78° C. bath and treated with a solution of 1M KHMDS (11.09 mL, 11.09 mmol) in THF dropwise over 2 minutes via syringe. After stirring for 15 minutes at −78° C., the reaction mixture was placed in a room temperature water bath for 15 minutes and then placed in a −78° C. bath for another 15 minutes before a solution of Intermediate S5D, (R)-benzyl 5,5,5-trifluoro-2-(trifluoromethylsulfonyloxy)pentanoate (4.55 g, 11.53 mmol) in 6 mL THF and 3 mL toluene was added over 2 minutes. The reaction mixture was stirred in −78° C. bath for 2 hours before being quenched with saturated aqueous NH4Cl and then warmed to room temperature. The mixture was diluted with brine and extracted with EtOAc. The organic layer was dried over MgSO4 filtered and concentrated. The residue was purified on silica gel column (330 g ISCO) eluting with a gradient of 0-30% EtOAc/CH2Cl2. Tubes were collected containing the product, which was concentrated to afford Intermediate S6A (2.394 g, 61% yield) containing about 30% of the (2R,3S) isomer.
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7]([NH:10][C:11]([C:13]3[CH:35]=[CH:34][N:16]4[C:17](=[O:33])[C:18](/C=C/C(O)=O)=[C:19]([N:21]5[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]5)[N:20]=[C:15]4[CH:14]=3)=[O:12])[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C1(C2N=C(NC(C3C=CN4C(=O)CC(=O)N=C4C=3)=O)SC=2)CCC1.CN1CCNCC1>>[CH:1]1([C:5]2[N:6]=[C:7]([NH:10][C:11]([C:13]3[CH:35]=[CH:34][N:16]4[C:17](=[O:33])[CH:18]=[C:19]([N:21]5[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]5)[N:20]=[C:15]4[CH:14]=3)=[O:12])[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCN(c2nc3cc(C(=O)Nc4nc(C5CCC5)cs4)ccn3c(=O)c2/C=C/C(=O)O)CC1
Agent: CN1CCNCC1
Agent: O=C1CC(=O)N2C=CC(C(=O)Nc3nc(C4CCC4)cs3)=CC2=N1
Product: CN1CCN(c2cc(=O)n3ccc(C(=O)Nc4nc(C5CCC5)cs4)cc3n2)CC1
Yield: 69 %

Procedure:
Reactions were performed in the same manner as in Example 8, (E) by using N8-(4-cyclobutyl-1,3-thiazol-2-yl)-2,4-dioxo-3,4-dihydro-2H-pyrido[1,2-a]pyrimidine-8-carboxamide (60 mg, 0.174 mmol) and N-methylpiperazine (60 μl, 1, 0.52 mmol) as regents to obtain 51.2 mg (69%) of the title compound.
Reaction SMILES: [N-]=[C:2]=[O:3].[C:4]1([CH3:11])[C:5]([CH3:10])=[CH:6][CH:7]=[CH:8][CH:9]=1>>[C:2]([OH:3])(=[O:3])[CH2:10][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:4][CH2:11][CH2:10][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:4]([CH3:11])[CH3:2]
Reactant: Cc1ccccc1C
Reactant: [N-]=C=O
Product: CC(C)CCCCCCCCCCCCCCC(=O)O
Temperature: 28 °C

Procedure:
Then 200 ml. xylene was added and 100 g n-C18 -isocyanate (0.339 mole) was dispersed in the mixture with stirring. The temperature was about 45° C. and the mixture was allowed to cool to about 28° C. The mixture containing a little floc was filtered and solvent removed by "Rotavapor". The solid was dissolved in cyclohexane, filtered and again recovered by solvent evaporation. It was again washed with cyclohexane to give a white, waxy solid. Nitrogen content was 8.6 wt. %.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([O:23][CH:24]([CH3:26])[CH3:25])=[C:15]([CH:27]=[O:28])[C:14]=2[CH3:29])=[CH:7][CH:6]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([O:23][CH:24]([CH3:26])[CH3:25])=[C:15]([CH2:27][OH:28])[C:14]=2[CH3:29])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C(C)(C)C)c(OC(C)C)c(C=O)c2C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(C#Cc2cc(C(C)(C)C)c(OC(C)C)c(CO)c2C)cc1
Reaction time: 1.5 h
Yield: 87.4 %

Procedure:
A stirred, cooled (ice bath) solution of [4-(5-tert-butyl-3-formyl-4-isopropoxy-2-methyl-phenylethynyl)-phenyl]-acetic acid methyl ester (Intermediate 142, 0.172 g, 0.42 mmol) in methanol (4 mL) was treated with sodium borohydride (0.02 g, 0.51 mmol) and the resulting reaction mixture was stirred for 1.5 h. The reaction mixture was quenched with water and extracted with diethyl ether. The organic phase was washed with water (×1) and brine (×1), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography over silica gel (230-400 mesh) using 15-20% ethyl acetate in hexane as the eluent to afford the title product as a white solid (0.15 g, 88%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)[NH:36][CH2:37][CH2:38][C@H:39]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:40][OH:41])C1C=CC=CC=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:24]([NH:36][CH2:37][CH2:38][C@H:39]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:40][OH:41])=[O:26])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCNC(=O)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCC[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.082 g (0.22 mmol) of N2-[(benzyloxy)carbonyl]-N5-(tert-butoxycarbonyl)-L-ornithine and 0.059 g (0.29 mmol) of benzyl{(3S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxybutyl}carbamate (Example 237A) are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 0.056 g (0.29 mmol) of EDC and 0.009 g (0.067 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is dried to constant weight under high vacuum.
Reaction SMILES: CN(C=O)C.[S:6]([Cl:10])(Cl)(=[O:8])=[O:7].[CH2:11]([C:13]1[S:17][C:16]2[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:15]=2[CH:14]=1)[CH3:12]>>[CH2:11]([C:13]1[S:17][C:16]2[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:15]=2[C:14]=1[S:6]([Cl:10])(=[O:8])=[O:7])[CH3:12]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCc1cc2cc(C)ccc2s1
Solvent: CN(C)C=O
Product: CCc1sc2ccc(C)cc2c1S(=O)(=O)Cl

Procedure:
2-ethyl-5-methylbenzo[b]thiophene-3-sulfonylchloride was prepared in the same manner as described in Example 40B. Reaction of DMF (6.5 mmoles, 0.50 ml), sulfurylchloride (5.5 mmoles, 0.44 ml) and 2-ethyl-5-methylbenzo[b]thiophene (3.2 mmoles, 0.57 g) yielded, after flash chromatography, using 2% ethyl acetate/hexanes, 0.58 g (66%) of an orange solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1Cl)[CH3:2].Cl.[CH2:14]([O:21][NH2:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[CH2:14]([O:21][NH:22][C:6]1[N:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([O:3][CH2:1][CH3:2])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NOCc1ccccc1
Reactant: CCOC(=O)c1cccnc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cccnc1NOCc1ccccc1
Yield: 52.3 %

Procedure:
2-Chloro-nicotinic acid ethyl ester (4.55 g, 24.6 mmol), O-benzylhydroxyamine hydrochloride (7.85 g, 49.2 mmol) and N,N-diisopropylethylamine (6.36 g, 49.2 mmol) in 10 mL 1,4-dioxane were reacted in a sealed tube at 120° C. for 48 hours. The reaction mix was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate. The aqueous layer was re-extracted with ethyl acetate (2×50 mL). The organic layers were combined and dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane and ethyl acetate (9:1) to provide the title compound (3.5 g, 53%). MS (DCI) m/z 273 (M+H)+.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]2[N:20]=[CH:19][CH:18]=[CH:17][C:11]=2[C:12]([O:14][CH2:15]C)=[O:13])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C(CC)CNC1N=CC=CC=1C(OCC)=[O:29])C>>[C:1]1([C@H:7]([N:9]2[C:10]3[N:20]=[CH:19][CH:18]=[CH:17][C:11]=3[C:12](=[O:13])[O:14][C:15]2=[O:29])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Reactant: CCOC(=O)c1cccnc1N[C@H](C)c1ccccc1
Product: C[C@H](c1ccccc1)n1c(=O)oc(=O)c2cccnc21

Procedure:
The title compound was prepared according to the procedure of Example 3B substituting the product of Example 57A for the product of Example 3A (0.250 g, 62%). 1H NMR (300 MHz, DMSO-d6) δ 1.86 (d, J=6.99 Hz, 3H), 6.65 (q, J=6.99 Hz, 1H), 7.27 (m, 3H), 7.40 (m, 3H), 8.43 (dd, J=7.72, 1.84 Hz, 1H), 8.73 (dd, J=4.96, 2.02 Hz, 1H).
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](O)=[CH:4][C:3]=1Cl.CN1CCN(C)C1=O.C(=O)([O-])[O-].[K+].[K+].C(N(CCCCCCCC)C1C=C(O)C=CC=1)CCCCCCC>O>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1c(Cl)cc(O)c2c1C(=O)c1ccccc1C2=O
Agent: CCCCCCCCN(CCCCCCCC)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: O=C1c2ccccc2C(=O)c2ccccc21
Temperature: 150 °C
Reaction time: 5 h

Procedure:
One part of 1-amino-2-chloro-4-hydroxyanthraquinone, 10 parts of 1,3-dimethyl-2-imidazolidinone, 1.0 part of potassium carbonate and 2.0 parts of N,N-di-n-octyl-m-aminophenol were mixed at room temperature, and then heated to 150° C. While this temperature was maintained, the reaction was conducted for 5 hours. The reaction mixture was cooled, then charged into 100 parts of water, extracted with toluene and thereafter purified through silica gel column chromatography to obtain an anthraquinone compound as coloring matter No. 1 (yield 90%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH:13]1([CH2:19][C@H:20]([N:24]2[C:28](=[O:29])[C@H:27]([CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[NH:26][C:25]2=[O:37])[C:21](O)=[O:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][C:5]1[N:6]=[C:2]([NH:1][C:21](=[O:22])[C@@H:20]([N:24]2[C:28](=[O:29])[C@H:27]([CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[NH:26][C:25]2=[O:37])[CH2:19][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[S:3][CH:4]=1)[CH3:12]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1C(=O)N[C@@H](CC2CCCCC2)C1=O
Product: CCOC(=O)Cc1csc(NC(=O)[C@H](CC2CCCCC2)N2C(=O)N[C@@H](CC3CCCCC3)C2=O)n1

Procedure:
By using the conditions described in Step (iv) of Example 17, ethyl 2-amino-4-thiazoleacetate was condensed with (S,S)-3-cyclohexyl-2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidinyl]propanoic acid [Example 17, Step (iii)] to give the title compound as a colorless foam: EI-HRMS m/e calcd. for C26H38N4O5S (M+) 519.2641, found 519.2620.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH:19]([CH3:24])[CH2:20][C:21]([OH:23])=O)=[C:8]2[CH3:25])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(Cl)(=O)C(C)(C)C.[CH:45]([C@@H:48]1[CH2:52][O:51][C:50](=[O:53])[NH:49]1)([CH3:47])[CH3:46].[Li]CCCC>C1COCC1>[Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH:19]([CH3:24])[CH2:20][C:21]([N:49]3[C@H:48]([CH:45]([CH3:47])[CH3:46])[CH2:52][O:51][C:50]3=[O:53])=[O:23])=[C:8]2[CH3:25])=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H]1COC(=O)N1
Reactant: COc1ccc2c(c1)c(CC(C)CC(=O)O)c(C)n2Cc1ccc(Br)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(CC(C)CC(=O)N1C(=O)OC[C@H]1C(C)C)c(C)n2Cc1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of acid from Step 6 (1.0 g, 2.3 mmol) in THF (20 mL) at 0° C. was added KHMDS (0.64M/toluene, 4.0 mL, 2.6 mmol) followed by pivaloyl chloride (0.31 mL, 2.6 mmol). After 30 rain at 0° C., the solution was cooled to -78° C., and a cloudy solution of (R)-4-isopropyl oxazolidinone (0.35 g, 2.7 mmol) and BuLi (1.6M/hexane, 1.7 mL, 2.7 mmol) in THF (20 mL) was added via double-tipped needle. After 10 min at -78° C., the reaction was warmed to 0° C. for 1 h, at which point it was quenched by the addition of saturated NH4Cl solution. Following EtOAc/H2O work-up, the two diastereomers were obtained by flash chromatography (1:5 EtOAc/hexane). isomer A=0.55 g, isomer B =0.52 g.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]([C:15]2[NH:23][C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[CH:16]=2)=[CH:11][CH:12]([CH3:14])[CH3:13])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]([C:15]2[NH:23][C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[CH:16]=2)[CH2:11][CH:12]([CH3:14])[CH3:13])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(C(=CC(C)C)c2cc3cccnc3[nH]2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOc1cccc(C(CC(C)C)c2cc3cccnc3[nH]2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.8 %

Procedure:
A solution of 2-(1-(3-ethoxy-phenyl)-3-methyl-but-1-enyl)-1H-pyrrolo[2,3-b]pyridine (1.3 g, 4.2 mmol) in methanol (30 mL) was treated with 10% palladium on carbon (130 mg). The reaction was stirred for 16 h at 25° C. under a balloon filled with hydrogen gas. The reaction mixture was filtered through a pad of celite and washed with methanol (2×20 mL). The filtrate was concentrated in vacuo. Silica gel column chromatography (30 g, ethyl acetate/petroleum ether: 1:10) afforded 2-(1-(3-ethoxy-phenyl)-3-methyl-butyl)-1H-pyrrolo[2,3-b]pyridine (800 mg, 62%) as a white solid: 1H NMR (300 MHz, CDCl3) δ ppm 9.37 (s, 1H), 8.15 (d, 1H, J=4.5 Hz), 7.83 (d, 1H, J=7.5 Hz), 7.20 (t, 1H, J=7.8 Hz), 7.01 (dd, 1H, J1=7.8 Hz, J2=4.8 Hz), 6.87-6.74 (m, 3H), 6.32 (s, 1H), 4.15 (t, 1H, J=8.1 Hz), 3.95 (q, 2H, J=6.9 Hz), 2.08-1.91 (m, 2H), 1.59-1.50 (m, 1H), 1.37 (t, 3H, J=6.9 Hz), 0.96 (s, 3H), 0.94 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([SH:7])=[N:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:14](O)([CH3:17])([CH3:16])[CH3:15].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>O>[NH2:1][C:2]1[S:6][C:5]([S:7][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1sc(S)nc1-c1ccccc1
Reactant: CC(C)(C)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)Sc1nc(-c2ccccc2)c(N)s1
Temperature: 20 °C
Yield: 82.4 %

Procedure:
To a suspension of 5-amino-2-mercapto-4-phenylthiazole (210 mg, 1.01 mmol) in water (1.0 ml) and tert-butanol (82 mg, 1.1 mmol) was added concentrated sulfuric acid (3.0 ml) with cooling to ca. 20° C. After 1.5 hr at ambient temperature a further portion of tert-butanol in water (300 μl, 1.0 M, 300 μmol) was added. After 1.5 hr the mixture was poured into excess aqueous sodium bicarbonate and extracted three times into dichloromethane (total 120 ml). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography on silica gel (ethyl acetate/hexanes) yielded 5-amino-2-(tert-butylsulfanyl)-4-phenylthiazole (220 mg, 82%).