Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1>O1CCOCC1.[Ru](=O)=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([CH2:8][CH2:9][CH2:10][C@@H:11]2[CH2:12][CH2:13][C@H:14]([NH2:15])[CH2:16][CH2:17]2)[CH2:3]1
Reactant: Cc1cccc(CCCc2ccc(N)cc2)c1
Agent: O=[Ru]=O
Solvent: C1COCCO1
Product: C[C@H]1CCC[C@H](CCC[C@H]2CC[C@@H](N)CC2)C1
Temperature: 140 °C

Procedure:
0.5 g of ruthenium dioxide is added to a solution of 63 g (0.28 mole) of 4-[3-(3-methylphenyl)-propyl]aniline in 100 ml of dioxane, and hydrogenation is carried out in a 300 ml stirred autoclave at 140° C. and under an H2 pressure of 300 bar until the pressure remains constant (about 3 hours). The discharged mixture is filtered under suction over kieselguhr, the filtrate is evaporated down under reduced pressure and the residue is subjected to fractional distilation to give 47 g (71% of theory) of a colorless oil of boiling point 100°-116° C./0.2 mm, consisting of about 30% of the cis isomer and 70% of the trans isomer (compound no. 64).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[C:33]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1)(=[O:36])[CH2:34][CH3:35]
Reactant: CCC(=O)Cl
Reactant: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCNCC4)c[nH]c13)OCO2
Product: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C(=O)CC)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-butoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A179) and propionyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [C:1]1([C:7]([NH:20][C:21]2[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:32]([C:34]3[O:35][CH:36]=[CH:37][CH:38]=3)=[O:33])/[C:27](O)=[O:28])[N:25]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:39]1([CH:45]([O:52][C:53]([C:55]2[N:56]3[C@H:59]([S:60][CH2:61][C:62]=2[CH2:63][S:64][C:65]2[N:70]4[N:71]=[C:72]([C:74]([O:76][CH:77]([C:84]5[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=5)[C:78]5[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=5)=[O:75])[N:73]=[C:69]4[N:68]=[C:67]([CH3:90])[CH:66]=2)[C@H:58]([NH2:91])[C:57]3=[O:92])=[O:54])[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:39]1([CH:45]([O:52][C:53]([C:55]2[N:56]3[C@H:59]([S:60][CH2:61][C:62]=2[CH2:63][S:64][C:65]2[N:70]4[N:71]=[C:72]([C:74]([O:76][CH:77]([C:84]5[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=5)[C:78]5[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=5)=[O:75])[N:73]=[C:69]4[N:68]=[C:67]([CH3:90])[CH:66]=2)[C@H:58]([NH:91][C:27](=[O:28])/[C:26](/[C:24]2[N:25]=[C:21]([NH:20][C:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[S:22][CH:23]=2)=[N:30]\[O:31][C:32]([C:34]2[O:35][CH:36]=[CH:37][CH:38]=2)=[O:33])[C:57]3=[O:92])=[O:54])[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](N)[C@H]3SC2)n2nc(C(=O)OC(c3ccccc3)c3ccccc3)nc2n1
Reactant: O=C(O)/C(=N\OC(=O)c1ccco1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(=O)c4ccco4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)n2nc(C(=O)OC(c3ccccc3)c3ccccc3)nc2n1
Temperature: -30 °C
Reaction time: 9 h
Yield: 73.8 %

Procedure:
The product obtained in Example 29 (3.1 g) and the product obtained in Example 15 (4.3 g) were dissolved in anhydrous dichloromethane (200 ml) with stirring, the faint yellow solution was cooled to -30° C., and a solution of dicyclohexylcarbodiimide (1.2 g) in anhydrous dichloromethane (30 ml) was dropwise added over a period of five minutes. The resulting faint yellow solution was allowed to stand at 0° C. for nine hours, the colorless crystals separated were removed by filtration, and the filtrate was washed with 50 ml of 1N aqueous citric acid, 50 ml of saturated sodium bicarbonate solution and 80 ml of saturated sodium chloride solution in that order and dried over anhydrous sodium sulfate. The dried filtrate was concentrated in vacuo, the yellow, viscous residue (6.8 g) was purified by silica gel column chromatography using ethyl acetate/n-hexane as eluent, yielding 5.3 g of the objective compound as faint yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH:18]1([C:21]2[C:26]([CH2:27][C:28](O)=[O:29])=[CH:25][N:24]=[C:23]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=3)[N:22]=2)[CH2:20][CH2:19]1.ClCC1C(C2CC2)=NC(C2C=CC(C(F)(F)F)=CC=2)=NC=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH:16][C:28](=[O:29])[CH2:27][C:26]2[C:21]([CH:18]3[CH2:19][CH2:20]3)=[N:22][C:23]([C:31]3[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=3)=[N:24][CH:25]=2)=[CH:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: O=C(O)Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)cc1
Agent: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)Cc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester [PCT Int. Appl. (2002), WO 2002/096895A1] was reacted with [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetic acid (prepared from 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) in analogy to the sequences described in examples 26D] and 26E]) to give 2-[4-({2-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetylamino}-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([OH:15])=O)[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:29][C@@H:30]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:31]([O:33][CH3:34])=[O:32].CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([NH:29][C@@H:30]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:31]([O:33][CH3:34])=[O:32])=[O:15])[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)C1(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H]1C[C@@H](NC(=O)OC(C)(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.4 %

Procedure:
To a stirred solution of (1S,3R)-3-(tert-butoxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (0.350 g, 1.44 mmol) in DCM (5 ml) EDCI (0.331 g, 1.73 mmol) and HOBt (0.234 g, 1.73 mmol) were added at 0° C. After 10 minutes, (S)-methyl 2-amino-4-methylpentanoate hydrochloride (0.780, 4.32 mmol) and Et3N (1.2 ml, 8.64 mmol) in DCM (5 ml) were added drop wise and the reaction mass was allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, sat. NaHCO3 solution, water, 1N HCl, water and saturated brine and the organic layer was concentrated under reduced pressure, the resulting crude was purified by silica gel column (100-200 mesh, elution 65% EtOAC in hexane) to afford the title compound as a solid. Wt: 0.210 g; Yield: 39.4%; 1H NMR (300 MHz, CDCl3): δ 5.56 (d, 1H), 4.75 (d, 1H, J=9 Hz), 4.70-4.60 (m, 1H), 3.88-3.79 (m, 1H), 3.73 (s, 3H), 2.48-2.25 (m, 2H), 2.14-1.99 (m, 1H), 1.70-1.48 (m, 3H), 1.43 (s, 9H), 1.32 (s, 3H), 0.95-0.91 (m, 9H); Mass: [M+Na]+ 393 (100%); IR (KBr, cm−1): 3344, 2960, 2873, 1743, 1689, 1664, 1531, 1458, 1366, 1271, 1174, 1050, 1028, 873, 827, 744; M.R: 100.5° C.-103.9° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:24])[C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:10]2)=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[CH:29]([Mg]Br)([CH3:31])[CH3:30]>C1COCC1.CN1CCCC1=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[C:15]([NH:14][C:11]1[CH:12]=[CH:13][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([CH:29]([CH3:31])[CH3:30])=[CH:3][C:4]=2[C:25]([F:28])([F:27])[F:26])[N:10]=1)=[O:24]
Reactant: O=C(Nc1ccn(Cc2ccc(Cl)cc2C(F)(F)F)n1)c1c(F)cccc1F
Reactant: CC(C)[Mg]Br
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CC(C)c1ccc(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
To a solution of N-(1-{[4-chloro-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-2,6-difluorobenzamide (for a preparation see Example 80)(100 mg, 0.241 mmol) in a mixture of THF (0.9 ml) and N-methyl-2-pyrrolidone (0.1 ml) was added iron(III) acetylacetonate (17 mg, 0.048 mmol, Aldrich). The resulting red solution was stirred for 10 min and then treated with a solution of 15% isopropylmagnesium bromide in THF (1.2 ml, 0.60 mmol, Fluorochem) at ambient temperature. The solution was stirred at room temperature under nitrogen overnight. The reaction mixture was quenched with methanol (1 ml) and the solvent removed in vacuo. The residue was dissolved in 1:1 MeOH:DMSO (2 ml) and purified by MDAP (Method B) on Sunfire C18 column using Acetonitrile-Water with a Formic acid modifier. The solvent was evaporated in vacuo to give the title compound as a yellow solid (26 mg); LCMS: (System 4) MH+=424, tRET=3.41 min.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:31])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:34][N:35]1[CH2:39][CH2:38][CH2:37][C@H:36]1[C:40]1[N:44]2[CH:45]=[C:46]([O:49][C@H:50]3[C:59]4[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=4)[C@@H:53]([NH2:60])[CH2:52][CH2:51]3)[CH:47]=[CH:48][C:43]2=[N:42][N:41]=1.CCN(C(C)C)C(C)C>C1COCC1.O>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:60][C@@H:53]2[C:54]3[C:59](=[CH:58][CH:57]=[CH:56][CH:55]=3)[C@H:50]([O:49][C:46]3[CH:47]=[CH:48][C:43]4[N:44]([C:40]([C@@H:36]5[CH2:37][CH2:38][CH2:39][N:35]5[CH3:34])=[N:41][N:42]=4)[CH:45]=3)[CH2:51][CH2:52]2)=[O:31])[N:8]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([O:23][Si:24]([C:27]([CH3:28])([CH3:30])[CH3:29])([CH3:25])[CH3:26])[CH:17]=2)[N:9]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cc(Cl)cc(O[Si](C)(C)C(C)(C)C)c2)n1
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cc(Cl)cc(O[Si](C)(C)C(C)(C)C)c4)c4ccccc43)cn12
Yield: 107.6 %

Procedure:
A solution of Intermediate 62d (193 mg, 0.35 mmol) and Intermediate E (115 mg, 0.32 mmol) and DIPEA (166 μL, 0.94 mmol) in THF (3.5 mL) was stirred at reflux for 24 h. The cooled reaction mixture was diluted with water and extracted with DCM. The combined organics were dried and concentrated in vacuo to give the title compound (265 mg, 99%). LCMS (Method 3): Rt 3.82 min, m/z 769 [MH+].
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.CO.[CH2:13](Cl)CCl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:13][O:9][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)=[O:10]
Reactant: Cc1cccc(C(=O)O)n1
Reactant: ClCCCl
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccc(C)n1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a suspension of 6-methyl-pyridine-2-carboxylic Acid (10 g, 72.9 mmol) in CH2Cl2 (200 mL) cooled to 0° C. is added MeOH (10 mL), 4-dimethylaminopyridine (11.6 g, 94.8 mmol), and EDC (18.2 g, 94.8 mmol). The mixture is stirred at RT for 6 h, washed with water and brine, and dried over Na2SO4. The mixture is filtered and concentrated in vacuo and the residue is chromatographed on silica gel (50% EtOAc/Hexanes) to yield the title compound, 9.66 g (92%), as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14]CC3C=CC=CC=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1>C(OCC)(=O)C.C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:22])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: COC(=O)Cn1ccc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)Cn1ccc2cc(O)ccc21
Reaction time: 16 h

Procedure:
Compound 72A (18.9 g, 64 mmol) was dissolved in 100 ml 1:1 ethyl acetate/ethanol. 200 mg 10% Pd/C was added followed by purging with hydrogen. The reaction was stirred vigorously under balloon pressure for 16 h. The reaction was filtered through Celite® and concentrated to an oil which was filtered through 0.45 uM filter to give a pale yellow oil which crystallized on standing. MS m/z 206 (M+1).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH:9]([CH3:11])[O:8][CH:7]([CH3:12])[CH2:6]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:33]>>[Cl:33][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH:9]([CH3:11])[O:8][CH:7]([CH3:12])[CH2:6]1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC1CN(CCCO)CC(C)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC1CN(CCCCl)CC(C)O1

Procedure:
This intermediate (2.3 g.) was prepared using the procedure described in Example 4c except using 5.0 g. (28 mmoles) of 4-(3-hydroxypropyl)-2,6-dimethylmorpholine and 9.5 g. (30 mmoles) of triphenylphosphine in 50 ml. of carbon tetrachloride and was isolated as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][N:13]=1.C(N(CC)CC)C.O>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:11][C:12]1[N:13]=[CH:14][C:15]([C:18]#[C:19][C:7]2[C:2]([Cl:1])=[N:3][C:4]([NH2:10])=[N:5][C:6]=2[CH3:9])=[CH:16][CH:17]=1
Reactant: C#Cc1ccc(N)nc1
Reactant: Cc1nc(N)nc(Cl)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(Cl)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 1.5 g (5.7 mmol) 4-chloro-5-iodo-6-methyl-pyrimidin-2-ylamine (GP3) and 1.7 g (15 mmol) 2-amino-5-ethynyl-pyridine (GP15) using 106 mg (0.56 mmol) CuI, 390 mg (0.56 mmol) PdCl2(PPh3)2 and 8 mL (55 mmol) triethylamine in 12 mL dry DMF. For the work-up water is added to the reaction mixture. The precipitate is collected, dried at 40° C. and re-crystallized from MeOH. Yield: 1.5 g (83%, approximately 80% pure).
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][O:9][C:10](=[O:33])[CH2:11][C:12]1[CH:17]=[C:16]([Br:18])[C:15]([O:19][C:20]2[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[C:23]([OH:29])=[C:22]([CH:30]=O)[CH:21]=2)=[C:14]([Br:32])[CH:13]=1>FC(F)(F)C(O)=O>[CH3:8][O:9][C:10](=[O:33])[CH2:11][C:12]1[CH:17]=[C:16]([Br:18])[C:15]([O:19][C:20]2[CH:21]=[C:22]([CH3:30])[C:23]([OH:29])=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:25]=2)=[C:14]([Br:32])[CH:13]=1
Reactant: COC(=O)Cc1cc(Br)c(Oc2cc(C=O)c(O)c(C(C)C)c2)c(Br)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1cc(Br)c(Oc2cc(C)c(O)c(C(C)C)c2)c(Br)c1
Reaction time: 12 h
Yield: 83.4 %

Procedure:
Triethylsilane was added to a mixture of methyl[3,5-dibromo-4-(3-formyl-4-hydroxy-5-isopropylphenoxy)phenyl]acetate (243 mg, 0.5 mmol) and trifluoroacetic acid (10 mL) at room temperature. After 12 hours stirring, the reaction mixture was concentrated via co-evaporated with toluene. The residue was purified on column (silica, gradient elution: n-heptane/ethyl acetate from 9:1 to 7:3) to give 197 mg (84%) of methyl[3,5-dibromo-4-(4-hydroxy-3-isopropyl-5-methylphenoxy)phenyl]acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][CH2:6]2.C(OC(=O)C)(=O)C.[N+:27]([O-])([OH:29])=[O:28].C(=O)(O)[O-].[Na+]>[N+](C)([O-])=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:27]([O-:29])=[O:28])[CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: C[N+](=O)[O-]
Product: COc1cc2c(cc1[N+](=O)[O-])CN(C(=O)OC(C)(C)C)CC2
Reaction time: 3 h

Procedure:
To a solution of the product of Example 53D (2.46 g, 9.35 mmol) in nitromethane (30 mL) at −10° C. was added acetic anhydride (5.7 g, 56.1 mmol) and concentrated nitric acid (0.88 g, 14 mmol). After stirring for 3 hours, the mixture was adjusted to pH 7 with aqueous sodium bicarbonate solution and extracted with dichloromethane (2×100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash chromatography eluting with 5:1 hexane:ethyl acetate to give the title compound. MS: 309 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:11][Si](C=[N+]=[N-])(C)C>CO.CCOCC>[CH3:1][C:2]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC1(C(=O)O)CCCCC1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C1(C)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Treat a solution of 1-methylcyclohexane carboxylic acid (7.11 g, 50.0 mmol) in MeOH (10 mL) and Et2O (40 mL) dropwise with trimethylsilyldiazomethane (2.0 M/hexanes; 26 mL, 52 mmol). Stir the reaction mixture at room temperature overnight, then concentrate under reduced pressure to yield the title compound as a clear, pale yellow oil (7.811 g, 50 mmol; 100%). MS(ES): m/z=156 [M+H].
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:26]=[CH2:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:31][C:32](=[CH2:37])[C:33]([O:35][CH3:36])=[O:34]>C1COCC1>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH2:31])[C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:26]=[CH2:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=Cc1ccccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Reactant: C=C(CBr)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=Cc1ccccc1-c1c(C2CCCCC2)c2ccc(C(=O)OC)cc2n1CC(=C)C(=O)OC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
Methyl 3-cyclohexyl-2-(2-vinylphenyl)-1H-indole-6-carboxylate (7, R2=H) 508 mg, 1.4 mmol) was dissolved in THF (5 mL) under N2 and cooled to 0° C. Sodium hydride (143 mg, 60% suspension in mineral oil, 3.57 mmol) was added and the mixture was stirred at 0° C. for 5 min, when a solution of methyl 2-(bromomethyl)acrylate (276 mg, 1.54 mmol) in THF (1.5 mL) was added dropwise. Stirring was continued for 30 min at 22° C. The reaction was quenched with a saturated aqueous solution of ammonium chloride (20 mL) and extracted with EtOAc (2×30 mL) and CH2Cl2 (30 mL). The organic extracts were combined and dried over sodium sulfate, filtered and concentrated. The residue was chromatographed on silica gel using hexane/ethyl acetate (0–20%) to afford the title compound as a pale yellow solid (641 mg, 99%). ESI-MS m/z 458 (MH+).
Reaction SMILES: [CH2:1]([N:8]([CH2:25][C@H:26]([O:39][CH:40]([O:42][CH2:43][CH3:44])[CH3:41])[CH2:27]OS(C1C=CC(C)=CC=1)(=O)=O)[C@@H:9]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1>[CH2:1]([N:8]1[CH2:25][C@H:26]([O:39][CH:40]([O:42][CH2:43][CH3:44])[CH3:41])[CH2:27][C@H:20]([C:21]([O:23][CH3:24])=[O:22])[C@H:9]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)O[C@H](COS(=O)(=O)c1ccc(C)cc1)CN(Cc1ccccc1)[C@@H](CC(=O)OC)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(C)O[C@@H]1C[C@H](C(=O)OC)[C@@H](C(=O)OCc2ccccc2)N(Cc2ccccc2)C1
Temperature: -78 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a solution of 1-benzyl 4-methyl (2S)-2-[benzyl((2S)-2-(1-ethoxyethoxy)-3-[(4-methylphenyl)sulfonyl]oxypropyl)amino]succinate (35.7 g, 0.0569 mol) in a mixture of tetrahydrofuran (95.5 mL, 1.18 mol) and toluene (490 mL, 4.6 mol) at −78 Celsius was added 1.00 M of Lithium hexamethyldisilazide in tetrahydrofuran (68.2 mL). The reaction was stirred at −78 Celsius overnight then allowed to warm up to −20 Celsius and stirred at −20 Celsius for 3 h. After quenched with aq. ammonium chloride, the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated to dry. The residue was applied on silica gel column, eluting with 0 to 20% EtOAc in hexane, to afford the product (18.1 g, 69.9%). MS (ESI): (M+H)+=456.2. The corresponding diastereoisomer was also obtained (4.52 g, 17.5%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]([NH:11][NH2:12])=[CH:9][C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][N:21]=[C:20]2[CH:26]=O.[CH:28]([C:30]1[N:34]([CH3:35])[CH:33]=[C:32]([C:36]#[N:37])[CH:31]=1)=O>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][N:21]=[C:20]2[CH2:26][N:12]1[C:28]([C:30]2[N:34]([CH3:35])[CH:33]=[C:32]([C:36]#[N:37])[CH:31]=2)=[C:9]2[C:10]([N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:6](=[O:15])[N:7]([CH3:14])[C:8]2=[O:13])=[N:11]1
Reactant: Cn1c(=O)cc(NN)n(CC2CC2)c1=O
Reactant: Cn1cc(C#N)cc1C=O
Reactant: O=Cc1n[nH]c2ccc(Cl)cc12
Product: Cn1cc(C#N)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1n[nH]c2ccc(Cl)cc12

Procedure:
This compound was made following the procedure described above, starting with 1-(cyclopropylmethyl)-6-hydrazino-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 5-chloro-1H-indazole-3-carbaldehyde, followed by 5-formyl-1-methyl-1H-pyrrole-3-carbonitrile. Mass: 489.10 (M+H).