Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]1([OH:18])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[O:12].C([Mg]Cl)(C)(C)C.Cl[P:26]([NH:36][C@H:37]([C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]/[CH:50]=[CH:51]\[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[O:40])[CH3:38])([O:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)=[O:27]>C1COCC1>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([O:28][P:26]([NH:36][C@@H:37]([CH3:38])[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]/[CH:50]=[CH:51]\[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[O:40])([O:9][CH2:8][C@H:5]2[O:4][C@@H:3]([N:10]3[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]3=[O:12])[C@:2]([CH3:1])([OH:18])[C@@H:6]2[OH:7])=[O:27])=[CH:34][CH:33]=1
Reactant: CCCCCCCC/C=C\CCCCCCCCOC(=O)[C@H](C)NP(=O)(Cl)Oc1ccc(Cl)cc1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=O
Agent: CC(C)(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCCOC(=O)[C@H](C)NP(=O)(OC[C@H]1O[C@@H](n2ccc(N)nc2=O)[C@](C)(O)[C@@H]1O)Oc1ccc(Cl)cc1
Temperature: -78 °C

Procedure:
Following the procedure described for Example 1, step 3, 2′-C-methylcytidine in THF (0.097 M) was cooled to −78° C., then tert-butylmagnesium chloride (as 1.0 M solution in THF, 2.2 eq.) was added followed by the addition of (9Z)-octadec-9-en-1-yl N-[chloro(4-chlorophenoxy)phosphoryl]-L-alaninate. The crude mixture was purified by column chromatography on silica gel (DCM:MeOH gradient from 90:10 to 80:20), the resulting solid was redissolved in DMSO and purified by RP-HPLC to afford the title compound as white powders. A 1:1.4* mixture of diastereoisomers at phosphorus was observed by 1H NMR.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:6][C:5]([CH2:29][C:30]#[N:31])([N:7]2[CH:11]=[C:10]([C:12]3[C:13]4[CH:20]=[CH:19][N:18](COCC[Si](C)(C)C)[C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[N:8]2)[CH2:4]1.C(O)(C(F)(F)F)=O>>[OH:1][CH2:2][CH:3]1[CH2:4][C:5]([CH2:29][C:30]#[N:31])([N:7]2[CH:11]=[C:10]([C:12]3[C:13]4[CH:20]=[CH:19][NH:18][C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[N:8]2)[CH2:6]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(CO)C4)c3)ncnc21
Solvent: O=C(O)C(F)(F)F
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CC(CO)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3-(hydroxymethyl)-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile (0.030 g, 0.000068 mol) was added 1.5 mL of TFA. The reaction was stirred at rt for 30 min, then evaporated to dryness. The crude mixture was dissolved in 1 mL of methanol and treated with 60 μL of ethylenediamine at rt for 5 h. The resulting mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired products as free bases. First peak retention time 0.766 min, LCMS calculated for C1-6H71N6O(M+H)+: 309.1; Found: 309.3. 1H NMR (400 MHz, DMSO-d6): δ 12.11(1H, br s), 8.67 (1H, s), 8.65 (1H, s), 8.37 (1H, s), 7.58 (1H, d, J=3.6), 7.02 (1H, d, J=3.6 Hz), 4.69 (1H, br s), 3.47 (2H, s), 3.41 (2H, br s), 2.53 (2H, m), 2.37 (2H, m) ppm. Second peak retention time 0.805 min, LCMS calculated for C16H17N6O(M+H)+: 309. 1; Found: 309.3. 1H NMR (400 MHz, DMSO-d6): δ 12.11(1H, br s), 8.80 (1H, s), 8.68 (1H, s), 8.40 (1H, s), 7.58 (1H, d, J=3.6 Hz), 7.07 (1H, d J=3.6 Hz), 4.78 (1H, br t, J=5.2 Hz), 3.47 (2H, br t, J=5.2 Hz), 3.36 (2H, s), 2.85 (2H, m), 2.29 (2H, m), ppm.
Reaction SMILES: O.[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=O)[C:6]2=[O:14].Cl.[NH2:16][NH:17][C:18]([NH2:20])=[O:19]>>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=[N:16][NH:17][C:18]([NH2:20])=[O:19])[C:6]2=[O:14]
Reactant: O=c1c(=O)c2ccc(O)cc2c1=O
Reactant: NNC(N)=O
Agent: Cl
Solvent: O
Product: NC(=O)NN=c1c(=O)c2ccc(O)cc2c1=O

Procedure:
5-hydroxyindan-1,2,3-trione, monohydrate, semicarbazide hydrochloride, reflux for 4 hours.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:21][C:20]=1[OH:34]>>[CH3:17][O:18][C:19]1[CH:24]=[C:23]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([NH:8][C@H:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:10])[N:7]=2)[CH:22]=[CH:21][C:20]=1[OH:34]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: C[C@H](Nc1cncc(Cl)n1)c1ccccc1
Product: COc1cc(-c2cncc(N[C@@H](C)c3ccccc3)n2)ccc1O
Yield: 69.8 %

Procedure:
In a procedure analogous to Example 2, reaction of 6-chloro-N-[(1S)-1-phenylethyl]pyrazin-2-amine (717.3 mg, 3.07 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (845 mg, 3.38 mmol) furnished the product (689 mg, 70%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:5]1[C:13](=[O:14])[NH:12][C:11]2[C:6]1=[N:7][C:8]([C:15]1[CH:16]=[N:17][N:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:19]=13)=[N:9][CH:10]=2)[CH3:4].[CH3:26]N(C=O)C.CI>>[OH:1][CH2:2][C@H:3]([N:5]1[C:13](=[O:14])[N:12]([CH3:26])[C:11]2[C:6]1=[N:7][C:8]([C:15]1[CH:16]=[N:17][N:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:19]=13)=[N:9][CH:10]=2)[CH3:4]
Reactant: C[C@H](CO)n1c(=O)[nH]c2cnc(-c3cnn4ccc(C#N)cc34)nc21
Reactant: CN(C)C=O
Solvent: CI
Product: C[C@H](CO)n1c(=O)n(C)c2cnc(-c3cnn4ccc(C#N)cc34)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To a solution of example 28 (20 mg, 0.06 mmol) in AcN (2 mL) and DMF (0.5 mL) silver (I) oxide (23 mg, 0.12 mmol) and methyl iodide (0.005 mL, 0.09 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through a plug of Celite® and the solvent was evaporated under reduced pressure. The crude residue was cromatographed on a silica gel flash system (ISCO Combiflash) using CH2Cl2/MeOH mixtures of increasing polarity as eluent to afford 6 mg of the desired product (29% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH3:23][N:24]1[CH2:29][CH2:28][C:27]2([C:41]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][CH2:37][NH:38][C:39]=4[CH:40]=3)[O:31][CH2:30]2)[CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:29][CH2:28][C:27]2([C:41]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][CH2:37][N:38]([C:20]([C:17]5[CH:16]=[CH:15][C:14]([C:3]6[CH:4]=[CH:5][C:6]([C:8]7[O:9][C:10]([CH3:13])=[N:11][N:12]=7)=[CH:7][C:2]=6[CH3:1])=[CH:19][CH:18]=5)=[O:21])[C:39]=4[CH:40]=3)[O:31][CH2:30]2)[CH2:26][CH2:25]1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCCC3
Reactant: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)o1
Product: Cc1nnc(-c2ccc(-c3ccc(C(=O)N4CCCc5cc6c(cc54)C4(CCN(C)CC4)CO6)cc3)c(C)c2)o1

Procedure:
The title compound was prepared from 2'-methyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-carboxylic acid (D11) and 2,3,5,6,7,8-hexahydro-1'-methylspiro[furo[2,3-g]quinoline-3,4'-piperidine] (D10) using a similar procedure to Example 1 as a white solid (62%). This was converted to its oxalate salt which was obtained as a white solid (mp 187-188° C.) and hydrochloride salt (mp 176-180° C.).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3].[CH2:20]([N:22]([CH2:32][CH3:33])[CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:21].C(OC(C)C)(C)C>>[CH2:32]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7](=[O:15])[C:6]3=[CH:16][S:17][C:18]([CH3:19])=[C:5]23)=[O:3])[CH2:27]1)[CH3:33]
Reactant: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O
Reactant: CCN(CC)CCCC1CCCNC1
Solvent: CC(C)OC(C)C
Product: CCN(CC)CCCC1CCCN(C(=O)N2c3ccccc3NC(=O)c3csc(C)c32)C1
Yield: 34 %

Procedure:
Prepared analogously to Example 4 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 3-[3-(diethylamino)propyl]piperidine in a yield of 34% of theory. Colourless crystals, m.p. 136.0°-137.5° C. (diisopropylether).
Reaction SMILES: [C:1]([CH2:4][N:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:6])([OH:3])=O.Cl.[CH3:18][NH2:19]>>[CH3:18][NH:19][C:1]([CH2:4][N:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:6])=[O:3]
Reactant: CN(CC(=O)O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CN
Agent: Cl
Product: CNC(=O)CN(C)Cc1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-[(N-carboxymethyl-N-methyl-amino)-methyl]-nitrobenzene and methylamine hydrochloride
Reaction SMILES: Cl[CH2:2][CH:3]1[S:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:5]([CH3:12])([CH3:11])[S:4]1.[OH-].[Na+].[CH3:15][NH2:16]>>[CH3:11][C:5]1([CH3:12])[CH2:6][C:7]([CH3:10])([CH3:9])[S:8][CH:3]([CH2:2][NH:16][CH3:15])[S:4]1
Reactant: CN
Reactant: CC1(C)CC(C)(C)SC(CCl)S1
Agent: [Na+]
Agent: [OH-]
Product: CNCC1SC(C)(C)CC(C)(C)S1
Temperature: 100 °C

Procedure:
2-Chloromethyl-4,4,6,6-tetramethyl-1,3-dithiane (60 grams) and 40% aqueous methylamine (160 ml) are charged into a pressure vessel and heated, with agitation, at a temperature of about 100° C. for a period of about 16 hours under autogeneous pressure. At the end of this period, the reaction mixture is cooled to room temperature and 16 grams of sodium hydroxide are added. The resulting mixture is extracted with methylene chloride. The extract is dried, then stripped of solvent to yield the desired product N-(4,4,6,6-tetramethyl-1,3-dithian-2-ylmethyl)methylamine.
Reaction SMILES: [H-].[K+].Br[C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.C([Li])(C)(C)C.[CH3:18][S:19]SC>O1CCCC1.[Cl-].[NH4+]>[CH3:18][S:19][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CSSC
Agent: [Cl-]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CSc1ccc2cc[nH]c2c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 67.3 %

Procedure:
To a stirred suspension of potassium hydride (30% dispersion in mineral oil, 0.68 g, 5.10 mmol) in dry tetrahydrofuran (20 mL) at 0° C., under Ar, was added a solution of 6-bromoindole (1.0 g, 5.1 mmol) in tetrahydrofuran (10 mL). After 15 mins, the solution was cooled to −78° C. and tert-butyllithium (1.7 M, 6.0 mL, 10 mmol) was added dropwise. The mixture was stirred for a further 15 mins and then dimethyl disulphide (0.92 mL, 10.2 mmol) was added dropwise. The solution was warmned gradually to room temperature, then diluted carefully with saturated ammonium chloride solution (20 mL). The mixture was extracted with ether (2×50 mL). The combined organic extracts were dried (magnesium sulfate), concentrated in vacuo and purified by column chromatography [SiO2; heptane-dichloromethane (1:1)] to give the product as a pale-yellow solid (0.56 g, 68%): mp. 91-92° C.; NMR δH (400 MHz, CDCl3) 2.51 (3H, s), 6.49 (1H, m), 7.09-7.16 (2H, m), 7.35 (1H, s), 7.54 (1H, d, J 8.2 Hz) and 8.09 (1H, br s); IR (Nujol)νmax/cm−1 3388, 2925, 1459, 1311, 1098, 810, 717 and 527.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][CH3:12])(=[O:10])[CH2:8][CH3:9].[N:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[C:19](OC)=[O:20].[Cl-].[NH4+]>O1CCCC1.O>[CH3:9][CH:8]([C:19]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][N:13]=1)=[O:20])[C:7]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cnccn1
Reactant: CCC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C)C(=O)c1cnccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
1.2 L of tetrahydrofuran and 87.8 g (0.78 mole) of potassium t-butoxide were added to a reactor and cooled to 0° C. 71.5 mL (0.74 mol) of methyl propionate was dropwise added to the reactor and stirred at 0° C. for 30 minutes. 60 g (0.434 mole) of the methyl pyrazine-2-carboxylate of Example 1 dissolved in 500 mL of tetrahydrofuran was dropwise added to the reactor for 30 minutes and stirred at a temperature of 20 to 25° C. for 3 hours. 0.5 L of distilled water and 0.5 L of saturated ammonium chloride solution were added to the reaction solution and stirred for 30 minutes. The resultant reaction solution was concentrated to a volume of 1.0 L and then extracted with 1.0 L of methylenechloride. The resultant extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to give 75.0 g of the titled compound as a dark brown viscous oil (yield 89.0%).
Reaction SMILES: [C:1]([C:9]1[N:10]=[CH:11][C:12]2[NH:13][C:14]3[C:19]([C:20]=2[C:21]=1[CH2:22][O:23][CH3:24])=[CH:18][C:17]([O:25][Si](C(C)C)(C(C)C)C(C)C)=[CH:16][CH:15]=3)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1>[C:1]([C:9]1[N:10]=[CH:11][C:12]2[NH:13][C:14]3[C:19]([C:20]=2[C:21]=1[CH2:22][O:23][CH3:24])=[CH:18][C:17]([OH:25])=[CH:16][CH:15]=3)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCc1c(C(=O)c2ccccc2)ncc2[nH]c3ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc3c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCc1c(C(=O)c2ccccc2)ncc2[nH]c3ccc(O)cc3c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
530 mg of 3-benzoyl-6-triisopropylsilyloxy-4-methoxymethyl-beta-carboline was dissolved in 7.5 ml of absolute tetrahydrofuran and stirred for 0.5 hour under argon at room temperature after adding 1.1 ml of a 1.1 molar tetrabutylammonium fluoride solution in tetrahydrofuran. After adding ethyl acetate, the organic phase was washed with saturated common salt solution, dried and concentrated by evaporation. 315 mg of the title compound was obtained after absorptive precipitation with ethyl acetate/petroleum ether, melting point 258° C.
Reaction SMILES: C(S[C:4](=[N:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:5]([CH3:7])[CH3:6])C.[C:15]([NH:23][NH2:24])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)CCC>[CH:5]([C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:23][N:24]=1)([CH3:7])[CH3:6]
Reactant: NNC(=O)c1ccccc1
Reactant: CCSC(=Nc1ccccc1)C(C)C
Solvent: CCCCO
Product: CC(C)c1nnc(-c2ccccc2)n1-c1ccccc1
Temperature: 130 °C
Reaction time: 7 h
Yield: 24 %

Procedure:
First, 6.1 g of N-[1-(ethylsulfanyl)isobutylidene]aniline, 3.4 g of benzoylhydrazine, and 30 mL of 1-butanol were put in a 200 mL recovery flask, and heated and stirred at 130° C. for 7 hours to be reacted. After the reaction, 1-butanol was distilled off under a reduced pressure to give an oily substance. This oily substance was purified by silica gel column chromatography. As developing solvents, first, dichloromethane was used, and then ethyl acetate was used. The resulting fraction was concentrated to give a white solid. The given solid was recrystallized from a mixed solvent of ethanol and hexane, so that 1.6 g of 3-isopropyl-4,5-diphenyl-4H-1,2,4-triazole was prepared as a white solid with a yield of 24%. The synthetic scheme of Step 1 is shown by (a-8).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[CH:24]([C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1B(O)O)=[O:25].O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>COCCOC.O.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>[CH:24]([C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1)=[O:25]
Reactant: COc1ccc(B(O)O)c(C=O)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CC3)c(C=O)c1
Yield: 40.5 %

Procedure:
To a solution of tert-butyl(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (0.600 g, 1.59 mmol) in DME (35 mL) was added 2-formyl-4-methoxybenzeneboronic acid (0.344 g, 1.91 mmol), tetrakis(triphenylphosphine)palladium(0) (0.110 g), barium hydroxide octahydrate (0.753 g, 2.39 mmol), and H2O (10 mL). The combined mixture was refluxed for 20 h. Once at room temperature, the mixture was taken up in H2O (300 mL) and extracted with EtOAc (3×100 mL). The combined extracts were dried over MgSO4 and stripped of solvent under reduced pressure. Purification by normal phase HPLC using 25% EtOAc in hexanes afforded 0.280 g (41%) of tert-butyl (6aS,10aR)-2-(2-formyl-4-methoxyphenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[O:14][CH2:15][C:16]([O:18]CC)=[O:17].[OH-].[Na+].Cl>CO>[C:16]([CH2:15][O:14][C:5]1[CH:6]=[C:7]([C:10]([F:11])([F:13])[F:12])[CH:8]=[CH:9][C:4]=1[C:3]([OH:21])=[O:2])([OH:18])=[O:17]
Reactant: CCOC(=O)COc1cc(C(F)(F)F)ccc1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1cc(C(F)(F)F)ccc1C(=O)O

Procedure:
A mixture of 2-Ethoxycarbonylmethoxy-4-trifluoromethyl-benzoic acid methyl ester (34 g), 10% NaOH (132.5 g) and methanol (45 ml) were mixed in one necked round flask. Resulting mixture was mixed at room temperature for 5 hrs. Acidified to pH 2 by 1 N HCl. Evaporated in vacuo. Filtrated and washed with water to obtain the product 5a.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]([N:27]1[C@H:30]([C@H:31]([C:33]([S:35][CH3:36])=S)[CH3:32])[C@@H:29]([C@H:37]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH3:38])[C:28]1=[O:47])=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:6])[CH:2]=[CH2:3]>C1(C)C=CC=CC=1>[Si:40]([O:39][C@@H:37]([C@H:29]1[C:28](=[O:47])[N:27]2[C@@H:30]1[C@@H:31]([CH3:32])[C:33]([S:35][CH3:36])=[C:7]2[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH3:38])([C:43]([CH3:45])([CH3:44])[CH3:46])([CH3:41])[CH3:42]
Reactant: C=CCOC(=O)C(N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](C)C(=S)SC)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=CCOC(=O)C1=C(SC)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Yield: 86.5 %

Procedure:
A solution of (3S,4S)-1-[1-(allyloxycarbonyl)-1-(triphenylphosphoranediyl)methyl]-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-{(methylthio)thiocarbonyl}ethyl]-2-oxoazetidine (325 mg) in toluene (3 ml) was heated under reflux for 4.5 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography [ethyl acetate-hexane (1:3, V/V)] to afford allyl (4R,5S,6S)-6-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-methyl-3-methylthio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (164 mg).
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1Cl.[C:10]([O:14][C:15](=[O:28])[NH:16][CH2:17][C:18]1([CH2:24][C:25](=O)[NH2:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([CH3:13])([CH3:12])[CH3:11].CCCCCC.CCOC(C)=O>CN(C=O)C>[C:10]([O:14][C:15](=[O:28])[NH:16][CH2:17][C:18]1([CH2:24][C:25]#[N:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCC1(CC(N)=O)CCCCC1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC1(CC#N)CCCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.9 %

Procedure:
Cyanuric chloride (39.5 g, 0.214 mol) was added to (1-carbamoylmethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (3) (116 g, 0.429 mol) in 400 mL DMF. An ice-water bath was used to moderate the exotherm, and the reaction mixture was stirred at room temperature for 1.5 hours. The mixture was poured into ice-water containing 120 g (1.43 mol) NaHCO3 and was extracted 4×EtOAc. The extracts were washed 1×water, 2× brine and dried over Na2SO4. Evaporation yielded an oil which was taken up in 3:1 hexane/EtOAc and filtered through silica gel. Evaporation yielded white crystals (86.5 g, 80%); mp 54-58° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[C@@H:10]([O:27][CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)[CH2:9]1)=O)(C)(C)C.[ClH:39]>>[ClH:39].[CH:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:37]=[CH:38][C:29]=1[CH2:28][O:27][C@@H:10]1[C@@H:11]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2cccc(-c3cccc(O)c3)c2)[C@@H](OCc2ccc3ccccc3c2)C1
Agent: Cl
Product: Oc1cccc(-c2cccc([C@H]3CCNC[C@@H]3OCc3ccc4ccccc4c3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (3R*,4R*)-4-(3′-hydroxy-biphenyl-3-yl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid t-butyl ester (96.5 mg, 0.19 mmol) and HCl (5M in 2-propanol, 2 mL, 10 mmol) is stirred for 1 h at RT. The reaction mixture is evaporated in vacuo and the residue purified using preparative HPLC (H2O/CH3CN). The combined pure fractions are treated with solid K2CO3 and CH3CN is removed in vacuo. The aqueous layer is extracted twice with CH2Cl2. The combined organic extracts are dried (Na2SO4) and evaporated in vacuo. The residue is stirred with HCl (4M in dioxane, 1 mL, 8 mmol) for 30 min. at RT. Evaporation of the solvent affords 3′-[(3R*,4R*)-3-(naphthalen-2-ylmethoxy)-piperidin-4-yl]-biphenyl-3-ol hydrochloride as a colourless white solid: MS 410.5 [M+H]+; Rf 0.11 (DCM/MeOH 9:1).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:6][CH2:5][CH2:4][NH:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C=O)C>[O:1]=[C:2]1[CH:7]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: O=C1NCCCC1CCc1ccc2cccnc2n1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCCC(CCc2ccc3cccnc3n2)C1=O
Reaction time: 0.5 h

Procedure:
A solution of 1-5 (0.28 g, 1.1 mmol) and DMF (10 mL) at -15° C. was treated with NaN(TMS)2 (1.2 mL, 1.2 mmol, 1M in hexanes) to give a red solution. After 30 min, the red solution was treated with ethyl bromoacetate (128 μL, 1.2 mmol), followed by continued stirring for 1 h. The reaction mixture was then quenched with sat. NH4Cl and then extracted with EtOAc (3×). The combined extracts were washed with brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 10% CH3OH/EtOAc) gave 1-6 as a yellow gum.