Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24].[CH:27]1([O:32][C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1>>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:39]([C:36]3[CH:35]=[CH:34][C:33]([O:32][CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:38][CH:37]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:25])=[O:24]
Reactant: Nc1ccc(OC2CCCC2)cc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Product: O=C1N(c2ccc(OC3CCCC3)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
Light brown crystalline solid. MS (ESI): 489.3 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-chlorobenzenesulfonyl chloride and 4-cyclopentyloxy-phenylamine (synthesis: Fortin et al.; Bioorganic and Medicinal Chemistry; 16; 2008; 7477).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24])=[O:19].N1C=CC=CC=1.[C:32](Cl)(=[O:54])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]>C(Cl)(Cl)Cl>[C:32]([CH:21]([CH:22]([CH2:23][OH:24])[OH:25])[O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])(=[O:54])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)C(OC(=O)CCCCCCCCCCCCCCCCC)C(O)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 g (279.3 mmol) of 1-monostearin is dissolved in 750 ml of warm chloroform (Note: the chloroform is washed three times with distilled water, dried over MgSO4, and filtered before use). 24.8 ml (307.2 mmol) of pyridine is then added to the solution. (Note: the pyridine is dried over 3A molecular sieves, manufactured by Linde, before use). 110 g (307.2 mmol) of behenoyl chloride is dissolved in 250 ml of washed chloroform and added dropwise to the well stirred solution. The reaction is gently warmed with a heating mantel and is stirred overnight (16 hrs.) Upon completion of the reaction, the solvent is removed under reduced pressure. The remaining solid/oil is transferred to a 2 liter beaker and 1 liter of acetone/ethanol 50:50 is added. The mixture is heated to boiling and the remaining solids filtered. The filtrate is then placed in a 50° C. incubator overnight and filtered. The filtrate is cooled to room temperature and any solid diacylglyceride is removed by suction filtration.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.[N:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.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>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:18]2[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=2)=[CH:3][C:4]=1[O:11][CH:12]([CH3:14])[CH3:13])([O-:10])=[O:9]
Reactant: CC(C)Oc1cc(Br)ccc1[N+](=O)[O-]
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)Oc1cc(-c2ccncc2)ccc1[N+](=O)[O-]
Yield: 74 %

Procedure:
A mixture of 10.0 g of 4-bromo-1-nitro-2-(propan-2-yloxy)benzene, 5.78 g of 4-pyridylboronic acid, 12.2 g of sodium carbonate and 1.0 g of bis(triphenylphosphine)dichloropalladium, in 200 ml of dioxane and 35 ml of water, is heated at 110° C. (bath) for 9 h. The mixture is diluted with ethyl acetate and water. The aqueous phase is extracted twice with ethyl acetate and then with dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated under vacuum. The residue is purified on 330 g of silica, elution being carried out with ethyl acetate/heptane (1/1 to 4/1), so as to obtain 7.35 g of 4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridine in the form of a pale yellow solid.
Reaction SMILES: [NH2:1][C@@:2]12[C@H:19]3[C@@H:10]([C@:11]4([CH3:21])[C@H:16]([CH2:17][CH2:18]3)[CH2:15][C@@H:14]([OH:20])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C@:6]1([CH3:7])[C@@H:5]([C:22]([O:24][CH3:25])=[O:23])[CH2:4][CH2:3]2.[C:26](N1C=CN=C1)(N1C=CN=C1)=[O:27].[NH2:38][C@@H:39]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:40][OH:41].[ClH:49]>C(Cl)Cl>[ClH:49].[NH2:1][C@@:2]12[C@H:19]3[C@@H:10]([C@:11]4([CH3:21])[C@H:16]([CH2:17][CH2:18]3)[CH2:15][C@@H:14]([O:20][C:26]([NH:38][CH:39]([CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:40][OH:41])=[O:27])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C@:6]1([CH3:7])[C@@H:5]([C:22]([O:24][CH3:25])=[O:23])[CH2:4][CH2:3]2
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: COC(=O)[C@H]1CC[C@]2(N)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@]2(N)[C@@H]3CC[C@@H]4C[C@@H](OC(=O)NC(CO)Cc5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 1.4 g (0.004 mole) of (3β,5β,14β,17β)-14-Amino-3-hydroxyandrostane-17-carboxylic Acid, Methyl Ester, prepared according to the procedure described in U.S. Pat. No. 4,885,280, incorporated by reference herein, in 40 ml of CH2Cl2 under N2 and stirring, is added 0.72 g (0.0044 mole) of 1,1'-carbonyldiimidazole. The solution is allowed to stir for 2 days and then 1.8 g (0.012 mole) of (S)-2-amino-3-phenyl-1-propanol is added. No product appeared to form (TLC) after 3 days of stirring and an additional 0.6 g (0.004 mole) of the amine is added and the solution is heated at boiling for 2 days. After cooling to ambient temperature, the solution is allowed to stir further for an additional 10 days. The solution is concentrated at reduced pressure and the residue is taken up with fresh CH2Cl2. The solution is washed with water until the washing is neutral. After drying over MgSO4, CH2Cl2 is removed under reduced pressure and the residual solid is purified by flash chromatography (5% MeOH/CH2Cl2, NH4OH). The fractions are combined and concentrated to yield the free base which is treated with ethanolic HCl to yield (3β(S),5β,14β,17β)-14-Amino-3-[[[[2-hydroxy-1-(phenylmethyl)ethyl]amino]carbonyl]oxy]androstane-17-carboxylic Acid, Methyl Ester Hydrochloride Final Product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C@H]5COCCN5)[CH:27]=4)[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17]2)[CH:5]=[C:6]([F:15])[C:7]=1[CH2:8][N:9]1[CH2:14]CO[CH2:11][CH2:10]1.[CH2:38]=[O:39].[CH3:40][OH:41]>C([BH3-])#N.[Na+]>[F:15][C:6]1[CH:5]=[C:4]([N:16]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:27]=[CH:28][C:29]([C@H:8]5[CH2:7][O:41][CH2:40][CH2:10][N:9]5[CH3:14])=[CH:30][CH:31]=4)[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17]2)[CH:3]=[C:2]([F:1])[C:7]=1[CH2:8][N:9]1[CH2:10][CH2:11][O:39][CH2:38][CH2:14]1
Reactant: C=O
Reactant: Fc1cc(-n2ccc3cnc(Nc4cccc([C@H]5COCCN5)c4)nc32)cc(F)c1CN1CCOCC1
Reactant: CO
Agent: [BH3-]C#N
Agent: [Na+]
Product: CN1CCOC[C@@H]1c1ccc(Nc2ncc3ccn(-c4cc(F)c(CN5CCOCC5)c(F)c4)c3n2)cc1

Procedure:
The compound is obtained by treating [7-(3,5-difluoro-4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-((S)-3-morpholin-3-yl-phenyl)-amine (Example 507) with formaldehyde in methanol and sodium cyanoborohydride at rt to 60° C. HPLC: tR=0.61 min (Method G); MS-ES: (M+H)+=521
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[NH2:11][CH2:12][CH2:13][OH:14].CC(C)([O-])C.[K+].O1CCCC1.[ClH:26].C(O)(C)C>CC1CCCO1>[ClH:26].[NH2:11][CH2:12][CH2:13][O:14][C:4]1[CH:3]=[C:2]([Br:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: NCCO
Reactant: N#Cc1ccc(Br)cc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC1CCCO1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: N#Cc1ccc(Br)cc1OCCN
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
Alternatively, reaction of 11 with 2-aminoethanol and potassium tert-butoxide displaces fluorine to give 2-(2-aminoethoxy)-4-bromobenzonitrile hydrochloride 37. Ring closure of 37 with trimethylaluminum gave 33 (Scheme 14). A solution of 11 (10 g, 50 mmol) and 2-aminoethanol (3.1 mL, 50.8 mmol) in 2-methyltetrahydrofuran (80 mL) was cooled to 0° C. and a solution of 1M potassium tert-butoxide in tetrahydrofuran (55 mL, 55 mmol) was slowly added while maintaining the solution temperature below 5° C. The reaction was stirred at 0° C. for 30 min until judged complete by HPLC at which point it was warmed to 25° C. A solution of 0.5M HCl in isopropanol (100 mL, 50 mmol) was added and the desired HCl salt 3 crystallized directly from the solution. The solid was collected by filtration and dried under vacuum with a nitrogen bleed to give 2-(2-aminoethoxy)-4-bromobenzonitrile hydrochloride 37 as a white solid. (12.1 g, 87% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH2:15](N)[CH3:16]>C1COCC1>[CH2:15]([NH:1][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])[CH3:16]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CCN
Solvent: C1CCOC1
Product: CCNc1cccc([N+](=O)[O-])c1C#N
Yield: 88 %

Procedure:
Prepared as in Example 90c from 2,6-dinitrobenzonitrile and a 2M ethylamine solution in THF in 88% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.13 (t, J=7.6 Hz, 3H), 3.26-3.33 (m, 2H), 6.59 (bt, J=5.2 Hz, NH), 7.22 (d, J=9.2 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.60 (t, J=8.4 Hz, 1H). MS 162 (M-Et).
Reaction SMILES: C1(SC2C=CC=CC=2)C=CC=CC=1.C[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([O:23]C)[CH:22]=1)N.[I:25]I.C(N(CC)CC)C.C(OC(=O)C)(=O)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[OH:15][C:16]1[CH:17]=[C:18]([I:25])[CH:20]=[C:21]([OH:23])[CH:22]=1
Reactant: II
Reactant: COc1cc(N)cc(OC)c1
Agent: CN(C)c1ccncc1
Agent: c1ccc(Sc2ccccc2)cc1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: Oc1cc(O)cc(I)c1
Reaction time: 16 h

Procedure:
Preparation of substituted iodobenzene 39, conversion of 38 to the corresponding thiol, and formation of diphenylsulfide 40: 3,5-Dihydroxyiodobenzene was prepared from 3,5-dimethoxyaniline (Aldrich) by diazotization and iodine introduction followed by demethylation of the methoxy groups all under standard conditions. This material (3.78 g 16.0 mmol) was dissolved in CH2Cl2 (30 mL). Triethylamine (11.15 mL, 80 mmol), acetic anhydride (4.55 mL, 48 mmol) and DMAP (390 mg, 3.2 mmol) were added and the reaction stirred for 16 h. The reaction was evaporated to dryness, and passed through a plug of silica gel eluting with 4:1 hexane:ethyl acetate to afford the desired product. This material (12.8 mmol) was dissolved in a mix of ethanol (32 mL) and benzene (16 mL). Potassium hydroxide (0.72 g, 12.8 mmol) was dissolved in 8 mL ethanol and added over 30 min. After 30 min the reaction was diluted with ether and washed with 0.5N H2SO4, sat NaHCO3, sat NaCl, dried over Na2SO4, and evaporated. The product was recrystallized from toluene to afford 86% yield of the monoacetate which was dissolved in CH2Cl2 (50 mL) and triethylamine (3.45 mL, 24.8 mmol), DMAP (0.3 g, 2.5 mmol) and benzoyl chloride (1.8 mL, 15.5 mmol) was added. The reaction was complete in 10 min then diluted with CH2Cl2 and washed with sat NH4Cl, sat NaHCO3, and sat NaCl. The solution was dried (Na2SO4) and evaporated. Purification was accomplished via silica chromatography 19:1 hexane:ethyl acetate to afford 4.4 g (95% yield) of desired product 39.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[SH:13].CS(O[CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[S:13][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1
Reactant: O=c1[nH]cc(S)c2cc(Br)ccc12
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(Sc2c[nH]c(=O)c3ccc(Br)cc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.2 %

Procedure:
To 6-bromo-4-sulfanylisoquinolin-1(2H)-one (Example 58a, 0.62 g) was added tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (0.676 g) and potassium carbonate (0.769 g). After thoroughly flushing with nitrogen, DMF (6 mL) was added and the reaction stirred at room temperature for 30 min. Further DMF (9 mL) was added, and the reaction stirred at 40° C. for 1 h. Further DMF (10 mL) was added and the reaction stirred at 50° C. for 16 h. The reaction was partitioned between ethyl acetate and water. The aqueous was extracted with further ethyl acetate (3×) and the combined organics were washed with saturated brine (3×100 mL). The organics were dried (MgSO4), filtered and evaporated under reduced pressure. DCM was added, and the resulting suspension was filtered. The filtrate was concentrated under reduced pressure, dissolved in the minimum volume of DCM and purified (SiO2 chromatography, elution with 50%-100% diethyl ether/isohexane followed by ethyl acetate flush) to afford the subtitle compound (0.353 g).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[Si:10]([CH3:13])([CH3:12])[CH3:11].[Li]CCCC.CON(C)[C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1)=[O:23]>C1COCC1.CCCCCC>[F:8][C:7]1[C:2]([F:1])=[C:3]([Si:10]([CH3:12])([CH3:11])[CH3:13])[CH:4]=[C:5]([CH3:9])[C:6]=1[C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1)=[O:23]
Reactant: Cc1cc(F)c(F)c([Si](C)(C)C)c1
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc([Si](C)(C)C)c(F)c(F)c1C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of (2,3-difluoro-5-methylphenyl)trimethylsilane (10 g, 0.05 mol) in anhydrous THF (100 mL) at −78° C., under nitrogen, was added dropwise a solution of 2.5 M n-BuLi in hexane (20 mL). After stirring for 1 hr at −78° C., a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (13.6 g, 0.05 mol) in anhydrous THF (60 mL) was added dropwise. After addition, the reaction mixture was allowed to warm to rt and stirred for 2 h. The mixture was quenched with saturated NH4Cl solution (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give (R)-tert-butyl 3-(2,3-difluoro-6-methyl-4-(trimethylsilyl)benzoyl)piperidine-1-carboxylate, which was purified by column chromatography on silica gel elating with hexane (2 g, 10%). 1H NMR δ 6.90 (m, 2H), 4.00 (m, 4H), 2.20 (s, 3H), 1.47 (s, 9H), 1.30 (m, 4H), 0.35 (s, 9H).
Reaction SMILES: I.[NH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:8]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[C:15](=[O:27])[O:14][N:13]=2)=[N:9][O:10][N:11]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[O:27]=[C:15]1[O:14][N:13]=[C:12]([C:8]2[C:7]([NH:6][CH2:5][CH2:4][CH2:3][NH:2][S:36]([CH3:35])(=[O:38])=[O:37])=[N:11][O:10][N:9]=2)[N:16]1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCCNc1nonc1-c1noc(=O)n1-c1cccc(C(F)(F)F)c1
Agent: I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCCCNc1nonc1-c1noc(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-{4-[(3-aminopropyl)amino]-1,2,5-oxadiazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5(4H)-one hydroiodide (from Example 15, Step F; 25 mg, 50 μmol) in dichloromethane (1 mL) was treated with triethylamine (17 μL, 0.12 mmol) and methanesulfonyl chloride (6 μL, 70 μmol) and stirred at 25° C. for 2 h. The reaction mixture was concentrated to give the intermediate, N-{3-[(4-{5-oxo-4-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1,2,4-oxadiazol-3-yl}-1,2,5-oxadiazol-3-yl)amino]propyl}methanesulfonamide, as a crude residue which was used without further purification. A solution of the crude intermediate in methanol (1 mL) was treated with 2 N NaOH (0.25 mL, 0.5 mmol) and stirred at 25° C. for 30 min. The reaction mixture was treated with acetic acid (50 μL, 0.9 mmol), filtered and purified by preparative LCMS to give the desired product (13 mg, 65%) as a solid. LCMS for C14H18F3N6O4S (M+H)+: m/z=423.1. 1H NMR (400 MHz, DMSO-d6): δ 11.6 (s, 1H), 9.11 (s, 1H), 7.37 (dd, J=8.0, 8.0 Hz, 1H), 7.20 (d, J=7.8 Hz, 1H), 7.07-7.01 (m, 2H), 6.96 (d, J=8.0 Hz, 1H), 6.20 (t, J=5.9 Hz, 1H), 3.27-3.22 (m, 2H), 2.99-2.94 (m, 2H), 2.87 (s, 3H), 1.78-1.71 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]([N:15]([CH3:17])[CH3:16])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[NH:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]([CH2:45][C:46]([OH:48])=[O:47])=[CH:37]1.[Cl:49][Si](C)(C)C>CC(=O)CC.CC(C)=O.CO>[ClH:49].[CH3:16][N:15]([CH3:17])[C:6]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:46](=[O:47])[CH2:45][C:38]2[C:39]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[NH:36][CH:37]=2)[CH2:8][CH2:7]1.[CH3:16][N:15]([CH3:17])[C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:46](=[O:48])[CH2:45][C:38]2[C:39]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[NH:36][CH:37]=2)[CH2:4][CH2:5]1
Reactant: CN(C)C1(c2ccccc2)CCC(CN)CC1
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCC(C)=O
Solvent: CC(C)=O
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)Cc2c[nH]c3ccccc23)CC1
Product: Cl
Reaction time: 24 h

Procedure:
The non-polar diastereoisomer of (4-aminomethyl-1-phenylcyclohexyl)dimethylamine (239 mg, 1.03 mmol.) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (428 mg, 1.6 mmol.) were added to a solution of 2-(1H-indol-3-yl)acetic acid (180 mg, 1.03 mmol.) in abs. methanol, and stirring was carried out for 24 h at RT. For working up, the mixture was concentrated and the residue was suspended in water (20 ml); 2M HCl (1.5 ml, pH 3) was added, with stirring, and washing was carried out with ether (3×5 ml). The aqueous phase was adjusted to pH 11 with 5M NaOH and extracted with EE (4×10 ml). The organic phase was washed with 1M NaOH (3 ml), dried, filtered and concentrated. The residue was the non-polar diastereoisomer of N-(4-dimethylamino-4-phenylcyclohexylmethyl)-2-(1H-indol-3-yl)acetamide, which was obtained in the form of a solid in a yield of 395 mg (98%). These 395 mg (1.01 mmol.) were dissolved in 2-butanone (5 ml) and acetone (3 ml), and chlorotrimethylsilane (193 μl, 1.52 mmol.) was added thereto. There immediately formed a colourless precipitate, which turned slightly beige in colour at RT. The precipitate was filtered off, washed with cold 2-butanone (2×1 ml) and cold ether (2×2 ml) and dried in vacuo. The hydrochloride of N-(4-dimethylamino-4-phenylcyclohexylmethyl)-2-(1H-indol-3-yl)acetamide was obtained in a yield of 341 mg (light-beige solid, m.p. 128–135° C.).
Reaction SMILES: C([C:5]1[CH:6]=[C:7]([CH:13]=[C:14](C(C)(C)C)[C:15]=1O)[CH:8]=[CH:9][C:10]([OH:12])=O)(C)(C)C.[CH2:21]([O:23][C:24]([CH2:26][S:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:25])[CH3:22].Cl.C(N=C=NCCCN(C)C)C.ClCCl>O>[CH2:21]([O:23][C:24]([CH2:26][S:27][CH2:28][CH2:29][N:30]([CH2:31][CH2:32][CH2:33][CH3:34])[C:10](=[O:12])[CH:9]=[CH:8][C:7]1[CH:6]=[CH:5][CH:15]=[CH:14][CH:13]=1)=[O:25])[CH3:22]
Reactant: CC(C)(C)c1cc(C=CC(=O)O)cc(C(C)(C)C)c1O
Reactant: CCCCNCCSCC(=O)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCCCN(CCSCC(=O)OCC)C(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105 %

Procedure:
First, 5.53 g of 3,5-di-t-butyl-4-hydroxycinnamic acid, 4.4 g of N-ethoxycarbonylmethylthioethyl-n-butylamine, and 4.0 g of 1-ethyl-3-(3dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added to 100 ml of dichloromethane and the mixture was agitated for 3 hours at room temperature. Then, this reaction mixture was poured into water, and after chloroform extraction the chloroform layer was dehydrated with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue so obtained was separated and purified by column chromatography on silica gel with chloroform, after which hexane was added and crystallization yielded 7.34 g of an N-ethoxycarbonylmethylthioethyl-N-n-butylcinnamamide derivative (yield 79.5%) in the form of white crystals.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:4]([CH3:14])[CH2:3]1.[C:15](O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[C:15]([O:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:4]([CH3:14])[CH2:3]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[C@H]1C[C@H](OC(=O)c2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.9 %

Procedure:
To a solution of the alcohol of step A (0.81 g, 4.0 mmol), benzoic acid (0.74 g, 6.0 mmol) and triphenylphosphine (2.11 g, 8.0 mmol) in toluene (20 mL) was added DIAD (1.67 mL, 8.0 mmol). After being stirred at room temperature for 4 hours, the solution was concentrated. The residue was purified by flash chromatography eluting with 0%, 5% and 20% EtOAc/hexanes provided 1.0 g of the title compound. MS calculated (M+H)+ 308, found 308.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](C=CN(C)C)=[CH:7][N:6]=1)=[O:4].I([O-])(=O)(=O)=O.[Na+].O.CO[CH:25]([O:28][CH3:29])[O:26][CH3:27]>CO.C(OCC)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH:25]([O:26][CH3:27])[O:28][CH3:29])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(OC)OC
Reactant: COC(=O)c1cnc(C=CN(C)C)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cnc(C(OC)OC)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
A mixture of 5-(2-dimethylamino-vinyl)-pyrazine-2-carboxylic acid methyl ester (3.00 g, 14.5 mmol) and sodium periodate (9.09 g, 43.5 mmol) in methanol (40 mL) at 0° C. was treated dropwise with water (80 mL). The mixture was stirred at 0° C. for 30 min and then at 25° C. for 30 min. The mixture was partitioned between a saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (50 mL). The aqueous later was separated and saturated with sodium chloride. The aqueous layer was then extracted with ethyl acetate (4×50 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford a red solid. The resulting solid was combined with trimethylorthoformate (15 mL) and methanol (40 mL) and then was treated with p-toluenesulfonic acid monohydrate (191 mg, 1 mmol). The reaction mixture was heated under reflux for 1.5 h and then cooled to 25° C. The reaction was diluted with ethyl acetate (100 mL) and washed with a saturated aqueous sodium bicarbonate solution (50 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 5-dimethoxymethyl-pyrazine-2-carboxylic acid methyl ester (2.26 g, 73%) as a yellow oil which was used without further purification.