Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10]1([C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])(=O)C.[Na+]>O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:5]=[C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:17]1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C#Cc3ccccc3)cc2)CCC1
Reactant: O=Cc1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(C3=C(c4ccccc4)c4ccccc4C3=O)cc2)CCC1
Temperature: 100 °C
Yield: 6.2 %

Procedure:
A mixture of 2-bromobenzaldehyde (92.5 mg, 0.5 mmol), tert-butyl 1-(4-(phenylethynyl)phenyl)cyclobutylcarbamate (347 mg, 1.0 mmol), sodium acetate (164 mg, 2.0 mmol), tetrabutylammonium chloride hydrate (147.7 mg, 0.50 mmol) and palladium acetate (5.6 mg, 0.025 mmol) in DMF (10 mL) was heated at 100° C. for 48 h. The reaction mixture was concentrated to dryness and was partitioned between ethyl acetate (30 mL) and water (30 mL). The organic phase was washed with water (30 mL), brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography (eluting with 10% ethyl acetate in hexane) to give title compound (14 mg, 6.2%). 1H NMR (500 MHz, CDCl3): 7.50 (d, 1H), 7.45-7.05 (m, 12H), 2.55-2.25 (m, 4H), 2.15-1.95 (m, 1H), 1.85-1.70 (m, 1H), 1.40-1.10 (br s, 9H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([NH2:12])([CH3:11])[CH3:10]>O>[CH:1](=[N:12][CH:9]([CH3:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: O=Cc1ccccc1
Solvent: O
Product: CC(C)N=Cc1ccccc1
Reaction time: 0.67 h
Yield: 105.8 %

Procedure:
To a three neck round bottom flask, equipped with a cold water condenser, 30 g of water and 26.5 g of benzaldehyde were added. The mixture was mixed using a magnetic stirrer for 3 minutes at room temperature. i-Propylamine (17.7 g) was added to the reaction flask in one portion, followed by vigorous stirring for 40 minutes. The agitation was stopped and the reaction mixture was allowed to stand for at least 15 minutes. The lower aqueous layer was separated from the reaction mixture. The upper layer was collected and dried over magnesium sulfate to give 38.9 g of product. This crude product could be further purified by distillation, collecting the fraction between 94°-95° C./18 mmHg. 1H NMR (300 Hz, CDCl3, ppm): 8.29 (1H, s), 7.70 (2H, m), 7.38 (3H, m), 3.53 (hep. J=6.3 Hz), 1.27 (9H, d, J=6.3 Hz); IR (NaCl film, cm-1): 3061, 3026, 2930, 2835, 1647, 1581, 1450, 1382, 1306, 1141,967, 755, 693.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([C:15]([O:17]CC)=[O:16])[N:12]=[C:11]2[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[OH-].[Na+].Cl>O1CCCC1.O.CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[N:12]=[C:11]2[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)c1cn(-c2cccc(OCC)c2)c(-c2ccc(F)cc2F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cccc(-n2cc(C(=O)O)nc2-c2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 0.10 g (0.27 mmol) of ethyl 1-(3-ethoxyphenyl)-2-(2,4-difluorophenyl)-1H-imidazole-4-carboxylate in 2 mL of tetrahydrofuran, 1 mL of water and 1 mL of methanol was added 0.20 mL (1.0 mmol) of 5.0 M NaOH solution. The reaction mixture was stirred at ambient temperature for 4 hrs. Hydrochloric acid (2.0 M) was then added to neutralize the reaction mixture. After removal of the organic solvents in vacuo, dichloromethane (10 mL) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane (5 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as a yellow foam. LC/MS 345.0 (M+1).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]([F:17])[C:13]([F:16])([F:15])[F:14])=[CH:7][CH:6]=1)(=O)C.[N+:18]([O-])([OH:20])=[O:19]>S(=O)(=O)(O)O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]([F:17])[C:13]([F:16])([F:15])[F:14])=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19]
Reactant: CC(=O)Nc1ccc(OC(F)C(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Nc1ccc(OC(F)C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h

Procedure:
18.8 g (0.08 moles) 4-acetylaminotetrafluoroethoxybenzene of Step 1 are dissolved, accompanied by ice cooling at 0° C., in 150 ml concentrated sulfuric acid. Nitration is carried out at the same temperature with a mixture of 10.3 ml (0.15 moles) concentrated nitric acid (d=1.4 g/ml) and 10 ml concentrated sulfuric acid. After standing overnight this mixture is poured onto approximately 500 g ice. A viscous oil precipitates. The oily phase is decanted and repeatedly washed with water. The oil is made to solidify by means of cooling and scraping. It is, according to DC, a mixture of acetylaminonitro- and aminonitro-compounds. It is then saponified by means of dissolving and boiling, with reflux, with methanol and concentrated hydrochloric acid and then neutralized with ammonia. The 4-amino-3-nitrotetrafluoroethoxybenzene precipitates. Yellow crystals with a melting point of 78° C. were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:17][C:18]1[C:19]([CH2:33][NH2:34])=[CH:20][C:21]2[N:25]=[CH:24][N:23]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:22]=2[CH:32]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:14]1([C:11]2[NH:12][N:13]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:34][CH2:33][C:19]4[C:18]([F:17])=[CH:32][C:22]5[N:23]([CH:26]6[CH2:31][CH2:30][CH2:29][CH2:28][O:27]6)[CH:24]=[N:25][C:21]=5[CH:20]=4)[N:7]=3)[CH:10]=2)[CH2:16][CH2:15]1
Reactant: NCc1cc2ncn(C3CCCCO3)c2cc1F
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Fc1cc2c(cc1CNc1nccc(Nc3cc(C4CC4)[nH]n3)n1)ncn2C1CCCCO1
Temperature: 120 °C
Yield: 39.9 %

Procedure:
A tube was charged with 53 (235 mg, 1.0 mmol), 106 (237 mg, 0.95 mmol), DIPEA (1.0 mL) and IPA (3 mL), degassed, sealed and heated at 120° C. overnight. The solvent was evaporated in vacuo to afford 170 mg (39%) of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)methyl)pyrimidine-2,4-diamine (108) as white solid: MS (ESI) m/z=449.2 [M+1]+.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Cl:15][C:16]1[N:24]=[C:23]2[C:19]([NH:20][CH:21]=[N:22]2)=[C:18](Cl)[N:17]=1>C(O)CCC>[CH:1]1([NH:5][C:18]2[N:17]=[C:16]([Cl:15])[N:24]=[C:23]3[C:19]=2[NH:20][CH:21]=[N:22]3)[CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCC1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Clc1nc(NC2CCC2)c2[nH]cnc2n1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
Cyclobutylamine (20 g, 0.28M) and N,N-diisopropylethylamine (50.4 ml, 0.28M) is added to a suspension of 2,6-dichloropurine (48.4 g, 0.25M) in n-butanol (480 ml). The mixture is stirred at 60° C. for 20 hours. The mnixture is cooled and the precipitate isolated by filtration, washed with n-butanol and dried under vacuum to give 6cyclobutylamino-2-chloropurine;ES+ (M−1) 222.5; mp 237.8° C. dec.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:11]=[C:12]([C:14](O)=[O:15])[CH:13]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]1[N:29]=[C:28]([C@H:30]([NH2:32])[CH3:31])[O:27][N:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:11]=[C:12]([C:14]([NH:32][C@@H:30]([C:28]3[O:27][N:26]=[C:25]([CH3:24])[N:29]=3)[CH3:31])=[O:15])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1noc([C@@H](C)N)n1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2)c(=O)n(-c2ccccn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc([C@@H](C)NC(=O)c2cc(-c3ccc(F)cc3)c(=O)n(-c3ccccn3)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a solution of 3-(4-fluorophenyl)-2-oxo-2H-1,2′-bipyridine-5-carboxylic acid (20.0 mg, 0.05 mmol) in DMF (0.5 mL) were added hydrochloride salt of (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine (13.6 mg, 0.07 mmol), HATU (0.5 M in DMF; 0.16 mL, 0.08 mml) and diisopropylethylamine (36 μL, 0.21 mmol). The mixture was stirred at ambient temperature. After 30 min, the mixture was purified by reverse chromatography (C-18, 95% water/acetonitrile→25% water/acetonitrile with 0.1% trifluoroacetic acid) to give the title compound (20 mg). HRMS 420.1470 (M+1). 1H NMR (400 MHz, CDCl3): δ 8.62 (d, J=4.8 Hz, 1H); 8.53 (d, J=2.5 Hz, 1H); 7.94-7.83 (m, 3H); 7.70 (dd, J=8.3, 5.4 Hz, 2H); 7.41 (t, J=5.8 Hz, 1H); 7.12 (t, J=8.5 Hz, 2H); 6.66 (d, J=7.7 Hz, 1H); 5.60-5.51 (m, 1H); 2.40 (s, 3H); 1.69 (d, J=7.1 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:17]1[N:18]([C:49]2[N:50]=[CH:51][N:52]=[C:53]([NH2:56])[C:54]=2[N:55]=1)[C@@H:19]1[O:48][C@H:38]([CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[C@@H:29]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C@H:20]1[O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>O1CCOCC1.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.O.CCOC(C)=O>[Si:22]([O:21][C@@H:20]1[C@H:29]([O:30][Si:31]([C:34]([CH3:35])([CH3:36])[CH3:37])([CH3:33])[CH3:32])[C@@H:38]([CH2:39][O:40][Si:41]([C:44]([CH3:45])([CH3:46])[CH3:47])([CH3:42])[CH3:43])[O:48][C@H:19]1[N:18]1[C:49]2[N:50]=[CH:51][N:52]=[C:53]([NH2:56])[C:54]=2[N:55]=[C:17]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)([C:25]([CH3:27])([CH3:28])[CH3:26])([CH3:23])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2c(Br)nc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2c(-c3cccnc3)nc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
Pyridine-3-boronic acid (0.59 g, 0.48 mmol) and Cs2CO3 (3.11 g, 9.57 mmol) were added to a solution of 2′,3′,5′-tris-O-(tert-butyldimethylsilyl)-8-bromoadenosine (13) (2.20 g, 3.19 mmol) and Pd(PPh3)4 (0.37 g, 0.32 mmol) in dioxane (50 ml) under argon. Water (10 ml) was added to dissolve all Cs2CO3. The solution was heated under reflux overnight. EtOAc (200 ml) was added to the cold reaction mixture, the resultant solution shaken with water (100 ml), the organic solution dried (MgSO4), evaporated and the residual material subjected to flash chromatography on silica gel using EtOAc:MeOH 99:1; yield 1.76 g (80%). HRESI: M+H 687.3900. Calc. for C33H58N6O4Si3+H, 687.3900. 1H NMR: (300 MHz, CDCl3); δ −0.41/−0.12/0.01/0.02/0.09/0.11 (18H, s, 3×Si(CH3)2), 0.67/0.85/0.86 (27H, s, 3×SiC(CH3)3), 3.71-4.12 (3H, m, H-5′, H-3′ or H-4′), 4.53-4.55 (1H, m, H-4′ or H-3′), 5.61-5.65 (1H, m, H-2′), 5.81 (1H, d, J 6.3 Hz, H-1′), 6.02 (2H, s, NH2), 7.38-7.42 (1H, m, H-5′), 8.09-8.12 (1H, m, H-4″), 8.30 (1H, s, H-2), 8.73-8.75 (1H, m, H-6″), 9.04-9.05 (1H, m, H-2″). 13C NMR: (75 MHz, CDCl3); δ −5.5/−5.4/−5.3/−4.7/−4.6/−4.5 (3×Si(CH3)2), 17.2/18.0/18.3 (3×SiC), 25.6/25.8/25.8 (3×SiC(CH3)3), 62.5 (C-5′), 71.7/72.4 (C-2′, C-3′), 85.5/88.9 (C-4′, C-1′), 120.1/123.1/125.7/136.9/149.9/150.4/151.0/151.1/152.6/155.6 (C-5, C-5″, C-3″, C-4″, C-6, C-8, C-6″, C-2″, C-2, C-4).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Br[CH2:14][CH2:15]Br>O.C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:11]#[N:12])[CH2:15][CH2:14]2)=[CH:6][CH:5]=1
Reactant: N#CCc1ccc(Br)cc1
Reactant: BrCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC1(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium hydroxide (14.3 g, 255 mmol) was dissolved in H2O (5 mL) and toluene (40 mL). 4-Bromophenylacetonitrile (5.0 g, 25.5 mmol) and tetrabutylammonium bromide (0.41 g, 1.3 mmol) was added, followed by 1,2-dibromoethane (3.25 mL, 38 mmol) dropwise over 10 minutes. The reaction was stirred at room temperature for 2 hours and then worked-up to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[C:6]([Br:12])[C:5]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].[N+:21]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br)([O-:23])=[O:22]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[C:6]([Br:12])[C:5]=1[O:13][CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=1
Reactant: COC(=O)c1cc(C=O)cc(Br)c1O
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C=O)cc(Br)c1OCc1cccc([N+](=O)[O-])c1
Temperature: 60 °C

Procedure:
A mixture of 3-bromo-5-formyl-2-hydroxy-benzoic acid methyl ester (518 mg), potassium carbonate (613 mg), tetrabutylammonium iodide (68 mg) and 3-nitrobenzyl bromide (525 mg) in DMF (10 ml) was heated at 60° C. for 5 h. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]2([CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]2)[NH:12][C:11](=[O:21])[C:10]=1[C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=1[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[CH2:1]([O:8][C:9]1[C:13]2([CH2:14][CH2:15][N:16]([O:19][CH3:20])[CH2:17][CH2:18]2)[N:12]([CH3:31])[C:11](=[O:21])[C:10]=1[C:22]1[C:23]([CH3:30])=[CH:24][C:25]([CH3:29])=[CH:26][C:27]=1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON1CCC2(CC1)NC(=O)C(c1c(C)cc(C)cc1C)=C2OCc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CON1CCC2(CC1)C(OCc1ccccc1)=C(c1c(C)cc(C)cc1C)C(=O)N2C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-benzyloxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (40.0 g, 98.4 mmol) in tetrahydrofuran (500 ml) at 0° C. was added a 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (108.3 ml, 108.3 mmol) dropwise over one hour. The mixture was stirred at 0° C. for 30 minutes and at room temperature for 30 minutes, then treated with methyl iodide (6.75 ml, 15.4 g, 108.2 mmol) dropwise at 0° C. over 10 minutes. Stirring was continued at room temperature overnight and the reaction mixture was quenched with cold saturated aqueous ammonium chloride. The layers were separated, the aqueous phase extracted twice with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulfate and concentrated. The residue was suspended in diethyl ether, stirred for 30 minutes, filtered and dried. Yield: 28.6 g of 4-benzyloxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound P3.5) as a solid, mp 139-141° C.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:3]=1[CH2:4][O:5][CH2:6][C@H:7]1[O:11][CH:10]([O:12][CH3:13])[C@H:9](CC([O-])=O)[C@H:8]1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27].C[O-:34].[Na+]>CO>[Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:3]=1[CH2:4][O:5][CH2:6][C@H:7]1[O:11][CH:10]([O:12][CH3:13])[C@H:9]([OH:34])[C@@H:8]1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27]
Reactant: COC1O[C@H](COCc2ccc(Cl)cc2Cl)[C@H](OCc2ccc(Cl)cc2Cl)[C@H]1CC(=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3R,4R,5R)-5-(2,4-dichloro-benzyloxymethyl)-4-(2,4-dichlorobenzyloxy)-2-methoxy-tetrahydrofuran-3-acetate I-1 (10 g, 19.1 mmol) in MeOH (150 ml) is added a solution of 30% NaOMe in MeOH (5.37 ml, 28.6 mmol, 1.5 equiv.) and the reaction is stirred at room temperature for 30 mins. The reaction mixture is concentrated and dissolved in ethyl acetate (180 ml), washed with 1 N HCl solution and saturated brine, dried (anhyd Na2SO4) and concentrated to give (3R,4S,5R)-5-(2,4-Dichlorobenzyloxymethyl)-4-(2,4-dichlorobenzyloxy)-2-methoxy-tetrahydrofuran-3-ol I-2 as yellowish oil. The obtained crude compound is used for the next step without further purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][C@H:12]1[C@@H:17]([SH:18])[CH2:16][CH2:15][CH2:14][O:13]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].O>CN(C)C=O>[CH2:3]([O:10][CH2:11][C@H:12]1[C@@H:17]([S:18][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])[CH2:16][CH2:15][CH2:14][O:13]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: S[C@H]1CCCO[C@H]1COCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCS[C@H]1CCCO[C@H]1COCc1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
0.27 g of a 55% w/w suspension of sodium hydride in mineral oil was suspended in 2 ml of dimethylformamide. To the suspension was added dropwise a solution of 1.210 g of dl-cis-2-benzyloxymethyl-3-mercaptotetrahydropyran (prepared as described in Preparation 16) in 5 ml of dimethylformamide, whilst ice-cooling the mixture. The reaction mixture was stirred at 60° C. for 1 hour, after which it was cooled to room temperature. A solution of 1.86 g of hexadecyl bromide in 3 ml of dimethylformamide was then added, and the mixture was stirred at room temperature for 1 hour. It was then poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography through 40 g of silica gel. The fraction eluted with mixtures of diethyl ether and hexane ranging from 3:97 to 10:90 by volume was collected to give 2.284 g of the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.O.[NH2:17]N.Cl.Cl.NN>C(O)CO>[NH:1]([C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:13])[F:14])[CH:8]=[CH:7][C:5]=2[N:6]=1)[NH2:17]
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: NN
Agent: Cl
Solvent: OCCO
Solvent: O
Product: NNc1nc2ccc(OC(F)(F)F)cc2s1
Temperature: 140 °C
Yield: 90.3 %

Procedure:
To a suspension of 93.6 g of 2-amino-6-trifluoromethoxybenzothiazole in 420 cm3 of ethylene glycol under a stream of nitrogen are added 48 g of hydrazine hydrate and 42 g of hydrazine dihydrochloride. The mixture is heated for 2 hours at 140° C. After cooling, the precipitate is filtered off and triturated with a water/diethyl ether mixture (1/1 by volume). 89.9 g of 2-hydrazino-6-trifluoromethoxybenzothiazole are thus obtained, melting at 208° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][C:5]([F:11])=[CH:4][N:3]=1.C(Cl)(=O)C(Cl)=O.C[N:19](C=O)C.C(OCC)(=O)C>ClCCl.[OH-].[NH4+].O>[Cl:1][C:2]1[C:7]([C:8]([NH2:19])=[O:9])=[CH:6][C:5]([F:11])=[CH:4][N:3]=1
Reactant: O=C(O)c1cc(F)cnc1Cl
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1cc(F)cnc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 809.8 %

Procedure:
To the suspension of 2-chloro-5-fluoropyridine-3-carboxylic acid (37.0 g, 210.8 mmol) in dichloromethane (555 mL) was added oxalyl chloride (56.2 g, 442.7 mmol) under nitrogen. DMF (1.54 g, 21.08 mmol) was added slowly to the reaction mixture. The mixture was stirred at room temperature for 2 h and dichloromethane was removed under reduced pressure. The residue was dissolved in THF (300 mL) and cooled down to 0° C. by ice bath. Ammonium hydroxide (28-30%, 113.0 mL, 1.8 mmol) was added in one portion. The mixture was stirred for another 15 min. The mixture was diluted into ethyl acetate (300 mL) and water (300 mL) and the phases were separated. The organic layer was washed with brine and dried over Na2SO4, filtered, and concentrated in vacuo to afford 29.8 g desired product as white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.53 (d, J=3.0 Hz, 1H), 8.11 (s, 1H), 8.00 (dd, J=8.0, 3.0 Hz, 1H), 7.89 (s, 1H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=1.11 minutes, (M+H) 175.02.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][CH:27]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[C@H:2]([C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:20]([OH:22])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])[CH3:11])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].CN(C=O)C.[CH2:45](Br)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[NH:1]([C:23]([O:25][CH2:26][CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[C:39]1=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:24])[C@H:2]([C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:20]([O:22][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])[CH3:11])=[O:8])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: CSCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1

Procedure:
The Fmoc-Met-Ala-Leu (SEQ ID NO: 3) is added into a round bottom flask with DMF and a magnetic stirrer. After the tripeptide is dissolved, benzyl bromide, followed by cesium carbonate, is added to the solution with stirring. The reaction mixture is stirred at room temperature for 1.5 hrs. Then, the reaction mixture is slowly poured into a flask with iced water. The precipitate is collected by suction filtration. The product, Fmoc-Met-Ala-Leu-OBn (SEQ ID NO: 3), is washed with water and placed in a vacuum desiccator.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH:11]=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH:15](Br)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-]>[CH:15]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[CH:6]=[C:7]1[CH:11]=[O:12])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1cc2ccc(Cl)cc2[nH]1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: O=Cc1cc2ccc(Cl)cc2n1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 42 h
Yield: 40 %

Procedure:
To 6-chloro-1H-indole-2-carbaldehyde (1 equiv.) in DMF at 0° C. was added NaH (1.25 equiv.) portionwise followed by benzhydryl bromide (1.46 equiv.) and Bu4NI (0.05 equiv.). The mixture was stirred at rt for 42 h before quenching with cold 0.4N HCl at 0° C. After neutralization, the aqueous layer was extracted with ether and the organic layer was washed with cold H2O and dried. Flash chromatography on silica gel gave 1-benzhydryl-6-chloro-1H-indole-2-carbaldehyde in 40% yield.