Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].I[CH:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].O>C(O)(C)C>[CH:11]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([CH3:13])[CH3:12]
Reactant: CC(C)I
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)Oc1cccc(C=O)c1
Yield: 66.7 %

Procedure:
3-Hydroxybenzaldehyde (5.60 g, 45.9 mmol) and 2-iodopropane (7.86 g, 46.2 mmol) were dissolved in 50 mL of isopropanol. Potassium carbonate (20 g, 145 mmol) was added, and the mixture was heated to reflux for 8 h, at which time TLC analysis indicated that the reaction had gone to completion. Water was added to dissolve all solids, and the mixture was extracted with ether (3×). The combined ether layer was washed with water, 2 M NaOH, again with water until clear (4×), and finally with brine. The solution was dried over MgSO4, filtered, and evaporated to give 5.03 g (67%) of the desired 3-isopropoxybenzaldehyde product as a pale oil. 1H NMR (C6D6) δ 9.62 (s, 1H), 7.29 (s, 1H), 7.03 (m, 1H), 6.91 (t, 1H), 6.84 (m, 1H), 4.03 (septet, 1H), 0.96 (d, 6H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15]O)=[C:11]([Cl:17])[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.CS([Cl:29])(=O)=O>ClCCl.C(OCC)(=O)C>[C:4]([Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][Cl:29])=[C:11]([Cl:17])[CH:10]=1)([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CO)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CCl)c(Cl)c1
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl[3-chloro-4-(chloromethyl)phenoxy]dimethylsilane (step 1, 500 mg, 1.83 mmol) in dichloromethane (5 mL) were added triethylamine (0.139 mL, 2.75 mmol) and methane sulfonylchloride (231 mg, 2.02 mmol) at room temperature. The mixture was stirred for 2 h at the same temperature. The mixture was diluted with ethyl acetate (100 mL), and the mixture washed with water and brine, dried over sodium sulfate and evaporated. The residue was purified by silica gel (40 g) eluting with hexane/ethyl acetate (10/1) to afford 580 mg (quant.) of the title compound as a colorless oil:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12]([OH:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.CI>[CH2:1]([O:8][C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12]([O:15][CH3:20])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(O)ccc1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1nc(OC)ccc1OCc1ccccc1
Yield: 48.3 %

Procedure:
Methyl 3-benzyloxy-6-hydroxy-picolinate (0.55 g) was dissolved in 55 ml of acetone and 20 ml of methyl iodide. Potassium carbonate (1.4 g) was added to the solution, and the mixture was refluxed for 3 hr. After cooling, the reaction solution was neutralized with 1 N hydrochloric acid, and was concentrated under the reduced pressure. Methylene chloride and water were then added to the concentrate to conduct extraction. The organic layer was dried over magnesium sulfate, and the dried organic layer was then concentrated under the reduced pressure. The residue was purified by column chromatography (chloroform-methanol) to give 0.28 g (yield 49%) of the title compound.
Reaction SMILES: [CH:1]1([NH:4][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH3:6])[CH2:3][CH2:2]1.[CH2:13]([C:15]1[C:20](=[O:21])[NH:19][C:18]([CH3:22])=[C:17]([C:23]2[S:27][C:26]([S:28](Cl)(=[O:30])=[O:29])=[CH:25][CH:24]=2)[CH:16]=1)[CH3:14]>ClCCl>[CH:1]1([N:4]([CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH3:6])[S:28]([C:26]2[S:27][C:23]([C:17]3[CH:16]=[C:15]([CH2:13][CH3:14])[C:20](=[O:21])[NH:19][C:18]=3[CH3:22])=[CH:24][CH:25]=2)(=[O:29])=[O:30])[CH2:3][CH2:2]1
Reactant: CC(NC1CC1)c1ccccn1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Solvent: ClCCl
Product: CCc1cc(-c2ccc(S(=O)(=O)N(C3CC3)C(C)c3ccccn3)s2)c(C)[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
A mixture of cyclopropyl(1-pyridin-2-yl)ethylamine (73.5 mg, 0.453 mmol), 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride (144 mg, 0.453 mmol), PS-piperidinomethyl (155 mg, 0.542 mmol, beads) and dichloromethane (5 mL) is stirred at room temperature overnight. The reaction mixture is filtered and the filtrate is evaporated. The residue is purified by chromatography on an ISCO Redisep 10 g cartridge eluting with ethyl acetate-5% methanol to afford 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonic acid cyclopropyl(1-pyridin-2-yl)ethylamide (85 mg, 43% yield) as a white solid. A hydrochloride salt is prepared by dissolving the amine (85 mg, 0.192 mmol) in methanol (2 mL), adding 1 M ethereal hydrochloric acid (0.3 mL), some methanol is removed, more ether added and the hydrochloride salt is collected by filtration (50 mg, 54% yield as an off white solid). RT=2.93 min; m/e=444; 1H NMR (δ, ppm): 11.84 (1H, br s), 8.6 (1H, d), 8.02 (1H, m), 7.69 (1H, d), 7.61 (1H, d), 7.50 (1H, m), 7.37 (1H, s), 5.24 (1H, d), 5.27 (2H, m), 2.40 (2H, m), 2.33 (3H, s), 1.53 (3H, d), 1.13 (3H, t), 0.6-0.96 (4H, m).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].[N+](=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N-]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH2:1]([O:3][CH:4]1[CH2:5][CH:8]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=COCC
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)C1CC1OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
A solution of ethyl vinyl ether (4.5 mL, 47 mmol, 4.9 equiv.) and rhodium(II) acetate dimer (20.0 mg, 45.2 μmol, 4.8 mol %) in DCM (20 mL) at ambient temperature was treated with ethyl 2-diazoacetate (1.00 mL, 9.51 mmol) in 0.1 mL portions over 10 mins, allowing effervescence to subside between additions. The resulting green solution was stirred at ambient temperature for 2 h and concentrated in vacuo. The residue was dissolved in diethyl ether and washed with water, and with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford crude ethyl 2-ethoxycyclopropanecarboxylate as a golden yellow oil (1.36 g, 90%) which was used without further purification.
Reaction SMILES: [C:1]1([N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:17]#[N:18].[Na+].O=O.C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[C:17]([CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:15][CH2:16][N:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)#[N:18]
Reactant: c1ccc(N2CCc3ccccc3C2)cc1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: O=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#CC1c2ccccc2CCN1c1ccccc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
N-phenyl-1,2,3,4-tetrahydroisoquinoline (1 mmol), RuCl3-nH2O (0.05 mmol) and sodium cyanide (1.2 mmol) were charged into a 25-ml side-arm flask, the interior of the reacting container was replaced by oxygen, and an oxygen balloon was attached to supply oxygen at 1 atm. Then, 1.7 ml of a mixed solvent of methanol-acetic acid (volume ratio 3/1) was added thereto at room temperature. Reaction was effected by stirring the mixed liquid at 60° C. for 4 hours. After the reaction mixture liquid was made alkaline with the addition of saturated sodium bicarbonate aqueous solution, the mixture was extracted with 10 ml ethyl acetate once and with 5 ml ethyl acetate twice. The extracted liquid thus obtained was washed with saturated saline solution, and dried over sodium sulfate, thereby obtaining an ethyl acetate solution of 1-cyano-N-phenyl-1,2,3,4-tetrahydroisoquinoline. After this solution was concentrated under reduced pressure, the mixture was analyzed by a 1H NMR internal standard method, which revealed the conversion rate of N-phenyl-1,2,3,4-tetrahydroisoquinoline being 91% with a yield of 1-cyano-N-phenyl-1,2,3,4-tetrahydroisoquinoline being 79% (vs. N-phenyl-1,2,3,4-tetrahydroisoquinoline). By using silica gel chromatography, 1-cyano-N-phenyl-1,2,3,4-tetrahydroisoquinoline was isolated at a yield of 76%.
Reaction SMILES: C(OC[N:10]1[CH:14]=[C:13](I)[N:12]=[CH:11]1)C1C=CC=CC=1.C([Mg]Br)C.[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH3:33])[CH:28]=[C:27]([C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:26]=[CH:25]2.[Cl-].[NH4+]>ClCCl.C1COCC1.O>[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH3:33])[CH:28]=[C:27]([C@@:34]([C:14]1[N:10]=[CH:11][NH:12][CH:13]=1)([OH:38])[CH:35]([CH3:36])[CH3:37])[CH:26]=[CH:25]2
Reactant: COc1cc2ccc(C(=O)C(C)C)cc2cc1OC
Reactant: Ic1cn(COCc2ccccc2)cn1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: COc1cc2ccc([C@](O)(c3c[nH]cn3)C(C)C)cc2cc1OC
Reaction time: 1 h
Yield: 71.5 %

Procedure:
1-benzyloxymethyl-4-iodoimidazole (31.5 g) was dissolved in dichloromethane (500 mL) under argon atmosphere. A solution of ethylmagnesium bromide in THF (0.96M; 110 mL) was added dropwise to the solution with keeping the reaction temperature below 8° C. and the mixture was stirred for 1 h. A solution of 6,7-dimethoxy-2-isobutyrylnaphthalene (31 g) in dichloromethane (50 mL) was added to the mixture and stirred at room temperature for 24 h. Saturated ammonium chloride solution (150 mL) and water (350 mL) were added to the mixture, and organic layer was concentrated. The residue was dissolved in THF (200 mL)-ethyl acetate (1 L), washed with water and brine, dried over Na2SO4 and concentrated in vacuo to one tenth of initial volume. The crystals were collected and washed with ethyl acetate to give the titled compound (23.4 g) as colorless crystals. Second crystals (4.53 g) were recovered from the mother liquor.
Reaction SMILES: [N:1]([C@@H:4]([CH3:9])[CH2:5][CH2:6][O:7][CH3:8])=[C:2]=S.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:18]2[N:19]=[C:20]([C:31]([CH3:37])([CH3:36])[C:32]([O:34][CH3:35])=[O:33])[NH:21][C:22]=2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])=[N:15][C:16]=1[OH:17].C1(N=C=NC2CCCCC2)CCCCC1>C(O)C>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:22]1[NH:21][C:20]([C:31]([CH3:37])([CH3:36])[C:32]([O:34][CH3:35])=[O:33])=[N:19][C:18]=1[C:14]1[N:15]=[C:16]2[O:17][C:2]([NH:1][C@@H:4]([CH3:9])[CH2:5][CH2:6][O:7][CH3:8])=[N:10][C:11]2=[CH:12][CH:13]=1
Reactant: COC(=O)C(C)(C)c1nc(-c2ccc(N)c(O)n2)c(-c2ccc(F)cc2F)[nH]1
Reactant: COCC[C@H](C)N=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCO
Product: COCC[C@H](C)Nc1nc2ccc(-c3nc(C(C)(C)C(=O)OC)[nH]c3-c3ccc(F)cc3F)nc2o1
Temperature: 50 °C
Yield: 73.5 %

Procedure:
(3S)-3-Isothiocyanato-1-methoxy-butane (24.68 g, 169.94 mmol) is added to a suspension of methyl 2-[4-(5-amino-6-hydroxy-2-pyridyl)-5-(2,4-difluorophenyl)-1H-imidazol-2-yl]-2-methyl-propanoate (55 g, 141.62 mmol) in ethanol (550 mL) at RT. The reaction mixture is stirred under reflux overnight and then cooled to 50° C. Dicyclohexylcarbodiimide (37.99 g, 184.10 mmol) is added to the mixture and the resulting suspension is stirred under reflux for 20 h. The reaction is allowed to reach RT and the solvent evaporated under reduced pressure. The residue is absorbed in silica gel and purified through a silica gel column (first using dichloromethane as an eluent to remove the most apolar impurities and then with dichloromethane/methanol 95:5 to elute the desired product) to afford the title compound (52 g, 74%) as a dark brown foam. LC-ES/MS m/z 500 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@@H:8]([NH:18][C:19](=[O:25])[O:20]C(C)(C)C)[C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])O)[CH:5]=[CH:4][CH:3]=1.Cl.C(N(C(C)C)CC)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([C@@H:8]2[C@@H:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[O:25][C:19](=[O:20])[NH:18]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](c1cccc(Br)n1)[C@H](O)c1ccccc1F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1N[C@H](c2cccc(Br)n2)[C@@H](c2ccccc2F)O1
Temperature: 45 °C
Reaction time: 0.25 h

Procedure:
To a solution of optically-enriched tert-butyl (1R,2R)-1-(6-bromopyridin-2-yl)-2-(2-fluorophenyl)-2-hydroxyethylcarbamate (375 mg, 0.912 mmol) in dichloromethane (4 mL) at room temperature was added hydrogen chloride (4M in dioxane, 3 mL, 12 mmol). After 15 min at room temperature, the reaction was warmed to 45° C. and held at that temperature for 15 min. The reaction was cooled and concentrated. The reaction was concentrated twice more from tetrahydrofuran. The resulting residue was suspended in tetrahydrofuran (10 mL), cooled to 0° C., and treated with diisopropylethylamine (0.319 mL, 1.82 mmol) and carbonyldiimidazole (222 mg, 1.368 mmol). After 5 min, the ice bath was removed and stirring continued for 3 h. The reaction was quenched by addition of 2M ammonia in methanol and concentrated. The resulting residue was suspended in dichloromethane, diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, and concentrated. Column chromatography (25%→50% EtOAc/Hex) gave 75 mg. 1H NMR (CDCl3) δ: 7.60-7.68 (m, 1H), 7.46-7.56 (m, 2H), 7.35-7.45 (m, 2H), 7.24 (td, J=7.7, 1.0 Hz, 1H), 7.12 (ddd, J=10.3, 8.3, 1.0 Hz, 1H), 7.03 (s, 1H), 5.80 (d, J=5.3 Hz, 1H), 4.93 (d, J=5.3 Hz, 1H). 13C NMR (CDCl3) δ: 160.9, 158.9, 158.4, 142.0, 139.2, 130.5, 127.8, 127.2, 125.0, 124.3, 119.6, 115.6, 78.5, 63.1. 19F NMR (CDCl3) δ: −121.48-113.54 (m, 1F). Mass spec.: 337.1 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[CH3:19].[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:22]=1[CH2:23]Br>>[C:15]([C:10]1[C:11](=[O:14])[N:12]([CH2:23][C:22]2[C:21]([Cl:20])=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:29])[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=2)[CH:9]=1)([OH:17])=[O:16]
Reactant: Clc1cccc(Cl)c1CBr
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Product: Cc1cc(-c2cc(C(=O)O)c(=O)n(Cc3c(Cl)cccc3Cl)n2)ccc1F
Yield: 90.3 %

Procedure:
Following the procedure of Example 1(6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 2,6-dichlorobenzyl bromide were reacted to yield a crude product. Without purification, the crude product was reacted further in accordance with the procedure of Example 1(7) to yield the title compound as a pale yellow solid (90.3%).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@@H:9]1[CH2:14][OH:15])=O)(C)(C)C.[ClH:16].O1CCOCC1>>[ClH:16].[OH:15][CH2:14][C@H:9]1[CH2:10][C@H:11]([CH3:13])[CH2:12][NH:8]1
Reactant: C[C@H]1C[C@H](CO)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CN[C@@H](CO)C1

Procedure:
(2R,4S)-4-Methylpyrrolidine-2-carboxylic acid described in J. Chem. Soc. C, pp. 514-522 (1971) is reacted with di-tert-butyl dicarbonate to give (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylic acid. (2R,4S)-1-tert-Butoxycarbonyl-4-methylpyrrolidine-2-carboxylic acid is reacted with methyl iodide in the presence of potassium carbonate in acetonitrile solvent to give methyl (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylate. Methyl (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylate is reduced with lithium borohydride to give (2R,4S)-1-tert-butoxycarbonyl-2-hydroxymethyl-4-methylpyrrolidine. (2R,4S)-1-tert-Butoxycarbonyl-2-hydroxymethyl-4-methylpyrrolidine is reacted with 4N hydrogen chloride-dioxane to give (2R,4S)-2-hydroxymethyl-4-methylpyrrolidine hydrochloride. (2R,4S)-2-Hydroxymethyl-4-methylpyrrolidine hydrochloride is reacted with acrylonitrile to give 3-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]propionitrile. In the same manner as in Example 1b (e) and using 3-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]propionitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-(2-(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]ethyl)-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]#[N:14])=[CH:10][C:9]=2[S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])=[CH:4][CH:3]=1.[Br:22]Br.O>O1CCOCC1>[Br:22][C:10]1[C:9]([S:15]([C:18]([F:19])([F:21])[F:20])(=[O:16])=[O:17])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:12][C:11]=1[C:13]#[N:14]
Reactant: BrBr
Reactant: N#Cc1cc(S(=O)(=O)C(F)(F)F)c(-c2ccc(Cl)cc2)[nH]1
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1[nH]c(-c2ccc(Cl)cc2)c(S(=O)(=O)C(F)(F)F)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
A solution of 5-(p-chlorophenyl)-4-[(trifluoromethyl)sulfonyl]pyrrole-2-carbonitrile (0.87 g, 0.0026 mol) in dioxane is cooled, treated with bromine (0.46 g, 0.00286 mol), stirred at room temperature for two hours, treated with additional bromine (0.21 g, 0.0013 mol), stirred overnight at room temperature, poured into water and extracted with ethyl acetate. The combined organic extracts are washed with water, saturated sodium meta-bisulfite solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a yellow syrup. Flash chromatography of the syrup using silica gel and a 1:4 ethyl acetate/hexanes solution gives the title product as a tan solid (0.27 g, mp 170°-185° C.) which is identified by 1HNMR spectral analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:30]=[C:31]([CH3:43])[C:32]3[N:36]=[C:35]([C@@H:37]4[CH2:41][CH2:40][CH2:39][O:38]4)[NH:34][C:33]=3[CH:42]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([O:28][C:29]5[CH:30]=[C:31]([CH3:43])[C:32]6[N:36]=[C:35]([C@@H:37]7[CH2:41][CH2:40][CH2:39][O:38]7)[NH:34][C:33]=6[CH:42]=5)[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2[nH]c([C@@H]3CCCO3)nc12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5nc([C@@H]6CCCO6)[nH]c5c4)ncn3)CC1)C(=O)N2

Procedure:
63 mg (0.23 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 70 mg (0.21 mmol) (S)-6-(6-chloropyrimidin-4-yloxy)-4-methyl-2-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazole and 0.08 mL (0.46 mmol) DIPEA in 2.0 mL DMF were stirred overnight at RT and for 2 h at 40° C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with 4M sodium hydroxide solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([CH:20]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)[S:18][CH:19]=2)=[CH:11][CH:10]=1.[F:26][C:27]([F:43])([F:42])[C:28]1[O:32][N:31]=[C:30]([C:33]2[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=2)[C:36](O)=[O:37])[N:29]=1>>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([CH:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:36]([C:35]4[CH:39]=[CH:40][CH:41]=[C:33]([C:30]5[N:29]=[C:28]([C:27]([F:42])([F:26])[F:43])[O:32][N:31]=5)[CH:34]=4)=[O:37])[CH2:21]3)[S:18][CH:19]=2)=[CH:11][CH:10]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: Fc1ccc(-c2csc(C3CCCNC3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCCC(c2nc(-c3ccc(F)cc3)cs2)C1
Yield: 28 %

Procedure:
This compound was synthesized from 4-(4-fluorophenyl)-2-(piperidin-3-yl)thiazole TFA salt and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (41 mg, yield 28%). 1H NMR (400 MHz, MeOD) δ 8.20-8.18 (m, 1H), 8.09 (m, 1H), 7.85 (m, 2H), 7.66-7.65 (d, J=4.3 Hz, 2H), 7.59 (m, 1H), 7.10-7.05 (t, J=8.4 Hz, 2H), 3.91 (m, 1H), 3.65 (m, 1H), 3.49-3.39 (m, 2H), 2.36-2.31 (m, 1H), 2.12-2.03 (m, 3H), 1.77-1.74 (m, 1H). MS (ESI) m/z: Calculated for C24H18F4N4O2S: 502.11. found: 503.1 (M+H)+
Reaction SMILES: [Li].[Cl:2][C:3]1[CH:8]=[C:7]([C:9]([O-])=[CH:10][C:11](=O)[C:12]([O:14]CC)=[O:13])[CH:6]=[CH:5][N:4]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[Cl:42][C:43]1[CH:44]=[C:45]([NH:50][NH2:51])[CH:46]=[CH:47][C:48]=1[F:49]>>[Cl:42][C:43]1[CH:44]=[C:45]([N:50]2[C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([Cl:2])[CH:8]=3)=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[N:51]2)[CH:46]=[CH:47][C:48]=1[F:49]
Reactant: NNc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)C(=O)C=C([O-])c1ccnc(Cl)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2ccnc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1

Procedure:
560 mg (2.14 mmol) of the compound of Example 19A is reacted analogously to the synthesis of the compound of Example 20A with 464 mg (2.36 mmol) of 3-chloro-4-fluorophenylhydrazine hydrochloride. After hydrolysis, 488 mg (65% of theory) of the title compound is obtained.
Reaction SMILES: C(CN1CCC[C@H]1C(N(CC1C=CC=CC=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=O)(O)=O.C(N(CC)CC)C.ClC(OCC(C)C)=[O:37].C1(N2CCNCC2)C=CC=CC=1>C(#N)C>[NH2:12][C@H:11]([C:10]([OH:17])=[O:37])[C@H:13]([CH2:15][CH3:16])[CH3:14]
Reactant: CC(C)COC(=O)Cl
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Agent: c1ccc(N2CCNCC2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)O
Yield: 223.4 %

Procedure:
A -5° C. solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (0.214 g, 0.58 mmol, 1.0 eq), and triethylamine (96 uL, 70 mg, 0.64 mol, 1.20 eq), in acetonitrile (6 mL) was treated with isobutyl chloroformate (83 uL, 86 mg, 0.63 mmol, 1.1 eq) followed by 4-phenylpiperazine (170 uL, 186 mg, 1.15 mmol, 2.0 eq). Workup as above provided 170 mg (57%) of L-isoleucine, N-[1-[2-(4-phenylpiperazine)-2-oxoethyl]-L-prolyl] benzylamide.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:19]([CH:20]=[O:21])=[C:18]([I:22])[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCO.[BH4-].[Na+]>>[Si:1]([O:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([N:15]2[C:19]([CH2:20][OH:21])=[C:18]([I:22])[CH:17]=[N:16]2)[CH2:13][CH2:14]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2ncc(I)c2C=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2ncc(I)c2CO)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-4-iodo-1H-pyrazole-5-carbaldehyde (50.0 mg, 0.115 mmol) in EtOH (3 mL, 50 mmol) was added sodium borohydride (6.53 mg, 0.173 mmol) at rt, and the mixture was stirred for 10 min. The solution was dry-loaded onto silica gel and purified via column chromatography, eluting with 3-5% EtOH/heptane. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z=437.08 (100) [MH+]. HPLC: tR=1.88 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@H:9]2[O:10][CH2:11][C@@H:12]([OH:13])[C@H:8]2[O:7][C@H:4]1[O:5][CH3:6].N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:1][O:2][C@@H:3]1[C@H:9]2[O:10][CH2:11][C@@H:12]([O:13][S:21]([CH3:20])(=[O:23])=[O:22])[C@H:8]2[O:7][C@H:4]1[O:5][CH3:6]
Reactant: CS(=O)(=O)Cl
Reactant: CO[C@@H]1O[C@H]2[C@H](OC[C@H]2O)[C@H]1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CO[C@@H]1O[C@H]2[C@H](OC[C@H]2OS(C)(=O)=O)[C@H]1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Methyl 3,6-anhydro-2-O-methyl-β-D-glucofuranoside (420 mg, 2.6 mmol) was dissolved in dichloromethane (10 mL) and pyridine (0.36 mL, 3.7 mmol) at 0° C. Methanesulfonyl chloride (0.14 mL, 3.1 mmol) was added and the resulting mixture was stirred at 0° C. for 1 hour then at room temperature for 2 hours. The reaction mixture was washed with water and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated to give methyl 3,6-anhydro-2-O -methyl-5-O-(methylsulfonyl)-β-D-glucofuranoside as a colorless oil, 669 mg, 95% yield, which was used without further purification.