Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:14]([O:17]C(Cl)=O)(Cl)Cl>O1CCCC1>[C:4]1([CH2:3][C@H:2]2[C:10](=[O:12])[O:11][C:14](=[O:17])[NH:1]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=C1N[C@@H](Cc2ccccc2)C(=O)O1

Procedure:
A mixture of 8.9 g of L-phenylalanine, 4.8 ml of trichloromethylchloroformate (Diphosgene), 70 ml of dry tetrahydrofuran and 0.135 g of activated carbon is heated in an oil bath at 55° C. for 2 hours, until the L-phenylalanine is in solution. The reaction is filtered through diatomaceous earth. The filtrate is concentrated in vacuo, treated with diethyl ether and hexane, and the resulting crystals are collected to give 1.04 g of the desired product.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].CI.[OH-].[K+].O1CCOC[CH2:14]1>O>[CH3:1][C:2]1([CH3:14])[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8]
Reactant: C1COCCO1
Reactant: CC1C(=O)CCC1=O
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: CC1(C)C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
Synthesized according to Agosta and Smith, J. Org. Chem., 35: 3856 (1970). A mixture of 2-methyl-1,3-cyclopentanedione (10.025 g, 89.4 mmol, Aldrich), methyl iodide (6.0 mL, 96.4 mmol, Aldrich), and KOH (5.097 g, 90.8 mmol) in water (25 mL)/dioxane (75 mL) was heated at reflux. After 5 hours, a solution of KOH (2 g) and MeI (2.4 mL) in water (5 mL)/dioxane (15 mL) was added and after another 3 hours at reflux, the solution was stirred at room temperature overnight. A solution of KOH (2 g) and MeI (2.4 mL) in water (5 mL)/dioxane (15 mL) was added to the overnight reaction and heating at reflux. After 4 hours, the mixture was cooled to room temperature and extracted with ether (1×100 mL, 3×75 mL). The combined ether extracts were evaporated, the residue combined with 10% HCl (50 mL), and the resulting mixture placed in a 120° C. oil bath until it began boiling (ca. 15 minutes). The mixture was cooled to room temperature, neutralized by addition of saturated NaHCO3 solution (150 mL) and the resulting mixture extracted with CH2Cl2 (4×75 mL). The combined CH2Cl2 solution was dried (MgSO4), filtered and evaporated to leave a brown oil (10.474 g, 83 mmol, 93%) which was used directly in the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH2:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:16][CH2:17][C:18](Cl)=[O:19]>ClCCl>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:18](=[O:19])[CH2:17][Cl:16])=[CH:3][CH:2]=1
Reactant: NCc1ccncc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)NCc1ccncc1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
The starting material was obtained as follows: A solution of 4-pyridylmethylamine (1.08 g) and triethylamine (1.0 g) in dichloromethane (25 ml) was added slowly over 30 minutes to a chilled, stirred solution of chloroacetyl chloride (1.2 g) in dichloromethane (7.5 ml). The reaction mixture was maintained at 0-5° C. throughout the addition, stirred for a further 30 minutes and allowed to warm to room temperature. The reaction mixture was washed with water (2×10 ml) and dried over MgSO4. Evaporation of the solvent under reduced pressure gave N-(4-pyridylmethyl)chloroacetamide as a brown oil, which was used immediately.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[C@@H:16]([CH3:17])[CH2:15][CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][C@H:47]([CH3:49])[CH2:46][N:45]3C(OC(C)(C)C)=O)=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].[CH3:57][O:58][C:59]([NH:61][C@H:62]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:63]([OH:65])=O)=[O:60].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>Cl.CCO>[CH3:57][O:58][C:59]([NH:61][C@H:62]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:63]([N:45]1[CH2:46][C@@H:47]([CH3:49])[CH2:48][C@H:44]1[C:42]1[NH:43][C:39]([C:34]2[CH:35]=[C:36]3[CH2:37][O:38][C:25]4[CH:24]=[C:23]5[C:28]([CH:29]=[CH:30][C:20]6[N:19]=[C:18]([C@@H:13]7[CH2:14][CH2:15][C@H:16]([CH3:17])[N:12]7[C:10](=[O:11])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:7]([CH3:9])[CH3:8])[NH:22][C:21]=65)=[CH:27][C:26]=4[C:31]3=[CH:32][CH:33]=2)=[CH:40][N:41]=1)=[O:65])=[O:60]
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(-c2cnc([C@@H]3C[C@H](C)CN3C(=O)OC(C)(C)C)[nH]2)ccc1-4)C(C)C
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(-c2cnc([C@@H]3C[C@H](C)CN3C(=O)[C@H](NC(=O)OC)c3ccccc3)[nH]2)ccc1-4)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl (2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate (80 mg, 0.11 mmol) in 1.25 N HCl in EtOH (2 mL) was heated to 50° C. for 3 h. The reaction was concentrated and the crude material dissolved in DMF (1.5 mL). To this solution was added a solution of (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (29 mg, 0.14 mmol) and COMU (52 mg, 0.12 mmol). To the resulting solution was added diisopropylethylamine (0.057 mL, 0.33 mmol). After stirring for 2 h at room temperature, the reaction was quenched with 1N HCl (0.200 mL) and purified by HPLC. After lyophilization, the TFA salt was dissolved in EtOAc and washed with saturated NaHCO3. The organic phase was dried over Na2SO4 and concentrated. The free base was then dissolved in MeCN/H2O and lyophilized to afford methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate: (42 mg, 45%). LCMS-ESI+: calculated for C48H52N8O7: 852.4; observed [M+1]+: 854.2.
Reaction SMILES: C1(OC)C=CC=CC=1.F.[NH2:10][C@H:11]([C:22]([OH:24])=[O:23])[CH2:12][CH2:13][CH2:14][NH:15]C(=N)N[N+]([O-])=O>>[NH2:10][C@H:11]([C:22]([OH:24])=[O:23])[CH2:12][CH2:13][CH2:14][NH2:15]
Reactant: N=C(NCCC[C@H](N)C(=O)O)N[N+](=O)[O-]
Agent: F
Solvent: COc1ccccc1
Product: NCCC[C@H](N)C(=O)O
Reaction time: 7 h

Procedure:
On this basis Suzuki et al. first carried out a solid-phase synthesis, in which a Boc-Asp(ONb)-Ser(Bzl)-Asp(ONb)-Pro-Arg(NO2) resin was produced stepwise from Boc-Arg(NO2)-OH, which was esterified to a chloromethylated styrene-copolymer resin, coupling with Boc-Asp-(ONb)-OH being performed in the last step. The resin was treated in traditional manner with a hydrogen fluoride anisole mixture, and the crude peptide obtained was hydrogenated for 7 hours to remove the (ONb) groups from Asp in the presence of Pd-on-carbon in water. Product was obtained in a yield of 22% calculated on Boc-Arg(NO2) resin used. Suzuki has not described analysis of side products, but it is well known that hydrogenation of Arg(NO2) gives rise to formation of ornithine, which it is difficult to remove.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[S:26]1(=[O:32])(=[O:31])[CH2:30][CH2:29][CH2:28][NH:27]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[N:7][C:2]([N:27]5[CH2:28][CH2:29][CH2:30][S:26]5(=[O:32])=[O:31])=[CH:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: O=S1(=O)CCCN1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)nn2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)nn2)CC1
Yield: 39.8 %

Procedure:
Using (6-chloropyridazin-3-yl) [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (179 mg) described in Preparation Example 233 and isothiazolidine 1,1-dioxide (61 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (88 mg) was obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=2)[N:11]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[CH:10]=1)=[O:8].[Br:23]N1C(=O)CCC1=O>CC(O)=O>[Br:23][C:5]1[S:1][C:2]([NH:6][C:7]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[CH:10]=2)=[O:8])=[N:3][CH:4]=1
Reactant: O=C(Nc1nccs1)c1cn(CC2CC2)c2cc(F)ccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: O=C(Nc1ncc(Br)s1)c1cn(CC2CC2)c2cc(F)ccc12
Yield: 32 %

Procedure:
1-Cyclopropylmethyl-6-fluoro-1H-indole-3-carboxylic acid thiazol-2-ylamide (2.5 mmol), N-bromosuccinimide (6 mmol) was stirred in HOAc (25 mL) over night at room temperature. The reaction mixture was evaporated to dryness and the crude product was purified by flash chromatography (Horizon, EtOAc-heptane) to give 1-cyclopropylmethyl-6-fluoro-1H-indole-3-carboxylic acid (5-bromo-thiazol-2-yl)-amide in 32% yield. A solution of 1-cyclopropylmethyl-6-fluoro-1H-indole-3-carboxylic acid (5-bromo-thiazol-2-yl)-amide (0.2 mmol), p-cresol (0.2 mmol) and potassium-t-butoxide (0.44 mmol) in DME (3 mL) was heated in a closed vessel in a Smith Creator microwave oven for 300 s at 120° C. Addition of water followed by extraction with DCM, drying of the organic phase followed by purification by preparative HPLC (Method E) gave the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:25][C:26]([O:28]CC)=[O:27])[C:4]([CH3:24])=[CH:5][C:6]=1[C:7](=[O:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[OH-].[Na+]>>[CH3:1][C:2]1[N:3]([CH2:25][C:26]([OH:28])=[O:27])[C:4]([CH3:24])=[CH:5][C:6]=1[C:7](=[O:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15]
Reactant: CCOC(=O)Cn1c(C)cc(C(=O)c2ccccc2S(=O)(=O)N2CCOCC2)c1C
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C(=O)c2ccccc2S(=O)(=O)N2CCOCC2)c(C)n1CC(=O)O
Yield: 48.7 %

Procedure:
General procedure I (step 1 and 2) was followed using ethyl 2-(2,5-dimethyl-3-(2-(morpholinosulfonyl)benzoyl)-1H-pyrrol-1-yl)acetate (0.0500 g, 0.115 mmol) and 1M sodium hydroxide solution (0.345 ml, 0.345 mmol) to afford 2-(2,5-dimethyl-3-(2-(morpholinosulfonyl)benzoyl)-1H-pyrrol-1-yl)acetic acid (22.8 mg, 0.0560 mmol, 49% yield). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.85 (d, 1H), 7.62 (ddd, 1H), 7.56 (app. td, 1H), 5.72 (s, 1H), 4.55 (s, 2H), 3.68-3.70 (m, 4H), 3.13-3.16 (m, 4H), 2.45 (s, 3H), 2.09 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[NH:13][CH2:14][CH2:15][N:16]=1.[Br:17]Br.N>CC(O)=O.[Hg](OC(C)=O)OC(C)=O>[Br:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([Br:17])[C:3]=1[NH:11][C:12]1[NH:13][CH2:14][CH2:15][N:16]=1
Reactant: BrBr
Reactant: Brc1c(NC2=NCCN2)ccc2nc[nH]c12
Agent: CC(=O)O[Hg]OC(C)=O
Agent: N
Solvent: CC(=O)O
Product: Brc1cc2nc[nH]c2c(Br)c1NC1=NCCN1
Yield: 86 %

Procedure:
To a solution of 4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole (0.2 g, 0.7 mmol) in 10 ml AcOH was added 200 mg of Hg(OAc)2 and few drops of Br2. Reaction mixture was concentrated in vacuo, yielding a dark oily residue, which was subjected to silica gel column chromatography (NH3 sat'd 30% MeOH/EtOAc) to provide 210 mg (0.58 mmol, 86%) of the desired product. The product obtained was converted to the fumarate salt and recrystallized from EtOH to afford 0.051 g (14%) of the product as a white solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:7][CH:6]=1)=O.[Cl-].[OH:27][NH3+:28].N1C=CC=CC=1>C(O)C>[F:1][C:2]([F:25])([F:24])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:7][CH:6]=1)=[N:28][OH:27]
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)C(F)(F)F)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: CCO
Solvent: c1ccncc1
Product: CCCCCCCCCCCCOc1ccc(C(=NO)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
15 g (41.8 mmol) of 2,2,2-trifluoro-1-(4-dodecyloxyphenyl)-ethanone are dissolved in 100 ml of ethanol. To the solution are added 3.5 g (50.2 mmol) of hydroxylammonium chloride and 10.1 ml (125.4 mmol) of pyridine. The reaction mixture is refluxed for two hours, and the solvent is distilled off by a rotary evaporator. The residue is poured into 100 ml of water, and extracted with 100 ml and then with 50 ml of ethyl acetate. The organic phase is washed with potassium hydrogen sulfate aqueous solution, water, and brine, dried over MgSO4, and concentrated. The residue is dissolved in 100 ml of methylene chloride. To the solution is added 4.2 g of conc. HCl. The reaction mixture is stirred at room temperature overnight, and poured into water. After the aqueous phase is removed, the organic phase is washed with water and brine, dried over MgSO4, and concentrated. The residue is purified by recrystallization from hexane, yielding 9.7 g of 2,2,2-trifluoro-1-(4-dodecyloxyphenyl)-ethanone oxime as a white solid with a melting point of 75-76° C. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 0.89(t, 3H), 1.21-1.40 (m, 16H), 1.40-1.52 (m, 2H), 1.80 (m, 2H), 3.99 (t, 2H), 6.97 (d, 2H), 7.53 (d, 2H), 8.43 (s, 1H). The spectrum indicates that the compound is a single isomer, which is tentatively assigned as Z-conformation. When sulfuric acid is used in place of HCl, 2,2,2-trifluoro-1-(4-dodecyloxyphenyl)-ethanone oxime of the single isomer is also obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:10](=[O:11])[NH:9][C:7]1=[S:8].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C>N1C=CC=CC=1>[C:20]([O:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:10](=[O:11])[NH:9][C:7]1=[S:8])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=c1cc(-c2ccccc2)n(COCCO)c(=S)[nH]1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(OCCOCn1c(-c2ccccc2)cc(=O)[nH]c1=S)c1ccccc1
Yield: 88.9 %

Procedure:
An amount of 294 mg (1 mmol) of 1-[(2-hydroxyethoxy)methyl]-6-phenylthiouracil was dissolved in 5 ml pyridine. To this solution 0.17 ml (1.5 mmol) of benzoyl chloride was added and the reaction mixture was allowed to react at room temperature for 2 hours. After the reaction, it was distributed between ethyl acetate and aqueous layers, and the said ethyl acetate layer then concentrated to dryness. The residue was crystallized from toluene to obtain 340 mg of 1-[(2-benzoyloxyethoxy)methyl]-6-phenylthiouracil (Yield: 85%). This was then suspended in 5 ml of toluene, and to this solution 449 mg (1.11 mmol) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4 diphosphetane-2,4-disulfide was added and the reaction mixture was allowed to react at 100° C. for 3 hours. After the reaction, the reaction mixture was distributed between ethyl acetate and aqueous layers, the ethyl actate layer concentrated to dryness. The residue was dissolved in 2 ml of tetrahydrofuran and 5 ml of ethanol. To this solution 2.25 ml of 1N sodium hydroxide aqueous solution was added and the reaction mixture was allowed to react at room temperature for 1 hour. It was then neutralized with hydrochloric acid, and concentrated to dryness. The residue was distributed between ethyl acetate and aqueous layers, and the said ethyl acetate layer was then concentrated to dryness. The resultant was dissolved in a small amount of chloroform, adsorbed on a silica gel column and eluted with 2.5% methanol/chloroform. The eluate was concentrated and dried to obtain a residue, which was crystallized from toluene to obtain 141 mg of the target compound (Yield: 53%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[NH:12][C:11]([CH:13]=[O:14])=[C:10](C(O)=O)[C:9]=1[CH2:18][CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[I:25]I>C(Cl)Cl.O>[CH2:18]([C:9]1[C:10]([I:25])=[C:11]([CH:13]=[O:14])[NH:12][C:8]=1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:19]
Reactant: CCc1c(C(=O)OC(C)(C)C)[nH]c(C=O)c1C(=O)O
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCc1c(C(=O)OC(C)(C)C)[nH]c(C=O)c1I
Temperature: 25 °C

Procedure:
To a solution of 5-(tert-butoxycarbonyl)-4-ethyl-2-formyl-1H-pyrrole-3-carboxylic acid (0.548 g, 2.05 mmol) in CH2Cl2 (8.30 mL) was added a solution of NaHCO3 (0.691 g, 8.21 mmol) water (8.2 mL). The mixture was stirred vigorously during the addition of a solution of KI (1.021 g, 6.15 mmol) and I2 (0.570 g, 2.23 mmol) in water (11.15 mL). The resultant mixture was heated to 45° C. for 60 min until the initial red/brown color faded. The reaction was cooled to ambient temperature and quenched with saturated aqueous Na2SO3 (25 ml) prior to separation of the phases. The aqueous layer was extracted with CH2Cl2 (1×30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The resultant residue was purified by normal phase chromatography (10-30% ethyl acetate/hexanes). Proton NMR for the product was consistent with the title compound. 1H NMR (500 MHz, CD3OD) δ 9.59 (s, 1H); 2.77 (q, J=7.6 Hz, 2H); 1.60 (s, 9H); 1.10 (t, J=7.6 Hz, 3H). HRMS (ES) exact mass calculated for C12H16INNaO3 (M+Na+): 372.0072. Found 372.0067.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([Cl:10])=[C:6]([CH:9]=1)[CH:7]=O.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.[O-]S([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C(Cl)Cl.CO.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([Cl:10])=[C:6]([CH2:7][NH:15][CH:12]2[CH2:14][CH2:13]2)[CH:9]=1
Reactant: O=Cc1cc(Br)cc(Cl)c1Cl
Reactant: NC1CC1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: Clc1cc(Br)cc(CNC2CC2)c1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5-Bromo-2,3-dichlorobenzaldehyde (1 eq.) from the previous step and cyclopropylamine (2 eq.) were combined in CH2Cl2 (0.1 M). To this was then added MgSO4 (1 eq.) and the resulting suspension was stirred at RT for 18 h. The insolubles were then removed via filtration through a pad of celite and the filtrate was concentrated in vacuo. The crude imine thus obtained was then re-taken up in a 2:1 (v/v) mixture of THF:MeOH (0.17 M). To this solution was added sodium borohydride (10 eq.) portionwise and the resulting mixture was stirred at RT for 48 h. The reaction was quenched with 1 N aq. HCl, neutralized with 1 N aq. NaOH and extracted with ether. The combined organic extracts were then washed with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[C:21]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:13][C:12]=2[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:33]1[O:34][C:35]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[CH:36][C:37](=[O:39])[CH:38]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[C:21]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:13][C:12]=2[C:11]([C:33]2[O:34][C:35]([N:40]3[CH2:41][CH2:42][O:43][CH2:44][CH2:45]3)=[CH:36][C:37](=[O:39])[CH:38]=2)=[CH:10][CH:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)c2c1Cc1ccccc1S2
Reactant: O=c1cc(Cl)oc(N2CCOCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cc(=O)cc(N3CCOCC3)o2)c2c1Cc1ccccc1S2
Temperature: 100 °C

Procedure:
[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-9H-thioxanthen-1-yl]-carbamic acid tert-butyl ester (2.90 g, 6.50 mmol) was introduced to a solution of 2-Chloro-6-morpholin-4-yl-pyran-4-one (3)(1.4 g, 6.50 mmol) in anhydrous dioxane (6 mL). Powdered K2CO3 (2.01 g, 14.50 mmol) was added and the mixture degassed (sonication for 20 mins then saturated with N2). To the degassed solution was added Tetrakis (triphenylphosphine) palladium (0.39 g) before it was degassed for a further 20 minutes. A reflux condenser was attached to the reaction vessel which was submerged into an oil bath maintained at 100° C. for 14 hours whereupon the golden mixture was cooled and diluted with EtOAc (50 ml) and then washed with water (20 ml) and saturated brine (20 ml). Organic extract was dried using MgSO4, filtered and concentrated in vacuo to give the title compound as a light brown oil that was used without further purification. m/z (LC-MS, ESP): 493 [M+H]+, R/T=4.41 mins.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:11][CH:12]([CH3:16])[C:13](O)=[O:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:13](=[O:14])[CH:12]([SH:11])[CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCc1ccccc1
Reactant: CC(S)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(S)C(=O)OCCCc1ccccc1

Procedure:
Into a 100 ml reaction flask equipped with reflux condenser, hot plate (with stirring apparatus contained within) and spin bar are placed 13.6 grams phenylpropyl alcohol; 4.0 grams of 2-mercaptopropionic acid; and 0.1 grams of para-toluene sulphonic acid. The reaction mass is maintained at reflux for a period of 9 hours with stirring. At the end of the 9 hour period, the reaction mass is cooled and fractionally distilled on a micro distillation apparatus yielding the compound having the structure: ##STR64## (as confirmed by GLC, mass spectral, NMR and IR analyses).
Reaction SMILES: [NH3:1].[CH3:2][N:3]([CH3:31])[CH:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[C:22]3[C:21]4[C@@H:20]([CH2:23][C:24]([F:30])([F:29])[C:25]([O:27]C)=O)[CH2:19][CH2:18][C:17]=4[S:16][C:15]=3[N:14]=[CH:13][N:12]=2)[CH2:6][CH2:5]1>C(O)C>[CH3:2][N:3]([CH3:31])[CH:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[C:22]3[C:21]4[C@@H:20]([CH2:23][C:24]([F:30])([F:29])[C:25]([NH2:1])=[O:27])[CH2:19][CH2:18][C:17]=4[S:16][C:15]=3[N:14]=[CH:13][N:12]=2)[CH2:6][CH2:5]1
Reactant: N
Reactant: COC(=O)C(F)(F)C[C@H]1CCc2sc3ncnc(OC4CCC(N(C)C)CC4)c3c21
Solvent: CCO
Product: CN(C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(F)(F)C(N)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of NH3 (g) was transferred into ethanol (20 mL) over 30 min. This was followed by the addition of methyl 3-[(3R)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]-2,2-difluoropropanoate (103 mg, 0.23 mmol, 1.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-016(Waters)): column: XBridge Prep C18 OBD column: 5 um, 19*150 mm; mobile phase: water (50 mM NH4HCO3) and CH3CN (14.0% CH3CN up to 33.0% in 12 min, up to 95.0% in 1 min, down to 14.0% in 2 min); Detector, UV 254/220 nm. The product was freeze-dried. This resulted in 3-[(3R)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]-2,2-difluoropropanamide (41.3 mg, 42%) as a white solid. 1H NMR (300 MHz, CD3OD): δ 8.51 (s, 1H), 5.30-5.23 (m, 1H), 3.66-3.51 (m, 1H), 3.32-2.70 (m, 4H), 2.51-2.01 (m, 13H), 1.74-1.44 (m, 4H). MS: m/z 425 (M+H)+.