Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:13]([O-])([O-])=O.[K+].[K+].ClC[CH2:21][C:22]([CH3:27])([CH3:26])[C:23]([O-:25])=[O:24]>CC#N>[CH3:21][C:22]([CH3:27])([CH3:26])[C:23]([O:25][CH2:13][N:10]1[CH:11]=[N:12][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)=[N:9]1)=[O:24]
Reactant: CC(C)(CCCl)C(=O)[O-]
Reactant: Brc1cccc(-c2nc[nH]n2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)C(=O)OCn1cnc(-c2cccc(Br)c2)n1
Reaction time: 0.33 h

Procedure:
A slurry of 3-(3-bromophenyl)-1H-1,2,4-triazole (58.5 g; 261 mmol; Step 1 above), anhydrous K2CO3 (43.2 g; 313 mmol), and chloromethylpivalate (45 mL; 313 mmol) in dry MeCN (250 mL) was heated to 80° C. (Note 1) for 1 hour. The mixture was cooled, solid was collected by filtration and the filtrate was concentrated in vacuo Residue from the filtaret was combined with the filtered solid and the whole was stirred with water approximately 20 minutes. Solid was collected by filtration, washed with water (×3) and recrystallized from MeOH/water, affording the title compound as a colorless solid. LC/MS (method E) tR 0.88 min, m/z 338, 340 (M+H, Br isotopes).
Reaction SMILES: [F:1][C:2]1[C:3]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[C-:30]#[N:31].[K+].[OH2:33]>CC#N>[C:21]([N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:5]3[N:4]=[C:3]([N:24]4[CH2:29][CH2:28][N:27]([C:30]([NH2:31])=[O:33])[CH2:26][CH2:25]4)[C:2]([F:1])=[CH:7][N:6]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17]1)(=[O:23])[CH3:22]
Reactant: [C-]#N
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCNCC4)n3)cc2)CC1
Reactant: O
Agent: [K+]
Solvent: CC#N
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCN(C(N)=O)CC4)n3)cc2)CC1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a suspension of 1-(4-(4-(5-fluoro-4-(piperazin-1-yl)pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (53 mg, 0.13 mmol) in CH3CN (2 mL), a solution of KCN (60 mg, 0.74 mmol) in H2O (2 mL) was added. The suspension became clear. The mixture was stirred at 70° C. for 3 h. It was then purified by HPLC to give the titled compound (15 mg). MS 443.3 (M+H); UV 201.8, 269.8 nm.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH:16]([CH:20]5[CH2:22][CH2:21]5)[CH2:15]4)[CH:12]=3)[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:28]=O>C(O)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH3:28])[CH:16]([CH:20]5[CH2:21][CH2:22]5)[CH2:15]4)[CH:12]=3)[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C=O
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNC(C4CC4)C3)c(F)cc2c1=O
Solvent: O=CO
Product: CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1C1CC1
Temperature: 100 °C

Procedure:
A mixture of 210 mg of 1-cyclopropyl-7-(3-cyclopropyl-1-piperazinyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.24 ml of 37% formaldehyde and 0.30 ml of 90% formic acid was heated at 100° C. for 4 hours, then allowed to cool and the excess reagents removed under reduced pressure. Water was added and the pH adjusted to 7 with 1N sodium hydroxide. The mixture was then extracted several times with chloroform:methanol (95:5), the extracts combined, dried, filtered and evaporated. The resulting oil was triturated with ether, giving 170 mg of the desired product.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26](OC(C)(C)C)=O)[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.[F:40][C:41]([F:54])([F:53])[O:42][C:43]1[CH:48]=[CH:47][C:46]([CH:49]=[CH:50]C=O)=[CH:45][CH:44]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH:50]=[CH:49][C:46]4[CH:45]=[CH:44][C:43]([O:42][C:41]([F:40])([F:53])[F:54])=[CH:48][CH:47]=4)[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: O=CC=Cc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCN(C[C@@]3(C)Cn4cc([N+](=O)[O-])nc4O3)CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@]1(CN2CCN(C3CCN(CC=Cc4ccc(OC(F)(F)F)cc4)CC3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 48.8 %

Procedure:
Tert-butyl (S)-4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]piperidine-1-carboxylate (750 mg, 1.66 mmol) was dissolved in methylene chloride (5 ml), trifluoroacetic acid (5 ml) was added followed by stirring at room temperature for 1.5 hours. The reaction mixture was concentrated. To the residue, methylene chloride (5 ml) and triethylamine (5 ml) were added, and the mixture was stirred at room temperature for 10 minutes and then concentrated. The residue was dissolved in 1,2-dichloroethane (20 ml), 3-(4-trifluoromethoxyphenyl)propenal (396 mg, 1.83 mmol) and sodium triacetoxyborohydride (564 mg, 2.66 mmol) were added followed by stirring at room temperature for 3.5 hours. The reaction solution was washed with a saturated sodium hydrogencarbonate solution (15 ml), water (20 ml), and a saturated saline solution (20 ml) in this order, and then dried over sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=10/1) and then recrystallized from methanol/water to obtain (S)-2-methyl-6-nitro-2-[4-{1-[3-(4-trifluoromethoxyphenyl)-2-propenyl]piperidin-4-yl}piperazin-1-ylmethyl]-2,3-dihydroimidazo[2,1-b]oxazole (446 mg, 49%) as a light yellow powder.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:18]1[N:19]=[CH:20][N:21]([CH3:30])[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1>>[C:1]1([NH:7][C:8]([C:20]2[N:21]([CH3:30])[C:22]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[C:18]([C:12]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=3[Cl:10])[N:19]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cn1cnc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Product: Cn1c(C(=O)Nc2ccccc2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
Using essentially the same procedure as Example 36, Method A, but using phenyl isocyanate (0.023 mL, 0.21 mmol), 4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1-methylimidazole (35 mg, 0.10 mmol) was converted to the title compound after purification by Prep TLC (25% ethyl acetate in hexanes). HPLC/MS: 456 (M+1), 458 (M+3); Rt=4.75 min.
Reaction SMILES: C[Si](Cl)(C)C.[C:6]1(=[O:13])[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[CH2:7]1.[CH:14]([C:16]1[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=1)=O.[F:24][C:25]([F:37])([F:36])[C:26]1[CH:27]=[C:28]([NH:32][C:33]([NH2:35])=[O:34])[CH:29]=[CH:30][CH:31]=1>CN(C)C=O.C(#N)C.O>[C:22]([C:19]1[N:20]=[CH:21][C:16]([CH:14]([C:7]2[C:8](=[O:12])[CH2:9][CH2:10][CH2:11][C:6]=2[OH:13])[NH:35][C:33]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:24])([F:36])[F:37])[CH:27]=2)=[O:34])=[CH:17][CH:18]=1)#[N:23]
Reactant: O=C1CCCC(=O)C1
Reactant: N#Cc1ccc(C=O)cn1
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Agent: C[Si](C)(C)Cl
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(NC(=O)Nc2cccc(C(F)(F)F)c2)C2=C(O)CCCC2=O)cn1
Temperature: 50 °C

Procedure:
Trimethylsilyl chloride (125 μL, 0.982 mmol) is added to a solution of cyclohexane-1,3-dione (100 mg, 0.892 mmol), 5-formylpicolinonitrile (118 mg, 0.892 mmol) and 1-(3-(tri-fluoromethyl)phenyl)urea (183 mg, 0.829 mmol) in a mixture of N,N-dimethylformamide (670 μL) and acetonitrile (1.2 mL), and the mixture is heated at 50° C. for 1 h. The reaction mixture is cooled to room temperature and poured into a mixture of water and ice. The mixture is filtered, and the precipitate is washed with water and dried under reduced pressure. Yield: 346 mg; ESI mass spectrum [M+H]+=431, Retention time HPLC: 0.67 min (V011_S01).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH2:12][C:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:15]([OH:17])=O)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl>[C:1]([N:9]1[CH2:14][CH2:13][CH2:12][C:11]2([CH2:18][C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:15]2=[O:17])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N1CCCC(Cc2ccccc2)(C(=O)O)C1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCCC2(Cc3ccccc3C2=O)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51.3 %

Procedure:
A mixture of 1-benzoyl-3-benzyl-piperidine-3-carboxylic acid (6.71 g, 20.7 mmol) and thionyl chloride (2.70 g, 22.77 mmol) in dry CH2Cl2 (25 mL) was heated to reflux for 30 min. The resulting solution was concentrated in vacuum to give alight brown oil. A solution of this oil in dry CH2Cl2 (25 mL) was added dropwise to a mixture of AlCl3 (3.59 g, 26.91 mmol) in CH2Cl2 (10 mL) at 0° C. The mixture was stirred for 15 min at 0° C. and then heated to reflux for 45 min. The mixture was cooled and poured onto crushed ice and 12 N aq HCl. The organic layer was separated, washed with 3 N aq HCl, saturated Na2CO3, water and brine. Finally the organic layer was concentrated to give a residue, which was purified by silica gel column chromatography (petroleum/ethyl acetate 5:1 to 1:1) to afford 1′-benzoylspiro[indene-2,3′-piperidin]-1(3H)-one (3.24 g, 51%). 1H NMR (CD3OD, 400 MHz): δ=1.61 (m, 4H), 2.68 (m, 2H), 3.46 (m, 4H), 7.34 (m, 8H), 7.64 (m, 2H).
Reaction SMILES: B.[I:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](O)=[O:11])[CH:6]=[CH:7][CH:8]=1.[Cl-].[NH4+]>C1COCC1>[I:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1cccc(I)c1
Agent: B
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OCCc1cccc(I)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
A solution of borane (1M, THF, 2.5 eq., 38.2 mL) was added dropwise to a stirred solution of (3-iodophenyl)acetic acid (4.0 g) in THF (100 mL) cooled to 0□C. The resulting mixture was stirred at 0 □C for 1 h then warmed to room temperature and stirred for a further 3 h. The mixture was poured into aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic phases were washed with brine, dried (sodium sulfate) and concentrated. The crude was purified by column chromatography (SPE cartridge, SiO2), using cyclohexane-ethyl acetate (70:30) as eluent to afford the title compound (3.5 g, 92% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:19])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]([O:15]CC)=[O:14])[C:6]=2[CH:18]=1.[Li+].[OH-].O.Cl>C1COCC1.C(O)(=O)C>[Cl:1][C:2]1[C:3]([Cl:19])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]([OH:15])=[O:14])[C:6]=2[CH:18]=1
Reactant: CCOC(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(O)CN1C(=O)COc2cc(Cl)c(Cl)cc21
Reaction time: 1 h

Procedure:
Ethyl (6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetate (52.6 g, 0.173 mol) and LiOH (8.31 g, 0.347 mol) were combined in 750 mL of THF and 150 mL of water and stirred at room temperature for 18 hours, after which time HPLC indicated loss of the starting material. 80 mL of concentrated HCl was added and the mixture was stirred for 1 hour, and then evaporated to dryness. The residue was dissolved in EtOAc and water was added. The layers were separated and the organic layer was washed with water (2×). The organic layer was dried over magnesium sulphate and concentrated to give 45.5 g (0.165 mol, 95%) of 6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetic acid. MS (ES) m/e 278 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[CH3:9][C:8]([NH:17][C:16]1[CH:18]=[CH:19][C:13]([F:12])=[CH:14][CH:15]=1)=[O:10]
Reactant: CC(=O)Cl
Reactant: Nc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Triethylamine (31 ml) and acetyl chloride (15 ml) were added dropwise to a chloroform (100 ml) solution of 4-fluoroaniline (22.3 g) in this order under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The thus-obtained solid was washed with water, collected by filtration, and recrystallized from ethanol-water to obtain colorless crystals of 4-fluoroacetanilide (25.5 g; yield, 83%).
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OP(Cl)(OC2C=CC=CC=2)=O)C=CC=CC=1.[NH2:34][C@@H:35]1[CH:40]2[CH2:41][CH2:42][N:37]([CH2:38][CH2:39]2)[CH2:36]1.CO>C(Cl)Cl>[N:37]12[CH2:42][CH2:41][CH:40]([CH2:39][CH2:38]1)[C@@H:35]([NH:34][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:16][CH:15]=1)[CH2:36]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
TEA (50 μL, 0.35 mmol) is added to a suspension of 4-phenoxybenzoic acid (75 mg, 0.35 mmol) in CH2Cl2 (1 mL). Diphenylchlorophosphate (62 μL, 0.3 mmol) is added and the resulting solution is stirred at room temperature for 30 minutes. A solution of (R)-3-aminoquinuclidine (1M in DMF, 0.2 mL, 0.2 mmol) is added and the resulting solution is stirred overnight at room temperature. MeOH is added and the mixture is poured through a column of AG50W×2 ion exchange resin (H+ form). The resin is washed with MeOH and then the product is eluted with 5% TEA in MeOH. The eluent is evaporated to dryness to yield the desired product (49 mg, 76%). MS for C20H22N2O2 (ESI) (M+H)+ m/z 323.
Reaction SMILES: [C:1]([C:4]1(C(O)=O)[CH:16]=[CH:15][C:14]2[N:13]([Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[C:12]3[CH2:11][CH2:10][CH:9]([N:27]([CH3:29])[CH3:28])[CH2:8][C:7]=3[C:6]=2[CH2:5]1)([OH:3])=O.[CH3:33][Li].C([O:37][CH2:38][CH3:39])C>O>[C:1]([C:4]1([C:38](=[O:37])[CH3:39])[CH:16]=[CH:15][C:14]2[N:13]([Si:17]([CH:21]([CH3:23])[CH3:22])([CH:24]([CH3:25])[CH3:26])[CH:18]([CH3:20])[CH3:19])[C:12]3[CH2:11][CH2:10][CH:9]([N:27]([CH3:29])[CH3:28])[CH2:8][C:7]=3[C:6]=2[CH2:5]1)(=[O:3])[CH3:33]
Reactant: CCOCC
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1c2c(c3c1CCC(N(C)C)C3)CC(C(=O)O)(C(=O)O)C=C2
Reactant: [Li]C
Solvent: O
Product: CC(=O)C1(C(C)=O)C=Cc2c(c3c(n2[Si](C(C)C)(C(C)C)C(C)C)CCC(N(C)C)C3)C1
Temperature: 25 °C
Yield: 69 %

Procedure:
To a solution of 2.0 gm (4.8 mMol) 6-carboxy-3-(dimethyl)amino-6-carboxy-9-triisopropylsilyl-1,2,3,4-tetrahydro-9H-carbazole in 100 mL diethyl ether at 0° C. were added 8 mL (9.6 mMol) methyllithium (1.2M in diethyl ether) over a 15 minute period. After an hour an additional 0.4 mL of the methyllithium solution were added. 0.4 mL additions were continued until all of the starting material had reacted. The reaction mixture was then allowed to warm to room temperature and to it was first added ice and then the reaction mixture was diluted with 100 mL of water. The mixture was shaken and the phases separated. The aqueous phase was twice extracted with 100 mL aliquots of fresh diethyl ether. All of the organic extracts were combined, washed with saturated aqueous sodium chloride and concentrated under reduced pressure. The residue was subjected to florisil chromatography, eluting sequentially with toluene, 9:1 toluene:ethyl acetate, 4:1 toluene:ethyl acetate, 1:1 toluene:ethyl acetate, and ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to give 1.37 gm (69%) of the desired product as a solid.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[O:11]=[CH:12][C@@H:13]([C@@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14]>CO.O>[O:1]=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[O:11]=[CH:12][C@H:13]([C@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14].[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Solvent: CO
Product: O=C[C@@H](O)[C@@H](O)[C@H](O)CO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)CO

Procedure:
By means of this process it is possible for example to epimerize an approximately 35% strength by weight solution of arabinose in 1:1 methanol/water to D-ribose with a conversion of 35% and a ribose selectivity of 91% without forming detectable amounts of D-lyxose or xylose. The sugar loss is only about 3%. The product solution thus obtained has only a slight yellow color. It can be concentrated to a dry substance content of about 70% to crystallize the bulk of the unconverted arabinose in at least 99% purity, which can be recycled into the epimerization.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([CH2:21][NH:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:20]=1)[CH2:5][N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].CCN(CC)CC.[Cl:34][C:35]1[C:36]([OH:46])=[C:37]([S:42](Cl)(=[O:44])=[O:43])[CH:38]=[C:39]([Cl:41])[CH:40]=1>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([CH2:21][N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:42]([C:37]2[CH:38]=[C:39]([Cl:41])[CH:40]=[C:35]([Cl:34])[C:36]=2[OH:46])(=[O:43])=[O:44])[CH:20]=1)[CH2:5][N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: CC(C)CNCc1cc(Cl)cc(CN(CC(C)C)C(=O)OC(C)(C)C)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CN(Cc1cc(Cl)cc(CN(CC(C)C)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
To a solution of tert-butyl 3-chloro-5-((isobutylamino)methyl)benzyl(isobutyl)carbamate (2.4 g, 6.27 mmol) in CH2Cl2 (30 mL) was added Et3N (1.3 mL, 9.40 mmol), followed by the addition of 3,5-dichloro-2-hydroxybenzenesulfonyl chloride (1.80 g, 6.89 mmol). The reaction mixture was stirred at rt for 2 h. The mixture was diluted with CH2Cl2 and water. The organic layer was washed with saturated NaHCO3 solution, NH4Cl solution, brine solution, and dried over MgSO4. The filtrate was concentrated and the residue was purified by silica gel flash chromatography. The column was eluted with hexane to 80% dichloromethane in hexane. The fractions containing the desired product were combined and concentrated to give colorless viscous solid (2.8 g, 72%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([NH2:11])[CH2:5][C@H:6]1[CH2:9][C@H:8]([CH3:10])[CH2:7]1.C(N(CC)C(C)C)(C)C.[Cl:22][C:23]1[CH:56]=[CH:55][CH:54]=[CH:53][C:24]=1[O:25][C:26]1[CH2:30]N([C@@H](CC2CCCCC2)C(NC2C=CN(CC(O)(C)C)N=2)=O)[C:28](=[O:52])[CH:27]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[CH:4]([N:11]1[CH2:30][C:26]([O:25][C:24]2[CH:53]=[CH:54][CH:55]=[CH:56][C:23]=2[Cl:22])=[CH:27][C:28]1=[O:52])[CH2:5][C@H:6]1[CH2:7][C@H:8]([CH3:10])[CH2:9]1
Reactant: COC(=O)C(N)C[C@H]1C[C@H](C)C1
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3ccccc3Cl)=CC2=O)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C(C[C@H]1C[C@H](C)C1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 80 °C
Yield: 34.5 %

Procedure:
In a small pressure bottle was placed a mixture of 2-amino-3-(trans-3-methyl-cyclobutyl)-propionic acid methyl ester (147 mg, 0.86 mmol), acetonitrile (6 mL) and N,N-diisopropylethylamine (220 μL, 1.03 mmol) which was heated to 80° C. To this mixture was added (E)-4-bromo-3-(2-chloro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 61, 276 mg, 0.86 mmol) and the tube sealed and heated at 100° C. overnight. The mixture was cooled to room temperature and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (40S column, 16% ethyl acetate/hexanes to 40% ethyl acetate/hexanes) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(trans-3-methyl-cyclobutyl)-propionic acid methyl ester (108 mg, 35%) as an amber oil: HR-ES-MS m/z calculated for C19H22NO4Cl [M+H]+ 364.1310, observed 364.1310.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[O:13]1[CH2:17][CH2:16][CH:15]([C:18]2([CH:22]=[O:23])[CH2:21][CH2:20][CH2:19]2)[CH2:14]1.CC#N>C1COCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:22]([C:18]1([CH:15]2[CH2:16][CH2:17][O:13][CH2:14]2)[CH2:19][CH2:20][CH2:21]1)[OH:23]
Reactant: Brc1ccccn1
Reactant: O=CC1(C2CCOC2)CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC#N
Product: OC(c1ccccn1)C1(C2CCOC2)CCC1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 11.4 %

Procedure:
To a solution of 2-bromopyridine (203 mg, 1.28 mmol) in THF (5 mL) was added 2.5N n-BuLi solution (0.6 mL, 1.54 mmol) dropwise and stirred at −78° C. for 1.5 hours. Then a solution of Example 284C (0.18 g, 1.17 mmol) in THF (2 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was quenched with aqueous NH4Cl solution and extracted with EtOAc (2×20 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by Prep-HPLC(C18 column, water (0.05% TFA):CH3CN, 55:45 to 85:15) to obtain the title compound as a colorless oil (31.2 mg, yield 11.5%). LC-MS: MS (M+H)+ 234.1; 1H NMR (400 MHz, CDCl3): δ 8.55 (d, J=4.8 Hz, 1H), 7.69-7.64 (m, 1H), 7.30 (d, J=7.6 Hz 1H), 7.26-7.22 (m, 1H), 4.71 (d, J=28.8 Hz, 1H), 4.53 (brs, 1H), 3.89-3.79 (m, 1.5H), 3.65-3.54 (m, 2H), 3.38 (t, J=8.6 Hz, 0.5H), 2.35-2.04 (m, 3H), 1.99-1.55 (m, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[N:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH2:20][NH2:21])[CH:17]=[CH:18][CH:19]=1>CS(C)=O>[Cl:12][C:4]1[N:3]=[C:2]([NH:21][CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=2)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1
Reactant: NCc1cccc(F)c1
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)c1
Solvent: CS(C)=O
Product: Fc1cccc(CNc2cc(C(F)(F)F)cc(Cl)n2)c1
Temperature: 90 °C
Yield: 44.8 %

Procedure:
To 2,6-dichloro-4-(trifluoromethyl)pyridine (250 mg, 1.157 mmol) was added DMSO (2 ml), TEA (0.194 ml, 1.389 mmol), and (3-fluorophenyl)methanamine (290 mg, 2.315 mmol). The reaction mixture was stirred at 90° C. until completion as indicated by LCMS, about 1 hour. To the crude reaction mixture was added 1.5 ml of DMSO, filtered and purified by prep LC. After lyophilization, 158 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 305.1 (MH+), rt= 1.21 min.
Reaction SMILES: [H-].[Na+].[C:3]([NH:7][S:8]([C:11]1[N:12]=[C:13]([C:17]2[N:18]([CH2:33][C:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:37]=[CH:36][CH:35]=3)[N:19]=[C:20]3[C:25]=2[C:24](=[O:26])[N:23]([CH3:27])[C:22](=[O:28])[N:21]3[CH2:29][CH:30]([CH3:32])[CH3:31])[N:14]([CH3:16])[CH:15]=1)(=[O:10])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:44]I>CN(C=O)C>[C:3]([N:7]([CH3:44])[S:8]([C:11]1[N:12]=[C:13]([C:17]2[N:18]([CH2:33][C:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:37]=[CH:36][CH:35]=3)[N:19]=[C:20]3[C:25]=2[C:24](=[O:26])[N:23]([CH3:27])[C:22](=[O:28])[N:21]3[CH2:29][CH:30]([CH3:32])[CH3:31])[N:14]([CH3:16])[CH:15]=1)(=[O:9])=[O:10])([CH3:5])([CH3:6])[CH3:4]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3nc(S(=O)(=O)NC(C)(C)C)cn3C)n(Cc3cccc4ccccc34)nc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3nc(S(=O)(=O)N(C)C(C)(C)C)cn3C)n(Cc3cccc4ccccc34)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
NaH (10 mg, 0.25 mmol) was added to a solution of the compound of Example 164 (84 mg, 0.14 mmol) and CH3I (100 μL) in 2 mL DMF. After warming to room temperature and stirring for 16 h, solvent was removed and the residue was partitioned between water and EtOAc. The EtOAc was separated and washed with brine. Drying and removal of solvent gave an oil that was purified by preparative reverse phase HPLC (45%-75% gradient of CH3CN-water with 0.1% TFA).