Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[N:11](S(C4C=CC=CC=4)(=O)=O)[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[OH-].[Na+].C([O-])([O-])=O.[K+].[K+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1.CO.O>[CH2:34]([N:11]1[C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[C:7]=2[CH:13]=[C:12]1[C:14]([OH:16])=[O:15])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1nnc2ccc3c(cc(C(=O)O)n3S(=O)(=O)c3ccccc3)n12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1nnc2ccc3c(cc(C(=O)O)n3Cc3ccccc3)n12
Reaction time: 1 h
Yield: 37.4 %

Procedure:
To a suspension of 1-methyl-6-(phenylsulfonyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid (0.106 g, 0.297 mmol, from Step 3) in THF (2 mL) and methanol (2 mL) was added 1.0 M NaOH (2 mL, 2 mmol) and the reaction was stirred for 1 hour. The reaction was diluted with methanol and was purified by preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). The eluent was evaporated and the resulting solid was dissolved in DMF (3 mL). K2CO3 (0.16 g, 1.2 mmol) followed by benzyl bromide (0.053 mL, 0.45 mmol) were added and the reaction was stirred overnight. The reaction was diluted with water and extracted with three portions of ethyl acetate. The combined extracts were washed with water, then brine, dried over sodium sulfate, filtered and concentrated. The residue was stirred with 1.0 N NaOH (2 mL) in THF (2 mL) and MeOH (2 mL) for 1 hour. Purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH) afforded product (34 mg, 37%). 1H NMR (300 MHz, CD3OD) δ 7.62 (dd, J=9.8, 0.7 Hz, 1H), 7.44 (d, J=0.6 Hz, 1H), 7.29 (d, J=9.8 Hz, 1H), 7.26-7.08 (m, 5H), 6.15 (s, 2H), 2.99 (s, 3H). LCMS (M+H)+: 307.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:27][CH:26]=2)[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11](B1OC(C)(C)C(C)(C)O1)=[CH:10][CH:9]=2)=[O:5])C.Br[C:36]1[N:41]=[CH:40][C:39]([NH:42][CH:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[CH:38][CH:37]=1>>[Cl:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:36]3[CH:37]=[CH:38][C:39]([NH:42][CH:43]4[CH2:47][CH2:46][CH2:45][CH2:44]4)=[CH:40][N:41]=3)[CH:12]=2)[N:7]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:27][CH:26]=2)[C:6]=1[C:4]([OH:3])=[O:5]
Reactant: CCOC(=O)c1c(Cl)c2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1-c1ccc(OC(C)C)cc1
Reactant: Brc1ccc(NC2CCCC2)cn1
Product: CC(C)Oc1ccc(-n2c(C(=O)O)c(Cl)c3cc(-c4ccc(NC5CCCC5)cn4)ccc32)cc1

Procedure:
The title compound was prepared in accordance with Example 8(b) from 3-chloro-1-(4-isopropoxyphenyl)-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-indole-2-carboxylic acid ethyl ester (see Example 35, Method 1, step (c)) and 6-bromopyrid-3-ylcyclopentylamine (see Example 45(b)), followed by ester hydrolysis according to Example 35, Method 3, step (b).
Reaction SMILES: [CH:1]1[C:14]2[N:13]([C:15](Cl)=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18]1[O:20][CH:19]1[CH2:21][OH:22].O1CC1>>[CH:1]1[C:14]2[N:13]([C:15]([O:22][CH2:21][CH:19]3[O:20][CH2:18]3)=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)N1c2ccccc2Sc2ccccc21
Reactant: OCC1CO1
Solvent: C1CO1
Product: O=C(OCC1CO1)N1c2ccccc2Sc2ccccc21

Procedure:
Phenothiazine N-carbonyl chloride, 1.5 g (6 mmol) and 6 mmol of glycidol were heated in a reflux apparatus equipped with a drying tube at 90° C. for 10 hours on an oil bath. Then the reflux apparatus was converted for distillation and the excess glycidol was removed under vacuum at this temperature. The resulting brown oil solidified upon cooling and was dissolved in chloroform, treated with charcoal, dried and evaporated to dryness. Recrystallization of the resulting solid from ethanol gave the product: 1.0 g (55%), tan crystals m.p. 92°-94° C. NMR: (CDCl3) 7.3, 8H, m, phenyl; 4.5, 2H, d, d, exocyclic --CH2 --; 3.4, 1H, m, CH; 2.9, 2H, m, endocyclic --CH2 --. IR: 1710, carbonyl; 1250, 900, oxirane; 750, aromatic.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[O:12][C:13](=O)[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH3:25].O>CC(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:9]=1[N:10]=[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[NH:25][C:13]2=[O:12])([O-:3])=[O:2]
Reactant: N
Reactant: O=c1oc(-c2cccc(C(F)(F)F)c2)nc2c([N+](=O)[O-])cccc12
Solvent: CC(C)O
Solvent: O
Product: O=c1[nH]c(-c2cccc(C(F)(F)F)c2)nc2c([N+](=O)[O-])cccc12
Temperature: 25 °C
Yield: 60.3 %

Procedure:
8-nitro-2-(3-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]oxazin-4-one 3 (150 mg, 0.45 mmol) was added to a solution of ammonia (5.0 mL, 10 mmol) in IPA. The reaction mixture was heated under gentle reflux for 12 h then cooled to room temperature. The reaction mixture was poured into H2O and the resulting precipitate was collected by filtration rinsed with H2O and dried under vacuum. The crude residue was recrystallized from EtOAc to give 8 (91 mg, 62% yield) as a yellow solid.
Reaction SMILES: [N+](CCCC)(CCCC)(CCCC)CCCC.[F-].[N:19]1([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([Si](C(C)C)(C(C)C)C(C)C)[CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1.CCOC(C)=O>[N:19]1([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(N2CCCCC2)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc2c(N3CCCCC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
Add nBu4NF (1.0M in THF, 3.2 mL, 3.2 mmol) to a solution of 3-piperidin-1-yl-1-triisopropylsilanyl-1H-indole (835 mg, 2.34 mmol) in THF (10 mL). Stir the red solution at RT for 1 h, then dilute with EtOAc (40 mL) and wash with satd NaHCO3 (20 mL). Dry, filter, and concentrate the organic solution then purify the crude material by flash chromatography, using a linear gradient of 100% hexanes to 40% EtOAc/hexanes. Obtain the title compound (347 mg, 74%) as a grey solid. MS (ES+) 201.1 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 7.65 (d, 1H, J=8.1), 7.59 (br s, 1H), 7.29 (d, 1H, J=8.4), 7.16 (t, 1H, J=7.5), 7.06 (t, 1H, J=7.9), 6.70 (s, 1H), 3.03 (m, 4H), 1.80 (m, 4H), 1.59 (m, 2H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)(=[O:4])=[O:3].[H-].[Na+].[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]([CH2:32][CH:33]([CH3:35])[CH3:34])[S:22]([C:25]2[C:26](Cl)=[N:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])=[CH:17][CH:16]=1.C([O-])(O)=O.[Na+]>C1COCC1.O>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]([CH2:32][CH:33]([CH3:35])[CH3:34])[S:22]([C:25]2[CH:26]=[N:27][C:28]([O:11][CH:8]3[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][CH2:9]3)=[CH:29][CH:30]=2)(=[O:24])=[O:23])=[CH:19][CH:20]=1
Reactant: CS(=O)(=O)N1CCC(O)CC1
Reactant: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1cccnc1Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(OC2CCN(S(C)(=O)=O)CC2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.3 %

Procedure:
To a solution of 1-methanesulfonyl-piperidin-4-ol (86 mg, 482 μmol) in anhydrous THF (5 mL) at room temperature was added NaH (60% dispersion in mineral oil, 21 mg, 526 μmol) and the reaction was stirred at room temperature for 15 minutes. Chloro-pyridine-3-sulfonic acid (4-fluoro-phenyl)-isobutyl-amide (150 mg, 439 μmol) was added and the reaction stirred at room temperature for 45 minutes then heated at 80° C. for 2 hours. Water and saturated NaHCO3 were added and then extracted with EtOAc, washed with brine, dried with Na2SO4 then concentrated and purified by silica gel column chromatography (0-25% EtOAc in cyclohexane) to give the title compound (137 mg). 1H NMR (400 MHz, DMSO): δ 8.30 (dd, J=2.6, 0.67 Hz, 1H), 7.75 (dd, J=8.8, 2.60 Hz, 1H), 7.19-7.20 (m, 4H), 6.97 (dd, J=8.8, 0.7 Hz, 1H), 5.23-5.25 (m, 1H), 3.39 (d, J=8.8 Hz, 4H), 3.13 (ddd, J=12.2, 8.56, 3.46 Hz, 2H), 2.91 (s, 3H), 2.04-2.09 (m, 2H), 1.78-1.80 (m, 2H), 1.44 (dd, J=13.6, 6.9 Hz, 1H), 0.85 (d, J=6.6 Hz, 6H). LCMS (m/z, Method B) ES+ 485.9 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]3[S:19][C:20]([CH3:24])=[C:21]([C:22]#[N:23])[C:13]=23)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.CS(C)=[O:27].[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]3[S:19][C:20]([CH3:24])=[C:21]([C:22]([NH2:23])=[O:27])[C:13]=23)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C#N)c(C)sc2n1
Reactant: CS(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C(N)=O)c(C)sc2n1
Temperature: 150 °C
Reaction time: 5 h

Procedure:
A mixture of 3-chloro-N-(3-cyano-2,6-dimethylthieno[2,3-b]pyridin-4-yl)benzenesulfonamide (Example 73) (119 mg, 0.315 mmol), DMSO (3 mL) and aqueous NaOH (3M) (1.05 mL, 3.15 mmol) was stirred at 150° C. for 5 h. The mixture was then cooled and acidified with 5M HCl to pH 3-4. Water (20 mL) was added and the mixture extracted with ethyl acetate (3×10 mL). The organic layer was then dried over MgSO4, filtered and concentrated. The residue was purified by normal phase chromatography, eluting with a gradient of 0-10% MeOH in DCM, and then further triturated with MeOH, to give the title compound (69 mg). LCMS (A) m/z: 396 [M+1]+, Rt 1.13 min (acidic).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3]/[CH:4]=[C:5](\[CH3:10])/[C:6]([O:8]C)=[O:7].[Li+:12].[OH-]>O1CCCC1.O>[CH3:1][N:2]([CH3:11])[CH2:3]/[CH:4]=[C:5](\[CH3:10])/[C:6]([O-:8])=[O:7].[Li+:12]
Reactant: COC(=O)/C(C)=C/CN(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C/C(=C\CN(C)C)C(=O)[O-]
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To methyl(2E)-4-(dimethylamino)-2-methylbut-2-enoate (238 mg, 1.51 mmol) in tetrahydrofuran (0.95 mL) and water (0.95 mL) was added LiOH (36 mg, 1.5 mmol). The solution was stirred at 40° C. for 4 hours before being frozen and lyophilized to afford a white semi-solid that was taken on to the next step as is. LRMS (ESI) calc'd for C7H13NO2 [M+]+: 144, found 144.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[N+:23]([O-])[CH:22]=[CH:21]3)(=[O:17])=[O:16])[C@@H:10]([CH3:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)OCC.[C:36]([O:40][C:41]([NH:43][CH2:44][CH2:45][SH:46])=[O:42])([CH3:39])([CH3:38])[CH3:37].C(N(CC)CC)C>ClCCl>[C:36]([O:40][C:41]([NH:43][CH2:44][CH2:45][S:46][C:24]1[C:25]2[C:20](=[CH:19][C:18]([S:15]([N:11]3[CH2:12][CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C@@H:10]3[CH3:29])(=[O:17])=[O:16])=[CH:27][CH:26]=2)[CH:21]=[CH:22][N:23]=1)=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)NCCS
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCCN1S(=O)(=O)c1ccc2c[n+]([O-])ccc2c1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCCN1S(=O)(=O)c1ccc2c(SCCNC(=O)OC(C)(C)C)nccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
320 mg of (S)-6-(4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl)isoquinoline 2-oxide was dissolved in dichloromethane, and 0.1 mL of ethyl chlorocarbonate, 0.42 mL of 2-(N-tert-butoxycarbonylamino)ethanethiol, and 0.21 mL of triethylamine were added at 0° C. The reaction solution was stirred at room temperature for 16 hours and then concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane:acetone=4:1) to obtain 223 mg of the compound of interest as a colorless oil (51%).
Reaction SMILES: [Sn](Cl)Cl.[C:4]1([S:10]([NH:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=2)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:12])=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(O)=O.[Na+]>C(O)C>[C:4]1([S:10]([NH:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=2)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:11])=[O:12])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CC(NS(=O)(=O)c1ccccc1)c1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC(NS(=O)(=O)c1ccccc1)c1cccc(N)c1

Procedure:
Tin(II) chloride (4.77 g) was added to a solution of ethyl 3-benzenesulphonylamino3-(3-nitrophenyl)-propionate from II.4a (2.0 g) in 60 ml of ethanol and the reaction mixture was heated under reflux for 2 h. After cooling, the solution was hydrolysed on ice and an NaHCO3 solution (5%) was added to pH=8. The mixture was then extracted with dichloromethane, and the org. phase was washed with NaCl, dried (MgSO4) and concentrated. A yellow oil was obtained (yield: 1.79 g).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[CH:9]=2)[C:4](=[O:27])[O:3]1.[ClH:28]>O1CCOCC1>[ClH:28].[CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[CH:9]=2)[C:4](=[O:27])[O:3]1
Reactant: C[C@@H]1Cc2cc(CCN3CCN(C(=O)OC(C)(C)C)CC3)ccc2C(=O)O1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1Cc2cc(CCN3CCNCC3)ccc2C(=O)O1

Procedure:
A solution of tert-butyl 4-{2-[(3R)-3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl]ethyl}piperazine-1-carboxylate (850 mg, 2.27 mmol) was stirred in 4N HCl in dioxane for 4 hours. The excess solvent was then removed to give the free amine as the HCl salt. LC-MS (IE, m/z): 275 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:13]=[N:14][C:15]([N:19]([CH3:21])[CH3:20])=[CH:16][C:17]=3[CH3:18])[N:7]([CH2:22][CH2:23][CH2:24][C:25](OCC)=[O:26])[C:6]=2[C:5]([CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[CH:4][CH:3]=1.[BH4-].[Li+].O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:13]=[N:14][C:15]([N:19]([CH3:21])[CH3:20])=[CH:16][C:17]=3[CH3:18])[N:7]([CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[C:6]=2[C:5]([CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCn1c(Nc2cnc(N(C)C)cc2C)nc2c(Cl)ccc(C(CC)CC)c21
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3cnc(N(C)C)cc3C)n(CCCCO)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.2 %

Procedure:
To a solution of ethyl 4-[4-chloro-2-{[6-(dimethylamino)-4-methylpyridin-3-yl]amino}-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (200 mg, 0.41 mmol) in tetrahydrofuran (4 mL) was added lithium borohydride (27 mg, 1.23 mmol) portionwise at 0° C. The mixture was warmed to room temperature and stirred for 24 hr. Water was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a solid, which was recrystallized from ethyl acetate to give the title compound (95 mg, 0.214 mmol, 52%) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[NH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7].C([Li])(C)(C)C.CON(C)[C:23](=[O:40])[CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[C:33]([O:38][CH3:39])=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:27][CH2:26]1.O>O1CCCC1.C(OCC)C>[CH3:39][O:38][C:33]1[C:32]([CH2:31][N:28]2[CH2:27][CH2:26][CH:25]([CH2:24][C:23](=[O:40])[C:2]3[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=3[NH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7])[CH2:30][CH2:29]2)=[CH:37][CH:36]=[CH:35][N:34]=1
Reactant: O=C(Nc1ccccc1Br)C(F)(F)F
Reactant: COc1ncccc1CN1CCC(CC(=O)N(C)OC)CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: COc1ncccc1CN1CCC(CC(=O)c2ccccc2NC(=O)C(F)(F)F)CC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
482 mg of 2-bromo-N-(trifluoroacetyl)aniline was dissolved in a mixed solvent of 1.8 ml of tetrahydrofuran and 1.8 ml of diethyl ether, and a 1.14M methyllithium diethyl ether solution was added dropwise thereinto at 0° C. After stirring for 10 minutes, the mixture was slowly charged by a cannular to a solution of 2.4 ml of 1.51 M tert-butyllithium and 4 ml of a diethyl ether solution cooled at −78° C. The mixture was stirred for 1 hour. Then, a mixed solution of 500 mg of N1-methoxy,N1-ethyl-2-[1-(2-methoxy-3-pyridyl)methyl]-4-piperidyl]acetamide obtained in Example 55 and 2 ml of tetrahydrofuran was added dropwise thereinto, and the mixture was further stirred for 20 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (ethyl acetate), to give 150 mg of the above compound as a yellow oil.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6](/[CH:8]=[CH:9]/[CH2:10]P(OCC)(OCC)=O)=[O:7].[CH:19]([C:21]1[N:26]2[CH:27]=[N:28][CH:29]=[C:25]2[CH:24]=[CH:23][CH:22]=1)=O>C1(C)C=CC=CC=1>[CH2:4]([O:5][C:6]([CH:8]=[CH:9][CH:10]=[CH:19][C:21]1[N:26]2[CH:27]=[N:28][CH:29]=[C:25]2[CH:24]=[CH:23][CH:22]=1)=[O:7])[CH3:3]
Reactant: O=Cc1cccc2cncn12
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C=CC=Cc1cccc2cncn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 150 mg of sodium hydride in 25 ml of toluene is added 550 mg of triethyl 4-phosphonocrotonate in a dropwise manner over a 10-minute period. The reaction mixture is maintained at 5° by cooling in an ice-water bath. On completion of the addition, 300 mg of 5-formylimidazol[1,5-a]pyridine is added to the reaction mixture which is then allowed to stir at room temperature for 1 hour. The reaction mixture is poured into 100 ml of ice water and extracted with 2×100 ml of ethyl acetate. The ethyl acetate extracts are combined and dried over magnesium sulfate, filtered and evaporated to dryness to yield an oily residue. This is purified by column chromatography on silica gel using a mixture of diethyl ether and ethyl acetate as eluent. Evaporation of the solvent under reduced pressure yields 5-(4-ethoxycarbonylbuta-1,3-dienyl)-imidazo[1,5-a]pyridine melting at 101°-103°.
Reaction SMILES: [C:1]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(C)([O-])C.[K+].[Br:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1[CH2:29]Cl.O>CN(C=O)C>[Br:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1[CH2:29][N:8]([C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: ClCc1ccncc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccncc1Br)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of 1.73 g of di-tert-butyl imidodicarbonate in DMF 16 ml was added 894 mg of potassium tert-butoxide under ice-cooling, followed by stirring at room temperature for 1 hour. To the reaction mixture was added a solution of 1.37 g of 3-bromo-4-(chloromethyl)pyridine in 3 ml of DMF under ice-cooling, followed by stirring at room temperature for 2 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2.32 g of di-tert-butyl [(3-bromopyridin-4-yl)methyl]imidodicarbonate.
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C1C2C(COC([NH:62][C@H:63]([C:67](O)=[O:68])[CH:64]([CH3:66])[CH3:65])=O)C3C(=CC=CC=3)C=2C=CC=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:62][C@H:63]([C:67]([O:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:68])[CH:64]([CH3:66])[CH3:65]
Reactant: O=C(O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)[C@H](N)C(=O)O[C@@H]1c2ccccc2C[C@@]1(Cc1ccc(C(=O)O)cc1)C1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.3 %

Procedure:
To a solution of 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (230 mg, 0.60 mmol), DCC (148 mg, 0.72 mmol) and DMAP (7 mg, 0.06 mmol) in ethyl acetate (12 mL), was added N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valine (193 mg, 0.60 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (250 mg) was dissolved in dry THF (8 mL) and cooled to 0° C. Dimethylamine (8 mL, 20% in THF) was added drop wise at N2 atmosphere and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 10% methanol in chloroform as an eluent to yield 105 mg (36%) of the title compound as an off white solid.
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]2[CH2:15][CH2:16][N:17](C(OCC3C=CC=CC=3)=O)[C@@H:10]1[C:11]([O:13]2)=[O:12])C1C=CC=CC=1.C(O)(=[O:30])C>O.[Pd]>[OH2:8].[OH:8][C@H:9]1[C@H:14]([OH:13])[CH2:15][CH2:16][NH:17][C@@H:10]1[C:11]([OH:12])=[O:30]
Reactant: O=C1O[C@@H]2CCN(C(=O)OCc3ccccc3)[C@H]1[C@H]2OCc1ccccc1
Reactant: CC(=O)O
Agent: [Pd]
Solvent: O
Product: O=C(O)[C@H]1NCC[C@@H](O)[C@@H]1O
Yield: 89 %

Procedure:
3-O-Benzyl-N-benzyloxycarbonyl-2,6-imino-2,5,6-trideoxy-D-lyxo-hexono-1,4-lactone (26) (321 mg, 0.875 mmol) was dissolved in a 2:1 mixture of acetic acid and water (10 ml) and stirred under hydrogen with palladium black (70 mg) for 48 hours. The reaction mixture was filtered through celite, the solvent removed and the product purified by flash chromatography (CMAW) and ion exchange chromatography. Freeze drying afforded (2S,3R,4R) 3,4-dihydroxypipecolic acid, monohydrate (140 mg, 89%) as a white crystalline solid, m.p. 253°-260° C. with decomposition, [α]20D -1.3° (c, 0.54 in water); νmax (KBr disc) 3390, 1595 (CO), 1400, 1080, 1060 and 890 cm-1 ; 1H NMR (D2O) δ 1.48-1.61 (1H, m, 5-H); 1.99 (1H, ddt, H-5', J5,5' 14.4 Hz, J5', 6;5',6';5',4 3.7 Hz); 2.88 (1H, ddd, 6-H, J6,6' 13.0 Hz, J5,6 11.9 Hz); 3.26 (1H, dt, H-6', J5,6' 3.7 Hz); 3.30 (1H, d, 2-H, J2,3 9.2 Hz); 3.52-3.61 (2H, m, H-3, H-4); 13C NMR (D2O) δ 28.33 (t, C-2); 41.13 (t, C-1); 61.51 (d, H-5); 70.24, 71.85 (2×d, C-3,4); 172.43 (s, C-1). m/z: 124 (M-2×H2O-H+, 100%), 98 (M-H2O-CO2H+, 95%), 116 (M-CO2H+, 75%), 162 (M+H+, 67%). (Found C, 40.16; H, 7.10; N, 7.56. C6H11NO4.H2O requires C, 40.22; H, 7.31; N, 7.82).