Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:9])([CH3:8])[C:6](=[O:10])[CH2:5][C:4]([CH3:12])([CH3:11])[C:3]=1[C:13]([O:15][CH3:16])=[O:14].[Li+].[CH3:18]C([N-]C(C)C)C.[Li]CCCC.N(C(C)C)C(C)C.CI.[NH4+].[Cl-]>C1COCC1>[CH3:1][C:2]1[C:7]([CH3:8])([CH3:9])[C:6](=[O:10])[CH:5]([CH3:18])[C:4]([CH3:11])([CH3:12])[C:3]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C1=C(C)C(C)(C)C(=O)CC1(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CI
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)C(C)(C)C(=O)C(C)C1(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of (2a) (1.0 g, 4.38 mmol) in THF (5 ml) was slowly added to a solution of LDA (freshly prepared from 3.13 ml BuLi 1.54M and 0.71 ml of iPr2NH) in THF (5 ml). The solution was stirred at −78° C. for 30 min and then a MeI (0.41 ml) was added. The mixture was stirred at −78° C. for 30 minutes then slowly warmed at room temperature After 1 hour a saturated solution of NH4Cl was added and the mixture was extracted with pentane. The organic layer was washed with saturated NH4Cl solution, bicarbonate, and brine. The collected organic layers were dried with MgSO4 and concentrated to dryness. The crude was purified by column chromatography (silicagel, cyclohexane/EtOAc 98/2). Yield 78%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=2)[CH:5]=[CH:6][C:7]=1C.[F:26]C1C=C(C2C=C(CO)C(=O)N(CC(C)C)N=2)C=CC=1F>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=2)[CH:5]=[CH:6][C:7]=1[F:26]
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1F
Reactant: CC(C)Cn1nc(-c2ccc(F)c(F)c2)cc(CO)c1=O
Product: CC(C)Cn1nc(-c2ccc(F)c(F)c2)cc(COS(C)(=O)=O)c1=O
Yield: 81.4 %

Procedure:
Following the procedure of Example 1 (9), 6-(3,4-difluorophenyl)-4-hydroxymethyl-2-isobutyl-2H-pyridazin-3-one was reacted to yield the title compound as colorless fine-needles (yield: 81.4%).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.I[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(P(CCCC)CCCC)CCC>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu](Br)Br>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[S:3][C:4]=2[CH:10]=1
Reactant: COc1ccc2nc(Br)sc2c1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: Br[Cu]Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COc1ccc2nc(-c3ccc([N+](=O)[O-])cc3)sc2c1
Temperature: 150 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
Under N2, in a sealed tube, to 22 (19.7 mmol) in DMF 50 ml, 1-iodo-4-nitrobenzene (21.6 mmol), cesium carbonate (19.6 mmol), palladium acetate (0.98 mmol), copper bromide (0.2 mmol) and tributylphosphine (1.9 mmol) were added. The reaction was stirred at 150° C. overnight and, after cooling to room temperature, the mixture was extracted with ethyl acetate. The organic layer was then washed (3 times) with water, dried over Na2SO4 and the solvent removed via a rotary evaporator. The residue was purified by chromatography on silica gel using 9:1 hexane/ethyl acetate as the eluent to yield 4.62 g (81%) of 23 as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[C:31]([F:32])=[CH:30][CH:29]=[C:28]([F:33])[C:9]=1[CH2:10][N:11]1[CH2:16][CH2:15][NH:14][C:13]2[N:17]=[CH:18][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[CH:22]=3)=[CH:20][C:12]1=2>>[Cl:7][C:8]1[C:31]([F:32])=[CH:30][CH:29]=[C:28]([F:33])[C:9]=1[CH2:10][N:11]1[CH2:16][CH2:15][NH:14][C:13]2[N:17]=[CH:18][C:19]([C:21]3[CH:22]=[CH:23][N:24]=[C:25]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH:26]=3)=[CH:20][C:12]1=2
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(-c4ccnc(Cl)c4)cc32)c1Cl
Reactant: C1COCCN1
Product: Fc1ccc(F)c(CN2CCNc3ncc(-c4ccnc(N5CCOCC5)c4)cc32)c1Cl
Yield: 21 %

Procedure:
Morpholine (2 mL) was added to 1-(2-chloro-3,6-difluorobenzyl)-7-(2-chloropyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (61 mg), and the mixture was heated in a microwave oven for two (2) hours at 180° C. The mixture was then concentrated, and the residue was purified through silica gel chromatography followed by preparative reversed-phase HPLC. The trifluoroacetic acid salt was neutralized with saturated sodium bicarbonate, and the free base extracted into methylene chloride, washed with brine and dried with magnesium sulfate. The solution was concentrated to give the title compound as a yellow solid (21% yield). M.p.=157° C., LCMS: m/z=458.07 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.38 (2H, t, J=4.7 Hz), 3.56 (4H, t, J=4.8 Hz), 3.62 (2H, t, J=4.5 Hz), 3.86 (4H, t, J=4.8 Hz), 4.58 (2H, s), 6.65 (1H, s), 6.76 (1H, d, J=5.1 Hz), 7.06 (2H, m), 7.16 (1H, m), 7.59 (2H, m), 8.22 (1H, d, J=5.1 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([NH:24][C@H:25]([CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=1)[C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]2[C:36]([CH3:38])([CH3:37])[O:35][B:34]([OH:39])[C:33]=2[CH:40]=1)=[O:27])=[O:23])[CH2:10][CH2:11][C:12]([O:14]CC1C=CC=CC=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.O.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([NH:24][C@H:25]([CH2:41][CH2:42][C:43]1[CH:44]=[CH:45][C:46]([C:49]([F:51])([F:52])[F:50])=[CH:47][CH:48]=1)[C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]2[C:36]([CH3:37])([CH3:38])[O:35][B:34]([OH:39])[C:33]=2[CH:40]=1)=[O:27])=[O:23])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)Nc1ccc2c(c1)B(O)OC2(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)Nc1ccc2c(c1)B(O)OC2(C)C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of (S)-benzyl 4-(tert-butoxycarbonylamino)-5-((R)-1-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-ylamino)-1-oxo-4-(4-(trifluoromethyl)phenyl)butan-2-ylamino)-5-oxopentanoate (1.8 g, 2.48 mmol) in a mixture of EtOH/H2O (20 mL/2 mL) was added Pd(OH)2/C (cat.). The mixture was stirred under a H2 atmosphere for 2 h. The mixture was filtered through Celite and washed with MeOH. The filtrate was evaporated to dryness under vacuum to produce (S)-4-(tert-butoxycarbonylamino)-5-((R)-1-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-ylamino)-1-oxo-4-(4-(trifluoromethyl)phenyl)butan-2-ylamino)-5-oxopentanoic acid (CLXXI) as a white foam (1.57 g, 2.48 mmol, 100% yield). ESIMS found for C30H37BF3N3O3 m/z 634.6 (M−H).
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12]C)=[O:10])=[C:5]([CH3:16])[CH:4]=1)=O.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20].[BH4-].[Na+]>CO>[CH2:17]([NH:21][CH2:1][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH3:16])[CH:4]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN
Reactant: CCOC(=O)COc1ccc(C=O)cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCNCc1ccc(OCC(=O)OC)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
To a solution of ethyl (4-formyl-2-methylphenoxy)acetate (0.65 g, 2.93 mmol) in anyhdrous methanol (12 mL) under nitrogen was added n-butylamine (0.3 mL, 3.07 mmol) and the resultant mixture stirred for 18 h at room temperature, prior to portion wise addition of sodium borohydride (0.144 g, 3.8 mmol). After 30 minutes stirring at room temperature the reaction was quenched by cautious addition of sat. sodium bicarbonate aq. and then extracted into ethyl acetate (2×40 mL). The organic solution was dried (MgSO4) and the solvents removed in vacuo to afford the title compound as a pale yellow oil (0.65 g).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:39]=[CH:38][C:20]([CH2:21][O:22][N:23]=[C:24]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[CH:19][CH:18]=1.CO.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:39]=[CH:38][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)\[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:19][CH:18]=1
Reactant: CCOC(=O)CCC(=NOCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCC(=O)O)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of ethyl 4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(3-pyridyl)butyrate (520 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(3-pyridyl)butyric acid (378 mg, yield 77%) as colorless crystals. m.p. 158-159° C.
Reaction SMILES: [OH:1][C:2]1([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][N:4]2[CH:8]=[N:9][CH:10]=[C:3]12.[H-].[Na+].[CH3:21]I.O>O1CCCC1.CN(C)C=O>[CH3:21][O:1][C:2]1([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][N:4]2[CH:8]=[N:9][CH:10]=[C:3]12
Reactant: N#Cc1ccc(C2(O)CCCn3cncc32)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC1(c2ccc(C#N)cc2)CCCn2cncc21
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A suspension of 0.63 mmol of 4-(8-hydroxyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)-benzonitrile (Example 19) in 2 ml of tetrahydrofuran is added at 0° C. to a suspension of 0.76 mmol of sodium hydride (60% dispersion in paraffin) in 1 ml of tetrahydrofuran. The reaction mixture is subsequently stirred at 20° C. for 30 minutes and then cooled again to 0° C. A solution of 0.63 mmol of methyl iodide in 3 ml of N,N-dimethylformamide is added dropwise and the reaction mixture is subsequently stirred at room temperature for 16 hours. The reaction mixture is poured into water and extracted with tertbutyl methyl ether (3×). The combined organic phases are dried over sodium sulphate and evaporated. The residue is digested with diethyl ether and the solid is isolated by filtration and dried. The title compound is obtained as a white solid. Rf=0.14 (toluene/methanol 85:15), Rt=4.92 (Gradient I).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][C:27](C(O)=O)=[CH:26][CH:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.BrC1C=CC([CH2:38][C:39]2([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:42][CH2:41][CH2:40]2)=CC=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:19]=[C:20]([C:24]4[CH:25]=[CH:26][C:27]([CH2:38][C:39]5([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:42][CH2:41][CH2:40]5)=[CH:28][CH:29]=4)[CH:21]=[CH:22][CH:23]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C1(Cc2ccc(Br)cc2)CCC1
Reactant: O=C(O)c1ccc(-c2cccc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Cc2ccc(-c3cccc(-n4cc(C(=O)NC5CC5)c(=O)c5cccnc54)c3)cc2)CCC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of NAPHTHYRIDNONE 3 (1.0 eq), ester from step 1 (1.5 eq), Na2CO3 (3.5eq; 2M in H2O), Pd(OAc)2 (0.05eq.) and PPh3 (0.15eq.) or PdCl2dppf (0.05 eq) in n-propanol-DMF (1:1, 0.1M) was stirred at 70° C. for 2 h. The mixture was cooled to rt, quenched with AcOH and diluted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (CH2Cl2/MeOH, 99:1) afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:17](=[CH2:21])[C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=1.C(OC(C)C)(C)C>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:21][CH:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH3:9])[CH:12]=1)[C:18]([OH:20])=[O:19]
Reactant: C=C(C(=O)O)c1cccc(OC)c1
Reactant: Nc1ccccc1S
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: COc1cccc(C(CSc2ccccc2N)C(=O)O)c1
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
7.6 ml of aminothiophenol were added to a solution of 8.9 g of the product of Step C and 130 ml of ethanol and the solution was stirred for 90 minutes at 95° C. and left to return to ambient temperature. The ethanol was eliminated under reduced pressure and 50 ml of isopropyl ether were added. Crystallization was started to obtain 7.2 of the expected product which was separated off and dried at 80° C. under reduced pressure. After chromatography of the mother liquors on silica (eluant: ethyl acetate-cyclohexane 1-1), 710 mg of pure product were obtained (Rf=0.16) which after crystallization from ether melted at 128° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=2)[CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].O>C(O)(=O)C>[C:15]([O:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=2)[CH:3]=1)(=[O:17])[CH3:16]
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc2cc(C(=O)O)ccc2c1
Yield: 97 %

Procedure:
18.8 g of 2-hydroxynaphthalene-6-carboxylic acid was reacted with 94 g of acetic anhydride in 94 g of acetic acid at 80° C. for 4 hours. The reaction liquid was poured to 500 g of water and the precipitate was filtrated and washed thoroughly with methanol and water and then dried to give 22.3 g of 2-acetoxynaphthalene-6-carboxylic acid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[CH:21]=[CH:20][C:11]([O:12][CH2:13][C@@H:14]3[CH2:19][CH2:18][CH2:17][CH2:16][NH:15]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[C:24]([O:28][C:29](=[O:32])[CH2:30]Br)([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>ClCCl.O>[C:24]([O:28][C:29](=[O:32])[CH2:30][N:15]1[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]1[CH2:13][O:12][C:11]1[CH:20]=[CH:21][C:8]([O:7][C:6]2[CH:22]=[CH:23][C:3]([Cl:2])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: Clc1ccc(Oc2ccc(OC[C@@H]3CCCCN3)cc2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)CN1CCCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 47.1 %

Procedure:
A solution of (S)-2-[4-(4-chloro-phenoxy)-phenoxymethyl]-piperidine hydrochloride (218 mg, 0.615 mmol), t-butylbromoacetate (150 mg, 0.769 mmol), and triethylamine (124 mg, 1.23 mmol) in dichloromethane (2.5 mL) was heated for 18 h at 30° C. The mixture was diluted with 5 mls of water and extracted with dichloromethane (8 mL). The aqueous layer was re-extracted with ethyl acetate (8 mL). The combined organic layers were dried over anhy. Na2SO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (125 mg, 47%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[OH-].[Na+].Br[CH2:14][CH2:15][OH:16]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:14][CH2:15][OH:16])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: OCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(OCCO)c1
Temperature: 60 °C

Procedure:
To a solution of 3-nitrophenol (10 g, 71.9 mmol) in DMF (40 ml) was added NaOH pellets (3.16 g, 79.1 mmol) and 2-bromoethanol (5.6 ml, 79.1 mmol). The reaction mixture was heated at 60° C. for 18 h. LCMS indicated 65% conversion to the required product. The reaction mixture was diluted with water (10 ml) and was slowly neutralised with 2M HCl. The reaction mixture was extracted with EtOAc (50 ml) and washed with water (50 ml). The EtOAc layer dried (Na2SO4), filtered and evaporated to dryness. Flash column chromatography purification eluting with 30% EtOAc/heptane gave the required product (8.2 g, 62% yield). LCMS purity 100%, m/z 184 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[O:8][C:7](=[O:9])[CH:6]=[C:5]([OH:10])[CH:4]=1)[CH3:2].[C:11](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>>[CH2:1]([C:3]1[O:8][C:7](=[O:9])[CH:6]=[C:5]([O:10][CH3:11])[CH:4]=1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCc1cc(O)cc(=O)o1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Product: CCc1cc(OC)cc(=O)o1
Temperature: 25 °C
Yield: 64 %

Procedure:
The following is based on the procedure disclosed in Deshpande, V. H. et al. Indian Journal of Chemistry, 35, pp. 790-793 (1996). Compound V (57.65 g, 411 mmol) was placed in an oven dried 2000 mL three-neck flask and dissolved in dry acetone (1500 ml). To this solution was added potassium carbonate (74 g, 540 mmoles) and dimethylsulfate (51 ml, 540 mmoles). The flask was equipped with a water condenser and mechanical stirrer. The mixture was heated to reflux for 3.5 hours. Analysis by LCMS showed reaction to be complete. Therefore the reaction was cooled to room temperature and the solids removed by filtration. The solvent of the filtrate was removed by rotary evaporation. The yellow oily residue left behind was purified by silica gel chromatography eluting with a gradient of 10% to 50% ethyl acetate in hexanes. The appropriate fractions were collected and concentrated by rotary evaporation to yield compound W (40.55 g, 61%) as a yellow solid. 1H NMR CDCl3 δ: 5.78 (s, 1H), 5.42 (s, 1H), 3.80 (s, 3H), 2.51 (q, 2H, J=8.0 Hz), 1.22 (t, 3H, J=8.0 Hz). ESMS m/z: 155 [M+H+].
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][CH2:14]3)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:19]N1C(=O)CCC1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O.CS(C)=O>[Br:19][C:13]1[CH2:14][C:15]2[C:11]([CH:12]=1)=[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)[CH:18]=[CH:17][CH:16]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1ccc(-c2cccc3c2C=CC3)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1ccc(-c2cccc3c2C=C(Br)C3)cc1
Yield: 94.3 %

Procedure:
Into a 500-ml glass reaction vessel, 15.4 g of 4-(4-i-propylphenyl)-indene (67 mmol), 7.2 ml of distilled water and 200 ml of DMSO were added. Then, 17 g (93 mmol) of N-bromosuccinimide was gradually added and the resultant mixture was stirred for 2 hours at room temperature. The reaction liquid was poured into 500 ml of distilled water, and the resultant mixture was extracted with 100 ml of toluene for 3 times. The resultant toluene layer was washed with saturated brine. Then, 2 g (11 mmol) of p-toluenesulfonic acid was added to the washed toluene layer and refluxed under heating while removing water. The reaction liquid was left to cool, washed with saturated brine and dried over sodium sulfate. Then, the sodium sulfate was removed by filtration and the resultant filtrate was evaporated under reduced pressure to remove the solvent. The resultant residue was purified by silica gel column chromatography to thereby obtain 19.8 g of 2-bromo-4-(4-i-propylphenyl)-indene as yellow liquid (yield: 96%).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[SH:11][C:12]1[N:16]([CH3:17])[N:15]=[N:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:11][C:12]2[N:16]([CH3:17])[N:15]=[N:14][N:13]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(Cl)s1
Reactant: Cn1nnnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2nnnn2C)s1
Temperature: 130 °C
Yield: 82.2 %

Procedure:
A mixture of 2-acetylamino-5-chlorothiazole (1.76 g), 5-mercapto1-methyl-1H-tetrazole (1.2 g) and potassium carbonate (2 g) in N,N-dimethylformamide (40 ml) was heated at 130° C. for 3 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The precipitates were collected by filtration, washed with water and dried vacuo to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 150 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-acetylamino-5-(1-methyl-1H-tetrazol-5-ylthio)thiazole (2.1 g, yield: 82.0%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C@H:18]2[C:30]([O:32][CH3:33])=[O:31])[C:13]1=[O:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][NH:20][CH2:19][C@H:18]2[C:30]([O:32][CH3:33])=[O:31])[C:13]1=[O:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CNCC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reaction time: 3 h
Yield: 73.1 %

Procedure:
(3R,4S)-1-tert-butyl 3-methyl 4-((3S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)piperidine-1,3-dicarboxylate (7.45 g) was dissolved in methylene chloride (20 mL) at room temperature under nitrogen, then TFA (10 mL) was added. After 3 hours, stripped the reaction 3 times from methylene chloride (25 mL). Obtained an oil which was dissolved in ethyl acetate (25 mL) and rinsed 4 times with 1.000 N NaOH (25 mL). The ethyl acetate layer was dried over sodium sulfate and stripped to give (3R,4S)-methyl 4-((3S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)piperidine-3-carboxylate (4.30 g) as a white glass. Yield=73%. LCMS detects (M+H)+=376.1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[C:13]([CH3:24])=[N:14][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:16]=1[CH3:17])=O)C>O1CCCC1>[CH3:24][C:13]1[C:12]([CH2:10][OH:9])=[C:16]([CH3:17])[N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:14]=1
Reactant: CCOC(=O)c1c(C)nn(-c2ccccn2)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nn(-c2ccccn2)c(C)c1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
Suspend lithium aluminum hydride (0.359 g, 9.46 mmol) in tetrahydrofuran (25 mL) at −10° C. and add 3,5-dimethyl-1-pyridin-2-yl-1H-pyrazole-4-carboxylic acid ethyl ester (1.160 g, 4.73 mmol) dropwise in tetrahydrofuran (5 mL). Allow the mixture to warm to 25° C. and stir for 4 hr. Cool the mixture to 0° C. then quench carefully with saturated sodium sulfate solution (1 mL). Allow the mixture to stir at room temperature for 2 hr. then filter off the precipitate, dry the solution and concentrate to give (3,5-dimethyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-methanol as a yellow solid (0.821 g, 86%).