Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:7]=2)[CH2:3][CH2:2]1.Cl[C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][N:26]=1.C(=O)([O-])O.[Na+]>CC(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:25]3[CH:34]=[CH:33][C:28]([C:29]([OH:31])=[O:30])=[CH:27][N:26]=3)[CH:7]=2)=[O:23])[CH2:2][CH2:3]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)O)cn1
Temperature: 90 °C

Procedure:
N-Cyclopropyl-5-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 4, 3.2 g), methyl 6-chloronicotinate (1.73 g), tetrakis(triphenylphosphine)palladium (210 mg) and aqueous sodium hydrogen carbonate (1M, 30 ml) were mixed in propan-2-ol (100 ml) and heated at 90° C. for 18 hours. The reaction was allowed to cool and the propan-2-ol removed under vacuum. The residue was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate (1M). The aqueous phase was acidified with hydrochloric acid (2N) and extracted with ethyl acetate (×2). The organic extracts were washed with brine, dried (magnesium sulphate) and reduced to dryness under vacuum. The resulting foam was triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinic acid as a solid. LCMS: MH+315, retention time 2.87 mins.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1(=O)[O:11][CH2:10][CH2:9][O:8]1.[C:13]1([C:23]2[N:28]=[N:27][N:26]=[C:25]([C:29]3[CH:34]=[CH:33]C(O)=[CH:31][C:30]=3[OH:36])[C:24]=2[C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[CH:39][CH:38]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[C:13]1([C:23]2[N:28]=[N:27][N:26]=[C:25]([C:29]3[CH:34]=[CH:33][C:7]([O:11][CH2:10][CH2:9][OH:8])=[CH:31][C:30]=3[OH:36])[C:24]=2[C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[CH:39][CH:38]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=C1OCCO1
Reactant: Oc1ccc(-c2nnnc(-c3cccc4ccccc34)c2-c2cccc3ccccc23)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1ccc(-c2nnnc(-c3cccc4ccccc34)c2-c2cccc3ccccc23)c(O)c1
Temperature: 140 °C

Procedure:
9.39 g of potassium carbonate and 4.39 g of ethylene carbonate are added to 20 g of the product from Example A6 in 200 ml of anhydrous DMF. The reaction mixture is heated at 140° C. for 18 h. The salts which precipitate are filtered off and washed with toluene. The combined organic phase is freed of solvent in vac. and used directly for the further reaction.
Reaction SMILES: [Al+3].[Cl-:2].[Cl-].[Cl-].[C:5]([C:9]([C:12]([O:15][C:16]([C:22](F)=[O:23])([C:18]([F:21])([F:20])[F:19])[F:17])([F:14])[F:13])([F:11])[F:10])([F:8])([F:7])[F:6]>ClC1C=CC=CC=1Cl>[C:5]([C:9]([C:12]([O:15][C:16]([C:22]([Cl:2])=[O:23])([C:18]([F:21])([F:20])[F:19])[F:17])([F:14])[F:13])([F:11])[F:10])([F:8])([F:7])[F:6]
Reactant: [Cl-]
Reactant: O=C(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: [Al+3]
Solvent: Clc1ccccc1Cl
Product: O=C(Cl)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Temperature: 6 °C

Procedure:
A mixture of AlCl3 and o-dichlorobenzene (4 mL) was treated with CF3CF2CF2OCF(CF3)COF (13.2 g, 40 mmol) and heated at 6 ° C. for 0.5 hr. Volatiles were removed by vacuum transfer (27 Pa) to give a mixture of two liquids. The lower layer was separated and distilled to provide 8.0 g of colorless liquid, bp ca. 65° C. GC analysis showed 99% purity. 19F NMR (F11): -81.32 (s, CF3), -81.94 (t, J=7.3 Hz, CF3), -79.05 and -84.98 (AB pattern, J=146 Hz, OCF2), -126.1 (d of m's, J=23, CF), -130.1 (s, CF2).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].C1CCN2C(=NCCC2)CC1.[Li+].[Cl-].[O:25]([C:32]1[CH:33]=[C:34]([C:38]23[CH2:45][CH2:44][C:41]([CH2:46][CH2:47][CH2:48][CH:49]=O)([CH2:42][CH2:43]2)[CH2:40][O:39]3)[CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC#N>[O:25]([C:32]1[CH:33]=[C:34]([C:38]23[CH2:45][CH2:44][C:41]([CH2:46][CH2:47][CH2:48]/[CH:49]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4])([CH2:42][CH2:43]2)[CH2:40][O:39]3)[CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=CCCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)/C=C/CCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Trimethyl phosphonoacetate (47 mg, 0.26 mmol) and DBU (39 mg, 0.26 mmol) were successively added to a 0° C. solution of LiCl (11 mg; 0.26 mmol) in MeCN (0.6 mL) under argon. The reaction mixture was stirred at 0° C. for 30 min, after which a solution of 120A compound [4-(1-(3-phenoxy-phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)butanal] (60 mg, 0.171 mmol) in MeCN (0.5 mL) was added. The reaction mixture was stirred at rt for 2 h, then was concentrated in vacuo. The residue was diluted with ether and successively washed with 1N aq. HCl, sat′d aq. NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was chromatographed (SiO2; continuous gradient of EtOAc/hexanes from 0 to 40%) to give the title compound as a white solid (65 mg, 89%). [MS+H]+=407, 1H NMR (400 MHz, CDCl3) δ 7.29-7.19 (m, 3H), 7.10-6.97 (m, 3H), 6.95-6.88 (m, 2H), 6.87-6.83 (m, 1H), 6.77 (ddd, J=8.0, 2.5, 0.9 Hz, 1H), 5.75 (dt, J=15.6, 1.5 Hz, 1H), 3.72 (s, 2H), 3.66 (s, 3H), 2.11 (qd, J=7.2, 1.5 Hz, 2H), 1.93 (dd, J=9.5, 5.3 Hz, 4H), 1.67-1.51 (m, 4H), 1.40-1.25 (m, 2H), 1.14-1.02 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:41])[C:22]([N:24]3[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30]C(=O)OCC4C=CC=CC=4)[CH2:25]3)=[O:23])[C:17]1=[O:42])(=[O:14])=[O:13])[CH:6]=[CH:5]2.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:30][C@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:22](=[O:23])[C@@H:21]([N:18]2[CH2:19][CH2:20][C@H:16]([NH:15][S:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=4)[CH:8]=3)(=[O:14])=[O:13])[C:17]2=[O:42])[CH3:41])[CH2:25]1
Reactant: C[C@@H](C(=O)N1CCC[C@H](NC(=O)OCc2ccccc2)C1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](C(=O)N1CCC[C@H](N)C1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 93 %

Procedure:
Benzyl(3S)-1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-ylcarbamate (0.128 g) was dissolved in DCM (3.5 ml) and treated with trifluoroacetic acid (10.5 ml) and stirred at room temperature for 6 h. The mixture was concentrated under reduced pressure and the residue purified by SPE (acid ion-exchange, eluting with ethyl acetate:methanol 9:1) to give the title compound (0.093 g) as a colourless oil.
Reaction SMILES: C([O:9][C@H:10]1[C@@H:15]([O:16]C(=O)C2C=CC=CC=2)[C@H:14]([O:25]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:34][O:35]C(=O)C2C=CC=CC=2)[O:12][C@@H:11]1[O:44][C@H:45]1[C@H:50]([O:51]C(=O)C2C=CC=CC=2)[C@@H:49]([CH2:60][O:61]C(=O)C2C=CC=CC=2)[O:48][C@H:47]([O:70][C@H:71]2[C@H:114]([O:115]C(=O)C3C=CC=CC=3)[C@@H:113]([CH2:124][O:125]C(=O)C3C=CC=CC=3)[O:112][C@H:73]([O:74][CH2:75][CH2:76][CH2:77][N:78]3[CH:82]=[C:81]([CH2:83][O:84][C@H:85]4[CH2:109][CH2:108][C@@:107]5([CH3:110])[CH:87]([CH2:88][CH2:89][C@@H:90]6[C@@H:106]5[CH2:105][CH2:104][C@@:103]5([CH3:111])[C@H:91]6[CH2:92][CH2:93][C@@H:94]5[C@H:95]([CH3:102])[CH2:96][CH2:97][CH2:98][CH:99]([CH3:101])[CH3:100])[CH2:86]4)[N:80]=[N:79]3)[C@H:72]2[O:134]C(=O)C2C=CC=CC=2)[C@H:46]1[O:143]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C[O-].[Na+]>C1COCC1.CO>[C@H:11]1([O:44][C@H:45]2[C@H:50]([OH:51])[C@@H:49]([CH2:60][OH:61])[O:48][C@H:47]([O:70][C@H:71]3[C@H:114]([OH:115])[C@@H:113]([CH2:124][OH:125])[O:112][C@H:73]([O:74][CH2:75][CH2:76][CH2:77][N:78]4[CH:82]=[C:81]([CH2:83][O:84][C@H:85]5[CH2:109][CH2:108][C@@:107]6([CH3:110])[CH:87]([CH2:88][CH2:89][C@@H:90]7[C@@H:106]6[CH2:105][CH2:104][C@@:103]6([CH3:111])[C@H:91]7[CH2:92][CH2:93][C@@H:94]6[C@H:95]([CH3:102])[CH2:96][CH2:97][CH2:98][CH:99]([CH3:101])[CH3:100])[CH2:86]5)[N:80]=[N:79]4)[C@H:72]3[OH:134])[C@H:46]2[OH:143])[O:12][C@H:13]([CH2:34][OH:35])[C@@H:14]([OH:25])[C@H:15]([OH:16])[C@@H:10]1[OH:9]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@@H](OCc5cn(CCCO[C@H]6O[C@H](COC(=O)c7ccccc7)[C@@H](OC(=O)c7ccccc7)[C@H](O[C@H]7O[C@H](COC(=O)c8ccccc8)[C@@H](OC(=O)c8ccccc8)[C@H](O[C@H]8O[C@H](COC(=O)c9ccccc9)[C@@H](OC(=O)c9ccccc9)[C@H](OC(=O)c9ccccc9)[C@@H]8OC(=O)c8ccccc8)[C@@H]7OC(=O)c7ccccc7)[C@@H]6OC(=O)c6ccccc6)nn5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@@H](OCc5cn(CCCO[C@H]6O[C@H](CO)[C@@H](O)[C@H](O[C@H]7O[C@H](CO)[C@@H](O)[C@H](O[C@H]8O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]8O)[C@@H]7O)[C@@H]6O)nn5)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 48 h

Procedure:
The perbenzoate 58 (70 mg, 0.0341 mmol) was dissolved in anhydrous THF (2 mL) and MeOH (2 mL). The mixture was treated with a solution of 11M NaOMe in MeOH (0.2 mL, 2.2 mmol). After stirring at r.t for 2 days, the white suspension was neutralized by addition of AG50WX8 resin (H+ form). The clear solution was separated from the resin by filtration. The resin was washed with MeOH (3×2 mL). The combined filtrate and washings were evaporated to dryness and dried in vacuum dessicator under P2O5 o/n to give the polyol 59, used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:18]2([CH3:21])[CH2:20][CH2:19]2)[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([NH2:17])[CH3:16])[N:8]=1.C([O-])(O)=O.[Na+].C1COCC1.Cl[C:33]([O:35][CH3:36])=[O:34]>C1COCC1.O>[Br:1][C:2]1[N:3]=[C:4]([C:18]2([CH3:21])[CH2:20][CH2:19]2)[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([NH:17][C:33](=[O:34])[O:35][CH3:36])[CH3:16])[N:8]=1
Reactant: C[C@H](N)CNc1nccc(-c2[nH]c(C3(C)CC3)nc2Br)n1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N[C@@H](C)CNc1nccc(-c2[nH]c(C3(C)CC3)nc2Br)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of (S)—N1-(4-(4-bromo-2-(1-methylcyclopropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)propane-1,2-diamine (2.02 g, 5.8 mmol) in THF-water (1:1, 60 mL) was cooled to 0° C. and then solid NaHCO3 (2.5 g, 30 mmol) was added with concomitant frothing. After 5 minutes a THF solution of methyl chloroformate (0.35 mL, 0.44 g, 4.60 mmol, freshly prepared 1.0 M solution) was added dropwise to the mixture. After 20 minutes, LCMS indicated only ˜70% conversion. Additional methylchloroformate solution (0.3 M in THF, 5 mL, 1.5 mmol) was added over 5 minutes. The reaction was maintained overnight, allowing the cooling bath to expire. LCMS indicated ˜90% conversion and additional methylchloroformate solution (0.3 M in THF, 5 mL, 1.5 mmol) at 0° C. over 5 minutes. After stirring at room temperature for 1 hour, LCMS indicated complete reaction. The reaction mixture was extracted with EtOAc. The organic phase was washed with brine and dried (Na2SO4), and concentrated to give (S)-methyl 1-(4-(4-bromo-2-(1-methylcyclopropyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate as a yellow solid (1.65 g): LCMS (m/z) 409.1 (MH+), tR=0.62 minute.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[C:15]([OH:17])=[O:16])[CH2:3][CH2:2]1.C[O-].[Na+].[CH3:21][O:22]C(OC)N(C)C>CO>[C:15]([C:11]1[N:10]([CH2:9][CH2:8][CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([CH:21]=[O:22])[CH2:2][CH2:3]2)[CH:14]=[CH:13][N:12]=1)([OH:17])=[O:16]
Reactant: COC(OC)N(C)C
Reactant: O=C(O)c1nccn1CCCC1CCNCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=CN1CCC(CCCn2ccnc2C(=O)O)CC1
Temperature: 80 °C

Procedure:
A mixture of 1-[3-(4-piperidinyl)propyl]-1H-imidazole-2-carboxylic acid 1.75 molar hydrochloride 0.65 molar hydrate (1.3 g, 0.0047M) and sodium methoxide (0.005M) in methanol (23 ml) was added to dimethylformamide dimethylacetal (15 ml) and heated at 80° C. for 8 hrs. The reaction mixture was filtered and stripped to dryness to give 4-[3-(2-carboxy-1H-imidazol-1-yl)propyl]-1-piperidine carboxaldehyde. The solution of the above piperidine carboxaldehyde dimethylacetal in methanol (5 ml) was then added to a mixture of 6-aminopenicillanic acid (0.81 g, 0.0037M) and diisopropylethylamine (0.4 ml) in chloroform (30 ml) at 0° C. The reaction was stirred at 0° C. 2 hrs and room temperature for 2 hrs. The solvent was removed and water (15 ml) was added. After being washed with ether, the aqueous solution, acidified to pH 3 to about 3.5, was purified on Sephadex LH 20 columns to give [2S-(2alpha,5alpha,6beta]-6-[[[1-[(3-(2-carboxy-1H-imidazol-1-yl)propyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hydrate (0.38 g, 17% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[F:24])=[CH:10][C:11]1[N:15]([CH3:16])[N:14]=[N:13][N:12]=1.C([Li])CCC.[CH:30](OCC)=[O:31]>O1CCCC1>[F:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[C:9]([C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[F:1])=[C:10]([C:11]1[N:15]([CH3:16])[N:14]=[N:13][N:12]=1)[CH:30]=[O:31]
Reactant: Cc1ccc(C(=Cc2nnnn2C)c2ccc(C)cc2F)c(F)c1
Reactant: CCOC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(=C(C=O)c2nnnn2C)c2ccc(C)cc2F)c(F)c1
Reaction time: 0.25 h
Yield: 37.3 %

Procedure:
To a solution of 1,1-bis(2-fluoro-4-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethene (1.6 g, 5.0 mmoles) in tetrahydrofuran (20 mL) at -78° C. was added butyl lithium (2.3 mL of a 2.2M solution, 5 mmoles). After stirring for 15 minutes, ethyl formate (0.44 g, 6.0 mmoles) was added and the solution stirred with cooling for 2 hours. The reaction was quenched with 1N hydrochloric acid and the mixture extracted with diethyl ether. The extracts were dried (MgSO4) and evaporated. The residue was crystallized from isopropyl acetate to give 0.66 g of the title compound; m.p.=154°-155° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[S:13](Cl)(=[O:15])=[O:14].[OH:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[NH2:21]>CO>[OH:17][C:18]1[CH:19]=[C:20]([NH:21][S:13]([C:4]2[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=2[O:2][CH3:1])(=[O:15])=[O:14])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1OC
Reactant: COc1ccc(N)cc1O
Solvent: CO
Product: COc1ccc(NS(=O)(=O)c2ccc(OC)c(OC)c2OC)cc1O
Reaction time: 1 h

Procedure:
To a solution of 2,3,4-trimethoxybenzenesulfonyl chloride (500 mg, 1.88 mmol) in methanol (mL) is added 3-hydroxy-4-methoxyaniline (523 mg, 3.76 mmol) at ambient temperature. The reaction is stirred for 1 h, the solvent is then evaporated and the crude product is purified by flash chromatography over silica.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:9]=2)=[CH:4][CH:3]=1.[CH3:25][C:26]([CH3:28])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C(O)(=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH:26]([CH3:28])[CH3:25])[CH2:15][CH2:14]3)[N:10]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: Clc1ccc(-c2cc(C3CCNCC3)n(-c3ccccc3)n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N1CCC(c2cc(-c3ccc(Cl)cc3)nn2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of INTERMEDIATE 5 (30 mg, 0.089 mmol) in DCM (0.5 mL) were added acetone (0.026 mL, 0.355 mmol), triacetoxyborohydride (75 mg, 0.355 mmol) and acetic acid (10.7 mg, 0.178 mmol). The mixture was stirred at room temperature overnight, quenched with 1 N NaOH, and extracted with EtOAc. The organic layer was washed with water, dried (MgSO4) and concentrated. The residue was purified by preparative TLC (4% MeOH/DCM) to give the title compound. LC-MS m/z 380.16 [M+H]+.
Reaction SMILES: [Na].O[CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][O:6][C:5]1=[O:10].Cl.[CH3:12][O:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>C(O)C>[CH3:12][O:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH:16][CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][O:6][C:5]1=[O:10]
Reactant: COc1ccccc1N
Reactant: O=C1OCCCC1=CO
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: COc1ccccc1NC=C1CCCOC1=O
Reaction time: 2 h
Yield: 54.2 %

Procedure:
The sodium salt of 3-(hydroxymethylene)-tetrahydropyran-2-one (25 g, 0.17 mol) and 2-methoxyaniline hydrochloride (32 g, 0.2 mol) in ethanol (750 ml) were warmed to 70° C. with stirring for 2 hours, then filtered hot. After evaporation of the ethanol, the crude product was taken up in dichloromethane, washed with dilute hydrochloric acid, dried and evaporated. Trituration with ether gave 3-(2-methoxyphenylaminomethylene)tetrahydropyran-2-one (21.5 g, 55%) as a mixture of E and Z isomers, m.p. 85°-100°.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:18](Cl)(=[O:20])[CH3:19]>C(Cl)Cl>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:19][CH:18]=[O:20]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)oc1ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=CCc1ccc2oc3ccccc3c2c1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of dibenzofuran (0.5 mmol) in anhydrous DCM was cooled to 0° C. AlCl3 (1.5 eq., 0.75 mmol) was added followed by a slow addition of acetyl chloride (1.5 eq., 0.75 mmol). The reaction mixture was stirred at 0° C. for 2-3 h or until the completion of reaction. The product was extracted with DCM and washed with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concenterated in vacuo to give dibenzofuran-2-ylethan-2-one.
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:6]=[C:7]([CH3:12])[C:8](Cl)=[N:9][CH:10]=1>COCCO>[Br:4][C:5]1[CH:6]=[C:7]([CH3:12])[C:8]([NH:2][NH2:3])=[N:9][CH:10]=1
Reactant: Cc1cc(Br)cnc1Cl
Reactant: NN
Solvent: O
Solvent: COCCO
Product: Cc1cc(Br)cnc1NN
Temperature: 120 °C
Reaction time: 30 h
Yield: 49.1 %

Procedure:
Hydrazine hydrate (119 mL, 2422 mmol) was added to a suspension of 5-bromo-2-chloro-3-methylpyridine (50 g, 242 mmol) in 2-methoxyethanol (250 mL). The resulting solution was stirred 30 h at 120° C. and concentrated. The yellow residue was purified by trituration with H2O to provide the title compound (24 g) as a colorless solid. tR: 0.39 min (LC-MS 2); ESI-MS: 201.9 [M+H]+ (LC-MS 2)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:18]O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:18])=[O:8]
Reactant: CO
Reactant: O=C(O)c1cc(O)ccc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 98 %

Procedure:
To MeOH (125 mL) was added 5-hydroxy-2-nitrobenzoic acid (1.02 g, 5.6 mmol) followed by dropwise addition of thionyl chloride (˜4 mL) and the mixture heated at reflux overnight. The solution was cooled to room temperature, concentrated in vacuo, reconcentrated twice from MeOH, dissolved in EtOAc, washed with H2O and brine, dried over MgSO4, filtered, and concentrated in vacuo to give methyl 5-hydroxy-2-nitrobenzoate (1.09 g, 5.5 mmol, 98%). 1H NMR (300 MHz, DMSO-d6) δ 11.38 (s, 1H), 8.05 (d, 1H), 7.03 (d, 1H), 7.01 (s, 1H), 3.82 (s, 3H); LC-MS (ESI) m/z 196 (M−H)+.
Reaction SMILES: O.[OH-].[Li+].[Br:4][C:5]1[CH:6]=[N:7][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22]C)=[O:21])[CH:18]=3)[C:13]([S:24][CH3:25])=[CH:12]2)=[N:9][CH:10]=1>C1COCC1.O>[Br:4][C:5]1[CH:6]=[N:7][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:22])=[O:21])[CH:18]=3)[C:13]([S:24][CH3:25])=[CH:12]2)=[N:9][CH:10]=1
Reactant: COC(=O)c1ccc2c(SC)cn(-c3ncc(Br)cn3)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)O)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Lithium hydroxide monohydrate (1.63 g, 39.78 mmol) was added to an ice-cooled suspension of 51b) (5 g, 13.26 mmol) in THF/water (1:1, 50 mL) and the resulting mixture was stirred at room temperature for 16 h. The solvents were removed under reduced pressure and the residue was dissolved in water (20 mL). The aqueous solution was washed with ethyl acetate (2×20 mL), acidified with sodium hydrogen sulfate and extracted with dichloromethane (3×50 mL). The combined organic layers were dried over sodium sulfate and evaporated. White solid. Yield: 4 g (83% of theory)
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][C:4](=C(C)C)[CH:3]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(=O)=[O:16].C(O)(C)C>C(OCC)(=O)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][C:4](=[O:16])[CH:3]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C=O
Reactant: CCOC(=O)C1C(=C(C)C)CC[C@H]1C
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1C(=O)CC[C@H]1C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
(2R)-Ethyl 2-methyl-5-(propan-2-ylidene)cyclopentanecarboxylate (24 g, 0.122 mol) in ethyl acetate (100 mL) was cooled to −68° C. with dry ice/isopropanol. Ozonized oxygen (5-7 ft3 h−1 of O2) was bubbled through the solution for 3.5 hours. The reaction mixture was flushed with nitrogen at room temperature until the color disappeared. The ethyl acetate was removed under vacuum and the residue was dissolved in 150 mL of acetic acid and cooled by ice water. Then 45 g of zinc powder were added. The solution was stirred for 30 minutes and then filtered. The filtrate was neutralized with 2N NaOH (1.3 L) and NaHCO3. The aqueous phase was extracted with ether (3×200 mL). The organic phase was combined, washed with water, dried and concentrated to afford (2R)-ethyl 2-methyl-5-oxocyclopentanecarboxylate (20 g, 96%). 1H NMR (CDCl3, 400 MHz) δ 4.21 (m, 2H), 2.77 (d, J=11.2 Hz, 1H), 2.60 (m, 1H), 2.50-2.10 (m, 3H), 1.42 (m, 1H), 1.33 (m, 3H), 1.23 (m, 3H).
Reaction SMILES: [C:1]1([C@@H:7]([CH2:10][CH3:11])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](=[O:17])[CH2:11][CH2:10][C@@H:7]([CH2:8][NH2:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC[C@@H](CN)c1ccccc1
Reactant: COc1ccccc1C(=O)Cl
Product: COc1ccccc1C(=O)CC[C@@H](CN)c1ccccc1

Procedure:
The title compound was prepared from 0.2 gm of (R)-(−)-2-phenylbutyl amine and 2-mL of 4 methoxybenzoyl chloride according to procedures described in Example 2.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[C:9]([O:11]C)[CH:8]=[C:7]([CH2:13][CH3:14])[C:4]=1[CH:5]=[O:6])[CH3:2].B(Br)(Br)Br>ClCCl>[CH2:13]([C:7]1[CH:8]=[C:9]([OH:11])[CH:10]=[C:3]([CH2:1][CH3:2])[C:4]=1[CH:5]=[O:6])[CH3:14]
Reactant: CCc1cc(OC)cc(CC)c1C=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1cc(O)cc(CC)c1C=O
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of 9.00 g (46.8 mmol)) 2,6-diethyl-4-methoxy-benzaldehyde in 50 ml dichloromethane at −78° C. was added 103 ml (103 mmol) of a 1 M solution of boron tribromide in dichloromethane and the reaction mixture was allowed to warm to room temperature and then heated at reflux for 16 h. The reaction mixture was quenched by pouring onto ice and the resulting mixture was then diluted with ethyl acetate and washed sequentially with water and with saturated brine. The phases were separated and the organic phase was dried over Na2SO4, filtered and concentrated in vacuo to afford 8.68 g (100%) of the title compound as a brown crystalline solid. MS (ISP): 177.4 ([M-H]−, 100%).