Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21](OC)=[O:22])[N:4]=1)#[N:2].[C:25]([O:29][C:30](=[O:37])[C:31]([CH2:35][NH2:36])([CH3:34])[CH2:32][CH3:33])([CH3:28])([CH3:27])[CH3:26]>CO>[C:25]([O:29][C:30](=[O:37])[C:31]([CH2:35][NH:36][C:21]([C:5]1[N:4]=[C:3]([C:1]#[N:2])[C:12]2[C:7]([C:6]=1[OH:20])=[CH:8][CH:9]=[C:10]([O:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:11]=2)=[O:22])([CH3:34])[CH2:32][CH3:33])([CH3:26])([CH3:27])[CH3:28]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CCC(C)(CN)C(=O)OC(C)(C)C
Solvent: CO
Product: CCC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)OC(C)(C)C

Procedure:
Methyl 1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (55 mg, 0.17 mmol) and 2-aminomethyl-2-methyl-butyric acid tert-butyl ester (88 mg of the crude, 0.47 mmol) in MeOH (3 mL) were heated at 140° C. in a microwave for 1 hour. The solvent was removed in vacuo and the residue oil was purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 60 mg. MS: (−) m/z 474.24 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])/[C:5](=[N:7]/[OH:8])/[NH2:6].[NH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=O)=[C:19]([Cl:26])[CH:18]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CC(=O)OCC.C(#N)C>[Cl:26][C:19]1[CH:18]=[C:17]([CH:25]=[CH:24][C:20]=1[C:21]1[O:8][N:7]=[C:5]([C:4]2[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH3:15])[CH3:14])=[C:2]([Cl:1])[CH:3]=2)[N:6]=1)[NH2:16]
Reactant: CC(C)Oc1ccc(/C(N)=N/O)cc1Cl
Reactant: Nc1ccc(C(=O)O)c(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(N)cc3Cl)n2)cc1Cl
Temperature: 120 °C
Yield: 67 %

Procedure:
(Z)-3-chloro-N′-hydroxy-4-isopropoxybenzimidamide (0.5 g, 2.187 mmol), 4-amino-2-chlorobenzoic acid (0.413 g, 2.405 mmol), DCC (0.496 g, 2.405 mmol), HOBT (0.368 g, 2.405 mmol) were placed in an 80 ml microwave vial and Acetonitrile (12.01 ml) was added. The reaction mixture was stirred for 5 minutes at room temperature before the addition of DIEA (0.840 ml, 4.81 mmol). The reaction mixture was heated to 120° C. for 30 min in a microwave. TLC (50% EA/Hept) indicated 4 spots Rf 0.8, 0.6, 0.5 and 0.3. LCMS (2007—9349) indicated by UV 16% (2.61 mins) to (M+H) 364.31. The solvent was removed and the crude material purified by FCC (50% EA/Hept) to afford 3-chloro-4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)aniline (534 mg, 1.466 mmol, 67.1% yield). LCMS (Table A, Method b) indicated a 99% by UV (3.10 mins) and 92% by ELSD (3.06 mins) to (M+H)+ 364.12.
Reaction SMILES: [CH3:1][O:2][C:3]1([CH2:18][NH:19]C(=O)OC(C)(C)C)[CH2:8][CH2:7][N:6]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:5][CH2:4]1.C(OC([NH:34][C:35]1[S:39][C:38]([C:40]2[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:41]=2[F:47])=[N:37][C:36]=1[C:48](O)=[O:49])=O)(C)(C)C>>[NH2:34][C:35]1[S:39][C:38]([C:40]2[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:41]=2[F:47])=[N:37][C:36]=1[C:48]([NH:15][C:10]1[CH:11]=[N:12][N:13]([CH3:14])[C:9]=1[N:6]1[CH2:5][CH2:4][C:3]([CH2:18][NH2:19])([O:2][CH3:1])[CH2:8][CH2:7]1)=[O:49]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: COC1(CNC(=O)OC(C)(C)C)CCN(c2c([N+](=O)[O-])cnn2C)CC1
Product: COC1(CN)CCN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnn2C)CC1
Yield: 7 %

Procedure:
Following the procedure for Example 101 starting from tert-butyl (4-methoxy-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid gave 458 as an off-white solid (30 mg, 7% over three steps). 1H NMR (400 MHz, d4-MeOD) δ 8.56 (s, 1H), 7.56-7.42 (m, 2H), 7.15 (t, J=8.7 Hz, 2H), 3.74 (s, 3H), 3.42-3.33 (m, 4H), 3.23 (s, 2H), 3.12-2.95 (m, 3H), 1.97 (d, J=13.6 Hz, 2H), 1.76-1.66 (m, 2H). LCMS (ES+) m/z 478 (M+1)
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][P:13](=[O:18])([O:16][CH3:17])[O:14][CH3:15].[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23](OC)=[O:24]>C1COCC1.C(O)(=O)C.O>[Cl:19][C:20]1[CH:21]=[C:22]([C:23](=[O:24])[CH2:12][P:13](=[O:18])([O:16][CH3:17])[O:14][CH3:15])[CH:27]=[CH:28][CH:29]=1
Reactant: COP(C)(=O)OC
Reactant: COC(=O)c1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COP(=O)(CC(=O)c1cccc(Cl)c1)OC
Temperature: -78 °C
Yield: 84.6 %

Procedure:
A solution of n-butyl lithium in hexane (1.63N, 45 ml, 73.3 mmol) was added dropwise to a solution of dimethyl methylphosphonate (9.1 g, 73.3 mmol) in 100 ml of anhydrous THF with stirring at -78° C. under argon atmosphere, and the mixture was stirred for 30 minutes. Then, methyl m-chlorobenzoate (5.0 g, 29.3 mmol) in 10 ml of anhydrous THF was further added dropwise and the mixture was stirred for 30 minutes. This reaction mixture was allowed to warm to 0° C., diluted with 4.4 ml of acetic acid and 10 ml of water, and concentrated. 30 ml of water was added to the residue and the mixture was extracted with ethyl acetate (50 ml×2). The combined ethyl acetate layers were washed with water (30 ml×1) and brine (30 ml×1), dried over anhydrous sodium sulfate, and concentrated. The residue was distilled under reduced pressure to give a colorless transparent oil of dimethyl 2-m-chlorophenyl-2-oxoethylphosphonate (6.5 g, 24.8 mmol, yield 84%, b.p. 144°-146° C./0.06 mmHg), which was assigned the structure by the following data:
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][N:10]1[C:14]2=[CH:15][N:16]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([Cl:31])[CH:29]=4)[CH:24]=[C:17]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:13]2[CH:12]=[N:11]1.O>CN(C)C=O>[Cl:1][C:26]1[CH:27]=[C:28]([Cl:31])[CH:29]=[C:30]2[C:25]=1[CH:24]=[C:17]1[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:13]3[CH:12]=[N:11][N:10]([CH3:9])[C:14]3=[CH:15][N:16]12
Reactant: CN1N=CN2C1=Cn1c(cc3ccc(Cl)cc31)-c1ccccc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN1N=CN2C1=Cn1c(cc3c(Cl)cc(Cl)cc31)-c1ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.7 %

Procedure:
A solution of 1.91 g N-chlorosuccinimide in 45 ml dimethylformamide was added dropwise to a solution of 3.33 g 1-methyl-12-chloro-4H-indolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]benzodiazepine in 100 ml dimethylformamide. The reaction mixture was stirred for three hours at room temperature. Upon addition of water and stirring overnight, a solid precipitated. This was collected, triturated with hexane and dried to yield 1.72 g. Recrystallization from methanol/water yielded 1.17 g solid, m.p. 266°-270° C.
Reaction SMILES: OC1C=CC(NC(C)(C)C)=CC=1.C1(NC(C)(C)C)C=CC=CC=1.NC(N)=O.[CH3:28][C:29]([NH:39][CH2:40][C:41]([C:43]1[CH:44]=[CH:45][C:46]([OH:52])=[C:47]([CH2:49][C:50]#[N:51])[CH:48]=1)=[O:42])([CH3:38])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>>[OH:52][C:46]1[CH:45]=[CH:44][C:43]([CH:41]([OH:42])[CH2:40][NH:39][C:29]([CH3:38])([CH3:28])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)=[CH:48][C:47]=1[CH2:49][C:50]#[N:51]
Reactant: CC(C)(Cc1ccc(O)cc1)NCC(=O)c1ccc(O)c(CC#N)c1
Agent: CC(C)(C)Nc1ccc(O)cc1
Agent: CC(C)(C)Nc1ccccc1
Agent: NC(N)=O
Product: CC(C)(Cc1ccc(O)cc1)NCC(O)c1ccc(O)c(CC#N)c1

Procedure:
The procedure of Example 1(c) is repeated with substitution of an equimolar amount of p-hydroxyphenyl-t-butylamine for phenyl-t-butylamine in that example. The resulting aminoketone, 5-[N-(1,1-dimethyl-2-p-hydroxyphenylethyl)glycyl]-2-hydroxyphenylacetonitrile, is reduced according to the procedure of Example 1(d) to yield 2-hydroxy-5-[1-hydroxy-2-[(1,1-dimethyl-2-p-hydroxyphenylethyl)amino]ethyl]benzeneacetonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[O:12][CH3:13])[CH3:2].ClC1C=C(C=CC=1OCC)C=[O:19]>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]([OH:19])=[O:9])=[CH:6][C:5]=1[O:12][CH3:13])[CH3:2]
Reactant: CCOc1ccc(C=O)cc1OC
Reactant: CCOc1ccc(C=O)cc1Cl
Product: CCOc1ccc(C(=O)O)cc1OC
Yield: 89 %

Procedure:
When the product of Step A was substituted for 3-chloro-4-ethoxybenzaldehyde in Example 49 Step A the identical process afforded the title compound in 89% yield. 1H-NMR CDCl3) 1.4 (tr, 3H, J=6.95 Hz); 3.83 (s, 3H); 4.07 (q, 2H, J=6.96, 13.9, Hz); 6.79 (d, 1H, J=8.4 Hz); 7.47 (s, 1H); 7.58 (d, 1H, J=8.33 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][S:12][CH3:13])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)O)=[C:17]([CH3:30])[CH:16]=1.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][S:12][CH3:13])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:21]([C:18]1[CH:19]=[CH:20][C:15]([F:14])=[CH:16][C:17]=1[CH3:30])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1
Reactant: CSCc1cc(F)cc2cc[nH]c12
Reactant: Cc1cc(F)ccc1C(O)c1ccc(F)cc1
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3)c[nH]c12
Product: CSCc1cc(F)cc2c(C(c3ccc(F)cc3)c3ccc(F)cc3C)c[nH]c12
Temperature: 80 °C
Reaction time: 4 h

Procedure:
The title compound was prepared starting from 500 mg (2.56 mmol) of the compound from Example 11A and 733 mg (2.56 mmol) of the compound from Example 82A in analogy to the synthesis of the compound from Example 278. A difference was that stirring at 80° C. was for only 4 h. 428 mg (39% of theory) of the target compound were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](Br)[C:3]=1[O:10][CH2:11][CH2:12]Br.[Li]CCCC.[C:19](=[O:21])=[O:20].CC(C)=O.C(=O)=O>C1COCC1.CCCCCC>[CH3:8][C:6]1[CH:5]=[C:4]([C:19]([OH:21])=[O:20])[C:3]2[O:10][CH2:11][CH2:12][C:2]=2[CH:7]=1
Reactant: Cc1cc(Br)c(OCCBr)c(Br)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: Cc1cc2c(c(C(=O)O)c1)OCC2
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a stirred solution of 2-(2,6-dibromo-4-methylphenyloxy)ethyl bromide (19) (5.82 g, 15.6 mmol) in dry THF (90 ml) and hexane (30 ml) under argon there was added 7.8 ml of n-BuLi (2.5M in hexane) at -78° C. (dry ice/acetone bath). After 30 minutes at -78° C., an additional 7.8 ml of n-BuLi was added. After an additional 1 hour stirring, the light yellow reaction solution was poured into a slurry of dry ice (prewashed with dry ether). After the mixture had come to room temperature, the precipitated white solid was collected on a filter, treated with 1N HCl to adjust the pH of the supernatant liquid to 1. The mixture was cooled briefly in the freezer, and the solid collected on a filter to afford 2.52 g (90.7%) of acid 20. The crude product was recrystallized from CH3OH/H2O to yield 1.70 g (61.2%) of 20 as a white solid, mp 177°-179° C. IR(KBr) 3420 (OH) and 1680(C=0) cm-1. NMR(CDCl3) δ 8.47 (br s, 1H, OH), 7.50 (s, 1H, aromatic proton), 7.15 (s, 1H, aromatic proton), 4.70 (t, 2H, J=9 Hz, OCH2), 3.20 (t, 2H, OCH2CH2), and 2.32 (s, 3H, CH3).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH:11]1([CH:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O.O1CCOCC1>[CH:11]1([CH:17]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[O:1][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([OH:7])=[O:6])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(O)c1cccc(O)c1
Reactant: OC(C1CCCCC1)C1CCCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(OC(C2CCCCC2)C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.6 %

Procedure:
To a solution of 3-hydroxybenzoic acid (1.61 g, 8.2 mmol), dicyclohexylmethanol (1.61 g, 8.2 mmol), triphenylphosphine (2.05 g, 7.82 mmol) and dioxane (35 ml) was added diethyl azodicarboxylate (1.41 ml, 8.94 mmol), and the resultant mixture was refluxed for 3 days. The reaction mixture was allowed to warm up to room temperature, poured into chilled water and extracted with diethyl ether. The organic layer was concentrated, and the residue was dissolved in a mixture of methanol (20 ml), tetrahydrofuran (6.5 ml) and water (2.0 ml), mixed with potassium hydroxide (1.16 g) and stirred for 2 hours. The mixture was poured into chilled water, acidified, and extracted with ethyl acetate. The organic layer was concentrated, and the resultant residue was recrystallized from hexane to give the titled compound (0.43 g, yield 18%).
Reaction SMILES: [C:1]([NH:22][C@H:23]([C:30]([OH:32])=[O:31])[CH2:24][O:25][P:26]([OH:29])([OH:28])=[O:27])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl.[CH3:34]OC(=O)[C@H]([C@@H](C)O)N>>[C:1]([NH:22][C@H:23]([C:30]([OH:32])=[O:31])[C@@H:24]([CH3:34])[O:25][P:26]([OH:29])([OH:28])=[O:27])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@@H](COP(=O)(O)O)C(=O)O
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Agent: Cl
Product: CCCCCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@H](C(=O)O)[C@@H](C)OP(=O)(O)O

Procedure:
This compound was prepared as described above for (6) using 1 mmol (170 mg) of L-threonine methyl ester hydrochloride; yield 97 mg, (40%); Rf 0.05-0.10 (system B); 1H-NMR (CD3SOCD3, 200 MHz) δ0.9-1.0 (t, 3H, ω-CH3); 1.2-1.4 (m, 11H, 4CH2 and CH3CHOP); 2.0-2.4 (m, 6H, 2CH2CH═CH and CH2CO); 2.7-2.9 (br s, 6H, 3HC═CHCH2CH═CH); 4.1-4.3 (m, 2H, 2CH); 5.2-5.4 (br s, 8H, 4HC═CH); 8.2-8.4 (m, 3H, NH and 2POH)
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])[N:9]=2)[CH2:4]1.C1COCC1.C(N(CC)CC)C.Cl[C:39]([O:41][CH2:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:40]>C(Cl)Cl.CN(C=O)C>[CH2:42]([O:41][C:39](=[O:40])[NH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])[N:9]=2)[CH2:4]1)[C:43]([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)COC(=O)Cl
Reactant: Cc1ccc2c(N3CC[C@@H](CN)C3)nc(-c3ccccc3O)nc2c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CC[C@@H](CNC(=O)OCC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
A mixture of 2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (200 mg, 0.6 mmol), THF (6.0 mL), and DMF (1 mL) was stirred under an N2 atmosphere. Triethylamine (0.166 mL, 1.2 mmol) was added, and the reaction was cooled in an ice bath. To this was added 1 M neopentyl chloroformate solution (89 μL in 600 μL THF, 0.6 mmol). After allowing the reaction mixture to warm to room temperature over a period of 30 minutes, CH2Cl2 was added to the reaction mixture, and it was washed once with water before it was dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 0-20% EtOAc in CH2Cl2/hexanes (1:1) gave neopentyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate (222 mg, 94%). LC/MS: m/z 449 (M+H)+ at 2.73 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, acetic acid-d4) δ 8.42 (dd, J=8.1, 1.8 Hz, 1H), 8.20 (d, J=8.7 Hz, 1H), 7.57 (s, 1H), 7.40-7.29 (m, 3H), 6.92-6.89 (m, 2H), 4.11-3.92 (m, 3H), 3.78-3.61 (m, 3H), 3.33-3.28 (m, 1H), 3.23-3.10 (m, 2H), 2.49 (s, 3H), 2.16-2.08 (m, 1H), 1.83-1.75 (m, 1H), 0.89 (s, 9H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[Cl:16].C1COCC1.[Br:22]Br>O>[Br:22][C:11]1[C:10]([Cl:9])=[C:15]([Cl:16])[CH:14]=[CH:13][N:12]=1
Reactant: Clc1ccncc1Cl
Reactant: BrBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1ccnc(Br)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of lithium diisopropylamide (7.0 mL, 2.0 M heptane/THF, 14.0 mmol) was added to a solution of 3,4-dichloropyridine (1.88 g, 12.7 mmol) and anhydrous THF (30 mL) at −78° C. under N2. After 1 h, bromine (0.71 mL, 14.0 mmol) was added. After an additional 30 min, the reaction was allowed to warm to rt and maintained for 30 min. The mixture was poured into water, extracted with EtOAc, dried, filtered, concentrated, and purified by silica gel chromatography (0→30% EtOAc/hexanes) to give 2-bromo-3,4-dichloropyridine after recrystallization from methanol. MS (ESI): 225.9.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][O:17][CH2:18][CH2:19]Br)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].C(C(C(C(O)=O)O)O)(O)=O.[NH:39]1[CH2:44][CH2:43][CH2:42][C@@H:41]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:40]1>CC(C)=O>[CH2:48]([O:47][C:45]([C@@H:41]1[CH2:42][CH2:43][CH2:44][N:39]([CH2:19][CH2:18][O:17][CH:16]=[C:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]2=3)[CH2:40]1)=[O:46])[CH3:49]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: BrCCOC=C1c2ccccc2CCc2ccccc21
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: CCOC(=O)[C@@H]1CCCN(CCOC=C2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.6 %

Procedure:
To a solution of 2-((10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)methoxy)ethylbromide (14.0 g, 42.5 mmol) in acetone (100 ml) was added potassium carbonate (23.5 g, 170 mmol), potassium iodide (0.7 g) and ethyl (R)-3-piperidinecarboxylate tartrate (19.6 g, 64 mmol). The suspension was stirred at room temperature for 3 days. The reaction mixture was filtered and the solvent was evaporated from the filtrate in vacuo. The oily residue was dissolved in ethyl acetate (150 ml). A 34% aqueous tartaric acid solution (100 ml) was added and pH was adjusted to 2.5 with a 4 M aqueous sodium hydroxide solution. The phases were separated and the organic phase was washed with a 2.5% aqueous solution of sodium bicarbonate (100 ml) and a 5% aqueous sodium bicarbonate solution (25 ml). The combined aqueous phases were extracted with ethyl acetate (100 ml). The combined organic phases were dried over magnesium sulphate. The solvent was evaporated in vacuo to give 12.0 g of (R)-N-(2-((10,11-dihydro-5H-dibenzo [a, d]cyclohepten-5-ylidene)methoxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil. TLC: rf=0.45 (SiO2 ; dichloromethane/methanol/acetic acid=20:2:1).
Reaction SMILES: C(O)=O.Cl[C:5]1[CH:6]=[C:7]([N:12]2[CH2:16][CH:15]([CH3:17])[C:14]([NH:18][CH:19]=[O:20])=[N:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11]>O>[Cl:11][C:10]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:16][CH:15]([CH3:17])[C:14]([NH:18][CH:19]=[O:20])=[N:13]2)=[CH:8][CH:9]=1
Reactant: CC1CN(c2ccc(Cl)c(Cl)c2)N=C1NC=O
Solvent: O=CO
Solvent: O
Product: CC1CN(c2ccc(Cl)cc2)N=C1NC=O
Reaction time: 3 h

Procedure:
A 2.2 g. amount of the preceding compound is dissolved in 10.0 ml. of a mixture of formic acid and acetic anhydride (Example 15). The mixture is allowed to remain at room temperature for 3 hours. Water is added and a yellow solid is collected by filtration. The solid is dissolved in dichloromethane. The solution is dried over anhydrous magnesium sulfate and filtered through a hydrous magnesium silicate. The filtrate is concentrated while adding hexane until turbidity occurs. The mixture is cooled and filtered to give 2.1 g. of the product of the Example as a white solid, m.p. 172°-174° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH2:18])[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:6])[CH3:5].[F:21][C:22]1[CH:23]=[C:24]([CH:29]([OH:33])[C:30](O)=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1>>[CH3:1][O:2][C:3](=[O:20])[C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH:18][C:30](=[O:31])[CH:29]([C:24]2[CH:25]=[C:26]([F:28])[CH:27]=[C:22]([F:21])[CH:23]=2)[OH:33])[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:5])[CH3:6]
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)C(=O)OC)cn1
Reactant: O=C(O)C(O)c1cc(F)cc(F)c1
Product: CCCC(NC(=O)C(O)c1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)C(=O)OC)cn1

Procedure:
2-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-2-methyl-propionic acid methyl ester was coupled with (3,5-Difluoro-phenyl)-hydroxy-acetic acid to provide the title compound: C13 NMR (100 MHz, CDCl3) 13.7, 13.8, 19.0, 19.1, 26.0, 35.3, 35.7, 53.0, 53.2, 53.3, 61.2, 61.3, 73.3, 73.4, 103.5, 103.7, 106.1, 106.3, 109.6, 109.8, 110.1, 131.6, 131.8, 137.0, 137.1, 144.0, 161.9, 164.3, 169.3, 169.6, 171.9, 172.0, 172.5; MS 453.20 m/z (M+1).
Reaction SMILES: CON(C)[C:4](=[O:21])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=1.[CH3:23][CH2:24][Mg]Br>C1COCC1.CCOCC>[CH:16]1([O:15][C:9]2[CH:8]=[C:7](/[CH:6]=[CH:5]/[C:4](=[O:21])[CH2:23][CH3:24])[CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CC[Mg]Br
Reactant: COc1ccc(/C=C/C(=O)N(C)OC)cc1OC1CCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(=O)/C=C/c1ccc(OC)c(OC2CCCC2)c1
Reaction time: 0.5 h
Yield: 34 %

Procedure:
To a solution of (E)-N-methoxy-N-methyl-3-(3-cyclopentoxy-4-methoxyphenyl)-prop-2-enamide (1.33 g, 4.36 mmol) in 8.0 mL of THF cooled to 0° C. was added CH3CH2MgBr (9 mL of 1.0M THF solution). The resulting solution was stirred for 30 min, diluted with ether and transferred to a separatory funnel. After washing with H2O, 1M H3PO4, and brine, the organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (4:1, hexanes:ethyl acetate) provided (E)-5-(3-cyclopentoxy-4-methoxyphenyl)-pent-4-en-3-one as a white solid (400 mg, 34%). 1H-NMR (300 MHz): δ 1.17 (t, 3, J=7.6), 2.69 (q, 2, J=7.3), 3.89 (s, 3), 6.59 (d, 1, J=16), 7.50 (d, 1, J=16). Anal. Calcd for C17H22O3 : C, 74.42; H, 8.08. Found: C, 74.52; H, 8.13.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([C@@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])[OH:7])=[O:5].[N-:16]=[N+:17]=[N-:18].[Na+].[I-].[Na+]>O>[N:16]([CH2:2][CH2:3][C:4]([C@@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])[OH:7])=[O:5])=[N+:17]=[N-:18]
Reactant: O=C(CCBr)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NCCC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
A 5L round bottom three-necked flask, equipped with a heating mantle, an overhead stirrer, and a thermometer, was charged with 150 gm bromoethylglucose (525 mmol). The oil was dissolved in 2 L water and treated with 68.3 gm sodium azide (1.05 mol, 2 equiv.; 65 gm/mol; Alfa-Aesar) followed by 7.9 gm sodium iodide (52.5 mmol, 0.08 equiv.; 149.89 gm/mol; Alfa-Aesar) and the solution warmed to 50 C and stirred overnight. The solution was cooled to room temperature and concentrated to dryness on the rotovap. The solid residue was digested with 3×500 mL of 5:1 vol. CHCl3:MeOH at 40 C. The combined organic portions were filtered and evaporated to dryness to afford azidoethylglucose (86 gm) as an off-white solid. TLC (20% MeOH/DCM; char with H2SO4): single spot, indistinguishable from the starting material.