Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([N:38]=[N+:39]=[N-:40])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([N:38]=[N+:39]=[N-:40])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OC(c1cccc(Cl)c1)c1cccc(OCc2ccccc2)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NC(c1cccc(Cl)c1)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (3-benzyloxyphenyl)(3-chlorophenyl)methanol, as described above in Step A, (4.0 g, 12.3 mmol) and diphenylphosphoryl azide (4.1 g, 14.9 mmol) in dry toluene (35 mL) at 0° C., was added 1,8-diazabicyclo[5.4.0]undec-7-ene (2.1 g, 13.8 mmol). The resulting mixture was allowed to warm to ambient temperature, and stirred under argon for 18 hours, then washed with 5% hydrochloric acid (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with hexane—2% EtOAc to yield the product as a colorless oil.
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[CH3:9][O:8][C:5]1[CH:4]=[C:3]([CH3:10])[C:2]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[CH:7][N:6]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1cc(C)c(Br)cn1
Product: COc1ccc(-c2cnc(OC)cc2C)cc1
Yield: 81 %

Procedure:
According to Scheme 30 Step 1: The title compound was prepared from 5-bromo-2-methoxy-4-methylpyridine (1 eq, 15.8 mmol, 3.20 g) and 4-methoxyphenylboronic acid (1.5 eq, 23.8 mmol, 3.61 g) according to the procedure described for Example 1 Step 3. Reaction conditions: 21 hours at 80° C. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 130 g SiO2) using AcOEt/MeOH (95/5) as the eluent to afford 2-methoxy-5-(4-methoxyphenyl)-4-methylpyridine (12.8 mmol, 2.94 g, 81%) as a light yellow solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:34][CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33][CH2:34]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CCC4)ccc4c3OCO4)ncnc12
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CCC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-cyclobutylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A174) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C@@H:8]([CH2:10][CH3:11])[NH2:9].Cl[C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[C:14]=1[N+:20]([O-:22])=[O:21].C(N(CC)C(C)C)(C)C>CC(O)C>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C@H:8]([NH:9][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([OH:19])[C:14]=1[N+:20]([O-:22])=[O:21])[CH2:10][CH3:11]
Reactant: O=c1[nH]ccc(Cl)c1[N+](=O)[O-]
Reactant: CC[C@@H](N)Cc1sccc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Cc1sccc1Cl)Nc1ccnc(O)c1[N+](=O)[O-]
Reaction time: 7 h

Procedure:
To a 3-neck 1 liter round bottom flask fitted with a mechanical stirrer, thermocouple, nitrogen inlet and a condenser is sequentially charged: 14.5 g of (R)-3-chloro-a-ethyl-2-thiopheneethanamine (Compound III), 10.9 grams of 4-chloro-3-nitropyridin-2(1H)-one (Compound II), 35 grams of 2-propanol (IPA) and 25 mL of N,N-diisopropylethylamine (DIPEA). The mixture is stirred at 70° C.±2° C. for 7 hours before the reaction is allowed to cool overnight to room temperature (22° C±3° C.). The mixture is concentrated to 41. 4 g. of a syrup which is subsequently dissolved in 425 ml of ethyl acetate. This solution is washed with 125 mL of water, 2×50 mL of 5N ammonium chloride solution and 2×50 mL of saturated sodium chloride solution before drying over sodium sulfate. The solution is filtered, concentrated, and the resulting solid collected by filtration to give Compound IV, m.p. 150-152° C. Mass Spec. (EI), m/z 328 (6%), 1HNMR (500 Mhz, DMSO) δ 0.91 (3H, t); 1.8-1.6 (2H, m); 3.1 (1H, m); 3.95 (1H, m); 5.9 (1H, d); 7.0 (1H, d); 7.3 (1H, dd); 7.5 (1H, d); 8.8 (1H, d); 11.1 (1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](=[S:8])[NH:6][CH:7]=1.C(N(CC)CC)C.[CH2:16](Br)[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]>CCO>[CH2:16]([S:8][C:5]1[N:6]=[CH:7][C:2]([Br:1])=[CH:3][N:4]=1)[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]
Reactant: O=C(CBr)c1ccccc1
Reactant: S=c1ncc(Br)c[nH]1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(CSc1ncc(Br)cn1)c1ccccc1
Reaction time: 1 h
Yield: 71 %

Procedure:
5-Bromopyrimidine-2-thione (10.5 mmol) was added to a solution of triethylamine (11.6 mmol) in EtOH (130 ml) and the mixture stirred for 15 min before addition of phenacyl bromide (10.5 mmol). The reaction mixture was stirred for 1 h before the solvent was removed at reduced pressure, the residue extracted with chloroform and the chloroform solution chromatographed on alumina (100 g, activity I); yield 71%, m.p. 107°-109° C. (iPrOH). 1H NMR (CDCl3): δ4.60 (CH2), 7.5-8.0 (Ph), 8.46 (H-4, H-6).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]#[C:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH:38]=O)=[N:30]1.N1CCCCC1>CO>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](/[CH:38]=[C:8]2\[O:9][C:5]3[C:4]([C:13]#[C:14][CH2:15][N:16]4[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:30]1
Reactant: COc1ccc2c(c1C#CCN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1C#CCN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A solution of tert-butyl 4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)prop-2-ynyl]piperazine-1-carboxylate (0.0500 g, 0.129 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0198 g, 0.136 mmol) and piperidine (0.0877 g, 0.103 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (Z)-4-(3-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}prop-2-ynyl)piperazine-1-carboxylate (0.0625 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.O=[C:12]1[CH2:16][S:15][CH2:14][CH:13]1[C:17](OC)=[O:18]>C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:17](=[O:18])[C:13]3[CH2:14][S:15][CH2:16][C:12]=3[NH:10][C:4]=2[CH:3]=1
Reactant: COC(=O)C1CSCC1=O
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: c1ccccc1
Product: O=C1Nc2cc(Cl)c(Cl)cc2NC2=C1CSC2
Temperature: 25 °C

Procedure:
A reaction mixture comprising 106 g. of 4,5-dichloro-o-phenylenediamine and 96 g. of tetrahydro-4-oxo-3-thiophene carboxylic acid, methyl ester in 4 liters of benzene is refluxed for 5 hours and then cooled overnight. The benzene is removed by distillation and replaced by toluene. The mixture is refluxed 2 hours, 10 ml. of water and 0.5 ml. of acetic acid are added and the mixture is refluxed overnight, cooled to room temperature and filtered. The solid is washed with three 100 ml. portions of toluene and air dried giving 6,7-dichloro-1,3,4,9-tetrahydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[N:20]=[N:19][C:18]=1[O:29][CH3:30])=O)(C)(C)C.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>ClCCl>[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32].[CH3:30][O:29][C:18]1[N:19]=[N:20][C:21]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:22][C:17]=1[C:9]1[NH:8][C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccccc2n1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1nnc(-c2ccncc2)cc1-c1cc2ccccc2[nH]1

Procedure:
A solution of 5.5 g 2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester and 5 ml TFA in 10 in 10 ml dichloromethane stirred for 18 h at room temperature. The solvent is evaporated and the crude product purified by suspended on water and collecting the precipitate.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][CH:18]1[O:23][CH2:22][CH2:21][NH:20][CH2:19]1.O>CS(C)=O>[CH3:17][CH:18]1[CH2:19][N:20]([C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=2)[CH2:21][CH2:22][O:23]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC1CNCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC1CN(c2ccc(N)cc2)CCO1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-fluoro-4-nitrobenzene (5.64 g, 40.0 mmol) and potassium carbonate (11.1 g, 80.0 mmol) in DMSO (30 mL) was added 2-methylmorpholine (4.05 g, 40.0 mmol), then the mixture was heated at 100° C. for 4 hours. This solution was poured on to water (300 mL) and extracted with EA (3×100 mL). The combined organic phase was washed with brine and dried. Filtered and Pd/C (1.0 g) was added to the filtrate, charged with H2, and stirred at room temperature overnight. The catalyst was filtered and the filtrate was concentrated to give product as a light red solid. MS (m/z): 193 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([N+:27]([O-])=O)=[C:7]([CH2:13][S:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1.O.NN>C(O)C.[Pd]>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([CH2:13][S:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:6]=1[NH2:27]
Reactant: COc1cc(CS(=O)(=O)c2cccc3ccccc23)c([N+](=O)[O-])c(OCCCl)c1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1cc(CS(=O)(=O)c2cccc3ccccc23)c(N)c(OCCCl)c1
Temperature: 60 °C

Procedure:
A mixture of 1-[3-(2-chloro-ethoxy)-5-methoxy-2-nitro-phenylmethanesulfonyl]-naphthalene (1.0 g, 2.5 mmoles) in ethanol (25 mL) was stirred under nitrogen in a round bottom flask at 60° C. 10% Pd/C was added, and the temperature was increased to 80° C. Hydrazine hydrate (2.0 mL) was added dropwise and the mixture was stirred at reflux for 3 hours. Reaction mixture was filtered off through Celite, and the solution was washed with H2O (3×), dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (1.0 g, 2.46 mmoles).
Reaction SMILES: Cl[C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:32])([F:31])[C:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][N:19]=[N:18]3)=[N:12][CH:13]=2)=[C:4](F)[CH:3]=1.BrCC1C=CC([C:42]#[N:43])=CC=1>>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:15]([OH:22])([CH2:16][N:17]1[CH:21]=[N:20][N:19]=[N:18]1)[C:14]([C:11]1[N:12]=[CH:13][C:8]([O:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([C:42]#[N:43])=[CH:34][CH:33]=2)=[CH:9][CH:10]=1)([F:32])[F:31]
Reactant: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(OCc2ccc(Cl)cc2F)cn1
Reactant: N#Cc1ccc(CBr)cc1
Product: N#Cc1ccc(COc2ccc(C(F)(F)C(O)(Cn3cnnn3)c3ccc(F)cc3F)nc2)cc1

Procedure:
Compound 9 was prepared in a similar manner to compound 1 from 4-(bromomethyl)benzonitrile to afford a white solid (80 mg, 33%). 1H NMR (500 MHz, CDCl3): δ 8.73 (s, 1H), 8.24 (s, 1H), 7.72 (d, J=7.5 Hz, 2H), 7.75-7.52 (m, 3H), 7.43 (br s, 1H), 7.39-7.35 (m, 1H), 7.31-7.29 (m, 1H), 6.78-6.74 (m, 1H), 6.70-6.67 (m, 1H), 5.51 (d, J=14.0 Hz, 1H), 5.18 (s, 2H), 5.13 (d, J=14.0 Hz, 1H). MS (ESI): m/z 485 [M+1]. HPLC: 97.12%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:54]=[C:55]([O:59][CH3:60])[C:56]=1[O:57][CH3:58])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([C:35]([C:37]3[N:41]([CH2:42][C:43]4[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=4)[C:40]4[CH:50]=[CH:51][CH:52]=[CH:53][C:39]=4[N:38]=3)=[O:36])[CH2:31][CH2:30]2)([C:13]2[CH:18]=[CH:17][C:16]([O:19][Si](C(C)(C)C)(C)C)=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[CH3:60][O:59][C:55]1[CH:54]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:56]=1[O:57][CH3:58])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:27][CH2:28][N:29]2[CH2:30][CH2:31][CH:32]([C:35]([C:37]3[N:41]([CH2:42][C:43]4[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=4)[C:40]4[CH:50]=[CH:51][CH:52]=[CH:53][C:39]=4[N:38]=3)=[O:36])[CH2:33][CH2:34]2)([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)C2)cc(OC)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(c3ccc(O)cc3)C2)cc(OC)c1OC
Reaction time: 0.5 h

Procedure:
Combine 1-(3,4,5-trimethoxy-benzoyl)-3-[2-[4-[1-(4-fluoro-benzyl)-1 H-benzoimidazole-2-carbonyl]-piperidin-1-yl]-ethyl]-3-(4-(t-butyldimethylsilyloxy)-phenyl)-pyrrolidine (6 mmol) and THF (20 mL). Cool using an ice bath. Add dropwise, a 1 M THF solution of tetrabutylammonium fluoride (7 mL). After 30 minutes, concentrate in vacuo to obtain a residue. Combine dichloromethane (50 mL) and the residue. Extract with water (3×15 mL), dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph on silica gel to obtain the title compound.
Reaction SMILES: [CH2:1]([N:5]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13]I)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[CH2:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([N:5]([C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([CH2:13][NH:45][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:15])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CI)C(=O)O)cc1
Reactant: NCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CNCc2ccccc2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-iodoacetyl-L-lysine (200 mg, 0.38 mmol, example 105, step B) by following the indications of general procedure H using DIEA (0.20 mL, 1.10 mmol) and benzylamine (320 mg, 2.99 mmol). The crude material was purified by preparative HPLC. The product was isolated as a solid (137 mg, 71% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9](Br)[CH2:10][Br:11].[OH-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][Br:11]
Reactant: BrCCBr
Reactant: Oc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccccc1OCCBr
Temperature: 100 °C

Procedure:
22.4 ml (0.2 mole) of 2-chlorophenol and 34.6 ml (0.4 mole) of ethylene dibromide are mixed and heated at 100° C. The mixture is stirred vigourously with 125 ml 1.6N NaOH, continued heat and stirred till the pH value to 7. Upon cooling, after filtrating the extracted solids, the mixed solution's organic layer is extracted with chloroform and rinsing the extracted solids with NaCl and MgSO4. The generated product is filled into silica gel chromatography columns. The mixture solution of Hexane and Ethylacetate was used as the eluent solution. Upon purification, until white crystallization 2(2-chlorophenoxy)ethylbromide is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[N+:12]=[N-:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:21][C:22]([F:35])([F:34])[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32])=[O:24]>CN(C)C=O>[F:21][C:22]([F:34])([F:35])[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[N+:12]=[N-:13])(=[O:9])=[O:10])=[CH:4][CH:3]=1)=[O:32])=[O:24]
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(N)cc1
Reactant: O=C(Cl)CCCCCNC(=O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NS(=O)(=O)c1ccc(NC(=O)CCCCCNC(=O)C(F)(F)F)cc1
Reaction time: 24 h

Procedure:
To 0.57 g (3 mmol) of para-amino-benzenesulfonyl azide dissolved in 5 mL dimethylformamide was added 0.9 mL (6 mmol) triethylamine, then the (2,2,2-trifluro-acetylamino)-hexanoyl chloride dissolved in 10 mL dimethylformamide was added dropwise. The mixture turned brown and was stirred under argon for 24 hrs. Solvent was evaporated, and the remaining oil was dissolved in 10 mL dichloromethane and left at room temperature for 1 hr. The precipitate was filtrated and the solution was evaporated to yield 1.10 g crude oil. The obtained compound was directly used in oligonucleotide synthesis.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[OH:11].[C:12](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[O:11][CH3:12]
Reactant: O=[N+]([O-])c1cccc(Br)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(Br)cccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
2-Bromo-6-nitrophenol (5.0 g, 22.9 mmol) was dissolved in DMF (3 mL), potassium carbonate (4.75 g, 34.4 mmol) was added and the reaction was stirred for 30 minutes. Next iodomethane (2.15 mL, 34.4 mmol) was added and the reaction was stirred overnight. The crude reaction was filtered, diluted with ethyl acetate and washed with brine (twice) and water (twice). The organic layer was dried over sodium sulfate, filtered and concentrated to provide 1-bromo-2-methoxy-3-nitrobenzene (5.12 g, 96%). LC retention time 0.92 [J].
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[O:18][C:17]([C@:19]([OH:25])([CH3:24])[C:20]([F:23])([F:22])[F:21])=[N:16][N:15]=2)=[N:4][C:5]([O:12][CH3:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:26]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>C(#N)C>[NH2:1][C:2]1[C:3]([C:14]2[O:18][C:17]([C@:19]([OH:25])([CH3:24])[C:20]([F:23])([F:22])[F:21])=[N:16][N:15]=2)=[N:4][C:5]([O:12][CH3:13])=[C:6]([C:8]([F:10])([F:9])[F:11])[C:7]=1[Cl:26]
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: COc1nc(-c2nnc([C@@](C)(O)C(F)(F)F)o2)c(N)cc1C(F)(F)F
Solvent: CC#N
Product: COc1nc(-c2nnc([C@@](C)(O)C(F)(F)F)o2)c(N)c(Cl)c1C(F)(F)F
Reaction time: 0.17 h

Procedure:
To (R)-2-(5-(3-amino-6-methoxy-5-(trifluoromethyl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)-1,1,1-trifluoropropan-2-ol (Example 2) (150 mg, 0.403 mmol) in acetonitrile (1 ml) was added trichloroisocyanuric acid (37.5 mg, 0.161 mmol) and the resulting mixture was heated using microwave radiation at 100° C. for 30 minutes followed by 125° C. for 10 minutes. The mixture was partitioned between EtOAc and water. The organic portion was separated and washed with sat.NaHCO3, brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-30% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: C(O[C:4](=[O:14])[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[NH2:15][C:16]1[O:20][N:19]=[C:18]([CH3:21])[CH:17]=1>O>[CH3:21][C:18]1[C:17]2[C:4]([OH:14])=[CH:5][C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:15][C:16]=2[O:20][N:19]=1
Reactant: Cc1cc(N)on1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: O
Product: Cc1noc2nc(-c3ccccc3)cc(O)c12
Temperature: 25 °C

Procedure:
19.2 g. of benzoylacetic acid ethyl ester (0.1 mol.) are added dropwise to a stirred mixture of 9.8 g. of 5-amino-3-methylisoxazole (0.1 mol.) and 50 g. of polyphosphorous acid heated to 120°-125°. After the reaction has occurred, which can be recognized by changing of the color to brown, the reaction mixture is heated for an additional half hour at 125°. After the mixture has cooled to room temperature, 250 ml. of water are added in portions and stirring is continued until the compound becomes crystalline. The collected 3-methyl-6-phenylisoxazolo[5,4-b]pyridin-4-ol is washed with water, dried and recrystallized from ethanol yielding 19.9 g. (88%), m.p. 281°-282°.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=O.[C:14]1([O:20][CH2:21][CH3:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([CH3:11])=[C:6]([CH2:7][C:17]2[CH:18]=[CH:19][C:14]([O:20][CH2:21][CH3:22])=[CH:15][CH:16]=2)[CH:10]=1
Reactant: COc1cc(C)c(C(=O)O)cc1Br
Reactant: CCOc1ccccc1
Product: CCOc1ccc(Cc2cc(Br)c(OC)cc2C)cc1

Procedure:
Then, the title compound (5.80 g) was synthesized from 5-bromo-4-methoxy-2-methylbenzoic acid (4.93 g, 0.0201 mol) and phenetole by a similar method as in Preparation Example 14.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23]>>[CH2:1]([S:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[C:21]2[S:17][C:18](=[O:23])[NH:19][C:20]2=[O:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(SCc2ccccc2)cc1
Reactant: O=C1CSC(=O)N1
Product: O=C1NC(=O)C(=Cc2ccc(SCc3ccccc3)cc2)S1

Procedure:
4-(Benzylthio)benzaldehyde (20.8 g) was fused with thiazolidine-2,4-dione according to the method of Example 5 to afford 15 g of present title product; m.p. 237°-238° C.
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[O:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12][CH2:11]1>CC#N>[Br:8][C:6]1[N:7]=[C:2]([NH:17][CH2:16][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)[C:3]([Cl:9])=[N:4][CH:5]=1
Reactant: NCC1CCOCC1
Reactant: Clc1ncc(Br)nc1Br
Solvent: CC#N
Product: Clc1ncc(Br)nc1NCC1CCOCC1
Temperature: 80 °C
Yield: 61.1 %

Procedure:
To a scintillation vial containing 3,5-dibromo-2-chloropyrazine (1 g, 3.67 mmol) and TEA (1.024 ml, 7.34 mmol) was added MeCN (5 ml) and (tetrahydro-2H-pyran-4-yl)methanamine (0.557 g, 3.67 mmol). The homogenous reaction mixture was capped, and heated to 80° C. in a oil bath for 4 hr. The reaction mixture was concentrated to dryness, diluted with EtOAc and sequentially washed with sat NaHCO3, and sat NaCl. The organic layer was dried Na2SO4, filtered and concentrated. The crude was purified by column chromatography on silica gel (20% EtOAc/Hexane) to yield 6-bromo-3-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (688 mg, 2.244 mmol, 61.1% yield), yield), LCMS (m/z): 308.0 (MH+), retention time=0.94 min, and 6-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (55 mg, 0.179 mmol, 4.89% yield), LCMS (m/z): 308.0 (MET), retention time=0.91 min.