Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](S)=[CH:4][CH:3]=1.CC1C=CC(S(O[CH:20]2[CH2:23][O:22][CH2:21]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O[O:31][S:32]([O-:34])=O.[K+]>CS(C)=O.O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:32]([CH:20]2[CH2:23][O:22][CH2:21]2)(=[O:34])=[O:31])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC2COC2)cc1
Reactant: O=S([O-])OO
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: O=S(=O)(c1ccc(Br)cc1)C1COC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-bromothiophenol (1.15 g, 6.08 mmol), oxetan-3-yl 4-methylbenzenesulfonate (1.66 g, 7.3 mmol), and cesium carbonate (3.96 g, 12.16 mmol) were suspended in DMSO (6 ml). The reaction mixture was stirred for 2 days at rt, then diluted with water and EtOAc. The aqueous phase was extracted with EtOAc (×2); and the combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography on a Biotage™ 50 g column by eluting with 5% to 75% EtOAc:Hexane. The major peak was isolated, concentrated and dissolved in MeOH (10 mL), THF (10 mL) and water (5 mL). Oxone (4.05 g, 6.59 mmol) was added and the reaction was stirred overnight at rt, and then diluted with water and EtOAc. The EtOAc phase was washed with water, Na2S2O3, and brine, and then dried over Na2SO4, filtered and concentrated to provide the desired product. 1H NMR δ 7.80-7.75 (m, 4H), 4.96 (t, 2H), 4.82 (t, 2H), 4.46 (pentet, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[NH2:11][CH:12]1[CH2:26][CH:15]2[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH:14]2[CH2:13]1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:11][CH:12]2[CH2:26][CH:15]3[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:18][CH:14]3[CH2:13]2)[C:5]([C:9]#[N:10])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CC2CC(N)CC2C1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Cl)ncc3C#N)CC2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.5 %

Procedure:
To a solution of 2,4-dichloropyrimidine-5-carbonitrile (600 mg, 3.4485 mmol) and tert-butyl 5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (936.8 mg, 4.139 mmol) in ethanol (50 mL) was added N,N-diethylethanamine (698.5 mg, 6.903 mmol). The mixture was stirred at rt for 3 h. Then it was concentrated under vacuo, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=5/1) to give the title product as yellow oil (332.5 mg, 26.50%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Li+].CC([N-]C(C)C)C.[NH:18]1[C:22](C2C=C(Cl)C=CC=2F)=[N:21][N:20]=[N:19]1.C(Cl)[Cl:32]>C1COCC1>[Cl:32][C:7]1([I:9])[CH:6]=[CH:5][CH:3]([NH2:4])[C:2]([C:22]2[NH:21][N:20]=[N:19][N:18]=2)([CH3:1])[CH2:8]1
Reactant: Fc1ccc(Cl)cc1-c1nnn[nH]1
Reactant: Cc1cc(I)ccc1N
Reactant: ClCCl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(c2nnn[nH]2)CC(Cl)(I)C=CC1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution of 2-methyl-4-iodoaniline (3.52 g, 0.0151 mol) in THF (25 mL) at −78° C., LDA (2 molar solution in THF, 11.33 mL, 0.02267 mol) was added dropwise. After stirring for 0.5 hours, a solution of 1-(tetrazol-5-yl)-2-fluoro-5-chlorobenzene (1.5 g, 0.00756 mol) in THF (15 mL) was added dropwise. The reaction was stirred for 16 hours as it warmed up to room temperature. The reaction mixture was quenched with aqueous conc. NH4Cl solution and extracted with CH2Cl2. The organic layer was dried (MgSO4) and the solvent removed giving a crude product as an oil. The oil with CH2Cl2→CH2Cl2:MeOH (9.7:0.3) gave 1.5 g (48%) of the desired product:
Reaction SMILES: [N:1]1([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:47][CH2:46][CH2:45][C@H:2]1[C:3]([NH:5][C@H:6]([C:13]([N:15]1[CH2:44][CH2:43][CH2:42][C@H:16]1[C:17]([NH:19][C@H:20]([C:28]([NH:30][C@H:31]([C:38]([O:40]C)=[O:39])[CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])=[O:14])[CH2:7][C:8]1[N:12]=[CH:11][NH:10][CH:9]=1)=[O:4].[OH-].[Na+].Cl.C(O)CCC.O>CO.O>[N:1]1([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:47][CH2:46][CH2:45][C@H:2]1[C:3]([NH:5][C@H:6]([C:13]([N:15]1[CH2:44][CH2:43][CH2:42][C@H:16]1[C:17]([NH:19][C@H:20]([C:28]([NH:30][C@H:31]([C:38]([OH:40])=[O:39])[CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])=[O:14])[CH2:7][C:8]1[N:12]=[CH:11][NH:10][CH:9]=1)=[O:4]
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Reaction time: 0.25 h

Procedure:
17.2 g of crude Boc-Pro-His-Pro-Phe-His-OMe are dissolved in 54 ml of MeOH, 650 ml of 0.1N NaOH are added, the whole is left to stand for 15 minutes at 25°, neutralised by the addition of 650 ml of 0.1N HCl concentratod to dryness. The residue is dissolved in 120 ml of H2O, the pH value is adjusted exactly to 6.8 and this solution is subjected in the system n-butanol/H2O to Craig partitioning over 500 stages; (K=2.8). The fractions that are pure according to thin layer chromagotraphy analysis are combined, concentrated to dryness, dissolved in H2O and lyophilised, yielding Boc-Pro-His-Pro-Phe-His-OH in amorphous form; Rf (A)=0,15; Rf (C)=0.42; Rf (E)=0.25.
Reaction SMILES: P([O-])(O)(O)=O.[Na+].Cl([O-])=[O:8].[Na+].[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[C@H:19]1[CH2:25][N:24]2[C:26]([CH:29]=[O:30])=[CH:27][N:28]=[C:23]2[C@H:22]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:21][CH2:20]1.CC(=CC)C>O1CCCC1.O.C(O)(C)(C)C>[C:34]([O:33][C:32]([NH:31][C@@H:22]1[CH2:21][CH2:20][C@@H:19]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=2[F:11])[CH2:25][N:24]2[C:26]([C:29]([OH:8])=[O:30])=[CH:27][N:28]=[C:23]12)=[O:38])([CH3:35])([CH3:37])[CH3:36]
Reactant: [O-][Cl+][O-]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C=O)cnc21
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C(=O)O)cnc21
Reaction time: 3 h

Procedure:
Sodium dihydrogen phosphate (127 mg, 0.92 mmol) and sodium chlorite (42 mg, 0.46 mmol) were added to a solution of tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-formyl-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (45 mg, 0.12 mmol) in tetrahydrofuran (0.8 mL), water (0.8 mL), tert-butanol (0.2 mL), and 2-methyl-2-butene (0.2 mL). After 3 h of vigorously stirring, the reaction mixture was quenched with saturated solution of ammonium chloride. The mixture was extracted with ethyl acetate (3×), and the combined organic extracts were washed with water, saturated brine, dried over sodium sulfate, filtered and concentrated. MS 408.1 (M+1).
Reaction SMILES: [C:1]([N:5]1[C:9]([OH:10])=[CH:8][C:7]([C:11]([F:14])([F:13])[F:12])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:34][CH:35]([F:38])[CH2:36]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[C:1]([N:5]1[C:9]([O:10][CH2:36][CH:35]([F:38])[F:34])=[CH:8][C:7]([C:11]([F:13])([F:14])[F:12])=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCC(F)F
Reactant: CC(C)(C)n1nc(C(F)(F)F)cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)n1nc(C(F)(F)F)cc1OCC(F)F
Reaction time: 5 h
Yield: 58.4 %

Procedure:
To a solution of 50.0 g (240.2 mmol) of 1-tert-butyl-5-hydroxy-3-trifluoromethyl-1H-pyrazole in 1000 ml of tetrahydrofuran were added 75.6 g (288.2 mmol) of triphenylphosphine and 23.7 g (288.8 mmol) of 2,2-difluoroethanol at room temperature, followed by stirring. Under ice-cooling, 58.3 g (288.3 mmol) of diisopropyl azodicarboxylate was added into the reaction solution, followed by 5 hours of stirring. After the completion of the reaction was confirmed, the reaction solution was poured into water and extracted with diethyl ether. The resulting organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was distilled under reduced pressure to obtain 38.2 g (yield: 58.4%) of 1-tert-butyl-5-(2,2-difluoroethoxy)-3-trifluoromethyl-1H-pyrazole.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[S:24][C:16]3=[N:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:15]3[CH2:14][CH2:13]2)(=O)=O)=CC=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[H-].[Na+].O>C(Cl)(Cl)Cl>[CH2:26]([NH:33][CH2:11][CH:12]1[S:24][C:16]2=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:15]2[CH2:14][CH2:13]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCn3c(nc4ccccc43)S2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: c1ccc(CNCC2CCn3c(nc4ccccc43)S2)cc1
Yield: 31.3 %

Procedure:
To a solution of 1.12 g of 3,4-dihydro-2-p-toluenesulfonyloxymethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole in chloroform (20 ml) was added with 0.41 g of benzylamine and a catalytic amount of sodium hydride, and refluxed for 11 hours. The reaction mixture was cooled and then condensed under reduced pressure. The residue was added with water, extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate. Chloroform was evaporated under reduced pressure. The residue was chromatographed on silica gel and eluted with chloroform to obtain 0.29 g (Yield: 31%) of the intended product, m.p. 155°-156° C.; IR νmaxKBr cm-1 : 3260, 3100-2800, 1600, 1430; Anal. Calcd. for C18H19N3S: C, 69.87; H, 6.19; N, 13.58; S, 10.36; Found: C, 70.00; H, 6.21; N, 13.69; S, 10.10.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[S:13][CH2:12][CH2:11][C:10](=[O:14])[C:9]=2[CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[C:4]([C:5]1[CH:6]=[CH:7][C:8]2[S:13][CH2:12][CH2:11][C:10](=[O:14])[C:9]=2[CH:15]=1)#[CH:3]
Reactant: C[Si](C)(C)C#Cc1ccc2c(c1)C(=O)CCS2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1ccc2c(c1)C(=O)CCS2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution containing 600.0 mg (2.25 mmol) of 2,3-dihydro-6-(2-trimethylsilylethynyl)-(4H)-1-benzothiopyran-4-one and 100.0 mg (0.72 mmol) K2CO3 in 15 ml MeOH was stirred at room temperature for 20 hours. The solution was diluted with H2O and extracted with Et2O. The combined organic layers were washed with H2O and saturated aqueous NaCl before being dried over MgSO4. Removal of the solvents under reduced preesure afforded the title compound as an orange solid. 1H NMR (CDCl3): δ 8.17 (1H, d, J=1.8 Hz), 7.40 (1H, dd, J=1.8, 8.2 Hz), 7.19 (1H, d, J=8.2 Hz), 3.22 (2H, t, J=6.3 Hz), 3.08 (1H, s) 2.94 (2H, t, J=6.3 Hz).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[O:7][CH2:8][CH2:9][O:10][C:5]=2[CH:4]=1.BrCC1CCCCO1.[O:21]=[C:22]1[C:30]2([C:34]3[CH:35]=[CH:36][C:37]([C:39]#[N:40])=[CH:38][C:33]=3[O:32][CH2:31]2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]1CC1C=CC=CN=1>>[O:7]1[C:6]2[CH:11]=[CH:12][C:3]([CH2:2][N:23]3[C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:30]4([C:34]5[CH:35]=[CH:36][C:37]([C:39]#[N:40])=[CH:38][C:33]=5[O:32][CH2:31]4)[C:22]3=[O:21])=[CH:4][C:5]=2[O:10][CH2:9][CH2:8]1
Reactant: ClCc1ccc2c(c1)OCCO2
Reactant: N#Cc1ccc2c(c1)OCC21C(=O)N(Cc2ccccn2)c2ccccc21
Agent: BrCC1CCCCO1
Product: N#Cc1ccc2c(c1)OCC21C(=O)N(Cc2ccc3c(c2)OCCO3)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 6-(chloromethyl)-2,3-dihydrobenzo[b][1,4]dioxine (Capilla, A. S. et al., Tetrahedron (2001), 57:8297) to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile was obtained (54%) as a colorless solid: mp 181-183° C. (dichloromethane/diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.29-7.16 (m, 1H), 7.15-6.97 (m, 3H), 6.89-6.75 (m, 5H), 5.04 (d, J=9.2 Hz, 1H), 4.94 (d, J=15.3 Hz, 1H), 4.80-4.67 (m, 2H), 4.25-4.19 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 176.2, 160.8, 143.8, 143.3, 142.2, 134.7, 131.3, 129.5, 128.5, 125.8, 124.4, 123.8, 123.7, 120.5, 118.5, 117.8, 116.3, 113.8, 113.3, 109.8, 80.2, 64.3 (2C), 57.8, 43.8.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9]([C:11]3[CH:16]=[C:15]([C:17]#[C:18][C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[C:25]([CH3:29])=[N:24][CH:23]=[CH:22]5)[N:14]=[C:13]([NH2:30])[CH:12]=3)=[N:8][CH:7]=[N:6][C:5]=2[C:4]([CH3:31])=[N:3]1.[CH3:32][CH2:33][N:34](C(C)C)C(C)C.Br[CH:42]([CH2:46][CH3:47])[C:43](Br)=[O:44].C(N)C>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:10]2[C:9]([C:11]3[CH:16]=[C:15]([C:17]#[C:18][C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[C:25]([CH3:29])=[N:24][CH:23]=[CH:22]5)[N:14]=[C:13]([NH:30][C:43](=[O:44])[CH:42]([NH:34][CH2:33][CH3:32])[CH2:46][CH3:47])[CH:12]=3)=[N:8][CH:7]=[N:6][C:5]=2[C:4]([CH3:31])=[N:3]1
Reactant: CCC(Br)C(=O)Br
Reactant: Cc1nccc2cc(C#Cc3cc(-c4ncnc5c(C)nn(C)c45)cc(N)n3)ccc12
Reactant: CCN(C(C)C)C(C)C
Agent: CCN
Solvent: Cc1ccccc1
Product: CCNC(CC)C(=O)Nc1cc(-c2ncnc3c(C)nn(C)c23)cc(C#Cc2ccc3c(C)nccc3c2)n1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A mixture of 4-{1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl}-6-[2-(1-methylisoquinolin-6-yl)ethynyl]pyridin-2-amine (30 mg, 74 μmol), toluene (200 μl) and DIPEA (57 μl, 333 μmol) is cooled to 0° C. 2-Bromobutanoyl bromide (29 μl, 0.24 mmol) in toluene (200 μl) is added dropwise. The mixture is warmed to 50° C. and stirring is continued for 16 h. Cooled to RT 2-bromobutanoyl bromide (29 μl, 0.24 mmol) in toluene (200 μl) is added dropwise. The mixture is stirred at 60° C. for 16 h before it is again cooled to RT. Ethanamine (aqueous solution 70 wt.-%, 1 ml) is added and the mixture stirred for 16 h at 80° C. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 3 mg (8%). HPLC-MS: M+H=519; tR=1.37 min (METHOD—1).
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:18])[N:7]([CH3:17])[C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([Cl:16])[CH:11]=[CH:10][CH:9]=2)=[O:4].[CH2:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:20].CCCCCCC>CO>[CH3:20][CH2:19][N:21]([C:3]([C:5]1[C:6](=[O:18])[N:7]([CH3:17])[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([Cl:16])[C:13]=2[C:14]=1[OH:15])=[O:4])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O
Reactant: CCNc1ccccc1
Solvent: CCCCCCC
Solvent: CO
Product: CCN(C(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Temperature: 25 °C
Yield: 98 %

Procedure:
Laquinimod acid was prepared according to the method described in U.S. Pat. No. 6,875,869: 5-Chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxylic acid methyl ester (3.0 g), N-ethylaniline (2 eq 2-2.88 ml), and heptane (60 ml) were heated and the volatiles, mainly heptane and formed methanol, (32 ml) distilled off during 6 hours and 35 minutes. After cooling to room temperature the crystalline suspension was filtered and the crystals were washed with heptane and dried in vacuum to yield laquinimod acid (3.94 g, 98%) as white to off-white crystals.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[C:12]([C:13]3[C:14]([NH:19][CH2:20][CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:11][S:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(O)C>O1CCCC1.C(OCC)(=O)C>[CH3:21][CH2:20][N:19]1[C:14]2[N:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]2[C:8](=[CH:9][S:10][CH:11]=2)[C:7]2[CH:6]=[CH:5][CH:4]=[N:3][C:2]1=2
Reactant: CCNc1ncccc1-c1cscc1-c1cccnc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCN1c2ncccc2-c2cscc2-c2cccnc21
Reaction time: 0.08 h

Procedure:
To a solution of 3-(2-fluoropyridin-3-yl)-4-(2-ethylaminopyridin-3-yl)thiophene (0.021 g) in tetrahydrofuran (1.5 mL was added potassium bistrimethylsilylamide (0.5M in toluene) until no yellow color appeared on addition of further reagent. The mixture was stirred for 5 minutes, ethanol was added, the mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. The residue was fractionated by chromatography to give 8-ethyl-thienyl[3',4':6,5]dipyrido[2,3-b:3',2'-f]azepine mp 140-142° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:15][C:4]1[CH:5]=[CH:6][C:7]([N:9]2[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10]2)=[N:8][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(N2CC[C@H](O)C2)n1
Solvent: ClC(Cl)Cl
Product: COc1nc(N2CC[C@H](O)C2)ccc1Br
Temperature: 8 °C
Reaction time: 5 h
Yield: 8.3 %

Procedure:
To a solution of (3S)-1-(6-methoxypyridin-2-yl)pyrrolidin-3-ol (1.6 g, 8.24 mmol) in chloroform (90 mL), was added N-bromosuccinimide (1.47 g, 8.24 mmol) at 0° C. with an ice bath. The reaction was allowed to stir at room temperature (8° C.) for 5 hour. TLC (petroleum ether/ethyl acetate) showed that the reaction was complete. The reaction mixture was evaporated to remove chloroform, dissolved in DCM (20 mL) and diluted with water (15 mL). The resulting mixture was separated and the aqueous phase was extracted with dichloromethane (25 mL*3). The combined organic phase was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether, 0-25% to give the title compound (187 mg, 8.5%) as a yellow gum. 1H NMR (400 MHz, CDCl3) ppm 7.46 (d, 1 H) 5.77 (d, 1 H) 4.44-4.59 (m, 1 H) 3.92 (s, 3 H) 3.37-3.61 (m, 4 H) 1.96-2.24 (m, 3 H).
Reaction SMILES: N[CH:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH:3]1C(OCC)=O.Cl.[OH2:20]>>[C:8]1([N:5]2[CH2:4][CH2:3][C:2](=[O:20])[C:6]2=[O:7])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C1CN(c2ccccc2)C(=O)C1N
Reactant: O
Agent: Cl
Product: O=C1CCN(c2ccccc2)C1=O

Procedure:
According to the procedure of Southwick [J. Org. Chem. 21, 1087 (1956)] the ethyl ester pyrrolidinone of Example S (1.0 g, 4.0 mmol) was suspended in 75 ml of 20% HCl/H2O and refluxed for 3.5 h The reaction was cooled and filtered and the filtrate was extracted with CHCl3 (4×150 ml). Concentration of the combined extracts gave an off-white solid (358 mg). 'NMR(300 MHZ, CDCl3) δ2.92 (t, 2H), 4.17 (t, 2H), 7.32 (t, 1H), 7.98 (t, 2H), 7.84 (d, 2H).
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25]I.[C:27]([O:31][C:32](=[O:65])[N:33]([C:41]1[C:42]([CH3:64])([CH3:63])[S:43](=[O:62])(=[O:61])[CH2:44][C@:45]([C:48]2[CH:53]=[C:52]([N+:54]([O-:56])=[O:55])[CH:51]=[CH:50][C:49]=2[CH2:57][CH2:58][CH2:59]O)([CH3:47])[N:46]=1)[C:34]([O:36]C(C)(C)C)=[O:35])([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[C:27]([O:31][C:32](=[O:65])[NH:33][C:41]1[C:42]([CH3:64])([CH3:63])[S:43](=[O:62])(=[O:61])[CH2:44][C@:45]([C:48]2[CH:53]=[C:52]([N+:54]([O-:56])=[O:55])[CH:51]=[CH:50][C:49]=2[CH2:57][CH2:58][CH2:59][I:25])([CH3:47])[N:46]=1)([CH3:30])([CH3:29])[CH3:28].[C:27]([O:31][C:32]([NH:33][C:34](=[O:35])[O-:36])=[O:65])([CH3:30])([CH3:28])[CH3:29]
Reactant: II
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@](C)(c2cc([N+](=O)[O-])ccc2CCCO)CS(=O)(=O)C1(C)C
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(=O)[O-]
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc([N+](=O)[O-])ccc2CCCI)CS(=O)(=O)C1(C)C
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 161.4 %

Procedure:
A solution of imidazole (64.5 mg, 0.948 mmol) and triphenylphosphine (99 mg, 0.379 mmol) in 1.5 ml DCM was cooled to 0° C. and iodine (96 mg, 0.379 mmol) was added. The mixture was stirred for 2 min at 0° C., then solution of (R)-tert-butyl-N-(5-(2-(3-hydroxypropyl)-5-nitrophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)-N-tert-butoxycarbonyl-carbamate (180 mg, 0.316 mmol) in 0.5 ml DCM was added. The mixture was removed from cooling bath and stirred at rt for 20 min. The mixture was directly loaded onto 12 g RediSep Gold column and eluted with 5-50% EtOAc in heptane to afford (R)-tert-butyl-N-(5-(2-(3-iodopropyl)-5-nitrophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate-N-tert-butoxycarbonyl-carbamate (173 mg, 0.255 mmol, 81% yield). LC/MS (ESI+) m/z=524 (M Boc−t-Bu).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH3:15])=[N+:12]([O-])[CH:13]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:18].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:15][Cl:18])=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(-c2ccc(F)cc2)c[n+]1[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1ccc(-c2ccc(CCl)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(4-fluorophenyl)-2-methylpyridine-N-oxide (2.9 g, 14.5 mmol) in CH2Cl2 (15 mL) is added a 1.5 mL portion of a CH2Cl2 (15 mL) solution of POCl3 (1.72 g, 1.7 mmol). Subsequently, the remainder of this POCl3 solution and a solution of triethylamine (1.76 g, 17.4 mmol) in CH2Cl2 (15 mL) are added simultaneously, so as to maintain reflux. After addition is complete the resulting solution is stirred at ambient temperature for 2 hours. The reaction mixture is then neutralized by addition of saturated NaHCO3 (50 mL). The organic phase is separated, dried over MgSO4 and concentrated in vacuo. Chromatography (silica gel, 1:1 EtOAc/hexanes) affords 5-(4-fluorophenyl)-2-(chloromethyl)pyridine as a yellow solid.
Reaction SMILES: Cl[CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)[C:3]#[N:4].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C.CCCCCC>[CH3:14][O:13][C:7]1[CH:6]=[C:5]([CH:2]([S:22][C:19]2[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=2)[C:3]#[N:4])[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: Cc1ccc(S)cc1
Reactant: COc1ccc(C(Cl)C#N)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(C(C#N)Sc2ccc(C)cc2)cc1OC
Yield: 65.4 %

Procedure:
A mixture of 4.12 g of α-chloro-3,4-dimethoxybenzeneacetonitrile (U.S. Pat. No. 4,833,162), 2.48 g of p-thiocresol, 2.76 g of potassium carbonate and 100 mL of acetonitrile is stirred at 65° C. overnight. After filtering off the salts, the reaction mixture is concentrated in vacuo leaving a golden oil. The oil is dissolved in a minimum amount of ethyl acetate and diluted with 3 volumes of hexane. Seeding gives 3.81 g of the desired compound as light yellow crystals.