Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)C.[CH2:8]([N:10]1[C:14]([O:15][C:16]2[CH:21]=[CH:20]C(C=O)=[CH:18][CH:17]=2)=[CH:13][C:12]([C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[C:27]#[N:28])=[N:11]1)[CH3:9].[CH3:32]O>>[CH3:1][O:4][CH:5]([O:7][CH3:32])[C:6]1[CH:20]=[CH:21][C:16]([O:15][C:14]2[N:10]([CH2:8][CH3:9])[N:11]=[C:12]([C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[C:27]#[N:28])[CH:13]=2)=[CH:17][CH:18]=1
Reactant: CO
Reactant: CCn1nc(-c2cccc(C#N)c2)cc1Oc1ccc(C=O)cc1
Reactant: CC(=O)OC(C)=O
Product: CCn1nc(-c2cccc(C#N)c2)cc1Oc1ccc(C(OC)OC)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
Acetic anhydride (0.24 mL, 3.3 mmol, 0.1 equiv) was added to a stirring solution of 3-[1-ethyl-5-(4-formylphenoxy)-1H-pyrazol-3-yl]benzonitrile (10.5 g, 33.0 mmol, 1 equiv) in methanol (66 mL). 4A molecular sieves were then added and the mixture was stirred at 50° C. for 3 hours. The sieves were filtered away and the filtrate was purified by flash chromatography (0-40% EtOAc:Hex) to give 3-{5-[4-(dimethoxymethyl)phenoxy]-1-ethyl-1H-pyrazol-3-yl}benzonitrile (77% yield). Calc'd (M+1) 364.2. Found: 364.1
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:15][C:16]#[N:17]>CC#N>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:15][C:16]#[N:17])[CH:2]=1
Reactant: Oc1cccnc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCOc1cccnc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 16 %

Procedure:
To a mixture of pyridin-3-ol (4.0 g, 42.1 mmol) and K2CO3 (6.96 g, 50.4 mmol) in CH3CN (6 mL) was added dropwise 2-bromoacetonitrile (2.52 g, 21.0 mmol) at rt and the mixture was stirred at rt for 40 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as a yellow solid (0.45 g, 16%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[C:27](Cl)(=O)[CH:28]=C.[C:32]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])[CH3:33]>>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[Cl:22])[CH2:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:24]([N:38]2[CH2:39][CH2:40][N:35]([C:32](=[O:34])[CH3:33])[CH2:36][CH2:37]2)=[O:26])[N:8]([C:6](=[O:7])[CH:27]=[CH2:28])[CH2:12]1
Reactant: C=CC(=O)Cl
Reactant: CC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)O
Product: C=CC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)N1CCN(C(C)=O)CC1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, acryloyl chloride, and 1-acetylpiperazine the title compound was obtained in 79% purity by LC/MS. MS(ESI+): m/z=467.6.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:37]2[CH2:41][C@H:40]([CH2:42][NH:43][C:44](=[O:46])[CH3:45])[O:39][C:38]2=[O:47])[CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([O:27]CC2C=CC(OC)=CC=2)=[N:10][C:11]([O:14][C@@H:15]2[CH2:20][O:19][C:18]3=[N:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][N:17]3[CH2:16]2)=[N:12][CH:13]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:37]2[CH2:41][C@H:40]([CH2:42][NH:43][C:44](=[O:46])[CH3:45])[O:39][C:38]2=[O:47])[CH:5]=[CH:6][C:7]=1[C:8]1[C:9](=[O:27])[NH:10][C:11]([O:14][C@@H:15]2[CH2:20][O:19][C:18]3=[N:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][N:17]3[CH2:16]2)=[N:12][CH:13]=1
Reactant: COc1ccc(COc2nc(O[C@@H]3COc4nc([N+](=O)[O-])cn4C3)ncc2-c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3cnc(O[C@@H]4COc5nc([N+](=O)[O-])cn5C4)[nH]c3=O)c(F)c2)C(=O)O1
Yield: 88.3 %

Procedure:
To a solution of (S,S)—N-(3-{3-Fluoro-4-[4-(4-methoxy-benzyloxy)-2-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxy)-pyrimidin-5-yl]-phenyl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide (60 mg, 0.092 mmol) in TFA/methylene chloride (3.0 mL, 1/1) was stirred at rt for 1 h. Solvents were evaporated and triturated with ether to give the title product (43 mg, 88%) as a pale yellow solid. ESI MS m/z 530.4 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([OH:15])[C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([OH:15])[C:12]([O:14][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: BrCc1ccccc1
Reactant: COc1ccc(C(O)C(=O)O)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(O)C(=O)OCc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
To 6C (830 mg, 3.9 mmol) in DMF (15 mL) was added cesium carbonate (2.6 g, 8.0 mmol) followed by benzyl bromide (0.6 mL, 5 mmol). After stirring at rt overnight, the reaction was diluted with water, and was extracted with ethyl acetate (2×30 mL). The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The resulting residue was purified via silica gel chromatography (0-40% ethyl acetate/hexanes) to provide 6D (520 mg, 44%). LC-MS 445.31 (M+H)+.
Reaction SMILES: [CH:1](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]2[C:39]([NH2:40])=[CH:38][C:37]([Br:41])=[CH:36][N:35]=2)=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:34]3=[N:35][CH:36]=[C:37]([Br:41])[CH:38]=[C:39]3[N:40]=[CH:1]2)=[CH:29][CH:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(OC)OC
Reactant: Nc1cc(Br)cnc1Nc1ccc(OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Brc1cnc2c(c1)ncn2-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Trimethyl orthoformate (9.0 mL, 81 mmol) and p-toluenesulphonic acid (384 mg, 2.0 mmol) were added to a solution of N2-[4-(benzyloxy)phenyl]-5-bromopyridine-2,3-diamine (3 g, 8.1 mmol) in dichloromethane (40 mL) and the reaction mixture stirred at rt for 4 h. Next, the precipitated material was collected by filtration, redissolved in CH2Cl2 and the solution washed with 10% NaOH(aq) (200 mL) and brine (200 mL), then dried over MgSO4 and concentrated in vacuo to afford 3-[4-(benzyloxy)phenyl]-6-bromo-3H-imidazo[4,5-b]pyridine. 1H NMR (400 MHz, CDCl3) δ 5.14 (s, 2H), 7.16 (d, J=8.8 Hz, 2H), 7.33-7.47 (m, 5H), 7.58 (d, J=8.8 Hz, 2H), 8.25 (s, 1H), 8.28 (d, J=2 Hz, 2H) and 8.46 (d, J=2 Hz, 2H); MS (ES+): m/z 380 [Br79MH+], 382 [Br81MH+].
Reaction SMILES: [CH2:1]([Si:3](Cl)([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[Br:9][CH2:10][C@@H:11]([C:13]1[CH:24]=[CH:23][C:16]2[O:17][C:18]([CH3:22])([CH3:21])[O:19][CH2:20][C:15]=2[CH:14]=1)[OH:12].N1C=CN=C1.CCCCCC>CN(C=O)C>[Br:9][CH2:10][C@H:11]([O:12][Si:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:1][CH3:2])[C:13]1[CH:24]=[CH:23][C:16]2[O:17][C:18]([CH3:22])([CH3:21])[O:19][CH2:20][C:15]=2[CH:14]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: CC1(C)OCc2cc([C@@H](O)CBr)ccc2O1
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)O[C@@H](CBr)c1ccc2c(c1)COC(C)(C)O2
Temperature: 15 °C
Yield: 99.9 %

Procedure:
Triethylsilyl chloride (205 g) was added dropwise to a stirred mixture of (1R)-2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (350 g) and imidazole (108.5 g) in DMF (875 ml) at 5° C. Upon complete addition the mixture was warmed to 15° C. and stirred, at this temperature for 1 h. n-Hexane (3500 ml) was then added to the mixture which was washed with water (3×1750 ml). The organic layer was dried over anhydrous MgSO4 before being filtered and concentrated under reduced pressure to give the title compound (488.6 g) as an oil, δ (DMSO-d6) 7.18 (1H, d, J 8.2 Hz), 7.10 (1H, s), 6.75 (1H, d, J 8.2 Hz), 4.83 (1H, m), 4.78 (2H, d, J 6.9 Hz), 3.55 (2H, m), 1.45 (6H, s), 0.84 (9H, t, J 8.1 Hz), 0.51 (6H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH:6]=[O:7].[N+:12]([CH2:15][CH3:16])([O-:14])=[O:13].[OH-].[Na+].C(O)(=O)C>CO>[F:11][C:10]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH:15]([N+:12]([O-:14])=[O:13])[CH3:16])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C=O)ccc1F
Reactant: CC[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(C(O)C(C)[N+](=O)[O-])ccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a flame dried 100 mL round bottom flask was added 3-methoxy-4-fluorobenzaldehyde (367 mg, 2.38 mmol) and this was dissolved in methanol (23 mL). The reaction solution was cooled to 0° C. and nitroethane (357 mg, 4.76 mmol) was added to it followed by 5M NaOH (0.476 mL, 2.38 mmol). The solution was stirred for 80 min at 0° C. after which acetic acid (2% solution, 32 mL) was added and stirred for an additional 30 min. The reaction mixture was concentrated and water (10 mL) was added. The solution was extracted with dichloromethane (4×20 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, and concentration to give afford an oil which was purified by silica gel flash chromatography using dichloromethane as eluant. Product (391 mg, 72%) product Was obtained as a colorless oil in a 1.88:1 ratio (A:B) of diastereomers. Pair A: 1H NMR (600 MHz, CDCl3): δ 7.07 (m, 1H), 7.0 (m, 1H), 6.8 (m, 1H), 5.34 (t, 1H, J=3 Hz), 4.65 (d of q, 1H, J=3.6, 6.6 Hz), 3.9 (s, 3H), 2.697 (d, 1H, J=3.6 Hz), 1.5 (d, 3H, J=6.6 Hz). 13C NMR (75 MHz, CDCl3): δ 153.3, 150.1, 147.44 (d, J=10.8 Hz), 134.1, 117.7 (d, J=7 Hz), 115.7 (d, J=18.6 Hz), 110.6, 86.8, 72.8, 55.8, 11.7. Pair B: NMR (600 MHz, CDCl3): δ 7.07 (m, 1H), 7.0 (m, 1H), 6.8 (m, 1H), 4.9 (d Of d, 1H, J=3.6, 9 Hz), 4.72 (m, 1H), 3.9 (s, 3H), 2.57 (d, 1H, J=4.2 Hz), 1.33 (d, 3H, J=5.4 Hz). 13C NMR (75 MHz, CDCl3): δ 153.8, 150.5, 147.76 (d, J=10.8 Hz), 134.1, 119 (d, J=7 Hz), 115.8 (d, J=18.6 Hz), 111, 87.7, 75.3, 55.8, 15.9. HRMS: Calc'd for C10H12FNO4 (M+Na): 252.0642; Found: 252.0643.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1.[F:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22](F)[CH:23]=1>>[F:17][C:18]1[CH:23]=[C:22]([N:3]2[CH:4]=[C:5]([C:7]#[C:8][C:9]3[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=3)[C:12]#[N:13])[N:6]=[C:2]2[CH3:1])[CH:21]=[N:20][CH:19]=1
Reactant: Fc1cncc(F)c1
Reactant: Cc1nc(C#Cc2cccc(C#N)c2)c[nH]1
Product: Cc1nc(C#Cc2cccc(C#N)c2)cn1-c1cncc(F)c1

Procedure:
The title compound, MS: m/e=303.5 (M+), was prepared in accordance with the general method of example 1 from 3-(2-methyl-1H-imidazol-4-ylethynyl)-benzonitrile and 3,5-difluoro-pyridine.
Reaction SMILES: [CH:1]([CH:5]1[CH2:10][C:9](=[O:11])[CH2:8][C:7](=[O:12])[CH2:6]1)([CH2:3][CH3:4])[CH3:2].[C:13]1([CH3:25])[CH:18]=[CH:17][C:16]([S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20])=[CH:15][CH:14]=1>C1C=CC=CC=1>[CH:1]([CH:5]1[CH2:6][C:7](=[O:12])[CH:8]([C:23](=[O:24])[NH:22][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:25])=[CH:14][CH:15]=2)(=[O:20])=[O:21])[C:9](=[O:11])[CH2:10]1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)C1CC(=O)CC(=O)C1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: c1ccccc1
Product: CCC(C)C1CC(=O)C(C(=O)NS(=O)(=O)c2ccc(C)cc2)C(=O)C1

Procedure:
Reaction of equimolar amounts of 5-sec.-butyl-1,3-cyclohexanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-sec.-BUTYL-2-(N-p-TOLUENESULFONYLCARBAMOYL)-1,3-CYCLOHEXANEDIONE, m.p. 92°-93° C. (corr.).
Reaction SMILES: Cl.C(OC([N:9]1[C@H:14]([C:15]2[NH:16][CH:17]=[C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH:26]=[C:25]([C:30]3[CH:35]=[CH:34][C:33]([C:36]5[N:37]=[C:38]([C@@H:41]6[CH2:46][C@:45]7([CH3:47])[C@@H:43]([CH2:44]7)[N:42]6C(OC(C)(C)C)=O)[NH:39][CH:40]=5)=[CH:32][CH:31]=3)[CH:24]=[CH:23]4)[N:19]=2)[CH2:13][C@:12]2([CH3:55])[C@H:10]1[CH2:11]2)=O)(C)(C)C>O1CCOCC1.CO>[CH3:47][C@:45]12[CH2:44][C@H:43]1[NH:42][C@H:41]([C:38]1[NH:39][CH:40]=[C:36]([C:33]3[CH:34]=[CH:35][C:30]([C:25]4[CH:24]=[CH:23][C:22]5[C:27](=[CH:28][CH:29]=[C:20]([C:18]6[N:19]=[C:15]([C@@H:14]7[CH2:13][C@:12]8([CH3:55])[C@@H:10]([CH2:11]8)[NH:9]7)[NH:16][CH:17]=6)[CH:21]=5)[CH:26]=4)=[CH:31][CH:32]=3)[N:37]=1)[CH2:46]2
Reactant: CC(C)(C)OC(=O)N1[C@H](c2nc(-c3ccc(-c4ccc5cc(-c6c[nH]c([C@@H]7C[C@@]8(C)C[C@H]8N7C(=O)OC(C)(C)C)n6)ccc5c4)cc3)c[nH]2)C[C@@]2(C)C[C@@H]12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@]12C[C@@H](c3nc(-c4ccc(-c5ccc6cc(-c7c[nH]c([C@@H]8C[C@@]9(C)C[C@H]9N8)n7)ccc6c5)cc4)c[nH]3)N[C@@H]1C2
Reaction time: 2 h

Procedure:
A solution of 4N HCl in dioxane (5 mL) was added to tert-butyl (1R,3S,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (48 mg. 0.066 mmol) in MeOH (1 mL) and stirred at ambient conditions for 2 hours, concentrated, and dried under vacuum. Tetra HCl salt (assume theoretical: 44 mg). LC-MS retention time 2.82 min; calcd. for C34H35N6: 527.29 m/z Found 527.26 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min and an analysis time of 5 min where Solvent A was 5% methanol/95% water/0.1% TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [Cl:1][C:2]1[N:20]=[CH:19][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[NH:15][CH:16]=[CH:17][N:18]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:27](I)([CH3:29])[CH3:28]>CN(C)C=O.O.CCOC(C)=O>[Cl:1][C:2]1[N:20]=[CH:19][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:27]([CH3:29])[CH3:28])[CH:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: Clc1cc2c(cn1)-c1nc(-c3ncc[nH]3)cn1CCO2
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)n1ccnc1-c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Temperature: 50 °C
Yield: 47.7 %

Procedure:
To a solution of 9-chloro-2-(1H-imidazol-2-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine (0.402 g, 1.4 mmol) in N,N-dimethylformamide (9.6 mL) was added Cs2CO3 (0.6 g, 2.0 mmol) followed by isopropyl iodide (0.2 mL, 2 mmol). The reaction mixture was heated at 50° C. for a 20 h period. The mixture was subsequently cooled to room temperature and diluted with water and EtOAc. The mixture was extracted twice with EtOAc, dried over MgSO4, filtered and concentrated. The resultant residue was purified by flash column chromatography (0-10% MeOH in dichloromethane). This procured 0.22 g (48% yield) of 9-chloro-2-(1-isopropyl-1H-imidazol-2-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine which was combined with L-prolinamide (0.152 g, 1.33 mmol) in N,N-dimethylacetamide (6.7 mL) and sealed in a pressure vessel. The mixture was heated at 150° C. was heated for 40 h at which point an additional amount of L-prolinamide (0.152 g, 1.33 mmol) was added and the mixture was continued to be heated for 12 h. Only 50% conversion was observed at the end of this period and heating was discontinued and the material was purified by rp-HPLC eluting with 0.1% NH4OH in acetonitrile to provide 19.8 mg (8% yield) of 377. MS(ESI+) m/z 408.2 (M+H+), calcd. 408.5. 1H NMR (400 MHz, DMSO) δ 9.03 (s, 1H), 7.58 (s, 1H), 7.43-7.26 (m, 2H), 6.89 (d, J=1.0 Hz, 2H), 5.94 (s, 1H), 5.72 (dt, J=13.6, 6.8 Hz, 1H), 4.56-4.38 (m, 4H), 4.29 (d, J=8.0 Hz, 1H), 3.59 (s, 1H), 2.17 (d, J=8.9 Hz, 1H), 1.98 (dd, J=31.1, 24.1 Hz, 4H), 1.44 (d, J=4.2 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([OH:14])=O)[S:11][C:7]=2[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:34][CH2:35][C:36]([C:38]1[S:42][C:41]2[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=2[C:39]=1[CH3:47])=[O:37].C(N(CC)CC)C>CN(C=O)C.O>[CH3:47][C:39]1[C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[S:42][C:38]=1[C:36](=[O:37])[CH2:35][NH:34][C:12]([C:10]1[S:11][C:7]2[C:6]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:14]
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)O)nc12
Reactant: Cc1c(C(=O)CN)sc2ccccc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCOCC2)c2sc(C(=O)NCC(=O)c3sc4ccccc4c3C)nc12
Reaction time: 48 h
Yield: 24.4 %

Procedure:
0.30 g 4-Methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid and 0.19 g 1,1′-carbonyl-diimidazole in 18 ml DMF were stirred at room temperature for 4 hours. 0.27 g 2-amino-1-(3-methyl-benzo[b]thiophen-2-yl)-ethanone hydrochloride and 0.16 ml triethylamine were added and stirring was continued for two days at room temperature. Water was added and the mixture was extracted with ethylacetate. Chromatography on silicagel with ethylacetate/hexane 4:6 yielded 0.12 g (23%) 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid [2-(3-methyl-benzo[b]thiophen-2-yl)-2-oxo-ethyl]-amide as a yellow solid; M.p.: 186–187° C.; MS (ISP): m/e=482 (M+H+).
Reaction SMILES: Br[C:2]1[C:14]([O:15][CH3:16])=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[C:5]([CH2:21][CH2:22][CH3:23])([CH2:18][CH2:19][CH3:20])[C:4]=2[CH:3]=1.[Cu][C:25]#[N:26].[C-:27]#[N:28].[K+]>CN(C)C=O.O>[C:27]([C:2]1[C:14]([O:15][CH3:16])=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([C:25]#[N:26])=[CH:9][CH:10]=3)[C:5]([CH2:21][CH2:22][CH3:23])([CH2:18][CH2:19][CH3:20])[C:4]=2[CH:3]=1)#[N:28]
Reactant: N#C[Cu]
Reactant: CCCC1(CCC)c2cc(Br)ccc2-c2cc(OC)c(Br)cc21
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC1(CCC)c2cc(C#N)ccc2-c2cc(OC)c(C#N)cc21
Temperature: 90 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
A mixture of 2,7-dibromo-9,9-dipropyl-3-methoxyfluorene (83 g, 0.19 mol), and copper(I) cyanide (50 g, 0.56 mol) in anhydrous dimethylformamide (70.0 mL) was stirred under reflux and argon for 18 hours. The reaction was allowed to cool to 90° C. and treated with a solution of potassium cyanide (100 g) in water (350 mL). The resulting mixture was stirred rapidly for a further 4.5 hours. The granular product was collected by filtration, crushed, washed with water and dried. The tan colored solid was extracted from a soxhlet with methylcyclohexane. Cooling and seeding of the methylcyclohexane extract afforded 2,7-dicyano-9,9-dipropyl-3-methoxyfluorene upon filtration (62.6 g; yield 99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5](I)[N:4]=1.[Cu](C#N)[C:13]#[N:14]>CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]([C:13]#[N:14])[N:4]=1
Reactant: COc1ccc(I)nc1OC
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: COc1ccc(C#N)nc1OC
Temperature: 150 °C

Procedure:
To a solution of 2,3-dimethoxy-6-iodopyridine (7-4, 24.0 g, 91 mmol) in DMF (181 mL) was added copper cyanide (9.73 g, 109 mmol) and heated to 150° C. for 20 minutes in a microwave reactor. The mixture was partitioned between water and EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by gradient elution on silica gel (0 to 40% EtOAc in hexanes) to yield the desired product (7-5) as an off-white crystalline powder. ESI+ MS [M+H]+ C8H8N2O2: 165.0 found, 165.1 required.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[O:13][CH:14]([F:19])[C:15]([F:18])([F:17])[F:16])([O-])=O.Cl.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>[Fe].C(O)C>[NH2:1][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[O:13][CH:14]([F:19])[C:15]([F:17])([F:18])[F:16]
Reactant: O=[N+]([O-])c1ccc(OC(F)C(F)(F)F)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCO
Product: Nc1ccc(OC(F)C(F)(F)F)c(N)c1
Reaction time: 2 h

Procedure:
89 g (0.31 moles) 2,4-dinitrotetrafluoroethoxybenzene, according to Step 1, 125 ml of a 50% aqueous solution of ethanol and 106.5 g iron powder (1.91 moles) are heated to 60°-70° C. in a water bath in a three-necked flask, which is equipped with a reflux condensor, drop addition funnel, stirrer and internal thermometer. Next, a solution of 6.5 ml concentrated hydrochloric acid in 30 ml 50% aqueous solution of ethanol is added dropwise so that the reduction takes place accompanied by reflux and gentle boiling. When the addition is terminated it is then stirred for 2 hours accompanied by reflux, allowed to cool and neutralized with alcoholic potassium hydroxide. Uncoverted iron and iron oxides are vacuum filtrated, accompanied by rewashing with ethanol. The solution is concentrated and the residue is distilled in the vacuum. 40 g (57% of the theoretical yield) of the free base is obtained which has a boiling range of 114°-117° C. at 106 Pascal. This product can be transformed into dihyrochloride with hydrochloric acid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC[N:16]=C=NCCCN(C)C.ON1C(=O)CCC1=O.[OH-].[NH4+]>O1CCCC1.CN(C)C=O>[NH2:16][C:11](=[O:13])[C@@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH3:10]
Reactant: CCN=C=NCCCN(C)C
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C1CCC(=O)N1O
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.5 %

Procedure:
To a solution containing Boc-L-alanine (1.0 g, 5.29 mmol) in a mixture of tetrahydrofuran (25 mL) and N,N-dimethylformamide (5 mL) were added EDAC (1.5 g, 7.82 mmol) and N-hydroxysuccinimide (0.91 g, 7.91 mmol) and the mixture was stirred at room temperature for 16 hours. Aqueous ammonium hydroxide solution (15 mL, 28%) was added and the mixture was stirred for 0.5 hours at room temperature. The reaction was partitioned between ethyl acetate and water, and the organic was washed with brine and dried over MgSO4, filtered and evaporated to give the product (0.483 g, 49% yield), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[C:6]([NH2:8])[CH:7]=1.C(Cl)CCl.C1C=CC2N([OH:23])N=NC=2C=1.[CH3:24][CH2:25][N:26]([CH:30](C)C)[CH:27](C)C>C(Cl)Cl>[NH2:8][C:6]1[CH:5]=[C:4]([NH:9][C:24](=[O:23])[CH2:25][N:26]([CH3:30])[CH3:27])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1cc(N)cc(Cl)c1
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(C)CC(=O)Nc1cc(N)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-benzene-1,3-diamine (3 g, 21 mmol) and dimethylamino-AcOH (2.2 g, 21 mmol) in CH2Cl2 (300 mL) was added EDC (5 g, 25 mmol), HOBt (2.9 g, 21 mmol), and DIEA (5 mL). The reaction mixture was stirred at RT overnight. Solvent was removed in vacuo and the residue was purified through flash chromatography on silica gel (0-8% MeOH in EtOAc) to give the desired compound.