Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]N(C)C=O.P(Cl)(Cl)(Cl)=O.[CH3:11][O:12][C:13]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:14]=1[NH:15]/[C:16](/[CH3:23])=[CH:17]\[C:18]([O:20][CH2:21][CH3:22])=[O:19]>ClC(Cl)C>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:13]([O:12][CH3:11])=[C:14]2[C:24]=1[CH:1]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]([CH3:23])=[N:15]2
Reactant: CN(C)C=O
Reactant: CCOC(=O)/C=C(/C)Nc1cc(OC)ccc1OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc2c(OC)ccc(OC)c2nc1C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 127.3 %

Procedure:
To a 0° C. solution of dimethylformamide (7.5 mL, 0.097 mol) in dichloroethane (20 mL) is added dropwise phosphorous oxychloride (9.0 mL, 0.097 mol). After stirring for 3.5 hours at room temperature, a solution of ethyl 3-(2,5-dimethoxyanilino)crotonate (25.8 g, 0.097 mol) in dichloroethane (130 mL) is added dropwise at 25° C. The resulting solution is heated at reflux temperature for 3 hours. After cooling to room temperature, the reaction is quenched by the addition of an aqueous ammonium chloride solution. Methylene chloride (200 mL) is added and the layers are separated. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue. The residue is purified by chromatography using silica gel and ethyl acetate in hexanes as eluant to yield the title compound (34 g, 100%) as a yellow solid identified by IR and NMR spectral analyses.
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH2:9][NH2:10])[CH2:3][CH2:2]1.C(#N)CO.CCOCC>O>[O:1]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]#[N:10])[CH2:3][CH2:2]1
Reactant: NCCN1CCCOCC1
Agent: N#CCO
Solvent: O
Solvent: CCOCC
Product: N#CCN1CCCOCC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
1,4-Oxazepane (292) (Turner, S. R. et al., PCT Int. Appl. WO 2000 040561, 2000) (4.95 g, 49.0 mmol) was added dropwise to a stirred aqueous solution of glycolonitrile (55%, 5.3 mL, 53.8 mmol) at 5° C. and stirred at 70° C. for 1 h. More aqueous glycolonitrile (55%, 0.96 mL, 6.13 mmol) was added and the mixture stirred for 30 min, cooled to 20° C. and Et2O (100 mL) and water (50 mL) were added. The aqueous layer was extracted with Et2O (4×30 mL), the combined organic fraction dried and the solvent evaporated to give nitrile 293 (3.24 g, 47%) as a pale yellow oil: 1H NMR δ 3.80-3.84 (m, 2H, H-5), 3.74-3.77 (m, 2H, H-3), 3.60 (s, 2H, CH2CN), 2.79-2.84 (m, 4H, H-2, H-7), 1.92-1.99 (m, 2H, H-6); HRMS calcd for C7H12N2O (M+) m/z 140.0950, found 140.0947.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([NH:19]C(=O)C)[CH:9]=[CH:10][C:11]=2[NH:15]C(=O)C)[C:6]1=[O:23])(=[O:3])[CH3:2].C(NC1CCC2C(=C(NC(=O)C)C=CC=2)C1=O)(=O)C>>[C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([NH2:19])[CH:9]=[CH:10][C:11]=2[NH2:15])[C:6]1=[O:23])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(NC(C)=O)c2c1CCC(NC(C)=O)C2=O
Agent: CC(=O)Nc1cccc2c1C(=O)C(NC(C)=O)CC2
Product: CC(=O)NC1CCc2c(N)ccc(N)c2C1=O

Procedure:
The reaction was carried out in the same manner as in Example 1-(4), except that 500 mg of the compound prepared in (1) above was used instead of 2,8-diacetylamino-1-tetralone of Example 1-(4), and post-treated to produce 290 mg of the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[NH:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[OH-].[K+].O>CN(C)C=O.C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][CH2:4][N:7]1[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=[N:6]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: BrCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: BrCCCn1nc2ccccc2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 22.8 %

Procedure:
To a solution of 1,3-dibromopropane (510 μl, 5.0 mmol) in dimethylformamide (10 ml) was added benzotriazole (600 mg, 5.0 mmol) and KOH (430 mg, 7.7 mmol). After stirring for 20 h at room temp, water (10 ml) and ethyl acetate (10 ml) were added. The phases were separated and the aqueous phase was re-extracted with ethyl acetate (3×15 ml). The combined organic phases were dried over MgSO4 and concentrated in vacuo, giving 1.44 g of the crude material. The crude product was purified by flash chromatography (0–10% methanol in DCM), yielding 274 mg (23%) of the title compound 62. TLC (5% methanol in DCM): Rf=0.7. 1H-NMR (400 MHz, CDCl3): δ=7.88–7.83 (2H, m); 7.41–7.36 (2H, m); 4.91 (2H, t); 3.44 (2H, t); 2.66 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[C:3]=1[C:4]#[N:5].[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([O:12][CH3:11])[CH:18]=2)[C:3]=1[C:4]#[N:5]
Reactant: COc1cccc(B(O)O)c1
Reactant: N#Cc1c(N)cccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cccc(-c2cccc(N)c2C#N)c1
Yield: 80.3 %

Procedure:
To a stirred solution of 2-amino-6-bromobenzonitrile (195 mg, 1.0 mmol) and (3-methoxyphenyl)boronic acid (300 mg, 2 mmol) in dioxane (2 mL) was added aqueous potassium carbonate (2.0 mmol, 0.7 mL). The reaction solution was degassed by bubbling N2 for 2 minutes. Palladium tetrakistriphenylphosphine (5% mol) was added to the reaction mixture and the reaction vessel was placed in a microwave reactor and irradiated at 165° C. for 20 minutes. The precipitate was removed by filtration and the filtrate concentrated. The residue was purified by HPLC (acetonitrile/water; 10-90% gradient, 25 minutes) to give the title compound as an off-white solid (180 mg, 80%). MS 225 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][CH:9]([F:50])[C:10]1[N:11]=[CH:12][C:13]([C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([F:49])=[C:23]([C@:25]34[CH2:33][O:32][C@H:31]([C:34]([F:37])([F:36])[F:35])[C@H:30]3[C:29](=[O:38])[N:28]([CH2:39][CH3:40])[C:27]([NH:41]C(=O)OC(C)(C)C)=[N:26]4)[CH:24]=2)=[O:17])=[N:14][CH:15]=1>C(Cl)Cl>[NH2:41][C:27]1[N:28]([CH2:39][CH3:40])[C:29](=[O:38])[C@@H:30]2[C@@H:31]([C:34]([F:37])([F:36])[F:35])[O:32][CH2:33][C@:25]2([C:23]2[CH:24]=[C:19]([NH:18][C:16]([C:13]3[CH:12]=[N:11][C:10]([CH:9]([F:50])[F:8])=[CH:15][N:14]=3)=[O:17])[CH:20]=[CH:21][C:22]=2[F:49])[N:26]=1
Reactant: CCN1C(=O)[C@@H]2[C@@H](C(F)(F)F)OC[C@]2(c2cc(NC(=O)c3cnc(C(F)F)cn3)ccc2F)N=C1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN1C(=O)[C@@H]2[C@@H](C(F)(F)F)OC[C@]2(c2cc(NC(=O)c3cnc(C(F)F)cn3)ccc2F)N=C1N
Yield: 86.6 %

Procedure:
Trifluoroacetic acid (1 mL) was added to a stirred solution of tert-butyl ((4aS,5S,7aS)-7a-(5-(5-(difluoromethyl)pyrazine-2-carboxamido)-2-fluorophenyl)-3-ethyl-4-oxo-5-(trifluoromethyl)-3,4,4a,5,7,7a-hexahydrofuro[3,4-d]pyrimidin-2-yl)carbamate (115 mg, 0.19 mmol) in DCM (1 mL) at RT. The volatiles were removed in vacuo and the residue was azeotroped with toluene (×1). The free base was isolated by loading this material on to a SCX cartridge (5 g) and eluting with MeOH (2×20 mL) and then 2M NH3 in MeOH (1×20 mL). The ammonia-methanol fraction was evaporated and the residue was treated with Et2O-hexanes to give a solid which was isolated by filtration and dried in vacuo to give the title compound (85 mg, cream solid). 1H NMR (400 MHz, MeOH-d4) δ ppm 1.12 (t, J=7.07 Hz, 3H) 3.65-3.81 (m, 2H) 3.94-4.03 (m, 1H) 4.29-4.35 (m, 1H) 4.36-4.41 (m, 1H) 4.56-4.66 (m, 1H) 6.95 (t, J=55.30 Hz, 1H) 7.19 (dd, J=11.49, 8.97 Hz, 1H) 7.74-7.81 (m, 1H) 7.97 (dd, J=6.95, 2.40 Hz, 1H) 9.02 (s, 1H) 9.40 (s, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19])(=[O:3])[CH3:2].C(Cl)(Cl)Cl.C(OO)(=[O:27])C>CO>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([S:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:27])[CH:8]=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(Sc2ccccc2)ccc1[N+](=O)[O-]
Reactant: CC(=O)OO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(S(=O)c2ccccc2)ccc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
3.5 G. of 2-acetamido-4-phenylthio-1-nitrobenzene is dissolved in 35 ml. chloroform and treated at -25° C to -20° C with 2.5 g. 40% peracetic acid in 5 ml. methanol. The reaction mixture is allowed to warm slowly to 20°-25° C where it is held for four hours, then washed with sodium bisulfate solution and then with sodium bicarbonate solution. Evaporation of the solvent leaves 2-acetamido-4-phenylsulfinyl-1-nitrobenzene as a gum. This is treated with 20 ml. methanol and 10 ml. 5N aqueous sodium hydroxide at 20°-25° C for one hour. The mixture is diluted with water and the crude product filtered off. Recrystallization from benzene yields pure 2-amino-1-nitro-4-phenylsulfinylbenzene. 2.7 G. of 2-amino-1-nitro-4-phenylsulfinylbenzene is hydrogenated in 270 ml. methanol in the presence of 2.7 g. 5% palladized charcoal at one atmosphere pressure, until the theoretical uptake of hydrogen has occurred. The catalyst is removed by filtration and the filtrate concentrated to dryness. The residue is triturated with hot benzene, affording pure 1,2-diamino-4-phenylsulfinylbenzene.
Reaction SMILES: [CH:1]1([C@@:7]([OH:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]C1.C([C@H]1OC(=O)[C@@](C2(O)CCCC2)(C2C=CC=CC=2)O1)(C)(C)C>>[CH:1]1([C@@:7]([OH:17])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCCC1
Agent: CC(C)(C)[C@H]1OC(=O)[C@](c2ccccc2)(C2(O)CCCC2)O1
Product: O=C(O)[C@](O)(c1ccccc1)C1CCCC1

Procedure:
This compound is prepared analogously to (R)-cyclohexyl-hydroxy-phenyl-acetic acid (Intermediate Siv) by replacing (2R,5S)-2-tert-butyl-5-(1-hydroxy-cyclohexyl)-5-phenyl-[1,3]dioxolan-4-one (step Siii) with (2R,5S)-2-tert-butyl-5-(1-hydroxy-cyclopentyl)-5-phenyl-[1,3]dioxolan-4-one.
Reaction SMILES: Cl[CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH2:3]1.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K].O>CN(C)C=O>[C:14]1(=[O:24])[N:18]([CH:2]2[C:8](=[O:9])[NH:7][C:6]3[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=3[O:4][CH2:3]2)[C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12
Reactant: O=C1Nc2ccccc2OCC1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2ccccc2OCC1N1C(=O)c2ccccc2C1=O
Reaction time: 1 h

Procedure:
A mixture of 0.989 g of 3-chloro-2,3-dihydro-1,5-benzoxazepin-4(5H)-one and 1.0 g of potassium phthalimide in 5 ml of dimethylformamide is warmed to 90° overnight. The reaction mixture is poured into 20 ml of water and stirring is continued for 1 hr. Isolation by vacuum filtration and drying at 60° in vacuo affords 3-phthalimido-2,3-dihydro-1,5-benzoxazepin-4(5H)-one; m.p. 188°-193°; NMR (DMSO, d6) δ 7.95 (s, 4), 6.61-7.40 (m, 5), 4.92 (d of d, 1), 4.01 (d, 2).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[C@H:10]([C:12]([OH:14])=O)[CH3:11])=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[C@H:10]([C:12]([NH:28][C:27]2[CH:29]=[CH:30][C:24]([F:23])=[CH:25][CH:26]=2)=[O:14])[CH3:11])=[CH:5][C:4]=1[C:19]([F:20])([F:21])[F:22])#[N:2]
Reactant: C[C@@H](C(=O)O)N(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: Nc1ccc(F)cc1
Product: C[C@@H](C(=O)Nc1ccc(F)cc1)N(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described for Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(cyclopropylmethyl)alanine and 4-fluoroaniline: 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.42 (m, 2H), 7.14 (d, J=2.5 Hz, 1H), 7.00-6.91 (m, 3H), 4.47 (q, J=7.0 Hz, 1H), 3.36 (m, 2H), 1.56 (d, J=7.1 Hz, 3H), 1.10 (m, 1H), 0.69 (m, 2H), 0.35 (m, 2H).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1.[CH3:8][C:9]1[O:14][CH2:13][N:12]([C:15]([CH3:19])([CH3:18])[CH:16]=[O:17])[C:11](=[O:20])[C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C.O>O1CCCC1.[Zn]>[CH:2]1([CH:16]([OH:17])[C:15]([N:12]2[C:11](=[O:20])[C:10]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[C:9]([CH3:8])[O:14][CH2:13]2)([CH3:19])[CH3:18])[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: BrC1C=CCCC1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C=O)CO1
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(O)C2C=CCCC2)CO1
Temperature: 20 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
A solution of 1-bromocyclohex-2-ene (7.2 g) in tetrahydrofuran was added dropwise during 0.5 hour to a stirred mixture of 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropionaldehyde (4.0 g) and zinc powder (3.2 g) in tetrahydrofuran below -20° C. under an inert atmosphere. The mixture was stirred for 1 hour below -20° C. and warmed to 20° C. Ethyl acetate and water were added and the organic phase washed (brine), dried (magnesium sulphate), evaporated and purified by silica gel column chromatography, eluting with n-hexane/ethyl acetate (5:2) to give 1-(cyclohex-2-enyl)-2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropan-1-ol (5.1 g), NMR: 1.41(s,3H), 1.53(s,3H), 1.85(s,3H), 1.40-2.05(6H), 2.24(1H), 3.49(1H), 4.32(d,1H), 5.1 1(d 5.24(d,1H), 5.60(1H), 5.76(1H), 7.20-7.40(5H).
Reaction SMILES: C([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[C:9]1[Br:20])C1C=CC=CC=1.[H-].[Na+].C(O[C@H](C)CCCCCl)(=O)C>CS(C)=O>[Br:20][C:9]1[NH:8][C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccccc1
Agent: CC(=O)O[C@H](C)CCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 167.5 %

Procedure:
To a stirring suspension of 7-benzyl-8-bromo-3-methylxanthine (10.06 g, 30.0 mmol) in anhydrous dimethylsulfoxide was added sodium hydride (864 mg, 36.0 mmol). After stirring at room temperature for 30 min, (R)-5-acetoxy-1-chlorohexane (5.9 g, 33.0 mmol) was added. After stirring at 70-75° C. for 12 hours, the mixture was cooled to room temperature, quenched with water (600 ml) and stirred at room temperature for 4 hours. The precipitate was filtered to provide (R)-1-(5-Acetoxyhexyl)-7-benzy)-8-bromo-3-methylxanthine (12.31 g, 86% yield) as a beige powder.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[S:5][C:6]=1[C:7]([C:9]1[C:14]([Cl:15])=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=1[Cl:17])=[O:8].O.C([O-])(O)=O.[Na+].CO.C(Cl)(Cl)Cl>FC(F)(F)C(O)=O>[NH2:1][C:2]1[N:3]=[C:4]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]3)=[CH:21][CH:20]=2)[S:5][C:6]=1[C:7]([C:9]1[C:10]([Cl:17])=[CH:11][C:12]([Cl:16])=[CH:13][C:14]=1[Cl:15])=[O:8]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(N)c(C(=O)c4c(Cl)cc(Cl)cc4Cl)s3)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: Nc1nc(Nc2ccc(N3CCNCC3)cc2)sc1C(=O)c1c(Cl)cc(Cl)cc1Cl
Reaction time: 0.33 h

Procedure:
The title compound was prepared as follows. {4-Amino-2-[4-(4-tert-butoxycarbonyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(2,4,6-trichloro-phenyl)-methanone (50 mg, 0.086 mmol) was stirred in trifluoroacetic acid (TFA; 0.5 mL) at 0° C. After 20 min at 0° C., a minimal amount of water was added, and sat aq NaHCO3 was used for neutralization. The resultant suspension was filtered to obtain a yellow paste, which gave a suspension with MeOH/CHCl3 and led to isolation of 22 mg (42%) of yellow amorphous powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]2)[CH:3]=1.[C:14]([O:18][C:19](=[O:27])[NH:20][C:21]1[S:22][CH:23]=[C:24]([CH3:26])[N:25]=1)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19](=[O:27])[NH:20][C:21]1[S:22][C:23]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]3)[CH:3]=2)=[C:24]([CH3:26])[N:25]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1csc(NC(=O)OC(C)(C)C)n1
Reactant: N#CC1(c2cc(Br)ccn2)CCC1
Product: Cc1nc(NC(=O)OC(C)(C)C)sc1-c1ccnc(C2(C#N)CCC2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
The title compound is prepared in analogy to the procedure described in Step 1.3, but using 1-(4-bromo-pyridin-2-yl)-cyclobutanecarbonitrile (Step 19.3) and (4-methyl-thiazol-2-yl)-carbamic acid tert-butyl ester (Step 18.4). The reaction mixture is stirred for 3 h at 100° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[CH:6]2.B(Br)(Br)Br>C(Cl)Cl>[CH3:12][C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([OH:2])=[CH:11][CH:10]=2
Reactant: COc1ccc2[nH]c(C)cc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2cc(O)ccc2[nH]1
Temperature: -78 °C
Reaction time: 4 h
Yield: 65.8 %

Procedure:
To a solution of 5-methoxy-2-methyl-1H-indole (5 g, 31 mmol) in methylene chloride (100 mL) at −78° C., was slowly added a solution of BBr3 in CH2Cl2 (1.0 M, 93 mL, 93 mmol). The reaction mixture was stirred at −78° C. for 4 hours and slowly warmed to room temperature. The reaction mixture was stirred at room temperature overnight, and cooled to 0° C. The reaction was quenched carefully with water at 0° C. The aqueous layer was made basic by adding saturated sodium bicarbonate solution, and then extracted with methylene chloride (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with EtOAc/Hexanes (25:75) to afford the title compound as a yellow solid (3.0 g, 60%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[C:6]([N+:16]([O-:18])=[O:17])[C:5]=1N.N([O-])=O.[Na+].[S-:25][C:26]#[N:27].[K+].C(=O)([O-])O.[Na+]>S(=O)(=O)(O)O.O.[Cu]SC#N>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[C:6]([N+:16]([O-:18])=[O:17])[C:5]=1[S:25][C:26]#[N:27]
Reactant: N#C[S-]
Reactant: COC(=O)c1cc(-c2cccnc2)cc([N+](=O)[O-])c1N
Agent: N#CS[Cu]
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: O
Product: COC(=O)c1cc(-c2cccnc2)cc([N+](=O)[O-])c1SC#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 2-Amino-3-nitro-5-pyridin-3-yl-benzoic acid methyl ester (0.92 g, 3.37 mmol) in aqueous sulfuric acid (50% v/v, 9 ml) was stirred at ambient temperature for 1 h before being cooled in an ice bath and treated over 5 min with an aqueous sodium nitrite solution (20% w/v, 1.4 ml). The mixture was stirred in the cold for 1.5 h before being treated with a solution of potassium thiocyanate (0.42 g) in water (1.0 ml) in one portion. The resultant mixture was stirred in the cold for 15 min and then added to a suspension of copper (I) thiocyanate (0.71 g) in water (2.8 ml) whilst cooling in an ice-bath. The mixture was stirred in the cold for 2 h and then heated to 70° C. for 20 min. After cooling to ambient temperature, the mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate (200 ml) and extracted with ethyl acetate (3×100 ml) which was washed with brine (200 ml) and dried (MgSO4). The solvent was removed in vacuo to give a residue which was purified by flash chromatography (silica) eluting with 80% to 100% ethyl acetate in 40-60 petroleum ether. The 3-Nitro-5-pyridin-3-yl-2-thiocyanato-benzoic acid methyl ester was obtained as a pale yellow solid (0.78 g, 74%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5]2=[CH:12][CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:4]2[N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].O>CN1C(=O)CCC1>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][N:8]=[CH:9][CH:10]=3)[C:5]3=[CH:12][CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:4]3[N:3]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1cccc2c1nc(Cl)c1ccncc12
Reactant: Nc1cccc(Cl)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1cccc2c1nc(Nc1cccc(Cl)c1)c1ccncc12
Yield: 45.3 %

Procedure:
Methyl 5-chlorobenzo[c][2,6]naphthyridine-7-carboxylate (1.0 eq, 48 mg, 0.176 mmol) and 3-chloroaniline (3.0 eq, 60 ul, 0.56 mmol) were stirred under microwave heating at 120° C. in NMP (0.3 ml) for 10 minutes. Water was added and the solid isolated by filtration. Trituration in methanol and filtration afforded methyl 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-7-carboxylate as a solid (29 mg, 45% yield). LCMS (ES): >85% pure, m/z 364 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([S:39]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)(=[O:41])=[O:40])[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(S(=O)(=O)c3ccccc3)CC2)cc1
Reaction time: 20 h
Yield: 71.8 %

Procedure:
A solution of N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (41 mg, 0.12 mmol) and pyridine (0.05 mL) in methylene chloride (3 mL) was treated with benzenesulfonyl chloride (0.014 mL, 0.11 mmol). After 20 h, the mixture was treated with silica gel (3 cm3) and concentrated in vacuo. The residue was chromatographed (silica gel, 50% hexanes/50% ethyl acetate to 30% hexanes/70% ethyl acetate). Recrystallization of the residue from hexanes/ethyl acetate yielded 39 mg (68%) of the title compound.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[CH2:19]([O:21][C:22]([CH2:24][S:25][C:26]1[S:27][C:28]([SH:31])=[N:29][N:30]=1)=[O:23])[CH3:20].COC(C1C(Cl)=C(Cl)C(C(OC)=O)=C(Cl)C=1Cl)=O.N>C(#N)C>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:31][C:28]3[S:27][C:26]([S:25][CH2:24][C:22]([O:21][CH2:19][CH3:20])=[O:23])=[N:30][N:29]=3)[CH2:15][S:14][C@H:9]12
Reactant: CCOC(=O)CSc1nnc(S)s1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COC(=O)c1c(Cl)c(Cl)c(C(=O)OC)c(Cl)c1Cl
Agent: N
Solvent: CC#N
Product: CCOC(=O)CSc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Temperature: 40 °C
Reaction time: 0.13 h
Yield: 92.8 %

Procedure:
A 8.0 ml portion of acetonitrile was added to 1.36 g of 7-ACA and 1.54 g of 2-ethoxycarbonylmethylthio-5-mercapto-1,3,4-thiadiazole, and the mixture was cooled to -40° to -30° C., followed by adding thereto dropwise 5.40 g of DCPA under stirring. The external bath was removed and the reaction mixture was stirred for 8 minutes, then warmed at 40° C. and stirred for 20 minutes to allow the reaction to proceed. The reaction solution was poured into 10 ml of ice-water, which was adjusted to pH 4.4 with 25% aqueous ammonia. The precipitated powder was recovered by filtration, washed with water and dried, thereby affording 2.08 g (92.7% of yield) of 7-amino-3-[(2-ethoxycarbonylmethylthio-1,3,4-thiadiazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid in the form of mud yellow powder.