Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[C:9]([O:13][C:14]([N:16]1[CH2:20][C:19](=[O:21])[CH2:18][C@@H:17]1[C@H:22]1[O:26][C:25]([CH3:28])([CH3:27])[N:24]([C:29](=[O:31])[CH3:30])[C@H:23]1[CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.O>[C:9]([O:13][C:14]([N:16]1[CH2:20][C@@:19]([OH:21])([C:2]([F:4])([F:3])[F:1])[CH2:18][C@@H:17]1[C@H:22]1[O:26][C:25]([CH3:27])([CH3:28])[N:24]([C:29](=[O:31])[CH3:30])[C@H:23]1[CH2:32][C:33]1[CH:34]=[C:35]([F:40])[CH:36]=[C:37]([F:39])[CH:38]=1)=[O:15])([CH3:10])([CH3:11])[CH3:12]
Reactant: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2CC(=O)CN2C(=O)OC(C)(C)C)OC1(C)C
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@](O)(C(F)(F)F)CN2C(=O)OC(C)(C)C)OC1(C)C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Add (trifluoromethyl)trimethylsilane (0.28 mL, 1.88 mmol) to an ice cold solution of (R)-2-[(4S,5S)-3-acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (0.50 g, 1.11 mmol) in tetrahydrofuran (10 mL). Add tetrabutylammonium fluoride (0.035 mL of 1M solution in tetrahydrofuran). Stir 2.5 hours and add tetrabutylammonium fluoride (2 mL of 1M solution in tetrahydrofuran) and stir 2 hours. Add saturated aqueous ammonium chloride (3 mL) and dilute with ethyl acetate and water. Wash organic layer with saturated aqueous sodium chloride, dry with magnesium sulfate and purify on silica gel with dichloromethane/ethyl acetate mixtures to give the desired compound and 10% hydroxy diastereomer as a foam (0.48 g, 83%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[C:14]([NH:16][C:17]([NH:22][CH3:23])=[N:18][CH2:19][CH2:20][SH:21])#[N:15]>C(O)C>[C:14]([NH:16][C:17]([NH:22][CH3:23])=[N:18][CH2:19][CH2:20][S:21][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])#[N:15]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CNC(=NCCS)NC#N
Solvent: CCO
Product: CNC(=NCCSc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])NC#N

Procedure:
A solution of cysteamine hydrochloride (5.68 g) in water (20 ml) was added to a suspension of N-cyano-N,S-dimethyl-isothiourea (6.46 g) in ethanol (100 ml). A solution of sodium hydroxide (4.0 g) in water (20 ml) was added to the mixture and the suspension was heated under reflux for 1 hour. The resulting clear solution was concentrated to remove ethanol, a little more water was added and the alkaline aqueous solution was extracted with ethyl acetate. The aqueous solution was adjusted to pH4 with hydrochloric acid and extracted with ethyl acetate. This latter organic extract was dried and evaporated to give N-cyano-N'-methyl-N"-(2-mercaptoethyl)guanidine (6.12 g) as a colourless oil. In order to characterise this product a solution of 2,4-dinitrochlorobenzene (7.7 g) in 95% ethanol (50 ml) was added to a solution of N-cyano-N'-methyl-N"-(2-mercaptoethyl)-guanidine (6.0 g) in 95% ethanol. The mixture was refluxed for 1 hour and cooled. The resulting crystalline solid (7.73 g) was collected and was triturated with a large volume of ether and was recrystallised from acetonitrile to afford N-cyano-N'-methyl-N"-[S-(2,4-dinitrophenyl)-2-mercaptoethyl]-guanidine, m.p. 210°-211° C.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:11]=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[CH:13]=[CH:14][C:15]=3[N+:16]([O-])=O)[CH:5]=2)[CH2:3][CH2:2]1.[Cl-].[NH4+].C([O-])(=O)C.[NH4+]>CO.C1COCC1.[Zn]>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:11]=[C:12]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[CH:13]=[CH:14][C:15]=3[NH2:16])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1ccc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)c1)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](Nc1ccc(N)c(Nc2cc(C3CC3)[nH]n2)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of (S)-N3-(5-cyclopropyl-1H-pyrazol-3-yl)-N1-[1-(4-fluorophenyl)ethyl]-4-nitrobenzene-1,3-diamine (Method 26; 0.37 g, 0.97 mmol) and Zinc dust (0.317 g, 4.85 mmol) in MeOH:THF (1:1, 24 ml) was slowly added saturated ammonium chloride (3.0 ml). The reaction mixture was stirred at 25° C. for 1 hr, to which was then added saturated ammonium acetate solution (5 ml). The resulting mixture was stirred for another 30 min. Zn dust was removed by filtration and washed with EtOAc (20 ml). The organic layer was separated, washed with brine (10 ml), dried over Na2SO4, and concentrated. The crude product was used directly for the next step without further purification. MS: Calcd: 351; Found: [M+H]+ 352.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[K+].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>CS(C)=O.O>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 41.39 g of 3-acetyl indole in 300 ml of dimethyl sulfoxide at 0° C. was added a solution of 18.6 g of potassium hydroxide in 20 ml of water. This mixture was stirred at 0° C. for 2 hours, then 47.6 ml of benzenesulfonyl chloride was added dropwise over 40 minutes. The mixture was stirred for an additional 30 mInutes, then poured into aqueous ammonium chloride and extracted several times with ether. The ether extracts were combined, washed with water, dried and evaporated, giving 59.8 g of 3-acetyl-N-phenylsulfonyl indole.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([CH3:12])(=[O:11])=[O:10].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:23][CH3:24])=[C:18]([CH:20]([NH2:22])[CH3:21])[CH:19]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:23][CH3:24])=[C:18]([CH:20]([NH:22][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[S:9]([CH3:12])(=[O:11])=[O:10])[CH3:21])[CH:19]=1
Reactant: CS(=O)(=O)c1ccc(F)cc1F
Reactant: COc1ccc(Cl)cc1C(C)N
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cl)cc1C(C)Nc1cc(F)ccc1S(C)(=O)=O
Yield: 0 %

Procedure:
2,4-Difluoro-1-(methylsulfonyl)benzene (0.55 g, 2.9 mmol), 1-(5-chloro-2-methoxyphenyl)ethanamine (0.57 g, 2.9 mmol) and N,N-diisopropylethylamine (0.77 g, 5.9 mmol) were stirred at 65° C. in dry acetonitrile (20 mL) for 24 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and purified by silica chromatography in 20% ethyl acetate in hexanes to collect the title compound (0.36 mg, 35% yield). 1H NMR (400 MHz, CDCl3): δ 7.74 (q, 1H), 7.18 (m, 2H), 6.84 (d, 1H), 6.79 (d, 1H), 6.42 (t, 1H), 6.17 (d, 1H), 4.78 (m, 1H), 3.91 (s, 3H), 3.08 (s, 3H), 1.52 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:45]=[CH:44][C:6]([CH2:7][N:8]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C:32](=[O:34])[CH3:33])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=[CH:5][CH:4]=1.[B-].[Na+].CO>C(Cl)Cl>[CH3:43][O:42][C:39]1[CH:38]=[CH:37][C:36]([CH2:35][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:45][CH:44]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:32]([OH:34])[CH3:33])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=[CH:41][CH:40]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)=O)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: [B-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)O)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.7 %

Procedure:
To a 150 mL round-bottomed flask was added 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanone (1 g, 1.640 mmol) and sodium borohydrate (0.06 g, 1.640 mmol) in DCM (10 mL)-MeOH (10 mL). The suspension was stirred at room temperature for 16 h. The solution was quenched by saturated NH4Cl, extracted the aqueous with DCM (3×), the combined organic was dried over MgSO4, concentrated in vacuum to provide 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanol (0.9 g, 90% yield) as a yellow solid. m/z (ESI positive ion) m/z: 612 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.36 (d, J=6.46 Hz, 3H) 2.57 (s, 3H) 3.74 (s, 3H) 3.91 (s, 3H) 4.75 (dd, J=6.26, 4.50 Hz, 1H) 4.83 (d, J=12.32 Hz, 4H) 5.25 (d, J=4.30 Hz, 1H) 6.82-6.97 (m, 4H) 7.19-7.35 (m, 4H) 7.98-8.14 (m, 2H) 8.30 (d, J=2.35 Hz, 1H) 8.78 (d, J=2.35 Hz, 1H) 11.68 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[N:11]([CH3:24])[C:12]([C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:13]([CH3:15])[CH:14]=1)[NH2:5].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:5][S:26]([CH3:25])(=[O:28])=[O:27])[CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[N:11]([CH3:24])[C:12]([C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:13]([CH3:15])[CH:14]=1
Reactant: Cc1cc(Cc2ccc(N)cc2F)n(C)c1C(=O)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1cc(Cc2ccc(NS(C)(=O)=O)cc2F)n(C)c1C(=O)c1ccccc1
Temperature: -5 °C
Yield: 62.4 %

Procedure:
3-Fluoro-4-[5-benzoyl-1,4-dimethyl-1H-pyrrol-2-ylmethyl]aniline (1.0 g, 3.1 mmol) [prepared as described in Example 1] was dissolved in pyridine (10 ml) and the solution was cooled to -5° C. Methanesulfonyl chloride (0.39 g, 3.4 mmol) was added and after 1 h the reaction mixture was poured into 1 M HCl/ice/water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated to dryness. The residue was crystallized from methylene chloride-methanol to give N-(3-fluoro-4-[5-benzoyl-1,4-dimethyl-1H-pyrrol-2-ylmethyl]phenyl}-methanesulfonamide (775 mg, 62%) as a solid, mp 165-167° C.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]Br.[CH3:17][N:18]([CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1)[CH2:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]([O:33][CH3:34])=[O:32])=[CH:30][C:25]=2[NH:24][C:23]1=[S:35]>O1CCCC1.C(OCC)(=O)C.O>[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][S:35][C:23]1[N:22]([CH2:21][CH2:20][CH2:19][N:18]([CH3:17])[CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[C:26]2[CH:27]=[CH:28][C:29]([C:31]([O:33][CH3:34])=[O:32])=[CH:30][C:25]=2[N:24]=1
Reactant: BrCc1cccc(Br)c1
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=S)n2CCCN(C)CCc1ccccn1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)nc(SCc1cccc(Br)c1)n2CCCN(C)CCc1ccccn1
Temperature: 20 °C
Reaction time: 15 h
Yield: 70 %

Procedure:
Triethylamine (0.82 ml, 1.6 eq) and 3-bromobenzylbromide (0.97 g, 1 eq) are added successively to a solution of methyl 1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-2-thioxo-2,3-dihydro-1H-benzimidazole-5-carboxylate (1.5 g) in tetrahydrofuran (30 ml). The mixture is stirred for 15 hours at approximately 20° C. then concentrated under reduced pressure at 40° C. The residue obtained is diluted in ethyl acetate and water. After decanting and extracting, the organic phases are washed with salt water, dried over sodium sulphate and concentrated under reduced pressure at 40° C. Purification by flash chromatography on silica gel (eluent: dichloromethane/methanol 95/5 to 90/10) produces the expected compound in the form of a colourless oil (1.5 g; 70% yield).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[OH:15].[CH2:16]([O:18][C:19](=[O:24])[CH:20]=[C:21](Cl)[CH3:22])[CH3:17]>O1CCCC1>[CH2:16]([O:18][C:19](=[O:24])[CH:20]=[C:21]([O:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:8]=1[Cl:7])[CH3:22])[CH3:17]
Reactant: CCOC(=O)C=C(C)Cl
Reactant: Oc1cccc(Cl)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C)Oc1cccc(Cl)c1Cl
Temperature: 23 °C
Yield: 76 %

Procedure:
Potassium t-butoxide (11.2 g, 0.100 mol) was added to a stirred solution of 2,3-dichlorophenol (8.2 g, 0.05 mol) in tetrahydrofuran (40 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (6.5 g, 0.044 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% sodium hydroxide solution followed by a saturated sodium chloride solution. The combined organic layers were separated, dried over sodium sulfate and concentrated in vacuo to afford 3-(2,3-dichoro-phenoxy)-but-2-enoic acid ethyl ester (9.20 g, 76%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)OC(C)(C)C)=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:3]=1.Br[C:26]1[C:27]([C:32]#[N:33])=[N:28][CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO.ClCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:7]=1)=[C:26]1[C:27](=[C:32]([NH2:33])[N:8]=2)[N:28]=[CH:29][CH:30]=[CH:31]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1B1OC(C)(C)C(C)(C)O1
Reactant: N#Cc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1nc2ccc(Cl)cc2c2cccnc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-carbamate (from step 2) (1.0 eq.) and 3-bromopicolino-nitrile (1.0 eq.) in toluene (0.44 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and 2N aqueous potassium carbonate solution (2.0 eq.). The reaction was heated to 100° C. and stirred overnight. After cooling to ambient temperature, the reaction content was diluted with 2% methanol in dichloromethane and water. The two phases were separated, and the aqueous layer was extracted twice with 2% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-50% ethyl acetate in hexane and then re-purified using 0-5% methanol in dichloromethane to give a solid. 1H NMR (acetone d-6): δ 9.08 (d, 1H), 8.96 (d, 1H), 8.45 (s, 1H), 7.86-7.89 (dd, 1H), 7.60 (d, 1H), 7.54 (d, 1H), 6.78 (br, 2H). LRMS [M+H]=230.1
Reaction SMILES: [C:1]1([P:7](=S)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:21].[Na+]>C(O)C(C)C>[C:1]1([P:7](=[O:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(C)CO
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To a mixture of isobutanol (50 ml), triphenylphosphine sulfide (7.0 g) and aqueous 5% sodium hydroxide (50 ml) is bubbled chlorine gas at 15° C. until no appreciable amount of the starting sulfide is detected on thin-layer chromatogram. The reaction mixture is allowed to stand for a while and the organic layer is taken. The layer is washed with water and concentrated to dryness. The residue is triturated with ether to give triphenylphosphine oxide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[OH:19])([O-])=[O:2].[OH-].[Na+].C1C2C(=O)C3C(=CC=CC=3)C=2C=CC=1.C=O.N(C1C=CC=CC=1)=NC1C=CC=CC=1>O.CO>[OH:19][C:13]1[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[N:11]1[N+:1]([O-:2])=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:10]1
Reactant: Cc1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: C=O
Agent: O=C1c2ccccc2-c2ccccc21
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(O)c(-n2nc3ccccc3[n+]2[O-])c1
Temperature: 65 °C

Procedure:
2-nitro-2'-hydroxy-5'-methylazobenzene 12.9 g was added to a mixture of methanol 60 ml, water 30 ml and 97% sodium hydroxide 12.4 g, and the resultant mixure was stirred while raising temperature to 65° C. Thereafter, the mixture was cooled to 40° C., and 9-fluorenone 0.8 g and then 80% paraformaldehyde 2.1 g were added to the mixture for 1 hour. The resultant mixture was then heated to the boiling point (75° C.), and was stirred at the boiling point for 6 hours, thus almost all of the azobenzene having disappeared to produce 2-(2-hydroxy-5-methylphenyl)benzotriazole-N-oxide.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9](Cl)=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([NH2:31])[CH2:27][CH2:26]1.[OH-].[Na+]>C1C=CC=CC=1>[C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9]([NH:31][N:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CN1CCN(N)CC1
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)NN1CCN(C)CC1
Yield: 49.3 %

Procedure:
4-acetylamino-5-chloro-2-methoxy benzoyl chloride (2.70 g, 0.0103 mole) in anhydrous benzene (100 ml) in the presence of triethylamine (1.1 g) was treated with 4-methyl-1-amino piperazine (1.18 g). After 6 hours the reaction mixture was basified with dilute sodium hydroxide and extracted with hot ethyl acetate. On cooling the extracts yielded 4-acetylamino-5-chloro-2-methoxy-N-[4-methyl-1-piperazinyl]benzamide (1.72 g), m.p. 198°-200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[F:10].C(NC(C)C)(C)C.[Li].CN(C)[CH:21]=[O:22].C(O)(=O)C>O1CCCC1.O>[Cl:1][C:2]1[C:3]([F:10])=[C:4]([C:5]([O:8][CH3:9])=[CH:6][CH:7]=1)[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: COc1ccc(Cl)c(F)c1
Agent: [Li]
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: CC(=O)O
Product: COc1ccc(Cl)c(F)c1C=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 83.5 %

Procedure:
To a solution of 4-chloro-3-fluoroanisole (10.2 g, 63.5 mmol, Oakwood) in tetrahydrofuran (100 mL) at −78° C. was added lithium diisopropyl amine (42.3 mL, 1.8 M in THF, 76.2 mmol) dropwise during a period of 15 min. The mixture was stirred at −78° C. for another 20 mins. Then N,N-dimethyl-formamide (5.9 mL, 76.2 mmol) was added in one portion. The mixture was stirred at −78° C. for 10 min, then quenched with acetic acid (15.6 g, 254 mmol) and followed by the addition of water (80 mL). The mixture was partitioned between ethyl acetate and water. The organic layer was separated, concentrated to give 3-chloro-2-fluoro-6-methoxy-benzaldehyde as a yellow solid (Yield: 10 g, 85%)
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:14])[C:4]([CH:6]1[CH2:9][CH:8]([CH2:10][C:11]([OH:13])=O)[CH2:7]1)=[O:5].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[F:37][C:38]([F:48])([F:47])[C:39]1[CH:40]=[C:41]([NH2:46])[C:42]([NH2:45])=[CH:43][CH:44]=1>C(Cl)Cl>[NH2:45][C:42]1[CH:43]=[CH:44][C:39]([C:38]([F:37])([F:47])[F:48])=[CH:40][C:41]=1[NH:46][C:11]([CH2:10][CH:8]1[CH2:7][CH:6]([C:4]([N:3]([O:2][CH3:1])[CH3:14])=[O:5])[CH2:9]1)=[O:13]
Reactant: CON(C)C(=O)C1CC(CC(=O)O)C1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CON(C)C(=O)C1CC(CC(=O)Nc2cc(C(F)(F)F)ccc2N)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 44 %

Procedure:
TEA (1.49 ml, 10.70 mmol) was added to a suspension of 2-{3-[methoxy(methyl)carbamoyl]cyclobutyl}acetic acid, EDC.HCl 1.18 g, 6.20 mmol), HOBt.xH2O (0.77 g, 5.69 mmol) in DCM (20 ml) at 0° C. and stirred for 5 min before the addition of 4-(trifluoromethyl)benzene-1,2-diamine (1.04 g, 10.34 mmol). This was stirred for a further 20 min at 0° C. then allowed to warm to RT. The reaction was monitored by LC MS, after 2 hours the reaction mixture was washed with 1N HCl (50 ml) then sat. NaHCO3 (50 ml). This was dried over Na2SO4, filtered and evaporated to dryness. Purification by silica gel column chromatography, eluting with EtOAc gave the desired product (0.83 g, 44%) as a beige solid; MS (ESI+) for C16H20N3O3 m/z 360.00 [M+H]+; HPLC purirty 90% (ret. time, 1.64 min); 1H NMR (500 MHz, MeOD) δH ppm 2.02-2.16 (2H, m), 2.31-2.68 (4H, m), 2.69-2.88 (1H, m), 3.18 (3H, d, J=4.41 Hz), 3.36-3.59 (1H, m), 3.65-3.76 (3H, m), 6.81-6.97 (1H, m), 7.02-7.27 (1H, m), 7.28-7.48 (1H, m).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[C:9]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])=[CH:8][CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:6]1[C:24]([O:26]C(C)(C)C)=O)=[N+]=[N-].C1(P([C:44]2[CH:49]=[CH:48]C=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCC(Cl)=O.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[F:17][C:11]1[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=1[C:9]1[C@H:5]2[N:6]([C:24](=[O:26])[N:1]([CH:48]3[CH2:49][CH2:44]3)[CH2:4]2)[C@H:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1C(CN=[N+]=[N-])C(c2cc(F)ccc2F)=CC1c1ccccc1
Agent: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1N(C2CC2)C[C@H]2C(c3cc(F)ccc3F)=C[C@@H](c3ccccc3)N12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of the azidocarbamate 2-1a (0.39 g, 0.95 mmol) in THF (10.0 mL) was treated with polystyrene bound triphenylphosphine and heated at 60° C. for 2 h. The reaction was quenched with water and heated at 60° C. for an additional hour. The reaction was diluted with EtOAc and filtered. The filtrate was washed with brine, dried over MgSO4, filtered and concentrated. A solution of this product (0.025 g, 0.07 mmol) in CH2Cl2 (3 mL) was treated with chloroacetyl chloride (0.007 g, 0.07 mmol) and triethylamine (0.007 g, 0.07 mmol) and stirred at rt for 2 h. The reaction was partitioned between dichloromethane and water. The organic solution was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was dissolved in 4M HCl/dioxane and stirred for 1 hr. The reaction was then made basic with 3N aq NaOH and stirred vigorously. After 2 h, the reaction mixture was extracted with EtOAc. The organic solution was washed with brine, dried over MgSO4, filtered and concentrated. The remaining oil was dissolved in CH3CN (0.5 mL) and purified on a Gilson automated system affixed with a YMC J'sphere H80 20×50 mm column (eluting with 5-95% CH3CN +0.1% TFA in water +0.11% TF A over 10 min) to afford pure 5-1.