Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.CS(N)(=O)=O.[CH3:41][N:42](C=O)[CH3:43]>>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=4)[C:7]([C:8]#[N:9])=[C:2]([N:42]([CH3:43])[CH3:41])[N:3]=3)[N:25]=2)=[CH:34][CH:33]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: CN(C)C=O
Agent: CS(N)(=O)=O
Product: CN(C)c1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N

Procedure:
At 100° C., 80 mg (0.15 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 28 mg (0.30 mmol) of methanesulfonamide were stirred in 1.5 ml of DMF overnight. After cooling, the crude product was purified by preparative HPLC (acetonitrile/water). This gave 41 mg (50% of theory) of the target compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH:15]1[CH:19]=[CH:18][CH:17]=[N:16]1.CCN(C(C)C)C(C)C>CCO>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[N:15]1[CH:19]=[CH:18][CH:17]=[N:16]1)([O-:14])=[O:13]
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1-n1cccn1
Temperature: 120 °C
Yield: 80.1 %

Procedure:
1-Fluoro-2-nitro-4-trifluoromethyl-benzene (209 mg, 1 mmol) was dissolved in EtOH (4.5 mL) in a 5 mL microwave reaction vessel. 1H-pyrazole (83.5 mg, 1.2 mmol), DIPEA (329 μL, 2 mmol) and a stirrbar was added followed by sealing of the reaction vessel. The reaction mixture was then heated in the microwave for 30 min at 120° C. The reaction was concentrated in vacuo and the residue purified by flash chromatography (Silica, Hexane: EtOAc) to afford the title compound (206 mg, 81%). LC/MS>95%, m/z (ESI+)=258 (MH+).
Reaction SMILES: [S:1](=[O:11])(=[O:10])([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:2].[C:12]([NH:15]C1C=CC(O)=CC=1)(=[O:14])[CH3:13].N1C=CC=CC=1>O1CCOCC1>[NH2:2][S:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:15][C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=1)(=[O:10])=[O:11]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: NS(=O)(=O)Oc1ccccc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(OS(N)(=O)=O)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
A reaction flask was charged with 43.8 g (0.252 mole) of sulfamic acid, phenyl ester; 12.6 g (0.084 mole) of 4-acetamidophenol, 9 ml of pyridine and 150 ml p-dioxane. The solution was heated at 75° C. for 18 hours. The solution was concentrated to a brown oil. The oil was portioned between 100 ml methylene chloride and 100 ml of 1.0 N sodium bicarbonate. The mixture was refrigerated overnight then filtered to collect 15.8 g of white solid. 1H NMR spectrum indicated pure product but contaminated with sodium bicarbonate. The solid was added to 100 ml H2O and the mixture stirred for one hour. The solid was collected and dried to give 8.4 g of solid, mp 180°-181° C.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH2:13]([N:20]1[CH2:25][CH2:24][NH:23][C@H:22]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH:28]=2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([CH:50]=[C:51]([C:53]([F:56])([F:55])[F:54])[CH:52]=1)[C:47](O)=[O:48].ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>ClCCl.O>[CH3:42][O:43][C:44]1[CH:45]=[C:46]([CH:50]=[C:51]([C:53]([F:54])([F:55])[F:56])[CH:52]=1)[C:47]([N:23]1[CH2:24][CH2:25][N:20]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:21][C@H:22]1[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH:28]=1)=[O:48]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(C[C@@H]2CN(Cc3ccccc3)CCN2)ccc1Cl
Reactant: COc1cc(C(=O)O)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCN(Cc3ccccc3)C[C@H]2Cc2ccc(Cl)c(O[Si](C)(C)C(C)(C)C)c2)cc(C(F)(F)F)c1
Reaction time: 6 h
Yield: 77.5 %

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.93 g) was added to a mixture of (2R)-4-benzyl-2-[4-chloro-3-(tert-butyldimethylsilyloxy)benzyl]-piperazine (2.90 g) and 3-methoxy-5-(trifluoromethyl)benzoic acid (1.48 g), 1-hydroxybenzotriazole (1.14 g) in dichloromethane (18 ml) at room temperature. After being stirred for 6 hours at the same temperature, the reaction mixture was poured into a mixed solvent of water (25 ml) and dichloromethane (15 ml). The aqueous layer was adjusted to pH 9 with aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (52 g) using a mixed solvent of hexane and ethyl acetate (2:1). The fractions containing the objective compound was collected and evaporated under reduced pressure to give a syrup of (2R)-1-[3-methoxy-5-(trifluoromethyl)-benzoyl]-2-[4-chloro-3-(tert-butyldimethylsilyloxy)benzyl]-4-benzylpiperazine (3.3 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[CH2:23][NH:22][C:21](=[O:24])[CH2:20][CH2:19][C:18]=2[CH:25]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(#N)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[CH2:23][N:22]([C:2]3[CH:11]=[C:10]([Cl:12])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)[C:21](=[O:24])[CH2:20][CH2:19][C:18]=2[CH:25]=1
Reactant: O=C1CCc2cc(Br)ccc2CN1
Reactant: Clc1cc(Cl)c2ccccc2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CC#N
Product: O=C1CCc2cc(Br)ccc2CN1c1cc(Cl)c2ccccc2n1
Temperature: 130 °C
Yield: 41.1 %

Procedure:
To a solution of 2,4-dichloroquinoline (196 mg, 1.0 mmol) in dioxane (4 mL) was added 7-bromo-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one (161 mg, 1.0 mmol), followed by tris(dibenzylideneacetone)dipalladium(0) (28 mg, 0.03 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (65 mg, 0.11 mmol), and potassium phosphate tribasic (212 mg, 1.0 mmol). The resultant mixture was refilled with nitrogen and heated at 130° C. overnight. After cooled to room temperature, the mixture was diluted with acetonitrile (10 mL), filtered, and washed with acetonitrile. The filtrate was concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel (hexane/ethyl acetate/ammonium hydroxide solution, 80:19:1) to give 165 mg of product as a white solid (yield was 42%). MS obsd. (ESI+) [(M+H)+] 401.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)=[C:4]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:3]=1.O.O.Cl[Sn]Cl>CO>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[C:4]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2C2CCCCC2)cc1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: Nc1ccc(Oc2ccc(Cl)cc2C2CCCCC2)cc1

Procedure:
The nitro intermediate (10 mmol) obtained above was dissolved in MeOH (20 mL), and treated with SnCl2.2H2O (50 mmol), according to General Procedure I. The reaction mixture was heated under reflux until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo and the residue was treated with 4.0 N aqueous NaOH to pH ˜8. The residue was extracted with EtOAc (2×50 mL), washed with 1.0 N aqueous NaOH, brine and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(4-chloro-2-cyclohexylphenoxy) aniline, which was used directly for further transformation without further purification.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:21]([I:22])=[CH:20][C:16]([C:17]([OH:19])=O)=[C:15]([F:23])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:36]1([S:40]([NH2:43])(=[O:42])=[O:41])[CH2:39][CH2:38][CH2:37]1.N12CCCN=C1CCCCC2.Cl>O1CCCC1.C(OCC)(=O)C>[C:1]12([CH2:11][O:12][C:13]3[C:21]([I:22])=[CH:20][C:16]([C:17]([NH:43][S:40]([N:36]4[CH2:39][CH2:38][CH2:37]4)(=[O:42])=[O:41])=[O:19])=[C:15]([F:23])[CH:14]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: NS(=O)(=O)N1CCC1
Reactant: O=C(O)c1cc(I)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(I)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: 70 °C
Reaction time: 16 h
Yield: 21.5 %

Procedure:
To a mixture of 4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid (1.75 g, 4.07 mmol) in anhydrous tetrahydrofuran (20 mL) was added 1,1′-carbonyldiimidazole (1.31 g, 8.10 mmol). The resulting mixture was heated at 70° C. for 30 minutes and then cooled to ambient temperature. Azetidine-1-sulfonamide (1.10 g, 8.10 mmol) was added followed by 1,8-diazabicyclo-[5.4.0]undec-7-ene (1.72 mL, 12.20 mmol) and the reaction mixture was stirred at ambient temperature for 16 hours. After addition of 1 N hydrochloric acid (5 mL) and diluting the mixture with ethyl acetate (150 mL), the organic phase was washed with 1 N hydrochloride acid (5 mL) and brine (10 mL); dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave a residue which was purified by silica gel column chromatography using 0-100% ethyl acetate in hexanes as eluent to afford the title compound as an off-white solid (0.48 g, 22%): 11H NMR (300 MHz, CDCl3) δ 8.51 (d, J=8.7 Hz, 1H), 6.56 (d, J=13.7 Hz, 1H), 3.90 (t, J=7.6 Hz, 4H), 3.59 (s, 2H), 2.35-2.15 (m, 2H), 2.12-1.99 (m, 3H), 1.83-1.63 (m, 12H); MS (ES−) m/z 547.1 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)[C@H:9]([OH:12])[CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[I:24]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([I:24])=[CH:14]2)[C@H:9]([OH:12])[CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: II
Reactant: OC[C@@H](O)[C@H](c1cccc(F)c1)n1ccc2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC[C@@H](O)[C@H](c1cccc(F)c1)n1cc(I)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
To a solution of (2S,3S)-3-indol-1-yl-3-(3-fluorophenyl)-propane-1,2-diol (EXAMPLE 47, Step 5, 1.34 g, 4.56 mmol) in N,N-dimethylformamide (20 mL) was added pulverized solid potassium hydroxide (0.76 g, 13.68 mmol). The mixture was stirred for 15 minutes under nitrogen at room temperature, whereupon iodine (1.21 g, 4.72 mmol) was added in one portion. The mixture was stirred for 30 minutes at room temperature, then poured into 100 mL of a 5% aqueous sodium thiosulfate solution. The solution was extracted 3 times with ethyl acetate and the combined extracts were washed 3 times with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Biotage chromatography (FlasH40i, silica, 40% ethyl acetate/hexane) to yield 0.91 g (48%) of (2S,3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indol-1-yl)propane-1,2-diol as a dark brown oil. MS (ES) m/z 411.9.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.Cl.[CH3:25][S:26]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:33][C:32]4[CH:31]=[CH:30][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:35][CH:34]=4)=[O:3])([CH2:9][CH2:8]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Agent: Cl
Product: CS(=O)(=O)c1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 18.7 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-methylsulfonylaniline hydrochloride (71.0 mg) were used to obtain ((2S,4S)-4-fluoro-1-[[N-[4-[N-(4-methylsulfonylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (13.8 mg).
Reaction SMILES: C(=O)(OC(C)(C)C)N.[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2([NH:22][C:23]([C@H:25]3[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][N:26]3C(OC(C)(C)C)=O)=[O:24])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)=[O:12]>>[CH3:30][C:28]1([CH3:31])[CH2:27][NH:26][C@@H:25]([C:23]([NH:22][C:19]2([C:16]3[CH:15]=[CH:14][C:13]([C:11]([O:10][CH3:9])=[O:12])=[CH:18][CH:17]=3)[CH2:21][CH2:20]2)=[O:24])[CH2:29]1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CC(C)(C)CN3C(=O)OC(C)(C)C)CC2)cc1
Agent: CC(C)(C)OC(N)=O
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CC(C)(C)CN3)CC2)cc1
Yield: 98 %

Procedure:
The title compound (D108) (70 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from (R)-tert-butyl 2-((1-(4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-4,4-dimethylpyrrolidine-1-carboxylate (D75) (94 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:16][C:17]([C:19]2[CH:20]=[C:21]3[C:26](=[C:27]([C:29]#[N:30])[CH:28]=2)[O:25][C:24]([CH3:32])([CH3:31])[CH2:23][C:22]3([CH3:34])[CH3:33])=[O:18])[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]([O:11]C(C)(C)C)=[O:10].C(O)=O>O1CCOCC1.C1COCC1.O>[C:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:16][C:17]([C:19]2[CH:20]=[C:21]3[C:26](=[C:27]([C:29]#[N:30])[CH:28]=2)[O:25][C:24]([CH3:31])([CH3:32])[CH2:23][C:22]3([CH3:34])[CH3:33])=[O:18])=[CH:3][C:2]=1[F:1])([OH:11])=[O:10]
Reactant: CC(C)(C)OC(=O)Cc1ccc(OC(=O)c2cc(C#N)c3c(c2)C(C)(C)CC(C)(C)O3)cc1F
Solvent: C1CCOC1
Solvent: O
Solvent: O=CO
Product: CC1(C)CC(C)(C)c2cc(C(=O)Oc3ccc(CC(=O)O)c(F)c3)cc(C#N)c2O1
Reaction time: 2 h
Yield: 74.3 %

Procedure:
A solution of 8-cyano-2,2,4,4-tetramethyl chroman-6-carboxylic acid-3-fluoro-4-tert-butoxycarbonylmethyl-phenyl ester (Compound 31, 0.084 g, 0.18 mmol) in 1,4-dioxane (4 mL) and THF (2 mL) was treated with formic acid (15 mL) at ambient temperature. After 2 h, the reaction mixture was diluted with water and extracted with diethyl ether. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product (0.055 g, 74%).
Reaction SMILES: CS[C:3]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][N+:5]([O-:7])=[O:6].[CH2:13]([O:15][CH2:16][CH2:17][O:18][C:19]1[N:24]=[C:23]([NH:25][NH2:26])[CH:22]=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1)[CH3:14]>C(O)C>[CH2:13]([O:15][CH2:16][CH2:17][O:18][C:19]1[N:24]=[C:23]([N:25]([C:4]([N+:5]([O-:7])=[O:6])=[CH:3][NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[NH2:26])[CH:22]=[C:21]([C:27]([F:30])([F:28])[F:29])[CH:20]=1)[CH3:14]
Reactant: CCOCCOc1cc(C(F)(F)F)cc(NN)n1
Reactant: CSC(=C[N+](=O)[O-])NS(C)(=O)=O
Solvent: CCO
Product: CCOCCOc1cc(C(F)(F)F)cc(N(N)C(=CNS(C)(=O)=O)[N+](=O)[O-])n1
Temperature: 25 °C
Yield: 34.2 %

Procedure:
1.40 g of N-(1-(methylthio)-2-nitroethenyl)methanesulfonamide (Intermediate No. 57), 1.80 g of 6-(2-ethoxyethoxy)-4-trifluoromethyl-2-pyridylhydrazine and 11 ml of ethanol were stirred for 15 hours under heating and refluxing and then cooled to room temperature, whereupon precipitated crystals were collected by filtration. The crystals obtained by filtration were washed with a small amount of ethanol and then dried to obtain 0.97 g of N-(1-(6-(2-ethoxyethoxy)-4-trifluoromethyl-2-pyridyl)hydrazino-2-nitroethenyl)methanesulfonamide (Compound No. 164) having a melting point of 153° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8]C(=O)[C:5]2=[CH:11][C:12]=1[F:13].FC1C=C(C(O)=O)C(=CC=1F)C(O)=O>CN1CCCC1=O.CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:11][C:12]=1[F:13])[C:9]([OH:10])=[O:8]
Reactant: O=C1OC(=O)c2cc(F)c(F)cc21
Agent: O=C(O)c1cc(F)c(F)cc1C(=O)O
Solvent: CN1CCCC1=O
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccc(F)c(F)c1

Procedure:
We have found that 4,5-difluorophthalic anhydride and 4,5-difluorophthalic acid may be decarboxylated in high yield to 3,4-difluorobenzoic acid in N-methyl-2-pyrrolidone or dimethyl acetamide using copper, copper oxide, copper salts, or halides and salts of Zn, Cd, Ag and Ni as a catalyst.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[C:29]([CH3:36])[CH:28]=1.CCOC(C)=O>C(O)C.C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:1]([O:8][CH:9]1[CH:14]([N+:15]([O-:17])=[O:16])[C:13]([C:30]2[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][C:29]=2[CH3:36])=[CH:12][CH:11]=[N:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1c(Cl)ccnc1OCc1ccccc1
Reactant: COc1ccc(B(O)O)c(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C2=CC=NC(OCc3ccccc3)C2[N+](=O)[O-])c(C)c1
Yield: 78 %

Procedure:
To a solution of 2-benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et al. WO 99/01454, which is incorporated herein by reference) (0.98 g, 3.7 mmol) in ethanol (10 mL) and toluene (40 mL), was added Na2CO3 (4.6 mL, 2M), 4-methoxy-2-methylphenyl boronic acid (1.0 g, 5.6 mmol), and Pd(PPh3)2Cl2 (0.156 g, 0.22 mmol) and the mixture was heated at reflux for 5 h. The reaction was cooled and poured into EtOAc and H2O (500 mL). The EtOAc layer was washed with H2O, brine, dried Na2SO4, filtered and concentrated in vacuo. Purification using flash chromatography (10% EtOAc/hexane) gave 1.01 g (78%) of 2-benzyloxy-4-(4-methoxy-2-methyl-phenyl)-3-nitro-2,3-dihydro-pyridine as a viscous oil; MS(AP) m/z 351.6 [(M+H)+, 100], 392.0 [(M+H+CH3CN)+, 35]. The purified intermediate was used in the following step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:8][C:9]=1[NH2:10])([O-])=O.FC1C=CC(C(O)=O)=CC=1>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:8][C:9]=1[NH2:10]
Reactant: CCOC(=O)N1CCN(c2ccc([N+](=O)[O-])c(N)n2)CC1
Agent: [Pd]
Agent: O=C(O)c1ccc(F)cc1
Solvent: CCO
Product: CCOC(=O)N1CCN(c2ccc(N)c(N)n2)CC1

Procedure:
5-Nitro-6-amino-2-(4-ethoxycarbonyl-1-piperazinyl)pyridine (4.5 g 15.2 mmol) in EtOH (200 ml) is hydrogenated at 1 atm over 10% Pd/C (1.5 g), filtered after hydrogen uptake was complete (2.5 h), combined with 4-fluorobenzoic acid (2.13 g 15.2 mmol) in EtOH (50 ml), evaporated to dryness and used without further purification in the following step.
Reaction SMILES: [C:1]([CH:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])(=[O:3])[CH3:2].[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH:15]=O.N1CCOCC1.Cl>O.C(O)C>[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH:15]=[CH:2][C:1]([CH:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])=[O:3]
Reactant: CC(=O)C1C(=O)CCC1=O
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: O
Solvent: C1COCCN1
Solvent: CCO
Product: O=C(C=Cc1ccc(Cl)c(Cl)c1)C1C(=O)CCC1=O
Yield: 37.4 %

Procedure:
2-Acetyl-1,3-cyclopentanedione (3.13 g.) was treated with 3,4-dichlorobenzaldehyde (4.36 g.) in 140 ml. of ethanol under reflux for 4 hours in the presence of 5 ml. of morpholine. After cooling, the reaction mixture was poured into 150 ml. of water containing 7 ml. of conc. hydrochloric acid. Deposited crystals were separated by filtration and washed with water, and dried. 2-(3,4-Dichlorocinnamoyl)-1,3-cyclopentanedione (2.48 g., 37%) was obtained which showed mp. 190°- 191° C. after recrystallization from dioxane.
Reaction SMILES: O[CH2:2][C@@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.[K].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C1(C)C=CC=CC=1>[O:33]=[C:31]1[C:30]2[C:29](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:28](=[O:38])[N:32]1[CH2:2][C@@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:4]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CO)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCO[C@@H](CN2C(=O)c3ccccc3C2=O)C1
Temperature: 35 °C
Reaction time: 4 h
Yield: 51.4 %

Procedure:
A mixture of (R)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (750 g, 3.45 mol) was stirred with triethylamine (577 mL, 4.14 mol) and toluene (6000 mL) at 3° C. under N2. Methanesulfonyl chloride (321 mL, 4.14 mol) was added over 2.5 hr, keeping the temperature at less than 15° C. When the addition was finished, the temperature was increased to 35° C., and water (2000 mL) was added. The phases were mixed for 10 min and then allowed to settle. The aqueous phase was drawn off and water (1500 mL) was added. The phases were mixed again for 10 min, and then the aqueous phase was removed. Toluene (4000 mL) was added to the vessel, and 2000 mL of distillate was removed under reduced pressure at 50° C. The temperature was then reduced to 20° C., and potassium phthalimide (864 g, 4.66 mol) and tetrabutylammonium bromide (111 g, 0.35 mol) were added. The mixture was stirred at 108° C. for 4 hr, and then cooled to 20° C. Water (1000 mL) and 5% aqueous NaOH (2500 mL) were added. The resulting mixture was stirred for 10 min. The phases were then allowed to settle, and the aqueous phase was removed. Water (2000 mL) was added, and the resulting mixture was stirred for an additional 10 min. The aqueous phase was then removed. A total of 7 L of distillate were removed under reduced pressure at a temperature ranging from 60 to 85° C. The vessel was cooled to 65° C., and heptanes (3000 mL) was added. The temperature was further decreased to 25° C., and the solution was seeded with crystalline sample of the title compound. The mixture was stirred for 1 hr until crystallization was well under way. After adding heptanes (2500 mL), the mixture was cooled to 10° C. and then stirred for an additional 24 hr. Afterward, the mixture was filtered, and the solid was washed with 800 mL of a cold solution of 10% toluene in heptanes and dried under mechanical vacuum oven at 45° C. for 16 hr to produce (S)-tert-butyl 2-((1,3-dioxoisoindolin-2-yl)methyl)morpholine-4-carboxylate (614 g, 51%) as a solid. 1H NMR (500 MHz, chloroform-d) δ ppm 1.38 (s, 9H), 2.69 (br. s., 1H), 2.92 (br. s., 1H), 3.37 (td, J=11.51, 2.76 Hz, 1H), 3.60 (dd, J=13.75, 4.53 Hz, 1H), 3.63-4.01 (m, 5H), 7.66 (dd, J=5.32, 3.03 Hz, 2H), 7.79 (dd, J=5.04, 3.07 Hz, 2H).