Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1.[CH3:16][O:17]C1C=C(C=CC=1)C=O.FC1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:17][CH3:16])[CH:7]=1
Reactant: COc1cccc(C=O)c1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Agent: O=Cc1ccc(F)cc1
Product: COC(=O)C(=O)C(Cl)c1cccc(OC)c1

Procedure:
This compound was synthesised as 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methyl ester but using 3-methoxybenzaldehyde instead 4-fluorobenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[C:6]([CH:8]=1)[NH2:7].[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:7][C:6]2[CH:8]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[O:20])=[CH:17][CH:16]=1
Reactant: Nc1cc(Cl)ccc1-c1nnn[nH]1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: O=C(Nc1cc(Cl)ccc1-c1nnn[nH]1)c1ccc(Cl)cc1
Yield: 37 %

Procedure:
The title compound was prepared essentially according to the method of Example 4, but using 5-Chloro-2-(1H-tetrazol-5-yl)aniline (1.0 mmol) and 4-chlorobenzoyl chloride to yield the desired product (126.3 mg, 37%). 1H NMR (400 MHz, d6-DMSO): δ 13.62 (s, 1H), 8.87 (s, 1H), 8.22 (m, 3H), 7.72 (s, 2H), 7.25 (s, 1H). MS (EI) for C14H9Cl2N5O: 334.165 (M+H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:15]([NH2:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[NH2:18][C:19]1[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[C:21]([CH3:28])[N:20]=1>>[NH2:18][C:19]1[N:24]=[C:23]([C:25]([NH:17][CH:15]([C:5]2[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[C:3]([F:2])[CH:4]=2)[CH3:16])=[O:26])[CH:22]=[C:21]([CH3:28])[N:20]=1
Reactant: CC(N)c1cnc(OCC(F)(F)F)c(F)c1
Reactant: Cc1cc(C(=O)O)nc(N)n1
Agent: Cl
Product: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(F)c2)nc(N)n1
Yield: 70 %

Procedure:
The title compound is prepared in 70% yield (170 mg, clear colorless oil) from (−)-1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (179 mg, 0.65 mmol, Amine-12, single enantiomer) and 2-amino-6-methylpyrimidine-4-carboxylic acid (100 mg, 0.65 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[O:23]=[C:24]1[NH:32][C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[N:25]1[CH:33]1[CH2:38][CH2:37][N:36]([C:39]2[N:44]=[CH:43][N:42]=[C:41]([C:45]([OH:47])=O)[CH:40]=2)[CH2:35][CH2:34]1.[N+:48]([C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][CH:59]=1)[NH:56][CH2:55][CH2:54]2)([O-:50])=[O:49].C(N(CC)CC)C>CN(C=O)C.O>[N+:48]([C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][CH:59]=1)[N:56]([C:45]([C:41]1[N:42]=[CH:43][N:44]=[C:39]([N:36]3[CH2:37][CH2:38][CH:33]([N:25]4[C:26]5[C:27](=[N:28][CH:29]=[CH:30][CH:31]=5)[NH:32][C:24]4=[O:23])[CH2:34][CH2:35]3)[CH:40]=1)=[O:47])[CH2:55][CH2:54]2)([O-:50])=[O:49]
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg (0.47 mmol) TBTU were added to 150 mg (0.44 mmol) 6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 75 mg (0.46 mmol) 5-nitro-2,3-dihydro-1H-indole, 100 μL and (0.712 mmol) triethylamine in 1.5 mL DMF and the mixture was stirred overnight at RT. The reaction mixture was poured onto 30 mL water. The precipitated product was suction filtered and dried at 50° C. in the CAD.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[C:18]=2[CH3:25])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].CCO>O>[C:23]([C:19]1[C:18]([CH3:25])=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:26])#[N:24]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C#N)c2C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(C#N)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
The mixture of 2-(3-cyano-2-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (3) (310 mg, 0.89 mmol), KOH (50% aqueous solution, 2 g, 17.8 mmol), EtOH (10 mL) and water (1 mL) are stirred in a 20 mL vial at 50° C. for 30 min. After concentration in vacuo, the residue is dissolved in water (5 mL) and acidified with conc. HCl until no more white precipitate came out of the water. The filtration affords 2-(3-cyano-2-methyl-benzoylamino)-indan-2-carboxylic acid (238) as white solid (270 mg, 95%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[CH3:14][N:15]([CH3:25])[CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.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]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([N:22]3[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][CH2:16][N:15]([CH3:14])[CH3:25])[CH2:20][CH2:21]3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: CN(C)CCCN1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CN(C)CCCN1CCN(c2ccc3c(=O)[nH]nc(Cl)c3c2)CC1
Yield: 18.8 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.578 mmol), 1-[3-(dimethylamino)propyl]piperazine (112 mg, 0.654 mmol), Pd2(dba)3 (53 mg, 0.0578 mmol), rac-BINAP (108 mg, 0.173 mmol) and NaOtBu (139 mg, 1.445 mmol) in DMA (5 mL) was heated at 85° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Preparatory HPLC afforded 4-chloro-6-[4-(3-dimethylamino-propyl)-piperazin-1-yl]-2H-phthalazin-1-one hydroformate (38 mg) as a pale brown solid, 1H (400 MHz, d6-DMSO) δ: 1.66 (m, 2H), 2.30 (s, 6H), 2.34 (t, 2H), 2.53 (m, 6H), 3.43 (m, 4H), 7.09 (d, 1H), 7.55 (dd, 1H), 8.03 (d, 1H), 8.15 (s, 1H), 12.50 (s, 1H) ppm; m/z (M+1) 350.08.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=[CH2:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[BH4-].[Na+].C[OH:25]>>[OH:25][CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:8]1[CH2:7][CH2:6][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:10][CH2:9]1
Reactant: CO
Reactant: C=CC(NC(=O)OC(C)(C)C)C1CCC2(CC1)OCCO2
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)NC(CCO)C1CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 250 mL round bottom flask was charge with tert-butyl (1-(1,4-dioxaspiro[4.5]decan-8-yl)allyl)carbamate (5.8 g, 18.6 mmol) and methanol (207 mL). The mixture was cooled to −78° C. and ozone was bubble through the solution at a rate of 3 L/min for 1 hour. The mixture turned pale blue in color after 30 minutes. After 1 hour air was bubble through the solution for 30 minutes until the blue color disappeared. Sodium borohydride (2.82 g, 74.5 mmol) was added to the mixture in 4 portions. The mixture was gradually warmed to room temperature. After 6 h at room temperature the mixture quenched with saturated aqueous ammonium chloride. Dilute with water and extract with ethyl acetate. Dry organic layer with MgSO4, filter, and concentrate in vacuo to give tert-butyl (3-hydroxy-1-(1,4-dioxaspiro[4.5]decan-8-yl)propyl)carbamate (5.1 g, 16.2 mmol) as a clear oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]#[N:24])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][NH2:24])=[CH:19][CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#CCCc1ccc(OCc2ccccc2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCCCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
LAH (570 mg, 0.015 mol, 1.5 eq) was dissolved in THF (30 ml), and to this solution was added dropwise a THF solution (50 ml) of 3-(4-benzyloxyphenyl)-propionitrile (2.37 g, 0.01 mol, 1.0 eq) under ice-cooling. After the completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. This reaction mixture was cooled with ice-cold water, and a saturated aqueous sodium sulfate solution (about 30-40 ml) was added. After filtration through Celite, the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (chloroform/metanol=10/1-5/1) to give 3-(4-benzyloxyphenyl)propylamine (1.2 g, 49.7%) as a pale-yellow amorphous compound.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:11]([OH:13])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[CH2:14](Br)[C:15]#[CH:16].C(NC(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[S:3][C:4]([C:11]([O:13][CH2:16][C:15]#[CH:14])=[O:12])=[C:5]([C:7]([F:8])([F:10])[F:9])[N:6]=1
Reactant: C#CCBr
Reactant: O=C(O)c1sc(Cl)nc1C(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: C#CCOC(=O)c1sc(Cl)nc1C(F)(F)F

Procedure:
A mixture of 4.63 g (0.02 mole) of 2-chloro-4-trifluoromethyl-5-thiazolecarboxylic acid, 2.42 g (0.02 mole) of propargyl bromide, 2.59 g (0.02 mole) of diisopropylamine, and 50 ml. of methylene chloride was stirred for 16 hours. The methylene chloride solution was washed successively with diluted hydrochloric acid and saturated sodium bicarbonate, dried (MgSO4) and concentrated under reduced pressure. The residue was Kugelrohr distilled to give propargyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate as a colorless liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:12]2[CH2:15][CH2:14][C:13]2=[O:16])[C:7]([CH3:11])=[CH:8][C:9]=1[CH3:10])([O-])=O>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([N:12]2[CH2:15][CH2:14][C:13]2=[O:16])[C:7]([CH3:11])=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1N1CCC1=O
Agent: [Ni]
Solvent: CO
Product: Cc1cc(C)c(N2CCC2=O)cc1N
Yield: 90.4 %

Procedure:
21.2 g (0.0965 mol) of the 1-(3'-nitro-4',6'-dimethylphenyl)-azetidin-2-one obtained according to a) are hydrogenated in 210 ml of methanol with 2 g of Raney nickel at 30°-35° under normal pressure. The reaction solution is filtered and evaporated. Recrystallisation of the crude product from methanol gives 16.6 g (90%) of crystals having a melting point of 123°-124°.
Reaction SMILES: O(CC)[C:2]([S-])=[S:3].[K+].[NH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[OH:16]>C(O)C>[CH3:15][C:13]1[CH:12]=[CH:11][C:10]2[O:16][C:2]([SH:3])=[N:8][C:9]=2[CH:14]=1
Reactant: Cc1ccc(O)c(N)c1
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CCO
Product: Cc1ccc2oc(S)nc2c1
Yield: 96.8 %

Procedure:
A mixture of potassium ethyl xanthate (16.0 g, 0.1 mol) and 2-amino-4-methylphenol (12.3 g, 0.1 mol) was dissolved in absolute ethanol (150 mL). The mixture was stirred at reflux overnight. After cooling, the reaction solvent was evaporated under reduced pressure. The resultant residue was dissolved in water (200 mL) and treated with HOAc to pH to 5. The resultant solid was filtered and dried to afford 5-methyl-2-mercaptobenzoxazole (16.0 g, 96% yield).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH2:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.CS([C:13]1[N:18]=[C:17]([C:19]2[C:20]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[N:21][N:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=23)[CH:16]=[CH:15][N:14]=1)(=O)=O>O>[F:38][C:35]1[CH:36]=[CH:37][C:32]([C:20]2[C:19]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]([NH:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[N:18]=3)=[C:23]3[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[CH:27][N:22]3[N:21]=2)=[CH:33][CH:34]=1
Reactant: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)nn3cc(C(F)(F)F)ccc23)n1
Reactant: NCCN1CCCC1
Solvent: O
Product: Fc1ccc(-c2nn3cc(C(F)(F)F)ccc3c2-c2ccnc(NCCN3CCCC3)n2)cc1

Procedure:
2-Pyrrolidin-1-ylethylamine (0.04 mL) and 4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl methyl sulfone (0.02 g) were mixed at room temperature and heated with an airgun until a homogenous melt was obtained (2 min). Upon cooling, water was added. The precipitated solid was filtered and dried to give the title compound as a beige solid (0.012 g); 1H NMR (CDCl3) δ 8.83(1H, s), 8.51(1H, d), 8.11(1H, d), 7.63(2H, dd), 7.43 (1H, dd), 7.15(2H, dd), 6.33(1H, d), 5.75(1H, bs), 3.58(2H, dt), 2.76(2H, t), 2.58(2H, bt), 1.81(2H, bm); m/z 471 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]([CH3:14])[CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:15][CH2:16][CH2:17][OH:18].[OH-].[Na+]>O>[CH3:13][N:12]([CH3:14])[C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[NH:15][CH2:16][CH2:17][OH:18]
Reactant: CN(C)c1ccc2nccc(Cl)c2c1
Reactant: NCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)c1ccc2nccc(NCCO)c2c1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A mixture of 4-chloro-6-dimethylaminoquinoline 12 (4.92 g, 24 mmol), prepared according to the method described by Riegel et al., J. Am. Chem. Soc., 1946, 68, 1264, and of 2-aminoethanol (43.99 g, 720 mmol) is heated, with magnetic stirring, at 150° C. for 15 min and then at 185° C. for 30 min. After returning to ambient temperature, the solid is suspended in 25 ml of a 10%, w/v, aqueous sodium hydroxide solution and 165 ml of water. The precipitate obtained is filtered through sintered glass, washed with water and then dried under vacuum. The product is obtained in the form of a white powder: 4.86 g (yield=88%).
Reaction SMILES: [NH:1]1[C:9]2[C:5](=[CH:6][C:7]([P:18]([O:23][CH2:24][CH3:25])(=[O:22])[O:19][CH2:20][CH3:21])([P:10]([O:15][CH2:16][CH3:17])(=[O:14])[O:11][CH2:12][CH3:13])[CH:8]=2)[CH:4]=[CH:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].[C:34]([S:37][CH2:38][CH2:39]I)(=[O:36])[CH3:35]>C1COCC1>[C:34]([S:37][CH2:38][CH2:39][C:8]1[C:7]([P:18]([O:23][CH2:24][CH3:25])(=[O:22])[O:19][CH2:20][CH3:21])([P:10]([O:11][CH2:12][CH3:13])(=[O:14])[O:15][CH2:16][CH3:17])[CH:6]=[C:5]2[C:9]=1[NH:1][CH2:2][CH:3]=[CH:4]2)(=[O:36])[CH3:35]
Reactant: CC(=O)SCCI
Reactant: CCOP(=O)(OCC)C1(P(=O)(OCC)OCC)C=C2C=CCNC2=C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C1(P(=O)(OCC)OCC)C=C2C=CCNC2=C1CCSC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of dihydro-1-pyrindine-6,6-bisphosphonic acid, tetraethyl ester (7.0 mmol) [prepared as described in Example A, Part I] in anhydrous THF (100 ml) at -78° C. under argon is added dropwise a pregenerated solution of lithium diisopropyl amide (7.0 mmol) in THF (10 ml). After stirring 30 minutes, to this is added 2-acetylthio-1-iodoethane (7.5 mmol) in THF (25 ml). The reaction mixture is stirred at -78° C. for 5 hours then allowed to warm to room temperature and stirred overnight. The reaction is quenched by the addition of saturated aqueous ammonium chloride and then extracted with diethyl ether. The organic layers are combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The desired product is purified by flash chromatography using a 5-10% isopropanol in methylene chloride gradient on silica gel.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[F:5][C:6]1[CH:11]=[C:10](/[CH:12]=[CH:13]/[N+:14]([O-])=O)[CH:9]=[C:8]([F:17])[C:7]=1[F:18]>C1COCC1>[CH2:1]([NH:4][CH:12]([C:10]1[CH:9]=[C:8]([F:17])[C:7]([F:18])=[C:6]([F:5])[CH:11]=1)[CH2:13][NH2:14])[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: O=[N+]([O-])/C=C/c1cc(F)c(F)c(F)c1
Solvent: C1CCOC1
Product: C=CCNC(CN)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Allylamine (9.8 mL) was added to a solution of 1,2,3-trifluoro-5-((E)-2-nitrovinyl)benzene (6.6 g) in THF (30 mL). The reaction solution was stirred at room temperature for 2.5 hours and then concentrated under reduced pressure. Zinc powder (10.6 g) was added to a solution of the residue in ethanol (35 mL) and concentrated hydrochloric acid (35 mL) at 0° C., and the reaction solution was stirred at 0° C. for 30 minutes and at room temperature for 15 hours. The reaction solution was added to ice-cold aqueous ammonia, and the reaction mixture was subjected to extraction with chloroform. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 7.52 g of a crude product of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[CH3:11])=[O:2].[OH:12][CH2:13][C:14]([NH:16][CH2:17][C@H:18]([OH:33])[CH2:19][O:20][C:21]1[C:26]([CH3:27])=[CH:25][C:24]([C:28](=[NH:31])[NH:29]O)=[CH:23][C:22]=1[CH3:32])=[O:15]>>[CH:1]([C:3]1[S:7][C:6]([C:8]2[O:10][N:31]=[C:28]([C:24]3[CH:23]=[C:22]([CH3:32])[C:21]([O:20][CH2:19][C@@H:18]([OH:33])[CH2:17][NH:16][C:14](=[O:15])[CH2:13][OH:12])=[C:26]([CH3:27])[CH:25]=3)[N:29]=2)=[CH:5][C:4]=1[CH3:11])=[O:2]
Reactant: Cc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Reactant: Cc1cc(C(=O)O)sc1C=O
Product: Cc1cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(C)c3)no2)sc1C=O

Procedure:
The title compound is prepared according to Method A starting from 5-formyl-4-methyl-thiophene-2-carboxylic acid and (S)-2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide; LC-MS*: tR=0.77 min; [M+1]+=445.92.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](C)=[CH:5][C:6]=1[S:7][S:8][C:9]1[CH:13]=[C:12](C)[O:11][C:10]=1[CH3:15]>CCCCCC>[CH3:15][C:10]1[O:11][CH:12]=[CH:13][C:9]=1[S:8][S:7][C:6]1[CH:5]=[CH:4][O:3][C:2]=1[CH3:1]
Reactant: Cc1cc(SSc2cc(C)oc2C)c(C)o1
Solvent: CCCCCC
Product: Cc1occc1SSc1ccoc1C

Procedure:
The thiol produced in Example III is oxidized under mild conditions by dissolving 5 g of the thiol in 100 cc of hexane. The solution is placed in a 250 cc flask equipped with a sparger supplied by an air source, a stirrer, and a heater. Air is bubbled in at room temperature at a rate of 20 ml/minute during 20 hours. Solvent is replaced as required in order to maintain the original volume of solution. At the end of the reaction period the solvent is flash-evaporated and the resulting mixture is purified by column chromatography to yield 3 g of bis(2-methyl-3-furyl) disulfide.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH:52]([CH3:54])[CH3:53])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2].C(N(C(C)C)CC)(C)C.[N+:67]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][C:71]=1[S:76](Cl)(=[O:78])=[O:77])([O-:69])=[O:68]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][S:76]([C:71]3[CH:72]=[CH:73][CH:74]=[CH:75][C:70]=3[N+:67]([O-:69])=[O:68])(=[O:77])=[O:78])[CH:46]([O:51][CH:52]([CH3:54])[CH3:53])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC(C)C)C3)C(C)CCC1=O)C(C)CC2OC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OS(=O)(=O)c4ccccc4[N+](=O)[O-])C(OC(C)C)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 23 h
Yield: 66.9 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-isopropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (158 mg) in dry methylene chloride (3.5 ml) was added an excess of diisopropylethyl amine (82 μl) and o-nitrophenylsulfonyl chloride (87 mg) followed by addition of 4-dimethylaminopyridine (58 mg). The mixture was stirred at room temperature for 23 hours at which time it was diluted with ethyl acetate, extracted from saturated sodium bicarbonate solution and washed with brine. The combined organics were dried over magnesium sulfate and the concentrate purified by flash chromatography on silica gel (ethyl acetate: hexane (1:1)+1% methanol to give the title compound (130 mg).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[F:21][C:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[CH:24][N:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:22]1[CH:27]=[C:26]([C:2]2[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=3)[N:3]=2)[CH:25]=[CH:24][N:23]=1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: OB(O)c1ccnc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccnc(F)c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To a solution of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (300.0 mg, 1.02 mmol) in dioxane (5 mL) was added 2-fluoropyridin-4-ylboronic acid (289.0 mg, 2.06 mmol), K3PO4 (435.0 mg, 2.05 mmol), Pd(PPh3)4 (60 mg, 0.05 mmol) and three drops water under an inert atmosphere of nitrogen. The resulting solution was stirred for 1 h at 90° C. and then quenched by the addition of water (50 mL). The resulting solution was extracted with dichloromethane (5×20 mL) and the organic layers combined, dried over anhydrous magnesium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 1%-5% ethyl acetate in petroleum ether to afford methyl 2-(2-fluoropyridin-4-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a yellow solid (250 mg, 69%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[N:11]=[C:12]([CH3:23])[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:5]=[N:6][CH:7]=1.[Cu][C:30]#[N:31]>CN1CCCC1=O>[C:30]([C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[N:11]=[C:12]([CH3:23])[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:5]=[N:6][CH:7]=1)#[N:31]
Reactant: N#C[Cu]
Reactant: CCOC(=O)CCCCc1c(C)nn2c(CC)ccc2c1-c1cncc(Br)c1
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCCCc1c(C)nn2c(CC)ccc2c1-c1cncc(C#N)c1
Temperature: 170 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
A mixture of ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (167 mg) and copper(I) cyanide (37 mg) in 1-methyl-2-pyrrolidinone (3 mL) was stirred at 170° C. for 4 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1–5:1) to give ethyl 5-[4-(5-cyano-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate as an yellow oil (88 mg).