Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O[CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[O:17][C:16]([C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)(C)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C)C=O>[N:26]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[O:17][C:16]([C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[N+:27]=[N-:28]
Reactant: CS(=O)(=O)OC1CCN(Cc2ccc(C(=O)N3CCCCC3)o2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CCN(Cc2ccc(C(=O)N3CCCCC3)o2)CC1
Temperature: 120 °C
Yield: 65.9 %

Procedure:
In 90 ml of dimethylformamide were dissolved 4.04 g (10.9 mmol) of Compound u and 7.1 g (109.2 mmol) of sodium azide and the solution was heated at 120° C. for 1.5 hours. The reaction mixture was allowed to stand for cooling and, then, the insolubles were filtered off. The filtrate was concentrated under reduced pressure. The residue was diluted with 120 ml of ethyl acetate and washed with 3 portions of saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was purified by silica gel column chromatography (chloroform-methanol=30:1) to give 2.28 g (65.9%) of 1-[5-(4-azidopiperidinomethyl)-2-furancarbonyl]piperidine (Compound v) as light yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:24])[S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:25](O)=[O:26])=[CH:9]2.Cl.C[N:30](C)CCCN=C=NCC.CN(C)C=O>O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:24])[S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:17])=[O:18])[CH:14]=1)[NH:11][C:10]([C:25]([NH2:30])=[O:26])=[CH:9]2
Reactant: CCN=C=NCCCN(C)C
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(N)=O)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.5 %

Procedure:
A mixture of 5-(2-methoxyethoxy)-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (1.05 g), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (590 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (750 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with aqueous citric acid solution, saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated to give the title compound (1.00 g, yield 94%) as colorless crystals. The crystals were recrystallized from acetone-hexane to give colorless prism crystals. melting point 214-215° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35](O)=[O:36])[CH:33]=2)[CH:28]=[CH:27]1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:35]([C:32]4[CH:33]=[C:34]5[C:29]([CH:28]=[CH:27][NH:26]5)=[CH:30][CH:31]=4)=[O:36])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccc5cc[nH]c5c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 1H-indole-6-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1.CS(O)(=O)=O.[CH2:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[OH:1][C:2]1[C:7]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1
Reactant: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Reactant: C=CCCCCCC
Agent: CS(=O)(=O)O
Product: CCCCCCCCc1cc(C)cc(-n2nc3ccccc3n2)c1O

Procedure:
In a flask fitted with an nitrogen blanket, stirrer, reflux condenser and addition funnel, 225 grams of 2-(2-hydroxy-5-methylphenyl)-2H-benzotriazole, 65 ml of methanesulfonic acid and 156 ml of 1-octene are heated at 120° C. for a six-hour period. Throughout said period another 467 ml of 1-octene is added to the reaction mixture. The mixture is then cooled and extracted with two 200 ml portions of methanolic potassium hydroxide solution (40 grams potassium hydroxide in 100 ml of methanol). The extracts are washed with 1×400 ml and then with 4×200 ml of heptane. Water (200 ml) is added to the heptane extracts and the upper heptane layer is separated, washed with 5×200 ml of aqueous methanol (methanol 2:water 1). The washed heptane layer is dried over anhydrous magnesium sulfate and treated with 1×10 grams and then 1×5 grams of an acidic absorbent clay (FILTROL 13). After removal of the clay absorbent, the heptane solution is vacuum stripped at 110° C./2 mm to give 23 grams of the above-named product as a yellow liquid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:13]([CH3:32])[C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C>[OH:3][CH:1]([C:4]1[CH:5]=[C:6]([N:13]([CH3:32])[C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[C:24]([O:30][CH3:31])[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=3)[CH2:18][CH2:17]2)=[O:15])[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])[CH3:2]
Reactant: COc1cc(OC)cc(N2CCN(C(=O)N(C)c3cc(C(C)=O)c(C)nc3OC)CC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(OC)cc(N2CCN(C(=O)N(C)c3cc(C(C)O)c(C)nc3OC)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
1-[N-(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)-N-methylaminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(0.47 mmol) was dissolved in anhydrous ethanol(15 ml) and thereto sodium borohydride(17.3 mg) was added, then followed by stirring at room temperature for 2 hrs. The resulting mixture was concentrated under the reduced pressure to remove ethanol and purified by column chromatography(ethylacetate:hexane=2:1) to obtain the titled compound.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12](Br)[CH:13]=[CH2:14].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[N+:1]([C:4]1[S:8][C:7]([C:9]([O:11][CH2:14][CH:13]=[CH2:12])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C=CCBr
Reactant: O=C(O)c1ccc([N+](=O)[O-])s1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ccc([N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.5 %

Procedure:
To a solution of 5-nitro-2-thiophenecarboxylic acid (20 g, 0.11 mol) in DMF (140 ml) were added sequentially allyl bromide (40 ml, 0.46 mol) and triethylamine (64 ml, 0.46 mol) with cooling to maintain the temperature of the reaction mixture below 30° C. After addition of the reagents, the reaction mixture was stirred for 3 hours at ambient temperature and then diluted with ethyl acetate. The solid which precipitated was filtered off, the filtrate washed with water, washed with saturated aqueous solution of sodium chloride, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel using a mixture of CH2Cl2 --petroleum ether (3:7) as eluent to give the title compound as a white solid (8.8 g, 38%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[CH2:7]2.Cl[C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>>[O:12]=[C:6]1[CH2:5][CH2:4][C:3]2[C:2]([O:1][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:7]1
Reactant: O=C1CCc2c(O)cccc2C1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1ccc(Oc2cccc3c2CCC(=O)C3)nc1
Yield: 52.7 %

Procedure:
Using a method similar to Intermediate 1, using 5-hydroxy-2-tetralone (J. Med. Chem. (1978), 21(9), 913-22) (1.98 g, 12.1 mmol), 6-chloronicotinamide (1.90 g, 12.1 mmol) and K2CO3 (2.52 g, 18.2 mmol) gives the title compound (1.80 g), after purification on silica gel (50% THF/DCM), as an amber foam. Mass spectrum (ion spray): m/z=283 (M+1); 1HNMR (DMSO-d6): 8.55 (s, 1H), 8.24 (d, 1H), 8.00 (s, 1H), 7.46 (s, 1H), 7.25 (d, 2H), 7.08 (m, 2H), 7.00 (d, 1H), 3.64 (s, 2H), 2.77 (t, 2H), 2.34 (t, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>CN(C)C=O.CCOCC>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(COc1ccc([N+](=O)[O-])cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
27.6 g (0.2 mol) of 4-nitrophenol are dissolved in 300 ml of dimethylformamide and, after addition of 27.6 g (0.2 mol) of dried potassium carbonate, the mixture is stirred at room temperature for 45 minutes. Thereafter, 50.4 g (0.22 mol=34.9 ml) of benzyl bromoacetate are added dropwise, while stirring, and the suspension is then heated at 80° C. (oil bath temperature) for 5 hours. The oil bath is then switched off and the suspension is stirred for a further 15 hours, during which the reaction mixture slowly comes to room temperature. The undissolved inorganic salts are filtered off with suction and the mother liquor is concentrated to dryness in vacuo. The residue is dissolved in methylene chloride and, after washing twice with water, the solution is dried over sodium sulphate, filtered and concentrated. The product obtained is suspended in ether and filtered off with suction. Yield: 55.4 g (96.4% of theory).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@@H:4]1[C:26](=[O:27])[N:6]2[C:7]([C:23]([OH:25])=[O:24])=[C:8]([CH2:11][S:12][C:13]3[N:17]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[N:16]=[N:15][N:14]=3)[CH2:9][S:10][C@H:5]12.C([O-])(=O)C.[K+].[CH3:33][CH:34]([CH3:44])[CH2:35][C:36]([O:38][CH:39](I)[CH:40]([CH3:42])[CH3:41])=[O:37].Cl>C(Cl)Cl.CN(C)C=O>[ClH:1].[ClH:1].[NH2:3][C@@H:4]1[C:26](=[O:27])[N:6]2[C:7]([C:23]([O:25][CH:39]([O:38][C:36](=[O:37])[CH2:35][CH:34]([CH3:44])[CH3:33])[CH:40]([CH3:42])[CH3:41])=[O:24])=[C:8]([CH2:11][S:12][C:13]3[N:17]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[N:16]=[N:15][N:14]=3)[CH2:9][S:10][C@H:5]12
Reactant: CC(C)CC(=O)OC(I)C(C)C
Reactant: CN(C)CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)CC(=O)OC(OC(=O)C1=C(CSc2nnnn2CCN(C)C)CS[C@@H]2[C@H](N)C(=O)N12)C(C)C
Temperature: 0 °C
Yield: 106 %

Procedure:
To 60 ml of dimethylformamide solution containing 4.22 g of 7β-amino-3-[[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thio]methyl]ceph-3-em-4-carboxylic acid dihydrochloride is added 1.67 g of potassium acetate. The mixture is cooled to 0° C. With stirring, 5.0 g of 1-iodo-2-methylpropyl 3-methylbutyrate is added dropwise to the solution, followed by stirring at 0° C. for 5 minutes. The reaction mixture is poured into a mixture of 60 ml of methylene chloride and 60 ml of 0.1N-HCl and the aqueous layer is separated. The aqueous solution is adjusted to pH 6.0 with a saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. To the methylene chloride solution is added water and the mixture is adjusted to pH 2.0 with 4N-HCl. The aqueous layer is separated and lyophilized to obtain 3.0 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Br:16])[CH:15]=1)[C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.O.NN>C(O)CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Br:16])[CH:15]=1)[CH2:5][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(c1cccnc1)c1cc(Br)cc(Br)c1
Agent: NN
Solvent: O
Solvent: OCCO
Product: Brc1cc(Br)cc(Cc2cccnc2)c1
Temperature: 80 °C

Procedure:
A solution of 3-(3,5-dibromobenzoyl)pyridine (Preparation 1; 19.0 g) and hydrazine hydrate (13.9 ml) in ethylene glycol (140 ml) was heated under reflux for 45 minutes. The volatile material was distilled off until the internal temperature reached 180° C., and then the reaction mixture was cooled to 80° C. Potassium hydroxide (7.80 g) was added and the resulting solution was heated under reflux for 30 minutes, cooled and then poured into water. The mixture was extracted several times with ethyl acetate, and the combined extracts were washed with water and dried (MgSO4). Evaporation under vacuum gave the title compound (16.38 g), m.p. 70°-72° C. (after crystallisation from ethyl acetate-hexane). Found: C,44.29; H,2.66; N,4.29. C12H9Br2N requires C,44.07; H,2.77; N,4.28%.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]1=[O:29].[OH-].[Na+]>>[O:29]=[C:15]1[N:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:30])=[O:2])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)CCCCCCCCCCn1c(=O)n(-c2ccccc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCCCCn1c(=O)n(-c2ccccc2)c2ccccc21

Procedure:
The product is produced as described in example 22 from 11 g. of 11-(2-oxo-3-phenyl-benzimidazolin-1-yl)-undecanoic acid methyl ester and 1.2 g. of NaOH.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2([CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C1C(=O)N([Br:42])C(=O)C1>>[Br:42][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3([CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH2:24][CH2:25]3)=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C2(CNC(=O)OC(C)(C)C)CC2)cc1
Reactant: O=C1CCC(=O)N1Br
Product: COc1cc(Br)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C2(CNC(=O)OC(C)(C)C)CC2)cc1
Yield: 54.2 %

Procedure:
Following General Procedure I, tert-butyl (1-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)cyclopropyl)methylcarbamate (750 mg, 1.57 mmol) was reacted with NBS (280 mg, 1.57 mmol)) to afford the desired product (473 mg, 54%) as a yellow solid: ESI MS m/z 555 [C27H27BrN2O4S+H]+.
Reaction SMILES: CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C.[C:20]([O:24][C:25]([NH:27][CH2:28][C:29]1[NH:40][C:32]2=[N:33][CH:34]=[C:35]([C:37]([OH:39])=O)[CH:36]=[C:31]2[N:30]=1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C1C=CC2N(O)N=NC=2C=1.[F:51][C:52]([F:56])([F:55])[CH2:53][NH2:54].CCN(C(C)C)C(C)C.C(Cl)CCl>>[C:20]([O:24][C:25](=[O:26])[NH:27][CH2:28][C:29]1[NH:40][C:32]2=[N:33][CH:34]=[C:35]([C:37]([NH:54][CH2:53][C:52]([F:56])([F:55])[F:51])=[O:39])[CH:36]=[C:31]2[N:30]=1)([CH3:21])([CH3:22])[CH3:23]
Reactant: NCC(F)(F)F
Reactant: CC(C)(C)OC(=O)NCc1nc2cc(C(=O)O)cnc2[nH]1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCc1nc2cc(C(=O)NCC(F)(F)F)cnc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
To a DMF 3 mL solution of 2-{[(tert-butoxycarbonyl)amino]methyl}-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (293 mg, 1.0 mmol) were added HOBt (162 mg, 1.2 mmol), 2,2,2-trifluoroethanamine (130 mg, 1.5 mmol), DIPEA (388 mg, 3.0 mmol) and EDC (288 mg, 1.5 mmol). The reaction mixture was stirred at room temperature overnight and was partitioned between EtOAc and water. The organic layer was washed with brine twice, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep TLC (MeOH/CH2Cl2=1/10, v/v) to give the title compound (0.26 g, 70%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].CCN(CC)CC.[Na+].[Cl-]>C(Cl)Cl>[CH3:24][S:25]([O:1][CH2:2][CH2:3][C@@H:4]([NH:16][C:17]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:23])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CCO)Cc1ccc(C(F)(F)F)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](CCOS(C)(=O)=O)Cc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
(S)-tert-Butyl 4-hydroxy-1-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate was dissolved in 60 mL DCM and cooled to 0° C. MsCl (773 mL, 10 mmol) and Et3N (1.67 mL, 12 mmol) were added and the reaction was stirred for 1.5 hours at 0° C. NaCl (saturated, aqueous) was added, and the mixture was extracted with DCM (3×100 mL), dried over MgSO4 and evaporated. The title compound was obtained as an off-white solid and used without further purification in the next step. LCMS (API-ES) m/z (%): 411.1 (100%, M++H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.FC1C=CC([N+]([O-])=O)=CC=1.[F:29][C:30]([F:40])([F:39])C1C=CC(CO)=CC=1>CO>[F:29][C:30]([F:40])([F:39])[C:18]1[CH:17]=[CH:16][C:4]([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)cc1
Agent: O=[N+]([O-])c1ccc(F)cc1
Solvent: CO
Product: O=[N+]([O-])c1ccc(OCc2ccc(C(F)(F)F)cc2)cc1

Procedure:
Prepared in analogy to 1-(3-fluorobenzyloxy)-4-nitro-benzene, starting from 4-fluoro nitrobenzene and 4-trifluoromethyl benzyl alcohol. Yield after recristallisation from methanol: 82% of a brownish solid. Mp=80.5-81.5° C.
Reaction SMILES: [NH:1]([CH2:7][CH2:8][CH2:9][C:10]#[N:11])[CH2:2][CH2:3][CH2:4][C:5]#[N:6].C(N(CC)CC)C.[CH2:19]([O:21][P:22](Cl)([O:24][CH2:25][CH3:26])=[O:23])[CH3:20]>ClCCl>[CH2:19]([O:21][P:22]([N:1]([CH2:2][CH2:3][CH2:4][C:5]#[N:6])[CH2:7][CH2:8][CH2:9][C:10]#[N:11])([O:24][CH2:25][CH3:26])=[O:23])[CH3:20]
Reactant: CCOP(=O)(Cl)OCC
Reactant: N#CCCCNCCCC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)N(CCCC#N)CCCC#N
Yield: 75 %

Procedure:
3,3′-Iminodipropyl cyanide (50 mmol) was dissolved in dichloromethane (100 ml). To the system was added triethylamine (10 ml), and then dropwise added at room temperature diethoxyphosphoryl chloride (50 mmol) in dicholormethane (60 ml) solution. The mixture was allowed to react at room temperature over night. The resultant was concentrated and performed to column chromatography (eluant: dichloromethane/methanol system) to obtain 9.7 g of a colorless transparent oily substance, yield 75%, MS[M]+=259.2 m/e.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:8]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]3[N:18]=[C:19]([NH:22][CH2:23][CH3:24])[N:20]=[CH:21][C:10]=3[C:9]2=[O:25])[CH:7]=1.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.O.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[CH2:23]([NH:22][C:19]1[N:20]=[CH:21][C:10]2[C:9](=[O:25])[N:8]([C:6]3[CH:7]=[C:2]([C:29]4[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=4)[CH:3]=[N:4][CH:5]=3)[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]=2[N:18]=1)[CH3:24]
Reactant: OB(O)c1ccncc1
Reactant: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cncc(Br)c1)C2=O
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cncc(-c3ccncc3)c1)C2=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 57.9 %

Procedure:
Compound 21 (80.0 mg, 0.198 mmol) obtained in Example 21 was dissolved in 1,4-dioxane/water=4/1 (5 mL), and the mixture was stirred at 80° C. for 2 hours after adding 4-pyridineboronic acid (73.0 mg, 0.595 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl2(dppf); 16.0 mg, 0.0198 mmol), and sodium carbonate (63.0 mg, 0.595 mmol). The reaction mixture was diluted by addition of ethyl acetate. Then, the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained upon concentration under reduced pressure was then purified by preparative TLC to give the title compound (Compound 22) (46.0 mg, 58%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([CH:16]([F:18])[CH3:17])[C:10]=2[F:19])[N:5]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:3]=1[Cl:24].Cl[C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[C:28](F)[C:27]=1C(F)C.NC1C(F)=C(Cl)N=C(C(OC)=O)C=1Cl.[F-].[Cs+].P(C1C=C(S([O-])(=O)=O)C=CC=1)(C1C=C(S([O-])(=O)=O)C=CC=1)C1C=C(S([O-])(=O)=O)C=CC=1.[Na+].[Na+].[Na+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(#N)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([CH:16]([F:18])[CH3:17])[C:10]=2[F:19])[N:5]=[C:4]([C:20]([O:22][CH2:23][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:21])[C:3]=1[Cl:24].[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([CH:16]([F:18])[CH3:17])[C:10]=2[F:19])[N:5]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:3]=1[Cl:24]
Reactant: CC(F)c1c(Cl)ccc(B2OC(C)(C)C(C)(C)O2)c1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COC(=O)c1nc(-c2ccc(Cl)c(C(C)F)c2F)c(F)c(N)c1Cl
Solvent: CC#N
Solvent: O
Product: CC(F)c1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)c(Cl)c(N)c2F)c1F
Temperature: 150 °C

Procedure:
Methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-(1-fluoroethyl)phenyl)-5-fluoropicolinate (Compound H). 2-(4-Chloro-2-fluoro-3-(1-fluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (510 mg, 1.7 mmol, 1.0 equivalent (equiv)) and methyl 4-amino-3,6-dichloro-5-fluoropicolinate (prepared by the methods described in U.S. Pat. No. 6,784,137 B2; 400 mg, 1.7 mmol, 1.0 equiv) were sequentially added to a 5 mL Biotage microwave vessel, followed by cesium fluoride (CsF; 510 mg, 3.3 mmol, 2.0 equiv), palladium(II) acetate (19 mg, 0.084 mmol, 0.05 equiv), and sodium 3,3′,3″-phosphinetriyltribenzenesulfonate (95 mg, 0.17 mmol, 0.10 equiv). A 3:1 mixture of water-acetonitrile (3.2 mL) was added and the resulting brown mixture was heated in a benchtop microwave at 150° C. for 5 min. The cooled reaction mixture was diluted with water (150 mL) and extracted with CH2Cl2 (4×50 mL). The combined organic extracts were dried with magnesium sulfate (MgSO4), gravity filtered, and concentrated by rotary evaporation. The residue was purified by reverse phase column chromatography (eluting with a 5% acetonitrile to 100% acetonitrile gradient) to afford the desired product, methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-(1-fluoroethyl)phenyl)-5-fluoropicolinate as a tan semisolid (220 mg, 35%): IR (thin film) 3475 (w), 3353 (m), 3204 (w), 3001 (w), 2955 (w), 1738 (s), 1711 (s), 1624 (s) cm−1; 1H NMR (300 MHz, CDCl3) δ 7.50 (m, 1H), 7.30 (m, 1H), 7.21 (d, J=2 Hz, 1H), 6.16 (dq, J=46, 7 Hz, 1H), 4.96 (br s, 2H), 3.97 (s, 3H), 1.75 (dd, J=23, 7 Hz, 3H); ESIMS m/z 379 ([M+H]+).