Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([Cl:14])=[C:8]2[C:3]=1[CH:4]=[C:5]([C:19]([O:21]CC)=[O:20])[CH:6]([C:15]([F:18])([F:17])[F:16])[O:7]2.C1COCC1.CCO.O[Li].O>O>[Cl:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([Cl:14])=[C:8]2[C:3]=1[CH:4]=[C:5]([C:19]([OH:21])=[O:20])[CH:6]([C:15]([F:17])([F:18])[F:16])[O:7]2
Reactant: CCOC(=O)C1=Cc2c(Cl)c(OC)cc(Cl)c2OC1C(F)(F)F
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(Cl)c2c(c1Cl)C=C(C(=O)O)C(C(F)(F)F)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
To a solution of the ester from Step 1 (0.174 g, 0.469 mmole) in a 7:2:1 THF:EtOH:H2O mixture (10 mL) was added LiOH.H2O (29.5 mg (0.704 mmole). The mixture was stirred at room temperature overnight and the solvent was removed in vacuo. The residue was redissolved in H2O, filtered (0.45 □ PTFE) and acidified with 1 N HCl. The resulting solid was filtered, washed with H2O and dried in vacuo to give 134 mg (83% yield) of the product as an yellow solid: ESHRMS m/z 340.9607 (M−H, C12H6C12F3O4, Calc'd 340.9590). 1H NMR (dmso-d6, 300 MHz) 13.70 (brs, 1H), 7.90 (s, 1H), 7.41 (s, 1H), 6.10 (q, 1H, J=7.1 Hz), 3.86 (s, 3H).
Reaction SMILES: CSC.B.[Br:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](O)=[O:15])=[CH:9][CH:8]=1.CO>C1COCC1>[Br:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=1
Reactant: O=C(O)Cc1ccc(CBr)cc1
Agent: B
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: OCCc1ccc(CBr)cc1
Reaction time: 1 h

Procedure:
Borane dimethylsulphide complex (2M in THF, 4.37 mL) was added dropwise to a solution of 2-(4-(bromomethyl)phenyl)acetic acid (1.0 g) in THF (20 mL) at 20° C. and the mixture stirred for 1 hour. Methanol was added dropwise until bubbling ceased and the solvent evaporated in vacuo. Purification was by silica gel chromatography eluting with 30% ethyl acetate in isohexane. The fractions containing product were combined and evaporated in vacuo to give the subtitled compound as a white crystalline solid. Yield 0.86 g.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7]([OH:19])[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1.[N+:21]([C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22]>>[CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7]([OH:19])[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1.[N+:21]([C:24]1[CH:25]=[C:26]([NH:30][C:31]([O-:8])=[O:32])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22]
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Agent: C[C@H]1[C@@H](O)O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Product: O=C([O-])Nc1cccc([N+](=O)[O-])c1

Procedure:
The title compound was similarly prepared from dihydroqinghaosu and m-nitrophenyl isocyanate as Example 3.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14](Br)=[CH:15][CH:16]=2)[CH2:11][C@H:10]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:15][CH:16]=2)[CH2:11][C@H:10]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(N[C@H]1Cc2cc(Br)ccc2N(Cc2ccccc2)C1)c1ccccc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: O=S(=O)(N[C@H]1Cc2cc(-c3ccccc3)ccc2N(Cc2ccccc2)C1)c1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
The title compound was also prepared using the following procedures: To a solution of 87C (510 mg, 1.11 mmol) in THF/MeOH (2:1, 15 mL) was added phenylboronic acid (272 mg, 2.22 mmol), followed by K2CO3 (613 mg, 4.44 mmol) and PXPd (30 mg, 0.056 mmol). The reaction mixture was stirred at 60° C. for 2 h, then additional amount of phenylboronic acid (54 mg, 0.44 mmol) and PXPd (16 mg, 0.028 mmol) were added. After 2 h at 60° C., same amount of phenylboronic acid and PXPd were added again to the reaction mixture to push completion of the reaction. After stirring at 60° C. for one more hour, the reaction was allowed to cool to RT and concentrated. The residue was partitioned between water and CH2Cl2, and the aqueous phase extracted with CH2Cl2 (50 mL×2). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was purified using chromatography (silica gel) eluting with EtOAc/hexane (0-60%) to afford the title compound (260 mg, 51%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]=[CH:10][N:9]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)CCCCCCCBr
Reactant: Brc1ccc(-c2nc[nH]c2-c2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCCCCCn1cnc(-c2ccc(Br)cc2)c1-c1ccc(Br)cc1
Yield: 71.2 %

Procedure:
4,5-Di-(4-bromophenyl)imidazole (2.13 g) was treated with ethyl 8-bromooctanoate (2 g) and K2CO3 (0.5 g) in 2-butanone as described in Example 9 to give ethyl 8-(4,5-di-(4-bromophenyl)imidazol-1-yl)-octanoate (2.2 g, 52%) as a pale yellow oil.; Found: C, 55.13; H, 5.19; N, 5.18; Br; 8.76%; C28H28Br2N2O2 requires: C, 54.76; H, 5.15; N, 5.11; Br, 29.15%
Reaction SMILES: [CH2:1]([Sn:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]>C1(C)C=CC=CC=1>[CH2:1]([SnH:5]([CH2:6][CH2:7][CH2:8][CH3:9])[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](=O)CCCC
Reactant: OCCCCCCO
Solvent: Cc1ccccc1
Product: CCCC[SnH](CCCC)OCCCCCCO
Reaction time: 6.5 h
Yield: 87 %

Procedure:
1 g (4.02 mmol) of dibutyltin oxide and 0.4747 g (4.02 mmol) of 1,6-hexanediol were introduced into a 100 ml reaction vessel equipped with a Dean-Stark device, and the atmosphere in the reaction vessel was replaced by argon. 70 ml of toluene was added, and the mixture was dehydrated by azeotropic distillation at 135° C. and stirred for 6.5 hours during which it became an uniform solution. After left overnight at room temperature, the precipitated white solids were filtered. The white solids were dried at 50° C. for 5 hours in vaccuo to give a 1,1-dibutylstanna-2,9-dioxanonane oligomer, 1.22 g (87.0% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][C:8]1=[O:16]>C(O)C>[OH:7][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][C:8]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:16]
Reactant: O=C1Cc2ccccc2O1
Reactant: C1COCCN1
Solvent: CCO
Product: O=C(Cc1ccccc1O)N1CCOCC1
Reaction time: 1 h
Yield: 90.9 %

Procedure:
27.3 g of morpholine are added in a single portion to a solution of 30 g of 2,3-dihydro-2-benzofuranone in 100 ml of ethanol, and the medium is stirred for 1 hour. The solvent is evaporated off under vacuum, the residual gum is taken up in isopropyl ether in the hot state and the medium is allowed to return to room temperature. The crystallized product is filtered, washed with isopropyl ether and dried. 45 g of white crystallized product are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[NH:8][N:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].[Cl:21][C:22]1[CH:31]=[CH:30][C:25]([CH:26]=[CH:27][CH2:28]Cl)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:31]=[CH:30][C:25]([CH:26]=[CH:27][CH2:28][N:8]2[C:7](=[O:20])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)=[N:9]2)=[CH:24][CH:23]=1
Reactant: ClCC=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Product: CCOC(=O)c1cc(-c2ccc(OC)cc2)nn(CC=Cc2ccc(Cl)cc2)c1=O
Yield: 85.7 %

Procedure:
Using 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and 4-chlorocinnamyl chloride as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 85.7%.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=2)[N:3]=1.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].CCN(CC)CC.C([O-])(O)=O.[Na+]>C1COCC1.CN(C=O)C>[C:35]([O:34][C:33]([NH:32][C@H:27]1[CH2:28][CH2:29][CH2:30][CH2:31][C@H:26]1[NH:25][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=2)[N:3]=1)=[O:39])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1Nc1cccc(S(C)(=O)=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1c(C#N)cc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc(S(C)(=O)=O)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 75.3 %

Procedure:
A mixture of methyl 6-chloro-4-cyano-2-(3-(methylsulfonyl)phenylamino)nicotinate (162.8 mg, 0.445 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (111.6 mg, 0.521 mmol) and Et3N (0.1 mL, 0.717 mmol) in THF (6 mL) and DMF (6.00 mL) was stirred at 60° C. for 12 h. After the mixture was cooled, saturated aq NaHCO3 (30 mL) was added and the mixture was extracted with EtOAc (2×30 mL). The organic layers were washed with saturated aq NaHCO3 (15 mL), water (15 mL) and brine (15 mL), were dried over anhydrous Na2SO4, and filtered through SiO2. The filtrate was concentrated under reduced pressure and the residue was washed with IPE to give the title compound as a yellow solid (182.2 mg, 75%). 1H-NMR (CDCl3) δ ppm 1.42-1.67 (m, 15H), 1.84-1.91 (m, 2H), 3.07 (s, 3H), 3.95-3.97 (m, 4H), 4.16-4.17 (m, 1H), 4.77 (s, 1H), 6.24 (s, 1H), 7.48-7.51 (m, 1H), 7.58-7.61 (m, 1H), 7.77-7.78 (m, 1H), 8.41 (s, 1H), 10.99 (s, 1H), 1H not detected.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:12][CH:13]=1)([O-])=O.O.C(=O)(O)[O-].[Na+]>C(O)C>[C:14]1([C:11]2[S:12][CH:13]=[C:9]([CH2:8][O:7][C:6]3[CH:5]=[C:4]([NH2:1])[CH:22]=[CH:21][CH:20]=3)[N:10]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1cccc(OCc2csc(-c3ccccc3)n2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cccc(OCc2csc(-c3ccccc3)n2)c1
Yield: 85 %

Procedure:
A solution of 16.0 g (0.05 mol) of 4-[(3-nitrophenoxy)methyl-2-phenylthiazole and 56.5 g (0.25 mol) of stannous chloride dihydrate in 300 ml of absolute ethanol is heated to reflux for 20 hours. The mixture is poured into 2 L of water and made alkaline by the addition of solid sodium bicarbonate. The mixture is extracted twice with 1 L of ethyl acetate. The combined ethyl acetate layers are washed twice with dilute aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain 12.0 g (85%) of an oil, which solidifies. The crystals, m.p. 75°-80° C., MS (CI) 283 (M+H), are used without further purification in subsequent reactions.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[C:13]([C:14](OCC)=[O:15])=[CH:12][N:11]=[C:10]([Cl:19])[CH:9]=1>C1COCC1>[NH2:7][C:8]1[CH:9]=[C:10]([Cl:19])[N:11]=[CH:12][C:13]=1[CH2:14][OH:15]
Reactant: CCOC(=O)c1cnc(Cl)cc1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1cc(Cl)ncc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
Treat a 0° C. suspension of lithium aluminum hydride (5.7 g, 150 mmol) in THF (150 mL), under N2, drop-wise with a solution of ethyl 4-amino-6-chloronicotinate (15 g, 75 mmol) in THF (50 mL), allow to warm to RT and stir for 3 h. Quench the mixture with 10% NaOH (5.7 mL), then water (5.7 mL), filter to remove solids, add water to the filtrate and extract with EtOAc (3×). Wash the combined organics with brine, dry and concentrate to give the title compound (10 g, 84%). 1H NMR (300 MHz, DMSO-d6): δ 7.79 (s, 1H), 6.53 (s, 1H), 6.17 (s, 2H), 5.10 (t, J=5.4 Hz, 1H), 4.36 (d, J=5.4 Hz, 2H).
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(Cl)(=O)C([Cl:28])=O>C(Cl)(Cl)Cl.CN(C)C=O>[CH2:1]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([Cl:28])=[O:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.4 %

Procedure:
A mixture of 50 g of p-(tetradecyloxy)benzoic acid and 28.46 g of oxalyl chloride in 500 ml of chloroform containing 10 drops of N,N-dimethylformamide is stirred for 18 hours at ambient temperature. The solvent is evaporated and the residue dissolved in ether, filtered and evaporated to give 54 g of the desired product as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:33][C:32](=[O:34])[NH:31][S:30]1(=[O:36])=[O:35])[CH2:12][CH:13]1[NH:19][C:18](=[O:20])[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[NH:15][C:14]1=[O:25])C1C=CC=CC=1>C(O)C.C(O)(=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:33][C:32](=[O:34])[NH:31][S:30]1(=[O:36])=[O:35])[CH2:12][CH:13]1[NH:19][C:18](=[O:20])[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[NH:15][C:14]1=[O:25]
Reactant: O=C1CN(c2ccc(CC3NC(=O)c4ccccc4NC3=O)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1CN(c2ccc(CC3NC(=O)c4ccccc4NC3=O)cc2O)S(=O)(=O)N1
Reaction time: 0.13 h

Procedure:
A solution of 3-[3-benzyloxy-4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-benzyl]-3,4-dihydro-1H-benzo[1,4]diazepine-2,5-dione (452 mg, 0.89 mmol) in ethanol-acetic acid (2:1, 12 mL) is hydrogenated over 10% palladium on charcoal catalyst (106 mg) at 50 psi for 24 h. The catalyst is filtered and the filtrate is evaporated to dryness. The residue is purified by LC-MS, on a Gilson-Micromass instrument using a Phenominex Luna, 5μ, 60×21.2 mm, C-8 column, a gradient of 5% to 100% over 8 min with solvent A (water, 0.1% trifluoroacetic acid) and B (MeCN, 0.1% trifluoroacetic acid) with flow rate 20 mL/min, UV detector at 215 nm and cone voltage setting at 30 V. The purification is conducted with several runs with 50 mg of crude material being used in each run (approximately 16 runs). Pure fractions are pooled and evaporated to dryness, the residue is dissolved in water-MeCN and the solution is filtered and the filtrate is concentrated to give 3-[3-hydroxy-4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-benzyl]-3,4-dihydro-1H-benzo[1,4]diazepine-2,5-dione as an amorphous solid: mp=180° C.; [M+1]+=417.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([NH:14][CH3:15])[N:11]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:9]=2)[CH:5]=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C.[CH3:35][N:36]1[C:40]([C:41]#[C:42][Si](C)(C)C)=[CH:39][N:38]=[CH:37]1>COCCOC.CCOC(C)=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.[Cu]I>[CH3:15][NH:14][C:12]1[N:11]=[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:9]=[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([C:42]#[C:41][C:40]3[N:36]([CH3:35])[CH:37]=[N:38][CH:39]=3)[CH:3]=2)[CH:13]=1
Reactant: CNc1cc(-c2cncc(Br)c2)cc(-c2ccccn2)n1
Reactant: Cn1cncc1C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CNc1cc(-c2cncc(C#Cc3cncn3C)c2)cc(-c2ccccn2)n1

Procedure:
To a solution of (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine (Example 2.1, step1) (1 eq, 0.147 mmol, 0.050 g) in DME (1 ml) is added potassium carbonate (1 eq, 0.147 mmol, 0.020 g), tetrakis(triphenylphosphine)palladium(0) (0.1 eq, 0.015 mmol, 17 mg), triethylamine (2 eq, 0.293 mmol, 0.041 ml) and 1-methyl-5-((trimethylsilyl)ethynyl)-1H-imidazole (1 eq, 0.147 mmol, 26.1 mg), followed by Copper (I) iodide (0.5 eq, 0.073 mmol, 14 mg). The reaction mixture is heated using microwave radiation at 70° C. for 2 hrs. The reaction mixture is dissolved in EtOAc and washed with water. The organic layer is washed with brine, dried over drying agent MgSO4, filtered and the organic solvent is reduced in vacuo. The crude residue is purified by reverse phase column chromatography (Isolute™ C18, 0-50% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 367.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][CH2:32][NH2:33])[C:6]=2[CH:34]=1.C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43].O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][CH2:32][NH:33][C:42](=[O:44])[CH3:43])[C:6]=2[CH:34]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCCN)c3cc(Cl)ccc32)cn1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCOC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)nc2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-chloro-5-(2-aminoethoxyl)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.14 g) in dichloromethane (5 ml) are added with stirring triethylamine (0.08 ml) and acetyl chloride (0.03 ml) under ice-cooling. The mixture is stirred at room temperature for 30 minutes, and thereto is added water, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-acetylaminoethoxy)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (85 mg) as colorless amorphous.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([N:11]2[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]2[CH3:17])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1>[CH3:17][C:12]1[N:11]([C:5]2[C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[C:3]([C:18]([F:21])([F:20])[F:19])[CH:4]=2)[C:15]([CH3:16])=[CH:14][CH:13]=1
Reactant: C1CCNC1
Reactant: Cc1ccc(C)n1-c1cc(C(F)(F)F)c(Br)nc1C(=O)O
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(C(F)(F)F)c(N2CCCC2)nc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 6-bromo-3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-(trifluoromethyl) picolinic acid (300 mg, 0.826 mmol) in THF (1 ml), pyrrolidine (0.136 ml, 1.652 mmol) was added. The orange solution was stirred at RT overnight. The reaction mixture was partitioned between 0.5M HCl (30 ml) and EtOAc (30 ml) and shaken. The organic portion was separated and washed with brine (30 ml), dried over MgSO4, filtered and concentrated in vacuo to give a red oil. The crude product was purified on silica eluting with 0-40% EtOAc in iso-hexane to afford the title product;
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[C:22]([CH3:27])=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29]([OH:31])=[O:30])C1C=CC=CC=1.C1(S(NCC2N(C)C(C(O)=O)=C(O)C(=O)C=2)(=O)=O)C=CC=CC=1>>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[C:22]([CH3:27])=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:19])=[O:20])[N:11]([CH3:28])[C:10]=1[C:29]([OH:31])=[O:30]
Reactant: Cc1ccccc1S(=O)(=O)NCc1cc(=O)c(OCc2ccccc2)c(C(=O)O)n1C
Agent: Cn1c(CNS(=O)(=O)c2ccccc2)cc(=O)c(O)c1C(=O)O
Product: Cc1ccccc1S(=O)(=O)NCc1cc(=O)c(O)c(C(=O)O)n1C
Yield: 9.4 %

Procedure:
3-Hydroxy-1-methyl-4-oxo-6-[(toluene-2-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid (30.0 mg, 9.41%, purified by Prep-HPLC) was synthesized as an off white solid from 3-benzyloxy-1-methyl-4-oxo-6-[(toluene-2-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid (13-02) (400.0 mg, 0.905 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (14-02).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].C([N+]1C=CC=CC=1)CCCCCCCCCCC.[C:24]([O:28][C:29]([NH:31][C@@H:32]1[CH2:37][C@@H:36]([C:38]([N:40]([CH3:42])[CH3:41])=[O:39])[CH2:35][CH2:34][C@H:33]1CS([O-])(=O)=O)=[O:30])([CH3:27])([CH3:26])[CH3:25].O>CN(C)C(=O)C.C(OCC)(=O)C>[C:24]([O:28][C:29](=[O:30])[NH:31][C@@H:32]1[CH2:37][C@@H:36]([C:38]([N:40]([CH3:41])[CH3:42])=[O:39])[CH2:35][CH2:34][C@H:33]1[N:1]=[N+:2]=[N-:3])([CH3:27])([CH3:26])[CH3:25]
Reactant: CN(C)C(=O)[C@H]1CC[C@@H](CS(=O)(=O)[O-])[C@H](NC(=O)OC(C)(C)C)C1
Reactant: [N-]=[N+]=[N-]
Agent: CCCCCCCCCCCC[n+]1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)C(=O)[C@H]1CC[C@@H](N=[N+]=[N-])[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
Sodium azide (7.14 g) and dodecylpyridinium chloride (7.80 g) were added at room temperature to a solution (40 mL) of (1R,2R,4S)-2-[(t-butoxycarbonyl)amino]-4-[(dimethylamino)carbonyl]cyclohexylmethanesulfonate (20.0 g) in N,N-dimethylacetamide (DMAC), followed by stirring at 60° C. for 72 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was washed with aqueous saturated sodium bicarbonate solution and water. The solvent was evaporated under reduced pressure, and a solvent mixture (300 mL) of n-hexane and ethyl acetate (5:1) was added to the residue. The mixture was stirred at room temperature for 1 hour, and the formed crystals were recovered by filtration. A solvent mixture (300 mL) of n-hexane and ethyl acetate (5:1) was added to the recovered crystals, followed by stirring/recovering by filtration twice, to thereby yield 4.6 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.Cl[CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[O:27]1[CH2:28][CH2:29][CH:24]([N:18]2[CH2:19][CH2:20][N:15]([C:12]3[CH:11]=[CH:10][C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:8][CH:7]=4)=[CH:14][N:13]=3)[CH2:16][CH2:17]2)[CH2:25][CH2:26]1
Reactant: ClC1CCOCC1
Reactant: FC(F)(F)c1ccc(-c2ccc(N3CCNCC3)nc2)cc1
Product: FC(F)(F)c1ccc(-c2ccc(N3CCN(C4CCOCC4)CC3)nc2)cc1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 57, starting from 4-(5-(4-trifluoromethylphenyl)pyridin-2-yl)piperazine and 4-chloro-tetrahydropyran.