Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][S:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:20](Cl)(=[O:22])[CH3:21].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][S:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([NH:17][C:20](=[O:22])[CH3:21])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccc2oc(SCc3ccc(Cl)cc3)nc2c1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2oc(SCc3ccc(Cl)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.1 %

Procedure:
To a solution of 2-(4-chlorobenzylthio)benzo[d]oxazol-5-amine (87 mg, 0.30 mmol) in dry pyridine (3 mL) at room temperature was added acetyl chloride (21 μL, 0.30 mmol). The resulting solution was stirred at room temperature for 16 h. Water was then added, the precipitate was collected by filtration, washed with diluted aqueous hydrochloric acid and then with water. Trituration with diethyl ether afforded 40 mg (40%) of the title compound (LCMS RT=6.40 min, MH+ 333.1)
Reaction SMILES: C=O.[C:3]([BH3-])#N.[Na+].[CH2:7]([NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:33])[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[N:31][CH:30]=[N:29]3)=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O)(=O)C>CO>[CH3:3][N:14]([CH:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:33])[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[N:31][CH:30]=[N:29]3)=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [BH3-]C#N
Reactant: O=C(c1ccc(-n2cncn2)cc1)N1CCC(NCc2ccccc2)CC1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(Cc1ccccc1)C1CCN(C(=O)c2ccc(-n3cncn3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.9 %

Procedure:
0.7 ml of a 37% aqueous formaldehyde solution and 0.21 g of sodium cyanoborohydride were added to 30 ml of a solution of 0.82 g of 4-benzylamino-1-[4-(1,2,4-triazol-1-yl)benzoyl]piperidine in methanol, under ice-cooling. To the mixture was dropwise added 0.7 ml of acetic acid. The mixture was stirred at room temperature for 1 hour and then subjected to distillation to remove the solvent. The residue was extracted with methylene chloride. The extract was washed with a 1N aqueous sodium hydroxide solution and water, dried with anhydrous magnesium sulfate, and then concentrated. The residue was purified by a silica gel column chromatography (eluant: methylene chloride/methanol=50/1), followed by recrystallization from methylene chloride-diethyl ether to obtain 0.28 g of 4-(N-methyl-N-benzylamino)-1-[4-(1,2,4-triazol-1-yl)benzoyl]piperidine as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH2:17])=[O:16])[CH2:10][CH2:9]2)=[C:4]([N+:18]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>C1COCC1.O.[Zn]>[NH2:18][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH2:17])=[O:16])[CH2:10][CH2:9]1
Reactant: NC(=O)CN1CCN(c2ccc(Br)cc2[N+](=O)[O-])CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)CN1CCN(c2ccc(Br)cc2N)CC1
Yield: 93.2 %

Procedure:
Using similar reaction conditions as described in step ii of Intermediate-27, 2-(4-(4-bromo-2-nitrophenyl)piperazin-1-yl)acetamide (600 mg, 1.74 mmol) was reduced using zinc dust (568 mg, 8.74 mmol) and ammonium chloride (461 mg, 8.74 mmol) in THF/water 10/10 ml to afford 508 mg (93% yield) of the titled product.
Reaction SMILES: [ClH:1].[N:2]1([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1>Cl>[ClH:1].[N:2]1([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(CN2CCCC2)cc1
Agent: Cl
Product: O=C(O)c1ccc(CN2CCCC2)cc1
Yield: 58.1 %

Procedure:
A solution of methyl 4-(1-pyrrolidinylmethyl)benzoate hydrochloride (3.18 g, 12.4 mmol) in 6N hydrochloric acid (30 ml) was stirred at 100° C. for 16 hrs. The solvent was evaporated under reduced pressure, and the residue was powderized with tetrahydrofuran to give the title compound (1.74 g).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([N:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)[CH2:16][CH:15]([C:29]([O:31]C)=[O:30])[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+]>>[O:4]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([N:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:21][CH:20]=4)[CH2:16][CH:15]([C:29]([OH:31])=[O:30])[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: COC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC3(CC2)OCCO3)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC3(CC2)OCCO3)C1

Procedure:
5.15 g (11.3 mmol) of the compound from Example 59A and 12.7 g (113 mmol) of potassium tert-butoxide were reacted according to the General Method 7A. Yield: 5.00 g (99% of theory)
Reaction SMILES: [C:1](=[O:5])([O:3][CH3:4])[NH2:2].S(=O)(=O)(O)O.[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([CH3:22])=[CH2:21])[CH:15]=1)=[CH2:13].C(=O)([O-])[O-].[Na+].[Na+].CCCCCCCCCCCCCCCC.CCCCCCCCCCCCCCCCCCCCC.[N-]=C=O.[N-]=C=O.CC(C)C1C=CC=C(C(C)C)C=1.[N-]=C=O.C(C1C(C)=C(C)C=CC=1)(C)=C>>[N-:2]=[C:1]=[O:3].[NH2:2][C:1]([O:3][CH2:4][CH3:11])=[O:5].[CH3:21][CH:20]([CH3:22])[C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:12]([CH3:13])[CH3:11])[CH:15]=1
Reactant: C=C(C)c1cccc(C(=C)C)c1
Reactant: COC(N)=O
Agent: C=C(C)c1cccc(C)c1C
Agent: CC(C)c1cccc(C(C)C)c1
Agent: CCCCCCCCCCCCCCCCCCCCC
Solvent: CCCCCCCCCCCCCCCC
Product: CCOC(N)=O
Temperature: 60 °C
Reaction time: 4.5 h

Procedure:
To a flask containing 59.30 g (789.92 mmoles) of molten methyl carbamate (85° C. oil bath) was added 260 mg (2.6 mmole) of conc.sulfuric acid. The temperature of the oil bath was then lowered to 60° C., and 14.79 g (93.61 mmoles) of m-DIPEB added dropwise to the reaction mixture. The reaction mixture was stirred 60° C. for 4.5 hours, and 500 mg of anhydrous sodium carbonate added to neutralize the acid catalyst. The mixture was stirred at 60° C. for another 30 minutes and then distilled under the vacuum 95°/30 mm Hg) to recover unreacted methyl carbamate (44.05 g; >90% recovery). GLC analyses of the white residue showed that m-TMXDU and m-TMU were formed in 65% and 24% yields, respectively. The solid was then mixed with 50 g of hexadecane and 1.66 g of heneicosane (GLC internal standard), and the mixture cracked at 265° C. for 4 hours. GLC analyses indicated that α,α,α',α'-tetramethyl meta-xylene diisocyanate (m-TMXDI) (45%), meta-isopropenyldimethylbenzene isocyanate (m-TMI) (10%) and α,α,α',α'-tetramethyl-meta-xylene monourethane monoisocyanate (m-TMXUI) (3%) were formed based on the m-DIPEB.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][C:11]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])(O)=O.[Na+]>C1COCC1.O>[C:2]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][C:11]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:9]2=[O:21])[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CC1(c2ccccc2)CCN(c2cccc(Br)c2)C(=O)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(c2ccccc2)CCN(c2cccc(-c3ccccc3)c2)C(=O)O1
Yield: 20.8 %

Procedure:
To a solution of 3-(3-bromophenyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (50 mg, 0.14 mmol) and phenylboronic acid (35 mg, 0.29 mmol) in THF (2 mL) was added a solution of NaHCO3 (31 mg, 0.29 mmol) in H2O (2 mL) followed by Pd(PPh3)Cl2 (9 mg, 0.01 mmol). The mixture was refluxed overnight. The mixture was concentrated to give the crude product, which was purified by column chromatography, followed by preparative HPLC to afford 3-(biphenyl-3-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (10 mg, 20%). 1H NMR: (400 MHz, CDCl3): δ 1.71 (s, 3H), 2.40 (m, 1H), 2.48 (m, 1H), 3.31 (m, 1H), 3.54 (m, 1H), 7.08 (m, 1H), 7.30 (m, 3H), 7.7.32-7.42 (m, 8H), 7.46 (m, 2H). LC-MS Method 3, tR=1.362 min, m/z=344. 1H NMR (CDCl3) 1.75 (s, 3H), 2.32-2.43 (m, 1H), 2.50 (m, 1H), 3.20 (m, 1H), 3.52 (m, 1H), 7.10 (d, 1H), 7.25-7.45 (m, 11H), 7.50 (d, 2H).
Reaction SMILES: ClN1C(=O)CCC1=O.[N:9]1([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]=[N:25][OH:26])=[CH:16][CH:15]=2)[CH:13]=[N:12][CH:11]=[N:10]1.[Cl:27][C:28]1[CH:33]=[C:32]([C:34]([C:36]([F:39])([F:38])[F:37])=[CH2:35])[CH:31]=[C:30]([Cl:40])[CH:29]=1.C(N(CC)CC)C>CN(C=O)C.O>[Cl:27][C:28]1[CH:33]=[C:32]([C:34]2([C:36]([F:39])([F:37])[F:38])[O:26][N:25]=[C:24]([C:17]3[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:14]([N:9]4[CH:13]=[N:12][CH:11]=[N:10]4)=[CH:15][CH:16]=3)[CH2:35]2)[CH:31]=[C:30]([Cl:40])[CH:29]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: ON=Cc1ccc(-n2cncn2)c2ccccc12
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(-n3cncn3)c3ccccc23)=NO1
Reaction time: 0.75 h
Yield: 64.1 %

Procedure:
N-chlorosuccinimid (220 mg) is added to a solution of 4-[1,2,4]triazol-1-yl-naphthalene-1-carbaldehyde oxime (390 mg) in DMF (5 ml). After 45 minutes at 40° C., the reaction is cold down to 0° C., and 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (394 mg, Example 1, step A) and triethylamine (0.25 ml) are added. The reaction is then further reacted at room temperature for 3 hours. Water is added (50 ml) and the reaction mixture is extracted two times with ethyl acetate. The organic phase is extracted, with a saturated aqueous solution of NaCl, dried over Na2SO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC: to yield 1-{4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-naphthalen-1-yl}-1H-[1,2,4]triazole (500 mg) as beige crystals. MS (HPLC/MS): 477 (MH+). Retention time: 5.20 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([NH:8][C:9]([CH3:14])([C:11](O)=[O:12])[CH3:10])[CH:7]=1>C(O)C.[Pd]>[CH3:10][C:9]1([CH3:14])[NH:8][C:6]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:7]=2)[NH:15][C:11]1=[O:12]
Reactant: CC(C)(Nc1cc(F)ccc1[N+](=O)[O-])C(=O)O
Agent: [Pd]
Solvent: CCO
Product: CC1(C)Nc2cc(F)ccc2NC1=O
Reaction time: 4 h

Procedure:
N-(5-Fluoro-2-nitrophenyl)-2-methylalanine is taken up in approximately 1 L of ethanol and divided into two lots for reduction. The reductions are done with 1.7-1.9 g of palladium on carbon (10%) under hydrogen at initial pressures of 41 and 43 psi. After 4 hr the reaction is judged complete and the catalyst is filtered off. The filtrates are combined after concentration (with heating) to about 100 ml, then further concentrated. The crude product is chromatographed on silica gel (900 ml) eluting with ethyl acetate/dichloromethane (20/80), the appropriate fractions are pooled and concentrated to give the title compound which is crystallized from methanol/dichloromethane/hexane, mp 146°-148°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:25][C:26]1[CH:31]=[C:30]([CH3:32])[N:29]2[N:33]=[C:34]([CH:36]=O)[N:35]=[C:28]2[N:27]=1.[Al+3].[Cl-].[Cl-].[Cl-].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[CH:15]([CH2:36][C:34]3[N:35]=[C:28]4[N:27]=[C:26]([CH3:25])[CH:31]=[C:30]([CH3:32])[N:29]4[N:33]=3)[C:14](=[O:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione from Step 1 below (1 g, 2.90 mmol) was combined with 5,7-Dimethyl-[1,2,4]triazolo[1,5-α]pyrimidine-2-carbaldehyde (0.5 g, 2.90 mmol) (described in Step 3 of example B(75)) in dry THF (15 mL) with magnetic stirring. To this solution was added AlCl3 (0.76 g, 5.81 mmol) as a soln in THF (6 mL) dropwise over 1 min. The resulting yellow solution was stirred at room temperature for 3 hours. The reaction was quenched with solid Na2CO3.10H2O (1.63 g, 5.81 mmol) and stirred at room temperature for 10 min. Next, the mixture was treated with MgSO4 (2.5 g) and the slurry allowed to stand for 1.5 hours. The yellow mixture was filtered through celite and the filtrate was concentrated. The crude residue was dissolved in EtOAc (50 mL) and treated with PtO2 and stirred with H2 (one balloon pressure). This was maintained for 1 hour then filtered through celite. The filtrate was concentrated and the residue chromatographed on silica gel eluting with CH2Cl2 through 0.75% MeOH in CH2Cl2 to yield the title compound as a white solid.
Reaction SMILES: [CH2:1]([CH:3]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([CH3:24])[CH:17]=2)(=[O:15])=[O:14])[C:11]2[C:6](=[CH:7][C:8]([F:26])=[C:9]([F:25])[CH:10]=2)[N:5]2[CH:27]=[CH:28][CH:29]=[C:4]12)[CH3:2].ClS([N:34]=[C:35]=O)(=O)=O.CN(C=O)C>C1COCC1>[CH2:1]([CH:3]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([CH3:24])[CH:17]=2)(=[O:15])=[O:14])[C:11]2[C:6](=[CH:7][C:8]([F:26])=[C:9]([F:25])[CH:10]=2)[N:5]2[C:27]([C:35]#[N:34])=[CH:28][CH:29]=[C:4]12)[CH3:2]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCC1c2cccn2-c2cc(F)c(F)cc2N1S(=O)(=O)c1ccc(OC)c(C)c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCC1c2ccc(C#N)n2-c2cc(F)c(F)cc2N1S(=O)(=O)c1ccc(OC)c(C)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a 250 ml round bottom flask with addition funnel was added 2 g (4.8 mmol) of the product from Example 4 and 50 ml of THF. The solution was cooled to −78° C. and 0.50 ml (5.76 mmol) of chlorosulfonyl isocyanate in 20 ml of THF added dropwise via the addition funnel. After the addition was complete the solution was stirred at this temperature for 3 hr until all of the product had disappeared by TLC. Added 1 ml of DMF and allowed the solution to warm to room temperature, whereupon product begins to form. After stirring overnight the reaction was quenched with saturated sodium bicarbonate solution, then extracted 3 times with ethyl acetate. The organic layers were combined, dried (MgSO4) and concentrated to afford an oil, which was chromatographed on silica gel eluting with 30% ethyl acetate:hexane to afford 1.81 g (83%) of product as a solid, which was recrystallized from ethyl acetate hexane, mp 176-178° C.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3([CH2:32][N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.[OH-].[OH-].[Pd+2]>[NH:14]1[CH2:15][CH:16]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3([CH2:32][N:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH2:17]1
Reactant: c1ccc(C(c2ccccc2)N2CC(COc3ccc(C4(CN5CCOCC5)CCOCC4)cc3)C2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: c1cc(C2(CN3CCOCC3)CCOCC2)ccc1OCC1CNC1
Reaction time: 16 h
Yield: 31.1 %

Procedure:
A solution of 4-{[4-(4-{[1-(benzhydryl)azetidin-3-yl]methoxy}phenyl)tetrahydro-2H-pyran-4-yl]methyl}-morpholine (1.0 g, 1.95 mmol) in ethanol (10 mL) was hydrogenated for 16 hours at room temperature at 60 psi in the presence of Pd(OH)2/C (150 mg, 15% w/w). 2N Hydrochloric acid (few drops) was added and the reaction mixture hydrogenated for 16 hours at 60° C. at 60 psi. The reaction mixture was basified with aqueous sodium carbonate and the mixture filtered over Arbocel® and rinsed with ethanol. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.4 to 90:10:1 by volume) to provide the title compound (210 mg, 31%). HRMS ESI+ m/z 347.2323 [MH]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]2[S:22][N:21]=[CH:20][N:19]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:33]=[C:32]2[C:28]([CH2:29][CH2:30][N:31]2[CH2:34][C:35](O)=[O:36])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)(O)[O-].[Na+]>CN(C=O)C>[O:1]=[C:2]1[CH2:7][N:6]([C:35](=[O:36])[CH2:34][N:31]2[C:32]3[C:28](=[CH:27][CH:26]=[C:25]([C:24]([F:38])([F:23])[F:39])[CH:33]=3)[CH2:29][CH2:30]2)[CH2:5][CH2:4][N:3]1[C:8]1[CH:9]=[CH:10][C:11]([S:14]([NH:17][C:18]2[S:22][N:21]=[CH:20][N:19]=2)(=[O:16])=[O:15])=[CH:12][CH:13]=1
Reactant: O=C(O)CN1CCc2ccc(C(F)(F)F)cc21
Reactant: O=C1CNCCN1c1ccc(S(=O)(=O)Nc2ncns2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: O=C(CN1CCc2ccc(C(F)(F)F)cc21)N1CCN(c2ccc(S(=O)(=O)Nc3ncns3)cc2)C(=O)C1
Yield: 100 %

Procedure:
Synthesized according to general procedure 14, method B. The reaction was set up with 4-(2-oxopiperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (50 mg, 0.15 mmol), 2-(6-(trifluoromethyl)indolin-1-yl)acetic acid (25 mg, 0.10 mmol), HATU reagent (76 mg, 0.20 mmol), sodium bicarbonate (17 mg, 0.20 mmol), and DMF (0.20 mL) to obtain the desired amide as a white solid (50 mg, 0.10 mmol, 32% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA), m/z: M+1 obs=565.0; tR=2.91 min.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl.[BH3-]C#N.[Na+]>CCO>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][NH:7]2
Reactant: Clc1cccc2ncccc12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: Clc1cccc2c1CCCN2
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Based on B. S. Rauckman et al., J. Med. Chem., 1989, 32, 1927-1935, 5-chloroquinoline (1.01 g, 6.2 mmol) was dissolved into anh. EtOH (30 mL) under N2 at RT. Concentrated HCl (2.14 mL, 24.8 mmol) was added, followed by the addition of the NaCNBH3 (1.56 g, 24.8 mmol). This produced a vigorous gas and heat evolution. The reaction was heated to 60° C. for 2 h, then cooled and stirred at RT for an additional 18 h. The reaction was quenched by adjusting the pH to approximately 9 with 2 N NaOH. This mixture was extracted 3 times with EtOAc. The EtOAc extracts were washed brine, combined, dried over Na2SO4, filtered, and concentrated, then eluted through a 17×2.5 cm column of silica gel (5%, 10%, 15%, 40% and 50% EtOAc/Hexane step gradient) giving 5-chloro-1,2,3,4-tetrahydroquinoline as a green oil: MS m/z 168=[M+H]+. Calc'd for C9H10NCl—167.05.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:21])[C@H:5]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:6][C:7](=[O:12])[C@H:8]([CH2:10][OH:11])[NH2:9].ClC1C([O:29][C:30](=O)[C@H:31]([CH2:43][C:44]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[NH:46][CH:45]=2)[NH:32][C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])=C(Cl)C(Cl)=C(Cl)C=1Cl.CN(C)C=O.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:21])[C@H:5]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:6][C:7](=[O:12])[C@H:8]([CH2:10][OH:11])[NH:9][C:30](=[O:29])[C@H:31]([CH2:43][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46][CH:45]=1)[NH:32][C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34]
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)OCc1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)CO
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
L-Seryl-L-tyrosine methyl ester hydrochloride (taken directly from part a) and 11.7 g. of Nα -benzyloxycarbonyl-L-tryptophan pentachlorophenyl ester [cf. Kovacs et al. J. Org. Chem. 32, 3696 (1967)] are dissolved in 60 ml. of dimethylformamide, cooled to -10° C. with stirring and treated with 28 ml. of triethylamine. The reaction is stirred 11/2 hours at -10° C. and allowed to warm to room temperature with stirring overnight. The mixture is filtered and the filtrate evaporated at 50° C. and reduced pressure. The residue is twice dissolved in methanol and the solvent removed under reduced pressure. The residue is then again taken into 30 ml. of methanol and precipitated by addition of 300 ml. of ether and 100 ml. of petroleum ether. The precipitated oil is obtained by decantation and stirred with 30 ml. of hot ethyl acetate. The product is obtained by cooling and precipitating by addition of ether and petroleum ether. It is further purified by repeating the precipitation from methanol with petroleum ether. The supernatant is decanted and the oil dried at 50° C. and under reduced pressure. The product thus obtained is a tan foam which can be crystallized from methanol, ether and petroleum ether by seeding; m.p. 149°-152° C.; [α]D23 -1.8° (c 1.00, methanol); ultraviolet in methanol, λmax 289.5 E11 92, λmax 280 E11 122.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([CH3:10])[CH:9]=1.Cl[CH2:13][C:14]([OH:16])=[O:15].Cl>O>[CH3:3][C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[O:11][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)CCl
Reactant: Cc1cc(C)cc(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C)cc(OCC(=O)O)c1
Temperature: 0 °C
Yield: 74.9 %

Procedure:
In a 2L 3-necked flask equipped with a mechanical stirrer and a condenser was placed a solution of sodium hydroxide (168 g, 4.2 mol) in water (1 L). 3,5-Dimethyl phenol (146.4 g, 1.2 mol) was added and the resulting mixture was stirred to get a solution. Chloroacetic acid (226.8 g, 2.4 mol) was added and the resulting mixture was heated on a steam bath for 4 hr. The reaction mixture was cooled in an ice-water bath and acidified with a mixture of concentrated hydrochloric acid (150 mL) and crushed-ice (100 g). After stirring for 30 min the solid was collected, washed with water (500 mL) and suspended in hexane (1 L). The suspension was stirred for 1 hr, solid collected and air dried to give 162 g (75%) of the 3,5-dimethylphenoxyacetic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][NH:31][CH2:30]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][N:31]([C:16]1[C:17]([F:19])=[C:18]3[C:13]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:14][C:15]=1[F:21])[CH2:30]2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Reactant: Clc1ccc2c(c1)CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(N3Cc4ccc(Cl)cc4C3)c(F)cc2c1=O
Yield: 10.2 %

Procedure:
178 mg of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 89 mg of 5-chloroisoindoline, 137 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 25 mg of the target compound.