Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:10][CH2:11][C:12]#N.C>O>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:12]([CH2:11][Cl:10])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: N#CCCl
Solvent: O
Product: ClCc1nc2cc(Br)cnc2[nH]1
Temperature: 100 °C

Procedure:
3.0 g of 5-bromo-2,3-diaminopyridine (S.-X. Cai et al., J. Med. Chem. 1997, 40(22), 3679-3686) in 120 g of polyphosphoric acid are heated at 160° C. for 0.5 h. The solution is cooled to 100° C. and 1.26 ml of chloroacetonitrile are added. Thereafter, the reaction mixture is heated to 170° C. for 22 h. After cooling, the polyphosphoric acid is hydrolysed with 81 ml of water. After reheating to 90° C., charcoal is added under vigorous stirring. Subsequently, the suspension is filtered through a celite pad while still hot (70° C.). The filter cake is rinsed with 85 ml of water. The filtrate is adjusted to pH 4 using 9.0 M aqueous sodium hydroxide solution. The precipitate is collected, suspended in 100 ml of hot methanol and filtered over celite. The filtrate is concentrated to dryness to afford 2.78 g of the title compound as a beige, amorphous solid of m.p. >325° C. MS: 246.2/248.2/250.3 (MH+, 77%/100%/25%). TLC: Rf=0.42 (dichloromethane/methanol 10:1 parts by volume).
Reaction SMILES: [C:1]1([C:7]2(NC)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:16]1[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:33][N:34]1C(=O)CCC1>>[Cl:22][C:21]1[C:16]([NH:34][CH2:33][C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:20]=1
Reactant: CNC1(c2ccccc2)CCCCC1
Reactant: CN1CCCC1=O
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: FC(F)(F)c1cnc(NCC2(c3ccccc3)CCCCC2)c(Cl)c1

Procedure:
was prepared from 475 mg of 1-phenyl-cyclohexyl-methylamine by reaction with 596 mg of 2,3-dichloro-5-trifluoromethyl-pyridine in the presence of 354 mg potassium carbonate in 2.5 ml of NMP at 80° C. for 1 hour. After dilution with 20 ml of water, the product was extracted with 30 ml of ethyl acetate and purified by chromatography on silica gel with the eluents dichloromethane:methanol=98:2 to obtain 469 mg g of a light yellow oil.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[N:45]([CH3:46])[N:44]=[CH:43][N:42]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:39]([C:41]2[N:45]([CH3:46])[N:44]=[CH:43][N:42]=2)=[O:40])[C:23]([F:35])=[C:24]([Cl:34])[C:25]=1[N:26]1[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Reactant: CON(C)C(=O)c1ncnn1C
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc(C(=O)c3ncnn3C)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting material: (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45) and N-methoxy-N, 1-dimethyl-1H-1,2,4-triazole-5-carboxamide (Intermediate 49).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.C([Cl:9])(=O)C.[NH2:10][C@@H:11]([C:14](O)=[O:15])[CH2:12][OH:13]>>[ClH:9].[NH2:10][C@H:11]([CH2:14][OH:15])[C:12]([O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)=[O:13]
Reactant: CC(=O)Cl
Reactant: N[C@H](CO)C(=O)O
Reactant: OCC1CC1
Product: Cl
Product: N[C@H](CO)C(=O)OCC1CC1
Reaction time: 0.17 h

Procedure:
Cyclopropylcarbinol (15 ml) is cooled to 0° C. and acetyl chloride (1.37 ml) is added. After being subjected to agitation for 10 minutes at 0° C., D-serine (750 mg) is added and the solution is brought to reflux for 2 hours. The reaction mixture is concentrated, recovered with a potassium carbonate saturated solution and extracted with ethyl acetate. The organic phase is dried on MgSO4, filtered and concentrated. The product is recovered in a minimum of methanol and a hydrochloric acid solution 1N is added in ether. The solvent is vacuum evaporated to obtain the desired product as a brown solid (250 mg). Melting point: 112-118° C.
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][NH2:7])([CH3:3])[CH3:2].[Cl:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:12](=O)[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=O.O.Cl>C(O)(=O)C>[ClH:8].[CH:1]([NH:4][CH2:5][CH2:6][N:7]1[C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=2[CH:13]=[C:12]1[C:11]1[CH:22]=[CH:23][C:24]([Cl:25])=[C:9]([Cl:8])[CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)NCCN
Reactant: O=C(CC1CCCCC1=O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)NCCn1c(-c2ccc(Cl)c(Cl)c2)cc2c1CCCC2

Procedure:
2.9 g (0.028 mole) of isopropylaminoethylamine are added dropwise to a stirred solution of 8.0 g (0.028 mole) of 2-(3,4-dichlorophenacyl)cyclohexanone in glacial acetic acid under nitrogen. After refluxing for 5 hours, ice and water are added and the pH of the aqueous solution is adjusted to 1 with dilute hydrochloric acid. The aqueous solution is washed with ether. The aqueous phase is made basic with sodium carbonate and extracted with ether. The ether solution is dried over sodium sulfate and concentrated to off-white solid, which is recrystallized twice from a methanol-ether mixture to give 1-(2-isopropylaminoethyl)-2-(3,4-dichlorophenyl)-4,5,6,7-tetrahydroindole hydrochloride as crystals, m.p. 207°-210° C.
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH3:11]O>S(=O)(=O)(O)O>[O:1]=[C:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:11])=[O:8]
Reactant: CO
Reactant: CC(=O)CCCCC(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCC(C)=O
Reaction time: 1.5 h

Procedure:
Dissolve 10 g 6-oxoheptanoic acid (69.4 mmol) in 100 ml methanol. Add a few drops of concentrated sulphuric acid and stir for 1.5 h under reflux. Then concentrate by evaporation. Take up in dichloromethane and wash once with satd. sodium hydrogencarbonate solution. Separate the phases, dry the organic phase and concentrate by evaporation. 10.1 g (91.1% of theor.) of the target compound is obtained.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2[O:17][C:16]3[CH:15]=[C:14]([OH:18])[CH:13]=[C:12]([OH:19])[C:11]=3[C:9](=[O:10])[CH:8]=2)=[CH:5][CH:6]=1.S(OC)(O[CH3:24])(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:24][O:18][C:14]1[CH:15]=[C:16]2[O:17][C:7]([C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=3)=[CH:8][C:9](=[O:10])[C:11]2=[C:12]([OH:19])[CH:13]=1
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)cc(O)c12
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(O)c2c(=O)cc(-c3ccccc3)oc2c1

Procedure:
Prepared from chrysin by warming with one equivalent of dimethyl sulphate in DMF with fine ground K2CO3. Fine, light yellow needles, mp 175-180 ° C. (lit. 163° C.). 1H NMR δ (DMSO-d6) 3.87 (s,OCH3), 6.39 (d. J=1.7 Hz, H-6), 6.80 (d, J=1.7 Hz, H-8), 7.02 (s,H-3), 7.58 (dd, J=J'=7.8 Hz. H-3'/5'), 7.60 (tt, J≈7.8 Hz, H-4'), 8.09 (d,J=7.8 Hz, H-2'/6') 12.80 (s, C-5-OH).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]2[CH2:11][CH2:10][N:9]([CH2:12][CH3:13])[CH2:8][CH2:7][C:6]=2[N:14]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[CH2:12]([N:9]1[CH2:10][CH2:11][C:5]2[N:4]=[CH:3][C:2]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:14][C:6]=2[CH2:7][CH2:8]1)[CH3:13]
Reactant: CCN1CCc2ncc(Cl)nc2CC1
Reactant: C1CNCCN1
Product: CCN1CCc2ncc(N3CCNCC3)nc2CC1
Temperature: 145 °C
Yield: 52.6 %

Procedure:
3 g 2-chloro-7-ethyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine are combined with 23.3 g piperazine and heated to 145° C. for 5 hours. Excess piperazine is distilled off and the residue is treated with dichloromethane and methanol. Precipitated product is suction filtered and purified by chromatography (Alox, dioxane/toluene/methanol/NH4OH 50/20/20/2). 1.95 g product are obtained.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[C:18]1([CH2:24][CH:25]=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)(Cl)Cl.O>[CH3:16][C:13]1([CH3:17])[N:12](/[CH:25]=[CH:24]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: O=CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1/C=C/c1ccccc1
Reaction time: 2 h
Yield: 5.2 %

Procedure:
A solution of 2-(adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one (50.0 mg, 0.213 mmol) prepared in Process 3 of Example 12 in chloroform (3 mL) was added sequentially with phenylacetaldehyde (25.6 mg, 0.213 mmol), sodium triacetoxyborohydride (67.8 mg, 0.320 mmol) and acetic acid (15.4 mg, 0.256 mmol) at room temperature, and the resultant was stirred at the same temperature for 2 hours. The reaction solution was added with water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, the obtained residue was purified using Preparatory Thin-Layer chromatography (hexane:ethyl acetate=4:1), and the title compound (3.70 mg, 5.20%) was obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:9]=1)=[O:6].[CH2:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[CH3:30].BrCC(Br)=[O:39].C(N(C(C)C)C(C)C)C.N1CCCC1>O1CCOCC1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:21]=[CH:22][C:23]([CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])=[C:2]([NH:1][C:30](=[O:39])[CH2:29][N:31]3[CH2:34][CH2:35][CH2:33][CH2:32]3)[CH:3]=2)=[CH:9][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1N
Reactant: CCN(CC)CC
Reactant: O=C(Br)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: C1CCNC1
Product: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1NC(=O)CN1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.3 %

Procedure:
3-Amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide (100 mg, 0.24 mmol) was dissolved in 1,4-dioxane (5.0 ml), treated with triethylamine (274 μl, 1.97 mmol) and 2-bromoacetyl bromide (121 μl, 1.39 mmol). The reaction was heated to reflux for 10 minutes, and stirred at room temperature for 18 hours. The reaction was quenched with water, and extracted twice with ethyl acetate. The ethyl acetate extracts were filtered, washed with water once, brine once, dried with MgSO4, evaporated to 158 mg of a crude brown oil, 3-(2-bromoacetamido)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide, which was used without further purification. Crude 3-(2-bromoacetamido)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl-methyl)benzamide (158 mg) was dissolved in DMF, treated with N-ethyl-N-isopropylpropan-2-amine (61 μl, 0.35 mmol) and pyrrolidine (27 μl, 0.32 mmol), and stirred at room temperature for 18 hours. The reaction was quenched with water and extracted with ethyl acetate twice. The ethyl acetate extracts were washed with water once, brine once, dried with MgSO4, evaporated to a tan solid which was purified by reverse phase HPLC to afford 27 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-(pyrrolidin-1-yl)acetamido)benzamide as a white powder. MS (Q1) 527 (M)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9](O)[CH:10]=[CH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)N.C([N:20](CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[C:1]1([CH2:7][CH2:8][CH:9]([NH:20][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:10]=[CH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: C=CC(O)CCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: NS(=O)(=O)O
Solvent: CN(C)C=O
Product: C=CC(CCc1ccccc1)NC(=O)c1ccccc1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
A Schlenk flask under argon was charged with {Ir(cod)Cl}2 (10 mg, 15 μmol, 3 mol %) and ligand (3,5-dioxa-4-phospha-cyclohepta[2,1-a; 3,4-a′]diphenyl-4-en)-dibenzo[b,f]azepine (12 mg, 30 μmol, 6 mol %). N,N-Dimethylformamide (2 mL) was added and the reaction mixture was stirred at 23° C. for 15 min. 5-Phenylpent-1-en-3-ol (81 mg, 0.50 mmol, 1 eq.) was added via syringe followed by the addition of solid sulfamic acid (49 mg, 0.50 mmol, 1 eq.). The resulting reaction mixture was heated to 50° C. Conversion was checked by disappearance of the starting material on TLC and/or by measuring 1H-NMR of an aliquot taken from the reaction mixture. After completion of the reaction (usually 3-4 hr), triethylamine (202 mg, 2.00 mmol, 4 eq.) and freshly distilled benzoyl chloride (141 mg, 1.00 mmol, 2 eq.) were added to the reaction mixture and the mixture was stirred for 4 hr at 23° C. Subsequently, the reaction mixture was partitioned between methylene chloride (10 mL) and water (10 mL). The aqueous layer was extracted with methylene chloride (3×15 mL). The combined organic layers were dried (sodium sulfate) and concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel using hexanes/ethyl acetate as an eluent afforded the title compound (97 mg, 0.37 mmol, yield 73%) as an off-white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[CH:16]=1)[CH2:9][C:8]2([CH3:29])[CH3:28])=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:28][C:8]1([CH3:29])[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[NH:11][CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[CH:16]=2)[CH2:9]1
Reactant: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(N3CCN(C)CC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCN(c2cccc(C3CC(C)(C)c4cc(C(=O)O)ccc4N3)c2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
To a stirred mixture solution of 4,4-dimethyl-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (610 mg, 1.49 mmol) in methanol (7.5 mL) and tetrahydrofuran (15 mL) was added 30% sodium hydroxide in water (7.5 mL). The reaction mixture was stirred at 60° C. for 16 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 4,4-dimethyl-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (564 mg, 99%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=380.2.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.N1C=CC=CC=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19].CCOC(C)=O>C1COCC1>[Cl:10][C:4]1[CH:3]=[C:2]([NH:1][C:18](=[O:19])[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(N)cc1Cl
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: N#Cc1ccc(NC(=O)Oc2ccccc2)cc1Cl
Temperature: 0 °C
Yield: 91.1 %

Procedure:
Dissolve 4-amino-2-chloro-benzonitrile (500 mg, 3.3 mmol) and pyridine (518 mg, 6.6 mmol) in THF (5 mL), cool to 0° C. and add slowly phenyl chloroformate (616 mg, 3.9 mmol). After addition, stir the reaction at room temperature for 2 hrs. TLC (EtOAc:PE=1:3) shows the reaction is complete. Add water, extract with DCM, separate the organic layer. Wash the organic layer with 1M HCl solution, brine sequentially, dry over anhydrous Na2SO4, and concentrate under reduced pressure to give the target compound (820 mg, 91.7%). MS: (M+1): 273.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH2:24])[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35](O)=[O:36])=[CH:32][CH:33]=2)[NH:28][CH:27]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH:24][C:35]([C:31]2[CH:30]=[C:29]3[C:34]([C:26]([Cl:25])=[CH:27][NH:28]3)=[CH:33][CH:32]=2)=[O:36])[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CCC(COCC(N)c2ccncc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccncc2)CC1

Procedure:
Using coupling method A, 4-[2-amino-2-(4-pyridinyl)-ethoxymethyl]piperidine-1-carboxylic acid tert-butyl ester (233 mg, 0.69 mmol) and 3-chloroindole-6-carboxylic acid (149 mg, 0.76 mmol) afforded, after purification (SiO2: 10 DCM:2 EtOAc:2 Hexane:3 isopropyl amine), 118 mg (33%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=[O:9])[CH2:7][Cl:8].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl-:8].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=[O:9])[CH2:7][N+:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccncc1
Reactant: COc1cccc(C(=O)CCl)c1
Product: COc1cccc(C(=O)C[n+]2ccccc2)c1
Product: [Cl-]
Yield: 93 %

Procedure:
The title compound was prepared similarly to Example 1 from 3-methoxyphenacyl chloride and pyridine in a yield of 93%.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[C:3]([O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[C:14]([C:22]([NH:24][C:25]3[CH:26]=[C:27](/[CH:31]=[CH:32]/[C:33]([O:35]CC)=[O:34])[CH:28]=[CH:29][CH:30]=3)=[O:23])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=[CH:10][CH:11]=1)=[O:4].O[Li].O>C1COCC1.O>[CH3:38][N:2]([CH3:1])[C:3]([O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[C:14]([C:22]([NH:24][C:25]3[CH:26]=[C:27](/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34])[CH:28]=[CH:29][CH:30]=3)=[O:23])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=[CH:10][CH:11]=1)=[O:4]
Reactant: CCOC(=O)/C=C/c1cccc(NC(=O)c2cc(-c3cccc(OC(=O)N(C)C)c3)cc3ccccc23)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)Oc1cccc(-c2cc(C(=O)Nc3cccc(/C=C/C(=O)O)c3)c3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
Compound 26 (0.23 mmol,) was dissolved in THF/H2O (1:1, 20 mL) mixture. LiOH.H2O (0.35 mmol,) was added to the reaction mixture and stirred at room temperature for 3 h. The reaction mixture was concentrated under vacuum to dryness. The resulting residue was adjusted to pH 5 with dilute HCl and extracted with ethyl acetate (3×10 mL), washed with water and brine. The organic layer was dried over Na2SO4, filtered, and the solvent was removed in vacuo. The resulting solid was purified using reverse phase column chromatography to afford pure 27 as a white solid.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[Cl-].[Al+3].[Cl-].[Cl-].[S:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1.O>[N+](C1C=CC=CC=1)([O-])=O>[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5]
Reactant: c1ccsc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)c1ccccc1C(=O)c1cccs1
Reaction time: 2 h
Yield: 26.8 %

Procedure:
A solution of 74.1 g (0.5 mole) of phthalic anhydride in 300 mL of nitrobenzene was treated with 147 g (1.1 mole) of aluminum chloride. The solution was stirred for two hours and 42.1 g (0.5 mole) of thiophene was added dropwise over 80 minutes at 40°-45°. The reaction was stirred at 50°-55° for two hours and then let sit at room temperature overnight. The reaction was poured into 2.8 L of cold water, stirred, separated, and the nitrobenzene was removed from the nitrobenzene layer by steam distillation. The residue was recrystallized from toluene to provide 31.1 g (27%) of 2-thienoylbenzoic acid, mp 141-143. The thienoylbenzoic acid was treated with methylhydrazine as described in Example 185 to provide 24.4 g (75%) of the phthalazinone product, mp 143-144, after recrystallization from ethyl acetate.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].[C:7]([OH:11])([CH3:10])([CH3:9])[CH3:8]>CCOCC>[C:7]([O:11][C:1](=[O:5])[C:2]([Cl:4])=[O:3])([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (232 μL, 2.8 mmol) and t-butyl alcohol (228 μL) were combined in ether (6.7 mL) under nitrogen at 0° C. The resulting mixture was stirred for 30 minutes at room temperature. The solvent was evaporated under vacuum to form chloro-oxo-acetic acid t-butyl ester, which was then dissolved in DCM (10 mL) and combined with (2S,4S)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-pentanoic acid ethyl ester (HCl salt; 667 mg, 1.8 mmol), which had been dissolved in DCM with Et3N (2.6 mL) at 0° C. The resulting mixture was stirred for 5 minutes at room temperature. The crude product was concentrated, dissolved in DCM and purified by flash chromatography (20-80% EtOAc/hexanes). The solvent was removed and the residue was dissolved in DCM (5 mL) and TFA (1 mL), and stirred for 1 hour. The product was dried under vacuum and purified by preparative HPLC to yield the title compound (135 mg, purity 95%). MS m/z [M+H]+ calc'd for C22H25NO6, 400.17; found 400.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[H-].[Na+].[CH2:27](Br)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[C:5]=1[N:12]([S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)(=[O:14])=[O:15])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: COC(=O)c1cccc(C=O)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCCCN(c1c(C=O)cccc1C(=O)OC)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
To a solution of 1.0 g (2.865 mmol) of the product of Example 321 in 7.5 mL of DMF was added 0.143 g (3.582 mmol) of 60% sodium hydride followed by 0.74 mL (4.30 mmol) of n-octyl bromide. The reaction was stirred overnight at room temperature then diluted with ether, washed with water, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel eluting with EtOAc/hexanes (1:3) to provide 0.592 g (49%) of the product as a white solid. Electrospray Mass Spec: 462.1 (M+H)+.