Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([P:13]2(=[O:20])[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)(=O)=O.CN([CH:26]=[O:27])C.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(C(C)C)C(C)C.[OH2:66]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:19][N:16]1[CH2:17][CH2:18][P:13]([C:10]2[CH:11]=[CH:12][C:7]([C:26]([OH:27])=[O:66])=[CH:8][CH:9]=2)(=[O:20])[CH2:14][CH2:15]1
Reactant: CN(C)C=O
Reactant: O
Reactant: CN1CCP(=O)(c2ccc(OS(=O)(=O)C(F)(F)F)cc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCP(=O)(c2ccc(C(=O)O)cc2)CC1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
4-(1-Methyl-4-oxido-1,4-azaphosphinan-4-yl)phenyl trifluoromethanesulfonate (0.18 g, 0.50 mmol) was made 0.25 M in 4:1 DMF:water and to this stirring solution was added palladium acetate (7 mg, 0.03 mmol), and DPPP (25 mg, 0.06 mmol). The resulting mixture was thoroughly degassed with bubbling carbon monoxide for 20 mins. DIPEA (130 mg, 1.01 mmol) was added and a CO balloon was attached. The resulting mixture was stirred at 70° C. for 16 h. The mixture was then cooled to ambient temperature and carried onto the subsequent reaction without purification. MS: cal'd 254 (MH+), exp 254 (MH+).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.[CH3:26][C:27]1[CH:31]=[C:30]([CH3:32])[NH:29][N:28]=1>>[C:17]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:14]([NH:13][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([N:28]3[C:27]([CH3:26])=[CH:31][C:30]([CH3:32])=[N:29]3)[N:11]=2)=[CH:19][CH:18]=1
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Cc1cc(C)[nH]n1
Product: Cc1cc(C)n(-c2nc(Nc3ccc(-c4ccccc4)cc3)c3ccccc3n2)n1

Procedure:
Was prepared according to Method B from 2,4-dichloroquinazoline, 4-aminobiphenyl and 3,5-dimethylpyrazole. Mp. 267.5-270.3° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][N:16]1[C:21]([NH:22][CH2:23][CH2:24][NH:25][C:26](=O)[C:27]2[CH:32]=CC([N+]([O-])=O)=CC=2)=[CH:20][C:19](=[O:37])[N:18]([CH3:38])[C:17]1=[O:39].[C:40]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:41]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:15][N:16]1[C:21]([N:22]2[CH2:23][CH2:24][N:25]([CH2:26][CH2:27][CH2:32][O:1][C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=3[N+:12]([O-:14])=[O:13])[CH2:41][CH2:40]2)=[CH:20][C:19](=[O:37])[N:18]([CH3:38])[C:17]1=[O:39]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: Cn1c(NCCNC(=O)c2ccc([N+](=O)[O-])cc2)cc(=O)n(C)c1=O
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCCN2CCN(c3cc(=O)n(C)c(=O)n3C)CC2)c([N+](=O)[O-])c1
Yield: 103.5 %

Procedure:
0.84 g of methyl 4-hydroxy-3-nitrobenzoate, 0.8 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound 139) and 0.88 g of triphenylphosphine were suspended in 14 ml of anhydrous tetrahydrofuran, followed by the addition of 0.54 g of diethyl azodicarboxylate. The thus-prepared mixture was treated in a similar manner to Example 84-(2), thereby obtaining 1.1 g of 1,3-dimethyl-6-{4-[3-(4-methoxycarbonyl-2-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione as an oily substance.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:12]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:21]=2)[CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O.O.CCOC(C)=O>[CH:29]1([O:28][C:22]2[CH:21]=[C:20]([C@@H:12]([C:9]3[CH:8]=[CH:7][C:6]([CH2:5][CH:4]=[O:3])=[CH:11][CH:10]=3)[CH2:13][C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[CH:25]=[CH:24][C:23]=2[O:26][CH3:27])[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CCOC(Cc1ccc([C@@H](Cc2ccncc2)c2ccc(OC)c(OC3CCCC3)c2)cc1)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc([C@H](Cc2ccncc2)c2ccc(CC=O)cc2)cc1OC1CCCC1
Temperature: 25 °C
Yield: 39.4 %

Procedure:
A solution of (R)-4-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]-phenylacetaldehyde diethyl acetal from Step 4 (1.14 g, 2.33 mmol), pyridinium p-toluenesulfonate (0.761 g, 3.03 mmol) in acetone (30 mL) and water (1.3 mL) was heated to reflux for 20 h. It was then allowed to cool to room temperature, diluted with EtOAc, successively washed with 5% aqueous NaHCO3 (2×) and brine, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica (EtOAc/hexane 3:2→7:3→4:1→1:0) to afford the title compound as a white foam (0.381 g, 39%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:16][S:17](Cl)(=[O:19])=[O:18].O>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([S:17]([CH3:16])(=[O:19])=[O:18])[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc([N+](=O)[O-])cn1S(C)(=O)=O
Temperature: 25 °C
Yield: 84.3 %

Procedure:
To a solution of 4-nitro-1H-pyrrole-2-carboxylic acid ethyl ester (2.0 g, 10.86 mmol) in anhydrous THF (54 mL) was added NaH (650 mg, 60% dispersion, 16.25 mmol) at room temperature. The suspension was stirred at room temperature for 30 minutes before the addition of methanesulfonyl chloride (1.87 g, 16.32 mmol). The reaction mixture was stirred at room temperature over night. Water was carefully added to the reaction solution, and the resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with aqueous NaHCO3 solution and brine, dried over MgSO4, filtered, and evaporated under reduced pressure to give a white solid (2.4 g, 84%). The crude product was used directly without purification. 1H NMR (500 MHz, DMSO-d6) δ8.36 (s, 1H), 7.60 (s, 1H), 4.33 (q, 2H), 4.02 (s, 3H), 2.51 (DMSO), 1.35 (t, 3H) ppm. MS (ES−): m/e=183.1 (M−Ms); LC/Method A/3.64 min.
Reaction SMILES: [O:1]=[C:2]1[CH:10]([C:11]2[C:16]3=[C:17]([CH3:23])[C:18]([C:20](O)=[O:21])=[CH:19][N:15]3[N:14]=[CH:13][N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:57][CH2:58][CH2:59][CH2:60][N:61]1[CH2:65][CH2:64][CH2:63][CH2:62]1.Cl>CN(C=O)C.ClCCl>[O:1]=[C:2]1[CH:10]([C:11]2[C:16]3=[C:17]([CH3:23])[C:18]([C:20]([NH:57][CH2:58][CH2:59][CH2:60][N:61]4[CH2:65][CH2:64][CH2:63][CH2:62]4)=[O:21])=[CH:19][N:15]3[N:14]=[CH:13][N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: NCCCN1CCCC1
Reactant: Cc1c(C(=O)O)cn2ncnc(C3C(=O)Nc4ccccc43)c12
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(C(=O)NCCCN2CCCC2)cn2ncnc(C3C(=O)Nc4ccccc43)c12
Reaction time: 0.17 h
Yield: 37.3 %

Procedure:
To a solution of Example 95 (50 mg, 0.16 mmol) in DMF (1 mL), dichloromethane (0.5 mL) were added PyBrop (113 mg, 0.24 mmol) and diisopropylethyl amine (0.08 mL, 0.5 mL). After 10 min, 1-(3-aminopropyl)pyrrolidine (61 mg, 0.48 mmol) was added. After 15 h, the reaction mixture was purified by preparative RP HPLC. The yellow oil obtained was converted to the HCl salt and lyophilized to afford a red orange solid (25 mg, 34%). MS: (M+H)+=419.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][C:11]([C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1)=[O:12].[H-].[Na+].CI.[C:25](OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]([CH3:25])[C:11]([C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1)=[O:12]
Reactant: CCOC(C)=O
Reactant: COc1ccc(Cl)c(CC(=O)c2ccc(=O)n(C)c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(Cl)c(C(C)C(=O)c2ccc(=O)n(C)c2)c1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-[2-(2-chloro-5-methoxy-phenyl)-acetyl]-1-methyl-1H-pyridin-2-one (9.35 g) in tetrahydrofuran (110 ml) was added sodium hydride (60% dispersion in mineral oil, 1.35 g) in three portions. The mixture was stirred at 40° C. for 1 h and then placed in an ice bath. Methyl iodide (5.01 g) was added dropwise. The mixture was stirred at 0° C. for 10 min and at room temperature for 2 h. Ethyl acetate was added and the mixture was washed with water and brine. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The residue was washed with cyclohexane, filtered and dried to give the title compound as an off-white solid (9.45 g). MS (m/e)=306.2 [M+H+].
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([CH3:45])([CH3:44])[CH2:15][N:16]1[C:21](=[O:22])[C:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:26][CH:25]=2)=[C:19]([CH2:38][CH2:39][CH3:40])[N:18]2[N:41]=[CH:42][N:43]=[C:17]12>C(OCC)(=O)C>[OH:13][C:14]([CH3:44])([CH3:45])[CH2:15][N:16]1[C:21](=[O:22])[C:20]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:3][C:4](=[O:7])[O:5][N:37]=3)=[CH:28][CH:29]=2)=[C:19]([CH2:38][CH2:39][CH3:40])[N:18]2[N:41]=[CH:42][N:43]=[C:17]12
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(C)(C)O)c2ncnn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(C)(C)O)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
A mixture of hydroxylammonium chloride (1.8 g), sodium hydrogen carbonate (2.9 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-(2-hydroxy-2-methylpropyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.76 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.33 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.2 g, 24%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][Br:36])=[CH:28][CH:27]=1)([O-:25])=[O:24]>CC#N>[Br-:36].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:35][CH2:34][CH2:33][O:32][C:29]3[CH:30]=[CH:31][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=3)([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: O=[N+]([O-])c1ccc(OCCCBr)cc1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OCCC[N+]23CCC(C(O)(c4ccccc4)c4ccccc4)(CC2)CC3)cc1
Product: [Br-]
Yield: 67 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0468 g, 0.159 mmol) and 3-bromopropyl 4-nitrophenyl ether (0.0550 g, 0.211 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0590 g, 67.0%). EI-MS m/z 473 (M+) Rt (2.06 min).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:23])[S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[C:10]([Cl:12])=[O:11])(=[O:6])=[O:5].C(N(CC)CC)C.[CH2:31]([OH:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[ClH:12].[CH2:31]([O:38][C:10](=[O:11])[C:9]1[CH:13]=[CH:14][C:15]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[C:7]([S:4](=[O:5])(=[O:6])[N:3]([CH3:23])[CH3:2])[CH:8]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CN1CCN(c2ccc(C(=O)Cl)cc2S(=O)(=O)N(C)C)CC1
Reactant: OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc(C(=O)OCc3ccccc3)cc2S(=O)(=O)N(C)C)CC1
Temperature: 25 °C

Procedure:
40 Grams of 3-dimethylsulfamoyl-4-(4-methylpiperazine-1-yl)-benzoylchloride-hydrochloride (0.1 mole) were dissolved in 0.5 l of benzyl alcohol. 50 Milliliters of triethylamine were added dropwise to the solution, while stirring at room temperature. The mixture was then heated for 10 minutes on the steam bath and was subsequently evaporated in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[NH:5].C([O:14][C:15]([CH:17]1[C:21](=O)[CH2:20][CH2:19][CH:18]1[CH3:23])=O)C>CCO>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([C:4]2[N:6]=[C:15]([OH:14])[C:17]3[CH:18]([CH3:23])[CH2:19][CH2:20][C:21]=3[N:5]=2)[CH:7]=1
Reactant: N=C(N)c1cc(Cl)ccc1F
Reactant: CCOC(=O)C1C(=O)CCC1C
Solvent: CCO
Product: CC1CCc2nc(-c3cc(Cl)ccc3F)nc(O)c21
Temperature: 80 °C
Yield: 35 %

Procedure:
To a solution of 2-fluoro-5-chlorobenzamidine (1.95 g, 11.27 mmol, 1.1 eq) in EtOH (20 ml) was added a solution of 2-methyl-5-oxo cyclopentanecarboxylic acid ethyl ester (prepared according to Wang, C.; Gu, X.; Yu, M. S.; Curran, D. P.: Tetrahedron, 1998, 29, 8355-8370; 1.60 g, 10.26 mmol, 1 eq) in ethanol (5 ml). The reaction mixture was heated to 80° C. overnight. The reaction mixture was cooled to r.t. and the solvent was removed in vacuo to give a crude residue which was purified by recrystallization from hot ethyl acetate to give 2-(5-chloro-2-fluorophenyl)-5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ol (1.0 g, 35%) as a white crystalline solid and the filtrate was further purified by flash column chromatography to give another 850 mg of 2-(5-chloro-2-fluorophenyl)-5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ol.
Reaction SMILES: C([Li])CCC.CN1CCCN(C)C1=[O:14].[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[CH2:22]1[CH2:26][O:25][CH2:24][CH2:23]1>Cl>[CH2:24]([O:25][C:26](=[O:14])[CH:22]=[C:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH3:23]
Reactant: CN1CCCN(C)C1=O
Reactant: C1CCOC1
Reactant: O=C1CCCCC1
Agent: Cl
Agent: [Li]CCCC
Product: CCOC(=O)C=C1CCCCC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
Triethylphosphonoacetate (5.0 g, 22.3 mmol) was dissolved in THF (25 mL) and cooled to −78° C. under a nitrogen blanket. n-Butyllithium (1.6 M in hexanes, 13.9 mL, 22.3 mmol) was added dropwise via syringe followed by the addition of 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone (3 mL). The reaction was stirred at −78° C. for 15 minutes. A solution of cyclohexanone (1.1 g, 11.2 mmol) dissolved in THF (5 mL) was added. The mixture was allowed to warm to room temperature, and stirred for 18 hours. The reaction was diluted with 1N HCl and extracted with EtOAc, then washed with water, dried (Na2SO4), and concentrated in vacuo to provide 1.7 g (89%) of Intermediate 3 as an oil. 1H NMR (DMSO-d6) δ: 1.15 (t, J=7 Hz, 3H), 1.55 (br s, 6H), 2.2 (br s, 2H), 2.75 (br s, 2H), 4.05 (q, J=7 Hz, 2H), 5.6 (s, 1H).
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[N:14]=1.[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25]>CCOCC>[CH2:20]([O:19][C:15]1[N:14]=[C:13]([Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])[CH:18]=[CH:17][CH:16]=1)[CH3:21]
Reactant: CCOc1cccc(Br)n1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(OCC)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 34.4 %

Procedure:
A 2.5M solution of n-butyllithium in hexane (4.5 ml, 11.3 mmol) was added to a stirred solution of 2-bromo-6-ethoxypyridine (Rec. Trav. chim., 1965, 84, 53; 2.1 g, 11.3 mmol) in anhydrous ether (25 ml), under nitrogen, at about −40° C. After about 20 minutes, tri-n-butyltin chloride (3.1 ml, 11.4 mmol) was slowly added and, after a further 15 minutes, the reaction mixture was allowed to warm to room temperature. The resulting mixture was quenched by the addition of aqueous ammonium chloride solution, then the organic phase separated, washed with water, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography, using an elution gradient of pentane:dichloromethane (100:0 to 80:20), to give the title compound (1.6 g, 34%) as a colourless oil. δ(CDCl3): 0.90 (t,9H), 1.08 (t,6H), 1.30-1.42 (m,9H), 1.58 (m,6H), 4.40 (q,2H), 6.53 (d,1H), 6.97 (d,1H), 7.39 (dd,1H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:19]=1>>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:30]([C:27]2[CH:26]=[CH:25][C:24]([C:20]3[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=3)=[CH:29][CH:28]=2)(=[O:31])=[O:32])[C:4]1=[O:17])#[N:13]
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Reactant: O=S(=O)(Cl)c1ccc(-c2cccnc2)cc1
Agent: Cl
Product: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3ccc(-c4cccnc4)cc3)C2=O)c1

Procedure:
The title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride (0.3 g, 1.2 mmol) as in EXAMPLE 24, Part B using 4-pyridin-3-ylbenzenesulfonyl chloride (0.57 g, 2.4 mmol) in place of 6-methoxynaphthalene-2-sulfonyl chloride. The crude product is purified by chromatography (2.5% MeOH/CH2Cl2 to 5% MeOH/CH2Cl2) to obtain a white solid (0.08 g, 0.18 mmol).
Reaction SMILES: C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC(OC)=CC=1)(O)C(O)=O)(=O)C1C=CC(OC)=CC=1.[C:31]1([C:37]2([CH2:42][CH2:43][OH:44])[CH2:41][CH2:40][NH:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O.C(=O)([O-])[O-].[K+].[K+].[CH3:52][O:53][C:54]1[CH:62]=[CH:61][C:60]([N:63]2[CH:67]=[N:66][N:65]=[N:64]2)=[CH:59][C:55]=1[C:56](Cl)=[O:57]>CC(C)=O>[CH3:52][O:53][C:54]1[CH:62]=[CH:61][C:60]([N:63]2[CH:67]=[N:66][N:65]=[N:64]2)=[CH:59][C:55]=1[C:56]([N:39]1[CH2:40][CH2:41][C:37]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([CH2:42][CH2:43][OH:44])[CH2:38]1)=[O:57]
Reactant: OCCC1(c2ccccc2)CCNC1
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)Cl
Agent: COc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCO)(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Combine (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt (3.49 g,6.48 mmol) and acetone (20 mL), water (6 mL), and potassium carbonate (2.70 g, 19.5 mmol). Cool to 0° C. in an ice bath. After 30 minutes, add dropwise a solution of 2-methoxy-5-(1H-tetrazol-1-yl)benzoyl chloride (7.4 mmol) in acetone (20 mL). Warm to ambient temperature. After 18 hours, partition the reaction mixture between ethyl acetate and saturated aqueous sodium bicarbonate solution. Separate the organic layer and extract with brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.[C:38]([OH:48])(=[O:47])[C@@H:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[OH:40].[Cl:49][C:50]1[CH:55]=[CH:54][C:53]([N:56]=[C:57]=[O:58])=[CH:52][CH:51]=1.O>ClCCl>[Cl:49][C:50]1[CH:55]=[CH:54][C:53]([NH:56][C:57]([O:40][C@H:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:38]([OH:48])=[O:47])=[O:58])=[CH:52][CH:51]=1
Reactant: O=C(O)[C@H](O)c1ccccc1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1)O[C@@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.1 400 mg (0.63 mmol) of dibutyltin dilaurate are added to a solution of 10.0 g (65.7 mmol) of (R)-mandelic acid and 10.0 g (65.1 mmol) of 4-chlorophenyl isocyanate in 100 ml of dichloromethane, and the mixture is stirred at room temperature for 24 hours. The reaction mixture is introduced into water and extracted with ethyl acetate. The organic phase is evaporated, giving (R)-(4-chlorophenylcarbamoyloxy)phenylacetic acid as a colourless solid; ESI 306.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][S:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:16]=[CH:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[CH:12](O)[C:11]=2[CH:22]=1>C1C=CC=CC=1>[Cl:3][CH:12]1[C:11]2[CH:22]=[C:7]([S:6][CH3:5])[CH:8]=[CH:9][C:10]=2[CH:16]=[CH:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]1=2
Reactant: CSc1ccc2c(c1)C(O)c1ccccc1C=C2
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CSc1ccc2c(c1)C(Cl)c1ccccc1C=C2

Procedure:
Molar excess (5 milliliters) of thionyl chloride was added to a solution of the 3-methylthio-5H-dibenzo[a,d]cyclohepten-5-ol intermediate in 45 milliliters of benzene and the resulting mixture heated under reflux for two hours to obtain a 5-chloro-3-methylthio-5H-dibenzo[a,d]cycloheptene (chloro compound) intermediate in the reaction mixture. The reaction mixture was subjected to reduced pressure to co-evaporate benzene and unreacted thionyl chloride, and the procedure repeated with several additions of benzene to obtain a purified chloro compound intermediate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]([C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:18]([NH:20][CH:21]1[CH2:23][CH2:22]1)=[O:19])[C:8]2=[O:28].[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[C:29]([NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]([C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:18]([NH:20][CH:21]1[CH2:22][CH2:23]1)=[O:19])[C:8]2=[O:28])(=[O:31])[CH3:30]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OCCN)cc2c1=O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)NCCOc1ccc2ncn(-c3cc(C(=O)NC4CC4)ccc3C)c(=O)c2c1

Procedure:
3-[6-(2-Aminoethoxy)-4-oxoquinazolin-3(4H)-yl]-N-cyclopropyl-4-methylbenzamide (0.1 g), acetyl chloride (0.025 ml), and triethylamine (0.074 ml) were stirred in methylene chloride (2 ml) under an atmosphere of argon for 2 hours at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water (2×), brine, dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting with 10% methanol/ethyl acetate gave the title compound (0.067 g) as a white solid; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 1.82 (s, 3H), 2.14 (s, 3H), 2.86 (m, 1H), 3.47 (m, 2H), 4.13 (m, 2H), 7.52 (m, 2H), 7.59 (s, 1H), 7.74 (d, 1H), 7.83 (s, 1H), 7.90 (d, 1H), 8.09 (t, 1H), 8.20 (s, 1H), 8.43 (d, 1); Mass Spectrum: M+H+ 421.
Reaction SMILES: C([O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=3)=[C:10]([Br:15])[C:11]2=[O:14])=[CH:7][CH:6]=1)(=O)C.C(OC1C=C2C(C(C3C=CC=CC=3)=C(Br)C2=O)=CC=1)(=O)C>>[Br:15][C:10]1[C:11](=[O:14])[C:12]2[C:8]([C:9]=1[C:16]1[CH:17]=[C:18]([F:23])[CH:19]=[C:20]([F:22])[CH:21]=1)=[CH:7][CH:6]=[C:5]([OH:4])[CH:13]=2
Reactant: CC(=O)Oc1ccc2c(c1)C(=O)C(Br)=C2c1cc(F)cc(F)c1
Agent: CC(=O)Oc1ccc2c(c1)C(=O)C(Br)=C2c1ccccc1
Product: O=C1C(Br)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Reaction time: 2.5 h
Yield: 64 %

Procedure:
The procedure of Step 5 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-1-oxo-1H-inden-6-yl acetate obtained in Step 4 as a starting material instead of 2-bromo-1-oxo-3-phenyl-1H-inden-6-yl acetate and being stirred for 2.5 h to obtain the title compound (64%).