Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)=[CH:2]1.Br[CH2:28]CCC1C2C(=CC=CC=2)CC=1>>[CH2:28]1[C:8]2[C:9](=[CH:1][CH:2]=[CH:6][CH:7]=2)[C:4]([CH2:3][CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([NH:18][C:19](=[O:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:17]2)=[CH:5]1
Reactant: BrCCCC1=CCc2ccccc21
Reactant: O=C(NC1CCN(CCC2=CCc3ccccc32)CC1)c1ccccc1
Product: O=C(NC1CCN(CCCC2=CCc3ccccc32)CC1)c1ccccc1

Procedure:
Prepared in a similar manner to the compound of Example 14 but using 3-(3-bromopropyl)indene in place of 3-(2-bromoethyl)indene. The title compound crystallised from isopropanol, m.p. 157°-9° C. (Found: C, 79.8; H, 8.1. N, 7.7. C24H28N2O requires C, 80.0; H, 7.8; N, 7.8%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]([C:22]3([CH2:25]OS(C)(=O)=O)[CH2:24][CH2:23]3)[O:13][N:12]=2)=[CH:7][CH:6]=1.[C-:31]#[N:32].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([C:22]3([CH2:25][C:31]#[N:32])[CH2:23][CH2:24]3)[O:13][N:12]=2)=[CH:9][CH:10]=1
Reactant: COCOc1ccc(-c2noc(C3(COS(C)(=O)=O)CC3)c2-c2ccccc2)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCOc1ccc(-c2noc(C3(CC#N)CC3)c2-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 100.6 %

Procedure:
To a mixture consisting of methanesulfonic acid 1-[3-(4-methoxymethoxy-phenyl)-4-phenyl-isoxazol-5-yl]-cyclopropylmethyl ester (synthetic intermediate prepared in Example 11, Step iv, 0.45 g) in N,N-dimethylformamide (4 mL) is added potassium cyanide (0.17 g.) The mixture is stirred at 80° C. for five hours and is subsequently diluted with ethyl acetate (30 mL.) The mixture is sequentially washed with water (15 mL) and brine solution (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the synthetic intermediate {1-[3-(4-methoxymethoxy-phenyl)-4-phenyl-isoxazol-5-yl]-cyclopropyl}-acetonitrile (0.38 g.)
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:13](=[O:16])([O-])[O-:14].[K+].[K+]>CN(C)C=O>[C:13]([CH:3]1[CH2:2][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][S:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1)([OH:14])=[O:16]
Reactant: O=C([O-])[O-]
Reactant: CC(C(=O)O)c1cccc(S)c1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C(=O)O)c1cccc(SCC2CCCCC2C(=O)O)c1
Temperature: 170 °C
Reaction time: 3 h
Yield: 192.6 %

Procedure:
To 2-(3-mercaptophenyl)propionic acid (2.7 g) were added cis-2-(hydroxymethyl)cyclohexanecarboxylic acid lactone (2.5 g), potassium carbonate (2.5 g) and dimethylformamide (25 ml). The mixture was heated with stirring for 3 hours in an oil bath maintained at 170° C. and evaporated to dryness under reduced pressure. The residue was dissolved in water, acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layers were washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give the title compound (4.6 g) as an oil. IR νmaxfilm cm-1 : 1700 (C=O). MS m/e: 322 (M+).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:24]4[CH:23]=[CH:22][CH:21]=[C:20]([F:19])[CH:25]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: OB(O)c1cccc(F)c1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc(F)c4)cc3CC[C@@H]12
Yield: 84.2 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 3-fluorophenylboronic acid (109 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 18 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 177 mg (84%) of the title compound as an amorphous foam. mp 116°-120°. FDMS: m/e=323. α[D]589 =+81.84 (c=0.47, chloroform).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH:14]=[CH:13][CH2:12][O:11]1)([O-])=O.[N+](C1C=CC=CC=1C1CC=CO1)([O-])=O>>[O:11]1[CH2:12][CH2:13][CH2:14][CH:10]1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccccc1C1C=CCO1
Agent: O=[N+]([O-])c1ccccc1C1CC=CO1
Product: Nc1ccccc1C1CCCO1

Procedure:
3a and 3b were carried through the reduction step to afford 2-tetrahydrofuran-2-yl-aniline (4) as set forth in Example 1.b (below). Analysis of this material revealed that both 3a and 3b were formed with the same major enantiomer, with an overall 70% ee. It is unknown whether the absolute stereochemistry of the major enantiomer was (R) or (S).
Reaction SMILES: N1C=C2C(N=CN2)=NC=1.[Cl:10][C:11]1[CH:12]=[C:13]([C:26]2[N:34]=[C:33]([CH3:35])[N:32]=[C:31]3[C:27]=2[N:28]=[CH:29][N:30]3C2CCCCO2)[C:14]([NH:17][C:18]2[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)=[N:15][CH:16]=1.Cl.[OH-].[Na+]>C1COCC1.C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[C:13]([C:26]2[N:34]=[C:33]([CH3:35])[N:32]=[C:31]3[C:27]=2[N:28]=[CH:29][NH:30]3)[C:14]([NH:17][C:18]2[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)=[N:15][CH:16]=1
Reactant: COc1ccc(Nc2ncc(Cl)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncc(Cl)cc2-c2nc(C)nc3[nH]cnc23)cn1
Temperature: 100 °C
Yield: 73.8 %

Procedure:
The title compound was prepared following the procedure described in Example 62, with the deprotection of the purine performed as follows. A glass microwave reaction vessel was charged with 5-chloro-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-amine (0.100 g, 0.221 mmol) and 1.0 M hydrochloric acid (1.106 mL, 1.106 mmol) in THF (2 ml). The reaction mixture was stirred and heated in a Discover model microwave reactor (CEM, Matthews, N.C.) at 100° C. for 10 minutes (100 watts, Powermax feature on). The mixture was diluted with DCM, made basic (pH about 12) with 1 N NaOH and allowed mixture to stir for 10 min. The precipitate was collected by filtration and washed with diethyl ether to give 5-chloro-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)pyridin-2-amine (0.060 g, 0.163 mmol, 73.7% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 13.83 (s, 1H); 10.24 (s, 1H); 8.54 (s, 1H); 8.18 (s, 2H); 8.06 (s, 1H); 3.85 (s, 3H); 2.73 (s, 3H); 1.62 (s, 2H). m/z (ESI, +ve ion) 367.9 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C1COCC1>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:10](=[O:12])/[CH:9]=[CH:8]/[C:4]2[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=2)[CH2:16][CH2:15]1
Reactant: CN1CCNCC1
Reactant: O=C(O)/C=C/c1cccc(O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CN1CCN(C(=O)/C=C/c2cccc(O)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
Under nitrogen, to a solution of (2E)-3-(3-hydroxyphenyl)-2-propenoic acid (330 mg, 2.0 mmol) in THF (20 mL), was added 1-methylpiperazine (400 mg, 4.0 mmol), HOBT (810 mg, 6.0 mmol), HBTU (760 mg, 2 mmol), followed with 4-methylmorpholine (670 μL, 6.0 mmol). This mixture was then stirred at rt for overnight. The reaction mixture was concentrated and the residue was purified with reverse phase HPLC (5% MeCN/H2O→60% MeCN/H2O) to afford the title compound as a white solid (397 mg, 81%). MS (S+) m/e 247 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:28](=[O:38])[NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=2)=[CH:20][C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:16])[CH2:5][NH:6]C(OC(C)(C)C)=O.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>C(Cl)Cl>[F:43][C:42]([F:45])([F:44])[C:40]([OH:46])=[O:41].[CH3:1][O:2][C:3](=[O:39])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:28](=[O:38])[NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=2)=[CH:20][C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:16])[CH2:5][NH2:6]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-3-tert-Butoxycarbonylamino-2-{[5-(3-hydroxy-benzylcarbamoyl)-3-phenyl-thiophene-2-carbonyl]-amino}-propionic acid methyl ester (0.148 g, 0.27 mmol) in DCM (5 mL) was added TFA (2.0 mL). The mixture was stirred at room temperature 1 h and evaporated. Isolate 0.23 g of crude product which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3][CH2:2]1.[C:16]1([C@@H:22]2[CH2:24][C@H:23]2[C:25](O)=[O:26])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[C:11]([O:10][C:9](=[O:15])[NH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:25]([CH:23]2[CH2:24][CH:22]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:26])[CH2:2][CH2:3]1)([CH3:12])([CH3:14])[CH3:13]
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC1CCN(C(=O)C2CC2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl piperidin-4-ylmethylcarbamate (Epsilon, 0.80 g, 3.73 mmol), (1R,2R)-2-phenylcyclopropanecarboxylic acid (T. Riley eta al, J. Med. Chem., 15, 1187, 1972) (0.61 g, 3.73 mmol), EDC (1.07 g, 5.60 mmol) and HOBt (0.76 g, 5.60 mmol) in DMF (10 mL) was stirred at RT for 2 h. The reaction mixture was diluted with ethyl acetate (200 mL), washed with aq. sat. NaHCO3 (50 mL), water (5×50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel 60 (90 g), eluting with 10:1-10:89-80 CH2Cl2:2-propanol:hexane to give the title compound. (1.22 g, 91.0%). M.S. (M+1): 359.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[CH2:17]([NH2:20])[CH2:18][CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(O)(=O)C>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH:20][CH2:17][CH2:18][CH3:19])[CH2:5][CH2:4]1
Reactant: CCCN
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCNC1CCC(c2ccccc2)(N(C)C)CC1

Procedure:
10.0 g 4-dimethylamino-4-phenyl-cyclohexanone were dissolved in 160 ml analytical grade tetrahydrofuran, and 2.72 g n-propylamine followed by 5.97 ml glacial acetic acid were added, while stirring in an ice-bath. 13.6 g sodium triacetoxyborohydride were then added in portions in the course of 15 minutes and the mixture was subsequently stirred for approx. 65 hours. For working up, 85 ml two molar sodium hydroxide solution were added dropwise (pH>10) and the mixture was extracted three times with 100 ml diethyl ether each time. The combined organic phases were then washed twice with 100 ml water each time, dried over sodium sulfate and filtered and the filtrate was concentrated. 5.00 g of the crude product obtained (9.79 g) were chromatographed over silica gel with diethyl ether, to which one percent by volume of aqueous ammonia solution (25 wt. %) was added, and an addition of methanol increasing from one to forty per cent by volume. 2.79 g of the nonpolar and 1.33 g of the polar diastereoisomer of N,N-dimethyl-1-phenyl-N′-propyl-cyclohexane-1,4-diamine were obtained. From a sample of 356 mg of the nonpolar diastereoisomer, 253 mg of the corresponding hydrochloride were obtained as described for example 1 with water and chlorotrimethylsilane in 2-butanone.
Reaction SMILES: C(OC(N1CCCCC1[CH2:14][NH:15][N:16]1[CH2:21][CH2:20][N:19]([S:22]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([Cl:35])[CH:31]=3)[CH:26]=2)(=[O:24])=[O:23])[CH2:18][C:17]1=[O:36])=O)(C)(C)C.CO.Cl.Cl.Cl[C:42]1[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=1>C(OCC)(=O)C.C(O)C.C(N(CC)CC)C>[Cl:35][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([S:22]([N:19]1[CH2:20][CH2:21][N:16]([N:15]([CH3:14])[CH:42]3[CH2:47][CH2:46][N:45]([C:42]4[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=4)[CH2:44][CH2:43]3)[C:17](=[O:36])[CH2:18]1)(=[O:23])=[O:24])[CH:34]=[CH:33]2
Reactant: Clc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CNN1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1=O
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1=O
Yield: 50.9 %

Procedure:
1-{[1-(tert-Butoxycarbonyl)piperidinyl]methylamino}-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (1.63 g) was combined with methanol (10 ml) and a 4N solution of hydrochloric acid in ethyl acetate (15 ml) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated and the residue obtained was combined with 4-chloropyridine hydrochloride (950 mg), triethylamine (3.8 g) and ethanol (100 ml), and reacted in a sealed tube at 150° C. for 15 hours. The reaction mixture was concentrated and the residue was combined with a 1N aqueous solution of sodium hydroxide, extracted with dichloromethane, dried and concentrated. The residue obtained was purified by a column chromatography (dichloromethane: 10% aqueous ammonia-containing methanol=20:1) and crystallized from ether to obtain the title compound (794 mg) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[S:20][C:19]([C:21]([O:23]C)=O)=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[NH:26]1[CH2:30][CH2:29][N:28]=[C:27]1[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH:39][CH3:40])=[CH:33][CH:32]=1.C[Al](C)C>C(Cl)Cl>[NH:28]1[CH2:29][CH2:30][N:26]=[C:27]1[C:31]1[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][N:39]([CH3:40])[C:21]([C:19]2[S:20][C:16]([CH2:15][N:13]([S:10]([C:6]3[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:25])(=[O:12])=[O:11])[CH3:14])=[N:17][N:18]=2)=[O:23])=[CH:35][CH:36]=1
Reactant: CNCCc1ccc(C2=NCCN2)cc1
Reactant: COC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)s1
Agent: C[Al](C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N(C)CCc3ccc(C4=NCCN4)cc3)s2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AT using methyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-thiadiazole-2-carboxylate (50 mg, 0.13 mmol), 2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylethanamine (110 mg, 0.54 mmol) and trimethylaluminium (2 M in toluene, 0.27 mL) in DCM (10 mL). A portion of the crude product was purified using prep method A, then prep method B.
Reaction SMILES: [C:1]1([C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:8][CH:9]2[N:12]([CH:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])O)[C:11](=[O:25])[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.S(Cl)([Cl:46])=O>O1CCCC1>[C:1]1([C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:8][CH:9]2[N:12]([CH:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[Cl:46])[C:11](=[O:25])[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(OCc1ccccc1)C(O)N1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)C(Cl)N1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To a solution of 4-(triphenylmethylthio)-1-(benzyloxycarbonylhydroxymethyl)azetidin-2-one (1.0 g) and pyridine (240 μl) in tetrahydrofuran (THF) (15 ml) at 0° C. under nitrogen was added slowly thionyl chloride (180 μl ). After 15 minutes the precipitate was collected by filtration and the filtrate evaporated. The residue was rapidly eluted through a short plug of silica gel using a 15 to 30% ethyl acetate/hexane solvent gradient to afford 4-(triphenylmethylthio)-1-(benzyloxycarbonylchloromethyl)azetidin-2-one (900 mg) as a 4:3 mixture of diastereomers.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=O)[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.ON1C2C=CC=CC=2N=N1.[CH2:37]([NH2:44])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:44][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:25])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCN
Reactant: O=C(O)CCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCNC(=O)CCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reaction time: 2 h
Yield: 86 %

Procedure:
Part C, Method 1. To a solution of 5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentanoic acid (2.0 g, 0.0057 mol) in N,N-dimethylformamide (25 mL) was added 1-hydroxybenzotriazole hydrate (0.93 g, 0.0069 mol) followed by a solution of heptylamine (1.10 mL, 0.86 g, 0.0074 mol) in N,N-dimethylformamide (10 mL). The reaction mixture was cooled to 0° and dicyclohexylcarbodiimide (1.42 g, 0.0069 mol) was added portionwise as a solid. The reaction mixture was stirred for 2 hours at 0° and then stirred for 48 hours at ambient temperature. The solids were filtered and washed with N,N-dimethylformamide. The filtrate was concentrated and the residue was chromatographed with 1:1 hexane-ethyl acetate. The resulting solid was recrystallized from acetonitrile and triturated with hexane to give 5-(4,5-diphenyl-1H-imidazol-2-ylthio)-N-heptylpentanamide (2.21 g, 0.0049 mol) as a white solid, mp 104°-106°. 1H NMR (CDCl3) δ 11.6(s,1H) , 7.6-7.1(m,10H), 6.1-6.0(m,1H), 3.1-2.8(m,4H), 2.2(t,2H,J=7 Hz), 1.9-1.7(m,2H), 1.7-1.5(m,2H), 1.4-1.1(m,10H), 0.9(t,3H,J=8 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]=[CH:7]2.CN(C=O)C.[CH3:18][C:19]([NH2:22])([CH3:21])[CH3:20]>O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:22][C:19]([CH3:21])([CH3:20])[CH3:18])[N:8]=[CH:7]2
Reactant: CC(C)(C)N
Reactant: Clc1ncc2cccc(Br)c2n1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)Nc1ncc2cccc(Br)c2n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 41.5 %

Procedure:
8-Bromo-2-chloroquinazoline (D-L Chiral Chemicals, LLC, Princeton, N.J.) (200 mg, 0.82 mmol) was treated with DMF (2.0 mL) and 2-methylpropan-2-amine (Aldrich Chemical Company, 0.44 mL, 4.11 mmol) and stirred at RT overnight (17 h). The reaction mixture was treated with water, extracted with EtOAc (30 mL), washed with brine (2×), dried over MgSO4, filtered and concentrated. The crude residue was purified on the ISCO Combiflash RF (12 g Thomson SingleStep column, using a gradient of 0-50% EtOAc in hexanes) affording 8-bromo-N-(tert-butyl)quinazolin-2-amine (374a) (94 mg, 0.34 mmol, 41% yield) as a light yellow amorphous solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.87 (1H, s), 7.95 (1H, dd, J=7.5, 1.3 Hz), 7.58 (1H, dd, J=7.9, 1.3 Hz), 7.05 (1H, t, J=7.7 Hz), 5.43 (1H, br. s.), 1.54 (9H, s). m/z (ESI, +ve ion) 280.0/282.0 (M+H)+. A 5-mL glass microwave reaction vessel was charged with 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (609) (120 mg, 0.46 mmol), K2PO4 (182 mg, 0.86 mmol), Pd2dba3 (Strem Chemicals, 13.07 mg, 0.014 mmol), Xphos (Strem Chemicals, 13.61 mg, 0.03 mmol) and 8-bromo-N-(tert-butyl)quinazolin-2-amine (374a) (80 mg, 0.29 mmol) in dioxane (2.5 mL) and water (0.80 mL). The reaction was stirred and heated in a heating block at 110° C. for 1 h. The reaction mixture was treated with water, extracted with EtOAc (30 mL), washed with brine and concentrated. The crude residue was purified on the ISCO Combiflash RF (25 g Thomson SingleStep column, using a gradient of 0-20% MeOH) affording 2-(2-(tert-butylamino)quinazolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (53.9 mg, 0.16 mmol, 56% yield) as a light yellow amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.37 (1H, br. s.), 9.17 (1H, s), 8.10 (1H, d, J=6.8 Hz), 7.64 (1H, d, J=7.0 Hz), 7.35 (1H, s), 7.25 (1H, t, J=7.6 Hz), 7.05 (1H, br. s.), 6.98 (1H, br. s.), 3.40-3.47 (3H, m), 2.92 (2H, br. s.), 1.52 (9H, s). m/z (ESI, +ve ion) 336.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=4[F:23])[C@H:14]([C:24]([NH:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([OH:33])[CH2:29][CH2:28]4)=[O:25])[N:13]([C@H](C4C=CC=CC=4)[C@@H](O)C4C=CC=CC=4)[C:12]43[CH2:53][CH2:52][C:51]([CH3:55])([CH3:54])[CH2:50][CH2:49]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[N+]([O-])([O-])=O.[NH4+].[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@:6]3([C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=4[F:23])[C@H:14]([C:24]([NH:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([OH:33])[CH2:29][CH2:28]4)=[O:25])[NH:13][C:12]43[CH2:49][CH2:50][C:51]([CH3:55])([CH3:54])[CH2:52][CH2:53]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CCC2(CC1)N([C@H](c1ccccc1)[C@@H](O)c1ccccc1)[C@@H](C(=O)N[C@H]1CC[C@H](O)CC1)[C@H](c1cccc(Cl)c1F)C21C(=O)Nc2cc(Cl)ccc21
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: O
Solvent: CC#N
Product: CC1(C)CCC2(CC1)N[C@@H](C(=O)N[C@H]1CC[C@H](O)CC1)[C@H](c1cccc(Cl)c1F)[C@]21C(=O)Nc2cc(Cl)ccc21
Reaction time: 0.17 h

Procedure:
The compound (230 mg, 0.29 mmol) obtained in Step 2 above was dissolved in acetonitrile (10 ml) and water (3 ml), cerium (IV) diammonium nitrate (318 mg, 0.58 mmol) was added under ice cooling and the resulting mixture was stirred for 10 minutes. Potassium carbonate (160 mg, 1.16 mmol) was added to the reaction mixture, the resulting mixture was stirred and then insoluble matter was removed by filtration through celite. The filtrate was diluted with ethyl acetate, washed with brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography [chloroform:methanol=100:0→30:1→20:1 (v/v)] to give 90 mg (53%) of the title compound as a pale yellow solid.