Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[CH3:23])[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].CN1CCOCC1.O>C(#N)C>[CH2:28]([O:27][C:25]([NH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[CH3:23])[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1)=[O:26])[CH3:29]
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc(C)c(-c2c3ccccc3nc3ccc(N)cc23)c1
Solvent: CC#N
Solvent: O
Solvent: CN1CCOCC1
Product: CCOC(=O)Nc1ccc2nc3ccccc3c(-c3cc(C)ccc3C)c2c1
Reaction time: 0.25 h

Procedure:
1.42 pbw of the compound 1d and 2.78 pbw of ethyl chloroformate were dissolved in 100 pbv of acetonitrile at 25° C. and 4.85 pbv of N-methylmorpholine were added. The temperature rose to 38° C. during this process. Stirring of the yellow solution was continued for 15 minutes, then it was poured into 400 pbv of water, and the mixture was stirred for 2 hours and the precipitated residue filtered off by suction. Yield: 1.3 pbw (72% of theory). Mp.: 200°-202° C.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Cl:15][C:16]1[CH:17]=[C:18]([C:23]([CH3:38])([CH3:37])[C:24]([CH:26]([C:32]([O:34]CC)=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:25])[CH:19]=[CH:20][C:21]=1[F:22]>OS(O)(=O)=O.C(OCC)C>[Cl:15][C:16]1[CH:17]=[C:18]2[C:19]([C:32]([OH:34])=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:24](=[O:25])[C:23]2([CH3:38])[CH3:37])=[CH:20][C:21]=1[F:22]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccc(F)c(Cl)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCOC(=O)C1=C(O)c2cc(F)c(Cl)cc2C(C)(C)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
P2O5 (1.43 g, 10.1 mmol) was suspended in H2SO4 (5.38 mL) and cooled to 0° C. Diethyl 2-(2-(3-chloro-4-fluorophenyl)-2-methylpropanoyl)malonate (3.62 g, 10.1 mmol) was added, and the reaction was stirred at 0° C. for 1 hour. The reaction mixture was poured into ice, diluted with 150 mL of diethyl ether, added to a separatory funnel, partitioned with water, washed with water (2×75 mL), separated, dried over Na2SO4, and concentrated in vacuo to the title compound (1.46 g) as a white amorphous solid after flash chromatography. MS m/e=313 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[C:20]3[CH2:19][CH2:18][CH2:17][C:16](=O)[C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH:3]=1.CN.[C:24]([BH3-])#[N:25].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[C:20]3[CH2:19][CH2:18][CH2:17][CH:16]([NH:25][CH3:24])[C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc2c1CCCC2=O
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNC1CCCc2c(Oc3cc(Cl)ccc3C#N)cccc21
Yield: 52.1 %

Procedure:
4-Chloro-2-(5-oxo-5,6,7,8-tetrahydronaphthalen-1-yloxy)benzonitrile (0.22 g, 0.74 mmol), methylamine (33% in ethanol, 0.7 mL, 5.6 mmol) and sodium cyanoborohydride (60 mg, 0.81 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (40 mL) for 6 days. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (70 mg, 0.60 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-(5-methylamino-5,6,7,8-tetrahydronaphthalen-1-yloxy)benzonitrile fumarate (134 mg, 42%) as a white solid.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[C:18]([Br:19])=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])=O)(C)(C)C.[ClH:20]>C(OCC)C>[ClH:20].[NH2:8][CH2:9][C:10]1[C:18]([Br:19])=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: CC(C)(C)OC(=O)NCc1c(Br)cccc1C(=O)O
Agent: Cl
Solvent: CCOCC
Product: NCc1c(Br)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 13 %

Procedure:
A mixture of 2-(tert-Butoxy carbonylamino-methyl)-3-bromo-benzoic acid (0.188 g, 0.57 mmol) in 2M HCl in diethyl ether (10 ml) was stirred at room temperature for 18 hours. The solvent was removed by evaporation under reduced pressure. The solid was diluted with ethyl acetate/dioxan (1:1) (10 ml) and stirred at room temperature for 1.5 hours. The solid was filtered off and dried to give the title compound (0.02 g, 13%) as a white solid.
Reaction SMILES: Br[C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.C([Li])CCC.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].[Cl-].[NH4+]>C1COCC1>[S:5]1[CH:6]=[C:2]([Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19])[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]1=2
Reactant: Brc1csc2ccccc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1csc2ccccc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
32.0 9 (150 mmol) of 3-bromo-benzo[b]thiophene are added dropwise at -78° C. to a solution of 150 mmol of n-butyllithium in 500 ml of anhydrous THF. The mixture is stirred at -78° C. for 1 h, 52.1 g (160 mmol) of tri-n-butyl-tin chloride are added and the mixture is allowed to warm to room temperature. For working-up, saturated ammonium chloride solution is added and the mixture is extracted with ether. After chromatography on silica gel using petroleum ether, 14.8 g (23 % of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]([CH3:31])=[C:11]([CH3:30])[C:12]=1[C:13]([C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([O:27]C)=[C:17]([CH3:29])[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C(Cl)Cl>>[CH2:1]([C:8]1[S:9][C:10]([CH3:31])=[C:11]([CH3:30])[C:12]=1[C:13]([C:15]1[CH:20]=[C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:18]([OH:27])=[C:17]([CH3:29])[CH:16]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(C)cc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc1-c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc(-c2ccccc2)c1O
Yield: 76.5 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using (2-benzyl-4,5-dimethyl-thiophen-3-yl)-(5-methyl-6-methoxy-biphen-3-yl)-methanone (1.68 g, 4.09 mmol) and 1M boron tribromide/CH2Cl2 (8.58 mL). Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave 1.29 g (80%) of the title compound. 1H NMR (DMSO-d6) δ1.83 (s, 3 H), 2.17 (s, 3 H), 2.25 (s, 3 H), 3.85 (s, 2 H), 7.07-7.10 (m, 2 H), 7.14-7.26 (m, 3 H), 7.33-7.43 (m, 6 H), 7.54 (d, 1 H), 9.31 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH:18]C(=O)OCC)[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[BrH:26]>O>[BrH:26].[BrH:26].[NH2:18][CH2:17][CH2:16][N:13]1[CH2:14][CH2:15][CH:10]([N:6]2[C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[NH:8][C:7]2=[O:9])[CH2:11][CH2:12]1
Reactant: CCOC(=O)NCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1
Agent: Br
Solvent: O
Product: NCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1

Procedure:
A mixture of 6.6 parts of ethyl {2-[4-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]ethyl }-carbamate, 60 parts of a hydrobromic acid solution 48% in water and 4 parts of water is stirred and refluxed for 2.50 hours. After cooling, the precipitated product is filtered off and crystallized from water, yielding 5.5 parts of 1- [1-(2-aminoethyl)-4-piperidinyl]-5-chloro-1,3-dihydro-2H-benzimidazol-2-one dihydrobromide; mp. > 300° C.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:21]([CH:22]4C[CH2:23]4)=[CH:20][C:16]([C:17]([OH:19])=O)=[C:15]([F:25])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C12(COC3C(C=C)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.C([CH:52]1[CH2:55][N:54]([S:56]([NH2:59])(=[O:58])=[O:57])[CH2:53]1)#N.N1(S(N)(=O)=O)CCC1>>[C:1]12([CH2:11][O:12][C:13]3[C:21]([CH:22]=[CH2:23])=[CH:20][C:16]([C:17]([NH:59][S:56]([N:54]4[CH2:55][CH2:52][CH2:53]4)(=[O:58])=[O:57])=[O:19])=[C:15]([F:25])[CH:14]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: N#CC1CN(S(N)(=O)=O)C1
Agent: C=Cc1cc(C(=O)O)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Agent: NS(=O)(=O)N1CCC1
Product: C=Cc1cc(C(=O)NS(=O)(=O)N2CCC2)c(F)cc1OCC12CC3CC(CC(C3)C1)C2

Procedure:
Following the procedure as described in Example 230 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(adamantan-1-ylmethoxy)-2-fluoro-5-vinylbenzoic acid and 3-cyanoazetidine-1-sulfonamide with azetidine-1-sulfonamide, the title compound was obtained as colorless solid (0.13 g, 36%): 1H NMR (300 MHz, DMSO-d6) δ 11.75 (s, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.04 (d, J=12.9 Hz, 1H), 6.91 (dd, J=11.3 Hz, 17.8 Hz, 1H), 5.93 (dd, J=1.0 Hz, 17.8 Hz, 1H), 5.37 (dd, J=1.0 Hz, 11.3 Hz, 1H), 4.06 (t, J=7.7 Hz, 4H), 3.67 (s, 2H), 2.23-2.12 (m, 2H), 2.00-1.99 (m, 3H), 1.75-1.64 (m, 12H); MS (ES+) m/z 449.1 (M+1); MS (ES−) m/z 447.3 (M−1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9].C(=O)(O)[O-:11].[Na+].[Br-].[Na+].ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O>CC(C)=O.CC1(C)N([O])C(C)(C)CCC1.C(O)(C)C>[O:9]=[C:5]1[NH:6][CH2:7][CH2:8][N:4]1[CH2:3][C:2]([OH:11])=[O:1]
Reactant: O=C1NCCN1CCO
Reactant: O=C([O-])O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: [Br-]
Solvent: CC(C)=O
Solvent: CC(C)O
Product: O=C(O)CN1CCNC1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
To a solution of 1-(2-hydroxy-ethyl)-imidazolidin-2-one (1.00 g, 7.68 mmol) in acetone (70 ml) was added 15% aqueous sodium bicarbonate (21 ml) to give a white slurry, which was then cooled to 0° C. (JOC 2003, 68, 4999-5001). Sodium bromide (0.16 g, 1.54 mmol) and TEMPO (0.024 g, 0.15 mmol) were added and the resulting mixture was stirred for 10 minutes followed by the addition of trichloroisocyanuric acid (3.57 g, 15.4 mmol) in four equal portions added every five minutes. The pale yellow slurry was warmed to 25° C. and stirred for an additional 12 hours to yield a yellow solution. Iso-propanol (9 ml) was added and the mixture was stirred for 45 minutes to give a white slurry, which was filtered through a Celite® cake. The filtrate was concentrated in vacuo, quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (50 ml). The aqueous phase was acidified with 4N HCl until pH ˜2 and then put on for continuous extraction with 5% methanol in methylene chloride (˜120 ml) for 16 hours. The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to yield (2-oxo-imidazolidin-1-yl)-acetic acid (0.530 g, 48%) as a white solid.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[C:7](=O)(O)[O-].[Na+].[CH3:12][O:13][C:14](=[O:29])[C:15]1[CH:24]=[C:23]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=1.IC>O.C(OCC)(=O)C.CN(C=O)C.C(O)C>[CH3:12][O:13][C:14](=[O:29])[C:15]1[CH:24]=[C:23]([S:25]([CH3:7])(=[O:27])=[O:26])[CH:22]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=1
Reactant: COC(=O)c1cc(C(=O)OC)cc(S(=O)(=O)Cl)c1
Reactant: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(C(=O)OC)cc(S(C)(=O)=O)c1
Temperature: 50 °C

Procedure:
Dissolve sodium sulfite (1.7 g, 13.51 mmol) and sodium bicarbonate (1.2 g, 14.19 mmol) in water (10 mL). Add 5-chlorosulfonyl-isophthalic acid dimethyl ester (2.0 g, 6.76 mmol) and ethanol (2 mL). Heat to 50° C. for 2 h, concentrate and dry the solid. Add DMF (40 mL) and iodomethane (4.56 g, 32 mmol) and stir at room temperature for 3 h. Dilute with ethyl acetate, wash with 10% aqueous potassium carbonate, 1 N lithium chloride and saturated aqueous sodium chloride. Dry (magnesium sulfate) and concentrate to give the title compound as a solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].CCOCC.[C:17](O)(=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].CS(O)(=O)=O>>[C:17]([O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: Oc1ccc2ccccc2c1
Agent: CS(=O)(=O)O
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCC(=O)Oc1ccc2ccccc2c1
Temperature: 220 °C

Procedure:
To a four neck round bottom flask fitted with nitrogen inlet, mechanical stirrer, temperature probe and condenser is charged 1100.40 g (1.84 moles) of the Alkoxylate from example 15 and 499.60 g (1.76 moles) of Stearic Acid. A catalytic amount of Methanesulfonic Acid (1.6 g) is charged and the reaction mixture is heated to 220° C. under nitrogen sparge. The reaction is monitored by measuring the acid value to an AV of preferably less than 5. Once the AV is reached, the temperature is cooled to 85° C. and the catalyst is neutralized with an equivalent molar amount of 45% KOH and washed once with water. The reaction is dried under vacuum yielding the desired product.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([I:11])[C:9]=1[OH:10])[CH:5]=[O:6].[H-].[Na+].[CH2:14](Cl)[O:15][CH2:16][CH2:17][O:18][CH3:19]>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([I:11])[C:9]=1[O:10][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:5]=[O:6]
Reactant: O=Cc1cc(I)c(O)c(I)c1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCOc1c(I)cc(C=O)cc1I
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69.7 %

Procedure:
To a stirred solution of 3,5-diiodo-4-hydroxybenzaldehyde (10.0 g, 26.7 mmol) in THF (267 mL) at 0° C. was added NaH (1.39 g, 34.7 mmol). After 0.5 h at this temperature, MEMCl (4.88 mL, 42.7 mmol) was added dropwise. The reaction mixture was stirred for another 15 min. at 0° C. and then at room temperature for 18 h. The resulting mixture was quenched with 0.1 N NaOH and extracted with Et2O (1000 mL). The organic layer was washed with 0.1 N NaOH (3×100 mL) and brine (100 mL) and then dried (MgSO4). After concentration, the residue was purified by flash chromatography (5 to 15% EtOAc/petroleum ether gradient) to afford the product (8.60 g, 69%) as a solid; 1H NMR (CDCl3) δ 3.44 (s, 3H), 3.67 (t, J=5.5 Hz, 2H), 4.16 (t, J=5.5 Hz, 2H), 5.34 (s, 2H), 8.29 (s, 2H), 9.82 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][O:8][C@H:7]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:6]1[CH:14]=[O:15])=[O:4].I[CH2:17][CH2:18][CH2:19][CH3:20].CN(P(N(C)C)(N(C)C)=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.CCOCC>[CH3:1][O:2][C:3]([C@:5]1([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:9][O:8][C@H:7]([C:10]([CH3:11])([CH3:12])[CH3:13])[N:6]1[CH:14]=[O:15])=[O:4]
Reactant: COC(=O)[C@@H]1CO[C@H](C(C)(C)C)N1C=O
Reactant: CCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCC[C@@]1(C(=O)OC)CO[C@H](C(C)(C)C)N1C=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
To a solution of (2R,4S)-2-tert-butyl-3-formyloxazolidine-4-carboxylic acid methyl ester (4.6 g, 21.4 mmol) [see D. Seebach, J. D. Aebi, M. Gander-Coquoz and R. Naef, Helv. Chim. Acta., 70, 1194 (1987)] in dry THF (120 mL) under N2 was added 1-iodobutane (12.2 mL, 106.8 mmol) and HMPA (12 mL). The mixture was cooled to −78° C. and a solution of sodium bis(trimethylsilyl)amide in THF (1 M, 32 mL, 32 mmol) was added dropwise over 15 minutes. After 2 h, the reaction mixture was warmed to 0° C. and quenched with saturated aqueous NH4Cl (200 mL). The quenched reaction mixture was diluted with ether (400 mL) and washed with water (3×200 mL) and brine (200 mL), then dried (Na2SO4) and filtered. Concentration of the filtrate and flash chromatography of the residue (20% ethyl acetate/hexanes) provided the title compound as a pale brown solid (4.0 g, 69%). MS(ES) m/e 272 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:25]([CH:29]1[CH2:34][CH2:33][CH:32](OS(C)(=O)=O)[CH2:31][CH2:30]1)([CH3:28])([CH3:27])[CH3:26]>CC(O)(C)C.CC(=O)CC>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH:32]3[CH2:33][CH2:34][CH:29]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:30][CH2:31]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC(OS(C)(=O)=O)CC1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)ccc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2cc(OC3CCC(C(C)(C)C)CC3)ccc2C1
Temperature: 100 °C
Yield: 58.6 %

Procedure:
A mixture of 6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.1 g, 4.4 mmol), cesium carbonate (4.3 g, 13 mmol), and methanesulfonic acid 4-tert-butyl-cyclohexyl ester (2.2 g, 8.8 mmol) in t-BuOH (12 mL) and 2-butanone (6.0 mL) was heated in a sealed vial at 100° C. overnight. The mixture was partitioned between water and ether. The organic phase was washed with water, dried over MgSO4, filtered and concentrated. The residue was purified via a silica gel column eluted with EtOAc in hexanes from 0 to 30% to give white precipitate (1.0 g, yield: 58%). 1H NMR (400 MHz, CDCl3) δ 6.99 (d, 1H), 6.74 (dd, 1H), 6.67 (d, 1H), 4.49 (s, 2H), 4.07 (m, 1H), 3.61 (s, 2H), 2.78 (m, 2H), 2.18 (d, 2H), 1.85 (d, 2H), 1.48 (s, 9H), 1.37 (m, 2H), 1.18-1.00 (m, 3H), 0.87 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][O:1][C:2]2[CH:15]=[CH:14][C:5]3[C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:7][O:8][C:4]=3[CH:3]=2)=[CH:19][CH:20]=1)[CH3:26]
Reactant: CCOc1ccc(CCl)cc1
Reactant: COC(=O)Cc1coc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(COc2ccc3c(CC(=O)OC)coc3c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
To a solution of methyl (6-hydroxy-1-benzofuran-3-yl)acetate (10.0 g, 48.5 mmol) in DMF (100 mL) were added 1-(chloromethyl)-4-ethoxybenzene (12.4 g, 72.7 mmol) and potassium carbonate (13.5 g, 97.0 mmol), and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed twice with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was washed with diethyl ether and hexane to give the title compound (15.8 g, yield 96%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([OH:11])=O)[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:45][C:46]1[CH:51]=[CH:50][C:49]([CH:52]2[CH2:66][N:56]3[C:57](=[O:65])[NH:58][C:59]4[CH:60]=[CH:61][CH:62]=[CH:63][C:64]=4[C:55]3=[N:54][CH2:53]2)=[CH:48][CH:47]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([CH:52]3[CH2:66][N:56]4[C:57](=[O:65])[NH:58][C:59]5[CH:60]=[CH:61][CH:62]=[CH:63][C:64]=5[C:55]4=[N:54][CH2:53]3)=[CH:48][CH:47]=2)=[O:11])[CH2:6][CH2:7]1
Reactant: CN1CCN(CC(=O)O)CC1
Reactant: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(CC(=O)Nc2ccc(C3CN=C4c5ccccc5NC(=O)N4C3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.5 %

Procedure:
A mixture of (4-Methyl-piperazin-1-yl)-acetic acid (3.2 mg, 0.020 mmol), N,N-diisopropylethylamine (0.017 mL, 0.10 mmol), and HBTU (9.1 mg, 0.024 mmol) in 0.6 mL DMF was stirred at rt for 10 minutes, then 3-(4-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (7.6 mg, 0.026 mmol) added and the reaction continued at rt. At 1.75 hours the reaction mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated to an oily solid. The residue was chromatographed eluting with 10% MeOH/CHCl3 containing Et3N. The obtained oily solid was then partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and evaporated to give the title compound as a white solid (4.8 mg, 73%). 1H NMR (CDCl3) δ: 9.14 (s, 1H), 8.99 (br. s, 1H), 8.11 (d, J=7.9 Hz, 1H), 7.58 (d, J=8.2 Hz, 2H), 7.38-7.44 (m, 1H), 7.22-7.27 (m, 2H), 7.12 (t, J=7.6 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 4.53 (dt, J=13.1, 3.6 Hz, 1H), 3.95 (dt, J=16.2, 3.6 Hz, 1H), 3.53-3.69 (m, 2H), 3.15 (s, 2H), 3.00-3.12 (m, 1H), 2.67 (br. s, 4H), 2.52 (br. s, 4H), 2.33 (s, 3H).
Reaction SMILES: [N:1]1([C:8]([NH:10][C@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:50]([O:54][C:55](=[O:73])[C@@H:56]([NH2:72])[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)=[CH:60][CH:59]=1)([CH3:53])([CH3:52])[CH3:51]>C(#N)C>[C:50]([O:54][C:55](=[O:73])[C@@H:56]([NH:72][C:12](=[O:14])[C@H:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)=[CH:60][CH:59]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)C[C@@H](NC(=O)N1CCCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)C[C@@H](NC(=O)N1CCCCCC1)C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
A solution of the product from Example AA ((R)-2-[(azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid) (1.0 g, 3.9 mmol) and triethylamine (1.1 mL, 7.8 mmol) in acetonitrile (15 mL) was treated with HBTU (1.54 g, 4.06 mmol). The resulting solution was treated with the product from Example A ((S)-2-amino-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (1.33 g, 4.06 mmol), and the resulting solution was stirred at room temperature for 30 minutes and allowed to stand overnight. The reaction mixture was concentrated and the residue dissolved in ethyl acetate (100 mL) and washed sequentially with 0.6 M aqueous NaHCO3 solution, saturated aqueous NaCl solution, and water. The organic phase was dried over MgSO4 and activated charcoal, filtered, and concentrated. The residue was purified by chromatography (silica gel, 25% ethyl acetate/hexane) to give the title compound as a white solid (1.9 g, 86%), mp=64-66° C.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[CH3:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1.[K+].[Br-]>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:22][C:23]2[CH:30]=[CH:29][C:26]([CH3:27])=[CH:25][CH:24]=2)[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: Cc1ccc(CCl)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Agent: [Br-]
Agent: [K+]
Product: Cc1ccc(CN2C(=O)C(CCO)Oc3ccccc32)cc1

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and G alkylating with 4-methylbenzyl chloride, in 50% overall yield. This material was crystallized from ether to afford a white solid, mp 92°-94° C.; IR (KBr) 3496, 1659, 1503, 1405, 1304, 1283, 1248, 1063, 801 cm-1 ; 1H NMR (CDCl3) δ2.18-2.36 (m, 5H), 3.91 (q, J=5.7, 2H), 4.83 (dd, J=7.4, 5.7, 1H), 5.12 (s, 2H), 6.90-7.00 (m, 4H), 7.13 (s, 4H); MH+ at m/z=298; Anal. Calc'd for C18H19NO3 : C, 72.71; H, 6.44; N, 4.71. Found: C, 72.71; H, 6.48; N, 4.65.