Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH2:17]1[C:20]2([CH2:23][NH:22][CH2:21]2)[CH2:19][O:18]1>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([N:22]2[CH2:23][C:20]3([CH2:17][O:18][CH2:19]3)[CH2:21]2)=[O:16])=[CH:5][CH:4]=1
Reactant: C1NCC12COC2
Reactant: COc1ccc(C(=O)O)c2c(C)cccc12
Product: COc1ccc(C(=O)N2CC3(COC3)C2)c2c(C)cccc12

Procedure:
4-Methoxy-8-methyl-1-naphthoic acid (Step-5 of Intermediate-22) was reacted with 2-oxa-6-azaspiro[3.3]heptane by following the similar procedure as described in Step-6 of Intermediate-22.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]([CH2:7][CH2:8][C:9]([OH:11])=O)[CH2:4][CH2:3]1.C(OC(=O)C)(=O)C>C(O)(C)C>[CH2:4]1[CH:5]2[N:6]([C:9](=[O:11])[CH2:8][CH2:7]2)[C:2](=[O:1])[CH2:3]1
Reactant: O=C(O)CCC1CCC(=O)N1
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)O
Product: O=C1CCC2CCC(=O)N12
Temperature: 90 °C
Reaction time: 6 h
Yield: 89.8 %

Procedure:
5-Oxo-2-pyrrolidinepropanoic acid (15.7 g, 0.1 mol) was added to 45 ml of acetic anhydride and the mixture was heated slowly to 90° C. and held at that temperature for six hours. The mixture was cooled and the volatile materials stripped off at a temperature of 60° C. under vacuum. The residue (14.2 g) was dissolved in 230 ml of isopropyl alcohol, the solution decolorized, filtered, and concentrated to 30 ml. This solution was cooled 0°-5° C. for two hours, and the solid which separated was collected by filtration, washed twice with 25-ml portions of isopropyl alcohol to yield 12.5 g (89.9%) of dihydro-1H-pyrrolizine-3,5-(2H,6H)-dione, mp 180.2°-181.8° C. which was found to be 99.5% pure by high pressure liquid chromatographic (HPLC) analysis.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1.[Mg].[C:11]([N:18]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>O1CCCC1>[Cl:9][C:4]1[CH:3]=[C:2]([C:20]2([OH:23])[CH2:21][CH2:22][N:18]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:19]2)[CH:7]=[C:6]([Cl:8])[CH:5]=1
Reactant: Clc1cc(Cl)cc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc(Cl)cc(Cl)c2)C1

Procedure:
Preparation according to Preparation 5: 1-bromo-3,5-dichlorobenzene (5.0 g, 22.1 mmol), dry tetrahydrofuran (100 mL), magnesium turnings (0.54 g, 24.3 mmol) and 1-N-boc-3-pyrrolidinone (3.25 g, 17.7 mmol). Yield: 2.1 g. MS m/z (rel. intensity, 70 eV) 332 (M+, 1), 232 (17), 231 (23), 230 (22), 57 (bp).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH:6]1([C:9](=O)[C:10](=[CH:32]OCC)[C:11]([C:13]2[C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:15][CH:14]=2)=[O:12])[CH2:8][CH2:7]1.Cl.[NH2:38][OH:39]>C(O)C.C(OCC)(=O)C>[CH:6]1([C:9]2[O:39][N:38]=[CH:32][C:10]=2[C:11]([C:13]2[C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:15][CH:14]=2)=[O:12])[CH2:8][CH2:7]1
Reactant: CCOC=C(C(=O)c1cnc(-c2ccccc2)n(-c2ccccc2)c1=O)C(=O)C1CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(c1cnoc1C1CC1)c1cnc(-c2ccccc2)n(-c2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Anhydrous sodium acetate (68 mg, 0.83 mmol) was added to a solution of 1-cyclopropyl-3-(1,6-dihydro-6-oxo-1,2-diphenyl-5-pyrimidinyl)-2-(ethoxymethylene)-1,3-propanedione (i.e. the product from Example 6, Step B) (171 mg, 0.41 mmol) in ethanol (4 mL) at 0° C. Hydroxylamine hydrochloride (29 mg, 0.42 mmol) was added and the resulting suspension was stirred at 0° C. for 30 min and then at ambient temperature for 2 h. The resulting mixture was diluted with ethyl acetate (20 mL) and ethanol (20 mL), concentrated onto 0.8 g silica gel, and the residue purified by medium pressure liquid chromatography using a 12 g silica gel column and eluting with 0 to 100% ethyl acetate in hexanes to obtain 14 mg of the title compound, a compound of the present invention as a yellow glassy solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:27][O:28][CH2:29][CH2:30][O:31][CH2:32]Cl>>[CH3:15][C:14]([C:11]1[CH:10]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:12]=1[O:13][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])[CH:8]=[O:9])([CH3:17])[CH3:16]
Reactant: COCCOCCl
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOc1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C
Yield: 75.7 %

Procedure:
A mixture of 11.7 g (0.05 mole) of 3,5-di-tert-butyl 4-hydroxybenzaldehyde and 19.4 g (0.15 mole) of diisopropylethylamine in 150 mL of CH1C12 is treated with 18.7 g (0.15 mole) of 2-methoxyethoxymethyl chloride (MEM-Cl) and the resulting solution is heated under reflux for 48 hours and evaporated to dryness. The residue is taken up in CH2Cl2, washed with IN HCl and brine, and dried with MgSO4. The solution is evaporated and the residue is filtered through flash grade silica gel, washing with 1:1 CH2Cl2 /n-hexane. Evaporation gives a tan oil, 12.2 g of 3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzaldehyde (76%) which is used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH3:13][N:14]=[C:15]=[S:16]>CCOCC>[CH3:13][NH:14][C:15]([N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)=[S:16]
Reactant: c1cnc(N2CCNCC2)cn1
Reactant: CN=C=S
Solvent: CCOCC
Product: CNC(=S)N1CCN(c2cnccn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6.56 g. of 1-(2-pyrazinyl)piperazine (U.S. Pat. No. 2,606,906) in 40 ml. of anhydrous ether is added a solution of 2.92 g. of methyl isothiocyanate in 40 ml. of anhydrous ether, dropwise over a periodof 10 minutes. This suspension is stirred for one hour and the solid is collected and washed. This solid is dissolved in a mixture of 200 ml. of benzene and 50 ml. of ethanol with heat and then cooled to room temperature over 48 hours. The resulting solid is dissolved in 400 ml. of ethanol:ethyl acetate (1:3), concentrated to 200 ml. and chilled. The resulting solid is collected giving 4.34 g. of the desired product as white crystals, m.p. 197°-200° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:17][C:11]3([CH2:16][CH2:15][S:14][CH2:13][CH2:12]3)[CH:10]=[C:9]([C:18](O)=[O:19])[C:8]=2[CH:21]=1)([O-:3])=[O:2].[C:22](N1C=CN=C1)([N:24]1C=CN=C1)=O.CN.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:22][NH:24][C:18]([C:9]1[C:8]2[CH:21]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[O:17][C:11]2([CH2:16][CH2:15][S:14][CH2:13][CH2:12]2)[CH:10]=1)=[O:19]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)C1=CC2(CCSCC2)Oc2ccc([N+](=O)[O-])cc21
Agent: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)C1=CC2(CCSCC2)Oc2ccc([N+](=O)[O-])cc21
Reaction time: 20 h
Yield: 33.6 %

Procedure:
To a mixture of 80 mg of 6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydrothiopyran]-4-carboxylic acid and 7 ml of tetrahydrofuran was added 80 mg of 1,1'-carbonyldiimidazole with stirring under ice-cooling and the mixture was stirred for 1 hour. 0.7 ml of 40% methylamine (methanol solution) was added therein and the mixture was stirred under ice-cooling for 1 hour and then at room temperature for 20 hours. An aqueous potassium carbonate solution was added therein and the reaction mixture was extracted with methylene chloride. An organic layer was washed with water and dried, and the solvent was distilled. The residue was purified according to silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) and further recrystallized by a mixed solvent of ethyl acetate and hexane to obtain 28 mg of N-methyl-6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydrothiopyran]-4-carboxamide with a melting point of 208°-209° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].O[N:21]=[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH2:31][OH:32])[CH:25]=1)[NH2:23]>>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:12][N:23]=[C:22]([C:24]3[CH:25]=[C:26]([CH2:30][CH2:31][OH:32])[CH:27]=[CH:28][CH:29]=3)[N:21]=2)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: NC(=NO)c1cccc(CCO)c1
Product: COCc1cc(-c2nc(-c3cccc(CCO)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was obtained following procedure described for example 54 step 1 but starting from Intermediate 28 (149.42 mg; 0.58 mmol) and Intermediate 73 (100.00 mg; 0.60 mmol). Purification by column chromatography (cHex/EtOAc from 9:1 to 8:2) gave the title compound as a colorless oil. 1H NMR (DMSO-d6, 300 MHz) δ 8.32 (d, J=1.5 Hz, 1H), 8.16 (dd, J=7.9, 1.8 Hz, 1H), 7.98-7.93 (m, 2H), 7.54-7.47 (m, 2H), 7.41 (d, J=7.9 Hz, 1H), 7.36-7.26 (m, 3H), 7.15-7.13 (m, 1H), 4.71 (t, J=5.2 Hz, 1H), 4.22 (d, J=12.7 Hz, 1H), 4.16 (d, J=12.7 Hz, 1H), 3.24 (s, 3H), 2.85 (t, J=6.7 Hz, 2H), 2.03 (s, 3H). LC/MS (Method B): 401.2 (M+H)+. HPLC (Method A) Rt 5.17 min (Purity: 98.2%).
Reaction SMILES: [C:1]1([CH2:11][NH:12][C:13](=[O:20])[NH:14][O:15][CH2:16][C:17]([OH:19])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:21][C@@H:22]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:49][CH:48]=1)[C:23]([N:25]([C@@H:37]([CH3:45])[CH:38]([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])[CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)=[O:24]>>[C:54]([O:53][C:50]1[CH:49]=[CH:48][C:47]([CH2:46][C@H:22]([NH:21][C:17](=[O:19])[CH2:16][O:15][NH:14][C:13]([NH:12][CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:20])[C:23]([N:25]([C@@H:37]([CH3:45])[CH:38]([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])[CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)=[O:24])=[CH:52][CH:51]=1)([CH3:57])([CH3:55])[CH3:56]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: O=C(O)CONC(=O)NCc1cccc2ccccc12
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CONC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(naphthalen-1-ylmethyl)ureidooxy)acetic acid (Compound VI-12) 81 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-2) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:13]([C:14]#[N:15])=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([O:16][CH2:17][CH3:18])[CH:6]=1)=[N+:2]=[N-:3].O1CCCC1.CN.[CH2:26]([N:28](CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH3:26][NH:28][C:9](=[O:11])[C:8]1[CH:12]=[C:13]([C:14]#[N:15])[C:5]([CH2:4][N:1]=[N+:2]=[N-:3])=[CH:6][C:7]=1[O:16][CH2:17][CH3:18]
Reactant: CCOc1cc(CN=[N+]=[N-])c(C#N)cc1C(=O)O
Reactant: CCN(CC)CC
Agent: CN
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc(CN=[N+]=[N-])c(C#N)cc1C(=O)NC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving 4-(azidomethyl)-5-cyano-2-ethoxybenzoic acid in dimethylformamide (20 ml), a 2M tetrahydrofuran solution of methylamine (4.2 ml), diethyl phosphonocyanidate (1.28 ml) and triethylamine (1.27 ml) were added while cooling on ice. The mixture was stirred at room temperature overnight, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to yield the title compound (931 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].Br[C:11]1[C:12](=[O:24])[N:13]([C:17]([CH:21]([CH3:23])[CH3:22])([CH3:20])[C:18]#[N:19])[C:14](=[O:16])[CH:15]=1>C(O)C>[C:18]([C:17]([N:13]1[C:12](=[O:24])[CH:11]=[C:15]([NH:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH2:4][OH:5])[C:14]1=[O:16])([CH3:20])[CH:21]([CH3:22])[CH3:23])#[N:19]
Reactant: CC(C)C(C)(C#N)N1C(=O)C=C(Br)C1=O
Reactant: Nc1ccccc1CO
Solvent: CCO
Product: CC(C)C(C)(C#N)N1C(=O)C=C(Nc2ccccc2CO)C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To o-aminobenzyl alcohol, (2 g, 0.0125 mol) and 3-bromo-α-isopropyl-α-methyl-2,5-dioxo-3-pyrroline-1-acetonitrile (2.7 g, 0.01 mol) is added absolute ethanol (100 ml) containing 3 g of 5 A pulverized sieves. The mixture is stirred for 20 hours at room temperature. The solvent is removed and the residue is purified through a silica gel dry column, eluant ether-hexane (2:1). Starting bromomaleimide is first recovered, followed by a bright yellow solid 1.89 g (60%), mp 39°-45° C. Anal. calcd. for C17H19N3O3 : C, 65.16; H, 6.11; N, 13.41. Found: C, 65.94; H, 6.21; N, 12.87.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:8][CH:9]=2)[N:4]([CH3:19])[CH:3]=1.[O:20]=[C:21]1[NH:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>[Cu]I.O.O1CCOCC1>[CH3:19][N:4]1[C:5]2=[N:6][C:7]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:8][CH:9]=[C:10]2[C:2]([N:26]2[CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:22][C:21]2=[O:20])=[CH:3]1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: Cn1cc(Br)c2ccc(OCc3ccccn3)nc21
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(N2CCN(C(=O)OC(C)(C)C)CC2=O)c2ccc(OCc3ccccn3)nc21
Temperature: 100 °C
Yield: 88.6 %

Procedure:
A mixture of 3-bromo-1-methyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridine (0.226 g, 0.71 mmol), tert-butyl 3-oxopiperazine-1-carboxylate (0.20 g, 1 mmol), copper (I) iodide (0.027 g, 0.142 mmol) and potassium phosphate (0.212 g, 1 mmol) is purged under a nitrogen atmosphere in a reaction tube. 1,4-Dioxane (3 mL) and N,N′-dimethylethylene diamine (0.031 mL, 0.288 mmol) are added, the tube sealed and the reaction mixture heated at 100° C. for 25 h. The reaction is cooled to room temperature, poured into water and extracted with EtOAc. The organic phase is dried over sodium sulphate, filtered and concentrated in vacuo. The residue is purified by column chromatography on silica eluting with hexane/EtOAc (1:1), followed by neat EtOAc, to give the title compound (0.275 g, 0.629 mmol) as a pale yellow solid. MS (m/z): 438 (M+1).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[CH3:16][C:17]1([CH3:29])[C:21]([CH3:23])([CH3:22])[O:20][B:19]([C:24]2[CH:25]=[N:26][NH:27][CH:28]=2)[O:18]1.[H-].[Na+]>CN(C=O)C>[OH:1][C:3]1([CH2:2][N:27]2[CH:28]=[C:24]([B:19]3[O:18][C:17]([CH3:29])([CH3:16])[C:21]([CH3:23])([CH3:22])[O:20]3)[CH:25]=[N:26]2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(O)(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
A reaction mixture of compound (3-2) (214 mg; 1.0 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3-3, 194 mg; 1.0 mmol) with NaH 60% dispersion in mineral oil (60 mg; 1.5 mmol) in 3 mL of DMF was stirred at 90° C. for 3 hours. The reaction mixture was partitioned between EtOAc (200 mL) and saturated NaHCO3 solution (50 mL) and brine (50 mL). The organic layer was dried (Na2SO4) and concentrated by vacuum to give 361 mg of (3-4) as a yellow grease (89% yield). 1H NMR (400 MHz, chloroform-D) δ ppm 1.21-1.34 (m, 12H) 1.39-1.50 (m, 9H) 1.56-1.78 (m, 4H) 3.14 (s, 2H) 3.72-3.91 (m, J=32.34 Hz, 2H) 4.05 (s, 2H) 7.65 (s, 1H) 7.80 (s, 1H) 8.00 (s, 1H). LCMS calcd for C20H34BN3O5 (M+H) 408, found 408. HPLC purity 85%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:16]([CH3:20])([CH3:19])[C:17]#[CH:18]>CCOCC.O.[Cu]Cl.[Cu]>[CH3:19][C:16]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:20])[C:17]#[CH:18]
Reactant: Nc1ccccc1
Reactant: C#CC(C)(C)Cl
Agent: Cl[Cu]
Agent: [Cu]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: C#CC(C)(C)Nc1ccccc1
Temperature: 15 °C

Procedure:
A mixture of aniline (21.8 g, 234 mmol) and triethylamine (26.6 g, 263.3 mmol) in 100 mL ether, 25 mL water, 0.2 g copper (I) chloride and 0.2 g copper bronze was prepared under nitrogen in a three-neck flask equipped with mechanical stirrer. 3-Chloro-3-methyl-1-butyne (20 g, 195 mmol) in ether (25 mL) was slowly added with stirring while maintaining an inside temperature at 10-20° C. After stirring for an additional 2 hours at room temperature, the mixture was poured into a mixture of 200 mL ether and 100 mL water. The ethereal layer was washed with cold water, dried for 15 minutes over anhydrous potassium carbonate and filtered, redried with potassium hydroxide pellets overnight. The solution was filtered and concentrated under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[CH:22]=O)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(O)C>[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]1[NH:9][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=2[N:8]=1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Nc1ccc(Br)cc1N
Reactant: CC(C)(C)OC(=O)N1CCCC1C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(Br)cc2[nH]1
Temperature: 80 °C
Yield: 55.5 %

Procedure:
A mixture of 4-bromo-benzene-1,2-diamine (2.4 g) and 2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.55 g) in ethanol (5 mL) was heated in microwave at 80° C. for 1 hour. Mixture was concentrated and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give 2-(6-bromo-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (2.6 g, yield 55%). LCMS-ESI−: calc'd for C16H20BrN3O2: 366.25. Found: 365.8 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[O:9][CH2:10][CH3:11].FC(F)(F)C(O)=O.[N:19]1([CH2:23][CH2:24][N:25]2[CH:29]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=3)[N:27]=[C:26]2[CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[N:19]1([CH2:23][CH2:24][N:25]2[CH:29]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([C:37]([F:40])([F:38])[F:39])[CH:31]=3)[N:27]=[C:26]2[CH:41]2[CH2:42][CH2:43][N:44]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=3[O:9][CH2:10][CH3:11])[CH2:45][CH2:46]2)[CH2:20][CH2:21][CH2:22]1
Reactant: Fc1ccc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)cc1C(F)(F)F
Reactant: CCOc1c(N)ncnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CCOc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
A reaction mixture of 6-Chloro-5-ethoxy-pyrimidin-4-ylamine (30.00 mg; 0.17 mmol; 1.00 eq.), 4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine trifluoroacetate (2) (107.92 mg; 0.17 mmol; 1.00 eq.), and Cs2CO3 (225.22 mg; 0.69 mmol; 4.00 eq.) in DMSO 1.0 ml was stirred at 120° C. for overnight. Purified the product by prep HPLC, collected title compound 27 mg, yield 24%. LC-MS: (M+1=534, obsd.=534).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][O:10][CH:11]([CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:12][N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][C:16]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[N:17][C:18]=2[NH2:22])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C1C(=O)N([Br:43])C(=O)C1>CC#N>[CH2:6]([O:5][P:4]([CH2:9][O:10][CH:11]([CH2:28][O:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:12][N:13]1[C:21]([Br:43])=[N:20][C:19]2[C:14]1=[N:15][C:16]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[N:17][C:18]=2[NH2:22])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOP(=O)(COC(COc1ccccc1)Cn1cnc2c(N)nc(OCCOC)nc21)OCC
Solvent: CC#N
Product: CCOP(=O)(COC(COc1ccccc1)Cn1c(Br)nc2c(N)nc(OCCOC)nc21)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the phosphonate prepared in step 2 (300 mg, 0.59 mmol) in CH3CN (5 ml) was added NBS (157 mg, 0.88 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The solvent was removed and the residue was washed with sat. aq Na2SO3 solution. The aqueous phase was extracted again with DCM. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by prep HPLC on a C18 column, eluting with a gradient of 5-95% CH3CN in H2O as solvent. 1H NMR (CDCl3) δ 1.19-1.27 (m, 6H), δ 3.40 (s, 3H), δ 3.68 (t, 2H), δ 3.84-3.3.88 (m, 1H), δ 3.93-4.10 (m, 8H), δ 4.30-4.36 (m, 4H), δ 6.30 (bs, 2H), δ 6.83-6.97 (m, 3H), δ 7.23-7.28 (m, 2H); MS: 588.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[O:4].[Cl:8][C:9]1[C:19]2[CH2:18][CH2:17][NH:16][CH2:15][CH:14]([C:20]3[CH:25]=[CH:24][C:23]([S:26](O)(=[O:28])=[O:27])=[CH:22][CH:21]=3)[C:13]=2[CH:12]=[C:11]2[O:30][CH2:31][O:32][C:10]=12.S(Cl)(Cl)=O>CN(C)C=O>[F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[O:4].[Cl:8][C:9]1[C:19]2[CH2:18][CH2:17][NH:16][CH2:15][CH:14]([C:20]3[CH:25]=[CH:24][C:23]([S:26](=[O:28])(=[O:27])[NH2:5])=[CH:22][CH:21]=3)[C:13]=2[CH:12]=[C:11]2[O:30][CH2:31][O:32][C:10]=12
Reactant: O=S(=O)(O)c1ccc(C2CNCCc3c2cc2c(c3Cl)OCO2)cc1
Agent: NC(=O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(C2CNCCc3c2cc2c(c3Cl)OCO2)cc1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
A mixture of 1.0 g (2.1 mmole) of the crude 6-chloro-7,8-methylenedioxy-1-(p-sulfophenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine trifluoroacetamide, 20 ml of thionyl chloride and 0.04 ml of dimethylformamide was heated at 80° for 2 hours. The thionyl chloride was evaporated in vacuo. The residue which is 6-chloro-7,8-methylenedioxy-1-(p-chlorosulfonylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine trifluoroacetamide was dissolved in tetrahydrofuran. The solution was added slowly to 40 ml of iced concentrated ammonium hydroxide. The mixture was stirred at room temperature for an hour, the pH was adjusted to 8 with hydrochloric acid and the product was extracted into ethyl acetate. The extracts were washed with water, dried, concentrated and applied to a column packed with 50 g of silica gel. The column was developed with a gradient of 24 to 35 percent of ethyl acetate in cyclohexane to give 0.5 g of 6-chloro-7,8-methylenedioxy-1-(p-sulfamylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine trifluoroacetamide. Field desorption mass spectroscopy showed an intense m/e at 476 which is consistent with the molecular ion. NMR and IR were consistent with the structure.