Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].O1CCCC1.[Br:23]N1C(=O)CCC1=O>CN(C)C=O>[CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([C:13]3[O:17][CH:16]=[N:15][C:14]=3[Br:23])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1nnc2ccc(-c3cnco3)cn12
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)c1nnc2ccc(-c3ocnc3Br)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
A clean, dry, 1 liter 4 neck round bottom flask equipped with mechanical stirring, nitrogen, temperature probe, and a dry ice/acetone bath, was charged with the product from step A (45.2 gr 0.198 moles) and N,N-dimethylformamide (271 ml). The pot was cooled below −60° C. and then lithium hexamethyldisilizane, 1 molar in tetrahydrofuran (198 ml 0.198 moles), was added while keeping the temperature below −60° C. After the addition was complete, the pot was further cooled to below −70° C. and stirred for 1 hour. While stirring, a solution of N-bromosuccinimide (35.24 g 0.198 moles) and N,N-dimethylformamide (105 ml), were stirred in a separate 500 ml round bottomed flask under nitrogen. After the one hour stir at −70° C., the solution of N-bromosuccinimide and N,N-dimethylformamide was slowly added to the anion keeping the temperature below −70° C. This temperature was critical to insure proper selectivity. After the addition was complete, the pot was stirred for one hour below −70° C. The batch was warmed to room temperature and quenched into methylene chloride (452 ml) and 1N sodium hydroxide (452 ml). The extraction was repeated with a second aliquot of methylene chloride (135 ml), and the combined organic layers washed with a second 1N sodium hydroxide (452 ml) wash. The organic layer was washed with saturated brine solution (452 ml), and dried over magnesium sulfate (50 gr). The magnesium sulfate was filtered off, washed with methylene chloride (135 ml) and the filtrate and wash combined for concentration. The methylene chloride was concentrated/displaced with isopropyl ether (226 ml) to a temperature of 42° C. A thick slurry formed upon cooling. The solids were granulated at 20 to 25° C. for two hours, filtered, washed with isopropyl ether (50 ml), and dried to afford 53.0 gr of light yellow solids, 96.4% purity (HPLC), 87% of theory.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([Cl:20])[CH:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH:24]([OH:28])[CH2:23]1>>[CH:12]([OH:19])=[O:28].[Cl:20][C:4]1[CH:3]=[C:2]([NH:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH:24]([OH:28])[CH2:23]2)[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=1
Reactant: NC1CCCC(O)C1
Reactant: O=C(Nc1nc2cc(Cl)cc(Cl)n2n1)c1cccnc1
Product: O=C(Nc1nc2cc(Cl)cc(NC3CCCC(O)C3)n2n1)c1cccnc1
Product: O=CO
Temperature: 120 °C

Procedure:
The title compound was prepared following procedure and work up described for example 118, but starting from N-(5,7-dichloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B10), 100 mg; 0.32 mmol; 1.0 eq) and 3-aminocyclohexanol (Betapharma, 187 mg; 1.62 mmol; 5.0 eq), heated at 120° C., filtered and dried under vacuum, purified by Mass Directed AutoPrep and lyophilized to give the title compound as a mixture of cis:trans isomers as a beige powder (9 mg, 7%). HPLC, Rt: 2.15 min. (purity 57.4%, isomer A), 2.28 min. (purity 34.7%, isomer B). LC/MS, M+(ESI): 386.9, M−(ESI): 384.9.
Reaction SMILES: OC[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]3[CH:19]=[C:20]4[C:25](=[C:26]([CH3:28])[CH:27]=3)[N:24]=[CH:23][C:22]([C:29]([NH2:31])=[O:30])=[C:21]4[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CC1(C)C(C)(C)OB(C2C=C[C:52]([CH:55](CC)[CH2:56][CH2:57][OH:58])=[CH:51]C=2)O1>>[OH:58][CH2:57][CH2:56][CH2:55][CH2:52][CH2:51][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]3[CH:19]=[C:20]4[C:25](=[C:26]([CH3:28])[CH:27]=3)[N:24]=[CH:23][C:22]([C:29]([NH2:31])=[O:30])=[C:21]4[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCC(CCO)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4ccc(-c5ccc(CO)cc5)cc4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4ccc(-c5ccc(CCCCCO)cc5)cc4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 65, using 3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]pentan-1-ol in place of 4-(hydroxymethyl)phenylboronic acid. ES/MS calcd. for C35H36N3O5S+ 610.2. Found m/z=610.3 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][C:22]([NH2:26])=[CH:23][C:24]=3[CH2:25][C@H:14]12)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][C:22]([NH:26][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:23][C:24]=3[CH2:25][C@H:14]12)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]2c3ccc(N)cc3C[C@@H]21
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]2c3ccc(NS(C)(=O)=O)cc3C[C@@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methylsulfonyl chloride (42 μL) is added to a solution of cis-7-amino-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridine-1-carboxylic acid tert-butyl ester (160 mg) and triethylamine (76 μL) in dichloromethane (3 mL) at room temperature. The solution is stirred for 1 h at room temperature and then aqueous NaHCO3 solution is added. The mixture is stirred vigorously for 20 min and then extracted with dichloromethane. The combined extract is concentrated and the residue is chromatographed (cyclohexane/ethyl acetate 7:3→1:9) to give the title compound. Yield: 120 mg (59% of theory); LC (method 1): tR=3.80 min; Mass spectrum (ESI−): m/z=365 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([C:25]3[CH:34]=[C:33]4[C:28]([CH2:29][CH2:30][NH:31][CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([NH2:35])[N:20]=2)[CH2:15][CH2:14]1>>[NH2:35][C:21]1[N:22]=[C:23]([C:25]2[CH:34]=[C:33]3[C:28]([CH2:29][CH2:30][N:31]([C:9]([NH:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)=[O:10])[CH2:32]3)=[CH:27][CH:26]=2)[CH:24]=[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]2)[N:20]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C=Nc1cccc(Cl)c1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Nc3cccc(Cl)c3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared from 3-chlorophenyl isocyanate and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt using procedures analogous to those for Example 5. Analytic LCMS (M+H)+: m/z=478.3/480.3.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]1([S-:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na+]>CN(C=O)C.[Cl-].[Na+].O>[NH2:1][C:2]1[N:10]=[C:9]([S:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [S-]c1ccccc1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(Sc2ccccc2)nc2c1ncn2Cc1ccccc1
Temperature: 100 °C
Yield: 88.8 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) and sodium thiophenolate (2 g, 15 mmol) were mixed in DMF (12 ml) and then the mixture was stirred under heating at 100° C. for 7.5 hours. To the reaction mixture was added brine and the mixture was extracted with ethyl acetate. The organic layer was dried on magnesium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (0.5% methanol/chloroform) to give the subject compound (228 mg, yield 89%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[C:8]([C:11]1[S:18][C:17]2[C:16]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:14]([CH2:31][O:32][CH3:33])[C:13]=2[C:12]=1[CH2:34][NH2+:35][CH2:36][CH:37]1[CH2:41][CH2:40]S(=O)(=O)[CH2:38]1)([OH:10])=[O:9].C1(C2C3SC(C(O)=O)=C(C=O)C=3N(COC)C=2C2C=CC=CC=2)CCCCC1.C(N)C1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:36]([NH:35][CH2:34][C:12]1[C:13]2[N:14]([CH2:31][O:32][CH3:33])[C:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:16]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)[C:17]=2[S:18][C:11]=1[C:8]([OH:10])=[O:9])[C:37]1[CH:41]=[CH:40][CH:3]=[CH:2][CH:38]=1.[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: O=C([O-])C(F)(F)F
Reactant: COCn1c(-c2ccccc2)c(C2CCCCC2)c2sc(C(=O)O)c(C[NH2+]CC3CCS(=O)(=O)C3)c21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: COCn1c(-c2ccccc2)c(C2CCCCC2)c2sc(C(=O)O)c(C=O)c21
Agent: [Na+]
Solvent: NCc1ccccc1
Solvent: ClCCCl
Product: COCn1c(-c2ccccc2)c(C2CCCCC2)c2sc(C(=O)O)c(CNCc3ccccc3)c21
Product: O=C(O)C(F)(F)F
Reaction time: 0.15 h
Yield: 39 %

Procedure:
Following the procedure described above for [2-carboxy-6-cyclohexyl-4-(methoxymethyl)-5-phenyl-4H-thieno[3,2-b]pyrrol-3-yl]-N-[(1,1-dioxidotetrahydro-3-thienyl)methyl]methanaminium trifluoroacetate (step 4), treatment of a solution (0.02 M) of 6-cyclohexyl-3-formyl-4-(methoxymethyl)-5-phenyl-4H-thieno[3,2-b]pyrrole-2-carboxylic acid in 1,2-dichloroethane with benzylamine (1.2 eq.) and sodium triacetoxyborohydride (1.5 eq.) gave a residue that was purified by RP-HPLC (Conditions: Waters X-TERRA MS C18, 10 micron, 19×150 mm; flow: 20 mL/min; Gradient: A: H2O+0.05% TFA; B: MeCN+0.05% TFA; 90% A isocratic for 2 min then linear to 10% A in 9 min) to afford the title compound (39%) as its TFA salt.
Reaction SMILES: C([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=O)NN.[C:13]([O:17]CC)(=O)[NH:14][NH2:15].C(Cl)([Cl:22])=O>C(OCC)C>[CH2:6]([O:5][NH:15][NH:14][C:13]([Cl:22])=[O:17])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: NNC(=O)OCc1ccccc1
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)NN
Solvent: CCOCC
Product: O=C(Cl)NNOCc1ccccc1

Procedure:
Example 1 was repeated but substituting benzyl carbazate (41.5 g, 0.25 mole) for the ethyl carbazate and using phosgene (30 ml, 0.4 mole) in diethyl ether. 2-Benzyloxyhydrazinecarbonyl chloride was isolated as a solid (53 g, 93%) mp 62°-64° C., whose ir spectrum was similar to that of 2-ethoxycarbonylhydrazinecarbonyl chloride.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:24])[N:11]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=[N:13]2)=[CH:8][C:7]=1[O:25][CH3:26].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10](=[O:24])[N:11]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=[N:13]3)=[CH:8][C:7]=2[O:25][CH3:26])[CH2:30][CH2:29]1
Reactant: CN1CCNCC1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCBr
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCN1CCN(C)CC1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 83 %

Procedure:
A suspension of 7-(3-bromopropoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (36.7 g, 86 mmol) in 1-methylpiperazine (370 ml) was stirred at 100° C. for 90 minutes. After removal of the volatiles under vacuum, the residue was partitioned between methylene chloride and aqueous ammonium chloride. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 7-(3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (31.9 gr, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[NH:8][C:7](=[O:12])[CH:6]=1)=[O:4].[CH3:13]OC(OC)N(C)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[N:8]([CH3:13])[C:7](=[O:12])[CH:6]=1)=[O:4]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1cc(C)[nH]c(=O)c1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)n(C)c(=O)c1
Temperature: 60 °C
Yield: 48.6 %

Procedure:
A suspension of the title compound of Example 33.1 (0.80 g, 4.8 mmol) and dimethylformamide dimethylacetal (3.2 mL, 24 mmol) in DMF (10 mL) was heated at 60° C. for 48 hours. The reaction mixture was concentrated and the residue was dissolved in dichloromethane and washed with water. The organic layer was concentrated. Recrystallization from ethyl acetate/heptane afforded the title compound (423 mg, 49%)
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CC(C)=O.C(=O)=O.[C:13]([C:15]1(O)[CH2:21][CH:20]2[N:22]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH:17]([CH2:18][CH2:19]2)[CH2:16]1)#[N:14].C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1>[C:13]([C:15]1[CH2:16][CH:17]2[N:22]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH:20]([CH2:19][CH2:18]2)[CH:21]=1)#[N:14]
Reactant: N#CC1(O)CC2CCC(C1)N2CC(F)(F)F
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: N#CC1=CC2CCC(C1)N2CC(F)(F)F
Temperature: 20 °C
Reaction time: 24 h
Yield: 57.5 %

Procedure:
An oven-dried 25 ml 3-necked round bottom flask was fitted with a reflux condenser, thermometer and magnetic stirrer and the apparatus filled with nitrogen. Phosphorous oxychloride (1.41 g, 9.1 mmol) and pyridine (6.53 g) were charged to the flask and the mixture then cooled to −10° C. in an acetone/Drikold™ bath. 3-Cyano-3-hydroxy-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane (0.97 g, 4.1 mmol—assumed, prepared in Step 1) was added in one portion and the resultant exotherm raised the reaction mass temperature to 20° C. The mixture was then heated to 80° C. and held at this temperature for 24 hours, after which the reaction mixture was cooled and stirred at ambient for 18 hours. The reaction mass was poured onto ice/water (50 ml) and solid sodium carbonate was added portionwise until the mixture was adjusted to pH8. The mixture was extracted with ethyl acetate (3×30 ml), the combined extracts were dried (Na2SO4), filtered and concentrated in vacuo to give 3-cyano-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]oct-2-ene (0.51 g, 51% yield from 8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octan-3-one; 60:40 exo:endo cyano).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([N:7]1[CH2:11][CH2:10][CH:9]([NH:12]C(OC(C)(C)C)=O)[CH2:8]1)=[O:6])[CH3:2].[C:21]([OH:27])([C:23]([F:26])([F:25])[F:24])=[O:22]>C(Cl)Cl>[F:24][C:23]([F:26])([F:25])[C:21]([OH:27])=[O:22].[CH2:1]([O:3][C:4](=[O:20])[C:5]([N:7]1[CH2:11][CH2:10][CH:9]([NH2:12])[CH2:8]1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)N1CCC(NC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(=O)N1CCC(N)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
106.2 (3-tert-Butoxycarbonylamino-pyrrolidin-1-yl)-oxo-acetic acid ethyl ester (1.5 g) was dissolved in CH2Cl2 (7 ml) and TFA (7 ml) was added. The mixture was stirred at 25° C. for 3 h, evaporated to dryness to yield crude (3-amino-pyrrolidin-1-yl)-oxo-acetic acid ethyl ester trifluoroacetate as red brown oil (1.57 g). MS 187.3 ([M+H]+)
Reaction SMILES: [C:1]1([CH:7](Cl)[N:8]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:9]2(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].C1([N:28]2[C:32]([SH:33])=[N:31][N:30]=[N:29]2)C=CC=CC=1>CN(C=O)C>[C:1]1([C:1]2([CH:7]([S:33][C:32]3[NH:31][N:30]=[N:29][N:28]=3)[N:8]3[C:18](=[O:19])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[S:9]3(=[O:10])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH2:6]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: O=C1c2ccccc2S(=O)(=O)N1C(Cl)c1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2S(=O)(=O)N1C(Sc1nnn[nH]1)C1(c2ccccc2)C=CC=CC1
Temperature: 25 °C
Yield: 63 %

Procedure:
A solution of 2.2 g (0.0071 mol) of 2-(phenyl-chloromethyl)saccharin and 1.4 g (0.0071 mol) of the sodium salt of 1-phenyl-5-mercaptotetrazole in 30 ml of DMF was heated at 55° for three and one half hours, then stirred at ambient temperature for about sixteen hours and poured into ice water containing dilute sodium bicarbonate. The solid which separated was collected, washed with water, air dried and chromatographed on silica gel, eluting with 98:2 MDC: diethyl ether, to give 2 g (63%) of 2-(1-phenyl-1H-tetrazol-5-ylthiophenylmethyl) saccharin, mp 192°-193 ° C.
Reaction SMILES: CC(C)([O-])C.[K+].F[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=O)[C:12]([CH3:20])([CH3:19])[NH:11]2.P(Cl)(OCC)(OCC)=O.[N+:30]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])#[C-:31]>C1COCC1>[CH3:19][C:12]1([CH3:20])[NH:11][C:10]2[C:15](=[CH:16][CH:17]=[CH:8][CH:9]=2)[N:14]2[CH:31]=[N:30][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:13]12
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CC1(C)Nc2cc(F)ccc2NC1=O
Agent: CC(C)(C)[O-]
Agent: CCOP(=O)(Cl)OCC
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncn2c1C(C)(C)Nc1ccccc1-2
Reaction time: 2 h

Procedure:
Potassium tert-butoxide (1 M, 4.54 ml) is added to 1,2,3,4-tetrahydro-3,3-dimethylquinoxalin-2-one (IV, EXAMPLE 2, 0.762 g) in THF (4 ml) at ice/saline temperature. The reaction is stirred for 40 min, at which time diethyl chlorophosphate (0.656 ml) is added. After stirring at ice-saline temperature for 2 hr, ethyl isocyanoacetate (0.562 g) is added, followed by potassium t-butoxide (1 M, 4.97 ml). The reaction is stirred for 3.5 hr, allowing it to slowly warm to 20°-25°. The reaction is then quenched with several drops of acetic acid and then partitioned between ethyl acetate, aqueous sodium bicarbonate and saline. The phases are separated and the organic phase is dried over magnesium sulfate, concentrated, and the resulting crude product chromatographed on silica gel (200 ml) eluting with methanol/dichloromethane (2/98). The appropriate fractions are pooled and concentrated to give the title compound, mp 145°-149°; NMR (CDCl3) 1.44, 1.74, 3.79, 4.40, 6.77, 6.82, 7.10, and 7.39 δ.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH2:5][NH:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH2:22][C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]4[CH:40]=[CH:39][C:38]5[O:37][CH2:36][O:35][C:34]=5[CH:33]=4)[CH2:27][CH2:26]3)=[O:24])=[CH:16][CH:15]=2)=[N:11][CH:12]=1.[CH:45](=O)[CH3:46].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH2:5][N:6]([CH2:45][CH3:46])[C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][NH:21][CH2:22][C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]4[CH:40]=[CH:39][C:38]5[O:37][CH2:36][O:35][C:34]=5[CH:33]=4)[CH2:27][CH2:26]3)=[O:24])=[CH:18][CH:19]=2)=[N:11][CH:12]=1
Reactant: CC=O
Reactant: O=C(CNCc1ccc(Oc2ccc(NCc3ccc(Cl)c(Cl)c3)cn2)cc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN(Cc1ccc(Cl)c(Cl)c1)c1ccc(Oc2ccc(CNCC(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-({4-[5-(3,4-dichlorobenzylamino)pyridin-2-yloxy]phenyl}methylamino)-1-(4-piperonylpiperazin-1-yl)ethanone (1.59 g, 2.5 mmol) was dissolved in dichloroethane (80 mL). To this solution were added acetoaldehyde (1.40 mL, 25.0 mmol) and sodium triacetyloxy borohydride (1.59 mL, 7.5 mmol) under ice cooling. To the resulting solution was added dropwise acetic acid (0.43 mL, 7.5 mmol), and this solution was stirred at room temperature for 16 hours. The resulting reaction solution was washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (chloroform:methanol=50:1). The obtained solid was recrystallized from ethanol, to thereby yield 0.65 g of the title compound.
Reaction SMILES: O=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH:4]2[CH2:3]1.[H-].[Na+].Br[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34].B>CN(C)C=O.CO>[Cl:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH2:13][CH2:14][NH:15][CH2:16][CH:4]2[CH2:3][CH2:2]1
Reactant: Clc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N1CCN2c3ccccc3NC(=O)CC2C1
Agent: B
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Clc1ccccc1CN1CCC2CNCCN2c2ccccc21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of Example 1C (50 mg, 0.16 mmol) in N,N-dimethylformamide (1 mL) was added sodium hydride (65%, 6.98 mg, 0.19 mmol). The solution was allowed to stir at room temperature for 1 hour before addition of 1-(bromomethyl)-2-chlorobenzene (37.2 mg, 0.181 mmol). The reaction mixture was stirred overnight. The solution was concentrated. To the concentrate was added tetrahydrofuran (10 mL) followed by borane (1 M in tetrahydrofuran, 1 mL, 1 mmol). The solution was heated in an 80° C. oil bath for 4 hours. Methanol (20 mL) was added and heating of the resultant solution was continued in the 80° C. bath for 1 hour before concentration. To the concentrate was added dichloromethane (10 mL), methanol (1 mL) and HCl (4 M in dioxane, 2 mL) Once LC/MS analysis indicated the reaction was complete the solution was concentrated and purified by preparative HPLC to afford the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 7.46 (d, J=8.85 Hz, 1H) 7.28-7.38 (m, 3H) 6.95 (dd, J=7.93, 1.53 Hz, 1H) 6.87-6.92 (m, 1H) 6.82-6.87 (m, 1H) 6.70 (dd, J=7.78, 1.37 Hz, 1H) 4.56 (d, J=16.17 Hz, 1H) 4.36 (d, J=16.48 Hz, 1H) 3.46-3.56 (m, 1H) 3.35-3.43 (m, 2H) 3.06-3.28 (m, 4H) 2.93-3.02 (m, 2H) 1.89-1.99 (m, 1H) 1.70-1.79 (m, 1H) MS (ESI) m/z 328.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([I:10])[CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N:30]([C:38](OC(C)C)=O)=NC(OC(C)C)=O.CC(C)(O)C#N>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:38]#[N:30])=[C:4]([I:10])[CH:3]=1
Reactant: OCc1ccc(Cl)cc1I
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CC(C)(O)C#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: N#CCc1ccc(Cl)cc1I
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(4-Chloro-2-iodophenyl)methanol (4.67 g, 17 mmol) and PPh3 (6 mL, 26 mmol) were stirred in Et2O at 0° C. Diisopropyl azodicarboxylate (5 mL, 26 mmol) was added dropwise, and the reaction was stirred for 20 minutes (a white precipitate formed). A solution of acetone cyanohydrin (2 mL, 26 mmol) in diethyl ether (5 mL) was added dropwise to the reaction. The resulting solution was stirred for 5 minutes at 0° C. and then allowed to warm to room temperature over two hours. The reaction was monitored by TLC and LCMS. The mixture was filtered, and the filtrate was concentrated in vacuo. Purification was done using silica flash chromatography with a gradient of 0-15% EtOAc/hexanes. MS m/e=278 (M+H)+.