Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][CH2:14][O:15][S:25]([CH3:24])(=[O:27])=[O:26])[N:12]=1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nc(CCO)cs1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1nc(CCOS(C)(=O)=O)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.1 %

Procedure:
To a solution of [4-(2-Hydroxy-ethyl)-thiazol-2-yl]-carbamic acid tert-butyl ester (5 g, 20 mmol) and triethyl amine (5.8 ml, 40 mmol) in DCM (50 ml) was added methanesulfonyl chloride (1.9 ml, 24 mmol) slowly over a period of 10-15 min. The reaction mixture was stirred at r.t. for 4 hr, quenched with brine (10 ml) and extracted in DCM (100 ml), dried over Na2SO4 and passed through a short column of silica gel bed and concentrated to obtain methanesulfonic acid 2-(2-tert-butoxycarbonylamino-thiazol-4-yl)-ethyl ester (6.0 g, 90%) which was used as such for the next step without further purification.
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH:7]=[C:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:3]=[CH2:4].P(Br)(Br)[Br:15]>>[Br:15][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:5][CH2:6][CH:7]=[C:8]([CH2:11][CH3:12])[CH2:9][CH3:10]
Reactant: C=CC(C)(O)CCC=C(CC)CC
Reactant: BrP(Br)Br
Product: CCC(=CCCC(C)=CCBr)CC

Procedure:
Following the procedure of Example 9, 3-methyl-7-ethyl-1,6-nonadien-3-ol and phosphorus tribromide are reacted to form 1-bromo-3-methyl-7-ethyl-2,6-nonadiene.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[C:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:27](O)(=O)CC(CC(O)=O)(C(O)=O)O>CCOC(C)=O.C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH3:27])[CH2:12][C:11]=2[C:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: Fc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)cc1Cl
Agent: C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN1CCc2c(c(-c3ccc(F)c(Cl)c3)cn2Cc2ccccc2)C1

Procedure:
The title compound (0.03 g) was prepared from 1-benzyl-3-(3-chloro-4-fluoro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (Example 2) and paraformaldehyde as in Example 35. The product was then dissolved in 1/1 EtOAc/CH2Cl2 and treated with 0.03 g (0.15 mmol) of citric acid to afford 0.05 g of the corresponding citrate salt. MS (ESI): exact mass calculated for C21H20ClFN2, 354.13. found, m/z 355.1 [M+H]+, 357.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.44-7.22 (m, 1H), 7.34 (t, J=7.7 Hz, 2H), 7.30-7.26 (m, 2H), 7.22 (t, J=9.1 Hz, 1H), 7.19-7.13 (m, 3H), 5.14 (s, 2H), 4.36 (s, 2H), 3.50 (t, J=5.8 Hz, 2H), 2.96 (s, 3H), 2.89 (t, J=5.8, 2H), 2.82-2.71 (m, 4H).
Reaction SMILES: ClC1C(O[C:9](=[O:16])[C@@H:10]2[CH2:14][CH2:13][C:12](=[O:15])[NH:11]2)=C(Cl)C(Cl)=C(Cl)C=1Cl.Cl.[NH2:22][C@H:23]([C:25]([NH2:27])=[O:26])[CH3:24].C(N1CCOCC1)C>CN(C)C=O>[NH:11]1[C:12](=[O:15])[CH2:13][CH2:14][C@H:10]1[C:9]([NH:22][C@H:23]([C:25]([NH2:27])=[O:26])[CH3:24])=[O:16]
Reactant: O=C1CC[C@@H](C(=O)Oc2c(Cl)c(Cl)c(Cl)c(Cl)c2Cl)N1
Reactant: C[C@H](N)C(N)=O
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(N)=O

Procedure:
3.75 g (10 mmols) of L-pyroglutamic acid pentachlorophenyl ester were stirred in 40 ml of dimethyl formamide with 1.5 g (12 mmols) of L-alanine amide hydrochloride and 1.54 ml (12 mmols) of N-ethylmorpholine for 4 hours. The solvent was distilled off in vacuo. The residue was dissolved in methanol and the solution was stirred successively with strongly basic and strongly acid ion exchangers. The exchanger was removed by filtration and concentration to dryness followed. The residue was triturated with ethyl acetate, dissolved in a little ethanol and precipitated with petroleum ether in the form of a resin that solidified under petroleum ether. Yield: 1.2 g, chromatographically unfirom without sharp melting point.
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13].CI.[C:18](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:18][O:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13]
Reactant: O=C([O-])[O-]
Reactant: On1c(C(F)(F)F)nc2ncc(Cl)cc21
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COn1c(C(F)(F)F)nc2ncc(Cl)cc21

Procedure:
1-Hydroxy-6-chloro-2-(trifluoromethyl)-1H-imidazo-(4,5-b)pyridine (5 grams), 80 milliliters of acetone, 5 milliliters of methyl iodide, and 10 grams of anhydrous potassium carbonate were mixed, heated and refluxed with stirring for twelve hours. The reaction mixture was then filtered, evaporated and eluted off of a silica column with diethyl ether, yielding the desired 1-methoxy-6-chloro-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine product. It was recrystallized from petroleum ether (boiling at 60°-80°C.). The product so obtained melted at 91°-2°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[C:11]([O:14][CH:15](OC(=O)C)[C:16]([CH3:18])=[CH2:17])(=[O:13])[CH3:12]>[Cl-].[Zn+2].[Cl-]>[C:11]([O:14][CH:15]=[C:16]([CH3:18])[CH2:17][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:9][CH3:10])[CH:5]=1)(=[O:13])[CH3:12]
Reactant: COc1ccccc1OC
Reactant: C=C(C)C(OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: COc1ccc(CC(C)=COC(C)=O)cc1OC
Temperature: 25.5 °C
Reaction time: 1.5 h
Yield: 95.1 %

Procedure:
In an argon gas atmosphere, a four necked flask having a capacity of 100 ml was charged with 69.2 g (500 m moles) of 1,2-dimethoxybenzene and 9.61 g (50 m moles) of 3,3-diacetoxy-2-methylpropene having a purity degree of 89.6% by mass. Then, the resultant mixture was mixed with 1.36 g (10 m moles) of zinc chloride at an internal temperature of 25 to 26° C. The mixture was stirred at an internal temperature of 25 to 26° C. for 1.5 hours to cause the mixed compounds to react with each other. After the reaction was completed, the resultant reaction liquid was washed three times with 50 ml of saturated aqueous sodium chloride solution. The resultant reaction liquid was subjected to a layer separation treatment, the resultant organic layer was collected and subjected to a distillation under reduced pressure (8 to 10 mmHg, 80 to 84° C.), the resultant residue was refined by a chromatography on silica gel using an elusion solvent:hexane/ethyl acetate mixture in a mixing ratio by volume of 10/1. The target 1-acetoxy-2-methyl-3-(3,4-dimethoxyphenyl)propene was obtained in a yield of 95.1% in an amount of 11.9 g in the form of a colorless liquid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:10])[CH:8]=O)(=[O:3])[CH3:2].[C:11]1([S:17]([C:20]#[N:21])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.B(OCCCC)(OCCCC)OCCCC.C(O)CCC>>[C:1]([O:4][C:5]1[C:20]([S:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)(=[O:19])=[O:18])=[N:21][CH:8]=[C:7]([CH3:10])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC=C(C)C=O
Reactant: N#CS(=O)(=O)c1ccccc1
Agent: CCCCOB(OCCCC)OCCCC
Solvent: CCCCO
Product: CC(=O)Oc1cc(C)cnc1S(=O)(=O)c1ccccc1
Temperature: 108 °C
Yield: 22.7 %

Procedure:
First, 5.0 g (39.6 mmol) of 4-acetoxy-2-methyl-2-butenal, 7.05 g (39.6 mmol) of benzenesulfonyl cyanide, 0.91 g (4.0 mmol) of tributyl borate and 1-butanol (0.59 g, 7.9 mmol) were introduced to a 3-necked flask (100 ml volume) equipped with a thermometer, a magnetic stirrer, a Dean-Stark water type distilling receiver and a condenser tube. Toluene (20 ml) was added as the solvent. Then the mixture was heated under reflux for 22 hours while agitating at an internal temperature of 108° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure to give the desired, crude product. The crude product was purified by silica gel column chromatography (eluting solvent: ethyl acetate/hexane =⅓) to give 2.62 g of 3-acetoxy-2-benzenesulfonyl-5-methylpyridine with the following properties as a brown, oily substance (yield of 24% based on benzenesulfonyl cyanide).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:26][CH3:27])=[CH:20][C:21]([C:23](=[O:25])[CH3:24])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:28]1([Mg]Br)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:26][CH3:27])=[CH:20][C:21]([C:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([OH:25])[CH3:24])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Br[Mg]c1ccccc1
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(C)=O)cc(OC)c21
Solvent: C1CCOC1
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(C)(O)c3ccccc3)cc(OC)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 171 %

Procedure:
A solution of 163 mg (0.445 mmol) 1-[2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-yl]-ethanone in 2 ml THF is treated with excess phenylmagnesiumbromide (prepared from 112 μl bromobenzene and 26 mg magnesium in 5 ml diethyl ether). The resulting mixture is stirred at room temperature for 1 h. The reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=2:1) to afford 109 mg of the title compound as an oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]([F:41])([F:40])[C:27]1[C:35]2[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=2[N:29]([CH2:36][C:37]([OH:39])=O)[N:28]=1.CCN(C(C)C)C(C)C.[CH3:51][C:52]1[N:53]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=2C)[C:54]([CH:57]([NH2:65])[CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[N:55][N:56]=1>CN(C=O)C>[CH3:51][C:52]1[N:53]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[C:54]([CH:57]([NH:65][C:37](=[O:39])[CH2:36][N:29]2[C:30]3[CH2:31][CH2:32][CH2:33][CH2:34][C:35]=3[C:27]([C:26]([F:25])([F:41])[F:40])=[N:28]2)[CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[N:55][N:56]=1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Reactant: Cc1ccccc1-n1c(C)nnc1C(N)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc(C(Cc2ccccc2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1-c1ccccc1
Reaction time: 0.17 h

Procedure:
HATU (40 mg, 0.105 mmol) was added to a solution of 2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid (25.0 mg, 0.1 mmol) and DIPEA (0.02 mL, 0.12 mmol) in DMF (0.3 mL). After 10 minutes, 10F (29.2 mg, 0.1 mmol) in 0.2 mL of DMF was added to the reaction. The reaction was stirred for 2 hours. LC/MS shows desired product with a small amount of acid. Purified reaction mixture on prep reverse phase HPLC using 20-80% B over 20 min. (A=0.1% TFA/H2O; B=0.1% TFA/Acetonitrile). Combined pure fractions as determined by LC/MS and lyophilized to provide the desired product. 1H NMR (400 MHz, DMSO) δ 9.16-8.86 (m, 1H), 7.39 (dd, J=16.8, 8.4 Hz, 2H), 7.28 (d, J=7.2 Hz, 1H), 7.16 (t, J=6.3 Hz, 3H), 6.90 (td, J=51.4, 7.6 Hz, 3H), 4.74-4.51 (m, 3H), 3.10 (s, 1H), 2.94 (dd, J=13.5, 8.9 Hz, 1H), 2.44-2.10 (m, 4H), 2.03 (d, J=4.7 Hz, 3H), 1.59 (s, 4H). MS (m/z) 509 [M+H]+.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][CH2:23][C:24]2=[O:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C2(C3C=CC=CC=3)OB(C)N3CCC[C@H]23)C=CC=CC=1.O1CCCC1.B>C1COCC1>[OH:29][C@@H:24]1[C:25]2[C:20](=[C:19]([O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:28]=[CH:27][CH:26]=2)[CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCCC2=O)(c1ccccc1)c1ccccc1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: C1CCOC1
Product: CC(C)(C)[Si](Oc1cccc2c1CCC[C@@H]2O)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 109.8 %

Procedure:
To a solution of 5-t-butyldiphenylsilyloxy-1-tetralone (2.9 g) and (R)-5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine (2.3 g) in THF (5 ml) was added borane tetrahydrofuran complex (7.1 ml, 1 M solution in THF) at -18° C. After being stirred for 30 minutes, the reaction was quenched with 1N HCl solution. The mixture was poured into a mixture of ethyl acetate and water. The organic layer was washed with 1N-HCl solution, sat. NaHCO3 and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford (1S)-1-hydroxy-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (3.2 g). MS (m/z): 401 (M+ -1) NMR (CDCl3, δ): 1.10 (9H, s), 1.8-2.2 (4H, m), 2.6-3.1 (2H, m), 4.79 (1H, t, J=4.8 Hz), 6.30 (1H, d, J=8 Hz), 6.77 (1H, t, J=8 Hz), 6.97 (1H, d, J=8 Hz), 7.3-7.9 (10H, m) HPLC; chiralcel AD, 2% isopropanol/hexane, 20.3 ml/min
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[CH:21]([CH2:26][CH2:27][CH3:28])[C:22]([O:24]C)=[O:23].[OH-].[Li+].Cl>O1CCOCC1.O>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[CH:21]([CH2:26][CH2:27][CH3:28])[C:22]([OH:24])=[O:23]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Temperature: 60 °C
Yield: 40.5 %

Procedure:
To a solution of methyl [2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate (0.100 g; 0.254 mmol) in a mixture of dioxane (5 mL) and water (1.3 mL) was added a 1N lithium hydroxide solution (2.55 mL; 2.55 mmol). The reaction mixture was heated at 60° C. for 8 h. After cooling to room temperature, the reaction mixture was acidified with 1N HCl (pH˜2) and partially concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulphatesulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.039 g (40%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]([CH2:20][CH3:21])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=2)[CH2:4][C@H:3]1[O:22][CH2:23][CH2:24][CH3:25].[Cl:26][C:27]1[N:28]=[C:29]([C:34](O)=[O:35])[NH:30][C:31]=1[CH2:32][CH3:33].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.ClCCl>[Cl:26][C:27]1[N:28]=[C:29]([C:34]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[O:9][C:10]([CH2:20][CH3:21])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=3)[CH2:4][C@H:3]2[O:22][CH2:23][CH2:24][CH3:25])=[O:35])[NH:30][C:31]=1[CH2:32][CH3:33]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OCCC)C2)oc1CC
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCCC)C2)oc1CC
Yield: 41.2 %

Procedure:
The same operation as in Example (106d) was performed using butyl cis(±)-2-(4-amino-3-propoxypiperidin-1-yl)-5-ethyl-1,3-oxazole-4-carboxylate obtained in Example (113h) (0.70 g, 2.0 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 0.2 g, 1 mmol), WSC hydrochloride (0.5 g, 2.5 mmol), HOBt (0.2 g, 1.5 mmol), dichloromethane (5 mL) and DMA (3 mL), to obtain 0.21 g of the title compound as a colorless amorphous solid (41%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@H:3]1[NH:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH2:17]([N:5]1[CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]([NH:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[CH2:4]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: CCOP(=O)(N[C@@H]1CNCC[C@H]1C)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOP(=O)(N[C@@H]1CN(Cc2ccccc2)CC[C@H]1C)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
A mixture of diethyl trans-4-methylpiperidin-3-ylphosphoramidate (0.63 g, 2.52 mmol), benzaldehyde (0.38 mL, 3.78 mmol) and acetic acid (0.29 mL, 5.03 mmol) in methanol (20 mL) was stirred at 0° C. for 30 minutes. NaCNBH3 (0.24 g, 3.78 mmol) was added at 0° C. The resulting solution was warmed to room temperature and stirred at room temperature for 1 hour. The solvent was removed in vacuo, and saturated sodium bicarbonate (20 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate) and concentrated in vacuo to give diethyl trans-1-benzyl-4-methylpiperidin-3-ylphosphoramidate (0.85 g, 99%), which was used directly in the next step without purification.
Reaction SMILES: C(C1C=CC([CH:9]2[CH2:18][C:17]3[C:12](=[CH:13][C:14]([N+:19]([O-])=O)=[CH:15][CH:16]=3)[C:11](=[O:22])[N:10]2CCCNC(=O)OC(C)(C)C)=CC=1)#N.[N+](C1C=C2C(CCNC2=O)=CC=1)([O-])=O.[H][H]>[Pd].CO>[NH2:19][C:14]1[CH:13]=[C:12]2[C:17]([CH2:18][CH2:9][NH:10][C:11]2=[O:22])=[CH:16][CH:15]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCCN1C(=O)c2cc([N+](=O)[O-])ccc2CC1c1ccc(C#N)cc1
Agent: [Pd]
Agent: O=C1NCCc2ccc([N+](=O)[O-])cc21
Solvent: CO
Product: Nc1ccc2c(c1)C(=O)NCC2

Procedure:
Compounds within the scope of the invention may be prepared as depicted in Scheme 1. In general, an aldehyde, such as 4-cyanobenzaldehyde, and an amine, such as N1-boc-1,3-diamino-n-propane can be reacted in a suitable solvent (eg., THF or chloroform) to form an imine intermediate. The solvent may then be evaporated under reduced pressure, and the residue redissolved in DMF. The imine is then reacted with 7-nitro-homopthallic anhydride, (i.e., 7-Nitro-1H-2-benzopyran-1,3(4H)-dione) to produce a 7-nitro-3,4-dihydroisoquinolin-1(2H)-one, such as tert-butyl (3-(3-(4-cyanophenyl)-7-nitro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propyl)carbamate (Intermediate 1). The nitro group of the 7-nitro-3,4-dihydroisoquinolin-1(2H)-one can then be treated with a reducing agent, such as hydrogen in the presence of 10% palladium on carbon, in a suitable solvent (MeOH) to give a 7-amino-3,4-dihydroisoquinolin-1(2H)-one, such as tert-butyl (3-(7-amino-3-(4-cyanophenyl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propyl)carbamate (Intermediate 13). The 7-amino-3,4-dihydroisoquinolin-1(2H)-one may be dissolved in a suitable solvent (eg., benzene) and then be treated with an organic isocyanates, such as 4-acetylphenyl isocyanates, in the presence of a strong base (eg, DIPEA) to produce a urea, such as tert-butyl {3-[7-({[(4-acetylphenyl)amino] carbonyl}amino)-3-(4-cyanophenyl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl]propyl}carbamate (Intermediate 23), a compound which falls under the scope of the invention. At this stage, those skilled in the art will appreciate that many additional compounds that fall under the scope of the invention may be prepared by performing various common chemical reactions. For instance, a sulfide group may be oxidized to sulfoxide or sulfone groups by treatment with a suitable oxidizing agent (eg., m-chloroperbenzoic acid). Or, for example, the t-butylcarbamate group may be removed by treatment with a strong acid, such as trifluoroacetic acid, to give an amine product, such as 1-(4-acetylphenyl)-3-[2-(2-aminoethyl)-3-(4-cyanophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl]urea (Compound 2). Details of certain specific chemical transformations are provided in the examples.
Reaction SMILES: [CH3:1][CH:2]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([NH2:19])[CH:15]=[CH:14]2)[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].CCN(CC)CC.[C:27]([O:35][CH2:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39](Cl)=[O:40])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C1C=CN=CC=1)C.C1COCC1>[C:27]([O:35][CH2:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39]([NH:19][C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[C:9]([O:8][CH:2]([CH3:1])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH:10]=[CH:11][CH:12]=2)[N:17]=1)=[O:40])(=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(CC(C)(C)C)Oc1cccc2ccc(N)nc12
Reactant: O=C(OCc1ccccc1C(=O)Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(CC(C)(C)C)Oc1cccc2ccc(NC(=O)c3ccccc3COC(=O)c3ccccc3)nc12
Reaction time: 8 h

Procedure:
To a 20 mL scintillation vial was added a stir bar, the title compound from Example 16 (100 mg, 0.388 mmol) and anhydr. THF (1.3 mL). To the resultant solution was added of Et3N (0.12 mL, 2.2 equiv), DMAP (5.0 mg, 1.06 equiv) and of 2-(benzoyloxymethyl)benzoyl chloride (116 mg, 1.1 equiv). The solution was stirred overnight, after which time the mixture was placed directly on a silica gel column and eluted with EtOAc/hexanes to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.23 (m, 1H), 8.16 (m, 1H), 7.92 (m, 2H), 7.72 (m, 1H), 7.55 (m, 4H), 7.38 (m, 4H), 7.24 (m, 1H), 5.51 (s, 2H), 4.82 (m, 1H), 1.88 (dd, 1H), 1.49 (dd, 1H), 1.34 (d, 3H), 0.92 (s, 9H); MS (DCI/NH3) m/z 497 [M+H]+.
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[N:10]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.CO.[Pd]>[C:1]([Si:5]([CH3:18])([CH3:17])[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
A solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-nitro-1H-pyrazole (500 mg, 1.80 mmol) in ethyl acetate (15 mL) and methanol (15 mL) was treated with 10% palladium on activated carbon (wet, 50 mg) The flask was charged with hydrogen gas via balloon. The reaction stirred at 25° C. for 16 h. The reaction was then filtered through a plug of silica gel (Merck, 60, 40-63 μm) layered with diatomaceous earth and concentrated in vacuo to afford 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (391 mg, 90%) as a yellow oil. 1H-NMR (400 MHz, DMSO-d6) δ 0.00 (6H, s), 0.83 (9H, s), 3.78 (2H, t, J=4.8 Hz), 3.87 (2H, t, J=6.0 Hz), 4.48 (2H, s), 5.33 (1H, d, J=2.0 Hz), 7.22 (1H, d, J=2.0 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][N:17](C(OCC3C=CC=CC=3)=O)[CH2:16][CH2:15]2)[C:10]1=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[O:30]=[C:10]1[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][CH2:12][N:11]1[CH:14]1[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C2CCNCC2)C1=O
Yield: 83 %

Procedure:
To a solution of (S)-benzyl 4-(3-(tert-butoxycarbonylamino)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (Preparation E, Step C, 7.0 g, 17 mmol) in methanol (300 mL) purged with nitrogen was added Pd/C (10%, 2 g) and the reaction was stirred overnight at ambient temperature under a balloon of hydrogen gas. The reaction was next purged with nitrogen and filtered through Celite®, and the filter cake was washed with methanol (about 100 mL). The combined organic phases were concentrated under vacuum to yield (S)-tert-butyl 2-oxo-1-(piperidin-4-yl)pyrrolidin-3-ylcarbamate (4.0 g, 83%)