Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([N:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:21][CH2:20]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C(#N)C>[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:20][CH2:21][N:22]([C:25]([N:27]3[CH2:28][CH2:29][N:30]([C:33]4[CH:34]=[CH:35][N:36]=[CH:37][C:38]=4[Cl:1])[CH2:31][CH2:32]3)=[O:26])[CH2:23][CH2:24]2)(=[O:17])=[O:18])=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(N1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)c2ccc(F)cc2)CC1
Solvent: CC#N
Product: O=C(N1CCN(c2ccncc2Cl)CC1)N1CCN(S(=O)(=O)c2ccc(F)cc2)CC1
Reaction time: 48 h
Yield: 68.3 %

Procedure:
N-Chlorosuccinimide (4.05 g) was added to a stirred suspension of 1-(4-fluorophenylsulphonyl)-4-[1-(4-pyridyl)piperazin-4-ylcarbonyl]piperazine (12.45 g) in acetonitrile (500 mL) at 20° C. The mixture was stirred for 48 hours and the acetonitrile evaporated. Water (200 mL) was added to the residue and the aqueous phase extracted with dichloromethane (3×200 mL). The organic extracts were dried and evaporated. The residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol (97:3) to give a foam on evaporation. Trituration with diethyl ether (250 mL) gave 1-(4-fluorophenylsulphonyl)-4-[1-(3-chloro-4-pyridyl)piperazin-4-ylcarbonyl]piperazine as a pale yellow solid (9.18 g): mp 143-144° C.: NMR (CDCl3): 3.04(t, 4H), 3.15(t, 4H), 3.41(t, 8H), 6.78(d, 1H), 7.21(d, 2H), 7.78(m, 2H), 8.33(d, 1H), 8.42(s, 1H); EI-MS m/z 468(M+H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)=[N:12]2)[CH2:7][CH2:6]1)=[O:4].[O:29]=[C:30]1[CH2:35][CH2:34][CH2:33][C:32](=[O:36])[NH:31]1>>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:13]2[C:14]([CH3:17])([CH3:18])[C:15](=[O:16])[N:11]([CH:8]3[CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH2:2][N:31]4[C:32](=[O:36])[CH2:33][CH2:34][CH2:35][C:30]4=[O:29])[CH2:10][CH2:9]3)[N:12]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: O=C1CCCC(=O)N1
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)CCl)CC3)C(=O)C2(C)C)cc1OC
Product: COc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)CCCC4=O)CC3)C(=O)C2(C)C)cc1OC

Procedure:
Prepared analogously as described for example 1 using 2-[1-(chloroacetyl)piperidin-4-yl]-5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound A1) and 2,6-dioxopiperidine as starting compounds.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]#[C:12][Si](C)(C)C)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1.[C:23](C1C=C2C(=CC=1)N(C1CCCCO1)N=C2)#[CH:24].C(C1C=C2C(=CC=1)N(C1CCCCO1)N=C2)#CCC>>[C:11]([C:10]1[C:2]([CH3:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[N:6]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[N:5]=[CH:4]2)#[C:12][CH2:23][CH3:24]
Reactant: Cc1c(C#C[Si](C)(C)C)ccc2c1cnn2C1CCCCO1
Reactant: C#Cc1ccc2c(cnn2C2CCCCO2)c1
Agent: CCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Product: CCC#Cc1ccc2c(cnn2C2CCCCO2)c1C

Procedure:
The title compound was prepared from 4-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-((trimethylsilyl)ethynyl)-1H-indazole following the procedures outlined for Intermediate 2 (step 2) and Intermediate 3. 1H NMR (300 MHz, DMSO-d6): δ 7.97 (s, 1H), 7.27 (d, 1H), 7.11 (d, 1H), 5.59 (dd, 1H), 3.58 (m, 1H), 3.50 (m, 1H), 2.38 (s, 3H), 2.17 (q, 2H), 2.13 (m, 1H), 1.77 (m, 2H), 1.50 (m, 1H), 1.36 (m, 2H), 0.98 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([CH2:10][C:11]([OH:13])=O)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.O=S(Cl)Cl.[C:20]1([O:26][CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.CO.CN(C=O)C>[Br:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([CH2:10][C:11]([C:23]2[CH:24]=[CH:25][C:20]([O:26][CH3:27])=[CH:21][CH:22]=2)=[O:13])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)c(OC)c(CC(=O)O)c1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cc2cc(OC)cc(Br)c2OC)cc1
Reaction time: 3 h
Yield: 75 %

Procedure:
To a cooled (0° C.) solution of 55 (2.8 g, 10 mmol) in CH2Cl2 (50 ml) was added SOCl2 (1.8 g, 15 mmol) and DMF (2 ml) and the reaction was stirred for 3 hr. The solution was concentrated and the resulting oil was taken up into dichloroethane (50 ml). The solution was cooled and anisole (2.0 g, 1 8.4 mmol) was added followed by AlCl3 (1.8 g, 13.8 mmol). The reaction was stirred for 1 hr and was then quenched with 2N HCl aq. The organic layer was dried over MgSO4, concentrated to give an oil which was taken up into MeOH and a solid crystallized. The solid was collected by filtration to give a white solid (2.3 g, 63%); Mp=91–93° C.; 1H NMR (DMSO-d6) δ 8.01 (d, 2 H, J=8.4 Hz), 7.10–7.05 (m, 3 H), 6.85 (d, 1 H, J=5.7 Hz), 4.35 (s, 2 H), 3.85 (s, 3 H), 3.72 (s, 3H), 3.59 (s, 3 H); MS 363/365 (M−H)−
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH:21]1([NH:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]2)[CH2:23][CH2:22]1>>[C:31]([N:28]1[CH2:27][CH2:26][CH:25]([N:24]([CH:21]2[CH2:23][CH2:22]2)[C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[CH2:30][CH2:29]1)(=[O:33])[CH3:32]
Reactant: CC(=O)N1CCC(NC2CC2)CC1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: CC(=O)N1CCC(N(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)C2CC2)CC1

Procedure:
The title compound was synthesized in analogy to Example 47 b), using 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid and 1-(4-(cyclopropylamino)piperidin-1-yl)ethanone (CAS 387358-46-5) as starting materials and isolated as colorless oil. MS (EI): m/e=449.6 [MH+].
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:14][N:15]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[N:16]1.[F-].[K+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:12]([C:8]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([C:18]2[CH:17]=[N:16][N:15]([CH3:14])[CH:19]=2)[N:11]=[CH:10][CH:9]=1)#[N:13]
Reactant: COC(=O)c1c(C#N)ccnc1Cl
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)c1c(C#N)ccnc1-c1cnn(C)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
A mixture of methyl 2-chloro-4-cyanonicotinate (730 mg, 3.71 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (927 mg, 4.46 mmol), trans-dichlorobis(triphenylphosphine)palladium (261 mg, 0.371 mmol) and potassium fluoride (2697 mg, 14.85 mmol) in DME (15 mL) was stirred at 120° C. for 1 h under microwave irradiation. The mixture was filtered through Celite, and the filtrate was diluted with H2O and EtOAc. The organic phase was washed with H2O and brine, dried over MgSO4, and evaporated. The residue was purified by chromatography on SiO2 to give the title compound as a pale yellow solid (470 mg, 52.3%). 1H NMR (500 MHz, CDCl3) δ ppm 3.97 (s, 3 H), 4.03 (s, 3 H), 7.41 (d, J=4.88 Hz, 1 H), 7.82 (s, 1 H), 7.91 (s, 1 H), 8.79 (d, J=4.88 Hz, 1 H). [M+H] calc'd for C12H10N4O2, 243; found, 243.
Reaction SMILES: Cl.Br[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH2:8]2.[CH3:13][N:14]1[C:18]([C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=2B(O)O)=[CH:17][CH:16]=[N:15]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[CH3:13][N:14]1[C:18]([C:19]2[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:20]=2[C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH2:5][CH2:6][NH:7][CH2:8]3)=[CH:17][CH:16]=[N:15]1
Reactant: Cn1nccc1-c1cc(C(F)(F)F)ccc1B(O)O
Reactant: Brc1cccc2c1CCNC2
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1cccc2c1CCNC2
Temperature: 90 °C

Procedure:
A vial was charged with 5-bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride (ASW Medchem, Brunswick, N.J., 400.42 mg, 1.367 mmol), (2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)boronic acid (Intermediate B, 443 mg, 1.640 mmol), potassium phosphate (1160 mg, 5.47 mmol), and Pd(AmPhos)2Cl2 (Sigma-Aldrich, St. Louis, Mo., 48.4 mg, 0.068 mmol). The vial was flushed with Ar (g), then dioxane (2928 μl) and water (976 μl) were added in sequence. The mixture was heated in a microwave reactor for 30 min at 90° C. After cooling to room temperature, the mixture was diluted with EtOAc, washed with water (and a small amount of brine to break up emulsions, 2×), washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was taken up in MeOH, then loaded onto a 10 g SCX-2 ion exchange column. The column was eluted with MeOH, then with 2M ammonia in MeOH. The basic filtrate was concentrated, and the residue was chromatographed on a 40 g silica gel column with 0 to 10% MeOH/DCM to provide 5-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline as a pale yellow solid. [M+H]+=358.1. 1H NMR (400 MHz, DMSO-d6) δ ppm=7.91-7.80 (m, 2H), 7.56 (d, J=8.0 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.09-6.95 (m, 2H), 6.84 (dd, J=1.3, 7.4 Hz, 1H), 5.96 (d, J=1.9 Hz, 1H), 3.85 (s, 2H), 3.52 (br. s., 3H), 2.93-2.84 (m, 1H), 2.79-2.67 (m, 1H), 2.48-2.39 (m, 1H), 2.09 (td, J=5.3, 16.7 Hz, 1H).
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][NH:5][CH3:6].C(N(CC)CC)C.[CH:14]([N:17]=[C:18]=[O:19])([CH3:16])[CH3:15]>O1CCCC1>[CH:14]([NH:17][C:18]([N:4]([CH3:3])[NH:5][CH3:6])=[O:19])([CH3:16])[CH3:15]
Reactant: CNNC
Reactant: CC(C)N=C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNN(C)C(=O)NC(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
To a solution of N,N'-dimethylhydrazine dihydrochloride (1.33 g) and triethylamine (2.02 g) in dry tetrahydrofuran (20 ml) which was cooled to 0° C., was added isopropyl isocyanate (851 mg). The mixture was stirred at 0° C. for 2 hours. After evaporation of the solvent, the residue was dissolved in ethyl acetate (50 ml). The solution was washed with 1 M sodium bicarbonate solution and water successively, and dried over magnesium sulfate. The solvent was evaporated to give N-(isopropylcarbamoyl)-N,N'-dimethylhydrazine (771 mg) as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[CH:12]1[C:19](=[O:20])[CH:18]2[CH:14]([CH2:15][C:16](=O)[CH2:17]2)[C:13]1=[O:22])[CH3:2].[C:23](#[N:27])[CH2:24][C:25]#[N:26].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[CH:12]1[C:19](=[O:20])[CH:18]2[CH:14]([CH2:15][C:16](=[C:24]([C:23]#[N:27])[C:25]#[N:26])[CH2:17]2)[C:13]1=[O:22])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C1C(=O)C2CC(=O)CC2C1=O
Reactant: N#CCC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCc1cc(C)cc(CC)c1C1C(=O)C2CC(=C(C#N)C#N)CC2C1=O

Procedure:
0.500 g (1.70 mmol) of 2-(2,6-diethyl-4-methylphenyl)tetrahydropentalene-1,3,5-trione (example I-a-4 from WO 2010/040460), 250 mg of malononitrile, 150 mg of ammonium acetate and 0.3 ml of glacial acetic acid in 30 ml of toluene are heated at reflux for 2 h. After cooling, the solvent is distilled off and the mixture is taken up in ethyl acetate, washed twice with water, then dried (magnesium sulphate) and concentrated on a rotary evaporator. What remains is a yellow oil which is chromatographed on silica gel using ethyl acetate/hexane 1:6. This gives 0.32 g (56%) of a colourless oil.
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:21]([O-:23])=[O:22])=[C:6]([CH2:9][S:10][C:11]3[N:16]=[C:15]([NH2:17])[CH:14]=[C:13]([NH2:18])[N+:12]=3[CH2:19]C)[CH2:7][S:8][C@H:3]12.NC1C(=O)N2C(C([O-])=O)=C(CSC3N=C(N)C=C(N)[N+]=3N)CS[C@H]12.NC1C(=O)N2C(C([O-])=O)=C(CSC3N=C(N)C(C)=C(N)[N+]=3C)CS[C@H]12.NC1C(=O)N2C(C([O-])=O)=C(CSC3N=C(N)C(C)=C(N)[N+]=3N)CS[C@H]12>>[NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:21]([O-:23])=[O:22])=[C:6]([CH2:9][S:10][C:11]3[N:16]=[C:15]([NH2:17])[CH:14]=[C:13]([NH2:18])[N+:12]=3[CH3:19])[CH2:7][S:8][C@H:3]12
Reactant: CC[n+]1c(N)cc(N)nc1SCC1=C(C(=O)[O-])N2C(=O)C(N)[C@H]2SC1
Agent: Cc1c(N)nc(SCC2=C(C(=O)[O-])N3C(=O)C(N)[C@H]3SC2)[n+](C)c1N
Agent: Cc1c(N)nc(SCC2=C(C(=O)[O-])N3C(=O)C(N)[C@H]3SC2)[n+](N)c1N
Agent: Nc1cc(N)[n+](N)c(SCC2=C(C(=O)[O-])N3C(=O)C(N)[C@H]3SC2)n1
Product: C[n+]1c(N)cc(N)nc1SCC1=C(C(=O)[O-])N2C(=O)C(N)[C@H]2SC1

Procedure:
7-amino-3-(4,6-diamino-1-ethylpyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate; 7-amino-3-(1,4,6-triaminopyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate; 7-amino-3-(4,6-diamino-1,5-dimethylpyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate; and 7-amino-3-(5-methyl-1,4,6-triaminopyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]23[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH:19]2[O:18][C:17]2[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:16]3=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1(O)C=CC=CC=1>>[F:29][C:27]1[CH:26]=[CH:25][C:17]2[O:18][CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:15]3([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[C:16]=2[CH:28]=1
Reactant: Fc1ccc2c(c1)C1(c3ccc(OCc4ccccc4)cc3)CCCCCC1O2
Solvent: Oc1ccccc1
Product: Oc1ccc(C23CCCCCC2Oc2ccc(F)cc23)cc1

Procedure:
The title compound 448 was synthesized starting from compound 32 using the procedure F as described for the synthesis of phenol 807. 1H-NMR (400 MHz, CDCl3): δ ppm 7.18-7.07 (m, 2H), 6.82 (dt, J=8.79, 8.79, 2.75 Hz, 1H), 6.78-6.69 (m, 3H), 6.62 (dd, J=8.20, 2.73 Hz, 1H), 5.08 (broad s, 1H), 4.91 (dd, J=7.30, 1.61 Hz, 1H), 2.45-2.26 (m, 1H), 2.23-1.95 (m, 2H), 1.82 (tdd, J=14.57, 12.67, 1.56, 1.56 Hz, 1H), 1.77-1.48 (m, 4H), 1.44-1.03 (m, 2H).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:8][N:7]=1)([O:3][CH2:4][CH3:5])=[O:2].[O:16]1CCOCC1>O>[C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[C:13]([CH3:14])[CH:15]=[O:16])=[CH:8][N:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1ccc(C=C(C)C)cn1
Reactant: C1COCCO1
Solvent: O
Product: CCOC(=O)c1ccc(C=C(C)C=O)cn1
Temperature: 100 °C
Yield: 53 %

Procedure:
A mixture of 5.0 g (45.0 mmol) of SeO2 and 4.25 g (20.7 mmol) of 1-(2-carbethoxy-5-pyridyl)-2-methyl-1-propene in 50 mL of dioxane and 2 mL of H2O was degassed three times under argon and then heated at 100° C. for 2 h. The mixture was filtered through Celite and washed with dioxane. The filtrate was concentrated and chromatographed on 150 g of silica gel (50% EtOAc/hexane and 75% EtOAc/hexane) to give 2.95 g of 3-(2-carbethoxy-5-pyridyl)-2-methyl-2-propenal as a yellow solid. Analytical LC (Radialpak B, 25% EtOAc/hexane) indicated about 5% of the Z isomer was present. Recrystallization from EtOAc/hexane gave 2.4 g (53% yield) of the pure E isomer as white crystals, mp 72°-73° C.; IR (mull) 1740, 1700, 1330, 1300, 1260, 1200, 1170, 1140, 1120, 1020, 920, 880, 830, 810, 720 cm-1 ; 1H NMR (CDCl3) δ1.50 (t, J=7 Hz, 3, CO2CH2CH3), 2.10 (s, 3, C=CCH3), 4.50 (q, J=7 Hz, 2, CO2CH2CH3), 7.35 (s, 1, C=CH), 8.02 (dd, J=2 Hz, J=8 Hz, 1, 4'--H), 8.27 (d, J=8 Hz, 1, 3'--H), 8.93 (d, J=1 Hz, 1, 6'--H), 9.70 (s, 1, CHO); MS calcd for C12H13NO3 219.0895, found 219.0907.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[O:4][CH2:5][O:6][P:7]([CH2:19][C:20]([O:22]CC1C=CC=CC=1)=[O:21])([CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:8]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[O:4][CH2:5][O:6][P:7]([CH2:19][C:20]([OH:22])=[O:21])([CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:8]
Reactant: CC(C)(C)C(=O)OCOP(=O)(CCCCc1ccccc1)CC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OCOP(=O)(CCCCc1ccccc1)CC(=O)O

Procedure:
[[(2,2-Dimethyl-1-oxopropoxy)methoxy](4-phenylbutyl)phosphinyl]acetic acid, phenylmethyl ester (2.95 g, 6.4 mmol) in 75 ml of ethyl acetate was hydrogenated at 48 psi over 10% palladium on charcoal catalyst (0.4 g) for 1 hour. The mixture was filtered through Celite and evaporated to dryness to give the title acid as a colorless oil which solidified to a solid, melting point 48°-50° C.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]2[C:14]([CH3:16])([CH3:15])[C@H:13]3[CH2:17][C@:10]2([CH3:18])[CH2:11][CH2:12]3)=[O:7])=[CH:4][C:3]=1[S:21]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([NH:36][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]2[C:14]([CH3:16])([CH3:15])[C@H:13]3[CH2:17][C@:10]2([CH3:18])[CH2:11][CH2:12]3)=[O:7])=[CH:4][C:3]=1[S:21]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)(=[O:23])=[O:22])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC1(C)C(NC(=O)c2ccc(Br)c(S(=O)(=O)N3CCCC3)c2)[C@@]2(C)CC[C@@H]1C2
Reactant: NCc1ccccc1
Product: CC1(C)C(NC(=O)c2ccc(NCc3ccccc3)c(S(=O)(=O)N3CCCC3)c2)[C@@]2(C)CC[C@@H]1C2

Procedure:
Compound 2N was prepared from 4-bromo-3-(pyrrolidin-1-ylsulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide 2.4.AiBa and benzylamine Ck following method 2c.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([OH:21])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:22][CH3:23])[C:9]=3[CH:8]2[S:24][CH2:25][CH2:26][C:27]([OH:29])=O)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[CH2:38]([O:40][P:41]([CH2:46][NH2:47])(=[O:45])[O:42][CH2:43][CH3:44])[CH3:39].C(Cl)CCl.P(=O)([O-])OCN>C(Cl)Cl>[CH2:38]([O:40][P:41]([CH2:46][NH:47][C:27](=[O:29])[CH2:26][CH2:25][S:24][CH:8]1[C:9]2[C:10]([O:22][CH3:23])=[C:11]3[C:16](=[C:17]([OH:21])[C:18]=2[C:19](=[O:20])[N:7]1[CH2:6][C:5]1[CH:30]=[CH:31][C:2]([F:1])=[CH:3][CH:4]=1)[N:15]=[CH:14][CH:13]=[CH:12]3)(=[O:45])[O:42][CH2:43][CH3:44])[CH3:39]
Reactant: COc1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2SCCC(=O)O
Reactant: CCOP(=O)(CN)OCC
Agent: NCO[PH](=O)[O-]
Agent: O=C(O)C(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOP(=O)(CNC(=O)CCSC1c2c(c(O)c3ncccc3c2OC)C(=O)N1Cc1ccc(F)cc1)OCC

Procedure:
To a solution of 24 (15 mg, 0.035 mmol) in 0.35 mL of CH2Cl2 (0.35 mL) was added diethyl(aminomethyl)phosphonate oxalate (27 mg, 0.105 mmol), EDC (20 mg, 0.105 mmol) and TEA (15 μL, 0.105 mmol). The solution was stirred at room temperature for 1 day when the same amount of the aminomethyl phosphonate, EDC and TEA were added. The reaction was stirred for another day when complete conversion of starting materials to the desired product was observed by LCMS. The product 26 was purified by reverse phase HPLC using 5-95% A. Buffer A contained CH3CN-1% HOAc and buffer B was H2O-1% HOAc. 1H NMR (300 MHz, CDCl3) δ 1.33-1.40 (m, 6H), 2.37-2.45 (m, 4H), 3.60-3.72 (m, 2H), 4.05 (s, 3H), 4.06-4.18 (m, 4H), 4.44 (d, 1H, J=15 Hz), 5.33 (d, 1H, J=14 Hz), 5.49 (s, 1H), 6.17 (br s, 1H), 6.98-7.08 (m, 2H), 7.33-7.43 (m, 2H), 7.55-7.63 (m, 1H), 8.50-8.57 (br d, 1H), 8.97 (br s, 1H); 31P (121.4 MHz, CDCl3) δ 22.7; 19F NMR (282.6 MHz, CDCl3) δ 62.6; EI MS (m/z) 590.4 [M−H]−, 614.2 [M+Na].
Reaction SMILES: C[S:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[CH2:23][CH2:22][CH2:21][N:13]3[C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O(C)[Na].CO.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.O>[SH:2][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]3[CH2:23][CH2:22][CH2:21][N:13]3[C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1
Reactant: CS(=O)c1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Agent: CO[Na]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.7 %

Procedure:
To 5 q (15.5 mmole) of 2-(4-methylsulfinylphenyl)3 (4-pyridyl)-6,7-dihydro [5H]-pyrrolo[1,2-a]-imidazole prepared as in Example 4 dissolved in 100 ml methylene chloride and cooled to 0° was added 9.7 q (46.4 mmole, 6.5 ml) of trifluoroacetic anhydride in 25 ml of methylene chloride. The mixture was heated to reflux for 1 hour. The reaction mixture was stripped on the rotovap, then treated with water, and extracted with methylene chloride. The extract was washed with 3N NaHCO3 and saturated NaCl and treated with Na2SO4, then stripped to leave 5.1 g of crude product. This material was dissolved in anhydrous methanol (50 ml) and treated with a 25% solution of NaOCH3 /MeOH (5 ml, 23 mmole). This mixture was stirred at room temperature for 3 hours, then poured onto ice water and neutralized with 3N NaHCO3. After removing most of the methanol on the rotovap, the residue was partitioned between methylene chloride and water. The organic layer was washed with water and saturated NaCl, treated with Na2SO4 and stripped. The residue was flash chromatographed on a silica gel column using a gradient of 1 to 5% MeOH in methylene chloride to give 3.1 g (10.5 mmole) of the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C>CO.O>[F:1][C:2]1[CH:9]=[C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5]
Reactant: C1COCCN1
Reactant: N#Cc1c(F)cc(F)cc1F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: N#Cc1c(F)cc(N2CCOCC2)cc1F
Temperature: 50 °C
Yield: 68.6 %

Procedure:
To a solution of 1.0 g (6.37 mmol) of 2,4,6-trifluorobenzonitrile in MeOH (25 mL) was added 0.6 mL (6.9 mmol) of morpholine and 1.2 mL (6.7 mmol) of N,N-diisopropylethylamine. The mixture was heated to 50° C. for 6 h then cooled to room temperature and diluted with H2O which caused a solid to precipitate from solution. The white solid was collected by filtration, washed with H2O and dried under vacuum to provide 0.98 g (68%) of 2,6-difluoro-4-morpholin-4-yl-benzonitrile as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]=O)=[C:8]([CH3:13])[C:6]=2[N:7]=1.CC(O)=O.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([NH:31][CH3:32])[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:31]([CH3:32])[CH:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)=[C:8]([CH3:13])[C:6]=2[N:7]=1
Reactant: Cc1c(C=O)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CNC1CCN(C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1c(CN(C)C2CCN(C)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reaction time: 0.25 h
Yield: 88 %

Procedure:
2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde (0.5 g) was dissolved in 10 mL of 1,2-DCE and 1.0 eq. AcOH and 1.3 eq. of 1-methyl-4-(methylamino)piperidine was added and the reaction was stirred 15 minutes followed by the addition of sodium triacetoxyborohydride. The reaction was stirred for 24 hours and product formation was confirmed by LCMS. The reaction was diluted with sat. NaHCO3, extracted with dichloromethane, dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc/hexanes) to give 0.61 g N-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,1-dimethylpiperidin-4-amine (88% yield). MS (Q1) 411 (M)+.