Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([C@H:19]1[C@@H:23]([C:24]2[N:28]3[C:29]4[CH:35]=[CH:34][N:33]([S:36]([C:39]5[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=5)(=[O:38])=[O:37])[C:30]=4[N:31]=[CH:32][C:27]3=[N:26][N:25]=2)[CH2:22][C:21](=O)[CH2:20]1)[CH3:18].C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[CH2:17]([C@H:19]1[C@@H:23]([C:24]2[N:28]3[C:29]4[CH:35]=[CH:34][N:33]([S:36]([C:39]5[CH:40]=[CH:41][C:42]([CH3:43])=[CH:44][CH:45]=5)(=[O:37])=[O:38])[C:30]=4[N:31]=[CH:32][C:27]3=[N:26][N:25]=2)[CH2:22]/[C:21](=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])/[CH2:20]1)[CH3:18]
Reactant: CC[C@@H]1CC(=O)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C1\C[C@@H](CC)[C@@H](c2nnc3cnc4c(ccn4S(=O)(=O)c4ccc(C)cc4)n23)C1
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
To a slurry of NaH (0.034 g, 0.85 mmol) in THF (5 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (0.177 mL, 0.886 mmol) at rt. After about 30 min, a solution of (3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone (0.300 g, 0.708 mmol, Preparation #25) in THF (1 mL) was added. After about 4 h, EtOAc (20 mL) and saturated aqueous NaHCO3 (20 mL) were added. The organic layer was separated, concd in vacuo, and purified by chromatography on silica gel (40 g) eluting with EtOAc/heptane/DCM (2:1:1) to provide (E)-ethyl 2-((3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylidene)acetate (0.260 g, 74%). LC/MS (Table 1, Method a) Rt=2.54 min; MS m/z: 494 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[CH:2].I[C:22]1[CH:30]=[C:26]([C:27]([OH:29])=[O:28])[C:25]([OH:31])=[CH:24][CH:23]=1>>[OH:31][C:25]1[CH:24]=[CH:23][C:22]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:9])[CH:20]=2)=[CH:30][C:26]=1[C:27]([OH:29])=[O:28]
Reactant: O=C(O)c1cc(I)ccc1O
Reactant: C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccc(O)c(C(=O)O)c2)c1)c1ccccc1
Yield: 45 %

Procedure:
In a manner similar to that describe in Example 434, a mixture of (S)-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 5-iodosalicyclic acid were reacted to give the title compound as a light tan solid (28 mg, 45%).
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[Na+].C(OO)(=O)C.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19]C=C)=[CH:14][CH:13]=1.O>ClCCl>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH:1]2[O:4][CH2:2]2)=[CH:14][CH:13]=1
Reactant: C=CCCc1ccc(Br)cc1
Reactant: CC(=O)[O-]
Agent: CC(=O)OO
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Brc1ccc(CCC2CO2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 156 %

Procedure:
To a sample of sodium acetate (2.50 g, 30.48 mmol, 0.63 equiv) under a N2 atmosphere was added a 32% solution (in dilute aqueous acetic acid) of peracetic acid (50 mL, 18.08 g, 237.74 mmol, 4.92 equiv). The mixture was stirred at rt for 10 min to completely dissolve the NaOAc. This peroxide solution was then added dropwise over a period of 5 min to a solution of alkene 11a (10.20 g, 4832 mmol, 1 equiv) in dichloromethane (100 mL) at rt. The mixture was heated at reflux temperature with stirring for 3 h. Monitoring by TLC (silica gel, hexanes) confirmed the completion of the reaction. Water (100 mL) was added and the organic phase separated. The aqueous phase was extracted with CH2Cl2 (3×100 mL), and the combined organic extracts were washed sequentially with a saturated solution of sodium hydrogencarbonate (2×), and brine, dried over anhydrous Na2SO4, and then concentrated. High-vacuum drying afforded the epoxide 12a (10.80 g, 47.56 mmol, 98%) as a clear oil: Rf˜0.2 (hexanes); 1H NMR (400 MHz, CDCl3): δ 1.73-1.92 (m, 2H), 2.45-2.49 (4-tet, 1H), 2.66-2.82 (m, 3H), 2.90-2.96 (m, 1H), 7.08 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 31.8, 34.2, 47.3, 51.7, 119.9, 130.3, 131.6, 140.3; HRMS (EI) Calcd. for C10H11BrO: 225.9993 (M+). Found: 225.9996.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:14])[NH:4][CH:3]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>C(O)CO.O>[OH:14][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)=[CH:3][N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc2c(=O)[nH]cc(Br)c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: OCCO
Product: COc1ccc2c(O)ncc(N3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 145 °C
Yield: 42.4 %

Procedure:
To a solution of 4-bromo-6-methoxyisoquinolin-1(2H)-one (0.5 g, 1.968 mmol) and tert-butyl piperazine-1-carboxylate (0.916 g, 4.92 mmol) in ethylene glycol (5 ml) was added DIPEA (1.0.31 ml, 5.90 mmol) and heated to 145° C. for overnight in sealed tube. The reaction mixture was diluted with water and extracted with ethyl acetate. Combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to get crude compound (0.3 g, 29.4%). The crude compound was taken for the next step without further purification. MS: MS m/z 260.20 (M++1).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1.Br[C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH:31]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[CH:23]=1)=[O:20]>>[CH:28]([C:24]1[CH:23]=[C:22]([NH:21][C:19](=[O:20])[C:18]2[CH:31]=[C:14]([N:11]3[CH2:10][CH2:9][C:7]4[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[CH2:12]3)[CH:15]=[N:16][CH:17]=2)[CH:27]=[CH:26][CH:25]=1)([CH3:30])[CH3:29]
Reactant: CSc1ncc2c(n1)CCNC2
Reactant: CC(C)c1cccc(NC(=O)c2cncc(Br)c2)c1
Product: CSc1ncc2c(n1)CCN(c1cncc(C(=O)Nc3cccc(C(C)C)c3)c1)C2

Procedure:
In a manner similar to that described for Example 138, 2-(methylsulfanyl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidine and 5-bromo-N-(3-isopropylphenyl)nicotinamide were converted to the title compound.
Reaction SMILES: C([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7](Cl)=[O:8])(=O)C.[CH3:14][NH:15][CH3:16].[OH-].[Na+].Cl>C1COCC1.O>[OH:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([N:15]([CH3:16])[CH3:14])=[O:8]
Reactant: CNC
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
A mixture of acetylsalicyloyl chloride (3.4 g, 17 mmol) in 120 mL of THF was added dropwise to 30 mL of 40% aqueous dimethylamine (66 mmol). The mixture was stirred at room temperature for 3 hours and then sodium hydroxide (4 g, 0.1 mmol) was added. The mixture was stirred at room temperature for approximately 60 hours and then poured into 20 mL of water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated. The residue was purified on silica gel by flash chromatography eluting with 6% methanol/methylene chloride to give 2-hydroxy-N,N-dimethylbenzamide (2.4 g, 14.53 mmol), m.p. 145°-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH:13](CC)[C:12]3=[N:18][N:19]=[C:20]([CH3:21])[N:11]3[C:10]3[CH:22]=[CH:23][CH:24]=[CH:25][C:9]2=3)=[CH:4][CH:3]=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12]3=[N:18][N:19]=[C:20]([CH3:21])[N:11]3[C:10]3[CH:22]=[CH:23][CH:24]=[CH:25][C:9]2=3)=[CH:4][CH:3]=1
Reactant: CCC1C(=O)N(c2ccc(Cl)cc2)c2ccccc2-n2c(C)nnc21
Solvent: C1CCOC1
Product: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)C(=O)C2
Reaction time: 12 h
Yield: 13.2 %

Procedure:
Into a 50 mL flask evacuated and brimmed with dry nitrogen, was charged with a solution of 6-(4-chlorophenyl)-4-ethyl-1-methyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-5(6H)-one (10.0 mg, 0.028 mmol) in tetrahydrofuran (5 mL). To this mixture was added borane-tetrahydrofuran complex solution (1 mol/L, 1 mL) slowly. The mixture was stirred for 12 hours at reflux, quenched by hydrochloric acid aqueous (1.0 mol/L, 1 mL) to adjust pH>7 and extracted with ethyl acetate (5 mL*3). The organic layer was concentrated to give a residue. The residue was purified by prep-HPLC (Phenomenex C18 (150 mm*21.2 mm*5 um), acetonitrile/water=1:100 (0.1% formic acid), flow rate: 30 mL/min) to give 6-(4-chlorophenyl)-1-methyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-5(6H)-one as an off-white solid (1.2 mg, 12%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C@@H:4]([N:8]=[C:9]=[O:10])[CH:5]([CH3:7])[CH3:6].[CH3:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[CH2:22][NH2:23].CCN(CC)CC>C(Cl)(Cl)Cl>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[CH2:22][NH:23][C:9](=[O:10])[NH:8][C@@H:4]([CH:5]([CH3:7])[CH3:6])[C:3]([O:2][CH3:1])=[O:11]
Reactant: COC(=O)[C@@H](N=C=O)C(C)C
Reactant: COc1ccc(CN)c(OC)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NC(=O)NCc1ccc(OC)cc1OC)C(C)C
Temperature: 25 °C

Procedure:
A solution of (S)-methyl-2-isocyanato-3-methylbutanoate (4.46 mL, 29.9 mmol) in CHCl3 (50 mL) was added drop-wise to a solution of (2,4-dimethoxyphenyl)-methanamine (5.00 g, 29.9 mmol) and NEt3 (8.34 mL, 59.8 mmol) in CHCl3 (100 mL) at ambient temperature. The resultant mixture was heated at 60° C. for 12 hours, then cooled to ambient temperature. The cooled reaction mixture was concentrated to provide (S)-methyl 2-(3-(2,4-dimethoxybenzyl)ureido)-3-methylbutanoate as a white solid, 1.25 g (13%). LCMS (APCI+) m/z 325 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15](I)=[CH:16][N:17]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:12]2=[CH:11][CH:10]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]([NH:43][CH:44]3[CH2:49][CH2:48][CH2:47][N:46]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:45]3)[CH:40]=[N:41][CH:42]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15]([C:37]3[CH:38]=[C:39]([NH:43][CH:44]4[CH2:49][CH2:48][CH2:47][N:46]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:45]4)[CH:40]=[N:41][CH:42]=3)=[CH:16][N:17]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:12]2=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2cncc(B3OC(C)(C)C(C)(C)O3)c2)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(-c4c(F)cccc4F)ccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(NC4CCCN(C(=O)OC(C)(C)C)C4)c3)c3nc(-c4c(F)cccc4F)ccc32)cc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 35 %

Procedure:
A suspension of 5-(2,6-difluorophenyl)-3-iodo-1-tosyl-1H-pyrrolo[3,2-b]pyridine (73 mg, 0.143 mmol) and crude tert-butyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-ylamino)piperidine-1-carboxylate (113 mg, 0.279 mmol) in toluene (1.000 mL) and EtOH (1 mL) was treated with Na2CO3, 2.0 M (0.143 mL, 0.286 mmol) and Pd(PPh3)4 (16.53 mg, 0.014 mmol, Strem). The reaction mixture was degassed, backfilled with argon and heated to 100° C. under N2. After 15 h, the reaction was cooled to 23° C., filtered through celite, and purified by silica gel chromatography (eluent: 0.5-10% MeOH/DCM), affording tert-butyl 3-(5-(5-(2,6-difluorophenyl)-1-tosyl-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-ylamino)piperidine-1-carboxylate (Rf=0.5 in 10% MeOH/DCM, desired product) (33 mg, 35%); along with a byproduct, tert-butyl 3-(5-(5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-ylamino)piperidine-1-carboxylate (Rf=0.2 in 10% MeOH/DCM, de-tosylated product) (31 mg, 43%). MS (ESI, pos. ion) m/z: 660.3 (M+1)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:16]1[CH2:24][O:23][CH2:22][C@H:21]([O:25]CC2C=CC=CC=2)[C@@H:20]([O:33]CC2C=CC=CC=2)[C@H:19]([CH3:41])[O:18][C:17]1=[O:42])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:11]([O:10][C:9]([N:8]([C@H:16]1[CH2:24][O:23][CH2:22][C@H:21]([OH:25])[C@@H:20]([OH:33])[C@H:19]([CH3:41])[O:18][C:17]1=[O:42])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:15])([CH3:12])([CH3:13])[CH3:14]
Reactant: C[C@@H]1OC(=O)[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)COC[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@@H]1OC(=O)[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)COC[C@H](O)[C@H]1O
Temperature: 45 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a solution of tert-butyl N-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-7,8-dibenzyloxy-9-methyl-2-oxo-1,5-dioxonan-3-yl]carbamate (3.8 g, 6.49 mmol) in EtOAc (10 mL) in a 50 mL high pressure reactor with a stir bar was added 5% Pd/C (500 mg, 0.235 mmol). After the reactor was sealed, it was evacuated and purged with H2 (4×), and then charged to ˜600 psi of H2 at room temperature. The reaction mixture was warmed to 45° C. and stirred for 5 h. The reaction mixture was filtered through a pad of Celite® and the filtrate concentrated to yield the title compound as a white foam (2.63 g, 100%): 1H NMR (400 MHz, CDCl3) δ 5.25 (dd, J=8.7, 2.8 Hz, 1H), 4.94-4.76 (m, 1H), 4.26 (dd, J=12.3, 2.9 Hz, 1H), 4.06 (dd, J=10.7, 1.3 Hz, 1H), 3.91 (dd, J=12.3, 8.7 Hz, 1H), 3.62-3.54 (m, 1H), 3.54-3.38 (m, 2H), 3.15 (d, J=4.0 Hz, 1H), 2.96 (d, J=3.5 Hz, 1H), 1.51 (s, 18H), 1.46 (d, J=6.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 168.63, 152.70, 83.18, 79.34, 77.96, 74.40, 74.25, 73.02, 58.54, 27.98, 18.60; ESIMS m/z 428.5 ([M+Na]+).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[NH:12][C:11]([C:14]3[C:15](=[O:30])[NH:16][CH:17]=[CH:18][C:19]=3[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-].C1COCC1.O[C@@H](C1C=CC=CC=1)CNC1C=CNC(=O)C=1C1NC2C(C(O)=O)=CC=CC=2N=1>O>[Cl:29][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][NH:20][C:19]2[CH:18]=[CH:17][NH:16][C:15](=[O:30])[C:14]=2[C:11]2[NH:12][C:13]3[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=[CH:8][C:9]=3[N:10]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1cccc2nc(-c3c(NCCc4cccc(Cl)c4)cc[nH]c3=O)[nH]c12
Agent: O=C(O)c1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc2nc(-c3c(NCCc4cccc(Cl)c4)cc[nH]c3=O)[nH]c12

Procedure:
2-{4-[2-(3-Chloro-phenyl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazole-4-carboxylic acid was synthesized from 2-{4-[2-(3-chloro-phenyl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazole-4-carboxylic acid methyl ester, LiOH, THF, and water using a similar procedure as 2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid yielding 2-{4-[2-(3-chloro-phenyl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazole-4-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]([CH3:16])[CH3:15])=[CH:10][C:9]=2[CH2:17][OH:18])=[CH:4][CH:3]=1>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:17]=[O:18])=[CH:10][C:11]([N:14]([CH3:15])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CN(C)c1ccc(-c2ccc(Br)cc2)c(CO)c1
Solvent: O
Product: CN(C)c1ccc(-c2ccc(Br)cc2)c(C=O)c1
Temperature: 40 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
IBX (3.29 g, 11.76 mmol) was added to a solution of (4′-bromo-4-(dimethylamino)biphenyl-2-yl)methanol (1.8 g, 5.88 mmol) in dmso (50 mL) and stirred at 40° C. for 3 hours. The reaction was diluted with water and extracted with diethyl ether. The ether layer was dried over MgSO4, filtered and evaporated to give the crude material. The crude product was purified on the Biotage (5-20% EtOAc:Hex) to give 4′-bromo-4-(dimethylamino)biphenyl-2-carbaldehyde (1.25 g, 4.11 mmol, 70% yield) as a yellow solid. 1H NMR (500 MHz, CHLOROFORM-d) δ 2.95-3.13 (m, 6H) 7.01 (dd, J=8.55, 3.05 Hz, 1H) 7.22 (m, 2H) 7.28-7.33 (m, 2H) 7.57 (m, 2H) 9.96 (s, 1H).
Reaction SMILES: C([O:3][P:4]([CH2:9][O:10][C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH:12]=1)(=[O:8])[O:5]CC)C.C[Si](I)(C)C.CO>ClCCl>[CH:12]1[C:13]2[NH:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[CH:22]=[CH:23][C:11]=1[O:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5]
Reactant: CCOP(=O)(COc1ccc2c(c1)[nH]c1ccccc12)OCC
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClCCl
Product: O=P(O)(O)COc1ccc2c(c1)[nH]c1ccccc12
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a stirred solution of diethyl-2-carbazolyloxymethylphosphonate (0.33 g, 1 mmol) dissolved in dry dichloromethane (8 ml) under an atmosphere of nitrogen was added trimethyl silyl iodide (0.6 ml). The red solution was stirred for 2 h then methanol (15 ml) was added. After 2 h the solvent was removed under reduced pressure and then water (20 ml) was added to the residue. The mixture was concentrated under reduced pressure. Water (20 ml) was added and the mixture was concentrated under reduced pressure. This was repeated four times to afford 2-carbazolyloxymethyl phosphonic acid as a yellow green solid (0.26 g, 95%), m.p. 291° C., High Resolution Mass Spec. Pound: 277.0496, C13H12NO4PM+ requires 277.0504. δH (270 MHz, DMSO-d6) 11.13 (1H, s), 7.983 (1H, d, J 5.7 Hz), 7.98 (1H, d, J 5.7 Hz), 7.42 (1H, d, J 8 Hz), 7.28 (1H, dd, J1 8 Hz, J2 8 Hz), 7.10 (1H, dd, J1 8 Hz, J2 8 Hz), 7.05 (1H, d, J 2 Hz), 6.81 (1H, dd, J1 8 Hz, J2 2 Hz), 4.17 (2H, d, J 10.2 Hz), λex (DMSO, nm) 385, λem 421.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.[CH2:16]([Li])[CH2:17][CH2:18][CH3:19].[CH3:21][O:22][C:23]1[CH:32]=[C:31]2[C:26]([CH2:27][CH2:28][CH2:29][C:30]2=[O:33])=[CH:25][CH:24]=1.C(I)CCC.CN(C)P(N(C)C)(N(C)C)=O.[Cl-].[NH4+]>O1CCCC1.CCOCC>[CH2:16]([CH:29]1[CH2:28][CH2:27][C:26]2[C:31](=[CH:32][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[C:30]1=[O:33])[CH2:17][CH2:18][CH3:19]
Reactant: [Li]CCCC
Reactant: COc1ccc2c(c1)C(=O)CCC2
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Solvent: CCCCI
Product: CCCCC1CCc2ccc(OC)cc2C1=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 24.3 %

Procedure:
To a -78° C. solution of lithium diisopropyl amide [from 4.37 ml (31.2 mmol) of diisopropyl amine in 28 ml tetrahydrofuran and 11.9 ml (29.8 mmol) of 2.5M n-butyllithium] was slowly added (over 15 minutes) a solution of 5.00 g (28.4 mmol) of 3,4-dihydro-7-methoxy-1(2H)-naphthalenone in 10 ml tetrahydrofuran. The resulting reaction mixture was stirred 10 minutes at -78° C. The cooling bath was then changed to a 0° C. ice-water bath, and was immediately followed by the rapid addition of 3.98 ml (35 mmol) of n-butyl iodide. Hexamethylphosphoramide (10.4 ml, 60 mmol) was then added and the resultant solution atirred at 25° C. for 2 hours. The reaction was added to a mixture of 200 ml saturated ammonium chloride and 300 ml ether. The organic layer was separated, washed with saturated ammonium chloride (200 ml), saturated sodium chloride (200 ml), dried over magnesium sulfate and evaporated to an oil, which was purified via column chromatography on 250 g of silica gel eluted with 5% ether-hexane to give 1.6 g (24%) of present title product as an oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[C:19]([CH3:20])=[C:18]([N:21]2[CH2:25][C@:24]3([CH3:30])[C@H:26]([OH:29])[CH2:27][CH2:28][N:23]3[C:22]2=[O:31])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[C:19]([CH3:20])=[C:18]([N:21]2[CH2:25][C@:24]3([CH3:30])[C:26](=[O:29])[CH2:27][CH2:28][N:23]3[C:22]2=[O:31])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: Cc1c(N2C[C@]3(C)[C@H](O)CCN3C2=O)ccc(C#N)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1c(N2C[C@]3(C)C(=O)CCN3C2=O)ccc(C#N)c1Cl
Reaction time: 0.33 h
Yield: 34.6 %

Procedure:
To a 2 M CH2Cl2 solution of oxalyl chloride (68 □L, 0.13 mmol) in CH2Cl2 (2 mL) at −78° C. was added DMSO (17□L, 0.25 mmol). After 20 min, a solution of (7R,7aR)-2-chloro-4-(7-hydroxy-7a-methyl-3-oxotetrahydropyrrolo[1,2-c]imidazol-2-yl)-3-methylbenzonitrile (58F) (17 mg, 0.06 mmol) in CH2Cl2 (1 mL) was added. After an additional 20 min at −78° C., triethylamine (62 □L, 0.47 mmol) was added, the cold bath was removed, and the reaction mixture was stirred for 20 min. Water was added and the layers were separated. The organic layer was washed with brine then dried (MgSO4), filtered and concentrated. The resulting residue was purified via preparative HPLC (YMC ODS C-18, 100×20 mm, eluting with 30-80% solvent B (A=90% H2O—10% CH3CN—0.1% TFA and B=10% H2O—90% CH3CN—0.1% TFA) over 15 min; Flow rate at 20 mL/min; UV detection at 220 nm) to provide the title compound (6.3 mg) as a white solid. LC/MS m/z 629 [2M+23]+.
Reaction SMILES: [I-].[CH2:2]([O:4][C:5]([NH+:7]1[CH2:15][C:14]2[CH:13]=[CH:12][N:11]([CH3:16])[CH2:10][C:9]=2[CH2:8]1)=[O:6])[CH3:3].[BH4-].[Na+].O.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:16][N:11]1[CH2:12][CH2:13][C:14]2[CH2:15][N:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH2:8][C:9]=2[CH2:10]1
Reactant: CCOC(=O)[NH+]1CC2=C(CN(C)C=C2)C1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [I-]
Solvent: O
Solvent: CO
Product: CCOC(=O)N1CC2=C(CN(C)CC2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
15.3 g (45.8 mmol) of 2-ethoxycarbonyl-5-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridinium iodide are dissolved in 100 ml of absolute methanol, the solution is cooled to 0° C., and 7 g (0.1 mol) of sodium borohydride are added in 0.5 g portions. The mixture is subsequently stirred for 2 hours at room temperature, 100 ml of water are added, and the mixture is treated with K2CO3 and extracted with CHCl3. The organic solutions are dried over K2CO3 and concentrated, and the residue is distilled.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:7][C:3]=1[C:4](O)=[O:5].CC[N:20]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[OH-].[NH4+]>C1COCC1.CN(C)C=O>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:7][C:3]=1[C:4]([NH2:20])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1ccc(CCN2CCCC2)cc1C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)c1cc(CCN2CCCC2)ccc1N
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-5-(2-pyrrolidin-1-yl-ethyl)-benzoic acid (0.41 g, 1.75 mmol) in a mixture of THF (5.1 mL) and N,N-dimethyl formamide (1.75 mL) was added EDCl (0.84 g, 4.37 mmol), followed by HOBt (0.71 mL, 5.25 mmol). The reaction mixture was stirred for 30 minutes. Then, N-methyl morpholine (0.67 mL, 6.12 mmol) was added, followed by 50% aqueous ammonium hydroxide (1.2 mL, 17.5 mmol). The resulting mixture was stirred at room temperature for 24 hours. Then, the solvent was reduced and the residue was extracted with methylene chloride. The combined organic layers were washed with brine, water, and dried over sodium sulfate. After solvent evaporation under high vacuum, the crude orange oil (0.72 g) was purified by column chromatography (silica gel 230-400 mesh; 5/95 methylene chloride/7 N ammonia in MeOH as eluent) to give pure 2-amino-5-(2-pyrrolidin-1-yl-ethyl)-benzamide as a light yellow viscous oil. Yield: 0.16 g (39.2%).