Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[CH3:21][C:22]([CH3:49])([CH3:48])[C:23]([O:25][CH2:26][N:27]1[N:31]=[N:30][C:29]([C:32]2[CH:33]=[C:34]3[C:44](=[CH:45][CH:46]=2)[O:43][C:37]2([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][C:35]3=[O:47])=[N:28]1)=[O:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>O.CN(C=O)C.C(N(CC)CC)C>[CH3:21][C:22]([CH3:49])([CH3:48])[C:23]([O:25][CH2:26][N:27]1[N:31]=[N:30][C:29]([C:32]2[CH:33]=[C:34]3[C:44](=[CH:45][CH:46]=2)[O:43][C:37]2([CH2:38][CH2:39][N:40]([C:9]([C:7]4[CH:6]=[C:5]([O:12][CH3:13])[C:4]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)=[C:3]([O:2][CH3:1])[CH:8]=4)=[O:11])[CH2:41][CH2:42]2)[CH2:36][C:35]3=[O:47])=[N:28]1)=[O:24]
Reactant: COc1cc(C(=O)O)cc(OC)c1-c1ccccc1
Reactant: CC(C)(C)C(=O)OCn1nnc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn(COC(=O)C(C)(C)C)n4)ccc2O3)cc(OC)c1-c1ccccc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Triethylamine (0.23 mL) and water (2.0 mL) were added to a DMF (6.0 mL) solution of 2,6-dimethoxy-biphenyl-4-carboxylic acid (258 mg), [5-(4-oxospiro[chroman-2,4′-piperidin]-6-yl)-tetrazol-2-yl]methyl 2,2-dimethylpropanoate hydrochloride (500 mg), WSC (288 mg) and HOBT (202 mg), and stirred at 90° C. for 1 hour. Water was added to it at room temperature, and a white precipitate was thus obtained. This was dried under reduced pressure to obtain the title compound as a colorless solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.40 (1H, d, J=2.2 Hz), 8.26 (1H, dd, J=8.8, 2.2 Hz), 7.38-7.18 (6H, m), 6.75 (2H, s), 6.64 (2H, s), 4.35-4.21 (1H, m), 3.68 (6H, s), 3.65-3.39 (2H, m), 3.29-3.25 (1H, m), 2.98 (2H, s), 2.14-1.92 (2H, m), 1.89-1.78 (2H, m), 1.14 (9H, s). MS [M+H]+=640.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:14]3[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[CH:8][C:9]=2[C:11]([OH:13])=O)[C:4]([CH:21]([CH3:23])[CH3:22])=[CH:3]1.[NH2:24][CH2:25][C:26]1[C:27](=[O:34])[NH:28][C:29]([CH3:33])=[CH:30][C:31]=1[CH3:32].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O>[CH3:32][C:31]1[CH:30]=[C:29]([CH3:33])[NH:28][C:27](=[O:34])[C:26]=1[CH2:25][NH:24][C:11]([C:9]1[CH:8]=[C:7]([C:14]2[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[C:4]2[CH:21]([CH3:22])[CH3:23])=[O:13]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: Cc1ccc(-c2cc(C(=O)O)c3c(c2)c(C(C)C)cn3C)cn1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Product: Cc1ccc(-c2cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c3c(c2)c(C(C)C)cn3C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
To a 20 mL vial was added 1-methyl-3-(1-methylethyl)-5-(6-methyl-3-pyridinyl)-1H-indole-7-carboxylic acid (0.10 g, 0.324 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (0.098 g, 0.519 mmol), 1-hydroxy-7-azabenzotriazole (0.088 g, 0.649 mmol) and EDC (0.124 g, 0.649 mmol). The reagents were diluted with DMSO (3 mL) and N-methylmorpholine (0.178 mL, 1.621 mmol). The mixture was stirred overnight, then slowly poured into ice-water (50 mL). The mixture was stirred for 10 min, then allowed to sit for 10 min. The mixture was then extracted with EtOAc (2×) and the combined organics washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was triturated with MTBE and the resulting solid dried in a vac oven at 45° C. for 4 h. Purified the solid by HPLC (Gilson; Sunfire 30×75 mm column; Gradient B: 10-65%; A: water+0.1% TFA; B: CH3CN+0.1% TFA). The residue was dissolved in 10% MeOH/DCM and treated with Silicycle carbonate resin (0.65 g) at 37° C. for 15 min. The mixture was allowed to cool to RT and was filtered through Celite. Concentrated in vacuo to give N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-methyl-3-(1-methylethyl)-5-(6-methyl-3-pyridinyl)-1H-indole-7-carboxamide (55 mg, 37.6% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (d, J=6.82 Hz, 6H) 2.11 (s, 3H) 2.24 (s, 3H) 3.16-3.28 (m, 1H) 3.33 (s, 3H) 3.68 (s, 3H) 4.36 (d, J=5.05 Hz, 2H) 5.87 (s, 1H) 7.11 (s, 1H) 7.28-7.37 (m, 2H) 7.86 (d, J=1.77 Hz, 1H) 7.98 (dd, J=8.08, 2.53 Hz, 1H) 8.50 (t, J=4.93 Hz, 1H) 8.77 (d, J=2.27 Hz, 1H) 11.50 (s, 1H). MS (ES) [M+H]+ 443.2.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=1.O>CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=3[C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:23]=2)[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 2-butylbenzimidazole (0.52 g) in DMF (4 ml) was added, under cooling with ice, sodium hydride (60% oil, 0.13 g), and then the mixture was stirred for 20 minutes. To the resultant mixture was added methyl 2-(4-bromomethylphenyl)benzoate (1.0 g), which was stirred for 1.5 hour at room temperature. To the mixture was added water, followed by extraction with ethyl acetate. The solvent was evaporated to dryness to give an oily residue. The oil was purified by column chromatography on silica gel to obtain a colorless oil (1.2 g, quantitatively).
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([CH3:12])([CH2:10][CH3:11])[C:8]#[N:9])[CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:26]=[CH:25][N:24]=[C:23]3[N:27](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:28]=[CH:29][C:22]=23)O1.C([O-])([O-])=O.[Na+].[Na+].O.CCOC(C)=O>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH:27]1[C:23]2=[N:24][CH:25]=[CH:26][C:21]([C:2]3[S:6][CH:5]=[C:4]([C:7]([CH3:12])([CH2:10][CH3:11])[C:8]#[N:9])[CH:3]=3)=[C:22]2[CH:29]=[N:28]1
Reactant: CCC(C)(C#N)c1csc(Br)c1
Reactant: CC1(C)OB(c2ccnc3c2cnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(C)(C#N)c1csc(-c2ccnc3[nH]ncc23)c1
Temperature: 150 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
A mixture of 2-(5-bromo-3-thienyl)-2-methyl-butanenitrile (789 mg, 3.232 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-pyrazolo[3,4-b]pyridine (1.750 g, 3232 mmol), Na2CO3 (4.848 mL of 2 M, 9.696 mmol) and tetrakis(triphenylphosphine) palladium(0) (112.0 mg, 0.09696 mmol) in DME (12 mL) was heated at 150° C. for 10 minutes in the microwave. The mixture was treated with water/EtOAc and the two layers separated. The organics were dried (MgSO4), filtered, concentrated and the resultant residue was dissolved in DCM (8 mL) and treated with triethylsilane (5 mL) and TFA (1.5 mL) at RT. The reaction was allowed to stir for 2 hours, concentrated in vacuo and purified by column chromatography (1:1 to 2:1 Petroleum ether/EtOAc) to give the required product (236 mg, 26% Yield). 1H NMR (CDCl3, 400 MHz) δ 1.06 (3H, m), 1.78 (3H, s), 2.05 (2H, m), 7.49 (1H, m), 7.53 (1H, m), 7.63 (1H, m), 8.42 (1H, m), 8.60 (1H, m); MS (ES+) 283.09
Reaction SMILES: [Br-].[K+].[CH2:3]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([CH2:19][OH:20])[CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[O-].[Na+].C(=O)(O)[O-].[Na+]>ClCCl.CC1(C)N([O])C(C)(C)CCC1>[CH2:3]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([CH:19]=[O:20])[CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(OCc1ccccc1)N1CCCC(CO)C1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Product: O=CC1CCCN(C(=O)OCc2ccccc2)C1
Reaction time: 0.08 h
Yield: 89.8 %

Procedure:
An aqueous solution (2 mL) of potassium bromide (983 mg, 8.26 mmol) was added to 1-benzyloxycarbonyl-3-piperidinyl methanol (2.00 g, 8.02 mmol) and 2,2,6,6-tetramethyl piperidine-N-oxyl (12.5 mg, 0.0802 mmol) in dichloromethane (20 mL). The mixture was stirred for 5 min while chilled in an ice bath. A 0.35 mol/L aqueous sodium hypochlorite solution (25.2 mL, 8.82 mmol) and sodium bicarbonate (1.96 g, 23.3 mmol) were added and the mixture was stirred for 10 min. Subsequently, the reaction mixture was extracted with ethyl acetate and the extract washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the residue by silica gel column chromatography (hexane:ethyl acetate=10:1->2:1) gave 1.78 g (90%) of the desired compound as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14].[Br:21][C:22]([CH2:24]Br)=[CH2:23].O>ClCCl>[Br:21][C:22](=[CH2:23])[CH2:24][NH:14][CH2:13][C:12]1[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=1[O:10][CH3:9]
Reactant: C=C(Br)CBr
Reactant: COc1ccc(CN)c(OC)c1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(Br)CNCc1ccc(OC)cc1OC
Reaction time: 18 h
Yield: 50.3 %

Procedure:
Triethylamine (16.0 mL, 114 mmol) was added to a solution of 2,4-dimethoxybenzylamine hydrochloride (11.1 g, 54.5 mmol) and 2,3-dibromopropene (10.9 g, 54.5 mmol) in dichloromethane (200 mL). After 18 h, water was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/5% (10% ammonium hydroxide/methanol)] gave the title compound (7.85 g).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][N+:16]([O-:18])=O)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C[O-].[Li+].[C:24]([C:26]1[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>[Ti](Cl)(Cl)(Cl)Cl.O.O1CCCC1.C(OCC)(=O)C.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:9]=[CH:10][C:11]([CH2:14][C:15]3[CH:25]=[C:24]([C:26]4[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=4)[O:18][N:16]=3)=[CH:12][CH:13]=2)=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])C=Cc1ccc(COc2ccc(F)cc2)nc1
Reactant: C#Cc1ccc(N)nc1N
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(-c2cc(Cc3ccc(COc4ccc(F)cc4)nc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13 %

Procedure:
To a methanol (5.00 mL) solution of 2-(4-fluoro-phenoxymethyl)-5-(2-nitro-vinyl)-pyridine (50.0 mg, 0.181 mmol) described in Manufacturing Example 72-1-3 was added lithium methoxide (13.7 mg, 0.362 mmol) under nitrogen atmosphere, which was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under a reduced pressure, and anhydrous dichloromethane (4.00 mL) and anhydrous tetrahydrofuran (2.00 mL) were added to the residue. Titanium (IV) tetrachloride (63.7 μL, 0.579 mmol) was added dropwise to the reaction mixture on a dry ice-ethanol bath (−78° C.), after which the system was stirred for 40 minutes at 0° C. Water and ethyl acetate were added to the reaction mixture on an ice bath (0° C.), and the organic layer was extracted with ethyl acetate. This organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure to obtain a crude product (43.0 mg). To a tetrahydrofuran (5.00 mL) solution of 3-ethynyl-pyridin-2,6-diamine (4.00 mg, 0.030 mmol) described in Manufacturing Example 13-1-3 and this crude product (20.0 mg) was added triethylamine (12.5 μL, 0.090 mmol), which was stirred for 2 hours at room temperature. Water was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (1.53 mg, 25.4%) as a ditrifluoroacetic acid salt.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH:3]=[CH:2]1.CCN(CC)CC.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(Cl)Cl>[CH2:4]1[C:5]2([CH2:10][CH2:9][N:8]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:7][CH2:6]2)[CH2:1][CH:2]=[CH:3]1
Reactant: C1=CCC2(C1)CCNCC2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC2(CC=CC2)CC1
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a solution of 8-azaspiro[4.5]dec-2-ene (2.74 g, 20 mmol) in Et3N (4.2 mL, 30 mmol) and DCM (100 mL) at 0° C. was added dropwise benzyl chloroformate (3.4 mL, 24 mmol). After 1 h, the solution was partitioned between H2O-DCM and the aqueous phase was extracted several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica, 10% EtOAc in hexanes) yielding the title compound (3.85 g, 71%) as a yellow oil: LCMS (ES) m/e 272 (M+H)+.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=O.O.[NH2:20][NH2:21]>C(O)C.C(OCC)(=O)C>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[C:7]1[C:6]2[CH:5]=[CH:4][S:3][C:2]=2[NH:20][N:21]=1
Reactant: O=C(c1ccc2ccccc2c1)c1ccsc1Cl
Reactant: NN
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: c1ccc2cc(-c3n[nH]c4sccc34)ccc2c1

Procedure:
To a solution of 0.61 g of (2-chlorothiophen-3-yl)-(naphthalen-2-yl)-methanone in 6 mL of ethanol was added 0.12 mL of hydrazine monohydrate at room temperature and heated under reflux for 2 days. The reaction solution was diluted with ethyl acetate, and the organic layer washed successively with saturated aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The resultant crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:30-1:5), to afford 32 mg of the title compound as colorless crystals.
Reaction SMILES: [OH-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].Cl.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH:18]([NH2:20])[CH3:19])=[CH:13][CH:12]=1.C(#N)C(CC#N)O>O.C(O)C>[NH2:6][C:5]1[NH:20][C:18]([CH3:19])=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[C:4]=1[C:3]#[N:7]
Reactant: N#CCC#N
Reactant: COc1ccc(C(=O)C(C)N)cc1
Agent: Cl
Agent: N#CCC(O)C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2c(C)[nH]c(N)c2C#N)cc1
Yield: 63.1 %

Procedure:
To a refluxing solution (150 mL) of ethanol and water (7/3), NaOH (2.2 g, 55 mmol) and malononitrile (2.64 g, 40 mmol) were added. Then 4′-methoxy-2-aminopropiophenone hydrochloride (5.9 g, 27.2 mmol) was added in several portions. After the solution was refluxed for 30 minutes., additional malonitrile (1.3 g, 20 mmol) and NaOH (1.1 g, 27.5 mmol) were added. It was refluxed for additional 30 minutes and then poured into water (100 mL) which resulted in a precipitation. It was then filtered and washed with water until no color was washed out. The solid was then dried under vacuum at 50° C. overnight to give 2-amino-3-cyano-4-(4-methoxyphenyl)-5-methylpyrrole, (3.9 g, 63%). MS: 228 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23]C(OC(C)(C)C)=O)[CH2:19][C@H:18]2[C:31]([OH:33])=[O:32])[C:13]1=[O:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[NH2:23][C@H:20]1[CH2:19][C@@H:18]([C:31]([OH:33])=[O:32])[C@@H:17]([N:14]2[CH2:15][CH2:16][C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[C:13]2=[O:34])[CH2:22][CH2:21]1.[C:37]([OH:39])([C:36]([F:41])([F:40])[F:35])=[O:38]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](C(=O)O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirring solution of (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (38 g, 0.0799 mol; see Example 1, Step 4) in dichloromethane (400 mL) was charged with trifluoroacetic acid (100 mL) at 0° C. The reaction was stirred for 2 h at room temperature and concentrated in vacuo. The residue was dissolved in dichloromethane (100 ml) and the resultant solution was added dropwise to diethyl ether (1500 ml) with stirring. The solid formed was collected with filtration and washed with diethyl ether (3×50 ml). The white solid was dried in vacuo to give (1R,2S,5R)-5-amino-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)cyclohexanecarboxylic acid as its TFA salt (35.5 g, 86%). The compound was used to next step without further purification. LC/MS found [M+H]+=376.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][CH2:12][CH2:13][CH2:14][OH:15])=[CH:6][CH:5]=1.CCN(CC)CC.[CH3:25][S:26](Cl)(=[O:28])=[O:27].O>ClCCl>[F:1][C:2]([F:16])([F:17])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]#[C:11][CH2:12][CH2:13][CH2:14][O:15][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC#Cc1ccc(OC(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCCCC#Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
To an ice-cooled solution of 5-(4-trifluoromethoxy-phenyl)-pent-4-yn-1-ol (2.02 g, 8.3 mmol; example 1 a]) and Et3N (1.73 ml, 12.4 mmol) in dichloromethane (100 ml) was added methanesulfonyl chloride (0.67 ml, 8.7 mmol) within 15 min keeping the temperature at 0-10° C. The reaction mixture was stirred at RT for 1 h 15 min. Water was added and after 5 min, the reaction was partitioned between ether and water. The aqueous layer was extracted again with ether (2×), the organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and concentrated to yield 2.5 g (7.7 mmol, 93%) of the title compound as light brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH3:18])[C:9]=2[C@H:19]([OH:22])[CH2:20][OH:21])=[CH:4][CH:3]=1.C(Cl)Cl.[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>N1C=CC=CC=1.C(OCC)(=O)C>[C:26]([O:21][CH2:20][C@H:19]([C:9]1[C:10]([CH3:18])=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[OH:22])(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1[C@H](O)CO
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1[C@H](O)COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (S)-1-(1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)ethane-1,2-diol (3G) (0.981 g, 3.14 mmol) in pyridine (5.0 mL)/DCM (15.0 mL) was added pivaloyl chloride (0.463 mL, 3.77 mmol). The reaction mixture was stirred for 5 h at room temperature and diluted with ethyl acetate. The organic layer was washed with 1 N HCl, saturated sodium bicarbonate solution, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 30% ethyl acetate/hexanes) to give 3H as a white solid (1.296 g). 1H-NMR: 300 MHz, (CDCl3): δ: 7.72 (d, J=8.1 Hz, 1H), 7.67 (s, 1H), 7.46-7.37 (m, 3H), 7.26-7.10 (m, 4H), 4.99 (dd, J=8.7, 3.0 Hz, 1H), 4.45 (dd, J=11.7, 9.7 Hz, 1H), 4.13 (dd, J=11.7, 3.3 Hz, 1H), 2.72 (s, 3H), 1.11 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:9]=[C:10]1[CH2:17][CH:16]2[CH:12]([CH2:13][CH:14]([C:18]([OH:20])=[O:19])[CH2:15]2)[CH2:11]1.CCN(C(C)C)C(C)C>C(#N)C.C(Cl)(Cl)Cl>[O:9]=[C:10]1[CH2:17][CH:16]2[CH:12]([CH2:13][CH:14]([C:18]([O:20][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[O:19])[CH2:15]2)[CH2:11]1
Reactant: BrCc1ccccc1
Reactant: O=C1CC2CC(C(=O)O)CC2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: O=C1CC2CC(C(=O)OCc3ccccc3)CC2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Neat (bromomethyl)benzene (531 mg) was added to a stirred mixture of 5-oxooctahydropentalene-2-carboxylic acid (435 mg) and DIPEA (0.542 mL) in acetonitrile (2.5 mL) and CHCl3 (2.5 mL) and the mixture was stirred at rt overnight. Reaction mixture was evaporated to dryness and purified by silica gel FCC (0-1% MeOH in DCM) to afford benzyl 5-oxooctahydropentalene-2-carboxylate which was isolated as an endo/exo isomeric mixture.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[P:9]([O-])([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])=[O:10].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([P:9](=[O:10])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CCOP(=O)([O-])OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOP(=O)(OCC)c1ccc(N)nc1

Procedure:
A mixture of 2-amino-5-bromopyridine (5 g, 0.029 mol; Aldrich Chemical Company, Inc., Milwaukee, Wis.), diethyl phosphate (5.02 g, 0.036 mol), triethylamine (4.4 g, 0.043 mol), Pd(OAc)2 (0.78 g, 3.4 mmol), triphenylphosphine (2.28 g, 8.7 mmol) in ethanol (100 mL) was refluxed for 14 hours under nitrogen. TLC (Petroleum ether/ethyl acetate=1:1) indicated that the reaction was complete. The resulting mixture was filtered, and the filtrate was concentrated in vacuo, the residue was purified by prep. HPLC to afford (I-25a) (4.3 g, 64.4%) as a white solid; m/z 231.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([CH2:19][S:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=3)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Sn](Cl)Cl.O>C(O)C.C(OCC)(=O)C>[NH2:27][C:23]1[CH:22]=[C:21]([S:20][CH2:19][C:12]2[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[N:14][C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:10][CH:11]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1CSc1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1CSc1cccc(N)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of N2-(3-fluorophenyl)-5-(((3-nitrophenyl)thio)methyl)-N4-propylpyrimidine-2,4-diamine (E19, 160 mg) in ethanol (4 mL) and ethyl acetate (8 mL), tin(II) chloride (739 mg) was added at room temperature, and the mixture was stirred at 70° C. for 1 hour. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added to the mixture. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 5-(((3-aminophenyl)thio)methyl)-N2-(3-fluorophenyl)-N4-propylpyrimidine-2,4-diamine (E20).