Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C(Cl)=C(Cl)C=CC=1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:22])=[C:15]2[C:20]=1[N:19]=[C:18]([CH3:21])[CH:17]=[CH:16]2.[C:23]1(=O)[O:28][C:26](=[O:27])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([N:22]2[C:26](=[O:27])[C:25]3=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]3[C:23]2=[O:28])=[C:15]2[C:20]=1[N:19]=[C:18]([CH3:21])[CH:17]=[CH:16]2
Reactant: Cc1ccc2c(N)ccc(Cl)c2n1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Clc1cccc(Cl)c1Cl
Product: Cc1ccc2c(N3C(=O)c4ccccc4C3=O)ccc(Cl)c2n1
Yield: 83.3 %

Procedure:
95 g of trichlorobenzene was added to 23.3 g (0.12 mole) of 8-chloro-5-amino-quinaldine and 18.0 g (0.12 mole) of phthalic anhydride, and the mixture was reacted under reflux for 2 hours at the boiling point. After cooling, the precipitated crystals were separated by filtration, and dried to afford 32 g (0.10 mole) of 8-chloro-5-phthalimidoquinaldine.
Reaction SMILES: COC1C=[C:5]([CH2:11][CH2:12][CH2:13]C(=O)C=C)[CH:6]=[CH:7][C:8]=1[O:9]C.C[O:19]C1C=C(CCCC(=O)CCN(CC)CC)C=CC=1OC>[OH-].[K+]>[CH2:12]([CH:11]1[C:5](=[O:19])[CH2:6][CH2:7][C:8]1=[O:9])[CH3:13]
Reactant: C=CC(=O)CCCc1ccc(OC)c(OC)c1
Reactant: CCN(CC)CCC(=O)CCCc1ccc(OC)c(OC)c1
Agent: [K+]
Agent: [OH-]
Product: CCC1C(=O)CCC1=O

Procedure:
Reflux 6-(3,4-dimethoxyphenyl)hex-1-en-3-one, containing a small amount of 6-(3,4-dimethoxyphenyl)-1-diethylaminohexan-3-one (6 g, produced by slow distillation of the latter substance) with 2-ethyl-cyclopentane-1,3-dione (3.5 g) in 0.12% anhydrous methanolic potassium hydroxide (10 cc) for 10 hours. Remove most of the methanol under reduced pressure, add benzene (25 cc) and ether (25 cc) and wash the solution with water, dilute aqueous potassium hydroxide, dilute hydrochloric acid and water. Dry and evaporate the solvent to give the triketone adduct 2-[6-(3,4-dimethoxyphenyl)-3-oxohexyl]-2-ethylcyclopentane-1,3-dione; infrared absorption (gum) 5.80, 6.25 μ (split peak).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@@H:3]([OH:33])[CH2:4][C@@H:5]([NH:20][C:21]([C@@H:23]([NH:28][C:29](=[O:32])[O:30][CH3:31])[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH2:41]([N:48]1[CH2:52][CH2:51][N:50]([C@@H:53]([C:57]([CH3:60])([CH3:59])[CH3:58])[C:54](O)=[O:55])[C:49]1=[O:61])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:41]([N:48]1[CH2:52][CH2:51][N:50]([C@@H:53]([C:57]([CH3:59])([CH3:58])[CH3:60])[C:54]([NH:1][C@@H:2]([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C@@H:3]([OH:33])[CH2:4][C@@H:5]([NH:20][C:21]([C@@H:23]([NH:28][C:29](=[O:32])[O:30][CH3:31])[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=3)=[CH:9][CH:8]=2)=[O:55])[C:49]1=[O:61])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2ccccc2)C1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccc(C)cn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccc(C)cn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.8 %

Procedure:
A solution containing the product from Example 92J (0.050 g, 0.092 mmol) in THF (1 mL) was treated with the product from Example 70A (0.028 g, 0.097 mmol), DEPBT (0.041 g, 0.137 mmol), and N,N-diisopropylethylamine (0.080 mL, 0.459 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (0.036 g, 48% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.83(s, 9H), 0.89(s, 9H), 1.60-1.49(m, 2H), 2.32(s, 3H), 2.60-2.53(m, 1H), 2.68-2.65(d, J=6.99 Hz, 2H), 2.88-2.75(m, 2H), 2.96-2.90(q, J=8.70 Hz, 1H), 3.24-3.15(m, 1H), 3.51(s, 3H), 3.71-3.61(m, 1H), 3.87-3.83(d, J=9.56 Hz, 1H), 4.09(s, 1H), 4.22-4.11 (m, 2H), 4.31(s, 2H), 4.56-4.53(d, J=7.72 Hz, 1H), 6.67-6.63(d, J=9.56 Hz, 1H), 7.08-7.02(m, 5H), 7.21-7.19(d, J=8.46 Hz, 2H), 7.31-7.26(m, 3H), 7.40-7.35(m, 2H), 7.50-7.46 (d, J=9.56 Hz, 1H), 7.68-7.64(dd, J=8.27, 2.02 Hz, 1H), 7.82-7.77(m, 2H), 7.88-7.85(d, J=8.09 Hz, 2H), 8.47-8.46(d, J=2.21 Hz, 1H).
Reaction SMILES: [OH:1][C:2]([CH3:27])([CH2:11][CH2:12][CH2:13][CH:14]([CH3:26])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:3][CH2:4][C:5](=O)[CH2:6][C:7](=O)C.[CH3:28][O:29][C:30]([CH2:32][C:33]([CH2:35][C:36]([O:38][CH3:39])=[O:37])=[O:34])=[O:31].[CH3:40][O-].[Na+]>CO>[OH:34][C:33]1[C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:40][C:6]([CH3:7])=[C:5]([CH2:4][CH2:3][C:2]([OH:1])([CH3:27])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:26])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:23])[CH3:24])[C:32]=1[C:30]([O:29][CH3:28])=[O:31]
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: CC(=O)CC(=O)CCC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(C)c(CCC(C)(O)CCCC(C)CCCC(C)CCCC(C)C)c(C(=O)OC)c1O
Temperature: 25 °C
Reaction time: 44 h

Procedure:
To a solution of 7-hydroxy-7,11,15,19-tetramethyleicosane-2,4-dione (72.5 g) and dimethyl acetonedicarboxylate (29.6 g) in methanol (190 ml) at 0° was added a solution of sodium methoxide in methanol (from 2.44 g of sodium and 90 ml of methanol). The solution was stirred at room temperature for 44 hr and was concentrated on a rotary evaporator to remove approx. 100 ml of methanol. The residual solution was poured onto ice (500 g) and 20% (v/v) aqueous hydrochloric acid (45 ml). The mixture was extracted with ether (3×300 ml) and the combined extracts were washed with brine and dried over anhydrous sodium sulfate and were concentrated on a rotary evaporator to give 91.65 g of crude dimethyl 2-hydroxy-5-methyl-6-(3-hydroxy-3,7,11,15-tetramethyl-hexadecanyl)-benzene-1,3-dicarboxylate as an orange oil. A 90.2 g portion of the oil was dissolved in ether (400 ml) and was washed with 20% by weight aqueous potassium carbonate (to remove the unreacted dimethyl acetonedicarboxylate), brine and was dried over anhydrous sodium sulfate. The solution was concentrated on a rotary evaporator to give 83.13 g of partially purified diester dimethyl 2-hydroxy-4-methyl-6-(3-hydroxy-3,7,11,15-tetramethyl-hexadecanyl)-benzene-1,3-dicarboxylate. The total material was chromatographed on 2.45 kg of silica gel eluting with 20-30% by volume ether in hexane to give 30.83 g of dimethyl 2-hydroxy-4-methyl-6-(3-hydroxy-3,7,11,15-tetramethyl-hexadecanyl)-benzene-1,3-dicarboxylate as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][CH2:30][O:31][C:24]=3[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][CH2:30][O:31][C:24]=4[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: FC(F)(F)c1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Reactant: c1nc[nH]n1
Product: FC(F)(F)c1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-trifluoromethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-trifluoromethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([CH3:8])=[C:3]1[C:9](=[O:13])[CH2:10][C:11]#[N:12].[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([CH3:8])=[C:3]1[C:9](=[O:13])[CH:10]([C:21](=[O:22])[NH:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]#[N:12]
Reactant: Cc1cc(C)n(C)c1C(=O)CC#N
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(C)n(C)c1C(=O)C(C#N)C(=O)Nc1ccccc1
Reaction time: 8 h

Procedure:
To the suspension of 1.0 g of 1,3,5-trimethyl-β-oxo-2-pyrrolpropionitrile in 30 ml of dry toluene and 0.7 g of anhydrous triethylamine, 0.75 g of phenylisocyanate are added while stirring. The mixture is warmed for 5 minutes at the steam cone and allowed to stand at room temperature overnight. It is filtered, the residue taken up in methanol and the solution acidified with N hydrochloric acid. The precipitate formed is collected, dissolved in N aqueous sodium hydroxide, re-precipitated with 5 N hydrochloric acid and washed with water, to yield the 1,3,5-trimethyl-β-oxo-α-phenylcarbamoyl-2-pyrrolpropionitrile melting at 172°-174°.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][N:9]2[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH2:22])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:5][CH:4]=1.[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27]Cl.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][N:9]2[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:22][CH2:27][CH2:26][CH2:25][N:24]([CH3:29])[CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:5][CH:4]=1
Reactant: Nc1ccc2ncnc(N3CCc4ccc(Cl)cc43)c2c1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN(C)CCCNc1ccc2ncnc(N3CCc4ccc(Cl)cc43)c2c1
Temperature: 120 °C

Procedure:
4-(6-Chloro-2,3-dihydro-indol-1-yl)-quinazolin-6-ylamine hydrochloride (0.525 g, 1.58 mmol) was combined with 2 mL of freshly distilled 3-dimethylaminopropyl chloride and heated to 120° C. for 1 hour. Yellow liquid was poured off and the remaining red glass was dissolved in water, basified to pH 11 with potassium carbonate, extracted with chloroform (2×50 mL), washed with brine, dried over magnesium sulfate, filtered and stripped to give 0.272 g yellow foam containing starting material and mono- and di-alkylated products. This foam was filtered through silica gel using chloroform, then the product was washed through the silica gel with 40% v/v methanol in chloroform and concentrated in vacuo. The residue was dissolved in methanol, treated with 1N HCl in methanol diluted with diethyl ether, filtered and dried under vacuum to afford a bright yellow solid, 0.0995 g (15%): M.P. 230° C. (dec):LC-MS: 382 (MH+), 384 ((M+2)H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.Br[CH2:10][C:11](=O)[C:12]([OH:14])=[O:13]>COCCOC.C(OCC)C>[BrH:8].[Br:8][C:5]1[CH:4]=[N:3][C:2]2[N:7]([C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:1]=2)[CH:6]=1
Reactant: O=C(O)C(=O)CBr
Reactant: Nc1ncc(Br)cn1
Solvent: CCOCC
Solvent: COCCOC
Product: Br
Product: O=C(O)c1cnc2ncc(Br)cn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-5-bromopyrimidine (3.79 g, 21.8 mmol) in 1,2-dimethoxyethane (200 mL) was added dropwise bromopyruvic acid (3.63 g, 21.8 mmol). The reaction mixture was stirred for 30 minutes, and then heated to reflux and stirred for 18 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure to obtain a solid. This solid was suspended in diethyl ether, and the suspension was filtered to isolate 6-bromaoimidazo[1,2-a]pyrimidine-2-carboxylic acid hydrobromide and 6-bromoimidazo[1,2-a]pyrimidine-3-carboxylic acid hydrobromide as a 1:1 mixture. To this mixture of carboxylic acids (1.30 g, 5.37 mmol) was added a solution of 4-(dimethylamino)pyridine (1.966 g, 16.12 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.095 g, 16.12 mmol) in t-butanol (5 mL) and dichloromethane (15 mL). The reaction mixture was stirred for 5 minutes, 2-chloro-5-trifluoromethylbenzezenesulfonamide (1.394 g, 5.374 mmol) was added, and the reaction mixture was stirred at room temperature overnight. Dichloromethane (200 mL) was then added, the mixture was extracted with 1 N hydrochloric acid (1×100 mL), and the separated organic phase was dried over magnesium sulfate and concentrated under reduced pressure to afford a crude solid. The crude solid was purified by chromatography on silica gel eluting with a methanol/dichloromethane gradient to afford as the first eluting isomer 59.9 mg of the title compound, a compound of this invention, as a white solid, m.p.>250° C. 1H NMR (CDCl3) δ 10.10 (br s, 1H), 8.46 (s, 1H), 8.27 (s, 1H), 7.86 (d, 1H), 7.54 (s, 1H), 7.38 (d, 1H), 7.09 (dd, 1H), 3.91 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[OH:12].[H-].[Na+].[C:15](Cl)([Cl:17])=[O:16]>O1CCCC1.C(Cl)Cl>[Cl:17][C:15]([O:12][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][C:4]=1[Cl:11])=[O:16]
Reactant: O=C(Cl)Cl
Reactant: O=[N+]([O-])c1cc(Cl)c(O)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Cl)Oc1c(Cl)cc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2,6-dichloro-4-nitrophenol (5.0 g, 24.0 mmol) in 10 ml of tetrahydrofuran is added dropwise to a suspension of sodium hydride (1.33 g, 50% NaH, 27.6 mmol) in 20 ml of THF. After the addition, stirring is continued for 1 hour at RT and is the mixture is then added dropwise to a solution of phosgene (14.0 g) in 50 ml of methylene chloride at -10°. The mixture is allowed to warm to RT and is purged with N2 to remove excess phosgene. The solvent is stripped and the residue is taken into methylene chloride. The precipitated sodium chloride is filtered and the filtrate is concentrated to give 2,6-dichloro-4-nitrophenyl chloroformate.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][C:7]2[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][C:6]1=2.I.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](SC)=[NH:24]>>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][C:7]2[CH:11]=[CH:12][C:13]([NH:15][C:23]([C:19]3[S:18][CH:22]=[CH:21][CH:20]=3)=[NH:24])=[CH:14][C:6]1=2
Reactant: CSC(=N)c1cccs1
Reactant: CN(C)CCN1CCOc2ccc(N)cc21
Agent: I
Product: CN(C)CCN1CCOc2ccc(NC(=N)c3cccs3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred ethanolic solution of 4-(2-(dimethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine (0.088 g, 0.398 mmol) under an argon atmosphere was added methyl thiophene-2-carbimidothioate hydroiodide (0.227 g, 0.795 mmol). The resulting faintly cloudy yellow mixture stirred overnight at room temperature. After 20 hours, argon was bubbled through the mixture, which was then concentrated to afford a residue. The residue was then partitioned between EtOAc (100 mL) and saturated NaHCO3 (˜10 mL) solution. The aqueous layer (pH ˜9) was further extracted with EtOAc, and the combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated to yield a yellow residue. Purification on silica gel (dry chromatography, eluting with 5-7.5% (2M NH3 MeOH)/CH2Cl2) yielded the title compound 9 as a yellow residue (70 mg, 53.3%). 1H NMR (DMSO-d6) δ 7.70 (d, 1H, J=2.7 Hz), 7.57 (d, 1H, J=5.0 Hz), 7.07 (dd, 1H, J=5.0, 3.7 Hz), 6.59 (d, 1H, J=8.2 Hz), 6.30 (brs, 2H), 6.14 (s, 1H), 6.00 (d, 1H, J=8.1 Hz), 4.18-4.02 (m, 2H), 3.41-3.25 (m, 4H+H2O), 2.41 (t, 2H, J=6.7 Hz), 2.17 (s, 6H); ESI-MS (m/z, %): 331 (MH+, 100).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[S:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].CN(C=[O:27])C>FC(F)(F)C([O-])=O.[Ag+]>[OH:27][CH2:2][C:3]1[N:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[S:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Reactant: CN(C)C=O
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CO
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of ethyl 4-(bromomethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate (50g, 0.127moles, 1eq) in dry DMF (300ml) under a positive N2flow was added silver trifluoroacetate (42.02g, 0.191moles, 1.5eq) all at once as a solid. This was stirred at room temperature for 3.5hrs. The reaction was partitioned between ethyl ether (1.5L) and water (500ml). The phases were separated and the organic phase washed twice with water (500ml). After separation of the phases, the organic fraction was dried with Na2SO4, filtered and concentrated in vacuo. The crude trifluoroacetate product was used without characterization. Ethanol (300ml) was added and the reaction was refluxed for 10hrs. After cooling to room temperature the ethanol was removed in vacuo to yield 42g (100%) of the title compound. The product was used without purification.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@H:12]2[C@@H:16]([OH:17])[CH2:15]N(C(OCC3C=CC=CC=3)=O)[CH2:13]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].N[C@@H]1C[O:32]C[C@H]1O>>[CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[CH2:13][O:32][CH2:15][C@H:16]2[OH:17])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCc1cnc(CC)c(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2O)n1
Reactant: N[C@@H]1COC[C@H]1O
Product: CCc1cnc(CC)c(N[C@@H]2COC[C@H]2O)n1

Procedure:
Following the procedure for the preparation of benzyl(3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylate but substituting trans-(+/−)-4-aminotetrahydrofuran-3-ol and making non-critical variations provided the title compound as an orange oil. IR (diffuse reflectance) 3356, 3255, 2972, 2938, 1587, 1511, 1464, 1453, 1396, 1337, 1185, 1099, 1064, 965, 888 cm−1; OAMS supporting ions at: ESI+ 238.1; MS (EI) m/z 237 (M+); HRMS (FAB) calcd for C12H19N3O2+H1 238.1555, found 238.1551.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21]>ClCCl.CN(C1C=CN=CC=1)C.O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:26])[CH3:25])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11]
Reactant: O=C(Cc1ccc(O)cc1Br)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)OCc2ccccc2)c(Br)c1
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of benzyl (2-bromo-4-hydroxyphenyl)acetate (2.00 g) in dichloromethane (30.0 mL) were added tert-butyl (chloro)dimethylsilane (1.13 g) and N,N-dimethyl-4-aminopyridine (913 mg) under ice-cooling, followed by stirring for 2 hours under ice-cooling. The reaction mixture was diluted with water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain benzyl (2-bromo-4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)acetate (2.63 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:12]([CH:16]=O)=[CH:13][S:14][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:18][O:19][C:20](=[O:33])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH3:32]>>[CH3:18][O:19][C:20](=[O:33])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[C:24]([CH2:16][C:12]2[C:11]([S:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)(=[O:9])=[O:10])=[CH:15][S:14][CH:13]=2)=[C:23]1[CH3:32]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1cscc1S(=O)(=O)c1ccc(Cl)cc1
Product: COC(=O)Cn1c(C)c(Cc2cscc2S(=O)(=O)c2ccc(Cl)cc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using 4-(4-chloro-benzenesulfonyl)thiophene-3-carbaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[N:15]=[N:14][C:13]([C:16]2[CH:30]=[CH:29][C:19]([C:20]([NH:22][C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25])=[O:21])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]2[N:15]=[N:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([NH:22][C:23]([CH3:27])([CH3:28])[C:24]([OH:26])=[O:25])=[O:21])=[CH:29][CH:30]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CC(C)(NC(=O)c1ccc(-c2ccc(Cl)nn2)cc1)C(=O)O
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)c1ccc(-c2ccc(Nc3cccc(Cl)c3)nn2)cc1)C(=O)O
Temperature: 100 °C

Procedure:
A 1-dram vial was charged with 3-chloroaniline (0.2 Ml, excess) and 2-[4(6-chloro-pyridazin-3-yl)-benzoylamino]-2-methyl-propionic acid (0.75 g) as a solid. The vial was heated to 100° C. for 1.5 h. The crude reaction mixture was then dissolved in 2 Ml DMF and then purified by reverse-phase preparative HPLC to afford the title compound: 1H NMR (400 MHz, DMSO-D6) δ ppm 1.47 (s, 6 H), 7.03 (dd, J=7.45, 1.64 Hz, 1 H), 7.28 (d, J=9.35 Hz, 1H), 7.36 (t, J=8.08 Hz, 1 H), 7.56 (dd, J=8.34, 1.26 Hz, 1 H), 7.99 (d, J=8.59 Hz, 2 H), 8.12-8.19 (m, 4 H),8.52 (s, 1 H), 9.71 (s, 1 H); (M+H)+ 411.0.
Reaction SMILES: [CH2:1]([CH2:5][C@H:6]([NH2:10])[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][NH2:4].[ClH:11].[NH3:12]>>[ClH:11].[NH4+:4].[NH4+:12].[NH2:10][C@@H:6]([CH2:5][CH2:1][CH2:2][CH2:3][NH2:4])[C:7]([O-:9])=[O:8].[NH2:10][C@@H:6]([CH2:5][CH2:1][CH2:2][CH2:3][NH2:4])[C:7]([O-:9])=[O:8]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: N
Agent: Cl
Product: NCCCC[C@H](N)C(=O)[O-]
Product: [NH4+]
Reaction time: 0.42 h

Procedure:
L(+)-lysine monohydrochloride (3.08 g, 16.86 mmol) was cooled in an ice bath, followed by addition of aqueous ammonia (15 mL). The reaction solution was stirred at the same temperature for 25 minutes and then concentrated under reduced pressure, and the resulting crude product (3.20 g) was directly used for the next step.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]3[CH2:22][CH2:21]3)[CH:18]=[N:19][C:4]=2[CH:3]=1.[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[O:35][CH3:36])[CH3:24].COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>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.O.CCOC(C)=O>[CH:20]1([N:17]2[C:5]3[C:6]([O:8][C@@H:9]([C@H:11]4[CH2:15][NH:14][C:13](=[O:16])[CH2:12]4)[CH3:10])=[N:7][C:2]([C:29]4[CH:30]=[CH:31][C:26]([O:25][CH2:23][CH3:24])=[C:27]([O:35][CH3:36])[CH:28]=4)=[CH:3][C:4]=3[N:19]=[CH:18]2)[CH2:22][CH2:21]1
Reactant: C[C@@H](Oc1nc(Br)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: CCOc1ccc(B(O)O)cc1OC
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: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CCOc1ccc(-c2cc3ncn(C4CC4)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC
Temperature: 105 °C

Procedure:
To a 25 ml 3-neck flask with condenser and magnetic stir bar was added (R)-4-((R)-1-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-on (100 mg, 0.27 mmol), (4-ethoxy-3-methoxyphenyl)boronic acid (64 mg, 0.33 mmol) and Pd(PPh3)4 (32 mg, 0.027 mmol) then evacuated and filled with N2 3×. Added 2 mL DME and 2N SODIUM CARBONATE (0.41 ml, 0.82 mmol) via syringe and heated in a 105° C. oil bath for 2 hrs at which time LC-MS indicated a complete reaction. Let cool, added EtOAc and water, separated, washed with brine, dried over Na2SO4, filtered and concentrated. Purified by chromatography: ISCO 50 g C18 reverse phase 0-30% water/acetonitrile/0.1% TFA. Partially concentrated under reduced pressure added EtOAc and sat.aq.bicarb, separated, washed with brine, dried over Na2SO4, filtered and concentrated to give a white solid.