Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][C:12]1([CH3:22])[CH2:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([OH:21])[C:14]=2[O:13]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:11][C:12]1([CH3:22])[CH2:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([O:21][C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=3)[C:14]=2[O:13]1
Reactant: CC1(C)Cc2cccc(O)c2O1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)Cc2cccc(Oc3ncccc3[N+](=O)[O-])c2O1
Temperature: 80 °C
Yield: 73.5 %

Procedure:
A solution of 2-chloro-3-nitropyridine (4.9 g, 30.9 mmol) in DMF (50 mL) was treated with 2,2-dimethyl-2,3-dihydrobenzofuran-7-ol (5.3 mL, 46.4 mmol) and cesium carbonate (30.2 g, 92.7 mmol). The mixture was heated at 80° C. for 10 h. The reaction was cooled to rt, and the mixture was poured in water (200 mL) with stirring. The yellow precipitate formed was filtered and washed with water, and recrystallized from ethanol (50 mL) to afford 134a as brown crystals (6.5 g, 73% yield). [M+H]+=287.16. 1H NMR (500 MHz, deuterochloroform) δ ppm 8.38 (dd, 1H, J=1.7 Hz, J=5.0 Hz), 8.31 (dd, 1H, J=5.0 Hz, J=1.7 Hz), 7.12 (dd, 1H, J=10.0 Hz, J=5.0 Hz), 7.05 (d, 1H, J=5.0 Hz), 7.00 (d, 1H, J=10.0 Hz), 6.86 (t, 1H, J=10.0 Hz), 3.05 (s, 2H), 1.39 (s, 6H); 13C (125 MHz, deuterochloroform) δ (ppm), 155.42, 151.76, 150.16, 136.03, 135.40, 134.04, 129.76, 122.60, 121.06, 120.37, 118.07, 88.40, 43.07, 27.98.
Reaction SMILES: C(OC([N:8]1[CH2:25][CH2:24][C@@H:11]2[N:12]([CH3:23])[C:13]3[C:14]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:16]=[CH:17][C:18]=3[C@H:10]2[CH:9]1Br)=O)(C)(C)C.[F:27][C:28]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:29]=1[NH2:30]>>[F:27][C:28]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:29]=1[NH:30][C:16]1[CH:15]=[C:14]([C:19]([F:21])([F:22])[F:20])[C:13]2[N:12]([CH3:23])[C@H:11]3[CH2:24][CH2:25][NH:8][CH2:9][C@H:10]3[C:18]=2[CH:17]=1
Reactant: Nc1ccc(F)cc1F
Reactant: CN1c2c(cccc2C(F)(F)F)[C@H]2C(Br)N(C(=O)OC(C)(C)C)CC[C@@H]21
Product: CN1c2c(cc(Nc3ccc(F)cc3F)cc2C(F)(F)F)[C@@H]2CNCC[C@@H]21

Procedure:
The title compound was prepared by following the general coupling procedure as a yellow solid (21 mg, 55%) from (4aS,9bR)-bromo-5-methyl-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 45, 41 mg, 0.095 mmol) and 2,4-difluoroaniline (39 mg, 0.30 mmol). MS (APCI): 384 (base, M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:24])[CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+].O>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:24])[CH2:11][CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(CCC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(C(O)CCC(O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
To a solution of the product from Example 1A (1.0 g, 3.05 mmol) in anhydrous THF (30 ml) at 0° C. was added sodium borohydride (0.357 g, 9.44 mmol). The resulting mixture was stirred at 50° C. overnight. The cooled mixture was poured into water, extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated in vacuo. The resulting solid was triturated with dichloromethane to give a tan solid that was collected by filtration and dried to give the title compound (0.82 gm, 81% yield).
Reaction SMILES: ClC1C=CC=CC=1.[CH2:8]([N:15]1[C:19](=[O:20])[CH:18]2[CH:21]([CH3:34])[CH:22]=[CH:23][CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N+:31]([O-:33])=[O:32])[CH:17]2[C:16]1=[O:35])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(OCC)(=O)C>[CH2:8]([N:15]1[C:19](=[O:20])[C:18]2=[C:21]([CH3:34])[CH:22]=[CH:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N+:31]([O-:33])=[O:32])=[C:17]2[C:16]1=[O:35])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC1C=CC(c2ccccc2[N+](=O)[O-])C2C(=O)N(Cc3ccccc3)C(=O)C12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Product: Cc1ccc(-c2ccccc2[N+](=O)[O-])c2c1C(=O)N(Cc1ccccc1)C2=O
Temperature: 25 °C
Yield: 40.4 %

Procedure:
30 ml of chlorobenzene was added to a mixture of 5.0 g of N-benzyl-3-methyl-6-(2-nitrophenyl)-1,2,3,6-tetrahydrophthalimide and 7.0 g of DDQ. The mixture was refluxed for 8 hours, then cooled to room temperature. Thereto was added 100 ml of ethyl acetate. The resulting mixture was washed with aqueous 10% potassium carbonate solution and an aqueous saturated sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=100/1 to 80/1), followed by recrystallization from ethanol to obtain 2.0 g (yield: 40%) of N-benzyl-3-methyl-6-(2-nitrophenyl)phthalimide as light yellow crystals.
Reaction SMILES: [OH:1][C@@H:2]([CH3:15])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11]CC)=[O:10])[N:6]=[C:5]1[CH3:14].[OH-].[Na+].Cl>CO.C1COCC1>[OH:1][C@@H:2]([CH3:15])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[N:6]=[C:5]1[CH3:14]
Reactant: CCOC(=O)c1cn(C[C@H](C)O)c(C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(C(=O)O)cn1C[C@H](C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
(S)-Ethyl 1-(2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxylate (0.655 mmol, 139 mg) was dissolved in methanol (0.5 ml) and THF (4 ml). NaOH 2 M (1.965 mmol, 0.982 ml) was added and the resulting mixture was stirred overnight at RT. The mixture was acidified (pH-5) with 1 M HCl and evaporated. Ethanol was added and the salts were removed by filtration. The filtrate was evaporated. 112 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.06 (d, 3H), 2.30 (s, 3H), 3.70-3.91 (m, 4H), 7.59 (s, 1H).
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][C@@H:8]([CH2:28][C:29]1[N:30]=[CH:31][S:32][CH:33]=1)[C:9](N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)CC(C)C)=[O:10])(C)(C)C.[O:35]1CCNC1=O.[OH-].[Li+].OO>>[S:32]1[CH:33]=[C:29]([CH2:28][C@H:8]([CH2:7][C:6]([OH:5])=[O:34])[C:9]([OH:10])=[O:35])[N:30]=[CH:31]1
Reactant: CC(C)C[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](CC(=O)OC(C)(C)C)Cc1cscn1
Reactant: O=C1NCCO1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)C[C@@H](Cc1cscn1)C(=O)O

Procedure:
4-{[1(S)-(Cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino}-4-oxo-3(R)-(4-thiazolylmethyl)butanoic acid tert-butyl ester: The latter 2-oxazolidinone derivative (4.02 g, 10.5 mmol) was reacted with lithium hydroxide-hydrogen peroxide according to the procedure of example 2, section (g) to give the monoprotected dicarboxylic acid of formula 2, i.e. the 4-tert-butyl ester of 2(R)-(4-thiazolylmethyl)butanedioic acid. Subsequent coupling of the latter compound (2.83 g, 10.4 mmol) with 2(S)-amino-1-cyclohexyl-6-methyl-3(R),4(S)-heptanediol hydrochloride (3.21 g, 11.5 mmol) according to the coupling procedure of example 2, section (g) gave the desired protected amido acid as a white solid (3.75 g, 72%); 1H NMR(CDCl3) δ8.70 (s, 1H), 7.10 (s,1H), 5.96 (d, J=8.3 Hz,1H), 4.40-4.25 (m,2H), 3.40-2.70 (m,6H), 2.40 (dd, J=4.4 Hz,16.8 Hz,1H), 1.95-1.10 (m,17H), 1.40 (s,9H), 0.90 (d, J=6.6 Hz,3H), 0.80 (d, J=6.4 Hz,3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.FC1C=C([C:36]2([OH:41])[CH2:40][CH2:39][O:38][CH2:37]2)C=C(F)C=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:4]1[CH:5]=[C:6]([C:36]2([OH:41])[CH2:40][CH2:39][O:38][CH2:37]2)[CH:7]=[C:2]([F:1])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Reactant: CC1(C)OB(c2c(F)cc(C3(O)CCOC3)cc2F)OC1(C)C
Product: O=C(O)c1csc(-c2c(F)cc(C3(O)CCOC3)cc2F)n1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with 3-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydrofuran-3-ol (Intermediate 143) gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14](I)=[CH:15][N:16]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:11]2=[CH:10][CH:9]=1.[CH3:28][S:29]([C:32]1[N:37]=[C:36]([N:38]2[CH2:43][CH2:42][CH:41]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:40][CH2:39]2)[CH:35]=[C:34]([Sn](C)(C)C)[N:33]=1)(=[O:31])=[O:30]>CN(C=O)C.C(Cl)Cl.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.[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14]([C:34]3[N:33]=[C:32]([S:29]([CH3:28])(=[O:30])=[O:31])[N:37]=[C:36]([N:38]4[CH2:43][CH2:42][CH:41]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:49])([CH3:48])[CH3:50])[CH2:40][CH2:39]4)[CH:35]=3)=[CH:15][N:16]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:11]2=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc([Sn](C)(C)C)nc(S(C)(=O)=O)n2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(-c4ccccc4F)ccc32)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cc(N4CCC(NC(=O)OC(C)(C)C)CC4)nc(S(C)(=O)=O)n3)c3nc(-c4ccccc4F)ccc32)cc1
Temperature: 100 °C
Yield: 58.6 %

Procedure:
A glass microwave reaction vessel was charged with 5-(2-fluorophenyl)-3-iodo-1-tosyl-1H-pyrrolo[3,2-b]pyridine (100 mg, 0.203 mmol) and tert-butyl 1-(2-(methylsulfonyl)-6-(trimethylstannyl)pyrimidin-4-yl)piperidin-4-ylcarbamate (105 mg, 0.203 mmol) in DMF (1.5 mL) followed by Pd(PPh3)4 (11.74 mg, 10.16 μmol) and CuI (7.8 mg, 0.041 mmol). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 1 h. The mixture was diluted with DCM and washed with water, and brine. The organic layer was dried with MgSO4, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 20-80% EtOAc in hexanes) to give tert-butyl 1-(6-(5-(2-fluorophenyl)-1-tosyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-2-(methylsulfonyl)pyrimidin-4-yl)piperidin-4-ylcarbamate (86 mg, 0.119 mmol, 58.7% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 721.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([O:15]CC)=[O:14])=[C:11]([C:18]([O:20]CC)=[O:19])[S:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]([OH:15])=[O:14])=[C:11]([C:18]([OH:20])=[O:19])[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1snc(-c2ccc(Cl)cc2)c1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1snc(-c2ccc(Cl)cc2)c1C(=O)O
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 4,5-diethyl 3-(4-chlorophenyl)-1,2-thiazole-4,5-dicarboxylate (3.28 g, 9.84 mmol, 1.00 equiv) in ethanol (20 mL) and a solution of sodium hydroxide (2.36 g, 59.00 mmol, 6.00 equiv) in water (20 mL). The resulting solution was stirred for 2.5 h at 90° C. in an oil bath. The pH value of the solution was adjusted to 3 with hydrogen chloride (1 mol/L). The resulting solution was extracted with 3×150 mL of dichloromethane. The organic layers were combined, washed with 1×10 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.86 g (69%) of 3-(4-chlororphenyl)-1,2-thiazole-4,5-dicarboxylic acid as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][OH:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][O:29][CH2:31][C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: BrCc1cccnc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCO)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCOCc4cccnc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 1-{4′-[4-(2-hydroxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3-bromomethyl-pyridine.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C1C(=O)N(Cl)C(=O)C1.[Cl:21][C:22]1[N:23]([C:32]2[CH:33]=[N:34][N:35]([CH2:37][CH2:38][CH3:39])[CH:36]=2)[C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[C:26]([Cl:31])[CH:25]=2>C(Cl)Cl.O>[Cl:21][C:22]1[N:23]([C:32]2[CH:33]=[N:34][N:35]([CH2:37][CH2:38][CH3:39])[CH:36]=2)[C:24]2[C:29]([C:30]=1[S:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:28][CH:27]=[C:26]([Cl:31])[CH:25]=2
Reactant: CCOC(=O)c1cccc(S)c1
Reactant: CCCn1cc(-n2c(Cl)cc3ccc(Cl)cc32)cn1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: O
Product: CCCn1cc(-n2c(Cl)c(Sc3cccc(C(=O)OCC)c3)c3ccc(Cl)cc32)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.6 %

Procedure:
To a stirred solution of ethyl 3-mercaptobenzoate (124.9 mg, 0.68 mmol) in CH2Cl2 (20 mL) under inert atmosphere was added NCS (109 mg, 0.81 mmol) at 0° C.; warmed to RT and stirred for 1 h. To this, compound 3 (200 mg, 0.68 mmol) was added at 0° C.; warmed to RT and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with CH2Cl2 (3×25 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. This was purified by preparative HPLC to afford compound 4 (15 mg, 5%) as colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.90 (s, 1H), 7.79-7.77 (m, 1H), 7.69 (s, 1H), 7.66 (s, 1H), 7.48 (d, J=9.0 Hz, 1H), 7.26-7.22 (m, 3H), 7.16 (d, J=9.0 Hz, 1H), 4.32 (q, J=7.5 Hz, 2H), 4.20 (t, J=7.0 Hz, 2H), 2.02-1.98 (m, 2H), 1.37-1.34 (t, J=7.5 Hz, 3H), 1.01 (t, J=7.0 Hz, 3H); LC-MS (ESI): 92.7%; m/z 475.8 (M+H+); (column: X Select C-18, 50×3.0 mm, 3.5 μm); RT 5.03 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5]([OH:7])=O.CO[C:16]1C=CC=C(OC)[C:17]=1C(Cl)=O.S(Cl)(Cl)=O>>[CH3:13][O:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[C:4]=1[C:5](=[O:7])[CH2:16][CH3:17]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: COc1cccc(OC)c1C(=O)O
Solvent: O=S(Cl)Cl
Product: CCC(=O)c1c(OC)cccc1OC

Procedure:
2,6-Dimethoxy-benzoic acid is converted to 2,6-dimethoxybenzoyl chloride III by treatment with thionyl chloride at 70° C. for 2 hours and after removal of excess thionyl chloride the residual III is dissolved in toluene and treated at -78° C. with a solution of triethylaluminum in toluene. This procedure provides 1-(2,6-dimethoxyphenyl)propan-1-one IV in two steps from the readily available precursor II.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:3]([NH:5][C@@H:6]([CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:7]([OH:17])[C:8]([NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:9])=[O:4].[CH:31]1[CH:36]=[C:35]2[C:37]3[CH:44]=[CH:43][CH:42]=[C:41]([C:45](O)=[O:46])[C:38]=3[C:39](=[O:40])[C:34]2=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[CH2:20]([O:19][CH2:18][CH:6]([NH:5][C:3](=[O:4])[C@H:2]([NH:1][C:45]([C:41]1[C:38]2[C:39](=[O:40])[C:34]3[C:35](=[CH:36][CH:31]=[CH:32][CH:33]=3)[C:37]=2[CH:44]=[CH:43][CH:42]=1)=[O:46])[CH2:27][CH:28]([CH3:29])[CH3:30])[CH:7]([OH:17])[C:8]([NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:9])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1cccc2c1C(=O)c1ccccc1-2
Reactant: CCOC(=O)CNC(=O)C(O)[C@H](COCc1ccccc1)NC(=O)[C@@H](N)CC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)C(O)C(COCc1ccccc1)NC(=O)[C@@H](CC(C)C)NC(=O)c1cccc2c1C(=O)c1ccccc1-2
Reaction time: 8 h
Yield: 84.8 %

Procedure:
Ethyl 2-[(3S)-3-[(2S)-2-amino-4-methylpentanoyl]amino-4-(benzyloxy)-2-hydroxyl butanoyl]aminoacetate (500 mg, 1.2 mmole), 9-Fluorenone-1-Carboxylic acid (266 mg, 1.2 mmole), and HBTU (587 mg, 1.6 mmole) were dissolved in DMF (10 mL). Et3N (330 ul, 2.4 mmole) was added and stirring was continued overnight. DMF was removed under reduced pressure. The residue was diluted with EtOAc and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated by rotary evaporation. Purification by chromatography (silica, EtOAc, Rf=0.3) afforded ethyl 2-(4-(benzyloxy)-2-hydroxy-3-[((2R)-4-methyl-2-[(9-oxo-9H-1-fluorenyl)carbonyl]aminopentanoyl)amino]butanoylamino)acetate as a white solid (641 mg, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([SH:22])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C[O-].[Na+].Cl[CH2:27][CH2:28]OS(C1C=CC(C)=CC=1)(=O)=O>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]3[C:11]([S:22][CH2:27][CH2:28]3)=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nc(S)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2nc3n(c2-c2ccc(OC)cc2)CCS3)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred slurry of 3.1 g (0.01 mole) 4,5 bis-(p-methoxyphenyl)-2-mercaptoimidazole [Anschutz and Schwickerath, Ann., 284, 24 (1895)] in 50 ml methanol was added 0.65 g (0.012 mole) of sodium methoxide. To the resulting solution was added 2.6 g (0.011 mole) 2-chloroethyl-p-toluenesulfonate in 10 ml methanol. The mixture was heated at reflux overnight. Another 0.5 g (0.002 mole) of 2-chloroethyl-p-toluenesulfonate was added and refluxing was continued another 2 hours. The mixture was poured into ice water and extracted with methylene chloride three times. The methylene chloride layers were dried and concentrated on a rotary evaporator. The residue was chromatographed on silica gel, eluting with chloroform. The product was obtained by trituration of fractions 4 and 5 with ether to give crystalline material, m.p. 149°-151°. Analysis by IR, NMR and CHN microanalysis indicated the product in a purity of about 85%.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>O>[N:9]1([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1cccc(F)n1
Reactant: C1CCNCC1
Solvent: O
Product: Nc1cccc(N2CCCCC2)n1
Temperature: 205 °C
Yield: 94.9 %

Procedure:
A suspension of 6-fluoropyridin-2-amine (500 mg, 4.4 mmol), piperidine (1.4 mL, 14.1 mmol) in water (0.5 mL) was heated to 205° C. in a microwave oven for 30 minutes. The reaction mixture was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give 6-(piperidin-1-yl)pyridin-2-amine (740 mg, 94%) as a light yellow oil. LC-MS: [M+H]+, 178.1, tR=0.974 min.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:18]([OH:20])[CH3:19]>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:3]=1[C:4]([O:20][CH2:18][CH3:19])=[O:5]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: CCO
Product: CCOC(=O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The 2-chloro-3-nitro-5-trifluoromethylbenzoyl chloride (5.5 g; 18 mmol), obtained in step b) of Example 1, is dissolved in ethanol (50 ml) and stirred for 1 hour at room temperature. After evaporating to dryness, the pasty solid is purified by filtration on silica (eluent: dichloromethane). 4.2 g of ethyl 2-chloro-3-nitro-5-trifluoromethylbenzoate are obtained in the form of a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([Br:11])[N:3]=1.[CH3:12][S-:13].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([S:13][CH3:12])[CH:5]=[C:4]([Br:11])[N:3]=1
Reactant: C[S-]
Reactant: O=[N+]([O-])c1cc(Br)nc(Br)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc(Br)nc(Br)c1
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a solution of 2,6-dibromo-4-nitro-pyridine (CAS 175422-04-5, 10.0 g, 35.5 mmol) in 60 mL of DMF was added at −10° C. sodium methanethiolate (2.61 g, 1.05 eq.) and the mixture stirred for 45 Min. at this temperature and for another 2 h at 0° C. Pouring onto crashed ice, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=97/3), yielded 8.55 g of the title compound as off-white crystals.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19](O)=[C:18]([CH3:23])[CH:17]=1)(=[O:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:1][CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[O:5][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:12](=[O:14])[CH3:13])=[CH:17][C:18]=1[CH3:23]
Reactant: CC(=O)Oc1ccc(O)c(C)c1
Reactant: O[C@@H](CCCl)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc(O[C@H](CCCl)c2ccccc2)c(C)c1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
A solution of (S)-(−)-3-chloro-1-phenyl-1-propanol (0.204 gm, 1.20 mMol), 4-acetoxy-2-methylphenol (0.200 gm, 1.20 mMol) and triphenylphosphine (0.346 g, 1.32 mMol) in 10 mL tetrahydrofuran was cooled to 0-5° C. under argon. This mixture was treated dropwise with di-isopropylazodicar-boxylate (0.26 mL, 1.32 mMol) in tetrahydrofuran (2 mL). The resulting mixture was stirred for 1 hour at 0-5° C. and was then allowed to warm to room temperature. After stirring at room temperature over night the reaction mixture was concentrated under reduced pressure and the residue triturated with 10% ethyl acetate in pentane and stirred until the suspended solid was crystalline. The suspension was filtered and the recovered crystalline solid washed with 10% ethyl acetate in pentane. The combined filtrates were concentrated under reduced pressure and the residue subjected to silica gel chromatography eluting with toluene. Fractions containing product were combined and concentrated under reduced pressure to provide 0.205 gm (54%) of the desired compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:28][C:29]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=1[C:36](=[O:40])[C:37]#[C:38][CH3:39]>>[F:28][C:29]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=1[C:36](=[O:40])/[CH:37]=[C:38](\[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])/[CH3:39]
Reactant: CC#CC(=O)c1cccc(F)c1F
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Product: C/C(=C/C(=O)c1cccc(F)c1F)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 12) from 120 mg (0.33 mmol) of Intermediate 45 and 59 mg (0.33 mmol) of Intermediate 40 to yield 32 mg (18% yield) of Example 38: TLC (DCM/MeOH (4:1): Rf=0.72; 1H NMR (DMSO-d6, 300 MHz) δ11.43 (d, 1H, J=9.8), 7.97 (m, 2H), 7.56 (m, 5 h), 7.28 (m, 1H), 7.19 (d, 2H, J=8.0) 6.91 (d, 2H, J=8.0), 5.34 (s, 1H), 4.21 (m, 3H), 3.21 (m, 2H), 2.98 (t, 2H, J=6.6), 2.84 9 m, 1H), 2.40 (s, 3H), 1.78 (s, 3H); low resolution MS (ES+)m/e 547 (MH+).