Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:32]2[CH2:31][CH2:30][N:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:34][CH2:33]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Reactant: COc1cccc(N2CCNCC2)c1
Product: COc1cccc(N2CCN(C(=O)Nc3nc4ccc(OC)cc4nc3OC)CC2)c1
Yield: 90 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(3-methoxyphenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 90%). H NMR (300 MHz, CDCl3): δ 3.27 (s, 4H), 3.75 (s, 4H), 3.79 (s, 3H), 3.89 (s, 3H), 4.12 (s, 3H), 6.44-6.57 (m, 3H), 7.14-7.22 (m, 4H), 7.72-7.75 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH:12]1[CH2:17][CH:16]([CH2:18][OH:19])[CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[C:38]([O:19][CH2:18][CH:16]1[CH2:17][CH:12]([N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:13][N:14]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:15]1)(=[O:40])[CH3:39]
Reactant: CC(C)CN(C(=O)OCc1ccccc1)C1CC(CO)CN(C(=O)OC(C)(C)C)C1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)OCC1CC(N(CC(C)C)C(=O)OCc2ccccc2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl 3-{[(benzyloxy)carbonyl](2-methylpropyl)amino}-5-(hydroxymethyl)piperidine-1-carboxylate (4.6 g) and triethylamine (2.3 ml) in ethyl acetate (25 ml) was added acetyl chloride (0.94 ml) under ice-cooling, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (5.09 g).
Reaction SMILES: C([NH:9][C:10]1[S:11][CH2:12][CH:13]2[CH2:18][N:17]([C:19]3[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)[CH2:16][C:14]2([C:26]2[CH:27]=[C:28]([NH:33][C:34]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][N:37]=3)=[O:35])[CH:29]=[CH:30][C:31]=2[F:32])[N:15]=1)(=O)C1C=CC=CC=1.Cl.CON.N1C=CC=CC=1.CS(C)=O>C(O)C>[NH2:9][C:10]1[S:11][CH2:12][CH:13]2[CH2:18][N:17]([C:19]3[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)[CH2:16][C:14]2([C:26]2[CH:27]=[C:28]([NH:33][C:34]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][N:37]=3)=[O:35])[CH:29]=[CH:30][C:31]=2[F:32])[N:15]=1
Reactant: O=C(NC1=NC2(c3cc(NC(=O)c4ccc(F)cn4)ccc3F)CN(c3ncc(F)cn3)CC2CS1)c1ccccc1
Agent: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: NC1=NC2(c3cc(NC(=O)c4ccc(F)cn4)ccc3F)CN(c3ncc(F)cn3)CC2CS1
Temperature: 70 °C
Reaction time: 4 h
Yield: 186.9 %

Procedure:
A mixture of N-[3-[2-benzamido-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-fluoro-pyridine-2-carboxamide (293 mg, 497 μmol), O-methylhydroxylamine hydrochloride (430 mg, 4.97 mmol) and pyridine (402 μL, 4.97 mmol) is heated in ethanol (13 mL) to 70° C. in a capped flask for 2.5 hours. Dimethyl sulfoxide (3 mL) is added and the mixture is heated at 70° C. overnight. Additional dimethyl sulfoxide (10 mL) is added and heating continued at 70° C. for 4 hours. Additional O-methylhydroxylamine hydrochloride (208 mg, 2.48 mmol) and pyridine (201 μL, 2.48 mmol) is added and the mixture is heated to 60° C. for 3 hours and the mixture is stirred for 3 days at room temperature. In a separate flask, a mixture of N-[3-[2-benzamido-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-fluoro-pyridine-2-carboxamide (276 mg, 468 μmol), O-methylhydroxylamine hydrochloride (405 mg, 4.68 mmol) and pyridine (478 μL, 4.68 mmol) is heated in ethanol (15 mL) and dimethyl sulfoxide (4 mL) at 70° C. in a capped flask overnight. Additional dimethyl sulfoxide (10 mL) is added and heating is continued at 70° C. for 4 hours. Additional O-methylhydroxylamine hydrochloride (195 mg, 2.34 mmol) and pyridine (189 μL, 2.34 mmol) is added and heating continued at 70° C. for 3 hours followed by stirring the mixture for 3 days at room temperature. The two reaction mixtures are combined and most of the solvent removed in vacuo. The crude product is purified on a SCX column using 3:1 dichloromethane:methanol and then 2:1 dichloromethane:7 N ammonia in methanol. The crude product is further purified over silica gel with a 20 minute 0.5% to 10% gradient of 7 N ammonia methanol in dichloromethane gradient to give the title compound (451 mg, 96%). ES/MS (m/e): 486 (M+H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=2)[N:16]=[CH:15][CH:14]=1>>[F:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[C:13]2[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:11])[CH:8]=2)[NH:3][C:2]=1[CH3:1]
Reactant: Cc1ccc2[nH]c(C)cc2c1
Reactant: Fc1ccc2nccc(Cl)c2c1
Product: Cc1ccc2[nH]c(C)c(-c3ccnc4ccc(F)cc34)c2c1

Procedure:
The sub-title compound was prepared by the method of Example 10 part a, using 2,5-dimethyl indole and 4-chloro-6-fluoroquinoline.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2.[I:24]I>O1CCCC1>[F:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([C:23]=1[I:24])=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: II
Reactant: Fc1cnc2ccccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Fc1cnc2ccccc2c1I
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 41.4 %

Procedure:
To a 0° C. solution of diisopropyl amine (2.8 mL, 27 mmol) in tetrahydrofuran (80 mL) was added dropwise butyl lithium (8.1 mL, 2.5 M solution in hexane, 27 mmol). After 10 min., the flask was cooled to −78° C. and 3-fluoro quinoline from Step B (3 g, 20 mmol) in 20 mL of tetrahydrofuran was added over 15 min. period. The stirring was continued for an additional 4 h., after which iodine (5.4 g, 21 mmol) in 10 mL of THF (tetrahydrofuran) was added and the reaction temperature was maintained at −78° C. for additional 2 h. The reaction was quenched by adding a mixture of water and tetrahydrofuran (25 mL, 1:9), and the resulting solution was extracted with ethyl acetate. The organic layers were combined, washed with water and brine. Purification by silica gel column gave the title compound (2.26 g, 40%). MS (ES) 148.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[CH:28][C:24]=2[C:25]([NH2:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: COc1cc(N)c(C(N)=O)cc1OC
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Product: COc1cc(Nc2nc(Cl)nc3c2ccn3S(=O)(=O)c2ccc(C)cc2)c(C(N)=O)cc1OC

Procedure:
Using General Protocol II and starting with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 8.8 mmol) and 2-amino-4,5-bis(methyloxy)benzamide (3.7 g, 18.9 mmol), 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4,5-bis(methyloxy)benzamide was isolated as a white solid (2.75 g, 62% Yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (s, 3 H), 3.77 (s, 3 H), 3.80 (s, 3 H), 6.60 (d, J=3.85 Hz, 1 H), 7.38 (s, 1 H), 7.44 (d, J=8.61 Hz, 2 H), 7.62 (s, 1 H), 7.71 (d, J=4.03 Hz, 1 H), 7.95 (d, J=8.42 Hz, 2 H), 8.21 (s, 1 H), 8.32 (s, 1 H), 12.70 (s, 1 H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[S:24][C:25]=1[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CC(C)=O>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=4)[S:24][C:25]=3[CH3:26])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1COc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 1 a], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with 4-bromomethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-thiazole in the presence of cesium carbonate and potassium iodide in acetone for 72 h at ambient temperature to give the title compound as colorless oil.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:10](=[CH2:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C(C)=CC=CC=1.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>[CH3:14]/[C:10](/[C:11]([OH:13])=[O:12])=[CH:9]\[C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:2][CH:3]=1
Reactant: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
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: Cc1ccccc1C
Product: C/C(=C\[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 8 h

Procedure:
A mixture of (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid (0.38 g, 1 mmol, Example 32 in WO 2009/090251), Pd(PPh3)4 (70 mg, 0.06 mmol), PPh3 (31.5 mg, 0.12 mmol) and sodium bicarbonate (0.27 g, 3.2 mmol) in 10 mL xylene is heated to reflux, and stirred overnight to afford (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pent-(E)-2-enoic acid as determined by HPLC analysis. Spectroscopic data as reported in Example 1 in WO 2008/031567.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[O:15]CC1C=CC=CC=1)=[O:5])[CH3:2]>[Pd].C(O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[OH:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cccc(OCc3ccccc3)c2[nH]1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2cccc(O)c2[nH]1
Reaction time: 1 h
Yield: 86.2 %

Procedure:
One gram of 10% palladium catalyst on active carbon is added to a solution of 22.2 g of 7-benzyloxyindole-2-carboxylic acid ethyl ester in 500 ml of ethanol and the mixture is hydrogenated for 1 hour with shaking under normal pressure. The reaction solution is then filtered and the filtrate evaporated to dryness under vacuum. The residue is recrystallized from ethanol, yielding 13.3 g of 7-hydroxyindole-2-carboxylic acid ethyl ester, mp 197°-199° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.Cl[Si](C)(C)C.[C:17]1([CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>C(Cl)Cl.C(N(CC)CC)C>[C:7]([C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([OH:9])=[O:8]
Reactant: O=C(Cl)CCCc1ccccc1
Reactant: NCc1ccc(C(=O)O)cc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCc1ccccc1)NCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(Aminomethyl)benzoic acid (3.6 g) is suspended in methylene chloride (100 mL), to which 15 mL triethylamine is added. Chlorotrimethylsilane (10 mL) is then added and the mixture allowed to stir at room temperature for 1 hr. The mixture is then cooled in an ice bath and 4-phenylbutyryl chloride (5.3 g) in methylene chloride (10 mL) is added dropwise and the resulting mixture stirred for 30 min at 0° C., followed by an additional 3 hrs at ambient temperature. The mixture is treated with 75 mL 1 N HCl, after which the organic layer is separated and extracted with 1 N HCl. The precipitate which had formed is recovered by filtration and recrystallized two times from methanol/1 N HCl to give pure N-(4-carboxybenzyl)-4-phenylbutyramide M.p. 178°-179° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C@H:8]([OH:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([C@H:8]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH3:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc([C@@H](C)O)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc([C@@H](C)OS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To a stirred solution of (R)-1-(6-methyl-pyridin-2-yl)-ethanol (175 mg, 1.28 mmol) and triethylamine (355 μl, 2.56 mmol) in DCM (5 mL) at 0° C. add methanesulfonyl chloride (148 μl, 1.92 mmol). Stir at 0° C. for 30 min and quench the reaction mixture with saturated aqueous NaHCO3 at the same temperature. Extract the mixture three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (8:2) to give the title compound as a colorless oil (274 mg, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[CH:5]2.[Cl:20]N1C(=O)CCC1=O>ClCCl.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[C:5]2[Cl:20]
Reactant: CN1CCN(C(=O)c2cc3cc(Br)ccc3[nH]2)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CN1CCN(C(=O)c2[nH]c3ccc(Br)cc3c2Cl)CC1
Reaction time: 18 h
Yield: 58.2 %

Procedure:
(5-Bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (Example 3, 0.27 g) in dichloromethane (3 mL) at ambient temperature was treated with N-chlorosuccinimide (0.103 g) and stirred for 18 h. The reaction mixture was diluted with ether, washed with water, saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated to give crude product. Purification via silica gel chromatography, eluting with 1-8% methanol/dichloromethane afforded the title compound (0.16 g). 1H NMR (400 MHz, CDCl3): δ 2.35 (3H), 2.52 (4H), 3.78 (4H), 7.23 (1H), 7.35 (1H), 7.74 (1H), 9.84 (1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[CH:4][CH:3]=1.O.NN>CCO>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][NH2:9])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(CN2C(=O)c3ccccc3C2=O)n1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cccc(CN)n1

Procedure:
2.5 mL of Diisopropylazodicarboxylate in 1.5 mL of THF was added dropwise to a solution of 250 mg of (6-methylpyridin-2-yl)methanol, 2.8 g of Triphenylphosphine and 1.6 g of isoindoline-1,3-dione in anhydrous THF at room temperature. The reaction was stirred for 2 hours and monitored by TLC. Upon complection, the solvent was concentrated, the crude material was extracted in water and Chloroform 3 times and dried over Magnesium Sulfate. The crude was purified via ISCO Combi-Flash to yield 2-((6-methylpyridin-2-yl)methyl)isoindoline-1,3-dione. 350 mg of 2-((6-methylpyridin-2-yl)methyl)isoindoline-1,3-dione was treated with 440 μL of Hydrazine Monohydrate in EtOH and refluxed for several hours to yield (6-methylpyridin-2-yl)methanamine. The crude (6-methylpyridin-2-yl)methanamine was evaporated and directly coupled to 50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-((6-methylpyridin-2-yl)methyl)terephthalamide. MS (Q1) 491.1 (M)+.
Reaction SMILES: CC1(C)[O:6][C:5](=[O:7])[CH:4]([CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=O)[O:3]1.[NH:17]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:18]1>>[OH:3][C@@H:4]([C@H:8]([C:9]([N:17]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)[CH2:18]1)=[O:11])[CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([OH:6])=[O:7]
Reactant: c1cc(C2CCNC2)ccn1
Reactant: CCCCC(C(=O)O)C1OC(C)(C)OC1=O
Product: CCCC[C@@H](C(=O)N1CCC(c2ccncc2)C1)[C@H](O)C(=O)O

Procedure:
The title compound is prepared from 2-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid B-5 and commercially available 4-pyrrolidin-3-yl-pyridine A-5 according to General Procedure B.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[N:16][C:17]([NH:19][C:20]3[CH:29]=[C:28]4[C:23]([CH2:24][CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27]4)=[CH:22][CH:21]=3)=[N:18][C:11]=2[N:10]2[CH:37]=[CH:38][N:39]=[C:9]12.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[N:16][C:17]([NH:19][C:20]3[CH:29]=[C:28]4[C:23]([CH2:24][CH2:25][NH:26][CH2:27]4)=[CH:22][CH:21]=3)=[N:18][C:11]=2[N:10]2[CH:37]=[CH:38][N:39]=[C:9]12.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Nc3ncc4c(=O)n(-c5ccccc5Cl)c5nccn5c4n3)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1c2cnc(Nc3ccc4c(c3)CNCC4)nc2n2ccnc2n1-c1ccccc1Cl

Procedure:
A mixture of Example 20 (0.357 g, 0.656 mmol) and trifluoroacetic acid (0.506 mL, 6.56 mmol) in CH2Cl2 (6 mL) was stirred at room temperature for 6 hours. The reaction mixture was concentrated and purified by HPLC as described in Example 1F to provide the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, CD3OD) δ ppm 3.14 (t, J=6.35 Hz, 2H), 3.54 (t, J=6.35 Hz, 2H), 4.43 (s, 2H), 7.07 (d, J=1.98 Hz, 1H), 7.31 (d, J=8.33 Hz, 1H), 7.52-7.63 (m, 3H), 7.66-7.72 (m, 2H), 7.76 (s, 1H), 7.87 (d, J=1.98 Hz, 1H), 9.18 (s, 1H). MS (ESI+) m/z 444.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17]I)[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][CH:21]=1.C[O-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C:10](=[CH2:17])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CI)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=C1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCC)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 45 °C
Reaction time: 18 h
Yield: 84.9 %

Procedure:
To a solution of (2S,3R,4R,5S,6S)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-iodomethyl-tetrahydro-pyran-3,4,5-triol (2.5 g, 4.82 mmole) in dry methanol (20 mL), sodium methoxide (2.58 g, 48.2 mmole) was added at 0° C. and stirred at 45° C. for 18 hours. The reaction mixture was diluted with water (50 mL) and extracted with DCM (2×200 mL). The crude product was purified by silica gel column chromatography (1% methanol in DCM) to furnish 1.6 g of (2S,3R,4R,5S)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methylene-tetrahydro-pyran-3,4,5-triol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:13]2[C:17]([CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[N:16][O:15][N:14]=2)=[N:11][OH:12])[CH:5]=[CH:6][C:7]=1[F:8].C1N=CN([C:35](N2C=NC=C2)=[O:36])C=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:35](=[O:36])[O:12][N:11]=[C:10]2[C:13]2[C:17]([CH2:18][O:19][Si:20]([CH:24]([CH3:26])[CH3:25])([CH:27]([CH3:29])[CH3:28])[CH:21]([CH3:22])[CH3:23])=[N:16][O:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)[Si](OCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Temperature: 70 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
N-(3-chloro-4-fluorophenyl)-N′-hydroxy-4-[(triisopropylsilyl)oxy]methyl-1,2,5-oxadiazole-3-carboximidamide (2.2 g, 5.0 mmol) was dissolved in anhydrous tetrahydrofuran (THF) (31 mL) followed by addition of N,N-carbonyldiimidazole (980 mg, 6 mmol). The reaction was heated to 70° C. and monitored by LCMS. Another 0.5 eq of N,N-carbonyldiimidazole was added and the reaction was stirred overnight at 70° C. The reaction was cooled and concentrated in vacuo. The crude oil was dissolved in chloroform and loaded onto a 120 g ISCO cartridge, eluted with 25% EtOAc/Hexane. The combined fractions were stripped to dryness to give the desired product as a white solid (1.74 g, 73%). 1H NMR (400 MHz, DMSO-d6) δ: 7.95 (m, 1H), 7.65 (m, 1H), 7.64 (m, 1H), 5.12 (s, 2H), 1.14 (m, 3H), 1.04 (d, J=7.0 Hz, 18H); MF═C20H26ClFN4O4Si; LCMS calculated for C20H27ClFN4O4Si(M+H)+: m/z=469.147.
Reaction SMILES: C([S:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[C:9]([O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)[CH:8]=1)(=S)OCC.[OH-].[K+].[BH4-].[Na+].OS(O)(=O)=O>CO.O.CCOC(C)=O>[CH:20]1([CH2:19][O:18][C:9]2[CH:8]=[C:7]([SH:6])[CH:12]=[CH:11][C:10]=2[NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:21][CH2:22]1
Reactant: CCOC(=S)Sc1ccc(NS(C)(=O)=O)c(OCC2CC2)c1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CS(=O)(=O)Nc1ccc(S)cc1OCC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
To a solution of crude S-3-(cyclopropylmethoxy)-4-(methylsulfonamido)-phenyl O-ethyl carbonodithioate (prepared as described in Step 7, 0.903 g, 2.497 mmol) in MeOH (15 ml), KOH (0.392 g, 6.99 mmol) was added followed by NaBH4 (0.071 g, 1.873 mmol), and the mixture was stirred at RT for 1 hour. NaBH4 (0.047 g, 1.249 mmol) was freshly added, and the mixture was stirred at RT for 1 hour. Then the mixture was acidified with 10% H2SO4 (until effervescence ceased). The residue was portioned between EtOAc and water, and the organic layer was washed with water, dried over na2SO4 and evaporated. The residue was purified by flash chromatography on silica gel cartridge (DCM:EtOAc=80:20) affording N-(2-(cyclopropylmethoxy)-4-mercaptophenyl)methanesulfonamide (0.222 g, 0.812 mmol, 32.5% yield, MS/ESI+ 295.9 [MNa]+).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:20]=3[CH2:19][O:18][C:17]2=[O:28])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:20]=3[CH2:19][O:18][C:17]2=[O:28])[CH2:12][CH2:13]1
Reactant: COc1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)OC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)OC2
Reaction time: 2 h

Procedure:
A solution of tert-butyl{1-[2-(7-methoxy-2-oxo-2H-3,1-benzoxazin-1(4H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 107) (319 mg, 0.78 mmol) in dichloromethane (8 mL) was treated at room temperature under vigorous stirring with a trifluoroacetic acid (0.75 mL, 10 mmol). After 2 hours, the reaction mixture was concentrated under reduced pressure to give 324 mg (quantitative) of product as a brown oil.