Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]1[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:11](=[O:17])[N:10]([CH2:18][C:19]([OH:21])=O)[N:9]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[Cl:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]1[N:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:11](=[O:17])[N:10]([CH2:18][C:19]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([C:23]([F:22])([F:32])[F:33])[CH:25]=2)=[O:21])[N:9]=1
Reactant: Cc1csc(-c2nn(CC(=O)O)c(=O)n2CC(C)C)c1Cl
Reactant: NCc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1csc(-c2nn(CC(=O)NCc3cccc(C(F)(F)F)c3)c(=O)n2CC(C)C)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40.0 mg (0.121 mmol) of 2-[3-(3-chloro-4-methyl-2-thienyl)-4-isobutyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 249A and 23.4 mg (0.133 mmol) of 3-trifluoromethyl-benzylamine are placed in 1.5 ml of DMF and treated with 19.7 mg (0.146 mmol) of HOBt. 30.2 mg (0.158 mmol) of EDC hydrochloride are added and the mixture is stirred overnight at RT. For the workup, the reaction mixture is stirred with about 15 ml of water and the resulting precipitate filtered off, washed with water and dried in vacuo. 43 mg (73% of theory) of the target compound are thus obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[OH-].[Na+].S(OC)(O[CH3:18])(=O)=O>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:18])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: COS(=O)(=O)OC
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(Br)cc1C(=O)O
Reaction time: 6 h

Procedure:
The starting material is prepared as follows: The solution of 110 g of 5-bromosalicylic acid in 900 ml of water and 48 g of sodium hydroxide is stirred while 60 ml of dimethyl sulfate are added. The mixture is stirred at 70° for 3 hours, whereupon 50 ml of 50% aqueous sodium hydroxide are added, followed slowly by 60 ml of dimethyl sulfate. After stirring at 70° for 6 hours the last step is repeated and the mixture warmed 17 hours longer. It is cooled in an ice bath, filtered, the filtrate stirred with methylene chloride and neutralized with cold 5 N aqueous hydrochloric acid. The organic phase is separated, dried and evaporated to yield the 5-bromo-2-methoxybenzoic acid melting at 115°-117°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:22](=[O:30])[CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>O1CCCC1.O>[CH2:7]([N:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:22](=[O:30])[CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)CCC(=O)Cl
Reactant: CCOC(=O)CNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCC(=O)N(CC(=O)OCC)Cc1ccccc1
Yield: 85.6 %

Procedure:
Potassium carbonate (110.4 g, 0.97 mol) was added in one portion to a solution of ethyl 2-(benzylamino)acetate (78 g, 0.4 mol) in tetrahydrofuran (500 mL) and water (200 mL). Ethyl 4-chloro-4-oxobutanoate (72.7 g, 0.485 mol) in anhydrous tetrahydrofuran (200 mL) was then added dropwise over a period of 1 hour to the mixture. The mixture was filtered, and the filtrate was washed with ethyl acetate. After the solvent was removed by evaporation, standard extractive workup with ethyl acetate (100 mL) to afford the title product as a yellow oil (110 g; yield=80%). LC-MS: m/z=322 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[N:12]=[C:13](O)[C:14]2[S:19][CH:18]=[CH:17][C:15]=2[N:16]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:13]1[C:14]2[S:19][CH:18]=[CH:17][C:15]=2[N:16]=[C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(-c2cnc3ccccc3n2)nc2ccsc12
Product: Clc1nc(-c2cnc3ccccc3n2)nc2ccsc12
Temperature: 25 °C

Procedure:
A solution of 2-(2-quinoxalinyl)thieno[3,2-d]pyrimidin-4-ol (150 mg, 0.54 mmol) in POCl3 (5 mL) was heated to reflux and maintained at reflux overnight. After cooling to rt, excess POCl3 was removed under reduced pressure to give the crude product which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[C:6]([F:18])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[CH:17][C:10]=12.Cl[C:21]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:24]=[C:23]([NH2:34])[N:22]=1>>[F:18][C:6]1[CH:5]=[C:4]([NH:19][C:21]2[CH:26]=[C:25]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[N:24]=[C:23]([NH2:34])[N:22]=2)[CH:3]=[C:2]([F:1])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[CH:17][C:10]=12
Reactant: Nc1nc(Cl)cc(-c2ccc(F)cc2)n1
Reactant: Nc1cc(F)c(Oc2ccnc3[nH]ccc23)c(F)c1
Product: Nc1nc(Nc2cc(F)c(Oc3ccnc4[nH]ccc34)c(F)c2)cc(-c2ccc(F)cc2)n1

Procedure:
Analogously to example 25, the title compound is synthesized from 100 mg (0.36 mmol) of [3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]amine (from example XXXIV) and 110 mg (0.36 mmol) of 4-chloro-6-(4-fluorophenyl)pyrimidine-2-amine (from example LIX). Purification by preparative HPLC gives the product.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH2:18][C:19]#[N:20])[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:21]=[N+:22]=[N-:23].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH2:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@H](CCC#N)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](CCc1nnn[nH]1)NC(=O)OCc1ccccc1
Temperature: 82.5 °C
Yield: 75 %

Procedure:
Into the same device as used in Example 1 were placed 77.3 g (0.28 mole) of methyl (2S)-2-benzyloxycarbonylamino-4-cyanobutyrate, 27.3 g (0.42 mole) of sodium azide, 57.7 g (0.42 mole) of triethylamine hydrochloride and 280 ml of toluene. Thereafter, the mixture was heated to a temperature of 82 to 83° C. to undergo a reaction for 24 hours. Subsequently the same procedure as in Example 1 was repeated, and crystals were collected by filtration. Further, the crystals were recrystallized from methanol and water, filtered and dried, giving 67.7 g (0.21 mole) of methyl (2S)-2-benzyloxycarbonylamino-4-(tetrazole-5-yl)butyrate (yield 75.8% based on methyl (2S)-2-benzyloxycarbonylamino-4-cyanobutyrate). The reaction is illustrated below with chemical formulas: ##STR27##
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[Br:8][C:6]1[CH:7]=[C:2]([N:1]([S:27]([CH3:26])(=[O:29])=[O:28])[S:27]([CH3:26])(=[O:29])=[O:28])[C:3]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[N:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ncc(Br)cc1N(S(C)(=O)=O)S(C)(=O)=O
Temperature: 25 °C
Yield: 51.5 %

Procedure:
A solution of tert-butyl 3-amino-5-bromopyridin-2-ylcarbamate (96.3 mg, 0.33 mmol) and diisopropylethylamine (128 uL, 074 mmol) in dichloromethane (2 mL) was cooled to 0° C., and to it was added methanesulfonyl chloride (52 uL, 0.67 mmol). The mixture was allowed to warm to rt over 2 h. The mixture was then diluted with dichloromethane and was then washed with aqueous citric acid (10%) followed by water. The organic phase was then dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (gradient, 100% hexanes to 70% hexanes:30% ethyl acetate) to provide tert-butyl 5-bromo-3-(N-(methylsulfonyl)methylsulfonamido)pyridin-2-ylcarbamate (77 mg, 0.17 mmol, 52% yield) as a colorless film. 1H NMR (400 MHz, CDCl3) δ 8.64 (d, 1H), 7.79 (d, 1H), 7.10 (s, 1H), 3.44 (s, 6H), 1.52 (s, 9H); MS (EI) for C12H18BrN3O6S2: 388, 390 (Br isotopes, MH+-t-butyl).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[N:25][CH:26]=1.O>CN(C)C=O>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:24]2[CH:23]=[CH:22][C:21]([CH2:20][O:16][C:13]3[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[N:2]4)=[CH:15][CH:14]=3)=[CH:26][N:25]=2)=[CH:32][CH:31]=1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: ClCc1ccc(-c2ccc(Cl)cc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(-c2ccc(COc3ccc(CCCCn4ccnn4)cc3)cn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
A solution of 91 mg (0.42 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 18 mg (0.44 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 100 mg (0.42 mmol) 5-Chloromethyl-2-(4-chloro-phenyl)-pyridine (GB 1147068) were added and stirred continued over night. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water, methanol/water 1:1 and diisopropylether. The residue was dried at 40° C. to give 121 mg (69%) of the title compound as light brown powder.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:19])=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]=[CH:4][N:3]=1.O[CH2:21][CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH2:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:9][C:10]=2[O:12][CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[N:5]=[CH:4][N:3]=1
Reactant: Oc1cc(OC2CCOCC2)c2c(Cl)ncnc2c1
Reactant: OCCCN1CCCC1
Product: Clc1ncnc2cc(OCCCN3CCCC3)cc(OC3CCOCC3)c12
Yield: 79.9 %

Procedure:
Using an analogous procedure to that described in Note [6] below Example 19, 4-chloro-7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline (0.112 g) was reacted with 1-(3-hydroxypropyl)pyrrolidine (0.062 g) to give 4-chloro-7-(3-pyrrolidin-1-ylpropoxy)-5-tetrahydropyran-4-yloxyquinazoline (0.125 g); NMR Spectrum: (CDCl3) 1.7–1.9 (m, 4H), 1.95–2.2 (m, 6H), 2.55 (br s, 4H), 2.65 (m, 2H), 3.65–3.75 (m, 2H), 4.0–4.1 (m, 2H), 4.2 (m, 2H), 4.75 (m, 1H), 6.6 (d, 1H), 6.95 (d, 1H), 8.8 (s, 1H); Mass Spectrum: M+H+ 392 and 394.
Reaction SMILES: [N:1]1([C:7](=[O:24])[CH2:8][CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[C:10]([OH:12])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:25]([O:29][C:30]([N:32]1[CH2:36][CH:35]([OH:37])[CH:34]([NH2:38])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>>[C:25]([O:29][C:30]([N:32]1[CH2:36][C:35](=[O:37])[CH:34]([NH:38][C:10](=[O:12])[CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[CH2:8][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:24])[CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CC(N)C(O)C1
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CC(=O)C(NC(=O)C(CC(=O)N2CCOCC2)CS(=O)(=O)Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid (120 mg, 0.34 mmol), 3-amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.74 mmol), prepared as in reference 13, EDC (0.3 g, 1.6 mmol), and HOBt (150 mg, 0.96 mmol) were combined. Dichloromethyl (10 mL) was added and then 4-methylmorpholine (0.5 mL). The mixture was stirred at ambient temperature for 2 hours. After dilution with ethyl acetate (200 mL) the solution was washed with 1N aqueous HCl (50 mL), saturated aqueous NaHCO3 (50 mL) and brine (50 mL), dried with MgSO4 and evaporated under vacuum. The pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in DMSO (5 mL). Triethylamine (0.5 mL) and then SO3 pyridine complex (150 mg) were added and the mixture was stiffed at ambient temperature for 3 hours. After dilution with ethyl acetate (100 mL), the solution was washed with water (50 mL) and brine, dried with MgSO4 and evaporated under vacuum. The residue was purified by flash chromatography on silica gel. Eluent: 5% methanol in ethyl acetate. Yield: 40 mg 3-(4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyrylamino)-4-oxo-1-pyrrolidine-1-carboxylic acid tert-butyl ester as white solid as mixture of diastereomers; 1H NMR: (DMSO) 8.80–8.66 (m, 1H), 7.42–7.34 (m, 5H), 4.52–4.41 (m, 2H), 4.34–4.20 (m, 1H), 3.98–3.88 (m, 1H), 3.82 (d, J=18.5 Hz, 1H), 3.70–3.05 (m, 13H), 2.70–2.52 (m, 2H), 1.41 (s, 9H); MS: (M+H)+ 538.
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][CH2:5][NH2:6].C(N(C(C)C)CC)(C)C.[F:16][CH:17]([F:47])[C:18]([N:20]1[C@H:24]([CH2:25][F:26])[C@@H:23]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[CH:35][C:36]([CH2:39]OS(C)(=O)=O)=[N:37][CH:38]=3)=[CH:29][CH:28]=2)[O:22][C:21]1([CH3:46])[CH3:45])=[O:19]>C(#N)C>[F:47][CH:17]([F:16])[C:18]([N:20]1[C@H:24]([CH2:25][F:26])[C@@H:23]([C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:38]=[N:37][C:36]([CH2:39][NH:6][CH2:5][CH2:4][CH2:3][F:2])=[CH:35][CH:34]=3)=[CH:31][CH:32]=2)[O:22][C:21]1([CH3:45])[CH3:46])=[O:19]
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(COS(C)(=O)=O)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Reactant: NCCCF
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)O[C@H](c2ccc(-c3ccc(CNCCCF)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a solution of 3-Fluoro-propylamine hydrochloride (0.072 g, 0.636 mmol) in acetonitrile (5 mL) is added diisopropylethylamine (0.082 mL, 0.636 mmol) at room temperature. After stirring for 30 minutes methane sulfonic acid 5-{4-[(4S,5R)-3-(2,2-difluoro-acetyl)-4-fluoromethyl-2,2-dimethyl-oxazolidin-5-yl]-phenyl}-pyridin-2-ylmethyl ester (0.1 g, 0.211 mmol) is added then the resulting mixture is stirred at room temperature for overnight. Solvent is evaporated under reduced pressure and the crude material is purified by combi-flash chromatography using 12% methanol in CH2Cl2 as an eluent to afford the title compound (0.093 g). 1H-NMR (400 MHz, DMSO-d6) δ: 1.52 (s, 3H), 1.60 (S, 3H), 2.06-2.14 (m, 2H), 3.57-3.60 (m, 2H), 4.35 (s, 2H), 4.49-4.51 (m, 1H), 4.52-4.56 (m, 0.5H), 4.57-4.63 (m, 1H), 4.64-4.70 (m, 1H), 4.83-4.86 (m, 0.5H), 4.93-4.97 (m, 1H), 5.28 (d, J=3.48 Hz, 1H), 6.66 (t, J=52.3 Hz, 1H), 7.61-7.65 (m, 3H), 7.84 (d, J=8.2 Hz, 2H), 8.21-8.23 (dd, J1=3.04 Hz, J2=8.16 Hz, 1H), 8.97 (d, J=1.96 Hz, 1H). LC-MS (m/z): [M+H]=454.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:11]=1[CH:12]=O>>[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:11]=1[CH:12]=[N:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: COc1cccc(F)c1C=O
Reactant: Nc1ccccc1O
Product: COc1cccc(F)c1C=Nc1ccccc1O
Yield: 99.8 %

Procedure:
Preparation analogous to Example 1, step a, from 2-aminophenol (7.08 g, 64.93 mmol) and 2-fluoro-6-methoxybenzaldehyde (10 g, 64.93 mmol) gave the title compound (15.9 g, 99%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:23])[N:9]([CH2:11][C:12]3[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:10]=[C:4]2[C:3]=1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(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>[CH3:22][C:13]1[C:12]([CH2:11][N:9]2[C:8](=[O:23])[N:5]3[CH:6]=[CH:7][C:2]([C:35]4[CH:36]=[CH:37][C:32]([C:31]([F:42])([F:41])[F:30])=[CH:33][CH:34]=4)=[C:3]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[C:4]3=[N:10]2)=[CH:17][CH:16]=[C:15]([C:18]([F:21])([F:20])[F:19])[N:14]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(Cl)ccn2c1=O
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(C(F)(F)F)cc3)ccn2c1=O
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 7-chloro-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (72 mg, 0.17 mmol), 4-trifluoromethylphenylboronic acid (65 mg, 0.34 mmol), and 2.0 M aqueous sodium carbonate (0.37 mL) in toluene (1.5 mL) was added (Ph3P)4Pd (30 mg, 0.025 mmol) in one portion, and the resulting yellow mixture was vigorously stirred under argon at 100° C. for 1.5 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The EtOAc layer was washed with water, then saturated aqueous NaCl twice, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluted with a gradient of EtOAc (0-80%) in hexanes to afford the desired product, which was contaminated with triphenylphosphine oxide. The product was further purified by preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 90% B over 12 min (A=90% water, 10% methanol and B=90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The yellow residue was dissolved in acetonitrile, frozen and lyophilized to afford 40 mg of the title compound as a light yellow powder. HPLC/MS: retention time=2.92 min, [M+H]+=530.4.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl>CN(C=O)C>[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26][N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=[C:3]1[CH2:2][OH:1]
Reactant: C[Si](C)(C)CCOCCl
Reactant: OCc1nc2ccccc2[nH]1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1c(CO)nc2ccccc21
Temperature: 60 °C
Yield: 43.7 %

Procedure:
To a stirred solution of 2-hydroxymethylbenzimidazole (31.94, 0.216 mol) in dry DMF (450 mL) was added N,N-diisopropylethylamine (90 mL, 0.52 mol) followed by 2-(trimethylsily)ethoxymethyl chloride (75% in pentane, 55 g, 0.25 mol) and the mixture heated to 60° C. for 2 h. The mixture was cooled to room temperature, concentrated under reduced pressure and partitioned between EtOAc (400 mL) and distilled water (700 mL). The phases were separated and the aqueous layer extracted with EtOAc (2×200 mL). The combined organic extracts were washed with brine (1×400 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. Purification of the crude oil by column chromatography on silica gel (4% MeOH/CH2Cl2) afforded the desired 1-(2-trimethylsilylethoxymethyl)-2-hydroxymethylbenzimidazole (26.28 g, 44%) as a yellow oil. 1H NMR (CDCl3) δ −0.04 (s, 9H), 0.89 (t, 2H, J=9 Hz), 1.75 (br s, 1H), 3.55 (t, 2H, J=9 Hz), 4.94 (s, 2H), 7.26-7.30 (m, 2H), 7.43-7.45 (m, 1H), 7.70-7.72 (m, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4](OS(C(F)(F)F)(=O)=O)[CH2:3][CH2:2]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][C:18]=1[N+:32]([O-:34])=[O:33].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:4]2[CH2:3][CH2:2][O:1][CH2:6][CH:5]=2)=[CH:19][C:18]=1[N+:32]([O-:34])=[O:33]
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Reactant: O=S(=O)(OC1=CCOCC1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C2=CCOCC2)cc1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 65.7 %

Procedure:
2.0 g Trifluoro-methanesulfonic acid 3,6-dihydro-2H-pyran-4-yl ester (8.6 mmol) and 2.89 g 2-(4-methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (10.3 mmol) were dissolved in a mixture of toluene (20 ml) and ethanol (50 ml) 0.35 g of dichloro (1,1′bis-(diphenylphosphine)ferrocene)palladium(II)dichloromethane (0.43 mmol) was added and heated to 85° C. Then aqueous sodium carbonate (2M) (10 ml) was added and the reaction kept at 85° C. for 45 min. After cooling to ambient temperature the reaction was extracted with ethyl acetate/water, the organic phase was dried over sodium sulfate and concentrated. Column chromatography on silica gel (n-heptane/ethyl acetate 4:1) yielded 1.33 g of 4-(4-methoxy-3-nitro-phenyl)-3,6-dihydro-2H-pyran (66%) as a yellow solid; M.p.: 117–120° C.
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=CN=3)CC3CC(CC(C3)C1)C2.[C@@H:25]12[CH2:31][C@@H:28]([CH2:29][CH2:30]1)[CH2:27][C@H:26]2[O:32][C:33]1[C:41]([CH:42]2[CH2:44][CH2:43]2)=[CH:40][C:36]([C:37]([OH:39])=O)=[C:35]([F:45])[CH:34]=1.COCCS(N)(=O)=O.[N:54]1([S:58]([NH2:61])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55]1>>[N:54]1([S:58]([NH:61][C:37](=[O:39])[C:36]2[CH:40]=[C:41]([CH:42]3[CH2:43][CH2:44]3)[C:33]([O:32][C@@H:26]3[CH2:27][C@H:28]4[CH2:31][C@@H:25]3[CH2:30][CH2:29]4)=[CH:34][C:35]=2[F:45])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: O=C(O)c1cc(C2CC2)c(O[C@@H]2C[C@@H]3CC[C@H]2C3)cc1F
Agent: COCCS(N)(=O)=O
Agent: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(O[C@@H]2C[C@@H]3CC[C@H]2C3)cc1F
Yield: 79 %

Procedure:
Following the procedure as described in Example 271 and making variations as required to replace 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with 4-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace 2-methoxyethanesulfonamide with azetidine-1-sulfonamide. Purification by silica gel column chromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gave the title compound as a colorless solid (0.11 g, 79%): 1H NMR (300 MHz, DMSO-d6) δ 11.54 (br s, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.84 (d, J=13.1 Hz, 1H), 4.82-4.73 (m, 1H), 4.00 (t, J=7.6 Hz, 4H), 2.60-2.54 (m, 1H), 2.25-2.19 (m, 1H), 2.18-2.05 (m, 3H), 2.04-1.93 (m, 1H), 1.91-1.80 (m, 1H), 1.61-1.49 (m, 1H), 1.46-1.17 (m, 4H), 0.98-0.81 (m, 3H), 0.68-0.60 (m, 2H); MS (ES+) m/z 409.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:9]([CH:12]=[O:13])=[CH:10][N:11]=2)[C:7]=1[CH3:8].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:8][C:7]1[N:6]2[C:9]([CH:12]=[O:13])=[CH:10][N:11]=[C:5]2[CH:4]=[CH:3][C:2]=1[C:16]1[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1c(Br)ccc2ncc(C=O)n12
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(-c2cccnc2)ccc2ncc(C=O)n12
Yield: 40 %

Procedure:
6-bromo-5-methylimidazo[1,2-a]pyridine-3-carbaldehyde (125 mg, 0.523 mmol), Pyridine-3-boronic acid (77.5 mg, 0.603 mmol), dichlorobis(triphenylphosphine) palladium (II) (36.7 mg, 0.05 mmol) and 2M aqueous Na2CO3 (2 ml) were dissolved in DMF (3 ml) and refluxed for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The solvent was evaporated to obtain crude product, which was purified by column chromatography (silica gel, 0.5% methanol in chloroform) to obtain the title compound. Yield: 40%; 1H NMR (DMSO-d6; 300 MHz): 69.90(s, 1H), 8.39 (s, 1H), 7.73 (d, 1H, J=9.6 Hz), 7.56 (d, 1H, J=9.3 Hz), 3.11 (s, 3H); MS: m/z 238 (M+1)+.