Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[N:15][CH:16]=2)=[N:8][C:7]([CH:28](OC)[O:29]C)=[N:6]1)[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O>CC(C)=O>[CH2:1]([N:5]1[C:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[N:15][CH:16]=2)=[N:8][C:7]([CH:28]=[O:29])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1nc(C(OC)OC)nc1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CCCCn1nc(C=O)nc1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1

Procedure:
The compound of Example 26 was treated with catalytic sulfuric acid in wet acetone at reflux. Purification gave 5-[2-[5-[[1-butyl-3-formyl-1H-1,2,4-triazol-5-yl]methyl]-2-pyridinyl)phenyl]-1H-tetrazole as a colorless solid: mp 167-168° C.; NMR (CDCl3) δ 0.94 (t, J=7 Hz, 3H), 1.35 (m, J=7 Hz, 2H), 1.88 (m, J=7 Hz, 2H), 4.22 (t, J=7 Hz, 2H), 4.29 (s, 2H), 7.37 (d, J=8 Hz, 1H), 7.46-7.55 (m, 3H), 7.44 (dd, J=8 and 2 Hz, 1H), 7.93-7.99 (m, 1H), 8.59 (d, J=2 Hz, 1H), 9.95 (s, 1H); MS(FAB) m/e (rel intensity) 389(100), 361(66), 346(26), 333(24), 305(17), 290(23); HRMS. Calc'd. for M+H: 389.1838. Found: 389.1829.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:12]=[C:13]([CH2:24][C:25]([OH:27])=[O:26])[CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:16]=3[OH:17])[NH:8]2)=[CH:4][C:3]=1[C:28]#[N:29].[NH2:30][OH:31]>CCO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:12]=[C:13]([CH2:24][C:25]([OH:27])=[O:26])[CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:16]=3[OH:17])[NH:8]2)=[CH:4][C:3]=1[C:28](=[NH:29])[NH:30][OH:31]
Reactant: N#Cc1cc2cc(-c3cc(CC(=O)O)cc(-c4ccccc4)c3O)[nH]c2cc1Cl
Reactant: NO
Solvent: CCO
Product: N=C(NO)c1cc2cc(-c3cc(CC(=O)O)cc(-c4ccccc4)c3O)[nH]c2cc1Cl

Procedure:
A solution of the cyano indole (17) (0.365 gr, 0.91 mmol) from above in dry EtOH (5 ml) was treated with an excess of Hydroxylamine (5 ml of 50 wt. % solution in water). The resulting reaction mixture was refluxed for 10 h. The solvent was removed by rotary evaporation, the residue was azeotroped with toluene to yield the title title compound (0.3-0.4 g).
Reaction SMILES: C(OC([NH:8][S:9](=[O:26])(=[O:25])[O:10][CH2:11][CH2:12][NH:13][S:14]([NH:17]C(OC(C)(C)C)=O)(=[O:16])=[O:15])=O)(C)(C)C.FC(F)(F)C(O)=O.ClCCl>ClCCl>[S:9](=[O:26])(=[O:25])([O:10][CH2:11][CH2:12][NH:13][S:14]([NH2:17])(=[O:15])=[O:16])[NH2:8]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCCOS(=O)(=O)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)NCCOS(N)(=O)=O
Temperature: 20 °C
Reaction time: 4 h
Yield: 89.3 %

Procedure:
To 1.5 g of 2-({[(tert-butoxycarbonyl)amino]sulfonyl}amino)ethyl tert-butoxycarbonylsulfamate in 30 ml of dichloromethane are added 30 ml of a 1/1 trifluoroacetic acid/dichloromethane mixture. After stirring for 4 hours at 20° C., the reaction mixture is concentrated under reduced pressure and taken up 3 times in ether and reevaporated. The white solid is taken up in dichloromethane and filtered under vacuum to give 700 mg of the desired product: 2-[(aminosulfonyl)amino]ethyl sulfamate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][N:6]=1)=[O:4].C1C=C([Cl:18])C=C(C(OO)=O)C=1.BrC1C=CC(C(OC)=O)=[N+]([O-])C=1.P(Cl)(Cl)(Cl)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([Cl:18])[N:6]=1)=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(Br)cn1
Agent: COC(=O)c1ccc(Br)c[n+]1[O-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(Br)c(Cl)n1
Temperature: 60 °C
Yield: 33 %

Procedure:
A mixture of 5-bromo-pyridine-2-carboxylic acid methyl ester (CAN 29682-15-3, 50 g, 0.23 mol) and m-CPBA (CAN 937-14-4, 80 g, 0.46 mol) in 400 mL dry methylene chloride was heated to 60° C. for 20 h. After that, the mixture was quenched with saturated sodium sulfite solution and extracted with ethyl acetate (2×200 mL). The organic layer was washed with brine (2×200 mL) and evaporated to dryness. The residue was purified by column chromatography (silica gel, 300 g, eluting with 15% ethyl acetate in petroleum ether) to obtain a brown oil. The brown oil, 5-bromo-2-(methoxycarbonyl)pyridine 1-oxide (30 g, 0.13 mol) was added into phosphoryl trichloride (CAN 10025-87-3, 80 mL) at 0° C. over 1 h, then the mixture was heated to 95° C. for 1 h. After that the mixture was evaporated to dryness, the residue was dissolved in water (50 mL), extracted with ethyl acetate (3×50 mL) and the organic layer was evaporated to dryness to obtain the product as a white solid (19 g, 59%); MS (EI): m/e=249.9 [M+H]+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[N:15][CH:16]=1.O>CN(C=O)C>[N+:17]([C:14]1[CH:13]=[CH:12][C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:16][N:15]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
8.1 Phenol (25 mmol) is dissolved in DMF (30 ml) and NaH (1.1 eq., 60% suspension in liquid paraffin) is added at 0° C. 5-Bromo-2-nitro-pyridine (1.0 eq.) in DMF (20 ml) is added and stirred 16 h at RT. The reaction solution is poured into water and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. 2-Nitro-5-phenoxy-pyridine is obtained after column chromatography (heptan/ethyl acetate) as a brown oil in a yield of 78%; HPLC (method A): 1.95 min; LC-MS: 1.678 min, 217.15 (M+H+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.[C:45]1([CH:51]2[CH:55](O)[CH2:54][CH2:53][CH2:52]2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C1COCC1.CCCCCC>[C:45]1([C@H:51]2[CH2:55][CH2:54][CH2:53][C@H:52]2[N:38]2[C:34](=[O:44])[C:35]3[C:36](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:37]2=[O:39])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: OC1CCCC1c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1c2ccccc2C(=O)N1[C@@H]1CCC[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 69.5 %

Procedure:
Scheme IB, step B: A 500 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer, reflux condenser, addition funnel and a nitrogen blanket is charged with triphenylphosphine (16.19 g, 61.73 mmol) and THF (200 mL). To the solution at 0° C. was added dropwise, a solution of diisopropyl azodicarboxylate (12.15 mL, 61.73 mmol) dissolved in THF (30 mL) over a period of 10 minutes. A massive precipitate formed immediately after addition. To the slurry was then added solid phthalimide (9.08 g, 61.73 mmol), followed by a solution of 5-phenylcyclopentane-1-ol (10.0 g, 61.73 mmol) dissolved in THF (30 mL) over a period of 20 minutes maintaining temperature at 0° C. to 5° C. (reaction mixture went into solution by the end of alcoholic substrate addition). Reaction was then stirred at 0° C. for 4.0 hours and brought to room temperature overnight for convenience. Quenched reaction with water (200 mL) and extracted organics with chloroform (200 mL). Washed the organic with water (100 mL) and dried with anhydrous magnesium sulfate. Subsequent filtration and concentration under reduced pressure afforded an oil which solidified on equilibrating to room temperature. To the precipitate was then added hexane (250.0 mL) with vigorous stirring. Filtered off triphenylphosphine oxide precipitate and concentrated filtrate to an oil. Silica gel plug filtration of the oil with 1:1 ethyl acetate:hexanes and subsequent concentration of product fractions afforded an off white precipitate of (+,−) Cis-2-(2-phenyl-cyclopentyl)-isoindole-1,3-dione (mass=12.5 g, 69.6%); 1H nmr (CDCl3) 6 1.6-1.8 (m, 1H), 2.0-2.1 (m, 1H), 2.2-2.35 (m, 2H), 2.4-2.68 (m, 2H), 3.39-3.5 (m, 1H), 5.0-5.1 (m, 1H), 6.9-7.15 (aromatic, 5H), 7.52-7.64 (aromatic, 4H); 13C (CDCl3) 6 25.4, 28.89, 30.56, 50.34, 54.60, 122.89, 126.44, 128.01, 128.41, 131.67, 139.68, 168.86).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](Cl)=[O:8].C(N(CC)CC)C.[NH2:17][C:18]1[CH:39]=[CH:38][C:21]([C:22]([N:24]2[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]2=3)=[O:23])=[CH:20][CH:19]=1>ClCCl>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([N:24]2[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]2=3)=[O:23])=[CH:38][CH:39]=1)=[O:8]
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3-c3ccccc32)cc1
Reactant: Cc1ccsc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccsc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3-c3ccccc32)cc1
Yield: 70.7 %

Procedure:
To 0.193 g (1.2 mmol) of 3-methylthiophene-2-carbonyl chloride in 3 ml of dichloromethane, cooled to 0° C., is added 209 μl of triethylamine. The mixture is stirred and 0.30 g (1 mmol) of 5-(4-aminobenzoyl)-5,6-dihydrophenanthridine is added. The mixture is stirred at room temperature overnight and then concentrated under vacuum. To the residue is added 30 ml of ethyl acetate and the mixture washed with 2 ml each of water, 2N citric acid, IM sodium bicarbonate and brine. The organic layer is dried (Na2SO4) and the solvent removed to give 0.30 g of solid. The solid is chromatographed on thick layer silica gel plates with ethyl acetate-hexane (1:1) as solvent to give 150 mg of product as a yellow foam.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:5]=1[OH:13])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:11])[CH3:12])=[CH:6][C:5]=1[OH:13]
Reactant: CC(C)c1ccc([N+](=O)[O-])c(O)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1ccc(N)c(O)c1
Yield: 80.1 %

Procedure:
To a solution of 2-nitro-5-isopropylphenol(1 g, 6.4 mmol) in methanol(50 mL) was added 10% Pd/C (100 mg). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5% MeOH/CH2Cl2) gave the desired product(775 mg, 93%). 1H NMR (CD3OD): d 6.71-6.44 (m, 3H), 2.73 (m, 1H), 1.20 (d, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH:15]2[CH:19]([OH:20])[CH2:18][NH:17][CH2:16]2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:22]([O-:25])([O-])=[O:23].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH:15]2[CH:19]([OH:20])[CH2:18][N:17]([CH2:13][CH2:8][NH:7][C:22]([O:25][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:23])[CH2:16]2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CC2CNCC2O)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCN1CC(O)C(Cc2cccc(NC(=O)OC(C)(C)C)n2)C1

Procedure:
A mixture of [6-(4-hydroxy-pyrrolidin-3-ylmethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester II-1 (0.01 mol), (2-bromo-ethyl)-carbamic acid tert-butyl (0.012 mol), anhydrous K2CO3 (0.02 mol) in 50 mL anhydrous DMF was stirred at room temperature overnight. Solids were filtered off. The filtrate was evaporated under reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, and evaporated in vacuo. The obtained residue was purified by column chromatography (silica gel, CH2Cl2:MeOH, 9:1). (57%)
Reaction SMILES: [Cl:1][C:2]1[C:31]([O:32][CH3:33])=[C:30]([Cl:34])[CH:29]=[C:28]([Cl:35])[C:3]=1[O:4][C@@H:5]([CH3:27])[C:6]([NH:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([CH2:23][CH3:24])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[C@@H:12]([F:25])[C@@H:11]1[OH:26])=[O:7].[C:36]([NH:43][C@H:44]([C:48](O)=[O:49])[CH:45]([CH3:47])[CH3:46])([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>>[C:39]([O:38][C:36]([NH:43][C@H:44]([C:48]([O:26][C@@H:11]1[C@@H:10]([CH2:9][NH:8][C:6](=[O:7])[C@@H:5]([O:4][C:3]2[C:28]([Cl:35])=[CH:29][C:30]([Cl:34])=[C:31]([O:32][CH3:33])[C:2]=2[Cl:1])[CH3:27])[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([CH2:23][CH3:24])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[C@H:12]1[F:25])=[O:49])[CH:45]([CH3:46])[CH3:47])=[O:37])([CH3:41])([CH3:42])[CH3:40]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCc1cn([C@@H]2O[C@H](CNC(=O)[C@H](C)Oc3c(Cl)cc(Cl)c(OC)c3Cl)[C@@H](O)[C@@H]2F)c(=O)[nH]c1=O
Product: CCc1cn([C@@H]2O[C@H](CNC(=O)[C@H](C)Oc3c(Cl)cc(Cl)c(OC)c3Cl)[C@@H](OC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)[C@@H]2F)c(=O)[nH]c1=O

Procedure:
Coupling of 1-[5-[2(S)-(2,4,6-trichloro-3-methoxyphenoxy)-propionamido]-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyluracil with N-Boc-L-valine in a manner analogous to that described in Example 1(A) gave 1-[3-O-[N-(tert-butoxycarbonyl)-L-valyl]-5-[2(S)-(2,4,6-trichloro-3-methoxyphenoxy)-propionamido]-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyluracil as a white solid, m.p. 147°-149° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:40]=[CH:39][C:24]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([OH:38])=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[C:23]([F:41])[CH:22]=1.[C:42]([O:46][C:47]([NH:49][CH2:50][CH2:51][CH2:52]O)=[O:48])([CH3:45])([CH3:44])[CH3:43].N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[C:42]([O:46][C:47]([NH:49][CH2:50][CH2:51][CH2:52][O:38][C:32]1[CH:31]=[C:30]2[C:35]([C:26]([NH:25][C:24]3[CH:39]=[CH:40][C:21]([Cl:20])=[CH:22][C:23]=3[F:41])=[N:27][CH:28]=[N:29]2)=[CH:34][C:33]=1[O:36][CH3:37])=[O:48])([CH3:45])([CH3:44])[CH3:43]
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
Triphenylphosphine (2.46 g, 9.3 mmol) was added to a suspension of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (1.0 g, 3.1 mmol), (prepared as described for the starting material in Example 2), in methylene chloride (25 ml) and the suspension stirred at 0° C. for 30 minutes. A solution of 3-(N-tert-butoxycarbonylamino)-1-propanol (0.65 g, 3.7 mmol) in methylene chloride (3 ml) was added and then diethyl azodicarboxylate (1.47 ml, 7.6 mmol) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred for 18 hours. The reaction mixture was diluted with methylene chloride and washed with aqueous sodium hydrogen carbonate solution, water and then brine. The resultant solution was dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol/triethylamine (100/0/0 and then 95/4/1) to give 7-(3-(N-tert-butoxycarbonylamino)propoxy)-4-(4chloro-2-fluoroanilino)-6-methoxyquinazoline (620 mg, 42%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([F:23])[CH:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:24][C:14]1[CH:13]=[CH:12][C:11]2[N:10]([N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([F:23])[CH:18]=2)[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1ccc(-c2nn3ccccc3c2-c2ccnc(F)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nn3cc(Br)ccc3c2-c2ccnc(F)c2)cc1
Temperature: 60 °C

Procedure:
To a solution of 2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridine (Example 27. 937 mg, 3.05 mmol) in DMF (20 mL) was added N-bromosuccinimide (651 mg, 3.66 mmol). The reaction mixture was heated at 60° C. for about 5 h and then allowed to cool to room temperature. Saturated sodium bicarbonate was added and the mixture was extracted with dichloromethane. The organic extracts were dried (MgSO4) and the solvents removed under vacuum. The residue was purified by silica gel chromatography to give the title compound. 0.604 g (50%). 1H NMR (CDCl3) δ 8.68 (s, 1H), 8.20 (d, 1H, J=5.4 Hz), 7.53 (m, 3H), 7.35 (dd, 1H, J=9.3, 1.2 Hz), 7.10 (m, 3H), 7.00 (s, 1H). MS (ES+ve) 387 (50, M+, M+3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([C@@H:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[C:36]([O:38]C)=[O:37])=[O:30])=[CH:25][CH:24]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:14][C:12]=2[N:13]=1>C1COCC1.O1CCOCC1.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([C@@H:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[C:36]([OH:38])=[O:37])=[O:30])=[CH:25][CH:24]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][C:19]([F:21])([F:20])[F:22])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(OC(F)(F)F)cc4s3)c(F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(OC(F)(F)F)cc4s3)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
In 250-mL round-bottom flask, methyl (1R,2R)-2-[(3′-fluoro-4′-{[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino}-1,1′-biphenyl-4-yl)carbonyl]cyclopentanecarboxylate (2.53 g, 4.53 mmol) was dissolved in 100 mL of 1:1 THF/dioxane containing 5.0 molar equivalents of 1 N aqueous NaOH. The mixture was stirred at rt overnight. The mixture was concentrated under reduced pressure to a volume of about 20 mL. Ethyl acetate (100 mL), water (30 mL), and 5.1 molar equivalents of 1 N aqueous HCl were added to the mixture. The mixture was transferred to a separation funnel. The organic layer was washed with water (1×50 mL), dried (Na2SO4), and concentrated under reduced pressure. The solid was ultrasonicated in 30 mL acetonitrile and filtered to give the desired compound as a white solid (1.96 g, 80%, 94.5% ee). 1H NMR (400 MHz, DMSO-d6) δ 12.20 (br s, 1 H), 10.60 (bs, 1 H), 8.70 (t, 1 H), 7.60–8.20 (m, 8 H), 7.30 (d, 2 H), 4.70 (q, 1 H), 3.20 (q, 1 H), 2.20 (m, 1 H), 2.00 (m, 1 H), 1.50–1.90 (m, 4 H); LC-MS m/z 545.3 (MH+), ret. time 3.93 min.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36]>>[NH2:26][C:24]1[C:25]2=[C:17]([C:14]3[CH:15]=[CH:16][C:10]4[S:9][C:8]([CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[N:12][C:11]=4[CH:13]=3)[CH:18]=[C:19]([CH:27]3[CH2:32][CH2:31][N:30]([CH2:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH2:29][CH2:28]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: CN(C)C(=O)CCl
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4sc(Cc5ccccc5)nc4c3)c12
Product: CN(C)C(=O)CN1CCC(c2cc(-c3ccc4sc(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Yield: 36.2 %

Procedure:
In a manner similar to the procedure described for the preparation of Example 355 and using 5-(2-benzyl-1,3-benzothiazol-5-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and 2-chloro-N,N-dimethylacetamide as starting material, 21.6 mg (36.2%) of the desired product was isolated. 1H NMR (400 MHz, CD2Cl2) δ 8.06 (s, 1H), 7.92 (d, 1H), 7.91 (s, 1H), 7.49 (d, 1H), 7.43-7.36 (m, 5H), 6.59 (s, 1H), 5.43 (s, 2H), 4.47 (s, 2H), 3.32-3.23 (m, 1H), 3.21 (s, 2H), 3.10 (s, 3H), 3.09-3.03 (m, 2H), 2.92 (s, 3H), 2.40-2.32 (m, 2H), 2.16-2.12 (m, 2H), 1.94-1.82 (m, 2H); LC-MS m/z[M+H]+ 526.2, RT 2.30 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:15])=[CH:4][C:5]([Cl:14])=[C:6]([CH:13]=1)[C:7](N(OC)C)=[O:8].[CH2:16]([C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1)[CH3:17]>O1CCCC1>[Br:1][C:2]1[C:3]([F:15])=[CH:4][C:5]([Cl:14])=[C:6]([C:7]([C:21]2[CH:22]=[CH:23][C:18]([CH2:16][CH3:17])=[CH:19][CH:20]=2)=[O:8])[CH:13]=1
Reactant: CON(C)C(=O)c1cc(Br)c(F)cc1Cl
Reactant: CCc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CCc1ccc(C(=O)c2cc(Br)c(F)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a solution of 5-bromo-2-chloro-4-fluoro-N-methoxy-N-methylbenzamide (936 mg, 3.17 mmol) in tetrahydrofuran (15 mL) was added (4-ethylphenyl)magnesium bromide (9.5 mmol, 9.5 mL, 1 M in tetrahydrofuran) at 0° C. The mixture was stirred at 25° C. for 1 hour, then the reaction was quenched with saturated ammonium chloride, and most of the tetrahydrofuran was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water; the organic layer was separated, washed with water, then with brine, and dried over sodium sulfate. The sample was concentrated and then purified by preparative thin layer chromatography (petroleum ether:ethyl acetate, 4:1) to provide pure product 31a as a white solid (995 mg, 88% yield). 1H-NMR (CDCl3, 400 MHz): δ 7.71 (d, J=8.4 Hz, 2H), 7.58 (d, J=6.8 Hz, 1H), 7.31 (d, J=8.4 Hz, 2H), 7.26 (d, J=6.8 Hz, 1H), 2.73 (q, J=8 Hz, 2H), 1.27 (t, J=8 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[CH2:32]([O:34][CH2:35][CH2:36][N:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]=[C:38]1[N:46]1[CH2:52][CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)[CH3:33]>ClCCl.CO>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:49]2[CH2:50][CH2:51][CH2:52][N:46]([C:38]3[N:37]([CH2:36][CH2:35][O:34][CH2:32][CH3:33])[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=4[N:39]=3)[CH2:47][CH2:48]2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8]1)=[O:6]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1ccc(OC)c(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)c1
Agent: I
Solvent: CO
Solvent: ClCCl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 102.1.2 using 1-(2,5-dimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) (0.55 g, 1.27 mmol) and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (0.71 g, 1.3 mmol) to give, after chromatography on silica gel eluting with dichloromethane/methanol/concentrated aqueous ammonia 95/5/0.05, the title compound: Rf=0.85 (silica gel, dichloromethane/methanol/concentrated aqueous ammonia 90/10/0.1).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[NH2:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C:18]3=[O:23])=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[NH2:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH2:3][C:2]#[CH:1])[CH2:19][C:18]3=[O:23])=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: C#CCBr
Reactant: Nc1ncnc2cc(CN3CCNCC3=O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C#CCN1CCN(Cc2ccc3c(N)ncnc3c2)C(=O)C1
Reaction time: 0.25 h
Yield: 67.7 %

Procedure:
Propargyl bromide (0.29 g, 1.95 mmol) is added to a solution containing 1-(4-amino-quinazolin-7-ylmethyl)-piperazin-2-one (0.5 g, 1.95 mmol), EXAMPLE 72, and K2CO3 (0.40 g, 2.93 mmol) in DMSO (10 mL) at ambient temperature. After 15 min, the reaction mixture is partitioned between aqueous NaHCO3 (100 mL) and CH2Cl2 (100 mL) and the layers are separated. The aqueous phase is subsequently saturated with NaCl and extracted three times with CHCl3 (50 mL). The combined organic phase is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified by flash silica gel chromatography (CH2Cl2 to 10% MeOH/CH2Cl2) to provide 390 mg (68%) of the title compound as a white solid. 1H NMR (300 MHz, CDCl3) δ2.68 (m, 1H), 3.13-3.37 (m, 6H), 4.07 (app q, J=5.2 Hz, 1H), 4.63 (s, 2H), 7.28 (dd, J=8.4, 1.4 Hz, 1H), 7.42 (s, 1H), 7.72 (br s, 2H), 8.14 (d, J=8.4 Hz, 1H), 8.34 (s, 1H) ppm; MS (ISP loop): m/z 296 (M+H).