Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:5]=2[N:4]([CH2:20][CH3:21])[C:3]1=[O:22].C(N(S(F)(F)[F:29])CC)C.O>C(Cl)Cl>[F:29][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:5]=2[N:4]([CH2:20][CH3:21])[C:3]1=[O:22]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCN1C(=O)C(O)N=C(c2ccccc2)c2cc(Cl)ccc21
Solvent: O
Solvent: ClCCl
Product: CCN1C(=O)C(F)N=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 0 °C
Yield: 57.1 %

Procedure:
A solution of 3.5 g (0.01 mol) of 3-hydroxy-1,3-dihydro-1-ethyl-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one in 7 ml of anhydrous methylene chloride was added dropwise to a stirred solution of 3.53 ml (0.028 mol) of diethylaminosulfur trifluoride in 84 ml of anhydrous methylene chloride cooled to -70°. The reaction mixture was allowed to warm slowly to 5° and then poured into 150 ml of ice and water. The lower organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure to give 2.84 g (90% yield) of crude product as light yellow crystals. Recrystallization from 200 ml of heptane gave 1.81 g (57% yield) of 3-fluoro-1,3-dihydro-1-ethyl-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one: mp 156°-158°; 1H nmr (DMSO-d6) δ 7.2-7.8 ppm (m, 8H), δ 5.85 ppm (d, 1H, J=57 Hz), δ 3.5-4.38 (m, 2H, methylene protons on nitrogen), δ 1.02 (t, 3H).
Reaction SMILES: C(O[N:4]=[CH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]1[CH:16]=[C:17]([C:21]([NH:23][CH:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)=[O:22])[CH:18]=[CH:19][CH:20]=1)C.[NH2:33][NH:34][C:35](=O)[CH2:36][N:37]([CH3:39])[CH3:38].C[O-].[Na+]>CO>[CH3:38][N:37]([CH2:36][C:35]1[N:4]=[C:5]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][N:10]=[C:9]3[C:15]2[CH:16]=[C:17]([C:21]([NH:23][CH:24]3[CH2:25][C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:32]3)=[O:22])[CH:18]=[CH:19][CH:20]=2)[NH:33][N:34]=1)[CH3:39]
Reactant: CCON=Cc1ccc2[nH]nc(-c3cccc(C(=O)NC4Cc5ccccc5C4)c3)c2c1
Reactant: CN(C)CC(=O)NN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1n[nH]c(-c2ccc3[nH]nc(-c4cccc(C(=O)NC5Cc6ccccc6C5)c4)c3c2)n1

Procedure:
The title compound was prepared according to the procedure of Example 367 C using (3-[5-(ethoxyiminomethyl)(1H-indazol-3-yl)]phenyl)-N-indan-2-ylcarboxamide.2HCl (360 mg, 0.72 mmol), N-amino-2-(dimethylamino) acetamide (254 mg, 2.17 mmol) and sodium methoxide (415 μL of a 25% w/w in methanol) in anhydrous methanol (4.0 mL) with a reaction time of 48 h. Purification of the residue by preparatory TLC using 50% ethyl acetate in methanol gave the desired product which was further purified by precipitation from methanol and ethyl acetate with hexanes and ethyl ether to give the title compound (86 mg, 25% yield) as a colorless powder 1H NMR (DMSO-d6) δ 13.9 (br s, 1H), 13.4 (br s, 1H), 8.85 (d, 1H), 8.6 (br s, 1H), 8.45 (s, 1H), 8.1–8.0 (m, 2H), 7.7–7.6 (m, 2H), 7.3–7.1 (m, 4H), 4.8–4.7 (m, 1H), 3.6 (br s, 2H), 3.25 (dd, 2H), 3.0 (dd, 2H), 2.2 (s, 6H); ES-MS (m/z) 478 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1

Procedure:
The title compound was prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert-butyl ester [CAS-No. 335255-65-7] (227 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K3) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow viscous oil (356 mg).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH3:10])[CH:6]=[CH:7][CH:8]=1.[BH4-].[Na+].[NH3:16]>C(O)C>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]([NH2:16])[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: N
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(N)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
Into a 150 mL 3-necked round bottom flask, was placed ethanol (25 mL). NH3 gas was added at 0° C. The mixture was stirred for 1 h at 0° C. Into a 150-mL sealed tube, was placed a solution of 1-(3-(trifluoromethyl)phenyl)ethanone (2 g, 10.64 mmol, 1.00 equiv) in ethanol (5 mL), and Ti[OCH(CH3)2]4 (6.04 g, 21.13 mmol, 2.00 equiv). This was followed by the addition of the above solution of NH3 (gas) in ethanol (25 mL). The mixture was stirred overnight at 48° C. To this was added NaBH4 (600 mg, 15.79 mmol, 1.48 equiv). The resulting solution was stirred for 3 h at room temperature. The resulting solution was diluted with 10 mL of ammonia and the solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (50:1). The product was obtained as 1 g (50%) of a yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[C:3]([N:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10](B3OC(C)(C)C(C)(C)O3)[CH:11]=2)[C@H:6]1[CH3:23])=[O:4].Br[C:27]1[C:36]([O:37][CH:38]([F:40])[F:39])=[C:35]2[C:30]([C:31](=[O:49])[C:32]([C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:33][N:34]2[CH:41]2[CH2:43][CH2:42]2)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C.[Pd].CC(C)=O>[CH:41]1([N:34]2[C:35]3[C:30](=[CH:29][CH:28]=[C:27]([C:10]4[CH:11]=[C:12]5[C:7](=[CH:8][CH:9]=4)[C@@H:6]([CH3:23])[N:5]([C:3](=[O:4])[C:2]([CH3:1])([CH3:24])[CH3:25])[CH2:13]5)[C:36]=3[O:37][CH:38]([F:40])[F:39])[C:31](=[O:49])[C:32]([C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:33]2)[CH2:42][CH2:43]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(Br)ccc2c1=O
Reactant: C[C@@H]1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN1C(=O)C(C)(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(-c3ccc4c(c3)CN(C(=O)C(C)(C)C)[C@@H]4C)ccc2c1=O
Yield: 96 %

Procedure:
In 15 ml of ethanol is dissolved 2.5 g of (R)-2-(2,2-dimethylpropanoyl)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline, and thereto are added 2.8 g of ethyl 7-bromo-1-cyclopropyl-8-difluoromethoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylate and 1.1 g of sodium carbonate. Subsequently, 150 mg of 10% palladium-activated carbon is added to the mixture in a nitrogen atmosphere and thereafter the resulting mixture is heated under reflux for 3 hours in the same atmosphere. The reaction mixture is cooled and thereafter added to a mixed solvent of 15 ml of water and 30 ml of acetone, and the crystals deposited are collected by filtration to obtain 3.6 g of ethyl (R)-1-cyclopropyl-8-difluoromethoxy-7-[2-(2,2-dimethylpropanoyl)-1-methyl-2,3-dihydro-1H-5-isoindolyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH3:6])(=[O:5])=[O:4].C(#N)C.Cl[C:11]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:14]([C:24]([O:26][CH3:27])=[O:25])=[C:13]([CH:28]([CH3:30])[CH3:29])[N:12]=1>O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[C:14]([C:24]([O:26][CH3:27])=[O:25])=[C:13]([CH:28]([CH3:30])[CH3:29])[N:12]=[C:11]([N:2]([CH3:1])[S:3]([CH3:6])(=[O:5])=[O:4])[N:16]=2)=[CH:18][CH:19]=1
Reactant: CNS(C)(=O)=O
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nc(Cl)nc1C(C)C
Solvent: CC#N
Solvent: O
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Temperature: 81.5 °C
Yield: 88.9 %

Procedure:
In a 25 mL-volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 546 mg (5 mmol.) of N-methylmethanesulfonamide, 551 mg (5 mmol.) of sodium t-pentoxide, 10 mL of acetonitrile, and 309 mg (1 mmol.) of 2-chloro-4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonylpyrimidine. The mixture was heated to 81-82° C. for 3 hours under refluxing, to carry out reaction. After the reaction was complete, the reaction mixture was cooled to room temperature. To the cooled mixture was added 10 mL of water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate portion was separated, and dried over anhydrous magnesium sulfate. The dried ethyl acetate portion was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (column: Wako Gel C-200, eluent: hexane/ethyl acetate (2:1, volume ratio)). There was obtained 339 mg of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesul-fonylamino)pyrimidine. The yield was 89% (based on the amount of 2-chloro-4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonylpyrimidine).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[N:29]1[CH2:34][CH2:33][O:32][C:31]2[CH:35]=[C:36]([S:39](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:41])=[O:40])[CH:37]=[CH:38][C:30]1=2.C(O)(=O)C>C1COCC1>[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=[CH:21][C:20]=1[N:29]1[CH2:34][CH2:33][O:32][C:31]2[CH:35]=[C:36]([S:39]([NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][N:3]=3)(=[O:40])=[O:41])[CH:37]=[CH:38][C:30]1=2
Reactant: Nc1ccncn1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ccncn1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Cl
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 10.9 %

Procedure:
A sealable vial was charged with 4-aminopyrimidine (0.101 g, 1.067 mmol) sealed with a septa cap and placed under an N2 atmosphere. THF (2 mL) was added and the solution was cooled to −78° C. Lithium bis(trimethylsilyl)amide, 1.0 M in THF (1.067 mL, 1.067 mmol) was added dropwise and the solution was maintained at −78° C. for 15 min. Perfluorophenyl 4-(2-chloro-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (INTERMEDIATE F, 0.543 g, 0.970 mmol) was added as a solution in THF (3 mL) and the solution was allowed to warm to rt, and the mixture was stirred for 40 min. To the solution was added acetic acid (0.2 mL) to provide a bright yellow/orange mixture. The mixture was concentrated to dryness. The residue was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (40 g), eluting with a gradient of 10% to 100% EtOAc in heptane, to provide 4-(2-chloro-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.050 g, 0.106 mmol) as tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.60-3.84 (m, 2 H) 4.24-4.48 (m, 2 H) 6.32 (d, J=8.51 Hz, 1 H) 6.98-7.05 (m, 1 H) 7.24-7.31 (m, 1 H) 7.34 (s, 1 H) 7.71-7.79 (m, 1 H) 7.82-7.89 (m, 1 H) 8.03-8.11 (m, 1 H) 8.31-8.43 (m, 1 H) 8.56-8.75 (m, 1 H). m/z (ESI) 471.0 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)=[C:13]([CH2:32][CH2:33][CH2:34][CH3:35])[N:12]=[C:11]2[CH3:36])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].C(OCC)(=O)C.O>C(O)C>[CH2:32]([C:13]1[N:12]=[C:11]([CH3:36])[N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([OH:3])[CH3:2])[CH:5]=2)[C:15](=[O:16])[C:14]=1[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:22][CH:23]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCc1nc(C)n(-c2cccc(C(C)=O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCCCc1nc(C)n(-c2cccc(C(C)O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 3 h

Procedure:
To a solution of 4′-{[1-(3-acetylphenyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (2.20 g) in ethanol (20 mL) was added sodium tetrahydroboron (0.18 g), and the mixture was stirred for 3 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.86 g, 84%).
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]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:29]1([C:35]2[O:39][C:38]([NH2:40])=[N:37][N:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[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][N:37]4[N:36]=[C:35]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[O:39][C:38]4=[NH:40])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Nc1nnc(-c2ccccc2)o1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Cn4nc(-c5ccccc5)oc4=N)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 3, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 5-phenyl-[1,3,4]oxadiazol-2-ylamine.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[CH:26])[CH2:20][CH2:19][C:18]4([O:24][CH2:23][CH2:22][O:21]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>N1CCCCC1.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[C:26][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:20][CH2:19][C:18]4([O:21][CH2:22][CH2:23][O:24]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Brc1ccncc1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC2(CC1)OCCO2
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCNCC1
Product: COc1ccc(C2(C#Cc3ccncc3)CCC3(CC2)OCCO3)cc1OC1CCCC1
Yield: 90.6 %

Procedure:
To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-1,1-(ethylenedioxy)cyclohexane (0.10 g, 0.28 mmol) and 4-bromopyridine (0.54 g, 2.8 mmol) in piperidine (1.5 mL) under an argon atmosphere were added tetrakis(triphenyl-phosphine)palladium(0) (0.013 g, 4%), copper(I) iodide (0.004 g, 6%) and a small crystal of triphenylphosphine, and the mixture was heated at 80°-85° C. for 0.5 h. Water was added, the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate),and was evaporated. Purification by flash chromatography, eluting with 35:65 ethyl acetate:hexanes, provided 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridylethynyl)-1,1-(ethylenedioxy)cyclohexane as a pale yellow oil (0.11 g, 93%). 1H-NMR (400 MHz, CDCl3) δ 8.56 (d, J=5.3 Hz, 2H), 7.33 (d, J=5.3 Hz, 2H), 7.16 (d, J=2.2 Hz, 1H), 7.09 (dd, J=8.5, 2.2 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 4.80 (m, 1H), 4.00 (m, 4H), 3.85 (s, 3H), 2.0-2.2 (m, 6H), 1.8-2.0 (m, 8H), 1.59 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=[O:2].[H][H]>[Pt].CN1CCOCC1>[O:10]([C:5]1[C:4]([NH:1][OH:2])=[CH:9][CH:8]=[CH:7][N:6]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1cccnc1Oc1ccccc1
Reactant: [H][H]
Agent: [Pt]
Solvent: CN1CCOCC1
Product: ONc1cccnc1Oc1ccccc1

Procedure:
A mixture of 9.2 g (43 mmol) of 3-nitro-2-phenoxypyridine (Example 1.a) and 100 ml of N-methylmorpholine was hydrogenated at room temperature (approximately 25° C.) and an H2 pressure of approximately 1.1 bar in the presence of 1 g of 5% platinum/charcoal (51% water; manufactured by Degussa). The hydrogen uptake ceased after approximately 2 hours. The catalyst was removed by filtration through active charcoal. The resulting solution was freed from solvent under reduced pressure ("high vacuum"). This gave 7.8 g (90%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:29]2[N:28]=[C:27]([C:20]3[C:21]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:18][CH:19]=3)[CH:32]=[CH:31][N:30]=2)[CH2:4][CH2:3]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: CN1CCC(N)CC1
Product: CN1CCC(Nc2nccc(-c3c[nH]c4ncccc34)n2)CC1
Yield: 40.9 %

Procedure:
Using the procedure of example 1, 1-methylpiperidin-4-ylamine (30 mg) was reacted with compound 1f (30 mg) to provide compound 61 (10.2 mg, 41%). 1H NMR (300 MHz, CD3OD) δ 8.92 (d, 1 H), 8.23 (d, 1 H), 8.15 (s, 1 H), 8.10 (d, 1 H), 7.25 (m, 1 H), 7.00 (d, 1 H), 3.96 (m, 1 H), 3.05 (m, 2 H), 2.45 (m, 2 H), 2.15 (m, 2 H), 1.95 (s, 3 H), 1.75 (m, 2H). MS (ESI) m/z: 309 (M+H)+.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[NH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:30])[C:5]([C:3]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 54.6 %

Procedure:
A mixture of 1,3-dibenzyl-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.088 mmol), β-alanine (624 mg, 7.0 mmol) and NaOMe solution (10.5 mL, 5.3 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (5-50% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 22 mg of the title compound as a light yellow solid. MS: (+) m/z 458.36 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]([CH:14]3[CH2:16][CH2:15]3)[C:11]([C@@H:17]([NH:19]C(OC(C)(C)C)=O)[CH3:18])=[N:10][C:9]=2[CH:8]=[CH:7][C:6]=1[F:27])=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]([CH:14]3[CH2:16][CH2:15]3)[C:11]([C@@H:17]([NH2:19])[CH3:18])=[N:10][C:9]=2[CH:8]=[CH:7][C:6]=1[F:27])=[O:4]
Reactant: COC(=O)c1c(F)ccc2nc([C@H](C)NC(=O)OC(C)(C)C)n(C3CC3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(F)ccc2nc([C@H](C)N)n(C3CC3)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-((S)-1-tert-butoxycarbonylaminoethyl)-3-cyclopropyl-5-fluoro-3H-benzoimidazole-4-carboxylic acid methyl ester (698 mg, 1.85 mmol) in DCM (3 mL) was added TFA (3 mL) and the reaction mixture stirred at RT for 2 h. The crude mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford 2-((S)-1-aminoethyl)-3-cyclopropyl-5-fluoro-3H-benzoimidazole-4-carboxylic acid methyl ester as a yellow oil. The resulting residue was treated with 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (486 mg, 2.03 mmol) and DIPEA (970 μL, 5.55 mmol) in n-butanol (3 mL). The reaction mixture was heated in a sealed vial for 20 h at 100° C. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) to afford the title compound (780 mg, 88% over 2 steps). LCMS (Method C): RT 2.91 min [M+H]+ 480.22.
Reaction SMILES: [C:1]1([S:7]([NH:10][CH2:11][CH2:12][S:13][CH:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][O:17][C:16]3[CH:25]=[CH:26][C:27]([C:29]([O:31]C)=[O:30])=[CH:28][C:15]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[C:1]1([S:7]([NH:10][CH2:11][CH2:12][S:13][CH:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][O:17][C:16]3[CH:25]=[CH:26][C:27]([C:29]([OH:31])=[O:30])=[CH:28][C:15]2=3)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2c(c1)C(SCCNS(=O)(=O)c1ccccc1)c1ccccc1CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(c1)C(SCCNS(=O)(=O)c1ccccc1)c1ccccc1CO2

Procedure:
Compound 1a, 9.90 g, obtained in Example 1 was dissolved in a solvent mixture of 200 ml of methanol and 20 ml of water and 2.70 g of sodium hydoxide was added to the solution. The mixture was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure and the resulting residue was dissolved in 200 ml of water. A pH was adjusted to 1.5 with 4N hydrochloric acid aqueous solution. The crystallized crude product was taken out by filtration and dried. The crude product was recrystallized from 300 ml of isopropanol to give 6.44 g of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=2)[OH:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1>C(Cl)Cl.O=[Mn]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=2)=[O:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(OC)cc(C(O)c2ccc(OC)c(F)c2)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1cc(OC)cc(C(=O)c2ccc(OC)c(F)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (3,5-dimethoxy-phenyl)-(3-fluoro-4-methoxy-phenyl)-methanol from above and activated MnO2 (10 g, 115 mmol) in methylene chloride (60 mL) was stirred at room temperature for 18 h. More MnO2 (7 g) was added and kept for overnight. The suspension was filtered thru a pad of Celite. Removal of solvent gave (3,5-dimethoxy-phenyl)-(3-fluoro-4-methoxy-phenyl)-methanone as an off-white solid (3.13 g, 56% yield 2 steps). The sample was used in the next step without further purification.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:33])[CH:21]([O:24][C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=2[CH3:32])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:51])[C@@H:15]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si](C(C)(C)C)(C)C)[CH2:37]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:33])[CH:21]([O:24][C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=2[CH3:32])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:51])[C@@H:15]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([OH:43])[CH2:37]2)=[CH:10]1
Reactant: CCC(Oc1cc(C)ccc1C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(Oc1cc(C)ccc1C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 21.9 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 1.32 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(2,5-dimethylphenoxy)butyryloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 52, above] and 43.0 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 0.20 g of the title compound as white crystals, melting at between 138° and 140° C.