Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:26]3[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]3)=[N:23][N:24]=2)[CH:3]=1.[CH3:35][O:36][C:37]1[C:42]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][N:38]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:33][CH:32]([N:29]1[CH2:30][CH2:31][N:26]([CH2:25][C:22]2[O:21][C:20]([C:4]3[CH:3]=[C:2]([C:40]4[CH:41]=[C:42]([NH:43][S:44]([CH3:47])(=[O:45])=[O:46])[C:37]([O:36][CH3:35])=[N:38][CH:39]=4)[CH:10]=[C:9]4[C:5]=3[CH:6]=[N:7][N:8]4[S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[N:24][N:23]=2)[CH2:27][CH2:28]1)[CH3:34]
Reactant: CC(C)N1CCN(Cc2nnc(-c3cc(Br)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)CC1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncc(-c2cc(-c3nnc(CN4CCN(C(C)C)CC4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(C)(=O)=O
Temperature: 60 °C
Yield: 100 %

Procedure:
To a solution of 6-bromo-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-(phenylsulfonyl)-1H-indazole (100 mg, 0.183 mmol) in 1,4-dioxane (2.5 ml) and water (0.250 ml) was added N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (78 mg, 0.238 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (26.8 mg, 0.037 mmol) and potassium phosphate tribasic (117 mg, 0.550 mmol). The mixture was heated under microwave irradiation at 60° C. for 10 min, then the solvent was removed in vacuo and the residue partitioned between dichloromethane (5 ml) and water (5 ml), separated by hydrophobic frit and purified by silica (5 g) cartridge using a gradient of dichloromethane and methanol to give the title compound as a brown solid (122 mg).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: FC(F)(F)c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Reactant: c1c[nH]cn1
Product: FC(F)(F)c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-trifluoromethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-trifluoromethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH2:18][OH:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2]
Reactant: CCCN(C)C(=O)c1cc(CO)cc(C(=O)OCC)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CCCN(C)C(=O)c1cc(C=O)cc(C(=O)OCC)c1
Temperature: 32 °C
Reaction time: 0.33 h
Yield: 90.6 %

Procedure:
Add a solution of 5-hydroxymethyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (600 mg, 2.15 mmol) dropwise to a mixture of Dess-Martin periodinane (1.06 g, 2.5 mmol) in dichloromethane (6.5 mL). Stir the exothermic reaction mixture (32° C.) for 20 min without additional heat. To the reaction mixture add diethyl ether (12 mL) and saturated aqueous sodium bicarbonate (12 mL). Separate the layers and wash the aqueous layer with diethyl ether (2×12 mL). Combine the organics and wash with saturated aqueous sodium bicarbonate (12 mL), saturated aqueous sodium chloride (12 mL), dry (magnesium sulfate), concentrate, and purify (silica gel chromatography, eluting with 50:50 ethyl acetate:hexanes) to give the title compound as an oil (0.54 g, 91%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:13]([CH3:15])[CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH2:16]([O:18][P:19](C1C=CC(C(C)C(OC)=O)=CC=1)([O:21][CH2:22][CH3:23])=[O:20])[CH3:17]>>[CH2:16]([O:18][P:19]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:13]([CH3:15])[CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1)([O:21][CH2:22][CH3:23])=[O:20])[CH3:17]
Reactant: CCOP(=O)(OCC)c1ccc(C(C)C(=O)OC)cc1
Reactant: COC(=O)C(c1ccc(Br)cc1)C(C)C
Product: CCOP(=O)(OCC)c1ccc(C(C(=O)OC)C(C)C)cc1

Procedure:
Compound 13-c was prepared from 13-b in a similar manner as the synthesis of 7-f. 1H NMR (300 MHz, CDCl3) δ0.69 (d, J=6.6 Hz, 3H), 1.04 (d, J=6.6 Hz, 3H), 1.20-1.39 (m, 6H), 2.31-2.39 (m, 1H), 3.17-3.23 (m, 1H), 4.04-4.20 (m, 4H), 7.42-7.45 (m, 2H), 7.71-7.78 (m, 2H). LC-MS: (M+H)+ 329.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[C:12]3=[CH:19][CH:20]=[CH:21][C:22]([C:23]([NH:25][NH2:26])=[O:24])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:27](OC(OCC)OCC)C>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[C:12]3[CH:19]=[CH:20][CH:21]=[C:22]([C:23]4[O:24][CH:27]=[N:26][N:25]=4)[C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)c1cccc2c1nc(Nc1cccc(Cl)c1)c1ccncc12
Reactant: CCOC(OCC)OCC
Product: Clc1cccc(Nc2nc3c(-c4nnco4)cccc3c3cnccc23)c1

Procedure:
5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-7-carbohydrazide (24 mg) was stirred in triethylorthoformate (1 ml) at 120° C. for 4 hours. The solid was filtered and triturated in CH2Cl2/MeOH. Impurities (mainly starting material) were removed by filtration and the filtrate containing the expecting compound was concentrated. The material was purified by preparative TLC on silica gel (5% methanol in CH2Cl2) to afford N-(3-chlorophenyl)-7-(1,3,4-oxadiazol-2-yl)benzo[c][2,6]naphthyridin-5-amine as a solid (8 mg). LCMS (ES): >95% pure, m/z 374 [M+1]+.
Reaction SMILES: [OH:1][CH:2]([CH2:22][CH3:23])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:21][C:20]3[CH2:19][NH:18][CH2:17][C:16]=3[CH2:15]2)=[CH:12][CH:13]=1)=[O:7].FC(F)(F)C([O-])=O.[Br:31][C:32]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:33]=1[C:34](O)=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[OH:1][CH:2]([CH2:22][CH3:23])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:21][C:20]3[CH2:19][N:18]([C:34](=[O:35])[C:33]4[CH:37]=[C:38]([O:41][CH3:42])[CH:39]=[CH:40][C:32]=4[Br:31])[CH2:17][C:16]=3[CH2:15]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CCC(O)CCNC(=O)c1ccc(N2CC3=C(CNC3)C2)nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Product: CCC(O)CCNC(=O)c1ccc(N2CC3=C(CN(C(=O)c4cc(OC)ccc4Br)C3)C2)nn1

Procedure:
N-(3-Hydroxypentyl)-6-(3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl)pyridazine-3-carboxamide, trifluoroacetate (466 mg, 0.464 mmol) were reacted with 2-bromo-5-methoxybenzoic acid after activation with HATU analogously to example 3f. M+H+: 530.02.
Reaction SMILES: CNC1CCCCC1NC.O1CCOCC1.Br[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1/[CH:24]=[C:25]1/[C:26](=[O:37])[C:27]2[C:32]([CH2:33][CH2:34]/1)=[CH:31][C:30]([O:35][CH3:36])=[CH:29][CH:28]=2.[Na+].[I-:39]>[Cu]I.O>[I:39][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1/[CH:24]=[C:25]1/[C:26](=[O:37])[C:27]2[C:32]([CH2:33][CH2:34]/1)=[CH:31][C:30]([O:35][CH3:36])=[CH:29][CH:28]=2
Reactant: COc1ccc2c(c1)CC/C(=C\c1ccncc1Br)C2=O
Reactant: [I-]
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2c(c1)CC/C(=C\c1ccncc1I)C2=O
Temperature: 110 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
In a Schlenk tube, N,N′-dimethyl-1,2-cyclohexanediamine 85% (32 μL, 0.20 mmol) and dioxane (2 mL) were added to a mixture of CuI (19.2 mg, 0.1 mmol), compound 87 (688 mg, 2.0 mmol) and NaI (600 mg, 4.00 mmol). The Schlenk tube was sealed with a Teflon cap and the reaction mixture was stirred at 110° C. for 24 h. After cooling, the resulting suspension was poured into water (20 mL), and extracted with dichloromethane (3×). The combined organic phases were dried over magnesium sulfate and concentrated to dryness. The product was allowed to crystallize at room temperature. The residue was purified by column chromatography on SiO2 (gradient of EtOAc in petroleum ether) to afford the title compound 88 as a yellow solid (Yield 703.8 mg, 90%).
Reaction SMILES: [C:1]([N:5]([C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([N:5]([C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(=O)N(c1ccccc1[N+](=O)[O-])C(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(=O)N(c1ccccc1N)C(C)(C)C

Procedure:
A solution of N-tert-butyl-N-ethoxalyl-2-nitroaniline (45 g) in absolute ethanol (500 ml) was hydrogenated at standard conditions (1 atm.) using 5% Pd/C (5 g) as catalyst. The catalyst was filtered off and the solvent was removed in vacuo. This left an oil, which crystallized upon standing, m.p. 64°-65° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[CH:11]=[C:10](Cl)[CH:9]=[CH:8][N:7]=1)=[O:5].[CH3:13][OH:14]>>[CH3:2][O:3][C:4]([C:6]1[CH:11]=[C:10]([O:14][CH3:13])[CH:9]=[CH:8][N:7]=1)=[O:5]
Reactant: COC(=O)c1cc(Cl)ccn1
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(OC)ccn1
Yield: 88 %

Procedure:
4-Chloropyridine-2-carboxylic acid methyl ester hydrochloride (25 g, 0.12 mol) was dissolved in methanol (200 ml) and heated at reflux for 66 h. The solvent was evaporated and the residue partitioned between dichloromethane and saturated sodium hydrogencarbonate solution. The organic layer was washed with brine, dried over sodium sulphate and concentrated to give 4-methoxypyridine-2-carboxylic acid methyl ester (17.6 g, 88%) as a yellow crystalline solid. 1H NMR (360 MHz, CDCl3) δH 3.91 (3H, s), 4.02 (3H, s), 6.98 (1H, dd, J 3 and 6), 7.67 (1H, d, J 3), 8.54 (1H, d, J 6).
Reaction SMILES: [NH:1]([CH2:3][C:4]([O-:6])=[O:5])[CH3:2].[Na+].COS(O)(=O)=O.CO[C:16](=[NH:18])[NH2:17]>>[O:5]=[C:4]([CH2:3][N:1]([C:16](=[NH:17])[NH2:18])[CH3:2])[OH:6]
Reactant: COC(=N)N
Reactant: CNCC(=O)[O-]
Agent: COS(=O)(=O)O
Agent: [Na+]
Product: CN(CC(=O)O)C(=N)N

Procedure:
JP 077364 describes the reaction of a solution of sodium sarcosinate with O-methylisourea methyl sulfate at pH 11 to give creatine.
Reaction SMILES: C(=O)=O.[H-].[Na+].[CH2:6]([OH:9])[CH2:7][CH3:8].[C:10]([Si:14]([CH3:17])([CH3:16])Cl)([CH3:13])([CH3:12])[CH3:11]>C1COCC1>[C:10]([Si:14]([CH3:17])([CH3:16])[O:9][CH2:6][CH2:7][CH3:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCO
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a dry-ice cooled suspension of 4.0 g of sodium hydride (60% dispersion in mineral oil) in 80 ml of anhydrous THF was dropwise added a solution of 7.44 ml of 1-propanol in 30 ml of the same solvent, and the mixture was slowly warmed to room temperature with continued stirring for 1 hr under nitrogen. A solution of 15.0 g of t-butyldimethylchlorosilane in 40 ml of THF was slowly added by syringe and continued stirring for 3 hr at room temperature. After distillation of the solvent, house vacuum distillation afforded the pure t-butyldimethyl-n-propoxysilane as a colorless liquid (106° C./house vacuum, 12.0 g, 69.2%). 1HNMR (CDCl3): δ 0.05 (s, 6H), 0.88 (t, J=7.5Hz, 3H), 0.89 (s, 9H), 1.53 (sextet, 2H), 3.56 (t, J=6.6 Hz, 2H). 13C-NMR (CDCl3): δ−5.08 (2C), 10.47 (1C), 18.58 (1C), 26.17 (3C), 26.21 (1C), 65.13 (1 C).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([S:23][CH3:24])[C:20]=1[O:21]C)[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[CH2:8]1)=[O:6].[Cl-].[Li+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([S:23][CH3:24])[C:20]=1[OH:21])[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[CH2:8]1)=[O:6]
Reactant: COc1c(Cl)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1SC
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CSc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(Cl)c1O
Temperature: 120 °C
Reaction time: 20 h
Yield: 86.4 %

Procedure:
3-(3-chloro-4-methoxy-5-methylsulfanylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (203 mg) was dissolved in N,N-dimethylformamide (2 mL), and lithium chloride (258 mg) was added to the solution, and then the mixture was stirred at 120° C. for 20 hours. To the reaction solution, 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized from n-hexane-diethylether to obtain the title compound (169 mg) as a brown crystal.
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH2:12]([OH:15])[C:13]#[CH:14].C(N(CC)CC)C>CCOC(C)=O>[CH2:12]([O:15][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2)[C:13]#[CH:14]
Reactant: C#CCO
Reactant: BrC12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#CCOC12CC3CC(CC(C3)C1)C2
Yield: 100.9 %

Procedure:
A mixture of 1-bromoadamantane (10.8 g, 50.2 mmol), propargyl alcohol (30 ml, 515 mmol) and triethylamine (7.0 ml, 50.3 mmol) were heated at reflux for 4 hours. The reaction mixture was diluted with EtOAc (70 ml) and was washed sequentially with water (100 ml) and brine (100 ml). The organic phase was dried over magnesium sulfate and the filtrate was evaporated to give the title compound (9.64 g, 100%). 1H NMR (CDCl3) 4.14 (2H, d, J=2.4 Hz), 2.36 (1H, t, J=2.4), 2.16 (3H, s), 1.80-1.79 (6H, m), 1.67-1.57 (6H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:8]([Br:22])[S:7][CH:6]=1)=[O:4].Cl.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]Cl)[CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[C:9]([N:10]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:30][C:26]2[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=2)=[C:8]([Br:22])[S:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1csc(Br)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1csc(Br)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.8 %

Procedure:
To a solution of 4.80 g (11.82 mmol) of the product of Example 17 dissolved in 5.0 mL of DMF was added 2.04 g (12.41 mmol) of 3-picolyl chloride hydrochloride and 4.89 g (35.46 mmol) of potassium carbonate. The reaction mixture was then stirred at room temperature for 18 h, diluted with water and extracted with ether. The organics were then extracted with 6N HCl solution and the aqueous acid layer was then basified with 6N NaOH solution and then extracted with ether. The resulting ether layer was dried over sodium sulfate, filtered and concentrated in vacuo to provide 4.16 g (71%) of the desired product as a tan solid. Electrospray Mass Spec: 498 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[CH2:23][CH2:22]3)[C:4]=1[O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=O.[CH2:29]([NH2:32])[CH2:30][CH3:31].COC1C(OC)=CC=C(C2C=C3C(=CC=2)C(=O)CC3)C=1OCC(C)(C)C(NC)=O>>[CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[CH2:23][CH2:22]3)[C:4]=1[O:5][CH2:6][C:7]([CH3:11])([CH3:12])[C:8]([NH:32][CH2:29][CH2:30][CH3:31])=[O:10]
Reactant: COc1ccc(-c2ccc3c(c2)CCC3=O)c(OCC(C)(C)C(=O)O)c1OC
Reactant: CCCN
Agent: CNC(=O)C(C)(C)COc1c(-c2ccc3c(c2)CCC3=O)ccc(OC)c1OC
Product: CCCNC(=O)C(C)(C)COc1c(-c2ccc3c(c2)CCC3=O)ccc(OC)c1OC

Procedure:
From 3-[2,3-Dimethoxy-6-(1-oxo-indan-5-yl)-phenoxy]-2,2-dimethyl-propionic acid (Compound 205) and propan-1-amine following the procedure for preparation of Compound 206. Purification by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) afforded the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[NH2:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1>>[NH:14]1[C:13]([NH:12][C:9]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=2)=[O:11])=[N:17][N:16]=[N:15]1
Reactant: Cc1ccc(C)c(C(=O)O)n1
Reactant: Nc1nnn[nH]1
Product: Cc1ccc(C)c(C(=O)Nc2nnn[nH]2)n1
Yield: 62 %

Procedure:
0.76 g of 3,6-dimethyl-2-pyridinecarboxylic acid, 0.82 g of N,N'-carbonyldiimidazole and 0.51 g of 5-aminotetrazole are treated in the same manner as described in Example 2. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and ethanol, whereby 0.68 g of N-(5-tetrazolyl)-3,6-dimethyl-2-pyridinecarboxamide is obtained.
Reaction SMILES: C(N[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=1[Br:17])(=O)C(C)(C)C.Cl.[Na].N([O-])=O.[Na+].[I-:24].[Na+]>O1CCOCC1.O.C(Cl)Cl>[Br:17][C:9]1[C:10]([O:15][CH3:16])=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=1[I:24]
Reactant: [I-]
Reactant: COc1c(Cl)ccc(NC(=O)C(C)(C)C)c1Br
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1c(Cl)ccc(I)c1Br
Reaction time: 0.33 h
Yield: 50 %

Procedure:
A solution of N-pivaloyl-2-bromo-4-chloro-3-methoxyaniline (3.7 g, 1.2 mmol) in dioxane (35 mL) was treated with concentrated hydrochloric acid (35 mL) and the solution heated under reflux for 2 hours. After the solution was cooled the pH was adjusted to 10 by addition of sodium hyrdroxide (50% solution) and extracted with ethyl ether (2×50 mL). The combined extracts were washed with brine, dried (sodium sulfate) and concentrated. The crude aniline was dissolved in 2N hydrochloric acid and sodium nitrite (750 mg, 11 mmol) was added and the solution stirred for 20 minutes. This solution was poured into a vigorously stirred solution of sodium iodide (3.3 g, 22 mmol) in water (20 mL) and methylene chloride (30 mL) and stirred for 20 minutes. The solution was then extracted with methylene chloride (2×25 mL) and the combined extracts washed with brine, dried (sodium sulfate) and concentrated. The residue was purified by chromatography (hexanes) to give 2-bromo-4-chloro-1-iodo-3-methoxybenzene (1.5 g, 0.6 mmol): LC/MS (m/z=267).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][CH2:31][C:32](O)=[O:33])([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:35])[CH3:16])=[CH:11][CH:10]=1.[CH3:36][NH2:37]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][CH2:31][C:32]([NH:37][CH3:36])=[O:33])([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:35])[CH3:16])=[CH:11][CH:10]=1
Reactant: CN
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCC(=O)O)(c2ccc(F)cc2)OC1=O
Product: CNC(=O)CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanoic acid following a procedure analogous to that described in Example 76 using methylamine in place of ammonia. LC-MS Method 3 tR=1.249 min, m/z=497.2; 1H NMR (CD3OD) 1.51 (m, 3H), 1.97 (s, 1H), 2.07-2.31 (m, 6H), 2.64-2.74 (s, 3H), 2.94 (d, 1H), 5.62 (m, 1H), 6.13 (s, 1H), 6.79-6.89 (m, 2H), 6.97 (m, 4H), 7.15 (s, 2H), 7.23 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:11]2[CH:10]=[C:9]([Se:12][C:13]3[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:23]CC)=[O:22])=[CH:15][CH:14]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)=[CH:4][CH2:3]1.O.[OH-].[Li+]>>[CH3:1][C:2]1([CH3:33])[C:11]2[CH:10]=[C:9]([Se:12][C:13]3[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:4][CH2:3]1
Reactant: CCOC(=O)/C=C/c1ccc([Se]c2ccc3c(c2)C(C)(C)CC=C3c2ccc(C)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C2=CCC(C)(C)c3cc([Se]c4ccc(/C=C/C(=O)O)cc4)ccc32)cc1

Procedure:
In a manner similar to that of Example 1g, by reacting 0.11 g (0.23 mmol) of ethyl(E)-3-[4-(8,8-dimethyl-5-p-tolyl-7,8-dihydro-2-naphthylselanyl)phenyl]acrylate with 0.11 g (2.6 mmol) of lithium hydroxide hydrate, a yellow solid is obtained (0.08 g; yield=78%).
Reaction SMILES: O[C@@H:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.C1(P([N:30]=[N+:31]=[N-:32])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.CCOC(C)=O>[N:30]([C@H:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1)=[N+:31]=[N-:32]
Reactant: COC(=O)c1ccc2c(c1)OCC[C@@H]2O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)OCC[C@H]2N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 3 L three-neck round-bottomed flask equipped with argon inlet/outlet, thermometer, and magnetic stirring was added (S)-methyl 4-hydroxychroman-7-carboxylate (71 g, 340 mmol) in 800 mL of toluene. The reaction vessel was cooled with a ice/salt bath, and treated with a solution of diphenylphosphoryl azide (88 mL, 407 mmol, Aldrich) in 200 mL toluene (internal temp.=−4° C.). After 10 min, a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (61 mL, 407 mmol, Aldrich) in toluene (350 mL) was added over 30 min (the internal temperature did not exceed 1° C.). The reaction mixture was warmed to room temp and stirred for 40 h. The reaction mixture was diluted with 800 mL EtOAc and washed with 1 M H3PO4, water, 5% NaHCO3, and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (10:1 hexane-EtOAc) to provide the title compound. MS (+ion ESI) m/z=234 (MH+).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][S:18]([NH:21][CH3:22])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:4]=1)#[N:2].O1CCOCC1.CCO.[H][H]>[Pd].C(N(CC)CC)C>[NH2:2][CH2:1][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][S:18]([NH:21][CH3:22])(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH:4]=1
Reactant: [H][H]
Reactant: CNS(=O)(=O)Cc1ccc(Oc2cc(C#N)nc(C)n2)cc1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CNS(=O)(=O)Cc1ccc(Oc2cc(CN)nc(C)n2)cc1
Reaction time: 4.5 h
Yield: 52.3 %

Procedure:
Combine palladium (18.54 g, 10% on charcoal), 1-[4-(6-cyano-2-methyl-pyrimidin-4-yl)oxyphenyl]-N-methyl-methanesulfonamide (46.34 g, 141.19 mmol), 1,4-Dioxane (278 mL), EtOH (185 mL), and triethylamine (78.7 mL) in a PARR reactor. Seal the PARR reactor and charge it with hydrogen (400 psi). Shake the reactor at room temperature for 4.5 h. Open the reactor and filter the contents through CELITE®. Collect and evaporate the filtrate to provide the title compound as a yellow solid (23.8 g, 48%). MS (m/z): 323 (M+1). Wash the CELITE® pad with a mixture of 1,4-dioxane/MeOH (6×500 mL); collect the filtrate; and evaporate the solvent to provide a second crop of the title compound as a yellow solid (pinky solid, 48%). MS (m/z): 323 (M+1).