Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[CH3:3][O:4][C:5]([CH:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1)=[O:6].[NH4+].[Cl-].C(Cl)Cl.C1[CH2:23][O:22][CH2:21]C1>CCCCCC.O>[CH3:3][O:4][C:5]([CH:7]1[CH2:12][CH2:11][C:10](=[CH:21][O:22][CH3:23])[CH2:9][CH2:8]1)=[O:6]
Reactant: COC(=O)C1CCC(=O)CC1
Reactant: C1CCOC1
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: O
Product: COC=C1CCC(C(=O)OC)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A 2 L three-necked flask equipped with thermometer, stirrer, liquid sealing, N2 protection and drying tube was used. 285.4 g of MTC and 400 ml of THF were added. The flask was placed into a tank with cold bath at −15° C., to obtain a white suspension. The temperature was controlled to be between −5° C. and −10° C., and a solution of 93.3 g of t-BUOK in 400 ml of THF was added dropwise. The colour was changed into bright orange firstly, and then changed gradually into dark. After the completion of addition by dropwise, the reaction was conducted for 0.5 hour. A solution of 100 g of 4-keto-cyclohexyl formic acid methyl ester in 100 ml of THF was added dropwise at a temperature of between −5° C. and −10° C., with the colour faded gradually. After the completion of addition, the cooling was shut off, the temperature was raised naturally to about 0° C. and the reaction was conducted for 1 hour under thermal retardation. A 200 ml aqueous solution of 10 g NH4Cl was added, and the temperature was controlled to be less than 10° C. 500 ml of CH2Cl2 was added for extraction. If there is undissolved substance, a small amount of water was added to dissolve it, and washed with water till neutrality. The organic phase was tan in color, dried with anhydrous Na2SO4, and the solvent was removed by a rotary evaporator, so as to obtain a liquid-solid mixture. 500 ml of n-hexane was added, pumping filtrated, and leached with 100 ml of n-hexane twice. The filtrate was passed through a silicagel column, and the solvent was removed by a rotary evaporator, to obtain 113.5 g of pale yellow liquid. Yield: 96%, GC purity: 95.9%.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=2)=[CH:5][CH:4]=[N:3]1.C1C(=O)N([I:23])C(=O)C1>C1COCC1>[I:23][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1cc(-c2ccnn2C)cs1
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2c(I)cnn2C)cs1
Temperature: 75 °C
Reaction time: 10 h
Yield: 42.9 %

Procedure:
To a solution of methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (700 mg, 3.15 mmol) in THF (5 mL) was added NIS (922 mg, 4.09 mmol) in one portion. The reaction mixture was stirred at 75° C. for 10 h, and then cooled to room temperature. The reaction mixture was concentrated and purified on silica gel (EtOAc/Hex 10-20%) to give the title compound (470 mg, 43%) as an off white solid: LC-MS (ES) m/z 350 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([NH2:16])[C:6]=2[CH:17]=1.[IH:18].CS[C:21]1[NH:22][CH2:23][CH2:24][N:25]=1.CCOCC>C(O)C>[IH:18].[NH:22]1[CH2:23][CH2:24][NH:25][C:21]1=[N:16][CH:7]1[C:6]2[CH:17]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[CH:11]=[CH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]1=2
Reactant: CSC1=NCCN1
Reactant: NC1c2ccccc2C=Cc2ccc(Br)cc21
Agent: I
Solvent: CCO
Solvent: CCOCC
Product: Brc1ccc2c(c1)C(N=C1NCCN1)c1ccccc1C=C2

Procedure:
6.90 grams (0.024 mole) of 3-bromo-5H-dibenzo[a,d]cycloheptene-5-ylamine, 2.95 grams (0.012 mole) of 2-methylmercapto-4,5-dihydroimidazole hydroiodide, and 65 milliliters of absolute ethanol were stirred together and refluxed for 28 hours. At the end of this period, the solvent was evaporated under reduced pressure and the residue triturated with five 100 milliliter portions of diethyl ether to obtain a purified residue. The purified residue was dissolved in 20 milliliters of absolute ethanol and 300 milliliters of ether added thereto whereupon a solid precipitated. The mixture was stirred thoroughly, the solvent decanted to obtain a residue which was placed on a Still-silica column and eluted with 5 percent methanol in chloroform. The eluted fractions were examined by thin layer chromatography (TLC), the homogeneous TLC fractions combined, and the solvent then vaporized to obtain the desired N-(2-imidazolidinylidene)-3-bromo-5H-dibenzo[a,d]cyclohepten-5-amine hydroiodide product as residue. The product was crystallized from chloroform to obtain purified product, m.p. 240°-241° C. (dec.). Elemental analyses were as follows: Calc'd for C18H17BrIN3 : C, 44.84; H, 3.55; N, 8.72. Found: C, 44.75; H, 3.48; N, 8.46.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH:22]([C:24]([NH2:26])=O)[O:21][C:20]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:19]=2[CH:39]=1.N1C=CC=CC=1>O1CCOCC1>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH:22]([C:24]#[N:26])[O:21][C:20]([CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]3)([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:19]=2[CH:39]=1
Reactant: NC(=O)C1Oc2ccc(Cl)cc2C(C2CCCCC2)(C2CCCCC2)O1
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#CC1Oc2ccc(Cl)cc2C(C2CCCCC2)(C2CCCCC2)O1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
4.19 ml Trifluoroacetic anhydride is added dropwise to a solution of 3.25 g 6-chloro-4,4-dicyclohexyl-4H-benzo[1,3]dioxine-2-carboxylic amide and 1.7 ml pyridine in 29 ml dioxane at 0° C. The reaction was stirred for 30 min at 0° C. and for 4 h at room temperature. The reaction mixture was then poured on ice water and stirred for 30 min. The precipitate was filtered, washed with water and dried over P2O5 under vaccum. Yield: 2.95 g.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([N:25]([CH:39]([CH3:41])[CH3:40])[C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]3)=[O:24])[CH:21]=2)[C:16]([CH3:43])([CH3:42])[C:15]1=[O:44])=O)C1C=CC=CC=1>[Pd].CO>[NH2:11][CH2:12][CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([N:25]([CH:39]([CH3:40])[CH3:41])[C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:27]3)=[O:24])[CH:21]=2)[C:16]([CH3:42])([CH3:43])[C:15]1=[O:44]
Reactant: CC(C)N(C(=O)c1ccc2c(c1)N(CCNC(=O)OCc1ccccc1)C(=O)C2(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)N(C(=O)c1ccc2c(c1)N(CCN)C(=O)C2(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl (3R)-3-[{[1-(2-{[(benzyloxy)carbonyl]amino}ethyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (800 mg) were added 10% Pd/C (400 mg) and methanol (30 ml), and the mixture was stirred at room temperature under hydrogen atmosphere for 2 hours. After the reaction was complete, the mixture was filtered and concentrated. The obtained residue (600 mg) was used in the subsequent reaction without further treatment.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[CH:34][C:6]([C:7]([O:22][CH2:23][C@H:24]2[O:29][CH2:28][C@H:27]([N:30]=[N+]=[N-])[CH2:26][C@@H:25]2[OH:33])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>N1C=CC=CC=1.N>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]([O:22][CH2:23][C@H:24]2[O:29][CH2:28][C@H:27]([NH2:30])[CH2:26][C@@H:25]2[OH:33])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:35][CH:34]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(C(OC[C@H]2OC[C@H](N=[N+]=[N-])C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2OC[C@H](N)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.9 %

Procedure:
1.1 g (2.3 mmole) of 6-O-DMT-1,5-anhydro-2-azido-2,3-dideoxy-D-glucitol (12) were dissolved in 11 ml of pyridine and 9 ml of 32% aqueous ammonia, then 1.0 g (3.9 mmole) of triphenylphosphane are added. The reaction mixture was stirred for 18 h at r.t. Thereafter the reaction mixture was evaporated. The residue was dissolved in 180 ml of ethyl acetate und washed twice with 100 ml of 5% sodium hydrogencarbonate solution. Organic layer was separated, dried over sodium sulfate, filtered and evaporated to dryness. The residue was dissolved in 5 ml of ethyl acetate and purified by flash-chromatography over silica gel (ethyl acetate/methanol/1% triethylamine gradient). Product fractions were combined, evaporated and dried at high vacuum to yield 0.94 g (91%) of a colorless foam.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])C.C1(P(C2CCCCC2)C2C=CC=CC=2C2[C:37]([O:38][CH3:39])=[CH:36][CH:35]=CC=2OC)CCCCC1.COCC=CB1OC(C)(C)C(C)(C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Na+].Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)C.O1CCCC1>[CH3:39][O:38][CH2:37]/[CH:36]=[CH:35]/[C:15]1[CH:16]=[CH:17][C:12]([N:9]2[C:10]([CH3:11])=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)=[N:13][CH:14]=1
Reactant: CCOC(=O)c1cnn(-c2ccc(Br)cn2)c1C
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COCC=CB1OC(C)(C)C(C)(C)O1
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COC/C=C/c1ccc(-n2ncc(C(=O)O)c2C)nc1
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 549.6 %

Procedure:
Tetrahydrofuran (4 ml) was added to 1-(5-bromopyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (620 mg) described in Reference Example 24(2), palladium (II) acetate (45 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos) (82 mg), 3-methoxy-1-propenylboronic acid pinacol ester (594 μl) and tripotassium phosphate (1.0 g), and stirred at 100° C. for 4.5 hours. Then, water (5 ml), 4N aqueous solution of sodium hydroxide (5 ml) and ethanol (5 ml) were added to the reaction solution and the mixture was stirred at 80° C. for two hours. The reaction solution was acidified by the addition of water and 1N hydrochloric acid aqueous solution, extracted with ethyl acetate and the solvent was evaporated in vacuo. The resulting solid was washed with water to give the titled compound (300 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].[NH4+].[C:35]([O:38][CH2:39]C)(=[O:37])C>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH3:39][O:38][C:35](=[O:37])[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(Br)cc2)c2ccccc2C)ccn1
Reactant: CCOC(C)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc([C@@H](CC(=O)c2ccnc(C)c2)c2ccccc2C)cc1
Temperature: 130 °C
Reaction time: 20 h
Yield: 87 %

Procedure:
To a solution of (R)-3-(4-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (example 142, step 2, 100 mg) in methanol (1.5 mL) and ethyl acetate (1.5 mL) were added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (10 mg), triethylamine (53.3 μL) at room temperature. The reaction mixture was stirred at 130° C. for 20 h under a carbon monoxide atmosphere (70 bar). A saturated aq. solution of ammonium chloride was added, the phases were separated and the inorganic one was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (ethyl acetate/n-heptane 0:1 to 1:0) to yield the title compound as a colourless oil (95 mg, 87%), MS (ESI+): m/z=374.1 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][C:8]([C:11]([O:13]C)=[O:12])=[CH:7][C:6]=2[C:5]([O:15][CH3:16])=[CH:4][CH:3]=1.[OH-].[Na+].CO>O>[F:1][C:2]1[C:10]2[S:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:6]=2[C:5]([O:15][CH3:16])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2c(OC)ccc(F)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(F)c2sc(C(=O)O)cc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
A mixture of methyl 7-fluoro-4-methoxy-1-benzothiophene-2-carboxylate (67.2 g, 280 mmol), sodium hydroxide (45 g, 1.12 mol), methanol (800 mL) and water (400 mL) were stirred at ambient overnight. The methanol was evaporated and the mixture cooled to 0° C. Acidified with concentrated hydrochloric acid and stirred for 20 mins. The yellow solid was filtered, washing with water (3×100 mL). Dried under vacuum at 45° C. overnight, over phosphorus pentoxide to give the title compound (61.4 g, 97%); δH (300 MHz, d6-DMSO) 8.10 (1H, d, ArH) 7.44 (1H, t, ArH) 7.00 (1H, m, ArH) and 4.02 (3H, s, OCH3).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:10]1[C@@:14]2([CH3:29])[CH2:15][CH2:16][C@@H:17]3[C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:21]4=[CH:20][CH:19]=[C:18]3[C@@H:13]2[CH2:12][CH2:11]1)/[CH:3]=[CH:4]/[C@@H:5]([CH:7]([CH3:9])[CH3:8])[CH3:6].[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>N1C=CC=CC=1>[CH3:1][C@@H:2]([C@@H:10]1[C@@:14]2([CH3:29])[CH2:15][CH2:16][C@@H:17]3[C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:21]4=[CH:20][CH:19]=[C:18]3[C@@H:13]2[CH2:12][CH2:11]1)/[CH:3]=[CH:4]/[C@@H:5]([CH:7]([CH3:8])[CH3:9])[CH3:6].[S:36]([C:33]1[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=1)([O-:27])(=[O:38])=[O:37]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)[C@@H](C)/C=C/[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
reacting ergosterol with p-toluenesulfonyl chloride in pyridine to obtain ergosterol tosylate;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[C:13](O)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:29][CH:28]=1.ClCCl.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[C:13]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:31][CH:32]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: O=C(O)[C@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc(Cl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(NC(=O)[C@H](Cc2c[nH]c3ccccc23)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 68.3 %

Procedure:
The procedure described in Example 180 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-3-(3-indolyl) propanoic acid (5 g) and ethyl 4-aminophenylacetate (2.36 g) were condensed in a mixed solvent of dichloromethane (100 ml) and acetonitrile (10 ml) in the presence of N,N'-dicyclohexylcarbodiimide (3.27 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from ethanol/acetonitrile (10/1) to obtain (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(3-indolyl)propanamide (4.86 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:20]([O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)[CH3:21].C(=O)([O-])[O-].[Na+].[Na+].CC1CCCO1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.C(#N)C>[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([NH:9][C:10]3[N:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:13]=[CH:12][N:11]=3)[CH:3]=2)[CH:26]=[CH:27][CH:28]=1)[CH3:21]
Reactant: Cc1cc(Br)cc(Nc2nccc(C(F)(F)F)n2)c1
Reactant: CCOc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CC1CCCO1
Solvent: CC#N
Product: CCOc1cccc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of N-(3-bromo-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine (70 mg, 0.211 mmol), (3-ethoxyphenyl)boronic acid (70.1 mg, 0.422 mmol), PdCl2(dppf)-CH2Cl2 adduct (34.4 mg, 0.042 mmol), aqueous sodium carbonate (2 M, 211 μL, 0.422 mmol), and 2-methyltetrahydrofuran (1054 μl) was heated to 60° C. for 14 hours. Upon cooling to room temperature, Si-Dimercaptotriazine (222 mg, 0.126 mmol) and acetonitrile (3 mL) were added to reaction mixture and stirred for 4 hours at room temperature. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by mass triggered reverse phase HPLC (57-91% acetonitrile in water+0.1% formic acid) to afford N-(3′-ethoxy-5-methylbiphenyl-3-yl)-4-(trifluoromethyl)pyrimidin-2-amine MS ESI calc'd. for C20H19F3N3O [M+H]+ 374, found 374. 1H NMR (600 MHz, DMSO) δ 10.17 (s, 1H), 8.79 (d, J=4.8 Hz, 1H), 7.89 (s, 1H), 7.48 (s, 1H), 7.32 (t, J=7.9 Hz, 1H), 7.23 (d, J=4.8 Hz, 1H), 7.14 (d, J=7.8 Hz, 1H), 7.12 (s, 1H), 7.09 (d, J=2.0 Hz, 1H), 6.88 (dd, J=2.2 Hz, 8.1 Hz, 1H), 4.05 (t, J=7.0 Hz, 2H), 2.32 (s, 3H), 1.32 (t, J=7.0 Hz, 3H).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:16]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].[ClH:29].O>C(O)C.ClCCl>[ClH:29].[C:21]1([C:17]2[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=2)[O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOc2cccc(-c3ccccc3)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCOc2cccc(-c3ccccc3)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above ester (1.4 g, 4 mmol) was dissolved in ethanol (30 ml) and 4N sodium hydroxide (4.5 ml) was added. The mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo to give a residue to which dichloromethane (175 ml) was added. The mixture was placed on an icebath and concentrated hydrochloric acid (2.1 ml) was added. The phases were separated and the organic phase was dried (Na2SO4). The solvent was evaporated in vacuo to give a residue which was dissolved in a mixture of dichloromethane (175 ml) and a small portion of water. The phases were separated and the organic phase was dried (Na2SO4). The solvent was evaporated in vacuo to give 0.4 g of the title compound as an oil.
Reaction SMILES: [OH-].[Na+:2].C([O:5][C:6](=[O:22])[CH2:7][C:8]1[N:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:9]=1)C>C1COCC1>[CH3:15][O:14][C:12]1[CH:11]=[C:10]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[N:9]=[C:8]([CH2:7][C:6]([O-:22])=[O:5])[N:13]=1.[Na+:2]
Reactant: CCOC(=O)Cc1nc(OC)cc(N2CCOCC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(N2CCOCC2)nc(CC(=O)[O-])n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
8.8 ml of 1N sodium hydroxide are added to a solution of 2.5 g of (4-methoxy-6-morpholin-4-ylpyrimidin-2-yl)acetic acid ethyl ester in 15 ml of THF. The reaction medium is stirred at ambient temperature for 48 hours and then concentrated under reduced pressure. After oven-drying under vacuum, 2.4 g of sodium (4-methoxy-6-morpholin-4-yl-pyrimidin-2-yl)acetate are obtained, which will be used as it is in the next step.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][CH2:23][O:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][CH2:23][O:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCC(OCCONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(OCCONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)CC1
Reaction time: 2 h
Yield: 99 %

Procedure:
A mixture of tert-butyl 4-{2-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethoxy}piperidine-1-carboxylate 72 (0.270 g, 0.521 mmol) and Pd/C (0.270 g) in methanol (25 mL) was hydrogenated at 35 psi at room temperature for 2 h. The mixture was filtered through a Celite pad and concentrated to provide 73 (0.221 g, 99%) as a light grey solid.
Reaction SMILES: [Cl:1][CH:2]([O:6][N:7]=[CH:8][C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].CO.[CH3:18]S(O)(=O)=O>ClCCCl>[Cl:1][CH:2]([O:6][N:7]=[CH:8][C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH3:18])=[O:4]
Reactant: CS(=O)(=O)O
Reactant: O=C(O)C(Cl)ON=Cc1ccccc1Cl
Solvent: CO
Solvent: ClCCCl
Product: COC(=O)C(Cl)ON=Cc1ccccc1Cl

Procedure:
A mixture of 12.4 gm. (0.050 mole) of 2,6-dichlorobenzylideneaminooxyacetic acid, 4.8 gm. (0.150 mole) of methanol and about 0.8 gm. of methanesulfonic acid in 15 ml. of 1,2-dichloroethane was refluxed for 15-16 hours. The cooled reaction mixture was then washed with cold, aqueous sodium bicarbonate, followed by a cold water wash. The organic phase was then concentrated under reduced pressure and at a mixture bath temperature of about 60° C. The resulting oil solidified on cooling. There were obtained 12.5 gm. (96%) of product melting at 58°-65° C. Purification by high vacuum distillation yielded material which, when allowed to crystallize, melted at 60°-62° C. (uncorrected).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:20][CH:21]([CH3:23])[CH3:22])=[C:4]([CH:17]([OH:19])[CH3:18])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15].C([N+](CCC)(CCC)CCC)CC.C[N+]1([O-])CCOCC1>>[Cl:1][C:2]1[C:3]([O:20][CH:21]([CH3:23])[CH3:22])=[C:4]([C:17](=[O:19])[CH3:18])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:12])([CH3:13])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)Oc1c(C(C)O)cc2c(c1Cl)OC(C)(C)C=C2C(C)C
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Product: CC(=O)c1cc2c(c(Cl)c1OC(C)C)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure M, 1-(8-chloro-7-isopropoxy-4-isopropyl-2,2-dimethyl-2H-chromene-6-yl)-ethanol (Compound 138, 0.92 g, 2.7 mmol), tetrapropylammonium perrunthenate (TPAP, 0.047 g, 0.14 mmol), and 4-methylmorpholine N-oxide (NMO, 0.47 g, 4.1 mmol) were reacted to give the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:28][C:29](=[O:42])[CH:30]([N:35]([CH3:41])[CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:31][CH:32]([CH3:34])[CH3:33])[C:17](=[O:27])NCCN2CCOCC2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:43][CH2:44][C:45]([NH2:48])([CH3:47])[CH3:46].[N-]=C=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:28][C:29](=[O:42])[CH:30]([N:35]([CH3:41])[CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:31][CH:32]([CH3:34])[CH3:33])[C:17](=[O:27])[NH:48][C:45]([CH3:47])([CH3:46])[CH2:44][OH:43])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCN(C)C(CC(C)C)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NCCN1CCOCC1
Reactant: CC(C)(N)CO
Agent: [N-]=C=O
Solvent: ClCCl
Product: CC(C)CCN(C)C(CC(C)C)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)CO
Reaction time: 48 h

Procedure:
A suspension of N-(2-methylbutyl)-N-methyl-leucine-tyrosine(OBn)-Kaiser oxime resin (Example 57, IIc) in CH2Cl2 was treated with 1.5 equivalents of 2-hydroxy-1,1-dimethylethylamine. The suspension was shaken for 48 hours. After the reaction was completed, additional CH2Cl2 and 1 equivalent of polymer supported isocyanate was added. After the suspension was shaken for 48 hours, the resin was filtered off, and the solvent was evaporated to yield the title product.