Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=4)=[CH:10]3)[C:6]=2[CH:22]=1.[CH:23]([N:26]1[CH2:31][CH2:30][CH:29]([SH:32])[CH2:28][CH2:27]1)([CH3:25])[CH3:24].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:23]([N:26]1[CH2:31][CH2:30][CH:29]([S:32][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[C:7](=[N:8][C:9]([C:15]5[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=5)=[CH:10]4)[C:6]=3[CH:22]=2)[CH2:28][CH2:27]1)([CH3:25])[CH3:24]
Reactant: Cc1ccnc(-c2cn3c(n2)-c2cc(Br)ccc2OCC3)c1
Reactant: CC(C)N1CCC(S)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccnc(-c2cn3c(n2)-c2cc(SC4CCN(C(C)C)CC4)ccc2OCC3)c1
Temperature: 120 °C
Yield: 77.3 %

Procedure:
A mixture of 9-bromo-2-(4-methylpyridin-2-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (147 mg, 0.411 mmol), 1-isopropylpiperidine-4-thiol (98 mg, 0.617 mmol), Pd2(dba)3 (19 mg, 5 mol %), XantPhos (24 mg, 10 mol %) and DIPEA (288 l, 1.64 mmol) in dioxane (5 mL) was purged with nitrogen and then heated at 120° C. for 1 h using microwave irradiation. The reaction mixture was then diluted with DCM (100 mL) and purified by column chromatography (Si-PCC, gradient 0-8% 2M NH3/MeOH in DCM followed by C18, gradient 10-50% MeOH in 0.5% TFA/H2O). The product containing fractions were combined and concentrated in vacuo and the resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The basic fractions were concentrated under reduced pressure affording the title compound as a colorless foam (138 mg, 77%). LCMS: RT1.79 min [M+H]+ 435.2
Reaction SMILES: [Na].C[O:3][C:4](=O)[CH2:5][C:6]1=[N:7][N:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:9](=[O:21])/[C:10]/1=[C:11](/[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)\[CH3:12].Cl>CC(O)C>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[N:8]1[C:9](=[O:21])[C:10]2=[C:11]([CH3:12])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:4](=[O:3])[CH:5]=[C:6]2[NH:7]1
Reactant: COC(=O)CC1=NN(c2ccccc2Cl)C(=O)/C1=C(\C)NCc1ccccn1
Agent: Cl
Agent: [Na]
Solvent: CC(C)O
Product: Cc1c2c(=O)n(-c3ccccc3Cl)[nH]c2cc(=O)n1Cc1ccccn1
Yield: 82 %

Procedure:
An isopropanolic solution of i-PrONa, obtained by dissolving of sodium (0.082 g, 3.57 mmol, 1 equiv) in i-PrOH (75 ml), was treated with methyl[(4E)-1-(2-chlorophenyl)-5-oxo-4-{1-[(pyridin-2-ylmethyl)amino]ethylidene}-4,5-dihydro-1H-pyrazol-3-yl]acetate (Compound of Formula (VIII) (1.42 g, 3.57 mmol, 1 equiv.). The reaction mixture was refluxed for 1 h, then cooled and neutralized to pH 7 by addition of 0.59 ml of a 20% aqueous HCl solution. 50 ml of i-PrOH were removed in vacuo and 25 ml of H2O were added before placing the flask in the fridge overnight. The white precipitate formed was filtered off, washed with water (2×5 ml), then with cyclohexane and dried in vacuo. 1.07 g of pure product 2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione was obtained. Yield 82%. 1H-NMR: (500 MHz, DMSO-d6, ppm): 2.78 (s, 3H), 5.41 (s, 2H), 5.66 (s, 1H), 7.31-7.28 (m, 1H), 7.32 (d, J=7.9 Hz, 1H), 7.50-7.47 (m, 2H), 7.60-7.56 (m, 1H), 7.66-7.64 (m, 1H), 7.79 (td, J 7.6, 1.9 Hz, 1H), 8.48 (m, 1H), 10.73 (s, br, 1H). MS (ESI+): 367.9; MS (ESI−): 365.7.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:17]=1)[C:10]([CH3:27])([CH3:26])[CH:9]2O)=[O:5])[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:17]=1)[C:10]([CH3:26])([CH3:27])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cccc(C(=O)OC)c1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)OC)c1)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.3 %

Procedure:
To a mixture of 4-hydroxy-2-(3-methoxycarbonyl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (13 g, 34 mmol) and triethylsilane (20 mL) at 25° C. was added trifluoroacetic acid (10 mL) dropwise. The resulting mixture was stirred at 25° C. for 2 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was triturated with methanol. The resulting precipitate was collected, dried in vacuo to afford 2-(3-methoxycarbonyl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.16 g, 25%) as a white solid: LC/MS m/e calcd for C22H25NO4 (M+H)+: 368.45, observed: 368.1.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.OO.C1C2C(=CC=CC=2)C=CC=1[OH:23]>>[C:9]1([OH:23])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: c1ccc2ccccc2c1
Agent: OO
Product: Oc1cccc2ccccc12

Procedure:
A process for the regioselective hydroxylation of naphthalene with hydrogen peroxide giving either α- or β-naphthol in high isomeric purity between about 92 and 98+% depending on the acid system employed to carry out the reaction which comprises reacting naphthalene with a molar excess of hydrogen peroxide in an acid system having an Ho acidity function of -11 or less to produce α-naphthol with an isomeric purity between about 92 and 98+% or in a superacidic system having an Ho acidity function in excess of -11 to produce β-naphthol with an isomeric purity between about 92 and 98+%.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])=[CH:19][CH:18]=2)=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.[K+].[Br-]>>[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[CH2:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][S:15][C:12]2[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:33])=[O:2])=[C:7]3[C:11]=2[CH2:10][CH2:9][CH2:8]3)=[CH:22][CH:21]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccc(F)cc3F)cc2)c2c1CCC2
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1ccc(SCc2ccc(OCc3ccc(F)cc3F)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 66A. mp 158-160° C.; IR (KBr) cm−1: 3065, 3043, 1751, 1510, 1433, 1239; 400 MHz 1H NMR (DMSO-d6): δ 12.94 (br(s), 1H), 7.51-7.61 (m, 1H), 7.21-7.30 (m, 1H); 7.01-7.16 (m, 4H) 6.83-6.92 (m, 2H), 6.57 (d, 1H, J=8.5 Hz), 5.01 (s, 2H), 4.61 (s, 2H), 3.94 (s, 2H), 2.76 (t, 2H, J=7.4 Hz), 2.68 (t, 2H, J=7.4 Hz), 1.90 (pentet, 2H); MS m/z 455 (M−1). Anal. Calc'd for C25H22F2O4S: C, 65.78; H, 4.86. found: C, 65.58; H, 4.83.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:3]=1[C:4]([N:6]=[S:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[O:5].C(=O)([O-])[O-].[K+].[K+].[Cl:26][C:27]1[C:28]([N:33]2[C:37]([C:38](Cl)=[O:39])=[CH:36][C:35]([C:41]([F:44])([F:43])[F:42])=[N:34]2)=[N:29][CH:30]=[CH:31][CH:32]=1.C(O)C>C1(C)C=CC=CC=1>[Cl:26][C:27]1[C:28]([N:33]2[C:37]([C:38]([NH:1][C:2]3[C:3]([C:4](=[O:5])[N:6]=[S:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:9])[CH3:10])=[CH:14][C:15]([Cl:19])=[CH:16][C:17]=3[Cl:18])=[O:39])=[CH:36][C:35]([C:41]([F:44])([F:42])[F:43])=[N:34]2)=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)S(=NC(=O)c1cc(Cl)cc(Cl)c1N)C(C)C
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)S(=NC(=O)c1cc(Cl)cc(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl)C(C)C
Reaction time: 6 h
Yield: 60.2 %

Procedure:
To a solution of the above obtained solution of 2-amino-3,5-dichloro-N-(bis-2-propyl-λ4-sulfanylidene)benzamide (6.7 mL; ˜3.6 mmol) was added potassium carbonate (0.60 g, 4.3 mmol, 1.20 equiv) and a solution of 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carbonyl chloride (1.34 g, 4.31 mmol, 1.20 equiv.) in toluene (10 mL) at room temperature. After 6 h at this temperature, the mixture poured onto water and treated with a small amount of ethanol under sonification. The resulting precipitate was collected by filtration, washed with water and diisopropyl ether and dried to obtain the title compound (1.29 g, 60%).
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[C:8]([C:14]#[N:15])[C:7]=1[Cl:16].[OH-:18].[Na+]>O>[C:14]([C:8]1[C:7]([Cl:16])=[C:6]([C:11]([Cl:12])=[CH:10][C:9]=1[Cl:13])[O:5][CH2:4][C:3]([OH:2])=[O:17])(=[O:18])[NH2:15]
Reactant: [OH-]
Reactant: COC(=O)COc1c(Cl)cc(Cl)c(C#N)c1Cl
Agent: [Na+]
Solvent: O
Product: NC(=O)c1c(Cl)cc(Cl)c(OCC(=O)O)c1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
29.4 g (0.1 mol) of 3-cyano-2,4,6-trichlorophenoxyacetic acid methyl ester are suspended in 300 ml of water. After addition of 35 ml of concentrated sodium hydroxide, the reaction mixture is heated at 60° C. until a clear solution is obtained. After filtration over active carbon, the solution is cooled and brought to pH 2 by dropwise addition of 50% concentrated hydrochloric acid. The mixture is stirred for 2 hours in an ice bath, after which the resultant precipitate is vacuum-filtered, washed with water and dried t 50° C., thus producing 25.4 g (85% of theory) of 3-carbamoyl-2,4,6-trichlorophenoxyacetic acid as a white powder, mp 261°-262° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15])=[O:7].[BH4-].[Li+].O.Cl>O1CCCC1>[OH:7][CH:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:15])=[O:16]
Reactant: NS(=O)(=O)c1ccccc1C(=O)c1cccs1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1C(O)c1cccs1
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
To a solution, at room temperature, of 0.5 g of the product of Example 3 dissolved in 30 mL of dry tetrahydrofuran was added 0.1 g of lithium tetrahydridoborate (LiBH4). After stirring for 0.5 hour, 30 mL of water was carefully added following by acidification with concentrated hydrochloric acid. The reaction was extracted with methylene chloride, washed with water and brine and dried (MgSO4). Filtration and concentration of the filtrate in vacuo afforded 0.5 g of the subject compound as a light green oil which was used as such in the following example.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([C:14](N2[C@@H](C(C)C)COC2=O)=[O:15])[CH2:11][C:12]#[N:13])=[C:6]([O:25][CH3:26])[CH:5]=1.OS([O-])(=O)=O.[K+].[O-]S([O-])(=O)=O.[Na+].[Na+]>O.C1COCC1>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([CH2:14][OH:15])[CH2:11][C:12]#[N:13])=[C:6]([O:25][CH3:26])[CH:5]=1
Reactant: COc1cc(Br)ccc1[C@H](CC#N)C(=O)N1C(=O)OC[C@@H]1C(C)C
Agent: O=S(=O)([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Br)ccc1[C@@H](CO)CC#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
A solution of sodium borohydride (389 mg) in water (1.82 mL) was added to a solution of (S)-3-(4-bromo-2-methoxy-phenyl)-4-((S)-4-isopropyl-2-oxo-oxazolidin-3-yl)-4-oxo-butyronitrile (749 mg, 1.895 mmol) in THF (6 mL) under nitrogen atmosphere. The mixture was stirred at room temperature for three hours. The reaction mixture was cooled to 0° C. and a solution of 10% KHSO4/Na2SO4 was carefully added. After the gas evolution stopped, the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified via flash chromatography (hexane/EtOAc, 7/3) to give 470 mg (92% yield) of (S)-3-(4-bromo-2-methoxy-phenyl)-4-hydroxy-butyronitrile.
Reaction SMILES: [Na:1].[CH3:2][C:3]1[C:4]([CH2:20][S:21]([C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)=[O:22])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]12[CH2:18][O:17][C:14]([CH3:19])([O:15][CH2:16]1)[O:13][CH2:12]2.[CH:32]1(C23OCC(CO)(CO2)CO3)C[CH2:33]1>>[Na:1].[CH:19]1([C:14]23[O:15][CH2:16][C:11]([CH2:10][O:9][C:8]4[CH:7]=[CH:6][N:5]=[C:4]([CH2:20][S:21]([C:23]5[NH:24][C:25]6[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=6[N:27]=5)=[O:22])[C:3]=4[CH3:2])([CH2:12][O:13]2)[CH2:18][O:17]3)[CH2:33][CH2:32]1
Reactant: Cc1c(OCC23COC(C)(OC2)OC3)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: OCC12COC(C3CC3)(OC1)OC2
Agent: [Na]
Product: Cc1c(OCC23COC(C4CC4)(OC2)OC3)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 3.2 %

Procedure:
The same procedure as in the steps (24b) to (24f) of Example 24 was repeated using (1-cyclopropyl-2,6,7-trioxabicyclo[2.2.2]oct-4-yl)methanol obtained in the step (37c) above to obtain the title compound (147 mg, total yield: 3.2%) as a light yellow solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[C:4]([O:6][CH3:7])=[O:5].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH:8]1([C@H:3]([N:2]=[C:14]=[O:16])[C:4]([O:6][CH3:7])=[O:5])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)[C@@H](N)C1CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H](N=C=O)C1CCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 215.8 %

Procedure:
A suspension of methyl (25)-amino(cyclopentyl)acetate hydrochloride (3.21 g, 16.57 mmol) in DCM (69 mL) and saturated NaHCO3(aq.) (132 mL) was cooled to 0° C. and treated with triphosgene (2.21 g, 7.46 mmol). The mixture was stirred at 0° C. for 3 hours, then warmed to 20° C. and diluted with DCM. The layers were separated, and the aqueous phase was re-extracted with DCM. The combined organic phases were washed with brine and dried over Na2SO4. Filtration and removal of the volatiles afforded the title compound (2.95 g, 97%) as an oily solid that was used directly in subsequent steps. 1H NMR (400 MHz, DMSO-d6) δ 4.36 (d, J=4.8 Hz, 1H), 3.73 (s, 1H), 2.35-2.24 (m, 1H), 1.76-1.24 (m, 8H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C)C=O>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]2[C:6](=[CH:7][N:8]([CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[N:9]=2)[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2nn(CCN3CCCC3)cc2c1
Temperature: 60 °C

Procedure:
A mixture of 5-Nitroindazole (1.00 g, 6.13 mmol) was dissolved in 20 mL of N,N-dimethylformamide and potassium carbonate (2.50 g, 18.1 mmol) was stirred for 30 minutes after which 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (1.56 g 9.17 mmol) was added. The mixture was heated to 60° C. for 6 hours, cooled to room temperature. The mixture was filtered through a plug of silica gel and rinsed with triethylamine/ethyl acetate (1/4) and the filtrate concentrated in vacuo. The residue was purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30). 1H NMR (300 MHz, DMSO-d6) ppm 1.64 (m, 4H), 2.48 (m, 4H), 2.99 (t, 2H, J=6.44), 4.62 (t, 2H, J=6.44), 7.78 (m, 1H), 8.00 (m, 1H), 8.83(m, 1H), 8.88 (m, 1H); MS (DCI/NH3) m/z 261 [M+H]+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:33][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][C:18]2[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=2[O:16][CH2:15][CH2:14][C@@H:9]2[CH2:10][C@@H:11]([OH:13])[CH2:12][N:8]2[CH3:6])[CH:31]=[CH:30][C:29]=1[F:32]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CCOc1ccc(F)cc1CCc1ccc(F)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C[C@H](O)C[C@H]1CCOc1ccc(F)cc1CCc1ccc(F)c(F)c1
Yield: 61.3 %

Procedure:
280 mg of (2R,4R)-1-t-butoxycarbonyl-2-[2-{2-[2-(3,4-difluorophenyl)-ethyl]-4-fluorophenoxy}ethyl]-4-hydroxypyrrolidine [prepared as described in step (b) above], 5 ml of tetrahydrofuran and 50 mg of lithium aluminum hydride were allowed to react together and subsequently treated in the same manner as described in step (b) of Example 1. The concentrated substance thus obtained was purified by silica gel column chromatography, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 140 mg (yield 63%) of the title compound as a colorless solid substance.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9](=[O:26])[C@@H:10]([NH:18]C(=O)OC(C)(C)C)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:5]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[N:4]1)[CH3:2].Cl>O1CCOCC1>[NH2:18][C@@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9]([NH:8][C:7]1[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[CH:6]=1)=[O:26]
Reactant: CCn1nc(-c2ccncc2)cc1NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCn1nc(-c2ccncc2)cc1NC(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
To a 25 ml flask was added tert-butyl (S)-1-(1-ethyl-3-(pyridin-4-yl)-1H-pyrazol-5-ylamino)-1-oxo-3-phenylpropan-2-ylcarbamate 101.1.A (568 mg, 1.30 mmole), 5 ml of 4N-hydrogen chloride solution in 1,4-dioxane, and 5 ml of 1,4-dioxane. The reaction was stirred at room temperature for 0.5 hours at which time the solvent was removed by rotary evaporation. The residue was suspended in ethyl acetate, and washed successively with saturated sodium bicarbonate, water and brine. The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo to give 101.1.B (380 mg, 87% yield) as colorless syrup. 1H NMR (400 MHz, CDCl3) δ ppm 9.71 (s, 1H), 8.61 (d, J=5.8 Hz, 2H), 7.69 (d, J=6.2 Hz, 2H), 7.39-7.26 (m, 5H), 6.88 (s, 1H), 4.07 (q, J=7.2 Hz, 2H), 3.85 (dd, J=8.8, 4.1 Hz, 1H), 3.36 (dd, J=13.8, 4.1 Hz, 1H), 2.93 (dd, J=13.9, 8.8 Hz, 1H), 2.96 (brs, 2H), 1.45 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:27])[NH:12][C:13]1[C:14]([CH3:26])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[C:20]([F:25])[CH:19]=1)[CH3:9].[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:26])[C:13]=3[NH:12][C:11]([O:10][C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:27])=[CH:19][C:20]=2[F:25])=[CH:35][CH:34]=1)[CH3:29]
Reactant: Cc1noc(-c2ccc(Br)c(F)c2)c1NC(=O)O[C@H](C)c1ccccc1Cl
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3Cl)cc2F)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-3-fluoro-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide (4′-{4-[(R)-1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-2′-fluoro-biphenyl-4-yl)-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 36, Step 7.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH3:21][N:22]1[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][C:23]1=[O:31]>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:28]([C:25]3[CH:26]=[CH:27][N:22]([CH3:21])[C:23](=[O:31])[CH:24]=3)=[O:29])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: Cn1ccc(C(=O)O)cc1=O
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: Cn1ccc(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1=O

Procedure:
Methyl-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 1-methyl-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid. MS calcd. for C23H19ClN3O3 [(M+H)+] 420.1, obsd. 420.0.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1>CO.[H][H].[Pd]>[N:5]1[C:4]2[NH:8][CH:9]=[CH:10][C:3]=2[CH:2]=[N:7][CH:6]=1
Reactant: [H][H]
Reactant: Clc1ncnc2[nH]ccc12
Agent: [Pd]
Solvent: CO
Product: c1ncc2cc[nH]c2n1
Yield: 99.1 %

Procedure:
As shown in FIG. 1—step i, 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (compound 1001) (130 mg, 0.847 mmol) was dissolved in 3 mL of methanol and hydrogenated under 1 atm of hydrogen over Pd—C 10% for 16 hours. Concentration to dryness provided 100 mg (98%) of 7H-pyrrolo[2,3-d]pyrimidine [compound 1002, 1H-NMR (CD3OD): δ 9.4 (s, 1H); 9.1 (s, 1H); 7.9 (s, 1H); 7.1 (s, 1H)].
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:28])[C:11]2[CH:17]=[C:16]([CH:18]=[CH:19][CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].I[C:30]1[CH:51]=[CH:50][C:33]([C:34]([NH:36][C@H:37]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[O:35])=[CH:32][CH:31]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH:22]1[O:21][CH2:20][C:19]([C:30]1[CH:51]=[CH:50][C:33]([C:34]([NH:36][C@H:37]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[O:35])=[CH:32][CH:31]=1)=[CH:18][C:16]1[CH:15]=[N:14][C:12]2[N:13]=[C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3])[N:9]=[C:10]([OH:28])[C:11]=2[CH:17]=1
Reactant: CC(C)(C)C(=O)Nc1nc(O)c2cc(C=CCOC3CCCCO3)cnc2n1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(I)cc1)C(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(C(=Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)COC2CCCCO2)cc1)C(=O)OCC
Reaction time: 12 h

Procedure:
A mixture containing 3.48 g (9 mm) of 2-pivaloylamino-4-hydroxy-6-(3-tetrahydropyr-2-yloxyprop-1-en-1-yl)-pyrido[2,3-d]pyrimidine, 3.12 g, (1.2 equiv.) of diethyl N-(4-iodobenzoyl)glutamate, 546 mg (20%) of tris(2-methylphenyl)phosphine, 201 mg (10%) of palladium acetate and 85.5 mg (5%) of cuprous iodide in 15 ml of triethylamine and 240 ml of acetonitrile was heated at reflux under nitrogen. After 12 hours., 1.17 g of diethyl N-(4-iodobenzoyl)glutamate was added and the reaction mixture was heated at reflux under nitrogen for an additional 12 hours. The reaction mixture then was concentrated under reduced pressure and the residue was chromatographed on silica gel, eluting with 20:1 ethyl acetate:hexane. (Recovered starting material can be recycled through the foregoing procedure.) The concentrated material was dissolved in 1:5 ethyl acetate:ether and this solution was refrigerated for 15 hours. The solid which formed was collected by filtration, washed with cold ethyl acetate and dried to yield diethyl N-[4-{1-(tetrahydropyr-2-yloxy)-3-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)prop-2-en-2-yl}benzoyl]glutamate. mp. 273°-275° C. Analysis calculated for C36H45N4O9 ; C, 62.50; H, 6.56; N, 10.12. Found: C, 62.21; H, 6.34; N, 9.83. NMR (CDCL3), delta, 1.24 (t, 3H, J=7 Hz), 1.32 (t 3H, J=7 Hz), 1.32 (s, 9H), 1.53-1.87 (m, 6H), 2.11-2.22 (m, 1H), 2.29-2.41 (m 1H), 2.42-2.58 (m, 2H), 3.53-3.59 (m, 1H), 3.80-3.88 (m, 1H), 4.13 (q, 2H, J=7 Hz), 4.25 (q, 2H, J=7 Hz), 4.33 (d, 1H, J=14 Hz), 4.62 (d, 1H, J=14 Hz), 4.75-4.83 (m, 2H), 6.84 (s, 1H), 7.12 (brs, 1H, NH, J =7 Hz), 7.31 (d, 2H, J=8.1 Hz), 7.79 (d, 2H, J=8.1 Hz), 8.13 (d, 1H, J=1.6 Hz), 8.34 (brs, NH), 8.42 (d, 1H, J=1.6 Hz), 11.99 (brs, NH).