Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:13][O:14][C:15]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)=[O:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1>>[CH3:13][O:14][C:15]([C:17]1([C:2]2[C:11]3[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]1)=[O:16]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Clc1ccc2c(Cl)ncnc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ncnc3cc(Cl)ccc23)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 135.5 %

Procedure:
To a stirred mixture of 4,7-Dichloroquinazoline (800 mg, 4 mmol) and piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (1.2 g, 5.2 mmol), as prepared in Example 1a, in a sealed vial at rt was added drop-wise a 1 M solution of LiHMDS in THF (6 mL, 6 mmol). The mixture was stirred at rt overnight. It was then quenched with aqueous NaH2PO4 and the mixture was extracted with DCM. The DCM layer was drawn off, washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain 2.2 g (>100%) of crude 4-(7-chloro-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (3a) as a yellow semi-solid which was used as such for the next step. Solid KOH (224 mg, 4 mmol) was added to a suspension of 4-(7-chloro-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (3a; 41 mg, 0. 1 mmol) in a 1:1 mixture of dioxane and water (1 mL). The mixture was stirred at 100° C. for 3 h. It was then cooled to rt and concentrated in vacuo. The residue was dissolved in DCM and washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain crude 4-(7-chloro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (3b). This was dissolved in 2 mL of 3M HCl/MeOH was stirred at rt for 1 h and then concentrated in vacuo to obtain crude 4-(7-chloro-quinazolin-4-yl)-piperidine (3c) as a di-HCl salt.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([CH2:22]C=C)[C@@:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1.[F:25][C:26]([F:48])([C:44]([F:47])([F:46])[F:45])[CH2:27][CH2:28][CH2:29][CH:30]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH:42]=[CH2:43])[C:31]([O:33]CC)=[O:32].ICCCC(F)(F)C(F)(F)F.C(OCC)(=O)CC(OCC)=O.ICCCCCCC=C>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([CH2:22][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH:30]([CH2:29][CH2:28][CH2:27][C:26]([F:25])([F:48])[C:44]([F:45])([F:46])[F:47])[C:31]([OH:33])=[O:32])[C@@:8]([C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1
Reactant: C=CC[C@H]1c2ccc(OC)cc2SC[C@@]1(C)c1ccc(OC)cc1
Reactant: C=CCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Agent: C=CCCCCCCI
Agent: FC(F)(F)C(F)(F)CCCI
Solvent: CCOC(=O)CC(=O)OCC
Product: C[C@@]1(c2ccc(O)cc2)CSc2cc(O)ccc2[C@@H]1CCCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the (3R,4R)-7-methoxy-3-(4-methoxy-phenyl)-3-methyl-4-(2-propenyl)thiochroman prepared in Example 2 and ethyl 2-(4,4,5,5,5-pentafluoropentyl)-9-decenoate separately prepared from 1-iodo-4,4,5,5,5-pentafluoropentane, diethyl malonate and 1-iodo-7-octene, a procedure analogous to that as shown in Example 2 or 3 was repeated to give 11-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoic acid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8]O.S(Cl)([Cl:12])=O>C(Cl)(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][Cl:12]
Reactant: O=S(Cl)Cl
Reactant: CN1CCCCC1CO
Solvent: ClC(Cl)Cl
Product: CN1CCCCC1CCl
Yield: 34 %

Procedure:
Treatment of 1-methyl-2-piperidinemethanol (12.9 g, 0.1 mol) with thionyl chloride (7.6 ml) in chloroform (40 ml), as described in example 3, gave 1-methyl-2-(chloromethyl) piperidine (5.0 g, 34%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:20])[CH2:11][N:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][CH2:14]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C1(C)C=CC(S(C2NC=CN=2)(=O)=O)=CC=1>C1COCC1>[CH2:1]([O:8][CH2:9][CH:10]1[O:20][CH2:14][CH2:13][N:12]([C:16]([CH3:17])([CH3:18])[CH3:19])[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)N(CCO)CC(O)COCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)c2ncc[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)N1CCOC(COCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
A solution of 1-(benzyloxy)-3-[tert-butyl(2-hydroxyethyl)amino]propan-2-ol (100 mg) in THF (20 mL) was stirred at room temperature under argon. Sodium hydride (60%, 35 mg) was added and the mixture was stirred for 2 hours. The mixture was cooled to ice bath temperature and para-toluenesulfonyl imidazole (79 mg) was added. After 30 minutes the mixture was warmed to room temperature and stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride and then partitioned between 1:1 brine/saturated aqueous sodium hydrogen carbonate and ethyl acetate. The organic layer was washed with 1:1 brine/saturated aqueous sodium hydrogen carbonate, dried (MgSO4), filtered and concentrated at reduced pressure. The residue was purified on the Isco™ Companion (12 g column: 0-10% MeOH in DCM) to give the title compound as a colourless oil (85 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([Br:17])[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.C1(C)C(S(O[CH2:28][C@@H:29]2[CH2:33][CH2:32][CH2:31][O:30]2)(=O)=O)=CC=CC=1.[OH-].[Na+]>CN(C)C=O>[O:30]1[CH2:31][CH2:32][CH2:33][C@H:29]1[CH2:28][NH:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([Br:17])[O:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccccc1S(=O)(=O)OC[C@@H]1CCCO1
Reactant: Nc1ncnc2oc(Br)c(-c3ccccc3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Brc1oc2ncnc(NC[C@@H]3CCCO3)c2c1-c1ccccc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 37.7 %

Procedure:
To a solution of 4-amino-5-phenyl-6-bromofuro-[2,3-d]pyrimidine (0.99 g, 3.4 mmol) in dimethyl formamide (10 mL) was added 2-(S)-(toluenesulfonyloxymethyl)-tetrahydrofuran (0.88 g, 3.4 mmol) and sodium hydroxide powder (0.15 g, 3.8 mmol). The resulting mixture was stirred at 120° C. for 2 h. The mixture was then partitioned between ethyl acetate and water and the organic layer washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude solid was purified by flash column chromatography (10% ethyl acetate/hexane) to yield the product as a white solid (0.48 g, 38%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7].[F:12][C:13]1[CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:17][CH:18]=1.Cl>CN(C)C=O.O>[F:12][C:13]1[CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:17][C:18]=1[NH:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccccc1N
Reactant: O=[N+]([O-])c1cccc(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1Nc1ccc([N+](=O)[O-])cc1F
Temperature: 80 °C

Procedure:
21.8 g (0.5 mol) of sodium hydride were added in portions to a solution of 59 g (0.5 mol) of 2-aminobenzonitrile and 53.2 ml (0.5 mol) of 3-fluoronitrobenzene in absolute dimethylformamide, whereby the reaction mixture warmed up to 80° C., with a change in colour from dark green to dark red. After the mixture had been cooled to room temperature, it was diluted with water and acidified with 2N hydrochloric acid, and the precipitate formed was filtered off. The precipitate was purified by chromatography over silica gel using dichloromethane, and the residue from evaporation of the product-containing fractions was thoroughly stirred with ether/petroleum ether 1:2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)=[O:4].[NH2:14][C:15]1[N:29]=[CH:28][C:27](Br)=[CH:26][C:16]=1[C:17]([NH:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[O:18].NC1N=CC(C2SC(CN3CCCCC3)=CC=2)=CC=1C(NC1C=CN=CC=1)=O>>[NH2:14][C:15]1[N:29]=[CH:28][C:27]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[O:4])=[CH:26][C:16]=1[C:17](=[O:18])[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Agent: Nc1ncc(-c2ccc(CN3CCCCC3)s2)cc1C(=O)Nc1ccncc1
Product: COC(=O)c1cccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)c1

Procedure:
(3-Methoxycarbonylphenyl)boronic acid and 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide are reacted analogously to “A1” step 2 to give methyl 3-[6-amino-5-(4-pyridylcarbamoyl)-3-pyridyl]benzoate.
Reaction SMILES: [Na].F[C:3]1[N:8]=[C:7]([C:9]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[CH3:15][OH:16]>>[CH3:15][O:16][C:3]1[N:8]=[C:7]([C:9]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1
Reactant: CO
Reactant: N#CC1(c2cccc(F)n2)CCC1
Agent: [Na]
Product: COc1cccc(C2(C#N)CCC2)n1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To stirred 6.0 mL of anhydrous methanol at 0° C. under nitrogen was added sodium metal (˜1 g) and the mixture stirred for 30 minutes. To this was added 1-(6-fluoropyridin-2-yl)cyclobutanecarbonitrile (1.6 g, 9.1 mmol, 1.0 equiv) and the resulting mixture heated to 75° C. for 45 minutes. The solution was cooled to room temperature and partitioned between water and EtOAc. The layers were separated, the aqueous phase was extracted with EtOAc, and the combined organic phases were washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo to give the desired product (1.7 g, 97%) as a colorless oil.
Reaction SMILES: [P:1]([O-:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:19]=[O:20]>C(N(CC)CC)C>[OH:20][CH2:19][P:1](=[O:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: C=O
Solvent: CCN(CC)CC
Product: O=P(CO)(OCc1ccccc1)OCc1ccccc1
Temperature: 55 °C

Procedure:
100 ml of dibenzyl phosphite, 12.5 g of paraformaldehyde and 6.2 ml of triethylamine were mixed together with stirring. On slow warming to 55° C., a temperature increase to 120° C. took place. The solution, which was now clear, was allowed to cool to 90° C. and was stirred at this temperature for a further 30 minutes. After cooling to room temperature, it was chromatographed on 1 kg of silica gel at elevated pressure (eluent: n-hexane/ethyl acetate 1:4). After concentrating the fractions and drying the residue in vacuo at 60° C. for 12 hours, 96.1 g of pure, oily dibenzyl hydroxymethylphosphonate were obtained, which was reacted without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[N:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:22][NH2:23]>C1COCC1>[N:1]1[CH:6]=[CH:5][C:4]([C:7]([NH:22][NH2:23])=[O:9])=[N:3][CH:2]=1
Reactant: O=C(O)c1ccncn1
Reactant: NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: NNC(=O)c1ccncn1
Temperature: 25 °C

Procedure:
To a solution of pyrimidine-4-carboxylic acid (1.0 g, 8.0 mmol) in THF (15 mL), N,N-Carbonyldiimidazole (1.4 g, 8.9 mmol) was added. After refluxing for 2 hours, hydrazine (0.8 g, 20 mmol) was added to the reaction mixture slowly with a syringe at 0° C. The reaction mixture was allowed to warm to room temperature slowly and then concentrated to yield the desired product as white solid. LCMS calculated for C5H7N4O (M+H): 139.1; found: 139.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[C:9](Cl)(=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1.Cl>O>[C:9]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])(=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: NCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(C(=O)NCCC(=O)O)c1
Reaction time: 5 h
Yield: 81.3 %

Procedure:
Ten grams of β-alanine and 9 g of sodium hydroxide were dissolved in 100 mL of purified water, and 17.4 g of m-anisoylchloride were added dropwise under freezing conditions. After stirring for five hours, hydrochloric acid was added and the pH was adjusted to 2 or less. After extraction with 500 mL of ethyl acetate, the product was desiccated over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was recrystallized with aqueous ethanol, and 18.5 g of the desired product was obtained (yield of 81%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][N:5]([CH3:15])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([OH:14])=O)[S:10][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:40])([F:39])[F:38])[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[O:28]=[C:27]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:29])[N:19]1[CH2:18][C@@H:17]([NH:16][C:12]([C:9]1[S:10][CH:11]=[C:7]([C:6]2[N:5]([CH3:15])[N:4]=[CH:3][C:2]=2[F:1])[CH:8]=1)=[O:14])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:39])([F:38])[F:40]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1ncc(F)c1-c1csc(C(=O)O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(F)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Reaction time: 1 h
Yield: 65.2 %

Procedure:
To a solution of 4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (84 mg, 0.372 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (130 mg, 0.372 mmol)[from Preparation 6], diisopropylethyl amine (323 uL, 1.86 mmol) in DCM (4 mL) was added PyBrop (208 mg, 0.446 mmol) in one portion. After 1 h, the reaction contents were partitioned between H2O/DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 0.5% MeOH-DCM) affording the title compound (135 mg, 65%) as a white solid: LCMS (ES) m/z=557 (M+H)+.
Reaction SMILES: C(OC(=O)[N:7]([CH2:33][C:34]1[CH:43]=[CH:42][C:37]2[O:38][CH2:39][CH2:40][O:41][C:36]=2[CH:35]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([C:28](=[O:31])[CH2:29][CH3:30])[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:32])[CH2:10][CH2:9]1)(C)(C)C.[ClH:45].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:45].[O:38]1[C:37]2[CH:42]=[CH:43][C:34]([CH2:33][NH:7][CH:8]3[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]4[C:25]5[C:20](=[C:21]([C:28](=[O:31])[CH2:29][CH3:30])[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=5)[CH:19]=[CH:18][C:17]4=[O:32])[CH2:10][CH2:9]3)=[CH:35][C:36]=2[O:41][CH2:40][CH2:39]1
Reactant: CCC(=O)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCC(=O)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C

Procedure:
To 1 mL of an ethyl acetate solution containing 30 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-2-oxo-5-propionylquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 1 mL of 4 mol/L hydrogen chloride/ethyl acetate was added, and stirred at room temperature. The resulting solid was filtered to give 18 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-5-propionyl-1,2-dihydro-2-oxoquinoline hydrochloride as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[OH:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[N:27]=[CH:26][CH:25]=[CH:24]2.[H-].[Na+]>CN(C=O)C>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:28]=3[N:27]=[CH:26][CH:25]=[CH:24]4)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: Oc1cccc2cccnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(Oc3cccc4cccnc34)ncn2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a 100-mL round-bottomed flask containing 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (0.30 g, 1.2 mmol) and 8-hydroxyquinoline (0.17 g, 1.2 mmol, Aldrich) in DMF (5 mL), was added NaH (56 mg, 1.4 mmol, 60% in mineral oil, Aldrich) at room temperature and the mixture was then stirred at room temperature for 48 h. After the solvent was removed in vacuum, EtOAc (25 mL) was added to the residue, and the mixture was washed with water (2×15 mL), dried over Na2SO4, filtered, and concentrated in vacuum. Silica gel chromatography (4:1 hexanes/EtOAc) afforded the title compound as a white solid. Mp: 155-157° C. MS (ESI, pos. ion) m/z: 368 (M+1). Anal. Calcd for C20H12F3N3O: C, 65.40; H, 3.29; N, 11.44. Found: C, 65.29; H, 3.25; N, 11.41.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1
Reactant: COc1ccc2cc(C)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2cc(CBr)ccc2c1
Temperature: 35 °C
Yield: 69.5 %

Procedure:
A solution of 2-methyl-6-methoxynaphthalene (4.lg, 23.8 mmole) and azoisobutyronitrile (80 mg) in dry carbon tetrachloride (30 ml) was heated to reflux with stirring. A slurry of N-bromosuccinimide (4.6 g, 25.8 mmole) and azoisobutyronitrile (20 mg) in dry carbon tetrachloride (10 ml) was added gradually over 2 hours. The resulting solution was heated under reflux for 30 minutes and then cooled to 35° C. The succinimide was filtered off and washed with carbon tetrachloride (5 ml). The filtrate was evaporated to dryness to afford a creamy coloured solid which was dried under vacuum at 40° C. It weighed 5.8 g and contained 70.3% 2-bromomethyl-6-methoxynaphthalene giving an activity yield of 69.5%.
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([CH2:22][CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:53])(=O)=O)=CC=1>O1CCCC1>[C:1]([O:5][C:6]([C@@:8]1([CH2:22][CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:31])([CH3:30])[CH3:32])([CH3:28])[CH3:27])[CH:12]([F:53])[C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](c1ccccc1)N1C[C@@](CCCO[Si](C)(C)C(C)(C)C)(C(=O)OC(C)(C)C)CC1=O
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@@](CCCO[Si](C)(C)C(C)(C)C)(C(=O)OC(C)(C)C)C(F)C1=O
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 26.1 %

Procedure:
(3S)-3-[3-(tert-Butyldimethylsilyloxy)-1-propyl]-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (30 g) was dissolved in tetrahydrofuran (280 mL), and the atmosphere was replaced with argon. Then, lithium hexamethyldisilazide (1.0 M solution in tetrahydrofuran) (78.0 mL) was added dropwise at −15° C., and the mixture was stirred at −5° C. for 30 minutes. After cooling to −15° C. again, a solution of N-fluorobenzenesulfonimide (26.6 g) in tetrahydrofuran (220 mL) was added dropwise, and the mixture was stirred at room temperature for 17 hours. The reaction solution was extracted with a 10% citric acid solution and ethyl acetate. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. Thereafter, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=9:1→8:2) to give 8.15 g of the title compound as a pale yellow solid.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([C:13]3[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]([CH3:22])([CH3:21])[CH:14]=3)=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.[N:30]([Si](C)(C)C)=[C:31]=[O:32]>ClCCl>[CH3:21][C:15]1([CH3:22])[CH2:16][CH2:17][C:18]([CH3:20])([CH3:19])[C:13]([C:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH2:1][N:2]([C:31]([NH2:30])=[O:32])[CH2:3][CH2:4]3)=[O:12])=[CH:14]1
Reactant: CC1(C)C=C(C(=O)c2ccc3c(c2)CCNC3)C(C)(C)CC1
Reactant: C[Si](C)(C)N=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C=C(C(=O)c2ccc3c(c2)CCN(C(N)=O)C3)C(C)(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of the product of Example 10j (59 mg, 0.2 mmol) in dichloromethane (5 mL) was added triethylamine (110 mg, 1.0 mmol) and isocyanatotrimethylsilane (94 mg, 0.8 mmol) and stirred at room temperature overnight. The mixture was diluted with dichloromethane and washed with water, saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound as a white solid (47 mg, Yield: 69%). Mp=78.6-79.7° C.; Rf 0.3 (10:1 dichloromethane/methanol); 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.53 (d, J=8.0 Hz, 2H), 7.17 (d, J=7.6 Hz, 1H), 5.79 (s, 1H), 4.63 (s, 2H), 4.52 (s, 2H), 3.64 (t, J=6.0 Hz, 2H), 2.94 (t, J=6.0 Hz, 2H), 1.59 (s, 4H), 1.24 (s, 6H), 1.06 (s, 6H) ppm; Mass spectrum (ESI +ve) m/z 341 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.O=[C:22]([CH2:26][CH2:27][C:28](O)=[O:29])[C:23]([OH:25])=[O:24]>C(O)C>[C:11]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:12]=[CH:13][CH:14]=[C:9]([N:8]2[C:28](=[O:29])[C:27]([CH2:26][CH2:22][C:23]([OH:25])=[O:24])=[N:1][C:2]3[CH:7]=[CH:6][CH:5]=[N:4][C:3]2=3)[CH:10]=1
Reactant: O=C(O)CCC(=O)C(=O)O
Reactant: Nc1cccnc1Nc1cccc(-c2ccccc2)c1
Solvent: CCO
Product: O=C(O)CCc1nc2cccnc2n(-c2cccc(-c3ccccc3)c2)c1=O
Yield: 44.6 %

Procedure:
A mixture of 3-amino-2-[(3-biphenylyl)amino]pyridine (350 mg) and 2-ketoglutaric acid (235 mg) in ethanol (5 ml) was stirred under reflux for 1 hour. After evaporation of the solvent, the residue was chromatographed on silica gel column (2.5%-3% methanol in chloroform) to give 4-(3-biphenylyl)-2-(2-carboxyethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (222 mg).