Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][C:18]([N:21]5[C@@H:25]([CH:26]([CH3:28])[CH3:27])[CH2:24][O:23][C:22]5=[O:29])=[N:17][C:16]=34)=[CH:8][CH:7]=2)=[N:2]1.C([O-])([O-])=O.[Cs+].[Cs+].[P:36]([O:48][CH2:49]Cl)([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>CN(C=O)C>[P:36]([O:48][CH2:49][N:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][C:18]([N:21]5[C@@H:25]([CH:26]([CH3:27])[CH3:28])[CH2:24][O:23][C:22]5=[O:29])=[N:17][C:16]=34)=[CH:10][CH:11]=2)=[N:2]1)([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:37]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)cc3)c2n1
Reactant: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COP(=O)(OC(C)(C)C)OC(C)(C)C)n4)cc3)c2n1
Temperature: 80 °C
Yield: 15.5 %

Procedure:
To a mixture of (S)-3-(3-(4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyloxazolidin-2-one (1.72 g, 4.42 mmol), Cs2CO3 (1.58 g, 4.86 mmol) and DMF (40 mL) was added di-tert-butyl chloromethyl phosphate (1.54 g, 5.96 mmol). The reaction mixture was heated at 80° C. for 2 hours. After cooling, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by column chromatography (1:1 to 4:1 EtOAc:hexane) to give (S)-di-tert-butyl (3-(4-(5-(4-isopropyl-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenyl)-1H-1,2,4-triazol-1-yl)methyl phosphate (0.42 g, 16%). LCMS (APCI+) m/z 612 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][C:31](O)=[O:32])[CH2:25]2)=[O:22])=[CH:17][CH:16]=1.[CH2:34]([CH2:36][NH2:37])[OH:35]>>[OH:35][CH2:34][CH2:36][NH:37][C:31]([CH2:30][N:26]1[CH2:27][CH2:28][CH2:29][CH:24]([NH:23][C:21](=[O:22])[C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:20][CH:19]=2)[CH2:25]1)=[O:32]
Reactant: NCCO
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCN(CC(=O)O)C2)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCN(CC(=O)NCCO)C2)cn1
Yield: 67 %

Procedure:
As described for example 42, (3-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-acetic acid (70 mg, 0.16 mmol) was converted, using ethanolamine instead of methylamine, to the title compound (52 mg, 67%) which was obtained as an off white solid. MS: m/e=494.3 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]1[S:10][C:9]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([C:20]([NH2:22])=[O:21])[C:13]=3[N:12]=2)=[CH:8][CH:7]=1.C=O.[C:25]([BH3-])#N.[Na+]>CO.O>[CH3:25][N:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]1[S:10][C:9]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([C:20]([NH2:22])=[O:21])[C:13]=3[N:12]=2)=[CH:8][CH:7]=1
Reactant: NC(=O)c1cccc2[nH]c(-c3ccc([C@H]4CCCN4)s3)nc12
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCC[C@@H]1c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)s1
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 16D (50 mg) in methanol (20 mL) was treated with 37 wt % formaldehyde in water (114 μL) and stirred overnight. Sodium cyanoborohydride (315 mg) was added, and the solution was stirred for 3 hours and concentrated. The concentrate was dissolved in methanol and TFA, and purified by HPLC (Zorbax C-8, 0.1% TFA/acetonitrile/water). 1H NMR (CD3OD) δ 2.30 (m, 2H), 2.47 (m, 1H), 2.74 (m, 1H), 2.94 (s, 3H), 3.31-3.40 (m, 1H), 3.88 (m, 1H), 4.81 (m, 1H), 7.40 (t, J=7.7 Hz, 1H), 7.51 (d, J=3.7 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.86 (d, J=4.0 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]#[C:11][C:12]1([O:25][C:26]([O:28][CH3:29])=[O:27])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH2:9][C:10]#[C:11][C:12]1([O:25][C:26]([O:28][CH3:29])=[O:27])[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:16][CH2:17]1
Reactant: COC(=O)OC1(C#CCO[Si](C)(C)C(C)(C)C)CCN(C(=O)OC(C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)OC1(C#CCO)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a solution of tert-butyl 4-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-4-((methoxycarbonyl)oxy)piperidine-1-carboxylate (450 mg, 1.02 mmol) in 30 mL of anhydrous THF was added TBAF (800.5 mg, 3.06 mmol) at 0° C. under N2. After stirring for 1 h at 0° C., the reaction mixture was quenched by sat. NH4Cl aq., and the resulting mixture was extracted with EtOAc (50 mL, 30 mL). The combined organic phase was washed with brine, dried over anhy. Na2SO4 and concentrated in vacuo. Column chromatography (15% PE/EtOAc) afforded 290 mg of title compound. MS (ES) M+H expected 313.25. found 313.47. 1H NMR (CHLOROFORM-d) δ: 4.36 (s, 2H), 4.21 (q, J=7.1 Hz, 2H), 3.80-3.70 (m, 2H), 3.41-3.29 (m, 2H), 2.24-2.13 (m, 2H), 2.00 (ddd, J=13.2, 9.3, 3.9 Hz, 2H), 1.95 (s, 1H), 1.48 (s, 9H), 1.34 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]([CH3:15])[C:8](OC(C)(C)C)=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[C:1]([O:5][CH2:6][CH:7]([CH3:15])[CH2:8][OH:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(COC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(CO)COC(C)(C)C
Yield: 88 %

Procedure:
Reduction of rac.-tert. butyl 3-tert.butoxy-2-methylpropionate was carried out with lithium aluminum hydride using the procedure described in Example 2. The resulting rac.-3-tert. butoxy-2-methyl-1-propanol was obtained in 88% yield as a colorless liquid. b.p. 70°-72° C. (10 mm Hg.).
Reaction SMILES: B1([C:7]2[C:12]([C:13]#[N:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)OCCCO1.Br[C:16]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[CH:19][C:17]=1[NH2:18].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH:23]([C:21]1[CH:20]=[CH:19][C:17]2[C:16](=[C:7]3[C:12](=[C:13]([NH2:14])[N:18]=2)[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH:22]=1)([CH3:25])[CH3:24]
Reactant: N#Cc1ccccc1B1OCCCO1
Reactant: CC(C)c1ccc(N)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)c1ccc2nc(N)c3ccccc3c2c1
Temperature: 25 °C

Procedure:
A 500 ml round bottom flask was charged with 12.2 grams (65.4 mmol) of 2-cyanophenylboronic acid propanediol ester, 14.0 g (65.4 mmol) of 2-bromo-4-isopropylaniline, 2.27 (2 mmol) tetrakis(triphenylphosphine)palladium, 18.0 g (131 mmol) of potassium carbonate, 150 ml toluene, and 50 ml ethanol. The reaction was heated to reflux under N2 for 18 hours. After cooling to room temperature the reaction was extracted with ethyl acetate and water. The organic washed with brine and then dried with magnesium sulfate. The solids were collected by filtration and the solvent removed from filtrate. The product was purified by silica gel chromatography using 94.5% dichloromethane, 5% methanol, 0.5% ammonium hydroxide as the eluent. The fractions containing the desired product were combined and the solvent removed. The product was confirmed by NMR and mass spectroscopy.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH2:24][CH2:25][CH2:26][CH3:27].[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[NH2:23][C:14]1[C:13]2[N:12]=[C:11]([CH2:24][CH2:25][CH2:26][CH3:27])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:36])=[O:35])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCN
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCNS(=O)(=O)c1ccccc1
Yield: 99.9 %

Procedure:
Using the general method of Example 242, 1-(8-aminooctyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 2.72 mmol) was reacted with benzenesulfonyl chloride (350 μL, 2.72 mmol) to provide 1.38 g of N-[8-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)octyl]benzenesulfonamide as an off white powder, m.p. 143–144° C. Analysis: Calculated for C28H37N5O2S: % C, 66.24; % H, 7.35; % N, 13.79. Found: % C, 66.08; % H, 7.25; % N, 13.72. Karl Fisher titration found 0.23% water.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[N+:12]([C:15]1[CH:24]=[CH:23][C:18](/[CH:19]=[CH:20]/[CH:21]=[O:22])=[CH:17][CH:16]=1)([O-:14])=[O:13].[N:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26]>ClCCl>[OH:26][N:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21](=[O:22])/[CH:20]=[CH:19]/[C:18]1[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:24][CH:23]=1
Reactant: O=Nc1ccccc1
Reactant: O=C/C=C/c1ccc([N+](=O)[O-])cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=C(/C=C/c1ccc([N+](=O)[O-])cc1)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (7.5 mg, 0.05 mmol) was added under argon to a solution of (E)-4-nitrocinnamaldehyde (177 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (18.2 mg, 0.05 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [Br:1][CH2:2][CH:3]([O:6]C)[O:4]C.C1(C)C(S(O)(=O)=O)=[CH:10][CH:11]=[CH:12][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>>[Br:1][CH2:2][CH:3]1[O:6][CH:12]([CH3:13])[CH:11]([CH3:10])[O:4]1
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1OC(CBr)OC1C
Temperature: 25 °C

Procedure:
2-Bromo-1,1-dimethoxyethane (188 grams) 2,3-butanediol (100 grams) and toluene sulfonic acid (0.1 grams) were charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer, and reflux condenser. The reaction mixture was heated to reflux for a period of about 2 hours. It was then cooled to room temperature, neutralized with potassium carbonate, and filtered. The filtrate was distilled, the desired product 2-bromomethyl-4,5-dimethyl-1,3-dioxolane being obtained as a fraction boiling at 82° C.-85° C. at a pressure of about 12 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:12])[CH:5]=[C:6]2[C:11]=1[CH2:10][CH2:9][CH2:8][CH2:7]2.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:1][C:2]1[NH:3][C:4](=[O:12])[C:5]([N+:13]([O-:15])=[O:14])=[C:6]2[C:11]=1[CH2:10][CH2:9][CH2:8][CH2:7]2
Reactant: Cc1[nH]c(=O)cc2c1CCCC2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1[nH]c(=O)c([N+](=O)[O-])c2c1CCCC2
Temperature: 0 °C

Procedure:
To a solution of 1.63 g of 2,3,5,6,7,8-hexahydro-1-methyl-3-oxoisoquinoline in 10 ml of acetic acid, 1 ml of concentrated sulfuric acid and 5 ml of concentrated nitric acid (d=1.42) were dropwise added under cooling on ice. After the reaction was completed, the reaction mixture was poured into ice water and deposited crystals were filtered out. There was obtained 1.0 g of 2,3,5,6,7,8-hexahydro-1-methyl-4-nitro-3-oxoisoquinoline. mp: 255° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.O.[NH2:17]N.Cl.Cl.NN>C(O)CO>[NH:1]([C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:13])[F:14])[CH:8]=[CH:7][C:5]=2[N:6]=1)[NH2:17]
Reactant: NN
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Agent: Cl
Solvent: O
Solvent: OCCO
Product: NNc1nc2ccc(OC(F)(F)F)cc2s1
Temperature: 140 °C
Yield: 90.3 %

Procedure:
To a suspension of 93.6 g of 2-amino-6-trifluoromethoxybenzothiazole in 420 cm3 of ethylene glycol under a stream of nitrogen are added 48 g of hydrazine hydrate and 42 g of hydrazine dihydrochloride. The mixture is heated for 2 hours at 140° C. After cooling, the precipitate is filtered off and triturated with a water/diethyl ether mixture (1/1 by volume). 89.9 g of 2-hydrazino-6-trifluoromethoxybenzothiazole are thus obtained, melting at 208° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]C1C2C(=CC=CC=2)NC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[N:16]([CH3:18])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c[nH]c2ccccc12
Reactant: c1ccc(COc2cccc3cc[nH]c23)cc1
Product: Cn1ccc2cccc(OCc3ccccc3)c21
Yield: 100 %

Procedure:
According to the procedure of Preparation 13 (a), except substituting 7-benzyloxyindole for the 3-methylindole, the title compound (4.8 g, 100%) was obtained as an amber oil: MS (ES) m/e 238.0 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3](=[CH2:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C1COCC1>[O:16]([CH2:2][C:3](=[CH2:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=C(CBr)C(=O)OCC
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=C(COc1ccccc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A solution of ethyl 2-bromomethylacrylate (2.00 g, 10.4 mmol, ref: Villieras, J. and Rambaud, M. Synthesis, 1982, 914) and phenol(975 mg, 1.0 eq) in dry THF (20 mL) under N2 at 0° C. was treated with anhydrous K2CO3 (1.43 g, 1.0 mol eq). No reaction was observed for 1 h. Anhydrous DMF (20 mL) was added and stirred for 2 h at 0° C. and for 1 h at room temperature. After evaporation of DMF, water(100 mL) was added, and the reaction was extracted with ethyl acetate (100 mL×2). The organic extract was washed with brine (100 mL), dried (anh. Na2SO4), filtered and concentrated. Flash chromatography (40% CH2Cl2/hexanes) gave 1.712 g (80%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:10].[Cl-].[Mg+2].[Cl-].[CH2:14]=[O:15].Cl>ClCCCl.C(N(CC)CC)C>[Cl:1][C:2]1[C:3]([OH:10])=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH:14]=[O:15]
Reactant: COc1cccc(O)c1Cl
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C=O)c(O)c1Cl
Temperature: 70 °C
Reaction time: 4 h
Yield: 94.7 %

Procedure:
To a solution of 2-chloro-3-methoxyphenol (19.3 g) in 1,2-dichloroethane (150 mL) were added triethylamine (73.7 g), magnesium chloride (57.8 g) and paraformaldehyde (36.5 g), and the mixture was stirred at 70° C. for 4 hr under nitrogen atmosphere. The reaction mixture was poured into 1N hydrochloric acid, and the precipitate was removed by filtration, and washed with dichloromethane. The organic layer was washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (21.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Clc1cc(-c2ccccc2)ncn1
Yield: 37 %

Procedure:
Into a 100-mL round-bottom flask equipped with a reflux pipe were put 5.1 g of 4,6-dichloropyrimidine, 8.2 g of phenylboronic acid, 7.16 g of sodium carbonate, 20 mL of acetonitrile, and 20 mL of water, and the air in the flask was replaced with nitrogen. To this mixture, 0.347 g of bis(triphenylphosphine)palladium(II) dichloride was added and the mixture was irradiated with microwaves (2.45 GHz, 100 W) for 1 hour. Further, 2.07 g of phenylboronic acid and 1.79 g of sodium carbonate were added and the mixture was irradiated with microwaves (2.45 GHz, 100 W) for 1 hour. An organic layer was extracted from the obtained mixture with the use of dichloromethane. The obtained organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The mixture was subjected to gravity filtration. A residue obtained by distilling off the solvent in the filtrate was purified by silica column chromatography with the use of dichloromethane as a developing solvent to give an objective substance as a white powder in a yield of 37%. Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). Synthesis Scheme (D-1) of Step 1 is shown below.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[C:12]([F:15])[C:11]([F:16])=[C:10]([F:17])[C:9]=2[F:18])=[C:6]([F:19])[C:5]([F:20])=[C:4](F)[C:3]=1[F:22].[CH2:23]([OH:26])[C:24]#[CH:25].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[CH2:23]([O:26][C:4]1[C:5]([F:20])=[C:6]([F:19])[C:7]([C:8]2[C:13]([F:14])=[C:12]([F:15])[C:11]([F:16])=[C:10]([F:17])[C:9]=2[F:18])=[C:2]([F:1])[C:3]=1[F:22])[C:24]#[CH:25]
Reactant: Fc1c(F)c(F)c(-c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Reactant: C#CCO
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C#CCOc1c(F)c(F)c(-c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of decafluorobiphenyl (1.67 g, 5 mmol), propargyl alcohol (0.58 ml), potassium carbonate (7.5 g), and 18-crown-6 (0.1 g) in 30 ml of toluene was stirred under reflux for 8 hours. After cooling to room temperature, 2 g of celite was added and the reaction mixture was filtered. The filtrate was evaporated on a rotavapor to remove most of the solvent and then the product was purified by preparative gas chromatography, giving 0.93 g (48%) of 4-propargyloxynonafluorobiphenyl which was used in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:48][O:49][CH:50]1[CH2:55][CH2:54][N:53]([CH2:56][C:57]2[CH:62]=[CH:61][C:60]([CH2:63][NH:64][CH3:65])=[CH:59][CH:58]=2)[CH2:52][CH2:51]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21]([N:64]([CH2:63][C:60]3[CH:59]=[CH:58][C:57]([CH2:56][N:53]4[CH2:54][CH2:55][CH:50]([O:49][CH3:48])[CH2:51][CH2:52]4)=[CH:62][CH:61]=3)[CH3:65])=[O:22])[N:20]=2)[CH3:14])(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)O)co2)c(C)c1
Reactant: CNCc1ccc(CN2CCC(OC)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)N(C)Cc3ccc(CN4CCC(OC)CC4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 2-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3-oxazole-4-carboxylic acid (40 mg, 0.11 mmol), EDCI (30 mg, 0.15 mmol), HOBt (23 mg, 0.17 mmol) DIPEA (0.04 mL, 0.22 mmol), 1-{4-[(4-methoxypiperidin-1-yl)methyl]phenyl}-N-methylmethanamine dihydrochloride (39 mg, 0.13 mmol) and DCM (5 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[CH:10][C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[Cl:20])=[C:4]2[N:3]=1.[OH-].[NH4+:22]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:22])[N:5]2[N:9]=[CH:10][C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[Cl:20])=[C:4]2[N:3]=1
Reactant: [NH4+]
Reactant: Clc1cc(Cl)n2ncc(Cc3cccc(Cl)c3Cl)c2n1
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1cc(Cl)nc2c(Cc3cccc(Cl)c3Cl)cnn12
Temperature: 40 °C
Reaction time: 30 h

Procedure:
To a suspension of 5,7-dichloro-3-[(2,3-dichlorophenyl)methyl]pyrazolo[1,5-a]pyrimidine (2 g, 5.8 mmol), and 30% ammonium hydroxide solution (3.32 g, 28.8 mmol) in 1,4-dioxane (25 mL) stirred at 40° C. for 30 hours. Reaction mixture was concentrated in vacuo. The residue was dissolved with ethyl acetate (250 mL) and 5% NaHCO3 solution (35 mL). Organic layer was separated, washed with brine (35 mL) and dried. The titled product was obtained and used for next step. (1.7 g, 90%); LC/MS: MS (ES+) m/e 327 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:13][CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[O:12])=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1>[CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[O:16][CH2:15][CH2:14][NH:13][C:11]([C:8]1[CH:7]=[CH:6][C:5]([C:4](=[O:27])[C:3]([OH:28])=[O:2])=[CH:10][CH:9]=1)=[O:12]
Reactant: COC(=O)C(=O)c1ccc(C(=O)NCCOc2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(=O)c1ccc(C(=O)NCCOc2ccc3ccccc3c2)cc1
Yield: 81.6 %

Procedure:
A solution of 4-[[[2-(2-naphthalenyloxy)ethyl]amino]carbonyl]-alpha-oxobenzeneacetic acid methyl ester (0.35 g) in methanol (5 mL) and tetrahydrofuran (5 mL) was treated with 1N sodium hydroxide (1 mL) and after 5 minutes the mixture was concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from acetone-hexane provided 0.275 g of purified 4-[[[2-(2-naphthalenyloxy)ethyl]amino]carbonyl]-alpha-oxobenzeneacetic acid as a colorless solid, mp 173°-175° C.
Reaction SMILES: [CH2:1]([N:8]1[C:17]([C:18](O)=[O:19])=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:27])[CH:14]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([NH:36][C:18]([C:17]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9](=[O:28])[C:10]2[C:15]([C:16]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:14][C:13]([Br:27])=[CH:12][CH:11]=2)=[O:19])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Product: O=C(NCc1ccccc1)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1

Procedure:
The present compound was synthesized by a method similar to that in Example 249 and using 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (250 mg) and benzylamine. Colorless crystals (210 mg).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]#[C:4][CH:5]=[N:6][OH:7].[Cl:10]N1C(=O)CCC1=O.O>CN(C=O)C>[OH:7][N:6]=[C:5]([Cl:10])[C:4]#[C:3][Si:2]([CH3:9])([CH3:8])[CH3:1]
Reactant: C[Si](C)(C)C#CC=NO
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#CC(Cl)=NO
Reaction time: 4 h

Procedure:
To a solution of 3-trimethylsilylprop-2-ynal oxime (Carreira, Erick M.; Lohse-Fraefel, Nina, Organic Letters, Volume 7, Issue 10, 2005, Pages 2011-20141, 68 g, 11.9 mmol) in 11.9 mL of DMF stirred at r.t. was added N-chlorosuccinimide (1.99 g, 14.8 mmol). After 4 h stirring, the solution was poured into water and extracted with Et2O. After the usual work-up, the residue (2.09 g) was used as it was for the next step.