Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15](F)[CH:14]=1.[OH:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1>C(OCC)(=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([CH:14]=1)[O:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2cc(Cl)ccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A DMF (4 mL) solution containing Na2CO3 (60 mg, 0.57 mmol), 4-chloro-2-fluoro-1-nitrobenzene (100 mg, 0.57 mmol) and methyl 4-hydroxybenzoate (87 mg, 0.57 mmol) was stirred at room temperature for 8 hours. HPLC analysis indicated ca. 85% product. The reaction solution was stirred for an additional 2 hours at 40° C. The solution was then diluted with ethyl acetate and washed with 1N NaOH. The organic phase was washed with water (3×), brine and dried over Na2SO4. The solution was filtered, concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (500 MHz, CDCl3): δ 8.11 (d, J=8.1 Hz, 2H); 8.01 (d, J=8.2 Hz, 1H); 7.31-7.27 (m, 1H); 7.11-7.07 (m, 3H); 3.95 (s, 3H). LCMS1 3.66 min. (M+H)=308.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([N:13]2[C:18](=[O:19])[NH:17][C:16](=[O:20])C(C#N)=[N:14]2)=[CH:8][C:7]=1[CH3:23].Cl.[C:30]([OH:33])(=[O:32])[CH3:31]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[O:5][C:6]1[C:7]([CH3:23])=[CH:8][C:9]([N:13]2[C:18](=[O:19])[NH:17][C:16](=[O:20])[C:31]([C:30]([OH:33])=[O:32])=[N:14]2)=[CH:10][C:11]=1[CH3:12]
Reactant: CC(=O)O
Reactant: COc1ccc(Oc2c(C)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2C)cc1Br
Agent: Cl
Product: COc1ccc(Oc2c(C)cc(-n3nc(C(=O)O)c(=O)[nH]c3=O)cc2C)cc1Br

Procedure:
A solution of 2-[4-(3-bromo-4-methoxy-phenoxy)-3,5-dimethyl-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (700 mg) of EXAMPLE 1, hydrochloric acid (5 ml) and acetic acid (5 ml) was heated to 120° C. for 3 h. The resulting solids were filtered, rinsed and dried to afford the title compound as a brown solid (593 mg). MS Calc.: 461.0; Found: 459.7 (M−1).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][C:21]([C:24]([OH:26])=O)([CH3:23])[CH3:22])[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCCCCC.C(OCC)(=O)C>C(OC(=O)C)C>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][C:21]([C:24](=[O:26])[N:30]([CH2:31][CH3:32])[CH2:28][CH3:29])([CH3:22])[CH3:23])[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNCC
Reactant: Cc1[nH]c2ccc(OC(C)(C)C(=O)O)cc2c1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCN(CC)C(=O)C(C)(C)Oc1ccc2[nH]c(C)c(C(=O)OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 9.3 %

Procedure:
5-(1-Carboxy-1-methyl-ethoxy)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (1.0 g, 2.76 mmol, 1.0 eq) was dissolved in ethylacetate (100 mL), and treated with diethylamine (0.241 g, 3.3 mmol, 1.2 eq) followed by HBTU (0.446 g, 3.3 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 24 hours and was followed by TLC (hexane/ethyl acetate 1/1). The reaction was quenched with aqueous sodium bicarbonate, extracted with ethyl acetate, and the organic layers dried over sodium sulfate, evaporated, and loaded on silica gel, followed by flash chromatography (hexane/ethyl acetate 1/1). 0.109 g of the product was obtained, 12% yield. LC/MS (ESI+) 422.52 (M+1) (C25H30N2O4).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10](OS(C(F)(F)F)(=O)=O)[CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:31]=[N+:32]=[N-:33].[Na+].[N-]=[N+]=[N-]>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH:10]([N:31]=[N+:32]=[N-:33])[CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1c2ccccc2C(=O)N1CC(COCc1ccccc1)OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(COCc1ccccc1)CN1C(=O)c2ccccc2C1=O

Procedure:
2-Benzyloxymethyl-2-(trifluoromethylsulfonyloxy) -1-phthalimido-ethane (8.5 g, 19.1 mmol) and sodium azide (2.5 g, 38.2 mmol) were stirred in dimethylformamide (80 ml) at 60° C. for 6 hours under nitrogen. TLC in several systems was inconclusive because the Rf of the product was identical to the Rf of the starting material. A small sample was worked up and IR indicated full conversion to the azide. The reaction mixture was transferred to a 1 l extraction funnel and distributed between ethyl acetate (350 ml) and water (130 ml). The aqueous phase was extracted with ethyl acetate (80 ml); the combined organic phases were washed with water (2×120 ml), dried over magnesium sulphate, filtered and concentrated in vacuo to a pale brown oil. Crystallisation was initiated by adding ether (7 ml). Crystals were collected on a glass sinter, washed with cold ether and dried under vacuum for 28 hours. Yield: 4.5 g (70%). The mother liquors were concentrated, diluted with ether and seeded with crystals from the first crop--yielding another 1 g. Total yield: 5.5 g (85%). The structure was confirmed by NMR and IR.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][NH2:11])=[CH:2]1.CCN(CC)CC.[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][NH:11][C:19](=[O:22])[CH2:20][CH3:21])=[CH:2]1
Reactant: CCC(=O)Cl
Reactant: NCc1c[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: CO
Product: CCC(=O)NCc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 4 h
Yield: 96.1 %

Procedure:
Compound 25 (1.00 g, 6.84 mmol) and Et3N (1.4 mL, 10.26 mmol) were dissolved in MeOH and cooled to 0° C. Propionyl chloride (633 mg, 6.84 mmol) was added dropwise and the reaction was stirred at room temperature for 4 hours. The volatiles were removed and the residue was taken up in CH2Cl2 (40 mL), washed with 10% citric acid (20 mL), satd. NaHCO3 (20 mL) and brine (20 mL). The organic layer was dried with Na2SO4, filtered and the volatiles were removed to yield 1.33 g of a white, crystalline solid (1.33 g, 96% yield). An analytical sample was recrystallized from EtOAc/hexanes. m.p.=91-92° C. 1H NMR (CDCl3) δ 8.80 (br s, 1H, NH), 7.62 (d, 1H, ArH, J=7.85 Hz), 7.38 (d, 1H, ArH, J=7.2 Hz), 7.20 (3H, ArH), 5.80 (br s, 1H, NH), 4.60 (d, 2H, ArCH2, J=5.1 Hz), 2.20 (q, 2H, COCH2CH3, J=7.6 Hz), 1.14 (t, 3H, COCH2CH3, J=7.6 Hz). 13C NMR (CDCl3) δ 173.6, 136.5, 126.6, 123.3, 122.5, 119.9, 118.8, 112.8, 111.4, 35.2, 29.7, 9.9. IR (KBr) vmax cm−1: 3405, 1891, 1634, 1532, 1097.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[Si:19]([CH3:22])([CH3:21])[CH3:20].[B:23](OC)([O:26]C)[O:24]C>C1COCC1>[Cl:13][C:14]1[CH:18]=[C:17]([B:23]([OH:26])[OH:24])[S:16][C:15]=1[Si:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: COB(OC)OC
Reactant: C[Si](C)(C)c1sccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)c1sc(B(O)O)cc1Cl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of diisopropyl amine (1.8 ml, 13 mmol) at 0° C. in 50 mL anhdrous THF under nitrogen was added butyllithium, 2.5 M in hexanes (4.6 ml, 12 mmol). The solution was allowed to stir 5 min and then was cooled to −78° C. (3-Chlorothiophen-2-yl)trimethylsilane (2.0 g, 10 mmol) in 5 mL THF at RT was added slowly via cannula, dropwise, over about 10 min. The resulting solution was allowed to stir for 30 min, at which point trimethyl borate (2.4 ml, 21 mmol) was added dropwise. The solution was allowed to stir for 1 h, and was then warmed to 0° C. and quenched by the addition of 25 mL of 2NHCl, and warmed to ambient temperature with stirring. The mixture was extracted three times with DCM, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a semisolid. Purification by silica gel chromatography, (0-40% EtOAc/hexanes) provided 4-chloro-5-(trimethylsilyl)thiophen-2-ylboronic acid as an off-white solid.
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[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27]>>[OH:27][CH2:26][CH:25]([NH:24][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)[CH2:28][OH:29]
Reactant: NC(CO)CO
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC(CO)CO)cn1
Yield: 87 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using 2-amino-1,3-propandiol instead of 2-aminoethyl isopropylether, to the title compound (215 mg, 87%) which was obtained as a colourless oil. MS: m/e=384.0 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]3[CH2:24][C:23]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[O:25]1[CH2:29][CH2:28][CH:27]([CH:30]=O)[CH2:26]1>>[O:25]1[CH2:29][CH2:28][CH:27]([CH2:30][N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]4[CH2:24][C:23]5[CH:22]=[CH:21][N:20]=[CH:19][C:18]=5[CH2:17]4)=[O:15])=[CH:9][CH:8]=3)[CH2:5][CH2:6]2)[CH2:26]1
Reactant: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccncc2C1
Reactant: O=CC1CCOC1
Product: O=C(Nc1ccc(C2CCN(CC3CCOC3)CC2)cc1)N1Cc2ccncc2C1

Procedure:
The title compound was prepared as described in Example 926, substituting N-(4-(piperidin-4-yl)phenyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxamide for N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxamide and tetrahydrofuran-3-carbaldehyde for isobutraldehyde. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.60 (s, 1H), 8.50 (d, J=5.0 Hz, 1H), 8.33 (s, 1H), 7.44 (m, 3H), 7.13 (m, 2H), 4.78 (m, 4H), 3.71 (m, 2H), 3.61 (q, J=7.6 Hz, 1H), 3.36 (m, 2H), 2.96 (m, 2H), 2.40 (m, 1H), 2.27 (m, 2H), 96 (m, 3H), 1.72 (m, 2H), 1.66-1.46 (m, 3H); MS (ESI(+)) m/e 407 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH:10]([N:20]=[N+]=[N-])[CH2:11][O:12]CC1C=CC=CC=1)[C:2]1C=CC=CC=1.[ClH:24].[H][H]>C(O)C.[Pd]>[ClH:24].[CH2:1]([O:8][C:9](=[O:23])[CH:10]([CH2:11][OH:12])[NH2:20])[CH3:2]
Reactant: [N-]=[N+]=NC(COCc1ccccc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(N)CO
Reaction time: 40 h
Yield: 95.5 %

Procedure:
1.56 grams (0.005 mole) of 2-azido-3-benzyloxypropionic acid benzyl ester were dissolved in 10 ml of absolute ethanol, 1.10 grams (0.03 mole) of dry hydrogen chloride led in, and the mixture treated with 0.20 grams of palladium on activated carbon (10%). This reaction mixture was hydrogenated in an autoclave for 40 hours at 25° C., and a hydrogen pressure of 20 bar. After filtration, the filtrate was concentrated on the rotary evaporator, and the residue recrystallized from ethanol/diethyl ether (volume ratio about 1:1). There were obtained 0.81 grams (96% of theory) of D,L-serine ethyl ester hydrochloride having a melting point of 102°-103.5° C. (Literature: 100°-102° C.
Reaction SMILES: C(OC(N1[CH2:12][CH:11]([CH:13]=O)[CH:10]2OC[C:17]([O:20][CH3:21])([O:18]C)[CH:9]12)=O)(C)(C)C.[C:22](Br)(Br)(Br)Br.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>ClCCl.CCCC(C)C>[CH3:17][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12].[CH3:22][CH2:21][O:20][C:17]([CH3:9])=[O:18]
Reactant: BrC(Br)(Br)Br
Reactant: COC1(OC)COC2C(C=O)CN(C(=O)OC(C)(C)C)C21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCC(C)C
Product: CCOC(C)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The aldehyde 9-1 (318.3 mg, 1.06 mmol) (see reference example 3) in 6 mL dichloromethane (DCM) was added dropwise to a solution of CBr4 (700 mg, 2.11 mmol) and Ph3P (1.10 g, 4.19 mmol) in 10 mL DCM, with cooling in an ice bath. After stirring at 0° C. for 2 h, the mixture was diluted with 30 mL iso-hexane and then filtered through a short Celite column. The column was washed with 20 mL i-hexane, followed by 3/1 i-hexane—DCM. The filtrate was concentrated in vacuo to give light yellow solids. Flash chromatography (silica, 3/1 i-hexane—EtOAc) gave compound 9-2 (339.5 mg, 70% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]Cl.C(OCC)(=O)C>CN1C(=O)CCC1>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: ClCc1ccccn1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2ccn(Cc3ccccn3)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere: to a solution of 1H-indole-6-carboxylic acid methyl ester (for synthesis see example 2a), 2.47 g, 14.1 mmol) in NMP (140 mL) was added Cs2CO3 (10.1 mg, 31 mmol) at 0° C. After stirring for 15 min 2-picolyl chloride hydrochloride (2.77 g, 16.9 mmol) was added and the mixture was stirred at room temperature for 18 h. Ethyl acetate (200 mL) was added and the mixture was washed with saturated aqueous ammonium chloride (3×150 mL) and brine (200 mL). The organic phase was dried (Na2SO4) and concentrated. The crude product was purified using column chromatography (ethyl acetate/heptane 1:3) to give the title compound as a colourless oil, which slowly crystallised on standing (2.72 g, 10.2 mmol, 72%).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:23]=[CH:22][C:6]([C:7]([C:9]2[C:17]([Cl:18])=[C:16]([Cl:19])[C:15]([Cl:20])=[C:14]([Cl:21])[C:10]=2[C:11]([OH:13])=O)=[O:8])=[CH:5][CH:4]=1.[CH2:25]([N:27]([CH2:39][CH3:40])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])[CH:29]=1)[CH3:26].C(OC(=O)C)(=O)C>CO>[CH2:35]([N:34]([CH2:37][CH3:38])[C:30]1[CH:29]=[C:28]([N:27]([CH2:25][CH3:26])[CH2:39][CH3:40])[CH:33]=[CH:32][C:31]=1[C:7]1([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:24])[CH3:1])=[CH:23][CH:22]=2)[C:9]2[C:10](=[C:14]([Cl:21])[C:15]([Cl:20])=[C:16]([Cl:19])[C:17]=2[Cl:18])[C:11](=[O:13])[O:8]1)[CH3:36]
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Reactant: CN(C)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: CCN(CC)c1ccc(C2(c3ccc(N(C)C)cc3)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c(N(CC)CC)c1
Temperature: 91 °C

Procedure:
A mixture of 2-(4-(dimethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (16.28 g.), N,N,N',N'-tetraethyl-m-phenylenediamine (9.68 g.) and acetic anhydride (10 ml.) was heated (at 91° C.) during two hours. Addition of methanol (20 ml., then 12 ml., then 10 ml.) afforded 3-(2,4-bis(diethylamino)phenyl)-3-(4-(dimethylamino)phenyl)-4,5,6,7-tetrachlorophthalide (I: X= (CH3CH2)2N, Y2 = H, Y4 = (CH3)2N, Z4 = Z5 = Z6 = Z7 = Cl) in three fractions (m.p. 174°- 176° C., m.p. 180° -181° C. and m.p. 180° -181° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9](Cl)(=[O:13])[C:10](Cl)=[O:11]>ClC1C=CC=CC=1Cl>[O:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:10](=[O:11])[C:9]1=[O:13]
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)C(=O)Cl
Solvent: Clc1ccccc1Cl
Product: O=c1[nH]c2ccccc2oc1=O
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
Ortho-aminophenol (21.8 g) in 200 ml of ortho-dichlorobenzene was added as a slurry to 18.3 ml oxalyl dichloride (1.05 mol eq) in 150 ml ortho-dichlorobenzene at about 100° C. with stirring. After the addition (about 30 min.), the reaction mixture was heated to about 70° C. and then kept at this temperature for approximately 1.5 hours. The reaction mixture was then cooled, filtered and the solid product, 4H-1,4-benzoxazin-2,3-dione was washed with ether to give 27 g., m.p. 265°-268° C.
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:22]S(C3C=CC(C)=CC=3)(=O)=O)=[N:8][N:9]3[C:14]=2[C:13]([CH3:15])=[N:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:33]([N:35]1[C:39]([CH2:40]O)=[N:38][CH:37]=[N:36]1)[CH3:34].[H-].[Na+].O>CN(C=O)C>[CH:1]1([C:6]2[C:7]([O:22][CH2:40][C:39]3[N:35]([CH2:33][CH3:34])[N:36]=[CH:37][N:38]=3)=[N:8][N:9]3[C:14]=2[C:13]([CH3:15])=[N:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCn1ncnc1CO
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4ccccc4)nnc(C)c3c2C2CCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ncnc1COc1nn2c(-c3ccccc3)nnc(C)c2c1C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To toluene-4-sulfonic acid 3-cyclopentyl-4-methyl-7-phenylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester (300 mg, 0.67 mmol) and (2-ethyl-2H-[1,2,4]triazol-3-yl)methanol (102 mg, 1.2 molar eq; prepared as described in EP-A-170073) in DMF (10 ml) was added sodium hydride (29.5 mg of a 60% dispersion in mineral oil; 1.2 molar eq) and the mixture was stirred at room temperature for 1 h. Water (90 ml) was added then the solution was extracted with diethyl ether (4×60 ml). The combined ether layers were washed with brine (1×100 ml), dried (Na2SO4), the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate in dichloromethane. 3-Cyclopentyl-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-4-methyl-7-phenylpyrazolo[1,5-d][1,2,4]triazine was isolated as a gum, which solidified upon trituration under diethyl ether/isohexane (144 mg, mp=112° C.). 1H NMR (360 MHz, CDCl3) δ 1.42 (3H, t, J=7.3 Hz), 1.66-1.95 (8H, m), 2.87 (3H, s), 3.43 (1H, m), 4.20 (2H, q, J=7.3 Hz), 5.55 (2H, s), 7.51-7.61 (3H, m), 7.93 (1H, s), 8.28-8.31 (2H, m); MS (ES+) m/e 403 [MH]+. Anal. Found C, 65.10; H, 6.06; N, 24.19%. C22H25N7O requires C, 65.49; H, 6.25; N, 24.06%.
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=[O:2].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1](=[O:2])[O:3]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1OCc2ccccc21
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OC(Br)c2ccccc21
Temperature: 15 °C

Procedure:
As taught by U.S. Pat. No. 3,860,579, recrystallized phthalide (50 g., 0.375 mol) and recrystallized N-bromosuccinimide (0.375 mol) were refluxed 4.5 hours in the presence of about 100 mgm α-azobutyronitrile in one liter CCl4. The mixture was cooled to about 15° C. and filtered to remove succinimide which was itself washed with about 100 ml. CCl4 and filtered. The combined CCl4 phases were concentrated in vacuo to about 150 ml. giving solid 3-bromophthalide which was collected by filtration, washed with about 50 ml. CCl4 and air-dried to yield 54 g. which weighed 50 g. after recrystallization from boiling cyclohexane, m.p. 84°-86° C. ##STR39##
Reaction SMILES: [C:1]([N:8]([CH3:42])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:30][C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:43][C:44]1[CH:49]=[CH:48][C:47](Br)=[CH:46][N:45]=1>>[NH2:43][C:44]1[N:45]=[CH:46][C:47]([C:33]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:31]([CH:32]=2)[CH2:30][N:15]([C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH:12]2[CH2:13][CH2:14][CH:9]([N:8]([CH3:42])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:5])[CH3:6])[CH2:10][CH2:11]2)=[CH:48][CH:49]=1
Reactant: Nc1ccc(Br)cn1
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(N)nc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 9 (1.10 g, 1.76 mmol) is coupled to 2-amino-5-bromopyridine (365 mg, 2.11 mmol) using Method A to give the title compound.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1.C(N(CC)CC)C.[N-]=C=O>CC(C)=O>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:2]2[C:3](=[O:7])[CH2:4][CH2:5][CH2:6][C:1]=2[OH:8])=[O:18])=[CH:12][CH:11]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: O=C1CCCC(=O)C1
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C1CCCC(O)=C1C(=O)Nc1ccc(Cl)cc1

Procedure:
A solution containing 8.5 parts of cyclohexane-1,3-dione, 11.5 parts of p-chlorophenylisocyanate and 7.6 parts of triethylamine in 200 parts of acetone is stirred and refluxed for two hours. The infrared spectrum then shows no isocyanate (band at 2270 cm-1). The solution is concentrated under reduced pressure to about 50 parts, with separation of a few crystals, and poured with stirring into 500 parts of 2-normal hydrochloric acid. The precipitated solid is collected by filtration and dried. The resulting solid is mixed with chloroform, 250 parts by volume, and filtered from 6.5 parts of insoluble by-product. Removal of chloroform from the filtrate leaves a light pink solid which is crystallized from alcohol to give 6.7 parts of nearly white solid, melting point 113°C.-114°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.[CH2:16]1[CH2:21][NH:20][CH2:19][CH:18]([C:22]([F:25])([F:24])[F:23])[CH2:17]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:20]1[CH2:21][CH2:16][CH2:17][CH:18]([C:22]([F:25])([F:24])[F:23])[CH2:19]1)=[O:15]
Reactant: FC(F)(F)C1CCCNC1
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Product: O=C(c1cnoc1-c1ccccc1Cl)N1CCCC(C(F)(F)F)C1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and DL-3-(trifluoromethyl)piperidine (9.2 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (11.6 mg). Calcd for C16H14ClF3N2O2: 358.0696, found 358.0702.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:11]2)[CH:3]=1.[C:27]([C:29]1[C:34]([F:35])=[CH:33][C:32](B(O)O)=[CH:31][C:30]=1[F:39])#[N:28].C([O-])(O)=O.[Na+]>O1CCOCC1.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:27]([C:29]1[C:34]([F:35])=[CH:33][C:32]([C:2]2[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]3[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:11]3)[CH:3]=2)=[CH:31][C:30]=1[F:39])#[N:28]
Reactant: CNc1nc(Cl)cc(N2C[C@@H](C(=O)NCc3ccccc3)CC[C@H]2C)n1
Reactant: N#Cc1c(F)cc(B(O)O)cc1F
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: [Na+]
Solvent: C1COCCO1
Product: CNc1nc(-c2cc(F)c(C#N)c(F)c2)cc(N2C[C@@H](C(=O)NCc3ccccc3)CC[C@H]2C)n1
Temperature: 100 °C

Procedure:
(3S,6R)-1-[6-chloro-2-(methylamino)-4-pyrimidinyl]-6-methyl-N-(phenylmethyl)-3-piperidinecarboxamide (100 mg, 0.267 mmol) and (4-cyano-3,5-difluorophenyl)boronic acid (73.4 mg, 0.401 mmol) were dissolved in 1,4-Dioxane (2 mL) in a 5 mL sealable vial then added saturated NaHCO3 (1 mL). Nitrogen gas was bubbled through the mixture for 10 min. Then Pd(Ph3P)4 (37.1 mg, 0.032 mmol) was added and nitrogen gas bubbled for an additional 5 min. The vial was capped the reaction was heat at 100° C. overnight. The reaction was diluted with water (5 mL) and then extracted with EtOAc (3×10 mL). Organic were combined, dried over MgSO4, filtered and concentrated. The yellow oil was then purified on a 10 g Biotage SNAP column with gradient of 0 to 40% EtOAc in Hexane. LC-MS (ES) m/z=477 [M+H]+.