Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:2]1=[O:3].[N+:12]([O-])([OH:14])=[O:13]>>[N+:12]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[O:1][C:2](=[O:3])[CH:4]=[CH:5]2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: O=c1ccc2ccccc2o1
Product: O=c1ccc2cc([N+](=O)[O-])ccc2o1
Yield: 85 %

Procedure:
In greater detail, coumarin (10 g, 68 mmol) was nitrated as described in the literature with an excess of fuming nitric acid overnight at room temperature to give 6-nitrocoumarin as the only major product. The 6-nitrocoumarin exhibited the following characteristics: Yield 85%. 1H NMR (DMSO-d6): 8.74 (d, J=3 Hz, 1H), 8.42 (dd, J=3, 9 Hz, 1H), 8.24 (d, J=10 Hz, 1H), 7.63 (d, J=9 Hz, 1H), 6.70 (d, J=10 Hz, 1H).
Reaction SMILES: C[O-].[Na+].C([O:7][C@@H:8]1[C@@H:13]([O:14]C(=O)C)[C@H:12]([O:18]C(=O)C)[C@@H:11]([CH2:22][O:23]C(=O)C)[O:10][C@H:9]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][C:34]2[CH:43]=[C:42]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=[CH:41]3)[C:35]=2[C:44](=[O:46])[CH3:45])[CH:28]=1)(=O)C.Cl>C1COCC1.CO>[OH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([OH:18])[C@@H:11]([CH2:22][OH:23])[O:10][C@H:9]1[C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=1)[CH2:33][C:34]1[CH:43]=[C:42]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=[CH:41]2)[C:35]=1[C:44](=[O:46])[CH3:45]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cccc(Cc3cc4cccccc-4c3C(C)=O)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)c1c(Cc2cccc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c2)cc2cccccc1-2
Reaction time: 2 h
Yield: 93.2 %

Procedure:
Sodium methoxide (16 mg) was added to a solution of (2S,3S,4R,5R,6R)-2-[3-[(1-acetylazulen-2-yl)methyl]phenyl]-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-3,4,5-triyl triacetate (0.09 g) in THF-methanol (ratio: 1:1, 6.0 ml) at 0° C. and the mixture was stirred for two hours. After neutralizing with a cation exchange resin, the reaction mixture was added to 10% aqueous solution of hydrochloric acid under cooling with ice. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 1-(2-[3-[(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]benzyl]azulen-1-yl)ethanone (0.06 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[F:20])=[C:6](B(O)O)[CH:7]=1.Cl.Cl[CH2:23][C:24]1[N:29]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.C(O)C>O.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[F:20])=[C:6]([CH2:23][C:24]2[N:29]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:27]=[CH:26][CH:25]=2)[CH:7]=1
Reactant: CCOC(=O)c1cccc(CCl)n1
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccc(Cl)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1
Temperature: 90 °C
Yield: 42.5 %

Procedure:
A mixture of 78.56 g (249.4 mmol) of (5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)boronic acid, 59.9 g (249.4 mol) of ethyl 6-(chloromethyl)-2-pyridinecarboxylate hydrochloride, 137.68 g (997.7 mol) of potassium carbonate and 28.89 g (24.95 mmol) of tetrakis(triphenylphoshine)palladium(0) in 1:1 toluene/ethanol (1840 ml) was stirred and heated at 90° C. under argon for 2 hours. Cooled, diluted with water/ether and filtered. Organic phase was washed with 2M hydrochloric acid and water, dried overnight (sodium sulphate), filtered and evaporated. Dissolved in dichloromethane, filtered to remove some insoluble material and the filtrate applied to a large column on the Biotage 75 and eluted with 15% ethyl acetate in hexane. Some purification but lower spot started to elute with product so eluent changed to ethyl acetate/hexane (1:1) and all fractions containing product combined and evaporated. Redissolved in dichloromethane and biotaged (chromatographed) again on same size column eluting with 4 litres of (3:1) dichloromethane/hexane changing to 5% ethanol in dichloromethane to remove the remaining product. Evaporated in vacuo and recrystallised from ethanol (1 litre) cooling to 20° C. in an ice bath then filtering off immediately to give 46 g of product. MLS (mother liquors) were left over the weekend when more solid separated which was filtered off but TLC showed this to be impurity and leaving very of this in the filtrate. MLS evaporated and recrystallised from ethanol (140 ml) to give 9.4 g of product. NMR and LC/MS of both products identical. (total yield of 55.4 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].C(Cl)Cl.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16].CCN(C(C)C)C(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: CC(C)(C)N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NS(=O)(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
2-Bromobenzenesulfonyl chloride (100.9 g, 394.9 mmol) was dissolved in DCM (500 mL, 8.0 mol) and cooled at 0° C. t-Butylamine (41.3 mL, 395 mmol) was added in 3 portions over approximately 1 minute. DIPEA (75.7 mL, 434 mmol) was immediately added in 3 portions over approximately 1 minute. The mixture was warmed to room temperature and stirred overnight. The product was washed with 1M H3PO4 (2×), with saturated. NaHCO3, and with saturated aqueous NaCl, then dried over MgSO4, filtered, and concentrated to yield 2-bromo-N-t-butyl-benzenesulfonamide (112 g) as a light brown solid.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:32]([C:35]2[S:36][C:37](Br)=[CH:38][CH:39]=2)(=[O:34])=[O:33])[CH:26]=1>>[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:32]([C:35]2[S:36][C:37]([C:13]#[C:12][C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]5[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=5)=[N:6][C:7]=34)=[CH:38][CH:39]=2)(=[O:33])=[O:34])[CH:26]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(Nc1cccnc1)c1ccc(Br)s1
Product: O=S(=O)(Nc1cccnc1)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (169 mg, 0.5 mmol) and commercially available 5-bromo-thiophene-2-sulfonic acid pyridin-3-ylamide [CAS-No. 439934-18-6] (160 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (220 mg, 76%). MS (ISN) 574.1 [(M−H)−]; mp 226° C.
Reaction SMILES: C(OC([N:11]([O:28][CH:29]=[C:30]=[O:31])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH:14]=1)=O)C1C=CC=CC=1.[H][H]>[C].[Pd].C(O)C>[CH3:27][N:24]1[CH2:25][CH2:26][N:21]([C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=2[O:19][CH3:20])[CH2:12][NH:11][O:28][CH:29]=[C:30]=[O:31])[CH2:22][CH2:23]1
Reactant: COc1ccc(CN(OC=C=O)C(=O)OCc2ccccc2)cc1N1CCN(C)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CNOC=C=O)cc1N1CCN(C)CC1
Yield: 109.8 %

Procedure:
A mixture comprising 3.26 g of N-benzyloxycarbonyl-3-(4-methylpiperazin-1-yl)-carbonylmethoxy-4-methoxybenzylamine, 0.5 g of 5% palladium carbon and 70 ml of ethanol, was stirred at 60° C. for 6 hours in a hydrogen atmosphere and further at room temperature overnight. Palladium carbon was filtered off, and then the filtrate was distilled off under reduced pressure to obtain 2.45 g of the above-identified compound as slightly brown oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:2]=1.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)#[CH:23]>CCCCCCC.CCOC(C)=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:23]#[C:22][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cnc3ccccc3c2)cc1
Reactant: C#Cc1ccc(N)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Nc1ccc(C#Cc2cnc3ccccc3c2)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid quinolin-3-yl ester and 4-ethynyl-phenylamine following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 6:4; yield (120 mg, 98%); 1H NMR δ (CDCl3): 8.98 (s, 1H), 8.34 (s, 1H), 8.21 (d, J=8.60 Hz, 1H), 7.87-7.71 (d m, 2H), 7.68-7.57 (m, 1H), 7.40 (d, J=8.36 Hz, 2H), 6.67 (d, J=8.38 Hz, 2H), 4.46 (br s, 2H); LCMS m/z: 244.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[SH:9][CH2:10][C:11](O)=O.[OH-].[Na+]>Cl>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=[C:11]1[CH2:10][SH:9]
Reactant: O=C(O)CS
Reactant: Nc1ccccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: SCc1nc2ccccc2[nH]1
Temperature: 60 °C
Reaction time: 48 h
Yield: 69.8 %

Procedure:
To 1,2-phenylenediamine (1.88 g, 17 mmol) in 50% v/v hydrochloric acid (20 ml) was added 2-mercaptoacetic acid (1.3 ml, 1.7 g, 19 mmol). The reaction mixture was heated, under nitrogen, at 60° C. then at 90° C. for 48 hours. Additional 2-mercaptoacetic acid (400 μA, 530 mg, 6 mmol) was added in this time. A sample was analyzed by HPLC. The reaction mixture was cooled and neutralized to pH 5 with 40% v/v NaOH. The resulting solid was washed with water (50 ml) and dried under vacuum to yield (1H-Benzo[d]imidazol-2-yl)-methanethiol 1.95 g, 93% yield, Rt=7.6 min, purity >95% together with disulfide (Rt=8.0 mins) 4%. 1H NMR (d6-DMSO, 400 MHz) 14.3 ppm (bs, 0.5H), 7.46 ppm (m, 2H), 7.13 (m, 2H), 4.17 ppm (s 0.1H). MS (Electrospray+) 164 m/z (M+), 131 m/z (M-SH).
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[S:5].[C:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=O)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>CO>[N:2](=[C:16]([O:18][CH2:19][CH3:20])[C:15](=[N:2][NH:3][C:4]([NH2:6])=[S:5])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:3][C:4]([NH2:6])=[S:5]
Reactant: NNC(N)=S
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: Cl
Solvent: CO
Product: CCOC(=NNC(N)=S)C(Cc1ccccc1)=NNC(N)=S
Temperature: 25 °C
Reaction time: 11 h
Yield: 100.8 %

Procedure:
Thiosemicarbazide hydrochloride (8.30 g, 65.1 mmol) was dissolved in a mixed solvent of methanol (50 mL) and distilled water (50 mL). To the solution was added ethyl benzoylacetate (17.0 mL, 98.2 mmol) and concentrated hydrochloric acid (1.00 mL, 12.0 mmol), and the mixture was stirred at room temperature for 11 hours. The deposited solid was collected by filtration, washed (methanol) and then dried to give 3 phenyl-3-thiosemicarbazonopropionic acid ethyl ester (thiosemicarbazone) (11.1 g, 64%).
Reaction SMILES: C(NCC)C.[CH2:6]([O:8][C:9](=[O:22])[CH:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)[C:11](O)=O)[CH3:7].C=O>O>[Cl:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][C:10](=[CH2:11])[C:9]([O:8][CH2:6][CH3:7])=[O:22]
Reactant: CCOC(=O)C(Cc1cccc(Cl)c1)C(=O)O
Agent: C=O
Solvent: CCNCC
Solvent: O
Product: C=C(Cc1cccc(Cl)c1)C(=O)OCC

Procedure:
Diethylamine (27.6 g, 39 ml) is added dropwise with shaking to 3-chlorobenzylmalonic acid monoethyl ester (90.0 g) [Chem. Ber. 92, 203 (1959)], in a flask cooled in a water bath. Aqueous formaldehyde (37%, 38 ml) is added dropwise with shaking and cooling as before. Gas is evolved, and the reaction mixture becomes lighter in color. The mixture is stirred at room temperature for 65 hours, then water (500 ml) is added, and the solution extracted with ether (2×350 ml). The combined ether solutions are washed with water (300 ml), 3N HCl (2×200 ml) and water (300 ml). The ether solution is dried over magnesium sulfate, and the solvent removed under reduced pressure to give ethyl α-(3-chlorobenzyl)acrylate as a yellow oil, NMR (CDCl3) δ: 7.15 (m, 4H), 6.22 (s, 1H), 5.45 (m, 1H), 4.13 (q, 2H), 3.58 (s, 2H), 1.23 (t, 3H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16](O)=[O:17])=[N:10][CH:9]=1.Cl>C1COCC1>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[C:15]([CH2:16][OH:17])[CH:19]=[CH:20][CH:21]=2)=[N:10][CH:9]=1
Reactant: Cc1cnc(-c2cccc(C(=O)O)c2)o1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cnc(-c2cccc(CO)c2)o1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
To a stirred suspension of LiAlH4 (0.29 g, 7.41 mmol) in THF (12 mL) a solution of 3-(5-methyloxazol-2-yl)benzoic acid [628297-39-2] (1.21 g, 5.84 mmol) in THF (3 mL) was added dropwise at 25° C. (exothermic) and the mixture was stirred at 35° C. for 30 min. The mixture was poured into 1N aqueous HCl solution and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash-column chromatography over silicagel (eluent: gradient 10%-100% ethyl acetate/heptane) to yield the title compound (0.88 g, 80%). [1H NMR (400 MHz, CHLOROFORM-d) ♀ ppm 8.00 (s, 1H), 7.87-7.93 (m, 1H), 7.42 (d, J=4.8 Hz, 2H), 6.82 (s, 1H), 4.75 (br. s., 2H), 2.39 (s, 3H); LCMS RtA=0.75, [M+H]+=190.1].
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].[NH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>>[C:22]([C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:11]2[C:12]3[C:7](=[C:6]([OH:31])[C:5]([C:3]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4])=[N:14][CH:13]=3)[CH:8]=[C:9]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:10]2=[O:24])=[CH:17][CH:18]=1)#[N:23]
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccc(C#N)cc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1ccc(Cn2c(=O)c(-c3ccccc3)cc3c(O)c(C(=O)NCCC(=O)O)ncc32)cc1
Temperature: 25 °C
Yield: 68.2 %

Procedure:
A mixture of 1-(4-cyano-benzyl)-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (40 mg, 0.097 mmol), β-alanine (694 mg, 7.9 mmol) and NaOMe solution (12 mL, 5.8 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH 2 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 31 mg of the title compound as a brown solid. MS: (−) m/z 467.24 (M−1).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([CH2:30][CH3:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][N:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:29]=[C:28]([CH2:30][CH3:31])[S:27][C:17]=2[N:18]=1
Reactant: CCc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCCc1ccc2c(c1)OCCO2
Product: CCc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyrazin-2-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C:12]1([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:16](=[O:26])[NH:17][C@@H:18]([C@H:23]([OH:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:41][C:42](OC(C)=O)=[O:43]>C1COCC1.C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C:12]1([C:16](=[O:26])[NH:17][C@@H:18]([C@H:23]([O:25][C:42](=[O:43])[CH3:41])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)[C@@H](NC(=O)C1(Cc2ccccc2)CCCN1C(=O)OCc1ccccc1)[C@@H](C)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)C1(Cc2ccccc2)CCCN1C(=O)OCc1ccccc1)[C@@H](C)OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
Compound 4 (3 g, 6.60 mmol) was dissolved in THF (30 mL), Et3N (1.11 mL, 7.92 mmol) and Ac2O (742 mg, 7.26 mmol) were added at RT. The reaction mixture was stirred at RT for 2 h. The volatiles were evaporated under reduced pressure and the residue obtained was diluted with CH2Cl2 and washed with dilute HCl. The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography using 30% EtOAc/Hexane as eluent to yield compound 5 (2.5 g, 76%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([OH:24])([CH3:23])[C:20](O)=[O:21])[CH:15]=3)[C:10]([CH3:25])=[N:9]2)[CH:5]=[CH:4][N:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[NH:51]1[CH2:54][CH:53]([OH:55])[CH2:52]1.C(N(CC)CC)C>CN(C=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([OH:24])([CH3:23])[C:20]([N:51]4[CH2:54][CH:53]([OH:55])[CH2:52]4)=[O:21])[CH:15]=3)[C:10]([CH3:25])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)C(=O)O)ccc12
Reactant: OC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)C(=O)N3CC(O)C3)ccc12
Reaction time: 18 h

Procedure:
To a solution of 4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-hydroxy-2-methylbut-3-ynoic acid (100 mg, 0.30 mmol) in DMF (3 mL) was introduced O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (225 mg, 0.59 mmol), azetidin-3-ol hydrochloride (65 mg, 0.59 mmol) and triethylamine (0.12 mL, 0.89 mmol). After 18 hr at RT, the solution was re-treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (225 mg, 0.59 mmol), azetidin-3-ol hydrochloride (65 mg, 0.59 mmol) and triethylamine (0.12 mL, 0.89 mmol). After 3 hr at RT, the reaction mixture was diluted with water (2 mL) and extracted with EtOAc (2×5 mL extractions). The combined organic extracts were washed with water (5 mL) and brine (5 ml), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by silica gel flash column chromatography (DCM containing a 2-10% gradient of methanol) furnished the title compound as a colorless solid: 1H NMR (500 MHz, DMSO) delta 1.64 (3H, s), 2.58 (3H, s), 3.58-3.75 (1H, m), 4.09-4.19 (1H, m), 4.19-4.28 (1H, m), 4.49 (1H, s), 4.63-4.76 (1H, m), 5.67-5.81 (1H, m), 6.14 (1H, d, J=17.5 Hz), 6.98 (2H, s), 7.05 (1H, d, J=5.5 Hz), 7.38 (1H, d, J=8.7 Hz), 7.87 (1H, dd, J=8.2, 1.8 Hz), 8.27 (1H, d, J=5.5 Hz), 8.87 (1H, s); LC-MS: m/z=+393.05 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[NH:8][C:9](=O)[C:10]([CH2:14][CH3:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:9]1[C:10]([CH2:14][CH3:15])=[C:11]([CH3:13])[N:12]=[C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)[nH]c1=O
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 66 %

Procedure:
An 100-mL round bottomed flask was charged 2-(5-Chloro-2-thienyl)-5-ethyl-4-methyl-1H-pyrimidin-6-one (4 g, 15.7 mmol). POCl3 (16 ml) was added. The resulting mixture was stirred at 90 C for 6 hr. After cooling to room temperature, the volatile material was removed under reduced pressure and the residue was with NaHCO3 aq (100 ml). Dichloromethane was added. The organic layer was separated and passed through a plug of silica gel, using dichloromethane as eluent to give the title compound as a solid (2.82 g, 66% yield).
Reaction SMILES: I[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)[CH:5]=[C:4]([CH3:18])[N:3]=1.[Cl:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[CH:22][N:21]=1>>[Cl:19][C:20]1[N:25]=[C:24]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:5]=[C:4]([CH3:18])[N:3]=2)[CH:23]=[CH:22][N:21]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(I)n1
Reactant: Clc1ccnc(Cl)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)n2)n1

Procedure:
The title compound was prepared from 2-iodo-6-methyl-4-(4-trifluoromethyl-phenyl)pyridine (example A.31) (10.89 g, 30 mmol) and commercially available 2,4-dichlorpyrimidine (4.47 g, 30 mmol) according to the general procedure IVc protocol b. Obtained as an off-white solid (7.2 g, 68%). MS (ISP) 350.2 [(M+H)+] and 352 [(M+2+H)+].
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Cc1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Reactant: c1nc[nH]n1
Product: Cc1cc2c(NCc3ccccc3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.C([Li])CCC.[CH3:17][C:18]1[CH2:23][CH2:22][CH2:21][C:20]([CH3:25])([CH3:24])[C:19]=1[CH:26]=[O:27]>O1CCCC1>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([CH:26]([C:19]3[C:20]([CH3:25])([CH3:24])[CH2:21][CH2:22][CH2:23][C:18]=3[CH3:17])[OH:27])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: Brc1ccc2ccncc2c1
Reactant: CC1=C(C=O)C(C)(C)CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C(O)c2ccc3ccncc3c2)C(C)(C)CCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 122.7 %

Procedure:
A solution of 7-bromoisoquinoline (958 mg, 4.6 mmol) in tetrahydrofuran (15 mL) was added dropwise into n-butyl lithium (1.6 M in hexane, 2.87 mL, 4.6 mmol) at −78° C. and stirred at −78° C. for 30 minutes. Then 2,6,6-trimethylcyclohex-1-enecarbaldehyde (350 mg, 2.3 mmol) in tetrahydrofuran (2 mL) was added and the reaction was stirred at −78° C. for 1 hour and then allowed to warm to room temperature. The reaction was quenched with saturated aqueous ammonium chloride and the organics were extracted with ethyl acetate. The organic phase was washed with 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 give the title compound (794 mg, Yield: 100%). Rf 0.5 (2:1 petroleum ether/ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 8.49 (d, J=5.6 Hz, 1H), 8.04 (s, 1H), 7.78 (s, 2H), 7.64 (d, J=5.6 Hz, 1H), 5.56 (s, 1H), 2.05-2.00 (m, 2H), 1.70-1.56 (m, 4H), 1.35 (s, 3H), 1.24 (s, 3H), 1.16 (s, 3H) ppm; Mass spectrum (ESI +ve) m/z 282 (M+H+).
Reaction SMILES: Cl.[CH:2]1([C:5]([CH:7]2[CH2:9][CH2:8]2)=[NH:6])[CH2:4][CH2:3]1.[Cl:10]([O-:14])(=[O:13])(=[O:12])=[O:11].[NH4+]>CS(C)=O>[Cl:10]([O-:14])(=[O:13])(=[O:12])=[O:11].[N+:6]12[CH2:9][CH2:8][CH2:7][C:5]=1[CH2:2][CH2:3][CH2:4]2
Reactant: N=C(C1CC1)C1CC1
Agent: Cl
Agent: [NH4+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CS(C)=O
Product: C1CC2=[N+](C1)CCC2
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a solution of dicyclopropylmethanimine hydrochloride (1.00 g, 6.87 mmol) in 6.0 ml of dimethyl sulfoxide was added 1.68 g (1.37 mmol) of ammonium perchlorate. The mixture was heated with stirring at 100° C. for 6 hours. The solvent was distilled out in vacuo and isobutyl alcohol (6 ml) was added to the residue. Precipitated crystals was obtained and recrystallized from ethanol to afford 1.15 g (Yield: 80%) of the desired compound.