Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)=[C:9]([CH3:20])[S:8][C:7]=1[NH2:21])=[O:5])[CH3:2].[C:22]1(=O)[O:27][C:25](=[O:26])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([Br:19])=[CH:17][CH:18]=2)=[C:9]([CH3:20])[S:8][C:7]=1[N:21]1[C:25](=[O:26])[C:24]2[C:23](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:22]1=[O:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N)sc(C)c1CCc1ccc(Br)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: CCOC(=O)c1c(N2C(=O)c3ccccc3C2=O)sc(C)c1CCc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
A mixture of 2-Amino-4-[2-(4-bromophenyl)ethyl]-5-methyl-thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 30, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.C(=O)=O.[CH2:7]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[CH2:7]([N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:2][CH2:1][OH:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C1CO1
Reactant: CCCCCCCCCCCCCCCCCCNCc1ccccc1
Agent: O=C=O
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCN(CCO)Cc1ccccc1
Reaction time: 3 h

Procedure:
40 ml of ethylene oxide cooled with dry ice are added dropwise into a mixture of 65.9 g of N-benzyl-octadecyl amine and 200 ml of methanol at room temperature within 2 hours; the mixture is stirred for further 3 hours, the solvent removed and the residue purified by column chromatography (silica gel//chloroform).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[NH2:6].[C:18]([CH:21]=[C:22]=[O:23])(=[O:20])[CH3:19]>CCOC(C)=O>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[C:5]([NH:6][C:22](=[O:23])[CH2:21][C:18](=[O:20])[CH3:19])[CH:7]=[CH:8][C:9]=1[N:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1
Reactant: CC(=O)C=C=O
Reactant: Nc1ccc(N2CCOCC2)c(C(F)(F)F)c1
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)Nc1ccc(N2CCOCC2)c(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
A mixture of 3-trifluoromethyl-4-morpholinoaniline (4.0 g, 16.2 mmol), EtOAc (30 mL) and acetyl ketene (2.73 g, 32.5 mmol) was stirred at 90° C. overnight. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a yellow solid (4.0 g, 75%).
Reaction SMILES: [CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:25][CH:24]=4)[CH:21]=3)[N:16]([S:35]([C:38]3[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:45][C@H:46]1[CH2:48][O:47]1.CCN(C(C)C)C(C)C>C(O)C>[CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[CH:25][C:26]([N:29]5[CH2:30][CH2:31][N:32]([CH2:45][C@@H:46]([OH:47])[CH3:48])[CH2:33][CH2:34]5)=[CH:27][CH:28]=4)[CH:21]=3)[N:16]([S:35]([C:38]3[CH:39]=[CH:40][C:41]([CH3:42])=[CH:43][CH:44]=3)(=[O:37])=[O:36])[CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Reactant: C[C@H]1CO1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cc4)cnc32)cc1
Yield: 62 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-phenethyl-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (175 mg. 0.244 mmol) was alkylated using (S)-2-methyloxirane (26 mg, 0.488 mmol), DIPEA (171 μL, 0.977 mmol) and ethanol (5 mL) to get 100 mg (62.1% yield) of the titled compound. MS: m/z=661.7 (M+1).
Reaction SMILES: [CH2:1]1[C:5](=[O:6])[N:4]([CH2:7][C:8]([NH2:10])=[O:9])[CH2:3][CH:2]1[OH:11].[C:12](Cl)(=[O:14])[CH3:13]>>[C:8]([CH2:7][N:4]1[CH2:3][CH:2]([O:11][C:12](=[O:14])[CH3:13])[CH2:1][C:5]1=[O:6])(=[O:9])[NH2:10]
Reactant: CC(=O)Cl
Reactant: NC(=O)CN1CC(O)CC1=O
Product: CC(=O)OC1CC(=O)N(CC(N)=O)C1

Procedure:
A mixture of 5.33 g oxiracetam and 44.3 ml acetyl chloride is heated at reflux for 15 min. After cooling, the solvent is evaporated in vacuo and the oil remaining is taken up in a little aqueous sodium bicarbonate, and solid sodium bicarbonate is added with stirring until neutrality is achieved. Most of the water present is removed by treating with methyl isobutyl ketone in vacuo, the residue is taken up with methylene chloride, dried with sodium sulphate and evaporated in vacuo. The oil remaining is triturated in isopropyl alcohol/diethyl ether and recrystallised from 20:80 isopropyl alcohol/isopropyl ether to give 1-carbamoylmethyl-4-acetoxy-2-pyrrolidone which when purified by chromatography melts at 84°-86° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].I.[CH:18]1([NH:21][C:22](=[NH:25])SC)[CH2:20][CH2:19]1>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:22]([NH2:25])=[N:21][CH:18]2[CH2:20][CH2:19]2)=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reactant: CSC(=N)NC1CC1
Agent: I
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCc1ccc(NC(N)=NC2CC2)cc1
Yield: 11.1 %

Procedure:
The compound (0.946 g) obtained in Example 82 was added to a mixture of N-cyclopropyl-S-methylisothiourea hydroiodide (1.0 g) and pyridine (10 ml) and heated under reflux for 2 days. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=2:1) to give 0.131 g of the titled compound (yield, 12%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Br:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].S(Cl)([Cl:19])(=O)=O.C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[Cl:19])=[CH:12][C:11]([Br:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)c1[nH]c2ccc(Br)cc2c1Cl
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 85.8 %

Procedure:
A mixture of 5-bromoindole-2-carboxylic acid ethyl ester (4.00 g, 14.9 mmol), sulfurylchloride (1.8 mL, 22.4 mmol) and benzene (125 mL) was stirred at 90° C. for 2.5 h. The mixture was cooled to room temperature, NaHCO3 (aq., sat.) was added and the mixture extracted with EtOAc. The combined extracts were washed with water, brine and dried over Na2SO4. Concentration and recrystallisation (from toluene) gave the sub-title compound (3.87 g 85%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1[C:25]([C:26]2[NH:27][CH:28]=[C:29]([CH3:31])[N:30]=2)=[CH:24][N:23]=[C:22]([NH:32][CH2:33][CH2:34][NH:35]C2N=CC(C#N)=CC=2)[N:21]=1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:35][CH2:34][CH2:33][NH:32][C:22]2[N:21]=[C:20]([C:14]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=3[Cl:12])[C:25]([C:26]3[NH:27][CH:28]=[C:29]([CH3:31])[N:30]=3)=[CH:24][N:23]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: Cc1c[nH]c(-c2cnc(NCCNc3ccc(C#N)cn3)nc2-c2ccc(Cl)cc2Cl)n1
Product: Cc1c[nH]c(-c2cnc(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc2-c2ccc(Cl)cc2Cl)n1

Procedure:
{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[4-(2,4-dichlorophenyl)-5-(4-methylimidazol-2-yl)pyrimidin-2-yl]amine was prepared from 2-amino-6-chloro-3-nitropyridine using the general method for 6-[(2-{[4-(2,4-dichlorophenyl)-5-(4-methylimidazol-2-yl)pyrimidin-2-yl]amino}ethyl)amino]pyridine-3-carbonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[O:16][CH:15]([CH2:18]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:14][C:13]=3[CH:12]=[C:11]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:36][NH2:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[O:16][CH:15]([CH2:18][NH:37][CH3:36])[CH2:14][C:13]=3[CH:12]=[C:11]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN
Reactant: COc1cccc(-c2cc(-c3ccccc3)cc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)c1
Product: CNCC1Cc2cc(-c3ccccc3)cc(-c3cccc(OC)c3)c2O1

Procedure:
The title compound was prepared (0.053 g, 67%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(3-methoxyphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.10 g, 0.21 mmol) and methylamine (0.30 g, 9.8 mmol). mp 206-209° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1Br)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[Cu](C#N)[C:36]#[N:37]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:36]#[N:37])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: N#C[Cu]C#N
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2Br)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C#N)n1
Temperature: 170 °C
Yield: 48.1 %

Procedure:
A solution of (3,5-bis-trifluoromethyl-benzyl)-(2-bromo-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amine (6 g, 10.6 mmol) in DMF (20 mL) at room temperature was deoxygenated by bubbling nitrogen gas through the solution for 10 minutes. Copper cyanide (CuCN) (1.14 g, 12.8 mmol) was added to the reaction mixture and it was heated to 170° C. for 16 hours. The reaction was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed twice with saturated aqueous ammonium chloride solution and then washed with brine. It was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (silica gel, 320 g) (eluted over a gradient 5-25% ethyl acetate and hexane) to give 2.59 g (95%) of the title compound as yellow oil. 1H NMR (400 MHz, CDCl3) δ 4.2 (s, 3H) 4.82 (s, 2H) 4.9 (s, 2H) 7.6 (dd, 1H) 7.7 (s, 2H) 7.8(s, 2H) 7.8 (dd, 1H). MS (ES+) Calc: 508.1, Found: 509.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:34])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:22]3[N:23]=[CH:24][CH:25]=[C:26]([C:27]([O:29]C(C)(C)C)=[O:28])[C:21]3=[N:20][N:19]=2)=[CH:14][CH:13]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:34])[NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:22]3[N:23]=[CH:24][CH:25]=[C:26]([C:27]([OH:29])=[O:28])[C:21]3=[N:20][N:19]=2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1ccnn2c(-c3ccc(NC(=O)Nc4ccccc4C(F)(F)F)cc3)nnc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2nnc3c(C(=O)O)ccnn23)cc1)Nc1ccccc1C(F)(F)F
Yield: 96.1 %

Procedure:
A solution of tert-butyl 3-(4-(3-(2-(trifluoromethyl)phenyl)ureido)phenyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate (66G) (58 mg, 0.12 mmol) in a mixed solvent of TFA (0.5 mL) and CH2Cl2 (0.5 mL) was stirred at room temperature for 3 h. Analysis by LC/MS indicated the starting material was consumed. The reaction was concentrated under reduced pressure, chased with CH2Cl2 (2×) and dried in high vacuum for 2 h to afford 51 mg of the title compound as a yellow solid. HPLC/MS (Method B): retention time=2.81 min, [M+H]+=443.3.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1.[C:12]([OH:21])(=[O:20])[C@H:13]([C@@H:15]([C:17]([OH:19])=[O:18])[OH:16])[OH:14]>CCO>[C:17]([C@H:15]([C@@H:13]([C:12]([OH:21])=[O:20])[OH:14])[OH:16])([OH:19])=[O:18].[NH:1]1[CH2:11][CH2:10][CH2:9][C@H:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1
Reactant: CCOC(=O)C1CCCNC1
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CCO
Product: CCOC(=O)[C@H]1CCCNC1
Temperature: 25 °C

Procedure:
Ethyl nipecotate (70.2 g, 0.446 mmol) and D-tartaric acid (67.0 g, 1.0 eq.) were dissolved in hot 95% EtOH (350 mL). The resulting solution was cooled to room temperature, filtered, and the crystals washed with ice-cold 95% EtOH. The product was then recrystallized from 95% EtOH (550 mL) to give ethyl (S)-nipecotate D-tartrate (38.5 g, 56% yield). The salt (38.5 g) was dissolved in water (300 mL), cooled to 0° C., and 3M NaOH was added until the pH was 9-10. The resulting solution was extracted with CH2Cl2 (5×100 mL) and the combined organics dried over Na2SO4, filtered, and concentrated under reduced pressure to give Compound (41) as a clear oil (19 g, 89% yield). CIMS: MH+=158.
Reaction SMILES: [CH2:1]([N:4]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5]1)[CH2:2][CH3:3].[F:15][C:16]([F:30])([F:29])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([N:4]1[CH2:5][CH:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:25]([C:22]3[CH:21]=[CH:20][C:19]([CH2:18][CH2:17][C:16]([F:15])([F:29])[F:30])=[CH:24][CH:23]=3)(=[O:27])=[O:26])=[CH:12][CH:13]=2)[CH2:7]1)[CH2:2][CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(CCC(F)(F)F)cc1
Reactant: CCCN1CC(c2ccc(N)cc2)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(CCC(F)(F)F)cc3)cc2)C1
Yield: 11.7 %

Procedure:
Following the same procedure as described in example 55, 4-(1-propyl-azetidin-3-yl)phenylamine (100 mg, 0.52 mmol) in CH2Cl2/pyridine 9:1 (12 ml) was treated with 4-(3,3,3-trifluoro-propyl)-benzenesulfonyl chloride (214 mg, 0.78 mmol). Purification of the crude product by flash column chromatography (CH2Cl2:methanol, 95:5) provided the title compound (26 mg, 11%) as a colourless gum.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[F-:13].[K+].O>CC#N>[C:8]([C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=[C:2]([F:13])[N:7]=1)#[N:9]
Reactant: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1nc(F)ccc1[N+](=O)[O-]
Reaction time: 18 h

Procedure:
A mixture of 6-chloro-2-cyano-3-nitropyridine [Colbry, N. L.; Elslager, E. F.; Werbel, L. M.; J. Het. Chem., 1984, 21, 1521-1525] (10.0 g, 0.054 mol) and KF (9.48 g, 0.163 mol) in MeCN (200 mL) is heated under reflux with stirring for 18 h, then poured into water and extracted with EtOAc. The extract is washed with water and worked up, and the residue is chromatographed on silica gel, eluting with EtOAc/petroleum ether (3:7), to give after removal of the solvent under reduced pressure 2-cyano-6-fluoro-3-nitropyridine (7.2 g, 79%). 1H NMR (CDCl3) δ 8.79 (1H, dd, J=9.0, 6.0 Hz), 7.48 (1H, dd, J=9.0, 3.0 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][CH:3]=1.Cl.[NH:13]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])N>C(O)C.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3[C:23]4[C:15](=[C:16]([C:17]([OH:19])=[O:18])[CH:20]=[CH:21][CH:22]=4)[NH:13][C:8]=32)=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: NNc1ccccc1C(=O)O
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc2c3c([nH]c12)-c1cc(Br)ccc1C3
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of 6-bromoindanone (0.447 g, 2.12 mmol) [Adamczyk, M. et al. J. Org. Chem. 1984, 49, 4226-4237] in ethanol (100 mL) was added a solution of 2-hydrazinobenzoic acid hydrochloride (0.800 g, 4.24 mmol) in deionized water (50 mL). The mixture was stirred for 1 h then cooled to 0° C. The precipitated hydrazone was vacuum filtered and dried in vacuo to afford 0.628 g (86%) of the title compound as a yellow solid: mp 186° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:7][C:8]([NH2:12])=[N:9]2)=[CH:4][CH:3]=1.[N:19]([C:22]1[C:23](=[O:28])[NH:24][CH:25]=[CH:26][CH:27]=1)=[C:20]=[O:21].C(N(C(C)C)CC)(C)C>>[NH2:12][C:8]1[CH:7]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([C:20]([NH:19][C:22]3[C:23](=[O:28])[NH:24][CH:25]=[CH:26][CH:27]=3)=[O:21])[CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: O=C=Nc1ccc[nH]c1=O
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCN(C(=O)Nc3ccc[nH]c3=O)CC2)c2ccc(Cl)cc2n1

Procedure:
As described example 159, 7-chloro-4-(1-piperazinyl)-2-quinolinamine, 3-isocyanato-2(1H)-pyridinone, and diisopropylethyl amine, are reacted to give the title product as a white solid. LC-MS: 399 (M++1). 1H NMR (DMSO-d6) δ 7.95 (m, 2H), 7.76 (d, 1H), 7.40 (s, 1H), 7.12 (m, 1H), 7.0 (d, 1H), 6.45 (m, 2H), 6.25 (s, 1H), 6.22 (m, 1H), 3.75 (m, 4H), 3.10 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.Cl[C:21]1[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:21]3[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: NCC1CCN(C(=O)OCc2ccc(Cl)cc2)CC1
Reactant: Fc1cnc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(OCc1ccc(Cl)cc1)N1CCC(CNc2ncc(F)cn2)CC1

Procedure:
A solution of (4-chloro-benzyl)-4-(aminomethyl)piperidine-1-carboxylate (INTERMEDIATE 2B) (0.10 g, 0.35 mmol), 2-chloro-5-fluoro-pyrimidine (0.047 g, 0.35 mmol) and triethylamine (0.099 mL, 0.71 mmol) in DMF (1 mL) was heated at 100° C. for 6 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2/IPA/hexanes) to give 4-[(5-fluoro-pyrimidin-2-ylamino)-methyl]-piperidine-1-carboxylic acid-4-chloro-benzyl ester. M.S. (M+1): 379.26
Reaction SMILES: [F:1][C:2]1[C:12]([C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[H-].[Na+].[CH2:27](Br)[C:28]#[CH:29].O>CN(C=O)C>[F:1][C:2]1[C:12]([C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=2)=[CH:11][C:5]2[N:6]([CH2:29][C:28]#[CH:27])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc3c(cc2F)OCC(=O)N3)c1=O
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCN1C(=O)COc2cc(F)c(-c3ccc(C(F)(F)F)n(C)c3=O)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
0.3 g (0.87 mmol) of 3-(7-fluoro-2,3-dihydro-1,4-benzoxazin-3-on-6-yl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone was dissolved in 1 ml of DMF, and 0.04 g (1 mmol) of 60% sodium hydride was added under cooling with ice, followed by stirring at room temperature for 15 minutes. Then, 0.12 g (1 mmol) of propargyl bromide was added thereto. The mixture was stirred at room temperature for 3 hours, then poured into water and extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and then, the obtained residue was purified by silica gel column chromatography to obtain 0.24 g (yield: 72%) of the desired product. Melting point: 166-168° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCOCC1>[CH2:24]([NH:31][C:6]1[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=[C:2]([NH2:1])[N:7]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Solvent: C1COCCO1
Product: Nc1nc(NCc2ccccc2)c([N+](=O)[O-])c(-c2ccco2)n1
Yield: 77.8 %

Procedure:
To a stirred solution of 335 mg (0.95 mmol) trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester in 20 ml dioxane was added 1.03 ml (9.46 mmol) benzylamine and the mixture heated at reflux for 1 hour. The reaction mixture was then concentrated in vacuo. Chromatography (ethyl acetate) followed by recrystallisation from ether/hexane afforded 230 mg (78%) N4-benzyl-6-furan-2-yl-5-nitro-pyrimidine-2,4-diamine as a yellow crystalline solid. ES-MS m/e (%): 312 (M+H+, 100).
Reaction SMILES: CC(O)=O.[CH3:5][C:6](=O)[CH2:7][C:8](=O)[CH3:9].C([O-])(=O)CO.[NH2:17][C:18]1[NH:22][N:21]=[C:20]([CH2:23][OH:24])[N:19]=1>CC(OC)(C)C>[CH3:5][C:6]1[CH:7]=[C:8]([CH3:9])[N:22]2[N:21]=[C:20]([CH2:23][OH:24])[N:19]=[C:18]2[N:17]=1
Reactant: CC(=O)CC(C)=O
Reactant: Nc1nc(CO)n[nH]1
Agent: O=C([O-])CO
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: Cc1cc(C)n2nc(CO)nc2n1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
To a 10 L reactor was charged HOAc (4.7 L), 2,4-Pentanedione (543 mL, 5.29 mol), and the glycolate salt of (5-amino-1H-1,2,4-triazol-3-yl)methanol (944 g, 4.96 mol). The mixture was heated to 100° C. until the solution was homogeneous. After reaching 100° C., the solution should be nearly homogeneous. The time at 100° C. should be ˜15–30 min. After this time, if the solution remains cloudy heating should be discontinued. The resulting solution was cooled to ambient temperature, and MTBE (16 L) was added and the mixture stirred for 30 min. The mixture was filtered through a 14″ Buchner, rinsed with MTBE (7 L), and dried in a vacuum oven overnight at 50° C. to provide 518 g (59%) of (5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methanol as a white solid. The filtrate contained significant product, so a second crop was isolated by charging the MTBE filtrates to a 22 L reactor and cooling to 0° C. MTBE (8 L) was added and stirred for 2 hours. The resulting slurry was filtered and dried to yield an additional 173.7 g (20%) of (5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methanol as a grey solid. Both crops were carried forward. 1H NMR (300 MHz, d6-DMSO): 2.57 (s, 3), 2.71 (d, 3, J=0.8), 4.63 (uneven d, 2, J=5.7), 5.49 (t, 1, J=6.2), 7.13 (d, 1, J=0.8).
Reaction SMILES: [CH:1]1([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.Cl>C(Cl)Cl>[CH:1]1([N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[S:26]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH2:4][CH2:3][CH2:2]1
Reactant: Fc1cccc(NC2CCC2)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(F)cc1)N(c1cccc(F)c1)C1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
To a solution of cyclobutyl-(3-fluoro-phenyl)-amine (447 mg, 2.7 mmol) in DCM (8 mL) was added pyridine (438 μL, 5.4 mmol) followed by 4-fluorobenzenesulfonyl chloride (633 mg, 3.3 mmol) in DCM (3 mL) and then the reaction was stirred at room temperature for 2 hrs. The reaction was left to stand at room temperature for 64 hours. 1 M aqueous HCl was added then extracted with DCM, filtered through a phase separator and then purified by silica gel column chromatography (0-50% DCM in cyclohexane) to give N-cyclobutyl-4-fluoro-N-(3-fluoro-phenyl)-benzenesulfonamide (756 mg, 2.3 mmol, 85%). LCMS (m/z, Method A) ES+ 324 [M+1]+.