Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[CH2:19]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCC=Cc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1OCC=Cc1ccccc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 59.1 %

Procedure:
In 200 ml of DMF, 41.4 g of N-hydroxyphthalimide and 18 g of potassium carbonate were suspended. Fifty grams of cinnamyl bromide were added, followed by stirring at 120° C. for 5 hours. After completion of the reaction, the reaction mixture was cooled and then poured into about 500 ml of water. Crystals thus precipitated were collected by filtration, dried and then recrystallized from a mixed solvent of acetone and isopropyl ether, thereby obtaining 41.9 g of N-cinnamyloxyphthalimide.
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]3[C:14](=[O:17])[O:15][CH2:16][C:12]=3[CH:11]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([CH2:30][C:31](=O)[CH3:32])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>>[CH3:20][O:21][C:22]1[CH:29]=[C:28]([CH2:30][CH:31]([N:5]2[CH2:6][CH2:7][N:2]([CH2:8][CH2:9][C:10]3[CH:11]=[C:12]4[C:13](=[CH:18][CH:19]=3)[C:14](=[O:17])[O:15][CH2:16]4)[CH2:3][CH2:4]2)[CH3:32])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Reactant: COc1cc(CC(C)=O)ccc1C#N
Agent: Cl
Product: COc1cc(CC(C)N2CCN(CCc3ccc4c(c3)COC4=O)CC2)ccc1C#N

Procedure:
2-Methoxy-4-[2-[4-[2-(1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]propyl]benzonitrile was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and 2-methoxy-4-(2-oxopropyl)benzonitrile. LC-MS (IE, m/z): 420.6 [M+1]+. (0.21 μM)
Reaction SMILES: Br[C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[F:18])=[N:4][N:5]([CH3:9])[C:6]=1[C:7]#[N:8].C([Sn](CCCC)(CCCC)[C:24]1[C:28]([CH3:29])=[CH:27][S:26][C:25]=1[CH3:30])CCC.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[CH3:30][C:25]1[S:26][CH:27]=[C:28]([CH3:29])[C:24]=1[C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[F:18])=[N:4][N:5]([CH3:9])[C:6]=1[C:7]#[N:8]
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(C)csc1C
Reactant: COc1ccc(-c2nn(C)c(C#N)c2Br)c(F)c1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(-c2nn(C)c(C#N)c2-c2c(C)csc2C)c(F)c1
Temperature: 85 °C
Yield: 31.1 %

Procedure:
4-bromo-3-(2-fluoro-4-methoxyphenyl)-1-methyl-1H-pyrazole-5-carbonitrile (49 mg, 0.16 mmol), tributyl(2,4-dimethylthiophen-3-yl)stannane (82.24 mg, 0.20 mmol), Pd2(dba)3 (14.44 mg, 0.02 mmol) and trio-tolylphosphine (9.6 mg, 0.03 mmol) were mixed with 1.5 mL DMF and the mixture was degassed under nitrogen in a vial. The vial was sealed and the reaction was heated at 85° C. over night. Water was added, the mixture was extracted with CH2Cl2 and the organic layer was concentrated. The crude product was purified on silica to give 4-(2,4-dimethylthiophen-3-yl)-3-(2-fluoro-4-methoxyphenyl)-1-methyl-1H-pyrazole-5-carbonitrile (17 mg, 32%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[CH3:9][O:10][C:11]([CH2:13][CH2:14][CH:15]=[C:16]([CH3:24])[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:24][C:16]([C:7]1[CH:8]=[C:1]([OH:2])[CH:3]=[CH:4][C:5]=1[OH:6])([CH2:15][CH2:14][CH2:13][C:11]([O:10][CH3:9])=[O:12])[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)CCC=C(C)CCCC(=O)OC
Reactant: Oc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)CCCC(C)(CCCC(=O)OC)c1cc(O)ccc1O

Procedure:
5.5 Parts of hydroquinone, 22,8 parts of 1,7-dimethoxycarbonyl-4-methylhept-3-ene and 1.0 parts of p-toluene sulphonic acid, are heated on a steam-bath for 3 days. After dilution with ether the reaction mixture is washed with sodium bicarbonate solution, water, evaporated and distilled to give dimethyl 5-methyl-5-(2,5-dihydroxyphenyl)-azelate, [formula (135)], b0.1 260°-269° C. with the following percentage composition by weight.
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1COCC1.[N:24]#[C:25][NH2:26].[Na].Cl>O>[C:1]([NH:26][C:25]#[N:24])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: N#CN
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCC(=O)NC#N
Reaction time: 43 h
Yield: 96.3 %

Procedure:
A solution of palmitoyl chloride (5.5 g, 0.020 mol) in 50 ml of freshly distilled dry THF was added drop-wise to a suspension of sodium cyanamide (3.84 g. 0.060 mol) in 150 ml of freshly distilled dry THF at ice bath temperature. After the addition, the ice bath was removed and the reaction was allowed to proceed at 25° C. for 43 hours. The solids that formed were filtered to yield 8.48 g of waxy solid residue. The residue was ground to a fine powder and stirred in 150 ml of distilled water at ice bath temperature. The resulting soapy suspension (pH 11) was acidified to pH 2 with 10% HCl, then filtered and air-dried to give 5.4 g (96.3% yield) of crude 6 as a white solid. This was dissolved in warm THF and the mixture filtered. The filtrate was concentrated in vacuo until the solution became slightly turbid. This material was crystallized from THF/petroleum ether to yield 3.6 g (crop 1) of white powder. The filtrate was concentrated and crystallized in the same fashion to yield additional 0.6 g (crop 2) of white powder (74.8% total yield), mp 62°-65° C. TLC: Rf =0.68 in ethyl acetate/petroleum ether/glacial acetic acid (10:20:1); IR (Nujol, cm-1) 3230 (NH), 2250 (C≡N), 1740 (C=O); NMR (Silanor C, δ from TMS) 1.3-1.6 (t, --CH2 --CH2 --C=O), 1-1.8 (m, --(CH2)13 --), 0.8-1 (t, CH3 --CH2 --); Anal. Calcd for C17H32N2O: C, 72.81; H, 11.50; N, 9.99. Found: C, 72.69; H, 11.65; N, 9.68.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:24])[F:23])=[O:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:32]([O:34][C:35]([C@@H:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[C:42](O)=[O:43])=[O:36])[CH3:33].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1CCCC1=O.C(OCC)(=O)C>[CH2:32]([O:34][C:35]([CH:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[C:42]([N:5]1[CH2:6][CH2:7][N:2]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:23])([F:25])[F:24])=[O:16])=[CH:10][CH:9]=2)[CH2:3][CH2:4]1)=[O:43])=[O:36])[CH3:33]
Reactant: CCOC(=O)[C@@H]1CCC[C@H]1C(=O)O
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCCC1C(=O)N1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
To a solution of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl-phenyl)-amide hydrochloride (212 mg, 0.435 mmol), racemic trans-cyclopentane-1,2-dicarboxylic acid monoethyl ester (81 mg, 0.435 mmol) and triethylamine (305 μL, 2.17 mmol) in 5 mL 1-methyl-2-pyrrolidinone was added (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP, 202 mg, 0.456 mmol) in one portion and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water, saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography (eluted with ethyl acetate/hexane) to yield rac-2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid ethyl ester as an amorphous solid (236 mg, 93%). ES-MS calcd for C30H31F3N4O5 (m/e) 584.60, obsd 585 (M+H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[NH3:11].O>C(O)C>[ClH:1].[NH2:11][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CCl)c1ccccc1
Reactant: N
Solvent: O
Solvent: CCO
Product: Cl
Product: NCC(=O)c1ccccc1
Reaction time: 8 h
Yield: 20 %

Procedure:
15.5 g of ω-chloroacetophenone are dissolved while stirring in 200 ml of ethanol saturated with ammonia. After standing overnight, the orange-coloured solution is poured onto 500 ml of water. The precipitating oil is separated off and taken up with 80 ml of 20% hydrochloric acid Concentration give 5 g (20% yield) of ω-aminoacetophenone hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31](F)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[CH3:35][CH2:36][N:37]([CH:41](C)C)[CH:38](C)C.C[N:45]1C(=O)CCC1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:33]=[CH:32][C:31]([NH:45][CH2:35][CH2:36][N:37]([CH3:41])[CH3:38])=[N:30][CH:29]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(F)nc4)ccc2OCC3)c(F)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN1CCCC1=O
Product: CN(C)CCNc1ccc(-c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cn1
Temperature: 150 °C
Yield: 13 %

Procedure:
2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (470 mg, 1.0 mmol), from the procedure for 249, 2-(N,N-Dimethyl)-ethylamine (90 mg, 1.2 mmol), DIPEA (340 mg, 3 mmol) and NMP (4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 150° C. for 120 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 296 (69 mg, yield: 13%). 1HNMR (DMSO-d6, 400 MHz): δ9.50 (s, 1H), 8.72 (s, 1H), 8.31 (s, 1H), 7.97-7.91 (m, 2H), 7.77-7.72 (m, 2H), 7.48-7.43 (m, 2H), 7.15 (s, 1H), 6.99 (s, 1H), 6.72 (d, J=4.4 Hz, 1H), 4.31 (s, 2H), 3.86 (s, 2H), 3.33 (s, 2H), 3.33 (s, 2H), 3.15 (s, 2H), 2.75 (s, 6H). ESI-MS: m/z=546 [M+H+]
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CN(C=O)C.[CH2:28](I)[CH3:29]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:28][CH3:29])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2)CC1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A mixture of 1-(tert-butyloxycarbonyl)-4-(4-hydroxyphenyl)piperazine (XXII, 0.602 g, 2.2 mmol) in dry THF (4 ml) is added to an ice-cooled slurry of sodium hydride (0.1013 g, 2.5 mmol--60% in oil) in THF (1 ml). DMF (15.3 ml) is added to solubilize the solids that had precipitated, after which ethyl iodide (0.34 ml, 4.3 mmol) is added. The ice/water bath is removed and the mixture stirred for five hr. Another portion of ethyl iodide (0.35 ml, 4.4 mmol) is added and the mixture is allowed ti stir over the weekend at 20-25°, at which time it is concentrated and the resulting solids are partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The combined organic phases are dried over magnesium sulfate, concentrated, and the residue chromatographed on silica gel eluting with methanol/dichloromethane (1/99) containing ammonium hydroxide (0.5%), followed by methanol/dichloromethane (2/98) containing ammonium hydroxide (0.5%). The appropriate fractions are pooled and concentrated to give 1-(tert-butyloxycarbonyl)-4-(4-ethoxyphenyl)piperazine (XXIII). 1-(Tert-butyloxycarbonyl)-4-(4-ethoxyphenyl)-piperazine (XXIII, 0.43 g) is dissolved in methanol and methanol saturated with hydrochloric acid gas is added. After stirring at 20-25° for 5 hours the slurry is concentrated and ether is added. The solids are collected, washed with ether, and dried to give 1-(4-ethoxyphenyl)piperazine dihydrochloride (XXIV), MS (m/z) 206; IR (mineral oil) 1253, 1511, 2542, 2432, 1475 and 2622 cm-1.
Reaction SMILES: C[O:2][C:3]1[C:8]2[CH2:9][C@@H:10]3[C@@H:15]([CH2:16][C:7]=2[CH:6]=[CH:5][CH:4]=1)[N:14]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:12][CH2:11]3.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[C:8]2[CH2:9][C@@H:10]3[C@@H:15]([CH2:16][C:7]=2[CH:6]=[CH:5][CH:4]=1)[N:14]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:12][CH2:11]3
Reactant: CCCN1CCC[C@@H]2Cc3c(cccc3OC)C[C@H]21
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CCCN1CCC[C@@H]2Cc3c(O)cccc3C[C@H]21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.6 g of trans-1,2,3,4,4a,5,10,10a-octahydro-6-methoxy-N-n-propylbenzo[g]quinoline are dissolved in 100 ml of methylene chloride. 1.5 ml of boron tribromide, dissolved in 20 ml of methylene chloride are added dropwise and the mixture is stirred for 1.5 hours at room temperature. An excess of methanol is added to the mixture which is then concentrated in vacuum. This is repeated twice.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:30]=[CH:29][C:12]([O:13][C:14]2[C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]=[C:16]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[N:15]=2)=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:30]=[CH:29][C:12]([O:13][C:14]2[C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]=[C:16]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[N:15]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2nc(-c3cccnc3)ncc2C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(Oc2nc(-c3cccnc3)ncc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 202.7 %

Procedure:
To a solution of Compound 17b (1.5 g; 3.6 mmol) in CH2Cl2 (30 mL) was adde TFA (10 mL). The solution was stirred at room temperature for 1.5 h, and the solvent was evaporated in vacuo. The residue was triturated with Et2O, collected the solid and dried to afford the title Compound 17c (2.25 g; 96% yield based on tri-TFA salt). MS: m/z 309.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O.C(N(CC)CC)C.[CH3:27][N:28]1[C:32](=[O:33])[CH2:31][C:30]([CH3:34])=[N:29]1.CC(C)(O)C#N>C(Cl)(=O)C(Cl)=O.CN(C)C=O>[OH:33][C:32]1[N:28]([CH3:27])[N:29]=[C:30]([CH3:34])[C:31]=1[C:9]([C:8]1[C:7]([CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:15][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:12]=1)=[O:11]
Reactant: COCCOCc1nc(C(F)(F)F)ccc1C(=O)O
Reactant: CC1=NN(C)C(=O)C1
Agent: CC(C)(O)C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCOCc1nc(C(F)(F)F)ccc1C(=O)c1c(C)nn(C)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
1.0 g (0.004 mol) of 2-(2-methoxyethoxymethyl)-6-trifluoromethylnicotinic acid is dissolved in 10 ml of oxalyl chloride. Three drops of dimethylformamide are added, and the mixture is stirred at room temperature for 1 hour. The mixture is then concentrated using a rotary evaporator, and the residue (2-(2-methoxyethoxymethyl)-6-trifluoromethylnicotinoyl chloride) is taken up in 10 ml of methylene chloride. At a temperature of 0° C., 0.84 ml (0.006 mol) of triethylamine and 0.45 g (0.004 mol) of 2,5-dimethyl-2,4-dihydropyrazol-3-one are added. After 2 hours at a temperature of 22° C. the solvent is removed using a vacuum rotary evaporator, and the residue that remains is dissolved in 10 ml of acetonitrile and, to rearrange the intermediate (2,5-dimethyl-2H-pyrazol-3-yl 2-(2-methoxyethoxymethyl)-6-trifluoromethytnicotinate), admixed with 0.1 ml of acetone cyanohydrin and 1.13 ml (0.008 mol) of triethyamine. The reaction solution is stirred at room temperature for four hours and then concentrated. The syrup that remains is chromatographed on silica gel. The viscous oil obtained by eluting with a mixture of toluene, ethyl alcohol, dioxane, triethylamine and water (100:40:20:20:5 parts by volume) is dissolved in ethyl acetate and washed successively with 10% hydrochloric acid and water. The organic solution is dried over Na2SO4 and concentrated, giving 0.93 g of (5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)-[2-(2-methoxyethoxymethyl)-6-trifluoromethylpyridin-3-yl]methanone in the form of a viscous oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=O)=[CH:12][CH:11]=1.[OH-].[NH4+].[OH-].[Na+]>>[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]2[NH:1][C:2]3=[N:3][CH:4]=[CH:5][CH:6]=[C:7]3[N:8]=2)=[CH:12][CH:11]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: Nc1cccnc1N
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc(-c2nc3cccnc3[nH]2)cc1
Temperature: 180 °C
Yield: 4.4 %

Procedure:
A mixture of 2,3-diaminopyridine (10.9 g, 0.1 mole), p-chlorobenzoic acid (16.0 g, 0.102 mole), and 150 g of polyphosphoric acid was heated at 180° C. in an oil bath for 31/2 hr. The reaction mixture was neutralized with concentrated ammonium hydroxide and basified with sodium hydroxide. The precipitate was filtered and washed with water. The solid was treated with dilute sodium hydroxide, filtered, washed with water, and dried under high vacuum at 60° C. overnight. A 3-g sample was dissolved in hot methanol, and the solution was treated with 3 g of charcoal, and filtered through a Celite pad. The product crystallized from the filtrate upon cooling. The precipitate was filtered, washed with methanol-water (2:1), and dried under high vacuum at 70° C. to give 1.0 g of the title compound, mp 305°-8° C. with sublimation.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:18]([O:25][C:26](Cl)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C>ClCCl>[CH2:18]([O:25][C:26](=[O:27])[NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccc(CN)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NCc1ccc(CNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A solution of 1,4-bis(aminomethyl)benzene (10.0 g, 74 mmol) and triethylamine (9.8 ml, 74 mmol) in dichloromethane (480 ml) was cooled to 0° C. and treated with a solution of benzylchloroformate (10.5 ml, 74 mmol) in dichloromethane (250 ml). The resulting mixture was allowed to warm gradually to room temperature of a period of 16 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (450 ml) and 1M aqueous sodium hydroxide (300 ml). The resulting biphasic mixture was filtered and the organic phase separated, dried (magnesium sulfate) and reduced in vacuo to give a waxy solid. Trituration with hot ethyl acetate followed by concentration of the liquors gave the title compound as a waxy solid (7.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:5].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([S:28](Cl)(=[O:30])=[O:29])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>N1C=CC=CC=1>[Br:17][C:14]1[CH:15]=[CH:16][C:2]([NH:1][S:28]([C:22]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:20]([O:19][CH3:18])[CH:21]=2)(=[O:30])=[O:29])=[C:3]([CH:13]=1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:5]
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1F
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(Br)cc2C(=O)c2ccccc2F)cc1OC

Procedure:
20 g of 2-amino-5-bromo-2'-fluorobenzophenone are heated at 85° C. for 48 hours in 120 ml of dry pyridine in the presence of 20 g of 3,4-dimethoxyphenylsulfonyl chloride. The mixture is cooled, poured into ice-cold water, the solid is filtered off, the solid is extracted with AcOEt, the organic phase is washed with water, a solution of hydrochloric acid (1N), water and then saline water. After drying over magnesium sulfate and evaporating the solvent under vacuum, a solid is obtained which is recrystallized from DCM/isopropyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][C:16]2[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:6]([CH:14]=1)[C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8].C(N)(N)=[O:24].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][C:16]2[C:17]([F:22])=[N+:18]([O-:24])[CH:19]=[CH:20][CH:21]=2)=[C:6]([C:7](=[O:8])[N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:14]=1
Reactant: CCN(CC)C(=O)c1cc(Br)ccc1Oc1cccnc1F
Reactant: NC(N)=O
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cc(Br)ccc1Oc1ccc[n+]([O-])c1F
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-N,N-diethyl-2-(2-fluoropyridin-3-yloxy)benzamide (1.4 g, 3.81 mmol) and urea peroxide (1.076 g, 11.44 mmol) in 10 mL of DCM at 0 C was added dropwise trifluoroacetic anhydride (1.601 mL, 11.44 mmol) and the resulting reaction was stirred overnight. LCMS showed only less than 50% of desired conversion. The mixture was evaporated to dryness, quenched with Sat. NaHCO3, extracted with EA, dried over Na2SO4, filtered and evaporated to dryness. CC (DCM to DCM/EA=3:1 to DCM/MeOH=100:2 to 100:5 to 100:10) gave 3-(4-bromo-2-(diethylcarbamoyl)phenoxy)-2-fluoropyridine 1-oxide as an offwhite solid.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.S(Cl)([Cl:19])=O.CN(C=O)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([Cl:19])=[O:8])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Br)nn1-c1ncccc1Cl

Procedure:
1.52 g of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid was dissolved in 10 ml of chloroform, 0.55 ml of thionyl chloride was dropwise added, and 0.05 ml of DMF was added, followed by reflux for 30 minutes. After the reaction liquid was stood to cool, the solvent was distilled off under reduced pressure to obtain crude product of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride. A mixed solution comprising the above crude product and 5 ml of chloroform was dropwise added to a mixed solution comprising 0.85 g of 4-methoxybenzyl alcohol, 1.11 ml of triethylamine and 20 ml of chloroform under cooling with ice, followed by stirring for 5 minutes and reaction at room temperature for 1.5 hours. The reaction solvent was distilled off under reduced pressure, and 50 ml of water was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 3/1) to obtain 1.6 g of the desired product (melting point: 83° C.).