Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:43])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([CH3:42])=[C:10]([O:15][C:16]2[C:21]([Br:22])=[CH:20][N:19]=[C:18]([NH:23][C:24]3[S:28][N:27]=[C:26]([CH:29]4[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]4)[N:25]=3)[CH:17]=2)[C:11]([CH3:14])=[N:12][CH:13]=1)=[O:7].[Cl:44]CCl.[ClH:47]>CO>[ClH:44].[ClH:47].[Br:22][C:21]1[C:16]([O:15][C:10]2[C:11]([CH3:14])=[N:12][CH:13]=[C:8]([C:9]=2[CH3:42])[C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:43])=[O:7])=[CH:17][C:18]([NH:23][C:24]2[S:28][N:27]=[C:26]([CH:29]3[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]3)[N:25]=2)=[N:19][CH:20]=1
Reactant: ClCCl
Reactant: Cc1ncc(C(=O)NCCN(C)C)c(C)c1Oc1cc(Nc2nc(C3CCN(C(=O)OC(C)(C)C)CC3)ns2)ncc1Br
Agent: Cl
Solvent: CO
Product: Cc1ncc(C(=O)NCCN(C)C)c(C)c1Oc1cc(Nc2nc(C3CCNCC3)ns2)ncc1Br
Reaction time: 8 h
Yield: 100 %

Procedure:
tert-Butyl 4-(5-(4-(5-((2-(dimethylamino)ethyl)carbamoyl)-2,4-dimethylpyridin-3-yloxy)-5-bromopyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate (prepared according to Example 9; 0.025 g, 0.037 mmol) was dissolved in a mixture of methanol:dichloromethane (1 mL each). HCl (4N in dioxane, 0.5 mL, 2.0 mmol) was added. The reaction stirred overnight. The solution was concentrated to give 5-(5-bromo-2-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-ylamino)pyridin-4-yloxy)-N-(2-(dimethylamino)ethyl)-4,6-dimethylnicotinamide dihydrochloride (0.028 g, 100% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.87-1.93 (m, 2H), 2.06-2.14 (m, 2H), 2.22 (s, 3H), 2.34 (s, 3H), 2.83 (s, 3H), 2.84 (s, 3H), 2.96-3.08 (m, 2H), 3.23-3.32 (m, 4H), 3.44-2.52 (m, 1H), 3.62-3.73 (m, 2H), 6.37 (s, 1H), 8.64 (s, 1H), 8.67 (s, 1H), 8.70 (s, 1H), 9.0 (s, 1H), 9.03 (t, 1H), 10.50 (s, 1H), 11.88 (s, 1H).
Reaction SMILES: C(S[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[C:13]([C:18]2[O:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:21][N:22]=2)[C:14]([NH2:17])=[N:15][CH:16]=1)(C)C.Cl[C:30]1[CH:31]=C(C(OO)=O)C=C[CH:35]=1.[S:40]([O-:44])([O-])(=[O:42])=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH:30]([S:40]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[C:13]([C:18]2[O:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:21][N:22]=2)[C:14]([NH2:17])=[N:15][CH:16]=1)(=[O:44])=[O:42])([CH3:31])[CH3:35]
Reactant: CC(C)Sc1ccccc1-c1cnc(N)c(-c2nnc(-c3ccccc3)o2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccccc1-c1cnc(N)c(-c2nnc(-c3ccccc3)o2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
5-(2-isopropylsulfanylphenyl)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine (40 mg, 0.1027 mmol) was dissolved in dichloromethane (10 mL) followed by the portionwise addition of 3-chlorobenzenecarboperoxoic acid (70.89 mg, 0.4108 mmol) over 10 min. The resulting mixture was stirred at room temperature for 2 h, and poured onto a 50/50 mixture of saturated aqueous sodium thiosulfate solution and saturated aqueous sodium bicarbonate solution (20 mL). The layers were separated and the organic layer was washed with dilute NaHCO3 solution (1×10 mL) and brine (1×10 mL) and then concentrated in vacuo to leave a solid. The solid was purified by column chromatography on silica eluting with 50% ether/petroleum ether to afford the product as a yellow solid. (20.25 mg, 36% yield); 1H NMR (400.0 MHz, CDCl3) d 1.4 (d, 6H), 4.48-4.52 (m, 1H), 7.0 (br s, 2H), 7.5-7.7 (m, 5H), 7.7-7.75 (m, 1H), 8.2 (d, 1H), 8.3 (d, 1H) and 8.55 (s, 1H) ppm; MS (ES+) 422.2
Reaction SMILES: [CH:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]Cl>ClC1C=CC=CC=1Cl>[CH:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: ClCCNCCCl
Reactant: Nc1ccccc1C1CCCCCC1
Agent: Cl
Solvent: Clc1ccccc1Cl
Product: c1ccc(N2CCNCC2)c(C2CCCCCC2)c1
Temperature: 200 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a solution of the 2-cycloheptylphenylamine (539 mg, 2.85 mmol) produced in Example (44b) in 1,2-dichlorobenzene (7 mL) was added bis(2-chloroethyl)amine hydrochloride (610 mg, 3.42 mmol), and the mixture was stirred at an external temperature of 200° C. under a nitrogen atmosphere. During the reaction, a nitrogen stream was blown into the reactor to remove the hydrogen chloride gas in the reactor. This procedure was repeated several times. After 8 hours, the mixture was air-cooled to room temperature. To the reaction mixture were added aqueous solution of potassium carbonate, ethyl acetate and methanol, and extraction was performed three times with ethyl acetate. The obtained organic layers were dried over anhydrous sodium sulfate, and then the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 540 mg of the title compound as a brown oil.
Reaction SMILES: [NH:1]([C:3]1[S:4][C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:8])[N:7]=1)[NH2:2].C([O:15][C:16](=O)[CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:18]([CH3:20])=O)C>C(O)C.O.C(O)(=O)C>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C:17]2[C:16](=[O:15])[N:1]([C:3]3[S:4][C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:8])[N:7]=3)[NH:2][C:18]=2[CH3:20])=[CH:27][CH:26]=1
Reactant: CCOC(=O)C(Cc1ccc(Cl)cc1)C(C)=O
Reactant: COC(=O)c1sc(NN)nc1C
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1sc(-n2[nH]c(C)c(Cc3ccc(Cl)cc3)c2=O)nc1C
Temperature: 25 °C
Yield: 42 %

Procedure:
To a solution of methyl 2-hydrazinyl-4-methylthiazole-5-carboxylate (0.25 g, 1.33 mmol) and 2-(4-chlorobenzyl)acetoacetic ethyl ester (0.24 g, 0.93 mmol) in ethanol (10 mL) and water (1 mL) was added 1 drop of acetic acid at ambient temperature. The reaction mixture was heated to reflux for 17 hours, cooled to ambient temperature. The precipitate was collected by filtration and titrated with ethyl ether to afford the title compound in 42% yield (0.22 g): 1H NMR (300 MHz, DMSO-d6) δ 7.27 (d, J=8.5 Hz, 2H), 7.21 (d, J=8.5 Hz, 2H), 3.78 (s, 3H), 3.52 (s, 2H), 2.58 (s, 3H), 2.14 (s, 3H); MS (ES+) m/z 378.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[CH:27][C:28]([C:31]3[S:32][C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[N:35]=3)=[N:29][CH:30]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O>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.C1COCC1>[S:32]1[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=[C:31]1[C:28]1[N:29]=[CH:30][C:25]([C:2]2[CH:7]=[N:6][C:5]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:4][CH:3]=2)=[CH:26][CH:27]=1
Reactant: Brc1ccc(-c2nc3ccccc3o2)nc1
Reactant: CC1(C)OB(c2ccc(-c3nc4ccccc4s3)nc2)OC1(C)C
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: C1CCOC1
Solvent: O
Product: c1ccc2oc(-c3ccc(-c4ccc(-c5nc6ccccc6s5)nc4)cn3)nc2c1
Yield: 84.8 %

Procedure:
Following the procedure for 17, 11 (0.558 g, 2.03 mmol), 16 (0.700 g, 2.07 mmol), tetrakis(triphenylphosphine)palladium(0) (117 mg, 102 μmol), Na2CO3 (1.59 g, 15.0 mmol), H2O (15 mL) and THF (25 mL) yielded an insoluble white solid (0.70 g, 84%) after filtration.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].O[CH:18]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:25][C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2>C(O)C.C(O)(=O)C>[Br:16][C:14]1[CH:13]=[CH:12][C:3]([C:4]([CH:6]([CH:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[O:25][C:26]3[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])=[C:2]([CH3:1])[CH:15]=1
Reactant: CCOC(=O)CC(=O)c1ccc(Br)cc1C
Reactant: OC1c2ccccc2Oc2ccccc21
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C(=O)c1ccc(Br)cc1C)C1c2ccccc2Oc2ccccc21

Procedure:
A solution of ethyl 2-methyl-4-bromobenzoylacetate (18.5 g, 65.0 mmol) was heated at 60° C. with 9-hydroxyxanthene (14.2 g, 71.5 mmol) in ethanol-acetic acid (1:1, 200 ml) for 40 h. The product was isolated as in Example 1 (iii), except the aqueous phase was extracted with diethyl ether. The crude product was purified on flash silica eluting with hexane-dichloromethane (3:2 then 1:1) to give ethyl 2-(4-bromo-2-methylbenzoyl)-2-(9H-xanthen-9-yl)acetate as an oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([CH2:11][CH2:12][O:13][CH3:14])[CH2:7][CH2:8][CH2:9][OH:10].C(Cl)(C(Cl)=O)=O.CS(C)=O.C(N(CC)CC)C.COCCC(CC=C)CO>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([CH2:11][CH2:12][O:13][CH3:14])[CH2:7][CH2:8][CH:9]=[O:10]
Reactant: COCCC(CCCO)C1OCCO1
Agent: C=CCC(CO)CCOC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COCCC(CCC=O)C1OCCO1
Yield: 80.8 %

Procedure:
The alcohol 7 (6 g, 29.37 mmol), prepared according to Example 6, was oxidized using 2M (COCl)2 (18 mL, 36 mmol), dry DMSO (5.1 mL, 72 mmol) and triethyl amine (20.7 mL, 144 mmol) analogous to the oxidation of the alcohol 4, as described in example 4. Similar work up as for 5 gave the aldehyde 8 (4.8 g, 81%) as a colorless oil. IR (KBr) υmax 2939, 2880, 2735, 1719, 1451, 1391, 1111, 1038, 947 cm−1: 1HNMR (CDCl3) δ1.45-2.85 (m, 5 H), 2.54 (t, J=6.8 Hz, 2 H), 3.31 (s, 3 H), 3.43-3.46 (m, 2 H), 3.83-3.95 (m, 4 H), 2.54 (t, J=6.8 Hz, 2 H), 3.31 (s, 3 H), 3.43-3.46 (m, 2 H), 3.83-3.95 (M, 4 H), 4.77 (d, J=3.3 Hz, 1 H), 9.76 (t, J=1.5 Hz, 1 H); 13CNMR (CDCl3) δ21.51, 29.23, 37.99, 41.72, 58.42, 64.81, 64.88, 70.66, 106.26, 202.39: mass spectrum (EI), m/z (rel intensity) 210 (33), 202 (M+, 3), 201 (15), 157 (19), 144 (27), 143 (38), 141 (19), 127 (17), 126 (1), 111 (30), 109 (12), 100 (4), 99 (11), 73 (100), 59 (10), 57 (8), 55 (12), 54 (5).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:25](C1C=CC=CC=1)([O-:27])=[O:26].[N+:34]([O-])([OH:36])=[O:35]>C(O)(=O)C>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([C:14]2[C:13]([C:8]3[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:18][C:17]([N+:34]([O-:36])=[O:35])=[CH:16][CH:15]=2)=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])c1ccccc1
Reactant: c1ccc(-c2ccccc2-c2ccccc2-c2ccccc2)cc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(-c2ccc([N+](=O)[O-])cc2-c2ccccc2-c2ccccc2)cc1

Procedure:
Quaterphenyl (2.00g) was stirred in a refluxing glacial acetic acid (225ml), nitrobenzene (225ml) mixture until dissolved. Fuming nitric acid (d 1.5, 15ml) in acetic acid (60ml) was added over ten minutes. The mixture was further refluxed for fifty minutes. Upon cooling the flask in ice, yellow crystals appeared. They were recrystallized from chlorobenzene (0.85g, 33%). Upon heating, the material became mobile at 307° C with previous softening but did not clear even at 340° C when slow charring ocurred.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[CH3:11][C:12]1([CH3:26])[C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:16]=2[NH:15][C:14](=[O:25])[O:13]1>>[CH3:11][C:12]1([CH3:26])[O:13][C:14](=[O:25])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[CH2:8][C:9]#[N:10])=[CH:18][C:17]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: N#CCc1ccccc1Br
Product: CC1(C)OC(=O)Nc2ccc(-c3ccccc3CC#N)cc21

Procedure:
Prepared according to procedure B from 2-bromophenylacetonitrile and (1,4-dihydro4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. White solid; mp 176-179° C.; 1H-NMR (DMSO-d6), δ10.31 (s, 1H), 7.53 (m, 1H), 7.48(m,2H), 7.22-7.32(m,3H), 6.98(d,1H; J=8.0 Hz), 3.90(s,2H), 1.64(s,6H). MS (+)APCI [M+H]+m/z =293. Anal. Calc. For C18H16N2O2: C, 73.95, H, 5.52, N, 9.58. Found: C,73.51, H, 5.70, N, 9.39.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([C:14]1[N:18]([CH3:19])[N:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=1[CH2:24][S:25][C:26]1[CH2:30][C:29]([CH3:32])([CH3:31])[O:28][N:27]=1)#[N:13].[OH2:33]>C(Cl)(Cl)Cl>[C:12]([C:14]1[N:18]([CH3:19])[N:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[C:15]=1[CH2:24][S:25]([C:26]1[CH2:30][C:29]([CH3:32])([CH3:31])[O:28][N:27]=1)(=[O:9])=[O:33])#[N:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O
Reactant: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(C)C2)c1C#N
Solvent: ClC(Cl)Cl
Product: Cn1nc(C(F)(F)F)c(CS(=O)(=O)C2=NOC(C)(C)C2)c1C#N
Reaction time: 1 h
Yield: 76.4 %

Procedure:
2.1 g of m-chloroperbenzoic acid (purity: 70%, 12.2 mmoles) was added, with ice-cooling, to a solution of 0.9 g of 3-(5-cyano-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline (crude compound) dissolved in 50 ml of chloroform. The mixture was stirred for 1 hour and then at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution, water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The resulting solid was washed with n-hexane to obtain 0.43 g (yield: 76.4%) of 3-(5-cyano-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline as a white powder (melting point: 105.0 to 108.0° C.).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:8][C:7](=[O:9])[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>C1COCC1>[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([O:1][CH2:2][C:3]2[NH:8][C:7](=[O:9])[CH:6]=[CH:5][CH:4]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: O=c1cccc(CO)[nH]1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1cccc(=O)[nH]1)c1ccc(F)cc1
Reaction time: 0.33 h
Yield: 32.48 %

Procedure:
In Example 5, 0.2006 grams (1.60 mmole) of 6-(hydroxymethyl)pyridine-2(1H)-one was suspended in 160 mL of THF in a 250 mL round bottom flask under the presence of argon gas. Then, 0.0671 g (1.68 mmole) of 60% NaH dispersed in mineral oil was added and the solution was stirred for 20 min. 0.19 mL (1.58 mmole) of 4-fluorobenzoyl chloride was dissolved in 20 mL of THF and added dropwise into the alcohol reaction mixture at a rate of 10 μL/min. The reaction stirred for 48 hours under the presence of argon gas before being quenched with 20 mL of water. The reaction was washed with ethyl acetate (4×20 mL), the organic layers combined, washed with saturated NaHCO3 (4×20 mL), washed with Brine (3×20 mL) and finally dried over MgSO4. The solvent was removed in vacuo to produce a dull yellow solid. The compound was purified by column chromatography(methanol/dichloromethane). The result was a fine white powder. (0.1287 grams, 32.48% Yield). 1H NMR (DMSO-d6, 500 MHz) δ: 5.12 (s, 2H) 6.29-6.41 (m, 2H) 7.38 (t, 2H) 7.45 (t, 1H) 8.08 (t, 2H) 11.74 (s, 1H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([Cl:25])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][N:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[CH:24]=[C:23]([Cl:25])[S:22][C:12]=2[N:13]=1
Reactant: NCc1ccccc1
Reactant: Clc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: Clc1cc2c(NCc3ccccc3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyrazin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-benzylamino-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([C:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=1)#[N:2].[Mg]>CO>[NH3:2].[C:1]([CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([N:13]3[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]3)[CH:7]=[CH:8][CH:9]=2)[CH2:4]1)#[N:2]
Reactant: CN1CCN(c2cccc3c2C=C(C#N)CC3)CC1
Agent: [Mg]
Solvent: CO
Product: CN1CCN(c2cccc3c2CC(C#N)CC3)CC1
Product: N
Temperature: 0 °C
Reaction time: 4 h
Yield: 139.2 %

Procedure:
2-Cyano-3,4-dihydro-8-[4-methyl(piperazin-1-yl)]-naphthalene (230 mg, 0.90 mmol) was dissolved in dry methanol (15 mL) and cooled to 0° C. Magnesium turnings (440 mg, 18 mmol) were added and the reaction mixture was stirred for 45 min at 0° C. and for 4 h at room temperature. The solvent was evaporated and 2 M hydrochloric acid (20 mL) was added to the residue. The mixture was stirred for 1 h, cooled on ice-bath and alkalized to pH 10 with 2 M ammonia. The solution was extracted with ethyl acetate (60+2×30 mL) and the organic phase was washed with brine (15 mL). Drying (MgSO4) and evaporation of the solvent gave 210 mg of a crude product. Purification by preparative TLC on silica using chloroform/methanol/conc. NH3 (95:5:0.5) afforded 160 mg (71% yield) of the title compound as a white solid: mp 111-112° C.; EIMS (70 eV) m/z (relative intensity) 255 (34, M+).
Reaction SMILES: [O:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].C(O)(=[O:13])C>>[C:2]([OH:1])(=[O:10])[CH:3]=[O:13].[C:9]1(=[O:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=C1Cc2ccccc2O1
Reactant: CC(=O)O
Product: O=C1CCCCC1
Product: O=CC(=O)O

Procedure:
More recently, J. C. Vallejos et al (FR 2.721.609) described a method for the preparation of 2-coumaranone by vapour phase catalytic dehydrogenation of the crude reaction product obtained from the condensation of glyoxylic acid with cyclohexanone in a pure acetic acid medium.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:10]=[C:9]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[NH:23][C:22]4[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:21]=4[N:20]=3)[CH2:14][C:13]2=[O:29])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[CH2:30]([N:32](CC)CC)C.C(O)(=O)C.N1C=CC=NN=1>C(O)C>[NH2:6][C:5]1[C:4]2[C:3](=[CH:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([CH2:18][C:19]4[NH:23][C:22]5[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:21]=5[N:20]=4)[CH2:14][C:13]3=[O:29])=[CH:8][CH:7]=2)[N:2]=[CH:30][N:32]=1
Reactant: CCN(CC)CC
Reactant: N#Cc1ccc(CN2CCC(Cc3nc4ccc(Cl)cc4[nH]3)CC2=O)cc1N
Agent: Cl
Agent: c1cnnnc1
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ncnc2cc(CN3CCC(Cc4nc5ccc(Cl)cc5[nH]4)CC3=O)ccc12
Yield: 84.9 %

Procedure:
To a solution of 2-Amino-4-[4-(6-chloro-1H-benzoimidazol-2-ylmethyl)-2-oxo-piperidin-1-ylmethyl]-benzonitrile hydrochloric acid salt (143 mg, 0.308 mmol), EXAMPLE 814, Part E, in 2 mL of ethanol is added triethylamine (0.05 mL, 0.366 mmol), glacial acetic acid (0.02 mL, 0.366 mmol) and triazine (15 mg, 0.183 mmol). The resulting mixture is refluxed overnight. The volatile solvents are removed on the rotovap, and the residue is purified by reverse phase HPLC (0-50% Acetonitrile/H2O). The desired product (110 mg, 55% yield) is isolated as a white powder with a melting point of 128-132 ° C. C22H21ClN6O MS m/z: 421, 423. Anal. calcd. for C22H21ClN6O: C, 48.12; H,3.57; N, 12.95. Found: C, 45.79; H, 3.68; N, 11.94. H NMR (CD3OD) δ: 8.67 (s, 1H); 8.31 (d, 1H, J=4.0 Hz); 7.83-7.55 (m, 5H); 4.93-4.73 (m, 2H); 3.48-3.42 (m, 2H); 3.31-3.21 (m, 2H); 2.71-2.58 (m, 2H); 2.43-2.33 (m, 1H); 2.07-2.01 (m, 1H); 1.82-1.69 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(C(C)C)C(C)C)C>CN(C1C=CN=CC=1)C.ClCCl>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[C:5]([C:6](=[O:7])[NH:8][CH3:9])=[CH:4][N:3]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CNC(=O)c1cnc(Cl)cc1-c1ccccc1C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccccc1C
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of 8.31 g (31.9 mmol) 6-chloro-N-methyl-4-o-tolyl-nicotinamide, 6.53 g (35.0 mmol) 1-tert-butoxycarbonyl piperazine, 16.7 ml (95.6 mmol) N-ethyldiisopropylamine and a catalytic amount of 4-(N,N-dimethylamino)-pyridine was heated at reflux over night. After cooling to room temperature the mixture was dissolved in dichloromethane and washed with two portions of 0.1 N aqueous hydrochloric acid solution. Drying with sodium sulfate and concentration gave 10.7 g of the crude product. Flash column chromatography afforded 6.28 g (48.0%) of the title compound as an off-white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([C:23](=[O:25])[CH3:24])=[C:18]([OH:26])[CH:17]=1.O>CN(C)C=O.C(OCC)(=O)C>[Br:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([C:23](=[O:25])[CH3:24])=[C:18]([O:26][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:17]=1
Reactant: CC(=O)c1cc(C)c(Br)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(C)c(Br)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium carbonate (1.45 g, 10.48 mmol) and benzyl bromide (0.65 ml, 5.50 mmol) were added to a solution of 1-(4-bromo-2-hydroxy-5-methylphenyl)ethanone (may be prepared as described in Description 10; 1.2 g, 5.24 mmol) in N,N-dimethylformamide (10 ml). The mixture was stirred at room temperature overnight. Water (20 ml) and ethyl acetate (30 ml) were added and the organic layer was separated, washed with water (2×20 ml), dried (MgSO4) and the solvent removed in vacuo. Purification by column chromatography (5-10% ethyl acetate/hexane) yielded the title compound. 607 mg.
Reaction SMILES: [C:1]1([S:7][C:8](Cl)(Cl)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:13]1[CH:18]=[CH:17][CH:16]=C[N:14]=1>C(N)=O>[C:1]1([S:7][C:8]2[CH:16]=[CH:17][CH:18]=[CH:13][N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1ccccn1
Reactant: ClC(Cl)(Cl)Sc1ccccc1
Solvent: NC=O
Product: c1ccc(Sc2ccccn2)cc1
Temperature: 75 °C
Yield: 62 %

Procedure:
A solution of phenyl(trichloromethyl)sulfane (0.25 g, 1.099 mmol) in formamide (16.40 ml) was degassed with nitrogen and treated with 2-chloropyridine (0.114 ml, 1.209 mmol). The reaction solution was heated at 75° C. overnight. GCMS indicates a yield of 62% of 2-(phenylthio)pyridine, and a 22% byproduct of disulfide.