Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[CH2:18][NH:19][C:20]([NH:22][C:23]1[N:24]=[C:25]2[CH:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:26]2=[N:27][CH:28]=1)=[O:21].O([CH2:48][C:49]([F:52])([F:51])[F:50])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[F:50][C:49]([F:52])([F:51])[CH2:48][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[CH2:18][NH:19][C:20]([NH:22][C:23]1[N:24]=[C:25]2[CH:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:26]2=[N:27][CH:28]=1)=[O:21]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NCC3CCCCN3)cnc21
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NCC3CCCCN3CC(F)(F)F)cnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
DIPEA (0.13 mL, 0.732 mmol) was added at 0° C. to a suspension of 1-piperidin-2-ylmethyl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride (0.080 g, 0.198 mmol) in 10 mL of DCM. The resulting mixture was stirred at RT for 15 minutes before adding 2,2,2-trifluoroethyl triflate (0.056 mL, 0.396 mmol) was added. The reaction mixture was stirred at RT overnight before being evaporated. The residue was purified by SiO2 flash chromatography to give 0.053 mg of racemic 1-[1-(2,2,2-trifluoro-ethyl)-piperidin-2-ylmethyl]-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (55% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:12]OC(OC)OC.S(=O)(=O)(O)O.N>CN(C)C(=O)C.CO>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:5])[NH:6][CH:12]=[N:11]2
Reactant: COC(OC)OC
Reactant: NC(=O)c1c(N)cccc1N
Agent: N
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CC(=O)N(C)C
Product: Nc1cccc2nc[nH]c(=O)c12

Procedure:
900 mg (5.958 mmol) 2,6-diaminobenzamide are dissolved in 3.6 ml N,N-dimethylacetamide and combined with 6.3 ml (57.01 mmol) trimethylorthoformate and 792 μl (8.865 mmol) 98% sulphuric acid. After 16 h at 25° C. the reaction mixture is taken up with 20 ml of methanol and the solvent is eliminated in vacuo. The residue is again taken up in 20 ml of methanol, neutralised with concentrated ammonia. The solvent is eliminated in vacuo and the residue purified by chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 7% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution are added.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[N:7]([OH:8])[C:6]([CH3:10])([CH3:9])[CH2:5][CH:4]([OH:11])[CH2:3]1.CN(CCN(CCN(C)C)C)C.Cl[CH:26]([CH3:36])[C:27]([NH:29][CH2:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])=[O:28]>Cl[Cu]>[CH3:35][N:33]([CH3:34])[CH2:32][CH2:31][CH2:30][NH:29][C:27](=[O:28])[CH:26]([O:8][N:7]1[C:2]([CH3:12])([CH3:1])[CH2:3][CH:4]([OH:11])[CH2:5][C:6]1([CH3:10])[CH3:9])[CH3:36]
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: CC(Cl)C(=O)NCCCN(C)C
Agent: Cl[Cu]
Agent: CN(C)CCN(C)CCN(C)C
Product: CC(ON1C(C)(C)CC(O)CC1(C)C)C(=O)NCCCN(C)C
Yield: 63 %

Procedure:
4-Hydroxy-TEMPO (25.84 g, 0.15 mol), CuCl (29.7 g, 0.3 mol), PMDETA (52.0 g, 0.3 mol) and 2-chloro-N-(3-dimethylamino-propyl)-propionamide (35.75 g, 0.18 mol) are reacted as described in Example A3. The final purification of the residue after the extractive workup is performed by crystallization from toluene (45 ml) and hexane (50 ml) to afford 31.13 g of the title compound as a white solid, mp. 85-88° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][CH:10](O)[CH2:9]1.[CH2:14]([N:16](CC)[CH2:17][CH3:18])[CH3:15].CS(Cl)(=O)=[O:23]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][CH:10]([N:16]2[CH2:17][CH2:18][O:23][CH2:15][CH2:14]2)[CH2:9]1
Reactant: CCN(CC)CC
Reactant: OC1CCN(c2ccccc2Br)C1
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: Brc1ccccc1N1CCC(N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1-(2-Bromophenyl)pyrrolidin-3-ol (1 g) was stirred in toluene (30 ml). Triethylamine (0.69 ml) was added and the solution was cooled in an ice-bath. Methane sulphonyl chloride (0.38 ml) was added dropwise. The reaction mixture was allowed to warm to room temperature over 2 h and stirred for a further 2.5 h. The mixture was filtered, washed through with toluene and the filtrate concentrated to ca. 20 ml in vacuo. Morpholine (10 ml) was then added and the solution stirred at room temperature overnight, a further portion of morpholine (10 ml) was added and the solution was heated at reflux for 24 h. Volatile materials were then removed in vacuo, the residue was diluted with water (40 ml) and extracted with diethyl ether (3×20 ml). The combined extracts were washed with brine, dried (MgSO4), filtered and evaporated. The residue was triturated with isohexane/diethyl ether and product collected by filtration as a yellow solid (0.93 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15]>C1COCC1.O>[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:13]([CH3:12])[S:14]([CH3:17])(=[O:16])=[O:15])[N:7]=1)#[N:9]
Reactant: CNS(C)(=O)=O
Reactant: N#Cc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(c1nccc(C#N)n1)S(C)(=O)=O
Reaction time: 0.33 h

Procedure:
To a solution of 2-chloropyrimidine-4-carbonitrile (0.20 g, 1.43 mmol) in THF was 60% NaH (0.05 g, 2.00 mmol) in mineral oil. After 20 minutes, N-methylmethanesulfonamide (0.22 g, 2.00 mmol) was added. After 3 hours, the reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 30% ethyl acetate in heptane. The major fractions were combined and the solvent was concentrated in vacuo to afford N-(4-cyano-pyrimidin-2-yl)-N-methyl-methanesulfonamide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[C:16]=1[NH2:25]>>[CH3:12][C:4]1[N:3]=[C:2]([NH:25][C:16]2[C:17]([O:23][CH3:24])=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:15]=2[O:14][CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1nc(Cl)c2ccccc2n1
Reactant: COc1cc(OC)c(N)c(OC)c1
Product: COc1cc(OC)c(Nc2nc(C)nc3ccccc23)c(OC)c1

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (89.3 mg, 0.5 mmol), 2,4,6-trimethoxy-phenylamine (91.6 mg, 0.5 mmol) by a procedure similar to example 78. 1H NMR (CDCl3): 7.86 (d, J=8.4 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.71 (t, J=6.6 Hz, 1H), 7.41 (t, J=8.1 Hz, 1H), 6.81 (brs, 1H), 6.25 (s, 2H), 3.87 (s, 3H), 3.79 (s, 6H), 2.57 (s, 3H).
Reaction SMILES: [F:1][S:2]([C:5]1[CH:6]=[C:7]([CH:25]=[CH:26][CH:27]=1)[C:8]([NH:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][C:15]([C:22](O)=[O:23])=[C:16]2[OH:21])=[O:9])(=[O:4])=[O:3].CN(C)C=O.S(Cl)([Cl:35])=O>ClCCl>[F:1][S:2]([C:5]1[CH:6]=[C:7]([CH:25]=[CH:26][CH:27]=1)[C:8]([NH:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][C:15]([C:22]([Cl:35])=[O:23])=[C:16]2[OH:21])=[O:9])(=[O:4])=[O:3]
Reactant: O=C(Nc1cccc2c(O)c(C(=O)O)ccc12)c1cccc(S(=O)(=O)F)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cccc2c(O)c(C(=O)Cl)ccc12)c1cccc(S(=O)(=O)F)c1
Temperature: 5 °C

Procedure:
5-(3-Fluorosulphonylbenzamido)-1-hydroxy-2-naphthoic acid (11) (10 g, 26 m.mole) was suspended in dry dichloromethane (200 ml), containing dimethylformamide (0.5 ml) and thionyl chloride (10.8 g, 91 m.mole). The mixture was heated under reflux with stirring for 2.5 hours, during which time the required acid chloride had crystallized as a pale yellow solid. After cooling to 5° C., the acid chloride was removed by filtration and washed with a little cold, dry dichloromethane.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:20][N:14]4[CH2:15][C:16](=[O:19])[NH:17][CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.O1CCCC1.[H-].[Na+].Br[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1>CN(C)C=O>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:20][N:14]4[CH2:15][C:16](=[O:19])[N:17]([CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=5)[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: O=C1CN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2CN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1CN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2CN1Cc1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
To a solution of the product from Example 201C (64 mg, 0.233 mmol) in 4:1 tetrahydrofuran:N,N-dimethylformamide (2 mL) was added sodium hydride (11.2 mg, 0.280 mmol). The resulting mixture was stirred at ambient temperate for 30 minutes, and 1-(bromomethyl)-3-(trifluoromethyl)benzene (42.8 μL, 0.280 mmol) was added. The mixture was stirred at ambient temperature for 1 hour and was then partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by chromatography on a 12 g silica gel column eluting with 5% ethyl acetate/hexanes for 3 minutes then a gradient to 100% ethyl acetate over 20 minutes. The title compound was obtained as a thick oil (13 mg, 13%). 1H NMR (300 MHz, methanol-d4) δ ppm 7.99 (dt, J=11.3, 5.7 Hz, 2H), 7.65-7.49 (m, 4H), 5.42 (dd, J=12.6, 5.1 Hz, 1H), 4.70 (d, J=3.7 Hz, 2H), 3.81-3.61 (m, 2H), 3.50-3.35 (m, 1H), 3.16 (dd, J=13.4, 8.3 Hz, 2H), 2.87 (qd, J=10.1, 4.9 Hz, 1H), 2.39 (dd, J=10.4, 5.0 Hz, 1H), 2.20-1.85 (m, 3H), 1.02-0.82 (m, 4H); MS (ESI) m/z 275 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH:8]=[C:9](Br)[S:10][C:6]=2[C:5]([C:12]([NH2:14])=[O:13])=[CH:4][N:3]=1.[CH3:15][C:16]1[CH:17]=[C:18](B(O)O)[S:19][CH:20]=1>>[NH2:1][C:2]1[C:7]2[CH:8]=[C:9]([C:18]3[S:19][CH:20]=[C:16]([CH3:15])[CH:17]=3)[S:10][C:6]=2[C:5]([C:12]([NH2:14])=[O:13])=[CH:4][N:3]=1
Reactant: Cc1csc(B(O)O)c1
Reactant: NC(=O)c1cnc(N)c2cc(Br)sc12
Product: Cc1csc(-c2cc3c(N)ncc(C(N)=O)c3s2)c1

Procedure:
19 was prepared from 4-amino-2-bromo-thieno[3,2-c]pyridine-7-carboxylic acid amide 17 and 4-methyl-2-thiopheneboronic acid according to the general procedure described in Example 2. 1H NMR (400 MHz, d6-DMSO) δ: 2.25 (s, 3H), 7.29 (s, 1H), 7.36 (s, 1H), 7.80 (br s, 1H), 8.14 (s, 1H), 8.40 (br s, 1H), 8.46 (s, 1H). MS (EI) m/z (M+H+) 290.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[I-:10].[Na+].ClOC(C)(C)C>C(#N)C.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([I:10])[C:3]=1[OH:9]
Reactant: [I-]
Reactant: Oc1ccc(Cl)cc1Cl
Agent: CC(C)(C)OCl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Oc1c(Cl)cc(Cl)cc1I
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 6.52 g (40 mmol) of 2,4-dichlorophenol and 7.76 g (52 mmol) of sodium iodide in 80 mL of acetonitrile and 16 mL of water at room temperature add 5.64 g (52 mmol) of tert-butyl hypochlorite dropwise over a period of 30 minutes. Stir the reaction mixture for 3 hours at ambient temperature. Dilute the reaction mixture with 200 mL of ethyl acetate. Wash the resulting organic solution successively with 5% aqueous sodium thiosulfate solution and brine and dry over anhydrous magnesium sulfate. Remove the solvent and then crystallize from hexanes to yield 5.9 g (51%) of (P9) as a slightly colored solid.
Reaction SMILES: Cl.[NH2:2][C:3](=[NH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[O-]CC.[Na+].Br[CH2:16][C:17]([C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[N:21]=[C:22]([F:30])[C:23]([CH3:29])=[N:24]2)=O>CCO>[NH2:10][C:3]1[NH:2][C:17]([C:19]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:20]=2[N:21]=[C:22]([F:30])[C:23]([CH3:29])=[N:24]3)=[CH:16][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=N)N
Reactant: Cc1nc2cccc(C(=O)CBr)c2nc1F
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cccc3nc(C)c(F)nc23)[nH]c1N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52.3 %

Procedure:
A glass microwave reaction vessel was charged with ethyl 3-amino-3-iminopropanoate hydrochloride (1.248 g, 7.49 mmol, Tyger Scientific, Inc., Ewing, N.J.) in EtOH (5 mL) and the solution was cooled to 0° C. Sodium ethoxide (21% w/w solution in EtOH; 2.80 mL, 7.49 mmol) was added dropwise and a precipitate was formed. After 10 min, 2-bromo-1-(3-fluoro-2-methylquinoxalin-5-yl)ethanone (Example 126h; 1.06 g, 3.74 mmol) was added, and the reaction was stirred at RT for 3 h. The reaction was quenched with water and extracted with DCM. The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified with silica gel chromatography (10-25% EtOAc in Hexanes) to give ethyl 2-amino-5-(3-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (615 mg, 1.957 mmol, 52% yield) as an orange solid. MS (ESI, pos. ion) m/z: 315.0 (M+1).
Reaction SMILES: [C:1]([O:20]CC(CO)O)(=[O:19])[CH2:2][CH2:3]CCCCCCCCCCCCCCC.CO[C:28]([C@@H:30](NC([C@@H](N)CC(O)=O)=O)[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=O.[CH2:47](O)[C@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C([O-])(=O)CCCCCCCCCCCCCCCCC.[Mg+2].C([O-])(=O)CCCCCCCCCCCCCCCCC>O>[OH:20][C:1]([CH:2]([C:35]1[CH:36]=[CH:37][C:32]([CH2:31][CH:30]([CH3:28])[CH3:47])=[CH:33][CH:34]=1)[CH3:3])=[O:19]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO
Agent: CCCCCCCCCCCCCCCCCC(=O)[O-]
Agent: [Mg+2]
Solvent: O
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Reaction time: 0.17 h

Procedure:
In a twin shell blender were placed 369.6 grams of the dried wet granulation of Example 3, 369.6 grams glyceryl monostearate (Myvaplex® 600, Eastman Chemical Co.), 33.2 grams of aspartame (The NutraSweet Co.), 21.6 grams of apple cinnamon durarome #860.310/TD 05.91 (Firminich Inc.), and 27.6 grams of an artificial special compound flavor (Firminish Inc.). This mixture was blended for 10 minutes after which 138.6 grams of Pregelatinized Starch (Starch 1500 Colorcon), 969.8 grams of granular mannitol, and 27.6 grams of crosslinked sodium carboxymethylcellulose (Accelerate™, FMC Corporation) were added to the blender. Mixing was continued for 10 more minutes, and then 19.4 grams of magnesium stearate was added to the blender. Mixing was completed in five minutes. Prior to adding each material to the blender, it was passed through a Number 30 US Standard Sieve. This mixture was then compressed into a tablet. The particle size distribution of the granulation used in this formulation was determined by using a Sonic Sifter, a vibrated stack of U.S. Standard Sieves in which each succeeding sieve is finer in mesh than the one above it. The amount of product retained on each sieve provides the percentage of particles larger than that sieve, but smaller then the next higher sieve. Particles having sizes in each mesh range were: 48.23%>297 microns (>50 mesh); 29.657% 177-297 microns (50-80 mesh); 5.39% 149-177 microns (80-100 mesh); 13.57% 74-149 microns (100-200 mesh); 3.17% 53-74 microns (200-270 mesh); and 5.00%<53 microns (<270 mesh). The loose bulk density of this material was 0.6164 grams/mL. The water content of the granulation was 1.50%. Properties of the chewable tablets include tablet thickness (3.25 mm, 0.1279 inch), hardness (5.37 kiloponds), and disintegration time in 37° C. purified water (184 seconds). All of these measurements were taken on ten tablets except disintegration time which used six tablets. The unpleasant flavor of ibuprofen was effectively masked by using the wet granulation in combination with other excipients.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][C:11]([CH2:16][CH2:17]O)([OH:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.CCOC(C)=O>C(Cl)Cl>[CH3:35][C:25]1[CH:30]=[CH:29][C:28]([S:31]([O-:15])(=[O:33])=[O:32])=[CH:27][CH:26]=1.[CH2:1]([N+:8]12[CH2:17][CH2:16][C:11]([OH:15])([CH2:10][CH2:9]1)[CH2:12][CH2:13][CH2:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCC1(O)CCCN(Cc2ccccc2)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: OC12CCC[N+](Cc3ccccc3)(CC1)CC2
Temperature: 0 °C
Reaction time: 3 h
Yield: 114.3 %

Procedure:
To a solution of 1-benzyl-4-(2-hydroxyethyl)azepan-4-ol (2.0 g) in DCM (20 mL) were added pyridine (4 mL) and p-toluenesulfonylchloride (1.68 g) at 0° C., followed by stirring at 0° C. for 3 hours and then at room temperature for overnight. The reaction mixture was concentrated under reduced pressure, alkalified by addition of a saturated aqueous NaHCO3 solution, and then extracted with EtOAc. The organic layer was washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure to obtain a pale red solid. EtOAc was added thereto and the solid was pulverized and collected by filtration to obtain 1-benzyl-5-hydroxy-1-azoniabicyclo[3.2.2]nonane 4-methylbenzenesulfonate (1.85 g) as a pale red powder.
Reaction SMILES: [C:1]([C:3]1([CH2:16][CH:17]2[CH2:19][CH2:18]2)[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1)#[N:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:1]([C:3]1([CH2:16][CH:17]2[CH2:19][CH2:18]2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(CC2CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1(CC2CC2)CCNCC1

Procedure:
A solution of tert-butyl 4-cyano-4-cyclopropylmethylpiperidine-1-carboxylate (I-2) (1.00 g, 3.78 mmol) in TFA (50 mL) and DCM (75 mL) was stirred at room temperature for 0.5 h then the volatile components removed in vacuo. The residue was partitioned between saturated sodium bicarbonate solution and DCM. The organic phase was separated and the aqueous phase re-extracted with DCM twice. The combined organic phase was washed with brine, dried (MgSO4) and the solvent removed in vacuo to leave 4-cyano-4-cyclopropylmethylpiperidine (I-8) as a glass. 1H NMR (500 MHz, CD3OD): δ 3.03 (d, J=13.1 Hz, 2 H), 2.88-2.82 (m, 2 H), 2.00 (d, J=11.7 Hz, 2 H), 1.55-1.49 (m, 4 H), 0.92-0.84 (m, 1 H), 0.57-0.55 (m, 2 H), 0.20 (q, J=5.0 Hz, 2 H).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:5].[H-].[Na+].[I-].[Na+].Cl[CH2:29][C:30]([NH2:32])=[O:31]>CN(C)C=O.O>[C:30]([CH2:29][O:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:5])(=[O:31])[NH2:32]
Reactant: NC(=O)CCl
Reactant: O=C(NCc1ccccn1)c1cc(OCC(F)(F)F)ccc1O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)COc1ccc(OCC(F)(F)F)cc1C(=O)NCc1ccccn1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A solution of 6.5 g (0.02 mole) of 2-hydroxy-N-(2-pyridylmethyl)-5-(2,2,2-trifluoroethoxy)benzamide in 20 ml of dimethylformamide was added dropwise to a suspension of 0.021 mole of sodium hydride in 10 ml dimethylformamide. The resulting mixture was stirred at about 25° C. for 30 minutes, at 60° C. for 30 minutes, and then 0.3 g of sodium iodide was added followed by the addition of a solution of 1.7 g (0.018 mole) of 2-chloroacetamide in 15 ml dry dimethylformamide. The reaction mixture was stirred for about 16 hours at 60° C. and then poured into 500 ml cold water. The resulting precipitate was collected and dried, then dissolved in a minimum of 5% methanol in chloroform and washed through a column of basic alumina. The eluent was evaporated to give a white solid which was recrystallized from about 300 ml of 3:4 water:ethanol to give 4.9 g of white crystalline 2-carbamoylmethoxy-N-(2-pyridylmethyl)-5-(2,2,2-trifluoroethoxy)benzamide.
Reaction SMILES: C[Al](C)C.[CH:5]1([CH2:8][NH2:9])[CH2:7][CH2:6]1.C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[C:22]([C:24]3[C:25]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[N:26][O:27][C:28]=3[C:29]([F:32])([F:31])[F:30])[N:21]=[CH:20]2)=[CH:15][CH:14]=1.O>O1CCOCC1>[CH:5]1([CH2:8][NH:9][C:12](=[O:11])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[C:22]([C:24]4[C:25]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)=[N:26][O:27][C:28]=4[C:29]([F:32])([F:31])[F:30])[N:21]=[CH:20]3)=[CH:15][CH:14]=2)[CH2:7][CH2:6]1
Reactant: NCC1CC1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Agent: C[Al](C)C
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCC1CC1)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Temperature: 90 °C
Yield: 78 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 338 μL, 0.68 mmol) and cyclopropanemethylamine (60.4 μL, 0.68 mmol) in dioxane (9 mL) was stirred at room temperature for 1 h and then a solution of 4-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid methyl ester (70 mg, 0.17 mmol) in dioxane (6 mL) was added. The resulting mixture was then heated at 85-95° C. overnight and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=60:40) afforded the title compound (60 mg, 78%) which was obtained as a colourless oil. MS: m/e=453.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[CH3:12].[CH:13]1([NH2:20])[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[C:10]2[C:9]([NH:19][CH:16]3[CH2:17][CH2:18][CH:13]([NH2:20])[CH2:14][CH2:15]3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[CH3:12]
Reactant: NC1CCC(N)CC1
Reactant: Cc1sc2ncnc(Cl)c2c1Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1sc2ncnc(NC3CCC(N)CC3)c2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
A solution of 5-bromo-4-chloro-6-methylthieno[2,3-d]pyrimidine (79 mg, 0.30 mmol, 1.00 equiv) in anhydrous DMF (5 mL) was added cyclohexane-1,4-diamine (171 mg, 1.50 mmol, 5.00 equiv) and triethylamine (91 mg, 0.90 mmol, 3.00 equiv) successively at room temperature. The resulting solution was stirred overnight at ambient temperature and then quenched with water. The resulting solution was extracted with 3×20 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to provide the resulted 1-N-[5-bromo-6-methylthieno[2,3-d]pyrimidin-4-yl]cyclohexane-1,4-diamine (90 mg, 88%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:11])=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[O:10][CH2:13][CH2:14][OH:15]
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OCCO)ccc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
A solution of 4-nitro-m-cresol (1.4 g, 9.4 mmol), 2-bromoethanol (1.0 mL, 0.014 mol) and potassium carbonate (3.3 g, 0.024 mol) in N,N-dimethylformamide (10 mL) was stirred with heating at 70° C. for 12 h. Cooled to ambient temperature, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel(hexane/ethyl acetate) to afford 2-(3-methyl-4-nitrophenoxy)ethanol as solid (1.3 g, y. 70%).