Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[CH3:14].C([Li])CCC.Cl[CH:21]([SiH3:23])Cl>CCCCCC.O>[CH3:21][SiH:23]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1
Reactant: Cc1ccccc1C
Reactant: [SiH3]C(Cl)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: C[SiH]1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 1 L rb flask equipped with a Teflon covered magnetic stirring bar and a reflux condenser was placed potassium tert-butoxide (36 g; 0.32 mol), o-xylene (17 mL; 0.15 mol) and 700 mL of hexanes. n-Butyllithium (128 mL; 2.5M) in hexane was added to the above mixture via a syringe. The red color of the o-xylene dianion appeared. The resulting mixture was heated to reflux for 1 h. The reaction mixture was cooled to room temp. The suspension of the dianion was transferred via a cannula to a sintered glass filter. The solvent was removed by suction filtration. The precipitated dianion was rinsed with fresh hexane. It was then resuspended in 500 mL of hexane and the suspension returned via a cannula to the original apparatus. Freshly distilled dichloromethylsilane (17 mL; 0.16 mol) was added. The mixture was stirred overnight a room temperature. 50 mL water was added. The organic layer was washed three times with water, dried over anhydrous calcium chloride, filtered and the solvents removed by evaporation under reduced pressure. The residue was purified by fractional distillation through a 15 cm vacuum jacketed Vigreux column. A central fraction, b.p. 43°-44° C./0.7 mmHg, was obtained. Yield: 5.5 g(25%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2)[CH3:6])=[O:4].C(N(CC)CC)C.Br[CH2:36][C:37](Cl)=[O:38].[CH3:40][NH:41][CH:42]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>ClCCl>[CH:42]1([N:41]([CH3:40])[CH2:36][C:37]([NH:1][CH2:2][C:3]([N:5]([C:7]2[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=2)[CH2:10][O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]3)[CH3:6])=[O:4])=[O:38])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: O=C(Cl)CBr
Reactant: CNC1CCCCCC1
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CN(C)C4CCCCCC4)c3Cl)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylquinoline (150 ml), triethylamine (0.077 ml) and dichloromethane (1.5 ml) was added bromoacetyl chloride (0.034 ml) in a dry ice-acetone bath. After 30 minutes, to the mixture was added N-methyl-N-cycloheptylamine (236 mg). The mixture was stirred for 3 hours at ambient temperature. The reaction mixture was washed with aqueous sodium bicarbonate solution, water and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography (dichloromethane-methanol) to yield 8-[3-[N-[(N-cycloheptyl-N-methylglycyl)glycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (151 mg) as amorphous.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:13]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][Cl:24])(=[O:18])[CH2:14][C:15]([CH3:17])=O.[NH2:25]/[C:26](/[CH3:32])=[CH:27]\[C:28]([O:30][CH3:31])=[O:29]>C(O)(C)C>[CH3:17][C:15]1[NH:25][C:26]([CH3:32])=[C:27]([C:28]([O:30][CH3:31])=[O:29])[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[C:2]([F:12])([F:11])[F:1])[C:14]=1[C:13]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][Cl:24])=[O:18]
Reactant: COC(=O)/C=C(/C)N
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: CC(=O)CC(=O)OCCCCCl
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCl)C1c1ccccc1C(F)(F)F

Procedure:
13.2 Grams of o-trifluoromethylbenzaldehyde, 14.6 g of 4-chlorobutyl acetoacetate and 8.8 g of methyl 3-aminocrotonate were added to 50 ml of isopropanol, and the whole mixture was refluxed by heating for 4 hours. The reaction mixture was concentrated, and the residue was purified by a silica gel column chromatography (eluant=chloroform) to yield 18.2 g of 4-chlorobutyl methyl 1,4-dihydro-2,6-dimethyl-4-(2-trifluoromethylphenyl)pyridine-3,5-dicarboxylate in the form of yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23](O)[C:24]([F:27])([F:26])[F:25])=[CH:4][CH:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+].O>CS(C)=O>[N:29]([CH:23]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[C:24]([F:27])([F:26])[F:25])=[N+:30]=[N-:31]
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Temperature: 110 °C
Reaction time: 20 h
Yield: 97.9 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (200 mg, 0.44 mmol) in tetrahydrofuran (4.0 mL) were added thionyl chloride (0.065 mL, 0.891 mmol) and 1 drop of N,N-dimethylformamide at room temperature. After stirring at room temperature for 2 hr, aqueous sodium hydrogen carbonate was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated an vacuo to give 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (200 mg, 0.43 mmol, 93%) as pale yellow solid. A mixture of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (68.6 mg, 0.146 mmol) and sodium azide (19 mg, 0.292 mmol) in dimethylsulfoxide (5.0 mL) was stirred at 110° C. for 20 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound (68.2 mg, 0.143 mmol, 98%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:18]=[CH:17][C:10]([CH:11]=[N:12][O:13][CH2:14][CH2:15][OH:16])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:20]1[CH:52]=[CH:51][C:23]([CH2:24][CH:25]2[S:29][C:28](=[O:30])[N:27]([C:31]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]2=[O:50])=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([C:7]2[CH:18]=[CH:17][C:10]([CH:11]=[N:12][O:13][CH2:14][CH2:15][O:16][C:20]3[CH:52]=[CH:51][C:23]([CH2:24][CH:25]4[S:29][C:28](=[O:30])[N:27]([C:31]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:26]4=[O:50])=[CH:22][CH:21]=3)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCON=Cc1ccc(-c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1SC(Cc2ccc(OCCON=Cc3ccc(-c4ccccc4)cc3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 86.3 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 483 mg of 2-(4-phenylbenzylideneaminooxy)ethanol (prepared as described in Preparation 9), 716 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 525 mg of triphenylphosphine and 348 mg of diethyl azodicarboxylate, 914 mg of the title compound were obtained as a crystalline powder, melting at 157-159° C.
Reaction SMILES: C([N:4]1[C:12]2[CH:11]=[C:10]3[C:13](=O)[C:14](=[O:16])[NH:15][C:9]3=[CH:8][C:7]=2[CH2:6][CH2:5]1)(=O)C.[CH:18]1[C:23]([NH:24][NH2:25])=[CH:22][CH:21]=[C:20]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:19]=1.Cl.[BrH:31]>O.CCO>[BrH:31].[O:16]=[C:14]1[NH:15][C:9]2=[CH:8][C:7]3[CH2:6][CH2:5][NH:4][C:12]=3[CH:11]=[C:10]2[C:13]1=[N:25][NH:24][C:23]1[CH:22]=[CH:21][C:20]([S:26]([NH2:29])(=[O:27])=[O:28])=[CH:19][CH:18]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: CC(=O)N1CCc2cc3c(cc21)C(=O)C(=O)N3
Agent: Br
Agent: Cl
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3cc4c(cc32)NCC4)cc1
Temperature: 25 °C
Yield: 17 %

Procedure:
A solution of 0.10 g (0.44 mmol) of 5-acetyl-1,5,6,7-tetrahydro-pyrrolo[2,3-f]indole-2,3-dione in 3 mL of conc. HBr was heated to 100° C. for 18 h. The mixture was cooled to ambient temperature, diluted with 10 mL of water and filtered. The filtrate was concentrated in vacuo and added to a solution of 0.05 g (0.2 mmol) 4-sulfonamidophenylhydrazine hydrochloride in 5 mL of EtOH, The mixture was heated to 80° C. for 1 h and cooled to ambient tempurature. The resulting solid was collected by vacuum filtration, washed with water and dried in a vacuum oven at 70° C. to afford the title compound as a tan solid (0.026 g, 17%): mp>250° C.; 1H NMR (DMSO-d6): δ 3.17 (t, J=7.8 Hz, 2H), 3.69 (t, J=7.8 Hz, 2H), 6.96 (s, 1H), 7.25 (s, 2H), 7.52 (s, 1H), 7.57 (d, J=8.8 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 10.65 (bs, 2H), 11.24 (s, 1H), 12.73 (s, 1H); APCI−MS: m/z 356 (M−H)−. Anal. Calcd for C16H15N5O3S.0.9 HBr.0.5 H2O: C, 43.75; H, 3.88; N, 15.94; S, 7.30. Found: C, 44.01; H, 4.14; N, 15.70; S, 7.12.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[F:11][C:12]1[CH:25]=[CH:24][C:15]2[N:16]3[C:21]([CH:22]=[O:23])=[CH:20][N:19]=[C:17]3[S:18][C:14]=2[CH:13]=1>CCOCC>[F:11][C:12]1[CH:25]=[CH:24][C:15]2[N:16]3[C:21]([CH:22]([CH2:3][CH2:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)[OH:23])=[CH:20][N:19]=[C:17]3[S:18][C:14]=2[CH:13]=1
Reactant: O=Cc1cnc2sc3cc(F)ccc3n12
Reactant: BrCCc1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: OC(CCc1ccccc1)c1cnc2sc3cc(F)ccc3n12

Procedure:
Magnesium (0.146 g) in anhydrous ether (15 mL) was treated with (2-bromoethyl)-benzene (0.82 mL) and reacted for 2.5 hours. The Grignard reagent was treated with solid 7-Fluoro-imidazo [2,1-b]benzothiazole-3-carboxaldehyde (Formula L-3) (0.44 g). Incomplete conversion was observed, an additional charge of Grignard reagent was added, and reacted for 24 hours. The reaction mixture was decanted into 5% ammonium chloride solution and extracted with ethyl acetate. The extract was washed, dried, and evaporated to a solid residue (0.60 g) of crude 7-Fluoro-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol (Formula L-4). Crystallization from isopropanol solution gave pure 7-Fluoro-α-(2-phenylethyl) imidazo[2,1-b]benzothiazole-3-methanol (Formula L-4), m.p. 195-196°. Anal. Calcd for C18H15FN2OS. C, 66.24; H, 4.63; N, 8.58; S, 9.82. Found: C, 66.08; H, 4.64; N, 8.48; S, 9.72. MS m/z 326 (M+), 235, 221, 205, 193, 179, 193, 179, 166, 152, and 91. IR (mull). 3301, 1547, 1486, 1321, 1260, 1208, 1200, 1133, and 1039 cm−1. NMR (CDCl3/CD3OD) δ2.33 (q, J=7.6 Hz, 2, CH2), 2.76-3.0 (m, 2, CH2), 5.00 (t, J=7.6 Hz, 1, CH), 7.1-7.4 (m, 9, ArH, CH), 8.01 (m, 1, ArH).
Reaction SMILES: N.[Li].[CH2:3]([OH:7])[CH2:4][C:5]#[CH:6].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>O1CCCC1>[CH2:3]([OH:7])[CH2:4][C:5]#[C:6][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C#CCCO
Reactant: CCCCCCCCBr
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Product: CCCCCCCCC#CCCO
Temperature: 0 °C

Procedure:
To a mixture of 500 ml of anhydrous ammonia and 100 mg of ferric nitrate in a 2 liter three necked flask equiped with a mechanical stirrer and dry ice condenser was added 3.12 g of lithium wire in small portions. When the blue color had discharged, 14.0 g of 3-butyn-1-ol in 100 ml of tetrahydrofuran was added over 15 minutes and the reaction mixture refluxed for 1 hour. A solution of 34.5 ml of 1-bromooctane in 200 ml of tetrahydrofuran was added and the reaction mixture was allowed to reflux for 90 minutes. At the end of this period the entire reaction mixture was poured onto 1 liter of ice and then saturated with salt. The resulting aqueous solution was extracted twice with 500 ml of ether and the combined ethereal solutions were washed with brine and dried over potassium carbonate. The ether was evaporated and the residue distilled to give 25.13 g of 3-dodecyn-1-ol, b.p. 87°-90° /0.5 mm.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:30]=[CH:29][C:8]([O:9][CH2:10][C:11]2(O)[O:15][C:14]3[CH:16]=[CH:17][C:18]([C:21](=[O:23])[CH3:22])=[C:19]([OH:20])[C:13]=3[C:12]2([CH2:25][CH2:26][CH3:27])O)=[CH:7][CH:6]=1.[OH-].[Na+]>C1COCC1.O>[C:3]([CH2:4][C:5]1[CH:30]=[CH:29][C:8]([O:9][CH2:10][CH:11]2[O:15][C:14]3[CH:16]=[CH:17][C:18]([C:21](=[O:23])[CH3:22])=[C:19]([OH:20])[C:13]=3[CH:12]2[CH2:25][CH2:26][CH3:27])=[CH:7][CH:6]=1)([OH:31])=[O:2]
Reactant: CCCC1(O)c2c(ccc(C(C)=O)c2O)OC1(O)COc1ccc(CC(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCC1c2c(ccc(C(C)=O)c2O)OC1COc1ccc(CC(=O)O)cc1
Reaction time: 3 h

Procedure:
The compound from Example 16 (650 mg, 1.63 moles) was taken up in 5 ml THF to which was added 1 N NaOH (4.2 ml). After three hours, the reaction volume wad diluted with H2O and the THF was removed in vacuo. The aqueous phase was wahsed with CHCl3, then acidified and extracted into CHCl3. The organic extract was dried and concentrated. The residue was triturated with ether to afford the title compound as a white solid which was recrystallized from toluene, m.p.: 104°-106°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[N:22]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CCOC(C)=O>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[C:7]([S:9]([N:25]2[CH2:24][CH2:23][N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26]2)(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: Cc1ccc(C)c(Oc2ccc(C#N)cc2S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(C)c(Oc2ccc(C#N)cc2S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 42 %

Procedure:
A solution of sulfonyl chloride 32 (0.160 g, 0.50 mmol), tert-butyl piperazine-1-carboxylate (0.121 g, 0.65 mmol), and TEA (0.066 g, 0.65 mmol) in DCM (5 mL) was stirred overnight at room temperature. The reaction was monitored with TLC (25% EtOAc in hexanes). The reaction mixture was concentrated in vacuo and the residual was redissolved with a minimal amount of DCM and chromatographed on normal-phase silica to produce compound 33 as a white powder (0.099 g, 42.0% yield, 100.0% pure). 1H NMR (500 MHz, DMSO-d6): δ 8.24 (d, J=2 Hz, 1H), 8.00 (dd, J1=2 Hz, J2=8 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.09 (d, J=8 Hz, 1H), 6.98 (s, 1H), 6.78 (d, J=8 Hz, 1H), 3.39 (m, 4H), 3.22 (m, 4H), 2.29 (s, 3H), 2.07 (s, 3H), 1.37 (s, 9H); MS (ESI, EI+): m/z=372 (MH+).
Reaction SMILES: [C:1]([C:3]1[C:16]2[N:15](C(OC(C)(C)C)=O)[C:14]3[C:9](=[CH:10][C:11]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:12][CH:13]=3)[S:8][C:7]=2[CH:6]=[C:5]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:4]=1)#[N:2].[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>ClCCl>[C:1]([C:3]1[C:16]2[C:7](=[S+:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[C:11]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[CH:10]=3)[CH:6]=[C:5]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:4]=1)#[N:2].[F:39][C:38]([F:41])([F:40])[C:36]([O-:42])=[O:37]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1c2ccc(N3CCOCC3)cc2Sc2cc(N3CCOCC3)cc(C#N)c21
Solvent: ClCCl
Product: N#Cc1cc(N2CCOCC2)cc2[s+]c3cc(N4CCOCC4)ccc3nc12
Product: O=C([O-])C(F)(F)F

Procedure:
Dissolved tert-butyl 1-cyano-3,7-dimorpholino-10H-phenothiazine-10-carboxylate (63.0 mg, 0.0.127 mmol) in dichloromethane (3 mL). Added TFA (2 mL, 27 mmol). Stirred until the reaction was complete by TLC and LC/MS (2 h).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[H-].[Na+].[F:12][C:13]([F:27])([F:26])[C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH2:17]Br>CN(C=O)C.C1COCC1>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH2:17][O:8][CH2:7][C:5]1[CH:4]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=[C:14]([C:13]([F:12])([F:26])[F:27])[CH:15]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC1(C)OCC(CO)O1
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc(C(F)(F)F)c1

Procedure:
To a stirred solution of solketal (0.151 mol) in DMF/THF (1:1, 300 ml) under a nitrogen atmosphere was added sodium hydride (1.2 equivalents of an 80% dispersion in mineral oil). The anion was allowed to form over one hour prior to addition of 3,5-bistrifluoromethylbenzyl bromide. The reaction was partitioned between ethyl acetate-saturated ammonium chloride after 1 h and the organic phase separated, dried (MgSO4), and concentrated to a yellow oil. Chromatography using pet. ether then 20% ethyl acetate-pet. ether as eluent gave 2,2-dimethyl- 1,3-dioxolane-4-methanol-3,5-bistrifluoromethylbenzyl ether as a yellow oil: (CDCl3) δ1.4 (3H, s), 1.45 (3H, s), 3.6-3.65 (2H, m), 3.7-3.8 (1H, m), 4.1-4.15 (1H, m), 4.3-4.4 (1H, m), 4.7 (2H, s), 7.8 (3H, s).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].CS(O)(=O)=O.[NH2:13][CH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1.N1C=CC=CC=1.C(C1C=CC(CNS(C=C)(=O)=O)=CC=1)#N>ClCCl>[C:14]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][S:4]([CH2:3][CH2:2][Cl:1])(=[O:6])=[O:5])=[CH:17][CH:16]=1)#[N:13]
Reactant: N#Cc1ccc(CN)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: C=CS(=O)(=O)NCc1ccc(C#N)cc1
Agent: CS(=O)(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(CNS(=O)(=O)CCCl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Chloroethane sulfonyl chloride (4.8 g, 0.029 mol) was added drop by drop to solution of 4-aminomethyl benzonitrile methan sulphonic acid salt acid (7 g, 0.029 mol) and pyridine (24 ml) in dry dichloromethane (25 ml) at −5° C. under nitrogen atmosphere. The reaction mixture was stirred at RT for 2 days and then partitioned between water and dichloromethane. The organic layer was washed with water and brine and dried over sodium sulfate. Solvent was evaporated under reduced pressure and the residue was purified by column chromatography over silica gel using 1% methanol in chloroform as eluent to give mixture of the sub-title compound and ethenesulfonic acid 4-cyano-benzylamide (3.4 g) as a solid. This was directly taken for next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[C:10]([N:15]3[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16]3)=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[N:28]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=1)=[C:29]=[O:30]>ClCCl>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[C:10]([N:15]3[CH2:19][CH2:18][CH:17]([NH:20][C:29]([NH:28][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=4)=[O:30])[CH2:16]3)=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:3][CH:2]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: NC1CCN(c2nccnc2OCc2ccncc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)NC1CCN(c2nccnc2OCc2ccncc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
To a solution of 1-[3-(pyridin-4-ylmethoxy)-pyrazin-2-yl]-pyrrolidin-3-ylamine (50 mg, 0.18 mmole), triethylamine (excess eq.) in dichloromethane was added 1-isocyanato-3-trifluoromethyl-benzene (37 mg, 0.198 mmole). The mixture was stirred at room temperature for 1 hour. The mixture was then concentrated in vacuo, and purified by preparative HPLC to give N-(1-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}pyrrolidin-3-yl)-N′-[3-(trifluoro-methyl)phenyl]urea (13.2 mg, 12.5% yield). 1H NMR (DMSO-d6) 8.80 (m, 3H), 7.97 (s, 1H), 7.90 (d, 2H), 7.68 (d, 1H), 7.4 (m, 2H), 7.3 (d, 1H), 7.2 (m, 1H), 6.8 (d, 1H), 5.3 (s, 2H), 4.25 (m, H), 3.9 (m, 1H), 3.75 (m, 2H), 3.6 (m, 1H), 2.40 (m, 1H), 1.85 (m, 1H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.Cl>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Fc1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(Oc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.2 %

Procedure:
4-Bromophenol (2 g, 11.5 mmol) is placed in 10 ml of anhydrous DMF under nitrogen. Sodium hydride (0.51 g, 127 mmol) is added. After stirring for 20 min at ambient temperature, 2-fluoropyridine (1.05 ml, 12.1 mmol) is added and the reaction medium is heated at 105° C. for 7 h. After hydrolysis, the pH is adjusted to 8 with a 1N aqueous solution of HCl. The reaction medium is then extracted with ethyl acetate. The organic phase is washed with a saturated aqueous sodium chloride solution, dried over MgSO4 and concentrated to dryness. The crude product obtained is chromatographed on silica gel, elution being carried out with a gradient of ethyl acetate in heptane ranging from 0% to 30%. 2.22 g of expected 2-(4-bromo-phenoxy)pyridine are obtained,
Reaction SMILES: [C:1]([C:4](C(OC(C)(C)C)=O)([CH2:19][CH2:20][CH2:21][CH:22]([O:28][C:29](=[O:31])[CH3:30])[CH2:23][O:24][CH2:25][CH2:26][CH3:27])[CH2:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1)(=[O:3])[CH3:2].C(C(CCCC(OC(=O)C)CCCCC)CCCC1C=CC(C(OCC)=O)=CC=1)(=O)C>>[C:1]([CH:4]([CH2:19][CH2:20][CH2:21][CH:22]([O:28][C:29](=[O:31])[CH3:30])[CH2:23][O:24][CH2:25][CH2:26][CH3:27])[CH2:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCCOCC(CCCC(CCCc1ccc(C(=O)OCC)cc1)(C(C)=O)C(=O)OC(C)(C)C)OC(C)=O
Agent: CCCCCC(CCCC(CCCc1ccc(C(=O)OCC)cc1)C(C)=O)OC(C)=O
Product: CCCOCC(CCCC(CCCc1ccc(C(=O)OCC)cc1)C(C)=O)OC(C)=O

Procedure:
This compound is prepared by the method described in Example 1, Step E, except that the product of Step B of the present example replaces ethyl 4-(4-acetyl-8-acetoxytridecyl)benzoate. The title compound is purified by column chromatography on silica gel and is obtained as a yellowish, viscous oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br.[H-].[Na+]>>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([F:14])[CH:16]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Reactant: Fc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(Cc1cccc(F)c1)n1cccc1

Procedure:
Prepared according to the benzylation condition used in Example 1 step b) from pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.), 3-fluorobenzyl bromide (1.0 eq.) and sodium hydride (1.3 eq.). ESI (m/z): 291 (M+H)+.