Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH2:2][CH:3]([SH:6])[CH2:4][SH:5].O=[C:8]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][CH2:9][C:8]1([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[S:6][CH:3]([CH2:4][SH:5])[CH2:2][S:1]1)[CH3:15]
Reactant: SCC(S)CS
Reactant: CCOC(=O)CCC(=O)CCC(=O)OCC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)CCC1(CCC(=O)OCC)SCC(CS)S1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40 %

Procedure:
A stirred solution of 1,2,3-trimercaptopropane (10.0 g, 0.071 mol) and diethyl 4-oxopimelate (16.43 g, 0.071 mol) in methylene chloride (300 ml) under nitrogen atmosphere was treated with boron trifluoride etherate (2 ml). After stirring for 3 days at room temperature, the reaction was quenched by addition of 200 ml of 5% sodium bicarbonate solution. The organic phase was separated and dried over anhydrous sodium sulfate. The drying agent was filtered and the filtrate concentrated on the rotary evaporator. The residue was chromatographed on silica gel using 5% ethyl acetate/hexane to give 10 g (40%) of the title compound as an oil.
Reaction SMILES: [CH2:1](P(=O)(OCC)OCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].C1OCCOCCOCCOCCOCCOC1.[Br:37][C:38]1[N:43]=[C:42]([CH:44]=O)[CH:41]=[CH:40][CH:39]=1>CN(C)C=O.C(O)C>[Br:37][C:38]1[CH:39]=[CH:40][CH:41]=[C:42](/[CH:44]=[CH:1]/[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:43]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Brc1cccc(/C=C/c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of diethyl benzylphosphonate (4.57 mL, 21.91 mmol) in dimethylformamide (50 mL) at room temperature was added sodium methoxide (2.367 g, 43.8 mmol) and 18-Crown-6 (2.316 g, 8.76 mmol). After stirring at room temperature for 5 min, the reaction was cooled to 0° C. and treated with 6-bromopicolinaldehyde (4.89 g, 26.3 mmol) as a solid in one portion. The ice bath was removed and the reaction stirred at room temperature for 1 h. The reaction was gradually warmed to 120° C. and held there for 2 h. The reaction was cooled to room temperature and poured into water (500 mL) with vigorous stirring. The resulting suspension was extracted with diethyl ether, washed with water (3×), then brine, dried over magnesium sulfate, and concentrated to an oil. The oil was dissolved in hexanes and reconcentrated to give something that appeared to be crashing out as a solid. The resulting residue (solid in oil) was suspended in ethanol, concentrated, and pumped under high vacuum to give a dark-colored, moist solid. The resulting residue was suspended in ethanol (total volume (solid+solution)=20 ml). The resulting suspension was placed in the freezer and held there overnight. The resulting precipitate was collected by filtration to give 2.46 g (43%) as a faint tan powder. 1H-NMR (CDCl3, 500 MHz) δ 7.69 (d, J=16.2, 1H), 7.60 (d, J=8.9, 2H), 7.53 (dd, J=7.9, 7.6, 1H), 7.41 (dd, J=7.6, 7.3, 2H), 7.31-7.38 (m, 3H), 7.11 (d, J=16.2, 1H). 13C-NMR (CDCl3, 126 MHz) δ 157.2, 142.3, 138.8, 136.3, 134.5, 128.9, 128.8, 127.4, 126.4, 126.2, 120.7.
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[Br:9][C:10]1[S:14][C:13]2=[N:15][CH:16]=[CH:17][N:12]2[N:11]=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[Br:9][C:10]1[S:14][C:13]2=[N:15][CH:16]=[C:17]([I:8])[N:12]2[N:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Brc1nn2ccnc2s1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1nn2c(I)cnc2s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
NIS (3.83 g, 16.2 mmol, 1.1 eq) was added to a solution of 2-bromo-imidazo[2,1-b][1,3,4]thiadiazole (3.0 g, 14.7 mmol, 1 eq) in dry DMF (50 mL). The mixture was stirred at RT for 4 h and then poured into aq. Na2S2O3 (10%) and diluted with EtOAc. The organic phase was washed with water, dried and concentrated to give the desired product (pale brown solid; 4.34 g, yield 89%). 1H (300 MHz, CDCl3): δ/ppm 7.29 (1H, s).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[C:12]([C:15]([F:18])([F:17])[F:16])[NH:11][C:10]=2[C:9](=[S:19])[NH:8][C:7]1=[O:20])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+].S(OC)(O[CH3:27])(=O)=O>O>[CH3:27][S:19][C:9]1[C:10]2[NH:11][C:12]([C:15]([F:16])([F:18])[F:17])=[N:13][C:14]=2[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7](=[O:20])[N:8]=1
Reactant: CCCCCn1c(=O)[nH]c(=S)c2[nH]c(C(F)(F)F)nc21
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCn1c(=O)nc(SC)c2[nH]c(C(F)(F)F)nc21
Temperature: 80 °C
Yield: 95.6 %

Procedure:
To a mixture of 3-pentyl-6-thioxo-8-(trifluoromethyl)-1,3,6,7-tetrahydro-2H-purin-2-one (0.15 g, 0.49 mmol) in a solution of sodium hydroxide in water (2 M, 2 mL) was added dimethyl sulfate (0.056 mL, 0.59 mmol). The reaction mixture was heated at 80° C. for 1.5 h, quenched with acetic acid and extracted with methylene chloride. The organic layer was dried (MgSO4), concentrate and purified by silica gel chromatography (0-20% EtOAc in hexane) to provide the product as a yellow solid (0.15 g, 95% yield). LCMS calculated for C12H16F3N4OS (M+H): 321.1; found: 321.1.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>ClCCl>[CH3:17][S:18]([O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1COS(C)(=O)=O
Reaction time: 2 h
Yield: 103.1 %

Procedure:
tert-butyl [(1S,2S)-2-(hydroxymethyl)cyclohexyl]carbamate (1.3 g, 5.68 mmol) was dissolved in dichloromethane (10 mL) and MsCl (0.52 mL, 6.75 mmol) was added drop wise at 0° C. Triethylamine (1 mL) was then added and the mixture stirred for 2 hours. The reaction mixture was quenched with ice and diluted in dichloromethane. Washed with a saturated solution of NaHCO3 and brine, dried and concentrated in vacuo to provide the tile compound as brown solid (1.8 g). MS (M+1): 308.16
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:16]=[C:15]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:14]=[CH:13][CH:12]=3)[S:10][C:3]=12.[CH3:25][C:26]1[NH:27][C:28]2[C:33]([CH:34]=1)=[CH:32][C:31]([NH2:35])=[CH:30][CH:29]=2>>[CH3:25][C:26]1[NH:27][C:28]2[C:33]([CH:34]=1)=[CH:32][C:31]([NH:35][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[N:16]=[C:15]([C:17]([N:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)=[O:18])[CH:14]=[CH:13][CH:12]=4)[S:10][C:3]=13)=[CH:30][CH:29]=2
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: O=C(c1cccc(-c2cc3nccc(Cl)c3s2)n1)N1CCOCC1
Product: Cc1cc2cc(Nc3ccnc4cc(-c5cccc(C(=O)N6CCOCC6)n5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from [6-(7-chloro-thieno[3,2-b]pyridin-2-yl)-pyridin-2-yl]-morpholin-4-yl-methanone and 2-methyl-5-aminoindole by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ8.10 (d, 1H), 7.98 (d, 1H), 7.89 (t, 1H), 7.83 (s, 1H), 7.56 (d, 1H), 7.33 (s, 1H), 7.29 (d, 1H), 6.96 (d, 1H), 6.61 (d, 1H), 6.11 (s, 1H), 3.74 (s, 4H), 3.49 (s, 4H), 2.42 (s, 3H); RP18-HPLC RT: 4.58 minutes; API MS: 470 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:34])[CH2:32][OH:33])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:35])[C@H:20]4[O:36][C:37](=[O:39])[CH3:38])=[O:17])[CH2:15][C@@:7]3([OH:40])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:41](N1C=CN=C1)([N:43]1[CH:47]=[CH:46][N:45]=[CH:44]1)=[O:42]>ClCCl.O>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:34])[CH2:32][O:33][C:41]([N:43]6[CH:47]=[CH:46][N:45]=[CH:44]6)=[O:42])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:35])[C@H:20]4[O:36][C:37](=[O:39])[CH3:38])=[O:17])[CH2:15][C@@:7]3([OH:40])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H](C(C)CO)CC[C@@H](C)[C@]2(O)[C@H]1OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Solvent: ClCCl
Solvent: O
Product: CC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H](C(C)COC(=O)n3ccnc3)CC[C@@H](C)[C@]2(O)[C@H]1OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Reaction time: 18 h
Yield: 45.7 %

Procedure:
To (1S,2R,4aS,5S,8R,8aR)-2-(acetyloxy)-8a-hydroxy-5-[2-hydroxy-1-methylethyl]-3,8-dimethyl-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate(Preparation 140, 0.30 g, 0.52 mmol) in dichloromethane was added 1,1′-carbonyldiimidazole (0.92 g, 0.57 mmol) and the reaction mixture was stirred for 18 h. The reaction mixture was diluted with water and extracted with dichloromethane. The organic extracts were washed with brine, dried and then concentrated in vacuo. The crude product was purified by flash chromatography eluting with ethyl acetate:hexane (2:1) to give the title compound (0.16 g, 46%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][NH2:12])[N:3]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>C(O)(=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][N:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:3]=1
Reactant: NNc1nc(N)nc2[nH]cnc12
Reactant: COc1ccc(C=O)cc1
Solvent: CC(=O)O
Product: COc1ccc(C=NNc2nc(N)nc3[nH]cnc23)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.4 %

Procedure:
2-Amino-6-hydrazino-9H-purine (1.0 g, 6.1 mmol) and p-anisaldehyde (1.24 g, 9.1 mmol) were added to acetic acid (40 ml), and the mixture was stirred for 4 hours at room temperature. After completion of reaction, the solvent was evaporated under reduced pressure so as to precipitate solid crystals. The crystals were recrystallized from DMF to obtain 1.13 g (yield 66%) of colorless powdery crystals (m.p.=174° C. (decomposed)).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3C(C)=NC(C)=C[CH:19]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.[Li]CCCC.[CH3:40][N:41]1C(C=O)=C[N:43]=[C:42]1[CH3:48]>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[N:41]([CH3:40])[C:42]([CH3:48])=[N:43][CH:19]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:29][CH:30]=1
Reactant: Cc1ncc(C=O)n1C
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -70 °C
Reaction time: 0.03 h

Procedure:
To a flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (2.0 g, 4.64 mmol, Intermediate 12: step d) was added THF (25 mL). The solution was cooled to −70° C. and then n-BuLi (2.5 M in hexanes, 1.8 mL, 4.5 mmol) was added dropwise. After 2 minutes, 1,2-dimethyl-1H-imidazole-5-carbaldehyde (720 mg, 5.8 mmol in 5 mL THF) was introduced. The reaction mixture was allowed to warm to 0° C. over 60 minutes at which time it was quenched with aqueous NH4Cl solution. The aqueous portion was extracted with EtOAc:THF (10:1, 5×50 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness. The solid was triturated with EtOAc:Et2O (1:1), collected by filtration and rinsed with additional Et2O and dried to afford the title compound. The mother liquors were concentrated and chromatographed on silica gel (3% MeOH-DCM increasing to 10% MeOH) to provide additional title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[N:6][CH:7]=1.CC1C=CC(N2C=C3C(C=CC([N+]([O-])=O)=C3)=N2)=NC=1>CCO.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH2:10][NH:9]2)=[N:6][CH:7]=1
Reactant: Cc1ccc(-n2ncc3cc([N+](=O)[O-])ccc32)nc1
Agent: [Pd]
Agent: Cc1ccc(-n2cc3cc([N+](=O)[O-])ccc3n2)nc1
Solvent: CCO
Product: Cc1ccc(N2NCc3cc(N)ccc32)nc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The mixture of 1-(5-methylpyridin-2-yl)-5-nitro-1H-indazole and 2-(5-methylpyridin-2-yl)-5-nitro-2H-indazole was dissolved in EtOH (20 ml), and 10% Pd/C (250 mg) was added. Under H2 atmosphere, the mixture was stirred at room temperature for 12 h, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with AcOEt/Hexane to give the title compound (61 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=CC=C[CH:9]=2)[N:5]=[C:4]([O:14][CH2:15][CH2:16][CH:17]([CH3:19])C)[CH:3]=1.ClC1C=C(Cl)N=[C:23]([C:28]2C=CC=[CH:30][CH:29]=2)N=1.ClC1C=C(Cl)N=C(C(C)C)N=1.C(C(CCCC)CO)C>CC(C)CCO>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([CH3:9])[CH3:13])[N:5]=[C:4]([O:14][CH2:15][CH:16]([CH2:17][CH3:19])[CH2:23][CH2:28][CH2:29][CH3:30])[CH:3]=1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Reactant: CC(C)CCOc1cc(Cl)nc(-c2ccccc2)n1
Agent: CC(C)c1nc(Cl)cc(Cl)n1
Solvent: CCCCC(CC)CO
Solvent: CC(C)CCO
Product: CCCCC(CC)COc1cc(Cl)nc(C(C)C)n1

Procedure:
The compound of Example 23 is prepared analogously to the compound of Example 3, with 4,6-dichloro-2-phenylpyrimidine being replaced by 4,6-dichloro-2-i-propylpyrimidine and 3-methylbutanol by 2-ethylhexanol.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19]([C:21]2[C:26]([N:27]3[N:31]=[CH:30][CH:29]=[N:28]3)=[CH:25][CH:24]=[CH:23]N=2)=[O:20])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.Cl.[CH3:33]N(C1C=NC(C(F)(F)F)=CN=1)[C@H]1CCC[C@@H]1N.N1N(C2C=CC=CC=2C(O)=O)N=CC=1>>[CH3:1][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:20])[C:21]2[CH:33]=[CH:23][CH:24]=[CH:25][C:26]=2[N:27]2[N:28]=[CH:29][CH:30]=[N:31]2)=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[N:7]=1
Reactant: Cc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1
Reactant: CN(c1cnc(C(F)(F)F)cn1)[C@H]1CCC[C@@H]1N
Agent: Cl
Agent: O=C(O)c1ccccc1-n1nccn1
Product: Cc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-{[3-methyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide (Example 76) from (1S,2S)-1-N-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 23; 60 mg, 0.20 mmol) and 2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1001401-62-2; 40 mg, 0.21 mmol) except this was purified only by column chromatography (silica, 0 to 100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[CH:15]([C:21]([OH:23])=[O:22])[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:13]=2[CH:12]=[C:11]([C:24]([CH3:32])([CH3:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O[C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)=O.N1C=CC=CC=1>CCCCC>[CH2:1]([O:8][C:9]1[C:14]2[CH:15]([C:21]([O:23][C:38]3[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=3)=[O:22])[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:13]=2[CH:12]=[C:11]([C:24]([CH3:31])([CH3:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: CCCCCCC(C)(C)c1cc(OCc2ccccc2)c2c(c1)OC(C)(C)CC2C(=O)O
Solvent: CCCCC
Solvent: c1ccncc1
Product: CCCCCCC(C)(C)c1cc(OCc2ccccc2)c2c(c1)OC(C)(C)CC2C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
A mixture of 3.3 g (7.53 mmole) 5-benzyloxy-2,2-dimethyl-7-(1,1-dimethylheptyl)-3,4-dihydro-2H-benzopyran-4-carboxylic acid, 5.0 g (21.3 mmole) p-nitrophenyl trifluoroacetate and 100 ml dry pyridine, under nitrogen, is stirred at room temperature for three hours. The pyridine is evaporated in vacuo, ethyl ether is added to the residue and this is washed with 1N sodium hydroxide, water, 10% hydrochloric acid, brine, dried (MgSO4) and the solvent evaporated to obtain 4.5 g crude oil. This is taken up in pentane and cooled to obtain 3.38 g of crystals, m.p. 87°-87.5° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:11])([CH3:10])[C:5]([O:7]CC)=O.[C:12](#[N:14])[CH3:13]>C1COCC1>[F:11][C:4]([F:3])([CH3:10])[C:5](=[O:7])[CH2:13][C:12]#[N:14]
Reactant: CCOC(=O)C(C)(F)F
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(F)(F)C(=O)CC#N
Temperature: 75 °C
Reaction time: 8 h

Procedure:
In a round bottomed flask flushed with argon, a suspension of sodium hydride 60% in mineral oil (1.30 g, 34 mmoles) was rinsed twice with hexane, and suspended in 20 mL of dry THF. The solution was heated to 75° C., and ethyl difluoropropionate (3.00 g, 22 mmoles) and acetonitrile (1.78 mL) in 5 ml of dry THF was added dropwise over 30 minutes. The temperature of the reaction was lowered to 65° C. and stirred overnight. The mixture was then concentrated to an oil and partitioned between water and ether, and extracted twice to remove any mineral oil and other impurities. The aqueous layer was acidified to pH=1 with 10% HCl, and the solution extracted twice. These extracts were dried over magnesium sulfate, filtered and concentrated to a crude oil. The crude product was purified using silica gel chromatography using a gradient of 10-40% ethyl acetate/hexane to afford 4,4-difluoro-3-oxo-pentanenitrile 1H(300 MHz, CDCl3) δ 3.95 (s, 2H), 1.86 (m, 3H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:8][C:9]([F:22])([F:21])[C:10]1[CH:11]=[CH:12][C:13]([CH:17]([CH3:20])[CH2:18][CH3:19])=[C:14]([OH:16])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:8][C:9]([F:21])([F:22])[C:10]1[CH:11]=[CH:12][C:13]([CH:17]([CH3:20])[CH2:18][CH3:19])=[C:14]([CH:15]=1)[O:16][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCC(C)c1ccc(C(F)(F)F)cc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)COc1cc(C(F)(F)F)ccc1C(C)CC
Temperature: 80 °C

Procedure:
2.5 ml of ethyl bromoacetate were added to 4 g of the product of Step C in 15 ml of dimethylsulfoxide and 4 g of potassium carbonate were added, followed by heating at 80° C. for 2 hours 30 minutes. The reaction medium was poured into iced water and extracted with methylene chloride. The extracts were dried and concentrated to dryness to obtain 5.10 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH2:5][NH:6][C:7](=[O:14])[C:8]([C:12]#[N:13])=[C:9]([CH3:11])[CH3:10].[CH3:19]OC(OC)N(C)C.O1CCCC1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH2:5][N:6]1[CH:19]=[CH:10][C:9]([CH3:11])=[C:8]([C:12]#[N:13])[C:7]1=[O:14]
Reactant: CC(C)=C(C#N)C(=O)NCc1ccc(Cl)c(Cl)c1
Reactant: COC(OC)N(C)C
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccn(Cc2ccc(Cl)c(Cl)c2)c(=O)c1C#N
Reaction time: 1 h

Procedure:
A solution of 42.8 g. (0.15 mole) of N-(3,4-dichlorobenzyl)-2-cyano-3-methylcrotonamide and 18.0 g. (0.15 mole) of N,N-dimethylformamide dimethyl acetal in 250 ml. of tetrahydrofuran is stirred at ambient temperature for 22 hr. followed by 1 hr. at reflux. The solvent is removed and the tacky solid residue is heated until molten. When evolution of dimethylamine subsides the reaction mixture is allowed to cool and the dark glassy residue is recrystallized from ethanol. The solid product is slurried in ether and isolated by filtration to give 15.79 g. (36%) of product as a brown powder: m.p. 177.5°-180.5° C.; ν (ethanol) 2210 (CN) and 1670 cm.-1 (C=O); δ 8.19 (d, 1H, H6), 7.2-7.8 (m, 3H, aromatic protons), 6.46 (d, 1H, H5), 5.16 (s, 2H, benzyl methylene), and 2.4 (s, 3H, methyl).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[C:11]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7].S(OC)(O[CH3:24])(=O)=O>O>[CH3:24][O:3][C:4]1[C:11]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7]
Reactant: COS(=O)(=O)OC
Reactant: Cc1ccccc1Sc1cccc(CO)c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1c(CO)cccc1Sc1ccccc1C
Yield: 96.9 %

Procedure:
A solution of potassium hydroxide (5.8 g) in water (30 ml) was added dropwise to a mixture of 2-hydroxy-3-(o-tolylthio)benzyl alcohol (8.3 g) and dimethyl sulfate (8.5 g) in 10 minutes at temperature below 60° C. with stirring, and the mixture was stirred at the same temperature for 10 minutes. The reaction mixture was treated in a similar manner to that of Example 21-(4). The resultant oily residue was purified by column chromatography (silica gel 150 g, benzene) to give oily 2-methoxy-3-(o-tolylthio)benzyl alcohol (8.5 g).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[CH2:9][N:8]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:35])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH3:34])=[CH:22][CH:21]=3)=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[I-].[CH3:37][N+:38](=[CH2:40])[CH3:39]>O1CCCC1.CCOCC>[CH:3]1[C:13]2[CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[CH2:9][N:8]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([N:26]([CH2:37][N:38]([CH3:40])[CH3:39])[C:27](=[O:35])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH3:34])=[CH:22][CH:21]=3)=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: C=[N+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)N(CN(C)C)c1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a suspension of 14 mg of 60% sodium hydride in oil, in 2 ml of tetrahydrofuran is added 0.13 g of N-[4-[(6,11-dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]phenyl]-2-methylbenzamide. The reactants are stirred for 1 hour and 62 mg of N,N-dimethyl-methylene ammonium iodide added followed by stirring for 2 hours. The mixture is diluted with 10 ml of ether and filtered. The filtrate is evaporated in vacuo to a residue which is stirred with hexanes to give 0.13 g of the desired product as a white solid, m.p. 131°-133° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH3:12])[C:5](O)=[O:6].C(C1NC=CN=1)([C:15]1[NH:16][CH:17]=CN=1)=O.C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH3:12])[C:5]([N:16]([CH3:17])[CH3:15])=[O:6]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CNc1ccc(C(=O)O)cc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CNc1ccc(C(=O)N(C)C)cc1Cl
Reaction time: 1 h

Procedure:
To 3-chloro-4-methylamino-benzoic acid (387 mg) in dry N. N-dimethylformamide (10 mL) was added carbonyl diimidazole (440 mg). After one hour, dimethylamine. HCl (221 mg) and triethylamine (0.38 mL) were added. The reaction mixture was stirred overnight, then diluted with ethyl acetate, washed with brine, dried (MgSO4) and the solvent removed in vacuo. Purification using flash chromatography yielded 3-chloro-N,N-dimethyl-4-methylamino-benzamide.
Reaction SMILES: [ClH:1].[CH2:2]([C:5]1[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=1)[C:3]#[CH:4].[CH2:11]([N:18]=[N+:19]=[N-:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[ClH:1].[CH2:11]([N:18]1[CH:4]=[C:3]([CH2:2][C:5]2[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=2)[N:20]=[N:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C#CCc1c[nH]c(N)n1
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: Cl
Product: Nc1nc(Cc2cn(Cc3ccccc3)nn2)c[nH]1
Yield: 86.1 %

Procedure:
4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.095 g, 0.603 mmol) was reacted with benzyl azide (0.096 g, 0.723 mmol) following the general procedure for click reactions outlined above to produce 4-(1-Benzyl-1H-[1,2,3]triazol-4-ylmethyl)-1H-imidazol 2-ylamine hydrochloride (0.151 g, 86%) of a pale yellow solid. 1H NMR (300 MHz, D2O) δ 7.79 (s, 1H), δ 7.42-7.35 (m, 5H), δ 6.43 (s, 1H), δ 5.58 (s, 2H), δ 3.86 (s, 2H) ppm; 13C δ 145.4, 136.6, 136.4, 128.8, 128.7, 126.9, 126.8, 126.3, 124.1, 121.8, 109.6, 53.3, 24.1 ppm; HRMS (ESI) calcd for C13H6N6O (M+) 254.1352. found 254.1352.