Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[CH3:6][CH:7]([O:10][C:11]1[N:12]=[N:13][C:14](Cl)=[CH:15][CH:16]=1)[CH2:8][CH3:9]>CO>[CH3:6][CH:7]([O:10][C:11]1[N:12]=[N:13][C:14]([S:5][CH2:2][CH:3]=[CH2:4])=[CH:15][CH:16]=1)[CH2:8][CH3:9]
Reactant: C=CCS
Reactant: CCC(C)Oc1ccc(Cl)nn1
Agent: [Na]
Solvent: CO
Product: C=CCSc1ccc(OC(C)CC)nn1

Procedure:
0.92 g(0.04 mol) of metallic sodium was dissolved in 120 ml of absolute methanol and then mixed with 3.98 ml(0.04 mol) of allylmercaptan. To this mixture was added 7.47 g(0.04 mol) of 3-(2-butoxy)-6-chloropyridazine. The reaction solution was refluxed for 24 hours and then treated according to the same manner as Example 1 to obtain the title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([Li])CCC.[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1([C:17]([C:19]2[CH:20]=[CH:21][C:22]([S:25][CH3:26])=[N:23][CH:24]=2)=O)[CH2:16][O:15]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1([C:17]([C:19]2[CH:20]=[CH:21][C:22]([S:25][CH3:26])=[N:23][CH:24]=2)=[CH2:1])[CH2:16][O:15]1
Reactant: [Li]CCCC
Reactant: CSc1ccc(C(=O)C2(c3ccc(F)cc3F)CO2)cn1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(c1ccc(SC)nc1)C1(c2ccc(F)cc2F)CO1
Temperature: 0 °C
Reaction time: 18 h
Yield: 90.7 %

Procedure:
A suspension of methyltriphenylphosphonium bromide (5.0 g, 14 mmol) in THF (70 ml) was treated with n-butyllithium (2.5M solution in hexane, 5.6 ml, 14 mmol) under an atmosphere of nitrogen at -70° C. After 15 minutes at -70° C. the mixture was warmed to 0° C. and then was treated dropwise with a solution of the product of part (v) (3.9 g, 13 mmol) in THF (40 ml). The mixture was stirred at room temperature for 18 hours and then evaporated under reduced pressure. The residue was partitioned between dichloromethane (50 ml) and water (30 ml). The organic phase was dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica by elution with ether/hexane (1:4) to provide the title compound as an orange oil, (3.6 g).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][C:5]1=[O:11])[C:2]#[CH:3].[CH3:12][S:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[C:18]([N+:25]([O-:27])=[O:26])[CH:17]=1)(=[O:15])=[O:14].C(N(CC)CC)C.[C-]#N.[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[N+:25]([C:18]1[CH:17]=[C:16]([S:13]([CH3:12])(=[O:15])=[O:14])[CH:24]=[CH:23][C:19]=1[C:20]([CH:6]1[C:5](=[O:11])[CH:4]([CH2:1][C:2]#[CH:3])[CH2:9][CH2:8][C:7]1=[O:10])=[O:21])([O-:27])=[O:26]
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c([N+](=O)[O-])c1
Reactant: C#CCC1CCC(=O)CC1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [C-]#N
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C#CCC1CCC(=O)C(C(=O)c2ccc(S(C)(=O)=O)cc2[N+](=O)[O-])C1=O
Reaction time: 3 h
Yield: 44.9 %

Procedure:
4Propargyl-1,3-cyclohexanedione (3.75 g, 25 mmol) and 4-methanesulfonyl-2-nitrobenzoyl chloride (6.06 g, 23 mmol) were dissolved in acetonitrile (100 mL) at 0° C. Triethylamine (9.6 mL, 69 mmol) was added. The mixture was then stirred for 3 hours. To the mixture was then added potassium cyanide (5.0 g) and 18-crown-6 ether (0.5 g) in one portion. The mixture was stirred for 3 days. After dilution with ether, the solution was washed with 1N HC1 and extracted with 5% K2CO3. The basic extract was acidified with concentrated HC1 and extracted with diethyl ether. The ether extract was washed with brine, dried over MgSO4, and concentrated under vacuum, yielding 3.9 g of the desired product, an orange solid, m.p. 65-70° C. The structure was confirmed by nuclear magnetic spectroscopy, infrared spectroscopy, and mass spectroscopy.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:12][NH2:13].[C:14](OCC)(=[O:20])[C:15](OCC)=[O:16]>>[C:14]1(=[O:20])[N:1]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH2:5][CH2:4][CH2:3][CH:2]2[CH2:12][NH:13][C:15]1=[O:16]
Reactant: CCOC(=O)C(=O)OCC
Reactant: NCC1CCCc2ccccc2N1
Product: O=C1NCC2CCCc3ccccc3N2C1=O
Reaction time: 2 h

Procedure:
A solution of Example 182E (0.282 g, 1.600 mmol) in diethyl oxalate (1.518 mL, 11.20 mmol) was heated at 140° C. for 1 hour and then at 180° C. for 2 hours. The crude mixture was purified by silica gel chromatography (Analogix IntelliFlash™ 280, SF24-40) eluting with dichloromethane, then with 2% methanol/dichloromethane, and then with 10% methanol/dichloromethane to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.66 (s, 1H), 7.37-7.17 (m, 4H), 3.91 (dd, J=12.8, 4.2, 1H), 3.49 (d, J=11.4, 1H), 3.19-3.13 (m, 1H), 2.71 (dd, J=18.6, 12.5, 1H), 2.56 (m, 1H), 2.02 (m, 2H), 1.86 (m, 1H), 1.42 (m, 1H); MS (ESI+) m/z 248.2 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]([C:6]1[N:10]([CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[CH:18]=[CH:19][C:20]([S:22](Cl)(=[O:24])=[O:23])=[CH:21][C:8]=2[N:7]=1)([CH3:5])[CH2:3][CH3:4].[NH:26]1[CH:30]=[CH:29][CH:28]=[N:27]1>CN(C1C=CN=CC=1)C.CC#N>[CH3:1][C:2]([C:6]1[N:10]([CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[CH:18]=[CH:19][C:20]([S:22]([N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)(=[O:24])=[O:23])=[CH:21][C:8]=2[N:7]=1)([CH3:5])[CH2:3][CH3:4]
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: c1cn[nH]c1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CCC(C)(C)c1nc2cc(S(=O)(=O)n3cccn3)ccc2n1CC1CCOCC1
Yield: 98 %

Procedure:
Following the same procedure in Example 1, Step A, using 2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride e (287 mg, 0.746 mmol) (see following Steps B, C, D and E for preparation), pyrazol (152 mg, 2.24 mmol) and DMAP (182 mg, 1.49 mmol) in MeCN (15 mL). The crude product was purified by MPLC using Hex/EtOAc (3:7) on silica gel to give 305 mg (98%) of a white solid as the title compound. 1H NMR (400 MHz, CHLOROFORM-D) δ 0.73 (t, J=7.52 Hz, 3 H), 1.37-1.52 (m, 4 H), 1.54 (s, 6 H), 1.90 (q, J=7.49 Hz, 2 H), 2.20-2.34 (m, 1 H), 3.24-3.34 (m, 2 H), 3.87-3.90 (m, 2 H), 4.34 (d, J=7.62 Hz, 2 H), 6.47 (dd, J=2.73, 1.56 Hz, 1 H), 7.73 (dd, J=1.56, 0.59 Hz, 1 H), 7.76 (dd, J=8.79, 0.39 Hz, 1 H), 7.86 (dd, J=8.8, 1.8 Hz, 1 H), 8.22-8.27 (m, 1 H), 8.31 (dd, J=2.73, 0.59 Hz, 1 H); MS (ESI) (M+H)+=417.3; Anal. Calcd for C21H28N4O3S+0.1H2O (418.35): C, 60.29; H, 6.79; N, 13.39. Found: C, 60.32; H, 6.58; N, 13.77.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=O)[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30].O1CCCC1.B.[Cl-].[Na+]>CN(C)C=O>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][CH2:10][NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:28])[CH3:29])[C@H:22]1[CH3:30]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccncc3)c(=O)c1Br)C2(C)C
Agent: B
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CCNCc3ccncc3)c(=O)c1Br)C2(C)C
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 95.2 %

Procedure:
2-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N-(pyridin-4-ylmethyl)acetamide (35 mg, 0.073 mmol) in N,N-dimethylformamide (1 mL) was mixed with a borane tetrahydrofuran complex (1.13 M in tetrahydrofuran, 78 μL, 0.088 mmol) under cooling with ice and stirred at room temperature for 5.5 hours. After completion of the reaction, the reaction solution was mixed with saturated aqueous sodium chloride and extracted with ethyl acetate. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (32 mg, 92% yield).
Reaction SMILES: Cl.Br[C:3]1[CH:19]=[CH:18][C:6]([CH2:7][CH2:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[CH2:11][NH:12][CH3:13])=[CH:5][CH:4]=1.C(N(CC)CC)C.[H][H].Cl>[Pd].C(O)C>[CH3:13][NH:12][CH2:11][C:10]1[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=1[CH2:8][CH2:7][C:6]1[CH:18]=[CH:19][CH:3]=[CH:4][CH:5]=1
Reactant: [H][H]
Reactant: CNCc1ccccc1CCc1ccc(Br)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CNCc1ccccc1CCc1ccccc1

Procedure:
A solution of 2.0 g. (0.00657 mole) of 2-(4-bromo-phenethyl)-N-methylbenzylamine hydrochloride in 200 ml. of absolute ethanol -- 1 ml. of triethylamine is shaken with hydrogen at atmospheric pressure and 25° C. over 400 mg. of 10% palladium on carbon until hydrogen uptake ceases. The catalyst is removed by filtration, the filtrate evaporated to dryness under reduced pressure, and the residue partitioned between aqueous sodium hydroxide and 1:1 ether-benzene. Evaporation of solvents from the washed and dried organic extract leaves the product as the residual oil. The oily base is converted to the hydrochloride salt by treating a solution in absolute ethanol with a slight excess of ethanolic hydrogen chloride. Dilution with absolute ether precipitates the hydrochloride as white crystals, m.p. 204°-206° C. After repeated recrystallizations from absolute ethanol-absolute ether, an analytical sample melts at 205°-206° C.
Reaction SMILES: C([O:3][C:4]([CH:6]([O:8][C:9]1[CH:25]=[CH:24][C:12]2[C:13](=[O:23])[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][O:16][C:11]=2[CH:10]=1)[CH3:7])=[O:5])C.O1CCOCC1.Cl>O>[OH:5][C:4]([CH:6]([O:8][C:9]1[CH:25]=[CH:24][C:12]2[C:13](=[O:23])[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][O:16][C:11]=2[CH:10]=1)[CH3:7])=[O:3]
Reactant: CCOC(=O)C(C)Oc1ccc2c(=O)c(-c3ccccc3)coc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(Oc1ccc2c(=O)c(-c3ccccc3)coc2c1)C(=O)O
Temperature: 0 °C
Yield: 93.2 %

Procedure:
A mixture of 20 g of 7-(1-ethoxycarbonylethyl)oxy-3-phenyl-4H-1-benzopyran-4-one, 200 ml of dioxane, 70 ml of hydrochloric acid and 150 ml of water was refluxed for 4 hours and poured into ice water. The resulting crystalline precipitate was collected by filtration and recrystallized from ethanol to give 17.1 g of 7-(1-hydroxycarbonylethyl)oxy-3-phenyl-4H-1-benzopyran-4-one as white crystals. m.p. 223° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:14]=[CH:15][CH:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]([C:26]1[CH:27]=[C:28](OB(O)O)[CH:29]=[CH:30][CH:31]=1)=[O:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:14]=[CH:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:30]4[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=4)[C:24]([O:23][CH3:22])=[O:25])[CH2:17]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C=CC1CCCNC1
Product: COC(=O)c1cccc(N2CCCC(C=Cc3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Yield: 35.7 %

Procedure:
Using 3-[2-[2-(4-chlorophenyl)-4-methylthiazol-5-yl]ethenyl]piperidine (153 mg, 0.480 mmol) and 3-(methoxycarbonyl)phenylboric acid (173 mg, 0.960 mmol), the same procedure was followed as in Example 2 to give 77.7 mg (36%) of the desired compound as a yellow powder.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16](=[O:23])[CH2:17][O:18][CH2:19][C:20]([OH:22])=[O:21])=[N+]=[N-].C(#N)C>O>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16](=[O:23])[CH2:17][O:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: [N-]=[N+]=NCCOCCOCCOCCNC(=O)COCC(=O)O
Solvent: O
Solvent: CC#N
Product: NCCOCCOCCOCCNC(=O)COCC(=O)O
Reaction time: 0.33 h

Procedure:
A solution of 17-azido-5-oxo-6-aza-3,9,12,15-tetraoxaheptadecanoic acid (8.36 g, 25.0 mmol) in water (100 ml) was reduced using H2 (g)-Pd/C (10%). The reaction was run until LC-MS analysis showed complete conversion of starting material (column Vydac 218TP54; solvents: A=water/0.1% TFA and B=acetonitrile/0.1% TFA; gradient 4-16% B over 20 min; flow 1.0 ml/min; UV detection at 214 and 284 nm, ES ionisation giving M+H at 335 for starting material and 309 for the product). The solution was filtered and used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[OH:22])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH3:23]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[OH:22])=[NH:23])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: N
Reactant: COc1ccc(CCC(=O)c2cc(F)ccc2O)cc1OC
Solvent: CO
Product: COc1ccc(CCC(=N)c2cc(F)ccc2O)cc1OC
Temperature: 60 °C
Yield: 32 %

Procedure:
A mixture of 1.72 g (5.6 mmol) 3-(3,4-dimethoxy-phenyl)-1-(5-fluoro-2-hydroxy-phenyl)-propan-1-one and 24 mL NH3 (7N) in methanol was heated to 60° C. for 16 h in a sealed tube. The mixture was concentrated and purified on silica eluting with a gradient formed from heptane and ethyl acetate. The product containing fractions were evaporated to yield 0.693 g (32%) of the title compound. MS (m/e): 304.1 (MH+).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1)[CH2:2][CH3:3].[Br:14]Br>C(OCC)C>[Br:14][CH2:12][C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[CH:10][CH:9]=1)=[O:13]
Reactant: CCCOc1ccc(C(C)=O)cc1
Reactant: BrBr
Solvent: CCOCC
Product: CCCOc1ccc(C(=O)CBr)cc1

Procedure:
To 133 g (750 mmole) of 4'-propoxyacetophenone dissolved in 500 ml of diethyl ether and heated to reflux was dropwise added 120 g (750 mmole) of bromine at a rate to maintain reflux and yet allow decolorization of the red color. The resulting organic solution was twice washed with 500 ml of water, washed once with 200 ml of brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. This mixture, upon analysis via gas chromatography was approximately 10% unbrominated starting material, 80% the desired monobrominated product, and 10% dibrominated compound. It was used as is in the next reaction. It could be crystallized from diethyl ether and hexane to yield pure monobrominated compound, a solid, mp 36°-38° C.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[N+:13]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:3]=1[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: NCCCCCCNC(=O)c1ccccc1
Agent: Cl
Product: O=C(NCCCCCCNc1c([N+](=O)[O-])cnc2ccccc12)c1ccccc1

Procedure:
Using the general method of Example 9 Part B, 4-chloro-3-nitroquinoline hydrochloride (10 g, 41 mmol) was reacted with N-(6-aminohexyl)benzamide to provide 12.85 g of N1-{6-[(3-nitroquinolin-4-yl)amino]hexyl}benzamide as a yellow crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1I.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[C:13]([C:20](OC)=[O:21])[CH:12]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:3]=1[C:14]1[CH:15]=[CH:16][C:11]([F:10])=[CH:12][C:13]=1[C:20](=[O:21])[NH:8]2
Reactant: COC(=O)c1cc(F)ccc1B(O)O
Reactant: Nc1nccc(Cl)c1I
Product: O=c1[nH]c2nccc(Cl)c2c2ccc(F)cc12
Yield: 21.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 1 using 4-chloro-3-iodopyridin-2-amine (1.20 g, 4.72 mmol) and 4-fluoro-2-methoxycarbonylphenylboronic acid (1.03 g, 5.19 mmol) to provide 411 (250 mg, 21% yield) as a solid. LC-MS (M+H=249, obsd.=249).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.[NH4+].[OH-:16]>O>[OH:16][CH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2
Reactant: [OH-]
Reactant: Oc1ccc(CCl)c2cccnc12
Agent: Cl
Agent: [NH4+]
Solvent: O
Product: OCc1ccc(O)c2ncccc12
Yield: 86.8 %

Procedure:
In a 500 ml Ehrlenmeyer flask with a magnetic stirrer, 23 grams (0.1 moles) of 5-chloromethyl-8-hydroxyquinoline hydrochloride and 200 ml of H2O were stirred, producing a bright yellow solution. NH4OH (7.0 grams; 0.2 moles) in concentrated form was added slowly. The color of the solution changed to amber. As the pH approached neutral, the color disappeared, and a precipitate formed. The precipitate was filtered, washed with water, and oven dried at 105° C. After drying, 15.2 grams (87% yield) of product was left.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C1COCC1>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:6][CH:5]=1
Reactant: C1CNCCN1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(CN2CCNCC2)cc1

Procedure:
Synthesized according to General Procedure A: 4-trifluoromethoxybenzyl bromide (4{17}, 5 g, 19.6 mmol, 1 equiv.), piperazine (10.1 g, 117.6 mmol, 6 equiv.), THF (42.8 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{17} (4.75 g, 93%) as a yellow liquid. 1H-NMR (500 MHz, CDCl3): δ 7.28 (d, 2H, J=8.0 Hz), 7.08 (d, 2H, J=8.0 Hz), 3.40 (s, 2H), 2.81 (t, 4H, J=5.0 Hz), 2.33 (br s, 4H), 1.51 (br s, 1H). 13C-NMR (125 MHz, CDCl3): δ 148.0, 136.9, 130.1, 120.5, 120.3 (q, JC-F=255.5 Hz), 62.6, 54.3, 45.9. 19F-NMR (375 MHz, CDCl3): −58.4.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:12](O)[CH2:13][OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:7]2[O:14][CH2:13][CH2:12][O:8]2)[CH:9]=1
Reactant: OCCO
Reactant: COc1ccc(I)cc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(I)cc1C1OCCO1

Procedure:
A solution of 1.0 grams (3.82 mmol) of the above aldehyde, 0.85 mL of ethylene glycol, 20 mg of p-toluenesulfonic acid and 42 mL of toluene was refluxed under nitrogen for 18 hours, cooled and concentrated in vacuo. The residue was redissolved in 50 mL of CH2Cl2, washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated to an oil. Chromatography on silica gel (10% ethyl acetate (EtOAc): 90% hexane) gave 2-(5-iodo-2-methoxyphenyl)-1,3-dioxolane as a clear oil, 0.68 grams (58%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:10]=[C:11]([CH3:24])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.I[CH3:26].[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:10]([CH3:26])[C:11]([CH3:24])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: Cc1nc(Sc2ccc(Cl)cc2)c(-c2ccc(S(C)(=O)=O)cc2)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(S(C)(=O)=O)cc2)c(Sc2ccc(Cl)cc2)n1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the product of Step 4 (0.38 g, 0.96 mmol) and iodomethane (1.0 mL, 1M solution in THF, 1.0 mmol) in THF (5 mL) at 5° C. under argon was added NaH (60% in mineral oil, 0.040 g, 1.0 mmol). After stirring at RT for 16 h, the reaction was partitioned between CH2Cl2 (10 mL) and H2O (20 mL). The organic layer was separated, washed with H2O, brine, dried with anhydrous Na2SO4 and concentrated. The residue was purified by crystallization from EtOAc/hexane to give the title compound. 1H NMR (400 MHz, CDCl3): 2.52 (3H, s), 3.03 (3H, s), 3.51 (3H, s), 6.91-6.99 (2H, m), 7.21-7.29 (2H, m), 7.88-7.94 (2H, m), 8.21-8.27 (2H, m). LC-MS: m/z 393.0 [M+H]+
Reaction SMILES: BrBr.[NH2:3][C:4]1[CH:5]=[C:6]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=2)[C:7]([F:11])=[CH:8][C:9]=1[Cl:10].[S-:23][C:24]#[N:25].[Na+].O>C(O)(=O)C>[NH2:25][C:24]1[S:23][C:5]2[C:6]([C:12]3[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=3)=[C:7]([F:11])[CH:8]=[C:9]([Cl:10])[C:4]=2[N:3]=1
Reactant: N#C[S-]
Reactant: Nc1cc(-c2ncc(C(F)(F)F)cc2Cl)c(F)cc1Cl
Agent: BrBr
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc2c(Cl)cc(F)c(-c3ncc(C(F)(F)F)cc3Cl)c2s1
Temperature: 25 °C
Reaction time: 10 h
Yield: 13 %

Procedure:
At about 20° C., a solution of 37 g (234 mmol) of bromine in 10 ml of glacial acetic acid was added over a period of 10 minutes to a solution of 38 g (117 mmol) of 2-(3-amino-4-chloro-6-fluorophenyl)-3-chloro-5-trifluoromethylpyridine and 38 g (468 mmol) of sodium thiocyanate in 500 ml of glacial acetic acid. The reaction mixture was subsequently stirred at room temperature for 10 hours and then poured into 2 l of water. The product was then extracted with 3×500 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate and (finally concentrated. The crude product was purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate =4:1→1:1). Yield: 13%; m.p.: 230-235° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:13]1([Mg]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[Cl:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][C:5]([OH:10])=[C:6]([CH:7]([OH:8])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=1
Reactant: Br[Mg]c1ccccc1
Reactant: COc1cc(O)c(C=O)cc1Cl
Solvent: C1CCOC1
Product: COc1cc(O)c(C(O)c2ccccc2)cc1Cl
Reaction time: 0.5 h

Procedure:
The above prepared 5-chloro-2-hydroxy-4-methoxy-benzaldehyde (example 36, step 1, 1.050 g, 5.63 mmol) was dissolved in 15 mL of abs. THF and treated at −15° C. with PhMgBr (15.5 mL of 1M [THF], 2.7 eq.) and the mixture kept at this temperature for 0.5 h. Careful pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=7/3) yielded 1.39 g of the title compound as light brown oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([C:12]2[N:16]([C:17]([CH3:20])([CH3:19])[CH3:18])[N:15]=[CH:14][C:13]=2[C:21](OCC)=[O:22])[CH:11]=[CH:10][CH:9]=[CH:8]1.O>O1CCCC1>[N:7]1([C:12]2[N:16]([C:17]([CH3:18])([CH3:19])[CH3:20])[N:15]=[CH:14][C:13]=2[CH2:21][OH:22])[CH:8]=[CH:9][CH:10]=[CH:11]1
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1-n1cccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)n1ncc(CO)c1-n1cccc1
Reaction time: 8 h
Yield: 94 %

Procedure:
1.30 g of lithium aluminum hydride was suspended in 50 ml of tetrahydrofuran and thereto, under a nitrogen atmosphere, a solution of 8.95 g of ethyl 5-(1H-pyrrol-1-yl)-1-t-butyl-1H-pyrazole-4-carboxylate in 20 ml of tetrahydrofuran was added dropwise over 15 minutes under ice-cooling. The mixture was stirred for 8 hours under ice-cooling. After water was added, the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 7.06 g of [5-(1H-pyrrol-1-yl)-1-t-butyl-1H-pyrazol-4-yl]methanol.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:50]([Cl:51])=[C:49]([Cl:52])[CH:48]=[CH:47][C:46]=1[C:53]([F:56])([F:55])[F:54]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:46]([C:53]([F:55])([F:56])[F:54])=[CH:47][CH:48]=[C:49]([Cl:52])[C:50]=3[Cl:51])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1CBr
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3c(C(F)(F)F)ccc(Cl)c3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-3,4-dichloro-1-(trifluoromethyl)benzene and isolated as white solid. MS (m/e): 509.3 (MH+).