Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C1C=CC(OC2CCN(S(C3(C(OC)=O)CCN([C:23]4[N:28]=[C:27](C(F)(F)F)[CH:26]=[CH:25][N:24]=4)CC3)(=O)=O)CC2)=CC=1.[N:41]1([S:47]([NH2:50])(=[O:49])=[O:48])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.C([O-])=O.[NH4+].C(=O)([O-])[O-].[K+].[K+].ClC1N=C(C(F)(F)F)C=CN=1>CO.CN(C)C=O>[N:24]1[CH:25]=[CH:26][CH:27]=[N:28][C:23]=1[NH:50][S:47]([N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)(=[O:49])=[O:48]
Reactant: COC(=O)C1(S(=O)(=O)N2CCC(Oc3ccc(C(F)(F)F)cc3)CC2)CCN(c2nccc(C(F)(F)F)n2)CC1
Reactant: NS(=O)(=O)N1CCCCC1
Agent: FC(F)(F)c1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: O=C[O-]
Solvent: CN(C)C=O
Solvent: CO
Product: O=S(=O)(Nc1ncccn1)N1CCCCC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
Part G: Preparation of methyl 4-[[4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]-sulfonyl]-1-[4-(trifluoromethyl)-2-pyrimidinyl]-4-piperidinecarboxylate. To a slurry of the piperidine sulfonamide from part F (6.3 g, 12.0 mmol) in methanol (25 mL) was added ammonium formate (2.2 g, 34.5 mmol). The system was purged with nitrogen for 10 min. The nitrogen stream was removed and palladium on carbon (1.2 g of 10 weight % on activated carbon, 50% water) was added. The reaction was refluxed for forty five min, cooled, filtered through Celite under N2, and concentrated in vacuo. The residue (4.5 g, 10 mmol) was dissolved in dry dimethylformamide (20 mL) and potassium carbonate (4.14 g, 30 mmol) and 2-chloro-4-trifluoromethylpyrimidine (2.4 mL, 20 mmol) were added. The reaction was stirred at 70° C. for 3 hr, and then concentrated in vacuo, The residue was taken up in ethyl acetate and filtered through Celite. The filtrate washed with water two times, saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated in vacuo. The product was recrystallized (methanol) to give the N-pyrimidinyl piperidine sulfonamide as a white solid (4.51 g, 76%).
Reaction SMILES: [O:1]1[CH2:9][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[Br-:10].[K+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.O1CCCC1.CCOCC>[Br:10][CH2:9][CH:2]([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8]
Reactant: [Br-]
Reactant: OCCCCCC1CO1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCCCCC(O)CBr

Procedure:
A mixture of 5 (120 mg, 0.9 mmol) in acetic acid-tetrahydrofuran (2 mL-0.4 mL) was treated with 0.3 mL of saturated aqueous potassium bromide solution at room temperature over 67 hours. It was then diluted with ether and poured into saturated aqueous sodium bicarbonate. The separated organic layer was washed with saturated sodium thiosulfite, saturated sodium chloride, and dried over magnesium sulfate. Evaporation of the solvent gave 127 mg of 7-bromo-6-hydroxy-1-heptanol (4).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]1.[CH3:27][O:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:31][C:30]=1[OH:44]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][N:24]([CH3:25])[CH3:26])[CH2:19][CH2:18]2)=[CH:3][C:2]([C:33]2[CH:32]=[CH:31][C:30]([OH:44])=[C:29]([O:28][CH3:27])[CH:34]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CN(C)CC1CCN(c2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N4CCC(CN(C)C)CC4)c3c2)ccc1O
Yield: 45.3 %

Procedure:
Following general procedure D, (6-bromo-4-{4-[(dimethylamino)methyl]piperidin-1-yl}quinolin-3-yl)(cyclopropyl)methanone (47 mg, 0.113 mmol) was reacted with 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (55 mg, 0.220 mmol) to afford the desired product (23.5 mg, 45%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.81 (s, 1H), 8.29 (d, J=1.6 Hz, 1H), 8.10-8.00 (m, 2H), 7.30 (d, J=2.0 Hz, 1H), 7.22 (dd, J=8.2, 2.1 Hz, 1H), 6.94 (d, J=8.2 Hz, 1H), 3.97 (s, 3H), 3.56 (d, J=12.6 Hz, 2H), 3.27-3.15 (m, 4H), 2.95 (s, 6H), 2.65-2.55 (m, 1H), 2.15-2.25 (m, 1H), 1.95 (d, J=12.6 Hz, 2H), 1.78-1.67 (m, 2H), 1.38-1.28 (m, 2H), 1.28-1.19 (m, 2H); ESI MS m/z 460 [C28H33N3O3+H]+; HPLC 95.9% (AUC), tR=9.74 min.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][CH:32]([O:35][CH2:36][CH:37]=[CH2:38])[CH2:31][CH2:30]1.I([O-])(=O)(=O)=[O:40].[Na+].C[Mg]Br.[Cl-].[NH4+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C.O.O1CCCC1.C(#N)C.[Os]=O.CC(C)=O>[O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:30][CH2:31][CH:32]([O:35][CH2:36][C:37](=[O:40])[CH3:38])[CH2:33][CH2:34]1
Reactant: C=CCOC1CCC(n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3ncnc23)CC1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os]
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: C[Mg]Br
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OCC(C)=O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 9.2 %

Procedure:
A mixture of 4′-({5-oxo-4-[4-(prop-2-en-1-yloxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (1.8 g), osmium oxide (7% immobilized catalyst, 0.92 g), sodium periodate (3.9 g), acetone (20 mL), acetonitrile (20 mL) and water (20 mL) was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate and water, and the insoluble material was filtered off through celite. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel chromatography was dissolved in tetrahydrofuran (20 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 1.9 mL) was added at −78° C. The reaction mixture was warmed to 0° C., and stirred for 16 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel chromatography was dissolved in acetonitrile (15 mL), 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.3 g) was added, and the mixture was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogen carbonate solution and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.17 g, 68%).
Reaction SMILES: [CH2:1](I)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:11]([NH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(C)=O>[CH2:11]([N:19]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)[CH2:1][CH2:2][CH3:3])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1cccc(CCNCCc2ccccc2)c1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCN(CCc1ccccc1)CCc1cccc(OC)c1
Reaction time: 5 h

Procedure:
1.1 ml of propyl iodide and 1.1 g of potassium carbonate were added to a solution of 1.1 g of the product of Step A in 15 ml of acetone and the mixture was refluxed with stirring for 5 hours. The acetone was distilled under reduced pressure and 50 ml of water were added thereto. The mixture was extracted 3 times with 20 ml of methylene chloride and the combined organic phases were washed with 70 ml of aqueous sodium chloride solution. The organic phases were dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure to obtain 1.25 g of N-phenethyl-N-propyl-3-methoxyphenethylamine in the form of an orange oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[C:21]([N+:28]([O-:30])=[O:29])=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH2:25]>>[CH3:18][O:19][C:20]1[C:21]([N+:28]([O-:30])=[O:29])=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH:25][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: COc1cc(N)c(C)cc1[N+](=O)[O-]
Product: COc1cc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c(C)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine (48 mg, 0.185 mmol) and 5-methoxy-2-methyl-4-nitroaniline (35 mg, 0.192 mmol) similar to Example 166 and was isolated as a white solid (mp 128-132° C., 11 mg, 0.027 mmol, 15%). 1H NMR (CDCl3): 9.62 (s, 1H), 8.68 (m, 2H), 7.79 (s, 1H), 7.73 (s, 1H), 7.48 (m, 1H), 7.01 (s, 1H), 4.02 (s, 3H), 2.63 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:6][CH2:5]1)=O.[CH2:7]([NH:9][CH2:10][CH3:11])[CH3:8]>CCCCCC.[Ti](Cl)(Cl)(Cl)Cl>[CH:4]1([C:2]([N:9]([CH2:10][CH3:11])[CH2:7][CH3:8])=[CH2:1])[CH2:6][CH2:5]1
Reactant: CC(=O)C1CC1
Reactant: CCNCC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCCCCC
Product: C=C(C1CC1)N(CC)CC
Reaction time: 5 h
Yield: 38.1 %

Procedure:
A solution of titanium tetrachloride (10.4 g) in n-hexane (30 ml) was added dropwise with stirring to a solution of cyclopropyl methyl ketone (8.4 g) and diethylamine (43.9 g) in n-hexane (100 ml) whilst maintaining the temperature below 25° C. The mixture was stirred for 5 hours, filtered and the filtrate was evaporated to dryness to give 1-cyclopropyl-1-diethylaminoethene (5.3 g) as a pale yellow oil, NMR (CDCl3)d=0.5-0.8(m, 4H), 1.1(t, 6H), 1.4(m, 1H), 3:2(q, 4H), 3.45(s, 1H), 3.5(s, 1 H).
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[OH:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[O:25][CH:24]([C:26]([OH:28])=[O:27])[CH2:23][C:22]=3[CH:29]=2)=[CH:14][CH:13]=1)[CH3:11].CC(C)=O>CS(C)=O>[OH:9][CH:10]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[O:25][CH:24]([C:26]([O:28][CH3:3])=[O:27])[CH2:23][C:22]=3[CH:29]=2)=[CH:16][CH:17]=1)[CH3:11]
Reactant: CC(O)c1ccc(-c2ccc3c(c2)CC(C(=O)O)O3)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Solvent: CS(C)=O
Product: COC(=O)C1Cc2cc(-c3ccc(C(C)O)cc3)ccc2O1

Procedure:
23.3 g of methyl iodide and 7.6 g of potassium carbonate were added to a mixture of 7.8 g of 6C, 200 ml of acetone and 50 ml of dimethylsulfoxide. The resulting suspension was heated under reflux for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was stirred with 400 ml of water, the water was decanted, and the residue was dissolved in tetrahydrofuran. The solution was filtered and the filtrate was concentrated. The residue was mixed with 50 g of silica gel and purified by dry column chromatography, a 9/1 v/v chloroform/tetrahydrofuran mixture being used as eluent. The band containing product was extracted with tetrahydrofuran, the solvent was evaporated from the extract under reduced pressure and the residue was dried in a vacuum oven. The residue was stirred with ether and the solid was collected and dried to give methyl 2,3-dihydro-5-(4-(1-hydroxyethyl)phenyl)-2-benzofurancarboxylate (6D), mp: 98°-100° C.
Reaction SMILES: ClCCl.Cl[C:5]1[N:10]=[C:9]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]2[CH2:26][O:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[O:12])[CH:8]=[CH:7][CH:6]=1.[C:34]1(B(O)O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O1CCOCC1.O>[C:34]1([C:5]2[N:10]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]3[CH2:26][O:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[O:12])[CH:8]=[CH:7][CH:6]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(Cl)n2)C(COc2cccnc2)C1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(-c3ccccc3)n2)C(COc2cccnc2)C1
Temperature: 80 °C

Procedure:
[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (1:1) (10 mg, 0.012 mmol) was added to a mixture of tert-butyl 4-(6-chloropicolinoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (100 mg, 0.231 mmol), benzeneboronic acid (56 mg, 0.46 mmol) and sodium carbonate (49 mg, 0.46 mmol) in toluene (4 mL), 1,4-dioxane (1 mL), and water (1 mL). The reaction mixture was heated to 80° C. overnight. Upon cooling to room temperature, the reaction mixture was filtered through Celite®, concentrated under reduced pressure, and purified by HPLC (10 to 90% MeCN/0.1% TFA in H2O/0.1% TFA gradient). This gave 143 mg of the title compound. LC-MS: RT=8.58 min, [M+H]+=475.9.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][C:21]([CH3:24])=[N:22][N:23]=3)=[CH:15][CH:14]=2)[CH:3]=1.[C:25]([C:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)([CH3:30])[CH3:29])([OH:27])=[O:26].C([O-])([O-])=O.[Cs+].[Cs+].O>COCCOC.C(#N)C>[CH3:9][O:8][C:6]1[N:7]=[C:2]([C:33]2[CH:32]=[C:31]([C:28]([CH3:30])([CH3:29])[C:25]([OH:27])=[O:26])[CH:36]=[CH:35][CH:34]=2)[CH:3]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][C:21]([CH3:24])=[N:22][N:23]=3)=[CH:15][CH:14]=2)[N:5]=1
Reactant: COc1nc(Cl)cc(NCCc2ccc(-c3nnc(C)o3)cc2)n1
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Solvent: COCCOC
Product: COc1nc(NCCc2ccc(-c3nnc(C)o3)cc2)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Reaction time: 3 h
Yield: 25.3 %

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-{2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-ethyl}-amine (0.16 g, 0.46 mmol), 3-(1-carboxy-1-methyl-ethyl)-phenyl boronic acid, [125 mg, 0.6 mmol, see Example 49(b), step 2], and Cs2CO3 (0.37 g, 1.15 mmol) in ethylene glycol dimethyl ether (8 mL), acetonitrile (10 mL), and water (2 mL) is degassed by bubbling with Argon gas for 5 minutes, and treated with 1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride (20 mg) at room temperature. After 3 h at 85° C., the mixture is diluted with water (15 mL), and extracted with EtOAc (2×15 mL). The extracts are dried (MgSO4), filtered, and concentrated. The residue is chromatographed on SiO2 eluting with 80% EtOAc in heptane to afford 2-[3-(2-methoxy-6-{2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-ethylamino}-pyrimidin-4-yl)-phenyl]-2-methyl-propionic acid [55 mg, Example 68]. LCMS: RT=1.82 minutes; MS: 474 (M+H); 1H NMR (300 MHz, CDCl3) □ 7.98-7.81 (4H, m), 7.5-7.27 (4H, m), 6.33 (1H, s), 3.97 (3H, s), 3.72-3.6 (2H, m), 2.92 (2H, t, J=6.5 Hz), 2.6 (3H, s), 1.6 (6H, s).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[Na+].[I-:13].OS(O)(=O)=O.II>[OH-].[Na+]>[I:13][C:10]1[C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=[C:3]([CH:11]=1)[CH:2]=[O:1]
Reactant: [I-]
Reactant: COc1cc(C=O)ccc1O
Agent: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COc1cc(C=O)cc(I)c1O
Temperature: 90 °C
Yield: 95.3 %

Procedure:
Vanillin (28.4 g, 200 mmole (millimole)) was dissolved in 1N NaOH (200 ml) and warmed to 90° C. to avoid precipitation of sodium vanillate. A 2 molar aqueous solution of NaI3.NaI (105 ml, 210 mmole I2) plus 3.55 molar aqueous H2SO4 (5 ml) was added over 3 hours with stirring. The iodine color was discharged, and a pale tan stirrable precipitate formed. The solution was then cooled to room temperature, acidified to pH 2-3 with 20% aqueous H2SO4, and extracted with 10% methanol/90% chloroform. The organic phase was dried (MgSO4) and the solvent stripped to yield 53 g (99%) of 5-iodovanillin, more than 95% pure as analyzed by nuclear magnetic resonance spectroscopy (NMR).
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: FC(F)(F)c1ccc(Cl)c(Cl)c1CBr
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
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+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([F:24])[F:23])=[C:14]([CH2:25][OH:26])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:29](Br)[CH3:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([F:24])[F:23])=[C:14]([CH2:25][O:26][CH2:29][CH3:30])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(CO)c(C(F)F)nc3N21
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Product: CCOCc1cc2c(nc1C(F)F)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
This compound was prepared in analogy to example 1, intermediate d) from (4R,9aR)-6-difluoromethyl-7-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (example 26, intermediate b), sodium hydride and ethyl bromide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[NH:19][N:20]=[CH:21][CH:22]=1.Cl>COCCO.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:17]=[C:18]3[NH:19][N:20]=[CH:21][C:22]=23)=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccncc1)c1ccc(F)cc1
Reactant: Nc1ccn[nH]1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: COCCO
Product: Fc1ccc(-c2nc3[nH]ncc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Yield: 47.2 %

Procedure:
In a volumetric flask, 1-(4-fluorophenyl)-2-(4-pyridyl)ethanone (23.56 g, 109.4 mmol, obtained in reference example 1) and 2-methoxyethanol (150 mL) were introduced. A solution of 3-amino-2H-pyrazole (10.00 g, 120.3 mmol) in 2-methoxyethanol (170 mL) and 37% HCl (3.23 g, 32.8 mmol) were added under argon atmosphere. This was heated to reflux for 3 days. It was allowed to cool and concentrated. The solid obtained was dissolved in CHCl3 (400 mL) and MeOH (50 mL) and washed with 0.1 N HCl (300 mL) and 1 N NaOH (300 mL). The organic phase was dried over Na2SO4 and concentrated to dryness, to afford 9.93 g of the desired product in solid cream form (yield: 47%)
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][OH:10].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.[OH-].[Na+]>CO.O>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][O:8][C:5]2[C:6](=[O:7])[CH:1]=[C:2]([CH2:9][OH:10])[O:3][CH:4]=2)=[CH:14][CH:13]=1
Reactant: O=c1cc(CO)occ1O
Reactant: Clc1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=c1cc(CO)occ1OCc1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
Kojic acid (637, 5.00 g, 35.2 mmol) and 4-chlorobenzyl bromide (557, 7.95 g, 38.7 mmol) were suspended in methanol (40 mL) in an 80 mL scaled tube. Sodium hydroxide in water (12 M, 2.93 mL) was added. The reaction was heated at 80° C. overnight. The resulting suspension was concentrated. Water was added and the mixture was filtered and washed with water to provide a brown solid. Washing with minimal methanol on the filter removed the brown color. A white solid (638, 7.58 g, 80%) was isolated. 1H-NMR was consistent with the desired compound.
Reaction SMILES: [H-].[Na+].[N:3]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>CN(C)C=O>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:6]1[CH2:7][CH2:8][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:5]1
Reactant: BrCc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccn2)CC1
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 0.28 g (0.71 mmol) of sodium hydride (60% mineral oil dispersion) in 5 mL anhydrous N,N-dimethylformamide at 0° C. was added 0.12 g (0.65 mmol) tert-butyl 1-piperazine-carboxylate. The resulting mixture was stirred under an atmosphere of nitrogen for 15 min and then allowed to warm to ambient temperature at which point 0.14 g (0.59 mmol) of 2-(bromomethyl)pyridine was added. After 4 h, quench the reaction with 25 mL cold water and extract the resulting solution with 25 mL ethyl acetate. The organic layer was washed with water (2×25 mL), dried over magnesium sulfate, filtered and evaporated in vacuo to afford the title compound which was purified by reverse-phase HPLC (TMC Pro-Pac C18; 10-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). LC/MS: m/z (ES) 278.1 (MH)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][S:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:6]=1[NH2:25].Cl.[N:27]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[NH:25][N:27]=[C:11]2[S:12]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: Nc1c(CS(=O)(=O)c2cccc3ccccc23)cccc1OCCCl
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2c(OCCCl)cccc12
Temperature: 3 °C

Procedure:
A mixture of 2-(2-chloro-ethoxy)-6-(naphthalene-1-sulfonylmethyl)-phenyl amine (0.97 g, 3 mmoles) in THF (7 mL), and 4M HCl (15 mL) was stirred in a round bottom flask, under nitrogen, at 3° C. A solution of sodium nitrite (0.21 g, 3.15 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.9 g, 2.7 mmoles).