Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CN=C1.Cl[C:7]1[N:8]=[C:9](NCC2C=CC(F)=CC=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:12]1[C:11]2[S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:10]=2[CH:9]=[N:8][CH:7]=1
Reactant: Fc1ccc(CNc2nc(Cl)nc3sc4c(c23)CCCC4)cc1
Agent: c1c[nH]cn1
Product: c1ccc2c(c1)sc1ncncc12

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5,6,7,8-tetrahydro-4-(4-fluorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5,6,7,8-tetrahydro-4-(4-fluorobenzylamino)-[1-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [I:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([O:10]C)[N:5]=[CH:4][CH:3]=1.[I-].[Na+].Cl[Si](C)(C)C>CC#N>[I:1][C:2]1[CH:3]=[CH:4][NH:5][C:6](=[O:10])[C:7]=1[CH:8]=[O:9]
Reactant: COc1nccc(I)c1C=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=Cc1c(I)cc[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
4-Iodo-2-methoxynicotinaldehyde (25 g, 83 mmol, prepared according to WO95/29917) and sodium iodide (37.0 g, 249 mmol) were combined in MeCN (500 mL). Chlorotrimethylsilane (31.4 mL, 249 mmol) was added dropwise over 15 min. The reaction mixture was stirred at RT for 2 h and then concentrated under vacuum. The crude product was suspended in a mixture of EtOAc, water, and saturated aqueous NaHCO3, then filtered to give a dark brown solid. This solid was triturated with MeCN to yield 4-iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde (12 g, yield 50.5%) as a yellow solid. MS (ESI) m/z: 250.0 (M+H+).
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Br:8][C:6]1[N:7]=[C:2]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([Cl:16])=[CH:25][C:24]=3[Cl:26])[CH2:20][CH2:21]2)[C:3](=[O:15])[N:4]([C@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: CC[C@@H](COC)n1cc(Br)nc(Br)c1=O
Reactant: Clc1cc(Cl)c2c(c1)CCN2
Product: CC[C@@H](COC)n1cc(Br)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 152-154° C.; 1H NMR (300 MHz, CDCl3): δ 7.18 (d, J=1.9 Hz, 1 H), 7.12 (s, 1 H), 7.10 (d, J=1.8 Hz, 1H), 4.93-4.89 (m, 1 H), 4.33 (t, J=7.9 Hz, 2 H), 3.67 (dd, J=10.6, 5.7 Hz, 1 H), 3.55 (dd, J=10.6, 3.3 Hz, 1H), 3.35 (s, 3 H), 3.12 (t, J=7.9 Hz, 2 H), 1.92-1.72 (m, 2 H), 0.93 (t, J=7.3 Hz, 3 H); HRMS (ESI) calcd for C17H19N3O2BrCl2 (M+H)+: 446.0038; found m/z 446.0050.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([C@@H:23]([CH3:27])[C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.[CH3:28][NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([C@@H:23]([CH3:27])[C:24]([N:29]([CH3:28])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: CNc1ccccc1
Reactant: C[C@@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)N(C)c1ccccc1)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 50 °C
Yield: 64.7 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (2.18 g, 0.0172 mole) was added slowly, dropwise, to a stirred and chilled (10° C.) suspension of (S)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0166 mole) in dry dimethylformamide (75 ml). The mixture was stirred at room temperature for 3 hours, heated at 50° C. for one hour and cooled to room temperature. An additional 0.0057 mole of oxalyl chloride was added and the mixture was stirred at room temperature for 30 minutes. N-Methylaniline (1.92 g, 0.0179 mole) was added and the reaction mixture was stirred at room temperature under nitrogen overnight. The mixture was poured into 400 ml of ice water and triethylamine (6 ml) was added. The precipitated solid was collected by filtration, rinsed with water, redissolved in hot isopropyl alcohol, treated with charcoal, filtered hot and allowed to cool. Addition of water caused a solid to form. The solid was collected by filtration, rinsed with water and dried under high vacuum overnight to give 4.2 g (65%) of title compound, mp 174°-177° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][S:13]([NH2:16])(=[O:15])=[O:14])=[CH:6][CH:5]=1)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH2:11][CH2:12][S:13]([NH2:16])(=[O:14])=[O:15])=[CH:8][CH:9]=1
Reactant: NS(=O)(=O)CCNc1ccc([N+](=O)[O-])cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(NCCS(N)(=O)=O)cc1
Yield: 79.7 %

Procedure:
1 g of 2-(4-nitrophenylamino)ethanesulfonamide (12) was suspended in 10 mL of ethanol. At room temperature, the suspension was poured onto a reductive solution of sodium hydrosulfite (8 g)—1N sodium hydroxide (30 mL). After decolorization, a precipitate formed. 0.7 g of crude product was isolated by suction-filtering and reslurrying in water.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)c1c[nH]c2ncc(Br)nc12
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
The mixture of 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (320 mg, 0.9 mmol), tert-butylamine (0.5 mL, 4.5 mmol) and HATU (684 mg, 1.8 mmol) in 50 mL of dry THF was stirred for 4 hours at room temperature. The reaction mixture was evaporated to dryness, then the residue was suspended in 50 mL of 0.5 N HCl, product extracted with ethyl acetate (50 mL×3), dried with sodium sulfate, filtered and concentrated to give 2-bromo-N-tert-butyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (258 mg, crude), material used in the next step without further purification. LCMS: (M+H)+=297/299; (M+Na)+=319/321.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:24].[OH-].[Na+].OO>C1COCC1.C(Cl)(Cl)Cl>[NH:19]1[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[N:16]=[C:15]1[CH:14]([CH:11]1[CH2:10][CH2:9][CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12]1)[OH:24]
Reactant: O
Reactant: C(=C1CCC(Cc2ccccc2)CC1)c1nc2ccccc2[nH]1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: OC(c1nc2ccccc2[nH]1)C1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Example 3 was prepared by the following procedure. To a stirred solution of 20 mg of 2-(4-benzyl-cyclohexylidenemethyl)-1H-benzimidazole in 10 mL of THF cooled in an ice bath was added 1 mL of 1M borane·TBF. After stirring for 24 h warming to room temperature, 0.5 mL of water was added followed by 0.5 mL of 6N sodium hydroxide and 0.5 mL of 30% hydrogen peroxide. After 30 min, the solution was diluted with 100 mL of chloroform, washed 2×10 mL of water, dried over magnesium sulfate and concentrated to dryness.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([CH:6]=[C:7](B(O)O)[N:8]2[CH3:11])=[CH:4][CH:3]=1.Br[C:16]1[C:21]([CH:22]=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:10]=[C:9]2[N:8]([CH3:11])[C:7]([C:19]3[CH:20]=[C:21]([CH:22]=[O:23])[CH:16]=[N:17][CH:18]=3)=[CH:6][C:5]2=[CH:4][CH:3]=1
Reactant: Cn1c(B(O)O)cc2ccc(Cl)nc21
Reactant: O=Cc1cccnc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1c(-c2cncc(C=O)c2)cc2ccc(Cl)nc21
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To 6-chloro-N-methyl-7-aza indole-2-boronic acid (1.00 g, 4.75 mmol) in dioxane (40 mL) under N2 was added 5 bromo-3-pyridine carbaldehyde (0.589 g, 3.17 mmol), aqueous Na2CO3 (2M, 4.75 mL, 9.50 mmol) and polymer bound Pd(PPh3)4 (1.760 g, 0.158 mmol). The reaction was stirred for 2 hours at 85° C. The reaction mixture was cooled to room temperature. The solids were filtered off and the precipitate was washed thoroughly with methanol. The filtrate was concentrated in vacuo to give a brown color oil. The crude was purified by silica gel flash chromatography using DCM-MeOH (90-10, v/v) to afford pure product 5-(6-Chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-pyridine-3-carbaldehyde as a solid. ESI-MS: m/z 272.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=O>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:34][C:20]2[NH:21][C:22]([CH3:33])=[C:23]([C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[O:25])[C:19]=2[CH3:18])[C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: Nc1ccc(-c2cccc3c2CC(=O)N3)cn1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(N)nc4)c32)c(C)c1C(=O)N1CCN(C)CC1

Procedure:
4-(6-Aminopyridin-3-yl)-1,3-dihydroindol-2-one (56 mg, 0.25 mmol) was condensed with 3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (69 mg, 0.275 mmol) to give the title compound.
Reaction SMILES: [OH-].[K+].CC([O:11]S(C1C=CC(C)=CC=1)(=O)=O)CCCCCC.Cl.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:40])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:27]=[O:28]>CO.C(O)(=O)C.O.C1(C)C=CC=CC=1>[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:40])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:27]([OH:11])=[O:28]
Reactant: CCCCCCC(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: CCCCCCC(C)Oc1ccc(C=O)cc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CO
Product: CCCCCCC(C)Oc1ccc(C(=O)O)cc1F
Temperature: 0 °C
Yield: 39 %

Procedure:
On the other hand, o-fluorophenol (500 g, 4.46 mols) was added to a solution of NaOH (1,250 g, 31.26 mols) dissolved in water (2 l), followed by dropwise adding chloroform (1,230 g), agitating the mixture at about 60° C. for 2 hours, acidifying it with sulfuric acid, filtering off the residue on heating, and recrystallizing the deposited crystals from a mixed solvent of water-methanol to obtain 3-fluoro-4-hydroxybenzaldehyde (35.3 g) having a m.p. of 119.5°~123.5° C. This product (30 g, 0.21 mol) was dissolved in methanol (300 ml), followed by adding and dissolving KOH (12 g, 0.21 mol), dropwise adding optically active p-toluenesulfonic acid 1-methyl-heptyl ester (65 g, 0.23 mol) prepared above, keeping the mixture under reflux for 4 hours, cooling, adding toluene (200 ml) and 6N-HCl (100 ml), washing the resulting toluene layer with 2N-NaOH aqueous solution, further washing with water till the washing layer became neutral, and distilling off toluene to obtain as residue, optically active 3-fluoro-4-(1-methyl-heptyloxy)-benzaldehyde (14.7 g). This product (10 g, 0.04 mol) was dissolved in acetic acid (200 ml), followed by dropwise adding a solution of chromic anhydride (4 g, 0.04 mol) dissolved in acetic acid (50 ml) and water (40 ml), agitating the mixture at 40°~50° C. for about 6 hours, pouring the resulting reaction material in ice water and filtering off the deposited crystals to obtain optically active 3-fluoro-4-(1-methyl-heptyloxy)-benzoic acid (6.1 g) having a m.p. of 57.2°~59.2° C., adding thionyl chloride (4.2 g, 0.035 mol) to the above product (6 g, 0.022 mol), heating the mixture under reflux with stirring for one hour, and distilling off excess thionyl chloride to obtain optically active 3-fluoro-4-(1-methyl-heptyloxy)-benzoic acid chloride (6.1 g).
Reaction SMILES: [C:1]1(=[O:34])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13](=[O:28])[C:14](=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:15]([CH3:17])=O)[C:4](=[O:29])[C:3]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:2]12.[CH3:35][O:36][C:37](=[O:42])/[CH:38]=[C:39](\[NH2:41])/[CH3:40]>C(O)(C)C>[CH3:40][C:39]1[NH:41][C:15]([CH3:17])=[C:14]([C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:5]2[C:1](=[O:34])[C:2]3=[CH:33][CH:32]=[CH:31][CH:30]=[C:3]3[C:4]2=[O:29])=[O:28])[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:38]=1[C:37]([O:36][CH3:35])=[O:42]
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCCCCCCN1C(=O)c2ccccc2C1=O
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCN2C(=O)c3ccccc3C2=O)C1c1cccc([N+](=O)[O-])c1

Procedure:
12.0 g (26 mmol) of 2-(3-nitrobenzylidene)-acetoacetic acid-(6-phthalimidohexyl)ester and 3.0 g (26 mmol) of 3-amino-crotonic acid methyl ester are boiled under reflux in 100 ml of isopropanol for 4 hours. After removal of the solvent by evaporation under vacuum, 15.0 g of a brownish yellow oil suitable for reactions without further purification are obtained.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19]([OH:21])=O)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.O.[OH:35][N:36]1C2C=CC=CC=2N=N1.NOC1CCCCO1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CN(C=O)C>[OH:35][NH:36][C:19](=[O:21])[CH:18]=[CH:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:12][CH:13]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C=Cc1ccc(NS(=O)(=O)c2ccccc2)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(C=Cc1ccc(NS(=O)(=O)c2ccccc2)cc1)NO
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.2 %

Procedure:
To a solution of 35 (200 mg, 0.660 mmol) in DMF (10 mL) at room temperature were added 1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI, 151 mg, 0.79 mmol), and 1-Hydroxybenzotriazole hydrate (HOBT, 134 mg, 0.99 mmol). The mixture was stirred 20 min. at room temperature then NH2OTHP (116 mg, 0.99 mmol) was added. The resulting mixture was heated at 50° C. for 24 h then the DMF solvent was evaporated under reduced pressure and the residue was dissolved in CH2Cl2, washed with a saturated aqueous solution of NaHCO3. The combined organic extracts were dried over (MgSO4) then condensed. The crude compound was purified by flash chromatography using Hexane/acetone (7:3) as solvent mixture. The residue was then dissolved in MeOH (10 mL) then 10-camphorsulfonic acid (CSA, 77 mg, 0.33 mmol) was added. The mixture was stirred 2 h at room temperature then the solvents were evaporated under reduced pressure at room temperature to avoid thermal decomposition. The crude product was purified by flash chromatography using CH2Cl2/MeOH (9:1) as solvent mixture giving compound 36 (116 mg, 55%) as a orange solid.
Reaction SMILES: [F:1][C:2]1([F:16])[O:7][C:6]2[CH:8]=C[C:10](C#N)=[CH:11][C:5]=2[O:4][C:3]1([F:15])[F:14].Cl.[C:18]([OH:21])(=[O:20])[CH3:19]>>[F:15][C:3]1([F:14])[O:4][C:5]2[CH:11]=[CH:10][C:19]([C:18]([OH:21])=[O:20])=[CH:8][C:6]=2[O:7][C:2]1([F:1])[F:16]
Reactant: CC(=O)O
Reactant: N#Cc1ccc2c(c1)OC(F)(F)C(F)(F)O2
Agent: Cl
Product: O=C(O)c1ccc2c(c1)OC(F)(F)C(F)(F)O2

Procedure:
To a solution of 2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxine-6-carbonitrile (5.0 g, 21.44 mmol) in acetic acid (20 ml) was added conc. hydrochloric acid (20 ml), and the mixture was heated under reflux overnight. The reaction solution was concentrated, and the precipitated crystals were filtered and washed with water to give the objective substance (4.76 g, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9]([O:14][CH3:15])=[C:8]([CH3:16])[C:4]=1[CH2:5][Mg]Br.C1[O:22][CH:18]1[C:19](=[CH2:21])[CH3:20].[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9]([O:14][CH3:15])=[C:8]([CH3:16])[C:4]=1[CH2:5][CH:20]=[C:19]([CH3:21])[CH2:18][OH:22]
Reactant: COc1c(C)c(C)c(OC)c(C[Mg]Br)c1C
Reactant: C=C(C)C1CO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1c(C)c(C)c(OC)c(CC=C(C)CO)c1C
Temperature: -78 °C
Reaction time: 3.5 h
Yield: 68.4 %

Procedure:
26.7 mmol of 2,5-dimethoxy-3,4,6-trimethylbenzylmagnesium bromide were treated at -78° C. with 3.6 g of lithium tetrachlorocuprate (Li2CuCl4) as a 0.1 molar solution in tetrahydrofuran. 2.2 g (26 mmol) of isoprene oxide were subsequently added. The mixture was thereupon stirred at -78° C. for 1 hour and at room temperature for 3-4 hours. 10 ml of saturated ammonium chloride were then added at 0° C. and the mixture was extracted with ether. After drying the ether extract over sodium sulphate, concentration and crystallization from ethyl ether at -20° C., there were obtained 4.7 g (75%) of 4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-2-butenol with a melting point of 85°-86° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:5][CH:4]=1>S(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][O:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[O:15])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCCCC(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: COc1ccc(CCCCCC(=O)OOC(=O)CCCCCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(4-Methoxyphenyl)hexanoic acid (3.7 g) is dissolved in thionyl chloride (5 ml) and the solution is stirred at room temperature overnight. The excess thionyl chloride is distilled off under reduced pressure and the residue is dissolved in petroleum ether (30 ml). Ice water (15 ml) is added to the solution and sodium peroxide (3 g) is added portionwise with ice-cooling and stirring. The mixture is extracted with chloroform and the extract is washed with water and dried. The solvent is then distilled off to give bis[6-(4-methoxyphenyl)hexanoyl]peroxide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].C1N=CN([C:21](N2C=NC=C2)=[S:22])C=1>O1CCCC1>[CH3:10][O:9][C:6]1[C:7]2[NH:8][C:21](=[S:22])[NH:1][C:2]=2[C:3]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[CH:4][CH:5]=1
Reactant: COc1ccc(CCN(C)C)c(N)c1N
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(CCN(C)C)c2[nH]c(=S)[nH]c12
Yield: 78.3 %

Procedure:
500 mg of N-[2-(2,3-diamino-4-methoxyphenyl)ethyl]-N,N-dimethylamine is heated for 3 hours under reflux with 50 ml of tetrahydrofuran and 430 mg of N,N'-thiocarbonyldiimidazole. After concentration, the residue is combined with water. The precipitate is recrystallized from ethanol, thus obtaining 470 mg of 7-methoxy-4-[2-(N,N-dimethylamino)ethyl]-2,3-dihydro-2-benzimidazolethione, mp 213°-216° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.[N:16]1([CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]([N:19]1[CH2:18][CH2:17][N:16]([CH2:22][C:23](=[O:24])[N:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:21][CH2:20]1)=[O:15]
Reactant: O=C(CN1CCNCC1)N1CCCC1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1C(=O)N1CCN(CC(=O)N2CCCC2)CC1
Temperature: 25 °C

Procedure:
5-Methyl-3-phenylisooxazole-4-carboxylic acid (40 mg, 0.197 mmol), piperazine acetic acid pyrrolidid (42.4 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H26N4O3: 382.2005, found 382.2016.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([Mg]Cl)[CH:18]([CH3:20])[CH3:19].Cl>C(OCC)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:10]([OH:11])[CH2:17][CH:18]([CH3:20])[CH3:19])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: CC(C)C[Mg]Cl
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(C(O)CC(C)C)cc1OC1CCCC1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a magnetically-stirred solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (25.0 mmol, 5.50 g) of Example 1A, in anhydrous ethyl ether (250 mL) at 0° C. is added isobutylmagnesium chloride (30 mmol, 15 mL; 2.0M solution in ethyl ether) dropwise over 20 minutes. The reaction mixture is allowed to stir while slowly warming to room temperature over 1 hour and is then poured into 1N HCl (250 mL) and partitioned with ethyl ether (200 mL). The aqueous phase is extracted with ethyl ether (200 mL) and the combined organics are washed with aqueous saturated NaHCO3 (200 mL), aqueous saturated NaCl (200 mL), and dried (MgSO4). Concentration in vacuo affords a yellow oil which is purified by flash chromatography (SiO2 : 1) methylene chloride, 2) 2% ethyl acetate/methylene chloride, 3) 5% ethyl acetate/methylene chloride) to give the title compound as a white solid (21.5 mmol, 5.98 g; 86 %).