Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]>CN(C)C=O.O>[OH:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: OCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCCCCOc1ccc(-c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
17 g of 4-phenylphenol (0.1 mol) was dissolved in 120 mL of N,N-dimethylformamide (hereafter abbreviated as DMF), 15.2 g of potassium carbonate powder (0.11 mol) was added with constant stirring, and the mixture was then stirred for one hour while heating at 90° C. Subsequently, 6-chloro-1-hexanol (14.3 g, 0.11 mol) was added dropwise to the mixture, and the reaction was allowed to proceed for 12 hours under constant stirring. Following confirmation by gas chromatography that the peaks derived from the raw materials had disappeared, the reaction mixture was diluted with water, and the precipitated solid was recovered by filtration. The resulting solid was then recrystallized from ethanol, yielding 23 g of 4-(6-hydroxyhexyloxy)phenylbenzene (yield: 85%).
Reaction SMILES: N[C:2](N)=[O:3].[CH:5]1([NH:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.N>O>[CH:5]1([N:11]2[CH2:12][CH2:13][CH2:14][NH:15][C:2]2=[O:3])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: NC(N)=O
Reactant: NCCCNC1CCCCC1
Agent: N
Solvent: O
Product: O=C1NCCCN1C1CCCCC1
Temperature: 25 °C

Procedure:
The reaction apparatus is a 500 ml flask, equipped with thermometer, reflux condenser and magnetic stirrer. The top of the reflux condenser is connected to a bubbler containing water. Before adding the reagents, the flask is weighed. Then 30 g of urea (0.5 mols) and 156 g of N-cyclohexyl-1,3-propanediamine (1 mol) are put into the flask, which is then slowly heated. Ammonia begins to evolve. Heating is continued until 18 g of ammonia have evolved. The reaction mixture is allowed to cool to room temperature. The solid which precipitates is separated by filtration on a Buchner funnel and dried in vacuo. The weight is 78 g and the melting point is 175° C. The raw reaction product is recrystallized from boiling ethanol. The melting point of the recrystallized product is 198° C. The nitrogen content is 15.25%, whereas the theoretical value is 15.37%. The structure of the product as confirmed by a combination of elemental analysis, 13C NMR and 1H NMR is determined as follows: ##STR3## The structure of this compound has been corroborated by IR and VPO molecular weight measurements. The elemental analysis is as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH2:21][CH3:22]>CN(C=O)C>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][C:11]([NH2:12])=[C:2]([NH:1][CH2:20][CH2:21][CH3:22])[CH:3]=1
Reactant: CCCI
Reactant: COC(=O)c1ccc(N)c(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNc1cc(C(=O)OC)ccc1N
Temperature: 25 °C
Reaction time: 22 h

Procedure:
In DMF (40 ml), methyl 3,4-diaminobenzoate (2.01 g) was dissolved and then the solution was added with potassium carbonate (2.00 g) and 1-iodopropane (1.4 ml), followed by stirring at room temperature for 22 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and washed with water, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (1.06 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:10])=[O:9])[CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1>>[C:8]([C:4]1[CH:3]=[C:2]([O:18][C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[NH2:11])[CH:7]=[CH:6][N:5]=1)(=[O:9])[NH2:10]
Reactant: Nc1cccc(O)c1
Reactant: NC(=O)c1cc(Cl)ccn1
Product: NC(=O)c1cc(Oc2cccc(N)c2)ccn1

Procedure:
Entry 44: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 3-aminophenol according to Method A1, Step 4 to form 3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C1a, 4-chloro-3-(trifluoromethylphenyl isocyanate was reacted with 3-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:10]=[C:11]2[C:21](=[CH:22][CH:23]=1)[O:20][C:14]1([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:13][C:12]2=O>C1COCC1.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[Br:8][C:9]1[CH:10]=[C:11]2[C:21](=[CH:22][CH:23]=1)[O:20][C:14]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[CH2:13]/[C:12]/2=[N:7]\[S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6]
Reactant: O=C1CC2(CCCCC2)Oc2ccc(Br)cc21
Reactant: CC(C)(C)S(N)=O
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)/N=C1\CC2(CCCCC2)Oc2ccc(Br)cc21
Yield: 51.4 %

Procedure:
The compound of 2-methylpropane-2-sulfinamide (29.54 g, 244.2 mmol) was added the solution of 6-bromospiro[chroman-2,1′-cyclohexan]-4-one (78.97 g, 268.6 mmol) in dry THF (900 mL), and then tetraisopropoxytitanium (193.1 g, 488.3 mmol) was added, The reaction mixture was reflux overnight. The mixture was removed in vacuo, and then quenched by brine, extracted with ethyl acetate. The ethyl acetate was dried over anhydrous Na2SO4, filtered, and evaporated to give (E)-N-(6-bromospiro[chroman-2,1′-cyclohexane]-4-ylidene)-2-methylpropane-2-sulfinamide (50 g, 40%). 1H NMR (CDCl3): 1.30 (s, 10H), 1.51 (m, 5H), 1.62 (m, 4H), 1.83 (d, 2H), 3.07(d, 1H), 3.43 (d, 1H), 5.29 (s, 2H), 6.79 (d, 1H), 7.41 (dd, 1H), 7.96 (d, 1H).
Reaction SMILES: [CH:1]([O:6][CH3:7])([O:4][CH3:5])OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:19]([O:26][CH:27]1[CH2:32][CH2:31]C(=O)[CH2:29][CH2:28]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+]>CO.ClCCl>[CH3:7][O:6][C:1]1([O:4][CH3:5])[CH2:29][CH2:28][CH:27]([O:26][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:32][CH2:31]1
Reactant: O=C1CCC(OCc2ccccc2)CC1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC1(OC)CCC(OCc2ccccc2)CC1
Reaction time: 8 h

Procedure:
529 mL of trimethyl orthoformate and 32 mg of p-toluene sulfonic acid were added to a solution of 4-benzyloxy cyclohexanone in 20 mL of dry methanol and the mixture was stirred overnight. 20 mL of saturated aqueous sodium bicarbonate solution and 20 mL of dichloromethane were added, the aqueous layer was extracted several times with dichloromethane and the combined organic layers were dried and evaporated to dryness to yield 1.50 g of the desired product, which was used without further purification.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11](F)([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[O:27])=[CH:24][C:23]=4[O:38][CH3:39])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.NCC(F)([C:46]([F:49])([F:48])[F:47])C(O)=O>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([C:46]([F:49])([F:48])[F:47])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[O:27])=[CH:24][C:23]=4[O:38][CH3:39])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NCC(F)(C(=O)O)C(F)(F)F
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(C(F)(F)F)C(=O)N2C

Procedure:
The title compound was synthesized using the analogous procedure to that described in connection with Compound 3 except that 2-(aminomethyl)-2,3,3,3-tetrafluoropropanoic acid was used as the starting material. The final product was purified on reversed phase HPLC as TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46-1.76 (m, 10 H) 1.83-2.09 (m, 4 H) 2.19 (s, 3 H) 2.80 (d, J=11.9 Hz, 2 H) 3.32 (s, 3 H) 3.69-3.81 (m, 1 H) 3.89 (t, 1 H) 3.94 (s, 3 H) 4.15-4.35 (q, 1 H) 4.72 (quin., J=8.1 Hz, 1 H) 7.48 (dd, J=1.77 Hz, 1 H) 7.50 (s, 1 H) 8.00 (s, 1 H) 8.10 (d, J=7.8 Hz, 1 H) 8.26 (d, J=8.3 Hz, 1 H) 8.32 (s, 1 H). [M+H] calc'd for C28H35F4N7O3 594; found 594.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([F:10])[C:5]([C:11]#[N:12])=[C:4](F)[C:3]=1[F:14].[Br-:15].[Na+]>O>[Br:15][C:4]1[C:3]([F:14])=[C:2]([F:1])[C:7]([C:8]#[N:9])=[C:6]([F:10])[C:5]=1[C:11]#[N:12]
Reactant: N#Cc1c(F)c(F)c(F)c(C#N)c1F
Reactant: [Br-]
Agent: [Na+]
Solvent: O
Product: N#Cc1c(F)c(F)c(Br)c(C#N)c1F
Temperature: 120 °C
Yield: 55 %

Procedure:
In a 3 liter reaction vessel, were added 200 g (1.00 mol) of tetrafluoroisophthalonitrile, 1 liter of N-dimethylformamide (DMF) and 102.7 g (1.00 mol) of sodium bromide (NaBr). This mixture was heated at 120° C. for 1 hour. Separately, 3 liter of water was poured to a 5 liter of beaker, and to which was poured the resulting reaction solution. After suction filtration, the residue was washed with water and hexane, and then dried in vacuo to offer 198.2 g of a white solid. The solid was purified by means of solid distillation to give 142.8 g (0.55 mol) of 4-bromo-2,5,6-trifluoroisophthalonitrile as a white solid (yield: 55%).
Reaction SMILES: Br[C:2]1[C:3]2[NH:10][CH:9]=[N:8][C:4]=2[CH:5]=[N:6][CH:7]=1.[C:11]([Si](C)(C)C)#[CH:12]>>[C:11]([C:2]1[C:3]2[NH:10][CH:9]=[N:8][C:4]=2[CH:5]=[N:6][CH:7]=1)#[CH:12]
Reactant: Brc1cncc2nc[nH]c12
Reactant: C#C[Si](C)(C)C
Product: C#Cc1cncc2nc[nH]c12

Procedure:
The title compound can be synthesized from 7-ethynyl-1H-imidazo[4,5-c]pyridine and 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for Example 1. 7-ethynyl-1H-imidazo[4,5-c]pyridine is prepared from 7-bromo-1H-imidazo[4,5-c]pyridine and ethynyltrimethylsilane according to the 2 steps procedure described in Example 1.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:28]([O:35][CH2:36][C:37](Cl)=[O:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][CH2:36][C:37]([N:24]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:21])([F:22])[F:20])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:27])=[O:2])[CH:6]=1)[CH2:25][CH3:26])=[O:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)COCc1ccccc1

Procedure:
(2′-{[(2-Benzyloxy-acetyl)-ethyl-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (Compound 1-92) was prepared by following the procedures outlined in Example 1 and using (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and benzyloxyacetyl chloride.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:22]([NH2:24])=[O:23])[CH:13]=[C:14]([C:17]4[CH:21]=[CH:20][S:19][CH:18]=4)[CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1.[CH2:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26].C(N(CC)CC)C>C(Cl)Cl>[CH2:25]([S:27]([N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:22]([NH2:24])=[O:23])[CH:13]=[C:14]([C:17]4[CH:21]=[CH:20][S:19][CH:18]=4)[CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1)(=[O:29])=[O:28])[CH3:26]
Reactant: CCS(=O)(=O)Cl
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCNCC3)n[nH]c12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccsc4)cc23)CC1

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 3-(4-piperidinyl)-5-(3-thienyl)-1H-indazole-7-carboxamide hydrochloride (Intermediate 19) (0.117 mmol) was reacted with ethane sulfonyl chloride (0.02 mL, 0.234 mmol) in the presence of triethylamine (0.04 mL, 0.468 mmol) in methylene chloride (10 mL) to give the title compound (9.4 mg, 19% for the last two steps)
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O.C(=O)([O-])[O-].[Na+].[Na+]>CO>[NH:4]1[CH2:5][CH2:6][CH:2]([CH:3]=[CH:12][C:11]2[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:9]([O:8][CH3:7])[CH:10]=2)[NH:1]1
Reactant: COc1ccc(C=O)cc1OC
Reactant: NC1CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C=CC2CCNN2)cc1OC
Reaction time: 12 h

Procedure:
3-Aminopyrrolidine is reacted with 3-(3,4-dimethoxybenzaldehyde, which is commercially available from Aldrich (Milwaukee, Wis.) in an inert solvent, for example methanol, in the presence of a base, for example sodium carbonate, and stirred for about 4–24 hours, preferably about 12 hours, at about room temperature. When the reaction is substantially complete, 4-(2-aza-2-pyrrolidin-3-ylvinyl)-1,2-dimethoxybenzene is isolated and purified by conventional means, and used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)=[O:14].[CH3:27][O-:28].[Na+].[NH4+].[Cl-]>CO>[CH3:27][O:28][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)=[O:14]
Reactant: Cc1nc2ncccc2c(Cl)c1C(=O)NCc1cccc(C(F)(F)F)c1
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COc1c(C(=O)NCc2cccc(C(F)(F)F)c2)c(C)nc2ncccc12
Yield: 20 %

Procedure:
4-Chloro-2-methyl-N-(3-(trifluoromethyl)benzyl)-1,8-naphthyridine-3-carboxamide (60.0 mg, 0.16 mmol) was dissolved in anhydrous MeOH (1.0 ml). NaOMe was added and the mixture refluxed for 15 h. The mixture was allowed to cool. NH4Cl (5.0 ml (sat)) was added and the product extracted with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated. Purification was done by flash chromatography (EtOAc/MeOH 98:2) giving 12.0 mg (20%) of the title compound.
Reaction SMILES: C(O)C.[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.Cl[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22]>C(N(CC)CC)C>[N+:21]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[NH:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][CH:5]=[CH:6]2)([O-:23])=[O:22]
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnccc1Nc1ccc2[nH]ccc2c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To 150 ml of absolute ethanol were added 1H-indol-5-amine (8.06 g), 4-chloro-3-nitropyridine (10.0 g) and triethylamine (8.5 ml), and this mixture was heated to 60° C. and stirred for 2 hours. The mixture was cooled, the ethanol evaporated, and the residue taken up in a water/ethyl acetate mixture. This was treated with Na2CO3 (aq) to adjust the pH to 10. The organic layer was collected, the aqueous layer extracted again with ethyl acetate, and the organics were combined, washed with water and dried (sat. NaCl, anh. MgSO4).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:26][O:27][CH2:28][CH2:29]Br>C1COCC1>[CH3:26][O:27][CH2:28][CH2:29][NH:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: COCCBr
Reactant: CCOC(=O)c1sc2nccnc2c1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1sc2nccnc2c1NCCOC
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
Ethyl 7-amino-thieno[2,3-b]pyrazine-6-carboxylate (1.0 g g, 4.48 mmol) prepared by the method of Schneller and Clough, J. Het. Chem., 12: 513 (1975), was treated with potassium bis(trimethylsilyl)amide (0.5M in toluene, 8.96 ml) in 15 ml THF at -70° C., and allowed to warm to room temperature. 2-Bromoethyl methyl ether (0.454 ml, 4.70 mmol) was added, and the reaction was stirred under N2 at 60° C. overnight. The mixture was cooled and evaporated, then purified by column chromatography on silica gel eluting with 1:9 ethyl acetate:hexanes to yield 0.640 g (51%) of the title compound as a yellow solid: 1H NMR (300 MHz, DMSO-d6) d 1.32 (t, 3H), 3.3 (s, 3H), 3.56 (t, 2H), 4.25 (q, 2H), 4.32 (t, 2H), 7.70 (br t, 1H), 8.76 (s, 1H), 8.77 (s, 1H); MS (DCI/NH3) m/e 282 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[F:12].[C:13]([Cu])#[N:14].[O-]S([O-])(=O)=O.[Na+].[Na+].CC(OC)(C)C>CN1C(=O)CCC1>[F:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([F:8])=[CH:7][C:2]=1[C:13]#[N:14]
Reactant: N#C[Cu]
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: COC(C)(C)C
Product: N#Cc1cc(F)c([N+](=O)[O-])cc1F
Temperature: 160 °C
Reaction time: 7.5 h
Yield: 68.1 %

Procedure:
A mixture of 1-bromo-2,5-difluoro-4-nitro-benzene (95 g, 399 mmol) and CuCN (71.8 g, 798 mmol) in NMP (700 mL) was set to a pre-heated 160° C. oil-base and stirred at 160° C. under N2 over 450 min. The mixture was cooled to RT, charged with Na2SO4 (300 g) and MTBE (1 L), and stirred for an additional 15 min. The resulting mixture was filtered and the filtrate was charged with 800 mL of water, then the separated aqueous layer was extracted with MTBE. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated. The material was recrystallized from EtOH/water (2/1) to yield 2,5-Difluoro-4-nitro-benzonitrile (50 g, 68% yield) as a pale brown solid. 1H NMR (400 MHz, CDCl3) δ 7.96-7.95 (dd, 1H), 7.67-7.64 (dd, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.CCN(CC)CC.[CH:17]([N:20]1[C:24]([C:25]2[N:34]=[C:33]3[N:27]([CH2:28][CH2:29][O:30][C:31]4[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][C:32]=43)[CH:26]=2)=[N:23][CH:22]=[N:21]1)([CH3:19])[CH3:18]>C(Cl)Cl>[CH:17]([N:20]1[C:24]([C:25]2[N:34]=[C:33]3[C:32]4[CH:35]=[C:36]([S:39]([N:6]5[CH2:7][CH2:8][CH:3]([N:2]([CH3:9])[CH3:1])[CH2:4][CH2:5]5)(=[O:41])=[O:40])[CH:37]=[CH:38][C:31]=4[O:30][CH2:29][CH2:28][N:27]3[CH:26]=2)=[N:23][CH:22]=[N:21]1)([CH3:19])[CH3:18]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)Cl)ccc1OCC2
Reactant: CN(C)C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)N3CCC(N(C)C)CC3)ccc1OCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of dimethyl-piperidin-4-yl-amine (45 mg, 0.35 mmol) and NEt3 (83 μL, 0.59 mmol) in DCM (15 mL) at 0° C. was added a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl chloride from Example 121 (93 mg, 0.12 mmol) in DCM (5 mL) and the resulting mixture warmed to RT after 10 min then stirred for 1 h. The reaction mixture was diluted with DCM, washed with a saturated aqueous NaHCO3 solution then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-16% MeOH in EtOAc) then freeze-dried from MeCN/H2O affording 131 (29 mg, 52%) as a white solid. LCMS: RT 2.83 min [M+H]+ 486.3. 1H NMR (DMSO, 400 MHz): δ 8.79 (1H, d, J=2.42 Hz), 8.00 (1H, s), 7.93 (1H, d, J=0.62 Hz), 7.63 (1H, dd, J=10.74, 2.40 Hz), 7.26 (1H, d, J=8.62 Hz), 5.72-5.71 (1H, m), 4.61-4.60 (4H, m), 3.60-3.57 (2H, m), 2.40-2.39 (2H, m), 2.15-2.05 (1H, m), 2.10 (6H, s), 1.77-1.73 (2H, m), 1.49 (6H, d, J=6.62 Hz), 1.46-1.37 (2H, m)
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4].[Na].[CH3:16][SH:17].O>CO>[CH3:16][S:17][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Reactant: CS
Agent: [Na]
Solvent: O
Solvent: CO
Product: CSCC(=O)c1ccc(C(F)(F)F)cc1
Yield: 97.7 %

Procedure:
To 13.2 g of 2-bromo-4'-(trifluoromethyl)acetophenone dissolved in 40 ml of methanol was added under ice-cooling 34.6 g of a 15% aqueous solution of methyl mercaptan sodium salt. After the reaction at room temperature for 1 hour with stirring, the resultant reaction mixture was poured into ice-cooled water and extracted with dichloromethane. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by evaporation of the solvent to obtain 11.3 g of oily product of 2-methylthio-4'-(trifluoromethyl)acetophenone (yield: 97.7%).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[CH2:11](OC(=O)CCCC(OCCC)=O)[CH2:12]C>>[CH2:11]([O:7][C:6](=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:10])=[O:9])[CH3:12]
Reactant: O=C(O)CCCCC(=O)O
Reactant: CCCOC(=O)CCCC(=O)OCCC
Product: CCOC(=O)CCCCC(=O)O

Procedure:
Hexane dioic acid monoethyl ester was prepared from hexane dioic acid through steps (a) and (b) discussed above in example 1, step 2 for the preparation of (III).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][NH2:11])=[N:8][CH:9]=1.C(N(CC)CC)C.[C:19](=S)=[S:20]>CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:19](=[S:20])[NH:11][CH:10]=2)[CH:9]=1
Reactant: S=C=S
Reactant: NCc1ccc(F)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: Fc1ccc2c[nH]c(=S)n2c1
Temperature: 75 °C
Yield: 33.5 %

Procedure:
In a round-bottomed flask, (5-fluoropyridin-2-yl)methylamine dihydrochloride (600 mg, 3.0 mmol) was suspended in methanol (16 ml). Triethylamine (1.4 ml, 10.0 mmol) was added followed by carbon disulfide (1.4 ml, 23.2 mmol). The reaction mixture was stirred at reflux (oil bath temperature=75° C.) overnight then cooled to room temperature and then concentrated. The residue was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane then the organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with EtOAc/hexanes (gradient 0-60% EtOAc) to afford 169 mg (33%) of 6-fluoro-2H-imidazo[1,5-a]pyridine-3-thione as an orange solid. 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 13.47 (br. s., 1H), 8.04 (dd, J=4.9, 1.1 Hz, 1H), 7.43-7.56 (m, 2H), 6.88 (ddd, J=10.0, 7.9, 2.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[F:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1.FC1C=CC=CC=1CBr.C1(C(Cl)=O)CCC1>>[F:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])=[O:16])=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Clc1ccccc1CBr
Agent: Fc1ccccc1CBr
Agent: O=C(Cl)C1CCC1
Product: O=C(Cc1ccccc1Cl)c1ccc(F)cc1
Yield: 34 %

Procedure:
Following a procedure similar to that described in Preparation 13, except that equivalent amounts of 2-chlorobenzyl bromide and 4-fluorobenzoyl chloride were used in place of the 2-fluorobenzyl bromide and cyclobutanecarbonyl chloride, the title compound was obtained as a colorless powder in a yield of 34%.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Br[CH2:22][C:23]1[O:24][CH:25]=[CH:26][C:27]=1[C:28]([O:30][CH3:31])=[O:29]>>[CH3:31][O:30][C:28]([C:27]1[CH:26]=[CH:25][O:24][C:23]=1[CH2:22][N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19])=[O:29]
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: COC(=O)c1ccoc1CBr
Product: COC(=O)c1ccoc1Cn1c(Oc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Yield: 33.5 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 2-bromomethyl-3-methoxycarbonylfurane were reacted by the same way with the example 1 to obtain the titled compound (133 mg, yield: 33.5%).