Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([F:13])[C:5]=1[CH:6]=[O:7]>CO.CCCCC>[Cl:3][C:4]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([F:13])[C:5]=1[CH2:6][OH:7]
Reactant: Cc1cc(F)c(C=O)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCC
Product: Cc1cc(F)c(CO)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
Sodium borohydride (1.42 g, 37.5 mmol) was added in portions to an ice-cooled solution of 2-chloro-6-fluoro-4-methylbenzaldehyde (6.25 g, 38.2 mmol) in methanol (56 mL); once addition was complete the reaction was allowed to warm rt with stirring over 1 h and then concentrated in vacuo. The residue was partitioned between ether and saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous re-extracted with ether. The organic layers were combined, washed with H2O, dried with MgSO4 and concentrated in vacuo to yield the crude product as an oil. This oil was diluted with pentane, cooled and stirred which resulted in a white solid. Filtration and drying in vacuo yielded the title compound (5.10 g, 29.2 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:26])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[O:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].O>N1C=CC=CC=1>[C:27]([O:26][C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][C:17]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)=[O:18])[CH2:12][CH2:13]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(CCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC1(c2ccc(Cl)cc2)CCN(CCCC(=O)c2ccc(F)cc2)CC1

Procedure:
4-(4-(4-Chlorophenyl)-4-hydroxy-1-piperidinyl)-1-(4-fluorophenyl)-1-butanone (20 g) and acetic acid anhydride (16 g) in 200 ml of dried pyridine (KOH pellets) were refluxed for 2 h. The mixture was poured into cold H2O (0° C.) (2 liters) and extracted with isopropylether (2×200 ml). The combined organic phases were dried (MgSO4) and the solvent evaporated. The title compound was obtained after column chromatography on silica gel (eluent, ethyl acetate/dichloromethane/methanol, 1:1:1). Yield 10.6 g (48%). Mp 106°-110° C. (from isopropyl ether). The hydrochloride salt was precipitated from acetone. Mp 215° C. According to TLC analysis the content of Haloperidol was 0.5%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[OH2:13].O.[Sn](Cl)Cl>CO>[NH2:10][C:4]1[C:5]([C:8]([NH2:9])=[O:13])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: O
Agent: Cl[Sn]Cl
Solvent: CO
Product: NC(=O)c1ncc(Br)cc1N
Temperature: 40 °C

Procedure:
To a solution of 5-bromo-3-nitropyridine-2-carbonitrile (4.71 g, 20.7 mmol) in MeOH (319 mL) under N2 was added tin(II) chloride dihydrate (27.97 g, 123.9 mmol). The reaction was heated to 40° C. for 40 minutes, concentrated in vacuo, and azeotroped with toluene. The residue was dissolved in ethyl acetate, and 10% aqueous sodium bicarbonate was added till the solution was basic. The aqueous layer was extracted 3× with CHCl3 and the combined organics were dried over Na2SO4, filtered and concentrated under vacuum to provide 3-amino-5-bromopyridine-2-carboxamide that gave a mass ion (ES+) of 218.2 for M+H+(81Br).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][N:10]=2)[CH2:2]1.[OH:23][C:24]1([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1>>[OH:23][C:24]1([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH2:25][CH2:26][CH:27]([N:1]2[CH2:2][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=4)[NH:11][N:10]=3)[CH2:4]2)[CH2:28][CH2:29]1
Reactant: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: O=C1CCC(O)(c2cccnc2)CC1
Product: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(O)(c3cccnc3)CC2)C1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide (as prepared in the previous step) and 4-hydroxy-4-pyridin-3-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH:10][C:11](=[O:22])[C:12]1[C:17]([O:18]C)=[CH:16][CH:15]=[CH:14][C:13]=1[O:20][CH3:21])[CH3:3].B(Br)(Br)[Br:24].O>ClCCl>[CH2:2]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH:10][C:11](=[O:22])[C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([Br:24])[C:13]=1[O:20][CH3:21])[CH3:3]
Reactant: CCN1CCCC1CNC(=O)c1c(OC)cccc1OC
Reactant: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCN1CCCC1CNC(=O)c1c(O)ccc(Br)c1OC
Yield: 80 %

Procedure:
To a solution of N-ethyl-2-(2,6-dimethoxybenzamidomethyl)pyrrolidine hydrochloride (23.0 g, 0.07 mole) in 300 ml of dry dichloromethane was added dropwise with stirring a solution of boron tribromide (17.5 g, 0.07 mole) in 25 ml of dry dichloromethane at 0° C. After the addition was completed the solution was allowed to reach room temperature over night. Water was added and pH adjusted to 7. The organic layer was washed with water and dried (MgSO4). The solvent was evaporated in vacuo affording the title compound as a viscous oil (20 g) which was judged by TLC and GC analysis to be sufficiently pure for use in the next step without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([F:18])[F:17])[C:8]2=[N:9][C:10]=1[NH2:11])=[O:4].[Li+:19].[OH-].[ClH:21]>C1COCC1.C1(C)C=CC=CC=1>[NH2:11][C:10]1[N:9]=[C:8]2[N:12]([CH2:15][CH:16]([F:18])[F:17])[CH:13]=[CH:14][C:7]2=[N:6][C:5]=1[C:3]([OH:4])=[O:2].[Li+:19].[Cl-:21]
Reactant: Cl
Reactant: COC(=O)c1nc2c(nc1N)N(CC(F)F)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Nc1nc2c(ccn2CC(F)F)nc1C(=O)O
Product: [Cl-]
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3-amino-5-(2,2-difluoro-ethyl)-6H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid methyl ester (192 mg, 0.749 mmol) in THF (3.8 ml) was added a solution of 1M LiOH (0.824 ml, 0.824 mmol) and the reaction mixture was stirred at r.t. for 20 h. At 0° C. 1M HCl (0.749 ml) was added and the mixture diluted with toluene (7.5 ml). The solvents were evaporated to provide the title compound together with LiCl as brown powder. This material was used for coupling reactions without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:14])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][O:25][CH2:26][C:27](O)=[O:28])=[C:18]([C:31]([O:33]C)=[O:32])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][O:25][CH2:26][C:27]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:28])=[C:18]([CH:17]=1)[C:31]([OH:33])=[O:32]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: Nc1ccccc1-c1ccc(F)cc1
Product: O=C(COCC(=O)Nc1ccccc1-c1ccc(F)cc1)Nc1ccc(Cl)cc1C(=O)O

Procedure:
Using the same method as in Example 1-(ii), 4′-fluoro-(1,1′-biphenyl)-2-amine was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-[((2-[(4′-fluorobiphenyl-2-yl)amino]-2-oxoethoxy)acetyl)amino]benzoic acid.methyl ester (yield: 60%).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([N+:16]([O-])=O)[CH:14]=2)[CH2:9][CH2:8]1)=[O:6].O.NN>CO.[Fe](Cl)(Cl)Cl>[CH3:21][N:2]([CH3:1])[CH2:3][CH2:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([NH2:16])[CH:14]=2)[CH2:9][CH2:8]1)=[O:6]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CCN(C)C)CC2
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1N)N(C(=O)CCN(C)C)CC2
Temperature: 64 °C
Reaction time: 12 h
Yield: 19 %

Procedure:
To N,N-dimethyl-3[5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]-3-oxo-1-propanamine (1.52 g, 5.4 mmol) in MeOH (50 mL) was added iron (III) chloride (0.220 g, 1.35 mmol, Aldrich) and activated carbon (2.0 g, Aldrich). The reaction mixture was stirred at 64° C. for 20 min before the dropwise addition of hydrazine hydrate (1.2 mL, 37.5 mmol, Aldrich) over 5 min. The reaction was kept stirring at 64° C. for additional 12 h. Filtration removed the solids and the filtrate was concentrated and purified via chromatography on SiO2 (0-10% 2 M NH3 in MeOH/DCM) to afford 1-[3-(dimethylamino)propanoyl]-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine (0.270 g, 19% Yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.72 (s, 1 H), 6.63 (s, 1 H), 3.95-4.15 (m, 2 H), 3.81 (s, 3 H), 3.76 (s, 2 H), 3.10 (t, J=8.43 Hz, 2 H), 2.83-2.96 (m, 2 H), 2.70 (t, J=7.15 Hz, 2 H), 2.41 (s, 6 H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:4]([C@@H:5]([OH:29])[CH2:6][C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH2:3]1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.Cl>N1C=CC=CC=1>[S:36]([O:1][C@@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:4]([C@@H:5]([O:29][S:36]([C:33]3[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=3)(=[O:38])=[O:37])[CH2:6][C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:17])[CH3:18])[CH2:3]1)([C:33]1[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=1)(=[O:38])=[O:37]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)=CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@H](O)[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)=CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@H](OS(=O)(=O)c4ccc(C)cc4)[C@@H]4C[C@H](OS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 48 h

Procedure:
3.5 g of 3α,6α-dihydroxy-5β-cholest-24-ene and 10.2 g of ρ-toluenesulfonyl chloride were dissolved in 90 ml of dry pyridine and then kept in a refrigerator for 48 hours. The mixture was poured into 300 ml of ice-water and the pH adjusted to 3 by adding concentrated HCl. After stirring for 30 minutes, the precipitate was removed by filtration, washed 4 times with 100 ml portions of water and dissolved in 300 ml of chloroform. The chloroform solution was washed with 30 ml of 5% sodium bicarbonate solution, four times with 50 ml of water solution, and dried. The solvent was evaporated and the residue dried. The yield was 5.1 g of a white solid (83%) identified from ir and nmr data as 3α,6α-ditosyloxy-5β-cholest-24-ene.
Reaction SMILES: [C:1](F)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1>>[C:1]([C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[CH:16][CH:17]=[C:8]([CH3:7])[CH:9]=2)[CH:14]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1ccc2ccccc2c1
Reactant: CC(C)C(=O)F
Product: Cc1ccc2cc(C(=O)C(C)C)ccc2c1

Procedure:
In the BF3 absorption tank, the isobutyryl fluoride solution absorbed BF3 contained in gas released from the acylation reactor, and no BF3 was detected in the analysis of gas purged from the BF3 absorption tank. In the complex preparation tank, the isobutyryl fluoride synthesis solution from the BF3 absorption tank further absorbed BF3 recovered from the distillation column, and in the acylation reactor, the resultant isobutyryl fluoride synthesis solution reacted with 2-methylnaphthalene to give 2-isobutyryl-6-methylnaphthalene.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCCBr)ccc2c1OCCC2=O

Procedure:
A mixture of 0.413 g (2.00 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, 3.0 g (13.05 mmol) of 1,5-dibromopentane, 1.4 g (10.13 mmol) of anhydrous granular potassium carbonate and 31 mL of 2-butanone was stirred and refluxed for 18 hr. The resulting slurry was filtered with suction and the solids were washed thoroughly with ethyl acetate. The filtrate and washes were combined and concentrated in vacuo and the residue was purified by flash chromatography on 75 g of silica gel, eluting with 4:1 hexane-ethyl acetate giving 0.627 g (88%) of the title compound as a white solid, mp 47°-48° C.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[S:7]1[C:11]2S[CH:13]=[CH:14][C:10]=2[CH2:9][CH2:8]1.C(Cl)CCC>O.CO>[S:3]1(=[O:5])(=[O:2])[C:11]2[S:7][CH:8]=[CH:9][C:10]=2[CH2:14][CH2:13]1
Reactant: c1cc2c(s1)SCC2
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCCCCl
Product: O=S1(=O)CCc2ccsc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
A solution of Oxone® (570 g, 0.92 mol) in H2O (2 L) was added to a stirred solution of 2,3-dihydrothieno[2,3-b]thiophene (44 g, 0.31 mol) in methanol (1 L). The reaction was stirred for 1.5 h at room temperature, and then extracted with ethyl acetate (5×1 L). The combined extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give a soft solid. This was treated with n-butyl chloride and filtered to give the title compound as a light tan solid (35 g, 65%). 1H NMR (300 MHz,DMSO-d6) 3.30(2H,t), 3.95(2H,t), 7.10(1H,d), 8.05(1H,d).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:20]1([C:26]2[N:27]=[C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([N:34]2[CH2:35][CH2:36][N:31]([C:28]3[S:29][CH:30]=[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:27]=3)[CH2:32][CH2:33]2)=[O:19])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: CC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Nc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)cs3)CC2)cc1
Yield: 14.7 %

Procedure:
A solution of 2,2,2-trichloroethyl [4-(acetylamino)phenyl]carbamate (200 mg, 0.614 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (150 mg, 0.614 mmol), diisopropylethylamine (0.107 ml, 0.614 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate to obtain the desired product (38.0 mg, 14.7%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[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[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: Nc1ccccc1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and aniline.
Reaction SMILES: C([C:4]1O[C:6](C(O)=O)=[CH:7][C:8](=[O:10])[CH:9]=1)(O)=O.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>CO>[CH:14]1([N:17]2[CH:4]=[CH:9][C:8](=[O:10])[CH:7]=[CH:6]2)[CH2:16][CH2:15]1
Reactant: NC1CC1
Reactant: O=C(O)c1cc(=O)cc(C(=O)O)o1
Solvent: CO
Product: O=c1ccn(C2CC2)cc1

Procedure:
The starting material may be obtained as follows. A solution of 2,6-dicarboxy-4-pyrone (10.0 g.) and cyclopropylamine (3.8 ml.) in MeOH (300 ml.) was stirred at room temperature overnight. The precipitated salt was filtered off, dried under vacuum and heated to 200° for 30 minutes. The resulting black gum was extracted with methylene chloride (3×150 ml.). The extracts were concentrated and purified by chromatography on Kieselgel 60 (100 g.) using methylene chloride/MeOH 100:0 to 80:20 v/v to give 1-cyclopropyl-4-pyridone (1.26 g.) as an oil having n.m.r. in CDCl3 :-1.03(m, 4H); 3.38(m, 1H); 6.3(d, 2H); 7.4(d, 2H). This material was chlorinated as described in the second part of Example 56 to give 4-chloro-1-cyclopropylpyridinium toluene-p-sulphonate.
Reaction SMILES: [C:1](O[K])([CH3:4])(C)C.[N+:7]([C:10]1[N:11]=[CH:12][NH:13][CH:14]=1)([O-:9])=[O:8].Br[CH2:16][CH2:17]Br>CN(C=O)C>[N+:7]([C:10]1[N:11]=[CH:12][N:13]([CH2:16][CH2:17][N:11]2[CH:4]=[C:1]([N+:7]([O-:9])=[O:8])[N:13]=[CH:12]2)[CH:14]=1)([O-:9])=[O:8]
Reactant: CC(C)(C)O[K]
Reactant: BrCCBr
Reactant: O=[N+]([O-])c1c[nH]cn1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cn(CCn2cnc([N+](=O)[O-])c2)cn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
tBuOK (5 g, 44 mmol) was added in portions to a suspension of 4-nitroimidazole in anhydrous DMF (100 mL) at 0° C., then the reaction mixture was stirred at r. t. for 3 h, a solution of 1,2-dibromoethane in anhydrous DMF (20 mL) was added into the above mixture. The reaction solution was stirred at r. t. for 3 days, and was poured into ice-water (200 mL) for standing up for 2 h, then filtered. The filtered cake was washed with EtOH/CH2Cl2 (1/1) and dried to provide 64 (2.3 g, 45%) as off-white solid, which was pure enough to be used next step.
Reaction SMILES: [C:1](OC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]([NH2:14])[CH2:12][NH2:13]>>[C:2]1([C:1]2[NH:13][CH2:12][CH2:11][N:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1
Reactant: NCCN
Product: c1ccc(C2=NCCN2)cc1
Yield: 95 %

Procedure:
The procedure described in Example 5 is followed except that 272 parts of methyl benzoate and 132 parts of ethylenediamine are employed. 277 parts of 2-phenylimidazoline (95% of theory, based on methyl benzoate employed) of boiling point 295° C./1,013 mbar are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:31](=[O:33])[NH2:32]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:23][C:24]([OH:26])=[O:25])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:31](=[O:33])[NH2:32]
Reactant: CC(C)(C)OC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2Cc1ccccc1Cl
Yield: 98.9 %

Procedure:
A solution of the {9-[(2-chlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester (46 mg, 0.1 mM) in 3 mL of trifluoroacetic acid was stirred at room temperature for 2 hours. The solvent was removed in vacuo. The residue was triturated with diethyl ether/hexanes, then dried in vacuo to afford 40 mg (98%) of the {9-[(2-chlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid as a white powder. 1H NMR (DMSO-d6) δ 12.9 (br s, 1H), 7.55 (s, 1H), 7.5 (d, 1H, J=8 Hz), 7.45 (s, 1H), 7.4-7.3 (m, 3H), 7.25 (t, 1H, J=8 Hz), 7.1-7.0 (m, 3H), 6.6 (d, 1H, J=8 Hz), 6.3 (d, 1H, J=8 Hz), 5.7 (s, 2H), and 4.8 (s, 2H). IR (KBr, cm−1) 3430, 1735, and 1635. MS (ES) m/e 407, 409.
Reaction SMILES: [C:1]([O:5]C)(=[O:4])[CH:2]=[CH2:3].[OH:7][CH2:8][CH2:9][C:10]1[NH:11][CH:12]=[CH:13][N:14]=1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.COC1C=CC(O)=CC=1>>[C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[OH:7][CH2:8][CH2:9][C:10]1[NH:11][CH:12]=[CH:13][N:14]=1
Reactant: C=CC(=O)OC
Agent: COc1ccc(O)cc1
Agent: OCCc1ncc[nH]1
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=CC(=O)O

Procedure:
At a temperature of 60° C., methyl acrylate (MA) and hydroxyethylimidazole (HEI) in a molar ratio of 5:1 were heated in the presence of 50 ppm of phenothiazine, 500 ppm of hydroquinone monomethyl ether and 1.25 mol % of a catalyst (based on hydroxyethylimidazole) for 5 h.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[F:28][C:29]1[C:35]([F:36])=[CH:34][C:32]([NH2:33])=[C:31]([O:37][CH3:38])[CH:30]=1>CCCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:6]([C:11]([NH:33][C:32]2[CH:34]=[C:35]([F:36])[C:29]([F:28])=[CH:30][C:31]=2[O:37][CH3:38])=[O:12])=[CH:7][N:8]=[CH:9][CH:10]=1
Reactant: COc1cc(F)c(F)cc1N
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(F)c(F)cc1NC(=O)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and 4,5-difluoro-2-methoxyaniline (commercially available; CAS RN 1017779-71-3) and using a gradient of n-heptane:ethyl acetate (100:0 to 40:60) for the chromatographic purification. White solid (80%). MS (ESI): m/z=425.027 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C[NH:13][CH2:14][CH2:15][CH3:16].O.[C:18](#N)C>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[NH:13][CH2:14][CH2:15][CH3:16])=[C:4]([CH3:18])[N:3]=1
Reactant: CCCNC
Reactant: CC#N
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Solvent: O
Product: CCCNn1cnc2c(C)nc(N)nc21
Temperature: 75 °C
Reaction time: 24 h

Procedure:
2-Amino-6-chloropurine (Sigma, lot #69F4064, 6.0 g, 35.4 mmol) was suspended in 75mL acetonitrile. N-Methylpropylamine (Aldrich, lot #00923AW. 10.0 g, 136.7 mmol) was added and the reaction stirred at 75° C. for 24 hours. The solvents were evaporated to give an oil. Stirring the oil with water yielded a solid which was filtered and dried to give 5.9 g (28.6 mmol, 81%); mp=181°C.
Reaction SMILES: [C:1]12([CH2:11][C:12](O)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1)[NH2:20]>>[CH3:25][O:24][C:22]1[CH:21]=[C:19]([NH:20][C:12](=[O:13])[CH2:11][C:1]23[CH2:8][CH:7]4[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]4)[CH2:10]2)[CH2:2]3)[CH:18]=[C:17]([O:16][CH3:15])[CH:23]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Product: COc1cc(NC(=O)CC23CC4CC(CC(C4)C2)C3)cc(OC)c1
Yield: 82.6 %

Procedure:
Prepared according to the method of Example 39 from 1-adamantaneacetic acid (3.0 g) and 3,5-dimethoxyaniline (3.0 g) to give the title compound as a white solid (4.2 g).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:40]>C(OCC)(=O)C.CC(O)C>[ClH:40].[F:1][C:2]1[C:3]([CH2:24][NH:25][CH3:26])=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(F)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cccc(F)c2)c(-c2cccnc2F)c1F
Reaction time: 3 h
Yield: 61 %

Procedure:
Tert-butyl ({4-fluoro-1-[(3-fluorophenyl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}methyl)methylcarbamate (527 mg) was dissolved in ethyl acetate (5 mL) and 2-propanol (3 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) was added at room temperature. The reaction mixture was stirred for 3 hr and concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 255 mg, 61%).