Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:29])([C:25]([F:28])([F:27])[F:26])[C:3]([F:24])([F:23])[C:4]([P:7]([C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])(=O)[OH:8])([F:6])[F:5].C1(P(Cl)(Cl)(Cl)[Cl:37])C=CC=CC=1>C(Cl)(Cl)Cl>[F:1][C:2]([F:29])([C:25]([F:28])([F:27])[F:26])[C:3]([F:24])([F:23])[C:4]([P:7]([Cl:37])([C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])=[O:8])([F:6])[F:5]
Reactant: O=P(O)(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: ClP(Cl)(Cl)(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=P(Cl)(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 0.83 h
Yield: 62.2 %

Procedure:
Variant a) 2.49 g (5.0 mmol) of bis(nonafluorobutyl)phosphinic acid are added dropwise at room temperature to a solution of 1.47 g (5.9 mmol) of phenyltetrachlorophosphorane in 3 cm3 of dry chloroform, and the mixture is stirred for a further 50 minutes. Chloroform is separated off by distillation, and bis(nonafluorobutyl)phosphinyl chloride is distilled off at atmospheric pressure, giving 1.62 g of bis(nonafluorobutyl)phosphinyl chloride, which corresponds to a yield of 63%, based on the phosphinic acid employed.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2cc[nH]c2c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)NCC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
6-Methyl indole (0.50 g, 3.8 mmol) was dissolved in glacial acetic acid (19.1 mL) and cooled to 0° C. Sodium cyanoborohydride (0.48 g, 7.6 mmol) was added portionwise and the mixture warmed to ambient temperature and stirred for 2 h. The reaction was diluted with water (8.0 mL), made alkaline with 40% aqueous NaOH and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (3×30 mL), dried over sodium sulfate, filtered and concentrated. Purification by column chromatography on silica gel (gradient elution, 0-100% EtOAc/petrol), gave the title compound (0.256 g, 51%) as a purple oil. 1H NMR (Me-d3-OD): 6.96 (1H, d), 6.53 (2H, d), 3.44 (2H, t), 2.94 (2H, t), 2.23 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[C:16]([N:21]2[C:25]([C:26](O)=O)=[CH:24][C:23]([C:29]([F:32])([F:31])[F:30])=[N:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>C(#N)C>[Cl:14][C:15]1[C:16]([N:21]2[C:25]([C:26]3[O:12][C:11](=[O:13])[C:10]4[C:2](=[CH:3][CH:4]=[C:5]5[CH:6]=[CH:7][NH:8][C:9]5=4)[N:1]=3)=[CH:24][C:23]([C:29]([F:32])([F:30])[F:31])=[N:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccc2cc[nH]c2c1C(=O)O
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2ccc3cc[nH]c3c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.4 %

Procedure:
To a suspension of 79 mg (0.45 mmol) of 6-amino-1H-indole-7-carboxylic acid in 7 mL of acetonitrile, is added 130 mg (0.45 mmol) of 2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid followed by 0.16 mL (2.06 mmol) of pyridine. The mixture is stirred at ambient temperature during 30 minutes. Then the suspension is cooled to 0° C. and 0.12 mL (1.57 mmol) of methanesulfonyl chloride is added dropwise. The mixture is stirred at 0° C. during 30 minutes and 2 hours at ambient temperature. After evaporation of the solvent, the residue is triturated with a minimum of cold water. The precipitate which is formed is filtrated and washed with cold water. The residue is then purified by column chromatography on silica gel with hexanes and ethyl acetate as eluents and 47.1 mg (0.11 mmol, 25%) of a yellowish solid are obtained; LC/MS:432/434 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([S:18][C:19]3[CH:20]=[C:21]([C:25]([OH:30])([CH2:28][CH3:29])[CH2:26][CH3:27])[CH:22]=[CH:23][CH:24]=3)=[CH:7][CH:8]=2)[N:3]=1.Cl[CH2:32][CH:33]=O.C(=O)(O)[O-].[Na+].O>O1CCOCC1>[C:12]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([S:18][C:19]4[CH:20]=[C:21]([C:25]([OH:30])([CH2:28][CH3:29])[CH2:26][CH3:27])[CH:22]=[CH:23][CH:24]=4)=[CH:7][CH:8]=3)[N:3]3[CH:32]=[CH:33][N:1]=[C:2]3[CH:11]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=CCCl
Reactant: CCC(O)(CC)c1cccc(Sc2ccc3c(-c4ccccc4)cc(N)nc3c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCC(O)(CC)c1cccc(Sc2ccc3c(-c4ccccc4)cc4nccn4c3c2)c1
Temperature: 80 °C

Procedure:
To 10q (200 mg, 0.48 mmol) in 1,4-dioxane (4 mL) was added chloroacetaldehyde (0.07 mL, 0.53 mmol), sodium bicarbonate (243 mg, 2.89 mmol), and water (2 mL). The mixture was heated to 80° C. for 5 hours, and then cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (30% EtOAc in hexanes) to give the desired product, 10r.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:16][C:17]1[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20].O>C1COCC1>[CH3:22][O:21][C:19]([C:18]1[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=1[CH2:16][S:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1)=[O:20]
Reactant: COC(=O)c1ccccc1CBr
Reactant: O=C(O)CCc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1CSc1ccc(CCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
3-(4-Mercaptophenyl)propanoic acid (2.0 g, 10.97 mmol) was dissolved in dry THF (60 ml) and cooled to 0° C. Sodium hydride (0.64 g, 24.1 mmol) was added. The mixture was stirred for 30 minutes, methyl 2-(bromomethyl)benzoate (2.77 g, 12.07 mmol) dissolved in dry THF (10 ml) was added dropwise. The solution was allowed to warm up to room temperature and was stirred overnight. Dropwise addition of water (10 ml) deactivated the remaining sodium hydride. The solvent was removed by evaporation, and the residue was acidified to pH 3 (HCl 1%). The water phase was washed with EtOAc (3×10 ml). The organic phases was combined, dried (MgSO4) and evaporated. The crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions was pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two potions of brine and dried (MgSO4). Removing the solvent by evaporation gave 2.26 gram of 3-(4-{[2-(methoxycarbonyl)benzyl]thio}phenyl)propanoic acid (yield 62.3%).
Reaction SMILES: [Cl:1][C:2]1C=CC2SC(CCl)=NC=2[CH:12]=1.[C:13]([NH:21][NH2:22])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:1][CH2:2][C:12]1[O:20][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:21][N:22]=1
Reactant: ClCc1nc2cc(Cl)ccc2s1
Reactant: NNC(=O)c1ccccc1
Product: ClCc1nnc(-c2ccccc2)o1

Procedure:
2-Chloromethyl-5-phenyl-[1,3,4]oxadiazole was prepared similarly to 5-chloro-2-chloromethyl-benzothiazole using benzoic acid hydrazide as the reagent.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:5])[CH3:4].Cl[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]>C1C=CC=CC=1>[CH2:10]([O:9][C:7]([NH:1][CH2:2][C@@H:3]([OH:5])[CH3:4])=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H](O)CN
Solvent: c1ccccc1
Product: C[C@H](O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-1-amino-2-propanol (9.76 g, 130 mmol)in anhydrous benzene (60 mL) at 0° C. was added benzyl chloroformate (10.23 g, 60 mmol) in anhydrous benzene (120 mL) slowly, in portions, over a period of 20 min while vigorously stirring under an atmosphere of nitrogen. The mixture was stirred for 1 hour at 0° C., then allowed to warm to room temperature and stirred for a further 2 hours. The mixture was washed with water (2×) and brine (2×) before the organic layer was dried over anhydrous MgSO4. Evaporation of all solvent gave the title product as an oil. 1H NMR (CDCl3) δ 1.22 (d, 3H,) 2.40 (bs, 1H), 3.07 (m, 1H), 3.37 (m, 1H)), 3.94 (m, 1H), 5.16 (s, 2H), 5.27 (m, 1H), 7.38 (m, 5H). MS m/z (electrospray) 232 [M+23]+ (100%), 166 (96).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[CH:5]=[O:6].[Cl:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1>>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:19][C:9]1[C:8]([F:11])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: Oc1cccc(Cl)c1
Reactant: O=Cc1cc(F)c(F)c(F)c1
Product: O=Cc1cc(F)c(Oc2cccc(Cl)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4,5-trifluorobenzaldehyde and 3-chlorophenol.
Reaction SMILES: [C:1]([O:7][CH2:8]C)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH:17]([CH2:23][CH2:24][CH3:25])[C:18]([O:20][CH2:21]C)=[O:19].Cl>CN(C=O)C.O>[C:3]([CH:2]([CH:17]([CH2:23][CH2:24][CH3:25])[C:18]([O:20][CH3:21])=[O:19])[C:1]([O:7][CH3:8])=[O:6])(=[O:4])[CH3:5]
Reactant: CCCC(Br)C(=O)OCC
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)C(C(C)=O)C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.9 %

Procedure:
To a solution of ethyl acetoacetate (64 mL; 504 mmol) in dry DMF (240 mL) under a nitrogen atmosphere was added potassium carbonate (69.6 g; 504 mmol), which has been dried at 120° C. for 12 h before its use. After stirring for 15 minutes at room temperature, ethyl 2-bromovalerate (81.6 mL; 480 mmol) was slowly added under nitrogen and the mixture was vigorously stirred at room temperature for 20 h. The reaction mixture was poured in water (240 mL) and neutralized by adding HCl 2N. The product was extracted with diethyl ether (2×240 mL) and the combined organic layers were dried over magnesium sulphate and concentrated under reduced pressure. The crude yellow oil was purified by distillation under reduced pressure (160° C./6 mbar) to give 61.8 g of the title compound as a colorless liquid (HPLC purity 60%). ESI/APCI(+): 259 (M+H);
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:17]O>>[CH3:17][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Br:11])[CH:9]=[CH:10][C:2]=1[NH2:1]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)ccc1N
Yield: 76 %

Procedure:
2-Amino-5-bromobenzoic acid (80 g, 0.37 mmol) was dissolved in MeOH (600 mL) and a solution of H2SO4 (50 mL) was slowly added. The reaction mixture was refluxed for 72 h, then concentrated. NaOH solution was added to adjust the pH to 10-11. The mixture was extracted with EtOAc (3×500 mL). The combined organic layer was dried over MgSO4, concentrated to afford the desired compound (65 g, yield: 76%) as a colorless oil, which is used directly in the next step without purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[CH2:12][CH:13]([C:16]#[N:17])[C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[CH2:12][C:13]([CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])([C:16]#[N:17])[C:14]#[N:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC(C#N)Cc1cccc(OCc2ccccc2)c1
Reactant: FC(F)(F)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1cccc(OCc2ccccc2)c1
Yield: 40.7 %

Procedure:
Using 0.52 g of (3-benzyloxybenzyl)malononitrile, 5 ml of N,N-dimethylformamide, 0.12 g of sodium hydride (60% in oil), and 0.34 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.28 g of 2-(3-(benzyloxy)benzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (88)).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](F)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH2:12]([O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[CH2:17][CH2:18][NH2:19])[CH3:13].C(N(CC)CC)C>C(O)(C)C>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:19][CH2:18][CH2:17][C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[O:14][CH2:12][CH3:13])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: CCOc1ccccc1CCN
Reactant: Fc1ccc2ncc(Br)n2n1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCOc1ccccc1CCNc1ccc2ncc(Br)n2n1
Temperature: 140 °C
Yield: 90.4 %

Procedure:
A mixture of 3-bromo-6-fluoro-imidazo[1,2-b]pyridazine (648 mg, 3 mmol), 2-ethoxy-phenethylamine (1 g, 6 mmol) and triethylamine (1 ml) in isopropyl alcohol (2 ml) was heated in a microwave at 140° C. for 20 min. The reaction mixture was concentrated and the residue was subjected to ISCO (40 g column), to gave the titled compound (980 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.47 (t, J=6.95 Hz, 3H) 3.04 (t, J=6.69 Hz, 2H) 3.64-3.72 (m, 2H) 4.06-4.17 (m, 2H) 4.97 (br. s., 1H) 6.40 (d, J=9.60 Hz, 1H) 6.87-7.02 (m, 2H) 7.17-7.32 (m, 2H) 7.47 (s, 1H) 7.54 (d, J=9.60 Hz, 1H). LRMS (ESI) m/z 361 and 363.1 [(M+H)]+, calc'd for C16H17BrN4O: 361.24.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11].C(N(C(C)C)CC)(C)C.[C:22]([O:25][CH2:26][C:27](Cl)=O)(=[O:24])[CH3:23]>ClCCl>[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:11]=[C:27]([CH2:26][O:25][C:22](=[O:24])[CH3:23])[NH:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:12]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COC(=O)c1cccc(N)c1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc2[nH]c(COC(C)=O)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a mixture of 2,3-diamino-benzoic acid methyl ester (40.8 mmol) and diisopropylethyl amine (8.5 mL, 49.0 mmol) in dichloromethane (80 mL) at −30° C. was added dropwise a solution of acetoxy acetyl chloride (4.8 mL, 44.9 mmol) in DCM (15 mL). The mixture was allowed to warm to room temperature and stirred overnight. The mixture was quenched with satd. ammonium chloride (50 mL), the layers separated and the aqueous phase extracted with DCM (60 mL). The combined organic layers were washed with brine and dried (MgSO4). The residue after concentration was dissolved in acetic acid (50 mL) and heated at 100° C. for 30 min. The solution was concentrated and purified by flash chromatography (eluent DCM-ethyl acetate 3:1, 2:1, 1:1) to give 2-acetoxymethyl-1H-benzoimidazole-4-carboxylic acid methyl ester (7.3 g, 72% yield over 2 steps) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][NH2:16])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[C:17](OCC)(OCC)(OCC)[CH2:18][CH3:19]>>[CH2:18]([C:19]1[N:5]2[C:6]3[C:11]([N:12]=[C:3]([O:2][CH3:1])[C:4]2=[N:15][N:16]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=3)[CH3:17]
Reactant: COc1ccc2nc(NN)c(OC)nc2c1
Reactant: CCOC(CC)(OCC)OCC
Product: CCc1nnc2c(OC)nc3cc(OC)ccc3n12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture consisting of 4.0 g. (0.018 mole) of 3,6-dimethoxy-2-hydrazinoquinoxaline, the product of Preparation E(d), and 50 ml. of triethyl orthopropionate was heated with mechanical stirring in a preheated oil bath at 100° C. overnight (~16 hours). The resulting reaction mixture was then cooled to room temperature (~20° C.), and the precipitate which formed was subsequently recovered by means of suction filtration and washed with ethanol to ultimately afford 3.3 g. (72%) of pure 4,7-dimethoxy-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 184°-188° C. Mass Spectrum: m/e, 258 (P); m/e, 228 (P-30).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][C:13]([CH2:15][Br:16])=[C:12]([CH2:17]Br)[CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C-:20]#[N:21].[Na+]>CS(C)=O>[C:1]1([CH3:19])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH2:11][C:12]([CH2:17][C:20]#[N:21])=[C:13]([CH2:15][Br:16])[CH2:14]2)(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N2CC(CBr)=C(CBr)C2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)N2CC(CBr)=C(CC#N)C2)cc1
Temperature: 25 °C
Yield: 57.6 %

Procedure:
10 g of N-(p-toluenesulfonyl)-3,4-bis(bromomethyl)-3-pyrroline, prepared in Preparation 5, was dissolved in 10 ml of dimethylsulfoxide (DMSO) and then heated in oil bath for 2 hours with refluxing. During the heating and refluxing, 1.5 g of sodium cyanide was added by small portion. The reaction mixture was cooled to room temperature and poured into ice water and then extracted with methylene chloride (200 ml×3). The extracts were combined, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography. 5 g of the title compound was obtained (yield 57%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)[CH3:5])[CH3:2].[OH-].[Li+].Cl>CO.O>[CH2:1]([O:3][CH:4]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1)[CH3:5])[CH3:2]
Reactant: CCOC(C)c1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOC(C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.5 %

Procedure:
To the solution of methyl 4-(1-ethoxyethyl)benzoate (191 mg, 0.92 mmol) in methanol and water (50 mL/10 mL) was added lithium hydroxide (100 mg, 4.2 mmol), the solution was stirred at room temperature for 12 hours. Then the solution was acidified by hydrogen chloride (1 N/mol) pH to 6, extracted with dichloromethane (80 mL*3), evaporated the solvent to give 4-(1-ethoxyethyl)benzoic acid (167 mg, 93%).
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].[CH3:28][N:29]([CH3:37])[C:30]1[C:31]([NH2:36])=[CH:32][CH:33]=[CH:34][CH:35]=1>>[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:36][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]([CH3:37])[CH3:28])=[O:12])=[CH:7][N:8]=[CH:9][CH:10]=1
Reactant: CN(C)c1ccccc1N
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Product: CN(C)c1ccccc1NC(=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 N,N-dimethylbenzene-1,2-diamine (commercially available, CAS RN 2836-03-5). The compound was purified by preparative HPLC (Phenomenex Gemini column) using a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2). Light brown foam (71%). MS (ESI): m/z=402.078 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:14][CH:13]=1.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([C:4]2[C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=2[OH:10])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:16][CH:17]=1
Reactant: Cc1cc(C)c(O)cc1C
Reactant: O=C(O)CCCCCC(O)c1ccc(F)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(O)c(C(CCCCCC(=O)O)c2ccc(F)cc2)c1C
Reaction time: 6 h
Yield: 85488.3 %

Procedure:
To a solution of 2,4,5-trimethylphenol (2.0 mg) and 7-(4-fluorophenyl)-7-hydroxyheptanoic acid (3.5 g) in toluene (60 ml) was added boron trifluoride ethyl ether (0.56 ml) at 70° C. and the reaction was carried out at the same temperature for 6 hours. After cooling in air, the reaction mixture was extracted by addition of water and ethyl acetate. The organic layer was washed in turn with water and saturated saline and dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate/hexane (1 : 5) and the objective compound was recrystallized from ethyl acetate/hexane to obtain 7-(4-fluorophenyl)-7-(2-hydroxy-3,5,6-trimethylphenyl)heptanoic acid (4.5 g) (Compound 1). The physical properties and spectrum data thereof are shown in Tables 3 and 4.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[CH:9]([CH3:11])[CH3:10].FC(F)(F)C(O)=O.[N:19]1([CH2:23][CH2:24][N:25]2[CH:29]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=3)[N:27]=[C:26]2[CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[N:19]1([CH2:23][CH2:24][N:25]2[CH:29]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([C:37]([F:40])([F:38])[F:39])[CH:31]=3)[N:27]=[C:26]2[CH:41]2[CH2:42][CH2:43][N:44]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=3[CH:9]([CH3:11])[CH3:10])[CH2:45][CH2:46]2)[CH2:20][CH2:21][CH2:22]1
Reactant: CC(C)c1c(N)ncnc1Cl
Reactant: Fc1ccc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Temperature: 120 °C
Reaction time: 96 h
Yield: 34.3 %

Procedure:
A reaction mixture of 6-Chloro-5-isopropyl-pyrimidin-4-ylamine (30.00 mg; 0.17 mmol; 1.00 eq.), 4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine trifluoroacetate (2) (109.16 mg; 0.17 mmol; 1.00 eq.), and Cs2CO3 (227.81 mg; 0.70 mmol; 4.00 eq.) in DMSO 1.0 ml was stirred at 120° C. for 4 days, purified by prep HPLC, collected title compound 31 mg, yield 27.7%. LC-MS: (M+1=532, obsd.=532).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[F:17]C1C=CC=C2C=1NC=C2C1CCNCC=1>>[F:17][C:3]1[CH:2]=[C:10]2[C:6]([C:7]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: Fc1cccc2c(C3=CCNCC3)c[nH]c12
Reactant: Fc1cccc2c(C3CCNCC3)c[nH]c12
Product: Fc1ccc2c(C3CCNCC3)c[nH]c2c1

Procedure:
Similarly prepared was 4-(7-fluoroindol-3-yl)-piperidine from 4-(7-fluoroindol-3-yl)-1,2,5,6-tetrahydropyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][C:7]=1[C:8]#[N:9].Cl[C:21]1[CH:22]=[C:23]2[N:30]([CH3:31])[C@@H:29]([CH3:32])[CH2:28][N:24]2[C:25](=[O:27])[N:26]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:21]2[CH:22]=[C:23]3[N:30]([CH3:31])[C@@H:29]([CH3:32])[CH2:28][N:24]3[C:25](=[O:27])[N:26]=2)=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(F)c(F)c1
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4ccc(F)c(F)c4)c(C#N)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 2-(3,4-difluorophenoxy)-5-(hydroxymethyl)benzonitrile and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH3:20][CH:21]1[CH2:26][NH:25][CH2:24][CH:23]([CH2:27][NH:28][CH3:29])[O:22]1>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:25]3[CH2:26][CH:21]([CH3:20])[O:22][CH:23]([CH2:27][NH:28][CH3:29])[CH2:24]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: CNCC1CNCC(C)O1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC(C)OC(CNC)C3)c(F)c21

Procedure:
By the use of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 6-methyl-2-(methylaminomethyl)morpholine, the reaction is similarly carried out as Example 1 to give 1-ethyl-6,8-difluoro-1,4-dihydro-7-[6-methyl-2-(methylaminomethyl)morpholino]-4-oxoquinoline-3-carboxylic acid.