Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]CCCC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:25][S:26](O)(=[O:28])=[O:27]>C(Cl)(Cl)Cl>[CH2:7]([C:1]1[CH:6]=[CH:5][C:4]([S:26]([Cl:25])(=[O:28])=[O:27])=[CH:3][CH:2]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=S(=O)(O)Cl
Reactant: CCCCCCCCCCCCCCCCCCc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 68 %

Procedure:
To a solution of 1-phenyloctadecane (0.69 g, 2.5 mmol) in CHCl3 (5 mL) was added chlorosulfonic acid (0.5 mL, 7.5 mmol) and the mixture was stirred at rt for 22 h. The mixture was poured on ice and extracted with CH2Cl2. The combined extracts were washed with water, a solution of NaHCO3, and water, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica gel (70-230 mesh) with hexane/ethyl acetate (49:1) to give the product as a white solid (0.63 g, 1.7 mmol, 68%), mp 32-33° C.; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, 3H, J=7.2 Hz), 1.25 (m, 22H), 1.65 (m, 2H), 2.72 (t, 2H, J=7.8 Hz), 7.42 (d, 2H, J=8.4 Hz), 7.93 (d, 2H, J=8.4 Hz); 13C NMR (75 MHz, CDCl3) 14.1, 22.6, 29.1, 29.3, 29.5, 29.6, 29.7, 30.9, 31.9, 36.0, 126.9, 129.5, 141.7, 151.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[F:63][C:64]([F:72])([F:71])[CH:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:68]1[CH2:69][CH2:70][CH:65]([C:64]([F:72])([F:71])[F:63])[CH2:66][CH2:67]1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: FC(F)(F)C1CCNCC1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCC(C(F)(F)F)CC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 4-trifluoromethyl-piperidine in DMSO at ambient temperature.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16][CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:19][CH2:18][CH2:17][Br:16])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: BrCCCOc1ccc(OCc2ccccc2)cc1
Yield: 41.6 %

Procedure:
A mixture of 4-benzyloxyphenol (50 g), 1,3-dibromopropane (101 g) and powdered anhydrous potassium carbonate (17.3 g) in acetone (500 ml) was stirred under reflux for 30 hours. The solids were removed by filtration and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in 300 ml of dichloromethane and the resulting solution was washed with 10% sodium hydroxide solution to remove unreacted p-benzyloxyphenol. The dichloromethane extract was dried over potassium carbonate, concentrated in vacuo and distilled giving 33.4 g of 1-benzyloxy-4-(3-bromopropoxy)benzene; bp 180°-195° (0.6 mm) (41% yield, 98% pure by gas chromatography). The structure was confirmed by mass spectrum analysis.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.C=O.[C:13]([O-])(=[O:15])C.[NH4+].[CH3:18][C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[C:21]([CH3:26])[C:20]=1[OH:27]>C(O)(=O)C>[CH3:25][C:24]1[C:19]([CH3:18])=[C:20]([OH:27])[C:21]([CH3:26])=[CH:22][C:23]=1[CH:13]=[O:15]
Reactant: CC(=O)[O-]
Reactant: Cc1ccc(C)c(O)c1C
Agent: C1N2CN3CN1CN(C2)C3
Agent: C=O
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1cc(C=O)c(C)c(C)c1O
Temperature: 120 °C
Yield: 75 %

Procedure:
Instead of hexamethylenetetramine as applied in Example 2A and 2B, formaldehyde and ammonium acetate in acetic acid were used for formylation as illustrated below. A 250 ml three neck round bottom flask equipped with a reflux condenser was charged with 20.4 g (0.15 mol) of 2,3,6-trimethylphenol. 100 ml acetic acid, 3.09 g (0.04 mol) of ammonium acetate and 3.243 g (0.04 mol) of formalin solution were added to it. The reaction mass was heated at 120° C. over a period of 2.5 hrs. The completion of reaction was confirmed by TLC. The reaction mass was poured into 400 ml ice cold water with stirring. The solid was filtered and washed with 2×50 ml process water. The product was dried under vacuum to afford 17 g (75%) of crude 2,3,5-trimethyl-4-hydroxy-benzaldehyde. The purification of crude product with 1% sodium hydroxide solution afforded 13 g (53%) of pure 2,3,5-trimethyl-4-hydroxyl-benzaldehyde.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([NH:11][NH2:12])[N:8]=[N:7][C:6]=1[Cl:13])([CH3:4])([CH3:3])[CH3:2].[Cl:14][CH:15]([Cl:19])[C:16](O)=O>C1(C)C=CC=CC=1>[C:1]([C:5]1[C:6]([Cl:13])=[N:7][N:8]2[C:16]([CH:15]([Cl:19])[Cl:14])=[N:12][N:11]=[C:9]2[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NN)nnc1Cl
Reactant: O=C(O)C(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc2nnc(C(Cl)Cl)n2nc1Cl
Yield: 74 %

Procedure:
4-t-Butyl-3-chloro-6-hydrazinopyridazine (9.5 g, 48 mmol) and dichloroacetic acid (20 ml) were heated in toluene (130 ml) under Dean Stark conditions for 2.5 hours. The toluene was removed and the residue was poured into water to precipitate the product as a brown solid. The product was purified by chromotography on silica gel using 10% ethyl acetate/dichloromethane as eluant to yield a yellow solid (10.4 g, 74%), 1H NMR (250 MHz, CDCl3) δ 1.59 (9H, s, t-Bu), 6.01 (1H, s, CH), 8.37 (1H, s, ArH); MS (ES+) m/e 293 [MH]+.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:26][N:27]=2)=[CH:19][CH:18]=1.[C:36](O)(=[O:42])/[CH:37]=[CH:38]/[CH2:39][CH2:40][CH3:41]>CN(C)C1C=CN=CC=1.ClCCl>[C:36]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[S:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:26][N:27]=2)=[CH:21][CH:22]=1)(=[O:42])/[CH:37]=[CH:38]/[CH2:39][CH2:40][CH3:41]
Reactant: CCC/C=C/C(=O)O
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC/C=C/C(=O)Oc1ccc(-c2ncc(CCCCCCCC)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
Dicyclohexylcarbodiimide (0.2 g) is added to a solution of 2-(4-hydroxyphenyl)-5-octylthiazole (0.25 g), (E)-hex-2-enoic acid, (0.1 g) 4-(dimethylamino)pyridine (0.05 g) and dichloromethane (20 cm3) at 0° C. under an atmosphere of nitrogen. The reaction mixture is stirred overnight at room temperature, filtered to remove inorganic material and the filtrate evaporated down. The residue is purified by column chromatography on silica gel using hexane/ethyl acetate (9/1 v/v) as eluent and recrystallisation from hexane to yield 0.15 g of 2-(4-[(E)-hex-2-enoyloxy]phenyl)-5-octylthiazole.
Reaction SMILES: [Mg].II.[Cl:4][C:5]1[CH:6]=[C:7](Br)[CH:8]=[CH:9][C:10]=1[Cl:11].[CH3:13][N:14]1[CH2:19][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH2:16][CH2:15]1.Cl>CCOCC>[CH3:13][N:14]1[CH2:15][CH2:16][CH:17]([C:7]2[CH:8]=[CH:9][C:10]([Cl:11])=[C:5]([Cl:4])[CH:6]=2)[CH:18]([C:20]([O:22][CH3:23])=[O:21])[CH2:19]1
Reactant: COC(=O)C1=CCCN(C)C1
Reactant: Clc1ccc(Br)cc1Cl
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: COC(=O)C1CN(C)CCC1c1ccc(Cl)c(Cl)c1
Temperature: -20 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To magnesium (5.5 g, 229 mmol) and a few crystals of iodine in anhydrous ether (20 mL) was added 3,4-dichlorobromobenzene (46.4 g, 206 mmol) in anhydrous ether (200 mL) at a rate sufficient to keep the reaction at reflux. After the addition was completed the reaction was heated at reflux for another 15 min. The reaction was cooled to −20° C. and arecoline (16 g, 103 mmol) in anhydrous ether (200 mL) was added over 20 min while keeping the temperature at −20° C. The reaction was stirred for another 2 hour at −20° C. and then heated to 0° C. Hydrochloric acid (4 N, 80 mL) was added and the pH adjusted to 1 using concentrated hydrochloric acid. The organic phase was separated off and the pH adjusted to 9 with concentrated ammonia. Extraction with ether (2×200 mL)afforded 24.6 g of the title compound as a brownish oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:10]=1[OH:19])([CH3:8])([CH3:7])[CH3:6].Cl>C(Cl)Cl>[CH3:16][C:15]([C:11]1[CH:12]=[C:13]([C:1](=[O:3])[CH3:2])[CH:14]=[C:9]([C:5]([CH3:8])([CH3:7])[CH3:6])[C:10]=1[OH:19])([CH3:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: Cl
Solvent: ClCCl
Product: CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: -4 °C

Procedure:
Under a nitrogen atmosphere, 6.89 ml of acetylchloride and 14.75 ml of stannic chloride were dissolved in 200 ml of methylene chloride and chilled to -4° C. To this was added 20 g of 2,6-di-t-butylphenol (in 100 ml of methylene chloride) over 10 minutes. The resultant mixture was stirred for 30 minutes at 0° C., then poured into a mixture of 400 ml of ice and 1N hydrochloric acid and stirred. The mixture separated into layers which were subsequently separated. The organic layer was washed with 100 ml of saturated sodium bicarbonate and 100 ml of brine. The organic layer was dried and the solvent evaporated to give 23.39 g of the desired subtitled intermediate.
Reaction SMILES: C[C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11](C(F)(F)F)=[CH:10][N:9]=2)[CH2:3]1.[Br:18]C1C=CC(Br)=CN=1>>[Br:18][C:11]1[CH:12]=[CH:13][C:8]([N:4]2[CH2:5][CH2:6][NH:7][CH2:2][CH2:3]2)=[N:9][CH:10]=1
Reactant: C[C@@H]1CN(c2ccc(C(F)(F)F)cn2)CCN1
Reactant: Brc1ccc(Br)nc1
Product: Brc1ccc(N2CCNCC2)nc1
Yield: 73 %

Procedure:
The title compound was prepared following the procedure of the Intermediate 15, but starting from 2,5-dibromopyridine. Purification by chromatography (DCM/MeOH 80/20) gave the title compound as a brown powder (73%). M+(ESI): 244.2. HPLC (Condition A), Rt: 1.1 min (HPLC purity: 79.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:15]3[CH:24]=[CH:23][NH:22][C:16]=3[C:17](=[O:21])[N:18]([CH3:20])[CH:19]=2)=[O:7])=[CH:4][CH:3]=1.FC(F)(F)CS(NC1C=CC(OC2CCCOC2)=C(C2C3C=CNC=3C(=O)N(C)C=2)C=1)(=O)=O>O1CCCC1>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH:6]([OH:7])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:15]3[CH:24]=[CH:23][NH:22][C:16]=3[C:17](=[O:21])[N:18]([CH3:20])[CH:19]=2)=[CH:4][CH:3]=1
Reactant: Cn1cc(-c2ccccc2C(=O)c2ccc(Cl)cc2)c2cc[nH]c2c1=O
Agent: Cn1cc(-c2cc(NS(=O)(=O)CC(F)(F)F)ccc2OC2CCCOC2)c2cc[nH]c2c1=O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccccc2C(O)c2ccc(Cl)cc2)c2cc[nH]c2c1=O
Yield: 83.3 %

Procedure:
A mixture of Example 139 (0.05 g, 0.138 mmol) and sodium tetrahydroborate (2) (5.21 mg, 0.138 mmol) in tetrahydrofuran (2 mL) was heated at 60° C. for 3 hours. The solvent was removed, and the residue was purified by reverse phase Preparative HPLC (10-80% acetonitrile in 0.1% TFA/water) to give the title compound (0.042 g, 0.115 mmol, 84% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.70 (s, 1H), 7.56 (d, J=7.63 Hz, 1H), 7.35-7.39 (m, 1H), 7.27-7.31 (m, 1H), 7.21-7.23 (m, 4H), 7.00 (d, J=8.54 Hz, 2H), 6.79 (s, 1H), 5.94 (t, J=2.29 Hz, 1H), 5.75 (s, 1H), 3.47 (s, 3H). MS (DCI+) m/z 365.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:20])[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:21]([F:24])([F:23])[F:22])[N:3]=1.C[NH:26][NH2:27]>C1COCC1>[NH:26]([C:2]1[N:7]=[C:6]([N:8]([CH3:20])[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:21]([F:24])([F:23])[F:22])[N:3]=1)[NH2:27]
Reactant: CN(c1ccc(OC(F)(F)F)cc1)c1cc(C(F)(F)F)nc(Cl)n1
Reactant: CNN
Solvent: C1CCOC1
Product: CN(c1ccc(OC(F)(F)F)cc1)c1cc(C(F)(F)F)nc(NN)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.5 %

Procedure:
To a solution of XXVIII (475 mg, 1.28 mmol) in dry THF (3 mL) was added methylhydrazine (273 μL, 5.13 mmol). The resulting solution was stirred at room temperature for 18 hrs, the solvent removed in vacuo and the residue taken up in CH2Cl2. The CH2Cl2 solution was washed with H2O, dried over MgSO4, filtered and CH2Cl2 evaporated in vacuo to afford XIX as a yellow oil (0.43 g, 88%): 1H NMR (DMSO-d6) δ 7.48 (app s, 2H), 7.47 (app s, 2H), 5.84 (s, 1H), 4.86 (bs, 2H), 3.42 (s, 3H), 3.19 (s, 3H); ESIUMS 381 (M+H), 366 (M−CH3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[S:13][CH:14]=[CH:15][N:16]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[CH:4][CH:3]=1
Reactant: Brc1nccs1
Reactant: OB(O)c1ccc(F)cc1
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: CCO
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2nccs2)cc1
Temperature: 95 °C
Reaction time: 5 h
Yield: 82.5 %

Procedure:
To a stirred solution of (4-fluorophenyl)boronic acid (10 g, 60.9 mmol) in toluene (70 mL) and ethanol (200 mL) was added 2-bromothiazole (12.7 g, 91.4 mmol) and Na2CO3 (2M, 100 mL, 19.39 g). The reaction mixture was purged with argon for 45 min, Pd(PPh3)4 (3.5 g, 3.04 mmol) added, and the mixture stirred at 95° C. for 5 h. The reaction mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution (2×100 mL), and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with ice-cold water (2×100 mL), followed by brine solution (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography (100-200 mesh silica gel; using 10% ethyl acetate in hexane) to obtain 2-(4-fluorophenyl)thiazole as white solid (9.0 g, 82% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.98 (dd, 2H), 7.88 (d, 1H); 7.91 (d, 1H), 7.88 (d, 1H), 7.31 (t, 2H); LC-MS m/z calculated for [M+H]+ 180.02 found 179.91.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[NH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:8][C:6]1[NH:5][C:4]2[C:3]([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)=[C:2]([NH:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:7]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: NCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(NCCN2CCOCC2)c2nc(-c3ccccc3)cc-2[nH]1
Yield: 43.4 %

Procedure:
This compound was prepared according to the method described in Example 26 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (0.10 g, 0.41 mmol), 4-(2-aminoethyl)morpholine (Aldrich Chemical Company) (0.270 g, 2.06 mmol) and K2CO3 (0.36 g, 2.60 mmol) in H2O (2.5 mL) to give crude pink solids. Recrystallization from EtOAc/MeOH gave 0.060 g (43%) of the title compound as a white solid. Mp: >280° C. 1H NMR (DMSO-d6; 500 MHz): δ 2.39 (s, 3), 3.61 (t, 4, J=4.5), 3.65 (q, 2, J=6.1), 4.04 (s, 2), 6.75 (s, 1), 6.81 (br s, 1), 7.38 (t, 1, J=7.4), 7.51 (t, 2, J=7.6), 7.78 (d, 2, J=7.6), 11.39 (s, 1). 13C NMR (CD3OD, 100 MHz): δ 26.3, 39.2, 55.9, 60.1, 68.8, 99.9, 127.3, 128.3, 130.6, 131.2, 134.0, 143.1, 149.8, 151.1, 161.5. MS m/z: 338 (M+1). Anal. Calcd for C19H23N5O. 0.25H2O: C, 66.74; H, 6.93; N, 20.48. Found: C, 66.84; H, 6.83; N, 20.39.
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:12].Cl.[N:14]1([CH2:20][C@@H:21]([C:33]2([OH:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CO>[ClH:12].[ClH:12].[C:1]1([CH:7]([CH3:11])[CH2:8][CH2:9][N:17]2[CH2:18][CH2:19][N:14]([CH2:20][C@@H:21]([C:33]3([OH:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=3)[CH2:15][CH2:16]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC1([C@H](CN2CCNCC2)c2cccc(OC(F)(F)F)c2)CCCCC1
Reactant: CC(CC=O)c1ccccc1
Agent: Cl
Solvent: CO
Product: CC(CCN1CCN(C[C@H](c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)CC1)c1ccccc1

Procedure:
In an analogous manner to Example 117, 1-{(1S-2-[4-(3-phenylbutyl)piperazin-1-yl]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride was prepared from 3-phenylbutyraldehyde and 1-{(1S)-2-piperazin-1-yl-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol (See Example 243). HRMS: calcd for C29H39F3N2O2, 504.29636; found (ESI, [H+M]+), 505.3025. [α]D25=−12° (c=0.0091 g/mL, MeOH); CD=+@268 nm.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:10]1[CH:14]=[C:13]([CH:15]=[O:16])[N:12]=[CH:11]1)[CH2:8][CH3:9].[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.O>[CH2:7]([N:10]1[CH:14]=[C:13]([CH2:15][OH:16])[N:12]=[CH:11]1)[CH2:8][CH3:9]
Reactant: CCCn1cnc(C=O)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCCn1cnc(CO)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of LAH (2.0 M in THF, 1.9 ml, 3.882 mmol) in THF (10 ml) was added dropwise a solution of 1-propyl-1H-imidazole-4-carbaldehyde (487 mg, 3.529 mmol) in THF (4 ml) at 0° C. After stirred at 0° C. for 5 min, water (0.2 ml), 15% NaOH (0.2 ml) was added dropwise to the reaction mixture under 0° C. The mixture was further stirred at room temperature for 2 hours. MgSO4 was added to the mixture and the solid was filtered away and the filtrate was concentrated in vacuo to get a yellow oil and used without further purification.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[N+:12]([O-])=O)[CH3:2].Cl>C(O)C>[CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[NH2:12])[CH3:2]
Reactant: CCNCc1cc(Br)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: CCNCc1cc(Br)ccc1N

Procedure:
Stannous chloride dihydrate (22.5 g, 0.1M) was added in one portion to .a stirred mixture of N-ethyl-5-bromo-2-nitrobenzylamine (8.5 g, 32.8 mmol) and 36% hydrochloric acid (20 ml, 0.22M) in ethanol (250 ml) at ambient temperature. There was an exothermic reaction (50° C.) and a yellow solution formed, which was stirred for 1 hour allowing it to cool. The solvent was evaporated at reduced pressure and the residue dissolved in ethanol (100 ml) and stirred while diluting with ether (200 ml) until crystallisation occurred. The yellow solid was filtered off and washed with ether to give N-ethyl-5-bromo-2-aminobenzylamine as a salt, from which the free base was isolated by stirring with 2N sodium hydroxide solution (150 ml) and extracting into ether. The organic layer was dried over anhydrous magnesium sulphate and evaporated to give an oil (4.2 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]([N:40]5[CH2:45][CH2:44][O:43][CH2:42][C@H:41]5[CH3:46])=[O:39])=[CH:34][N:33]=4)[C:28](=[O:47])[N:27]([CH3:48])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.ClCCl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]([N:40]5[CH2:45][CH2:44][O:43][CH2:42][C@H:41]5[CH3:46])=[O:39])=[CH:34][N:33]=4)[C:28](=[O:47])[N:27]([CH3:48])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@@H]1COCCN1C(=O)c1ccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: C[C@@H]1COCCN1C(=O)c1ccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A solution of 132d (120 mg, 0.18 mmol) in methanol/dichloromethane (4/4 mL) was added NaBH4 (15 mg, 0.60 mmol). The mixture was stirred at room temperature for 1 h and quenched with water (2 mL). It was then evaporated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 132 (60 mg, 50%) as a white solid. MS-ESI: [M+H]+ 654.3. 1H NMR (500 MHz, MeOD-d4) δ 8.94 (d, J=2.5 Hz, 1H), 8.61 (d, J=5.0 Hz, 1H), 8.51 (d, J=2.5 Hz, 1H), 8.35 (d, J=2.0 Hz, 1H) 7.88 (d, J=1.5 Hz, 1H), 7.75 (d, J=1.5 Hz, 1H), 7.72-7.69 (m, 1H), 7.65 (d, J=5.0 Hz, 1H), 7.61 (d, J=2.5 Hz, 1H), 7.13 (d, J=7.5 Hz, 1H), 4.62-4.58 (m, 2H), 4.36-4.31 (m, 1H), 3.61-3.84 (m, 2H), 3.71-3.67 (m, overlap, 5H), 3.56-3.47 (m, 2H), 1.47 (s, 9H), 1.39 (d, J=7.0 Hz, 3H).
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[OH:8].[Cl:9][C:10]1[C:11](F)=[CH:12][C:13]([F:23])=[C:14]([CH:22]=1)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.C(OCC)(=O)C>[C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[O:8][C:11]1[C:10]([Cl:9])=[CH:22][C:14]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[C:13]([F:23])[CH:12]=1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: O[C@H]1C[C@@H]2CC[C@H]1C2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(O[C@H]2C[C@@H]3CC[C@H]2C3)cc1F
Temperature: 80 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
A mixture of (1S,2S,4R)-bicyclo[2.2.1]heptan-2-ol (1.0 g, 8.92 mmol), tert-butyl 5-chloro-2,4-difluorobenzoate (2.88 g, 11.60 mmol), and cesium carbonate (5.81 g, 17.84 mmol) in anhydrous dimethylsulfoxide (12 mL) was heated in a sealed tube at 80° C. for 18 hours, then at 115° C. for 1 hour. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (80 mL), washed with water (30 mL), saturated ammonium chloride (40 mL) and brine (40 mL); dried over anhydrous sodium sulfate; filtered and concentrated in vacuo. The residue was triturated with methanol to provide the title compound (0.76 g, 25%): 1H NMR (300 MHz, CDCl3) δ 7.84 (d, J=7.5 Hz, 1H), 6.57 (d, J=12.4 Hz, 1H), 4.22-4.17 (m, 1H), 2.51-2.46 (m, 1H), 2.38-2.31 (m, 1H), 1.83-1.67 (m, 2H), 1.66-1.58 (m, 1H), 1.56 (s, 9H), 1.52-1.42 (m, 2H), 1.26-1.09 (m, 3H); MS (ES+) m/z 285.0, 287.0 (M-55).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:21](O)=[O:22]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:21]([C:20]2[CH:19]=[C:18]([Cl:17])[CH:26]=[C:25]([Cl:27])[CH:24]=2)[OH:22])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1cc(Cl)cc(Cl)c1)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 3,5-dichlorobenzoic acid