Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][OH:13])=[CH:6][C:5]=1C.[H-].[Na+].[N+:18]([C:21]1[CH:26]=[C:25]([S:27]([C:30]([F:33])([F:32])[F:31])(=[O:29])=[O:28])[CH:24]=[CH:23][C:22]=1Cl)([O-:20])=[O:19]>>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][O:13][C:22]2[CH:23]=[CH:24][C:25]([S:27]([C:30]([F:32])([F:33])[F:31])(=[O:29])=[O:28])=[CH:26][C:21]=2[N+:18]([O-:20])=[O:19])=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Reactant: COC(=O)c1ccc(OCCO)cc1C
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1ccc(OCCOc2ccc(S(=O)(=O)C(F)(F)F)cc2[N+](=O)[O-])cc1

Procedure:
Using procedure as in Example 10, a reaction of methyl 4-(2-hydroxyethoxy)benzoic acid methyl ester (100 mg, 0.51 mmol), NaH (22 mg, 1.1 equiv.) and 2-nitro-4-(trifluoromethylsulfonyl)chlorobenzene (148 mg, 1 equiv.) afforded 4-[2-(2-nitro-4-trifluoromethanesulfonyl-phenoxy)-ethoxy]-benzoic acid methyl ester. 1HNMR (300 MHz, DMSO-d6) δ 8.64 (d, J=2.5 Hz, 1H), 8.39 (dd, J=2.5 & 8.9 Hz, 1H), 7.89 (d, J=8.8 Hz, 2H), 7.83 (d, J=8.9 Hz, 1H), 7.06 (d, J=8.8 Hz, 2H), 4.76 (m, 2H), 4.46 (m, 2H), 3.80 (s, 3H, OCH3). MS-EI m/z 449 [M+].
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[C:8]([F:9])=[CH:7][C:6]([N+:10]([O-:12])=[O:11])=[C:5](F)[CH:4]=1.[CH3:15][O-:16].[Na+]>>[CH3:1][N:2]([CH3:14])[C:3]1[C:8]([F:9])=[CH:7][C:6]([N+:10]([O-:12])=[O:11])=[C:5]([O:16][CH3:15])[CH:4]=1
Reactant: CN(C)c1cc(F)c([N+](=O)[O-])cc1F
Reactant: C[O-]
Agent: [Na+]
Product: COc1cc(N(C)C)c(F)cc1[N+](=O)[O-]

Procedure:
2.0 g (10 mmol) of 4-dimethylamino-2,5-difluoronitrobenzene (18) is treated with sodium methoxide according to general method F to give Compound 19 after chromatography on silica gel.
Reaction SMILES: C1([C:7]2[CH:8]=[C:9](OC)[C:10]([N+:15]([O-:17])=[O:16])=[C:11]([CH:14]=2)[C:12]#[N:13])C=CC=CC=1.B(Br)(Br)Br.C(OCC)(=[O:26])C>ClCCl>[C:12]([C:11]1[CH:14]=[C:7]([OH:26])[CH:8]=[CH:9][C:10]=1[N+:15]([O-:17])=[O:16])#[N:13]
Reactant: COc1cc(-c2ccccc2)cc(C#N)c1[N+](=O)[O-]
Reactant: CCOC(C)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1cc(O)ccc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 96 %

Procedure:
To a 0° C. solution of 578 mg (2.28 mmol) 5-phenyl-methoxy-2-nitrobenzonitrile, prepared according to the procedure of E. Elslager, et. al., J. Heterocyclic Chem. 1972, 9, 759-773, in 5 mL of dichloromethane at 0° C. was added 2.6 mL (2.62 mmol, 1.15 equiv) of a 1.0 M solution of boron tribromide in dichloromethane. After the reaction mixture was stirred for 3 h, it was diluted with ethyl acetate, washed sequentially with 1N aqueous sodium hydrogen sulfate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to give 357 mg (96%) of the title compound which was used without further purification: 1H NMR (400 MHz, CD3OD) δ8.17 (d, 1H, J=9.2 Hz), 7.03 (d, 1H, J=2.7 Hz), 6.92 (dd, 1H, J=2.7, 9.3 Hz).
Reaction SMILES: [H-].[Na+].C([O:7][C:8](=[O:18])[CH2:9][CH:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11](O)=O)(C)(C)C.O>C1COCC1>[CH2:14]([CH:10]1[CH2:11][O:18][C:8](=[O:7])[CH2:9]1)[CH:15]([CH3:16])[CH3:17]
Reactant: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC1COC(=O)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 104.9 %

Procedure:
Triethyl phosphonoacetate (1.13 mL, 5.70 mmol) was added dropwise to a stirring suspension of sodium hydride (0.22 g of a 60% dispersion in oil, 5.43 mmol) in THF (15 mL) at 0° C. under argon. After 20 minutes, ketone 3 (0.75 g, 5.43 mmol) in THF (6 mL) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 16 hours. Water (5 mL) was added, and the mixture was extracted with ether (15 mL×3). The combined organic fractions were washed with brine and dried (MgSO4). The solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane/ethyl acetate, 95:5) to give the ester 4 (0.81 g, 72%) as a colorless oil; Rf(heptane/ethyl acetate, 8:2) 0.66; νmax(film)/cm−1 1715 (C═O), 1652 (C═C); δH (400 MHz; CDCl3): 5.80 (1H, quint, J=2.2, CHCO2Et), 4.15 (2H, q, J=7.1, CO2CH2Me), 2.79 (1H, dd, J=19.5, 8.1), 2.69 (1H, ddt, J=19.8, 7.3, 2.3), 2.47 (1H, dd, J=17.3, 7.2), 2.34 (1H, ddt, J=17.3, 5.6, 1.8), 2.14 (1H, m), 2.02 (1H, m), 1.60–1.22 (8H, m); m/z (ES+) 209 (M+H, 57%), 455 (2M+K, 67).
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)[C:5]#N)[CH3:3].[Cl:17][C:18]1[CH:23]=[CH:22]C([Mg]Br)=[CH:20][CH:19]=1.[Cl-].[NH4+].O>CCOCC>[Cl:17][C:18]1[CH:23]=[CH:22][C:5]([CH:4]([N:2]([CH3:3])[CH3:1])[CH:7]2[CH2:16][CH2:15][C:10]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:9][CH2:8]2)=[CH:20][CH:19]=1
Reactant: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Reactant: Clc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CN(C)C(c1ccc(Cl)cc1)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of the aminonitrile 4 (22.43 g, 100 mmol) in absolute ether (100 ml) was added dropwise to a 1 M solution of 4-chlorophenylmagnesium bromide in ether (200 ml, 200 mmol) under argon and while cooling with ice, and the mixture was stirred at RT for 20 hours. The reaction mixture was worked up by adding saturated ammonium chloride solution (100 ml) and water (100 ml) while cooling with ice, and extracting the mixture with diethyl ether (3×100 ml). The organic phase was washed with water and saturated sodium chloride solution, dried and concentrated.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[Cl:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[O:42][CH:43]([CH3:45])[CH3:44])[C:36]([OH:38])=O.O[NH:47][C:48]([C:50]1[C:51]2[CH:52]=[CH:53][N:54]=[CH:55][C:56]=2[CH:57]=[CH:58][CH:59]=1)=[NH:49]>>[Cl:32][C:33]1[CH:34]=[C:35]([C:36]2[O:38][N:49]=[C:48]([C:50]3[CH:59]=[CH:58][CH:57]=[C:56]4[C:51]=3[CH:52]=[CH:53][N:54]=[CH:55]4)[N:47]=2)[CH:39]=[CH:40][C:41]=1[O:42][CH:43]([CH3:45])[CH3:44]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: N=C(NO)c1cccc2cnccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4cnccc34)no2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.8 %

Procedure:
A microwave vial was charged with HATU (2.5 g, 6.57 mmol), triethylamine (1.48 ml, 10.7 mmol), 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D3; 1.15 g, 5.34 mmol) and N-hydroxy-5-isoquinolinecarboximidamide (D1; 1 g, 5.34 mmol). The solution was stirred at room temperature for 30 minutes. The reaction vessel was sealed and heated under microwave irradiation at 130° C. for 120 min. After cooling, the reaction mixture was filtered. The isolated grey-brown solid was washed with acetonitrile before being dried in vacuo at 60° C. to give the title compound as a grey solid (738 mg, 37%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.[Li]CCCC.CN([CH:25]=[O:26])C.[Cl-].[NH4+]>C1COCC1>[C:13]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:25]=[O:26])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCN(CC)c1ccc(Br)cc1C(C)(C)C
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(C=O)cc1C(C)(C)C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 102.2 %

Procedure:
3.6 g (13 mmol) of (4-bromo-2-tert-butylphenyl)-diethylamine are diluted in 100 ml of THF, under a stream of nitrogen. The medium is cooled to −78° C. and then 7.8 ml (20 mmol) of a 2.5M solution of nBuLi are added. After stirring for 45 minutes, 1.5 ml (20 mmol) of DMF are added and the solution is brought back to ambient temperature. After 15 minutes, the mixture is poured into a saturated solution of ammonium chloride and then extracted twice with ethyl acetate. The organic phase is dried over sodium sulphate and then concentrated to dryness. 3.1 g of 3-tert-butyl-4-diethylaminobenzaldehyde are obtained in the form of a yellow oil (yield=100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([CH2:19][CH3:20])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:17][CH3:18])=[C:12]([CH:16]=1)[C:13](O)=[O:14])=[O:5])[CH3:2].ClC(OCC)=O.C(N(CC)CC)C>O1CCCC1>[OH:14][CH2:13][C:12]1[CH:16]=[C:8]([CH:9]=[CH:10][C:11]=1[O:17][CH3:18])[CH2:7][CH:6]([CH2:19][CH3:20])[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(C(=O)O)c1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CC)Cc1ccc(OC)c(CO)c1
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
0.50 g of 5-[2-(ethoxycarbonyl)butyl]-2-methoxybenzoic acid was dissolved in 8 ml tetrahydrofuran, and 0.20 ml ethyl chloroformate and 0.29 ml triethylamine were added under ice-cooling. After the reaction solution was stirred for 10 minutes under ice-cooling, insoluble matters were filtered off. The mother liquor was ice-cooled again, and 10 L water and 136 mg sodium borohydride were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction product, followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (3:1), 0.47 g of ethyl 2-[3-(hydroxymethyl)-4-methoxybenzyl]butanoate was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[C:17]1([CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:27][CH2:26][CH2:25][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1
Reactant: NCCCCc1ccccc1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Clc1nc(NCCCCc2ccccc2)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-(4-phenylbutylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-phenylbutylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:22]2[S:23][CH:24]=[CH:25][C:26]=2Br)=[N:15][NH:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>COC(O)C.CCOC(C)=O.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[S:23][CH:24]=[CH:25][C:26]=3[N:16]([CH2:17][C:18]([F:21])([F:20])[F:19])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=NNCC(F)(F)F)c2sccc2Br)CC1
Agent: [Cu]I
Agent: COC(C)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nn(CC(F)(F)F)c3ccsc23)CC1
Temperature: 75 °C
Yield: 104.7 %

Procedure:
4-{(3-Bromo-thiophen-2-yl)-[(2,2,2-trifluoro-ethyl)-hydrazono]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (2.34 g, 4.98 mmol) was mixed with CuI (50 mg), CsCO3 (1.9 g, 1.2 eq) in methoxyethanol (25 mL). The mixture was heated to 75° C. for 1 hour. The mixture was then diluted with EtOAc and filtered. The filtrate was evaporated and the residue was purified via chromatography (eluted with 0-10% MeOH in DCM) yielding 2.03 g (>95%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.S(Cl)([Cl:19])(=O)=O>ClCCl>[Cl:19][CH:5]([C:6](=[O:14])[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)[CH2:4][C:3]([O:2][CH3:1])=[O:15]
Reactant: COC(=O)CCC(=O)c1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)CC(Cl)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 179 g (0.79 mole) of methyl-3-(4-chlorobenzoyl)propionate in 175 mL of dichloromethane was cooled to 0° and treated dropwise with 69.8 mL (117.3 g; 0.86 mole, d=1.68) of sulfuryl chloride. After the addition was complete, the cold bath was removed, and the reaction mixture was allowed to warm to room temperature while stirring overnight. The mixture was treated with 100 mL of water and basified cautiously with 50% sodium hydroxide. The layers were separated, the dichloromethane layer dried over magnesium sulfate and evaporated under reduced pressure (245.3 g). The residue was purified by vacuum distillation (135° C./0.3 mm) to obtain three fractions for a total of 198.6 g (96%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29]C(=O)C)[CH:24]=3)[S:10][C:11]=2[C:12]2[N:16]=[CH:15][N:14]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.CO.[OH-].[Na+]>C(OCC)(=O)C.O>[C:1]1([C:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=3)[S:10][C:11]=2[C:12]2[N:16]=[CH:15][N:14]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[N:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1cc(-c2nc(-c3ccccc3)c(-c3ncn(C4CCCCO4)n3)s2)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(-c2nc(-c3ccccc3)c(-c3ncn(C4CCCCO4)n3)s2)ccn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
To N-(4-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}pyridin-2-yl)acetamide (2.0 g, 4.4 mmol) prepared in the same manner as above in a mixed solvent (88 mL) of tetrahydrofuran/methanol (1:1) was added 1N aqueous sodium hydroxide solution (44 mL, 44.0 mmol), and the mixture was stirred at 60° C. for 3 hr. The reaction solution was cooled to room temperature, and diluted with ethyl acetate (300 mL) and water (150 mL). The aqueous layer was separated and extracted with ethyl acetate (200 mL), and the combined organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained solid was washed with diethyl ether (25 mL) and hexane (25 mL) to give the title compound (1.6 g, 87%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH:15]=[O:16])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[CH2:18][C:19]1[C:20]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=2[S:22][CH:23]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:20]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:8]2[C:13]([C:14]=1[CH:15]=[O:16])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1C=O
Reactant: Fc1ccc2scc(CBr)c2c1
Product: CCOC(=O)c1c(C=O)c2ccccc2n1Cc1csc2ccc(F)cc12

Procedure:
Using general procedure B, 3-formyl-1H-indole-2-carboxylic acid ethyl ester was coupled with 3-bromomethyl-5-fluoro-benzo[b]thiophene (Lit. 18) to give 1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-3-formyl-1H-indole-2-carboxylic acid ethyl ester as white solid. MS: 382.3 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:15]=[CH:14][C:3]=1[C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]1=[O:13])=[O:5].[Br:22]Br>C(Cl)Cl>[Br:22][CH:8]1[CH2:9][CH2:10][C:11](=[O:12])[CH:6]([C:4](=[O:5])[C:3]2[CH:14]=[CH:15][C:16]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:17][C:2]=2[Cl:1])[C:7]1=[O:13]
Reactant: CS(=O)(=O)c1ccc(C(=O)C2C(=O)CCCC2=O)c(Cl)c1
Reactant: BrBr
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(=O)C2C(=O)CCC(Br)C2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 115.8 %

Procedure:
2-(2-Chloro-4-methanesulfonylbenzoyl)-cyclohexane-1,3-dione (6.6 g, 0.02 mole) was dissolved in 50 ml of methylene chloride. Bromine (2.9 g, 0.018 mole) dissolved in 50 ml of methylene chloride was added dropwise over a period of 75 minutes to the above solution which was cooled with a dry ice-isopropanol bath. Upon completion of the addition, the reaction mixture was stirred an additional 2 hours at room temperature. The reaction mixture was then concentrated under vacuum to afford 8.5 g of the desired product as a semi-solid. It was identified as such by nuclear magnetic resonance spectroscopy, infrared spectroscopy, and mass spectroscopy. The product can be further purified by column chromatography.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[CH2:5][CH2:6][N:7]1[C:11](=[O:12])[CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[S:9][CH:8]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>CS(C)=O>[CH3:1][N:2]([CH3:3])[CH2:5][CH2:6][N:7]1[C:11](=[O:12])[CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[S:9][CH:8]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: CNC
Reactant: CCCCCCCCCC1SC(c2cccnc2)N(CCCl)C1=O
Solvent: CS(C)=O
Product: CCCCCCCCCC1SC(c2cccnc2)N(CCN(C)C)C1=O
Temperature: 100 °C
Yield: 99.1 %

Procedure:
A 50% aqueous dimethylamine solution (1.0 ml, 11 mmol) was added to a solution of trans-isomer (128 mg, 0.35 mmol) of 3-(2-chloroethyl)-5-(n-nonyl)-2-(3-pyridyl)thiazolidin-4-one in dimethylsulfoxide (3 ml). The mixture, placed in a sealed tube, was heated at 100° C. for 2 hours. After removal of the solvent by evaporation under reduced pressure, the residue was dissolved in chloroform (30 ml). The solution was washed twice with saturated aqueous NaHCO3 and dried. Removal of the chloroform gave the intended trans-isomer (131 mg, 100% of theoretical) of 3-(2-dimethylaminoethyl)-5-(n-nonyl)-2-(3-pyridyl)thiazolidin-4-one in oily form. IR (CHCl3) [cm-1 ]; 2930, 2860, 1670, 1580, 1355. NMR (δ, CDCl3, ppm); 2.15 (6 H, s), 2.24 (1 H, dt, 12.87 and 5.61 Hz), 2.46 (1 H, ddd, 12.87, 7.20 and 5.94 Hz), 2.69 (1 H, ddd, 14.19, 7.20 and 5.61 Hz), 3.80 (1 H, ddd, 14.19, 5.94 and 5.61 Hz), 4.03 (1 H, ddd, 8.58, 3.96 and 1.98 Hz), 5.86 (1 H, d, 1.98 Hz).
Reaction SMILES: C(NC(=O)[O-])C.[OH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:12]([CH3:20])[CH:13]3[CH2:17][NH:16][CH2:15][CH:14]3[C:18]=2[CH:19]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br>>[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:12]([CH3:20])[CH:13]3[CH2:17][NH:16][CH2:15][CH:14]3[C:18]=2[CH:19]=1
Reactant: Fc1cccc(CBr)c1
Reactant: CC1c2ccc(O)cc2C2CNCC12
Agent: CCNC(=O)[O-]
Product: CC1c2ccc(OCc3cccc(F)c3)cc2C2CNCC12

Procedure:
The subtitle compound was prepared by the method of Example 43, Step B utilizing N-ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 43, Step A) (0.1 mmol) and 3-fluorobenzyl bromide. The crude product was obtained without further purification. MS calculated for C22H24FNO3+H: 370, observed: 370.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([F:36])[CH:28]=1.C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:27]4[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([F:36])[CH:28]=4)[CH2:21][CH2:20]3)=[CH:17][CH:18]=2)=[O:25])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCNCC3)cc2)c1
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCN(c4ccc(C(=O)O)c(F)c4)CC3)cc2)c1

Procedure:
4-{4-[4-(3-tert-Butyl-phenylcarbamoyl)-phenyl]-piperidin-1-yl}-2-fluoro-benzoic acid was synthesized from N-(3-tert-butyl-phenyl)-4-piperidin-4-yl-benzamide and 4-bromo-2-fluoro-benzoic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above.
Reaction SMILES: [CH3:1][NH:2][C:3](C1N(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)N=CN=1)=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]3[C:43]=2[CH2:44][N:45]2[CH:49]=[N:48][C:47]([C:50](OC)=[O:51])=[N:46]2)=[CH:31][CH:30]=1.CNC>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]3[C:43]=2[CH2:44][N:45]2[CH:49]=[N:48][C:47]([C:50]([N:2]([CH3:3])[CH3:1])=[O:51])=[N:46]2)=[CH:31][CH:30]=1
Reactant: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Reactant: COC(=O)c1ncn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)n1
Agent: CNC
Product: CN(C)C(=O)c1ncn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)n1

Procedure:
The title compound was prepared according to the procedure described for compound 68 from methyl 1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate and dimethylamine. 1H-NMR (400 MHz, CDCl3, δ) 8.65 (d, J=6.9 Hz, 1H), 7.88 (s, 1H), 7.85 (d, J=8.5 Hz, 2H), 7.66 (d, J=9.1 Hz, 1H), 7.45 (d, J=8.5 Hz, 2H), 7.28 (m, 1H), 6.89 (m, 1H), 6.04 (s, 2H), 3.15 (s, 3H), 3.06 (s, 3H) ppm; m/e 381, 383.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(O)(=O)C.[Cl:9][C:10]1[CH:11]=[C:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:14][C:15]=1[CH:16]=O.C([BH3-])#N.[Na+]>CO.CCCCCCC.C(OCC)(=O)C>[Cl:9][C:10]1[CH:11]=[C:12]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][NH:4][CH:1]1[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: O=Cc1ccc(-c2ccccc2)cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCCCCCC
Product: Clc1cc(-c2ccccc2)ccc1CNC1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.1 %

Procedure:
To a cooled solution of 1.82 ml (26 mmol) of cyclopropylamine and 1.90 ml (33 mmol) of acetic acid, together with 3 g of 3 Å molecular sieves, in 45 ml of methanol, are added 2.85 g (13.1 mmol) of 3-chlorobiphenyl-4-carbaldehyde. The reaction mixture is stirred for 4 hrs at reflux. The reaction mixture is then cooled to ambient temperature and 1.24 g (19.7 mmol) of sodium cyanoborohydride are slowly added. The reaction mixture is further stirred for 2 hrs at reflux. The solvent is removed under vacuum and 100 ml of water are then added to the residue and the pH is adjusted to 10 with sodium hydroxyde. The watery layer is extracted three times with dichloromethane (3×50 ml); the combined organic layers are filtered over a phase separator filter to yield after concentration 11.61 g of a yellow oil. Column chromatography (gradient heptane/ethyl acetate) yielded 2.84 g (79% yield) of N-[(3-chlorobiphenyl-4-yl)methyl]cyclopropanamine as a colourless oil (M+H=258).
Reaction SMILES: FC1C=C(CC=O)C=CC=1.FC1C=C(C=CC(C(C)C)C(OCC)=O)C=CC=1.[OH-].[K+].CO.O.[F:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]([CH:47]([CH3:49])[CH3:48])[C:44]([OH:46])=[O:45])[CH:38]=[CH:39][CH:40]=1.[C:50]([CH:52](O)[C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([O:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:54]=1)#[N:51]>>[F:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]([CH:47]([CH3:49])[CH3:48])[C:44]([O:46][CH:52]([C:50]#[N:51])[C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([O:59][C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=3)[CH:54]=2)=[O:45])[CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)C(C=Cc1cccc(F)c1)C(=O)O
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Agent: CCOC(=O)C(C=Cc1cccc(F)c1)C(C)C
Agent: O=CCc1cccc(F)c1
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)C(C=Cc1cccc(F)c1)C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1

Procedure:
3-Fluorophenylacetaldehyde is converted into ethyl 4-(3-fluorophenyl)-2-isopropyl-3-butenoate using the reaction of Example 9. The ester is hydrolyzed using KOH/MeOH/H2O to 4-(3-fluorophenyl)-2-isopropyl-3-butenoic acid, which is converted to the acid chloride and reacted with α-cyano-m-phenoxybenzyl alcohol to yield α-cyano-m-phenoxybenzyl 4-(3-fluorophenyl)-2-isopropyl-3-butenoate, MS m/e 429 (M+).