Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[N:3]1[CH2:7][CH2:6][NH:5][C:4]1=[S:8].[C:11](Cl)([Cl:13])=[O:12]>C(Cl)Cl>[Cl:13][C:11]([N:3]1[CH2:7][CH2:6][NH:5][C:4]1=[S:8])=[O:12]
Reactant: C[Si](C)(C)N1CCNC1=S
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)N1CCNC1=S
Temperature: 0 °C
Reaction time: 24 h

Procedure:
50 parts by weight of 1-trimethylsilyl-imidazolidine-2-thione in 150 parts by volume of methylene chloride were treated with 35 parts by weight of phosgene in 50 parts by volume of methylene chloride over the course of 2 hours at 0°C. The mixture was stirred for 24 hours at 0°C, the methylene chloride was subsequently stripped off, and the residue was dried in a high vacuum. Semi-solid mass, incompletely soluble in acetone.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([NH:14][C:15](=[O:30])[CH2:16][C:17](=O)[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH:28]=[CH:27][N:26]=[N:25]3)[CH:19]=2)=[CH:12][C:11]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[F:38])=[C:10]([N:39]([CH3:41])[CH3:40])[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:38][C:32]1[C:33]([F:37])=[CH:34][CH:35]=[CH:36][C:31]=1[C:11]1[C:10]([N:39]([CH3:41])[CH3:40])=[CH:9][C:8]2[N:7]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N:24]4[CH:28]=[CH:27][N:26]=[N:25]4)[CH:19]=3)[CH2:16][C:15](=[O:30])[NH:14][C:13]=2[CH:12]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1-c1cccc(F)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1-c1cccc(F)c1F)NC(=O)CC(c1cccc(-n3ccnn3)c1)=N2

Procedure:
The title compound was prepared from {2-dimethylamino-2′,3′-difluoro-5-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example M8) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (47 mg).
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>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:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[N:6]([S:7]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=2)=[CH:29][CH:28]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
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+]
Product: CN(Cc1cc(-c2ccc(F)cc2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (4-fluorophenyl)boronic acid (195 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 293 mg, 94%).
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH2:9][C@@H:4]([CH2:5][CH2:6][C@H:7]2[C:10]([NH:12][NH:13][C:14]([C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17]2C(OC(C)(C)C)=O)=[O:15])=[O:11])[N:3]1[O:29][S:30]([OH:33])(=[O:32])=[O:31].FC(F)(F)C(O)=O>C(Cl)Cl>[O:1]=[C:2]1[N:8]2[CH2:9][C@@H:4]([CH2:5][CH2:6][C@H:7]2[C:10]([NH:12][NH:13][C:14]([C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][NH:17]2)=[O:15])=[O:11])[N:3]1[O:29][S:30]([OH:33])(=[O:32])=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O)[C@@H]1CCCCN1
Reaction time: 1 h

Procedure:
To a solution tert-butyl (2S)-2-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate 273 (0.30 g, 0.61 mmol) in DCM (30 mL) was added trifluoroacetic acid (2.42 mL, 31.38 mmol) dropwise at 0° C. The reaction mixture was stirred for 1 h then evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with a mixture of MeOH:ether (1:5, 6×) and the white solid was collected by centrifugation to give (2S,5R)-7-oxo-N′-[(2S)-piperidin-2-ylcarbonyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide Compound 43 (Table 2) (0.09 g, 38%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=O.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCNC1
Reactant: O=Cc1cc(F)cc(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cc(F)cc(CN2CCCC2)c1
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
3,5-Difluorobenzaldehyde (2.0 mL, 18.24 mmol), pyrrolidine (1.8 mL, 21.56 mmol), and sodium triacetoxyborohydride (5.8 g, 27.4 mmol) were stirred in THF (50 mL) for 16 h at room temperature. Saturated aqueous NaHCO3 (30 mL) was added and after stirring for 30 min, EtOAc (50 mL) was added. The organic phase was separated and washed with brine, dried over MgSO4 and concentrated to afford 2.65 g (74%) of 1-(3,5-difluorobenzyl)pyrrolidine as a slightly cloudy oil: 1H NMR (CDCl3) δ 6.88-6.83 (m, 1H), 6.68-6.63 (m, 2H), 3.59 (s, 2H), 2.53-2.48 (m, 4H), 1.80-1.77 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][Cl:24]>CC(CC(C)C)=O>[C:1]([O:5][C:6](=[O:14])[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:22][CH2:23][Cl:24])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(O)cc1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CC(C)(C)OC(=O)c1ccc(OCCCl)cc1
Yield: 93.1 %

Procedure:
A mixture containing 0.79 g (4.1 mmol) of 4-hydroxy-benzoic acid tert-butyl ester, 1.13 g (8.14 mmol) of K2CO3 and 1.6 mL (16.3 mmol) of 1-bromo-2-chloro-ethane in 10 mL of isobutyl methyl ketone was refluxed for 5 hours. After filtering, the solvent was removed under reduced pressure affording 0.98 g (94% yield) of 4-(2-chloro-ethoxy)-benzoic acid tert-butyl ester.
Reaction SMILES: B(F)(F)F.[CH3:5]COCC.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:15]([OH:17])=[O:16]>CO>[CH3:5][O:16][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[C:12]([O:11][CH3:10])[CH:13]=1
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CCOCC
Agent: FB(F)F
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Yield: 101.8 %

Procedure:
Boron trifluoride diethyl etherate (2 mL, 16.3 mmol) was added to a suspension of 3-methoxy-4-nitrobenzoic acid (1.0 g, 5.07 mmol) in anhydrous methanol (15 mL) and the resulting mixture was heated at reflux for 24 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between water and dichloromethane; the aqueous layer was extracted 3 times with dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified over a silica gel plug (EtOAc/hexane from 40/60 to 50/50) to give 1.09 g of 3-methoxy-4-nitro-benzoic acid methyl ester as a pale yellow solid.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:16][N:15]=1.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>C1COCC1>[F:13][C:14]1[C:19]([B:25]([OH:30])[OH:26])=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:16][N:15]=1
Reactant: COCCOc1ccc(F)nc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COCCOc1cnc(F)c(B(O)O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a stirred solution of diisopropylamine (Aldrich, 3.03 mL, 21.2 mmol) in THF (30 mL) in 250 mL round-bottomed flask, nBuLi (Aldrich, 2.5 M in hexanes, 8.12 mL, 20.3 mmol) was added slowly at 0° C. The mixture was stirred at 0° C. for 30 min. The mixture was cooled to −78° C. and 2-fluoro-5-(2-methoxyethoxy)pyridine (1.58 g, 9.23 mmol) in a total of 5 mL THF was added slowly. The orange mixture was stirred at that temperature for 30 min then triisopropyl borate (Aldrich, 4.72 mL, 20.3 mmol) in a total of 5 mL of THF was added slowly. The mixture was stirred at −78° C. for 10 min, then the cold bath was removed and the mixture was stirred at room temperature for 1 h. 1N NaOH (about 70 mL) was added and the layers were separated. The aqueous phase was washed with EtOAc (50 mL) and acidified to about pH 5 with 5 N HCl. The aq phase was extracted with EtOAc (4×50 mL). The combined organic phases were washed with saturated aqueous sodium chloride (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-fluoro-5-(2-methoxyethoxy)pyridin-3-ylboronic acid (1.76 g, 89% yield) as a pale yellow residue. This material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[NH:11][C:10](=O)[CH:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=1
Reactant: O=c1cc(-c2ccc(Cl)cc2)cc(C(F)(F)F)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)cc(Cl)n1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-6-trifluoromethyl-1H-pyridin-2-one (29.5 g, 108 mmol) and phosphoryl chloride (49.2 mL, 539 mmol) according to the general procedure Ia to d preparation of chlorides. Obtained as a light brown solid (19.7 g, 62%). MS (ISP) 292.1 [(M+H)+], 294 [(M+2+H)+] and 296 [(M+4+H)+].
Reaction SMILES: C(O[C:5]1([CH3:14])[CH:9]=[CH:8][C:7](=[O:10])[CH:6]1[CH2:11][CH:12]=[CH2:13])(=O)C.[C:15]([O-:19])(=[O:18])[CH2:16][CH3:17].[Na+]>C(O)(=O)CC>[CH2:11]([C:6]1[C:7](=[O:10])[CH2:8][CH:9]([O:19][C:15](=[O:18])[CH2:16][CH3:17])[C:5]=1[CH3:14])[CH:12]=[CH2:13]
Reactant: CCC(=O)[O-]
Reactant: C=CCC1C(=O)C=CC1(C)OC(C)=O
Agent: [Na+]
Solvent: CCC(=O)O
Product: C=CCC1=C(C)C(OC(=O)CC)CC1=O
Reaction time: 6 h
Yield: 148.5 %

Procedure:
In the same apparatus as in Example 1, 3-acetoxy-2-allyl-3-methyl-4-cyclopentenone (19.4 g), propionic acid (70 ml) and sodium propionate (5 g) were charged and agitated at 110° to 120° C. for 6 hours. After the completion of the reaction, propionic acid was evaporated off under reduced pressure. The residue was extracted with toluene (70 ml) and water (40 ml) and treated as in Example 1 to obtain 2-allyl-4-propionyloxy-3-methyl-2-cyclopentenone (16.1 g). Yield, 83%. B.P., 115°-120° C./0.1-0.2 mmHg.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:10])[CH:6]=[CH:7][CH:8]=1.Cl.N1C=CC=CC=1>Cl.O>[OH:2][C:3]1[CH:4]=[C:5]([CH:9]([CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(C)CCCc2ccccc2)c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(CCCc1ccccc1)c1cccc(O)c1
Temperature: 190 °C

Procedure:
A mixture of 2-(3-methoxyphenyl)-5-phenylpentane (18.4 g.) and pyridine hydrochloride (94 g.) under nitrogen is heated to 190° C. for 2 hours with vigorous stirring. The reaction mixture is cooled, dissolved in 6 N hydrochloric acid (200 ml.) and diluted with water to 600 ml. The aqueous solution is extracted with ethyl acetate (4×100 ml.), the ethyl acetate extracts dried over sodium sulfate and concentrated under vacuum to yield the crude product. The product is purified by silica gel chromatography.
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:38]4[CH:43]=[CH:42][C:41]([C:44]([O:46]C)=[O:45])=[CH:40][C:39]=4[CH3:48])[C:33]([F:37])=[CH:34][C:35]=3[F:36])[C@H:14]2[CH3:49])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[OH-].[Li+].O>O1CCOCC1>[F:51][C:2]([F:1])([F:50])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:38]4[CH:43]=[CH:42][C:41]([C:44]([OH:46])=[O:45])=[CH:40][C:39]=4[CH3:48])[C:33]([F:37])=[CH:34][C:35]=3[F:36])[C@H:14]2[CH3:49])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2cc(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c(F)cc2F)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C(=O)O)ccc1-c1cc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c(F)cc1F

Procedure:
methyl 2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′,6′-difluoro-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (73.5 mg, 0.10 mmol), lithium hydroxide monohydrate (42 mg, 1 mmol), water (1 mL) and 1,4-dioxane (2 mL) were stirred at room temperature for 2 hrs. Volatiles were removed under reduced pressure. Pot residue was dissolved in a MeCN/1N HCl (aq) mixture and purified by reverse-phase prep-HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting w/a MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v) gradient mixture. Corresponding fractions were pooled & evaporated in vacuo to afford the title compound. LCMS (ESI) calc.=717.14; found=718.17 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 8.04 (s, 1H), 7.97 (d, J=8 Hz, 1H), 7.88 (s, 1H), 7.74-7.67 (m, 4H), 7.51-7.45 (m, 1H), 7.34 (d, J=8 Hz, 1H), 7.19 (br s, 1H), 7.09 (t, J=9 Hz, 1H), 5.59 (d, J=8 Hz, 1H), 5.08-4.80 (m, 1H), 4.20-3.78 (m, 2H), 2.32 (s, 3H), 0.62 (s, 3H).
Reaction SMILES: N[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([O:12][CH2:13][O:14][CH3:15])[CH:7]([CH2:16][CH2:17][CH:18](N(CCC)CCC)[CH3:19])[CH2:6]2.C(=O)([O-])[O-].[K+].[K+].C([C:38]1[CH:48]=[CH:47][CH:46]=[C:40]2[C:41]([NH:43][C:44](=[O:45])[C:39]=12)=[O:42])(OCC)=O.O>CN(C=O)C>[CH2:41]([N:43]([CH2:44][CH2:39][CH3:38])[CH2:19][CH2:18][CH2:17][CH2:16][CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][N:43]3[C:44](=[O:45])[C:39]4[C:40](=[CH:46][CH:47]=[CH:48][CH:38]=4)[C:41]3=[O:42])[CH:4]=2)[CH:8]1[O:12][CH2:13][O:14][CH3:15])[CH2:40][CH3:46]
Reactant: CCCN(CCC)C(C)CCC1Cc2cc(CN)ccc2C1OCOC
Reactant: CCOC(=O)c1cccc2c1C(=O)NC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(CCC)CCCCC1Cc2cc(CN3C(=O)c4ccccc4C3=O)ccc2C1OCOC
Temperature: 25 °C
Reaction time: 3 h
Yield: 130.9 %

Procedure:
The compound (189 mg) obtained in Example 11-10 was dissolved in DMF (5.6 ml) and added with potassium carbonate (108.5 mg) and carbethoxyphthalimide (172.0 mg) and the whole was stirred at room temperature for 3 hours. The reaction solution was added with water and subjected to extraction with chloroform. The extract was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (253 mg) as a yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](Cl)=[O:19]>N1C=CC=CC=1>[CH3:12][O:11][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:18]([C:14]3[O:13][CH:17]=[CH:16][CH:15]=3)=[O:19])[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccco1
Reactant: COc1cccc2sc(N)nc12
Solvent: c1ccncc1
Product: COc1cccc2sc(NC(=O)c3ccco3)nc12

Procedure:
Using 2-amino-4-methoxy-benzothiazole and furan-2-carboxylic acid chloride in pyridine the title compound was obtained as a tan solid (100% yield), MS: m/e=274.1 (M+).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[C:18]1([CH2:24][C@H:25]2[CH2:30][C@H:29]([N:31]3[CH2:36][CH2:35][CH:34]([N:37]4[C:41]5[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=5[NH:39][C:38]4=[O:46])[CH2:33][CH2:32]3)[CH2:28][CH2:27][NH:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([N:26]1[CH2:27][CH2:28][C@@H:29]([N:31]2[CH2:36][CH2:35][CH:34]([N:37]3[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=4[NH:39][C:38]3=[O:46])[CH2:33][CH2:32]2)[CH2:30][C@@H:25]1[CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:7]
Reactant: O=c1[nH]c2ccccc2n1C1CCN([C@@H]2CCN[C@@H](Cc3ccccc3)C2)CC1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@@H](N2CCC(n3c(=O)[nH]c4ccccc43)CC2)C[C@@H]1Cc1ccccc1

Procedure:
Using the same reaction procedure as described in example B5, 3,5-bis(trifluoromethyl)benzoyl chloride was reacted with intermediate 8 to form (±)-trans-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]-2-(phenylmethyl)piperidine (compound 43, mp. 156.1° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([NH2:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:17][C:18]1[N:19]([CH:27]2[CH2:31][CH2:30][O:29]C2=O)[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=1.C[Al](C)C>[OH-].[NH4+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]([CH3:14])[CH3:15])=[C:11]([NH:16][CH:27]([N:19]3[CH:20]=[C:21]([C:23]([F:25])([F:26])[F:24])[N:22]=[C:18]3[CH3:17])[CH2:31][CH2:30][OH:29])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)c1c(N)cnn1-c1ccc(F)cc1
Reactant: Cc1nc(C(F)(F)F)cn1C1CCOC1=O
Agent: C[Al](C)C
Agent: [NH4+]
Agent: [OH-]
Product: Cc1nc(C(F)(F)F)cn1C(CCO)Nc1cnn(-c2ccc(F)cc2)c1C(C)C
Temperature: 55 °C
Yield: 23.5 %

Procedure:
A mixture of 1-(4-fluorophenyl)-5-isopropyl-pyrazol-4-amine (0.070 g, 0.32 mmol), 3-[2-methyl-4-(trifluoromethyl)imidazol-1-yl]tetrahydrofuran-2-one (0.070 g, 0.30 mmol) and AlMe3 (0.50 mL, 1.0 mmol, 2 M/toluene) was heated at 55° C. for 1.5 hrs. The mixture was then cooled to room temperature, diluted with aqueous ammonium hydroxide, and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (SiO2, 0˜20% MeOH/CH2Cl2 gradient elution) to give 3-[[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]amino]-3-[2-methyl-4-(trifluoromethyl)imidazol-1-yl]propan-1-ol (0.030 g, 24%).
Reaction SMILES: [C:1]1([NH:11][C:12]([N:14]2[CH2:19][CH2:18][NH:17][C@H:16]([C@@H:20]([NH:22][C:23]3[N:28]=[C:27]([N:29]4[C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=5[N:31]=[CH:30]4)[CH:26]=[CH:25][N:24]=3)[CH3:21])[CH2:15]2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH:44]=O)[CH:39]=1.C([BH3-])#N.[Na+]>>[CH3:21][C@@H:20]1[N:22]([C:23]2[N:28]=[C:27]([N:29]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[N:31]=[CH:30]3)[CH:26]=[CH:25][N:24]=2)[CH:44]([C:40]2[CH:39]=[N:38][CH:43]=[CH:42][CH:41]=2)[N:17]2[C@H:16]1[CH2:15][N:14]([C:12](=[O:13])[NH:11][C:1]1[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=1)[CH2:19][CH2:18]2
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)[C@@H]1CN(C(=O)Nc2cccc3ccccc23)CCN1
Reactant: O=Cc1cccnc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H]1[C@@H]2CN(C(=O)Nc3cccc4ccccc34)CCN2C(c2cccnc2)N1c1nccc(-n2cnc3ccccc32)n1

Procedure:
The title compound was prepared from 2-[1-(4-(N-naphth-1-yl-carbamoyl) piperazin-2-yl)-ethylamino]-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 36, Step C; 18.2 mg), 3-pyridinecarboxaldehyde (23.7 mg), and sodium cyanoborohydride (4.6 mg) according to the procedure described in Example 14, Step G. Mass spectrum (ESI) 582.2 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[CH:18]=[C:17]([C:19]([OH:21])=O)[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH:28]1[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH2:29]1>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[CH:18]=[C:17]([C:19]([N:28]5[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH2:29]5)=[O:21])[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1
Reactant: OC1CCNCC1
Product: O=C(c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1)N1CCC(O)CC1

Procedure:
45 mg of 2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylic acid 14 was coupled to piperidin-4-ol via General Procedure B. The product was purified via reverse phase HPLC to give 46.6 mg of 123 MS (Q1) 465.1 (M)+.
Reaction SMILES: [NH2:1][C:2]1[C:9]([I:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.CC(C)([O-])C.[K+].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1COCC1>[C:6]([C:5]1[C:4]([C:11]([F:14])([F:12])[F:13])=[CH:3][C:2]([NH:1][S:22]([CH3:21])(=[O:24])=[O:23])=[C:9]([I:10])[CH:8]=1)#[N:7]
Reactant: N#Cc1cc(I)c(N)cc1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cc(C(F)(F)F)c(C#N)cc1I

Procedure:
4-Amino-5-iodo-2-trifluoromethyl-benzonitrile (8.04 g, 25.77 mmoles) was dissolved in anhydrous THF (60 mL), stirred under a nitrogen atmosphere and cooled in an ice/brine bath for 20 min. 1.0 M potassium tert-butoxide in THF (82 mL, 82 mmoles) was added and the reaction mixture was stirred for 20 min. Methanesulfonyl chloride (3.2 mL, 41.18 mmoles) was then added and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was quenched with 1N HCl (90 mL) and extracted with dichloromethane (3×100 mL). The organic extracts were diluted with diethyl ether and a white solid precipitated. The solid was filtered, washed and dried to yield the title compound. The filtrate was concentrated to a crude orange solid. The compound was purified by column chromatography (SiO2, 100% CH2Cl2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH3:10])=[CH:5][CH:4]=1.Cl.[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([CH2:20][O:21][NH2:22])=[CH:18][CH:17]=1)([O-:15])=[O:14]>>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([CH2:20][O:21]/[N:22]=[C:9](/[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)\[CH3:10])=[CH:23][CH:24]=1)([O-:15])=[O:14]
Reactant: NOCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(C(C)=O)cc1
Agent: Cl
Product: COc1ccc(/C(C)=N/OCc2ccc([N+](=O)[O-])cc2)cc1
Yield: 67.9 %

Procedure:
4′-Methoxyacetophenone (21) (150 mg, 1.00 mmol) was condensed with compound 19 (225 mg, 1.10 mmol) according to the general procedure II-A defined above. After heating the reaction mixture for 2 h it was cooled and the resulting solid filtered off and washed with cold isopropanol (3.0 mL) to afford the title compound CP30253 (204 mg, 68%) as a pale-yellow solid, m.p. 88.2-89.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([CH:16]=1)[C:7]([NH:12][CH2:13][CH2:14][CH3:15])=[N:8][CH2:9][CH2:10][CH3:11].[H][H]>C1COCC1.[Ni].CCO>[NH2:17][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][C:6]=1[C:7]([NH:12][CH2:13][CH2:14][CH3:15])=[N:8][CH2:9][CH2:10][CH3:11]
Reactant: [H][H]
Reactant: CCCN=C(NCCC)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCN=C(NCCC)c1cc(Cl)ccc1N

Procedure:
27.4 g (0.097 mol) of 5-chloro-2-nitro-N,N′-dipropylbenzamidine are dissolved in 200 ml of THF and are hydrogenated in the presence of 15 g Ra—Ni/EtOH at room temperature for 5 hours (take up of hydrogen: 94%). Then the catalyst is filtered off and the solvent removed in a water jet vacuum. The residue is purified by column chromatography on silica gel (eluant: hexane/THF 1:1, then THF). Yield: 11.9 g of 2-amino-5-chloro-N,N′-dipropylbenzamidine in the form of a brown oil (1H-NMR (CDCl3);.ppm/multiplicity/number of H's): 0.91/m/6H; 1.56/m/4H; 3.10/m (broad)/4H, 3.75/s(broad)/2H; 6.63/d/1H; 7.02/d/1H; 7.10/dd/1H.