Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:11]=3[CH:12]=2)[S:6][CH:7]=1.[I-].[K+].[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>CN(C)C=O.[Cl-].[Na+].O>[C:20]([NH:24][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:11]=3[CH:12]=2)[S:6][CH:7]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: Oc1ccc2oc(-c3nc(CCl)cs3)cc2c1
Reactant: CC(C)(C)N
Agent: [Cl-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)NCc1csc(-c2cc3cc(O)ccc3o2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-chloromethyl-2-(5-hydroxybenzofuran-2-yl)thiazole (1.38 g), potassium iodide 0.58 g) and tert-butylamine (6 ml) in N,N-dimethylformamide (6 ml) was stirred overnight at ambient temperature, poured into brine and extracted with ethyl acetate. The extract was washed with water and brine. The solution was dried over magnesium sulfate and concentrated under reduced pressure. The resulting precipitate were washed with ethyl acetate to give 4-(tert-butylaminomethyl)-2-(5-hydroxybenzofuran-2-yl)thiazole (1.18 g).
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([S:7]([C:10]([CH3:23])([CH3:22])[CH:11]([CH:17]([O:20][CH3:21])[O:18][CH3:19])[CH2:12][C:13]([O:15]C)=[O:14])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(O)C.[OH-].[Na+]>O>[C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([S:7]([C:10]([CH3:22])([CH3:23])[CH:11]([CH:17]([O:18][CH3:19])[O:20][CH3:21])[CH2:12][C:13]([OH:15])=[O:14])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: COC(=O)CC(C(OC)OC)C(C)(C)S(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC(OC)C(CC(=O)O)C(C)(C)S(=O)(=O)c1ccc(C)cc1

Procedure:
1 g of the product of Step A was added to a mixture of 20 ml of ethanol and 20 ml of aqueous 2 N sodium hydroxide solution and the mixture was refluxed for 17 hours and was cooled and poured into water. The mixture was extracted with methylene chloride and the organic phase was evaporated to dryness to obtain 4-p-tolylsulfonyl-4-methyl-3-dimethoxymethyl-pentanoic acid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][C:5]=1[C:20]1[N:24]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)[N:23]=[CH:22][CH:21]=1.[C:33](Cl)(=[O:35])[CH3:34].O>C1COCC1>[C:33]([N:6]1[C:5]([C:20]2[N:24]([C:25]3[CH:26]=[CH:27][C:28]([C:29]#[N:30])=[CH:31][CH:32]=3)[N:23]=[CH:22][CH:21]=2)=[C:4]([CH3:3])[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]1=[O:19])(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)[nH]c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)n1c(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reaction time: 1 h

Procedure:
Sodium hydride (12.5 mg of a 60% dispersion in mineral oil, 0.31 mmol) was added to a stirred suspension of 4-(5-{5-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-1H-pyrazol-1-yl)benzonitrile (Example 1) (102 mg, 0.25 mmol) in THF (5.0 mL) under a nitrogen atmosphere. This resulted in degassing and the formation of a yellow solution. Acetyl chloride (0.022 mL, 0.5 mmol) was added and the mixture was stirred for 1 h then left to stand for 16 h. Water (10 mL) was added and the mixture was extracted with EtOAc (2×10 mL). The combined organic phase was dried (sodium sulfate) and concentrated in vacuo. The residue was purified by flash column chromatography (2 g Si II SPE eluted with DCM then 10% EtOAc in DCM). Concentration of the appropriate fractions in vacua gave the title compound which was freeze-dried from acetonitrile/water to afford a fluffy white solid (56 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:22](COCC[Si](C)(C)C)[C:21]([NH:31][C@H:32]3[CH2:36][O:35][C@@H:34]4[C@H:37]([NH:40]C(=O)OC(C)(C)C)[CH2:38][O:39][C@H:33]34)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C(Cl)Cl.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>CO>[F:54][C:53]([F:56])([F:55])[C:51]([OH:57])=[O:52].[Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([NH:31][C@@H:32]3[C@H:33]4[O:39][CH2:38][C@@H:37]([NH2:40])[C@H:34]4[O:35][CH2:36]3)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2Nc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2n1COCC[Si](C)(C)C
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2Nc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1

Procedure:
Tert-butyl N-[(3S,3aR,6R,6aR)-3-[[6-chloro-5-(4-phenylphenyl)-1-(2-trimethylsilylethoxy-methyl)imidazo[4,5-b]pyridin-2-yl]amino]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]carbamate (1.1 mg, 0.0016 mmol) was dissolved in TFA (0.2 mL) and DCM (0.5 mL) and stirred at room temperature for 1 hour. Then the reaction mixture was evaporated to give an oil, which was dissolved in methanol (0.5 mL) and purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-80% acetonitrile/water+0.05% TFA gradient. The desired fractions were lyophilized to give the title compound as a solid. Major isomer LC-MS: calculated for C24H22ClN5O2 447.15 observed m/e: 448.24 (M+H)+ (Rt 0.96/2 min); 1H NMR δ (ppm) (CD3OD): 7.82 (s, 1H), 7.76 (ABq, 4H), 7.71 (d, 2H), 7.49 (dd, 2H), 7.39 (dd, 1H), 4.90 (m, 1H), 4.79 (d, 1H), 4.52 (br d, 1H), 4.28 (dd, 1H), 4.20-4.12 (m, 2H), 3.96 (m, 1H) and 3.82 (dd, 1H).
Reaction SMILES: O1CCCC1.[CH:6]1([OH:10])[CH2:9][CH2:8][CH2:7]1.[H-].[Na+].[Br:13][C:14]1[N:31]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:17]2[CH:18]=[N:19][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21](=[O:22])[C:16]=2[C:15]=1[CH2:40]Br>O>[Br:13][C:14]1[N:31]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:17]2[CH:18]=[N:19][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21](=[O:22])[C:16]=2[C:15]=1[CH2:40][O:10][CH:6]1[CH2:9][CH2:8][CH2:7]1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CBr)c(Br)n2COCC[Si](C)(C)C)c1=O
Reactant: OC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1ncc2c(c(COC3CCC3)c(Br)n2COCC[Si](C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
To 10 ml of dehydrated tetrahydrofuran solution containing 0.89 g (12 mmol) of cyclobutanol was added 0.25 g (6.2 mmol) of sodium hydride (60% dispersed material in mineral oil) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. To the mixture was further added 0.70 g (1.2 mmol) of 2-bromo-3-bromomethyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one obtained in Reference example 25-(a), and the mixture was stirred at 45° C. for 1 hour. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=7:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 561 mg of the title compound as a pale yellowish oil. (Yield: 82%)
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]([C:15]([O:17]C)=O)=[CH:3][CH:2]=1.C[N:20](C)CCN.N#N>C(O)CC>[CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]([C:15]([NH2:20])=[O:17])=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc2cc3ccccc3nc12
Reactant: CN(C)CCN
Agent: N#N
Solvent: CCCO
Product: NC(=O)c1cccc2cc3ccccc3nc12
Yield: 80.4 %

Procedure:
A solution of 8a (1.83 g, 7.72 mmol) and N,N-dimethylethylenediamine (3.40 g, 38.6 mmol) in propan-1-ol (80 ml) was flushed with N2, and the mixture was heated at reflux for three days under N2. Solvent was then removed under reduced pressure, and the residue was partitioned between CH2Cl2 (100 ml) and 1M Na2CO3 (100 ml). The organic layer was evaporated and the residue chromatographed on alumina, eluting with CH2Cl2 /MeOH (199:1) to give N-[2-dimethylamino)ethyl]acridine-4-carboxamide 3a (1.38 g, 61%), mp (diHCl salt) 191-195° C., identical with an authentic sample.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([S:18][C:19]2[CH:20]=[C:21]([CH2:25][OH:26])[CH:22]=[CH:23][CH:24]=2)=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>C(Cl)Cl.C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([S:18][C:19]2[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=2)[CH:25]=[O:26])=[C:9]1[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Sc2cccc(CO)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: Cc1c(Sc2cccc(C=O)c2)c2ccc(Cl)cc2n1Cc1ccccc1

Procedure:
[3-(1-Benzyl-6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-methanol (0.750 g, 1.9 mmol) was dissolved in DCM:ACN (9:1, 20 mL) then 4-methylmorpholine N-oxide (0.334 g, 2.85 mmol) and tetrapropylammonium perruthenate (0.067 g, 0.19 mmol) were added. After 30 minutes the reaction mixture was concentrated and loaded directly onto a silica gel column. Silica gel chromatography (0-30% EtOAc in hexanes) provided the title compound.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[C:18]([CH3:33])=[N:19][C:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)[CH:13]=2)[CH2:8][CH2:7]1)C.[Li+].[OH-]>>[CH3:33][C:18]1[C:17]([CH2:16][O:15][C:12]2[CH:13]=[C:14]3[C:9]([CH2:8][CH2:7][N:6]3[CH2:5][C:4]([OH:34])=[O:3])=[CH:10][CH:11]=2)=[CH:22][CH:21]=[C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:27][CH:28]=2)[N:19]=1
Reactant: CCOC(=O)CN1CCc2ccc(OCc3ccc(-c4ccc(C(F)(F)F)cc4)nc3C)cc21
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1COc1ccc2c(c1)N(CC(=O)O)CC2

Procedure:
In analogy to the procedure described in example 5 g], {6-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-2,3-dihydro-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain {6-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-2,3-dihydro-indol-1-yl}-acetic acid as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[C:6]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[C:15](Cl)(Cl)=[S:16]>O1CCOCC1.O>[CH3:1][C:2]1[C:7]([N:8]=[C:15]=[S:16])=[C:6]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(N2CCCCC2)c1N
Reactant: S=C(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(N2CCCCC2)c1N=C=S

Procedure:
Reaction of 6-methyl-2-piperidinoaniline (6.4 g) in dioxan (20 ml) and water (65 ml) with thiophosgene (5.7 g) at 0° C. for 30 minutes and at room temperature for 2 hours gave 6-methyl-2-piperidinophenyl isothiocyanate as an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][CH2:10][C:11]#[N:12])[C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[N:4]=1.Cl.[NH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[OH:19][NH:18][C:11](=[NH:12])[CH2:10][CH2:9][CH2:8][N:7]1[C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[N:4]=[C:3]1[CH2:2][OH:1]
Reactant: NO
Reactant: N#CCCCn1c(CO)nc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N=C(CCCn1c(CO)nc2ccccc21)NO
Temperature: 80 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A mixture containing 4-(2-hydroxymethyl-benzoimidazol-1-yl)-butyronitrile, 25a, (40.0 g, 186 mmol), hydroxylamine hydrochloride (46.5 g, 0.689 mole) and potassium carbonate (51.4 g, 0.372 mole) in ethanol (400 mL) and water (200 mL) was heated at 80° C. and stirred overnight. The solvents were removed in vacuo and water was added. The white precipitate was collected by filtration, washed with water and dried in vacuo to afford N-hydroxy-4-(2-hydroxymethyl-benzoimidazol-1-yl)-butyramidine (35.8 g, 78%) as a white solid:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16](=[CH2:20])[CH2:17][CH2:18][NH2:19])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:21])[CH:11]=2)[CH:6]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31].C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16](=[CH2:20])[CH2:17][CH2:18][NH:19][S:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[Cl:23])(=[O:32])=[O:31])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:21])[CH:11]=2)[CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: C=C(CCN)c1c(C)c(CC(=O)OC)cc2ccc(F)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(CCNS(=O)(=O)c1ccccc1Cl)c1c(C)c(CC(=O)OC)cc2ccc(F)cc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of [4-(3-amino-1-methylene-propyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (120 mg, 0.398 mmol) in THF (4 mL) was cooled to 0° C. and the solid 2-chlorobenzene-1-sulfonyl chloride (168 mg, 0.796 mmol) was added followed by N,N-diisopropylethylamine (154 mg, 209 μL, 1.19 mmol). After stirring for 2 hours at 0° C., the cooling bath was removed and the reaction mixture was warmed to room temperature. The reaction mixture was stirred at room temperature for 15 hours, then diluted with water and brine. The resulting mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to afford a viscous oil. Flash chromatography (40 g ISCO column, 100% hexanes ramped to 50% ethyl acetate in hexanes) provided {4-[3-(2-chloro-benzenesulfonylamino)-1-methylene-propyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester as a viscous oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.04-8.07 (m, 1H), 7.74 (dd, J=9.00, 5.80 Hz, 1H), 7.62 (s, 1H), 7.49-7.54 (m, 2H), 7.40 (dd, J=7.65, 2.89 Hz, 1H), 7.32 (dd, J=11.20, 2.60 Hz, 1H), 7.19 (td, J=8.60, 2.40 Hz, 1H), 5.52 (q, J=1.40 Hz, 1H), 5.08-5.10 (m, 1H), 5.03 (t, J=6.40 Hz, 1H), 3.80 (s, 2H), 3.73 (s, 3H), 3.09-3.16 (m, 2H), 2.51 (t, J=7.00 Hz, 2H), 2.31 (s, 3H). MS cald. for C24H24ClFNO4S [(M+H)+] 476.1, obsd. 476.1.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:11]=1[C:12]1[CH:13]=[CH:14][C:15]([Br:25])=[CH:16][C:17]=1[C:18]2=[N:23]O.C(O)C.C(O)(=O)C>O.[Zn]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:11]=1[C:12]1[CH:13]=[CH:14][C:15]([Br:25])=[CH:16][C:17]=1[CH:18]2[NH2:23]
Reactant: ON=C1c2cc(Br)ccc2-c2c1cccc2-c1nc2ccccc2[nH]1
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: NC1c2cc(Br)ccc2-c2c(-c3nc4ccccc4[nH]3)cccc21
Temperature: 25 °C
Reaction time: 19 h
Yield: 224 %

Procedure:
Place 500 mg of 5-(1H-benzimidazol-2-yl)-2-bromo -9H-fluoren-9-one oxime (Z,E) in suspension in a mixture of 3.5 ml of water, 7 ml of ethanol and 3.5 ml of acetic acid. Add 335 mg of powdered zinc and stir at room temperature for 19 hours. The insoluble residues are filtered over sintered glass and rinsed with ethanol. Evaporation of the solvent under reduced pressure is a colourless foam which is taken up in suspension in 100 ml of water. The pH of the supernatant is then brought to 9 by the addition of a 1N aqueous solution of sodium hydroxide, and the persisting precipitate is filtered off, and washed with 3 times 50 ml of water and twice 100 ml of isopropyl ether. After drying at 50° C. in an oven under vacuum, in this way we obtain 1.08 g of 5-(1H-benzimidazol-2-yl)-2-bromo-9H-fluorene-9(R,S)-amine, in the form of a white powder which is used as it is in the following stage.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[N:7]=[C:8]([C:13]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:17]2=O)=[O:14])[NH:9][C:10]=1[CH2:11][CH3:12].C([BH3-])#N.[Na+].C(O)(=O)C>O1CCCC1>[Cl:5][C:6]1[N:7]=[C:8]([C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:18][C@H:17]2[NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:14])[NH:9][C:10]=1[CH2:11][CH3:12]
Reactant: CCc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2=O)nc1Cl
Reactant: NC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC2CC2)nc1Cl
Temperature: 50 °C
Reaction time: 15 h
Yield: 15 %

Procedure:
Cyclopropylamine (249 μL, 3.59 mmol) was added to a solution of tert-butyl 4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-oxopiperidine-1-carboxylate obtained in Example (201c) (190 mg, 0.512 mmol) in tetrahydrofuran (6 mL), and the mixture was heated under reflux at 50° C. for four hours. The reaction solution was concentrated under reduced pressure, and then tetrahydrofuran (3 mL) and methanol (3 mL) were added. Cyclopropylamine (71.0 μL, 0.102 mmol), sodium cyanoborohydride (97.0 mg, 1.54 mmol) and acetic acid (293 μL, 5.12 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with ethyl acetate. The resulting organic layer was washed with brine, and dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography and preparative TLC (eluent: chloroform:methanol=10:1 v/v) to obtain 34 mg of the cis isomer of the title compound (16%) as a pale yellow oily substance and 32 mg of the trans isomer of the title compound (15%) as a pale yellow oily substance.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:19])[C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1.[CH3:20][C:21]1[C:22](=[O:50])[N:23]([C:38]2[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[C:40]([C:46]([F:49])([F:48])[F:47])[CH:39]=2)[C:24](=[O:37])[C:25]=1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>O1CCCC1.C(OCC)(=O)C>[C:42]([C:41]1[CH:44]=[CH:45][C:38]([N:23]2[C:22](=[O:50])[C:21]([CH3:20])=[C:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][N:34]([C:17]([NH:16][C:13]4[CH:14]=[CH:15][C:10]([N:9]([CH3:19])[CH3:8])=[CH:11][CH:12]=4)=[O:18])[CH2:33][CH2:32]3)[C:24]2=[O:37])=[CH:39][C:40]=1[C:46]([F:47])([F:49])[F:48])#[N:43]
Reactant: CC1=C(CCCCCN2CCNCC2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: CN(C)c1ccc(N=C=O)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC1=C(CCCCCN2CCN(C(=O)Nc3ccc(N(C)C)cc3)CC2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.2 ml of a solution of triethylamine in tetrahydrofuran (1.5 mol/l) and 7 mg of 4-(dimethylamino)phenylisocyanate in 0.4 ml of tetrahydrofuran were added to a solution of 9 mg of 4-[2,5-dihydro-3-methyl-2,5-dioxo-4-[5-(piperazin-1-yl)pentyl]-1H-pyrrol-1-yl]-2-(trifluoromethyl)benzonitrile in 0.4 ml of tetrahydrofuran, and the mixture was stirred for 8 hours at room temperature. For working-up, the reaction mixture was diluted with ethyl acetate and washed with semi-saturated sodium bicarbonate solution. After the organic phase was concentrated by evaporation, it was chromatographed with methanol/dichloromethane on silica gel, and 3 mg of the title compound was thus obtained as a yellowish oil.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:36])[O:23][CH:24]([C:26]4[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=4)[CH3:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[H-].[Na+].I[CH2:42][CH3:43]>CN(C=O)C>[CH2:42]([N:21]([C:18]1[CH:17]=[CH:16][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:37])[F:38])=[CH:5][CH:6]=3)[N:11]=2)=[CH:20][CH:19]=1)[C:22](=[O:36])[O:23][CH:24]([C:26]1[CH:27]=[N:28][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:30][CH:31]=1)[CH3:25])[CH3:43]
Reactant: CCI
Reactant: CC(OC(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)c1ccc(C(F)(F)F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)c1ccc(C(F)(F)F)nc1)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.1 %

Procedure:
1-(6-(Trifluoromethyl)pyridin-3-yl)ethyl 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenylcarbamate (54 mg, 0.10 mmol) was dissolved in anhydrous DMF (0.5 mL) under N2 and cooled to 0° C. NaH (60% suspension in mineral oil; 4.4 mg, 0.11 mmol) was added, and the mixture was stirred for 10 min at 0° C. Iodoethane (9 μL, 0.11 mmol) was added, and the mixture was warmed to ambient temperature and stirred for 1 h. Additional NaH (4 mg) and iodoethane (5 μL) were added at ambient temperature to promote complete consumption of the starting material. The mixture was quenched with aqueous NH4Cl and extracted with 80% EtOAc/hexanes (×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The crude product was applied to a silica gel column, and elution with a 15% to 40% to 80% EtOAc/hexanes gradient provided the title compound (52.1 mg, 91%) as a light yellow oil: IR 3111, 2983, 2936, 1707, 1519, 1340, 1268, 1155 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.62 (s, J=10.6 Hz, 1H), 8.58 (s, 1H), 8.21 (d, J=8.5 Hz, 2H), 7.81 (d, J=9.0 Hz, 2H), 7.73-7.58 (m, 2H), 7.40 (d, J=8.5 Hz, 2H), 7.30 (d, J=8.5 Hz, 2H), 5.95 (q, J=6.6 Hz, 1H), 3.84-3.70 (m, 2H), 1.53 (d, J=6.2 Hz, 3H), 1.19 (t, J=7.1 Hz, 3H); HRMS-FAB (m/z) [M+H]+ calcd for C26H21F6N5O3, 565.1549. found, 565.1568.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([CH3:10])[CH3:9])[C:3]=1[S:11](Cl)(=[O:13])=[O:12].[CH3:15][P:16]([CH2:22][OH:23])(=[O:21])[O:17][CH:18]([CH3:20])[CH3:19].[OH-].[Na+]>C(Cl)Cl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.[Cl-].[NH4+].O>[CH3:15][P:16]([CH2:22][O:23][S:11]([C:3]1[C:4]([CH:8]([CH3:9])[CH3:10])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:12])=[O:13])(=[O:21])[O:17][CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)OP(C)(=O)CO
Reactant: CC(C)c1cccc(Cl)c1S(=O)(=O)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: CC(C)OP(C)(=O)COS(=O)(=O)c1c(Cl)cccc1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.9 %

Procedure:
To a solution of 2.5 g of 2-chloro-6-isopropylbenzenesulfonyl chloride (Example 9) and 1.15 g of O-isopropyl P-methyl(hydroxymethyl)phosphinate (Example 22, Method C) dissolved in 35 ml of methylene chloride at 5° C. was added 0.23 g of benzyltriethylammonium chloride followed by 2.5 ml of 20% aqueous sodium hydroxide. The reaction mixture was allowed to warm to room temperature over 1 hour then was stirred overnight. The pale yellow mixture was diluted with saturated ammonium chloride, 25 ml, and water, 25 ml, then the layers were separated and the aqueous phase was extracted with three 50 ml portions of methylene chloride. The combined organic layers were washed with brine, dried with magnesium sulfate, filtered, and concentrated to give 3.6 of a semisolid which was flash chromatographed on silica gel using 70% ethyl acetate/30% hexanes. Similar fractions were combined to give a white solid which was recrystallized from ether and hexanes to yield 1.0 g of desired product, mp 69.5°-70.5° C.