Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[NH:12][C:11]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#N)=[CH:17][CH:16]=3)=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(C1C=CC(C(=O)C(O)=[O:33])=CC=1)#N.Cl.ClC1C=C(NN)C=CC=1Cl.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[NH:12][C:11]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[O:33])=[CH:17][CH:16]=3)=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#Cc1ccc(C(=O)C(=O)O)cc1
Reactant: N#Cc1ccc(-c2nn(-c3ccc(Cl)c(Cl)c3)c(=O)[nH]2)cc1
Agent: Cl
Agent: NNc1ccc(Cl)c(Cl)c1
Solvent: O
Product: O=Cc1ccc(-c2nn(-c3ccc(Cl)c(Cl)c3)c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-[1-(3,4-Dichloro-phenyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-benzonitrile. A suspension of 4-cyanophenyl-oxo-acetic acid (100 mg, 0.571 mmol), (3,4-dichlorophenyl)hydrazine hydrochloride (122 mg, 0.571 mmol), 12.1 N HCl (5 uL, 0.057 mmol), and H2O (˜10 mL) in a 25 mL reaction vial was stirred vigorously at ambient temperature for 24 h. The hydrazone was obtained by vacuum filtration and placed into a 100 mL round bottom flask with a magnetic stir bar. The flask was then supplemented with triethylamine (0.08 mL, 0.571 mmol), diphenylphosphoryl azide (157 mg, 0.571 mmol), and toluene (20 mL) before heating at 110° C. for 1 h. Upon cooling the contents were quenched with 10% NaOH (aq) and made acidic (pH 1) with conc. HCl. Precipitation was allowed for 15 min before the intermediate was obtained by vacuum filtration and dried overnight in a 45° C. vacuum oven (16 mg, 8%). The nitrile was reduced to the aldehyde using DIBAL under conditions previously described.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.Cl[C:22]1[O:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1.N12CCCN=C1CCCCC2>O1CCOCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:22]4[O:23][C:24]5[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=5[N:26]=4)[CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: Clc1nc2ccccc2o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(c3nc4ccccc4o3)CC2)nn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
To the 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.080 g, 0.290 mmol) in dioxane (7 mL) was added 2-chlorobenzooxazole (0.053 g, 0.34 mmol) followed by the addition of 1,8-diazabicyclo[5,4,0]undec-7-ene (0.132 mL, 0.87 mmol) and tetra-n-butylammonium iodide (3 mg). The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate, then washed with citric acid, sodium bicarbonate and brine solution. The organic layer was separated, and dried over anhydrous Na2SO4, and evaporated. The residue was purified by recrystallization from n-hexane to yield the title compound as a white powder in 44% yield (0.050 g). 1H NMR (300 MHz, CDCl3) δ 8.07 (d, J=9.5 Hz, 1H), 7.99 (t, J=5.3 Hz, 1H), 7.39 (d, J=7.4 Hz, 1H), 7.28 (d, J=7.8 Hz, 1H), 7.19 (m, 1H), 7.05 (m, 2H), 3.92 (m, 8H), 3.55 (m, 2H), 1.48 (m, 2H), 0.79 (m, 1H), 0.46 (m, 2H), 0.07 (m, 2H). MS (ES+) m/z 393 (M+1).
Reaction SMILES: C(C1C=C(C(C)C)C=C(C(C)C)C=1S(NN=[C:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])(=O)=O)(C)C.[CH:33](=[O:42])[C:34]1[C:35](OC)=[CH:36][CH:37]=[CH:38][CH:39]=1>>[CH:34]1([CH:33]([OH:42])[C:21]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:22][CH2:23][N:24]([CH3:25])[CH3:26])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: COc1ccccc1C=O
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)NN=C(CCN(C)C)c2ccccc2)c(C(C)C)c1
Product: CN(C)CC=C(c1ccccc1)C(O)C1CCCCC1
Yield: 60.3 %

Procedure:
By using a method similar to that described in Example 22, but starting from β-dimethylaminopropiophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (20 g) and from o-anisaldehyde (6.5 g), 4-dimethylamino-1-(2-methoxyphenyl)-2-phenyl-2-buten-1-ol (Z) (7.2 g) is obtained in the form of a white powder melting at 77° C. after recrystallisation from a mixture (85 cc) of petroleum ether and isopropyl ether (70/30 by volume).
Reaction SMILES: C(=O)=O.[Na].[CH3:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH2:7].CO.O1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:9]1[C:10]2[C:11](=[CH:17][C:18]3[C:8]([CH:9]=2)=[CH:6][CH:5]=[CH:20][CH:19]=3)[CH:12]=[CH:13][C:8]=1[C:6]([CH3:5])=[CH2:7]
Reactant: C=C(C)c1ccccc1
Reactant: C1CCOC1
Agent: O=C=O
Agent: [Na]
Solvent: CO
Product: C=C(C)c1ccc2cc3ccccc3cc2c1
Temperature: -40 °C
Reaction time: 24 h

Procedure:
About 100 milliliters of tetrahydrofuran is vacuum distilled into a light tight ampule containing the above monomer, the ampule chilled to the temperature of dry ice (approximately -40° C) and about 5 milliliters of initiator solution (5 × 10-5 moles of the sodium salt of alphamethyl styrene tetramer in tetrahydrofuran) injected into the ampule through a side arm on the ampule. Polymerization of the monomer commences upon the introduction of the initiator into the ampule. After about 24 hours of continuous stirring at -40° C, the contents of the ampule are emptied into a flask containing methanol thereby quenching the polymerization reaction and precipitating the polymer. The polymer solids are recovered from the methanol solution by filtration, dried and reprecipitated from benzene with methanol. Yield: 8.0 grams of white polymer, Mw 280,000, Mw /Mn 1.74.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[NH:5][C:6](=[O:22])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[N:32](=[CH:40][CH2:41]Cl)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(=O)CC>[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:41][CH2:40][N:32]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:26][CH:25]=1)[NH:5][C:6](=[O:22])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1
Reactant: ClCC=NCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)[C@H](Cc1ccc(OCCN2CCCCCC2)cc1)NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1

Procedure:
The title compound was prepared via O-alkylation of N-(toluene-4-sulfonyl)-L-prolyl-L-tyrosine methyl ester with 2-(hexamethylene-imino)ethyl chloride in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide to provide a solid, mp=60-65° C.
Reaction SMILES: C(OC([NH:8][C:9]([CH3:37])([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([N:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:23][CH2:24][CH3:25])[CH:21]=1)[C:16](O)=[O:17])=O)(C)(C)C.B.C1COCC1>C1COCC1>[NH2:8][C:9]([CH3:37])([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:21]=[C:20]([N:22]([CH2:23][CH2:24][CH3:25])[S:26]([CH3:29])(=[O:28])=[O:27])[CH:19]=[C:15]([CH2:16][OH:17])[CH:14]=1
Reactant: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C(=O)O)c1)S(C)(=O)=O
Agent: B
Solvent: C1CCOC1
Product: CCCN(c1cc(CO)cc(COCC(C)(N)Cc2ccccc2)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3({2-[(tert-butoxycarbonyl)amino]-2-methyl-3-phenylpropoxy}methyl)-5-[(methylsulfonyl)(propyl)amino]benzoic acid (intermediate XI, 145 mg, 0.271 mmol) in THF (2 mL) cooled to 0° C. was added BH3-THF (1.356 mL, 1.356 mmol, 1 M in THP). After 10 min, the reaction mixture was allowed to warm to rt and stirred for 60 h. The reaction mixture was cooled back down to 0° C. and carefully quenched with MeOH. The mixture was concentrated to half its original volume and diluted with EtOAc and water. Following dilution, the organic layer was extracted, washed with sat. aq. NaHCO3 and brine, dried over sodium sulfate and concentrated in vacuo to provide N-[3-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-5-(hydroxymethyl)phenyl]-N-propylmethanesulfonamide as a white foam. 1H NMR (400 MHz, CDCl3) δ 7.33 (s, 1H), 7.29 (s, 1H), 7.28-7.20 (m, 4H), 7.17-7.13 (m, 2H), 4.74 (s, 2H), 4.60-4.51 (m, 3H), 3.63 (t, J=7.2 Hz, 2H), 3.53 (A of AB, d, J=8.8 Hz, 1H), 3.43 (B of AB, d, J=8.8 Hz, 1H), 3.12 (A of AB, d, J=13.2 Hz, 1H), 2.93 (B of AB, d, J=13.2 Hz, 1H), 2.88 (s, 3H), 1.55-1.45 (m, 2H), 1.46 (s, 9H), 1.25 (s, 3H), 0.91 (t, J=7.3 Hz, 3H).
Reaction SMILES: [C:1]([NH:9][CH:10]([C:15]([OH:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:2]1([C:1]2[O:17][C:15](=[O:16])[CH:10]([CH2:11][CH2:12][CH2:13][CH3:14])[N:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC(NC(=O)c1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CCCCC1N=C(c2ccccc2)OC1=O
Reaction time: 8 h

Procedure:
N-(Benzoyl)-D,L-norleucine (40 g., 170 mmole) is taken into 300 ml. of tetrahydrofuran with stirring in an ice bath. To this is added dropwise dicyclohexylcarbodiimide (38.52 g., 187 mmole) in tetrahydrofuran (195 ml.). After 15 minutes the bath is removed and the reaction is allowed to run overnight. The dicyclohexylurea is filtered off and the filtrate is concentrated to dryness. The crude product (31.7 g.) is purified on silica gel in hexane:ether (2:1) to give 2-phenyl-4-butyl-5(4H)-oxazolone. This product crystallizes neat when refrigerated.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.C(OC(=O)[C@@H](OC)CC1C=CC(O[CH2:27][CH2:28][Br:29])=CC=1)C>>[Br:29][CH2:28][CH2:27][O:7][C:4]1[CH:3]=[CH:2][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: Oc1ccc(-c2ccccc2)cc1
Product: BrCCOc1ccc(-c2ccccc2)cc1

Procedure:
The title compound was prepared from biphenyl-4-ol via the same procedure used for the preparation of (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) to produce a white solid. MS (ES) for C14H13BrO [M−H]−: 279.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NCCCCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: OCCCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 24 %

Procedure:
The title compound (g, 24%) was prepared as described in example 1 but using 5-aminopentanol instead of cis-2-buten-1,4-diol in the reaction with trityl chloride.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>COCCOCCOC>[N:12]1([C:2]2[N:3]=[CH:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: Clc1cc2ccccc2cn1
Reactant: C1CNCCN1
Solvent: COCCOCCOC
Product: c1ccc2cc(N3CCNCC3)ncc2c1
Yield: 92.1 %

Procedure:
2.0 g of 3-chloroisoquinoline are boiled under reflux for 120 hours with 20 g of piperazine in 100 ml of diethylene glycol dimethyl ether. Working up as in Example 1 gives 2.4 g of 3-(piperazin-1-yl)-isoquinoline, melting point 95°-96°; its hydrochloride decomposes at 266°-268° C.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1>C(O)(=O)C>[O:11]=[C:1]1[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:6])[N:12]1[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:17][CH:18]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1ccc(CC(=O)O)cc1
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(N2C(=O)c3ccccc3C2=O)cc1

Procedure:
Phthalic acid anhydride (15.1 g, 102 mmol) and 4-amino phenyl acetic acid (15.2 g, 102 mmol) were dissolved in acetic acid and heated at reflux for 1 hour. Upon cooling on an ice bath, the product crystallized. The solid was filtered off, washed with water, and dried under vacuum overnight. The yield of the title compound was 24.1 g (86%) as an off white solid.
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:26]=[CH:25][C:16]3[N:17]([CH2:23][CH3:24])[C:18](=[O:22])[N:19]([CH2:20][CH3:21])[C:15]=3[CH:14]=2)[C:10]([C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)=[N:9]1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH2:23]([N:17]1[C:16]2[CH:25]=[CH:26][C:13]([C:11]3[C:10]([C:27]4[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=4)=[N:9][N:8]([CH2:7][C:6]([OH:34])=[O:5])[CH:12]=3)=[CH:14][C:15]=2[N:19]([CH2:20][CH3:21])[C:18]1=[O:22])[CH3:24]
Reactant: CCn1c(=O)n(CC)c2cc(-c3cn(CC(=O)OC(C)(C)C)nc3-c3cccc(C)c3)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(=O)n(CC)c2cc(-c3cn(CC(=O)O)nc3-c3cccc(C)c3)ccc21
Temperature: 23 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
[4-(1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-3-m-tolyl-pyrazol-1-yl]-acetic acid tert-butyl ester (0.122 g) was diluted with dichloromethane (1 mL) and trifluoroacetic acid (0.5 mL). Upon stirring for 18 hours at 23° C. the mixture was concentrated to give [4-(1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-3-m-tolyl-pyrazol-1-yl]-acetic acid (0.107 g).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[Si:5]([O-:9])([O-:8])([O-:7])[O-:6].[Na+].[Na+].[Na+].[Na+].[CH:14](=[O:20])[C:15]1[O:19][CH:18]=[CH:17][CH:16]=1>>[Si:5]([OH:9])([OH:8])([OH:7])[OH:6].[NH2:1][C:2]([NH2:4])=[S:3].[CH:14](=[O:20])[C:15]1[O:19][CH:18]=[CH:17][CH:16]=1
Reactant: [O-][Si]([O-])([O-])[O-]
Agent: NC(N)=S
Agent: [Na+]
Solvent: O=Cc1ccco1
Product: O[Si](O)(O)O

Procedure:
About 1 mol of thiourea (Component B), 1 mol of hydrated silica (Component A), 0.5 mol of sodium silicate (Component A) and 2 mols of furfural (Component C) are mixed, then heated to 60° C. to 100° C. for 20 to 120 minutes, thereby producing a poly(furfural thiourea silicate) resinous product.
Reaction SMILES: [F:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[O:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1.C([BH3-])#N.[Na+]>CO.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[F:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]2[N:6]([CH:10]3[CH2:11][CH2:12][N:13]([CH:22]4[CH2:23][CH2:24][O:19][CH2:20][CH2:21]4)[CH2:14][CH2:15]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1F)[nH]c(=O)n2C1CCNCC1
Reactant: O=C1CCOCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CO
Product: Cc1cc2c(cc1F)[nH]c(=O)n2C1CCN(C2CCOCC2)CC1
Reaction time: 1.5 h

Procedure:
5-Fluoro-6-methyl-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one (D30) (0.64 mmol, 160 mg) in methanol (3 mL) was treated under argon at room temperature with tetrahydro-4H-pyran-4-one (1.28 mmol, 128 mg, 2 eq), then titanium tetra-isopropoxide (1.28 mmol, 364 mg, 2 eq). The mixture was stirred under argon for 1.5 h, then sodium cyanoborohydride (1.28 mmol, 80.4 mg, 2 eq) was added and stirred for 1.5 h. The mixture was loaded on an SCX cartridge, washed with 6 CV methanol and eluted with 6 CV 2M ammonia in methanol and dichloromethane. The eluate was concentrated under reduced pressure and purified 5-100% 2 m NH3 in MeOH/DCM to give 5-fluoro-6-methyl-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one, which was transformed into the corresponding HCl salt (0.27 mmol, 100 mg, 42% yield), using 1M HCl in diethyl ether. M+H=334.12
Reaction SMILES: C[Si](C)(C)CCOCN1C2C=CC=CC=2N=C1[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][N:17]=1>O1CCOCC1.CCOC(C)=O>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[N:17]1
Reactant: C[Si](C)(C)CCOCn1c(-c2n[nH]c3ccccc23)nc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: c1ccc2[nH]ncc2c1

Procedure:
Preparation of 6-[5-methoxy-2-hydroxymethyl-4-(2-trimethylsilanyl-ethoxymethoxy)phenyl]-1-(2-trimethylsilanyl)-ethoxymethyl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-indazole: 6-Iodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl-ethoxymethyl]-1H-benzoimidazol-2-yl}-1H-indazole [Example 24(a), step (v)] (300 mg, 0.48 mmol) and [4-methoxy-5-(2-trimethylsilanyl)-ethoxymethoxy-2-trimethylstannanyl-phenyl]-methanol (282 mg, 0.63 mmol) were stirred in dioxane (8 mL) under argon at 98° C. for 16 h. The reaction was allowed to cool and was diluted with EtOAc. Organics were washed with sat NaHCO3 and brine, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography (20% EtOAc/hexanes) gave 224 mg (60%) of 6-[5-methoxy-2-hydroxymethyl(2-trimethylsilanyl-ethoxymethoxy)-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-3-[1-(2-trimethylsilanyl)-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-indazol as a faint yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.70 (d, 1H, J=8.4 Hz), 7.89-7.92 (m, 1H), 7.63-7.66 (m, 2H), 7.34-7.41 (m, 4H), 6.91 (s, 1H), 6.29 (s, 2H), 5.83 (s, 2H), 5.36 (s, 2H), 4.55 (s, 2H), 3.78-3.92 (m, 5H), 3.59-3.70 (m, 4H), 0.83-1.04 (m, 6H), 0.03 (s, 9H); 40.04 (s, 9H), −0.13 (s, 9 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:20][CH3:21])[C:5]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Br[CH:23]([CH3:38])[CH2:24][CH2:25][CH2:26][N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37].C(N(CC)CC)C.Br>CC(C)=O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:5]2[C:4]([O:20][CH3:21])=[CH:3][C:2]([NH:1][CH:23]([CH3:38])[CH2:24][CH2:25][CH2:26][N:27]3[C:31](=[O:32])[C:30]4=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]4[C:28]3=[O:37])=[C:11]3[C:6]=2[CH:7]=[CH:8][CH:9]=[N:10]3)=[CH:14][CH:15]=1
Reactant: CC(Br)CCCN1C(=O)c2ccccc2C1=O
Reactant: COc1cc(N)c2ncccc2c1Oc1ccc(Cl)cc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COc1cc(NC(C)CCCN2C(=O)c3ccccc3C2=O)c2ncccc2c1Oc1ccc(Cl)cc1
Yield: 79.5 %

Procedure:
A stirred mixture of 8-amino-5-(4-chlorophenoxy)- 6-methoxyquinoline (6.2 g, 0.02 mole), 4-bromo-1-phthalimidopentane (6.0 g, 0.02 mole), and triethylamine (2.0 g, 0.02 mole) was heated at 130°-135° for 12 hr. The cooled mixture was extractively treated with arm acetone (50 ml), cooled, and triethylamine hydrobromide collected (3.2 g, 89%). The filtrates were concentrated to dryness, and the residues taken up in chloroform, then treated with 48% hydrobromic acid. The chloroform layer was dried and concentrated, then absolute ether added to precipitate the hydrobromide of the desired compound (8.2 g, 70% yield). As obtained, the hydrobromide melted 194°-198°; following crystallization from ethanol, mp 214°-215°. It analyzed as a monohydrate. The base was liberated as a crystalline solid of mp 75°-77°.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Reactant: C1COCCN1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCOCC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and morpholine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=373.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=O)=[CH:5][CH:4]=[N:3]1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[CH3:1][N:2]1[C:6]([CH2:7][NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1C=O
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cn1nccc1CNc1ccc(C(F)(F)F)cc1
Reaction time: 0.17 h
Yield: 81.1 %

Procedure:
Acetic acid (0.87 mL) was added to a chloroform (10 mL) solution that contained 1-methyl-1H-pyrazol-5-carbaldehyde (1.00 g) and 4-aminobenzotrifluoride (1.76 g) at a room temperature, and the obtained solution was then stirred for 10 minutes. Thereafter, sodium triacetoxyborohydride (2.89 g) was added to the reaction solution, and the obtained mixture was then stirred for 5.5 hours. Thereafter, a saturated sodium hydrogencarbonate aqueous solution was added to the reaction solution, and the obtained mixture was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated under a reduced pressure. The obtained solid was washed with diisopropyl ether, so as to obtain the title compound (1.88 g) in the form of a light yellow solid.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28](=N)[C:29]([CH3:32])([CH3:31])[CH3:30]>>[C:29]([C:28]1[N:2]=[C:1]([N:3]2[CH2:4][CH2:5][CH:6]([N:9]([CH:23]3[CH2:25][CH2:24]3)[C:10](=[O:22])[C:11]3[CH:12]=[CH:13][C:14]([C:17]4[O:21][CH:20]=[N:19][CH:18]=4)=[CH:15][CH:16]=3)[CH2:7][CH2:8]2)[O:26][N:27]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)C(=N)NO
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Product: CC(C)(C)c1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-2,2-dimethyl-propionamidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.68 min; Mass spectrum (ESI+): m/z=436 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[C:3]#[C:4][CH2:5][O:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:10][C:9]([CH3:11])=[CH:8][CH2:7][O:6][CH2:5][C:4]#[C:3][C:2]([C:12]1[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=1)=[O:1]
Reactant: COc1cc(C(O)C#CCOCC=C(C)C)cc(OC)c1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cc(C(=O)C#CCOCC=C(C)C)cc(OC)c1OC
Reaction time: 3 h

Procedure:
A solution of 30 g (93.6 mmol) of 1-hydroxy-4-[(3-methyl-2-butenyl)oxy]-1-(3,4,5-trimethoxyphenyl)-2-butyne in 350 ml of methylene chloride was added dropwise at 0° to a suspension of 122 g (1.4 mol) of manganese dioxide in 500 ml of methylene chloride. The reaction mixture was stirred at 0° for 3 hours, filtered over magnesium sulphate and concentrated. Flash chromatography of the residue on 1000 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1) and subsequent crystallization of the product from ether/hexane yielded 4-[(3-methyl-2-butenyl)oxy]-1-(3,4,5-trimethoxyphenyl)-2-butyn-1-one of melting point 32°.