Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].Cl.[CH2:24]([SH:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C=O.C(OCC)(=O)C>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([S:31][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:12])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8]
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: SCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)SCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 124.8 %

Procedure:
Z-Arg-OH.HCl (6 g, 8.7 mmoles) and benzyl mercaptan (4.2 ml, 17.4 mmoles) are dissolved in dimethylformamide (DMF) and cooled to 0° C. DCC (3.6 g, 8.7 mmoles), dissolved in DMF, is then added to the above reaction mixture, stirred at 0° C. for 30 minutes, then stirred overnight at room temperature. The precipitate formed is removed by filtration and the filtrate is concentrated under vacuum to yield an oil. This oily residue is dissolved in ethyl acetate and washed, successively, with 0.1 N HCl, 5% NaHCO3, and saturated aqueous NaCl. The organic layer is dried over anhydrous Na2SO4 and the solvent removed by evaporation. The crude product is purified by silica gel column, using a CHCl3 /methanol system, yielding 4.5 g of the product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[NH:8][N:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].[Cl:21][C:22]1[CH:31]=[CH:30][C:25]([CH:26]=[CH:27][CH2:28]Cl)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:31]=[CH:30][C:25]([CH:26]=[CH:27][CH2:28][N:8]2[C:7](=[O:20])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)=[N:9]2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Reactant: ClCC=Cc1ccc(Cl)cc1
Product: CCOC(=O)c1cc(-c2ccc(OC)cc2)nn(CC=Cc2ccc(Cl)cc2)c1=O
Yield: 85.7 %

Procedure:
Using 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and 4-chlorocinnamyl chloride as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 85.7%.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1)=[O:4].[CH3:23][S:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][C:2]([CH3:22])([CH3:21])[C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([CH2:29][C:28]4[CH:31]=[CH:32][C:25]([S:24][CH3:23])=[CH:26][CH:27]=4)[CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1)=[O:4]
Reactant: CSc1ccc(C=O)cc1
Reactant: CC(C)(C)C(=O)n1ncc2cc(NC3CCCNC3)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CSc1ccc(CN2CCCC(Nc3ccc4c(cnn4C(=O)C(C)(C)C)c3)C2)cc1
Yield: 71.6 %

Procedure:
Into a 25 mL round bottom flask were combined 2,2-dimethyl-1-(5-(piperidin-3-ylamino)-1H-indazol-1-yl)propan-1-one (0.250 g, 0.8 mmol), 1,2-dichloroethane (5 mL), 4-(methylthio)benzaldehyde (0.127 g, 0.8 mmol), glacial acetic acid (50 μL, 0.8 mmol), and sodium triacetoxyborohydride (0.229 g, 1.1 mmol). The reaction was evacuated and refilled with nitrogen. The reaction was monitored by HPLC and was complete upon the disappearance of the starting amine. The reaction was diluted with saturated sodium bicarbonate (10 mL) and dichloromethane (5 mL). After mixing, the organic phase was isolated, dried over MgSO4, filtered and concentrated to give the crude product. Chromatography of the residue on silica gel gave the title compound as an off-white solid (250 mg, 69%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH:13][C:14]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][N:17]=2)=[O:15])=[N:2]1.O.[OH-].[Li+]>O1CCCC1.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH:13][C:14]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]=2)=[O:15])=[N:2]1
Reactant: COC(=O)c1ccc(C(=O)NCCNc2nsc3ccccc23)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(=O)NCCNc2nsc3ccccc23)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
Methyl 6-(2(benzo[d]isothiazol-3-ylamino)ethylcarbamoyl)nicotinate (211 mg, 0.6 mmol) was dissolved in a mixture of tetrahydrofuran (5 mL) and water (0.5 mL) and treated with lithium hydroxide monohydrate (100 mg, 2.4 mmol). The reaction mixture was stirred at room temperature overnight. The tetrahydrofuran was removed under vacuum and the residue was diluted with water. Dropwise addition of 50% aqueous hydrochloric acid gave a white solid, which was collected by vacuum filtration and dried to yield 6-(2-(benzo[d]isothiazol-3-ylamino)ethylcarbamoyl)nicotinic acid (130 mg) as a white solid. 1H NMR (300 MHz, CDCl3/DMSO-d6): 9.02 (m, 1H), 8.83 (broad s, 1H), 8.32 (m, 1H), 8.10 (d, 1H), 7.95 (d, 1H), 7.68 (d, 1H), 7.39 (t, 1H), 7.25 (t, 1H), 3.71 ppm (m, 4H). MW=342 confirmed by LC-MS, tr=10.56 min (Method Y) MH+=343
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]([OH:14])=[O:13].[CH3:15][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:10])([F:11])[F:9])[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cn1nc(C(F)(F)F)c(C(=O)O)c1Cl
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1c(C(F)(F)F)nn(C)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (1.00 g, 4.38 mmol) in benzene (5.83 mL) and methanol (2.92 mL) at room temperature was added 2M trimethylsilyldiazomethane (8.75 mL). The resulting solution was stirred at room temperature for 3 hours. Solvent was removed at reduced pressure on a rotary evaporator to yield the title compound (1.06 g, 4.38 mmol, 100% yield) as a white solid. MS m/z 243 (MH+). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 3.82 (s, 3H) 3.89 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:25][C:26]1[N:31]=[CH:30][C:29]([C:32]([NH:34]O)=[NH:33])=[CH:28][N:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]4[O:24][N:34]=[C:32]([C:29]5[CH:28]=[N:27][C:26]([NH2:25])=[N:31][CH:30]=5)[N:33]=4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N=C(NO)c1cnc(N)nc1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Product: Nc1ncc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(Cl)c(Cl)c5)nc34)n2)cn1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.9) (188 mg, 0.5 mmol) and 2-amino-N-hydroxy-pyrimidine-5-carboxamidine (example B.5) (115 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (180 mg, 73%). MS (EI) 492.0 [(M)+]; mp 300° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[F:24][C:25]([F:32])([F:31])[C:26](OCC)=[O:27]>C(Cl)Cl>[F:24][C:25]([F:32])([F:31])[C:26]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCOC(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)C(F)(F)F)CC1
Reaction time: 20 h

Procedure:
To a suspension of tert-butyl 4-aminopiperidine-1-carboxylate (48.7 g, 0.243 mol) and DIPEA (130 mL, 0.749 mol) in DCM (250 mL) was added ethyl trifluoroacetate (35.6 mL, 0.300 mol) dropwise while stirring. After 20 hours, the solution was washed with citric acid solution (200 mL×3, 10% w/v aq) and sodium bicarbonate solution (200 mL×3, conc aq), dried (MgSO4), and filtered through silica (24 g). The silica was washed with DCM and the combined eluant was partially concentrated (100 mL), and used directly in the next step. APCI/MS calcd. for C12H19F3N2O3 296.1. found m/z=294.9 (M−1).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]2[CH2:24][C@@H:23]([O:25][CH2:26][CH2:27][O:28]C3CCCCO3)[C@H:22]([O:35][CH2:36][O:37][CH3:38])[CH2:21]2)[N:15]=1.C(=O)(O)[O-].[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]2[CH2:24][C@@H:23]([O:25][CH2:26][CH2:27][OH:28])[C@H:22]([O:35][CH2:36][O:37][CH3:38])[CH2:21]2)[N:15]=1
Reactant: COCO[C@@H]1CN(c2cccc(Br)n2)C[C@H]1OCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCO[C@@H]1CN(c2cccc(Br)n2)C[C@H]1OCCO
Reaction time: 0.5 h

Procedure:
2.26 g p-toluenesulfonic acid monohydrate was added dropwise little by little into a solution of 60 ml of methanol containing 17.09 g of 2-bromo-6-[(3R,4R)-3-methoxymethyloxy-4-[2-(tetrahydro-2H-2-pyranyloxy)ethyl]oxypyrrolidine-1-yl]pyridine in an ice bath. After stirring for 30 minutes under ice-cooling, it was stirred at room temperature for 2 hours. 377 mg of p-toluenesulfonic acid monohydrate was further added thereto, followed by stirring for 2 hours. Then, the reaction solution was poured into aqueous saturated sodium bicarbonate and extracted twice with ethyl acetate. The organic phase was washed with brine and the solvent was removed. The residue was filtered through silica gel, to give 13.14 g of the target compound.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C.[C:22]([O:28][CH2:29][CH2:30][CH2:31]Br)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C>[N:3]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:31][CH2:30][CH2:29][O:28][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:11][CH2:10]1
Reactant: CC(C)(C)C(=O)OCCCBr
Reactant: c1cnc(N2CCNCC2)nc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCCCN1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 164.1 %

Procedure:
To a stirred solution of N-(2-pyrimidinyl)piperazine dihydrochloride (4.25 g, 0.0179 mol) and triethylamine (6.06 g, 0.06 mol) in DMF was added 3-bromopropyl pivalate (4.0 g, 0.0179 mol) and the solution was stirred overnight at room temperature. The solvent was evaporated and the residue dissolved in CH2Cl2. The CH2Cl2 extract was washed with water, dried (anhydrous Na2SO4) and evaporated to afford 9.0 g of crude title compound. Purification by HPLC and conversion to the dihydrochloride with ethereal HCl yielded the product, mp. 178°-180° C.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([N:14]1[C:19](=[O:20])[C:18]2=[C:21]([Cl:24])[CH:22]=[CH:23][N:17]2[N:16]=[C:15]1[CH:25]=CN(C)C)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([N:14]1[C:19](=[O:20])[C:18]2=[C:21]([Cl:24])[CH:22]=[CH:23][N:17]2[N:16]=[C:15]1[CH:25]=[O:2])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CN(C)C=Cc1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.3 %

Procedure:
Sodium periodate (17.3 g, 80.7 mmol) was added to a pH 7.0 buffered solution (75 mL) of 3-benzyl-5-chloro-2-(2-dimethylamino-vinyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (5.3 g, 16.1 mmol) in THF (150 mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was filtered through Celite® and the solids washed with CHCl3 (100 ml). The filtrate was wash with saturated NaCl (2×50 mL), dried (Na2SO4), filtered and concentrated in vacuo. The solid was azeotroped with toluene (2×50 mL) to afford the title compound as a solid (4.6 g, 100%): TLC, Rf=0.5 (2/1 hexane/EtOAc, UV); 1H NMR (CDCl3) δ 9.34 (s, 1H), 7.33 (m, 1H), 7.16–7.27 (m, 5H), 6.60 (m, 1H), 5.62 (s, 2H).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:14]([N:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][N:19]2[CH:27]=[CH:28][CH:29]=[C:18]2[CH2:17]1)=[O:15].[Cl:30][C:31]([Cl:36])([Cl:35])[C:32](Cl)=[O:33]>O1CCOCC1>[Cl:30][C:31]([Cl:36])([Cl:35])[C:32]([C:27]1[N:19]2[C:18]([CH2:17][N:16]([C:14]([C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[CH2:12][C:13]=4[CH:1]=3)=[O:15])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20]2)=[CH:29][CH:28]=1)=[O:33]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: O=C(c1ccc2c(c1)Cc1ccccc1-2)N1Cc2cccn2Cc2ccccc21
Solvent: C1COCCO1
Product: O=C(c1ccc2c(c1)Cc1ccccc1-2)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Temperature: 25 °C
Yield: 88.6 %

Procedure:
To 25 mL of 1,4-dioxane was added 0.59 g (0.0016 mol) of 10-(9H-fluoren-2-ylcarbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine opf Step A followed by the addition of 0.31 g (0.0017 mol) of trichloroacetyl chloride. The solution was heated under reflux for 10 minutes, cooled to room temperature and poured into ice water with stirring The precipitate was collected, washed with water and dried yielding 0.74 g of title compound which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([OH:11])[CH:5]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]O)=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([O:11][CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(Cl)c(O)c1
Reactant: OCCc1ccc(Cl)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(OCCc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
g (5.36 mmol) of 4-Chloro-3-hydroxy-benzoic acid methyl ester was dissolved in 40 ml of anhydrous tetrahydrofuran. To this solution was added 0.923 g (5.9 mmol) of 2-(4-chloro-phenyl)-ethanol, 5.35 g (equivalent to 16.1 mmol PPh3) of triphenylphosphine derivatized polystyrene and 2.80 g (16.1 mmol) of DEAD. The solution was shaken for 16 h at RT. The polymer was filtered off and washed with ethyl acetate. The solvent was removed under reduced pressure. The residue was taken-up in ethyl acetate and the solution was washed three times with water and twice with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/5). Yield 1.6 g. LC-MS (ES+): m/e=325 (M)+
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:39][O:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:46]3[CH2:47][CH2:48][N:43]([CH2:42][CH2:41][O:40][CH3:39])[CH2:44][CH2:45]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: COCCN1CCNCC1
Product: COCCN1CCN(C(=O)N2C(c3ccc(C(C)(C)C)cc3OC(C)C)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(2-methoxy-ethyl)-piperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C38H49N4O3Cl2 [(M+H)+] 679.3176, observed 679.3180.
Reaction SMILES: C(OC([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=O)C1C=CC=CC=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:40][CH2:41][CH2:42][OH:43]>ClCCl.O>[NH2:11][C:12]([CH3:16])([CH3:17])[C:13]([NH:40][CH2:41][CH2:42][OH:43])=[O:15]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(N)C(=O)NCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
To a solution of 2-benzyloxycarbonylamino-2-methyl-propionic acid (0.5 g) in dichloromethane (5 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.61 g), 1-hydroxybenzotriazole (0.43 g) and 2-aminoethanol (1.16 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added water, and the resulting mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (5 mL). To the solution was added 10% palladium-carbon powder (0.10 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give 2-(2-amino-2-methylpropionyl-amino)ethanol (0.11 g). To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole (70 mg) in N,N-dimethylformamide (0.5 mL) were added 1-ethyl-3-(3-di-methylaminopropyl)carbodiimide hydrochloride (32 mg), 1-hydroxybenzotriazole (23 mg) and 2-(2-amino-2-methyl-propionylamino)ethanol (0.11 g), and the mixture was stirred at room temperature overnight. The insoluble material was removed by filtration, 5 mol/L aqueous sodium hydroxide solution (0.25 mL) was added to the filtrate, and the resulting mixture was stirred at room temperature for 1 hour. To the mixture was added acetic acid (0.09 mL), and the mixture was diluted with water (1 mL). The insoluble material was removed by filtration, and the filtrate was purified by preparative reverse phase column chromatography (Shiseido CAPCELL PAK UG120 ODS, 5 μL, 120 Å, 20×50 mm, flow rate 30 mL/minute linear gradient, water/methanol=90/10-10/90) to give 3-(β-D-glucopyranosyloxy)-4-(4-{(1E)-3-[1-(2-hydroxyethylcarbamoyl)-1-methylethylcarbamoyl]prop-1-enyl}phenyl)methyl)-5-isopropyl-1H-pyrazole (14 mg). This material was dissolved in methanol (0.5 mL). To the solution was added 10% palladium-carbon powder (7 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (11 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)=[O:5].Br[CH:14]([CH3:16])[CH3:15].O>CN(C=O)C>[CH:14]([O:12][C:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:5])[CH3:3])=[CH:7][CH:8]=1)([CH3:16])[CH3:15]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
Sodium hydride (1.32 g, 33 mmol, 60% suspension in mineral oil) was suspended in anhydrous DMF (20 mL). A solution of 4-hydroxy acetophenone (4.08 g, 30 mmol) in anhydrous DMF (20 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 30 min. A solution of 2-bromopropane (4.61 g, 37.5 mmol) in anhydrous DMF (10 mL) was added slowly. The reaction mixture was stirred at room temperature overnight. Water (100 mL) was added. The mixture was extracted with ethyl acetate (2×100 mL). The organic layer was washed with water (3×50 mL) and brine (50 mL). Dried over anhydrous Na2SO4. Removal of solvent gave 1-(4-isopropoxy phenyl)ethanone as a pale yellow solid (3.52 g, 66%). To a stirred solution of 2-methoxy-5-pyrrolidin-1-ylmethyl nicotinic acid methyl ester (0.5 g, 2.0 mmol) and 1-(4-isopropoxy phenyl)ethanone in anhydrous DMF (10 mL), sodium hydride (96 mg, 2.4 mmol, 60% suspension in mineral oil) was added in small portions under nitrogen. The reaction mixture was stirred overnight at room temperature. Reaction mixture was stirred at 80° C. for 1 hours. Water (30 mL) was added. The mixture was extracted with chloroform (150 mL). The organic layer was washed with water (30 mL) and brine (30 mL). Dried over anhydrous Na2SO4. Removal of solvent gave brown solid (0.66 g) which was used in next step without further purification. The above solid (0.626 g, 1.58 mmol) and pyridine hydrochloride (1.18 g, 15.8 mmol) were mixed together and stirred at 190° C. for 20 min. Cooled to room temperature. Water (10 mL) was added, neutralized to pH ˜9. The mixture was extracted with chloroform (2×100 mL). The organic layer was washed with brine (50 mL) and dried (Na2SO4). Removal of the solvent gave 2-(4-isopropoxy phenyl)-6-pyrrolidin-1-ylmethyl pyrano[2,3-b]pyridine-one (0.237 g, 41%) as yellow solid. To a solution of the above compound in anhydrous CH2Cl2 (10 mL) was added 1.0 M solution of hydrogen chloride in ether dropwise. The reaction mixture was stirred for 10 min. The solvent was removed under reduced pressure. The residue was washed with hexane and ether. Purified by triturating with 10% methanol in ether to give 2-(4-isopropoxyphenyl)-6-(pyrrolidin-1-ylmethyl)-4H-pyrano[2,3-b]pyridin-4-one hydrochloride (0.20 g, 83%) as yellow solid. MS (ES) m/z: 264 (M); MP 261-263° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:36][C:37]1[N:38]([CH3:42])[CH:39]=[CH:40][N:41]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH3:42][N:38]1[CH:39]=[CH:40][N:41]=[C:37]1[CH2:36][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(O)c4)nc4ccccc34)ccc21
Reactant: Cn1ccnc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1ccnc1COc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1

Procedure:
A solution of tert-butyl 5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (50 mg, 0.11 mmol), 2-(chloromethyl)-1-methyl-1H-imidazole (22 mg, 0.13 mmol), KI (22 mg, 0.13 mmol), K2CO3 (76 mg, 0.55 mmol) in anhydrous DMF (1.2 mL) was heated at 50° C. for 100 minutes. Added 1.2 equivalents each of 2-(chloromethyl)-1-methyl-1H-imidazole and KI and heated for another 35 minutes. Added 2.4 equivalents each of 2-(chloromethyl)-1-methyl-1H-imidazole and KI along with 2.0 equivalents of K2CO3 and heated for 1 h. The solution was diluted with CH2Cl2 and washed with aqueous saturated NaCl (2×). The organic phase was dried under Na2SO4 and concentrated in vacuo to afford tert-butyl 5-(2-(3-((1-methyl-1H-imidazol-2-yl)methoxy)-phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate.