Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[N:6].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([O:24][CH:25]4[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]4)=[N:21][CH:20]=[N:19][C:18]=3[O:17][C:16]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C1COCC1.ClCCl>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:23]3[C:22]([O:24][CH:25]4[CH2:30][CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][C:5]#[N:6])[CH2:26]4)=[N:21][CH:20]=[N:19][C:18]=3[O:17][C:16]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OC4CCCNC4)c23)cc1
Reactant: N#CCCCBr
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OC4CCCN(CCCC#N)C4)c23)cc1
Temperature: 25 °C

Procedure:
Add 147.5 mg (0.996 mmol) of 4-bromobutyronitrile at RT to a mixture of 200 mg (0.498 mmol) of (+/−)-5-(4-methoxyphenyl)-6-phenyl-4-(piperidin-3-yloxy)furo[2,3-d]pyrimidine, 0.25 ml (1.5 mmol) of diisopropylethylamine and 8.3 mg of potassium iodide in 2 ml of THF. The mixture is stirred under reflux for 10 h. After adding a further 0.25 ml (1.5 mmol) of diisopropylethylamine and 147.5 mg (0.996 mmol) of 4-bromobutyronitrile, continue to stir under reflux overnight. After cooling to RT, dilute with dichloromethane, wash with satd. sodium hydrogencarbonate solution, remove the organic phase, dry over sodium sulphate and concentrate under reduced pressure. After purifying the residue by means of preparative RP-HPLC (eluent: acetonitrile/water gradient) 189 mg of the target product are obtained (81.1% of theory).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11]([OH:13])=[O:12])=O.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:2]([C:3]1[O:12][C:11](=[O:13])[CH:10]=[C:9]2[C:8]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:7]=3[O:6][C:5]=12)([CH3:21])([CH3:20])[CH3:1]
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc2oc3c(C(C)(C)C)oc(=O)cc3c2c1
Temperature: 25 °C

Procedure:
Dissolve 98 mg [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid from the Step B Example 1, 176 μL DIEA, and 114 mg HOBt in 3.5 mL dry DMF. Add 97.1 mg EDC and let the mixture stir at room temperature over night. It was purified directly on RP-HPLC using 50-70% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound as yellow solid. 1H NMR (CDCl3, 500 MHz) 7.34 (dd, J=1.3 & 8.4 Hz, 1H), 7.25˜7.29 (m, 2H), 6.54 (s, 1H), 3.92 (s, 3H), 1.52 (s, 9H). LC-MS: 3.55 min. (M+H=273.1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:15][O:16][C:17](=[O:20])[CH2:18]Br.C(N(C(C)C)CC)(C)C>CO>[CH3:15][O:16][C:17](=[O:20])[CH2:18][N:12]1[CH2:13][CH2:14][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:10][CH2:11]1
Reactant: COc1cccc(C2CCNCC2)c1
Reactant: COC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)CN1CCC(c2cccc(OC)c2)CC1
Yield: 90.4 %

Procedure:
A mixture of 4-(3-Methoxy-phenyl)-piperidine (0.8 g, 4.2 mmol), methylbromoacetate (1.28 g, 8.38 mmol), diisopropylethylamine (3.7 mL, 21 mmol) and MeOH (40 mL) was refluxed for 3 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between water and EtOAc and extracted. The organic layer was washed with water, brine, dried and concentrated in vacuo to give the title compound as an oil (1.0 g, 91% yield). MS(ESI) 264.2 (M+H+)
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]([OH:18])=O)[CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1.[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25]([NH:28][C:16]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]2[CH2:5][CH2:4][CH:3]([N:2]([CH3:1])[CH3:19])[CH2:15][C:14]3=2)=[O:18])=[CH:24][CH:23]=1
Reactant: COc1ccc(N)cn1
Reactant: CN(C)C1CCc2[nH]c3ccc(C(=O)O)cc3c2C1
Product: COc1ccc(NC(=O)c2ccc3[nH]c4c(c3c2)CC(N(C)C)CC4)cn1
Yield: 14 %

Procedure:
Beginning with 7.4 mg (0.029 mMol) 3-dimethylamino-1,2,3,4-tetrahydro-9H-carbazole-6-carboxylic acid and 6-methoxy-3-aminopyridine, 1.8 mg (14%) of the title compound were recovered.
Reaction SMILES: C(COC)OC.[NH2:7][C:8]1[CH:15]=[CH:14][C:13](Br)=[CH:12][C:9]=1[C:10]#[N:11].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O>[NH2:7][C:8]1[CH:15]=[CH:14][C:13]([C:22]2[CH:23]=[CH:24][C:19]([C:18]([F:29])([F:28])[F:17])=[CH:20][CH:21]=2)=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: N#Cc1cc(Br)ccc1N
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To dimethoxyethane (100 mL) and water (50 mL) was added 2-amino-5-bromo-benzonitrile (8.1 g), 4-trifluoromethyl-phenyl-boronic acid (8.6 g) and potassium carbonate (18.7 g), nitrogen was bobbled through the mixture for 10 minutes. Under a nitrogen atmosphere was bis(triphenyl-phosphine)palladium (II) chloride (0.3 g) added, the reaction mixture was heated at reflux overnight, then cooled to room temperature and added water (150 mL). The mixture was extracted with ethyl acetate, the organic phase was washed with water (50 mL) and brine (50 mL), then dried with magnesium sulfate and evaporated to an oil. The product was purified by column chromatography. Yield 8.36 g of white powder. Similarly was made:
Reaction SMILES: C([NH+](CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([NH:29][CH:30]([CH2:34][CH2:35][CH2:36]C)C([O-])=O)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1.C(N(CC)CC)C.[CH:45]1[C:50]([F:51])=[C:49]([F:52])[C:48]([O:53][C:54]([C:56](F)(F)F)=[O:55])=[C:47]([F:60])[C:46]=1[F:61]>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([NH:29][CH2:30][CH2:34][CH2:35][CH2:36][CH2:56][C:54]([O:53][C:48]2[C:49]([F:52])=[C:50]([F:51])[CH:45]=[C:46]([F:61])[C:47]=2[F:60])=[O:55])([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:14][CH:15]=1
Reactant: CCCCC(NC(c1ccccc1)(c1ccccc1)c1ccc(OC)cc1)C(=O)[O-]
Reactant: O=C(Oc1c(F)c(F)cc(F)c1F)C(F)(F)F
Agent: CC[NH+](CC)CC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(NCCCCCC(=O)Oc2c(F)c(F)cc(F)c2F)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
The acid 6 obtained as described above (2.2 g, 4.4 mmol) was dissolved in anhydrous CH2Cl2 and treated with 1 ml of triethylamine followed by 0.8 ml of 2,3,5,6-tetrafluorophenyltrifluoroacetate. After being kept at room temperature for 30 min, the reaction was concentrated to an oil (crude 7), which then was re-suspended in 20% ethyl acetate/80% hexane and applied to a silica gel column. Elution with 15% ethyl acetate/85% hexane and concentration of the pure product fractions afforded 2.0 g (82%) of the TFP ester (7) as a colorless, viscous oil.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[C:8]([OH:11])(=[S:10])[CH3:9].[N:12]1([CH2:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][NH:30][C:31](=[O:36])[CH2:32][CH2:33][CH2:34]Cl)[CH:20]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(OCC)(=O)C>[N:12]1([CH2:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][NH:30][C:31](=[O:36])[CH2:32][CH2:33][CH2:34][S:10][C:8](=[O:11])[CH3:9])[CH:20]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: CC(O)=S
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)SCCCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.50 g of sodium hydride (as a 55% w/w dispersion in mineral oil) was added to 80 ml of dimethylformamide under an atmosphere of nitrogen gas, and then 10 ml of a dimethylformamide solution containing 0.81 ml of thioacetic acid was added to the resulting mixture. The mixture was then stirred at room temperature for 30 minutes. At the end of this time, 30 ml of a dimethylformamide solution containing 3.79 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) were added to the mixture, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate was then added to the reaction mixture, which was then washed with a saturated aqueous solution of sodium hydrogencarbonate and water. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:19 by volume mixture of methanol and ethyl acetate as the eluent, to give 5.04 g (a quantitative yield) of the title compound as an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]1)=[O:17].[ClH:44].CO>>[ClH:44].[ClH:44].[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)=[O:26])[CH2:22][NH:21][CH2:20]1)=[O:17]
Reactant: CC(C)CN(C(=O)c1nc2ccccc2n1CCCCCO)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCCCCO)[C@@H]1CNC[C@H](C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
tert-Butyl (3S,5R)-3-[{[1-(5-hydroxypentyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (100 mg) was dissolved in 10-20% hydrogen chloride-methanol (5 ml), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, and the residue was subjected to reversed-phase preparative HPLC and the eluted fraction was concentrated under reduced pressure. The residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. 10-20% Hydrogen chloride-methanol (3 ml) was added and the mixture was stirred for 5 min. The solvent was evaporated under reduced pressure to give the object product (34 mg).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[NH:17][NH2:18]>>[C:21]([O:20][C:16]([NH:17][N:18]=[C:12]1[CH2:13][CH2:14][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][CH2:11]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(C)(C)[Si](C)(C)OC1CCCCC1=O
Product: CC(C)(C)OC(=O)NN=C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 70 °C
Yield: 90.1 %

Procedure:
tert-Butyldimethylsilyloxy-cyclohexanone (3.146 g, 97%, 13.36 mmol, CAS #55145-45-4, purchased from Aldrich) was dissolved in hexanes (24 mL). tert-Butyl carbazate (1.80 g, 98%, 13.35 mmol) was added and the mixture was heated at 70° C. for 3 hours. Upon cooling to room temperature a white solid precipitated out of solution. The solid was collected by filtration, washed with hexanes and dried to give N′-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexylidene]-hydrazinecarboxylic acid tert-butyl ester (4.12 g, 90%).
Reaction SMILES: [C:1]([O:9][CH2:10][C@:11]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:12]1[CH:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:34])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C@@H:20]([OH:33])[CH2:19][CH2:18]3)[CH2:15][CH2:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[C:1]([O:9][CH2:10][C@:11]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:34])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:31])([CH3:32])[C:20](=[O:33])[CH2:19][CH2:18]3)[CH2:15][CH2:14]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)[C@@H]1CC[C@]2(COC(=O)c3ccccc3)CC[C@]3(C)C(CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(COC(=O)c3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude material containing ((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-3a-yl)methyl benzoate (2.98 g, 5.45 mmol) from page above was dissolved in CH2Cl2 (50 ml) and treated with PCC (1.762 g, 8.18 mmol). The mixture was stirred at rt for 2 h. TLC showed no starting material and one less polar product. The mixture was filtered through celite and silica gel and the filtrate was concentrated in vacuo to afford the title compound as a white solid
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:40][Si:41]([CH3:48])([CH3:47])[CH2:42][CH2:43][O:44][CH2:45]Cl.[Cl-].[NH4+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[N:14]([CH2:45][O:44][CH2:43][CH2:42][Si:41]([CH3:48])([CH3:47])[CH3:40])[C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(-c3ccnc(OCc4ccccc4)c3)cc2)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(-c3ccnc(OCc4ccccc4)c3)cc2)n1COCC[Si](C)(C)C
Reaction time: 0.08 h

Procedure:
To a solution of 2-{5-[4-(2-Benzyloxy-pyridin-4-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.530 g) in DMF (5.0 mL) at 0° C. was added 60% sodium hydride (0.047 g). After stirring for 5 minutes, 2-(trimethylsilyl)ethoxylmethyl chloride was added and reaction mixture stirred for 2 hours. Saturated ammonium chloride was added and mixture was extracted with ethyl acetate (2×). Organic layer was washed with 5% lithium chloride solution (2×), brine and dried (MgSO4). Concentrated and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexanes) to give 2-[5-[4-(2-Benzyloxy-pyridin-4-yl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.495 g). LCMS-ESI+: calc'd for C36H47N4O4Si: 627.87 (M+H+). Found: 627.1 (M+H+). A mixture of 2-[5-[4-(2-Benzyloxy-pyridin-4-yl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.495 g) and 10% Pd/C (0.023 g) in ethanol (5.5 mL) was stirred under hydrogen atmosphere for 1 hour. Reaction mixture was filtered through a pad of Celite, which was washed with methanol. The filtrate was concentrated and purified by flash column chromatography (silica gel, 0 to 10% methanol/ethyl acetate) to give 2-[5-[4-(2-Oxo-1,2-dihydro-pyridin-4-yl)-phenyl]-1-(2-trimethyl silanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.3027 g): LCMS-ESI+: calc'd for C29H41N4O4Si: 537.47 (M+H+). Found: 537.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:5][NH:6][C:7](=[O:17])[CH:8]=[C:9]1[C:13](=[O:14])OC(C)(C)[O:10]1.[CH2:22]=[N:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CO>>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:5][NH:6][C:7]([C:8]1[CH2:22][N:23]([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:13](=[O:14])[C:9]=1[OH:10])=[O:17]
Reactant: C=NCCN1CCOCC1
Reactant: CC1(C)OC(=O)C(=CC(=O)NCc2ccc(F)c(F)c2)O1
Solvent: CO
Product: O=C(NCc1ccc(F)c(F)c1)C1=C(O)C(=O)N(CCN2CCOCC2)C1
Temperature: 25 °C
Yield: 31 %

Procedure:
A mixture of N-(3,4-difluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetamide (58 mg, 0.195 mmol) and a 0.2 mmol solution of methylene-(2-morpholin-4-yl-ethyl)-amine in methanol (1.1 mL, 0.22 mmol) was heated at 70° C. for 1 h. The reaction mixture was cooled to room temperature and purified by preparative HPLC using methanol/water (0.1% TFA) as the eluent. The fractions containing the product were combined and concentrated to give the title compound as a hydroscopic yellow powder (30 mg, 31% yield). 1H NMR (500 MHz, DMSO) δ: 11.95 (1H, br s), 9.56 (1H, br s), 8.03 (1H, t, J=6.1 Hz), 7.41–7.30 (2H, m), 7.15–7.12 (1H, m), 4.41 (2H, d, J=6.1 Hz), 4.04 (2H, s), 4.02–3.93 (2H, m), 3.82–3.77 (2H, m), 3.65–3.51 (4H, m), 3.45–3.41 (2H, m), 3.15–3.06 (2H, m). HRMS calcd for C18H20F2N3O4 (M+H): 380.1422. found: 380.1424.
Reaction SMILES: CON(C)[C:4]([C:6]1([CH3:9])[CH2:8][CH2:7]1)=[O:5].[CH2:11]([Mg]Br)[CH:12]=[CH2:13]>O1CCCC1>[CH3:9][C:6]1([C:4](=[O:5])[CH2:13][CH:12]=[CH2:11])[CH2:8][CH2:7]1
Reactant: CON(C)C(=O)C1(C)CC1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCC(=O)C1(C)CC1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a solution of N-methoxy-N,1-dimethylcyclopropanecarboxamide (C50) (18 g, 0.126 mol) in tetrahydrofuran (360 mL) was added a solution of allylmagnesium bromide (1.0 M in diethyl ether, 500 mL, 0.5 mol) drop-wise at −60° C. The mixture was stirred at −60° C. for 1 hour, then was quenched with saturated aqueous ammonium chloride solution (50 mL). The reaction was extracted with dichloromethane (2×500 mL), the organic layers were washed with saturated aqueous sodium chloride solution (200 mL), dried, and concentrated in vacuo to give the product as a yellow oil, which was used directly in the next step.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH:24]([CH3:26])[CH3:25])[C:5]1([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15].CCN(C(C)C)C(C)C.[C:36]([N:39]1[CH2:44][CH2:43][N:42]([C:45](Cl)=[O:46])[CH2:41][CH2:40]1)(=[O:38])[CH3:37]>C(Cl)Cl>[Br:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([N:4]([CH:24]([CH3:26])[CH3:25])[CH2:3][CH2:2][NH:1][C:45]([N:42]3[CH2:43][CH2:44][N:39]([C:36](=[O:38])[CH3:37])[CH2:40][CH2:41]3)=[O:46])([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[C:6](=[O:15])[NH:7]2)=[CH:12][CH:11]=1
Reactant: CC(C)N(CCN)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Br)ccc21
Reactant: CC(=O)N1CCN(C(=O)Cl)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)NCCN(C(C)C)C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Br)ccc32)CC1
Reaction time: 8 h

Procedure:
To a solution of rac-3-[(2-Amino-ethyl)-isopropyl-amino]-6-bromo-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (270 mg, 0.48 mmol) and DIPEA (167 uL, 0.96 mmol) in 5 mL of DCM was added 4-acetyl-piperazine-1-carbonyl chloride (137 mg, 0.72 mmol) at room temperature, and stirred at same temperature overnight. The reaction mixture was rinsed with 20 mL water. The organic layer was dried over Na2SO4, and concentrated in vacuo, then purified by flash column chromatopgraphy to 180 mg white solid. MS: [M+H]+=590.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:6][CH:7]=[C:8]([I:10])[CH:9]=1)=[O:4].[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>>[I:10][C:8]1[CH:9]=[C:5]([C:3]([O:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:4])[NH:6][CH:7]=1
Reactant: OCc1ccccc1
Reactant: O=C(c1cc(I)c[nH]1)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)c1cc(I)c[nH]1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 2,2,2-trichloro-1-(4-iodo-1H-pyrrol-2-yl)ethanone (4.0 g, 12 mmol), benzyl alcohol (9.0 mL, 87 mmol), and triethylamine (2.5 mL, 18 mmol) in a round flask was heated at 60° C. with stirring for 2 h. After cooling, the volatiles were removed under reduced pressure to afford the crude product which was directly used in the next reaction without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH3:22])[C:15]([CH3:24])([CH3:23])[CH2:14]2)[N:5]=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][C:34]([CH3:37])([CH3:36])[N:33]([O:38][CH3:39])[C:32]([CH3:41])([CH3:40])[CH2:31]2)[N:3]=1.[NH:42]([CH2:46][CH2:47][OH:48])[CH2:43][CH2:44][OH:45]>>[OH:45][CH2:44][CH2:43][N:42]([CH2:46][CH2:47][OH:48])[C:2]1[N:3]=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][C:34]([CH3:36])([CH3:37])[N:33]([O:38][CH3:39])[C:32]([CH3:40])([CH3:41])[CH2:31]2)[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH3:22])[C:15]([CH3:23])([CH3:24])[CH2:14]2)[N:7]=1
Reactant: CON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OC)C(C)(C)C3)n2)CC1(C)C
Reactant: OCCNCCO
Product: CON1C(C)(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(OC)C(C)(C)C3)nc(N(CCO)CCO)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of 2-chloro-4,6-bis[N-(1-methoxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine and diethanolamine according to the procedure of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:29](=[O:34])[C:30]([O:32]C)=[O:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:29]([C:30]([OH:32])=[O:31])=[O:34])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)Cl
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Product: C[C@H](NC(=O)C(=O)O)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 5 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and methyl cloro(oxo)acetate (18 mg, 150 μmol). Yield 19 mg (88%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([NH:20]C(=O)C4C=CC=CC=4)=[S:19])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.I[CH3:30]>CC(C)=O>[CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([S:20][CH3:30])=[NH:19])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CC=C(c2c[nH]c3ccc(NC(=S)NC(=O)c4ccccc4)cc23)CC1
Reactant: CI
Solvent: CC(C)=O
Product: CSC(=N)Nc1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Yield: 19.1 %

Procedure:
A solution of compound 64 (0.2 g, 0.698 mmol) in acetone (10 mL) was treated with iodomethane (0.26 mL, 4.189 mmol) at room temperature and the resulting solution was refluxed for over night (14 h). The reaction was brought to room temperature and solvent was evaporated. The crude was diluted with sat. NaHCO3 solution (10 mL) and compound was extracted into CH2Cl2 (2×20 mL). The combined CH2Cl2 layer was washed with brine (10 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 5:95) to obtain compound 74 (0.04 g, 19%) as a solid. mp 260-162° C.; 1H NMR (DMSO-d6) δ 2.29 (s, 3H), 2.33 (s, 3H), 2.50-2.59 (m, 4H), 3.06 (brs, 2H), 6.01 (s, 1H), 6.64 (brs, 1H), 7.22-7.30 (m, 3H), 10.91 (s, 1H); ESI-MS m/z (%): 301 (M+, 36), 285 (55), 258 (66), 242 (100).