Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8](=[O:23])[CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[O:16][C:15]([CH3:21])([CH3:20])[CH:14]4[O:22][CH:13]4[C:12]=3[CH:11]=2)=[CH:4][CH:3]=1.[NH3:26]>C(O)C>[NH2:26][CH:13]1[C:12]2[C:17](=[CH:18][CH:19]=[C:10]([CH2:9][C:8]([NH:7][CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:23])[CH:11]=2)[O:16][C:15]([CH3:21])([CH3:20])[CH:14]1[OH:22]
Reactant: N
Reactant: CC1(C)Oc2ccc(CC(=O)NCc3ccc(Cl)cc3)cc2C2OC21
Solvent: CCO
Product: CC1(C)Oc2ccc(CC(=O)NCc3ccc(Cl)cc3)cc2C(N)C1O
Temperature: 50 °C
Reaction time: 16 h

Procedure:
The N-(4-chlorobenzyl)-2-(2,2-dimethyl-1a,7b-dihydro-2H-oxireno[c]chromen-6-yl) acetamide obtained above was immediately poured into a mixture of so much ethanol and 25%-strength aqueous ammonia solution (6:5 v/v) that a 0.2 M solution of the compound was obtained, and the resulting solution was stirred for 16 hours at 50° C. Then the solution was allowed to cool to room temperature, and the solvent was largely evaporated at reduced pressure. The remaining residue was chromatographed on silica gel (mobile phase: gradient dichloromethane/methanol/25%-strength aqueous ammonia solution 97.5:2:0.5 to 90:9.5:0.5 v/v/v). Drying of the product fractions yielded 7.3 g 2-(4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-N-4-chlorobenzyl acetamide, which was used without further purification for the subsequent reaction. The other regioisomer, 2-[3-amino-4-hydroxy-2,2-dimethylchromen-6-yl]-N-4-chlorobenzyl acetamide, was not observed.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:13]Br)=[C:6]([CH:12]=1)[C:7]([O:9]CC)=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:30])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>C(O)C>[Br:1][C:2]1[CH:12]=[C:6]2[C:5]([CH2:13][N:15]([C:16]3[CH:17]=[CH:18][C:19]([CH:22]([CH3:30])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:20][CH:21]=3)[C:7]2=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(N)cc1
Reactant: CCOC(=O)c1cc(Br)ccc1CBr
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)OC(C)(C)C)c1ccc(N2Cc3ccc(Br)cc3C2=O)cc1
Temperature: 100 °C
Yield: 38.7 %

Procedure:
A mixture of ethyl 5-bromo-2-(bromomethyl)benzoate (4.00 g, 12.4 mmol), tert-butyl 2-(4-aminophenyl)propanoate (3.4 g, 15.4 mmol) and N,N-diisopropylethylamine (1.98 g, 15.4 mmol) in ethanol (120 mL) was heated in a sealed tube at 100° C. overnight. After this time, the mixture was cooled with an ice bath and the solids collected by filtration to afford tert-butyl 2-(4-(6-bromo-1-oxoisoindolin-2-yl)phenyl)propanoate (2.00 g, 39%) as a white solid: mp 164-165° C.: 1H NMR (300 MHz, CDCl3) δ 8.06 (d, J=1.7 Hz, 1H), 7.81-7.77 (m, 2H), 7.71 (dd, J=8.0, 1.8 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.38-7.34 (m, 2H), 4.81 (s, 2H), 3.63 (q, J=7.1 Hz, 1H), 1.46 (d, J=7.2 Hz, 3H), 1.41 (s, 9H); ESI MS m/z 448 [M+H+CH3OH]+.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].N=C1CC(C)CCN1.[NH2:13][N:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1>>[C:1]([OH:4])(=[O:3])[CH3:2].[NH2:13][N:14]1[CH:23]=[CH:22][C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[CH2:15]1
Reactant: NN1C=Cc2ccccc2C1
Agent: CC1CCNC(=N)C1
Solvent: CC(=O)O
Product: NN1C=CC2=C(CCCC2)C1

Procedure:
The method of preparation of 2-imino-4-methylpiperidine acetate was used to convert 2-aminoisoquinoline to the title compound except platinum oxide was used as the catalyst. The product was triturated with EtOH to give a white solid. The analysis of the product was found to be consistent with the proposed structure. 1H NMR (D2O): δ 7.35 (d, J=6 Hz, 1H); 6.55 (d, J=6 Hz, 1H); 2.6-2.5 (m, 2H); 2.20-2.10 (m, 2H); 1.75 (s, 3H); 1.70-1.50 (m, 4H).
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[C:8](=[O:26])[NH:7][C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]1=2)(=[O:3])[CH3:2].Cl[CH2:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][C:34]=1[CH3:43].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C=O)C.C(Cl)Cl>[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[C:8](=[O:26])[N:7]([CH2:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][C:34]=2[CH3:43])[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]1=2)(=[O:3])[CH3:2]
Reactant: Cc1ccc2ccccc2c1CCl
Reactant: CC(=O)N1c2ccccc2NC(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccccc2N(Cc2c(C)ccc3ccccc23)C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.2 %

Procedure:
To a rt solution of tert-butyl(S)-1-((2S,3S)-1-acetyl-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (72 mg, 172 μmol) in DMF (430 μl) was added 1-(chloromethyl)-2-methylnaphthalene (39.4 mg, 206 μmol), cesium carbonate (72.9 mg, 224 μmol), and sodium iodide (33.5 mg, 224 μmol). The reaction was stirred at rt for 16 h, then diluted with CH2Cl2, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((2S,3S)-1-acetyl-2-methyl-5-((2-methylnaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (73.1 mg, 74%) as an off-white solid. MS m/z 595 (MNa)+.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([N:23]1[CH2:40][CH2:39][C:26]2([C:30](=[O:31])[N:29]([C:32]3[CH2:33][O:34][C:35](=[O:38])[C:36]=3[CH3:37])[CH2:28][CH2:27]2)[CH2:25][CH2:24]1)[CH2:11][C:12]1[C:13]([CH3:22])=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[O:16][CH2:15]2)(C(C)(C)C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:8][CH2:9][CH:10]([N:23]1[CH2:40][CH2:39][C:26]2([C:30](=[O:31])[N:29]([C:32]3[CH2:33][O:34][C:35](=[O:38])[C:36]=3[CH3:37])[CH2:28][CH2:27]2)[CH2:25][CH2:24]1)[CH2:11][C:12]1[C:13]([CH3:22])=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[O:16][CH2:15]2
Reactant: CC1=C(N2CCC3(CCN(C(CO[Si](C)(C)C(C)(C)C)Cc4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1=C(N2CCC3(CCN(C(CO)Cc4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 8-(1-((tert-butyldimethylsilyl)oxy)-3-(4-methyl-1-oxo-1,3-dihydro isobenzofuran-5-yl)propan-2-yl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (0.10 g, 0.18 mmol) in DCM (3 mL) was added trifluoroacetic acid (3 mL) at 0° C. After stirring at room temperature for 24 h, solvent was removed under reduced pressure and the residue was purified by preparative-HPLC to give the title compound, which was separated by SFC chiral chromatography into two single enantiomers Isomer A (faster eluting) and Isomer B (slower eluting. Column: CHIRALPAK AD 250×30 mm I.D., 20 μm; Mobile phase: Supercritical CO2EtOH (0.2% NH3H2O)=45/55; Flow rate: 80 ml/min. For both isomers: LC-MS (ESI, m/z): 455 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C)C=O>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[CH:9][N:8]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Reaction time: 18 h

Procedure:
A mixture of 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine (906 mg), sodium hydride (120 mg, of a 60% dispersion in mineral oil) and dry dimethylformamide (30 ml) was stirred at ambient temperature under nitrogen for 30 minutes. Ethyl bromoacetate (0.5 g) in dimethylformamide (10 ml) was added over 5 minutes at 0-5° C. with stirring. The mixture was stirred for 30 minutes at ambient temperature and then allowed to stand for 18 hours. The mixture was evaporated under vacuum and the residue was triturated with water and ether. The solid obtained was collected by filtration, washed with water and then with ether to give ethyl 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]acetate, m.p. 161-161.3° C.
Reaction SMILES: [C:1]([CH:4]1[C:11](=[CH2:12])[CH2:10][S:9][CH:8]2[N:5]1[C:6](=[O:21])[CH:7]2[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([OH:3])=[O:2].[C:22]1([C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N+]=[N-])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)(=O)C>[CH:28]([O:2][C:1]([CH:4]1[C:11](=[CH2:12])[CH2:10][S:9][CH:8]2[N:5]1[C:6](=[O:21])[CH:7]2[NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])=[O:3])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C=C1CSC2C(NC(=O)OC(C)(C)C)C(=O)N2C1C(=O)O
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: C=C1CSC2C(NC(=O)OC(C)(C)C)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Yield: 66.2 %

Procedure:
2-Carboxy-7-tert.-butoxycarbonylamino-3-methylene-8-oxo-5-thia-1-aza-bicyclo[4.2.0]octane (21.3 g) is esterified with diphenyldiazomethane (11.2 g) in accordance with the procedure of Example 1. 2-Benzhydryloxycarbonyl-7-tert.-butoxycarbonylamino-3-methylene-8-oxo-5-thia-1-aza-bicyclo[4.2.0]octane (18.35 g) is obtained in the form of white crystals (m.p.=135°-7° C. after recrystallisation from ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[C:16]([C:17]([OH:19])=O)=[C:5]2[N:6]=[C:7]([O:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[CH:8]=[CH:9][N:4]2[N:3]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:49][C:50]1[CH:55]=[CH:54][N:53]=[CH:52][C:51]=1[NH2:56]>CN1C(=O)CCC1>[NH2:1][C:2]1[C:16]([C:17]([NH:56][C:51]2[CH:52]=[N:53][CH:54]=[CH:55][C:50]=2[CH3:49])=[O:19])=[C:5]2[N:6]=[C:7]([O:10][CH2:11][CH2:12][N:13]([CH3:14])[CH3:15])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Cc1ccncc1N
Reactant: CN(C)CCOc1ccn2nc(N)c(C(=O)O)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1ccncc1NC(=O)c1c(N)nn2ccc(OCCN(C)C)nc12
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 42 %

Procedure:
To a suspension of 2-amino-5-[2-(dimethylamino)ethoxy]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (100 mg, 0.377 mmol) in NMP (667 μL) was added Et3N (46.54 mg, 64.1 μL, 0.4599 mmol) in one portion. The mixture was stirred for 10 minutes before adding TBTU (Boron Tetrafluoride Ion) (136.3 mg, 0.4245 mmol), portionwise, over 5 minutes. The mixture was allowed to stir at room temperature for 20 mins. 4-Methylpyridin-3-amine (40.77 mg, 0.377 mmol) was added and the mixture was heated to 100° C. for 4 hours. The mixture was filtered through a silica gel pad and eluted with DCM initially followed by 20/80 MeOH/DCM. The residue was further purified by preparative HPLC to provide compound I-C-3 (42% yield). LC-MS (M+H)+=356.2; 1H NMR (500 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.38 (brs, 1H), 9.20 (brs, 1H), 8.82 (d, 1H), 8.50-8.43 (m, 1H), 7.66-7.6 (m, 1H), 6.62 (d, 1H), 6.50 (brs, 2H), 4.81-4.78 (m, 2H), 3.63-3.60 (m, 2H), 2.95 (s, 6H), 2.55 (s, 3H);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][PH:12](=[O:14])[OH:13])=[CH:4][CH:3]=1.[C:15]1([CH2:21][O:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30](O)[C:31]([N:33]2[CH2:47][CH2:46][CH2:45][C@H:34]2[C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])=[O:32])=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>O1CCCC1.C(OCC)(=O)C>[C:15]1([CH2:21][O:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:14][PH:12]([CH2:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:13])[C:31]([N:33]2[CH2:47][CH2:46][CH2:45][C@H:34]2[C:35]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])=[O:32])=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[PH](O)CCCCc1ccc(F)cc1
Reactant: O=C(NCCCC[C@H](O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NCCCC[C@H](O[PH](=O)CCCCc1ccc(F)cc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[4-(4-Fluorophenyl)butyl]phosphinic acid, 1-adamantanamine salt (1.18 g.) is partitioned between 1.0N hydrochloric acid and ethyl acetate. The organic phase is washed with brine and dried over anhydrous sodium sulfate. The mixture is evaporated to give 696 mg. of [4-(4-fluorophenyl)butyl]phosphinic acid. This acid (696 mg., 3.22 mmole, 1.5 eq.) is dissolved in dry tetrahydrofuran (15 ml.), combined with 1-[(S)-6-[[(phenylmethoxy)carbonyl]amino]-2-hydroxy-1-oxohexyl]-L-proline, phenylmethyl ester (1.01 g., 2.15 mmole, 1 eq.) and treated with dicyclohexylcarbodiimide (664 mg., 3.22 mmole, 1.5 eq.) and dimethylaminopyridine (39 mg., 0.15 eq.). The white suspension is stirred under argon for 1 hour at room temperature, then diluted with ethyl acetate, and filtered to remove dicyclohexyl urea. The filtrate is washed with 5% potassium bisulfate, saturated sodium bicarbonate, and brine, then dried over anhydrous sodium sulfate, and evaporated to an oily residue. Chromatography on a 3/4 inch pad of SiliCAR CC-7 silica gel eluting with ethyl ether:acetone (8:2) removes impurities. Product containing fractions are pooled and evaporated to give crude 1-[(S)-6-[[(phenylmethoxy)carbonyl]amino]-2-[[[4-(4-fluorophenyl)butyl]phosphinyl]oxy]-1-oxohexyl]-L-proline, phenylmethyl ester as an oil. TLC (silica gel; ethyl ether:acetone, 8:2) Rf =0.09.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:3]1=[O:20].C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]#[C:29][CH3:30]>CN(C)C=O.C(OCC)(=O)C>[CH2:27]([N:8]1[C:9]2[C:10](=[O:11])[N:2]([CH3:1])[C:3](=[O:20])[N:4]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[C:5]=2[N:6]=[CH:7]1)[C:28]#[C:29][CH3:30]
Reactant: CC#CCBr
Reactant: Cn1c(=O)c2[nH]cnc2n(COC(=O)C(C)(C)C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCn1cnc2c1c(=O)n(C)c(=O)n2COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,2-Dimethylpropionic acid [1-methyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl]methyl ester (1.871 g) was dissolved in N,N-dimethylformamide (30 ml), potassium carbonate (1.5 g) and 2-butynyl bromide (0.7 ml) were added to the solution, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and washed with water and 1N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then, the solvent was removed by distillation. The residue was purified by silica gel column chromatography to give 2.12 g of the title compound from the elution fraction of hexane-ethyl acetate (3:2).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]2[C:5]([C:6]3[CH2:7][CH2:8][CH2:9][C:10](=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[C:17]([Si](C)(C)C)([F:20])([F:19])[F:18].[F-].[Cs+]>C1COCC1>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]2[C:5]([C:6]3[CH2:7][CH2:8][CH2:9][C:10]([C:17]([F:20])([F:19])[F:18])([OH:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C1CCCc2c1[nH]c1c(Cl)c(Cl)ccc21
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)CCCc2c1[nH]c1c(Cl)c(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
7,8-Dichloro-2,3,4,9-tetrahydro-1H-carbazol-1-one (0.2 g, 0.78 mmol) was dissolved in anhydrous THF (5 mL), cooled to 0° C., and CF3TMS (1.2 mL, 8.7 mmol) followed by CsF (0.36 mg, 2.3 mmol) were added and stirred for 30 min. at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for an additional 2 h, quenched with saturated NH4Cl and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude compound which was purified by column chromatography [EtOAc-hexane (1:4) as eluant] to provide the title compound as a yellow syrup (0.05 g, 19%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.32 (bs, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.21 (d, J=8.5 Hz, 1H), 2.85-2.81 (m, 1H), 2.73-2.70 (m, 1H), 2.68 (s, 1H), 2.29-2.24 (m, 1H), 2.13-2.11 (m, 2H), 2.03-2.01 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=2)[C:20]([O:22][CH3:23])=[O:21])O1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:8][C:5]1[N:6]=[N:7][C:2]([C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=2)[C:20]([O:22][CH3:23])=[O:21])=[CH:3][CH:4]=1
Reactant: COC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Nc1ccc(Cl)nn1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cccc(-c2ccc(N)nn2)c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 83.6 %

Procedure:
To a mixture of 6-chloropyridazin-3-amine (5 g, 38.6 mmol), methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (15.2 g, 58 mmol), Pd2(dba)3 (2.22 g, 3.86 mmol), X-phos (7.35 g, 15.44 mmol) and Na2CO3 (12.3 g, 115.8 mmol) in dioxane (150 mL) and water (15 mL) was heated to 100° C. with stirring for 6 h under N2. The solvent was removed in vacuo and the resulting residue was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=20:1) to give methyl 3-(6-aminopyridazin-3-yl)benzoate (7.4 g, 84%) as a white solid. LC-MS: [M+H]+, 230.1, tR=1.111 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[N:15]=[C:14]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[N:13]([CH3:22])[C:12]=3[CH:11]=[C:10]([C:23]([O:25]C)=[O:24])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[CH3:30]O>>[CH3:30][C:9]1[C:10]([C:23]([OH:25])=[O:24])=[CH:11][C:12]2[N:13]([CH3:22])[C:14]([CH2:17][C:18]([OH:21])([CH3:19])[CH3:20])=[N:15][C:16]=2[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)c2nc(CC(C)(C)O)n(C)c2c1
Reactant: CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(C(=O)O)cc2c(nc(CC(C)(C)O)n2C)c1-c1ccc(F)cc1
Temperature: 100 °C

Procedure:
To a solution of methyl 4-(4-fluorophenyl)-2-(2-hydroxy-2-methylpropyl)-1-methyl-1H-benzimidazole-6-carboxylate (83.7 mg, 0.235 mmol) in MeOH (0.500 mL) was added sodium hydroxide (0.705 mL, 1M, 0.705 mmol). Reaction heated in the microwave at 100° C. for 15 min. HCl (0.352 mL, 2M, 0.705 mmol) was added and the reaction mixture was concentrated. Title compound used as-is with three sodium chloride salts without further purification (122 mg): LC-MS [M+1]=343.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH:15]([CH3:17])[CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH2:32][CH2:33][CH2:34]Cl)=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1.C(N(CC)CC)C.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][C:45]1=[O:50]>COCCO>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH:15]([CH3:17])[CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH2:32][CH2:33][CH2:34][N:47]3[CH2:48][CH2:49][N:44]([CH3:43])[C:45](=[O:50])[CH2:46]3)=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1
Reactant: CN1CCNCC1=O
Reactant: COc1cc2c(Nc3c(Cl)cc(C#CCOC(C)C)c4c3OCO4)ncnc2cc1OCCCCl
Solvent: COCCO
Solvent: CCN(CC)CC
Product: COc1cc2c(Nc3c(Cl)cc(C#CCOC(C)C)c4c3OCO4)ncnc2cc1OCCCN1CCN(C)C(=O)C1
Reaction time: 7 h
Yield: 50.3 %

Procedure:
A mixture of N-[5-chloro-7-(3-isopropoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (0.22 g, 0.43 mmol), triethylamine (0.29 ml, 2.13 mmol), 1-methylpiperazin-2-one (0.24 g, 2.13 mmol) in 2-methoxyethanol (3 ml) was heated to 80 C for 12 hours and then at 100 C for 7 hours. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane and water. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with a mixture of 2-8% methanol in dichloromethane to give the product as an light orange solid (0.129 g, 51%). NMR Spectrum: (DMSOd6) 1.18 (d, 6H), 1.98 (m, 2H), 2.52 (t, 2H under DMSO), 2.72 (t, 2H), 2.88 (s, 3H), 3.04 (s, 2H), 3.34 (t, 2H under H2O), 3.83 (m, 1H), 3.97 (s, 3H), 4.22 (t, 2H), 4.42 (s, 2H), 6.17 (s, 2H), 7.15 (s, 1H), 7.21 (s, 1H), 7.83 (s, 1H), 8.34 (s, 1H), 9.52 (s, 1H). Mass Spectrum: M+H+ 596 and M+H− 594.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15](=[O:45])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[C:24]([NH:27][C:28]([CH:30]4[CH2:34][CH2:33][CH2:32][N:31]4[C:35]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[O:36])=[O:29])[S:25][CH:26]=3)=[CH:18][CH:17]=2)[CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:38]([O:37][C:35]([N:31]1[CH2:32][CH2:33][CH2:34][CH:30]1[C:28](=[O:29])[NH:27][C:24]1[S:25][CH:26]=[C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:15](=[O:45])[NH:14][CH:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[CH:17][CH:18]=2)[N:23]=1)=[O:36])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(NC(=O)c2ccc(-c3csc(NC(=O)C4CCCN4C(=O)OCc4ccccc4)n3)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CCCNC1)c1ccc(-c2csc(NC(=O)C3CCCN3C(=O)OCc3ccccc3)n2)cc1
Temperature: 25 °C

Procedure:
3-(4-{2-[(1-Benzyloxycarbonyl-pyrrolidine-2-carbonyl)-amino]-thiazol-4-yl}-benzoylamino)-piperidine-1-carboxylic acid tert butyl ester (Compound 5336, Example 336, 100 mg, 0.16 mmol) was dissolved in 4 mL of 1:1 solution of CH2Cl2/TFA and stirred for 1.5 at room temperature. Reaction mixture was evaporated under reduced pressure to give pure desired product. MS: 534.2(M+H+); H1 NMR (MeOH-d4): δ(ppm) (HCl salt)12.47 (s, 1H), 9.52 (s, 1H), 8.64 (s, 1H), 7.95 (m, 5H), 7.50 (br s, 2H), 7.08 (d, 2H), 5.03 (m, 2H), 4.49 (m, 1H), 4.12 (m, 1H), 3.68-2.96 (m, 6H), 2.28 (m, 1H), 1.90 (m, 8H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[C:5]([O:18][CH3:19])=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:34]=[CH:33][C:24]2[S:25][C:26]([S:29](Cl)(=[O:31])=[O:30])=[C:27]([CH3:28])[C:23]=2[CH:22]=1>>[OH:10][CH2:9][CH2:8][C:7]1[C:6]([N:11]2[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]2)=[C:5]([O:18][CH3:19])[CH:4]=[CH:3][C:2]=1[NH:1][S:29]([C:26]1[S:25][C:24]2[CH:33]=[CH:34][C:21]([Cl:20])=[CH:22][C:23]=2[C:27]=1[CH3:28])(=[O:31])=[O:30]
Reactant: COc1ccc(N)c(CCO)c1N1CCN(C)CC1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Product: COc1ccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c(CCO)c1N1CCN(C)CC1

Procedure:
The title compound (E126) was prepared from 2-[6-amino-3-methoxy-2-(4-methylpiperazin-1-yl)phenyl]ethanol (D32) (74 mg, 0.28 mmol) and 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (78 mg, 0.28 mmol) using the method of Example 1 (18 mg, 13%). MH+=510.