Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:17]([F:18])=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[C:4]([F:19])[CH:3]=1.[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([C:27](O)=[O:28])[C:23](=[O:30])[N:22]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl.CCOC(C)=O>[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([C:27]([NH:1][C:2]2[C:17]([F:18])=[CH:16][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=3)=[C:4]([F:19])[CH:3]=2)=[O:28])[C:23](=[O:30])[N:22]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NC(=O)c1cc(Oc2cc(F)c(N)cc2F)ccn1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Nc2cc(F)c(Oc3ccnc(C(N)=O)c3)cc2F)c(=O)n(-c2ccccc2)n1C
Temperature: 45 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
To a solution of 4-(4-amino-2,5-difluorophenoxy)picolinamide (200 mg, 0.76 mmol), and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (165 mg, 0.75 mmol) in DCM (10 mL) was added EDCI (175 mg, 0.93 mmol), and HOAT (26 mg, 0.15 mmol). The reaction was stirred at 45° C. for 16 hours, cooled to rt and diluted with EtOAc (20 mL). The solid was collected through filtration, dried at 45° C. in vacuo overnight to give the title compound as a white solid (230 mg, 63.7%).
Reaction SMILES: [C:1]1([C:7]2([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH2:16][Cl:17].O.CCCCCC>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[Cl:17][CH2:16][C:4]1[CH:5]=[CH:6][C:1]([C:7]2([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8]2)=[CH:2][CH:3]=1
Reactant: COCCl
Reactant: COC(=O)C1(c2ccccc2)CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)C1(c2ccc(CCl)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of methyl 1-phenylcyclopropanecarboxylate (8.5 g) in methylene chloride (70 ml) was added titanium tetrachloride (8.0 ml) under ice-cooling. To this solution was added dropwise a solution of methoxymethyl chloride (5.5 ml) in methylene chloride (30 ml) under ice-cooling. The mixture was stirred at room temperature for 5 hr and left standing overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with an aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give a pale-brown oil. The oil was subjected to silica gel column chromatography (developing solvent; hexane:ethyl acetate=4:1) to give the title compound (7.9 g) as a colorless oil.
Reaction SMILES: C([O:5][C:6](=[O:46])[CH2:7][NH:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)[N:14]([CH:16]([C:20]2[N:29]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:28](=[O:37])[C:27]3[C:22](=[CH:23][C:24]([Cl:38])=[CH:25][CH:26]=3)[N:21]=2)[CH:17]([CH3:19])[CH3:18])[CH:15]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:30]([N:29]1[C:28](=[O:37])[C:27]2[C:22](=[CH:23][C:24]([Cl:38])=[CH:25][CH:26]=2)[N:21]=[C:20]1[CH:16]([N:14]1[CH:15]=[C:11]([CH2:10][CH2:9][NH:8][CH2:7][C:6]([OH:46])=[O:5])[N:12]=[C:13]1[C:39]1[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=1)[CH:17]([CH3:19])[CH3:18])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1ccc(-c2nc(CCNCC(=O)OC(C)(C)C)cn2C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2nc(CCNCC(=O)O)cn2C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Yield: 74 %

Procedure:
A solution of (2-{1-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-2-p-tolyl-1H-imidazol-4-yl}-ethylamino)-acetic acid tert-butyl ester (99.6 mg., 0.155 mmol) and trifluoroacetic acid (8 mL) in methylene chloride (4 mL) was stirred at room temperature for 3.0 h. The reaction was concentrated in vacuo and the residue was triturated with diethyl ether and dried to provide the title compound as a white solid (67 mg., 53%). MS(ES+) m/e 584 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12.C([N-]C(C)C)(C)C.[Li+].CCCCCCC.[O:28]1CCC[CH2:29]1.C(C1C=CC=CC=1)C.CN(C)C=O>O1CCCC1.O.ClCCl>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[C:11]([CH:29]=[O:28])[S:12][C:3]=12
Reactant: N#Cc1cnc2ccsc2c1Cl
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: O
Product: N#Cc1cnc2cc(C=O)sc2c1Cl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 27 %

Procedure:
To a solution of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.03 mmol) in 6 mL of tetrahydrofuran at −78° C. is added dropwise 2.0 M lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene (0.645 mL, 1.29 mmol). After stirring for 40 minutes, N,N-dimethylformamide (99 mg, 1.35 mmol) is added dropwise over 5 minutes. The reaction mixture is stirred at −78° C. for 4 hours, then dichloromethane is added and the reaction mixture is allowed to warm to room temperature. Water is added and the organic phase is separated and the aqueous phase is extracted with dichloromethane. The organic phases are combined and washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by preparative thin layer chromatography developing with 30% ethyl acetate in hexane to provide 62 mg of 7-chloro-2-formylthieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 188-189° C.; 1H NMR (DMSO-d6) δ 8.72 (s, 1H), 9.26 (s, 1H), 10.28 (s, 1H); MS 221.9, 223.9 (M−H)−.
Reaction SMILES: Cl.C(OC([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]1[C:18]1[C:19](F)=[N:20][CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:23]=1)=O)(C)(C)C.[OH2:31]>O1CCOCC1>[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]1[C:18]1[C:19](=[O:31])[NH:20][CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:23]=1
Reactant: O
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(-c3ccccc3)cnc2F)cc2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]cc(-c2ccccc2)cc1-c1cc2ccccc2[nH]1
Temperature: 25 °C
Yield: 30 %

Procedure:
Concentrated HCl (0.5 mL) was added dropwise to a stirred solution of 2-(2-fluoro-5-phenyl-pyridin-3-yl)-indole-1-carboxylic acid tert-butyl ester (113 mg, 0.29 mmol, 1.0 eq.) in dioxane (6 mL) and water (2 mL). The reaction was heated at reflux overnight. The reaction was cooled to ambient temperature and the solvent removed in vacuo. The crude residue was partitioned between water (10 mL) and EtOAc (15 mL) and the aqueous layer extracted with EtOAc (3×15 mL). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by column chromatography on SiO2, eluting with 50% EtOAc/petroleum ether to 100% EtOAc to 10% MeOH/DCM to give the desired product as a yellow solid (25 mg, 0.09 mmol, 30%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]([NH2:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[C:16]([C:20]1[CH:43]=[CH:42][C:23]([CH2:24][NH:25][C:26](NC(C2C=CC(NS(C)(=O)=O)=CC=2)C)=[O:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:20]1[CH:43]=[CH:42][C:23]([CH2:24][NH:25][C:26]([NH:15][CH:13]([C:4]2[CH:5]=[CH:6][C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:2]([F:1])[CH:3]=2)[CH3:14])=[O:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(NC(=O)NCc1ccc(C(C)(C)C)cc1)c1ccc(NS(C)(=O)=O)cc1
Reactant: CC(N)c1ccc(NS(C)(=O)=O)c(F)c1
Product: CC(NC(=O)NCc1ccc(C(C)(C)C)cc1)c1ccc(NS(C)(=O)=O)c(F)c1

Procedure:
Through similar procedure to that in Example 102 excepting 1-[3-Fluoro-4-(methylsulfonylamino)phenyl]ethyl amine (13-12) as a starting material, N-(4-t-Butylbenzyl)-N′-{1-[4-(methylsulfonylamino)phenyl]ethyl}urea (23-1, MK-82) having following physicochemical properties was synthesized:
Reaction SMILES: C([C:5](=[CH2:9])[C:6]([NH2:8])=[O:7])(C)(C)C.[C:10]1([CH3:16])[CH:15]=CC=C[CH:11]=1.N(C(C)(C)C#N)=NC(C)(C)C#N>CCCCCC>[C:10]([NH:8][C:6](=[O:7])[CH:5]=[CH2:9])([CH3:16])([CH3:15])[CH3:11]
Reactant: Cc1ccccc1
Reactant: C=C(C(N)=O)C(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCC
Product: C=CC(=O)NC(C)(C)C
Temperature: 80 °C

Procedure:
A mixture of 50.0 g of t-butylacrylamide and 250 ml of toluene was heated at 80° C. with stirring under a nitrogen atmosphere in a 500 ml three-necked flask. 10 ml of a toluene solution containing 500 mg of azobisisobutyronitrile was added thereto as a polymerization initiator, whereby polymerization was initiated. After polymerization for 3 hours, the polymerization solution was cooled and poured into 1 liter of hexane. The solids thus-deposited were collected by filtration, washed with hexane and dried with heating under a reduced pressure to obtain 47.9 g of P-57.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].[CH3:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[C:26](N)[CH:27]=[CH:28][CH:29]=2)[N:24]=1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[N:24]=[C:23]([CH3:22])[CH:32]=[CH:31]2)(=[O:3])[CH3:2]
Reactant: Cc1ccc2cccc(N)c2n1
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cccc3ccc(C)nc23)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a stirred solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 66 mg (0.417 mmol) of 2-methylquinolin-8-amine was added. The resulting mixture was stirred at room temperature for one hour and the final product was collected by filtration and washed with diethylether to yield the title compound (97 mg, 93.3% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=1.[Br-:16]>[Al+3].[Cl-].[Cl-].[Cl-]>[Br:16][CH:10]([CH2:11][CH2:12][CH2:13][CH3:14])[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:15]
Reactant: CCCCCC(=O)c1ccc(OC)cc1
Reactant: [Br-]
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCC(Br)C(=O)c1ccc(OC)cc1
Yield: 93.4 %

Procedure:
A procedure similar to step 3 of Example 1 was used. 1-(4-methoxy-phenyl)-hexan-1-one prepared in the step 2 and bromide were used as starting materials, and anhydrous AlCl3 was used as catalyst. The crude product obtained was distilled under a reduced pressure and purified by a silica gel column chromatography eluted with petroleum ether and ethyl acetate (20:1) to give a product as a white solid in a yield of 93.4%, mp: 54-55 └. 1H-NMR (CDCl3, 400 MHz) δ: 0.92 (3H, t, J=7.2 Hz, CH3), 1.30˜1.60 (4H, m, CH2CH2), 2.05˜2.25 (2H, m, CH2CHBr), 3.89 (3H, s, OCH3), 5.11 (1H, t, J=7.2 Hz, CHBr), 6.96 (2H, d, J=8.80 Hz, ArH), 8.01 (2H, d, J=8.80 Hz, ArH); ESI-MS m/e (%): 286.1 (M+2, 2), 284.1 (M, 2), 230.0 (3), 228.0 (3), 205.1 (5), 135.1 (100).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH2:12][N:13]([CH3:15])[CH3:14])[CH2:8][NH:9]2)=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>N1C=CC=CC=1.C1COCC1>[C:16]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH2:12][N:13]([CH3:15])[CH3:14])[CH2:8][NH:9]2)=[CH:4][CH:3]=1)(=[O:18])[CH3:17]
Reactant: CN(C)CC1CNc2cc(N)ccc2C1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)NCC(CN(C)C)C2
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
To a solution of 7-amino-3-(N,N-dimethylamino)methyl-1,2,3,4-tetrahydroquinoline (300 mg) in pyridine (3 ml) was added a solution of acetic anhydride (150 mg) in THF (1 ml) and stirring was continued for 30 minutes. The reaction mixture was purified by alumina column chromatography (eluent; ethyl acetate to ethyl acetate/methanol=20:1) and the resulting crystals were washed with IPE to obtain the entitled compound (275 mg).
Reaction SMILES: [N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@@H:17]([C:25]([NH:27]N)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].N[CH2:40][C:41]([NH:43][C@H:44]([C:49]([NH:51][C@H:52]([C:57]([NH2:59])=[O:58])[CH2:53][CH2:54][S:55][CH3:56])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42].Cl>>[N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][CH2:40][C:41]([NH:43][C@H:44]([C:49]([NH:51][C@H:52]([C:57]([NH2:59])=[O:58])[CH2:53][CH2:54][S:55][CH3:56])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CN)C(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@H](Cc1ccccc1)C(=O)NN
Agent: Cl
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 79 %

Procedure:
Condensation of BocPro-Phe-DPheNHNH2 (2.44 g.) and HGly-Leu-MetNH2 hydrochloride salt (1.6 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocPro-Phe-Phe-Gly-Leu-MetNH2 in 79% yield. De-t-butoxycarbonylation of BocPro-Phe-Phe-Gly-Leu-MetNH2 using hydrogen chloride in acetic acid gave HPro-Phe-Phe-Gly-Leu-MetNH2, which was isolated as the amorphous white solid hydrochloride salt monohydrate in 31% yield.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[C:20]([O:34][CH:35]4[CH2:38][CH2:37][CH2:36]4)=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]([C:29]([O:31][CH3:32])=[O:30])[C@@H:24]([CH3:33])[CH2:23][CH2:22]4)[CH:16]=[N:15]2)[CH:10]([O:39][CH3:40])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:35]1([O:34][C:20]2[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH:10]4[O:39][CH3:40])[CH:18]=3)=[CH:28][CH:27]=[C:26]3[C:21]=2[CH2:22][CH2:23][C@H:24]([CH3:33])[N:25]3[C:29]([O:31][CH3:32])=[O:30])[CH2:36][CH2:37][CH2:38]1
Reactant: COC(=O)N1c2ccc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4OC)c3)c(OC3CCC3)c2CC[C@@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N1c2ccc(-c3cnn(C4CCNCC4OC)c3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
A 25-mL round-bottom flask was charged with (2S)-methyl 6-(1-(1-(tert-butoxycarbonyl)-3-methoxypiperidin-4-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (40 mg, 0.07 mmol), dichloromethane (3 mL), and trifluoroacetic acid (1 mL). The resulting solution stirred for 1 h at room temperature. The reaction mixture was concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: Xbridge RP C18, 19×150 mm, 5 um; Mobile Phase water (0.05% trifluoroacetic acid), acetonitrile (15% to 43% acetonitrile in 9 min, flow rate: 20 mL/min); Detector, 254/220 nm. The fractions were combined and concentrated under vacuum and the residue was further purified via reverse phase chromatography (acetonitrile/water (0.05% ammonium bicarbonate)=5/95-95/5). The fractions were combined, concentrated and lyophilized to afford methyl (2S)-5-cyclobutoxy-6-[1-(3-methoxypiperidin-4-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (14 mg, 43%) as an off-white solid. 1H NMR (300 MHz, CD3OD) δ ppm 1.10-1.20 (m, 3H), 1.25-1.50 (m, 2H), 1.50-1.70 (m, 1H), 1.95-2.52 (m, 8H), 2.80-3.10 (m, 2H), 3.10-3.35 (m, 4H), 3.55-3.90 (m, 6H), 4.05-3.15 (m, 1H), 4.40-4.65 (m, 2H), 7.18-7.35 (m, 2H), 7.93 (s, 1H), 8.01-8.12 (m, 2H). MS (ESI, pos. ion) m/z 455 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])(F)[C:3](O)=O.FC(F)(F)C(O)=O.[O:15]1[CH2:18][CH:17]([N:19]2[CH:23]=[C:22]([C:24]3[N:29]=[C:28]([C:30]4[CH:31]=[N:32][N:33]([C:35]5([CH2:39][C:40]#[N:41])[CH2:38][NH:37][CH2:36]5)[CH:34]=4)[N:27]4[CH:42]=[CH:43][N:44]=[C:26]4[CH:25]=3)[CH:21]=[N:20]2)[CH2:16]1.FC(F)(F)S(OCC(F)F)(=O)=O.C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:1][CH:2]([F:7])[CH2:3][N:37]1[CH2:36][C:35]([CH2:39][C:40]#[N:41])([N:33]2[CH:34]=[C:30]([C:28]3[N:27]4[CH:42]=[CH:43][N:44]=[C:26]4[CH:25]=[C:24]([C:22]4[CH:21]=[N:20][N:19]([CH:17]5[CH2:16][O:15][CH2:18]5)[CH:23]=4)[N:29]=3)[CH:31]=[N:32]2)[CH2:38]1
Reactant: N#CCC1(n2cc(-c3nc(-c4cnn(C5COC5)c4)cc4nccn34)cn2)CNC1
Reactant: O=C(O)C(F)(F)F
Agent: O=S(=O)(OCC(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CCC1(n2cc(-c3nc(-c4cnn(C5COC5)c4)cc4nccn34)cn2)CN(CC(F)F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.4 %

Procedure:
2-(3-(4-(7-(1-(Oxetan-3-yl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile bis(2,2,2-trifluoroacetate) (0.080 g, 0.089 mmol), 2,2-difluoroethyl trifluoromethanesulfonate (0.038 g, 0.178 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.093 mL, 0.534 mmol) were suspended in DMF (5 mL) and stirred at ambient temperature for 1 hour. The reaction mixture was partitioned between saturated aqueous NaHCO3 and EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography, eluting with 2.5-3.5% (9:1 MeOH:NH4OH)/DCM to provide 2-(1-(2,2-difluoro ethyl)-3-(4-(7-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (0.005 g, 0.011 mmol, 12% yield). MS (apci) m/z=466.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[N:31]1[CH:36]=[CH:35][C:34]([C:37]([NH:39][NH2:40])=O)=[N:33][CH:32]=1>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:37]([C:34]3[CH:35]=[CH:36][N:31]=[CH:32][N:33]=3)=[N:39][N:40]=[C:14]2[CH2:13]1)=[O:11]
Reactant: NNC(=O)c1ccncn1
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(Cl)c(F)c1Cl)N1CCn2c(nnc2-c2ccncn2)C1
Temperature: 25 °C

Procedure:
To a solution of 4-[(2,4-dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37) (0.364 g, 1.25 mmol) in Dichloromethane (DCM) (3 mL) was added triethyloxonium tetrafluoroborate (0.249 g, 1.313 mmol). The solution was then stirred, under argon, for 10 minutes before 4-pyrimidinecarbohydrazide (commercially available from e.g. Anichem, J&W PharmLab or Bepharm, 0.207 g, 1.500 mmol) was added. The solution was then stirred for a further hour before the solvent was concentrated and n-butanol (3.00 mL) was added. The solution was then stirred, under argon and reflux, for 3 hours before being cooled to room temperature. The solvent was then evaporated in vacuo and the remaining residue was purified by flash chromatography (Biotage SP4, 25M cartridge) with a gradient of 0-10% 2M NH3/MeOH in DCM. TLC confirmed product location and the solvent from the combined fractions were evaporated in vacuo. The remaining residue was then further purified by mass-direct automated HPLC, before the solvent was again evaporated in vacuo. The remaining solid was then triturated in ether before being dried in a vacuum oven to yield the product in 0.132 g.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([CH2:24][N:25]4[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][C:33]5[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=5)[CH2:27][CH2:26]4)=[CH:23][C:18]=3[N:17]=[C:16]2[NH:39][C:40]2[C:48]3[C:43](=[CH:44][CH:45]=[C:46]([C:49]4[CH:50]=[N:51][CH:52]=[CH:53][C:54]=4[O:55][CH3:56])[CH:47]=3)[N:42](COCC[Si](C)(C)C)[N:41]=2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C>Cl>[CH3:56][O:55][C:54]1[CH:53]=[CH:52][N:51]=[CH:50][C:49]=1[C:46]1[CH:47]=[C:48]2[C:43](=[CH:44][CH:45]=1)[NH:42][N:41]=[C:40]2[NH:39][C:16]1[N:15]([CH:12]2[CH2:13][CH2:14][CH:9]([OH:8])[CH2:10][CH2:11]2)[C:19]2[CH:20]=[CH:21][C:22]([CH2:24][N:25]3[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][C:33]4[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=4)[CH2:29][CH2:30]3)=[CH:23][C:18]=2[N:17]=1
Reactant: COc1ccncc1-c1ccc2c(c1)c(Nc1nc3cc(CN4CCN(CCc5ccncc5)CC4)ccc3n1C1CCC(O[Si](C)(C)C(C)(C)C)CC1)nn2COCC[Si](C)(C)C
Agent: Cl
Product: COc1ccncc1-c1ccc2[nH]nc(Nc3nc4cc(CN5CCN(CCc6ccncc6)CC5)ccc4n3C3CCC(O)CC3)c2c1
Yield: 37.1 %

Procedure:
In a 20 mL vial was added N-(1-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-5-((4-(2-(pyridin-4-yl)ethyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(4-methoxypyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-amine (31 mg, 0.000034 mol) ethanol (1.20 mL) and 0.01M hydrogen chloride (300 uL). The reaction mixture was brought to reflux and maintained at reflux for 1 hour. The reaction mixture was concentrated to a brownish residue and purified by HPLC yielding 8.3 mg of the title compound as the bis TFA salt as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[N:18]=2)[CH:12]=1)[S:6]([CH3:9])(=[O:8])=[O:7].[CH3:33][O:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37](O)=[O:38]>>[OH:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][NH:23][C:19]2[N:18]=[C:17]([C:13]3[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=3)[CH2:10][N:5]([S:6]([CH3:9])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2][NH:1][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=3[O:34][CH3:33])[CH:22]=[CH:21][N:20]=2)=[CH:31][CH:30]=1
Reactant: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Reactant: COc1ccccc1C(=O)O
Product: COc1ccccc1C(=O)NCCCN(Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1)S(C)(=O)=O

Procedure:
Compound 2, was coupled with 2-methoxybenzoic acid following procedure K. LC-MS showed the product had the expected M+H+ of 590. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.2 (d, 1H) 8.0 (s, 1H) 7.9 (s, 1H) 7.7 (t, 1H) 7.5 (m, 5H), 7.1 (d, 1H), 6.9 (d, 2H), 6.8 (d, 2H), 4.5 (s, 2H), 3.8 (s, 3H), δ 3.7 (t, 2H), 3.5 (t, 2H), 3.3 (t, 2H), 2.9 (t, 2H), δ 2.8 (s, 3H), δ 1.8 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]23[CH2:24][CH2:23][CH2:22][CH:21]=[C:8]2[N:9]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)[C:10](=[O:12])[NH:11]3)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CN(C=O)C>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][C:8]12[CH2:21][CH2:22][CH2:23][CH2:24][C:7]1([CH2:6][C:5]1[CH:25]=[CH:26][C:2]([Br:1])=[CH:3][CH:4]=1)[NH:11][C:10](=[O:12])[N:9]2[C:13]1[CH:14]=[C:15]([Cl:20])[CH:16]=[C:17]([Cl:19])[CH:18]=1)[CH3:35]
Reactant: CCOC(=O)CBr
Reactant: O=C1NC2(Cc3ccc(Br)cc3)CCCC=C2N1c1cc(Cl)cc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC12CCCCC1(Cc1ccc(Br)cc1)NC(=O)N2c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3a-(4-Bromo-benzyl)-1-(3,5-dichlorophenyl)-1,3,3a,4,5,6-hexahydro-benzimidazol-2-one (190 mg) (0.42 mmol) in DMF (5 ml) was carefully dropped on a suspension of NaH 60% (20.2 mg) (1.2 eq) in DMF (5 ml) at RT. The reaction mixture was stirred 1 h at RT, then ethyl bromoacetate (0.094 ml) (2.0 eq) was added. After one night at RT, the mixture was heated to 100° C. for 8 h, then the reaction mixture was poured on water and extracted with tBuOMe. The organic layer was washed with water, dried over Na2SO4 and concentrated. The residue was purified on SiO2 chromatography (eluent EtOAc/cyclohexane—1/10) to give [7a-(4-Bromo-benzyl)-3-(3,5-dichlorophenyl)-2-oxo-2,3,5,6,7,7a-hexahydro-benzimidazol-3a-yl]-acetic acid ethyl ester (30.2 mg) as a yellow oil. 1H NMR (CDCl3): 7.35 (2H, d), 7.10 (1H, m), 6.95 (2H, d), 6.8 (2H, m), 4.95 (1H, m), 4.45 (1H, d), 4.2 (2H, q), 3.7 (1H, d), 2.9 (1H, d), 2.8 (1H, d), 2.45-2.1 (2H, m), 2.0-1.8 (4H, m), 1.25 (3H, t).