Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:50][CH:51]1[C@H:55]2[C@H:56](OC3CCCCO3)[N:57](C(OC(C)(C)C)=O)[C:58]3[CH:65]=[CH:64][C:63]([O:66][CH3:67])=[CH:62][C:59]=3[C:60](=[O:61])[N:54]2[CH2:53][CH2:52]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]1[C@H:23]2[C@H:24](OC3CCCCO3)[N:25](C(OC(C)(C)C)=O)[C:26]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:27]=3[C:28](=[O:29])[N:22]2[CH2:21][CH2:20]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:17]([O:18][CH:19]1[C@@H:23]2[CH:24]=[N:25][C:26]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:27]=3[C:28](=[O:29])[N:22]2[CH2:21][CH2:20]1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:50][CH:51]1[C@@H:55]2[CH:56]=[N:57][C:58]3[CH:65]=[CH:64][C:63]([O:66][CH3:67])=[CH:62][C:59]=3[C:60](=[O:61])[N:54]2[CH2:53][CH2:52]1
Reactant: COc1ccc2c(c1)C(=O)N1CCC(OCCCCCCCCCCOC3CCN4C(=O)c5cc(OC)ccc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)[C@H]1[C@H](OC1CCCCO1)N2C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)C(=O)N1CCC(OCCCCCCCCCCOC3CCN4C(=O)c5cc(OC)ccc5N=C[C@@H]34)[C@@H]1C=N2
Reaction time: 1 h
Yield: 94.1 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 15h (180 mg, 0.17 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 16h (103 mg, 0.16 mmol, 96%) as a solid: [α]20D=+500° (c=0.11, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.26-1.50 (m, 12H, 14-H, 14′-H, 15-H, 15′-H, 16-H, 16′-H), 1.82-1.91 (m, 4H, 13-H, 13′-H), 1.98-2.09 (m, 4H, 2-H, 2′-H), 2.25-2.35 (m, 4H, 1-H, 1′-H), 3.54-3.61 (m, 2H, 3-H, 3′-H), 3.69-3.73 (m, 2H, 11a-H, 11a′-H), 3.78-3.83 (m, 2H, 3-H, 3′-H), 3.93 (s, 6H, 7-OMe, 7′-OMe), 3.98-4.14 (m, 4H, 12-H, 12′-H), 6.79 (s, 2H, 9-H, 9′-H), 7.50 (s, 2H, 6-H, 6′-H), 7.65 (d, 2H, J=4.4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 25.8, 28.8, 29.3, 29.4, 29.6, 46.6, 53.7, 56.1, 69.0. 110.4, 111.6, 120.0, 140.6, 147.8, 150.9, 162.3, 164.6; IR (neat): 2928, 1599, 1557, 1505, 1455, 1430, 1382, 1261, 1216, 1092, 1019 cm−1; MS (FAB) m/z (relative intensity) 695 ([M+2×MeOH]+., 8), 663 ([M+MeOH]+., 16), 631 (M+., 100).
Reaction SMILES: C1(N([C@H]2CC[C@H](CC)CC2)C(=O)NC2SC(SC[C:16](O)=[O:17])=CN=2)CCCC1.[C:28]([CH:32]1[CH2:37][CH2:36][CH:35]([NH:38][CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:34][CH2:33]1)([CH3:31])([CH3:30])[CH3:29].C([O:46][C:47](=[O:58])[C:48]([S:51][C:52]1[S:56][C:55]([NH2:57])=[N:54][CH:53]=1)([CH3:50])[CH3:49])C>>[C:28]([C@H:32]1[CH2:37][CH2:36][C@H:35]([N:38]([CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[C:16](=[O:17])[NH:57][C:55]2[S:56][C:52]([S:51][C:48]([CH3:50])([CH3:49])[C:47]([OH:46])=[O:58])=[CH:53][N:54]=2)[CH2:34][CH2:33]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Reactant: CC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Reactant: CC(C)(C)C1CCC(NC2CCCC2)CC1
Product: CC(C)(Sc1cnc(NC(=O)N(C2CCCC2)[C@H]2CC[C@H](C(C)(C)C)CC2)s1)C(=O)O

Procedure:
Prepared in a similar manner to {2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid (Example 38) via (4-tert-butyl-cyclohexyl)-cyclopentyl-amine and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester to give the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:9](=[O:12])([O-])[O-:10].[K+].[K+].CN(C)[C:17](=[O:19])[CH3:18]>O>[CH2:2]([O:19][C:17]1[CH:2]=[C:3]([CH:4]=[CH:5][CH:18]=1)[C:9]([OH:10])=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C([O-])[O-]
Reactant: CCCCCCCBr
Reactant: CC(=O)N(C)C
Agent: [K+]
Solvent: O
Product: CCCCCCCOc1cccc(C(=O)O)c1
Yield: 84 %

Procedure:
In a 2-liter three-necked flask were placed 100 g of methyl 3-hydroxybenzonate, 143 g of 1-bromoheptane, 140 g of potassium carbonate and 300 of N,N-dimethylacetamide (DMAc), and were vigorously stirred for 2 hours with a mechanical stirrer while the flask was heated in oil bath under reflux. After the obtained reaction mixture was cooled, it was poured into 1 l of water, and was extracted with ethyl acetate. Subsequently, the extract was dried under anhydrous sodium sulfate. After the extract was concentrated by removing the solvent in vacuo, the resultant residue was dissolved in 200 ml of methanol. Then, an aqueous solution (40 ml) containing potassium hydroxide of 8.4 g was dropwise added gradually to the ethanol solution and refluxed under heating for 1 hour. After the resultant reaction mixture was cooled, the precipitated crystals were filtered, and the resultant crystals were dissolved in 1.5 l of water. To the solution, 60 ml of concentrated hydrochloric acid was added. Then, the precipitated crystals were filtered in vacuo, washed with ice water and dried to obtain the above compound (2-4a) of 130 g (yield: 84%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:22]([S:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[F:30])=[CH:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[ClH:41].CO>C(Cl)(Cl)Cl>[ClH:1].[ClH:41].[Cl:1][C:2]1[C:3]([CH:22]([S:31]([C:34]2[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=2)(=[O:32])=[O:33])[C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[F:30])=[CH:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(C(c3cc(F)ccc3F)S(=O)(=O)c3ccc(Cl)cc3)c(Cl)cn2)CC1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)c1cc(NC2CCNCC2)ncc1Cl
Reaction time: 2 h
Yield: 84 %

Procedure:
To t-butyl 4-[[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]piperidine-1-carboxylate (41 mg, 0.067 mmol) was added a 20% hydrochloric acid-methanol solution. The resulting mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue thus obtained was dissolved in chloroform, followed by further concentration. The amorphous substance thus obtained was dried under reduced pressure to afford the title compound (34 mg, 84%).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[N:15]=[C:14]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:33][N:32]([CH2:34][CH2:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH2:31]5)[CH:27]=[CH:26][C:23]=4[C:24]=3[N:25]=2)[N:13]([CH:40]([CH3:42])[CH3:41])[N:12]=1)C1C=CC=CC=1>[Pd]>[CH:40]([N:13]1[C:14]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:31][N:32]([CH2:34][CH2:35][S:36]([CH3:39])(=[O:37])=[O:38])[CH2:33]5)[CH:27]=[CH:26][C:23]=4[C:24]=3[N:25]=2)=[N:15][C:11]([NH2:10])=[N:12]1)([CH3:42])[CH3:41]
Reactant: CC(C)n1nc(NC(=O)OCc2ccccc2)nc1-c1nc2c(s1)CCOc1cc(C3CN(CCS(C)(=O)=O)C3)ccc1-2
Agent: [Pd]
Product: CC(C)n1nc(N)nc1-c1nc2c(s1)CCOc1cc(C3CN(CCS(C)(=O)=O)C3)ccc1-2
Reaction time: 72 h

Procedure:
A suspension of (1-isopropyl-5-{8-[1-(2-methanesulfonyl-ethyl)-azetidin-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-1H-[1,2,4]triazol-3-yl)-carbamic acid benzyl ester (157 mg, 0.25 mmol) in IMS (25 mL) was treated with a slurry of palladium on carbon (50 mg, 50% in water) and the mixture was stirred under an atmosphere of hydrogen for 3 days. More palladium on carbon was added and the mixture stirred for another 18 hours before being filtered through celite. The filtrate was concentrated in vacuo and the residue purified by reverse-phase preparative HPLC (Gemini C18 column, gradient 10-90% MeOH in H2O+0.1% HCO2H) to give 463 as a white solid after freeze drying (43 mg, 35%). LCMS: RT=6.30 min, [M+H]+=489. 1H NMR δ (ppm) (DMSO-d6): 8.22 (1H, d, J=8.18 Hz), 7.14 (1H, dd, J=8.25, 1.81 Hz), 6.99 (1H, d, J=1.77 Hz), 5.67-5.59 (1H, m), 5.54 (2H, s), 4.30 (2H, t, J=5.02 Hz), 3.63-3.50 (3H, m), 3.10 (4H, t, J=6.28 Hz), 3.01 (3H, s), 2.78 (2H, t, J=6.83 Hz), 1.42 (6H, d, J=6.58 Hz). 2 Protons obscured by water peak
Reaction SMILES: [CH:1]1([N:7]([CH3:25])[C:8]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[H][H].[CH3:30]I>CN(C=O)C>[CH3:30][N:20]1[C:21]2[C:16](=[CH:15][C:14]([O:13][CH2:12][CH2:11][CH2:10][C:8]([N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH3:25])=[O:9])=[CH:23][CH:22]=2)[CH2:17][CH2:18][C:19]1=[O:24]
Reactant: CI
Reactant: [H][H]
Reactant: CN(C(=O)CCCOc1ccc2c(c1)CCC(=O)N2)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CN1C(=O)CCc2cc(OCCCC(=O)N(C)C3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1.7 g of 6-[3-(N-cyclohexyl-N-methylaminocarbonyl)propoxy]-3,4-dihydrocarbostyril in 50 ml of DMF is added 0.3 g of sodium hydroxide at room temperature under agitation. After the end of hydrogen generation, 1 ml of methyl iodide is added dropwise to the solution and the mixture is agitated at room temperature for 3 hours. After the reaction, the solvent is distilled off under reduced pressure and the residue is dissolved in 200 ml of chloroform. The chloroform layer is washed with an aqueous K2CO3 solution and water and then dried with anhydrous Na2SO4. After filtering out the inorganic matter, the mother liquor is concentrated and the residue is recrystallized from ligroin to obtain 0.9 g of 1-methyl-6-[3-(N-cyclohexyl-N-methylaminocarbonyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with melting point of 104.5°-106.5° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:32][CH2:31][C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[NH:28][C:27]3=[O:37])[CH2:22][CH2:21]2)=[O:19])[C:13]([O:15]C)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].O.[OH-].[Li+]>CCO>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH:17][C:18]([N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH2:32][CH2:31][C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[NH:28][C:27]3=[O:37])[CH2:24][CH2:25]2)=[O:19])[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2]
Reactant: CCc1ccc(CC(NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)OC)cc1CC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCc1ccc(CC(NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
26 g of the crude product described in 3d) were dissolved in 200 mL EtOH, combined with 2.3 g (55 mmol) of lithium hydroxide hydrate and stirred overnight at RT. The reaction solution was concentrated by evaporation in vacuo, the residue was taken up with water, extracted with diethyl ether, acidified with citric acid solution and exhaustively extracted with EtOAc. The combined organic phases were dried over MgSO4 and evaporated down in vacuo.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH:20]=[C:21]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[CH2:25][CH2:24][C:23]4[CH:32]=[CH:33][CH:34]=[CH:35][C:22]3=4)[CH2:14][CH2:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-].[Na+].[Cl:38]CCl.Cl>C(O)C>[ClH:38].[CH:32]1[C:23]2[CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:21](=[CH:20][CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][N:12]([C:7]4[C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=[CH:9][N:8]=4)[CH2:17][CH2:16]3)[C:22]=2[CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)c1cccnc1N1CCN(CCC=C2c3ccccc3CCc3ccccc32)CC1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccnc1N1CCN(CCC=C2c3ccccc3CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A mixture of the above ester (2.1 g, 4.5 mmol) and 20% sodium hydroxide (3.0 ml) in ethanol (21 ml) was stirred at room temperature for 16 h. The solution was poured into dichloromethane (250 ml) and acidified with 2 N hydrochloric acid. The organic phase was washed with water (10 ml), dried (MgSO4) and the solvent evaporated in vacuo. The foamy residue was stripped with acetone and crystallized from acetone, affording 1.5 g (70%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[N:3]=1.[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>C1COCC1.O.CCOC(C)=O>[Br:1][C:2]1[N:3]2[C:10](=[O:11])[NH:9][N:8]=[C:4]2[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cccc(Br)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1[nH]nc2cccc(Br)n12
Reaction time: 1 h
Yield: 63.9 %

Procedure:
To a solution of 2-2 (1.1 g, 5.85 mmol) in THF (50 mL) was added carbonyldiimidazole (1.14 g, 7.02 mmol), and the mixture was stirred for 1 h. The reaction was diluted with water (150 mL) and EtOAc (150 mL), causing a precipitate to form. The mixture was filtered through a sintered glass filter, yielding 0.8 g (64%) of 2-3 as a tan solid. 1H NMR (300 MHz, CHCl3-d) δ 9.34 (s, 1H), 7.03 (m, 1H), 6.85 (m, 1H), 6.59 (m, 1H).
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]([O:10][C:11]([N:13]1[C@@H:18]([C@@H:19]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C@@H:20]([N:30]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)[CH2:17][O:16][C@@H:15]([O:53][CH2:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:14]1[CH3:59])=[O:12])([CH3:9])([CH3:8])[CH3:7].CC(C)([O-])C.[K+].IC.CN(P(N(C)C)N(C)C)C>O1CCCC1>[C:6]([O:10][C:11]([N:13]1[C@@H:18]([C@@H:19]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C@@H:20]([N:30]([CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:21][C:22]2[CH:27]=[C:26]([F:28])[C:25]([CH3:1])=[C:24]([F:29])[CH:23]=2)[CH2:17][O:16][C@@H:15]([O:53][CH2:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:14]1[CH3:59])=[O:12])([CH3:8])([CH3:7])[CH3:9]
Reactant: C[C@H]1[C@H](OCC(C)(C)C)OC[C@H]([C@@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)N1C(=O)OC(C)(C)C
Reactant: [Li]CCCC
Agent: CC(C)(C)[O-]
Agent: CN(C)P(N(C)C)N(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(F)cc(C[C@@H]([C@H](OCc2ccccc2)[C@H]2CO[C@@H](OCC(C)(C)C)[C@H](C)N2C(=O)OC(C)(C)C)N(Cc2ccccc2)Cc2ccccc2)cc1F
Reaction time: 0.17 h
Yield: 55.3 %

Procedure:
Add n-butyllithium (252 μL, 0.404 mmol, 1.6 M in hexanes) dropwise over 5 minutes to a solution of (2R,3S,5R)-5-[(1S,2S)-1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-2-(2,2-dimethylpropoxy)-3-methylmorpholine-4-carboxylic acid tert-butyl ester (0.30 g, 0.404 mmol) in tetrahydrofuran (0.6 mL) at −78° C. Add potassium tert-butoxide (0.404 mL, 1 M in tetrahydrofuran) dropwise over 10 minutes and stir the reaction mixture for an additional 10 minutes. Add iodomethane (25.1 μL, 0.404 mmol) followed by a solution of hexamethylphosphorus triamide (53.7 μL, 0.294 mmol) in tetrahydrofuran (40.4 μL). Stir reaction mixture at −78° C. for 1 hour. Remove cooling bath and stir for 20 minutes. Add water (20 mL) and extract with ethyl acetate (2×50 mL). Wash combined organic layers with water (3×20 mL), dry over magnesium sulfate, and concentrate under reduced pressure. Subject residue to silica gel chromatography, eluting with hexanes containing 0-10% diethyl ether, to provide the desired compound 0.169 g (55.3%) as a white foam.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]4[N:24]=[CH:25][CH:26]=[CH:27][C:15]=4[N:14]3[C:28]=2[C:29]2[CH:34]=[CH:33][C:32]([C:35]3([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:38][CH2:37][CH2:36]3)=[CH:31][CH:30]=2)=[CH:7][CH:6]=1)=[S:3].Br[CH2:48][C:49](OCC)=[O:50]>CCO.C1COCC1.C(Cl)(Cl)Cl>[O:50]=[C:49]1[CH2:48][S:3][C:2]([NH:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]3[N:12]=[C:13]4[C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=5[NH:17][C:16]5[N:24]=[CH:25][CH:26]=[CH:27][C:15]=5[N:14]4[C:28]=3[C:29]3[CH:34]=[CH:33][C:32]([C:35]4([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:43])([CH3:45])[CH3:44])[CH2:36][CH2:37][CH2:38]4)=[CH:31][CH:30]=3)=[CH:9][CH:10]=2)=[N:1]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(NC(N)=S)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: CCOC(=O)CBr
Solvent: CCO
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(NC5=NC(=O)CS5)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 70 °C
Yield: 91.7 %

Procedure:
To a solution of tert-butyl {1-[4-(2-{4-[(aminocarbonothioyl)amino]phenyl}-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (53 mg, 0.083 mmol) in EtOH (2 mL), THF (1 mL) and CHCl3 (1 mL) was added ethyl bromoacetate (0.01 mL, 0.09 mmol). The reaction was heated at 70° C., 1.5 h. The reaction mixture was cooled to room temperature, then concentrated. Purification by column chromatography (SiO2, 50% to 100% EtOAc in hexane) gave the title compound as a yellow solid (51 mg, 91%). 1HNMR (CDCl3) 400 MHz δ: 8.16 (d, J=8.0 Hz, 1H), 8.02-8.01 (m, 1H), 7.62-7.61 (m, 2H), 7.40-7.35 (m, 2H), 7.32-7.29 (m, 1H), 7.20-7.13 (m, 3H), 7.05-7.04 (m, 2H), 6.96 (d, J=8.0 Hz, 1H), 6.80-6.78 (m, 1H), 6.60 (dd, J=8.0, 4.6 Hz, 1H), 6.36 (br s, 1H), 5.18 (br s, 1H), 3.90-3.88 (m, 2H), 2.54-2.52 (m, 4H), 2.16-2.12 (m, 1H), 1.92-1.90 (m, 1H), 1.39 (br s, 9H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=[O:12])=[CH:3][N:2]=1.C(N1[CH:25]=[CH:24]N=C1)(N1C=CN=C1)=O.[C:26](=O)=O.N1C=CN=C1.[Na]>O1CCCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([O:13][CH2:26][CH2:24][CH3:25])=[O:12])=[CH:3][N:2]=1
Reactant: O=C=O
Reactant: O=C(O)c1cnnc2ccccc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Na]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CCCOC(=O)c1cnnc2ccccc12
Reaction time: 2 h

Procedure:
A suspension of 870 mg of 1, and 850 mg of carbonyidimidazole (CDII) in 30 ml of tetrahydrofuran (THF) was stirred at room temperature until CO2 evolution ceased (ca. 30 minutes). After being stirred for 2 hours, the resulting mixture was treated with 320 mg of dry nypropanol and 3 drops of a 0.1 M solution of sodium imidazole in THE. The mixture was held at room temperature overnight, then the solvent was evaporated and the residue was partitioned between water and ether. The etheral extract was washed with saturated sodium bicarbonate solution, then with brine, then dried (MgSO4) and stripped in a rotary evaporator. The residue was chromatographed over silica gel, using a 1:1 v:v mixture of cyclohexane and ethyl acetate as eluent, to give 5, as a yellow oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[S:13][CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[NH:10]2)=[C:4]([CH2:18][CH2:19][CH3:20])[CH:3]=1.[C:21]([Cu])#[N:22]>CN(C=O)C>[C:21]([C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[S:13][CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[NH:10]2)=[C:4]([CH2:18][CH2:19][CH3:20])[CH:3]=1)#[N:22]
Reactant: CCCc1cc(I)ccc1N=C1NC2(CCCC2)CS1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: CCCc1cc(C#N)ccc1N=C1NC2(CCCC2)CS1
Temperature: 25 °C
Yield: 64.3 %

Procedure:
4-Iodo-2-n-propylaniline was converted into 4-iodo-2-n-propylphenyl isothiocyanate in a manner analogous to Method A2b. Concurrently, 1-amino-1-(hydroxymethyl)cyclopentane was converted to the chloromethyl analogue, then reacted with the isothiocyanate in a manner analogous to Method C2a to give 2-(4-iodo-2-propylphenylimino)-3-thia-1-azaspiro[4.4]nonane. A slurry of 2-(4-iodo-2-propylphenylimino)-3-thia-1-azaspiro[4.4]nonane (0.54 g, 1.35 mmol) and CuCN (0.24 g, 2.70 mmol) in DMF (4 mL) was heated at 140° C. overnight. The resulting mixture was cooled to room temp, concentrated under reduced pressure and purified by flash chromatography (10% EtOAc/hex) to give 2-(4-cyano-2-propylphenylimino)-3-thia-1-azaspiro[4.4]nonane as a white solid (0.26 g, 65%): TLC (30% EtOAc/hex) Rf0.37.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:24]=4)[N:17]=2)[CH:13]=[CH:12][S:11]3)[CH:5]=[CH:6][CH:7]=1.NC1C=C(C2N=C3N(C=2C2C=CN=C(NC4C=CC=C(OCCCN5CCOCC5)C=4)N=2)C=CS3)C=CC=1.[C:75]1([CH2:81][C:82](Cl)=[O:83])[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1.FC1C=CC=C(F)C=1C(Cl)=O>>[N:31]1([CH2:30][CH2:29][C:25]2[CH:24]=[C:23]([NH:22][C:18]3[N:17]=[C:16]([C:15]4[N:14]5[C:10]([S:11][CH:12]=[CH:13]5)=[N:9][C:8]=4[C:4]4[CH:3]=[C:2]([NH:1][C:82](=[O:83])[CH2:81][C:75]5[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=5)[CH:7]=[CH:6][CH:5]=4)[CH:21]=[CH:20][N:19]=3)[CH:28]=[CH:27][CH:26]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1cccc(-c2nc3sccn3c2-c2ccnc(Nc3cccc(CCN4CCOCC4)c3)n2)c1
Agent: Nc1cccc(-c2nc3sccn3c2-c2ccnc(Nc3cccc(OCCCN4CCOCC4)c3)n2)c1
Agent: O=C(Cl)c1c(F)cccc1F
Product: O=C(Cc1ccccc1)Nc1cccc(-c2nc3sccn3c2-c2ccnc(Nc3cccc(CCN4CCOCC4)c3)n2)c1

Procedure:
The title compound was prepared as described in EXAMPLE 297, with the following substitutions: 4-(6-(3-aminophenyl)imidazo[2,1-b]thiazol-5-yl)-N-(3-(2-morpholinoethyl)phenyl)pyrimidin-2-amine for 4-(6-(3-aminophenyl)imidazo[2,1-b]thiazol-5-yl)-N-(3-(3-morpholinopropoxy)phenyl)pyrimidin-2-amine and 2-phenylacetyl chloride for 2,6-difluorobenzoyl chloride. (ESI(+)) m/e 616 (M+H)+; (ESI(−)) m/e 614 (M−H)−; 1H-NMR (300 MHz, DMSO-d6) □ 10.29 (s, 1H), 9.62 (s, 1H), 8.80 (d, 1H), 8.26 (d, 1H), 7.88 (t, 1H), 7.68-7.74 (m, 1H), 7.54-7.61 (m, 2H), 7.49 (d, 1H), 7.40 (t, 1H), 7.18-7.36 (m, 6H), 6.86 (d, 1H), 6.59 (d, 1H), 3.65 (s, 2H), 3.53-3.60 (m, 4H), 3.17 (d, 1H), 2.68-2.76 (m, 2H), 2.52-2.56 (m, 1H), 2.38-2.43 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][NH2:41]>C1COCC1.CCOC(C)=O>[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][NH:41][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:26][CH:25]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:21])=[O:22]
Reactant: COCCOCCN
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCOCCNS(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)n2)c1
Yield: 68.4 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available 2-(2-methoxy-ethoxy)-ethylamine [CAS-no. 31576-51-9] (0.244 mg, 2.04 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.160 g, 68%) as a light yellow oil. MS (ISP) 572.2 [(M+H)+].