Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:28]=[CH:27][C:5]2[N:6]([CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]5[OH:24])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[O:29]1[CH2:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30]1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[O:29]1[CH2:30][CH:31]=[C:32]([C:2]2[CH:28]=[CH:27][C:5]3[N:6]([CH2:9][C:10]4[CH:26]=[CH:25][C:13]5[N:14]=[C:15]([NH:17][C@@H:18]6[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]6[OH:24])[S:16][C:12]=5[CH:11]=4)[CH:7]=[N:8][C:4]=3[CH:3]=2)[CH2:33][CH2:34]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(I)ccc43)cc2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(C5=CCOCC5)ccc43)cc2s1
Temperature: 100 °C
Yield: 19.9 %

Procedure:
A stirred mixture of (1R,2R)-2-((6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (300 mg, 0.59 mmol) from Step 5 of Example 183, 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (188 mg, 0.89 mmol), Na2CO3 (126 mg, 1.19 mmol), 1,4-dioxane (3 mL) and water (0.5 mL) was purged with a stream of nitrogen for 10 min. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (44 mg, 0.59 mmol) was added and the mixture was heated at 100° C. for 2 h. The reaction mixture was cooled to rt and partitioned between EtOAc and water. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 30:1 DCM: MeOH and then by reverse-phase preparative HPLC to afford (1R,2R)-2-((6-((5-(3,6-dihydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (54 mg, 20%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.67 (d, J=1.5 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.35 (m, 1H), 7.29 (d, J=8.1 Hz, 1H), 7.18 (m, 1H), 6.19 (s, 1H), 5.46 (s, 2H), 4.71 (d, J=5.1 Hz, 1H), 4.22 (d, J=2.7 Hz, 2H), 3.81-3.84 (m, 2H), 3.51 (m, 1H), 3.38 (m, 1H), 2.02 (m, 1H), 2.00 (m, 1H), 1.61 (br s, 2H), 1.14-1.29 (m, 4H); LCMS (ESI) m/z 460 (M+H)+.
Reaction SMILES: [C:1]([C:3](=[C:9]([S:12][CH3:13])SC)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH2:14]([N:16]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)[CH2:17][CH3:18])[CH3:15]>>[CH2:14]([N:16]([C:19]1[CH:20]=[CH:21][C:22]([NH:23][C:9]([S:12][CH3:13])=[C:3]([C:1]#[N:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:24][CH:25]=1)[CH2:17][CH3:18])[CH3:15]
Reactant: CCOC(=O)C(C#N)=C(SC)SC
Reactant: CCN(CC)c1ccc(N)cc1
Product: CCOC(=O)C(C#N)=C(Nc1ccc(N(CC)CC)cc1)SC
Yield: 81 %

Procedure:
21.7 g of ethyl 2-cyano-3,3-bis(methylthio)acrylate and 16.5 g of 4-(N,N-diethylamino)aniline are heated for 2 hours at 120° C. The residue is purified by chromatography on a silica column, the eluent being a toluene/ethanol (97/3) mixture; the expected product is recrystallised from cyclohexane. M.p.=100° C. (Yield 81%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[Cl:19])[CH2:9][OH:10])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:22]I.[Cl-].[NH4+]>O1CCCC1>[Cl:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[O:11][CH:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=1)[CH2:9][O:10][CH3:22]
Reactant: Nc1nccc(C(CO)Oc2ccc(F)cc2Cl)n1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCC(Oc1ccc(F)cc1Cl)c1ccnc(N)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(2-aminopyrimidin-4-yl)-2-(2-chloro-4-fluorophenoxy)ethanol (21a) (185 mg) in dry tetrahydrofuran under nitrogen atmosphere was added sodium hydride (23 mg, 60% dispersion in oil) and the mixture was stirred at room temperature for 10 minutes, then methyl iodide (0.045 mL) was added. The mixture was stirred at room temperature for an additional for 45 minutes, poured onto sat aq ammonium chloride solution then extracted with ethyl acetate, washed with brine, dried over sodium sulfate and in vacuo. Purification by column chromatography eluting with 10 to 100% ether in heptane afforded the title compound (60 mg) as an oil that solidified upon standing, MS (ES): m/z 298 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)(=[O:3])[CH3:2].[N:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:24]=[O:25].CO>C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[C:18]([NH:22][C:24]([NH:23][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:25])[CH:19]=[CH:20][CH:21]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CN=C=O
Reactant: CC(=O)OCCCCCCOCCCCc1cccc(N)c1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CNC(=O)Nc1cccc(CCCCOCCCCCCOC(C)=O)c1
Reaction time: 0.5 h

Procedure:
6-[4-(3-Aminophenyl)butoxy]hexyl acetate (2.84 g) in CH2Cl2 (30 ml) was treated with ethyl isocyanatoacetate (1.2 ml). After 0.75 h the mixture was treated with MeOH (2 ml) and stirred for 0.5 h. The mixture was concentrated, purified on a 10 g silica Bond Elut cartridge eluting with Et2O-petroleum ether(1:1) and then with Et2O to give the title compound (3.33 g) ES+ve 437 (MH)+.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/4)=[C:9]3[N:8]=[C:7](S(C)(=O)=O)[N:6]=2)[CH2:3][CH2:2]1.C1(NC2N3N=CC(/C=C4/C(=O)NC(=O)N/4)=C3N=C(S(C)=O)N=2)CC1.[CH:50]1([CH2:53][NH2:54])[CH2:52][CH2:51]1.O>CN1C(=O)CCC1.C(Cl)Cl>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/4)=[C:9]3[N:8]=[C:7]([NH:54][CH2:53][CH:50]3[CH2:52][CH2:51]3)[N:6]=2)[CH2:3][CH2:2]1
Reactant: NCC1CC1
Reactant: CS(=O)(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Agent: CS(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)nc(NCC4CC4)nc23)N1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A (1:1) mixture of (Z)-5-((4-(cyclopropylamino)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione and (Z)-5-((4-(cyclopropylamino)-2-(methylsulfinyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione (36 mg) was suspended in NMP (0.2 ml). Cyclopropylmethylamine (88 uL) was added and the mixture stirred at room temperature for 15 minutes. Water and methylene chloride were added and the resulting precipitate was filtered. After triturating in a mixture of ethyl acetate and hexanes, (Z)-5-((4-(cyclopropylamino)-2-(cyclopropylmethylamino)pyrazolo[1,5-a][1,3,5]triazin-8-yl) methylene)imidazolidine-2,4-dione was isolated as a yellow solid.). LCMS (ES):>95% pure, m/z 355 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH:34]=O)=[CH:4][N:3]=1.[NH:36]1[CH2:40][CH2:39][CH:38]([NH:41]C(=O)OC(C)(C)C)[CH2:37]1.Cl.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][N:36]2[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37]2)=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: COc1cc(-c2csc3c(/C=C/C=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc(-c2csc3c(/C=C/CN4CCC(N)C4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Yield: 19.7 %

Procedure:
N-(4-{4-Amino-7-[(1E)-3-oxoprop-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (100 mg, 0.207 mmol) and tert-butyl pyrrolidin-3-ylcarbamate (115.7 mg, 0.621 mmol) were reacted according to General Procedure B. The crude product (135 mg, 0.207 mmol) was dissolved in methanol (1 mL) and treated with 6.0 M hydrochloric acid in 1,4 dioxane (0.518 mL, 2.07 mmol) and heated to 55 degrees Celsius for 4 hours. The mixture was cooled to room temperature then 1M sodium carbonate solution (5 mL) was added and product was extracted with ethyl acetate (3×10 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The product was purified via flash chromatography to furnish the title compound as an ivory powder (22.5 mg, 0.0408 mmol): LCMS (Conditions a): MH−=551 RT=3.62 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.51 (1 H), 7.97 (2 H), 7.72 (1 H), 7.63 (2 H), 7.36 (2 H), 7.21 (1 H), 7.15 (1 H), 7.07 (1 H), 6.70 (1 H), 6.26 (1 H), 5.65 (1 H), 4.04 (3 H), 3.91 (3 H), 3.51 (1 H), 3.29 (2 H), 2.71 (2 H), 2.45 (2 H), 2.10 (1 H), 1.53 (1 H).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:9][CH2:8][NH:7][C:6]1=[O:10])[CH2:2][CH:3]=[CH2:4].[H-].[Na+].[Cl:13][C:14]1[C:18]([N:19]([CH2:25][CH3:26])[C:20](=[O:24])[CH2:21][CH2:22]I)=[CH:17][N:16]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[N:15]=1.O>CN(C=O)C>[CH2:1]([CH:5]1[CH2:9][CH2:8][N:7]([CH2:22][CH2:21][C:20]([N:19]([C:18]2[C:14]([Cl:13])=[N:15][N:16]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[CH:17]=2)[CH2:25][CH3:26])=[O:24])[C:6]1=[O:10])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCC1CCNC1=O
Reactant: CCN(C(=O)CCI)c1cn(-c2cccnc2)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCC1CCN(CCC(=O)N(CC)c2cn(-c3cccnc3)nc2Cl)C1=O
Reaction time: 0.75 h

Procedure:
To 3-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylpropan amide (0.500 g, 1.60 mmol) in acetone (8 mL) was added sodium iodide (0.359 g, 2.40 mmol). The reaction was heated to reflux for 24 hours. The reaction product was filtered and concentrated to provide N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-iodopropanamide (0.363 g, 0.898 mmol), which was used immediately without further purification. To 3-(but-3-en-1-yl)pyrrolidin-2-one (0.125 g, 0.898 mmol) dissolved in DMF (4.49 ml) was added sodium hydride (60% in mineral oil, 0.0360 g, 0.898 mmol). The reaction stirred for 45 minutes. Then, N-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-iodopropanamide (0.363 g, 0.898 mmol) was added as a solution in DMF (2 mL). The reaction mixture was allowed to stir at room temperature overnight. The reaction product was poured into water, extracted with diethyl ether, and washed with brine. The organics were dried and concentrated to give an oil that was purified by flash column chromatography using 0-60% acetone/hexanes as eluent providing the title compound as a clear, colorless oil. (0.257 g, 69%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[O:26]C(=O)O[C:23]2=O)=[CH:18][CH:17]=1.C[O-].[Na+].CO>C1COCC1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([OH:26])[C:23]2[N:6]=[C:4]([OH:5])[C:3]3[C:2](=[CH:10][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:8][CH:7]=3)[N:1]=2)=[CH:18][CH:17]=1
Reactant: O=C1OC(=O)C(c2ccc(F)cc2)O1
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1N
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Oc1nc(C(O)c2ccc(F)cc2)nc2cc(C(F)(F)F)ccc12
Temperature: 50 °C

Procedure:
To 2-amino-4-(trifluoromethyl)benzamide (840 mg, 4.16 mmol), in THF (15 mL) was added 5-(4-fluorophenyl)-1,3-dioxolane-2,4-dione from Example 16 (1225 mg, 6.24 mmol) and the mixture was heated at 50° C. for 4 h. The solvent was evaporated and the crude 2-(2-(4-fluorophenyl)-2-hydroxyacetamido)-4-(trifluoromethyl)benzamide was dissolved in MeOH (10 mL), added 0.5 M sodium methoxide in MeOH (2.5 mL, 1.25 mmol) and the reaction mixture was heated at 50° C. for 1 h. The solvent was evaporated and then 1N hydrochloric acid was added. The mixture was extracted with EtOAc and the organic phase was dried over sodium sulfate and concentrated in vacuo to afford crude 2-((4-fluorophenyl)(hydroxy)methyl)-7-(trifluoromethyl)quinazolin-4-ol, which was used in next reaction without purification. LC-MS (ESI) m/z 339 (M+Na)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:19][S:20][C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][N:27]([C:31](=[O:33])[CH3:32])[CH2:28]3)=[CH:23][CH:22]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.F[C:35](F)(F)[C:36](O)=O>C(Cl)(Cl)Cl>[CH2:17]([O:16][C:14]([C:11]1([CH2:19][S:20][C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][N:27]([C:31](=[O:33])[CH3:32])[CH2:28]3)=[CH:23][CH:22]=2)[CH2:10][CH2:9][N:8]([C:36]2[CH:35]=[CH:13][N:8]=[CH:9][CH:10]=2)[CH2:13][CH2:12]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)C1(CSc2ccc3c(c2)CN(C(C)=O)CC3)CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1(CSc2ccc3c(c2)CN(C(C)=O)CC3)CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-(2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-ylthiomethyl)-4-ethoxycarbonylpiperidine-1-carboxylic acid tert-butyl ester (221 mg) in chloroform (0.5 ml) was added trifluoroacetic acid (1 ml), and the mixture was stirred at room temperature for 10 min. After completion of the reaction, the solvent was evaporated and to the obtained residue were added ethanol (3 ml), triethylamine (0.39 ml) and 4-chloropyridine hydrochloride (70 mg). The mixture was stirred in a sealed tube at 150° C. for 2 days. After completion of the reaction, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (5% methanol-chloroform) and dried under reduced pressure to give the title compound (63 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[CH2:14][O:15][CH2:16][CH2:17][CH2:18][OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(C)=O.O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[CH2:14][O:15][CH2:16][CH2:17][CH:18]=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1COCCCO
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1COCCC=O
Temperature: 0 °C
Yield: 52.7 %

Procedure:
In methylene chloride (43 ml) were dissolved 3-((2S,4S)-1-(tert-butoxycarbonyl)-4-fluoro-2-pyrrolidinylmethoxy)propanol (2.84 g, 9.30 mmol), triethylamine (7.78 ml, 55.8 mmol) and DMSO (6.61 ml, 93.7 mmol). Under stirring at 0° C., a pyridine-sulfur trioxide complex (4.44 g, 27.9 mmol) was added dropwise to the resulting solution. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 2 hours. Water (50 ml) was added to the residue obtained by distilling off the solvent under reduced pressure, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 50 g), whereby hexane/ethyl acetate (4/1) eluate fractions, the title compound (1.35 g, 53%) was obtained as a colorless oil.
Reaction SMILES: Cl[C:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=[O:3].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]([CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[C:2]([N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)=[O:3])=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Reactant: CCN(CC)CCNc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC)CCN(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 18.2 %

Procedure:
tert-Butyl 4-chlorocarbonyl-piperazine-1-carboxylate (0.97 g, 3.9 mmol) was added to a solution of 4-chloro-N-(2-(diethylamino)ethyl)benzenamine (884 mg, 3.9 mmol) and N,N-diisopropylethylamine (1.9 mL, 11.7 mmol) in DCM (8 mL). The reaction mixture was heated at reflux for 20 hours. The mixture was cooled to room temperature, quenched with saturated NH4Cl (10 mL), and extracted with DCM (2×20 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel chromatography to give tert-butyl 4-(N-(4-chlorophenyl)-N-(2-(diethylamino)ethyl)carbamoyl)piperazine-1-carboxylate (311 mg, 18%). MS (APCI+) [M+H]+439.4. 1H NMR (CDCl3, 400 MHz) δ□7.29 (d, J=8.8 Hz, 2H), 7.09 (d, J=8.8 Hz, 2H), 3.70-3.66 (m, 2H), 3.45-3.42 (m, 2H), 3.24-3.21 (m, 4H), 3.15-3.12 (m, 2H), 2.61-2.57 (m, 2H), 2.52 (q, J=7.2 Hz, 4H), 1.42 (s, 9H), 0.99 (t, J=7.2 Hz, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:34])[N:25]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH3:26])=[CH:20][C:19]=2[F:35])[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[ClH:33].[ClH:33].[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([N:25]([CH3:26])[C:24](=[O:34])[C:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][CH2:14][N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[C:19]([F:35])[CH:20]=2)=[CH:28][CH:29]=1
Reactant: CN(C(=O)c1ccc(OCCCN2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C(=O)c1ccc(OCCCN2CCNCC2)c(F)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
4-(3-{4-[(4-Chloro-phenyl)-methyl-carbamoyl]-2-fluoro-phenoxy}-propyl)-piperazine-1-carboxylic acid tert-butyl ester from Example E71.1 (210 mg, 0.4 mmol) was dissolved in 4M HCl in dioxan (5 ml) and stirred for 1 h at room temperature. Solvents were concentrated in vacuo and azeotroped with toluene to yield the title compound (184 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[S:25][CH:24]3[CH:26]=[C:27](Br)[S:28][CH:23]3[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:31][O:32][C:33](=[O:53])[NH:34][CH:35]([C:39]([N:41]1[CH2:45][CH2:44][CH2:43][CH:42]1[C:46]1[NH:47][C:48]([C:51]#[CH:52])=[CH:49][N:50]=1)=[O:40])[CH:36]([CH3:38])[CH3:37].C(N(CC)CC)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:30])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[S:25][CH:24]3[CH:26]=[C:27]([C:52]#[C:51][C:48]4[NH:47][C:46]([CH:42]5[CH2:43][CH2:44][CH2:45][N:41]5[C:39](=[O:40])[CH:35]([NH:34][C:33]([O:32][CH3:31])=[O:53])[CH:36]([CH3:38])[CH3:37])=[N:50][CH:49]=4)[S:28][CH:23]3[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: C#Cc1cnc(C2CCCN2C(=O)C(NC(=O)OC)C(C)C)[nH]1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(C2=CC3SC(Br)=CC3S2)[nH]1)C(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(C#CC2=CC3SC(c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)=CC3S2)[nH]1)C(C)C
Temperature: 85 °C
Yield: 17.8 %

Procedure:
(1-{2-[5-(5-Bromo-3a,6a-dihydro-thieno[3,2-b]thiophen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (140 mg, 0.440 mmol), {1-[2-(5-Ethynyl-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (130 mg, 0.254 mmol), Pd(PPh3)4 (29 mg, 0.0254 mmol), CuI (10 mg, 0.0508 mmol) and triethylamine (0.354 mmol, 2.54 mmol) were combined in DMF (2.5 mL) and degassed with N2 for 17 min. The reaction was heated to 85° C. for 4 h then cooled to RT, diluted with EtOAc and washed with saturated aqueous NaHCO3 (2×) and brine. The organic layer was dried over MgSO4, filtered and concentrated. The crude residue was purified by HPLC chromatography to afford the title compound (34 mg, 18%). MS (ESI) m/z 749 [M+H]+.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Cl[CH2:13][C:14]([OH:16])=[O:15].Cl>CS(C)=O.O>[CH2:1]([O:9][CH2:13][C:14]([OH:16])=[O:15])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCCc1ccccc1
Reactant: O=C(O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)COCCc1ccccc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 75.3 %

Procedure:
To a stirred mixture of phenethyl alcohol (1.0 g, 8.18 mmol) in DMSO (16 mL) under nitrogen flow, NaH (0.39 g, 16.37 mmol) was added in one portion and the mixture was stirred at 60° C. for 10 min. Following the addition of chloroacetic acid (0.77 g, 8.18 mmol), the reaction mixture was heated at 80° C. for 3 h. The cooled mixture was then poured into H2O and the aqueous phase acidified to pH 1.0 with a 2.0 N HCl solution. The aqueous phase was then extracted with EtOAc (3×20 mL), and the combined organic phase washed with brine and dried over Na2SO4 to afford the title compound (1.11 g, 75%), which was used in the following step without further purification. 1H NMR (DMSO-d6): δ 2.83 (t, J=7.0 Hz, 2H), 3.67 (t, J=7.0 Hz, 2H), 4.00 (s, 2H), 7.15-7.32 (m, 5H), 12.64 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[O:6][CH2:7][C:8](O)([CH3:19])[C:9]3[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.CCN(S(F)(F)[F:29])CC.BrC1C=CC2OCC(F)(F)C3SC(C(OCC)=O)=NC=3C=2C=1>>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[O:6][CH2:7][C:8]([F:29])([CH3:19])[C:9]3[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOC(=O)c1nc2c(s1)C(C)(O)COc1ccc(Br)cc1-2
Agent: CCOC(=O)c1nc2c(s1)C(F)(F)COc1ccc(Br)cc1-2
Product: CCOC(=O)c1nc2c(s1)C(C)(F)COc1ccc(Br)cc1-2

Procedure:
The title compound was prepared from ethyl 9-bromo-4-hydroxy-4-methyl-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate and DAST as described in the synthesis of ethyl 9-bromo-4,4-difluoro-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate.
Reaction SMILES: [CH3:1]OC(OC)N(C)C.FC(F)(F)C(O)=O.[CH3:16][N:17]([CH2:19][C:20]1[C:28]([OH:29])=[C:27]([F:30])[CH:26]=[C:25]2[C:21]=1[CH:22]=[CH:23][N:24]2[S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH3:18]>CN(C=O)C>[F:30][C:27]1[CH:26]=[C:25]2[C:21]([CH:22]=[CH:23][N:24]2[S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[C:20]([CH2:19][N:17]([CH3:16])[CH3:18])[C:28]=1[O:29][CH3:1]
Reactant: CN(C)Cc1c(O)c(F)cc2c1ccn2S(=O)(=O)c1ccccc1
Reactant: COC(OC)N(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1c(F)cc2c(ccn2S(=O)(=O)c2ccccc2)c1CN(C)C

Procedure:
N,N-dimethylformamide dimethyl acetal (0.964 ml, 7.233 mmol) was added to a solution of 4-[(dimethylamino)methyl]-6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol (252 mg, 0.723 mmol; Example 146) in DMF (8 ml) and the mixture was divided into two tubes and heated in microwave oven at 180 0 C for 180 s. Solvent was evaporated and residue purified on Gilson HPLC using 30-70% MeCN in 50 nM ammonium bicarbonate buffer as eluent (Xterra). Yield: 101.7 mg (39%); white solid. MS (ESI+) for C18H19FN2O3S m/z 363 (M+H)+.