Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6]2[C:7]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:23])[C@@H:20]([CH3:22])[NH2:21])=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:24][C:2]1([CH3:1])[C:6]2[C:7]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[C:19](=[O:23])[C@@H:20]([CH3:22])[NH:21][C:33]4=[O:35])=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@@H](N)C(=O)Nc1ccc(Oc2cccc3c2C(C)(C)CO3)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1NC(=O)N(c2ccc(Oc3cccc4c3C(C)(C)CO4)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 140.1 %

Procedure:
To a solution of N1-{4-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]phenyl}-D-alaninamide (Intermediate 57, 66 mg) in dichloromethane (20 ml, SCRC) was added triethylamine (0.085 ml, 0.607 mmol, SCRC). Triphosgene (24.00 mg, 0.081 mmol, SCRC) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature for 0.5 hours. The mixture was quenched with water (20 ml) and it was extracted with dichloromethane (3 times 50 ml, SCRC). The combined organic layers were dried, evaporated and purified by column chromatography on silica gel with EtAc/PE (1/30) as eluents to afford the title compound as a white solid (40 mg).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:48](=[O:49])[N:13]3[C:14]([C:32]([O:34]C(C4C=CC=CC=4)C4C=CC=CC=4)=[S:33])=[C:15]([C:18]4[S:19][C:20]([CH2:23][NH:24]C(OC(C)(C)C)=O)=[N:21][N:22]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53].C(OC(C)C)(C)C>ClCCl.C1(OC)C=CC=CC=1>[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53].[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:48](=[O:49])[N:13]3[C:14]([C:32]([OH:34])=[S:33])=[C:15]([C:18]4[S:19][C:20]([CH2:23][NH2:24])=[N:21][N:22]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NCc1nnc(C2=C(C(=S)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)Cc4ccccc4)[C@H]3SC2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Product: NCc1nnc(C2=C(C(O)=S)N3C(=O)[C@@H](NC(=O)Cc4ccccc4)[C@H]3SC2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of benzhydryl 7β-(2-phenylacetamido)-3-(5-tert-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-yl)thio-3-cephem-4-carboxylate (683 mg) in a mixture of dichloromethane (2.1 ml) and anisole (0.7 ml) was added trifluoroacetic acid (1.4 ml) under ice-cooling. The mixture was stirred at the same temperature for 30 minutes and at room temperature for 3 hours. The reaction mixture was poured into diisopropyl ether (70 ml). The precipitate was collected by filtration and dried over to give 7β-(2-phenylacetamido)-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thio-3-cephem-4-carboxylic acid trifluoroacetic acid salt (525 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][N:17]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](=O)([O-])O.[K+].IC>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][N:17]=1)[C:12]([O:14][CH3:18])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccnc(OCc2ccccc2)c1
Reactant: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccnc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 97.7 %

Procedure:
To a suspension of 2-(benzyloxy)isonicotinic acid (12.6 g) and potassium hydrogencarbonate (8.3 g) in N,N-dimethylformamide (180 mL) was added dropwise iodomethane (4.8 mL) under ice-cooling, and then stirred at room temperature for 7 hours. The reaction solution was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride (×3), and then dried over anhydrous sodium sulfate and concentrated to give the title compound as a brown oil (13.07 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.Br[CH2:13][CH2:14]Cl.[OH-].[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:14][CH2:13]2)=[C:4]([F:11])[CH:3]=1
Reactant: ClCCBr
Reactant: N#CCc1ccc(Br)cc1F
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: N#CC1(c2ccc(Br)cc2F)CC1
Temperature: 25 °C
Yield: 438.7 %

Procedure:
A solution of the compound (22.6 g, 23.36 mmol) obtained in Example 14-1), 1-bromo-2-chloroethane (18.9 g, 132 mmol), benzyltriethylammonium chloride (0.48 g, 2.34 mmol), and potassium hydroxide (41.5 g, 739 mmol) in water (40 mL) was stirred at 40° C. for 9 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate, and the organic layer was washed with water, a 1 M aqueous hydrochloric acid solution, and saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Isco Combiflash, 40 g, hexane:ethyl acetate=0:100 to 100:0, gradient) to obtain the title compound (24.6 g, 97%) as a black oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:33]=1)[O:7][CH2:8][C:9]1[CH:19]=[C:18]([CH2:20][N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[C:29]([OH:30])[C:24]=4[N:23]=[C:22]3[CH2:31][OH:32])[CH:17]=[CH:16][C:10]=1/[C:11]/2=[C:12](/[CH3:15])\[C:13]#[N:14].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])(=O)=O.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[O:32]([CH2:31][C:22]1[N:21]([CH2:20][C:18]2[CH:17]=[CH:16][C:10]3/[C:11](=[C:12](/[CH3:15])\[C:13]#[N:14])/[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:33][C:6]=4[O:7][CH2:8][C:9]=3[CH:19]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([OH:30])[C:24]=2[N:23]=1)[Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49]
Reactant: C/C(C#N)=C1/c2ccc(Cn3c(CO)nc4c(O)cccc43)cc2COc2cc(F)ccc21
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: ClCCl
Product: C/C(C#N)=C1/c2ccc(Cn3c(CO[Si](C)(C)C(C)(C)C)nc4c(O)cccc43)cc2COc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
[step 1] (E)-2-(3-fluoro-8-{[4-hydroxy-2-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl]methyl}dibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (245 mg, 0.56 mmol) obtained in Reference Example 2A, step 4 was dissolved in dichloromethane (2.8 mL), 2,6-lutidine (0.22 mL, 1.89 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (0.38 mL, 1.67 mmol) were added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted 3 times with chloroform. The combined organic layers were washed with 1 mol/L hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in methanol (2.8 mL), potassium carbonate (384 mg, 2.77 mmol) was added, and the mixture was stirred at room temperature for 13 hr. Water was added to the mixture, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 v/v-85/15 v/v) to give (E)-2-[8-({2-[(tert-butyldimethylsiloxy)methyl]-4-hydroxy-1H-benzo[d]imidazol-1-yl}methyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (203 mg, 66%).
Reaction SMILES: [Cl:1][C:2]([Cl:8])=[CH:3][CH:4]=[C:5]([CH3:7])[CH3:6].[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].O.[Cl-].[Li+].Cl>O.C(OCC)(=O)C>[C:9]([C:11]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:4]([CH:3]=[C:2]([Cl:8])[Cl:1])[C:5]1([CH3:7])[CH3:6])#[N:10]
Reactant: CCOC(=O)CC#N
Reactant: CC(C)=CC=C(Cl)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(C#N)C(C=C(Cl)Cl)C1(C)C
Temperature: 80 °C
Yield: 63.4 %

Procedure:
151 Parts of 1,1-dichloro-4-methylpenta-1,3-diene, 113 parts of ethyl cyanoacetate, 200 parts of cupric acetate monohydrate, 148 parts of cupric chloride, 62.6 parts of lithium chloride monohydrate and 900 parts of ethyl acetate are stirred in an atmosphere of nitrogen. The temperature is raised to 80° C. and maintained at 80°-81° C. for 5 hours. After cooling, the reaction mixture was stirred with 1180 parts of hydrochloric acid (s.g. 1.18) and 1500 parts of water for 10 minutes. The organic layer was separated and extracted twice with 590 parts of hydrochloric acid (s.g. 1.18) in 500 parts of water. The ethyl acetate solution was diluted with 900 parts of ethyl acetate and the solution washed four times with 500 parts of water. The ethyl acetate solution is evaporated by heating to 87° C. at 20 mm Hg pressure to yield 201 parts of ethyl 1-cyano- 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylate (estimated strength 82.7% equivalent to 63.4% yield).
Reaction SMILES: [Cl:1][CH:2](S(C1C=CC=CC=1)=O)[C:3]([O:24][CH3:25])=[C:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C:18](=[CH:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[OH-:34].[Na+].O.C(Cl)Cl>C1COCC1.CO.CC(C)=O>[Cl:1][CH:2]=[C:3]([O:24][CH3:25])[C@:4]1([OH:34])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C:18](=[CH:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: [OH-]
Reactant: COC(=C1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]12C)C(Cl)S(=O)c1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=CCl)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Reaction time: 24 h

Procedure:
To a solution of 21-chloro-20-methoxy-21-(phenylsulfinyl)pregna-4,9(11),17(20)-trien-3-one (VI, Example 3, 100 mg) in THF (2 ml), methanol (0.45 ml) and acetone (0.3 ml) at 0° under nitrogen is added a solution of sodium hydroxide (5 N, 0.04 ml). The mixture is brought to 20°-25° and is allowed to stir for 24 hr. The mixture is poured into a mixture of water (25 ml) and methylene chloride (10 ml). The layers are separated and the aqueous layer is extracted with methylene chloride (2×5 ml). The organic extracts are combined and washed with water (10 ml), dried over sodium sulfate and concentrated under reduced pressure to give the title compound.
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[O:11]1[CH:17]2[CH:12]1[CH2:13][CH:14]([C:18](OC)=[O:19])[CH2:15][CH2:16]2.N12CCN(CC1)CC2.C1(C)C=CC=CC=1>CO>[CH2:1]([O:10][C:18]([CH:14]1[CH2:15][CH2:16][CH:17]2[O:11][CH:12]2[CH2:13]1)=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCO
Reactant: COC(=O)C1CCC2OC2C1
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCCCCCCOC(=O)C1CCC2OC2C1

Procedure:
To a 3-neck 250 mL flask equipped with an argon inlet, stir bar and distillation apparatus was added 1-nonanol (19.99 g, 0.14 mol, obtained from Sigma-Aldrich), methyl 3,4-epoxycyclohexanecarboxylate (ERL-4140, 23.80 g, 0.15 mol, obtained from Dow Chemical Company), 1,4-diazabicyclo[2.2.2]octane (DABCO™, 3.96 g, 35 mmol, obtained from Sigma-Aldrich) and toluene (60 mL). The reaction mixture was refluxed until methanol ceased collecting in the receiving flask and the completion of the reaction was confirmed by 1H NMR spectroscopy. The still pot from the distillation was diluted with toluene (60 mL) and washed with brine (3×60 mL). The organic layer was separated, dried over MgSO4 and filtered. The solvent was removed in vacuo. The excess methyl 3,4-epoxycyclohexane carboxylate was removed via Kugelrohr distillation under reduced vacuum to give 33.39 g (90%) of a clear, colorless oil of nonyl-3,4-epoxycylohexanecarboxylate 1H NMR (CDCl3, δ): 4.06 (td, J=6.7, 1.9 Hz, 2H), 3.25-3.10 (m, 2H), 2.55-2.42 (m, 1H), 2.31-1.27 (m, 20H), 0.88 (t, J=6.7 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH:22]=2)[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.Cl[C:24]1[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:27]=[CH:26][N:25]=1>>[Cl:1][C:2]1[N:3]=[C:4]([C:17]2[CH2:18][CH2:19][N:20]([C:24]3[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:21][CH:22]=2)[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][CH:8]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: FC(F)(F)c1ccc(-c2[nH]c(C3=CCNCC3)nc2Cl)cc1
Product: FC(F)(F)c1ccc(-c2[nH]c(C3=CCN(c4ncccc4C(F)(F)F)CC3)nc2Cl)cc1

Procedure:
4-[4-Chloro-5-(4-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-1,2,3,6-tetrahydropyridine from step (b) above reacted with 2-chloro-3-trifluoromethyl-pyridine (251 mg, 1.39 mmol, TCI America) under the conditions of Example 22(d) to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 473 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:18][N:19]([CH3:21])[CH3:20])[C:15]([O-:17])=O)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[K+].CCN=C=NCCCN(C)C.[CH:34]1[CH:35]=[CH:36][C:37]2N(O)N=[N:40][C:38]=2[CH:39]=1.NC1C=CC=CC=1>CN(C=O)C>[NH:40]([C:15](=[O:17])[CH:14]([C:11]1[CH:10]=[CH:9][C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:13][CH:12]=1)[CH2:18][N:19]([CH3:21])[CH3:20])[C:38]1[CH:39]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CN(C)CC(C(=O)[O-])c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Nc1ccccc1
Product: CN(C)CC(C(=O)Nc1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 0.08 h

Procedure:
Crude potassium 2-[4-(tert-butoxycarbonyl)phenyl]-3-(dimethylamino)propanoate (925 mg, ˜2.79 mmol), EDCI (803 mg, 4.19 mmol), and HOBT (491 mg, 3.63 mg) were combined in DMF (15 mL) and stirred for 5 minutes before adding aniline (331 μL, 3.63 mmol). The reaction was stirred at room temperature for 3 h. Additional EDCI (200 mg) was added, and the reaction was stirred for another 3 h. The mixture was concentrated and purified by reverse phase HPLC (50-95% MeCN/water). The resulting residue was dissolved in EtOAc, neutralized with sat. NaHCO3, washed with brine, dried (MgSO4), and concentrated to give tert-butyl 4-{2-anilino-1-[(dimethylamino)methyl]-2-oxoethyl}benzoate as a white solid. 1H NMR (CDCl3) δ 7.97 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 7.21 (dd, J=8.5, 7.3 Hz, 2H), 6.77 (t, J=7.3 Hz, 1H), 6.72 (d, J=7.9 Hz, 2H), 4.22 (dd, J=8.8, 5.0 Hz, 1H), 3.80 (dd, J=13.8, 9.1 Hz, 1H), 3.40 (dd, J=13.6, 4.8 Hz, 1H), 2.95 (s, 3H), 2.74 (s, 3H), 1.58 (s, 9H). MS (ESI) calcd [M+H]+ 369.2, found 369.2.
Reaction SMILES: CC(CC)[O-].CC(CC)[O-].CC(CC)[O-].[Al+3].[CH2:17]([C:23]1[CH:24]=[CH:25][C:26]2[CH:27]=[C:28]3[C:41]([C:42](=O)[C:43]=2[CH:44]=1)=[CH:40][C:39]1[C:30]([C:31](=O)[C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[C:34]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH:33]=2)=[CH:29]3)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C1(O)CCCCC1>[CH2:17]([C:23]1[CH:24]=[CH:25][C:26]2[C:43](=[CH:42][C:41]3[C:28]([CH:27]=2)=[CH:29][C:30]2[C:39](=[CH:38][C:37]4[C:32]([CH:31]=2)=[CH:33][C:34]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:35][CH:36]=4)[CH:40]=3)[CH:44]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCc1ccc2c(c1)C(=O)c1cc3c(cc1=C2)C(=O)c1cc(CCCCCC)ccc1C=3
Agent: CCC(C)[O-]
Agent: [Al+3]
Solvent: OC1CCCCC1
Product: CCCCCCc1ccc2cc3cc4cc5cc(CCCCCC)ccc5cc4cc3cc2c1
Temperature: 145 °C

Procedure:
A mixture of 5.69 grams of aluminum tri(sec-butoxide) and 49.1 mLs of cyclohexanol was made. To this was added 2.21 grams 3,10-Dihexylpentacene-5,12-dione. The reaction mixture was heated to 145° C. for 24 hours. The mixture was cooled to room temperature and the solid isolated by centrifugation. The solid was stirred with 40 mLs of cyclohexanol and centrifuged two times. The solid was collected by filtration and washed with THF to give 2,9-dihexylpentacene.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:17][CH:16]([CH3:18])[O:15][CH:14]([CH3:19])[CH2:13]2)=[C:8]([CH:11]=1)[CH:9]=O)(=[O:3])[CH3:2].[NH:20]1[C:27](=[O:28])[CH2:26][C:24](=[O:25])[NH:23][C:21]1=[O:22]>C(O)(C)C>[C:1]([C:4]1[CH:11]=[C:8]2[C:7](=[CH:6][CH:5]=1)[N:12]1[CH2:17][CH:16]([CH3:18])[O:15][CH:14]([CH3:19])[CH:13]1[C:26]1([C:24](=[O:25])[NH:23][C:21](=[O:22])[NH:20][C:27]1=[O:28])[CH2:9]2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(N2CC(C)OC(C)C2)c(C=O)c1
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CC(C)O
Product: CC(=O)c1ccc2c(c1)CC1(C(=O)NC(=O)NC1=O)C1C(C)OC(C)CN21
Reaction time: 8 h
Yield: 99.4 %

Procedure:
5-Acetyl-2-(2,6-dimethylmorpholin-4-yl)benzaldehyde (from Step 3, 0.34 g, 1.3 mmol) and barbituric acid (0.175 g, 1.36 mmol) are dissolved in isopropanol (6 ml) and heated at reflux for 1 hour. The cooled reaction mixture is stored at 0° C. overnight. The light yellow solid is isolated by filtration, washed with cold isopropanol and dried in a vacuum oven (20 Torr, 90° C.) for 2 days to afford 0.48 g (100%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.8, 11.45, 7.70, 7.52, 6.92, 4.36, 4.21, 3.82, 3.76, 3.60, 3.53, 3.43, 2.90, 2.40, 1.15, 0.92.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:36])=[CH:20][N:19]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C>[Cl:36][C:21]1[C:22]([NH:24][C:25]2[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CNC(=O)c1cccc(C)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CNC(=O)c1cccc(C)c1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl
Temperature: 120 °C
Yield: 29.7 %

Procedure:
3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (76 mg, 0.34 mmol, 1.0 eq), 2-(2,5-dichloro-pyrimidin-4-ylamino)-3,N-dimethyl-benzamide (118 mg, 0.38 mmol, 1.1 eq), and 10-camphorsulfonic acid (88 mg, 0.38 mmol, 1.1 eq) were dissolved in IPA (3 mL) and heated at 120° C. in a microwave for 40 minutes. The reaction was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (20 mL) and washed with sat NaHCO3 (20 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by amine capped silica gel chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain 2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-3,N-dimethyl-benzamide as a pale yellow foam (50 mg, 30%). LCMS (m/e) 495 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.51 (s, 1H), 8.04 (s, 1H), 7.45-7.35 (m, 2H), 7.32-7.22 (m 1H), 7.11 (s, 1H), 6.98 (d, 1H, J=8.1 Hz), 6.85 (d, 1H, J=7.9 Hz), 6.78 (s, 1H), 6.06-5.97 (m, 1H), 3.55 (t, 2H, J=5.7 Hz), 3.39 (s, 3H), 2.89 (d, 3H, J=4.9 Hz), 2.88-2.82 (m, 2H), 2.75 (t, 2H, J=5.7 Hz), 2.73-2.62 (m, 6H), 2.27 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH2:8])[CH:7]=1.Cl[C:17]1[CH:26]=[CH:25][N:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][C:21]([CH3:27])=[N:22]2>>[CH3:27][C:21]1[N:22]=[C:23]2[C:18]([C:17]([NH:8][C:6]3[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[O:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:26][CH:25]=[N:24]2)=[CH:19][CH:20]=1
Reactant: Cc1ccc(Oc2ccccc2)c(N)c1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc(Oc2ccccc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 41b (65 mg, 0.36 mmol) was reacted with the product from Example 1d following the procedure from Example 1g giving the tile compound that was triturated with ether giving the product as a hydrochloride salt (12 mg, 8.8%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.95 (t, J=7.73 Hz, 3H) 1.82 (q, J=7.72 Hz, 2H) 2.97 (dd, J=7.73 Hz, 2H) 6.68 (d, J=6.99 Hz, 1H) 6.99 (d, J=7.72 Hz, 2H) 7.12 (dd, J=8.82 Hz, 2H) 7.30 (dd, J=8.09 Hz, 2H) 7.66 (dd, J=8.82 Hz, J=2.58 Hz, 1H) 7.71 (d, J=2.2 Hz, 1H) 7.77 (d, J=8.82 Hz, 1H) 8.52 (d, J=6.98 Hz, 1H) 9.07 (d, J=8.82 Hz, 1H) 11.26 (br s, 1H) 14.45 (brs, 1H); MS (ESI+) m/z 390 (M−Cl)+; (ESI−) m/z 388(M−HCl)−.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.CC1C(O)CC(=[O:23])C=1CC=C.Cl>O1CCCC1>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([OH:23])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCC1=C(C)C(O)CC1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 5 °C
Reaction time: 48 h
Yield: 51.8 %

Procedure:
11.6 g of triethylamine and then 21.9 g of p-toluene sulfonyl chloride were added at -50° C under an inert atmosphere to a mixture of 11.6 g of (R) allethrolone in 100 ml of tetrahydrofuran and the mixture was stirred for 48 hours at 5° C after which it was poured with stirring into aqueous 0.1N hydrochloric acid solution. The aqueous phase was extracted with chloroform and the organic extracts were washed with water, dried and evaporated to dryness. The 29 g of residue was chromatographed over silica gel and was eluted with a 95-5 benzene-ethyl acetate mixture to obtain 6.8 g of p-toluene sulfonate of (R) allethrolone.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]([C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([NH:18][C:19]2[C:23]3[CH:24]=[C:25]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])[CH:26]=[CH:27][C:22]=3[O:21][C:20]=2[C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=2)=[O:34])=[O:17])[CH2:12][CH2:11]1)[CH3:9])=[O:7])(=O)C.[OH-].[Na+].Cl>O1CCCC1.CO.C(Cl)(Cl)Cl>[CH3:31][N:30]([CH3:32])[C:28]([C:25]1[CH:26]=[CH:27][C:22]2[O:21][C:20]([C:33]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=3)=[O:34])=[C:19]([NH:18][C:16]([C@H:13]3[CH2:14][CH2:15][C@H:10]([N:8]([C:6](=[O:7])[CH2:5][OH:4])[CH3:9])[CH2:11][CH2:12]3)=[O:17])[C:23]=2[CH:24]=1)=[O:29]
Reactant: CC(=O)OCC(=O)N(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc(C(=O)N(C)C)cc23)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C(=O)c1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N(C)C(=O)CO)CC3)c2c1
Reaction time: 4 h

Procedure:
Trans-3-[4-(N-acetoxyacetyl-N-methylamino)cyclohexylcarbonylamino]-5-dimethylaminocarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (91 mg) obtained in Example 398 is dissolved in tetrahydrofuran/methanol (2:3, 5 ml), and thereto is added at room temperature 2N aqueous sodium hydroxide solution (300 μl), and the mixture is stirred for 4 hours. The reaction solution is acidified with diluted hydrochloric acid, and the mixture is diluted with chloroform. The mixture is dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by recycle HPLC to give the title compound (44 mg).