Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([NH:8][CH:9]([CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](OC)=[O:11])=[O:7])[CH3:4].C(O)C.[C:30]([O:34][CH2:35][CH3:36])(=[O:33])[CH:31]=[CH2:32]>C1C=CC=CC=1>[CH2:3]([O:5][C:6]([N:8]1[CH2:32][CH:31]([C:30]([O:34][CH2:35][CH3:36])=[O:33])[C:10](=[O:11])[CH:9]1[CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:7])[CH3:4]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)NC(C(=O)OC)C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: CCOC(=O)C1CN(C(=O)OCC)C(C(c2ccccc2)c2ccccc2)C1=O
Temperature: 25 °C

Procedure:
To a suspension of 80% sodium hydride (2.48 g, 83 mmol) in benzene (50 ml) was slowly added a solution of methyl 2- ethoxycarbonylamino- 3,3-diphenylpropanoate (Example 1b, 27.0 g, 83 mmol) in benzene (200 ml) and the mixture then heated at reflux for 1 h. Ethanol (1.0 ml) followed by ethyl acrylate (8.95 ml, 83 mmol) were added and the reaction heated at reflux for 2 h, the solvent was then distilled off and the residue allowed to cool to room temperature. A solution of the residue in water was added to a concentrated sulphuric acid/ice mixture and the product extracted into ethyl acetate. The organic phase was washed with saturated brine and dried (MgSO4). The residue was chromatographed on silica gel in dichloromethane/methanol (97:3) to give 1,4-bis(ethoxycarbonyl)-2-(diphenylmethyl)-pyrrolidin-3-one, m/z (CI+) 396(MH). A solution of this oil in 1.0M oxalic acid was heated at reflux for 8 h, cooled and the product extracted into chloroform. After separation the chloroform was removed in vacuo and the residue chromatographed on silica gel using ethyl acetate/hexane (1:4) as eluant to give 2-(diphenylmethyl)-1-ethoxycarbonylpyrrolidin-3 -one. 1H NMR (250 MHz, CDCl3) δ7.14-7.52 (10H, m), 4.80 (1H, br s), 4.68 (1H, vbr s), 4.18 (2H, br q), 3.94 (1H, vbs), 3.06 (1H, m), 2.34 (1H, m), 1.76 (1H, m), 1.22 (3H, t, J=7.0 Hz). m/z (CI+) 324(MH).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=2)[CH:12]=[C:13]([Cl:28])[C:14]=1[CH2:15][C@@H:16]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:17]1=[O:27].[CH3:40][N:41]=[C:42]=[O:43]>C(Cl)Cl>[CH3:40][NH:41][C:42]([N:24]1[CH2:23][CH2:22][CH:21]([N:18]2[CH2:19][CH2:20][C@@H:16]([CH2:15][C:14]3[C:13]([Cl:28])=[CH:12][C:11]([C:29]4[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:37])[F:38])=[CH:31][CH:30]=4)=[CH:10][C:9]=3[Cl:8])[C:17]2=[O:27])[CH2:26][CH2:25]1)=[O:43]
Reactant: CN=C=O
Reactant: O=C1[C@H](Cc2c(Cl)cc(-c3ccc(OC(F)(F)F)cc3)cc2Cl)CCN1C1CCNCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)N1CCC(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(OC(F)(F)F)cc4)cc3Cl)C2=O)CC1
Yield: 37.8 %

Procedure:
Treat a solution of (R)-3-(3,5-Dichloro-4′-trifluoromethoxy-biphenyl-4-ylmethyl)-1-piperidin-4-yl-pyrrolidin-2-one trifluoroacetic acid (Preparation 33) (85 mg, 0.17 mmol) in CH2Cl2 (4 mL) with methyl isocyanate (11 mg, 0.19 mmol). Stir the reaction overnight at room temperature. Quench the reaction with 1N HCl and extract with Et2O. Wash the organic with brine, dry over MgSO4, and filter. Purify the crude by silica gel column chromatography using Hexanes:EtOAc to elute pure product. Remove the solvent to afford 0.035 g (37%) of product. MS (m/e): 544 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[N:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.C(O)(C)C>C(OC(=O)C)(=O)C>[N+:11]([C:8]1[CH:7]=[C:4]([CH:5]=[CH:20][C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)[CH:3]=[C:2]([OH:1])[C:9]=1[OH:10])([O-:13])=[O:12]
Reactant: Cc1ccncc1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)O
Product: O=[N+]([O-])c1cc(C=Cc2ccncc2)cc(O)c1O

Procedure:
A solution containing 2.0 g (0.011 mole) of 3,4-dihydroxy5-nitrobenzaldehyde and 2.23 g (0.024 mole) of 4-picoline in 9.0 ml of acetic anhydride was refluxed for 1 h. About 15 ml of isopropanol was then added and the solution was cooled to 0° C. where upon the diacetyl-derivative of the desired product crystallized. After filtration the product was suspended in 100 ml of 0.5 N hydrochloric acid and refluxed for 1.5 h. After cooling the precipitate was filtered, washed with water and acetone and dried. Yield 1.89 g (67%), m.p. above 350° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:11]([C:26](=[O:31])N(OC)C)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li][CH3:33]>C1COCC1.CCOCC>[C:26]([C@@H:11]1[CH2:10][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:14][CH2:13][C@@H:12]1[NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:31])[CH3:33]
Reactant: [Li]C
Reactant: CON(C)C(=O)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: -22 °C
Reaction time: 0.67 h

Procedure:
Benzyl (1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-(methoxy(methyl)carbamoyl)cyclohexylcarbamate (4.0 g) was dissolved in THF (40 mL) and cooled to −22° C. prior to the addition of 1.6 M MeLi (14.5 mL) in Et2O. After 40 min at −22° C., the reaction was quenched with 0.5 N HCl solution and extracted with EtOAc (2×). The organic extracts were combined, washed with brine, dried (MgSO4), filtered, and concentrated. The resulting residue was purified by flash chromatography to afford benzyl (1S,2R,4R)-2-acetyl-4 -(tert-butyldimethylsilyloxy)cyclohexylcarbamate (5.7 g). MS found: (M+H)+=406.3.
Reaction SMILES: [CH:1]1([NH:4][NH2:5])[CH2:3][CH2:2]1.[F:6][C:7]([F:19])([F:18])[C:8](=O)[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[CH:1]1([N:4]2[C:8]([C:7]([F:6])([F:18])[F:19])=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=O)CC(=O)C(F)(F)F
Reactant: NNC1CC1
Product: CCOC(=O)c1cc(C(F)(F)F)n(C2CC2)n1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 17.3 using cyclopropylhydrazine (Step 17.2) and ethyl 5,5,5-trifluoro-2,4-dioxopentanoate at 100° C. for 2 hr. The crude product was purified by silica gel column chromatography (Hexane/EtOAc 9:1). tR: 1.10 min (LC-MS 2); ESI-MS: 249 [M+H]+ (LC-MS 2); Rf=0.17 (hexane/EtOAc 9:1).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([CH3:13])=[N:7][C:6]=2[N:5]([CH3:14])[C:3]1=[O:4].C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>CN(C=O)C.O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32][N:9]3[C:10]4[C:11](=[O:12])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:14])[C:6]=4[N:7]=[C:8]3[CH3:13])=[CH:30][CH:29]=2)=[O:27])=[CH:36][CH:37]=1
Reactant: Cc1nc2c([nH]1)c(=O)n(C)c(=O)n2C
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2c(c(=O)n(C)c(=O)n2C)n1Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
To a solution of 1,3,8-trimethylxanthine (0.97 g) in DMF (20 ml) were added potassium carbonate (0.83 g) and 4-(4-chlorobenzoyl)benzyl bromide (1.55 g) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was washed with acetone to provide the title compound as white powder (1.34 g, 61%). 1H-NMR (CDCl3) δ: 2.46(3H,s), 3.41(3H,s), 3.60(3H,s), 5.63(2H,s), 7.25-7.80(8H,m).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:16]=2[CH3:28])=[O:14])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].C(=O)([O-])[O-].[K+].[K+].Cl[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>O.O1CCCC1>[NH2:4]/[C:2](=[N:3]\[C:36](=[O:37])[O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)/[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[C:16]=2[CH3:28])=[O:14])=[CH:7][CH:6]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cc(C(=O)NCc2ccc(C(=N)N)cc2)c(C)n1-c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NCc2ccc(/C(N)=N/C(=O)OCc3ccccc3)cc2)c(C)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
115 mg of N-[(4-carbamimidoylphenyl)methyl]-1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3-carboxamide hydrochloride and 115 mg of potassium carbonate were dissolved in 1.4 ml of water and 7 ml of tetrahydrofuran. The mixture was stirred at room temperature, and 0.04 ml of benzyl chloroformate (Sigma-Aldrich) added. Stirring was continued for 1 h, following which the organic layer is removed, and dried in vacuo to obtain the synthetic target. The mass of the compound was verified using LC/MS/MS.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:29](=[O:30])[N:5]2[C:6]([C:13]([O:15]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:14])=[C:7](/[CH:10]=[CH:11]\[CH3:12])[CH2:8][S:9][C@H:4]12.C(=O)(O)[O-].[Na+].[NH2:36][C:37]1[S:38][CH:39]=[C:40](/[C:42](=[N:55]/[O:56][CH3:57])/[C:43](ON2C3C=CC=CC=3N=N2)=[O:44])[N:41]=1>CN(C=O)C>[NH2:36][C:37]1[S:38][CH:39]=[C:40](/[C:42](=[N:55]/[O:56][CH3:57])/[C:43]([NH:2][CH:3]2[C:29](=[O:30])[N:5]3[C:6]([C:13]([OH:15])=[O:14])=[C:7](/[CH:10]=[CH:11]/[CH3:12])[CH2:8][S:9][C@H:4]23)=[O:44])[N:41]=1
Reactant: C/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Reactant: CO/N=C(\C(=O)On1nnc2ccccc21)c1csc(N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C/C=C/C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Reaction time: 0.5 h
Yield: 117 %

Procedure:
To a stirred solution of 7-amino-3-trans-propenyl derivatives XIII (E, R3 =R4a =H) (720 mg, 3 m moles) and sodium bicarbonate (504 mg, 6 m moles) in 50% DMF (60 ml) was added 1-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetoxy]benzotriazole (954 mg, 3 m moles) and the mixture was stirred for 30 min. An additional amount of the active ester (1.81 g, 6 m moles) was added in four portions at 30-min intervals. The mixture was stirred for additional 2 hr at room temperature and passed through a column packed with the packing of prepPAK-C18 cartridge (300 ml, Waters). The column was washed with water and then eluted successively with 10% methanol and 20% methanol. Fractions of 20% methanol eluate showing a peak at retention time 5.57 min by HPLC* were collected and evaporated to dryness. The residue was dissolved in methanol and filtered. The filtrate was concentrated to 5 ml and the residue was triturated with a mixture of ether-isopropyl ether to give 805 mg (63%) of the title compound, melting at 180° C. (grad. dec.), 80% pure by HPLC*.
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][CH2:6][CH2:7][CH2:8][P:9]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)(=[O:11])[OH:10].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[CH:23]=O.C(O)(=O)C>CO>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[CH2:23][NH:5][CH2:6][CH2:7][CH2:8][P:9]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)(=[O:10])[OH:11]
Reactant: NCCCP(=O)(O)CC1CCCCC1
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=P(O)(CCCNCc1cc(Cl)cc(Cl)c1)CC1CCCCC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
2.0 g of sodium cyanoborohydride are added in portions to a solution of 6.27 g of 3-aminopropyl-(cyclohexylmethyl)-phosphinic acid and 5.0 g of 3,5-dichlorobenzaldehyde and 1.91 g of glacial acetic acid in 50 ml of anhydrous methanol and the mixture is stirred at room temperature for 4 days. The solvent is removed, the white residue is taken up in 2.0M hydrochloric acid and filtered. The filtrate is concentrated to dryness by evaporation and the white solid that remains behind is suspended in ethyl acetate, filtered off and crystallised from propanol, yielding 3-[(3,5-dichlorobenzyl)-amino]-propyl-(cyclohexylmethyl)-phosphinic acid, m.p. 231°-233°.
Reaction SMILES: C(=O)(O)[O-].[K+].[CH3:6][O:7][C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][CH:14]2[NH:18][CH2:17][CH2:16][S:15]2)=[CH:10][CH:9]=1.[Cl:21][CH2:22][C:23](Cl)=[O:24]>O.C(OCC)(=O)C>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH:14]2[N:18]([C:23](=[O:24])[CH2:22][Cl:21])[CH2:17][CH2:16][S:15]2)=[CH:19][CH:20]=1
Reactant: COc1ccc(OCC2NCCS2)cc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(OCC2SCCN2C(=O)CCl)cc1

Procedure:
A solution of 26 g of potassium bicarbonate in 55 ml of water was added under storing stirring to a solution of 2-(4-methoxy-phenoxymethyl)thiazolidine (54,5 g) in 550 ml of ethyl acetate cooled at 0°-5° C. The mixture was added with a solution of α-chloro-acetylchloride (19,2 ml) in ethyl acetate (50 ml) for 1 hour, under strong stirring and external cooling. Stirring was continued for 2 more hours, then the phases were separated. After washing of the organic phase with water, 5% aqueous NaHCO3 and water, and drying over Na2SO4, the mixture was evaporated to dryness to give 54,5 g of 2-(4-methoxy-phenoxymethyl)-3-α-chloroacetyl-thiazolidine, m.p. 51°-53° C. (from isopropyl alcohol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[CH2:21]([O:24][C:25]1[N:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1)[C:22]#[CH:23]>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:31]([C:28]3[CH:27]=[N:26][C:25]([O:24][CH2:21][C:22]#[CH:23])=[CH:30][N:29]=3)=[O:32])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: C#CCOc1cnc(C(=O)O)cn1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Product: C#CCOc1cnc(C(=O)Nc2ccc(F)c([C@]3(C)C[C@@H](C(F)(F)F)OC(N)=N3)c2)cn1

Procedure:
The title compound was synthesized by procedures and steps analogous to those described in Method F (Example 32) above, but using (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (intermediate 4i) and 5-(prop-2-yn-1-yloxy)pyrazine-2-carboxylic acid (J. Med. Chem. 2013, 56, 3980). The desired product was purified by reversed-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 80% over 20 min. The product containing fractions were combined and neutralized with 1N NaOH solution. The free-based product was extracted with DCM. The organic phase was dried over Na2SO4 and the solvent was removed under reduced pressure to afford the title compound. MS m/z=452.1 [M+H]+. Calculated for C20H17ClF4N5O3: 451.1
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C([Li])CCC.[C:13]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=1)#N.[Cl-].[NH4+].[O:24]1CCCC1>CCCCCC>[Cl:1][C:2]1[S:3][C:4]([C:13]([C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[O:24])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1ccnc(C#N)c1
Reactant: Cc1csc(Cl)n1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Product: Cc1ccnc(C(=O)c2sc(Cl)nc2C)c1
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 2-chloro-4-methylthiazole (6.35 g) in tetrahydrofuran (50 ml) was added a solution of n-butyllithium in n-hexane (1.66M, 34.35 ml) dropwise at −70° C. under a nitrogen atmosphere, and the mixture was stirred for 20 minutes at −70° C. To the resultant mixture was added a solution of 2-cyano-4-methylpyridine (3.74 g) in tetrahydrofuran (30 ml) dropwise at −70° C., and the mixture was stirred for 15 minutes. The mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography (silica gel 240 g, n-hexane:ethyl acetate=10:1) to give 2-chloro-4-methyl-5-(4-methylpyridin-2-ylcarbonyl)thiazole (1.64 g).
Reaction SMILES: CS(C)=O.CCN(C(C)C)C(C)C.[F:14][C:15]([F:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:16][NH:17][C:18]1[C:19]([F:28])=[C:20]([CH2:25][CH2:26][OH:27])[C:21]([Cl:24])=[CH:22][CH:23]=1>C(Cl)Cl>[F:35][C:15]([F:14])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:16][NH:17][C:18]1[C:19]([F:28])=[C:20]([CH2:25][CH:26]=[O:27])[C:21]([Cl:24])=[CH:22][CH:23]=1
Reactant: OCCc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=CCc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Reaction time: 3.5 h
Yield: 99.2 %

Procedure:
To a solution of DMSO (1.03 mL, 14.5 mmol), DIEA (1.99 mL, 11.4 mmol), and 2-{3-[(2,2-difluoro-2-phenylethyl)amino]-6-chloro-2-fluorophenyl}ethanol (1.45 g, 4.4 mmol), as prepared according to the procedure in the preceding step, in DCM (140 mL) in an ice-bath was added sulfur trioxide pyridine complex (1.82 g, 11.4 mmol) and stirred at the same temperature for 3.5 hours. The mixture was diluted with DCM (300 mL), washed with 10% citric acid (3 times), H2O, and brine, dried over Na2SO4, and concentrated to give the title compound (1.43 g, 99% yield) as an orange oil, that was used without further purification.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:33]=[CH:34][CH:35]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19]([C:21]2[S:31][C:24]3=[N:25][C:26]([NH:29][CH3:30])=[CH:27][N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].ClC1N=C2SC(C(NC3C=C(NC(=O)C4C=CC=C(C(C#N)(C)C)C=4)C=CC=3C)=O)=CC2=NC=1.NC[CH2:72][N:73]([CH3:75])[CH3:74]>>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:33]=[CH:34][CH:35]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19]([C:21]2[S:31][C:24]3=[N:25][C:26]([NH:29][CH2:30][CH2:72][N:73]([CH3:75])[CH3:74])=[CH:27][N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: CN(C)CCN
Reactant: CNc1cnc2cc(C(=O)Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)sc2n1
Agent: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(Cl)nc2s1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(NCCN(C)C)nc2s1
Yield: 36 %

Procedure:
Preparation analogous to 96a by using 3-chloro-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 95 (0.061 mmol, 30 mg) and 1-amino-2-dimethylaminoethane (1.531 mmol, 167 μL, 135 mg) to give N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-3-(2-(dimethylamino)ethylamino)thieno[2,3-b]pyrazine-6-carboxamide 96c (12 mg, 36%). NMR (400 MHz, DMSO-d6) 1.75 (s, 6H), 2.22 (s, 6H), 2.24 (s, 3H), 3.45 (q, J=5.9 Hz, 2H), 7.28 (d, J=8.2 Hz, 1H), 7.61 (m, 2H), 7.75 (m, 2H), 7.82 (d, J=2.0 Hz, 1H), 7.95 (d, J=7.4 Hz, 1H), 8.05 (s, 1H), 8.19 (s, 1H), 8.24 (s, 1H), 10.07 (s, 1H), 10.33 (s, 1H). (m/z)=542 (M+H)+.
Reaction SMILES: C(O[CH2:5][CH:6]=[CH2:7])(=O)C.C(N(CC)CC)C.CN(C)C(=NC)N(C)C.[CH2:24]([CH:31]1[C:35](=[O:36])[O:34][C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[CH2:7]([C:31]1([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:35](=[O:36])[O:34][C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N:32]1)[CH:6]=[CH2:5]
Reactant: C=CCOC(C)=O
Reactant: O=C1OC(c2ccccc2)=NC1Cc1ccccc1
Agent: CN=C(N(C)C)N(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCC1(Cc2ccccc2)N=C(c2ccccc2)OC1=O

Procedure:
Allyl acetate (21.6 μL, 200 μmol) was added to a solution of triethylamine (56 μL, 400 μmol) or pentamethylguanidine (51.7 mg, 400 μmol) and 4-benzyl-2-phenyl-2-oxazolin-5-one (450 μmol) in acetonitrile (1 mL). Then a preformed solution of bis(η3 -allyl)di-,μ-chlorodipalladium (II) (1.8 mg, 4.9 μmol) and ligand 1 (10.4 mg, 15.1 μmol) in acetonitrile (1 mL) was added via cannula. The reaction mixture was quenched with aqueous phosphate buffer (pH 7, 40 ml) and extracted with CH2Cl2 (3×30 mL). The combined organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether-AcOEt (95:5) to give 4-allyl-4-benzyl-2-phenyl-2-oxazolin-5-one. ##STR15##
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])C.C(Cl)(=[O:10])C.Cl.[OH:13][C:14]1[C:15]([CH:30]([CH3:33])[CH:31]=[CH2:32])=[CH:16][C:17]([CH3:29])=[C:18]2[C:26]=1C(NC)C1[CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]1>C(Cl)(Cl)Cl.O>[OH:13][C:14]1[C:15]([CH:30]([CH3:33])[CH:31]=[CH2:32])=[CH:16][C:17]([CH3:29])=[C:18]2[C:26]=1[CH:4]([N:3]([CH3:1])[C:6](=[O:10])[CH3:7])[CH:5]1[CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CCN(CC)CC
Reactant: CC(=O)Cl
Reactant: C=CC(C)c1cc(C)c2c(c1O)C(NC)C1CCCCC21
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=CC(C)c1cc(C)c2c(c1O)C(N(C)C(C)=O)C1CCCCC21

Procedure:
5.4 Milliliters of triethylamine and then 1.43 ml of acetyl chloride were added dropwise to a solution of a chloroform solution containing 5.0 g of 8-hydroxy-5-methyl-9-methylamino-7-(1-methyl-2-propenyl)-1,2,3,4,4a,9a-hexahydrofluorene hydrochloride with stirring under ice-cooling, followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture and extraction was effected with chloroform. The extract was dried with magnesium sulfate and the solvent was distilled off. The residue was purified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:4) and then recrystallized from ethanol to obtain 4.36 g of 8-hydroxy-5-methyl-9-(N-methyl-N-acetylamino)-7-(1-methyl-2-propenyl)-1,2,3,4,4a,9a-hexahydrofluorene.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[CH:13]=[CH:12]2)=[O:10])=[C:4]([Cl:20])[CH:3]=1.[CH3:21][O:22][C:23](Cl)=[O:24].ClC1C=CC=C(Cl)C=1C(N1C2C=CN=C(NC(=O)OC)C=2C=C1)=O>>[Cl:8][C:6]1[CH:7]=[C:2]([NH:1][C:23](=[O:24])[O:22][CH3:21])[CH:3]=[C:4]([Cl:20])[C:5]=1[C:9]([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH:13]=[CH:12]1)=[O:10]
Reactant: COC(=O)Cl
Reactant: Nc1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1
Agent: COC(=O)Nc1nccc2c1ccn2C(=O)c1c(Cl)cccc1Cl
Product: COC(=O)Nc1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1

Procedure:
Methyl [3,5-dichloro-4-(1H-pyrrolo[3,2-c]pyridin-1-ylcarbonyl)phenyl]carbamate (Compound No. 79) was prepared by treating (4-amino-2,6-dichlorophenyl)(1H-pyrrolo[3,2-c]pyridin-1-yl)methanone with methylchloroformate following a procedure similar to the one used for methyl [1-(2,6-dichlorobenzoyl)-1H-pyrrolo[3,2-c]pyridin-4-yl]carbamate (Compound No. 74).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1CN)[C@H](C(O)=O)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)C=[O:25].ON1C2N=CC=CC=2N=N1.Cl.CN(C)[CH2:40][CH2:41][CH2:42][N:43]=[C:44]=NCC>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:14]1[CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:40][C:41]=2[CH2:42][NH:43][C:44]1=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCN=C=NCCCN(C)C
Reactant: C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)c1ccccc1CN
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2CNC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-N-t-butyloxycarbonyl(2-aminomethylphenyl)alanine (353 mg), N,N-dimethylformamide (10 mL), dichloromethane (50 mL), 1-hydroxy-7-azabenzotriazole (252 mg), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (180 mg) was stirred at room temperature for 1 h. The solvent was removed under vacuum and the residue was dissolved ethyl acetate (100 mL). This solution was washed sequentially with 1.0 M aqueous hydrochloric acid (50 mL twice), 1.0 M aqueous sodium hydroxide (50 mL), water (50 mL), and brine (50 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum to obtain (S)-4-(t-butyloxycarbonylamino)-2,3,4,5-tetrahydro-2-benzazepin-3(1H)-one (315 mg).