Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([NH2:17])=[N:14][CH:15]=[CH:16][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.CN1CC[O:22][CH2:21][CH2:20]1.C(Cl)(=O)C>C1COCC1>[NH2:17][C:13]1[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:21](=[O:22])[CH3:20])=[CH:7][CH:6]=3)=[CH:9][S:10][C:11]=2[CH:16]=[CH:15][N:14]=1
Reactant: CN1CCOCC1
Reactant: Nc1ccc(-c2csc3ccnc(N)c23)cc1
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Product: CC(=O)Nc1ccc(-c2csc3ccnc(N)c23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
A −30° C. solution of Example 17A (0.1 g, 0.41 mmol) and N-methylmorpholine (0.03 mL, 0.41 mmol) in THF (5 mL) was treated dropwise with acetyl chloride (0.03 mL, 0.41 mmol), stirred for 1 hour, warmed to 0° C. over 1 hour, quenched with water, and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated to provide 111 mg of the desired product. Rf=0.24 (5% methanol/dichloromethane).
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:35])[C:8]1=[O:36])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[OH:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:35])[C:8]1=[O:36]
Reactant: CC(C)CCc1c(Oc2cccc(OC(F)(F)F)c2)cnc2c1c(=O)n(CCCOC=O)c(=O)n2C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)CCc1c(Oc2cccc(OC(F)(F)F)c2)cnc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.2 %

Procedure:
To a solution of 3-(5-isopentyl-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenoxy)-1,2-dihydro pyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (50 mg, 0.098 mmol) in THF (2 mL) and water (2 mL was added LiOH.H2O (8.2 mg, 0.196 mmol). The reaction was stirred at RT for 30 min then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 3-(3-hydroxypropyl)-5-isopentyl-1-methyl-6-(3-(trifluoromethoxy)phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (10 mg, 20.0% yield) as a white solid. 1H NMR (DMSO-d6) δ: 8.57 (s, 1H), 7.49 (t, J=8.8 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.98-6.95 (m, 2H), 4.51 (t, J=5.6 Hz, 1H), 4.02-3.97 (m, 2H), 3.58 (s, 3H), 3.50-3.45 (m, 2H), 3.15-3.10 (m, 2H), 1.77-1.70 (m, 2H), 1.54-1.50 (m, 1H), 1.32-1.23 (m, 2H), 0.79 (d, J=6.8 Hz, 6H). LCMS: MH+ 482 and TR=3.447 min.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][SH:3].[C:8]([O:12][C:13](=[O:38])[NH:14][CH2:15][CH2:16][NH:17][C:18]1[C:23]([C:24](=[O:33])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:22][N:21]=[C:20](S(C)(=O)=O)[N:19]=1)([CH3:11])([CH3:10])[CH3:9].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][S:3][C:20]1[N:19]=[C:18]([NH:17][CH2:16][CH2:15][NH:14][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:38])[C:23]([C:24](=[O:33])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:22][N:21]=1)[CH3:7]
Reactant: CCOC(=O)CS
Reactant: CC(C)(C)OC(=O)NCCNc1nc(S(C)(=O)=O)ncc1C(=O)Nc1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)CSc1ncc(C(=O)Nc2ccc(F)cc2)c(NCCNC(=O)OC(C)(C)C)n1
Reaction time: 8 h
Yield: 58.3 %

Procedure:
Ethyl thioglycolate (73 μL, 0.66 mmol) was added to a solution of {2-[5-(4-fluorophenylcarbamoyl)-2-methylsulfonyl-pyrimidin-4-ylamino]-ethyl}carbamic acid tert-butyl ester (0.30 g, 0.66 mmol) and DIPEA (117 μL, 0.66 mmol) in DMF (1.5 mL). The resulting solution was stirred under N2 overnight. The reaction mixture was then diluted with ethyl acetate (20 mL) and washed with water (10 mL), 1 N HCl (3×10 mL), water (10 mL), saturated NaHCO3 (3×10 mL), water (10 mL), saturated NaCl (20 mL) and dried over MgSO4. Following filtration, the solvent was removed by rotary evaporation to yield the titled product (0.19 g, 58%) as an off-white solid. 1H NMR: (d6-DMSO) δ 10.25 (s, 1H), 8.63 (m, 1H), 8.57 (s, 1H), 7.65 (m, 2H), 7.16 (m, 2H), 6.91 (t, 1H), 4.08 (q, 2H), 3.96 (s, 2H), 3.44 (m, 2H), 3.08 (m, 2H), 1.31 (s, 9H), 1.16 (t, 3H); HPLC: Rt=4.41 min; MS (ESI): m/z 492.44 (M−H)−.
Reaction SMILES: C(OC(=O)[N:10]([CH2:34][C:35]([CH3:41])([CH3:40])[CH2:36][CH2:37][C:38]#[N:39])[CH2:11][C@H:12]([OH:33])[C@H:13]([NH:21][C:22]([O:24][C@@H:25]1[C@H:32]2[C@H:28]([O:29][CH2:30][CH2:31]2)[O:27][CH2:26]1)=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.[Pd]>[O:27]1[C@H:28]2[O:29][CH2:30][CH2:31][C@H:32]2[C@@H:25]([O:24][C:22](=[O:23])[NH:21][C@@H:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@H:12]([OH:33])[CH2:11][NH:10][CH2:34][C:35]([CH3:40])([CH3:41])[CH2:36][CH2:37][C:38]#[N:39])[CH2:26]1
Reactant: [H][H]
Reactant: CC(C)(CCC#N)CN(C[C@H](O)[C@@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(CCC#N)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21
Reaction time: 16 h

Procedure:
A solution of (2S,3R)-(4-Cyano-2,2-dimethyl-butyl)-[3-((3R,3aS,6aR)hexahydro-furo[2,3-b]furan-3-yloxycarbonylamino)-2-hydroxy-4-phenyl-butyl]-carbamic acid benzyl ester (0.740 g, 1.28 mmol) in EtOAc at ambient temperature was treated with 10% palladium on carbon (0.075 g) and stirred under a balloon of hydrogen. After stirring 16 h the mixture was filtered and solvent was removed in vacuo to give desired product as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:9]([C:10]2([CH3:13])[CH2:12][CH2:11]2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br-:14].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.CO>[Br:14][C:7]1[CH:8]=[C:9]([C:10]2([CH3:13])[CH2:11][CH2:12]2)[C:2]([OH:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: CC1(c2cccc(C=O)c2O)CC1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: CC1(c2cc(Br)cc(C=O)c2O)CC1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 92.8 %

Procedure:
To a solution 128 (0.34 g, 1.9 mmol) in DCM-MeOH (3:2, 20 mL) was added tetrabutylammonium tribromide (0.98 g, 2.0 mmol) and the resulting mixture was stirred at RT for 75 min. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and water. The EtOAc layer was washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with EtOAc/hexane to afford 0.45 g (91%) of 5-bromo-2-hydroxy-3-(1-methylcyclopropyl)benzaldehyde (130) as a light yellow solid.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3].[CH3:20][N:21]([CH3:34])[CH2:22][CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][NH2:33])[CH2:27][CH2:26]1>C(OC)(C)(C)C>[CH3:34][N:21]([CH3:20])[CH2:22][CH2:23][CH2:24][CH:25]1[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][NH:33][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7](=[O:15])[C:6]3=[CH:16][S:17][C:18]([CH3:19])=[C:5]23)=[O:3])[CH2:29][CH2:30]1
Reactant: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O
Reactant: CN(C)CCCC1CCN(CCN)CC1
Solvent: COC(C)(C)C
Product: Cc1scc2c1N(C(=O)NCCN1CCC(CCCN(C)C)CC1)c1ccccc1NC2=O
Yield: 17 %

Procedure:
Prepared analogously to Example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2-[4-[3-(dimethylamino)propyl]-piperidin-l-yl]ethanamine in a yield of 17% of theory. Colourless crystals, m.p. >300° C. (t-butylmethyl ether).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1/[C:10](/[CH2:34][CH3:35])=[C:11](\[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([O:31]CC)=[O:30])=[CH:23][CH:22]=1)/[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][N:16]=[CH:15]2.C(O)C.[Li+].[OH-]>O>[Cl:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1/[C:10](/[CH2:34][CH3:35])=[C:11](\[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])=[CH:23][CH:22]=1)/[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][N:16]=[CH:15]2
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccc(F)cc2Cl)c2ccc3[nH]ncc3c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC/C(=C(/c1ccc(/C=C/C(=O)O)cc1)c1ccc2[nH]ncc2c1)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
A round-bottom flask equipped with a magnetic stir bar was charged with (E)-ethyl 3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate hydrochloride (198.5 g, 388 mmol; Compound 194) and ethyl alcohol (517 mL). A solution of LiOH (27.9 g, 1164 mmol) in water (388 mL) was added, and the mixture was stirred at room temperature overnight. The ethyl alcohol was removed by rotary evaporation, and the remaining solution was cooled to 0° C. and acidified with 2M aqueous HCl to pH 3. Dichloromethane (500 mL) was added, the mixture was stirred, and then the layers were separated. The organic layer was washed with water, washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was passed through a silica column (800 g, 5% MeOH in DCM) and concentrated. The product was then dissolved in DCM (400 mL), and acetonitrile (500 mL) was added. Approximately 200 mL of DCM was removed by rotary evaporation (solids began to precipitate). Acetonitrile (550 mL) was added followed by water (25 mL). The mixture was stirred at room temperature for 2 h. The solvent was decanted, and then acetonitrile:DCM (10:1; 550 mL) was added. The mixture stirred at room temperature for 1.5 h, the solvent was again decanted, and then acetonitrile:DCM (10:1; 550 mL) was added. The mixture was again stirred at room temperature for 1.5 h and then filtered. The solids were resuspended in acetonitrile:DCM (10:1; 550 mL), stirred at room temperature for 1.5 h, filtered, and washed to give the title compound (123.9 g) as an off-white powder. 1H NMR (DMSO-d6): δ 13.12 (s, 1H), 12.34 (br, 1H), 8.11 (d, 1H), 7.69 (s, 1H), 7.56 (d, 1H), 7.44-7.33 (m, 5H), 7.21-7.10 (m, 2H), 6.96 (d, 2H), 6.38 (d, 1H), 2.34 (q, 2H), 0.90 (t, 3H); LCMS: 447 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[CH3:27])[C:6]1[N:7]=[C:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[S:9][C:10]=1[C:11]#[N:12])=[O:4].[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C)C=O.CCOC(C)=O>[N:28]([CH2:2][C:3]([N:5]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[CH3:27])[C:6]1[N:7]=[C:8]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[S:9][C:10]=1[C:11]#[N:12])=[O:4])=[N+:29]=[N-:30]
Reactant: Cc1c(Cl)cccc1CN(C(=O)CCl)c1nc(N2CCOCC2)sc1C#N
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1CN(C(=O)CN=[N+]=[N-])c1nc(N2CCOCC2)sc1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
To a solution of 2-chloro-N-[(3-chloro-2-methylphenyl)methyl]-N-[5-cyano-2-(4-morpholinyl)-1,3-thiazol-4-yl]acetamide (200 mg, 0.470 mmol) (prepared according to the procedures of example 59) in N,N-Dimethylformamide (DMF) (2 mL) was added sodium azide (92 mg, 1.410 mmol) at rt. The mixture was stirred at rt for 3 hr before diluted in 100 ml EtOAc and washed with 20 mL H2O twice. The organic layer was concentrated to give 200 mg crude product (99%), which was used in the next step without further purification. LC/MS (ES) m/z=432.2 (M+H).
Reaction SMILES: [N+](C1C=CC(N)=C(C(F)(F)F)C=1)([O-])=O.[N+:15]([C:18]1[CH:24]=[CH:23][C:21](N)=[CH:20][C:19]=1[C:25]([F:28])([F:27])[F:26])([O-:17])=[O:16]>>[F:26][C:25]([F:27])([F:28])[C:19]1[CH:20]=[CH:21][CH:23]=[CH:24][C:18]=1[N+:15]([O-:17])=[O:16]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: Nc1ccc([N+](=O)[O-])cc1C(F)(F)F
Product: O=[N+]([O-])c1ccccc1C(F)(F)F

Procedure:
The precipitate was filtered and air-dried to give 3.5 g (85%) of the product which had a melting point of 85°-89° C. It consisted of 92-93% of the required 4-nitro-2-trifluoromethylaniline which was contaminated with 4-nitro-3-trifluoromethylaniline produced from the 2-trifluoromethylnitrobenzene which had contaminated the starting material. According to 1H-NMR (200 MHz) the product contained less than 1% of the disulphide.
Reaction SMILES: OC(C(F)(F)F)=O.[CH:8]([N:11]1[C:15]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=4[C:24]=3[N:25]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].C(N(CC)CC)C.[CH3:43][N:44]([CH3:50])[S:45]([CH:48]=[CH2:49])(=[O:47])=[O:46]>>[CH3:43][N:44]([CH3:50])[S:45]([CH2:48][CH2:49][N:33]1[CH2:34][CH2:35][CH:30]([C:28]2[CH:27]=[CH:26][C:23]3[C:24]4[N:25]=[C:16]([C:15]5[N:11]([CH:8]([CH3:10])[CH3:9])[N:12]=[CH:13][N:14]=5)[S:17][C:18]=4[CH2:19][CH2:20][O:21][C:22]=3[CH:29]=2)[CH2:31][CH2:32]1)(=[O:47])=[O:46]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCNCC3)ccc1-2
Reactant: C=CS(=O)(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCN(CCS(=O)(=O)N(C)C)CC3)ccc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
To a solution of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 375 (188 mg, 0.37 mmol) and triethylamine (0.18 mL, 1.3 mmol) in IMS (3 mL) was added ethenesulfonic acid dimethylamide and the reaction mixture stirred at RT for 18 h before being concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 5% MeOH in DCM) to give 499 as a beige solid (145 mg, 74%). LCMS: RT=3.47 min, [M+H]+=531. 1H NMR δ (ppm) (DMSO-d6): 8.23 (1 H, d, J=8.19 Hz), 8.05 (1 H, s), 7.04 (1 H, dd, J=8.26, 1.80 Hz), 6.88 (1 H, d, J=1.76 Hz), 5.82-5.72 (1 H, m), 4.30 (2 H, t, J=5.02 Hz), 3.37 (2 H, t, J=5.04 Hz), 3.19 (2 H, t, J=7.23 Hz), 2.95 (2 H, d, J=10.97 Hz), 2.75 (6 H, s), 2.65 (2 H, t, J=7.25 Hz), 2.04 (2 H, t, J=11.43 Hz), 1.75 (2 H, d, J=12.62 Hz), 1.67-1.53 (2 H, m), 1.50 (6 H, d, J=6.58 Hz). 1 H obscured by solvent
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[C:10]([OH:12])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:46][C:47]1[S:48][CH:49]=[C:50]([C:52]2[CH:63]=[CH:62][C:55]([C:56]([NH:58][CH:59]3[CH2:61][CH2:60]3)=[O:57])=[CH:54][CH:53]=2)[N:51]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[C:10](=[O:12])[NH:46][C:47]1[S:48][CH:49]=[C:50]([C:52]2[CH:53]=[CH:54][C:55]([C:56](=[O:57])[NH:58][CH:59]3[CH2:61][CH2:60]3)=[CH:62][CH:63]=2)[N:51]=1)=[O:4]
Reactant: COC(=O)[C@@H]1CCC[C@@H]1C(=O)O
Reactant: Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CCC[C@@H]1C(=O)Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Reaction time: 0.25 h

Procedure:
Rac-cis-cyclopentane-1,2-dicarboxylic acid monomethyl ester (172 mg) was dissolved in DMF (5 mL) and treated with HATU (1.1 eq. 470 mg) and DIEA (3 eq, 500 μL) and stirred for 15 minutes. Then 4-(2-amino-thiazol-4-yl)-N-cyclopropyl-benzamide (1 eq, 260 mg) was added and the mixture stirred at ambient temperature overnight. The reaction was cooled, filtered and the solvents removed. The resulting mixture was redissolved in 5 ml of 90% DMF, 10% water with 0.1% TFA and purified by reverse phase HPLC to give the product. MS: 414.5.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:28][C:29]([F:41])([F:40])[C:30]1[CH:31]=[C:32]([S:36]([NH2:39])(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:39][S:36]([C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([C:29]([F:28])([F:40])[F:41])[CH:31]=3)(=[O:38])=[O:37])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: NS(=O)(=O)c1cccc(C(F)(F)F)c1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 3-(trifluoromethyl)-benzenesulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method B described hereinabove. Yield (35%); 1H NMR (d6-DMSO) δ 8.22–8.08 (m, 3H), 7.86 (t, J=7.7 Hz, 1H), 7.42–7.07 (m, 13H), 6.84 (d, J=8.0 Hz, 2H), 6.40 (d, J=15.7 Hz, 1H), 2.35 (q, J=7.3 Hz, 2H), 0.82 (t, J=7.3 Hz, 3H); APcI m/z: 562 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH:37]([OH:39])[CH3:38]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][CH2:36][CH:37]([OH:39])[CH3:38])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Reactant: CC(O)CN
Product: CC(O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 1-amino-2-propanol using methods similar to Example 563 to provide a white solid: 1H NMR (CDCl3) δ 10.42 (1H, b), 8.56 (1H, s), 8.30 (1H, s), 7.25 (2H, dd, J=5, 9 Hz), 6.99 (2H, dd, J=9 Hz), 4.39 (2H, t, J=7 Hz), 4.16 (2H, s), 4.04-4.12 (1H, m), 3.60-3.67 (1H, m), 3.54 (2H, t, J=8 Hz), 3.34-3.42 (3H, m), 2.36 (2H, b), 1.73-1.80 (4H, m), 1.28 (3H, d, J=6 Hz); ES+ MS: 497 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[C:29]([CH3:36])[CH:28]=1)#[N:26]>O1CCCC1>[C:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31](=[O:32])[CH:5]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[C:4]([O:3][CH2:1][CH3:2])=[O:14])=[C:29]([CH3:36])[CH:28]=1)#[N:26]
Reactant: CCOC(=O)Cc1ccc(OC)cc1
Reactant: Cc1cc(C#N)ccc1C(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)c1ccc(C#N)cc1C)c1ccc(OC)cc1
Reaction time: 0.25 h
Yield: 88.7 %

Procedure:
To a solution of (4-methoxy-phenyl)-acetic acid ethyl ester (25.96 g, 133.7 mmol) in anhydrous tetrahydrofuran (200 mL) was added lithium hexamethyldisilazide (200 mL, 1 M) at −78° C. under nitrogen. After being stirred for 15 min., a solution of A-5 (4-cyano-2-methylbenzoyl chloride) (24 g, 133.6 mmol) in anhydrous tetrahydrofuran (150 mL) was added dropwise, and the resulting mixture was stirred at room temperature overnight for 16 h. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride solution (200 mL), and the resultant mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over anhydrous sodium sulfate (20 g), filtered, and evaporated. The residue was purified on silica gel column (petroleum ether/ethyl acetate=25:1) to give A-6 (ethyl 3-(4-cyano-2-methylphenyl)-2-(4-methoxyphenyl)-3-oxopropanoate) (40 g, yield 88.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[H-].[Na+].[I-].[K+].Br[CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)=[CH:22][CH:21]=1)[C:16]([O:18][CH3:19])=[O:17]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:19][O:18][C:16](=[O:17])[CH:15]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:9])[CH:4]=1)[C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)C(Br)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Reactant: Cc1cc(O)ccc1Cl
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(Oc1ccc(Cl)c(C)c1)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Yield: 105.9 %

Procedure:
As described in Example 30, a mixture of 2.86 g of 4-chloro-3-methylphenol, 0.80 g of 60% sodium hydride-oil dispersion, 3.32 g of potassium iodide, one ml of hexamethylphosphoramide and 8.52 g of methyl bromo{p-[3-(p-chlorophenoxy)propoxy]phenyl}acetate in 70 ml of tetrahydrofuran is refluxed for 18 hours and worked-up to give 10.1 g of gum. The gum is crystallized from petroleum ether containing a small amount of ether to give 7.7 g of white crystals. Purification by chromatography over silica gel with dichloromethane and recrystallization from petroleum ether-ether and benzene-hexane gives crystals, mp 74°-76° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)=[CH:8][C:3]=1[C:4](OC)=[O:5].[BH4-].[Li+].Cl>C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)=[CH:8][C:3]=1[CH2:4][OH:5]
Reactant: COC(=O)c1cc(-n2cnnn2)ccc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc(-n2cnnn2)ccc1Cl
Reaction time: 16 h

Procedure:
The product from Step B was taken up in 30 mL of THF and 160 mg of lithium borohydride was added. The reaction was stirred for 16 h and was then poured into dilute HCl solution and extracted twice with ethyl acetate. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated. When taken up in 50% ethyl acetate in hexanes, the product partially precipitated to give white solid after filtration. The mother liquor was concentrated and additional product was obtained by flash chromatography eluting with 1% HOAc/50% ethyl acetate in hexanes to obtain a total of 400 mg of title compound. T.l.c. (50% ethyl acetate in hexanes) Rf =0.4
Reaction SMILES: [Na].[CH:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]=O)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C1(NC2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>O.C(O)CCC>[CH:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: O=Nc1ccc(Nc2ccccc2)cc1
Agent: [Na]
Agent: c1ccc(Nc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCO
Product: Nc1ccc(Nc2ccccc2)cc1
Yield: 95 %

Procedure:
In this example the sodium salt of p-nitrosodiphenylamine was hydrogenated in a continuous manner over a fixed bed of catalyst. Diphenylamine (338 g, 2 mols) was converted to the sodium salt of p-nitrosodiphenylamine as in Example 2. A solution of approximately equal weights of toluene and 1-butanol was added to dilute the solution of the sodium salt to a concentration of about 13.5 wt. %, and enough water was added to dissolve all the inorganic salts present in the aqueous phase. The two phases were separated and simultaneously pumped into a tube reactor over a 0.4 wt. % palladium on charcoal catalyst at 125° C., 1000 psig hydrogen pressure at 1 liquid hourly space velocity based on total liquid. Thin layer chromatography indicated 100% conversion of p-nitrosodiphenylamine. Distillation of the residue after separation of the aqueous phase and removal of the organic solvents gave 95% p-aminodiphenylamine exclusive of losses from column hold-up.