Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[O:22][CH3:23])=[CH:9][CH:8]=[C:7]([S:24]([N:27](CC1C=CC(OC)=CC=1)[C:28]1[S:29][CH:30]=[CH:31][N:32]=1)(=[O:26])=[O:25])[CH:6]=2.C(Cl)Cl.C(O)(C(F)(F)F)=O>CO>[NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=1[O:22][CH3:23])=[CH:9][CH:8]=[C:7]([S:24]([NH:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1)(=[O:26])=[O:25])[CH:6]=2
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)c(N)cnc3c2)cc1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(F)(F)F)ccc1-c1c(N)cnc2cc(S(=O)(=O)Nc3nccs3)ccc12
Reaction time: 1 h
Yield: 87.3 %

Procedure:
A round-bottom flask was charged with 3-amino-4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)quinoline-7-sulfonamide (Intermediate NNNN; 42.59 mg, 0.071 mmol), DCM (1 mL) and TFA (0.5 mL). The mixture was stirred for 1 h, then diluted with MeOH and concentrated. The residue was taken up in DCM and loaded onto a 500-mg SCX-2 ion exchange column (Biotage, LLC). The column was eluted with MeOH, then with 2N ammonia in methanol. The basic fractions were combined and concentrated. The residue was concentrated from DCM to give 3-amino-4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)quinoline-7-sulfonamide (30 mg, 0.062 mmol, 88% yield) as a light-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=12.72 (br. s., 1H), 8.65 (s, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.59 (dd, J=2.0, 8.9 Hz, 1H), 7.52-7.44 (m, 2H), 7.42-7.35 (m, 1H), 7.24 (d, J=4.7 Hz, 1H), 7.08 (d, J=8.9 Hz, 1H), 6.81 (d, J=4.6 Hz, 1H), 5.62 (s, 2H), 3.75 (s, 3H); m/z (ESI) 481.2 (M+H)+.
Reaction SMILES: [NH3:1].[O:2]=[C:3]1[N:7]([CH2:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=O)[N:6]=C(C(F)(F)F)O1>C(#N)C>[NH2:6][N:7]1[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[NH:1][C:3]1=[O:2]
Reactant: N
Reactant: CC(C)(C)C(=O)Cn1nc(C(F)(F)F)oc1=O
Solvent: CC#N
Product: CC(C)(C)c1cn(N)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
75 ml of aqueous ammonia solution (25%) are added to a solution of 25.6 g of 2,3-dihydro-2-oxo-3-tert-butylcarbonylmethyl-5-trifluoromethyl-1,3,4-oxadiazole in 100 ml of acetonitrile. After the slightly exothermal reaction has subsided, the reaction mixture is stirred for 2 hours at room temperature and then for 14 hours at 80° and then evaporated, the residue is treated with trichloromethane, and the trichloromethane mixture is freed from the undissolved components, dried and evaporated. The residue is triturated with diethyl ether and subjected to filtration with suction. This gives the tide compound in the form of pale yellow crystals which melt at 197-200°.
Reaction SMILES: [C:1](OC)([CH3:4])([CH3:3])[CH3:2].[F:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1>C(Cl)Cl.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[C:1]([C:13]1[CH:12]=[CH:11][C:10]([OH:14])=[CH:9][C:8]=1[F:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(C)(C)C
Reactant: Oc1cccc(F)c1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)c1ccc(O)cc1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
Zirconiumtetrachloride (11.7 g, 50 mmol) in DCM (130 ml), tert-butylmethylether (4.44 g, 50 mmol), and 3-fluorophenol (5.6 g, 50 mmol) were mixed at room temperature and the reaction mixture was stirred for 2 hours at 50° C. The reaction was quenched with water and the whole was extracted with ethylacetate and dried over magnesium sulfate. After filtration, evaporation gave a crude residue, which was purified by silica gel column chromatography, eluting with gradually from hexane only to hexane/ethylacetate (9:1), to afford 4.25 g (51% yield) of the title compound as white solids.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)=[O:3].[CH3:20][N:21]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[CH2:30][CH2:31][NH2:32])[CH3:22].C(OC(C)C)(C)C>>[CH3:22][N:21]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[CH2:30][CH2:31][NH:32][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)=[O:3])[CH3:20]
Reactant: CN(C)CC1CCCCN1CCN
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ccccc21
Solvent: CC(C)OC(C)C
Product: CN(C)CC1CCCCN1CCNC(=O)N1c2ccccc2NC(=O)c2ccccc21
Yield: 73 %

Procedure:
Prepared analogously to Example 2 from 5-(chlorocarbonyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 2-[2-[(dimethylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 73% of theory. Colourless crystals, m.p. 152°-154° C. (diisopropylether).
Reaction SMILES: C([O:8][C:9]1[C:10]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)=[C:11]([C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[NH:19][CH:18]=2)=[O:16])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>[Pd].CO.O1CCCC1>[Cl:26][C:23]1[CH:24]=[C:25]2[C:17]([C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[C:10]=3[O:27][CH2:28][CH:29]3[CH2:31][CH2:30]3)=[O:16])=[CH:18][NH:19][C:20]2=[N:21][CH:22]=1
Reactant: O=C(c1cccc(OCc2ccccc2)c1OCC1CC1)c1c[nH]c2ncc(Cl)cc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(c1cccc(O)c1OCC1CC1)c1c[nH]c2ncc(Cl)cc12
Reaction time: 8 h
Yield: 32.3 %

Procedure:
A mixture of [3-benzyloxy-2-cyclopropylmethoxy-phenyl]-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (132, 0.92 g, 2.13 mmol) and palladium on carbon (100 mg, 10%, 0.5 mmol) in methanol (60 mL) and tetrahydrofuran (60 mL) was stirred under an atmosphere of hydrogen overnight. After filtering off of catalyst and removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a white solid (133, 236 mg, 32%).
Reaction SMILES: CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2C)CCCCC1.[CH:33]([Si:36]([CH:53]([CH3:55])[CH3:54])([CH:50]([CH3:52])[CH3:51])[O:37][C@H:38]1[C:44]2=[N:45][CH:46]=[CH:47][CH:48]=[C:43]2[C:42](=[O:49])[CH2:41][CH2:40][CH2:39]1)([CH3:35])[CH3:34].Br[C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([F:63])[C:58]=1[F:64]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[F:63][C:59]1[C:58]([F:64])=[CH:57][CH:62]=[CH:61][C:60]=1[C@@H:41]1[CH2:40][CH2:39][C@@H:38]([O:37][Si:36]([CH:33]([CH3:35])[CH3:34])([CH:50]([CH3:52])[CH3:51])[CH:53]([CH3:55])[CH3:54])[C:44]2=[N:45][CH:46]=[CH:47][CH:48]=[C:43]2[C:42]1=[O:49]
Reactant: CC(C)[Si](O[C@@H]1CCCC(=O)c2cccnc21)(C(C)C)C(C)C
Reactant: Fc1cccc(Br)c1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)C(=O)c2cccnc21)(C(C)C)C(C)C
Temperature: 80 °C
Reaction time: 20 h

Procedure:
See Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360-1370. In an oven-dried 1 L flask was Sodium tert-butoxide (13.19 g, 137 mmol), PALLADIUM(II) ACETATE (0.948 g, 4.22 mmol), and 2-(Dicyclohexylphosphino)-2′-methylbiphenyl (1.539 g, 4.22 mmol) weighed in a nitrogen bag. (R)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one (35.21 g, 106 mmol), Toluene (106 mL) (degassed in the original bottle by nitrogen gas), and 1-bromo-2,3-difluorobenzene (14.18 mL, 127 mmol) were added under nitrogen. The flask stirred at 80° C. in a pre-heated oil bath for 20 h. Volatiles were stripped off and the residue was partitioned between EtOAc (400 ml) and water (400 ml). The layers were separated. The aqueous layer was extracted with EtOAc (50 ml). The combined organic layer was washed with brine, dried and concentrated to a dark oil. It was passed through a plug of silica gel (loaded with CH2Cl2 and eluted with EtOAc/hexane up to 30% EtOAc). The crude product was obtained as a dark red oil (86% mass recovery),. 1H NMR showed approximately 6/1 ratio of the desired trans isomer to the cis isomer. MS(ESI)[M+H+]=446.21.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH2:18]([O:20][C:21](=[O:25])[CH2:22][CH2:23][NH2:24])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:25])[CH2:22][CH2:23][NH:24][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]2)=[CH:16][CH:15]=1)[CH3:19]
Reactant: CCOC(=O)CCN
Reactant: O=C1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Product: CCOC(=O)CCNC(=O)c1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-oxo-piperidine-1-yl)-benzoic acid (which was obtained in Example 151) and beta-alanine ethyl ester hydrochloride according to the procedure of Example 154 as a yellowish solid; 1H NMR (300 MHz, CDCl3) δ 1.28 (t, J=7.1 Hz, 3H), 2.56 (t, J=6.1 Hz, 4H), 2.64 (t, J=5.7 Hz, 2H), 3.55-3.65 (m, 6H), 4.15 (q, J=7.1 Hz, 2H), 6.82 (t, J=5.7 Hz, 1H), 6.95 (d, J=8.9 Hz, 2H), 7.70 (d, J=8.9 Hz, 2H); MS (ES) m/z: 319.1 (MH+).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:20][NH2:21]>C(O)CCC>[CH3:18][C:14]1[N:13]=[C:12]([O:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([C:3]([NH:20][NH2:21])=[O:2])[CH2:6][CH2:7]2)[CH:17]=[CH:16][CH:15]=1
Reactant: NN
Reactant: COC(=O)[C@H]1CC[C@H](Oc2cccc(C)n2)CC1
Solvent: O
Solvent: CCCCO
Product: Cc1cccc(O[C@H]2CC[C@H](C(=O)NN)CC2)n1
Temperature: 125 °C

Procedure:
A mixture of trans-4-(6-methyl-pyridin-2-yloxy)-cyclohexanecarboxylic acid methyl ester (0.62 g, 2.5 mmol) and hydrazine hydrate (0.55 ml, 11 mmol) in n-butanol (1 ml) was heated at 125° C. for 4 h. After cooling to room temperature the reaction mixture was partitioned between dichloromethane (75 ml) and water (75 ml). The aqueous layer was washed with dichloromethane/75 ml). The combined organic layers were washed with water (75 ml) and brine (75 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.48 g, 86%) as white solid, which was used in the next step without further purification. MS m/e: 250 (M+H+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11].C([Li])CCC.CN(C)[CH:23]=[O:24].O>O1CCCC1>[F:1][C:2]1[C:7]([CH:23]=[O:24])=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11]
Reactant: CC(C)S(=O)(=O)Nc1ccc(F)cc1F
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)S(=O)(=O)Nc1ccc(F)c(C=O)c1F
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To propane-2-sulfonic acid (2,4-difluoro-phenyl)-amide (59, 2.35 g, 9.95 mmol) in tetrahydrofuran (70 mL) under an atmosphere of nitrogen cooled with a dry ice/acetone bath was added 1.60 M of n-butyllithium (1.60 M in hexane, 6.53 mL, 10.45 mmol). The reaction was stirred for 40 minutes, and then another portion of n-butyllithium (1.60 M in hexane, 6.84 mL, 10.94 mmol). The reaction was stirred for 1 hour and N,N-dimethylformamide (0.92 mL, 11.9 mmol) was added. The reaction was allowed to warm to room temperature overnight. The reaction was poured into water extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated and purified by silica gel column chromatography (dichloromethane/methanol 5%) to give the compound (60, 1.4 g, 53.4%). MS (ESI) [M−H+]−=263.4.
Reaction SMILES: CCCP(=O)=O.[Cl:7][C:8]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([O:16][CH3:17])=[C:10]([Cl:18])[C:9]=1[C:19]1[C:28]2[N:27]=[CH:26][CH:25]=[N:24][C:23]=2[C:22]([C:29]([OH:31])=O)=[CH:21][CH:20]=1.[CH2:32]([N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=2)[CH2:36][CH2:35]1)[CH3:33].CCN(CC)CC>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O.O>[CH2:32]([N:34]1[CH2:35][CH2:36][N:37]([C:40]2[CH:46]=[CH:45][C:43]([NH:44][C:29]([C:22]3[C:23]4[N:24]=[CH:25][CH:26]=[N:27][C:28]=4[C:19]([C:9]4[C:8]([Cl:7])=[C:13]([O:14][CH3:15])[CH:12]=[C:11]([O:16][CH3:17])[C:10]=4[Cl:18])=[CH:20][CH:21]=3)=[O:31])=[CH:42][CH:41]=2)[CH2:38][CH2:39]1)[CH3:33]
Reactant: CCN1CCN(c2ccc(N)cc2)CC1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3nccnc23)c1Cl
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN1CCN(c2ccc(NC(=O)c3ccc(-c4c(Cl)c(OC)cc(OC)c4Cl)c4nccnc34)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of propylphosphonic anhydride (50% in DMF, 0.31 mL, 0.53 mmol, 2 equiv), 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (100 mg, 0.26 mmol) (Step 1.1), 4-(4-ethylpiperazin-1-yl)-aniline (Step 1.9) (65 mg, 0.32 mmol, 1.2 equiv), DMAP (2 mg), and Et3N (0.37 mL, 2.65 mmol, 10 equiv) in DMF (2.0 mL), was stirred for 18 h at rt, under an argon atmosphere. The reaction mixture was diluted with EtOAc and H2O. The aqueous layer was separated and extracted with EtOAc. The combined organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by trituration in Et2O to afford the title compound as a yellow solid: ES-MS: 565.9 [M+H]+; tR=4.26 min (System 1).
Reaction SMILES: [O:1]=[C:2]1[C@H:18]2[N:6]([C@H:7]([CH2:19][CH2:20][CH2:21][NH:22]C(=O)OCC3C=CC=CC=3)[C:8]3[NH:9][C:10]4[C:15]([C:16]=3[CH2:17]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:5](=[O:33])[C@@H:4]2[CH2:34][CH2:35][CH2:36][N:3]12>CO.[Pd]>[NH2:22][CH2:21][CH2:20][CH2:19][C@@H:7]1[C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH2:17][C@H:18]2[C:2](=[O:1])[N:3]4[CH2:36][CH2:35][CH2:34][C@H:4]4[C:5](=[O:33])[N:6]12)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: O=C(NCCC[C@@H]1c2[nH]c3ccccc3c2C[C@H]2C(=O)N3CCC[C@H]3C(=O)N12)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NCCC[C@@H]1c2[nH]c3ccccc3c2C[C@H]2C(=O)N3CCC[C@H]3C(=O)N12
Yield: 95 %

Procedure:
The solution of benzyl 3-[(5aS,12R,14aS)-5,14-dioxo-2,3,5a,6,11,12,14,14a-octahydro-1H,5H-pyrrolo[1″,2″:4′,5′]pyrazino[2′,1′:6,1]pyrido[3,4-b]indol-12-yl]propylcarbamate (0.1 mmol) in methanol (2.0 ml) was stirred under hydrogen (1.5 atm) in the presence of 5% Palladium on carbon for 1 hour. The solid was removed by filtration, and the solution was evaporated to afford (5aS,12R,14aS)-12-(3-aminopropyl)-1,2,3,5a,6,11,12,14a-octahydro-5H,14H-pyrrolo[1″,2″:4′,5′]pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-5,14-dione (95%). The (5aS,12S,14aS)-12-(3-aminopropyl)-1,2,3,5a,6,11,12,14a-octahydro-5H,14H-pyrrolo[1″,2″:4′,5′]pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-5,14-dione was prepared in a similar manner, but using 3-[(5aS,12S,14aS)-5,14-dioxo-2,3,5a,6,11,12,14,14a-octahydro-1H,5H-pyrrolo[1″,2″:4′,5′]pyrazino[2′,1′:6,1]pyrido [3,4-b]indol-12-yl]propylcarbamate as starting material. ESIMS (MH+): 29a, 353.2; 29b, 353.2.
Reaction SMILES: [F:1][C:2]([F:15])([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](OCC)=[O:4].[BH4-].[Na+].O>CO.C(OCC)(=O)C>[F:1][C:2]([F:15])([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][OH:4]
Reactant: CCOC(=O)C(F)(F)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: OCC(F)(F)Cc1ccccc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
To a cooled solution of Intermediate 90 (2.2 g, 10.3 mmol) in methanol (30 mL) was added sodium borohydride (1.94 g, 51 mmol). The mixture was stirred at 5° C. for 20 minutes and at room temperature for 2 hours. To the crude reaction was added water (1 mL) and the solvents reduced under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and washed with brine (2×25 mL), dried (Na2SO4), and concentrated. Purification by column chromatography with silica gel eluting with ethyl acetate/n-hexane 1:5 gave the title compound (0.75 g, 42%) as oil.
Reaction SMILES: [CH3:1][P:2]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[N+:14]([O-])=O)(=[O:6])[O:3][CH2:4][CH3:5]>CO.[Pd]>[CH3:1][P:2]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[NH2:14])(=[O:6])[O:3][CH2:4][CH3:5]
Reactant: CCOP(C)(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCOP(C)(=O)c1cc(Cl)ccc1N
Reaction time: 1 h

Procedure:
Ethyl P-methyl-2-nitro-5-chlorophenylphosphinate (1.7 g, 7.5 mmol) dissolved in methanol (25 ml) is added to 200 mg of 5% palladium on carbon. The mixture is hydrogenated at 32 psi for 1 hour. The catalyst is then filtered off and the filtrate is evaporated to dryness to give ethyl P-methyl-2-amino-5-chlorophenylphosphinate.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]([NH:28][NH2:29])=[O:27]>>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:29][NH:28][C:26]([C:22]1[O:21][CH:25]=[CH:24][CH:23]=1)=[O:27])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)c1ccco1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Product: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)c1ccco1
Yield: 37.9 %

Procedure:
Following a procedure analogous to Example 27, from the carboxylic acid (6b, 552 mg, 2.00 mmol) of Example 9 or 16 and furan-2-carbohydrazide (390 mg, prepared following a procedure analogous to Reference Example 6 from the compound described in Reference Example 3), 291.8 mg of the title compound was afforded (yield 37.9%).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH2:17]([CH:19]([CH2:23][CH2:24][CH2:25][CH3:26])[C:20](O)=[O:21])[CH3:18]>>[CH:11]1([C:8]2[NH:7][C:6](=[O:16])[C:5]([CH:2]([NH:1][C:20](=[O:21])[CH:19]([CH2:17][CH3:18])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCCCC(CC)C(=O)O
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Product: CCCCC(CC)C(=O)NC(CC)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 58A, 150 mg (0.67 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 97 mg (0.67 mmol) 2-ethyl-hexanoic acid and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:11]1C=CC=CC=1>CC#N.CCOC(C)=O>[C:8](=[O:9])([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[NH2:11]
Reactant: c1ccncc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Intermediates 10 to 18 were prepared by treatment of the appropriate aminoheterocycle intermediate with 1 equivalent of phenylchloroformate in dry CH3CN and 1 equivalent of pyridine. The reagents were stirred at rt for 4 h, diluted with EtOAc, washed with NaHCO3, and dried over MgSO4. The material was purified by FCC to provide pure phenyl carbamate intermediates.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]([CH3:4])[OH:3].[CH2:9](I)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>[Ag]=O>[CH2:9]([O:3][CH:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCOC(=O)C(C)O
Reactant: CCCCCCCCI
Agent: O=[Ag]
Product: CCCCCCCCOC(C)C(=O)OCC
Yield: 40.3 %

Procedure:
98 g of ethyl lactate, 380 g of octyl iodide and 245 g of silver oxide were stirred at 60° C. for 16 hours. After removal of the insoluble matter by filtration, the mixture was distilled in vacuo to obtain 77 g of ethyl 2-octyloxypropionate as a fraction of 110°-130° C./3 mmHg.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:14].C([O:19][C:20](=[O:33])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][C:24]=1[C:31]#[CH:32])(C)(C)C>>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][C:20]([OH:33])=[O:19])=[C:24]([C:31]#[C:32][C:2]2[CH:7]=[C:6]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=2[CH3:14])[CH:25]=1)#[N:30]
Reactant: CCCS(=O)(=O)c1ccc(C)c(Br)c1
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Product: CCCS(=O)(=O)c1ccc(C)c(C#Cc2cc(C#N)ccc2OCC(=O)O)c1

Procedure:
Following the general method as outlined in Example 37, starting from 2-bromo-1-methyl-4-(propylsulfonyl)benzene (Intermediate 37) and tert-butyl(4-cyano-2-ethynylphenoxy)acetate (Intermediate 46), the title compound was obtained as a white solid after purification by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4](=[C:9]([CH3:14])[S:10][C:11]=2[CH:12]=O)[N:5]=[C:6]([CH3:8])[CH:7]=1.Cl.[NH2:16]O.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[C:3]2[C:4](=[C:9]([CH3:14])[S:10][C:11]=2[C:12]#[N:16])[N:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: NO
Reactant: Cc1cc(Cl)c2c(C=O)sc(C)c2n1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)c2c(C#N)sc(C)c2n1

Procedure:
4-Chloro-2,7-dimethylthieno[3,4-b]pyridine-5-carboxaldehyde is reacted with hydroxylamine hydrochloride and phosphoryl chloride by standard procedures to give 4-chloro-2,7-dimethylthieno[3,4-b]pyridine-5-carbonitrile.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][O:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([O:18][CH3:19])=[CH:8][C:7]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[K+].[Br-]>>[CH3:19][O:18][C:9]1[CH:10]=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]([O:5][CH2:4][C:3]([OH:26])=[O:2])=[C:7]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:8]=1
Reactant: COC(=O)COc1c(-c2ccccc2)cc(OC)cc1-c1ccccc1
Agent: [Br-]
Agent: [K+]
Product: COc1cc(-c2ccccc2)c(OCC(=O)O)c(-c2ccccc2)c1

Procedure:
The title compound was prepared as a white solid (0.099 g, 91%) from (5′-methoxy-[1,1′;3′,1″]terphenyl-2′-yloxy)acetic acid methyl ester using a procedure similar to step 2 of Example 36, mp 143-145° C.; 1H NMR (DMSO-d6) δ 3.65 (s, 2H), 3.80 (s, 3H), 6.89 (s, 2H), 7.33-7.39 (m, 2H), 7.39-7.45 (m, 4H), 7.57-7.61 (m, 4H), 12.40-12.46 (bs, 1H); IR (KBr) 3380, 3080, 2920, 2890, 2810, 1770, 1740, 1600, 1575, 1495, 1470, 1425, 1360, 1240, 1210, 1180, 1160, 1070, 1045, 755, and 700 cm−1; mass spectrum [EI], m/z 334 (M)+; Anal. Calcd. for C21H18O4.0.25H2O: C, 74.43; H, 5.50; N, 0.00, Found: C, 74.21; H, 5.49; N, 0.09.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH2:11][OH:12].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]([C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)[CH:11]=[O:12]
Reactant: OCC(Cc1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=CC(Cc1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-(2,4-dichlorophenyl)-2-(4-chorophenyl)propanol (Step B, 0.89 g, 2.8 mmol) in 20 mL CH2Cl2 was added crushed activated molecular sieves (4 g). After stirring at room temperature for 10 min, pyridinium chlorochromate (0.90 g, 4.2 mmol) was added. After stirring at room temperature for 1 h, CELITE diatomaceous earth (4 g) was added followed by 100 mL ether. The resulting mixture was filtered through a silica gel pad, which was washed with ether (2×50 mL). The filtrate was concentrated to dryness and azeotroped with toluene to give the title compound, which was used without further purification.