Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([C:24]([NH:26][NH:27][C:28]([NH:30][CH3:31])=O)=O)[CH2:7]1)(=[O:4])=[O:3].O.N.[S:34](=O)(=O)(O)O>>[CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([C:24]2[S:34][C:28]([NH:30][CH3:31])=[N:27][N:26]=2)[CH2:7]1)(=[O:4])=[O:3]
Reactant: CNC(=O)NNC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(O)O
Agent: N
Solvent: O
Product: CNc1nnc([C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)s1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A suspension of (2S,4R)-4-methanesulfonyloxy-2-(4-methylsemicarbazidocarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.00 g) in concentrated sulfuric acid (20 ml) was stirred at 0°-5° C. for 3 hours. The reaction mixture was poured into ice-water (200 ml), adjusted to pH 9 with concentrated ammonia water, extracted with dichloromethane (100 ml), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (1:99,V/V) to give (2S,4R)-4-methanesulfonyloxy-2-{5-(methylamino)-1,3,4-thiadiazol-2-yl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.94 g).
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=O.CCN(CC)CC.C(Cl)(=O)C(C)(C)C.[CH2:25]([C@H:32]1[CH2:36][O:35][C:34](=[O:37])[NH:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Li]CCCC.[Li]>C(OCC)(=O)C.C1COCC1>[CH2:25]([C@H:32]1[CH2:36][O:35][C:34](=[O:37])[N:33]1[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][C:2](=[O:1])[CH3:10])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(=O)CCCCC(=O)O
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)CCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 6-oxo-heptanoic acid 7-1(100 g, 694 mmol), NEt3 (111.3 ml, 763.4 mmol) and THF (2000 mL) at -78° C. was added pivaloyl chloride (98.7 ml, 763.4 mmol). The mixture was warmed to 0° C. for 1.0 h and then recooled to -78° C. To a stirred solution of (S)-(-)-4-benzyl-2-oxazolidinone (136 g, 763.4 mmol) and THF (2000 ml) at -78° C. was added nBuLi (306 ml, 765 mmol, 2.5M in hexanes) dropwise over 30 minutes. After 20 minutes, the lithium reagent was transferred to the mixed anhydride via cannula. After 20 minutes, the reaction was warmed to 0° C. for 1.0 h. The mixture was diluted with ethyl acetate, washed with sat. NaHCO3, brine, and dried over MgSO4. Following evaporative removal of the solvent, the residue was azeotroped with xylenes to give 7-2 as a colorless foam.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]([CH:23]([CH3:25])[CH3:24])[CH3:22])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:26])[C:4]=1[CH2:27][CH2:28][C:29](O)=[O:30])[CH3:2].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:74]([NH:81][CH2:82][CH2:83][NH2:84])([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75]>CN(C=O)C>[C:77]([O:76][C:74](=[O:75])[NH:81][CH2:82][CH2:83][NH:84][C:29](=[O:30])[CH2:28][CH2:27][C:4]1[C:5]([CH3:26])=[CH:6][C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]([CH:23]([CH3:25])[CH3:24])[CH3:22])[CH:15]=3)[O:11][N:10]=2)=[CH:8][C:3]=1[CH2:1][CH3:2])([CH3:78])([CH3:79])[CH3:80]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(C)C(C)C)c3)n2)cc(C)c1CCC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(C)C(C)C)c3)n2)cc(C)c1CCC(=O)NCCNC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a solution of 3-(2-ethyl-4-{5-[2-(isopropyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenyl)-propionic acid (41 mg, 0.097 mmol) and DIPEA (38 mg, 0.291 mmol) in DMF (3 mL) is added PyBOP (56 mg, 0.107 mmol) at 0° C. The mixture is stirred for 15 min at 0° C. before N-BOC-ethylenediamine (17 mg, 0.107 mmol) is added and stirring is continued for 1 h at 0° C. The reaction is quenched with 2 mL water, and the mixture is diluted in sat. aq. NaHCO3-solution, and extracted three times with diethyl ether. The combined org. extracts are dried over MgSO4, filtered and dried to give crude {2-[3-(2-ethyl-4-{5-[2-(isopropyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenyl)-propionylamino]-ethyl}-carbamic acid tert-butyl ester (44 mg). This material is dissolved in 4 N HCl in dioxane (5 mL) and the mixture is stirred at rt for 18 h. The solvent is evaporated and the crude product is purified on prep. TLC plates with DCM containing 6% of 7 N NH3 in methanol to give N-(2-amino-ethyl)-3-(2-ethyl-4-{5-[2-(isopropyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenyl)-propionamide (23 mg) as a yellow solid; LC-MS: tR=0.72 min; [M+1]+=465.32.
Reaction SMILES: [OH:1][CH:2]([CH:10]1[CH2:14][CH2:13][C:12](=[O:15])[CH:11]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>C(OCC)(=O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[OH:1][CH:2]([C@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[C@H:11]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC#CC(O)C1CCC(=O)C1CCCCCCC(=O)O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Product: CCCCCC=CC(O)[C@H]1CCC(=O)[C@H]1CCCCCCC(=O)O

Procedure:
A solution of 2-(1-hydroxy-2-octynyl)-5-oxocyclopentaneheptanoic acid (1.12 g), described in Example 3, in 20 ml of ethyl acetate is subjected to hydrogenation with Lindlar catalyst (200 mg) to yield the title compound which is purified by chromatography on silica gel. [Lindlar catalyst is a mixture of palladium and lead oxide on calcium carbonate, H. Lindlar, Helv. Chim. Acta, 35, 446 (1952)]. The title compound has νmaxfilm (broad OH absorption) 1730, 1710 cm-1 ; nmr (CDCl3) δ 5.54 (m, 2H), 7.14 (broad, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:20])(C)(C)C.[Cl:22][C:23]1[CH:24]=[C:25]([C:29]2OC(C)(C)O[C:31](=[O:37])[CH:30]=2)[CH:26]=[CH:27][CH:28]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:22][C:23]1[CH:24]=[C:25]([C:29]2[CH2:30][C:31](=[O:37])[NH:20][C:9]3[CH:10]=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(Cl)c2)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(Cl)c2)=Nc2ccc(-c3ccccc3)cc2N1
Yield: 54.2 %

Procedure:
Prepared from (3-amino-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G9) (284 mg, 1.0 mmol) and 6-(3-Chloro-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J6) (358 mg, 1.2 mmol) according to the general procedure K. The obtained material (339 mg) was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (188 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:27]2[CH2:36][CH2:35][C:30]3([O:34][CH2:33][CH2:32][O:31]3)[CH2:29][CH2:28]2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[CH3:37]I.[H-].[Na+]>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:27]2[CH2:36][CH2:35][C:30]3([O:34][CH2:33][CH2:32][O:31]3)[CH2:29][CH2:28]2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:21][CH2:22][C@H:23]([O:26][CH3:37])[CH2:24][CH2:25]1)[C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(C2CCC3(CC2)OCCO3)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1sc(C2CCC3(CC2)OCCO3)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC)CC1

Procedure:
The product from step II (922 mg, 1.77 mmol) was treated with methyl iodide (2.21 mL, 35.48 mmol) and 60% oil suspension of sodium hydride (142 mg, 3.54 mmol) using procedure described in step I of example 4 to afford 1.143 g (100%) of crude 5-(1,4-dioxa-spiro[4.5]dec-8-yl)-3-[(trans-4-methoxy-cyclohexyl)-(trans-4-methyl-cyclohexane-carbonyl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.[CH2:14]([C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1)[CH3:15]>C(N(CC)CC)C>[CH2:14]([C:16]1[CH:17]=[C:18]([N:22]2[CH2:23][CH2:24][N:25]([CH2:8][C:7]3[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:26][CH2:27]2)[CH:19]=[CH:20][CH:21]=1)[CH3:15]
Reactant: CCc1cccc(N2CCNCC2)c1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1cccc(N2CCN(Cc3ccc([N+](=O)[O-])cc3)CC2)c1

Procedure:
In the manner given in Example 1A, p-nitrobenzyl chloride is reacted with 1-(3-ethylphenyl)piperazine dihydrochloride in the presence of triethylamine to give 1-(3-ethylphenyl)-4-(p-nitrobenzyl)piperazine.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:11][CH2:12][CH3:13])[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[CH3:8])C.C(O)CCO.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[O:3]1[CH2:1][CH2:13][CH2:12][O:11][CH:4]1[C:5](=[O:10])[CH:6]=[C:7]([CH3:8])[CH3:9]
Reactant: CCOC(OCC)C(=O)C=C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCCCO
Solvent: c1ccccc1
Product: CC(C)=CC(=O)C1OCCCO1
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 64.2 %

Procedure:
A solution of 1b (1.02 g, 5.49 mmol) and 1,3-propanediol (0.600 mL, 8.23 mmol) in benzene (10.8 mL) was treated with p-toluenesulfonic acid (522 mg, 2.75 mmol). The reaction mixture was stirred at 80° C. for 4.5 h. Saturated aqueous NaHCO3 was added, and the mixture was extracted with Et2O. The organic extract was washed (water), dried (Na2SO4), concentrated to a brown liquid, and chromatographed [silica, hexanes/EtOAc (5:1)] to afford a yellow liquid (600 mg, 64%): 1H NMR δ 1.40-1.45 (m, 1H), 1.96 (s, 3H), 2.20 (s, 3H), 2.12-2.25 (m, 1H), 3.83-3.92 (m, 2H), 4.20-4.26 (m, 2H), 4.79 (s, 1H), 6.42 (s, 1H); 13C NMR δ 21.7, 25.9, 28.5, 67.3, 101.4, 119.0, 161.2, 192.1; ESI-MS obsd 193.0833, calcd 193.0835 [(M+Na)+, M=C9H14O3].
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[CH:20][C:19]=1I)[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2].[CH2:31]=[N:32]O.N1C(C)=CC=CC=1C.[N+](C1C=CC=CC=1)([O-])=O>[Cu]I>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[CH:20][C:19]=1[C:31]#[N:32])[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2]
Reactant: CCN(CC)c1ccc(N=Nc2c(I)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Reactant: C=NO
Agent: [Cu]I
Solvent: Cc1cccc(C)n1
Solvent: O=[N+]([O-])c1ccccc1
Product: CCN(CC)c1ccc(N=Nc2c(C#N)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Temperature: 95 °C

Procedure:
A stirred mixture of 3-acetylamino-4-(2'-iodo-4',6'-dinitrophenylazo)-N,N-diethylaniline (4.8 parts), copper (I) iodide (2.0 parts), formaldoxime trimer (1.75 parts), 2,6-lutidine (2.15 parts), and nitrobenzene (150 parts) was heated to 95° C. for 10 hours when thin layer chromatography showed reaction to be complete. Isolation of the product as in Example 1 gave 3-acetylamino 4-(2'-cyano-4',6'-dinitrophenylazo)-N,N-diethylaniline (infra red spectrum identical with that of authentic material).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=O.[F:23][C:24]([F:32])([F:31])[C:25](=[O:30])[CH2:26][C:27](=O)[CH3:28].C(O)(C)C>CCCCCCC.C(OCC)(=O)C>[F:23][C:24]([F:32])([F:31])[C:25]([C:26]1[C:27]([CH3:28])=[N:1][C:2]2[C:3]([C:13]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[CH:4][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:7]=2)=[O:30]
Reactant: COc1ccc(C(=O)c2cc(OC(F)(F)F)ccc2N)cc1
Reactant: CC(=O)CC(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CC(C)O
Product: COc1ccc(-c2c(C(=O)C(F)(F)F)c(C)nc3ccc(OC(F)(F)F)cc23)cc1
Reaction time: 17 h
Yield: 58 %

Procedure:
The title compound was prepared from (2-Amino-5-trifluoromethoxy-phenyl)-(4-methoxy-phenyl)-methanone [example A8] and 1,1,1-trifluoro-2,4-pentanedione according to the procedure of example 1, except that the solvent was isopropanol, the reaction time was of 17 h and a grandient of heptane/ethyl acetate was used. Yield: 58%; MS: m/z=429 (M).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:28]([C:32](=[O:48])[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[CH:35][CH:34]=1)=[C:27](OS(C(F)(F)F)(=O)=O)[CH:26]=[CH:25]2.C([O-])([O-])=O.[Na+].[Na+].OB1[C:68]2[CH:69]=[CH:70][CH:71]=[CH:72][C:67]=2[CH2:66][O:65]1>COCCOC.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=1[C:27]1[CH:26]=[CH:25][C:24]2[C:29](=[CH:30][CH:31]=[C:22]([O:21][CH3:20])[CH:23]=2)[C:28]=1[C:32]([C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:37][CH:38]=1)=[O:48]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: OB1OCc2ccccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3CO)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
Add Pd(OAc)2 (15 mg, 0.07 mmol) and Ph3P (47 mg, 0.18 mmol) to a stirred solution of trifluoro-methanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (600 mg, 1.1 mmol) in DME at r.t. Add Na2CO3 solution (2 mL of 2 M) followed by 1-hydroxy-2,1-benzoxaborolane (200 mg, 1.5 mmol). Stir at r.t. for 2 h and heat gently (˜50° C.) for 6 h. Dilute with CH2Cl2 and wash with water and brine, dry over MgSO4, filter and concentrate. Purify the crude product by flash chromatography (0-5% (2M NH3 in MeOH)/CH2Cl2 to yield [2-(2-hydroxymethyl-phenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (171 mg, 31%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:15]=[C:16]([NH:20][C:21]2[C:26]([N+:27]([O-])=O)=[CH:25][CH:24]=[CH:23][N:22]=2)[CH:17]=[CH:18][CH:19]=1)=[O:12].Cl.C(=O)(O)[O-].[Na+]>C(O)C.[Fe]>[NH2:27][C:26]1[C:21]([NH:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([NH:13][C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[O:12])[CH:15]=2)=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Nc1cccc(Nc2ncccc2[N+](=O)[O-])c1)c1ccc2ccccc2c1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: Nc1cccnc1Nc1cccc(NC(=O)c2ccc3ccccc3c2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A mixture of 2-[3-(2-naphthoylamino)phenylamino]-3-nitropyridine (948 mg), iron powder (0.55 g) and hydrochloric acid (35%, 2 ml) in ethanol (8 ml) was stirred at 80° C. for 30 minutes. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 3-amino-2-[3-(2-naphthoylamino)phenylamino]pyridine (682 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4]([C:6]1[CH:19]=[CH:18][C:9]([CH:10](O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].S(Cl)([Cl:24])=O>ClCCl>[CH2:1]([N:3]([CH2:20][CH3:21])[C:4]([C:6]1[CH:19]=[CH:18][C:9]([CH:10]([Cl:24])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc(C(O)c2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(C(Cl)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 4-(N,N-diethylcarbamoyl)benzhydryl alcohol (61.35 g, 216.5 mmol) was dissolved in 1500 mL of dichloromethane and 23.69 mL (324.8 mmol) of thionyl chloride was added dropwise. The reaction solution was stirred overnight at room temperature and the solvent was removed under vacuum. The crude product was redissolved in 800 mL of toluene and the solvent again was removed under vacuum to eliminate excess thionyl chloride, providing crude 4-(N,N-diethylcarbamoyl)benzhydryl chloride as a dark oil. Crude yield=100%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12](=[O:17])[CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:1]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[O:11][C:12](=[O:17])[CH2:13][C:14]2([CH3:16])[CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)=CC(=O)Oc1ccc(C(C)(C)C)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(C)(C)c1ccc2c(c1)C(C)(C)CC(=O)O2
Yield: 35.2 %

Procedure:
To a solution of 3-methylbut-2-enoic acid 4-tert-butylphenyl ester (23 g, 99 mmol) in 50 mL of carbon disulfide (CS2) was added 19.8 g of aluminum chloride (AlCl3) portionwise over the course of 1 hour, a very exothermic reaction. After stirring for several hours, TLC showed the reaction was complete. The reaction mixture was concentrated under a stream of nitrogen gas, and the residue poured over ice and extracted with ethyl acetate. The organics were combined, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified on silica pad (0% to 5% ethyl acetate-hexanes) to give 8.1 g of 6-tert-butyl-4,4-dimethylchroman-2-one as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)=[N:17][CH:18]=2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[CH2:34](C([Sn])=C(CCCC)CCCC)[CH2:35]CC.[Cl-].[Li+].[F-].[K+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][C:2]1[C:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)=[N:17][CH:18]=2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH:34]=[CH2:35])[CH:3]=1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: COC(=O)c1cc(Cc2ccc(-c3ccnc(C)c3)nc2)c(C)cc1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [F-]
Solvent: CN(C)C=O
Product: C=Cc1cc(C)c(Cc2ccc(-c3ccnc(C)c3)nc2)cc1C(=O)OC
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl 4-methyl-5-((2′-methyl-[2,4′-bipyridine]-5-yl)methyl)-2-(((trifluoromethyl)sulfonyl)oxy)benzoate (0.21 g) in DMF (4.00 mL) were added tributylvinyltin (0.19 mL), trans-dichlorobis(triphenylphosphine)palladium(II) (0.02 g) and lithium chloride (0.14 g), and the mixture was stirred at 90° C. for 1.5 hr under argon atmosphere. To the reaction mixture was added aqueous potassium fluoride solution, and the precipitated insoluble substance was removed by filtration through Celite. The filtrate was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.11 g).
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[N+:9]([O-:12])(O)=[O:10].[CH:13]12[CH2:30][CH:20]([CH2:21][N:22]([C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH2:23]1)[C:19]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=1>C(Cl)Cl>[N+:9]([C:17]1[CH:16]=[CH:15][C:14]2[CH:13]3[CH2:30][CH:20]([CH2:21][N:22]([C:24](=[O:29])[C:25]([F:27])([F:26])[F:28])[CH2:23]3)[C:19]=2[CH:18]=1)([O-:12])=[O:10]
Reactant: O=C(N1CC2CC(C1)c1ccccc12)C(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N1CC2CC(C1)c1cc([N+](=O)[O-])ccc12)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
(Based on the method described by Coon, C. L.; Blucher, W. G.; Hill, M. E. J. Org. Chem. 1973, 25, 4243.) To a solution of trifluoromethanesulfonic acid (2.4 ml, 13.7 mmol) in CH2Cl2 (10 ml) stirred at 0° C. was slowly added nitric acid (0.58 ml, 27.4 mmol) generating a white precipitate. After 10 minutes the resulting mixture was cooled to −78° C. and treated with 1-(10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (3.5 g, 13.7 mmol) in CH2Cl2 (15 ml) dropwise from an addition funnel over 5 minutes. The reaction was stirred at −78° C. for 30 minutes then warmed to 0° C. for 1 hour. The reaction mixture was poured into a vigorously stirred ice (100 g). The layers were separated and the aqueous layer extracted with CH2Cl2 (3×30 ml). The organic layer was combined and washed with H2O (3×30 ml). The combined organic layer was washed with saturated aqueous NaHCO3 solution (20 mL) and H2O (20 mL) then dried through a cotton plug and concentrated to give an orange oil that solidified on standing (4.2 g). Chromatography yielded pure product as a crystalline solid (3.2 g, 78%). (TLC 30% ethyl acetate/hexanes Rf 0.23). 1H NMR (400 MHz, CDCl3) δ 8.12 (br d, J=8.0 Hz, 1H), 8.08 (br s, 1H), 7.37 (br d, J=8.0 Hz, 1H), 4.38 (br d, J=12.6 Hz, 1H), 3.94 (br d, J=12.6 Hz, 1H), 3.59 (br d, J=12.6 Hz, 1H), 3.43–3.35 (m, 2H), 3.18 (br d, J=12.6 Hz, 1H), 2.48 (m, 1H), 2.07 (d, J=10.8 Hz, 1H). GCMS m/e 300 (M+).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:13]2[C:8](=[C:9]([NH2:14])[CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1.[CH2:15]([OH:17])[CH3:16]>>[CH2:15]([O:17][C:4]1[C:13]2[C:8](=[C:9]([NH2:14])[CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1)[CH3:16]
Reactant: Nc1cccc2c(Cl)ccnc12
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Product: CCOc1ccnc2c(N)cccc12
Temperature: 110 °C

Procedure:
To a solution of ethanol (5 mL) was added NaH (141 mg, 5.6 mmol, 95%) at 0° C. and the reaction mixture was stirred at rt for 30 min. before 4-chloroquinolin-8-amine (200 mg, 1.12 mmol) was added to the reaction mixture. Then the reaction mixture was heated in a sealed tube at 110° C. for 12 h before it was quenched with 1N HCl. Then the reaction mixture was extracted with chloroform and the organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 140 mg of the title product. MS [M+H]+: 189.15.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([NH:19]C(OCC)=O)[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:25])[CH2:10][CH:9]=1.C[O-].[K+].CO.C(O)C>O>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[NH:12][C:11](=[O:25])[CH2:10][CH:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]=2[CH:15]=1
Reactant: CCOC(=O)Nc1ccc2c(c1)C(c1ccccc1Cl)=CCC(=O)N2
Agent: C[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: Nc1ccc2c(c1)C(c1ccccc1Cl)=CCC(=O)N2

Procedure:
13.0 g of ethyl 5-(2-chlorophenyl)-2,3-dihydro-2-oxo-1H-1-benzazepine-7-carbamate are heated to boiling under reflux for 13 hours together with 39 g of potassium methylate in a mixture of in each case 215 ml of methanol, ethanol and water. After evaporation of the organic solvents, the residue is extracted with chloroform. The residue from the chloroform extract is crystallized from ethyl acetate. There is obtained 7-amino-5-(2-chlorophenyl)-1,3-dihydro-2H-1-benzazepin-2-one of melting point 192°.