Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[C:2]([N:5]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH:12]([NH:18][CH2:19][CH2:20][CH3:21])[CH2:13]2)[CH2:6][CH3:7])(=O)[CH3:3]>O1CCCC1>[ClH:1].[ClH:1].[CH2:6]([N:5]([CH2:2][CH3:3])[C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH:12]([NH:18][CH2:19][CH2:20][CH3:21])[CH2:13]2)[CH3:7]
Reactant: CCCNC1CCc2c(cccc2N(CC)C(C)=O)C1
Agent: Cl
Solvent: C1CCOC1
Product: CCCNC1CCc2c(cccc2N(CC)CC)C1

Procedure:
Starting from 1.03 g (0.0033 mol) of 5-(N-acetyl-N-ethylamino)-2-n-propylamino-tetraline-hydrochloride (Example 4.7.8) which is converted into the base, the title compound is obtained in base form by reduction in 30 ml of absolute tetrahydrofuran analogously to Example 4.5.1 c), but using 3.3 ml of 2-molar diborandimethylsulphide complex solution in tetrahydrofuran as the reducing agent. This base is purified by filtering over 16 g of aluminium oxide (activity stage III, neutral) using methylene chloride as solvent and is crystallised analogously to Example 4.1.1 in the form of the dihydrochloride which is obtained in a yield of 0.54 g (49.1%) and with a melting point of 201° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10](N(OC)C)=[O:11])=[N:4][CH:5]=[C:6]([S:8][CH3:9])[N:7]=1.CC(C[AlH]CC(C)C)C.Cl>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH:10]=[O:11])=[N:4][CH:5]=[C:6]([S:8][CH3:9])[N:7]=1
Reactant: CON(C)C(=O)c1ncc(SC)nc1Cl
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CSc1cnc(C=O)c(Cl)n1
Temperature: 78 °C
Reaction time: 2 h

Procedure:
To a solution of 55C (750 mg, 3.03 mmol) in THF at 78° C., DIBAL-H (3.33 mL, 3.33 mmol) in toluene was added to the solution slowly. Then, it was stirred for 2 hours at 78° C. HCl (4 mL, 1 N) was added to the solution and warmed to 0° C. The mixture was stirred for 20 minutes at 0° C. then extracted with EtOAc twice. The organic layer was dried and concentrated to provide the crude product which was used without further purification. MS (m/z) 189 [M+H]+.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH2:13]([N:20]1[CH2:24][CH2:23][C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][OH:33])(O)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:13]([N:20]1[CH2:24][CH2:23][C:22]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:32][O:33]2)[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: OCc1ccccc1C1(O)CCN(Cc2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(CN2CCC3(C2)OCc2ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
Diethyl azodicarboxylate (4.44 mL, 0.0282 mol) in 1 ml of THF was added to a mixture of 1-benzyl-3-[2-(hydroxymethyl)phenyl]pyrrolidin-3-ol (3.50 g, 0.0124 mol) and triphenylphosphine (7.40 g, 0.0282 mol) in tetrahydrofuran (50 mL, 0.6 mol) at room temperature. The mixture was stirred at room temperature overnight. The reaction solution was concentrated and the residue was flash chromatographed on silica gel column with 50% AcOEt in hexanes to give the desired compound (1.5 g, 46% yield). MS (ESI): 266.1 (M+H+).
Reaction SMILES: [C@H:1]([N:5]([CH3:26])[C:6]1[C:7]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16](O)=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2].C(N(CC)CC)C.[CH3:34][C:35]([NH2:38])([CH3:37])[CH3:36].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>ClCCl.O>[C:35]([NH:38][C:16]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:6]([N:5]([C@@H:1]([CH2:3][CH3:4])[CH3:2])[CH3:26])=[N:15]2)=[O:17])([CH3:37])([CH3:36])[CH3:34]
Reactant: CC(C)(C)N
Reactant: CC[C@@H](C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC[C@@H](C)N(C)c1nc2cc(C(=O)NC(C)(C)C)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-(sec-butyl(methyl)amino)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid (500 mg, 1.42 mmol) in dichloromethane (30 mL) was added triethylamine (348 mg, 3.44 mmol), 2-methylpropan-2-amine (197 mg, 2.7 mmol), and T3P (12 mL), and the reaction mixture was stirred overnight at room temperature. The resulting solution was diluted with water (150 mL) and extracted with dichloromethane (4×50 mL), the organic layers combined and dried over anhydrous magnesium sulfate and concentrated in vacuo to afford (R)—N-tert-butyl-3-(sec-butyl(methyl)amino)-2-(4-fluorophenyl)quinoxaline-6-carboxamide as a yellow solid (750 mg, crude).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][C:23]=1[C:37]([OH:40])([CH3:39])[CH3:38].C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:3]=[C:4]([NH:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:5]=[C:6]([O:8][CH3:9])[N:7]=2)=[CH:24][C:23]=1[C:37]([OH:40])([CH3:38])[CH3:39]
Reactant: COc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Reactant: CC(C)(O)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2ccc(Cl)c(C(C)(C)O)c2)n1
Yield: 19.9 %

Procedure:
A solution of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine (0.58 g), 2-[2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propan-2-ol (0.63 g), Cs2CO3 (1.36 g) and tetrakis(triphenylphosphine)palladium (0) (50 mg) in water (8 mL)/DME (32 mL) is heated at 90° C. for 16 h. The solution is poured into water and extracted with EtOAc (2×200 mL). The organic layer is dried over sodium sulfate, filtered, evaporated in vacuo. The residue is chromatographed on silica gel eluting with EtOAc to afford 2-(2-chloro-5-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-propan-2-ol (162 mg, Example 98). MS: 466 (M+H); 1H NMR (300 MHz, DMSO) □8.2 (m, 1H); 7.8, (d, 1H, J=0.3 Hz); 7.5-7.7 (m, 2H); 7.4 (d, 2H, J=0.4 Hz); 7.3 (m, 1H); 7.3 (s, 1H); 6.6 (s, 1H); 4.2 (s, 3H); 4 (s,3H); 3.8 (m, 2H); 3.05 (t, 2H); 1.55 (s, 6H). IC50=110 nM
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[CH:24](O)[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C(C)=CC=CC=1.C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:28]1([NH:27][CH:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:26])[N:16]2[CH2:15][CH2:14][CH2:13][N:10]2[CH2:11][CH:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccccc1
Reactant: O=C1c2ccccc2C(O)N1CCCN1CC=C(c2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1C
Product: O=C1c2ccccc2C(Nc2ccccc2)N1CCCN1CC=C(c2ccccc2)CC1
Reaction time: 9 h
Yield: 93.8 %

Procedure:
Para-toluenesulphonic acid (50 mg) is added to an agitated solution of 2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-3-hydroxy-1-isoindolinone (5 g) and aniline (1.7 g) in xylene (100 cc) at a temperature close to 20° C. in a Dean Stark apparatus. Agitation is continued for 9 hours at a temperature close to 135° C. After cooling to a temperature close to 20° C., the solution is washed with aqueous sodium bicarbonate solution (2×50 cc) then with distilled water (2×30 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 80° C. The residue obtained is dissolved in methylene chloride (10 cc) and poured onto silica (100 g) contained in a column of 2 cm diameter. Elution is carried out with a mixture of methylene chloride and methanol (95-5 by volume) (1300 cc) and the corresponding eluate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa). The precipitate formed is recrystallized from boiling acetonitrile (30 cc). 5.7 g of 3-phenylamino-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone are obtained, melting at 119° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:7]([C:11]2[O:12][CH:13]=[CH:14][N:15]=2)=[N:8][C:9]=1[NH2:10])([O-])=O>[Pd].C(O)C>[O:12]1[CH:13]=[CH:14][N:15]=[C:11]1[C:7]1[C:6]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:5][C:4]([NH2:1])=[C:9]([NH2:10])[N:8]=1
Reactant: Nc1nc(-c2ncco2)c(-c2ccncc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(-c2ccncc2)c(-c2ncco2)nc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
A suspension of 5-nitro-2-(1,3-oxazol-2-yl)-3,4′-bipyridin-6-amine (0.089 g, 0.31 mmol) and palladium on carbon (10%, 20 mg) in ethanol (15 mL) was placed under a hydrogen atmosphere (balloon) and stirred at room temperature. After 3 hours, the mixture was filtered through Celite® and the filtrate was evaporated. Trituration with diethyl ether gave the title compound (0.077 g, 97%) as a pale orange solid.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:9][C:8](=[O:10])[NH:7][C:6]1([CH3:12])[CH3:11])=[O:4].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][CH2:2][C:3]([N:5]1[CH2:9][C:8](=[O:10])[NH:7][C:6]1([CH3:12])[CH3:11])=[O:4])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: CC1(C)NC(=O)CN1C(=O)CBr
Product: CC1(C)NC(=O)CN1C(=O)CNCc1ccccc1

Procedure:
A solution of 1-(2-bromoacetyl)-2,2-dimethyl-4-imidazolidinone (1.9 g) in 8.8 ml of benzylamine was stirred at room temperature for 4 hours. The excess of benzylamine was removed under reduced pressure (about 5 mmHg) at 80° C. The residue was taken up with ethyl acetate and the precipitate filtered off. The filtrate was evaporated and the residue was chromatographed on a silica gel column by eluting with dichloromethane/methanol 7:3. The selected fractions were collected and evaporated. Trituration of the residue with ether gave 1 g of the title compound as a white powder, m.p. 131°-132° C.
Reaction SMILES: N#N.[CH2:3]([P:7]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH3:6].[N-:16]([S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])[S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18].[C:31](=O)(OC)OC>CO>[F:30][C:27]([F:28])([F:29])[S:24]([N-:16][S:17]([C:20]([F:21])([F:22])[F:23])(=[O:18])=[O:19])(=[O:25])=[O:26].[CH3:31][P+:7]([CH2:3][CH2:4][CH2:5][CH3:6])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCP(CCCC)CCCC
Reactant: COC(=O)OC
Agent: N#N
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CO
Product: CCCC[P+](C)(CCCC)CCCC
Temperature: 0 °C

Procedure:
In an reactor wherein air was replaced by N2, 300.0 g (1.5 mol) of tributyl phosphine and 1000 mL of methanol were added and cooled to about 0° C. by a ice-bath. 427.6 g (1.5 mol) of trifluoromethanesulfonimide was then added dropwise under strong stirring, and 202.0 g (2.2 mol) of dimethyl carbonate was also added afterwards. After one hour of reaction and mixing, the reaction mixture was transferred to an autoclave, wherein air was removed prior to heating. After 6 hours of reaction at temperature of 180° C. and pressure of from 1.6 MPa to 1.7 MPa, the crude product was obtained after distilling off the unreacted materials and solvent. 705.7 g of methyl tributyl phosphonium bis(trifluoromethanesulfonyl)amide was obtained after washing and drying at 60° C. and 0.1 kPa for 4 hours.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[S:11][C:10]([NH:12][C:13]([C:15]3[CH:31]=[CH:30][C:18]([O:19][C@@H:20]4[CH2:25][CH2:24][C@H:23]([C:26]([O:28]C)=[O:27])[CH2:22][CH2:21]4)=[CH:17][CH:16]=3)=[O:14])=[N:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>O1CCCC1.CO.O>[CH:1]1([NH:6][C:7]2[S:11][C:10]([NH:12][C:13]([C:15]3[CH:31]=[CH:30][C:18]([O:19][C@@H:20]4[CH2:25][CH2:24][C@H:23]([C:26]([OH:28])=[O:27])[CH2:22][CH2:21]4)=[CH:17][CH:16]=3)=[O:14])=[N:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)Nc3nnc(NC4CCCC4)s3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(Nc1nnc(NC2CCCC2)s1)c1ccc(O[C@H]2CC[C@@H](C(=O)O)CC2)cc1
Reaction time: 18 h
Yield: 0.1 %

Procedure:
0.310 g of methyl cis-4-[4-(5-cyclopentylamino[1.3.4]thiadiazol-2-ylcarbamoyl)-phenoxy]cyclohexanecarboxylate (0.70 mmol, 1 eq.) is placed in 8 mL of a tetrahydrofuran/methanol mixture. 112 mg of sodium hydroxide (2.79 mmol, 4 eq.) dissolved in 6 mL of water are added and stirring is continued for 18 hours. The reaction medium is evaporated. The residue is taken up in water and washed twice with diethyl ether. The aqueous phase is partially concentrated and acidified with an aqueous 6% sulfur dioxide solution. The aqueous phase is partially concentrated, drained and washed successively with water and with diethyl ether. 0.19 mg of cis-4-[4-(5-cyclopentylamino[1.3.4]thiadiazol-2-ylcarbamoyl)phenoxy]cyclohexanecarboxylic acid is obtained.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C1C2C(=CC=NC=2)C=CN=1.C(#N)CC#N.CC[O:28][C:29](CC(CC(OCC)=O)=O)=[O:30].C(C1C2C(=CN=CC=2)C=NC=1)=O>>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[N:2][CH:1]=2)[C:6]([C:29]([OH:30])=[O:28])=[CH:7][N:8]=1
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Reactant: c1cc2c(cn1)CNCC2
Agent: O=Cc1cncc2cnccc12
Agent: c1cc2ccncc2cn1
Solvent: N#CCC#N
Product: O=C(O)c1cncc2cnccc12

Procedure:
In contrast to the 1,2,3,4-tetrahydroisoquinolines, there are rather few examples of synthetic methods for 1,2,3,4-tetrahydro-2,7-naphthyridines in the literature. One important method to prepare 1,2,3,4-tetrahydro-2,7-naphthyridine is the regio-selective catalytic reduction of 2,7-naphthyridine (Eur. J. Med. Chem. Ther. 1996, 31(11), 875-888). The synthesis of 2,7-naphthyridine and some derivatives thereof has been described in the literature. One classical route involves several steps and starts with the acid catalysed condensation of malononitrile with diethyl 1,3-acetonedicarboxylate (J. Chem. Soc. 1960, 3513-3515; see also J. Heterocycl. Chem. 1970, 7, 419-421). A slightly different route to 2,7-naphthyridine involves oxidation of 4-formyl-2,7-naphthyridine to give 2,7-naphthyridine-4-carboxylic acid followed by decarboxylation (Synthesis 1973, 46-47). A completely different method is based on the internal Diels-Alder reaction of N-(ethoxycarbonyl)-N-(but-3-ynyl)amino-methylpyrazine and gives a mixture of 1,2,3,4-tetrahydro-2,7-naphthyridine and 5,6,7,8-tetrahydro-1,7-naphthyridine after hydrolysis of the carbamate group (WO 02/064574).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:13][CH:14]=3)[C:9](=[O:26])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:27]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[Cl-].[Na+]>C(Cl)(Cl)(Cl)Cl.[W]>[Br:27][CH:8]1[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][CH:14]=2)[C:9]1=[O:26]
Reactant: O=C1C=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc21
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1c2cc(OCCCc3ccccc3)ccc2C(c2ccccc2)C1Br
Yield: 59.5 %

Procedure:
3-Phenyl-6-(3-phenylpropoxy)indene-1-one (200 mg, 0.586 mmol) was dissolved in carbon tetrachloride, and N-bromosuccinimide (313 mg, 1.75 mmol) and 2,2′-azobisisobutyronitrile (9.7 mg) were added thereto. Then, the mixture was refluxed for 1 hour under a 375 W tungsten lamp. After the reaction was completed, saturated sodium chloride was added thereto and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate, concentrated, and the resulting residue was purified by column chromatography (ethyl acetate:hexane=1:5) to obtain title compound (147 mg, yield 60%) as a red solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5].[Cl:13][C:14]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:15]=1[C:16]([N:18]=[C:19]=[O:20])=[O:17]>CN1CCCC1=O>[Cl:13][C:14]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:15]=1[C:16]([NH:18][C:19]([NH:5][C:4]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1])=[O:20])=[O:17]
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Reactant: COc1ccc([N+](=O)[O-])cc1N
Solvent: CN1CCCC1=O
Product: COc1ccc([N+](=O)[O-])cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Yield: 96.7 %

Procedure:
1 g (5.9 mmol) of 2-methoxy-5-nitroaniline were admixed with 1.3 g (5.9 mmol) of 2-chloro-4,5-difluorobenzoyl isocyanate from stage a in 2 ml of N-methylpyrrolidone and reacted at room temperature for one hour. The precipitate was filtered off, washed twice with 5 ml of acetonitrile each time and dried under high vacuum. 2.2 g of the desired product were obtained which were used in stage c without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]2[CH:9]=[C:8]([C:11]([OH:13])=O)[C:7]=2[CH:6]=[CH:5][C:4]=1[O:14][CH3:15].C1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[CH2:28]([NH2:31])[CH:29]=[CH2:30]>O.C(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:10]2[CH:9]=[C:8]([C:11]([NH:31][CH2:28][CH:29]=[CH2:30])=[O:13])[C:7]=2[CH:6]=[CH:5][C:4]=1[O:14][CH3:15]
Reactant: C=CCN
Reactant: COc1ccc2c(c1OC)C=C2C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccccc1
Product: C=CCNC(=O)C1=Cc2c1ccc(OC)c2OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3,4-dimethoxybenzocyclobutene-1-carboxylic acid and 400 mL benzene was stirred under N2 at 0° as oxalyl chloride (40.6 mL, 0.47 mole) was added dropwise. The reaction mixture was stirred for 2 hours at room temperature, then solvents were evaporated. Benzene was added and evaporated. The acid chloride was dissolved in CH2Cl2 (200 mL) and was added dropwise to a stirred, 0° solution of allylamine (8.5 mL, 0.11 mole), triethylamine (59 mL), and CH2Cl2 (212 mL). The reaction mixture was stirred for 1 hour at room temperature, then water was added. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with 1N HCl, saturated aqueous NaHCO3, saturated aqueous NaCl, dried (MgSO4), filtered, and evaporated (in-vacuo) to yield 19.8 g cream colored solid, (84%); mp 98°-9°; M+ 247.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[S:12][C:13]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[NH2:10][C:11]1[S:12][C:13]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17]
Reactant: NC(=O)c1cc(-c2ccc(F)cc2F)sc1NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: NC(=O)c1cc(-c2ccc(F)cc2F)sc1N
Temperature: 25 °C

Procedure:
A suspension of benzyl[3-(aminocarbonyl)-5-(2,4-difluorophenyl)-2-thienyl]carbamate (240 mg, 0.618 mmol) and 10% palladium on carbon (326 mg, 0.306 mmol) in ethanol (130 mL) was placed under a hydrogen atmosphere by performing 5×15 second vacuum/hydrogen purge (supplied by balloon) fill cycles while vigorously stirring the mixture. The reaction was heated to reflux for 18 hours and then allowed to cool to ambient temperature. The suspension was filtered; the filtrate was collected and concentrated to yield the title compound as a light yellow solid.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C[O-].[Na+].[CH2:14]([O:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([CH2:26]Cl)[C:21]=1[CH3:28])[CH2:15][CH2:16][CH2:17][CH3:18]>CO.C(OCC)(=O)C>[CH2:14]([O:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([CH2:26][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[C:21]=1[CH3:28])[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCOc1ccnc(CCl)c1C
Reactant: Sc1nc2ccccc2[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C

Procedure:
To a liquid prepared by dissolving with stirring 7.5 g (0.052 mol, 1.0 eq.) of 2-mercaptobenzimidazole and 61.5 g (0.319 mol, 5.8 eq.) of a 28% sodium methoxide solution in 120 mL of methanol, a liquid prepared by dissolving the whole amount of 4-pentyloxy-2-chloromethyl-3-methylpyridine in 180 mL of methanol was added at 30° C. Subsequently, the mixture was heated to reflux for one hour and cooled, and then methanol was solid dried under reduced pressure. A yellow brown oily residue resulting therefrom was dissolved in 250 mL of ethyl acetate, and then the organic layer was washed with 100 mL of water. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated to dryness. The resulting residue was purified by silica gel column chromatography, and then was concentrated to dryness, to obtain 6.9 g of amorphous solidified product. The product was recrystallized from an ethyl acetate/1-hexane mixed liquid, to obtain 4.3 g of colorless crystals (HPLC: 98.5 Area %, yield 10.6%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:34][CH:35]=[CH2:36])([CH2:14][O:15][C:16]2[CH:21]=[C:20]([CH3:22])[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[C:18]([CH3:33])[CH:17]=2)[CH2:11]C=C)=[CH:6][CH:5]=1>C(Cl)Cl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1>[CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:14][O:15][C:16]3[CH:17]=[C:18]([CH3:33])[C:19]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:25][CH:24]=4)=[C:20]([CH3:22])[CH:21]=3)[CH2:11][CH:36]=[CH:35][CH2:34]2)=[CH:6][CH:5]=1
Reactant: C=CCC(CC=C)(COc1cc(C)c(-c2ccc(C(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)OC)cc1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2)c(C)c1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Product: COC(=O)c1ccc(C2(COc3cc(C)c(-c4ccc(C(F)(F)F)cc4)c(C)c3)CC=CC2)cc1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
A solution of 4-[1-allyl-1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxymethyl)-but-3-enyl]-benzoic acid methyl ester (6.0 mL of 0.11M stock solution in CH2Cl2, 0.578 g, 1.14 mmol) in CH2Cl2 (570 mL) is treated with [1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)-(tricyclohexylphosphine)ruthenium] (0.101 g, 0.1192 mmol) at 35° C. for 1 h, cooled to room temperature, and concentrated. The residue is loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 40% to afford the title compound (0.458 g, 84%) as a colorless syrup. 1H NMR (CDCl3): δ 7.98-7.96 (m, 2H), 7.63 (d, J=8.3 Hz, 2H), 7.44-7.41 (m, 2H), 7.20 (d, J=8.1 Hz, 2H), 6.58 (s, 2H), 5.77 (s, 2H), 3.99 (s, 2H), 3.89 (s, 3H), 2.87 (d, J=14.3 Hz, 2H), 2.77 (d, J=14.9 Hz, 2H), 1.92 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5](N(OC)C)=[O:6].Br[Mg][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([F:25])[CH:18]=1>>[Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:5]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([F:25])[CH:18]=2)=[O:6])[CH:11]=[CH:12][CH:13]=1
Reactant: CON(C)C(=O)c1cccc(Cl)c1F
Reactant: COc1ccc([Mg]Br)cc1F
Product: COc1ccc(C(=O)c2cccc(Cl)c2F)cc1F

Procedure:
Prepared according to Method A step B from 3-chloro-2-fluoro-N-methoxy-N-methylbenzamide (4.0 g, 18.4 mmol) and bromo(3-fluoro-4-methoxyphenyl)magnesium (100 mL, 2M in diethyl ether). The title compound was obtained as a white solid (1.65 g, 5.85 mmol, 32%).