Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:19]1[S:20][CH:21]=[CH:22][N:23]=1.C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC=CC=1)([O-])=O>C(OCC)(=O)C.[Cu]>[CH:1](/[C:9]1[N:10]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1)=[CH:2]\[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C(=Cc1nc2ccccc2[nH]1)c1ccccc1
Reactant: Brc1nccs1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=[N+]([O-])c1ccccc1
Product: C(=C/c1nc2ccccc2n1-c1nccs1)\c1ccccc1
Yield: 65.6 %

Procedure:
A stirred mixture of 2-styryl-1H-benzimidazole (220 mg, 1 mmol), 2-bromothiazole (328 mg, 2 mmol), potassium carbonate (138 mg, 1 mmol), copper bronze (20 mg) and nitrobenzene (10 ml) was heated to reflux under a nitrogen atmosphere for 7 h. The cooled reaction mixture was diluted with ethyl acetate (150 ml) and filtered through a pad of celite. The filtrate was washed consecutively with water (50 ml), and brine (50 ml), dried (magnesium sulfate) and concentrated to dryness. Column chromatography (silica gel, 100 g; n-hexane/ethyl acetate (9/1 to 3/1)) gave 199 mg of the titled compound as an orange oil, which was solidified on standing at room temperature. Recrystallization from isopropyl ether gave 117 mg (39%) of the titled compound as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])I.[F:15][C:16]1[CH:22]=[C:21](I)[CH:20]=[CH:19][C:17]=1[NH2:18]>CS(C)=O.[Cu]>[F:15][C:16]1[CH:22]=[C:21]([C:5]([F:8])([F:7])[C:4]([F:10])([F:9])[C:3]([F:12])([F:11])[C:2]([F:14])([F:13])[F:1])[CH:20]=[CH:19][C:17]=1[NH2:18]
Reactant: Nc1ccc(I)cc1F
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: [Cu]
Solvent: CS(C)=O
Product: Nc1ccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 61.1 %

Procedure:
A dispersion of 1,1,1,2,2,3,3,4,4-nonafluoro-4-iodobutane (3.50 9, 10.1 mmol), 2-fluoro-4-iodoaniline (2.00 g, 8.4 mmol) and copper bronze (1.93 g, 30.4 mmol) in DMSO (10 ml) was stirred at 120° C. for 15 h. Copper(I) iodide was removed by filtration through Celite®. Et2O (100 ml) was used to wash the Celite® plug. Water (100 ml) was then added to the filtrate and the mixture stirred at RT for 5 min. The organic layer was separated and washed 5× with water to remove DMSO, dried (Na2SO4) and concentrated. Flash chromatography on silica gel (10% EtOAc/Hexane) afforded 2-fluoro-4-(1,1,2,2,3,3,4,4,4-nonafluorobutyl) aniline (1.69 g, 61%). 1H NMR [300 MHz, CDCl3] δ 7.25-7.14 (m, 2H), 6.86-6.74 (m, 1H), 4.07 (br s, 1H). LCMS (ACPI−) 328 (100%).
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12](Br)=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.[Cu][C:22]#[N:23].N.O>CN1CCCC1=O>[C:22]([C:12]1[CH:11]=[C:10]2[C:15]([C:16]([CH3:18])([CH3:19])[CH2:17][NH:8][CH2:9]2)=[CH:14][CH:13]=1)#[N:23]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Br)ccc2C(C)(C)C1
Reactant: N#C[Cu]
Agent: N
Solvent: O
Solvent: CN1CCCC1=O
Product: CC1(C)CNCc2cc(C#N)ccc21
Yield: 86.4 %

Procedure:
A mixture of N-tert-butyloxycarbonyl-7-bromo-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline (4.2 g, 0.01236 mol) and copper (I) cyanide (2.2 g, 0.0247 mol) in N-methylpyrrolidinone (120 ml) was heated at vigorous reflux for 2 hours. On cooling the mix was poured into 0.880 ammonia (300 ml) and water (300 ml) and extracted into ethyl acetate (4×200 ml). Combined organic extracts were washed with 1:10.880 ammonia:water (3×150 ml), water (3×200 ml) and brine (150 ml) and dried (Na2SO4). Solvent was removed in vacuo to afford the title compound as a pale brown solid (1.99 g, 86%).
Reaction SMILES: CO.[F:3][C:4]1[CH:28]=[CH:27][C:7]([NH:8][C:9]2[CH:18]=[C:17](/[CH:19]=[CH:20]/[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:16]=[CH:15][C:10]=2[C:11]([O:13]C)=[O:12])=[CH:6][CH:5]=1.[OH-].[Na+]>O1CCCC1>[F:3][C:4]1[CH:28]=[CH:27][C:7]([NH:8][C:9]2[CH:18]=[C:17](/[CH:19]=[CH:20]/[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:16]=[CH:15][C:10]=2[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(/C=C/c2ccccc2)cc1Nc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(/C=C/c2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixed solution of methanol 2 mL and tetrahydrofuran 2 mL of the obtained methyl 2-(4-fluoroanilino)-4-((E)-2-phenylvinyl)benzoate was added 2.0 mol/L sodium hydroxide aqueous solution 2.5 mL at room temperature, and it was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure, water was added to it, and it was adjusted to pH4.0 with 1.0 mol/L hydrochloric acid. Solid matter was filtrated, and it was refined by silica gel column chromatography [eluent; hexane:ethyl acetate=2:1] to give 2-(4-fluoroanilino)-4-((E)-2-phenylvinyl)benzoic acid 58 mg.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[N:6]1[C:10]2[CH:11]=[C:12]([N+:23]([O-])=O)[C:13]([N+:20]([O-])=O)=[C:14]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[C:9]=2[NH:8][S:7]1>[Fe].C(O)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[N:6]1[C:10]2[CH:11]=[C:12]([NH2:23])[C:13]([NH2:20])=[C:14]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[C:9]=2[NH:8][S:7]1
Reactant: O=[N+]([O-])c1cc2c(c(-c3cccs3)c1[N+](=O)[O-])NSN2c1cccs1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cc2c(c(-c3cccs3)c1N)NSN2c1cccs1
Yield: 96.1 %

Procedure:
The 1,4-di(2-thienyl)-5,6-dinitro-2,1,3-benzothiadiazole (502 mg, 1.29 mmol) synthesized above was added to acetic acid (40 mL) together with iron dust (878 mg, 15.72 mmol) and reacted at 90° C. for 24 hours. The resulting solution was poured to distilled water and extracted with ether. The organic solvent layer was dried to obtain 1,4-di(2-thienyl)-5,6-diamino-2,1,3-benzothiadiazole (410 mg, 1.24 mmol, yield: 96%) as yellowish brown solid. 1H NMR (400 MHz, CDCl3, ppm): δ 7.56 (dd, 2H, J=5.5 Hz, J=1.1 Hz), 7.38 (dd, 2H, J=3.3 Hz, J=1.1 Hz), 7.26 (t, 2H, J=4.7 Hz), 4.38 (br, 4H).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:15]([C:23]1[CH:24]=[C:25]([CH2:29][CH:30](O)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:26]=[CH:27][CH:28]=1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C(C)=CC=CC=1>[C:15]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:26]=[CH:27][CH:28]=1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)CC(O)Cc1cccc(C(=O)c2ccccc2)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1C
Product: CCOC(=O)CC=Cc1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C

Procedure:
315 mg of phosphoric anhydride were added to a solution of 1.12 g of ethyl 4-(m-benzoyl-phenyl)-3-hydroxy-butyrate in 20 ml of xylene and the mixture was refluxed for 2 hours and then cooled to room temperature. The organic phase was washed with water, then with an aqueous saturated sodium bicarbonate solution and then water, dried over sodium sulfate, treated with activated carbon, filtered and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with methylene chloride which was evaporated to dryness to obtain ethyl 4-(m-benzoyl-phenyl)-3-butenoate whose ultraviolet spectrum was in accord with the structure.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[N:14]=[C:13]([C:16]1[N:17]([C:25]4[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=4)[N:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[O:12][C:11]3=[O:32])=[N:7][C:6]([C:33]([F:36])([F:35])[F:34])=[CH:5][CH:4]=2.[CH3:37][NH2:38]>C1COCC1>[CH3:37][NH:38][C:11]([C:10]1[CH:9]=[C:8]2[C:3]([CH:4]=[CH:5][C:6]([C:33]([F:35])([F:34])[F:36])=[N:7]2)=[C:2]([Cl:1])[C:15]=1[NH:14][C:13]([C:16]1[N:17]([C:25]2[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=2)[N:18]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:20]=1)=[O:12])=[O:32]
Reactant: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2c(Cl)c3ccc(C(F)(F)F)nc3cc12
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cc2nc(C(F)(F)F)ccc2c(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl

Procedure:
9-Chloro-2-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-6-trifluoromethyl-3-oxa-1,5-diaza-anthracen-4-one is reacted with methylamine in THF analogously to the procedure given in step i) of example H-18. The title product is obtained as yellow crystals after flash column chromatography eluting with 1:1 hexane:ethyl acetate. m.p.: 235-237° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:5]=[C:6]([C:10](=O)[CH:11]=O)[CH:7]=[CH:8][CH:9]=1.I.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:27][NH2:28])=[NH:26])=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:27]=[N:28][CH:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:15])([F:14])[F:1])[CH:5]=3)[N:26]=2)=[CH:23][CH:24]=1
Reactant: O=CC(=O)c1cccc(OC(F)(F)F)c1
Reactant: COc1ccc(C(=N)NN)cc1
Agent: I
Product: COc1ccc(-c2nncc(-c3cccc(OC(F)(F)F)c3)n2)cc1

Procedure:
(3-Trifluoromethoxyphenyl)oxoacetaldehyde was reacted with 4-methoxybenzenecarboximidic hydrazide hydriodide salt (2.39 g, 8.16 mmol) using the method described in Example 1 to give 3-(4-methoxyphenyl)-5-(3-trifluoromethoxyphenyl)-[1,2,4]triazine as a yellow solid (1.10 g): δH (400 MHz, CDCl3) 3.92 (3H, s), 7.06-7.10 (2H, m), 7.45-7.49 (1H, m), 7.64 (1H, t, J 8.2 Hz), 8.14-8.18 (2H, m), 8.59-8.63 (2H, m), 9.53 (1H, s); m/z (ES+) 348.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([CH2:12][OH:13])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[F:16][CH:17]([F:28])[O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25](O)=[O:26])=[N:23][CH:24]=1>>[F:28][CH:17]([F:16])[O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8]([CH2:12][OH:13])=[C:7]([CH3:14])[C:6]=3[CH:15]=2)=[O:26])=[N:23][CH:24]=1
Reactant: CC1=C(CO)CCCc2ccc(N)cc21
Reactant: O=C(O)c1ccc(OC(F)F)cn1
Product: CC1=C(CO)CCCc2ccc(NC(=O)c3ccc(OC(F)F)cn3)cc21

Procedure:
In a manner similar to the procedure of step 3A, (E)-(2-amino-9-methyl-6,7-dihydro-5H-benzo[7]annulen-8-yl)methanol from preparation J was coupled with 5-(difluoromethoxy)picolinic acid from preparation K to afford the titled compound of step 46A. LCMS (M+H)+=375.27, 1H NMR (500 HMz, chloroform-d) δ 9.81 (s, 1H), 8.46 (d, J=2.1 Hz, 1H), 8.32 (dd, J=8.6, 0.5 Hz, 1H), 7.68-7.64 (m, 2H), 7.55 (dd, J=8.1, 2.3 Hz, 1H), 7.18 (d, J=8.1 Hz, 1H), 6.81-6.51 (m, 1H), 4.39 (s, 2H), 2.56-2.51 (m, 2H), 2.14 (s, 3H), 2.10 (quin, J=7.1 Hz, 2H), 2.00-1.96 (m, 2H), 1.89 (br. s., 1H).
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22][C@H:23]([NH2:26])[CH2:24][CH3:25]>CS(C)=O>[C@H:23]([NH:26][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)([CH2:24][CH3:25])[CH3:22]
Reactant: CC[C@H](C)N
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Solvent: CS(C)=O
Product: CC[C@@H](C)Nc1nc2cc(C(=O)OC)ccc2nc1-c1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.439 mmol, 1.00 equiv), (S)-butan-2-amine (2 mL), DMSO (1 mL). The resulting solution was stirred overnight at 60° C. in an oil bath. The resulting mixture was concentrated under vacuum and diluted with H2O. The resulting solids were collected by filtration. The residue was applied onto a silica gel column with PE/EA (50:1). This resulted in 114 mg of (R)-methyl 3-(sec-butylamino)-2-phenylquinoxaline-6-carboxylate as yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[CH2:14][NH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20](=[O:24])[N:19]([CH2:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:18]=1[CH3:36].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[CH2:14][NH:15][C:21]1[C:20](=[O:24])[N:19]([CH2:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:18]([CH3:36])=[C:17]([Cl:16])[N:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Reactant: NC[C@@H]1COCCN1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(Cl)nc(NC[C@@H]2COCCN2Cc2ccccc2)c(=O)n1CC(=O)OCc1ccccc1
Yield: 32.9 %

Procedure:
A solution of [(3R)-4-benzylmorpholinyl]methylamine (preparation 95) (4.2 g, 20.4 mmol), benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (1 g, 3.06 mmol), and triethylamine (0.7 ml, 5.0 mmol) in ethyl acetate (25 ml) was heated under reflux for 18 hrs. The cooled reaction mixture was diluted with ethyl acetate, washed with water, then brine, dried over MgSO4 and concentrated under reduced pressure. The residual brown oil was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (0:100 to 100:0) to give the title compound as a white solid, (500 mg, 32%). LRMS: m/z=515 (M+18)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[NH:10][CH:9]=[N:8][C:7]=1[CH3:11].[CH2:12]([C:19]1[C:20](=[O:28])[NH:21][C:22](SC)=[N:23][C:24]=1[CH3:25])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:11][C:7]1[N:8]=[CH:9][NH:10][C:6]=1[CH2:5][S:4][CH2:3][CH2:2][NH:1][C:22]1[NH:21][C:20](=[O:28])[C:19]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:24]([CH3:25])[N:23]=1
Reactant: CSc1nc(C)c(Cc2ccccc2)c(=O)[nH]1
Reactant: Cc1nc[nH]c1CSCCN
Product: Cc1nc[nH]c1CSCCNc1nc(C)c(Cc2ccccc2)c(=O)[nH]1
Yield: 65.9 %

Procedure:
An intimate mixture of 5-(2-aminoethyl)thiomethyl-4-methylimidazole (1.28 gms) and 5-benzyl-6-methyl-2-methylthio-4-pyrimidone (1.84 gms) was heated at 150°-160° C. (oil-bath temperature) for 41/2 hours. The mixture was cooled, washed with water and recrystallised from isopropanol to give 2-[-2-(4-methyl-5-imidazolylmethylthio)ethylamino]-5-benzyl-6-methyl-4-pyrimidone (1.82 gms) m.p.= 140°-141.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[OH:18][CH2:19][CH2:20][O:21][C:22]1[CH:31]=[CH:30][C:25]([O:26][CH2:27][CH2:28]O)=[CH:24][CH:23]=1.Cl.CN(C)CCCN=C=NCC.CCN(CC)CC>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:28][CH2:27][O:26][C:25]1[CH:30]=[CH:31][C:22]([O:21][CH2:20][CH2:19][OH:18])=[CH:23][CH:24]=1)=[O:15])[CH:7]=[CH:6]2
Reactant: OCCOc1ccc(OCCO)cc1
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2cc([C@H](C)C(=O)OCCOc3ccc(OCCO)cc3)ccc2c1
Yield: 79.1 %

Procedure:
A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 4.27 g, 18.5 mmol), hydroquinone bis(2-hydroxyethyl)ether (10.6 g, 53.3 mmol), N,N-dimethylaminopyridine (DMAP, 2.71 g, 22.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.34 g, 48.7 mmol) and NEt3 (13 mL, 93.3 mmol) in DMF (100 mL) was stirred at ambient temperature overnight. The reaction mixture was evaporated to dryness under vacuum and the residue was partitioned between HCl (3N, 100 mL) and CH2Cl2 (200 mL). The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated. The product was separated by silica gel column chromatography eluting with EtOAc/hexane (1:1, Rf=0.15) and then recrystalized from ethyl ether and hexane to give the title compound as a white solid (6.01 g, 31% yield). Mp 76-78° C. 1H NMR (CDCl3) δ 7.7-7.64 (m, 3H), 7.42-7.38 (m, 1H), 7.15-7.08 (m, 2H), 6.74-6.72 (m 4H), 4.45-4.36 (m, 2H), 4.1-3.85 (m, 7H), 3.90 (s, 3H), 2.13 (br. t, 1H), 1.58 (d, J=7.2 Hz, 3H). 13C NMR (CDCl3) δ 174.6, 157.5, 153.0, 152.8, 135.4, 133.6, 129.2, 128.8, 127.1, 126.1, 125.9, 118.8, 115.7, 115.3, 105.5, 69.7, 66.6, 63.1, 61.4, 55.2, 45.2, 18.4. MS(API) m/z 428 (M+NH4)+. Anal. calcd. for C24H26O6: C, 70.23; H, 6.38. Found: C, 70.01; H, 6.39.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH:9]=O)[CH2:3][CH2:2]1.[N+:14]([CH3:17])([O-:16])=[O:15].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:13]=[CH:12][CH:11]=[C:8](/[CH:9]=[CH:17]/[N+:14]([O-:16])=[O:15])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1cccc(OCC2CC2)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1cccc(OCC2CC2)c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 69.4 %

Procedure:
A mixture of 3-cyclopropylmethoxy-benzaldehyde (4.32 g, 24.5 mmol) described in Manufacturing Example 66-1-1, nitromethane (2.64 mL, 49 mmol), ammonium acetate (2.83 g, 36.8 mmol) and acetic acid (40 mL) was stirred for 5 hours at 100° C. This mixture was cooled to room temperature, concentrated under a reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1-1:1) to obtain the title compound (3.73 g, 69%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][C@H:24]4[CH2:29][CH2:28][C@@H:27]([C:30]([CH3:34])([CH3:33])[CH2:31][CH3:32])[CH2:26][CH2:25]4)[CH:19]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Li+].O1CCCC1.O>>[C:30]([C@@H:27]1[CH2:28][CH2:29][C@H:24]([O:23][C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([CH2:12][N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)[CH:22]=[CH:21]3)[CH2:25][CH2:26]1)([CH2:31][CH3:32])([CH3:33])[CH3:34]
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(O[C@H]4CC[C@@H](C(C)(C)CC)CC4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(C)(C)[C@H]1CC[C@@H](Oc2ccc3cc(CN4CCC(C(=O)O)CC4)ccc3c2)CC1

Procedure:
A solution of 1-{6-[cis-4-(1,1-dimethyl-propyl)-cyclohexyloxy]-naphthalen-2-ylmethyl}-piperidine-4-carboxylic acid ethyl ester (0.382 g, 0.820 mmol) and lithium hydroxide (196 mg, 8.20 mmol) in tetrahydrofuran (3.32 mL, 41.0 mmol) and water (0.738 mL, 41.0 mmol) was stirred at room temperature overnight. LCMS showed a single desired product peak Rt=1.78 min, m/z=438.40 [M+1], 100%. The solvent was concentrated and neutralized with concentrated HCl. The solid was suspended with water and filtered and washed thoroughly with water and ether then dried to give a white solid (86.9 mg, 24%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.81-0.90 (m, 9H), 1.19-1.70 (m, 10H), 2.19 (d, J=13.99 Hz, 2H), 2.67 (s, 2H), 4.45 (s, 2H), 4.78 (t, J=2.45 Hz, 1H), 7.26 (dd, J=8.91, 2.45 Hz, 1H), 7.31 (d, J=2.26 Hz, 1H), 7.53 (dd, J=8.50, 1.73 Hz, 1H), 7.86 (dd, J=8.69, 3.42 Hz, 2H), 7.96 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:4]=2[CH:5]=[N:6][CH:7]=1.S(Cl)([Cl:16])=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[C:3]2[O:10][C:9]([C:11]([Cl:16])=[O:13])=[CH:8][C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2cncc(Cl)c2o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Cl)c1cc2cncc(Cl)c2o1

Procedure:
7-Chloro-furo[3,2-c]pyridine-2-carboxylic acid (prepared according to the method of Example 132, Step A, 8.94 g, 45.2 mmol) was combined with thionyl chloride (30 mL) and sodium carbonate (9.59 g, 90.5 mmol) and heated to reflux for 16 h under nitrogen atmosphere. The cooled mixture was diluted with dichloromethane and filtered. The filtrate was evaporated to give the title compound of Example 132, Step B as an orange oil, 9.19 g (94%). The acid chloride was used directly without further purification.
Reaction SMILES: [CH3:1][C:2]([NH2:8])([CH2:4][CH:5]([OH:7])[CH3:6])[CH3:3].[CH:9](=O)[CH3:10].C1(C)C=CC=CC=1>O>[CH3:9][CH:10]1[NH:8][C:2]([CH3:3])([CH3:1])[CH2:4][CH:5]([CH3:6])[O:7]1
Reactant: CC(O)CC(C)(C)N
Reactant: CC=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC1CC(C)(C)NC(C)O1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
1,170 parts by weight of 2-methyl-2-aminopentan-4-ol is placed in a stirred flask. With external cooling, 440 parts by weight of acetaldehyde is run in over a period of about 40 minutes at 15°-20° C. The reaction mixture is stirred for a further 15 minutes at 20° C. After the addition of 600 parts by volume of toluene, 182 parts by weight of water is separated off over a period of 2 hours by azeotropic distillation. The reaction product is subjected to fractional distillation. After removal of the solvent there is obtained 1,372 parts by weight of 2,4,4,6-tetramethyltetrahydro-1,3-oxazine with a purity (according to gas chromatography) of 98%, equivalent to a yield of 94% of theory, based on 2-methyl-2-aminopentan-4-ol.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[O:14][CH2:15][CH3:16])=[CH:11][CH:10]=[CH:9][C:8]=2[NH:17][C:18](=[O:27])[C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26])(=O)[NH2:2].S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[O:14][CH2:15][CH3:16])=[CH:11][CH:10]=[CH:9][C:8]=2[NH:17][C:18](=[O:27])[C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26])#[N:2]
Reactant: CCOc1c(C(N)=O)cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCOc1c(C#N)cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
To a solution of 3-carbamoyl-8-(2,6-dichlorobenzoylamino)-4-ethoxyquinoline (122 mg) in dimethylformamide was added thionyl chloride (53.9 mg), and the mixture was stirred for 30 minutes at ambient temperature. The mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate-n-hexane) to give 3-cyano-8-(2,6-dichlorobenzoylamino)-4-ethoxyquinoline (89.9 mg).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[C:30]([C:31]#[N:32])=[CH:29][C:10]([C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][C@H:15]2[O:27][CH3:28])=[O:12])=[C:9]([O:33][CH3:34])[CH:8]=1.[OH-:35].[NH4+]>>[NH2:6][C:7]1[CH:8]=[C:9]([O:33][CH3:34])[C:10]([C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][C@H:15]2[O:27][CH3:28])=[O:12])=[CH:29][C:30]=1[C:31]([NH2:32])=[O:35]
Reactant: [OH-]
Reactant: COc1cc(N)c(C#N)cc1C(=O)N[C@H]1CCN(Cc2ccccc2)C[C@H]1OC
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: COc1cc(N)c(C(N)=O)cc1C(=O)N[C@H]1CCN(Cc2ccccc2)C[C@H]1OC
Reaction time: 8 h

Procedure:
285 Parts of sulfuric acid were cooled in an ice-bath and 15.5 parts of cis-4-amino-5-cyano-2-methoxy-N-[3-methoxy-1-(phenylmethyl)-4-piperidinyl]benzamide were added portionwise while cooling. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was poured onto ice-water and the whole was alkalized with ammonium hydroxide. The product was filtered off and stirred in a mixture of trichloromethane and water. The product was filtered off again and dried, yielding 15.0 parts of cis-4-amino-6-methoxy-N1 -[3-methoxy-1-(phenylmethyl)-4-piperidinyl]-1,3-benzenedicarboxamide (compound 236).