Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])=[N:4][N:3]=1.[N:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:23]=[O:24].N(CC([O-])=O)=C=O>C1COCC1.C(OCC)C>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][NH:22][C:23]([NH:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])=[N:4][N:3]=1)=[O:24])[CH3:30]
Reactant: Nc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Reactant: CCOC(=O)CN=C=O
Agent: O=C=NCC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CNC(=O)Nc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
A suspension of [4-(5-Amino-[1,3,4]oxadiazol-2-yl)-pyridin-3-yl]-(2-fluoro-4-iodo-phenyl)-amine (0.200 g, 0.504 mmol) in dry THF (3 mL) was treated with ethyl isocyanatoacetate (0.077 g, 0.596 mmol). The reaction mixture was stirred at RT overnight. More isocyanatoacetate (0.083 g, 0.643 mmol) was added, and the mixture was stirred for another 72 hrs. The material was diluted with diethyl ether (2 mL), filtered and dried under high vacuum for 2 h to afford a yellow solid product (0.144 g, 0.274 mmol, 54%) LC/MS (Method A) [5.53 min; 527(M+1)]
Reaction SMILES: [C:1]([C:4]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([OH:3])=[O:2]>C(O)C.O>[CH3:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:5]2[C:4]=1[C:1](=[O:2])[O:3][C:4]([C:1]([OH:3])=[O:2])=[CH:6]2
Reactant: Cc1cccc(C=O)c1C(=O)O
Solvent: CCO
Solvent: O
Product: Cc1cccc2cc(C(=O)O)oc(=O)c12

Procedure:
8- Methylisocoumarin -3- carboxylic acid, mp. (EtOH-H2O) 236°-7°, (Found: C, 64.66; H, 3.95. C11H8O4 requires C, 64.70; H, 3.95), was prepared from 2 -carboxy -3- methylbenzaldehyde by an analogous procedure to that described in Example 1.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH3:3].[OH:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].C(OC1C=C(C=CC=1)C(O)=O)CC>>[CH2:1]([O:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH3:3]
Reactant: CCCBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CCCOc1cccc(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCOc1ccc(C(=O)O)cc1

Procedure:
The reaction of propyl bromide and ethyl 4-hydroxybenzoate in the presence of potassium carbonate was performed as described for Compound 24 to give 4-Propoxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.58 (s, COOH); 7.86 (d, J=8.8, 2 arom. H); 6.97 (d, J=8.8, 2 arom. H); 3.97 (t, CH3CH2CH2O); 1.72 (m, CH3CH2CH2O); 0.96 (t, CH3CH2CH2O). 13C-NMR (100 MHz, d6-DMSO): 166.99 (—C═O); 162.29; 131.33 (2 arom. C); 122.78; 114.18 (2 arom. C); 69.21; 21.90; 10.30.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][NH:40][C@@H:41]([CH3:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:22])[N:40]([CH3:39])[C@H:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH3:48])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:13][CH:14]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CN[C@@H](C)c1ccccc1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)N(C)[C@@H](C)c4ccccc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 54 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and (S)-N,α-dimethylbenzylamine: yield 54%.
Reaction SMILES: [CH3:1][C:2]1(/[CH:10]=[CH:11]/[CH:12]=[O:13])[C:7](=[CH2:8])[CH:6]2[CH2:9][CH:3]1[CH:4]=[CH:5]2>CCO.O.[Ni]>[CH3:1][C:2]1([CH2:10][CH2:11][CH:12]=[O:13])[C:7](=[CH2:8])[CH:6]2[CH2:9][CH:3]1[CH2:4][CH2:5]2
Reactant: C=C1C2C=CC(C2)C1(C)/C=C/C=O
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: C=C1C2CCC(C2)C1(C)CCC=O
Yield: 85 %

Procedure:
Obtained in 85% yield by hydrogenation of 23 (2.0-mol-equiv. of H2) over Raney-Ni (5% by weight) at 0° in EtOH/H2O 95:5. (90% based on the recovered SM). For analyses, see H. Sonawane, R. Harikisan, N. S. Bellur, J. R. Ahuja, D. J. Kulkarni, J. Org. Chem. 1991, 56, 1434; M. Saito, M. Kawamura, K. Ogasawara, Tetr. Lett. 1995, 36, 9003; D. Solas, J. Wolinsky, J. Org. Chem. 1983, 48, 1988; P. A. Christenson, B. J. Willis, J. Org. Chem. 1979, 44, 2012.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:25])([F:24])[CH2:9][O:10][C:11]1[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=1[O:13][CH2:14][C:15](OCC)=[O:16].S([O-])([O-])(=O)=O.[Na+].[Na+].O>O1CCCC1>[F:7][C:8]([F:24])([F:25])[CH2:9][O:10][C:11]1[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=1[O:13][CH2:14][CH2:15][OH:16]
Reactant: CCOC(=O)COc1ccccc1OCC(F)(F)F
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCCOc1ccccc1OCC(F)(F)F
Yield: 92.9 %

Procedure:
To a suspension of lithium aluminum hydride (79 mg) in dry tetrahydrofuran (1 ml) was added dropwise a solution of ethyl 2-(2,2,2-trifluoroethoxy)phenoxyacetate (270 mg) in dry tetrahydrofuran (3 ml) with stirring under ice cooling, and the mixture was reacted at room temperature for 40 minutes. To the reaction mixture were added anhydrous sodium sulfate and water with stirring. The insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of hexane and ethyl acetate (2/1) as eluent to give 213 mg of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol as an oil.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[Br:16]N1C(=O)CCC1=O.O>CN(C=O)C>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([Br:16])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2ccccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c2ccccc2c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 80.9 %

Procedure:
5.00 g of N-ethylcarbazole was dissolved in 130 ml of dehydrated DMF in a flask whose atmosphere was replaced with argon. This solution was cooled to 0° C., 4.60 g of N-bromosuccinimide was charged as 5 divided fractions for 3 hours. After raising the temperature to room temperature and stirring for 12 hours, the reaction liquid was thrown into iced water and filtrated. The residue was washed with water and methanol, and dried under reduced-pressure to give 6.28 g crude product. It was purified with silica gel column chromatography (eluent: cyclohexane containing 0.1% triethylamine), and 5.68 g of N-ethyl-3-bromo carbazole was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.S(Cl)(Cl)=O.Cl.[NH2:18][C:19]1([C:25]([O:27][CH3:28])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH2:8][C:9]([NH:18][C:19]2([C:25]([O:27][CH3:28])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:11])[CH:7]=1
Reactant: Cc1ccc(Br)cc1CC(=O)O
Reactant: COC(=O)C1(N)CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(NC(=O)Cc2cc(Br)ccc2C)CCCCC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2.06 g (9.00 mmol) of (5-bromo-2-methylphenyl)acetic acid (described in EP 1791816 and WO 2006/29799) were dissolved in 3.7 ml (51.3 mmol) of thionyl chloride. The reaction mixture was stirred at 80° C. for 2 h and then concentrated. The residue was dissolved in 20 ml of dichloromethane. 2.09 g (10.8 mmol) of methyl 1-aminocyclohexanecarboxylate hydrochloride were dissolved in 25 ml of dichloromethane, 55 mg (0.45 mmol) of 4-dimethylaminopyridine and 3.1 ml (22.5 mmol) of triethylamine were added and the mixture was stirred at room temperature for 0.5 h. The solution of the acid chloride was added dropwise, and the mixture was stirred at room temperature for 36 h. The mixture was then diluted with diluted with dichloromethane, washed with water, 1N aqueous hydrogen chloride solution and saturated aqueous sodium bicarbonate solution, dried, filtered and concentrated. This gave 2.80 g (84% of theory) of the title compound.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24](Br)[CH:25](Br)[CH3:26])=[C:20]([F:29])[C:19]=3[F:30])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].O>COC(C)(C)C>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#[C:25][CH3:26])=[C:20]([F:29])[C:19]=3[F:30])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(-c2ccc(-c3ccc(C(Br)C(C)Br)c(F)c3F)cc2)cc1
Solvent: COC(C)(C)C
Solvent: O
Product: CC#Cc1ccc(-c2ccc(-c3ccc(CCCCC)cc3)cc2)c(F)c1F
Yield: 67.9 %

Procedure:
2.5 g of potassium tert.butylate are added to a solution of 4.3 g of crude 1-[4-(4-pentylphenyl)-phenyl]-2,3-difluoro-4-(1,2-dibromopropyl)-benzene in 200 ml of tert.butyl methyl ether and the reaction mixture is heated at reflux temperature for 4.5 hours. Thereafter, it is cooled, treated with 50 ml of water and partitioned between water and diethyl ether. The combined organic phases are dried over anhydrous magnesium sulphate, the solvent is evaporated and the residue is chroma-tograped on silica gel with 5% ethyl acetate in petroleum ether. Filtration over Alox (CAMAG, neutral, activity grade 1) and fractional crystallization from ethyl acetate gives 2.04 g of 1-[4-(4-pentylphenyl)-phenyl]-2,3-difluoro-4-(1-propynyl)-benzene, m.p. (C-SB) 135.7° C.; SB -N 173° C.; cl.p. (N-I) about 210° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:9])=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>O1CCCC1.C1(C)C=CC=CC=1>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8](=[O:9])[CH:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:15][CH:14]=1
Reactant: COc1ccc(C(=O)Cc2ccncc2)cc1
Reactant: COC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)CC(C(=O)c1ccc(OC)cc1)c1ccncc1
Reaction time: 0.5 h

Procedure:
Under an argon, 2-(4-pyridyl)-4′-methoxyacetophenone (J. Am. Chem. Soc., 112, 2163-3168, 1990: Dimitrios Stefanidis and John W. Bunting; 9.6 g, 42.3 mmol) was suspended in tetrahydrofuran (200 ml), and under ice cooling, lithium diisopropylamide (2.0 M solution; 25 ml, 50.0 mmol) was added. At the same temperature, the mixture was stirred for 30 minutes. Methyl bromoacetate (6.0 ml, 63.4 mmol) was then added dropwise, and the mixture was stirred under ice cooling for 1 hour and then at room temperature for 2 hours. The reaction mixture was diluted with toluene. The mixture was washed successively with 2 N hydrochloric acid, water and a brine, and was then dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was separated and purified by chromatography on a silica gel column [silica gel: 100 g, hexane/ethyl acetate (1/2)], whereby the title compound (10.63 g, 84.1%) was obtained as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)cc2)CC1
Reaction time: 3 h
Yield: 98 %

Procedure:
4-(4-Nitro-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (3.6 g) was diluted with ethanol (50 mL) and 10% Pd/C (400 mg) was added. The mixture was placed on a Parr shaker for hydrogenation at 50 psi for 3 hr The mixture was filtered and the solvent was removed to afford 4-(4-amino-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (3.2 g, 99% yield) as amorphous purple semi-solid. ES-MS for C16H25N3O2 calcd. (m/e) 291, observed 292 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH:9]1[CH2:10][CH2:11][C:12]2([F:15])[F:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([OH:19])(=[O:18])[CH3:17]>CC#N>[C:16]([O:19][C@@H:9]1[CH2:10][CH2:11][C:12]([F:15])([F:14])[C@H:13]1[NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)O
Reactant: FC1(F)CCC2C1N2Cc1ccccc1
Solvent: CC#N
Product: CC(=O)O[C@@H]1CCC(F)(F)[C@H]1NCc1ccccc1
Temperature: 80 °C

Procedure:
To a stirred solution of 6-benzyl-2,2-difluoro-6-azabicyclo[3.1.0]hexane (25 mg, 0.11 mmol) in CH3CN (1 mL), acetic acid (1 mL) was added at room temperature. The reaction mixture was heated to 80° C. for 16 h, cooled to room temperature and concentrated in vacuo. Purification of the residue on a silica gel column with 0 to 20% EtOAc/Hexanes afforded trans-2-(benzylamino)-3,3-difluorocyclopentyl acetate. MS ESI calc'd. for C14H17F2NO2 [M+H]+ 270. found 270.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:46]=[CH:45][N:14]3[C:15](=[O:44])[C:16]([C:30]4[N:34]([CH2:35][C:36]5[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=5)[N:33]=[N:32][N:31]=4)=[C:17](OS(C4C=CC(C)=CC=4)(=O)=O)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>O1CCCC1>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:46]=[CH:45][N:14]3[C:15](=[O:44])[C:16]([C:30]4[N:34]([CH2:35][C:36]5[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=5)[N:33]=[N:32][N:31]=4)=[C:17]([N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(Cn2nnnc2-c2c(OS(=O)(=O)c3ccc(C)cc3)nc3cc(CCc4nc(C(C)C)cs4)ccn3c2=O)cc1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: COc1ccc(Cn2nnnc2-c2c(N3CCOCC3)nc3cc(CCc4nc(C(C)C)cs4)ccn3c2=O)cc1
Reaction time: 8 h
Yield: 59 %

Procedure:
The 8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-2-tosyloxy-3-[(4-methoxybenzyl)-tetrazol-5-yl]-4H-pyrido[1,2-a]pyrimidin-4-one (61 mg) obtained in (B) was dissolved in tetrahydrofuran (1 ml), added with morpholine (40 ml) at room temperature, and stirred overnight at the same temperature. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography to obtain the title compound (31 mg, 59%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]2[N:12]3[N:13]=[C:14]([CH3:22])[CH:15]=[C:16]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]3=[N:10][C:9]=2[CH3:23])=[C:5]([Br:7])[N:6]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C([O-])([O-])=O.[Cs+].[Cs+].N>CO.CCOC(C)=O.CCCCCC.C1COCC1>[Br:7][C:5]1[N:6]=[C:2]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[S:3][C:4]=1[C:8]1[N:12]2[N:13]=[C:14]([CH3:22])[CH:15]=[C:16]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]2=[N:10][C:9]=1[CH3:23]
Reactant: C1COCCN1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)nc3Br)c(C)nc12
Agent: N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(N4CCOCC4)nc3Br)c(C)nc12
Temperature: 120 °C
Yield: 71.2 %

Procedure:
100 mg (0.22 mmol) of 3-(2,4-Dibromo-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.22 mmol), 96 mg of morpholine (1.1 mmol) and 215 mg of Cs2CO3 (0.66 mmol) are put in a 4 ml vial with dry THF, and the vial is capped with a Teflon cap. The vial is heated at 120° C. for overnight. The reaction mixture is applied onto a silica-gel chromatography column (Hexane:AcOEt:2 M NH3 in MeOH=9:3:1) to give 72.7 mg of the title compound. Yield 71%. mass spectrum (m/e): 465 (M+1); 1H-NMR (CDCl3): 6.73 (s, 1H), 3.87 (t, 4H, J=5.1 Hz), 3.58 (t, 4H, J=5.1 Hz), 3.35 (m, 1H), 2.57 (s, 3H), 2.53 (s, 3H), 1.86 (m, 4H), 0.90 (t, 6H, J=7.5 Hz).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([CH2:36][C:37](O)=[O:38])=[CH:35][C:30]=2[O:29][CH2:28]1>>[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([CH2:36][C:37]([NH:26][C@H:23]3[CH2:22][CH2:21][C@H:20]([CH2:19][CH2:18][N:15]4[CH2:16][CH2:17][CH:12]([C:11]5[C:6]6[CH2:5][CH2:4][O:3][C:7]=6[CH:8]=[CH:9][CH:10]=5)[CH2:13][CH2:14]4)[CH2:25][CH2:24]3)=[O:38])=[CH:35][C:30]=2[O:29][CH2:28]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Agent: Cl
Product: O=C(Cc1ccc2c(c1)OCO2)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (112 mg, 92%), MS (ISP) m/z=491.3 [(M+H)+], mp 209° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 2-benzo[1,3]dioxol-5-yl-acetic acid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][C@@H:6]1[C:12](=[O:13])[O:11][C:9](=[O:10])[CH2:8][CH2:7]1)=[O:4].[Al+3].[Cl-].[Cl-].[Cl-].Cl.C(O[CH2:25][CH3:26])(=O)C>C1C=CC=CC=1>[C:9]([CH2:8][CH2:7][C@H:6]([NH:5][C:3](=[O:4])[C:2]([F:15])([F:14])[F:1])[C:12]([OH:11])=[O:13])(=[O:10])[C:26]1[CH:25]=[CH:8][CH:7]=[CH:6][CH:12]=1
Reactant: O=C1CC[C@H](NC(=O)C(F)(F)F)C(=O)O1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(CC[C@H](NC(=O)C(F)(F)F)C(=O)O)c1ccccc1
Temperature: 0 °C

Procedure:
Heat at reflux for 3 hours a mixture of N-trifluoroacetyl-L-glutamic anhydride (18.0 g, 80 mmol) and AlCl3 (23.5 g, 177 mmol) in dry benzene (400 ml). Allow to cool, treat with ice (400 ml), conc. HCl (100 ml), and ethyl acetate (EtOAc) (400 ml). Dry the organic layer and concentrate to obtain the title compound as a brown crystalline solid (25 g).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[CH2:15]Br)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([C:25]1([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:18]([C:25]1([OH:31])[CH2:30][CH2:29][N:28]([CH2:15][C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:8][CH:9]=2)=[O:17])[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: O=C(CBr)Nc1ccc(C2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(CN1CCC(O)(Cc2ccccc2)CC1)Nc1ccc(C2CCCCC2)cc1
Reaction time: 1 h

Procedure:
A mixture of N-(4-cyclohexyl-phenyl)-2-bromoacetamide (29.6 mg, 0.10 mmol), 4-benzyl-4-hydroxypiperidine (19.1 mg, 0.10 mmol), and potassium carbonate (13.8 mg, 0.1 mmol) in dimethyl sulfoxide (1.0 mL) was stirred 1 hour. The mixture was filtered through a short pad of Celite in a pasteur pipet TLC Rf 0.21 (silica gel, 50:50 hexane/ethyl acetate), 0.14 (reverse phase, 80:20 methanol/water); HPLC: 5.89 min (C18 Cartridge column (Perkin Elmer/PE Xpress #0258-0164) 20:80 Acetonitrile/water to 95:5 acetonitrile/water); LC-MS: 407 (M+H+). The filtrate was tested directly in the in vitro biological assays.
Reaction SMILES: [H-].[Na+:2].[CH3:3][O:4][CH:5]([O:9][CH3:10])[CH2:6][C:7]#[N:8].[CH:11](OC)=[O:12]>C(OCC)C>[C:7](/[C:6](/[CH:5]([O:9][CH3:10])[O:4][CH3:3])=[CH:11]\[O-:12])#[N:8].[Na+:2]
Reactant: COC=O
Reactant: COC(CC#N)OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: COC(OC)/C(C#N)=C/[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.2 %

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 2.52 g, 63.0 mmol) in diethylether (75 mL) was added 3,3-dimethoxypropanenitrile (6.17 mL, 55.0 mmol) followed by methyl formate (6.74 mL, 110 mmol). The solution was stirred for 3 days at RT. The resulting solid was collected by vacuum filtration and washed with ether to afford sodium (E)-2-cyano-3,3-dimethoxyprop-1-en-1-olate (4.2 g, 25.4 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:20])[CH:18]=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:16])[CH:10]=3.Cl.Cl[CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:20])[CH:18]=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH:10]=3
Reactant: ClCc1cccnc1
Reactant: O=c1ccn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Agent: Cl
Product: O=c1ccn2c3c(cc(OCc4cccnc4)cc13)Sc1ccc(Br)cc1-2
Yield: 72.2 %

Procedure:
According to Example 34, the compound (170 mg) produced in Example 58 was reacted with 3-chloromethylpyridine hydrochloride (155 mg) to obtain the title compound (155 mg; 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][OH:12])=[O:10])[CH:5]=[CH:6][CH:7]=1>C(C(CC)=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:2]([CH2:3][CH3:4])([CH2:7][CH3:6])[O:12][NH:11][C:9]2=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NO)Nc1cccc(Cl)c1
Solvent: CCC(=O)CC
Product: CCC1(CC)ONC(=O)N1c1cccc(Cl)c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
18.7 g. of N-(3-chlorophenyl)-N'-hydroxy-urea are added to 116 g. of diethyl ketone. The reaction is stirred at 90° C. for 1 hour. The reaction mixture is then evaporated to dryness and the residue is recrystallized from a mixture of methanol and water.
Reaction SMILES: [F:1][C:2]1[CH:42]=[CH:41][C:5]([C:6]([NH:8][C@:9]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[C:33]([O:38][CH:39]=[CH2:40])[CH:32]=2)([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[CH:4][C:3]=1[C:43]([F:46])([F:45])[F:44].[Zn](CC)[CH2:48]C.C(I)I>C1(C)C=CC=CC=1>[CH:39]1([O:38][C:33]2[CH:32]=[C:31]([C@@:9]([NH:8][C:6](=[O:7])[C:5]3[CH:41]=[CH:42][C:2]([F:1])=[C:3]([C:43]([F:46])([F:45])[F:44])[CH:4]=3)([C:17]3[CH:22]=[C:21]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:20]=[C:19]([F:30])[CH:18]=3)[CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:36]=[CH:35][C:34]=2[F:37])[CH2:48][CH2:40]1
Reactant: C=COc1cc([C@@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Reactant: CC[Zn]CC
Solvent: ICI
Solvent: Cc1ccccc1
Product: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(OC2CC2)c1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
To a solution of (R)-4-fluoro-N-(1-(4-fluoro-3-(vinyloxy)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide (66 mg, 0.10 mmol) in 0.5 ml toluene was added Et2Zn (1 N, 0.2 ml, 0.2 mmol), followed by CH2I2 (16 ml, 0.2 mmol). The reaction mixture was stirred at 120° C. for 3 h. The reaction mixture was quenched by addition of 1 N HCl and the aqueous layer was extracted with CH2Cl2. The organic layer was washed with sat. NaHCO3 and concentrated under reduced pressure. The resulting residue was purified by ISCO silica gel column using 0 to 50% to EtOAc in hexane as eluting solvents and Prep HPLC (phenomenex AXIA Luna 75×30 mm, 5u column eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) to afford (R)—N-(1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide (Example 305) as white lyophillate (36 mg, 52% yield). LCMS: RT=4.268 min [M+H] 672.3 (4 min Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm. NMR: 400 MHz 1H (CDCl3) ppm 0.45-0.73 (m, 4H), 3.51-3.59 (m, 1H), 3.76 (d, J=13.18 Hz, 1H), 4.22 (d, J=12.74 Hz, 1H), 6.13-6.44 (m, 1H), 6.66-6.76 (m, 3H), 6.97-7.08 (m, 3H), 7.10-7.23 (m, 5H), 7.42-7.50 (m, 1H), 7.95-8.03 (m, 2H).