Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]1[CH:17]2[CH2:18][C:19]3([NH2:22])[CH2:21][CH:15]([CH2:16]2)[CH2:14][CH:13]1[CH2:20]3>C1(C)C=CC=CC=1>[C:19]12([NH:22][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:1]([OH:6])=[O:11])[CH2:20][CH:13]3[CH2:14][CH:15]([CH2:16][CH:17]([CH2:12]3)[CH2:18]1)[CH2:21]2
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccc1C(=O)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.3 %

Procedure:
A mixture of 25 g (0.17 mole) of phthalic anhydride and 100 ml of toluene was prepared. To this mixture was added a solution of approximately 25.5 g (0.17 mole) of adamantamine in 100 ml of toluene. The resulting mixture was stirred at room temperature for 15 hours. The solid was collected by vacuum filtration and dried in a vacuum oven at room temperature to yield approximately 49 g of N-adamantylphthalamic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[C:9]2[CH3:23])=[CH:4][C:3]=1[Cl:24].[O:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1>>[Cl:24][C:3]1[CH:4]=[C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[C:9]2[CH3:23])[CH:6]=[CH:7][C:2]=1[C:27]1[CH:28]=[CH:29][O:25][CH:26]=1
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(Br)c(Cl)c1
Reactant: OB(O)c1ccoc1
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(-c2ccoc2)c(Cl)c1

Procedure:
The title compound was prepared according to the procedure of Example 35 using 1-(4-bromo-3-chlorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole instead of 1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole and 3-furanboronic acid instead of 2-furanboronic acid in step 4.
Reaction SMILES: [H-].[Na+:2].CS(C)=O.[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][C:13]([OH:15])=[O:14]>COCCOC>[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][C:13]([O-:15])=[O:14].[Na+:2]
Reactant: O=C(O)Cc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CS(C)=O
Product: O=C([O-])Cc1cccs1

Procedure:
To a suspension of 1.9 g. of sodium hydride (63% content) in 60 ml. of a mixture of dimethyl sulphoxide and 1,2-dimethoxyethane (2:1), there were added dropwise 3.7 ml. of thiolacetic acid at 0° C. with stirring under an atmosphere of nitrogen to give a sodium thiolacetate solution. To the reaction solution thus obtained, there was added a solution of 8.4 g. of methyl 9α,11α-bis-(p-toluenesulphonyloxy)-15α-(2-tetrahydropyranyloxy)-prosta-cis-5,trans-13-dienoate (prepared as described in Reference Example 5) in 30 ml. of a mixture of dimethyl sulphoxide and 1,2-dimethoxyethane (2:1) at 0° C., and the reaction mixture was stirred for 20 hours at room temperature. The reaction mixture was then poured into 500 ml. of ice-water, extracted with ethyl acetate, and the extract washed with an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel, first using a mixture of benzene and ethyl acetate (20:1) as eluent to give 5 g. of the title compound contaminated with by-products, and then by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (5:1) as eluent to give 2.35 g. of the title compound having the following physical characteristics:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[C:8](=O)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].[Br-].[CH3:22][O:23][C:24]([CH2:26][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:25].[H-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2/[C:8](=[CH:26]/[C:24]([O:23][CH3:22])=[O:25])/[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: COC(=O)c1nc2c(s1)C(=O)COc1ccc(Br)cc1-2
Reactant: COC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C1\COc2ccc(Br)cc2-c2nc(C(=O)OC)sc21
Temperature: 70 °C
Yield: 43.5 %

Procedure:
To a stirred solution of 9-Bromo-4-oxo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (100 mg, 0.28 mmol) in THF (7 mL), was added Methoxycarbonylmethyl(triphenyl)phosphonium Bromide (120 mg, 0.28 mmol), NaH (6.8 mg, 0.28 mmol). The reaction mixture was heated to 70° C. overnight. The mixture was cooled to room temperature and partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated in vacuo, and purified by flash column chromatography to afford 9-Bromo-4-[1-methoxycarbonyl-meth-(E)-ylidene]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (50 mg, 43%) as a light yellow solid. LC-MS (ESI & APCI): 412.3 (M+2).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=3)[C:16]=2[O:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:30][CH:29]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:46]>CN(C)C=O>[C:1]([N:5]([CH3:46])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=3)[C:16]=2[O:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]3[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]3)=[CH:30][CH:29]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(=O)(=O)NC(C)(C)C)cc3)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(=O)(=O)N(C)C(C)(C)C)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 599.8 %

Procedure:
To a stirring room temperature solution of the product of Example 62 (79 mg, 0.013 mmol) in dimethylformamide (5 mL) add 60% sodium hydride (6 mg, 0.15 mmol). Stir this mixture at ambient temperature for 10 minutes and then add iodomethane (0.014 mL, 0.15 mmol). Stir the reaction for 30 minutes at ambient temperature then quench it with brine. Extract the resulting aqueous mixture into ethyl acetate. Wash the combined extracts with brine; dry (sodium sulfate) and concentrate them in vacuo. Purify the resulting material on a Chromatotron (silica gel; 3%-10% MeOH gradient in CH2Cl2) to obtain 47 mg of the title compound (68%). MS (IS+) m/e 603 (M+1).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:32]=[CH:33][CH:34]=1)[CH2:10][N:11]1[CH2:31][CH2:30][C:14]2([O:19][CH2:18][CH2:17][N:16]([C:20]([C:22]3[N:23]=[C:24]([CH:27]([CH3:29])[CH3:28])[S:25][CH:26]=3)=[O:21])[CH2:15]2)[CH2:13][CH2:12]1)C.O>C(O)(=O)C>[CH:27]([C:24]1[S:25][CH:26]=[C:22]([C:20]([N:16]2[CH2:15][C:14]3([CH2:13][CH2:12][N:11]([CH2:10][C:9]4[CH:8]=[C:7]([CH:34]=[CH:33][CH:32]=4)[O:6][CH2:5][CH:4]=[O:3])[CH2:31][CH2:30]3)[O:19][CH2:18][CH2:17]2)=[O:21])[N:23]=1)([CH3:29])[CH3:28]
Reactant: CCOC(COc1cccc(CN2CCC3(CC2)CN(C(=O)c2csc(C(C)C)n2)CCO3)c1)OCC
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(OCC=O)c4)CC3)C2)cs1
Temperature: 65 °C

Procedure:
A solution of (9-(3-(2,2-diethoxyethoxy)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 64, step a) (0.36 g) in acetic acid (20 mL) was treated with water (20 mL) and the reaction mixture then heated at 65° C. for 18 hours under nitrogen. The solvents were evaporated under reduced pressure and the residue was azeotroped with toluene to afford the subtitled compound. Yield 0.31 g. Used directly.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[N:15]=[C:14]([CH3:16])[C:13]([CH3:17])=[N:12][C:11]=1[CH3:18].[CH2:19]([C:25](=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:26]=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O1CCCC1>[CH2:19]([C:25](=[CH:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH:26]([OH:27])[CH2:18][C:11]1[C:10]([CH3:9])=[N:15][C:14]([CH3:16])=[C:13]([CH3:17])[N:12]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: Cc1nc(C)c(C)nc1C
Reactant: CCCCCCC(C=O)=Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCC(=Cc1ccccc1)C(O)Cc1nc(C)c(C)nc1C
Temperature: 25 °C
Yield: 113.5 %

Procedure:
To a solution of lithium diisopropylamide (1.5 Molar, 73.3 mL, 0.11 mole) in 150 mL of tetrahydrofuran at -78° C. is added slowly a solution of tetramethylpyrazine (13.6 g, 0.1 mole) in 100 mL of tetrahydrofuran. The mixture is allowed to warm to room temperature and then cooled to -78° C. A solution of α-hexylcinnamaldehyde (23.7 g, 0.11 mole) in 100 mL of tetrahydrofuran is added dropwise over 15 minutes. The solution is allowed to warm to room temperature, and then poured into an ice/dilute hydrochloric acid mixture. The organic layer is separated and washed with saturated solutions of sodium bicarbonate and sodium chloride. The solution is dried over anhydrous magnesium sulfate. After filtration of drying agent and evaporation of solvent, a yield of 40 g of crude material is obtained. A volatile fraction in the crude material is removed by distillation at below 85° C. under 0.15 torr of mercury. The residue is crystallized from a mixture of ethyl acetate-hexane. The product is obtained as a fine needle, M.P. 61°-62° C. Yield 26 g (70%). NMR and IR confirm the structure.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+].[C:14](OC(=O)C)(=[O:16])[CH3:15].Cl>C(OCC)(=O)C>[C:14]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ccc(C(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(=O)NCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(aminomethyl)benzoic acid (20.46 g) in ethyl acetate (100 ml) was added an aqueous solution (100 ml) of sodium hydroxide (12 g) and acetic anhydride (14 ml) was further added at 5-7° C. The reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was made acidic with 10% hydrochloric acid and extracted with ethyl acetate:ethanol (10:1). The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a pale-yellow solid (27.2 g). The obtained solid was crystallized from ethyl acetate:ethanol (1:1, 500 ml) to give the title compound (16.7 g) as white crystals, m.p.=200-202° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH3:18][S:19](Cl)(=[O:21])=[O:20].O>C(Cl)Cl>[CH3:18][S:19]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:21])=[O:20]
Reactant: CCOC(=O)COc1cccc(CCCO)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)COc1cccc(CCCOS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl [3-(3-hydroxypropyl)phenoxy]acetate (107.4 g) in DCM (1.07 L) was added TEA (113 mL) at ambient temperature. Methanesulfonyl chloride (45.4 mL) was added dropwise to the mixture at 0° C. The mixture was stirred for 1 hour at ambient temperature and water (1 L) was added to the mixture at the same temperature. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo to afford ethyl (3-{3-[(methylsulfonyl)oxy]propyl}phenoxy)acetate (155.5 g) as a yellow oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][CH2:30][CH2:31][N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:25][CH:26]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc(O)cc4)nc23)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc(OCCN5CCOCC5)cc4)nc23)cc1
Temperature: 70 °C

Procedure:
To a suspension of [8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-methoxy-phenyl)-amine (150.0 mg, 0.3803 mmol) in dichloromethane (10 mL, was added dropwise 1.0 M of boron tribromide in dichloromethane (1.2 mL, 1.2 mmol). The mixture was stirred for 1 hour at room temperature then methanol (5 mL) was added slowly. The mixture was evaporated to dryness. Additional methanol (10 mL) was added and the mixture was evaporated to dryness. The brown solid was suspended in saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to a solid. 4-[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenol was isolated without further purification as a light brown solid (0.115 g, 80%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.47 (dd, J=6.7, 0.9 Hz, 1H), 8.22 (d, J=8.4 Hz, 2H), 8.08 (d, J=8.5 Hz, 2H), 7.64 (dd, J=7.4, 0.8 Hz, 1H), 7.44 (d, J=8.7 Hz, 2H), 7.00 (dd, J=7.1, 7.1 Hz, 1H), 6.84 (d, J=8.6 Hz, 2H), 6.73 (s, 1H), 4.72 (br s, 1H), 3.09 (s, 3H). MS=381 (MH)+. 26b) A suspension of 4-[8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenol (50.0 mg, 0.131 mmol), 4-(2-chloroethyl)-morpholine hydrochloride (27.0 mg, 0.145 mmol) and potassium carbonate (36.0 mg, 0.260 mmol) in acetonitrile (1 mL) was heated at 70° C. for 18 hours. The mixture was cooled to room temperature, diluted with acetonitrile (10 mL), filtered through a plug of diatomaceous earth and evaporated to an orange resin. The residue was purified via chromatography utilizing an ISCO automated purification apparatus with silica gel column (12 g) and 0%→10% methanol:dichloromethane solvent gradient. The title compound, [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-amine, was isolated as a yellow foam (0.047 g, 72%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.47 (d, J=6.5 Hz, 1H), 8.23 (d, J=8.4 Hz, 2H), 8.07 (d, J=8.3 Hz, 2H), 7.64 (d, J=7.4 Hz, 1H), 7.51-7.46 (m, 2H), 7.00 (t, J=7.0 Hz, 1H), 6.96-6.90 (m, 2H), 6.73 (s, 1H), 4.12 (t, J=5.8 Hz, 2H), 3.77-3.72 (m, 4H), 3.10 (s, 3H), 2.80 (t, J=5.6 Hz, 2H), 2.62-2.55 (m, 4H). MS=494 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.Cl.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH2:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH:31][C:10](=[O:12])[C:9]1[CH:8]=[CH:7][C:6]([O:5][C:4]2[CH:15]=[CH:16][CH:17]=[C:2]([F:1])[CH:3]=2)=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccc(Oc2cccc(F)c2)cc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Oc2cccc(F)c2)cc1
Yield: 20.5 %

Procedure:
A solution of 4-(3-fluorophenoxy)benzoic acid (0.180 g, 0.775 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.180 g; 0.775 mmol), HATU (0.324 g; 0.852 mmol) and N,N-diisopropylethylamine (0.334 mL; 1.94 mmol) in DMF (5 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 2 to 20% ethyl acetate in dichloromethane and 20 to 100% ethyl acetate in heptane) to yield 0.065 g (20%) of the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Br[C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=1>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: FC(F)(F)c1ccnc(Br)c1
Product: Cc1onc(-c2ccccc2)c1C#Cc1cc(C(F)(F)F)ccn1
Yield: 76 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-bromo-4-(trifluoromethyl)pyridine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 124 mg, 76%) which was obtained as an off-white solid. MS: m/e=329.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]([C:12](=[NH:21])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[CH:23](=[C:25]([C:30](OC)=[O:31])[C:26]([O:28][CH3:29])=[O:27])[CH3:24]>CO>[CH3:29][O:28][C:26]([CH:25]1[C:30](=[O:31])[N:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:12]([CH:8]([NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:22])[CH:9]([CH3:11])[CH3:10])=[N:21][CH:23]1[CH3:24])=[O:27]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=N)NCc1ccccc1
Reactant: CC=C(C(=O)OC)C(=O)OC
Solvent: CO
Product: COC(=O)C1C(=O)N(Cc2ccccc2)C(C(NC(=O)OC(C)(C)C)C(C)C)=NC1C
Temperature: 110 °C
Reaction time: 5 h
Yield: 64.2 %

Procedure:
To a solution of [(R)-1-(N-Benzyl-carbamimidoyl)-2-methyl-propyl]-carbamic acid t-butyl ester (7.08 g, 23 mMol) in MeOH (15 mL) was added Dimethyl ethylidenemalonate (3.64 g, 23 mMol). The reaction was slowly heated to 110° C. allowing the MeOH to distill off. The reaction was stirred for 5 h at 110° C. then allowed to cool to RT. Purification by flash chromatography (25% EtOAc, hexane) gave the title compound (6.37 g, 64%) as an oil: ˜(3:1) mixture of diastereomers by LCMS; MS (ES) m/e 432.2 and 432.4 (M+H)+.
Reaction SMILES: [Ti](Cl)(Cl)(Cl)[Cl:2].C1(C)C=CC=CC=1.[Cl-:13].[C:14]1([N:20]2[CH2:28][CH2:27][N:26]([Ti+3:29])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Cl-]>C(OCC)C>[Cl-:2].[Cl-:13].[C:14]1([N:20]2[CH2:28][CH2:27][N:26]([Ti+2:29])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cl[Ti](Cl)(Cl)Cl
Reactant: [Ti+3]N1CCNCCN(c2ccccc2)CC1
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: [Ti+2]N1CCNCCN(c2ccccc2)CC1
Temperature: 40 °C

Procedure:
Separately, 0.647 g (3.41 millimoles) of titanium tetrachloride was dissolved in 20 milliliters of diethyl ether at −50° C. The resulting solution was dropwise added at −60° C. over 2 hours to the toluene mixed solution prepared previously, and the resulting mixture was then heated to 40° C. and then subjected to reaction for a further 6 hours. Subsequently, the reaction mixture obtained was subjected to recrystallization from a hexane/methylene chloride mixed solvent to isolate the product, thereby obtaining N-phenyl-1,4,7-triazacyclononanyltitanium chloride in a yield of 35%.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[C:13]([O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15]2)C1C=CC=CC=1>C(O)C.[Pd]>[ClH:1].[OH:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[C:13]([O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15]2
Reactant: CCOC(=O)c1cc2cccc(OCc3ccccc3)c2cc1OCCN1CCCCC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc2cccc(O)c2cc1OCCN1CCCCC1
Yield: 61 %

Procedure:
A solution of 8.8 g (0.019 mole) of ethyl 5-benzyloxy-3-(2-piperidinoethoxy)-2-naphthoate hydrochloride in 240 cc ethanol was treated with 1.0 g of 10 percent palladium on carbon and hydrogenated at room temperature. The reaction mixture was filtered and the solvent removed in vacuo. The residue, weighing 7.5 g on recrystallization from acetonitrile furnished ethyl 5-hydroxy-3-(2-piperidinoethoxy)-2-naphthoate-hydrochloride, m.p. 153°-6° C. in 61 percent yield (4.4 g).
Reaction SMILES: [Cl-].[NH4+].O.[CH:4]1([O:10][C:11]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:12]=2[C:13]#[N:14])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>[Fe].C(O)C>[NH2:19][C:16]1[CH:17]=[CH:18][C:11]([O:10][CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)=[C:12]([CH:15]=1)[C:13]#[N:14]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1OC1CCCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: N#Cc1cc(N)ccc1OC1CCCCC1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
Subsequently, ammonium chloride (1.8 g) and iron powder (9.2 g) were added to a mixed solvent of water (32 ml) and ethanol (130 ml), and the mixture was heated to 65° C. Then, ethanol solution (4 ml) containing 2-cyclohexyloxy-5-nitrobenzonitrile (11.6 g) was added dropwise over 20 min and the mixture was stirred at a refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of diisopropyl ether-n-hexane to give the title compound (9.5 g), melting point: 59° C.
Reaction SMILES: [Br-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].[NH2-].[Na+].O=[C:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH2:43][CH:42]([CH2:44][O:45][CH3:46])[O:41][C:40]3=[O:47])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1.O>O1CCCC1>[CH3:46][O:45][CH2:44][CH:42]1[O:41][C:40](=[O:47])[N:39]([C:36]2[CH:37]=[CH:38][C:33]([CH:30]3[CH2:31][CH2:32][C:27](=[C:2]([CH3:4])[CH3:3])[CH2:28][CH2:29]3)=[CH:34][CH:35]=2)[CH2:43]1
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COCC1CN(c2ccc(C3CCC(=O)CC3)cc2)C(=O)O1
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCC1CN(c2ccc(C3CCC(=C(C)C)CC3)cc2)C(=O)O1

Procedure:
1.60 g (3.3 mmol) of isopropyl-triphenylphosphonium bromide/sodium amide mixture in 30 ml of tetrahydrofuran were stirred at room temperature for 1 hour. Then, a solution of 1.0 g (3.3 mmol) of (RS)-3-[4-(4-oxo-cyclohexyl)-phenyl]-5-methoxymethyl-oxazolidin-2-one in 25 ml of tetrahydrofuran was added dropwise. After boiling at reflux over the weekend the mixture was poured into 100 ml of water and extracted three times with 50 ml of dichloromethane each time. After chromatography over silica gel with ethyl acetate/hexane 1:2 and recrystallization from n-hexane 120 mg (11%) were obtained as white crystals with m.p. 89°-91°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([OH:16])=O)[O:11][N:10]=2)=[C:5]([F:17])[CH:4]=1)#[N:2].[CH:18]1([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[O:32][N:31]=[C:30]([CH:33]([CH3:35])[CH3:34])[N:29]=3)[CH2:24][CH2:23]2)[CH2:20][CH2:19]1>>[CH:18]1([N:21]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[O:32][N:31]=[C:30]([CH:33]([CH3:35])[CH3:34])[N:29]=3)[CH2:24][CH2:23]2)[C:14]([C:12]2[O:11][N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[F:17])[CH:13]=2)=[O:16])[CH2:19][CH2:20]1
Reactant: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1
Reactant: N#Cc1ccc(-c2cc(C(=O)O)on2)c(F)c1
Product: CC(C)c1noc(N2CCC(N(C(=O)c3cc(-c4ccc(C#N)cc4F)no3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from 3-(4-cyano-2-fluoro-phenyl)-isoxazole-5-carboxylic acid and cyclopropyl-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine following a procedure analogous to that described in Example 18. LC (method 18): tR=1.23 min; Mass spectrum (ESI+): m/z=465 [M+H]+.