Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.CCN(CC)CC.[C:20]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)#[CH:21]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:20]#[C:21][C:2]2[C:10]3[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=3)[NH:4][N:3]=2)[CH:23]=1
Reactant: C#Cc1cccnc1
Reactant: O=Cc1ccc2c(I)n[nH]c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=Cc1ccc2c(C#Cc3cccnc3)n[nH]c2c1
Temperature: 100 °C
Yield: 90.6 %

Procedure:
To a solution of 3-iodo-1H-indazole-6-carbaldehyde (136 mg, 0.5 mmol), Pd(PPh3)2Cl2 (14 mg, 0.02 mmol) and CuI (7.6 mg, 0.04 mmol) in DMF (3 mL) was added Et3N (5 mL), followed by 3-ethynylpyridine (77 mg, 0.75 mmol). The resulting mixture was heated at 100° C. (oil temp.) for 45 min. After removal of Et3N, the residue was loaded directly onto a silical gel column. Flash chromatography (eluent: hex to ethyl acetate), followed by trituration with water and suction filtration gave the title compound (112 mg, 91%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 14.16 (s, 1H), 10.16 (s, 1H), 8.90 (s, 1H), 6.64 (d, J=4.0 Hz, 1H), 8.26 (s, 1H), 8.12 (d, J=8.0 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.52 (dd, J=8.0 Hz, J=5.2 Hz, 1H); MS ESI 248.0 [M+H]+, calcd for [C15H9N3O+H]+ 248.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([O:18][C:19]([O:21]C2C=CC=CC=2)=O)[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:33].C(O)(=O)C>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:33][C:19](=[O:21])[O:18][C:9]=2[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCCC(OC(=O)Oc1ccccc1)C(=O)c1ccc(F)cc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)CCCc1oc(=O)[nH]c1-c1ccc(F)cc1

Procedure:
A mixture of ethyl 6-(4-fluorophenyl)-6-oxo-5-phenoxycarbonyloxyhexanoate (18.0 g), ammonium acetate (17.8 g) and acetic acid (100 ml) was stirred with heating under reflux for 2 hours. The reaction mixture was poured into water (500 ml) and extracted with ethyl acetate (200 ml×2), and the extract was washed with water (200 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 4-[4-(4-fluorophenyl)-2-oxo-4-oxazolin-5-yl]butanoate was obtained as an oil (7.67 g, 56%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Br:9]Br.O>ClCCCC>[Br:9][CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: BrBr
Reactant: COC(=O)CC(C)=O
Solvent: O
Solvent: CCCCCl
Product: COC(=O)CC(=O)CBr
Temperature: 0 °C
Reaction time: 8 h
Yield: 110.2 %

Procedure:
22.7 kg of methyl acetoacetate was dissolved in 113.3 kg of 1-chlorobutane and cooled to 0° C. To this mixture was added dropwise 31.4 kg of bromine at 5° C. over 2 hours, and the mixture was thereafter kept at that temperature for 8 hours. The reaction mixture was cooled to −10° C. and added dropwise to 22.7 kg of water at a temperature 10° C. or less in 2 hours, then washed and separated to give an organic layer. The obtained organic layers were concentrated under reduced pressure at a temperature of 40° C. or less to give 42.0 kg of crude methyl 4-bromoacetoacetate. The gas chromatography analysis indicated that the content of methyl 4-bromoacetoacetate in the crude product was 65.3% (27.4 kg, 72% yield), wherein the content of 1-chlorobutane was 19.7%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[F:13][C:14]([F:21])([F:20])[C:15](B(O)O)=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[CH3:12][C:4]1[CH:3]=[C:2]([C:15]([C:14]([F:21])([F:20])[F:13])=[CH2:16])[CH:7]=[C:6]([CH3:8])[C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1cc(Br)cc(C)c1[N+](=O)[O-]
Reactant: C=C(B(O)O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1cc(C)c([N+](=O)[O-])c(C)c1)C(F)(F)F
Temperature: 25 °C
Yield: 105.1 %

Procedure:
5-bromo-1,3-dimethyl-2-nitrobenzene (10.0 g), [1-(trifluoromethyl)vinyl]boronic acid (purity: 60%, 13.4 g) and potassium carbonate (14.4 g) was dissolved in the mixed solvent of THF and water, which was then degassed three times. To the solution was added dichloro bis(triphenylphosphine) palladium (II) (1.5 g), and the mixture was heated to reflux for 3 hours under argon atmosphere. The mixture was cooled to room temperature and then poured into water, which was then extracted twice with ethyl acetate. The organic layer was combined, which was then washed with water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield 1,3-dimethyl-2-nitro-5-[1-(trifluoromethyl)vinyl]benzene (11.2 g). 1H-NMR (CDCl3) δ: 2.34 (6H, s), 5.78-5.80 (1H, m), 6.03-6.04 (1H, m), 7.20 (2H, s).
Reaction SMILES: [K+].COC1C=C(C=CC=1S(O)(=O)=O)C([O-])=O.[Cl:17][S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][C:22]=1[O:30][CH3:31])(=[O:20])=[O:19].[C:32]([NH2:36])([CH3:35])([CH3:34])[CH3:33]>>[CH3:31][O:30][C:22]1[CH:23]=[C:24]([C:25]([NH:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:26])[CH:28]=[CH:29][C:21]=1[S:18]([Cl:17])(=[O:20])=[O:19]
Reactant: CC(C)(C)N
Reactant: COc1cc(C(=O)Cl)ccc1S(=O)(=O)Cl
Agent: COc1cc(C(=O)[O-])ccc1S(=O)(=O)O
Agent: [K+]
Product: COc1cc(C(=O)NC(C)(C)C)ccc1S(=O)(=O)Cl
Yield: 92 %

Procedure:
Reacting the 3-methoxy-4-sulfobenzoic acid mono-potassium salt with an inorganic acid halogenide the 4-chlorosulfonyl-3-methoxybenzoyl chloride is obtained. To our surprise we have found that at lower temperature, in an appropriate solvent the t-butylamine reacts selectively with the aromatic acid chloride. Thus, the desired 2-methoxy-4-(N-t-butylaminocarbonyl)benzenesulfonyl chloride is obtained in 92% yield, with a purity of 96%, so it can be used without further purification for the synthesis of drug substances.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:21]=2)=[O:18])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>N1C=CC=CC=1>[CH2:9]([O:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:21]=2)=[O:18])=[CH:3][C:2]=1[NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(CC(=O)Nc2cccc(C3CCCCC3)c2)ccc1OCc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(CC(=O)Nc2cccc(C3CCCCC3)c2)ccc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
3-Amino-4-benzyloxy-N-(3-cyclohexylphenyl)phenylacetamide (the compound of Example 33) (200 mg) is dissolved in pyridine (5 ml), and thereto is added dropwise methanesulfonyl chloride (111 mg), and the mixture is stirred for 0.5 hour. Water is added to the mixture, and the mixture is extracted with ethyl acetate. The organic layer is dried under sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give 4-benzyloxy-N-(3-cyclohexylphenyl)-3-methanesulfonylaminophenyl-acetamide (200 mg). This product is dissolved in ethanol (10 ml), and thereto is added 10% palladium on carbon (20 mg). The mixture is subjected to catalytic hydrogenation at 25° C. The catalyst is removed by filtration, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 10% chloroform/methanol) to give the desired compound (120 mg).
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)=O.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH:4]1[N:3]=[CH:1][N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: O=CNCc1ccccn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: c1ccn2cncc2c1
Reaction time: 16 h
Yield: 84.6 %

Procedure:
2-Formamidomethylpyridine (39 g., 0.29 mole) was dissolved in 150 ml. of benzene. Phosphorus oxychloride (100 ml.) was added dropwise at such a rate that the reaction began to reflux. By external heating, reflux was maintained for 3.5 hours. After standing approximately 16 hours at room temperature, the reaction was concentrated to an oil. The oil was poured onto approximately 300 g. of ice, the mixture made basic (approximately pH 10) with 10 N sodium hydroxide, and extracted with three 300 ml. portions of methylene chloride. The aqueous was made more basic and extracted with a further three 300 ml. portions of methylene chloride. All of the extracts were combined, back-washed with 75 ml. of water and concentrated to yield crystalline imidazo[3,4-a]pyridine (29 g., Rf 0.25 on thin layer chromatography on silica gel with ethylene acetate/5% acetic acid as eluant).
Reaction SMILES: N1C=CC=CC=1.C(B1OB(C=C)OB([CH:17]=[CH2:18])O1)=C.[CH2:19]([O:26][C:27]1[N:28]=[N:29][C:30](Cl)=[CH:31][C:32]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH2:19]([O:26][C:27]1[N:28]=[N:29][C:30]([CH:17]=[CH2:18])=[CH:31][C:32]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Temperature: 80 °C
Yield: 75.3 %

Procedure:
A vessel containing 2,4,6-triethenyl-1,3,5,2,4,6-trioxatriborinane compound with pyridine (1:1) (1.105 g, 4.59 mmol), 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1, 3 g, 9.18 mmol) and potassium carbonate (3.17 g, 22.95 mmol) was evacuated and flushed with nitrogen. Dioxane (30 ml) and water (3 ml) were added in vacuo and the reaction was degassed before tetrakis(triphenyl-phosphine)palladium(0) (0.530 g, 0.459 mmol) was added. The resulting mixture was then heated at 80° C. for 18 hours and upon cooling, was diluted with ethyl acetate and washed with saturated aqueous sodium carbonate solution. The organics were dried (MgSO4), filtered and solvent removed in vacuo to give a brown oil. This was purified by column chromatography (silica, eluting with 0-30% ethyl acetate in petrol) to afford 3,4-bis(benzyloxy)-6-ethenylpyridazine (1.1 g, 38% yield).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12]>ClCCl>[Br:1][C:15]1[CH:14]=[CH:13][C:11]([NH2:12])=[C:10]([F:9])[CH:16]=1
Reactant: Nc1ccccc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Nc1ccc(Br)cc1F
Temperature: 0 °C
Yield: 105.3 %

Procedure:
N-Bromosuccinimide (160.4 g, 0.90 mol) was added in small portions to a stirred, cooled solution of 2-fluoroaniline (100.0 g, 0.90 mol) in dry dichloromethane (400 ml). The stirred mixture was allowed to warm to 0° C. over 45 min, washed with water and dried (MgSO4). The solvent was removed in vacuo to yield a red solid (180 g) which was steam distilled to give a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH2:18][CH3:19])=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]1[C:24](=O)[C:25](=[O:30])[C:26]=1[O:27]CC)[CH3:21]>C(O)C>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:24]4[C:25](=[O:30])[C:26](=[O:27])[C:23]=4[O:22][CH2:20][CH3:21])=[CH:7][CH:6]=3)=[C:9]([CH2:18][CH3:19])[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: CCc1sc2ncnc(N)c2c1-c1ccc(N)cc1
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2ccc(-c3c(CC)sc4ncnc(N)c34)cc2)c(=O)c1=O
Yield: 55.8 %

Procedure:
A mixture of Example 78A (0.135 g, 0.5 mmol) and 3,4-diethoxy-3-cyclobutene-1,2-dione (0.22 mL, 1.5 mmol) in ethanol (5 mL) was heated at 70-80° C. for 48 hours, then filtered while still hot. The filtrate was concentrated and the resulting residue was washed with hexanes and diethyl ether, and dried to provide 0.11 g of the desired product. MS (ESI(+)) m/e 395 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=O)[CH2:4][CH2:3]1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:26][CH2:25][CH:24]([N:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[CH2:8][N:5]2[CH2:6][CH2:7][C:2]([F:30])([F:1])[CH2:3][CH2:4]2)=[CH:34][CH:33]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(CN2CCC(F)(F)CC2)n3-c2ccc(Cl)cc2)CC1
Yield: 57 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 140, intermediate a)), 4-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown foam (57%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][C@H:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37])[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].Cl>O.CN(C)C(=O)C>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][C@H:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: Cc1ccccc1[C@@H](N)CC(=O)O
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccccc1[C@H](CC(=O)O)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 150 °C
Yield: 90 %

Procedure:
1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.156 mmol) was combined in an oven-dried flask with 3-(S)-amino-3-o-tolyl-propionic acid (84 mg, 0.468 mmol) (commercially available from Combi-Blocks SS-1801) and N,N-dimethylacetamide (1.5 mL) was added with stirring. Solid sodium methoxide (25 mg, 0.468 mmol) was added and the reaction was heated to 150° C. in an oil bath for approximately five hours. The reaction was cooled and the solution diluted with five volumes of water. The solution was acidified to pH 3 with 1M hydrochloric acid to induce precipitation. Filtration of the solid followed by vacuum drying provided the desired product in 90% yield. LC-MS ESI−: 466 (M−1)−.
Reaction SMILES: C([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17](O)=O)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[NH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>ClCCl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[CH2:23]([N:21]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:20])[S:12][CH:13]=1)[CH2:22][CH2:27][CH2:26][CH2:25][CH2:29][CH3:30]
Reactant: Nc1cccnc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)O)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1cccnc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained using {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid synthesized in Example 3 and 3-aminopyridine as starting materials and by an operation similar to that of Example 293-1 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure, azeotroped with diethyl ether, and the precipitated solid was collected by filtration to give the title compound.
Reaction SMILES: [Na].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[C:12](OCC)(=[O:19])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.O>C(O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:12](=[O:19])[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:10]#[N:11])=[CH:5][CH:4]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: CCOC(=O)c1ccncc1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: N#CC(C(=O)c1ccncc1)c1ccc(F)cc1

Procedure:
Sodium (2.48 g) was dissolved in dry ethanol (37 ml) under nitrogen atmosphere. To the solution was added 4-fluorophenylacetonitrile (11.65 g) and ethyl isonicotinate (16.41 ml) and the solution was refluxed for 3 hours. The reaction mixture was cooled and poured into water. The ethanol of the mixture was removed under reduced pressure. The resulting aqueous solution was washed with ether and neutralized with diluted hydrochloric acid. The separated solid was collected, washed with water and dried to give 2-(4-fluorophenyl)-3-oxo-3-(pyridin-4-yl)propanenitrile (16.43 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[CH:13][CH:12]=2)[CH:7]=1)=O)C.[NH3:25]>CCO>[C:21]([Si:18]([CH3:20])([CH3:19])[O:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:7]=[C:6]([C:4]([NH2:25])=[O:3])[O:10][N:9]=2)=[CH:12][CH:13]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CCOC(=O)c1cc(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)no1
Reactant: N
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 35 %

Procedure:
3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-isoxazole-5-carboxylic acid ethyl ester (which may be prepared as described in Preparation of Intermediate 12; 500 mg, 1.4 mmol) was dissolved in a saturated solution of NH3 in EtOH (200 mL). The mixture was stirred at room temperature for 60 h. The solvent was evaporated and the residue was purified by chromatography (50-60% EtOAc/hexanes) to give 3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (160 mg, 35%) as a white solid.
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[Cl:16])[C@@H:12]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C@H:11](O)[CH2:10]2.[CH2:23]([N:25](CC)CC)C.CN>O1CCCC1.C(O)C>[Cl:16][C:15]1[CH:14]=[C:10]2[C:9](=[CH:8][C:7]=1[Cl:6])[C@@H:13]([NH:25][CH3:23])[C@H:12]([N:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1)[CH2:11]2
Reactant: CCN(CC)CC
Reactant: O[C@@H]1Cc2cc(Cl)c(Cl)cc2[C@H]1N1CCCC1
Agent: CN
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CN[C@@H]1c2cc(Cl)c(Cl)cc2C[C@H]1N1CCCC1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
A solution of 17 ml of methane sulfonyl chloride in 3 ml of tetrahydrofuran was added dropwise at -20° C. to a mixture of 5 g of the product of Step E, 40 ml of tetrahydrofuran and 4 ml of triethylamine and after stirring for 15 minutes at -20° C., the temperature was raised to 0° C. and 20 ml of methylamine in ethanol were added. The mixture was stirred for 22 hours and was evaporated to dryness. The residue was diluted with water and after the addition of a few drops of sodium hydroxide solution, the mixture was extracted with ethyl acetate. The organic phase was washed with aqueous sodium chloride solution, dried and evaporated to dryness under reduced pressure to obtain 5.7 g of residue. The latter was chromatographed on silica and eluted with a 8-1-1 ethyl acetate-methanol-triethylamine mixture and after standing at 4° C., 4.91 g of the desired crystalline product melting at ≈55° C. were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[O:30][CH2:31][CH2:32][CH2:33]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CO.C(O)CCC>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH2:33][CH2:32][CH2:31][O:30][C:24]3[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:23]=3[Cl:22])[CH2:11][CH2:10]2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)C2CCNCC2)cc1
Reactant: ClCCCOc1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Solvent: CO
Product: Fc1ccc(C(c2ccc(F)cc2)C2CCN(CCCOc3c(Cl)cccc3Cl)CC2)cc1

Procedure:
A mixture of 4-[bis(4-fluorophenyl)methyl]piperidine (free base 6.90 g, 0.024 mole), 1,3-dichloro-2-(3-chloropropoxy)benzene (5.72 g, 0.024 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated overnight at gentle reflux in 350 m l of 1-butanol containing potassium iodide (0.2 g). The reaction was concentrated to dryness. The residue was partitioned several times between chloroform and water. The chloroform layer was dried, filtered, and solvent removed to give an oil. The oil was placed in the refrigerator overnight in 50 ml of methanol. A white solid was obtained and dried in vacuo overnight at 80° C. A yield of 3.26 g (27.7%) of white, crystalline solid, m.p. 101.5°-103° C., was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:13]([CH2:14][C:15]2[CH:19]=[C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:17][N:16]=2)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[Cl:25][C:22]1[S:21][C:20]([C:18]2[O:17][N:16]=[C:15]([CH2:14][N:13]3[C:8]4=[N:9][CH:10]=[CH:11][CH:12]=[C:7]4[N:6]=[C:5]3[C:3]([OH:4])=[O:2])[CH:19]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1nc2cccnc2n1Cc1cc(-c2ccc(Cl)s2)on1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc2cccnc2n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
175.0 mg (0.46 mmol) 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3H-imidazo[4,5-b]pyridine-2-carboxylic acid methyl ester were added to a solution of 19.6 mg (0.82 mmol) LiOH in 6 mL THF and 2 mL H2O. The reaction mixture was stirred for 2 h at 60° C., cooled to room temperature and acidified (pH=2) by the addition of a half concentrated HCl-solution. The precipitate was filtered off and washed with water to give pure 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3H-imidazo[4,5-b] pyridine-2-carboxylic acid as a brown crystalline solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:2]=1.C([Li])(C)(C)C.[O:20]=[C:21]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:22]1>C1COCC1.CCCCC>[C:10]([O:9][C:8]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][C:4]=1[C:21]1([OH:20])[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:22]1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1cccnc1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnccc1C1(O)CCN(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 25.5 %

Procedure:
To a flame-dried round bottomed flask with thermometer side-arm, equipped with a stir bar, was added tert-butyl pyridin-3-ylcarbamate (1.104 g, 0.005684 mol) in 75 mL THF under inert atmosphere. The solution was cooled to −78° C. and then 1.7 M of tert-butyllithium in pentane (7.4 mL) was added dropwise. The resulting solution was stirred for 2 h at −78° C., followed by the addition of benzyl 3-oxopyrrolidine-1-carboxylate (1.038 g, 0.004736 mol) in 75 mL THF. The reaction was allowed to warm to rt and stirred for 5 hrs. The reaction mixture was quenched with saturated ammonium chloride, diluted with water and extracted with ethyl acetate. The combined organic phases were treated with brine and then magnesium sulfate, filtered, and concentrated. The crude product was purified by combiflash using 50-80% ethyl acetate/hexane to recover the starting material (0.9 g) and then 100% ethyl acetate to obtain the product (0.5 g). The product was verrified by LCMS and NMR data.