Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:15]=[CH:14][C:10]([CH:11]=[N:12][OH:13])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].ClN1C(=O)CCC1=O.[C:26]([O:30][CH2:31][CH3:32])(=[O:29])[C:27]#[CH:28].C(N(CC)CC)C>CN(C=O)C.CCOCC>[CH2:31]([O:30][C:26]([C:27]1[O:13][N:12]=[C:11]([C:10]2[CH:14]=[CH:15][C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:17])[CH3:16])=[CH:8][CH:9]=2)[CH:28]=1)=[O:29])[CH3:32]
Reactant: C#CC(=O)OCC
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=NO)cc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)no1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 2 %

Procedure:
4-(tert-Butyl-dimethyl-silanyloxy)-benzaldehyde oxime (which may be prepared according to the procedure described in Kao, Y. T. R. et al. US 20110212975 page 17; ˜20 g, ˜80 mmol) was dissolved in DMF (50 mL) and the solution was cooled to 0° C. N-Chlorosuccinimide (12.8 g, 96 mmol) was added in portions. The reaction mixture was stirred at 0° C. for 30 min, allowed to warm to room temperature and stirred at room temperature for 1.5 h. The reaction mixture was poured into ice-water (100 mL) and the resulting suspension was extracted with EtOAc (100 mL). The organic extract was dried over Na2SO4, filtered, and evaporated. Et2O (120 mL) was added to the residue, and then a solution of ethyl propiolate (16 mL, 158 mmol) and triethylamine (12 mL) in Et2O (120 mL) was added dropwise. The mixture was stirred at room temperature for 48 h. The reaction mixture was filtered and the filtrate was evaporated to give a brown oil which was purified by filtration through a silica gel plug (eluting with 12% EtOAc/hexanes) followed by silica gel chromatography. Final purification was accomplished using preparatory supercritical fluid chromatography (100 bar CO2 modified with 10% MeOH, flow rate of 2 mL/min at 30° C.) to give 3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-isoxazole-5-carboxylic acid ethyl ester (600 mg, 2%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][C:12]1([CH3:22])[CH2:16][C:15]2=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=[C:14]2[O:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][C:12]1([CH3:22])[CH2:16][C:15]2[C:17]([O:21][C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=3)=[CH:18][CH:19]=[CH:20][C:14]=2[O:13]1
Reactant: CC1(C)Cc2c(O)cccc2O1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(Oc3ccc([N+](=O)[O-])cn3)cccc2O1
Yield: 68.8 %

Procedure:
In a microwave vial, 2-chloro-5-nitropyridine (97 mg, 0.609 mmol) was dissolved in 3 mL of dimethylformamide. 2,2-dimethyl-2,3-dihydro-1-benzofuran-4-ol (100 mg, 0.609 mmol) and potassium carbonate (253 mg, 1.827 mmol) were added. The reaction mixture was heated under microwave irradiation for 1 hour at 110 C. The reaction mixture was filtered. The filtrated solid was washed with dichloromethane (5 ml). The volatiles were evaporated under vacuum. The crude compound was dissolved in dichloromethane (8 ml) and brine was added (8 ml). The compound was extracted 2 times with dichloromethane (2×8 ml) and 2 times with ethylacetate (2×8 ml). Combined organic layers were dried over sodium sulphate and evaporated. The residue was purified by silica gel chromatography (Companion system, 12 g Si cartridge) with cyclohexane/ethyl acetate from 100:0 to 80:20 as eluents affording the title compound (120 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[C:23]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])#[CH:24]>[Cu]I.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.O1CCCC1>[NH2:28][C:27]1[CH:26]=[C:25]([C:23]#[C:24][C:2]2[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[N:6][CH:7]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: C#Cc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)Nc1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cncc(C#Cc2cccc(N)c2)c1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 26.6 %

Procedure:
Into the reaction flask were added tert-butyl (5-bromopyridin-3-yl)carbamate (2.00 g, 7.32 mmol), copper(I) iodide (56 mg, 0.29 mmol), bis(triphenylphosphine)palladium(II) chloride (0.20 g, 0.29 mmol), tetrahydrofuran (20 mL) and triethylamine (1.1 mL, 8.0 mmol). The reaction mixture was stirred under N2 bubbling for 5 min. 3-Ethynylaniline (0.849 g, 7.3 mmol) was then added. The reaction mixture was heated at 50° C. overnight. After removal of the solvent, the residue was treated with EtOAc and water. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude was purified by silica gel column chromatography to give the desired product as a yellow gel (0.60 g, 49%). LCMS for C14H12N3O2 ([M-(tBu)+H]+H)+: m/z=254.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:10][C:11]3[C:12]([N:23]=2)=[N:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=3)[CH:6]=[CH:7][CH:8]=1.[B].C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.Cl.[N:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50]Cl)[CH:45]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH2:50][C:46]3[CH:45]=[N:44][CH:49]=[CH:48][CH:47]=3)[C:11]3[C:12]([N:23]=2)=[N:13][CH:14]=[C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:16]=3)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2nc3ncc(-c4ccccc4)cc3[nH]2)c1
Reactant: ClCc1cccnc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: Cl
Agent: [B]
Solvent: CN(C)C=O
Product: COc1cccc(-c2nc3ncc(-c4ccccc4)cc3n2Cc2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
A mixture of 2-(3-methoxyphenyl)-6-phenyl-1H-imidazo[4,5-b]pyridine (Compound of Example 1) (80 mg), 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine resin (PS-BEMP, 2.2 mmol/g) (326 mg) and N,N-dimethyl formamide (4.5 ml) was shaken at room temperature for 1 hour. To the mixture was added 3-pyridylmethylchloride hydrochloride (52 mg), and the mixture was further shaken at room temperature for 15 hours. Purification was carried out in a manner similar to Example 222 to obtain 2-(3-methoxyphenyl)-6-phenyl-1-(3-pyridylmethyl)-1H-imidazo[4,5-b]pyridine (67 mg, 65%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:16][CH2:17][CH3:18])[C:3]=1[C:19](O)=[O:20].[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[S:24]1[CH:25]=[CH:26][N:27]=[C:23]1[NH:22][C:19]([C:3]1[C:4]([CH2:16][CH2:17][CH3:18])=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([F:15])([F:14])[F:13])=[O:20]
Reactant: CCCc1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)O
Reactant: Nc1nccs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CCCc1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Yield: 31.3 %

Procedure:
Using the procedure of Step F of Example 6, 6.3 g of the acid of Step E and 2.1 g of 2-amino-thiazole were reacted in the presence of dicyclohexylcarbodiimide in dimethylformamide to obtain 2.5 g of N-(2-thiazolyl)-4-hydroxy-2-n-propyl-8-trifluoromethyl-quinoline-3-carboxamide in the form of colorless crystals melting at 222° C after crystallization from acetic acid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([S:19][CH3:20])[C:3]=1[C:21]([C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[CH3:30])=[O:22].C(=O)(O)[O-:32].[Na+].ClC1C=C(C=CC=1)C(OO)=O.[OH2:47]>C1COCC1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([S:19]([CH3:20])(=[O:32])=[O:47])[C:3]=1[C:21]([C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[CH3:30])=[O:22]
Reactant: CSc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C(=O)c1cc(C)ccc1C
Reactant: O=C([O-])O
Reactant: O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C)c(C(=O)c2c(S(C)(=O)=O)nn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2N)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of 200 mg (0.42 mmol) of [5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methylsulfanyl-1H-pyrazol-4-yl]-(2,5-dimethylphenyl)methanone in 10 mL of THF was added 0.176 g (2.10 mmol) of anhydrous sodium bicarbonate followed by a solution of 145 mg (0.42 mmol) of 3-chloroperoxybenzoic acid in 8 mL of THF. After two hours at room temperature, 0.5 g of sodium bicarbonate and an additional 290 mg (0.84 mmol) of 3-chloroperoxybenzoic acid was added. The reaction mixture was heated briefly to 50° C., let cool and stirred overnight at room temperature. The reaction mixture was added to water and the product was extracted into ethyl acetate. The organic extracts were washed with dilute sodium bicarbonate solution and then dried and evaporated. The title compound was crystallized from ether to give 150 mg (70% yield) of colorless crystals, m.p. 193.5-194.5° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][CH2:9][C:10]([C:13]1[CH:17]=[C:16]([NH:18][C:19](=[O:32])[C:20]([CH3:31])([S:22]([CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH3:21])[O:15][N:14]=1)([CH3:12])[CH3:11].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:11][C:10]([C:13]1[CH:17]=[C:16]([NH:18][C:19](=[O:32])[C:20]([CH3:31])([S:22]([CH:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)(=[O:24])=[O:23])[CH3:21])[O:15][N:14]=1)([CH3:12])[CH2:9][O:8][C:1](=[O:3])[CH3:2]
Reactant: CC(C)(CO)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCC(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
Acetic anhydride (24 uL, 0.26 mmol) and a catalytic amount of DMAP are added in sequence to a solution of N-[3-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide (80.0 mg, 0.21 mmol) and pyridine (21 uL, 0.26 mmol) in anhydrous DCM (2.1 mL). The solution is stirred at room temperature until complete consumption of starting material. After removal of the solvent under reduced pressure, the crude is purified by silica gel column chromatography to afford 71 mg of acetic acid 2-methyl-2-{5-[2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionylamino]-isoxazol-3-yl}-propyl ester. Yield: 80%; m/z 417 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]2)=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:26]2)=[N:23][CH:24]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(N)cn2)C1
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Yield: 91.1 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with (R)-tert-butyl 1-(5-aminopyridin-2-yl)piperidin-3-ylcarbamate (439 mg, 1.5 mmol) to afford the desired product (516 mg, 91%) as a yellow solid:: ESI MS m/z 566 [C28H32BrN5O3+H]+.
Reaction SMILES: [CH:1]([N:4]1[CH2:8][C:7]2([CH2:14][O:13][C:12]3[CH:15]=[CH:16][C:17]([N+:19]([O-])=O)=[CH:18][C:11]=3[O:10][CH2:9]2)[O:6][CH:5]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:19][C:17]1[CH:16]=[CH:15][C:12]2[O:13][CH2:14][C:7]3([CH2:9][O:10][C:11]=2[CH:18]=1)[O:6][CH:5]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[N:4]([CH:1]([CH3:2])[CH3:3])[CH2:8]3
Reactant: CC(C)N1CC2(COc3ccc([N+](=O)[O-])cc3OC2)OC1c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)N1CC2(COc3ccc(N)cc3OC2)OC1c1ccccc1

Procedure:
3'-isopropyl-7-nitro-2'-phenyl-3,4-dihydro-2H-1,5-benzodioxepin-3-spiro-5'-oxazolidine (370 mg.; 1 mmole) in ethyl acetate (10 ml.) is hydrogenated at room temperature and pressure in the presence of 5% palladium on charcoal (50 mg.). When 3 moles of hydrogen has been absorbed (73 ml. at 23° C.) the catalyst is filtered off and the filtrate evaporated to a solid foam; yield 340 mg. (100%). Because of the lability of this compound, it is used in the next stage without purification.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:22]=O)[CH:18]=3)[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]1.C(O)C.C([BH3-])#N.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:22][N:24]4[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]4)[CH:18]=3)[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3n2)CC1
Reactant: O=C(O)C1CCNCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CN4CCC(C(=O)O)CC4)ccc3n2)CC1
Temperature: 25 °C

Procedure:
To the solution of 2-(4-tert-butyl-cyclohexyloxy)-quinoline-6-carbaldehyde (350 mg, 1.1 mmol) and piperidine-4-carboxylic acid (145 mg, 1.12 mmol) in ethanol (8 mL, 100 mmol) was heated to reflux for 2 h. The yellow solution was cooled to rt and sodium cyanoborohydride (84.8 mg, 1.35 mmol) was added and was heated to reflux for 1 h. After cooled down to rt, citric acid was added and concentrated down. The solid was suspended in water and filtrate, and the collected solid was washed thoroughly with water. HPLC purification of the solid gives the product. 77 mg, yield: 16%. ESI-MS (M+1)+: 425.00.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[OH:20]>CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[OH:20]
Reactant: COCOc1ccccc1Cc1cccc(OC)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COc1cccc(Cc2ccccc2O)c1O

Procedure:
(2-Methoxymethoxyphenyl)(2-hydroxy-3-methoxyphenyl)methane (3.95 g, 14 mmol) was dissolved in 150 ml of methanol containing 0.026 g of p-toluene sulfonic acid and the mixture was heated at reflux overnight. The volatiles were then removed by evaporation under reduced pressure and the solid that remained was taken up in ether. The ethereal solution was extracted with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The white solid residue was dried to obtain 3.66 g (99 percent of theory) of the title compound. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li]C(C)(C)C.[CH:15]1[C:20]([CH:21]=[O:22])=[CH:19][C:18]2[O:23][CH2:24][O:25][C:17]=2[CH:16]=1>C1COCC1>[S:1]1[C:5]([CH:21]([OH:22])[C:20]2[CH:15]=[CH:16][C:17]3[O:25][CH2:24][O:23][C:18]=3[CH:19]=2)=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: c1ccc2sccc2c1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: OC(c1ccc2c(c1)OCO2)c1cc2ccccc2s1

Procedure:
a-(2-Benzo[b]thienyl)-3,4-(methylenedioxy)benzyl alcohol was prepared by the method of Example 40A using benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 M, 9.7 mmoles, 5.7 ml), piperonal (8.9 mmoles, 1.0 g) and THF (20 ml). Flash chromatography (20% ethyl acetate/hexanes) provided 1.6 g (74%) of a yellow solid.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[CH3:21][C:22]1[CH:23]=[CH:24][C:25]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[C:26]([CH:28]=1)[NH2:27]>CN(C)C1C=CN=CC=1.O>[CH3:21][C:22]1[CH:23]=[CH:24][C:25]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[C:26]([NH:27][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:28]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Cc1ccc(N2CCCCC2)c(N)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(N2CCCCC2)c(NC(=O)c2ccncc2)c1
Reaction time: 19 h
Yield: 28.8 %

Procedure:
Isonicotinoyl chloride hydrochloride (172 mg, 0.966 mmol, commercially available product), triethylamine (340 μl, 2.44 mmol), and a catalytic amount of 4-(dimethylamino) pyridine were sequentially added at room temperature to a dichloromethane (5 ml) solution of 5-methyl-2-(1-piperidinyl)aniline (155 mg, 0.815 mmol), obtained as described in Referential Example 16-2. The resulting mixture was stirred for 19 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10 g, hexane/ethyl acetate=1/1). Thus, N-[5-methyl-2-(1-piperidinyl)phenyl]isonicotinamide (GIF-0342) (69.5 mg, 28.8%) was yielded as a colorless solid.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:25])=[C:7]2[CH2:23][CH2:22][N:21]([CH3:24])[C:8]2=[N:9][C:10]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:3])[CH3:2]>C1C=CC=CC=1.[O-2].[O-2].[O-2].[Ni+3].[Ni+3]>[C:1]([O:4][C:5]1[C:6]([CH3:25])=[C:7]2[CH:23]=[CH:22][N:21]([CH3:24])[C:8]2=[N:9][C:10]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCc1nc2c(c(C)c1OC(C)=O)CCN2C
Agent: [Ni+3]
Agent: [O-2]
Solvent: c1ccccc1
Product: CCCCCCCCCCc1nc2c(ccn2C)c(C)c1OC(C)=O

Procedure:
To a solution containing 51 mg (0.15 mmol) of 2b in 4 mL of benzene was added 42 mg (0.46 mmol) of nickel peroxide. The reaction was stirred at reflux for 18 h. The reaction mixture was filtered through a silica gel plug and washed with three 20-mL portions of benzene, followed by two 20-mL portions of ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under diminished pressure. The residue was purified via flash chromatography on a silica gel column (27×1.7 cm). Step gradient elution with 1:10→1:4 ethyl acetate-hexanes as eluent gave 6-decyl-1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl acetate (2e) as a colorless oil: yield 50 mg (48%); silica gel TLC Rf 0.35 (3:7 ethyl acetate-hexanes); 1H NMR (CDCl3) δ 1.05 (t, 3H, J=7.2 Hz), 1.39-1.52 (m, 14H), 1.76 (quint, 2H, J=8.0 Hz), 2.17 (s, 3H), 2.43 (s, 3H), 2.58 (t, 2H, J=8.0 Hz), 3.41 (s, 3H), 6.27 (d, 1H, J=3.6 Hz), 6.92 (d, 1H, J=3.6 Hz).
Reaction SMILES: CN.O=[C:4]1[CH2:20][CH2:19][C:7]2([CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH2:8]2)[CH2:6][CH2:5]1.[BH3-][C:22]#[N:23].[Na+]>>[CH3:22][NH:23][CH:4]1[CH2:20][CH2:19][C:7]2([CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH2:8]2)[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)C1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Product: CNC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a solution of methylamine (33% [w/w] in EtOH, 7.42 g, 79.0 mmol) was added tert-butyl 8-oxo-2-azaspiro[4.5]decane-2-carboxylate (4 g, 15.80 mmol), the reaction mixture was stirred at rt overnight. To the mixture was added NaBH3CN (2.98 g, 47.4 mmol), and the reaction mixture was stirred at rt for another 2 h and concentrated in vacuo. The residue was diluted with H2O (50 mL) and the resulting mixture was extracted with DCM (80 mL×3). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the product as yellow oil (3.2 g, 75.7%).
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([O:10][CH3:11])[CH:3]=1.C(Cl)Cl.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>O>[CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH:6][C:16](=[O:17])[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1cc(C)c(C)cc1N
Solvent: O
Solvent: ClCCl
Product: COc1cc(C)c(C)cc1NC(=O)Oc1ccccc1
Reaction time: 2 h
Yield: 98 %

Procedure:
To 4,5-dimethyl-2-methoxyaniline(4.50 g, 0.03 mol), methylene chloride(100 ml) was added and phenyl chloroformate(4.80 g, 0.03 mol) was added slowly. The resulting solution was stirred for 2 hrs and thereto water(150 ml) was added, and extracted with methylene chloride and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: CCCCC(CC(=O)c1ccc(OC)nc1)c1ccc(Br)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCC(CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1

Procedure:
In analogy to example 162, step 2, 3-(4-bromo-phenyl)-1-(6-methoxy-pyridin-3-yl)-heptan-1-one was reacted with concentrated aqueous HCl in 1,4-dioxane to give the title compound as a colorless foam, MS (ESI+): m/z=362.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]([NH2:39])([CH2:23][C:24]#[C:25][CH2:26][N:27]3[CH2:32][CH2:31][N:30]([C:33](C(C)(C)C)=[O:34])[CH2:29][CH2:28]3)[C:19]([O:21]C)=[O:20])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C=[O:41].C#C.[C:44](NC(=O)[O-])([CH3:47])([CH3:46])[CH3:45]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([C:18]([NH2:39])([CH2:23][C:24]#[C:25][CH2:26][N:27]3[CH2:32][CH2:31][N:30]([C:33]([O:41][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:34])[CH2:29][CH2:28]3)[C:19]([OH:21])=[O:20])(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: C=O
Reactant: CC(C)(C)NC(=O)[O-]
Reactant: COC(=O)C(N)(CC#CCN1CCN(C(=O)C(C)(C)C)CC1)S(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Agent: C#C
Product: COc1ccc(-c2ccc(S(=O)(=O)C(N)(CC#CCN3CCN(C(=O)OC(C)(C)C)CC3)C(=O)O)cc2)cc1

Procedure:
Methyl 2-{[4′-methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl}-amino-6-(4N-tert-butylcarbonylpiperazin-1N-yl)-hex-4ynoate: N-tert-butoxycarbonyl-1,4-piperazine (8.14 g, 4.37 mmol) is coupled with paraformaldehyde (143 mg, 4.7 mmol wrt. monomer) and free acetylene 38e (1.48 g, 3.97 mmol) as described for compound 31a to give the title compound as a pale yellow syrup which soildified upon standing.