Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[C:17]([O:19][CH3:20])=[O:18])[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7].O[CH:22]1[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:29][C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2>C(O)C.C(O)(=O)C>[CH:24]1[C:23]2[CH:22]([CH:8]([C:6](=[O:7])[C:5]3[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[O:29][C:28]=2[CH:27]=[CH:26][CH:25]=1
Reactant: OC1c2ccccc2Oc2ccccc21
Reactant: CCOC(=O)CC(=O)c1ccc(C(=O)OC)c(OC)c1
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C(=O)c1ccc(C(=O)OC)c(OC)c1)C1c2ccccc2Oc2ccccc21
Temperature: 25 °C

Procedure:
To a stirred solution of ethyl 3-methoxy-4-methoxycarbonylbenzoylacetate (4.1 g, 14.6 mmol) in a mixture of ethanol (30 ml) and acetic acid (30 ml) was added portionwise 9-hydroxyxanthene (3.2 g, 16.1 mmol). After stirring for 2 weeks at room temperature, the solution was concentrated in vacuo, diluted with water and extracted with dichloromethane (2×). The combined extracts were washed with a saturated solution of sodium bicarbonate, water and dried over magnesium sulphate. Filtration and evaporation gave ethyl 2-(9H-xanthen-9-yl)-2-(3-methoxy-4-methoxycarbonyl-benzoyl)acetate as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][N:29]([CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[C:23]([C:22]1[CH:25]=[C:18]([NH:17][C:14]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[CH3:13])=[O:16])[CH:19]=[CH:20][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:28][CH2:27]1)#[N:24]
Reactant: N#Cc1cc(N)ccc1N1CCN(C2CCOCC2)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(F)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCN(C4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Yield: 45.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid (0.6 g) and 5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile (0.8 g), the title compound (0.6 g) was obtained, melting point: 240° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[CH2:4][CH2:5][S:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:27][C:26]([C:28](OC)=[O:29])=[C:25]([N:32]=[CH:33]N(C)C)[CH:24]=2)=[CH:19][CH:18]=1.C1(O)C=CC=CC=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[S:27][C:26]3[C:28](=[O:29])[N:11]([C:10]4[CH:9]=[CH:8][C:7]([S:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:14][CH3:15])=[CH:13][CH:12]=4)[CH:33]=[N:32][C:25]=3[CH:24]=2)=[CH:21][CH:22]=1
Reactant: CCN(CC)CCSc1ccc(N)cc1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Solvent: Oc1ccccc1
Product: CCN(CC)CCSc1ccc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Temperature: 190 °C
Reaction time: 8 h

Procedure:
The mixture of 4-{[2-(diethylamino)ethyl]sulfanyl}aniline (1.0 mmol, 271 mg), amidine (methyl 5-(4-chlorophenyl)-3-{[(dimethylamino)methylidene]amino]2-thiophenecarboxylate, 1.0 mmol, 322 mg, the preparation of which may be found in the Example J13) and phenol (350 mg) was heated to 190° C. for 20 minutes. The mixture was cooled to room temperature and then washed with methanol. The crude solid product was collected by filtration and then was dissolved in minimum amount of dichlomethane. Adding methanol slowly and let sitting overnight, the title compound was precipitated out as white solid (180 mg, 39%). 1H NMR (CDCl3): δ 1.05 (6H, t, J=7.2 Hz), 2.61 (4H, q, J=7.1 Hz), 2.78 (2H, t, J=7.6 Hz), 3.10 (2H, t, J=7.6 Hz), 7.34 (2H, d, J=8.6 Hz), 7.45 (4H, m, overlapping), 7.53 (1H, s), 7.65 (2H, d, J=8.5 Hz), 8.12 (1H, s). LCMS m/z=470 (m+H+).
Reaction SMILES: O=[C:2]1[CH2:11][N:10]2[C@H:12]3[CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][C@H:13]3[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.[CH:23](I)([CH3:25])[CH3:24]>>[CH:23]([N:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C@@H:13]4[CH2:14][NH:15][CH2:16][CH2:17][C@@H:12]4[N:10]([C:9]=23)[CH2:11][CH2:2]1)([CH3:25])[CH3:24]
Reactant: CC(C)I
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Product: CC(C)N1CCN2c3c(cccc31)[C@@H]1CNCC[C@@H]12

Procedure:
Utilizing the material from Example 255 Step A, the title compound was prepared in analogous fashion using isopropyl iodide as the alkyl halide and following the procedure of Step B-D of Example 255, as a viscous brown liquid. 1H NMR (CDCl3, 300 MHz) δ 1.18 (d, 6H), 1.60-1.67 (m, 1H), 1.71-1.94 (m, 2H), 2.63-2.75 (m, 2H), 2.81-2.95 (m, 2H), 2.99-3.20 (m, 2H), 3.30-3.55 (m, 3H), 3.99-4.12 (m, 1H), 6.45 (d, J=7.4 Hz, 2H), 6.65 (t, J=7.3 Hz, 1H) ppm. MS (CI): 258 (M+H+).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH2:14])(=[O:13])=[O:12].[H][H]>[Pd].C(OCC)(=O)C>[F:16][C:2]([F:1])([F:15])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH2:14])(=[O:13])=[O:12]
Reactant: NS(=O)(=O)c1ccccc1C=CC(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccccc1CCC(F)(F)F

Procedure:
A mixture of 50.2 g of 2-(3,3,3-trifluoro-1-propenyl)phenylsulfonamide, 500 ml of ethyl acetate and 5 g of a 5% Pd/C catalyst is shaken for 1/2 hour at 20°-25° C. in a hydrogen atmosphere The catalyst is then filtered off, the mixture is concentrated by evaporation, and the residue is crystallised from a mixture of methylene chloride and ether to thus yield 49.6 g of 2-(3,3,3-trifluoropropyl)phenylsulfonamide, m.p. 148°-149° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][O:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[CH:11]=O)=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:23][O:24][C:25]([CH2:27]P(OC)(OC)=O)=[O:26]>>[CH3:1][C:2]1[O:6][C:5]([CH2:7][O:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[CH:11]=[CH:27][C:25]([O:24][CH3:23])=[O:26])=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1oc(COc2ccccc2C=O)nc1-c1ccccc1
Reactant: COC(=O)CP(=O)(OC)OC
Product: COC(=O)C=Cc1ccccc1OCc1nc(-c2ccccc2)c(C)o1

Procedure:
According to the method described for Reference Example 22, 2-(5-methyl-4-phenyl-2-oxazolylmethoxy)benzaldehyde was allowed to react with trimethyl phosphonoacetate to give methyl 2-(5-methyl-4-phenyl-2-oxazolylmethoxy)cinnamate. Recrystallization from ethyl acetate--chloroform-ether gave colorless prisms, m.p.128°-129° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH2:11](O)[CH3:12]>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][CH3:12])=[O:7])=[CH:4][N:3]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CCO
Product: CCOC(=O)c1ccc(N)nc1

Procedure:
To a suspension of 1.3 g(9.4 mmol) 6-aminonicotinic acid in 100 mL of ethanol, was bubbled in dry hydrochloric acid at 0 C, then the solution was refluxed until all the solids dissolved. The solvents were removed under reduced pressure, the residue dissolved in ethyl acetate, washed with saturated sodium bicarbonate, brine and concentrated to afford 1.37 g of a white solid, m/e=166(M+H).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[NH2:20][C:21]1[S:22][C:23]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26](O)=[O:27])[N:25]=1>>[NH2:20][C:21]1[S:22][C:23]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:27])[N:25]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Reactant: Cc1cccc(-c2sc(N)nc2C(=O)O)c1
Product: Cc1cccc(-c2sc(N)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-Amino-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.24 min; [M+H]+=493.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N+](C1C=C(S(O[CH2:36][C@@H:37]2[CH2:39][O:38]2)(=O)=O)C=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[CH:4][C:5]([O:12][CH2:36][C@@H:37]2[CH2:39][O:38]2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: COC(=O)c1cc(Cl)c(OCc2ccc(OC)cc2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1cc(Cl)c(OCc2ccc(OC)cc2)cc1OC[C@@H]1CO1
Reaction time: 8 h
Yield: 79.7 %

Procedure:
A mixture of methyl 5-chloro-2-hydroxy-4-[(4-methoxybenzyl)oxy]benzoate (1.78 g, 5.5 mmol), (2S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (1.43 g, 5.5 mmol) and cesiumcarbonate (2.15 g, 6.6 mmol) in NMP (15 mL) was stirred at room temperture overnight. Water was added to the mixture and it was then extracted with with ethyl acetate three times. The combined organinc layers was washed with water, dried over sodium sulphate and solvent was removed in vacuo. The residue was purified by silica gel flash chromatography (ethyl acetate/heptane 10-30%), (1.66 g, 79%) of the title compound was obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)/[CH:4]=[CH:5]/[Cl:6].[CH3:8][O:9][C:10]([CH:12]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:11].O>C1(C)C=CC=CC=1>[Cl:6]/[CH:5]=[CH:4]/[C:3]([CH2:2][Cl:1])=[CH:12][C:10]([O:9][CH3:8])=[O:11]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(/C=C/Cl)CCl
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C=C(/C=C/Cl)CCl
Yield: 14.1 %

Procedure:
trans 1,4-Dichlorobut-3-en-2-one(0.56 g, 4.0 mmol) in toluene (10 ml) was stirred with methoxycarbonylmethylenetriphenyl phosphorane (1.32 g, 4.0 mmol) at 90° C. for sixteen hours. Water (50 ml) was added and the mixture extracted with ether (50 ml, 2×25 ml). The extracts were dried (Na2SO4) and evaporated to give the title compound (0.11 g, 14%), spectral details as in Example 11.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.I[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1>O1CCCC1.C(OCC)C.[Cl-].[Zn+2].[Cl-]>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1
Reactant: c1cscn1
Reactant: COC(=O)c1ccc(I)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2nccs2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a −70° C., stirred solution of thiazole (270 μL, 3.8 mmol) in tetrahydrofuran (10 mL) is added n-butyl lithium (2.6 mL of a 1.6 M solution in hexanes, 4.2 mmol). After 30 min, zinc chloride (11.4 mL of a 1.0 M solution in diethyl ether, 11.4 mmol) is added. The reaction mixture is warmed to 0° C. and methyl 4-iodobenzoate (1 g, 3.8 mmol) and palladium(0)tetrakis(triphenylphosphine) (530 mg, 0.4 mmol) are added. The reaction mixture is heated at 70° C. for 20 h under argon, cooled to room temperature, and then partitioned between ethyl acetate and water. The organic layer is washed with water, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (3:1 hexanes/ethyl acetate) yields the title compound. 1H NMR (300 MHz, CDCl3) δ 8.14-8.03 (m, 4H), 7.93-7.92 (m, 1H), 7.42-7.41 (m, 1H), 3.95 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][CH3:12].[C:13](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:13])=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCOc1cc(O)ccc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCCOc1cc(OC)ccc1Br
Yield: 97.1 %

Procedure:
To a solution of 4-bromo-3-propoxy-phenol (500 mg, 2.164 mmol) in acetone (10 mL) were added potassium carbonate (299 mg, 2.164 mmol) and methyl iodide (674 μL, 10.82 mmol). The reaction mixture was heated at gentle reflux for 12 h. The solvent was removed and the residue was taken in diethyl ether (50 mL). The white solid was filtered off, and the filtrated was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 5-10% ethyl acetate in hexanes yielded 1-bromo-4-methoxy-2-propoxy-benzene as a clear oil (515 mg, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][C@@:11]2([C:16]([OH:18])=O)[CH2:15][CH2:14][O:13][CH2:12]2)=[O:9])[CH:5]=[N:6][CH:7]=1.[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[C:36]([F:39])([F:38])[F:37])=[CH:23][CH:22]=1>>[NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH:3]=1)[C:8]([NH:10][C@@:11]1([C:16](=[O:18])[NH:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=3[C:36]([F:37])([F:38])[F:39])=[CH:25][CH:26]=2)[CH2:15][CH2:14][O:13][CH2:12]1)=[O:9]
Reactant: Nc1cncc(C(=O)N[C@@]2(C(=O)O)CCOC2)c1
Reactant: COc1ccc(Nc2ccc(CN)cc2)c(C(F)(F)F)c1
Product: COc1ccc(Nc2ccc(CNC(=O)[C@]3(NC(=O)c4cncc(N)c4)CCOC3)cc2)c(C(F)(F)F)c1
Yield: 32 %

Procedure:
Analogously to Example 1e), (S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid (1.00 mmol) was reacted with (4-aminomethyl-phenyl)-(4-methoxy-2-trifluoromethyl-phenyl)-amine (1.00 mMol, from Example 4b)). The product was obtained in a yield of 32% of theory.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[CH:18])[CH:15]=3)[C:10]([C:19](N(C)C)=O)=[N:9]2)[CH:5]=[CH:4][N:3]=1.[Li+].CC([N-]C(C)C)C.[CH3:32][Si:33]([CH3:47])([CH3:46])[CH2:34][CH2:35][O:36][CH2:37][N:38]1[CH:42]=[CH:41][N:40]=[C:39]1[C:43](=[O:45])[CH3:44]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:43]([C:39]4[N:38]([CH2:37][O:36][CH2:35][CH2:34][Si:33]([CH3:32])([CH3:47])[CH3:46])[CH:42]=[CH:41][N:40]=4)([OH:45])[CH3:44])[CH:15]=3)[C:10]([CH3:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)c1nccn1COCC[Si](C)(C)C
Reactant: C#Cc1ccc2c(C(=O)N(C)C)nn(-c3ccnc(N)n3)c2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3nccn3COCC[Si](C)(C)C)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2-aminopyrimidin-4-yl)-6-ethynyl-N,N-dimethylindazole-3-carboxamide (200 mg, 0.8 mmol) in THF (2 mL) at −78° C. under nitrogen was added 2M LDA in THF (1.40 mL, 2.81 mmol). After 1 hour, 1-(1-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)ethanone (771.45 mg, 3.21 mmol) in THF (1.0 mL) was added. After stirring for 15 minutes, the reaction mixture was allowed to warm to RT and stirred for 2 hr. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (3 mL) and the volatiles were removed in vacuo. The reaction mixture was diluted with DCM (10 ml) and washed with water (2 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Biotage, 1-12% methanol gradient in DCM) to surrender the title compound as a yellow solid: 1H NMR (500 MHz, DMSO) delta −0.19 (9H, s), 0.83-0.77 (2H, m), 2.01 (3H, s), 2.57 (3H, s), 3.59-3.49 (2H, m), 5.62 (1H, d, J=10.3 Hz), 5.78 (1H, d, J=10.2 Hz), 6.42 (1H, s), 6.86 (1H, d, J=1.1 Hz), 6.96 (2H, s), 7.03 (1 H, d, J=5.5 Hz), 7.27 (1H, d, J=1.0 Hz), 7.36 (1H, dd, J=8.1, 1.1 Hz), 7.84 (1H, d, J=8.2 Hz), 8.25 (1H, d, J=5.5 Hz), 8.85 (1H, s); LC-MS: m/z=+490.10 (M+H)+
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].I[C:16]1[N:17]([CH3:21])[CH:18]=[CH:19][N:20]=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[N:17]([CH3:21])[CH:18]=[CH:19][N:20]=1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: Cn1ccnc1I
Product: Cc1onc(-c2ccccc2)c1C#Cc1nccn1C
Yield: 30 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (73 mg, 0.40 mmol) was converted (using 2-iodo-1-methyl-1H-imidazole instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 32 mg, 30%) which was obtained as a light brown solid. MS: m/e=264.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:12]=1)[C:7]([NH2:9])=[O:8])([O-])=O.[H][H]>[Pd].C1COCC1>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:12]=1)[C:7]([NH2:9])=[O:8]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(C(N)=O)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(N)cc(C(N)=O)c1
Reaction time: 4 h
Yield: 90.5 %

Procedure:
A mixture of 4.75 g of 3-nitro-5-(octadecyloxy)benzamide and 1.0 g of 10% palladium on carbon in 750 ml of THF was shaken in a hydrogen atmosphere at room temperature until uptake ceased after 4 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to a solid which was recrystallized from methanol to give 4.0 g (91% yield, mp 139°-143°) of 3-amino-5-(octadecyloxy)benzamide.
Reaction SMILES: [CH3:1][O:2][C:3]([O:6][CH3:7])([CH3:5])[CH3:4].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[I:25][C:26](=[CH2:32])[CH2:27][C@H](O)CO>ClCCl>[I:25][C:26](=[CH2:27])[CH2:32][C@H:1]1[CH2:7][O:6][C:3]([CH3:5])([CH3:4])[O:2]1
Reactant: C=C(I)C[C@H](O)CO
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C=C(I)C[C@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,2-Dimethoxypropane and pyridinium p-toluenesulfonate (PPTS) are added to a solution of (S)-4-iodopent-4-ene-1,2-diol in dichloromethane and the mixture stirred at room temperature for 2 hours. Solvents are removed under reduced pressure and the crude product purified by flash chromatography using ethyl acetate/hexane (1:10) eluant.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:11][C:12]1[CH:13]=[C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH:15]=[CH:16][C:17]=1B1OC(C)(C)C(C)(C)O1>>[F:11][C:12]1[CH:13]=[C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][C:34]2[N:35]=[CH:36][CH:37]=[CH:38][N:39]=2)[CH:15]=[CH:16][C:17]=1[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]cnc2c1
Reactant: CC1(C)OB(c2ccc(-c3ccccc3Oc3ncccn3)cc2F)OC1(C)C
Product: Fc1cc(-c2ccccc2Oc2ncccn2)ccc1-c1cnc2[nH]cnc2c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 6-bromo-3H-imidazo[4,5-b]pyridine and 2-((3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-yl)oxy)pyrimidine. MS (ESI): mass calcd. for C22H14FN5O, 383.12; m/z found, 384.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.55-8.52 (m, 1H), 8.51-8.47 (d, J=4.9, 2H), 8.43 (s, 1H), 8.19-8.14 (t, J=1.7, 1H), 7.59-7.55 (dd, J=7.7, 1.8, 1H), 7.55-7.47 (m, 2H), 7.46-7.40 (m, 2H), 7.39-7.33 (dd, J=11.9, 1.7, 1H), 7.30-7.25 (dd, J=8.0, 1.2, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([NH:18][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1Nc1cccc(Cl)c1
Temperature: 140 °C
Yield: 22.2 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (317 mg, 2.0 mmol), 3-chlorophenylamine (0.212 mL, 2.0 mmol) and potassium carbonate (829 mg, 6.0 mmol) in DMF (3 mL) was heated at 140° C. for 30 min using microwave irradiation. After cooling to RT, the reaction mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic fractions were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting brown oil (370 mg) was purified by column chromatography (Si—PCC, gradient 0-100% DCM in cyclohexane) to afford the title compound as a red solid (111 mg, 22%). LCMS (Method B): RT 3.95 min [M+H]+ 250.0.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.[F:17][C:18]([F:42])([F:41])[CH2:19][NH:20][C:21]([C:23]1([CH2:36][CH2:37][CH2:38][CH2:39]Br)[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22]>>[F:17][C:18]([F:41])([F:42])[CH2:19][NH:20][C:21]([C:23]1([CH2:36][CH2:37][CH2:38][CH2:39][N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][N:7]=3)[CH2:14][CH2:13]2)[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc(C(F)(F)F)cn3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-(5-trifluoromethyl-pyridin-2-yl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][C:13](=O)[CH2:14][O:15][CH2:16][CH3:17])=[C:10]([NH:19][CH2:20][CH2:21][CH2:22][C:23]#[CH:24])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[Cl:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:14][O:15][CH2:16][CH3:17])[N:19]([CH2:20][CH2:21][CH2:22][C:23]#[CH:24])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: C#CCCCNc1c(NC(=O)COCC)c(Cl)nc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C#CCCCn1c(COCC)nc2c(Cl)nc3ccccc3c21

Procedure:
A solution of N-[2-chloro-4-(pent-4-ynylamino)quinolin-3-yl]-2-ethoxyacetamide (10.23 g, 29.58 mmol) and 6 M aqueous potassium carbonate (7.40 mL, 44.4 mmol) in 9:1 ethanol/water (100 mL) was heated at 50° C. for 16 hours. The volatiles were removed under reduced pressure and the resulting slurry was partitioned between ethyl acetate and water. The organic phase was washed with water (2×) and brine (2×), dried over magnesium sulfate, filtered, and concentrated to afford 4-chloro-2-(ethoxymethyl)-1-pent-4-ynyl-1H-imidazo[4,5-c]quinoline as a slightly impure tan solid (9.5 g).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8](=[O:28])[C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([CH3:27])=[CH:19]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[BH3-]C#N.[Na+]>C(O)(C(F)(F)F)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:28])[C:9]2[CH:10]=[CH:11][C:12]([S:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]([CH3:27])[CH2:19]3)(=[O:16])=[O:17])=[CH:13][CH:14]=2)=[CH:29][CH:30]=1
Reactant: Cc1cn(S(=O)(=O)c2ccc(C(=O)NCc3ccc(F)cc3)cc2)c2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC1CN(S(=O)(=O)c2ccc(C(=O)NCc3ccc(F)cc3)cc2)c2ccccc21
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 70.7 %

Procedure:
Add N-(4-Fluoro-benzyl)-4-(3-methyl-indole-1-sulfonyl)-benzamide (0.106 g, 0.25 mmol) portionwise to a stirring mixture of NaCNBH3 (0.074 g, 1.2 mmol) in TFA (5.0 mL) at 0 to 5° C. under N2. Stir the mixture for 15 minutes at 0-5° C., allow to war to ambient temperature and stir for 1 h. add NaCNBH3 (0.074 g, 1.2 mmol) and stir the reaction is for 2 h dilute with H2O (13.0 mL) and work up as described in the above example. Chromatograph and elute with EtOAc-hexane (0-50%) to give 0.075 g of the title compound: Mass spectrum (m/e) (M+H) 425.1335; found 425.1341.