Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][O:9][CH:10]=2)[N:3]=[CH:2]1.[CH3:17][C:18]([C:20]1[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=1)=[O:19].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[C:11]1([C:7]2[C:6]([C:4]3[N:3]=[CH:2][N:1]([C:23]4[CH:24]=[CH:25][C:20]([C:18](=[O:19])[CH3:17])=[CH:21][CH:22]=4)[CH:5]=3)=[CH:10][O:9][N:8]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: c1ccc(-c2nocc2-c2c[nH]cn2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-n2cnc(-c3conc3-c3ccccc3)c2)cc1
Temperature: 120 °C
Yield: 21.9 %

Procedure:
To a solution of 4-(1H-imidazol-4-yl)-3-phenyl-isoxazole (106 mg, 0.5 mmol) in DMF (2.5 mL) was added 4-fluoroacetophenone (61 mL, 0.5 mmol) and potassium carbonate (138 mg, 1.0 mmol) and the resulting mixture heated at 120° C. overnight. The resulting mixture was then poured into HCl (1 N, 200 mL) and extracted with ethyl acetate which was then washed with brine, dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 0:100) afforded the title compound (36 mg, 22%) which was obtained as a light yellow solid. MS: m/e=330.1 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:12][C:13]([CH:15]1[N:20]2[C:21](=[O:40])[CH:22]([NH:27][C:28]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)=[O:29])[CH2:23][CH:24]=[CH:25][CH2:26][CH:19]2[CH2:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[O:6].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:1][CH:2]1[CH:3]([NH:12][C:13]([CH:15]2[N:20]3[C:21](=[O:40])[CH:22]([NH:27][C:28]([C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:31]=4)=[O:29])[CH2:23][CH:24]=[CH:25][CH2:26][CH:19]3[CH2:18][CH2:17][CH2:16]2)=[O:14])[CH2:4][C:5](=[O:6])[N:7]1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)NC(=O)CC(CO)NC(=O)C1CCCC2CC=CCC(NC(=O)c3ccc4ccccc4c3)C(=O)N21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)N1C(=O)CC(NC(=O)C2CCCC3CC=CCC(NC(=O)c4ccc5ccccc5c4)C(=O)N32)C1O
Reaction time: 2 h

Procedure:
7-[(Naphthalene-2-carbonyl)-amino]-6-oxo-1,3,4,6,7,8,11,11a-octahydro-2H-pyrido[1,2-a]azocine-4-carboxylic acid (1-hydroxymethyl-3-methanesulfonylamino-3-oxo-propyl)-amide, 117, (49 mg) is dissolved in 5 mL methylene chloride and cooled to 0 deg. Dess-Martin periodinane (90 mg) is added, and the reaction is strirred for 2 h at 0 deg. Saturated aqueous sodium bicarbonate solution is added and the mixture is extracted with ethyl acetate. The combined opganic layers are dried over sodium sulfate powder and the product is purified over silica (2% methanol in methylene chloride) to afford the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[C:12]1([C:18]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=O)=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C>CO>[C:12]1([C:18]2[C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:1][C:2]3[C:3](=[CH:4][CH:5]=[CH:6][C:7]=3[NH2:8])[N:9]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Reactant: Nc1cccc([N+](=O)[O-])c1N
Solvent: CO
Solvent: CC(=O)O
Product: Nc1cccc2nc(-c3ccccc3)c(-c3ccccc3)nc12

Procedure:
1.53 g (10 mmol) of 2,3-diaminonitrobenzene and 2.00 g (9.6 mmol) of benzil were placed in four-necked flask, to which 30 g of a solvent of acetic acid and methanol at a mixing ratio of 1:1 was added for dissolution. Subsequently, the mixture was reacted at a reaction temperature of 70° C. for 2 hours. After the reaction, the solvent was removed and the resulting product was extracted with a silica gel column (ethyl acetate:hexane=1:1).
Reaction SMILES: C(OC([N:8]([C:26]1[CH:30]=[C:29]([CH3:31])[N:28](C(OC(C)(C)C)=O)[N:27]=1)[C:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH:17]=2)[C:12](=[O:22])[N:11]([CH:23]([CH3:25])[CH3:24])[N:10]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[CH:23]([N:11]1[C:12](=[O:22])[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([C:19]([OH:21])=[O:20])[CH:14]=2)[C:9]([NH:8][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)=[N:10]1)([CH3:25])[CH3:24]
Reactant: Cc1cc(N(C(=O)OC(C)(C)C)c2nn(C(C)C)c(=O)c3cc(C(=O)O)ccc23)nn1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2nn(C(C)C)c(=O)c3cc(C(=O)O)ccc23)n[nH]1
Reaction time: 48 h

Procedure:
1-[tert-Butoxycarbonyl-(1-tert-butoxycarbonyl-5-methyl-1H-pyrazol-3-yl)-amino]-3-isopropyl-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid (13.0 mg, 0.02 mmol) was dissolved in a 20% trifluoroacetic acid (TFA)/DCM solution (2 ml) and the reaction mixture was stirred for 48 hours. After this time, the reaction mixture was concentrated and the resulting residue was triturated with diethyl ether to give the title compound (Example M-1) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[CH3:11][CH:12]([N:14]1[C:18]([C:19]2[C:24]([OH:25])=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:17][CH:16]=[N:15]1)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC#N.O>[CH:12]([N:14]1[C:18]([C:19]2[C:24]([O:25][CH2:2][C:3]3[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=3[CH:5]=[O:6])=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:17][CH:16]=[N:15]1)([CH3:13])[CH3:11]
Reactant: O=Cc1ccccc1CBr
Reactant: CC(C)n1nccc1-c1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)n1nccc1-c1ncccc1OCc1ccccc1C=O
Temperature: 25 °C
Reaction time: 0.13 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 2-(bromomethyl)benzaldehyde (150 mg, 0.75 mmol, 1.00 equiv) in CH3CN (25 mL). 2-[1-(Propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-ol (150 mg, 0.74 mmol, 1.00 equiv), potassium carbonate (210 mg, 1.52 mmol, 2.00 equiv), and KI (40 mg, 0.30 equiv) were added to the reaction. The resulting solution was heated to reflux for 6 h, and then it was cooled to rt. The resulting solution was diluted with 20 mL of H2O, and then it was extracted with 3×20 mL of ethyl acetate. The combined organic layers were washed with 1×30 mL of brine and concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm, mobile phase, water with 0.05% TFA and MeCN (38.0% MeCN up to 55.0% in 8 min); Detector, nm. This provided 98.6 mg (41%) of 2-[([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]oxy)methyl]benzaldehyde as a light yellow solid; 1HNMR (300 MHz, CDCl3, ppm): 10.01 (s, 1H), 8.43 (m, 1H), 7.88 (m, 1H), 7.86 (m, 1H), 7.61-7.79 (m, 6H), 6.61 (d, J=2.1 Hz, 1H), 5.60 (s, 2H), 4.69-4.78 (m, 1H), 1.46 (d, J=6.6 Hz, 6H); (ES, m/z): 322 [M+1]+.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:6][CH:5]=1.[2H-].[Al+3].[Li+].[2H-].[2H-].[2H-]>>[Si:15]([O:14][CH2:13][CH2:12][O:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][CH:6]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: COC(=O)c1ccc(COCCO[Si](C)(C)C(C)(C)C)cc1
Agent: [2H-]
Agent: [Al+3]
Agent: [Li+]
Product: CC(C)(C)[Si](C)(C)OCCOCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 87.5 %

Procedure:
To a solution of the product of Example 8B (610 mg, 1.857 mmol) in THE (19 mL) at 0° C. was added a 1M solution (in THF) of lithium aluminum deuteride (1.9 mL, 1.857 mmol) dropwise. After completion of addition the ice bath was removed and the reaction was stirred at room temperature for 3.5 hours under nitrogen atmosphere, monitoring by TLC (3:1 pentane:ethyl acetate). The reaction was then diluted with water and extracted with ethyl acetate (2 times). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a clear oil (482 mg, 86% yield). The material was taken to the next step without further purification. 1H NMR (600 MHz, CDCl3): 7.33 (s, 4H), 4.56 (s, 2H), 0.89 (s, 9H), 0.06 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C@:9]23[CH2:16][C@H:15]([NH2:17])[CH2:14][N:13]2[C:12](=[O:18])[N:11]([C:19]2[CH:24]=[C:23]([Cl:25])[N:22]=[C:21]([Cl:26])[CH:20]=2)[C:10]3=[O:27])=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.Cl[C:42]([O:44][CH3:45])=[O:43]>C1COCC1>[F:31][C:2]([F:30])([F:1])[O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C@:9]23[CH2:16][C@H:15]([NH:17][C:42]([O:44][CH3:45])=[O:43])[CH2:14][N:13]2[C:12](=[O:18])[N:11]([C:19]2[CH:24]=[C:23]([Cl:25])[N:22]=[C:21]([Cl:26])[CH:20]=2)[C:10]3=[O:27])=[CH:6][CH:5]=1
Reactant: N[C@@H]1CN2C(=O)N(c3cc(Cl)nc(Cl)c3)C(=O)[C@@]2(Cc2ccc(OC(F)(F)F)cc2)C1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@@H]1CN2C(=O)N(c3cc(Cl)nc(Cl)c3)C(=O)[C@@]2(Cc2ccc(OC(F)(F)F)cc2)C1
Reaction time: 3 h

Procedure:
To a solution of the compound from Example 63 (0.075 g) in THF (4 mL) was added DIEA (0.10 mL) and methyl chloroformate (0.020 mL). After 3 hours, the reaction was concentrated and purified by chromatography (silica gel; 98:2 CH2Cl2/methanol, Chromatotron) to afford the titled compound (0.0715 g): MS (m/z) 533 [MH+]. mp 119.8° C.
Reaction SMILES: [CH3:1][N:2]([C:10]1([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1)C(=O)OC(C)(C)C.Cl.[C:23]([O-:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([O-:28])=[O:27].C(O)(=O)/C=C/C(O)=O>O1CCOCC1.CCOCC>[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27].[CH3:1][NH:2][C:10]1([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:11][CH2:12]1
Reactant: CN(C(=O)OC(C)(C)C)C1(CCOc2cccnc2)CC1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CNC1(CCOc2cccnc2)CC1

Procedure:
A solution of 1.2 g of the product obtained in Step 1 dissolved in 5 ml of dioxane and 4 ml of 4N hydrochloric acid in dioxan is stirred for 20 hours at ambient temperature and then 10 ml of ether are added. The precipitate formed is separated off, taken up in 15 ml of water and made alkaline by the addition of potassium carbonate. The aqueous phase is then extracted with dichloromethane. The organic phases are subjected to customary treatment which, after concentration under reduced pressure, allows the expected product to be obtained, which is converted into its fumarate form by treatment with an ethanolic solution of fumaric acid.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:10][O:11][C:12]1[CH:23]=[CH:22][C:15]([C:16]([O:18][CH2:19][CH2:20]Cl)=[O:17])=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:23]=[CH:22][C:15]([C:16]([O:18][CH2:19][CH2:20][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[C:2]2[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:17])=[CH:14][CH:13]=1
Reactant: c1ccc2[nH]cnc2c1
Reactant: COc1ccc(C(=O)OCCCl)cc1
Product: COc1ccc(C(=O)OCCn2c(-c3ccccc3)nc3ccccc32)cc1
Yield: 71 %

Procedure:
The procedure of Synthesis Example 10 was repeated except that benzimidazole was used instead of the 1-aza-18-crown-6, and 2-chloroethyl 4-methoxybenzoate was used instead of the 2-chloroethyl benzoate, to give 2-(2-phenyl-1H-benzimidazol-1-yl)ethyl 4-methoxybenzoate in a yield of 71%.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]([CH3:30])([CH3:29])[C:24]([O:26]CC)=[O:25])[CH:8]=2)[N:3]=1.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]([CH3:30])([CH3:29])[C:24]([OH:26])=[O:25])[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)C(C)(C)c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
2.4 g of ethyl 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-methylpropanoate are dissolved in 40 ml of tetrahydrofuran, and 25 ml of 2N sodium hydroxide solution are added. The mixture is stirred at 50° C. for 4 h and subsequently evaporated in vacuo. The mixture is then adjusted to pH2 using 7 ml of 25% hydrochloric acid with ice-cooling, with yellow crystals precipitating. The precipitate obtained is filtered off and dried in vacuo. Yield: 2.0 g (90%) of 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-methylpropanoic acid;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:34][CH2:35][CH2:36][NH:37][C:38]1[N:46]=[C:45]([Cl:47])[N:44]=[C:43]2[C:39]=1[N:40]=[CH:41][N:42]2[CH:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:34][CH2:35][CH2:36][NH:37][C:38]1[N:46]=[C:45]([Cl:47])[N:44]=[C:43]2[C:39]=1[N:40]=[CH:41][N:42]2[CH:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1)=[O:7]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
190 mg of 3-chlorobenzoic acid, 205 mg of 1-hydroxybenzotriazole hydrate, 287 mg of 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 4 ml of dichloromethane are mixed together, 280 mg of the product obtained in Stage 1 of Example 7 is added and the reaction medium is agitated for 5 hours and 30 minutes at ambient temperature. Water is added, followed by extracting with methylene chloride, drying, evaporating the solvents, recrystallizing from ether, separating, drying and 334 mg of expected product is collected.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].Br[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>O1CCCC1>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CCOC(=O)C(C)Br
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (2.0 g, 8.4 mmole) and ethyl 2-bromopropanoate (1.52 g, 8.4 mmole) in tetrahydrofuran (50 ml) was added triethylamine (0.85 g, 8.4 mmole) The mixture was stirred at room temperature for 20 hours. Solids were removed by filtration and the filtrate was added to diethyl ether (75 ml) and then washed with 1 N hydrochloric acid (50 ml), dried over magnesium sulfate, filtered, and concentrated in vacuo to an oil. Chromatography on silica gel gave the title compound
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11](B3OCC(C)(C)CO3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[N:25]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Br[C:40]1[CH:41]=[CH:42][C:43]([NH2:46])=[N:44][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:46][C:43]1[N:44]=[CH:45][C:40]([C:11]2[CH:10]=[CH:9][C:8]([NH:21][C:22]([C:24]3[N:25]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:37])[CH3:38])[CH:26]=[C:27]([C:29]#[N:30])[N:28]=3)=[O:23])=[C:7]([C:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=3)[CH:12]=2)=[CH:41][CH:42]=1
Reactant: CC1(C)COB(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)OC1
Reactant: Nc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(-c2ccc(N)nc2)cc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78 %

Procedure:
To a mixture of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-phenyl]-amide (as prepared in the previous step, 32.0 mg, 0.0600 mmol), 5-bromo-pyridin-2-ylamine (10.4 mg, 0.0660 mmol) and Pd(PPh3)4 (7.0 mg, 0.0060 mmol) in 1.0 mL of 1,4-dioxane was added 2.0 M Na2CO3 aqueous solution (0.24 mL, 0.48 mmol). The resulting mixture was stirred at 80. C for 6 h under Ar. After cooling to RT, the mixture was treated with 30 mL of EtOAc, washed with H2O (3×15 mL) and brine (10 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (2-3% MeOH/DCM) to afford 24 mg (78%) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C28H34N6O2Si, 515.3 (M+H), found 515.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH2:18][CH2:19][CH2:20]Cl)([CH3:7])[CH3:6])[CH3:2].[CH2:23]([C:26]1[C:34]2[O:33][N:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[C:30]=2[CH:29]=[CH:28][C:27]=1[OH:39])[CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C=O)C>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:7])([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH2:18][CH2:19][CH2:20][O:39][C:27]1[CH:28]=[CH:29][C:30]2[C:31]([C:35]([F:38])([F:37])[F:36])=[N:32][O:33][C:34]=2[C:26]=1[CH2:23][CH2:24][CH3:25])[CH3:6])[CH3:2]
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)noc12
Reactant: CCOC(=O)C(C)(C)Oc1cccc2c1ccn2CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(OCCCn2ccc3c(OC(C)(C)C(=O)OCC)cccc32)ccc2c(C(F)(F)F)noc12
Temperature: 110 °C
Yield: 84.8 %

Procedure:
A mixture of 2-[1-(3-chloropropyl)-1H-indol-4-yloxy]-2-methylpropionic acid ethyl ester (0.100 g, 0.31 mmol, 1.0 eq), 7-propyl-3-trifluoromethyl-benzo[d]isoxazol-6-ol (0.076 g, 0.31 mmol, 1.0 eq), potassium carbonate (0.064 g, 0.46 mmol, 1.5 eq), potassium iodide (0.010 g, 0.06 mmol, 0.2 eq), and DMF (3 mL) was heated at 110° C. for 1.5 hours. The reaction mixture was cooled to room temperature before 20 mL of water was added. The mixture was then extracted with ethyl acetate (2×20 mL). The organic layer was collected, combined, washed with water (6×20 mL) and brine (2×20 mL), and dried over anhydrous Na2SO4. The solvent was removed in vacuo to give an oily residue, which was purified by filtering through a short silica column using hexane/ethyl acetate (95/5) as an eluant to afford 2-methyl-2-{1-[3-(7-propyl-3-trifluoromethyl-benzo[d]isoxazol-6-yloxy)-propyl]-1H-indol-4-yloxy}-propionic acid ethyl ester (0.140 g, yield: 85%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][OH:7])[CH3:2].[H-].[Na+].Cl[C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][S:14][N:15]=1.O>O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][O:7][C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][S:14][N:15]=1)[CH3:2]
Reactant: CCOCCCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-ethoxy-1-propanol (940 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14]N)=[CH:11][CH:10]=1.O>C(O)CCC>[Br:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14][C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][CH:10]=1
Reactant: NCCc1ccc(Br)cc1
Reactant: Nc1ccccn1
Solvent: O
Solvent: CCCCO
Product: Nc1ncccc1CCc1ccc(Br)cc1
Temperature: 230 °C
Yield: 24.8 %

Procedure:
In a sealed tube, a mixture of 1.9 g (20.4 mmol) of 2-aminopyridine and 6.1 g (30.6 mmol) of 4-bromophenethylamine dissolved in butanol (10 ml) is heated at 230° C. for 1 hour by microwave. The mixture, cooled to room temperature, is poured into water (50 ml) and extracted with ethyl acetate (3×100 ml), and the combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue is purified by flash chromatography on a column of silica gel (eluent: dichloromethane/ethyl acetate, from 0% to 50% ethyl acetate). 1.4 g of product are obtained in the form of a white powder. Yield: 24%. Melting point: 71° C. MH+: 278.1 (tr: 3.71 min., condition 1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH3:22])=[N:14][N:15]2[CH2:18][C:19](=[O:21])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH3:22])=[N:14][N:15]2[CH2:18][CH:19]([OH:21])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cn1nc(C)c2ccc(OCc3ccccc3)cc21
Solvent: CO
Product: Cc1nn(CC(C)O)c2cc(OCc3ccccc3)ccc12
Yield: 18.4 %

Procedure:
A solution of the product from Step C (3.3 g, 5.5 mmol) in MeOH (10 ml) was treated as described for Example 1, Step C to give an oil (0.30 g, 10%): MS (ES) m/z 297 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12].OP(O)(O)=O>>[CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]1[S:6][C:7]([C:11](=[O:13])[CH3:12])=[CH:8][CH:9]=1
Reactant: COC(=O)Cc1cccs1
Reactant: CC(=O)OC(C)=O
Agent: O=P(O)(O)O
Product: COC(=O)Cc1ccc(C(C)=O)s1

Procedure:
A mixture of 2-thienylacetic acid methyl ester, 1.41 g. (0.01 mol) and acetic anhydride, 4.2 g. (0.04 mol) was heated at 70°-80° C. and 0.2 g. of 85% H3PO4 was added dropwise with mechanical stirring. The reaction was somewhat exothermic but cooling was not necessary. The mixture was maintained between 70°-80° C. for 3 hrs., and then, poured onto ice-water followed by extraction with ether. Organic layer was washed with water several times, dried over anhyd. MgSO4 and evaporated. The residue was distilled at 2 mmHg and a fraction between 160° C. and 172° C. was collected. This material was gradually crystallized and could be recrystallized from the mixture of light-petroleum and benzene. m.p. 43°-44° C. Yield; 1.39 g. (76.5%)
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH2:7])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([NH:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCNS(C)(=O)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
N-Acetylethylenediamine (10.2 g, 100 mmol) and triethylamine (15 ml, 10.9 g, 108 mmol) were dissolved in dichloromethane (300 ml) and the solution cooled to 0° C. Methanesulphonyl chloride (8 ml, 11.8 g, 103 mmol) was dissolved in dichloromethane (10 ml) and added dropwise, and stirring was continued at 0° C. for 3 hours. The dichloromethane was removed in vacuo, and the residue was suspended in a mixture of ether and acetone, removing the insoluble material by filtration. The filtrate was concentrated in vacuo to give the title compound as a pale brown gum (14.5 g, 88.3 mmol, 88%); δH [2H6]DMSO 7.93 (1H,br t), 7.05 (1H,t), 3.11 (2H,t), 2.97 (2H,t), 2.89 (3H,s), 2.09 (3H,s).