Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.C(O)(=O)C.[Br:16]Br>>[Br:16][CH2:10][C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:11]
Reactant: BrBr
Reactant: COc1cccc(C(C)=O)c1
Solvent: CC(=O)O
Product: COc1cccc(C(=O)CBr)c1
Yield: 32.8 %

Procedure:
Reaction of 1-(3-methoxy-phenyl)-ethanone (5.0 g, 33.30 mmol), acetic acid (1.9 mL, 33.30 mmol), and bromine (1.9 mL, 38.30 mmol) followed by recrystallisation from cold EtOAc/Hexane gave the title compound (2.5 g, 33%) as a yellow powder. 1H NMR (300 MHz, CDCl3) δ 3.87 (s, 3H), 4.46 (s, 2H), 7.16 (d, 1H, J=8.4 Hz), 7.63 (dd, 1H, J=8.1, 8.1 Hz), 7.52 (s, 1H), 7.56 (d, 1H, J=7.5 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]2[C:13]([CH3:14])=[C:12]([CH3:15])[C:11]([OH:16])=[CH:10][C:8]=2[CH:9]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[OH:2][CH2:3][C:5]1[O:6][C:7]2[C:13]([CH3:14])=[C:12]([CH3:15])[C:11]([OH:16])=[CH:10][C:8]=2[CH:9]=1
Reactant: COC(=O)c1cc2cc(O)c(C)c(C)c2o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(O)cc2cc(CO)oc2c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.1 %

Procedure:
5-Hydroxy-6,7-dimethyl-benzofuran-2-carboxylic acid methyl ester (231 mg) prepared as in Example 2, was dissolved in THF and lithium aluminum hydride (93 mg) was added. The mixture was stirred at room temperature for 4 h. Then the solution was poured into water and extracted with ethylacetate. The ethyl acetate was washed with water and brine, dried over MgSO4 and concentrated. Purification by silica gel column eluting with 50% EtOAc in hexane gave 89 mg of 2-Hydroxymethyl-6,7-dimethyl-benzofuran-5-ol. 1HNMR (CD3OD, 300 MHz) δ: 6.75, 1H), 6.47(s, 1H), 4.61 (s, 2H), 2.37(s, 3H), 2.20(s, 3H) ppm. 13CNMR (CD3OD, 75 MHz) δ: 155.87, 150.51, 148.68, 124.69, 119.93, 119.20, 103.01, 101.62, 56.32, 10.43, 10.29 ppm. MS: 175(M−OH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[F:12][C:13]1[CH:30]=[CH:29][C:16]([CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:28])[C:25](O)=[O:26])[CH2:20][CH2:19]2)=[CH:15][CH:14]=1>O>[F:12][C:13]1[CH:30]=[CH:29][C:16]([CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:28])[C:25]([NH:1][C:2]3[CH:3]=[CH:4][C:5]4[O:9][C:8](=[O:10])[NH:7][C:6]=4[CH:11]=3)=[O:26])[CH2:22][CH2:23]2)=[CH:15][CH:14]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: Nc1ccc2oc(=O)[nH]c2c1
Solvent: O
Product: O=C(Nc1ccc2oc(=O)[nH]c2c1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from 5-amino-3H-benzoxazol-2-one [J. Med. Chem., 10, 408. (1967)] and [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b) according to the method described in Example 2. Melting Point: 226-231° C. (water)
Reaction SMILES: C([O:3][C:4](=[O:22])[CH:5]([O:20][CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:9][CH:8]=1)C.O[C:24]1[CH:37]=[CH:36][C:27]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:29])=[CH:26][CH:25]=1>>[C:28]([C:30]1[CH:35]=[CH:34][C:33]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]#[C:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:20][CH3:21])[C:4]([OH:3])=[O:22])=[CH:12][CH:11]=2)=[CH:32][CH:31]=1)(=[O:29])[C:27]1[CH:36]=[CH:37][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)C(Cc1ccc(C#CCCCCO)cc1)OC
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Product: CO[C@@H](Cc1ccc(C#CCCCCOc2ccc(C(=O)c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from 3-[4-(6-Hydroxy-hex-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 49, Step A) and 4-hydroxybenzophenone via the standard Mitsunobu coupling-hydrolysis procedure (Standard Procedure A) to produce the title compound. MS(ES) for C29H28O5 [M+H]+: 457.2.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:34]=[C:33]3[C:29]([C:30]([NH:43][C:44](=[O:48])[CH2:45][CH2:46][CH3:47])=[N:31][N:32]3COCC[Si](C)(C)C)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.C(OCC)(=O)C>O1CCCC1>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:34]=[C:33]3[C:29]([C:30]([NH:43][C:44](=[O:48])[CH2:45][CH2:46][CH3:47])=[N:31][NH:32]3)=[CH:28][CH:27]=2)=[CH:24][CH:25]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(Cl)cc3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(Cl)cc3)ccc12
Temperature: 65 °C

Procedure:
9.5 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to a solution of 600 mg of N-[6-(4-chlorophenyl)-1-[[2-(trimethylsilyl)ethoxy]-methyl]-1H-indazol-3-yl]butanamide, prepared previously, in 20 cm3 of tetrahydrofuran, the reaction medium is then heated at about 65° C. for 18 hours and the heating is stopped to add 40 cm3 of ethyl acetate. The organic phase is washed with 2×30 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 30 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 50° C.), 238 mg of N-[6-(4-chlorophenyl)-1H-indazol-3-yl]butanamide are obtained in the form of a beige-coloured powder.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][NH2:9])[CH2:2][CH2:3][CH3:4].[C:10]([NH:13][NH:14][C:15](N)=[O:16])(N)=[O:11]>CN1CCCC1=O>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][N:9]1[C:15](=[O:16])[NH:14][NH:13][C:10]1=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCCN
Reactant: NC(=O)NNC(N)=O
Solvent: CN1CCCC1=O
Product: CCCCOCCCn1c(=O)[nH][nH]c1=O

Procedure:
131 g of 3-butoxy propylamine and 120 g of hydrazodicarbonamide are stirred in 300 ml of N-methyl pyrrolidone for 1 hour at 150° C., for 2 hours at 175° C. and for 6 hours at 200° C. A deposit is precipitated on cooling which is isolated by filtration under suction and recrystallised from cyclohexane, giving 152 g (75% of the theoretical yield) of 4-(3-butoxypropyl)-1,2,4-triazolidine-3,5-dione in the form of colourless crystals melting at 83° to 85° C.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)=[CH:8][N:9]=1)(=O)C.O1CCCC1.Cl>C(O)C>[NH2:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)=[CH:8][N:9]=1
Reactant: CC(=O)Nc1ncc(Sc2ccc(C(F)(F)F)cn2)s1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ncc(Sc2ccc(C(F)(F)F)cn2)s1
Yield: 75.6 %

Procedure:
A mixture of 2-acetylamino-5-(5-trifluoromethylpyridin-2-ylthio)thiazole (3.2 g) in a mixture of ethanol (60 ml), tetrahydrofuran (30 ml) and aqueous 6N-hydrochloric acid (10 ml) was refluxed for 3 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The solution was adjusted to pH 8.5 using aqueous sodium bicarbonate and extracted with mixture of tetrahydrofuran and ethyl acetate (1:1) and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 150 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-5-(5-trifluoromethylpyridin-2-ylthio)thiazole (2.1 g, yield: 75.8%). mp: 135°-138° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[S:12][C:13]3[CH:19]=[C:18]([NH:20][C:21]([NH2:23])=[S:22])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:4][CH:3]=1.[CH2:24](I)[CH3:25]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[S:12][C:13]3[CH:19]=[C:18]([NH:20][C:21](=[NH:23])[S:22][CH2:24][CH3:25])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:4][CH:3]=1
Reactant: NC(=S)Nc1ccc2nc(NCCc3ccc(Br)cc3)sc2c1
Reactant: CCI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCSC(=N)Nc1ccc2nc(NCCc3ccc(Br)cc3)sc2c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 23 %

Procedure:
{2-[2-(4-Bromo-phenyl)-ethylamino]-benzothiazol-6-yl}-thiourea (Example 39, 51.3 mg, 0.126 mmol) was dissolved in dry DMF (0.5 mL). Ethyl iodide (11 μl, 1.1 eq) was added and the yellow solution stirred at room temperature for 23 hours. The solution was diluted with ethyl acetate (10 mL) and extracted with ice water (2 mL) followed by ice cold brine (3×2 mL). The product was dried over MgSO4, filtered and concentrated to give a yellow oil. The product was purified by chromatography on silica gel (5% 2M ammonia/methanol in CH2Cl2) to give the isothiourea (12.5 mg, 23%). The product was dissolved in methanol (1.0 mL) and acidified with 1.0 M HCl in ether (4 mL). The orange precipitate was collected by filtration and washed with hexanes (6.0 mg, 10%). MS (M+1, 435, 437).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.F[C:8]1[C:19]2=[C:20]3[N:15]([C:16](=[CH2:21])[CH2:17][CH2:18]2)[CH:14]=[C:13]([C:22]([OH:24])=[O:23])[C:12](=[O:25])[C:11]3=[CH:10][C:9]=1[F:26]>CS(C)=O>[F:26][C:9]1[CH:10]=[C:11]2[C:20]3[N:15]([CH:14]=[C:13]([C:22]([OH:24])=[O:23])[C:12]2=[O:25])[C:16](=[CH2:21])[CH2:17][CH2:18][C:19]=3[C:8]=1[N:4]1[CH2:5][CH2:6][CH:2]([OH:1])[CH2:3]1
Reactant: OC1CCNC1
Reactant: C=C1CCc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CS(C)=O
Product: C=C1CCc2c(N3CCC(O)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 22.5 %

Procedure:
4 ml of dimethyl sulfoxide and 100 mg of 3-hydroxypyrrolidine were added to 100 mg of 8,9-difluoro-5-methylene-1-oxo-6,7-dihydro-1H,5H-benzo(ij)quinolizine-2-carboxylic acid and the resulting mixture was allowed to react for 2 hours at 120° C. The solvent was distilled off. The residue was purified by silica gel column chromatography and purified by preparative thin layer chromatography on silica gel and then recrystallized from a mixture of ethanol and chloroform to give 28 mg of 9-fluoro-8-(3-hydroxy-1-pyrrolidinyl)-5-methylene-1-oxo-6,7-dihydro-1H,5H-benzo(ij)quinolizine-2-carboxylic acid as microcrystals with mp 190°-196° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]([F:23])([F:35])[F:36])=[CH:31][CH:30]=3)=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccccc1
Product: CCOC(=O)c1cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2n1Cc1ccccc1

Procedure:
The title compound was prepared from ethyl 5-bromo-1-benzyl-1H-indole-2-carboxylate and 4-(trifluoromethoxy)phenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil. Mass spectrum (ESI, [M+H]+) m/z 440. 1HNMR (400 MHz, DMSO-d6): δ 8.01 (s, 1H), 7.79 (d, 2H, J=8.86 Hz), 7.67 (d, 1H, J=8.85 Hz), 7.62 (dd, 1H, J=8.70 and 1.68 Hz), 7.44-7.42 (m, 2H), 7.28-7.20 (m, 3H), 7.04 (d, 2H, J=7.94 Hz), 5.88 (s, 2H), 4.28 (q, 2H), and 1.29 ppm (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:23])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=2)=[C:5]([O:24][CH2:25][C:26]([O:28]C)=[O:27])[C:4]=1[CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33].[OH-].[K+].Cl>CO>[C:26]([CH2:25][O:24][C:5]1[C:4]([CH2:30][CH2:31][CH:32]([CH3:33])[CH3:34])=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[C:6]=1[C:11](=[O:23])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=1)([OH:28])=[O:27]
Reactant: COC(=O)COc1c(CCC(C)C)c(OC)cc(OC)c1C(=O)CCc1ccc(O)c(OC)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2OCC(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Then, 12.0 g of 1-(4,6-dimethoxy-2-methoxycarbonylmethoxy-3-isopentylphenyl)-3-(4-hydroxy-3-methoxyphenyl)-1-propanone was dissolved in 120 ml of methanol, and 70 ml of a 5% aqueous solution of potassium hydroxide was added to the solution and the mixture was stirred at room temperature for 20 minutes. Then, the reaction mixture was made weakly acidic by addition of dilute hydrochloric acid, and the solvent was removed by distillation and the residue was crystallized from ethyl acetate/diethyl ether/hexane to obtain 9.7 g (yield=of 1-(2-carboxymethoxy-4,6-dimethoxy-3-isopentylphenyl)-3-(4-hydroxy-3-methoxyphenyl)-1-propanone in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[CH:6][CH:7]=1.S(Cl)([Cl:13])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([Cl:13])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)Cl)cc1
Temperature: 25 °C

Procedure:
p-Toluic acid (100 g, 0.734 mol) (Tokyo Chemical Industry Co., Ltd.) and toluene (500 mL) (Wako Pure Chemical Industries, Ltd.) were placed into a sufficiently dried recovery flask (egg plant flask), and p-toluic acid was dissolved. Thionyl chloride (132.4 mL, 1.84 mol) (Wako Pure Chemical Industries, Ltd.) was added dropwise to this solution for 1 hour. After the dropwise addition, the solution was heated and refluxed for 2 hours. After the reaction, the temperature was cooled to room temperature, and then remaining thionyl chloride and remaining toluene were evaporated by using a rotary evaporator. Toluene (200 mL) was added to an obtained concentrate, and the concentrating operation was repeated twice. A finally obtained residue was dissolved in tetrahydrofuran (200 mL) (Wako Pure Chemical Industries, Ltd.), which was used in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([OH:15])=O)=[CH:8][CH:7]=[CH:6]2.S(Cl)([Cl:18])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([Cl:18])=[O:15])=[CH:8][CH:7]=[CH:6]2
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2c(C(=O)O)cccc2c1
Product: COc1ccc2c(C(=O)Cl)cccc2c1
Temperature: 25 °C

Procedure:
Under an argon atmosphere, 6-methoxy-1-naphthoic acid (synthesized by the process of J. D. Moseley and J. P. Gilday, Tetrahedron, 62, 4690-4697 (2006)) (1.20 g, 5.93 mmol) was dissolved in thionyl chloride (5.00 mL, 68.8 mmol) and the solution was heated to reflux for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to give the crude product of 6-methoxy-1-naphthoyl chloride (22) as a colorless oil. The product was used in the following reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:21]=[CH:20][C:14]([C:15](=[NH:19])OCC)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[F:28][C:29]([F:33])([F:32])[CH2:30][NH2:31]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:12]=[CH:13][C:14]([C:15](=[NH:19])[NH:31][CH2:30][C:29]([F:33])([F:32])[F:28])=[CH:20][CH:21]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: NCC(F)(F)F
Reactant: CCOC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Solvent: CO
Product: N=C(NCC(F)(F)F)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml of a 0.075 M methanol solution, 0.15 mmol) was treated with 2,2,2-trifluoroethanamine (18 μl, 0.23 mmol) via procedure W to afford 56 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2,2,2-trifluoroethyl)carbamimidoyl)benzamide. MS (Q1) 433 (M)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:34])[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[N:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[CH:22]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[N:31][CH:30]=[C:29]([CH3:33])[N:28]=4)[CH:22]=3)[CH2:18][C:17](=[O:34])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cncc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(C)cc3NC(=O)OC(C)(C)C)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cncc(-c2cccc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (4-chloro-5-methyl-2-{3-[3-(6-methyl-pyrazin-2-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M116) (0.46 g, 0.93 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (270 mg, 77%).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[I:13]N1C(=O)CCC1=O>ClCCCl.O1CCCC1>[I:13][C:12]1[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12
Reactant: CC(C)c1cc2ccccn2n1
Reactant: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(C)c1nn2ccccc2c1I
Yield: 93.9 %

Procedure:
2-Isopropyl-pyrazolo[1,5-a]pyridine (18.42 g, 115 mmol) and N-iodosuccinimide (28.45 g, 126 mmol) were dissolved in a mixture of 1,2-dichloroethane (300 ml) and tetrahydrofuran (300 ml). The mixture was stirred at reflux for 18 hours. The mixture was cooled and concentrated in vacuo. The crude material was purified by silica gel flash chromatography (0 to 20% ethyl acetate in hexanes) to give 30.9 g (94%) of 3-iodo-2-isopropyl-pyrazolo[1,5-a]pyridine. 1H-NMR (250 MHz, CDCl3) δ 8.36 (d, J=7.0 Hz, 1H), 7.36 (d, J=9.0 Hz, 1H), 7.12 (t, J=7.9 Hz, 1H), 6.67 (t, J=7.6 Hz, 1H), 3.20 (sept, J=7.0 Hz, 1H), 1.37 (d, J=6.8 Hz, 6H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[N:6][CH:7]=1.Br[CH:20]([C:22](=[O:25])[CH2:23][CH3:24])[CH3:21].C(N(CC)C(C)C)(C)C>C1COCC1>[I:1][C:2]1[CH:3]=[CH:4][C:5](=[N:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[N:6]([CH:20]([C:22](=[O:25])[CH2:23][CH3:24])[CH3:21])[CH:7]=1
Reactant: CCC(=O)C(C)Br
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(I)cn2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(=O)C(C)n1cc(I)ccc1=NS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.5 %

Procedure:
To a stirred solution of N-(5-iodopyridin-2-yl)-4-methylbenzenesulfonamide (3 g) and 2-bromopentan-3-one (3.3 g) in THF (50 ml) was added N,N-diisopropylethylamine (5.6 ml) at 0° C., and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo, poured into saturated NaHCO3 solution and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, concentrated in vacuo and purified by silica gel column chromatography (hexane/EtOAc) to afford the title compound (1.6 g) as a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][C:12]=1[CH3:13].[OH:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33]C)=[O:32])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:13][C:12]1[O:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:9][C:8]=1[CH2:7][O:6][C:5]1[CH:4]=[C:3]([CH:22]=[CH:21][CH:20]=1)[CH2:2][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:28][CH:29]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(COc2ccc(CC(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
A mixture of 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.89 g), methyl 2-(4-hydroxyphenyl)acetate (0.50 g), anhydrous potassium carbonate (0.49 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 3 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give colorless crystals from a fraction eluted with ethyl acetate-hexane (1:4, v/v). To a mixture of the obtained crystal, tetrahydrofuran (6 mL) and methanol (6 mL) was added a 1N aqueous sodium hydroxide solution (6 mL) and the mixture was stirred at room temperature for 2 hrs. Dilute hydrochloric acid was added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (1.13 g, 93%) of 2-[4-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 179-180° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][C:7]([CH3:12])=[N:6][C:5]=2[S:4][C:3]=1[CH3:13].C(OCC)(=O)C.[CH3:20][N:21](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[NH2:11][C:9]1[CH:8]=[C:7]([CH3:12])[N:6]=[C:5]2[S:4][C:3]([CH3:13])=[C:2]([C:20]#[N:21])[C:10]=12
Reactant: CN(C)C=O
Reactant: Cc1cc(N)c2c(Br)c(C)sc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1cc(N)c2c(C#N)c(C)sc2n1
Temperature: 140 °C

Procedure:
A mixture of 3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-amine (Description 8) (200 mg, 0.778 mmol), zinc cyanide (183 mg, 1.556 mmol) and tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.078 mmol) in DMF (5 mL) was heated in a microwave at 140° C. for 1 h. Another batch of 3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-amine (200 mg, 0.778 mmol) was subjected to the same conditions. The mixtures were then combined and ethyl acetate (50 mL) added. The resulting mixture was washed with saturated NaHCO3 (20 mL) followed by brine (20 mL×2) and the organic layer dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-40% ethyl acetate in cyclohexane, to give the title compound (237.7 mg). LCMS (A) m/z: 204 [M+1]+, Rt 0.61 min (acidic).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:16]([O:18][SiH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[CH3:17]>CN(C)C=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([Si:19]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])[O:18][CH2:16][CH3:17])=[CH:3][CH:4]=1
Reactant: Brc1ccc(I)cc1
Reactant: CCO[SiH](OCC)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCO[Si](OCC)(OCC)c1ccc(Br)cc1
Yield: 81 %

Procedure:
At first, a mixture of 4-iodo-bromobenzene (2.60 g, 9.19 mmol), t-butylammoniumiodido (3.39 g, 9.18 mmol) and [Rh(cod)(CH3CN)2] (105 mg, 0.277 mmol) was added with dimethylformamide (DMF: 26 mL) and triethylamine (2.56 mL, 18.4 mmol). Then, triethoxysilane (1.87 mL, 10.1 mmol) was added dropwise thereto at 0° C. The resultant mixture was stirred under a nitrogen atmosphere at 80° C. for one hour to obtain a reaction mixture. Subsequently, a solvent in the reaction mixture was distilled with a vacuum pump. Under a nitrogen atmosphere, the residue was extracted with ether, filtered with celite, and concentrated to obtain a crude product. Thereafter, the crude product thus obtained was purified by Kugel distillation, and thereby 4-bromo-triethoxysilylbenzene was obtained (2.38 g, 81% yield).