Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[N:30]1([C:35]2[CH:40]=[C:39]([CH2:41][NH2:42])[CH:38]=[C:37]([C:43]3[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=3)[N:36]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([NH:42][CH2:41][C:39]3[CH:38]=[C:37]([C:43]4[CH:44]=[CH:45][C:46]([C:49]([F:52])([F:50])[F:51])=[CH:47][CH:48]=4)[N:36]=[C:35]([N:30]4[CH2:31][CH2:32][CH2:33][CH2:34]4)[CH:40]=3)=[O:16])[CH2:12][CH2:13]2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: CCN(C1(C(=O)O)CC1)S(=O)(=O)c1ccc(Cl)s1
Reactant: NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCCC2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: CCN(C1(C(=O)NCc2cc(-c3ccc(C(F)(F)F)cc3)nc(N3CCCC3)c2)CC1)S(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Yield: 38.6 %

Procedure:
A solution of acid 18 (0.24 g, 0.76 mmol) in THF (20 mL) was added with DEPC (0.15 mL, 1.3 mol eq) and the mixture was stirred at room temperature for several minutes. Then [2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27A (0.27 g, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was suspended in EtOAc and washed with water (1×50 mL) and brine. After drying over Na2SO4, the separated organic phase was evaporated under reduced pressure and the residue was purified by flash chromatography (1:1 EtOAc:Petroleum ether) to afford a pale yellow solid (0.18 g) after crystallization from a mixture of ethyl ether/petroleum ether. Yield=38%, 1HNMR (DMSO, 200 MHz) δ 0.86 (t, 3H), 1.21 (m, 4H), 1.91 (m, 4H), 3.42 (m, 6H), 4.21 (d, 2H, J=6.2), 6.26 (s, 1H), 6.45 (s, 1H), 7.27 (d, 1H, J=4), 7.58 (d, 1H, J=3.8), 7.82 (d, 2H, J=7.8), 8.21 (d, 2H, J=8.1), 8.41 (t, 1H); [M+1] 613.11 (C27H28ClF3N4O3S2 requires 612.12).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[Li]CCCC.[C:22](=[O:24])=[O:23]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][C:9]([C:22]([OH:24])=[O:23])=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidine 4 (2.5 g) was cooled to −78° C. in 50 mL of THF before adding 1.3 eq of a 2.5M solution of nBuLi in hexanes. The reaction was stirred at −78° C. for 30 minutes before warming to −40° C. for several minutes to allow for complete formation of the Lithium anion. The reaction was then re-cooled to −78° C. and carbon dioxide gas evolved from dry ice was bubbled in via cannula to the reaction solution for 1 hour. The reaction was then slowly warmed to 0° C. over 30 minutes and the THF was concentrated by rotovap. The reaction was then quenched with water and extracted with Ethyl Acetate to remove any 2-chloro-4-morpholinothieno[3,2-d]pyrimidine. The aqueous layer was then brought to pH of 2-3 by adding concentrated HCl. The resultant solid that crashed out of the aqueous layer was then collected by Buchner funnel, rinsed with water and dried overnight under vacuum to yield 2.65 g of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid. 500 mg of this intermediate was then subjected to Procedure A. Upon extraction into Ethyl Acetate, the product remains in the aqueous layer and is treated with 20 eq of Amberlite IR-120 ion-exchange resin for 2 hours or until the solution becomes cloudy. The solution is first filtered thru a coarse Filter Flask to remove the resin and is then filtered thru a Buchner funnel to collect the 637 mg of 2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 as a light brown solid.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.[Cl:18][C:19]1[S:23][N:22]=[C:21]([C:24]2[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=2)[N:20]=1>ClCCl.N1C=CC=CC=1>[Cl:18][C:19]1[S:23][N:22]=[C:21]([C:24]2[S:28][C:27]([S:29]([NH:14][C:13]3[CH:15]=[C:9]([N:4]4[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]4)[CH:10]=[CH:11][C:12]=3[O:16][CH3:17])(=[O:31])=[O:30])=[CH:26][CH:25]=2)[N:20]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2nsc(Cl)n2)s1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2nsc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)aniline (D4) (33 mg, 0.14 mmol) in dichloromethane (2 ml) and pyridine (0.5 ml) was treated with 5-(5-chloro-1,2,4-thiadiazol-3-yl)-2-thiophenesulfonyl chloride (50 mg, 0.17 mmol) and the resulting mixture stirred at room temperature overnight. The mixture was then concentrated in vacuo, co-evaporated with toluene and the crude product purified by mass directed autoprep HPLC to afford the desired product which was characterized as the hydrochloride salt. MS (ES+) m/e 500/502 [M+H]+.
Reaction SMILES: C(O[C:4](=[O:11])[CH2:5][C:6](=O)[CH:7]([CH3:9])[CH3:8])C.Cl.[N+:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([NH2:21])=[NH:20])([O-:15])=[O:14]>>[CH:7]([C:6]1[N:21]=[C:19]([C:18]2[CH:22]=[CH:23][CH:24]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=2)[N:20]=[C:4]([OH:11])[CH:5]=1)([CH3:8])[CH3:9]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: N=C(N)c1cccc([N+](=O)[O-])c1
Agent: Cl
Product: CC(C)c1cc(O)nc(-c2cccc([N+](=O)[O-])c2)n1

Procedure:
The title compound was prepared from 4-methyl-3-oxo-pentanoic acid ethyl ester and 3-nitro-benzamidine hydrochloride according to general procedure 1. 1H NMR (DMSO-d6, 400 MHz) δ 1.25 (d, J=6.9 Hz, 6H), 2.80-2.92 (m, 1H), 6.37 (s, 1H), 7.83 (t, J=8.0 Hz, 1H), 8.40 (dd, J=7.5, 2.3 Hz, 2H), 8.62 (d, J=7.5 Hz, 1H) 9.01 (s, 1H), 12.50 (br s, 1H); MS: m/z (ESI) 260 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:10]([CH:11]([C:13](=[O:15])[CH3:14])[CH3:12])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[CH3:23][Mg+].[Br-].O>C1COCC1>[OH:15][C:13]([CH3:23])([CH3:14])[CH:11]([N:10]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])=[C:2]1[CH3:1])[CH3:12]
Reactant: C[Mg+]
Reactant: CC(=O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2cccnc21
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)OC(C)(C)C)c2cccnc2n1C(C)C(C)(C)O
Temperature: -78 °C
Reaction time: 3 h
Yield: 47.1 %

Procedure:
To a solution of tert-butyl 2-methyl-1-(3-oxobutan-2-yl)-1H pyrrolo[2,3-b]pyridine-3-carboxylate (0.6 g, 2 mmol) in THF (10 mL) were added CH3MgBr (2 mL, 6 mmol) at −78° C. The mixture was stirred at −78° C. for 3 hr. Water (4 mL) was added and the mixture was extracted by ethyl acetate (30 mL*3). The organic layer was washed with brine and dried over sodium sulfate. The crude product was concentrated and purified by pre-TLC (eluted: petroleum ether/ethyl acetate=4/1) to give tert-butyl 1-(3-hydroxy-3-methylbutan-2yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (300 mg, 49%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][O:9][C:10]2[N:11]=[C:12]([NH2:49])[C:13]3[N:14]=[CH:15][N:16]([C:47]=3[N:48]=2)[C@@H:17]2[O:46][C@H:36]([CH2:37][O:38][Si](C(C)(C)C)(C)C)[C@@H:27]([O:28][Si](C(C)(C)C)(C)C)[C@H:18]2[O:19][Si](C(C)(C)C)(C)C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].[NH4+]>CO>[CH:1]1([CH2:7][CH2:8][O:9][C:10]2[N:11]=[C:12]([NH2:49])[C:13]3[N:14]=[CH:15][N:16]([C:47]=3[N:48]=2)[C@@H:17]2[O:46][C@H:36]([CH2:37][OH:38])[C@@H:27]([OH:28])[C@H:18]2[OH:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N)nc(OCCC4CCCCC4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Product: Nc1nc(OCCC2CCCCC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 100-mL one-neck round bottom flask was added under a nitrogen atmosphere 2-[2-(cyclohexyl)ethoxy]-2′,3′,5′-tri-O-(TERT-butyldimethylsilyl)-adenosine (3.3 g, Example 10), anhydrous methanol (50 mL), and ammonium fluoride (1.7 g, 45.8 mmol). The resulting solution was heated to reflux for 24 hours, at which time HPLC indicated the disappearance of starting material. The reaction was cooled to room temperature, concentrated in vacuo on a rotary evaporator, and the resultant solids partitioned between ethyl acetate (50 mL) and water (30 mL). The mixture was stirred for 10 minutes, the layers separated, and the aqueous portion extracted with additional ethyl acetate (50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated to a light yellow solid. The product was purified by passing the oil through a plug of silica gel, eluting with CH2Cl2, 2% methanol in CH2Cl2, 5% methanol in CH2Cl2, and 10% methanol in CH2Cl2. Fractions containing the product were combined and concentrated at reduced pressure to afford the desired product as a white solid. 1.2 g (39%). m.p.: 105–112° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[CH:13]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=[O:14].[Li]C1C=CC=CN=1>CCOCC>[OH:14][CH:13]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[C:15]1[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=1
Reactant: Brc1cccnc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Li]CCCC
Agent: [Li]c1ccccn1
Solvent: CCOCC
Product: COC(=O)c1ccc(C(O)c2cccnc2)cc1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 64.4 %

Procedure:
To a cooled solution (-78° C.) of 10.6 mL (0.11 mol) of 3-bromopyridine in 1.2 L of anhydrous Et2O was added dropwise 93.8 mL (0.15 mol) of 1.6 M n-BuLi in hexanes over 1 h period. The turbid yellow solution was stirred at -78° C. for 25 min, and then 24.62 g (0.15 mol) of methyl 4-formylbenzoate in 300 mL of Et2O was cannulated to the lithiopyridine solution. The mixture was continually stirred at -78° C. for 2 h and at room temperature for 2 more h. The reaction was quenched with 400 mL of brine and 200 mL of H2O. The organic layer was separated and the aqueous layer was extracted with 3×1.0 L of CH2Cl2. To the combined organic layer was added 200 mL of MeOH to dissolve the product which precipitated out. This was then dried over MgSO4 and concentrated. The crude product was crystallized from MeOH to afford 17.24 g (64%) of a white solid: mp 151° C.; 1H NMR (CDCl3) δ 8.62 (br s, 1H), 8.51 (br s, 1H), 8.02 (d, J=8.3 Hz, 2H), 7.70 (d, J=7.9 Hz, 1H), 7.45 (d, J=8.3 Hz, 2H), 7.30 (br s, 1H), 5.93 (s, 1H), 3.90 (s, 3H), 2.92 (br s, 1H); FDMS 244 (M+1). Anal. (C14H13NO3.0.16C2H4O) C, H, N.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=O)[C:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B>O1CCCC1>[F:22][C:19]([F:20])([F:21])[C:18]([CH3:23])([OH:24])[CH2:17][NH:16][C:13]1[CH:12]=[CH:11][C:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:8])=[O:9])=[CH:15][CH:14]=1
Reactant: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Agent: B
Solvent: C1CCOC1
Product: CC(O)(CNc1ccc(S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 33.5 %

Procedure:
To a solution of N-(4-phenylsulfonylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (0.5 g, 1.33 mmol) in tetrahydrofuran (10 mL) at 0° C. was added a solution of borane in tetrahydrofuran (3.14 mL of 1.0M, 3.14 mmol) in a dropwise manner. The mixture was stirred at 0° C. for 15 minutes and was then refluxed for 18 hours. Excess borane was quenched by the careful addition of methanol. Evaporation of the mixture gave a white solid. The solid was partitioned between an aqueous sodium bicarbonate solution and dichloromethane. The combined organic extracts were dried and evaporated to yield the title compound (0.16 g); mp 145°-146° C.; NMR 1.27 (s,3, CH3), 3.32 (d,2, CH2), 6.13 (s,1, OH), 6.70 (m,1, NH), 6.82 (d,2, J=8.8, Ar), 7.58 (m,5, Ar), 7.84 (d,2, J=7.7, Ar); MS: m/z=360 (M+1). Analysis for C16H16F3NO3S.0.75 H2O: Calculated: C, 51.54; H, 4.73; N, 3.76; Found: C, 51.63; H, 4.38; N, 3.70.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](O)=[O:14])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(Cc2ccccc2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC1CCN(Cc2ccccc2)C1
Temperature: 0 °C

Procedure:
35 g (0.16 mol) of N-benzyl-2-pyrrolidone-3-carboxylic acid dissolved in 250 ml of absolute tetrahydrofuran is added dropwize, with stirring, to 12.2 g (0.32 mol) of lithium aluminium hydride in 350 ml of absolute tetrahydrofuran. After refluxing for 6 hours, 18.2 ml of water, 12.2 ml of 15% sodium hydroxide solution and 36.6 ml of water are added, whilst cooling with ice water. The precipitate formed is suction filtered and washed with tetrahydrofuran. The combined filtrates are concentrated by evaporation in vacuo and the residue obtained is purified over 900 g of aluminium oxide (neutral, activity II) with methylene chloride and then with increasing amounts of ethanol (up to 2%). Yield: 16 g (52.3% of theory), Rf value: 0.42 (aluminium oxide, neutral, eluant: 5% ethanol in methylene chloride).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([CH:17]([CH3:19])[CH3:18])=[CH:21][CH:22]=2)=[O:28])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: CC(C)c1ccc(N=C=O)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(C(C)C)cc2)cc1-c1c(Br)cnn1C
Yield: 50 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.035 g, 0.12 mmol) was treated with 4-isopropylphenyl isocyanate (0.022 g, 21.0 μL, 0.13 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.10 to afford Compound 23 (0.028 g, 0.06 mmol, 50%) as a solid film. LCMS m/z (%)=443 (M+H79Br, 100), 445 (M+H81Br, 99). 1H NMR (400 MHz, acetone-d6) δ: 8.08 (s, 1H), 8.00 (s, 1H), 7.68 (dd, J=2.6, 8.9 Hz, 1H), 7.49 (s, 1H), 7.40-7.46 (m, 3H), 7.09-7.17 (m, 3H), 3.81 (s, 3H), 3.68 (s, 3H), 2.78-2.92 (m, 1H), 1.21 (s, 3H), 1.20 (s, 3H).
Reaction SMILES: [O:1]=[C:2]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]([OH:18])=O)[C:3](=[O:9])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1.[NH:19]([C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([CH3:31])[N:22]=1)[NH2:20].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:31][C:23]1[N:22]=[C:21]([NH:19][NH:20][C:16]([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][N:10]2[C:2](=[O:1])[C:3](=[O:9])[C:4]2[S:5][CH:6]=[CH:7][CH:8]=2)=[O:18])[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=1
Reactant: Cc1cc(C(F)(F)F)cc(NN)n1
Reactant: O=C(C(=O)N1CCCCC1C(=O)O)c1cccs1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(F)(F)F)cc(NNC(=O)C2CCCCN2C(=O)C(=O)c2cccs2)n1

Procedure:
From Intermediate 3 (267 mg, 1 mmol), 2-hydrazino-6-methyl-4-trifluoromethylpyridine (191 mg, 1 mmol), PyBrop (466 mg, 1 mmol), DMAP (122 mg) and DIEA (2 mL) in THF (30 mL), using the same procedure for Compound 1, the title compound was obtained as a white solid; 110 mg (25%). MS (m/z) 441 (M+1).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][C:16]2[CH:28]=[C:27]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:26]=[CH:25][C:17]=2[C:18]([O:20]C(C)(C)C)=[O:19])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][C:16]2[CH:28]=[C:27]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:26]=[CH:25][C:17]=2[C:18]([OH:20])=[O:19])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(/C=C/C(=O)Nc2cc(Oc3ccccc3)ccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Oc1ccc(/C=C/C(=O)Nc2cc(Oc3ccccc3)ccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-((E)-3-(4-acetoxyphenyl)acrylamido)-4-phenoxybenzoate and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the obtained residue was purified with reversed-phase silica gel column chromatography [eluent; 60-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to obtain 34 mg of 2-((E)-3-(4-acetoxyphenyl)acrylamido)-4-phenoxybenzoic acid as white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][CH2:15][S:16]([O:19]C3C=CC=CC=3)(=[O:18])=O)[CH:12]=2)[NH:7][CH:6]=1.[CH3:27][NH2:28]>N1C=CC=CC=1>[CH3:26][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][CH2:15][S:16]([NH:28][CH3:27])(=[O:18])=[O:19])[CH:12]=2)[NH:7][CH:6]=1
Reactant: CN(C)CCc1c[nH]c2ccc(CCS(=O)(=O)Oc3ccccc3)cc12
Reactant: CN
Solvent: c1ccncc1
Product: CNS(=O)(=O)CCc1ccc2[nH]cc(CCN(C)C)c2c1

Procedure:
The product of stage (v) (70 mg) in a saturated solution of methylamine in pyridine (4 ml) was heated at 100° in a "reactival" for 1.5 h. The mixture was concentrated and the residue oil purified by column chromatography (B) to give the title compound as an oil (7 mg), which was shown by n.m.r. and t.l.c. (B, Rf 0.3) to be identical with the product of Example 10 method (I).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([F:11])=[N:7][NH:8]2)=[C:4]([N+:12]([O-])=O)[CH:3]=1.BrC1C=C2C(C=NN2)=C([N+]([O-])=O)C=1.S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>CO.C(OCC)(=O)C.C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5]2[C:6]([F:11])=[N:7][NH:8][C:9]=2[CH:10]=1
Reactant: O=[N+]([O-])c1cc(Br)cc2[nH]nc(F)c12
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: O=[N+]([O-])c1cc(Br)cc2[nH]ncc12
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(Br)cc2[nH]nc(F)c12
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A mixture of 6-bromo-3-fluoro-4-nitro-1H-indazole and 6-bromo-4-nitro-1H-indazole (3:2) (187 mg) was dissolved in methanol (6 ml) and water (1.2 ml) and treated with sodium dithionate (519 mg). The solution was stirred for 2 h at 20° C. then left to stand for 3 days. This solution was then treated with sodium dithionite (438 mg) and stirred at 20° C. for 20 h. The solution was filtered through a filter tube, the residue washed with methanol (5 ml) then the combined filtrates were evaporated to dryness to give a yellow solid. This was treated with ethyl acetate (10 ml) and water (10 ml) and the solid dissolved. The organic phase was separated, dried with sodium sulphate, filtered then evaporated to give a pale yellow solid. This solid was treated with DCM (5 ml), methanol (5 ml) and ethyl acetate (10 ml), but some white solid did not dissolve. The supernatant was pipetted off, then blown to dryness to give a yellow solid which was dissolved in 1:1 methanol:DMSO (1 ml) and purified by mass directed preparative HPLC (Method A). The residue was azeotroped with methanol (5 ml) to give the title compound (19 mg) as a white solid.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][C:10](=[O:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:21]=[C:22]([Mg]Br)[CH:23]=[CH:24][C:25]=1[Cl:26].ClC1C=CC(C2(O)CN(C(C3C=CC=CC=3)C3C=CC=CC=3)C2)=CC=1>>[Cl:19][C:20]1[CH:21]=[C:22]([C:10]2([OH:12])[CH2:11][N:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Clc1ccc([Mg]Br)cc1Cl
Agent: OC1(c2ccc(Cl)cc2)CN(C(c2ccccc2)c2ccccc2)C1
Product: OC1(c2ccc(Cl)c(Cl)c2)CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
This compound was prepared from compound (3) and 3,4-dichlorophenylmagnesium bromide using the procedure described for compound (4).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[CH2:14]([N:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23](B(O)O)[CH:24]=2)[C:19]1=[O:30])[CH2:15][CH2:16][CH3:17]>>[CH2:14]([N:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:2]3[CH:3]=[N:4][CH:5]=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:7]=3)[CH:24]=2)[C:19]1=[O:30])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN1Cc2cc(B(O)O)ccc2C1=O
Reactant: Brc1cncc(-c2ccccc2)c1
Product: CCCCN1Cc2cc(-c3cncc(-c4ccccc4)c3)ccc2C1=O
Yield: 14 %

Procedure:
As described for Example 23 starting from 3-bromo-5-phenylpyridine (50 mg, 0.214 mmol, commercially available) and 2-butyl-1-oxoisoindolin-5-ylboronic acid (49.8 mg, 0.214 mmol, s. above). Yield 14% (10 mg).
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:8]=1[OH:15].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[C:13]([C:11]1[CH:10]=[CH:9][C:8]2[O:15][CH2:2][C:3](=[O:4])[NH:6][C:7]=2[CH:12]=1)#[N:14]
Reactant: O=C(Cl)CCl
Reactant: N#Cc1ccc(O)c(N)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)NC(=O)CO2
Temperature: 0 °C
Yield: 60.5 %

Procedure:
Chloroacetyl chloride (3.12 ml, 38 mmol) was added dropwise to a solution of 2-amino-4-cyanophenol (4.96 g, 37 mmol), triethylamine (10.98 ml, 78 mmol) and 4-(dimethylamino)pyridine (0.09 g, 0.74 mmol) in dry dichloromethane (40 ml) maintained at 0° C. The solution refluxed for 24 h. The reaction mixture was cooled, and the organic layer was washed with phosphoric acid (0.5 M), saturated sodium bicarbonate, water and brine, then dried with anhydrous magnesium sulfate. The organic layer was filtered, then evaporated to dryness. The residue was recrystalized from ethanol to afford 3.9 g (60%) of the titled compound. (mp 243–245° C.).
Reaction SMILES: [F-].[K+].[F:3][CH:4]([F:21])[O:5][C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][CH:7]=1.[NH2:22][C:23]1[N:28]=[C:27](Cl)[N:26]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[C:24]=1[O:34][CH3:35].P(C1C=C(S([O-])(=O)=O)C=CC=1)(C1C=C(S([O-])(=O)=O)C=CC=1)C1C=C(S([O-])(=O)=O)C=CC=1>CCOC(C)=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[NH2:22][C:23]1[N:28]=[C:27]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH:4]([F:3])[F:21])=[CH:11][CH:10]=2)[N:26]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[C:24]=1[O:34][CH3:35]
Reactant: COC(=O)c1nc(Cl)nc(N)c1OC
Reactant: CC1(C)OB(c2ccc(OC(F)F)cc2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2ccc(OC(F)F)cc2)nc(N)c1OC
Temperature: 25 °C
Reaction time: 0.1 h
Yield: 39.8 %

Procedure:
To a 5-mL microwave safe vial was added potassium fluoride (0.151 g, 2.59 mmol), palladium (II) acetate (0.012 g, 0.052 mmol), 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.28 g, 1.037 mmol), methyl 6-amino-2-chloro-5-methoxypyrimidine-4-carboxylate (0.226 g, 1.037 mmol), and 3,3′,3″-phosphinetriyltribenzenesulfonate (0.052 g, 0.104 mmol). A mixture of water (1 mL) and acetonitrile (2 mL) was added and the reaction was capped and placed in a Biotage Initiator™ microwave reactor for 6 min at 160° C., with external IR-sensor temperature monitoring from the side of the vessel. Upon cooling to room temperature, the reaction mixture was diluted with EtOAc (50 mL) and water (50 mL). An additional extraction using CH2Cl2 (50 mL) was combined with the EtOAc and dried over of Na2SO4 (50 g) after the CH2Cl2 layer was filtered through cotton plug. The combined organics were concentrated on a rotary evaporator and the residue was purified using a Teledyne ISCO purification system with a gradient eluent system of CH2Cl2 and EtOAc to yield the title compound as a tan solid (134.4 mg).