Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[S:5][C:6]=1Br.C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)OC1>O1CCOCC1.O.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>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[S:5][C:6]=1[C:24]1[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Reactant: O=C(O)c1cc(Br)c(Br)s1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nccc1-c1sc(C(=O)O)cc1Br
Temperature: 80 °C

Procedure:
To a solution of 4,5-dibromo-2-thiophenecarboxylic acid (1 g, 3.5 mmol) in dioxane/H2O (5:1, 18 mL) was added K2CO3 (1.9 g, 13.98 mmol), tetrakistriphenylphosphine Pd(0) (201 mg, 0.175 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (678 mg, 3.5 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 12 h and was then partitioned between 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ˜3 with 3M HCl and washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (˜1 g, quant.): LC-MS (ES) m/z=288 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].[OH:18]O>ClCCl.O.C[Re](=O)(=O)=O.[O-2].[Mn+4].[O-2]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N+:11]([O-:18])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:14]([F:17])([F:15])[F:16]
Reactant: OO
Reactant: Fc1ccc(-c2ccncc2)cc1C(F)(F)F
Agent: C[Re](=O)(=O)=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: O
Solvent: ClCCl
Product: [O-][n+]1ccc(-c2ccc(F)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
Then, 4-(4-fluoro-3-trifluoromethyl-phenyl)-pyridine-1-oxide 74 was prepared as follows. To a solution of compound 73 (2.49 g, 10.3 mmol) in dichloromethane (10 mL) was added methyltrioxorhenium(VII) (0.128 g, 0.515 mmol), followed by hydrogen peroxide in water (30%, 5.15 mL). The reaction mixture was stirred at room temperature for 16 hours. Manganese (IV) oxide (0.050 g) was added. The mixture was stirred for another 30 minutes. The organic layer was separated. The aqueous layer was extracted with more dichloromethane (2×10 mL). The combined organic phase was washed with brine (3×30 mL), dried over MgSO4 and filtered. After evaporating the solvent, the crude material was loaded to a silica gel column, eluting with 10% methanol in ethyl acetate to give a white solid 74 (2.51 g, 94%). 1H-NMR (CDCl3, 400 MHz) δ 7.35 (t, J=9.3 Hz, 1H), 7.49 (d, J=7.2 Hz, 2H), 7.74–7.82 (m, 2H), 8.30 (d, J=7.1 Hz, 2H); MS (DCI) m/z 258, 259 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH2:11][CH2:12][CH3:13])[C:8]([OH:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:15]([O-])([OH:17])=[O:16]>[N+](C)([O-])=O>[F:1][C:2]1[C:3]([C:4]([OH:6])=[O:5])=[C:7]([N+:15]([O-:17])=[O:16])[C:8]([OH:14])=[C:9]([CH2:11][CH2:12][CH3:13])[CH:10]=1
Reactant: O=[N+]([O-])O
Reactant: CCCc1cc(F)c(C(=O)O)cc1O
Solvent: C[N+](=O)[O-]
Product: CCCc1cc(F)c(C(=O)O)c([N+](=O)[O-])c1O
Temperature: 40 °C
Yield: 48 %

Procedure:
2-Fluoro-5-hydroxy-4-propylbenzoic acid (500 mg, 2.52 mmol) was dissolved in nitromethane (50 mL) through heating to 40° C. and nitric acid (90%, 120 μL, 2.52 mmol) was added. After 10 min at 40° C. followed by reaction at room temperature for 2 h the solvent was evaporated. The residue was dissolved in EtOAc (150 mL), washed with brine (10 mL), dried (MgSO4) and concentrated to dryness giving 640 mg of crude product. Subsequent purification by flash chromatography (SiO2, EtOAc-HOAc 50:1) afforded pure 6-fluoro-3-hydroxy-2-nitro-4-propylbenzoic acid (294 mg). Mp: 128.0°-129.0° C. 1H NMR (DMSO-d6); δ10.2 (br, 1H), 7.39 (d, J=10.4 Hz, 1H), 2.63 (t, J=7.6 Hz, 2H), 1.55 (m, J=7.5 HZ, 2H), 0.89 (t, J=7.4 Hz, 3H). 13C NMR (DMSO-d6): δ162.49, 151.66 (d, J=245 Hz), 143.69, 138.74 (d, J=5 Hz), 138.17 (d, J=8 Hz), 120.25 (d, J=23 Hz), 113.82 (d, J=21 Hz), 31.44, 21.92, 13.60. MS (EI, 70 eV): m/z (rel. int) 243 (M+, 88).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([C@@H:8]([NH2:10])[CH3:9])=[N:6][CH:7]=1.Cl[C:12]1[N:17]=[C:16]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[C:15]([CH3:25])=[CH:14][N:13]=1.CCN(C(C)C)C(C)C>CCCCO>[F:1][C:2]1[CH:3]=[N:4][C:5]([C@@H:8]([NH:10][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=3)[C:15]([CH3:25])=[CH:14][N:13]=2)[CH3:9])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2C)n[nH]1
Reactant: C[C@H](N)c1ncc(F)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ncc2C)n[nH]1
Temperature: 180 °C
Yield: 36.3 %

Procedure:
A microwave reaction vessel was charged with (S)-1-(5-fluoropyrimidin-2-yl)ethanamine (Method 7, 111 mg, 0.63 mmol), 2-chloro-5-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 22, 0.50 g, 1.77 mmol), and DIPEA (0.225 mL, 1.26 mmol). Anhydrous n-BuOH (2.1 ml) was added, and the tube was sealed and heated in a microwave reactor at 180° C. for 4 hours. The solvent was removed under reduced pressure and the residue was purified by Gilson (5-95% MeCN/H2O, 15 minutes) to give the titled compound as solid (75 mg) 1H NMR (300 MHz, DMSO-d6) δ 10.08 (s, 1H) 8.93 (s, 2H) 8.70 (s, 1H) 7.74 (s, 1H) 5.98 (s, 1H) 4.79-5.44 (m, 1H) 2.23 (s, 3H) 2.10 (s, 3H) 1.57 (d, 3H); m/z 330.
Reaction SMILES: [NH2:1][C:2]([CH3:10])([CH2:5][S:6]([CH3:9])(=[O:8])=[O:7])[C:3]#[N:4].CCN(C(C)C)C(C)C.[C:20](Cl)(=[O:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:22]([O:21][C:20](=[O:29])[NH:1][C:2]([C:3]#[N:4])([CH3:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(N)(C#N)CS(C)(=O)=O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C#N)(CS(C)(=O)=O)NC(=O)OCc1ccccc1
Temperature: 45 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
To a solution of 2-Amino-3-methanesulfonyl-2-methyl-propionitrile (Example 80a, 5.01 g, 30.9 mmol) in dry THF (119 mL) was added DIEA (12.1 mL, 67.9 mmol) and benzyl carbonochloridate (CAN 501-53-1, 5.57 mL, 37.1 mmol). Reaction was stirred at 45° C. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethylacetate and was extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic layer was dried over sodium sulfate and evaporated down to dryness. The crude was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (8.12, 89%) as a yellow oil. MS (ESI, m/z): 297.5 (M+H+).
Reaction SMILES: [C:1]1(=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=N)[NH:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=N)[NH:2]1.[CH3:21][N:22]1[C:29](=[O:30])[CH2:28][C:26](=[O:27])[N:25]([CH3:31])[C:23]1=[O:24]>CN1C(=O)CCC1.C(O)(=O)C>[CH3:31][N:25]1[C:26](=[O:27])[C:28](=[C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11](=[C:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3](=[C:28]4[C:29](=[O:30])[N:22]([CH3:21])[C:23](=[O:24])[N:25]([CH3:31])[C:26]4=[O:27])[NH:2]3)[NH:12]2)[C:29](=[O:30])[N:22]([CH3:21])[C:23]1=[O:24]
Reactant: N=C1NC(=C2NC(=N)c3ccccc32)c2ccccc21
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: CN1C(=O)C(=c2[nH]c(=c3[nH]c(=C4C(=O)N(C)C(=O)N(C)C4=O)c4ccccc34)c3ccccc23)C(=O)N(C)C1=O
Temperature: 25 °C

Procedure:
10 g of [1,1′]biisoindolylidene-3,3′-diimine and 18.1 g of 1,3-dimethyl-barbituric acid are stirred in a mixture of 160 ml of NMP and 40 ml of glacial acetic acid at reflux for 5 hours. After cooling to room temperature the suspension is filtered and the filter product is washed with ethanol and then water and dried at 60° C. This gives 14.5 g (70%) of a virtually black powder of a compound of the following formula
Reaction SMILES: CI.Cl[CH2:4][CH2:5][CH2:6][N:7]([CH3:9])[CH3:8].[CH3:10][C:11]1[C:21]2[CH:20]=[CH:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16](=[O:26])[C:15]=2[CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>CCOCC>[CH3:10][C:11]1[C:21]2[CH:20]=[CH:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16]([CH2:4][CH2:5][CH2:6][N:7]([CH3:9])[CH3:8])([OH:26])[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: CN(C)CCCCl
Reactant: Cc1cccc2c(=O)c3ccccc3ccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CI
Product: Cc1cccc2c1C=Cc1ccccc1C2(O)CCCN(C)C
Temperature: 45 °C
Reaction time: 5 h

Procedure:
20 g. of Gilman alloy are covered with 40 ml. of dry ether and treated with 0.5 ml. of methyl iodide. After the vigorous reaction has subsided somewhat, a solution containing 80 ml. of 1-chloro-3-dimethylaminopropane in 360 ml. of dry ether is added dropwise in such a way that the reaction mixture is maintained at boiling. The mixture is stirred at 45° C. under reflux conditions for an additional 5 hours. The reaction mixture is then cooled with ice-water and a solution containing 43.6 g. of 1-methyl-5H-dibenzo[a,d]cyclohepten-5-one in 820 ml. of dry ether is added over a one-hour period. Subsequently, the mixture is boiled and stirred at reflux for another 17 hours. After about 12 hours, it is once more cooled with ice water and decomposed with a cold saturated ammonium chloride solution. The organic layer is separated, washed with water, dried over sodium sulfate and evaporated. The 1-methyl-5-(3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene obtained is recrystallized from high-boiling petroleum ether and has a melting point of 141°-143° C.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[O:17][C:16]([C:19](O)=[O:20])=[CH:15][C:14]3=[O:22])[CH2:5][CH2:4]1.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.[NH2:40][C:41]1[CH:46]=[CH:45][C:44]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:43][C:42]=1O>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:2][N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[O:17][C:16]([C:19]([NH:40][C:41]2[CH:42]=[CH:43][C:44]([N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)=[CH:45][CH:46]=2)=[O:20])=[CH:15][C:14]3=[O:22])[CH2:7][CH2:8]1
Reactant: CN1CCN(c2cccc3c(=O)cc(C(=O)O)oc23)CC1
Reactant: Nc1ccc(N2CCOCC2)cc1O
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c(=O)cc(C(=O)Nc4ccc(N5CCOCC5)cc4)oc23)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
8-(4-methyl-1-piperazinyl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) (400 mg, 1.23 mmol) was suspended in anhydrous N,N-dimethylformamide (20 ml) and triethylamine (0.69 ml, 4.92 mmol) was added to give a clear solution. The following were added in order: 1-hydroxybenzotriazole (HOBt (205 mg, mol)), O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-pentamethylene-uronium tetrafluoroborate (TBTU (435 mg, 3.1 mmol)) then 4-(dimethylamino)pyridine (25 mg). After stirring for 5 min at room temperature, 4-(4-morpholinyl)aniline (Reference Example 21) (220 mg, mmol). The reaction stirred overnight at room temperature. The solution was concentrated in vacuo, the remains were partitioned between chloroform/saturated sodium bicarbonate, extracted (×3) with chloroform, dried (MgSO4) and concentrated in vacuo to give the crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:17])[C:12](=[CH2:16])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[F:29][C:30]([F:47])([F:46])[O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[C:42]([CH2:44][NH2:45])[CH:41]=[CH:40][N:39]=2)=[CH:34][CH:33]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH3:17])[C:12](=[CH2:16])[C:13]([NH:45][CH2:44][C:42]2[CH:41]=[CH:40][N:39]=[C:38]([C:35]3[CH:34]=[CH:33][C:32]([O:31][C:30]([F:47])([F:29])[F:46])=[CH:37][CH:36]=3)[CH:43]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: C=C(C(=O)O)N(C)S(=O)(=O)c1ccc(Cl)cc1
Reactant: NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1)N(C)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 18 %

Procedure:
A solution of acid 4C (0.50 g, 1.8 mmol) in THF (30 mL) was added with DEPC (0.35 mL, 1.3 mol eq) and the mixture stirred at room temperature several minutes. Then [2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 21B (0.53 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 and brine. The separated organic phase was dried over an. Na2SO4 and evaporated under reduced pressure. The residue was purified by flash chromatography (7:3 EtOAc:Petroleum ether) to afford a pale yellow viscous oil (0.17 g). Yield=18%, 1HNMR (DMSO, 200 MHz) δ 2.98 (s, 3H), 4.22 (d, 2H), 5.08 (s, 1H), 5.85 (s, 1H), 7.4 (m, 3H), 7.65 (dd, 4H, J=8), 7.95 (s, 1H), 8.2 (d, 2H), 8.58 (d, 1H), 8.95 (t, 1H); [M+1] 525.93 (C23H19ClF3N3O4S requires 525.07).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]([NH2:29])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:30](=O)[CH3:31].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]([NH:29][CH2:30][CH3:31])=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(N)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCNc1nn(C(=O)OC(C)(C)C)c2ccc(C3C(C#N)=C(C)NC(C)=C3C#N)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a stirred mixture of 13.40 g (25.74 mmol) 3-amino-5-(3,5-dicyano-1,4-dihydro-2,6-dimethyl-4-pyridinyl)-1H-indazole-1-carboxylic acid tert-butyl ester, from Synthetic Example 18, in 335 mL dry methanol, was added 2.19 mL acetaldehyde and 2.06 mL glacial acetic acid and the resulting mixture was stirred overnight at room temperature. The reaction was cooled (ice bath) before 3.24 g sodium cyanoborohydride was added in three portions. The mixture was stirred overnight at room temperature before the reaction was concentrated to roughly half volume under vacuum. The residue was partitioned between EtOAc and saturated aqueous sodium hydrogen carbonate solution and the organic extract washed with saturated aqueous sodium chloride solution and concentrated under vacuum. The residue was taken up in hot EtOAc and allowed to cool to room temperature before being triturated with diisopropyl ether. The stirred suspension was cooled (ice bath), filtered and the crude product washed with diisopropyl ether. The product was dried under vacuum to afford 5-(3,5-dicyano-1,4-dihydro-2,6-dimethyl-4-pyridinyl)-3-(ethylamino)-1H-indazole-1-carboxylic acid tert-butyl ester (8.25 g, 76.6%) (Cpd. No. 117, Table 2). 1H-NMR (DMSO-D6, 300 MHz): δ=9.54 (br s, 1H), 7.86 (d, 1H), 7.73 (m, 1H), 7.41 (dd, 1H), 6.82 (t, 1H), 4.47 (s, 1H), 3.26-3.34 (partially obscured by solvent, m, 2H), 2.02 (s, 6H), 1.57 (s, 9H), 1.21 (t, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][CH:12]=[C:11]([CH2:14][OH:15])[CH:10]=1.C[N+]1([O-])CCOCC1>C(#N)C.C(OCC)(=O)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][CH:12]=[C:11]([CH:14]=[O:15])[CH:10]=1
Reactant: OCc1c[nH]c(-c2c(F)cccc2F)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1c[nH]c(-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To a solution (26 mL) of [5-(2,6-difluorophenyl)-1H-pyrrol-3-yl]methanol (2.56 g) in acetonitrile were added tetra-n-propylammonium perruthenate (430 mg), N-methylmorpholine N-oxide (2.15 g) and molecular sieves 4 A powder (5 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (60 mL) and filtered through celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as pale-red crystals (yield 1.94 g, 77%).
Reaction SMILES: CN[C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]([NH:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([CH3:31])[N:26]=[CH:25]4)=[O:20])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[OH-:32].[K+]>CO.O>[CH3:31][N:27]1[C:28]2[C:24](=[CH:23][C:22]([NH:21][C:19]([NH:18][C:14]3[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=3)[O:11][C:9]3[CH:8]=[CH:7][N:6]=[C:5]([C:3]([OH:32])=[O:4])[CH:10]=3)=[O:20])=[CH:30][CH:29]=2)[CH:25]=[N:26]1
Reactant: CNC(=O)c1cc(Oc2cccc(NC(=O)Nc3ccc4c(cnn4C)c3)c2)ccn1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cn1ncc2cc(NC(=O)Nc3cccc(Oc4ccnc(C(=O)O)c4)c3)ccc21
Temperature: 40 °C
Yield: 717.6 %

Procedure:
A mixture of N-methyl-4-[3-({[(1-methyl-1H-indazol-5-yl)amino]carbonyl}amino)-phenoxy]pyridine-2-carboxamide (80 mg, 0.19 mmol) and powdered potassium hydroxide (0.03 g, 0.56 mmol) was dissolved in MeOH/H2O (4 mL, 3:1), and the reaction mixture was heated at 40° C. for 3 h. The solvent was removed in vacuo, the crude residue dissolved in H2O (5 mL), and precipitated on being neutralized with aq. 1N HCl. The precipitated solid was washed with water and then CH2Cl2 to give 0.55 g (70%) of the carboxylic acid. 1H-NMR (DMSO-d6) δ 9.97 (s, 1H), 9.77 (s, 1H), 8.46 (d, 1H), 7.93 (s, 1H), 7.90 (s, 1H), 7.51 (d, 1H), 7.43-7.34 (m, 5H), 7.07 (dd, 1H), 6.73 (dd, 1H), 3.97 (s, 3H); MS LC-MS (M+H)+=404.1, RT=2.45 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.Cl[C:13]([F:19])([F:18])C(OC)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:18][CH:13]([F:19])[O:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: COC(=O)C(F)(F)Cl
Reactant: O=[N+]([O-])c1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Br)cc1OC(F)F
Temperature: 120 °C
Reaction time: 1 h
Yield: 30.5 %

Procedure:
5-Bromo-2-nitrophenol (1 g, 4.59 mmol) and methyl 2-chloro-2,2-difluoroacetate (991 mg, 6.9 mmol) were dissolved in dry DMF (3 mL). Potassium carbonate (1.27 g, 9.18 mmol) was added and the reaction was stirred at 120° C. for 1 hour. The reaction was cooled to room temperature and diluted with ethyl acetate (20 mL). The organic solution was washed with water (20 mL), brine (20 mL), dried over sodium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 20% dichloromethane in hexanes to afford the title compound as a dark brown oil (375 mg, 30%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH2:9]O)[CH:5]=[CH:4][N:3]=1.CN(C=O)C.O=P(Cl)(Cl)[Cl:18]>N#N>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][Cl:18])[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccnc(Cl)c1Cl
Reactant: O=P(Cl)(Cl)Cl
Agent: N#N
Solvent: CN(C)C=O
Product: ClCc1ccnc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2,3-Dichloro-pyridin-4-yl)-methanol (0.256 g, 1.44 mmol) was dissolved in 5 mL anhydrous under N2. Anhydrous DMF (o. 111 mL, 1.44 mmol) was added followed by dropwise addition of POCl3 (0.134 mL, 1.44 mmol). The reaction was stirred at RT overnight. After 16 h the reaction was quenched by the addition of sat aq NaHCO3. The mixture was extracted 3× with DCM. The organic phases were dried over Na2SO4, filtered, and concentrated to provide the pure titled compound. 1H NMR (CDCl3) δ 8.33 (d, 1H, J=4.9 Hz), 7.44 (d, 1H, J=4.9 Hz), 4.68 (s, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[O:15]1>>[CH3:19][C:18]1([CH3:20])[C:14]([CH3:13])([CH3:28])[O:15][B:16]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:2][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=3)=[CH:23][CH:22]=2)[O:17]1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Product: CC1(C)OB(c2ccc(OCc3ccc4ccccc4c3)cc2)OC1(C)C
Yield: 85 %

Procedure:
Alkylation of 2-Bromomethyl-naphthalene with 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol was carried out according to procedures in Step 5A in Example 2A to give 4,4,5,5-Tetramethyl-2-[4-(naphthalen-2-ylmethoxy)-phenyl]-[1,3,2]dioxaborolane in 85% yield. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.3 (s, 12 H) 5.3 (s, 2 H) 7.0 (d, J=8.6 Hz, 2 H) 7.5 (m, 2 H) 7.5 (dd, J=8.3, 1.8 Hz, 1 H) 7.8 (d, J=8.6 Hz, 2 H) 7.9 (m, 4 H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12].Cl[CH2:15][S:16]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17].CC(C)([O-])C.[K+].Cl>C1COCC1>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH2:15][S:16]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)(=[O:17])=[O:18])[CH:8]=[CH:9][CH:10]=1
Reactant: O=S(=O)(CCl)c1cccc2ccccc12
Reactant: O=[N+]([O-])c1ccccc1OCCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(CS(=O)(=O)c2cccc3ccccc23)cccc1OCCCl
Reaction time: 5 h
Yield: 50 %

Procedure:
A mixture of 1-(2-chloro-ethoxy)-2-nitrobenzene (1.2 g, 6 mmoles) and 1-chloromethane-sulfonyl-naphthalene (2.16 g, 9 mmoles) was stirred in THF (50 ml) at −78° C., in a round bottom flask under nitrogen. A solution of 1M potassium t-butoxide was added drop wise (18 mL, 18 mmoles) over a half an hour period. Temperature was allowed to rise to −40° C., and the reaction mixture was stirred at this temperature for 5 hours. The reaction mixture was poured into cold 2N HCl, extracted with EtOAc, dried over Na2SO4, and concentrated under vacuum. Compound was recrystallized from CH2Cl2/hexane to afford the title compound as an off-white solid (1.4 g, 3 mmoles).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.O.[C:15]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]1([CH3:13])[CH:2]=[CH:3][C:4]([C:7]2([C:10]([O:12][CH3:15])=[O:11])[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccc(C2(C(=O)O)CC2)cc1
Solvent: O
Solvent: CO
Product: COC(=O)C1(c2ccc(C)cc2)CC1
Temperature: 75 °C
Reaction time: 16 h
Yield: 969.3 %

Procedure:
To a stirred solution of 1-(p-tolyl)cyclopropanecarboxylic acid (6 g, 34.05 mmol) in methanol (48 mL), was added para-toluenesulphonic acid monohydrate (0.648 g, 3.405 mmol). The reaction was stirred at 75° C. for 16 hours. The mixture was concentrated under reduced pressure, and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium bicarbonate solution (×2), brine and dried (magnesium sulfate), filtered, and concentrated under reduced pressure to afford the title compound as an orange oil (6.279 g, 97%). The material was used directly in the next step with no further purification.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH:8]1[NH:12][C:11](=[O:13])[CH2:10][CH2:9]1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCCCCC.O1CCCC1>[C:14]([N:12]1[CH:8]([O:7][CH3:6])[CH2:9][CH2:10][C:11]1=[O:13])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC1CCC(=O)N1
Reactant: O=C(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC1CCC(=O)N1C(=O)c1ccccc1
Yield: 41.5 %

Procedure:
20.8 cm3 of a 1.5M solution of butyllithium in hexane is added at -70° C. to a solution of 3.8 g of 5-methoxy pyrrolidin-2-one in 160 cm3 of tetrahydrofuran. This temperature is maintained for 20 minutes, then 4.69 g of benzoyl chloride in solution in tetrahydrofuran is added. After allowing to return to ambient temperature, the mixture is concentrated to dryness and chromatographed on silica (eluent: hexane-ethyl acetate 1-1). 3 g of expected product is obtained. m.p. =92°-94° C. crystallized from isopropyl ether.