Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.C([O-])([O-])=O.[K+].[K+]>CCO.O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=C1NCCc2ccc(O)cc21
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C1NCCc2ccc(OCCCCBr)cc21
Reaction time: 8 h
Yield: 64.3 %

Procedure:
A mixture of intermediate 19 (196 mg, 1.2 mmol), 1,4-dibromobutane (0.43 mL, 3.6 mmol) and anhydrous K2CO3 (166 mg, 1.22 mmol) was dissolved in EtOH (4 mL) and the solution was heated to reflux and stirred overnight. The mixture was diluted with water and extracted with EtOAc. The combined EtOAc layers were washed with water, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with PE/EtOAc=3:1) to give 7-(4-bromobutoxy)-3,4-dihydroisoquinolin-1(2H)-one (intermediate 21) (230 mg, 63%) as a white solid.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:9]2=[N:10][C:11]([Cl:23])=[C:12]([O:14]C(=O)C3C=CC=CC=3)[CH:13]=[C:8]2[CH:7]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][CH2:2][O:3][C:4]([C:6]1[N:24]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[C:9]2=[N:10][C:11]([Cl:23])=[C:12]([OH:14])[CH:13]=[C:8]2[CH:7]=1)=[O:5]
Reactant: CCOC(=O)c1cc2cc(OC(=O)c3ccccc3)c(Cl)nc2n1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cc2cc(O)c(Cl)nc2n1C(=O)OC(C)(C)C

Procedure:
This compound was prepared in analogy to example 3, intermediate d) from 5-benzoyloxy-6-chloro-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester and potassium carbonate.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]3[C:20]([C:27]4[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:34])=[N:21][O:22][C:23]=3[CH:24]([CH3:26])[CH3:25])=[CH:15][CH:16]=2)=[CH:6][CH:5]=1.[OH-].[Na+].O>CO>[Cl:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:34])[C:27]=1[C:20]1[C:19]([CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:35])=[O:2])=[CH:9][CH:8]=3)=[CH:16][CH:15]=2)=[C:23]([CH:24]([CH3:26])[CH3:25])[O:22][N:21]=1
Reactant: COC(=O)c1ccc(Oc2ccc(OCc3c(-c4c(Cl)cccc4Cl)noc3C(C)C)nc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(Oc2ccc(C(=O)O)cc2)cn1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
To a solution of 4-{6-[3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethoxy]-pyridin-3-yloxy}-benzoic acid methyl ester (0.070 g, 0.14 mmol) in methanol (5 ml) was added NaOH (0.104 g, 2.6 mmol) and water (0.25 ml) and the reaction mixture was stirred at room temperature for 30 h. Then solvent was evaporated, water (1.5 ml) was added and the mixture was acidified to pH 6 with 1N hydrochloric acid and the resulting solution was extracted with ethyl acetate. The extract was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to afford 4-{6-[3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethoxy]-pyridin-3-yloxy}-benzoic acid as colorless oil. Yield: 0.037 g (53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1CCCC1.C1(=O)C2C(=CC=CC=2)CCC1>CO>[CH:14](=[C:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: O=Cc1ccccc1
Agent: O=C1CCCc2ccccc21
Solvent: C1CCNC1
Solvent: CO
Product: COc1ccc2c(c1)CCC(=Cc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 63.3 %

Procedure:
To a stirred solution of 6-methoxy-1-tetralone (0.227 mol, 40 gm) and benzaldehyde (0.272 mol, 27.5 mL) in 450 mL of methanol was added pyrrolidine (0.272 mol, 23.6 mL). The mixture was stirred at room temperature for about 4 days until TLC indicated that no starting tetralone was present. The mixture was concentrated in vacuo, then dissolved in EtOAc, washed with four portions of 10% HCl, two portions of saturated NaHCO3 solution, and one portion of brine. The solvent was removed in vacuo and the crude oil was triturated with diethyl ether to afford 38 g of the title compound of this Example 1B, m.p. 100-102° C. Analysis calculated for C18H16O2 : 264.1146. Found: 264.1149.
Reaction SMILES: [N:1]([CH:4]([CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:5])=[N+]=[N-]>CO.Cl.O=[Pt]=O>[NH2:1][CH:4]([CH:6]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:5]
Reactant: CC(C)CC(c1ccccc1)C(C)N=[N+]=[N-]
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: CC(C)CC(c1ccccc1)C(C)N
Reaction time: 2 h

Procedure:
To a solution of 32 mg 2-azido-5-methyl-3-phenylhexane in 1 mL MeOH and 2 drops of 1.2 N HCl, 4 mg PtO2 was added and the solution was stirred under H2 atmosphere for 2 h. The reaction was filtered through a pad of CELITE diatomaceotis earth and the pad was rinsed with MeOH. The combined filtrate was concentrated to give the desired product. 1H NMR: (500 MHz, CDCl3): δ 0.86 (m, 6H), 0.99 (d, 3H), 1.25 (m, 1H), 1.54 (m, 1H), 1.77 (m, 1H), 2.73 (m, 1H), 3.19 (m, 1H), 7.2-7.4 (m, 5H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C@@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:17][CH:18]=C)=[O:15])[CH:10]([CH:28]=C)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[C:14](=[O:15])[C@@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH2:17][CH:18]=[CH:28][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(Cc2ccccc2)CC1C=C
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1CC=CC2CN(Cc3ccccc3)CCN2C1=O
Yield: 44 %

Procedure:
tert-Butyl (1S)-1-[(4-benzyl-2-vinyl-1-piperazinyl)carbonyl]-3-butenylcarbamate (250 mg, 0.63 mmol) and Grubb's catalyst (26 mg, 0.03 mmol) were combined in toluene (32 mL) at room temperature. This mixture was degassed via vacuum-argon three times at room temperature. Then CH2Cl2 (32 mL) was added in one portion. The reaction mixture was heated at reflux for 5 days, then concentrated in vacuo. The residue was purified by SGC (4:1 hex-EtOAc) to give the title product (103 mg, 44%) as a yellow powder. The 1H NMR spectrum was consistent with the presence of one diastereomer, not assigned. (300 MHz, CDCl3) δ 7.35-7.27 (m, 5H), 5.76-5.72 (m, 2H), 5.67-5.58 (m, 1H), 5.35-5.01 (m, 1H), 4.68 (br s, 1H), 4.00 (m, 1H), 3.64 (d, 1H, J=13.1 Hz), 3.42 (d, 1H, J=13.2 Hz), 3.09 (dt, 1H, J=13.5, 4.1 Hz), 2.91-2.86 (m, 1H), 2.76-2.72 (m, 2H), 2.26-2.00 (m, 3H), 1.44 (s, 9H) ppm.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:18]=[C:6]2[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:9]=[C:10]([NH2:11])[N:5]2[N:4]=1.C1(C2[O:27]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1.C(OC(=O)C)C.CO>ClCCl>[CH3:1][S:2]([C:3]1[N:18]=[C:6]2[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:9]=[C:10]([NH2:11])[N:5]2[N:4]=1)=[O:27]
Reactant: CSc1nc2cc(-c3ccccn3)cc(N)n2n1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CS(=O)c1nc2cc(-c3ccccn3)cc(N)n2n1
Yield: 56 %

Procedure:
8.66 g (0.034 mol) 2-Methylsulfanyl-7-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine in 850 ml dichloromethane were oxidised with a solution of 17.6 g (0.067 mol) 3-phenyl-2-(phenylsulfonyl)oxaziridine in 150 ml dichloromethane overnight. Chromatography on aluminiumoxide (dichloromethane/ methanol 97:3) and on silicagel (ethylacetate/methanol 9:1) yielded 5.2 g (57%) 2-methanesulfinyl-7-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine, MS m/e (%):274 (M+H+,100).
Reaction SMILES: C(C(CC)CNCC1SC(C2C=C3C(=C(C(N)=O)C=2)NC=C3C2CCN(S(CC)(=O)=O)CC2)=CC=1)C.[CH:37]([C:39]1[S:43][C:42]([B:44]([OH:46])[OH:45])=[CH:41][CH:40]=1)=O.[CH2:47]([O:50][CH2:51][CH2:52][CH2:53][NH2:54])[CH2:48][CH3:49].[BH3-]C#N.[Na+]>>[CH2:47]([O:50][CH2:51][CH2:52][CH2:53][NH:54][CH2:37][C:39]1[S:43][C:42]([B:44]([OH:46])[OH:45])=[CH:41][CH:40]=1)[CH2:48][CH3:49]
Reactant: CCCOCCCN
Reactant: O=Cc1ccc(B(O)O)s1
Agent: CCC(CC)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCOCCCNCc1ccc(B(O)O)s1
Yield: 36.5 %

Procedure:
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [3-(propyloxy)propyl]amine (38 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[3-(propyloxy)propyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[3-(propyloxy)propyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). The crude product was purified twice on an Agilent MDAP using the procedure shown in preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide. The purified product was washed with a 20:4:1 mixture of hexanes/EtOAc/MeOH (2.5 mL), taken up in EtOAc (2 mL) and washed with saturated K2CO3 (1 mL). The organic layer was concentrated to give to give 1.4 mg of the title compound (2%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:11]3[C:16]([F:17])=[CH:15][N:14]=[C:13](Cl)[N:12]=3)=[CH:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:19][C@H:20]([C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[NH2:25][C:24]1[CH:23]=[C:22]([C@@H:20]([NH:19][C:13]2[N:12]=[C:11]([C:8]3[N:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]4=[N:10][CH:9]=3)[C:16]([F:17])=[CH:15][N:14]=2)[CH3:21])[CH:28]=[CH:27][CH:26]=1
Reactant: C[C@H](N)c1cccc(N)c1
Reactant: Fc1cnc(Cl)nc1-c1cnc2c(Cl)cccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@H](Nc1ncc(F)c(-c2cnc3c(Cl)cccn23)n1)c1cccc(N)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 20.5 %

Procedure:
90 mg of the 8-chloro-3-(2-chloro-5-fluoropyrimidin-4-yl)imidazo[1,2-a]pyridine [125-2] was dissolved in 3 mL of dimethylsulfoxide, then 46.6 mg of 3-[(1S)-1-aminoethyl]aniline and 100 mg of potassium carbonate were added thereto, and stirred at 60° C. for 5 hours. The reaction mixture was cooled back to room temperature, and purified by preparative reversed phase liquid chromatography. Thereto, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and 25 mg of N-[(1S)-1-(3-aminophenyl)ethyl]-4-(8-chloroimidazo[1,2-a]pyridin-3-yl)-5-fluoropyrimidine-2-amine [125-3] was obtained as a brown oily product.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:10])=[N:5][CH:6]=[CH:7][C:8]=1[Cl:9].[SH:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]([F:22])([F:21])[F:20])[N:13]=1.C(N(CC)CC)C>C(O)C>[Cl:10][C:4]1[C:3]([CH2:2][S:11][C:12]2[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]([F:22])([F:20])[F:21])[N:13]=2)=[C:8]([Cl:9])[CH:7]=[CH:6][N:5]=1
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Reactant: Clc1ccnc(Cl)c1CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: Oc1cc(C(F)(F)F)nc(SCc2c(Cl)ccnc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
A mixture of 3-(bromomethyl)-2,4-dichloropyridine (2.9 g, 12.3 mmol), 2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol (1.2 g, 6.1 mmol), and triethylamine (1.3 mL, 9.3 mmol) in absolute ethanol (25 mL) was stirred at room temperature overnight. The mixture was evaporated to dryness. The residue was dissolved in EtOAc (80 mL). The solution was extracted with water (3×50 mL) and 1 N NaOH (1×50 mL). The organic layer was recovered, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-5% MeOH/DCM), affording the title compound (475 mg, 22% yield); 1H NMR (400 MHz, DMSO-d6): δ 4.75 (s, 2H), 6.72 (s, 1H), 7.69 (d, 1H, J=5.3 Hz), 8.36 (d, 1H, J=5.3 Hz); M+ 357.
Reaction SMILES: C(OC([N:8]1[CH2:28][CH2:27][N:11]2[C:12](=[O:26])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16](/[CH:19]=[CH:20]\[CH3:21])=[CH:15][C:14]=3[C:22]([F:25])([F:24])[F:23])=O)(C)(C)C.[ClH:29]>CCOCC.O>[ClH:29].[CH:19](/[C:16]1[CH:17]=[C:18]2[C:13]([C:12](=[O:26])[N:11]3[CH2:27][CH2:28][NH:8][CH2:9][C@H:10]32)=[C:14]([C:22]([F:24])([F:25])[F:23])[CH:15]=1)=[CH:20]/[CH3:21]
Reactant: C/C=C\c1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: C/C=C\c1cc2c(c(C(F)(F)F)c1)C(=O)N1CCNC[C@@H]21
Reaction time: 1 h

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(cis-1-propenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (40 mg, 0.1 mmol) in dry ether (2 mL) was added hydrochloric acid (1 mL). The reaction was stirred for 1 h and then conc. in vacuo to a white solid. The solid was dissolved in water and lyophilized to 24 mg of a white solid. MS (ESI) 297 (M−Cl).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc3[nH]ccc23)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cccc3[nH]ccc23)CC1
Reaction time: 8 h
Yield: 96.6 %

Procedure:
A mixture of 4-(1H-Indol-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 4-6 (670 mg, 2.24 mmol) and 10% Pd/C (70 mg) in ethanol (75 mL) was placed under H2 atmosphere on the parr shaker at 50 psi, and was shaken overnight. The reaction mixture was filtered through a plug of celite capped with a glass filter. The filtrate was concentrated to afford (650 mg, 96%) of 4-(1H-Indol-4-yl)-piperidine-1-carboxylic acid tert-butyl ester 4-7. Step 6
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6](B(O)O)[CH:7]=1.I[C:14]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:15]=1[F:24].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.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>[F:20][C:19]1[C:18]([F:21])=[C:17]([F:22])[C:16]([F:23])=[C:15]([F:24])[C:14]=1[C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:11][CH3:12]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: Fc1c(F)c(F)c(I)c(F)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(F)cc1-c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Yield: 277.5 %

Procedure:
Compound 1 (6.3 g, 3.7 mmol, 1 equiv) and iodopentafluorobenzene (5.5 mL, 4 mmol, 1.2 equiv) were dissolved in toluene (120 mL). 1.0 M Potassium carbonate solution (120 mL), tetrabutylammonium bromide (600 mg), and tetrakis(triphenylphosphine)palladium(0) (2.1 g, 1.8 mmol, 0.05 equiv) were added. Nitrogen was sparged through the mixture for 10 minutes. The reaction was refluxed 18 hours, then cooled to room temperature. The layers were separated and the aqueous layer was extracted with methyl tert-butyl ether (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified over silica gel (100 g), eluting with a gradient of 0 to 4% ethyl acetate in heptane to give 2,3,4,5,5′,6-hexafluoro-2′-methoxy-1,1′-biphenyl (2) (3.0 g, 28% yield) as an off-white solid.
Reaction SMILES: [C:1](=O)([O:37]C1C=CC=CC=1)[O:2][C:3]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][CH3:36])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])(=[O:16])=[O:15])[C:4]1=[O:27].[CH3:45][C:46]1[N:51]=[C:50]([N:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)[CH:49]=[CH:48][CH:47]=1>CN(C=O)C>[CH3:45][C:46]1[N:51]=[C:50]([N:52]2[CH2:57][CH2:56][N:55]([C:1]([O:2][C:3]3([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH2:35][CH3:36])[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=4)[N:5]([S:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=4[O:25][CH3:26])(=[O:16])=[O:15])[C:4]3=[O:27])=[O:37])[CH2:54][CH2:53]2)[CH:49]=[CH:48][CH:47]=1
Reactant: Cc1cccc(N2CCNCC2)n1
Reactant: CCOc1ccccc1C1(OC(=O)Oc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(C#N)cc21
Solvent: CN(C)C=O
Product: CCOc1ccccc1C1(OC(=O)N2CCN(c3cccc(C)n3)CC2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(C#N)cc21
Yield: 89.6 %

Procedure:
0.1 g (0.16 mmol) of intermediate 1d and 115 mg (0.65 mmol) of 1-(6-methylpyridin-2-yl)piperazine were stirred in 3 ml of DMF at 100° C. for 20 minutes. The reaction mixture was then poured into 30 ml of ice-water/K2CO3. The resulting precipitate was isolated and crystallized from a little methanol, resulting 0.1 g of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](I)=[N:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH2:19]([Sn:23]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])Cl)[CH2:20][CH2:21][CH3:22]>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn:23]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:19][CH2:20][CH2:21][CH3:22])=[N:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CCn1nc(I)c2ccc(Cl)cc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(CC)c2cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 58 %

Procedure:
To a solution of 6-chloro-1-ethyl-3-iodo-1H-indazole (150 mg, 0.47 mmol) in THF (3 mL) at 0° C. was slowly added isopropylmagnesium chloride (2.0 M in THF, 0.28 mL, 0.56 mmol). The bright yellow heterogeneous reaction mixture was stirred at 0° C. for 20 min then tributylchlorostannane (0.15 mL, 0.56 mmol) was added dropwise. Stirring was continued at 0° C. for 20 min then at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EtOAc (2×). The combined organics were washed with brine then dried over MgSO4 and concentrated. The exact reaction was repeated once more on the same scale. The residues from the two runs were combined and purified by silica gel chromatography with 10% to 50% EtOAc/heptane (0.5% Et3N) to provide 128 mg (29%) of 6-chloro-1-ethyl-3-tributylstannanyl-1H-indazole as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=2)[CH:3]=1.[NH3:22]>CO>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:22])=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=2)[CH:3]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1cc(C)cc(C)c1
Reactant: N
Solvent: CO
Product: Cc1cc(C)cc(Nc2cc(Cl)nnc2C(N)=O)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a solution of ethyl 6-chloro-4-(3,5-dimethylphenylamino)pyridazine-3-carboxylate (104 mg, 340 μmol) in methanol was added ammonia in methanol (4.86 mL, 34.0 mmol) and stirred at 50° C. for 16 h. The mixture was concentrated to give 6-chloro-4-(3,5-dimethylphenylamino)pyridazine-3-carboxamide (90 mg, 325 μmol, 96%) as a brown solid, which was used directly without purification. 1H NMR (400 MHz, DMSO-d) δ ppm 10.84 (s, 1H), 8.72 (s, 1H), 8.08 (s, 1H), 7.12 (s, 1H), 6.98 (s, 2H), 6.98 (s, 1H), 6.93 (s, 1H), 2.30 (s, 6H); MS (EI/CI) m/z: 276.9 [M+H].
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[O:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[CH:18][CH:19]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.BrBr.[C:28]([OH:31])(=[O:30])[CH3:29]>>[C:28]([O:31][C:19]1[CH:18]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[O:16][C:15]=1[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:8]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)O
Reactant: COc1ccc(-c2ccc(-c3ccccn3)o2)cc1OC1CCCC1
Agent: BrBr
Product: COc1ccc(-c2oc(-c3ccccn3)cc2OC(C)=O)cc1OC1CCCC1
Yield: 31 %

Procedure:
A mixture of 2-(3-Cyclopentyloxy-4-methoxyphenyl)-5-(2-pyridyl)furan, (50 mg) from example 2, in acetic acid (2 ml) and bromine were stirred for 15 mins. at room temperature. The reaction mixture was quenched with sodium sulfite extracted with EtOAc dried with sodium sulfate and evaporated in vacuo to afford the unexpected title compound as a beige solid in 31% yield. 1H NMR (300 MHz, CDCl3): δ 1.6 (m, 2H), 1.98-1.8 (m, 6H), 2.3 (s, 3H), 3.88 (s, 3H), 4.82 (m, 1H), 6.91 (dd, 1H), 7.10 (m, 1H), 7.25 (s, 1H), 7.35 (dd, 2H), 7.7 (bs, 2H), 8.58 (d, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:12]=[C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:38])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30]C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1>>[NH2:2][C:3]1[N:12]=[C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:38])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:15][CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCC(=O)N1CCC(c2nc(N)nc3ccccc23)CC1
Agent: Cl
Product: NCCCCCCCCCCC(=O)N1CCC(c2nc(N)nc3ccccc23)CC1
Yield: 95.1 %

Procedure:
By a procedure similar to that described in Example 284, the titled compound (130 mg) as hydrochloride was prepared from 2-amino-4-[1-(11-t-butoxycarbonylaminoundecanoyl)-4-piperidinyl]quinazoline (170 mg) obtained in Example 29.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1)=[O:3].[Br:18]Br>C(O)(=O)C>[F:17][C:14]([F:15])([F:16])[C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH2:1][Br:18])[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=1
Reactant: BrBr
Reactant: CC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: O=C(CBr)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a stirred solution of 3,5-bis(trifluoromethyl)acetophenone (50.0 g, 195.2 mmol) in acetic acid (200 mL) was added dropwise at 90° C. bromine (31.2 g, 195.2 mmol). After the initiation of the reaction (3-4 drops), the oil bath was removed and the mixture was stirred at room temperature for 1 h. To this mixture was added water (50 mL) and the mixture was concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate (500 mL) and water (500 mL). The organic layer was separated and washed with saturated sodium hydrogen carbonate (250 mL×2), and saturated sodium chloride (250 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give 1-[3,5-bis(trifluoromethyl)phenyl]-2-bromoethanone (57.65 g, 88%) as a colorless solid.