Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:14]N1C(=O)CCC1=O>CN(C=O)C.OS([O-])=O.[Na+].CCOC(C)=O>[Br:14][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([S:10]([NH2:13])(=[O:11])=[O:12])[CH:5]=2)[NH:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: NS(=O)(=O)c1ccc2[nH]ccc2c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc2[nH]cc(Br)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
To a solution of 1H-indole-5-sulfonamide (Intermediate 54, 100 mg, 0.51 mmol) in DMF (2.0 mL) was added N-bromosuccinimide (91 mg, 0.51 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature for 30 min and then diluted with sat. aq. NaHSO3 solution and EtOAc. The organic layer was washed with sat. aq. NaCl solution, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified using preparative HPLC to give the title compound (90 mg, 61%) as a white solid after lyophilization. 1H NMR (DMSO-d6) δ 11.88 (br s, 1H), 7.94 (d, J=8.1 Hz, 1H), 7.75 (d, J=2.6 Hz, 1H), 7.65-7.63 (m, 1H), 7.59-7.57 (m, 1H), 7.21 (s, 2H); MS (ESI+) m/z 277.1 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][CH:27]([CH3:30])[CH2:28][CH3:29])=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.ClCCl>[CH2:2]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][CH:27]([CH3:30])[CH2:28][CH3:29])=[O:24])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9]
Reactant: C=CCCCCCCBr
Reactant: CCC(C)COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: C=CCCCCCCOc1ccc(-c2ccc(C(=O)OCC(C)CC)cc2)cc1
Yield: 76.9 %

Procedure:
5.1 g of 8-bromo-1-octene, 8.2 g of 2-methylbutyl 4'-hydroxybiphenyl-4-carboxylate, and 4.0 g of potassium carbonate were refluxed in acetone for 20 hours. After the conclusion of the reaction, the reaction product was diluted with dichloromethane, and the inorganic matters were removed by filtration. The solvent was distilled out under reduced pressure, and the residue was purified by column chromatography to obtain 8.1 g of the objective 2-methylbutyl 4'-(7-octenyloxy)biphenyl-4-carboxylate. (Yield: 77%)
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1.[Br:8][C:9]1[N:10]=[C:11]([CH:29]2[CH2:31][CH2:30]2)[N:12]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:13]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16](Cl)[N:15]=1.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Na+].[Na+]>CN1C(=O)CCC1>[Br:8][C:9]1[N:10]=[C:11]([CH:29]2[CH2:31][CH2:30]2)[N:12]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[C:13]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:7][CH2:6][C:3]2([C:2]#[N:1])[CH2:5][CH2:4]2)[N:15]=1
Reactant: N#CC1(CN)CC1
Reactant: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(NCC2(C#N)CC2)n1
Temperature: 110 °C
Yield: 65.1 %

Procedure:
A mixture of 1-(aminomethyl)cyclopropanecarbonitrile (0.67 g, 7.0 mmol), 4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine (2.01 g, 4.7 mmol), DIEA (1.64 ml, 9.35 mmol), Na2CO3 (0.99 g, 9.4 mmol) and NMP (2 mL) was heated at 110° C. for 25 hours. The reaction mixture was allowed to cool to room temperature and partitioned between EtOAc (10 mL) and water (20 mL). The layers were separated and the organic portion was sequentially washed with water (20 mL), brine (10 mL), and concentrated. The resulting residue was purified by flash chromatography on silica gel eluting with an EtOAc-heptane (0-50%) gradient to provide 1-((4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)methyl)cyclopropanecarbonitrile (1.50 g, 3.06 mmol, 66%) as a white foam. LCMS (m/z) 491.1 (MH+), tR=0.99 minute.
Reaction SMILES: [CH3:1][C:2]1[C:3](/[C:7](=[N:14]\[O:15][CH2:16][C:17]2[N:22]=[C:21]([N:23]3C(=O)C4C(=CC=CC=4)C3=O)[CH:20]=[CH:19][CH:18]=2)/[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4][S:5][N:6]=1.O.NN>C1COCC1>[CH3:1][C:2]1[C:3](/[C:7](=[N:14]\[O:15][CH2:16][C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=2)/[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:4][S:5][N:6]=1
Reactant: Cc1nsnc1/C(=N\OCc1cccc(N2C(=O)c3ccccc3C2=O)n1)c1ccccc1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: Cc1nsnc1/C(=N\OCc1cccc(N)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 75 %

Procedure:
To a stirred solution of 2-{6-[({[(Z)-(4-methyl-1,2,5-thiadiazol-3-yl)(phenyl)methylene]amino}-oxy)methyl]pyridin-2-yl}-1H-isoindole-1,3(2H)-dione (49 g, 91 mmol) in dry THF (800 mL) was added hydrazine hydrate (22.2 mL, 457 mmol). The reaction mixture was stirred at room temperature for 14 h, then insolubles were removed by filtration and washed with THF. The filtrates were combined and concentrated in vacuo. Purification of the residual oil on silica gel afforded 6-[({[(Z)-(4-methyl-1,2,5-thiadiazol-3-yl)(phenyl)methylene]amino}oxy)-methyl]pyridin-2-amine as a yellow oil [22.2 g, yield 75%; HPLC/MS: m/z=326 (M+H); log P(HCOOH)=1.54].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]2[N:19]([CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:18]3[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=3[N:12]2[C:13](=[O:16])[C:14]=1[OH:15])=[O:8].C(N(CC)CC)C.[S:43](Cl)([CH3:46])(=[O:45])=[O:44]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]2[N:19]([CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][N:25]([S:43]([CH3:46])(=[O:45])=[O:44])[CH2:26][CH2:27]3)[C:18]3[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=3[N:12]2[C:13](=[O:16])[C:14]=1[O:15][S:43]([CH3:46])(=[O:45])=[O:44])=[O:8]
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)c1nc2n(CCN3CCNCC3)c3ccccc3n2c(=O)c1O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1c(C(=O)NCc2ccc(Cl)c(Cl)c2)nc2n(CCN3CCN(S(C)(=O)=O)CC3)c3ccccc3n2c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.3 %

Procedure:
3-Hydroxy-4-oxo-10-(2-piperazin-1-yl-ethyl)-4,10-dihydro-benzo[4,5]imidazo[1,2-α]pyrimidine-2-carboxylic acid, 3,4-dichloro-benzylamide (Example 15.5) (75 mg, 0.146 mmol) and triethylamine (60 μL, 0.31 mmol) were dissolved in dichloromethane (1 mL) and to this was added mesyl chloride (18 μL, 0.31 mmol). The reaction was stirred at room temperature for 15 minutes after which time the solvents were concentrated in vacuo and the residue purified by column chromatography (95:4.5:0.5 dichloromethane: methanol: aqueous ammonia) to afford the desired product (65 mg, 76%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:21])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:11][C:4]=2[CH:3]=1.O.[NH2:23][NH2:24]>>[NH:23]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:21])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:11][C:4]=2[CH:3]=1)[NH2:24]
Reactant: NN
Reactant: COc1ccc(C(=O)N2CCc3nnc(Cl)cc3C2)cc1
Solvent: O
Product: COc1ccc(C(=O)N2CCc3nnc(NN)cc3C2)cc1

Procedure:
10.5 g of 3-chloro-5,6,7,8-tetrahydro-6-(p-methoxybenzoyl)pyrido[4,3-c]pyridazine and 100 cc of hydrazine hydrate are stirred at a bath temperature of 100° for 1 hour. The title compound has a M.P. of 169°-172° (decomp., from 95% ethanol).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]([S:23]([C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[O:34][CH3:35])(=[O:25])=[O:24])[C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[N:13]=1)(C)(C)C>C(Cl)Cl.Cl.O1CCOCC1>[CH3:35][O:34][C:27]1[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:26]=1[S:23]([N:8]([CH2:7][C:6]([OH:36])=[O:5])[C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[N:13]=1)(=[O:24])=[O:25]
Reactant: COc1ccc(OC)c(S(=O)(=O)N(CC(=O)OC(C)(C)C)c2nc(-c3ccc(C(C)C)cc3)cs2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(OC)c(S(=O)(=O)N(CC(=O)O)c2nc(-c3ccc(C(C)C)cc3)cs2)c1

Procedure:
{(2,5-Dimethoxy-benzenesulfonyl)-[4-(4-isopropyl-phenyl)-thiazol-2-yl]-amino}-acetic acid was prepared following general procedure G1 using a solution of {(2,5-dimethoxy-benzenesulfonyl)-[4-(4-isopropyl-phenyl)-thiazol-2-yl]-amino}-acetic acid tert-butyl ester (96.8 mg, 0.182 mmol) in DCM (3 mL) and 4 N HCl solution in dioxane (2.5 mL) followed by trituration in hexanes to give {(2,5-Dimethoxy-benzenesulfonyl)-[4-(4-isopropyl-phenyl)-thiazol-2-yl]-amino}-acetic acid. 1H-NMR (400 MHz, CDCl3): 7.64 (d, 2H), 7.55 (d, 1H), 7.09-7.26 (m, 3H), 6.87 (d, 1H), 4.85 (s, 2H), 3.82 (s, 3H), 3.66 (s, 3H), 2.92 (sept, 1H), 1.25 (d, 6H); LCMS m/z: 477 (M+1)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:18][NH2:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][CH:14]([NH:19][CH3:18])[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNC1CCC(Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 1.6 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and methylamine (20 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (1 mg) and a syn-form compound (1 mg).
Reaction SMILES: C(OC([NH:8][CH:9]([C:14]([CH3:18])([CH3:17])[CH:15]=[CH2:16])[C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH:9]([C:14]([CH3:18])([CH3:17])[CH:15]=[CH2:16])[C:10]([O:12][CH3:13])=[O:11]
Reactant: C=CC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC(C)(C)C(N)C(=O)OC
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a solution of methyl 2(R/S)-(tert-butoxycarbonyl)amino-3,3-dimethyl-4-pentenoate (4.97 g, 19.3 mmol) in 50 mL of dichloromethane at 0° C. was added 16.5 mL of trifluoroacetic acid. After 2 hours, the solution was concentrated and the residue was dissolved in 100 mL of dichloromethane and washed with sat. aq. sodium bicarbonate (50 mL). The organic layer was dried over sodium sulfate and concentrated to give methyl 2(R/S)-amino-3,3-dimethyl-4-pentenoate (2.30 g), which was dissolved in 50 mL of dichloromethane and cooled to 0° C. Triethylamine (8.1 mL, 58 mmol) was added, followed by addition of 4-(4-fluorophenoxy)benzenesulfonyl chloride (6.71 g, 21.3 mmol). The reaction was allowed to warm to room temperature and stirred for 18 hours and then washed 3 N hydrochloric acid (125 mL), dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 20% ethyl acetate in hexane, to yield 4.41 g (61%) of methyl 2(R/S)-[4-(4-fluorophenoxy)benzenesulfonyl]amino-3,3-dimethyl-4-pentenoate as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([CH2:16][CH2:17][C:18]2[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=2)[O:9][C:10]=1[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1.Br[CH2:26][C:27]([O:29][CH3:30])=[O:28]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([CH2:16][CH2:17][C:18]2[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=2)[O:24][CH2:26][C:27]([O:29][CH3:30])=[O:28])[O:9][C:10]=1[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)CBr
Reactant: Oc1cccc(CCc2nc(-c3cccs3)c(-c3cccs3)o2)c1
Product: COC(=O)COc1cccc(CCc2nc(-c3cccs3)c(-c3cccs3)o2)c1

Procedure:
Reaction of 3-[2-[4,5-di(2-thienyl)-2-oxazolyl]-ethyl]phenol with methyl bromoacetate according to the procedure of Example 29 provided the title compound.
Reaction SMILES: [Br-].[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].CC(C)([O-])C.[K+].C(NC1C=C([C:43]2[C:48]([C:49]([C:51]3[C:52]([C:57]4C=CC=[C:59]([NH:63][C:64](=[O:66])[CH3:65])[CH:58]=4)=NC=C[CH:56]=3)=O)=[CH:47][CH:46]=[CH:45][N:44]=2)C=CC=1)(=O)C>O1CCCC1>[C:64]([NH:63][C:59]1[CH:56]=[C:51](/[C:49](/[C:48]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)=[CH:7]\[CH2:6][CH2:5][CH2:4][C:2]#[N:3])[CH:52]=[CH:57][CH:58]=1)(=[O:66])[CH3:65]
Reactant: N#CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)Nc1cccc(-c2ncccc2C(=O)c2cccnc2-c2cccc(NC(C)=O)c2)c1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(/C(=C\CCCC#N)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 25.5 g of 4-cyanobutyl-triphenylphosphonium bromide and 14 g of potassium tert.butoxide in 200 ml of tetrahydrofuran are added, at -40° C., 12 g of 3-acetylaminophenyl-3-pyridylketone. The mixture is stirred for 3 hours at ambient temperature and the reaction mixture is decomposed by the addition of 50 ml of ice water. The mixture is concentrated by evaporation, the residue is taken up in water and extracted with ethyl acetate. The organic phase is evaporated down and the residue is purified over a silica gel column with dichloromethane/ethanol=40:1. The product fraction is evaporated down and the residue is recrystallised from ethyl acetate/diisopropylether.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C@@H:12]([CH3:16])[CH2:13][O:14][CH3:15])[CH:10]=1)[C:5]([OH:7])=[O:6].F[C:18]1[CH:19]=[CH:20][C:21]2[S:27](=[O:29])(=[O:28])[N:26]([CH3:30])[CH2:25][CH2:24][O:23][C:22]=2[CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:30][N:26]1[CH2:25][CH2:24][O:23][C:22]2[CH:31]=[C:18]([O:1][C:2]3[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C@@H:12]([CH3:16])[CH2:13][O:14][CH3:15])[CH:10]=3)[C:5]([OH:7])=[O:6])[CH:19]=[CH:20][C:21]=2[S:27]1(=[O:29])=[O:28]
Reactant: CN1CCOc2cc(F)ccc2S1(=O)=O
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCN(C)S3(=O)=O)cc(C(=O)O)c1
Temperature: 120 °C
Reaction time: 28 h
Yield: 57.1 %

Procedure:
A mixture of 3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoic acid (0.2 g, 0.88 mmol), 7-fluoro-2-methyl-3,4-dihydro-2H-5,1,2-benzoxathiazepine 1,1-dioxide (205 mg, 0.88 mmol) and potassium carbonate (244 mg, 1.77 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 120° C. for 28 hours. The solvent was removed in vacuo and water (50 mL) and ethyl acetate (50 mL) added. The ethyl acetate layer was separated and discarded and the aqueous layer acidified and extracted into ethyl acetate (2×50 mL). The combined organics were washed with brine, dried (MgSO4), filtered and the solvent removed in vacuo to give the desired compound as a brown oil (0.22 g) which was used in the following steps without further purification. m/z 436 (M−H)−
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10](=[O:15])[CH2:11][N:12]([CH3:14])[CH3:13].[CH3:20][Mg]I.[Mg].CI>CCOCC>[CH3:13][N:12]([CH3:14])[CH2:11][C:10]([C:6]1[N:5]([CH2:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=2[F:1])[CH:9]=[CH:8][CH:7]=1)([OH:15])[CH3:20]
Reactant: C[Mg]I
Reactant: CN(C)CC(=O)c1cccn1Cc1ccccc1F
Agent: [Mg]
Solvent: CCOCC
Solvent: CI
Product: CN(C)CC(C)(O)c1cccn1Cc1ccccc1F

Procedure:
A solution of 16.0 g of 1-(o-fluorobenzyl)-2-(dimethylaminoacetyl)pyrrole, free base of Example 3a, in 60 ml of ether is treated with a solution of methylmagnesium iodide, prepared from 2.7 g of magnesium turnings and 15.3 g of methyl iodide, in 40 ml of ether according to the procedure described in Example 9a to produce a crude yellow oil of 1-(dimethylamino)2-[1-(o-fluorobenzyl)-2-pyrryl]-2-hydroxypropane. Distillation at 130°-138° C./0.1 mm affords the product as a faintly yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH2:26][C:27]5[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[C:29](F)[CH:28]=5)[CH2:22][CH2:21]4)[C:13]=3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:37][CH2:38][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH2:26][C:27]5[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[C:29]([NH:37][CH2:38][C:39]6[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=6)[CH:28]=5)[CH2:22][CH2:21]4)[C:13]=3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-c2nc3c(N4CCN(Cc5ccc([N+](=O)[O-])c(F)c5)CC4)cccc3[nH]2)cc1
Reactant: NCc1cccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(-c2nc3c(N4CCN(Cc5ccc([N+](=O)[O-])c(NCc6cccnc6)c5)CC4)cccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To a mixture of 2-(4-tert-Butyl-phenyl)-4-[4-(3-fluoro-4-nitro-benzyl)-piperazin-1-yl]-1H-benzoimidazole (75 mg, 0.15 mMol) in dimethylformamide (2 mL) under nitrogen was added 3-(Aminomethyl) pyridine (0.078 mL, 0.77 mMol) and the resulting solution stirred overnight at room temperature. Upon arrival the reaction mixture was diluted with ethyl acetate (50 mL) and washed three times with water (50 mL) followed by brine (50 mL). The organics were dried with magnesium sulfate, filtered, and evaporated to dryness. Purification by flash column chromatography on silica gel and 5% methanol in dichloromethane as eluant yielded 50 mg of (5-{4-[2-(4-tert-Butyl-phenyl)-1H-benzoimidazol -4-yl]-piperazin-1-ylmethyl}-2-nitro-phenyl)-pyridin-3-ylmethyl-amine as a yellow-orange solid (56% yield). 1H NMR (CDCl3): δ=9.24 (s, 1H), 8.66 (s, 1H), 8.55 (m, 1H), 8.43 (m, 1H), 8.16 (d, 1H, J=7.5 Hz), 8.03 (m, 1H), 7.93 (d, 2H, J=7.5 Hz), 7.69 (d, 1H, J=6.0 Hz), 7.49 (d, 2H, J=7.5 Hz), 7.14 (m, 1H), 7.04 (d, 1H, J=6.0 Hz), 6.87 (s, 1H), 6.73 (m, 1H), 6.59 (d, 1H, J=6.0 Hz), 4.60 (m, 2H), 3.55 (m, 6H), 2.68 (m, 4H), 1.34 (s, 9H). LC/MS (Method A), rt=1.05 mins., purity=98.5%, calculated mass=575, [M+H]+=576, [M−H]−=574.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.Cl.[F:7][C:8]1[C:13]([OH:14])=[C:12]([F:15])[C:11]([F:16])=[C:10]([F:17])[C:9]=1[F:18]>>[CH3:1][Si:2]([CH3:5])([CH3:4])[O:14][C:13]1[C:12]([F:15])=[C:11]([F:16])[C:10]([F:17])=[C:9]([F:18])[C:8]=1[F:7]
Reactant: C[Si](C)(C)Cl
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Product: C[Si](C)(C)Oc1c(F)c(F)c(F)c(F)c1F
Reaction time: 0.5 h

Procedure:
In a manner similar to Example 1, 2.5 mol of boiling trimethylchlorosilane was placed without solvent in a 2-liter reactor which contained, instead of the packed column, a reflux condenser (nitrogen gas flooded, with hydrogen chloride exhaust), and about 2 mol (370 g) of pentafluorophenol (m.p. 39° C.) in molten form was fed into it over a period of 30 minutes. The reactor temperature then rose to about 124° C. As boiling continued the temperature rose to about 160° C. in 90 minutes. Then a distillation was performed at about 300 mbar and 118° C. The yield of trimethylpentafluorophenoxysilane was virtually quantitative.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[N:12]=[C:13](Br)[CH:14]=[C:15]([O:16][CH3:17])[C:10]3=[N:9][C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([C:25]3([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].O.CO[CH2:46][CH2:47]OC>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>[CH3:17][O:16][C:15]1[C:10]2[N:11]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH2:26][CH2:27][CH2:28]4)=[CH:21][CH:20]=3)[N:9]=2)[N:12]=[C:13]([CH:46]=[CH2:47])[CH:14]=1
Reactant: COCCOC
Reactant: COc1cc(Br)nn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc12
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
Product: C=Cc1cc(OC)c2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Reaction time: 0.17 h
Yield: 92 %

Procedure:
A mixture of tert-butyl (1-{4-[3-phenyl-6-bromo-8-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-7 (0.30 g, 0.54 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.006 g, 0.005 mmol, 10 mol %) in 1,2-dimethoxyethane (4 mL) was stirred under an argon atmosphere for 10 min, then was sequentially treated with K2CO3 (0.075 g, 0.54 mmol, 1.0 eq), water (1.5 mL) and vinylboronic acid anhydride pyridine complex (prepared as described in J. Org. Chem. 2002, 67, 4968; 0.13 g, 0.54 mmol, 1.0 eq). The resulting mixture was heated at the reflux temperature for 16 h, then was added to water (15 mL). The resulting mixture was extracted with EtOAc (2×25 mL). The combined organic phases were washed with water (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; Snap 10 g cartridge, 100% hexane 1.5 min, gradient to 80% hexane/20% EtOAc 1.0 min, 80% hexane/20% EtOAc 2.0 min, gradient to 50% hexane/50% EtOAc 3.0 min, 50% hexane/50% EtOAc 4.0 min, gradient to 100% EtOAc 4.5 min, 100% EtOAc 7.7 min) to give tert-butyl {1-[4-(8-methoxy-3-phenyl-6-vinylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (0.25 g, 92%):
Reaction SMILES: [OH:1][C:2]1([C:6]2[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]([O:16][CH:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[CH:7]=2)[CH2:5][O:4][CH2:3]1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.OS(O)(=O)=O>[NH:20]1[CH2:19][CH2:18][CH:17]([O:16][C:8]2[CH:7]=[C:6]([C:2]3([OH:1])[CH2:5][O:4][CH2:3]3)[CH:11]=[C:10]([C:12]([F:13])([F:15])[F:14])[N:9]=2)[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C3(O)COC3)cc(C(F)(F)F)n2)CC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: OC1(c2cc(OC3CCNCC3)nc(C(F)(F)F)c2)COC1
Reaction time: 8 h

Procedure:
A solution of tert-butyl 4-{[4-(3-hydroxyoxetan-3-yl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidine-1-carboxylate (0.080 g, 0.17 mmol, from Step 2) in 1,4-dioxane (1.0 mL) was treated with a few drops of water and six drops of concentrated H2SO4 and was stirred overnight. The mixture was made basic with 10 mL of saturated sodium bicarbonate solution and the product was extracted with three portions of DCM. The combined extracts were dried over sodium sulfate, filtered and concentrated to afford crude product, which was used directly in the next step (44 mg, 81%). 1H NMR (300 MHz, CDCl3) δ 7.58 (d, J=1.2 Hz, 1H), 7.18 (s, 1H), 5.22 (tt, J=8.2, 3.9 Hz, 1H), 4.91 (d, J=7.4 Hz, 2H), 4.78 (d, J=7.4 Hz, 2H), 3.10 (dt, J=11.9, 4.3 Hz, 2H), 2.79 (ddd, J=12.5, 9.1, 3.1 Hz, 2H), 2.16-1.98 (m, 2H), 1.70 (dtd, J=12.7, 8.8, 3.8 Hz, 2H). 19F NMR (282 MHz, CDCl3) δ −68.76 (s). LCMS (M+H)+: 319.1.