Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8]2)=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].C(=O)([O-])[O-].[Na+].[Na+].[Cl:50][C:51]1[S:52][CH:53]=[CH:54][C:55]=1Br>CN(C=O)C.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>[Cl:50][C:51]1[S:52][CH:53]=[CH:54][C:55]=1[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(CN2CCOC(c3ccccc3)C2)cc1
Reactant: Clc1sccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: CN(C)C=O
Product: Clc1sccc1-c1ccc(CN2CCOC(c3ccccc3)C2)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 10.8 %

Procedure:
91 mg of 4-(4-Bromo-benzyl)-2-phenyl-morpholine was combined with 77 mg of bis(pinacolato)diboron, 81 mg of potassium acetate, 16 mg tetrakis(triphenylphosphine)palladium(0), and 1.9 mL DMF. The mixture was heated in a microwave reactor at 120° C. for 7 minutes and cooled. 0.7 mL of 2M aqueous sodium carbonate was added along with 81 mg of 2-Chloro-3-bromothiophene in 0.12 mL DMF. The mixture was heated in the microwave reactor for an additional 5 minutes at 120° C. The reaction was cooled and filtered through Celite, washing with methylene chloride. The residue was diluted with 4 mL DCM and 130 mg of MP-TsOH resin (4.2 mmol/g loading) was added and the mixture agitated at room temperature overnight. The solution is filtered and the resin is then washed with 2M N3 in methanol to liberate product. The resin is washed several times with methylene chloride, concentrated in vacuo and purified by reverse phase HPLC. 10.9 mg of product is obtained as oil, 10% yield. ES MS m/z 398
Reaction SMILES: CS(Cl)(=O)=O.C(OC(=O)[NH:12][C:13]([C:15]1[S:16][C:17]([S:38][CH3:39])=[C:18]([S:20]([C:23]2[CH:24]=[C:25]([C:29]3[C:34]([CH2:35]O)=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:37])[CH:26]=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH:19]=1)=[NH:14])(C)(C)C.C(N(C(C)C)CC)(C)C.C[N:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>C(Cl)Cl>[CH3:37][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([CH2:35][N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)[C:29]=1[C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([S:20]([C:18]2[CH:19]=[C:15]([C:13]([NH2:12])=[NH:14])[S:16][C:17]=2[S:38][CH3:39])(=[O:21])=[O:22])[CH:24]=1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2CO)c1
Reactant: CN1CCOCC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2CN2CCOCC2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (100 μL) was added over 1 min to a 0° C. solution of {[4-(6′-hydroxymethyl-2′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (Example 5: step c) (30 mg)) and diisopropylethylamine (0.25 mL) in DCM (10 mL). The solution was stirred for 1 h at 0° C. and warmed to rt. 4-Methylmorpholine (0.5 mL) was added and the solution was stirred for 3 h at rt. The volatile components were removed in vacuo and the residue was treated with 1:1 TFA/DCM (10 mL) for 2 h at rt. The solvent was removed in vacuo and the residue was purified by preparative HPLC (C18-column, 10–70% CH3CN over 30 min) which yielded the title compound as a opaque glass (6.8 mg). 1H-NMR (CD3OD): δ 8.40 (s, 1H), 8.13 (ddd, 1H, J=1.2, 1.9, 7.9 Hz), 7.97 (t, 1H, J=1.6 Hz), 7.82 (t, 1H, J=7.9 Hz), 7.61 (m, 2H), 7.49 (m, 2H), 4.15 (d, 1H, J=13.5 Hz), 4.07 (d, 1H, J=13.5 Hz), 3.82 (br s, 4H), 2.75 (s, 3H), 2.18 (s, 2H), 2.03 (s, 3H), 1.31 (s, 2H). ESI-MS (m/z): Calcd. for C24H27N3O3S3 (M+H): 502.1; found: 502.1.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([S:21]([C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)(=[O:23])=[O:22])[CH2:17][CH2:16]1)=[O:14]>C1COCC1>[CH2:3]([O:10][CH2:12][C:13]([N:15]1[CH2:16][CH2:17][N:18]([S:21]([C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)(=[O:22])=[O:23])[CH2:19][CH2:20]1)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(COCc1ccccc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
To a suspension of sodium hydride (35.88 mg, 60 percent in oil) in dry THF (20 mL) cooled to 0° C. under nitrogen atmosphere, a solution of benzylalcohol (0.09 g, 0.717 mmol) in THF (1 mL) was added drop wise to the mixture over 25 minutes, and the mixture was brought to room temperature and stirred for 2 h. The reaction was again cooled to 0° C., to which a solution of 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 5) in THF (20 mL) was added drop wise over 30 minutes. After being stirred for over night at room temperature, the reaction mixture was poured into ice cold water and extracted with ethyl acetate (2×10 mL). The organic layer was washed with brine solution and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resultant crude product was purified by column chromatography on silica gel (hexane:ethyl acetate:1:1) to obtain the title product (60 mg, 24%) as an off-white solid.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=2[O-])=[CH:3][CH:2]=1.COS(OC)(=O)=O.[C-:24]#[N:25].[Na+]>C(O)(C)C>[C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[N:10]=[C:11]([C:24]#[N:25])[CH:12]=[CH:13][CH:14]=2)=[CH:3][CH:2]=1
Reactant: [C-]#N
Reactant: Cc1ccc(C=Cc2cccc[n+]2[O-])cc1
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)O
Product: Cc1ccc(C=Cc2cccc(C#N)n2)cc1

Procedure:
In a variation to the procedure referred to in example1, 2-(2-p-tolyl-vinyl)-pyridine 1-oxide (9.8 g, 46 mmol) was reacted first with dimethylsulfate (5.8 g, 46 mmol) and then with NaCN (2.74 g, 56 mmol). After extraction and crystallization 6-(2-p-tolyl-vinyl)-pyridine-2-carbonitrile (5.8 g, 57%) was obtained as a yellow crystalline material. Mp. 137–138° C. (isopropanol), MS: m/e=220 (M+)
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:12][C:13]([CH3:25])([CH3:24])[CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:25][C:13]([NH:12][C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])([CH3:24])[CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22]
Reactant: CC(C)(N)CCNC(=O)OC(C)(C)C
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])c(NC(C)(C)CCNC(=O)OC(C)(C)C)c1

Procedure:
2.0 g (12.9 mmol) 3-fluoro-4-nitro-toluene, 2.6 g (13.0 mmol) tert-butyl (3-amino-3-methyl-butyl)-carbamate and 2.3 g (16.8 mmol) potassium carbonate are stirred overnight at ambient temperature in 20 mL DMF. The solvent is distilled off and the residue is combined with ethyl acetate. The mixture is washed repeatedly with water, dried with sodium sulphate and the solvent is eliminated. 4.8 g yellow oil. Mass spectroscopy: [M+H]+=338.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8](Cl)[N:9]=[CH:10][C:5]=2[S:4][CH:3]=1.C(O)(C)C.[NH3:16]>>[Br:1][C:2]1[C:6]2[N:7]=[C:8]([NH2:16])[N:9]=[CH:10][C:5]=2[S:4][CH:3]=1
Reactant: Clc1ncc2scc(Br)c2n1
Reactant: N
Solvent: CC(C)O
Product: Nc1ncc2scc(Br)c2n1
Temperature: 100 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
7-Bromo-2-chlorothieno[3,2-d]pyrimidine (1.0 g, 4.03 mmol) was dissolved in 2.0 M ammonia isopropanol (10 mL) and stirred at 100° C. for 48 hours in a sealed reactor. The reaction mixture was cooled to room temperature and then concentrated. Purification by chromatography (50% ethyl acetate/hexane) yielded a brown solid compound (560 mg, 60% yield).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@H:10]([NH:16][C:17]([C:19]1[S:20][C:21]3[C:27](Br)=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2.[C:29]([NH:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:31])[CH3:30].[OH-].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:7].[C:29]([NH:32][C:33]1[CH:38]=[C:37]([C:27]2[C:21]3[S:20][C:19]([C:17]([NH:16][C@H:10]4[CH:11]5[CH2:14][CH2:15][N:8]([CH2:13][CH2:12]5)[CH2:9]4)=[O:18])=[CH:23][C:22]=3[CH:24]=[CH:25][CH:26]=2)[CH:36]=[CH:35][CH:34]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: O=C(N[C@@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)sc23)c1
Temperature: 80 °C

Procedure:
0.67 ml of 2 M sodium carbonate solution and 18.3 mg (0.02 mmol) of PdCl2(dppf) are added to a mixture of 200 mg (0.45 mmol) of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 22A) and 80.2 mg (0.45 mmol) of 3-(acetamido)phenylboronic acid in 2 ml of DMF. The reaction mixture is heated at 80° C. for 17 h. A further 40.1 mg (0.22 mmol) of 3-(acetamido)phenylboronic acid, 1.34 ml of 1N sodium hydroxide solution and 73.2 mg (0.09 mmol) of PdCl2(dppf) are added, and the mixture is heated at 70° C. for a further 18 h. Cooling is followed by filtration through kieselguhr and purification by preparative HPLC. The product fractions are concentrated, taken up in a 5:1 mixture of methanol and 1N hydrochloric acid and again concentrated. Drying under high vacuum results in 124.5 mg (59% of theory) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][C@H:6]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH2:8][N:7]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH3:3].CCN(C(C)C)C(C)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:3][CH:2]([N:4]([CH2:5][C@H:6]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:9][CH2:8][N:7]1[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[S:36]([CH3:35])(=[O:38])=[O:37])[CH3:1]
Reactant: CC(C)NC[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N(C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C)S(C)(=O)=O
Reaction time: 1 h
Yield: 74.6 %

Procedure:
A 500-mL round-bottomed flask was charged with di-tert-butyl (2S)-2-(((1-methylethyl)amino)methyl)-1,4-piperazinedicarboxylate (0.69 g, 1.9 mmol), DMAP (0.0358 g, 0.293 mmol), DIPEA (1.40 mL, 8.05 mmol) and CH2Cl2 (8 mL). To this mixture was added methanesulfonyl chloride (0.299 mL, 3.86 mmol) at room temperature. After 20 min at room temperature additional methanesulfonyl chloride (0.10 mL, 1.3 mmol) was added and stirring was continued at room temperature for an additional 1 h. The reaction mixture was partitioned between water (30 mL) and CH2Cl2 (20 mL). The aqueous phase was extracted with CH2Cl2 (30 mL) and the combined organic extracts were washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (50 g of silica gel, 0 to 50% EtOAc in hexanes) to afford di-tert-butyl (2R)-2-(((1-methylethyl)(methylsulfonyl)amino)methyl)-1,4-piperazinedicarboxylate (0.617 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11][O:12][CH2:13]Cl>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:11][O:12][CH3:13])([OH:8])[CH2:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC1(O)C=CC(Br)=CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Commercially available 4-bromophenol (17.3 g) was dissolved in N,N-dimethylformamide (90 ml), to which sodium hydride (2.64 g) was added while cooled in ice. After stirring at room temperature overnight, chloromethyl methyl ether (8.35 ml) was added, and the admixture was stirred for a further 1 hour. The reaction mixture was partitioned between water and ethyl acetate, and the ethyl acetate layer was dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by column chromatography on silica gel eluting with hexane/acetone to obtain 18.25 g of the title compound (yield: 84%).
Reaction SMILES: [CH2:1]([CH2:13]N)[CH2:2][C:3](P([O-])(O)=O)(P(O)(O)=O)[OH:4].[Na+:15].[OH-].[Na+].[N+:18]([C:21]1C=CC=[CH:26][C:22]=1C(Cl)=O)([O-])=O.[CH2:30]([CH2:42][NH2:43])[CH2:31][C:32]([P:38]([OH:41])([OH:40])=[O:39])([P:34]([OH:37])([OH:36])=[O:35])[OH:33]>O.C1COCC1>[NH2:18][C:21]1[CH:13]=[CH:1][C:2]([C:3]([NH2:43])=[O:4])=[CH:26][CH:22]=1.[CH2:30]([CH2:42][NH2:43])[CH2:31][C:32]([P:34]([O-:36])([OH:37])=[O:35])([P:38]([OH:41])([OH:40])=[O:39])[OH:33].[Na+:15]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: NCCCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: NCCCC(O)(P(=O)([O-])O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The 4-aminobenzamide of alendronate sodium was prepared as follows. In a 500 mL beaker, 54 g (166 mmol) of sodium alendronate was dissolved in 150 mL of DI water with a pH adjusted to 11 with concentrated NaOH. Nitrobenzoyl chloride, 28 g (150 mmol), dissolved in 100 mL of THF, was added dropwise into the aqueous alendronate solution. The pH was kept at 11 with additional NaOH solution during the addition. After the addition was complete, the solution was stirred for another 2 hours at room temperature. THF was removed in vacuo, and the pH of the solution was adjusted to 4. The resulting precipitate, which was collected by filtration at room temperature, was primarily nitrobenzoic acid and was discarded. The solution was kept at 4° C. overnight, and the resulting precipitate was collected by filtration, washed with DI water, and dried. The resulting solid weighted approximately 56 g (86%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][C@@H:14]1[CH2:17][C@H:16]([OH:18])[CH2:15]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.O>ClCCl>[CH2:6]([O:13][C@@H:14]1[CH2:17][C@H:16]([O:18][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1C[C@@H](OCc2ccccc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)O[C@H]1C[C@@H](OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 103.9 %

Procedure:
Methanesulfonyl chloride (0.44 ml, 5.7 mmol) was added dropwise to a stirred solution of cis-3-benzyloxy-1-hydroxycyclobutane (0.85 g, 4.77 mmol) and triethylamine (1.0 ml, 7.2 mmol) in dry dichloromethane (15 ml) at 0° C. under nitrogen. The white suspension was stirred at 0° C. for 1.5 h then poured into water (50 ml) and extracted with dichloromethane (2×30 ml). The extracts were dried (Na2SO4), filtered and concentrated. The oil was filtered through a plug of silica gel, eluting with ethyl acetate, to give cis-3-benzyloxy-1-methanesulfonyloxycyclobutane (1.27 g, 100%) as a yellow oil; 1H NMR (250 MHz, CDCl3) δ 2.26-2.39 (2H, m), 2.77-2.91 (2H, m), 2.97 (3H, s), 3.74 (1H, qn, J=7 Hz), 4.42 (2H, s), 4.68 (1H, qn, J=7 Hz), 7.26-7.42 (5H, m).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:28]([CH:38]3[CH2:40][CH2:39]3)CC3C=CC(OC)=CC=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=4)=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.[Br-].[Li+].[CH3:43][C:44]1([CH3:47])[CH2:46][O:45]1.C(O)(C(F)(F)F)=O>CO>[Cl:27][C:23]1[CH:22]=[C:21]([NH:20][C:18]([C:15]2[N:13]3[N:14]=[C:9]([NH:8][C@H:5]4[CH2:6][CH2:7][C@H:2]([NH:1][CH2:43][C:44]([OH:45])([CH3:47])[CH3:46])[CH2:3][CH2:4]4)[CH:10]=[C:11]([NH:28][CH:38]4[CH2:39][CH2:40]4)[C:12]3=[N:17][CH:16]=2)=[O:19])[CH:26]=[CH:25][N:24]=1
Reactant: CC1(C)CO1
Reactant: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccnc(Cl)c4)cnc23)C2CC2)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)(O)CN[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4ccnc(Cl)c4)n3n2)CC1
Reaction time: 0.17 h

Procedure:
A solution of 6-((trans)-4-aminocyclohexylamino)-N-(2-chloropyridin-4-yl)-8-(cyclopropyl(4-methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (100 mg, 0.178 mmol), lithium bromide (0.774 mg, 8.91 μmol) and 2,2-dimethyloxirane (12.85 mg, 0.178 mmol) in MeOH (5 mL) was stirred at 50° C. for 7 hrs. The reaction mixture was concentrated down, diluted in methanol (1 mL) and treated with TFA (0.824 mL, 10.69 mmol). After 10 minutes, the reaction mixture was concentrated, diluted with methanol and purified by preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 30% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA) to isolate N-(2-chloropyridin-4-yl)-8-(cyclopropylamino)-6-((trans)-4-(2-hydroxy-2-methylpropylamino)cyclohexylamino)imidazo[1,2-b]pyridazine-3-carboxamide (41.9 mg, 0.082 mmol, 45.8% yield) as a white solid. LC/MS (BEH C18 2.1×50 mm 1.7u, Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2.2 min with 1 min hold time, Flow rate=2 mL/min, detection at 254 nm, Solvent A: 100% water/0.05% TFA; Solvent B: 100% ACN/0.05% TFA). Rt=0.71 minutes. [M+H]=513.3. 1H NMR (400 MHz, MeOD) δ ppm 8.47 (2H, s), 7.96-8.08 (1H, m), 7.52-7.70 (1H, m), 6.44 (1H, s), 3.69-3.92 (1H, m), 3.15-3.30 (1H, m), 3.05 (2H, s), 2.60-2.77 (1H, m), 2.36-2.48 (2H, m), 2.17-2.37 (2H, m), 1.60-1.80 (2H, m), 1.41-1.62 (2H, m), 1.35 (6H, s), 0.87-1.05 (2H, m), 0.63-0.78 (2H, m)
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH3:17][O:18][CH2:19][CH2:20][N:21]([CH2:24][CH2:25][C:26]#[N:27])[S:22]Cl.C(N(CC)CC)C.S(=O)(=O)(O)O>ClCCl>[CH3:17][O:18][CH2:19][CH2:20][N:21]([CH2:24][CH2:25][C:26]#[N:27])[S:22][N:2]([CH3:1])[C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COCCN(CCC#N)SCl
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCN(CCC#N)SN(C)C(=O)Oc1cccc2c1OC(C)(C)C2
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A 19.9 g (0.09 mole) quantity of 2,3-dihydro-2,2-dimethylbenzofuran-7-yl N-methyl-carbamate was poured into 100 ml of a dichloromethane solution containing 19.45 g (0.1 mole) of N-(2-methoxyethyl)-N-cyanoethylaminosulfenyl-chloride. The mixture was agitated by a stirrer and 18 g (0.18 mole) of triethylamine was added dropwise thereto at less than 10° C. over a period of 30 minutes. Thereafter the mixture was stirred at the same temperature for 2 hours. A 5% aqueous solution of sulfuric acid was added to the mixture until a pH of 6 was achieved. The dichloromethane solution was washed with a 5% aqueous solution of sodium hydrogencarbonate and with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated at reduced pressure, giving 31.8 g of a yellowish brown oily product in a yield of 84.0%.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[N:6][N:7]([CH3:17])[C:8]=2[C:9]2[CH:10]=[C:11]([C:14]([OH:16])=O)[S:12][CH:13]=2)[CH2:3][CH2:2]1.[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40])[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH:1]1([C:4]2[CH:5]=[N:6][N:7]([CH3:17])[C:8]=2[C:9]2[CH:10]=[C:11]([C:14]([NH:18][C@@H:19]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]([F:42])([F:40])[F:41])[CH2:20][N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:31])=[O:16])[S:12][CH:13]=2)[CH2:2][CH2:3]1
Reactant: Cn1ncc(C2CC2)c1-c1csc(C(=O)O)c1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1ncc(C2CC2)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (105 mg, 0.42 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (152 mg, 0.39 mmol) [prepared according to Preparation 6] and PyBrop (246 mg, 0.52 mmol) in Chloroform (6 mL). DIEA (370 μL, 2.19 mmol) was added and the mixture stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (171 mg, 66%): LC-MS (ES) m/z=579 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[S:5][C:6]=1[CH3:7].C(=O)([O-])[O-].[K+].[K+].[CH3:18][N:19]1[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=[N:20]1>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:7][C:6]1[S:5][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:3][C:2]=1[C:23]1[N:19]([CH3:18])[N:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1cc(Br)c(C)s1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)c(C)s1

Procedure:
A solution of methyl 4-bromo-5-methyl-2-thiophenecarboxylate (2 g, 8.51 mmol)[prepared in Preparation 10], potassium carbonate (5.88 g, 42.5 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.12 g, 10.21 mmol)[prepared according to Preparation 7] and bis(tri-t-butylphosphine)palladium(0) (0.22 g, 0.43 mmol) in 1,4-Dioxane (35 ml) and H2O (7 ml) was stirred at 80° C. in a sealed tube for 1 h. The reaction mixture was then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 25% EtOAc in hexanes) affording methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate. This reaction was run in several batches (1 g, 3×2 g) which were combined for workup and purification affording the title compound (5.5 g, 78% combined yield) as a viscous yellow oil: LC-MS (ES) m/e 236 (M+H)+.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5](O)[C:6]#[C:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CCOCC.N1C=CC=CC=1>[Br:2][CH2:5][C:6]#[C:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CC#CCO
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCC/C=C\C/C=C\CC#CCBr
Temperature: 23 °C
Yield: 236.2 %

Procedure:
A solution of phosphorus tribromide (0.47 g, 1.73 mmol) in absolute ether (0.5 ml) was added dropwise during five minutes to a mixture of (Z,Z)-5,8-tetradecadien-2-yn-1-ol (1.03 g, 5 mmol), and dry pyridine (14 mg, 0.18 mmol) in 8 ml of absolute ether. The reaction mixture was heated under reflux for 2.5 h, cooled to 23° C., then poured onto ice-water. It was extracted three times with ether. The combined ether extracts were washed with dilute aqueous sodium bicarbonate solution, water, dried over Na2SO4 and concentrated in vacuo. Evaporative distillation of the crude product at 145°-148° C./0.15 mm afforded 1.1 g (80.5%) of (Z,Z)-1-bromo-5,8-tetradecadien-2-yne as a pale yellow oil.