Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27]>O.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([O:17][CH2:25][C:26](=[O:27])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCCC1CC(=O)OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
2-Carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (2.86 g) and sodium carbonate (0.62 g) were dissolved in water (30 ml) using gentle warming. A solution of 2-bromoacetophenone (2.33 g) in ethanol (60 ml) was then added and the mixture boiled for 2 h. the mixture was cooled to room temperature and stood for 16 h. The mixture was again boiled for 2 h. solvent removed at reduced pressure and the residue partitioned between water and ethyl acetate. The organic phase was dried (MgSO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 1:1 ethyl acetate:pentane) to give the title compound (3.14 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[S:8][C:9]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=4)[CH:17]=[CH:16][C:15]=3[CH3:34])=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>>[C:31]([C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:18]1[CH:17]=[CH:16][C:15]([CH3:34])=[C:14]([NH:13][C:11]([C:9]2[S:8][C:6]3=[N:7][C:2]([C:37]4[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=4)=[CH:3][N:4]=[C:5]3[CH:10]=2)=[O:12])[CH:19]=1)=[O:33])([CH3:30])[CH3:29])#[N:32]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(Cl)nc2s1
Reactant: OB(O)c1cccnc1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(-c3cccnc3)nc2s1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 1.8 %

Procedure:
A mixture of 3-chloro-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 95 (204 mmol, 100 mg), pyridine-3-boronic acid (0.306 mmol, 37 mg), potassium phosphate, tribasic (0.408, 87 mg), (0.05 eq, 9 mg), and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.1 eq, 9 mg) was stirred at 100° C. for 30 min. Evaporated to dryness and purified by chromatography (0-100% ethyl acetate in CH2Cl2) and HPLC to yield N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-3-(pyridin-3-yl)thieno[2,3-b]pyrazine-6-carboxamide 96j (3 mg, 2%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.29 (s, 3H), 7.32 (d, J=8.2 Hz, 1H), 7.62 (m, 3H), 7.76 (d, J=7.8 Hz, 1H), 7.90 (s, 1H), 7.96 (d, J=7.8 Hz, 1H), 8.06 (s, 1H), 8.59 (s, 1H), 8.64 (m, 1H), 8.75 (m, 1H), 9.45 (s, 1H), 9.58 (s, 1H), 10.38 (s, 1H), 10.54 (s, 1H). (m/z)=534 (M+H)+.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[Cl:18][C:19]1[N:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([CH:42]=[CH:43][CH:44]=2)[CH2:28][N:29]([CH3:41])[C:30](=[O:40])[CH2:31][NH:32]C(=O)OC(C)(C)C)=[CH:21][N:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[ClH:2].[ClH:18].[Cl:1][C:11]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:12]1[CH2:17][CH2:16][N:15]([C:19]2[N:20]=[CH:21][C:22]([C:25]3[CH:44]=[CH:43][CH:42]=[C:27]([CH2:28][N:29]([C:30](=[O:40])[CH2:31][NH2:32])[CH3:41])[CH:26]=3)=[CH:23][N:24]=2)[CH2:14][CH2:13]1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(N2CCNCC2)cc1Cl
Reactant: CN(Cc1cccc(-c2cnc(Cl)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cccc(-c2cnc(N3CCN(c4ccc(C(=O)O)cc4Cl)CC3)nc2)c1)C(=O)CN
Temperature: 130 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
3 chloro-4-(piperazin-1-yl)benzoic acid hydrochloride (142 mg) was suspended in DMF (3 ml), and tert-butyl (2-{[3-(2-chloropyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (190 mg) and DIPEA (371 mg) were added thereto, followed by stirring at 130° C. overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH). The product was dissolved in dioxane, and 4 M hydrogen chloride/dioxane (1 ml) was added thereto, followed by stirring at room temperature overnight. The precipitated solid was collected by filtration to obtain 3-chloro-4-{4-[5-(3-{[glycyl(methyl)amino)methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}benzoic acid dihydrochloride (72 mg).
Reaction SMILES: [N+:1]([C:4]1[N:9]=[C:8]([NH2:10])[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:11]N1C(=O)CCC1=O>CC#N>[Br:11][C:5]1[CH:6]=[CH:7][C:8]([NH2:10])=[N:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1ccc(Br)c([N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a stirred solution of 6-nitro-pyridin-2-ylamine (9) (5.1 g, 18.4 mmol) in MeCN (125 mL) under nitrogen atmosphere, N-bromosuccinimide (3.43 g, 19.3 mmol) was added at 0° C. After 1 hour, another portion of N-bromosuccinimide (3.57 g, 20.1 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirring was continued overnight. The product was precipitated by addition of water (125 mL). The slurry was cooled to 0° C. and precipitated product was isolated by filtration, washed with premixed MeCN:water (1:1) and dried under vacuum at 40° C. to afford 3.8 g of 5-bromo-6-nitro-pyridin-2-ylamine (2).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([OH:9])[N:3]=1.C([O-])(=O)C.[Na+].O.Br[CH:17]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=1)[CH:18]=O>CO>[CH3:31][O:30][C:28](=[O:29])[C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][C:17]2[C:5]3[C:4](=[O:9])[NH:3][C:2]([NH2:1])=[N:7][C:6]=3[NH:8][CH:18]=2)=[CH:23][CH:24]=1
Reactant: Nc1cc(O)nc(N)n1
Reactant: COC(=O)c1ccc(CCC(Br)C=O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(CCc2c[nH]c3nc(N)[nH]c(=O)c23)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To 1.69 g (13.4 mmol) of 2,4-diamino-6-hydroxypyrimidine, 2.20 g (26.8 mmol) of sodium acetate and 20 ml of water at 80° C. were added 3.82 g (13.4 mmol) of 2-bromo-4-(4-carbomethoxyphenyl)butanal, prepared in Preparation 2, in 7 ml of methanol over 5 minutes. The mixture was maintained at 80° C. for 5 minutes, cooled to room temperature and stirred for 30 minutes. The mixture was filtered, washed with water, and dried for 18 hours at 50° C. @10 torr to provide 3.32 g of 4-(2-[2-amino-4-oxo-3,7-dihydropyrrolo[2,3 -d]pyrimidin-5-yl]ethyl)benzoic acid methyl ester (m.p. >220° C.) in a yield of 79.4 percent. The remaining filtrate was cooled to 5° C. and filtered to provide an additional 0.069 g of the above product, for a combined yield of 81 percent. 1H NMR (DMSO-d6)δ2.80 (m, 2H), 2.93 (m, 2H), 3.78 (s, 3H), 5.97 (s, 2H), 6.26 (d, J =2.0 Hz, 1H), 7.28 (d, J=8.2 Hz, 2H), 7.80 (d, J=8.2 Hz, 2H), 10.12 (s, 1H), 10.58 (s, 1H); FDMS 312 (M+), Anal. for C16H16N4O3, Calcd: C, 61.53; H, 5.16; N, 17.94; Found: C, 61.79; H, 5.33; N, 17.66.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:14]([NH:15][NH2:16])=[CH:13][C:11](=[O:12])[N:10]([CH2:17][CH2:18][CH3:19])[C:8]2=[O:9])=[CH:4][CH:3]=1.[CH3:22][N:23]=[C:24]=S.CO>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:14]3[NH:15][N:16]=[C:22]([NH:23][CH3:24])[C:13]=3[C:11](=[O:12])[N:10]([CH2:17][CH2:18][CH3:19])[C:8]2=[O:9])=[CH:20][CH:21]=1
Reactant: CN=C=S
Reactant: CCCn1c(=O)cc(NN)n(Cc2ccc(F)cc2)c1=O
Solvent: CN(C)C=O
Solvent: CO
Product: CCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccc(F)cc2)c1=O
Yield: 36 %

Procedure:
A solution of 1-(4-fluorobenzyl)-6-hydrazino-3-propyluracil (1.5 g, 5.1 mM) and methyl isothiocyanate (1.2 ml, 17 mM) in DMF (20 ml) was heated at 120° C. for 24 hours. To the solution was added 50% methanol (10 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/methanol/water gave pale yellow crystals (0.62 g, 36%), m.p. 262°-265° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7](=O)[C:6]=2[CH:11]=1.Cl.[NH:13]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])N>C(O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3[C:23]4[C:15](=[C:16]([C:17]([OH:19])=[O:18])[CH:20]=[CH:21][CH:22]=4)[NH:13][C:7]=3[C:6]=2[CH:11]=1
Reactant: O=C1COc2ccc(Br)cc21
Reactant: NNc1ccccc1C(=O)O
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccc2c1[nH]c1c3cc(Br)ccc3oc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
To a solution of 5-bromo-3(2H)-benzofuranone (3.10 g, 14.6 mmol) [Ellingboe, J. et al., J. Med. Chem. 1992,35 (7), 1176-1183] in ethanol (100 mL) was added a solution of 2-hydrazinobenzoic acid hydrochloride (5.49 g, 29.1 mmol) in deionized water (200 mL). The mixture was stirred for one hour at room temperature and then allowed to sit while cooled (0° C.). Vacuum filtration and drying in vacuo afforded 3.65 g (72%) of the title compound as a brown solid: mp 195° C.(dec) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([NH:27][C:28]3[NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].Cl[CH2:45][CH:46]=[C:47]([CH3:49])[CH3:48]>>[CH3:43][O:42][C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([NH:27][C:28]3[N:29]([CH2:45][CH:46]=[C:47]([CH3:49])[CH3:48])[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[N:32]=3)[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: CC(C)=CCCl
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4CC=C(C)C)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 7.1 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine (prepared from (−)-3-(2-hydroxyethyl)-3-phenylpyrrolidine (R,R)-di-p-anisoyltartaric acid salt) and 1-chloro-3-methylbut-2-ene to give the title compound.
Reaction SMILES: [CH2:1]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Br-].[C:15]([CH2:18][CH2:19][CH2:20][CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:17])=[O:16]>C1COCC1>[CH2:1]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH:21][CH2:20][CH2:19][CH2:18][C:15]([OH:17])=[O:16])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(C=O)cc1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCCCc1ccc(C=CCCCC(=O)O)cc1
Yield: 47.8 %

Procedure:
This compound was synthesized from p-pentylbenzaldehyde (3.52 g, 20 mmol, prepared from p-pentylbenzoyl chloride and lithium tri(t-butoxy)aluminum hydride) and 4-carboxybutyltriphenylphosphonium bromide (8.86 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Kugelrohr distillation (bp 147-151° C./0.05 torr) afforded the product (2.49 g, 48%). IR: 3400-2500, 1725 cm-1 ; 1H-NMR: 0.90 (t, 3H), 1.28 (m, 6H), 1.82 (m, 2H), 1.37 (m, 4H), 2.57 (t, 2H), 5.55+6.10 (m, 1H), 6.38 (m, 1H), 7.10 (m, 4H), 10.50 (bs, 1H). Anal. Calcd. for C17H24O2 : C, 78.42, H, 9.29%; Found: C, 78.22, H, 9.27%. Z:E=35:65.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[CH:10]=2)[N:5]([CH2:20][CH2:21][CH2:22][C:23](=[O:32])[NH:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[C:4]=1[CH2:33][O:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1)=[O:2].C([OH:49])(C)(C)C.CC(=CC)C>O>[CH:15]1([C:13]([NH:12][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]([CH2:20][CH2:21][CH2:22][C:23](=[O:32])[NH:24][S:25]([C:28]([F:29])([F:30])[F:31])(=[O:27])=[O:26])[C:4]([CH2:33][O:34][C:35]2[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=2)=[C:3]3[C:1]([OH:49])=[O:2])=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: O=Cc1c(COc2ccc3ccccc3c2)n(CCCC(=O)NS(=O)(=O)C(F)(F)F)c2ccc(NC(=O)C3CCCC3)cc12
Reactant: CC(C)(C)O
Agent: CC=C(C)C
Solvent: O
Product: O=C(CCCn1c(COc2ccc3ccccc3c2)c(C(=O)O)c2cc(NC(=O)C3CCCC3)ccc21)NS(=O)(=O)C(F)(F)F
Temperature: 60 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
The product of Step 1, Example 53B (1 eq) was weighed into a flask along with NaH2PO4 (12 eq), t-butyl alcohol (0.12 M), water (0.12 M), 2-methyl-2-butene (50 eq) and to this mixture was added NaO2Cl (11.8 eq) at 25° C. Reaction mixture was then heated at 60° C., 3 h and left overnight at 25° C. Workup with ethyl acetate/water followed by chromatographic purification and triturations with CH2Cl2/hexane (1:1) afforded the desired product in 57% yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[OH-].[K+].[CH3:15][CH2:16][O:17][C:18](Cl)=[O:19].Cl>>[CH2:16]([O:17][C:18]([O:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1)=[O:19])[CH3:15]
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)Oc1ccc(/C=C/C(=O)O)cc1
Temperature: 10 °C
Yield: 83.6 %

Procedure:
67 g (400 mmol) of (2E)-3-(4-hydroxyphenyl)prop-2-enoic acid is added to a mixture of 57.4 g (880 mmol) of potassium hydroxide in 600 ml at 0° C. 46.6 mL (480 mmol) of ethyl chloridocarbonate are added dropwise so that the temperature is maintained to 10° C. The reaction mixture is subsequently allowed to react for 2 hours at 25° C. and then acidified to pH=1 with 200 mL of a 25% HCl solution- The precipitate is filtered off and washed with 500 mL of water. The residue is crystallized in 2 L of toluene and dried under vacuum to yield 79 g (74%) of pure (2E)-3-{4-[(ethoxycarbonyl)oxy]phenyl}prop-2-enoic acid as a white powder.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[Br:16]Br>CCOCC>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1](=[O:3])[CH2:2][Br:16])=[CH:5][CH:6]=1)#[N:9]
Reactant: BrBr
Reactant: CC(=O)c1ccc(C#N)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: N#Cc1ccc(C(=O)CBr)cc1
Reaction time: 0.5 h

Procedure:
4-Acetylbenzonitrile (14.5 g, 100 mmol) was dissolved in anhydrous ether (150 ml). Aluminium chloride (catalytic amount) was added to the solution. Bromine (5.1 ml, 100 mmol) was added dropwise at room temperature and the solution stirred for 1/2 h. A precipitate formed and was collected and dried to yield p-cyanophenacyl bromide, m.p. 85°-86° C. (19.34 g, 86%); δH (CDCl3) 7.80 and 8.10(4H, ABq, aryl), 4.45(2H, s, CH2).
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][C:6]([NH:8][C:9]1([C:15]([OH:17])=O)[CH2:14][O:13][CH2:12][O:11][CH2:10]1)=[O:7].[CH2:20]([O:22][C:23](=[O:33])[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)[CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.N1C(C)=CC(C)=CC=1C>CS(C)=O>[CH2:20]([O:22][C:23](=[O:33])/[CH:24]=[CH:25]/[C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:15]([C:9]2([NH:8][C:6]([O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:19])[CH3:18])=[O:7])[CH2:10][O:11][CH2:12][O:13][CH2:14]2)=[O:17])=[CH:30][CH:31]=1)[CH3:21]
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Reactant: C[Si](C)(C)CCOC(=O)NC1(C(=O)O)COCOC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CS(C)=O
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)/C=C/c1ccc(NC(=O)C2(NC(=O)OCC[Si](C)(C)C)COCOC2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
5-(2-trimethylsilanylethoxycarbonylamino)-1,3-dioxane-5-carboxylic acid from above (0.050 g, 0.17 mmol), ethyl-4-aminocinnamate (0.036 g, 0.19 mmol), HATU (0.098 g, 0.26 mmol), HOAt (0.035 g, 0.26 mmol) and 2,4,6-collidine (0.062 mL, 0.51 mmol) were combined in anhydrous DMSO (1 mL). The solution was warmed to 60° C. and stirred for 6 h before another 1.5 equivalents of HATU was added and stirring was continued for another 2 hours to ensure complete consumption of the acid. The reaction mixture was diluted with dichloromethane and washed with 1N HCl (×2). The organic phase was dried with MgSO4, filtered and concentrated. The residue was subjected to flash chromatography to afford 0.043 g (54%) of the protected amide derivative as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8](OS(C(F)(F)F)(=O)=O)=[CH:7][CH:6]=2.C(N(C(C)C)CC)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH3:71][C:72]1[CH:73]=[CH:74][C:75]2[N:76]([C:78]([SH:81])=[N:79][N:80]=2)[N:77]=1.C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([S:81][C:78]1[N:76]3[N:77]=[C:72]([CH3:71])[CH:73]=[CH:74][C:75]3=[N:80][N:79]=1)=[CH:7][CH:6]=2
Reactant: Cc1ccc2nnc(S)n2n1
Reactant: O=S(=O)(Oc1ccc2ncc(Br)cc2c1)C(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc2nnc(Sc3ccc4ncc(Br)cc4c3)n2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
A solution of trifluoromethanesulfonic acid 3-bromo-quinolin-6-yl ester (973 mg, 2.74 mmol), diisopropylethylamine (0.87 mL, 4.98 mmol) in DMF (9 mL) under nitrogen was degassed by bubbling in nitrogen for 20 min. Tris(dibenzylideneacetone)dipalladium (114 mg, 0.124 mmol, Strem catalyst) and Xantphos (144 mg, 0.249 mmol) were added together in one portion, followed by 6-methyl-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol (450 mg, 2.49 mmol) under a stream of nitrogen. The reaction mixture was stirred at 100° C. for 1 h. The reaction mixture was cooled to room temperature and 500 mg of activated decolorizing charcoal were added. The suspension was stirred for 2.5 h, and the mixture was directly filtered through a plug of silica gel, using DMF as eluent. The solvent was evaporated in vacuo, and the residue was partitioned between water and 10% methanol/dichloromethane. The organic layer was separated and adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-5% methanol/dichloromethane afforded 534 mg of 3-bromo-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline as a cream-colored solid (58% yield).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[NH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: COC(=O)CCCN
Product: COC(=O)CCCNS(=O)(=O)c1ccc2ccccc2c1
Yield: 94 %

Procedure:
Using an analogous procedure to that described in Example 2, 2-naphthylsulphonyl chloride was reacted with methyl 4-aminobutyrate to give methyl 4-(2-naphthalenesulphonamido)butyrate in 94% yield.
Reaction SMILES: [Cl:1][C:2]1[C:20]([CH3:21])=[CH:19][CH:18]=[C:4]2[C:5]([N:7]([C:10]3([C:16]#[N:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:8](=[O:9])[C:3]=12)=[O:6].S(=O)(=O)(O)[OH:23].O>C(Cl)Cl>[Cl:1][C:2]1[C:20]([CH3:21])=[CH:19][CH:18]=[C:4]2[C:5]([N:7]([C:10]3([C:16]([NH2:17])=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3)[C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: Cc1ccc2c(c1Cl)C(=O)N(C1(C#N)CCCCC1)C2=O
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: Cc1ccc2c(c1Cl)C(=O)N(C1(C(N)=O)CCCCC1)C2=O
Reaction time: 4 h
Yield: 62 %

Procedure:
A solution of about 4.35 g (14.4 mmol) of 3-chloro-N-(1-cyanocyclohexyl)-4-methylphthalimide in about 50 ml methylene chloride is added to concentrated sulfuric acid and water at less than 10° C. with rapid stirring. The reaction mixture is stirred very vigorously at ambient temperatures for 4 hours (reaction complete by thin layer chromatography), poured over crushed ice and extracted with about 450 ml methylene chloride. The organic extracts are combined and concentrated in vacuo to give a white fluffy precipitate. The precipitate is filtered and air dried to give the title product, 2.86 g (62% yield), mp 192° C.-208° C., identified by infrared and NMR analysis.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C.[F:30][C:31]1[C:37]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:36][CH:35]=[CH:34][C:32]=1[NH2:33]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:16])[NH:33][C:32]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][C:39]([F:40])([F:41])[F:42])[C:31]=2[F:30])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cccc(OC(F)(F)F)c1F
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)Nc1cccc(OC(F)(F)F)c1F
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
To a solution of (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (1.83 g, 8.07 mmol) in dry THF (45 mL) at −20° C. under nitrogen atmosphere was added triethylamine (3.32 mL, 23.8 mmol) followed by ethylchloroformate (0.775 mL, 8.07 mmol) dropwise. The reaction mixture was stirred at −20° C. for 90 min and a solution of 2-fluoro-3-(trifluoromethoxy)aniline (prepared as described in Part C, 1.5 g, 7.69 mmol) in dry THF (5 mL) was added. The reaction mixture was further stirred at −20° C. for 1 h, warmed up to RT and stirred at 65° C. for 16 h until completion of the reaction. The reaction mixture was diluted with EtOAC, washed with a saturated aqueous solution of NaHCO3 (×3) and brine, dried (phase separator) and concentrated under reduced pressure. The crude residue was purified via flash column chromatography on silica gel (EtOAc/c-hexane 1:1) to give the desired material as a colorless oil. MS: 427 [M+Na]+, 304.9 [MH−Boc]+; tR (HPLC conditions c): 5.23 min.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][NH:5][C:4](=[O:11])[CH:3]=1.[F:12][C:13]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:14]=1[NH2:15].O>CCO.Cl>[F:12][C:13]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][NH:5][C:4](=[O:11])[CH:3]=1
Reactant: O=c1cc(Cl)c([N+](=O)[O-])c[nH]1
Reactant: Nc1ccc(I)cc1F
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=c1cc(Nc2ccc(I)cc2F)c([N+](=O)[O-])c[nH]1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 45 %

Procedure:
To the mixture of 4-chloro-5-nitropyridin-2(1H)-one (90.1 mg, 0.517 mmol) and 2-fluoro-4-iodoaniline (137.5 mg, 0.58 mmol) dissolved in EtOH (5 mL) was added 6 drops of HCl (37% wt in water). The reaction vessel was closed and heated at 90° C. for 48 hours. After cooling to room temperature, water was added, and the solution was stirred at room temperature for 20 min. The precipitate was filtered, washed with water, dried under vacuum and used for the next reaction without further purification. (87.3 mg, 45% yield).