Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].CCN(C(C)C)C(C)C.[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH2:42][CH2:43][C:44](SC1C=CC(F)=CC=1)=[O:45])[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C.O>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][NH:2][C:44](=[O:45])[CH2:43][CH2:42][C@H:31]([NH:30][C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29])[C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)Sc1ccc(F)cc1)C(=O)OCc1ccccc1
Reactant: NCC(=O)OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)NCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 90.6 %

Procedure:
A solution of benzyl 2-aminoacetate hydrochloride (17.6 mg, 0.0871 mmol) and DIPEA (0.0152 ml, 0.0871 mmol) in DMF (0.0871 ml) was added to a solution of (S)-benzyl 2-((tert-butoxycarbonyl)amino)-5-((4-fluorophenyl)thio)-5-oxopentanoate (Compound 5e-2) (30.0 mg, 0.0670 mmol) in DMF (0.463 ml) and water (0.220 ml), and the mixture was stirred at 50° C. for six hours. The reaction mixture was then purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=70/30→20/80) to afford (S)-benzyl 5-((2-(benzyloxy)-2-oxoethyl)amino)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoate (Compound 5d-2) (29.4 mg, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]#[N:16])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].C(Cl)(C)=O.[NH3:27]>C1(C)C=CC=CC=1.CO>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15](=[NH:27])[NH2:16])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:19]([F:20])([F:21])[F:22]
Reactant: N
Reactant: N#CCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Solvent: CO
Solvent: CC(=O)Cl
Solvent: Cc1ccccc1
Product: N=C(N)CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a solution of 3-(4-(4-chloro-3-(trifluoromethyl)phenoxy)phenyl)propanenitrile (1 g, 3.07 mmol) in toluene (4 mL) and methanol (1 mL) was added dropwise AcCl (1.091 mL, 15.35 mmol) at 0° C. in 5 min. The mixture was stirred at room temperature for 2 h. The mixture was cooled to 0° C. in an ice bath, and ammonia (4.39 mL, 30.7 mmol) in methanol was added dropwise in 5 min. The mixture was stirred at room temperature overnight. The mixture was filtered to remove the solid, and the solid was washed with toluene (20 mL) and methanol (20 mL). The combined filtrate was concentrated in vacuo, the residue was triturated with diethyl ether, the resulting white solid was collected by filtration, washed with diethyl ether and dried in vacuo to afford the title compound (0.85 g, 2.242 mmol, 73.0% yield) as white solid. LCMS: rt=1.17 min, [M+H+]=343
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(OC)(O[CH3:16])(=O)=O>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:16])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: COS(=O)(=O)OC
Product: COc1ccc(C(C)(C)C)cc1

Procedure:
reacting 4-tert-butylphenol with dimethyl sulfate to produce 4-tert-butylanisole;
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[CH3:23][O:24][C:25]1[CH:50]=[CH:49][C:48]([N:51]2[CH:55]=[N:54][N:53]=[N:52]2)=[CH:47][C:26]=1[C:27]([N:29]1[CH2:33][CH2:32][C:31]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([CH2:34][CH2:35]OS(C)(=O)=O)[CH2:30]1)=[O:28].C(N(CC)CC)C.C(OCC)(=O)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.ClCCl>[CH3:23][O:24][C:25]1[CH:50]=[CH:49][C:48]([N:51]2[CH:55]=[N:54][N:53]=[N:52]2)=[CH:47][C:26]=1[C:27]([N:29]1[CH2:33][CH2:32][C:31]([CH2:34][CH2:35][N:20]2[CH2:19][CH2:18][CH:17]([NH:16][C:8]3[N:7]([CH2:6][C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)[CH2:22][CH2:21]2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:30]1)=[O:28]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: c1coc(Cn2c(NC3CCNCC3)nc3ccccc32)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCN2CCC(Nc3nc4ccccc4n3Cc3ccco3)CC2)(c2ccccc2)C1
Reaction time: 42 h

Procedure:
Combine (1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (0.236 g, 0.8 mmol), 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-(2-hydroxyethyl)-3-phenylpyrrolidine (R,R)-di-p-anisoyltartaric acid salt) (0.38 g, 0.80 mmol), triethylamine (0.133 mL, 7.2 mmol), and tetrabutylammonium iodide (30 mg) in acetonitrile (11.4 mL). Heat to reflux. After 42 hours, cool, dilute the reaction mixture with dichloromethane, and extract with water. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give the title compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.[Br:14][C:15]1[C:16](F)=[C:17]2[C:23]([NH:24][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=3)=[CH:22][NH:21][C:18]2=[N:19][CH:20]=1.CC#N.O>CCCCO>[Br:14][C:15]1[C:16]([N:1]2[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)=[C:17]2[C:23]([NH:24][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=3)=[CH:22][NH:21][C:18]2=[N:19][CH:20]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccnc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: CC#N
Solvent: O
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Temperature: 160 °C
Reaction time: 24 h
Yield: 35.1 %

Procedure:
(R)-tert-Butyl pyrrolidin-3-ylcarbamate (333 mg, 1.79 mmol) was added to N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (200 mg, 0.597 mmol) in n-BuOH (3 mL), and the reaction was stirred at 160° C. for 24 hours. The reaction was concentrated to dryness, and then the residue was purified by chromatography (SP4, C-18 25M+ column, gradient of 10-90% CH3CN/water, 30CV) to yield (R)-tert-butyl 1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate (105 mg, 35.1% yield) as a solid.
Reaction SMILES: CO[C:3](=[O:27])[CH:4]([NH:11][C:12](=[O:26])[CH:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:28][NH2:29]>CCO.C1COCC1>[C:22]([O:21][C:19](=[O:20])[NH:18][CH:13]([C:12](=[O:26])[NH:11][CH:4]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C:3](=[O:27])[NH:29][CH3:28])[C:14]([CH3:17])([CH3:15])[CH3:16])([CH3:24])([CH3:25])[CH3:23]
Reactant: CN
Reactant: COC(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)C1CCCCC1
Solvent: C1CCOC1
Solvent: CCO
Product: CNC(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)C1CCCCC1
Yield: 95 %

Procedure:
To compound 63 in EtOH-THF 1:2 was added a large excess of methylamine (30% in water) and left at rt. for 2 weeks. The solution was concentrated to dryness and the residue subjected to a short silica gel column eluted with 2% MeOH in dichloromethane to give a pure (>95%) product M+H+384.5.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]([N:23]1[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]1)=[O:22].B(Br)(Br)Br>>[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22]
Reactant: COc1cccc(-c2ccc3c(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)c(OC)ccc3c2)c1
Agent: BrB(Br)Br
Product: O=C(c1c(O)ccc2cc(-c3cccc(O)c3)ccc12)N1CCNCC1
Yield: 60 %

Procedure:
The compound is prepared by reaction of tert-butyl 4-(2-methoxy-6-(3-methoxyphenyl)-1-naphthoyl)piperazine-1-carboxylate (200 mg, 0.42 mmol, 1 eq) with boron tribromide solution (2.5 ml, 2.52 mmol, 6 eq) according to method G. Purification by column chromatography was not necessary. Extraction of the aqueous phase with ethyl acetate yields the desired product in a yield of 60%, 88 mg.
Reaction SMILES: [CH2:1]([C:3]1([C:9]([O:11]CC2C=CC=CC=2)=[O:10])[CH2:6][C:5]([F:8])([F:7])[CH2:4]1)[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:1]([C:3]1([C:9]([OH:11])=[O:10])[CH2:4][C:5]([F:7])([F:8])[CH2:6]1)[CH3:2]
Reactant: CCC1(C(=O)OCc2ccccc2)CC(F)(F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC1(C(=O)O)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.7 %

Procedure:
To a solution of Intermediate 301A (0.2 g, 0.787 mmol) in ethanol (5 mL) and water (1 mL) was added a 5N aq. solution of NaOH (0.787 mL, 3.93 mmol) and the reaction mixture was stirred at RT for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water and extracted with diethyl ether (3×5 mL). The pH of the aqueous solution was adjusted to 7.0 using a 2N aq. solution of HCl and the aqueous phase was extracted with DCM (3×10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford Intermediate 301B as a pale yellow liquid (50 mg, 38.7%). 1H NMR (300 MHz, DMSO-d6) δ ppm 12.63-12.75 (m, 1H), 2.80-2.97 (m, 2H), 2.57-245 (m, 2H), 1.77 (q, J=7.55 Hz, 2H), 0.81 (t, J=7.37 Hz, 3H).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.[CH3:12][NH2:13]>C(#N)C>[CH3:7][C:5]1[N:6]=[C:2]([NH:13][CH3:12])[S:3][C:4]=1[S:8]([NH2:11])(=[O:10])=[O:9]
Reactant: Cc1nc(Cl)sc1S(N)(=O)=O
Reactant: CN
Solvent: CC#N
Product: CNc1nc(C)c(S(N)(=O)=O)s1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
At room temperature, 144 g (0.576 mol) of 2-chloro-4-methyl-1,3-thiazole-5-sulphonamide are initially charged in 600 ml of acetonitrile, and 147 g (1.9 mol) of a 40% strength aqueous methylamine solution are metered in at room temperature. The reaction mixture is stirred at 50° C. for 6 h and then concentrated using a rotary evaporator. The residue is admixed with water, filtered off with suction and dried.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([CH:19]=[CH2:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[N:6]=1.B1C2CCCC1CCC2.C1C[O:33]CC1>>[F:1][C:2]1[CH:18]=[C:17]([CH2:19][CH2:20][OH:33])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[N:6]=1
Reactant: C1CCOC1
Reactant: C=Cc1ccc(Oc2cccc(C(F)(F)F)n2)c(F)c1
Agent: B1C2CCCC1CCC2
Product: OCCc1ccc(Oc2cccc(C(F)(F)F)n2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
To a solution of 2-(2-fluoro-4-vinylphenoxy)-6-(trifluoromethyl)pyridine (0.342 mL, 1.554 mmol) in THF (10 mL) was added 9-BBN (4.66 mL, 2.330 mmol) at 0° C. The mixture was stirred at room temperature overnight, and quenched with water (2 mL), followed by aq. NaOH (3 M, 4 mL), and 30% H2O2 (5 mL). The reaction mixture was stirred at 50° C. for 2 h. Then the THF and some water was removed under reduced pressure, and the residue was diluted with EA. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, concentrated and purified by flash chromatography to afford the title compound (183 mg, 39.1% yield) as a colorless oil. LCMS: rt=2.45 min
Reaction SMILES: [C:1]([C:3]1[C:4]([F:14])=[C:5]([O:12][CH3:13])[CH:6]=[C:7]([O:10][CH3:11])[C:8]=1[F:9])#[CH:2].Br[C:16]1[N:17]=[C:18]2[CH:24]=[CH:23][N:22]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:19]2=[N:20][CH:21]=1.C(N(CC)CC)C>CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:14][C:4]1[C:5]([O:12][CH3:13])=[CH:6][C:7]([O:10][CH3:11])=[C:8]([F:9])[C:3]=1[C:1]#[C:2][C:16]1[N:17]=[C:18]2[CH:24]=[CH:23][N:22]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:19]2=[N:20][CH:21]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2nc(Br)cnc21
Reactant: C#Cc1c(F)c(OC)cc(OC)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(OC)c(F)c(C#Cc2cnc3c(ccn3S(=O)(=O)c3ccccc3)n2)c1F
Reaction time: 14 h
Yield: 62.6 %

Procedure:
To a stirred solution of 3-ethynyl-2,4-difluoro-1,5-dimethoxybenzene (340 mg, 1.72 mmol) and 2-bromo-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (696 mg, 2.06 mmol, from Example 1, Step 1) in N,N-dimethylformamide (4 mL), copper(I) iodide (26 mg, 0.14 mmol), bis(triphenylphosphine)palladium(II) chloride (60.0 mg, 0.0885 mmol) and triethylamine (0.36 mL, 2.6 mmol) were added sequentially at room temperature. After 14 hours, the reaction was quenched with saturated aq. NH4Cl, then extracted with methylene chloride. The combined organic layers were dried over MgSO4, then concentrated. The residue was purified on silica gel (eluting with 0 to 50% ethyl acetate (EtOAc) in hexanes) to give the desired product (490 mg, 63%). LCMS calculated for C22H15F2N3O4S (M+H)+: m/z=456.1. Found: 456.1.
Reaction SMILES: [NH2:1][CH:2]([C:6]#[N:7])[C:3]([NH2:5])=[O:4].CC1C=C(C=C(C)N=1)CCl.[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:28])[N:27]=1)[C:22](O)=[O:23]>N1C=CC=CC=1.S(Cl)(Cl)=O>[NH2:5][C:3](=[O:4])[CH:2]([NH:1][C:22](=[O:23])[C:21]1[CH:25]=[C:26]([CH3:28])[N:27]=[C:19]([CH3:18])[CH:20]=1)[C:6]#[N:7]
Reactant: N#CC(N)C(N)=O
Reactant: Cc1cc(C(=O)O)cc(C)n1
Agent: Cc1cc(CCl)cc(C)n1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)NC(C#N)C(N)=O)cc(C)n1
Yield: 43.8 %

Procedure:
2-amino 2-cyano acetamide (1.4 g, 0.01473 mol, 1 eq) in pyridine (15 ml) is stirred for 1 h at room temperature, to this 2,6-dimethyl isonicotinyl chloride (2.5 g, 0.1473 mol, 1 eq) [prepared by stirring a mixture of 2,6-dimethyl isonicotinic acid (2.5 g, 0.0465 mol, 1 eq) in thionyl chloride (15 ml) at 85° C. for 2 hr, thionyl chloride was removed in vacuum under nitrogen] is added at 0° C. and the reaction mixture is stirred at room temperature for 14 h, after the completion of the reaction pyridine is removed under vacuum and the crude product is purified by column chromatography to afford (1.5 g) of the titled compound;
Reaction SMILES: Br.[CH:2]1([C:5]2[CH:6]=[CH:7][C:8]([CH:13]=[O:14])=[N:9][C:10]=2[O:11]C)[CH2:4][CH2:3]1.O>O1CCOCC1>[CH:2]1([C:5]2[C:10](=[O:11])[NH:9][C:8]([CH:13]=[O:14])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1
Reactant: COc1nc(C=O)ccc1C1CC1
Agent: Br
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1ccc(C2CC2)c(=O)[nH]1
Temperature: 65 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
48% hydrobromic acid (3 mL) was added to a solution of 5-cyclopropyl-6-methoxypyridine-2-carbaldehyde obtained in Reference Example 1-51(6) (437 mg) in 1,4-dioxane (6 mL), and the mixture was stirred at 65° C. for two hours. The reaction solution was poured into water, followed by extraction with chloroform/methanol (2:1). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25→0:100) to give 5-cyclopropyl-6-oxo-1,6-dihydropyridine-2-carbaldehyde as a yellow powder (278 mg, 69%).
Reaction SMILES: I[C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[Cu](C#N)[C:18]#[N:19]>CN1C(=O)CCC1.CCOC(C)=O>[C:18]([C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])#[N:19]
Reactant: COC(=O)c1snc(-c2ccccc2)c1I
Reactant: N#C[Cu]C#N
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)c1snc(-c2ccccc2)c1C#N
Temperature: 100 °C
Yield: 84.8 %

Procedure:
To a solution of methyl 4-iodo-3-phenylisothiazole-5-carboxylate (Preparation 103D, 600 mg, 1.738 mmol) in NMP (2 mL) was added copper cyanide (311 mg, 3.48 mmol). The resulting mixture was heated at 100° C. in a microwave reactor for 45 min. The reaction mixture was diluted with EtOAc (40 mL), filtered, washed with water (2×20 mL), brine (10 mL) and concentrated. Flash chromatography gave methyl 4-cyano-3-phenylisothiazole-5-carboxylate (360 mg, 1.474 mmol, 85% yield) as a white solid. The compound had an LC/MS M+1=245.1.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.Cl.[N+:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:30]=[C:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[S:32][CH:33]=1)([O-:22])=[O:21]>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:37]1[CH2:38][CH2:39][N:34]([C:31]2[S:32][CH:33]=[C:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N+:20]([O-:22])=[O:21])[N:30]=2)[CH2:35][CH2:36]1)=[O:9])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccccc1-c1csc(N2CCNCC2)n1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc(-c3ccccc3[N+](=O)[O-])cs2)CC1
Yield: 61 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-[4-(2-nitro-phenyl)-thiazol-2-yl]-piperazine dihydrochloride. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a yellow crystalline solid (yield 61%). MS (m/e): 531.3 (M+H+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1
Reactant: COC(=O)c1cc(OC)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cc(OC)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
A suspension of dimethyl-5-methoxy-isophthalate (6.4 g, 28.5 mmol) in methanol (143 mL) was treated with 1 N sodium hydroxide (25.6 mL, 25.6 mmol). The reaction was left stirring overnight at room temperature. After the solution was concentrated, the residue was dissolved in water and transferred to a separatory funnel. The aqueous layer was washed with dichloromethane (3 times) and then acidified with 1 N HCl to pH 2. Ethyl acetate was used to extract the precipitate, which was then washed with brine and dried over anhydrous sodium sulfate. After removal of solvent in vacuo, 4.5 g (75%) of 5-methoxyisophthalic acid monomethyl ester was isolated as a white solid. 1H NMR (DMSO), δ(ppm): 8.17 (m, 1H), 7.60 (m, 2H), 3.80 (s, 3H), 3.76 (s, 3H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH2:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>ClCCl>[C:5]([CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:11][CH2:10][CH2:9][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:7])[CH3:6]
Reactant: CCCCCCCCCCCCCCCc1ccccc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCCCCC(CCCc1ccccc1)C(C)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 500-ml-three-necked round-bottomed flask, with an efficient cooling was charged with aluminium chloride (5.82 g, 43.67 mmol) and dichloromethane (100 ml). Acetyl chloride (3.42 g, 43.67 mmol) was added to the vigorously stirred reaction mixture over a period of 15 minutes. Pentadecyl benzene (10 g, 34.66 mmol) was added over a period of 30 minutes; the clear solution was stirred at 0° C. for 2 hours and allowed to warm to room temperature. The reaction mixture was poured in ice and extracted with dichloromethane (3×100 ml), the combined organic layers was washed with 1 N hydrochloric acid (2×30 ml) and water (3×50 ml), dried over sodium sulfate and the solvent was evaporated to obtain 4-acetyl pentadecyl benzene as a low melting faint yellow solid. The yield was 10 g (87% of theoretical).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[C:8]=1[O:9][CH3:10])=[O:2].[C:23]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH:1]([C:3]1[CH:4]=[C:5]([S:19]([NH:22][C:31](=[O:32])[CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:21])=[O:20])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[C:8]=1[O:9][CH3:10])=[O:2]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: COc1ccccc1-c1cc(S(N)(=O)=O)cc(C=O)c1OC
Product: COc1ccccc1-c1cc(S(=O)(=O)NC(=O)CCc2ccccc2)cc(C=O)c1OC

Procedure:
Proceeding as in Reference 21, but substituting 5-formyl-6,2′-dimethoxy-biphenyl-3-sulfonamide and 3-phenylpropionyl chloride, gave 5-formyl-6,2′-dimethoxy-N-(3-phenylpropionyl)-biphenyl-3-sulfonamide.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[NH:5]([C:7]1[S:11][N:10]=[C:9]([C:12]([Cl:15])([Cl:14])[Cl:13])[N:8]=1)[NH2:6]>>[Cl:15][C:12]([Cl:13])([Cl:14])[C:9]1[N:8]=[C:7]([NH:5][N:6]=[C:2]([CH3:4])[CH3:1])[S:11][N:10]=1
Reactant: NNc1nc(C(Cl)(Cl)Cl)ns1
Reactant: CC(C)=O
Product: CC(C)=NNc1nc(C(Cl)(Cl)Cl)ns1
Yield: 79 %

Procedure:
A mixture of 5 ml (3.9 g, 0.068 mole) acetone and 2.4 g (0.01 mole) 5-hydrazino-3-trichloromethyl-1,2,4-thiadiazole was heated 0.5 hour on a steam bath. The solid that was left after evaporation of the excess acetone was recrystallized from ligroin to yield 0.95 g (mp. 75°-77° C.). A second crop of 1.2 g (mp. 66° C.) was obtained after concentration of the solvent. Total yield was 2.15 g (79% yield).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:19]3[C:10]([C:11]4[CH:12]=[C:13]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C:14]([C:20]5[CH:25]=[CH:24][C:23]([C:26]6([NH:34]C(=O)OC(C)(C)C)[CH2:29][C:28]7([O:33][CH2:32][CH2:31][O:30]7)[CH2:27]6)=[CH:22][CH:21]=5)=[N:15][C:16]=4[CH:17]=[CH:18]3)=[N:9][N:8]=2)[N:4]=[CH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:19]3[C:10]([C:11]4[CH:12]=[C:13]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C:14]([C:20]5[CH:21]=[CH:22][C:23]([C:26]6([NH2:34])[CH2:29][C:28]7([O:33][CH2:32][CH2:31][O:30]7)[CH2:27]6)=[CH:24][CH:25]=5)=[N:15][C:16]=4[CH:17]=[CH:18]3)=[N:9][N:8]=2)[N:4]=[CH:3]1
Reactant: Cn1cnc(-c2nnc3c4cc(-c5ccccc5)c(-c5ccc(C6(NC(=O)OC(C)(C)C)CC7(C6)OCCO7)cc5)nc4ccn23)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cnc(-c2nnc3c4cc(-c5ccccc5)c(-c5ccc(C6(N)CC7(C6)OCCO7)cc5)nc4ccn23)c1

Procedure:
To a solution of tert-butyl (2-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}-5,8-dioxaspiro[3.4]oct-2-yl) (1-11) in DCM (50 mL) was added TFA (50 mL) at rt under N2 for 2 hours. The reaction was quenched with 1N NaOH (650 mL), poured into saturated sodium bicarbonate, extracted with chloroform, dried over sodium sulfate, filtered and concentrated. The crude residue was recrystallized from methanol to give 2-{4-[3-(1-methyl-1/1-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}-5,8-dioxaspiro[3.4]octan-2-amine (1-12) as a white solid. HRMS (M+H)+: observed=530.2315, calculated=530.2299.