Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31]6[C:36]([CH:37]=5)=[CH:35][CH:34]=[CH:33][CH:32]=6)[CH:26]=4)[N:21]=[CH:20][C:19]=3[C:38]([OH:40])=[O:39])=[CH:13][C:12]=2[C:41]([F:44])([F:43])[F:42])[CH2:7][CH2:6]1)(=[O:4])[CH2:2][CH3:3].Cl[C:46](Cl)([O:48]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:18]4[C:27]5[CH:26]=[C:25]([C:28]6[CH:29]=[N:30][C:31]7[C:36]([CH:37]=6)=[CH:35][CH:34]=[CH:33][CH:32]=7)[CH:24]=[CH:23][C:22]=5[N:21]=[CH:20][C:19]=4[C:38](=[O:40])[O:39][C:46]3=[O:48])=[CH:13][C:12]=2[C:41]([F:42])([F:43])[F:44])[CH2:9][CH2:10]1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)N1CCN(c2ccc(Nc3c(C(=O)O)cnc4ccc(-c5cnc6ccccc6c5)cc34)cc2C(F)(F)F)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)N1CCN(c2ccc(-n3c(=O)oc(=O)c4cnc5ccc(-c6cnc7ccccc7c6)cc5c43)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.3 %

Procedure:
The crude compound 5.5 4′-(4-(4-propionylpiperazin-1-yl)-3(trifluoromethyl)phenylamino)-3,6′-biquinoline-3′-carboxylic acid (20 mg, 0.033 mmol, 1 equiv.) in CH2Cl2 (3 mL) at 0° C. was added triphosgene (10 mg, 0.033 mmol, 1 equiv.) and DIEA (17 μL, 0.1 mmol, 3 equiv.). The resulting solution was warmed to room temperature in 3 hours and further stirred for 1 hour before being quenched with NaHCO3 (sat. 1 mL) and extracted with CH2Cl2 (5 mL×2). The organic phase was dried over Na2SO4 and the residue was purified via preparative LC-MS (CH3CN: H2O) to afford the desired product 5.6 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)-1H-[1,3]oxazino[5,4-c]quinoline-2,4-dione (1.3 mg). LC-MS (M+H): 626.20
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:4]#[C:5][CH2:6][CH2:7][C:17]1[C:15]2[N:16]=[CH:12][O:13][C:14]=2[C:20]([OH:21])=[CH:19][CH:18]=1.[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][C:12]1[O:13][C:14]2[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2cccc(O)c2o1
Product: Oc1ccc(CCC#Cc2ccccn2)c2ncoc12
Product: Oc1cccc2nc(CCC#Cc3ccccn3)oc12
Yield: 16.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (110 mg, 0.69 mmol) and 2-(but-3-ynyl)benzo[d]oxazol-7-ol (130 mg, 0.69 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 10 mg (38 μmol, 5%) of 2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazol-7-ol.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]1[O:6][C:7](=[O:21])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:4].Cl[C:23]1[C:24]2[CH:31]=[CH:30][S:29][C:25]=2[N:26]=[CH:27][N:28]=1.C(N(CC)CC)C>CC(O)(C)C>[C:15]1([C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:21])[O:6][C:5]=2[CH:3]([NH:2][C:23]2[C:24]3[CH:31]=[CH:30][S:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH3:4])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(N)c1oc(=O)c2ccccc2c1-c1ccccc1
Reactant: Clc1ncnc2sccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: CC(Nc1ncnc2sccc12)c1oc(=O)c2ccccc2c1-c1ccccc1
Yield: 46.7 %

Procedure:
3-(1-aminoethyl)-4-phenyl-1H-isochromen-1-one hydrochloride (intermediate E2 50 mg, 0.166 mmol), 4-chlorothieno[2,3-d]pyrimidine (36.8 mg, 0.215 mmol), triethylamine (0.046 ml, 0.331 mmol) were reacted in 2-methylpropan-2-ol (1 ml) at 80° C. for 6 hrs and at 50° C. for 60 hrs. 4-Chlorothieno[2,3-d]pyrimidine (5.7 mg, 0.033 mmol), triethylamine (0.09 ml, 0.066 mmol) were added and the mixture reacted at 90° C. for 4 hrs. The crude was purified via reverse phase chromatography with a Biotage C18 30 g SNAP column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%) to give the title compound (31 mg, 47%).
Reaction SMILES: O.[Li+].[C:3]([O-:13])(=[O:12])[C:4]1[NH:11][C:9](=[O:10])[NH:8][C:6](=[O:7])[CH:5]=1.Cl>CN(C=O)C>[OH:10][C:9]1[N:11]=[C:4]([C:3]([OH:13])=[O:12])[CH:5]=[C:6]([OH:7])[N:8]=1
Reactant: O=C([O-])c1cc(=O)[nH]c(=O)[nH]1
Agent: Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cc(O)nc(O)n1
Temperature: 70 °C

Procedure:
23.00 g (127.74 mmol) orotic acid lithium salt monohydrate in 400 mL DMF were heated to 70° C. and at this temperature hydrochloric acid was added batchwise within 2 h. The reaction mixture was stirred for a further hour at 70° C. and then evaporated down in vacuo. The residue was stirred with water, suction filtered and dried at 50° C. in the CAD.
Reaction SMILES: [C:1]1([C:7]2([CH2:17]N)[CH2:16][CH2:15][C:10]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:21](B)#[N:22].[Na].[C:25](O)(=O)C>C(#N)C.C(Cl)(Cl)Cl.CO>[CH3:25][N:22]([CH3:21])[CH2:17][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1
Reactant: CC(=O)O
Reactant: NCC1(c2ccccc2)CCC2(CC1)OCCO2
Reactant: BC#N
Agent: C=O
Agent: [Na]
Solvent: CO
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CN(C)CC1(c2ccccc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The title compound of step 4 (5.40 g, 21.8 mmol) was dissolved in acetonitrile (150 mL), and a cloudy solution was formed. Aqueous 37% formalin solution (30.6 mL, 407 mmol) was added. The batch was stirred for 20 min at RT and then mixed with sodium cyanoboron hydride (5.76 g, 91.7 mmol). The reaction was followed by DC in chloroform/methanol (9:1). After 4 h the solution was adjusted to pH 7 with acetic acid and concentrated to low volume in a vacuum. The residue was taken up in chloroform, washed with NaHCO3 solution and the aqueous phase extracted with ether. The combined organic phases were dried over Na2SO4 and concentrated to low volume in a vacuum. The raw product was purified by flash chromatography with chloroform/methanol (50:1→20:1→9:1).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH:6]([C:8]2[C:16]3[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=[C:14]([C:17]4[CH:21]=[C:20]([CH:22]=O)[S:19][CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1(=[O:28])=[O:27].[NH:30]1[CH2:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[N:30]1([CH2:22][C:20]2[S:19][CH:18]=[C:17]([C:14]3[CH:15]=[C:16]4[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=3)[NH:10][CH:9]=[C:8]4[CH:6]3[CH2:5][CH2:4][S:3](=[O:28])(=[O:27])[C:2]([CH3:1])([CH3:29])[CH2:7]3)[CH:21]=2)[CH2:33][CH2:32][CH2:31]1
Reactant: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CCS1(=O)=O
Reactant: C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCC5)c4)cc23)CCS1(=O)=O
Yield: 36.3 %

Procedure:
3-(2,2-Dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (30 mg, 0.070 mmol) was dissolved in dimethyl sulfoxide (1.5 mL) and put in a microwave vial. The mixture was stirred and 1-2 drops of acetic acid and azetidine (0.047 mL, 0.697 mmol) was added. The mixture was left stirring 30 minutes at 23° C., before adding sodium triacetoxyborohydride polymer bound (299 mg, 0.697 mmol). The vial was sealed using a silicon septum, and the mixture left stirring 16 h at 23° C. Based on LCMS only 60-70% of conversion was observed. The sodium triacetoxyborohydride polymer bound was removed by filtration. The crude product was purified by preparative HPLC (NH4OH buffer). The desired fractions were concentrated, giving 12 mg of the title compound.
Reaction SMILES: [O:1]=[C:2]([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:9](O)[CH3:10].S(=O)(=O)(O)O.O>C1C=CC=CC=1>[O:1]=[C:2]([CH3:8])[CH2:3][CH2:4][C:5]([O:7][CH2:9][CH3:10])=[O:6]
Reactant: CCO
Reactant: CC(=O)CCC(=O)O
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)CCC(C)=O

Procedure:
100 g (0.86 mol) of 4-oxopentanoic acid, 150 g of ethanol and 1 ml of sulfuric acid in 200 ml of benzene were refluxed until water separation in the Dean-Stark trap ceased. The cooled reaction mixture was washed with water, sodium carbonate solution and again with water and then dried under reflux with the Dean-Stark trap. When removal of the water phase was complete, the solvent was removed by distillation and the residue was distilled under reduced pressure. Boiling point 85-87° C./16 mm Hg, yield 105.5 g (85%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:7][C:6]=1[CH3:17])=O.[NH2:18][C:19]([NH2:21])=[S:20]>CCO>[CH2:13]([O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([C:3]2[N:18]=[C:19]([NH2:21])[S:20][CH:2]=2)=[C:6]([CH3:17])[CH:7]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: Cc1cc(OCC(C)C)cc(C)c1C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1cc(OCC(C)C)cc(C)c1-c1csc(N)n1
Yield: 81.6 %

Procedure:
A mixture of 2-bromo-1-(4-isobutoxy-2,6-dimethylphenyl)ethanone (5.84 g, 19.5 mmol) and thiourea (1.49 g, 19.6 mmol) in 95% EtOH (28 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (30 mL). The solids were filtered and dried under vacuum to give 4-(4-isobutoxy-2,6-dimethylphenyl)thiazol-2-amine (4.4 g) as white solids in 82% yield: 1H NMR (500 MHz, CDCl3) δ 6.61 (s, 2 H), 6.24 (s, 1H), 3.70 (d, J=6.5 Hz, 2 H), 2.15 (s, 6 H), 2.07 (m, 1H), 1.01 (d, J=6.7 Hz, 6 H).
Reaction SMILES: Cl.[Si]([O:19][CH2:20][CH2:21][C:22]1[C:23](=[O:51])[N:24]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:38][C@H:37]([CH2:39][NH:40][C:41]([C:43]4[S:44][C:45]([Cl:48])=[CH:46][CH:47]=4)=[O:42])[O:36][C:35]3=[O:49])=[CH:30][C:29]=2[CH3:50])[CH:25]=[CH:26][CH:27]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>CO.ClCCl>[Cl:48][C:45]1[S:44][C:43]([C:41]([NH:40][CH2:39][C@@H:37]2[O:36][C:35](=[O:49])[N:34]([C:31]3[CH:32]=[CH:33][C:28]([N:24]4[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][CH2:20][OH:19])[C:23]4=[O:51])=[C:29]([CH3:50])[CH:30]=3)[CH2:38]2)=[O:42])=[CH:47][CH:46]=1
Reactant: Cc1cc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)ccc1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)ccc1-n1cccc(CCO)c1=O
Reaction time: 1 h

Procedure:
With ice-cooling, 400 ml of 1.25N hydrochloric acid in methanol are added to 43.8 g (60.3 mmol) of the compound from Example 17A. After 1 h, the mixture is diluted with dichloromethane, and the aqueous phase is then separated off. The organic phase is washed twice with water, dried over sodium sulphate and, after filtration, concentrated to dryness under reduced pressure. The residue is applied to silica gel and chromatographed using a gradient of cyclohexane and ethyl acetate. The product-containing fractions are combined and concentrated to dryness under reduced pressure. This gives 19.6 g (66% of theory) of the desired product.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:8][C:9]2[NH:10][CH:11]=[CH:12][N:13]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)#[N:17].O>CN(C)C=O>[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][O:1][C:2]2[C:3]([CH2:8][C:9]3[NH:13][CH:12]=[CH:11][N:10]=3)=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:20][CH:19]=1)#[N:17]
Reactant: Oc1cccnc1Cc1ncc[nH]1
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(COc2cccnc2Cc2ncc[nH]2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 120.7 %

Procedure:
A solution of 3-hydroxy-2-(1-imidazolylmethyl)-pyridine (6.0 g) in dry N,N-dimethylformamide (100 ml) was cooled to 5° C. and stirred under nitrogen. Sodium hydride (1.8 g as a dispersion in mineral oil) was added and the mixture was stirred for 1 hour at room temperature and then cooled to 0° C. A solution of 4-cyano-benzylbromide (6.8 g) in dry N,N-dimethylformamide (25 ml) was added and the mixture stirred at room temperature for a further 3 hours and allowed to stand overnight. Water (250 ml) was added and the aqueous solution extracted with ethyl acetate (4×100 ml). The organic extracts were combined, washed with water, dried over MgSO4 and evaporated to yield a solid. Recrystallization from ethyl acetate gave 3-(4-cyanobenzyloxy)-2-(1-imidazolylmethyl)pyridine (12.0 g), m.p. 159° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13].[CH:17]([Mg]Br)=[CH2:18].CCOCC>C1(C)C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:12]([OH:13])[CH:17]=[CH2:18])[CH:14]=[CH:15][CH:16]=1
Reactant: C=C[Mg]Br
Reactant: O=Cc1cccc(COC2CCCCO2)c1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=CC(O)c1cccc(COC2CCCCO2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To the aldehyde of Step 10 (85 g, 386 mmol) in toluene (1 L) at 0° C. was slowly added vinyl magnesium bromide in Et2O (450 mL, 1M, 450 mmol) over a 30 minute period. After stirring for 1 hr at 0° C., the reaction mixture was quenched with 25% aq. NH4OAc and extracted with EtOAc (3×). Evaporation and purification by flash chromatography (15%→25% EtOAc in toluene) yielded 82 g (86%) of the title compound.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:29]=[CH:28][C:9]([C:10]([C:12]2[C:21]([O:22]C)=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:17]3)=[O:11])=[CH:8][CH:7]=1>C(Cl)Cl.[Cl-].[Na+].O>[F:5][C:6]1[CH:29]=[CH:28][C:9]([C:10]([C:12]2[C:21]([OH:22])=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16]([S:24]([NH2:27])(=[O:25])=[O:26])=[CH:17]3)=[O:11])=[CH:8][CH:7]=1
Reactant: COc1ccc2cc(S(N)(=O)=O)ccc2c1C(=O)c1ccc(F)cc1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)c1ccc2c(C(=O)c3ccc(F)cc3)c(O)ccc2c1
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
Boron tribromide (55.7 ml, 1M solution in methylene chloride) was added to a suspension of 5-(4-fluorobenzoyl)-6-methoxy-2-naphthalenesulfonamide (5 g, 14 mmol), [prepared as described in example 1], in methylene chloride (100 ml) at 0° C. After 30 minutes, the reaction mixture was poured into brine and the product was extracted into methylene chloride. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness in vacuo. The crude product was purified by chromatography (silica gel, gradient elution, 20-80% ethyl acetate/hexane) to afford 4.0 g of 5-(4-fluorobenzoyl)-6-hydroxy-2-naphthalenesulfonamide as a solid (83% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH:18][C:19]2[CH:28]=[CH:27][C:26]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:20]=2[C:29]([O:31]C)=[O:30])(=[O:17])=[O:16])[CH2:3][CH2:2]1.[CH2:33]([CH:35]([CH2:38][CH3:39])[CH:36]=O)[CH3:34].C([BH3-])#N.[Li+].[OH-]>CN(C=O)C.C(O)(=O)C>[CH2:33]([CH:35]([CH2:38][CH3:39])[CH2:36][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH:18][C:19]2[CH:28]=[CH:27][C:26]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:20]=2[C:29]([OH:31])=[O:30])(=[O:17])=[O:16])[CH2:3][CH2:2]1)[CH3:34]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2NCC2CCNCC2)ccc2c1CCCC2
Reactant: CCC(C=O)CC
Agent: [BH3-]C#N
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCC(CC)CN1CCC(CNc2ccccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)CCCC3)CC1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 20.5 %

Procedure:
A mixture of Example 557B (0.026 g, 0.06 mmol) in DMF (2.5 mL) was treated with acetic acid (0.01 mL) and 2-ethylbutanal (0.025 g, 0.06 mmol). The mixture was shaken at 50° C. for 20 minutes, treated with macroporous polystyrene bound cyanoborohydride resin (85 mg, 0.2 mmol), shaken at 70° C. for 5 hours, and filtered. The filtrate was concentrated, dissolved in 1 mL 2:1 dioxane water, treated with LiOH (25 mg, 0.6 mmol) and heated to 160° C. for 30 minutes in a microwave reactor. The reaction mixture was concentrated and the residues purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product (6.5 mg). MS (ESI(+)) m/e 528 (M+H)+; (ESI(−)) m/e 526 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 7.51 (dd, 1H), 7.38 (dt, 1H), 6.94 (d, 1H), 6.84 (d, 1H), 6.62 (m, 2H), 6.07 (m, 1H), 3.13 (m, 2H), 2.95-2.80, (m, 4H), 2.66 (m, 4H), 1.83 (m, 3H), 1.66 (m, 5H), 1.34 (m, 6H), 0.85 (t, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Cl-].[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][Zn+]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:34][C:33]5[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=5[F:31])[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Reactant: Fc1ccccc1C[Zn+]
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Cl-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3ccccc3F)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-fluoro-benzylzinc chloride following a procedure analogous to that described in Step 6 of Intermediate 1; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 6): tR=1.29 min; Mass spectrum (ESI+): m/z=501 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.ClCCl.[C:16]1(B(O)O)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>CN(C)C=O>[NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([C:24]2[C:25]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:21]=[CH:22][CH:23]=2)=[CH:6][N:7]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: COC(=O)c1nc(Br)cnc1N
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1nc(-c2cccc3ccccc23)cnc1N
Temperature: 87.5 °C
Yield: 38.7 %

Procedure:
To a solution of methyl 3-amino-6-bromopyrazine-2-carboxylate (0.18 g, 0.74 mmol) in N,N-dimethylformamide (10 mL) were added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1, 60 mg, 0.07 mmol), 1-naphthylboronic acid (0.32 g, 1.89 mmol), and triethylamine (0.15g, 1.52 mmol). The solution was degassed with nitrogen for 3-5 min. The reaction was then heated to 85-90° C. overnight. The reaction was cooled to room temperature and diluted with ethyl acetate (300 mL). The crude solution was passed through a pad of silica gel under vacuum. The filtrate was washed with saturated aqueous sodium bicarbonate (50 mL) and saturated aqueous sodium chloride (50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated at reduced pressure to afford impure product. Column purification on silica (8:2 hexanes/ethyl acetate) afforded methyl 3-amino-6-naphthalen-1-ylpyrazine-2-carboxylate (80 mg, 39% yield) as yellow solid: 1H NMR (400 MHz, CDCl3): δ 8.52 (br s, 1H), 8.12 (br s, 1H), 7.92 (m, 2H), 7.52 (m, 5H), 4.02 (s, 3H); MS (EI) for C16H13N3O2: 280 (MHz).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li+].CC([N-]C(C)C)C.[Br:32][C:33]1[N:38]=[C:37]([CH:39]=O)[CH:36]=[CH:35][CH:34]=1.O>C1COCC1>[Br:32][C:33]1[CH:34]=[CH:35][CH:36]=[C:37](/[CH:39]=[CH:2]/[O:3][CH3:4])[N:38]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(Br)n1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CO/C=C/c1cccc(Br)n1
Temperature: -10 °C
Reaction time: 1 h
Yield: 21.9 %

Procedure:
To a suspension of (methoxymethyl)triphenylphosphonium chloride (7.37 g, 21.5 mmol) in THF (100 mL) at −10° C. was added LDA (1.8M in THF/hexane/ethylbenzene, 11.94 mL, 21.5 mmol). The resulting red suspension was stirred at −10° C. for 1 h. To this was added a solution of 6-bromopyridine-2-carboxaldehyde (2.0 g, 10.8 mmol) in THF (60 mL). The resulting colourless suspension was slowly warmed to r.t. over 2.5 h. The reaction mixture was poured into water and extracted with Et2O (3×75 mL). The combined organic phases were washed with brine, dried (MgSO4) and concentrated in vacuo to give a pale yellow oil. Purification by column chromatography (SiO2, 20:1 heptane:EtOAc) gave the title compound (506 mg, 22%) as a yellow oil. δH (CDCl3) 7.61 (1H, d, J 12.6 Hz), 7.37 (1H, t, J 7.7 Hz), 7.16 (1H, dd, J 7.9 and 0.8 Hz), 6.98 (1H, dd, J 7.5 and 0.6 Hz), 5.78 (1H, d, J 12.6 Hz), 3.73 (3H, s). LCMS (ES+) 215.97 (M+H)+, RT 3.50 minutes (Method 1).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][O:13][C:14]([C:16]1[CH:21]=[C:20]([NH:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:19]=[CH:18][C:17]=1[S:28]([NH2:31])(=[O:30])=[O:29])=[O:15].[CH3:32][O:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[N:37]=[C:36]([NH:42][C:43](OC2C=CC=CC=2)=[O:44])[N:35]=1.C1(S(N)(=O)=O)C=CC=CC=1.N1C=CC=NC=1>C(#N)C>[CH3:41][O:40][C:38]1[CH:39]=[C:34]([O:33][CH3:32])[N:35]=[C:36]([NH:42][C:43]([NH:31][S:28]([C:17]2[CH:18]=[CH:19][C:20]([NH:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:21][C:16]=2[C:14]([O:13][CH3:12])=[O:15])(=[O:30])=[O:29])=[O:44])[N:37]=1
Reactant: COC(=O)CNc1ccc(S(N)(=O)=O)c(C(=O)OC)c1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: NS(=O)(=O)c1ccccc1
Solvent: c1cncnc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CNc1ccc(S(=O)(=O)NC(=O)Nc2nc(OC)cc(OC)n2)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.6 ml of DBU are added dropwise at 0° C. to a mixture of 0.87 g of 2-methoxycarbony1-4-(N-methoxycarbonylmethyl-amino)benzenesulfonamide and 0.90 g of 4,6-dimethoxy-2-phenoxycarbonylaminopyrimidine in 10 ml of acetonitrile. The reaction solution is then stirred at room temperature for 6 h. After removal of the solvent by distillation the residue is taken up in water and washed with diethyl ether. After acidification of the aqueous phase with concentrated hydrochloric acid (pH=1) the sulfonylurea which is separated out is stirred in a little methanol. The colorless solid is separated off by filtration and dried to give 1.18 g of N-[(4,6-dimethoxpyrimidin-2-yl)aminocarbonyl]-2-methoxycarbony1-4-(N-methoxycarbonyl-methylamino)benzenesulfonamide7 m.p.: 184°-186° C. (decomposition). The above process is repeated using the following starting quantities: 31.8 g of the benzene-sulfonamide employed, 58.0 9 of the pyrimidine employed, 150 ml of acetonitrile and 39.4 ml of DBU. After reaction at room temperature for 4 h and work-up as described above, 45.0 g of product with a melting point of 187°-189° C. are obtained.