Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH:22]1[CH:26]=[C:25]([CH2:27][CH2:28][NH2:29])[N:24]=[CH:23]1>>[NH:22]1[CH:26]=[C:25]([CH2:27][CH2:28][NH:29][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[N:24]=[CH:23]1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: NCCc1c[nH]cn1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NCCc3c[nH]cn3)cc2c1=O
Yield: 37 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (20 mg, 0.0628 mmol) is reacted with 2-(1H-imidazol-4-yl)-ethylamine according to the GPA affording 9.6 mg (37%) of a red powder. Rt=2.65 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[N:6][CH:7]=1.CC1(C)C(C)(C)[O:19][B:18](B2OC(C)(C)C(C)(C)O2)[O:17]1.C([O-])(=O)C.[K+].B(O)O>O1CCOCC1>[C:10]([NH:9][CH2:8][C:5]1[N:6]=[CH:7][C:2]([B:18]([OH:19])[OH:17])=[CH:3][CH:4]=1)(=[O:14])[CH:11]([CH3:13])[CH3:12]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: CC(C)C(=O)NCc1ccc(Br)cn1
Agent: CC(=O)[O-]
Agent: OBO
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)C(=O)NCc1ccc(B(O)O)cn1
Temperature: 25 °C
Yield: 99 %

Procedure:
A mixture N-((5-bromopyridin-2-yl)methyl)isobutyramide (228 mg, 0.887 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (293 mg, 1.153 mmol), PdCl2(dppf)-CH2Cl2Adduct (72.4 mg, 0.089 mmol) and potassium acetate (218 mg, 2.217 mmol) in Dioxane (6 mL) was heated to 70° C. for 3 hr. LCMS indicated that the major product was boronic acid. After cooling to rt, the reaction mixture was filtered through celite and the filtrate was concentrated to afford (6-(isobutyramidomethyl)pyridin-3-yl)boronic acid (195 mg, 0.878 mmol, 99% yield) as a brown oil. The material was used as is in the next step. The yield is assumed to be quantitative. MS (ES+) m/z: 223.1 (M+H); LC retention time: 0.43 min (analytical LCMS Method B).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH2:23]([C:25]1[S:26][CH:27]=[C:28]([CH2:30][NH2:31])[N:29]=1)[CH3:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:17])([F:19])[F:18])=[N:12][CH:11]=[C:10]([CH:9]=2)[C:20]([NH:31][CH2:30][C:28]2[N:29]=[C:25]([CH2:23][CH3:24])[S:26][CH:27]=2)=[O:21])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: CCc1nc(CN)cs1
Product: CCc1nc(CNC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)cs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAS Registry No. 1018782-82-5) and 2-ethyl-4-thiazolemethanamine as starting materials; LC-MS (UV peak area/ESI) 98%, 456.074 (M+H)+.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH2:4]([C:6]1[S:7][C:8]([C:11]([OH:13])=[O:12])=[CH:9][N:10]=1)[CH3:5]>C(Cl)Cl>[CH2:4]([C:6]1[S:7][C:8]([C:11]([O:13][CH3:3])=[O:12])=[CH:9][N:10]=1)[CH3:5]
Reactant: C=[N+]=[N-]
Reactant: CCc1ncc(C(=O)O)s1
Solvent: ClCCl
Product: CCc1ncc(C(=O)OC)s1

Procedure:
A solution of diazomethane in methylene chloride was added to a suspension of 10.45 g of 2-ethyl-thiazole-5-carboxylic acid in 30 ml of methylene chloride until efferversence stopped and the methylene chloride was distilled. The oily residue was chromatographed over silica and was eluted with a 1:1 mixture of benzene-ethyl acetate to obtain 11.3 g of methyl 2-ethyl-thiazole-5-carboxylate.
Reaction SMILES: C([O:8][C:9]1[CH:32]=[CH:31][C:12]([CH2:13][C@H:14]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C@H:15]([OH:22])[CH2:16][NH:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>O1CCCC1.[Pd]>[OH:22][C@H:15]([CH2:16][NH:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C@@H:14]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:13][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:32][CH:31]=1
Reactant: CC(C)CNC[C@@H](O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)CNC[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Yield: 103.2 %

Procedure:
To a stirred solution of tert-butyl (1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-(isobutylamino)propylcarbamate (0.5 g, 1.1 mmol) in anhydrous tetrahydrofuran (12 mL) was added 0.5 g of palladium (on charcoal, 10% Pd, Degussa type). The mixture was stirred under an atmospheric pressure of hydrogen for 12 hours. The catalyst was filtered and the solvent was removed under reduced pressure resulting in 0.4 g (98%) of the title compound. 1H-NMR (CDCl3): δ 0.92 (6H,dd), 1.35 (9H,s), 1.83 (1H,m), 2.44-2.55 (2H,m), 2.73-2.85 (4H,m), 3.49 (1H,m), 3.70-3.79 (1H,m,b), 4.66 (1H,d), 6.72 (2H,d), 7.05 (2H,d).
Reaction SMILES: C1(C[N:8]2[C:12](=[O:13])[C:11]([CH3:17])([CH2:14][CH2:15][CH3:16])[N:10]([CH3:18])[S:9]2(=[O:20])=[O:19])C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:17][C:11]1([CH2:14][CH2:15][CH3:16])[N:10]([CH3:18])[S:9](=[O:20])(=[O:19])[NH:8][C:12]1=[O:13]
Reactant: CCCC1(C)C(=O)N(Cc2ccccc2)S(=O)(=O)N1C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCCC1(C)C(=O)NS(=O)(=O)N1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.3 %

Procedure:
To a solution of 2-phenylmethyl-4-methyl-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (8.78 g, 29.62 mmol) in 250 ml of dry methanol was added 1.5 g of 10% Pd/C followed by ammonium formate (5.6 g, 88.68 mmol), and the mixture was stirred at room temperature for 4 hours. After adding an additional ammonium formate (2×3 equiv), the mixture was heated at 80°-90° C. overnight, cooled, filtered through a pad of CELITE® and the residue was washed with methanol. The combined filtrate was concentrated in vacuo to afford 5.7 g of 4-methyl-4 -propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula IV: R1 =propyl; R2 =CH3 ; R3 =CH3) as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[O:9][N:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.CN(C)[C:15]1[O:16][C:17](=[O:25])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:20]=1>C(O)(=O)C>[F:12][C:3]1[C:2]([N:1]2[C:17](=[O:25])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[NH:20][C:15]2=[O:16])=[CH:11][C:6]2[C:7]([CH3:10])=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: Cc1noc2cc(F)c(N)cc12
Reactant: CN(C)c1nc(C(F)(F)F)cc(=O)o1
Solvent: CC(=O)O
Product: Cc1noc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc12
Temperature: 25 °C
Yield: 73.3 %

Procedure:
A mixture of 5-amino-6-fluoro-3-methyl-1,2-benzisoxazole (4.85 g, 0.029 mol) and 2-dimethylamino-4-(trifluoromethyl)-6H-1,3-oxazin-6-one (6.70 g, 0.0320 mol) in acetic acid is refluxed for 90 minutes, cooled to room temperature, and poured into an ice-water mixture. The resultant aqueous mixture is filtered to obtain a solid. The solid is air-dried and dissolved in ethyl acetate. The resultant organic solution is washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title product as a yellow solid (7.00 g, mp 235-237° C.) which is identified by NMR spectral analyses.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[N:5]([CH:12]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:22]([O:34][CH3:35])[CH:21]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][CH:7](OC)OC)[CH3:2].Cl.[OH-].[Na+].[C:40](OCC)(=[O:42])C.CCCCCC>CC(C)=O>[CH2:1]([O:3][C:4]([N:5]1[CH:6]=[CH:7][C:25]2[C:20](=[CH:21][C:22]([O:34][CH3:35])=[C:23]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:24]=2)[CH:12]1[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([O:42][CH3:40])[CH:19]=1)=[O:36])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)N(CC(OC)OC)C(Cc1ccccc1)c1ccc(OCc2ccccc2)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CCOC(=O)N1C=Cc2cc(OCc3ccccc3)c(OC)cc2C1Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
To a stirred solution of [1-(4-benzyloxy-3-methoxy-phenyl)-2-phenyl-ethyl]-(2,2-dimethoxy-ethyl)-carbamic acid ethyl ester (100 mg, 0.19 mmol) in acetone (5 mL) was added 6N hydrochloric acid (1 mL) at 0° C. The reaction mixture was stirred at room temperature for 18 hrs and neutralized by addition of 6N aqueous sodium hydroxide solution. The solvent was evaporated and the aqueous phase was extracted with dichloromethane (3×25 μL). The combined extracts were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) afforded 6-benzyloxy-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (60 g, 85% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:8][C@H:7]1[CH2:19][OH:20])=[O:5])[CH3:2].C(N(CC)CC)C.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClCCl>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:16])([CH3:18])[CH3:17])([CH3:13])[CH3:14])[CH2:8][C@H:7]1[CH2:19][O:20][S:34]([C:31]1[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=1)(=[O:36])=[O:35])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
To a cold (0° C.) solution of (1R,2R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-hydroxymethyl-cyclopentanecarboxylic acid ethyl ester (example 68 step 4, 500 mg) and triethyl amine (836 mg) in dichloromethane (5 mL) was added toluene-4-sulfonyl chloride (1.53 g). The reaction mixture was stirred overnight at room temperature then partitioned between hydrochloric acid (1N) and dichloromethane. The aqueous layers was extracted with dichloromethane and the combined organic layers were washed with half saturated aqueous solution of sodium hydrogenocarbonate and brine, then dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with a gradient of cyclohexane/ethyl acetate (1:0 to 19:1 v/v) as eluant to afford the title compound (602 mg, 80%) as a yellow liquid.
Reaction SMILES: ClC1C=CC(S(N[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](CCCCCC2C=NC=CC=2)(C(OCC)=O)[C:19]([O:21]CC)=[O:20])(=O)=O)=CC=1.O.C(=O)(O)[O-].[Na+]>Cl.C(O)(=O)C>[C:19]([OH:21])(=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCOC(=O)C(CCCCCCNS(=O)(=O)c1ccc(Cl)cc1)(CCCCCc1cccnc1)C(=O)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCC(=O)O

Procedure:
A solution of 1.4 g of ethyl 8-(p-chlorophenylsulfonamido)-2-[5-(3-pyridyl)-pentyl]-2-(ethoxycarbonyl)-octanoate in 50 ml of 6N HCl and 10 ml of acetic acid is heated to reflux for 23 h after which time it is evaporated to give an oil. This is treated with water, the solution is neutralized with solid sodium bicarbonate to a pH of 6.4 and extracted with ethyl acetate. The ethyl acetate extract is dried over magnesium sulfate, filtered and concentrated to give crude product which is further purified by chromatography on silica gel [(1) ethyl acetate as eluent, (2) preparative thin layer chromatography with ethyl acetate/acetic acid 99.5:0.5] to give 8-(p-chlorophenylsulfonamido)-2-[5-(3-pyridyl)pentyl])-octanoic acid as an oil, NMR (CDCl3): delta 7.77 (d,2H), 7.4 (d,2H), 2.85 (t,2H), 2.55 (t,2H).
Reaction SMILES: FC(F)O[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]([OH:15])=[O:14].[F:17][CH:18]([F:29])[O:19]C1C=C2C(C=CN2)=CC=1>>[F:17][CH:18]([F:29])[O:19][C:12]1[CH:11]=[C:10]2[C:6]([C:7]([C:13]([OH:15])=[O:14])=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1c[nH]c2ccc(OC(F)F)cc12
Reactant: FC(F)Oc1ccc2cc[nH]c2c1
Product: O=C(O)c1c[nH]c2cc(OC(F)F)ccc12

Procedure:
Prepared as for 5-(difluoromethoxy)-1H-indole-3-carboxylic acid (Example 6) starting with 6-difluoromethoxyindole (WO 97/45408 A1). MS (m/e) 227.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:3][CH2:2]1.Cl[CH2:13][CH2:14][CH2:15][N:16]1[C:21]2[C:22]([F:27])=[CH:23][CH:24]=[C:25]([F:26])[C:20]=2[O:19][CH2:18][C:17]1=[O:28].C([O-])([O-])=O.[K+].[K+]>>[CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][N:9]([CH2:13][CH2:14][CH2:15][N:16]3[C:21]4[C:22]([F:27])=[CH:23][CH:24]=[C:25]([F:26])[C:20]=4[O:19][CH2:18][C:17]3=[O:28])[CH2:8][CH2:7]2)[CH2:2][CH2:3]1
Reactant: C1CC(OCC2CC2)CCN1
Reactant: O=C1COc2c(F)ccc(F)c2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1COc2c(F)ccc(F)c2N1CCCN1CCC(OCC2CC2)CC1
Yield: 37.3 %

Procedure:
4-Cyclopropylmethoxypiperidine (0.085 g, 0.55 mmol), 4-(3-chloropropyl)-5,8-difluoro-4H-benzo[1,4]oxazin-3-one (0.146 g, 0.56 mmol), K2CO3 (0.152 g, 1.1 mmol), and KI (0.164 g, 1.1 mmol) were mixed according to GP3. Purified by prep TLC (SiO2; Heptanes/EtOAc 1:1) to give the title compound (0.078 g, 37%). 1H NMR (CDCl3) δ 6.82-6.69 (m, 2H), 4.57 (s, 2H), 4.07-4.03 (m, 2H), 3.31-3.22 (m, 3H), 2.72-2.64 (m, 2H), 2.32 (t, J=7.2 Hz, 2H), 2.02 (t, J=10.4 Hz, 2H), 1.88-1.76 (m, 4H), 1.59-1.48 (m, 2H), 1.07-0.95 (m, 2H), 0.53-0.47 (m, 2H), 0.19-0.14 (m, 2H); 13C NMR (CDCl3) δ 164.6, 148.3 (dd, J=243.3 Hz, J=2.7 Hz), 147.7 (dd, J=243.9, J=2.8 Hz), 136.6 (dd, J=11.2 Hz, J=4.9 Hz), 120.0 (d, J=11.1 Hz), 111.2 (dd, J=20.4 Hz, J=9.6 Hz), 110.3 (dd, J=24.8 Hz, J=7.7 Hz), 75.0, 72.6, 68.6, 55.6, 51.5, 42.7 (d, J=10.8 Hz), 31.5, 25.7 (d, J=2.7 Hz), 11.1, 3.2.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](SC)=[C:18]([C:21]#[N:22])[C:19]#[N:20])=[CH:12][CH:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.[NH2:26][NH2:27]>CO>[NH2:20][C:19]1[NH:27][N:26]=[C:17]([NH:16][C:13]2[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[CH:11][CH:12]=2)[C:18]=1[C:21]#[N:22]
Reactant: NN
Reactant: CSC(Nc1ccc(CNC(=O)OC(C)(C)C)cc1)=C(C#N)C#N
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(Nc2n[nH]c(N)c2C#N)cc1

Procedure:
A mixture of 117.8 g (342 mmol) of 3-[4-(N-Boc-aminomethyl)-phenylamino)2-cyano-3-methylmercaptoacrylonitrile, 20.54 ml (41.45 mmol) of hydrazine hydrate and 750 ml of methanol is heated under reflux for 3 hours and then concentrated by evaporation in vacuo at 50° C., yielding 5-amino-3-[4-(N-Boc-aminomethyl)-phenylamino]-4-cyano pyrazole in the form of an amorphous residue; TLC-Rf=0.28 (methylene chloride/methanol [9:1]).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]2([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][OH:27])=[CH:21][CH:20]=3)[CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.F[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][C:13]2([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][O:27][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[CH:21][CH:20]=3)[CH2:14][CH2:15][CH2:16][CH2:17]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Fc1ccccn1
Reactant: O=S(=O)(NCC1(Cc2ccc(CCO)cc2)CCCC1)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=S(=O)(NCC1(Cc2ccc(CCOc3ccccn3)cc2)CCCC1)c1ccc(Cl)cc1
Reaction time: 0.07 h
Yield: 22.3 %

Procedure:
A mixture of 30 mg (0.074 mmol) of 4-chloro-N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl]benzenesulfonamide (EP 472449), 130 μl (1.48 mmol) of 2-fluoropyridine and 16.576 mg (0.148 mmol) of potassium carbonate is irradiated in a microwave oven (600 W max.), at a maximum temperature of 120° C. for 4 minutes. The crude reaction medium is purified by preparative LC-MS to give 8 mg of the expected compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[O:25][C:26]([CH3:29])=[CH:27][CH:28]=2)[O:22][CH:23]=1>>[N:12]1([CH2:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:18][C:19]3[N:20]=[C:21]([C:24]4[O:25][C:26]([CH3:29])=[CH:27][CH:28]=4)[O:22][CH:23]=3)=[CH:3][CH:4]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Oc1ccc(CCCCn2ccnc2)cc1
Reactant: Cc1ccc(-c2nc(CCl)co2)o1
Product: Cc1ccc(-c2nc(COc3ccc(CCCCn4ccnc4)cc3)co2)o1
Yield: 99 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[4-(4-hydroxyphenyl)butyl]imidazole was allowed to react with 4-chloromethyl-2-(5-methyl-2-furyl)oxazole to give 4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-(5-methyl-2-furyl)oxazole. The yield was 99%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 91-92° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1Br)[CH:18]([NH:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][CH:25]=1)[CH2:17][CH2:16]2)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]([Cu])#[N:38].N>CN1C(=O)CCC1>[CH2:1]([O:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[C:37]#[N:38])[CH:18]([NH:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][CH:25]=1)[CH2:17][CH2:16]2)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCc3cc(NC(=O)COCc4ccccc4)c(Br)cc32)cc1
Reactant: N#C[Cu]
Agent: N
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)c1ccc(NC2CCc3cc(NC(=O)COCc4ccccc4)c(C#N)cc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.4 %

Procedure:
To a stirred solution of tert-butyl 4-[N-(5-(2-benzyloxyethanoylamino)-6-bromoindan-1-yl)amino]benzoate (0.210 g, 0.38 mmol) in anhydrous NMP (2.2 ml) was added CuCN (0.068 g, 0.76 mmol). The reaction flask was placed in an oil bath preheated to 150° C. and it was stirred at this temperature for 3 h under argon. The mixture was then allowed to cool to room temperature and poured into a mixture of liquid ammonia (d=0.88, 2 ml) and ice-water (5 ml). This mixture was stirred at room temperature for 5 min, the brown precipitate was then collected by filtration and washed with water. This precipitate was then suspended in CH2Cl2 (70 ml), dried (Na2SO4), and concentrated in vacuo. Purification of the residue by column chromatography, on elution with 35% AcOEt in hexane, afforded a brown solid (0.084 g, 45%); mp 194-195° C.; 1H-NMR (250 MHz, CDCl3, TMS) 1.55 (s, 9H, C(CH3)3), 1.95, 2.64 (2×m, 1H each, 2-CH2 indanyl), 2.99 (m, 2H, 3-CH2 indanyl), 4.13, 4.72 (2×s, 2H each, PhCH2 and OCH2CO), 4.22 (d, J=8.1 Hz, 1H, N10—H), 5.05 (m, 1H, 1-CH indanyl), 6.65 (d, J=8.7 Hz, 2H, 3,5-ArH), 7.39 (m, 5H, PhCH2), 7.54, 8.37 (2×s, 1H each, 4-H and 7-H), 7.86 (d, J=8.7 Hz, 2H, 2,6-ArH), 9.06 (s, 1H, CONH); MS (ESI, m/z) 520 {(M+Na)+, 100%,}; Found: C, 72.26; H, 6.26; N, 8.41; C30H31N3O4 requires C, 72.41; H, 6.28; N, 8.44%.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11](O)=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[N:14]3)=[CH:9][CH:8]=2)=[C:5]([CH3:21])[O:4][N:3]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:11]1[C:10]2[C:15](=[CH:16][C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:21])=[CH:8][CH:9]=2)[N:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]
Reactant: Cc1noc(C)c1-c1ccc2c(O)c([N+](=O)[O-])cnc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1noc(C)c1-c1ccc2c(Cl)c([N+](=O)[O-])cnc2c1
Yield: 75 %

Procedure:
A suspension of 7-(3,5-dimethyl-4-isoxazolyl)-3-nitro-4-quinolinol (for a preparation see intermediate 15, 5 g, 17 mmol) in POCl3 (50 ml) was refluxed overnight. After cooling the solvent was evaporated in vacuo. The resulting residue was poured over saturated aqueous Sodium hydrogen carbonate, extracted with DCM, washed with water, dried over Na2SO4. The solvent was evaporated under reduce pressure to give the title compound as a light brown solid (4 g, 75%). 1H NMR (300 MHz, CDCl3, ppm) δ: 9.23 (s, 1H), 8.45 (d, J=8.9 Hz, 1H), 8.04 (d, J=1.5 Hz, 1H), 7.67 (dd, J=8.9, 1.5 Hz, 1H), 2.47 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16][C:17]2[CH:18]=[N:19][C:20](F)=[C:21]([Cl:23])[CH:22]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8].[C:25]1([OH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[Cl:1][C:2]1[C:3]([O:16][C:17]2[CH:18]=[N:19][C:20]([O:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:21]([Cl:23])[CH:22]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8]
Reactant: Oc1ccccc1
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2cnc(F)c(Cl)c2)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2cnc(Oc3ccccc3)c(Cl)c2)cc1F
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 66.2 %

Procedure:
To a solution of 5-chloro-4-[(5-chloro-6-fluoropyridin-3-yl)oxy]-2-fluoro-N-(methylsulfonyl)benzamide (Example 19, 100 mg, 0.25 mmol) and phenol (71 mg, 0.76 mmol) in DMSO (1 mL) was added Cs2CO3 (246 mg, 0.76 mmol) at room temperature under N2. The resulting mixture was stirred at 100° C. for 45 minutes. The reaction mixture was allowed to cool to room temperature. The reaction was quenched with water, and acidified with 1N aqueous citric acid solution. The mixture was extracted with DCM (3×3 mL) and filtered through a phase separation cartridge. The organic phase was washed with brine (3 mL), and filtered through a phase separation cartridge. The filtrate was dried by N2 blowing to give a crude product that was purified by reverse phase column chromatography eluting with 5-95% CH3CN in water to give a crude white solid. The solid was purified using trituration with heptane/acetone 9/1 to give the title compound (78 mg, 65%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[N:6][CH:7]=1.[Cu][C:20]#[N:21]>>[C:11]([C:10]1[CH:13]=[C:14]([CH2:17][OH:18])[CH:15]=[CH:16][C:9]=1[O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([CH:3]=1)[C:20]#[N:21])#[N:12]
Reactant: N#Cc1cc(CO)ccc1Oc1cncc(Br)c1
Reactant: N#C[Cu]
Product: N#Cc1cncc(Oc2ccc(CO)cc2C#N)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D5 starting from 2-((5-bromopyridin-3-yl)oxy)-5-(hydroxymethyl)benzonitrile and copper(I) cyanide.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[C:11]([O:14][C:15](=O)[CH3:16])(=[O:13])[CH3:12]>C(O)C>[C:11]([O:14][CH2:15][C:16]1[NH:10][C:8](=[O:9])[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=1)(=[O:13])[CH3:12]
Reactant: NC(=O)c1nccnc1N
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Product: CC(=O)OCc1nc2nccnc2c(=O)[nH]1

Procedure:
Obtained using the procedure described in Example 1, starting with 5.3 g (0.038 mole) of 3-amino-2-pyrazinecarboxamide, 34.5 g (0.157 mole) of triethyl orthopropoxyacetate and 34.5 ml of acetic anhydride. Refluxing time: 1 hour 45 minutes. Yld: 5.4 g (65%), m.p. 210°-212° C. (ethanol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1cccc(Br)c1
Product: CC(=O)NCCc1cccc(Br)c1

Procedure:
In close analogy to the procedure described above, 2-(3-bromo-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.