Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([NH:27][C:28](=O)[O:29]C)[N:20]=1.C[Al](C)C.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:26][O:25][C:23]1[CH:24]=[C:19]([O:18][CH3:17])[N:20]=[C:21]([NH:27][C:28]([NH:16][S:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)(=[O:14])=[O:15])=[O:29])[N:22]=1
Reactant: COC(=O)Nc1nc(OC)cc(OC)n1
Reactant: NS(=O)(=O)c1ccccc1-c1ccccn1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2-c2ccccn2)n1
Yield: 42.3 %

Procedure:
A solution of 1.2 g of the compound from Example 2 and 1.3 g of methyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate in 50 ml of methylene chloride was stirred under nitrogen and 3.4 ml of a 2N solution of trimethylaluminum in toluene was added. After heating at reflux for 4 days, the solution was cooled to 0°, 3 ml of 2N HCl (aq.) was added, the mixture was partitioned between methylene chloride and water. The organic layer was concentrated and the residue was chromatographed on silica gel to afford 0.9 g of the product, m.p. 175°-176°. NMR (DMSO-d6)δ: 3.8 (s, 6), 6.0 (s, 1), 7.2-8.3 (m). m/e (M+ +1) 416. IR 1700 cm-1.
Reaction SMILES: [CH2:1]([C:3]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([C:36]([F:39])([F:38])[F:37])([OH:35])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=1)([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[C:8]([CH3:21])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH2:41]([O:43][C:44](=[O:53])[CH2:45][C:46]1[CH:47]=[N:48][C:49](Cl)=[CH:50][CH:51]=1)[CH3:42].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[CH2:41]([O:43][C:44](=[O:53])[CH2:45][C:46]1[CH:47]=[N:48][C:49]([C:9]2[CH:10]=[CH:11][C:6]([C:3]([CH2:4][CH3:5])([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([OH:35])([C:36]([F:37])([F:39])[F:38])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=3)[CH2:1][CH3:2])=[CH:7][C:8]=2[CH3:21])=[CH:50][CH:51]=1)[CH3:42]
Reactant: CCOC(=O)Cc1ccc(Cl)nc1
Reactant: CCC(CC)(c1ccc(CCC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2ccc(C(CC)(CC)c3ccc(CCC(O)(C(F)(F)F)C(F)(F)F)c(C)c3)cc2C)nc1
Temperature: 140 °C
Yield: 40.6 %

Procedure:
N,N-Dimethylformamide (0.7 mL) was added to 4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-butan-2-ol (Example 27-(2); 60 mg, 0.105 mmol), (6-chloro-pyridin-3-yl)acetic acid ethyl ester (40 mg, 0.201 mmol), tetrakis(triphenylphosphine)palladium (0) (23 mg, 0.02 mmol) and potassium phosphate (63.9 mg, 0.30 mmol). The mixture was stirred with microwave heating at 140° C. for seven minutes in a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (hexane/ethyl acetate=5/1) to give the title compound (26 mg, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[CH3:11][O:12][C:13](=[O:31])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22](Cl)[C:23]3[CH:28]=[C:27]([Cl:29])[S:26][C:24]=3[N:25]=2)=[CH:16][CH:15]=1>>[CH3:11][O:12][C:13](=[O:31])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:23]3[CH:28]=[C:27]([Cl:29])[S:26][C:24]=3[N:25]=2)=[CH:16][CH:15]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(Cl)sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(Cl)c(Cl)c3)c3cc(Cl)sc3n2)cc1

Procedure:
The reaction procedure as above in wherein 3,4-dichlorobenzylamine is reacted with 4-(4-chloro-6-chloro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dichlorobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:21]#[N:22])[C:17]([O:19]C)=[CH:18][C:13]=2[NH:12][C:11](=[O:23])[CH2:10][N:9]=1.[Cl-].[Cl-].[Cl-].[Al+3]>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:21]#[N:22])[C:17]([OH:19])=[CH:18][C:13]=2[NH:12][C:11](=[O:23])[CH2:10][N:9]=1
Reactant: COc1cc2c(cc1C#N)C(c1ccccc1Cl)=NCC(=O)N2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: N#Cc1cc2c(cc1O)NC(=O)CN=C2c1ccccc1Cl
Reaction time: 48 h
Yield: 138.7 %

Procedure:
A solution of 1.2 g (0.0037 mole) of 5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-methoxy-2H-1,4-benzodiazepin-2-one (Ib, prepared in Example 30) in 100 mL of 1,2-dichloroethane was stirred with 2.5 g (0.0187 mole) of aluminum trichloride at 42° C. for 8 hours, after which an additional 2.5 g of aluminum trichloride was added. Heating and stirring was continued for another 48 hours after which time an additional 2.5 g of aluminum trichloride was added. After 6 hours, the mixture was cooled and then poured onto ice water. The water was extracted with dichloromethane-methanol-tetrahydrofuran (80:10:10), and the extract washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1.6 g of crude 5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-hydroxy-2H-1,4-benzodiazepin-2-one (Iqq). Purification by silica gel chromatography, eluting with ethyl acetate-methanol (90:10) yielded 1.17 g of 5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-hydroxy-2H-1,4-benzodiazepin-2-one (Iqq) (MH+/Z=312) which was of sufficient purity for use in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](I)[CH3:21]>CN(C=O)C.O>[CH2:20]([O:7][C:6](=[O:8])[C:5]1[C:9]([CH3:11])=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[O:12][CH3:13])[CH3:21]
Reactant: CCI
Reactant: COc1cc(Br)cc(C)c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)cc(Br)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a stirred solution of 4-bromo-2-methoxy-6-methyl-benzoic acid (synthesized according to the methods described in sections a) to d) of example 10) (10.7 g, 43.7 mmol) in DMF (90 ml) are added potassium carbonate (12.1 g, 87.3 mmol) and ethyl iodide (17.5 ml, 218 mmol) and the resulting mixture is stirred at room temperature for 2 h. After completion of reaction the reaction mixture is diluted with water (200 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers are washed with water (2×30 ml), brine (2×30 ml), dried over sodium sulfate and concentrated in vacuo yielding 4-bromo-2-methoxy-6-methyl-benzoic acid ethyl ester (10.5 g, 39 mmol, 89%).
Reaction SMILES: [CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=3[CH:21]=4)[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2].[CH:30](=O)[CH2:31][CH2:32][CH2:33][CH2:34]C>>[CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=3[C:21]=4[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2]
Reactant: CCCCCC=O
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3c(F)cc(F)cc3nc2-1
Product: CCCCCc1c2c(nc3cc(F)cc(F)c13)-c1cc3c(c(=O)n1C2)COC(=O)C[C@]3(O)CC

Procedure:
The product of Example 100 is treated with hexanal according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][OH:15])=[C:12]([CH:16]([CH3:18])[CH3:17])[CH:11]=[N:10]1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23](O)=[CH:22][C:21]=1[CH3:27].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:23]2[CH:24]=[CH:25][C:20]([NH2:19])=[C:21]([CH3:27])[CH:22]=2)=[C:12]([CH:16]([CH3:18])[CH3:17])[CH:11]=[N:10]1
Reactant: CC(C)c1cnn(-c2c(Cl)cccc2Cl)c1CO
Reactant: Cc1cc(O)ccc1N
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
To a 0° C. solution of [2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-methanol (3.0 g, 10.6 mmol), 4-amino-3-methyl-phenol (2.0 g, 15.8 mmol), and tri-n-butylphosphine (3.2 g, 15.8 mmol) in toluene (30 mL) is added a solution of 1,1′-(Azodicarbonyl)-dipiperidine (4.0 g, 15.8 mmol) in toluene (40 mL). The reaction mixture is allowed to warm to room temperature and is stirred for 3.0 h. The reaction mixture is partitioned between EtOAc (50 mL) and water (60 mL). The organic layer is washed with brine (60 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography (EtOAc/Hexane) to afford the title compound as a solid (2.3 g, 56%). LC-ES/MS m/e 390.0 (M+1).
Reaction SMILES: Cl.C[O:3][C:4](=O)[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[OH-].[NH4+:16]>O>[NH2:6][C@@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([NH2:16])=[O:3]
Reactant: [NH4+]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: O
Product: NC(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 59 %

Procedure:
A mixture of L-phenylalanine methyl ester hydrochloride (6.50 g, 30.1 mmol) and ammonium hydroxide solution (28% in water, 15 mL) in water (60 mL) was stirred at ambient temperature for 64 h. The aqueous layer was extracted with dichloromethane (6×100 mL), and the combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford (S)-2-amino-3-phenylpropanamide as a colorless solid in 59% yield (2.92 g): 1H NMR (300 MHz, DMSO-d6) 6 7.38-7.21 (m, 5H), 7.12 (br s, 1H), 5.44 (br s, 1H), 3.63 (dd, J=9.5, 3.9 Hz, 1H), 3.28 (dd, J=13.7, 3.9 Hz, 1H), 2.72 (dd, J=13.7, 9.5 Hz, 1H), 1.41 (br s, 2H).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH:17]12[CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH:18]2[CH2:24][C:25](Cl)=[O:26]>>[CH:17]12[CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH:18]2[CH2:24][C:25]([NH:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4])=[O:26]
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Reactant: O=C(Cl)CC1CC2CCC1C2
Product: CCC(NC(=O)CC1CC2CCC1C2)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 150 mg (0.67 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 130 mg (0.74 mmol) bicyclo[2.2.1]hept-2-ylacetyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: CC([O-])(C)C.[K+].[NH2:7][C:8]1[N:13]=[C:12]([NH2:14])[C:11]([CH2:15][C:16]2[CH:17]=[C:18]([OH:26])[C:19]3[CH:20]=[CH:21][N:22]([CH3:25])[C:23]=3[CH:24]=2)=[CH:10][N:9]=1.[CH3:27][CH:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>CN(C)C=O>[NH2:7][C:8]1[N:13]=[C:12]([NH2:14])[C:11]([CH2:15][C:16]2[CH:24]=[C:23]3[C:19]([CH:20]=[CH:21][N:22]3[CH3:25])=[C:18]([O:26][S:30]([CH:28]([CH3:29])[CH3:27])(=[O:32])=[O:31])[CH:17]=2)=[CH:10][N:9]=1
Reactant: Cn1ccc2c(O)cc(Cc3cnc(N)nc3N)cc21
Reactant: CC(C)S(=O)(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)Oc1cc(Cc2cnc(N)nc2N)cc2c1ccn2C
Yield: 37.4 %

Procedure:
Potassium tert-butylate (150 mg, 1.31 mmol) was added at 0° C. (ice bath) to a solution of 6-(2,4-diamino-pyrimidin-5-ylmethyl)-1-methyl-1H-indol-4-ol (Example 4; 293 mg, 1.09 mmol) in N,N-dimethylformamide (33 mL). After 30 min the solution was treated with propane-2-sulfonyl chloride (190 mg, 1.31 mmol), and the ice bath was removed. After 2.5 h the reaction mixture was poured into ice water, set to pH 9-10 with 25% aqueous ammonia solution, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried (MgSO4), and evaporated. Column chromatography (SiO2; CH2Cl2/MeOH/NH4OH19:1:0.05) afforded the title compound (153 mg, 37%). White solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][N:3]=1.[Br-].[CH:18]1([CH2:24][Zn+])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1.CCOC(C)=O>[C:13]([O:12][C:10]([NH:9][CH2:8][C:5]1[CH:4]=[N:3][C:2]([CH2:24][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:7][CH:6]=1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)nc1
Reactant: [Zn+]CC1CCCCC1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(CC2CCCCC2)nc1
Temperature: 60 °C
Yield: 68 %

Procedure:
Dissolve 2-bromo-5-tert-butoxycarbonylaminomethyl-pyridine (500 mg, 1.74 mmol) in anhydrous THF (5 mL) in a sealed tube. Degas the solution, purge with nitrogen and add 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (127 mg, 0.174 mmol) and 0.5 M cyclohexylmethylzinc bromide in THF (10.4 mL, 5.22 mmol). Heat the mixture at 60° C. overnight. Cool to room temperature and dilute the reaction mixture with EtOAc. Add water and filter the precipitate over Celite®. Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (4:1, 3:2) to give the desired intermediate as an oil (359 mg, 68%). MS (ES+) m/z: 305 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:20]3[C:15](=[C:16]([F:22])[CH:17]=[CH:18][C:19]=3[F:21])[O:14][CH2:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][CH2:26][OH:27].C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[C:20]3[C:15](=[C:16]([F:22])[CH:17]=[CH:18][C:19]=3[F:21])[O:14][CH2:13][CH:12]2[NH:23][CH2:24][CH2:25][CH2:26][OH:27])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: NCCCO
Reactant: O=S(=O)(C1=CCOc2c(F)ccc(F)c21)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Cl)cc1)C1c2c(F)ccc(F)c2OCC1NCCCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(4-Chloro-benzenesulfonyl)-5,8-difluoro-2H-chromene (0.3 g, 0.88 mmole) was dissolved in 15 ml THF and 3-aminopropanol (1 ml) was added. The mixture was stirred at room temperature for 30 minutes. 50 saturated Na2CO3 solution and 50 ml EtOAc were added. The organic layer washed with water (50 ml), brine (50 ml), dried over Na2SO4 and concentrated. The product was purified by column (EtOAc/hexane from 50/50 to 100/0 in 45 minutes). Yield: 0.31 g, 84%. 1H NMR (CDCl3 400 MHz) δ 7.69 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.1 Hz), 6.99 (td, J=9.5, 5.1 Hz, 1H), 6.38 (td, J=9.5, 3.7 HZ, 1H), 4.80 (dd, J=12.5, 2.9 Hz, 1H), 4.53 (s, 1H), 4.43 (d, J=11.8 Hz, 1H), 3.78 (s, 1H), 3.61 (t, J=5.9 Hz, 2H), 2.86-2.71 (m, 2H), 2.25 (bs, 1H), 1.57 (p, J=5.9 Hz, 2H).
Reaction SMILES: [Li]CCCC.Br[C:7]1[S:11][CH:10]=[N:9][CH:8]=1.[Sn:12](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16].Cl>C1COCC1.CCCCCC>[CH2:21]([Sn:12]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:17][CH2:18][CH2:19][CH3:20])[C:7]1[S:11][CH:10]=[N:9][CH:8]=1)[CH2:22][CH2:23][CH3:24]
Reactant: Brc1cncs1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cncs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
A hexane solution of n-BuLi (4.14 mL, 10 mmol) was added dropwise to an anhydrous tetrahydrofuran solution of 5-bromothiazole (0.46 mL, 5.0 mmol) at −78° C. under nitrogen atmosphere over a period of 30 minutes, and the mixture was stirred for 1 hour. A solution of n-Bu3SnCl (1.41 mL, 5.0 mmol) in THF was then added dropwise over a period of 30 minutes at −78° C., and after stirring for 2 hours, the mixture was raised to room temperature and stirred for another hour. Three drops of a 1N HCl solution were added, and the organic layer was extracted from the aqueous layer twice with 10 mL of ether. The solvent was distilled away to yield the title compound (650 mg, 35 mL).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:32][C:33]1[C:34]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:42][CH:41]=2)=[N:35][CH:36]=[C:37]([OH:39])[CH:38]=1.[CH2:55](O)[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62]>O1CCCC1>[F:32][C:33]1[C:34]([C:40]2[CH:41]=[CH:42][C:43]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:44][CH:45]=2)=[N:35][CH:36]=[C:37]([O:39][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[CH:38]=1
Reactant: CCCCCCCCO
Reactant: CCCCCCCCOc1ccc(-c2ncc(O)cc2F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ncc(OCCCCCCCC)cc2F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
2.00 g (11.5 mmol) of diethyl azodicarboxylate are added dropwise at 0° C. to 3.00 g (11.5 mmol) of triphenylphosphine in 50 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 30 minutes. 2.42 g (7.7 mmol) of 3-fluoro-5-hydroxy-2-(4-octyloxyphenyl)pyridine and 1.00 g (7.7 mmol) of 1-octanol are subsequently added. After a reaction time of 18 hours at room temperature, the solvent is removed by distillation and the residue is purified by chromatography (silica gel/hexane: ethyl acetate 95:5). Recrystallization from acetonitrile gives 1.38 g of 3-fluoro-5-octyloxy-2-(4-octyloxyphenyl)pyridine. ##STR18## The compound has the phase sequence: X 51.3 (42.5) SA 50 N 69 I.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C([Li])CCC.[O:17]1[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH2:18]1>O1CCCC1>[Cl:1][C:2]1[C:3]2[C:10]([C:19]3([OH:23])[CH2:20][CH2:21][CH2:22][O:17][CH2:18]3)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]cc(I)c12
Reactant: O=C1CCCOC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2c[nH]c3ncnc(Cl)c23)CCCOC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a −78° C. solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.5 g, 5.4 mmol) in tetrahydrofuran (50 mL) was added n-butyllithium (2.5 M, 6.4 mL, 16.1 mmol) drop-wise. After the reaction mixture had been stirred at −78° C. for 2 hours, it was treated with dihydro-2H-pyran-3(4H)-one (1.61 g, 16.1 mmol), warmed to room temperature, and stirred for 18 hours. The reaction was quenched with water (50 mL), and the aqueous layer was extracted with ethyl acetate (3×30 mL); the combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated. Silica gel chromatography (Gradient: 0% to 50% ethyl acetate in petroleum ether) afforded the product as a yellow oil. Yield: 200 mg, 0.79 mmol, 15%. LCMS m/z 254.0 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[C:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>>[C:18]([C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])(=[O:29])=[O:28])=[CH:25][CH:26]=1)(=[O:20])[CH3:19]
Reactant: Cc1ncccc1C(=O)c1cc(Cl)ccc1N
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2cccnc2C)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2 amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and 4-acetyl-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3) δ 10.79 (br s, 1H, NH), 8.65 (dd, 1H, J=4.8 Hz, J=1.8 Hz), 7.98 (d, 2H, J=8.8 Hz), 7.92 (d, 2H, J=8.8 Hz), 7.79 (d, 1H, J=9.2 Hz), 7.50 (dd, 1H, J=9.0 Hz, J=2.2 Hz), 7.22 (dd, 1H, J=7.7 Hz, J=1.5 Hz), 7.16 (m, 2H), 2.60 (s, 3H), 2.36 (s, 3H). MS: m/z 429 (M+1).
Reaction SMILES: COCCOC[O:7][C:8]1[C:9]([Se:22][C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][N:24]=2)=[CH:10][C:11]2[C:12]([CH3:21])([CH3:20])[CH2:13][CH2:14][C:15]([CH3:19])([CH3:18])[C:16]=2[CH:17]=1.S(=O)(=O)(O)O.C(O)C>C1COCC1>[OH:7][C:8]1[C:9]([Se:22][C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][N:24]=2)=[CH:10][C:11]2[C:12]([CH3:20])([CH3:21])[CH2:13][CH2:14][C:15]([CH3:19])([CH3:18])[C:16]=2[CH:17]=1
Reactant: CCOC(=O)c1ccc([Se]c2cc3c(cc2OCOCCOC)C(C)(C)CCC3(C)C)nc1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc([Se]c2cc3c(cc2O)C(C)(C)CCC3(C)C)nc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 93 %

Procedure:
A mixture of ethyl 6-(3-methoxyethoxymethoxy5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanyl)nicotinate (2.6 g, 5 mmol), concentrated sulphuric acid (535 μl), ethanol (75 ml) and THF (25 ml) is stirred for 3 days at room temperature. The reaction medium is extracted with ethyl ether. The organic phase is washed twice with water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum. The solid obtained is washed with ethyl ether. 2.01 g (93%) of the expected compound are obtained in the form of an orange-coloured powder. m.p.=138° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Cl[C:16]1[C:21]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH3:29])[N:23]=2)=[CH:20][CH:19]=[CH:18][N:17]=1.C(Cl)Cl>O>[Br:7][C:8]1[N:13]=[CH:12][C:11]([O:14][C:16]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH3:29])[N:23]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:10][CH:9]=1
Reactant: Oc1ccc(Br)nc1
Reactant: CNc1nccc(-c2cccnc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Product: CNc1nccc(-c2cccnc2Oc2ccc(Br)nc2)n1
Temperature: 125 °C

Procedure:
To a slurry of cesium carbonate (8.9 g, 27 mmol) and 6-bromopyridin-3-ol (2.6 g, 15 mmol) was added 4-(2-chloropyridin-3-yl)-N-methylpyrimidin-2-amine (3.0 g, 14 mmol). The reaction mixture was sealed and heated to 125° C. for 16 h. The mixture was cooled and diluted with water and the aqueous solution was extracted with DCM (3×75 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a brown oil, which was taken up in a little DCM and purified on an ISCO 120 g column, eluting with a gradient of 0-100% EtOAc/DCM, to afford 4-(2-(6-bromopyridin-3-yloxy)pyridin-3-yl)-N-methylpyrimidin-2-amine as an off-white solid. MS m/z=295 [M+H]+. Calc'd for C15H12BrN5O: 358.2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-])=O.[S-:14][C:15]#[N:16].[NH4+].O>S1(CCCC1)(=O)=O>[NH2:16][C:15]1[S:14][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N:1]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: Nc1nc2cc([N+](=O)[O-])ccc2s1
Temperature: 150 °C
Yield: 134.7 %

Procedure:
A suspension of 5.06 g of 2,4-dinitrochlorobenzene and 7.6 g of ammonium thiocyanate in 25 ml of sulpholane is heated, with stirring, to 150° C. and maintained at this temperature for 1.5 hours. The product is discharged into 300 ml of water, and the solid is filtered off with suction and washed with water. After drying, 6.57 g of crude 2-amino-5-nitrobenzothiazole are obtained. The identity was confirmed by TLC comparison (TLC=thin-layer chromatography) with authentic material.