Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[C:9]=1[OH:15].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC#N>[CH2:16]([O:15][C:9]1[C:8]([Br:7])=[CH:13][CH:12]=[CH:11][C:10]=1[Br:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1c(Br)cccc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1cccc(Br)c1OCc1ccccc1
Temperature: 23 °C
Reaction time: 48 h

Procedure:
Powdered K2CO3 (27.6 g, 200 mmol, 2.0 equiv) was added to a solution of 2,6-dibromophenol (14) (25.0 g, 100 mmol, 1.0 equiv) in MeCN (300 mL). Benzyl bromide (18.0 g, 12.5 mL, 105 mmol, 1.05 equiv) was added slowly to the light blue suspension. The reaction temperature increased only from 22 to 24° C. over 5 min. The reaction suspension was heated at reflux for 6 hr, allowed to cool to room temperature and stand for 48 hr. The mixture was filtered, solids were washed with EtOAc (300 mL) and the filtrate was concentrated under reduced pressure. The residual oil was dissolved in 1:1 MTBE/heptanes (500 mL), the solution washed with 10% NaOH (100 mL), H2O (100 mL), brine (100 mL), dried over Na2SO4, filtered and the solution concentrated under reduced pressure giving 36.9 g (108%) of crude 15 as a yellow oil that crystallized after pumping on high vacuum for 1.5 hr. Crude 15 was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH3:13][O:14][NH:15][CH3:16].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([N:15]([O:14][CH3:13])[CH3:16])=[O:7]
Reactant: COc1ncccc1C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncccc1C(=O)N(C)OC
Temperature: 0 °C
Reaction time: 18 h
Yield: 50.4 %

Procedure:
To a stirred ice-cooled mixture of 2-methoxy-nicotinic acid (1.43 g, 9.31 mmol) and O,N-dimethyl-hydroxylamine hydrochloride (1.0 g, 10.3 mmol) in DCM (50 mL) was added DIPEA (6.4 mL, 37.3 mmol). EDCI (2.14 g, 11.1 mmol) was added portionwise over 5 minutes. After 18 hours, the reaction mixture was washed successively with saturated sodium bicarbonate and water. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 50 to 75% EtOAc in cyclohexane) to afford the title compound (0.92 g, 51%) as a colourless oil. LCMS (Method A): RT=2.48 min, [M+H]+=197.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3](=[O:22])[NH:4][C:5]1[CH:10]=[C:9]([CH2:11][NH:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=O)[CH:8]=[CH:7][N:6]=1.[CH3:24][O:25][C:26]([C:28]1[N:29]([CH3:38])[N:30]=[C:31]2[C:36]=1[CH:35]=[CH:34][C:33]([NH2:37])=[CH:32]2)=[O:27].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:24][O:25][C:26]([C:28]1[N:29]([CH3:38])[N:30]=[C:31]2[C:36]=1[CH:35]=[CH:34][C:33]([NH:37][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=1[NH:12][CH2:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([NH:4][C:3]([N:2]([CH3:1])[CH3:23])=[O:22])[CH:10]=1)=[CH:32]2)=[O:27]
Reactant: CN(C)C(=O)Nc1cc(CNc2ccccc2C(=O)O)ccn1
Reactant: COC(=O)c1c2ccc(N)cc2nn1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)c1c2ccc(NC(=O)c3ccccc3NCc3ccnc(NC(=O)N(C)C)c3)cc2nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.2 %

Procedure:
2-{[2-(3,3-Dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoic acid (112 mg, 0.35 mmol), 6-amino-2-methyl-2H-indazole-3-carboxylic acid methyl ester (62 mg, 0.3 mmol), N-methylmorpholine (0.09 mL, 0.82 mmol) and HATU (152 mg, 0.4 mmol) were suspended in dry DMF (3 mL) and stirred at rt overnight. The reaction mixture was concentrated in vacuo and the residue partitioned between dichloromethane. The organic phase was washed consecutively with saturated aqueous sodium hydrogencarbonate solution, water and brine, dried and concentrated in vacuo. The residue was purified by chromatography on Isolute® flash silica gel (Separtis) (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 9:1) to give 6-(2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoylamino)-2-methyl-2H-indazole-3-carboxylic acid methyl ester (53 mg, 35%) as a solid; 1H-NMR (300 MHz, d6-DMSO) 10.30 (1H, s), 8.79 (1H, s), 8.30 (1H, m), 8.15 (1H, d), 7.92-7.99 (2H, m), 7.82 (1H, s), 7.75 (1H, dd), 7.62 (1H, dd), 7.25-7.29 (1H, m), 6.93-6.96 (1H, m), 6.68 (1H, t), 6.55 (1H, d), 4.45 (2H, d), 4.41 (3H, s), 3.99 (3H, s), 2.92 (6H, s); m/z (ES+) 502 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C@@H:12]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C@H:11]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH:10]([CH2:44][O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=3)[O:9]2)=[CH:4][C:3]=1CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:76]([Br:80])(Br)(Br)Br>O1CCCC1>[Br:80][CH2:76][C:3]1[CH:4]=[C:5]([C@H:8]2[C@@H:13]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[C@@H:12]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C@H:11]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH:10]([CH2:44][O:45][CH2:46][C:47]3[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=3)[O:9]2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: COc1ccc(COCC2O[C@@H](c3ccc(Cl)c(CO)c3)[C@@H](OCc3ccc(OC)cc3)[C@@H](OCc3ccc(OC)cc3)[C@@H]2OCc2ccc(OC)cc2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(COCC2O[C@@H](c3ccc(Cl)c(CBr)c3)[C@@H](OCc3ccc(OC)cc3)[C@@H](OCc3ccc(OC)cc3)[C@@H]2OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
To a solution of the product from step D (0.36 g, 0.46 mmol) in tetrahydrofuran (5.0 mL) at 0° C. was added triphenylphosphine (0.36 g, 1.38 mmol), followed by dropwise addition of a solution of carbon tetrabromide (0.46 g, 1.38 mmol) in tetrahydrofuran (5.0 mL). The reaction mixture was allowed to warm to room temperature and stirred for 8 hours. The reaction solution was then quenched by addition of methanol and stirred for 15 minutes at room temperature. The resultant mixture was concentrated to dryness and the residue obtained was purified by flash column chromatography (eluent: hexanes/ethyl acetate 95:5 to 60:40) to give (2S,3R,4R,5R)-2-(3-(bromomethyl)-4-chlorophenyl)-3,4,5-tris(4-methoxybenzyloxy)-6-((4-methoxybenzyloxy)methyl)tetrahydro-2H-pyran (0.31 g, partial pure) as a light yellow oil, which was used in the next step without further purification.
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:13])[NH:5][C:6]2[C:11]\1=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2.O/C=C1\C(=O)NC2C\1=CC=CC=2.[NH2:26][C:27]1[CH:31]=[CH:30][NH:29][N:28]=1>O1CCCC1>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4](=[O:13])[C:3]2=[CH:2][NH:26][C:27]1[CH:31]=[CH:30][NH:29][N:28]=1
Reactant: Nc1cc[nH]n1
Reactant: O=C1Nc2ccc(Cl)cc2/C1=C/O
Agent: O=C1Nc2ccccc2/C1=C/O
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C1=CNc1cc[nH]n1

Procedure:
The named compound is prepared by substituting E & Z-3-[(hydroxy)-methylene]-5-chloro-1,3-dihydro-indol-2-one for E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-5-chloro-1,3-dihydro-indol-2-one is reacted with 0.300 gms 3-aminopyrazole by refluxing in tetrahydrofuran.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[C@H:3]([NH:11][C:12](=[O:21])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]([CH3:23])([CH3:22])[C@H:3]([NH:11][C:12](=[O:21])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)OC(=O)[C@@H](NC(=O)COc1ccccc1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@H](NC(=O)COc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the product from Example 54A (0.012 g, 0.038 mmol) in dichloromethane (0.2 mL) was treated with trifluoroacetic acid (0.2 mL) and the reaction was stirred at 25° C. for 1 hour and concentrated. The concentrate was azeotroped with toluene to give the title compound, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([CH2:15][Cl:16])[N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>C1COCC1>[Cl:24][CH2:25][C:26]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[N:9]=[C:10]([CH2:15][Cl:16])[CH:11]=[C:12]([OH:14])[N:13]=2)=[CH:4][CH:3]=1)=[O:27]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(-c2nc(O)cc(CCl)n2)nc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccc(-c2nc(O)cc(CCl)n2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound of example 49 (0.40 g, 0.16 mmol) in THF (4 mL) at 0° C. was added triethylamine (0.025 g, 0.25 mmol) and chloroacetylchloride (0.0285 g, 0.25 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 1% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]2[O:29][C:28]([CH3:30])=[N:27][C:26]=2[CH:31]=1)[C:18]([OH:20])=[O:19]>>[C:18]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]2[O:29][C:28]([CH3:30])=[N:27][C:26]=2[CH:31]=1)([OH:20])=[O:19]
Reactant: Cc1nc2cc(CC(N)C(=O)O)ccc2o1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: Cc1nc2cc(CC(Nc3nc4ccc(Cl)cc4cc3C(=O)O)C(=O)O)ccc2o1

Procedure:
In close analogy to the procedure described in Example 32, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-(2-methyl-benzooxazol-5-yl)-propionic acid to provide the title compound in good yield.
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([Br:12])[C:9]([Br:11])=[CH:10][C:4]=2[N:3]=1.[N+:13]([O-])([O-:15])=[O:14].[K+]>OS(O)(=O)=O>[Br:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Br:11])[C:8]([Br:12])=[C:7]([N+:13]([O-:15])=[O:14])[C:5]=2[N:6]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Brc1nc2cc(Br)c(Br)cc2[nH]1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1c(Br)c(Br)cc2[nH]c(Br)nc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
2,5,6-tribromo-1H-1,3-benzodiazole (Method 1) (1.4 mmol, 500 mg) was dissolved in concentrated H2SO4 (4 ml). Then KNO3 (1.7 mmol, 171 mg) was added in one portion at 0° C. The resulting mixture was stirred at 0° C. for 3 h and at RT overnight. The mixture was poured onto ice. The product was filtered and washed with water to afford compound 2,5,6-tribromo-4-nitro-1H-1,3-benzodiazole (487 mg). 1H NMR (600 MHz, DMSO) δ 14.33 (s, 1H), 8.22 (s, 1H).; m/z 399.7; rt 3.0 min.
Reaction SMILES: [NH2:1][C:2]1[S:6][CH:5]=[C:4]([C:7]#[N:8])[C:3]=1[C:9]1[CH:14]=[N:13][CH:12]=[CH:11][N:10]=1.Cl.[N:16]1[C:25]2[C:20](=[C:21]([CH2:26][C:27](O)=[O:28])[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>>[C:7]([C:4]1[C:3]([C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)=[C:2]([NH:1][C:27](=[O:28])[CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:20]=2[CH:19]=[CH:18][CH:17]=[N:16]3)[S:6][CH:5]=1)#[N:8]
Reactant: O=C(O)Cc1cccc2ncccc12
Reactant: N#Cc1csc(N)c1-c1cnccn1
Agent: Cl
Product: N#Cc1csc(NC(=O)Cc2cccc3ncccc23)c1-c1cnccn1

Procedure:
The title compound was synthesized from 5-amino-4-(pyrazin-2-yl)thiophene-3-carbonitrile (30.5 mg, 0.15 mmol) and 2-(quinolin-5-yl)acetic acid hydrochloride (36 mg, 0.16 mmol) according to protocol A. The product was purified by HPLC method [4], retention time=1.393 min; MS(ESI) 372.1 (MH+); 1H NMR (300 MHz, CD3OD) δ 9.30 (d, J=1.5 Hz, 1H), 9.06 (dd, J=4.8, 1.3 Hz, 1H), 8.99 (d, J=8.5 Hz, 1H), 8.51 (d, J=2.6 Hz, 1H), 8.29 (t, J=1.9 Hz, 1H), 8.20 (d, J=8.6 Hz, 1H), 8.09 (dd, J=8.6, 7.1 Hz, 1H), 7.95 (s, 1H), 7.93 (d, J=6.7 Hz, 1H), 7.86 (dd, J=8.6, 4.9 Hz, 1H), 4.55 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[NH:34][CH3:35].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[N:34]([CH3:35])[C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:23])([F:24])[F:25])[CH:16]=2)(=[O:14])=[O:13])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10]
Reactant: CNc1ccc(F)cc1F
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ccc(F)cc1F

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (100 mg, 0.24 mmol), (2,4-difluoro-phenyl)-methyl-amine (103 mg, 0.72 mmol), BOP (137 mg, 0.31 mmol), DIEA (265 L, 1.44 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (2,4-difluoro-phenyl)-methyl-amide: MS m/z: (M+H) 541.0.
Reaction SMILES: C[Al](C)C.[CH:5]1([CH2:8][NH2:9])[CH2:7][CH2:6]1.C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[C:22]([C:24]3[C:25]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[N:26][O:27][C:28]=3[C:29]([F:32])([F:31])[F:30])[N:21]=[CH:20]2)=[CH:15][CH:14]=1.O>O1CCOCC1>[CH:5]1([CH2:8][NH:9][C:12](=[O:11])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[C:22]([C:24]4[C:25]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)=[N:26][O:27][C:28]=4[C:29]([F:32])([F:31])[F:30])[N:21]=[CH:20]3)=[CH:15][CH:14]=2)[CH2:7][CH2:6]1
Reactant: NCC1CC1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: O=C(NCC1CC1)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Temperature: 90 °C
Yield: 78 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 338 μL, 0.68 mmol) and cyclopropanemethylamine (60.4 μL, 0.68 mmol) in dioxane (9 mL) was stirred at room temperature for 1 h and then a solution of 4-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid methyl ester (70 mg, 0.17 mmol) in dioxane (6 mL) was added. The resulting mixture was then heated at 85-95° C. overnight and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=60:40) afforded the title compound (60 mg, 78%) which was obtained as a colourless oil. MS: m/e=453.3 [M+H]+.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1.[CH:30]1([CH2:33][S:34](Cl)(=[O:36])=[O:35])[CH2:32][CH2:31]1>>[CH:30]1([CH2:33][S:34]([N:3]2[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[O:11])[CH2:4]2)(=[O:36])=[O:35])[CH2:32][CH2:31]1
Reactant: O=S(=O)(Cl)CC1CC1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCNC3)cnc21
Agent: Cl
Product: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCN(S(=O)(=O)CC4CC4)C3)cnc21

Procedure:
1-(1-Cyclopropylmethanesulfonyl-piperidin-3-yl)-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea was prepared in the same manner from 1-piperidin-3-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride and cyclopropyl-methanesulfonyl chloride.
Reaction SMILES: Cl[C:2]1[C:7]([Br:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][NH:14][CH3:15]>>[Br:8][C:7]1[C:2]([N:14]([CH3:15])[CH3:13])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: CNC
Reactant: FC(F)(F)c1cnc(Cl)c(Br)c1
Product: CN(C)c1ncc(C(F)(F)F)cc1Br
Yield: 82 %

Procedure:
2-Chloro-3-bromo-5-trifluoromethylpyridine (509 mg, 1.95 mmol) was treated with ethanolic dimethylamine solution (10 ml) and heated at reflux for 2 hrs before being concentrated. The residue was partitioned between water (10 ml) and ethyl acetate (10 ml), and the organic phase washed with brine (10 ml) and dried (Na2SO4). The solution was then concentrated to give the product as a yellow oil (430 mg, 82% yield).
Reaction SMILES: ClC1C=C(C2O[C:11]([C:23]([N:25]3[CH2:29][C:28](=[O:30])NC3)=O)=CC=2C2C=C(C#N)C=C(F)C=2)C=CC=1F.[C:31]([C:33]1[CH:34]=[C:35]([C:40]2[CH:41]=[C:42]([C:53](OCC)=[O:54])[O:43][C:44]=2[C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]#[N:52])[CH:46]=2)[CH:36]=[C:37]([F:39])[CH:38]=1)#[N:32]>>[C:51]([C:47]1[CH:46]=[C:45]([C:44]2[O:43][C:42]([C:53]([N:25]3[CH2:23][CH2:11][O:30][CH2:28][CH2:29]3)=[O:54])=[CH:41][C:40]=2[C:35]2[CH:34]=[C:33]([C:31]#[N:32])[CH:38]=[C:37]([F:39])[CH:36]=2)[CH:50]=[CH:49][CH:48]=1)#[N:52]
Reactant: N#Cc1cc(F)cc(-c2cc(C(=O)N3CNC(=O)C3)oc2-c2ccc(F)c(Cl)c2)c1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(C#N)c2)c(-c2cccc(C#N)c2)o1
Product: N#Cc1cc(F)cc(-c2cc(C(=O)N3CCOCC3)oc2-c2cccc(C#N)c2)c1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 31 starting with the compound from Example 17A. 32.1 mg (58% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=O)=[C:4]([CH3:8])[S:5][C:6]=1[CH3:7].Cl[C:14]1[N:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=1>CO>[CH3:8][C:4]1[S:5][C:6]([CH3:7])=[C:2]2[C:3]=1[C:9](=[O:11])[N:19]1[CH:18]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:16]=[CH:15][C:14]1=[N:1]2
Reactant: COC(=O)c1c(C)sc(C)c1N
Reactant: COC(=O)c1ccc(Cl)nc1
Solvent: CO
Product: COC(=O)c1ccc2nc3c(C)sc(C)c3c(=O)n2c1
Temperature: 180 °C

Procedure:
A mixture of 2.5 g (0.0113 mol) of 4-amino-2,5-dimethyl-3-thiophenecarboxylic acid, methyl ester and 2.5 g (0.0113 mol) of 6-chloro-3-pyridinecarboxylic acid, methyl ester (Alfred Bader Chemical Company) is heated in an oil bath at 180° C. for thirty minutes. The mixture is cooled, dissolved in hot methanol, cooled and 0.3 g of 1,3-dimethyl-10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid, methyl ester is collected; mp 209°-210° C. after recrystallization from methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([NH2:10])=[O:9].[CH3:11][C:12]([CH3:14])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[Br:7][C:5]1[S:4][C:3]2[C:8](=[O:9])[NH:10][C:12]([CH3:14])([CH3:11])[NH:1][C:2]=2[CH:6]=1
Reactant: CC(C)=O
Reactant: NC(=O)c1sc(Br)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)NC(=O)c2sc(Br)cc2N1
Temperature: 70 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A mixture of 3-amino-5-bromothiophene-2-carboxamide (0.118 g, 0.530 mmol), acetone (2.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (1.0 mL) was stirred for 1 h at 70° C. The mixture was poured into sat. aqueous sodium hydrogen carbonate (100 mL). Extraction with ethyl acetate (70 mL), washing with brine, drying over magnesium sulfate, filtration and concentration at reduced pressure gave the title compound (0.125 g, 90%) as a brown solid:
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][O:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14](B3OC(C)(C)C(C)(C)O3)=[C:13]([F:26])[CH:12]=2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].Br[C:28]1[CH:33]=[C:32]([F:34])[C:31]([C:35]([F:50])([F:49])[O:36][C:37]2[CH:38]=[C:39]([F:48])[C:40]([C:44]([F:47])([F:46])[F:45])=[C:41]([F:43])[CH:42]=2)=[C:30]([F:51])[CH:29]=1>>[CH2:1]([CH:5]1[CH2:10][O:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:28]3[CH:29]=[C:30]([F:51])[C:31]([C:35]([O:36][C:37]4[CH:42]=[C:41]([F:43])[C:40]([C:44]([F:45])([F:47])[F:46])=[C:39]([F:48])[CH:38]=4)([F:49])[F:50])=[C:32]([F:34])[CH:33]=3)=[C:13]([F:26])[CH:12]=2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)OC1
Reactant: Fc1cc(OC(F)(F)c2c(F)cc(Br)cc2F)cc(F)c1C(F)(F)F
Product: CCCCC1CCC(c2ccc(-c3cc(F)c(C(F)(F)Oc4cc(F)c(C(F)(F)F)c(F)c4)c(F)c3)c(F)c2)OC1

Procedure:
The compound according to the invention is prepared analogously to Example 2 by Suzuki coupling of 5-butyl-2-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]tetrahydropyran to 5-((4-bromo-2,6-difluorophenyl)difluoromethoxy)-1,3-difluoro-2-(trifluoromethyl)benzene. 5-Butyl-2-{4′-[(3,5-difluoro-4-trifluoromethylphenoxy)difluoromethyl]-2,3′,5′-trifluorobiphenyl-4-yl}tetrahydropyran is obtained as a colourless solid having an m.p. of 88° C. The successful synthesis is confirmed perfectly by NMR spectroscopy (1H, 19F, 13C) and mass spectroscopy (EI).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Br)=[CH:8][N:9]=1)(=[O:3])[CH3:2].Cl.[SH:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: Sc1cccnc1
Reactant: CC(=O)Nc1ncc(Br)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2cccnc2)s1
Temperature: 90 °C
Yield: 79.2 %

Procedure:
A mixture of 2-acetylamino-5-bromothiazole (1 g), 3-mercaptopyridine hydrochloride (1 g) and potassium carbonate (1.5 g) in N,N-dimethylformamide (10 ml) was heated at 90° C. for 4.5 hours with stirring. The reaction mixture was poured into ice water. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-acetylamino-5-(3-pyridylthio)thiazole (0.9 g, yield: 81.8%). mp: 203°-205° C. (dec.) IR (Nujol): 3170, 1700, 1570, 1300 cm-1
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:31][C:12]2[N:13]=[CH:14][N:15]=[C:16]([NH:17][C:18]3[C:19]([O:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[N:20][CH:21]=[CH:22][CH:23]=3)[C:11]=2[C:10]=1[CH3:32])=[O:8].ClC1C=CC=C(C(OO)=[O:41])C=1>ClCCl>[CH3:1][S:2]([CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:31][C:12]2[N:13]=[CH:14][N:15]=[C:16]([NH:17][C:18]3[C:19]([O:24][CH:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[N:20][CH:21]=[CH:22][CH:23]=3)[C:11]=2[C:10]=1[CH3:32])=[O:8])=[O:41]
Reactant: CSCCCNC(=O)c1sc2ncnc(Nc3cccnc3OC3CCOCC3)c2c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1c(C(=O)NCCCS(C)=O)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12
Temperature: 25 °C

Procedure:
A mixture of 100 mg (0.21 mmol) 5-methyl-4-[2-(tetrahydro-pyran-4-yloxy)-pyridin-3-ylamino]-thieno[2,3-d]pyrimidine-6-carboxylic acid (3-methylsulfanyl-propyl)-amide, 52 mg (0.21 mmol) 3-chloro-perbenzoic acid and 5 ml dichloromethane was stirred at room temperature over night. Then the mixture was extracted with water. The organic phase was dried over magnesium sulfate. After filtration the filtrate was evaporated. DMF was added to the residue. The precipitate was isolated by filtration.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([F:21])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:22])[CH:5]=1)([O-])=O.[H][H]>[Ni].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([F:21])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:22])[CH:5]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1C(=O)c2ccc(F)cc2C1=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1N1C(=O)c2ccc(F)cc2C1=O

Procedure:
The mixture of 10.0 g of N-(4-nitro-o-tolyl)-4-fluorophthalimide, 500 ml of ethyl acetate and 5 g of Raney nickel is hydrogenated at 3.1 atm. and room temperature until the hydrogen uptake ceases. It is filtered, evaporated, and the residue recrystallized from ethanol, to yield the N-(4-amino-o-tolyl)-4-fluorophthalimide, melting at 180°-182°.