Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23][C:24](O)=[O:25])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH3:34][O:35][C:36]([N:38]1[CH2:42][CH2:41][NH:40][S:39]1(=[O:44])=[O:43])=[O:37]>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23][C:24]([N:40]5[S:39](=[O:44])(=[O:43])[N:38]([C:36]([O:35][CH3:34])=[O:37])[CH2:42][CH2:41]5)=[O:25])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:32])([F:31])[F:33])[CH:3]=1
Reactant: COC(=O)N1CCNS1(=O)=O
Reactant: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Product: COC(=O)N1CCN(C(=O)CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)S1(=O)=O

Procedure:
Methyl 5-{[(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}-methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]acetyl}-1,2,5-thiadiazolidine-2-carboxylate 1,1-dioxide was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}-methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]acetic acid (from Example 4) and 1,1-dioxo-1λ6-[1,2,5]thiadiazolidine-2-carboxylic acid methyl ester (from Example 339) following General Procedure C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[N:12]=[C:11]([N:13]([CH3:18])[CH:14]([CH3:17])[CH2:15][CH3:16])[CH:10]=[N:9][CH:8]=1.O.CN([CH:23]=[O:24])C>>[Cl:6][C:7]1[C:8]([CH:23]=[O:24])=[N:9][CH:10]=[C:11]([N:13]([CH3:18])[CH:14]([CH3:17])[CH2:15][CH3:16])[N:12]=1
Reactant: CCC(C)N(C)c1cncc(Cl)n1
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCC(C)N(C)c1cnc(C=O)c(Cl)n1
Reaction time: 0.25 h
Yield: 88 %

Procedure:
Phosphoryl chloride (1.33 mL) was added dropwise to DMF (5 mL) at 0° C. The mixture was stirred for 15 min, and a solution of 6-chloro-N-methyl-N-(1-methylpropyl)pyrazin-2-amine (1.43 g) in DMF (1 mL) was added dropwise thereto. The mixture was stirred at 80° C. for 18 hr, water (5 mL) was added at 0° C., and the mixture was stirred at room temperature for 1.5 hr. The mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 10'50% ethyl acetate/hexane) to give the title compound (1.43 g, 88%) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[NH:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27]([OH:29])=O)=[CH:24][CH:25]=2)[CH:20]=[CH:19]1>>[NH:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27]([NH:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:27]([C:23]5[CH:22]=[C:21]6[C:26](=[CH:25][CH:24]=5)[NH:18][CH:19]=[CH:20]6)=[O:29])=[CH:13][CH:12]=3)[N:6]=[CH:5]4)=[O:29])=[CH:24][CH:25]=2)[CH:20]=[CH:19]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: Nc1ccc(-n2ncc3cc(N)ccc32)cc1
Product: O=C(Nc1ccc(-n2ncc3cc(NC(=O)c4ccc5[nH]ccc5c4)ccc32)cc1)c1ccc2[nH]ccc2c1

Procedure:
Compound 527 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)indazole and 1H-indole-5-carboxylic acid. [M+H]+ calcd for C31H22N6O2: 511.18; found: 511.03.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[S:17]([NH:20][C:21]1[C:26](Cl)=[N:25][C:24]([Cl:28])=[CH:23][N:22]=1)(=[O:19])=[O:18]>>[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[S:17]([NH:20][C:21]1[C:26]([O:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[N:25][C:24]([Cl:28])=[CH:23][N:22]=1)(=[O:19])=[O:18]
Reactant: OCc1ccncc1
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Product: O=S(=O)(Nc1ncc(Cl)nc1OCc1ccncc1)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 31b using pyridine-4-methanol (0.4 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.4 g). Yield 0.47 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[I:11]N1C(=O)CCC1=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([I:11])=[CH:9][N:10]=2)[N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1ccc2nccn2n1
Solvent: CC#N
Product: Clc1ccc2ncc(I)n2n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 69.4 %

Procedure:
14 g of 6-chloroimidazo[1,2-b]pyridazine (Example 1.0) were suspended in 364 ml of acetonitrile, and 20.51 g of N-iodosuccinimide were added. The mixture was stirred at RT for 19 hours. A further 4.31 g of N-iodosuccinimide were added, and the mixture was stirred for 24 hours. The reaction was cooled and the precipitated solid was filtered off with suction, washed with acetonitrile and dried. 17.67 g of the desired product are obtained.
Reaction SMILES: Cl[C:2]1[C:10]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][C:5](C(O)=O)=[C:4](C)[CH:3]=1.[C:16](OC)([O:20][CH3:21])([O:18]C)[CH3:17].C1(C)C=CC=CC=1>O1CCOCC1>[CH3:14][S:11]([C:10]1[C:9]([S:11]([CH3:10])(=[O:13])=[O:12])=[CH:5][C:17]([C:16]([O:20][CH3:21])=[O:18])=[C:3]([CH3:4])[CH:2]=1)(=[O:13])=[O:12]
Reactant: COC(C)(OC)OC
Reactant: Cc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A solution of 29.5 g of 4-chloro-5-methanesulfonyl-2-methylbenzoic acid and 18.39 g of trimethyl orthoacetate in 100 ml of dioxane was refluxed until the acid had reacted completely. 150 ml of toluene were added, and the solvent was removed to the extent that the mixture still remained stirrable. 150 ml of 1-methyl-2-pyrrolidone (NMP) and 15.8 g of sodium methanesulfinate were subsequently added, and the mixture was stirred at 80° C. for 5 h. After addition of a further 5.3 g of sodium methanesulfinate, the mixture was stirred for 25 h. Conventional work-up gave methyl 4,5-bismethanesulfonyl-2-methylbenzoate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[CH:5]=[O:6]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=Cc1ccc(N2CCOCC2)c(Br)c1
Yield: 58.2 %

Procedure:
EX-604A) To a pyridine (15 mL) solution of 3-bromo-4-fluorobenzaldehyde (1.0 g, 4.9 mmol) was added morpholine (0.5 mL, 5.7 mmol) and K2CO3 (0.69 g, 5.0 mmol), and the slurry was refluxed for 18 h. The solvent was removed, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSO4) and evaporated to a yellow oil. Purification by flash chromatography on silica gel eluting with 15% ethyl acetate in hexane gave 0.77 g (58%) of the desired 3-bromo-4-(4-morpholinyl)benzaldehyde product as an white solid. 1H NMR (CDCl3) δ3.18 (m, 4H), 3.90 (m, 4H), 7.10 (d, 1H), 7.78 (d, 1H), 8.07 (s, 1H), 9.83 (s, 1H).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[Br:9][C:10]1[CH:11]=[C:12]([C:16](=[O:24])[CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH:13]=[CH:14][CH:15]=1>O1CCCC1>[Br:9][C:10]1[CH:11]=[C:12]([C:16](=[O:24])/[C:17](/[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:3]/[N:4]([CH3:5])[CH3:6])[CH:13]=[CH:14][CH:15]=1
Reactant: COC(OC)N(C)C
Reactant: O=C(Cc1ccncc1)c1cccc(Br)c1
Solvent: C1CCOC1
Product: CN(C)/C=C(/C(=O)c1cccc(Br)c1)c1ccncc1
Temperature: 65 °C
Reaction time: 6 h
Yield: 93 %

Procedure:
Dimethylformamide dimethylacetal (15 mL) were added to a solution of 7.2 g (0.026 ol) of 1-(3-bromophenyl)-2-pyridin-4-ylethanone in 15 ml of dry tetrahydrofuran. After stirring at 65° C. for 6 hours, the solvent was removed under reduced pressure. 8 g (93% yield) of the title compound as an oil were obtained and employed in the next step without any further purification.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19](=[O:31])[NH:20][CH:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:22]CO)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[CH2:11]([O:18][C:19](=[O:31])[NH:20][CH:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:22][CH2:2][CH:1]=[O:5])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(NC(CCO)c1ccccc1)OCc1ccccc1
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CCCC(NC(=O)OCc1ccccc1)c1ccccc1
Temperature: -50 °C
Reaction time: 0.25 h
Yield: 95.6 %

Procedure:
To a stirred solution of oxalyl chloride (1.6 mL, 18.2 mmol) in methylene chloride (20 mL) at −50° C. was added drop-wise a solution of DMSO (2.84 g, 36.4 mmol). The resulting mixture was stirred at −50° C. for 15 minutes, and a solution of (3-hydroxy-1-phenyl-propyl)-carbamic acid benzyl ester (4.7 g, 16.53 mmol) in methylene chloride 35 mL). The mixture was stirred at −50° C. for 15 minutes, then TEA (11.5 mL, 82.7 mmol) was added. The mixture was stirred for five minutes at −50° C., then allowed to stir at room temperature for 30 minutes. The reaction mixture was washed with 5% aqueous HCl, dried over MgSO4, filtered and concentrated under reduced pressure to give 4.7 g (100%) of (4-oxo-1-phenyl-butyl)-carbamic acid benzyl ester as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:8][CH2:7]1)[CH2:2][CH2:3][C:4]#[CH:5].[CH3:24][NH2:25]>C1COCC1>[CH3:24][NH:25][C:12]([N:9]1[CH2:8][CH2:7][N:6]([CH2:1][CH2:2][CH2:3][C:4]#[CH:5])[CH2:11][CH2:10]1)=[O:14]
Reactant: CN
Reactant: C#CCCCN1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Solvent: C1CCOC1
Product: C#CCCCN1CCN(C(=O)NC)CC1

Procedure:
A solution of 4-nitrophenyl 4-(pent-4-ynyl)piperazine-1-carboxylate (1.37 g) in THF (10 mL) was treated with 40% aq. MeNH2 (10 mL) at 70 C for 2 h. The mixture was concentrated and diluted with conc. NH4OH (5 mL) and water (15 mL). Extraction (DCM, 80 mL) and concentration gave N-methyl-4-(pent-4-ynyl)piperazine-1-carboxamide (0.659 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[C:9]([OH:11])=[N:10][C:5]2=[N:4][CH:3]=1.[CH3:20][S-:21].[Na+].CN1CCCC1=O>CCOC(C)=O>[CH3:20][S:21][C:2]1[N:7]=[C:6]2[N:8]([C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[C:9]([OH:11])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: C[S-]
Reactant: C[C@@H](c1ccccc1)n1c(O)nc2ncc(Br)nc21
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CSc1cnc2nc(O)n([C@@H](C)c3ccccc3)c2n1
Temperature: 180 °C
Yield: 24 %

Procedure:
A thick-walled microwave bottle equipped with a stirbar was charged with (S)-6-bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2-ol (1.0 equiv), sodium thiomethoxide (4.5 equiv), and N-methylpyrrolidone (10 volume equivalents). The bottle was fitted with a septum and cap and heated to 180° C. in a microwave for 30 min. The reaction mixture was then diluted with 100 volume equivalents of EtOAc and washed with 4×100 volume equivalents of water and 1×100 volume equivalents of brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Reverse-phase preparative HPLC (20%-80% MeCN/H2O) provided the title compound (24%) as a white solid. LCMS m/z (APCI)=287.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:4][C:3]=1[CH2:17][OH:18]>CC#N.O=[Mn]=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:4][C:3]=1[CH:17]=[O:18]
Reactant: O=C(CC(F)(F)F)NCc1ccc(Cl)c(CO)c1
Agent: O=[Mn]=O
Solvent: CC#N
Product: O=Cc1cc(CNC(=O)CC(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
MnO2 (1.44 g, 14.9 mmol) was added to a sol. of N-(4-chloro-3-hydroxymethyl-benzyl)-3,3,3-trifluoro-propionamide (841 mg, 2.99 mmol) in CH3CN (60 mL). The mixture was stirred at rt for 3 h. MnO2 (1.44 g, 14.9 mmol) was added again, and the mixture was stirred for 90 min. The mixture was filtered over celite, and the precipitate was washed with CH3CN and CH2Cl2. The solvents were removed under reduced pressure, and the residue was dried under high vacuum, yielding the crude title compound (840 mg, quantitative yield) that was used further without purification. LC-MS: tR=0.84 min; ES+: 341.21.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].O>C(OCC)C>[Cl:13][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[Cl:12])[C:4](=[O:5])[CH2:3][Br:1]
Reactant: BrBr
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Product: O=C(CBr)c1ccc(Cl)c(Cl)c1

Procedure:
Bromine in a quantity of 10.2 ml (0.2 mol) is added dropwise to a mixture of 37.8 g 3.4-dichloroacetophenone and approx. 1.0 g anhydrous AlCl3 in 600 ml dry diethylether while stirring and cooling in ice. After stirring for 0.5 hr at 0° C. and 1.5 hr at room temperature, 30 ml water are added slowly. The organic phase is separated, washed twice with water, dried and evaporated to dryness. A small amount of petroleum ether (40-60) is added to the residue and the mixture is stirred at approx. 0° C. The desired 3.4-dichlorophenacylbromide is obtained as a crystalline material in a yield of 39.8 g (74%); melting point 55°-58° C.; TLC (CH2Cl2)=0.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17](/[CH:20]=[CH:21]/[CH2:22]Cl)[CH2:16][CH2:15]2)[CH3:11])=[CH:4][CH:3]=1.[CH2:25]([NH:28][CH3:29])[CH:26]=[CH2:27]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17](/[CH:20]=[CH:21]/[CH2:22][N:28]([CH2:25][CH:26]=[CH2:27])[CH3:29])[CH2:16][CH2:15]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(CC[C@H]1CC[C@H](/C=C/CCl)CC1)C(=O)Oc1ccc(Cl)cc1
Reactant: C=CCNC
Solvent: CC(=O)N(C)C
Product: C=CCN(C)C/C=C/[C@H]1CC[C@H](CCN(C)C(=O)Oc2ccc(Cl)cc2)CC1

Procedure:
In analogy to the method described in example 12.1, trans-{2-[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic acid 4-chloro-phenyl ester was reacted with N-allyl-methyl-amine in N,N-dimethylacetamide at room temperature to yield trans-(2-{4-[3-(allyl-methyl-amino)-(E)-propenyl]-cyclohexyl}-ethyl)-methyl-carbamic acid 4-chloro-phenyl ester as light yellow viscous oil, MS: 405 (MH+, 1Cl).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[CH:7]([Si:10]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])Cl)([CH3:9])[CH3:8].N1C=CN=C1>CN(C=O)C.C(OC(=O)C)C>[CH:1]1([O:6][Si:10]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[CH:7]([CH3:9])[CH3:8])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: OC1C=CCC1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)[Si](OC1C=CCC1)(C(C)C)C(C)C

Procedure:
A solution of 2-cyclopentenol (K. Alder, F. H. Flock, Chem. Ber. 1956, 89, 1732.) (2.31 g, 27.5 mmol), (triisopropyl)chlorsilane (5.30 g, 5.9 mL, 27.5 mmol), imidazole (2.06 g, 30.2 mmol) in DMF (50 mL) was stirred at room temperature for 3 h and for an additional hour at 50° C. Then the solution was diluted with ethylacetate, washed 4 times with water and dried over sodium sulfate. Evaporation of the solvent yielded in 6.32 g (96%) of the silylether 513/13 as a colourless liquid. No major impurities were visible in the 1H-NMR-spectrum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:19]=2)=[CH:16][CH:15]=[CH:14][N:13]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=4)[N:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ncc(N)cc1F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 116.1 %

Procedure:
A solution of THF (3 mL) containing 5-fluoro-6-methoxypyridin-3-amine (87 mg, 0.613 mmol) (Anichem) and 4-(2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 52; 182 mg, 0.409 mmol) was cooled to 0° C. in an ice bath and treated dropwise with 1 M LiHMDS (1.226 mL, 1.226 mmol). The solution was stirred at this temperature for 1.5 h and quenched with a saturated solution of NH4Cl. The product was extracted with EtOAc (15 mL), dried over MgSO4, filtered and concentrated to give crude 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (269.7 mg, 0.475 mmol) as a bright yellow amorphous solid which was used in the next step without further purification. m/z (ESI, +ve ion) 568.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.94 (1H, s); 8.82 (1H, dd, J=7.8, 2.0 Hz); 8.29 (1H, dd, J=4.8, 2.1 Hz); 8.05 (1H, dd, J=12.3, 2.2 Hz); 7.97 (1H, d, J=2.3 Hz); 7.20 (4H, dd, J=10.6, 8.6 Hz); 6.86 (4H, t, J=9.0 Hz); 6.78 (1H, dd, J=7.8, 4.7 Hz); 4.84 (2H, br. s.); 4.83 (2H, br. s.); 4.01 (3H, s); 3.81 (3H, s); 3.79 (3H, s); 2.58 (3H, s).
Reaction SMILES: Br[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=2[F:15])=[CH:6][N:7]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([NH2:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+].CC#N>CCOC(C)=O>[Br:14][C:12]1[CH:11]=[CH:10][C:9]([F:15])=[C:8]([C:5]2[N:4]=[N:3][C:2]([NH:26][C:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[F:16])([CH3:25])[CH3:24])=[N:7][CH:6]=2)[CH:13]=1
Reactant: CC(C)(N)c1ccccc1F
Reactant: Fc1ccc(Br)cc1-c1cnc(Br)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(Nc1ncc(-c2cc(Br)ccc2F)nn1)c1ccccc1F
Yield: 67.6 %

Procedure:
3-Bromo-6-(5-bromo-2-fluorophenyl)-1,2,4-triazine (2.8 g, 8.4 mmol), 2-(2-fluorophenyl)propan-2-amine (2.0 g, 12.6 mmol), K2CO3 (2.3 g, 16.8 mmol) and CH3CN (20 mL) was heated to 90° C. The reaction mixture was diluted with EtOAc and washed with satd. aq. NaHCO3 and brine. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified using silica gel chromatography to afford a yellow solid (2.3 g), m/z=406.1 [M+H].
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][C:16]1([CH3:22])[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1>>[CH3:15][C:16]1([CH3:22])[CH2:21][CH2:20][CH2:19][N:18]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:17]1
Reactant: CC1(C)CCCNC1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: CC1(C)CCCN(c2nnc(N)nc2-c2ccccc2)C1
Yield: 9.6 %

Procedure:
6-(3,3-Dimethylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine (54 mg, 10%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.50 g, 1.99 mmol) and 3,3-dimethylpiperidine (0.27 g, 2.39 mmol) according to the general procedure of Example 2.
Reaction SMILES: [NH3:1].O.C[O:4][C:5]([C:7]1[C:12]([CH3:13])=[C:11]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:9][C:8]=1[S:17](Cl)(=[O:19])=[O:18])=O>O1CCCC1>[CH3:13][C:12]1[C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=[C:8]2[C:7]=1[C:5](=[O:4])[NH:1][S:17]2(=[O:19])=[O:18]
Reactant: COC(=O)c1c(S(=O)(=O)Cl)ccc([N+](=O)[O-])c1C
Reactant: N
Solvent: O
Solvent: C1CCOC1
Product: Cc1c([N+](=O)[O-])ccc2c1C(=O)NS2(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
104 ml of 25 percent ammonia solution are initially taken, 100 ml of water are added and a solution of 48.7 g (0.166 mol) of 2-methoxycarbonyl-3-methyl-4-nitrobenzenesulfonyl chloride in 70 ml of tetrahydrofuran is then added dropwise at 10° C. After stirring at 25° C. for three hours, water and THF are removed by concentration on a rotary evaporator, and the residue which remains is stirred with ethyl acetate, filtered off with suction and washed with ethyl acetate. After drying under reduced pressure, 34 g (0.131 mol)=79% of theory of a white solid of m.p.: 312° C. (dec.) are obtained.
Reaction SMILES: [CH3:1]N(C=O)C.[Br:6][C:7]1[C:12]([OH:13])=[CH:11][C:10]([Cl:14])=[CH:9][N:8]=1.[H-].[Na+].CI>O>[Br:6][C:7]1[C:12]([O:13][CH3:1])=[CH:11][C:10]([Cl:14])=[CH:9][N:8]=1
Reactant: CN(C)C=O
Reactant: Oc1cc(Cl)cnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COc1cc(Cl)cnc1Br

Procedure:
To a DMF (60 mL) solution containing 2-bromo-5-chloro-3-hydroxypyridine (19.95 g, 95.7 mmol) at 0° C. was added NaH (2.53 g, 105.3 mmol) portion wise. After the cessation of H2 evolution, CH3I (14.26 g, 100.5 mmol) was added dropwise and the reaction stirred ~16 h. Water (1.9 mL) was added and the solvent removed under reduced pressure. The concentrate was triturated with 5 portions of CH2Cl2. The combined organic phases were washed with sat. NaCl solution, dried with K2CO3, filtered, and concentrated in vacuo. Silica gel chromatography (95:5 Hexane:EtOAc) of the concentrate afforded the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH3:11][C:12]1[C:16](C(B(O)O)=O)=[C:15]([CH3:22])[O:14][N:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C>[S:9]1[CH:8]=[CH:7][C:6]2[CH:10]=[C:2]([C:16]3[C:12]([CH3:11])=[N:13][O:14][C:15]=3[CH3:22])[CH:3]=[CH:4][C:5]1=2
Reactant: Cc1noc(C)c1C(=O)B(O)O
Reactant: Brc1ccc2sccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1noc(C)c1-c1ccc2sccc2c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 60.2 %

Procedure:
To a solution of 5-bromo-1-benzothiophene (ABCR, CAS: 133150-64-8, 1.0 6 g, 5.0 mmol) in dimethoxyethane (60 mL) and ethanol (6.0 mL) was added 3,5-dimethyl-4-isoxazoylboronic acid (1.0 g, 7.5 mmol), and 2 m sodium carbonate (2.0 mL). The reaction mixture was degassed 2-3 times, tetrakis-(triphenylphosphine)palladium (0.813 g, 0.7 mmol) was added, and the mixture was stirred for 6 h at 80° C. and concentrated. The residue was taken up in water and extracted with ethyl acetate. The organics were washed, dried and concentrated. The crude product was chromatographed on silica gel using heptane/ethyl acetate as eluent to obtain 4-benzo[b]thiophen-5-yl-3,5-dimethyl-isoxazole (0.69 g) as a light yellow solid. MS (ISP): m/e 230.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=S)[NH:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:3].N.OO>CO>[O:3]=[C:2]1[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:10][C:11]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[N:1]1
Reactant: COc1ccc(C(=O)NC(=S)Nc2ccccc2C(N)=O)cc1
Agent: N
Agent: OO
Solvent: CO
Product: COc1ccc(C(=O)Nc2nc(=O)c3ccccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.7 %

Procedure:
To a stirred mixture of 9.9 g of the above benzamide, 100 ml of methanolic ammonia and 100 ml of methanol was added 22 ml of 30% hydrogen peroxide. The reaction was cooled because of an exotherm and then stirred overnight at room temperature. The solid was collected, partially dissolved in 800 ml of acetonitrile and filtered. The filtrate was chilled, giving 0.95 g of the desired product as white crystals, mp 235°-236° C. (dec.).