Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH:7]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17](F)[C:16]=1[N+:23]([O-:25])=[O:24])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].[NH3:27]>CO>[C:1]([O:5][C:6](=[O:26])[CH:7]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([NH2:27])[C:16]=1[N+:23]([O-:25])=[O:24])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1cc(F)cc(F)c1[N+](=O)[O-]
Solvent: CO
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1cc(F)cc(N)c1[N+](=O)[O-]
Temperature: 85 °C

Procedure:
To the crude 2-(3,5-Difluoro-2-nitro-phenyl)-malonic acid di-tert-butyl ester (62 g, 0.42 mol) was added 700 mL of 2M ammonia in methanol in a pressure bottle. The vessel was sealed and heated to 85° C. for 18 hours. The reaction mixture was cooled and the vessel opened carefully and the methanol solution concentrated to provide 140 g of crude material. LCMS [M+Na]-393; 1H NMR (500 MHz, DMSO) δ 6.76 (dd, J=10.8 2.8 Hz, 1H), 6.29 (dd, J=10.8, 2.8 Hz, 1H), 4.99 (brs, 2H), 4.80 (s, 1H), 1.40 (m, 18H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.[Cl-].O[NH3+].C([N:17](C(C)C)CC)(C)C.[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](Cl)=[O:29].C(N=C=NC(C)C)(C)C>CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2[N:17]=[C:28]([C:24]3[O:23][CH:27]=[CH:26][CH:25]=3)[O:29][N:7]=2)=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C#N
Reactant: O=C(Cl)c1ccco1
Reactant: CCN(C(C)C)C(C)C
Agent: CC(C)N=C=NC(C)C
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CO
Product: Cc1cc(Cl)ccc1-c1noc(-c2ccco2)n1
Yield: 28.8 %

Procedure:
In a 500 mL round-bottom flask, 4-chloro-2-methylbenzonitrile (10 g, 66 mmol) was dissolved in 200 mL of methanol. To the mixture was added hydroxylammonium chloride (4.56 g, 66 mmol) followed by DIEA (diisopropylethylamine) (23 mL, 132 mmol). The mixture was heated at reflux for overnight. The solvents were removed. The residue was dissolved in 200 mL of CHCl3. To the mixture was added 2-furoyl chloride (10.5 ml, 66 mmol) followed by DIEA (23 mL, 132 mmol). After reaction completion, the mixture was extracted with chloroform and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was dissolved in 200 mL of dioxanes. To the mixture was added 1 eq of DIC (N,N′-diisopropylcarbodiimide) followed by 1 eq of DIEA. The mixture was then heated at reflux overnight. After reaction completion, the mixture was cooled down. The solvents were removed in vacuo. The residue was then extracted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography on silica gel in a 0-20% ethyl acetate/hexanes gradient to afford 4.96 g of the desired compound 3-(4-Chloro-2-methyl-phenyl)-5-furan-2-yl[1,2,4]oxadiazole as a white powder in an overall yield of 28.8%.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12])=[CH:4][CH:3]=1.IC1C=CC(N)=CC=1.C(#N)CC#N.O.[NH2:29][NH2:30]>>[NH2:14][C:13]1[C:10](=[N:9][NH:8][C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)[C:11]([NH2:12])=[N:30][N:29]=1
Reactant: N#CC(C#N)=NNc1ccc(I)cc1
Reactant: NN
Agent: Nc1ccc(I)cc1
Solvent: O
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1ccc(I)cc1
Yield: 70 %

Procedure:
This compound was prepared using 148 mg (0.5 mmol) of 2-[(4-iodophenyl)hydrazono]-malononitrile, which was derived from 4-iodoaniline (219 mg, 101.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. The hydrazine hydrate was added to the solution at a temperature of 75° C. despite the fact that the starting material had not fully dissolved. The solution cleared briefly and then a precipitate formed. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 114 mg (70%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:10])=[C:4]([Cl:11])[N:3]=1.S(=O)(=O)(O)[OH:13]>[O-2].[O-2].[O-2].[Cr+6]>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]([C:9]([OH:13])=[O:10])=[C:6]([Cl:8])[N:7]=1
Reactant: O=Cc1c(Cl)nc(Cl)nc1Cl
Reactant: O=S(=O)(O)O
Agent: [Cr+6]
Agent: [O-2]
Product: O=C(O)c1c(Cl)nc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a solution of 63.3 g (0.3 mol) of 2,4,6-trichloro-5-formylpyrimidine in 300 ml of fuming sulfuric acid (SO3 content 25%) are added in flake form 24 g (0.24 mol) of chromium trioxide, and the mixture is stirred for 20 hours. The temperature rises within about one hour to 45°-50° C., and then falls again to room temperature (20°-25° C.). The reaction solution is poured into ice water, and the precipitate is filtered off and washed with a small amount of ice-water. The reaction product is dissolved in diethyl ether; the solution is then dried over sodium sulfate and subsequently evaporated to dryness. The yield is 55.4 g (81.2%) of 2,4,6-trichloropyrimidine-5-carboxylic acid, m.p. about 150° C. The melting point can be raised to 155°-157° C. by recrystallisation of the product from chloroform.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:37]([C:39]1[C:40]([N:49]2[CH2:54][CH2:53][CH:52]([CH2:55][CH2:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH2:51][CH2:50]2)=[CH:41][C:42]([O:46][CH2:47][CH3:48])=[C:43]([CH:45]=1)[NH2:44])[CH3:38].Cl.O1CCOCC1.N>CO>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:44][C:43]3[CH:45]=[C:39]([CH2:37][CH3:38])[C:40]([N:49]4[CH2:50][CH2:51][CH:52]([CH2:55][CH2:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH2:53][CH2:54]4)=[CH:41][C:42]=3[O:46][CH2:47][CH3:48])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(CC)cc1N
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cl
Agent: N
Solvent: CO
Solvent: C1COCCO1
Product: CCOc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(CC)cc1Nc1nccc(-c2c(-c3ccc(OCC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 180 °C
Yield: 58 %

Procedure:
In a microwave vial with septum cap, 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (0.148 g, 0.293 mmol) and 5-ethyl-2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperidinyl}aniline (0.104 g, 0.293 mmol) were taken up in 1,1,1-trifluoroethanol (1.5 mL) and 4M HCl in dioxane (0.147 mL, 0.587 mmol) was added. The vial was sealed and heated in the microwave at 180° C. for 40 min. Reaction was complete by MS, it was cooled to rt, neutralized with 7N ammonia in MeOH, and concentrated in vacuo onto silica gel and flash chromatographed. The desired fractions were combined and concentrated and the resulting solid was triturated with diethyl ether, filtered and air dried to give the title compound (0.14 g, 0.17 mmol, 58%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.70 (s, 1H), 9.29 (d, J=6.8 Hz, 1H), 8.34 (s, 1H), 8.23 (d, J=5.2 Hz, 1H), 8.03 (s, 1H), 7.61-7.79 (m, 2H), 7.55 (s, 1H), 7.29-7.48 (m, 2H), 7.08-7.28 (m, 3H), 6.89 (t, J=6.8 Hz, 1H), 6.76 (s, 1H), 6.56 (d, J=5.1 Hz, 1H), 4.23 (q, J=6.7 Hz, 2H), 4.03 (q, J=6.9 Hz, 2H), 3.07-3.20 (m, 2H), 2.84-3.04 (m, 5H), 2.60 (t, J=10.9 Hz, 2H), 2.51 (q, J=7.5 Hz, 2H), 1.75 (d, J=11.2 Hz, 2H), 1.60-1.70 (m, 2H), 1.35-1.55 (m, 4H), 1.15-1.36 (m, 5H), 1.05 (td, J=7.2, 1.9 Hz, 3H). MS (M+H, ES+) 824.
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10](OC)=[CH:11][C:12]=3[C@@:13]32[CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)=[CH:4][CH:3]=1.[F:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1.[O:35]1[CH2:40][CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH2:37][CH2:36]1>>[O:35]1[CH2:36][CH:37]=[C:38]([C:10]2[CH:9]=[C:8]([F:24])[C:7]3[O:6][C:5]4[C:14](=[CH:15][C:2]([C:31]5[C:26]([F:25])=[N:27][CH:28]=[CH:29][CH:30]=5)=[CH:3][CH:4]=4)[C@@:13]4([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]4)[C:12]=3[CH:11]=2)[CH2:39][CH2:40]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: COc1cc(F)c2c(c1)[C@]1(CCOC(N)=N1)c1cc(Br)ccc1O2
Reactant: OB(O)c1cccnc1F
Product: NC1=N[C@@]2(CCO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(C3=CCOCC3)cc12

Procedure:
The title compound was synthesized by steps analogous to those described in method A7 above, but using intermediate 20B, 2-fluoropyridin-3-ylboronic acid and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:21]=1[NH2:22]>>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: COc1ccc(C)cc1N
Product: COc1ccc(C)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-methoxy-5-methylaniline (40 mg, 0.290 mmol) similar to Example 58 and isolated as a yellow solid (41 mg, 59%). 1H NMR (CDCl3): 9.66 (d, J=1.8 Hz, 1H), 8.74-8.70 (m, 2H), 7.98 (s, 1H), 7.55 (s, 1H), 7.44-7.40 (m, 1H), 6.99-6.95 (m, 1H), 6.88 (s, 1H), 6.85 (s, 1H), 3.89 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[N:20][N:21]([CH2:23][CH2:24][CH2:25]Br)[N:22]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].[CH3:31][NH:32][CH3:33]>C(#N)C>[CH3:31][N:32]([CH3:33])[CH2:25][CH2:24][CH2:23][N:21]1[N:20]=[N:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[C:5]([OH:30])[C:6]=3[CH2:27][CH2:28][CH3:29])=[CH:13][CH:14]=2)=[N:22]1
Reactant: CCCc1c(COc2ccc(-c3nnn(CCCBr)n3)cc2)ccc(C(C)=O)c1O
Reactant: CNC
Solvent: CC#N
Product: CCCc1c(COc2ccc(-c3nnn(CCCN(C)C)n3)cc2)ccc(C(C)=O)c1O
Temperature: 0 °C
Reaction time: 5 h
Yield: 88.5 %

Procedure:
5-[4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl]-2-(3-bromopropyl)-2H-tetrazole (2.8 g, 0.006 mol) was dissolved in acetonitrile and cooled to 10 approximately 0° C. Dimethylamine (anhydrous, excess) was cooled in the reagent bottle before it was opened then added to the cool acetonitrile solution. The solution was maintained at approximately 0° C. with an ice bath while it was stirred (approximately 5 hours). The reaction mixture was then concentrated in vacuo. Water was added and the resultant solution was extracted with ethyl acetate. The ethyl acetate layers were combined, washed with water and dried over sodium sulfate. The dried ethyl acetate layers were concentrated and the resultant residue was chromatographed by HPLC (preparatoryscale, silica gel column, eluted isocratically with a mixture of 9.5 : 0.5 methylene chloride:methanol to which 0.05% of diethylamine had been added to yield 2.3 g, 88.5% yield of the title product: m.p. 89°-91° C.; n.m.r.: (300 MHz, CDCl3) δ: 1.0 (t, 2H); 1.6 (m, 2H); 2.1 (t, 2H); 2.2 (s, 6H); 2.3, (t, 2H); 2.4 (t, 2H); 2.6 (s, 3H); 2.7 (t, 2H); 4.7 (t, 2H); 5.2 (s, 2H); 7.1 (2d, 3H); 7.6 (d, 1H); 8.1 (d, 2H); 12.7 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1cccc(F)c1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(F)c3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-fluoro-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[N:10][N:11]3[C:16](O)=[C:15]([CH3:18])[C:14]([CH3:19])=[N:13][C:12]=23)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.O=P(Cl)(Cl)[Cl:38].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:38][C:16]1[N:11]2[N:10]=[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:12]2[N:13]=[C:14]([CH3:19])[C:15]=1[CH3:18]
Reactant: Cc1nc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn2c(O)c1C
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1nc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn2c(Cl)c1C
Temperature: 100 °C

Procedure:
To a slurry of 3-(4-chlorophenyl)-2-(2-chlorophenyl)-5,6-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ol (I-4A-1a; 0.277 g, 0.721 mmol) and diisopropylethylamine (0.188 ml, 1.08 mmol) in toluene (7.2 ml) at room temperature was added POCl3 (0.336 ml, 3.60 mmol), dropwise. The mixture was heated at 100° C. for 7 hours, cooled to room temperature, and then slowly added to a stirred mixture of ice, saturated aqueous sodium bicarbonate and ethyl acetate. The aqueous layer was separated and extracted with additional ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), and then concentrated, in vacuo, to afford the crude product. Purification on a Biotage™ Flash 40S column using 0–8% ethyl acetate in hexanes as eluant afforded I-4A-1b (146 mg, 50%) as a yellow solid: +ESI MS (M+1) 402.0; 1H NMR (400 MHz, CD2Cl2) δ 7.55–7.35 (m, 6H), 7.25 (d, J=8.7 Hz, 2H), 2.66 (s, 3H), 2.47 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:15])=[N:4][N:5](CC(O)=O)[C:6]=1[C:7]([F:10])([F:9])[F:8].[C:16](Cl)(=[O:20])[C:17](Cl)=O.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[C:32]([NH:34][CH3:35])[CH:31]=[N:30]2)=[CH:25][CH:24]=1.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:6]([C:7]([F:8])([F:9])[F:10])=[N:5][N:4]([CH2:17][C:16]([N:34]([C:32]2[CH:31]=[N:30][N:29]([C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)[CH:33]=2)[CH3:35])=[O:20])[C:3]=1[CH3:15]
Reactant: CNc1cnn(-c2ccc(F)cc2)c1
Reactant: Cc1nn(CC(=O)O)c(C(F)(F)F)c1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N(C)c1cnn(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
To a solution of 2-[4-chloro-3-methyl-5-(trifluoromethyl)pyrazol-1-yl]acetic acid (0.070 g, 0.29 mmol) in CH2Cl2 (2 mL) was added oxalyl chloride (0.10 mL, 1.16 mmol) and DMF (1 drop). The mixture was stirred for 30 min at room temperature and concentrated in vacuo. The solid obtained was transferred to another flask containing 1-(4-fluorophenyl)-N-methylpyrazol-4-amine (0.056 g, 0.29 mmol) and NEt3 (0.20 mL, 1.4 mmol) in CH2Cl2 (3 mL). The reaction mixture was stirred for 30 min at room temperature, quenched with water (50 mL), and extracted with ethyl acetate (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (SiO2, 0-50% EtOAc/CH2Cl2 gradient elution) to give the title compound (0.045 g, 37%). 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.70 (s, 1H), 7.64 (m, 2H), 7.17 (dd, J=8.4, 8.4 Hz, 2H), 4.80 (s, 2H), 3.28 (s, 3H); MS: (ES) m/z calculated for C17H14ClF4N5O [M+H]+ 416.1, found 416.1.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.[C:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])[CH3:28].C(N(CC)CC)C.CN(C)C=O>O>[C:27]([N:30]1[CH2:35][CH2:34][N:33]([CH2:2][C:3]2[S:7][C:6]([C:8]3[NH:9][C:10]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:17]([CH3:26])[S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])=[N:5][CH:4]=2)[CH2:32][CH2:31]1)(=[O:29])[CH3:28]
Reactant: CN(c1cccc2cc(-c3ncc(CCl)s3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(Cc2cnc(-c3cc4cccc(N(C)S(=O)(=O)c5cccs5)c4[nH]3)s2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
A mixture of N-{2-[5-(chloromethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (0.40 g), 1-acetylpiperazine (0.24 g), triethylamine (0.26 ml) and N,N-dimethylformamide (15 ml) was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to basic silica gel column chromatography to give the title compound (0.33 g, yield 68%) as colorless crystals from a fraction eluted with ethyl acetate. melting point 177-178° C.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:4]([CH3:18])[C:3]=1[CH:19]=[O:20].[CH3:21][O-:22].[Na+]>CO>[CH3:21][O:22][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:4]([CH3:18])[C:3]=1[CH:19]=[O:20]
Reactant: C[O-]
Reactant: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(Br)c1C=O
Agent: [Na+]
Solvent: CO
Product: COc1nc(-c2cccc(OC(F)(F)F)c2)n(C)c1C=O
Temperature: 25 °C

Procedure:
A solution of 1.00 g (2.9 mmol) of 5-bromo-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazole-4-carbaldehyde in 25 ml of MeOH was treated with 3.20 ml (17.3 mmol) sodium methoxide-solution (5.4 molar in MeOH) and then stirred at reflux for 48 hours. After cooling down to RT, the solvent was evaporated, cold water and EtOAc were added and the mixture then extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (n-heptane/EtOAc 4:1 to 1:1) to give 0.926 g (quant.) of the title compound as light yellow solid. MS: 301.1 (MH+).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1>>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH:1][N:2]2[N:11]=[C:10]([S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:21])=[O:31])=[CH:25][CH:24]=1
Reactant: Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(Br)cc1
Product: O=C(Cc1ccc(Br)cc1)Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O

Procedure:
The product from Example 68B and 2-(4-bromophenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.56 (d, J=8.1, 1H), 8.38 (dd, J=8.0, 0.9, 1H), 8.14-8.08 (m, 1H), 8.01 (ddd, J=7.3, 4.4, 1.2, 3H), 7.80 (ddd, J=7.0, 4.0, 1.2, 1H), 7.68 (dd, J=10.6, 5.0, 2H), 7.58-7.51 (m, 2H), 7.25 (d, J=8.4, 2H), 3.66 (s, 2H); MS (ESI+) M/Z 498 (M+H)+, 515 (M+NH4)+, 556 (M+CH3CN+NH4)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][C:5](=[O:9])[CH2:4]1.[NH2:10][C:11]1[CH:18]=[C:17](OCCOC)[C:14]([C:15]#[N:16])=[CH:13][N:12]=1>>[NH2:10][C:11]1[CH:18]=[C:17]([O:1][CH2:2][CH:3]2[CH2:8][CH2:7][NH:6][C:5](=[O:9])[CH2:4]2)[C:14]([C:15]#[N:16])=[CH:13][N:12]=1
Reactant: O=C1CC(CO)CCN1
Reactant: COCCOc1cc(N)ncc1C#N
Product: N#Cc1cnc(N)cc1OCC1CCNC(=O)C1

Procedure:
From (racemic) 4-(hydroxymethyl)piperidin-2-one, synthesized in an analogous manner to intermediate 20, the title compound was obtained as a beige solid. (UPLC-MS 6) tR 0.42; ESI-MS 247.2 [M+H]+.
Reaction SMILES: [I:1][C:2]1[C:6]2=[N:7][C:8]([C:11]([OH:13])=[O:12])=[CH:9][CH:10]=[C:5]2[N:4]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:3]=1.[C:24](Cl)(=O)C(Cl)=O.CO>C(Cl)Cl.CN(C=O)C>[I:1][C:2]1[C:6]2=[N:7][C:8]([C:11]([O:13][CH3:24])=[O:12])=[CH:9][CH:10]=[C:5]2[N:4]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:15])=[O:16])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(C(=O)O)ccc32)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(n1)c(I)cn2S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a suspension of 3-iodo-1-((4-methylphenyl)sulfonyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylic acid (0.750 g, 1.696 mmol) in DCM (8.5 mL) and a few drops of DMF was added oxalyl chloride (0.259 mL, 2.97 mmol) at RT. After 30 min, the reaction was cooled to 0° C., MeOH was added and the mixture was stirred for 30 min. The mixture was then concentrated. To the yellow solid was added H2O and the mixture was extracted with DCM (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give methyl 3-iodo-1-((4-methylphenyl)sulfonyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylate (0.700 g, 1.534 mmol, 90%) as a pale yellow solid. MS (ESI, pos. ion) m/z: 457.0 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 2.38 (3H, s), 4.01 (3H, s), 7.27-7.32 (2H, m), 7.75-7.81 (2H, m), 8.02 (1H, s), 8.18 (1H, d, J=8.80 Hz), 8.34 (1H, d, J=8.61 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[C:5]([F:18])=[CH:4][N:3]=[C:2]([NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[C:20]([OH:19])[CH:21]=3)[N:7]=2)=[CH:10][CH:11]=1)[CH3:17]
Reactant: CCOc1ccc(Nc2nc(Cl)ncc2F)cc1
Reactant: Nc1cccc(O)c1
Product: CCOc1ccc(Nc2nc(Nc3cccc(O)c3)ncc2F)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(4-ethoxyphenyl)-5-fluoro-4-pyrimidineamine with 3-hydroxyaniline gave N4-(4-ethoxyphenyl)-N2-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.79 (d, 1H, J=4.2 Hz), 7.54 (dd, 2H, J=2.4 and 7.2 Hz), 7.05-6.97 (m, 3H), 6.87 (dd, 2H, J=2.4 and 4.2 Hz), 6.41 (m, 1H), 4.02 (q, 2H, J=6.6 Hz), 1.38 (t, 3H, J=6.9 Hz); 19F NMR (CD3OD): −47444; LCMS: ret. time: 21.15 min.; purity: 98%; MS (m/e): 341 (MH+).