Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4](=[O:18])[C@@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:6].[F:20][C:21]([F:34])([F:33])[C:22]1[CH:23]=[C:24](Br)[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1.C([Mg]Cl)(C)C>C1COCC1>[F:20][C:21]([F:33])([F:34])[C:22]1[CH:23]=[C:24]([C:4](=[O:18])[C@@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:6])[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -10 °C
Reaction time: 0.08 h

Procedure:
Benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (6 kg, 22.5 mol) and 3,5-bis(trifluoromethyl)bromobenzene (4.85 L, 28.1 mol) are dissolved in anhydrous THF (24 L). The solution is purged with nitrogen to remove distilled oxygen. The solution is cooled to −10° C. and i-PrMgCl in THF (56.4 mol) is slowly added (2 h) to the reaction via addition funnel, maintaining a reaction temperature ≦−5° C. The solution is allowed to warm to 20° C. and aged overnight at 20° C. The reaction is then cooled to −10° C. under nitrogen and is quenched slowly over 2 h into 5N HCl (14 L) that is maintained at 0-5° C. MTBE (60 L) is added and the biphasic mixture is agitated for 5 min. After warming to 20-25° C., it is allowed to settle for 30 min, and then the layers are separated. The organic layer is washed with water twice (12 L).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[N:6]=1.[F:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[C:35]1[CH:36]=[N:37][C:38]([NH2:41])=[N:39][CH:40]=1>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=2[O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[N:6]=2)[CH:23]=[CH:22][C:21]=1[C:35]1[CH:40]=[N:39][C:38]([NH2:41])=[N:37][CH:36]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: FC(F)(F)c1nccc(Oc2ccccc2Br)n1
Product: Nc1ncc(-c2ccc(-c3ccccc3Oc3ccnc(C(F)(F)F)n3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 4-(2-bromophenoxy)-2-(trifluoromethyl)pyrimidine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C21H13F4N5O, 427.11; m/z found, 428.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.78 (d, J=5.7, 1H), 8.37 (m, 2H), 7.57 (dd, J=7.5, 1.8, 1H), 7.48 (m, 3H), 7.39 (dd, J=8.0, 1.3, 1H), 7.33-7.22 (m, 3H), 6.85 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]2([C:37](O)=[O:38])[CH2:36][CH2:35]2)=[O:33])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:37]([C:34]5([C:32]([NH:31][C:28]6[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=6)=[O:33])[CH2:36][CH2:35]5)=[O:38])=[CH:3][CH:4]=4)=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:20][CH2:21]1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cn2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3)ccc2n1)C1CC1
Yield: 44.5 %

Procedure:
Using N-[6-(4-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.486 mmol), N,N-dimethylacetamide (3.0 mL), 1-[(4-fluorophenyl)carbamoyl]cyclopropanecarboxylic acid (163 mg, 0.730 mmol), HATU (277 mg, 0.730 mmol) and N,N-diisopropylethylamine (127 μL, 0.730 mmol) and in the same manner as in Example 8, the title compound (111 mg, 44%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[NH2:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][C:28]2[S:29][CH:30]=[CH:31][N:32]=2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: Nc1nccs1
Product: O=C(Nc1nccs1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2-aminothiazole via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(thiazol-2-yl)terephthalamide. MS (Q1) 469 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH2:15])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[S:16]1[C:20]2[CH:21]=[C:22]([C:25]3([C:28](O)=O)[CH2:27][CH2:26]3)[CH:23]=[CH:24][C:19]=2[N:18]=[CH:17]1>P(Cl)(Cl)(Cl)=O>[S:16]1[C:20]2[CH:21]=[C:22]([C:25]3([C:28]4[N:12]5[N:13]=[C:8]([C:5]6[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=6)[CH:9]=[N:10][C:11]5=[N:14][N:15]=4)[CH2:27][CH2:26]3)[CH:23]=[CH:24][C:19]=2[N:18]=[CH:17]1
Reactant: NNc1ncc(-c2ccc(Br)cc2)nn1
Reactant: O=C(O)C1(c2ccc3ncsc3c2)CC1
Solvent: O=P(Cl)(Cl)Cl
Product: Brc1ccc(-c2cnc3nnc(C4(c5ccc6ncsc6c5)CC4)n3n2)cc1
Temperature: 130 °C

Procedure:
A mixture of 6-(4-bromophenyl)-3-hydrazino-1,2,4-triazine (20.0 mg, 0.0752 mmol) and 1-(1,3-benzothiazol-6-yl)cyclopropanecarboxylic acid (16.5 mg, 0.0752 mmol) in phosphoryl chloride (1 mL) was heated at 130° C. for 8 h. The volatiles were removed under reduced pressure. The residue was dissolved in methanol, and purified by RP-HPLC (pH=10) to give the desired product. LCMC: (M+H)+=448.9/451.0.
Reaction SMILES: [CH3:1][NH:2][CH3:3].N.[C:5]([CH2:10][C:11]1[O:12][C:13]([SH:16])=[N:14][N:15]=1)(OCC)=[O:6]>>[CH3:1][N:2]([CH3:3])[C:5]([CH2:10][C:11]1[O:12][C:13]([SH:16])=[N:14][N:15]=1)=[O:6]
Reactant: CNC
Reactant: CCOC(=O)Cc1nnc(S)o1
Agent: N
Product: CN(C)C(=O)Cc1nnc(S)o1

Procedure:
Substitution of dimethylamine in the procedure of Example 17 in place of ammonia in the reaction with 2-carbethoxymethyl-1,3,4-oxadiazole-5-thiol gives 2-(N,N-dimethylcarbamoylmethyl)-1,3,4-oxadiazole-5-thiol.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6](C#N)=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].Cl.[CH3:15][NH:16][CH3:17].C(N(CC)CC)C>C(Cl)Cl>[CH3:15][N:16]([CH2:2][C:3]1[CH:10]=[CH:9][CH:6]=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12])[CH3:17]
Reactant: N#Cc1ccc(CBr)c([N+](=O)[O-])c1
Reactant: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a stirred mixture of 4-(bromomethyl)-3-nitrobenzonitrile (5.00 g, 20.74 mmol) (prepared according to the method described in WO 07/024,945 A1) and dimethylamine hydrochloride (2.03 g, 24.89 mmol) in CH2Cl2 (70 mL) was added triethylamine (6.30 g, 62.23 mmol) dropwise at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was diluted with water (20 mL) and extracted with CH2Cl2 (3×100 mL). The CH2Cl2 solution was dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 4-((dimethylamino)methyl)-3-nitrobenzene (3.58 g, 84%) as an orange solid. 1H NMR (400 MHz, CDCl3): δ 8.15 (br s, 1H), 7.92 (br s, 1H), 7.85 (br d, 1H, J=7.2 Hz), 3.80 (s, 2H), 2.27 (s, 6 H).
Reaction SMILES: [Br-].[C:2]([C:6]1[CH:31]=[CH:30][C:9]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][CH:7]=1)([O:4][CH3:5])=[O:3].[CH:32]([C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1)=O.C1(C)C=CC=CC=1.C[O-].[Na+]>CO>[C:38]([C:37]1[CH:42]=[CH:43][C:34]([CH:32]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]([C:2]([O:4][CH3:5])=[O:3])=[CH:31][CH:30]=2)=[CH:35][CH:36]=1)([O:40][CH3:41])=[O:39]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(C=Cc2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
To a 2 L 3-neck round bottom flask fitted with a glass stopper, rubber septum, and reflux condenser with a nitrogen inlet tube, was added 126.35 g (251 mmol) (4-carbomethoxy)benzyltriphenylphosphonium bromide, 49.45 g (302 mmol) methyl 4-formylbenzoate, and 632 mL 2:1 methanol:toluene. After the starting material dissolved, 63.2 mL (277 mmol) 25% sodium methoxide solution in methanol was added dropwise over several minutes. The reaction vessel was heated at reflux for 30 minutes. After cooling to room temperature, the reaction vessel was cooled at 0° C. for several hours. The resulting precipitate was filtered and dried in a vacuum oven to afford 59.0 g (79%) 4,4'-bis(carbomethoxy)stilbene as a 7:3 mixture of cis:trans isomers.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1/[CH:12]=[CH:13]/[NH:14][CH:15]=[O:16].[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[CH:15]([NH:14]/[CH:13]=[CH:12]/[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[O:1][C:17](=[O:19])[CH3:18])=[O:16]
Reactant: CC(=O)OC(C)=O
Reactant: O=CN/C=C/c1c(O)ccc2ccccc12
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2ccccc2c1/C=C/NC=O
Yield: 90 %

Procedure:
To a cooled solution of (E)-N-[2-(2-hydroxynaphth-1-yl) ethenyl] formamide (2133 mg, 10 mmol) in dry pyridine (5 ml) is added acetic anhydride (2042 mg, 20 mmol) and the mixture maintained at 0°-5° overnight. Thereupon the mixture is concentrated under vacuum, the residue dissolved in dichloromethane, the organic layer washed with water and then evaporated under reduced pressure. The crude product is crystallized from chloroform/methanol to yield pure title compound in 90% yield (2300 mg).
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([Cl:11])[C:5]=2[NH:4][CH:3]=1.[CH3:12]N(C)C=O.[H-].[Na+].CI>C(OCC)(=O)C>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([Cl:11])[C:5]=2[N:4]([CH3:12])[CH:3]=1
Reactant: CN(C)C=O
Reactant: Clc1ncnc2c(Br)c[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Product: Cn1cc(Br)c2ncnc(Cl)c21
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To 7-bromo-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (147 mg), N,N-dimethylformamide (10 mL) was added, and NaH (36 mg) was further added thereto, followed by stirring for 30 min. Subsequently, methyl iodide was added thereto, and the reaction mixture was heated to 50° C. and stirred for 2 hours. After completion of the reaction, the reaction mixture was mixed with ethyl acetate and washed with water. The washed mixture was dried over anhydrous sodium sulfate, and filtered and distilled under reduced pressure to obtain the title compound.
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([C:29]([O:31][CH3:32])=[O:30])=[CH:11][C:12]([Cl:28])=[C:13]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH:14]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:12]([Cl:28])=[CH:11][C:10]=1[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)c1cc(Cl)c(N2CCN(C(=O)OC(C)(C)C)CC2)cc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Cl)c(N2CCNCC2)cc1N
Yield: 119.1 %

Procedure:
A solution of tert-butyl 4-(5-(tert-butoxycarbonylamino)-2-chloro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (130 mg, 0.277 mmol) and TFA (0.4 mL, 5.19 mmol) in DCM (0.4 mL) was stirred at RT for one hour. Solvent was evaporated in vacuo to give 89 mg of methyl 2-amino-5-chloro-4-(piperazin-1-yl)benzoate. HPLC/MS showed MS (ESI+) (m/z) 270 ([M+H]+).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.C([O:35][C@@H:36]([CH3:40])[C:37](Cl)=[O:38])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][N:29]([C:37](=[O:38])[C@@H:36]([OH:35])[CH3:40])[CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCNC1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCN(C(=O)[C@H](C)O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f9) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C(OC(=O)[N:7]([CH:15]1[CH2:17][CH2:16]1)[C@H:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[F:14])(C)(C)C.Cl[C:20]1[N:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][N:21]=1>>[CH:15]1([NH:7][C@H:8]2[CH2:13][CH2:12][N:11]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][N:21]=3)[CH2:10][C@H:9]2[F:14])[CH2:16][CH2:17]1
Reactant: CCc1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N(C1CC1)[C@H]1CCNC[C@H]1F
Product: CCc1cnc(N2CC[C@H](NC3CC3)[C@H](F)C2)nc1

Procedure:
The title compound is prepared from cyclopropyl-[(3R,4S)-3-fluoro-piperidin-4-yl]-carbamic acid tert-butyl ester and 2-chloro-5-ethyl-pyrimidine following a procedure analogous to that described for Intermediate 73.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:18])[CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1.C(N(C(C)C)C(C)C)C>CCCCO>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12](=[O:18])[CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCC(CC)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)C(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 160 °C
Reaction time: 16 h
Yield: 57.6 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-ethylbutanamide (225 mg, 0.686 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (412 mg, 2.06 mmol), and N-ethyl-N-isopropylpropan-2-amine (239 μL, 1.37 mmol) in n-BuOH (5 mL) was purged under N2 and stirred at 160° C. in a sealed tube for 16 hours. The solvent was then removed in vacuo, and the liquid residue was purified by C-18 reverse phase column chromatography (Biotage Flash 25M+; C-18) on Biotage SP4 unit eluting with a gradient of 15-90% CH3CN/water (25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(2-ethylbutanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (201 mg, 58% yield) as a solid. LCMS (APCI+) m/z 508, 510 (M+H)+, Retention time=4.15 minutes (Method 2).
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.CO.[CH3:34][N:35]([CH3:61])[CH2:36][CH2:37][CH2:38][C:39]#[C:40][C:41]1[CH:42]=[N:43][C:44]([NH:47][S:48]([C:51]2[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][CH:52]=2)(=[O:50])=[O:49])=[N:45][CH:46]=1>C1COCC1>[CH3:61][N:35]([CH3:34])[CH2:36][CH2:37][CH2:38][C:39]#[C:40][C:41]1[CH:42]=[N:43][C:44]([N:47]([CH3:1])[S:48]([C:51]2[CH:52]=[CH:53][C:54]([C:57]([F:60])([F:58])[F:59])=[CH:55][CH:56]=2)(=[O:49])=[O:50])=[N:45][CH:46]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CN(C)CCCC#Cc1cnc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)nc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CCCC#Cc1cnc(N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)nc1
Temperature: 25 °C
Yield: 23.4 %

Procedure:
A solution of 127 mg (0.485 mmol) triphenylphosphine in 0.5 ml THF was treated at 0° C. with 0.075 ml (0.485 mmol) DEAD, then with 0.016 ml (0.388 mmol) methanol and finally with 80 mg (0.19 mmol) of N-[5-(5-Dimethylamino-pent-1-ynyl)-pyrimidin-2-yl]-4-trifluoromethyl-benzenesulfonamide in 0.3 ml THF. The reaction mixture was stirred over night at RT, evaporated and extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phases were dried over Na2SO4, evaporated and purified by flash column chromatography on silica gel with CH2Cl2/MeOH (99:1 to 95:5) to yield 19 mg (23%) of N-[5-(5-Dimethylamino-pent-1-ynyl)-pyrimidin-2-yl]-N-methyl-4-trifluoromethyl-benzenesulfonamide, MS: 427 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:18][O:19][C:20]([C:22]1[CH:39]=[CH:38][CH:37]=[CH:36][C:23]=1[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([OH:35])=O)=[CH:28][CH:27]=1)=[O:21].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:33](=[O:35])[CH2:32][C:29]1[CH:28]=[CH:27][C:26]([O:25][CH2:24][C:23]2[CH:36]=[CH:37][CH:38]=[CH:39][C:22]=2[C:20]([O:19][CH3:18])=[O:21])=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccccc1COc1ccc(CC(=O)O)cc1
Reactant: CCCCCCCNCc1ccc(F)cc1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)Cc1ccc(OCc2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
N-(2,4-Difluorobenzyl)-N-heptylamine (106 mg, 0.44 mmol) was added into (4-{[2-(methoxycarbonyl)benzyl]oxy}phenyl)acetic acid (120 mg, 0.4 mmol) in DCM (10 ml) and followed by EDC (84.3 mg, 0.44 mmol) and then DMAP (54 mg, 0.44 mmol). The mixture was stirred at room temperature overnight, and then washed with 1% hydrochloric acid, water and brine and dried with magnesium sulphate and evaporated. Chromatography of the residue on a column (ISOLUTE®SI, 5 g/15 ml) using DCM and MeOH/DCM (0.5:99.5) as eluant gave 155 mg desired product, yield 74%.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1>C(O)(=O)C>[C:22]1([CH3:25])[CH:23]=[CH:24][C:19]([N:18]2[C:10](=[O:11])[C:5]3=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:6]3[C:7]2=[O:9])=[CH:20][CH:21]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C1OC(=O)c2c1cc([N+](=O)[O-])cc2[N+](=O)[O-]
Solvent: CC(=O)O
Product: Cc1ccc(N2C(=O)c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3C2=O)cc1
Yield: 85.1 %

Procedure:
2 kg (8.4 mols) of 3,5-dinitrophthalic anhydride and 897 g (8.4 mols) of p-toluidine in 6.2 l of glacial acetic acid are kept under reflux for 3 hours. After cooling, the mixture is filtered, the residue is rinsed with 2 l of water and then suspended in 25 l of water, and the product is filtered off and dried at 100° C. in vacuo. 2,339 g (85% of theory) of N-(p-toluyl)-3,5-dinitrophthalimide are obtained; melting point: 182°-3° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[N:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH2:31]>>[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH:31][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[N:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1
Reactant: CN(C)CCNc1ncc2c(-c3ccnc(S(C)(=O)=O)n3)n[nH]c2n1
Reactant: NCc1cccc(Cl)c1
Product: CN(C)CCNc1ncc2c(-c3ccnc(NCc4cccc(Cl)c4)n3)n[nH]c2n1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
The mixture of N′-[3-(2-methanesulfonyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-N,N-dimethyl-ethane-1,2-diamine (from Example 23 supra) (160 mg, crude) and 3-chlorobenzylamine (236 mg, 1.67 mmol) was heated at 130° C. with stirring for 3 hours. The resulting oil was purified by chromatography (silica gel, 7 g, 200-300 mesh, eluting with dichloromethane:methanol, 10:1) and further purified by prep-HPLC. Concentrated HCl was added to the fractions with product and concentrated under reduced pressure to give N-{3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-N′,N′-dimethyl-ethane-1,2-diamine; hydrochloride. (Yield 26 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)CC)C>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1c(F)c(N2CCNCC2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 1.0 g (3.35 mmole) of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3quinolinecarboxylic acid, 1.15 g (13.4 mmole) of piperazine, 1.36 g (13.35 mmole) of triethylamine and 60 ml of acetonitrile is refluxed for three hours and then stirred at room temperature for 16 hours. The precipitate is removed by filtration, washed with acetonitrile and dried in vacuo at 60° C. to give 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid, mp 257°-259° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:17])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:6]=2.N1C=CC=CC=1.[CH3:24][C:25]1[S:26][CH:27]=[C:28]([C:30](Cl)=[O:31])[N:29]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:17][C:30]([C:28]2[N:29]=[C:25]([CH3:24])[S:26][CH:27]=2)=[O:31])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:6]=2
Reactant: Cc1nc(C(=O)Cl)cs1
Reactant: Nc1cc(Br)cc2nn(C3CCCCO3)cc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc(C(=O)Nc2cc(Br)cc3nn(C4CCCCO4)cc23)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a round bottom flask was introduced 6-bromo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (2.77 g) dissolved in DCM (120 ml) followed by the addition of pyridine (1.135 ml). The reaction mixture was left to stir for a few minutes before the addition of 2-methyl-1,3-thiazole-4-carbonyl chloride (2.267 g). The reaction mixture was left to stir at RT for 1 h. After this time the reaction mixture was extracted between DCM and saturated sodium bicarbonate aq. The extracted organic layer was dried down. The crude was dissolved in DCM and adsorbed onto fluorisil before purification by solid loading on companion using Si Column (40 g) eluting with 40-100% ethyl acetate in cyclohexane. The appropriate fractions were combined and evaporated to dryness to yield the title compound, 2.6 g.