Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH3:7])([OH:6])[CH3:5].Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:10]>>[C:9](=[O:10])([O:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1)[O:6][C:4]([CH3:7])([CH3:5])[CH2:3][O:2][CH3:1]
Reactant: COCC(C)(C)O
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Product: COCC(C)(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Yield: 87 %

Procedure:
1-Methoxy-2-methyl-2-propanol (3.50 ml, 30 mmol) was treated with 4-nitrophenyl chloroformate according to conditions similar to the ones described above with respect to Intermediate 2, Step 2 to provide, after purification by column chromatography over silica gel (eluting with Hexanes/EtOAc 99:1 to 70:30), 1-methoxy-2-methylpropan-2-yl 4-nitrophenyl carbonate (7.02 g, 87% yield) as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ 8.26 (d, J=9.2 Hz, 2H), 7.36 (d, J=9.2 Hz, 2H), 3.56 (s, 3H), 3.43 (s, 3H), 1.57 (s, 6H).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=3)[C:20]([C:28]3[N:29]=[C:30]4[C:36]([C:37](O)=[O:38])=[CH:35][N:34]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:31]4=[N:32][CH:33]=3)=[N:19]2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=[N:63][C:58]2[CH:59]=CC=N[C:57]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)(C)C>CN(C=O)C>[CH:58]([NH:63][C:37]([C:36]1[C:30]2[C:31](=[N:32][CH:33]=[C:28]([C:20]3[C:21]4[C:26](=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[N:18]([CH:16]4[CH2:17][N:14]([CH:1]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)[CH2:15]4)[N:19]=3)[N:29]=2)[N:34]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:46])([CH3:47])[CH3:45])[CH:35]=1)=[O:38])([CH3:59])[CH3:57]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(-c3nn(C4CN(C(c5ccccc5)c5ccccc5)C4)c4cc(F)ccc34)cnc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)N
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C4CN(C(c5ccccc5)c5ccccc5)C4)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
To a solution of 2-[1-(1-benzhydryl-azetidin-3-yl)-6-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (130 mg, 0.20 mmol) in DMF (2 mL) were added HATU (84 mg, 0.22 mmol) and isopropylamine (86 μL, 1.00 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (2×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 50% EtOAc/hexanes to isolate 74 mg (54%) of 2-[1-(1-benzhydryl-azetidin-3-yl)-6-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide as an off-white foamy solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38].[NH2:39][CH2:40][CH2:41][N:42](C)[C:43](=O)OC(C)(C)C>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:39][CH2:40][CH2:41][NH:42][CH3:43])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38]
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: Cc1ccc(NC(=O)c2cccs2)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: CNCCNc1nc(-c2cc(NC(=O)c3cccs3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1

Procedure:
The title compound was prepared as described in Example 2 from N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-2-thiophenecarboxamide and 1,1-dimethylethyl (2-aminoethyl)methylcarbamate: LC-MS m/z 547 (M+H)+, 1.80 min (ret time).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=2[F:35])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([CH2:16][N:17]([CH2:25][CH3:26])C(=O)OC(C)(C)C)([F:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].Cl>C(#N)C.O1CCOCC1>[CH2:25]([NH:17][CH2:16][C:13]1([F:15])[CH2:14][N:11]([C:9]([C:4]2[C:3]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=3[F:35])=[C:2]([F:1])[C:7]([F:8])=[CH:6][CH:5]=2)=[O:10])[CH2:12]1)[CH3:26]
Reactant: CCN(CC1(F)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: CCNCC1(F)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Yield: 27.3 %

Procedure:
To the 1,1-dimethylethyl [{1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-fluoroazetidin-3-yl]methyl}ethylcarbamate (19.0 mg, 0.031 mmol) in acetonitrile (1.0 mL) added a solution 4.0N hydrogen chloride in dioxane (1.0 mL). After 1.5 hr the solution was concentrated in vacuo. The residue was purified by preparative reverse phase HPLC to afford the title compound (4.30 mg, 27%). 1H NMR (400 MHz, CDCl3): 8.25 (s, 1H), 7.33 (dd, 1H), 7.33-7.25 (m, 1H), 7.18-7.14 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.58 (m, 1H), 4.33-4.05 (br m, 4H), 3.07-2.95 (br m, 2H), 2.65 (q, 2H), 1.08 (t, 3H); MS (EI) for C19H18F4IN3O: 508 (MH+).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([Br:27])=[CH:20][C:19]=1Br)[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2].[CH2:29]=[N:30]O.N1C(C)=CC=CC=1C.[N+](C1C=CC=CC=1)([O-])=O>[Cu]I>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([Br:27])=[CH:20][C:19]=1[C:29]#[N:30])[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2]
Reactant: C=NO
Reactant: CCN(CC)c1ccc(N=Nc2c(Br)cc(Br)cc2[N+](=O)[O-])c(NC(C)=O)c1
Agent: [Cu]I
Solvent: Cc1cccc(C)n1
Solvent: O=[N+]([O-])c1ccccc1
Product: CCN(CC)c1ccc(N=Nc2c(C#N)cc(Br)cc2[N+](=O)[O-])c(NC(C)=O)c1
Temperature: 90 °C
Yield: 18.3 %

Procedure:
A stirred mixture of 3-acetylamino-4-(2',4'-dibromo-6'-nitrophenylazo)-N,N-diethylaniline (5.3 parts), copper (I) iodide (1.9 parts), formaldoxime trimer (1.8 parts), 2,6-lutidine (2.15 parts), and nitrobenzene (100 parts), was heated to 90° C. for 10 hours when thin layer chromatography showed reaction to be effectively complete. The mixture was filtered, cooled, and the solvent was removed by steam distillation. Crystallisation of the solid product from ethanol gave 3-acetylamino-4-(2'-cyano-4'-bromo-6'-nitrophenylazo)-N,N-diethylaniline (Found; C, 49.5; H, 4.3; Br, 17.7; N, 18.3. C19H19BrN6O3 requires C, 49.65; H, 4.15; Br, 17.4; N, 18.3%)
Reaction SMILES: C1(C)C(C)=CC=CC=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-])=O)=[CH:12][CH:11]=1>[Pt].CC(C)=O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH2:22])=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(Cl)cc1
Agent: [Pt]
Solvent: Cc1ccccc1C
Solvent: CC(C)=O
Product: Nc1ccccc1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
In a 20 ml autoclave were placed 1 g of xylene, 6 mg of a Pt/C catalyst (containing 1% by weight of Pt with respect to the weight of carbon) and 0.25 g (1 mmol) of 4′-chloro-2-nitrobiphenyl obtained in example 1.4. The mixture was stirred under hydrogen pressure (7-8 bar) at 100° C. until the starting material had disappeared (monitoring via HPLC). After completion of the reaction the mixture was cooled to ambient temperature and diluted with 15 ml of acetone. The catalyst was filtered off and the filtrate was evaporated in vacuo yielding 0.2 g (91% of theory) of the title compound in a purity of 93% (HPLC % by weight).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[OH-].[Na+].C(=O)(O)[O-].[Na+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>O.C(O)C>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NCCCCCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCCCNc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 97 %

Procedure:
5 g (38.11 mmol) of 6-aminocaproic acid are dissolved in 50 ml of water in the presence of 1.5 g (1 eq) of sodium hydroxide and 4.2 g (1.3 eq) of sodium bicarbonate in a 250 ml three-necked flask equipped with a reflux condenser and a thermometer. A solution of 4.9 ml (1.2 eq) of 4-fluoronitrobenzene in 50 ml of ethanol is run into the mixture, which mixture is subsequently brought to reflux (85°-90° C.) for 48 hours. The mixture is cooled and then extracted 3 times with dichloromethane. The aqueous phase is acidified to pH˜3 with 5N hydrochloric acid. A yellow precipitate is formed; the mixture is left overnight in a refrigerator. The precipitate is pulled dry and washed with water and with acetone. After drying, 9.3 g of a yellow product are obtained, i.e. a final yield of 97%.
Reaction SMILES: S(Cl)(Cl)=O.[N:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C@H:16]3[CH2:21][CH2:20][C@H:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]3)[O:13][N:12]=2)=[CH:7][CH:6]=1.[CH2:25](O)[CH2:26][CH3:27]>>[CH2:25]([O:23][C:22]([C@H:19]1[CH2:18][CH2:17][C@H:16]([C:14]2[O:13][N:12]=[C:11]([C:8]3[CH:9]=[CH:10][N:5]=[CH:6][CH:7]=3)[N:15]=2)[CH2:21][CH2:20]1)=[O:24])[CH2:26][CH3:27]
Reactant: O=C(O)[C@H]1CC[C@H](c2nc(-c3ccncc3)no2)CC1
Reactant: CCCO
Solvent: O=S(Cl)Cl
Product: CCCOC(=O)[C@H]1CC[C@H](c2nc(-c3ccncc3)no2)CC1

Procedure:
Thionyl chloride (11.5 μl, 0.1 mmol) was added to a solution of trans-4-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-yl)cyclohexanecarboxylic acid (Preparation 4, 22 mg, 0.08 mmol) in 1-propanol (2 ml). The mixture was heated under reflux for 2 h, cooled and the solvent removed in vacuo. The residue was dissolved in EtOAc (10 ml), washed with saturated aqueous NaHCO3 (3 ml) and brine (5 ml), then dried (MgSO4). Removal of the solvent afforded the title compound. RT=3.67 min, m/z (ES+)=316.3 [M+H]+.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][N:8]=1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>CN(C)C=O>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([S:3][C:4]2[N:5]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:7][N:8]=2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: Sc1nccn1-c1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Sc2nccn2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.6 %

Procedure:
To a mixture of 0.6 g (13.6 mmoles) of 50% sodium hydride in mineral oil and 8 ml of N,N-dimethylformamide was added 2.0 g (11.4 mmoles) of 2-mercapto-1-phenylimidazole. After stirring for 10 minutes the mixture was cooled in an icebath and 2.1 g (14.8 mmoles) of 1-fluoro-4-nitrobenzene was added. After stirring for 20 minutes, the mixture was warmed to room temperature and stirred for 3 hours. Ice was added and the mixture partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The organics were dried and concentrated. The residue was recrystallized from dichloromethane/petroleum ether (bp 30°-60° C.) to give 0.9 g (27%) of the product as off-white prisms, mp 123°-125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]([OH:17])=O)=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.[OH:25][C@H:26]1[CH2:30][CH2:29][NH:28][CH2:27]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[CH2:18]([C@H:14]([NH:13][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:12])[C:15]([N:28]1[CH2:29][CH2:30][C@H:26]([OH:25])[CH2:27]1)=[O:17])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Reactant: O[C@H]1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CC[C@H](O)C1)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-phenylpropionic acid (EXAMPLE 42, 50 mg, 0.15 mmol) in DMF (3 mL) was added 3-(S)-hydroxypyrrolidine (13.9 mg, 0.16 mmol), HOBt (20 mg, 0.15 mmol) and DIPEA (51 μL, 0.29 mmol). After 5 min, EDCI (36 mg, 0.19 mmol) was added and the reaction stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between water (20 mL) and ethyl acetate (3×20 mL), dried (MgSO4) and concentrated in vacuo. Purification via chromatography on silica gel eluting with methanol/dichloromethane (4:96) gave the title compound as a white solid. m/z (ES+)=413 [M+H]+; RT=3.20 min.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:23](OCC)=[O:24].[O-]CC.[Na+].Cl>C(O)C>[OH:24][CH:23]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)cc1
Temperature: 78 °C
Yield: 67.7 %

Procedure:
N-[4-(2-Oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-acetamide (1.15 g, 3.90 mmol) and ethyl formate (0.95 mL, 11.70 mmol) were dissolved in anhydrous ethanol (8.00 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (4.40 mL, 11.70 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 3 with dropwise addition of 1M HCl(aq). The dark orange precipitate that formed was filtered then re-dissolved in EtOH (25 mL). The ethanolic solution was made basic with the addition of 1 M NaOH(aq) (4 mL). The basic solution then was re-acidified to pH 1 with 1 M HCl(aq) (10 mL) causing the formation of a pale orange precipitate. This suspension was filtered yielding an orange solid as the pure N-[4-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-acetamide (0.852 g, 2.64 mmol, 68%).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:13]=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C1C(=O)N([I:24])C(=O)C1>C(#N)C>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([I:24])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCC(CC)c1cc(C)nn2cc(C)nc12
Solvent: CC#N
Product: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (5.1 g, 0.023 moles) and 50 mL of dry acetonitrile are added to a nitrogen purged flask and are cooled to 0° C. NIS (5.54 g, 0.025 moles) in 90 mL of dry acetonitrile is added. The bath is allowed to come to room temperature, and the reaction to stir overnight. The solvents are evaporated. The residue is taken up in ethyl acetate, washed two times with 50% aqueous solution of sodium thiosulfate and with brine. The organic layer is dried over sodium sulfate, filtered, and evaporated to a residue again. The crude product is triturated in a small amount of acetonitrile, and a solid is filter off. The trituration is repeated several times to obtain the title compound as a light tan solid weighing 7.29 g (0.021 moles, 91%). 1H-NMR (DMSO-d6), δ 6.96 (s, 1H); 3.0-3.3 (m, 1H); 2.51 (s, 3H); 2.35 (s, 3H); 1.71-1.80 (m, 4H); 0.71 (t, J=7.48 hz, 6H) ppm. MS/ES+=344 (100%, M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH2:9]Br)[C:3]=1[Cl:11].[C-:12]#[N:13].[K+]>C(O)C.O>[Br:1][C:2]1[C:3]([Cl:11])=[C:4]([CH2:9][C:12]#[N:13])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: Fc1ccc(Br)c(Cl)c1CBr
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1c(F)ccc(Br)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
A solution of 1-bromo-3-bromomethyl-2-chloro-4-fluoro-benzene (9.945 g) (Example 4.2) in absolute ethanol (40 ml) was added dropwise to a solution of potassium cyanide (2.38 g) in water (2 ml) under heating over a period of 30 minutes. The reaction mixture was heated to reflux for 7 hours. The reaction mixture was then allowed to cool to ambient temperature and then stored at ambient temperature for 16 hours. The mixture was filtered and the filtrate concentrated. The residue was dissolved in ethyl acetate, dried over magnesium sulfate and concentrated to give (3-bromo-2-chloro-6-fluoro-phenyl)-acetonitrile as a pale yellow oil (8.19 g). 1H-NMR (400 MHz, CDCl3): 3.89 (d, 2H), 7.00 (t, 1H), 7.64 (dd, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.[C:30]1(=O)[CH2:34][CH2:33][C:32](=[O:35])[CH2:31]1.C([BH3-])#N.[Na+].CCN(C(C)C)C(C)C>CO>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:30]4[CH2:34][CH2:33][C:32](=[O:35])[CH:31]=4)[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: O=C1CCC(=O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C5=CC(=O)CC5)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (43 mg, 0.1 mmol), cyclopentane-1,3-dione (89 mg, 9.1 mmol), sodium cyanoborohydride (19 mg, 0.3 mmol) and DIEA (0.2 mL, 11 mmol) in MeOH (1 mL) was stirred in a sealed vial at 60° C. After 2.5 h, additional sodium cyanoborohydride (19 mg, 0.3 mmol) was added and the reaction continued to stir at 60° C. overnight. The mixture was purified by RP-HPLC to give 3-(4-(4-(5-Chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)cyclopent-2-en-one as an off white solid; 1H NMR (400 MHz, DMSO-d6) δ 9.97 (br s, 1H), 9.83 (br s, 1H), 8.90 (s, 1H), 8.32 (d, J=6.8 Hz, 1H), 7.88 (d, J=12.8 Hz, 1H), 6.97 (s, 1H), 6.04 (s, 1H), 5.30 (br s, 1H), 4.71 (d, J=12.0 Hz, 2H), 4.04 (t, J=12.4 Hz, 2H), 3.84 (m, 1H), 3.53 (m, 2H), 3.13 (m, 2H), 3.08 (s, 3H), 2.96 (s, 3H), 2.59-2.40 (m, 4H); ESMS m/z 496.2 (M+H+).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]([F:25])([F:24])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2C(C(O)=O)=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1>ClCCl.CN(C)C=O>[F:7][C:8]([F:24])([F:25])[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:1]([C:2]([Cl:4])=[O:3])=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1

Procedure:
170 ml of oxalyl chloride are added dropwise at 0° C. to a suspension of 30 g (0.113 mol) of 4′-trifluoromethyl-biphenyl-2-carboxylic acid in 500 ml of dichloromethane and 0.2 ml of dimethylformamide. After the reaction has ended the reaction mixture is concentrated by distillation and the 4′-trifluoromethyl-biphenyl-2-carboxylic acid chloride is further reacted as a crude product.