Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:19][C:20]([CH3:25])=[CH:21][C:22](Cl)=[O:23]>ClCCl>[C:1]([NH:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:7]([NH:8][C:22](=[O:23])[CH:21]=[C:20]([CH3:25])[CH3:19])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(C)=CC(=O)Cl
Reactant: CC(=O)Nc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cccc(NC(=O)C=C(C)C)c1

Procedure:
56.7 g. (0.42 mole) 3-acetamidoaniline in 400 ml. dichloromethane and 65 ml. (0.46 mol) triethylamine are mixed, while cooling with ice, with 59.0 g. (0.46 mole) 3,3-dimethylacryloyl chloride and stirred for 2 hours at ambient temperature. The solution is thereafter extracted with water and the separated organic phase is dried over anhydrous sodium sulphate, evaporated and the residue mixed with ethyl acetate. Upon standing in a refrigerator, crystals separate out. Yield 45.7 g. (47% of theory); m.p. 144°-148° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[C:10]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:3][CH:2]=1.C(Cl)Cl.C(N(CC)CC)C.[N:31]([C:34]1[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[C:36]([C:44]([F:47])([F:46])[F:45])[CH:35]=1)=[C:32]=[O:33]>CCOC(C)=O>[F:41][C:40]([F:42])([F:43])[C:38]1[CH:39]=[C:34]([NH:31][C:32]([N:18]2[CH2:19][CH2:20][N:15]([C:10]3[C:9]([O:8][CH2:7][C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[N:14][CH:13]=[CH:12][N:11]=3)[CH2:16][CH2:17]2)=[O:33])[CH:35]=[C:36]([C:44]([F:47])([F:45])[F:46])[CH:37]=1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: c1cc(COc2nccnc2N2CCNCC2)ccn1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nccnc2OCc2ccncc2)CC1
Reaction time: 3 h
Yield: 31.3 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 3′-(pyridin-4-ylmethoxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.3 g, 0.97 mmol, 1.0 eq.), dry CH2Cl2 (3 mL), triethyl amine (TEA) (0.54 g, 0.4 mL, 5.1 mmol, 5 eq) and was then cooled in an ice bath. 1-Isocyanato-3,5-bis-trifluoromethyl-benzene (0.29 g, 0.2 ml, 1.2 mmol, 1.2 eq.) was then added drop wise to the reaction mixture. Total reaction time was 3 hours at which point the reaction was diluted with 3× the volume EtOAc. This solution was then washed 3× with NaHCO3 and 2× with brine. The organic layer was dried with Na2SO4, concentrated, and the solid was columned with a Biotage system using a gradient. The initial eluent was 1:1 ethyl acetate/hexane followed by an eluent 3:1 ethyl acetate/hexane. The solvent was then removed and dried under high vacuum to yield the title compound (0.16 g, 32% yield) as a solid. 1H NMR (CDCl3) 8.63 (d, 2H), 7.90 (s, 2H), 7.81 (d, 1H), 7.62 (d, 1H), 7.54 (s, 1H), 7.34 (d, 2H), 7.26 (s, 2H), 6.78 (s, 1H), 5.48 (s, 2H), 3.67 (m, 8H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].Br[CH2:12][CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH4+].[Cl-]>CN(C=O)C>[CH2:15]([O:14][CH2:13][CH2:12][N:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]1=[O:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCCOCc1ccccc1
Reactant: O=c1ccc(Br)c[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=c1ccc(Br)cn1CCOCc1ccccc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 5-bromo-2(1 h)-pyridone (2000 mg, 11.5 mmol) in DMF (15 mL) at 0° C. was added NaH (60% dispersion in mineral oil, 552 mg, 23.0 mmol). After 1 h then 1-((2-bromoethoxy)methyl)benzene (2.00 mL, 12.6 mmol) was added. The reaction mixture was heated to 50° C. for 18 h. NH4Cl (satd.) was added and the mixture was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc (50 mL) and the combined organic was washed with satd. NH4Cl and dried over MgSO4. The organic was concentrated to an oil by repeatedly azeotroping with toluene. This residue was purified on 40 grams of silica eluting with 15-30% of EtOAc/hexanes to give a colorless oil that crystallized upon sitting for 2 weeks. MS (ESI pos. ion) m/z (MH+): 308/310. Calc'd exact mass for C14H14BrNO2: 307. 1H NMR (400 MHz, Chloroform-d) δ ppm 3.71-3.76 (m, 2 H) 4.08-4.13 (m, 2 H) 4.48 (s, 2 H) 6.46 (d, J=9.78 Hz, 1H) 7.21-7.38 (m, 6 H) 7.54 (d, J=2.74 Hz, 1 H).
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[NH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=1.[I-].[Na+].Cl[Si](C)(C)C.C(=O)(O)[O-].[Na+]>C(#N)C>[CH3:37][C:34]1[CH:35]=[CH:36][N:23]2[C:24]=1[C:25](=[O:33])[N:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]([C@@H:19]([NH:18][C:16]1[C:17]3[C:9]([C:7]4[NH:8][C:3](=[O:2])[CH:4]=[CH:5][CH:6]=4)=[CH:10][NH:11][C:12]=3[N:13]=[CH:14][N:15]=1)[CH3:20])=[N:22]2
Reactant: COc1cccc(-c2c[nH]c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)n1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cccc(=O)[nH]5)c34)n(-c3ccccc3)c(=O)c12
Temperature: 40 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
(S)-2-(1-((5-(6-Methoxypyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (22 mg, 0.02 mmol) was dissolved in 440 μl acetonitrile. Sodium iodide (35 md, 0.24 mmol) and chlorotrimethylsilane (30 μl, 0.24 mmol) were added. The reaction mixture was stirred at 40° C. for 8 h. The mixture was poured into 10 mL of sodium bicarbonate solution and extracted twice with ethyl acetate. The organics were dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified using SP1® purification system (0% to 10%, dichloromethane-2-propanol) to give 4 mg (34% yield) of the title compound as a solid. Purity 93%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C@@H:13]([C:15]1[CH:27]=[CH:26][C:18]([C:19](OC(C)(C)C)=[O:20])=[CH:17][CH:16]=1)[CH3:14])=[O:11].FC(F)(F)C(O)=O.CN(C([O:42][N:43]1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[Si](ON)(C(C)(C)C)(C)C.Cl>CS(C)=O.C(Cl)Cl>[OH:42][NH:43][C:19]([C:18]1[CH:26]=[CH:27][C:15]([C@H:13]([NH:12][C:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)=[O:11])[CH3:14])=[CH:16][CH:17]=1)=[O:20]
Reactant: C[C@@H](NC(=O)c1cc2ccccc2o1)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CC(C)(C)[Si](C)(C)ON
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1cc2ccccc2o1)c1ccc(C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 24 %

Procedure:
To a 2-dram vial containing tert-butyl 4-{(1R)-1-[(1-benzofuran-2-ylcarbonyl)amino]ethyl}benzoate was added DCM (2.5 mL), and trifluoroacetic acid (0.28 mL, 3.60 mmol). The mixture was stirred at rt for 6 h then evaporated to give an oil residue. To the residue was added HATU (0.10 g, 0.27 mmol), triethylamine (0.25 mL, 1.80 mmol), and DCM (2.5 mL). After stirring at rt for 30 min, O-(tert-butyldimethylsilyl)hydroxylamine (0.053 g, 0.360 mmol) was added. The mixture was stirred at rt for 2 h, then the solvent was completely removed to give a sticky brown oil. To this oil residue was added hydrochloric acid (4.0 mL, 1% v/v in IPA). After stirring at rt for 30 min, the solvent was evaporated to dryness to give a solid. To the solid was then added DMSO (1.1 mL). The solution was filtered and purified by Gilson prep-HPLC [25-50% MeCN—H2O] to give N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-benzofuran-2-carboxamide (0.0148 g, 24%) as a white solid. LC-MS: (FA) ES+ 325; 1H NMR (Methanol-d4, 400 MHz) δ 7.71 (m, 3H), 7.60 (d, J=8.5 Hz, 1H), 7.50 (m, 3H), 7.45 (t, J=7.0 Hz, 1H), 7.31 (t, J=7.8 Hz, 1H), 5.30 (q, J=7.2 Hz, 1H), 1.61 (d, J=7.0 Hz, 3H).
Reaction SMILES: [Si]([O:18][C@@H:19]([CH3:46])[C:20]([N:22]1[N:26]=[C:25]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[F:34])[S:24][C@:23]1([CH2:41][O:42][CH2:43][O:44][CH3:45])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:21])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.F[C:48]1C=CC(F)=CC=1C1S[C@@](CO)(C2C=CC=CC=2)N(C(=O)[C@@H](OC)C)N=1>>[F:34][C:28]1[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=1[C:25]1[S:24][C@:23]([CH2:41][O:42][CH2:43][O:44][CH3:45])([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:22]([C:20](=[O:21])[C@@H:19]([O:18][CH3:48])[CH3:46])[N:26]=1
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CO)c1ccccc1
Reactant: COCOC[C@]1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)[C@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Product: COCOC[C@]1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)[C@H](C)OC

Procedure:
Prepared as previously described in Example 83 using (S)-2-(tert-butyldiphenylsilyloxy)-1-((S)-5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)propan-1-one from Step C. MS ESI (+) m/z 437 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.53 (m, 1H), 7.43 (m, 2H), 7.37 (m, 2H), 7.31 (m, 1H), 7.11 (m, 2H), 4.76 (m, 4H), 4.47 (d, 1H, J=10 Hz), 3.41 (s, 3H), 3.35 (s, 3H), 1.47 (d, 3H, J=7 Hz). Stereochemistry was assigned by inference from (S)-1-((R)-5-(2,5-difluorophenyl)-2-(hydroxymethyl)-2-phenyl-1,3,4-thiadiazol-3 (2H)-yl)-2-methoxypropan-1-one.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:16][C:17]1[C:22]([N:23]2[CH2:28][C@@H:27]3[CH2:29][C@H:24]2[CH2:25][NH:26]3)=[CH:21][CH:20]=[CH:19][N:18]=1.CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[CH3:8][CH:2]([CH3:1])/[CH:3]=[CH:4]/[C:5]([N:26]1[CH2:25][C@@H:24]2[CH2:29][C@H:27]1[CH2:28][N:23]2[C:22]1[C:17]([CH3:16])=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:7]
Reactant: Cc1ncccc1N1C[C@@H]2C[C@H]1CN2
Reactant: CC(C)/C=C/C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ncccc1N1C[C@@H]2C[C@H]1CN2C(=O)/C=C/C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
(E)-4-Methylpent-2-enoic acid (57 mg, 0.5 mmol) was dissolved in dichloromethane (2 ml), oxalyl chloride (42 μl, 0.5 mmol) and one drop of DMF were added and the resulting solution was stirred at room temperature for 15 minutes. This solution was added to a solution of (1S,4S)-5-(2-methyl-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane hydrochloride (66 mg, 0.3 mmol) in DCM (2 ml). DIPEA (175 μl, 1 mmol) was added and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 59 mg of a solid (0.21 mmol, 69%).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[NH2:16][CH:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[C:18]1([CH:17]([NH:16][C:2]2[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc(NC(c2ccccc2)c2ccccc2)nc1C(F)(F)F
Yield: 76.6 %

Procedure:
A reaction vessel was charged with 120 ml of toluene and 11.0 g (42.4 mmol) of ethyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate (prepared as described in U.S. Pat. No. 4,199,506). Then, 15.5 g (86 mmol) of aminodiphenylmethane was added in one portion. The resulting yellowish-orange solution was refluxed under nitrogen for 9 days. Then, solvent was removed from the mixture under reduced pressure to yield a yellowish-orange solid material, which was flash chromatographed (~38 ml/min) on silica gel using 10% ethyl acetate in hexane solvent. There was obtained 13.2 g of a thick yellow oil which solidified upon standing to a yellow solid product (m.p.=92°-95° C.) identified in Table I.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][CH3:47])=[C:37]([O:48][CH2:49][CH3:50])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:49]([O:48][C:37]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)[CH:40]=[CH:39][C:38]=1[O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][CH3:47])[CH3:50]
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1OCC
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300mg), 3-ethoxy-4-(2-propoxyethoxy)phenyl borate (171 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was refluxed for 6 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:3) to give crystals, which were recrystallized from ethanol to give colorless crystals of 7-[3-ethoxy-4-(2-propoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 73) (237 mg).
Reaction SMILES: Br.[NH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([Br:19])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl[CH2:30][CH2:31][N:32]=[C:33]=[O:34].[H-].[Na+]>CN(C=O)C.O>[Br:19][C:8]1[C:7]2[C:6]3[C:14](=[CH:15][C:3]([N:2]4[CH2:30][CH2:31][NH:32][C:33]4=[O:34])=[CH:4][CH:5]=3)[NH:13][C:12]=2[C:11]([C:16]([NH2:18])=[O:17])=[CH:10][CH:9]=1
Reactant: O=C=NCCCl
Reactant: NC(=O)c1ccc(Br)c2c1[nH]c1cc(N)ccc12
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc(Br)c2c1[nH]c1cc(N3CCNC3=O)ccc12
Reaction time: 2 h
Yield: 60.4 %

Procedure:
A solution of 7-amino-4-bromo-9H-carbazole-1-carboxamide hydrobromide (Example 54-2, 700 mg, 1.818 mmol) and DIEA (0.381 mL, 2.182 mmol) in DMF (5 mL) was treated with 1-chloro-2-isocyanatoethane (230 mg, 2.182 mmol). After 2 h, the mixture was treated with NaH (60% in mineral oil, 582 mg, 14.54 mmol). After 10 min, the mixture was diluted with water. The precipitate was collected by filtration, dried, triturated with methanol, collected again by filtration and dried to provide 4-bromo-7-(2-oxoimidazolidin-1-yl)-9H-carbazole-1-carboxamide as a light yellow solid (410 mg, 60%). 1H NMR (400 MHz, DMSO-d6) δ 11.55 (1 H, s), 8.46 (1 H, d, J=8.80 Hz), 8.16 (1 H, br. s.), 7.92 (1 H, s), 7.77 (1 H, d, J=8.14 Hz), 7.63-7.68 (1 H, m), 7.52 (1 H, br. s.), 7.36-7.41 (1 H, m), 6.99 (1 H, s), 3.92-3.98 (2 H, m), 3.43-3.50 (2 H, m). Mass spectrum m/z 373, 375 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:16]=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH:16]=[N:15]2)[N:3]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCn1cc(-c2ccc(F)cc2)cn1
Product: FCc1cccc(C#CCCn2cc(-c3ccc(F)cc3)cn2)n1
Yield: 38.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (49 mg, 0.26 mmol) and 1-but-3-ynyl-4-(4-fluoro-phenyl)-1H-pyrazole (50 mg, 0.23 mmol, Example 140(A)). Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 29 mg (88 μmol, 38%) of 2-(fluoromethyl)-6-(4-(4-(4-fluorophenyl)-1H-pyrazol-1-yl)but-1-ynyl)pyridine as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[OH:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:36]2[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][OH:30])[CH2:34][CH2:35]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: OCCN1CCNCC1
Reactant: Cc1ccc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: Cc1ccc(-c2cc3cc(CN4CCN(CCO)CC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 97.5 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methyl-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (100 mg, 0.256 mmol) was dissolved in acetonitrile (8 mL), and the solution was treated with 1-(2-hydroxyethyl)piperazine (133 mg, 1.02 mmol), acetic acid (0.307 mL, 5.12 mmol) and sodium triacetoxyborohydride (218 mg, 1.02 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with sodium carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-methyl-7-(1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)pyperazin-1-ylmethyl]indol-2-yl)isoindolinone (126 mg, yield 98%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].[CH:9]([C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1)=[O:10].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:9]([C:11]1[CH:16]=[C:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[Cl:8])[CH:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Clc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=Cc1cccc(-c2ccccc2Cl)c1

Procedure:
To a solution of 2-bromochlorobenzene (0.24 mL, 2 mmol) and 3-formylbenzeneboronic acid (0.35 g, 2.2 mmol) in toluene (20 mL) were added 2M aq. sodium carbonate (2.6 mL) followed by (Ph3P)4Pd (0.34 g, 0.3 mmol). The resulting reaction mixture was refluxed for 3 h, cooled and diluted ethyl acetate. The organic phase was washed with water, saturated aq. sodium bicarbonate, brine and dried over sodium sulfate. The filtrate was concentrated in vacuo and the residue obtained was purified by chromatography (hexane:ethyl acetate; 4:1) to yield the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[CH2:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[Si](C)(C)[O:23][C:24]([CH:26]=[CH2:27])=[CH2:25].Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[F:20])[CH2:27][CH2:26][C:24](=[O:23])[CH2:25][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C=CC(=C)O[Si](C)(C)C
Reactant: C=C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 130 °C
Yield: 89.3 %

Procedure:
A solution of 2-[1-[(4-chlorophenyl)sulfonyl]ethenyl]-1,4-difluorobenzene (Example 3) (100 g, 0.32 mol) in xylenes (500 ml) was azeotropically distilled at 38° C., 20 mmHg, until 300 mL solvent had been removed. 2-Trimethylsilyloxybutadiene (90.4 g, 0.64 mol) was then added under a nitrogen atmosphere and the mixture heated to 130° C. After the reaction was completed, the mixture was distilled in vacuo to remove residual diene, whilst maintaining a constant volume by the addition of xylenes (400 mL). The mixture was cooled to 50° C. and THF (500 mL) and 3M HCl (424 mL, 1.27 mol) were added. After the hydrolysis was complete, the layers were separated. The organic layer was washed with water (300 mL) and then concentrated by atmospheric distillation until 350 mL of solvent had been removed. The solution was allowed to cool until crystallisation started, heptane (600 mL) was added and the resulting mixture cooled to ambient. The solids were filtered and washed sequentially with heptane:xylenes (3:1, 200 ml) and then heptane (200 ml). Drying overnight in vacuo at 40° C. furnished 4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexanone (110 g, 90% yield). 1H NMR CDCl3 7.43-7.37 (4H, m), 7.22-7.1 (2H, m), 6.97-6.9 (1H, m), 3.05-2.98 (4H, m) and 2.61-2.53 (4H, m).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([NH:9][C:10]1[N:14]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][N:16]=2)[N:13]=[CH:12][CH:11]=1)(=[O:8])[CH2:6][CH3:7].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:5]([NH:9][C:10]1[N:14]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][N:16]=2)[N:13]=[CH:12][C:11]=1[N+:1]([O-:4])=[O:2])(=[O:8])[CH2:6][CH3:7]
Reactant: CCC(=O)Nc1ccnn1-c1ncc(Cl)cc1Cl
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCC(=O)Nc1c([N+](=O)[O-])cnn1-c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
1.5 ml (0.033 mole) of 98% strength nitric acid are added to 9.0 g (0.032 mole) of 5-propionamido-1-(3,5-dichloro-pyrid-2-yl)-pyrazole and 3.2 ml (0.035 mole) of acetic anhydride in 35 ml of glacial acetic acid at 10° C. and the mixture is stirred at room temperature for 6 hours. For working up, the mixture is concentrated in vacuo, the residue is taken up in 100 ml of methylene chloride and the mixture is neutralized with sodium bicarbonate solution, washed with sodium chloride solution, dried over magnesium sulphate and freed from the solvent in vacuo. 9.3 g (89% of theory) of 5-propionamido-1-(3,5-dichloropyrid-2-yl)-4-nitro-pyrazole of melting point 53° C.-56° C. are obtained.