Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([CH:12]([F:14])[F:13])=[CH:10][C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:8][C:7]=12)#[CH:2].Br[C:26]1[S:30][C:29]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:28][CH:27]=1>>[F:13][CH:12]([F:14])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:26]3[S:30][C:29]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:28][CH:27]=3)=[C:7]2[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-difluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.15) (169 mg, 0.5 mmol) and commercially available 5-bromo-thiophene-2-sulfonamide (121 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (180 mg, 72%). MS (ISN) 497.0 [(M−H)−]; mp 225° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[F:20][C:21]([F:29])([F:28])[C:22]([C:24]([F:27])([F:26])[F:25])=[S:23]>C1(C)C=CC=CC=1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[CH:11]=[C:10]([C:22]([C:24]([F:27])([F:26])[F:25])([C:21]([F:29])([F:28])[F:20])[SH:23])[NH:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: FC(F)(F)C(=S)C(F)(F)F
Reactant: Fc1ccc(-c2cc[nH]c2-c2ccc(F)cc2)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2cc(C(S)(C(F)(F)F)C(F)(F)F)[nH]c2-c2ccc(F)cc2)cc1
Yield: 22.9 %

Procedure:
Into a solution of 2.6 g (0.01 mole) of 2,3-bis(4-fluorophenyl)-1H-pyrrole in 100 ml toluene was distilled 2.0 g (0.011 mole) of hexafluorothioacetone, prepared by pyrolysis of the dimer according to the method of W. J. Middleton et al., J. Org. Chem., 30, 1375 (1965). The mixture was stirred at room temperature approximately one-half hour, then was concentrated by rotary evaporation. The residue was purified by chromatography on silica gel, eluting with hexane/toluene (80/20). The chromatographed product was recrystallized from hexane to give 1.0 g of product, m.p. 114°-115°.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:35])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:28][C:27]3[CH:26]=[N:25][N:24]([CH3:29])[C:23]=3[NH:22][C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]2=3)=[O:18])=[CH:13][C:12]=1[CH3:34])([CH3:6])([CH3:5])[CH3:4].CI.[CH3:38]COC(C)=O>CN(C=O)C>[C:3]([O:7][C:8](=[O:35])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:28][C:27]3[CH:26]=[N:25][N:24]([CH3:29])[C:23]=3[N:22]([CH3:38])[C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]2=3)=[O:18])=[CH:13][C:12]=1[CH3:34])([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3N(C)c3ccccc32)ccc1CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36 %

Procedure:
Sodium hydride (14 mg, 0.34 mmol) was added to a solution of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionic acid tert-butyl ester from Example E45 (125 mg, 0.28 mmol) in DMF (2 ml) at 0° C. The mixture was stirred for 20 min at room temperature then cooled down to 0° C. Methyl iodide (0.09 ml, 1.4 mmol) was added and the mixture was stirred for 20 h at room temperature. EtOAc was added and the mixture was washed with 0.3M KHSO4 then brine, dried, concentrated in vacuo and azeotroped with toluene. The residue was purified by flash chromatography on silica gel through an isolute (eluant; EtOAc) to yield the title compound (46 mg, 36%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH2:24][C:25]([NH2:27])=[O:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@:13]2([CH2:23][CH2:24][C:25]([NH2:27])=[O:26])[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:32]4[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:17][CH:18]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)OC1=O
Reactant: OB(O)c1ccncc1
Product: C[C@@H](c1ccc(-c2ccncc2)cc1)N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanamide and pyridine-4-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=0.906 min, m/z=448.1; 1H NMR (CDCl3) 1.59 (d, 3H), 2.15 (m, 1H), 2.24-2.32 (m, 4H), 2.45 (m, 1H), 3.07 (m, 2H), 5.66 (m, 1H), 5.71 (m, 1H), 5.84 (m, 1H), 7.03 (m, 2H), 7.05 (m, 2H), 7.22 (m, 1H), 7.25 (m, 1H), 7.50 (d, 2H), 7.93 (d, 2H), 8.84 (d, 2H).
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][SH:8].[CH3:15]I>CO.C[O-].[Na+]>[CH3:15][S:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CI
Reactant: SCc1ccccc1-c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CSCc1ccccc1-c1ccccc1
Temperature: 60 °C
Yield: 77 %

Procedure:
A mixture of biphenyl-2-yl-methanethiol (4 g, 20 mmol) in methanol (27 mL) and sodium methoxide in methanol (0.5 M, 40 mL) was heated at 60° C. for 0.5 h, cooled, treated with methyl iodide (3.7 mL, 60 mmol) and re-heated at 60° C. for 0.5 h. After cooling to room temperature, the reaction mixture was quenched with ice-water, acidified (pH˜2) and extracted with ethyl acetate (3×50 mL). Combined organic layer was washed with water (1×50 mL) and brine (1×50 mL), dried (MgSO4), and concentrated to give a crude product that was passed through a bed of silica (solvent: ethyl acetate) to give 3.3 g of 2-methylsulfanylmethyl-biphenyl (yellow oil) that was directly used in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]C(=O)N(C)C)=[C:4]([Cl:15])[CH:3]=1.[OH-].[K+].Cl>C(O)C.O>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([SH:9])=[C:4]([Cl:15])[CH:3]=1
Reactant: CN(C)C(=O)Sc1c(Cl)cc(N)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)c(S)c(Cl)c1
Temperature: 95 °C
Yield: 68.7 %

Procedure:
A solution of dimethyl-thiocarbamic acid S-(4-amino-2,6-dichloro-phenyl) ester (81) (2.0 g, 7.5 mmol) in ethanol was treated with a 3N aqueous potassium hydroxide solution. The reaction was heated to 95° C. for 2 d. At this time, the reaction was cooled to 25° C. and was then acidified to pH=2 with a 3N aqueous hydrochloric acid solution. This solution was diluted with water (500 mL) and then was extracted with ethyl acetate (2×250 mL). The organics were dried with magnesium sulfate, filtered, and concentrated under vacuumto an orange solid. The solid was slurried in chloroform, collected by filtration and washed with chloroform. The filtrate was concentrated under vacuum and purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 85:15 petroleum ether/ethyl acetate) to afford 4-amino-2,6-dichloro-benzenethiol (82) (1.0 g, 69%) as a white solid; EI(+)-HRMS m/e calcd for C6H5Cl2NS (M+) 192.9520, found 192.9519. Exact Mass=192.9520; Molecular weight=194.08
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[N+:11]([C:14]1[CH:15]=[C:16]([S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20])[S:17][CH:18]=1)([O-:13])=[O:12]>C(#N)C>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:23]([NH:22][S:19]([C:16]2[S:17][CH:18]=[C:14]([N+:11]([O-:13])=[O:12])[CH:15]=2)(=[O:21])=[O:20])=[O:24])[N:7]=1
Reactant: COc1cc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1cc([N+](=O)[O-])cs1
Solvent: CC#N
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cc([N+](=O)[O-])cs2)n1
Temperature: 25 °C

Procedure:
To 1.4 g of 2-amino-4-methoxy-6-methylpyrimidine in 25 ml of anhydrous acetonitrile was added 2.4 g of 4-nitrothiophene-2-sulfonyl isocyanate with stirring at ambient temperature. After stirring for sixteen hours, the mixture was filtered and the precipitate washed with 1-chlorobutane. It melted at 155° with decomposition and showed an infrared absorption spectrum with peaks at 1700, 1620 and 1570 cm-1 consistent for the desired structure.
Reaction SMILES: Cl[C:2]([F:7])([F:6])[C:3]([O-])=O.[Na+].[CH:9]1[C:19]2[CH:18]=C[C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[C:14](=[O:24])[C:13]=2[CH:12]=[CH:11][CH:10]=1.O>COCCOCCOC>[F:6][C:2]1([F:7])[CH:18]2[CH:3]1[C:23]1[CH:22]=[CH:21][CH:20]=[CH:16][C:15]=1[C:14](=[O:24])[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:19]=12
Reactant: O=C([O-])C(F)(F)Cl
Reactant: O=c1c2ccccc2ccc2ccccc12
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: O=C1c2ccccc2C2C(c3ccccc31)C2(F)F
Yield: 45.1 %

Procedure:
A solution of sodium chlorodifluoroacetate (350 g) in diglyme (1400 mL) was added dropwise over 4 to 8 hours, preferably over 6 hours, to a solution of 5H-dibenzo[a,d]cyclo-hepten-5-one (25 g) in diglyme (500 mL), with stirring, and under nitrogen, maintaining the reaction temperature at 160°-165° C. The cooled reaction mixture was poured into water (1.8 L) and extracted with ether (1.8 L). The organic phase was washed with water, dried over sodium sulfate (Na2SO4), and evaporated. The residue was recrystallized from ethanol, then from acetone/hexane to give 14 g of 1,1-difluoro-1a,10b-dihydrodibenzo[a,e]cyclopropa[c]-cyclohepten-6(1H)-one.
Reaction SMILES: [OH:1][B:2]([OH:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH2:13](O)[CH2:14][CH2:15]O>C1(C)C=CC=CC=1>[O:1]1[CH2:15][CH2:14][CH2:13][O:12][B:2]1[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: OCCCO
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(B2OCCCO2)cc1
Reaction time: 6 h

Procedure:
A mixture of 4-(dihydroxyboryl)benzoic acid (30.00 g, 181 mmol) and 1,3-propanediol (15.20 g, 200 mmol) in toluene (750 mL) at 140° C. was stirred for 6 hours while collecting the water removed by azeotrope formation. The mixture was concentrated to provide the desired product.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(N=[N+]=[N-])cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: [N-]=[N+]=Nc1ccc(CBr)cc1
Temperature: 25 °C
Yield: 104.7 %

Procedure:
A mixture of p-azidotoluene (3.9 g), N-bromosuccinimide (5.5 g) and azobisisobutyronitrile (1.0 g) in carbon tetrachloride (30 ml) was heated under reflux in the dark under nitrogen for 18 h. The reaction mixture was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was dissolved in ether (50 ml) and filtered. Evaporation of solvent gave an oil (6.5 g) which was chromatographed on silica gel (200 g, Merck 7734). Elution with petroleum ether (b.p.40°-60°) gave the title compound as an oil (2.37 g). I.R. (Neat) 2120 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.Br[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N+:29]=1[O-:34]>O1CCOCC1.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>[C:22]([O:21][C:20]([NH:19][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[CH:15]=[C:16]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N+:29]=4[O-:34])[S:17][C:10]=23)=[C:2]([F:1])[CH:3]=1)=[O:26])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: [O-][n+]1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3cc(-c4cccc[n+]4[O-])sc23)c(F)c1
Yield: 57 %

Procedure:
A solution of 431 (460 mg, 0.94 mmol), 2-bromopyridine N-oxide (420 mg, 2.41 mmol), bistrimethyltin (294 μL, 465 mg, 1.42 mmol) and Pd(PPh3)4 (109 mg, 0.09 mmol) in dioxane (10 mL) was heated to reflux for 8 hrs under nitrogen. The reaction mixture was concentrated and purified by flash chromatography using the gradient 5-20% MeOH in EtOAc as an eluent yielding 432 (243 mg, 57% yield). LCMS: (M+H) 454.1.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=3)[N:7]=[C:6]([C:18]([F:21])([F:20])[F:19])[CH:5]=2)[CH2:3][CH2:2]1.[Cl:22]N1C(=O)CCC1=O>CN(C=O)C>[Cl:22][C:5]1[C:6]([C:18]([F:19])([F:20])[F:21])=[N:7][N:8]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=2)[C:4]=1[CH:1]1[CH2:2][CH2:3]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=[N+]([O-])c1ccc(-n2nc(C(F)(F)F)cc2C2CC2)nc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2nc(C(F)(F)F)c(Cl)c2C2CC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.2 %

Procedure:
Intermediate 16 (1.5 g, 5.0 mmol) was dissolved in DMF and to this N-Chlorosuccinimide (0.8 g, 6 mmol) was added at 0° C. Then reaction was allowed to stir at rt for 2 h. After completion of the reaction, work up (EtOAc) and purification afforded the title compound (0.802 g). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.34 (d, J 2.5, 1H), 8.65 (dd, J 2.5, 9, 1H), 8.09 (d, J 9, 1H), 2.48-2.38 (m, 1H), 1.13-1.03 (m, 2H), 0.90-0.82 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:23][C@@H:24]([C:26]5[O:27][CH:28]=[C:29]([CH2:31]OS(C)(=O)=O)[N:30]=5)[CH3:25])=[O:22])=[CH:19][N:18]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[C-:45]#[N:46].[Na+]>CN(C=O)C>[C:45]([CH2:31][C:29]1[N:30]=[C:26]([C@H:24]([NH:23][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:42])([CH3:44])[CH3:43])[CH:19]=2)=[O:22])[CH3:25])[O:27][CH:28]=1)#[N:46]
Reactant: [C-]#N
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1nc(COS(C)(=O)=O)co1
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1nc(CC#N)co1
Temperature: 80 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
In a round-bottomed flask, methanesulfonic acid 2-((R)-1-{[2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-ethyl)-oxazol-4-ylmethyl ester (146 mg, 0.18 mmol) was dissolved in DMF (0.5 ml). Sodium cyanide (27 mg, 0.55 mmol) was added and the reaction mixture was stirred at 80° C. overnight. The reaction was cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-60% EtOAc) to isolate 37 mg (36%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyanomethyl-oxazol-2-yl)-ethyl]-amide as a yellow solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O>[F:12][C:8]1[C:9]([N+:1]([O-:4])=[O:2])=[CH:10][CH:11]=[C:6]([F:5])[C:7]=1[C:13]1[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])O
Reactant: Fc1cccc(F)c1-c1ccncc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(F)c(-c2ccncc2)c1F
Reaction time: 0.75 h
Yield: 88 %

Procedure:
A mixture of cold (0° C.) concentrated nitric acid (20.4 ml) and concentrated sulfuric acid (20.4 ml) was added in portions to a stirred solution of 10 g 4-(2,6-difluorophenyl)-pyridine in 56 ml concentrated sulfuric acid at 0° C. After 45 minutes at 0° C., the mixture was poured onto ice and the resulting solution was neutralized with solid sodium bicarbonate. The neutralized solution was then extracted twice with ethyl acetate and the organic extracts were dried and evaporated to give the product as a white solid of m p. 110°-112° C. (10.9 g, 88% yield). NMR (CDC13, 60 MHz): 8.8 (m, 2H), 8.2 (m, 1H), 7.0-7.6 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:45][S:46]([NH2:49])(=[O:48])=[O:47].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:45][S:46]([NH:49][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:20])([F:19])[F:1])[CH:4]=2)=[CH:11][CH:12]=1)(=[O:48])=[O:47]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1ccc(Nc2cccc(C(F)(F)F)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC(=O)c1ccc(Nc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 170.2 %

Procedure:
To a solution of 4-(3-(trifluoromethyl)phenylamino)benzoic acid (150 mg, 0.533 mmol) in DMF (4 mL) were added HATU (243 mg, 0.640 mmol), methanesulfonamide (152 mg, 1.60 mmol) and DIPEA (0.296 mL) and the reaction stirred at room temperature for 16 hours. Methanesulfonamide (152 mg, 1.60 mmol) was added and the reaction stirred at room temperature for 72 hours. After this time the reaction was quenched by the addition of potassium hydrogen sulfate (20 mL) and the aqueous extracted with dichlormethane (3×20 mL). The combined organics were washed with brine (40 mL), filtered through a phase separation cartridge and then the solvent was removed under reduced pressure to give an oil (325 mg). The crude was purified by preparative HPLC to give the title compound.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=4[N:14]([CH3:22])[CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][C:25]=1[C:34]([F:37])([F:36])[F:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([N:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:20]5[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=5[N:14]([CH3:22])[CH:13]=4)=[CH:9][CH:10]=3)[CH2:5][CH2:4]2)=[O:32])=[CH:26][C:25]=1[C:34]([F:35])([F:36])[F:37]
Reactant: Cn1cc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1ccc(F)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1cc(-c2ccc3c(c2)CCN3C(=O)Cc2ccc(F)c(C(F)(F)F)c2)c2c(N)ncnc21
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
A solution of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2HCl (150 mg, 0.443 mmol), [4-fluoro-3-(trifluoromethyl)phenyl]acetic acid (99 mg, 0.443 mmol), HATU (169 mg, 0.443 mmol), and DIEA (0.310 mL, 1.774 mmol) was stirred at room temperature overnight. LCMS analysis indicated good conversion, so the resulting suspension was poured into water (10 mL) and stirred for 30 min, forming a precipitate. This precipitate was collected by filtration, dried at the pump for an hour, then adsorbed onto silica and purified by flash chromatography (0-8% MeOH in EtOAc, 12-g column) to afford 5-(1-{[4-fluoro-3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (198 mg, 95% yield) as a white solid. LC-MS (ES) m/z=470 [M+H]+. 1H NMR (400 MHz, DMSO-d6) ppm 3.26 (t, J=8.46 Hz, 2H), 3.74 (s, 3H), 4.02 (s, 2H), 4.27 (t, J=8.34 Hz, 2H), 5.91-6.20 (m, 2H), 7.19-7.29 (m, 2H), 7.33 (s, 1H), 7.50 (t, J=9.73 Hz, 1H), 7.64-7.70 (m, 1H), 7.73 (d, J=6.57 Hz, 1H), 8.11 (d, J=8.34 Hz, 1H), 8.15 (s, 1H).
Reaction SMILES: I[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH2:10].[CH3:11][S:12]([C:15]([S:34]([CH3:37])(=[O:36])=[O:35])=[N:16][CH2:17][C:18]([N:20]1[CH:24]2[CH2:25][CH:26]3[C:29]([CH3:31])([CH3:30])[C:23]2([CH2:28][CH2:27]3)[CH2:22][S:21]1(=[O:33])=[O:32])=[O:19])(=[O:14])=[O:13]>>[CH3:11][S:12]([C:15]([S:34]([CH3:37])(=[O:36])=[O:35])=[N:16][CH:17]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH2:10])[C:18]([N:20]1[CH:24]2[CH2:25][CH:26]3[C:29]([CH3:31])([CH3:30])[C:23]2([CH2:28][CH2:27]3)[CH2:22][S:21]1(=[O:32])=[O:33])=[O:19])(=[O:14])=[O:13]
Reactant: C=Cc1ccccc1CI
Reactant: CC1(C)C2CCC13CS(=O)(=O)N(C(=O)CN=C(S(C)(=O)=O)S(C)(=O)=O)C3C2
Product: C=Cc1ccccc1CC(N=C(S(C)(=O)=O)S(C)(=O)=O)C(=O)N1C2CC3CCC2(CS1(=O)=O)C3(C)C

Procedure:
In step c, the appropriate 1-iodomethyl-2-vinyl-benzene derivative of structure (3) is subjected to an addition, elimination reaction with 2-(bis-methylsulfonyl-methyleneamino)-1-(10,10-dimethyl-3,3-dioxo-3-thia-4-aza-tricyclo[5.2.1.0 1,5]dec-4-yl)-ethanone (4) to give the corresponding 2-(bis-methylsulfonyl-methyleneamino)-1-(10,10-dimethyl-3,3-dioxo-3-thia-4-aza-tricyclo[5.2.1.0 1,5]dec-4-yl)-3-(2-vinyl-phenyl)-propan-1-one derivative of structure (5).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][OH:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].N1C=CN=C1.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(Cl)Cl>[C:18]([Si:21]([CH3:23])([CH3:22])[O:11][CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)([CH3:20])([CH3:19])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1cccc(CO)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
A solution of compound 2 (4.7 g, 0.03 mol) and imidazole (2.71 g, 0.04 mol) in dry CH2Cl2 (30 mL) under N2 atmosphere at 0° C. was added a solution of TBDMS-Cl (5.08 g, 0.033 mol) in CH2Cl2 (15 mL) and allowed to stir at room temperature for 2 h. The precipitated solid was isolated by filtration and washed with CH2Cl2 (5×20 mL). The filtrate and combined CH2Cl2 fractions were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude mass was purified by column chromatography (silica gel, eluant=3:7 mixture of ethyl acetate and hexane) to afford compound 3 (7.2 g, 90%) as a liquid.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([N:19]1[CH2:27][CH:26]2[CH:21]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:23][CH2:24][C:25]2=[O:28])[CH2:20]1)=[O:18])=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([N:19]1[CH2:27][CH:26]2[CH:21]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:23][CH2:24][C:25]2=[O:28])[CH2:20]1)=[O:18]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Agent: Cl
Solvent: C1COCCO1
Product: NCc1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Yield: 61.4 %

Procedure:
(3aRS,7aRS)-2-[(2-(tert-butoxycarbonylaminomethyl)phenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (1 g) is treated with a 5.7N solution (10 cc) of hydrochloric acid in dry dioxane at 20° C. for 16 hours. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is solidified by scratching with isopropyl ether and reprecipitated by cooling a solution in boiling acetonitrile (20 cc). The solid is drained, washed with isopropyl ether and dried. The solid is dissolved in water, the solution is filtered, rendered alkaline to pH 10 by the action of a decinormal sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and filtered and the filtrate is treated with a 3N solution (1 cc) of hydrochloric acid in dioxane. The precipitate is drained, washed with isopropyl ether and dried. (3aRS,7aRS)-2-[(2-aminomethylphenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (0.5 g) is obtained in the form of a cream-white solid.