Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[O:10](CC)CC.Cl.[C:16]1([C:22]2([C:35]#N)[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC1C=CC=CC=1>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:35]([C:22]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)=[O:10])=[CH:4][CH:5]=1
Reactant: N#CC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: Fc1ccc(Br)cc1
Reactant: CCOCC
Agent: Cl
Agent: [Mg]
Solvent: Cc1ccccc1
Product: O=C(c1ccc(F)cc1)C1(c2ccccc2)CCN(Cc2ccccc2)CC1
Yield: 81 %

Procedure:
To a stirred and refluxing Grignard-complex previously prepared starting from 14.6 parts of magnesium and 105 parts of 1-bromo-4-fluorobenzene in 450 parts of 1,1'-oxybisethane, was added dropwise a solution of 94 parts of 4-phenyl-1-(phenylmethyl)-4-piperidinecarbonitrile monohyrochloride in 360 parts of methylbenzene. About 250 parts of 1,1'-oxybisethane were distilled off at an internal temperature of 60°-65° C. The turbid solution was stirred and refluxed for 5 hours. The reaction mixture was decomposed with a saturate ammonium chloride solution in water. The layers were separated and the organic phase was dried, filtered and evaporated. The oily residue was boiled in a dilute hydrochloric acid solution. After cooling, the whole was alkalized with ammonium hydroxide and extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of 2-propanol and 2,2'-oxybispropane, yielding 91 parts (81%) of (4-fluorophenyl)[4-phenyl-1-(phenylmethyl)-4-piperidinyl]methanone; mp. 147.6° C. (intermediate 13).
Reaction SMILES: BrCC([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])([CH3:14])[CH3:13])=O.[C:22]([NH2:25])(=[S:24])[CH3:23].[CH2:26](O)[CH3:27]>>[CH3:14][C:12]([NH:15][C:16](=[O:21])[C:17]([F:18])([F:19])[F:20])([CH3:13])[CH2:11][C:6]1[CH:5]=[CH:10][C:9]([C:26]2[N:25]=[C:22]([CH3:23])[S:24][CH:27]=2)=[CH:8][CH:7]=1
Reactant: CCO
Reactant: CC(N)=S
Reactant: CC(C)(Cc1ccccc1C(=O)CBr)NC(=O)C(F)(F)F
Product: Cc1nc(-c2ccc(CC(C)(C)NC(=O)C(F)(F)F)cc2)cs1
Temperature: 80 °C

Procedure:
In a round-bottomed flask, N-[2-(bromoacetyl-phenyl)-1,1-dimethyl-ethyl]-2,2,2-trifluoroacetamide (388 mg, 1.06 mmol) and thioacetamide (80 mg, 1.06 mmol) were dissolved in ethanol (10 ml), and the mixture was heated to about 80° C. for about two and one-half hours. The reaction mixture was then concentrated in vacuo to an oil which was carried into the next reaction without further purification. LRMS ([M+1]+)=343.2.
Reaction SMILES: II.[CH2:3](Br)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH:22]([O:24][CH2:25][CH3:26])=[O:23].OS(O)(=O)=O>CCOCC>[CH:22]([O:24][CH:25]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:26][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:23]
Reactant: CCOC=O
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCBr
Agent: II
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)OC=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.9 %

Procedure:
To a suspension of Mg turnings (1.64 g, 67.4 mmol) with one crystal of iodine in 500 mL of anhydrous ether under nitrogen was added a solution of linoleyl bromide (II, 18.5 g, 56.1 mmol) in 250 mL of anhydrous ether at room temperature. The resulting mixture was refluxed under nitrogen overnight. The mixture was cooled to room temperature. To the cloudy mixture under nitrogen was added dropwise ethyl formate (4.24 g, 57.2 mmol). Upon addition, the mixture was stirred at room temperature overnight. The mixture was treated with 10% H2SO4 aqueous solution (250 mL). The ether phase was separated and aqueous phase extracted with ether (150 mL). The combined organic phase was washed with water (400 mL), brine (300 mL), and then dried over anhydrous Na2SO4. Evaporation of the solvent gave 17.8 g of yellowish oil as a crude product (III). The crude product was used directly in the following step without further purification.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[C:18](=[O:29])[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=1[F:28])(C)(C)C.FC(F)(F)C(O)=O>ClCCl.O>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][NH:19][C:18]([C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]([OH:30])=[O:5])=[O:29])=[C:22]([F:28])[CH:23]=1
Reactant: CC(C)(C)OC(=O)COc1ccc([N+](=O)[O-])cc1C(=O)NCc1ccc(Br)cc1F
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COc1ccc([N+](=O)[O-])cc1C(=O)NCc1ccc(Br)cc1F
Reaction time: 24 h
Yield: 92 %

Procedure:
A solution of [2-(4-bromo-2-fluoro-benzylcarbamoyl)-4-nitro- phenoxy]-acetic acid tert-butyl ester in dichloromethane (11mL, 0.2 M) was treated with trifluoroacetic acid (3.0 mL, 4.44 g. 39.0 mmol) and stirred for 24 h. The reaction was diluted with H2O and extracted with ethyl acetate (3×). The combined organic extracts were washed with H2O (2×), saturated aq NaCl, dried over MGSO4, filtered and concentrated to a crude solid that was recrystallized from heptane and ethyl acetate to give [2-(4-bromo-2-fluoro-benzylcarbamoyl)-4-nitro-phenoxy]-acetic acid as a white crystalline solid (0.98 g, 92%); Rf 0.10 (10% ethyl acetate in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 9.14 (br t, J=6.0 Hz, 1H), 8.58 (d, J=3.3 Hz, 1H), 8.34 (dd, J1=9.0 Hz, J2=3.0 Hz, 1H), 7.52 (br dd, J1=9.3 Hz, J2=3.0 Hz, 1H), 7.43-7.32 ( m, 3H), 5.02 (s, 2H), 4.52 (d, J=6.0 Hz, 2H). ESI-LC/MS m/z calcd for C16H12BrFN2O6: 426.0 found 427.0 (M+1)+. Anal. calcd for C16H12BrFN2O6: C, 25 44.99; H, 2.83; N, 6.56. Found C, 44.97; H, 2.83; N, 6.47.
Reaction SMILES: Br[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1>>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: O=C1C=C(Br)CCC1
Product: COc1cccc(C2=CC(=O)CCC2)c1
Yield: 88 %

Procedure:
Synthesized from 3-bromocyclohex-2-enone and 3-methoxyphenylboronic acid according to the general procedure described for the Suzuki coupling. Purification by automated flash chromatography using gradient elution (0 to 80% ethyl acetate/hexanes) yielded the product (141 mg, 88%) as a pale yellow solid. 1H NMR (300 MHz, CDCl3): δ 7.30 (t, J=8.0 Hz, 1H), 7.10 (dd, J=8.0, 0.8 Hz, 1H), 7.03 (t, J=2.2 Hz, 1H), 6.93 (dd, J=8.3, 2.5 Hz, 1H), 6.39 (bs, 1H), 3.82 (s, 3H), 2.75 (td, J=6.1, 0.8 Hz, 2H), 2.48 (t, J=6.3 Hz, 2H), 2.14 (quintet, J=6.1 Hz, 2H).
Reaction SMILES: [OH:1][C@@H:2]([CH:4]1[CH:7]([C:8]([O:10]CC2C=CC=CC=2)=[O:9])[NH:6][C:5]1=[O:18])[CH3:3]>CO.[Pd]>[OH:1][C@@H:2]([CH:4]1[CH:7]([C:8]([OH:10])=[O:9])[NH:6][C:5]1=[O:18])[CH3:3]
Reactant: C[C@@H](O)C1C(=O)NC1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@@H](O)C1C(=O)NC1C(=O)O

Procedure:
3(b) 500 mg of the benzyl 3-[(R)-1-hydroxyethyl]-2-oxoazetidine-4-carboxylate (prepared as described in above) were dissolved in 5 ml of methanol, and the mixture was hydrogenated in the presence of 100 mg of a 10% w/w palladium-on-carbon catalyst at room temperature for 2 hours. At the end of this time, the catalyst was removed by filtration. The filtrate was concentrated by evaporation under reduced pressure, to give 310 mg of the title compound as a colorless oil.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:12][CH:13]=[CH2:14])=O)(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(Cl)Cl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[F:17][C:16]([F:18])([F:19])[C:15]([N:11]([CH2:12][CH:13]=[CH2:14])[CH2:10][CH2:9][NH2:8])=[O:20]
Reactant: C=CCN(CCNC(=O)OC(C)(C)C)C(=O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCN(CCN)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve N-(t-butyloxycarbonyl)-N'-(trifluoroacetyl)-N'-(allyl)-ethylenediamine (1.95 mmol) in methylene chloride (7 mL) and add trifluoroacetic acid (2.6mL). Stir at room temperature for 1 hour then evaporate the solvent in vacuo to give N'-(trifluoroacetyl)-N'-(allyl)-ethylenediamine trifluoroacetate.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[NH:23][C:22](=[O:24])[C:21]4[C:16](=[CH:17][C:18]([O:27][CH3:28])=[CH:19][C:20]=4[O:25][CH3:26])[N:15]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:29][N:30]([CH3:34])[C:31](Cl)=[O:32].CCN(CC)CC.[OH-].[Na+]>C1COCC1>[CH3:26][O:25][C:20]1[CH:19]=[C:18]([O:27][CH3:28])[CH:17]=[C:16]2[C:21]=1[C:22](=[O:24])[NH:23][C:14]([C:11]1[CH:12]=[CH:13][C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][C:31](=[O:32])[N:30]([CH3:34])[CH3:29])[CH2:7][CH2:6]3)=[CH:9][CH:10]=1)=[N:15]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(N)CC4)cc3)nc2c1
Reactant: CN(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(NC(=O)N(C)C)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.4 %

Procedure:
A mixture of 2-(4-(4-aminopiperidin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.105 g, 0.28 mmol), dimethylcarbamic chloride (0.032 g, 0.30 mmol), and Et3N (0.085 g, 0.84 mmol) in THF (10 mL) was stirred at room temperature for 18 hours. The mixture was then heated at reflux for 24 hours, then cooled to room temperature. 2 M NaOH (20 mL) was added and the mixture was stirred for 30 minutes. The reaction mixture was adjusted to pH 8, extracted with CH2Cl2 (3×100 mL), dried over anhydrous MgSO4, filtered, and concentrated. The residue was dissolved in CHCl3/MeOH and concentrated, then CH3CN was added and concentrated to afford the title compound as a white solid (0.065 g, 51%): 1H NMR (300 MHz, CDCl3): δ 11.72 (s, 1H), 8.08 (d, J=9.0 Hz, 2H), 7.00 (d, J=9.0 Hz, 2H), 6.78 (d, J=2.2 Hz, 1H), 6.46 (d, J=2.2 Hz, 1H), 5.99 (d, J=7.8 Hz, 1H), 3.90-3.94 (m, 2H), 3.88 (s, 3H), 3.83 (s, 3H), 3.66-3.69 (m, 1H), 2.88-2.93 (m, 2H), 2.76 (s, 6H), 1.75-1.80 (m, 2H), 1.45-1.52 (m, 2H); ESI MS m/z 452 [M+H]+.
Reaction SMILES: C1(NS(=O)(=O)O)CCCCC1.[CH2:12]([N:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[NH:21])[CH2:13][CH2:14][CH3:15].[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=1[N:30]=[C:31]=[O:32]>>[CH2:12]([N:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[N:21][C:31]([NH:30][C:24]1[C:23]([CH3:22])=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:29])=[O:32])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN1CCCC1=N
Reactant: Cc1cccc(C)c1N=C=O
Agent: O=S(=O)(O)NC1CCCCC1
Product: CCCCN1CCCC1=NC(=O)Nc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The cyclohexylsulfamic acid salt of 1-n-butyl-2-iminopyrrolidine (15.97 g.; 0.05 mole) is converted to free base (7.01 g.; 0.05 mole) in the usual manner. After drying over K2CO3, the benzene solution is filtered through diatomaceous earth and 7.36 g. (0.05 mole) of 2,6-dimethylphenylisocyanate is added. The reaction mixture is stirred at room temperature for 31/2 hours and then evaporated to dryness in vacuo leaving an oily residue which crystallizes on cooling. Recrystallization from ethylacetate yields the pure product, 1-(1-n-butyl-2-pyrrolidylidene)-3-(2,6-dimethylphenyl)urea, m.p.=93°-95° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[CH3:19][N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:26][CH:23]1[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]1)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Reactant: CN1CCC(N)CC1
Product: COc1ccc2nc3cc(Cl)ccc3c(NC3CCN(C)CC3)c2c1

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 6,9-dichloro-2-methoxyacridine and 1-methylpiperidin-4-amine, the title compound was obtained; MS (Found M+1=356).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13].CC([O-])(C)C.[K+].C1COCC1.C(O)(=O)C>C1COCC1.O>[C:15]1([S:12]([CH2:11][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(CCl)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccccc1CS(=O)(=O)c1ccccc1
Temperature: -30 °C
Yield: 81 %

Procedure:
A solution of nitrobenzene (3.08 g, 25.0 mmol) and chloromethylphenylsulfone (4.76 g, 25.0 mmol) in dry THF is cooled to −50° C. and treated with 1.0M KOtBu/THF (55.0 mL, 55.0 mmol). The reaction is allowed to warm to −30° C. over 1 h, treated with glacial acetic acid (3.6 mL), warmed to 20° C., treated with water and extracted with CH2Cl2. The combined extracts are dried over MgSO4 and concentrated in vacuo. Chromatography (1:1 ethyl acetate:hexanes) of the resultant residue give the title product as a white solid, 5.62 g, (81% yield), mp 106-108° C., identified by mass spectral and HNMR analyses.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](OC(F)(F)F)[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:3]=1.[OH:30][C@H:31]1[CH2:35][NH:34][C:33](=[O:36])[CH2:32]1.[C:37](=O)([O-])[O-].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>ClCCl.[Cu]I.COCCOCCOC>[O:29]=[S:20]1(=[O:28])[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[CH2:23][N:17]([C:4]2[CH:3]=[C:2]([N:34]3[CH2:35][C@H:31]([OH:30])[CH2:32][C:33]3=[O:36])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:37])[CH:10]=3)[N:5]=2)[CH2:18][CH2:19]1
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(OC(F)(F)F)ccc3n2)Cc2ccccc21
Reactant: O=C1C[C@@H](O)CN1
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOCCOC
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3C[C@H](O)CC3=O)c2c1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (400 mg, 0.96 mol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1), (4R)-4-hydroxypyrrolidin-2-one (116.3 mg, 1.15 mmol), copper(I) iodide (90 mg, 0.47 mmol), potassium carbonate (265 mg, 1.92 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.1 mL, 0.63 mmol) and diethylene glycol dimethyl ether (10 mL) was heated with stirring in a 10 mL of microwave process vial for 2 hours at 140° C. The mixture was diluted with dichloromethane, washed with water. The aqueous was back extracted with dichloromethane. The combined organic layer was dried over sodium sulfate, filtered, concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 160 mg of produce as a gray solid. MS obsd. (ESI+) [(M+H)+] 438, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.96 (d, J=7.2 Hz, 1 H), 7.88 (dd, J=1.2, 8.0 Hz, 1 H), 7.64 (td, J=1.2, 7.6 Hz, 1 H), 7.56 (d, J=8.8 Hz, 1 H), 7.48 (dd, J=6.8, 7.6 Hz, 1 H), 7.40 (m, 2 H), 7.24 (s, 1 H), 5.51 (d, J=3.6 Hz, 1 H), 5.13 (s, 2 H), 5.55 (d, J=2.4 Hz, 1 H), 4.41 (brs, 2 H), 4.08 (dd, J=4.8, 10.0 Hz, 1 H), 3.66 (s, 2 H), 3.52 (d, J=9.6 Hz, 1 H), 2.87 (dd, J=6.4, 16.8 Hz, 1 H), 2.36 (dd, J=2.0, 16.8 Hz, 1 H), 2.36 (s, 3 H).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][C:4]#[CH:5].Br[C:8]1[CH:9]=[C:10]2[C:14](=[C:15]([Cl:17])[CH:16]=1)[C:13](=[O:18])[N:12]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)[CH2:11]2.C(Cl)(Cl)Cl.CO>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:17][C:15]1[CH:16]=[C:8]([C:5]#[C:4][CH2:3][N:2]([CH3:6])[CH3:1])[CH:9]=[C:10]2[C:14]=1[C:13](=[O:18])[N:12]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)[CH2:11]2
Reactant: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(C)CC#Cc1cc(Cl)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 103 %

Procedure:
A mixture of dimethyl-prop-2-ynyl-amine (0.036 mL, 0.32 mmol), 5-bromo-7-chloro-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.120 g, 0.28 mmol), PdCl2(PPh3)2 (0.011 g, 0.015 mmol), and CuI (0.0028 g, 0.015 mmol) in diisopropyl amine (4 mL) was stirred at 100° C. for 2 h. Workup and silica gel column chromatography using 10:1 CHCl3-MeOH afforded 7-chloro-5-(3-dimethylamino-prop-1-ynyl)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.122 g, 79%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.36 (s, 6H), 3.44 (s, 2H), 4.21 (s, 2H), 4.77 (s, 2H), 7.14-7.36 (m, 5H), 7.43 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])[CH3:4].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[OH:1][CH2:2][C@@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])[CH3:4]
Reactant: C[C@@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: C[C@@H](CO)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35.7 %

Procedure:
In a sealed 25 mL round-bottom flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide (41 mg, 0.080 mmol) and TFA (0.6 ml, 7.8 mmol) were combined with dichloromethane (2 ml) to give an orange solution. The reaction mixture was stirred at room temperature until the consumption of starting material (2.5 h). The reaction mixture was then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (2 mL) and ethylenediamine (400 μl, 5.9 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (9:1 dichloromethane/MeOH) to afford 11 mg (36%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide as an off-white solid. MS: [M+H]+=385; 1H NMR (300 MHz, DMSO-d6) δ: 12.84 (br. s., 1H), 9.13 (s, 1H), 8.66 (d, J=8.7 Hz, 1H), 8.43 (s, 1H), 8.21 (d, J=8.3 Hz, 1H), 7.91-8.04 (m, 1H), 7.32 (dd, J=8.7, 1.5 Hz, 1H), 5.09 (t, J=5.1 Hz, 1H), 4.18 (s, 3H), 4.08-4.33 (m, 1H), 3.58 (t, J=4.7 Hz, 2H), 1.28 (d, J=6.8 Hz, 3H).
Reaction SMILES: O([C:8]1[CH:9]=[C:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[CH:12][CH:13]=1)C1C=CC=CC=1.[C:20](C1C=C(CC(O)=O)C=CC=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.S(=O)(=O)(O)O>C(O)C>[C:20]([C:8]1[CH:9]=[C:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[CH:12][CH:13]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)Cc1cccc(C(=O)c2ccccc2)c1
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2)c1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)Cc1cccc(C(=O)c2ccccc2)c1

Procedure:
The procedure is as in Example 33 for the preparation of ethyl (3-phenoxyphenyl)acetate, starting with (3-benzoylphenyl)acetic acid (16.6 g) and 36N aqueous sulphuric acid solution (2 cc) in ethanol (200 cc). Ethyl (3-benzoylphenyl)acetate (16.8 g) is obtained in the form of a brown oil, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C.O>CN1CCCC1=O>[F:8][C:4]1[N:3]=[C:2]([NH:16][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(CN)cc1
Reactant: Fc1cccc(F)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2cccc(F)n2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To 2,6-difluoro-pyridine (49, 100 g, 869 mmol) in 500 mL of N-methylpyrrolidinone, 4-methoxy-benzylamine (77, 136 mL, 1.043 mol) and N,N-diisopropylethylamine (304 mL, 1.738 mol) were added. The reaction was stirred at 90° C. overnight, then poured into 8 L of water. The precipitate collected by filtration and washed with water, then taken up in ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was triturated with heptane and collected by filtration to provide the desired compound (78, 151 g, 650 mmol, 74.8% yield).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.O>[OH:28][CH2:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](CO)C2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](CO)C2)c(-c2cncnc2)c1

Procedure:
(R)-5-Bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 75.1, 60 mg, 0.13 mmol), pyrimidin-5-ylboronic acid (24.2 mg, 0.196 mmol), Pd(PPh3)2Cl2 (9.15 mg, 0.013 mmol) and Na2CO3 (41.5 mg, 0.391 mmol) were added to a MW vial and treated with a mixture of DME (553 μL), water (158 μL) and EtOH (79 μL). The vial was sealed, evacuated/purged with argon and was subjected to MW irradiation at 80° C. for 2 h. The RM was diluted with THF (1 mL), treated with Si-Thiol (Silicycle, 1.27 mmol/g, 51.3 mg, 0.065 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 12, 25% for 0.2 min then 25% to 55% in 12 min) to yield the title compound as a white solid. UPLC-MS (condition 1) tR=2.13 min, m/z=460.1-461.1 [M+H]+, m/z=458.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.53-1.64 (m, 1H) 1.81-1.90 (m, 1H) 2.19-2.28 (m, 1H) 2.97 (dd, J=10.76, 6.85 Hz, 1H) 3.15-3.39 (m, 5H) 4.61 (t, J=5.01 Hz, 1H) 7.35 (d, J=8.80 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.09 (d, J=2.20 Hz, 1H) 8.79 (d, J=2.20 Hz, 1H) 8.89 (s, 2H) 9.19 (s, 1H) 10.17 (s, 1H).