Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2].Br[C:14]1[S:18][C:17]([C:19]([O:21]CC)=[O:20])=[N:16][C:15]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([C:31]#[N:32])[CH:25]=1.C(=O)(O)[O-].[Na+]>COCCOC.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>[C:31]([C:26]1[CH:25]=[C:24]([C:15]2[N:16]=[C:17]([C:19]([OH:21])=[O:20])[S:18][C:14]=2[C:5]2[CH:6]=[C:7]([F:9])[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:29]=[CH:28][C:27]=1[F:30])#[N:32]
Reactant: CCOC(=O)c1nc(-c2ccc(F)c(C#N)c2)c(Br)s1
Reactant: N#Cc1cc(F)cc(B(O)O)c1
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: COCCOC
Solvent: O
Product: N#Cc1cc(F)cc(-c2sc(C(=O)O)nc2-c2ccc(F)c(C#N)c2)c1

Procedure:
At room temperature, 244 mg (1.48 mmol) of the boronic acid from Example 22A are added to 350 mg (0.985 mmol) of the compound from Example 29A and 56.9 mg (0.049 mmol) of tetrakis(triphenylphosphine)palladium in 26 ml of DME. 252 mg (3.01 mmol) of sodium bicarbonate in 11 ml of water are subsequently added, and the mixture is stirred under, reflux for 1 h. The reaction solution is subsequently concentrated under reduced pressure and the residue is taken up in ethyl acetate and washed with a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). 97.6 mg (16% of theory) of the title compound having a purity of 61% are obtained.
Reaction SMILES: C([Li])(C)(C)C.C1C[O:9][CH2:8]C1.[CH2:11]([O:13][CH:14]([O:26][CH2:27][CH3:28])[N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24]#[N:25])=[CH:16]1)[CH3:12]>CN(C=O)C>[CH2:11]([O:13][CH:14]([O:26][CH2:27][CH3:28])[N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24]#[N:25])=[C:16]1[CH:8]=[O:9])[CH3:12]
Reactant: CCOC(OCC)n1cc(C#N)c2ccccc21
Reactant: C1CCOC1
Agent: [Li]C(C)(C)C
Solvent: CN(C)C=O
Product: CCOC(OCC)n1c(C=O)c(C#N)c2ccccc21
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl lithium (18.1 mL, 31 mmol, 1.7M in pentane) was added to a THF (100 mL) solution of 1-diethoxymethyl-1H-indole-3-carbonitrile (6.83 g, 28 mmol) at −78° C. The mixture was warmed to 10° C., stirred for 30 min at this temperature, cooled to −78° C. and heated with DMF (20 mL). The mixture was warmed to 10° C., stirred for 30 min at this temperature, cooled to −78° C. and quenched with a saturated aqueous solution of NaHCO3. The resulting mixture was treated with ether (200 mL); the organic layer was washed with water and brine, dried and evaporated to dryness. NMR (300 MHz, CDCl3, 8): 10.24 (s, 1H), 8.10 (d, J=7.7 Hz, 1H), 7.91 (d, J=7.7 Hz, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.43 (t, J=7.5 Hz, 1H), 7.34 (s, 1H), 3.80 (m, 2H), 3.52 (m, 2H), 1.26 (t, J=6.4 Hz, 1H).
Reaction SMILES: [NH2:1][NH2:2].[OH-].[Na+].[CH2:5]([O:12][C@H:13]([C@H:16]([C@@H:25]([C@@H:34]([CH2:36][O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[OH:35])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:14]=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO.O1CCCC1>[NH:1]([C:14]([C@@H:13]([C@H:16]([C@@H:25]([C@@H:34]([CH2:36][O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[OH:35])[O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:12][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:15])[NH2:2]
Reactant: NN
Reactant: O=C[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NNC(=O)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Temperature: 50 °C
Reaction time: 168 h

Procedure:
1.77 g (55.5 mmoles) of anhydrous hydrazine (which has been twice distilled over NaOH) are dissolved in 3 ml of absolute methanol and the solution is cooled in an ice bath. While stirring 3.0 g (5.55 mmoles) of 2,3,4,6-tetra-O-benzyl-D-glucose dissolved in 15 ml of absolute tetra-hydrofuran were added dropwise. After a few minutes the ice bath is removed and the solution is heated to 50° C. At this temperature the mixture is stirred for 7 days in closed flasks. Following this the excess hydrazine is drawn off with the solvent at room temperature in a rotary evaporator. For removal of the last traces of hydrazine the substance is dried for 48 hours with an oil pump running. A colorless viscous sirup remained, yield: 3.05 g (100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:22]=1[C:9]1([CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:22]=1[C:9]1([CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1)[CH2:8][CH:7]2[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)CC1CC2(CCN(C(=O)OC(C)(C)C)CC2)c2c(Br)cccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CC1CC2(CCNCC2)c2c(Br)cccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 100-mL of flask was charged with (±)-tert-butyl 7-bromo-3-(2-ethoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (500 mg, 1.1 mmol) dissolved in 20% TFA in CH2Cl2 solution (15 mL) at 0° C. The mixture was stirred for 0.5 h at 0° C. Then the mixture was concentrated to give crude (±)-ethyl 2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:15]([CH2:16][OH:17])[NH:14][C:13]1=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClS([N:23]=[C:24]=[O:25])(=O)=O.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:15]([CH2:16][O:17][C:24](=[O:25])[NH2:23])[NH:14][C:13]1=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C(N[C@@H]1C(=O)N[C@@H]1CO)OCc1ccccc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)OC[C@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
In 16 ml of dry dichloromethane is dissolved 0.50 g of (3S,4S)-3-benzyloxycarbonylamino-4-hydroxymethyl-2-azetidinone obtained in Example 37 and, on cooling at -15° C., 0.368 g of chlorosulfonyl isocyanate is added, followed by stirring for 30 minutes. A 15-ml aqueous solution of 0.72 g of sodium sulfite is added and the solution is warmed to room temperature, followed by stirring for 1 hour. The dichloromethane is distilled off under reduced pressure and the residue is extracted twice with ethyl acetate-tetrahydrofuran (3:1, v/v). The extract is washed with aqueous sodium chloride, dried over mangesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography [eluent: chloroform-ethyl acetate-methanol (40:55:5, v/v/v)] to give 0.323 g of (3S,4S)-3-benzyloxycarbonylamino-4-carbamoyloxymethyl-2-azetidinone.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH2:7]([NH2:9])[CH3:8]>CO>[CH3:6][O:5][C:1](=[O:4])[CH2:2][CH2:3][NH:9][CH2:7][CH3:8]
Reactant: CCN
Reactant: C=CC(=O)OC
Solvent: CO
Product: CCNCCC(=O)OC
Temperature: -20 °C
Reaction time: 2 h
Yield: 30.3 %

Procedure:
Methyl acrylate (5.22 g, 60.6 mmol) is dissolved in methanol (20 mL) and cooled to −20° C. Ethylamine (2 M in tetrahydrofuran, 47 mL, 94 mmol) is added via addition funnel and the reaction is allowed to stir at −20° C. for 2 hours. Solvents were then removed in vacuo and the residue is distilled under reduced pressure to afford the title compound as a colorless liquid (2.41 g, 30% yield). 1H NMR (CDCl3) δ 1.11 (t, 3H, J=7.02 Hz), 2.53 (t, 2H, J=6.58 Hz), 2.66 (q, 2H, J=7.02 Hz), 2.89 (t, 2H, J=6.58 Hz), 3.69 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[F:7][C:8]([F:21])([F:20])[C:9]1[CH:10]=[C:11]([CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1)[NH2:12]>>[F:7][C:8]([F:20])([F:21])[C:9]1[CH:10]=[C:11]([NH:12][C:1](=[O:5])[C:2]([NH:12][C:11]2[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=[C:9]([C:8]([F:7])([F:20])[F:21])[CH:10]=2)=[O:3])[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)C(=O)Cl
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Into a 250 mnL Schlenk vessel was placed 100 mL of dry TBF, 3.50 g of oxalyl chloride and 12.4 g of 3,5-bis(trifluoromethyl)aniline. The mixture was refluxed under argon for 12 hours and then allowed to cool. All of the solvent was removed in vacuo to leave a pale brown solid. This was washed with hexane and toluene and pumped dry. Yield 10.33 g.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16](OC)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].CO>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][OH:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCCc1ccccc1OCc1ccccc1
Temperature: 45 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a solution of methyl (2-benzyloxyphenyl)acetate (935 mg) in tetrahydrofuran (9.4 ml) was added sodium borohydride (600 mg) and the suspension was heated to 45° C. A mixture of methanol (3 ml) and tetrahydrofuran (6 ml) was added dropwise to the mixture and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane and quenched by 1 N aqueous hydrochloric acid solution. The organic layer was washed with brine, dried and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel [eluting with ethyl acetate - n-hexane (1:1)] to afford 2-(2-benzyloxyphenyl)ethanol (764 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:15]([O-:17])=[O:16])=[CH:5][C:4]=2[N:3]=1.[NH2:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>CN1C(=O)CCC1.CO>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][NH:18][C:2]2[C:11]3[CH:12]=[CH:13][S:14][C:10]=3[C:9]3[CH:8]=[CH:7][C:6]([C:15]([OH:17])=[O:16])=[CH:5][C:4]=3[N:3]=2)[CH:21]=1
Reactant: NCc1cccnc1
Reactant: O=C([O-])c1ccc2c(c1)nc(Cl)c1ccsc12
Solvent: CN1CCCC1=O
Solvent: CO
Product: O=C(O)c1ccc2c(c1)nc(NCc1cccnc1)c1ccsc12
Temperature: 120 °C
Reaction time: 17 h
Yield: 62 %

Procedure:
4-chlorothieno[3,2-c]quinoline-7-carboxylate (10 mg, 0.036 mmol) was suspended in NMP (0.1 ml) and 3-aminomethylpyridine (0.1 ml). The mixture was heated in a microwave oven at 120° C. for 10 nm. The reaction mixture was dissolved in a mixture of NMP and MeOH and the ester intermediate purified by preparative HPLC. After genevac evaporation of the solvents, the resulting solid was dissolved in a 1:1 mixture of THF and MeOH (0.6 ml). 5N aqueous LiOH (0.2 ml) was added and the mixture stirred at room temperature for 17 hrs. Water and aqueous HCl were added and the solution of 4-(pyridin-3-ylmethylamino)thieno[3,2-c]quinoline-7-carboxylic acid was purified by preparative HPLC. Removal of the solvents by genevac evaporation provided compound 4-(pyridin-3-ylmethylamino)thieno[3,2-c]quinoline-7-carboxylic acid as a white solid (10 mg, 62% yield). LCMS (ES): 95% pure, m/z 336 [M+1]+. 1H NMR (CDCl3, 400 MHz) δ 5.23 (s, 2H), 7.71-7.78 (m, 4H), 8.11 (d, J=5.6, 1H), 8.47 (d, J=8.0, 1H), 8.49 (d, J=0.8, 1H), 8.62 (d, J=5.2, 1H), 8.97 (s, 1H) ppm.
Reaction SMILES: F[C:2](F)(F)C([O-])=O.[CH2:8]([NH2+:15][CH:16]1[CH2:21][CH2:20][CH:19]([C@H:22]([CH3:40])[C@H:23]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:24]([N:26]2[CH2:30][CH2:29][C@H:28]([F:31])[CH2:27]2)=[O:25])[CH2:18][CH2:17]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(OCC)(=O)C>[C:36]([O:35][C:33](=[O:34])[NH:32][C@H:23]([C:24]([N:26]1[CH2:30][CH2:29][C@H:28]([F:31])[CH2:27]1)=[O:25])[C@H:22]([CH:19]1[CH2:20][CH2:21][CH:16]([N:15]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:2])[CH2:17][CH2:18]1)[CH3:40])([CH3:39])([CH3:38])[CH3:37]
Reactant: C[C@@H](C1CCC([NH2+]Cc2ccccc2)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Reactant: O=C([O-])C(F)(F)F
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@@H](C1CCC(N(C)Cc2ccccc2)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1

Procedure:
To a solution of the material prepared in Step A (0.25 g, 0.54 mmol) in methanol (6 mL) was added a 37% aqueous solution of formaldehyde (0.10 mL, 1.62 mmol), followed by sodium triacetoxyborohydride (0.46 g, 2.16 mmol). After 3 h at ambient temperature the reaction was diluted with 100 mL of ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried (magnesium sulfate) and concentrated in vacuo, affording the title compound as a clear oil. This material was used without further purification. LC/MS 476.5 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.F[C:14]1[CH:15]=C2C(=C[CH:23]=1)NC(=O)C=N2.C(=O)([O-])[O-].[K+].[K+].C(I)C=C>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:12])[N:9]2[CH2:15][CH:14]=[CH2:23])=[CH:4][CH:3]=1
Reactant: O=c1cnc2cc(F)ccc2[nH]1
Reactant: O=c1cnc2ccc(F)cc2[nH]1
Agent: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1c(=O)cnc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1:2 mixture of 7-fluoro-2(1H)-quinoxalinone and 6-fluoro-2(1H)-quinoxalinone (20 g, 0.122 mol) in dry DMF (250 ml) and anhydrous potassium carbonate (50.5 g, 0.38 mol) was treated with allyl iodide (12.3 ml, 0.134 mol) and the mixture was stirred at rt for 2 hours. The reaction mixture was evaporated to dryness, water was added and the mixture was extracted (3×) with DCM, washed with water, dried (sodium sulphate) and evaporated. It was chromatographed, twice, on silica gel, eluting with 0-40% ethyl acetate-hexane. The early fractions gave 7-fluoro-1-(2-propen-1-yl)-2(1H)-quinoxalinone (4.7 g) [later fractions contained the isomeric 6-fluoro-isomer (6.7 g)].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][C:22](OC)=[CH:23][C:17]=3[S:16][CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH2:27][C:28]1([NH2:32])[CH2:31][O:30][CH2:29]1>>[NH2:32][C:28]1([CH2:27][NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16][CH2:15][CH2:14]3)[CH:3]=2)[CH2:31][O:30][CH2:29]1
Reactant: COc1ccc2c(c1)SCCN(c1cc(Cl)c3cc(C)ccc3n1)C2
Reactant: NCC1(N)COC1
Product: Cc1ccc2nc(N3CCSc4ccccc4C3)cc(NCC3(N)COC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 4-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine in Example 1-1) and 3-aminomethyl-oxetan-3-ylamine. MS obsd. (ESI+) [(M+H)+] 407, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (s, 1 H), 7.74-7.67 (t, 2 H), 7.61 (d, J=8.4 Hz, 1 H), 7.55 (d, J=7.6 Hz, 1 H), 7.32 (t, 1 H), 7.26 (t, 1 H), 6.27 (s, 1 H), 5.19 (s, 2 H), 4.77-4.70 (m, 4 H), 4.35 (s, 2 H), 4.12 (s, 2 H), 3.16 (t, J=9.6 Hz, 2 H), 2.49 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22](Br)[CH:23]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1.B(O)(O)[C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:31]=4)[CH:23]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3cc(Br)ccc3C2=O)cc1
Product: Nc1ccccc1NC(=O)c1ccc(CN2Cc3cc(-c4ccc5ccccc5c4)ccc3C2=O)cc1
Reaction time: 0.33 h
Yield: 61 %

Procedure:
The procedure of Example 2 was repeated except that N-(2-aminophenyl)-4-((5-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 56 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and naphthalen-2-yl-2-boronic acid instead of phenyl boronic acid were used, and the reaction was performed for 20 mins, to obtain the title compound (61%).
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[C:14](=[O:18])[CH2:15][C:16]#[N:17])C.C(O)(=O)C.C([O-])(=O)C.[NH4+].C(N)(=O)C>C1C=CC=CC=1>[OH:18][C:14]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:7]=[C:8]([CH3:9])[C:15]=1[C:16]#[N:17]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: CC(N)=O
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: Cc1cc2ccccc2c(O)c1C#N
Temperature: 160 °C
Yield: 40.5 %

Procedure:
Phenyl-2-propanone (24.93 g, 0.178 mol) was combined with ethylcyanoacetate (19.8 mL, 0.180 mol), acetic acid (8.0 mL, 0.14 mol), ammonium acetate (2.82 g, 0.0370 mol) and 80 mL of benzene in a round bottom flask equipped with a Dean-Stark trap and condenser cooled by a chiller. The reaction was heated to 160° C. for 4 h. The mixture was removed from heat and the trap drained so that the mixture could be concentrated by distilling off excess (˜50 mL) benzene. The solution contained crude (E)-ethyl 2-cyano-3-methyl-4-phenylbut-2-enoate. The concentrated mixture was removed from heat and heat adjusted to 240° C. Acetamide (50.9483 g, 0.862 mol) was added, and a Claisen head attached to distill any ethanol resulting while the mixture was heated at 240° C. for 60-90 minutes. The mixture was cooled to ˜100° C., and poured into room temperature water to quench the reaction. A clumpy orange solid was formed, removed by filtration and triturated with ice cold absolute EtOH. The solid was filtered off and the process repeated 4 times to harvest additional material. The resulting product was a pale yellow fine powder (13.20 g, 36% yield). 1H-NMR: (300 MHz, DMSO-d6): δ 11.28 (s, 1H); 8.24 (d, J=8.4 Hz, 1H); 7.80 (d, J=8.0 Hz, 1H); 7.62-7.58 (m, 1H); 7.52-7.48 (m, 1H); 7.34 (s, 1H); 2.47 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH3:11])=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14].C(O)(=O)C>O1CCOCC1>[OH:1][C:2]1[C:7]2[C:8]([CH3:11])=[C:9](/[CH:14]=[CH:13]/[C:12]([O:16][CH2:17][CH3:18])=[O:15])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1coc2cccc(O)c12
Reactant: C=CC(=O)OCC
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1oc2cccc(O)c2c1C
Yield: 20.3 %

Procedure:
A mixture of 4-hydroxy-3-methylbenzofuran (2.9 g, 20 mmoles) palladium III acetate (4.5 g, 20 mmoles), ethyl acrylate (2 g, 20 mmoles), acetic acid (50 ml) and dioxane (200 ml) was refluxed for 3 hours. The mixture was filtered and the filtrate concentrated and chromatographed to obtain 1 g of the title compound after recrystallization from toluene, m.p. 180°-182° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([CH3:14])([CH3:13])[C:10]([NH2:12])=[O:11])#[CH:2].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([Cl:23])=[CH:18][N:17]=1.CCN(CC)CC>O1CCOCC1.[Cu]I.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>[Cl:15][C:16]1[N:21]=[C:20]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]([CH3:14])([CH3:13])[C:10]([NH2:12])=[O:11])[C:19]([Cl:23])=[CH:18][N:17]=1
Reactant: C#Cc1ccccc1C(C)(C)C(N)=O
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C(N)=O)c1ccccc1C#Cc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
A mixture of 2-(2-ethynylphenyl)-2-methylpropanamide A36 (0.060 g, 0.32 mmol), 2,4,5-trichloropyrimidine (48 μL, 0.42 mmol) and Et3N (0.18 mL, 1.3 mmol) in 1,4-dioxane (5 mL) was bubbled with N2 for 10 minutes. CuI (0.001 g, 0.006 mmol) and PdCl2(PPh3)2 (0.002 g, 0.003 mmol) were added and the reaction mixture was stirred at room temperature under a N2 atmosphere for 5.5 hours. The volatiles were removed in vacuo and the residue was purified by column chromatography (Biotage Isolera, 12 g SiO2 cartridge, 10-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A37 as an off-white solid (0.067 g, 63%). LCMS-D: rt 3.33 min; m/z 334 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[C:11]([C@@H:33]2[CH2:37][NH:36][C@H:35]([C:38]([OH:40])=[O:39])[CH2:34]2)[CH:12]=[CH:13][C:14]=1[C:15]1[S:16][C:17]2[C:22]([N:23]=1)=[CH:21][CH:20]=[C:19]([C:24]1([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:26][CH2:25]1)[N:18]=2.[C:41]([BH3-])#N.[Na+]>C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[C:11]([C@@H:33]2[CH2:37][N:36]([CH3:41])[C@H:35]([C:38]([OH:40])=[O:39])[CH2:34]2)[CH:12]=[CH:13][C:14]=1[C:15]1[S:16][C:17]2[C:22]([N:23]=1)=[CH:21][CH:20]=[C:19]([C:24]1([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][CH2:26]1)[N:18]=2
Reactant: [BH3-]C#N
Reactant: O=C(O)[C@@H]1C[C@H](c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CN1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN1C[C@@H](c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
To a slurry of (2S,4R)-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)pyrrolidine-2-carboxylic acid trifluoroacetic acid salt (0.048 g, 0.084 mmol) formaldehyde (0.050 mL, 0.67 mmol) acetic acid (0.048 mL, 0.84 mmol) in 2 mL ACN was added sodium cyanoborohydride (0.011 g, 0.17 mmol). After 1 h, the reaction mixture was concentrated, dissolved in DMSO/TFA, and purified by RPHPLC, gradient of ACN/TFA in H2O/TFA to give (2S,4R)-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)-1-methylpyrrolidine-2-carboxylic acid trifluoroacetic acid salt as a solid. MS (ESI) m/z: Calculated: 473.2; Observed: 474.1 (M++1).
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)=O.[C:20]([NH:23][CH2:24][CH2:25][NH2:26])(=[O:22])[CH3:21]>C(O)(=O)C>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([C:8]2[N:26]([CH2:25][CH2:24][NH:23][C:20](=[O:22])[CH3:21])[CH:2]=[CH:6][CH:7]=2)[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: CC(=O)NCCN
Reactant: COc1ccc(C(=O)CCC2OCCO2)cc1OC
Solvent: CC(=O)O
Product: COc1ccc(-c2cccn2CCNC(C)=O)cc1OC
Yield: 38.1 %

Procedure:
3-(1,3-Dioxolan-2-yl)-3',4'-dimethoxypropiophenone (6.3 g) was dissolved in 30 ml of acetic acid and added under argon and while stirring to a solution of 4.9 g of N-acetylethylenediamine in 50 ml of acetic acid. The reaction mixture was heated to reflux overnight, the acetic acid was subsequently removed in a vacuum. The residue was taken up in 150 ml of methylene chloride and washed with a mixture of 100 ml of saturated sodium hydrogen carbonate solution and 150 ml of 2N sodium hydroxide solution. The aqueous phase was back-extracted three times with 100 ml of methylene chloride each time, the organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 7.3 g of dark brown oil, was chromatographed on 250 g of silica gel with ethyl acetate as the eluent. 2.6 g (38%) of N-[2-[2-(3,4-dimethoxyphenyl)pyrrol-1-yl]-ethyl]acetamide were isolated as a brown oil.