Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH3:15])=[CH:4][C:5]([F:14])=[C:6]([CH:13]=1)[C:7]([NH:9][CH:10]1[CH2:12][CH2:11]1)=[O:8].[CH:16]1([CH2:19][NH:20][C:21](=[O:37])[C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.C(=O)([O-])O.[Na+]>CC(O)C.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:10]1([NH:9][C:7]([C:6]2[CH:13]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([C:21]([NH:20][CH2:19][CH:16]4[CH2:18][CH2:17]4)=[O:37])=[CH:23][CH:24]=3)[C:3]([CH3:15])=[CH:4][C:5]=2[F:14])=[O:8])[CH2:12][CH2:11]1
Reactant: CC1(C)OB(c2ccc(C(=O)NCC3CC3)cc2)OC1(C)C
Reactant: Cc1cc(F)c(C(=O)NC2CC2)cc1Br
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: CC(C)O
Product: Cc1cc(F)c(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Temperature: 90 °C

Procedure:
5-Bromo-N-cyclopropyl-2-fluoro-4-methylbenzamide (Intermediate 22, 30 mg), N-cyclopropylmethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamide (28 mg), tetrakis(triphenylphosphine)palladium (1 mg) and aqueous sodiumhydrogen carbonate (1M, 0.5 ml) were mixed in propan-2-ol (2 ml) and heated at 90° C. under nitrogen for 24 hrs. The reaction was absorbed onto silica and applied to a SPE (Si, 5 g) and eluted with an ethyl acetate/cyclohexane gradient (0–100% ethyl acetate). The product fractions were reduced to dryness under vacuum and the residue recrystallised from ethyl acetate to give N3-cyclopropyl-N4′-(cyclopropylmethyl)-4-fluoro-6-methyl-1,1′-biphenyl-3,4′-dicarboxamide.
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9](Br)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[C:19]1([C:9]2[C:8]3[C:17]4=[C:16]5[C:5](=[CH:6][CH:7]=3)[CH:4]=[CH:3][C:2]([Br:1])=[C:15]5[CH:14]=[CH:13][C:12]4=[CH:11][CH:10]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc2ccc3c(Br)ccc4ccc1c2c43
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
Product: Brc1ccc2ccc3c(-c4ccccc4)ccc4ccc1c2c43
Temperature: 100 °C
Yield: 64.9 %

Procedure:
Next, 18.0 g (50.0 mmol) of 1,6-dibromopyrene, 6.10 g (50.0 mmol) of phenylboronic acid, and 1.16 g (1.0 mmol, 2 mol %) of tetrakis(triphenylphosphine)palladium(0) were loaded into a 300-ml three-necked flask, and air in the container was replaced with argon. Further, 150 ml of toluene and 75 ml (3 eq) of a 2M aqueous solution of sodium carbonate were added to the mixture, and the whole was refluxed under heat in an oil bath at 100° C. for 8 hours. After one night, the precipitate was separated by filtration, and the filtrate (toluene solution) was purified by column chromatography, whereby 11.6 g of 1-phenyl-6-bromopyrene were obtained (64.6% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10](=[O:12])[NH:9][C@H:8]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@H:7]3[C:6]=2[CH:5]=[C:4]([CH2:23][CH2:24][CH3:25])[CH:3]=1.Br[C:27]1C=CC(C(N(CC)CC)=O)=C(Cl)C=1>>[Cl:1][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:27])[C@H:8]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:15][C@@H:7]3[C:6]=2[CH:5]=[C:4]([CH2:23][CH2:24][CH3:25])[CH:3]=1
Reactant: CCCc1cc(Cl)c2c(c1)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1NC2=O
Reactant: CCN(CC)C(=O)c1ccc(Br)cc1Cl
Product: CCCc1cc(Cl)c2c(c1)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1N(C)C2=O

Procedure:
Following the procedure described in Example 15, Part A, (3aR,9bS)-tert-butyl 6-chloro-5-oxo-8-propyl-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate, the first eluting compound from Example 23, Part J, was converted into the title compound. LRMS (ESI): 379.17/381.15 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([P:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Mg].[Si:22](OCC)([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25]>O1CCCC1>[CH2:24]([O:23][Si:22]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])[C:2]1[CH:7]=[CH:6][C:5]([P:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1)[CH3:25]
Reactant: Brc1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCO[Si](OCC)(OCC)OCC
Agent: [Mg]
Solvent: C1CCOC1
Product: CCO[Si](OCC)(OCC)c1ccc(P(c2ccccc2)c2ccccc2)cc1
Temperature: 55 °C
Yield: 63.6 %

Procedure:
To a Grignard reagent solution prepared from 4-bromophenyl diphenylphosphine (36 g, 0.1 mol) and magnesium (2.43 g, 0.10 g atom) in 130 ml of dry tetrahydrofuran, tetraethyl orthosilicate (54 g, 0.21 mol) is added and the solution heated at 55° C for 4 hours. The solvent is removed in vacuum leaving 27 grams of clear liquid, analyzing 50 percent product by gas-liquid chromatography. A sample separated by this means gave a H'NMR, delta (C6D6): 8.84 (t, 9H); 3.74 (q, 6H); 6.90-7.90 (m, 14H), consistent with the structure expected. The yield is 32 percent.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19](Br)[S:20][CH:21]=3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.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>[CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:31]#[C:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[S:20][CH:21]=3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)c3csc(Br)n3)cc2)C1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C1CCN(c2ccc(NC(=O)c3csc(C#Cc4ccccc4)n3)cc2)C1
Temperature: 150 °C

Procedure:
2-Bromothiazole-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (100 mg) was dissolved in tetrahydrofuran (2 ml), and phenylacetylene (52 mg), triethylamine (52 mg), triphenylphosphine (17 mg), bis(triphenylphosphine)palladium dichloride (89 mg) and copper (I) iodide (9.6 mg) were added. The reaction mixture was heated at 150° C. in a microwave apparatus for 3 minutes and then concentrated. The residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 416.55 (C24H24N4OS); MS (ESI): 417 (M+H+).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:42])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[CH2:29][CH2:28][C:27]([CH3:32])([CH3:31])[CH2:26][C:25]=5[N:24]([CH3:33])[N:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:42])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[CH2:29][CH2:28][C:27]([CH3:31])([CH3:32])[CH2:26][C:25]=5[N:24]([CH3:33])[N:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:6]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4c3CCC(C)(C)C4)nc12)C(=O)N1CC(C#N)C1
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4c3CCC(C)(C)C4)nc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
To a solution of 5-(2-trimethylsilanyl-ethoxymethyl)-2-(1,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (40 mg, 0.068 mmol) in CH2Cl2 (3 mL) was added TFA (1.5 mL, 19.5 mmol). The yellow reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was redissolved in CH2Cl2 (3 mL) and ethylenediamine (0.3 mL, 4.44 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 h then quenched with water and extracted with CH2Cl2 (3×). The combined organics were concentrated to a yellow oily solid. Trituration with EtOAc/Et2O gave 17 mg (55%) of 2-(1,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as an off-white solid. MS (M+H)+=461; 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 8.94 (d, J=2.0 Hz, 1H), 8.34-8.44 (m, 2H), 4.46-4.74 (m, 3H), 4.10-4.21 (m, 1H), 4.02 (dd, J=9.9, 6.4 Hz, 1H), 3.78-3.86 (m, 1H), 3.77 (s, 3H), 2.98-3.08 (m, 1H), 2.85-2.94 (m, 1H), 2.45 (s, 2H), 1.52 (t, J=6.4 Hz, 2H), 1.29-1.39 (m, 3H), 1.03 (s, 6H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([NH:20][NH2:21])=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17]>C(O)C.O>[CH:1](=[N:21][NH:20][C:14]1[CH:13]=[CH:12][C:11]([Cl:10])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NNc1ccc(Cl)cc1C(=O)O
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(Cl)ccc1NN=Cc1ccccc1
Reaction time: 1 h

Procedure:
A solution of benzaldehyde (1.48 g) in ethanol (10 ml) was added to a stirred suspension of 5-chloro-2-hydrazinobenzoic acid hydrochloride (described in U.S. Pat. No. 4,105,766; 5.2 g) in water (100 ml). Stirring was continued for 1 hour. The mixture was then left unstirred for 16 hours and then extracted with ether. The extracts were dried (MgSO4) and evaporated to give 2-(benzylidenehydrazino)-5-chlorobenzoic acid (3.5 g) which was used without purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1)=[O:7].[BH4-].[Na+]>CO.C(OCC)(=O)C.O>[OH:7][CH:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)c2nccs2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CC[C@H](C(O)c2nccs2)CC1
Reaction time: 1 h

Procedure:
To a solution of methyl trans-4-(1,3-thiazol-2-ylcarbonyl)cyclohexanecarboxylate (500 mg, 1.97 mmol) in methanol (20 mL) was added sodium borohydride (224 mg, 5.92 mmol) and the solution was stirred for one hour. The solution was then diluted with ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography to afford methyl trans-4-[hydroxy(1,3-thiazol-2-yl)methyl]cyclohexanecarboxylate. MS ESI calc'd. for C12H18NO3S [M+H]+ 256. found 256. 1H NMR (500 MHz, DMSO-d6) δ 7.70 (d, J=3.2 Hz, 1H), 7.58 (d, J=3.2 Hz, 1H), 6.10 (d, J=5.2 Hz, 1H), 4.59 (t, J=5.1 Hz, 1H), 3.54 (s, 3H), 2.21-2.11 (m, 1H), 1.92-1.83 (m, 2H), 1.75-1.64 (m, 1H), 1.64-1.53 (m, 2H), 1.33-1.11 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:7]2[C:8]3[C:13]([N:14]=[CH:15][C:6]2=[N:5][N:4]=1)=[CH:12][C:11]([Cl:16])=[C:10]([Cl:17])[CH:9]=3.[OH:20]O>CC(O)=O>[F:19][C:2]([F:1])([F:18])[C:3]1[N:7]2[C:8]3[C:13]([NH:14][C:15](=[O:20])[C:6]2=[N:5][N:4]=1)=[CH:12][C:11]([Cl:16])=[C:10]([Cl:17])[CH:9]=3
Reactant: FC(F)(F)c1nnc2cnc3cc(Cl)c(Cl)cc3n12
Reactant: OO
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2n2c(C(F)(F)F)nnc12
Temperature: 55 °C

Procedure:
800 mg (2.3 mmol) of the quinoxaline (9) was stirred in 22 ml HOAc, and 7 ml of 30% H2O2 was added. The reaction mixture was heated to 55° C. for 16 hours, and then cooled to room temperature. Filtering and drying the product yielded 330 mg of 1-trifluoromethyl-7,8-dichloro-1,2,4-triazolo [4,3-a]quinoxalin-4(5H)-one (10).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:24][C:25]([C:27]2[CH:36]=[C:35]([C:37]([NH:39][CH:40]([C:50]([O:52][CH3:53])=[O:51])[CH2:41][CH2:42][C:43]([O:45]C(C)(C)C)=[O:44])=[O:38])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:24][C:25]([C:27]2[CH:36]=[C:35]([C:37]([NH:39][CH:40]([C:50]([O:52][CH3:53])=[O:51])[CH2:41][CH2:42][C:43]([OH:45])=[O:44])=[O:38])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c2cc(C(=O)NC(CCC(=O)OC(C)(C)C)C(=O)OC)c3ccccc3n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)O)NC(=O)c2cc(C(=O)NC(CCC(=O)O)C(=O)OC)c3ccccc3n2)CC1
Yield: 115.5 %

Procedure:
Alternatively, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-[(1-(methoxycarbonyl)-3-(1,1-dimethylethoxycarbonyl)propyl)aminocarbonyl]quinoline (41 mg, 0.055 mmol) was treated with trifluoroacetic acid:methylene chloride (1:1, 0.6 mL) at ambient temperature for 2 hours. Evaporation of the reaction mixture, followed by dilution with methylene chloride, and repeated evaporation of the solvent gave 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-[(1-(methoxycarbonyl)-3-carboxypropyl)aminocarbonyl]quinoline (40 mg) as a trifluoroacetic acid salt; NMR (CD3OD) 1.25 (t, 3), 1.95 (m, 1), 2.18 (m, 2), 2.40 (m, 1), 2.45–2.55 (m, 4), 3.45–3.92 (m, 11), 4.16 (q, 2), 4.80 (m, 1), 5.25 (m, 1), 7.72 (t, 1), 7.86 (t, 1), 8.21–8.26 (m, 3) ppm.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:17])[CH3:16])[C@H:10]1[CH3:18].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:16])[CH3:17])[C@H:10]1[CH3:18]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cn[nH]c(=O)c1Br)C2(C)C
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Br)c1=O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 88.3 %

Procedure:
4-Bromo-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one (600 mg, 1.84 mmol) in N,N-dimethylformamide (6 mL) was mixed with ethyl bromoacetate (306 μL, 2.76 mmol) and potassium carbonate (381 mg, 2.76 mmol) at room temperature and stirred at 80° C. for 1.5 hours. After cooling, the reaction solution was mixed with saturated aqueous ammonium chloride and extracted with ethyl acetate. The resulting organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform/ethyl acetate=8/1) to give the desired product (670 mg, 88% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]([CH3:16])[C:13]([OH:15])=O)[C:7]1=[O:17])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:49][O:50][C:51](=[O:85])[NH:52][CH:53]([C:57]([N:59]1[CH2:63][CH2:62][CH2:61][CH:60]1[C:64]1[NH:65][C:66]([C:69]2[CH:74]=[CH:73][C:72]([C:75]3[CH:80]=[CH:79][C:78]([C:81](=[O:84])[CH2:82][NH2:83])=[CH:77][CH:76]=3)=[CH:71][CH:70]=2)=[CH:67][N:68]=1)=[O:58])[CH:54]([CH3:56])[CH3:55]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]([C:13](=[O:15])[NH:83][CH2:82][C:81]([C:78]2[CH:79]=[CH:80][C:75]([C:72]3[CH:71]=[CH:70][C:69]([C:66]4[NH:65][C:64]([CH:60]5[CH2:61][CH2:62][CH2:63][N:59]5[C:57](=[O:58])[CH:53]([NH:52][C:51]([O:50][CH3:49])=[O:85])[CH:54]([CH3:56])[CH3:55])=[N:68][CH:67]=4)=[CH:74][CH:73]=3)=[CH:76][CH:77]=2)=[O:84])[CH3:16])[C:7]1=[O:17]
Reactant: COC(=O)NC1CCCN(C(C)C(=O)O)C1=O
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(C(=O)CN)cc3)cc2)[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)NC1CCCN(C(C)C(=O)NCC(=O)c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)C1=O
Yield: 100 %

Procedure:
A solution of 2-(3-methoxycarbonylamino-2-oxo-piperidin-1-yl)-propionic acid (48.5 mg, 0.20 mmol), HATU (91 mg, 0.24 mmol), and 4-methylmorpholine (109 μL, 0.99 mmol) in dimethylformamide (5 mL) was stirred at ambient temperature for 5 minutes. [1-(2-{5-[4′-(2-Amino-acetyl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (100 mg, 0.20 mmol) was added to the reaction mixture. After 40 minutes the solvent was removed under reduced pressure and the resulting residue was taken up in ethyl acetate (10 mL). The resulting mixture contained a solid and was subjected to flash chromatography with eluent of (10% methanol in ethyl acetate) and hexane followed by 30% methanol in DCM. The product-containing fractions were combined and the solvent was removed under reduced pressure to provide (1-{1-[2-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-2-oxo-ethylcarbamoyl]-ethyl}-2-oxo-piperidin-3-yl)-carbamic acid methyl ester (149 mg, 0.20 mmol, 99%). C38H47N7O8 calculated 729.4 observed [M+1]+ 730.6; rt=1.78 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1B(O)O.[NH2:12][C:13]1[C:14]([C:20]([O:22][CH3:23])=[O:21])=[N:15][C:16](Br)=[CH:17][N:18]=1.CCN(C(C)C)C(C)C>O1CCOCC1.O.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[NH2:12][C:13]1[C:14]([C:20]([O:22][CH3:23])=[O:21])=[N:15][C:16]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])=[CH:17][N:18]=1
Reactant: COC(=O)c1nc(Br)cnc1N
Reactant: OB(O)c1c(F)cccc1F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1nc(-c2c(F)cccc2F)cnc1N
Temperature: 100 °C
Yield: 88.4 %

Procedure:
A solution of (2,6-difluorophenyl)boronic acid (270 mg, 1.7 mmol), methyl 3-amino-6-bromopyrazine-2-carboxylate (from Ark Pharm, 250 mg, 1.1 mmol), bis(tri-tert-butylphosphine) palladium (82 mg, 0.16 mmol), and DIPEA (370 μL, 2.1 mmol) in 1,4-dioxane (4 mL) and water (320 μL) in a vial was deoxygenated and purged with nitrogen several times. The vial was sealed and the reaction mixture was heated at 100° C. in the sealed vial for 14 h. The crude reaction mixture was filtered through a pad of diatomaceous earth and the inorganics were washed thoroughly with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (40 g silica gel column, eluting with 0-50% EtOAc in hexanes) to afford the sub-title compound (258 mg, 91% yield). LC/MS (ESI) calc. for C12H10F2N3O2(M+H)+: m/z=266.1. found: 266.0.
Reaction SMILES: C1COC2(N)N(C(NC3C=CC4OC(CO)=CC=4C=3)=NC=C2F)O1.[F:25][C:26]1[C:27]([NH:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([OH:53])[CH:48]=2)=[N:28][C:29]([NH:32][C:33]2[CH:34]=[CH:35][C:36]3[O:40][C:39]([C:41](OC)=[O:42])=[CH:38][C:37]=3[CH:45]=2)=[N:30][CH:31]=1.CC(C[AlH]CC(C)C)C>>[F:25][C:26]1[C:27]([NH:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([OH:53])[CH:48]=2)=[N:28][C:29]([NH:32][C:33]2[CH:34]=[CH:35][C:36]3[O:40][C:39]([CH2:41][OH:42])=[CH:38][C:37]=3[CH:45]=2)=[N:30][CH:31]=1
Reactant: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2o1
Agent: CC(C)C[AlH]CC(C)C
Agent: NC12OCCON1C(Nc1ccc3oc(CO)cc3c1)=NC=C2F
Product: OCc1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2o1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxy)-5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-2,4-pyrimidinediamine, 5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine was reduced with DIBALH to yield 5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.37 (s, 1H), 9.17 (s, 1H), 9.12 (s, 1H), 8.06 (d, 1H, J=3.9 Hz), 8.01 (d, 1H, J=1.8 Hz), 7.41-7.35 (m, 2H), 7.26 (d, 1H, J=8.1 Hz), 7.11-7.05 (m, 2H), 6.60 (s, 1H), 6.51 (dd, 1H, J=2.4 and 8.4 Hz), 5.41 (t, 1H, J=6.0 Hz), 4.51 (d, 2H, J=5.7 Hz); LCMS: ret. time: 16.21 min.; purity: 95%; MS (m/e): 367 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:4][CH:3]=1.[Cl:23][CH2:24][CH2:25][N:26]=[C:27]=[O:28]>C1COCC1>[Cl:23][CH2:24][CH2:25][NH:26][C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:6][CH:7]=1)=[O:28]
Reactant: O=C=NCCCl
Reactant: CCn1c(-c2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Solvent: C1CCOC1
Product: CCn1c(-c2ccc(NC(=O)NCCCl)cc2)c(C#N)c2ccc(OC)cc21
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (50 mg, 0.172 mmole) in THF (2 mL) was added 2-chloroethyl isocyanate (22 uL, 0.258 mmole) at room temperature. After stirring overnight at reflux, the reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate. The resulting semi-solid was triturated with hexane and the precipitate collected was collected by filtration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford (62 mg, 91%) of 1-(2-chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-urea.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[C@H:10]([CH3:32])[NH:11][C:12](=[O:31])[C@H:13]([CH3:30])[N:14]([C:16](=[O:29])[C@H:17]([CH:26]([CH3:28])[CH3:27])[NH:18]C(OC(C)(C)C)=O)[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][C:9](=[O:33])[C@H:10]([CH3:32])[NH:11][C:12](=[O:31])[C@H:13]([CH3:30])[N:14]([C:16](=[O:29])[C@H:17]([CH:26]([CH3:28])[CH3:27])[NH2:18])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](N)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Temperature: -15 °C

Procedure:
A stirred solution of 17 g (0.0367 mole) Boc-L-valyl-N-methyl-L-alanyl-L-alanine benzyl ester in 170 ml of dry dichloromethane was cooled at -10° C. as 85 ml of trifluoroacetic acid, previously cooled at -15° C., was added. After 16 hours -5° C., the reaction was carefully poured with good stirring into a mixture of 93 g of sodium bicarbonate, ice, and 250 ml of dichloromethane. The organic layer was separated and the aqueous layer was extracted with another 75 ml of dichloromethane. The combined organic layers were washed with 3×75 ml of saturated sodium bicarbonate solution, dried over magnesium sulfate, and evaporated to give 12.8 g (96% of theory) of crude product which was used in step 5 without further purification. FAB m.s. showed a molecular ion peak at 364.